Donna Glynn Cirrhosis is the end-stage consequence of progressive hepatic fibrosis affecting normal liver function. It is a serious, irreversible disease—the result of exposure to persistent toxins and resulting in liver failure and death. The most common causes of cirrhosis in the United States are alcoholic liver disease, hepatitis C, non alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).1 Various pharmacotherapeutics including acetaminophen, amiodarone, methotrexate, isoniazid, varied antibiotics, and carbon tetrachloride are also associated with cirrhosis. The cause can be inherited or idiopathic, but primary and secondary biliary cirrhosis, infections, viruses, hemochromatosis, polycystic liver disease, right-sided heart failure, autoimmune hepatitis, and other disorders play a key role in the development of cirrhosis (Box 130-1). Fibrosis, the replacement of normally functioning liver tissue by injured scar tissue, results in varied-size nodules that impair function. In advanced stages, the impaired hepatic vasculature results in a shunting of the portal and arterial blood supply, causing portal hypertension, obstructive biliary channels, destruction of liver cells, hepatocellular carcinoma, and eventual liver failure.2 Liver biopsy is necessary in the diagnosis of cirrhosis to stage the severity of the fibrosis and to establish a plan of care. Cirrhosis is typically classified as micronodular, macronodular, or mixed.3 Micronodular cirrhosis, often associated with alcoholic liver disease, occurs when the repeated presence of an offending agent prevents the regeneration of normal tissue. As a result, the regenerating tissue produces small nodules that have limited functional abilities. As the disease progresses, the liver becomes smaller in size and the nodules become larger with diffuse fat accumulation. Macronodular cirrhosis is seen in chronic viral hepatitis and hepatocellular carcinoma and is distinguished by larger nodules (2 to 3 cm [ Data regarding the prevalence and progression of cirrhosis are limited and variable, likely because of undiagnosed cirrhosis in the adult population. In the United States, 36,427 deaths were attributed to cirrhosis in 2013.4 The Model for End-Stage Liver Disease (MELD) is a prognostic tool for cirrhosis. Based on the underlying cause of the cirrhosis and the serum creatinine, bilirubin, and international normalized ratio (INR), the MELD tool is used as a prediction tool for patients with cirrhosis and for prioritizing candidates for liver transplantation (www.mdcalc.com/meld-score-model-for-end-stage-liver-disease-12-and-older).2,5,6 The prognosis of cirrhosis depends on the cause and classification of the disease. If the cirrhosis is related to alcohol or hepatotoxic drugs, the major factor that determines survival is the patient’s ability to stop drinking alcohol or taking hepatotoxic drugs. Primary biliary cirrhosis (PBC) is the autoimmune destruction of the intrahepatic bile ducts and eventual development of cirrhosis and liver failure. Hepatocellular injury occurs when the liver is continually exposed to toxins (e.g., alcohol, elevated triglycerides) or diseases (e.g., hepatitis) that produce toxemia, inflammation, ischemia, and necrosis of the hepatic tissue. The persistent inflammation and necrosis stimulate hepatocellular regeneration, causing the development of fibrous (scar) tissue such as collagen by fibroblasts. As the regeneration process progresses, rigid nodules form, distorting the normal surrounding hepatic tissue. This deformation produces increased resistance to normal blood circulation, decreased blood flow, and even obstruction of normal portal venous flow, resulting in decreased liver functional abilities.2,6 Portal hypertension develops when increased hydrostatic pressure within the portal venous circulation occurs, the result of inflammation and obstruction of blood flow. As cirrhosis progresses, the rising pressure in the portal circulation will increase resistance to portal venous flow. Collateral circulation develops new vascular channels and shunts that bypass areas of obstruction to maintain adequate blood flow.2,6 The collateral path to portal circulation occurs most commonly in the peritoneum, retroperitoneum, and thoracic cavities, but also in the rectum, esophagus, and gastric areas. The complications of the collateral circulation include ascites, splenomegaly, and esophageal varices. These collateral vessels contain varicosities susceptible to spontaneous rupture, hemorrhage, and subsequent death. The onset of symptoms can be insidious, and patients with cirrhosis can be asymptomatic. In PBC, the earliest reported symptoms include pruritus, weight loss, and fatigue.5 Other concerns associated with cirrhosis are nonspecific and include weakness, malaise, dark urine, or pale stools. As the patient’s condition worsens, anorexia is present and is often associated with nausea and vomiting. Hematemesis can also be a common presenting concern. Abdominal pain, if present, is related to ascites and the stretching of the muscles around the enlarged liver. Chest pain caused by cardiomegaly has also been reported. Menstrual abnormalities, impotence, and sterility are other concerns. Neuropsychiatric symptoms such as difficulty concentrating, irritability, and confusion are associated with liver function failure. Jaundice is a late-stage presenting symptom. The initial clinical presentation of patients with advanced cirrhosis is common. A careful history, particularly a personal history of alcohol, toxic drug, or substance use and a specific review of the patient’s social and work history, can identify high-risk behaviors such as intravenous drug use. Additional information necessary includes a thorough review of all medications, including herbal and over-the-counter products; allergies; past medical history; and family history. A history of recent blood transfusion or residence in an area of high hepatitis virus incidence also can suggest the diagnosis of cirrhosis. Jaundice, spider angiomata, gynecomastia, ascites, splenomegaly, palmar erythema, digital clubbing, and asterixis may be the presenting signs of cirrhosis. Low-grade fever, anorexia, and right upper quadrant pain can be present. The liver may be nodular, firm, enlarged, or shrunken (seen in late stages of cirrhosis), and the spleen may be enlarged. A fluid wave and increased abdominal girth will be evident if ascites is present. The presence of high pressures in the portal circulation often leads to the development of a venous hum (best heard over the epigastrium) and rectal and esophageal varices. As a result of the fluid shifts, peripheral edema is found in the feet, legs, and hands. Delirium, lethargy, and coma occur in the later stages of cirrhosis.5 Other physical signs associated with cirrhosis include weight loss; tremors; cheilosis or glossitis; spider angiomata on the face, chest, and abdomen; palmar erythema; Dupuytren contracture; horizontal white bands on nail beds (Muehrcke nails); whitening of the proximal two thirds of the nails and reddening of the remainder (Terry nails); digital clubbing; gynecomastia and testicular atrophy in men; and changes in body hair distribution in women. A sweet breath odor may be discernable in patients, referred to as fetor hepaticus. Asterixis, or liver flap, can be elicited with severe cases of liver failure.3 In patients with portal hypertension, a Cruveilhier-Baumgarten murmur may be heard. This murmur is described as a venous hum and is best auscultated over the epigastrium, and may be augmented by the Valsalva maneuver.5 In the early stages of cirrhosis, there are often no significant diagnostic findings. It is with the presence of laboratory abnormalities that the potential for liver dysfunction is questioned. No single diagnostic biochemical marker is available regarding cirrhosis. Although not found in all patients, hypoalbuminemia, elevated serum protein, hyperbilirubinemia, and elevated liver enzymes (aspartate transaminase [AST] and alanine aminotransferase [ALT]) all indicate hepatocellular inflammation or injury. ALT is used to evaluate acute versus chronic liver injury. The alkaline phosphatase and γ-glutamyl transpeptidase levels are also often elevated. The evaluation of liver function test results and the decision to proceed with further testing and possible biopsy are based on the history and physical examination findings.3 Prothrombin time (PT), partial thromboplastin time (PPT), and serum albumin should be evaluated to determine hepatic synthesis and clotting function2; such measurements are a useful tool in the MELD score. Albumin synthesis is directly correlated to liver function, and levels of albumin will decrease as the cirrhosis advances. In addition, decreased levels of platelets are common in patients with chronic liver disease, placing the patient at increased risk for bleeding.2,7 The Lok index is an online calculator that uses blood chemistries to determine the likelihood of cirrhosis in patients with hepatitis C virus. The index uses the platelet count, AST, ALT, and INR to assess that probability.8 Additional diagnostics depend on the patient presentation, but it is important to determine the exact cause of the cirrhosis in newly diagnosed patients. Initial serologic workups may include a screen for antimitochondrial antibodies (a marker of PBC that distinguishes PBC from secondary biliary cirrhosis), antinuclear antibodies, anti–smooth muscle antibodies, antibodies to hepatitis C, hepatitis B surface antigen, and antibodies to hepatitis B core antigen and surface antigen. Fasting serum ferritin, transferrin saturation, and total iron-binding capacity should be obtained to exclude hereditary hemochromatosis.2 If the transferrin saturation is significantly elevated (>45%), genetic testing for hereditary hemochromatosis (C282Y and H63D) is indicated. FibroTest (FT) is a serum marker that combines the quantitative results of five serum markers (α2-macroglobulin, haptoglobin, γ-glutamyl transpeptidase, total bilirubin, and apolipoprotein A-I) with the patient age and gender and provides a measure of the degree of fibrosis in the liver.9 Other abnormalities in laboratory results are common. Pancytopenia, anemia (frequently macrocytic), thrombocytopenia, abnormal clotting mechanisms, and prolongation of PT all contribute to an increased potential for gastrointestinal bleeding.7 Hyponatremia can indicate advanced illness, but other electrolyte abnormalities and renal insufficiency are also common. Ultrasound is used to assess liver size, portal circulation, and the presence of occult ascites or tumor. The imaging will also detect portal hypertension, ascites, and portal vein thrombosis. Computed tomography (CT) is not used to diagnosis cirrhosis, and the benefits of magnetic resonance imaging (MRI) in the diagnosis and management of cirrhosis are still unclear. Non invasive serum and radiologic markers for staging and diagnosis of fibrosis and cirrhosis are being studied. 9 However, at this time, liver biopsy, unless contraindicated, is still necessary for the diagnosis of cirrhosis and staging of fibrosis.9 A biopsy specimen may be obtained by a radiographically guided percutaneous procedure or via the transjugular or laparoscopic route. Bleeding is a concern because of the risk of platelet abnormalities. However, in patients with a history of heavy alcohol use and ascites, liver biopsy is not necessary if the clinical, laboratory, and ultrasound results strongly support the diagnosis of cirrhosis. Magnetic resonance elastography (MRE) estimates liver stiffness resulting from fibrosis. MRE is a safe, effective method of evaluating fibrosis in patients with chronic hepatitis C.10
Cirrhosis
Definition and Epidemiology
to 
inches] in diameter) that may contain their own blood supply. The larger nodules resemble scar tissue and also have limited functional abilities. Mixed-form cirrhosis, a combination of both macronodules and micronodules, has mixed characteristics, and liver functions are also varied.3
Pathophysiology
Clinical Presentation
Physical Examination
Diagnostics
Cirrhosis
Chapter 130
