0409-Cirrhosis of the Liver

Section 4

IX Cirrhosis of the Liver

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Ramón Bataller, MD, FACP

Liver Unit, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Barcelona, Catalonia, Spain

Pere Ginès, MD, FACP

Liver Unit, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Barcelona, Catalonia, Spain

10.2310/7900.S04C09

Definition

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Cirrhosis is the most advanced stage of most types of chronic liver disease. Cirrhosis is defined as a diffuse disorganization of normal hepatic structure by extensive fibrosis associated with regenerative nodules. Hepatic fibrosis is potentially reversible if the causative agent is removed. However, advanced cirrhosis leads to major alterations in the hepatic vascular bed and is usually irreversible. ¹ Cirrhosis is a progressive and severe clinical condition associated with considerable morbidity and high mortality. It leads to a wide spectrum of characteristic clinical manifestations, mainly attributable to hepatic insufficiency and portal hypertension. ² Major complications include ascites, gastrointestinal (GI) bleeding, hepatic encephalopathy (HE), renal failure, bacterial infections, and coagulopathy. In recent years, major advances have been made in the understanding of the natural history and pathophysiology of cirrhosis and in the treatment of its complications, leading to improved management, quality of life, and life expectancy. Cirrhosis is also a risk factor for developing hepatocellular carcinoma (HCC). Decompensated cirrhosis carries a poor short-term prognosis, and orthotopic liver transplantation (OLT) is often indicated.

Epidemiology

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Cirrhosis is the ninth leading cause of death in the United States. ³ Chronic liver disease and cirrhosis cause 4 to 5% of deaths for people between the ages of 45 and 54 years and result in about 30,000 deaths each year in the United States. The annual incidence of newly diagnosed chronic liver disease in the United States is 72.3 cases per 100,000 persons. The prevalence of chronic liver disease and cirrhosis is 5.5 million cases. Over 60% of cases are male. Cirrhosis is more common among Hispanic whites and American Indians, being the sixth cause of death in these groups. The economic impact of cirrhosis is considerable ($1.5 billion in direct costs and $234 million in indirect costs in 2000). In 2000, there were 360,000 hospital charges for chronic liver disease or cirrhosis.

Etiology and Genetic Factors

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The main etiologic factors of liver cirrhosis may be grouped into seven categories [ seeTable 1 ]. Some patients may have more than one of these factors. The main causes of cirrhosis in the United States are hepatitis C virus (HCV) infection and excessive alcohol consumption, which account for two-thirds of cases. Other major causes are hepatitis B virus (HBV) infection, autoimmune hepatitis, chronic cholestasis (primary biliary cirrhosis [PBC] and primary sclerosing cholangitis [PSC]), and genetic metabolic diseases (hemochromatosis and Wilson disease). As a result of the current epidemic of obesity, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are increasingly recognized as a major cause of cirrhosis. Many patients diagnosed with so-called cryptogenic cirrhosis have had features of metabolic syndrome, suggesting a role for NAFLD and NASH in the pathogenesis of this type of cirrhosis. To identify the etiology of liver cirrhosis, data should be obtained from the medical history, physical examination findings, laboratory tests, and liver biopsy if indicated [ seeTable 2 ]. The identification of the cause of cirrhosis is important in terms of the management (e.g., antiviral therapy in hepatitis B or C infection, phlebotomies in hemochromatosis).

Cirrhosis is a complex disease in which many genes interact with environmental factors. ⁴ Nongenetic factors that influence the progression to cirrhosis include age, alcohol intake, immunosuppressive therapy, and HIV infection. Genetic factors involved in the pathogenesis of cirrhosis are not well known. These factors may explain the broad spectrum of responses to the same etiologic agent found in patients with chronic liver disease. Polymorphisms in genes encoding immunoregulatory proteins, proinflammatory cytokines, and fibrogenic mediators may influence the outcome of conditions that may cause chronic liver injury (alcoholism, chronic HCV infection, autoimmune disorders), as well as modulate the progression of chronic hepatitis to cirrhosis.

Pathogenesis

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early phase: liver fibrogenesis

Figure 1. Liver Biopsy in Chronic Hepatitis C Infection.

Cirrhosis is the end stage of many forms of chronic liver disease characterized by progressive fibrosis. Hepatic fibrosis is the result of the wound-healing response of the liver to repeated injury. ⁵ Fibrosis consists of the accumulation of extracellular matrix (ECM) proteins, mainly fibrillar collagen, as the result of both increased ECM synthesis and decreased degradation of matrix. Myofibroblasts, mostly derived from hepatic stellate cells, are the main ECM-producing cells in the injured liver. Following chronic injury, stellate cells activate into fibrogenic (smooth muscle a-actin-positive) cells [see Figure 1 ]. Key mediators of this process include inflammatory cytokines, transforming growth factor-b1 , and angiotensin II.

The pathogenesis of liver fibrosis differs depending on the underlying cause. In alcohol-induced liver disease, lipopolysaccharide derived from gut bacteria is elevated in portal blood and activates Kupffer cells to release reactive oxygen species and cytokines, activating stellate cells and promoting hepatocytes to undergo apoptosis. The pathogenesis of HCV-induced liver fibrosis is poorly understood. HCV infects hepatocytes, causing oxidative stress and inducing the recruitment of inflammatory cells. Both factors lead to stellate cell activation. In chronic cholestatic disorders, such as PBC, T lymphocytes and cytokines mediate persistent bile duct damage. Biliary epithelial cells secrete fibrogenic mediators, activating neighboring portal myofibroblasts to secrete ECM. Eventually, perisinusoidal stellate cells become activated and fibrotic bands develop. The pathogenesis of liver fibrosis attributed to NASH is also poorly understood. Accumulation of free fatty acids within hepatocytes leads to oxidative stress and insulin resistance, which, in turn, leads to elevated serum levels of free fatty acids. Intrahepatic secretion of proinflammatory cytokines promotes hepatocyte apoptosis and the recruitment of inflammatory cells, leading to progressive fibrosis.

cirrhosis

Bridging fibrosis is associated with profound abnormalities in the hepatic microcirculation. ⁶ Capillarization of the hepatic sinusoids occurs, and new vessels form within the fibrous sheath. There is a local predominance of vasoconstrictors over vasodilators, resulting in a tonic contraction of perisinusoidal stellate cells that increases vascular resistance. Moreover, thrombosis in small vessels occurs and intrahepatic arterial shunts develop. Hepatocytes proliferate in ischemic areas in a disorganized manner, forming regenerative nodules. Pressure in the portal venous system progressively increases, leading to the development of portocollateral veins and to esophageal and gastric varices. ⁷ Portal hypertension is caused by both increased portal venous inflow and increased hepatic vascular resistance. This latter component is attributable to endothelial dysfunction and impaired intrahepatic synthesis of vasodilators such as nitric oxide. ⁸ This dynamic component accounts for approximately 30% of the intrahepatic resistance in cirrhosis and is an important target for future therapy. In contrast to what occurs in the liver, systemic vascular resistance in patients with cirrhosis is decreased, which eventually markedly activates systemic vasoconstrictor and salt-retaining systems that worsen portal hypertension and favor ascites formation. Hepatocellular function is progressively impaired, and there is decreased function of the reticuloendothelial system, leading to endotoxinemia and increased risk of bacterial infections. Eventually, hepatocellular function fails, leading to severe coagulopathy and HE. A profound circulatory dysfunction caused by impaired myocardial function and decreased systemic vascular resistance is frequently seen. In very late stages of cirrhosis, renal vasoconstriction develops, leading to hepatorenal syndrome (HRS). In this phase of the disease, most patients die unless OLT is rapidly performed.

Diagnosis

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clinical manifestations

Cirrhosis can be clinically silent and discovered incidentally by imaging studies performed for other reasons, at laparotomy or autopsy. In many cases, the symptoms are insidious in onset and include generalized weakness, anorexia, malaise, and weight loss. ⁹ Skeletal muscle mass frequently decreases. " Compensated" cirrhosis is defined by the absence of symptoms or the presence of minor symptoms. Eventually, the clinical manifestations of hepatocellular dysfunction and portal hypertension ensue, including bleeding from gastroesophageal varices, ascites and neuropsychiatric symptoms, and progressive jaundice. The abrupt onset of one of these complications may be the first presenting symptom of cirrhosis. Coagulopathy is typically found in patients with advanced cirrhosis. Progressive obstruction to bile flow in patients with PBS and PSC leads to skin hyperpigmentation, jaundice, pruritus, and xanthelasmas. In these patients, malnutrition secondary to anorexia, fat malabsorption, and increased catabolism is common. Fat-soluble vitamin deficiency is also frequently found in cirrhosis. In alcohol-related liver disease, extrahepatic symptoms related to the nervous system, the heart, and the pancreas can also be present.

physical findings

Figure 2. Ascites in Advanced Cirrhosis.

Cirrhotic patients show typical physical findings, yet the physical examination can be normal in patients with early cirrhosis. The liver is enlarged and is palpable in the early phases of the disease. In advanced cirrhosis, liver size usually decreases. Splenomegaly is a common finding. Ascites and/or peripheral edema may be present, and a collateral venous circulation can be observed in the abdomen. Patients with HE show altered mental status, decreased consciousness, and asterixis. Other signs typical of cirrhosis include muscle wasting, palmar erythema, vascular spiders, gynecomastia, axillary hair loss, testicular atrophy, and fetor hepaticus. In alcoholic patients, Dupuytren contractures, parotid gland enlargement, and peripheral neuropathy can be noted. Skin hyperpigmentation is typical of patients with cholestatic disorders (i.e., PBC) and/or hemochromatosis. Advanced cirrhotic patients are severely malnourished, ascites is prominent, and neuropsychiatric symptoms are common [ seeFigure 2 ].

Blood Tests

Liver tests are commonly abnormal. Serum aspartate aminotransferase (AST) levels are frequently elevated, but levels > 300 U/L are uncommon. Serum levels of alanine aminotransferase (ALT) may be relatively low (AST/ALT > 2). Serum prothrombin time (or the international normalized ratio [INR]) is frequently increased; reflecting reduced synthesis of clotting factors, most notably the vitamin K-dependent factors. Serum albumin levels are decreased mainly because of poor hepatocellular synthesis. Total serum Y-globulin concentration increases in advanced cirrhosis because of the impaired reticuloendothelial function and increased blood levels of bacterial products. Alkaline phosphatase is usually only moderately increased, except in patients with biliary diseases (i.e., PBC, PSC), who show makedly increased levels of alkaline phosphatase and Y-glutamyltranspeptidase, associated in some cases with increased bilirubin levels. Anemia is fairly common and usually normocytic, but it may be microcytic, hypochromic from chronic GI bleeding, macrocytic from folate deficiency (in alcoholism), or hemolytic. Hypersplenism can lead to leukopenia and thrombocytopenia. Serum cholesterol and triglyceride levels may be increased in patients with biliary obstruction, whereas they are actually low in patients with advanced cirrhosis of nonbiliary origin. Cirrhotic patients may develop glucose intolerance and diabetes mellitus, mainly attributable to insulin resistance. Central hyperventilation may lead to chronic respiratory alkalosis with a low serum bicarbonate concentration. Dietary deficiency and increased urinary losses cause hypomagnesemia and hypophosphatemia. Renal failure, as estimated by elevated serum creatinine and blood urea concentrations, and hyponatremia can be observed in patients with cirrhosis, especially those with ascites.

Imaging Studies

Figure 3. Ultrasonography: Cirrhosis from Chronic Hepatitis C.

Real-time ultrasonography (US), in combination with color flow Doppler US, is the most useful tool in the evaluation of patients with cirrhosis. ¹⁰ US is useful for demonstrating the morphologic characteristics of cirrhosis, including irregular or nodular liver edges, an altered structure, and the presence of signs of portal hypertension, such as portocollateral veins [ seeFigure 3 ]. US is also useful for detecting hepatic steatosis, ascites, splenomegaly, and portal vein thrombosis. In patients with cholestasis, it helps rule out extrahepatic causes of cholestasis. Doppler US provides useful information on portal hemodynamics and can detect reversal of portal blood flow. US examination is particularly helpful in detecting hepatic tumors such as HCC. Demonstration of tumor vascularization by Doppler US and/or injection of ultrasonography contrast is valuable for differenting regenerating nodules from HCC. Dynamic studies using computed tomography (CT) and magnetic resonance imaging (MRI) are also useful in the assessment of cirrhosis and the diagnosis of hepatic tumors previously detected by US. The use of CT or MRI for HCC screening in patients with cirrhosis is limited by the high cost. Transient elastography is a new technique that assesses liver stiffness based on the velocity of an elastic wave via an intercostally placed transmitter. It helps differentiate cirrhosis from milder fibrosis and also can predict the degree of portal hypertension. The examination is limited by morbid obesity, ascites, and small intercostal spaces. ¹¹

Liver Biopsy

Liver biopsy can unequivocally establish the presence of cirrhosis. ¹² It helps determine its cause and provide information on the extent of liver damage. Liver biopsy is usually performed using a percutaneous approach that should not be used in patients with severe coagulopathy (INR greater than 1.5 and/or platelet count less than 50,000/µL ³ ), and it must be used with caution in patients with severe obesity. The limitations of liver biopsy include its invasiveness and the potential for sampling error, especially in patients with macronodular cirrhosis. Transjugular liver biopsy is indicated in patients with severe coagulopathy or ascites and allows the measurement of portal pressure. ¹³ However, the amount of tissue obtained is small, and in some cases, the diagnosis of cirrhosis cannot be made. In selected cases, liver biopsy can be performed during laparoscopy. This is generally reserved for staging cancer or for ascites of unknown origin. Histologic findings that define cirrhosis include extensive fibrosis and regenerative nodules. The degree of infiltration of inflammatory cells depends on the activity of the underlying disease. Micronodular cirrhosis is characterized by the presence of uniformly small nodules (< 3 mm in diameter), whereas in macronodular cirrhosis, nodules vary in size (3 mm to 2 cm in diameter) and contain a normal lobular structure (portal tracts, terminal hepatic venules). In some cases, histologic findings help identify the causative agent of cirrhosis: periportal lymphocyte infiltration in HCV-induced cirrhosis; Mallory bodies, neutrophilic infiltration, and steatosis in alcohol-induced cirrhosis and/or NASH; biliary involvement in PBC; or massive iron deposition in hemochromatosis. In advanced cirrhosis, however, histologic findings may be similar regardless of the underlying disease.

General Management

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Cirrhotic patients should be examined periodically. Compensated cirrhotic patients should be seen two to three times/year. At diagnosis, extensive medical history and laboratory tests, including viral serologies, should be performed to identify the causative agent. An endoscopic examination should be done to assess the presence and size of esophageal varices. Abdominal US should be performed at diagnosis and every 6 months to detect early HCC. The criteria for OLT should be periodically evaluated, and major clinical complications (i.e., bacterial infections, renal impairment, GI bleeding) should be actively prevented. ¹⁴ Many patients complain of anorexia, and care should be taken to ensure that they receive adequate caloric and protein intake. Patients frequently benefit from the addition of nutritional supplements. Zinc deficiency is commonly observed and should be treated. Zinc sulfate (50-200 mg/day) may be effective in the treatment of muscle cramps. Pruritus is a common complaint in cirrhotic patients, especially in those with chronic cholestasis (PBC and PSC). Drugs that may provide relief against pruritus include cholestyramine, ursodeoxycholic acid, naltrexone, rifampicin, and ondansetron. Some men with cirrhosis suffer from hypogonadism. Men with severe symptoms of hypogonadism may undergo therapy with topical testosterone preparations, although their safety and efficacy are not well studied. Patients with cirrhosis may develop osteoporosis. Supplementation with calcium and vitamin D is important in patients at high risk for osteoporosis, especially patients with chronic cholestasis and those receiving corticosteroids for autoimmune hepatitis. Detection of decreased osteopenia using bone densitometry studies also may prompt institution of therapy with an aminobisphosphonate (e.g., alendronate sodium). Mild exercise, including walking and even swimming, should be encouraged in patients with compensated cirrhosis. Debilitated patients frequently benefit from formal exercise programs supervised by a physical therapist. Patients with cirrhosis should receive vaccination to protect them against hepatitis A. Other protective measures include vaccination against hepatitis B, pneumococci, and influenza. Potential hepatotoxic medications should be avoided. Patients with ascites should not receive nonsteroidal antiinflammatory drugs or nephrotoxic antibiotics (e.g., aminoglycosides), because they may induce GI bleeding and/or renal failure. Surgery and general anesthesia carry increased risks in patients with cirrhosis, particularly in those with portal hypertension, and may lead to hepatic decompensation.

Specific Measures

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compensated cirrhosis

Specific medical therapies may be applied to different liver diseases to diminish disease progression. However, these therapies become progressively less effective as chronic liver disease evolves into cirrhosis. In patients with compensated cirrhosis, specific therapies prevent the development of clinical complications and therefore delay the need for liver transplantation. Treatment with pegylated interferon plus ribavirin should be considered in patients with compensated cirrhosis as the result of HCV infection, yet the rate of sustained viral response is lower than that in noncirrhotic patients. ¹⁵ Viral eradication almost completely eliminates the risk of hepatic decompensation. ¹⁶ Maintenance treatment with interferon for patients who have not responded to interferon-ribavirin treatment is under investigation. Selected patients with decompensated cirrhosis from HCV awaiting OLT may also be treated with pegylated interferon plus ribavirin. ¹⁷ In these patients, treatment can be initiated several months before OLT to prevent graft reinfection.

In patients with HBV-related cirrhosis, lamivudine appears to be a safe and effective antiviral agent that may improve or stabilize liver disease in selected patients with advanced cirrhosis and active HBV replication. ¹⁸ However, viral resistance to lamivudine can develop with prolonged treatment. Adefovir, telbivudine, and entecavir are other antiviral agents that have high activity against both wild-type and lamivudine-resistant HBV.

The most effective measure for patients with alcohol-induced cirrhosis is to stop drinking. ¹⁹ Abstinence can stabilize and even improve liver function. Psychological support is highly recommended to achieve prolonged alcohol abstinence. Nutritional support is advisable in all alcoholic patients. Colchicine may improve the outcome, yet its use is hampered by undesirable side effects. ²⁰ In cases of superimposed alcoholic hepatitis, glucocorticoid treatment (40 mg/day of prednisone for 4 weeks followed by tapering of therapy for 1 or 2 weeks) or pentoxifylline (400 mg every 8 hours) improves short-term survival. ²¹

In patients with PBC, ursodeoxycholic acid (13 to 15 mg/kg/day) relieves pruritus, improves biochemical blood tests, and prolongs survival. ²² Although ursodiol may decrease the need for OLT, its usefulness in PBC in cirrhotic patients is limited. Other treatments (glucocorticoids, colchicine, azathioprine) are not indicated since they are associated with severe side effects. No specific therapy improves the outcome of patients with PSC, yet ursodeoxycholic acid has beneficial effects on biochemical parameters. In patients with cirrhosis attributed to autoimmune hepatitis, immunosuppressant therapy should be used with caution since it may favor infections; also, necroinflammatory injury at this stage of the disease is usually mild. Finally, patients with cirrhosis attributed to genetic metabolic diseases such as hemochromatosis and Wilson disease benefit from phlebotomies and copper chelators (i.e., d -penicillamine, trientine, or zinc), respectively.

decompensated cirrhosis

Ascites

Ascites is the most frequent complication of cirrhosis. ²³ It impairs quality of life and increases the risk of bacterial infections. It is primarily caused by splanchnic vasodilatation attributable to increased synthesis of vasodilators (i.e., nitric oxide). Severe splanchnic vasodilatation decreases effective arterial blood volume, which activates systemic vasoconstrictor and sodium-retaining factors. In advanced cirrhosis, solute-free water excretion is also impaired and renal vasoconstriction develops, leading to dilutional hyponatremia and HRS, respectively.

Figure 4. Transjugular Intrahepatic Portosystemic Shunt (TIPS).

Ascites can be graded into three groups: grade 1 ascites is detected only by US; grade 2 ascites is moderate with patent distention of the abdomen; and grade 3 ascites is tense, with marked abdominal distention [ seeFigure 2 ]. The first step in the evaluation of patients with new-onset ascites is to rule out nonhepatic causes of ascites (e.g., peritoneal tuberculosis or malignancies). Besides serum tests, US examination is useful for confirming signs of cirrhosis, ruling out HCC, and detecting portal vein thrombosis. Ascitic fluid should be examined in patients with new-onset ascites, suspected spontaneous bacterial peritonitis (SBP), HE, or GI bleeding. Cell count, albumin and total protein concentration of ascites fluid, and culture of the fluid in blood culture bottles should be performed. Renal function and hemodyamic parameters should also be assessed in all patients. The initial management of ascites includes a reduction in sodium intake to 60 to 90 mEq/day, equivalent to 1.5 to 2 g of salt/day. Salt restriction should be prescribed, along with adequate calorie and protein intake to maintain the nutritional status. Fluid intake should be restricted to less than 1,000 mL only in patients with significant dilutional hyponatremia (serum sodium < 130 mmol/L of in the presence of ascites and/or edema). Patients with moderate-volume ascites can achieve a negative sodium balance and loss of ascitic fluid with spironolactone (50 to 200 mg/day) or amiloride (5 to 10 mg/day). Low doses of furosemide (20 to 40 mg/day) may also be added. The efficacy of other mineralocorticoid antagonists, such as canrenoate and eplerenone, has not been extensively evaluated. Patients should be followed closely to avoid excessive diuresis. The recommended weight loss to prevent renal failure is 0.3 to 0.5 kg/day in patients without peripheral edema and 0.8 to 1 kg/day in those with peripheral edema. Patients with large-volume ascites should be treated initially with large-volume paracentesis. Plasma expanders should be given to prevent paracentesis-induced circulatory dysfunction and renal failure. ²⁴ Albumin is the plasma expander of choice if more than 5 L of ascitic fluid is removed; 8 g of intravenous albumin per 1 L of ascitic fluid removed can be given. Spironolactone (100 to 400 mg/day) with or without furosemide (40 to 160 mg/day) should be given to prevent recurrence of ascites after large-volume paracentesis. Doses of diuretics should then be adjusted individually according to diuretic responses. Between 5 and 10% of patients have refractory ascites, which is defined as a lack of response to high doses of diuretics or occurrence of adverse effects (e.g., renal failure, HE, hyponatremia, hyperkalemia) that preclude their use. Current therapeutic strategies for patients with refractory ascites include repeated large-volume paracentesis with albumin infusion and a transjugular intrahepatic portosystemic shunt (TIPS) [ seeFigure 4 ]. A TIPS is effective in preventing the recurrence of ascites. However, it does not improve survival, is associated with a high rate of shunt stenosis, favors HE, and is less cost-effective than repeated paracentesis. ²⁵ A TIPS is probably indicated for patients without severe liver failure or HE who have loculated fluid that cannot be treated with paracentesis and for those who do not tolerate repeated paracentesis. Patients with ascites should be evaluated for OLT since the survival rate at 5 years is 30 to 40%. Patients with refractory ascites, SBP, or HRS have a poor prognosis, and prioritization for OLT should be considered. Dilutional hyponatremia is present in 30 to 35% of hospitalized patients with cirrhosis and ascites. ²⁶ It is secondary to an impaired renal solute-free water excretion attributable to nonosmotic secretion of the antidiuretic hormone. Although the hyponatremia is commonly asymptomatic, it may favor the development of HE. The management consists of fluid restriction (1,000 mL/day) and discontinuance of diuretics. However, these measures do not correct the hyponatremia in many cases. Preliminary data with vaptans, aquaretic drugs that promote solute-free water excretion by antagonizing the vasopressin V2 receptors in the nephron, suggest that this class of drugs may improve both ascites and dilutional hyponatremia, although their effect on survival remains to be documented.

Hepatorenal Syndrome

HRS is the most severe complication of cirrhosis. ²⁷ It is a functional renal failure caused by extreme renal vasoconstriction. The diagnostic criteria of HRS are well established [ seeTable 3 ]. There are two clinical types of HRS. Type 1 is characterized by progressive oliguria and a rapid rise in serum creatinine concentration to a level greater than 2.5 mg/dL. The survival of these patients is extremely poor. Type 2 is defined by a moderate and stable increase in the serum creatinine concentration and is frequently associated with refractory ascites. HRS may occur spontaneously or following precipitating conditions such as SBP, acute alcoholic hepatitis, or large-volume paracentesis without plasma expansion. The initial approach to the evaluation of sudden worsening of renal function in a patient with cirrhosis includes (a) exclusion of iatrogenic or other causes of renal failure, (b) extensive evaluation for and treatment of sepsis, and (c) excluding volume depletion by clinical assessment and a therapeutic challenge with albumin (1 g/kg or up to 100 g) given intravenously. Type 1 HRS adds points to the Model for End-Stage Liver Disease (MELD) score used to predict mortality in patients with cirrhosis treated medically. Liver transplantation is the only definitive treatment of HRS, and the outcomes depend on successful treatment of HRS prior to transplantation. For patients with type 1 HRS, the combination of a vasoconstrictor (terlipressin, midrodine, or norepinephrine) with intravenous albumin infusion improves renal function in approximately 40% of patients. ²⁸ A TIPS is another effective approach for patients with HRS, yet its use is not recommended for patients with severe liver dysfunction. These treatments may serve as a bridge to OLT. Liver transplantation is the treatment of choice, yet its applicability is limited by the poor survival of these patients. In subjects with cirrhosis and severe sepsis, adrenal insufficiency commonly occurs. In this setting, hydrocortisone (50 mg/6 hr) may improve the hemodynamic abnormalities of sepsis and improve survival. ²⁹

Spontaneous Bacterial Peritonitis

SBP is a severe infection found in 15 to 25% of cirrhotic patients hospitalized with ascites. ³⁰ Predisposing factors include severe liver insufficiency and low protein content in ascitic fluid (1.5 g/dL). SBP appears to be related to the translocation of GI tract bacteria to the mesenteric lymph nodes. Clinical manifestations are variable, ranging from no symptoms to a severe picture of peritonitis and sepsis. SBP should also be suspected in cirrhotic patients with worsening renal and/or liver function with no apparent cause. The most common causative organisms are Escherichia coli , Klebsiella species, and other gram-negative enteric organisms. SBP is diagnosed by the presence of more than 250 neutrophil cells per microliter of ascitic fluid or when analysis of ascitic fluid with urine strips is positive for leukocyte esterase (3 ⁺ or 4 ⁺ ). Less than 50% of cases of SBP have a positive ascitic fluid culture. SBP should initially be treated empirically. The most commonly used regimen is a 5- to 7-day course of third-generation cephalosporin (e.g., cefotaxime 2 g/8-12 hr; ceftriaxone 1 g/24 hr). Development of HRS in SBP is common and is the most important predictor of mortality. Administration of albumin at a dose of 1.5 g/kg when SBP is diagnosed and 1 g/kg 48 hours later reduces the risk of HRS and lowers mortality from 30 to 10%. ³¹ The response to therapy for SBP can be monitored by the presence of signs of infection and by the neutrophil count in ascitic fluid. After SBP resolution, patients have a 70% chance of recurrence within 1 year. Secondary prophylaxis can reduce the recurrence rate to 20%. ³² The standard treatment includes norfloxacin at 400 mg/day orally. The 1-year survival probability after an episode of SBP is only 40%. Accordingly, eligible patients should be evaluated for OLT after resolution of SBP.

Primary prophylaxis should be considered in patients with cirrhosis and low ascitic protein levels (< 1.5 g/dL) with advanced liver failure (Child-Pugh score ³ 9 points with a serum bilirubin level ³ 3 mg/dL) or impaired renal function (serum creatinine ³ 1.2 mg/dL, blood urea nitrogen ³ 25 mg/dL, or serum sodium £ 130 mEq/L). Primary prophylaxis with fluoroquinolones such as norfloxacin (400 mg/day) or ciprofloxacin (500 mg/day) reduces the incidence of SBP, delays the development of HRS, and improves survival. ³³

Variceal Bleeding

Rupture of gastroesophageal varices as the result of portal hypertension is a severe and frequent complication of cirrhosis. ³⁴ Portal hypertension is caused by increased intrahepatic vascular resistance and increased portal venous blood flow attributable to splanchnic vasodilatation. It is recommended that all patients with cirrhosis be screened for gastroesophageal varices. The risk of bleeding from esophageal varices depends on the degree of portal hypertension, variceal diameter, endoscopic " red signs," and liver failure. Subjects with " high-risk" varices should be targeted for primary prophylaxis (see below). Those without varices should have follow-up endoscopy in 2 years or at the time of clinical decompensation. Those with small varices and preserved hepatic function (low-risk varices) should have repeat endoscopy at 1-year intervals. ³⁵ Although nonselective beta blockers (nadolol or propranolol) are the treatment of choice for primary prophylaxis, there are a number of limitations to their use. ³⁶ They should be given in a stepwise fashion, increasing the dose until the resting heart rate decreases by 25% of the baseline value. Another approach is to eradicate varices by repeated sessions of endoscopic variceal band ligation. Pharmacologic therapy and endoscopic therapy are equally effective in reducing the risk of bleeding, by 40 to 50%. ³⁷ Endoscopic treatment should be offered to those cirrhotics in whom the administration of beta blockers is contraindicated. A combination of variceal band ligation and beta blockers seems to be more effective than beta blockers alone and is being evaluated in large clinical trials. The initial therapy for acute variceal bleeding should be directed at correcting hypovolemia, achieving hemostasis, and preventing severe complications (such as renal failure, bacterial infections, and HE). Volume replacement and the need for blood transfusion should be considered. Excessive transfusion should be avoided since it may increase portal pressure and favor variceal rebleeding. Fresh frozen plasma and platelets, although frequently used, do not reliably correct coagulopathy and can induce volume overload. Endotracheal intubation should be considered in patients with HE and those requiring aggressive sedation to perform endoscopy. Antibiotics (third-generation cephalosporins such as ceftriaxone 1 g once daily or cefotaxime 2 g every 12 hours for 7 days) decrease the rate of bacterial infections and improve outcome. ³⁸ Hemostatic treatments include vasoconstrictor drugs, endoscopic band ligation, and surgical portosystemic shunts or TIPSs. Vasoactive drugs that are effective in controlling variceal bleeding include octreotide (100 µg bolus followed by 50 µg/hr for 5 days), terlipressin (2 mg every 4 hours for the first 48 hours and then 1 mg every 4 hours for up to 5 days), and somatostatin (bolus of 250 µg, followed by an infusion of 250 µg/hr for 5 days. ³⁹ Pharmacologic therapy controls variceal bleeding in 75 to 80% of cases. Cirrhotic patients with upper GI bleeding should initially be treated with a vasoactive drug. If the endoscopic examination confirms that esophageal varices are the source of the hemorrhage, variceal band ligation should be performed and drug therapy maintained for 5 days to prevent early variceal rebleeding. This approach controls bleeding in most patients. In patients with massive bleeding, balloon tamponade may temporarily help in controlling the hemorrhage. Therapeutic endoscopy can be repeated in patients who rebleed. In hemodynamically unstable patients or patients with several rebleeding episodes, TIPSs and/or surgical portosystemic shunts should be considered. ⁴⁰ A TIPS controls bleeding in more than 90% of cases and is preferred over shunt surgery because it is associated with less morbidity and mortality. However, it can impair liver function in patients with advanced cirrhosis. Patients with preserved liver function (Child class A) may benefit from shunt surgery (i.e., mesocaval shunt).

Because of the high rate of spontaneous rebleeding (60%), secondary prophylaxis of variceal bleeding is recommended. Drug therapy with nonselective beta blockers and repeated sessions of variceal band ligation are similarly effective. The beneficial effect of beta blockers should be ensured with the measurement of hepatic venous pressure gradient (HVPG), if available. A reduction of HVPG to less than 12 mm Hg and/or a pressure reduction of 20% from baseline reduces variceal rebleeding. ⁴¹ The combination of oral beta blockers plus endoscopic band ligation may be more effective than either treatment alone, and this combined approach is being evaluated. A TIPS and/or a surgical portosystemic shunt should be considered for patients who rebleed despite drug therapy and endoscopic treatment. Gastric varices tend to bleed at a lower HVPG than esophageal varices and bleed more severely. Once gastric variceal bleeding occurs, both cyanoacrylate injection sclerotherapy and TIPS have been used effectively to establish hemostasis and prevent rebleeding. ⁴²

Hepatopulmonary Syndrome and Portopulmonary Hypertension

Hepatopulmonary syndrome (HPS) develops in some patients with liver cirrhosis and is characterized by hypoxemia attributable to intrapulmonary shunting and/or a lung ventilation-perfusion mismatch caused by pulmonary vasodilation. ⁴³ Patients with HPS have no apparent parenchymal lung disease but have orthodeoxia, the unusual finding of increased hypoxemia with the change from a supine to a standing position. ⁴⁴ Other typical manifestations include exertional dyspnea, platypnea, and digital clubbing. The diagnostic workup includes arterial blood gas measurements, contrast-enhanced echocardiography, and technetium-99m-labeled macroaggregated albumin brain scanning. Pulmonary angiography may be necessary to detect discrete arteriovenous communications. Pharmacologic agents, such as almitrine bismesylate, prostaglandin F _2a , indomethacin, somatostatin, and methylene blue, have been used to treat HPS, but the results have been disappointing. Although TIPS may improve oxygenation, OLT is the only curative treatment. About 80% of patients with HPS eventually have improved oxygenation 6 months after OLT. ⁴⁵

Portopulmonary hypertension occurs in 2 to 8% of the patients with cirrhosis. The diagnosis is made by performing an echocardiography and/or a right heart catheterization to confirm that pulmonary artery pressure is elevated. Medical treatment with prostacyclin (prostaglandin I ₂ ) or bosentan often fails. In patients with severe pulmonary hypertension (mean pulmonary arterial pressure > 40 to 45 mm Hg), OLT is contraindicated in many centers. ⁴⁶

Hepatic Encephalopathy

HE is a syndrome observed in patients with advanced cirrhosis that is characterized by personality changes, intellectual impairment, neuromuscular symptoms, and a depressed level of consciousness. ⁴⁷ Several mechanisms have been implicated in the genesis of HE. ³⁶ Hyperammonemia is caused by increased gut synthesis, decreased hepatic uptake, and impaired muscle capacity to clear ammonia. GI bleeding and hypovolemia increase the release of renal ammonia to the circulation. The cerebral production of glutamine increases and results in glial dysfunction. Infections and the subsequent inflammatory response to infection can precipitate HE by altering microglial function. Decreased cerebral blood flow caused by local cerebral vasoconstriction may also play a role. ⁴⁸ Finally, an increase in brain water content and low-grade brain edema attributable to increased osmotically active solutes may play a pathogenic role. Patients with " hepatic parkinsonism" generally exhibit increased manganese deposition in the globus pallidus. The symptoms of HE are graded on a scale of 0 to 4 [ seeTable 4 ].

The diagnosis of HE is based on altered mental status and neuromuscular signs in the absence of any specific mental or neurologic disease. Typical findings on physical examination include asterixis and fetor hepaticus. An elevated arterial or free venous serum ammonia level is commonly found. Patients usually show electroencephalographic changes of high-amplitude low-frequency waves and triphasic waves. CT and MRI studies of the brain may be important in ruling out neurologic diseases. Depending on its clinical feautures, HE has been categorized as episodic, persistent, or minimal. Minimal encephalopathy was recently proposed to identify patients with subtle manifestations of HE that cannot be detected by standard clinical examination. ⁴⁹ The common precipitating factors of HE include diuretic therapy, renal failure, GI bleeding, bacterial infections, and constipation. Dietary protein overload is an infrequent cause of worsening encephalopathy. Medications, notably opiates, benzodiazepines, antidepressants, and antipsychotic agents, also may worsen the symptoms of encephalopathy. Surgical portosystemic shunts and TIPSs favor the development of encephalopathy. The differential diagnosis for HE includes intracranial lesions, central nervous system infections, metabolic encephalopathy, toxic encephalopathy attributable to alcohol or drugs, and postseizure encephalopathy.

In the initial management of HE, precipitants should be identified and corrected. ⁵⁰ Lactulose and/or lactitol are helpful in patients with acute onset of severe encephalopathy symptoms and in patients with milder, chronic symptoms. ⁵¹ Lactulose and lactitol stimulate the passage of ammonia from tissues into the gut lumen (and stool) and inhibit intestinal ammonia production. Initial lactulose dosing is 30 mL orally once or twice daily. Dosing is increased until the patient has two to four loose stools per day. Dosing should be reduced if the patient complains of diarrhea, abdominal cramping, or bloating. Higher doses of lactulose may be administered via either a nasogastric tube or a rectal tube to hospitalized patients with severe encephalopathy. Neomycin (2 to 6 g/day), metronidazole (250 mg/day), rifaximin (1,200 mg/day), and other oral antibiotics (vancomycin, paromomycin, and fluoroquinolones) serve as second-line agents, but their efficacy has been convincingly demonstrated. ^52,53 Antibiotics act by decreasing the colonic concentration of ammoniagenic bacteria. Other chemicals capable of decreasing blood ammonia levels are l -ornithine l -aspartate (available in Europe) and sodium benzoate. Short-term use of flumazenil, a benzodiazepine receptor antagonist, may have beneficial effects on short-term awakening from deeper stages of encephalopathy. Low-protein diets are not recommended since they worsen the catabolic status of these patients and may favor malnutrition. In patients with portosystemic shunts including TIPSs, shunt diameter reduction can be considered when HE is severe and does not respond to medical therapy. In patients with persistent encephalopathy and relatively well-preserved liver function, the possibility of a large spontaneous portosystemic shunt should be considered because improvement in HE can occur after radiologic closure. Because HE carries a poor short-term prognosis, patients with episodic and/or permanent encephalopathy should be evaluated for OLT.

Hepatocellular Carcinoma

HCC is a major cause of mortality among patients with cirrhosis. ⁵⁴ The annual incidence of HCC in cirrhosis attributable to HCV is 3 to 5%. Surveillance to detect early HCC is based on the use of US every 4 to 6 months. In nodules smaller than 1 cm, which are malignant in less than 50% of cases, close follow-up is recommended. HCC diagnosis is based on elevated serum a-fetoprotein levels; US, helical CT, and MRI findings; and positive cytohistology. The prognosis of HCC at early stages relies on tumor status, liver function, and the treatment applied. Different staging systems (Barcelona Cancer Liver Center, Okuda, etc) use tumor characteristics and liver function to classify patients with HCC. ⁵⁵ Unfortunately, many HCC patients are still diagnosed at advanced stages that preclude the use of curative treatments. The 3-year survival rates of patients at intermediate and advanced stages are 65% and 16%, respectively. Curative treatments for HCC include surgical resection, OLT, and percutaneous ablation. Resection and OLT achieve the best outcomes in well-selected candidates (5-year survival, 60 to 70%), whereas percutaneous treatments provide worse results (5-year survival, 40 to 50%). Transplantation is the ideal treatment for patients with a single lesion 5 cm or less in diameter or with up to three lesions, all less than 3 cm in diameter, and decompensated cirrhosis. ⁵⁶ Arterial embolization may improve quality of life and, in some cases, even improve survival. Tamoxifen does not seem to have a significant beneficial effect. Sorafenib, a multikinase inhibitor, modestly improves survival in patients with advanced HCC. ⁵⁷

Indications for Liver Transplantation

OLT plays a key role in the management of advanced cirrhotic patients. ⁵⁸ In the United States, more than 3,000 liver transplantations are performed each year. However, because there are many more candidates for transplantation than available donor livers, the selection and timing of patient referral are critical. Biochemical indexes vary, depending on whether liver disease is caused by hepatocellular conditions or chronic cholestatic liver disorders [ seeTable 5 ]. Patients with a serum bilirubin level higher than 3 mg/dL in noncholestatic disease or lower than 5 mg/dL in cholestatic disorders, a prothrombin time prolonged by more than 5 seconds, or a serum albumin level lower than 2.5 g/dL should be referred for transplant workup. Clinical criteria include HCC, HE, refractory ascites, recurrent variceal bleeding, SBP, and intractable pruritus. The clinical complications of cholestatic liver disease, such as intractable pruritus, recurrent bacterial cholangitis, and progressive bone disease, often warrant liver transplantation before HE or variceal hemorrhage develops. Contraindications for OLT include severe cardiovascular or pulmonary disease, active drug or alcohol abuse, malignancy outside the liver, sepsis, or psychosocial problems that might jeopardize the patient's ability to follow the medical regimen after transplantation. The presence of HIV infection was once considered a relative contraindication to OLT. However, successful liver transplantation is now being performed in patients with no detectable HIV viral load as the result of antiretroviral therapy. Advances in surgical technique, organ preservation, and immunosuppression have resulted in dramatic improvements in postoperative survival over the last two decades. ⁵⁹ In the early 1980s, the percentages of patients surviving 1 year and 5 years after liver transplantation were only 70% and 15%, respectively. Now, patients can anticipate a 1-year survival rate of 85% and a 5-year survival rate above 70%. Quality of life after liver transplantation is good in most cases. Approximately 15% of patients listed as candidates die while waiting for OLT because of donor organ shortages. Strategies to improve the current donor organ shortage include programs to increase public awareness of the importance of organ donation, increased use of living donor liver transplantation for pediatric recipients, and exploration of the efficacy and safety of living donor liver transplantation in adults. ⁶⁰

Prognosis

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The prognosis of patients with cirrhosis depends on the underlying disease, the occurrence of major complications (ascites, GI bleeding, encephalopathy, HRS, bacterial infections), the degree of liver insufficiency, and the existence of HCC. In patients with compensated cirrhosis, the probability of developing major clinical complications and the survival probability rate at 10 years are 58% and 47%, respectively. For patients with decompensated cirrhosis, prognosis can be estimated by the Child-Pugh classification and, more recently, by the MELD score. ⁶¹ The variables included in the Child-Pugh score reflect the synthetic (albumin and prothrombin time) and elimination (bilirubin) functions of the liver and major complications (ascites and encephalopathy). In contrast, the MELD score includes only numeric variables that reflect liver function (prothrombin time and bilirubin) and renal function (serum creatinine). The principal advantage of the MELD score is that it is based on objective variables selected by their influence on prognosis; also, the MELD score is continuous, which helps scoring individuals more precisely among large populations. ⁶² However, the MELD score has not been validated in some clinical situations. For example, in patients with type 1 HRS, the MELD score may underestimate the patient's survival. ^63,64 Currently, the MELD score is used by most US transplant centers for patient allocation on the waiting list for liver transplantation.

Ramón Bataller, MD, has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

Pere Ginès, MD, has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

References

---

1.Desmet VJ, Roskams T: Cirrhosis reversal: a duel between dogma and myth. J Hepatol 200440:860, .

2.Afdhal NH: The natural history of hepatitis C. Semin Liver Dis 200424:3, . [PMID 15346240]

3.Vong S, Bell BP: Chronic liver disease mortality in the United States, 1990-1998. Hepatology 200439:476, .

4.Bataller R, North KE, Brenner DA: Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology 200337:493, . [PMID 12601343]

5.Bataller R, Brenner DA: Liver fibrosis. J Clin Invest 2005115:209, . [PMID 15690074]

6.Roskams T, Baptista A, Bianchi L: Histopathology of portal hypertension: a practical guideline. Histopathology 200342:2, . [PMID 12493019]

7.Groszmann RJ, Abraldes JG: Portal hypertension: from bedside to bench. J Clin Gastroenterol 200539:S125, . [PMID 15758647]

8.Bosch J: Vascular deterioration in cirrhosis: the big picture. J Clin Gastroenterol 200741:S247, . [PMID 17975472]

9.Schuppan D, Afdhal NH: Liver cirrhosis. Lancet 2008371:838, . [PMID 18328931]

10.Murakami T, Mochizuki K, Nakamura H: Imaging evaluation of the cirrhotic liver. Semin Liver Dis 200121:213, . [PMID 11436573]

11.Castera L, Forns X, Alberti A: Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol 200848:835, . [PMID 18334275]

12.Dienstag JL: The role of liver biopsy in chronic hepatitis C. Hepatology 200236:S152, . [PMID 12407589]

13.McCormack G, Nolan N, McCormick PA: Transjuglar liver biopsy: a review. Ir Med J 200194:11, . [PMID 11322217]

14.Cardenas A, Gines P: Management of complications of cirrhosis in patients awaiting liver transplantation. J Hepatol 200542:S124, . [PMID 15777567]

15.Everson GT, Hoefs JC, Seeff LB: Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: Lessons from the HALT-C Trial. Hepatology 200644:1675, . [PMID 17133499]

16.Fartoux L, Degos F, Trépo C: Effect of prolonged interferon therapy on the outcome of hepatitis C virus-related cirrhosis: a randomized trial. Clin Gastroenterol Hepatol 20075:502, .

17.Forns X, Garcia-Retortillo M, Serrano T: Antiviral therapy of patients with decompensated cirrhosis to prevent recurrence of hepatitis C after liver transplantation. J Hepatol 200339:389, . [PMID 12927925]

18.Lai CJ, Terrault NA: Antiviral therapy in patients with chronic hepatitis B and cirrhosis. Gastroenterol Clin North Am 200433:629, . [PMID 15324948]

19.Levitsky J, Mailliard ME: Diagnosis and therapy of alcoholic liver disease. Semin Liver Dis 200424:233, . [PMID 15349802]

20.Rambaldi A, Gluud C: Colchicine for alcoholic and non-alcoholic liver fibrosis and cirrhosis. Cochrane Database Syst Rev 20053:CD002148, .

21.O'Shea RS, McCullough AJ: Treatment of alcoholic hepatitis. Clin Liver Dis 20059:103, . [PMID 15763232]

22.Oo YH, Neuberger J: Options for treatment of primary biliary cirrhosis. Drugs 200464:2261, . [PMID 15456326]

23.Ginès P, Cárdenas A, Arroyo V, Rodés J: Management of cirrhosis and ascites. N Engl J Med 2004350:1646, .

24.Gines P, Tito L, Arroyo V: Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 198894:1493, . [PMID 3360270]

25.Gines P, Uriz J, Calahorra B: Transjugular intrahepatic portosystemic shunting versus paracentesis plus albumin for refractory ascites in cirrhosis. Gastroenterology 2002123:1839, . [PMID 12454841]

26.Ginès P, Cárdenas A: The management of ascites and hyponatremia in cirrhosis. Semin Liver Dis 200828:43, .

27.Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V: Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 200756:1310, .

28.Martín-Llahí M, Pépin MN, Guevara M: Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology 2008134:1352, .

29.Fernández J, Escorsell A, Zabalza M: Adrenal insufficiency in patients with cirrhosis and septic shock: Effect of treatment with hydrocortisone on survival. Hepatology 200644:1288, .

30.Tandon P, Garcia-Tsao G: Bacterial infections, sepsis, and multiorgan failure in cirrhosis. Semin Liver Dis 200828:26, . [PMID 18293275]

31.Fernandez J, Bauer TM, Navasa M: Diagnosis, treatment and prevention of spontaneous bacterial peritonitis. Baillieres Best Pract Res Clin Gastroenterol 200014:975, . [PMID 11139350]

32.Sort P, Navasa M, Arroyo V: Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999341:403, . [PMID 10432325]

33.Fernández J, Navasa M, Planas R: Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 2007133:818, .

34.Garcia-Pagan JC, De Gottardi A, Bosch J: Review article: the modern management of portal hypertension–primary and secondary prophylaxis of variceal bleeding in cirrhotic patients. Aliment Pharmacol Ther 200828:178, .

35.Sanyal AJ, Bosch J, Blei A: Portal hypertension and its complications. Gastroenterology 2008134:1715, . [PMID 18471549]

36.Jutabha R, Jensen DM, Martin P: Randomized study comparing banding and propranolol to prevent initial variceal hemorrhage in cirrhotics with high-risk esophageal varices. Gastroenterology 2005128:870, . [PMID 15825071]

37.Norberto L, Polese L, Cillo U: A randomized study comparing ligation with propranolol for primary prophylaxis of variceal bleeding in candidates for liver transplantation. Liver Transpl 200713:1272, . [PMID 17370331]

38.Fernández J, Ruiz del Arbol L, Gómez C: Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterology 2006131:1049, .

39.Abraldes JG, Bosch J: The treatment of acute variceal bleeding. J Clin Gastroenterol 200741:S312, . [PMID 17975482]

40.Henderson JM: Surgery versus transjugular intrahepatic portal systemic shunt in the treatment of severe variceal bleeding. Clin Liver Dis 200610:599, . [PMID 17162230]

41.Merkel C, Bolognesi M, Sacerdoti D: The hemodynamic response to medical treatment of portal hypertension as a predictor of clinical effectiveness in the primary prophylaxis of variceal bleeding in cirrhosis. Hepatology 200032:930, . [PMID 11050041]

42.Tan PC, Hou MC, Lin HC: A randomized trial of endoscopic treatment of acute gastric variceal hemorrhage: N-butyl-2-cyanoacrylate injection versus band ligation. Hepatology 200643:690, . [PMID 16557539]

43.Hoeper MM, Krowka MJ, Strassburg CP: Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 2004363:1461, . [PMID 15121411]

44.Lima BL, Franca AV, Pazin-Filho A: Frequency, clinical characteristics, and respiratory parameters of hepatopulmonary syndrome. Mayo Clin Proc 200479:42, . [PMID 14708947]

45.Swanson KL, Wiesner RH, Krowka MJ: Natural history of hepatopulmonary syndrome: Impact of liver transplantation. Hepatology 200541:1122, . [PMID 15828054]

46.Herve P, Le Pavec J, Sztrymf B: Pulmonary vascular abnormalities in cirrhosis. Best Pract Res Clin Gastroenterol 200721:141, . [PMID 17223502]

47.Ferenci P, Lockwood A, Mullen K: Hepatic encephalopathy quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 200235:716, . [PMID 11870389]

48.Butterworth RF: Pathogenesis of hepatic encephalopathy: new insights from neuroimaging and molecular studies. J Hepatol 200339:278, . [PMID 12873828]

49.Ortiz M, Jacas C, Cordoba J: Minimal hepatic encephalopathy: diagnosis, clinical significance and recommendations. J Hepatol 200542:S45, . [PMID 15777572]

50.Blei AT: Treatment of hepatic encephalopathy. Lancet 2005365:1383, . [PMID 15836876]

51.Morgan MY, Hawley KE: Lactitol vs. lactulose in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double-blind, randomized trial. Hepatology 19877:1278, . [PMID 3315932]

52.Bongaerts G, Severijnen R, Timmerman H: Effect of antibiotics, prebiotics and probiotics in treatment for hepatic encephalopathy. Med Hypotheses 200564:64, . [PMID 15533613]

53.Mas A, Rodes J, Sunyer L: Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial. J Hepatol 200338:51, . [PMID 12480560]

54.Llovet JM, Burroughs A, Bruix J: Hepatocellular carcinoma. Lancet 2003362:1907, . [PMID 14667750]

55.Llovet JM, Fuster J, Bruix J: The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl 200410:S115, . [PMID 14762851]

56.Brown KA: Liver transplantation. Curr Opin Gastroenterol 200521:331, . [PMID 15818154]

57.Llovet JM, Ricci S, Mazzaferro V: Sorafenib improves survival in advanced hepatocellular carcinoma (HCC): results of a phase III randomized placebo-controlled trial (SHARP trial). J Clin Oncol 200725:18S, .

58.Brown KA: Liver transplantation. Curr Opin Gastroenterol 200521:331, . [PMID 15818154]

59.Tra TT, Nissen N, Poordad FF: Advances in liver transplantation. New strategies and current care expand access, enhance survival. Postgrad Med 2004115:73-6,, .

60.White SA, Al-Mukhtar A, Lodge JP, Pollard SG: Progress in living donor liver transplantation. Transplant Proc 200436:2720, . [PMID 15621133]

61.Durand F, Valla D: Assessment of the prognosis of cirrhosis: Child-Pugh versus MELD. J Hepatol 200542:S100, . [PMID 15777564]

62.Kamath PS, Wiesner RH, Malinchoc M: A model to predict survival in patients with end-stage liver disease. Hepatology 200133:464, . [PMID 11172350]

63.Alessandria C, Ozdogan O, Guevara M: MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantationHepatology:1282, 200541:1282, .

64.Londoño MC, Cárdenas A, Guevara M: MELD score and serum sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation. Gut 200756:1283, .