Cirrhosis is a chronic diffuse liver disease that is characterized by fibrosis and nodule formation. Fibrosis is not synonymous with cirrhosis. Nodule formation with disturbed architecture is essential for the diagnosis of cirrhosis. The condition results from liver cell necrosis and the collapse of hepatic lobules due to many factors such as inflammation or ischemia. Recovery occurs with formation of diffuse fibrous septa and nodular regrowth of hepatocytes. Thus, the ultimate histologic pattern is the same regardless of etiology. Liver cell necrosis is often absent when the liver is ultimately examined either by biopsy or at post mortem.

Known causes of cirrhosis account for about 90-95% of the cases. Most common etiologies include alcoholism, autoimmune chronic hepatitis and chronic viral hepatitis (Table 14). Less common causes include hemochromatosis, primary biliary cirrhosis, sclerosing cholangitis, drug-induced liver disease and chronic biliary obstruction. Other causes include a₁-antitrypsin deficiency, severe steatohepatitis in the morbidly obese and Wilson's disease. The remaining 5-10% of patients with cirrhosis of the liver have no known cause, a condition termed cryptogenic cirrhosis. Over the last 10 years, the rate of cryptogenic cirrhosis has fallen from 30% to current levels. The most likely cause for this fall has been the availability of testing for hepatitis C.

The etiology of the cirrhosis usually cannot be determined by the pathologic appearance of the liver (with some notable exceptions, including hemochromatosis and a₁-antitrypsin deficiency). Terms previously used such as portal cirrhosis or postnecrotic cirrhosis have been replaced by classifications that include three anatomic categories.

Micronodular cirrhosis is characterized by thick, regular septa, by regenerating small nodules of uniform size and by involvement of every lobule. Often associated with the persistence of the injurious agent, this may represent the liver's relative impairment for regeneration, as may be seen in alcoholism, old age, ischemia and malnutrition.

Macronodular cirrhosis is characterized by nodules of variable size, some containing large areas of intact or regenerating parenchyma within each large nodule.

Mixed macronodular and micronodular cirrhosis may result from vigorous regrowth in a previous micronodular cirrhosis (Figure 12).

The clinical features of cirrhosis relate to those features that are peculiar to the cause of the cirrhosis but more importantly to the magnitude of the hepatocellular failure and the presence of portal hypertension, along with the ability of the surviving hepatocytes to compensate for the loss. Thus, patients often are categorized as having latent, compensated disease or active, decompensated disease, each having its own clinical pathologic correlations. In the fully compensated state, there may be no symptoms whatever, the disease being suspected by a finding of an enlarged liver or spleen. With progression of the disease, features of hepatocellular failure and portal hypertension emerge.

With hepatocellular failure, patients may complain of weakness, fatigue, weight loss and a general deterioration of health. Physical examination may reveal the stigmata of chronic liver disease, although these are often missing in those with chronic viral hepatitis (see Section 2).

The ease of diagnosis of cirrhosis is dependent on the degree of liver decompensation. A high index of suspicion is necessary; the condition may be revealed only by a positive history of excess alcohol ingestion along with the finding of hepatomegaly. Thorough inquiry into all the risk factors for acquisition of viral hepatitis needs to be made, including blood transfusion, injection drug use (ever), tattoos, body piercing and multiple sexual partners. In decompensated disease, the diagnosis is much easier; the clinical features of ascites, asterixis, variceal hemorrhage, jaundice and other signs of hepatocellular failure may be present.

Biochemical tests attempt to identify the specific etiology of the liver disease and to assess the degree of hepatocellular dysfunction. With deteriorating hepatic function, albumin falls, serum bilirubin rises and the INR/prothrombin time becomes increased and not correctable by parenteral vitamin K. Liver enzymes, while helpful in assessing ongoing activity, are not of much help in assessment of the functional severity, as serum aminotransferases may be only mildly elevated despite severe liver disease. Alkaline phosphatase is usually raised, but the level does not reflect the degree of hepatic dysfunction. Commonly a normochromic, normocytic anemia is found, with target cells noted in the blood smear. Occasionally a macrocytic anemia presents, but if gastrointestinal bleeding has been occurring, the anemia may be microcytic as a result of iron loss. Depressed leukocyte and platelet counts may be present secondary to hypersplenism. The urine often contains urobilinogen and bilirubin if the patient is jaundiced. Patients with ascites exhibit a marked reduction in urinary sodium excretion. The radioisotope scan will show patchy uptake by the liver with redistribution to the spleen and bone marrow. Increased radioisotope uptake in the bone marrow (on scan) is reflected by uptake in the spine. Ultrasound of the abdomen is the most helpful imaging test and will reveal an inhomogeneous nodular liver with splenomegaly. A CT scan is rarely needed. These tests do not establish the diagnosis of cirrhosis, which can be made only by a liver biopsy with histologic examination. Liver biopsy may also be helpful in establishing an etiology and degree of activity of the underlying process. When a persistent coagulopathy or ascites is present, biopsy via the transjugular route is necessary.

Prognosis depends on the degree of hepatocellular function and the etiology, as well as on whether any causative agents can be removed. Clearly the prognosis is improved if the alcoholic patient can abstain, if the patient with hemochromatosis has iron removed by venesection or if excessive copper is removed in those with Wilson's disease. In addition, vigorous medical care may prolong life and delay or prevent eventual complications such as ascites and variceal bleeding. All cirrhotics should be advised to avoid aspirin or NSAIDs (which promote GI bleeding and ascites), aminoglycoside antibiotics (which promote renal failure), ACE inhibitors (which promote ascites) and narcotics (which promote encephalopathy). All episodes of infection should be treated promptly, as septicemia leads to rapid deterioration in a cirrhotic. Beta blockers should be considered for prophylaxis against variceal hemorrhage in all cirrhotics with grade II or larger varices. Once decompensated liver disease is present (jaundice, ascites, neurologic impairment, bleeding, coagulopathy, hyponatremia) the prognosis is poor and liver transplant should be considered, if appropriate.

Clearly, where there is a specific treatment for the underlying etiology of the liver disease this should be offered. All patients should consume a healthy, adequate diet and avoid alcohol. Otherwise the management is that of regular surveillance and early detection of hepatocellular failure. Hepatocellular failure or decompensated cirrhosis may be manifested by any of the following: coagulopathy, jaundice (in noncholestatic liver disease), hepatic encephalopathy, variceal bleeding or ascites. The Child-Pugh classification of cirrhosis, which is a very useful guide to calculate the risk of an invasive procedure, takes into account these variables, plus nutritional status (Table 15). Once decompensation occurs, management includes the control of ascites, avoidance of drugs that are poorly metabolized by the liver and the prompt treatment of infection and variceal hemorrhage. Liver transplantation is now becoming the treatment of choice for many with end-stage decompensated liver disease (see Section 15).