Chronic hepatitis B
Alcoholic cirrhosisPrimary biliary cirrhosis
Primary sclerosing cholangitis
Autoimmune hepatitis
Hemochromatosis
Nonalcoholic fatty liver disease
Cryptogenic
Secondary biliary cirrhosisα1-Antitrypsin deficiency
Wilson disease
Sarcoidosis
Cystic fibrosis
Drug-induced (methotrexate,
amiodarone)
Glycogen storage disease

When all other causes of cirrhosis are excluded, the diagnosis is idiopathic (cryptogenic) cirrhosis. This disorder may result from an immunological or viral disease process that cannot be detected by serological assays or from “burned-out” NAFLD. Cryptogenic cirrhosis may account for 10–20% of all cases with cirrhosis; it is clinically indistinguishable from other common causes.

Portal hypertension

Pressure gradients in portal circulation follow Ohm’s law, which states that the pressure gradient is equal to the product of flow and resistance. Portal hypertension occurs if there is increased splanchnic flow or increased resistance in the hepatic vasculature. In cirrhosis, both mechanisms contribute to the development of portal hypertension. Nodular regeneration and fibrosis in the space of Disse increase postsinusoidal and sinusoidal resistance, respectively. Cirrhosis is also accompanied by increased splanchnic flow from decreased tone in the splanchnic arterioles. The mechanisms responsible for splanchnic arteriolar vasodilation are poorly understood but may involve nitric oxide. In extrahepatic causes of portal hypertension, such as portal vein thrombosis or massive splenomegaly, either increased resistance or increased flow is the principal mechanism of increased portal pressure. The anatomical site of increased flow or resistance has been used to classify portal hypertension into prehepatic, intrahepatic, and posthepatic portal hypertension (Table 42.2). Intrahepatic causes are often further subdivided into presinusoidal, sinusoidal, and postsinusoidal according to the site of increased resistance. This subclassification has limited value because many forms of cirrhosis may involve more than one site of vascular distortion in relationship to the sinusoids.

Table 42.2 Classification and differential diagnosis of portal hypertension

Prehepatic causes
Portal vein thrombosis
Splenic vein thrombosis
Arterioportal fistula
Splenomegaly

Intrahepatic causes
Cirrhosis
Fulminant hepatitis
Veno-occlusive disease
Budd–Chiari syndrome
Schistosomiasis
Metastatic malignancy

Posthepatic causes
Right ventricular failure
Constrictive pericarditis
Inferior vena cava web

Clinical presentation

Although patients with early cirrhosis may be asymptomatic, cirrhosis is typified by a general decline in health with nonspecific complaints of anorexia, weight loss, malaise, fatigue, and weakness. More advanced disease may present with one of the complications of portal hypertension.

Endocrine manifestations

Patients with cirrhosis may manifest several endocrine disturbances. The prevalence of diabetes mellitus increases in all forms of cirrhosis but particularly in patients with hemochromatosis, alcoholic liver disease, or hepatitis C. Hypogonadism in males and females is also common in hemochromatosis and alcoholic liver disease, primarily because of the direct gonadal toxicities of iron and alcohol, respectively. In addition, androgenic steroids may bypass metabolism in the liver and subsequently undergo conversion in adipose tissue to the estrogenic steroid estrone. Increased plasma estrogen levels may lead to gynecomastia, telangiectasia, and palmar erythema.

Pulmonary manifestations

End-stage liver disease is often accompanied by pulmonary disorders. Chronic hyperventilation is probably caused by the same central nervous system alterations responsible for hepatic encephalopathy. Patients may have hypoxemia because of mismatches of ventilation and perfusion induced by ascites, which restrict the ventilation of dependent lung spaces. The hepatopulmonary syndrome, a distinct form of right-to-left shunting with impaired gas exchange caused by intrapulmonary vascular dilation, is increasingly recognized. This condition is potentially reversible by transplantation. Portopulmonary hypertension, in contrast, is caused by pulmonary vasoconstriction, which produces markedly elevated pulmonary pressure and is a relative contraindication to liver transplantation. Patients with or without ascites may develop a transudative pleural effusion, termed hepatic hydrothorax, which may impair respiratory function. Hydrothorax probably develops from ascites traversing pores in the diaphragm. The onset of hepatic hydrothorax often signals rapid clinical deterioration.

Renal manifestations

Numerous disturbances of sodium and water homeostasis are observed in cirrhosis but the most devastating complication is renal failure caused by the hepatorenal syndrome. In its most severe form, hepatorenal syndrome type I progresses to oliguric renal failure and prerenal physiology despite adequate filling pressure. It is associated with extreme intrarenal vasoconstriction that leads to sodium retention. Potential precipitants include intravascular volume depletion from hemorrhage, diuretics, or paracentesis. Alternative causes of renal failure include acute tubular necrosis caused by hypovolemia, nephrotoxic drugs, nonsteroidal anti-inflammatory agents, and radiocontrast agents. These disorders can often be distinguished from hepatorenal syndrome on the basis of a normal or elevated urine sodium concentration. Pulmonary artery catheter placement or central venous pressure monitoring should be considered because they facilitate optimal management of volume status. Hepatorenal syndrome type 1 usually is irreversible without transplantation. A milder form, hepatorenal syndrome type 2, affects many cirrhotics and is characterized by a mildly depressed glomerular filtration rate and marked sodium and water retention refractory to diuretics.

Diagnostic investigation

Laboratory results

Liver chemistry values are obtained in essentially all patients with suspected liver disease or portal hypertension but the patterns and degrees of abnormality are variable and are determined by the primary disorder. Notably, patients with pathological evidence of cirrhosis may have normal biochemical profiles. Coagulation profiles, complete blood counts, electrolytes, and albumin should all be obtained. Patients with advanced cirrhosis will have a prolonged prothrombin time and a decrease in serum albumin levels because of impaired hepatic synthetic function. Protein malnutrition and vitamin K deficiency, which are particularly common in alcoholics, may also produce these abnormalities. Patients with portal hypertension may have thrombocytopenia, anemia, or leukopenia on the basis of congestive hypersplenism. Thrombocytopenia from splenic sequestration rarely is less than 30,000 per µl; lower levels suggest an alternative diagnosis, such as drug-induced, immune-mediated, or disseminated intravascular coagulation-associated thrombocytopenia. In addition to splenic sequestration, anemia may result from gastrointestinal hemorrhage, nutritional deficiencies (e.g. folate, iron, or vitamin B₁₂), or hemolysis. Hyponatremia, hypokalemia, and renal insufficiency are common complications of the altered renal hemodynamics and sodium and water homeostasis observed in cirrhosis.

An accurate determination of the cause of cirrhosis requires a serological evaluation, whose extent is largely dictated by the clinical setting. The initial screen should include serum assays for antibody to hepatitis C, antibodies to hepatitis B core antigen and surface antigen, hepatitis B surface antigen, antimitochondrial antibodies, antinuclear antibodies, anti-smooth muscle antibodies, ferritin, transferrin, total iron-binding capacity, and serum protein electrophoresis to measure the α1 band and γ-globulins. Patients younger than age 50 should be screened for Wilson disease with an assay of serum ceruloplasmin. In the second stage, selected patients may require specialized studies based on the preliminary results above, for example, hepatitis C viral RNA, hepatitis B DNA.