Most of the cases showed some degree of anemia.

syndrome in some of them being as early as days.

tion, usually above 100 ng /ml.

of this syndrome [14].

collaterals [14].

**4.4. Liver biopsy:**

4. Serum protein S,C, liedin factor

**4.3. Inferior vena cava angiogram:**

**4.2. Ultrasonographic scaning of the liver:**


#### **5. Management of Hepatic veno-occlusive disease:**

No effective therapy until now especially in this type of Egyptian children. The target of available line is, may be, to reduce the complications, to reduce the stress of the patients and keep the patients in nearly comfortable life, but the following measures could be used safely [14].

#### **5.1. Preventive measures:**


#### **5.2. Conservative measures :**


#### **5.3. Medical treatment:**


#### **5.4. Surgical treatment [18].**

*5.4.1. Treatment of ascites :*


#### *5.4.2. Treatment of portal hypertension:*


(6-8 g/l removed) in a one day hospitalization regime. The incidence of complications and the clinical course of the disease, as estimated by the probability of readmission to hospital, causes of re-admission, probability of survival and causes of death, were comparable to those reported by the same group of investigators in patients treated with repeated large-

Egyptian Hepatic Veno-Occlusive Disease: Surgical Point of View

http://dx.doi.org/10.5772/50685

555

In conclusion, these studies demonstrate that mobilization of ascites by paracentesis associat‐ ed with intravenous albumin infusion does not impair systemic haemodynamics and renal function in patients with cirrhosis and tense ascites. Therapeutic paracentesis should be the treatment of choice for cirrhotic patients admitted to hospital with tense ascites, because it is more effective in mobilizing associated with a lower incidence of complications and reduce the duration of hospitalization. To avoid re-accumulation of ascites, patients treated with paracent‐ esis require dietary sodium restriction and administration of diuretics after the procedures.

Subsequently, a trial was performed to establish whether intravenous albumin infusion is necessary in cirrhotic patients with tense ascites treated with repeated large-volume para‐ centesis. It was observed that paracentesis plus intravenous albumin does not induce signifi‐ cant changes in standard renal function testes, plasma renin activity and plasma aldosterone concentration. In contrast, paracentesis without albumin was associated with a significant increase in blood urea nitrogen, a marked elevation in plasma renin activity and plasma al‐ dosterone concentration, and a significant reduction in serum sodium concentration. The number of patients developing hyponatremia and renal impairment was remarkably higher in patients treated with repeated large-volume paracentesis without intravenous albumin infusion. There are two detailed investigations assessing the effects of large-volume para‐ centesis without albumin infusion on systemic haemodynamics vasoactive hormones and renal function. A significant increase in cardiac output was observed 1 hour after treatment in both studies. Some hours later, however, a significant drop below baseline values was ob‐ served in cardiac output, pulmonary wedge capillary pressure and central venous pressure. Plasma renin activity increased and plasma atrial natriuretic peptide concentration de‐ creased. The adverse effects observed after complete mobilization of ascites by paracentesis without albumin expansion did not occur in patients in whom ascites was only partially mo‐ bilized by paracentesis without colloid replacement. In conclusion, these studies demon‐ strate that complete mobilization of ascites by paracentesis without plasma volume expansion is followed by a reduction in effective intravascular volume, which leads to acti‐ vation of the renin-aldosterone system and may impair renal function. The infusion of intra‐ venous albumin is an important measure to prevent these abnormalities in cirrhotic patients

Five randomized controlled trials and one prospective study aimed at investigating whether albumin can be substituted by less expensive plasma expanders (dextran-70, dextran-40, Haemaccel 5% and isotonic saline) have recently been reported. It has been observed that total or repeated large-volume paracentesis associated with intravenous administration of dex‐ tran-70 or Haemaccel is not associated with significant changes in renal and hepatic func‐ tion. The incidence of hyponatremia, renal impairment and hepatic encephalopathy in patients receiving dextran-70 or Haemaccel was comparable with that in patients receiving albumin.

with tense ascites treated with large-volume or total paracentesis.

volume paracentesis.

#### *5.4.3. Liver transplantation:*

**•** It is now a part of the therapeutic armamentarium for this condition.

### **6. Therapeutic paracentesis [21].**

The first study re-evaluating paracentesis as a treatment of cirrhotic patients with ascites consisted of a randomized controlled trial comparing repeated large-volume paracentesis (4-6 l/day until the disappearance of ascites) plus intravenous albumin infusion (40g after each tap) with standard diuretic therapy (frusemide plus spironolactone) in I17 patients with tense ascites and avid sodium retention who were admitted to several hospitals in the Barcelona area. This study, later confirmed by two more trials performed in Milan and Bar‐ celona, showed the following results:

1. paracentesis was more effective than diuretics in eliminating ascites (96.5 versus 72.8%);

2. paracentesis plus albumin infusion did not induce significant changes in hepatic and renal function, serum electrolytes, cardiac output, plasma volume, plasma renin activity and plas‐ ma concentration of noradrenaline and antidiuretic hormone.

3. the incidence of hyponatremia, hepatic encephalopathy and renal impairment was much lower in patients treated with paracentesis.

4. the duration of hospital stay was lower in patients treated with paracentesis.

5. there were no significant probability of re-admission, probability of survival and causes of death between the two groups of patients.

Tito et al., later investigated whether ascites can be safely mobilized by total paracentesis (complete removal of ascites by a single paracentesis) plus intravenous albumin infusion (6-8 g/l removed) in a one day hospitalization regime. The incidence of complications and the clinical course of the disease, as estimated by the probability of readmission to hospital, causes of re-admission, probability of survival and causes of death, were comparable to those reported by the same group of investigators in patients treated with repeated largevolume paracentesis.

**5.4. Surgical treatment [18].**

**•** Frequent aspiration (partial or full)

**•** LeVeen, peritoneojagular shunt.

*5.4.2. Treatment of portal hypertension:*

bypass to drain arterial blood flow.

**6. Therapeutic paracentesis [21].**

celona, showed the following results:

lower in patients treated with paracentesis.

death between the two groups of patients.

*5.4.3. Liver transplantation:*

**•** TIPS ( transjagular intrahepatic portosystemic shunt)

**•** Hepatic and portal decompression for interactable ascites.

**•** Porto-systemic shunt as porto-caval, spleno-renal or meso-atrial.

**•** It is now a part of the therapeutic armamentarium for this condition.

ma concentration of noradrenaline and antidiuretic hormone.

**•** Acute venous obstruction could be treated by hepatofugal portal flow via veno-venous

The first study re-evaluating paracentesis as a treatment of cirrhotic patients with ascites consisted of a randomized controlled trial comparing repeated large-volume paracentesis (4-6 l/day until the disappearance of ascites) plus intravenous albumin infusion (40g after each tap) with standard diuretic therapy (frusemide plus spironolactone) in I17 patients with tense ascites and avid sodium retention who were admitted to several hospitals in the Barcelona area. This study, later confirmed by two more trials performed in Milan and Bar‐

1. paracentesis was more effective than diuretics in eliminating ascites (96.5 versus 72.8%); 2. paracentesis plus albumin infusion did not induce significant changes in hepatic and renal function, serum electrolytes, cardiac output, plasma volume, plasma renin activity and plas‐

3. the incidence of hyponatremia, hepatic encephalopathy and renal impairment was much

5. there were no significant probability of re-admission, probability of survival and causes of

Tito et al., later investigated whether ascites can be safely mobilized by total paracentesis (complete removal of ascites by a single paracentesis) plus intravenous albumin infusion

4. the duration of hospital stay was lower in patients treated with paracentesis.

*5.4.1. Treatment of ascites :*

554 Hepatic Surgery

In conclusion, these studies demonstrate that mobilization of ascites by paracentesis associat‐ ed with intravenous albumin infusion does not impair systemic haemodynamics and renal function in patients with cirrhosis and tense ascites. Therapeutic paracentesis should be the treatment of choice for cirrhotic patients admitted to hospital with tense ascites, because it is more effective in mobilizing associated with a lower incidence of complications and reduce the duration of hospitalization. To avoid re-accumulation of ascites, patients treated with paracent‐ esis require dietary sodium restriction and administration of diuretics after the procedures.

Subsequently, a trial was performed to establish whether intravenous albumin infusion is necessary in cirrhotic patients with tense ascites treated with repeated large-volume para‐ centesis. It was observed that paracentesis plus intravenous albumin does not induce signifi‐ cant changes in standard renal function testes, plasma renin activity and plasma aldosterone concentration. In contrast, paracentesis without albumin was associated with a significant increase in blood urea nitrogen, a marked elevation in plasma renin activity and plasma al‐ dosterone concentration, and a significant reduction in serum sodium concentration. The number of patients developing hyponatremia and renal impairment was remarkably higher in patients treated with repeated large-volume paracentesis without intravenous albumin infusion. There are two detailed investigations assessing the effects of large-volume para‐ centesis without albumin infusion on systemic haemodynamics vasoactive hormones and renal function. A significant increase in cardiac output was observed 1 hour after treatment in both studies. Some hours later, however, a significant drop below baseline values was ob‐ served in cardiac output, pulmonary wedge capillary pressure and central venous pressure. Plasma renin activity increased and plasma atrial natriuretic peptide concentration de‐ creased. The adverse effects observed after complete mobilization of ascites by paracentesis without albumin expansion did not occur in patients in whom ascites was only partially mo‐ bilized by paracentesis without colloid replacement. In conclusion, these studies demon‐ strate that complete mobilization of ascites by paracentesis without plasma volume expansion is followed by a reduction in effective intravascular volume, which leads to acti‐ vation of the renin-aldosterone system and may impair renal function. The infusion of intra‐ venous albumin is an important measure to prevent these abnormalities in cirrhotic patients with tense ascites treated with large-volume or total paracentesis.

Five randomized controlled trials and one prospective study aimed at investigating whether albumin can be substituted by less expensive plasma expanders (dextran-70, dextran-40, Haemaccel 5% and isotonic saline) have recently been reported. It has been observed that total or repeated large-volume paracentesis associated with intravenous administration of dex‐ tran-70 or Haemaccel is not associated with significant changes in renal and hepatic func‐ tion. The incidence of hyponatremia, renal impairment and hepatic encephalopathy in patients receiving dextran-70 or Haemaccel was comparable with that in patients receiving albumin. In one study, patients treated with dextran-70 showed a significant increase in plasma renin activity and aldosterone concentration. In a more recent study, however, therapeutic paracent‐ esis plus intravenous dextran-70 administration was not associated with significant changes in plasma renin activity, which was measured 24 and 96 hours after the treatment. Cabrera et al., in one study including 14 patients, have suggested that intravenous isotonic saline infu‐ sion can also be a safe and cost effective alternative plasma expander in cirrhotics with tense ascites treated with paracentesis. Further studies are obviously needed to confirm their find‐ ings. It seems that dextran-40 is not as effective as albumin in preventing renal and electro‐ lyte complications after therapeutic paracentesis, as renal impairment and/or hyponatremia developed after treatment in a relatively high proportion of patients.

The intravenous infusion of ascitic fluid through the shunt is associated with an increase in circulating blood volume and cardiac output. Since arterial pressure does not rise, there is a concomitant reduction in peripheral vascular resistance. These hemodynamic changes are associated with an increase in the plasma concentration of atrial natriuretic factor and a sup‐ pression of plasma levels of renin, aldosterone, noradrenaline and antidiuretic hormone. Urine volume and free water clearance increase in most patients. However, there is signifi‐ cant natriuresis in less than half of the patients, demonstrating that the PVS does not com‐ pletely correct the abnormal sodium-retaining state associated with cirrhosis. Finally, in cirrhotic patients with moderate FRF, the PVS may improve renal blood flow and glomeru‐ lar filtration rate. These hemodynamic and hormonal changes persist in most cases and a significant proportion of patients remains with minimal or no ascites despite a moderate so‐ dium restriction and low diuretic dosage. There are also two studies that suggest that PVS has a positive effect on the nutritional status of patients in whom the shunt functions for a prolonged period of time. Despite these positive effects of PVS, there are a large number of complications, which may occur early in the postoperative period or at any time during fol‐

Egyptian Hepatic Veno-Occlusive Disease: Surgical Point of View

http://dx.doi.org/10.5772/50685

557

The role of PVS in the management of cirrhotic patients with ascitcs is still not well estab‐ lished. Only one prospective study showed that PVS is superior to conventional medical therapy in the management of ascites and in improving survival. By contrast, four random‐ ized studies have failed to demonstrate a longer survival time in cirrhotic patients with as‐ cites treated with PVS compared with medical therapy. Of these studies, that which was performed by Stanley et al., 1989 [22], is worth mentioning. They compared PVS with medi‐ cal treatment (diuretics and occasional paracentesis) in 299 patients with cirrhosis and re‐ fractory or recurrent ascites. Although early mortality and probability of survival after randomization were similar in both therapeutic groups, PVS was more effective in the man‐ agement of ascites than was conventional medical therapy, as indicated by shorter duration of first hospitalization, longer time to recurrence of ascites, and lower diuretic requirements during follow-up. However, these results are not surprising, because PVS was compared

The effect of PVS on survival in patients with FRF has also been studied in a randomized controlled trial. The treated patients had some improvement in renal function, but their sur‐ vival was unaffected. Several studies have shown that morbidity and survival of cirrhotic patients treated with PVS correlate with the degree of impairment of liver and renal func‐ tion. Therefore, the best results with this procedure should be expected to occur in those few

Acute bacterial infection is the most serious early complication. Staphylococcus aureus is a frequent isolate and represents the operative contamination of the shunt in some cases. The prosthesis is usually colonized and the infection cannot be eradicated in most cases unless the shunt is removed a high mortality can be expected. The prophylactic administration of anti-staphylococcal antibiotics 24 hours before and 48 hours after surgery reduces the inci‐

with a treatment that by definition was known to be ineffective.

**7.1. Early complications of peritoneovenous shunting**

patients with diuretic-resistant ascites and preserved hepatic function [23].

low-up [19], [20].

Recently, a multicenter randomized trial comparing therapeutic paracentesis with PVS in cirrhotic patients with refractory or recurrent ascites has been published. More than 40 pa‐ tients were included in each group. Both treatments were equally effective in mobilizing the ascites during the first hospital stay, although the duration of hospitalization was signifi‐ cantly longer in the shunt group. There were also no significant differences between both groups in the number of patients who developed complications or died. The number of readmissions for any reason or for ascites, was significantly higher, and the time to first readmission for any reason and for ascites significantly shorter in the paracentesis group than in the shunt group. The total time in hospital during follow-up, however, was similar in the two groups. The probability of shunt obstruction was 40 % at 1 -year follow-up. The proba‐ bility of survival was similar in both groups. In conclusion, this trial shows that, although the LeVeen shunt was better than paracentesis in the long-term control of ascites, it did not reduce the total time in hospital nor prolong survival. On the other hand, patients treated with PVS required frequent re-operations due to obstruction of the prosthesis. Therapeutic paracentesis is therefore an alternative treatment to LeVeen shunt in cirrhotic patients with refractory ascites.

#### **7. Peritoneovenous Shunting**

In 1974 LeVeen [19], and colleagues developed a pressure-activated one-way valve for use in a peritoneovenous shunt (PVS). This device consists of a perforated intra-abdominal tube connected through a one-way pressure sensitive valve to a silicone tube that traverses the subcutaneous tissue up to the neck, where it enters one of the jugular veins (usually the in‐ ternal jugular vein). The tip of the intravenous tube is located in the superior vena cava, near the right atrium or in the right atrium itself. The shunt produces a sustained circulating blood volume expansion by continuous passage of ascitic fluid to the general circulation. Flow in the shunt is maintained if there is a 3-5 cm H2O pressure gradient between the ab‐ dominal cavity and the superior vena cava. A loss of this gradient causes the valve to close, preventing blood from flowing back into the tubing. Two additional shunts have been intro‐ duced Denver and Cordis-Hakim. These latter shunts include a pumping mechanism that allows flow to be increased or a partially occluded shunt to be cleared.

The intravenous infusion of ascitic fluid through the shunt is associated with an increase in circulating blood volume and cardiac output. Since arterial pressure does not rise, there is a concomitant reduction in peripheral vascular resistance. These hemodynamic changes are associated with an increase in the plasma concentration of atrial natriuretic factor and a sup‐ pression of plasma levels of renin, aldosterone, noradrenaline and antidiuretic hormone. Urine volume and free water clearance increase in most patients. However, there is signifi‐ cant natriuresis in less than half of the patients, demonstrating that the PVS does not com‐ pletely correct the abnormal sodium-retaining state associated with cirrhosis. Finally, in cirrhotic patients with moderate FRF, the PVS may improve renal blood flow and glomeru‐ lar filtration rate. These hemodynamic and hormonal changes persist in most cases and a significant proportion of patients remains with minimal or no ascites despite a moderate so‐ dium restriction and low diuretic dosage. There are also two studies that suggest that PVS has a positive effect on the nutritional status of patients in whom the shunt functions for a prolonged period of time. Despite these positive effects of PVS, there are a large number of complications, which may occur early in the postoperative period or at any time during fol‐ low-up [19], [20].

The role of PVS in the management of cirrhotic patients with ascitcs is still not well estab‐ lished. Only one prospective study showed that PVS is superior to conventional medical therapy in the management of ascites and in improving survival. By contrast, four random‐ ized studies have failed to demonstrate a longer survival time in cirrhotic patients with as‐ cites treated with PVS compared with medical therapy. Of these studies, that which was performed by Stanley et al., 1989 [22], is worth mentioning. They compared PVS with medi‐ cal treatment (diuretics and occasional paracentesis) in 299 patients with cirrhosis and re‐ fractory or recurrent ascites. Although early mortality and probability of survival after randomization were similar in both therapeutic groups, PVS was more effective in the man‐ agement of ascites than was conventional medical therapy, as indicated by shorter duration of first hospitalization, longer time to recurrence of ascites, and lower diuretic requirements during follow-up. However, these results are not surprising, because PVS was compared with a treatment that by definition was known to be ineffective.

The effect of PVS on survival in patients with FRF has also been studied in a randomized controlled trial. The treated patients had some improvement in renal function, but their sur‐ vival was unaffected. Several studies have shown that morbidity and survival of cirrhotic patients treated with PVS correlate with the degree of impairment of liver and renal func‐ tion. Therefore, the best results with this procedure should be expected to occur in those few patients with diuretic-resistant ascites and preserved hepatic function [23].

#### **7.1. Early complications of peritoneovenous shunting**

In one study, patients treated with dextran-70 showed a significant increase in plasma renin activity and aldosterone concentration. In a more recent study, however, therapeutic paracent‐ esis plus intravenous dextran-70 administration was not associated with significant changes in plasma renin activity, which was measured 24 and 96 hours after the treatment. Cabrera et al., in one study including 14 patients, have suggested that intravenous isotonic saline infu‐ sion can also be a safe and cost effective alternative plasma expander in cirrhotics with tense ascites treated with paracentesis. Further studies are obviously needed to confirm their find‐ ings. It seems that dextran-40 is not as effective as albumin in preventing renal and electro‐ lyte complications after therapeutic paracentesis, as renal impairment and/or hyponatremia

Recently, a multicenter randomized trial comparing therapeutic paracentesis with PVS in cirrhotic patients with refractory or recurrent ascites has been published. More than 40 pa‐ tients were included in each group. Both treatments were equally effective in mobilizing the ascites during the first hospital stay, although the duration of hospitalization was signifi‐ cantly longer in the shunt group. There were also no significant differences between both groups in the number of patients who developed complications or died. The number of readmissions for any reason or for ascites, was significantly higher, and the time to first readmission for any reason and for ascites significantly shorter in the paracentesis group than in the shunt group. The total time in hospital during follow-up, however, was similar in the two groups. The probability of shunt obstruction was 40 % at 1 -year follow-up. The proba‐ bility of survival was similar in both groups. In conclusion, this trial shows that, although the LeVeen shunt was better than paracentesis in the long-term control of ascites, it did not reduce the total time in hospital nor prolong survival. On the other hand, patients treated with PVS required frequent re-operations due to obstruction of the prosthesis. Therapeutic paracentesis is therefore an alternative treatment to LeVeen shunt in cirrhotic patients with

In 1974 LeVeen [19], and colleagues developed a pressure-activated one-way valve for use in a peritoneovenous shunt (PVS). This device consists of a perforated intra-abdominal tube connected through a one-way pressure sensitive valve to a silicone tube that traverses the subcutaneous tissue up to the neck, where it enters one of the jugular veins (usually the in‐ ternal jugular vein). The tip of the intravenous tube is located in the superior vena cava, near the right atrium or in the right atrium itself. The shunt produces a sustained circulating blood volume expansion by continuous passage of ascitic fluid to the general circulation. Flow in the shunt is maintained if there is a 3-5 cm H2O pressure gradient between the ab‐ dominal cavity and the superior vena cava. A loss of this gradient causes the valve to close, preventing blood from flowing back into the tubing. Two additional shunts have been intro‐ duced Denver and Cordis-Hakim. These latter shunts include a pumping mechanism that

allows flow to be increased or a partially occluded shunt to be cleared.

developed after treatment in a relatively high proportion of patients.

refractory ascites.

556 Hepatic Surgery

**7. Peritoneovenous Shunting**

Acute bacterial infection is the most serious early complication. Staphylococcus aureus is a frequent isolate and represents the operative contamination of the shunt in some cases. The prosthesis is usually colonized and the infection cannot be eradicated in most cases unless the shunt is removed a high mortality can be expected. The prophylactic administration of anti-staphylococcal antibiotics 24 hours before and 48 hours after surgery reduces the inci‐ dence of early postoperative infection. Biochemical disseminated intravascular coagulation (DIC) is seen in practically every cirrhotic patient treated with PVS in the early postopera‐ tive period. Bleeding caused by DIC develops most commonly in those patients with se‐ vere liver disease, but is now very uncommon, because many surgeons remove the ascitic fluid before inserting the shunt and replace it with normal saline. DIC is thought to devel‐ op because of infusion of factors present in ascitic fluid that activate coagulation (thrombo‐ plastin, activated clotting factors, endotoxin, collagen, plasminogen activator and fibrin split products). Postoperative fever, probably related to the passage of endotoxin contained in the ascitic fluid to the general circulation, is almost a constant and disappears spontaneous‐ ly within the second postoperative week. Rapid expansion of the plasma volume is associ‐ ated with a rise in portal pressure and may increase the risk of variceal haemorrhage. This complication can also be prevented by removing most ascitic fluid before the insertion of the shunt [24].

successfully in patients with portal hypertension. Similar good results were soon reported with the self-expanding Wall stent. Percutaneous portography was used in the early cases to facilitate transjugular portal vein puncture. With increasing experience this has been re‐

Egyptian Hepatic Veno-Occlusive Disease: Surgical Point of View

http://dx.doi.org/10.5772/50685

559

There is now an increasing array of equipment available for transjugular intrahepatic porto‐ sytemic shunt (TIPS) insertion. The most widely used needles are a standard transjugular bi‐ opsy needle with a straight or reversed bevel (Cook Ltd) or the Richter needle which has a tapered tip and a blunt obturator (Angiomed, Karlsruhe, Germany). Another set with a blunt cannula, through which is passed a sharp style is also available (Cook). There is also a wider choice with regard to the type and dimensions of metal stent. In addition to the origi‐ nal Palmaz and Wall stents, there is the Strecker stent and the Memotherm stent (Angiomed, Karlsruhe, Germany). Claimed advantages for these new stents are increased radioopacity

A recent randomized controlled study compared the Palmaz and Wall stent in 90 patients and found little difference in outcome. Early shunt thrombosis was more likely with the Wall stent (9%), whereas stenosis of the hepatic vein was more likely with the Palmaz stent

As yet the long-term expectations of TIPS have not been fulfilled in those clinical situations in which long-term efficacy is needed as prevention of variceal rebleeding, ascites, cirrhotic hydrothorax, Budd-Chiari syndrome, and long-term amelioration of clinical status before liver transplantation. All these indications need controlled trials against current best optimal management before TIPS is used routinely even for an individual patient. The high stent ob‐ struction rate is the most important limiting factor, but change in stent shape, coating mate‐

The complications of TIPS are significant if elective and long-term use is considered, thus the need for trials before new therapies are introduced. In an emergency situation the complica‐ tions due to TIPS are an acceptable risk, but again information from controlled trials is needed. This is particularly true when TIPS is used as a short-term bridge to liver transplantation. TIPS will have a place in the treatment of cirrhotic patients. At present short-term rather than long-term indications appear to be where TIPS will have more beneficial effects [28].

Liver transplantation for Budd–Chiari syndrome: A European study on 248 patients from 51 centers ) [31]: The results of liver transplantation for Budd–Chiari syndrome (BCS) are poor‐ ly known and the role and timing of the procedure are still controversial. The aim of this study was to investigate the results of transplantation for BCS, focusing on overall outcome, on prognostic factors and on the impact of the underlying disease. Methods: An enquiry on 248 patients representing 84% of the patients transplanted for BCS in the European Liver Transplantation Registry between 1988 and 1999. Results: Of the 248 patients, 70.4% were

placed by ultrasound guidance in most centers [28].

(I3%). Experience with the other stents is limited.

rial or other technical aspects may overcome this [30].

**9. Liver transplantation: and hepatic venous obstruction**

(Strecker stent) and improved delivery systems (Memo stent) [29].

#### **7.2. Long-term complications of peritoneovenous shunting**

Obstruction of the shunt is the most common complication during follow-up. It occurs in more than 30% of patients and is usually due to deposition of fibrin within the valve or the intravenous catheter, thrombotic obstruction of the venous limb of the prosthesis, or throm‐ bosis of the superior vena cava or right atrium initiated at the venous end of the shunt or damaged endothelium. Shunt obstruction is generally associated with ascites re-accumula‐ tion. Shunt patency can be assessed by Doppler ultrasound or by technetium 99m scintigra‐ phy using intraperitoneal radioisotope injection. If the obstruction is confirmed, a shuntogram after the injection of contrast into the proximal limb of the shunt may identify the site of obstruction. Venography or digital angiography is necessary in the case of ob‐ struction of the venous tip of the shunt. Superior vena cava syndrome secondary to total ob‐ struction of the vein and pulmonary embolism are much less common. It is not clear that the insertion of a titanium tip into the venous end of the LeVeen shunt prevents thrombotic ob‐ struction and the development of superior vena cava thrombosis. Finally, another long-term complication of PVS is small-bowel obstruction, which occurs in approximately 10% of pa‐ tients and is due to intraperitoneal fibrosis [25].

#### **8. Transjugular intrahepatic portosystemic shunt (TIPS)**

The feasibility of intrahepatic portosystemic shunting was first demonstrated by Rosch and colleagues 1969 in pigs. Colapinto et al; 1982 [27] reported the first application of this techni‐ que to humans. This was attempted following transhepatic obliteration of varices in 20 se‐ verely ill patients with variceal hemorrhage. The authors inflated a balloon catheter in the intrahepatic track and left it there for 12 hours. In an initial report all six shunts studied were patent 12 hours after the procedure and one was still patent at autopsy 6 weeks late.

Many demonstrated prolonged patency of the shunt for up to 10 months and ease of recan‐ alizing the radiopaque shunt when occlusion occurred. This expandable stent was then used successfully in patients with portal hypertension. Similar good results were soon reported with the self-expanding Wall stent. Percutaneous portography was used in the early cases to facilitate transjugular portal vein puncture. With increasing experience this has been re‐ placed by ultrasound guidance in most centers [28].

dence of early postoperative infection. Biochemical disseminated intravascular coagulation (DIC) is seen in practically every cirrhotic patient treated with PVS in the early postopera‐ tive period. Bleeding caused by DIC develops most commonly in those patients with se‐ vere liver disease, but is now very uncommon, because many surgeons remove the ascitic fluid before inserting the shunt and replace it with normal saline. DIC is thought to devel‐ op because of infusion of factors present in ascitic fluid that activate coagulation (thrombo‐ plastin, activated clotting factors, endotoxin, collagen, plasminogen activator and fibrin split products). Postoperative fever, probably related to the passage of endotoxin contained in the ascitic fluid to the general circulation, is almost a constant and disappears spontaneous‐ ly within the second postoperative week. Rapid expansion of the plasma volume is associ‐ ated with a rise in portal pressure and may increase the risk of variceal haemorrhage. This complication can also be prevented by removing most ascitic fluid before the insertion of

Obstruction of the shunt is the most common complication during follow-up. It occurs in more than 30% of patients and is usually due to deposition of fibrin within the valve or the intravenous catheter, thrombotic obstruction of the venous limb of the prosthesis, or throm‐ bosis of the superior vena cava or right atrium initiated at the venous end of the shunt or damaged endothelium. Shunt obstruction is generally associated with ascites re-accumula‐ tion. Shunt patency can be assessed by Doppler ultrasound or by technetium 99m scintigra‐ phy using intraperitoneal radioisotope injection. If the obstruction is confirmed, a shuntogram after the injection of contrast into the proximal limb of the shunt may identify the site of obstruction. Venography or digital angiography is necessary in the case of ob‐ struction of the venous tip of the shunt. Superior vena cava syndrome secondary to total ob‐ struction of the vein and pulmonary embolism are much less common. It is not clear that the insertion of a titanium tip into the venous end of the LeVeen shunt prevents thrombotic ob‐ struction and the development of superior vena cava thrombosis. Finally, another long-term complication of PVS is small-bowel obstruction, which occurs in approximately 10% of pa‐

The feasibility of intrahepatic portosystemic shunting was first demonstrated by Rosch and colleagues 1969 in pigs. Colapinto et al; 1982 [27] reported the first application of this techni‐ que to humans. This was attempted following transhepatic obliteration of varices in 20 se‐ verely ill patients with variceal hemorrhage. The authors inflated a balloon catheter in the intrahepatic track and left it there for 12 hours. In an initial report all six shunts studied were patent 12 hours after the procedure and one was still patent at autopsy 6 weeks late.

Many demonstrated prolonged patency of the shunt for up to 10 months and ease of recan‐ alizing the radiopaque shunt when occlusion occurred. This expandable stent was then used

the shunt [24].

558 Hepatic Surgery

**7.2. Long-term complications of peritoneovenous shunting**

tients and is due to intraperitoneal fibrosis [25].

**8. Transjugular intrahepatic portosystemic shunt (TIPS)**

There is now an increasing array of equipment available for transjugular intrahepatic porto‐ sytemic shunt (TIPS) insertion. The most widely used needles are a standard transjugular bi‐ opsy needle with a straight or reversed bevel (Cook Ltd) or the Richter needle which has a tapered tip and a blunt obturator (Angiomed, Karlsruhe, Germany). Another set with a blunt cannula, through which is passed a sharp style is also available (Cook). There is also a wider choice with regard to the type and dimensions of metal stent. In addition to the origi‐ nal Palmaz and Wall stents, there is the Strecker stent and the Memotherm stent (Angiomed, Karlsruhe, Germany). Claimed advantages for these new stents are increased radioopacity (Strecker stent) and improved delivery systems (Memo stent) [29].

A recent randomized controlled study compared the Palmaz and Wall stent in 90 patients and found little difference in outcome. Early shunt thrombosis was more likely with the Wall stent (9%), whereas stenosis of the hepatic vein was more likely with the Palmaz stent (I3%). Experience with the other stents is limited.

As yet the long-term expectations of TIPS have not been fulfilled in those clinical situations in which long-term efficacy is needed as prevention of variceal rebleeding, ascites, cirrhotic hydrothorax, Budd-Chiari syndrome, and long-term amelioration of clinical status before liver transplantation. All these indications need controlled trials against current best optimal management before TIPS is used routinely even for an individual patient. The high stent ob‐ struction rate is the most important limiting factor, but change in stent shape, coating mate‐ rial or other technical aspects may overcome this [30].

The complications of TIPS are significant if elective and long-term use is considered, thus the need for trials before new therapies are introduced. In an emergency situation the complica‐ tions due to TIPS are an acceptable risk, but again information from controlled trials is needed. This is particularly true when TIPS is used as a short-term bridge to liver transplantation. TIPS will have a place in the treatment of cirrhotic patients. At present short-term rather than long-term indications appear to be where TIPS will have more beneficial effects [28].

#### **9. Liver transplantation: and hepatic venous obstruction**

Liver transplantation for Budd–Chiari syndrome: A European study on 248 patients from 51 centers ) [31]: The results of liver transplantation for Budd–Chiari syndrome (BCS) are poor‐ ly known and the role and timing of the procedure are still controversial. The aim of this study was to investigate the results of transplantation for BCS, focusing on overall outcome, on prognostic factors and on the impact of the underlying disease. Methods: An enquiry on 248 patients representing 84% of the patients transplanted for BCS in the European Liver Transplantation Registry between 1988 and 1999. Results: Of the 248 patients, 70.4% were female and 29.6% male. The mean age was 35.7 years. The overall actuarial survival was 76% at 1 year, 71% at 5 years and 68% at 10 years. 77% of deaths occurred in the first 3 months: 47% were due to infection and multiple organ failure, and 18% to graft failure or hepatic artery thrombosis. Late mortality (>1 year) occurred in nine patients, due to BCS re‐ currence in four of them. The only pre-transplant predictors of mortality on multivariate analysis (Cox) were impaired renal function and a history of a shunt.

[6] Shirai, M., Nagashima, K., Iwasaki, S., & Mori, W. (1987). A light and scanning elec‐ tron microscopic study of hepatic veno-occlusive disease. *Acta Path Jpn*, 37(12),

Egyptian Hepatic Veno-Occlusive Disease: Surgical Point of View

http://dx.doi.org/10.5772/50685

561

[7] Hashem, M. (1939). Etiology and Pathology of types of liver cirrhosis in Egyptian

[8] Mohabbat, O., Srivastava, R. N., Younos, M. S., Sedio, G. G., Merzad, A. A., & Aram, G. N. (1967). An outbreak of Hepatic Veno-occlusive Disease due to toxic Alkaloid in

[9] Wilmot, F. C., & Robertson, G. W. (1920). Senecio disease and cirrhosis of liver due to

[10] El Gholmy, A., El Nabaway, M., Khatab, M., Shukry, Gabr. M., El Sibie, B., Aidaro, S., & Soliman, L. (1956). Infantile liver cirrhosis of Egypt. *Gaz Egypt Ped Assoc*, 4, 320.

[11] Safouh, M. A., Shehata, A., & Elwi, A. (1965). Veno occlusive disease in Egyptian

[12] Mc Lean, E. K. (1969). The early sinusoidal lesion in experimental veno occlusive dis‐

[13] Mellis, C., & Bale, P. M. (1976). Famelial hepatic Veno occlusive disease with proba‐

[14] Mc Dermott, W. V., & Ridker, P. M. (1990). The Budd-Chiari syndrome and hepatic veno occlusive. Recognition and treatment. *Archives of surgery*, 125(4), 525-527.

[15] Nattakom, T. V., Charlton, A., & Wilmore, D. W. (1995). Use of Vitamine E. and glu‐ tamine in the successful treatment of severe VOD following bone marrow transplan‐

[16] Fogteloo, A. J., Smid, W. M., Kok, T., Van Der Meer, J., Van Imhoff, G. W., & Daenen, S. (1993). Successful treatment of veno occlusive disease of the liver with urokinase in

[17] Simpson, D. R., Browett, P. J., Doak, P. B., & Palmer, S. J. (1994). Successful treatment of veno occlusive disease with recombinant tissue plasminogen activator in a patient

[18] Cuenoud, P. F., & Mosiman, F. (1992). Surgical treatment of Budd-Chiari syndrome

[19] Le Veen, H. H., Christoudias, G., Moon, J. P., et al. (1974). Peritoneovenous shunting

[20] Le Veen, H. H., Vujic, ., D'Ovidio, N. J., & Hutto, R. B. (1984). Peritoneovenous shunt

requiring peritoneal dialysis. *Bone Marrow Transplantation*, 14(4), 635-636.

ease of the liver. *British Journal of Experimental Pathology*, 223 -22.

a patient with non-hodgkin's lymphoma. *Leukemia*, 7(5), 760-763.

ble immune deficiency. *J Pediatrics*, 88, 236-242.

tation. *Nutritionin Clinical Practice*, 10(1), 16-18.

and VOD. *Helvetica Chirurgica Acta*, 58(6), 805-808.

occlusion: Etiology. diagnosis, therapy. *Ann Surg*, 212-223.

for ascites. *Ann Surg*, 180, 580-591.

1961-711.

children. *J Egypt Med Association*, 22, 1-36.

senecio boisoning. *Lancet*, 11, 848-849.

Children. *Arch Path*, 79, 505.

herbal tea in north western Afghanistan. *Lancet*, 7950, 269.

#### **10. Conclusions**

Liver transplantation for BCS is an effective treatment, irrespective of the underlying cause, and should be considered before renal failure occurs [31].

#### **Acknowledgements**

We would like to thank all the staff of pediatric department, at National Liver Institute, Me‐ noufya University for supporting our work.

#### **Author details**

Elsayed Ibrahim Salama\*

Address all correspondence to: elsayedsalama5@yahoo.com

Pediatric Department, National, Menoufia University, Egypt

#### **References**


[6] Shirai, M., Nagashima, K., Iwasaki, S., & Mori, W. (1987). A light and scanning elec‐ tron microscopic study of hepatic veno-occlusive disease. *Acta Path Jpn*, 37(12), 1961-711.

female and 29.6% male. The mean age was 35.7 years. The overall actuarial survival was 76% at 1 year, 71% at 5 years and 68% at 10 years. 77% of deaths occurred in the first 3 months: 47% were due to infection and multiple organ failure, and 18% to graft failure or hepatic artery thrombosis. Late mortality (>1 year) occurred in nine patients, due to BCS re‐ currence in four of them. The only pre-transplant predictors of mortality on multivariate

Liver transplantation for BCS is an effective treatment, irrespective of the underlying cause,

We would like to thank all the staff of pediatric department, at National Liver Institute, Me‐

[1] Al, Hasany. M., & Mohamed, A. (1970). Veno occlusive disease of Liver in Iraq. *Ar‐*

[4] Stein, H. (1957). Veno-occlusive disease of the liver in African children. *Br Med J*, 1,

[5] Tandon, B. N., Tandon, R., Tandon, H. D., Narndrunat, L., & Joghi, Y. K. (1976). An epidemic of veno-occlusive disease of liver in central India. *Lancet*, 271-272.

[2] Rollins, B. J. (1989). Hepatic Veno-occlusive Disease. *Am J of Med*, 8, 297.

[3] Bras, G., Jeliffe, D. B., & Stuart, K. L. (1954). *Arch Path, Chicago*, 57, 285.

analysis (Cox) were impaired renal function and a history of a shunt.

and should be considered before renal failure occurs [31].

Address all correspondence to: elsayedsalama5@yahoo.com

Pediatric Department, National, Menoufia University, Egypt

*chives of disease in childhood*, 45(243), 722-724.

noufya University for supporting our work.

**10. Conclusions**

560 Hepatic Surgery

**Acknowledgements**

**Author details**

**References**

1496.

Elsayed Ibrahim Salama\*


[21] Salemo, F., Badalamenti, S., Incerti, P., et al. (1987). Repeated paracentesis and IV al‐ bumin infusion to treat "tense " ascites in cirrhotic patients a safe alternative therapy. *J Hepatol*, 5, 102-108.

**Chapter 24**

**Progressive Familial Intrahepatic Cholestasis**

Neonatal cholestasis is one of the commonest presentations in the field of pediatric hepatol‐ ogy and gastroenterology and constitutes the major indication for liver transplantation be‐ low two years of age. Unfortunately, in spite of being common, fewer categories are amenable to curative or palliative therapy. Moreover, delayed referral to specialized centers is still a problem adding a more difficulty to neonatal cholestasis management. Hepatobili‐ ary surgery is a major line of therapy in some etiologies of neonatal cholestasis. Biliary atre‐ sia, choledochal cyst, spontaneous perforation of the bile duct and inspissated bile syndrome are among the commonest known causes for hepatobiliary surgeons. However, there is less orientation about other causes, resulting in progression to cirrhosis and end stage liver disease without being diagnosed. One of these is the progressive familial intrahe‐

PFIC is an autosomal recessive liver disorder characterized by an intrahepatic cholestasis due to bile canalicular transport defects. It is subdivided into three types with slightly different clinical, biochemical and histological features. PFIC types 1, 2 and 3 are due to mutations in *ATP8B1* (adenosine triphosphatase, type 8B, member 1), *ABCB11* (adeno‐ sine triphosphate-binding cassette, subfamily B, member 11) and *ABCB4* (adenosine tri‐ phosphate-binding cassette, subfamily B, member 4) genes, respectively. Each of these genes encodes a hepatocanalicular transporter which is essential for the proper secretion

PFIC1 and PFIC2 usually appear in the first months of life, whereas onset of PFIC3 may also oc‐ cur later in infancy, in childhood or even during young adulthood. The shared main clinical manifestations in all types are cholestasis and pruritus. PFIC represents 10-15 % of causes of cholestasis in children and 10-15% of indications of liver transplantations in children [3].

> © 2013 Sira and Sira; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 Sira and Sira; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

distribution, and reproduction in any medium, provided the original work is properly cited.

Ahmad Mohamed Sira and Mostafa Mohamed Sira

Additional information is available at the end of the chapter

patic cholestasis (PFIC) group of diseases [1].

and formation of bile [2].

http://dx.doi.org/10.5772/51769

**1. Introduction**


## **Progressive Familial Intrahepatic Cholestasis**

Ahmad Mohamed Sira and Mostafa Mohamed Sira

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/51769

### **1. Introduction**

[21] Salemo, F., Badalamenti, S., Incerti, P., et al. (1987). Repeated paracentesis and IV al‐ bumin infusion to treat "tense " ascites in cirrhotic patients a safe alternative therapy.

[22] Stanley, A. M., Ochi, S., Lee, K. K., et al. (1989). Peritoneovenous shunting as com‐ pared with medical treatment in patients with alcoholic cirrhosis and massive ascites.

[23] Stanley, M. M. (1985). PVS in patients with cirrhotic ascites and end-stage renal fail‐

[24] Smajda, C., Tridart, D., & Franco, D. (1986). Recurrent ascites due to central venous

[25] Sale, H. H., Dudley, F. J., Merret, A., et al. (1983). Coagulopathy of peritoneovenous shunt studies on the pathogenic role of ascitic fluid collagen and value of antiplatelet

[26] Rosch, J., Hanafee, W. N., & Snow, H. (1969). Transjugular portal venography and ra‐ diological portocaval shunt: an experimental study. *Radiology*, 92, 1112-1114.

[27] Colapinto, R. F., Stonell, R. D., Birch, S. J., et al. (1982). Creation of an intrahepatic portosystemic shunt with a Gruntzig balloon catheter. *Can Med Assoc*, 126, 267-268.

[28] Haag, K., Noldge, G., Sellinger, M., Ochs, A., Gerok, W., & Rossle, M. (1992). Transju‐ gular intrahepatic portosystemic stent shunt (TIPS). Monitoring of function by color

[29] Palmaz, I. C., Sibbit, R. R., Reuter, S. R., Garcia, F., & Tio, F. O. (1985). Expandable intraheptic portacaval shunt stents. Early experience in the dog. *Am J Roentgenol*, 145,

[30] Conn, H. (1993). Transjugular intrahepatic portal systemic shunts: the state of the art.

[31] Gilles, Mentha., Giostra, Emiliano, Majno, Pietro E., Bechstein, Wolf. O., Neuhaus, Peter., O'Grady, John., Praseedom, Raaj. K., Burroughs, Andrew. K., Treut, Yves. P., Kirkegaard, Preben., Rogiers, Xavier., Ericzon, Goran -Bo., Hockersted, Krister., Adam, René., & Juergen, Klempnaue. (2005). Liver transplantation for Budd-Chiari syndrome: A European study on 248 patients from 51 centres. *Sciences*, 50(3), 540-546.

thrombosis after peritoneojugular (LeVeen) shunt. *Surgery*, 100, 535-540.

*J Hepatol*, 5, 102-108.

562 Hepatic Surgery

*N Engl J Med*, 321, 1632-1638.

ure. *Am Kidney Dis*, 6, 185-187.

therapy. *Gut*, 24, 412-417.

821-825.

*Hepatology*, 17, 148-158.

duplex sonography. *Gastroenterology*, 102, 817.

Neonatal cholestasis is one of the commonest presentations in the field of pediatric hepatol‐ ogy and gastroenterology and constitutes the major indication for liver transplantation be‐ low two years of age. Unfortunately, in spite of being common, fewer categories are amenable to curative or palliative therapy. Moreover, delayed referral to specialized centers is still a problem adding a more difficulty to neonatal cholestasis management. Hepatobili‐ ary surgery is a major line of therapy in some etiologies of neonatal cholestasis. Biliary atre‐ sia, choledochal cyst, spontaneous perforation of the bile duct and inspissated bile syndrome are among the commonest known causes for hepatobiliary surgeons. However, there is less orientation about other causes, resulting in progression to cirrhosis and end stage liver disease without being diagnosed. One of these is the progressive familial intrahe‐ patic cholestasis (PFIC) group of diseases [1].

PFIC is an autosomal recessive liver disorder characterized by an intrahepatic cholestasis due to bile canalicular transport defects. It is subdivided into three types with slightly different clinical, biochemical and histological features. PFIC types 1, 2 and 3 are due to mutations in *ATP8B1* (adenosine triphosphatase, type 8B, member 1), *ABCB11* (adeno‐ sine triphosphate-binding cassette, subfamily B, member 11) and *ABCB4* (adenosine tri‐ phosphate-binding cassette, subfamily B, member 4) genes, respectively. Each of these genes encodes a hepatocanalicular transporter which is essential for the proper secretion and formation of bile [2].

PFIC1 and PFIC2 usually appear in the first months of life, whereas onset of PFIC3 may also oc‐ cur later in infancy, in childhood or even during young adulthood. The shared main clinical manifestations in all types are cholestasis and pruritus. PFIC represents 10-15 % of causes of cholestasis in children and 10-15% of indications of liver transplantations in children [3].

© 2013 Sira and Sira; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Sira and Sira; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

In this chapter, we want to highlight the etiology, pathophysiology, clinical presentation and the role of surgery in the management of this disease category, especially that medical thera‐ py is of limited value in a magnitude of cases. Moreover, liver transplant is not without sig‐ nificant side effects. So, raising the orientation about this not uncommon condition will help in timely surgical intervention and improving patients' outcome.

### **2. Historical background**

This disorder was first described by Clayton in 1965, and was termed Byler's disease after an American Amish kindred in which it was discovered [4]. Clinical features included severe pru‐ ritus, steatorrhea, poor growth and progression to cirrhosis in early childhood. A prominent finding was a low or normal serum gamma glutamyl transpeptidase (GGT), which was dis‐ cordant with the severe cholestasis. Since its discovery, similar clinical features were described in non-Amish children. Therefore, the more descriptive term, PFIC, is preferred [5].

However, this PFIC nomenclature is not always entirely satisfactory. A preferable term is "bile canalicular transport disorders," especially as it has become apparent that these genetic disorders have numerous clinical phenotypes across all age brackets. For example, benign recurrent intrahepatic cholestasis (BRIC) and intrahepatic cholestasis of pregnancy (ICP) can occur in association with abnormalities in any of the three affected genes [2,6]. However, the PFIC nomenclature is still in use due to its popularity in the literature.

Abbreviations: FIC1: familial intrahepatic cholestasis 1; BSEP: bile salt export pump; MDR3: multidrug resistence pro‐

Progressive Familial Intrahepatic Cholestasis http://dx.doi.org/10.5772/51769 565

**Figure 1.** A schematic representation of the hepatocyte with its canalicular membrane transporters involved in bile formation. FIC1 is an aminophospholipid flippase, encoded by the *ATP8B1* (*FIC1*) gene. BSEP (bile salt export pump) (formerly sister of P-glycoprotein "SPGP") is a bile acids transporter to the bile canalicular lumen against a high concen‐ tration gradient. It is encoded by the *ABCB11* (*BSEP*) gene. The MDR3 is a phospholipid transporter. It is encoded by the

The most widely accepted hypothesis for FIC1 function is that of an aminophospholipid flippase, translocating phospholipids such as phosphatidylserine from the outer to the inner leaflet of the plasma membrane [13]. So, deficiency of FIC1 in the hepatocyte results in the loss of asymmetric distribution of phospholipids in the canalicular membrane, decreasing both membrane stability and function of transmembrane transporters including the bile salt export pump (BSEP) and, as such, causing bile salt retention in hepatocytes with consequent

Different studies have shown that ATP8B1 deficiency is associated with diminished FXR (farnesoid X receptor) activity. The FXR is a nuclear receptor that is highly expressed in the liver and regulates bile acid homeostasis so as to reduce its hepatocyte toxicity. Diminished FXR activity leads to upregulation of bile acid synthesis, reduced expression of the canalicu‐ lar BSEP, and increased expression of the ileal apical sodium dependent bile acid transport‐ er (ASBT). The net effect of these changes would be increased synthesis of bile acids and diminished its canalicular excretion, coupled with enhanced reabsorption of intestinal bile

ATP8B1 is abundantly expressed in a wide variety of tissues such as the small intestine, bladder and stomach and to a lesser extent also in the liver and pancreas. This results in the multitude of the extrahepatic manifestations such as the hearing loss, pancreatitis and diar‐ rhea, found in patients with ATP8B1 deficiency [19,20]. Over 50 distinct mutations in

defective bile formation; resulting in cholestasis [14-16].

acids, yielding marked hepatocyte bile acid overload [17,18].

tein 3.

*ABCB4* (*MDR3*) gene.

Benign recurrent intrahepatic cholestasis, first described in 1959, is an intermittent form of intrahepatic cholestasis characterized by variable periods of intense pruritus often associat‐ ed with jaundice [7]. The age of onset is variable, but it typically occurs during childhood or adolescence. The severity and duration of attacks also vary and triggering features are not well known. The benign designation of BRIC refers to the general lack of progressive liver disease, although the pruritus is far from benign during an intense episode [8-10].

As the clinical spectrum between BRIC and PFIC (formerly named Byler's disease) may be a continuum, thus the historical nomenclature of Byler's disease and BRIC may be outdated [11]. So, many clinicians now refer to all these diseases in a general sense as ATP8B1, ABCB11 and ABCB4 deficiency diseases to express the wide continuum of disease severity between the PFIC and BRIC phenotypes [2].

#### **3. Etiology and pathophysiology**

#### **3.1. PFIC 1 (ATP8B1 "FIC-1" deficiency)**

PFIC1 is an autosomal recessive disease caused by mutations in *ATP8B1* (formerly named *FIC1*) gene on chromosome 18, locus q21-22. This gene encodes a transporter localized on the canalicular membrane of hepatocytes (Figure 1), named FIC1 (ATP8B1), a P-type ATPase [12].

In this chapter, we want to highlight the etiology, pathophysiology, clinical presentation and the role of surgery in the management of this disease category, especially that medical thera‐ py is of limited value in a magnitude of cases. Moreover, liver transplant is not without sig‐ nificant side effects. So, raising the orientation about this not uncommon condition will help

This disorder was first described by Clayton in 1965, and was termed Byler's disease after an American Amish kindred in which it was discovered [4]. Clinical features included severe pru‐ ritus, steatorrhea, poor growth and progression to cirrhosis in early childhood. A prominent finding was a low or normal serum gamma glutamyl transpeptidase (GGT), which was dis‐ cordant with the severe cholestasis. Since its discovery, similar clinical features were described

However, this PFIC nomenclature is not always entirely satisfactory. A preferable term is "bile canalicular transport disorders," especially as it has become apparent that these genetic disorders have numerous clinical phenotypes across all age brackets. For example, benign recurrent intrahepatic cholestasis (BRIC) and intrahepatic cholestasis of pregnancy (ICP) can occur in association with abnormalities in any of the three affected genes [2,6]. However, the

Benign recurrent intrahepatic cholestasis, first described in 1959, is an intermittent form of intrahepatic cholestasis characterized by variable periods of intense pruritus often associat‐ ed with jaundice [7]. The age of onset is variable, but it typically occurs during childhood or adolescence. The severity and duration of attacks also vary and triggering features are not well known. The benign designation of BRIC refers to the general lack of progressive liver

As the clinical spectrum between BRIC and PFIC (formerly named Byler's disease) may be a continuum, thus the historical nomenclature of Byler's disease and BRIC may be outdated [11]. So, many clinicians now refer to all these diseases in a general sense as ATP8B1, ABCB11 and ABCB4 deficiency diseases to express the wide continuum of disease severity

PFIC1 is an autosomal recessive disease caused by mutations in *ATP8B1* (formerly named *FIC1*) gene on chromosome 18, locus q21-22. This gene encodes a transporter localized on the canalicular membrane of hepatocytes (Figure 1), named FIC1 (ATP8B1), a P-type ATPase [12].

in non-Amish children. Therefore, the more descriptive term, PFIC, is preferred [5].

disease, although the pruritus is far from benign during an intense episode [8-10].

PFIC nomenclature is still in use due to its popularity in the literature.

between the PFIC and BRIC phenotypes [2].

**3. Etiology and pathophysiology**

**3.1. PFIC 1 (ATP8B1 "FIC-1" deficiency)**

in timely surgical intervention and improving patients' outcome.

**2. Historical background**

564 Hepatic Surgery

**Figure 1.** A schematic representation of the hepatocyte with its canalicular membrane transporters involved in bile formation. FIC1 is an aminophospholipid flippase, encoded by the *ATP8B1* (*FIC1*) gene. BSEP (bile salt export pump) (formerly sister of P-glycoprotein "SPGP") is a bile acids transporter to the bile canalicular lumen against a high concen‐ tration gradient. It is encoded by the *ABCB11* (*BSEP*) gene. The MDR3 is a phospholipid transporter. It is encoded by the *ABCB4* (*MDR3*) gene.

The most widely accepted hypothesis for FIC1 function is that of an aminophospholipid flippase, translocating phospholipids such as phosphatidylserine from the outer to the inner leaflet of the plasma membrane [13]. So, deficiency of FIC1 in the hepatocyte results in the loss of asymmetric distribution of phospholipids in the canalicular membrane, decreasing both membrane stability and function of transmembrane transporters including the bile salt export pump (BSEP) and, as such, causing bile salt retention in hepatocytes with consequent defective bile formation; resulting in cholestasis [14-16].

Different studies have shown that ATP8B1 deficiency is associated with diminished FXR (farnesoid X receptor) activity. The FXR is a nuclear receptor that is highly expressed in the liver and regulates bile acid homeostasis so as to reduce its hepatocyte toxicity. Diminished FXR activity leads to upregulation of bile acid synthesis, reduced expression of the canalicu‐ lar BSEP, and increased expression of the ileal apical sodium dependent bile acid transport‐ er (ASBT). The net effect of these changes would be increased synthesis of bile acids and diminished its canalicular excretion, coupled with enhanced reabsorption of intestinal bile acids, yielding marked hepatocyte bile acid overload [17,18].

ATP8B1 is abundantly expressed in a wide variety of tissues such as the small intestine, bladder and stomach and to a lesser extent also in the liver and pancreas. This results in the multitude of the extrahepatic manifestations such as the hearing loss, pancreatitis and diar‐ rhea, found in patients with ATP8B1 deficiency [19,20]. Over 50 distinct mutations in ATP8B1 are described. The mutations G308V found in Amish, D554N found in Inuits and I661T are amongst the most frequently detected [21,22].

**3.3. PFIC 3 (ABCB4 "MDR3" deficiency)**

and the lithogenicity of bile [2,38].

levels are elevated. It is explained by:

protein affected by missense mutations.

**4. Clinical picture**

therefore additional genes might be involved [2,45].

ing pregnancy, with postnatal resolution [2].

PFIC3 is an autosomal recessive disorder due to mutations in the *ABCB4* (formerly named *MDR3*) gene located on chromosome 7, locus q21, which codes for the class III multidrug resistance P-glycoprotein (MDR3). MDR3 is located exclusively on the canalicular mem‐ brane of the hepatocyte and serves as a phospholipid translocator (Figure 1) essential for

Progressive Familial Intrahepatic Cholestasis http://dx.doi.org/10.5772/51769 567

PC in bile normally protects cholangiocytes from bile salt toxicity by forming mixed micelles with it. However, a mutation of the *ABCB4* gene results in decreased biliary PC secretion and high biliary bile salt -to-PC ratio, leading to bile duct injury (cholangitis and ductular proliferation). Also, a decreased biliary PC concentration leads to high biliary cholesterol to-PC ratio. The high biliary cholesterol saturation promotes crystallization of cholesterol

Whereas biliary bile salt concentrations are normal in patients with PFIC3, serum bile salt

**1.** Downregulation of the bile acid importers to the hepatocyte, NTCP (Na+/taurocholate cotransporting polypeptide) and OATP (organic acid transporting polypeptide) [39]. **2.** Upregulation of the bile acid exporter from hepatocyte at the sinusoidal membrane, MRP4 (multidrug resistance–related protein 4), mediating bile salt efflux into serum [40].

Over 45 disease-causing mutations in *ABCB4* have been identified [41]. Children with mis‐ sense mutations seem to have a less severe phenotype, with later onset of disease, slower progression and better response to treatment, as compared to patients with mutations lead‐ ing to a truncated protein [42]. Possibly this is due to residual transport activity in MDR3

Heterozygous mutations in the *ABCB4* gene can also cause or predispose for a variety of other liver diseases, such as adult biliary cirrhosis, cholelithiasis, transient neonatal cholestasis, drug induced cholestasis and ICP. Mutations can even lead to a cascade of several phenotypes in one

A small proportion of PFIC phenotypes are not due to mutations in these three genes and

Mutations in *ATP8B1* and *ABCB11* can result both in progressive cholestatic disease termed PFIC1 and PFIC2, as well as in episodic cholestasis, referred to as BRIC type 1 and 2 respec‐ tively. This suggests that PFIC and BRIC are the two ends of a clinical spectrum, with differ‐ ent degrees of severity in between. Therefore, these diseases are preferably referred to as ATP8B1 deficiency and ABCB11 deficiency. While mutations in *ABCB4* can result in pro‐ gressive cholestatic disease only designated PFIC type 3. Similarly PFIC3 is best designated as *ABCB4* deficiency. Heterozygous mutations in any of these three genes can also be associ‐ ated with ICP. It is a transient form of cholestasis, characterized by the onset of pruritus dur‐

patient, indicating the wide phenotypical spectrum of ABCB4 deficiency [43,44].

biliary phospholipid (e.g. phosphatidylcholine "PC") secretion [37].

In vitro studies showed that ATP8B1 deficiency due to common missense mutations such as G308V, D554N and I661T, can be regarded as a protein folding disease, with different de‐ grees of retention of the mutant protein in the endoplasmic reticulum, resulting in a de‐ creased protein expression at the plasma membrane [23]. The pathophysiologic concept of being a protein folding disease can be used in new therapeutic interventions [24]. Incubation at a reduced temperature could improve proper folding of some of the mutated proteins. Similarly, the pharmacological chaperone 4-phenylbutyrate acid (4-PBA) could stabilize misfolded proteins, partially restoring cell surface expression [25].

Mutations in ATP8B1 are also responsible for:


#### **3.2. PFIC 2 (ABCB11 "BSEP" deficiency)**

PFIC2 is an autosomal recessive disease caused by mutations in the *ABCB11* (formerly named *BSEP*) gene encoding the BSEP, a liver-specific adenosine triphosphate (ATP)-bind‐ ing cassette transporter formerly known as sister of P-glycoprotein (SPGP). BSEP is located in the hepatocyte canalicular membrane (Figure 1). *ABCB11* gene is located on chromosome 2, locus q24 [29-31].

The defective canalicular BSEP expression leads to markedly diminished bile salt secretion. This leads to bile secretory failure with secondary retention of bile salts and other biliary con‐ stituents in the hepatocytes leading to progressive liver damage and progressive cholestasis. BSEP deficiency represents also a phenotypic continuum between BRIC2 and PFIC2. Different mutations may cause different kinds of BSEP dysfunction, including protein lack, misfolded protein, or protein not delivered from the Golgi to the bile canalicular membrane [31].

Generally missense mutations, e.g. E297G or D482G, lead to a less severe phenotype than mu‐ tations that are predicted to result in premature protein truncation or total failure of protein production [31,32]. In vitro, the residual transport function of mutant proteins correlates with the phenotypic differences between BRIC2 and PFIC2, with generally a diminished function in BRIC2 mutants, while complete abolishment is more often seen in PFIC2 mutants [33].

Heterozygous *ABCB11* mutations have also been identified in cases of ICP (ICP2) [34], drug induced cholestasis [35] and transient neonatal cholestasis [36].

#### **3.3. PFIC 3 (ABCB4 "MDR3" deficiency)**

ATP8B1 are described. The mutations G308V found in Amish, D554N found in Inuits and

In vitro studies showed that ATP8B1 deficiency due to common missense mutations such as G308V, D554N and I661T, can be regarded as a protein folding disease, with different de‐ grees of retention of the mutant protein in the endoplasmic reticulum, resulting in a de‐ creased protein expression at the plasma membrane [23]. The pathophysiologic concept of being a protein folding disease can be used in new therapeutic interventions [24]. Incubation at a reduced temperature could improve proper folding of some of the mutated proteins. Similarly, the pharmacological chaperone 4-phenylbutyrate acid (4-PBA) could stabilize

**4.** Down regulation of CFTR (cystic fibrosis transmembrane regulator): ATP8B1 is highly expressed in biliary epithelial cells, and when it is abnormal in PFIC1, CFTR down reg‐ ulation in cholangiocytes has been reported which could contribute to impairment of

PFIC2 is an autosomal recessive disease caused by mutations in the *ABCB11* (formerly named *BSEP*) gene encoding the BSEP, a liver-specific adenosine triphosphate (ATP)-bind‐ ing cassette transporter formerly known as sister of P-glycoprotein (SPGP). BSEP is located in the hepatocyte canalicular membrane (Figure 1). *ABCB11* gene is located on chromosome

The defective canalicular BSEP expression leads to markedly diminished bile salt secretion. This leads to bile secretory failure with secondary retention of bile salts and other biliary con‐ stituents in the hepatocytes leading to progressive liver damage and progressive cholestasis. BSEP deficiency represents also a phenotypic continuum between BRIC2 and PFIC2. Different mutations may cause different kinds of BSEP dysfunction, including protein lack, misfolded

Generally missense mutations, e.g. E297G or D482G, lead to a less severe phenotype than mu‐ tations that are predicted to result in premature protein truncation or total failure of protein production [31,32]. In vitro, the residual transport function of mutant proteins correlates with the phenotypic differences between BRIC2 and PFIC2, with generally a diminished function in

Heterozygous *ABCB11* mutations have also been identified in cases of ICP (ICP2) [34], drug

protein, or protein not delivered from the Golgi to the bile canalicular membrane [31].

BRIC2 mutants, while complete abolishment is more often seen in PFIC2 mutants [33].

induced cholestasis [35] and transient neonatal cholestasis [36].

I661T are amongst the most frequently detected [21,22].

misfolded proteins, partially restoring cell surface expression [25].

**1.** Greenland Eskimo cholestasis (Nielsen syndrome) [26].

**2.** Benign recurrent intrahepatic cholestasis-1 (BRIC1) [12].

**3.** Intrahepatic cholestasis of pregnancy-1 (ICP1) [27].

Mutations in ATP8B1 are also responsible for:

bile secretion [28].

566 Hepatic Surgery

2, locus q24 [29-31].

**3.2. PFIC 2 (ABCB11 "BSEP" deficiency)**

PFIC3 is an autosomal recessive disorder due to mutations in the *ABCB4* (formerly named *MDR3*) gene located on chromosome 7, locus q21, which codes for the class III multidrug resistance P-glycoprotein (MDR3). MDR3 is located exclusively on the canalicular mem‐ brane of the hepatocyte and serves as a phospholipid translocator (Figure 1) essential for biliary phospholipid (e.g. phosphatidylcholine "PC") secretion [37].

PC in bile normally protects cholangiocytes from bile salt toxicity by forming mixed micelles with it. However, a mutation of the *ABCB4* gene results in decreased biliary PC secretion and high biliary bile salt -to-PC ratio, leading to bile duct injury (cholangitis and ductular proliferation). Also, a decreased biliary PC concentration leads to high biliary cholesterol to-PC ratio. The high biliary cholesterol saturation promotes crystallization of cholesterol and the lithogenicity of bile [2,38].

Whereas biliary bile salt concentrations are normal in patients with PFIC3, serum bile salt levels are elevated. It is explained by:


Over 45 disease-causing mutations in *ABCB4* have been identified [41]. Children with mis‐ sense mutations seem to have a less severe phenotype, with later onset of disease, slower progression and better response to treatment, as compared to patients with mutations lead‐ ing to a truncated protein [42]. Possibly this is due to residual transport activity in MDR3 protein affected by missense mutations.

Heterozygous mutations in the *ABCB4* gene can also cause or predispose for a variety of other liver diseases, such as adult biliary cirrhosis, cholelithiasis, transient neonatal cholestasis, drug induced cholestasis and ICP. Mutations can even lead to a cascade of several phenotypes in one patient, indicating the wide phenotypical spectrum of ABCB4 deficiency [43,44].

A small proportion of PFIC phenotypes are not due to mutations in these three genes and therefore additional genes might be involved [2,45].

#### **4. Clinical picture**

Mutations in *ATP8B1* and *ABCB11* can result both in progressive cholestatic disease termed PFIC1 and PFIC2, as well as in episodic cholestasis, referred to as BRIC type 1 and 2 respec‐ tively. This suggests that PFIC and BRIC are the two ends of a clinical spectrum, with differ‐ ent degrees of severity in between. Therefore, these diseases are preferably referred to as ATP8B1 deficiency and ABCB11 deficiency. While mutations in *ABCB4* can result in pro‐ gressive cholestatic disease only designated PFIC type 3. Similarly PFIC3 is best designated as *ABCB4* deficiency. Heterozygous mutations in any of these three genes can also be associ‐ ated with ICP. It is a transient form of cholestasis, characterized by the onset of pruritus dur‐ ing pregnancy, with postnatal resolution [2].

Pruritus is the prominent clinical feature of PFIC; however, until an episode of jaundice in‐ tervenes, the diagnosis is often overlooked. Even then, because of the rarity of the condition, children sometimes receive a misdiagnosis of obstructive jaundice caused by the occasional‐ ly associated choledocholithiasis in PFIC types 2 and 3 [5].

though the pruritus is far from benign during an intense episode [10]. Two types of BRIC are present according to the gene defect. BRIC1 is due to a mutation of *ATP8B1* gene and

Progressive Familial Intrahepatic Cholestasis http://dx.doi.org/10.5772/51769 569

The age of presentation of the first attack of jaundice ranges from 1–50 years, but jaundice usually occurs before the age of twenty years. Attacks usually are preceded by a minor illness and consist of a preicteric phase of 2–4 weeks (characterized by malaise, anorexia, and pruritus) and an icteric phase that may last from 1–18 months. In some patients, hor‐ monal factors such as the use of oral contraceptives and pregnancy have been associated with precipitation of an attack [10,47]. Patients may have severe coughing during epi‐

During the icteric phase, the concentrations of serum bile acid, bilirubin, and alkaline phosphatase (ALP) are increased. Serum GGT concentration, however, remains low. Liver biopsy results are very benign, often showing no pathologic change even during an epi‐ sode. Some specimens show hepatocellular cholestasis and cholate injury, mostly centri‐ lobular. During the asymptomatic period, all parameters (clinical, laboratory and liver

The initial presentation and the evolution seem to be more severe than PFIC1, with per‐ manent jaundice from the first months of life and rapid appearance of cirrhosis and liver

Early hepatocellular carcinoma (before one year of age) may complicate the course of PFIC2 [3]. Up to 15% of the patients with ABCB11 deficiency will develop hepatocellular carcinoma (HCC) or cholangiocarcinoma. Close surveillance for hepatobiliary malignancy

At diagnosis, the cholestasis in ABCB11 deficiency results in a more detectable fat-soluble

The development of cholelithiasis in approximately one third of the patients, probably due to the low bile salt concentration in bile, secondary to impaired BSEP function, which

**•** Patients fitting the phenotype of BRIC have been described with mutations in *ABCB11.*

The age of onset and total number of recurrent episodes were highly variable. Choleli‐ thiasis occurred in many patients with BRIC2. Several patients had a relatively early onset of the disease and developed permanent cholestasis as adults after initial periods

**•** PFIC2 affected children differ from those with PFIC1 in some important respects:

They do not have extrahepatic involvement such as pancreatitis or diarrhea [45].

BRIC2, due to *ABCB11* gene mutations.

histology) are normal [49].

**4.2. PFIC2 "Byler's syndrome"**

failure within the first years of life [3].

vitamin deficiency manifestations [45].

of recurrent attacks.

is therefore warranted in these patients [31,32,45].

might cause supersaturation of cholesterol [32].

They are called BRIC2 and are characterized by:

sodes, as is seen sometimes in patients with PFIC1 [48].

#### **4.1. PFIC1 "Byler's disease"**

	- **•** Persistent diarrhea with fat malabsorption and protein loss, leading to poor growth and short stature.
	- **•** Bouts of pancreatitis.
	- **•** Recurrent pneumonia may also compromise growth.
	- **•** Sensorineural hearing loss may occur.

BRIC is an intermittent form of intrahepatic cholestasis characterized by variable periods of intense pruritus often associated with jaundice, separated by symptom-free intervals. The benign designation of BRIC refers to the general lack of progressive liver disease, al‐ though the pruritus is far from benign during an intense episode [10]. Two types of BRIC are present according to the gene defect. BRIC1 is due to a mutation of *ATP8B1* gene and BRIC2, due to *ABCB11* gene mutations.

The age of presentation of the first attack of jaundice ranges from 1–50 years, but jaundice usually occurs before the age of twenty years. Attacks usually are preceded by a minor illness and consist of a preicteric phase of 2–4 weeks (characterized by malaise, anorexia, and pruritus) and an icteric phase that may last from 1–18 months. In some patients, hor‐ monal factors such as the use of oral contraceptives and pregnancy have been associated with precipitation of an attack [10,47]. Patients may have severe coughing during epi‐ sodes, as is seen sometimes in patients with PFIC1 [48].

During the icteric phase, the concentrations of serum bile acid, bilirubin, and alkaline phosphatase (ALP) are increased. Serum GGT concentration, however, remains low. Liver biopsy results are very benign, often showing no pathologic change even during an epi‐ sode. Some specimens show hepatocellular cholestasis and cholate injury, mostly centri‐ lobular. During the asymptomatic period, all parameters (clinical, laboratory and liver histology) are normal [49].

#### **4.2. PFIC2 "Byler's syndrome"**

Pruritus is the prominent clinical feature of PFIC; however, until an episode of jaundice in‐ tervenes, the diagnosis is often overlooked. Even then, because of the rarity of the condition, children sometimes receive a misdiagnosis of obstructive jaundice caused by the occasional‐

**•** Cholestasis is a major clinical sign in PFIC1 as in all PFIC forms. It usually appears in the first months of life in patients with PFIC1, and is characterized by recurrent episodes of jaundice, which become permanent later in the course of the disease [3]. The variable clin‐

**1.** *Jaundice*: It presents with conjugated hyperbilirubinemia in the first 3–6 months of life.

**2.** *Pruritus*: It is the dominant feature in the majority of patients and is often out of propor‐ tion to the level of jaundice [46]. It may initially vary in intensity and may be exacerbat‐ ed during intercurrent illness. Pruritus may not be noticed until 6 months of age because the neural pathways necessary for concerted scratching are not fully devel‐ oped. However, affected infants often are irritable and sleep poorly with onset of cho‐ lestasis. Scratching is usually evident first as digging at the ears and eyes, which are the first areas to show evidence of excoriation. By one year of age, patients may show gen‐ eralized mutilation of skin, usually most severe on the extensor surfaces of the arms and legs and on the flanks of the back. The pruritus is very disabling and often re‐

**3.** *Hepatomegaly* is present early in life and persists with progression to cirrhosis. The rate of progression to cirrhosis is variable, but usually develops in early childhood without

**•** Persistent diarrhea with fat malabsorption and protein loss, leading to poor growth

**•** As it has been mentioned before, ATP8B1 deficiency can lead to a continuum of disease severity ranging from the progressive form PFIC1 to the recurrent form, BRIC1. BRIC1

BRIC is an intermittent form of intrahepatic cholestasis characterized by variable periods of intense pruritus often associated with jaundice, separated by symptom-free intervals. The benign designation of BRIC refers to the general lack of progressive liver disease, al‐

treatment. With progression to cirrhosis splenomegaly develops.

**4.** *Fat-soluble vitamin deficiencies*, including rickets, may be severe.

**•** Recurrent pneumonia may also compromise growth.

**•** Sensorineural hearing loss may occur.

will be discussed briefly in the next paragraphs.

ly associated choledocholithiasis in PFIC types 2 and 3 [5].

The degree of jaundice may vary [46].

sponds poorly to medical therapies [12,45].

**5.** *Extrahepatic disorders* [19]:

and short stature. **•** Bouts of pancreatitis.

**4.1. PFIC1 "Byler's disease"**

ical features are:

568 Hepatic Surgery

**•** PFIC2 affected children differ from those with PFIC1 in some important respects:

The initial presentation and the evolution seem to be more severe than PFIC1, with per‐ manent jaundice from the first months of life and rapid appearance of cirrhosis and liver failure within the first years of life [3].

They do not have extrahepatic involvement such as pancreatitis or diarrhea [45].

Early hepatocellular carcinoma (before one year of age) may complicate the course of PFIC2 [3]. Up to 15% of the patients with ABCB11 deficiency will develop hepatocellular carcinoma (HCC) or cholangiocarcinoma. Close surveillance for hepatobiliary malignancy is therefore warranted in these patients [31,32,45].

At diagnosis, the cholestasis in ABCB11 deficiency results in a more detectable fat-soluble vitamin deficiency manifestations [45].

The development of cholelithiasis in approximately one third of the patients, probably due to the low bile salt concentration in bile, secondary to impaired BSEP function, which might cause supersaturation of cholesterol [32].

**•** Patients fitting the phenotype of BRIC have been described with mutations in *ABCB11.* They are called BRIC2 and are characterized by:

The age of onset and total number of recurrent episodes were highly variable. Choleli‐ thiasis occurred in many patients with BRIC2. Several patients had a relatively early onset of the disease and developed permanent cholestasis as adults after initial periods of recurrent attacks.

Occasionally BRIC will progress to the more severe and permanent form of PFIC, indi‐ cative of a clinical continuum, with intermediate phenotypes between mild and pro‐ gressive disease [2,11].

**•** *Serum GGT* is repeatedly normal or low in PFIC1 & PFIC2, while it is elevated in PFIC3 often more than ten times the normal value. In PFIC1 and PFIC2, the serum GGT concentration may increase to greater than 100 IU/L in patients receiving micro‐

Progressive Familial Intrahepatic Cholestasis http://dx.doi.org/10.5772/51769 571

The mechanism for the low serum concentration of GGT in PFIC1 and 2 is not clear. GGT is normally bound to the canalicular membrane by a glycosyl phosphatidyl inosi‐ tol (GPI) anchor. In obstructive cholestasis, when excessive amounts of bile salts accu‐ mulate in the canalicular lumen under increased pressure, GGT is released from the membrane by detergent action and refluxes back into serum, possibly via leaky inter‐ cellular junctions. However, in PFIC and BRIC types 1 and 2, the reduced concentra‐ tions of biliary bile acids preserve canalicular GGT localization. This explanation is not entirely satisfactory as serum GGT is elevated in most other forms of intrahepatic cho‐ lestasis in which biliary bile acid levels are low. Preliminary studies indicate that some canalicular proteins, including GGT and carcinoembryonic antigen (CEA), are poorly expressed at the canaliculus in PFIC1 and 2. It is possible that low serum GGT levels re‐ sult from the lack of canalicular GGT available for elution as well as from the inade‐

quate concentrations of intracanalicular bile acids to act as detergents [51,52].

**•** *Serum cholesterol*: it is characteristically low or normal in all the three types [3].

**•** *Alpha-fetoprotein*: it is elevated at diagnosis in PFIC2 than that in PFIC1 [12,45].

**•** *Absent serum lipoprotein X (LPX) in PFIC3*: because measurement of biliary phospholi‐ pids is impractical in the evaluation of most patients, measurement of serum LPX may serve as a surrogate marker for PFIC3. LPX is the predominant lipoprotein in the plasma of cholestatic patients. LPX is absent from the serum of patients with ho‐ mozygous *ABCB4* mutations. LPX is probably composed of biliary vesicles that are formed at the subapical compartment of the hepatocyte, transcytosed to sinusoidal membrane, and released into plasma. This process is absolutely dependent on MDR3,

Biliary bile analysis is performed on gallbladder bile or on bile collected by duodenal aspira‐ tion (pure choledochal bile). In case of gallbladder punction, bile contamination by blood may falsify bile analysis. In case of duodenal aspiration, bile dilution or bile contamination

The biliary bile salt concentration is dramatically decreased (<1 mmol/L) in PFIC2 patients [54] and only mildly decreased in PFIC1 patients (3–8 mmol/L) [19]. The normal concentration of biliary primary bile salts distinguishes PFIC3 patients from those with PFIC1 and PFIC2 [42].

**•** *Serum bile acid concentration*: it is elevated in all the three types [44,45].

but the precise mechanism has not been defined [50,53].

by alimentary phospholipids may falsify bile analysis [3].

**•** *Serum transaminases*: In PFIC1 serum transaminases are mildly elevated. While in pa‐ tients with PFIC2, serum transaminases levels are usually elevated to at least five times normal values. In PFIC3, serum aminotransferases, conjugated bilirubin, and

somal inducers such as phenobarbital and rifampicin [51].

ALP are all significantly elevated [2,45].

**2.** *Biliary bile analysis*:

#### **4.3. PFIC3 "MDR3 deficiency"**

Mutations in the *ABCB4* gene can cause or predispose to a variety of liver diseases with dif‐ ferent age of presentation. Moreover, it can even lead to a cascade of several phenotypes in one patient, indicating the wide phenotypical spectrum of ABCB4 deficiency [43].

	- **•** *Cholestasis* developing within the first year of life in about one third of patients and rarely in the neonatal period. It may also manifest later in infancy, in childhood or even in young adulthood [3,45].
	- **•** *Pruritus* occurs less frequently than in the other types of PFIC and is usually mild.
	- **•** *Jaundice* may be less prominent than pruritus.
	- **•** *Height and weight* may be below normal as the disease progresses.
	- **•** *Hepatomegaly*, and at later stages splenomegaly, as a manifestation of portal hyperten‐ sion is often observed. Liver disease tends to evolve slowly to biliary cirrhosis with or without overt cholestatic jaundice [42,50].
	- **•** *Cholelithiasis* may develop in older children.
	- **•** *No extrahepatic features* or occurrence of malignancies are described in association with PFIC3 [42,50].

#### **5. Diagnosis**

Diagnosis is dependent firstly on suspicion. The most alarming point making PFIC in the scope of diagnosis is the presence of significant pruritus out of proportion to the level of jaundice especially in the setting of low GGT. However, accurate diagnosis is dependent on a constellation of a clinical, biochemical, radiological, histopathological, immunohistochemi‐ cal studies and finally can be confirmed by genetic testing for mutations (Table 1).

**1.** *Biochemical parameters*:

**•** *Serum GGT* is repeatedly normal or low in PFIC1 & PFIC2, while it is elevated in PFIC3 often more than ten times the normal value. In PFIC1 and PFIC2, the serum GGT concentration may increase to greater than 100 IU/L in patients receiving micro‐ somal inducers such as phenobarbital and rifampicin [51].

The mechanism for the low serum concentration of GGT in PFIC1 and 2 is not clear. GGT is normally bound to the canalicular membrane by a glycosyl phosphatidyl inosi‐ tol (GPI) anchor. In obstructive cholestasis, when excessive amounts of bile salts accu‐ mulate in the canalicular lumen under increased pressure, GGT is released from the membrane by detergent action and refluxes back into serum, possibly via leaky inter‐ cellular junctions. However, in PFIC and BRIC types 1 and 2, the reduced concentra‐ tions of biliary bile acids preserve canalicular GGT localization. This explanation is not entirely satisfactory as serum GGT is elevated in most other forms of intrahepatic cho‐ lestasis in which biliary bile acid levels are low. Preliminary studies indicate that some canalicular proteins, including GGT and carcinoembryonic antigen (CEA), are poorly expressed at the canaliculus in PFIC1 and 2. It is possible that low serum GGT levels re‐ sult from the lack of canalicular GGT available for elution as well as from the inade‐ quate concentrations of intracanalicular bile acids to act as detergents [51,52].


Occasionally BRIC will progress to the more severe and permanent form of PFIC, indi‐ cative of a clinical continuum, with intermediate phenotypes between mild and pro‐

Mutations in the *ABCB4* gene can cause or predispose to a variety of liver diseases with dif‐ ferent age of presentation. Moreover, it can even lead to a cascade of several phenotypes in

**•** *Cholestasis* developing within the first year of life in about one third of patients and rarely in the neonatal period. It may also manifest later in infancy, in childhood or

**•** *Pruritus* occurs less frequently than in the other types of PFIC and is usually mild.

**•** *Hepatomegaly*, and at later stages splenomegaly, as a manifestation of portal hyperten‐ sion is often observed. Liver disease tends to evolve slowly to biliary cirrhosis with

**•** *No extrahepatic features* or occurrence of malignancies are described in association

**2.** *Adult biliary cirrhosis*: gastrointestinal bleeding due to portal hypertension and cirrhosis

**3.** *ICP*: some cases of ICP have been associated with heterozygous mutations in *ABCB4* [43].

**4.** Heterozygous mutations in the *ABCB4* gene can also cause or predispose for transient

Diagnosis is dependent firstly on suspicion. The most alarming point making PFIC in the scope of diagnosis is the presence of significant pruritus out of proportion to the level of jaundice especially in the setting of low GGT. However, accurate diagnosis is dependent on a constellation of a clinical, biochemical, radiological, histopathological, immunohistochemi‐

cal studies and finally can be confirmed by genetic testing for mutations (Table 1).

may be the presenting symptom in adolescent or young adult patients [3].

one patient, indicating the wide phenotypical spectrum of ABCB4 deficiency [43].

**•** *Height and weight* may be below normal as the disease progresses.

gressive disease [2,11].

570 Hepatic Surgery

**4.3. PFIC3 "MDR3 deficiency"**

**1.** *PFIC3*: it is characterized by:

with PFIC3 [42,50].

**5. Diagnosis**

**1.** *Biochemical parameters*:

even in young adulthood [3,45].

**•** *Jaundice* may be less prominent than pruritus.

or without overt cholestatic jaundice [42,50].

neonatal cholestasis and drug induced cholestasis [44].

**•** *Cholelithiasis* may develop in older children.

Biliary bile analysis is performed on gallbladder bile or on bile collected by duodenal aspira‐ tion (pure choledochal bile). In case of gallbladder punction, bile contamination by blood may falsify bile analysis. In case of duodenal aspiration, bile dilution or bile contamination by alimentary phospholipids may falsify bile analysis [3].

The biliary bile salt concentration is dramatically decreased (<1 mmol/L) in PFIC2 patients [54] and only mildly decreased in PFIC1 patients (3–8 mmol/L) [19]. The normal concentration of biliary primary bile salts distinguishes PFIC3 patients from those with PFIC1 and PFIC2 [42].

In PFIC3 patients, the cardinal feature is the dramatically decreased biliary phospholipid level (1–15% of total biliary lipids; normal range 19–24%). Biliary bile salt-to-phospholi‐ pid is approximately 5-fold higher than in wild type bile, as is also biliary cholesterol-tophospholipid [3].

Commercially available MDR3 and BSEP antibodies allow liver immunostaining to be per‐ formed. Absence of canalicular or mild immunostaining is in favor of a gene defect. Howev‐ er, normal staining does not exclude a gene defect as a mutation may induce a loss of

Molecular analysis remains the definitive diagnostic technique for PFIC. Gene analysis is usually performed by DNA sequencing of the 27 coding exons (coding exons 2-28) of the *ATP8B1*, *ABCB11*, and *ABCB4* genes and their splice junctions [3]. The use of a resequensing chip dedicated to genetic cholestasis could facilitate identification of gene mutation [55].

PFIC-1 PFIC-2 PFIC-3

Present Absent Absent

PFIC1, BRIC1, and ICP PFIC2, BRIC2, and ICP PFIC3, ICP, adult

More elevated --

Giant cell hepatitis

Amorphous bile (EM)

BSEP staining in the majority of patients

(LM)

Cholelithiasis Absent Increased incidence Increased incidence

Gene defect ATP8B1 (FIC1) ABCB11 (BSEP) ABCB4 (MDR3) Locus 18q21-22 2q24 7q21 Transport defect Aminophospholipid Bile acid Phospholipids

Onset of cholestasis Neonatal Neonatal Variable Pruritus Severe Severe Moderate

HCC No Risk from the 1st year No

GGT Normal or low Normal or low Elevated Transaminases Mildly elevated More elevated Elevated Bile acids Elevated More elevated Elevated Cholesterol Normal Normal Normal

Byler syndrome ABCB11 deficiency BSEP deficiency

Impaired canalicular bile salt transport secondary to malfunction of BSEP

ABCB4 deficiency MDR3 deficiency

Progressive Familial Intrahepatic Cholestasis http://dx.doi.org/10.5772/51769 573

Impaired canalicular translocation of phosphatidylcholine

biliary cirrhosis, cholelithiasis, transient neonatal cholestasis, drug induced cholestasis

Ductular proliferation

Absent or reduced MDR3 staining in about 50 % of patients

(LM)

3

function but normal synthesis [31,42].

Synonyms Byler disease

Pathophysiology Impaired inward

Alpha fetoprotein Not significantly

**Table 1.** Summary of the criteria of different PFIC types.

Histopathological Bland cholestasis (LM)

elevated

Coarse granular bile (EM)

Immunohistochemical -- Absent or reduced

Clinical picture:

Extrahepatic manifestations

Biochemical:

Clinical spectrum of gene defect

ATP8B1 deficiency FIC1 deficiency

translocation of aminophospholipids over cellular membranes

**6.** *Genetic testing*:

#### **3.** *Radiological*:

Initial ultrasonography of the liver is performed to exclude biliary tract disease. Typically, ultrasonography is normal but may reveal a huge gallbladder in PFIC3. Sometimes, biliary stones may be identified in both PFIC2 and PFIC3 [3].

Cholangiography performed in a limited number of patients with PFIC3 showed a nor‐ mal biliary tree, excluding sclerosing cholangitis, and allowed bile to be collected for bili‐ ary lipid analysis [42].

	- **•** *In PFIC1*

Light microscopy (LM): on routine hematoxylin and eosin (H & E) staining, liver biopsy shows bland cholestasis with almost no inflammation. It shows canalicular bile plugs of distinctive color. Small-duct paucity may be present. Fibrosis starts early, with approxi‐ mately 75 % of patients having some fibrosis by 2 years of age. Fibrosis may appear ini‐ tially either as pericentral sclerosis or portal fibrosis, or sometimes both. Portal to central bridging then develops in association with lacy lobular fibrosis and eventually leads to cirrhosis. Proliferating bile ductules are observed at the edge of the portal tracts in patients with significant fibrosis. The rate of progression of the fibrosis is highly vari‐ able but correlates loosely with the severity of the clinical disease [45].

On electron microscopy (EM), canalicular bile plugs shows characteristic granular appearance "chunky bile".

**•** *In PFIC2*

LM: on H & E stains, there is inflammation with giant cell hepatitis, fibrosis and duct reaction [45].

On EM, bile appears amorphous [45].

**•** *In PFIC3*

LM: on H & E stains, bile ductular proliferation and mixed inflammatory infiltrates are observed in the early stages despite patency of intra- and extrahepatic bile ducts. Cholestasis with slight giant cell transformation and isolated eosinophilic ne‐ crotic hepatocytes may also be present. Periductal sclerosis affecting the interlobu‐ lar bile ducts eventually occurs. Extensive portal fibrosis evolves into biliary cirrhosis in older children [42].

EM of liver has not been reported in proven cases.

**5.** *Immunohistochemical staining*:

3

Commercially available MDR3 and BSEP antibodies allow liver immunostaining to be per‐ formed. Absence of canalicular or mild immunostaining is in favor of a gene defect. Howev‐ er, normal staining does not exclude a gene defect as a mutation may induce a loss of function but normal synthesis [31,42].

#### **6.** *Genetic testing*:

In PFIC3 patients, the cardinal feature is the dramatically decreased biliary phospholipid level (1–15% of total biliary lipids; normal range 19–24%). Biliary bile salt-to-phospholi‐ pid is approximately 5-fold higher than in wild type bile, as is also biliary cholesterol-to-

Initial ultrasonography of the liver is performed to exclude biliary tract disease. Typically, ultrasonography is normal but may reveal a huge gallbladder in PFIC3. Sometimes, biliary

Cholangiography performed in a limited number of patients with PFIC3 showed a nor‐ mal biliary tree, excluding sclerosing cholangitis, and allowed bile to be collected for bili‐

Light microscopy (LM): on routine hematoxylin and eosin (H & E) staining, liver biopsy shows bland cholestasis with almost no inflammation. It shows canalicular bile plugs of distinctive color. Small-duct paucity may be present. Fibrosis starts early, with approxi‐ mately 75 % of patients having some fibrosis by 2 years of age. Fibrosis may appear ini‐ tially either as pericentral sclerosis or portal fibrosis, or sometimes both. Portal to central bridging then develops in association with lacy lobular fibrosis and eventually leads to cirrhosis. Proliferating bile ductules are observed at the edge of the portal tracts in patients with significant fibrosis. The rate of progression of the fibrosis is highly vari‐

On electron microscopy (EM), canalicular bile plugs shows characteristic granular

LM: on H & E stains, there is inflammation with giant cell hepatitis, fibrosis and duct

LM: on H & E stains, bile ductular proliferation and mixed inflammatory infiltrates are observed in the early stages despite patency of intra- and extrahepatic bile ducts. Cholestasis with slight giant cell transformation and isolated eosinophilic ne‐ crotic hepatocytes may also be present. Periductal sclerosis affecting the interlobu‐ lar bile ducts eventually occurs. Extensive portal fibrosis evolves into biliary

able but correlates loosely with the severity of the clinical disease [45].

stones may be identified in both PFIC2 and PFIC3 [3].

phospholipid [3]. **3.** *Radiological*:

572 Hepatic Surgery

ary lipid analysis [42].

**•** *In PFIC1*

**•** *In PFIC2*

**•** *In PFIC3*

reaction [45].

**4.** *Histopathology: Liver biopsy shows*:

appearance "chunky bile".

On EM, bile appears amorphous [45].

cirrhosis in older children [42].

**5.** *Immunohistochemical staining*:

EM of liver has not been reported in proven cases.

Molecular analysis remains the definitive diagnostic technique for PFIC. Gene analysis is usually performed by DNA sequencing of the 27 coding exons (coding exons 2-28) of the *ATP8B1*, *ABCB11*, and *ABCB4* genes and their splice junctions [3]. The use of a resequensing chip dedicated to genetic cholestasis could facilitate identification of gene mutation [55].


### **6. Differential diagnosis**

Two groups of diseases are in differential diagnosis with PFIC group of disorders. For PFIC1 and PFIC2, it is to be differentiated from other cholestatic disorders with low GGT. While for PFIC3, when it presents early it, is to be differentiated from cholestatic disorders with high GGT and when it presents in an older age, childhood or adolescence, it is to be differentiated from other causes of chronic liver diseases at respective ages.

tive therapy for those who did not respond to medical treatment [66,67]. Later on, less invasive non-transplant surgical approaches were proposed and undertaken early in the course of the disease with promising initial results [68]. In this section, a brief overview

Progressive Familial Intrahepatic Cholestasis http://dx.doi.org/10.5772/51769 575

Unfortunately, most forms of medical therapy for PFIC types 1, 2, and 3 are of limited effec‐ tiveness. Nevertheless, several treatment modalities can be used in specific patients to im‐

**•** *Cholestyramine* is an anion-exchange resin that binds bile salts, preventing their re-absorp‐ tion in the enterohepatic circulation. In PFIC, relief of pruritus and normalization of bio‐ chemical parameters is only described rarely with cholestyramine. However, in patients

**•** *Rifampicin*, although it accelerates the hepatic detoxification and excretion of compounds, such as bilirubin and bile salts, it has been used with limited efficacy in patients with

**•** *Ursodeoxycholic acid (UDCA)* is a relatively hydrophilic bile salt, which is less cytotoxic than endogenous bile salts. Upon oral administration (20 mg/kg/day), it will partially re‐ place endogenous bile salts in the bile salt pool, reducing injury of the hepatocytes during cholestasis. In PFIC3 regular administration of UDCA normalizes liver function tests and improves clinical parameters in up to 50% of the patients. The therapeutic effect appears to be dependent on the type of mutation, with premature stop codons leading to a trun‐ cated protein being associated with nearly no response to therapy. UDCA should there‐ fore be the first choice in the initial therapeutic management of patients with ABCB4 deficiency, especially when a missense mutation in the corresponding gene is found [42]. In patients with PFIC1 or PFIC2, the results of UDCA treatment are conflicting, ranging

In this respect, the recommended treatment strategy is to start with UDCA therapy in all types of PFIC, especially PFIC3. If no appropriate response, especially regarding pruri‐ tus, add the other medical lines of therapy. Those who will not respond are shifted to

Surgical treatment for PFIC is an important major line of therapy. If no complete clinical or biochemical improvement is obtained with medical therapy, more invasive therapy such as

Interruption of the enterohepatic circulation through biliary diversion has yielded excellent clinical, biochemical, and histologic response in a number of children with PFIC, provided the procedure is performed before the development of significant hepatic fibrosis [46]. It reduces

PFIC [51]. Nevertheless, in patients with BRIC it can completely abort an episode.

about the different lines of management for PFIC patients will be given.

prove quality of life or prevent progression of the disease [2,69].

with BRIC it can be helpful in shortening episodes [2].

from clear improvement to no effect at all.

biliary diversion or even liver transplantation is necessary [2,70].

surgical treatment [3,45,65,66].

**7.2. Surgical treatment**

**7.1. Medical therapy**

	- **1.** Inborn errors of bile acid metabolism [6].
	- **2.** Familial hypercholanemia: familial hypercholanemia represents a PFIC-like disorder due to a bile canalicular tight junction protein defect combined with a defect of pri‐ mary bile acid conjugation. Cholestasis is due to impaired transport of unconjugated bile acids into bile and to bile leakage into plasma through abnormal canalicular tight junctions increasing paracellular permeability [56].
	- **3.** Arthrogryposis- renal dysfunction cholestasis (ARC) syndrome is a complex dis‐ ease due to mutation of *VPS33B* involved in intracellular trafficking and targeting of apical proteins. The gene defect results in a loss of apical protein expression in the liver and kidneys [57].
	- **1.** Biliary atresia [58].
	- **2.** Neonatal sclerosing cholangitis [59].
	- **3.** Congenital cytomegalovirus (CMV) infection.
	- **4.** Alpha1-antitrypsin deficiency disease [60].
	- **5.** North American Indian Childhood Cirrhosis (NAIC) [61].
	- **6.** Aagenaes syndrome (hereditary cholestasis with lymphedema): a very rare familial cholestatic disorder with cholestasis and lower limb edema [62].
	- **1.** Chronic viral hepatitis.
	- **2.** Autoimmune liver diseases: autoimmune hepatitis and autoimmune sclerosing cholangitis.
	- **3.** Metabolic liver disorders, e.g., Wilson disease and alpha1-antitrypsin deficiency.

#### **7. Treatment**

Initial treatment of PFIC includes the use of cholestyramine, ursodeoxycholic acid, rifampi‐ cin, and phenobarbital [63-65]. Until the late 1980s, liver transplantation was the only effec‐ tive therapy for those who did not respond to medical treatment [66,67]. Later on, less invasive non-transplant surgical approaches were proposed and undertaken early in the course of the disease with promising initial results [68]. In this section, a brief overview about the different lines of management for PFIC patients will be given.

#### **7.1. Medical therapy**

**6. Differential diagnosis**

574 Hepatic Surgery

**•** *Cholestasis with low GGT*:

**1.** Inborn errors of bile acid metabolism [6].

the liver and kidneys [57].

**2.** Neonatal sclerosing cholangitis [59].

**3.** Congenital cytomegalovirus (CMV) infection. **4.** Alpha1-antitrypsin deficiency disease [60].

**5.** North American Indian Childhood Cirrhosis (NAIC) [61].

cholestatic disorder with cholestasis and lower limb edema [62].

**•** *Cholestasis with high GGT*: **1.** Biliary atresia [58].

**•** *Causes of chronic liver disease*: **1.** Chronic viral hepatitis.

cholangitis.

**7. Treatment**

Two groups of diseases are in differential diagnosis with PFIC group of disorders. For PFIC1 and PFIC2, it is to be differentiated from other cholestatic disorders with low GGT. While for PFIC3, when it presents early it, is to be differentiated from cholestatic disorders with high GGT and when it presents in an older age, childhood or adolescence, it is to be

**2.** Familial hypercholanemia: familial hypercholanemia represents a PFIC-like disorder due to a bile canalicular tight junction protein defect combined with a defect of pri‐ mary bile acid conjugation. Cholestasis is due to impaired transport of unconjugated bile acids into bile and to bile leakage into plasma through abnormal canalicular tight

**3.** Arthrogryposis- renal dysfunction cholestasis (ARC) syndrome is a complex dis‐ ease due to mutation of *VPS33B* involved in intracellular trafficking and targeting of apical proteins. The gene defect results in a loss of apical protein expression in

**6.** Aagenaes syndrome (hereditary cholestasis with lymphedema): a very rare familial

**2.** Autoimmune liver diseases: autoimmune hepatitis and autoimmune sclerosing

**3.** Metabolic liver disorders, e.g., Wilson disease and alpha1-antitrypsin deficiency.

Initial treatment of PFIC includes the use of cholestyramine, ursodeoxycholic acid, rifampi‐ cin, and phenobarbital [63-65]. Until the late 1980s, liver transplantation was the only effec‐

differentiated from other causes of chronic liver diseases at respective ages.

junctions increasing paracellular permeability [56].

Unfortunately, most forms of medical therapy for PFIC types 1, 2, and 3 are of limited effec‐ tiveness. Nevertheless, several treatment modalities can be used in specific patients to im‐ prove quality of life or prevent progression of the disease [2,69].


In this respect, the recommended treatment strategy is to start with UDCA therapy in all types of PFIC, especially PFIC3. If no appropriate response, especially regarding pruri‐ tus, add the other medical lines of therapy. Those who will not respond are shifted to surgical treatment [3,45,65,66].

#### **7.2. Surgical treatment**

Surgical treatment for PFIC is an important major line of therapy. If no complete clinical or biochemical improvement is obtained with medical therapy, more invasive therapy such as biliary diversion or even liver transplantation is necessary [2,70].

Interruption of the enterohepatic circulation through biliary diversion has yielded excellent clinical, biochemical, and histologic response in a number of children with PFIC, provided the procedure is performed before the development of significant hepatic fibrosis [46]. It reduces the accumulation of toxic bile salts by decreasing their intestinal re-uptake. It is unclear if these approaches are optimal for specific genetic forms of PFIC rather than others. It is possible that these interventions may be best for severe PFIC1 and milder phenotypic variants of PFIC2. Na‐ sobiliary drainage may help to select potential responders to biliary diversion [71].

There are three major non-transplant surgical techniques to permanently interrupt the enter‐ ohepatic circulation, namely partial external biliary diversion (PEBD), ileal bypass (IB) and partial internal biliary diversion (PIBD).

**•** *Partial external biliary diversion (PEBD)*:

PEBD interrupts the enterohepatic circulation of bile salts by partially diverting bile from the gallbladder through a loop of jejunum connecting the gallbladder to the abdominal skin [72].

In 1988, Whitington and Whitington [68] introduced cholecystojejunocutaneostomy as a PEBD for the surgical treatment of PFIC, to increase the elimination of bile acids accumulat‐ ed within the body and thus control the intractable pruritus. In this procedure, one end of a loop of jejunum is anastamosed to the dome of the gallbladder, whereas the other is used to form a cutaneous ostomy (Figure 2A). Bile in the gallbladder then flows either out of the os‐ tomy or into the intestine. Typically 30–50% of bile drains out of the ostomy and is discard‐ ed. Two variants on the original PEBD have also been described; one using a laparoscopic technique [73] and the other using an appendiceal conduit [74].

**Figure 2.** A seven years old child diagnosed as PFIC2 underwent PEBD at the age of 2 years old with good outcome. He had recurrent bleeding from the osteal opening (a). Endoscopy through the osteal opening (b) showed free jejunal

Progressive Familial Intrahepatic Cholestasis http://dx.doi.org/10.5772/51769 577

Although most of PFIC patients and their parents tolerate well PEBD with its external bili‐ ary fistula and the need for stoma care, sometimes it becomes a real problem, particularly for children of school age and teenagers, who may feel uncomfortable to participate in all activities with their friends. Moreover, there is still a group of patients who cannot undergo PEBD because of a previous cholecystectomy, or who develop postoperative electrolyte in‐

To deal with these problems, an IB technique was proposed. In IB, the terminal ileum is skipped by an ileocolonic anastomosis. It was developed as an alternative treatment to PEBD, that avoids a long-term stoma complications. In 1994, Whitington et al. described a good initial outcome of IB in two patients after cholecystectomy, but a chronic diarrhea oc‐ curred one year later. In 1998, Holland et al. described this procedure in PFIC children after cholecystectomy. All patients were supplemented with vitamin B12 and folic acid. Interest‐ ingly, no diarrhea was reported postoperatively. Early results were very promising, with a relief of pruritus and normalization of bilirubin level. Nevertheless, relapse of cholestatsis occurred in half of the patients. The authors underline that IB is not as effective as PEBD and therefore it should not be considered as the primary treatment in children with PFIC [5,51].

The rational of this technique was that the vast majority of intestinal bile salts are reabsor‐ bed in the distal ileum; that is the distal 15% of the small intestine. Therefore, exclusion of this segment of intestine may lead to bile acid wasting. The small intestine is transected at a point that demarcates the distal 15% of the small intestine, and a blind loop is formed with the distal ileal segment. The proximal loop of the intestine is sewn end-to-side to the cecum, completing the internal bypass of the distal ileum. Accurate assessment of the appropriate

loop (c) till its proximal end at the gall bladder (d). The source of bleeding was the stoma itself.

**•** *Terminal ileal exclusion or ileal bypass (IB)*:

balance due to the excessive daily amount of bile [5,76].

Results of PEBD are promising with respect to pruritus, jaundice and histology, both in pa‐ tients with PFIC1 and PFIC2, with at least partial improvement in more than 75% of the pa‐ tients [66,72]. Although this seems promising, at present it is unclear whether in patients responding to PEBD liver transplantation can also be avoided at long-term follow-up [75]. Moreover, some patients do not benefit from biliary surgery at all. Obviously in these pa‐ tients liver transplantation should be considered [72].

The type of mutation seems to be associated with the outcome of PEBD, with better progno‐ sis in disease caused by milder mutations, especially for the ABCB11 mutations E297G and D482G [32,45]. However, when severe fibrosis is already present at the moment of PEBD, prognosis is worse [72]. One patient with PFIC3 who underwent PEBD was described in lit‐ erature; this patient showed no improvement [67].

No serious PEBD complications are reported, although problems with the stoma (stenosis, recurrent bleeding) (Figure 2) sometimes make a re-operation necessary. In addition ex‐ cessive stomal losses can cause dehydration and electrolyte imbalance, while cholangitis can also develop [72,75].

The permanent character of the PEBD makes it less suitable for patients with episodic cho‐ lestasis (BRIC). In these patients temporary nasobiliary drainage (NBD) to interrupt the en‐ terohepatic circulation can be endoscopically introduced. This procedure is effective in most of these patients, resolving pruritus and normalising bile salts within short time [10,71].

**Figure 2.** A seven years old child diagnosed as PFIC2 underwent PEBD at the age of 2 years old with good outcome. He had recurrent bleeding from the osteal opening (a). Endoscopy through the osteal opening (b) showed free jejunal loop (c) till its proximal end at the gall bladder (d). The source of bleeding was the stoma itself.

#### **•** *Terminal ileal exclusion or ileal bypass (IB)*:

the accumulation of toxic bile salts by decreasing their intestinal re-uptake. It is unclear if these approaches are optimal for specific genetic forms of PFIC rather than others. It is possible that these interventions may be best for severe PFIC1 and milder phenotypic variants of PFIC2. Na‐

There are three major non-transplant surgical techniques to permanently interrupt the enter‐ ohepatic circulation, namely partial external biliary diversion (PEBD), ileal bypass (IB) and

PEBD interrupts the enterohepatic circulation of bile salts by partially diverting bile from the gallbladder through a loop of jejunum connecting the gallbladder to the abdominal skin [72].

In 1988, Whitington and Whitington [68] introduced cholecystojejunocutaneostomy as a PEBD for the surgical treatment of PFIC, to increase the elimination of bile acids accumulat‐ ed within the body and thus control the intractable pruritus. In this procedure, one end of a loop of jejunum is anastamosed to the dome of the gallbladder, whereas the other is used to form a cutaneous ostomy (Figure 2A). Bile in the gallbladder then flows either out of the os‐ tomy or into the intestine. Typically 30–50% of bile drains out of the ostomy and is discard‐ ed. Two variants on the original PEBD have also been described; one using a laparoscopic

Results of PEBD are promising with respect to pruritus, jaundice and histology, both in pa‐ tients with PFIC1 and PFIC2, with at least partial improvement in more than 75% of the pa‐ tients [66,72]. Although this seems promising, at present it is unclear whether in patients responding to PEBD liver transplantation can also be avoided at long-term follow-up [75]. Moreover, some patients do not benefit from biliary surgery at all. Obviously in these pa‐

The type of mutation seems to be associated with the outcome of PEBD, with better progno‐ sis in disease caused by milder mutations, especially for the ABCB11 mutations E297G and D482G [32,45]. However, when severe fibrosis is already present at the moment of PEBD, prognosis is worse [72]. One patient with PFIC3 who underwent PEBD was described in lit‐

No serious PEBD complications are reported, although problems with the stoma (stenosis, recurrent bleeding) (Figure 2) sometimes make a re-operation necessary. In addition ex‐ cessive stomal losses can cause dehydration and electrolyte imbalance, while cholangitis

The permanent character of the PEBD makes it less suitable for patients with episodic cho‐ lestasis (BRIC). In these patients temporary nasobiliary drainage (NBD) to interrupt the en‐ terohepatic circulation can be endoscopically introduced. This procedure is effective in most of these patients, resolving pruritus and normalising bile salts within short time [10,71].

sobiliary drainage may help to select potential responders to biliary diversion [71].

partial internal biliary diversion (PIBD).

576 Hepatic Surgery

**•** *Partial external biliary diversion (PEBD)*:

technique [73] and the other using an appendiceal conduit [74].

tients liver transplantation should be considered [72].

erature; this patient showed no improvement [67].

can also develop [72,75].

Although most of PFIC patients and their parents tolerate well PEBD with its external bili‐ ary fistula and the need for stoma care, sometimes it becomes a real problem, particularly for children of school age and teenagers, who may feel uncomfortable to participate in all activities with their friends. Moreover, there is still a group of patients who cannot undergo PEBD because of a previous cholecystectomy, or who develop postoperative electrolyte in‐ balance due to the excessive daily amount of bile [5,76].

To deal with these problems, an IB technique was proposed. In IB, the terminal ileum is skipped by an ileocolonic anastomosis. It was developed as an alternative treatment to PEBD, that avoids a long-term stoma complications. In 1994, Whitington et al. described a good initial outcome of IB in two patients after cholecystectomy, but a chronic diarrhea oc‐ curred one year later. In 1998, Holland et al. described this procedure in PFIC children after cholecystectomy. All patients were supplemented with vitamin B12 and folic acid. Interest‐ ingly, no diarrhea was reported postoperatively. Early results were very promising, with a relief of pruritus and normalization of bilirubin level. Nevertheless, relapse of cholestatsis occurred in half of the patients. The authors underline that IB is not as effective as PEBD and therefore it should not be considered as the primary treatment in children with PFIC [5,51].

The rational of this technique was that the vast majority of intestinal bile salts are reabsor‐ bed in the distal ileum; that is the distal 15% of the small intestine. Therefore, exclusion of this segment of intestine may lead to bile acid wasting. The small intestine is transected at a point that demarcates the distal 15% of the small intestine, and a blind loop is formed with the distal ileal segment. The proximal loop of the intestine is sewn end-to-side to the cecum, completing the internal bypass of the distal ileum. Accurate assessment of the appropriate amount of ileum for bypass is likely to be critical; too little is unlikely to be therapeutic and too much is likely to yield bile acid–induced diarrhea. Mutational analysis may be used eventually to predict which patients are most likely to benefit from surgery. After IB, symp‐ toms may recur within one year requiring conversion to PEBD [5,77].

In contrast, in PFIC1, liver transplantation is potentially fraught with a number of potential complications related to the extrahepatic expression of the *ATP8B1* gene. The most promi‐ nent posttransplantation problems include intractable diarrhea, hepatic steatosis, poor growth, and recurrent pancreatitis. Worsening diarrhea post liver transplant might be due to an imbalance between bile salt excretion and re-absorption, since the hepatic graft ex‐ cretes a normal amount of bile salts, whereas the intestine remains functionally impaired. The resulting increased amount of bile salts in the ileum and colon induces or worsens diar‐ rhea, which might respond to cholestyramine treatment [19,85]. Therefore, in PFIC1, nontransplant surgical approaches should be considered the preferred first-line of therapy.

Progressive Familial Intrahepatic Cholestasis http://dx.doi.org/10.5772/51769 579

In summary, children with PFIC do better with non-transplant surgical interventions than they do with the natural history of disease, which is uniformly fatal. Successful outcomes have been demonstrated, with marked improvements in clinical symptoms, laboratory val‐ ues, growth and histology. It appears that the success rate is high enough that many patients may do better with a non-transplant procedure than transplant given the posttransplant morbidities associated with immunotherapy. Those with more advanced disease are most likely to have a poor outcome with non-transplant surgical procedures. This may encourage clinicians to consider a surgical intervention early in the course of disease before significant

Some authors proposed that the treatment strategy is to perform PEBD rapidly after diagno‐ sis in patients with PFIC1 & PFIC2 and to consider OLT when treatment fails. In patients with PFIC3, UDCA treatment is the first-line therapy; if not successful it is followed by liver transplantation. In patients with episodic cholestasis (BRIC) medical treatment with rifampi‐ cin with or without cholestyramine can be attempted at the start of an attack. If medication is not successful in aborting the cholestatic episode NBD can be performed [2,69]. In BRIC patients who progress to a more permanent form of cholestasis, or in patients with very fre‐

New and future therapies for PFIC patients include hepatocyte transplantation, the use of nuclear receptor ligands, enhancing the expression of the mutated transporter protein by

Hepatocyte transplantation has been successful in partially repopulating the liver, diminish‐ ing pathology in a mouse model of ABCB4 deficiency, but unfortunately not yet in patients [86]. In ABCB11 deficiency it is doubtful whether hepatocyte transplantation is a good thera‐

Certain nuclear receptors regulate bile formation. The key nuclear receptor in bile formation is the bile salt sensor FXR. Activated FXR transactivates a number of genes, resulting in im‐ proved bile salt excretion and detoxification. Targeting FXR with synthetic ligands is ex‐

A pharmacological chaperone is defined as a small molecule that specifically binds to its tar‐ get protein and induces or promotes proper folding and trafficking of the protein [88]. Some

quent or debilitating attacks, a biliary diversion can be considered [69].

employing chaperones and mutation specific therapy [2,69].

peutic option since possible premalignant cells are left in place.

plored as a possible therapeutic option for cholestasis syndromes [87].

hepatic scarring develops [76].

**7.3. New and future therapies**

**•** *Partial internal biliary diversion (PIBD)*:

PIBD interrupts the enterohepatic circulation of bile salts by partially diverting bile from the gallbladder through a loop of jejunum connecting the gallbladder to the colon [46,76].

This operation combines the advantages of partially diverting the biliary flow from the en‐ terohepatic cycle (such as the PEBD does), while at the same time avoiding an external bili‐ ary fistula. In addition, this operation lacks the potential for malabsorption that may result from partially excluding the terminal ileum from the intestinal transit. There is, however, a potential for choleretic diarrhea, which may result from large amounts of bile salts entering the colon. Because of this, it was strongly emphasized that the conduit should be made at least 15 cm long to create a certain resistance to the bile flow; it is believed that this stimu‐ lates a certain amount of bile to flow through the normal biliary tract to the duodenum. This problem occurred in a transient way in a few of the patients and it can be controlled with the use of cholestyramine for a limited span of time [46].

Through an upper midline abdominal incision, the gallbladder and the liver are evaluated. An intestinal conduit is constructed using a 15- to 20-cm segment of midjejunum, which is sutured initially to the gallbladder wall and then terminolaterally to the midportion of the ascending colon. The distal end of the jejunum is slightly tapered in a way that the jejunum could reach the colon in an isoperistaltic direction to prevent colonic contents from entering the conduit. The clinical and laboratory results described for PIBD make it a very attractive surgical option for the treatment of PFICs in children with a normal gallbladder. However, long-term follow-up is necessary to evaluate late results and eventual complications associ‐ ated with this technique [46].

If all previously described therapies fails in controlling pruritus, when there is an endstage PFIC liver disease, or when the disease is progressive despite treatment; orthotopic liver transplantation (OLT) remains the only alternative [78-80]. Before the development of liver transplantation, therapy for these patients was generally ineffective. With the ad‐ vent of liver transplantation, many PFIC patients were treated with this life-saving proce‐ dure [70,78]. At one time, PFIC was among the 5 most common indications for liver transplantation in children [81,82].

Although OLT is associated with serious surgical risks and lifetime immunosuppressive therapy is necessary, it usually gives complete correction of phenotype in patients with PFIC2 and PFIC3 deficiency in which the disease is hepatocyte specific. However, phenotyp‐ ic recurrence of severe PFIC2 deficiency post-transplantation can occur as a result of the for‐ mation of autoantibodies against BSEP [83,84]. Intensifying immunosuppressive therapy may resolve this problem.

In contrast, in PFIC1, liver transplantation is potentially fraught with a number of potential complications related to the extrahepatic expression of the *ATP8B1* gene. The most promi‐ nent posttransplantation problems include intractable diarrhea, hepatic steatosis, poor growth, and recurrent pancreatitis. Worsening diarrhea post liver transplant might be due to an imbalance between bile salt excretion and re-absorption, since the hepatic graft ex‐ cretes a normal amount of bile salts, whereas the intestine remains functionally impaired. The resulting increased amount of bile salts in the ileum and colon induces or worsens diar‐ rhea, which might respond to cholestyramine treatment [19,85]. Therefore, in PFIC1, nontransplant surgical approaches should be considered the preferred first-line of therapy.

In summary, children with PFIC do better with non-transplant surgical interventions than they do with the natural history of disease, which is uniformly fatal. Successful outcomes have been demonstrated, with marked improvements in clinical symptoms, laboratory val‐ ues, growth and histology. It appears that the success rate is high enough that many patients may do better with a non-transplant procedure than transplant given the posttransplant morbidities associated with immunotherapy. Those with more advanced disease are most likely to have a poor outcome with non-transplant surgical procedures. This may encourage clinicians to consider a surgical intervention early in the course of disease before significant hepatic scarring develops [76].

Some authors proposed that the treatment strategy is to perform PEBD rapidly after diagno‐ sis in patients with PFIC1 & PFIC2 and to consider OLT when treatment fails. In patients with PFIC3, UDCA treatment is the first-line therapy; if not successful it is followed by liver transplantation. In patients with episodic cholestasis (BRIC) medical treatment with rifampi‐ cin with or without cholestyramine can be attempted at the start of an attack. If medication is not successful in aborting the cholestatic episode NBD can be performed [2,69]. In BRIC patients who progress to a more permanent form of cholestasis, or in patients with very fre‐ quent or debilitating attacks, a biliary diversion can be considered [69].

#### **7.3. New and future therapies**

amount of ileum for bypass is likely to be critical; too little is unlikely to be therapeutic and too much is likely to yield bile acid–induced diarrhea. Mutational analysis may be used eventually to predict which patients are most likely to benefit from surgery. After IB, symp‐

PIBD interrupts the enterohepatic circulation of bile salts by partially diverting bile from the

This operation combines the advantages of partially diverting the biliary flow from the en‐ terohepatic cycle (such as the PEBD does), while at the same time avoiding an external bili‐ ary fistula. In addition, this operation lacks the potential for malabsorption that may result from partially excluding the terminal ileum from the intestinal transit. There is, however, a potential for choleretic diarrhea, which may result from large amounts of bile salts entering the colon. Because of this, it was strongly emphasized that the conduit should be made at least 15 cm long to create a certain resistance to the bile flow; it is believed that this stimu‐ lates a certain amount of bile to flow through the normal biliary tract to the duodenum. This problem occurred in a transient way in a few of the patients and it can be controlled with

Through an upper midline abdominal incision, the gallbladder and the liver are evaluated. An intestinal conduit is constructed using a 15- to 20-cm segment of midjejunum, which is sutured initially to the gallbladder wall and then terminolaterally to the midportion of the ascending colon. The distal end of the jejunum is slightly tapered in a way that the jejunum could reach the colon in an isoperistaltic direction to prevent colonic contents from entering the conduit. The clinical and laboratory results described for PIBD make it a very attractive surgical option for the treatment of PFICs in children with a normal gallbladder. However, long-term follow-up is necessary to evaluate late results and eventual complications associ‐

If all previously described therapies fails in controlling pruritus, when there is an endstage PFIC liver disease, or when the disease is progressive despite treatment; orthotopic liver transplantation (OLT) remains the only alternative [78-80]. Before the development of liver transplantation, therapy for these patients was generally ineffective. With the ad‐ vent of liver transplantation, many PFIC patients were treated with this life-saving proce‐ dure [70,78]. At one time, PFIC was among the 5 most common indications for liver

Although OLT is associated with serious surgical risks and lifetime immunosuppressive therapy is necessary, it usually gives complete correction of phenotype in patients with PFIC2 and PFIC3 deficiency in which the disease is hepatocyte specific. However, phenotyp‐ ic recurrence of severe PFIC2 deficiency post-transplantation can occur as a result of the for‐ mation of autoantibodies against BSEP [83,84]. Intensifying immunosuppressive therapy

gallbladder through a loop of jejunum connecting the gallbladder to the colon [46,76].

toms may recur within one year requiring conversion to PEBD [5,77].

the use of cholestyramine for a limited span of time [46].

ated with this technique [46].

transplantation in children [81,82].

may resolve this problem.

**•** *Partial internal biliary diversion (PIBD)*:

578 Hepatic Surgery

New and future therapies for PFIC patients include hepatocyte transplantation, the use of nuclear receptor ligands, enhancing the expression of the mutated transporter protein by employing chaperones and mutation specific therapy [2,69].

Hepatocyte transplantation has been successful in partially repopulating the liver, diminish‐ ing pathology in a mouse model of ABCB4 deficiency, but unfortunately not yet in patients [86]. In ABCB11 deficiency it is doubtful whether hepatocyte transplantation is a good thera‐ peutic option since possible premalignant cells are left in place.

Certain nuclear receptors regulate bile formation. The key nuclear receptor in bile formation is the bile salt sensor FXR. Activated FXR transactivates a number of genes, resulting in im‐ proved bile salt excretion and detoxification. Targeting FXR with synthetic ligands is ex‐ plored as a possible therapeutic option for cholestasis syndromes [87].

A pharmacological chaperone is defined as a small molecule that specifically binds to its tar‐ get protein and induces or promotes proper folding and trafficking of the protein [88]. Some researchers have investigated the usefulness of pharmacological chaperones for treatment of diseases caused by folding-defective membrane proteins [24,89,90]. Pharmacological chaper‐ ones such as 4-phenylbutyrate acid (4-PBA) have been shown to stabilize proteins misfolded due to missense mutations, thereby preventing degradation in the endoplasmic reticulum. In vitro, 4-PBA enhances cell surface protein expression for some of the missense mutations found in ATP8B1 deficiency and ABCB11 deficiency [25,91]. Misawa et al [24], showed that bile acids do act as pharmacological chaperones of E297G BSEP. They also described the dis‐ covery and structural development of non-steroidal compounds with potent pharmacologi‐ cal chaperone activity for E297G BSEP.

[8] Luketic, V. A., & Shiffman, M. L. (2004). Benign recurrent intrahepatic cholestasis.

Progressive Familial Intrahepatic Cholestasis http://dx.doi.org/10.5772/51769 581

[9] Folvik, G., Hilde, O., & Helge, G. O. (2012). Benign recurrent intrahepatic cholestasis: review and long-term follow-up of five cases. *Scand J Gastroenterol*, 47(4), 482-488.

[10] Toros, A. B., Ozerdenen, F., Bektas, H., & Sari, N. D. (2012). A case report: nasobiliary drainage inducing remission in benign recurrent intrahepatic cholestasis. *Turk J Gas‐*

[11] Van Ooteghem, N. A., Klomp, L. W., van Berge-Henegouwen, G. P., & Houwen, R. H. (2002). Benign recurrent intrahepatic cholestasis progressing to progressive fami‐ lial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum. *J Hepatol*,

[12] Van Mil, S. W., Klomp, L. W., Bull, L. N., & Houwen, R. H. (2001). FIC1 disease: a spectrum of intrahepatic cholestatic disorders. *Semin Liver Dis*, 21(4), 535-544.

[13] Verhulst, P. M., van der Velden, L. M., Oorschot, V., van Faassen, E. E., Klumper‐ man, J., Houwen, R. H., Pomorski, T. G., Holthuis, J. C., & Klomp, L. W. (2010). A flippase-independent function of ATP8B1, the protein affected in familial intrahepat‐ ic cholestasis type 1, is required for apical protein expression and microvillus forma‐

[14] Cai, S. Y., Gautam, S., Nguyen, T., Soroka, C. J., Rahner, C., & Boyer, J. L. (2009). ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepa‐ tocytes, but FXR expression and activity are maintained. *Gastroenterology*, 1060-1069.

[15] Paulusma, C. C., Groen, A., Kunne, C., Ho-Mok, K. S., Spijkerboer, A. L., Rudi de, Waart. D., Hoek, F. J., Vreeling, H., Hoeben, K. A., van Marle, J., Pawlikowska, L., Bull, L. N., Hofmann, A. F., Knisely, A. S., & Oude, Elferink. R. P. (2006). Atp8b1 de‐ ficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile

[16] Paulusma, C. C., de Waart, D. R., Kunne, C., Mok, K. S., & Elferink, R. P. (2009). Ac‐ tivity of the bile salt export pump (ABCB11) is critically dependent on canalicular

[17] Alvarez, L., Jara, P., Sanchez-Sabate, E., Hierro, L., Larrauri, J., Diaz, M. C., Camare‐ na, C., De la Vega, A., Frauca, E., Lopez-Collazo, E., & Lapunzina, P. (2004). Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mu‐

[18] Chen, F., Ananthanarayanan, M., Emre, S., Neimark, E., Bull, L. N., Knisely, A. S., Strautnieks, S. S., Thompson, R. J., Magid, M. S., Gordon, R., Balasubramanian, N., Suchy, F. J., & Shneider, B. L. (2004). Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity. *Gastroenterology*,

tion in polarized epithelial cells. *Hepatology*, 51(6), 2049-2060.

salts and impairs bile salt transport. *Hepatology*, 44(1), 195-204.

membrane cholesterol content. *J Biol Chem*, 284(15), 9947-9954.

tation in ATP8B1. *Hum Mol Genet*, 13(20), 2451-2460.

*Clin Liver Dis*, 8(1), 133-149, vii.

*troenterol*, 23(1), 75-78.

36(3), 439-443.

126(3), 756-764.

#### **Author details**

Ahmad Mohamed Sira\* and Mostafa Mohamed Sira

\*Address all correspondence to: asira@liver-eg.org

Department of Pediatric Hepatology, National Liver Institute, Menofiya University, Egypt

#### **References**


[8] Luketic, V. A., & Shiffman, M. L. (2004). Benign recurrent intrahepatic cholestasis. *Clin Liver Dis*, 8(1), 133-149, vii.

researchers have investigated the usefulness of pharmacological chaperones for treatment of diseases caused by folding-defective membrane proteins [24,89,90]. Pharmacological chaper‐ ones such as 4-phenylbutyrate acid (4-PBA) have been shown to stabilize proteins misfolded due to missense mutations, thereby preventing degradation in the endoplasmic reticulum. In vitro, 4-PBA enhances cell surface protein expression for some of the missense mutations found in ATP8B1 deficiency and ABCB11 deficiency [25,91]. Misawa et al [24], showed that bile acids do act as pharmacological chaperones of E297G BSEP. They also described the dis‐ covery and structural development of non-steroidal compounds with potent pharmacologi‐

and Mostafa Mohamed Sira

practice: neonatal cholestasis. *Eur J Pediatr*, 170(3), 279-284.

pregnancy. *Best Pract Res Clin Gastroenterol*, 24(5), 541-553.

lial intrahepatic cholestasis. *Orphanet J Rare Dis*, 4(1).

tive" jaundice. *Lancet*, 2(7105), 686-690.

Department of Pediatric Hepatology, National Liver Institute, Menofiya University, Egypt

[1] De Bruyne, R., Van Biervliet, S., Vande, Velde S., & Van Winckel, M. (2011). Clinical

[2] Van der Woerd, W. L., van Mil, S. W., Stapelbroek, J. M., Klomp, L. W., van de Graaf, S. F., & Houwen, R. H. (2010). Familial cholestasis: progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of

[3] Davit-Spraul, A., Gonzales, E., Baussan, C., & Jacquemin, E. (2009). Progressive fami‐

[4] Clayton, R. J., Iber, F. L., Ruebner, B. H., & McKusick, V. A. (1969). Byler disease. Fa‐ tal familial intrahepatic cholestasis in an Amish kindred. *Am J Dis Child*, 117(1),

[5] Hollands, C. M., Rivera-Pedrogo, F. J., Gonzalez-Vallina, R., Loret-de-Mola, O., Nah‐ mad, M., & Burnweit, C. A. (1998). Ileal exclusion for Byler's disease: an alternative surgical approach with promising early results for pruritus. *J Pediatr Surg;*, 33(2),

[6] Jankowska, I., & Socha, P. (2012). Progressive familial intrahepatic cholestasis and in‐ born errors of bile acid synthesis. *Clin Res Hepatol Gastroenterol*, 36(3), 271-274.

[7] Summerskill, W. H., & Walshe, J. M. (1959). Benign recurrent intrahepatic "obstruc‐

cal chaperone activity for E297G BSEP.

\*Address all correspondence to: asira@liver-eg.org

**Author details**

580 Hepatic Surgery

**References**

112-124.

220-224.

Ahmad Mohamed Sira\*


[19] Lykavieris, P., van Mil, S., Cresteil, D., Fabre, M., Hadchouel, M., Klomp, L., Bernard, O., & Jacquemin, E. (2003). Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation. *J Hepatol*, 39(3), 447-452.

[29] Gerloff, T., Stieger, B., Hagenbuch, B., Madon, J., Landmann, L., Roth, J., Hofmann, A. F., & Meier, P. J. (1998). The sister of P-glycoprotein represents the canalicular bile

Progressive Familial Intrahepatic Cholestasis http://dx.doi.org/10.5772/51769 583

[30] Strautnieks, S. S., Bull, L. N., Knisely, A. S., Kocoshis, S. A., Dahl, N., Arnell, H., So‐ kal, E., Dahan, K., Childs, S., Ling, V., Tanner, M. S., Kagalwalla, A. F., Nemeth, A., Pawlowska, J., Baker, A., Mieli-Vergani, G., Freimer, N. B., Gardiner, R. M., & Thompson, R. J. (1998). A gene encoding a liver-specific ABC transporter is mutated

[31] Strautnieks, S. S., Byrne, J. A., Pawlikowska, L., Cebecauerova, D., Rayner, A., Dut‐ ton, L., Meier, Y., Antoniou, A., Stieger, B., Arnell, H., Ozcay, F., Al-Hussaini, H. F., Bassas, A. F., Verkade, H. J., Fischler, B., Nemeth, A., Kotalova, R., Shneider, B. L., Cielecka-Kuszyk, J., Mc Clean, P., Whitington, P. F., Sokal, E., Jirsa, M., Wali, S. H., Jankowska, I., Pawlowska, J., Mieli-Vergani, G., Knisely, A. S., Bull, L. N., & Thomp‐ son, R. J. (2008). Severe bile salt export pump deficiency: 82 different ABCB11 muta‐

[32] Pawlikowska, L., Strautnieks, S., Jankowska, I., Czubkowski, P., Emerick, K., Anto‐ niou, A., Wanty, C., Fischler, B., Jacquemin, E., Wali, S., Blanchard, S., Nielsen, I. M., Bourke, B., Mc Quaid, S., Lacaille, F., Byrne, J. A., van Eerde, A. M., Kolho, K. L., Klomp, L., Houwen, R., Bacchetti, P., Lobritto, S., Hupertz, V., Mc Clean, P., Mieli-Vergani, G., Shneider, B., Nemeth, A., Sokal, E., Freimer, N. B., Knisely, A. S., Rosen‐ thal, P., Whitington, P. F., Pawlowska, J., Thompson, R. J., & Bull, L. N. (2010). Differences in presentation and progression between severe FIC1 and BSEP deficien‐

[33] Kagawa, T., Watanabe, N., Mochizuki, K., Numari, A., Ikeno, Y., Itoh, J., Tanaka, H., Arias, I. M., & Mine, T. (2008). Phenotypic differences in PFIC2 and BRIC2 correlate with protein stability of mutant Bsep and impaired taurocholate secretion in MDCK

[34] Pauli-Magnus, C., Lang, T., Meier, Y., Zodan-Marin, T., Jung, D., Breymann, C., Zim‐ mermann, R., Kenngott, S., Beuers, U., Reichel, C., Kerb, R., Penger, A., Meier, P. J., & Kullak-Ublick, G. A. (2004). Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahe‐

[35] Pauli-Magnus, C., & Meier, P. J. (2006). Hepatobiliary transporters and drug-induced

[36] Hermeziu, B., Sanlaville, D., Girard, M., Leonard, C., Lyonnet, S., & Jacquemin, E. (2006). Heterozygous bile salt export pump deficiency: a possible genetic predisposi‐ tion to transient neonatal cholestasis. *J Pediatr Gastroenterol Nutr*, 42(1), 114-116.

[37] De Vree, J. M., Jacquemin, E., Sturm, E., Cresteil, D., Bosma, P. J., Aten, J., Deleuze, J. F., Desrochers, M., Burdelski, M., Bernard, O., Oude Elferink, R. P., & Hadchouel, M.

salt export pump of mammalian liver. *J Biol Chem*, 273(16), 10046-10050.

in progressive familial intrahepatic cholestasis. *Nat Genet*, 20(3), 233-238.

tions in 109 families. *Gastroenterology*, 134(4), 1203-1214.

II cells. *Am J Physiol Gastrointest Liver Physiol*, 294(1), G 58-67.

patic cholestasis of pregnancy. *Pharmacogenetics*, 14(2), 91-102.

cies. *J Hepatol*, 53(1), 170-178.

cholestasis. *Hepatology*, 44(4), 778-787.


[29] Gerloff, T., Stieger, B., Hagenbuch, B., Madon, J., Landmann, L., Roth, J., Hofmann, A. F., & Meier, P. J. (1998). The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. *J Biol Chem*, 273(16), 10046-10050.

[19] Lykavieris, P., van Mil, S., Cresteil, D., Fabre, M., Hadchouel, M., Klomp, L., Bernard, O., & Jacquemin, E. (2003). Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: no catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation. *J Hepatol*, 39(3), 447-452. [20] Stapelbroek, J. M., Peters, T. A., van Beurden, D. H., Curfs, J. H., Joosten, A., Beynon, A. J., van Leeuwen, B. M., van der Velden, L. M., Bull, L., Oude, Elferink R. P., van Zanten, B. A., Klomp, L. W., & Houwen, R. H. (2009). ATP8B1 is essential for main‐

[21] Klomp, L. W., Vargas, J. C., van Mil, S. W., Pawlikowska, L., Strautnieks, S. S., van Eijk, M. J., Juijn, J. A., Pabon-Pena, C., Smith, L. B., De Young, J. A., Byrne, J. A., Gombert, J., van der Brugge, G., Berger, R., Jankowska, I., Pawlowska, J., Villa, E., Knisely, A. S., Thompson, R. J., Freimer, N. B., Houwen, R. H., & Bull, L. N. (2004). Characterization of mutations in ATP8B1 associated with hereditary cholestasis. *Hep‐*

[22] Liu, L. Y., Wang, X. H., Wang, Z. L., Zhu, Q. R., & Wang, J. S. (2010). Characterization of ATP8B1 gene mutations and a hot-linked mutation found in Chinese children with progressive intrahepatic cholestasis and low GGT. *J Pediatr Gastroenterol Nutr*, 50(2),

[23] Folmer, D. E., van der Mark, V. A., Ho-Mok, K. S., Oude Elferink, R. P., & Paulusma, C. C. (2009). Differential effects of progressive familial intrahepatic cholestasis type 1 and benign recurrent intrahepatic cholestasis type 1 mutations on canalicular locali‐

[24] Misawa, T., Hayashi, H., Sugiyama, Y., & Hashimoto, Y. (2012). Discovery and struc‐ tural development of small molecules that enhance transport activity of bile salt ex‐ port pump mutant associated with progressive familial intrahepatic cholestasis type

[25] Van der Velden, L. M., Stapelbroek, J. M., Krieger, E., van den Berghe, P. V., Berger, R., Verhulst, P. M., Holthuis, J. C., Houwen, R. H., Klomp, L. W., & van de Graaf, S. F. (2010). Folding defects in P-type ATP 8B1 associated with hereditary cholestasis

[26] Klomp, L. W., Bull, L. N., Knisely, A. S., van Der Doelen, M. A., Juijn, J. A., Berger, R., Forget, S., Nielsen, I. M., Eiberg, H., & Houwen, R. H. (2000). A missense mutation in FIC1 is associated with greenland familial cholestasis. *Hepatology*, 32(6), 1337-1341. [27] Mullenbach, R., Bennett, A., Tetlow, N., Patel, N., Hamilton, G., Cheng, F., Cham‐ bers, J., Howard, R., Taylor-Robinson, S. D., & Williamson, C. (2005). ATP8B1 muta‐ tions in British cases with intrahepatic cholestasis of pregnancy. *Gut*, 54(6), 829-834. [28] Demeilliers, C., Jacquemin, E., Barbu, V., Mergey, M., Paye, F., Fouassier, L., Chignard, N., Housset, C., & Lomri, N. E. (2006). Altered hepatobiliary gene expres‐ sions in PFIC1: ATP8B1 gene defect is associated with CFTR downregulation. *Hepa‐*

are ameliorated by 4-phenylbutyrate. *Hepatology*, 51(1), 286-296.

zation of ATP8B1. *Hepatology*, 50(5), 1597-1605.

taining normal hearing. *Proc Natl Acad Sci*, U S A, 106(24), 9709-9714.

*atology*, 40(1), 27-38.

2. *Bioorg Med Chem.*

*tology*, 43(5), 1125-1134.

179-183.

582 Hepatic Surgery


(1998). Mutations in the MDR3 gene cause progressive familial intrahepatic cholesta‐ sis. *Proc Natl Acad Sci*, U S A, 95(1), 282-287.

[48] Chatila, R., Bergasa, N. V., Lagarde, S., & West, A. B. (1996). Intractable cough and abnormal pulmonary function in benign recurrent intrahepatic cholestasis. *Am J Gas‐*

Progressive Familial Intrahepatic Cholestasis http://dx.doi.org/10.5772/51769 585

[49] Mizuochi, T., Kimura, A., Tanaka, A., Muto, A., Nittono, H., Seki, Y., Takahashi, T., Kurosawa, T., Kage, M., Takikawa, H., & Matsuishi, T. (2012). Characterization of urinary bile acids in a pediatric BRIC-1 patient: Effect of rifampicin treatment. *Clin*

[50] Jacquemin, E. (2001). Role of multidrug resistance 3 deficiency in pediatric and adult

[51] Whitington, P. F., Freese, D. K., Alonso, E. M., Schwarzenberg, S. J., & Sharp, H. L. (1994). Clinical and biochemical findings in progressive familial intrahepatic choles‐

[52] Cabrera-Abreu, J. C., & Green, A. (2002). Gamma-glutamyltransferase: value of its

[53] Elferink, R. P., Ottenhoff, R., van Marle, J., Frijters, C. M., Smith, A. J., & Groen, A. K. (1998). Class III P-glycoproteins mediate the formation of lipoprotein X in the mouse.

[54] Jansen, P. L., Strautnieks, S. S., Jacquemin, E., Hadchouel, M., Sokal, E. M., Hooiveld, G. J., Koning, J. H., De Jager-Krikken, A., Kuipers, F., Stellaard, F., Bijleveld, C. M., Gouw, A., Van Goor, H., Thompson, R. J., & Muller, M. (1999). Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic

[55] Liu, C., Aronow, B. J., Jegga, A. G., Wang, N., Miethke, A., Mourya, R., & Bezerra, J. A. (2007). Novel resequencing chip customized to diagnose mutations in patients with inherited syndromes of intrahepatic cholestasis. *Gastroenterology*, 132(1),

[56] Carlton, V. E., Harris, B. Z., Puffenberger, E. G., Batta, A. K., Knisely, A. S., Robinson, D. L., Strauss, K. A., Shneider, B. L., Lim, W. A., Salen, G., Morton, D. H., & Bull, L. N. (2003). Complex inheritance of familial hypercholanemia with associated muta‐

[57] Gissen, P., Johnson, C. A., Morgan, N. V., Stapelbroek, J. M., Forshew, T., Cooper, W. N., Mc Kiernan, P. J., Klomp, L. W., Morris, A. A., Wraith, J. E., Mc Clean, P., Lynch, S. A., Thompson, R. J., Lo, B., Quarrell, O. W., Di Rocco, M., Trembath, R. C., Mandel, H., Wali, S., Karet, F. E., Knisely, A. S., Houwen, R. H., Kelly, D. A., & Maher, E. R. (2004). Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome. *Nat*

liver disease: one gene for three diseases. *Semin Liver Dis*, 21(4), 551-562.

*troenterol*, 91(10), 2215-2219.

*Chim Acta*, 413(15-16), 1301-1304.

*J Clin Invest*, 102(9), 1749-1757.

119-126.

*Genet*, 36(4), 400-404.

tasis. *J Pediatr Gastroenterol Nutr*, 18(2), 134-141.

cholestasis. *Gastroenterology*, 117(6), 1370-1379.

tions in TJP2 and BAAT. *Nat Genet*, 34(1), 91-96.

measurement in paediatrics. *Ann Clin Biochem*, 39(pt1), 22-5.


[48] Chatila, R., Bergasa, N. V., Lagarde, S., & West, A. B. (1996). Intractable cough and abnormal pulmonary function in benign recurrent intrahepatic cholestasis. *Am J Gas‐ troenterol*, 91(10), 2215-2219.

(1998). Mutations in the MDR3 gene cause progressive familial intrahepatic cholesta‐

[38] Oude Elferink, R. P., & Paulusma, C. C. (2007). Function and pathophysiological im‐ portance of ABCB4 (MDR3 P-glycoprotein). *Pflugers Arch*, 453(5), 601-610.

[39] Noe, J., Kullak-Ublick, G. A., Jochum, W., Stieger, B., Kerb, R., Haberl, M., Mull‐ haupt, B., Meier, P. J., & Pauli-Magnus, C. (2005). Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic

[40] Keitel, V., Burdelski, M., Warskulat, U., Kuhlkamp, T., Keppler, D., Haussinger, D., & Kubitz, R. (2005). Expression and localization of hepatobiliary transport proteins in

[41] Degiorgio, D., Colombo, C., Seia, M., Porcaro, L., Costantino, L., Zazzeron, L., Bordo, D., & Coviello, D. A. (2007). Molecular characterization and structural implications of 25 new ABCB4 mutations in progressive familial intrahepatic cholestasis type 3

[42] Jacquemin, E., De Vree, J. M., Cresteil, D., Sokal, E. M., Sturm, E., Dumont, M., Scheffer, G. L., Paul, M., Burdelski, M., Bosma, P. J., Bernard, O., Hadchouel, M., & Elferink, R. P. (2001). The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. *Gastroenterology*, 120(6), 1448-1458.

[43] Lucena, J. F., Herrero, J. I., Quiroga, J., Sangro, B., Garcia-Foncillas, J., Zabalegui, N., Sola, J., Herraiz, M., Medina, J. F., & Prieto, J. (2003). A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cir‐

[44] Gonzales, E., Davit-Spraul, A., Baussan, C., Buffet, C., Maurice, M., & Jacquemin, E. (2009). Liver diseases related to MDR3 (ABCB4) gene deficiency. *Front Biosci*, 14,

[45] Davit-Spraul, A., Fabre, M., Branchereau, S., Baussan, C., Gonzales, E., Stieger, B., Bernard, O., & Jacquemin, E. (2010). ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholesta‐ sis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history.

[46] Bustorff-Silva, J., Sbraggia Neto, L., Olimpio, H., de Alcantara, R. V., Matsushima, E., De Tommaso, A. M., Brandao, M. A., & Hessel, G. (2007). Partial internal biliary di‐ version through a cholecystojejunocolonic anastomosis--a novel surgical approach for patients with progressive familial intrahepatic cholestasis: a preliminary report. *J*

[47] Jansen, P. L., & Sturm, E. (2003). Genetic cholestasis, causes and consequences for

progressive familial intrahepatic cholestasis. *Hepatology*, 41(5), 1160-1172.

sis. *Proc Natl Acad Sci*, U S A, 95(1), 282-287.

584 Hepatic Surgery

cholestasis. *J Hepatol*, 43(3), 536-543.

(PFIC3). *Eur J Hum Genet*, 15(12), 1230-1238.

rhosis. *Gastroenterology*, 124(4), 1037-1042.

4242-4256.

*Hepatology*, 51(5), 1645-1655.

*Pediatr Surg*, 42(8), 1337-1340.

hepatobiliary transport. *Liver Int*, 23(5), 315-322.


[58] Moreira, R. K., Cabral, R., Cowles, R. A., & Lobritto, S. J. (2012). Biliary atresia: a mul‐ tidisciplinary approach to diagnosis and management. *Arch Pathol Lab Med*, 136(7), 746-760.

[70] Kaur, S., Sharma, D., Wadhwa, N., Gupta, S., Chowdhary, S. K., & Sibal, A. (2012). Therapeutic interventions in progressive familial intrahepatic cholestasis: experience

Progressive Familial Intrahepatic Cholestasis http://dx.doi.org/10.5772/51769 587

[71] Stapelbroek, J. M., van Erpecum, K. J., Klomp, L. W., Venneman, N. G., Schwartz, T. P., van Berge Henegouwen, G. P., Devlin, J., van Nieuwkerk, C. M., Knisely, A. S-, & Houwen, R. H. (2006). Nasobiliary drainage induces long-lasting remission in benign

[72] Schukfeh, N., Metzelder, M. L., Petersen, C., Reismann, M., Pfister, E. D., Ure, B. M., & Kuebler, J. F. (2012). Normalization of serum bile acids after partial external biliary diversion indicates an excellent long-term outcome in children with progressive fam‐

[73] Metzelder, M. L., Bottlander, M., Melter, M., Petersen, C., & Ure, B. M. (2005). Lapa‐ roscopic partial external biliary diversion procedure in progressive familial intrahe‐

[74] Rebhandl, W., Felberbauer, F. X., Turnbull, J., Paya, K., Barcik, U., Huber, W. D., Whitington, P. F., & Horcher, E. (1999). Biliary diversion by use of the appendix (cholecystoappendicostomy) in progressive familial intrahepatic cholestasis. *J Pediatr*

[75] Arnell, H., Bergdahl, S., Papadogiannakis, N., Nemeth, A., & Fischler, B. (2008). Pre‐ operative observations and short-term outcome after partial external biliary diver‐ sion in 13 patients with progressive familial intrahepatic cholestasis. *J Pediatr Surg*,

[76] Davis, A. R., Rosenthal, P., & Newman, T. B. (2009). Nontransplant surgical interven‐ tions in progressive familial intrahepatic cholestasis. *J Pediatr Surg*, 44(4), 821-827.

[77] Kalicinski, P. J., Ismail, H., Jankowska, I., Kaminski, A., Pawlowska, J., Drewniak, T., Markiewicz, M., & Szymczak, M. (2003). Surgical treatment of progressive familial intrahepatic cholestasis: comparison of partial external biliary diversion and ileal by‐

[78] Bassas, A., Chehab, M., Hebby, H., Al, Shahed. M., Al Husseini, H., Al Zahrani, A., & Wali, S. (2003). Living related liver transplantation in 13 cases of progressive familial

[79] Englert, C., Grabhorn, E., Richter, A., Rogiers, X., Burdelski, M., & Ganschow, R. (2007). Liver transplantation in children with progressive familial intrahepatic cho‐

[80] Torri, E., Lucianetti, A., Pinelli, D., Corno, V., Guizzetti, M., Maldini, G., Zambelli, M., Bertani, A., Melzi, M. L., Alberti, D., Doffria, E., Giovanelli, M., Torre, G., Spada, M., Gridelli, B., & Colledan, M. (2005). Orthotopic liver transplantation for Byler's

from a tertiary care centre in north India. *Indian J Pediatr*, 79(2), 270-273.

recurrent intrahepatic cholestasis. *Hepatology*, 43(1), 51-53.

ilial intrahepatic cholestasis. *J Pediatr Surg*, 47(3), 501-505.

*Gastroenterol Nutr*, 28(2), 217-219.

pass. *Eur J Pediatr Surg*, 13(5), 307-311.

lestasis. *Transplantation*, 84(10), 1361-1363.

disease. *Transplant Proc*, 37(2), 1149-1150.

intrahepatic cholestasis. *Transplant Proc*, 35(8), 3003-3005.

43(7), 1312-1320.

patic cholestasis: a new approach. *Surg Endosc*, 19(12), 1641-1643.


[70] Kaur, S., Sharma, D., Wadhwa, N., Gupta, S., Chowdhary, S. K., & Sibal, A. (2012). Therapeutic interventions in progressive familial intrahepatic cholestasis: experience from a tertiary care centre in north India. *Indian J Pediatr*, 79(2), 270-273.

[58] Moreira, R. K., Cabral, R., Cowles, R. A., & Lobritto, S. J. (2012). Biliary atresia: a mul‐ tidisciplinary approach to diagnosis and management. *Arch Pathol Lab Med*, 136(7),

[59] Hadj-Rabia, S., Baala, L., Vabres, P., Hamel-Teillac, D., Jacquemin, E., Fabre, M., Lyonnet, S., De Prost, Y., Munnich, A., Hadchouel, M., & Smahi, A. (2004). Claudin-1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: a tight

[60] Stoller, J. K., & Aboussouan, L. S. (2012). A review of alpha1-antitrypsin deficiency.

[61] Chagnon, P., Michaud, J., Mitchell, G., Mercier, J., Marion, J. F., Drouin, E., Rasquin-Weber, A., Hudson, T. J., & Richter, A. (2002). A missense mutation (R565W) in cir‐ hin (FLJ14728) in North American Indian childhood cirrhosis. *Am J Hum Genet*, 71(6),

[62] Bull, L. N., Roche, E., Song, E. J., Pedersen, J., Knisely, A. S., van Der Hagen, C. B., Eiklid, K., Aagenaes, O., & Freimer, N. B. (2000). Mapping of the locus for cholesta‐ sis-lymphedema syndrome (Aagenaes syndrome) to a 6.6-cM interval on chromo‐

[63] Lazaridis, K. N., Gores, G. J., & Lindor, K. D. (2001). Ursodeoxycholic acid 'mecha‐ nisms of action and clinical use in hepatobiliary disorders'. *J Hepatol*, 35(1), 134-146.

[64] Cohran, V. C., & Heubi, J. E. (2003). Treatment of Pediatric Cholestatic Liver Disease.

[65] Jacquemin, E., Hermans, D., Myara, A., Habes, D., Debray, D., Hadchouel, M., Sokal, E. M., & Bernard, O. (1997). Ursodeoxycholic acid therapy in pediatric patients with

[66] Ismail, H., Kalicinski, P., Markiewicz, M., Jankowska, I., Pawlowska, J., Kluge, P., Eli‐ adou, E., Kaminski, A., Szymczak, M., Drewniak, T., & Revillon, Y. (1999). Treatment of progressive familial intrahepatic cholestasis: liver transplantation or partial exter‐

[67] Wanty, C., Joomye, R., Van Hoorebeek, N., Paul, K., Otte, J. B., Reding, R., & Sokal, E. M. (2004). Fifteen years single center experience in the management of progressive familial intrahepatic cholestasis of infancy. *Acta Gastroenterol Belg*, 67(4), 313-319.

[68] Whitington, P. F., & Whitington, G. L. (1988). Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. *Gastroenter‐*

[69] Stapelbroek, J. M., van Erpecum, K. J., Klomp, L. W., & Houwen, R. H. (2010). Liver disease associated with canalicular transport defects: current and future therapies. *J*

progressive familial intrahepatic cholestasis. *Hepatology*, 25(3), 519-523.

junction disease. *Gastroenterology*, 127(5), 1386-1390.

*Am J Respir Crit Care Med*, 185(3), 246-259.

some 15q. *Am J Hum Genet*, 67(4), 994-999.

*Curr Treat Options Gastroenterol*, 6(5), 403-415.

nal biliary diversion. *Pediatr Transplant*, 3(3), 219-224.

746-760.

586 Hepatic Surgery

1443-1449.

*ology*, 95(1), 130-136.

*Hepatol*, 52(2), 258-271.


[81] Esquivel, C. O., Iwatsuki, S., Gordon, R. D., Marsh, W. W., Jr., Koneru, B., Makowka, L., Tzakis, A. G., Todo, S., & Starzl, T. E. (1987). Indications for pediatric liver trans‐ plantation. *J Pediatr*, 111(6), Pt 2, 1039-1045.

**Chapter 25**

**Management of Hepatobiliary Trauma**

**2. Mechanism of injury and anatomic consideration:**

The liver is the most commonly injured solid abdominal organ, despite its relative protected location [1, 2]. Treatment of traumatic liver injuries is based on patient physiology, mecha‐ nism and degree of injury, associated abdominal and extra-abdominal injuries and local ex‐ pertise. Non-operative management has evolved into the treatment of choice for most patients with blunt liver injuries who are hemodynamically stable and success rates for nonoperative management commonly are greater than 95%. With the sweeping shift towards the non-operative management, most hepatic injuries can be treated conservatively [3, 4, 5]. More recently several authors have highlighted an excessive use of non-operative manage‐ ment (NOM), which for some high grade liver injuries is pushed far beyond the reasonable limits, carrying increased morbidity at short and long term, such as bilomas, biliary fistula, early or late haemorrhage, false aneurysm, arterio-venous fistulae, haemobilia, liver abscess, and liver necrosis [5]. Incidence of complications attributed to NOM increases in concert with the grade of injury. In a series of 337 patients with liver injury grades III-V treated non-opera‐ tively, those with grade III had a complication rate of 1%, grade IV 21%, and grade V 63% [6].

Road traffic accident, antisocial violent behaviours, industrial and farming accidents are the commonest mode of injury to the liver. Though the liver is protected by the rib cage, as the largest solid organ in the abdomen, the liver is particularly vulnerable to the ability of com‐ pressive abdominal blows to rupture its relatively thin capsule. The vasculature consists of wide-bore, thin-walled vessels with a high blood flow, and injury is usually associated with significant blood loss. Blunt trauma in a road traffic accident, or fall from a height, may re‐ sult in a deceleration injury as the liver continues to move on impact. This leads to tears at

> © 2013 Jagad et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 Jagad et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

distribution, and reproduction in any medium, provided the original work is properly cited.

Rajan Jagad, Ashok Thorat and Wei-Chen Lee

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52107

**1. Introduction:**


### **Management of Hepatobiliary Trauma**

Rajan Jagad, Ashok Thorat and Wei-Chen Lee

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52107

#### **1. Introduction:**

[81] Esquivel, C. O., Iwatsuki, S., Gordon, R. D., Marsh, W. W., Jr., Koneru, B., Makowka, L., Tzakis, A. G., Todo, S., & Starzl, T. E. (1987). Indications for pediatric liver trans‐

[82] Whitington, P. F, & Balistreri, W. F. (1991). Liver transplantation in pediatrics: indica‐ tions, contraindications, and pretransplant management. *J Pediatr*, 118(2), 169-177.

[83] Keitel, V., Burdelski, M., Vojnisek, Z., Schmitt, L., Haussinger, D., & Kubitz, R. (2009). De novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: a novel mechanism of cholestasis. *Hepatology*, 50(2),

[84] Jara, P., Hierro, L., Martinez-Fernandez, P., Alvarez-Doforno, R., Yanez, F., Diaz, M. C., Camarena, C., De la Vega, A., Frauca, E., Munoz-Bartolo, G., Lopez-Santamaria, M., Larrauri, J., & Alvarez, L. (2009). Recurrence of bile salt export pump deficiency

[85] Egawa, H., Yorifuji, T., Sumazaki, R., Kimura, A., Hasegawa, M., & Tanaka, K. (2002). Intractable diarrhea after liver transplantation for Byler's disease: successful

[86] De Vree, J. M., Ottenhoff, R., Bosma, P. J., Smith, A. J., Aten, J., & Oude Elferink, R. P. (2000). Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis. *Gastroenterology*, 119(6), 1720-1730.

[87] Zollner, G., & Trauner, M. (2009). Nuclear receptors as therapeutic targets in choles‐

[88] Morello, J. P., Petaja-Repo, U. E., Bichet, D. G., & Bouvier, M. (2000). Pharmacological chaperones: a new twist on receptor folding. *Trends Pharmacol Sci*, 21(12), 466-469.

[89] Chen, Y., & Liu-Chen, L. Y. (2009). Chaperone-like effects of cell-permeant ligands on

[90] Ohgane, K., Dodo, K., & Hashimoto, Y. (2010). Retinobenzaldehydes as proper-traf‐ ficking inducers of folding-defective P23H rhodopsin mutant responsible for retinitis

[91] Hayashi, H., & Sugiyama, Y. (2007). 4-phenylbutyrate enhances the cell surface ex‐ pression and the transport capacity of wild-type and mutated bile salt export pumps.

[92] Hacein-Bey-Abina, S., von Kalle, C., Schmidt, M., Le Deist, F., Wulffraat, N., Mc In‐ tyre, E., Radford, I., Villeval, J. L., Fraser, C. C., Cavazzana-Calvo, M., & Fischer, A. (2003). A serious adverse event after successful gene therapy for X-linked severe

after liver transplantation. *N Engl J Med*, 361(14), 1359-1367.

treatment with bile adsorptive resin. *Liver Transpl*, 8(8), 714-716.

tatic liver diseases. *Br J Pharmacol*, 156(1), 7-27.

opioid receptors. *Front Biosci*, 14, 634-643.

*Hepatology*, 45(6), 1506-1516.

pigmentosa. *Bioorg Med Chem*, 18(19), 7022-7028.

combined immunodeficiency. *N Engl J Med*, 348(3), 255-256.

plantation. *J Pediatr*, 111(6), Pt 2, 1039-1045.

510-517.

588 Hepatic Surgery

The liver is the most commonly injured solid abdominal organ, despite its relative protected location [1, 2]. Treatment of traumatic liver injuries is based on patient physiology, mecha‐ nism and degree of injury, associated abdominal and extra-abdominal injuries and local ex‐ pertise. Non-operative management has evolved into the treatment of choice for most patients with blunt liver injuries who are hemodynamically stable and success rates for nonoperative management commonly are greater than 95%. With the sweeping shift towards the non-operative management, most hepatic injuries can be treated conservatively [3, 4, 5].

More recently several authors have highlighted an excessive use of non-operative manage‐ ment (NOM), which for some high grade liver injuries is pushed far beyond the reasonable limits, carrying increased morbidity at short and long term, such as bilomas, biliary fistula, early or late haemorrhage, false aneurysm, arterio-venous fistulae, haemobilia, liver abscess, and liver necrosis [5]. Incidence of complications attributed to NOM increases in concert with the grade of injury. In a series of 337 patients with liver injury grades III-V treated non-opera‐ tively, those with grade III had a complication rate of 1%, grade IV 21%, and grade V 63% [6].

#### **2. Mechanism of injury and anatomic consideration:**

Road traffic accident, antisocial violent behaviours, industrial and farming accidents are the commonest mode of injury to the liver. Though the liver is protected by the rib cage, as the largest solid organ in the abdomen, the liver is particularly vulnerable to the ability of com‐ pressive abdominal blows to rupture its relatively thin capsule. The vasculature consists of wide-bore, thin-walled vessels with a high blood flow, and injury is usually associated with significant blood loss. Blunt trauma in a road traffic accident, or fall from a height, may re‐ sult in a deceleration injury as the liver continues to move on impact. This leads to tears at

© 2013 Jagad et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Jagad et al.; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

sites of fixation to the diaphragm and abdominal wall. A well-recognised deceleration injury involves a fracture between the posterior sector (segments VI and VII) and the anterior sec‐ tor (segments V and VIII) of the right lobe. This type of injury can lead to rupture of right hepatic vein and significant bleeding. In contrast, direct blow on right upper abdomen dur‐ ing vehicular accident or direct blow by a weapon or fist can lead to stellate type of injury to the central liver (segment IV, V and VIII). This type of injury can lead to massive bleeding from portal vein or hepatic vein and can also lead to bile duct injury.

**Liver organ injuriy scale**

VI Hepatic avulsion

**Table 1.** Liver Organ Injury Scale.

**4. Early Measures:**

III Hematoma Subcapsular,>50% surface area or expanding; ruptured subcapsular or

Management of Hepatobiliary Trauma http://dx.doi.org/10.5772/52107 591

IV Hematoma Parenchymal disruption involving 25%-75% of hepatic lobe or 1-3 Couinaud

V Laceration Parenchymal disruption involving >75% of hepatic lobe >3 Couinaud

It is generally accepted that initial resuscitation and management is the same as for any pa‐ tient with major trauma and should follow the Advanced Trauma Life Support (ATLS) prin‐ ciples of aggressive fluid resuscitation, guided by monitoring of central venous pressure and urinary output [7]. Management should also be directed toward avoidance of any of the sin‐ ister triad of hypothermia, coagulopathy, and acidosis, which are associated with signifi‐ cantly increased mortality. Mechanisms to avoid hypothermia are standard now in major centres and include the use of rewarming blankets and heat exchanger pumps for rapid in‐

The next management phase depends largely on the response to resuscitation and the stability of the patient. Liver injury should be suspected in all patients with blunt or penetrating thora‐ coabdominal trauma but particularly in shocked patients with blunt or penetrating trauma to the right side. There are two major determinants to consider when making decisions in sus‐ pected liver trauma: hemodynamic stability and mechanism of injury. In general, hemody‐ namic instability or peritonism makes decision-making in trauma more straightforward, although ultimately, the surgical procedure required may be complex. Management decisions are more challenging when patients are hemodynamically stable as the array of potential ther‐ apeutic modalities are substantial and the patient's future clinical course is unknown [9].

The appropriate evaluation and management of liver injuries results from an organized ap‐ proach to abdominal trauma. Experience and technical developments over the past several decades make the current approach both logical and effective. It is generally accepted that ini‐

Vascular Juxtahepatic venous injuries; ie, retrohepatic vena cava/central major

parenchymal hematoma

segments within a single lobe

segments within a single lobe

hepatic vein

**4.1. Resuscitation and treatment of Hemodynamic instability:**

fusion of resuscitation fluids and blood [8].

**4.2. Advanced Trauma Life Support:**

Laceration >3cm parenchymal depth

Penetrating injuries may be associated with a significant vascular injury. For example, a stab injury may cause major bleeding from one of the three hepatic veins or the vena cava and also from the portal vein or hepatic artery if it involves the hilum. Gunshots may similarly disrupt these major vessels; this disruption may be much more marked than with stab wounds due to the cavitation effect, particularly with bullets from high-velocity weapons.

The connection between the thin-walled hepatic veins and the inferior vena cava (IVC), at the site where the ligamentous mechanism anchors the liver to the diaphragm and posterior abdominal wall, represents a vulnerable area, particularly to shearing forces during blunt injury. Disruption here leads to the ''juxtahepatic'' venous injuries, which are usually associ‐ ated with major blood loss and present a particularly challenging management problem.

#### **3. Grade of liver injury:**

The severity of liver injuries ranges from the relatively inconsequential minor capsular tear to extensive disruption of both lobes with associated hepatic vein, portal vein, or vena caval injury. Several classifications have been advised to grade the liver injury and management accordingly. Following table shows the grade of liver injury. Grade I & II are successfully managed non-operatively in most cases. Grade IV and onward injuries will eventually re‐ quire emergency exploration. Grade III injuries require observation and if such patients are hemodynamically stable will recover with conservative treatment. Such patients should be closely followed in ICU with serial monitoring of hemoglobin and hematocrit level along with cardio-respiratory monitoring. Any fall in hematocrit or hemodynamic instability not responding to fluid resuscitation warrants urgent exploration.



**Table 1.** Liver Organ Injury Scale.

sites of fixation to the diaphragm and abdominal wall. A well-recognised deceleration injury involves a fracture between the posterior sector (segments VI and VII) and the anterior sec‐ tor (segments V and VIII) of the right lobe. This type of injury can lead to rupture of right hepatic vein and significant bleeding. In contrast, direct blow on right upper abdomen dur‐ ing vehicular accident or direct blow by a weapon or fist can lead to stellate type of injury to the central liver (segment IV, V and VIII). This type of injury can lead to massive bleeding

Penetrating injuries may be associated with a significant vascular injury. For example, a stab injury may cause major bleeding from one of the three hepatic veins or the vena cava and also from the portal vein or hepatic artery if it involves the hilum. Gunshots may similarly disrupt these major vessels; this disruption may be much more marked than with stab wounds due to the cavitation effect, particularly with bullets from high-velocity weapons.

The connection between the thin-walled hepatic veins and the inferior vena cava (IVC), at the site where the ligamentous mechanism anchors the liver to the diaphragm and posterior abdominal wall, represents a vulnerable area, particularly to shearing forces during blunt injury. Disruption here leads to the ''juxtahepatic'' venous injuries, which are usually associ‐ ated with major blood loss and present a particularly challenging management problem.

The severity of liver injuries ranges from the relatively inconsequential minor capsular tear to extensive disruption of both lobes with associated hepatic vein, portal vein, or vena caval injury. Several classifications have been advised to grade the liver injury and management accordingly. Following table shows the grade of liver injury. Grade I & II are successfully managed non-operatively in most cases. Grade IV and onward injuries will eventually re‐ quire emergency exploration. Grade III injuries require observation and if such patients are hemodynamically stable will recover with conservative treatment. Such patients should be closely followed in ICU with serial monitoring of hemoglobin and hematocrit level along with cardio-respiratory monitoring. Any fall in hematocrit or hemodynamic instability not

II Hematoma Subcapsular, <10%-50% surface area; intraparenchymal, <10 cm in diameter

from portal vein or hepatic vein and can also lead to bile duct injury.

responding to fluid resuscitation warrants urgent exploration.

I Hematoma Subcapsular, <10% surface area

Laceration Capsular tear, < 1 cm parenchymal depth

Laceration 1-3 cm parenchymal depth, <10 in Length

**3. Grade of liver injury:**

590 Hepatic Surgery

**Liver organ injuriy scale**

**Grade description**

#### **4. Early Measures:**

#### **4.1. Resuscitation and treatment of Hemodynamic instability:**

It is generally accepted that initial resuscitation and management is the same as for any pa‐ tient with major trauma and should follow the Advanced Trauma Life Support (ATLS) prin‐ ciples of aggressive fluid resuscitation, guided by monitoring of central venous pressure and urinary output [7]. Management should also be directed toward avoidance of any of the sin‐ ister triad of hypothermia, coagulopathy, and acidosis, which are associated with signifi‐ cantly increased mortality. Mechanisms to avoid hypothermia are standard now in major centres and include the use of rewarming blankets and heat exchanger pumps for rapid in‐ fusion of resuscitation fluids and blood [8].

The next management phase depends largely on the response to resuscitation and the stability of the patient. Liver injury should be suspected in all patients with blunt or penetrating thora‐ coabdominal trauma but particularly in shocked patients with blunt or penetrating trauma to the right side. There are two major determinants to consider when making decisions in sus‐ pected liver trauma: hemodynamic stability and mechanism of injury. In general, hemody‐ namic instability or peritonism makes decision-making in trauma more straightforward, although ultimately, the surgical procedure required may be complex. Management decisions are more challenging when patients are hemodynamically stable as the array of potential ther‐ apeutic modalities are substantial and the patient's future clinical course is unknown [9].

#### **4.2. Advanced Trauma Life Support:**

The appropriate evaluation and management of liver injuries results from an organized ap‐ proach to abdominal trauma. Experience and technical developments over the past several decades make the current approach both logical and effective. It is generally accepted that ini‐ tial resuscitation and management is the same as for any patient with major trauma and should follow the Advanced Trauma Life Support (ATLS) principles of aggressive fluid resuscitation, guided by monitoring of central venous pressure and urinary output [7]. Management should also be directed toward avoidance of any of the sinister triad of hypothermia, coagulopathy, and acidosis, which are associated with significantly increased mortality.

negatives is ever present, the combination of a negative ultrasound scan and normal clinical examination and observations almost excludes liver injury in the event of significant blunt

Management of Hepatobiliary Trauma http://dx.doi.org/10.5772/52107 593

The wide availability of high-resolution CT has changed the manner in which blunt abdomi‐ nal trauma is diagnosed and managed (figure 1). Currently, multi-detector computed tomog‐ raphy (MDCT) scanning with intravenous contrast is the gold standard diagnostic modality in

CT has a sensitivity of 92% to 97% and a specificity of 98.7% for detection of liver injury. The type and grade of liver injury, the volume of hemoperitoneum, and differentiation between clotted blood and active bleeding can be identified. In addition to increasing the rate of detec‐ tion of liver lesions following trauma, CT has also helped to improve the understanding of the course of liver injuries [19]. CT scan also allows diagnosis of associated intraperitoneal and ret‐ roperitoneal injuries, including splenic, renal, bowel, and chest trauma, and pelvic fractures.

Even though NOM has proven to be of tremendous benefit, a couple of controversies re‐ garding the current management of trauma patients should be discussed. Advances in CT technology have improved the practitioner's ability to determine the degree of injury and to identify patients who are more likely to fail NOM. However, until now, MDCT scanning has not been able to differentiate, in a precise manner, among which patients should be treated conservatively, which would benefit from angio-embolization and which would respond

**Figure 1.** CT scan images of blunt abdominal trauma patients. (A) CT scan of liver showing intraparenchymal hemato‐ ma in segment VI. (B) CT scan of liver showing intraparenchymal hematoma in segment VI and extending to segment

Although CT is the investigative gold standard, it is important to remember that it involves exposure to high levels of ionising radiation and the use of intravenous contrast may com‐ promise renal function. In the majority of hospitals the use of CT requires movement of the patient away from adequate resuscitation facilities to the X-ray department, highlighting the

hemodynamically stable patients with intra-abdominal fluid detected with FAST.

trauma [12, 18].

**4.4. Computed Tomography:**

best to a surgical response.

VII and V.

#### **4.3. Focused assessment by ultrasound for trauma (FAST):**

Ultrasonography (USG) is the most important and readily available investigation for any pa‐ tient with blunt or sharp abdominal injury. It is particularly useful for detecting injury to parenchymal organs and the presence of free intraperitoneal fluid or blood. USG is a quick, non-invasive, inexpensive, and transportable tool, used with increasing frequency in the ini‐ tial workup of patients with abdominal trauma [10].

The particular relevance to major liver injury is the focused assessment by ultrasound for trauma (FAST), often performed in the emergency department, which involves a rapid ex‐ amination of several areas, namely, the pericardial region, right upper quadrant (includ‐ ing Morrison's pouch), left upper quadrant, and the pelvis, specifically looking for free fluid. One of the main limitations of USG is that parenchymal injuries, sometimes rele‐ vant and requiring surgical or embolization therapy, may be present without combined per‐ itoneal fluid [11,12].

On the basis of detection of free fluid or parenchymal injury, the sensitivity of USG has been found to be 72% to 95% for abdominal organ injuries, 51% to 92% for liver lesions, and 98% for grade III or higher liver injuries [13]. Richards et al reported 56% and 68% sensitivity of FAST and complete USG, respectively, in detecting childhood abdominal trauma [11].

Detection of peritoneal fluid is the first step in FAST. Fluid in the right upper quadrant or in the right upper quadrant and pelvic recess suggests hepatic injury, as opposed to splenic, renal, or enteric injury [14]. Fluid limited to the left upper quadrant or to both upper quad‐ rants is not seen in patients with isolated liver trauma [14]. Hemoperitoneum recognition must prompt further imaging, but its absence does not definitely exclude parenchymal in‐ jury. Clinical assessment and observation are also relevant in combination with USG. With special reference to liver trauma, it has been noted that patients with negative USG results but with an aspartate aminotransferase level of greater than 360 IU/L should undergo CT imaging because of potentially overlooked hepatic injury, whereas patients with normal lev‐ els can be effectively discharged [15].

Although FAST provides a rapid assessment of liver disruption and intraperitoneal bleed‐ ing, it is a limited scan that is highly operator dependent. It is very important to note that a negative FAST scan does not safely rule out injury [12, 16]. Due to the operator dependence of the modality, different end points, and inconsistent comparative gold standards in the studies, the reported specificities, sensitivities, and overall accuracies are variable [17]. It has been demonstrated that up to a quarter of hepatic and splenic injuries, as well as renal, blad‐ der, pancreatic, mesenteric, and gut injuries, can be missed if ultrasound is used as the pri‐ mary investigative modality in the stable patient. However, while the possibility of false negatives is ever present, the combination of a negative ultrasound scan and normal clinical examination and observations almost excludes liver injury in the event of significant blunt trauma [12, 18].

#### **4.4. Computed Tomography:**

tial resuscitation and management is the same as for any patient with major trauma and should follow the Advanced Trauma Life Support (ATLS) principles of aggressive fluid resuscitation, guided by monitoring of central venous pressure and urinary output [7]. Management should also be directed toward avoidance of any of the sinister triad of hypothermia, coagulopathy,

Ultrasonography (USG) is the most important and readily available investigation for any pa‐ tient with blunt or sharp abdominal injury. It is particularly useful for detecting injury to parenchymal organs and the presence of free intraperitoneal fluid or blood. USG is a quick, non-invasive, inexpensive, and transportable tool, used with increasing frequency in the ini‐

The particular relevance to major liver injury is the focused assessment by ultrasound for trauma (FAST), often performed in the emergency department, which involves a rapid ex‐ amination of several areas, namely, the pericardial region, right upper quadrant (includ‐ ing Morrison's pouch), left upper quadrant, and the pelvis, specifically looking for free fluid. One of the main limitations of USG is that parenchymal injuries, sometimes rele‐ vant and requiring surgical or embolization therapy, may be present without combined per‐

On the basis of detection of free fluid or parenchymal injury, the sensitivity of USG has been found to be 72% to 95% for abdominal organ injuries, 51% to 92% for liver lesions, and 98% for grade III or higher liver injuries [13]. Richards et al reported 56% and 68% sensitivity of FAST and complete USG, respectively, in detecting childhood abdominal trauma [11].

Detection of peritoneal fluid is the first step in FAST. Fluid in the right upper quadrant or in the right upper quadrant and pelvic recess suggests hepatic injury, as opposed to splenic, renal, or enteric injury [14]. Fluid limited to the left upper quadrant or to both upper quad‐ rants is not seen in patients with isolated liver trauma [14]. Hemoperitoneum recognition must prompt further imaging, but its absence does not definitely exclude parenchymal in‐ jury. Clinical assessment and observation are also relevant in combination with USG. With special reference to liver trauma, it has been noted that patients with negative USG results but with an aspartate aminotransferase level of greater than 360 IU/L should undergo CT imaging because of potentially overlooked hepatic injury, whereas patients with normal lev‐

Although FAST provides a rapid assessment of liver disruption and intraperitoneal bleed‐ ing, it is a limited scan that is highly operator dependent. It is very important to note that a negative FAST scan does not safely rule out injury [12, 16]. Due to the operator dependence of the modality, different end points, and inconsistent comparative gold standards in the studies, the reported specificities, sensitivities, and overall accuracies are variable [17]. It has been demonstrated that up to a quarter of hepatic and splenic injuries, as well as renal, blad‐ der, pancreatic, mesenteric, and gut injuries, can be missed if ultrasound is used as the pri‐ mary investigative modality in the stable patient. However, while the possibility of false

and acidosis, which are associated with significantly increased mortality.

**4.3. Focused assessment by ultrasound for trauma (FAST):**

tial workup of patients with abdominal trauma [10].

itoneal fluid [11,12].

592 Hepatic Surgery

els can be effectively discharged [15].

The wide availability of high-resolution CT has changed the manner in which blunt abdomi‐ nal trauma is diagnosed and managed (figure 1). Currently, multi-detector computed tomog‐ raphy (MDCT) scanning with intravenous contrast is the gold standard diagnostic modality in hemodynamically stable patients with intra-abdominal fluid detected with FAST.

CT has a sensitivity of 92% to 97% and a specificity of 98.7% for detection of liver injury. The type and grade of liver injury, the volume of hemoperitoneum, and differentiation between clotted blood and active bleeding can be identified. In addition to increasing the rate of detec‐ tion of liver lesions following trauma, CT has also helped to improve the understanding of the course of liver injuries [19]. CT scan also allows diagnosis of associated intraperitoneal and ret‐ roperitoneal injuries, including splenic, renal, bowel, and chest trauma, and pelvic fractures.

Even though NOM has proven to be of tremendous benefit, a couple of controversies re‐ garding the current management of trauma patients should be discussed. Advances in CT technology have improved the practitioner's ability to determine the degree of injury and to identify patients who are more likely to fail NOM. However, until now, MDCT scanning has not been able to differentiate, in a precise manner, among which patients should be treated conservatively, which would benefit from angio-embolization and which would respond best to a surgical response.

**Figure 1.** CT scan images of blunt abdominal trauma patients. (A) CT scan of liver showing intraparenchymal hemato‐ ma in segment VI. (B) CT scan of liver showing intraparenchymal hematoma in segment VI and extending to segment VII and V.

Although CT is the investigative gold standard, it is important to remember that it involves exposure to high levels of ionising radiation and the use of intravenous contrast may com‐ promise renal function. In the majority of hospitals the use of CT requires movement of the patient away from adequate resuscitation facilities to the X-ray department, highlighting the importance of hemodynamic stability in patients with abdominal trauma being considered for CT examination [16].

are more challenging when patients are hemodynamically stable as the array of potential therapeutic modalities are substantial and the patient's future clinical course is unknown [9].

Management of Hepatobiliary Trauma http://dx.doi.org/10.5772/52107 595

Hogarth Pringle, in 1908, provided the first description of operative management of liver trauma. Unfortunately, all eight patients died and Pringle recommended conservative nonoperative management of these patients. In the modern surgical literature, non-operative management was first reported in 1972 and has been one of the most significant changes in

Initiated in pediatric trauma patients [25], nonsurgical management of blunt liver trauma has become recognized as an appropriate treatment option for hemodynamically stable

With the wide availability and improved quality of CT scanning, and the more modern, less invasive intervention options, such as angio-embolization, NOM has evolved into the treat‐ ment of choice for hemodynamically stable patients. Although angio-embolization has been defined the logical augmentation of damage control techniques for controlling hemorrhage, the overall liver-related complication rate can be as high as 60.6% with 42.2% incidence of major hepatic necrosis [28]. Non-operative management (NOM) consists of close observa‐ tion of the patient completed with angio-embolization, if necessary. Observational manage‐ ment involves admission to a unit and the monitoring of vital signs, with strict bed rest, frequent monitoring of hemoglobin concentration and serial abdominal examinations [29].

**i.** Realization that more than 50% of liver injuries stop bleeding spontaneously at the

**ii.** Availability of CT scan imaging for better assessment of grade of liver injury and

**vi.** The introduction of angio-embolization which allows patients with specific CT

Given the availability of angio-embolization, trauma surgeons are more likely to initiate non-operative treatment, even in higher grade injuries, because, in the event of failure, inter‐ vention in the form of angio-embolization is possible and, in the event of angio-emboliza‐ tion failure, surgical intervention is possible. Criteria for non-operative management include foremost, hemodynamic stability, absence of other abdominal injuries that require laparoto‐ my, immediate availability of resources including a fully staffed operating room, and a vigi‐ lant surgeon. While non-operative management was initially introduced for minor injuries,

the treatment of liver injuries over the last two decades [23, 24].

Following factors contribute to conservative management of liver trauma:

**iii.** The success of non-operative management in paediatric patients

**v.** Improved critical care management in specialized unit

**iv.** Knowledge that the liver has tremendous capacity of healing after injury,

findings to potentially be treated in a minimally invasive manner.

adult patients with blunt hepatic injury [26, 27].

time of exploration

associated injuries

**5.1. Non operative management:**

#### **4.5. Diagnostic laparoscopy:**

The use of laparoscopy for trauma patients has been slower to evolve partly due to factors inherent in the trauma population and some limitations of the laparoscopic technique. Ini‐ tially, the evaluation of peritoneal violation in hemodynamically stable patients was seen as the greatest benefit of laparoscopy for trauma [20]. Improvements in laparoscopic training and technology have enabled an increase in the use of diagnostic and therapeutic proce‐ dures in trauma patients.

**Figure 2.** Algorithm - Advanced trauma life support, FAST- focused assessment by ultrasound for trauma. ATLS for managing liver trauma patients.

There are a number of series describing the successful haemostasis of minor liver injuries, in both the civilian [21] and military setting [22], although it is likely that these were self-limit‐ ing injuries anyway.

#### **5. Management of hepatic Trauma:**

There are two major determinants to consider when making decisions in suspected liver trauma: hemodynamic stability and mechanism of injury. In general, hemodynamic instabil‐ ity or peritonism makes decision-making in trauma more straightforward, although ulti‐ mately, the surgical procedure required may be complex (figure 2). Management decisions are more challenging when patients are hemodynamically stable as the array of potential therapeutic modalities are substantial and the patient's future clinical course is unknown [9].

#### **5.1. Non operative management:**

importance of hemodynamic stability in patients with abdominal trauma being considered

The use of laparoscopy for trauma patients has been slower to evolve partly due to factors inherent in the trauma population and some limitations of the laparoscopic technique. Ini‐ tially, the evaluation of peritoneal violation in hemodynamically stable patients was seen as the greatest benefit of laparoscopy for trauma [20]. Improvements in laparoscopic training and technology have enabled an increase in the use of diagnostic and therapeutic proce‐

**Figure 2.** Algorithm - Advanced trauma life support, FAST- focused assessment by ultrasound for trauma. ATLS for

There are a number of series describing the successful haemostasis of minor liver injuries, in both the civilian [21] and military setting [22], although it is likely that these were self-limit‐

There are two major determinants to consider when making decisions in suspected liver trauma: hemodynamic stability and mechanism of injury. In general, hemodynamic instabil‐ ity or peritonism makes decision-making in trauma more straightforward, although ulti‐ mately, the surgical procedure required may be complex (figure 2). Management decisions

for CT examination [16].

594 Hepatic Surgery

dures in trauma patients.

managing liver trauma patients.

**5. Management of hepatic Trauma:**

ing injuries anyway.

**4.5. Diagnostic laparoscopy:**

Hogarth Pringle, in 1908, provided the first description of operative management of liver trauma. Unfortunately, all eight patients died and Pringle recommended conservative nonoperative management of these patients. In the modern surgical literature, non-operative management was first reported in 1972 and has been one of the most significant changes in the treatment of liver injuries over the last two decades [23, 24].

Initiated in pediatric trauma patients [25], nonsurgical management of blunt liver trauma has become recognized as an appropriate treatment option for hemodynamically stable adult patients with blunt hepatic injury [26, 27].

With the wide availability and improved quality of CT scanning, and the more modern, less invasive intervention options, such as angio-embolization, NOM has evolved into the treat‐ ment of choice for hemodynamically stable patients. Although angio-embolization has been defined the logical augmentation of damage control techniques for controlling hemorrhage, the overall liver-related complication rate can be as high as 60.6% with 42.2% incidence of major hepatic necrosis [28]. Non-operative management (NOM) consists of close observa‐ tion of the patient completed with angio-embolization, if necessary. Observational manage‐ ment involves admission to a unit and the monitoring of vital signs, with strict bed rest, frequent monitoring of hemoglobin concentration and serial abdominal examinations [29].

Following factors contribute to conservative management of liver trauma:


Given the availability of angio-embolization, trauma surgeons are more likely to initiate non-operative treatment, even in higher grade injuries, because, in the event of failure, inter‐ vention in the form of angio-embolization is possible and, in the event of angio-emboliza‐ tion failure, surgical intervention is possible. Criteria for non-operative management include foremost, hemodynamic stability, absence of other abdominal injuries that require laparoto‐ my, immediate availability of resources including a fully staffed operating room, and a vigi‐ lant surgeon. While non-operative management was initially introduced for minor injuries, it was soon in vogue for more severe injuries (grades III–V) [6, 30]. Close observation and repeated scans are usually recommended to document non-expansion of hematoma and healing of the injuries over time. The shift towards non-operative management of liver inju‐ ries has resulted in a lower mortality rate, but still a significant percentage of complications [31]. The current reported success rate of non-operative management of hepatic trauma ranges from 82% to 100%. Twenty-five percent of patients with blunt hepatic injury man‐ aged non-operatively, 92% of whom have grade IV or V injury will require an intervention for complications [5].

High grade liver injury (>3) treated with NOM and angio-embolization may be associated with severe complications like liver necrosis, bile leaks and severe sepsis. Mortality has been noted in up to 11% of patients in high grade liver injury treated conservatively [35]. Al‐ though angio-embolization has been defined the logical augmentation of damage control techniques for controlling hemorrhage, the overall liver-related complication rate can be as high as 60.6% with 42.2% incidence of major hepatic necrosis [28]. Early liver lobectomy in such cases required lesser number of procedures and achieved lower complication rate and lower mortality compared to less aggressive approaches such as serial operative debride‐

Management of Hepatobiliary Trauma http://dx.doi.org/10.5772/52107 597

TAE of blunt hepatic injury was first recognized as a safe and effective treatment for the control of recurrent postoperative hemorrhage, hemobilia and hepatic artery-portal vein fis‐ tulas in the late 1970s [37]. Hashimoto et al. [38] also showed the efficacy of emergency TAE in four patients with severe complex hepatic injury and suggested that this method may be useful in nonsurgical management of unstable patients with severe hepatic injury. This mul‐ tidisciplinary approach to the management of complex hepatic injuries is becoming much more important as the role of interventional radiology expands. Denton et al. [39] reported successful use of a combination of arterial embolization and transhepatic venous stenting in the management of a grade V injury involving the retrohepatic vena cava in a patient whose injury had been temporarily controlled by perihepatic packing. Recent more extensive series of angiography for control of hepatic haemorrhage have reported increasing success, with identification and control of bleeding rates ranging from 68 to 87%. [40] Angiography and embolization or stenting is a very useful adjunctive technique in the stable patient who is being managed non-operatively or in the patient who either has been stabilised by perihe‐

The recent literature reveals that the increased use of angio-embolization and decreased mor‐ tality rates result in increased frequencies of severe complications, such as liver necrosis, bile leakage and intra-abdominal abscesses [28, 32, 41]. Indications of angiography in hemo‐ dynamically stable patients are high grade liver injury in CT scan, evidence of arterial vas‐ cular injury, and the presence of hepatic venous injury [41]. Angio-embolization can be used immediately after a damage control laparotomy as part of the primary haemorrhage con‐ trol strategy [42]. Alternatively, angio-embolization can be used in post-operative patients to manage ongoing bleeding not associated with hemodynamic compromise [32]. This can involve not only angio-embolization, but also the placement of stents to reconstruct vascu‐

Bile leaks are a frequent complication in the non-operative management of liver injuries, oc‐ curring in 6% to 20% of cases. Bile leaks present either as trauma, drainage of bile through

ments and/or percutaneous drainage [36].

patic packing or has re-bled after a period of initial stability.

**5.3. Complications of non-operative management:**

**5.2. Transarterial Embolization (TAE):**

lature [39].

*5.3.1. Biliary complications:*

Despite the reduction of mortality that has been achieved using angio-embolization, some studies describe a rise in severe but treatable complications such as hepatic necrosis, ab‐ scesses or bile leakage [6, 28]. Gallbladder ischemia, hepatic parenchymal necrosis and bilo‐ ma may also occur, and in patients with a high grade liver injury (grade 4 and 5) the incidence of complications can be high [32].

A determinant of the success of NOM is the level of cooperation between different special‐ ists in the hospital. Good teamwork among the trauma surgeon, the anaesthesiologist and the interventional radiologist leads to a quicker understanding of the underlying injuries and thus shortens the time between entering the hospital and the initiation of therapeutic interventions. This seems obvious in level 1 trauma centers, but can be a matter of concern, especially in level II or III trauma centers.

While there has been considerable debate about the grade of liver injury and the acceptable volume of hemoperitoneum, it is now generally accepted that the ultimate decisive factor in favour of non-operative management is the hemodynamic stability of the patient, irrespec‐ tive of the grade of injury or the volume of hemoperitoneum. It is also essential that appro‐ priate clinical and radiological follow-up is arranged [33].

The rate of liver-related complications is low, and generally ranges from 0% to 7% [31]. Liv‐ er-related complication rates in high-grade liver injury patients are 11-13% and can be pre‐ dicted by the grade of liver injury and the volume of packed red blood cells transfused at 24 hours post-injury [6, 34]. Incidence of complications attributed to NOM increases in concert with the grade of injury. In a series of 337 patients with liver injury grades III-V treated nonoperatively, those with grade III had a complication rate of 1%, grade IV 21%, and grade V 63% [6]. Patients with grades IV and V injuries are more likely to require operation, and to have complications of non-operative treatment. Therefore, although it is not essential to per‐ form liver resection at the first laparotomy, if bleeding has been effectively controlled, in‐ creasing evidence suggests that liver resection should be considered as a surgical option in patients with complex liver injury, as an initial or delayed strategy, which can be accom‐ plished with low mortality and liver related morbidity in experienced hands [3].

Some of the complications related to conservative management of liver injuries are bile leaks, liver abscess, delayed haemorrhage, false aneurysm, arterio-venous fistulae, haemo‐ bilia, liver and gall bladder necrosis. Carrillo described complications in up to 85% of pa‐ tients with a high (≥4) Abbreviated Injury Score (AIS) in a series of 32 patients who were treated non-operatively [27].

High grade liver injury (>3) treated with NOM and angio-embolization may be associated with severe complications like liver necrosis, bile leaks and severe sepsis. Mortality has been noted in up to 11% of patients in high grade liver injury treated conservatively [35]. Al‐ though angio-embolization has been defined the logical augmentation of damage control techniques for controlling hemorrhage, the overall liver-related complication rate can be as high as 60.6% with 42.2% incidence of major hepatic necrosis [28]. Early liver lobectomy in such cases required lesser number of procedures and achieved lower complication rate and lower mortality compared to less aggressive approaches such as serial operative debride‐ ments and/or percutaneous drainage [36].

#### **5.2. Transarterial Embolization (TAE):**

it was soon in vogue for more severe injuries (grades III–V) [6, 30]. Close observation and repeated scans are usually recommended to document non-expansion of hematoma and healing of the injuries over time. The shift towards non-operative management of liver inju‐ ries has resulted in a lower mortality rate, but still a significant percentage of complications [31]. The current reported success rate of non-operative management of hepatic trauma ranges from 82% to 100%. Twenty-five percent of patients with blunt hepatic injury man‐ aged non-operatively, 92% of whom have grade IV or V injury will require an intervention

Despite the reduction of mortality that has been achieved using angio-embolization, some studies describe a rise in severe but treatable complications such as hepatic necrosis, ab‐ scesses or bile leakage [6, 28]. Gallbladder ischemia, hepatic parenchymal necrosis and bilo‐ ma may also occur, and in patients with a high grade liver injury (grade 4 and 5) the

A determinant of the success of NOM is the level of cooperation between different special‐ ists in the hospital. Good teamwork among the trauma surgeon, the anaesthesiologist and the interventional radiologist leads to a quicker understanding of the underlying injuries and thus shortens the time between entering the hospital and the initiation of therapeutic interventions. This seems obvious in level 1 trauma centers, but can be a matter of concern,

While there has been considerable debate about the grade of liver injury and the acceptable volume of hemoperitoneum, it is now generally accepted that the ultimate decisive factor in favour of non-operative management is the hemodynamic stability of the patient, irrespec‐ tive of the grade of injury or the volume of hemoperitoneum. It is also essential that appro‐

The rate of liver-related complications is low, and generally ranges from 0% to 7% [31]. Liv‐ er-related complication rates in high-grade liver injury patients are 11-13% and can be pre‐ dicted by the grade of liver injury and the volume of packed red blood cells transfused at 24 hours post-injury [6, 34]. Incidence of complications attributed to NOM increases in concert with the grade of injury. In a series of 337 patients with liver injury grades III-V treated nonoperatively, those with grade III had a complication rate of 1%, grade IV 21%, and grade V 63% [6]. Patients with grades IV and V injuries are more likely to require operation, and to have complications of non-operative treatment. Therefore, although it is not essential to per‐ form liver resection at the first laparotomy, if bleeding has been effectively controlled, in‐ creasing evidence suggests that liver resection should be considered as a surgical option in patients with complex liver injury, as an initial or delayed strategy, which can be accom‐

plished with low mortality and liver related morbidity in experienced hands [3].

Some of the complications related to conservative management of liver injuries are bile leaks, liver abscess, delayed haemorrhage, false aneurysm, arterio-venous fistulae, haemo‐ bilia, liver and gall bladder necrosis. Carrillo described complications in up to 85% of pa‐ tients with a high (≥4) Abbreviated Injury Score (AIS) in a series of 32 patients who were

for complications [5].

596 Hepatic Surgery

incidence of complications can be high [32].

especially in level II or III trauma centers.

treated non-operatively [27].

priate clinical and radiological follow-up is arranged [33].

TAE of blunt hepatic injury was first recognized as a safe and effective treatment for the control of recurrent postoperative hemorrhage, hemobilia and hepatic artery-portal vein fis‐ tulas in the late 1970s [37]. Hashimoto et al. [38] also showed the efficacy of emergency TAE in four patients with severe complex hepatic injury and suggested that this method may be useful in nonsurgical management of unstable patients with severe hepatic injury. This mul‐ tidisciplinary approach to the management of complex hepatic injuries is becoming much more important as the role of interventional radiology expands. Denton et al. [39] reported successful use of a combination of arterial embolization and transhepatic venous stenting in the management of a grade V injury involving the retrohepatic vena cava in a patient whose injury had been temporarily controlled by perihepatic packing. Recent more extensive series of angiography for control of hepatic haemorrhage have reported increasing success, with identification and control of bleeding rates ranging from 68 to 87%. [40] Angiography and embolization or stenting is a very useful adjunctive technique in the stable patient who is being managed non-operatively or in the patient who either has been stabilised by perihe‐ patic packing or has re-bled after a period of initial stability.

The recent literature reveals that the increased use of angio-embolization and decreased mor‐ tality rates result in increased frequencies of severe complications, such as liver necrosis, bile leakage and intra-abdominal abscesses [28, 32, 41]. Indications of angiography in hemo‐ dynamically stable patients are high grade liver injury in CT scan, evidence of arterial vas‐ cular injury, and the presence of hepatic venous injury [41]. Angio-embolization can be used immediately after a damage control laparotomy as part of the primary haemorrhage con‐ trol strategy [42]. Alternatively, angio-embolization can be used in post-operative patients to manage ongoing bleeding not associated with hemodynamic compromise [32]. This can involve not only angio-embolization, but also the placement of stents to reconstruct vascu‐ lature [39].

#### **5.3. Complications of non-operative management:**

#### *5.3.1. Biliary complications:*

Bile leaks are a frequent complication in the non-operative management of liver injuries, oc‐ curring in 6% to 20% of cases. Bile leaks present either as trauma, drainage of bile through surgically placed drain, or percutaneously placed catheter to drain biloma. The time of pre‐ sentation of biliary leaks is variable. Ultrasound and CT scan are used to diagnose a biloma, whereas a hepatobiliary iminodiacetic acid scan is used to show an active bile leak.

If a major liver injury is encountered, immediate control of bleeding is an absolute priority because the greatest threat to the patient's life at this juncture is exsanguination. Liver should immediately be manually closed and compressed. Patients with massive hemoperi‐ toneum are at risk of coagulopathy, hypothermia and acidosis. Measures should be taken to prevent and treat all these consequences of massive bleeding. If this still does not control the bleeding, pedicle occlusion (Pringle manoeuvre) should be applied using an atraumatic vas‐ cular clamp or non-crushing bowel clamp. If bleeding stops after Pringle manoeuvre, the bleeding is from branches of portal vein or hepatic artery. If bleeding continuous after this manoeuvre, the bleeding is likely to be from hepatic vein or IVC. The time of Pringle ma‐ noeuvre is controversial, but it can be applied up to 1 hour without compromising the blood

Management of Hepatobiliary Trauma http://dx.doi.org/10.5772/52107 599

The concept of damage control was introduced by Stone et al [45] in the 1980s and promul‐ gated by the group at Ben Taub in 1992 [46]. This came after the report by Denver General in

After trauma, hemostasis was not possible as patients were hypothermic, acidotic, and re‐ ceiving large volumes of packed red cells before blood component or fresh blood [47]. This led to the concept of the "bloody vicious cycle." The term "damage control" was popular‐ ized by the group at the University of Pennsylvania in the 1993 [48]. They described initial control of haemorrhage and contamination followed by packing and temporary abdominal closure, ICU restoration of normal physiology, and delayed definitive repair of intra-ab‐ dominal injuries. The decision for damage control should be made very early in the opera‐ tion before the onset of severe coagulopathy, acidosis, and hypothermia. Early institution of

The damage control concept is very appropriate for the management of major liver injuries. The three key factors that interact to produce a deteriorating metabolic situation are hypo‐ thermia, coagulopathy, and acidosis. Patients in this condition are at the limit of their phys‐ iological reserve and persistence with prolonged and complex surgical repair attempts will cause exceptionally high mortality [50]. Early recognition of hypo-thermia, coagulopathy, and acidosis is the key to the damage control approach. It is recommended that definitive surgery should cease and a damage control approach be adopted when hypothermia is dete‐

cal oozing or prothrombin time greater than 50% above normal), or when acidosis exists

Once the patient is stabilized, patient is returned to the operation theatre and definitive sur‐

Tamponade which is achieved by manual compression that can then be maintained by packs, which can also be manually compressed if bleeding continues. Packs placed in an an‐

C is reached, when coagulopathy has developed (nonsurgi‐

packing as a damage control technique has been shown to lessen mortality [49].

supply to the liver.

*5.4.1. Damage control surgery:*

riorating or a temperature of 34o

gery is undertaken if needed.

*5.4.2. Perihepatic packing:*

(pH<7.2 despite adequate volume resuscitation).

patients sustaining fatal hepatic hemorrhage.

Majority of bile leaks can be treated by ultrasound or CT-guided percutaneous drainage or ERCP and stenting.

#### *5.3.2. Delayed haemorrhage:*

The prevalence of delayed haemorrhage following non-operative management of blunt liver injury ranges from 1.7 to 5.9% [27, 43]. The mechanism of delayed hemorrhage may be relat‐ ed to an expanding injury or to a pseudoaneurysm induced by a biloma which eventually causes an expanding hematoma and free rupture into the peritoneal cavity. Early bleeding episodes are attributed directly to the traumatic insult, while late hemorrhage is probably related to infectious hepatic complications. Angio-embolization may prove an useful techni‐ que to deal with such complications.

#### **5.4. Operative management:**

Patients with associated liver and spleen injuries are twice as likely to fail non-operative therapy as those with only a single organ injured [44]. Missing associated intra-abdominal injury and delayed treatment, significantly affects the outcome. This occurs more often in conjunction with liver than with splenic injury, especially pancreas and bowel injury are sig‐ nificantly associated with liver injury in blunt trauma.

Patients with high grade liver injury who are hemodynamically unstable require surgi‐ cal management. Failure of NOM also requires urgent exploration and appropriate sur‐ gical management.

Anesthesia must ensure that blood products are already in the room. The massive transfu‐ sion protocol should be activated so that the blood bank is always ahead of the patient's needs for packed red blood cells, fresh frozen plasma, platelets, and cryoprecipitate. Ade‐ quate vascular access and arterial blood pressure monitoring are essential. It is important to preferentially have venous access above the diaphragm. Resuscitation fluids infused under pressure through femoral access will exacerbate hepatic venous bleeding, at times dramati‐ cally so. Massive transfusion protocols should be activated early to prevent any delay in re‐ suscitation with blood products.

The most widely adopted incision for the patient with liver trauma is a long midline laparot‐ omy, which can be extended to the right chest if a posterior right lobe injury, major hepatic venous injury, or vena caval injury is encountered. An effective alternative, which gives good exposure and avoids a thoracotomy, is a right subcostal extension. A bilateral subcos‐ tal incision is sometimes favoured by hepatobiliary surgeons if there is an obvious penetrat‐ ing through-and-through liver injury. This allows excellent exposure of the right lobe of the liver, the hepatic veins, and vena cava without having to open the chest or diaphragm; how‐ ever, it does compromise access to the lower abdomen.

If a major liver injury is encountered, immediate control of bleeding is an absolute priority because the greatest threat to the patient's life at this juncture is exsanguination. Liver should immediately be manually closed and compressed. Patients with massive hemoperi‐ toneum are at risk of coagulopathy, hypothermia and acidosis. Measures should be taken to prevent and treat all these consequences of massive bleeding. If this still does not control the bleeding, pedicle occlusion (Pringle manoeuvre) should be applied using an atraumatic vas‐ cular clamp or non-crushing bowel clamp. If bleeding stops after Pringle manoeuvre, the bleeding is from branches of portal vein or hepatic artery. If bleeding continuous after this manoeuvre, the bleeding is likely to be from hepatic vein or IVC. The time of Pringle ma‐ noeuvre is controversial, but it can be applied up to 1 hour without compromising the blood supply to the liver.

#### *5.4.1. Damage control surgery:*

surgically placed drain, or percutaneously placed catheter to drain biloma. The time of pre‐ sentation of biliary leaks is variable. Ultrasound and CT scan are used to diagnose a biloma,

Majority of bile leaks can be treated by ultrasound or CT-guided percutaneous drainage or

The prevalence of delayed haemorrhage following non-operative management of blunt liver injury ranges from 1.7 to 5.9% [27, 43]. The mechanism of delayed hemorrhage may be relat‐ ed to an expanding injury or to a pseudoaneurysm induced by a biloma which eventually causes an expanding hematoma and free rupture into the peritoneal cavity. Early bleeding episodes are attributed directly to the traumatic insult, while late hemorrhage is probably related to infectious hepatic complications. Angio-embolization may prove an useful techni‐

Patients with associated liver and spleen injuries are twice as likely to fail non-operative therapy as those with only a single organ injured [44]. Missing associated intra-abdominal injury and delayed treatment, significantly affects the outcome. This occurs more often in conjunction with liver than with splenic injury, especially pancreas and bowel injury are sig‐

Patients with high grade liver injury who are hemodynamically unstable require surgi‐ cal management. Failure of NOM also requires urgent exploration and appropriate sur‐

Anesthesia must ensure that blood products are already in the room. The massive transfu‐ sion protocol should be activated so that the blood bank is always ahead of the patient's needs for packed red blood cells, fresh frozen plasma, platelets, and cryoprecipitate. Ade‐ quate vascular access and arterial blood pressure monitoring are essential. It is important to preferentially have venous access above the diaphragm. Resuscitation fluids infused under pressure through femoral access will exacerbate hepatic venous bleeding, at times dramati‐ cally so. Massive transfusion protocols should be activated early to prevent any delay in re‐

The most widely adopted incision for the patient with liver trauma is a long midline laparot‐ omy, which can be extended to the right chest if a posterior right lobe injury, major hepatic venous injury, or vena caval injury is encountered. An effective alternative, which gives good exposure and avoids a thoracotomy, is a right subcostal extension. A bilateral subcos‐ tal incision is sometimes favoured by hepatobiliary surgeons if there is an obvious penetrat‐ ing through-and-through liver injury. This allows excellent exposure of the right lobe of the liver, the hepatic veins, and vena cava without having to open the chest or diaphragm; how‐

whereas a hepatobiliary iminodiacetic acid scan is used to show an active bile leak.

ERCP and stenting.

598 Hepatic Surgery

*5.3.2. Delayed haemorrhage:*

que to deal with such complications.

nificantly associated with liver injury in blunt trauma.

ever, it does compromise access to the lower abdomen.

**5.4. Operative management:**

gical management.

suscitation with blood products.

The concept of damage control was introduced by Stone et al [45] in the 1980s and promul‐ gated by the group at Ben Taub in 1992 [46]. This came after the report by Denver General in patients sustaining fatal hepatic hemorrhage.

After trauma, hemostasis was not possible as patients were hypothermic, acidotic, and re‐ ceiving large volumes of packed red cells before blood component or fresh blood [47]. This led to the concept of the "bloody vicious cycle." The term "damage control" was popular‐ ized by the group at the University of Pennsylvania in the 1993 [48]. They described initial control of haemorrhage and contamination followed by packing and temporary abdominal closure, ICU restoration of normal physiology, and delayed definitive repair of intra-ab‐ dominal injuries. The decision for damage control should be made very early in the opera‐ tion before the onset of severe coagulopathy, acidosis, and hypothermia. Early institution of packing as a damage control technique has been shown to lessen mortality [49].

The damage control concept is very appropriate for the management of major liver injuries. The three key factors that interact to produce a deteriorating metabolic situation are hypo‐ thermia, coagulopathy, and acidosis. Patients in this condition are at the limit of their phys‐ iological reserve and persistence with prolonged and complex surgical repair attempts will cause exceptionally high mortality [50]. Early recognition of hypo-thermia, coagulopathy, and acidosis is the key to the damage control approach. It is recommended that definitive surgery should cease and a damage control approach be adopted when hypothermia is dete‐ riorating or a temperature of 34o C is reached, when coagulopathy has developed (nonsurgi‐ cal oozing or prothrombin time greater than 50% above normal), or when acidosis exists (pH<7.2 despite adequate volume resuscitation).

Once the patient is stabilized, patient is returned to the operation theatre and definitive sur‐ gery is undertaken if needed.

#### *5.4.2. Perihepatic packing:*

Tamponade which is achieved by manual compression that can then be maintained by packs, which can also be manually compressed if bleeding continues. Packs placed in an an‐ terio-posterior axis will often distract the injured liver further and worsen the bleeding. The lobes of the liver must be compressed back to normal position, essentially back toward mid‐ line. Simultaneously, the liver is pushed toward the diaphragm. Maintenance of this ana‐ tomic compression by the first or second assistant is critical to reduce bleeding as the surgeon assesses the liver injury or mobilizes the liver. Perihepatic packing can help to maintain this tamponade. Most minor venous bleeding and small lacerations to the paren‐ chyma can be temporized by this manoeuvre. Haemostatic agents such as surgicell, throm‐ bin-soaked gel foam, or fibrin glue are useful adjuncts.

drawback of this procedure is ischemic necrosis and infection of the liver parenchyma. However, some advocate hepatorrhaphy for "hard-to-reach" areas such as the dome and

Management of Hepatobiliary Trauma http://dx.doi.org/10.5772/52107 601

Mesh-wrapping is a quick and technically feasible method to achieve definitive hemostasis in severe liver trauma. It can be combined ideally with conventional procedures. Meshwrapping technique provides a highly selective, tight compression confined to the liver and does not produce an increased intra-abdominal pressure. Emphasis should be given in two important technical aspects while mesh wrapping. First, the traumatized liver has to be slung with the mesh under enough tension to create a tamponade effect. In addition the mesh should be attached into two anchoring stable points. The diaphragmatic crus and the falciform ligament provide the best options to stabilize the mesh. The mesh is resorbable and therefore reoperation for removal is not necessary. Furthermore, the resulting product

of mesh hydrolysis has a bacteriostatic effect, minimizing the risk of infection [60].

Combined hepatotomy and selective vascular ligation has emerged as the preferred method of management for major hepatic venous, portal venous, and arterial injuries in many cen‐ tres [61]. For control of major vascular injuries, Pachter et al. recommend a rapid and exten‐ sive finger fracture, often through normal parenchyma, to reach the site of injury. However, it is important to emphasise that with a major hepatic venous injury, significant haemor‐ rhage may occur while attempting to extend a deep liver laceration and that this bleeding will not be controlled by a Pringle clamp and increased morbidity may be incurred. Hepa‐ totomy is done under Pringle manoeuvre and finger fracture method is used to divide the parenchyma to ligate the bleeding vessels. Pringle clamp is released intermittently to identi‐

This refers to removal of devitalised parenchyma using the line of injury as the boundary of the resection rather than standard anatomical planes [62]. Resectional debridement is indi‐ cated for peripheral portion of nonviable hepatic parenchyma. Debridement is rarely a tech‐ nique practised in isolation and is frequently used in conjunction with inflow control and hepatotomy. This allows for haemorrhage control prior to resection of all devitalised tissue while usually involves crossing traditional anatomical boundaries hence the term "non-ana‐ tomical resection". All devitalized tissues should be removed without making any attempt

Except in rare circumstances, the amount of tissue removed should not be more than 25% of the liver. In some cases simple completion of an extensive parenchymal avulsion may suf‐ fice, e.g., when there has been an avulsion of the posterior sector of the right lobe (segments VI and VII). This type of injury is often associated with a right hepatic vein laceration and

to resect normal parenchyma. Operative time should be as short as possible.

posterior portion of the right lobe.

*5.4.4. Hepatotomy and selective vascular ligation:*

*5.4.3.1. Mesh Wrapping:*

fy bleeding vessels.

*5.4.5. Non-anatomical resection of liver:*

Packing is not as effective for the injuries to the left hemiliver, because with the abdomen open, there is insufficient abdominal and thoracic wall anterior to the left hemiliver to pro‐ vide adequate compression. Fortunately, haemorrhage from the left hemiliver can be con‐ trolled by dividing the left triangular and left coronary ligaments and compressing the left hemiliver between the hands.

Packs must be placed around the liver to reconstitute its anatomical shape. Packs should never be inserted into the hepatic wound, as it will tear the vessels and will increase the bleeding. It is also important to avoid excessive packing, as compression of IVC can lead to resultant decreased venous return, and reduces left ventricular filling. Excessive packing can also lead to compartment syndrome and multi-organ failure [51]. Conversely under-packing is associated with increased transfusion requirements and unplanned re-look laparotomies [52]. To reduce the risk of abdominal compartment syndrome, some advocate closing the upper part of the wound to enhance the tamponade effect but leaving the lower two-thirds open and temporarily covered with a silastic sheet sutured to the skin edges [53, 54].

Perihepatic packing will control profuse haemorrhage in up to 80% of patients undergoing laparotomy and will allow intraoperative resuscitation (resuscitative packing) [50, 55]. In the management of severe injuries of the liver, packing has emerged as the key to effective dam‐ age control [56]. However, more definitive ''therapeutic'' packing is also a very effective technique, particularly when used judiciously to prevent the cascade of hypothermia, coa‐ gulopathy, and acidosis [57].

Once the patient is stabilized, temporary closure of the abdomen is done and patient is shift‐ ed to the ICU. Packs can be removed after 36-48 hours. Broad spectrum antibiotics should be started to prevent sepsis. The exact timing of the removal of packs is controversial, but they should not be removed before 24 hours as this is related to re-bleeding and leaving them in place for 24 hours or more does improve outcome [58]. Even delayed removal (up to 1 week) has been reported without increasing the morbidity [59]. During removal, the packs should gently be removed after soaking with saline. Liver should be checked for re- bleed‐ ing and if adequate hemostasis is achieved, closure of the abdomen can be done after put‐ ting a drain.

#### *5.4.3. Hepatorrhaphy:*

This is an older technique which involves passing deep parenchymal sutures to bring dis‐ rupted tissue together compressing bleeding vessels and reducing dead space. The major drawback of this procedure is ischemic necrosis and infection of the liver parenchyma. However, some advocate hepatorrhaphy for "hard-to-reach" areas such as the dome and posterior portion of the right lobe.

#### *5.4.3.1. Mesh Wrapping:*

terio-posterior axis will often distract the injured liver further and worsen the bleeding. The lobes of the liver must be compressed back to normal position, essentially back toward mid‐ line. Simultaneously, the liver is pushed toward the diaphragm. Maintenance of this ana‐ tomic compression by the first or second assistant is critical to reduce bleeding as the surgeon assesses the liver injury or mobilizes the liver. Perihepatic packing can help to maintain this tamponade. Most minor venous bleeding and small lacerations to the paren‐ chyma can be temporized by this manoeuvre. Haemostatic agents such as surgicell, throm‐

Packing is not as effective for the injuries to the left hemiliver, because with the abdomen open, there is insufficient abdominal and thoracic wall anterior to the left hemiliver to pro‐ vide adequate compression. Fortunately, haemorrhage from the left hemiliver can be con‐ trolled by dividing the left triangular and left coronary ligaments and compressing the left

Packs must be placed around the liver to reconstitute its anatomical shape. Packs should never be inserted into the hepatic wound, as it will tear the vessels and will increase the bleeding. It is also important to avoid excessive packing, as compression of IVC can lead to resultant decreased venous return, and reduces left ventricular filling. Excessive packing can also lead to compartment syndrome and multi-organ failure [51]. Conversely under-packing is associated with increased transfusion requirements and unplanned re-look laparotomies [52]. To reduce the risk of abdominal compartment syndrome, some advocate closing the upper part of the wound to enhance the tamponade effect but leaving the lower two-thirds

open and temporarily covered with a silastic sheet sutured to the skin edges [53, 54].

Perihepatic packing will control profuse haemorrhage in up to 80% of patients undergoing laparotomy and will allow intraoperative resuscitation (resuscitative packing) [50, 55]. In the management of severe injuries of the liver, packing has emerged as the key to effective dam‐ age control [56]. However, more definitive ''therapeutic'' packing is also a very effective technique, particularly when used judiciously to prevent the cascade of hypothermia, coa‐

Once the patient is stabilized, temporary closure of the abdomen is done and patient is shift‐ ed to the ICU. Packs can be removed after 36-48 hours. Broad spectrum antibiotics should be started to prevent sepsis. The exact timing of the removal of packs is controversial, but they should not be removed before 24 hours as this is related to re-bleeding and leaving them in place for 24 hours or more does improve outcome [58]. Even delayed removal (up to 1 week) has been reported without increasing the morbidity [59]. During removal, the packs should gently be removed after soaking with saline. Liver should be checked for re- bleed‐ ing and if adequate hemostasis is achieved, closure of the abdomen can be done after put‐

This is an older technique which involves passing deep parenchymal sutures to bring dis‐ rupted tissue together compressing bleeding vessels and reducing dead space. The major

bin-soaked gel foam, or fibrin glue are useful adjuncts.

hemiliver between the hands.

600 Hepatic Surgery

gulopathy, and acidosis [57].

ting a drain.

*5.4.3. Hepatorrhaphy:*

Mesh-wrapping is a quick and technically feasible method to achieve definitive hemostasis in severe liver trauma. It can be combined ideally with conventional procedures. Meshwrapping technique provides a highly selective, tight compression confined to the liver and does not produce an increased intra-abdominal pressure. Emphasis should be given in two important technical aspects while mesh wrapping. First, the traumatized liver has to be slung with the mesh under enough tension to create a tamponade effect. In addition the mesh should be attached into two anchoring stable points. The diaphragmatic crus and the falciform ligament provide the best options to stabilize the mesh. The mesh is resorbable and therefore reoperation for removal is not necessary. Furthermore, the resulting product of mesh hydrolysis has a bacteriostatic effect, minimizing the risk of infection [60].

#### *5.4.4. Hepatotomy and selective vascular ligation:*

Combined hepatotomy and selective vascular ligation has emerged as the preferred method of management for major hepatic venous, portal venous, and arterial injuries in many cen‐ tres [61]. For control of major vascular injuries, Pachter et al. recommend a rapid and exten‐ sive finger fracture, often through normal parenchyma, to reach the site of injury. However, it is important to emphasise that with a major hepatic venous injury, significant haemor‐ rhage may occur while attempting to extend a deep liver laceration and that this bleeding will not be controlled by a Pringle clamp and increased morbidity may be incurred. Hepa‐ totomy is done under Pringle manoeuvre and finger fracture method is used to divide the parenchyma to ligate the bleeding vessels. Pringle clamp is released intermittently to identi‐ fy bleeding vessels.

#### *5.4.5. Non-anatomical resection of liver:*

This refers to removal of devitalised parenchyma using the line of injury as the boundary of the resection rather than standard anatomical planes [62]. Resectional debridement is indi‐ cated for peripheral portion of nonviable hepatic parenchyma. Debridement is rarely a tech‐ nique practised in isolation and is frequently used in conjunction with inflow control and hepatotomy. This allows for haemorrhage control prior to resection of all devitalised tissue while usually involves crossing traditional anatomical boundaries hence the term "non-ana‐ tomical resection". All devitalized tissues should be removed without making any attempt to resect normal parenchyma. Operative time should be as short as possible.

Except in rare circumstances, the amount of tissue removed should not be more than 25% of the liver. In some cases simple completion of an extensive parenchymal avulsion may suf‐ fice, e.g., when there has been an avulsion of the posterior sector of the right lobe (segments VI and VII). This type of injury is often associated with a right hepatic vein laceration and completion of the ''resection'' will allow control and suture of this. In such situations, vascu‐ lar stapling devices are extremely useful for rapid and secure division of major veins.

*5.4.9. Liver transplantation:*

ble only in specialist centres.

**6.1. Postoperative haemorrhage:**

tween 36 hours and 72 hours.

**6.2. Sepsis and abscess:**

type of patients.

**6.3. Biloma:**

and then patients should be reassessed.

8.1% to 30% [68].

**6. Postoperative complications and mortality:**

This remains a therapy of last resort limited to specialist centres with the literature limited to occasional case reports and series [67]. While liver transplantation may be life-saving for major liver trauma, the logistical problems will mean that it remains a limited option, availa‐

Management of Hepatobiliary Trauma http://dx.doi.org/10.5772/52107 603

Overall mortality for patients with hepatic injuries is approximately 10%. The most common cause of death is exsanguination, followed by MODS and intracranial haemorrhage. Liver trauma is a morbid injury with complication rates from recent series ranges from between

Primary exsanguinating haemorrhage is a major source of mortality, but most studies report secondary haemorrhage occurring in 3- 6% of survivors with no significant difference be‐ tween blunt and penetrating mechanisms [69]. Surgical haemorrhage (ie discrete bleeding) and disseminated intravascular coagulation account for the majority of causes in even pro‐ portions. In patients managed by peri-hepatic packing, patients who had packs removed at <36hrs had more episodes of haemorrhage requiring re-packing than those with removal be‐

In most instances of persistent postoperative haemorrhage, the patient is best served by be‐ ing returned to the operation room. Angiography with embolization may be considered in selected patients. If the reason for haemorrhage is coagulopathy, it should be corrected first

Post-operative sepsis occurs in 12-32% of patients. Minor morbidity occurs with urinary tract, surgical wound and respiratory tract sepsis. More serious are intra-abdominal abscess‐ es which occur in up 24% of patients and are associated with concomitant bowel injury,

An abdominal CT with intravenous and oral contrast should be performed to diagnose the cause of sepsis. Majority of the abscesses can be drained percutaneously under USG or CTguidance; however, infected hematoma and infected necrotic liver tissue cannot be expected to respond to percutaneous drainage. Operative drainage may be a better option in such

Bilomas are loculated collection of bile, which is with or without infection. CT-guided per‐ cutaneous drainage is the best option for infected bilomas. If the biloma is sterile, it will

higher grades of liver injury (IV and V) and massive transfusion [70].

#### *5.4.6. Anatomical resection of liver:*

The final alternative for patients with extensive injury to one hemiliver is anatomic hepatic resection. In elective circumstances, anatomic hemi-hepatectomies can be performed with excellent results; however, in the setting of trauma, the mortality associated with this proce‐ dure exceeds 50% in most series [63, 64]. This, plus the fact that the time and magnitude of the surgery goes against the later principles of conservative surgery and damage control, has resulted in anatomical resection being practised rarely and it is now performed in only approximately 2–4% major liver trauma cases [51].

Hepatic resection for an injured segment of the liver definitively controls bleeding, potential bile leak, and removes devitalized tissue. However, the role of hepatic resection in the man‐ agement of liver injury remains controversial. The traditional poor results and lack of enthu‐ siasm for this technique have been contradicted by the results of some recent series particularly that from Strong et al. who achieved excellent results in a series of 37 patients, 11 of whom (33%) had grade V juxtahepatic venous injuries [61]. These results probably re‐ flect the fact that this procedure was performed in a specialist liver resection and transplan‐ tation unit, and while the majority of liver injuries continue to be managed initially in trauma centres or district hospitals, it is likely that more conservative and damage control procedures will remain the most widely practised techniques.

#### *5.4.7. Intrahepatic balloon tamponade:*

Intrahepatic balloon tamponade is useful for transhepatic penetrating injury. A device can either be fashioned from a Foley catheter and Penrose drain [65] or a Sengstaken-Blakemore tube. The device is gently delivered into the length of the tract and then inflated, often with a radio-opaque contrast fluid so integrity and position can be later confirmed radiologically if required. Once the patient is stabilized and coagulation and acidosis is corrected, the bal‐ loon can be deflated and removed during re-laparotomy.

#### *5.4.8. Total vascular exclusion:*

Total vascular exclusion of liver is sometimes used for extensive retrohepatic venous inju‐ ries. The technique involves clamping of the portal triad and infra- and supra-hepatic IVC and therefore requires experience with mobilisation of the liver as done in liver resection and transplantation. Excellent results were reported for this technique by Khaneja et al. [66] who used it to manage grade V penetrating injuries with 90% of patients surviving the oper‐ ation and an overall survival rate of 70%.

The major drawback of this technique is decreased venous return due to clamping of IVC. This will lead to further hypotension in patient who is already in hypothermia and hypoten‐ sion. This procedure can only be feasible in experienced hand in high volume centres.

#### *5.4.9. Liver transplantation:*

completion of the ''resection'' will allow control and suture of this. In such situations, vascu‐

The final alternative for patients with extensive injury to one hemiliver is anatomic hepatic resection. In elective circumstances, anatomic hemi-hepatectomies can be performed with excellent results; however, in the setting of trauma, the mortality associated with this proce‐ dure exceeds 50% in most series [63, 64]. This, plus the fact that the time and magnitude of the surgery goes against the later principles of conservative surgery and damage control, has resulted in anatomical resection being practised rarely and it is now performed in only

Hepatic resection for an injured segment of the liver definitively controls bleeding, potential bile leak, and removes devitalized tissue. However, the role of hepatic resection in the man‐ agement of liver injury remains controversial. The traditional poor results and lack of enthu‐ siasm for this technique have been contradicted by the results of some recent series particularly that from Strong et al. who achieved excellent results in a series of 37 patients, 11 of whom (33%) had grade V juxtahepatic venous injuries [61]. These results probably re‐ flect the fact that this procedure was performed in a specialist liver resection and transplan‐ tation unit, and while the majority of liver injuries continue to be managed initially in trauma centres or district hospitals, it is likely that more conservative and damage control

Intrahepatic balloon tamponade is useful for transhepatic penetrating injury. A device can either be fashioned from a Foley catheter and Penrose drain [65] or a Sengstaken-Blakemore tube. The device is gently delivered into the length of the tract and then inflated, often with a radio-opaque contrast fluid so integrity and position can be later confirmed radiologically if required. Once the patient is stabilized and coagulation and acidosis is corrected, the bal‐

Total vascular exclusion of liver is sometimes used for extensive retrohepatic venous inju‐ ries. The technique involves clamping of the portal triad and infra- and supra-hepatic IVC and therefore requires experience with mobilisation of the liver as done in liver resection and transplantation. Excellent results were reported for this technique by Khaneja et al. [66] who used it to manage grade V penetrating injuries with 90% of patients surviving the oper‐

The major drawback of this technique is decreased venous return due to clamping of IVC. This will lead to further hypotension in patient who is already in hypothermia and hypoten‐ sion. This procedure can only be feasible in experienced hand in high volume centres.

lar stapling devices are extremely useful for rapid and secure division of major veins.

*5.4.6. Anatomical resection of liver:*

602 Hepatic Surgery

*5.4.7. Intrahepatic balloon tamponade:*

*5.4.8. Total vascular exclusion:*

ation and an overall survival rate of 70%.

approximately 2–4% major liver trauma cases [51].

procedures will remain the most widely practised techniques.

loon can be deflated and removed during re-laparotomy.

This remains a therapy of last resort limited to specialist centres with the literature limited to occasional case reports and series [67]. While liver transplantation may be life-saving for major liver trauma, the logistical problems will mean that it remains a limited option, availa‐ ble only in specialist centres.

### **6. Postoperative complications and mortality:**

Overall mortality for patients with hepatic injuries is approximately 10%. The most common cause of death is exsanguination, followed by MODS and intracranial haemorrhage. Liver trauma is a morbid injury with complication rates from recent series ranges from between 8.1% to 30% [68].

#### **6.1. Postoperative haemorrhage:**

Primary exsanguinating haemorrhage is a major source of mortality, but most studies report secondary haemorrhage occurring in 3- 6% of survivors with no significant difference be‐ tween blunt and penetrating mechanisms [69]. Surgical haemorrhage (ie discrete bleeding) and disseminated intravascular coagulation account for the majority of causes in even pro‐ portions. In patients managed by peri-hepatic packing, patients who had packs removed at <36hrs had more episodes of haemorrhage requiring re-packing than those with removal be‐ tween 36 hours and 72 hours.

In most instances of persistent postoperative haemorrhage, the patient is best served by be‐ ing returned to the operation room. Angiography with embolization may be considered in selected patients. If the reason for haemorrhage is coagulopathy, it should be corrected first and then patients should be reassessed.

#### **6.2. Sepsis and abscess:**

Post-operative sepsis occurs in 12-32% of patients. Minor morbidity occurs with urinary tract, surgical wound and respiratory tract sepsis. More serious are intra-abdominal abscess‐ es which occur in up 24% of patients and are associated with concomitant bowel injury, higher grades of liver injury (IV and V) and massive transfusion [70].

An abdominal CT with intravenous and oral contrast should be performed to diagnose the cause of sepsis. Majority of the abscesses can be drained percutaneously under USG or CTguidance; however, infected hematoma and infected necrotic liver tissue cannot be expected to respond to percutaneous drainage. Operative drainage may be a better option in such type of patients.

#### **6.3. Biloma:**

Bilomas are loculated collection of bile, which is with or without infection. CT-guided per‐ cutaneous drainage is the best option for infected bilomas. If the biloma is sterile, it will eventually be resorbed. Biliary ascites is caused by disruption of major bile duct. Reopera‐ tion after the establishment of appropriate drainage is the prudent course.

the first signs of coagulopathy. Formal anatomical resection carries a high morbidity when used for haemorrhage control, although in an experienced centre this may be appropriate. Hepatorrhaphy has become discouraged due to complications of sepsis and bleeding, but

Management of Hepatobiliary Trauma http://dx.doi.org/10.5772/52107 605

Division of Liver and Transplantation Surgery, Department of General Surgery, Chang-Gung Memorial Hospital at Linkou, Chang-Gung University College of Medicine, Taiwan

[1] Miller, P. R., Croce, M. A., Bee, T. K., et al. (2002). Associated injuries in blunt solid organ trauma: the implications for missed injury in non-operative management. *J*

[2] Shanmuganathan, K., Mirvis, S. E., & Chiu, W. C. (2004). Penetrating torso trauma: triple-contrast helical CT in peritoneal violation and organ injury. *A prospective study*

[3] Polanco, P., Leon, S., Pineda, J., et al. (2008). Hepatic resection in the management of

[4] Badger, S. A., Barclay, R., Diamond, T., et al. (2009). Management of liver trauma.

[5] Trunkey, D.D. (2004). Hepatic trauma: contemporary management. *Surg Clin North*

[6] Kozar, R. A., Moore, J. B., Niles, S. E., et al. (1999). Complications of non-operative management of high-grade blunt hepatic injuries. *J Trauma 2005* 59:1066-1071.

[7] American College of Surgeons. (1997). Advanced Trauma Life Support manual.

[8] Peng, R. Y., & Bongard, F. S. (1999). Hypothermia in trauma patients. *J Am Coll Surg*,

[9] Mac, Kenzie. S., Kortbeek, J. B., Mulloy, R., & Hameed, S. M. (2004). Recent experien‐ ces with a multidisciplinary approach to complex hepatic trauma. *Injury*, 35, 869-77.

complex injury to the liver. *J Trauma*, 65(6), 1264-9, 1269-70.

may be a useful technique in penetrating trauma where the liver is difficult to access.

, Ashok Thorat and Wei-Chen Lee

**Author details**

\*Address all correspondence to:

*Trauma*, 53, 238-242.

*World J Surg*, 33, 2522-37.

*Am*, 84, 437-50.

188, 688-696.

*in 200 patients. Radiology*, 231, 775-784.

*American College of Surgeons*, Chicago, IL.

Rajan Jagad\*

**References**

Biliary fistulas occur in approximately 3% of the patients with major liver injury [71]. They are usually of little consequences and generally close without specific treatment.

#### **7. Injuries to the Bile ducts and gall bladder:**

Extrahepatic bile ducts are rarely injured during blunt or penetrating abdominal inju‐ ries [72, 73]. Diagnosis is usually made during surgery or sometimes postoperatively. Man‐ agement of bile duct injury detected postoperatively has already been described. If laparotomy is performed for patient with trauma, collection of bile in to the right up‐ per quadrant suggest major bile duct injury. Sometimes it is very difficult to detect the site of bile duct injury, as associated disruption of liver parenchyma and haemor‐ rhage makes detection a challenging task.

Management of bile duct injury is further complicated by small calibre and thin wall of the bile duct. Bile duct injury ranges from small laceration to tissue loss or complete disruption. Primary repair may be attempted when there is small laceration and no tissue loss. When there is a tissue loss or the laceration is larger than 25% to 50% of the diameter of the duct, the treatment option is a Roux-en-Y choledocho-jejunostomy [74, 75]. Isolated injury to left or right hepatic duct is even more challenging and should only be managed by experienced hepatobiliary surgeon. If expertise is not available, large bore tube should be kept and pa‐ tient should be transferred to higher centre. If both the ducts are injured, both the ducts should be intubated by separate tubes and brought out. Elective repair should be undertak‐ en once the patient is stable and after adequate assessment of injury by cholangiogram.

Injury to the gall bladder is treated either by repair or cholecystectomy.

#### **8. Summary:**

The management of injuries of the liver has evolved significantly throughout the last two decades. Non-operative techniques for the management of grade IV–V injuries in stable pa‐ tients have been established, although there is a higher failure rate for these injuries com‐ pared with grade I–III injuries. Because of the progress that has been made in the quality and wide availability of the MDCT scan combined with minimally invasive intervention op‐ tions like angio-embolization, NOM has evolved to be the treatment of choice for hemody‐ namically stable patients. In terms of surgical management there has been a definite move away from major, time-consuming procedures toward conservative surgery and damage control. The preferred surgical technique for inaccessible bleeding within a laceration is rap‐ id finger fracture hepatotomy, Kelly –crush hepatic transection and direct suture or ligation. Prolonged attempts at surgical control and repair should be avoided, and definitive perihe‐ patic packing should be employed at an early stage in the persistently unstable patient or at the first signs of coagulopathy. Formal anatomical resection carries a high morbidity when used for haemorrhage control, although in an experienced centre this may be appropriate. Hepatorrhaphy has become discouraged due to complications of sepsis and bleeding, but may be a useful technique in penetrating trauma where the liver is difficult to access.

#### **Author details**

eventually be resorbed. Biliary ascites is caused by disruption of major bile duct. Reopera‐

Biliary fistulas occur in approximately 3% of the patients with major liver injury [71]. They

Extrahepatic bile ducts are rarely injured during blunt or penetrating abdominal inju‐ ries [72, 73]. Diagnosis is usually made during surgery or sometimes postoperatively. Man‐ agement of bile duct injury detected postoperatively has already been described. If laparotomy is performed for patient with trauma, collection of bile in to the right up‐ per quadrant suggest major bile duct injury. Sometimes it is very difficult to detect the site of bile duct injury, as associated disruption of liver parenchyma and haemor‐

Management of bile duct injury is further complicated by small calibre and thin wall of the bile duct. Bile duct injury ranges from small laceration to tissue loss or complete disruption. Primary repair may be attempted when there is small laceration and no tissue loss. When there is a tissue loss or the laceration is larger than 25% to 50% of the diameter of the duct, the treatment option is a Roux-en-Y choledocho-jejunostomy [74, 75]. Isolated injury to left or right hepatic duct is even more challenging and should only be managed by experienced hepatobiliary surgeon. If expertise is not available, large bore tube should be kept and pa‐ tient should be transferred to higher centre. If both the ducts are injured, both the ducts should be intubated by separate tubes and brought out. Elective repair should be undertak‐ en once the patient is stable and after adequate assessment of injury by cholangiogram.

The management of injuries of the liver has evolved significantly throughout the last two decades. Non-operative techniques for the management of grade IV–V injuries in stable pa‐ tients have been established, although there is a higher failure rate for these injuries com‐ pared with grade I–III injuries. Because of the progress that has been made in the quality and wide availability of the MDCT scan combined with minimally invasive intervention op‐ tions like angio-embolization, NOM has evolved to be the treatment of choice for hemody‐ namically stable patients. In terms of surgical management there has been a definite move away from major, time-consuming procedures toward conservative surgery and damage control. The preferred surgical technique for inaccessible bleeding within a laceration is rap‐ id finger fracture hepatotomy, Kelly –crush hepatic transection and direct suture or ligation. Prolonged attempts at surgical control and repair should be avoided, and definitive perihe‐ patic packing should be employed at an early stage in the persistently unstable patient or at

tion after the establishment of appropriate drainage is the prudent course.

Injury to the gall bladder is treated either by repair or cholecystectomy.

**7. Injuries to the Bile ducts and gall bladder:**

rhage makes detection a challenging task.

**8. Summary:**

604 Hepatic Surgery

are usually of little consequences and generally close without specific treatment.

Rajan Jagad\* , Ashok Thorat and Wei-Chen Lee

\*Address all correspondence to:

Division of Liver and Transplantation Surgery, Department of General Surgery, Chang-Gung Memorial Hospital at Linkou, Chang-Gung University College of Medicine, Taiwan

#### **References**


[10] Dolich, M. O., Mc Kenney, M. G., Varela, J. E., Compton, R. P., Mc Kenney, K. L., & Cohn, S. M. (2001). ultrasounds for blunt abdominal trauma. *J Trauma*, 50, 108-112.

[25] Cywes, B. S., Rode, H., & Millar, A. J. (1985). Blunt liver trauma in children: nonoper‐

Management of Hepatobiliary Trauma http://dx.doi.org/10.5772/52107 607

[26] Sherman, H. F., Savage, B. A., Jones, L. M., et al. (1994). Nonoperative management

[27] Carrillo, E. H., Spain, D. A., Wohltmann, C. D., et al. (1999). Interventional techni‐ ques are useful adjuncts in nonoperative management of hepatic injuries. *J Trauma*,

[28] Dabbs, D. N., Stein, D. M., & Scalea, T. M. (2009). Major hepatic necrosis: a common complication after angioembolization for treatment of high-grade liver injuries. *J*

[29] Pachter, H. L., Guth, A. A., Hofstetter, S. R., & Spencer, F. C. (1998). Changing pat‐ terns in the management of splenic trauma: the impact of nonoperative management.

[30] Meyer, A. A., Crass, R. A., Lim, R. C., et al. (1985). Selective nonoperative manage‐ ment of blunt liver injury using computed tomography. *Arch Surg*, 120, 550-554.

[31] Velamhaos, G. C., Konstantinos, T., Radan, R., Chan, L., Rhee, P., Tillou, A., & Deme‐ triades, D. (2003). High success with nonoperative management of blunt hepatic

[32] Misselbeck, T. S., Teicher, E. J., Cipolle, M. D., Pasquale, M. D., Shah, K. T., Dangle‐ ben, D. A., & Badellino, M. M. (2009). Hepatic angioembolization in trauma patients:

[33] Yaman, I., Nazli, O., Tugrul, T., et al. (2007). Surgical treatment of hepatic injury: morbidity and mortality analysis of 109 cases. *Hepatogastroenterology*, 54, 1507-1511.

[34] Kozar, R. A., Moore, F. A., Cothren, C. C., Moore, E. E., Sena, M., Bulger, E. M., Mill‐ er, C. C., Eastridge, B., Acheson, E., Brundage, S. I., Tataria, M., Mc Carthy, M., & Holcomb, J. B. (2006). Risk factors for hepatic morbidity following nonoperative

[35] Goldman, R., Zilkoski, M., Mullins, R., Mayberry, J., Deveney, C., & Trunkey, D. (2003). Delayed celiotomy for the treatment of bile leak, compartment syndrome, and other hazards of nonoperative management of blunt liver injury. *Am J Surg*, 185(5),

[36] Dabbs, D. N., Stein, D. M., Philosophe, B., & Scalea, T. M. (2010). Treatment of major hepatic necrosis: lobectomy versus serial debridement. *J Trauma*, 69(3), 562-7.

[37] Hashimoto, 5., Hiramatsu, K., Ido, K., Yosii, H., et al. (1990). Expanding role of emer‐ gency embolization in the management of severe blunt hepatic trauma. *Cardiovasc In‐*

of blunt hepatic injuries: safe at any grade? *J Trauma*, 37, 616-621.

ative management. *J Pediatr Surg*, 20, 14-18.

46, 619-624.

492-7.

*tervent Radiol*, 1, 193-199.

*Trauma*, 66(3), 621-7.

*Ann Surg*, 227, 708-717.

trauma. *Arch Surg*, 138, 475-81.

indications and complications. *J Trauma*, 67, 769-773.

management: multicenter study. *Arch Surg*, 141, 451-8.


[25] Cywes, B. S., Rode, H., & Millar, A. J. (1985). Blunt liver trauma in children: nonoper‐ ative management. *J Pediatr Surg*, 20, 14-18.

[10] Dolich, M. O., Mc Kenney, M. G., Varela, J. E., Compton, R. P., Mc Kenney, K. L., & Cohn, S. M. (2001). ultrasounds for blunt abdominal trauma. *J Trauma*, 50, 108-112.

[11] Richards, J. R., Knopf, N. A., Wang, L., & Mc Gahan, J. P. (2002). Blunt abdominal trauma in children: evaluation with emergency US. *Radiology*, 222, 749-754.

[12] Sirlin, C. B., Brown, M. A., Andrade-Barreto, O. A., et al. (2004). Blunt abdominal trauma: clinical value of negative screening US scans. *Radiology*, 230, 661-668.

[13] Poletti, P. A., Kinkel, K., Vermeulen, B., Irmay, F., Unger, P. F., & Terrier, F. (2003). Blunt abdominal trauma: should US be used to detect both free fluid and organ inju‐

[14] Sirlin, C. B., Casola, G., Brown, M. A., Patel, N., Bendavid, E. J., & Hoyt, D. B. (2001). Patterns of fluid accumulation on screening ultrasonography for blunt abdominal

[15] Stassen, N. A., Lukan, J. K., Carrillo, E. H., et al. (2002). Examination of the role of abdominal computed tomography in the evaluation of victims of trauma with in‐ creased aspartate aminotransferase in the era of focused abdominal sonography for

[16] Jansen, J. O., Yule, S. R., & Loudon, M. A. (2008). Investigation of blunt abdominal

[17] Rozycki, G. S., Ballard, R. B., Feliciano, D. V., et al. (1998). Surgeonperformed ultra‐ sound for the assessment of truncal injuries: lessons learned from 1540 patients. *Ann*

[18] Stengel, D., Bauwens, K., Sehouli, J., et al. (2005). Emergency ultrasound based algo‐ rithms for diagnosing blunt abdominal trauma. *Cochrane Database Syst Rev*

[19] Taourel, P., Vernhet, H., Suau, A., et al. (2007). Vascular emergencies in liver trauma.

[21] Kawahara, N. T., Alster, C., Fujimura, I., Poggetti, R. S., & Birolini, D. (2009). Stand‐ ard examination system for laparoscopy in penetrating abdominal trauma. *J Trauma*,

[22] Israelit, S. H., & Krausz, M. M. (2006). Laparoscopic management of a combat milita‐

[23] Haan, J. M., Bocchicchio, G. V., Kramer, N., et al. (2005). Nonoperative management

[24] Stein, D. M., & Scalea, T. M. (2006). Nonoperative management of spleen and liver

[20] Smith, R.S. (2001). Cavitary endoscopy in trauma. *Scand J Surg.*, 91, 67-71.

ry injury during the Lebanon War in August., *J Trauma*, 108-10.

of blunt splenic injury: a 5-year experience. *J Trauma*, 58, 492-498.

injuries. *J Intensive Care Med*, 21, 296-304.

trauma: comparison with site of injury. *J Ultrasound Med*, 20, 351-357.

ries? *Radiology*, 227, 95-103.

606 Hepatic Surgery

trauma. *Surgery*, 132, 642-646.

trauma. *BMJ*, 336, 938-942.

*Surg*, 228, 557-567.

*Eur J Radiol*, 64, 73-82.

(2):CD004446.

67:589.


[38] Denton, J. R., Moore, E. E., & Coldwell, D. M. (1997). Multimodality treatment for grade 5 hepatic injuries: 'perihepatic packing', arterial embolisation and venous stenting. *J Trauma*, 42, 964-968.

[53] Cue, J. I., Cryer, H. G., Miller, F. B., et al. (1990). Packing and planned re-exploration for hepatic and retroperitoneal haemorrhage: critical refinements of a useful techni‐

Management of Hepatobiliary Trauma http://dx.doi.org/10.5772/52107 609

[54] Nicol, A. J., Hommes, M., Primrose, R., et al. (2007). Packing for control of hemor‐

[56] Moore, F. A., Moore, E. E., & Seagraves, A. (1985). Non-resectional management of

[57] Walt A.J. (1986). Discussion: packing for control of hepatic haemorrhage. *J Trauma*,

[58] Balogh, Z., Mc Kinley, B. A., Cox, C. S., et al. (2003). Abdominal compartment syn‐ drome: the cause or the effect of multiple organ failure? *Shock*, 20, 483-492.

[59] Meldrum, D. R., Moore, F. A., Moore, E. E., et al. (1997). Prospective characterisation and selective management of the abdominal compartment syndrome. *Am J Surg*, 174,

[60] Dellaportas, D., Nastos, C., Psychogiou, V., Tympa, A., et al. (2011). Iatrogenic liver trauma managed with mesh-wrapping and ligation of portal vein branch: A case re‐

[61] Fang, J. F., Chen, R. J., Lin, B. C., et al. (2000). Blunt hepatic injury: minimal interven‐

[62] Duane, T. M., Como, J. J., Bochichio, G. V., et al. (2004). Re-evaluating the manage‐

[63] Jacobson, L. E., Kirton, O. C., & Gomez, G. A. (1992). The use of an absorbable mesh

[64] Poggetti, R. S., & Moore, E. E. (1992). Balloon tamponade for bilobar transfixing hep‐

[65] Khaneja, S. C., Pizzi, W. F., Barie, P. S., et al. (1997). Management of penetrating jux‐ tahepatic inferior vena cava injuries under total vascular exclusion. *J Am Coll Surg*,

[66] Angstadt, J., Jarrell, B., Moritz, M., et al. (1989). Surgical management of severe liver

[67] Aldrete, J. S., Halpern, N. B., Ward, S., & Wright, J. O. (1979). Factors determining the mortality and morbidity in hepatic injuries. Analysis of 108 cases., *Ann Surg*, 189,

[68] Degiannis, E., Levy, R. D., Sa, F. C. S., Velmahos, G. C., Mokoena, T., & Daponte, A. (1995). Gunshot injuries of the liver : The Baragwanath experience. *Surgery I:*,

ment and outcomes of severe blunt liver injury. *J Trauma*, 57, 494-500.

wrap in the management of major liver injuries. *Surgery* 111:455.

trauma: a role for liver transplantation., *J Trauma*, 29, 606-8.

rhage in major liver trauma. *World J Surg*, 31, 569-574.

major hepatic trauma. *Am J Surg*, 150, 725-729.

port. *Int J Surg Case Rep.*, 2(8), 261-263.

atic gunshot wounds., *J Trauma*, 33:694.

tion in the policy of treatment. *J Trauma* 49:722-728.

[55] Krige, J.E.J. (2000). Liver fracture and bleeding. *Br J Surg*, 87, 1615-1616.

que. *J Trauma*, 30, 1007-1013.

26, 741-756.

667-673.

184, 469-474.

466-74.

359-364.


[38] Denton, J. R., Moore, E. E., & Coldwell, D. M. (1997). Multimodality treatment for grade 5 hepatic injuries: 'perihepatic packing', arterial embolisation and venous

[39] Asensio, J. A., Demetriades, D., Chahwan, S., et al. (2000). Approach to the manage‐

[40] Gaarder, C., Naess, P. A., Eken, T., Skaga, N. O., Pillgram-Larsen, J., Klow, N. E., et al. (2007). Liver injuries- improved results with a formal protocol including angiogra‐

[41] Lin, B. C., Wong, Y. C., Lim, K. E., et al. (2010). Management of ongoing arterial hae‐ morrhage after damage control laparotomy: optimal timing and efficacy of transarte‐

[42] Griffen, M., Ochoa, J., & Boulanger, B. R. (2000). A minimally invasive approach to

[43] Malhotra, A. K., Latifi, R., Fabian, T. C., et al. (2003). Multiplicity of solid organ in‐ jury: influence on management and outcomes after blunt abdominal trauma. *J Trau‐*

[44] Stone, H. H., Strom, P. R., & Mullins, R. J. (1983). Management of the major coagul‐

[45] Burch, J. M., Ortiz, V. B., Richardson, R. J., Martin, R. R., Mattox, K. L., & Jordan, G. L. (1992). Abbreviated laparotomy and planned reoperation for critically injured pa‐

[46] Elerding, S. C., Arragon, G. E., & Moore, E. E. (1979). Fatal hepatic hemorrhage after

[47] Rotondo, M. F., Schwab, C. W., Mc Gonigal, M. D., et al. (1993). Damage control': an approach for improved survival in exsanguinating penetrating abdominal injury., *J*

[48] Asensio, J. A., Roldan, G., Petrone, P., et al. (2003). Operative management and out‐ comes in 103 AAST-OIS grades IV and V complex hepatic injuries: trauma surgeons

[49] Hoey, B. A., & Schwab, C. W. (2002). Damage control surgery. *Scand J Surg*, 91,

[50] Parks, R. W., Chrysos, E., & Diamond, T. (1999). Management of liver trauma. *Br J*

[51] Aydin, U., Yazici, P., Zeytunlu, M., & Coker, A. (2008). Is it more dangerous to per‐

[52] Sheridan, R., Driscoll, D., & Felsen, R. (1997). Packing and temporary closure in liver

form inadequate packing?, *World J Emerg Surg*, 3:1.

still need to operate, but angioembolization helps. J Trauma.; , 54, 647-654.

stenting. *J Trauma*, 42, 964-968.

608 Hepatic Surgery

phy., *Injury*, 38, 1075-1083.

*ma*, 54, 925-9.

rial embolisation. *Injury*, 41, 44-9.

tients., *Ann Surg.*, 215, 476-483.

trauma., *Am J Surg*, 138, 883-888.

*Trauma.*, 35, 375-383.

92-103.

*Surg*, 86, 1121-35.

injury. *Injury*, 28, 711-712.

ment of complex hepatic injuries. *J Trauma*, 48, 66-72.

bile peritonitis after blunt liver injury. *Am Surg*, 66, 309-12.

opathy with onset during laparotomy., *Ann Surg.*, 197, 532-535.


[69] Caruso, D. M., Battistella, F. D., Owings, J. T., Lee, S. L., & Samaco, R. C. (1999). Peri‐ hepatic packing of major liver injuries: complications and mortality. *Arch Surg*, 134:958.

**Chapter 26**

**Hepatic Trauma**

http://dx.doi.org/10.5772/52793

the liver by a liver transplant [5].

than 9000 deaths per year.

our approach in the management of liver trauma [14].

**1. Introduction**

Bilal O. Al-Jiffry and Owaid AlMalki

Additional information is available at the end of the chapter

The word liver was derived from the old English word "life'' [1]. Survival without the liver is impossible for more than a few hours except in very unusual circumstances. The liver is the largest intra-abdominal solid organ; with its friable parenchyma, its thin capsule, and its relatively fixed position in relation to the spine, makes it particularly prone to injury. As a result of its larger size and proximity to the ribs, the right hemi-liver is injured more com‐ monly than the left. It's the second most commonly injured organ in abdominal trauma, but damage to the liver is the most common cause of death after abdominal injury [2], [3]. Man‐ agement of Liver Trauma may vary widely from non operative management (NOM) with or without angioembolization to Damage Control Surgery (DCS) [4]. DCS is mainly centered on stopping the bleeding by packing, Pringles, and vascular exclusion to totally replacing

Although blunt liver trauma accounts for 15-20% of abdominal injuries, it is responsible for more than 50% of deaths resulting from blunt abdominal trauma. The mortality rate is higher with blunt abdominal trauma than with penetrating injuries[6]. In Europe, blunt trauma predominates (80-90 per cent of all liver injuries)[6]-[8], while penetrating injuries account for 66 per cent of liver trauma in South Africa [9] and up to 88 per cent in North America [10]-[13]. Unfortunately, we don't have enough data for the Arab coun‐ tries though we are one of the highest countries in motor vehicle accidents with more

As a result of this high mortality rate, emergency surgery was frequently indicated in pa‐ tients with hepatic injury in the past. However, advances in diagnostic imaging, better mon‐ itoring facilities and the introduction of damage control strategy in trauma has influenced

> © 2013 Al-Jiffry and AlMalki; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 Al-Jiffry and Al Malki; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.


### **Chapter 26**

### **Hepatic Trauma**

[69] Caruso, D. M., Battistella, F. D., Owings, J. T., Lee, S. L., & Samaco, R. C. (1999). Peri‐ hepatic packing of major liver injuries: complications and mortality. *Arch Surg*,

[70] Donovan, A. J., Michaelian, M. J., & Yellin, A. E. (1973). Anatomical hepatic lobecto‐

[71] Fabian, T. C., Croce, M. A., Stanford, G. G., et al. (1991). Factors affecting morbidity

[72] Jurkovich, G. J., Hoyt, D. B., Moore, F. A., et al. (1995). Portal triad inuries: a multi-

[73] Sheldon, G. F., Lim, R. C., Yee, E. S., et al. (1985). Management of injuries to the porta

[74] Feliciano, D. V., Bitando, C. V., Burch, J. M., et al. (1985). Management of traumatic

[75] Bade, P. G., Thomson, S. R., Hirshberg, A., et al. (1989). Surgical options in traumatic

injuries to the extrahepatic biliary ducts. *Am J Surg* 150:705.

injury to the extrahepatic biliary tract. *Br J Surg* 76:256.

134:958.

610 Hepatic Surgery

my in trauma to the liver. *Surgery* 73:833.

after liver trauma. *Ann Surg* 213:540.

institutional study: *J trauma* 39:426.

hepatis. *Ann Surg* 202: 539.

Bilal O. Al-Jiffry and Owaid AlMalki

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52793

### **1. Introduction**

The word liver was derived from the old English word "life'' [1]. Survival without the liver is impossible for more than a few hours except in very unusual circumstances. The liver is the largest intra-abdominal solid organ; with its friable parenchyma, its thin capsule, and its relatively fixed position in relation to the spine, makes it particularly prone to injury. As a result of its larger size and proximity to the ribs, the right hemi-liver is injured more com‐ monly than the left. It's the second most commonly injured organ in abdominal trauma, but damage to the liver is the most common cause of death after abdominal injury [2], [3]. Man‐ agement of Liver Trauma may vary widely from non operative management (NOM) with or without angioembolization to Damage Control Surgery (DCS) [4]. DCS is mainly centered on stopping the bleeding by packing, Pringles, and vascular exclusion to totally replacing the liver by a liver transplant [5].

Although blunt liver trauma accounts for 15-20% of abdominal injuries, it is responsible for more than 50% of deaths resulting from blunt abdominal trauma. The mortality rate is higher with blunt abdominal trauma than with penetrating injuries[6]. In Europe, blunt trauma predominates (80-90 per cent of all liver injuries)[6]-[8], while penetrating injuries account for 66 per cent of liver trauma in South Africa [9] and up to 88 per cent in North America [10]-[13]. Unfortunately, we don't have enough data for the Arab coun‐ tries though we are one of the highest countries in motor vehicle accidents with more than 9000 deaths per year.

As a result of this high mortality rate, emergency surgery was frequently indicated in pa‐ tients with hepatic injury in the past. However, advances in diagnostic imaging, better mon‐ itoring facilities and the introduction of damage control strategy in trauma has influenced our approach in the management of liver trauma [14].

© 2013 Al-Jiffry and AlMalki; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 Al-Jiffry and Al Malki; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **2. Anatomy**

In this part we will describe the anatomy of the liver and its attachments in relation to what is needed in liver trauma, to achieve good mobilization with haemorrhage control to reach the first stage of damage control.

**2.2. Gross anatomy**

section (segment 4). **•** Visceral Surface:

bare area of the liver.

**•** Posterior Surface (fig 2):

**Figure 2.** Visceral surface of the Liver

The liver has three surfaces [16]

This is covered with peritoneum to act as a sheath around the liver. In the midline the falci‐ form ligament is attached and divides the liver into the right and left anatomical liver, or better descried it runs between the left lateral section (segment 2 and 3) and the left medial

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The sharp inferior border of the liver joins the diaphragmatic surface with the visceral sur‐ face of the liver. The main structures are lined in an H shaped. The cross part is made of the porta hepatis (hilum of the liver). The right limb is made of the inferior vena cava. The left limb is made of the contiuity of the fissures for the ligamentum teres anteriorly and the liga‐ mentum venosum posteriorly. On the left side lies the caudate lobe and on the right lies the

**•** Diaphragmatic Surface:

#### **2.1. Surface anatomy**

It's important to know the location of the liver and its surface anatomy to be able to choose the best incision, to determine if it is involved in a penetrating trauma, and to think of it when you have a chest trauma especially on the right lower chest. When viewed from the front (fig. 1), the normal liver surface markings are [15]:

Upper margin: at the xiphisternal joint arching upwords on both sides. On the left it runs for 7-8cm from the mid-line. On the right, it reaches the fifth rib.

Right boarder: it curves downword from the seventh to the eleventh rib in the mid axillary line.

Inferior boarder: along a line that joins both right lower and upper left points.

**Figure 1.** Surface anatomy of the liver

#### **2.2. Gross anatomy**

**2. Anatomy**

612 Hepatic Surgery

the first stage of damage control.

**Figure 1.** Surface anatomy of the liver

front (fig. 1), the normal liver surface markings are [15]:

7-8cm from the mid-line. On the right, it reaches the fifth rib.

**2.1. Surface anatomy**

line.

In this part we will describe the anatomy of the liver and its attachments in relation to what is needed in liver trauma, to achieve good mobilization with haemorrhage control to reach

It's important to know the location of the liver and its surface anatomy to be able to choose the best incision, to determine if it is involved in a penetrating trauma, and to think of it when you have a chest trauma especially on the right lower chest. When viewed from the

Upper margin: at the xiphisternal joint arching upwords on both sides. On the left it runs for

Right boarder: it curves downword from the seventh to the eleventh rib in the mid axillary

Inferior boarder: along a line that joins both right lower and upper left points.

The liver has three surfaces [16]

**•** Diaphragmatic Surface:

This is covered with peritoneum to act as a sheath around the liver. In the midline the falci‐ form ligament is attached and divides the liver into the right and left anatomical liver, or better descried it runs between the left lateral section (segment 2 and 3) and the left medial section (segment 4).

**•** Visceral Surface:

The sharp inferior border of the liver joins the diaphragmatic surface with the visceral sur‐ face of the liver. The main structures are lined in an H shaped. The cross part is made of the porta hepatis (hilum of the liver). The right limb is made of the inferior vena cava. The left limb is made of the contiuity of the fissures for the ligamentum teres anteriorly and the liga‐ mentum venosum posteriorly. On the left side lies the caudate lobe and on the right lies the bare area of the liver.

**•** Posterior Surface (fig 2):

**Figure 2.** Visceral surface of the Liver

The IVC runs in the centre of the posterior surface. A firous band called the ligamentum venae cavae (hepato-caval ligament) covers part of the IVC posteriorly. The rest of the poste‐ rior surface is made of by the ligaments (the left and right triangular ligaments, and the cor‐ onary ligament) which attach the liver to the diaphragm.

#### **2.3. Ligaments of the liver**

The falciform ligament consists of two closely layers of peritoneum. The ligamentum teres runs on its free edge with a small paraumbilical vein. On the right it forms the upper layer of the coronary ligament, witch continues inferiorly to form the right triangular ligament, then to the lower coronary ligament. On the left, the falciform ligament forms the anterior layer of the left triangular ligament. (fig 3 &4)

**Figure 4.** Posterior surface of the liver and its ligaments

The caudate lobe is the dorsal portion of the liver lying posteriorly and embracing the retro‐ hepatic IVC in a semi circumferential fashion. It lies between the IVC posteriorly, the portal triad inferiorly and the hepatic veins superiorly. There is a series of short hepatic veins which drains directly from the caudate lobe to the retrohepatic IVC. Thus it is surrounded

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Glisson's capsule which covers the liver extends into the liver at the hilus and covers the portal triad were it is called the Glisson's sheath. With relation to liver trauma it is impor‐ tant to know only the extrahepatic portion of the Glissonian pedicle which is called the hep‐ atodudenal ligament. This is very important when a Pringle manoeuvre is needed. It usually composed of connective tissue and peritoneum up to the hepatic hilum. They surround the portal vein posteriorly, the hepatic artery anteriorly and to the left, and the common bile

by important structures that can be involved in liver trauma 17 (Fig 5).

**2.4. Caudate lobe**

**2.5. The glissonian sheath**

duct anteriorly and to the right (fig 6) 18.

**Figure 3.** Diaphragmatic surface of the liver and its ligaments

**Figure 4.** Posterior surface of the liver and its ligaments

#### **2.4. Caudate lobe**

The IVC runs in the centre of the posterior surface. A firous band called the ligamentum venae cavae (hepato-caval ligament) covers part of the IVC posteriorly. The rest of the poste‐ rior surface is made of by the ligaments (the left and right triangular ligaments, and the cor‐

The falciform ligament consists of two closely layers of peritoneum. The ligamentum teres runs on its free edge with a small paraumbilical vein. On the right it forms the upper layer of the coronary ligament, witch continues inferiorly to form the right triangular ligament, then to the lower coronary ligament. On the left, the falciform ligament forms the anterior

onary ligament) which attach the liver to the diaphragm.

layer of the left triangular ligament. (fig 3 &4)

**Figure 3.** Diaphragmatic surface of the liver and its ligaments

**2.3. Ligaments of the liver**

614 Hepatic Surgery

The caudate lobe is the dorsal portion of the liver lying posteriorly and embracing the retro‐ hepatic IVC in a semi circumferential fashion. It lies between the IVC posteriorly, the portal triad inferiorly and the hepatic veins superiorly. There is a series of short hepatic veins which drains directly from the caudate lobe to the retrohepatic IVC. Thus it is surrounded by important structures that can be involved in liver trauma 17 (Fig 5).

#### **2.5. The glissonian sheath**

Glisson's capsule which covers the liver extends into the liver at the hilus and covers the portal triad were it is called the Glisson's sheath. With relation to liver trauma it is impor‐ tant to know only the extrahepatic portion of the Glissonian pedicle which is called the hep‐ atodudenal ligament. This is very important when a Pringle manoeuvre is needed. It usually composed of connective tissue and peritoneum up to the hepatic hilum. They surround the portal vein posteriorly, the hepatic artery anteriorly and to the left, and the common bile duct anteriorly and to the right (fig 6) 18.

**2.6. Retrohepatic IVC and its branches (fig 7)**

which drain the right and left diaphragm.

**Figure 7.** The abdominal inferior vena cava and its suprarenal branches

are prone to injury.

right liver [19].

In relation to liver trauma we can divide the retrohepatic IVC into four parts:

multiple variations that can exist and its knowledge is important in liver surgery.

The suprahepatic group; which is composed of both right and left inferior phrenic veins

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The hepatic veins; which are composed of the right, middle and left hepatic vein. There are

The retrohepatic group; which is composed of short veins that drain part of the right hemiliver and the caudate lobe directly into the IVC. These veins are short and very fragile and

Lastly, the infrahepatic group; which consists mainly of both the right and left adrenal veins. These veins are frequently injured in trauma and if not considered during mobilizing the

**Figure 5.** The caudate lobe: front view

**Figure 6.** Structures within the glissonian sheath

#### **2.6. Retrohepatic IVC and its branches (fig 7)**

**Figure 5.** The caudate lobe: front view

616 Hepatic Surgery

**Figure 6.** Structures within the glissonian sheath

In relation to liver trauma we can divide the retrohepatic IVC into four parts:

The suprahepatic group; which is composed of both right and left inferior phrenic veins which drain the right and left diaphragm.

The hepatic veins; which are composed of the right, middle and left hepatic vein. There are multiple variations that can exist and its knowledge is important in liver surgery.

The retrohepatic group; which is composed of short veins that drain part of the right hemiliver and the caudate lobe directly into the IVC. These veins are short and very fragile and are prone to injury.

Lastly, the infrahepatic group; which consists mainly of both the right and left adrenal veins. These veins are frequently injured in trauma and if not considered during mobilizing the right liver [19].

**Figure 7.** The abdominal inferior vena cava and its suprarenal branches

#### **3. Mechanism**

Penetrating and blunt trauma are the two principal mechanisms for liver trauma. Motor ve‐ hicle accidents account for the majority of blunt trauma, whereas knife and gunshot wounds constitute the major cause of penetrating injuries

have sustained a stab wound to the abdomen and are haemodynamically unstable. If the pa‐ tient is stable and a liver injury is suspected, imaging studies should be performed [21]-[23] However, haemodynamically stable patients with suspected liver injury can be investigated

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Ultrasonography (FAST) has gained increased acceptance, particularly in the emergency de‐ partment, for the rapid evaluation of patients with blunt or penetrating abdominal trauma [24]-[29]. It is cheap, portable and noninvasive, compare to peritoneal lavage and it does not use radiation or iodinated contrast media [30]-[32]. Its sensitivity for the presence of intraabdominal fluid in patients with trauma ranges from 75 to 93.8% and the specificity from 97 to 100% [24]-[25]. However, some pitfalls remain in abdominal ultrasonography. Injuries at the dome or lateral segments of the liver can easily by missed with ultrasound, especially in the presence of ileus or if the patient cannot cooperate because of pain. Hepatic laceration or hematomas are usually difficult to distinguish, especially in the acute phase, because they

Kalogeropoulu and colleagues (2006) demonstrated the usefulness of contrast enhanced ul‐ trasonography in penetrating liver trauma [35]. It increases the sensitivity and the specificity of ultrasound in evaluation of abdominal trauma not only in detection of free peritoneal flu‐ id but also in the visualization of the parenchymal lacerations. The use of contrast in addi‐ tion to the conventional ultrasound scanning does not significantly prolong the examination time, compared with a contrast enhanced CT scan. Furthermore repeated doses of the con‐ trast can be injected to scan the rest of the solid abdominal organs such spleen and kidneys if a more complex trauma is suspected [35]. However, US is operator dependent, were you may not find an expert ultrasonographer in the middle of the night. In addition, US contrast

Computed tomography (CT) is the gold standard investigation for the evaluation of a stable patient with suspected liver trauma [36]-[39]. CT has high sensitivity and specificity for de‐ tecting liver injuries which increase as the time between injury and scanning increases, evi‐ dently because haematomas and lacerations become better defined [40]. Contrast-enhanced CT, is accurate in localizing the site and extent of liver and associated injuries, providing vi‐ tal information for treatment in patients. CT without intravenous contrast enhancement is of limited value in hepatic trauma, but it can be useful in identifying or following up a hemo‐

CT scanning allows reasonably accurate grading of liver injuries and provides crude quanti‐ tation of the degree of hemoperitoneum. CT scanning is mandatory for patients with blunt trauma whose liver injury is to be managed nonoperatively. CT has also been useful for de‐ tecting missile tracts in penetrating trauma patients. Such information is imperative for sur‐ geons who want to attempt nonoperative management of penetrating wounds [44]-[47]

Although CT is very useful in the evaluation of stable patients with abdominal trauma, most authors agree that unstable patients, with either blunt or penetrating trauma, are unlikely to benefit from this investigation because of the valuable time that it requires [44] (Fig 8)

at this stage to define the nature of the injury.

are isoechoic to the normal liver [33]-[34].

is not wildly available in every casualty.

peritoneum [41]-[43].

Two types of blunt liver trauma have been described: deceleration (shearing) injuries occur in motor vehicle accidents and in falls from a height where there is movement of the liver in its relatively fixed position, thereby producing a laceration of its relatively thin capsule and parenchyma at the sites of attachment to the diaphragm[13].

The other type of liver injuries is crush injury. Crush injuries follow direct trauma to the ab‐ domen over the liver area. Decelerating injuries typically create lacerations between the right posterior section (segments 6 and 7) and the right anterior section (segments 5 and 8), which can extend to involve major vessels. Crush injuries can lead to damage to the central portion of the liver (segment 4, 5 and 8) and also may cause bleeding from the caudate lobe (segment 1)[12]-[13]. Blunt trauma can cause parenchymal hepatic injury with intact Glis‐ son's capsule, leading to an intraparenchymal or subcapsular haematoma[12]-[13].

Penetrating injuries are usually associated with gunshot or stab wounds, with the former usually resulting in more tissue damage due to the cavitation effect as the bullet traverses the liver substance [13]-[20]. These injuries usually require surgery more often than blunt in‐ juries when the liver is involved.

#### **4. Diagnosis**

Signs and symptoms of hepatic injuries are related to the amount of blood loss, peritoneal irritation, right upper quadrant tenderness, and guarding. Rebound abdominal tenderness is common but nonspecific. Occasionally, patients with blunt abdominal trauma do well ini‐ tially, but they subsequently develop a liver abscess, presumably due to unrecognized liver damage. These patients present with signs and symptoms of deep-seated infection [21]. Pa‐ tients may present with severe peritonism due to bile peritonitis resulting from bile leaks. Signs of blood loss, such as shock, hypotension, and a falling hematocrit level, may domi‐ nate the picture [21] As resuscitation proceeds, a detailed physical examination is carried out. Most conventional texts emphasis the need for a careful history and physical examina‐ tion of the abdomen. While this is undoubted importance, it is extremely difficult to assess the abdomen in the trauma situation as the history may not be available and all the existing physical signs are misleading. Fresh blood is not a peritoneal irritant [22]. The mechanism of injury is critically important in assessing the potential for abdominal injury. This informa‐ tion may be obtained from the patient, relatives, police or emergency care personnel [22]

Following initial assessment, a conscious patient, who is haemodynamically unstable fol‐ lowing blunt trauma and has generalized peritonism, should undergo immediate laparoto‐ my without further investigation [13]. Urgent laparotomy is also indicated in patients who have sustained a stab wound to the abdomen and are haemodynamically unstable. If the pa‐ tient is stable and a liver injury is suspected, imaging studies should be performed [21]-[23] However, haemodynamically stable patients with suspected liver injury can be investigated at this stage to define the nature of the injury.

**3. Mechanism**

618 Hepatic Surgery

constitute the major cause of penetrating injuries

juries when the liver is involved.

**4. Diagnosis**

parenchyma at the sites of attachment to the diaphragm[13].

Penetrating and blunt trauma are the two principal mechanisms for liver trauma. Motor ve‐ hicle accidents account for the majority of blunt trauma, whereas knife and gunshot wounds

Two types of blunt liver trauma have been described: deceleration (shearing) injuries occur in motor vehicle accidents and in falls from a height where there is movement of the liver in its relatively fixed position, thereby producing a laceration of its relatively thin capsule and

The other type of liver injuries is crush injury. Crush injuries follow direct trauma to the ab‐ domen over the liver area. Decelerating injuries typically create lacerations between the right posterior section (segments 6 and 7) and the right anterior section (segments 5 and 8), which can extend to involve major vessels. Crush injuries can lead to damage to the central portion of the liver (segment 4, 5 and 8) and also may cause bleeding from the caudate lobe (segment 1)[12]-[13]. Blunt trauma can cause parenchymal hepatic injury with intact Glis‐

Penetrating injuries are usually associated with gunshot or stab wounds, with the former usually resulting in more tissue damage due to the cavitation effect as the bullet traverses the liver substance [13]-[20]. These injuries usually require surgery more often than blunt in‐

Signs and symptoms of hepatic injuries are related to the amount of blood loss, peritoneal irritation, right upper quadrant tenderness, and guarding. Rebound abdominal tenderness is common but nonspecific. Occasionally, patients with blunt abdominal trauma do well ini‐ tially, but they subsequently develop a liver abscess, presumably due to unrecognized liver damage. These patients present with signs and symptoms of deep-seated infection [21]. Pa‐ tients may present with severe peritonism due to bile peritonitis resulting from bile leaks. Signs of blood loss, such as shock, hypotension, and a falling hematocrit level, may domi‐ nate the picture [21] As resuscitation proceeds, a detailed physical examination is carried out. Most conventional texts emphasis the need for a careful history and physical examina‐ tion of the abdomen. While this is undoubted importance, it is extremely difficult to assess the abdomen in the trauma situation as the history may not be available and all the existing physical signs are misleading. Fresh blood is not a peritoneal irritant [22]. The mechanism of injury is critically important in assessing the potential for abdominal injury. This informa‐ tion may be obtained from the patient, relatives, police or emergency care personnel [22]

Following initial assessment, a conscious patient, who is haemodynamically unstable fol‐ lowing blunt trauma and has generalized peritonism, should undergo immediate laparoto‐ my without further investigation [13]. Urgent laparotomy is also indicated in patients who

son's capsule, leading to an intraparenchymal or subcapsular haematoma[12]-[13].

Ultrasonography (FAST) has gained increased acceptance, particularly in the emergency de‐ partment, for the rapid evaluation of patients with blunt or penetrating abdominal trauma [24]-[29]. It is cheap, portable and noninvasive, compare to peritoneal lavage and it does not use radiation or iodinated contrast media [30]-[32]. Its sensitivity for the presence of intraabdominal fluid in patients with trauma ranges from 75 to 93.8% and the specificity from 97 to 100% [24]-[25]. However, some pitfalls remain in abdominal ultrasonography. Injuries at the dome or lateral segments of the liver can easily by missed with ultrasound, especially in the presence of ileus or if the patient cannot cooperate because of pain. Hepatic laceration or hematomas are usually difficult to distinguish, especially in the acute phase, because they are isoechoic to the normal liver [33]-[34].

Kalogeropoulu and colleagues (2006) demonstrated the usefulness of contrast enhanced ul‐ trasonography in penetrating liver trauma [35]. It increases the sensitivity and the specificity of ultrasound in evaluation of abdominal trauma not only in detection of free peritoneal flu‐ id but also in the visualization of the parenchymal lacerations. The use of contrast in addi‐ tion to the conventional ultrasound scanning does not significantly prolong the examination time, compared with a contrast enhanced CT scan. Furthermore repeated doses of the con‐ trast can be injected to scan the rest of the solid abdominal organs such spleen and kidneys if a more complex trauma is suspected [35]. However, US is operator dependent, were you may not find an expert ultrasonographer in the middle of the night. In addition, US contrast is not wildly available in every casualty.

Computed tomography (CT) is the gold standard investigation for the evaluation of a stable patient with suspected liver trauma [36]-[39]. CT has high sensitivity and specificity for de‐ tecting liver injuries which increase as the time between injury and scanning increases, evi‐ dently because haematomas and lacerations become better defined [40]. Contrast-enhanced CT, is accurate in localizing the site and extent of liver and associated injuries, providing vi‐ tal information for treatment in patients. CT without intravenous contrast enhancement is of limited value in hepatic trauma, but it can be useful in identifying or following up a hemo‐ peritoneum [41]-[43].

CT scanning allows reasonably accurate grading of liver injuries and provides crude quanti‐ tation of the degree of hemoperitoneum. CT scanning is mandatory for patients with blunt trauma whose liver injury is to be managed nonoperatively. CT has also been useful for de‐ tecting missile tracts in penetrating trauma patients. Such information is imperative for sur‐ geons who want to attempt nonoperative management of penetrating wounds [44]-[47]

Although CT is very useful in the evaluation of stable patients with abdominal trauma, most authors agree that unstable patients, with either blunt or penetrating trauma, are unlikely to benefit from this investigation because of the valuable time that it requires [44] (Fig 8)

nificant advantage over CT scanning for routine evaluation of acute abdominal trauma. Ex‐ perience is insufficient for assessing the value of the special circumstances mentioned above. Sufficient experience has not been gained in the use of MRI to establish false-positive and

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Angiography has no role in the evaluation of unstable patients. However, if the patient is stable, cross-sectional imaging may provide sufficient detail to treat the patient conserva‐ tively. A dynamic angiographic study may demonstrate the site of active bleeding. This when combined with angiographic embolization, especially in high-grade liver injury is of significant value and may be the only treatment required [51]-[52]. Although angiography is useful in selected patients, both false-positive and false-negative results occur in patients

Endoscopic retrograde cholangiopancreatography (ERCP) may help in the delineation of the biliary tree in patient with liver trauma, and stents may be used to treat biliary Leaks [53]-

Diagnostic laparoscopy has been used successfully in patients with abdominal trauma [55]- [58], and laparoscopic fibrin glue in managing liver injuries has also been reported [60].The benefits of laparoscopic assessment include reducing negative and non-therapeutic laparot‐ omy rates, patient morbidity rates, hospital stay and treatment costs [56]-[57]. Raphael and colleagues(1999) reviewed 37 studies with more than 1,900 trauma patients (including those with liver trauma), and laparoscopy was analyzed as a screening, diagnostic, or therapeutic

false-negative findings [6]

with hepatic trauma [6]

**Figure 9.** ERCP demonstrating a bile leak from the main right duct

[54] (Fig 9).

**Figure 8.** A CT demonstrating a grade 4 liver injury that was treated surgically

False-positive errors in the diagnosis of liver injury with CT scans may occur as a result of beam-hardening artifacts from adjacent ribs, which can mimic contusion or hematoma. An air-contrast level within the stomach in a patient with a nasogastric tube can produce streak artifacts throughout the left lateral section of the liver; these may mimic intrahepatic lacera‐ tions and/or hemorrhage. The nature of these artifacts can be confirmed if the patient is scanned in a decubitus position [48].

False-negative findings may occur in the setting of a fatty liver only when contrast-enhanced CT scan are obtained. On these images, the enhanced fatty liver may become isoattenuating relative to the laceration or hematoma. In this situation, a nonenhanced CT scan may pro‐ vide useful information regarding hepatic injury. Focal fatty infiltration may also mimic hepatic hematoma, laceration, or infarction. Hepatic lacerations with a branching pattern can mimic unopacified portal or hepatic veins or dilated intrahepatic bile ducts. Careful evaluation of all branching intrahepatic structures is important and the diagnosis is made with serial images to differentiate the various structures [48]-[49]

MRI has a limited role in the evaluation of blunt abdominal trauma, and it has no advantage over CT scanning. Theoretically, MRI can be used in follow-up monitoring of patients with blunt abdominal trauma, and MRI may be useful in young and pregnant women with ab‐ dominal trauma in whom the radiation dose is a concern [6], [50].

MRCP has been used in the assessment of pancreatic duct trauma and its sequelae, and it can be used to image biliary trauma. Another potential use of MRI is in patients with renal failure and in patients who are allergic to radiographic contrast medium. MRI offers no sig‐ nificant advantage over CT scanning for routine evaluation of acute abdominal trauma. Ex‐ perience is insufficient for assessing the value of the special circumstances mentioned above. Sufficient experience has not been gained in the use of MRI to establish false-positive and false-negative findings [6]

Angiography has no role in the evaluation of unstable patients. However, if the patient is stable, cross-sectional imaging may provide sufficient detail to treat the patient conserva‐ tively. A dynamic angiographic study may demonstrate the site of active bleeding. This when combined with angiographic embolization, especially in high-grade liver injury is of significant value and may be the only treatment required [51]-[52]. Although angiography is useful in selected patients, both false-positive and false-negative results occur in patients with hepatic trauma [6]

Endoscopic retrograde cholangiopancreatography (ERCP) may help in the delineation of the biliary tree in patient with liver trauma, and stents may be used to treat biliary Leaks [53]- [54] (Fig 9).

**Figure 9.** ERCP demonstrating a bile leak from the main right duct

**Figure 8.** A CT demonstrating a grade 4 liver injury that was treated surgically

with serial images to differentiate the various structures [48]-[49]

dominal trauma in whom the radiation dose is a concern [6], [50].

scanned in a decubitus position [48].

620 Hepatic Surgery

False-positive errors in the diagnosis of liver injury with CT scans may occur as a result of beam-hardening artifacts from adjacent ribs, which can mimic contusion or hematoma. An air-contrast level within the stomach in a patient with a nasogastric tube can produce streak artifacts throughout the left lateral section of the liver; these may mimic intrahepatic lacera‐ tions and/or hemorrhage. The nature of these artifacts can be confirmed if the patient is

False-negative findings may occur in the setting of a fatty liver only when contrast-enhanced CT scan are obtained. On these images, the enhanced fatty liver may become isoattenuating relative to the laceration or hematoma. In this situation, a nonenhanced CT scan may pro‐ vide useful information regarding hepatic injury. Focal fatty infiltration may also mimic hepatic hematoma, laceration, or infarction. Hepatic lacerations with a branching pattern can mimic unopacified portal or hepatic veins or dilated intrahepatic bile ducts. Careful evaluation of all branching intrahepatic structures is important and the diagnosis is made

MRI has a limited role in the evaluation of blunt abdominal trauma, and it has no advantage over CT scanning. Theoretically, MRI can be used in follow-up monitoring of patients with blunt abdominal trauma, and MRI may be useful in young and pregnant women with ab‐

MRCP has been used in the assessment of pancreatic duct trauma and its sequelae, and it can be used to image biliary trauma. Another potential use of MRI is in patients with renal failure and in patients who are allergic to radiographic contrast medium. MRI offers no sig‐ Diagnostic laparoscopy has been used successfully in patients with abdominal trauma [55]- [58], and laparoscopic fibrin glue in managing liver injuries has also been reported [60].The benefits of laparoscopic assessment include reducing negative and non-therapeutic laparot‐ omy rates, patient morbidity rates, hospital stay and treatment costs [56]-[57]. Raphael and colleagues(1999) reviewed 37 studies with more than 1,900 trauma patients (including those with liver trauma), and laparoscopy was analyzed as a screening, diagnostic, or therapeutic tool. They came out with the conclusion that "Laparoscopy has been applied safely and ef‐ fectively as a screening tool in stable patients with acute trauma. Because of the large num‐ ber of missed injuries when used as a diagnostic tool, its value in this context is limited. Laparoscopy has been reported infrequently as a therapeutic tool in selected patients, and its use in this context requires further study.[61].

#### **5. Classification of liver injury**

Liver trauma ranges from a minor capsular tear, with or without parenchymal injury, to ex‐ tensive disruption involving both hemi liver with associated hepatic vein or vena caval in‐ jury. In 1989, the Organ Injury Scaling Committee of the American Association for the Surgery of Trauma produced a Hepatic Injury Scale [62] by which hepatic injuries are de‐ scribed in most major trauma centers (Table 1). Grade I or II injuries are considered minor; they represent 80-90 per cent of all cases and usually require minimal or no operative treat‐ ment [1], [63]. Grade III-V injuries are generally considered severe and often require surgical intervention, while grade VI injuries are regarded as incompatible with survival.

**Figure 10.** Grade 1 liver injury treated non surgically

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**Figure 11.** Grade 2 liver injury


**Table 1.** Classification of liver injury

**Figure 10.** Grade 1 liver injury treated non surgically

tool. They came out with the conclusion that "Laparoscopy has been applied safely and ef‐ fectively as a screening tool in stable patients with acute trauma. Because of the large num‐ ber of missed injuries when used as a diagnostic tool, its value in this context is limited. Laparoscopy has been reported infrequently as a therapeutic tool in selected patients, and

Liver trauma ranges from a minor capsular tear, with or without parenchymal injury, to ex‐ tensive disruption involving both hemi liver with associated hepatic vein or vena caval in‐ jury. In 1989, the Organ Injury Scaling Committee of the American Association for the Surgery of Trauma produced a Hepatic Injury Scale [62] by which hepatic injuries are de‐ scribed in most major trauma centers (Table 1). Grade I or II injuries are considered minor; they represent 80-90 per cent of all cases and usually require minimal or no operative treat‐ ment [1], [63]. Grade III-V injuries are generally considered severe and often require surgical

> Subcapsular, < 10% surface area Capsular tear, < 1cm parenchymal depth

Subcapsular, 10% to 50% surface area Capsular tear, 1-3cm parenchymal depth and < 10cm in length

> Subcapsular, > 50% surface area or expanding Intraparenchymal hematoma > 2cm or expanding Capsular tear, >3cm parenchymal depth

Ruptured intraparenchymal hematoma with active bleeding Parenchymal disruption involving 25-50% of hepatic lobe

Parenchymal disruption involving >50% of hepatic lobe Juxtahepatic venous injuries

intervention, while grade VI injuries are regarded as incompatible with survival.

**Grade Type of Injury Description of injury**

VI Vascular Hepatic avulsion

its use in this context requires further study.[61].

**5. Classification of liver injury**

622 Hepatic Surgery

I (fig 10) Hematoma

II (Fig 11) Hematoma

III (Fig 12) Hematoma

IV (Fig 13) Hematoma

V Laceration

**Table 1.** Classification of liver injury

Laceration

Laceration

Laceration

Laceration

Vascular

**Figure 11.** Grade 2 liver injury

**6. Management**

**6.1. Non operative**

had not occurred.

**•** haemodynamic stability

**•** absence of peritoneal sign

**•** Facility of immediate surgery

**•** Absence of other organ injuries

more feasible and more successful.

**•** Availability of CT

**•** Monitor in ICU

for NOM:

the primacy of operative treatment [64].

The countercurrent argument was that nonoperative treatment (NOM) was associated with virtually a 100% mortality rate, so all patients with suspected or diagnosed liver injuries must have an operation. Improved mortality rates during and after World War II assured

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Three observations prompted the move towards nonoperative treatment. First, the practice of nonoperative treatment was initially advocated for splenic injuries and then extended to the liver. The success in children led to attempts of nonoperative treatment in adults [65]- [66] Second, the high rate of nontherapeutic operations in many patients with blunt hepatic injuries was not in patients' best interest. Third, the advent of CT scanning greatly facilitated both diagnosis and grading of injuries and gave some reassurance that the intestinal injuries

There has been several reports started since 1985, were Trunkey *etal* [67], defined the criteria

These criteria has become more and more less strict, were multiple reports are trending more to NOM [3]. There is no time limit for NOM, continues monitoring is the only key to take the patient to the operating room [68]. Other reports even went to the extreme as if the patient had risk factors by the injury severity score (ISS) [69] and all patients should be treat‐ ed first by NOM regardless of their trauma [70]. However, all of these reports mentioned that this is possible with the addition of angiography and embolization that made the NOM

The success rate of nonoperative treatment has been remarkably high. The necessity for op‐ erations for ongoing hemorrhage has been reported to be from 5% to 15%. There remains a

Nonoperative treatment of abdominal stab wounds has been practiced successfully in nu‐ merous centers and is on the rise. NOM of gunshot wounds has been more controversial, however, many reports are calling to add these group of patients to the NOM group [76]- [79] Demetriades and colleagues(2006) reported 152 patients with penetrating solid organ injuries. 28.4% of all liver injuries were successfully managed nonoperatively [80]. However,

concern over missed bowel injuries that have been reported from 1% to 3%.[71]-[75].

**Figure 12.** Grade 3 liver injury that was treated non surgically

**Figure 13.** Grade 4 liver injury that was treated non surgically

#### **6. Management**

#### **6.1. Non operative**

The countercurrent argument was that nonoperative treatment (NOM) was associated with virtually a 100% mortality rate, so all patients with suspected or diagnosed liver injuries must have an operation. Improved mortality rates during and after World War II assured the primacy of operative treatment [64].

Three observations prompted the move towards nonoperative treatment. First, the practice of nonoperative treatment was initially advocated for splenic injuries and then extended to the liver. The success in children led to attempts of nonoperative treatment in adults [65]- [66] Second, the high rate of nontherapeutic operations in many patients with blunt hepatic injuries was not in patients' best interest. Third, the advent of CT scanning greatly facilitated both diagnosis and grading of injuries and gave some reassurance that the intestinal injuries had not occurred.

There has been several reports started since 1985, were Trunkey *etal* [67], defined the criteria for NOM:


**Figure 12.** Grade 3 liver injury that was treated non surgically

624 Hepatic Surgery

**Figure 13.** Grade 4 liver injury that was treated non surgically


These criteria has become more and more less strict, were multiple reports are trending more to NOM [3]. There is no time limit for NOM, continues monitoring is the only key to take the patient to the operating room [68]. Other reports even went to the extreme as if the patient had risk factors by the injury severity score (ISS) [69] and all patients should be treat‐ ed first by NOM regardless of their trauma [70]. However, all of these reports mentioned that this is possible with the addition of angiography and embolization that made the NOM more feasible and more successful.

The success rate of nonoperative treatment has been remarkably high. The necessity for op‐ erations for ongoing hemorrhage has been reported to be from 5% to 15%. There remains a concern over missed bowel injuries that have been reported from 1% to 3%.[71]-[75].

Nonoperative treatment of abdominal stab wounds has been practiced successfully in nu‐ merous centers and is on the rise. NOM of gunshot wounds has been more controversial, however, many reports are calling to add these group of patients to the NOM group [76]- [79] Demetriades and colleagues(2006) reported 152 patients with penetrating solid organ injuries. 28.4% of all liver injuries were successfully managed nonoperatively [80]. However, in the last few years NOM has emerged a huge mile stone. Appropriately selected patients with liver gunshot injuries deemed feasible, safe, and effective, regardless of the liver injury severity [77]. However, they all mentioned that CT scan was mandatory before adopting the NOM. Another report stated that regardless of the grade of liver trauma, NOM is safe and effective in appropriately selected patients with liver gun shoot injuries treated in centers with suitable facilities [79].

DCS includes perihepatic packing and partial abdominal closure or Bogota bag. Usually an average of six laparotomy pads can be packed to get the tamponade effect between the liver and the abdominal wall. The timing of re-exploration is controversy but usually 12-24 hours

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**Figure 15.** Packs as it was done in the first DCS were the bleeding stopped, fingers demonstrating the liver laceration

Even 30 years after the resurrection of packing as a treatment alternative, it remains an im‐ portant part of the armamentarium of surgeons in managing difficult hepatic injuries. It is always better to have a patient with packs to come and deal with on another day, than try‐ ing to stop the bleeding with no success, especially if the surgeon has limited experience, which usually happens in the first operation. As many hospitals have a general surgeon on-

If a major liver injury is encountered, initial control of bleeding can be achieved with tempo‐ rary tamponade of the right upper quadrant using packs, portal triad occlusion (Pringle ma‐ noeuvre) (Fig 16a &b), bimanual compression of the liver or even manual compression of the abdominal aorta above the coeliac trunk [83]-[84]. Attempts to evaluate the liver injury before adequate resuscitation may result in further blood loss and worsening hypotension.

call with limited liver or trauma experience.

is safe time for re-exploration were the patients condition permits (fig 15).

#### **6.2. Operative**

#### *6.2.1. Damage control surgery*

As the first intention when taking the patient to the operating room is to do damage control surgery (DCS). This usually implies saving the patient's life and stopping the bleeding. This will make the patient more stable and in a better physiologically and hemodynamically state to be able to have the definitive treatment.

Skin preparation should allow for extension of a midline abdominal incision to a median sternotomy or right thoracotomy, if necessary, for adequate exposure of posterior liver injuries [81]-[82]. If the indication for surgery is an obvious penetrating through-andthrough liver injury, or the patient failed the NOM and is clear liver injury only a bilat‐ eral subcostal incision is a useful alternative and has been adopted by some to have better liver exposure (fig 14).

**Figure 14.** Mobilization of the right hemi-liver to achieve excellent exposure of the injury

DCS includes perihepatic packing and partial abdominal closure or Bogota bag. Usually an average of six laparotomy pads can be packed to get the tamponade effect between the liver and the abdominal wall. The timing of re-exploration is controversy but usually 12-24 hours is safe time for re-exploration were the patients condition permits (fig 15).

in the last few years NOM has emerged a huge mile stone. Appropriately selected patients with liver gunshot injuries deemed feasible, safe, and effective, regardless of the liver injury severity [77]. However, they all mentioned that CT scan was mandatory before adopting the NOM. Another report stated that regardless of the grade of liver trauma, NOM is safe and effective in appropriately selected patients with liver gun shoot injuries treated in centers

As the first intention when taking the patient to the operating room is to do damage control surgery (DCS). This usually implies saving the patient's life and stopping the bleeding. This will make the patient more stable and in a better physiologically and hemodynamically state

Skin preparation should allow for extension of a midline abdominal incision to a median sternotomy or right thoracotomy, if necessary, for adequate exposure of posterior liver injuries [81]-[82]. If the indication for surgery is an obvious penetrating through-andthrough liver injury, or the patient failed the NOM and is clear liver injury only a bilat‐ eral subcostal incision is a useful alternative and has been adopted by some to have

**Figure 14.** Mobilization of the right hemi-liver to achieve excellent exposure of the injury

with suitable facilities [79].

*6.2.1. Damage control surgery*

better liver exposure (fig 14).

to be able to have the definitive treatment.

**6.2. Operative**

626 Hepatic Surgery

**Figure 15.** Packs as it was done in the first DCS were the bleeding stopped, fingers demonstrating the liver laceration

Even 30 years after the resurrection of packing as a treatment alternative, it remains an im‐ portant part of the armamentarium of surgeons in managing difficult hepatic injuries. It is always better to have a patient with packs to come and deal with on another day, than try‐ ing to stop the bleeding with no success, especially if the surgeon has limited experience, which usually happens in the first operation. As many hospitals have a general surgeon oncall with limited liver or trauma experience.

If a major liver injury is encountered, initial control of bleeding can be achieved with tempo‐ rary tamponade of the right upper quadrant using packs, portal triad occlusion (Pringle ma‐ noeuvre) (Fig 16a &b), bimanual compression of the liver or even manual compression of the abdominal aorta above the coeliac trunk [83]-[84]. Attempts to evaluate the liver injury before adequate resuscitation may result in further blood loss and worsening hypotension.

Digital compression of the portal triad (Pringle manoeuvre) can be used diagnostically and compression can be maintained with an atraumatic vascular clamp if haemorrhage decreas‐ es [85]. The clamp should be occluded only to the degree necessary to compress the blood vessels in order not to injure the common bile duct. If haemorrhage is unaffected by portal triad occlusion, major vena cava injury or atypical vascular anatomy should be suspected 86-87 Although the permitted occlusion time of the portal triad is controversial, most au‐ thors now agree that clamping of the hepatic pedicle for up to 1h is well tolerated with no

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After initial intraoperative resuscitation, the liver must be mobilized adequately to allow a thorough examination of the damaged area, unless the injury is already accessible through the incision [81,84,89] The liver is mobilized by dividing the falciform, triangular and coro‐ nary ligaments, and by placing abdominal packs posteriorly to maintain this position [90]. This manoeuvre allows the surgeon to determine the nature and severity of the injury and to decide on the necessary surgical technique. Care should be taken to avoid impairing venous return, by either excessive lifting and/or rotation of the mobilized liver, or excessive packing

There are several tricks to stop the bleeding other than the one mentioned before, however we advise that most of these should be done by experienced surgeons in a stable patient or if the patient is still bleeding after trying the previous methods mentioned. Several specific modalities began to be used more often to treat arterial bleeding. Hepatorrhaphy was used with increased frequency. When the arterial bleeding occurred deep within the hepatic pa‐ renchyma, a tractotomy was advocated to expose and suture ligate the arterial flow. But

control of deep arterial bleeding was often technically difficult to accomplish.[91]-[93]

In response to futile attempts to directly suture ligate arterial bleeding, Dr Aaron's group performed ligation of the hepatic artery.[94] Initially performed at the Louisville General Hospital to control arterial hemorrhage from a ruptured hepatic adenoma, Mays found this technique useful to control arterial bleeding in trauma patients. A literal explosion in its use occurred in Louisville, and surgeons there proposed it to prevent rebleeding.[95]- [96] A high rate of infection led to reconsideration of its use, and it was subsequently used less frequently [103], although it remained an operation that could occasionally be

Major venous bleeding was recognized as a major source of mortality, particularly in pa‐ tients who had been in high-speed motor vehicle crashes. The nearly uniform lethality of retrohepatic vena caval injuries with attempt at direct repair led to the development of the atriocaval shunt. This technique, developed by Schrock and associates, [99] theoreti‐ cally bypassed the caval injury and allowed direct suture repair of the cava itself and main hepatic veins. The operation required opening the chest to expose the atria. This bi‐ cavitary exposure accelerated hypothermia and coagulopathy in many patients. Conse‐ quently, the mortality rate remained high, but the concept of direct repair of this deadly

adverse effects on liver function [81],[88]

causing caval compression [90].

life-saving.97-98

injury was very important.

**Figure 16.** a. Tape inserted around the portal triad. b. Pringles manouver were the clamp is gently applied to occlude the portal triad

Digital compression of the portal triad (Pringle manoeuvre) can be used diagnostically and compression can be maintained with an atraumatic vascular clamp if haemorrhage decreas‐ es [85]. The clamp should be occluded only to the degree necessary to compress the blood vessels in order not to injure the common bile duct. If haemorrhage is unaffected by portal triad occlusion, major vena cava injury or atypical vascular anatomy should be suspected 86-87 Although the permitted occlusion time of the portal triad is controversial, most au‐ thors now agree that clamping of the hepatic pedicle for up to 1h is well tolerated with no adverse effects on liver function [81],[88]

(a)

628 Hepatic Surgery

(b)

the portal triad

**Figure 16.** a. Tape inserted around the portal triad. b. Pringles manouver were the clamp is gently applied to occlude

After initial intraoperative resuscitation, the liver must be mobilized adequately to allow a thorough examination of the damaged area, unless the injury is already accessible through the incision [81,84,89] The liver is mobilized by dividing the falciform, triangular and coro‐ nary ligaments, and by placing abdominal packs posteriorly to maintain this position [90]. This manoeuvre allows the surgeon to determine the nature and severity of the injury and to decide on the necessary surgical technique. Care should be taken to avoid impairing venous return, by either excessive lifting and/or rotation of the mobilized liver, or excessive packing causing caval compression [90].

There are several tricks to stop the bleeding other than the one mentioned before, however we advise that most of these should be done by experienced surgeons in a stable patient or if the patient is still bleeding after trying the previous methods mentioned. Several specific modalities began to be used more often to treat arterial bleeding. Hepatorrhaphy was used with increased frequency. When the arterial bleeding occurred deep within the hepatic pa‐ renchyma, a tractotomy was advocated to expose and suture ligate the arterial flow. But control of deep arterial bleeding was often technically difficult to accomplish.[91]-[93]

In response to futile attempts to directly suture ligate arterial bleeding, Dr Aaron's group performed ligation of the hepatic artery.[94] Initially performed at the Louisville General Hospital to control arterial hemorrhage from a ruptured hepatic adenoma, Mays found this technique useful to control arterial bleeding in trauma patients. A literal explosion in its use occurred in Louisville, and surgeons there proposed it to prevent rebleeding.[95]- [96] A high rate of infection led to reconsideration of its use, and it was subsequently used less frequently [103], although it remained an operation that could occasionally be life-saving.97-98

Major venous bleeding was recognized as a major source of mortality, particularly in pa‐ tients who had been in high-speed motor vehicle crashes. The nearly uniform lethality of retrohepatic vena caval injuries with attempt at direct repair led to the development of the atriocaval shunt. This technique, developed by Schrock and associates, [99] theoreti‐ cally bypassed the caval injury and allowed direct suture repair of the cava itself and main hepatic veins. The operation required opening the chest to expose the atria. This bi‐ cavitary exposure accelerated hypothermia and coagulopathy in many patients. Conse‐ quently, the mortality rate remained high, but the concept of direct repair of this deadly injury was very important.

Both previously mentioned bleeding problems often were treated initially with temporary inflow occlusion by clamping the portal triad. The concept of inflow occlusion actually pre‐ dated Pringle, [85] but his work published in 1908 was rediscovered and popularized in the 1960s after rarely being mentioned in the literature for more than 50 years.

Diffuse bleeding from damaged or devitalized liver increasingly required surgical treat‐ ment. Reports on civilian liver injuries from the 1950s generally cautioned against debride‐ ment of damaged liver for fear it would worsen preexisting hemorrhage. Absorbable gauze packing and drainage were mostly used for this problem. As the forces of injury increased, other techniques were required.

Resectioned debridement was increasingly used. There was a brief flurry of activity with use of major anatomic resections, but the high mortality rate of this procedure led to discontinu‐ ing its use in most centers.[100]-[101] The omental pedicle described for liver injury in 1910 and mentioned occasionally through the years was reintroduced by Stone and Lamb[102] and gained widespread popularity.

In summary; as a general surgeon facing a major hepatic injury in the middle of the night think of NOM and try not to rush to the operating room unless clearly indicated. However, if you were forced to the operating room do the minimal to stop the bleeding (DCS). If major procedure is required, the decision must be made early in the operation were technical /clin‐ ical expertise and speed are critical. Plan definitive surgeries in a stable patient were optimal condition ably.

**Figure 17.** Full mobilization in a second look operation to stop the bleeding and to do definitive surgery.

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**Figure 18.** Liver necrosis following embolization with NOM for bleeding. The patient was treated by right hemi hepa‐

tectomy because the necrosis could not be drained radiologically.

#### *6.2.2. Definitive surgery*

This is usually carried out in a stable patient by an experienced surgeon at a second stage to deal with a certain problem (Fig 17). One of the commonest problem is bile leak and collec‐ tion with an incidence of 6-20 %. This is usually after the patient recovered, were they devel‐ op an intra-abdominal collection that is best treated by a radiological applied drain. Then it can be investigated by MRCP or ERCP. The MRCP is non invasive, however with the collec‐ tion it can have very little input. ERCP is advocated by some to be much better were the leak is identified and can be treated by sphinctrotomy and a stent [104] with very high success rate [105]. However, some of these patients fail and require surgical ligation of the leak which is much easier when the location is identified pre-operatively and a stent is in place to increase the success rate.

Another reason to go to the operating room is liver necrosis and abscess formation that occurs when bleeding stoops and demarcation of the live is obvious. Liver necrosis might increase with attempts to stop the bleeding with angioembolization in NOM or by arterial ligation and packing in DCS.The best option will be to drain the abscess radio‐ logically were this might be sufficient. However, if not we advise operative drainage and an anatomical liver resection to maintain adequate live tissue and maintain a good vas‐ cular supply. This should be carried out by an experienced liver surgeon to get the best result (Fig 18).

Both previously mentioned bleeding problems often were treated initially with temporary inflow occlusion by clamping the portal triad. The concept of inflow occlusion actually pre‐ dated Pringle, [85] but his work published in 1908 was rediscovered and popularized in the

Diffuse bleeding from damaged or devitalized liver increasingly required surgical treat‐ ment. Reports on civilian liver injuries from the 1950s generally cautioned against debride‐ ment of damaged liver for fear it would worsen preexisting hemorrhage. Absorbable gauze packing and drainage were mostly used for this problem. As the forces of injury increased,

Resectioned debridement was increasingly used. There was a brief flurry of activity with use of major anatomic resections, but the high mortality rate of this procedure led to discontinu‐ ing its use in most centers.[100]-[101] The omental pedicle described for liver injury in 1910 and mentioned occasionally through the years was reintroduced by Stone and Lamb[102]

In summary; as a general surgeon facing a major hepatic injury in the middle of the night think of NOM and try not to rush to the operating room unless clearly indicated. However, if you were forced to the operating room do the minimal to stop the bleeding (DCS). If major procedure is required, the decision must be made early in the operation were technical /clin‐ ical expertise and speed are critical. Plan definitive surgeries in a stable patient were optimal

This is usually carried out in a stable patient by an experienced surgeon at a second stage to deal with a certain problem (Fig 17). One of the commonest problem is bile leak and collec‐ tion with an incidence of 6-20 %. This is usually after the patient recovered, were they devel‐ op an intra-abdominal collection that is best treated by a radiological applied drain. Then it can be investigated by MRCP or ERCP. The MRCP is non invasive, however with the collec‐ tion it can have very little input. ERCP is advocated by some to be much better were the leak is identified and can be treated by sphinctrotomy and a stent [104] with very high success rate [105]. However, some of these patients fail and require surgical ligation of the leak which is much easier when the location is identified pre-operatively and a stent is in place to

Another reason to go to the operating room is liver necrosis and abscess formation that occurs when bleeding stoops and demarcation of the live is obvious. Liver necrosis might increase with attempts to stop the bleeding with angioembolization in NOM or by arterial ligation and packing in DCS.The best option will be to drain the abscess radio‐ logically were this might be sufficient. However, if not we advise operative drainage and an anatomical liver resection to maintain adequate live tissue and maintain a good vas‐ cular supply. This should be carried out by an experienced liver surgeon to get the best

1960s after rarely being mentioned in the literature for more than 50 years.

other techniques were required.

and gained widespread popularity.

condition ably.

630 Hepatic Surgery

*6.2.2. Definitive surgery*

increase the success rate.

result (Fig 18).

**Figure 17.** Full mobilization in a second look operation to stop the bleeding and to do definitive surgery.

**Figure 18.** Liver necrosis following embolization with NOM for bleeding. The patient was treated by right hemi hepa‐ tectomy because the necrosis could not be drained radiologically.

Liver resection might be necessary with reported frequency of 2% to 5% in most series, with an overall mortality of 17.8% and morbidity around 30%.[106-108] (Fig 19).

(a)

(b)

failed NOM, drain left in place.

**Figure 20.** a. Failed NOM showing the bleeding from the liver dome. b. Same patient with grade 4 liver injury that

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633

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**Figure 19.** Liver trauma which was treated with a right posterior sectionectomy (seg 6&7)

Liver transplantation has been reported in the literature as an extreme intervention in cases of severe and complicated hepatic trauma. The main indications for liver transplant in such cases were uncontrollable bleeding and postoperative hepatic insufficiency. Liver transplant for trauma is a rare condition with 20 cases described in the literature [109]. Esquivel *et al.* first reported the use of liver transplantation in two patients with progressive hepatic failure and uncontrollable bleeding. [110]. The transplant decision is difficult because usual criteria are not validated, liver's potential recovery is difficult to evaluate and sepsis and head inju‐ ries often associated, complicating the decision because of their own prognosis. [111].

#### **7. Complications**

#### **7.1. Non operative**

The most common complication of NOM is failure, ending with the patient in the operating room. This is even more serious, because the patient most of the time is in a worse state than what he was and bleeding (the leading cause) is still ongoing. This also is more profound if it occurs in the middle of the night or with a surgeon of limited liver expertise. It should be borne in mind that this most common complication usually arises as a result of inappropri‐ ate selection of a patient for conservative management [23]. The failure rate ranges from 6-10% [68, 112] especially when it was combined with arterial emobolization, however, the incidence of liver necrosis was higher [113] (Fig 20a &b).

Liver resection might be necessary with reported frequency of 2% to 5% in most series, with

an overall mortality of 17.8% and morbidity around 30%.[106-108] (Fig 19).

**Figure 19.** Liver trauma which was treated with a right posterior sectionectomy (seg 6&7)

incidence of liver necrosis was higher [113] (Fig 20a &b).

**7. Complications**

632 Hepatic Surgery

**7.1. Non operative**

Liver transplantation has been reported in the literature as an extreme intervention in cases of severe and complicated hepatic trauma. The main indications for liver transplant in such cases were uncontrollable bleeding and postoperative hepatic insufficiency. Liver transplant for trauma is a rare condition with 20 cases described in the literature [109]. Esquivel *et al.* first reported the use of liver transplantation in two patients with progressive hepatic failure and uncontrollable bleeding. [110]. The transplant decision is difficult because usual criteria are not validated, liver's potential recovery is difficult to evaluate and sepsis and head inju‐

ries often associated, complicating the decision because of their own prognosis. [111].

The most common complication of NOM is failure, ending with the patient in the operating room. This is even more serious, because the patient most of the time is in a worse state than what he was and bleeding (the leading cause) is still ongoing. This also is more profound if it occurs in the middle of the night or with a surgeon of limited liver expertise. It should be borne in mind that this most common complication usually arises as a result of inappropri‐ ate selection of a patient for conservative management [23]. The failure rate ranges from 6-10% [68, 112] especially when it was combined with arterial emobolization, however, the

**Figure 20.** a. Failed NOM showing the bleeding from the liver dome. b. Same patient with grade 4 liver injury that failed NOM, drain left in place.

Complications can arise from injuries that have not been recognized at the time of initial presentation or /and become apparent after initial delay. Associated injuries seem to be the most important factors predisposing to postoperative problems [114]-[117].

**8. Outcome**

lent regeneration capability (Fig 21).

**Figure 21.** Liver regeneration post resection of the right liver

cent)[10-11].

multiple organ failure [131].

The mortality rate from liver trauma has fallen from 66 per cent in World War I, to 27 per cent in World War II, to current levels of 10-15 per cent [8],[10],[12],[128]-[129]. Better knowl‐ edge of liver pathophysiology and anatomy, and enhanced resuscitation, anaesthesia and in‐ tensive care, have contributed to this improvement. Schweizer et al,(1993) compared outcome to grade of injury. The overall mortality was 12% [9], specially with the livers excel‐

Hepatic Trauma

635

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The mechanism of injury has an important bearing on mortality rate with blunt trauma car‐ rying a higher mortality rate (10-30 per cent)[130]. than penetrating liver trauma (0-10 per

While most early deaths in patients with liver trauma seem to be due to uncontrolled hae‐ morrhage and associated injuries, most late deaths result from head injuries and sepsis with

In a recent multicenter study, hepatic complications developed in 5% (13 of 264) of patients with grade 3 injuries, 22% (36 of 166) of patients with grade 4 injuries, and 52% (12 of 23) of patients with grade 5 injuries. Univariate analysis revealed 24-hour crystalloid, total and first 24-hour packed red blood cells, fresh frozen plasma, platelet, and cryoprecipitate re‐ quirements and liver injury grade to be significant, but only liver injury grade and 24-hour transfusion requirement predicted complications by multivariable analysis. They came out with the Conclusion that NOM of high-grade liver injuries is associated with significant morbidity and correlates with grade of liver injury. Screening patients with transfusion re‐ quirements and high-grade injuries may result in earlier diagnosis and treatment of hepaticrelated complications [118]. We have discussed in the previous section the management of each of these complications as a part of the operative management to liver trauma.

#### **7.2. Operative**

Rebleeding in the postoperative period is a challenging problem. Delayed haemorrhage is the most common complication of the non-operative management of hepatic injuries and is the usual indication for a delayed operation [119]. Coagulopathy, inadequate initial surgical repair and missed retrohepatic venous injury may result in further haemorrhage. Confirmed coagulation defects should be corrected as rapidly as possible with fresh frozen plasma and platelet transfusions.

Some authors recommend reoperation after transfusion of 10 units of blood in 24 h [120], however the limit of 6 units in the first 12 h seems to be more reasonable [121]-[122]. In cases with slow rebleeding when the limit of 6 units has not been exceeded, embolization of the bleeding vessels may be helpful [122]. Multiple bleeding vessels is usually the cause of fail‐ ure because the vascular lesions distal to the area of embolization with rich collateral circu‐ lation, or bleeding from the portal or hepatic veins [123]-[125]

Late complications like sepsis, bile leak and liver failure occur at a later stage. Intra-abdomi‐ nal sepsis in the postoperative period occurs in approximately 7-12 per cent of patients 126 Predisposing factors include the presence of shock and increased transfusion requirements, increased severity of liver injury, associated injuries such as small bowel or colonic perfora‐ tion, the use of perihepatic packs, superficial suturing of deep lacerations with intrahepatic haematoma formation, and the presence of devitalized parenchyma. Adequate initial surgi‐ cal management in an effort to reduce transfusion requirements, with debridement of all de‐ vitalized tissue and early removal of perihepatic packs, has been recommended to reduce the incidence of septic complications [81],.

Arteriovenous fistula is not an uncommon complication with an incidence of less than 3%. It can manifest after liver injury as an arterioportal fistula that can result in portal hypaerten‐ sion and is usually treated by embolization [127].

#### **8. Outcome**

Complications can arise from injuries that have not been recognized at the time of initial presentation or /and become apparent after initial delay. Associated injuries seem to be the

In a recent multicenter study, hepatic complications developed in 5% (13 of 264) of patients with grade 3 injuries, 22% (36 of 166) of patients with grade 4 injuries, and 52% (12 of 23) of patients with grade 5 injuries. Univariate analysis revealed 24-hour crystalloid, total and first 24-hour packed red blood cells, fresh frozen plasma, platelet, and cryoprecipitate re‐ quirements and liver injury grade to be significant, but only liver injury grade and 24-hour transfusion requirement predicted complications by multivariable analysis. They came out with the Conclusion that NOM of high-grade liver injuries is associated with significant morbidity and correlates with grade of liver injury. Screening patients with transfusion re‐ quirements and high-grade injuries may result in earlier diagnosis and treatment of hepaticrelated complications [118]. We have discussed in the previous section the management of

most important factors predisposing to postoperative problems [114]-[117].

each of these complications as a part of the operative management to liver trauma.

Rebleeding in the postoperative period is a challenging problem. Delayed haemorrhage is the most common complication of the non-operative management of hepatic injuries and is the usual indication for a delayed operation [119]. Coagulopathy, inadequate initial surgical repair and missed retrohepatic venous injury may result in further haemorrhage. Confirmed coagulation defects should be corrected as rapidly as possible with fresh frozen plasma and

Some authors recommend reoperation after transfusion of 10 units of blood in 24 h [120], however the limit of 6 units in the first 12 h seems to be more reasonable [121]-[122]. In cases with slow rebleeding when the limit of 6 units has not been exceeded, embolization of the bleeding vessels may be helpful [122]. Multiple bleeding vessels is usually the cause of fail‐ ure because the vascular lesions distal to the area of embolization with rich collateral circu‐

Late complications like sepsis, bile leak and liver failure occur at a later stage. Intra-abdomi‐ nal sepsis in the postoperative period occurs in approximately 7-12 per cent of patients 126 Predisposing factors include the presence of shock and increased transfusion requirements, increased severity of liver injury, associated injuries such as small bowel or colonic perfora‐ tion, the use of perihepatic packs, superficial suturing of deep lacerations with intrahepatic haematoma formation, and the presence of devitalized parenchyma. Adequate initial surgi‐ cal management in an effort to reduce transfusion requirements, with debridement of all de‐ vitalized tissue and early removal of perihepatic packs, has been recommended to reduce

Arteriovenous fistula is not an uncommon complication with an incidence of less than 3%. It can manifest after liver injury as an arterioportal fistula that can result in portal hypaerten‐

lation, or bleeding from the portal or hepatic veins [123]-[125]

the incidence of septic complications [81],.

sion and is usually treated by embolization [127].

**7.2. Operative**

634 Hepatic Surgery

platelet transfusions.

The mortality rate from liver trauma has fallen from 66 per cent in World War I, to 27 per cent in World War II, to current levels of 10-15 per cent [8],[10],[12],[128]-[129]. Better knowl‐ edge of liver pathophysiology and anatomy, and enhanced resuscitation, anaesthesia and in‐ tensive care, have contributed to this improvement. Schweizer et al,(1993) compared outcome to grade of injury. The overall mortality was 12% [9], specially with the livers excel‐ lent regeneration capability (Fig 21).

**Figure 21.** Liver regeneration post resection of the right liver

The mechanism of injury has an important bearing on mortality rate with blunt trauma car‐ rying a higher mortality rate (10-30 per cent)[130]. than penetrating liver trauma (0-10 per cent)[10-11].

While most early deaths in patients with liver trauma seem to be due to uncontrolled hae‐ morrhage and associated injuries, most late deaths result from head injuries and sepsis with multiple organ failure [131].

#### **Author details**

Bilal O. Al-Jiffry1,2 and Owaid AlMalki1

1 Surgery, Taif University, Taif, Saudi Arabia

2 Surgery, AlHada Military Hospital, Taif, Saudi Arabia

#### **References**

[1] Wachtel T. Critical care concepts in the management of abdominal trauma. Crit Care Nurs Q. 1994;17(2):34-50.

[13] Park RW, Chrysos E, Diamond T, Management of liver trauma. Br J Surg

Hepatic Trauma

637

http://dx.doi.org/10.5772/52793

[14] Parray FQ, Wani ML, Malik AA, Thakur N, Wani RA, Naqash SH, Chowdri NA, Wa‐ ni KA, Bijli AH, Irshad I, Nayeem-Ul-Hassan. Evaluating a conservative approach to managing liver injuries in Kashmir, India. J Emerg Trauma Shock. 2011 Oct;4(4):483-7

[15] Liver resection and liver transplantation: the anatomy of the liver and associated structures. Jamieson Glyn, Launois B. In: The Anatomy of General Surgical Opera‐ tion, Ed. Jamieson GG. Elsevier Churchill Livingstone, Edinburgh 2nd Ed. 2006.

[17] Peng SY. Isolated caudate lobe resection. In: Hepatocellular Carcinoma, Ed. Law WY,

[18] Kawarada Y, Das BC, Taoka H. Anatomy of the hepatic hilar area: the plate system.

[19] Scheuerlein H, Kockerling F. The anatomy of the liver. In: liver surgery, Operative techniques and Avoidance of Complications. J.A. Barth, Heidelberg.2001, pp 9-38.

[20] Sherlock DJ, Bismuth H. Secondary surgery for liver trauma. Br J Surg 1991; 78:

[21] Arrillo EH, Wohltmann C, Evolution in the treatment of complex blunt liver injuries.

[22] Paterson-Brown, Core topics in general and emergency surgery; third edition 2005.

[24] . Bain IM, Kirby RM, Tiwary P, et al. Survey of abdominal ultrasound and diagnostic peritoneal lavage for suspected intra-abdominal injury following blunt trauma. In‐

[25] Bode PJ, Edwards MJR, Kruit MC, van Vugt AB. Sonography in a clinical algorithm for early evaluation of 1671 patients with blunt abdominal trauma. Am J Radiol.

[26] Kimura A, Otsuka T. Emergency center ultrasonography in the evaluation of hemo‐

[27] Hoffmann R, Nerlich M, Muggia-Sullam M, Pohlemann T, Wippermann B, Regel G et al. Blunt abdominal trauma in cases of multiple trauma evaluated by ultrasonogra‐

[28] Pachter HL, Feliciano DV. Complex hepatic injuries. Surg Clin North Am 1996; 76:

phy: a prospective analysis of 291 patients. J Trauma 1992; 32: 452-8.

peritoneum: a prospective study. J Trauma 1991; 31: 20-3.

[23] Garden, hepatobiliary and pancreatic surgery; third edition 2003. Elsevier 331-347

[16] Gray`s anatomy of the human body, twentieth edition, Philadelphia , 2000.

world Scientific Singapore2008. Chapter 26, pp 465-489

Journal of HBP surgery 2000; 7: 580-586.

Curr Probl Surg 2,001 Jan; 38(1): 1-60.

1999;86:1121-35.

Chapter2, pp 8-23

1313-17.

Elsevier 239-257

jury. 1999;29:65–71.

1999;172:905–911.

763-82.


[13] Park RW, Chrysos E, Diamond T, Management of liver trauma. Br J Surg 1999;86:1121-35.

**Author details**

636 Hepatic Surgery

**References**

Bilal O. Al-Jiffry1,2 and Owaid AlMalki1

Nurs Q. 1994;17(2):34-50.

Acta 1989; 55: 597-612.

1997; 35: 10-15.

438-45.

1433-8.

iotomy. Ann Surg 1984; 199: 467-74.

plant center experience. Am Surg. 2012 Jan;78(1):20-5

Bauchtrauma. Unfallchirurgie 1982; 85: 524-8.

traumatic liver injuries. Br J Surg 1993; 80: 86-8.

[6] A. Nawaz Khan H. Vadeyar Liver Trauma emedicine September 2005

1 Surgery, Taif University, Taif, Saudi Arabia

2 Surgery, AlHada Military Hospital, Taif, Saudi Arabia

[1] Wachtel T. Critical care concepts in the management of abdominal trauma. Crit Care

[3] Cox EF. Blunt abdominal trauma. A five 5-year analysis of 870 patients requiring cel‐

[4] Clemente N, Di Saverio S, Giorgini E, Biscardi A, Villani S, Senatore G, Filicori F, An‐ tonacci N, Baldoni F, Tugnoli G. Management and outcome of 308 cases of liver trau‐ ma in Bologna Trauma Center in 10 years. Ann Ital Chir. 2011 Sep-Oct;82(5):351-9 [5] Li Petri S, Gruttadauria S, Pagano D, Echeverri GJ, Di Francesco F, Cintorino D, Spa‐ da M, Gridelli B. Surgical management of complex liver trauma: a single liver trans‐

[7] Matsch T, Begquist D, Hedelin M, Findblack B. Leberverletzungen nachstumpfem

[8] Schweizer W, Tanner S, Baer HU, Huber A, Berchtold R, Blumgart LH. Diagnostik und Therapie von Leberverletzungen beim polytraumatisierten Patienten. Helv Chir

[9] Schweizer W, Tanner S, Baer HU, Lerut J, Huber A, Gertsch P et al. Management of

[10] Krige JE, Bornman PC, Terblanche J. Liver trauma in 446 patients. South Afr J Surg

[11] Feliciano DV, Mattox KL, Jordan GL Jr, Burch JM, Bitando CG, Cruse PA. Manage‐ ment of 1000 consecutive cases of hepatic trauma (1979-1984). Ann Surg 1986; 204:

[12] Cogbill TH, Moore EE, Jurkovich GJ, Feliciano DV, Morris JA, Mucha P. Severe hep‐ atic trauma: a multi-center experience with 1335 liver injuries. J Trauma 1988; 28:

[2] Feliciano DV. Surgery for liver trauma. Surg Clin North Am 1989; 69: 273-84.


[29] Carrillo EH, Platz A, Miller FB, Richardson JD, Polk HC Jr. Non-operative manage‐ ment of blunt hepatic trauma. Br J Surg 1998; 85: 461-8.

[44] Meredith JW, Trunkey DD. CT scanning in acute abdominal injuries. Surg Clin North

Hepatic Trauma

639

http://dx.doi.org/10.5772/52793

[45] Federle MP, Jeffrey RB. Hemoperitoneum studied by computed tomography. Radiol‐

[46] Federle MP, Goldberg HI, Kaiser JA, et al.. Evaluation of abdominal trauma by com‐

[47] Toombs BD, Lester RC, Ben-Menachem Y, et al.. Computed tomography in blunt

[48] McGehee M, Kier R, Cohn SM, McCarthy SM: Comparison of MRI with postcontrast CT for the evaluation of acute abdominal trauma. J Comput Assist Tomogr 1993

[49] Shuman WP. CT of blunt abdominal trauma in adults. Radiology 1997; 205: 297-306.

[50] Vock P, MRI. In: Blumgart LH (ed.) Surgery of the liver and biliary tract, 2nd edn. Ed‐

[51] Poletti PA, Mirvis SE, Shanmuganathan K, et al: CT criteria for management of blunt liver trauma: correlation with angiographic and surgical findings. Radiology 2000

[52] Hagiwara A, Yukioka T, Ohta S et al. non-surgical management of patients with blunt hepatic injury; efficacy of transcatheter arterial embolization. Am J Roentgenol

[53] Carrillo EH, Spain DA, Wohltmann CD et al.Interventional techniques are useful ad‐ juncts in the non-operative management of hepatic injuries. J Trauma 1999;46:619-22.

[54] Sugimoto K, Asari Y, Sakaguchi T et al. ERCP in the non-surgical management o

[55] Sosa JL, Markley M, Sleeman D, Puente I, Carrillo E. Laparoscopy in abdominal gun‐

[56] Sosa JL, Arrillaga A, Puente I, Sleeman D, Ginzburg E, Martin L. Laparoscopy in 121 consecutive patients with abdominal gunshot wounds. J Trauma 1995; 39: 501-6.

[57] Ditmars ML, Bongard F. Laparoscopy for triage of penetrating trauma: the decision

[58] Hallfeld KK, Trupka AW, Erhard J et al. Emergency laparoscopy for abdominal stab

[59] Chen RJ, Fang JF,Lin BC et al. selective application of laparoscopy and fibrin glue in the failure of non-operative management of blunt hepatic trauma. J Trau‐

Am. 1988;68:255–268.

ogy. 1983;148:187–192.

May-Jun; 17(3): 410-3.

Aug; 216(2): 418-27

1997; 169:1151-6.

ma1998;44:691-5.

puted tomography. Radiology. 1981;138:637–644.

trauma. Rad Clin North Am. 1981;19:17–35.

inburgh: Churchill Livingstone, 1994; pp271-82.

blunt liver trauma. J Trauma 1993;35:192-9.

shot wounds. Surg Laparosc Endosc 1993; 3: 417-19.

to explore. J Laparoendosc Surg 1996; 6: 285-91

wounds. Surg Endosco 1998; 12:907-10.


[44] Meredith JW, Trunkey DD. CT scanning in acute abdominal injuries. Surg Clin North Am. 1988;68:255–268.

[29] Carrillo EH, Platz A, Miller FB, Richardson JD, Polk HC Jr. Non-operative manage‐

[30] Goletti O, Ghiselli G, Lippolis PV, Chiarugi M, Braccini G, Macaluso C et al. The role of ultrasonography in blunt abdominal trauma: results in 250 consecutive cases. J

[31] Rozycki GS, Ochsner MG, Schmidt JA, Frankel HL, Davis TP, Wang D et al. A pro‐ spective study of surgeon-performed ultrasound as the primary adjuvant modality

[32] McKenney MG, Martin L, Lentz K, Lopez C, Sleeman D, Aristide G et al. 1000 con‐ secutive ultrasounds for blunt abdominal trauma. J Trauma 1996; 40: 607-12.

[33] Richards JR, McGahan JP, Pali MJ, Bohnen PA. (1999) Sonographic detection of blunt hepatic trauma: hemoperitoneum and parencymal patterns of injury. J Trauma.

[34] Soto JA, Morales C, Murena F, Sanabria A, Guevara JM, Suarez T. Penetrating stab wounds to the abdomen: use of serial US and contrast enhanced CT in stable pa‐

[35] Hochmuth A, Fleck M, Hauff P, et al. First experience in using a new ultrasound mode and ultrasound contrast agent in the diagnosis of blunt renal trauma: a feasibil‐ ity study in an animal model. [Preliminary report]. Invest Radiol. 2000;35:205–211.

[36] Adam A, Roddie ME. CT of the liver and biliary tract. In:Blumgart LH (ed.) surgery of the liver and the biliary tract, 2nd edn. Edinburgh: Churchil Livingstone, 1994;pp

[37] Safi F, Weiner S, Poch B et al. surgical management of liver rupture. : Chirurgie

[38] Cachecho R, Clas D, Gersin K et al. Evolution in the management of the complex liv‐

[39] Strong RW. The management of blunt liver injuries. Aust NZ J Surg 1999; 69:609-16.

[40] Toombs BD, Sandler CM, Rauschkolb EN, Strax R, Harle TS. Assessment of hepatic injuries with computed tomography. J Comput Assist Tomogr 1982; 6: 72-5.

[41] Carrillo EH, Wohltmann C, Evolution in the treatment of complex blunt liver inju‐

[42] Casillas VJ, Amendola MA, et al, Imaging of nontraumatic hemorrhagic hepatic le‐

[43] Fang JF, Chen RJ, Wong YC, et al: Classification and treatment of pooling of contrast material on computed tomographic scan of blunt hepatic trauma. J Trauma 2000 Dec;

er injury at a level 1 trauma center. J Trauma 1998; 45:79-82.

ries. Curr Probl Surg 2001 Jan; 38(1): 1-60.

sions. Radiographics 2000 Mar-Apr; 20(2): 367-78.

ment of blunt hepatic trauma. Br J Surg 1998; 85: 461-8.

for injured patient assessment. J Trauma 1995; 39: 492-500.

Trauma 1994; 36: 178-81.

638 Hepatic Surgery

1999;47:1092–1097.

243-70.

1999,70:253-8.

49(6): 1083-8.

tients. Radiology. 2001;220:365–371.


[60] Pilcher CJ, Wesolowski MS, Jawad MA. Laparoscopic applications for abdominal trauma injuries. AORN J 1996; 64: 366-75.

[76] Schnüriger B, Talving P, Barbarino R, Barmparas G, Inaba K, Demetriades D. Current practice and the role of the CT in the management of penetrating liver injuries at a

Hepatic Trauma

641

http://dx.doi.org/10.5772/52793

[77] Navsaria PH, Nicol AJ, Krige JE, Edu S. Selective nonoperative management of liver

[78] Velmahos GC, Constantinou C, Tillou A, Brown CV, Salim A, Demetriades D. Ab‐ dominal computed tomographic scan for patients with gunshot wounds to the abdo‐ men selected for nonoperative management. J Trauma. 2005 Nov;59(5):1155-60;

[79] Omoshoro-Jones JA, Nicol AJ, Navsaria PH, Zellweger R, Krige JE, Kahn DH. Selec‐ tive non-operative management of liver gunshot injuries. Br J Surg. 2005 Jul;92(7):

[80] Demetriades,Demetrios, Selective nonoperative management of penetrating abdomi‐

[81] Wilson RH, Moorehead RJ. Hepatic traumaand its management. Injury

[83] Feliciano DV, Pachter HL. Hepatic trauma revisited. Curr Probl Surg 1989; 26:

[84] Canizaro PC, Pessa ME. Management of massive hemorrhage associated with ab‐

[85] Pringle JH. Notes on the arrest of hemorrhage due to trauma. Ann Surg. 1908;48:546–

[86] Moore EE, Edgar J. Poth Lecture. Critical decisions in the management of hepatic

[87] Walt AJ, Bender JS. Injuries of the liver. In: Schwartz SI, Ellis H, eds. Maingot's Ab‐ dominal Operations. Vol. 2. Norwalk, Connecticut: Appleton-Century-Crofts, 1985:

[88] Shuman WP. CT of blunt abdominal trauma in adult . radiology 1997; 205: 297-306.

[89] Smadja C, Traynor O, Blumgart LH. Delayed hepatic resection for major liver injury.

[90] Ochsner MG, Jaffain JH, Golocovsky M. Jones RC. Major hepatic trauma. Surg clin

[91] Lucas CE, Ledgerwood AM. Prospective evaluation of hemostatic techniques for liv‐

[82] Stain SC, Yellin AE, Donovan AJ. Hepatic trauma. Arch Surg 1988; 123: 1251-5.

Level I trauma center. J Emerg Trauma Shock. 2011 Jan;4(1):53-7

gunshot injuries. Ann Surg. 2009 Apr;249(4):653-6

nal solid organ injuries. Ann. Surg 2006;244:pp620-28

dominal trauma. Surg Clin North Am 1990; 70: 621-34.

trauma. Am J Surg 1984; 148: 712-16.

discussion 1160-1

1991;22:439-45.

453-524

566.

1577-90.

Br J Surg 1982; 69: 361-4.

north am 1993;73:337-52.

er injuries. J Trauma. 1976;16:442–451.

890-5


[76] Schnüriger B, Talving P, Barbarino R, Barmparas G, Inaba K, Demetriades D. Current practice and the role of the CT in the management of penetrating liver injuries at a Level I trauma center. J Emerg Trauma Shock. 2011 Jan;4(1):53-7

[60] Pilcher CJ, Wesolowski MS, Jawad MA. Laparoscopic applications for abdominal

[61] Raphael T, Villavicencio , John A.Aucar. Analysis of laparoscopy in trauma. JACS

[62] Moore EE, Shackford SR, Pachter HL, McAninch JW, Browner BD, Champion HR et al. Organ injury scaling: spleen, liver and kidney. J Trauma 1989; 29: 1664-6.

[63] 14 Ochsner MG, Jaffin JH, Golocovsky M, Jones RC. Major hepatic trauma. Surg Clin

[64] David Richardson, changes in the management of injuries to the liver and spleen.

[65] Richie JP, Fonkalsrud EN. Subcapsular hematoma of the liver. Arch Surg.

[66] Karp MP, Cooney DR, Pros GA, et al.. The non-operative management of pediatric

[67] Meyers AA, Crass RA, Lim RA, et al.. Selective non-operative management of blunt

[68] Parks NA, Davis JW, Forman D, Lemaster D. Observation for nonoperative manage‐ ment of blunt liver injuries: how long is long enough? J Trauma. 2011 Mar;70(3):626-9

[69] Norrman G, Tingstedt B, Ekelund M, Andersson R. Non-operative management of blunt liver trauma: feasible and safe also in centres with a low trauma incidence.

[70] Letoublon C, Chen Y, Arvieux C, Voirin D, Morra I, Broux C, Risse O. Delayed celiot‐ omy or laparoscopy as part of the nonoperative management of blunt hepatic trau‐

[71] Marx JA, Moore EE, Jordan RC, et al.. Limitations of computed tomography in the evaluation of acute abdominal trauma—prospective randomized study. J Trauma.

[72] Buckman RF, Piano G, Dunham CM, et al.. Major bowel and diaphragmatic injuries associated with blunt spleen or liver rupture. J Trauma. 1988;28:1317–1321.

[73] Fischer RP, Miller-Crotchet P, Reed RL. The hazards of non-operative management

[74] Kemmeter PR, Hoedema RE, Foote JA, et al. Concomitant blunt enteric injuries with injuries of the liver and spleen (a dilemma for trauma surgeons). Am Surg.

[75] Sherk JP, Oakes DD. Intestinal injuries missed by computed tomography. J Trauma.

of adults with blunt abdominal injury. J Trauma. 1988;28:1445–1449.

liver injury using computed tomography. Arch Surg. 1985;120:550–554

trauma injuries. AORN J 1996; 64: 366-75.

1999;189:pp11-20.

640 Hepatic Surgery

1972;104:781–784

1985;25:933–938.

2001;267:221–226.

1990;30:1–7.

North Am 1993; 73: 337-52.

JACS May 2005 pages 648-669

HPB (Oxford). 2009 Feb;11(1):50-6

ma. World J Surg. 2008 Jun;32(6):1189-93

hepatic trauma. J Pediatr Surg. 1983;18:512–518.


[92] Feliciano DV, Mattox KL, Jordan GL, et al.. The management of 1000 consecutive cas‐ es of hepatic trauma. Ann Surg. 1988;204:438–495.

[110] Liver replacement after massive hepatic trauma. Esquivel CO, Bernardos A, Makow‐

Hepatic Trauma

643

http://dx.doi.org/10.5772/52793

[111] Delis SG, Bakoyiannis A, Selvaggi G, Weppler D, Levi D, Tzakis AG. Liver transplan‐ tation for severe hepatic trauma: experience from a single center. World J Gastroen‐

[112] Clemente N, Di Saverio S, Giorgini E, Biscardi A, Villani S, Senatore G, Filicori F, An‐ tonacci N, Baldoni F, Tugnoli G. Management and outcome of 308 cases of liver trau‐ ma in Bologna Trauma Center in 10 years. Ann Ital Chir. 2011 Sep-Oct;82(5):351-9 [113] Beuran M, Nego I, Ispas AT, Păun S, Runcanu A, Lupu G, Venter D. Nonoperative management of high degree hepatic trauma in the patient with risk factors for fail‐

[114] Fabian TC, Croce MA, Stanford GG, Payne LW, Mangiante EC, Voeller GR et al. Fac‐ tors affecting morbidity following hepatic trauma. A prospective analysis of 482 inju‐

[115] 126 Flint LM, Mays ET, Aaron WS, Fulton RL, Polk HC. Selectivity in the manage‐

[116] Bender JS, Geller ER, Wilson RF. Intra-abdominal sepsis following liver trauma. J

[117] Menegaux F, Langlois P, Chigot JP. Severe blunt trauma of the liver: study of mortal‐

[118] Rosemary A. Kozar, Frederick A. Moore, C. Clay Cothren, ; Risk Factors for Hepatic Morbidity Following Nonoperative Management Multicenter Study Arch Surg.

[119] Carrillo EH, Platz A, Miller FB, Richardson JD, Polk HC Jr. Non-operative manage‐

[120] Cue JI, Cryer HG, Miller FB, Richardson JD, Polk HC Jr. Packing and planned reex‐ ploration for hepatic and retroperitoneal hemorrhage: critical refinements of a useful

[121] Beal SL. Fatal hepatic hemorrhage: an unresolved problem in the management of

[122] De Toma G, Mingoli A, Modini C, Cavallaro A, Stipa S. The value of angiography and selective hepatic artery embolization for continuous bleeding after surgery in liv‐

[123] Brick SH, Taylor GA, Potter BM, Eichelberger MR. Hepatic and splenic injury in chil‐ dren: role of CT in the decision for laparotomy. Radiology 1987; 165: 643-6.

[124] Krige JEJ, Bornman PC, Terblanche J. Therapeutic perihepatic packing in complex

ka L, Iwatsuki S, Gordon RD, Starzl TE. J Trauma. 1987 Jul;27(7):800-2

ure: have we gone too far? J Med Life. 2010 Jul-Sep;3(3):289-96

ment of hepatic trauma. Ann Surg 1977; 185: 613-18.

ment of blunt hepatic trauma. Br J Surg 1998; 85: 461-8.

terol 2009;15:1641-4.

ries. Ann Surg 1991; 213: 540-8.

ity factors. J Trauma 1993; 35: 865-9.

technique. J Trauma 1990; 30: 1007-13

liver trauma. Br J Surg 1992; 79: 43-6.

complex liver injuries. J Trauma 1990; 30: 163-9.

er trauma: case reports. J Trauma 1994; 37: 508-11.

Trauma 1989; 29: 1140-5.

2006;141:451-459.


[110] Liver replacement after massive hepatic trauma. Esquivel CO, Bernardos A, Makow‐ ka L, Iwatsuki S, Gordon RD, Starzl TE. J Trauma. 1987 Jul;27(7):800-2

[92] Feliciano DV, Mattox KL, Jordan GL, et al.. The management of 1000 consecutive cas‐

[93] Trunkey DD, Shires GT, McClellan R. Management of liver trauma in 811 consecu‐

[94] Morris JA, Eddy VA, Blinman TA, et al.. The staged celiotomy for trauma (issues in

[95] Aaron WS, Fulton RL, Mays ET. Selective ligation of the hepatic artery for trauma of

[96] Mays ET, Conti S, Fallahzadkh H, et al.. Hepatic artery ligation. Surgery.

[98] Flint LM, Polk HC. Selective hepatic artery ligation (limitations and failures). J Trau‐

[99] Schrock T, Blaisdell FW, Mathewson C, et al.. Management of blunt trauma to the liv‐

[100] FA, Moore EE, Seagraves A. Non-resectional management of major hepatic trauma.

[101] Walt AJ. The mythology of hepatic trauma or babel revisited. Amer J Surg.

[102] Stone HH, Lamb JM. Use of pedicled omentum as an autogenous pack for control of hemorrhage in major injuries of the liver. Surg Gynecol Obstet. 1975;141:92–94.

[103] Carmona RH, Peck D, Lim RC. The role of packing and re-operation in severe hepat‐

[104] Wahl WL, Brandt MM, Hemmila MR, Arbabi S. Diagnosis and management of bile leaks after blunt liver injury. Surgery. 2005 Oct;138(4):742-7; discussion 747-8

[105] Sugimoto K, Asari Y, Sakaguchi T et al. ERCP in the non-surgical management o

[106] Pachter HL, Spencer FC, Hofstetter SR, et al. Significant trends in the treatment of hepatic injuries. Experience with 411 injuries. Ann Surg 1992;215:492–500.

[107] Polanco P, Leon S, Pineda J, et al. Hepatic resection in the management of complex

[108] Richardson JD, Franklin GA, Lukan JK, et al. Evolution in the management of hepatic

[109] Honore C, et al. Liver transplantation for hepatic trauma: Discussion about a case

injury to the liver. J Trauma 2008;65(6):1264–9 [discussion: 1269–70].

and its management. J Emerg Trauma Shock. 2011 Jan;4(1):137-9.

trauma: a 25-year perspective. Ann Surg 2000;232:324–30.

es of hepatic trauma. Ann Surg. 1988;204:438–495.

the liver. Surg Gynecol Obstet. 1975;141:187–189.

[97] Mays ET. Hepatic trauma. Curr Prob Surg. 1976;13:1–86.

er and hepatic veins. Arch Surg. 1968;96:698–704.

unpacking and reconstruction). Ann Surg. 1993;217:576–586.

tive patients. Ann Surg. 1974;179:722–728.

1979;86:536–543

642 Hepatic Surgery

ma. 1979;19:319–323.

1978;135:1218.

Amer J Surg. 1985;150:725–729.

ic trauma. J Trauma. 1984;24:779–784.

blunt liver trauma. J Trauma 1993;35:192-9.


[125] Tisnado J, Beachley MC, Cho SR. Control of intrahepatic bleeding by superselective

[126] Morimoto RY, Birolini D, Junqueira AR Jr, Poggetti R, Horita LT. Balloon tamponade

[127] Oishi AJ, Nagorney DM Portl hypertension, variceal bleeding and high output car‐ diac failure secondary to an intrahepatic arterioportal fistula. HPB surg 1993;7:53-9.

[128] Pachter HL, Liang HG, Hofstetter SR. Liver and biliary tract trauma. In: Moore EE, Mattox KL, Feliciano DV, eds. Trauma. 2nd ed. Norwalk, Connecticut: Appleton and

[129] Helling TS, Morse G, McNabney WK, Beggs CW, Behrends SH et al. Treatment of liver injuries at level I and level II centres in a multi-institutional metropolitan trau‐ ma system. The Midwest Trauma Society Liver Trauma Study Group. J Trauma 1997;

[130] Sherman HF,Savage BA, Jones LM et al. non-operative management of blunt hepatic

[131] Cox EF, Flancbaum L, Dauterive AH, Paulson RL. Blunt trauma to the liver. Analysis of management and mortality in 323 consecutive patients. Ann Surg 1988; 207: 126-34

injuries: safe at any grade? J Trauma 1994; 37:616-21.

embolization of the middle hepatic artery. South Med J 1982; 75: 70-1.

for transfixing lesions of the liver. Surg Gynecol Obstet 1987; 164: 87-8.

Lange, 1991: 441-63.

42: 1091-6.

644 Hepatic Surgery

### *Edited by Hesham Abdeldayem*

Longmire, called it a "hostile" organ because it welcomes malignant cells and sepsis so warmly, bleeds so copiously, and is often the ?rst organ to be injured in blunt abdominal trauma. To balance these negative factors, the liver has two great attributes: its ability to regenerate after massive loss of substance, and its ability, in many cases, to forgive insult. This book covers a wide spectrum of topics including, history of liver surgery, surgical anatomy of the liver, techniques of liver resection, benign and malignant liver tumors, portal hypertension, and liver trauma. Some important topics were covered in more than one chapter like liver trauma, portal hypertension and pediatric liver tumors.

Hepatic Surgery

Hepatic Surgery

*Edited by Hesham Abdeldayem*

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