**Pulmonary Complications of Liver Cirrhosis: A Concise Review**

Nwe Ni Than

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96 Liver Cirrhosis - Update and Current Challenges

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Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68620

#### **Abstract**

Pulmonary complications, in the form of hepatopulmonary syndrome (HPS), portopulmonary hypertension (PPH), and hepatic hydrothorax (HH), are rare occurrences in patients with portal hypertension and liver cirrhosis. These complications are associated with high morbidity and mortality. The only effective therapy is liver transplantation in patients who are suitable. In this chapter, each condition will be outlined in detail from clinical presentations to diagnosis and treatment as well as the challenges that clinicians may have encountered in managing patients with these complications.

**Keywords:** hepatopulmonary syndrome, portopulmonary hypertension, hepatic hydrothorax, liver transplantation

## **1. Introduction**

Pulmonary complications in patients with chronic liver disease and portal hypertension include hepatopulmonary syndrome (HPS), portopulmonary complications (PPH), and hepatic hydrothorax (HH) (**Figure 1**). They are associated with increased morbidity and mortality and therefore, high suspicion of index is required to make earlier diagnosis and subsequently, to early treatment. The only effective treatment is liver transplantation (LT). All patients suitable for liver transplantation should be screened for potential pulmonary complications because earlier diagnosis gives better survival post liver transplantation. HPS is more common than PPH and HH, and the best chance of survival in these patients is LT. Among all the three conditions, HH carries the best prognosis.

© 2017 The Author(s). Licensee InTech. 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.

**Figure 1.** A step-wise approach to pulmonary complications of liver cirrhosis.

### **2. Hepatopulmonary syndrome**

#### **2.1. Background**

Hepatopulmonary syndrome (HPS) is first described in 1977 by Kennedy and Knudson [1] and defined as a defect in arterial oxygenation caused by the presence of intrapulmonary vascular dilatation (IVPD) in the context of portal hypertension [2] (**Figure 2**). The estimated prevalence of HPS in liver cirrhosis is 4–32% [3]. In patients who were accessed for LT, the prevalence of HPS is approximately 10–30% [4]. HPS is usually diagnosed during the sixth decade of life and there is no specific association with gender or underlying cause of liver disease or model of end stage liver disease (MELD) [4, 5]. The established 5-year survival rate was 20% for HPS patients versus 32–63% for patients without HPS [5, 6].

**Figure 2.** The sequence in development of HPS in liver cirrhosis.

#### **2.2. Clinical features**

Most patients with HPS present with dyspnea, orthopnea, platypnea, cyanosis, spider naevi, and finger clubbing [3, 7]. Platypnoea or orthodeoxia is defined as the presence of shortness of breath (dyspnoea) that worsens while sitting or standing and relieved by lying down. It is a common feature described in patients with HPS [7]. When patients with liver cirrhosis present with shortness of breath, the investigations should be done as early as feasible to avoid the delay in the diagnosis. Early diagnosis leads to reduction in patient's morbidity and mortality. The severity of HPS can be distinguished based on the level of hypoxemia as per the European Respiratory Task Force (**Table 1**) [8].


**Table 1.** The severity of HPS as per level of hypoxaemia.

#### **2.3. Pathogenesis**

**2. Hepatopulmonary syndrome**

**Figure 1.** A step-wise approach to pulmonary complications of liver cirrhosis.

Hepato-pulmonary syndrome

98 Liver Cirrhosis - Update and Current Challenges

Pathogenesis 1) Impaired oxygenaon 2) Intra-pulmonary vasodilataon 3) background of portal hypertension

Invesgaons Pulse oximetry Arterial blood gas

CXR Contrast ECHO Macroaggreated perfusion

scan

Treatment Oxygen

Liver transplantaon in case of suitable paents

Hepatopulmonary syndrome (HPS) is first described in 1977 by Kennedy and Knudson [1] and defined as a defect in arterial oxygenation caused by the presence of intrapulmonary vascular dilatation (IVPD) in the context of portal hypertension [2] (**Figure 2**). The estimated prevalence of HPS in liver cirrhosis is 4–32% [3]. In patients who were accessed for LT, the prevalence of HPS is approximately 10–30% [4]. HPS is usually diagnosed during the sixth decade of life and there is no specific association with gender or underlying cause of liver disease or model of end stage liver disease (MELD) [4, 5]. The established 5-year survival rate

Pulmonary complicaons

Porto-pulmonary

Pathogenesis 1) elevated mean arterial

2) increased pulmonary vascular resistance 3) background of portal hypertension Invesgaons Pulse oximetry Arterial blood gas

Transthoracic echocardiogram Right heart catheterisaon

Oral agents: Prostacyclin analogues

(prostanoids)/Phosphodiester ase 5 inhibitors and endothelin receptor antagonists Liver transplantaon in case of suitable paents

pressure

CXR

Treatment Oxygen

hypertension Hepac hydrothorax

Pathogenesis 1) renin-angiotensin acvaon causing sodium and water retenon 2) fluid translocaon through small defect in diaphragma

Invesgaons Pulse oximetry Arterial blood gas

Treatment

Medical: dietary educaon, diurecs, pleural aspiraon, thoracocentesis, paracentesis Non-surgical procedures: TIPSS, Pleux drain Surgical: pleurodesis, shunt surgery and repair of diaphragmac defect and finally liver transplantaon when all others are not eecve.

CXR Transthoracic echocardiogram

was 20% for HPS patients versus 32–63% for patients without HPS [5, 6].

**2.1. Background**

The pathogenesis of HPS is still unclear but the hallmark is thought to be due to intrapulmonary vasodilatation (IVPD), especially at the level of pre-capillary and capillary vasodilation [7]. IVPD is mediated by a number of endogenous vasoactive molecules, mainly endothelin-1 (ET-1) and nitric oxide (NO) [3, 9]. Portal hypertension increased the production of vasoconstrictor ET-1, which stimulates the production of the ETB receptor at the level of the pulmonary microcirculation, with subsequent increase in eNOS activity causing vasodilatation [7, 9]. As a result of IVPD, nearly 20% or more of the cardiac output bypasses the functioning alveoli [2]. IVPD then causes arterial deoxygenation by three mechanisms: ventilation/perfusion mismatch, intrapulmonary shunting, and limitation of oxygen diffusion [7].

Angiogenesis is also considered to be an important phenomenon in the development of HPS [10] through upregulation of the vascular endothelial growth factor. Other mechanism suggested from experimental studies was vasodilation via increased carbon monoxide production through haem oxygenase [7]. The proposed pathogenesis of HPS was shown in **Figure 3**.

**Figure 3.** The pathogenesis of hepatopulmonary syndrome.

#### **2.4. Investigations**

In most centers, patients will usually undergo routine cardiopulmonary investigations during LT assessment. Bedside pulse oximetry is the first line screening investigation and oxygen saturation of less than 96%, has a sensitivity of 100% and specificity of 88% to detect PaO<sup>2</sup> < 70 mmHg [7, 11]. Arterial blood gas (ABG) sampling is required for the diagnosis of HPS to calculate the Alveolar-arterial (A-a) gradient [7]. PA-aO<sup>2</sup> gradient is the most important marker in diagnosing early stage of HPS [7] and the European Respiratory Society Task Force recommends a PA-aO<sup>2</sup> ≥ 15 mmHg for the diagnosis of HPS and the level of PaO<sup>2</sup> will determine the severity of the HPS [10] (**Table 1**). In suspected patients with HPS, ABG was performed on room air with patient sitting down first and the procedure is repeated 15 to 20 minutes in the standing up position. Orthodeoxia, which manifests as a decrease in PaO<sup>2</sup> of ≥4 mmHg or ≥5% from the supine to the upright position [12], and the increase in PaO<sup>2</sup> while breathing 100% oxygen, which should reach above 300 mmHg [7]. Orthodeoxia is a consequence of the increased V/Q mismatch and decreased cardiac output following the change from the supine to the upright position [7].

Chest radiography shows prominent pulmonary vascular markings in bilateral lower lobes, but finding is not specific for HPS [2]. Pulmonary function test should be performed to rule out other associated intrinsic pulmonary disorders. Contrast-enhanced echocardiography is the most sensitive test to demonstrate intrapulmonary shunting disease [2]. It is done using intravenous injections of agitated saline or indocyanine green to produce bubbles of at least 15 microns in diameter [2]. Normally, these microbubbles are trapped in the pulmonary vasculature and absorbed, but in intracardiac right to left shunts, these microbubbles are seen in the left heart within the first three cardiac cycles [7]. In HPS, the bubbles are seen in the left heart after the third heartbeat, usually between the third and sixth heartbeat due to intra-pulmonary shunting [2]. Studies have shown that transesophageal echocardiography is more sensitive than transthoracic echocardiography in demonstrating intrapulmonary shunting [7].

of vasoconstrictor ET-1, which stimulates the production of the ETB receptor at the level of the pulmonary microcirculation, with subsequent increase in eNOS activity causing vasodilatation [7, 9]. As a result of IVPD, nearly 20% or more of the cardiac output bypasses the functioning alveoli [2]. IVPD then causes arterial deoxygenation by three mechanisms: ventilation/perfusion mismatch, intrapulmonary shunting, and limitation of oxygen diffusion [7]. Angiogenesis is also considered to be an important phenomenon in the development of HPS [10] through upregulation of the vascular endothelial growth factor. Other mechanism suggested from experimental studies was vasodilation via increased carbon monoxide production through haem oxygenase [7]. The proposed pathogenesis of HPS was shown in **Figure 3**.

In most centers, patients will usually undergo routine cardiopulmonary investigations during LT assessment. Bedside pulse oximetry is the first line screening investigation and oxygen satu-

[7, 11]. Arterial blood gas (ABG) sampling is required for the diagnosis of HPS to calculate the

early stage of HPS [7] and the European Respiratory Society Task Force recommends a PA-aO<sup>2</sup>

[10] (**Table 1**). In suspected patients with HPS, ABG was performed on room air with patient sitting down first and the procedure is repeated 15 to 20 minutes in the standing up position.

reach above 300 mmHg [7]. Orthodeoxia is a consequence of the increased V/Q mismatch and decreased cardiac output following the change from the supine to the upright position [7].

< 70 mmHg

≥

gradient is the most important marker in diagnosing

will determine the severity of the HPS

of ≥4 mmHg or ≥5% from the supine to

while breathing 100% oxygen, which should

ration of less than 96%, has a sensitivity of 100% and specificity of 88% to detect PaO<sup>2</sup>

**2.4. Investigations**

Alveolar-arterial (A-a) gradient [7]. PA-aO<sup>2</sup>

**Figure 3.** The pathogenesis of hepatopulmonary syndrome.

100 Liver Cirrhosis - Update and Current Challenges

15 mmHg for the diagnosis of HPS and the level of PaO<sup>2</sup>

Orthodeoxia, which manifests as a decrease in PaO<sup>2</sup>

the upright position [12], and the increase in PaO<sup>2</sup>

99 m Technetium-macroaggregated albumin (Tc-99 m MAA) lung perfusion scan is used widely in the diagnosis of HPS (**Figure 4**). Albumin macroaggregates with more than 20 μm in diameter are normally entrapped in the pulmonary vasculature [2]. In patients with intrapulmonary shunts, these albumin macroaggregates escape from the pulmonary vasculature and are taken up by other organs [2]. Normally, less than 5% of isotope reaches brain circulation compared to the lung, but in HPS patients, the fraction is more than 6% [7]. The major disadvantage of Tc-99 m MAA scan is its inability to differentiate intra-cardiac from intrapulmonary shunting. Pulmonary angiography is invasive, and hence, it is only reserved for those who did not have response to 100% oxygen therapy [7]. The baseline investigations and the findings found in HPS are illustrated in **Table 2**.

**Figure 4.** Whole body (Tc-99 m MAA) scan showed an increased uptake in within the lungs and thyroid with well visualization in the brain, kidneys, and liver.


**Table 2.** Screening and investigative methods used in HPS.

#### **2.5. Treatment**

#### *2.5.1. Medical treatment*

Patients who experience severe dyspnea at rest and evidence of hypoxemia clinically should receive oxygen therapy [10]. Many studies have looked into treatment of HPS with nitric oxide inhalation, low consumption of L-arginine using methylene blue, aspirin, antibiotic usage to reduce intestine's bacterial translocation, somatostatin, indomethacin, garlic, and transjugular intrahepatic portosystemic shunt (TIPS), but none of them have not shown any particular benefit as long-term treatment of HPS [7].

Recent pilot randomized controlled study with norfloxacin did not show any improvement in gas exchange of HPS patient [13]. Initial studies suggested that garlic may have a role in the treatment of HPS by altering nitric oxide production [7]. A recent randomized controlled trial showed garlic supplementation, which was associated with a 24.66% increase in baseline arterial oxygen levels and 28.35% decrease in alveolar-arterial oxygen gradient [14]. It also shown that garlic supplementation may be beneficial in patients with HPS for the reversal of intrapulmonary shunts as well as for reducing hypoxemia and mortality, although study with higher number of patients are required to show clinical effectiveness [14].

One of the factors involved in the pathogenesis of HPS was tumor necrosis factor-alpha (TNF-a) and overproduction of TNF-a cause vasodilatation [4]. Hence, treatment with pentoxifylline (an inhibitor of TNF-a) although in recent pilot study [15] showed that pentoxifylline did not improve arterial oxygenation in advanced HPS, and tolerance was limited by gastrointestinal toxicity.

Enhanced pulmonary production of nitric oxide (NO) has been implicated in the pathogenesis of HPS, and NO inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME) in both animals and humans with HPS has improved arterial hypoxemia [16]. A study [16] investigating the effect of nebulized L-NAME in patients with HPS showed that the treatment decreased exhaled NO, mixed venous nitrite/nitrate, and cardiac output although systematic and pulmonary vascular resistance were increased. In contrast, ventilation-perfusion mismatching, intrapulmonary shunt, and, in turn, arterial deoxygenation remained unchanged [16].

#### *2.5.2. Transjugular intrahepatic portosystemic shunt (TIPSS)*

Recent systematic reviews of 10 studies with 12 patients showed that TIPSS is technically feasible to perform in patients with HPS, but overall benefit is unclear [17]. The current management did not advise TIPSS in patients with HPS.

#### *2.5.3. Liver transplantation (LT)*

**2.5. Treatment**

*2.5.1. Medical treatment*

benefit as long-term treatment of HPS [7].

**Screening methods Findings**

102 Liver Cirrhosis - Update and Current Challenges

Diagnostic tests Findings Arterial blood gas analysis AaO<sup>2</sup>

**Table 2.** Screening and investigative methods used in HPS.

Pulse oximetry Oxygen saturation <96% Chest radiograph Increased vascular markings Lung function tests Normal or reduction FVC or FEV1

99 m Tc-MAA Cerebral uptake ≥6%

Patients who experience severe dyspnea at rest and evidence of hypoxemia clinically should receive oxygen therapy [10]. Many studies have looked into treatment of HPS with nitric oxide inhalation, low consumption of L-arginine using methylene blue, aspirin, antibiotic usage to reduce intestine's bacterial translocation, somatostatin, indomethacin, garlic, and transjugular intrahepatic portosystemic shunt (TIPS), but none of them have not shown any particular

Reduction in diffusing capacity of the lungs for carbon

≥ 20 mmHg (in patients above 64 years of age)

monoxide (DLCO-co)

≥ 15 mmHg or

AaO<sup>2</sup>

Contrast echocardiography Bubbles in the left cavities between the fourth and sixth beat

Recent pilot randomized controlled study with norfloxacin did not show any improvement in gas exchange of HPS patient [13]. Initial studies suggested that garlic may have a role in the treatment of HPS by altering nitric oxide production [7]. A recent randomized controlled trial showed garlic supplementation, which was associated with a 24.66% increase in baseline arterial oxygen levels and 28.35% decrease in alveolar-arterial oxygen gradient [14]. It also shown that garlic supplementation may be beneficial in patients with HPS for the reversal of intrapulmonary shunts as well as for reducing hypoxemia and mortality, although study with

One of the factors involved in the pathogenesis of HPS was tumor necrosis factor-alpha (TNF-a) and overproduction of TNF-a cause vasodilatation [4]. Hence, treatment with pentoxifylline (an inhibitor of TNF-a) although in recent pilot study [15] showed that pentoxifylline did not improve arterial oxygenation in advanced HPS, and tolerance was limited by gastrointestinal toxicity.

Enhanced pulmonary production of nitric oxide (NO) has been implicated in the pathogenesis of HPS, and NO inhibition with N(G)-nitro-L-arginine methyl ester (L-NAME) in both animals and humans with HPS has improved arterial hypoxemia [16]. A study [16] investigating the effect of nebulized L-NAME in patients with HPS showed that

higher number of patients are required to show clinical effectiveness [14].

The only effective treatment available for HPS is liver transplantation (LT), although LT is invasive and carries a high risk. Hence, patients should be accessed thoroughly prior to consideration of LT. After LT, 85% patients had significant improvement in gas exchange, although it can take up to 1 year for the abnormalities to normalize [2]. The mortality is higher for patient with HPS who underwent LT than those without HPS and the mortality is higher for those with marked hypoxemia (PaO<sup>2</sup> < 50 mmHg) and intrapulmonary shunting (shunt fraction > 20%) [2]. The established 5-year survival rate was 23% for HPS patients and 67% for patients without HPS [18]. For patients with HPS who are on LT waiting list should be monitored closely to prevent worsening of the conditions. The most challenging post LT is severe hypoxemia post-operative period with prolonged respiratory weaning that often resulted in death. Ten-year survival after LT in HPS patients stands at 64% [10] and post LT mortality rates obtained in these studies range between 7.7 and 33% [10].

Recent study showed that patients with HPS presented higher cardiac output, lower systemic vascular resistance, and higher progesterone and estradiol levels than patients without HPS [19]. The study showed that LT produced normalization of intrapulmonary vasodilatation in all patients as well as hyperdynamic circulation and hence, is a useful therapeutic option in patients with HPS [19]. Normalization of sex hormone levels after LT suggests that they could play a pathogenic role in the development of HPS [19].

#### *2.5.4. Other treatment options*

One of the recent management options for life-threatening hypoxemia in HPS patients is extracorporeal membrane oxygenation (ECMO) [20]. Monsel et al. reported the use of ECMO in preparation of LT in patients with refractory hypoxemia caused by a combination of acute respiratory distress syndrome (ARDS) and HPS [21]. The preliminary data showed that ECMO allowed the performance of successful LT by controlling gas exchange [3]. Auzinger et al. also reported the successful case of using ECMO for severe refractory hypoxemia after LT in HPS patients [20]. It could facilitate early ventilator weaning, thus prevented the need for the prolonged use of sedation and reduced complication associated with interventions [20]. However, the effectiveness of ECMO still has to be proven by future randomized trials.

## **3. Portopulmonary hypertension**

#### **3.1. Background**

Portopulmonary syndrome (PPH) was first described in 1951 by Mantz and Craige [22]. PPH is characterized by the presence of elevated mean pulmonary hypertension in patients with portal hypertension due to increased pulmonary vascular resistance [4]. It is found in 2–10% of patients with cirrhosis [2] and reported among 5–8% of the patients with CLD who have undergone liver transplantation [23].

A recent retrospective review conducted in treatment-naïve patients with PPH within the United Kingdom national registry showed that patients with PPH had survival rates of 85, 60, and 35% at 1, 3, and 5 years [24]. The study mentioned that the prevalence of PPH was found to be 0.85 cases per 1 million and the mean age of diagnosis was 53 years [24]. Alcohol and hepatitis C were found to be the most common causes of PPH [24].

PPH results from arterial vasoconstriction linked to remodeling of the vasculature of the lung caused by prolonged portal hypertension and subsequently lead to pulmonary arterial hypertension (PAH) [9]. The condition is more common in females and in patients with autoimmune hepatitis [7, 25]. PPH can occur at any age but more common in fourth or fifth decade of life [4]. PPH occurs 4–7 years after patients are diagnosed with portal hypertension [26]. The severity of liver disease does not correlate with the severity of PPH. Without treatment, estimated 1-year survival in PPH is around 60% [23, 27].

#### **3.2. Clinical features**

Most patients are asymptomatic but clinical features of liver disease will be apparent. Patients usually present with features of right-sided heart failure such as dyspnea, orthopnea, chest pain, fatigue, and syncope [9]. On clinical examination, patient may present with tricuspid regurgitation murmur, loud pulmonary (P2) sound, diastolic murmur of pulmonary regurgitation, and features of right-sided heart failure evident by the presence of elevated jugular venous pressure, pulsatile liver, peripheral edema, and ascites [9]. The severity of PPH is classified based on degree of MPAP values: mild (25–35 mmHg), moderate (35–50 mmHg), and severe (>50 mmHg) [9].

The European Cardiologic Society and the European Respiratory Society Task Force have defined the diagnostic criteria for PPH as follow in **Table 3** [28]. According to the World Health Organization classification, PPH is located within PAH group 1 [29].

#### **Diagnostic criteria for PPH**

Mean pulmonary arterial pressure (mPAP) >25 mmHg Pulmonary vascular resistance (PVR) >240 dyn s cm−5 Pulmonary capillary wedge pressure <15 mmHg

**Table 3.** Diagnostic criteria for portopulmonary hypertension (PPH).

#### **3.3. Pathogenesis**

**3. Portopulmonary hypertension**

104 Liver Cirrhosis - Update and Current Challenges

undergone liver transplantation [23].

Portopulmonary syndrome (PPH) was first described in 1951 by Mantz and Craige [22]. PPH is characterized by the presence of elevated mean pulmonary hypertension in patients with portal hypertension due to increased pulmonary vascular resistance [4]. It is found in 2–10% of patients with cirrhosis [2] and reported among 5–8% of the patients with CLD who have

A recent retrospective review conducted in treatment-naïve patients with PPH within the United Kingdom national registry showed that patients with PPH had survival rates of 85, 60, and 35% at 1, 3, and 5 years [24]. The study mentioned that the prevalence of PPH was found to be 0.85 cases per 1 million and the mean age of diagnosis was 53 years [24]. Alcohol and

PPH results from arterial vasoconstriction linked to remodeling of the vasculature of the lung caused by prolonged portal hypertension and subsequently lead to pulmonary arterial hypertension (PAH) [9]. The condition is more common in females and in patients with autoimmune hepatitis [7, 25]. PPH can occur at any age but more common in fourth or fifth decade of life [4]. PPH occurs 4–7 years after patients are diagnosed with portal hypertension [26]. The severity of liver disease does not correlate with the severity of PPH. Without treatment,

Most patients are asymptomatic but clinical features of liver disease will be apparent. Patients usually present with features of right-sided heart failure such as dyspnea, orthopnea, chest pain, fatigue, and syncope [9]. On clinical examination, patient may present with tricuspid regurgitation murmur, loud pulmonary (P2) sound, diastolic murmur of pulmonary regurgitation, and features of right-sided heart failure evident by the presence of elevated jugular venous pressure, pulsatile liver, peripheral edema, and ascites [9]. The severity of PPH is classified based on degree of MPAP values: mild (25–35 mmHg), moderate (35–50 mmHg), and severe (>50 mmHg)

The European Cardiologic Society and the European Respiratory Society Task Force have defined the diagnostic criteria for PPH as follow in **Table 3** [28]. According to the World

Health Organization classification, PPH is located within PAH group 1 [29].

hepatitis C were found to be the most common causes of PPH [24].

estimated 1-year survival in PPH is around 60% [23, 27].

**3.1. Background**

**3.2. Clinical features**

**Diagnostic criteria for PPH**

Mean pulmonary arterial pressure (mPAP) >25 mmHg Pulmonary vascular resistance (PVR) >240 dyn s cm−5 Pulmonary capillary wedge pressure <15 mmHg

**Table 3.** Diagnostic criteria for portopulmonary hypertension (PPH).

[9].

The exact pathophysiology behind PPH is poorly understood but histologically, it is thought to be similar to the pathogenesis of idiopathic pulmonary arterial hypertension (PAH) [29]. Hyperdynamic circulatory state and high cardiac output are the hallmarks in most of the patients with PPH leading to increased shear stress on the pulmonary circulation [29]. Due to vascular shear stress, vasoactive, proliferative, and angiogenic mediators (including endothelin 1 (ET-1), vasoactive intestinal peptide, serotonin, thromboxane A2, interleukin 1, glucagon, and secretin) were released which lead to arterial changes seen in PPH [2, 4, 23, 27]. The main pathological abnormalities include proliferate arteriopathy, obliteration of the vascular lumen by endothelial and smooth muscle cells, formation of plexiform lesions, necrotizing arteritis, fibrinoid necrosis, and *in-situ* thrombi [23, 27]. Due to portosystemic shunts, bacterial endotoxins were found in pulmonary circulation from gastrointestinal tract and the recruitment of interstitial macrophages to clear those endotoxins also contribute to the development of PPH [30].

Genetic polymorphisms may play a role in the development of PPH. Finally, vasodilating mediators, such as nitric oxide (NO) and prostaglandin I<sup>2</sup> (prostacyclin), may be decreased in PPH [29]. Prostacyclin synthase, the enzyme responsible for prostacyclin synthesis, has been demonstrated to be deficient in the pulmonary endothelium of patients with PPH [4]. The illustration pathogenesis of PPH is shown in **Figure 5**.

#### **3.4. Investigations**

Since patient can be asymptomatic, high suspicion is required to diagnose this condition earlier, which can lead to earlier treatment and better prognosis. All baseline investigations such as ECG, CXR, blood gas analysis, and lung function tests have poor prognostic yield and did not reflect severity of PPH. In patient with PPH, CXR might show a prominent main pulmonary artery, cardiomegaly due to enlarged right cardiac chambers, and increased vascularity in the upper lobes [2, 4, 9]. Pulmonary function tests in patients with PPH would show decreased lung diffusion capacity and reduced lung volume [2, 4]. In arterial blood gas analyses, hypoxemia and hypocapnia associated with an elevated alveolar-arterial oxygen gradient would be seen [2].

Transthoracic echocardiogram showed right ventricular hypertrophy and right atrium dilatation, which is not usually specific to PPH [23, 27]. Transthoracic echocardiogram (TTE) is the screening tool used initially and it can identify patients with elevated pulmonary arterial systolic pressure (PASP). In those patients with elevated PASP, the next investigation is right heart catheter which can confirm the diagnosis of PPH. Usually, RV systolic pressure <30 mmHg was used to exclude PPH and if it is >50, patient is highly likely to have PPH [23]. Cardiac output (CO), mean pulmonary arterial pressure (mPAP), mean pulmonary arterial occlusion pressure (mPAOP), and pulmonary vascular resistance (PVR) can help to determine the nature and severity of the PPH [2, 27]. There are three main causes of elevated mPAP in liver disease patients and those are cirrhotic cardiomyopathy due to left ventricular dysfunction, the typical high-output state of cirrhosis, and PPH [27]. **Table 4** illustrates the difference findings noted in each condition.

**Figure 5.** The pathogenesis of portopulmonary hypertension.


**Table 4.** The difference findings for each conditions.

The severity of PPH and the progression of disease during the course of disease in patients with portal hypertension can only be investigated through invasive right heart catheterization. Hence, it will be useful to develop a sensitive biomarker which can detect disease presence, predict the severity, and treatment response. A recent prospective multicentre case-control study which studied the plasma level of macrophage migration inhibitory factor (MIF) in PPH patients seemed to show promising results [31]. It showed that MIF was higher in both the systemic and pulmonary circulations of patients with PPH compared with controls and correlated with hemodynamic indices of disease severity [31]. High levels of MIF were associated with an increased risk of death and MIF production may play a role in disease pathogenesis of PPH [31]. MIF can be an ideal novel biomarker in detecting disease presence and severity [31].

#### **3.5. Treatment**

Treatment strategies for PPH are derived from studies of idiopathic PAH and the aim of therapy is to provide symptomatic relief, to improve the quality of life and exercise capacity, and to facilitate liver transplant [23]. The only effective treatment in patients with PPH is liver transplantation in patients who are suitable after careful assessment. Medical therapies that have been tried for PPH include endothelin receptor antagonists, phosphodiesterase 5 inhibitors, and prostacyclin analogs [2, 23, 27]. There are limited data evaluating the long-term survival of patients with PPH managed with medical therapy alone. Recent study from UK showed that phosphodiesterase 5 inhibitors were the most frequently used targeted therapy (63%) followed by prostacyclin analogs (12.7%), and endothelin receptor antagonists (10%) [32].

#### *3.5.1. General medical treatment*

In patient with significant hypoxemia, oxygen therapy is needed for improvement of symptoms. For those with significant edema and ascites, diuretics should be initiated. In patients with PPH, they are at risk of thrombosis and hence anticoagulation is recommended. However, in patients with liver cirrhosis had increased risk of variceal bleeding due to underlying portal hypertension and clinical judgment is required prior to starting anticoagulation in these group of patients.

Calcium channel blockers can be used due to their acute vasoreactive properties in PAH but can be dangerous in patients with PPH since it can result in worsening of portal hypertension because of their mesenteric dilatation properties [2, 23, 27]. TIPSS are not recommended in PPH since it can deteriorate PPH because of acute increase in preload causing increased cardiac output and mPAP, and then leads to worsening right ventricular strain and dysfunction [29].

#### *3.5.2. Specific therapies for PPH*

The therapies specific for PPH targeted to improve pulmonary vasoconstriction and vascular remodeling by altering three pathways: Prostacyclin analogs (prostanoids), phosphodiesterase 5 inhibitors, and endothelin receptor antagonists [2, 9, 27, 33]. Pulmonary vasodilators treatment should be employed with the aim of lowering mPAP < 35 mmHg, to minimize the risk of graft failure and to improve the overall outcome [42].

#### *3.5.3. Prostacyclin derivatives*

The severity of PPH and the progression of disease during the course of disease in patients with portal hypertension can only be investigated through invasive right heart catheterization. Hence, it will be useful to develop a sensitive biomarker which can detect disease presence, predict the severity, and treatment response. A recent prospective multicentre case-control study which studied the plasma level of macrophage migration inhibitory factor (MIF) in PPH patients seemed to show promising results [31]. It showed that MIF was higher in both the systemic and pulmonary circulations of patients with PPH compared with controls and correlated with hemodynamic indices of disease severity [31]. High levels of MIF were associated with an increased risk of death and MIF production may play a role in disease pathogenesis of PPH [31]. MIF can be an ideal novel biomarker in detecting disease presence and

**Cardiac output mPAP mPAPOP PVR**

Hyperdynamic state Elevated Elevated Normal Decreased LV dysfunction Low Elevated Elevated Elevated PPH Low Elevated Low Elevated

**Figure 5.** The pathogenesis of portopulmonary hypertension.

106 Liver Cirrhosis - Update and Current Challenges

**Table 4.** The difference findings for each conditions.

Treatment strategies for PPH are derived from studies of idiopathic PAH and the aim of therapy is to provide symptomatic relief, to improve the quality of life and exercise capacity, and to facilitate liver transplant [23]. The only effective treatment in patients with PPH is liver transplantation in patients who are suitable after careful assessment. Medical therapies that have

severity [31].

**3.5. Treatment**

They are potent pulmonary as well as systemic vasodilators, and have antiplatelet aggregating and antiproliferative effects [27]. The most commonly used prostacyclin is epoprostenol and it is the only treatment that has been shown to improve survival in idiopathic PAH [27].

#### *3.5.4. Endothelin receptor antagonists*

Bosentan is an oral dual effective, nonselective receptor antagonist that blocks both endothelin A and B receptors [27], and it has been shown to be effective in the treatment of PPH showing clinical, functional, and hemodynamic benefits without significant hepatotoxicity in some small retrospective case series [29]. Bosentan is probably the therapy of choice for patients with PPH as it potentially improves pulmonary as well as portal hypertension [29]. It is potentially hepatotoxic and may cause deterioration in liver enzymes in about 10% of patients, and hence, close monitoring is needed [29]. A recent study showed that Child-Pugh B cirrhosis with PPH had significantly larger hemodynamic improvement with bosentan treatment [34]. It was also found that plasma concentrations of bosentan were higher in patients with child B cirrhosis than those observed in idiopathic PAH [34].

#### *3.5.5. Phosphodiesterase 5 inhibitors*

Phosphodiesterase-5 inhibitor therapy is efficacious in other causes of WHO group I pulmonary arterial hypertension [32]. They inhibit the growth of pulmonary vascular smooth muscle cells and lower mean pulmonary artery pressure and pulmonary vascular resistance by mediating vasodilation through guanosine monophosphate [2, 27]. Sildenafil is commonly used in PPH and reported to be effective in reducing mPAP and PVR [29]. Sildenafil is approved in a dose of 20 mg three times a day for treatment of PPH [35], and it should be considered as a bridging therapy before liver transplant for patients with PPH to delay the progression of the disease.

A recent single center retrospective study showed that sildenafil therapy resulted in improvement of WHO functional class with significant decrease in PVR, mPAP, and increase in cardiac output but no change in 6-min walk test over the period of 6 months treatment [32]. A recent retrospective study of all patients with PPH treated by oral pulmonary vasoactive drugs (PVD) (bosentan, ambrisentan, sildenafil, tadalafil) showed that oral PVD improved MPAP, PVR, and 6-min walk distance [36]. The study showed that oral PVD are safe, better tolerated in patients with cirrhosis, and did not showed any worsening of cirrhosis and these treatments improved hemodynamic conditions allowing patients access to liver transplantation eligibility [36].

#### *3.5.6. Liver transplantation*

LT is the definitive therapy for patient with PPH when medical therapy fails. LT should be considered in patients with mean pulmonary artery pressure (MPAP) <35 mmHg or MPAP between 35 and 50 mmHg with pulmonary vascular resistance (PVR) <250 dyn s cm−5 [23, 37]. PPH is diagnosed in 2–6% of liver transplantation (LT) candidates [38]. Without LT, the survival rate for patients with PPH was found to be 38% at 3 years and 28% at 5 years [37]. Due to the severity of the condition and high mortality associated with it, patient with PPH should be assessed careful before considering LT. Perioperative mortality in patients with mean PAP >35 mmHg is significantly higher compared to those with mPAP < 35 mmHg [4, 23]. The outcome is worse in patients with moderate to severe PPH [mean pulmonary artery pressure (MPAP) ≥ 35 mm Hg] and associated with a perioperative mortality rate of 50% [37, 38].

Therefore, patient should be treated with medical therapy while awaiting LT to delay the progression of disease as well as to improve perioperative risk. The goal of therapy in patients with PPH, who are candidates for liver transplants, is to reduce mPAP <35 mmHg and the PVR < 400 dyn s cm−5 before proceeding to liver transplant [29].

Patients on liver transplant waiting list are prioritized based on the model of end-stage liver disease (MELD) score but in patients with PPH, potentially important factors such as severity of PPH is not included which may affect survival. Recent retrospective cohort study of patients in the Organ Procurement Transplantation Network (OPTN) database with hemodynamics consistent with PPH [defined as mean pulmonary arterial pressure (mPAP) >25 mmHg and pulmonary vascular resistance (PVR) ≥ 240 dynes.sec.cm-5 who were approved for a PPH-MELD exception between 2006 and 2014 showed that initial native MELD score and initial PVR were the only significant univariate predictors of waitlist mortality and remained significant predictors in a multivariate model [39]. The study showed that PVR and mPAP were not significant predictors of post-transplant mortality [39].

According to the European Respiratory Society Task Force, patients with mean pulmonary artery pressure < 35 mmHg can undergo a liver transplant, patients with mean pulmonary artery pressure of 35–45 mmHg should receive vasodilator therapy before transplant, and patients with mean pulmonary artery pressure > 45 mmHg should receive vasodilator therapy only [4, 7].

## **4. Hepatic hydrothorax**

#### **4.1. Background**

It was also found that plasma concentrations of bosentan were higher in patients with child B

Phosphodiesterase-5 inhibitor therapy is efficacious in other causes of WHO group I pulmonary arterial hypertension [32]. They inhibit the growth of pulmonary vascular smooth muscle cells and lower mean pulmonary artery pressure and pulmonary vascular resistance by mediating vasodilation through guanosine monophosphate [2, 27]. Sildenafil is commonly used in PPH and reported to be effective in reducing mPAP and PVR [29]. Sildenafil is approved in a dose of 20 mg three times a day for treatment of PPH [35], and it should be considered as a bridging therapy before liver transplant for patients with PPH to delay the progression of the disease.

A recent single center retrospective study showed that sildenafil therapy resulted in improvement of WHO functional class with significant decrease in PVR, mPAP, and increase in cardiac output but no change in 6-min walk test over the period of 6 months treatment [32]. A recent retrospective study of all patients with PPH treated by oral pulmonary vasoactive drugs (PVD) (bosentan, ambrisentan, sildenafil, tadalafil) showed that oral PVD improved MPAP, PVR, and 6-min walk distance [36]. The study showed that oral PVD are safe, better tolerated in patients with cirrhosis, and did not showed any worsening of cirrhosis and these treatments improved hemodynamic conditions allowing patients access to liver transplantation eligibility [36].

LT is the definitive therapy for patient with PPH when medical therapy fails. LT should be considered in patients with mean pulmonary artery pressure (MPAP) <35 mmHg or MPAP between 35 and 50 mmHg with pulmonary vascular resistance (PVR) <250 dyn s cm−5 [23, 37]. PPH is diagnosed in 2–6% of liver transplantation (LT) candidates [38]. Without LT, the survival rate for patients with PPH was found to be 38% at 3 years and 28% at 5 years [37]. Due to the severity of the condition and high mortality associated with it, patient with PPH should be assessed careful before considering LT. Perioperative mortality in patients with mean PAP >35 mmHg is significantly higher compared to those with mPAP < 35 mmHg [4, 23]. The outcome is worse in patients with moderate to severe PPH [mean pulmonary artery pressure (MPAP) ≥ 35 mm Hg] and associated with a perioperative mortality rate of 50% [37, 38].

Therefore, patient should be treated with medical therapy while awaiting LT to delay the progression of disease as well as to improve perioperative risk. The goal of therapy in patients with PPH, who are candidates for liver transplants, is to reduce mPAP <35 mmHg and the

Patients on liver transplant waiting list are prioritized based on the model of end-stage liver disease (MELD) score but in patients with PPH, potentially important factors such as severity of PPH is not included which may affect survival. Recent retrospective cohort study of patients in the Organ Procurement Transplantation Network (OPTN) database with hemodynamics consistent with PPH [defined as mean pulmonary arterial pressure (mPAP) >25 mmHg and

PVR < 400 dyn s cm−5 before proceeding to liver transplant [29].

cirrhosis than those observed in idiopathic PAH [34].

*3.5.5. Phosphodiesterase 5 inhibitors*

108 Liver Cirrhosis - Update and Current Challenges

*3.5.6. Liver transplantation*

Hepatic hydrothorax (HH) is a more common clinical entity compared to HPS and PPH and carries the best prognosis [9]. HH accounts for 2–3% of total pleural effusions [40]. However, in patients with portal hypertension, HH occurred in 5–10% of cases [41].

HH is caused by the accumulation of transudative effusion in patients who did not have underlying cardiopulmonary disease [42]. Majority of HH was noted on right side in 79.5% of cases followed by left sided and bilateral in 17.5 and 3%, respectively [40].

Since the pleural space is relatively small compared to the abdominal cavity with low compliance of the thoracic cavity, patients can become symptomatic with as little as 500 ml accumulation of fluid [42]. Like ascites, HH can become spontaneously infected, a condition known as spontaneous bacterial empyema (SBEM), which carries a mortality of up to 20% [42]. The incidence of SBEM was noted to be 13% in a prospective study [43] and interestingly, up to 40% of SBEM patients are not associated with incidence of spontaneous bacterial peritonitis (SBP) [43].

#### **4.2. Clinical features**

The clinical presentation is usually found in patients with cirrhosis and portal hypertension, i.e., ascites, spider naevi, asterixis, hepatosplenomegaly, and caput medusa. Patients with HH can present with pulmonary symptoms as in shortness of breath, cough, hypoxemia, or respiratory failure associated with large pleural effusions [40]. SBEM should always be suspected when patients develop fever, pleuritic chest pain, or features of liver decompensation.

#### **4.3. Pathogenesis**

The pathogenesis of HH is similar to those leading to ascites in portal hypertension [40, 41]. Portal hypertension and splanchnic vasodilatation are the main pathways leading to fluid accumulation as a result of decrease in effective blood volume which then activate renin-angiotensin system leading to sodium and water retention [9]. Particularly in HH, it is thought to be a consequence of ascitic fluid translocation through congenital diaphragmatic defects into the pleural cavity [42]. These defects, normally covered with pleuroperitoneum, were most frequently seen in the right hemi-diaphragm and usually smaller than 1 cm in size [42]. Ascites accumulation increases the intraperitoneal pressure which causes rupture of the pleuroperitoneal membrane and as a result, ascitic fluid can move into the low pressure pleural space [42]. This explanation for the appearance of hepatic hydrothorax is supported by studies showing intraperitoneal-injected radiotracer activity in the pleural fluid of such patients [44]. HH can happen due to hypoalbuminemia resulting in decreased colloid osmotic pressure [45] and lymphatic leakage from the thoracic duct [46].

#### **4.4. Investigations**

Patients with portal hypertension with pulmonary clinical features should be investigated thoroughly to rule out other causes of pulmonary and cardiac disorders. HPS and PPH should be investigated as part of differential diagnosis. The presence of pleural effusions is usually detected by thorough respiratory examination with findings of dullness to percussion, mediastinal shift, diminished or inaudible breath sounds, and pleural friction rub. In clinically suspected patients, pleural effusions can be confirmed with one of the imaging modalities such as chest X-ray (**Figure 6**), ultrasound scan, or CT chest. Echocardiogram should be performed to rule out underlying cardiac causes of effusions.

**Figure 6.** Chest X-ray showed the presence of right-sided pleural effusion.

Pleural fluid should be examined to rule out other causes leading to pleural fluid such as infection, inflammation, and malignancy. Pleural fluid should be aspirated using ultrasound and the sample should be sent for cell count, gram stain, culture, cytology, pH, total protein, albumin, lactate dehydrogenase (LDH), and amylase. Diagnosis of transudate is based on Light's criteria, which is shown in **Table 5** [47], since HH is transudate in nature.

*Light's criteria* Pleural fluid total protein/serum total protein ratio <0.5 Pleural fluid LDH/serum LDH <0.6 Pleural fluid LDH < two thirds of the upper limit of normal serum LDH *Other investigative parameters* Total protein <2.5 g/dl Pleural fluid lactic dehydrogenase (LDH) <200 IU Serum pleural to fluid albumin gradient >1.1 g/dl Glucose level similar to that of serum pH 7.4–7.55 Polymorphonuclear count <250 cells/mm<sup>3</sup>

**Table 5.** Characteristics of pleural fluid in HH.

In patients with SBEM, pleural fluid has high Polymorphonuclear cell counts >250 cells/mm<sup>3</sup> with positive culture or >500 cells/mm<sup>3</sup> in patients with negative culture without any evidence of underlying chest infection/pneumonia or exudative features of infection [40].

#### **4.5. Treatment**

consequence of ascitic fluid translocation through congenital diaphragmatic defects into the pleural cavity [42]. These defects, normally covered with pleuroperitoneum, were most frequently seen in the right hemi-diaphragm and usually smaller than 1 cm in size [42]. Ascites accumulation increases the intraperitoneal pressure which causes rupture of the pleuroperitoneal membrane and as a result, ascitic fluid can move into the low pressure pleural space [42]. This explanation for the appearance of hepatic hydrothorax is supported by studies showing intraperitoneal-injected radiotracer activity in the pleural fluid of such patients [44]. HH can happen due to hypoalbuminemia resulting in decreased colloid osmotic pressure [45] and lym-

Patients with portal hypertension with pulmonary clinical features should be investigated thoroughly to rule out other causes of pulmonary and cardiac disorders. HPS and PPH should be investigated as part of differential diagnosis. The presence of pleural effusions is usually detected by thorough respiratory examination with findings of dullness to percussion, mediastinal shift, diminished or inaudible breath sounds, and pleural friction rub. In clinically suspected patients, pleural effusions can be confirmed with one of the imaging modalities such as chest X-ray (**Figure 6**), ultrasound scan, or CT chest. Echocardiogram should be performed

phatic leakage from the thoracic duct [46].

110 Liver Cirrhosis - Update and Current Challenges

to rule out underlying cardiac causes of effusions.

**Figure 6.** Chest X-ray showed the presence of right-sided pleural effusion.

**4.4. Investigations**

#### *4.5.1. Medical therapy*

The role of medical therapies is to relieve symptoms and prevent the complications of HH in patients awaiting liver transplantation or to palliate symptoms in those who are not transplant candidate [42]. Treatment is similar to the treatment of ascites which include dietary salt restriction, diuretic therapy, and drainage of fluid either from abdomen or pleural space.

The management of dietary sodium is important to prevent re-accumulation of fluids and dietary education should be given to patients. Diuretic therapies with furosemide 40–80 mg once daily with or without addition of spironolactone 50–400 mg OD are used in patients who are tolerant of diuretic therapy. Urinary sodium should be checked before and during therapy to adjust diuretic dosage as per clinical response. In patients with refractory ascites, the other treatment modalities can be used. These include paracentesis, thoracentesis, insertion of chest drain tube, indwelling tunneled pleural catheter (PleurX) insertion, insertion of transjugular intrahepatic portosystemic shunt (TIPSS), pleurodesis, shunt surgery, and repair of diaphragmatic defect [40, 41, 48–51]. Each treatment has its own advantages and disadvantages and should be selected as per patient's clinical condition.

In patients with HH and large volume ascites, ascites should be drained before draining pleural fluid to prevent the rapid accumulation of fluid in the pleural space after thoracentesis due to decreased intrathoracic pressure [40]. Thoracentesis is used for large pleural effusion in patient with significant dyspnea. Pleural fluid should be drained not more than 2 L of fluid at any time point to prevent expansion pulmonary edema. If patients required regular thoracentesis, they should be considered for therapies that provide long term symptom relief. Indwelling tunneled pleural catheter (PleurX) insertion is usually considered for patients in palliative setting.

TIPSS is effective in controlling ascites and hepatic hydrothorax, although the procedure did not improve the prognosis of patients with end-stage liver cirrhosis [40, 51]. TIPSS should be considered in patients with compensated liver cirrhosis and the factors associated with increased mortality in patients who had TIPSS are age >60 years, Child Pugh class C, presence of pre-TIPSS high model for end-stage liver disease (MELD) score >15 and high pre-TIPS creatinine levels >2 mg/dl [51]. Patients whose had high risk features described above should be considered for LT.

In patients with SBEM, the management is to treat underlying infection with broad spectrum antibiotics with or without inserting large bore chest drain tube.

#### *4.5.2. Liver transplantation*

In patients with refractory ascites who are Child Pugh C cirrhosis, LT should be considered first prior to other therapies. The presence of HH does not lead to more post-operative complications, and long-term survival is similar to other indications of liver transplantation [40, 41]. Patient should be managed conservatively with medical therapy while awaiting LT.

## **5. Conclusion**

Pulmonary complications (HPS, PPH, and HH) are rare occurrence in patients with liver cirrhosis and portal hypertension. In patients with these conditions carry a significant morbidity and mortality and therefore, strong clinical suspicion is required to make earlier diagnosis. There are multiple medical therapies available for each condition in literature but most of the treatments are not effective. The only effective treatment that alters the clinical prognosis is liver transplantation and hence, patients with these conditions should be screened and assessed for the suitability of LT.

## **Author details**

Nwe Ni Than

Address all correspondence to: nwenithan@gmail.com

Royal Free London NHS Foundation Trust, London, United Kingdom

## **References**

of diaphragmatic defect [40, 41, 48–51]. Each treatment has its own advantages and disadvan-

In patients with HH and large volume ascites, ascites should be drained before draining pleural fluid to prevent the rapid accumulation of fluid in the pleural space after thoracentesis due to decreased intrathoracic pressure [40]. Thoracentesis is used for large pleural effusion in patient with significant dyspnea. Pleural fluid should be drained not more than 2 L of fluid at any time point to prevent expansion pulmonary edema. If patients required regular thoracentesis, they should be considered for therapies that provide long term symptom relief. Indwelling tunneled pleural catheter (PleurX) insertion is usually considered for patients in palliative setting. TIPSS is effective in controlling ascites and hepatic hydrothorax, although the procedure did not improve the prognosis of patients with end-stage liver cirrhosis [40, 51]. TIPSS should be considered in patients with compensated liver cirrhosis and the factors associated with increased mortality in patients who had TIPSS are age >60 years, Child Pugh class C, presence of pre-TIPSS high model for end-stage liver disease (MELD) score >15 and high pre-TIPS creatinine levels >2 mg/dl [51]. Patients whose had high risk features described above should

In patients with SBEM, the management is to treat underlying infection with broad spectrum

In patients with refractory ascites who are Child Pugh C cirrhosis, LT should be considered first prior to other therapies. The presence of HH does not lead to more post-operative complications, and long-term survival is similar to other indications of liver transplantation [40, 41].

Pulmonary complications (HPS, PPH, and HH) are rare occurrence in patients with liver cirrhosis and portal hypertension. In patients with these conditions carry a significant morbidity and mortality and therefore, strong clinical suspicion is required to make earlier diagnosis. There are multiple medical therapies available for each condition in literature but most of the treatments are not effective. The only effective treatment that alters the clinical prognosis is liver transplantation and hence, patients with these conditions should be screened and assessed for the suitability of LT.

Patient should be managed conservatively with medical therapy while awaiting LT.

tages and should be selected as per patient's clinical condition.

antibiotics with or without inserting large bore chest drain tube.

Address all correspondence to: nwenithan@gmail.com

Royal Free London NHS Foundation Trust, London, United Kingdom

be considered for LT.

112 Liver Cirrhosis - Update and Current Challenges

*4.5.2. Liver transplantation*

**5. Conclusion**

**Author details**

Nwe Ni Than


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## **Ascites: Causes, Diagnosis, and Treatment**

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Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68868

#### **Abstract**

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Ascites is a pathological accumulation of fluid in the peritoneal cavity. Cirrhosis is the most common cause of ascites, representing for 85% of cases. More than one cause may be responsible for the development of ascites (multifactorial). Development of ascites is a poor prognostic event in the natural history of cirrhosis, with approximately 15 and 44% of patients with ascites succumbing in 1 and 5 years, respectively. Patients with cirrhosis need referral for liver transplantation after development of ascites. Proper history and physical examination are important in diagnosing the cause of ascites. Diagnostic paracentesis and abdominal sonogram should be performed during initial evaluation. Low salt diet and diuretic are the initial treatment option, and large volume paracentesis is an option for non‐responder to diuretics. Transjugular intrahepatic portosystemic stent‐shunt (TIPS) is highly valuable in properly selected patients.

**Keywords:** ascites, pathogenesis, diagnosis, diuretics, paracentesis, TIPS

### **1. Introduction**

Ascites is defined as the pathological accumulation of excess fluid in the peritoneal cavity. Normally, the peritoneal cavity contains 25–50 mL of ascitic fluid, which allows for the movement of bowel loops past one other and helps hydrate serosal surfaces. With ascites, this fluid is not static within the peritoneal cavity, but is rather in a continuous exchange with the circulation through a large capillary bed under the visceral peritoneum, with about half the volume entering and leaving the peritoneal cavity every hour. Furthermore, the constituents of the fluid are in dynamic equilibrium with those of the plasma. However, the daily absorption of fluid from the peritoneal cavity back to the circulation is limited, and the maximum absorption of fluid out of the peritoneum is approximately 850 mL/d. Thus, the development of clinically significant ascites occurs when the rate of ascites formation exceeds the rate of

© 2017 The Author(s). Licensee InTech. 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.

ascites reabsorption. For easily‐controllable ascites, on the other hand, the volume of fluid that spills into the peritoneal cavity can be reduced below this absorption threshold. This is the case at the early stages of hepatic decompensating when ascites is responsive to a reduced intake of dietary sodium and to moderate doses of diuretics.

Cirrhosis is the most common cause of ascites, representing 85% of all cases of ascites [1]. In patients with cirrhosis, ascites due to portal hypertension (PHT) is primarily related to an inability to excrete adequate amounts of sodium into urine, leading to a positive sodium balance. Other causes of ascites include malignancy, heart failure, tuberculosis, alcoholic hepatitis, Budd‐Chiari syndrome, and nephrogenic ascites [2]. More than one cause may be responsible for the development of ascites (multifactorial), such as the development of tuberculosis, heart failure, or peritoneal carcinomatosis in patients with cirrhosis and ascites [1]. Ascites is the most common complication of cirrhosis, as approximately 50% of patients with "compensated" cirrhosis develop ascites during 10 years of follow up [3]. The development of ascites is a poor prognostic event in the natural history of cirrhosis, with approximately 15% of patients succumbing in 1 year and 44% succumbing in 5 years [4]. Thus, these patients need to be referred for liver transplantation. Patients with cirrhosis and ascites are at high risk for other complications, including refractory ascites, spontaneous bacterial peritonitis (SBP), hyponatremia, or hepatorenal syndrome (HRS). The absence of these ascites‐related complications qualifies ascites as uncomplicated [5]. Poor prognostic factors in patients with cirrhosis include hyponatremia, low arterial pressure, increased serum creatinine, and low urine sodium [6]. Among these factors, only serum creatinine is included in the Model for End‐stage Liver Disease (MELD score) used for patient allocation for liver transplantation. Furthermore, serum creatinine has limitations in estimating glomerular filtration rate in cirrhosis [7], which usually underestimates the mortality risk in patients with ascites [8].

## **2. Pathogenesis of ascites in patients with liver cirrhosis**

#### **2.1. Pathogenesis and perpetuation of the ascites syndrome**

Major factors involved in the complex pathogenesis of ascites are portal and sinusoidal hypertension, arterial vasodilatation, and neurohumoral activation, all leading to sodium and water retention [10, 11].

The pathogenesis of ascites is complex and not fully understood. The triad of portal hypertension, arterial vasodilatation, and neurohumoral activation, leading to sodium and water retention, explains, to large extent, the formation of ascites [9]. In fact, the direct cause of ascites formation in patients with cirrhosis is sodium retention, caused by decreased renal sodium excretion. The impairment in the renal ability to excrete sodium is considered the earliest manifestation of renal dysfunction in cirrhosis as shown by reduced natriuretic response to acute administration of sodium chloride [10]. Sodium retention in cirrhosis is mainly due to an increased tubular sodium reabsorption rather than decreased filtration of sodium. However, in the late stage of the disease, when hepatorenal syndrome develops, sodium retention is caused by both increased reabsorption and decreased filtration. Sodium retention progresses with the advancement of liver disease; in the late stages of the disease, sodium retention becomes very high and the urinary sodium excretion may approach to zero. Sodium retention precedes the onset of ascites by few days, indicating that it is a cause and not a consequence of the accumulation of fluid within the abdominal cavity [10].

ascites reabsorption. For easily‐controllable ascites, on the other hand, the volume of fluid that spills into the peritoneal cavity can be reduced below this absorption threshold. This is the case at the early stages of hepatic decompensating when ascites is responsive to a reduced

Cirrhosis is the most common cause of ascites, representing 85% of all cases of ascites [1]. In patients with cirrhosis, ascites due to portal hypertension (PHT) is primarily related to an inability to excrete adequate amounts of sodium into urine, leading to a positive sodium balance. Other causes of ascites include malignancy, heart failure, tuberculosis, alcoholic hepatitis, Budd‐Chiari syndrome, and nephrogenic ascites [2]. More than one cause may be responsible for the development of ascites (multifactorial), such as the development of tuberculosis, heart failure, or peritoneal carcinomatosis in patients with cirrhosis and ascites [1]. Ascites is the most common complication of cirrhosis, as approximately 50% of patients with "compensated" cirrhosis develop ascites during 10 years of follow up [3]. The development of ascites is a poor prognostic event in the natural history of cirrhosis, with approximately 15% of patients succumbing in 1 year and 44% succumbing in 5 years [4]. Thus, these patients need to be referred for liver transplantation. Patients with cirrhosis and ascites are at high risk for other complications, including refractory ascites, spontaneous bacterial peritonitis (SBP), hyponatremia, or hepatorenal syndrome (HRS). The absence of these ascites‐related complications qualifies ascites as uncomplicated [5]. Poor prognostic factors in patients with cirrhosis include hyponatremia, low arterial pressure, increased serum creatinine, and low urine sodium [6]. Among these factors, only serum creatinine is included in the Model for End‐stage Liver Disease (MELD score) used for patient allocation for liver transplantation. Furthermore, serum creatinine has limitations in estimating glomerular filtration rate in cirrhosis [7], which usually underestimates the mortality risk in patients with ascites [8].

intake of dietary sodium and to moderate doses of diuretics.

118 Liver Cirrhosis - Update and Current Challenges

**2. Pathogenesis of ascites in patients with liver cirrhosis**

Major factors involved in the complex pathogenesis of ascites are portal and sinusoidal hypertension, arterial vasodilatation, and neurohumoral activation, all leading to sodium and water

The pathogenesis of ascites is complex and not fully understood. The triad of portal hypertension, arterial vasodilatation, and neurohumoral activation, leading to sodium and water retention, explains, to large extent, the formation of ascites [9]. In fact, the direct cause of ascites formation in patients with cirrhosis is sodium retention, caused by decreased renal sodium excretion. The impairment in the renal ability to excrete sodium is considered the earliest manifestation of renal dysfunction in cirrhosis as shown by reduced natriuretic response to acute administration of sodium chloride [10]. Sodium retention in cirrhosis is mainly due to an increased tubular sodium reabsorption rather than decreased filtration of sodium. However, in the late stage of the disease, when hepatorenal syndrome develops,

**2.1. Pathogenesis and perpetuation of the ascites syndrome**

retention [10, 11].

Portal hypertension (PHT) plays a major role in the development of ascites in patients with liver cirrhosis. The increased sinusoidal hydrostatic pressure and splanchnic capillary pressure are essential, and ascites usually develops in patients with a hepatic venous pressure gradient greater than 12 mmHg [11]. Patients with liver cirrhosis without portal hypertension do not develop ascites. In addition, lowering portal pressure in patients with cirrhosis and portal hypertension after surgical or radiological portosystemic shunts usually leads to better control of ascites. Sinusoidal or post sinusoidal portal hypertension is required for the development of ascites. On the other hand, presinusoidal hypertension alone, such as portal vein thrombosis (PVT), usually does not cause ascites unless associated with another contributing factor.

Additionally, portal hypertension results in increased level of vasodilator substances, e.g., nitric oxide (NO). This causes splanchnic and peripheral vasodilation and decreased effective blood volume leading to decreased renal blood flow and, subsequently, activation of the renin‐angiotensin‐aldosterone system (RAAS), sympathetic overactivity, and non‐osmotic release of vasopressin [6, 12]. Renin is secreted from the renal juxtaglomerular apparatus secondary to changes in blood volume, changes in serum sodium, and increased activity of the sympathetic nervous system. In turn, renin will convert angiotensinogen to angiotensin I, which is then converted to angiotensin II by angiotensin‐converting enzymes (ACE) in the lungs. Angiotensin II stimulates the release of aldosterone from the zona glomerulosa of the adrenal cortex [12]. Aldosterone stimulates sodium reabsorption in the distal tubule. Similarly, the renal sympathetic nervous activity stimulates sodium reabsorption in the proximal tubule, loop of Henle, and distal and collecting tubules. In patients with cirrhosis and portal hypertension, both the secondary hyperaldosteronism and the increased activity of the renal sympathetic nervous system play an important role in the pathogenesis of sodium retention. This excess sodium retention and the associated hypervolemia causing increased hydrostatic pressure will lead to excess transudation from both the hepatic sinusoids and the splanchnic capillaries, exceeding the re‐absorptive capacity of the peritoneal surface and lymphatic system, which results in the development of ascites. Indeed, the formation of ascites depends on the balance between the hepatic sinusoidal and splanchnic filtration on the one hand and the lymph drainage on the other hand. Contrary to earlier theories, decreased plasma oncotic pressure has no role in the formation of ascites, and low plasma albumin level has little effect on the rate of ascites formation [13].

Furthermore, three theories of ascites formation have been proposed: underfilling, overflow, and peripheral arterial vasodilation (**Table 1**). The underfilling theory suggests that portal hypertension leads to increased filtration of fluid from the hepatic sinusoids and the splanchnic capillaries, leading to decreased effective circulating blood volume. This activates the plasma renin, angiotensin, aldosterone, and sympathetic nervous system, resulting in renal


**Table 1.** Pathogenesis of ascites.

sodium and water retention. The overflow theory suggests that the primary abnormality is increased renal reabsorption of sodium unrelated to decreased blood volume. Several hypotheses that aim to explain this abnormality have been suggested including decreased hepatic synthesis of a natriuretic agent, decreased hepatic clearance of sodium retaining agent, or a primary hepatorenal reflex of unknown etiology. This overflow theory was supported by the observation that patients with cirrhosis have intravascular hypervolemia rather than hypovolemia, and sodium retention precedes ascites formation [14]. Nevertheless, both the underfill and overflow theories do not fully explain the formation of ascites and lack strong, supporting evidence. Finally, the arterial vasodilation hypothesis includes components of both the underfill and overflow theories. It suggests that portal hypertension leads to vasodilation, which causes decreased effective arterial blood volume and hyperdynamic circulation. This in turn activates neurohumoral systems leading to sodium retention and expansion of plasma volume, causing overflow of fluid into the peritoneal cavity. The theory also states that ascites formation is caused initially by underfilling of the intravascular compartment and is maintained by expansion of the intravascular compartment [12]. Moreover, the forward theory of ascites formation is a new modification of the vasodilation theory combining arterial underfilling with a forward increase in splanchnic capillary pressure and filtration with increased lymph formation [15].

Nitric oxide (NO) is the main vasodilator implicated in the systemic vasodilatation, and is primarily synthesized in the systemic vascular endothelium by NO synthase [16, 17]. Patients with portal hypertension have evidence of increased NO synthesis [18]. Calcitonin gene‐related peptide (CGRP) and adrenomedullin are also potent vasodilatating factors, which have been found in increased levels especially in patients with ascites and hepatorenal syndrome (HRS) [18]. There is also evidence of increased resistance to vasoconstrictive substances, such as noradrenaline, angiotensin II, and vasopressin, which are most likely related to changes in receptor affinity, down‐regulation of receptors, and to post‐receptor defects related to increased NO expression [19]. Furthermore, alterations in vascular compliance is considered [20, 21], evidence show that it precedes neurohumoral activation and renal sodium and water retention [18].

Another mechanism that may contribute to ascites formation is renal resistance to atrial natriuretic peptide (ANP). ANP is a potent natriuretic peptide released from the cardiac atria in response to expansion of the intravascular volume. In compensated cirrhosis, ANP helps to maintain sodium balance by antagonizing the effect of antinatriuretic factors (aldosterone and sympathetic overactivity). In later stages, renal resistance to ANP develops and leads to sodium retention [22].

The severity of renal sodium retention parallels the progression of cirrhosis due to the accentuation of the underlying vascular hemodynamic abnormalities and the associated activation of neurohumoral vasoactive mechanisms leading to avid renal reabsorption of sodium and water in the advanced stage of cirrhosis [15]. Furthermore, with progression of cirrhosis, renal perfusion and glomerular filtration rate progressively decline, leading to increased sodium reabsorption at the proximal convoluted tubule and decrease in its delivery to distal segments of the nephron [15]. Thus, in late stages of cirrhosis, renal sodium reabsorption mainly occurs proximal to the site of action of both the spironolactone and the loop diuretics rendering them ineffective. In addition, the increased resistance to vasoconstrictive substances, such as noradrenaline, angiotensin II, and vasopressin, accentuate the relative underfilling of the effective arterial blood volume, which aggravates the hypovolemic effects of diuretics, precluding the continuation of effective dosages of diuretics [23]. Accordingly, refractoriness to diuretic treatment is the end result of the accentuation of the hemodynamic abnormalities characterizing advanced cirrhosis. With further progression of liver disease and increased accentuation of these renal and vascular changes, these same mechanisms lead to hyponatremia and hepatorenal syndrome.

## **3. Evaluation of patients with ascites**

sodium and water retention. The overflow theory suggests that the primary abnormality is increased renal reabsorption of sodium unrelated to decreased blood volume. Several hypotheses that aim to explain this abnormality have been suggested including decreased hepatic synthesis of a natriuretic agent, decreased hepatic clearance of sodium retaining agent, or a primary hepatorenal reflex of unknown etiology. This overflow theory was supported by the observation that patients with cirrhosis have intravascular hypervolemia rather than hypovolemia, and sodium retention precedes ascites formation [14]. Nevertheless, both the underfill and overflow theories do not fully explain the formation of ascites and lack strong, supporting evidence. Finally, the arterial vasodilation hypothesis includes components of both the underfill and overflow theories. It suggests that portal hypertension leads to vasodilation, which causes decreased effective arterial blood volume and hyperdynamic circulation. This in turn activates neurohumoral systems leading to sodium retention and expansion of plasma volume, causing overflow of fluid into the peritoneal cavity. The theory also states that ascites formation is caused initially by underfilling of the intravascular compartment and is maintained by expansion of the intravascular compartment [12]. Moreover, the forward theory of ascites formation is a new modification of the vasodilation theory combining arterial underfilling with a forward increase in splanchnic capillary pressure and filtration with increased

1 Under filling theory: increased filtration of fluid from the hepatic sinusoids and the splanchnic capillaries,

3 Peripheral arterial vasodilation: portal hypertension leads to vasodilation, which causes decreased effective

2 Overflow theory: increased renal reabsorption of sodium unrelated to decreased blood volume

leading to decreased effective circulating blood volume

arterial blood volume and hyperdynamic circulation

4 Renal resistance to atrial natriuretic peptide

120 Liver Cirrhosis - Update and Current Challenges

**Table 1.** Pathogenesis of ascites.

Nitric oxide (NO) is the main vasodilator implicated in the systemic vasodilatation, and is primarily synthesized in the systemic vascular endothelium by NO synthase [16, 17]. Patients with portal hypertension have evidence of increased NO synthesis [18]. Calcitonin gene‐related peptide (CGRP) and adrenomedullin are also potent vasodilatating factors, which have been found in increased levels especially in patients with ascites and hepatorenal syndrome (HRS) [18]. There is also evidence of increased resistance to vasoconstrictive substances, such as noradrenaline, angiotensin II, and vasopressin, which are most likely related to changes in receptor affinity, down‐regulation of receptors, and to post‐receptor defects related to increased NO expression [19]. Furthermore, alterations in vascular compliance is considered [20, 21], evidence show that it precedes neurohumoral activation and renal

Another mechanism that may contribute to ascites formation is renal resistance to atrial natriuretic peptide (ANP). ANP is a potent natriuretic peptide released from the cardiac atria in response to expansion of the intravascular volume. In compensated cirrhosis, ANP helps to maintain sodium balance by antagonizing the effect of antinatriuretic factors (aldosterone

lymph formation [15].

sodium and water retention [18].

The diagnosis of ascites is suspected based on the patient history and physical examination, and usually confirmed by abdominal ultrasound. The cause of ascites is identified based on the history, physical examination, laboratory tests, abdominal imaging, and ascitic fluid analysis. Patients with ascites usually present with abdominal distention, which may also be associated with abdominal discomfort, early satiety, weight gain, and shortness of breath. In addition, patients usually have symptoms and signs of the underlying cause of ascites. Since cirrhosis is the most common cause of ascites [1], history and physical examination should be directed for symptoms and signs of cirrhosis as well as risk factors for development of cirrhosis. Patients with cirrhosis may have other symptoms associated with hepatic decompensation, such as hepatic encephalopathy jaundice or gastrointestinal bleeding. Physical examination of patients with ascites due to liver cirrhosis usually reveals spider angioma, palmar erythema, jaundice, muscle wasting, gynecomastia, leukonychia, parotid enlargement, and abdominal wall collaterals. The liver and spleen may be palpable. Patients also need to be investigated for risk factors for cirrhosis including alcohol, viral hepatitis B and C, autoimmune liver disease, and other causes of cirrhosis. Those who lack an apparent cause for cirrhosis should also be questioned about lifetime body weight and diabetes as nonalcoholic steatohepatitis has been identified to be the cause of cirrhosis in many of these patients [24].

In addition to the clinical evaluation for cirrhosis, patients with ascites need to be evaluated for other causes including alcoholic hepatitis, heart failure, malignancy (peritoneal carcinomatosis, massive liver metastases, etc.), pancreatitis, nephrotic syndrome, tuberculous peritonitis, acute liver failure, Budd‐Chiari syndrome, and sinusoidal obstruction syndrome. Patients with malignant ascites may have symptoms related to the underlying malignancy, such as weight loss, whereas patients with ascites due to heart failure may have dyspnea, orthopnea, congested neck veins, and lower limb edema. Approximately 5% of ascites patients have 2 or more causes of ascites formation, i.e., "multifactorial" ascites. Most commonly, this presents as cirrhosis with another etiology as peritoneal tuberculosis. Laboratory test abnormalities seen in patients with ascites are related to the underlying cause of the ascites. Laboratory test abnormalities seen in patients with ascites are related to the underlying cause of the ascites. Patients with cirrhosis or heart failure usually have abnormal liver tests, increased serum bilirubin, hypoalbuminemia, elevated international normalized ratio (INR) in addition to thrombocytopenia, anemia, and leukopenia. Patients suspected of having ascites should have abdominal ultrasound to confirm the presence of ascites and to look for possible causes such as cirrhosis or malignancy. Ultrasound is probably the most cost‐effective imaging modality. In patients with cirrhosis, ultrasound may reveal evidence of liver cirrhosis and portal hypertension including dilation of the portal vein to ≥13 mm, dilation of the splenic vein to ≥11 mm, reduction in portal venous blood flow velocity, splenomegaly (diameter >12 cm), and recanalization of the umbilical vein. Furthermore, ultrasound may also reveal evidence of hepatocellular carcinoma (HCC), which can be further evaluated with CT or magnetic MRI. Cardiac evaluation and echocardiography may also be needed to differentiate between cardiac ascites and cirrhotic ascites. Ascites due to cardiomyopathy can mimic that due to alcoholic cirrhosis. Pulmonary hypertension can also lead to heart failure and ascites. Jugular venous distension is present in the patients with cardiac ascites, but not in the ascites due to cirrhosis. Measuring the blood level of brain natriuretic peptide or pro‐brain natriuretic peptide can help differentiating ascites due to heart failure (level usually about 6100 pg/ml) from ascites due to cirrhosis (166 pg/ml) [25].

#### **4. Diagnostic paracentesis**

Once the presence of ascites is confirmed, diagnostic paracentesis should be done to identify the cause of ascites and to rule out infection of the ascitic fluid. Abdominal paracentesis is indicated for all patients with new onset ascites [26]. Abdominal paracentesis is a safe procedure, and minor complications are rarely reported. The most common complication is abdominal wall hematomas, occurring in less than 1% of patients despite having abnormal prothrombin time in majority of cases [27]. This indicates that giving blood products such as platelets and fresh‐frozen plasma before paracenteses is not needed [27, 28]. Routine tests of coagulation do not reflect bleeding risk in patients with cirrhosis; these patients usually have normal global coagulation because of a balanced deficiency of procoagulants and anticoagulants. Although more serious complications (hemoperitoneum or bowel entry by the paracenteses needle) may occur [28], they are rare (<1/1000 paracenteses) and should not deter the performance of this procedure. Bleeding complications occur mainly in patients with cirrhosis who have impaired renal function tests due to the associated platelet dysfunction in these patients [29]. Coagulopathy should preclude paracentesis only when there is clinically evident hyperfibrinolysis or clinically evident disseminated intravascular coagulation. A shortened euglobulin clot lysis time (<120 minutes) documents hyperfibrinolysis [30]. Epsilon aminocaproic acid can be used to treat hyperfibrinolysis, and paracentesis can be performed after the lysis time has normalized on treatment [31].

## **5. Evaluation of ascitic fluid**

acute liver failure, Budd‐Chiari syndrome, and sinusoidal obstruction syndrome. Patients with malignant ascites may have symptoms related to the underlying malignancy, such as weight loss, whereas patients with ascites due to heart failure may have dyspnea, orthopnea, congested neck veins, and lower limb edema. Approximately 5% of ascites patients have 2 or more causes of ascites formation, i.e., "multifactorial" ascites. Most commonly, this presents as cirrhosis with another etiology as peritoneal tuberculosis. Laboratory test abnormalities seen in patients with ascites are related to the underlying cause of the ascites. Laboratory test abnormalities seen in patients with ascites are related to the underlying cause of the ascites. Patients with cirrhosis or heart failure usually have abnormal liver tests, increased serum bilirubin, hypoalbuminemia, elevated international normalized ratio (INR) in addition to thrombocytopenia, anemia, and leukopenia. Patients suspected of having ascites should have abdominal ultrasound to confirm the presence of ascites and to look for possible causes such as cirrhosis or malignancy. Ultrasound is probably the most cost‐effective imaging modality. In patients with cirrhosis, ultrasound may reveal evidence of liver cirrhosis and portal hypertension including dilation of the portal vein to ≥13 mm, dilation of the splenic vein to ≥11 mm, reduction in portal venous blood flow velocity, splenomegaly (diameter >12 cm), and recanalization of the umbilical vein. Furthermore, ultrasound may also reveal evidence of hepatocellular carcinoma (HCC), which can be further evaluated with CT or magnetic MRI. Cardiac evaluation and echocardiography may also be needed to differentiate between cardiac ascites and cirrhotic ascites. Ascites due to cardiomyopathy can mimic that due to alcoholic cirrhosis. Pulmonary hypertension can also lead to heart failure and ascites. Jugular venous distension is present in the patients with cardiac ascites, but not in the ascites due to cirrhosis. Measuring the blood level of brain natriuretic peptide or pro‐brain natriuretic peptide can help differentiating ascites due to heart

failure (level usually about 6100 pg/ml) from ascites due to cirrhosis (166 pg/ml) [25].

Once the presence of ascites is confirmed, diagnostic paracentesis should be done to identify the cause of ascites and to rule out infection of the ascitic fluid. Abdominal paracentesis is indicated for all patients with new onset ascites [26]. Abdominal paracentesis is a safe procedure, and minor complications are rarely reported. The most common complication is abdominal wall hematomas, occurring in less than 1% of patients despite having abnormal prothrombin time in majority of cases [27]. This indicates that giving blood products such as platelets and fresh‐frozen plasma before paracenteses is not needed [27, 28]. Routine tests of coagulation do not reflect bleeding risk in patients with cirrhosis; these patients usually have normal global coagulation because of a balanced deficiency of procoagulants and anticoagulants. Although more serious complications (hemoperitoneum or bowel entry by the paracenteses needle) may occur [28], they are rare (<1/1000 paracenteses) and should not deter the performance of this procedure. Bleeding complications occur mainly in patients with cirrhosis who have impaired renal function tests due to the associated platelet dysfunction in these patients [29]. Coagulopathy should preclude paracentesis only when there is clinically evident hyperfibrinolysis or clinically evident disseminated intravascular coagulation. A shortened euglobulin clot lysis time (<120 minutes) documents hyperfibrinolysis [30]. Epsilon aminocaproic acid

**4. Diagnostic paracentesis**

122 Liver Cirrhosis - Update and Current Challenges

The basic tests ordered on ascitic fluid samples include an analysis of the appearance, serum‐to‐ascites albumin gradient (SAAG), cell count and differential, culture, and total protein [26]. Fluid appearance can range from water‐clear to frankly purulent, bloody, or chylous. The ascitic fluid cell count with the differential is the most important test performed on ascitic fluid to rule out infection since ascitic fluid infection is a treatable cause of deterioration as well as a preventable cause of death in patients with cirrhosis and ascites. Early diagnosis and proper treatment of ascitic fluid infection are crucial in patients with cirrhosis and ascites. Antibiotic treatment should be initiated in patients with a neutrophil count of ≥250/mm [32].

Culture of the ascitic fluid should be done in patients with new onset ascites, patients admitted to the hospital for ascites, in patients who develop fever or abdominal pain, and also in patients with cirrhosis who develop unexplained deterioration: increasing jaundice, azotemia, acidosis, or encephalopathy [32]. To increase the sensitivity of detecting bacterial growth in ascitic fluid, the ascitic fluid should be inoculated into blood culture bottles at the bedside; ascitic fluid culture is positive in only 50% of patients with spontaneous bacterial peritonitis (SBP) by older methods, compared to approximately 80%, if the fluid is inoculated into blood culture bottles at the bedside and prior to administration of antibiotics [33, 34]. A single dose of an effective antibiotic usually leads to a negative bacterial culture [35].

Initially, ascitic fluid was classified as an exudate or transudate based on total protein concentration. Recently, this exudate/transudate classification has been replaced by the SAAG, which is a more useful measure for determining the presence or absence of portal hypertension [1, 36]. However, the ascitic fluid total protein concentration remains of some value as patients with an ascitic fluid protein of <1 g/dL have a high risk of SBP requiring prophylactic antibiotics [37]. The SAAG is easily calculated by subtracting the ascitic fluid albumin value from the serum albumin value, which should be obtained the same day. The SAAG accurately identifies the presence of portal hypertension; SAAG ≥1.1 g/dL (≥11 g/L) predicts that the patient has portal hypertension with 97% accuracy, while SAAG <1.1 g/dL (<11 g/L) indicates that the patient does not have portal hypertension [1].

While SAAG in patients with ascites due to heart failure can be affected with diuretics, the SAAG in the setting of cirrhosis remains stable unless portal pressure decreases significantly [38]. If the results of these tests are abnormal, further testing can be performed on another ascitic fluid sample. These additional ascitic fluid tests are requested based on the clinical scenario. The following is a list of tests that can be conducted to test for ascites.

• Glucose concentration: White blood cells, bacteria, and malignant cells consume glucose; thus, the concentration of glucose may be low in peritoneal carcinomatosis and bowel perforation [35, 39].


## **6. Treatment of ascites**

Proper management depends on the cause of ascites. Patients with high SAAG (portal hypertensive) ascites usually respond to dietary salt restriction and diuretics. Conversely, patients with low SAAG ascites (with the exception of nephrotic ascites) do not respond to dietary salt restriction and diuretics; treatment of ascites in these patients depends on successful treatment of the underlying disorder. Improvement of cirrhosis alone can lead to control of ascites and better response to diuretics. This is particularly true for patients with alcoholic liver disease [50], Hepatitis B virus (HBV)‐related liver disease [51], and autoimmune hepatitis, where specific treatment of cause of cirrhosis by ceasing alcohol consumption, HBV antiviral therapy, or immunosuppression can lead to regression of cirrhosis and better control of ascites.

The approach for the treatment of ascites depends on the grade of ascites. According to the International Ascites Club, ascites is classified into three grades according to the severity of ascites [5].

Grade 1—Mild ascites detectable only by ultrasound examination.

Grade 2—Moderate ascites with moderate abdominal distension.

Grade 3—Marked ascites with marked abdominal distension.

Currently, there are no recommendations for the treatment of grade 1 ascites. Grade 2 ascites can be treated with dietary sodium restriction and diuretics. Grade 3 ascites can be treated with initial large volume paracentesis followed by dietary sodium restriction and diuretics [52].

## **7. First‐line therapy for ascites**

#### **7.1. Dietary sodium restriction**

• Lactate dehydrogenase (LDH) concentration: The ascitic fluid/serum (AF/S) ratio of LDH is about 0.4 in cirrhotic ascites without infection. In SBP, the ascitic fluid LDH level rises such that the ascitic fluid/serum (AF/S) ratio of LDH approaches 1.0. In the case of bowel perforation, or peritoneal carcinomatosis, the ascitic fluid/serum (AF/S) ratio of LDH is

• Gram stain: The sensitivity of ascitic fluid gram stain is only 10%. The main benefit of gram stain of ascitic fluid is to differentiate between SBP and bowel perforation where there is

• Amylase concentration: The ascitic fluid amylase concentration is increased in pancreatitis

• Tests for tuberculous peritonitis: A variety of tests have been used for the detection of tuberculous peritonitis including direct smear, culture, cell count with predominance of mononuclear cells, and adenosine deaminase. Only patients at high risk for tuberculous peritonitis should have testing for mycobacteria on the first ascitic fluid specimen. The sensitivity of smear of ascitic fluid for mycobacteria is almost zero [43], while the sensitivity of fluid culture for mycobacteria reaches 50% [44]. Polymerase chain reaction testing for mycobacteria, laparoscopy with biopsy, and mycobacterial culture of tubercles are the

• Cytology: It should be requested only if malignant ascites is suspected. The sensitivity of ascitic fluid cytology in peritoneal carcinomatosis is approximately 100% [46]. However, because not all cases of malignant ascites are associated with peritoneal carcinomatosis, the overall sensitivity of cytology smears for the detection of malignant ascites is 58–75% [47].

• Triglyceride concentration: Chylous ascites has a triglyceride content greater than 200 mg/dL

• Bilirubin concentration: Ascitic fluid bilirubin value greater than the serum suggests bowel

Proper management depends on the cause of ascites. Patients with high SAAG (portal hypertensive) ascites usually respond to dietary salt restriction and diuretics. Conversely, patients with low SAAG ascites (with the exception of nephrotic ascites) do not respond to dietary salt restriction and diuretics; treatment of ascites in these patients depends on successful treatment of the underlying disorder. Improvement of cirrhosis alone can lead to control of ascites and better response to diuretics. This is particularly true for patients with alcoholic liver disease [50], Hepatitis B virus (HBV)‐related liver disease [51], and autoimmune hepatitis, where specific treatment of cause of cirrhosis by ceasing alcohol consumption, HBV antiviral therapy, or immunosuppression can lead to regression of cirrhosis and better control of ascites.

polymicrobial growth in bowel perforation and monomicrobial growth in SBP [41].

most rapid and accurate methods of diagnosing tuberculous peritonitis [45].

Hepatocellular carcinoma (HCC) rarely metastasizes to the peritoneum.

(2.26 mmol/L) and usually greater than 1000 mg/dL (11.3 mmol/L) [48].

or bowel perforation reaching approximately 2000 unit/L [42].

greater than 1.0 [40].

124 Liver Cirrhosis - Update and Current Challenges

perforation or biliary leak [49].

**6. Treatment of ascites**

The first‐line treatment of patients with cirrhosis and ascites is dietary sodium restriction (2000 mg per day [88 mmol per day]) [53]. This is generally equivalent to a no added salt diet, and avoiding pre‐prepared meals. More strict sodium restriction may improve mobilization of ascites, although it is not recommended because it is less palatable and may worsen the already existing malnutrition in patients with cirrhosis. Total non‐urinary sodium excretion is less than 10 mmol per day in afebrile patients with cirrhosis without diarrhea [54]. Based on that, ascites can be controlled if urinary excretion of sodium exceeds 78 mmol per day (88 mmol intake per day − 10 mmol nonurinary excretion per day) in patients on restricted sodium diet. However, only 10–15% of patients have urinary excretion of sodium greater than 78 mmol per day and only those patients can be considered for dietary sodium restriction alone. Measurement of urinary sodium excretion is a helpful parameter to assess compliance with dietary sodium restriction. Patients with urinary excretion of sodium greater than 78 mmol per day without improvement of ascites are not compliant with salt restriction. Urinary sodium excretion can be measured by random urinary sodium concentrations, 24‐hour urinary sodium or urine sodium/potassium ratio.

#### **7.2. Diuretics**

Renal sodium retention in the setting of liver cirrhosis and ascites is due to increased proximal and distal tubular reabsorption of sodium [55, 56]. The mechanism of increased proximal tubular reabsorption of sodium is not completely understood, while the increased sodium reabsorption in the distal tubule is due to hyperaldosteronism [55]. In patients with liver cirrhosis, secondary hyperaldosteronism is a major factor promoting renal sodium retention in the distal tubules and collecting ducts of the nephron. Clinical trials have shown that spironolactone is the drug of choice for the initial treatment of ascites. Spironolactone achieves a better natriuresis than "loop" diuretics in cirrhotic patients with ascites [56]. Although spironolactone is effective for mobilization of ascites, most patients will eventually require both diuretics. Furthermore, starting with both drugs is more effective in achieving rapid mobilization of ascites and maintaining normokalemia [57, 58].

The initial doses of both diuretics are 100 mg/d for spironolactone and 40 mg/d for furosemide. If inadequate, the dose can be increased every 3–5 days to a maximum dose of 400 mg aldactone and 160 mg of furosemide [53]. The target of diuretic therapy is to achieve 0.5 kg/ day weight loss in patients without peripheral edema and up to 1 kg/day in patients with peripheral edema while monitoring renal function and sodium [59]. Furosemide can be temporarily withheld in patients presenting with hypokalemia; this is very common in the setting of alcoholic hepatitis. Patients with parenchymal renal disease or post liver transplantation may tolerate less spironolactone than usual because of hyperkalemia. Single morning dosing maximizes compliance. Dosing more than once daily reduces compliance and can cause nocturia. The use of diuretics may be associated with several complications such as renal failure, electrolyte disorders, muscle cramps, and hepatic encephalopathy [30, 31, 55–57, 59–63].

Gynecomastia is the main side effect of spironolactone, but metabolic acidosis with or without hyperkalemia may also occur in patients with renal impairment. Other side effects of furosemide include potassium depletion, metabolic hypochloremic alkalosis, and hyponatremia, as well as hypovolemia, leading to renal dysfunction. The use of intravenous furosemide is not recommended, as it may cause an acute reduction in renal perfusion and subsequent azotemia in patients with cirrhosis and ascites. Amiloride (10–40 mg per day) is another aldosterone antagonist and can replace spironolactone in patients with tender gynecomastia. However, amiloride is more expensive and has been shown to be less effective than spironolactone [61]. Triamterene, metolazone, and hydrochlorothiazide have also been used to treat ascites [64].

Hydrochlorothiazide can also cause rapid development of hyponatremia when added to the combination of spironolactone and furosemide; it should be used with extreme caution or avoided entirely.

While patients are on diuretics, monitoring of body weight, blood pressure, orthostatic symptoms, and serum electrolytes, urea, and creatinine levels needs to be checked regularly. If weight loss is inadequate, assessment of urinary sodium excretion needs to be done by urine sodium/potassium ratio or by 24‐hour urine sodium. Patients who are excreting urine sodium/potassium greater than 1‐ or 24‐hour urine sodium greater than 78 mmol per day and not losing weight are not compliant with dietary sodium restriction. These patients should not be labeled as diuretic‐resistant that require second‐line therapy. On the other hand, in patients who are not losing weight and their urinary sodium excretion is less than 1‐ or 24‐hour urine sodium less than 78 mmol per day, the dose of diuretic needs to be increased gradually [26]. Following mobilization of ascites, diuretics should be reduced to maintain patients with minimal or no ascites to avoid diuretic‐induced complications.

In patients with ascites and lower limb edema, there is no limit for daily weight loss due to the use of diuretics because there is no limit for mobilization of fluid from the interstitial fluid to the vascular compartment [65]. However, in patients with ascites and no lower limb edema, daily weight loss of 0.5 kg is a reasonable daily maximum as this is likely the maximum daily mobilized fluid from ascites to the vascular compartment. Diuretics should be stopped if the patient has hepatic encephalopathy, rising serum creatinine (>2.0 mg/dl) while on diuretics or if there is hyponatremia (<120 mmol/L) not corrected with fluid restriction [26].

Dietary sodium restriction and a dual diuretic regimen with spironolactone and furosemide have been shown to be effective in more than 90% of patients in achieving a reduction in the volume of ascites to acceptable levels [58]. Less than 10% of patients with cirrhosis and ascites are refractory to standard medical therapy [30, 56–58, 66, 67].

Patients with liver cirrhosis are in a state of systemic and splanchnic vasodilatation caused by nitric oxide and other vasodilators. Blood pressure is maintained in these patients due to the compensatory increased levels of vasopressin, angiotensin, and aldosterone and sympathetic overactivity [68]. The use of drugs, which decrease the level or antagonize the effect of these hormones, is expected to lower blood pressure and affect survival of those patients. These include angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and beta blockers [69]; these drugs should be avoided in patients with ascites and in the rare situation where the benefit of using these drugs overweighs their risks, and blood pressure and renal function must be monitored carefully to avoid rapid development of renal failure.

Other drugs that should be avoided in patients with ascites are Prostaglandin inhibitors such as nonsteroidal anti‐inflammatory drugs. These drugs antagonize the vasodilator effect of prostaglandins on renal artery causing reduction of urinary sodium excretion and can also cause azotemia [70]. Only unusual patients whose risk of an ischemic cardiac or neurologic event exceeds the risk of worsening azotemia or gut bleeding should take low dose aspirin.

#### **7.3. Single large volume paracentesis (LVP)**

is effective for mobilization of ascites, most patients will eventually require both diuretics. Furthermore, starting with both drugs is more effective in achieving rapid mobilization of asci-

The initial doses of both diuretics are 100 mg/d for spironolactone and 40 mg/d for furosemide. If inadequate, the dose can be increased every 3–5 days to a maximum dose of 400 mg aldactone and 160 mg of furosemide [53]. The target of diuretic therapy is to achieve 0.5 kg/ day weight loss in patients without peripheral edema and up to 1 kg/day in patients with peripheral edema while monitoring renal function and sodium [59]. Furosemide can be temporarily withheld in patients presenting with hypokalemia; this is very common in the setting of alcoholic hepatitis. Patients with parenchymal renal disease or post liver transplantation may tolerate less spironolactone than usual because of hyperkalemia. Single morning dosing maximizes compliance. Dosing more than once daily reduces compliance and can cause nocturia. The use of diuretics may be associated with several complications such as renal failure, electrolyte disorders, muscle cramps, and hepatic encephalopathy [30, 31, 55–57, 59–63].

Gynecomastia is the main side effect of spironolactone, but metabolic acidosis with or without hyperkalemia may also occur in patients with renal impairment. Other side effects of furosemide include potassium depletion, metabolic hypochloremic alkalosis, and hyponatremia, as well as hypovolemia, leading to renal dysfunction. The use of intravenous furosemide is not recommended, as it may cause an acute reduction in renal perfusion and subsequent azotemia in patients with cirrhosis and ascites. Amiloride (10–40 mg per day) is another aldosterone antagonist and can replace spironolactone in patients with tender gynecomastia. However, amiloride is more expensive and has been shown to be less effective than spironolactone [61]. Triamterene, metolazone, and hydrochlorothiazide have also been used to treat ascites [64].

Hydrochlorothiazide can also cause rapid development of hyponatremia when added to the combination of spironolactone and furosemide; it should be used with extreme caution or

While patients are on diuretics, monitoring of body weight, blood pressure, orthostatic symptoms, and serum electrolytes, urea, and creatinine levels needs to be checked regularly. If weight loss is inadequate, assessment of urinary sodium excretion needs to be done by urine sodium/potassium ratio or by 24‐hour urine sodium. Patients who are excreting urine sodium/potassium greater than 1‐ or 24‐hour urine sodium greater than 78 mmol per day and not losing weight are not compliant with dietary sodium restriction. These patients should not be labeled as diuretic‐resistant that require second‐line therapy. On the other hand, in patients who are not losing weight and their urinary sodium excretion is less than 1‐ or 24‐hour urine sodium less than 78 mmol per day, the dose of diuretic needs to be increased gradually [26]. Following mobilization of ascites, diuretics should be reduced to maintain patients with mini-

In patients with ascites and lower limb edema, there is no limit for daily weight loss due to the use of diuretics because there is no limit for mobilization of fluid from the interstitial fluid to the vascular compartment [65]. However, in patients with ascites and no lower limb edema, daily weight loss of 0.5 kg is a reasonable daily maximum as this is likely the maximum daily

mal or no ascites to avoid diuretic‐induced complications.

tes and maintaining normokalemia [57, 58].

126 Liver Cirrhosis - Update and Current Challenges

avoided entirely.

Large volume paracentesis is associated with circulatory dysfunction called post paracentesis circulatory dysfunction (PPCD). It leads to complication in patients with liver cirrhosis including rapid accumulation of ascites [71–74], development of HRS and/or water retention leading to dilutional hyponatremia [72], further increase of portal pressure [75], and shortened survival [73]. The most effective method to preventing circulatory dysfunction after LVP is the administration of albumin [73]. Large volumes of fluid have been safely removed with the concomitant administration of intravenous albumin (6–8 g/L of fluid removed) [76]. However, single 5‐L paracentesis can be performed safely without albumin infusion [77]. LVP with albumin is the best treatment option in patients with grade 3 ascites; it is more effective and safer than diuretics as it is associated with less hyponatremia, renal impairment, and hepatic encephalopathy. There were no differences between the two approaches with respect to hospital readmission or survival [71–73, 78–81]. LVP is a safe procedure, and the risk of local complications, such as hemorrhage or bowel perforation, is extremely low [29].

Additionally, although paracentesis removes the fluid more rapidly than does careful diuresis, paracentesis does nothing to correct the underlying problem that led to the initial ascites formation, i.e., sodium retention, and it should not be viewed as first‐line therapy for all patients with ascites. Dietary sodium restriction and diuretics should follow paracentesis to prevent or decrease fluid re‐accumulation.

## **8. Refractory ascites**

Refractory ascites is defined as ascites that is unresponsive to a sodium‐restricted diet and high doses of diuretics or recurs rapidly after therapeutic paracentesis [82]. Refractory ascites is classified as diuretic‐resistant ascites when there is poor control of ascites as well as low urinary sodium excretion (<78 mmol/d), despite maximal diuretics or diuretic intractable ascites, where the use of high‐dose diuretics is not applicable due to development of clinically significant complications of diuretics [5]. Once the patient is considered diuretic‐resistant, diuretics should be discontinued and these patients will need second‐line therapy. The European guideline recommends discontinuing diuretics if the urine sodium is <30 mmol/day during diuretic therapy. Oral midodrine 7.5 mg three times daily has been shown to increase urine volume, urine sodium, mean arterial pressure, and survival in patients with refractory ascites. Midodrine can be added to diuretics to increase blood pressure and theoretically convert diuretic‐resistant patients back to diuretic‐sensitive [83]. Once ascites becomes refractory to medical treatment, the median survival of patients is approximately 6 months [82, 84–86].

Hence, patients with refractory ascites should be considered for liver transplantation. The MELD score system which predicts survival in patients with cirrhosis [87, 88] does not include low arterial pressure, low serum sodium, low urine sodium, or Child‐Turcotte‐Pugh (CTP) score, all of which are important prognostic factors [84–88]. Consequently, patients with refractory ascites may have a poor prognosis despite a relatively low MELD score (e.g., <18). For these reasons, inclusion of additional parameters in the MELD score, such as serum sodium, is suggested [88–90].

### **9. Second‐line therapy for ascites**

Patients with refractory ascites who do not respond to first‐line therapy of dietary sodium restriction and diuretics may benefit from second‐line therapy. Second‐line therapy for ascites includes serial therapeutic paracenteses, transjugular intrahepatic portosystemic stent‐shunt (TIPS), peritoneovenous shunt (PVS), and liver transplantation.

#### **9.1. Serial therapeutic paracenteses**

Serial paracenteses is a safe option for patients with refractory ascites. Large volume paracenteses up to total paracenteses can be done on regular basis or in demand. Diuretics can be stopped in these patients, especially if urine sodium is still <30 mmol/day, but dietary sodium restriction should be maintained to decrease the rate of fluid accumulation. The frequency of paracenteses depends on the patient's compliance with the low‐sodium diet. Patients who need more frequent taping than 10 L every 2 weeks are not compliant with diet. Paracentesis of large volume of ascitic fluid is associated with changes in electrolytes, plasma renin, aldosterone, and angiotensin levels and may also develop acute rise of serum creatinine [72–74]. An albumin infusion of 6–8 g/L of fluid removed given during paracenteses, or shortly after, abolishes these hormonal changes and appears to improve survival [73]. Up to 5 L of ascites can be taped safely without the need for albumin infusion [77]. An alternative approach with similar efficacy to albumin infusion is intravenous terlipressin (1 mg at onset of paracentesis, 1 mg at 8 hours, and 1 mg at 16 hours) as well as midodrine orally (for 72 hours after paracentesis) [83, 91].

#### **9.2. Transjugular intrahepatic portosystemic stent‐shunt (TIPS)**

**8. Refractory ascites**

128 Liver Cirrhosis - Update and Current Challenges

sodium, is suggested [88–90].

**9. Second‐line therapy for ascites**

**9.1. Serial therapeutic paracenteses**

(TIPS), peritoneovenous shunt (PVS), and liver transplantation.

Refractory ascites is defined as ascites that is unresponsive to a sodium‐restricted diet and high doses of diuretics or recurs rapidly after therapeutic paracentesis [82]. Refractory ascites is classified as diuretic‐resistant ascites when there is poor control of ascites as well as low urinary sodium excretion (<78 mmol/d), despite maximal diuretics or diuretic intractable ascites, where the use of high‐dose diuretics is not applicable due to development of clinically significant complications of diuretics [5]. Once the patient is considered diuretic‐resistant, diuretics should be discontinued and these patients will need second‐line therapy. The European guideline recommends discontinuing diuretics if the urine sodium is <30 mmol/day during diuretic therapy. Oral midodrine 7.5 mg three times daily has been shown to increase urine volume, urine sodium, mean arterial pressure, and survival in patients with refractory ascites. Midodrine can be added to diuretics to increase blood pressure and theoretically convert diuretic‐resistant patients back to diuretic‐sensitive [83]. Once ascites becomes refractory to medical treatment, the median survival of patients is approximately 6 months [82, 84–86].

Hence, patients with refractory ascites should be considered for liver transplantation. The MELD score system which predicts survival in patients with cirrhosis [87, 88] does not include low arterial pressure, low serum sodium, low urine sodium, or Child‐Turcotte‐Pugh (CTP) score, all of which are important prognostic factors [84–88]. Consequently, patients with refractory ascites may have a poor prognosis despite a relatively low MELD score (e.g., <18). For these reasons, inclusion of additional parameters in the MELD score, such as serum

Patients with refractory ascites who do not respond to first‐line therapy of dietary sodium restriction and diuretics may benefit from second‐line therapy. Second‐line therapy for ascites includes serial therapeutic paracenteses, transjugular intrahepatic portosystemic stent‐shunt

Serial paracenteses is a safe option for patients with refractory ascites. Large volume paracenteses up to total paracenteses can be done on regular basis or in demand. Diuretics can be stopped in these patients, especially if urine sodium is still <30 mmol/day, but dietary sodium restriction should be maintained to decrease the rate of fluid accumulation. The frequency of paracenteses depends on the patient's compliance with the low‐sodium diet. Patients who need more frequent taping than 10 L every 2 weeks are not compliant with diet. Paracentesis of large volume of ascitic fluid is associated with changes in electrolytes, plasma renin, aldosterone, and angiotensin levels and may also develop acute rise of serum creatinine [72–74]. An albumin infusion of 6–8 g/L of fluid removed given during paracenteses, or shortly after, abolishes these hormonal changes and appears to improve survival [73]. Up to 5 L of ascites can be taped safely without the need for albumin infusion [77]. An alternative approach with TIPS is a side‐to‐side portosystemic shunt created between the portal vein and the hepatic vein via intrahepatic self expandable stent [92–96]. TIPS can achieve portal decompression, and therefore prevention of complications of portal hypertension such as variceal bleeding, ascites, and hydrothorax. Additionally, TIPS increases glomerular filtration and urine output, promotes natriuresis, and reduces the plasma renin activity, aldosterone, and noradrenaline levels causing improvement of renal dysfunction related to the circulatory and hormonal changes in cirrhotic patients [97–99]. The main indication for TIPS is refractory ascites, uncontrolled acute variceal bleeding, and secondary prevention of gastric variceal bleed. It may have a role in hydrothorax, hepatorenal, and hepatopulmonary syndrome [100].

Early studies comparing TIPS with large volume paracentesis were disappointing. Despite better control of ascites in patients undergoing TIPS, there was no survival advantage in TIPS in addition to increased morbidity due to hepatic encephalopathy and deterioration of liver function [94]. This can be explained by poor patient selection in early experience with TIPS. However, in the meantime, better selection of patients for TIPS together with the use of polytetrafluorethylene (PFTE)‐covered stents resulted in high response rate comparable with surgical shunts. The good results of TIPS obviate the need for surgical shunt [101, 102]. Recent studies had shown that TIPS is not only more effective in control of ascites than repeated large volume paracentesis but also improves survival [92, 93, 95, 96].

The main complication of TIPS is the development of hepatic encephalopathy which is more reported with TIPS than with repeated large volume paracentesis [103–107]. Other complications include shunt thrombosis and stenosis. Uncovered stents are complicated by stenosis in up to approximately 80% of cases [11, 108]. TIPS usually converts diuretic‐resistant patients into diuretic‐sensitive patients, therefore diuretics and dietary salt restriction must be started in these patients to maintain control of ascites. Absolute and relative contraindication to TIPS insertion includes congestive heart failure, severe pulmonary hypertension, severe hepatic decompensation, recurrent portosystemic encephalopathy, polycystic liver disease, hepatic abscess, and hepatocellular carcinoma [100].

## **10. Third‐line therapy for ascites**

#### **10.1. Peritoneovenous shunts**

The peritoneovenous shunt (PVS) has been widely used as a suitable alternative to repeated large volume paracentesis in patients with refractory ascites [109]. The negative pressure in the chest allows fluid to move from the high‐pressure intraperitonium to the chest through the one‐way valve tube through subcutaneous tissue of the chest wall to the internal jugular vein to the superior vena cava. Among the various complications associated with PVS, the most common one is the obstruction of the prosthesis, which occurs in 40–60% of patients during first year of follow‐up [110]. This procedure has a very limited use due to high complication rate, low long‐term patency rate without survival advantage [58, 111]. However, it can be used in patients with refractory ascites who are not candidate for TIPS or liver transplant or for serial paracenteses because of multiple abdominal scars or distance from a physician willing and capable of performing paracenteses (**Table 2**).


**Table 2.** Treatment of ascites.

## **11. Conclusion**

Liver cirrhosis is the main cause of ascites; ascites in the setting of liver cirrhosis is caused by portal hypertension that leads to vasodilation, with decreased effective arterial blood volume and hyperdynamic circulation. SAAG and ascitic fluid cell count are an important diagnostic tools.

The first‐line therapy is low salt diet and diuretics, which is effective in nearly 90% of patients, LVP with albumin is the best treatment option in patients with intractable ascites, and TIPS can be used in selected patients with good results. Surgical shunt for ascites is almost obsolete.

## **Author details**

Mohamed Omar Amer<sup>1</sup> and Hussien Elsiesy2,3\*

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


## **References**

[1] Runyon BA, et al. The serum‐ascites albumin gradient is superior to the exudate‐transudate concept in the differential diagnosis of ascites. Annals of Internal Medicine. 1992;**117**(3):215‐220

[2] Greenberger NJ, Blumberg RS, Burakoff R, Ascites & spontaneous bacterial peritonitis. Current Diagnosis & Treatment: Gastroenterology, Hepatology, & Endoscopy. 2nd ed. New York: McGraw‐Hill; 2012. p. 515

most common one is the obstruction of the prosthesis, which occurs in 40–60% of patients during first year of follow‐up [110]. This procedure has a very limited use due to high complication rate, low long‐term patency rate without survival advantage [58, 111]. However, it can be used in patients with refractory ascites who are not candidate for TIPS or liver transplant or for serial paracenteses because of multiple abdominal scars or distance from a physician

‐ Diuretic

‐ Single large volume paracentesis

‐ Transjugular intrahepatic portosystemic stent‐shunt

Liver cirrhosis is the main cause of ascites; ascites in the setting of liver cirrhosis is caused by portal hypertension that leads to vasodilation, with decreased effective arterial blood volume and hyperdynamic circulation. SAAG and ascitic fluid cell count are an important diagnostic tools. The first‐line therapy is low salt diet and diuretics, which is effective in nearly 90% of patients, LVP with albumin is the best treatment option in patients with intractable ascites, and TIPS can be used in selected patients with good results. Surgical shunt for ascites is almost obsolete.

[1] Runyon BA, et al. The serum‐ascites albumin gradient is superior to the exudate‐transudate concept in the differential diagnosis of ascites. Annals of Internal Medicine.

and Hussien Elsiesy2,3\*

2 King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia

1 National Liver Institute, Minoufiya University, Minoufiya, Egypt

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

3 Alfaisal University, Riyadh, Saudi Arabia

willing and capable of performing paracenteses (**Table 2**).

First line ‐ Dietary sodium restriction

Second line ‐ Serial therapeutic paracenteses

Third line ‐ Peritoneovenous shunts

**11. Conclusion**

**Table 2.** Treatment of ascites.

130 Liver Cirrhosis - Update and Current Challenges

**Author details**

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Mohamed Omar Amer<sup>1</sup>


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## **Chapter 7**

## **Nutritional Status in Liver Cirrhosis**

Kazuyuki Suzuki, Ryujin Endo and Akinobu Kato

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68828

#### **Abstract**

The metabolism of many nutritional elements (carbohydrate, protein, fat, vitamins, and minerals) is gradually disturbed with progressive chronic liver diseases. In particular, protein‐energy malnutrition (PEM) is known as the most characteristic manifestation of liver cirrhosis (LC) and is closely related to its prognosis. Recently, while sarcopenia (loss of muscle mass and strength or physical performance) has been discussed as an indepen‐ dent factor associated with prognosis in patients with LC, obesity and insulin resistance in patients with LC also contribute to carcinogenesis in LC. Deficiencies of zinc and car‐ nitine are involved in the malnutrition in LC and are associated with hyperammonemia, which is related to the pathogenesis of hepatic encephalopathy. Because the nutritional and metabolic disturbances in LC are fundamentally influenced by many factors, such as the severity of liver damage, the existence of portal‐systemic shunting, and inflam‐ mation, proper nutritional assessment is necessary for the nutritional management of patients with LC.

**Keywords:** liver cirrhosis, malnutrition, protein‐energy malnutrition, sarcopenia, glucose intolerance

## **1. Introduction**

The liver plays a central role in the metabolism of many nutritional elements (carbohydrate, protein, fat, vitamins, and minerals). The metabolism of these nutritional elements is gradu‐ ally disturbed with progressive chronic liver disease. Protein‐energy malnutrition (PEM) is the most characteristic manifestation and is closely related to the prognosis and the quality of life in liver cirrhosis (LC) [1–7]. PEM can lead to muscle atrophy and reduced strength [8–12],

© 2017 The Author(s). Licensee InTech. 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.

which is defined as sarcopenia and has recently been considered an independent prognostic factor in LC with PEM [13–16], while overweight or obesity has been seen as one of the impor‐ tant factors related to carcinogenesis in LC [17]. The relationships among PEM, sarcopenia, and prognosis in LC are shown in **Figure 1**. Furthermore, glucose intolerance or diabetes mellitus (DM) is also an independent factor related to carcinogenesis in LC [18–23]. Serum zinc (Zn) and carnitine (CA) status are involved in the malnutrition in LC and are associated with hyper‐ ammonemia, which is related to the pathogenesis of hepatic encephalopathy (HE) [24–31].

Malnutrition in LC is affected by many factors, such as the severity of liver damage, the exis‐ tence of portal‐systemic shunting, and inflammation [10, 32]. Therefore, for the proper nutri‐ tional management of patients with LC, precise nutritional assessment is needed.

**Figure 1.** Relationships among protein‐energy malnutrition, sarcopenia, and prognosis in liver cirrhosis patients.

This chapter focuses on the association between nutritional assessment and malnutrition in patients with LC.

## **2. Nutritional assessments**

Recommended nutritional assessments in patients with LC are shown in **Table 1**. Static and dynamic status of nutrition should be necessary. Dietary assessment by a skilled dietitian is the first step in assessing nutritional status. Simple and easy applied methods, such as the subjective global assessment (SGA), mini nutritional assessment (MNA), and anthropometric parameters, are recommended in the assessment of nutritional status [32]. Biomarkers representing serum albumin (Alb) are important to assess nutritional status. However, because many biomarkers

#### **1. Static status of nutrition**

which is defined as sarcopenia and has recently been considered an independent prognostic factor in LC with PEM [13–16], while overweight or obesity has been seen as one of the impor‐ tant factors related to carcinogenesis in LC [17]. The relationships among PEM, sarcopenia, and prognosis in LC are shown in **Figure 1**. Furthermore, glucose intolerance or diabetes mellitus (DM) is also an independent factor related to carcinogenesis in LC [18–23]. Serum zinc (Zn) and carnitine (CA) status are involved in the malnutrition in LC and are associated with hyper‐ ammonemia, which is related to the pathogenesis of hepatic encephalopathy (HE) [24–31].

Malnutrition in LC is affected by many factors, such as the severity of liver damage, the exis‐ tence of portal‐systemic shunting, and inflammation [10, 32]. Therefore, for the proper nutri‐

This chapter focuses on the association between nutritional assessment and malnutrition in

**Figure 1.** Relationships among protein‐energy malnutrition, sarcopenia, and prognosis in liver cirrhosis patients.

Recommended nutritional assessments in patients with LC are shown in **Table 1**. Static and dynamic status of nutrition should be necessary. Dietary assessment by a skilled dietitian is the first step in assessing nutritional status. Simple and easy applied methods, such as the subjective global assessment (SGA), mini nutritional assessment (MNA), and anthropometric parameters, are recommended in the assessment of nutritional status [32]. Biomarkers representing serum albumin (Alb) are important to assess nutritional status. However, because many biomarkers

patients with LC.

**2. Nutritional assessments**

140 Liver Cirrhosis - Update and Current Challenges

tional management of patients with LC, precise nutritional assessment is needed.


Height, body weight, body mass index, anthropometric parameters,

bioelectrical impedance analysis (BIA)

**c.** Biomarkers

Red blood cell count, hemoglobin, routine liver function tests, cholesterol, cholinesterase, albumin, rapid turnover proteins, adipocytokines (adiponectin, leptin, resistin, etc.), tumor necrosis factor‐α, ghrelin, vitamins, minerals, creatinine height index in urine

**d.** Immune reaction

Total lymphocyte count, delated cutaneous hypersensitivity, purified protein derivate of tuberculin

**e.** Imaging

Computer tomography (abdomen)

	- **a.** Energy metabolism using indirect calorimetry
	- **b.** Nitrogen balance
	- **c.** Biomarkers: plasma free amino acids pattern (Fischer ratio and BTR\* )
	- **d.** Urinary 3‐methylhistidine excretion

\* Fischer ratio, branched chain amino acids (BCAA)/phenylalanine + tyrosine; BTR, BCAA/tyrosine ratio.

**Table 1.** Recommended nutritional assessment in patients with liver cirrhosis.

are often affected by complications such as infection and renal dysfunction, the data must be carefully interpreted. Energy metabolism assessment (e.g., resting energy expenditure (REE), nonprotein respiratory quotient (npQR), and substrate oxidation rates for glucose, protein, and fat) using indirect calorimetry is the most useful method to assess whether patients with LC have PEM [32–35]. However, this method cannot be used routinely and easily to examine out‐ patients, because the indirect calorimeter has a high cost, and it takes time to perform the test.

#### **2.1. Changes of body composition**

Analysis of body composition includes height, body weight, body mass index (BMI), and anthropometric parameters. Anthropometric parameters include percent ideal body weight (IBM), triceps skin fold thickness (TSF), arm circumference (AC), and arm muscle circumfer‐ ence (AMC). Among these parameters, TSF and AMC are significantly correlated with muscle volume or the volume of total body fat mass [34, 35]. However, these parameters cannot be accurately estimated in patients with LC who have edema and/or ascites. Recently, new methods of body mass composition analysis using computer tomography and bioelectrical impedance analysis have been developed in daily clinical practice, but this method also can‐ not provide accurate results in patients with LC who have edema and/or ascites [12–14].

In various chronic liver diseases including LC, several previous reports have shown skeletal muscle loss using anthropometric parameters [1–4, 11]. This status has recently been defined as sarcopenia, which shows loss of muscle mass and muscle strength or physical performance [8–12]. Although multiple factors, including differences in the etiology of LC, duration of disease, and the severity of liver damage, are related to the prevalence of sarcopenia in LC, sarcopenia is seen in approximately 30–70% of patients with LC [11–14, 35]. Additionally, a recent study showed that sarcopenia is a risk factor for recurrence in LC patients with hepa‐ tocellular carcinoma who undergo curative treatment [14].

Muscle mass is the result of a dynamic balance between protein synthesis and degradation [36–39]. This balance is regulated by two major branches of AKT (also known as protein kinase B) signaling pathways: the AKT/mammalian target of rapamycin (mTOR) pathway that con‐ trols protein synthesis and the AKT/forkhead box O (FOXO) pathway that controls protein degradation. Recent reports have shown that myostatin, a member of the transforming growth factor‐β superfamily, has emerged as a key regulator of skeletal muscle mass [39]. Myostatin is also a key mediator between energy metabolism and endurance capacity of skeletal muscle [37–39].

On the other hand, the prevalence of LC patients with obesity has increased in the last decade [17]. The definition of obesity is different between Japan and European countries (body mass index (BMI) ≥ 25 kg/m<sup>2</sup> in Japan and ≥30 kg/m<sup>2</sup> in European countries). Obesity in patients with LC is associated with insulin resistance, which has been discussed as an important factor in carcinogenesis in LC [17–22].

#### **2.2. Changes of biomarkers**

Serum Alb is a main secretion protein synthesized by the liver and has multiple functions, such as the maintenance of colloid osmotic pressure, ligand binding and transport, and enzymatic and antioxidative activities [40, 41]. The synthesis and degradation rates of Alb in patients with LC are decreased compared with those in healthy individuals whose liver function is normal. In particular, the half‐life of serum Alb is extended in patients with LC [42]. The serum Alb concentration is affected by the volume of daily food intake, digestion and absorption from the intestine, the degree of severity of liver damage, the imbalances of various hormone dynam‐ ics, and nutritional and catabolic status, such as that conferred by infections and burns [43]. However, serum Alb concentration is still frequently used as a biomarker of malnutrition and as an item of both the Child‐Pugh classification score and the modified end‐stage liver disease (MELD) score [44, 45]. Serum Alb is microheterogeneous with oxidized and reduced forms. Serum Alb concentration decreases, while the ratio of oxidized Alb increases, with LC pro‐ gression [46, 47]. A recent report has shown that this ratio improved in patients with LC after supplemental treatment with a branched‐chain amino acid (BCAA; valine, leucine, and iso‐ leucine)‐enriched formula [48]. These findings suggest that the oxidative status of serum Alb could provide a better assessment of malnutrition, though the measurement of serum levels of oxidized and reduced forms of Alb is time‐consuming and inconvenient in the clinical setting.

Rapid turnover proteins such as transthyretin (prealbumin), retinol‐binding protein, and trans‐ ferrin are useful biomarkers of short‐term nutritional status in patients with LC. The half‐life time is 2 days for transthyretin, 0.4–0.7 days for retinol‐binding protein, and 7–10 days for transferrin [49, 50]. These proteins are also influenced by baseline conditions such as surgery, infection, and anemia [50]. Recent reports have suggested that serum retinol‐binding protein 4 (RBP‐4) is a biomarker for assessing malnutrition in patients with LC. Serum RBP‐4 levels are decreased in patients with LC and directly related to the severity of liver damage according to the Child‐Pugh classification, while these levels are not correlated with insulin resistance [51, 52].

as sarcopenia, which shows loss of muscle mass and muscle strength or physical performance [8–12]. Although multiple factors, including differences in the etiology of LC, duration of disease, and the severity of liver damage, are related to the prevalence of sarcopenia in LC, sarcopenia is seen in approximately 30–70% of patients with LC [11–14, 35]. Additionally, a recent study showed that sarcopenia is a risk factor for recurrence in LC patients with hepa‐

Muscle mass is the result of a dynamic balance between protein synthesis and degradation [36–39]. This balance is regulated by two major branches of AKT (also known as protein kinase B) signaling pathways: the AKT/mammalian target of rapamycin (mTOR) pathway that con‐ trols protein synthesis and the AKT/forkhead box O (FOXO) pathway that controls protein degradation. Recent reports have shown that myostatin, a member of the transforming growth factor‐β superfamily, has emerged as a key regulator of skeletal muscle mass [39]. Myostatin is also a key mediator between energy metabolism and endurance capacity of skeletal muscle

On the other hand, the prevalence of LC patients with obesity has increased in the last decade [17]. The definition of obesity is different between Japan and European countries (body mass

with LC is associated with insulin resistance, which has been discussed as an important factor

Serum Alb is a main secretion protein synthesized by the liver and has multiple functions, such as the maintenance of colloid osmotic pressure, ligand binding and transport, and enzymatic and antioxidative activities [40, 41]. The synthesis and degradation rates of Alb in patients with LC are decreased compared with those in healthy individuals whose liver function is normal. In particular, the half‐life of serum Alb is extended in patients with LC [42]. The serum Alb concentration is affected by the volume of daily food intake, digestion and absorption from the intestine, the degree of severity of liver damage, the imbalances of various hormone dynam‐ ics, and nutritional and catabolic status, such as that conferred by infections and burns [43]. However, serum Alb concentration is still frequently used as a biomarker of malnutrition and as an item of both the Child‐Pugh classification score and the modified end‐stage liver disease (MELD) score [44, 45]. Serum Alb is microheterogeneous with oxidized and reduced forms. Serum Alb concentration decreases, while the ratio of oxidized Alb increases, with LC pro‐ gression [46, 47]. A recent report has shown that this ratio improved in patients with LC after supplemental treatment with a branched‐chain amino acid (BCAA; valine, leucine, and iso‐ leucine)‐enriched formula [48]. These findings suggest that the oxidative status of serum Alb could provide a better assessment of malnutrition, though the measurement of serum levels of oxidized and reduced forms of Alb is time‐consuming and inconvenient in the clinical setting. Rapid turnover proteins such as transthyretin (prealbumin), retinol‐binding protein, and trans‐ ferrin are useful biomarkers of short‐term nutritional status in patients with LC. The half‐life time is 2 days for transthyretin, 0.4–0.7 days for retinol‐binding protein, and 7–10 days for transferrin [49, 50]. These proteins are also influenced by baseline conditions such as surgery, infection, and

in European countries). Obesity in patients

in Japan and ≥30 kg/m<sup>2</sup>

tocellular carcinoma who undergo curative treatment [14].

[37–39].

index (BMI) ≥ 25 kg/m<sup>2</sup>

in carcinogenesis in LC [17–22].

142 Liver Cirrhosis - Update and Current Challenges

**2.2. Changes of biomarkers**

The profiles of plasma amino acids show characteristic changes in patients with LC. In particular, the plasma concentration of BCAAs is decreased, while that of aromatic amino acids (AAA; phenylalanine (Phe) and tyrosine (Tyr)) is increased, resulting in a decreased BCAA/ AAA molar ratio (namely, the Fischer ratio) or the BCAA/Tyr ratio (BTR) [53–55]. BCAA is mainly metabolized and used to detoxify ammonia and for energy production in the skeletal muscle. AAA is metabolized in the liver and is a representative precursor of a neurotransmitter (dopamine) and a pseudo‐neurotransmitter (octopamine), which are closely associated with the pathogenesis of HE [53]. The plasma Fischer ratio and serum BTR are significantly correlated with the serum Alb concentration and the severity of liver damage according to the Child‐Pugh classification (**Figure 2**), but not with the degree of HE [32, 55]. Furthermore, serum BTR can help predict a decrease in serum Alb concentration associated with chronic liver diseases [56].

Adipocytokines are also biomarkers of nutritional status in patients with LC. Leptin, adipo‐ nectin, and resistin are representative peptide hormones that are produced by adipose tissue, and they are closely associated with insulin resistance and arteriosclerosis [32]. Serum leptin levels are higher in females than males among healthy individuals and patients with LC. These levels are correlated with AMC and TSF, but they are not correlated with the severity of liver

**Figure 2.** Plasma branched‐chain amino acids, tyrosine, and the branched‐chain amino acid to tyrosine ratio in patients with liver cirrhosis. Seventy cirrhotic patients with or without hepatocellular carcinoma who were admitted to Iwate Medical University Hospital were investigated. Serum amino acid concentrations were measured by an enzymatic method. The severity of liver damage was classified into grades A, B, and C based on the Child‐Pugh classification. BCAA, branched‐chain amino acid (valine + leucine + isoleucine); BTR, BCAA/tyrosine ratio. Each value is shown as the mean ± standard deviation. \*P < 0.05, \*\*P < 0.01 (Kruskal‐Wallis test). (), number of patients with LC.

damage [57–59]. Plasma adiponectin assumes three forms: low molecular weight, medium molecular weight, and high molecular weight [60–62]. In patients with LC, the high molecular weight form of plasma adiponectin is significantly increased compared with healthy individu‐ als and is correlated with the severity of liver damage [32, 62]. Plasma resistin levels associated with insulin resistance are also correlated with the severity of liver damage in patients with LC [63, 64].

Ghrelin, an orexigenic hormone and stimulator of growth hormone, is mainly found in the gastric wall [65, 66]. Ghrelin plays a role in the hypothalamic centers to regulate feeding and caloric intake [65–67]. Furthermore, ghrelin controls feeding behavior and the long‐term regulation of body weight in association with leptin in the hypothalamic centers [66, 67]. The plasma ghrelin level has been considered a marker of pathological conditions such as obesity, insulin resistance, type 2 DM, and hypertension. However, the plasma ghrelin level in patients with LC was controversial in previous reports [68–70]. Our study has shown that the plasma ghrelin level (desacyl form) is higher in LC patients than in healthy controls, while it is not correlated with the severity of liver damage. Rather, the plasma ghrelin level is sig‐ nificantly correlated with BMI, AMC, TSF, and non‐protein respiratory quotient (npRQ) [70].

Vitamins (fat‐soluble: A, D, E, and K, and water‐soluble: thiamine, riboflavin, niacin, B<sup>6</sup> , B12, C, and folate), carnitine (CA), minerals, trace elements (copper, zinc, iron, manganese, and sele‐ nium), and hormones (insulin‐like growth factor 1, insulin‐like growth factor‐binding protein 3, reverse triiodothyronine, etc.) need to be examined when assessing the nutritional status of LC patients. In particular, evaluations of serum zinc and CA (total CA, free CA, and acyl‐CA) are necessary in LC patients with sarcopenia and hyperammonemia [23–32].

#### **2.3. Disturbances of energy metabolism**

PEM is a characteristic state of malnutrition in advanced LC and is closely associated with the survival rate, the carcinogenic risk, and the outcome of liver transplantation in patients with LC. The serum Alb concentration is generally a marker of protein malnutrition. The npRQ using indirect calorimetry is a marker of energy malnutrition [71]. Therefore, indirect calorimetry would be the best method to assess PEM. The results of REE, npRQ, and the oxidation rates of three nutrients (carbohydrate, protein, and fat) are obtained by indirect calorimetry. Many previous reports indicated that the npRQ decreases, the oxidation rate of fat increases, and the oxidation rate of carbohydrate decreases according to the Child‐Pugh classification [5, 72, 73]. It has been considered that a decreased npRQ (<0.85) after an over‐ night fast predicts a catabolic state and is related to a lower survival rate in LC patients [5]. Decreased carbohydrate oxidation is explained by both the lower production rate of glucose from glycogen in the liver and decreases in peripheral glucose use due to insulin resistance [74]. In fact, patients with LC cannot store sufficient glycogen due to liver atrophy, and their energy generation pattern after an overnight fast is equivalent to that observed in healthy individuals after 2–3 days of starvation [74, 75]. Increased fat oxidation is caused by an increased rate of lipolysis in fat tissue [76]. Our earlier results are generally similar to previ‐ ous reports (**Figures 3** and **4**). However, because measurement by indirect calorimetry is not easy, it cannot be routinely performed in outpatients with LC. The serum free fatty acid (FAA)

**Figure 3.** Nonprotein respiratory quotients in patients with liver cirrhosis. Eighty‐one cirrhotic patients with or without hepatocellular carcinoma who were admitted to Iwate Medical University Hospital were investigated. Energy metabolism was measured by indirect calorimetry (Deltatrac‐II Metabolic Monitor, Datax Division Inst. Corp., Helsinki, Finland) in the morning after overnight fasting. npRQ, nonprotein respiratory quotient. Each value is shown as the mean ± standard deviation. \*P < 0.05 (compared to grade A). ( ), number of patients with LC.

concentration has recently been reported as an alternative marker to represent npRQ mea‐ sured by indirect calorimetry to evaluate energy malnutrition in LC [77]. The serum FFA con‐ centration is also a predictor of minimal hepatic encephalopathy diagnosed by computerized neuropsychological testing [78]. Furthermore, our previous study showed that the serum FAA concentration is correlated with the serum acyl‐CA to total CA ratio, which would indi‐ rectly reflect intracellular mitochondrial function [30]. These findings suggest that the serum FAA concentration in the fasting state may be useful in the assessment of nutritional status in patients with LC.

#### **2.4. Glucose intolerance and diabetes mellitus**

damage [57–59]. Plasma adiponectin assumes three forms: low molecular weight, medium molecular weight, and high molecular weight [60–62]. In patients with LC, the high molecular weight form of plasma adiponectin is significantly increased compared with healthy individu‐ als and is correlated with the severity of liver damage [32, 62]. Plasma resistin levels associated with insulin resistance are also correlated with the severity of liver damage in patients with

Ghrelin, an orexigenic hormone and stimulator of growth hormone, is mainly found in the gastric wall [65, 66]. Ghrelin plays a role in the hypothalamic centers to regulate feeding and caloric intake [65–67]. Furthermore, ghrelin controls feeding behavior and the long‐term regulation of body weight in association with leptin in the hypothalamic centers [66, 67]. The plasma ghrelin level has been considered a marker of pathological conditions such as obesity, insulin resistance, type 2 DM, and hypertension. However, the plasma ghrelin level in patients with LC was controversial in previous reports [68–70]. Our study has shown that the plasma ghrelin level (desacyl form) is higher in LC patients than in healthy controls, while it is not correlated with the severity of liver damage. Rather, the plasma ghrelin level is sig‐ nificantly correlated with BMI, AMC, TSF, and non‐protein respiratory quotient (npRQ) [70].

Vitamins (fat‐soluble: A, D, E, and K, and water‐soluble: thiamine, riboflavin, niacin, B<sup>6</sup>

are necessary in LC patients with sarcopenia and hyperammonemia [23–32].

**2.3. Disturbances of energy metabolism**

and folate), carnitine (CA), minerals, trace elements (copper, zinc, iron, manganese, and sele‐ nium), and hormones (insulin‐like growth factor 1, insulin‐like growth factor‐binding protein 3, reverse triiodothyronine, etc.) need to be examined when assessing the nutritional status of LC patients. In particular, evaluations of serum zinc and CA (total CA, free CA, and acyl‐CA)

PEM is a characteristic state of malnutrition in advanced LC and is closely associated with the survival rate, the carcinogenic risk, and the outcome of liver transplantation in patients with LC. The serum Alb concentration is generally a marker of protein malnutrition. The npRQ using indirect calorimetry is a marker of energy malnutrition [71]. Therefore, indirect calorimetry would be the best method to assess PEM. The results of REE, npRQ, and the oxidation rates of three nutrients (carbohydrate, protein, and fat) are obtained by indirect calorimetry. Many previous reports indicated that the npRQ decreases, the oxidation rate of fat increases, and the oxidation rate of carbohydrate decreases according to the Child‐Pugh classification [5, 72, 73]. It has been considered that a decreased npRQ (<0.85) after an over‐ night fast predicts a catabolic state and is related to a lower survival rate in LC patients [5]. Decreased carbohydrate oxidation is explained by both the lower production rate of glucose from glycogen in the liver and decreases in peripheral glucose use due to insulin resistance [74]. In fact, patients with LC cannot store sufficient glycogen due to liver atrophy, and their energy generation pattern after an overnight fast is equivalent to that observed in healthy individuals after 2–3 days of starvation [74, 75]. Increased fat oxidation is caused by an increased rate of lipolysis in fat tissue [76]. Our earlier results are generally similar to previ‐ ous reports (**Figures 3** and **4**). However, because measurement by indirect calorimetry is not easy, it cannot be routinely performed in outpatients with LC. The serum free fatty acid (FAA)

, B12, C,

LC [63, 64].

144 Liver Cirrhosis - Update and Current Challenges

Glucose intolerance and/or diabetes mellitus is seen in about 30% of patients with LC, though 80% of LC patients have a normal fasting blood glucose level [79]. These manifestations are mainly caused by obesity and increased insulin resistance and hepatitis C virus (HCV) infec‐ tion. HCV is a major cause of LC and is induced by increased insulin resistance, excess secre‐ tion of pancreatic β cells, and portal‐systemic shunting [80, 81]. However, insulin resistance improves after eradication of HCV [82]. Age, sex, smoking, excessive alcohol intake, and chronic viral infection (hepatitis B virus and HCV) are established risk factors for HCC [20]. Furthermore, many recent studies have reported that obesity and DM are risk factors for HCC [17–22]. These findings suggest that not only PEM, but also obesity and glucose intolerance or DM might be important factors in the nutritional status that affect the prognosis of LC.

**Figure 4.** Substrate oxidation rates of glucose, fat, and protein using indirect calorimetry in patients with liver cirrhosis. Eighty‐one cirrhotic patients with or without hepatocellular carcinoma who were admitted to Iwate Medical University Hospital were investigated. Energy metabolism was measured using indirect calorimetry (Deltatrac‐II Metabolic Monitor, Datax Division Inst. Corp., Helsinki, Finland) in the morning after overnight fasting. Each value is shown as the mean. \*P < 0.05 (compared to grade A). ( ), number of patients with LC.

### **3. Nutritional management**

Based on previous many studies associated with malnutrition including obesity and glu‐ cose impairment (DM) in patients with LC, several guidelines on enteral nutrition have been proposed [83–85]. Here, flow chart on nutritional managements for patients with LC shows in **Figure 5**. The recommended dietary managements include energy, protein, fat, sodium chloride, iron, and other nutrient requirement. However, recommended energy intake and protein intake are different between Japan and European Society for paren‐ teral and enteral Nutrition (ESPEN) guidelines (energy intake: 25–35 kcal/kg/day in Japan guideline and 35–40 kcal/kg/day in ESPEN guidelines, and protein intake: 1.0–1.5 g/kg/day in Japan guideline and 1.2–1.5 g/kg/day in ESPEN guidelines). Energy intake should be reduced (25 kcal/kg/day) in patients complicated with DM [85]. Moreover, protein intake involves the protein content of BCAA formulas (BCAA granules or BCAA‐enriched nutri‐ ent mixture), and it should be reduced to 0.5–0.7 g/kg/day in patients with protein intoler‐ ance [85]. Late evening snack (LES) reduces overnight catabolic state in patients with LC

**Figure 5.** Flow chart on nutritional managements for patients with liver cirrhosis.

[86–89]. LES is particularly recommended to the patients with PEM and also useful for managing the blood glucose level in patients with glucose intolerance or DM [90]. As LES, snacks (approximately amounts of 200 kcal) and BCAA‐enriched nutrient mixture are usu‐ ally used. As excess deposition of iron in the liver causes oxidative stress and also promotes hepatocarcinogenesis, so unless severe anemia is observed, an iron‐restricted diet 6 mg/kg/ day) should be the standard [85, 91]. Zinc supplementation improves the status of hyper‐ ammonemia [24–26].

### **4. Conclusion**

**3. Nutritional management**

146 Liver Cirrhosis - Update and Current Challenges

the mean. \*P < 0.05 (compared to grade A). ( ), number of patients with LC.

Based on previous many studies associated with malnutrition including obesity and glu‐ cose impairment (DM) in patients with LC, several guidelines on enteral nutrition have been proposed [83–85]. Here, flow chart on nutritional managements for patients with LC shows in **Figure 5**. The recommended dietary managements include energy, protein, fat, sodium chloride, iron, and other nutrient requirement. However, recommended energy intake and protein intake are different between Japan and European Society for paren‐ teral and enteral Nutrition (ESPEN) guidelines (energy intake: 25–35 kcal/kg/day in Japan guideline and 35–40 kcal/kg/day in ESPEN guidelines, and protein intake: 1.0–1.5 g/kg/day in Japan guideline and 1.2–1.5 g/kg/day in ESPEN guidelines). Energy intake should be reduced (25 kcal/kg/day) in patients complicated with DM [85]. Moreover, protein intake involves the protein content of BCAA formulas (BCAA granules or BCAA‐enriched nutri‐ ent mixture), and it should be reduced to 0.5–0.7 g/kg/day in patients with protein intoler‐ ance [85]. Late evening snack (LES) reduces overnight catabolic state in patients with LC

**Figure 4.** Substrate oxidation rates of glucose, fat, and protein using indirect calorimetry in patients with liver cirrhosis. Eighty‐one cirrhotic patients with or without hepatocellular carcinoma who were admitted to Iwate Medical University Hospital were investigated. Energy metabolism was measured using indirect calorimetry (Deltatrac‐II Metabolic Monitor, Datax Division Inst. Corp., Helsinki, Finland) in the morning after overnight fasting. Each value is shown as

> Nutritional assessment in patients with LC is necessary for the appropriate management of LC patients. PEM, sarcopenia, and obesity are closely associated with adverse outcomes such as liver failure and HCC, as well as graft survival after liver transplantation in patients with LC. However, traditional and newly developed methods of measuring nutritional status are confounded by the changes in metabolism, body composition, and immune function that occur in LC independent of nutritional status. Further studies of precise assessments of mal‐ nutrition are needed to improve the prognosis of patients with LC.

#### **Acknowledgements**

The authors would like to thank Dr Yasuhiro Takikawa, Professor at the Division of Hepatology, Department of Internal Medicine, Iwate Medical University, for his assistance in creating this article.

## **Author details**

Kazuyuki Suzuki<sup>1</sup> \*, Ryujin Endo<sup>2</sup> and Akinobu Kato<sup>3</sup>

\*Address all correspondence to: kasuzuki@morioka‐u.ac.jp

1 Department of Nutritional Science, Morioka University, Takizawa, Japan

2 Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Japan

3 Department of Gastroenterology, Morioka Municipal Hospital, Morioka, Japan

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## **Portal Vein Thrombosis in Patients with Liver Cirrhosis**

Anca Trifan, Carol Stanciu and Irina Girleanu

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68929

#### **Abstract**

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154 Liver Cirrhosis - Update and Current Challenges

The myth that patients with liver cirrhosis are "auto‐anticoagulated" is outdated, and evidence shows that these patients frequently experience thrombosis. Portal vein throm‐ bosis (PVT), although considered as rare, it gradually increases complications that are more likely to occur during late‐stage liver cirrhosis. The aim of this chapter is to perform a review of nonmalignant portal vein thrombosis in cirrhosis, in terms of prevalence, pathogenesis, diagnosis, clinical course, and management. Studies were identified by a search strategy using MEDLINE and EMBASE databases. For the MEDLINE search, we used the following terms: ("liver cirrhosis" [MeSH Terms] OR "cirrhosis" [All Fields] OR "cirrhosis" [All Fields]) AND ("portal vein" [MeSH Terms] OR "portal vein" [All Fields]) AND ("Thrombosis" [MeSH Terms]). For the EMBASE search, we used the fol‐ lowing terms: (cirrhosis OR phrase liver cirrhosis) AND (phrase thrombosis/OR phrase vein thrombosis/OR phrase thrombosis prevention/OR phrase portal vein thrombosis/ OR phrase liver vein thrombosis/OR phrase mesenteric vein thrombosis/OR thrombosis). Studies were considered eligible if they referred to any aspect of prevalence, pathophysi‐ ology, clinical presentation, diagnosis and management, or therapy of PVT in cirrhosis. We put forward possible responses to these unsettled issues starting with prevalence, pathogenesis, and treatment options.

**Keywords:** liver cirrhosis, portal vein thrombosis, treatment

## **1. Introduction**

Portal vein thrombosis (PVT) is frequently associated with cirrhosis, mostly in patients with advanced liver disease or hepatocellular carcinoma (HCC). The physiopathology of PVT

© 2017 The Author(s). Licensee InTech. 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.

development is still under debate, and at the moment, there is a lot of controversy regarding the most efficient treatment. Moreover, the outcome in cirrhotics with PVT awaiting a liver transplant or the influence of thrombosis on posttransplant survival and morbidity is still unknown.

## **2. Epidemiology of portal vein thrombosis in liver cirrhosis**

PVT is rarely diagnosed in the general population, the prevalence as reported by autopsy‐ based studies being up to 1% [1]. Genetic or acquired thrombophilia, mieloproliferative dis‐ eases, acute pancreatitis, acute cholecystitis, or other inflammations in the abdominal cavity are the main causes of noncirrhotic PVT [2].

In cirrhosis, PVT prevalence varies between 0.6 and 28% depending on the diagnostic method: imaging exam, during surgery for liver transplantation, or autopsy reports [3–5]. In the last years, PVT prevalence has increased as a result of the widespread use of imaging techniques, such as Doppler ultrasonography, computed tomography, or magnetic resonance, but its exact value is still not known. Studies based on ultrasonography results reported a preva‐ lence of 10–28% in cirrhotic patients, excluding those with HCC [2]. The prevalence of PVT in liver transplant candidates is similar to that in other cirrhotic patients with the same degree of liver disease, although MELD and Child‐Pugh scores were higher in patients with PVT, confirming the fact that PVT prevalence increases with the severity of liver cirrhosis. Thus, PVT prevalence is low (1%) in compensated liver cirrhosis and up to 28% in decompensated liver cirrhosis [6–8]. Association between liver cirrhosis and malignancies, especially HCC, may increase PVT prevalence up to 44% [6].

If data on the prevalence of PVT are frequently reported, those on the incidence, however, are quite scanty. Maruyama et al. in a retrospective analysis of 150 patients with cirrhosis, fol‐ lowed up for a median period of 66 months, reported a cumulative overall incidence of PVT of 12.8% at 1 year, 18.6% at 3 years, 20% at 5 years, and 38.7% at 8–10 years [9]. Moreover, the incidence of PVT in patients awaiting liver transplant was reported to be 7% after one‐year follow‐up [10].

## **3. Pathogenesis of portal vein thrombosis in cirrhosis**

Pathogenesis of PVT in patients with cirrhosis still remains uncertain, although some authors consider PVT a complication of liver disease. However, its development is unpredictable and the risk factors are not well recognized. According to Virchow's triad, venous thrombosis is the result of the coexistence of low blood flow, endothelial injury, and a hypercoagulable state. For these reasons, PVT in cirrhosis could be developing as a consequence of portal hyperten‐ sion, associated with endothelial dysfunction and a relative hypercoagulable state [11, 12].

Portal hypertension is characterized by a reduced portal flow due to increased intrahepatic vascular resistance. This phenomenon is further increased as liver disease progresses [13], representing one of the risk factors that determine the increased incidence of PVT in advanced liver disease as compared to early compensated cirrhosis. This hypothesis was confirmed in one prospective study, which demonstrated that the reduced portal flow velocity below 15 cm/s was the only independent variable correlated with the risk of developing PVT at 1‐year follow‐up [13].

development is still under debate, and at the moment, there is a lot of controversy regarding the most efficient treatment. Moreover, the outcome in cirrhotics with PVT awaiting a liver transplant or the influence of thrombosis on posttransplant survival and morbidity is still

PVT is rarely diagnosed in the general population, the prevalence as reported by autopsy‐ based studies being up to 1% [1]. Genetic or acquired thrombophilia, mieloproliferative dis‐ eases, acute pancreatitis, acute cholecystitis, or other inflammations in the abdominal cavity

In cirrhosis, PVT prevalence varies between 0.6 and 28% depending on the diagnostic method: imaging exam, during surgery for liver transplantation, or autopsy reports [3–5]. In the last years, PVT prevalence has increased as a result of the widespread use of imaging techniques, such as Doppler ultrasonography, computed tomography, or magnetic resonance, but its exact value is still not known. Studies based on ultrasonography results reported a preva‐ lence of 10–28% in cirrhotic patients, excluding those with HCC [2]. The prevalence of PVT in liver transplant candidates is similar to that in other cirrhotic patients with the same degree of liver disease, although MELD and Child‐Pugh scores were higher in patients with PVT, confirming the fact that PVT prevalence increases with the severity of liver cirrhosis. Thus, PVT prevalence is low (1%) in compensated liver cirrhosis and up to 28% in decompensated liver cirrhosis [6–8]. Association between liver cirrhosis and malignancies, especially HCC,

If data on the prevalence of PVT are frequently reported, those on the incidence, however, are quite scanty. Maruyama et al. in a retrospective analysis of 150 patients with cirrhosis, fol‐ lowed up for a median period of 66 months, reported a cumulative overall incidence of PVT of 12.8% at 1 year, 18.6% at 3 years, 20% at 5 years, and 38.7% at 8–10 years [9]. Moreover, the incidence of PVT in patients awaiting liver transplant was reported to be 7% after one‐year

Pathogenesis of PVT in patients with cirrhosis still remains uncertain, although some authors consider PVT a complication of liver disease. However, its development is unpredictable and the risk factors are not well recognized. According to Virchow's triad, venous thrombosis is the result of the coexistence of low blood flow, endothelial injury, and a hypercoagulable state. For these reasons, PVT in cirrhosis could be developing as a consequence of portal hyperten‐ sion, associated with endothelial dysfunction and a relative hypercoagulable state [11, 12].

**2. Epidemiology of portal vein thrombosis in liver cirrhosis**

are the main causes of noncirrhotic PVT [2].

may increase PVT prevalence up to 44% [6].

**3. Pathogenesis of portal vein thrombosis in cirrhosis**

follow‐up [10].

unknown.

156 Liver Cirrhosis - Update and Current Challenges

Advanced cirrhosis is associated with profound and complex coagulation defects, involving procoagulant and anticoagulant factors, fibrinolytic system, and platelets number and func‐ tion [12]. The net result of all of these defects may be a prothrombotic state, which is likely to be related with the increased endothelial synthesis of von Willebrand factor (vWf) and an increased level of factor VIII, combined with low levels of hepatic anticoagulation agents such as antithrombin III, protein C and S [14, 15].

A number of different inherited and acquired disorders have been also considered as predispos‐ ing factors for PVT in patients with cirrhosis, although with variable degree of evidence [16–18]. One study found antiphospholipids antibodies in more than half of cirrhotic patients with PVT [19], whereas variable association of newly recognized risk factors for inherited thrombosis such as the Q506 polymorphism in the gene coding for factor V or the G20210A change in the prothrombin gene (PTHR A20210) has been reported in patients with cirrhosis complicated by PVT [16, 20, 21]. None of these changes were confirmed as independent risk factors for PVT in liver cirrhosis. PAI‐1 4G‐4G and MTHFR 677TT screening of patients could be useful, especially in alcoholic or cryptogenic cirrhosis, to identify patients in which new drug therapies based on the inhibition of the hepatic stellate cell activation could be easily assessed [22].

Thrombocytopenia was considered for a long time a risk factor for bleeding in patients with liver cirrhosis, but recent reports did not confirm this hypothesis. Some studies showed abnormalities of platelet aggregation in patients with cirrhosis [23, 24], which was attributed to decreased serum levels of clotting factors [23], impaired production of thromboxane A2 and arachidonic acid, or impairment in adhesion molecules [25, 26]. This theory was con‐ firmed by multiple electrode aggregometry, which demonstrated a decreased aggregation activity of platelets, although this phenomenon was not observed under stimulation by ris‐ tocetin. This finding implies that the cause of platelet hyporeactivity does not lie in defective transmembrane or postmembrane signaling pathway, while platelet activity was positively correlated with the number of platelets. Interestingly, platelet activity was significantly lower in the PVT group than in the non‐PVT group, although the platelet count was not significantly different in either group. A clear reason for this finding was not given, and it is suggested that adaptive changes in platelet function occur after the development of PVT [27]. Some studies consider the degree of thrombocytopenia to be an independent risk factor for PVT, which may seem paradoxical since low platelet count should logically predispose to bleeding. Possibly, as cirrhosis and portal hypertension progress, the resultant decrease in portal flow outweighs a protective effect of low platelet count against thrombosis [27].

Another factor associated with PVT development in liver cirrhosis is endothelial dysfunction. Portal hypertension and inversion of portal vein flow are among the factors associated with endo‐ thelial dysfunction. Endotoxemia is another factor that contributes to endothelial dysfunction in cirrhotic patients with PVT. The biological consequences of systemic endotoxemia are low‐grade inflammation and peripheral vasodilatation [27]. *In vitro* studies have revealed that lipopoly‐ saccharides, even in low concentrations, may stimulate vWf release from the endothelium [14]. Moreover, Violi et al. provided evidence of a direct correlation between endotoxemia and the ongoing prothrombotic state in the portal venous system [28]. Therefore, it is plausible that endo‐ toxemia, in combination with the coexisting increased vWf release frequently found in cirrhosis, together with portal hypertension may trigger prothrombotic mechanisms, the development of endotoxemia being a surrogate marker of disease severity in patients with cirrhosis [29].

Besides the common risk factors for PVT, other predisposing conditions such as variceal sclerotherapy, liver malignancy, abdominal surgery, or sepsis were described. The roles of sclerotherapy and cyanoacrylate glue injection as potential trigger factors for PVT are contro‐ versial, but they were reported in the literature [30]. Such associations could occur as a result of selection bias in patients with more severe portal hypertension. Surgical procedures for portal hypertension were also associated with an increased incidence of PVT [31, 32]. Among them, pericardial devascularization with splenectomy, and splenorenal shunts are associated with an increased risk of PVT [33].

Along with the sluggish portal flow [19] and the presence of liver malignancies (i.e., hepato‐ cellular carcinoma), other acquired local (abdominal surgery, trauma or bacterial infection, and portacaval shunts), or general (sepsis and myeloproliferative disorders) factors have been claimed as possible causes of PVT in patients with liver cirrhosis [12–16].

The main consequences of PVT are related to the extension of the thrombus and include intes‐ tinal ischemia and acute/chronic portal hypertension. Gastrointestinal bleeding due to portal hypertension following PVT has been reported as a major cause of death in patients with cirrhosis [34]. The pathogenesis of PVT in such patients remains unclear, although decreased portal vein blood flow, a hypercoagulable state, and systemic inflammation may be of impor‐ tance. Despite the great number of risk factors for PVT in liver cirrhosis, thrombosis itself should be considered a multifactorial disease, and the likelihood of developing PVT increases in direct proportion to the number of risk factors present in each patient.

## **4. Diagnosis of portal vein thrombosis**

PVT diagnosis in cirrhotic patients involves clinical suspicion with further imagistic confir‐ mation. According to the moment of diagnosis, this particular type of venous thrombosis could be classified as:


#### **4.1. Clinical presentation**

Another factor associated with PVT development in liver cirrhosis is endothelial dysfunction. Portal hypertension and inversion of portal vein flow are among the factors associated with endo‐ thelial dysfunction. Endotoxemia is another factor that contributes to endothelial dysfunction in cirrhotic patients with PVT. The biological consequences of systemic endotoxemia are low‐grade inflammation and peripheral vasodilatation [27]. *In vitro* studies have revealed that lipopoly‐ saccharides, even in low concentrations, may stimulate vWf release from the endothelium [14]. Moreover, Violi et al. provided evidence of a direct correlation between endotoxemia and the ongoing prothrombotic state in the portal venous system [28]. Therefore, it is plausible that endo‐ toxemia, in combination with the coexisting increased vWf release frequently found in cirrhosis, together with portal hypertension may trigger prothrombotic mechanisms, the development of

endotoxemia being a surrogate marker of disease severity in patients with cirrhosis [29].

with an increased risk of PVT [33].

158 Liver Cirrhosis - Update and Current Challenges

Besides the common risk factors for PVT, other predisposing conditions such as variceal sclerotherapy, liver malignancy, abdominal surgery, or sepsis were described. The roles of sclerotherapy and cyanoacrylate glue injection as potential trigger factors for PVT are contro‐ versial, but they were reported in the literature [30]. Such associations could occur as a result of selection bias in patients with more severe portal hypertension. Surgical procedures for portal hypertension were also associated with an increased incidence of PVT [31, 32]. Among them, pericardial devascularization with splenectomy, and splenorenal shunts are associated

Along with the sluggish portal flow [19] and the presence of liver malignancies (i.e., hepato‐ cellular carcinoma), other acquired local (abdominal surgery, trauma or bacterial infection, and portacaval shunts), or general (sepsis and myeloproliferative disorders) factors have been

The main consequences of PVT are related to the extension of the thrombus and include intes‐ tinal ischemia and acute/chronic portal hypertension. Gastrointestinal bleeding due to portal hypertension following PVT has been reported as a major cause of death in patients with cirrhosis [34]. The pathogenesis of PVT in such patients remains unclear, although decreased portal vein blood flow, a hypercoagulable state, and systemic inflammation may be of impor‐ tance. Despite the great number of risk factors for PVT in liver cirrhosis, thrombosis itself should be considered a multifactorial disease, and the likelihood of developing PVT increases

PVT diagnosis in cirrhotic patients involves clinical suspicion with further imagistic confir‐ mation. According to the moment of diagnosis, this particular type of venous thrombosis

• *acute*: sudden formation of a thrombus within the portal vein, with or without involvement

• *chronic:* the obstructed portal vein is replaced by collateral veins bypassing the thrombosed

claimed as possible causes of PVT in patients with liver cirrhosis [12–16].

in direct proportion to the number of risk factors present in each patient.

**4. Diagnosis of portal vein thrombosis**

of the mesenteric and/or splenic vein [35];

could be classified as:

vein [36].

PVT is frequently diagnosed in asymptomatic cirrhotic patients by routine abdominal ultra‐ sound (US). In most of these cases, PVT is chronic with partial obstruction. Acute partial or total PVT is frequently symptomatic, and it is associated with decompensation or further decompensation of liver disease.

The symptoms and signs of acute PVT could be represented by severe abdominal or lumbar pain with sudden onset, progressive over days, without peritoneal signs when the superior mesenteric vein is involved, functional ileus, ascites, or variceal bleeding. The majority of the patients with acute PVT associate systemic inflammatory response syndrome in the absence of sepsis. If the symptoms are not resolved in 5–7 days or liver cirrhosis is complicated by fur‐ ther decompensation and clinical deterioration, mesenteric vein involvement with complete loss of blood flow should be suspected.

Chronic PVT is asymptomatic in most cases. The pain is a sign of mesenteric vein thrombosis and bowel ischemia. Although there is a minimal change in the hepatic arterial blood supply, the portal pressure is increased, with the development of portosystemic collaterals and an increased risk of variceal bleeding. This fact supports the Baveno VI recommendations stating that it is mandatory to perform screening endoscopy in all patients diagnosed with chronic PVT within 6 months from the acute episode if a complete recanalization of thrombosis is not achieved [36]. A total of 22% of patients without varices at initial endoscopy will develop this condition in 3 years [37]. Therefore, a follow‐up endoscopy should be performed in subjects without varices at the baseline [36].

With regard to primary prevention of bleeding, no randomized controlled trial compared the effectiveness of nonselective beta‐blockers versus endoscopic band ligation in PVT. In this scenario, as well as in the context of the acute bleeding and secondary prophylaxis, Baveno VI recommends following the guidelines on PH in cirrhosis [36]. Besides prehepatic portal hypertension, portal cholangiopathy is another context associated with chronic PVT. Patients develop jaundice, abdominal pain, and episodes of cholangitis.

#### **4.2. Imaging evaluation: abdominal ultrasound**

When PVT is suspected, ultrasound is the first‐line imaging method to be used, since it holds an accuracy ranging from 88 to 98% for the detection of PVT with a sensitivity and specific‐ ity of 80–100% in the majority of studies [38, 39]. The sensitivity of ultrasound is particu‐ larly high in complete PVT, while the risk of false‐negative results occurs only in incomplete PVT [40] and isolated superior mesenteric vein thrombosis [38]. In two‐dimensional (2‐D) Gray‐Scale ultrasonography, a thrombus appears as a hypo/isoechoic material occupying part of (partial thrombosis) or the entire vessel (complete thrombosis). The normal portal vein can be eventually replaced by multiple tortuous vessels with hepatopetal flow, a condition named as "cavernomatous transformation" or "cavernoma," easily detected with Doppler ultra‐ sound. Color/power and pulsed Doppler should be mandatorily used to confirm whether the vessel has a remnant blood flow, to help differentiate high‐degree partial thrombosis from complete thrombosis. The reliability of ultrasonography in the detection of PVT improves with the operator's experience, and whenever PVT is clinically suspected, ultrasonography should be performed by experienced operators [41]. Ultrasonography suffers from other limi‐ tations such as reduced visualization in obese individuals and in case of abundant bowel gas, and impossibility to assess bowel ischemia. This should be suspected in case of ascites and/ or high blood lactate levels. Ultrasound is sufficient to diagnose PVT in patients with a good acoustic window, but when ultrasonography is insufficient, a second‐line cross‐sectional imaging method should be considered to confirm or exclude the diagnosis.

#### **4.3. Imaging evaluation: computed tomography and magnetic resonance**

Contrast‐enhanced four phase (pre‐contrast, arterial, portal, and late) CT (CECT) and con‐ trast‐enhanced MRI (CEMRI) can be used, with CT is preferred in unstable patients with acute abdominal symptoms. Advantages of MR and CT over US include the possibility of detecting bowel ischemia, septic foci and intraabdominal malignancies, and higher sensitiv‐ ity in the detection of thrombosis in the splenic and superior mesenteric vein. Among the well‐known drawbacks of CT are exposure to ionizing radiation, the risk of allergic reac‐ tions, and nephrotoxicity. CEMRI is also contraindicated in patients with acute renal failure because of the risk of nephrogenic systemic fibrosis. Once PVT is diagnosed, CECT or CEMRI is mandatory to evaluate the extent of thrombosis and to allow a detailed mapping of porto‐ systemic collaterals, crucial to the planning of interventions aimed at recanalizing the portal venous system. It should be considered that clinical consequences of PVT mainly depend on the number of vessels completely occluded [42], as well as the degree of collateralization in chronic cases. Furthermore, the presence of ascites is a predictor of the lack of response to anticoagulation and should be reported [42]. Several classification/staging systems have been developed, but they rely heavily on anatomical considerations. The most commonly cited and used in clinical trials is the one proposed by Yerdel et al. [43]. However, there is no validated classification to be used in clinical practice in order to personalize risk assessment and guide therapy [44].

Both Doppler ultrasonography and multiphasic‐computed tomography have high sensi‐ tivity and specificity for PVT detection [45]. Doppler US is highly accurate in detecting thrombosis involving the trunk of the portal vein and intrahepatic branches, also providing additional information regarding the portal flow and its direction. CT is better at assess‐ ing the superior mesenteric vein, spontaneous portosystemic shunts, renal veins, and the inferior vena cava. While a CT exam is generally performed at the time of initial evalua‐ tion for liver transplant, Doppler ultrasound is appropriate for follow‐up imaging as it can be performed repetitively and does not have the risks of intravenous iodine contrast and radiation.

#### **4.4. Imaging evaluation: malignant versus nonmalignant PVT**

Patients with cirrhosis or neoplastic disease may develop either benign or malignant PVT. In patients with HCC, it is essential to radiologically distinguish tumor invasion of the main trunk or the branches of the portal vein as the cause for PVT versus bland thrombus in the portal vein because this could determine the proper therapeutic approach and their prognosis. This is not without implications since the major vascular tumoral invasion is an absolute con‐ traindication to transplant, while bland PVT in the presence of HCC needs to be approached similarly to a non‐HCC setting [45]. Tumor‐related PVT is usually detected in portal vein branches adjacent to and in direct continuity of the tumor, and is often associated with a high alpha‐fetoprotein level.

Until recently, imaging differentiation of the benign from the malignant PVT has depended on the findings of contrast enhancement and luminal expansion on abdominal ultrasound, CT, or MRI. Signs of malignant PVT on ultrasound include an expansive aspect mass inside the lumen, with heterogeneous aspect and disruption of portal vein walls. Color/power‐Doppler ultrasound shows signs of neovascularization within the mass, and pulsed Doppler could confirm arterial flow with a high resistance index associated with malignant PVT. One of the most sensitive and with small additionally methods for malignant PVT diagnosis is contrast ultrasound. In contrast to bland PVT, which remains unenhanced in all phases, a malignant PVT shows the same contrast‐behavior as HCC—rapid wash‐out (hypoperfusion in compari‐ son to the rest of the liver parenchyma) in the portal/late phase.

Enhancement or an increase in density or intensity on CT or MRI, respectively, after con‐ trast administration could also establish the diagnosis of malignant PVT. Conversely, absent enhancement confirms bland thrombus.

Careful screening for PVT is important in all patients with cirrhosis and in those under eval‐ uation for liver transplantation. Repeated imaging at specified intervals—usually every 3 months, during the pretransplant waiting period—is also recommended in order to detect thrombosis that may develop during follow‐up [7]. Patients who develop unexplained wors‐ ening of liver functions or gastrointestinal bleeding despite adequate prophylaxis should also be evaluated for PVT of recent onset.

## **5. Management of portal vein thrombosis**

should be performed by experienced operators [41]. Ultrasonography suffers from other limi‐ tations such as reduced visualization in obese individuals and in case of abundant bowel gas, and impossibility to assess bowel ischemia. This should be suspected in case of ascites and/ or high blood lactate levels. Ultrasound is sufficient to diagnose PVT in patients with a good acoustic window, but when ultrasonography is insufficient, a second‐line cross‐sectional

Contrast‐enhanced four phase (pre‐contrast, arterial, portal, and late) CT (CECT) and con‐ trast‐enhanced MRI (CEMRI) can be used, with CT is preferred in unstable patients with acute abdominal symptoms. Advantages of MR and CT over US include the possibility of detecting bowel ischemia, septic foci and intraabdominal malignancies, and higher sensitiv‐ ity in the detection of thrombosis in the splenic and superior mesenteric vein. Among the well‐known drawbacks of CT are exposure to ionizing radiation, the risk of allergic reac‐ tions, and nephrotoxicity. CEMRI is also contraindicated in patients with acute renal failure because of the risk of nephrogenic systemic fibrosis. Once PVT is diagnosed, CECT or CEMRI is mandatory to evaluate the extent of thrombosis and to allow a detailed mapping of porto‐ systemic collaterals, crucial to the planning of interventions aimed at recanalizing the portal venous system. It should be considered that clinical consequences of PVT mainly depend on the number of vessels completely occluded [42], as well as the degree of collateralization in chronic cases. Furthermore, the presence of ascites is a predictor of the lack of response to anticoagulation and should be reported [42]. Several classification/staging systems have been developed, but they rely heavily on anatomical considerations. The most commonly cited and used in clinical trials is the one proposed by Yerdel et al. [43]. However, there is no validated classification to be used in clinical practice in order to personalize risk assessment

Both Doppler ultrasonography and multiphasic‐computed tomography have high sensi‐ tivity and specificity for PVT detection [45]. Doppler US is highly accurate in detecting thrombosis involving the trunk of the portal vein and intrahepatic branches, also providing additional information regarding the portal flow and its direction. CT is better at assess‐ ing the superior mesenteric vein, spontaneous portosystemic shunts, renal veins, and the inferior vena cava. While a CT exam is generally performed at the time of initial evalua‐ tion for liver transplant, Doppler ultrasound is appropriate for follow‐up imaging as it can be performed repetitively and does not have the risks of intravenous iodine contrast and

Patients with cirrhosis or neoplastic disease may develop either benign or malignant PVT. In patients with HCC, it is essential to radiologically distinguish tumor invasion of the main trunk or the branches of the portal vein as the cause for PVT versus bland thrombus in the portal vein because this could determine the proper therapeutic approach and their prognosis.

**4.4. Imaging evaluation: malignant versus nonmalignant PVT**

imaging method should be considered to confirm or exclude the diagnosis.

**4.3. Imaging evaluation: computed tomography and magnetic resonance**

and guide therapy [44].

160 Liver Cirrhosis - Update and Current Challenges

radiation.

Nowadays, there are two main possibilities of PVT treatment: anticoagulation with low‐ molecular‐weight heparin (LMWH) or oral anticoagulants, and transjugular intrahepatic por‐ tosystemic shunt (TIPS). The best therapeutic solution is still under debate, but the final goal is to prevent PVT extension to the mesenteric veins and achieve PVT recanalization (**Figure 1**).

#### **5.1. Anticoagulant treatment for PVT in cirrhotic patients**

Anticoagulant treatment in cirrhotic patients who are not on a liver transplant list may be considered if the superior mesenteric vein is involved or the patient carries a known pro‐ thrombotic condition [36].

Some studies have reported that spontaneous recanalization of the portal vein in the absence of an anticoagulant treatment is unusual. In the study by Francoz et al., no patient achieved recanalization in the absence of anticoagulation, while 42% achieved recanalization while

**Figure 1.** Algorithm for the diagnosis and management of PVT in liver cirrhosis.

under anticoagulant therapy [46]. Senzolo et al. reported thrombus progression in 75% of patients who did not receive anticoagulant treatment, compared to only 15% of treated patients [47].

There are limited studies reporting on the use of anticoagulation for PVT in patients with cirrhosis. In all these studies, complete recanalization has been described in 33–45% of cases, while partial portal vein recanalization was observed in 15–35% of cases [46, 48, 49]. In a study by Senzolo et al., prospectively enrolling 56 individuals (35 treated and 21 controls), complete recanalization was achieved in 36% of subjects and partial recanalization in 27%, after therapy with LMWH (mean 5.5 months) [47]. The time between diagnosis and antico‐ agulation—under 6 months—was the most important factor positively associated with portal vein recanalization. In a study from Spain, by Delgado et al., including 55 cirrhotic patients, the majority of them (75%) diagnosed with partial PVT, complete portal vein recanalization was achieved in 45% of cases after a median duration of therapy of 6.3 months with vitamin K antagonists (VKA) or LMWH [48]. In this study, the only predictive factor for achieving complete portal vein recanalization was also early initiation of anticoagulation therapy after diagnosis, in less than 14 days.

Nowadays, there are no clear data regarding the duration of anticoagulant treatment, although Amitrano et al. treated 28 patients with LMWH and demonstrated that after 6 months, com‐ plete portal vein recanalization was achieved in 33% of cases and partial portal vein recana‐ lization was observed in 50%. In individuals with partial response to therapy, anticoagulant treatment was continued for more than 6 months, and 86% of these patients achieved com‐ plete recanalization [50].

The rate of PVT recanalization depends not only on the time of PVT diagnosis, but also on the type of PVT in most of the cases: complete or partial, tumoral or nontumoral. As shown by most studies, recanalization is uncommon in patients with complete thrombosis, but anticoag‐ ulation is still indicated in order to prevent the extension of the thrombus [46–50]. However, it is unclear what proportion of these patients would have recanalized spontaneously and, more importantly, whether they derived any clinical benefit from anticoagulation. This hypothesis was raised by other studies with conflicting results. Maruyama et al. reported a spontane‐ ous improvement in 47.6%, unchanged appearance in 45.2%, and progression in only 7.2%. There was no significant difference in the natural course of thrombosis, based on the degree of obstruction or the location of the thrombus, and recurrence of PVT after spontaneous resolu‐ tion was observed in 21.4% [9]. Our data also confirmed Maruyama's study results. We dem‐ onstrated that in most of the cirrhotic patients diagnosed with PVT, the thrombus remained with the same dimensions or disappeared without any therapeutical intervention [51].

For cirrhotic patients diagnosed with PVT awaiting for a liver transplant, it is important to achieve recanalization and thus achieve a physiological portal vein anastomosis in order to ensure portal flow to the graft. Transplanting patients with PVT extended to the superior mesenteric vein or with extensive portal vein thrombosis is associated with higher morbidity and mortality, PVT being a predictor of posttransplant mortality in some studies [43, 52, 53].

An important objective in the management of PVT in cirrhotic patients awaiting liver trans‐ plantation is to achieve recanalization for the end‐to‐end portal vein anastomosis to be surgi‐ cally possible. Another objective is to prevent extension of the thrombus to the splenic and superior mesenteric vein, since these veins can also be used to restore portal flow to the graft in case the main portal vein is thrombosed. In the event that neither the portal vein nor the supe‐ rior mesenteric vein can be used, nonanatomical techniques to restore portal flow are possible, but these are associated with increased morbidity and mortality. Francoz et al. compared 19 individuals with cirrhosis and PVT on the waiting list for liver transplantation who received anticoagulation therapy (VKA) with 10 individuals not receiving therapy. A total of 42% of treated individuals achieved complete PV recanalization. None of the untreated patients had recanalization, and, in fact, PVT progressed in 60 % in the untreated group. Moreover, antico‐ agulation therapy did not increase blood loss during liver transplantation [46].

under anticoagulant therapy [46]. Senzolo et al. reported thrombus progression in 75% of patients who did not receive anticoagulant treatment, compared to only 15% of treated

No ancoagulaon Ancoagulaon PVT progression TIPS

LT candidates- screening every 6 months

Non-LT candidates

Imaging follow-up every 3 months

Progressive PVT

Evaluate PVT extension Evaluate risk factors Evaluate presence of

HCC

There are limited studies reporting on the use of anticoagulation for PVT in patients with cirrhosis. In all these studies, complete recanalization has been described in 33–45% of cases, while partial portal vein recanalization was observed in 15–35% of cases [46, 48, 49]. In a study by Senzolo et al., prospectively enrolling 56 individuals (35 treated and 21 controls), complete recanalization was achieved in 36% of subjects and partial recanalization in 27%, after therapy with LMWH (mean 5.5 months) [47]. The time between diagnosis and antico‐ agulation—under 6 months—was the most important factor positively associated with portal vein recanalization. In a study from Spain, by Delgado et al., including 55 cirrhotic patients, the majority of them (75%) diagnosed with partial PVT, complete portal vein recanalization was achieved in 45% of cases after a median duration of therapy of 6.3 months with vitamin K antagonists (VKA) or LMWH [48]. In this study, the only predictive factor for achieving complete portal vein recanalization was also early initiation of anticoagulation therapy after

patients [47].

diagnosis, in less than 14 days.

Clinical suspicion of PVT

162 Liver Cirrhosis - Update and Current Challenges

LT candidates and trunk PVT or progressive PVT

Abdominal ultrasound, Doppler, CT, MRI

**PVT confirmed**

Large esophageal varices

BB+endoscopic therapy

Platelets<50.000/mm3

**Figure 1.** Algorithm for the diagnosis and management of PVT in liver cirrhosis.

YES NO

The rationale for treating PVT in patients with cirrhosis is that it increases morbidity compared to matched cirrhotics without PVT, although there is controversy regarding the influence of PVT on the natural course of liver cirrhosis. PVT has been reported to be independently associated with a higher risk of failure in controlling acute variceal bleeding as well as rebleeding [44]. The occurrence of PVT has also been shown to increase mortality, which has been observed even in patients with lower Child‐Pugh scores [46]. Recanalization of PVT has also been reported to reduce esophageal variceal pressure, improving morbidity, and mortality rates [44].

There are no clear recommendations for an optimal anticoagulation regimen for the treatment of PVT in patients with cirrhosis. Monitoring of anticoagulation regimen is complex in the cirrhotic patient and, therefore, choosing between different anticoagulants (LMWH, VKA, or the new oral anticoagulants) is a difficult decision. LMWH is less practical for patients, since it necessitates daily subcutaneous injections, although it does not affect INR values and, conse‐ quently, does not interfere with MELD or Child scoring. There is, however, limited informa‐ tion on the pharmacodynamic profile of LMWH in cirrhotic individuals.

Cirrhotic patients often have an increased volume of distribution because of fluid overload, and this makes it difficult to determine the optimal dose of LMWH. Moreover, the major route of *elimination* of the *LMWH* is through the *kidneys,* and, since many patients with cirrhosis have renal insufficiency, the half‐life of LMWH is increased. The only method of LMWH treatment monitoring validated until known is by determining the anti‐Xa activity, but this method is unreliable in cirrhosis [35, 55].

The primary problem with VKA is determining the adequate anticoagulation in patient with cirrhosis who already has an altered abnormal prothrombin time. Most studies have targeted an INR of 2–3 [54]. Based on an empirical experience not relying on randomized studies, if the baseline INR is over 2, it is difficult to determine if a given dose of VKA ensures adequate anti‐ coagulation. It may also be difficult to determine the optimal INR target for dose adjustment. There is also a potential risk of further lowering of protein C levels with the use of VKA, and this could theoretically increase the prothrombotic imbalance of individuals with cirrhosis.

The new oral anticoagulants—thrombin inhibitors and inhibitors of activated factor X such as dabigatran and rivaroxaban—offer the advantage of oral administration, the absence of labo‐ ratory monitoring, and an antithrombin‐independent mechanism of action [54]. However, there are a few reports regarding their use in cirrhotic patients, most of them isolated cases. One of the major disadvantages of these new anticoagulants was the absence of an antidote. This problem was solved for dabigratan and also for rivaroxaban, which could be the new class of anticoagulants preferred in PVT treatment. In cirrhotic patients, it may be necessary to reverse anticoagulation during episodes of inadvertent bleeding or at the time of surgery. While the effect of VKA can be expertly reversed by fresh‐frozen plasma or prothrombin com‐ plex concentrate, there is no potent and rapidly acting antidote to reverse the effect of LMWH or the newer thrombin inhibitors.

Even if the anticoagulant treatment seems to be the same in patients with liver cirrhosis, it is uncertain whether it is beneficial to anticoagulate asymptomatic patients who are detected with PVT incidentally on imaging [35, 55].

The impact of PVT on the natural history of cirrhosis remains a matter of great debate, and the clinical benefits of PV recanalization have fully demonstrated [50]. Despite this, there is evi‐ dence that cirrhotic individuals with PVT awaiting for liver transplantation should be treated with anticoagulation therapy because complete or partial portal vein recanalization has been associated with a better 2‐year survival rate after liver transplantation (82–83%) compared to individuals with complete PVT (50%) [46]. Other situations where anticoagulation is expected to be beneficial are cirrhotic patients with acute PVT with extension to the superior mesenteric vein [35, 55]. Cirrhotic patients with well‐documented prothrombotic disorder should obvi‐ ously be considered for anticoagulation. Patients with cavernomatous transformation of the portal vein have been excluded from most trials since such patients are not expected to benefit from anticoagulation.

#### **5.2. TIPS and thrombolysis for PVT in cirrhotic patients**

in patients with lower Child‐Pugh scores [46]. Recanalization of PVT has also been reported to

There are no clear recommendations for an optimal anticoagulation regimen for the treatment of PVT in patients with cirrhosis. Monitoring of anticoagulation regimen is complex in the cirrhotic patient and, therefore, choosing between different anticoagulants (LMWH, VKA, or the new oral anticoagulants) is a difficult decision. LMWH is less practical for patients, since it necessitates daily subcutaneous injections, although it does not affect INR values and, conse‐ quently, does not interfere with MELD or Child scoring. There is, however, limited informa‐

Cirrhotic patients often have an increased volume of distribution because of fluid overload, and this makes it difficult to determine the optimal dose of LMWH. Moreover, the major route of *elimination* of the *LMWH* is through the *kidneys,* and, since many patients with cirrhosis have renal insufficiency, the half‐life of LMWH is increased. The only method of LMWH treatment monitoring validated until known is by determining the anti‐Xa activity, but this

The primary problem with VKA is determining the adequate anticoagulation in patient with cirrhosis who already has an altered abnormal prothrombin time. Most studies have targeted an INR of 2–3 [54]. Based on an empirical experience not relying on randomized studies, if the baseline INR is over 2, it is difficult to determine if a given dose of VKA ensures adequate anti‐ coagulation. It may also be difficult to determine the optimal INR target for dose adjustment. There is also a potential risk of further lowering of protein C levels with the use of VKA, and this could theoretically increase the prothrombotic imbalance of individuals with cirrhosis.

The new oral anticoagulants—thrombin inhibitors and inhibitors of activated factor X such as dabigatran and rivaroxaban—offer the advantage of oral administration, the absence of labo‐ ratory monitoring, and an antithrombin‐independent mechanism of action [54]. However, there are a few reports regarding their use in cirrhotic patients, most of them isolated cases. One of the major disadvantages of these new anticoagulants was the absence of an antidote. This problem was solved for dabigratan and also for rivaroxaban, which could be the new class of anticoagulants preferred in PVT treatment. In cirrhotic patients, it may be necessary to reverse anticoagulation during episodes of inadvertent bleeding or at the time of surgery. While the effect of VKA can be expertly reversed by fresh‐frozen plasma or prothrombin com‐ plex concentrate, there is no potent and rapidly acting antidote to reverse the effect of LMWH

Even if the anticoagulant treatment seems to be the same in patients with liver cirrhosis, it is uncertain whether it is beneficial to anticoagulate asymptomatic patients who are detected

The impact of PVT on the natural history of cirrhosis remains a matter of great debate, and the clinical benefits of PV recanalization have fully demonstrated [50]. Despite this, there is evi‐ dence that cirrhotic individuals with PVT awaiting for liver transplantation should be treated with anticoagulation therapy because complete or partial portal vein recanalization has been associated with a better 2‐year survival rate after liver transplantation (82–83%) compared to

reduce esophageal variceal pressure, improving morbidity, and mortality rates [44].

tion on the pharmacodynamic profile of LMWH in cirrhotic individuals.

method is unreliable in cirrhosis [35, 55].

164 Liver Cirrhosis - Update and Current Challenges

or the newer thrombin inhibitors.

with PVT incidentally on imaging [35, 55].

The use of transjugular intrahepatic portosystemic shunt (TIPS) has also been reported to recana‐ lize the portal vein and also prevent rethrombosis by restoring portal flow through the shunt [56– 59]. TIPS insertion and recanalization is associated with mechanical thrombectomy. However, in such cases, TIPS is expected to be technically challenging with a higher failure rate and should be attempted only in experienced centers. Systemic or *in situ* thrombolysis has been reported in cirrhotic patients with PVT [60]. In noncirrhotic patients with acute PVT, rates of recanalization have been dismal with attempted thrombolysis. There has also been a high incidence of major bleeding [60]. There are no data to support this option in this setting. TIPS promotes the dis‐ solution or decrease in PVT, splenic, or mesenteric veins, in the US population of patients with predominantly compensated liver cirrhosis of various etiologies [57, 58].

## **6. Portal vein thrombosis and liver transplantation**

Most of the studies on liver transplant patients with PVT revealed higher technical difficulties and mortality, postoperative complications, in the PVT group compared with those without PVT. The higher morbidity and mortality is multifactorial and is related to a more complex surgical procedure, increased requirement of blood transfusions, higher risk of complica‐ tions such as primary nonfunction or dysfunction, hepatic artery thrombosis, postoperative pancreatitis, sepsis, or renal failure [61, 62]. Moreover, there is a high risk of 9–42% of PVT rethrombosis [63]. Patients with Child‐Pugh class C cirrhosis, complete PVT, and alcoholic etiology of hepatic disease have a higher risk of PVT rethrombosis after liver transplant. Of a pooled total of 169 patients with partial PVT, 7 (4%) developed rethrombosis in contrast with 14 of 114 patients with complete PVT (12.3%) [63].

The main treatment indication is early anticoagulation with low‐molecular‐weight heparin unless it is contraindicated for surgical reasons, although randomized controlled trials are lacking. Moreover, there is no consensus on how long anticoagulation should be continued posttransplant. In the absence of prothrombotic state, there is no evidence that pretransplant PVT justifies long‐term anticoagulation posttransplantation. Mortality is related to the grade of preoperative PVT. The 30‐day mortality in patients undergoing liver transplantation with or without PVT has been reported as 10.5% versus 7.7%, respectively [63]. The 1‐year mortal‐ ity was also reported to be significantly higher in a systematic review according to the pres‐ ence (18.8%) or absence (15.3%) of PVT [63]. The 30‐day mortality has been reported to vary between 3.8% for grade 1 and 2 PVT, and going up to 27% for grade 4 PVT [64]. Preoperative PVT seems to influence early outcome more than long‐term results, with the maximum decrease in survival occurring in the first year, and medium‐term results with or without PVT appearing to be comparable if early mortality is excluded [65].

For many years, PVT had been considered as an absolute contraindication to liver transplanta‐ tion [66]. The first successful surgery for complete PVT was reported by Shaw et al. in 1985 [66]. Nowadays, the innovations in surgical techniques have made it possible to overcome problems due to PVT during transplantation. The stage of liver disease and the collateral circulation increase the complexity of surgical techniques and pose a challenge for the surgery, because it is very important to have an adequate portal inflow of the graft to maintain the liver function.

In order to establish if the patient has a surgical indication, preoperative assessment must evaluate the correct stage and grade of PVT based on a spiral CT scan or a magnetic resonance venogram. For surgical purposes, Yerdel et al. have classified PVT into four grades [43]:

Grade 1: Partially thrombosed portal vein, where the thrombus occupies less than 50% of the lumen.

Grade 2: More than 50% occlusion of the portal vein, including total occlusions, with or without extension into the superior mesenteric vein.

Grade 3: Complete thrombosis of both the portal vein and the proximal superior mes‐ enteric vein.

Grade 4: Complete thrombosis of the portal vein, proximal, and distal superior mesen‐ teric vein.

There are several available surgical techniques for PVT reconstruction during liver transplant surgery. All the techniques vary according to the degree and the anatomical spread of the PVT [65].


is the persistence of portal hypertension associated with an increased risk of bleeding from gastroesophageal varices, which may occur in up to 50% of such cases [65].

Rodriguez‐Castro, in a systematic review, reported that among 49 patients with portacaval hemitransposition, 20% had episodes of variceal bleeding, 58% had persistent ascites, and 26% presented with renal dysfunction after liver transplantation [66]. An alternative to porta‐ caval hemitransposition is renoportal transposition, where the recipient portal vein is anasto‐ mosed to the left renal vein [65].

## **7. Conclusion**

PVT seems to influence early outcome more than long‐term results, with the maximum decrease in survival occurring in the first year, and medium‐term results with or without PVT

For many years, PVT had been considered as an absolute contraindication to liver transplanta‐ tion [66]. The first successful surgery for complete PVT was reported by Shaw et al. in 1985 [66]. Nowadays, the innovations in surgical techniques have made it possible to overcome problems due to PVT during transplantation. The stage of liver disease and the collateral circulation increase the complexity of surgical techniques and pose a challenge for the surgery, because it is very important to have an adequate portal inflow of the graft to maintain the liver function. In order to establish if the patient has a surgical indication, preoperative assessment must evaluate the correct stage and grade of PVT based on a spiral CT scan or a magnetic resonance venogram. For surgical purposes, Yerdel et al. have classified PVT into four grades [43]:

Grade 1: Partially thrombosed portal vein, where the thrombus occupies less than 50%

Grade 2: More than 50% occlusion of the portal vein, including total occlusions, with or

Grade 3: Complete thrombosis of both the portal vein and the proximal superior mes‐

Grade 4: Complete thrombosis of the portal vein, proximal, and distal superior mesen‐

There are several available surgical techniques for PVT reconstruction during liver transplant surgery. All the techniques vary according to the degree and the anatomical spread of the

**1.** Portal vein thrombectomy (for Yerdel grade 1 and 2 PVT) and direct anastomosis of donor and recipient portal vein. A recent study suggested that 75–90% of transplants performed in patients with PVT, and the thrombosis could be managed only by thrombectomy [61]. After completion of the thrombectomy, adequate flow in the recipient portal vein or supe‐ rior mesenteric vein must be confirmed by releasing the vascular clamp before proceeding

**2.** In cases of Yerdel grade 2 or grade 3 occlusions, an anastomosis may be required between the graft portal vein and the recipient superior mesenteric vein. The anastomosis uses a section of the donor iliac vein as a graft. The presence of a large collateral vein may provide an alterna‐ tive portal inflow, although extraanatomical vessels are more fragile and prone to thrombosis.

**3.** Arterialization of the portal vein: anastomosis of the graft portal vein to the recipient arte‐

**4.** Portacaval hemitransposition: an anastomosis of the graft portal vein is made to the supra‐ renal recipient inferior vena cava. The disadvantage of classic portacaval hemitransposition

appearing to be comparable if early mortality is excluded [65].

without extension into the superior mesenteric vein.

of the lumen.

166 Liver Cirrhosis - Update and Current Challenges

enteric vein.

teric vein.

with the anastomosis.

rial inflow.

PVT [65].

PVT is a highly heterogeneous entity regarding its underlying risk factors and the association with liver cirrhosis independently of the disease stage. Although significant advances have been made in the field of PVT associated with liver cirrhosis in recent years, many important questions still remain unanswered. Most critical issue that requires future studies is the influ‐ ence of PVT on natural course of liver cirrhosis according to the new classification, and it has to establish the risk‐benefit ratio of anticoagulant treatment in different groups of patients, including the role of the new oral anticoagulant.

## **Abbreviations**


## **Author details**

Anca Trifan1,2\*, Carol Stanciu2 and Irina Girleanu1,2

\*Address all correspondence to: ancatrifan@yahoo.com

1 "Grigore T. Popa" University of Medicine and Pharmacy, Iaşi, Romania

2 Institute of Gastroenterology and Hepatology, Iaşi, Romania

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## **Hemodynamic Optimization Strategies in Anesthesia Care for Liver Transplantation**

Alexander A. Vitin, Dana Tomescu and Leonard Azamfirei

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.68416

#### **Abstract**

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In this chapter, aspects of hemodynamic regulation in the end-stage liver disease (ESLD) patient, factors, contributing to the hemodynamic profile, coagulation-related problems, blood products transfusion tactics and problems, and hemodynamic optimization strategies during different stages of liver transplantation procedure—specifically what, when, and how to correct, with special attention to vasoactive agents use, will be discussed.

**Keywords:** liver transplantation, anesthesia, hemodynamic optimization, vasoactive agents, transfusion management

## **1. Introduction**

Inseparable part of liver transplantation procedure, anesthesia, and perioperative care for the liver transplant recipient has made a remarkable progress during last decades, becoming a clinical specialty with well-defined goals, requirements, and approaches. Today, with a rapid expansion of liver transplant programs worldwide and growing numbers of liver transplant procedures performed, many aspects of anesthesia care, complicated and risky in the relatively recent past, have become routine and safe. And yet some problems remain unresolved, still posing a challenge for anesthesiologist in the field. Despite incessant and plentiful research, investigating literally every imaginable aspect and angle of the anesthesia and perioperative care for liver transplant recipient, and myriad of publications coming out every year, no consensus has been reached so far as for the best choice of anesthesia induction and maintenance, intraoperative hemodynamics management, fluid and blood products transfusion, patient's monitoring, and more. One of the most important time- and effort-consuming

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aspects of anesthesia care, expanding well beyond proper intraoperative time onto the first long hours of ICU stay, is patient's hemodynamic management. Its multicomponent nature, sometimes a very short time resolution in the decision-making process, poorly predictable course of patients reactions, overall instability with rapid, oftentimes detrimental and lifethreatening changes makes management of patient's hemodynamics an extremely challenging and complicating task.

## **2. Factors contributing to hemodynamic profile of the ESLD patient**

Typical hemodynamic pattern of end-stage liver disease (ESLD) patients includes high cardiac output (CO)/cardiac index (CI)—hyperdynamic circulation pattern, with normal-to-low mean blood pressure, variable central venous pressure (CVP), along with general arterial and venous vasodilatation due to substantially decreased systemic vascular resistance (SVR). The hyperdynamic circulation is thought to be a compensatory change, induced by splanchnic and peripheral vasodilatation, reducing the effective blood volume. This, and also decreased perfusion pressures, leads to a diminished renal blood flow in cirrhotic patients, which in turn stimulates the renin-angiotensin-aldosterone system and antidiuretic hormone production, resulting in renal artery vasoconstriction, sodium retention, and volume expansion. Worsening liver disease results in progressive vasodilatation, making the hyperdynamic circulation and renal artery vasoconstriction more pronounced [1].

Arterial vascular tone is regulated by complex interactions of different vasoactive substances, namely catecholamines and NO complex. In ESLD patients, sensitivity of β-adrenoreceptors is relatively decreased, causing cardiovascular response to endogenic catecholamines substantially attenuated [2]. Plasma-free norepinephrine and epinephrine levels are significantly higher. Fraction of epinephrine, contributing to total catecholamines, increased up to 50% (normal: about 17%). Dopamine concentration is unchanged [3].

In recent years, nitric oxide (NO) has been recognized as the most important vasodilator of the splanchnic and systemic circulation. Cytokines, especially TNF-α, are considered to be NO inducers. Endothelial NO synthase has been found as a main source of the vascular NO overproduction in the splanchnic arterial circulation [4–6].

Augmented intrahepatic vascular resistance due to sinusoidal constriction is considered the major cause of portal hypertension. Hepatic stellate cells (HSC) provide a basis for control of sinusoidal vascular tone and an arrangement for sinusoidal constriction and hepatic blood flow (HBF) reduction. The dynamic part of hepatic resistance is caused by active contraction/ relaxation of HSC. Portocaval collaterals divert up to 80% of blood flow away from liver [7].

Cardiomyopathy plays a substantial role in the hemodynamic profile and cardiovascular compensation mechanisms in a cirrhotic patient. The characteristic features of cirrhotic cardiomyopathy include an attenuated systolic or diastolic response to stress stimuli, structural and histological changes of myocardium, electrophysiological abnormalities, and increased concentrations of serum markers, suggestive of cardiac stress. The impaired cardiovascular responsiveness in cirrhosis is likely related to a combination of factors that include among other reasons, β-adrenergic receptor dysfunction and reduction of β-adrenergic receptor density in cirrhotic patients. Recently, it has been found that, in cirrhotic patients, the control of vascular tone by Ca++ and K+ channels is altered. The calcium channel dysfunction, leading to decreased cardiomyocyte contractility, was demonstrated in an animal model study [2, 8–10].

aspects of anesthesia care, expanding well beyond proper intraoperative time onto the first long hours of ICU stay, is patient's hemodynamic management. Its multicomponent nature, sometimes a very short time resolution in the decision-making process, poorly predictable course of patients reactions, overall instability with rapid, oftentimes detrimental and lifethreatening changes makes management of patient's hemodynamics an extremely challeng-

**2. Factors contributing to hemodynamic profile of the ESLD patient**

culation and renal artery vasoconstriction more pronounced [1].

(normal: about 17%). Dopamine concentration is unchanged [3].

overproduction in the splanchnic arterial circulation [4–6].

Typical hemodynamic pattern of end-stage liver disease (ESLD) patients includes high cardiac output (CO)/cardiac index (CI)—hyperdynamic circulation pattern, with normal-to-low mean blood pressure, variable central venous pressure (CVP), along with general arterial and venous vasodilatation due to substantially decreased systemic vascular resistance (SVR). The hyperdynamic circulation is thought to be a compensatory change, induced by splanchnic and peripheral vasodilatation, reducing the effective blood volume. This, and also decreased perfusion pressures, leads to a diminished renal blood flow in cirrhotic patients, which in turn stimulates the renin-angiotensin-aldosterone system and antidiuretic hormone production, resulting in renal artery vasoconstriction, sodium retention, and volume expansion. Worsening liver disease results in progressive vasodilatation, making the hyperdynamic cir-

Arterial vascular tone is regulated by complex interactions of different vasoactive substances, namely catecholamines and NO complex. In ESLD patients, sensitivity of β-adrenoreceptors is relatively decreased, causing cardiovascular response to endogenic catecholamines substantially attenuated [2]. Plasma-free norepinephrine and epinephrine levels are significantly higher. Fraction of epinephrine, contributing to total catecholamines, increased up to 50%

In recent years, nitric oxide (NO) has been recognized as the most important vasodilator of the splanchnic and systemic circulation. Cytokines, especially TNF-α, are considered to be NO inducers. Endothelial NO synthase has been found as a main source of the vascular NO

Augmented intrahepatic vascular resistance due to sinusoidal constriction is considered the major cause of portal hypertension. Hepatic stellate cells (HSC) provide a basis for control of sinusoidal vascular tone and an arrangement for sinusoidal constriction and hepatic blood flow (HBF) reduction. The dynamic part of hepatic resistance is caused by active contraction/ relaxation of HSC. Portocaval collaterals divert up to 80% of blood flow away from liver [7]. Cardiomyopathy plays a substantial role in the hemodynamic profile and cardiovascular compensation mechanisms in a cirrhotic patient. The characteristic features of cirrhotic cardiomyopathy include an attenuated systolic or diastolic response to stress stimuli, structural and histological changes of myocardium, electrophysiological abnormalities, and increased concentrations of serum markers, suggestive of cardiac stress. The impaired cardiovascular

ing and complicating task.

174 Liver Cirrhosis - Update and Current Challenges

Albeit commonly overlooked, many of these pathogenic mechanisms resulted in RV overload with gradual dilatation and impaired contractile function, leading to elevated mean pulmonary artery pressure (MPAP). Despite characteristically increased resting CO, ventricular contractile response is, actually, substantially attenuated. Cardiomyopathy may contribute to portopulmonary hypertension.

However, overt severe Congestive Heart Failure (CHF) is rare. Increased intra-abdominal pressure (ascites) contributes to both portal and PA hypertension [11].

Pulmonary vascular changes in cirrhosis are often quite substantial. They include portopulmonary hypertension (POPH) syndrome, which entails development of pulmonary hypertension in a cirrhotic patient with portal hypertension, and also hepatopulmonary syndrome, which is, essentially, increased pathological shunting and V/Q mismatch due to development of the arteriovenous malformations in the lung, resulting in hypoxemia. Portopulmonary hypertension is less prevalent than hepatopulmonary syndrome with an estimated prevalence of about 5%.

POPH is best defined as pulmonary arterial hypertension (PAH). Necessary conditions include presence of portal hypertension and absence of other secondary causes of PH, such as valvular disease, chronic thromboembolism, collagen vascular disease, or exposure to certain drugs or toxins. Current diagnostic criteria include the presence of portal hypertension (either inferred from the presence of splenomegaly, thrombocytopenia, portosystemic shunts, esophageal varices or portal vein abnormalities, or confirmed by hemodynamic measurements), but not necessarily the presence of cirrhosis; and hemodynamic parameters, specifically MPAP >25 mmHg at rest, >30 mmHg with exercise/stress, PCWP<15 mmHg, PVR>120 dynes/s/cm5 , and transpulmonary gradient >10 mmHg [12–16].

A most common suggested mechanism for POPH maintains that the increased blood flow (high cardiac output) in chronic liver disease causes pulmonary vascular wall shear stress, which can trigger the dysregulation of numerous vasoactive substances. The presence of portosystemic shunts may lead to the shunting of vasoactive substances from the splanchnic to the pulmonary circulation, causing deleterious effects in the pulmonary vasculature [17, 18].

The severity of hepatopulmonary syndrome is classified according to the degree of arterial hypoxemia, specifically mild (PaO<sup>2</sup> of 60–80 mm Hg), moderate (50–60 mm Hg), and severe (<50 mm Hg). Intrapulmonary vascular dilation leads to increased V/Q mismatching plus a degree of intrapulmonary shunting of deoxygenated, mixed venous blood. Both these mechanisms cause systemic arterial hypoxemia [19–22]. Impairment of hypoxic pulmonary vasoconstriction means that gravitational effects on pulmonary blood flow are poorly tolerated. Many authors observed at least partial resolution of the hepatopulmonary syndrome following liver transplant [23, 24].

A common complication of liver disease and portal hypertension is the accumulation of ascites, whereas the presence of significant ascites sometimes compromises respiratory function mostly by creating the restrictive pattern of lung mechanics, a more significant complication is the presence of fluid in the thorax, termed hepatic hydrothorax. Hydrothorax may exacerbate the restriction pattern even further, sometimes leading to atelectasis development, with associated V/Q mismatch and intrapulmonary shunt that adds to already pre-existing hypoxemia, and also to increase of PA pressure.

## **3. Hemodynamic changes during orthotopic liver transplant surgery**

#### **3.1. Anesthesia-related factors**

From the days, when the first successful liver transplantation surgery was performed to this day, anesthesiologists all over the world, despite plenty of ongoing and already published research works in the field, have not yet arrived at a consensus, let alone adopted unified guidelines or protocols of the anesthetic technique for liver transplantation surgery.

Since anesthesia-related systemic hemodynamic changes are well described elsewhere, the only aspect of these effects, specifically an impact of anesthesia factors and adjuvant drugs on hepatic blood flow (HBF) and oxygen delivery, needs to be discussed here. The degree to which the hemodynamic changes, caused by anesthetic agents, take place in patients with advanced liver disease, depends on the patient's particular hemodynamics, volume status and compensation pattern, nature of the surgical procedure, and many other factors. Patients with cirrhosis may be more sensitive to hepatic hypoperfusion, and may be more susceptible to liver injury (such as administration of a hepatotoxic drug, rapid blood loss).

It has been shown that practically all general anesthesia techniques, regardless of drug combinations, in the absence of surgical stimulation, reduce the HBF by about 30%. It appears that the systemic arterial blood pressure is a main determinant of hepatic blood as the hepatic artery exhibits almost no autoregulatory capacity [25]. Commonly used IV induction anesthetic agent, etomidate, along with maintaining well the systemic hemodynamic parameters at baseline levels, only moderately reduces the HBF in a dose-dependent manner, and causes the increase in hepatic arterial resistance (by 40%).

Propofol, however, has shown an ability to preserve baseline levels of the HBF, as long as systemic hemodynamic changes were insignificant [26].

Use of isoflurane and sevoflurane for anesthesia maintenance, albeit being associated with minimal-to-moderate global reduction of HBF, has not been found to be associated with any significant influence on arterial hepatic blood flow or oxygen transport and extraction ratio in the liver. Short-action opioids, fentanyl in particular, has shown no discernible effect on HBF [27–31].

Other potential perioperative causes of a reduction of HBF include mechanical ventilation, positive end-expiratory pressure, systemic hypotension due to hypovolemia, hemorrhage, etc., and hypoxemia. Beta (β)-blockers, alpha (α)-agonists, H<sup>2</sup> blockers, hypocapnia, alkalosis, and hypoglycemia have been found to be associated with moderate HBF reduction. Dopamine (3 mcg/kg/min), epinephrine (from 0.01 mcg/kg/min), hypercapnia, acidosis, and hypoxemia, however, are among the factors that actually can increase HBF [32, 33].

With a substantial variety of anesthetic techniques currently in use and with full awareness of ESLD hemodynamic profile specifics and patient-to-patient variety in that respect, it appears to be reasonable to set hemodynamic goals (i.e., hemodynamic parameters to possibly maintain) for anesthesia care for liver transplant. These should include mean arterial pressure (MAP) around 75–85 mmHg, Heart rate (HR): <100/min, Central venous pressure (CVP): <20 mmHg, Mean Pulmonary Artery Pressure (MPAP): <25 mmHg, CO/CI: >4 L/min/>2 L/min m2 , Systemic Vascular Resistance (SVR): >500 dynes/s/cm−5, and mixed venous SvO2: >75%.

#### **3.2. Surgery-related factors**

A common complication of liver disease and portal hypertension is the accumulation of ascites, whereas the presence of significant ascites sometimes compromises respiratory function mostly by creating the restrictive pattern of lung mechanics, a more significant complication is the presence of fluid in the thorax, termed hepatic hydrothorax. Hydrothorax may exacerbate the restriction pattern even further, sometimes leading to atelectasis development, with associated V/Q mismatch and intrapulmonary shunt that adds to already pre-existing hypoxemia,

**3. Hemodynamic changes during orthotopic liver transplant surgery**

guidelines or protocols of the anesthetic technique for liver transplantation surgery.

From the days, when the first successful liver transplantation surgery was performed to this day, anesthesiologists all over the world, despite plenty of ongoing and already published research works in the field, have not yet arrived at a consensus, let alone adopted unified

Since anesthesia-related systemic hemodynamic changes are well described elsewhere, the only aspect of these effects, specifically an impact of anesthesia factors and adjuvant drugs on hepatic blood flow (HBF) and oxygen delivery, needs to be discussed here. The degree to which the hemodynamic changes, caused by anesthetic agents, take place in patients with advanced liver disease, depends on the patient's particular hemodynamics, volume status and compensation pattern, nature of the surgical procedure, and many other factors. Patients with cirrhosis may be more sensitive to hepatic hypoperfusion, and may be more susceptible to liver injury (such as administration of a hepatotoxic drug,

It has been shown that practically all general anesthesia techniques, regardless of drug combinations, in the absence of surgical stimulation, reduce the HBF by about 30%. It appears that the systemic arterial blood pressure is a main determinant of hepatic blood as the hepatic artery exhibits almost no autoregulatory capacity [25]. Commonly used IV induction anesthetic agent, etomidate, along with maintaining well the systemic hemodynamic parameters at baseline levels, only moderately reduces the HBF in a dose-dependent manner, and causes

Propofol, however, has shown an ability to preserve baseline levels of the HBF, as long as

Use of isoflurane and sevoflurane for anesthesia maintenance, albeit being associated with minimal-to-moderate global reduction of HBF, has not been found to be associated with any significant influence on arterial hepatic blood flow or oxygen transport and extraction ratio in the liver. Short-action opioids, fentanyl in particular, has shown no discernible effect on HBF [27–31].

Other potential perioperative causes of a reduction of HBF include mechanical ventilation, positive end-expiratory pressure, systemic hypotension due to hypovolemia, hemorrhage,

losis, and hypoglycemia have been found to be associated with moderate HBF reduction.

blockers, hypocapnia, alka-

and also to increase of PA pressure.

176 Liver Cirrhosis - Update and Current Challenges

**3.1. Anesthesia-related factors**

rapid blood loss).

the increase in hepatic arterial resistance (by 40%).

systemic hemodynamic changes were insignificant [26].

etc., and hypoxemia. Beta (β)-blockers, alpha (α)-agonists, H<sup>2</sup>

The course of liver transplantation surgery includes four stages. During preanhepatic, or dissection phase, the diseased liver is being dissected and prepared for removal. Portal vein clamping, followed by hepatic artery and IVC clamp, heralds the start of anhepatic phase, during which part of the diseased liver is being removed from the body and being replaced by the donor's organ. Vascular anastomoses are being performed, followed by organ reperfusion phase, the shortest one with most significant hemodynamic impact. After venous blood flow restoration in the transplanted organ, postreperfusion phase include common hepatic arterial anastomosis, cholecyctectomy, and bile duct reconstruction.

During preanhepatic (dissection) phase, laparotomy, often followed by ascites evacuation, causes drop of intra-abdominal pressure, with rapid splanchnic volume increase (i.e., mesenteric blood pooling) ensued. Ongoing blood loss at this stage may be very substantial, due to abundance of venous collaterals in cases with longstanding portal hypertension, and also in cases of re-do transplants, or cases with significant adhesions after previous surgeries. Decrease of venous return, ongoing blood loss, fluid shift, and developing acidosis further contribute to CO/CI and mean arterial blood pressure (MABP) decrease.

Portal cross clamp, which portends the anhepatic stage start, causes variable (20–30% of baseline) degree of venous return decrease. However, in cases of well-developed portocaval collaterals (longstanding portal hypertension), this loss of preclamp venous return may be less significant, around 15–20%, and generally well tolerated. IVC complete cross-clamp oftentimes leads to a more substantial and poorly tolerated (approximately 50%) decrease of venous return, whereas IVC partial clamp causes variable, about 25–50%, decrease of venous return [34, 35]. ESLD patients have very limited ability, if any, to compensate for the rapid decrease in venous return with systemic vasoconstriction due to inherent low SVR. Venovenous bypass (VVB) may present a possible solution to compensate for decreased venous return. Hemodynamic instability following test clamping of IVC is the most common indication for initiating VVB [36]. It has been suggested [37] that hypotension (30% decrease in MAP) or a decrease in cardiac index (50%) during a 5-min test period of hepatic vascular occlusion can be used to identify the group of patients who require VVB. Other indications of the VVB include presence of pulmonary hypertension, impaired ventricular function from previous myocardial infarction, ischemic heart disease, and cardiomyopathy [38]. In patients with pulmonary hypertension, excessive fluid loading to compensate for hemodynamic changes during anhepatic phase may result in acute right ventricular dysfunction. Patients with cardiomyopathy have impaired left ventricular function, and consequently a limited ability to generate adequate CO in the face of the increase in SVR during the anhepatic phase. These patients, too, may benefit from ameliorative effect of the preload associated with VVB. Some centers use VVB in patients with impaired renal function (i.e., hepato-renal syndrome) in order to prevent further kidneys damage during the anhepatic phase and to reduce the need for postoperative renal support. Among the advantages of VVB, some researchers listed the ability to reduce hemodynamic instability during anhepatic phase. It is useful in patients with pulmonary hypertension and cardiomyopathy who tolerate anhepatic period poorly. VVB has been shown to maintain intraoperative renal function [39, 40]. It also helps to maintain cerebral perfusion pressure in patients with acute fulminant failure by avoiding rapid swings in blood pressure, and, at least theoretically, may reduce blood loss [41]. However, VVB is not devoid of certain disadvantages. It does not guarantee normal perfusion of abdominal organs and lower limbs, since venous return never could be maintained at prebypass levels. The pump could only provide up to 2 L/min output (most commonly, only 1.5–1.8 L/min), which is, however comparable with low-to-normal levels of CO, cannot ensure the normal or even near-normal level of preload [42]. There is neither evidence of general(patient- and organ survival) outcome improvement, nor that it's use reduces or prevents the occurrence of postoperative renal failure [43]. VVB may exacerbate coagulation problems and cause excessive bleeding by inducing hemolysis, platelet depletion.

Graft reperfusion causes major hemodynamic changes along with possible substantial endorgan injury. These may include direct myocardial injury, resulting in tachy/bradyarrhytmias and cardiac arrest, profound vasoplegia, acute interstitial pulmonary oedema, leading to further RV overload/acute insufficiency, raise of pulmonary artery pressure (PAP) and CVP. Blood loss, hemodilution, hypovolemia, temperature drop, and rapidly developing lactic acidosis contribute to decreased sensitivity to catecholamines and efficiency of vasopressors. All these factors lead to rapid drop of SVR, resulting in a decrease of MABP with or without CO/CI decrease. Postreperfusion syndrome (PRS) was defined as a more than 30% decrease of MABP from that in the anhepatic stage, longer than for 1 min during the first 5 min after reperfusion of the liver graft [44–46].

In the postreperfusion period, the major factors of hemodynamic instability include ongoing blood loss, exacerbated by consumption coagulopathy in the face of very limited or almost nonexisting production of coagulation factors by the liver graft. Hypocalcemia, resulting from the effects of citrate-containing blood conservation solution, associated with transfusion of large amounts of RBC, exacerbates reduction of myocardial contractility caused by recent reperfusion. Acidemia, mostly due to lactic acidosis, substantially decreases efficacy of vaso-active agents.

### **4. Blood loss and coagulopathy management**

#### **4.1. Blood loss estimation and prediction factors**

Blood loss during OLT is a well-known major factor of morbidity/mortality and overall hemodynamic instability, varying from just hundreds of ml up to dozens of liters. Predisposing factors for major blood loss may include pre-existing + ongoing consumption and dilution coagulopathy (i.e., preoperative prothrombin time (PT), International normalized ratio (INR) and platelets numbers, factor V levels, etc.), MELD score >25, severe portal hypertension, "hostile abdomen" —postlaparotomy, re-do orthotopic liver transplant (OLT), long ischemia times, aged/marginal quality donor organ, donor-recipient organ size discrepancy, long, traumatic liver dissection, and surgeon-related factors.

Substantial number of studies reported no statistically significant correlations between blood loss and most of aforementioned parameters, particularly in respect to MELD score [47] and INR [48].

To date, blood loss and associated massive blood transfusion during OLTs remain difficult to predict [49]. Intraoperative blood salvage technique provides at least some way for blood loss estimation, with considerable approximation. Correspondent guidelines, based on calculations of hematocrit during blood loss (25–30%) and that of returned red blood cells by Cell-Saver (approximately 55–65% depending on Cell-Saver model), have been developed. Authors calculated estimated blood loss by multiplying the total volume of Cell-Saver returned RBCs by factor 3.4–4.0 [50, 51].

#### **4.2. Coagulopathy: mechanisms and assessment**

with cardiomyopathy have impaired left ventricular function, and consequently a limited ability to generate adequate CO in the face of the increase in SVR during the anhepatic phase. These patients, too, may benefit from ameliorative effect of the preload associated with VVB. Some centers use VVB in patients with impaired renal function (i.e., hepato-renal syndrome) in order to prevent further kidneys damage during the anhepatic phase and to reduce the need for postoperative renal support. Among the advantages of VVB, some researchers listed the ability to reduce hemodynamic instability during anhepatic phase. It is useful in patients with pulmonary hypertension and cardiomyopathy who tolerate anhepatic period poorly. VVB has been shown to maintain intraoperative renal function [39, 40]. It also helps to maintain cerebral perfusion pressure in patients with acute fulminant failure by avoiding rapid swings in blood pressure, and, at least theoretically, may reduce blood loss [41]. However, VVB is not devoid of certain disadvantages. It does not guarantee normal perfusion of abdominal organs and lower limbs, since venous return never could be maintained at prebypass levels. The pump could only provide up to 2 L/min output (most commonly, only 1.5–1.8 L/min), which is, however comparable with low-to-normal levels of CO, cannot ensure the normal or even near-normal level of preload [42]. There is neither evidence of general(patient- and organ survival) outcome improvement, nor that it's use reduces or prevents the occurrence of postoperative renal failure [43]. VVB may exacerbate coagulation problems and cause exces-

Graft reperfusion causes major hemodynamic changes along with possible substantial endorgan injury. These may include direct myocardial injury, resulting in tachy/bradyarrhytmias and cardiac arrest, profound vasoplegia, acute interstitial pulmonary oedema, leading to further RV overload/acute insufficiency, raise of pulmonary artery pressure (PAP) and CVP. Blood loss, hemodilution, hypovolemia, temperature drop, and rapidly developing lactic acidosis contribute to decreased sensitivity to catecholamines and efficiency of vasopressors. All these factors lead to rapid drop of SVR, resulting in a decrease of MABP with or without CO/CI decrease. Postreperfusion syndrome (PRS) was defined as a more than 30% decrease of MABP from that in the anhepatic stage, longer than for 1 min during the first 5 min after

In the postreperfusion period, the major factors of hemodynamic instability include ongoing blood loss, exacerbated by consumption coagulopathy in the face of very limited or almost nonexisting production of coagulation factors by the liver graft. Hypocalcemia, resulting from the effects of citrate-containing blood conservation solution, associated with transfusion of large amounts of RBC, exacerbates reduction of myocardial contractility caused by recent reperfusion. Acidemia, mostly due to lactic acidosis, substantially decreases efficacy of vaso-active agents.

Blood loss during OLT is a well-known major factor of morbidity/mortality and overall hemodynamic instability, varying from just hundreds of ml up to dozens of liters. Predisposing

sive bleeding by inducing hemolysis, platelet depletion.

**4. Blood loss and coagulopathy management**

**4.1. Blood loss estimation and prediction factors**

reperfusion of the liver graft [44–46].

178 Liver Cirrhosis - Update and Current Challenges

Of all the aforementioned factors, coagulopathy presents by far the most important and potentially most correctable problem, contributing to overall blood loss and, therefore, hemodynamic instability. Bleeding during OLT is multifactorial due both to surgical trauma and to coagulation defects. Coagulation defect in ESLD patients include impaired coagulation factor synthesis, dysfunction of coagulation factors, increased consumption, and fibrinolysis. Commonly, the levels of factor VII and protein C decrease first, followed by reductions in factors V, II, and X levels [52]. Platelet function is also affected by liver disease, and thrombocytopenia is common. Predisposing factors include hypersplenism secondary to portal hypertension, decreased thrombopoietin synthesis, immune complex-associated platelet clearance, and reticuloendothelial destruction [53].

During the dissection phase of the transplant, excessive bleeding is related to the technical difficulties during the liver dissection, and presence of portal hypertension, with large dilated collaterals [54].

During the anhepatic phase, coagulation factor synthesis is practically nonexistent, and ongoing factors consumption exacerbate the bleeding.

Right after graft reperfusion, profound coagulation abnormalities are very common. Factors that contribute to excessive bleeding in postreperfusion period include platelet entrapment in the sinusoids of the donor liver, a global reduction of all coagulation factors (mainly due to increased consumption, and partially due to hemodilution), and decreased level of antifibrinolytic factors [55, 56].

Method of thromboelastography (TEG) allows a rapid graphic assessment of the functional clotting status and degree of fibrinolysis. In various studies, the amount of RBCs and fresh frozen plasma (FFP) usage has been significantly reduced when TEG monitoring that was compared to the conventional "clinician-directed" transfusion management [57, 58]. Although the usefulness of TEG in complex coagulation defects has been questioned [59], recent studies have shown, that the use of TEG can reduce the number of blood products transfused [58].

#### **4.3. Hemotransfusion requirements and strategies**

Blood transfusion therapy remains a critical component of anesthetic management and perioperative care in OLT. Multiple studies have shown a large variability in the use of blood products among different centers and among individual anesthesiologists within the same center [60]. The decision of when to transfuse RBCs, remains debatable. Some authors recommend keeping the hematocrit between 30 and 35%; others think it advisable and acceptable to maintain it between 26 and 28% [61, 62]. The modern trends have shown a substantial change from a transfusion of 10–20 units to 0–5.

The standard indication for fresh frozen plasma (FFP) infusion is coagulation defect treatment. FFP is expected to improve complex coagulation disorders in case of severe bleeding as it contains all coagulation factors and inhibitors. However, Freeman et al. [62] maintain that FFP administration is not essential during OLT, and that platelets and fibrinogen concentrates may be given when platelet count and fibrinogen level fall below 50,000 mm<sup>3</sup> and 1 g/L. In some centers, the trigger point is INR lower than two, which remains controversial. It has been shown that TE-guided coagulation defect management generally lowers the FFP amount. There is currently no consensus on the volume of FFP or rate of infusion required; in common practice, 10–15 mL/kg are usually administered. Because of the lack of universally accepted guidelines, the amount and timing of FFP administration during OLT are still guided by experienced clinical judgment, local practices, and coagulation tests (including TEG).

Although there is no consensus regarding the appropriate threshold value [64], platelet concentrates are frequently administered during OLT to address "oozing" on the operation field that likely could be attributed to the lack clot formation ability. Inter-center indications for platelet transfusion vary, but it seems that the current trend is to administer platelet transfusions pretty much regardless of the absolute PLT count.

It has been shown in many studies that the massive use of blood products during OLT is associated with increase in morbidity and mortality [65, 66]. It has been demonstrated that the intraoperative transfusion of red blood cells (RBCs) is associated with increase of postoperative mortality, specifically reduce survival rates at six months (63.8 vs. 83.3%) and at 5 years (34.5 vs. 49.2%), thus became a major prediction factor of mortality [59, 67, 68]. Higher intraoperative RBC transfusion requirements are associated with higher reintervention rates. Patients, who undergo reintervention, have three times higher mortality than those who do not have reinterventions [69, 70]. All blood products (RBCs, fresh frozen plasma (FFP), and platelets) have been shown to be negatively associated with graft survival at 1 and 5 years by univariate analysis [71]. Recent studies show that FFP and platelet transfusions are linked to the development of ALI/ARDS [71]. Pereboom et al. demonstrated, that platelet transfusion during OLTx is associated with increased postoperative mortality due to transfusion-related acute lung injury (TRALI)/ARDS [63]. Intraoperative platelet transfusions have been identified as a strong independent risk factor for patient survival after OLT in addition to RBCs [72]. Studies have demonstrated that platelets are involved in the pathogenesis of reperfusion injury of the liver graft by inducing endothelial cell apoptosis. This effect is independent of ischemia-related endothelial cell injury [73].

#### **4.4. Ways of blood loss reduction**

frozen plasma (FFP) usage has been significantly reduced when TEG monitoring that was compared to the conventional "clinician-directed" transfusion management [57, 58]. Although the usefulness of TEG in complex coagulation defects has been questioned [59], recent studies have shown, that the use of TEG can reduce the number of blood products transfused [58].

Blood transfusion therapy remains a critical component of anesthetic management and perioperative care in OLT. Multiple studies have shown a large variability in the use of blood products among different centers and among individual anesthesiologists within the same center [60]. The decision of when to transfuse RBCs, remains debatable. Some authors recommend keeping the hematocrit between 30 and 35%; others think it advisable and acceptable to maintain it between 26 and 28% [61, 62]. The modern trends have shown a substantial change

The standard indication for fresh frozen plasma (FFP) infusion is coagulation defect treatment. FFP is expected to improve complex coagulation disorders in case of severe bleeding as it contains all coagulation factors and inhibitors. However, Freeman et al. [62] maintain that FFP administration is not essential during OLT, and that platelets and fibrinogen concentrates may be given when platelet count and fibrinogen level fall below 50,000 mm<sup>3</sup>

1 g/L. In some centers, the trigger point is INR lower than two, which remains controversial. It has been shown that TE-guided coagulation defect management generally lowers the FFP amount. There is currently no consensus on the volume of FFP or rate of infusion required; in common practice, 10–15 mL/kg are usually administered. Because of the lack of universally accepted guidelines, the amount and timing of FFP administration during OLT are still guided by experienced clinical judgment, local practices, and coagulation tests (including TEG).

Although there is no consensus regarding the appropriate threshold value [64], platelet concentrates are frequently administered during OLT to address "oozing" on the operation field that likely could be attributed to the lack clot formation ability. Inter-center indications for platelet transfusion vary, but it seems that the current trend is to administer platelet transfu-

It has been shown in many studies that the massive use of blood products during OLT is associated with increase in morbidity and mortality [65, 66]. It has been demonstrated that the intraoperative transfusion of red blood cells (RBCs) is associated with increase of postoperative mortality, specifically reduce survival rates at six months (63.8 vs. 83.3%) and at 5 years (34.5 vs. 49.2%), thus became a major prediction factor of mortality [59, 67, 68]. Higher intraoperative RBC transfusion requirements are associated with higher reintervention rates. Patients, who undergo reintervention, have three times higher mortality than those who do not have reinterventions [69, 70]. All blood products (RBCs, fresh frozen plasma (FFP), and platelets) have been shown to be negatively associated with graft survival at 1 and 5 years by univariate analysis [71]. Recent studies show that FFP and platelet transfusions are linked to the development of ALI/ARDS [71]. Pereboom et al. demonstrated, that platelet transfusion during OLTx is associated with increased postoperative mortality due to transfusion-related

and

**4.3. Hemotransfusion requirements and strategies**

sions pretty much regardless of the absolute PLT count.

from a transfusion of 10–20 units to 0–5.

180 Liver Cirrhosis - Update and Current Challenges

Ways of blood loss reduction include surgical techniques such as Piggy-back technique with IVC preservation—partial Inferior vena cava (IVC) clamp, and anesthesia management options, such as maintaining the low CVP, minimal hemodilution with limited crystalloids infusion, and vasoactive agents use. Discussion of surgical techniques is beyond the scope of this review; however, anesthetic management options and techniques, intended to reduce blood loss during OLT are in the focus of discussion.

#### *4.4.1. Fluid management and "low CVP" paradigm*

Balanced fluid administration and maintaining relative hypovolemia have been advocated by many authors. A low CVP has been recommended to minimize blood loss during dissection stage of the liver transplantation. Massicotte et al. [74, 75] reported that maintaining a low CVP before the anhepatic phase was an efficient technique to decrease blood loss and transfusion rate. However, low CVP is associated with increased risk of complications, such as tissue hypoperfusion, development of lactic acidosis and renal failure, and also significant morbidity and mortality [76]. As it has been observed, increase in serum creatinine level, indications for dialysis, and 30-days mortality were higher in group of liver transplant patients, where CVP has been kept at low levels (around 3–5 smH<sup>2</sup> O), in order to avoid venous congestion of the graft. However, no supportive evidence has been found for decreasing CVP and effective circulating blood volume during OLT levels, currently accepted in some centers for liver resection [77]. Due to the lack of adequately powered, randomized, prospective controlled trials further investigations are needed to determine which patients would benefit from restrictive volume management in the intraoperative period of OLT.

#### *4.4.2. Blood salvage technique during OLT*

The use of intraoperative blood salvage and autologous blood transfusion has been for a long time an important method to reduce the need for allogeneic blood and the associated complications [78]. It has been demonstrated, that, for systematic use of Cell Saver salvaged blood in 75 OLT cases, retransfusion volume was enough and adequate in 65% of the cases [79].

The resultant hematocrit after Cell Saver processing ranges between 50 and 80% [80]. The safety of cell-salvaging procedure has been widely demonstrated [81]. Use of intraoperative autologous transfusion resulted in conservation of RBCs and reduction in exposure to homologous blood and blood components [82, 83]. Use of Cell Saver during OLT made it possible to recover up to 50% of blood loss [84]. Substantial reduction in FFP and a lesser reduction in platelet requirement have also been seen.

Nonetheless, blood-salvaging techniques during OLT are still being considered as controversial. Some studies have reported relatively higher blood loss, increased incidence of fibrinolysis, and cost rise [85, 86].The increased blood loss in recipients, receiving Cell Saver blood has been attributed to the release of fibrinolytic compounds from blood cells in the collected blood and/or from the transplanted liver [87]. These findings, however, have not dissuaded the anesthesiologists from using Cell Saver during OLTs; in fact, this method is gaining wider popularity, and becoming almost a standard of care in many centers around the world.

## **5. Vasoactive agents applied pharmacology and use in hemodynamic management during OLT**

Hemodynamic instability during OLT due to blood loss, graft reperfusion, and postreperfusion vascular tone adjustment, substantial fluid shift oftentimes necessitates the use of vasoactive agents. Different vasopressors, such as dopamine, dobutamine, epinephrine, norepinephrine, phenylephrine, vasopressin, and, more recently, terlipressin and octreotide have been used for hemodynamic optimization and end-organ perfusion improvement during OLTs for decades [88, 89].

Norepinephrine and phenylephrine have a universal vasoconstrictor effect due to α-receptor stimulation, thus effectively increasing systemic vascular resistance, while decreasing cardiac index, peripheral and portal blood flow [90–93]. However, norepinephrine in higher doses causes severe peripheral vasospasm and promotes metabolic (lactic) acidosis [88]. Phenylephrine increases SVR and MPAP, while it decreases CO/CI, peripheral, and portal BF [93], and does not affect portal VP during the dissection phase. CVP is often increased and does not seem to reflect cardiac filling [94].

Epinephrine and norepinephrine decrease liver and kidney tissue perfusion, thereby reducing lactate clearance, promote lactic acidosis, cause temporary alterations of hepatic macro- and microcirculation (return to baseline 2 h after onset of infusion). Dose-dependent progressive decline of hepatic macro- (33–75% reduction) and microcirculation (39–58% reduction) was found in transplanted livers. Norepinephrine has a direct constrictor effect on liver sinusoids, thereby reducing hepatic blood volume/flow and aggravating portal hypertension, and demonstrates effects similar to those of vasopressin effects on CO/CI and SVR [95], does not increase HBF, hepatic DO2 or VO2, and does not improve the hepatic lactate extraction ratio [96]. Vasopressin increases SVR, decreases MPAP; normalizes CO/CI, and potentially, CVP; maintains mean BP; decreases portal pressure, HBF, and systemic blood flow (SBF); improves impaired renal function; enhances diuresis, and thus improves Na balance and lactate elimination; enhances platelet aggregation; and increases levels of Profactor VIII and von Willebrand factor, and does not promote lactic acidosis. Its use after reperfusion, albeit having been shown beneficial by many authors, remains controversial, mainly due to splanchnic flow restriction effect with potential impairment of portal flow to the graft. Vasopressin has been demonstrated to have a dose-dependent vasoconstrictor effect on the peripheral vasculature with substantial SVR increases, while having little effect on heart rate, systemic arterial blood pressure, and CI in normotensive patients [97]. The ability of vasopressin to selectively constrict splanchnic vasculature, and thus decrease portal blood flow, is thought to constitute a physiological basis for variceal bleeding control by a higher vasopressin (0.4 U/min) dose [98, 99]. Vasopressin decreases portal vein pressure and flow in the native liver during liver transplantation [100]. Authors' own study has shown that use of low-dose vasopressin (0.04 U/min) infusion in an attempt to reduce blood loss seems to be a promising and a feasible technique. Vasopressin decreases portal vein pressure and blood flow in the native liver, as do terlipressin and octreotide [101]. A low-dose vasopressin (0.04 U/min) infusion apparently exerts only a minimal effect on the general hemodynamics. Low-dose vasopressin infusion is proved to be safe: to date, no cases of liver graft damage have been documented. To the contrary, cases where a high-dose of vasopressin (0.8 U) bolus, followed by a vasopressin infusion (4U/h) to attenuate refractory hypotension secondary to graft reperfusion, was used without causing any identifiable liver graft damage, have been reported [102]. Vasopressin has been shown to have a stimulation effect on lactate production by liver cells and adipose tissue in the septic model [103], and to be able to decrease blood loss during pre- and anhepatic phases of OLT (namely, EBL before graft reperfusion has been decreased by 50.2% [104] **Figure 1**)

Nonetheless, blood-salvaging techniques during OLT are still being considered as controversial. Some studies have reported relatively higher blood loss, increased incidence of fibrinolysis, and cost rise [85, 86].The increased blood loss in recipients, receiving Cell Saver blood has been attributed to the release of fibrinolytic compounds from blood cells in the collected blood and/or from the transplanted liver [87]. These findings, however, have not dissuaded the anesthesiologists from using Cell Saver during OLTs; in fact, this method is gaining wider popularity, and becoming almost a standard of care in many centers around the world.

**5. Vasoactive agents applied pharmacology and use in hemodynamic** 

Hemodynamic instability during OLT due to blood loss, graft reperfusion, and postreperfusion vascular tone adjustment, substantial fluid shift oftentimes necessitates the use of vasoactive agents. Different vasopressors, such as dopamine, dobutamine, epinephrine, norepinephrine, phenylephrine, vasopressin, and, more recently, terlipressin and octreotide have been used for hemodynamic optimization and end-organ perfusion improvement during

Norepinephrine and phenylephrine have a universal vasoconstrictor effect due to α-receptor stimulation, thus effectively increasing systemic vascular resistance, while decreasing cardiac index, peripheral and portal blood flow [90–93]. However, norepinephrine in higher doses causes severe peripheral vasospasm and promotes metabolic (lactic) acidosis [88]. Phenylephrine increases SVR and MPAP, while it decreases CO/CI, peripheral, and portal BF [93], and does not affect portal VP during the dissection phase. CVP is often increased and

Epinephrine and norepinephrine decrease liver and kidney tissue perfusion, thereby reducing lactate clearance, promote lactic acidosis, cause temporary alterations of hepatic macro- and microcirculation (return to baseline 2 h after onset of infusion). Dose-dependent progressive decline of hepatic macro- (33–75% reduction) and microcirculation (39–58% reduction) was found in transplanted livers. Norepinephrine has a direct constrictor effect on liver sinusoids, thereby reducing hepatic blood volume/flow and aggravating portal hypertension, and demonstrates effects similar to those of vasopressin effects on CO/CI and SVR [95], does not increase HBF, hepatic DO2 or VO2, and does not improve the hepatic lactate extraction ratio [96]. Vasopressin increases SVR, decreases MPAP; normalizes CO/CI, and potentially, CVP; maintains mean BP; decreases portal pressure, HBF, and systemic blood flow (SBF); improves impaired renal function; enhances diuresis, and thus improves Na balance and lactate elimination; enhances platelet aggregation; and increases levels of Profactor VIII and von Willebrand factor, and does not promote lactic acidosis. Its use after reperfusion, albeit having been shown beneficial by many authors, remains controversial, mainly due to splanchnic flow restriction effect with potential impairment of portal flow to the graft. Vasopressin has been demonstrated to have a dose-dependent vasoconstrictor effect on the peripheral vasculature with substantial SVR increases, while having little effect on heart rate, systemic arterial blood pressure, and CI in normotensive patients [97]. The ability of vasopressin to selectively

**management during OLT**

182 Liver Cirrhosis - Update and Current Challenges

OLTs for decades [88, 89].

does not seem to reflect cardiac filling [94].

**Figure 1.** Blood loss decrease in pre-reperfusion stages of OLT: comparison of low-dose vasopressin and phenylephrine infusions.

#### **5.1. Suggested algorithm of vasoactive agents used during anesthesia for OLT**

Phenylephrine, epinephrine, norepinephrine, dopamine, and vasopressin are commonly used during different stages of OLT. The task of attaining hemodynamic stability sometimes dictates concomitant use of two or more vasoactive agents (**Figure 2**).

Intraoperative use of dopamine, 3 mcg/kg/min in OLT is intended to preserve and protect the adequate renal function, especially in cases of hepatorenal syndrome [105]. Higher rates of dopamine infusion, 5–10 to 20 mcg/kg/min, increase cardiac output and SVR. However, gaining CO/CI increase at the expense of tachycardia and, potentially, some rhythm disturbances makes dopamine a less desirable agent.

Early in the perunhepatic (dissection) stage of the surgery, phenylephrine infusion may be started, along with already running dopamine and low-dose vasopressin. Due to phenylephrine's almost purely α-mimetic activity, its use actually addresses the low SVR problem, a main culprit for low MABP in majority of cases, provided that volume status correction and maintenance is being performed properly. In the majority of cases, phenylephrine infusion continues throughout the case. Providers in the other centers prefer and advocate early norepinephrine-only infusion be started, while others combine these agents [106].

Anhepatic stage often presents a challenge in terms of maintaining of hemodynamic stability. Rapid decrease in venous return; therefore, potential drop of CO, exacerbated by significant blood loss, usually necessitates more aggressive approach. Along with increase of norepinephrine (and phenylephrine, if its infusion is running along with the former), epinephrine may be added, with the purpose of using its β-stimulation activity. In preparation graft reperfusion,

**Figure 2.** Use of different vasoactive agents throughout the whole of the OLT procedure.

some authors actually recommend "pretreatment" [107] with epinephrine and phenylephrine combination for postreperfusion syndrome prevention.

**5.1. Suggested algorithm of vasoactive agents used during anesthesia for OLT**

tates concomitant use of two or more vasoactive agents (**Figure 2**).

makes dopamine a less desirable agent.

184 Liver Cirrhosis - Update and Current Challenges

Phenylephrine, epinephrine, norepinephrine, dopamine, and vasopressin are commonly used during different stages of OLT. The task of attaining hemodynamic stability sometimes dic-

Intraoperative use of dopamine, 3 mcg/kg/min in OLT is intended to preserve and protect the adequate renal function, especially in cases of hepatorenal syndrome [105]. Higher rates of dopamine infusion, 5–10 to 20 mcg/kg/min, increase cardiac output and SVR. However, gaining CO/CI increase at the expense of tachycardia and, potentially, some rhythm disturbances

Early in the perunhepatic (dissection) stage of the surgery, phenylephrine infusion may be started, along with already running dopamine and low-dose vasopressin. Due to phenylephrine's almost purely α-mimetic activity, its use actually addresses the low SVR problem, a main culprit for low MABP in majority of cases, provided that volume status correction and maintenance is being performed properly. In the majority of cases, phenylephrine infusion continues throughout the case. Providers in the other centers prefer and advocate early

Anhepatic stage often presents a challenge in terms of maintaining of hemodynamic stability. Rapid decrease in venous return; therefore, potential drop of CO, exacerbated by significant blood loss, usually necessitates more aggressive approach. Along with increase of norepinephrine (and phenylephrine, if its infusion is running along with the former), epinephrine may be added, with the purpose of using its β-stimulation activity. In preparation graft reperfusion,

norepinephrine-only infusion be started, while others combine these agents [106].

**Figure 2.** Use of different vasoactive agents throughout the whole of the OLT procedure.

Graft reperfusion and postreperfusion syndrome presents a most significant challenge for hemodynamic management. Many different techniques and drug combinations has been tested and recommended for rapid hemodynamic recovery after liver graft reperfusion. Along with vasoactive agents and their combinations that are already in use by the time of a graft reperfusion, other agents has been successfully used (Figure 1). Vasopressin in small boluses, 1–2 U, may be highly efficient in opposing the significant and rapid decrease of SVR, and calcium chloride, up to 100 mg, may enhance inotropic effects of epinephrine [108]. Another agent, namely Methylene Blue, 2 mg/kg, has been reported as very efficient and "last resort" drug for prolonged and profound hypotension, refractory to treatment with other vasoactive drugs [109].

The presence of significant metabolic, mainly lactic, acidosis is a well-known cause of decreased vasoactive agent's efficiency [110]. To overcome hyporesponsiveness to vasopressors, sodium bicarbonate infusion may be necessary. THAM infusion provides a fast and efficient way of acidosis reversal and returning pH closer to the physiological range [111].

In certain cases, shortly after even seemingly uneventful graft reperfusion, PAP and CVP start to rise and graft congestion ensues. Reasons for this pulmonary pressure surge include postreperfusion left ventricle diastolic dysfunction as a result of direct myocardial injury, caused by free oxygen radicals containing metabolic substances, relative overload due to rapid transfusion of substantial amounts of blood products, interstitial pulmonary edema with PVR increase, and more. Graft congestion causes substantial perfusion and oxygen delivery impairment in the newly transplanted liver, that delays normal function restoration, specifically restart of coagulation components synthesis, which, in turn, exacerbates and prolongs the coagulation deficit. To address this problem, infusion rates of vasoactive drugs should be adjusted to the best possible balance of MAP and PAP, blood products transfusion rate (but not necessarily volume) should be decreased, diuretics (Furosemide) may be administered, and infusion of nitroglycerin, starting at 1 mcg/kg/min, may be commenced, as blood pressure tolerates. Nitroglycerin has proved to be an effective agent for treatment of pulmonary hypertension. It has been shown that nitroglycerin infusion resulted in pulmonary vascular resistance decrease by 43%, and mean pulmonary artery pressure decrease by 19% [112].

Hemodynamic management of postreperfusion stage of liver transplantation procedure consists of continuation of vasoactive agents infusion and usually involves a gradual decrease of infusion rates and also weaning from most aggressive vasopressors, like epinephrine. In substantial percentage of the cases, despite the adequate volume status restoration and coagulation defect complete reversal, the necessity for vasoactive drugs persists. Hemodynamic optimization continues well beyond the actual end of the surgery, oftentimes for a few days in critical care units.

Choice and dosage of vasoactive agents at every stage of OLT depend and should be guided by hemodynamic parameters. We suggest the allocation to all the patient population undergoing liver transplantation surgery, in three groups, according to hemodynamic parameters: compensated (MAP 80–100 mmHg, SVR > 600 dynes/s/cm5 ), subcompensated (MAP 60–70 mmHg, SVR 300–600 dynes/s/cm5 ), and decompensated (MAP <50 mmHg, SVR <200–250 dynes/s/cm5 )


Suggested algorithm of vasoactive agents use and dosage is summarized in **Table 1**.

Dop—dopamine; Phen—phenylephrine; NE—norepinephrine; Epi—epinehrine, all dosage in mcg/kg/min; Vas vasopressin, units/min; Ca—calcium chloride, mg; MB—Methylene Blue, mg/kg; Bic—sodium bicarbonate, mEq.

**Table 1.** Algorithm of vasoactive agents use and dosage during OLT.

#### **6. Conclusion**

Hemodynamic optimization during liver transplant surgery presents very complex, challenging, sometimes formidable task, many aspects of which remain unclear, thus warrant further research. A wide variety of anesthetic techniques and standards, institutional policies, hemodynamic triggers for vasoactive agents use and transfusion thresholds, arriving at the even nation-wide consensus, let alone worldwide, remain extremely difficult, if not mere a unrealistic task. Nonetheless, introduction of comprehensive guidelines, based on most common clinical practices and realities of perioperative hemodynamic management appears to be not only conceivable but rather timely and a necessary enterprise. Once introduced, such guidelines may lay the ground for successful and safe intra and perioperative practices and also provide support for much-needed research efforts in this complicated area of transplant anesthesia practice.

## **Author details**

Suggested algorithm of vasoactive agents use and dosage is summarized in **Table 1**.

**OLT stage MAP 80–100, SVR>600 MAP 60–70, SVR 300–600 MAP<50, SVR <200–250**

Dissection Dop 3 Dop 3 Dop 5–10

An-hepatic Dop 3 Dop 3 Dop 5–10

Reperfusion Dop 3–5 Dop 3–5 Dop 3–5

**Agent Dose Agent Dose Agent Dose**

Phen 0.2–0.4 Phen 0.4–0.6 Phen 0.6–1.0 Vas 0.04 Vas 0.04 Vas 0.04–0.08

Phen 0.2–0.4 Phen 0.4–0.8 Phen 0.8–1.2 Vas 0.04 NE 0.01–0.03 NE 0.04–0.08

Phen 0.2–0.6 Phen 0.6–0.8 Phen 0.8–1.2 Ca 500 NE 0.04–0.08 NE 0.06–0.1

Dop 3 Dop 3 Dop 3–5 Phen 0.02–0.06 Phen 0.4–0.8 Phen 6–1.0

Dop—dopamine; Phen—phenylephrine; NE—norepinephrine; Epi—epinehrine, all dosage in mcg/kg/min; Vas vasopressin, units/min; Ca—calcium chloride, mg; MB—Methylene Blue, mg/kg; Bic—sodium bicarbonate, mEq.

Vas 0.04 Epi 0.01–0.03

Epi 0.02–0.04 Epi 0.04–0.08 Ca 1000 Vas 3–5 Vas 1–2 Ca 1000–2000

NE 0.02–0.04 NE 0.08–0.1

NE 0.01–0.03

Vas 0.04–0.08

MB 1–1.5 Bic 50–100

Epi 0.02–0.04

**Hemodynamics**

186 Liver Cirrhosis - Update and Current Challenges

Hemodynamic optimization during liver transplant surgery presents very complex, challenging, sometimes formidable task, many aspects of which remain unclear, thus warrant further research. A wide variety of anesthetic techniques and standards, institutional policies,

**6. Conclusion**

**Table 1.** Algorithm of vasoactive agents use and dosage during OLT.

Postreperfusion Alexander A. Vitin<sup>1</sup> \*, Dana Tomescu<sup>2</sup> and Leonard Azamfirei<sup>3</sup>

\*Address all correspondence to: vitin@uw.edu

1 Department of Anesthesiology, University of Washington, Seattle, WA, USA

2 Department of Anesthesia and Intensive Care "Carol Davila", University of Medicine and Pharmacy, Fundeni Clinical Institute, Bucharest, Romania

3 University of Medicine and Pharmacy Tîrgu Mureș, Tîrgu Mureș, Romania

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