Overviews of Portal Hypertension

**3**

**Chapter 1**

**Abstract**

**1. Introduction**

of liver cirrhosis.

Brief Review of Portal

Hypertension Related

The pathologic increase in the pressure gradient between portal vein and inferior venacava is called portal hypertension. Increased portal blood flow and increased resistance in the portal venous system cause portal hypertension. The structural components and the functional components contribute to the resistance. Hepatic venous pressure gradient (HVPG) reflects the degree of portal pressure in liver disease. HVPG is calculated as the difference between the wedged hepatic venous pressure (WHVP) and the free hepatic venous pressure (FHVP). Clinically significant portal hypertension (CSPH) is defined as HVPG ≥10. Different values of HVPG have been defined as threshold for different consequences of portal hypertension. Variceal hemorrhage, portal hypertensive gastropathy, ascites, colopathy, biliopathy and hepatopulmonary syndrome are main complications of portal hypertension. Besides nonselective beta blockers, other drugs like statins, antioxidants, antidiabetic, anti-inflammatory and antiapoptotic drugs have also been seen to be effective in reducing portal pressure.

**Keywords:** portal hypertension, Hepatic venous pressure gradient (HVPG), variceal hemorrhage, hepatopulmonary syndrome, cirrhotic cardiomyopathy

ish). He used the word "cirrhosis" in the textbook published by him [3].

by portal vein and finally to the systemic circulation.

Vesalius [1] was the person who drew an anatomical picture of the portal venous system in 1543 and described a case of bleeding hemorrhoids and suggested that this was due to a dilatation of the portal branches. Glisson [2] at a dissection in London, in 1650 established that blood was collected from the gastrointestinal tract

Morgagni described a patient who had died from gastrointestinal hemorrhage: at the autopsy, dilatation of the splenic vein and of the short gastric veins were found. The name cirrhosis was introduced in 1819, in Paris, by Renè Laennec, deriving from two words of the antique Greek: Skirros (hard, fibrotic) and Kirrhos (yellow-

Dusaussey [4], wrote an important thesis 'Studies on esophageal varices in liver cirrhosis', in 1872. He believed that the obstruction to portal flow was a consequence

Gilbert [5] introduced the term portal hypertension in 1902. A 'pressure close to that in the portal vein' without opening the abdomen, was obtained by puncturing one of the dilated abdominal wall veins (the caput medusae) by Davidson [6].

Complications

*Achyut Bikram Hamal*

#### **Chapter 1**

## Brief Review of Portal Hypertension Related Complications

*Achyut Bikram Hamal*

#### **Abstract**

The pathologic increase in the pressure gradient between portal vein and inferior venacava is called portal hypertension. Increased portal blood flow and increased resistance in the portal venous system cause portal hypertension. The structural components and the functional components contribute to the resistance. Hepatic venous pressure gradient (HVPG) reflects the degree of portal pressure in liver disease. HVPG is calculated as the difference between the wedged hepatic venous pressure (WHVP) and the free hepatic venous pressure (FHVP). Clinically significant portal hypertension (CSPH) is defined as HVPG ≥10. Different values of HVPG have been defined as threshold for different consequences of portal hypertension. Variceal hemorrhage, portal hypertensive gastropathy, ascites, colopathy, biliopathy and hepatopulmonary syndrome are main complications of portal hypertension. Besides nonselective beta blockers, other drugs like statins, antioxidants, antidiabetic, anti-inflammatory and antiapoptotic drugs have also been seen to be effective in reducing portal pressure.

**Keywords:** portal hypertension, Hepatic venous pressure gradient (HVPG), variceal hemorrhage, hepatopulmonary syndrome, cirrhotic cardiomyopathy

#### **1. Introduction**

Vesalius [1] was the person who drew an anatomical picture of the portal venous system in 1543 and described a case of bleeding hemorrhoids and suggested that this was due to a dilatation of the portal branches. Glisson [2] at a dissection in London, in 1650 established that blood was collected from the gastrointestinal tract by portal vein and finally to the systemic circulation.

Morgagni described a patient who had died from gastrointestinal hemorrhage: at the autopsy, dilatation of the splenic vein and of the short gastric veins were found.

The name cirrhosis was introduced in 1819, in Paris, by Renè Laennec, deriving from two words of the antique Greek: Skirros (hard, fibrotic) and Kirrhos (yellowish). He used the word "cirrhosis" in the textbook published by him [3].

Dusaussey [4], wrote an important thesis 'Studies on esophageal varices in liver cirrhosis', in 1872. He believed that the obstruction to portal flow was a consequence of liver cirrhosis.

Gilbert [5] introduced the term portal hypertension in 1902. A 'pressure close to that in the portal vein' without opening the abdomen, was obtained by puncturing one of the dilated abdominal wall veins (the caput medusae) by Davidson [6].

Thompson (1937) [7] directly measured portal pressure for the first time, with the open abdomen, the pressure in the portal vein and in the inferior vena cava. In 1953 Lebon et al. [8] diagnosed portal hypertension by percutaneous measurement of the intrasplenic pressure.

#### **2. Definition**

Patients with portal hypertension are identified when they present to hospitals or clinic after they have complications such as ascites, gastrointestinal bleeding, hepatic encephalopathy or hypersplenism. The pressure gradient between the portal vein and the inferior vena cava (the so-called portal perfusion pressure of the liver or portal pressure gradient) increases to greater than the normal range of values (1–5 mm Hg) when there is pathologic increase in portal pressure, which is called portal hypertension [9].

#### **3. Portal pressure measurement and its importance**

While evaluating them the need for the evaluating the underlying cirrhosis, the degree of portal hypertension, the site of obstruction and the presence of collateral circulation makes the diagnosis of portal hypertension complete [10]. As the disease progresses, the amount of fibrosis increases and in parallel the portal pressure rises corresponding to worsening in the prognosis. Direct or indirect measurement of portal pressure can be done with various methods.

Measurement of the hepatic venous pressure gradient (HVPG) is the gold standard technique used to quantify the degree portal hypertension in liver disease. Diagnosis, classification, and monitoring of portal hypertension, risk stratification, identification of candidates for liver resection, and monitoring efficacy of β-adrenergic blockers are the main clinical applications of HVPG measurements.

HVPG is calculated as the difference between the wedged hepatic venous pressure (WHVP) and the free hepatic venous pressure (FHVP) [11]. The WHVP is measured by occluding a main hepatic vein which causes the static column of blood to transmit the pressure that is present in the preceding vascular territory i. e. the hepatic sinusoids. This measurement, in the absence of presinusoidal obstruction, reflects portal pressure [12]. The FHVP is a measure of the pressure of unoccluded hepatic vein. HVPG calculated with right atrial pressure shows a worse correlation with clinical outcomes, therefore FHVP should be used [13]. There are several methods to measure portal pressure as enumerated in **Table 1**.

The changes in HVPG are due to the alterations in the intrahepatic resistance, collateral resistance, portal blood inflow or their combination [14]. Dynamic factors such as hepatic vascular tone and mechanical factors such as fibrosis, thrombosis and formation of regenerative nodules cause the alterations in HVPG.

The complications of portal hypertension increase as HVPG increases. Clinical manifestations and complications occur at a threshold of HVPG of 10 mm Hg, which is called clinically significant portal hypertension (CSPH). Different thresholds of HVPG correlate with different prognostic significance (**Table 2**).

#### **3.1 Technique of measurement of HVPG**

Under sedation a balloon-tipped catheter is introduced through the central line inserted into the right internal jugular vein, usually under ultrasound guidance [28].

**5**

**Table 2.**

the femoral approach can be used.

The catheter is advanced through the right atrium into the inferior venacava (IVC) under fluoroscopic guidance and then pushed into the right hepatic vein. Alternatively,

*Different thresholds of hepatic venous pressure gradient (HVPG) correlated with prognostic significance.*

*Brief Review of Portal Hypertension Related Complications*

**SN Methods Procedures**

Ascitic fluid analysis

(SAAG) ≥ 1.1

femoral approach

5. Intrasplenic pressure Placement of a needle percutaneously in the substance of the spleen.

catheter.

High risk of recurrence after liver transplantation [16]

Serum Ascitic Albumin Gradient

supraclavicular or internal jugular approach.

Open-ended catheter placed in one of the hepatic veins via a

Double-lumen balloon catheter placed in the hepatic vein via a

The portal vein can be catheterized directly, either by a trans hepatic approach or by a catheter placed via the umbilical vein. The added advantage is that collaterals can be embolized while this procedure. Angiography can be performed at the same time

Portal pressure measurements should be obtained prior to the injection of contrast, which in itself can alter pressures.

Percutaneous catheterization of an intrahepatic branch of the portal vein with a thin Chiba needle; a catheter is passed via the

Requires dissection to expose the umbilical vein; may require dilation of the umbilical vein to facilitate advancement of the

to minimize the number of procedures performed.

intrahepatic branch into the main portal vein.

Portal hypertension

Gradient (HVPG)

of the portal pressure

*DOI: http://dx.doi.org/10.5772/intechopen.96646*

1. Indirect estimation of

2. Hepatic Vein Pressure

3. Direct measurement

4. Intrahepatic portal

6. Umbilical vein catheter

< 5 mm Hg Normal

*Different methods of measuring portal pressure.*

**HVPG Clinical characteristics**

5–10 mm Hg Mild portal hypertension

>12 mm Hg Variceal bleeding [22, 23] >16 mm Hg High mortality [24]

>6 mm Hg Progression of chronic viral hepatitis [15]

>10 mm Hg Esophageal variceal development [17, 18]

>10 mm Hg Clinically significant Portal hypertension (CSPH)

Decompensation with ascites [19] Hepatocellular carcinoma (HCC) [20] Decompensation after Hepatic resection [21]

>20 mm Hg Failure to control bleeding in acute variceal bleed [25] Low 1-year survival >22 mm Hg High mortality in severe alcoholic hepatitis [26] >30 mm Hg Spontaneous bacterial peritonitis (SBP) [27]

**Table 1.**

vein pressure

gradient


*Brief Review of Portal Hypertension Related Complications DOI: http://dx.doi.org/10.5772/intechopen.96646*

#### **Table 1.**

*Portal Hypertension - Recent Advances*

of the intrasplenic pressure.

portal hypertension [9].

measurements.

**2. Definition**

Thompson (1937) [7] directly measured portal pressure for the first time, with the open abdomen, the pressure in the portal vein and in the inferior vena cava. In 1953 Lebon et al. [8] diagnosed portal hypertension by percutaneous measurement

Patients with portal hypertension are identified when they present to hospitals or clinic after they have complications such as ascites, gastrointestinal bleeding, hepatic encephalopathy or hypersplenism. The pressure gradient between the portal vein and the inferior vena cava (the so-called portal perfusion pressure of the liver or portal pressure gradient) increases to greater than the normal range of values (1–5 mm Hg) when there is pathologic increase in portal pressure, which is called

While evaluating them the need for the evaluating the underlying cirrhosis, the degree of portal hypertension, the site of obstruction and the presence of collateral circulation makes the diagnosis of portal hypertension complete [10]. As the disease progresses, the amount of fibrosis increases and in parallel the portal pressure rises corresponding to worsening in the prognosis. Direct or indirect measurement of

Measurement of the hepatic venous pressure gradient (HVPG) is the gold standard technique used to quantify the degree portal hypertension in liver disease. Diagnosis, classification, and monitoring of portal hypertension, risk stratification, identification of candidates for liver resection, and monitoring efficacy of β-adrenergic blockers are the main clinical applications of HVPG

HVPG is calculated as the difference between the wedged hepatic venous pressure (WHVP) and the free hepatic venous pressure (FHVP) [11]. The WHVP is measured by occluding a main hepatic vein which causes the static column of blood to transmit the pressure that is present in the preceding vascular territory i. e. the hepatic sinusoids. This measurement, in the absence of presinusoidal obstruction, reflects portal pressure [12]. The FHVP is a measure of the pressure of unoccluded hepatic vein. HVPG calculated with right atrial pressure shows a worse correlation with clinical outcomes, therefore FHVP should be used [13]. There are several

The changes in HVPG are due to the alterations in the intrahepatic resistance, collateral resistance, portal blood inflow or their combination [14]. Dynamic factors such as hepatic vascular tone and mechanical factors such as fibrosis, thrombosis

The complications of portal hypertension increase as HVPG increases. Clinical manifestations and complications occur at a threshold of HVPG of 10 mm Hg, which is called clinically significant portal hypertension (CSPH). Different thresh-

Under sedation a balloon-tipped catheter is introduced through the central line inserted into the right internal jugular vein, usually under ultrasound guidance [28].

**3. Portal pressure measurement and its importance**

methods to measure portal pressure as enumerated in **Table 1**.

**3.1 Technique of measurement of HVPG**

and formation of regenerative nodules cause the alterations in HVPG.

olds of HVPG correlate with different prognostic significance (**Table 2**).

portal pressure can be done with various methods.

**4**

*Different methods of measuring portal pressure.*


#### **Table 2.**

*Different thresholds of hepatic venous pressure gradient (HVPG) correlated with prognostic significance.*

The catheter is advanced through the right atrium into the inferior venacava (IVC) under fluoroscopic guidance and then pushed into the right hepatic vein. Alternatively, the femoral approach can be used.

FHVP is obtained after the catheter is maintained in the hepatic vein 2 to 4 cm from its takeoff from the IVC. Typically, the difference in pressure between the IVC (measured at the hepatic vein ostium) and hepatic vein is ≤1 mmHg. If the difference is >1 mmHg it means the catheter is placed too deep into the hepatic vein. After this, WHVP is measured after the hepatic vein is occluded by inflating the balloon at the tip of the catheter. A small amount of contrast dye (5 mL) or carbon dioxide (if allergic to the contrast) is injected to confirm that the hepatic vein is occluded so that no reflux of the dye above the balloon or should washout via communications with other hepatic veins. Around 3 each measurements of wedged and free hepatic venous pressure are made each time with the stability of the value for at least 45–60 seconds [29]. Finally, the HVPG is calculated by subtracting the FHVP from the WHVP.

The findings of hemodynamic measurements in patients with intrahepatic portal hypertension are enumerated [28] in **Table 3**.

At the same time along with HVPG measurement include transjugular liver biopsy, measurement of hepatic blood flow and indocyanine green clearance, and wedged hepatic retrograde portography using carbon dioxide can be done. Complications during the procedure can be arrhythmia or injury to the local site.

#### **3.2 Noninvasive tests**

Though these noninvasive tests cannot replace HVPG measurement for confirming the diagnosis of portal hypertension, ultrasonogram and transient elastography may be helpful.

#### *3.2.1 Ultrasonography*

Portal hypertension findings in transabdominal ultrasound are [28]:



**7**

*Brief Review of Portal Hypertension Related Complications*

≥21.1 kPa is likely to have portal hypertension [28].

**4. Pathophysiology of portal hypertension**

related to both flow and resistance.

**4.1 Etiology of portal hypertension**

Congenital portal vein stenosis Cavernomatosis of the portal vein

Presinusoidal: Schistosomiasis

Primary Biliary Cirrhosis (Early)

Sinusoidal: Acute alcoholic Hepatitis Liver cirrhosis independent of etiology

Partial nodular transformation Nodular regenerative hyperplasia

Arsenic, copper sulfate and Vinyl chloride poisoning.

Splenic vein thrombosis Portal vein thrombosis

Arteriovenous fistula Tropical splenomegaly

Chronic active hepatitis Congenital hepatic fibrosis Hepatic artery portal vein fistula

Transient elastography using ultrasound is a noninvasive method for detecting hepatic fibrosis. Studies are also looking at it as an option for noninvasively diagnosing

A value <13.6 kPa can be used to rule out portal hypertension, whereas a value

With the concept of physics, it is important to note that portal hypertension is

Pressure (P) equals flow (Q ) times resistance (R), demonstrated by the formula.

P = Q X R

radius. The pathophysiology of portal hypertension is explained in **Figure 1**.

Various etiologies of portal hypertension can be enumerated as:

Resistance is a function of the length and radius as shown by the formula R = 8n

, where n is the coefficient of viscosity, L is the length of the vessel, and r is the

*DOI: http://dx.doi.org/10.5772/intechopen.96646*

*3.2.2 Transient elastography*

portal hypertension.

L/IIr4

**Prehepatic**

**Intrahepatic**

Sarcoidosis

Porto-sclerosis

Amyloidosis Tuberculosis Wilsons disease Hemochromatosis Mastocytosis

Amyloidosis

Hypervitaminosis A

Drugs

#### **Table 3.**

*Hemodynamic measurements in portal hypertension.*

#### *3.2.2 Transient elastography*

*Portal Hypertension - Recent Advances*

**3.2 Noninvasive tests**

may be helpful.

• Ascites

diameter

*3.2.1 Ultrasonography*

portal hypertension are enumerated [28] in **Table 3**.

FHVP is obtained after the catheter is maintained in the hepatic vein 2 to 4 cm from its takeoff from the IVC. Typically, the difference in pressure between the IVC (measured at the hepatic vein ostium) and hepatic vein is ≤1 mmHg. If the difference is >1 mmHg it means the catheter is placed too deep into the hepatic vein. After this, WHVP is measured after the hepatic vein is occluded by inflating the balloon at the tip of the catheter. A small amount of contrast dye (5 mL) or carbon dioxide (if allergic to the contrast) is injected to confirm that the hepatic vein is occluded so that no reflux of the dye above the balloon or should washout via communications with other hepatic veins. Around 3 each measurements of wedged and free hepatic venous pressure are made each time with the stability of the value for at least 45–60 seconds [29]. Finally, the HVPG is calculated by subtracting the FHVP from the WHVP. The findings of hemodynamic measurements in patients with intrahepatic

At the same time along with HVPG measurement include transjugular liver biopsy, measurement of hepatic blood flow and indocyanine green clearance, and wedged hepatic retrograde portography using carbon dioxide can be done. Complications during the procedure can be arrhythmia or injury to the local site.

Though these noninvasive tests cannot replace HVPG measurement for confirming the diagnosis of portal hypertension, ultrasonogram and transient elastography

)

Portal hypertension findings in transabdominal ultrasound are [28]:

• Coarse echotexture of liver with irregular margin and dull edge

• Portosystemic collaterals (patent-paraumbilical vein, splenorenal collaterals,

• Decreased or no respiratory variation in splenic and superior mesenteric vein

**Hemodynamic measurement Presinusoidal Sinusoidal Post-sinusoidal** FHVP (a) Normal Sinusoidal Increased WHVP (b) Normal or mild increased Increased Increased HVPG (b-a) Normal or mild increased Increased Normal

• Splenomegaly (> 13 cm or Splenic index >20 cm2

• Reversal of flow in the portal vein and left gastric vein

• Portal/splenic/superior mesenteric vein thrombosis

• Portal flow mean velocity < 12 cm/second

dilated left and short gastric veins)

• Portal vein diameter > 13 mm

*Hemodynamic measurements in portal hypertension.*

**6**

**Table 3.**

Transient elastography using ultrasound is a noninvasive method for detecting hepatic fibrosis. Studies are also looking at it as an option for noninvasively diagnosing portal hypertension.

A value <13.6 kPa can be used to rule out portal hypertension, whereas a value ≥21.1 kPa is likely to have portal hypertension [28].

#### **4. Pathophysiology of portal hypertension**

With the concept of physics, it is important to note that portal hypertension is related to both flow and resistance.

Pressure (P) equals flow (Q ) times resistance (R), demonstrated by the formula.

$$\mathbf{P} = \mathbf{Q} \cdot \mathbf{X} \,\mathbf{R}$$

Resistance is a function of the length and radius as shown by the formula R = 8n L/IIr4 , where n is the coefficient of viscosity, L is the length of the vessel, and r is the radius. The pathophysiology of portal hypertension is explained in **Figure 1**.

#### **4.1 Etiology of portal hypertension**

Various etiologies of portal hypertension can be enumerated as: **Prehepatic** Splenic vein thrombosis Portal vein thrombosis Congenital portal vein stenosis Cavernomatosis of the portal vein Arteriovenous fistula Tropical splenomegaly **Intrahepatic** Presinusoidal: Schistosomiasis Sarcoidosis Primary Biliary Cirrhosis (Early) Chronic active hepatitis Congenital hepatic fibrosis Hepatic artery portal vein fistula Porto-sclerosis Drugs Arsenic, copper sulfate and Vinyl chloride poisoning. Amyloidosis Tuberculosis Wilsons disease Hemochromatosis Mastocytosis Sinusoidal: Acute alcoholic Hepatitis Liver cirrhosis independent of etiology Amyloidosis Partial nodular transformation Nodular regenerative hyperplasia Hypervitaminosis A

#### **Figure 1.**

*Pathophysiology of portal hypertension.*

Cytotoxic drugs Acute fatty liver of pregnancy Peliosis hepatitis Polycystic liver disease Idiopathic portal hypertension Metastatic malignant disease Post-sinusoidal: Veno-occlusive disease Alcoholic central hyaline sclerosis **Post-hepatic** Budd-Chiari syndrome Congenital malformations and thrombosis of the inferior vena cava Constrictive pericarditis Congenital heart diseases Cardiomyopathy Tricuspid valve diseases

#### **Miscellaneous**

Arteriovenous fistulas (splenic, aorto-mesenteric, aorto-portal, and hepatic artery-portal vein)

Formation of collateral circulation connects the portal blood vessels to systemic circulation, bypassing the liver and leading to portal hypertension [30]. Sometimes, when a pathological process causes occlusion of the splenic vein and the resultant

**9**

*Brief Review of Portal Hypertension Related Complications*

less than 5% of all patients with portal hypertension [33].

tions or features of liver cirrhosis with the presence of splenomegaly.

Iatrogenic splenic vein injury, ectopic spleen, colonic tumor infiltration, peri-renal abscess, post liver transplantation, Hodgkin's disease, retro-peritoneal fibrosis, pancreatic transplantation, and spontaneous thrombus formation are among the less common causes of splenic vein thrombosis that can lead to left sided

Patients with portal hypertension are usually asymptomatic until they develop

elevated splenic bed venous pressure causes formation of gastric varices which can lead to hematemesis it is called sinistral portal hypertension. Sinistral portal hypertension is a rare, less than 1%, but life-threatening cause of upper gastric bleeding. In fact, the name sinistral portal hypertension is a misnomer since portal pressure is usually within the normal range in these cases. Other names for sinistral portal hypertension are left sided portal hypertension, segmental, regional, localized, compartmental, lineal, or spleno-portal hypertension [31–33]. It accounts for

Chronic pancreatitis, pancreatic cancer, pancreatic cysts and neuroendocrine tumor are common causes of sinistral portal hypertension. Most involved vessel in pancreatitis-related splanchnic vein thrombosis is splenic vein followed by portal vein and mesenteric vein. It is mainly related to pancreatic inflammation and compression by pancreatic pseudocyst [34]. Around 8% of patients of chronic pancreatitis experience splenic vein thrombosis, the majority do not experience any form of symptomatic GI bleeding [35]. They present with hypersplenism, abdominal pain and gastrointestinal bleeding. They should undergo gastroscopy evaluation in search of varices. Suspicion of this portal hypertension should be done when patient has gastric varices only in fundus with or without any aberrant liver func-

*DOI: http://dx.doi.org/10.5772/intechopen.96646*

hypertension [31, 32].

1.Variceal hemorrhage

6.Hepatic hydrothorax

3.Ascites

**5. Complications of portal hypertension**

2.Portal hypertensive gastropathy (PHG)

4.Spontaneous bacterial peritonitis

7.Hepatopulmonary syndrome (HPS)

8.Porto-pulmonary hypertension (POPH)

5.Hepatorenal syndrome (HRS)

9.Portal hypertensive colopathy

10.Cirrhotic cardiomyopathy

11.Portal Biliopathy

complications. Complications of portal hypertension include:

#### *Brief Review of Portal Hypertension Related Complications DOI: http://dx.doi.org/10.5772/intechopen.96646*

*Portal Hypertension - Recent Advances*

**8**

Cytotoxic drugs

*Pathophysiology of portal hypertension.*

**Figure 1.**

Peliosis hepatitis Polycystic liver disease

**Post-hepatic**

Cardiomyopathy Tricuspid valve diseases

**Miscellaneous**

artery-portal vein)

Budd-Chiari syndrome

Constrictive pericarditis Congenital heart diseases

Acute fatty liver of pregnancy

Idiopathic portal hypertension Metastatic malignant disease

Post-sinusoidal: Veno-occlusive disease Alcoholic central hyaline sclerosis

Congenital malformations and thrombosis of the inferior vena cava

Arteriovenous fistulas (splenic, aorto-mesenteric, aorto-portal, and hepatic

Formation of collateral circulation connects the portal blood vessels to systemic circulation, bypassing the liver and leading to portal hypertension [30]. Sometimes, when a pathological process causes occlusion of the splenic vein and the resultant

elevated splenic bed venous pressure causes formation of gastric varices which can lead to hematemesis it is called sinistral portal hypertension. Sinistral portal hypertension is a rare, less than 1%, but life-threatening cause of upper gastric bleeding. In fact, the name sinistral portal hypertension is a misnomer since portal pressure is usually within the normal range in these cases. Other names for sinistral portal hypertension are left sided portal hypertension, segmental, regional, localized, compartmental, lineal, or spleno-portal hypertension [31–33]. It accounts for less than 5% of all patients with portal hypertension [33].

Chronic pancreatitis, pancreatic cancer, pancreatic cysts and neuroendocrine tumor are common causes of sinistral portal hypertension. Most involved vessel in pancreatitis-related splanchnic vein thrombosis is splenic vein followed by portal vein and mesenteric vein. It is mainly related to pancreatic inflammation and compression by pancreatic pseudocyst [34]. Around 8% of patients of chronic pancreatitis experience splenic vein thrombosis, the majority do not experience any form of symptomatic GI bleeding [35]. They present with hypersplenism, abdominal pain and gastrointestinal bleeding. They should undergo gastroscopy evaluation in search of varices. Suspicion of this portal hypertension should be done when patient has gastric varices only in fundus with or without any aberrant liver functions or features of liver cirrhosis with the presence of splenomegaly.

Iatrogenic splenic vein injury, ectopic spleen, colonic tumor infiltration, peri-renal abscess, post liver transplantation, Hodgkin's disease, retro-peritoneal fibrosis, pancreatic transplantation, and spontaneous thrombus formation are among the less common causes of splenic vein thrombosis that can lead to left sided hypertension [31, 32].

#### **5. Complications of portal hypertension**

Patients with portal hypertension are usually asymptomatic until they develop complications. Complications of portal hypertension include:


#### **5.1 Variceal hemorrhage**

Bleeding occurs in 30%–40% of patients with cirrhosis and varices [36]. The incidence of first variceal bleeding is about 12–15% per year in patients with cirrhosis and esophageal varices and mortality ranges from 17% - 57% in patients at first episode of variceal bleeding [37]. Carbonell et al. has also estimated mortality during the first episode of bleeding to be 15–20% but with Child Pugh C, it is around 30% [38].

The preventive measures advocated are beta blockers and endoscopic variceal ligation (EVL). Beta blockers provide protection against rebleeding after index hemorrhage while local obliteration of varices is done by EVL.

Nonselective beta blockers have been used daily in patients with cirrhosis and portal hypertension with varices either for primary or secondary prophylaxis. Recommended agents for primary prophylaxis of variceal hemorrhage are propranolol and nadolol [39, 40].

Secondary prophylaxis with nonspecific beta blocker (NSBB) has been shown to be effective in decreasing both the risk of recurrent bleeding and mortality [41, 42]. Without secondary prophylaxis, rebleeding occurs in approximately 60% to 70% of patients, usually within one to two years of the index hemorrhagic event [43]. Most used NSBB for secondary prophylaxis is propranolol but carvedilol can also be used. The decrease in HR at 6 weeks was significantly higher in carvedilol than propranolol group (p = 0.036). The rebleeding at least once within 6 months was also higher in propranolol group than carvedilol group (32 vs. 22.7%) [44].

#### **5.2 Portal hypertensive Gastropathy**

It is the characteristic appearance which is a mosaic-like pattern or a diffuse, erythematous and reticular cobblestone pattern of gastric mucosa consisting of small polygonal areas, with or without superimposed red punctate lesions, >2 mm in diameter and a depressed white border [45–47]. PHG is classified as mild or severe.

Mild PHG has features like fine pink speckling (scarlatina-type rash), and mosaic pattern (snakeskin appearance) and Severe one has discrete red spots or diffuse hemorrhagic lesion [48].

The prevalence of PHG in Nepalese population with Chronic Liver Diseases (CLD) was 67 percent [49] though it varies significantly from 16 to 100 percentage [50]. Acute bleeding in PHG is estimated to occur in 2 to 12 percent [51].

#### **5.3 Ascites**

Patients with cirrhosis with portal hypertension may present with ascites leading to distension of abdomen and dyspnea. They will have flank fullness with dullness on examination. The grading of ascites as graded by International Club for Ascites are [52]:


Ascites may range from mild to refractory. Mild to moderate ascites should be managed by modest salt restriction and combination of loop diuretics and potassium sparing diuretics.

**11**

are as-.

*Brief Review of Portal Hypertension Related Complications*

Ultrasonographic detection of mild ascites is either pelvic or perihepatic or peri splenic ascites, while moderate ascites is presence of pelvic and perihepatic and perisplenic ascites, and marked ascites is diffuse ascites in the peritoneal

Diuretics should be added in a stepwise fashion along with sodium restriction. Gross ascites should be treated with therapeutic paracentesis followed by colloid volume expansion, and diuretic therapy. Sometimes refractory ascites is managed by repeated large volume paracentesis or insertion of a transjugular intrahepatic

Spontaneous bacterial peritonitis occurs with a prevalence of 10–25% in cirrhotic patients with ascites [54]. It can be community acquired, health care associ-

Major pathogenic organisms are *E. coli* (24.3%), followed by *Klebsiella pneumoniae* (12.0%) and *Enterococcus faecium* (10.5%). Nosocomial SBP has significantly higher proportion of Enterococcus (27.7% vs. 6.1%, P < 0.001) than community acquired SBP. Nosocomial SBP has a poorer outcome than community acquired pneumonia (24.6% vs. 36.8%; P = 0.016). The independent predictors for 30-day mortality are nosocomial infection, Child-Pugh classification, hepatocellular

Suspicion of nosocomial SBP should be done in a patient with SBP with a history of ICU stay during the previous 3 months or on prophylactic antibiotics for infection or had antibiotic treatment during previous 3 months or had a recent intervention in the hospital setting. Resistance to 3rd generation cephalosporins and

Recently, Elsadek et al. found that Patients with SBP (n = 60) have significantly higher serum PEC index than those with sterile ascites (n = 118) (41.0/31.2–93.0 vs. 9.9/5.9–15.0, P < 0.001) and it distinguished culture positive cases significantly

Diagnostic paracentesis should be performed in all patients who present with [57] (1) compatible signs or symptoms (abdominal pain and/or tenderness on palpation, fever, and chills); (2) impairment of the hepatic or renal function; (3)

in the absence of an intra-abdominal and surgically treatable source of infection. Other potential diagnostic methods are leukocyte esterase reagent strips (LERS), measurement of leukocyte-derived proteins such as granulocyte elastase and lactoferrin, detection of bacterial DNA using polymerase chain reaction (PCR) and

HRS occurs in the setting of advanced cirrhosis and portal hypertension [58] with prevalence of 13–45 percentage [59]. It is characterized by peripheral arterial vasodilatation and intrarenal vasoconstriction with decrease in renal blood flow and renal dysfunction. The most recent proposed diagnostic criteria for HRS-AKI

• Cirrhosis with ascites; acute liver failure; acute-on-chronic liver failure

in ascitic fluid

*DOI: http://dx.doi.org/10.5772/intechopen.96646*

portosystemic stent shunt (TIPS) [53].

**5.4 Spontaneous bacterial peritonitis (SBP)**

carcinoma, renal failure and hepatic encephalopathy [54].

quinolones has been documented in 40–50% of such cases [55].

unexplained hepatic encephalopathy; (4) gastrointestinal bleeding. SBP is diagnosed by polymorphonuclear cells ≥250 cells/mm3

detecting bacterial DNA in SBP ascites using in situ hybridization [57].

cavity [52].

ated or nosocomial.

(P < 0.001) [56].

**5.5 Hepatorenal syndrome (HRS)**

Diagnostic Criteria for HRS-AKI [60].

*Portal Hypertension - Recent Advances*

Bleeding occurs in 30%–40% of patients with cirrhosis and varices [36]. The incidence of first variceal bleeding is about 12–15% per year in patients with cirrhosis and esophageal varices and mortality ranges from 17% - 57% in patients at first episode of variceal bleeding [37]. Carbonell et al. has also estimated mortality during the first episode of bleeding to be 15–20% but with Child Pugh C, it is around 30% [38]. The preventive measures advocated are beta blockers and endoscopic variceal ligation (EVL). Beta blockers provide protection against rebleeding after index

Nonselective beta blockers have been used daily in patients with cirrhosis and portal hypertension with varices either for primary or secondary prophylaxis. Recommended agents for primary prophylaxis of variceal hemorrhage are pro-

Secondary prophylaxis with nonspecific beta blocker (NSBB) has been shown to be effective in decreasing both the risk of recurrent bleeding and mortality [41, 42]. Without secondary prophylaxis, rebleeding occurs in approximately 60% to 70% of patients, usually within one to two years of the index hemorrhagic event [43]. Most used NSBB for secondary prophylaxis is propranolol but carvedilol can also be used. The decrease in HR at 6 weeks was significantly higher in carvedilol than propranolol group (p = 0.036). The rebleeding at least once within 6 months was also higher

It is the characteristic appearance which is a mosaic-like pattern or a diffuse, erythematous and reticular cobblestone pattern of gastric mucosa consisting of small polygonal areas, with or without superimposed red punctate lesions, >2 mm in diameter and a depressed white border [45–47]. PHG is classified as mild or severe. Mild PHG has features like fine pink speckling (scarlatina-type rash), and mosaic pattern (snakeskin appearance) and Severe one has discrete red spots or

The prevalence of PHG in Nepalese population with Chronic Liver Diseases (CLD) was 67 percent [49] though it varies significantly from 16 to 100 percentage

Patients with cirrhosis with portal hypertension may present with ascites leading to distension of abdomen and dyspnea. They will have flank fullness with dullness on examination. The grading of ascites as graded by International Club for Ascites

• Grade 2 – Moderate ascites manifested by moderate symmetrical distension of

Ascites may range from mild to refractory. Mild to moderate ascites should be managed by modest salt restriction and combination of loop diuretics and

[50]. Acute bleeding in PHG is estimated to occur in 2 to 12 percent [51].

• Grade 1 – Mild ascites detectable only by ultrasound examination

• Grade 3 – Large or gross ascites with marked abdominal distension

hemorrhage while local obliteration of varices is done by EVL.

in propranolol group than carvedilol group (32 vs. 22.7%) [44].

**5.1 Variceal hemorrhage**

pranolol and nadolol [39, 40].

**5.2 Portal hypertensive Gastropathy**

diffuse hemorrhagic lesion [48].

**5.3 Ascites**

are [52]:

the abdomen

potassium sparing diuretics.

**10**

Ultrasonographic detection of mild ascites is either pelvic or perihepatic or peri splenic ascites, while moderate ascites is presence of pelvic and perihepatic and perisplenic ascites, and marked ascites is diffuse ascites in the peritoneal cavity [52].

Diuretics should be added in a stepwise fashion along with sodium restriction. Gross ascites should be treated with therapeutic paracentesis followed by colloid volume expansion, and diuretic therapy. Sometimes refractory ascites is managed by repeated large volume paracentesis or insertion of a transjugular intrahepatic portosystemic stent shunt (TIPS) [53].

#### **5.4 Spontaneous bacterial peritonitis (SBP)**

Spontaneous bacterial peritonitis occurs with a prevalence of 10–25% in cirrhotic patients with ascites [54]. It can be community acquired, health care associated or nosocomial.

Major pathogenic organisms are *E. coli* (24.3%), followed by *Klebsiella pneumoniae* (12.0%) and *Enterococcus faecium* (10.5%). Nosocomial SBP has significantly higher proportion of Enterococcus (27.7% vs. 6.1%, P < 0.001) than community acquired SBP. Nosocomial SBP has a poorer outcome than community acquired pneumonia (24.6% vs. 36.8%; P = 0.016). The independent predictors for 30-day mortality are nosocomial infection, Child-Pugh classification, hepatocellular carcinoma, renal failure and hepatic encephalopathy [54].

Suspicion of nosocomial SBP should be done in a patient with SBP with a history of ICU stay during the previous 3 months or on prophylactic antibiotics for infection or had antibiotic treatment during previous 3 months or had a recent intervention in the hospital setting. Resistance to 3rd generation cephalosporins and quinolones has been documented in 40–50% of such cases [55].

Recently, Elsadek et al. found that Patients with SBP (n = 60) have significantly higher serum PEC index than those with sterile ascites (n = 118) (41.0/31.2–93.0 vs. 9.9/5.9–15.0, P < 0.001) and it distinguished culture positive cases significantly (P < 0.001) [56].

Diagnostic paracentesis should be performed in all patients who present with [57] (1) compatible signs or symptoms (abdominal pain and/or tenderness on palpation, fever, and chills); (2) impairment of the hepatic or renal function; (3) unexplained hepatic encephalopathy; (4) gastrointestinal bleeding.

SBP is diagnosed by polymorphonuclear cells ≥250 cells/mm3 in ascitic fluid in the absence of an intra-abdominal and surgically treatable source of infection. Other potential diagnostic methods are leukocyte esterase reagent strips (LERS), measurement of leukocyte-derived proteins such as granulocyte elastase and lactoferrin, detection of bacterial DNA using polymerase chain reaction (PCR) and detecting bacterial DNA in SBP ascites using in situ hybridization [57].

#### **5.5 Hepatorenal syndrome (HRS)**

HRS occurs in the setting of advanced cirrhosis and portal hypertension [58] with prevalence of 13–45 percentage [59]. It is characterized by peripheral arterial vasodilatation and intrarenal vasoconstriction with decrease in renal blood flow and renal dysfunction. The most recent proposed diagnostic criteria for HRS-AKI are as-.

Diagnostic Criteria for HRS-AKI [60].

• Cirrhosis with ascites; acute liver failure; acute-on-chronic liver failure


\*The evaluation of this parameter requires a urinary catheter.

\*\*This criterion would not be included in cases of known pre-existing structural chronic kidney disease (e. g. diabetic or hypertensive nephropathy). AKI, acute kidney injury; FENa, fractional excretion of sodium; HRS, hepatorenal syndrome.

Nowadays, HRS has been classified as HRS-AKI and HRS-NAKI. The diagnosis. of HRS-NAKI has been proposed to be made in the context of CKD, or AKD that does not meet the criteria for AKI and lasts for <90 days.

HRS-AKD is defined as a percent increase in sCr <50% or as an eGFR <60 min/ ml per 1.73 m2 for <3 months with the fulfillment of the ICA criteria for HRS.

HRS-CKD defined as an eGFR <60 ml/min per 1.73 m2 for ≥3 months with the fulfillment of the ICA criteria.

Treatment can be done with terlipressin with albumin as medical treatment or with liver transplantation.

#### **5.6 Hepatic hydrothorax**

Hepatic hydrothorax (HH) is defined as the excessive (> 500 mL) accumulation of transudate fluid in the pleural cavity in patients with decompensated liver cirrhosis (LC) with exclusion of cardiopulmonary and pleural diseases [61]. It is present in 5–10% of cirrhotic patients. Right sided HH is common accounting for almost 85% of cases followed by left sided (13%). The mechanism of HH is due to negative intrathoracic pressure and liver acting as piston which results the ascitic fluid to move from the peritoneal cavity into the pleural space through small defects located mainly on the right side of the diaphragmatic tendon [61, 62]. Huang et al. [63] classified diaphragmatic defects into four types: (1) Type 1 - no obvious defects; (2) Type 2 – blebs lying on the diaphragm; (3) Type 3 – broken defects (fenestrations) in the diaphragm; (4) Type 4 – multiple gaps in the diaphragm.

The diagnostic criteria [61] for HH are listed in **Table 4**.

The options for treatment for refractory HH are low sodium diet with therapeutic thoracocentesis, pleurodesis, mesh repair of diaphragmatic defects, transjugular

**13**

been seen [65].

mesenteric vasodilatation.

*Brief Review of Portal Hypertension Related Complications*

intrahepatic portosystemic shunt (TIPS), pleuro-venous or peritoneo-venous

**Criteria Values**

< 250/mm3 < 25 g/L < 0.5 > 0.6 > 1.1 < 0.6 > 7.4

HPS is defined as a disorder in pulmonary oxygenation, caused by intrapulmonary. vasodilatation and, less commonly, by pleural and pulmonary arteriovenous communications occurring in the clinical setting of portal hypertension. HPS has been reported in 10% of patients with chronic viral hepatitis in 15–23% of those

1.Hypoxia with partial pressure of oxygen <80 mmHg or alveolar–arterial oxygen gradient ≥15 mmHg in ambient air (≥20 mmHg in patients older than 65 years).

2.Pulmonary vascular defect with positive findings on contrast-enhanced echocardiography (i.e., microbubble opacification of the left heart chambers three to six cycles after right atrial passage) or abnormal uptake in the brain (>6%)

Spontaneous resolution of HPS is less likely and the definite treatment is liver transplantation however long-term oxygen therapy remains the most frequently recommended therapy for symptoms in patients with severe hypoxaemia. No established medical therapy is found however some improvement in Pao2 with garlic has

Vasoconstriction, vascular remodeling, and proliferative and thrombotic events within the pulmonary circulation lead to POPH. The presence of portal hypertension, hemodynamic measurements of mean pulmonary artery pressure > 25 mmHg at rest, mean pulmonary capillary wedge pressure < 15 mmHg, and pulmonary

POPH is commonly diagnosed during fifth decade of life, 4–7 years after the presence of portal hypertension has been established [67]. Symptoms include dyspnea, fatigue, light headedness, and orthopnea in patients with liver cirrhosis or portal hypertension. Diuretics can be used for symptomatic control with close monitoring. Calcium channel blockers can worsen portal hypertension by causing

shunting though liver transplantation is the definite therapy.

with cirrhosis and in 28% of those with Budd-Chiari syndrome [64].

**5.7 Hepato-pulmonary syndrome (HPS)**

The diagnostic criteria for HPS are [64]:

with radioactive lung-perfusion scanning.

vascular resistance >240 dynes/cm−5 confirm POPH [66].

**5.8 Portopulmonary syndrome (POPH)**

*DOI: http://dx.doi.org/10.5772/intechopen.96646*

Pleural effusion total protein/serum total protein ratio Pleural effusion Lactate dehydrogenase (LDH)/serum LDH ratio

Pleural effusion glucose level is equal to serum glucose

Count of white blood cells in pleural fluid Pleural effusion total protein level

Pleural effusion albumin/serum albumin ratio Pleural effusion bilirubin /serum bilirubin ratio

*The diagnostic criteria for hepatic hydrothorax.*

pH

level

**Table 4.**


#### **Table 4.**

*Portal Hypertension - Recent Advances*

100 gm/day

• Absence of shock

being highly predictive)

fulfillment of the ICA criteria.

with liver transplantation.

**5.6 Hepatic hydrothorax**

syndrome.

and/or urinary output ≤0.5 ml/kg B.W. ≥ 6 h\*

• No current or recent treatment with nephrotoxic drugs

\*The evaluation of this parameter requires a urinary catheter.

does not meet the criteria for AKI and lasts for <90 days.

in the diaphragm; (4) Type 4 – multiple gaps in the diaphragm. The diagnostic criteria [61] for HH are listed in **Table 4**.

• Increase in serum creatinine ≥0.3 mg/dl within 48 h or ≥ 50% from baseline value according to International Club of Ascites (ICA) consensus document

• No full or partial response, according to the ICA consensus, after at least 2 days of diuretic withdrawal and volume expansion with albumin. The recommended dose of albumin is 1 gm/kg of body weight per day to a maximum of

• Absence of parenchymal disease as indicated by proteinuria >500 mg/day, micro-hematuria (>50 red blood cells per high power field), urinary injury biomarkers (if available) and/or abnormal renal ultrasonography\*\*.

• Suggestion of renal vasoconstriction with FENa of <0.2% (with levels <0.1%

\*\*This criterion would not be included in cases of known pre-existing structural chronic kidney disease (e. g. diabetic or hypertensive nephropathy). AKI, acute kidney injury; FENa, fractional excretion of sodium; HRS, hepatorenal

Nowadays, HRS has been classified as HRS-AKI and HRS-NAKI. The diagnosis. of HRS-NAKI has been proposed to be made in the context of CKD, or AKD that

HRS-AKD is defined as a percent increase in sCr <50% or as an eGFR <60 min/

HRS-CKD defined as an eGFR <60 ml/min per 1.73 m2 for ≥3 months with the

Treatment can be done with terlipressin with albumin as medical treatment or

Hepatic hydrothorax (HH) is defined as the excessive (> 500 mL) accumulation of transudate fluid in the pleural cavity in patients with decompensated liver cirrhosis (LC) with exclusion of cardiopulmonary and pleural diseases [61]. It is present in 5–10% of cirrhotic patients. Right sided HH is common accounting for almost 85% of cases followed by left sided (13%). The mechanism of HH is due to negative intrathoracic pressure and liver acting as piston which results the ascitic fluid to move from the peritoneal cavity into the pleural space through small defects located mainly on the right side of the diaphragmatic tendon [61, 62]. Huang et al. [63] classified diaphragmatic defects into four types: (1) Type 1 - no obvious defects; (2) Type 2 – blebs lying on the diaphragm; (3) Type 3 – broken defects (fenestrations)

The options for treatment for refractory HH are low sodium diet with therapeutic thoracocentesis, pleurodesis, mesh repair of diaphragmatic defects, transjugular

ml per 1.73 m2 for <3 months with the fulfillment of the ICA criteria for HRS.

**12**

*The diagnostic criteria for hepatic hydrothorax.*

intrahepatic portosystemic shunt (TIPS), pleuro-venous or peritoneo-venous shunting though liver transplantation is the definite therapy.

#### **5.7 Hepato-pulmonary syndrome (HPS)**

HPS is defined as a disorder in pulmonary oxygenation, caused by intrapulmonary. vasodilatation and, less commonly, by pleural and pulmonary arteriovenous communications occurring in the clinical setting of portal hypertension. HPS has been reported in 10% of patients with chronic viral hepatitis in 15–23% of those with cirrhosis and in 28% of those with Budd-Chiari syndrome [64].

The diagnostic criteria for HPS are [64]:


Spontaneous resolution of HPS is less likely and the definite treatment is liver transplantation however long-term oxygen therapy remains the most frequently recommended therapy for symptoms in patients with severe hypoxaemia. No established medical therapy is found however some improvement in Pao2 with garlic has been seen [65].

#### **5.8 Portopulmonary syndrome (POPH)**

Vasoconstriction, vascular remodeling, and proliferative and thrombotic events within the pulmonary circulation lead to POPH. The presence of portal hypertension, hemodynamic measurements of mean pulmonary artery pressure > 25 mmHg at rest, mean pulmonary capillary wedge pressure < 15 mmHg, and pulmonary vascular resistance >240 dynes/cm−5 confirm POPH [66].

POPH is commonly diagnosed during fifth decade of life, 4–7 years after the presence of portal hypertension has been established [67]. Symptoms include dyspnea, fatigue, light headedness, and orthopnea in patients with liver cirrhosis or portal hypertension. Diuretics can be used for symptomatic control with close monitoring. Calcium channel blockers can worsen portal hypertension by causing mesenteric vasodilatation.

#### **5.9 Portal hypertensive colopathy**

Severe portal hypertension can cause lower gastrointestinal bleeding and cause anemia. Portal hypertensive colopathy has been defined endoscopically in patients with vascular ectasia, redness, and blue vein. Vascular ectasia is classified into two types: type 1, solitary vascular ectasia; and type 2, diffuse vascular ectasia. Overall portal hypertensive colopathy is found in 2/3rd of the cirrhotic patients including solitary vascular ectasia in 36%, diffuse vascular ectasia in 42%, red ness in 21% and blue vein in 12 percent [68]. Worsening of Child Pugh class and decrease in platelet count increases prevalence of portal hypertensive colopathy in patients with liver cirrhosis warranting colonoscopy to prevent lower gastrointestinal bleeding.

#### **5.10 Cirrhotic cardiomyopathy**

The diagnostic criteria of cirrhotic cardiomyopathy [69] are enumerated in **Table 5**. Decreased cardiac responsiveness (chronotropic and inotropic incompetence) through the defect in cardiac β-adrenergic receptor signaling is the main mechanism for systolic dysfunction in cirrhotic cardiomyopathy. The presence of cardiodepressant substances such as nitric oxide (NO) and carbon monoxide (CO) and endogenous cannabinoids also play role [70, 71]. Potential mechanisms for diastolic dysfunction are alteration in collagen configuration, sodium retention and activation of renin angiotensin aldosterone System (RAAS) [72].

Salt and fluid restriction, diuretics and afterload reduction are the aspects of treatment in cirrhotic cardiomyopathy. Compared with non-cirrhotics the benefit of β-blockers in cirrhotic heart failure is not clear. The use of non-selective β-blocker has been shown to reduce prolonged QT interval toward normal values in patients with cirrhosis along with some beneficial effect in improving electromechanical uncoupling [73]. Possible cure for cirrhotic cardiomyopathy is liver transplantation.

#### **5.11 Portal biliopathy**

Presence of biliary abnormalities in patients with non-cirrhotic/non-neoplastic extrahepatic portal vein obstruction (EHPVO) and portal cavernoma (PC) is called


**15**

*Brief Review of Portal Hypertension Related Complications*

**cavernoma**

portal biliopathy. Compression of bile ducts by PC and/or to ischemic damage secondary to an altered biliary vascularization in EHPVO and PC leads to contribution

**Biliopathy Liver** 

Preclinic Yes No Normal No No

changes

changes

changes

**function tests**

Normal or abnormal

**Symptoms Complications**

No No

Abnormal yes No

Abnormal Yes Yes

Normally, epicholedochal venous plexus of Saint and the paracholedochal plexus of Petren, whose normal diameter does not exceed 1 mm, are responsible for the venous drainage of the biliary tree. Dilation of plexus of Saint causes fine irregularities in biliary walls while dilation of plexus of Petren causes extrinsic compression in chronic portal vein obstruction. Patients present with jaundice, cholangitis, cholecystitis, abdominal pain, and cholelithiasis. Around 5%–38% of patients develop biliary symptoms [74]. Dhiman et al. [75] identified four stages in PB progression (**Table 6**). On the aspect of treatment, surgical porto-systemic shunt or transjugular intrahepatic porto-systemic shunt can be performed, and treatment on the biliary stenosis includes endoscopic (Endoscopic retrograde cholangiopancreatography with endoscopic sphincterotomy, balloon dilation, stone extraction, stent placement) and surgical (bilioenteric anastomosis, cholecystectomy) approaches are

Besides different surgeries with portosystemic shunting, there are newer drugs developed for reduction of portal pressure. Few drugs which have been seen to be

Obeticholic acid (OCA), a semisynthetic FXR agonist tested in preclinical models of cirrhosis has shown beneficial effects as transcriptional modulator on PH

Statins have antioxidative, antiproliferative and anti-inflammatory effects, and

They have shown strong hepatosinusoidal protective effects in preclinical models of chronic liver diseases, ultimately leading to reduction in portal pressure [78, 79]. Simvastatin has shown beneficial effects when administered alone or

by reducing the intrahepatic vascular resistance (IHVR) [76].

*DOI: http://dx.doi.org/10.5772/intechopen.96646*

Asymptomatic Yes Early

Symptomatic Yes Advanced

Complicated Yes Advanced

*Characteristics of four stages in portal biliopathy natural history.*

**Stage Portal** 

used for decompression of portal cavernoma.

**6.1 Farnesoid X receptor (FXR) agonists**

can improve endothelial dysfunction [77].

combined with beta blockers [80, 81].

**6. Future perspectives**

beneficial are:

**6.2 Statins**

of this complication.

**Table 6.**

#### **Table 5.**

*Diagnostic criteria for cirrhotic cardiomyopathy.*


#### **Table 6.**

*Portal Hypertension - Recent Advances*

**5.9 Portal hypertensive colopathy**

**5.10 Cirrhotic cardiomyopathy**

**5.11 Portal biliopathy**

Severe portal hypertension can cause lower gastrointestinal bleeding and cause anemia. Portal hypertensive colopathy has been defined endoscopically in patients with vascular ectasia, redness, and blue vein. Vascular ectasia is classified into two types: type 1, solitary vascular ectasia; and type 2, diffuse vascular ectasia. Overall portal hypertensive colopathy is found in 2/3rd of the cirrhotic patients including solitary vascular ectasia in 36%, diffuse vascular ectasia in 42%, red ness in 21% and blue vein in 12 percent [68]. Worsening of Child Pugh class and decrease in platelet count increases prevalence of portal hypertensive colopathy in patients with liver cirrhosis warranting colonoscopy to prevent lower gastrointestinal bleeding.

The diagnostic criteria of cirrhotic cardiomyopathy [69] are enumerated in **Table 5**. Decreased cardiac responsiveness (chronotropic and inotropic incompetence) through the defect in cardiac β-adrenergic receptor signaling is the main mechanism for systolic dysfunction in cirrhotic cardiomyopathy. The presence of cardiodepressant substances such as nitric oxide (NO) and carbon monoxide (CO) and endogenous cannabinoids also play role [70, 71]. Potential mechanisms for diastolic dysfunction are alteration in collagen configuration, sodium retention and

Salt and fluid restriction, diuretics and afterload reduction are the aspects of treatment in cirrhotic cardiomyopathy. Compared with non-cirrhotics the benefit of β-blockers in cirrhotic heart failure is not clear. The use of non-selective β-blocker has been shown to reduce prolonged QT interval toward normal values in patients with cirrhosis along with some beneficial effect in improving electromechanical uncoupling [73]. Possible cure for cirrhotic cardiomyopathy is liver transplantation.

Presence of biliary abnormalities in patients with non-cirrhotic/non-neoplastic extrahepatic portal vein obstruction (EHPVO) and portal cavernoma (PC) is called

Prolonged isovolumetric relaxation time > 80 ms

Increased brain natriuretic peptide or pro-peptide

Diastolic dysfunction Early diastolic atrial filling (E/A ratio) < 1.0 (age corrected) Deceleration time (DT) > 200 ms

Supportive criteria Electrophysiological abnormalities (prolongation of QT) Abnormal chronotropic response Electromechanical uncoupling

> Enlarged left atrium Increased myocardial mass

Increased troponin I

*Diagnostic criteria for cirrhotic cardiomyopathy.*

Blunted increase in cardiac output with exercise or pharmacological stimuli

activation of renin angiotensin aldosterone System (RAAS) [72].

Systolic dysfunction Resting ejection fraction <55%

**14**

**Table 5.**

*Characteristics of four stages in portal biliopathy natural history.*

portal biliopathy. Compression of bile ducts by PC and/or to ischemic damage secondary to an altered biliary vascularization in EHPVO and PC leads to contribution of this complication.

Normally, epicholedochal venous plexus of Saint and the paracholedochal plexus of Petren, whose normal diameter does not exceed 1 mm, are responsible for the venous drainage of the biliary tree. Dilation of plexus of Saint causes fine irregularities in biliary walls while dilation of plexus of Petren causes extrinsic compression in chronic portal vein obstruction. Patients present with jaundice, cholangitis, cholecystitis, abdominal pain, and cholelithiasis. Around 5%–38% of patients develop biliary symptoms [74]. Dhiman et al. [75] identified four stages in PB progression (**Table 6**).

On the aspect of treatment, surgical porto-systemic shunt or transjugular intrahepatic porto-systemic shunt can be performed, and treatment on the biliary stenosis includes endoscopic (Endoscopic retrograde cholangiopancreatography with endoscopic sphincterotomy, balloon dilation, stone extraction, stent placement) and surgical (bilioenteric anastomosis, cholecystectomy) approaches are used for decompression of portal cavernoma.

#### **6. Future perspectives**

Besides different surgeries with portosystemic shunting, there are newer drugs developed for reduction of portal pressure. Few drugs which have been seen to be beneficial are:

#### **6.1 Farnesoid X receptor (FXR) agonists**

Obeticholic acid (OCA), a semisynthetic FXR agonist tested in preclinical models of cirrhosis has shown beneficial effects as transcriptional modulator on PH by reducing the intrahepatic vascular resistance (IHVR) [76].

#### **6.2 Statins**

Statins have antioxidative, antiproliferative and anti-inflammatory effects, and can improve endothelial dysfunction [77].

They have shown strong hepatosinusoidal protective effects in preclinical models of chronic liver diseases, ultimately leading to reduction in portal pressure [78, 79]. Simvastatin has shown beneficial effects when administered alone or combined with beta blockers [80, 81].

#### **6.3 Anti-apoptotic drugs**

Emricasan has been seen to improve portal pressure and IHVR compared with vehicle-treated rats, in addition to improved liver function and microcirculation, and finally with improved liver sinusoidal endothelial cell (LSEC) and hepatic stellate cells (HSC) phenotype and reduced inflammation [82].

#### **6.4 Anticoagulants**

Rivaroxaban, direct inhibitor of factor Xa has been shown to reduce liver microthrombosis, HSC activation and portal pressure in experimental models of cirrhosis [83].

#### **6.5 Antidiabetic drugs**

Liraglutide has shown antifibrotic effects in NASH patients, thus with high probabilities of success as a treatment for portal hypertension and chronic liver disease [84]. Metformin has shown to improve liver hemodynamic and fibrosis by a reduction in inflammation and oxidative stress [85].

#### **6.6 Anti-inflammatory agents**

Anti-inflammatory drugs such as rapamycin have reduced portal pressure in rats with Portal hypertension due to its intrahepatic and extrahepatic effects [86, 87].

#### **6.7 Taurine**

Taurine has pleiotropic effects. A small cohort of patients with clinically significant PH (HVPG >12 mmHg) has reported reduction in portal pressure [88]. Thus, consumption of low carbonated 'energy drinks' rich in taurine may have a positive impact in portal hypertension.

#### **7. Conclusion**

Portal Hypertension is responsible for many complications in liver cirrhosis. Reduction of portal pressure decreases the rate of complications in advanced liver diseases. This can improve the quality of life and increase the survival of such patients.

**17**

**Author details**

Achyut Bikram Hamal

Nepal Police Hospital, Kathmandu, Nepal

provided the original work is properly cited.

\*Address all correspondence to: abhamal@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is 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,

*Brief Review of Portal Hypertension Related Complications*

*DOI: http://dx.doi.org/10.5772/intechopen.96646*

### **Conflict of interest**

None.

*Brief Review of Portal Hypertension Related Complications DOI: http://dx.doi.org/10.5772/intechopen.96646*

*Portal Hypertension - Recent Advances*

Emricasan has been seen to improve portal pressure and IHVR compared with vehicle-treated rats, in addition to improved liver function and microcirculation, and finally with improved liver sinusoidal endothelial cell (LSEC) and hepatic stel-

Rivaroxaban, direct inhibitor of factor Xa has been shown to reduce liver microthrombosis, HSC activation and portal pressure in experimental models of

Liraglutide has shown antifibrotic effects in NASH patients, thus with high probabilities of success as a treatment for portal hypertension and chronic liver disease [84]. Metformin has shown to improve liver hemodynamic and fibrosis by a

Anti-inflammatory drugs such as rapamycin have reduced portal pressure in rats with Portal hypertension due to its intrahepatic and extrahepatic effects [86, 87].

Taurine has pleiotropic effects. A small cohort of patients with clinically significant PH (HVPG >12 mmHg) has reported reduction in portal pressure [88]. Thus, consumption of low carbonated 'energy drinks' rich in taurine may have a positive

Portal Hypertension is responsible for many complications in liver cirrhosis. Reduction of portal pressure decreases the rate of complications in advanced liver diseases. This can improve the quality of life and increase the survival of such patients.

late cells (HSC) phenotype and reduced inflammation [82].

reduction in inflammation and oxidative stress [85].

**6.3 Anti-apoptotic drugs**

**6.4 Anticoagulants**

**6.5 Antidiabetic drugs**

**6.6 Anti-inflammatory agents**

impact in portal hypertension.

cirrhosis [83].

**6.7 Taurine**

**7. Conclusion**

**Conflict of interest**

None.

**16**

#### **Author details**

Achyut Bikram Hamal Nepal Police Hospital, Kathmandu, Nepal

\*Address all correspondence to: abhamal@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is 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.

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529-539.

*Brief Review of Portal Hypertension Related Complications DOI: http://dx.doi.org/10.5772/intechopen.96646*

cirrhotic portal hypertension in rats through inhibition of mTORC1 but not mTORC2. PLoS One 2014; 9: e83908.

*Portal Hypertension - Recent Advances*

747-752.

[71] Van Obbergh L, Vallieres Y, Blaise G. Cardiac modifications occurring in the ascitic rat with biliary cirrhosis are nitric oxide related. J Hepatol. 1996;24:

[79] Abraldes JG, Rodríguez-Vilarrupla A, Graupera M, et al. Simvastatin treatment improves liver sinusoidal endothelial dysfunction in CCl4 cirrhotic rats. J Hepatol 2007; 46: 1040-1046.

[80] Pollo-Flores P, Soldan M, Santos UC, et al. Three months of simvastatin therapy vs. placebo for severe portal hypertension in cirrhosis: a randomized controlled trial. Dig Liver Dis 2015; 47:

[81] Abraldes JG, Villanueva C, Aracil C, et al. Addition of simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis. Gastroenterology 2016; 150:

[82] Gracia-Sancho J, Contreras PC, Vila S, et al. The pan caspase inhibitor emricasan improves the hepatic microcirculatory dysfunction of CCl4-cirrhotic rats leading to portal hypertension amelioration and cirrhosis regression. Hepatology 2016; 64:

[83] Vilaseca M, García-Calderó H, Lafoz E, et al. The anticoagulant rivaroxaban lowers portal hypertension in cirrhotic rats mainly by deactivating hepatic stellate cells. Hepatology 2017;

[84] Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic

steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebocontrolled phase 2 study. Lancet 2016;

[85] Tripathi DM, Erice E, Lafoz E, et al. Metformin reduces hepatic resistance and portal pressure in cirrhotic rats. Am J Physiol Gastrointest Liver Physiol

[86] Wang W, Yan J, Wang H, et al. Rapamycin ameliorates inflammation and fibrosis in the early phase of

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[72] Wong F. Cirrhotic cardiomyopathy.

Hepatol Int. 2009; 3:294-304.

[73] Henriksen JH, Bendtsen F, Hansen EF, Moller S. Acute nonselective beta-adrenergic blockade reduces prolonged frequency-adjusted Q-T interval (QTc) in patients with cirrhosis. J Hepatol. 2004; 40:239-246.

[74] Franceschet I, Zanetto A, Ferrarese A, Burra P, Senzolo M. Therapeutic approaches for portal biliopathy: A systematic review. World J Gastroenterol. 2016 Dec 7;

Chawla Y, Behera A, Varma V,

[75] Dhiman RK, Saraswat VA, Valla DC,

Agarwal S, Duseja A, Puri P, Kalra N, et al. Portal cavernoma cholangiopathy: consensus statement of a working party of the Indian national association for study of the liver. J Clin Exp Hepatol.

[76] Verbeke L, Farre R, Trebicka J, Komuta M, Roskams T, Klein S, Elst IV, Windmolders P, Vanuytsel T, Nevens F, Laleman W. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology. 2014 Jun;

[77] Pose E, Trebicka J, Mookerjee RP, Angeli P, Ginès P. Statins: old drugs as new therapy for liver diseases? Journal of hepatology. 2019 Jan 1;70(1):194-202.

[78] Trebicka J, Hennenberg M, Laleman W, et al. Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase. Hepatology 2007; 46: 242-253.

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2014;4: S2–S14.

59(6):2286-2298.

**22**

[87] Mejias M, Garcia-Pras E, Gallego J, et al. Relevance of the mTOR signaling pathway in the pathophysiology of splenomegaly in rats with chronic portal hypertension. J Hepatol 2010; 52: 529-539.

[88] Schwarzer R, Kivaranovic D, Mandorfer M, Paternostro R, Wolrab D, Heinisch B, Reiberger T, Ferlitsch M, Gerner C, Trauner M, Peck-Radosavljevic M. Randomised clinical study: the effects of oral taurine 6 g/day vs placebo on portal hypertension. Alimentary pharmacology & therapeutics. 2018 Jan; 47(1):86-94.

**25**

**Chapter 2**

**Abstract**

*Reda A. Zbaida*

pediatric portal hypertension.

**1. Introduction**

bleeding. [1]

**2. Embryology**

3rd week of gestation.

selective shunts, non-selective shunts

which leads to hyperdynamic circulation.

flattened and is circumferential. [2]

Pediatric Portal Hypertension

Portal hypertension is increased intravascular pressure of the portal vein. The prevalence of causes in children is different from adults ones. The commonest cause of pediatric portal hypertension is the extra-hepatic portal hypertension, comparing with an adult where liver cirrhosis is the comments cause. Also, taking into consideration, the fundamental physiological differences between the two age groups. These elements are making the attempt to extrapolate the adult guidelines to the pediatric age group unpractical. On the other hand, the limitation of well-designed studies in the pediatric age group makes reaching a consensus about the safety and efficiency of primary prophylaxis of variceal bleeding difficult. In contrast, there were enough data to recommend the secondary prophylaxis of variceal bleeding and the safety and efficiency of Meso-Rex shunt for portal hypertension have been confirmed. These indicate the necessity of further studies to reach a complete algorithm of guidelines for

**Keywords:** portal hypertension, children, esophageal varices, variceal bleeding,

The portal hypertension is caused by an increased resistance to venous flow in portal vein. Which leads to an increase to pressure in the portal circulation. It is a result of chronic liver disease, obstruction of portal vein, or portosystemic shunt,

The normal hepatic venous pressure gradient (HVPG) correlates with normal portal pressure which is 1–4 mm Hg. A pressure gradient of more than 10 mm Hg links to esophageal varices. The pressure 12 mm Hg predicts the risk of active

The most common complication of pediatric portal hypertension is acute variceal bleeding. The grading system of the Japanese Research Society for Portal Hypertension of esophageal varices is as follows: grade 1: flattened by insufflation, grade 2: not flattened by insufflation but is not circumferential, grade 3: not

The three main venous embryo systems will be recognizable by the end of the

## **Chapter 2** Pediatric Portal Hypertension

*Reda A. Zbaida*

### **Abstract**

Portal hypertension is increased intravascular pressure of the portal vein. The prevalence of causes in children is different from adults ones. The commonest cause of pediatric portal hypertension is the extra-hepatic portal hypertension, comparing with an adult where liver cirrhosis is the comments cause. Also, taking into consideration, the fundamental physiological differences between the two age groups. These elements are making the attempt to extrapolate the adult guidelines to the pediatric age group unpractical. On the other hand, the limitation of well-designed studies in the pediatric age group makes reaching a consensus about the safety and efficiency of primary prophylaxis of variceal bleeding difficult. In contrast, there were enough data to recommend the secondary prophylaxis of variceal bleeding and the safety and efficiency of Meso-Rex shunt for portal hypertension have been confirmed. These indicate the necessity of further studies to reach a complete algorithm of guidelines for pediatric portal hypertension.

**Keywords:** portal hypertension, children, esophageal varices, variceal bleeding, selective shunts, non-selective shunts

#### **1. Introduction**

The portal hypertension is caused by an increased resistance to venous flow in portal vein. Which leads to an increase to pressure in the portal circulation. It is a result of chronic liver disease, obstruction of portal vein, or portosystemic shunt, which leads to hyperdynamic circulation.

The normal hepatic venous pressure gradient (HVPG) correlates with normal portal pressure which is 1–4 mm Hg. A pressure gradient of more than 10 mm Hg links to esophageal varices. The pressure 12 mm Hg predicts the risk of active bleeding. [1]

The most common complication of pediatric portal hypertension is acute variceal bleeding. The grading system of the Japanese Research Society for Portal Hypertension of esophageal varices is as follows: grade 1: flattened by insufflation, grade 2: not flattened by insufflation but is not circumferential, grade 3: not flattened and is circumferential. [2]

#### **2. Embryology**

The three main venous embryo systems will be recognizable by the end of the 3rd week of gestation.

They include (1) the 2 cardinal veins which drain the embryo blood (intraembryonic system). To the sinus venosus (primitive atrium). The other two are extraembryonic systems, one of them transports the blood from the yolk sac to the heart (sinus venosus) which is called (2) the vitelline veins (two pairs). Finally, (3) the 2 umbilical veins transport the oxygenated blood from the placenta to the embryo's heart. [3]

The hepatic bud starts branching off from the caudal end of the foregut, which expands into the transversum septum (Mesenchymal tissue in the pericardiac area). The cephalic part of the hepatic bud will eventually form the liver. And the caudal part will form the biliary tree and the gall bladder. During liver development, the primitive liver tissue in the transversum septum is in close contact with the two extraembryonic venous systems (**Figure 1**).

**27**

*Pediatric Portal Hypertension*

anastomosis. [4]

liver surface anatomy.

*DOI: http://dx.doi.org/10.5772/intechopen.95243*

finally the subdiaphragmatic anastomosis.

the definitive fetal portal circulation is formed. [4]

takes 15–20 days for complete closure. [3]

**3. Anatomy and collateral circulation**

branches continue breaking down up to the sinusoids.

true surgical division of the liver into right and left lobes. [5]

vitelline veins and umbilical veins.

The portal circulation of the liver develops between the 4th and 6th weeks, which is the result of a complex interaction between a primitive liver and a pair of

Initially, the vitelline veins form 4 sites of anastomoses between each other in their way to the sinus venosus, which are the caudal-ventral anastomosis, middle dorsal (they named according to their relation to the foregut), subhepatic, and

A net of smaller anastomoses between the right and the left vitelline veins extend in the area between the subdiaphragmatic and the subhepatic anastomoses in the same site where the hepatic bud will proliferate and develop to form the liver (the caudal part of the septum transversum). Synchronously, the umbilical veins in their way to the sinus venosus each vein are divided into 2 branches. One runs in parallel to the primitive liver and the other one ends in the liver parenchyma. The right umbilical vein and its branches atrophy in the 4th week. Also, the direct branch to the sinus venosus disappears in the same period. But the left branch of the umbilical vein to the liver parenchyma persists. It increases in size gradually inside liver parenchyma till communicates with the left end of the subhepatic anastomosis of the vitelline veins. That is known as a portal sinus. So, all the oxygenated blood is conveyed to the liver via the left umbilical vein. Due to massive blood influx to the liver, one of the anastomosing veins between the subhepatic and subdiaphragmatic anastomoses increases in size tremendously (Ductus venosus) to accommodate the oxygenated blood from the portal sinus to sinus venosus via a subdiaphragmatic

The future portal vein is formed of the inferior section of the left vitelline vein, middle dorsal anastomosis, and the superior section of the right vitelline vein. By end of this process in the 6th week, the S-shape portal vein starts to appear. By this,

The next major event happens at birth when the umbilical blood flow ceases. Subsequently, intravascular pressure in the umbilical vein and the ductus venosus drop and obliterating of these veins start within minutes after birth, which usually

The portal vein is formed by the union of the superior mesenteric and the splenic veins behind the neck of the pancreas. It passes behind the first part of the duodenum, then it runs in the free edge of the lesser momentum posterior to the common bile duct (on the right side) and hepatic artery proper (on the left side) up to the porta hepatis where it divides into right and the left portal veins. Both main

There is a specific pattern of the breakdown of the portal vein, the biliary duct, and hepatic arteries within the liver parenchyma, which does not correlate with the

The Cantlie's line extends from the inferior vena cava to the fundus of the gall bladder, which divides the liver into right and left lobes. Cantlie's line represents the

The description of further portal triad breakdowns and its correlation with hepatic veins is delineated by a French surgeon and anatomist "Claude Couinaud", depending on his framework that every half further divides into sectors, and a hepatic sector according to Couinaud system (**Figure 2**) is a region bounded by 2 hepatic veins or a hepatic vein and the hepatic edge. And the segment in the region

#### **Figure 1.**

*Schematic drawing represents the relation between the primitive hepatic bud and the major fetal venous systems. (Courtesy of Collardeau-Frachon and Scoazec et al. [4]. All the rights reserved).*

#### *Pediatric Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.95243*

*Portal Hypertension - Recent Advances*

extraembryonic venous systems (**Figure 1**).

embryo's heart. [3]

They include (1) the 2 cardinal veins which drain the embryo blood (intraembryonic system). To the sinus venosus (primitive atrium). The other two are extraembryonic systems, one of them transports the blood from the yolk sac to the heart (sinus venosus) which is called (2) the vitelline veins (two pairs). Finally, (3) the 2 umbilical veins transport the oxygenated blood from the placenta to the

The hepatic bud starts branching off from the caudal end of the foregut, which expands into the transversum septum (Mesenchymal tissue in the pericardiac area). The cephalic part of the hepatic bud will eventually form the liver. And the caudal part will form the biliary tree and the gall bladder. During liver development, the primitive liver tissue in the transversum septum is in close contact with the two

*Schematic drawing represents the relation between the primitive hepatic bud and the major fetal venous* 

*systems. (Courtesy of Collardeau-Frachon and Scoazec et al. [4]. All the rights reserved).*

**26**

**Figure 1.**

The portal circulation of the liver develops between the 4th and 6th weeks, which is the result of a complex interaction between a primitive liver and a pair of vitelline veins and umbilical veins.

Initially, the vitelline veins form 4 sites of anastomoses between each other in their way to the sinus venosus, which are the caudal-ventral anastomosis, middle dorsal (they named according to their relation to the foregut), subhepatic, and finally the subdiaphragmatic anastomosis.

A net of smaller anastomoses between the right and the left vitelline veins extend in the area between the subdiaphragmatic and the subhepatic anastomoses in the same site where the hepatic bud will proliferate and develop to form the liver (the caudal part of the septum transversum). Synchronously, the umbilical veins in their way to the sinus venosus each vein are divided into 2 branches. One runs in parallel to the primitive liver and the other one ends in the liver parenchyma. The right umbilical vein and its branches atrophy in the 4th week. Also, the direct branch to the sinus venosus disappears in the same period. But the left branch of the umbilical vein to the liver parenchyma persists. It increases in size gradually inside liver parenchyma till communicates with the left end of the subhepatic anastomosis of the vitelline veins. That is known as a portal sinus. So, all the oxygenated blood is conveyed to the liver via the left umbilical vein. Due to massive blood influx to the liver, one of the anastomosing veins between the subhepatic and subdiaphragmatic anastomoses increases in size tremendously (Ductus venosus) to accommodate the oxygenated blood from the portal sinus to sinus venosus via a subdiaphragmatic anastomosis. [4]

The future portal vein is formed of the inferior section of the left vitelline vein, middle dorsal anastomosis, and the superior section of the right vitelline vein. By end of this process in the 6th week, the S-shape portal vein starts to appear. By this, the definitive fetal portal circulation is formed. [4]

The next major event happens at birth when the umbilical blood flow ceases. Subsequently, intravascular pressure in the umbilical vein and the ductus venosus drop and obliterating of these veins start within minutes after birth, which usually takes 15–20 days for complete closure. [3]

#### **3. Anatomy and collateral circulation**

The portal vein is formed by the union of the superior mesenteric and the splenic veins behind the neck of the pancreas. It passes behind the first part of the duodenum, then it runs in the free edge of the lesser momentum posterior to the common bile duct (on the right side) and hepatic artery proper (on the left side) up to the porta hepatis where it divides into right and the left portal veins. Both main branches continue breaking down up to the sinusoids.

There is a specific pattern of the breakdown of the portal vein, the biliary duct, and hepatic arteries within the liver parenchyma, which does not correlate with the liver surface anatomy.

The Cantlie's line extends from the inferior vena cava to the fundus of the gall bladder, which divides the liver into right and left lobes. Cantlie's line represents the true surgical division of the liver into right and left lobes. [5]

The description of further portal triad breakdowns and its correlation with hepatic veins is delineated by a French surgeon and anatomist "Claude Couinaud", depending on his framework that every half further divides into sectors, and a hepatic sector according to Couinaud system (**Figure 2**) is a region bounded by 2 hepatic veins or a hepatic vein and the hepatic edge. And the segment in the region

#### **Figure 2.**

*Drawing represents the Couinaud system and the relation of left portal vein to ligamentous teres in the umbilical fissure. (Courtesy of John E. Skandalakis et al. [6], All rights reserved).*

of the liver that has an independent portal triad (separate branches from the portal vein, the hepatic artery, and the biliary duct) supplies it. These anatomical facts guide the hepatobiliary surgeons to execute the hepatectomy (right or left) and segmentectomy precisely. [7]

The location of the Rex recess has an important surgical application in pediatric portal hypertension. That is where a branch from the left portal branch lies in the porto-umbilical fissure between the left lateral sector (segments II, III) and the left medial sector (segment IV). In intrauterine life, the left portal branch in the recess of Rex was communicating with the left umbilical vein. The fibrous remnant of the left umbilical postnatally known as ligamentous teres can be used as a reliable anatomical landmark for the recess of the Rex, which is surgically accessible and connecting it to the mesenteric vessel (superior mesenteric vein) via graft to bypass the portal occlusion and avoid the cavernoma, which is a net of collaterals formed after the portal obstruction in the area of porta hepatis. A portal vein occlusion is the commonest cause of portal hypertension in the pediatric age group.

Another important anatomical aspect of portal hypertension is the collateral anastomoses [8] between the portal and systemic circulations. Under normal circumstances, the mesenteric vein returns to the liver via the portal vein, then to the inferior vena cava (systemic circulation) via the hepatic veins to reach finally, the right atrium of the heart. This normal pathway would be interrupted in portal hypertension where the resistance to blood flow in the portal circulation is increased. This forces the blood to use the porto-systemic anastomoses as alternative pathways to reach the systemic circulation, which are negligible in normal situations. But in portal hypertension, these anastomoses increase in size with the increased potentiality of hemorrhage (ex: esophageal varices).

These anastomoses are as follows:

• The esophageal branches of the left gastric vein (a tributary of the portal circulation) anastomose with esophageal branches of hemiazygos vein (systemic circulation).

**29**

*Pediatric Portal Hypertension*

circulation).

**4. Causes**

hepatic lesions.

mation or malignancy. [10]

portal venous flow. [11]

*DOI: http://dx.doi.org/10.5772/intechopen.95243*

of the anterior abdominal wall.

ing the portal system to the systemic system.

• The anastomosis between the superior rectal vein (portal circulation) with the middle and inferior rectal veins (systemic circulation) in the anal canal.

• Paraumbilical anastomoses (caput medusa) are the communication between tributaries of portal vein which run in the falciform with the superficial veins

• The communications between veins of ascending colon, descending colon, and duodenum (portal circulation) with the left renal vein (systemic

• The veins of Retzius connect retroperitoneally between tributaries of inferior vena cava and tributaries of the superior and inferior mesenteric veins.

• The accessory portal system of sappey is a set of diaphragmatic veins connect-

The spectrum of causes is arranged in the pre-hepatic, the hepatic, and the post-

The portosystemic shunt is another cause of portal hypertension which can be surgical or iatrogenic cause or congenital shunts. Lautz et al. proposed a classification for congenital portosystemic shunts which divide them into 2 types. Type I with no intrahepatic portal venous flow. Type II with some intrahepatic

• *Hepatic lesions:* Hepatic cellular injury of any cause (e.g. Biliary atresia, Schistosomiasis) stimulates collagen deposition via activated stellate cells,

• *Post-hepatic lesions:* They include the hepatic veno-occlusive disease. [13] Busulfan containing regimes use for a bone marrow ablation in the bone marrow transplant considered are risk factors for hepatic veno-occlusive disease, because of hepatic and endothelial cellular injuries, which cause hepatic venules obstruction leading to venous congestion and eventually, to portal hypertension. Budd-Chiari syndrome is another cause of post-hepatic obstruction. Although it is uncommon in the pediatric age group, Budd-Chiari syndrome does occur in children. The level of obstruction can be at any level from the hepatic veins up to the level of the aortocaval junction. The most underlying cause of Budd-Chiari syndrome in children is the hypercoagulable

which leads to an increase resistance to venous outflow. [12]

state (Protein C, S deficiency, antithrombin III deficiency). [14]

• *Pre-hepatic lesions:* Extra-hepatic portal vein obstruction is the commonest cause of portal hypertension. The underlying cause of portal thrombosis is unidentifiable in most cases. [9] But it links to the predisposing factors. They are an injury to the portal vein in the cannulation of the umbilical vein, dehydration, abdominal sepsis, omphalitis, and hypercoagulable state. Another factor is the extra-mural compression like enlarged lymph node due to inflam-


### **4. Causes**

*Portal Hypertension - Recent Advances*

segmentectomy precisely. [7]

**Figure 2.**

of the liver that has an independent portal triad (separate branches from the portal vein, the hepatic artery, and the biliary duct) supplies it. These anatomical facts guide the hepatobiliary surgeons to execute the hepatectomy (right or left) and

*Drawing represents the Couinaud system and the relation of left portal vein to ligamentous teres in the* 

*umbilical fissure. (Courtesy of John E. Skandalakis et al. [6], All rights reserved).*

the commonest cause of portal hypertension in the pediatric age group.

increased potentiality of hemorrhage (ex: esophageal varices).

These anastomoses are as follows:

circulation).

Another important anatomical aspect of portal hypertension is the collateral anastomoses [8] between the portal and systemic circulations. Under normal circumstances, the mesenteric vein returns to the liver via the portal vein, then to the inferior vena cava (systemic circulation) via the hepatic veins to reach finally, the right atrium of the heart. This normal pathway would be interrupted in portal hypertension where the resistance to blood flow in the portal circulation is increased. This forces the blood to use the porto-systemic anastomoses as alternative pathways to reach the systemic circulation, which are negligible in normal situations. But in portal hypertension, these anastomoses increase in size with the

• The esophageal branches of the left gastric vein (a tributary of the portal circulation) anastomose with esophageal branches of hemiazygos vein (systemic

The location of the Rex recess has an important surgical application in pediatric portal hypertension. That is where a branch from the left portal branch lies in the porto-umbilical fissure between the left lateral sector (segments II, III) and the left medial sector (segment IV). In intrauterine life, the left portal branch in the recess of Rex was communicating with the left umbilical vein. The fibrous remnant of the left umbilical postnatally known as ligamentous teres can be used as a reliable anatomical landmark for the recess of the Rex, which is surgically accessible and connecting it to the mesenteric vessel (superior mesenteric vein) via graft to bypass the portal occlusion and avoid the cavernoma, which is a net of collaterals formed after the portal obstruction in the area of porta hepatis. A portal vein occlusion is

**28**

The spectrum of causes is arranged in the pre-hepatic, the hepatic, and the posthepatic lesions.

• *Pre-hepatic lesions:* Extra-hepatic portal vein obstruction is the commonest cause of portal hypertension. The underlying cause of portal thrombosis is unidentifiable in most cases. [9] But it links to the predisposing factors. They are an injury to the portal vein in the cannulation of the umbilical vein, dehydration, abdominal sepsis, omphalitis, and hypercoagulable state. Another factor is the extra-mural compression like enlarged lymph node due to inflammation or malignancy. [10]

The portosystemic shunt is another cause of portal hypertension which can be surgical or iatrogenic cause or congenital shunts. Lautz et al. proposed a classification for congenital portosystemic shunts which divide them into 2 types. Type I with no intrahepatic portal venous flow. Type II with some intrahepatic portal venous flow. [11]


### **5. Clinical presentations**

How the pediatric patient with portal hypertension is presented depends on 2 essential factors: (1) the site of the obstruction (2) whether the patient has liver cirrhosis or not.


**31**

*Pediatric Portal Hypertension*

**6. Work up**

damage.

• *Blood investigation:*

*DOI: http://dx.doi.org/10.5772/intechopen.95243*

product of hemoglobin breakdown. [23]

gation usually indicate hypersplenism.

variceal banding or sclerotherapy. [25]

Patients with portal hypertension may present with signs of liver disease if the underlying cause of portal hypertension is the damage of liver parenchyma. For example, *Ascites* develops due to 2 important factors: (1) protein synthesis failure in the liver which impairs the intravascular oncotic pressure (2) dilated abdominal vascular capillaries and lymphatic microcirculation as a result of the increased portal hydrostatic pressure. [22] *Jaundice* is another sign of decompensated liver function. It happens due to the inability of the liver to process the bilirubin as one

• *Complete blood count (CBC):* It is useful to identify the presence of and type of anemia. Also, it is essential in the management of acute variceal bleeding. The presence of thrombocytopenia and leukopenia in portal hypertension investi-

• *Liver function test:* It assesses the functionality of the liver. That will help to point toward the underlying cause of portal hypertension with help of other investigation modalities (see later). Low protein level (albumin) and prolonged coagulation profile indicate the impaired synthetic ability of the liver. The increased bilirubin level and hepatic enzymes indicate hepatocellular

• *Renal function test:* It assesses dehydration especially in acute variceal bleeding, and impaired renal function test associated with liver diseases, like congenital

Other investigations are requested according to the clinical status of the patients. Blood glucose will be low in decompensated liver cirrhosis and it is low in glycogen storage disease. Also, the ammonia level is indicated to confirm the diagnosis of encephalopathy. The coagulation screen in liver cirrhosis is prolonged. But in the extra-hepatic portal thrombosis, the coagulation profile shows secondary hypercoagulable abnormalities. [24] It will be reversed after the obstruction is overcomed.

• *Endoscopy:* It is an essential tool in portal hypertension management. It confirms the presence of varices in the esophagus and the stomach and identifies the cause of the upper GI bleeding whether from varices or other origins like hemorrhagic gastritis or Mallory-Weiss syndrome. Also, in cases of acute upper GI bleeding are not responsive to medical management, endoscopy offers an important therapeutic option to control the variceal bleeding whether via

• *Radiological modalities:* The first radiological modality in use as part of the diagnosis armamentarium is an abdominal ultrasound with Doppler. It provides a lot of important and useful information, which include the size, echogenicity of the liver, and presence of the cysts or nodules. It also delineates the status of the intra and extra biliary tree, the patency of the portal vein, and the presence of the cavernoma in the porta hepatis. The size and echogenicity of the spleen are demonstrated in the abdominal ultrasound. And by assessing the vascularity of the abdomen it can provide valuable information for the surgical team

hepatic fibrosis which linked to polycystic kidney disease.

*Pediatric Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.95243*

Patients with portal hypertension may present with signs of liver disease if the underlying cause of portal hypertension is the damage of liver parenchyma. For example, *Ascites* develops due to 2 important factors: (1) protein synthesis failure in the liver which impairs the intravascular oncotic pressure (2) dilated abdominal vascular capillaries and lymphatic microcirculation as a result of the increased portal hydrostatic pressure. [22] *Jaundice* is another sign of decompensated liver function. It happens due to the inability of the liver to process the bilirubin as one product of hemoglobin breakdown. [23]

#### **6. Work up**

*Portal Hypertension - Recent Advances*

How the pediatric patient with portal hypertension is presented depends on 2 essential factors: (1) the site of the obstruction (2) whether the patient has liver

• *Upper GI bleeding:* It is a frightening and common presenting symptom of portal hypertension in the pediatric age group. About 70% of the extra-hepatic portal hypertension cases present with upper GI bleeding, which is the common cause of pediatric portal hypertension presented. [10] But since the liver parenchyma and functions are preserved for decades in the extra-hepatic portal hypertension at the time of the presentation almost all the patients have a normal liver function. For this reason, most of these patients recovered without serious complications with a low mortality rate. This is true for all patients with compensated liver function presented with upper GI bleeding. Unfortunately, this is not the case for patients with decompensated liver disease (cirrhosis). Mathieu Duche et al. in their study reported that 1/5 of patients with cirrhosis developed life-threatening complications after upper GI

• *Portal hypertensive gastropathy:* It is gastric lesions related to portal hypertensive disease. It ranges from erythema to diffuse gastritis. It is an occasional cause of upper GI bleeding. But it most commonly causes iron deficiency anemia due to

• *Splenomegaly and hypersplenism:* Splenomegaly alone could be the presenting symptom in the extra-hepatic portal hypertension, in this scenario usually there are no other hepatic signs and symptoms, which necessitates excluding hematologic causes. If the patient has cirrhosis, the signs, and symptoms of liver disease (e.g. spider naevi, jaundice, ascites) will be presented with *splenomegaly*. *Splenomegaly* imposes a significant risk in adolescent patients due to the type of sports and activities involved in this age group. It may lead to a spleen rupture and catastrophic bleeding. Splenectomy may be the only option in these patients, who do not complaint about avoiding contact sports. Also, these patients may develop hypersplenism (*splenomegaly,* with thrombocytopenia and leukopenia). [17] Although the *hepatomegaly* is not common in pediatric portal hypertension. But it could be associated with Budd-Chiari syndrome

• *Encephalopathy:* It is a known complication of liver cirrhosis. But it can be associated with normal liver function in the extra-hepatic portal hypertension patients caused by port-systemic shunts, whether it is congenital or systemic shunts. It could be manifested as learning difficulties and behavior abnormalities. [19]

• *Pulmonary related disorders: Pulmonary hypertension* is associated with portal hypertension with or without liver disease. [20] It is caused by increased vascular resistance due to pulmonary vasoconstriction as a result of shunting vasoactive substance to the systemic circulation whether is due to prehepatic shunting or inability of the liver to process the proteins (liver cirrhosis). And the *hepatopulmonary syndrome* is the contrast to *pulmonary hypertension,* which present with dyspnea and hypoxia resulting from pulmonary arteriovenous shunting and partial oxygenation of the blood due to massive capillary dilation as a response to vasodilators proteins bypassed to the systemic circulation. [21]

chronic blood loss, which also may manifest as melena. [16]

and congenital hepatic fibrosis. [14, 18]

**5. Clinical presentations**

cirrhosis or not.

bleeds. [15]

**30**


Other investigations are requested according to the clinical status of the patients. Blood glucose will be low in decompensated liver cirrhosis and it is low in glycogen storage disease. Also, the ammonia level is indicated to confirm the diagnosis of encephalopathy. The coagulation screen in liver cirrhosis is prolonged. But in the extra-hepatic portal thrombosis, the coagulation profile shows secondary hypercoagulable abnormalities. [24] It will be reversed after the obstruction is overcomed.


such as the patency of the superior mesenteric, renal, and splenic veins. The neck Doppler ultrasound plays an important role in planning for surgical intervention, by confirming the patency of Jugular veins. This allows using one of them as an autologous graft provided both veins are patent. [26] Furthermore, the distance between the veins can assess the possibility of shunting between them like the distance between the renal and the spleen veins to assess the possibility of the splenorenal shunting. It may also pick up the portosystemic shunting. But the computed tomography angiography and magnetic resonance angiography are more accurate to pick up such anomalies. The later radiological modalities are usually the second step in the work up to delineate the anatomy more accurately. Invasive radiological investigations are required in specific cases. For example, the wedged hepatic venography is required in the congenital porto-systemic shunts [27] and to check the patency of the left portal vein tributary in the Rex recess to assess the possibility of Rex shunt.

#### **7. Management of acute variceal bleeding**

The upper GI bleeding can be the first presenting symptom of pediatric portal hypertension, especially when the extra-hepatic portal vein thrombosis is the underlying cause of portal hypertension. The mortality risk from the first variceal bleeding is less than 1% in pediatric portal hypertension. [28] This is due to 2 facts. First, portal hypertension in children develops early in course of the pathology, which leads subsequently to early variceal formation in children who have wellcompensated liver function. Thus, the ability of the children's recover is better comparing with adults (adult mortality rate ranging from 7 to 15%). Secondly, improved medical management reduce the mortality rate in all age groups. [12]

The management of acute variceal bleeding should start with securing the airway. Insertion 2 large cannulas withdraw the blood simultaneously for urgent investigations, which should include complete blood count, blood crossmatch, urea and electrolytes, liver function test, and blood clotting profile. The other blood tests as the medical situation are mandatory. [12]

The volume replacement should start as soon as possible with crystalloids and packed red blood cells aiming to maintain the hemoglobin at or above 7 g/dL. [25] This strategy prevents tissue hypoxia which reduces lactic acid accumulation in the tissues and blood. Therefore, blood acidosis becomes less likely. Eventually, the impairment of clotting factors (proteins) function also becomes less likely. This strategy hinders the slipping towards deleterious complications of disseminated intravascular coagulopathy. The insertion of the nasogastric tube is also beneficial in observing the continuity of the bleeding and evacuating the blood of the stomach. Evacuation of the blood from the stomach has significant importance in cirrhotic patients to prevent encephalopathy. The octreotide is a synthetic analogue of somatostatin, which reduces the portal venous inflow by constriction of the splanchnic arterioles via a direct effect on the arteriole smooth muscles. It is started as a bolus dose (1 mcg/kg) followed by infusion (1 mcg/kg/H) usually for 4–5 days, which is often followed endoscopy after controlling the bleeding. [29] The only accepted situations to use endoscopic sclerotherapy in children should be acute bleeding not responding to the medical management with technical difficulty to apply band and infant's cases where there is no banding device available for them. There is a randomized trial showing the administration of erythromycin intravenously by 30 minutes before the endoscopy improves visibility and reduces the time of the procedure. [30] In a situation where medical management (including the endoscopy) fails to stop the bleeding, urgent shunt surgery or trans-jugular

**33**

*Pediatric Portal Hypertension*

**8. Primary prophylaxis**

*DOI: http://dx.doi.org/10.5772/intechopen.95243*

the vital signs are monitored closely.

intrahepatic portosystemic shunt (TIPS) should be performed. The optimal environment for the management of these patients is the intensive care unit, where all

The primary prophylaxis aims to prevent the first variceal bleeding. The efficiency of the primary prophylaxis is well established in adult by screening the portal hypertension patients and identify the high-risk elements for variceal bleeding like the large size of varices (Grade 2,3), presence of the red wale on varices' surface, and the severity of the liver disease. [31] Using the endoscopic banding and/or non-selective beta-blockers which act by decreasing the portal pressure via un-opposed action of alfa-receptor on the splanchnic arterioles and decreasing the cardiac output. Sclerotherapy is not recommended for primary prophylaxis because of increased mortality in one randomized study which is forced the discontinuity of this study. [32] Regarding the children, there is no consensus about the primary prophylaxis in the pediatric age group because there is no substantial data to decide which patients need screening and what are the predictive factors for variceal presence. [28] Some studies indicate that the presence of varices in children should be related to low albumin levels, increased size of the spleen, and thrombocytopenia. But there is a need for larger, well designed randomized studies to standardize these predictive factors for children. Also, the necessity for general anesthesia for endoscopic sessions in children is another worrying point. The deleterious effect of general anesthesia on the neurodevelopment of children is well documented. [33] And the recurrence of esophageal varices after eradication is common if the underlying cause of portal hypertension is not treated. There is increased incidence of gastric varices and portal hypertensive gastropathy after eradication of esophageal varices. The same is true regarding the non-selective beta-blocker. There is no properly designed randomized study to assess the therapeutic doses and the safety of the drug in children [34]. Taking into account the mortality rate due to the first variceal bleeding is exceedingly low (1%). All these points together came against standardizing the primary prophylaxis in children. But in special circumstances, the primary prophylaxis in children is justifiable like the child living away from the

medical facilities which may necessitate primary prophylaxis.

and efficiency of non-selective beat-blockers. [28, 35]

The secondary prophylaxis is the prevention of recurrence of variceal bleeding after the first variceal bleeding. Secondary prophylaxis is recommended in children due to the high recurrence rate after the first bleeding and enough data supporting the efficiency and safety of endoscopic banding and superior to endoscopic sclerotherapy therapy. As in the primary prophylaxis, no enough data support the safety

TIPS refers to an establishment of intrahepatic portosystemic by inserting a stent (a communication) between the portal and hepatic veins. [36] It can be used in acute variceal bleeding uncontrolled by other means. Also, it is considered a good option for bridging to liver transplant for patients who have cirrhosis to improve the

**9. Secondary prophylaxis**

**10. Radiological intervention**

intrahepatic portosystemic shunt (TIPS) should be performed. The optimal environment for the management of these patients is the intensive care unit, where all the vital signs are monitored closely.

### **8. Primary prophylaxis**

*Portal Hypertension - Recent Advances*

such as the patency of the superior mesenteric, renal, and splenic veins. The neck Doppler ultrasound plays an important role in planning for surgical intervention, by confirming the patency of Jugular veins. This allows using one of them as an autologous graft provided both veins are patent. [26] Furthermore, the distance between the veins can assess the possibility of shunting between them like the distance between the renal and the spleen veins to assess the possibility of the splenorenal shunting. It may also pick up the portosystemic shunting. But the computed tomography angiography and magnetic resonance angiography are more accurate to pick up such anomalies. The later radiological modalities are usually the second step in the work up to delineate the anatomy more accurately. Invasive radiological investigations are required in specific cases. For example, the wedged hepatic venography is required in the congenital porto-systemic shunts [27] and to check the patency of the left portal vein

tributary in the Rex recess to assess the possibility of Rex shunt.

The upper GI bleeding can be the first presenting symptom of pediatric portal

The volume replacement should start as soon as possible with crystalloids and packed red blood cells aiming to maintain the hemoglobin at or above 7 g/dL. [25] This strategy prevents tissue hypoxia which reduces lactic acid accumulation in the tissues and blood. Therefore, blood acidosis becomes less likely. Eventually, the impairment of clotting factors (proteins) function also becomes less likely. This strategy hinders the slipping towards deleterious complications of disseminated intravascular coagulopathy. The insertion of the nasogastric tube is also beneficial in observing the continuity of the bleeding and evacuating the blood of the stomach. Evacuation of the blood from the stomach has significant importance in cirrhotic patients to prevent encephalopathy. The octreotide is a synthetic analogue of somatostatin, which reduces the portal venous inflow by constriction of the splanchnic arterioles via a direct effect on the arteriole smooth muscles. It is started as a bolus dose (1 mcg/kg) followed by infusion (1 mcg/kg/H) usually for 4–5 days, which is often followed endoscopy after controlling the bleeding. [29] The only accepted situations to use endoscopic sclerotherapy in children should be acute bleeding not responding to the medical management with technical difficulty to apply band and infant's cases where there is no banding device available for them. There is a randomized trial showing the administration of erythromycin intravenously by 30 minutes before the endoscopy improves visibility and reduces the time of the procedure. [30] In a situation where medical management (including the endoscopy) fails to stop the bleeding, urgent shunt surgery or trans-jugular

hypertension, especially when the extra-hepatic portal vein thrombosis is the underlying cause of portal hypertension. The mortality risk from the first variceal bleeding is less than 1% in pediatric portal hypertension. [28] This is due to 2 facts. First, portal hypertension in children develops early in course of the pathology, which leads subsequently to early variceal formation in children who have wellcompensated liver function. Thus, the ability of the children's recover is better comparing with adults (adult mortality rate ranging from 7 to 15%). Secondly, improved medical management reduce the mortality rate in all age groups. [12] The management of acute variceal bleeding should start with securing the airway. Insertion 2 large cannulas withdraw the blood simultaneously for urgent investigations, which should include complete blood count, blood crossmatch, urea and electrolytes, liver function test, and blood clotting profile. The other blood tests

**7. Management of acute variceal bleeding**

as the medical situation are mandatory. [12]

**32**

The primary prophylaxis aims to prevent the first variceal bleeding. The efficiency of the primary prophylaxis is well established in adult by screening the portal hypertension patients and identify the high-risk elements for variceal bleeding like the large size of varices (Grade 2,3), presence of the red wale on varices' surface, and the severity of the liver disease. [31] Using the endoscopic banding and/or non-selective beta-blockers which act by decreasing the portal pressure via un-opposed action of alfa-receptor on the splanchnic arterioles and decreasing the cardiac output. Sclerotherapy is not recommended for primary prophylaxis because of increased mortality in one randomized study which is forced the discontinuity of this study. [32] Regarding the children, there is no consensus about the primary prophylaxis in the pediatric age group because there is no substantial data to decide which patients need screening and what are the predictive factors for variceal presence. [28] Some studies indicate that the presence of varices in children should be related to low albumin levels, increased size of the spleen, and thrombocytopenia. But there is a need for larger, well designed randomized studies to standardize these predictive factors for children. Also, the necessity for general anesthesia for endoscopic sessions in children is another worrying point. The deleterious effect of general anesthesia on the neurodevelopment of children is well documented. [33] And the recurrence of esophageal varices after eradication is common if the underlying cause of portal hypertension is not treated. There is increased incidence of gastric varices and portal hypertensive gastropathy after eradication of esophageal varices. The same is true regarding the non-selective beta-blocker. There is no properly designed randomized study to assess the therapeutic doses and the safety of the drug in children [34]. Taking into account the mortality rate due to the first variceal bleeding is exceedingly low (1%). All these points together came against standardizing the primary prophylaxis in children. But in special circumstances, the primary prophylaxis in children is justifiable like the child living away from the medical facilities which may necessitate primary prophylaxis.

#### **9. Secondary prophylaxis**

The secondary prophylaxis is the prevention of recurrence of variceal bleeding after the first variceal bleeding. Secondary prophylaxis is recommended in children due to the high recurrence rate after the first bleeding and enough data supporting the efficiency and safety of endoscopic banding and superior to endoscopic sclerotherapy therapy. As in the primary prophylaxis, no enough data support the safety and efficiency of non-selective beat-blockers. [28, 35]

#### **10. Radiological intervention**

TIPS refers to an establishment of intrahepatic portosystemic by inserting a stent (a communication) between the portal and hepatic veins. [36] It can be used in acute variceal bleeding uncontrolled by other means. Also, it is considered a good option for bridging to liver transplant for patients who have cirrhosis to improve the severe symptoms (e.g. Massive ascites). In this scenario, TIPS is considered an ideal option by avoiding abdominal operation with subsequent adhesions and fibrosis, which makes the liver transplant operation much easier. [26]

This technique is considered as a non-selective shunt where most of the portal blood diverted to the systemic circulation which participates in encephalopathy. Also, TIPS has potential complications, which are shunt stenosis/thrombosis, bleeding, and dislodge of the stent to the right atrium. [26, 34]

#### **11. Surgical shunts**

The type of surgery depends on the level of obstruction (pre-hepatic, hepatic. Post-hepatic).

Pre-hepatic portal vein thrombosis with suitable anatomy means a patent left portal vein in the umbilical fissure and the patent superior mesenteric vein. They connect via graft whether synthetic or autologous, but as a rule in pediatric surgery, the use of autologous graft is always preferred whenever it is possible due to the fact the graft grows with the child. The most used autologous graft is one of the internal jugular veins after making sure the contralateral one patent pre-operatively by doppler ultrasound. After the anastomosis has been established, the porto-systemic circulation is re-established. Another important point that the liver parenchyma in the extrahepatic portal thrombosis is preserved for a long time. Based on this fact the functionality of the liver is expected to recover after re-establishing the portosystemic circulation. Fortunately, the data of the surgical outcome confirms this concept. The secondary coagulation abnormalities, hepatopulmonary syndrome, liver adenomas, encephalopathy, and neurocognitive all will be reverted after successful Rex shunt. [37] And for the congenital portosystemic shunt the surgical ligation of the shunt when it is technically feasible. [27]

When the cause of portal hypertension is liver cirrhosis in the modern era the suitable option is a liver transplant. [38]

There are other surgical options for portal hypertension which are considered palliative rather than therapeutic: (1) Selective shunt: the technique is known as distal splenorenal shunt (Warren shunt). The principle of this technique is diverting part of the portal circulation to the systemic circulation by dividing the splenic vein and anastomosing the distal end to the left renal vein. It helps to reduce gastroesophageal variceal pressure subsequently reducing the bleeding potentials. Also, hypersplenism and encephalopathy are improved. But the issue with this shunt is that with time the selective shunt becomes non-selective due to the formation of collaterals. [26]

(2) Non-selective shunt: its principle is based on diverting the whole portal circulation to systemic circulation by mobilization of the superior mesenteric vein and creation of side to side anastomosis with inferior vena cava or by used graft to connect the 2 veins whether synthetic or autologous grafts. This technique is not preferred in children because of the high-risk encephalopathy and deleterious effect on the cognitive ability of the children. [38]

**35**

**Author details**

Reda A. Zbaida

Pediatric Surgery Department, Stellenbosch University, Cape Town, South Africa

© 2021 The Author(s). Licensee IntechOpen. This chapter is 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,

\*Address all correspondence to: redazbida@yahoo.co.uk

provided the original work is properly cited.

*Pediatric Portal Hypertension*

*DOI: http://dx.doi.org/10.5772/intechopen.95243*

*Pediatric Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.95243*

*Portal Hypertension - Recent Advances*

**11. Surgical shunts**

Post-hepatic).

collaterals. [26]

severe symptoms (e.g. Massive ascites). In this scenario, TIPS is considered an ideal option by avoiding abdominal operation with subsequent adhesions and fibrosis,

This technique is considered as a non-selective shunt where most of the portal blood diverted to the systemic circulation which participates in encephalopathy. Also, TIPS has potential complications, which are shunt stenosis/thrombosis, bleed-

The type of surgery depends on the level of obstruction (pre-hepatic, hepatic.

Pre-hepatic portal vein thrombosis with suitable anatomy means a patent left portal vein in the umbilical fissure and the patent superior mesenteric vein. They connect via graft whether synthetic or autologous, but as a rule in pediatric surgery, the use of autologous graft is always preferred whenever it is possible due to the fact the graft grows with the child. The most used autologous graft is one of the internal jugular veins after making sure the contralateral one patent pre-operatively by doppler ultrasound. After the anastomosis has been established, the porto-systemic circulation is re-established. Another important point that the liver parenchyma in the extrahepatic portal thrombosis is preserved for a long time. Based on this fact the functionality of the liver is expected to recover after re-establishing the portosystemic circulation. Fortunately, the data of the surgical outcome confirms this concept. The secondary coagulation abnormalities, hepatopulmonary syndrome, liver adenomas, encephalopathy, and neurocognitive all will be reverted after successful Rex shunt. [37] And for the congenital portosystemic shunt the surgical

When the cause of portal hypertension is liver cirrhosis in the modern era the

There are other surgical options for portal hypertension which are considered palliative rather than therapeutic: (1) Selective shunt: the technique is known as distal splenorenal shunt (Warren shunt). The principle of this technique is diverting part of the portal circulation to the systemic circulation by dividing the splenic vein and anastomosing the distal end to the left renal vein. It helps to reduce gastroesophageal variceal pressure subsequently reducing the bleeding potentials. Also, hypersplenism and encephalopathy are improved. But the issue with this shunt is that with time the selective shunt becomes non-selective due to the formation of

(2) Non-selective shunt: its principle is based on diverting the whole portal circulation to systemic circulation by mobilization of the superior mesenteric vein and creation of side to side anastomosis with inferior vena cava or by used graft to connect the 2 veins whether synthetic or autologous grafts. This technique is not preferred in children because of the high-risk encephalopathy and deleterious effect

which makes the liver transplant operation much easier. [26]

ing, and dislodge of the stent to the right atrium. [26, 34]

ligation of the shunt when it is technically feasible. [27]

suitable option is a liver transplant. [38]

on the cognitive ability of the children. [38]

**34**

#### **Author details**

Reda A. Zbaida Pediatric Surgery Department, Stellenbosch University, Cape Town, South Africa

\*Address all correspondence to: redazbida@yahoo.co.uk

© 2021 The Author(s). Licensee IntechOpen. This chapter is 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.

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#### *Pediatric Portal Hypertension DOI: http://dx.doi.org/10.5772/intechopen.95243*

[18] Alvarez F, Bernard O, Brunelle F, Hadchouel M, Leblanc A, Odièvre M, et al. Congenital hepatic fibrosis in children. J Pediatr. 1981;99(3):370-5.

[19] D'Antiga L, Dacchille P, Boniver C, Poledri S, Schiff S, Zancan L, et al. Clues for minimal hepatic encephalopathy in children with noncirrhotic portal hypertension. J Pediatr Gastroenterol Nutr. 2014;59(6):689-94.

[20] Cosarderelioglu C, Cosar AM, Gurakar M, Pustavoitau A, Russell SD, Dagher NN, et al. Portopulmonary hypertension and liver transplant: Recent review of the literature. Exp Clin Transplant. 2016;14(2):113-20.

[21] Karrer FM, Wallace BJ, Estrada AE. Late complications of biliary atresia: hepatopulmonary syndrome and portopulmonary hypertension. Pediatr Surg Int [Internet]. 2017;33(12):1335- 40. Available from: http://dx.doi. org/10.1007/s00383-017-4176-2

[22] Bavdekar A, Thakur N. Ascites in Children. Indian J Pediatr [Internet]. 2016;83(11):1334-40. Available from: http://dx.doi.org/10.1007/ s12098-016-2168-1

[23] Rodwell VW. Harper's Illustrated Biochemistery. McGraw-Hill Eduction: Thrity-Fir; 2018

[24] Robson SC, Kahn D, Kruskal J, Bird AR, Kirsch RE. Disordered hemostasis in extrahepatic portal hypertension. Hepatology. 1993;18(4):853-7.

[25] D'Antiga L. Medical management of esophageal varices and portal hypertension in children. Semin Pediatr Surg [Internet]. 2012;21(3):211- 8. Available from: http://dx.doi. org/10.1053/j.sempedsurg.2012.05.004

[26] de Ville de Goyet J, D'Ambrosio G, Grimaldi C. Surgical management of portal hypertension in children. Semin Pediatr Surg [Internet]. 2012;21(3):219- 32. Available from: http://dx.doi. org/10.1053/j.sempedsurg.2012.05.005

[27] Guérin F, Blanc T, Gauthier F, Abella SF, Branchereau S. Congenital portosystemic vascular malformations. Semin Pediatr Surg [Internet]. 2012;21(3):233-44. Available from: http://dx.doi.org/10.1053/j. sempedsurg.2012.05.006

[28] Shneider BL, de Ville de Goyet J, Leung DH, Srivastava A, Ling SC, Duché M, et al. Primary prophylaxis of variceal bleeding in children and the role of MesoRex Bypass: Summary of the Baveno VI Pediatric Satellite Symposium. Hepatology. 2016;63(4):1368-80.

[29] Eroglu Y, Emerick KM, Whitingon PF, Alonso EM. Octreotide therapy for control of acute gastrointestinal bleeding in children. J Pediatr Gastroenterol Nutr. 2004;38(1):41-7.

[30] Altraif I, Handoo FA, Aljumah A, Alalwan A, Dafalla M, Saeed AM, et al. Effect of erythromycin before endoscopy in patients presenting with variceal bleeding: A prospective, randomized, double-blind, placebocontrolled trial. Gastrointest Endosc [Internet]. 2011;73(2):245-50. Available from: http://dx.doi.org/10.1016/j. gie.2010.09.043

[31] Bari K, Garcia-Tsao G. Treatment of portal hypertension. World J Gastroenterol. 2012;18(11):1166-75.

[32] North American Symptomatic Carotid Endarterectomy Trial Collaborators. The New England Journal of Medicine Downloaded from nejm. org at INSERM DISC DOC on October 6, 2015. For personal use only. No other uses without permission. Copyright © 1991 Massachusetts Medical Society. All rights reserved. N Engl J Med. 1991;325:445-53.

**36**

*Portal Hypertension - Recent Advances*

[1] Merkel C, Montagnese S. Hepatic venous pressure gradient measurement in clinical hepatology. Dig Liver Dis.

Etiology and long-term outcome of extrahepatic portal vein obstruction in children. World J Gastroenterol.

[11] Lautz TB, Tantemsapya N, Rowell E, Superina RA. Management and classification of type II congenital portosystemic shunts. J Pediatr Surg [Internet]. 2011;46(2):308-14. Available from: http://dx.doi.org/10.1016/j.

[12] Chapin CA, Bass LM. Cirrhosis and Portal Hypertension in the Pediatric Population. Clin Liver Dis [Internet]. 2018;22(4):735-52. Available from: https://doi.org/10.1016/j.cld.2018.06.007

[13] Cesaro S, Pillon M, Talenti E, Toffolutti T, Calore E, Tridello G, et al. A prospective survey on incidence, risk factors and therapy of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation. Haematologica. 2005;90(10):1396-404.

[14] Nobre S, Khanna R, Bab N, Kyrana E, Height S, Karani J, et al. Primary Budd-Chiari Syndrome in Children: King's College Hospital Experience. J Pediatr Gastroenterol

[15] Duché M, Ducot B, Ackermann O, Guérin F, Jacquemin E, Bernard O. Portal hypertension in children: Highrisk varices, primary prophylaxis and consequences of bleeding. J Hepatol.

[16] El-Rifai N, Mention K, Guimber D, Michaud L, Boman F, Turck D, et al. Gastropathy and gastritis in children with portal hypertension. J Pediatr Gastroenterol Nutr. 2007;45(1):137-40.

Management of portal hypertension in children. World J Gastroenterol.

Nutr. 2017;65(1):93-6.

2017;66(2):320-7.

[17] Gugig R, Rosenthal P.

2012;18(11):1176-84.

2010;16(39):4968-72.

jpedsurg.2010.11.009

[2] Shneider BL, Bosch J, De Franchis R, Emre SH, Groszmann RJ, Ling SC, et al. Portal hypertension in children: Expert pediatric opinion on the report of the Baveno v consensus workshop on methodology of diagnosis and therapy in portal hypertension. Pediatr

Transplant. 2012;16(5):426-37.

Med Embryol. :300-4.

Rec. 2008;291(6):614-27.

N Am 84 (2004) 413-435

2014;27(5):764-9.

mpsur.2014.10.004

[5] Juza RM, Pauli EM. Clinical and surgical anatomy of the liver: A review for clinicians. Clin Anat.

[3] Embryology G, Embryology S. part one General Embryology. Langman'S

[4] Collardeau-Frachon S, Scoazec JY. Vascular development and differentiation during human liver organogenesis. Anat

[6] John E. Skandalakis et al., Surg Clin

[7] Mahadevan V. Anatomy of the liver. Surg (United Kingdom) [Internet]. 2020;38(8):427-31. Available from: http://dx.doi.org/10.1016/j.

[8] LAWRENCE E. WINESKI P. Snell's clinical anatomy by Regions. Vol. 53, Wolters Kluwer. 2019. 2019 p.

[9] Abd El-Hamid N, Taylor RM, Marinello D, Mufti GJ, Patel R, Mieli-Vergani G, et al. Aetiology and management of extrahepatic portal vein obstruction in children: king's college hospital experience. J Pediatr Gastroenterol Nutr. 2008;47(5):630-4.

[10] Weiss B, Shteyer E, Vivante A, Berkowitz D, Reif S, Weizman Z, et al.

**References**

2011;43(10):762-7.

[33] Wang X, Xu Z, Miao CH. Current clinical evidence on the effect of general anesthesia on neurodevelopment in children: An updated systematic review with meta-regression. PLoS One. 2014;9(1).

[34] Bozic MA, Puri K, Molleston JP. Screening and Prophylaxis for Varices in Children with Liver Disease. Curr Gastroenterol Rep. 2015;17(7).

[35] Dos Santos JMR, Ferreira AR, Fagundes EDT, Ferreira APS, Ferreira LS, Magalhães MCR, et al. Endoscopic and pharmacological secondary prophylaxis in children and adolescents with esophageal varices. J Pediatr Gastroenterol Nutr. 2013;56(1):93-8.

[36] Di Giorgio A, Agazzi R, Alberti D, Colledan M, D'Antiga L. Feasibility and efficacy of transjugular intrahepatic portosystemic shunt (TIPS) in children. J Pediatr Gastroenterol Nutr. 2012;54(5):594-600.

[37] Di Francesco F, Grimaldi C, De Ville De Goyet J. Meso-Rex bypass - A procedure to cure prehepatic portal hypertension: The insight and the inside. J Am Coll Surg [Internet]. 2014;218(2):e23-36. Available from: http://dx.doi.org/10.1016/j. jamcollsurg.2013.10.024

[38] Scholz S, Sharif K. Surgery for portal hypertension in children. Curr Gastroenterol Rep. 2011;13(3):279-85.

**39**

**Chapter 3**

**Abstract**

**1. Introduction**

*and Jinfeng Yang*

Sinusoidal Obstruction Syndrome

Sinusoidal obstructive syndrome (SOS) is a fibrous occlusive disease of hepatic sinusoids or hepatic venules. Small hepatic blood vessel damage, especially hepatic sinusoidal endothelial cell damage, is its main feature. Based on etiology, SOS is mainly classified into pyrrolidine alkaloids-related SOS, hematopoietic stem cell transplantation-related SOS, and SOS of unknown etiology. In recent years, the incidence of SOS has been increasing. However, due to the complexity of the etiology, the lack of specificity in clinical manifestations, the difficulty of early diagnosis, and the limited treatment options, it often leads to poor treatment effects and even death. This chapter aims to analyze and organize the pathogenesis, pathological characteristics, diagnosis, treatment, and prognosis of different types of SOS, to

*Yanxia Fei, Yanhua Peng, Huiping Sun, Shuangfa Zou* 

provide certain references for the prevention and treatment of the disease.

SOS, hematopoietic stem cell transplantation-related SOS

**Keywords:** sinusoidal obstructions syndrome, hepatic vascular endothelial injury, hepatic venous pressure gradient, nonportal cirrhosis, pyrrolidine alkaloids-related

Hepatic sinusoidal obstruction syndrome (SOS), formerly known as a hepatic

veno-occlusive disease (HVOD), is an intrahepatic hepatic sinusoidal portal hypertension caused by obstruction of the hepatic sinusoidal outflow tract due to endothelial cell injury. The main features of SOS are luminal narrowing or occlusion due to endothelial cell injury of the hepatic blood sinusoids, small hepatic veins, and interlobular veins. This causes intrahepatic stasis, hepatic injury and intrahepatic sinusoidal portal hypertension as a characteristic hepatic vasculogenic disease. Its clinical manifestations are mainly pain in the liver area, jaundice, ascites and hepatomegaly. The first cases were documented in South Africa in 1920 when cirrhosis was thought to be caused by groundsel poisoning [1]. In 1953, Hill et al. reported that more than 100 Jamaican children developed "Serous Hepatosis" from the consumption of Senecio (also known as groundsel) [2]. In 1954, Bras and Jelliffe et al. used the term hepatic veno-occlusive disease (HVOD) in their report [3]. Since then, with the recognition of HVOD, in 2002, Deleve et al. suggested that it would be more appropriately named SOS [4, 5], which is now generally accepted and adopted by scholars. The etiology of SOS is diverse, with different etiologies in China and Western countries. Depending on the etiology, it is mainly divided into hematopoietic stem cell transplantation-induced SOS (HSCT-SOS) and pyrrolidine alkaloids-induced SOS (PA-SOS). In the West, SOS is usually associated with myeloablative pretreatment before HSCT, and the incidence of HSCT-SOS

#### **Chapter 3**

*Portal Hypertension - Recent Advances*

2014;9(1).

2013;56(1):93-8.

2012;54(5):594-600.

jamcollsurg.2013.10.024

[33] Wang X, Xu Z, Miao CH. Current clinical evidence on the effect of general anesthesia on neurodevelopment in children: An updated systematic review with meta-regression. PLoS One.

[34] Bozic MA, Puri K, Molleston JP. Screening and Prophylaxis for Varices in Children with Liver Disease. Curr Gastroenterol Rep. 2015;17(7).

[35] Dos Santos JMR, Ferreira AR, Fagundes EDT, Ferreira APS, Ferreira LS, Magalhães MCR, et al. Endoscopic and pharmacological secondary prophylaxis in children and adolescents with esophageal varices. J Pediatr Gastroenterol Nutr.

[36] Di Giorgio A, Agazzi R, Alberti D, Colledan M, D'Antiga L. Feasibility and efficacy of transjugular intrahepatic portosystemic shunt (TIPS) in

children. J Pediatr Gastroenterol Nutr.

[37] Di Francesco F, Grimaldi C, De Ville De Goyet J. Meso-Rex bypass - A procedure to cure prehepatic portal hypertension: The insight and the inside. J Am Coll Surg [Internet]. 2014;218(2):e23-36. Available from: http://dx.doi.org/10.1016/j.

[38] Scholz S, Sharif K. Surgery for portal hypertension in children. Curr Gastroenterol Rep. 2011;13(3):279-85.

**38**

## Sinusoidal Obstruction Syndrome

*Yanxia Fei, Yanhua Peng, Huiping Sun, Shuangfa Zou and Jinfeng Yang*

#### **Abstract**

Sinusoidal obstructive syndrome (SOS) is a fibrous occlusive disease of hepatic sinusoids or hepatic venules. Small hepatic blood vessel damage, especially hepatic sinusoidal endothelial cell damage, is its main feature. Based on etiology, SOS is mainly classified into pyrrolidine alkaloids-related SOS, hematopoietic stem cell transplantation-related SOS, and SOS of unknown etiology. In recent years, the incidence of SOS has been increasing. However, due to the complexity of the etiology, the lack of specificity in clinical manifestations, the difficulty of early diagnosis, and the limited treatment options, it often leads to poor treatment effects and even death. This chapter aims to analyze and organize the pathogenesis, pathological characteristics, diagnosis, treatment, and prognosis of different types of SOS, to provide certain references for the prevention and treatment of the disease.

**Keywords:** sinusoidal obstructions syndrome, hepatic vascular endothelial injury, hepatic venous pressure gradient, nonportal cirrhosis, pyrrolidine alkaloids-related SOS, hematopoietic stem cell transplantation-related SOS

#### **1. Introduction**

Hepatic sinusoidal obstruction syndrome (SOS), formerly known as a hepatic veno-occlusive disease (HVOD), is an intrahepatic hepatic sinusoidal portal hypertension caused by obstruction of the hepatic sinusoidal outflow tract due to endothelial cell injury. The main features of SOS are luminal narrowing or occlusion due to endothelial cell injury of the hepatic blood sinusoids, small hepatic veins, and interlobular veins. This causes intrahepatic stasis, hepatic injury and intrahepatic sinusoidal portal hypertension as a characteristic hepatic vasculogenic disease. Its clinical manifestations are mainly pain in the liver area, jaundice, ascites and hepatomegaly. The first cases were documented in South Africa in 1920 when cirrhosis was thought to be caused by groundsel poisoning [1]. In 1953, Hill et al. reported that more than 100 Jamaican children developed "Serous Hepatosis" from the consumption of Senecio (also known as groundsel) [2]. In 1954, Bras and Jelliffe et al. used the term hepatic veno-occlusive disease (HVOD) in their report [3]. Since then, with the recognition of HVOD, in 2002, Deleve et al. suggested that it would be more appropriately named SOS [4, 5], which is now generally accepted and adopted by scholars. The etiology of SOS is diverse, with different etiologies in China and Western countries. Depending on the etiology, it is mainly divided into hematopoietic stem cell transplantation-induced SOS (HSCT-SOS) and pyrrolidine alkaloids-induced SOS (PA-SOS). In the West, SOS is usually associated with myeloablative pretreatment before HSCT, and the incidence of HSCT-SOS

ranges from 5.3% to 13.7% [6], even up to 60% in pediatric high-risk populations [7–9], and is an important complication and major obstacle of HSCT. In China, on the other hand, SOS is usually associated with oral intake of plants containing PA, with 50.0% to 88.6% of SOS caused by the consumption of sedum Tusanqi [10]. In recent years, the incidence of SOS has been increasing, but the complex etiology, lack of specificity of clinical manifestations, difficulties in early diagnosis and limited therapeutic means often lead to poor treatment outcomes and even death. The mortality rate of patients with multiple organ failure is greater than 80% [11]. However, the pathogenesis of the disease is not known. The existing guidelines are limited to "the SOS associated with hematopoietic stem cell transplantation in Western countries" and the "Nanjing criteria" developed by the Hepatobiliary Diseases Committee of the Chinese Society of Gastroenterology to diagnose and treatment of PA–HSOS [12, 13]. To this end, this section focuses on the research progress in the pathogenesis, clinical manifestations, diagnosis, treatment, prognosis, and preventive measures of SOS.

### **2. Etiology**

#### **2.1 Hematopoietic stem cell transplantation**

HSCT is considered a major etiology of SOS in the West and is associated with high-dose chemotherapeutic drug pretreatment. Also, age, type of transplantation, secondary transplantation, cytokines produced by damaged tissues, endogenous microorganisms translocated by damaged mucosal barriers, immune factors, previous history of liver disease, systemic irradiation, local procoagulant status, and platelet adhesion are also risk factors for the development of HSCT-SOS [14–16].

#### **2.2 Consumption of plants containing pyrrolidine alkaloids (PA)**

In developing countries, such as China, Southeast Asian countries, and African countries, SOS is mainly caused by the consumption of plants containing PA. Plants containing PA are widely distributed around the world, and more than 300 of the more than 6000 species of plants are known to contain PA. For example, senecio, Tusanqi, lily, retrorsine, comfrey, etc. [17]. Since Chinese herbal medicine is widely used in China, SOS is mainly caused by poisoning with Tusanqi [18, 19]. In 1980, Hou et al. [20] reported for the first time two clinical cases of SOS caused by the administration of Tusanqi in China, which attracted widespread attention of clinicians, and since then, cases of SOS caused by Tusanqi have been reported throughout the country. PA and its hydrolysis products are not toxic, but when they reach the liver, they are deoxygenated by cytochrome P450 enzyme (CYP) 3A to form pyrrole-like derivatives. This metabolite binds to DNA/RNA in hepatocytes, thus affecting protein synthesis and inhibiting cell division, which in turn causes severe damage to the liver [21].

#### **2.3 After radiation and chemotherapy**

In addition to the above two common types, it has also been reported that SOS is associated with chemotherapy and radiotherapy for solid tumors, such as chemotherapy with cyclophosphamide. Common SOS-related drugs are cyclophosphamide, busulfan, dacarbazine, 6-mercaptopurine, 6-thioguanine, dacarbazine, actinomycin D, gemtuzumab, melphalan, oxaliplatin, cytarabine, and uratan [21].

**41**

**Figure 1.**

*Sinusoidal Obstruction Syndrome*

*DOI: http://dx.doi.org/10.5772/intechopen.96370*

Recent reports say that SOS is associated with the use of immunosuppressive drugs [22]. As in the case of treatment with immunosuppressive agents after orthotopic liver transplantation, immune dysregulation is a direct cause of induction of SOS. Thus the indications for immunosuppressive agents, including azathioprine, also seem to be risk factors for SOS. This makes it difficult for researchers to establish the relationship between SOS and immunosuppression. Researchers believe that immune-related injury-induced damage is related to the

The hepatic sinusoids are small vessels that constitute the hepatic microcirculation and are composed of hepatic sinusoidal endothelial cells (SEC) while being restricted by hepatic stellate cells. Therefore, the permeability of hepatic sinusoids is large, which facilitates the exchange of substances between hepatocytes and blood flow. When SOS occurs sinusoidal endothelial cells are damaged and shed, then migrate to the central veins of the hepatic lobules, leading to the formation of centripetal non-thrombotic obstruction of the hepatic sinusoids and central veins. Subsequently, coupled with the accumulation of erythrocytes and non-cellular debris, the formation of thrombus is another important factor that disrupts hepatic microcirculation and increases hepatic vascular resistance. A cascade of actions and interactions, as well as activation of exo-clotting factors, oxidative stress, and altered vascular permeability, all contributes to varying degrees to the obstruction of normal blood flow and increased venous resistance. This ultimately leads to portal hypertension, hepatic dysfunction and ascites retention [23] (**Figure 1**). Damage to SEC is manifested by intracellular glutathione depletion, decreased nitric oxide, and increased expression of matrix metalloproteinase (MMP) and vascular endothelial growth factor (VEGF). In addition to this, cytokines secreted by

*Snusoidal obstruction syndrome (SOS) pathogenesis. Damage to the endothelial cells of the hepatic sinusoids due to HSCT or PA, etc.* → *blockage of the hepatic sinusoidal outflow tract* → *damage to the endothelial cells* 

*of the small and central hepatic veins* → *portal hypertension.*

**2.4 After immune drug treatment**

pathogenesis of these rare lesions.

**3. Pathological mechanism**

#### **2.4 After immune drug treatment**

*Portal Hypertension - Recent Advances*

sis, and preventive measures of SOS.

severe damage to the liver [21].

**2.3 After radiation and chemotherapy**

**2.1 Hematopoietic stem cell transplantation**

**2. Etiology**

ranges from 5.3% to 13.7% [6], even up to 60% in pediatric high-risk populations [7–9], and is an important complication and major obstacle of HSCT. In China, on the other hand, SOS is usually associated with oral intake of plants containing PA, with 50.0% to 88.6% of SOS caused by the consumption of sedum Tusanqi [10]. In recent years, the incidence of SOS has been increasing, but the complex etiology, lack of specificity of clinical manifestations, difficulties in early diagnosis and limited therapeutic means often lead to poor treatment outcomes and even death. The mortality rate of patients with multiple organ failure is greater than 80% [11]. However, the pathogenesis of the disease is not known. The existing guidelines are limited to "the SOS associated with hematopoietic stem cell transplantation in Western countries" and the "Nanjing criteria" developed by the Hepatobiliary Diseases Committee of the Chinese Society of Gastroenterology to diagnose and treatment of PA–HSOS [12, 13]. To this end, this section focuses on the research progress in the pathogenesis, clinical manifestations, diagnosis, treatment, progno-

HSCT is considered a major etiology of SOS in the West and is associated with high-dose chemotherapeutic drug pretreatment. Also, age, type of transplantation, secondary transplantation, cytokines produced by damaged tissues, endogenous microorganisms translocated by damaged mucosal barriers, immune factors, previous history of liver disease, systemic irradiation, local procoagulant status, and platelet adhesion are also risk factors for the development of HSCT-SOS [14–16].

In developing countries, such as China, Southeast Asian countries, and African

countries, SOS is mainly caused by the consumption of plants containing PA. Plants containing PA are widely distributed around the world, and more than 300 of the more than 6000 species of plants are known to contain PA. For example, senecio, Tusanqi, lily, retrorsine, comfrey, etc. [17]. Since Chinese herbal medicine is widely used in China, SOS is mainly caused by poisoning with Tusanqi [18, 19]. In 1980, Hou et al. [20] reported for the first time two clinical cases of SOS caused by the administration of Tusanqi in China, which attracted widespread attention of clinicians, and since then, cases of SOS caused by Tusanqi have been reported throughout the country. PA and its hydrolysis products are not toxic, but when they reach the liver, they are deoxygenated by cytochrome P450 enzyme (CYP) 3A to form pyrrole-like derivatives. This metabolite binds to DNA/RNA in hepatocytes, thus affecting protein synthesis and inhibiting cell division, which in turn causes

In addition to the above two common types, it has also been reported that SOS is associated with chemotherapy and radiotherapy for solid tumors, such as chemotherapy with cyclophosphamide. Common SOS-related drugs are cyclophosphamide, busulfan, dacarbazine, 6-mercaptopurine, 6-thioguanine, dacarbazine, actinomycin D, gemtuzumab, melphalan, oxaliplatin, cytarabine, and uratan [21].

**2.2 Consumption of plants containing pyrrolidine alkaloids (PA)**

**40**

Recent reports say that SOS is associated with the use of immunosuppressive drugs [22]. As in the case of treatment with immunosuppressive agents after orthotopic liver transplantation, immune dysregulation is a direct cause of induction of SOS. Thus the indications for immunosuppressive agents, including azathioprine, also seem to be risk factors for SOS. This makes it difficult for researchers to establish the relationship between SOS and immunosuppression. Researchers believe that immune-related injury-induced damage is related to the pathogenesis of these rare lesions.

### **3. Pathological mechanism**

The hepatic sinusoids are small vessels that constitute the hepatic microcirculation and are composed of hepatic sinusoidal endothelial cells (SEC) while being restricted by hepatic stellate cells. Therefore, the permeability of hepatic sinusoids is large, which facilitates the exchange of substances between hepatocytes and blood flow. When SOS occurs sinusoidal endothelial cells are damaged and shed, then migrate to the central veins of the hepatic lobules, leading to the formation of centripetal non-thrombotic obstruction of the hepatic sinusoids and central veins. Subsequently, coupled with the accumulation of erythrocytes and non-cellular debris, the formation of thrombus is another important factor that disrupts hepatic microcirculation and increases hepatic vascular resistance. A cascade of actions and interactions, as well as activation of exo-clotting factors, oxidative stress, and altered vascular permeability, all contributes to varying degrees to the obstruction of normal blood flow and increased venous resistance. This ultimately leads to portal hypertension, hepatic dysfunction and ascites retention [23] (**Figure 1**). Damage to SEC is manifested by intracellular glutathione depletion, decreased nitric oxide, and increased expression of matrix metalloproteinase (MMP) and vascular endothelial growth factor (VEGF). In addition to this, cytokines secreted by

#### **Figure 1.**

*Snusoidal obstruction syndrome (SOS) pathogenesis. Damage to the endothelial cells of the hepatic sinusoids due to HSCT or PA, etc.* → *blockage of the hepatic sinusoidal outflow tract* → *damage to the endothelial cells of the small and central hepatic veins* → *portal hypertension.*

the damaged SEC lead to a weakened mucosal barrier between cells. This promotes the escape of erythrocytes, leukocytes, and platelets between hepatocytes and hepatic sinusoidal SEC, contributing to the initiation of inflammatory processes and thrombus formation [24, 25].

In HSCT-SOS, patients receiving high doses of toxic drugs (e.g., cyclophosphamide and leucovorin) during treatment are the cause of initial endothelial cell injury, which can lead to SOS, graft-versus-host disease (GVHD), capillary leak syndrome, implantation syndrome, and diffuse alveolar hemorrhage [26, 27]. In PA-SOS, the typical pathological changes are swelling, injury, and detachment of SEC in zone III of the hepatic acinus. The predominance of lesions in zone III of the hepatic acinus in PA-SOS is due to the abundance of CYP3A and the relative lack of glutathione (GSH) in this region. By constructing an animal model, Deleve et al. found that early damage to the endothelium of the hepatic sinusoids and central veins occurred before the development of veno-occlusive lesions, and that coagulative necrosis of hepatocytes occurred later than endothelial damage [3]. Besides, Harb et al. found that bone marrow progenitor cells were able to replace endothelial cells and thus repair the injury, while monocrotaline was able to inhibit endothelial progenitor cells in the bone marrow and circulation [28]. Therefore, PA damage to bone marrow progenitor cells and thus inhibition of endothelial cell repair may be another important pathogenetic mechanism. When SOS occurs, the hepatic sinusoidal stasis and dilatation; hepatic cord compression and atrophy; hepatocyte degeneration and necrosis; and central small vein occlusion and fibrosis are seen under light microscopy [29].

#### **4. Clinical presentation**

The main symptoms of SOS are non-specific: with or without ascites, pain, hepatomegaly, and jaundice. Clinical manifestations range from very few symptoms to multi-organ failure leading to patient death. The clinical manifestations of HSCT-SOS and PA-SOS differ in several aspects.

HSCT-SOS usually presents with abdominal distention, hepatomegaly, pain in the liver area, ascites, jaundice, loss of appetite, and weakness [30]. HSCT-SOS has a rapid onset, usually occurring within 21 d after bone marrow transplantation. And the proportion of seriously ill patients and mortality is high, most of them die from multi-organ dysfunction syndrome and sepsis [11]. A European multicenter study [6] graded SOS according to the severity of the disease: mild (about 8%) is self-limiting and recovers without special treatment; moderate (about 64%) recovers with aggressive treatment, and severe (about 28%) often leads to death because of progression, or no improvement after 100 d of treatment. In 2016, the European Society for Blood and Marrow Transplantation updated the HSCT-SOS scale, as shown in **Table 1** [26]. Due to the marked differences in incidence, genetic susceptibility, clinical presentation, prevention, treatment, and outcome between age groups, the European Society for Blood and Marrow Transplantation proposed new criteria specifically for SOS/VOD in children in 2018, as shown in **Table 2** [31].

PA-SOS mainly presents with abdominal distention and ascites [32], only about half of the patients present with hepatomegaly or jaundice, and a few patients have hepatoceles [33]. Most patients with PA-SOS have insignificant elevations in serum alanine aminotransferase, serum aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transferase, and total bilirubin levels. PA-SOS occurs after a variable incubation period, which is usually about 30 d after drug administration and maybe up to several years. It can develop in both children and adults. In addition, PA-SOS

**43**

**Table 2.**

*Sinusoidal Obstruction Syndrome*

Time since first clinical symptoms of SOS/VOD

Bilirubin (mg/dL) Bilirubin (μmol/L)

Renal function (baseline at transplant)

LFT (ALT, AST, GLDH)

Bilirubin (mg/dL) Bilirubin (μmol/L)

Renal function GFR (mL/min)

Pulmonary function (oxygen requirement)

**Table 1.**

*DOI: http://dx.doi.org/10.5772/intechopen.96370*

⩾2 and < 3 ⩾34 and < 51

Transaminases ⩽2 × normal >2 and

*failure; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.*

*New EBMT criteria for severity grading of a suspected SOS/VOD in adults.*

⩽2 × normal >2 and

< 2 < 34

Coagulation Normal Normal Impaired

*SOS/VOD, sinusoidal obstruction syndrome/veno-occlusive disease.*

*EBMT criteria for grading the severity of suspected hepatic SOS/VOD in children.*

Persistent RT < 3 days 3–7 days > 7 days

Bilirubin kinetics Doubling

*Mild Moderate Sever Very sever*

>7 Days 5–7 Days ⩽4 Days Any time

⩾5 and < 8 ⩾85 and < 136

within 48 h

45 and ⩽8 × normal

<1.2 ⩾ 1.2 and < 1.5 ⩾1.5 and < 2 ⩾2 or others signs

*Mild Moderate Sever Very sever*

⩾3 and < 5 ⩾51 and < 85

⩽5 × normal

Weight increase < 5% ⩾5% and < 10% ⩾5% and < 10% ⩾10%

*EBMT, European society for Blood and Marrow Transplantation; MDO, multi-organ dysfunction; MOF, multi-organ* 

⩽5 × normal

Ascites Minimal Moderate Necessity for paracentesis (external

Bilirubin kinetics Doubling within 48 h

CNS Normal Normal Normal New onset cognitive

*EBMT, European society for Blood and Marrow Transplantation; ALT, alanine transaminase; AST, aspartate transaminase; CNS, central nervous system; CPAP, continuous positive airway pressure; CTCAE, Common Terminology Criteria for Adverse Events; GFR, glomerular filtration rate; GLDH, glutamate dehydrogenase; LFT, liver function test; MOD/MOF, multi-organ dysfunction/multi-organ failure; RT, refractory thrombocytopenia;* 

*-MOD/MOF*

⩾8 ⩾136

48 × Normal

of MOD/MOF

*-MOD/MOF*

Impaired coagulation with need for replacement of coagulation factors

impairment

>5

⩾ 2 ⩾ 34

drainage)

CPAP)

coagulation

89–60 59–30 29–15 <15(renal failure)

< 2 L/min < 2 L/min Invasive pulmonary ventilation (including

#### *Sinusoidal Obstruction Syndrome DOI: http://dx.doi.org/10.5772/intechopen.96370*


*EBMT, European society for Blood and Marrow Transplantation; MDO, multi-organ dysfunction; MOF, multi-organ failure; SOS, sinusoidal obstruction syndrome; VOD, veno-occlusive disease.*

#### **Table 1.**

*Portal Hypertension - Recent Advances*

and thrombus formation [24, 25].

**4. Clinical presentation**

SOS and PA-SOS differ in several aspects.

the damaged SEC lead to a weakened mucosal barrier between cells. This promotes the escape of erythrocytes, leukocytes, and platelets between hepatocytes and hepatic sinusoidal SEC, contributing to the initiation of inflammatory processes

In HSCT-SOS, patients receiving high doses of toxic drugs (e.g., cyclophosphamide and leucovorin) during treatment are the cause of initial endothelial cell injury, which can lead to SOS, graft-versus-host disease (GVHD), capillary leak syndrome, implantation syndrome, and diffuse alveolar hemorrhage [26, 27]. In PA-SOS, the typical pathological changes are swelling, injury, and detachment of SEC in zone III of the hepatic acinus. The predominance of lesions in zone III of the hepatic acinus in PA-SOS is due to the abundance of CYP3A and the relative lack of glutathione (GSH) in this region. By constructing an animal model, Deleve et al. found that early damage to the endothelium of the hepatic sinusoids and central veins occurred before the development of veno-occlusive lesions, and that coagulative necrosis of hepatocytes occurred later than endothelial damage [3]. Besides, Harb et al. found that bone marrow progenitor cells were able to replace endothelial cells and thus repair the injury, while monocrotaline was able to inhibit endothelial progenitor cells in the bone marrow and circulation [28]. Therefore, PA damage to bone marrow progenitor cells and thus inhibition of endothelial cell repair may be another important pathogenetic mechanism. When SOS occurs, the hepatic sinusoidal stasis and dilatation; hepatic cord compression and atrophy; hepatocyte degeneration and necrosis; and central

small vein occlusion and fibrosis are seen under light microscopy [29].

The main symptoms of SOS are non-specific: with or without ascites, pain, hepatomegaly, and jaundice. Clinical manifestations range from very few symptoms to multi-organ failure leading to patient death. The clinical manifestations of HSCT-

HSCT-SOS usually presents with abdominal distention, hepatomegaly, pain in the liver area, ascites, jaundice, loss of appetite, and weakness [30]. HSCT-SOS has a rapid onset, usually occurring within 21 d after bone marrow transplantation. And the proportion of seriously ill patients and mortality is high, most of them die from multi-organ dysfunction syndrome and sepsis [11]. A European multicenter study [6] graded SOS according to the severity of the disease: mild (about 8%) is self-limiting and recovers without special treatment; moderate (about 64%) recovers with aggressive treatment, and severe (about 28%) often leads to death because of progression, or no improvement after 100 d of treatment. In 2016, the European Society for Blood and Marrow Transplantation updated the HSCT-SOS scale, as shown in **Table 1** [26]. Due to the marked differences in incidence, genetic susceptibility, clinical presentation, prevention, treatment, and outcome between age groups, the European Society for Blood and Marrow Transplantation proposed new criteria specifically for SOS/VOD in children in 2018, as shown in **Table 2** [31]. PA-SOS mainly presents with abdominal distention and ascites [32], only about half of the patients present with hepatomegaly or jaundice, and a few patients have hepatoceles [33]. Most patients with PA-SOS have insignificant elevations in serum alanine aminotransferase, serum aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transferase, and total bilirubin levels. PA-SOS occurs after a variable incubation period, which is usually about 30 d after drug administration and maybe up to several years. It can develop in both children and adults. In addition, PA-SOS

**42**

*New EBMT criteria for severity grading of a suspected SOS/VOD in adults.*


*EBMT, European society for Blood and Marrow Transplantation; ALT, alanine transaminase; AST, aspartate transaminase; CNS, central nervous system; CPAP, continuous positive airway pressure; CTCAE, Common Terminology Criteria for Adverse Events; GFR, glomerular filtration rate; GLDH, glutamate dehydrogenase; LFT, liver function test; MOD/MOF, multi-organ dysfunction/multi-organ failure; RT, refractory thrombocytopenia; SOS/VOD, sinusoidal obstruction syndrome/veno-occlusive disease.*

#### **Table 2.**

*EBMT criteria for grading the severity of suspected hepatic SOS/VOD in children.*

has a lower rate of severe disease than HSCT-SOS [34, 35], and mortality is generally around 40%, with most deaths due to progressive liver failure and infection [36, 37]. Since PA-SOS is associated with extensive fibrosis in the central region of the lobules and histological examination shows venous-centered cirrhosis, it is difficult to distinguish from other causes of chronic lesions of cirrhosis.

#### **5. Diagnosis**

#### **5.1 Symptoms and signs**

Pain in the liver area, hepatomegaly, jaundice, ascites, and significant weight gain in a short period are more common.

#### **5.2 Pathology**

The biopsy is the gold standard for confirming the diagnosis of SOS. Liver histology is characterized by bruising of the liver tissue, dilatation of the hepatic sinusoids, swelling and damage to the endothelial cells of the hepatic sinusoids, and shedding. In particular, the thickening, fibrosis, luminal narrowing, and even occlusion of small hepatic veins are typical of the disease. However, hepatic stasis and swelling are associated with a high risk of puncture and can be falsely negative due to heterogeneous intrahepatic lesions.

#### **5.3 Laboratory tests**

Serum total bilirubin (TBil) or other liver functions (alanine aminotransferase, aspartate aminotransferase, total bile acids, and albumin).

#### **5.4 Radiographic examinations**

Ultrasonography shows a thin inner diameter of the hepatic vein (< 5 mm) with a smooth lining and luminal patency and a slowed flow velocity in the hepatic vein (< 20 cm/s). This is different from hepatic vein stenosis (Bard-Chiari syndrome). Also, the hepatic sinusoids and small venous lesions are not uniformly distributed within the liver in patients with SOS. As a result, areas of tissue bruising and necrosis may be distributed in a map-like fashion and appear on ultrasound images as heterogeneous intrahepatic echogenicity. Enhanced CT or MRI of the abdomen has diagnostic value, shows that the contrast in the portal and delayed phases is obstructed at the end of the portal branches and fails to enter the hepatic lobe segmental veins, resulting in unrepresented hepatic veins.

#### **5.5 Hepatic venous pressure gradient measurement**

The difference between free hepatic venous pressure and wedge pressure is the "hepatic venous pressure gradient (HVPG), measured by puncture of the internal jugular or femoral vein. When HVPG >5 mmHg, it indicates the presence of portal hypertension in cirrhosis. When HVPG >10 mmHg, the diagnostic specificity of SOS is 91%, and the chance of esophagogastric variceal bleeding and seroperitoneum will be greatly increased. The internationally recognized diagnostic criteria for HSCT-SOS are Seattle criteria, Baltimore criteria [38], and pediatric criteria [31], and PA-SOS diagnosis is mainly based on Nanjing criteria [13]. Several accepted diagnostic criteria are listed in **Table 3**.

**45**

*HSCT—SOS* **Seattle criteria**

2 of the following 3 items within 20 d after bone marrow HSCT:

•

Serum TBil ≥34.2

umol/L;

•

Hepatomegaly with hepatic pain;

•

Otherwise unexplained weight gain on

three consecutive days despite the use

• •

Typical enhanced CT or MRI presentation.

The diagnosis was confirmed by pathology with the following

typical pathological findings: swelling, damage, and loss of

endothelial cells in the hepatic sinusoids of zone III of the

hepatic acinus, and significant dilatation and congestion of the

hepatic sinusoids.

Elevated serum TBil or other liver function abnormalities;

of diuretics or a weight gain 45% above

baseline value;

•

Hepatomegaly (best if confirmed by imag-

ing) above baseline value;

•

Ascites (best if confirmed by imaging)

above baseline value;

•

Rising bilirubin from a baseline value on

3 consecutive days or bilirubin ⩾2 mg/dL

within 72 h.

*SOS, sinusoidal obstruction syndrome; HSCT-SOS, hematopoietic stem cell transplantation-induced SOS; PA-SOS, pyrrolidine alkaloids-induced SOS; CT, computed tomography; MIR, magnetic resonance* 

*imaging.*

**Table 3.**

*Diagnostic criteria for hepatic SOS.*

•

Hepatomegaly or pain in

• original;

Weight gain more than 5% of the

the liver area;

•

Ascites or weight gain

• Ascites.

exceeding 2% of the

original.

**Baltimore criteria**

Serum TBil ≥34.2 pmo/L and within

21 d after bone marrow HSCT, 2 of

the following 3 items were present

simultaneously:

**criteria for children**

The presence of two or more of the

followinga:

•

Onexplained consumptive and transfusion-

refractory thrombocytopeniab;

•

*Sinusoidal Obstruction Syndrome*

*PA—SOS* **Nanjing criteria**

Have a clear history of PA-containing plant consumption, while

excluding other known causes of liver injury, and present with

3 of the following or confirmed by pathology:

Abdominal distention and/or pain in the liver region,

hepatomegaly and ascites;

*DOI: http://dx.doi.org/10.5772/intechopen.96370*


**Table 3.**

*Diagnostic criteria for hepatic SOS.*

*Sinusoidal Obstruction Syndrome DOI: http://dx.doi.org/10.5772/intechopen.96370*

*Portal Hypertension - Recent Advances*

**5. Diagnosis**

**5.2 Pathology**

**5.3 Laboratory tests**

**5.1 Symptoms and signs**

gain in a short period are more common.

due to heterogeneous intrahepatic lesions.

**5.4 Radiographic examinations**

aspartate aminotransferase, total bile acids, and albumin).

segmental veins, resulting in unrepresented hepatic veins.

**5.5 Hepatic venous pressure gradient measurement**

accepted diagnostic criteria are listed in **Table 3**.

has a lower rate of severe disease than HSCT-SOS [34, 35], and mortality is generally around 40%, with most deaths due to progressive liver failure and infection [36, 37]. Since PA-SOS is associated with extensive fibrosis in the central region of the lobules and histological examination shows venous-centered cirrhosis, it is

Pain in the liver area, hepatomegaly, jaundice, ascites, and significant weight

The biopsy is the gold standard for confirming the diagnosis of SOS. Liver histology is characterized by bruising of the liver tissue, dilatation of the hepatic sinusoids, swelling and damage to the endothelial cells of the hepatic sinusoids, and shedding. In particular, the thickening, fibrosis, luminal narrowing, and even occlusion of small hepatic veins are typical of the disease. However, hepatic stasis and swelling are associated with a high risk of puncture and can be falsely negative

Serum total bilirubin (TBil) or other liver functions (alanine aminotransferase,

Ultrasonography shows a thin inner diameter of the hepatic vein (< 5 mm) with a smooth lining and luminal patency and a slowed flow velocity in the hepatic vein (< 20 cm/s). This is different from hepatic vein stenosis (Bard-Chiari syndrome). Also, the hepatic sinusoids and small venous lesions are not uniformly distributed within the liver in patients with SOS. As a result, areas of tissue bruising and necrosis may be distributed in a map-like fashion and appear on ultrasound images as heterogeneous intrahepatic echogenicity. Enhanced CT or MRI of the abdomen has diagnostic value, shows that the contrast in the portal and delayed phases is obstructed at the end of the portal branches and fails to enter the hepatic lobe

The difference between free hepatic venous pressure and wedge pressure is the "hepatic venous pressure gradient (HVPG), measured by puncture of the internal jugular or femoral vein. When HVPG >5 mmHg, it indicates the presence of portal hypertension in cirrhosis. When HVPG >10 mmHg, the diagnostic specificity of SOS is 91%, and the chance of esophagogastric variceal bleeding and seroperitoneum will be greatly increased. The internationally recognized diagnostic criteria for HSCT-SOS are Seattle criteria, Baltimore criteria [38], and pediatric criteria [31], and PA-SOS diagnosis is mainly based on Nanjing criteria [13]. Several

difficult to distinguish from other causes of chronic lesions of cirrhosis.

**44**

#### **6. Treatment**

The principles of treatment for SOS include discontinuing the use of plants containing PA in suspected patients and starting symptomatic and supportive treatment as soon as possible.

#### **6.1 symptomatic and supportive treatment**

Symptomatic and supportive treatment is particularly important for patients in the acute or subacute phase, including hepatoprotection, diuresis, nutritional support, protein and vitamin supplementation, and improvement of microcirculation. Oral furosemide and spironolactone are preferred as diuretics. If ascites are severe and not responding to pharmacological therapy, peritoneal drainage may be considered. For patients with fluid retention and severe renal failure, hemodialysis or hemofiltration should be performed. Patients with multiple organ failures should be admitted to the intensive care unit. In most patients, symptomatic and supportive treatment can reduce water-sodium retention, repair damaged hepatocytes, and promote recovery of liver function, but it cannot significantly reverse pathophysiological changes and needs to be combined with other treatments together [39].

#### **6.2 Anticoagulant therapy**

For patients in the acute or subacute phase, anticoagulation should be started as early as possible unless there are contraindications (including severe bleeding or bleeding tendency). The preferred choice is low-molecular-weight heparin at the recommended dose of 100 IU/kg, administered subcutaneously every 12 hours. In China, the cure rate of patients with PA-SOS treated with low-molecular heparin in the past was up to 70.7–88.9% [40–43]. Monitoring is not required in most patients because of the low side effects of low molecular heparin, but it should be used with caution in patients with renal failure. Oral warfarin, the oral anticoagulant of choice for longterm treatment, can also be administered. Its efficacy is evaluated by monitoring the international standardized ratio of prothrombin time (recommended 2.0 to 3.0). However, warfarin therapy has a narrow dose range, a wide variation in individual response, and a vulnerability to various food and drug interactions for efficacy. An imageological should be performed after 2 weeks of anticoagulation therapy, and clinical manifestations and liver function should be evaluated. If treatment is effective, anticoagulation therapy can be continued for up to 3 months. Conversely, if it is ineffective, treatment should be discontinued and alternative therapies may be considered.

#### **6.3 Glucocorticoid**

High-dose hormone therapy may be efficacious for HSCT-SOS, but the risk of infection is a concern and the level of evidence is low. The efficacy of glucocorticoid therapy for PA-SOS is also controversial [12, 44–46].

#### **6.4 Defibrotide**

Defibrotide (DF) is an effective drug for the prevention and treatment of HSCT-SOS and can be used to treat severe HSCT-HSOS [12]. DF has anti-ischemic, anti-inflammatory, anti-thrombotic, and thrombolytic activities as well as protecting the small vessel endothelium and inhibiting fibrin deposition. The mechanism may be the protection of endothelial cells and the maintenance of thrombus-fibrinolytic balance. However, the effectiveness of DF has not been tested in PA-SOS because its use for the treatment of SOS has not yet been approved in China.

**47**

*Sinusoidal Obstruction Syndrome*

**6.5 Interventional therapy**

**6.6 Liver transplantation**

**6.7 Other**

treatment of PA-SOS.

**7. Conclusion**

**Acknowledgements**

**Conflict of interest**

The authors declare no conflict of interest.

*DOI: http://dx.doi.org/10.5772/intechopen.96370*

Transjugular intrahepatic portosystemic shunt (TIPS) can be performed when

Liver transplantation is an effective treatment for various end-stage liver diseases, and it can be considered in patients with liver failure who have failed after the above treatments. Liver transplantation has been reported to improve the prognosis of

Antithrombin III [50], recombinant human soluble thrombomodulin [51], N-acetyl-L-cysteine [52], and recombinant human tissue-plasminogen activator (t-PA) [53] have also been studied and reported for the treatment of HSCT-SOS. However, the efficacy of these drugs is unknown, and they lack evidence in the

In conclusion, there is no specific treatment for SOS and the prognosis of patients is poor, and only liver transplantation can prolong the survival time of patients with advanced disease. Therefore, the emphasis is on prevention, including pretreatment of transplantation and early treatment of underlying blood disorders to decrease the incidence and severity of HSCT-SOS, and increasing awareness of Chinese herbs such as Tusanqi to avoid accidental ingestion to reduce the incidence of PA-SOS. Besides, early diagnosis and assessment of patient risk through biomark-

This work was financially supported by Hunan Provincial Natural Science Foundation of China (Grant No. 2020JJ4421 and 2019JJ80020 and 2019JJ40180).

Prognosis: The overall morbidity and mortality rate is 20% to 50%. Mild patients heal better; most moderate patients can improve after symptomatic management and other treatments, and the morbidity and mortality rate is about 25%; severe patients are often complicated by multi-organ failure and have a morbidity and

medical treatment is ineffective. TIPS is effective in reducing portal pressure, improving clinical symptoms (ascites, hepatic distension, etc.), and preventing esophagogastric variceal hemorrhage [47]. TIPS is effective in patients with PA-SOS who have failed symptomatic treatment and require management of ascites and portal hypertension [48]. However, TIPS for acute HSCT-SOS has had variable results in one case report, with 5 of 10 patients dying after 10 days of TIPS placement, but the other 5 patients recovering significantly [49]. We need a longer

follow-up to determine whether TIPS improves patient prognosis.

patients with HSCT-SOS, but there are fewer reports on PA-SOS [38].

mortality rate of more than 90% despite active treatment [54].

ers is an effective tool for disease prevention and management [55].

#### **6.5 Interventional therapy**

*Portal Hypertension - Recent Advances*

treatment as soon as possible.

**6.2 Anticoagulant therapy**

**6.3 Glucocorticoid**

**6.4 Defibrotide**

**6.1 symptomatic and supportive treatment**

The principles of treatment for SOS include discontinuing the use of plants containing PA in suspected patients and starting symptomatic and supportive

Symptomatic and supportive treatment is particularly important for patients in the acute or subacute phase, including hepatoprotection, diuresis, nutritional support, protein and vitamin supplementation, and improvement of microcirculation. Oral furosemide and spironolactone are preferred as diuretics. If ascites are severe and not responding to pharmacological therapy, peritoneal drainage may be considered. For patients with fluid retention and severe renal failure, hemodialysis or hemofiltration should be performed. Patients with multiple organ failures should be admitted to the intensive care unit. In most patients, symptomatic and supportive treatment can reduce water-sodium retention, repair damaged hepatocytes, and promote recovery of liver function, but it cannot significantly reverse pathophysiological changes and needs to be combined with other treatments together [39].

For patients in the acute or subacute phase, anticoagulation should be started as early as possible unless there are contraindications (including severe bleeding or bleeding tendency). The preferred choice is low-molecular-weight heparin at the recommended dose of 100 IU/kg, administered subcutaneously every 12 hours. In China, the cure rate of patients with PA-SOS treated with low-molecular heparin in the past was up to 70.7–88.9% [40–43]. Monitoring is not required in most patients because of the low side effects of low molecular heparin, but it should be used with caution in patients with renal failure. Oral warfarin, the oral anticoagulant of choice for longterm treatment, can also be administered. Its efficacy is evaluated by monitoring the international standardized ratio of prothrombin time (recommended 2.0 to 3.0). However, warfarin therapy has a narrow dose range, a wide variation in individual response, and a vulnerability to various food and drug interactions for efficacy. An imageological should be performed after 2 weeks of anticoagulation therapy, and clinical manifestations and liver function should be evaluated. If treatment is effective, anticoagulation therapy can be continued for up to 3 months. Conversely, if it is ineffective, treatment should be discontinued and alternative therapies may be considered.

High-dose hormone therapy may be efficacious for HSCT-SOS, but the risk of infection is a concern and the level of evidence is low. The efficacy of glucocorticoid

Defibrotide (DF) is an effective drug for the prevention and treatment of HSCT-SOS and can be used to treat severe HSCT-HSOS [12]. DF has anti-ischemic, anti-inflammatory, anti-thrombotic, and thrombolytic activities as well as protecting the small vessel endothelium and inhibiting fibrin deposition. The mechanism may be the protection of endothelial cells and the maintenance of thrombus-fibrinolytic balance. However, the effectiveness of DF has not been tested in PA-SOS because its use for the treatment of SOS has not yet been approved in China.

therapy for PA-SOS is also controversial [12, 44–46].

**6. Treatment**

**46**

Transjugular intrahepatic portosystemic shunt (TIPS) can be performed when medical treatment is ineffective. TIPS is effective in reducing portal pressure, improving clinical symptoms (ascites, hepatic distension, etc.), and preventing esophagogastric variceal hemorrhage [47]. TIPS is effective in patients with PA-SOS who have failed symptomatic treatment and require management of ascites and portal hypertension [48]. However, TIPS for acute HSCT-SOS has had variable results in one case report, with 5 of 10 patients dying after 10 days of TIPS placement, but the other 5 patients recovering significantly [49]. We need a longer follow-up to determine whether TIPS improves patient prognosis.

#### **6.6 Liver transplantation**

Liver transplantation is an effective treatment for various end-stage liver diseases, and it can be considered in patients with liver failure who have failed after the above treatments. Liver transplantation has been reported to improve the prognosis of patients with HSCT-SOS, but there are fewer reports on PA-SOS [38].

#### **6.7 Other**

Antithrombin III [50], recombinant human soluble thrombomodulin [51], N-acetyl-L-cysteine [52], and recombinant human tissue-plasminogen activator (t-PA) [53] have also been studied and reported for the treatment of HSCT-SOS. However, the efficacy of these drugs is unknown, and they lack evidence in the treatment of PA-SOS.

Prognosis: The overall morbidity and mortality rate is 20% to 50%. Mild patients heal better; most moderate patients can improve after symptomatic management and other treatments, and the morbidity and mortality rate is about 25%; severe patients are often complicated by multi-organ failure and have a morbidity and mortality rate of more than 90% despite active treatment [54].

#### **7. Conclusion**

In conclusion, there is no specific treatment for SOS and the prognosis of patients is poor, and only liver transplantation can prolong the survival time of patients with advanced disease. Therefore, the emphasis is on prevention, including pretreatment of transplantation and early treatment of underlying blood disorders to decrease the incidence and severity of HSCT-SOS, and increasing awareness of Chinese herbs such as Tusanqi to avoid accidental ingestion to reduce the incidence of PA-SOS. Besides, early diagnosis and assessment of patient risk through biomarkers is an effective tool for disease prevention and management [55].

#### **Acknowledgements**

This work was financially supported by Hunan Provincial Natural Science Foundation of China (Grant No. 2020JJ4421 and 2019JJ80020 and 2019JJ40180).

#### **Conflict of interest**

The authors declare no conflict of interest.

*Portal Hypertension - Recent Advances*

### **Author details**

Yanxia Fei, Yanhua Peng, Huiping Sun, Shuangfa Zou and Jinfeng Yang\* Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China

\*Address all correspondence to: yangjinfeng@hnca.org.cn

© 2021 The Author(s). Licensee IntechOpen. This chapter is 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.

**49**

*Sinusoidal Obstruction Syndrome*

[1] Lédinghen V de, Villate A,

clinre.2020.03.019.

**References**

bmj.1.4802.117.

*DOI: http://dx.doi.org/10.5772/intechopen.96370*

Robin M, et al. Sinusoidal obstruction syndrome[J]. Clinics and research in hepatology and gastroenterology, 2020, 44(4):480-485. DOI: 10.1016/j.

Lancet, 2012, 379(9823):1301-1309. DOI: 10.1016/S0140-6736(11)61938-7.

[8] Barker C C, Butzner J D, Anderson R A, et al. Incidence, survival and risk factors for the development of veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients[J]. Bone marrow

transplantation, 2003, 32(1):79-87. DOI:

[9] Cesaro S, Pillon M, Talenti E, et al. A prospective survey on incidence, risk factors and therapy of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation[J]. Haematologica,

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2005, 90(10):1396-1404.

[10] Zhuge Y, Liu Y, Xie W, et al. Expert consensus on the clinical management of pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome[J]. Journal of gastroenterology and hepatology, 2019, 34(4):634-642. DOI: 10.1111/jgh.14612.

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[12] Dignan F L, Wynn R F, Hadzic N, et al. BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation[J]. British journal of haematology, 2013,

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[2] Hill K R, Rhodes K, Stafford J L, et al. Serous hepatosis: a pathogenesis of hepatic fibrosis in Jamaican children[J]. British medical journal, 1953, 1(4802):117-122. DOI: 10.1136/

[3] Bras G, Jelliffe D B, Stuart K L. Veno-occlusive disease of liver with nonportal type of cirrhosis, occurring in Jamaica[J]. A.M.A. archives of pathology, 1954, 57(4):285-300.

[4] DeLeve L D, McCuskey R S, Wang X, et al. Characterization of a reproducible rat model of hepatic veno-occlusive disease[J]. Hepatology (Baltimore, Md.), 1999, 29(6):1779-1791. DOI:

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McDonald G B. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease) [J]. Seminars in liver disease, 2002, 22(1):27-42. DOI: 10.1055/s-2002-23204.

[6] Carreras E, Bertz H, Arcese W, et al. Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: a prospective cohort study of the European Group for Blood and Marrow Transplantation. European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party[J]. Blood, 1998,

[7] Corbacioglu S, Cesaro S, Faraci M, et al. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial[J]. The

*Sinusoidal Obstruction Syndrome DOI: http://dx.doi.org/10.5772/intechopen.96370*

#### **References**

*Portal Hypertension - Recent Advances*

**48**

**Author details**

Yanxia Fei, Yanhua Peng, Huiping Sun, Shuangfa Zou and Jinfeng Yang\* Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of

© 2021 The Author(s). Licensee IntechOpen. This chapter is 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,

Medicine, Central South University, Changsha, Hunan, China

\*Address all correspondence to: yangjinfeng@hnca.org.cn

provided the original work is properly cited.

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[2] Hill K R, Rhodes K, Stafford J L, et al. Serous hepatosis: a pathogenesis of hepatic fibrosis in Jamaican children[J]. British medical journal, 1953, 1(4802):117-122. DOI: 10.1136/ bmj.1.4802.117.

[3] Bras G, Jelliffe D B, Stuart K L. Veno-occlusive disease of liver with nonportal type of cirrhosis, occurring in Jamaica[J]. A.M.A. archives of pathology, 1954, 57(4):285-300.

[4] DeLeve L D, McCuskey R S, Wang X, et al. Characterization of a reproducible rat model of hepatic veno-occlusive disease[J]. Hepatology (Baltimore, Md.), 1999, 29(6):1779-1791. DOI: 10.1002/hep.510290615.

[5] DeLeve L D, Shulman H M, McDonald G B. Toxic injury to hepatic sinusoids: sinusoidal obstruction syndrome (veno-occlusive disease) [J]. Seminars in liver disease, 2002, 22(1):27-42. DOI: 10.1055/s-2002-23204.

[6] Carreras E, Bertz H, Arcese W, et al. Incidence and outcome of hepatic veno-occlusive disease after blood or marrow transplantation: a prospective cohort study of the European Group for Blood and Marrow Transplantation. European Group for Blood and Marrow Transplantation Chronic Leukemia Working Party[J]. Blood, 1998, 92(10):3599-3604.

[7] Corbacioglu S, Cesaro S, Faraci M, et al. Defibrotide for prophylaxis of hepatic veno-occlusive disease in paediatric haemopoietic stem-cell transplantation: an open-label, phase 3, randomised controlled trial[J]. The

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[8] Barker C C, Butzner J D, Anderson R A, et al. Incidence, survival and risk factors for the development of veno-occlusive disease in pediatric hematopoietic stem cell transplant recipients[J]. Bone marrow transplantation, 2003, 32(1):79-87. DOI: 10.1038/sj.bmt.1704069.

[9] Cesaro S, Pillon M, Talenti E, et al. A prospective survey on incidence, risk factors and therapy of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation[J]. Haematologica, 2005, 90(10):1396-1404.

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[12] Dignan F L, Wynn R F, Hadzic N, et al. BCSH/BSBMT guideline: diagnosis and management of veno-occlusive disease (sinusoidal obstruction syndrome) following haematopoietic stem cell transplantation[J]. British journal of haematology, 2013, 163(4):444-457. DOI: 10.1111/bjh.12558.

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[35] Kalayoglu-Besisik S, Yenerel M N, Caliskan Y, et al. Time-related changes in the incidence, severity, and clinical outcome of hepatic venoocclusive disease in hematopoietic stem cell transplantation patients during the past 10 years[J]. Transplantation proceedings, 2005, 37(5):2285-2289. DOI: 10.1016/j. transproceed.2005.03.025.

[36] Carreras E. How I manage sinusoidal obstruction syndrome after haematopoietic cell transplantation[J]. British journal of haematology, 2015, 168(4):481-491. DOI: 10.1111/ bjh.13215.

[37] Zhou C-Z, Wang R-F, Lv W-F, et al. Transjugular intrahepatic portosystemic shunt for pyrrolizidine alkaloid-related hepatic sinusoidal obstruction syndrome[J]. World journal of gastroenterology, 2020, 26(24):3472- 3483. DOI: 10.3748/wjg.v26.i24.3472.

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[54] Lu Junzhu, Zhan Jun. Research progress on sinusoidal obstruction

**53**

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DOI: 10.1038/bmt.2017.43.

838. (in Chinese)

*DOI: http://dx.doi.org/10.5772/intechopen.96370*

syndrome caused by drug-induced liver injury[J]. New Med, 2017,48(12):833*Sinusoidal Obstruction Syndrome DOI: http://dx.doi.org/10.5772/intechopen.96370*

*Portal Hypertension - Recent Advances*

[41] Chen S, Li CL, Gao YY. The

Med. Radio. 2010, 18: 154-156.

[42] Xu XJ, Chen HT, Shan GD.

(in Chinese)

(in Chinese)

(in Chinese)

veno-occlusive disease. Chin. J. Dig. 2012, 32: 620-624. (in Chinese)

portosystemic stent-shunt (TIPS)[J]. Haematologica, 1996, 81(6):536-539.

[48] Azoulay D, Castaing D, Lemoine A,

et al. Transjugular intrahepatic portosystemic shunt (TIPS) for severe veno-occlusive disease of the liver following bone marrow transplantation[J]. Bone marrow transplantation, 2000, 25(9):987-992.

DOI: 10.1038/sj.bmt.1702386.

(in Chinese)

[49] Chen S, Li CL, Gao YY. The

[51] Nakamura D, Yoshimitsu M, Kawada H, et al. Recombinant human soluble thrombomodulin for the treatment of hepatic sinusoidal obstructive syndrome post allogeneic hematopoietic SCT[J]. Bone marrow transplantation, 2012, 47(3):463-464.

DOI: 10.1038/bmt.2011.103.

sj.bmt.1705969.

[52] Barkholt L, Remberger M, Hassan Z, et al. A prospective randomized study using N-acetyl-L-cysteine for early liver toxicity after allogeneic hematopoietic stem cell transplantation[J]. Bone marrow transplantation, 2008, 41(9):785-790. DOI: 10.1038/

[53] Yoon J-H, Min W-S, Kim H-J, et al. Experiences of t-PA use in moderate-tosevere hepatic veno-occlusive disease after hematopoietic SCT: is it still reasonable to use t-PA?[J]. Bone marrow transplantation, 2013, 48(12):1562- 1568. DOI: 10.1038/bmt.2013.101.

[54] Lu Junzhu, Zhan Jun. Research progress on sinusoidal obstruction

diagnostic value of Doppler ultrasound in hepatic veno-occlusive disease. Chin. Med. Radio. 2010, 18: 154-156.

[50] Xu XJ, Chen HT, Shan GD. Analysis of clinical practice in hepatic sinusoidal obstruction disease induced by Tusanqi. Chin. J. Crit. Care Med. (Electronic Edition) 2010, 03: 178-80. (in Chinese)

diagnostic value of Doppler ultrasound in hepatic veno-occlusive disease. Chin.

Analysis of clinical practice in hepatic sinusoidal obstruction disease induced by Tusanqi. Chin. J. Crit. Care Med. (Electronic Edition) 2010, 03: 178-80.

[43] Song Y, Fan YH. Clinical features of hepatic veno-occlusive disease induced by gynura root: analysis of 102 cases. J. Clin. Hepatol. 2011, 27: 496-499.

[44] Zhu H, Chu Y, Huo J, et al. Effect of prednisone on transforming growth factor-β1, connective tissue growth factor, nuclear factor-κBp65 and tumor necrosis factor-α expression in a murine model of hepatic sinusoidal obstruction

syndrome induced by Gynura segetum[J]. Hepatology research: the official journal of the Japan Society of Hepatology, 2011, 41(8):795-803. DOI: 10.1111/j.1872-034X.2011.00830.x.

[45] Zhang YT, Li S, Zhou DH et al. Clinical features of sinusoidal obstruction syndrome: an analysis of 35 cases and literature review. J.Clin.

Hepatol. 2013, 29: 936-939.

[46] Xu JM. A multi-center analysis of hepatic veno-occlusive disease in China. 11th CGC. HangZhou. 2011, 42-4

[47] La Rubia J de, Carral A, Montes H, et al. Successful treatment of hepatic veno-occlusive disease in a peripheral blood progenitor cell transplant

patient with a transjugular intrahepatic

(in Chinese)

(in Chinese)

**52**

syndrome caused by drug-induced liver injury[J]. New Med, 2017,48(12):833- 838. (in Chinese)

[55] Weischendorff S, Kielsen K, Sengeløv H, et al. Associations between levels of insulin-like growth factor 1 and sinusoidal obstruction syndrome after allogeneic haematopoietic stem cell transplantation[J]. Bone marrow transplantation, 2017, 52(6):863-869. DOI: 10.1038/bmt.2017.43.

**55**

Section 2

Pathogenesis of Portal

Hypertension

Section 2
