ACP medicine, 3rd Edition

Gastroenterology

Cirrhosis of the Liver

Ramón Bataller MD1

Pere GinèS MD2

1Liver Unit, Institut de Malalties Digestives i Metabòliques Hospital Clinic, Barcelona, Spain

2Liver Unit, Institut de Malalties Digestives i Metabòliques Hospital Clinic, Barcelona, Spain

The authors have no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

October 2005

Cirrhosis is the most advanced stage of most types of chronic liver disease. It is defined as a diffuse disorganization of normal hepatic structure by extensive fibrosis associated with regenerative nodules. Fibrosis is potentially reversible if the causative agent is removed. However, advanced cirrhosis comprises major alterations in the hepatic vascular bed and is usually irreversible.1 Clinically, cirrhosis is associated with high morbidity and mortality. It leads to a wide spectrum of characteristic clinical manifestations, mainly from hepatic insufficiency and portal hypertension.2 Major complications include ascites, renal failure, gastrointestinal bleeding, encephalopathy, bacterial infections, and coagulopathy. Cirrhosis is also a risk factor for developing hepatocellular carcinoma (HCC). Decompensated cirrhosis carries a poor prognosis, in both the short and the long term, and orthotopic liver transplantation (OLT) is often indicated.

Epidemiology

Cirrhosis is the ninth leading cause of death in the United States.3 Chronic liver disease and cirrhosis cause 4% to 5% of deaths in persons 45 to 54 years of age and result in about 30,000 deaths each year. The incidence of newly diagnosed cases of chronic liver disease in the United States is 72.3 per 100,000 population. The prevalence of chronic liver disease and cirrhosis is 5.5 million cases. Over 60% of patients are male. Cirrhosis is more common in Hispanic whites and Native Americans; it is the sixth leading cause of death in those two populations. The economic impact of cirrhosis is considerable, with $1.5 billion in direct costs and $234 million in indirect costs in 2000.4 In 2002, there were 421,000 hospitalizations for chronic liver disease and cirrhosis.5

Etiology and Genetic Factors

In the United States, the main causes of cirrhosis are hepatitis C virus (HCV) infection and alcoholic liver disease, which account for two thirds of all cirrhosis 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) [seeTable 1]. With the current epidemic of obesity, nonalcoholic steatohepatitis (NASH) is increasingly being recognized as a major cause of cirrhosis. Many patients diagnosed with cryptogenic cirrhosis have a history of metabolic syndrome, suggesting a role for NASH in the pathogenesis of their cirrhosis.

Table 1 Main Causes of Cirrhosis

Viral diseases

Hepatitis B

Hepatitis C

Hepatitis D

Autoimmune diseases

Autoimmune hepatitis

Primary biliary cirrhosis

Primary sclerosing cholangitis

Graft versus host disease

Hepatotoxic agents

Alcohol abuse

Drugs (e.g., methotrexate, α-methyldopa, amiodarone)

Vitamin A intoxication

Acquired metabolic diseases

Nonalcoholic steatohepatitis

Vascular diseases

Chronic right-sided heart failure

Budd-Chiari syndrome

Veno-occlusive disease

Inferior vena cava thrombosis

Genetic diseases

Wilson disease

Hemochromatosis

Type IV glycogen storage disease

Tyrosinemia

α1-Antitrypsin deficiency

Miscellaneous

Secondary biliary cirrhosis

Cryptogenic

Many genes interact with environmental factors to cause cirrhosis.6 Nongenetic factors that influence progression to cirrhosis include age, alcohol intake, immunosuppressive therapy, and HIV infection. Genetic factors involved in the pathogenesis of cirrhosis are not well known, but they 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, inflammatory cytokines, and fibrogenic mediators influence the occurrence of conditions that may cause chronic liver injury (e.g., alcohol abuse, chronic HCV infection, and autoimmune disorders), as well as modulate the progression of chronic hepatitis to cirrhosis.

Pathogenesis

EARLY PHASE: LIVER FIBROGENESIS

Cirrhosis is the end stage of many forms of chronic liver disease that are characterized by progressive fibrosis. Hepatic fibrosis is the result of the wound-healing response of the liver to repeated injury.7 It consists of the accumulation of extracellular matrix (ECM) proteins, mainly fibrillar collagen, from both increased ECM synthesis and decreased degradation. Myofibro blasts, mostly derived from hepatic stellate cells, are the main ECM-producing cells in the injured liver. Chronic injury promotes the activation of stellate cells into fibrogenic myofibroblasts [see Figure 1]. Key mediators of this process include inflammatory cytokines, transforming growth factor-1 (TGF-1), and angiotensin II. The pathogenesis of liver fibrosis varies with the underlying cause. In alcohol-induced liver disease, lipopolysaccharide levels are elevated in portal blood; the lipopolysaccharide activates Kupffer cells to release reactive oxygen species and cytokines, activating stellate cells and sensitizing 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 cells and cytokines mediate persistent bile duct damage. Biliary cells secrete fibrogenic mediators that activate neighboring portal myofibroblasts to secrete ECM. Eventually, perisinusoidal stellate cells become activated and fibrotic bands develop. The pathogenesis of liver fibrosis in NASH is poorly understood, but a so-called two-hit model has been proposed: first, hyperglycemia and insulin resistance lead to elevated serum levels of free fatty acids, resulting in hepatic steatosis; second, oxidative stress and inflammatory cytokines promote hepatocyte apoptosis and the recruitment of inflammatory cells, leading to progressive fibrosis.

 

Figure 1. Liver Biopsy in Chronic Hepatitis C Infection

Immunohistochemical analysis of accumulation of fibrogenic myofibroblasts (smooth muscle [α-actin-positive] cells) in a liver biopsy specimen from a 56-year-old man with liver cirrhosis from chronic hepatitis C infection. The patient was admitted for the study of new-onset ascites. Myofibroblasts mainly accumulate in fibrous septa. Some activated hepatic stellate cells can be observed around hepatic sinusoids (arrow). (a) Magnification: x40; (b) magnification: x600.

CIRRHOSIS

Bridging fibrosis is associated with profound abnormalities in hepatic microcirculation.8 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 esophageal varices.9 The resulting portal hypertension leads to splanchnic vasodilatation, which increases hepatic venous blood flow. Systemic vascular resistance is decreased, and eventually, there is a marked activation of systemic vasoconstrictor systems that worsen portal hypertension and favor ascites formation. Hepatocellular function is progressively impaired, and there is decreased function of the reticuloendo-thelial system, leading to endotoxemia and the increased risk of bacterial infections. Eventually, hepatocellular function fails, resulting in severe coagulopathy and hepatic encephalopathy. A profound circulatory dysfunction from impaired myocardial function and decreased systemic vascular resistance is frequently seen. In very late stages of cirrhosis, renal vasoconstriction develops, leading to the hepatorenal syndrome (HRS). In this phase of the disease, most patients die unless an OLT is rapidly performed.

Diagnosis

The diagnostic process in a patient with suspected cirrhosis is intended to determine the presence, severity, and cause of the condition. Data obtained from the history, physical examination, laboratory tests, and liver biopsy are used to identify the etiology of cirrhosis [seeTable 2].

Table 2 Identification of the Main Causes of Cirrhosis

Cause

Diagnostic Method

Alcohol-related

Medical history (also obtained from relatives), urinary alcohol levels, histologic findings

Hepatitis C virus (HCV)

Anti-HCV antibodies, HCV RNA assay

Hepatitis B virus (HBV)

HBsAg, HBV DNA assay

Hepatitis D virus (HDV)

Anti-delta IgM or IgG

Autoimmune disease

Antitissue antibodies (ANA, LKM, ASMA), hypergammaglobulinemia, histologic findings

Primary biliary cirrhosis

AMA, histologic findings

Primary sclerosing cholangitis

Severe cholestasis; detection of biliary tract abnormalities by magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRI/MRCP) or ERCP; ANCA; presence of inflammatory bowel disease; histologic findings

Wilson disease

Serum ceruloplasmin levels, Kayser-Heischer rings, copper content in the liver, genetic studies

Hemochromatosis

Serum ferritin levels, total iron binding capacity, iron content in the liver, genetic studies

Nonalcoholic steatohepatitis

Metabolic syndrome, histologic findings (may be absent in cirrhosis), absence of alcohol abuse

AMA—antimitochondrial antibodies   ANA—antinuclear antibody   ANCA—antineutrophil cytoplasmic autoantibodies   ASMA—anti-smooth muscle antibodies   ERCP—endoscopic retrograde cholangiopancreatography   HBsAg—hepatitis B surface antigen   LKM—liver/kidney microsomal antibody

CLINICAL MANIFESTATIONS

Cirrhosis can be clinically silent, and some cases are discovered incidentally at laparotomy or autopsy. In many patients, symptoms are insidious in onset and include generalized weakness, anorexia, malaise, and weight loss. Skeletal muscle mass is frequently reduced. So-called compensated cirrhosis is defined by the absence of symptoms or the presence of only minor symptoms. Eventually, most patients exhibit the clinical manifestations of hepatocellular dysfunction and portal hypertension, including progressive jaundice, bleeding from gastroesophageal varices, ascites, and neuropsychiatric symptoms. The abrupt onset of one of these complications may be the first manifestation of cirrhosis. Coagulopathy and subsequent mucosal bleeding typically occur in patients with advanced cirrhosis. Progressive obstruction to bile flow, which is especially common in patients with PBC and PSC, leads to skin hyperpigmentation, jaundice, pruritus, and xanthelasmas. Patients who have progressed to such conditions often experience malnutrition secondary to anorexia, fat malabsorption, and increased catabolism. Deficiency of fat-soluble vitamins is also frequently found in patients with cirrhosis. In patients with alcohol-induced liver disease, extrahepatic symptoms related to the nervous system, the heart, and the pancreas can also be present.

PHYSICAL EXAMINATION FINDINGS

Physical examination can be normal in patients with early cirrhosis. More commonly, the liver is enlarged initially and is palpable. In advanced cirrhosis, liver size usually decreases. Splenomegaly is a common finding. Ascites, peripheral edema, or both may be present, and collateral venous circulation can be observed in the abdomen. Patients with hepatic encephalopathy have 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 (e.g., PBC) or hemochromatosis. Advanced cirrhosis is commonly marked by severe malnourishment, prominent ascites, and neuropsychiatric symptoms [see Figure 2].

 

Figure 2. Ascites in Advanced Cirrhosis

Photograph of a 45-year-old patient with advanced cirrhosis from alcohol-induced liver disease. The patient was admitted because of tense ascites, and a superimposed acute alcoholic hepatitis was diagnosed. A large-volume paracentesis followed by albumin administration was performed.

LABORATORY STUDIES

Blood Tests

Liver function test results are commonly abnormal in patients with cirrhosis. Serum aspartate aminotransferase (AST) levels are frequently elevated, but levels above 300 U/L are uncommon. Serum levels of alanine aminotransferase (ALT) may be relatively low (AST/ALT ratio greater than 2). Serum prothrombin time is frequently prolonged, reflecting reduced synthesis of clotting proteins, most notably the vitamin K-dependent factors. Serum albumin levels are decreased, mainly because of poor hepatocellular synthesis. Total serum globulin concentration increases in advanced cirrhosis, as a result of poor reticuloendothelial function and increased blood levels of bacterial products. The alkaline phosphatase concentration is usually only moderately increased, except in patients with biliary diseases (i.e., PBC or PSC), who show markedly increased levels of alkaline phosphatase and γ-glutamyl transpeptidase, which in some cases are associated with increased bilirubin levels. Anemia is fairly common; it is 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. Cholesterol and triglyceride levels may be increased in patients with biliary obstruction, whereas they are low in patients with advanced cirrhosis of nonbiliary origin. Cirrhotic patients may develop glucose intolerance and diabetes mellitus, mainly because of insulin resistance. Central hyperventilation may lead to respiratory alkalosis. Dietary deficiency and increased urinary losses cause hypomagnesemia and hypophosphatemia. Renal failure, as indicated by elevated creatinine and blood urea nitrogen levels, and hyponatremia can be observed in cirrhotic patients with ascites.

Imaging Studies

Real-time ultrasonography, in combination with color flow Doppler, is the most useful tool in the evaluation of patients with cirrhosis.10Ultrasonography is useful for demonstrating the morphologic characteristics of cirrhosis, including irregular or nodular liver edges, altered structure, and signs of portal hypertension such as portocollateral veins. It is also useful to detect hepatic steatosis, ascites, splenomegaly, and portal vein thrombosis. In patients with cholestasis, ultrasonography helps rule out extrahepatic causes of jaundice. Doppler ultrasonography provides useful information on portal hemodynamics and can detect reversal of portal blood flow [see Figure 3]. Ultrasound examination is particularly helpful for detecting hepatic tumors such as HCC. Demonstration of tumor vascularization by Doppler ultrasonography, with or without injection of ultrasound contrast, is valuable in the differentiation of regenerating nodules from HCC. Dynamic studies using computed tomography and magnetic resonance imaging are also useful in the assessment of cirrhosis and the diagnosis of hepatic tumors previously detected by ultrasonography. The use of CT or MRI to screen for HCC in patients with cirrhosis is limited by the high cost of these techniques.

 

Figure 3. Ultrasound: Cirrhosis from Chronic Hepatitis C

Real-time ultrasound images of a 56-year-old man with liver cirrhosis from chronic hepatitis C. The patient had a compensated cirrhosis and was undergoing liver ultrasonography plus determination of α-fetoprotein serum levels every 6 months to screen for hepatocellular carcinoma. (a) The liver showed irregular edges (arrow) and an altered structure. (b) A patent portal vein thrombosis was detected (arrow).

Liver Biopsy

Liver biopsy can unequivocally establish the presence of cirrhosis.11 Liver biopsy helps determine the cause of cirrhosis, as well as provides information on the extent of liver damage. The biopsy is usually performed using a percutaneous approach, but percutaneous biopsy should not be used in patients with severe coagulopathy (i.e., those with an international normalized ratio [INR] greater than 1.5 or a platelet count less than 50,000/µl), and it must be used with caution in patients with ascites or severe obesity. Limitations of liver biopsy are that it is an invasive procedure and that sampling error can occur (i.e., false negative results), especially in patients with macronodular cirrhosis.

Transjugular liver biopsy offers an alternative to percutaneous biopsy. Trans jugular liver biopsy can be used in patients with ascites; is indicated in patients with severe coagulopathy; and allows the measurement of portal pressure.12 However, the amount of tissue obtain ed is limited, and often, the diagnosis of cirrhosis cannot be made. In selected cases, liver biopsy can be performed during laparoscopy. This approach is generally reserved for the staging of 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 (diameter < 3 mm), whereas in macro nodular cirrhosis, nodules vary in size (diameter 3 mm to 5 cm) and contain some normal lobular structure (e.g., portal tracts or terminal hepatic venules).

In some cases, histologic findings help identify the causative agent of cirrhosis, such as periportal lymphocyte infiltration in HCV-induced cirrhosis; Mallory bodies, polymorphonuclear leukocyte (PMN) infiltration, and steatosis in alcohol-induced cirrhosis and NASH; biliary involvement in PBC; and massive iron deposition in hemochromatosis. In advanced cirrhosis, however, different underlying diseases may have similar histologic findings.

Management

GENERAL MEASURES

Cirrhotic patients should undergo regular follow-up. Patients with compensated cirrhosis should be seen two or three times a year. At diagnosis, an extensive medical history should be taken and laboratory tests, including viral serologies, performed to identify the causative agent. Endoscopic examination should be done to assess the presence and size of esophageal varices. Abdominal ultrasonography and α-fetoprotein serum measurements should be performed at diagnosis and every 6 months thereafter to detect early HCC. Criteria for OLT should be reviewed periodically, and major clinical complications (i.e., bacterial infections, renal impairment, and GI bleeding) should be actively prevented.13 Many patients complain of anorexia, and care should be taken to ensure that patients take in adequate calories and protein. Nutritional supplements are often beneficial. Zinc deficiency is common and should be treated. Zinc sulfate (50 to 200 mg/day) may be effective in the treatment of muscle cramps and is adjunctive therapy for hepatic encephalopathy. Pruritus is a common complaint in cirrhotic patients, especially in those with chronic cholestasis (i.e., PBC and PSC). Drugs that may provide relief for pruritus include cholestyramine, ursodeoxycholic acid, naltrexone, rifampicin, and ondansetron. Some men suffer from hypo gonadism; those with severe symptoms can be treated 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. Evidence of decreased bone mineralization from bone densitometry studies also may prompt institution of therapy with a bisphosphonate (e.g., alendronate). Mild exercise, including walking or 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 be vaccinated against hepatitis A. Other protective measures include vaccination against hepatitis B, pneumococcal infection, and influenza. Potential hepatotoxic medications should be avoided. Patients with ascites should not receive nonsteroidal anti-inflammatory drugs (NSAIDs) or nephrotoxic antibiotics (e.g., aminoglycosides). NSAID use may predispose patients with cirrhosis to development of renal failure or GI bleeding. Surgery and general anesthesia carry increased risks in patients with cirrhosis, particularly those with portal hypertension, and may lead to hepatic decompensation.

COMPENSATED CIRRHOSIS

Specific medical therapies may be applied to different liver diseases to diminish disease progression. However, these therapies may become progressively less effective if 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 from HCV infection, although the rate of sustained response is lower than in noncirrhotic patients.14 Moreover, antiviral treatment may worsen existing anemia or thrombocytopenia, and drug discontinuance is frequent. In patients with HBV-related cirrhosis, lamivudine appears to be a safe and effective antiviral agent, which may improve or stabilize liver disease in selected patients with advanced cirrhosis and active HBV replication.15 However, viral resistance can develop with prolonged treatment. Adefovir and entecavir are newer antiviral agents that have activity against both wild-type and lamivudine-resistant HBV. The most effective measure for patients with alcohol-induced cirrhosis is to stop drinking.16 Abstinence can stabilize and may dramatically improve liver function. Psychological support is highly recommended to help patients achieve prolonged alcohol abstinence. Nutritional support is advisable in all alcoholic patients. Although small clinical trials have shown improvement in survival and reversal of cirrhosis with colchicine treatment, a randomized, controlled trial found that in patients with advanced alcoholic cirrhosis, there was no reduction in overall or liver-specific mortality with colchicine; although liver histology improved to septal fibrosis in a minority of patients after 24 months of treatment, rates of improvement were similar with placebo and colchicine.17

In cases of superimposed alcoholic hepatitis, treatment with glucocorticoids (40 mg/day for 4 weeks followed by tapering of therapy for 1 or 2 weeks) or pentoxifylline (400 mg three times daily) increases short-term survival.18 In patients with PBC, ursodiol (13 to 15 mg/kg/day) relieves pruritus and improves blood chemistry test results.19 Although ursodiol may decrease the need for OLT, its usefulness in cirrhotic patients is limited. Other treatments (e.g., glucocorticoids, colchicine, azathioprine) are not indicated, because they are associated with severe side effects. No specific therapy improves the outcome of patients with PSC, but ursodiol does have beneficial effects on biochemical parameters. In patients with cirrhosis from autoimmune hepatitis, immunosuppressant therapy (e.g., glucocorticoids) should be used with caution because it may favor infections, and necroinflammatory injury at this stage of the disease is usually mild. Patients with cirrhosis resulting from hemochromatosis benefit from phlebotomies to reduce iron stores [see 5:II Red Blood Cell Function and Disorders of Iron Metabolism]; those with Wilson disease benefit from treatment with copper chelators (i.e., D-penicillamine or trientine) or zinc [see 11:XV Parkinson Disease and Other Movement Disorders].

DECOMPENSATED CIRRHOSIS

Ascites

Ascites is the most frequent complication of cirrhosis.20 It impairs quality of life and increases the risk of bacterial infections. It is caused primarily by splanchnic vasodilatation from increased synthesis of vasodilators (e.g., 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. Ascites can be graded into three groups: grade 1 ascites is clinically silent and detectable only by ultrasonography; grade 2 ascites is moderate, with patent distention of the abdomen; and grade 3 ascites is tense, with marked abdominal distention.

The first step in the evaluation of patients with new-onset ascites is to rule out extrahepatic causes (e.g., tuberculosis and malignancies). Besides serum tests, ultrasonography is useful to confirm signs of cirrhosis, rule out HCC, and detect portal vein thrombosis. Ascitic fluid should be examined in patients with new-onset ascites, suspected spontaneous bacterial peritonitis (SBP), encephalopathy, or GI bleeding. Measurements should be done of cell counts, albumin and total protein concentrations, and culture in blood culture bottles. Renal function and circulatory status should also be assessed in all patients.

The initial management of ascites includes reduction of sodium intake to 60 to 90 mEq/day. In patients with dilutional hyponatremia (i.e., a serum sodium concentration of 130 mmol/L in the presence of ascites or edema), fluid intake should be restricted to less than 1,000 ml/day, although compliance is problematic. 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 be also added; however, patients should be followed closely to avoid excessive diuresis. The recommended weight loss to prevent renal failure is 300 to 500 g/day in patients without peripheral edema and 800 to 1,000 g/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.21 Albumin is the plasma expander of choice if more than 5 L of ascitic fluid is removed (8 g of I.V. albumin for each 1 L of ascitic fluid removed). Spironolactone (100 to 400 mg/day), with or without furosemide (40 to 160 mg/day), can be given to prevent recurrence of ascites. Doses of diuretics should be adjusted according to diuretic response.

Refractory ascites, which is defined as a lack of response to high doses of diuretics or the occurrence of side effects (e.g., renal failure, encephalopathy, hyponatremia, or hyperkalemia) that preclude the use of diuretics, occurs in 5% to 10% of patients with ascites. Current therapeutic strategies for patients with refractory ascites include repeated large-volume paracentesis with plasma expanders and transjugular intrahepatic portosystemic shunting (TIPS) [see Figures 4a and 4b]. TIPS is effective in preventing ascites recurrence, but it does not improve survival.22 The principal drawbacks of TIPS are the high rates of shunt stenosis and hepatic encephalopathy. The use of polytetrafluoroethylene-covered prostheses for TIPS can improve patency rates and decrease clinical relapses and the need for reintervention, without increasing the risk of encephalopathy.23 TIPS is indicated for patients without severe liver failure or encephalopathy 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, because their 5-year survival rate is only 30% to 40%. Patients with refractory ascites, SBP, or HRS have a worse prognosis, and prioritization in the waiting list should be considered.

 

Figure 4a. Stent Used in Transjugular Intrahepatic Portosystemic Shunting

Transjugular intrahepatic portosystemic shunting is basically indicated for patients with variceal bleeding and refractory ascites. It consists of an autoexpandable stent, which is inserted using a transjugular approach.

 

Figure 4b. Shunt Between Portal Vein and Inferior Vena Cava

The stent (arrow) creates a shunt between a portal vein branch and the inferior vena cava.

Dilutional hyponatremia is present in 30% to 35% of hospitalized patients with cirrhosis and ascites.24 It reflects impaired excretion of renal solute free water caused by nonosmotic hypersecretion of antidiuretic hormone. Although dilutional hyponatremia is commonly asymptomatic, it may favor the development of hepatic encephalopathy. Management consists of fluid restriction (1,000 ml/day) and discontinuance of diuretics; however, these measures do not correct hyponatremia in many cases. Vasopressin type 2 receptor antagonists are being evaluated for the management of hyponatremia, but they are not available in the United States.

Hepatorenal Syndrome

HRS is the most severe complication of patients with cirrhosis.25 It is a functional renal failure resulting from extreme renal vasoconstriction [see 10:VI Acute Renal Failure]. HRS may occur spontaneously or after precipitating conditions such as SBP, acute alcoholic hepatitis, or large-volume paracentesis without plasma expansion. Diagnostic criteria for HRS have been established [see Table 3].26

Table 3 Diagnostic Criteria for Hepatorenal Syndrome*

Major Criteria Low glomerular filtration rate, as indicated by serum creatinine level > 1.5 mg/dl or 24-hr creatinine clearance < 40 ml/min
Absence of shock, ongoing bacterial infection, fluid losses, and current treatment with nephrotoxic drugs
No sustained improvement in renal function (decrease in serum creatinine to ≤ 1.5 mg/dl or increase in creatinine clearance to ≥ 40 ml/min) after diuretic withdrawal and expansion of plasma volume with 1.5 L of a plasma expander
Proteinuria < 500 mg/day and no ultrasound evidence of obstructive uropathy or parenchymal renal disease
Additional Criteria
Urinary volume < 500 ml/day
Urinary sodium level < 10 mEq/L
Urinary osmolality > plasma osmolality
Urinary red blood cells < 50 cells/high-power field
Serum sodium concentration < 130 mEq/L

* According to the International Ascites Club.26

There are two clinical types of HRS. Type 1 is characterized by progressive oliguria and a rapid rise of the serum creatinine concentration to more than 2.5 mg/dl. Survival of patients with type 1 HRS 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.

In type 1 HRS, the use of vasoconstrictors (e.g., terlipressin, midrodine, and norepinephrine) plus intravenous albumin improves renal function in more than half of patients.27 TIPS is effective for patients with HRS, but 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, but its applicability is limited by the poor survival of these patients.

Spontaneous Bacterial Peritonitis

SBP is a severe infection found in 15% to 25% of cirrhotic patients hospitalized with ascites.28 Predisposing factors include severe liver insufficiency and low protein content in ascitic fluid (< 1 g/dl). SBP appears to be related to the translocation of GI tract bacteria from the mesenteric lymph nodes. Clinical manifestations are variable, ranging from no symptoms to a severe picture of peritonitis [see 7:XXI Peritonitis and Intra-abdominal Abscesses]. SBP should also be suspected in cirrhotic patients with impairment of renal or liver function that has no apparent cause.

The most common causative organisms are Escherichia coli, Streptococcus pneumoniae, Klebsiella species, and other gram-negative enteric organisms. SBP is diagnosed when the ascitic fluid has more than 250 PMNs/µl or is positive for leukocyte esterase (3+ or 4+) on urine dipstick testing. Culture results of ascitic fluid are positive in fewer than 50% of patients.

SBP should be treated empirically. The most commonly used regimen is a 5- to 7-day course of a third-generation cephalosporin (e.g., cefotaxime, 2 g every 8 to 12 hours, or ceftriaxone, 1 g/day).29 Alternatives include oral of loxacin and other intravenous antibiotics with activity against gram-negative enteric organisms. Development of renal failure during SBP is common and is the most important predictor of mortality. Administration of albumin at a dose of 1.5 g/kg at diagnosis and 1 g/kg 48 hours later prevents renal failure and reduces mortality from 30% to 10%.30 Response to therapy is indicated by decreases in the signs of infection and in the PMN count in ascitic fluid. After SBP resolution, patients have a 70% chance of recurrence within 1 year. Prophylactic antibiotic therapy can reduce the recurrence rate of SBP to 20%.31 Current prophylactic regimens include norfloxacin, 400 mg/day, and trimethoprim-sulfamethoxazole, one double-strength tablet 5 days a week. 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.

Variceal Bleeding

Rupture of gastroesophageal varices because of portal hypertension is a severe and frequent complication of cirrhosis.32 Portal hypertension is caused by increased intrahepatic vascular resistance, as well as increased portal blood flow secondary to splanchnic vasodilatation. It is recommended that all patients with cirrhosis be screened for gastroesophageal varices and that those with large varices be offered primary prophylaxis. If esophageal varices are very small or absent, it is recommended that an endoscopic examination be performed every 2 years.

Primary prophylaxis of variceal bleeding should be initiated in patients with medium-size to large varices. Nonselective beta blockers (e.g., nadolol or propranolol) are the treatment of choice. They should be given in a stepwise fashion, with the dose being increased until the resting heart rate decreases by 25% of the baseline value. However, there are a number of limitations to the use of beta blockers in such patients (e.g., hypotension).33 Alternatively, varices can be eradicated by repeated sessions of endoscopic variceal band ligation, although this is more commonly done in Europe than in the United States. Pharmacologic therapy and endoscopic therapy are similarly effective; both reduce the risk of bleeding by 40% to 50%.34 Endoscopic treatment should be offered to cirrhotic patients in whom the use of beta blockers is contraindicated. The 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.35

Acute variceal bleeding

Initial therapy for acute variceal bleeding should be directed at correcting hypovolemia, achieving hemostasis, and preventing severe complications (e.g., renal failure, bacterial infections, and hepatic encephalopathy).32 Volume replacement, as well as the need for blood transfusion, should be considered. Excessive transfusion should be avoided, because it may increase portal pressure and favor variceal rebleeding. In patients with hepatic encephalopathy and those requiring aggressive sedation for endoscopic examination, endotracheal intubation should be considered. Antibiotics (norfloxacin, 400 mg/day, or cefotaxime, 2 g every 12 hours; both for 7 days) decrease the rate of bacterial infections and improve outcome.28 Hemostatic treatments include vasoactive drugs, endoscopic band ligation, and surgical portosystemic shunts or TIPS. Vasoactive drugs that are effective in controlling variceal bleeding include octreotide (100 µg bolus, followed by 50 µg/hr for 5 days); alternatives currently unavailable in the United States are terlipressin (2 mg every 4 hours for the first 48 hours, 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).36

Pharmacologic therapy controls variceal bleeding in 75% to 80% of cases. Cirrhotic patients with upper gastrointestinal bleeding should be initially 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. A repeat session of therapeutic endoscopy can be performed in patients who rebleed. In patients who are hemodynamically unstable or who experience several rebleeding episodes, TIPS or surgical portosystemic shunts or both should be considered.37,38 TIPS controls bleeding in more than 90% of cases and is preferred over shunt surgery because it is associated with lower morbidity and mortality. However, TIPS can impair liver function in patients with advanced cirrhosis. Patients with preserved liver function (Child-Pugh class A) may also benefit from shunt surgery (i.e., H-graft portacaval shunt or mesocaval shunt).

Because of the high rate of rebleeding (60%), secondary prophylaxis is recommended. Drug therapy with nonselective beta blockers and repeated sessions of variceal band ligation are similarly effective.39 The beneficial effect of beta blockers should be confirmed by the hepatic venous pressure portal gradient (HVPG), if this is available. A reduction of HVPG to less than 12 mm Hg or by 20% protects patients from variceal rebleeding.40 The combination of beta blockers and endoscopic band ligation seems to be more effective than either treatment used alone; this combined approach is being evaluated. TIPS, surgical portosystemic shunting, or both should be considered for patients who rebleed despite drug therapy and endoscopic treatment.

Hepatopulmonary Syndrome

The hepatopulmonary syndrome (HPS), which is characterized by hypoxemia from intrapulmonary shunting, a ventilation-perfusion mismatch, or both, develops in some patients with cirrhosis.41 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. Other typical manifestations include exertional dyspnea, platypnea, and digital clubbing.42 The diagnostic workup includes arterial blood gas measurements, contrast-enhanced echocardiography, and scanning with technetium-99m-labeled macroaggregated albumin. Pulmonary angiography may be necessary to detect discrete arteriovenous communications. Pharmacologic agents, such as almitrine bismesylate, prosta glandin F2α, indomethacin, somatostatin, and methylene blue, have been used to treat HPS, but results have been disappointing. Although TIPS may improve oxygenation, OLT is the only curative treatment; by 6 months after OLT, about 80% of patients with HPS have improved oxygenation.43

Hepatic Encephalopathy

Hepatic encephalopathy is a syndrome observed in patients with advanced cirrhosis that is marked by personality changes, intellectual impairment, neuromuscular dysfunction, and a depressed level of consciousness.44 The pathogenesis involves altered brain-energy metabolism and increased permeability of the blood-brain barrier, facilitating the passage of neurotoxins.45 Putative neurotoxins include short-chain fatty acids, mercaptans, false neurotransmitters (e.g., tyramine, octopamine, and β-phenylethanolamines), ammonia, and γ-aminobutyric acid.46

The diagnosis of hepatic encephalopathy is made on the basis of altered mental status and neuromuscular signs in the absence of any specific mental or neurologic disease. Hepatic encephalopathy is classified into five grades, according to clinical severity [see Table 4]. In addition, hepatic encephalopathy can be classified as episodic, persistent, or minimal. Minimal encephalopathy refers to patients with subtle manifestations of hepatic encephalopathy that cannot be detected by standard clinical examination.47

Table 4 Grading of Hepatic Encephalopathy

Grade

Clinical Manifestations

0 (subclinical)

Normal mental status, but minimal changes in memory, concentration, intellectual function, and coordination

1

Mild confusion, euphoria or depression, decreased attention, slowing of ability to perform mental tasks, irritability, disorder of sleep pattern (i.e., inverted sleep cycle)

2

Drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behavior, intermittent disorientation (usually for time)

3

Somnolent but arousable, unable to perform mental tasks, disorientation to time and place, marked confusion, amnesia, occasional fits of rage, speech is present but incomprehensible

4

Coma, with or without response to painful stimuli

Typical findings on physical examination include asterixis and fetor hepaticus. The serum ammonia level (arterial or free venous) is commonly elevated. Electroencephalography usually shows high-amplitude low-frequency waves and triphasic waves. CT scan and MRI studies of the brain may be important in ruling out neurologic diseases.

Common precipitating factors of hepatic encephalopathy 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 encephalopathy symptoms. Surgical portosystemic shunts and TIPS favor the development of encephalopathy. The differential diagnosis for hepatic encephalopathy includes intracranial lesions, central nervous system infections, metabolic encephalopathy, toxic encephalopathy from alcohol or drugs, organic brain syndrome, and postseizure encephalopathy. In the initial management of hepatic encephalopathy, precipitants should be identified and corrected.48 Lactulose, lactitol (not available in the United States), or both are helpful in patients with the acute onset of severe encephalopathy symptoms and in patients with milder, chronic symptoms.49 Lactulose stimulates the passage of ammonia from tissues into the gut lumen and inhibits intestinal ammonia production. The initial lactulose dosage is 30 ml orally once or twice a day. The dose is increased until the patient has two to four loose stools a day. The dose should be reduced if the patient complains of diarrhea, abdominal cramping, or bloating. In hospitalized patients with severe encephalopathy, higher doses of lactulose may be administered via either a nasogastric tube or a rectal tube.50 Neomycin (2 to 6 g/day), metronidazole (250 mg/day), rifaximin (1,200 mg/day), and other antibiotics (e.g., oral vancomycin, paromomycin, and oral quinolones) serve as second-line agents.51 Antibiotics work 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. Low-protein diets are not recommended, because they worsen the catabolic status of these patients and may cause malnutrition. In patients with portosystemic shunts, including TIPS, shunt-diameter reduction can be considered when hepatic encephalopathy is severe and does not respond to medical therapy. Because hepatic encephalopathy carries a poor prognosis, patients with episodic or permanent encephalopathy should be evaluated for OLT. The specific prognosis of patients with minimal encephalopathy is still unknown.

Hepatocellular Carcinoma

HCC is currently the main cause of mortality in cirrhotic patients.52 The annual incidence of HCC in cirrhosis from HCV is 3% to 5%. Surveillance to detect early HCC involves the use of ultrasound examination and serum α-fetoprotein measurement every 6 months. In patients with 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 α-fetoprotein levels, ultrasonography, helical CT and MRI findings, and positive cytohistology. The prognosis in patients with early-stage HCC depends on tumor status, liver function, and the treatment applied. Different staging systems (e.g., Barcelona Clinic Liver Cancer [BCLC] or Okuda) use tumor characteristics and liver function to classify patients with HCC.53 Unfortunately, many HCC patients are diagnosed at advanced stages of disease that preclude the use of curative treatments. The 3-year survival rates of patients at intermediate and advanced stages of HCC are 65% and 16%, respectively. Curative treatments for HCC include surgical resection, OLT, and percutaneous ablation. In well-selected patients, resection and OLT achieve the best outcomes, with 5-year survival rates of 60% to 70%, whereas 5-year survival rates with percutaneous treatments are only 40% to 50%. Transplantation is the ideal treatment for patients with one tumor and decompensated cirrhosis or multicentric small tumors.54 Arterial embolization may improve quality of life and, in some cases, even increase survival. Tamoxifen does not seem to have a significant beneficial effect.

Indications for Liver Transplantation

OLT is a central tool for the management of advanced cirrhosis.55 In the United States, more than 3,000 liver transplants are performed each year. However, because there are many more candidates for transplantation than there are available donor livers, the selection and timing of patient referral are critical. The general indications for OLT are broadly categorized as clinical and biochemical [see Table 5]. Biochemical indexes vary, depending on whether liver disease is caused by hepatocellular conditions or chronic cholestatic disorders. Patients should be referred for transplant workup if the serum bilirubin level is greater than 3 mg/dl in noncholestatic disease or greater than 5 mg/dl in cholestatic disorders; if the prothrombin time is prolonged by more than 5 seconds; or if the serum albumin level is below 2.5 g/dl. Clinical criteria include HCC, hepatic encephalopathy, 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 hepatic encephalopathy or variceal hemorrhage develops. HCV-infected patients with decompensated cirrhosis awaiting OLT can be treated with pegylated interferon plus ribavirin; in these patients, treatment can be initiated several months before OLT to prevent graft reinfection.56

Table 5 Indications for Liver Transplantation

Disease

Criteria

Hepatocellular liver disease

Serum bilirubin > 3 mg/dl

Serum albumin < 2.5 g/dl

Prothrombin time > 5 sec above control

Cholestatic liver disease

Serum bilirubin > 5 mg/dl

Intractable pruritus

Progressive bone disease

Recurrent bacterial cholangitis

Both hepatocellular and cholestatic liver disease

Recurrent or severe hepatic encephalopathy

Refractory ascites

Spontaneous bacterial peritonitis

Recurrent portal hypertensive bleeding

Progressive malnutrition

Hepatocellular carcinoma

< 3 nodules

No nodule > 5 cm

No portal invasion

Contraindications for OLT include severe cardiovascular or pulmonary disease, active drug or alcohol abuse, malignancy outside the liver, sepsis, or psychosocial problems that may jeopardize a patient's ability to follow medical regimens after transplantation. The presence of HIV infection was considered a contraindication to transplantation, but successful liver transplantations are now being performed in patients in whom anti retroviral therapy has eliminated any detectable HIV viral load. Additional clinical study is required before OLT can be offered routinely to such patients.

In the United States, the Model for End-Stage Liver Disease (MELD) is the scoring system used by most liver transplant centers for determining priority for OLT.57 MELD relies primarily on the bilirubin level, INR, and creatinine level to determine a patient's risk of dying within 3 months if OLT is not performed.58 Patients' scores are calculated continuously while they are on the waiting list for OLT. Scores typically range from 6 (less ill) to 40 (gravely ill). A MELD calculator is available on the Internet (http://www.unos.org/resources/MeldPeldCalculator.asp?index=98).

Advances in surgical technique, organ preservation, and immunosuppression have resulted in dramatic improvements in postoperative survival over the past 2 decades.59 In the early 1980s, 1-year and 5-year survival after liver transplantation were only 70% and 15%, respectively; the current rates are 85% and more than 70%. In most cases, patients can anticipate a good quality of life after liver transplantation.

Approximately 15% of patients listed as candidates for liver transplantation die before a donor organ becomes available. Strategies to improve the current donor organ shortage include programs to increase public awareness of the importance of organ donation, increased utilization of living-donor liver transplantation for pediatric recipients, and exploration of the efficacy and safety of living-donor liver transplantation in adults.60

Prognosis

The prognosis of patients with cirrhosis depends on the underlying disease, the occurrence of major complications (i.e., ascites, GI bleeding, encephalopathy, HRS, or bacterial infections), the degree of liver insufficiency, and the existence of HCC. In patients with compensated cirrhosis, the 10-year probability of major clinical complications is 58% and that of survival is 47%. For patients with decompensated cirrhosis, prognosis can be estimated by the older Child-Pugh classification and 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, as well as major complications (ascites and encephalopathy). In contrast, the MELD score includes only numeric variables that reflect liver function (INR and bilirubin level) and renal function (creatinine level). The principal advantages of the MELD score are that it is based on objective variables selected for their influence on prognosis and that continuous recalculation helps in scoring individuals more precisely among large populations.58 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 survival.62

References

  1. Desmet VJ, Roskams T: Cirrhosis reversal: a duel between dogma and myth. J Hepatol 40:860, 2004
  2. Afdhal NH: The natural history of hepatitis C. Semin Liver Dis 24(suppl 2):3, 2004
  3. Vong S, Bell BP: Chronic liver disease mortality in the United States, 1990–1998. Hepatology 39:476, 2004
  4. Sandler RS, Everhart JE, Donowitz M, et al: The burden of selected digestive diseases in the United States. Gastroenterology 122:1500, 2002
  5. Kozak LJ, Owings MF, Hall MJ: National Hospital Discharge Survey: 2002 annual summary with detailed diagnosis and procedure data. National Center for Health Statistics. Vital Health Stat 13:1, 2005
  6. Bataller R, North KE, Brenner DA: Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal. Hepatology 37:493, 2003
  7. Bataller R, Brenner DA: Liver fibrosis. J Clin Invest 115:209, 2005
  8. Roskams T, Baptista A, Bianchi L, et al: Histopathology of portal hypertension: a practical guideline. Histopathology 42:2, 2003
  9. Groszmann RJ, Abraldes JG: Portal hypertension: from bedside to bench. J Clin Gastroenterol 39:S125, 2005
  10. Murakami T, Mochizuki K, Nakamura H: Imaging evaluation of the cirrhotic liver. Semin Liver Dis 21:213, 2001
  11. Dienstag JL: The role of liver biopsy in chronic hepatitis C. Hepatology 36:S152, 2002
  12. McCormack G, Nolan N, McCormick PA: Transjugular liver biopsy: a review. Ir Med J 94:11, 2001
  13. Cardenas A, Gines P: Management of complications of cirrhosis in patients awaiting liver transplantation. J Hepatol 42(suppl):S124, 2005
  14. Wright TL: Treatment of patients with hepatitis C and cirrhosis. Hepatology 36:S185, 2002
  15. Lai CJ, Terrault NA: Antiviral therapy in patients with chronic hepatitis B and cirrhosis. Gastroenterol Clin North Am 33:629, 2004
  16. Levitsky J, Mailliard ME: Diagnosis and therapy of alcoholic liver disease. Semin Liver Dis 24:233, 2004
  17. Morgan TR, Weiss DG, Nemchausky B, et al: Colchicine treatment of alcoholic cirrhosis: a randomized, placebo-controlled clinical trial of patient survival. Gastroenterology 128:882, 2005
  18. O'shea RS, McCullough AJ: Treatment of alcoholic hepatitis. Clin Liver Dis 9:103, 2005
  19. Oo YH, Neuberger J: Options for treatment of primary biliary cirrhosis. Drugs 64:2261, 2004
  20. Gines P, Cardenas A, Arroyo V, et al: Management of cirrhosis and ascites. N Engl J Med 350:1646, 2004
  21. Gines P, Tito L, Arroyo V, et al: Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis. Gastroenterology 94:1493, 1988
  22. Gines P, Uriz J, Calahorra B, et al: Transjugular intrahepatic portosystemic shunting versus paracentesis plus albumin for refractory ascites in cirrhosis. Gastroenterology 123:1839, 2004
  23. Bureau C, Garcia-Pagan JC, Otal P, et al: Improved clinical outcome using polytet rafluoroethylene-coated stents for TIPS: results of a randomized study. Gastroenterology 126:469, 2004
  24. Cardenas A, Gines P: Pathogenesis and treatment of fluid and electrolyte imbalance in cirrhosis. Semin Nephrol 21:308, 2001
  25. Gines P, Guevara M, Arroyo V, et al: Hepatorenal syndrome. Lancet 362:1819, 2003
  26. Arroyo V, Gines P, Gerbes AL, et al: Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 23:164, 1996
  27. Ortega R, Gines P, Uriz J, et al: Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study. Hepatology 36:941, 2002
  28. Garcia-Tsao G: Bacterial infections in cirrhosis. Can J Gastroenterol 18:405, 2004
  29. Fernandez J, Bauer TM, Navasa M, et al: Diagnosis, treatment and prevention of spontaneous bacterial peritonitis. Baillieres Best Pract Res Clin Gastroenterol 14:975, 2000
  30. Sort P, Navasa M, Arroyo V, et al: Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 341:403, 1999
  31. Gines P, Rimola A, Planas R, et al: Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology 12:716, 1990
  32. Bosch J, Abraldes JG: Management of gastrointestinal bleeding in patients with cirrhosis of the liver. Semin Hematol 41:8, 2004
  33. Bernard B, Lebrec D, Mathurin P, et al: Propranolol and sclerotherapy in the prevention of gastrointestinal rebleeding in patients with cirrhosis: a meta-analysis. J Hepatol 26:312, 1997
  34. Jutabha R, Jensen DM, Martin P, et al: Randomized study comparing banding and propranolol to prevent initial variceal hemorrhage in cirrhotics with high-risk esophageal varices. Gastroenterology 128:870, 2005
  35. Chalasani N, Boyer TD: Primary prophylaxis against variceal bleeding: beta-blockers, endoscopic ligation, or both? Am J Gastroenterol 100:805, 2005
  36. de Franchis R: Somatostatin, somatostatin analogues and other vasoactive drugs in the treatment of bleeding oesophageal varices. Dig Liver Dis 36(suppl 1):S93, 2004
  37. Vangeli M, Patch D, Burroughs AK: Salvage tips for uncontrolled variceal bleeding. J Hepatol 37:703, 2002
  38. Neuhaus P, Blumhardt G: Surgery for portal hypertension. Hepatogastroenterology 38:355, 1991
  39. Patch D, Sabin CA, Goulis J, et al: A randomized, controlled trial of medical therapy versus endoscopic ligation for the prevention of variceal rebleeding in patients with cirrhosis. Gastroenterology 123:1013, 2002
  40. Merkel C, Bolognesi M, Sacerdoti D, et al: 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 32:930, 2000
  41. Hoeper MM, Krowka MJ, Strassburg CP: Portopulmonary hypertension and hepatopulmonary syndrome. Lancet 363:1461, 2004
  42. Lima BL, Franca AV, Pazin-Filho A, et al: Frequency, clinical characteristics, and respiratory parameters of hepatopulmonary syndrome. Mayo Clin Proc 79:42, 2004
  43. Swanson KL, Wiesner RH, Krowka MJ: Natural history of hepatopulmonary syndrome: impact of liver transplantation. Hepatology 41:1122, 2005
  44. Ferenci P, Lockwood A, Mullen K, et al: Hepatic encephalopathy—definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 35:716, 2002
  45. Butterworth RF: Pathogenesis of hepatic encephalopathy: new insights from neuroimaging and molecular studies. J Hepatol 39:278, 2003
  46. Jones EA: Ammonia, the GABA neurotransmitter system, and hepatic encephalopathy. Metab Brain Dis 17:275, 2002
  47. Ortiz M, Jacas C, Cordoba J: Minimal hepatic encephalopathy: diagnosis, clinical significance and recommendations. J Hepatol 42(suppl):S45, 2005
  48. Blei AT: Treatment of hepatic encephalopathy. Lancet 365:1383, 2005
  49. Morgan MY, Hawley KE: Lactitol vs. lactulose in the treatment of acute hepatic encephalopathy in cirrhotic patients: a double-blind, randomized trial. Hepatology 7:1278, 1987
  50. Bongaerts G, Severijnen R, Timmerman H: Effect of antibiotics, prebiotics and probiotics in treatment for hepatic encephalopathy. Med Hypotheses 64:64, 2005
  51. Mas A, Rodes J, Sunyer L, et al: 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 38:51, 2003
  52. Llovet JM, Burroughs A, Bruix J: Hepatocellular carcinoma. Lancet 362:1907, 2003
  53. Llovet JM, Fuster J, Bruix J: The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl 10:S115, 2004
  54. Schwartz M: Liver transplantation for hepatocellular carcinoma. Gastroenterology 127:S268, 2004
  55. Brown KA: Liver transplantation. Curr Opin Gastroenterol 21:331, 2005
  56. Forns X, Garcia-Retortillo M, Serrano T, et al: Antiviral therapy of patients with decompensated cirrhosis to prevent recurrence of hepatitis C after liver transplantation. J Hepatol 39:389, 2003
  57. Freeman RB Jr: MELD and liver allocation: continuous quality improvement. Hepatology 40:787, 2004
  58. Kamath PS, Wiesner RH, Malinchoc M, et al: A model to predict survival in patients with end-stage liver disease. Hepatology 33:464, 2001
  59. Tra TT, Nissen N, Poordad FF, et al: Advances in liver transplantation: new strategies and current care expand access, enhance survival. Postgrad Med 115:73, 2004
  60. White SA, Al-Mukhtar A, Lodge JP, et al: Progress in living donor liver transplantation. Transplant Proc 36:2720, 2004
  61. Durand F, Valla D: Assessment of the prognosis of cirrhosis: Child-Pugh versus MELD. J Hepatol 42(suppl):S100, 2005
  62. Alessandria C, Ozdogan O, Guevara M, et al: MELD score and clinical type predict prognosis in hepatorenal syndrome: relevance to liver transplantation. Hepatology 41:1282, 2005

Editors: Dale, David C.; Federman, Daniel D.