Practice Essentials Cirrhosis is defined histologically as a diffuse hepatic process characterized by fibrosis and the conversion of normal liver

architecture into structurally abnormal nodules. The progression of liver injury to cirrhosis may occur over weeks to years. Essential update: Recommendations for safe drug use in cirrhosis In a recent review, Lewis and Stine provided recommendations, including the following, on the safe use of medications in patients with cirrhosis[1, 2] :

Lower medication doses should generally be used, particularly in patients with significant liver dysfunction Opioid analgesics, anxiolytics, and sedatives, which can precipitate hepatic encephalopathy, should be used cautiously Nonsteroidal anti-inflammatory drugs (NSAIDs), which can cause renal failure and gastrointestinal (GI) bleeding in patients in cirrhosis, should not be used If used at low doses (2-3 g or less, daily) for short periods, paracetamol (acetaminophen) can be used safely as a first-line pain treatment Statins are safe to administer to patients with cirrhosis. Proton-pump inhibitors and histamine-2 blockers should be used only for valid indications, since they may lead to serious infections in patients with cirrhosis Signs and symptoms Some patients with cirrhosis are completely asymptomatic and have a reasonably normal life expectancy. Other individuals have a multitude of the most severe symptoms of end-stage liver disease and a limited chance for survival. Commonsigns and symptoms may stem from decreased hepatic synthetic function (eg, coagulopathy), portal hypertension (eg, variceal bleeding), or decreased detoxification capabilities of the liver (eg, hepatic encephalopathy). Portal hypertension Portal hypertension can have prehepatic, intrahepatic, or posthepatic causes. Budd-Chiari syndrome, a posthepatic cause, is characterized by the following symptoms:

Hepatomegaly Abdominal pain Ascites Ascites is suggested by the following findings on physical examination: Abdominal distention Bulging flanks Shifting dullness Elicitation of a "puddle sign" in patients in the knee-elbow position Hepatic encephalopathy The symptoms of hepatic encephalopathy may range from mild to severe and may be observed in as many as 70% of patients with cirrhosis. Symptoms are graded on the following scale:

Grade 0 - Subclinical; normal mental status but minimal changes in memory, concentration, intellectual function, coordination Grade 1 - Mild confusion, euphoria or depression, decreased attention, slowing of ability to perform mental tasks, irritability, disorder of sleep pattern (ie, inverted sleep cycle) Grade 2 - Drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behavior, intermittent disorientation (usually with regard to time) Grade 3 - Somnolent, but arousable, state; inability to perform mental tasks; disorientation with regard to time and place; marked confusion; amnesia; occasional fits of rage; speech is present but incomprehensible Grade 4 - Coma, with or without response to painful stimuli Findings on physical examination in hepatic encephalopathy include asterixis and fetor hepaticus. Additional signs and symptoms Many patients with cirrhosis experience fatigue, anorexia, weight loss, and muscle wasting. Cutaneous manifestations of cirrhosis include jaundice, spider angiomata, skin telangiectasias ("paper money skin"), palmar erythema, white nails, disappearance of lunulae, and finger clubbing, especially in the setting of hepatopulmonary syndrome. Diagnosis Hepatorenal syndrome Hepatorenal syndrome is diagnosed when a creatinine clearance rate of less than 40mL/min is present or when a serum creatinine level of greater than 1.5mg/dL, a urine volume of less than 500mL/day, and a urine sodium level of less than 10mEq/L are present.[3] Urine osmolality is greater than plasma osmolality. Portal hypertension During angiography, a catheter may be placed selectively via either the transjugular or transfemoral route into the hepatic vein to measure portal pressure. Hepatic encephalopathy An elevated arterial or free venous serum ammonia level is the classic laboratory abnormality reported in patients with hepatic encephalopathy. Electroencephalography may be helpful in the initial workup of a patient with cirrhosis and altered mental status, when ruling out seizure activity may be necessary. Computed tomography (CT) scanning and MRI studies of the brain may be important in ruling out intracranial lesions when the diagnosis of hepatic encephalopathy is in question. Ascites

Paracentesis is essential in determining whether ascites is caused by portal hypertension or by another process. Management Specific medical therapies may be applied to many liver diseases in an effort to diminish symptoms and to prevent or forestall the development of cirrhosis. Examples of such treatments include the following:

Prednisone and azathioprine - For autoimmune hepatitis Interferon and other antiviral agents - For hepatitis B and C Phlebotomy - For hemochromatosis Ursodeoxycholic acid - For primary biliary cirrhosis Trientine and zinc - For Wilson disease Once cirrhosis develops, treatment is aimed at the management of complications as they arise. Examples include the following: Hepatorenal syndrome - Kidney function usually recovers when patients with cirrhosis and hepatorenal syndrome undergo liver transplantation; patients with early hepatorenal syndrome may be salvaged by aggressive expansion of intravascular volume with albumin and fresh frozen plasma and by avoidance of diuretics Hepatic encephalopathy - Pharmacologic treatment includes the administration of lactulose and antibiotics Ascites - Treatment can include sodium restriction and the use of diuretics, large-volume paracentesis, and shunts (peritoneovenous, portosystemic, transjugular intrahepatic portosystemic) Liver transplantation Patients should be referred for consideration for liver transplantation after the first signs of hepatic decompensation. Overview Cirrhosis represents the final common histologic pathway for a wide variety of chronic liver diseases. The term cirrhosis was first introduced by Laennec in 1826. It is derived from the Greek term scirrhus and refers to the orange or tawny surface of the liver seen at autopsy. Cirrhosis is defined histologically as a diffuse hepatic process characterized by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules. The progression of liver injury to cirrhosis may occur over weeks to years. Indeed, patients with hepatitis C may have chronic hepatitis for as long as 40 years before progressing to cirrhosis. Many forms of liver injury are marked by fibrosis, which is defined as an excess deposition of the components of the extracellular matrix (ie, collagens, glycoproteins, proteoglycans) within the liver. This response to liver injury potentially is reversible. In contrast, in most patients, cirrhosis is not a reversible process. In addition to fibrosis, the complications of cirrhosis include, but are not limited to, portal hypertension, ascites, hepatorenal syndrome, and hepatic encephalopathy. Often a poor correlation exists between histologic findings in cirrhosis and the clinical picture. Some patients with cirrhosis are completely asymptomatic and have a reasonably normal life expectancy. Other individuals have a multitude of the most severe symptoms of end-stage liver disease and have a limited chance for survival. Common signs and symptoms may stem from decreased hepatic synthetic function (eg, coagulopathy), decreased detoxification capabilities of the liver (eg, hepatic encephalopathy), or portal hypertension (eg, variceal bleeding). Patient education For patient education information, see the Mental Health Center, as well asAlcoholism. In August 2012, the Centers for Disease Control and Prevention (CDC) expanded their existing, risk-based testing guidelines to recommend a 1time blood test for hepatitis C virus (HCV) infection in baby boomersthe generation born between 1945 and 1965, who account for approximately three fourths of all chronic HCV infections in the United Stateswithout prior ascertainment of HCV risk (seeRecommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 19451965).[4] One-time HCV testing in this population could identify nearly 808,600 additional people with chronic infection. All individuals identified with HCV should be screened and/or managed for alcohol abuse, followed by referral to preventative and/or treatment services, as appropriate. Epidemiology Chronic liver disease and cirrhosis result in about 35,000 deaths each year in the United States. Cirrhosis is the ninth leading cause of death in the United States and is responsible for 1.2% of all US deaths. Many patients die from the disease in their fifth or sixth decade of life. Each year, 2000 additional deaths are attributed to fulminant hepatic failure (FHF). FHF may be caused viral hepatitis (eg, hepatitis A and B), drugs (eg, acetaminophen), toxins (eg, Amanita phalloides, the yellow death-cap mushroom), autoimmune hepatitis, Wilson disease, or a variety of less common etiologies. Cryptogenic causes are responsible for one third of fulminant cases. Patients with the syndrome of FHF have a 50-80% mortality rate unless they are salvaged by liver transplantation. Etiology Alcoholic liver disease once was considered to be the predominant source of cirrhosis in the United States, but hepatitis C has emerged as the nation's leading cause of chronic hepatitis and cirrhosis. Many cases of cryptogenic cirrhosis appear to have resulted from nonalcoholic fatty liver disease (NAFLD). When cases of cryptogenic cirrhosis are reviewed, many patients have 1 or more of the classic risk factors for NAFLD: obesity, diabetes, and hypertriglyceridemia.[5] It is postulated that steatosis may regress in some patients as hepatic fibrosis progresses, making the histologic diagnosis of NAFLD difficult. Up to one third of Americans have NAFLD. About 2-3% of Americans have nonalcoholic steatohepatitis (NASH), in which fat deposition in the hepatocyte is complicated by liver inflammation and fibrosis. It is estimated that 10% of patients with NASH will ultimately develop cirrhosis. NAFLD and NASH are anticipated to have a major impact on the United States' public health infrastructure. Most common causes of cirrhosis in the United States

Hepatitis C (26%) Alcoholic liver disease (21%)

Hepatitis C plus alcoholic liver disease (15%) Cryptogenic causes (18%) - Many cases actually are due to NAFLD Hepatitis B - May be coincident with hepatitis D (15%) Miscellaneous (5%) Miscellaneous causes of chronic liver disease and cirrhosis Autoimmune hepatitis Primary biliary cirrhosis Secondary biliary cirrhosis - Associated with chronic extrahepatic bile duct obstruction Primary sclerosing cholangitis Hemochromatosis Wilson disease Alpha-1 antitrypsin deficiency Granulomatous disease - Eg, sarcoidosis Type IV glycogen storage disease Drug-induced liver disease - Eg, methotrexate, alpha methyldopa, amiodarone Venous outflow obstruction - Eg, Budd-Chiari syndrome, veno-occlusive disease Chronic right-sided heart failure Tricuspid regurgitation Hepatic Fibrosis The development of hepatic fibrosis reflects an alteration in the normally balanced processes of extracellular matrix production and degradation.[6] The extracellular matrix, the normal scaffolding for hepatocytes, is composed of collagens (especially types I, III, and V), glycoproteins, and proteoglycans. Stellate cells, located in the perisinusoidal space, are essential for the production of extracellular matrix. Stellate cells, which were once known as Ito cells, lipocytes, or perisinusoidal cells, may become activated into collagen-forming cells by a variety of paracrine factors. Such factors may be released by hepatocytes, Kupffer cells, and sinusoidal endothelium following liver injury. As an example, increased levels of the cytokine transforming growth factor beta1 (TGF-beta1) are observed in patients with chronic hepatitis C and those with cirrhosis. TGF-beta1, in turn, stimulates activated stellate cells to produce type I collagen. Increased collagen deposition in the space of Disse (the space between hepatocytes and sinusoids) and the diminution of the size of endothelial fenestrae lead to the capillarization of sinusoids. Activated stellate cells also have contractile properties. Capillarization and constriction of sinusoids by stellate cells contribute to the development of portal hypertension. Future drug strategies to prevent fibrosis may focus on reducing hepatic inflammation, inhibiting stellate cell activation, inhibiting the fibrogenic activities of stellate cells, and stimulating matrix degradation. Portal Hypertension Causes The normal liver has the ability to accommodate large changes in portal blood flow without appreciable alterations in portal pressure. Portal hypertension results from a combination of increased portal venous inflow and increased resistance to portal blood flow. Patients with cirrhosis demonstrate increased splanchnic arterial flow and, accordingly, increased splanchnic venous inflow into the liver. Increased splanchnic arterial flow is explained partly by decreased peripheral vascular resistance and increased cardiac output in the patient with cirrhosis. Nitric oxide appears to be the major driving force for this phenomenon. [7] Furthermore, evidence for splanchnic vasodilation exists. Putative splanchnic vasodilators include glucagon, vasoactive intestinal peptide, substance P, prostacyclin, bile acids, tumor necrosis factor-alpha (TNF-alpha), and nitric oxide. Increased resistance across the sinusoidal vascular bed of the liver is caused by fixed factors and dynamic factors. Two thirds of intrahepatic vascular resistance can be explained by fixed changes in the hepatic architecture. Such changes include the formation of regenerating nodules and, after the production of collagen by activated stellate cells, deposition of the collagen within the space of Disse. Dynamic factors account for one third of intrahepatic vascular resistance. Stellate cells serve as contractile cells for adjacent hepatic endothelial cells. The nitric oxide produced by the endothelial cells, in turn, controls the relative degree of vasodilation or vasoconstriction produced by the stellate cells. In cirrhosis, decreased local production of nitric oxide by endothelial cells permits stellate cell contraction, with resulting vasoconstriction of the hepatic sinusoid. (This contrasts with the peripheral circulation, where there are high circulating levels of nitric oxide in cirrhosis.) Increased local levels of vasoconstricting chemicals, such as endothelin, may also contribute to sinusoidal vasoconstriction. The portal hypertension of cirrhosis is caused by the disruption of hepatic sinusoids. However, portal hypertension may be observed in a variety of noncirrhotic conditions. Prehepatic causes Prehepatic causes include splenic vein thrombosis and portal vein thrombosis. These conditions commonly are associated with hypercoagulable states and with malignancy (eg, pancreatic cancer). Intrahepatic causes Intrahepatic causes of portal hypertension are divided into presinusoidal, sinusoidal, and postsinusoidal conditions. The classic sinusoidal cause of portal hypertension is cirrhosis. The classic form of presinusoidal portal hypertension is caused by the deposition of Schistosoma oocytes in presinusoidal portal venules, with the subsequent development of granulomata and portal fibrosis. Schistosomiasis is the most common noncirrhotic cause of variceal bleeding worldwide. Schistosoma mansoniinfection is described in Puerto Rico, Central and South America, the Middle East, and Africa. S japonicum is described in the Far East. S hematobium, observed in the Middle East and Africa, can produce portal fibrosis but more commonly is associated with urinary tract deposition of eggs.

The classic postsinusoidal condition is an entity known as veno-occlusive disease. Obliteration of the terminal hepatic venules may result from ingestion of pyrrolizidine alkaloids in Comfrey tea or Jamaican bush tea or following the high-dose chemotherapy that precedes bone marrow transplantation. Posthepatic causes Posthepatic causes of portal hypertension may include chronic right-sided heart failure and tricuspid regurgitation and obstructing lesions of the hepatic veins and inferior vena cava. The latter conditions, and the symptoms they produce, are termed Budd-Chiari syndrome. Predisposing conditions include hypercoagulable states, tumor invasion into the hepatic vein or inferior vena cava, and membranous obstruction of the inferior vena cava. Inferior vena cava webs are observed most commonly in South and East Asia and are postulated to be due to nutritional factors. Symptoms of Budd-Chiari syndrome are attributed to decreased outflow of blood from the liver, with resulting hepatic congestion and portal hypertension. These symptoms include hepatomegaly, abdominal pain, and ascites. Cirrhosis ensues only later in the course of disease. Differentiating Budd-Chiari syndrome from cirrhosis by history or physical examination may be difficult. Thus, Budd-Chiari syndrome must be included in the differential diagnosis of conditions that produce ascites and varices. Hepatic vein patency is checked most readily by performing abdominal ultrasonography, with Doppler examination of the hepatic vessels. Abdominal computed tomography (CT) scanning with intravenous (IV) contrast, abdominal magnetic resonance imaging (MRI), and visceral angiography also may provide information regarding the patency of hepatic vessels. Measurement Widespread use of the transjugular intrahepatic portosystemic shunt (TIPS) procedure in the 1990s for the management of variceal bleeding led to a resurgence of clinicians' interest in measuring portal pressure. During angiography, a catheter may be placed selectively via either the transjugular or transfemoral route into the hepatic vein. In the healthy patient, free hepatic vein pressure (FHVP) is equal to inferior vena cava pressure. FHVP is used as an internal zero reference point. Wedged hepatic venous pressure (WHVP) is measured by inflating a balloon at the catheter tip, thus occluding a hepatic vein branch. Measurement of the WHVP provides a close approximation of portal pressure. The WHVP actually is slightly lower than the portal pressure because of some dissipation of pressure in the sinusoidal bed. The WHVP and portal pressure are elevated in patients with sinusoidal portal hypertension, as is observed in cirrhosis. Complications The hepatic venous pressure gradient (HVPG) is defined as the difference in pressure between the portal vein and the inferior vena cava. Thus, the HVPG is equal to the WHVP value minus the FHVP value (ie, HVPG = WHVP - FHVP). The normal HVPG is 3-6mm Hg. Portal hypertension is defined as a sustained elevation of portal pressure above normal. An HVPG of 8mm Hg is believed to be the threshold above which ascites potentially can develop. An HVPG of 12mm Hg is the threshold for the potential formation of varices. High portal pressures may predispose patients to an increased risk of variceal hemorrhage.[8] Ascites Ascites, which is an accumulation of excessive fluid within the peritoneal cavity, can be a complication of either hepatic or nonhepatic disease. The 4 most common causes of ascites in North America and Europe are cirrhosis, neoplasm, congestive heart failure, and tuberculous peritonitis. In the past, ascites was classified as being a transudate or an exudate. In transudative ascites, fluid was said to cross the liver capsule because of an imbalance in Starling forces. In general, ascites protein would be less than 2.5g/dL in this form of ascites. A classic cause of transudative ascites would be portal hypertension secondary to cirrhosis and congestive heart failure. In exudative ascites, fluid was said to weep from an inflamed or tumor-laden peritoneum. In general, ascites protein in exudative ascites would be greater than 2.5g/dL. Causes of the condition would include peritoneal carcinomatosis and tuberculous peritonitis. Nonperitoneal causes Attributing ascites to diseases of nonperitoneal or peritoneal origin is more useful. Thanks to the work of Bruce Runyon, the serum-ascites albumin gradient (SAAG) has come into common clinical use for differentiating these conditions. Nonperitoneal diseases produce ascites with a SAAG greater than 1.1g/dL. (See Table 1, below.)[9] Table 1. Nonperitoneal Causes of Ascites[10] (Open Table in a new window) Causes of Nonperitoneal Ascites Examples Intrahepatic portal hypertension Cirrhosis

Fulminant hepatic failure

Veno-occlusive disease

Extrahepatic portal hypertension

Hepatic vein obstruction (ie, Budd-Chiari syndrome)

Congestive heart failure

Hypoalbuminemia

Nephrotic syndrome

Protein-losing enteropathy Malnutrition

Miscellaneous disorders

Myxedema

Ovarian tumors

Pancreatic ascites

Biliary ascites

Chylous

Secondary to malignancy

Secondary to trauma

Secondary to portal hypertension

Chylous ascites, caused by obstruction of the thoracic duct or cisterna chyli, most often is due to malignancy (eg, lymphoma) but occasionally is observed postoperatively and following radiation injury. Chylous ascites also may be observed in the setting of cirrhosis. The triglyceride concentration of the ascites is greater than 110mg/dL and greater than that observed in plasma. Patients should be placed on a low-fat diet that is supplemented with medium-chain triglycerides. Treatment with diuretics and large-volume paracentesis may be required. Peritoneal causes Peritoneal diseases produce ascites with a SAAG of less than 1.1g/dL. (See Table 2, below.) Table 2. Peritoneal Causes of Ascites[10] (Open Table in a new window) Causes of Peritoneal Ascites Examples Malignant ascites Primary peritoneal mesothelioma

Secondary peritoneal carcinomatosis

Granulomatous peritonitis

Tuberculous peritonitis

Fungal and parasitic infections (eg, Candida,

Histoplasma, Cryptococcus, Schistosoma mansoni, Strongyloides, Entamoeba histolytica)

Sarcoidosis

Foreign bodies (ie, talc, cotton and wood fibers,

starch, barium)

Vasculitis

Systemic lupus erythematosus

Henoch-Schnlein purpura

Miscellaneous disorders

Eosinophilic gastroenteritis

Whipple disease

Endometriosis

The role of portal hypertension in the pathogenesis of cirrhotic ascites The formation of ascites in cirrhosis depends on the presence of unfavorable Starling forces within the hepatic sinusoid and on some degree of renal dysfunction. Patients with cirrhosis are observed to have increased hepatic lymphatic flow. Fluid and plasma proteins diffuse freely across the highly permeable sinusoidal endothelium into the space of Disse. Fluid in the space of Disse, in turn, enters the lymphatic channels that run within the portal and central venous areas of the liver. Because the transsinusoidal oncotic gradient is approximately zero, the increased sinusoidal pressure that develops in portal hypertension increases the amount of fluid entering the space of Disse. When the increased hepatic lymph production observed in portal hypertension exceeds the ability of the cisterna chyli and thoracic duct to clear the lymph, fluid crosses into the liver interstitium. Fluid may then extravasate across the liver capsule into the peritoneal cavity. The role of renal dysfunction in the pathogenesis of cirrhotic ascites Patients with cirrhosis experience sodium retention, impaired free-water excretion, and intravascular volume overload. These abnormalities may occur even in the setting of a normal glomerular filtration rate. They are, to some extent, due to increased levels of renin and aldosterone. The peripheral arterial vasodilation hypothesis states that splanchnic arterial vasodilation, driven by high nitric oxide levels, leads to intravascular underfilling. This causes stimulation of the renin-angiotensin system and the sympathetic nervous system and also results in antidiuretic hormone release. These events are followed by an increase in sodium and water retention and in plasma volume, as well as by the overflow of ascites into the peritoneal cavity. Clinical features of ascites Ascites is suggested by the presence of the following findings upon physical examination:

Abdominal distention Bulging flanks Shifting dullness Elicitation of a "puddle sign" in patients in the knee-elbow position A fluid wave may be elicited in patients with massive tense ascites. However, physical examination findings are much less sensitive than abdominal ultrasonography, which can detect as little as 30mL of fluid. Furthermore, ultrasonography with Doppler can help to assess the patency of hepatic vessels. Factors associated with worsening of ascites include excess fluid or salt intake, malignancy, venous occlusion (eg, Budd-Chiari syndrome), progressive liver disease, and spontaneous bacterial peritonitis (SBP). Spontaneous bacterial peritonitis SBP is observed in 15-26% of patients hospitalized with ascites. The syndrome arises most commonly in patients whose low-protein ascites (< 1g/dL) contains low levels of complement, resulting in decreased opsonic activity. SBP appears to be caused by the translocation of gastrointestinal (GI) tract bacteria across the gut wall and also by the hematogenous spread of bacteria. The most common causative organisms are Escherichia coli, Streptococcus pneumoniae, Klebsiellaspecies, and other gram-negative enteric organisms.[11] Classic SBP is diagnosed by the presence of neutrocytosis, which is defined as greater than 250 polymorphonuclear cells (PMNs) per mm3 of ascites, in the setting of a positive ascites culture. Culture-negative neutrocytic ascites is observed more commonly. Both conditions represent serious infections that carry a 20-30% mortality rate. The most commonly used regimen in the treatment of SBP is a 5-day course of cefotaxime at 1-2g intravenously every 8 hours.[12] Alternatives include oral ofloxacin and other IV antibiotics with activity against gram-negative enteric organisms. Many authorities advise repeat paracentesis in 48-72 hours to document a decrease in the ascites PMN count to less than 250 cells/mm 3 and to ensure the efficacy of therapy.

Once SBP develops, patients have a 70% chance of redeveloping the condition within 1 year. Prophylactic antibiotic therapy can reduce the recurrence rate of SBP to 20%. Some of the regimens used in the prophylaxis of SBP include norfloxacin at 400mg orally every day [13] and trimethoprim-sulfamethoxazole at 1 double-strength tablet 5 days per week.[14] Therapy with norfloxacin at 400mg orally twice per day for 7 days can reduce serious bacterial infection in patients with cirrhosis who have GI bleeding. One study noted that the 37% incidence of serious bacterial infection was reduced to 10% when treatment with norfloxacin was instituted.[15] Furthermore, it can be argued that all patients with low-protein ascites should undergo prophylactic therapy (eg, with norfloxacin 400mg daily PO) at the time of hospital admission, given the high incidence of hospital-acquired SBP.[16] Hernias Umbilical and inguinal hernias are common in patients with moderate and massive ascites. The use of an elastic abdominal binder may protect the skin overlying a protruding umbilical hernia from maceration and may help to prevent rupture and subsequent infection. Timely, large-volume paracentesis also may help to prevent this disastrous complication. Umbilical hernias should not undergo elective repair unless patients are significantly symptomatic or their hernias are irreducible. As with all other surgeries in patients with cirrhosis, herniorrhaphy carries multiple potential risks, such as intraoperative bleeding, postoperative infection, and liver failure, because of anesthesia-induced reductions in hepatic blood flow. However, these risks become acceptable in patients with severe symptoms from their hernia. Urgent surgery is necessary in the patient whose hernia has been complicated by bowel incarceration. Other complications of massive ascites Patients with massive ascites may experience abdominal discomfort, depressed appetite, and decreased oral intake. Diaphragmatic elevation may lead to symptoms of dyspnea. Pleural effusions may result from the passage of ascitic fluid across channels in the diaphragm. Paracentesis in the diagnosis of ascites Paracentesis is essential in determining whether ascites is caused by portal hypertension or by another process. Ascites studies also are used to rule out infection and malignancy. Paracentesis should be performed in all patients with either new onset of ascites or worsening ascites. Paracentesis also should be performed when SBP is suggested by the presence of abdominal pain, fever, leukocytosis, or worsening hepatic encephalopathy. Some argue that paracentesis should be performed in all patients with cirrhosis who have ascites at the time of hospitalization, given the significant possibility of asymptomatic SBP. (See Table 3, below.) Table 3. Ascites Tests (Open Table in a new window) Routine Cell count Albumin Culture Total protein Optional Glucose (minimal use) Special Cytology

Lactate dehydrogenase Tuberculosis smear and culture Gram stain Triglycerides (to rule out chylous ascites) Bilirubin (to rule out biliary leak when clinically suspected) Amylase (to rule out pancreatic duct leak when clinically suspected)

Ascitic fluid with more than 250 PMNs/mm 3 defines neutrocytic ascites and SBP. Many cases of ascites fluid with more than 1000 PMNs/mm 3 (and certainly >5000 PMNs/mm3) are associated with appendicitis or a perforated viscus with resulting bacterial peritonitis. Appropriate radiologic studies must be performed in such patients to rule out surgical causes of peritonitis. Lymphocyte-predominant ascites raises concerns about the possibility of underlying malignancy or tuberculosis. Similarly, grossly bloody ascites may be observed in malignancy and tuberculosis. (Bloody ascites is seen infrequently in uncomplicated cirrhosis.) A common clinical dilemma is how to interpret the ascites PMN count in the setting of bloody ascites. This author recommends subtraction of 1 PMN for every 250 red blood cells (RBCs) in ascites to ascertain a corrected PMN count. The yield of ascites culture studies may be increased by directly inoculating 10mL of ascites into aerobic and anaerobic culture bottles at the patient's bedside.[17] Medical treatment of ascites Therapy for ascites should be tailored to the patient's needs. Some patients with mild ascites respond to sodium restriction or diuretics taken once or twice per week. Other patients require aggressive diuretic therapy, careful monitoring of electrolytes, and occasional hospitalization to facilitate even more intensive diuresis. The development of massive ascites that is refractory to medical therapy has dire prognostic implications, with only 50% of patients surviving 6 months.[18] Sodium restriction Salt restriction is the first line of therapy. In general, patients begin with a diet containing less than 2000mg of sodium daily. Some patients with refractory ascites require a diet containing less than 500mg of sodium daily. However, ensuring that patients do not construct diets that might place them at risk for calorie and protein malnutrition is important. Indeed, the benefit of commercially available liquid nutritional supplements (which often contain moderate amounts of sodium) often exceeds the risk of slightly increasing the patient's salt intake. Diuretics Diuretics should be considered the second line of therapy. Spironolactone (Aldactone) blocks the aldosterone receptor at the distal tubule. It is dosed at 50-300mg once daily. Although the drug has a relatively short half-life, its blockade of the aldosterone receptor lasts for at least 24 hours. Adverse effects of spironolactone include hyperkalemia, gynecomastia, and lactation. Other potassium-sparing diuretics, including amiloride and triamterene, may be used as alternative agents, especially in patients complaining of gynecomastia.

Furosemide (Lasix) may be used as a solo agent or in combination with spironolactone. The drug blocks sodium reuptake in the loop of Henle. It is dosed at 40-240mg daily in 1-2 divided doses. Patients infrequently need potassium repletion when furosemide is dosed in combination with spironolactone. An Italian study by Angeli et al found sequential dosing with a potassium-sparing diuretic plus furosemide to be superior for patients with moderate ascites without renal failure when compared with potassium-sparing diuretic monotherapy.[19] Aggressive diuretic therapy in hospitalized patients with massive ascites can safely induce a weight loss of 0.5-1kg daily, provided that patients undergo careful monitoring of renal function. Diuretic therapy should be held in the event of electrolyte disturbances, azotemia, or induction of hepatic encephalopathy. Albumin Thus far, evidence-based medicine has not firmly supported the use of albumin as an aid to diuresis in the patient with cirrhosis who is hospitalized. The author's anecdotal experience suggests that albumin may increase the efficacy and safety of diuretics. The author's practice in hospitalized patients who are hypoalbuminemic is to administer IV furosemide following IV infusion of albumin at 25g twice daily, in addition to providing ongoing therapy with spironolactone. One article supported the use of chronic albumin infusions to achieve diuresis in patients with diuretic-resistant ascites.[20] Albumin infusion may protect against the development of renal insufficiency in patients with SBP. Patients receiving cefotaxime and albumin at 1g/kg daily experienced a lower risk of renal failure and a lower in-hospital mortality rate than patients treated with cefotaxime and conventional fluid management.[21] V2 receptor antagonists Vasopressin V2 receptor antagonists are a class of agents with the potential to increase free-water excretion, improve diuresis, and decrease the need for paracentesis. However, no such agent has received US Food and Drug Administration (FDA) approval for this indication. Tolvaptan (Samsca, Otsuka Pharmaceutical Co; Tokyo, Japan) is an oral V2 receptor antagonist; it received FDA approval in 2009 only for the management of hyponatremia. A black box warning cautions against treatment initiation in outpatients. Furthermore, it may be associated with an increased incidence of GI bleeding in patients with cirrhosis. The author advises against its use for ascites management at this time. Large-volume paracentesis Aggressive diuretic therapy is ineffective in controlling ascites in approximately 5-10% of patients. Such patients with massive ascites may need to undergo large-volume paracentesis to receive relief from symptoms of abdominal discomfort, anorexia, or dyspnea. The procedure also may help to reduce the risk of umbilical hernia rupture. Large-volume paracentesis was first used in ancient times. It fell out of favor from the 1950s through the 1980s with the advent of diuretic therapy and following a handful of case reports describing paracentesis-induced azotemia. In 1987, Gines and colleagues demonstrated that large-volume paracentesis could be performed with minimal or no impact on renal function.[22] This and other studies showed that 5-15L of ascites could be removed safely at one time. Large-volume paracentesis is thought to be safe in patients with peripheral edema and in patients not currently treated with diuretics. Debate exists whether colloid infusions (eg, with 5-10g of albumin per 1L of ascites removed) are necessary to prevent intravascular volume depletion in patients who are receiving ongoing diuretic therapy or in patients with mild or moderate, underlying renal insufficiency. Peritoneovenous shunts LeVeen shunts and Denver shunts are devices that permit the return of ascites fluid and proteins to the intravascular space. Plastic tubing inserted subcutaneously under local anesthesia connects the peritoneal cavity to the internal jugular vein or subclavian vein via a pumping chamber. These devices are successful at relieving ascites and reversing protein loss in some patients. However, shunts may clot and require replacement in 30% of patients. Serious complications are observed in at least 10% of the recipients of these devices, including peritoneal infection, sepsis, disseminated intravascular coagulation, congestive heart failure, and death. The author considers peritoneovenous shunts to be a last resort for patients with refractory ascites who are not candidates for TIPS or liver transplantation. The safety of repeat large-volume paracentesis procedures may actually outweigh the safety of peritoneovenous shunt placement. Portosystemic shunts and transjugular intrahepatic portosystemic shunts The prime indication for portocaval shunt surgery is the management of refractory variceal bleeding. Since 1945, however, the medical field has recognized that portocaval shunts, by decompressing the hepatic sinusoid, may improve ascites. The performance of a side-to-side portocaval shunt for ascites management must be weighed against the approximate 5% mortality rate associated with this surgery and the chance (as high as 30%) of inducing hepatic encephalopathy. A TIPS is an effective tool in managing massive ascites in some patients. Ideally, TIPS placement produces a decrease in sinusoidal pressure and in plasma renin and aldosterone levels, with subsequent improved urinary sodium excretion. In one study, 74% of patients with refractory ascites achieved complete remission of ascites within 3 months of TIPS placement.[23] Typically, about one half of appropriately selected patients undergoing TIPS achieve significant relief of ascites. Multiple studies have demonstrated that a TIPS is superior to large-volume paracentesis when it comes to the control of ascites.[24] One metaanalysis of individual patient data demonstrated an improvement in transplant-free life expectancy in patients whose massive ascites was treated with a TIPS, as opposed to large-volume paracentesis.[25] However, creation of a TIPS has the potential to worsen preexisting hepatic encephalopathy and exacerbate liver dysfunction in patients with severe, underlying liver failure.[26] Both a pre-TIPS bilirubin level of greater than 3mg/dL and a pre-TIPS Model for End-Stage Liver Disease (MELD) score of greater than 18 (see the MELD Score calculator) are associated with an increased mortality rate when a TIPS is created for the management of ascites. [27, 28] In the author's opinion, TIPS use should be reserved for patients with Child Class B cirrhosis or patients with Child Class C cirrhosis without severe coagulopathy or encephalopathy. In the 1990s, shunt stenosis was observed in one half of cases within 1 year of TIPS placement, necessitating angiographic revision. Although the advent of coated stents appears to be reducing the incidence of shunt stenosis, patients must still be willing to return to the hospital for Doppler and angiographic follow-up of TIPS patency. Liver transplantation

Patients with massive ascites have 1-year survival rate of less than 50%. Liver transplantation should be considered as a potential means of salvaging the patient prior to the onset of intractable liver failure or hepatorenal syndrome. Hepatorenal Syndrome This syndrome represents a continuum of renal dysfunction that may be observed in patients with a combination of cirrhosis and ascites. Hepatorenal syndrome is caused by the vasoconstriction of large and small renal arteries and the impaired renal perfusion that results. [29] The syndrome may represent an imbalance between renal vasoconstrictors and vasodilators. Plasma levels of a number of vasoconstricting substancesincluding angiotensin, antidiuretic hormone, and norepinephrineare elevated in patients with cirrhosis. Renal perfusion appears to be protected by vasodilators, including prostaglandins E2 and I2 and atrial natriuretic factor. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis. They may potentiate renal vasoconstriction, with a resulting drop in glomerular filtration. Thus, the use of NSAIDs is contraindicated in patients with decompensated cirrhosis. Most patients with hepatorenal syndrome are noted to have minimal histologic changes in the kidneys. Kidney function usually recovers when patients with cirrhosis and hepatorenal syndrome undergo liver transplantation. In fact, a kidney donated by a patient dying from hepatorenal syndrome functions normally when transplanted into a renal transplant recipient. Types of hepatorenal syndrome Hepatorenal syndrome progression may be slow (type II) or rapid (type I). [30] Type I disease frequently is accompanied by rapidly progressive liver failure. Hemodialysis offers temporary support for such patients. These individuals are salvaged only by performance of liver transplantation. Exceptions to this rule are the patients with fulminant hepatic failure (FHF) or severe alcoholic hepatitis who spontaneously recover liver and kidney function. In type II hepatorenal syndrome, patients may have stable or slowly progressive renal insufficiency. Many such patients develop ascites that is resistant to management with diuretics. Diagnosis Hepatorenal syndrome is diagnosed when a creatinine clearance rate of less than 40mL/min is present or when a serum creatinine level of greater than 1.5mg/dL, a urine volume of less than 500mL/day, and a urine sodium level of less than 10mEq/L are present.[3] Urine osmolality is greater than plasma osmolality. In hepatorenal syndrome, renal dysfunction cannot be explained by preexisting kidney disease, prerenal azotemia, the use of diuretics, or exposure to nephrotoxins. Clinically, the diagnosis may be reached if central venous pressure is determined to be normal or if no improvement of renal function occurs following the infusion of at least 1.5L of a plasma expander. Treatment Nephrotoxic medications, including aminoglycoside antibiotics, should be avoided in patients with cirrhosis. Patients with early hepatorenal syndrome may be salvaged by aggressive expansion of intravascular volume with albumin and fresh frozen plasma and by avoidance of diuretics. The use of renal-dose dopamine is not effective. A number of investigators have employed systemic vasoconstrictors in an attempt to reverse the effects of nitric oxide on peripheral arterial vasodilation. In Europe, administration of IV terlipressin (an analog of vasopressin not available in the United States) improved renal dysfunction in patients with hepatorenal syndrome.[31, 32] A combination of midodrine (an oral alpha agonist), subcutaneous octreotide, and albumin infusion has also been demonstrated to improve renal function in small cohorts of patients with hepatorenal syndrome.[33] Hepatic Encephalopathy Hepatic encephalopathy, a syndrome observed in some patients with cirrhosis, is marked by personality changes, intellectual impairment, and a depressed level of consciousness. The diversion of portal blood into the systemic circulation appears to be a prerequisite for the syndrome. Indeed, hepatic encephalopathy may develop in patients without cirrhosis who undergo portocaval shunt surgery. Pathogenesis A number of theories have been postulated to explain the pathogenesis of hepatic encephalopathy in patients with cirrhosis. Patients may have altered brain energy metabolism and increased permeability of the blood-brain barrier. The latter may facilitate the passage of neurotoxins into the brain. Putative neurotoxins include short-chain fatty acids, mercaptans, false neurotransmitters (eg, tyramine, octopamine, beta phenylethanolamines), ammonia, and gamma-aminobutyric acid (GABA). Ammonia hypothesis Ammonia is produced in the GI tract by bacterial degradation of amines, amino acids, purines, and urea. Normally, ammonia is detoxified in the liver by conversion to urea and glutamine. In liver disease or portosystemic shunting, portal blood ammonia is not converted efficiently to urea. Increased levels of ammonia may enter the systemic circulation because of portosystemic shunting. Ammonia has multiple neurotoxic effects, including alteration of the transit of amino acids, water, and electrolytes across the neuronal membrane. Ammonia also can inhibit the generation of excitatory and inhibitory postsynaptic potentials. Therapeutic strategies to reduce serum ammonia levels tend to improve hepatic encephalopathy. However, approximately 10% of patients with significant encephalopathy have normal serum ammonia levels. Furthermore, many patients with cirrhosis have elevated ammonia levels without evidence of encephalopathy. Gamma-aminobutyric acid hypothesis GABA is a neuroinhibitory substance produced in the GI tract. It was postulated that GABA crosses the extrapermeable blood-brain barriers of patients with cirrhosis and then interacts with supersensitive postsynaptic GABA receptors.[34]This would lead to the generation of inhibitory postsynaptic potentials. Clinically, this interaction was believed to produce the symptoms of hepatic encephalopathy. Subsequent work has suggested that brain GABA levels are not increased in patients with cirrhosis. However, brain levels of neurosteroids are increased in patients with cirrhosis.[35]They are capable of binding to their receptor within the neuronal GABA receptor complex and can increase inhibitory neurotransmission. Some investigators currently contend that neurosteroids may play a key role in hepatic encephalopathy.[36] Clinical features

The symptoms of hepatic encephalopathy may range from mild to severe and may be observed in as many as 70% of patients with cirrhosis. Symptoms are graded on the following scale:

Grade 0 - Subclinical; normal mental status but minimal changes in memory, concentration, intellectual function, coordination Grade 1 - Mild confusion, euphoria or depression, decreased attention, slowing of ability to perform mental tasks, irritability, disorder of sleep pattern (ie, inverted sleep cycle) Grade 2 - Drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behavior, intermittent disorientation (usually with regard to time) Grade 3 - Somnolent, but arousable, state; inability to perform mental tasks; disorientation with regard to time and place; marked confusion; amnesia; occasional fits of rage; speech is present but incomprehensible Grade 4 - Coma, with or without response to painful stimuli Patients with mild and moderate hepatic encephalopathy demonstrate decreased short-term memory and concentration on mental status testing. Findings on physical examination include asterixis and fetor hepaticus. Laboratory abnormalities An elevated arterial or free venous serum ammonia level is the classic laboratory abnormality reported in patients with hepatic encephalopathy. This finding may aid in the assignment of a correct diagnosis to a patient with cirrhosis who presents with altered mental status. However, serial ammonia measurements are inferior to clinical assessment in gauging improvement or deterioration in patients under therapy for hepatic encephalopathy. No utility exists for checking the ammonia level in a patient with cirrhosis who does not have hepatic encephalopathy. Some patients with hepatic encephalopathy have the classic, but nonspecific, electroencephalogram (EEG) changes of high-amplitude lowfrequency waves and triphasic waves. Electroencephalography may be helpful in the initial workup of a patient with cirrhosis and altered mental status, when ruling out seizure activity may be necessary. CT scan and MRI studies of the brain may be important in ruling out intracranial lesions when the diagnosis of hepatic encephalopathy is in question. Common precipitants Some patients with a history of hepatic encephalopathy have normal mental status when under medical therapy. Others have chronic memory impairment in spite of medical management. Both groups of patients are subject to episodes of worsened encephalopathy. Common precipitants of hyperammonemia and worsening mental status are as follows:

Diuretic therapy Hypovolemia Renal failure GI bleeding Infection Constipation Dietary protein overload is an infrequent cause of worsening encephalopathy. Medications, notably opiates, benzodiazepines, antidepressants, and antipsychotic agents, also may worsen encephalopathic symptoms. Differential diagnosis Conditions to consider in the differential diagnosis of encephalopathy include the following:

Intracranial lesions - Eg, subdural hematoma, intracranial bleeding, cerebrovascular accident, tumor, abscess Infections - Eg, meningitis, encephalitis, abscess Metabolic encephalopathy - Eg, hypoglycemia, electrolyte imbalance, anoxia, hypercarbia, uremia Hyperammonemia from other causes - Eg, secondary to ureterosigmoidostomy, inherited urea cycle disorders Toxic encephalopathy due to alcohol - Eg, acute intoxication, alcohol withdrawal, Wernicke encephalopathy Toxic encephalopathy due to drugs - Eg, sedative-hypnotics, antidepressants, antipsychotic agents, salicylates Organic brain syndrome Postseizure encephalopathy Management Nonhepatic causes of altered mental function must be excluded in patients with cirrhosis who have worsening mental function. A check of the blood ammonia level may be helpful in such patients. Medications that depress central nervous system (CNS) function, especially benzodiazepines, should be avoided. Precipitants of hepatic encephalopathy should be corrected (eg, hypovolemia, metabolic disturbances, GI bleeding, infection, constipation). Lactulose Lactulose is helpful in patients with the acute onset of severe encephalopathy symptoms and in patients with milder, chronic symptoms. This nonabsorbable disaccharide stimulates the passage of ammonia from tissues into the gut lumen and inhibits intestinal ammonia production. Initial lactulose dosing is 30mL orally once or twice daily. Dosing is increased until the patient has 2-4 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 or rectal tube to hospitalized patients with severe encephalopathy. Other cathartics, including colonic lavage solutions that contain polyethylene glycol (PEG) (eg, Go-Lytely), also may be effective in patients with severe encephalopathy. In a study, Sharma et al concluded that the use of lactulose effectively prevents hepatic encephalopathy recurrence in cirrhosis. Patients with cirrhosis recovering from hepatic encephalopathy were randomized to receive lactulose (n = 61) or placebo (n = 64). Over a median follow-up of 14 months, 12 patients (19.6%) in the lactulose group developed hepatic encephalopathy, compared with 30 patients (46.8%) in the placebo group.[37] The authors

Antibiotics Neomycin and other antibiotics (eg, metronidazole, oral vancomycin, paromomycin, oral quinolones) serve as second-line agents. They work by decreasing the colonic concentration of ammoniagenic bacteria. Neomycin dosing is 250-1000mg orally 2-4 times daily. Treatment with neomycin may be complicated by ototoxicity and nephrotoxicity. Rifaximin (Xifaxan, Salix Pharmaceuticals, Inc, Morrisville, NC) is a nonabsorbable antibiotic that received FDA approval in 2004 for the treatment of travelers' diarrhea and was given approval in 2010 for the reduction of recurrent hepatic encephalopathy. Its use is also being studied in irritable bowel syndrome. Data from Europe suggest that rifaximin can decrease colonic levels of ammoniagenic bacteria, with resulting improvement in the symptoms of hepatic encephalopathy. A double-blind, placebo-controlled trial, indicated that rifaximin can prevent the occurrence hepatic encephalopathy. In the study, 299 patients whose recurrent hepatic encephalopathy was in remission received either rifaximin 550mg or placebo twice daily. Each group also received lactulose. Breakthrough episodes of hepatic encephalopathy occurred in 22% of patients treated with rifaximin and in 46% of patients who were given placebo, while hepatic encephalopathy related hospitalization occurred in 14% of rifaximin patients and in 23% of placebo patients.[38] Rifaximin also appeared to be more effective than lactulose in trials that compared the 2 drugs head-to-head.[39] Other drugs Other chemicals capable of decreasing blood ammonia levels are L-ornithine L-aspartate (available in Europe) and sodium benzoate.[40] Protein restriction Low-protein diets were recommended routinely in the past for patients with cirrhosis. High levels of aromatic amino acids contained in animal proteins were believed to lead to increased blood levels of the false neurotransmitters tyramine and octopamine, with resultant worsening of encephalopathic symptoms. In this author's experience, the vast majority of patients can tolerate a protein-rich diet (>1.2g/kg daily) that includes well-cooked chicken, fish, vegetable protein, and, if needed, protein supplements. Protein restriction is rarely necessary in patients with symptoms of chronic encephalopathy. Many patients with cirrhosis have protein-calorie malnutrition at baseline; the routine restriction of dietary protein intake increases their risk for worsening malnutrition. In the author's opinion, protein restriction is infrequently valuable in patients with an acute flare-up of symptoms of hepatic encephalopathy. One study randomized hospitalized patients with hepatic encephalopathy to receive either a normal-protein diet or a low-protein diet, in addition to standard treatment measures, and found no difference between the 2 groups in outcomes for hepatic encephalopathy.[41] Other Manifestations of Cirrhosis All chronic liver diseases that progress to cirrhosis have in common the histologic features of hepatic fibrosis and nodular regeneration. However, patients' signs and symptoms may vary, depending on the underlying etiology of the disease. As an example, patients with end-stage liver disease caused by hepatitis C may develop profound muscle wasting, marked ascites, and severe hepatic encephalopathy, with only mild jaundice. In contrast, patients with end-stage primary biliary cirrhosis may be deeply icteric, with no evidence of muscle wasting. These patients may complain of extreme fatigue and pruritus and have no complications of portal hypertension. In both cases, medical management is focused on the relief of symptoms. Liver transplantation should be considered as a potential therapeutic option, given the inexorable course of most cases of end-stage liver disease. Many patients with cirrhosis experience fatigue, anorexia, weight loss, and muscle wasting. Cutaneous manifestations of cirrhosis include jaundice, spider angiomata, skin telangiectasias (termed "paper money skin" by Dame Sheila Sherlock), palmar erythema, white nails, disappearance of lunulae, and finger clubbing, especially in the setting of hepatopulmonary syndrome. Patients with cirrhosis may experience increased conversion of androgenic steroids into estrogens in skin, adipose tissue, muscle, and bone. Males may develop gynecomastia and impotence. Loss of axillary and pubic hair is noted in men and women. Hyperestrogenemia also may explain spider angiomata and palmar erythema. Hematologic manifestations Anemia may result from folate deficiency, hemolysis, or hypersplenism.[42]Thrombocytopenia usually is secondary to hypersplenism and decreased levels of thrombopoietin. Coagulopathy results from decreased hepatic production of coagulation factors. If cholestasis is present, decreased micelle entry into the small intestine leads to decreased vitamin K absorption, with resulting reduction in hepatic production of factors II, VII, IX, and X. Patients with cirrhosis also may experience fibrinolysis and disseminated intravascular coagulation. Pulmonary and cardiac manifestations Patients with cirrhosis may have impaired pulmonary function. Pleural effusions and the diaphragmatic elevation caused by massive ascites may alter ventilation-perfusion relations. Interstitial edema or dilated precapillary pulmonary vessels may reduce pulmonary diffusing capacity. Patients also may have hepatopulmonary syndrome (HPS). In this condition, pulmonary arteriovenous anastomoses result in arteriovenous shunting. HPS is a potentially progressive and life-threatening complication of cirrhosis. Classic HPS is marked by the symptom of platypnea and the finding of orthodeoxia, but the syndrome must be considered in any patient with cirrhosis who has evidence of oxygen desaturation. HPS is detected most readily by echocardiographic visualization of late-appearing bubbles in the left atrium following the injection of agitated saline. Patients can receive a diagnosis of HPS when their PaO2 is less than 70mm Hg. Some cases of HPS may be corrected by liver transplantation. In fact, a patient's course to liver transplantation may be expedited when his or her PaO 2 is less than 60mm Hg. Portopulmonary hypertension (PPHTN) is observed in up to 6% of patients with cirrhosis. Its etiology is unknown. PPHTN is defined as the presence of a mean pulmonary artery pressure of greater than 25mm Hg in the setting of a normal pulmonary capillary wedge pressure. Routine Doppler echocardiography is performed as part of many liver transplant programs to rule out the interval development of PPHTN in patients on the transplant waiting list. Indeed, the presence of a mean pulmonary pressure of greater than 35mm Hg significantly increases the risks of liver transplant surgery. Patients who develop severe PPHTN may require aggressive medical therapy in an effort to stabilize pulmonary artery pressures and to decrease their chance of perioperative mortality. Hepatocellular carcinoma and cholangiocarcinoma

Hepatocellular carcinoma (HCC) ultimately arises in 10-25% of patients with cirrhosis in the United States. It typically occurs in about of 3% of patients per year, when the etiology of cirrhosis is hepatitis B, hepatitis C, or alcohol. It develops more commonly in patients with underlying hereditary hemochromatosis or alpha-1 antitrypsin deficiency. HCC is observed less commonly in primary biliary cirrhosis and is a rare complication of Wilson disease. Cholangiocarcinoma occurs in approximately 10% of patients with primary sclerosing cholangitis. Early diagnosis of HCC is critical because it is potentially curable through either liver resection or liver transplant. Other diseases Other conditions that appear with increased incidence in patients with cirrhosis include peptic ulcer disease, diabetes, and gallstones. Assessment of the Severity of Cirrhosis For many years, the most common prognostic tool used in patients with cirrhosis was the Child-Turcotte-Pugh (CTP) system. Child and Turcotte first introduced their scoring system in 1964 as a means of predicting the operative mortality associated with portocaval shunt surgery. Pugh's revised system in 1973 substituted albumin for the less specific variable of nutritional status. [43]Subsequent revisions have used the International Normalized Ratio (INR) in addition to prothrombin time. Epidemiologic work shows that the CTP score may predict life expectancy in patients with advanced cirrhosis. A CTP score of 10 or greater is associated with a 50% chance of death within 1 year. (See Table 4, below.) Table 4. Child-Turcotte-Pugh Scoring System for Cirrhosis (Open Table in a new window) Clinical Variable Encephalopathy Ascites Bilirubin (mg/dL) Bilirubin in PBC* or PSC** (mg/dL) Albumin (g/dL) 1 Point None Absent <2 <4 >3.5 2 Points Grade 1-2 Slight 2-3 4-10 2.8-3.5 3 Points Grade 3-4 Moderate or large >3 10 < 2.8

Prothrombin time(seconds prolonged or INR) < 4 s or INR < 1.7 4-6 s or INR 1.7-2.3 >6 s or INR >2.3 *PBC = Primary biliary cirrhosis

**PSC = Primary sclerosing cholangitis

Child Class A = 5-6 points, Child Class B = 7-9 points, Child Class C = 10-15 points

Since 2002, liver transplant programs in the United States have used the Model for End-Stage Liver Disease (MELD) scoring system to assess the relative severity of patients' liver disease. Patients may receive a MELD score of 6-40 points (see theMELD Score calculator). The 3-month mortality statistics are associated with the following MELD scores[44] :

MELD score of less than 9 - 2.9% mortality MELD score of 10-19 - 7.7% mortality MELD score of 20-29 - 23.5% mortality MELD score of 30-39 - 60% mortality MELD score of greater than 40 - 81% mortality Pharmacologic Treatment Specific medical therapies may be applied to many liver diseases in an effort to diminish symptoms and to prevent or forestall the development of cirrhosis. Examples include prednisone and azathioprine for autoimmune hepatitis, interferon and other antiviral agents for hepatitis B and C, phlebotomy for hemochromatosis, ursodeoxycholic acid for primary biliary cirrhosis, and trientine and zinc for Wilson disease. These therapies become progressively less effective if chronic liver disease evolves into cirrhosis. Once cirrhosis develops, treatment is aimed at the management of complications as they arise. Certainly variceal bleeding, ascites, and hepatic encephalopathy are among the most serious complications experienced by patients with cirrhosis. However, attention also must be paid to patients' chronic constitutional complaints. Zinc deficiency Zinc deficiency commonly is observed in patients with cirrhosis. Treatment with zinc sulfate at 220mg orally twice daily may improve dysgeusia and can stimulate appetite. Furthermore, zinc is effective in the treatment of muscle cramps and is adjunctive therapy for hepatic encephalopathy. Pruritus

Pruritus is a common complaint in cholestatic liver diseases (eg, primary biliary cirrhosis) and in noncholestatic chronic liver diseases (eg, hepatitis C). Although increased serum bile acid levels once were thought to be the cause of pruritus, endogenous opioids are more likely to be the culprit pruritogen. Mild itching complaints may respond to treatment with antihistamines and topical ammonium lactate. Cholestyramine is the mainstay of therapy for the pruritus of liver disease. To avoid compromising GI absorption, care should be taken to avoid coadministration of this organic anion binder with any other medication. Other medications that may provide relief against pruritus include antihistamines (eg, diphenhydramine, hydroxyzine), ursodeoxycholic acid, ammonium lactate 12% skin cream (Lac-Hydrin, Westwood-Squibb Pharmaceuticals, Inc, Princeton, NJ), doxepin, and rifampin. Naltrexone, an opiate (an opioid antagonist), may be effective but is often poorly tolerated. Gabapentin is an unreliable therapy. Patients with severe pruritus may require institution of ultraviolet light therapy or plasmapheresis. Hypogonadism Some male patients suffer from hypogonadism. Patients with severe symptoms may undergo therapy with topical testosterone preparations, although their safety and efficacy is not well studied. Similarly, the utility and safety of growth hormone therapy remains unclear. Osteoporosis 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 or primary biliary cirrhosis and patients receiving corticosteroids for autoimmune hepatitis. The discovery on bone densitometry studies of decreased bone mineralization may prompt the institution of therapy with an aminobisphosphonate (eg, alendronate sodium). Vaccination Patients with chronic liver disease should receive vaccination to protect them against hepatitis A. Other protective measures include vaccination against influenza and pneumococci. Drug hepatotoxicity in the patient with cirrhosis The institution of any new medical therapy warrants the performance of more frequent liver chemistries; patients with liver disease can ill afford to have drug-induced liver disease superimposed on their condition. Medications associated with drug-induced liver disease include the following:

NSAIDs Isoniazid Valproic acid Erythromycin Amoxicillin/clavulanate Ketoconazole Chlorpromazine Ezetimibe Statins Hepatic 3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors are frequently associated with mild elevations of alanine aminotransferase (ALT) levels. However, severe hepatotoxicity is reported infrequently.[45] The literature suggests that statins can be used safely in most patients with chronic liver disease.[46] Certainly, liver chemistries should be followed frequently after the initiation of therapy. In a study of the effects of statins in 58 patients with primary biliary cirrhosis, Rajab and Kaplan concluded that statin use is safe in patients with this condition.[47] Individuals in the study were on statins for a median period of 41 months, with ALT levels measured every 3 months. The authors found that these levels did not increase, being slightly elevated when statin treatment began and normal by the last follow-up analysis. Patients did not complain of muscle pain or weakness, and serum cholesterol levels fell by 30%. Analgesics The use of analgesics in patients with cirrhosis can be problematic. Although high-dose acetaminophen is a well-known hepatotoxin, most hepatologists permit the use of acetaminophen in patients with cirrhosis at doses of up to 2000mg daily. NSAID use may predispose patients with cirrhosis to develop GI bleeding. Patients with decompensated cirrhosis are at risk for NSAID-induced renal insufficiency, presumably because of prostaglandin inhibition and worsening of renal blood flow. Opiate analgesics are not contraindicated but must be used with caution in patients with preexisting hepatic encephalopathy on account of the drugs' potential to worsen underlying mental function. Other drugs Aminoglycoside antibiotics are considered obligate nephrotoxins in patients with cirrhosis and should be avoided. Low-dose estrogens and progesterone appear to be safe in the setting of liver disease. Nutrition and Exercise Many patients complain of anorexia, which may be compounded by the direct compression of ascites on the GI tract. Care should be taken to ensure that patients receive adequate calories and protein in their diets. Patients frequently benefit from the addition of commonly available liquid and powdered nutritional supplements to the diet. Only rarely can patients not tolerate proteins in the form of chicken, fish, vegetables, and nutritional supplements. Institution of a low-protein diet out of concern that hepatic encephalopathy may develop places the patient at risk for profound muscle wasting. The 2010 practice guidelines for alcoholic liver disease published by the American Association for the Study of Liver Diseases and the American College of Gastroenterology recommend aggressive treatment of protein calorie malnutrition in patients with alcoholic cirrhosis. Multiple feedings per day, including breakfast and a snack at night, are specified. [48] Regular exercise, including walking and even swimming, should be encouraged in patients with cirrhosis, to prevent these patients from slipping into a vicious cycle of inactivity and muscle wasting. Debilitated patients frequently benefit from a formal exercise program supervised by a physical therapist.

Surgical Risks Surgery and general anesthesia carry increased risks in the patient with cirrhosis. Anesthesia reduces cardiac output, induces splanchnic vasodilation, and causes a 30-50% reduction in hepatic blood flow. This places the cirrhotic liver at additional risk for decompensation. Surgery is said to be safe in the setting of mild chronic hepatitis. Its risk in patients with severe chronic hepatitis is unknown. Patients with wellcompensated cirrhosis have increased, but acceptable, morbidity and mortality risks. Care should be taken to avoid postoperative infection, fluid overload, unnecessary sedatives and analgesics, and potentially hepatotoxic and nephrotoxic drugs (eg, aminoglycoside antibiotics). In the prelaparoscopic era, a study of nonshunt abdominal surgeries demonstrated a 10% mortality rate for patients with Child Class A cirrhosis, as opposed to a 30% mortality rate for patients with Child Class B cirrhosis and a 75% mortality rate for patients with Child Class C cirrhosis.[49] Although cholecystectomy was among the riskier surgeries noted, several reports have described the successful performance of laparoscopic cholecystectomy in patients with Child Class A or B cirrhosis. [50] Studies have used the MELD score as a tool in predicting postoperative outcomes in abdominal surgery (see the MELD Score calculator). In one study, a preoperative MELD score of greater than 14 was a better predictor of postoperative death than Child Class C status. [51] In a study of patients with cirrhosis who underwent major digestive, orthopedic, or cardiovascular surgery, the preoperative MELD scores and their associated 30-day postoperative mortality rates were as follows[52] :

MELD score of 7 or less - 5.7% mortality MELD score of 8-11 - 10.3% mortality MELD score of 12-15 - 25.4% mortality MELD score of 16-20 - 44% mortality MELD score of 21-25 - 53.8% mortality MELD score of greater than 26 - 90% mortality The benefits and the risks of surgery should be carefully weighed before advising the patient with cirrhosis to undergo surgery. Liver Transplantation Liver transplantation has emerged as an important strategy in the management of patients with decompensated cirrhosis. Patients should be referred for consideration for liver transplantation after the first signs of hepatic decompensation. Advances in surgical technique, organ preservation, and immunosuppression have resulted in dramatic improvements in postoperative survival. In the early 1980s, the percentage of patients surviving 1 year and 5 years after liver transplant were only 70% and 15%, respectively. Now, patients can anticipate a 1-year survival rate of 85-90% and a 5-year survival rate of higher than 70%. Quality of life after liver transplant is good or excellent in most cases. Contraindications to transplant Contraindications for liver transplantation include severe cardiovascular or pulmonary disease, active drug or alcohol abuse, malignancy outside the liver, sepsis, or psychosocial problems that might jeopardize patients' abilities to follow their medical regimens after transplant. According to the 2010 guidelines for alcoholic liver disease from the American Association for the Study of Liver Diseases, patients whose endstage liver disease is alcohol related should be considered as candidates for transplantation after a medical and psychosocial evaluation that includes formal assessment of the probability of long-term abstinence.[48] The presence of the human immunodeficiency virus (HIV) in the bloodstream also is a contraindication to transplant. However, successful liver transplantations are now being performed in patients with no detectable HIV viral load due to antiretroviral therapy. [53] Additional clinical study is required before liver transplantation can be offered routinely to such patients. Organ allocation Approximately 6500 liver transplants are performed in the United States each year. An increasing number of lives are saved each year by transplant. However, the number of diagnosed cases of cirrhosis is rising, fueled in part by the hepatitis C epidemic and by the growing number of cases of nonalcoholic fatty liver disease (NAFLD). This has resulted in a dramatic increase in the number of patients listed as candidates for liver transplantation. Approximately 12-15% of patients listed as candidates die while waiting because of the relatively static number of organ donations. 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 and adult recipients, organ donation after cardiac death, and the use of extended criteria donors (ECDs). An ECD "deviates in some aspect from the ideal donor." One example of an ECD organ is the hepatitis C-infected liver with minimal fibrosis that is transplanted into a hepatitis C-infected recipient. Such transplants have been performed successfully for a number of years. Other examples of ECDs include donors older than 70 years and donors with relatively fatty livers. The need for a more efficient and equitable system of organ allocation resulted in dramatic changes in United States organ allocation policy in 2002.[54] Previously, patients who were accepted as liver transplant candidates with 7-9 CTP points (Child Class B) received low priority on the transplant waiting list maintained by the United Network for Organ Sharing (UNOS). Patients with 10 or more CTP points (Child Class C) received a higher priority. Emergent liver transplantation at UNOS status 1 was reserved primarily for noncirrhotic patients suffering from fulminant hepatic failure. Since 2002, livers from deceased donors (ie, cadaveric organs) have been allocated to cirrhotic patients using the MELD scoring system and the Pediatric End-Stage Liver Disease (PELD) scoring system[44] (see the MELD Score calculator and the PELD Score calculator). In the MELD scoring system for adults, a patient receives a score based on the following formula: MELD score = 0.957 x Loge (creatinine mg/dL) + 0.378 x Loge (bilirubin mg/dL) + 1.120 x Loge (INR) + 0.643 As an example, a cirrhotic patient with a creatinine level of 1.9mg/dL, a bilirubin level of 4.2mg/dL, and an INR of 1.2 would receive the following score: MELD score = (0.957 x Loge 1.9) + (0.378 x Loge 4.2) + (1.120 x Loge 1.2) + 0.643 = 2.039

That value is then multiplied by 10 to give the patient a risk score of 20. Patients' MELD scores are recalculated every time they undergo laboratory testing. Patients may be assigned a maximum MELD score of 40 points. The PELD system uses a somewhat different formula: PELD score = 0.480 x Loge(total bilirubin mg/dL) + 1.857 x Loge (INR) - 0.687 x Loge (albumin g/dL) + 0.436 if the patient is younger than 1 year + 0.667 if the patient has growth failure (< 2 standard deviations). This value is multiplied by 10 to give a final risk score. Within any region of the country, a donor organ in a particular ABO blood group is allocated to the cirrhotic patient within the same blood group who has the highest MELD or PELD score. Special rules have been developed to address potentially life-threatening liver disease complications, such as hepatocellular carcinoma and hepatopulmonary syndrome. Patients with these conditions, as well as other exceptional cases, can receive a higher MELD or PELD score than that calculated from creatinine, bilirubin, and INR alone. The timing of the transplant surgery for patients on the transplant waiting list is a key issue. Typically, it is believed that the risks of the transplant may exceed the benefits when the MELD score is less than 15. However, when the MELD score is greater than 15, the benefits of the transplant typically exceed the risks.[55]Needless to say, there can be many exceptions to this so-called rule. Living donor liver transplantation The advent of living donor liver transplantation (LDLT) has introduced a new variable into any discussion of the timing of transplantation. LDLT has the potential to make liver transplantation an elective procedure not only for the cirrhotic patient with significant complications but also for the cirrhotic patient with a poor quality of life. LDLT became a reality for pediatric recipients in 1988 and for adult recipients a decade later. The procedure arose from advances in surgical technique and a worsening shortage of deceased donor organs. In LDLT, up to 60% of a healthy volunteer donor's liver can be surgically resected and transplanted into the abdomen of a needful recipient. Graft survival in LDLT recipients is on par with that seen in the recipients of deceased donor organs. However, LDLT has its limitations. The most obvious problem is the low, but real, risk of serious operative complications for the healthy volunteer liver donor. It is estimated that about 0.4% of the more than 3000 healthy liver donors worldwide over the last decade have died as a consequence of their surgery. Thus, transplant programs must maximize donor safety. They must also ensure that the benefits of LDLT to the potential recipient offset the risks to the donor. Furthermore, not every potential recipient is sufficiently stable to undergo safe and effective LDLT. Indeed, the recipient's risk of posttransplant mortality increases when his or her MELD score is greater than 25. In the author's opinion, LDLT should not be performed in such recipients. Liver donation after cardiac death The shortage of donor organs has spurred interest in the use of liver allografts from non heart beating donors (NHBDs). Typically, an NHBD is an individual who has sustained irreversible neurologic damage but whose clinical condition does not meet formal brain death criteria. Knowing this, a prospective donor's family will give consent for withdrawal of care and for organ donation. The donor is then brought to the operating room, with the anticipation that withdrawal of ventilator support will result in the cessation of the patient's cardiopulmonary function. Once death is declared, organ procurement surgery can proceed. In contrast to the organ procured from a heart-beating donor (HBD), the allograft obtained from an NHBD may be subject to considerable warm ischemia time before it is perfused with cold preservative solution. A review comparing the results of liver transplantation using allografts from 144 NHBDs and 26,856 HBDs over an 8-year period found better outcomes in HBD transplant recipients.[56] One- and 3-year graft survival rates were 70% and 63%, respectively, with organs from NHBDs, as opposed to 80% and 72%, respectively, with organs from HBDs. Higher rates of primary nonfunction and retransplantation were seen in the recipients of allografts from NHBDs. Other authors have described a higher incidence of hepatic artery stenosis, hepatic abscesses, and bilomas in the recipients of allografts from NHBDs.[57] It is possible that improved results will be seen by limiting donor age, by minimizing donor warm ischemia time, and by not attempting to transplant livers from NHBDs into recipients who are severely ill. The future of liver transplantation Exciting new technical advances also may help to improve patients' chances of survival. In the future, expanded use of hepatocyte transplantation may occur. In this therapy, a splenic artery catheter is used to deliver billions of cryopreserved hepatocytes into the spleen of a patient who has end-stage liver disease. The patient then undergoes routine immunosuppression. This strategy has been employed successfully in a small number of patients with cirrhosis and fulminant hepatic failure (FHF) who were not candidates for liver transplant surgery. Bioartificial livers may see increased application in the care of patients with FHF and, perhaps, cirrhosis. The 2 most studied devices are composed of semipermeable capillary hollow fiber membranes enclosed in a plastic shell. Either human C3A hepatoma cells or pig hepatocytes are attached to the exterior surface of the membranes as blood from the patient is pumped through the device. Intracranial pressure and hepatic encephalopathy improved in some patients with FHF who were assisted with these devices. However, currently available bioartificial livers have not yet fulfilled the goals of biotransforming and removing toxins while supplying the patient with clotting factors and growth factors. Xenotransplantation may come into use during the next decade. To date, all attempts at xenotransplantation in humans have suffered from severe, early humoral or late cellular rejection and have resulted in patient death. Advances in genetic engineering may lead to the development of swine whose livers are more likely to undergo graft acceptance when transplanted into humans. Once this obstacle is overcome, a determination can be made as to whether a swine liver is an effective substitute for a human liver. Most importantly, the medical world awaits the development of medical therapies that forestall the development of hepatic fibrosis long before patients develop cirrhosis and its complications. Patient Monitoring Patients with cirrhosis should undergo routine follow-up monitoring of their complete blood count, renal and liver chemistries, and prothrombin time. The author's policy is to monitor stable patients 3-4 times per year. Surveillance of esophageal varices The author performs routine diagnostic endoscopy to determine whether the patient has asymptomatic esophageal varices. Follow-up endoscopy is performed in 2 years if varices are not present. If varices are present, treatment is initiated with a nonselective beta blocker (eg, propranolol,

nadolol), aiming for a 25% reduction in heart rate. Such therapy offers effective primary prophylaxis against new onset of variceal bleeding.[58] Patients with large esophageal varices should undergo prophylactic endoscopic variceal ligation. Surveillance for hepatocellular carcinoma The incidence of hepatocellular carcinoma (HCC) has risen in the United States. The practice guidelines of the American Association for the Study of Liver Diseases recommend that patients with cirrhosis undergo surveillance for HCC with ultrasonography every 6 months. [59] The discovery of a liver nodule should prompt the performance of a 4-phase CT scan or an MRI scan (ie, unenhanced, arterial, venous, and delayed phases). Lesions that enhance in the arterial phase and exhibit "washout" in the delayed phases are highly suggestive of HCC. Many authors contend that the combination of arterial enhancement and washout on CT scanning or MRI offers greater diagnostic power for HCC than does guided liver biopsy.[60, 61] Indeed, guided liver biopsies have a 20-30% false negative rate in making the diagnosis of HCC. Current guidelines support the use of CT scanning and MRI in confirming the presence of HCC. Biopsy is not required in order to define a lesion as HCC.[59] However, CT scanning or ultrasonographically guided liver biopsy may be useful when a nodules enhancement characteristics ar e not typical for HCC. Patients with a diagnosis of HCC and no evidence of extrahepatic disease, as determined by chest and abdominal CT scans and by bone scan, should be offered curative therapy. Commonly, this therapy entails liver resection surgery for patients with Child Class A cirrhosis and an accelerated course to liver transplantation for patients with Child Class B or C cirrhosis. Patients who are awaiting liver transplantation are often offered minimally invasive therapies in an effort to keep tumors from spreading. These therapies include percutaneous injection therapy with ethanol, radiofrequency and microwave thermal ablation, chemoembolization, intensitymodulated radiation therapy, and radioembolization.