Clinical Features of Liver Disease

Etiology

Acute liver disease may result from a variety of etiologic agents, the most common of which are viral hepatitis, acetaminophen overdose, idiosyncratic reaction to medicines, excessive alcohol intake, autoimmune diseases, metabolic disorders, and circulatory disorders. Viral hepatitis accounts for 72% of cases of acute hepatitis, and infections with hepatitis A and B viruses account for most of these cases. Acute infection with hepatitis C virus (HCV) is usually subclinical, and clinical manifestations occur in only about 15% of patients. Infection with hepatitis D virus usually occurs in intravenous drug users, either as a superinfection in those already infected with hepatitis B virus (HBV) or as a coinfection acquired simultaneously with HBV. Acute hepatitis due to hepatitis E virus (HEV) occurs in endemic areas that include Central and Southeast Asia, North and West Africa, and Mexico. Sporadic cases occur in the rest of the world.

All five viruses have been implicated in ALF; however, ALF due to HCV is rarely seen in the Western Hemisphere, with most cases being reported from Japan and Taiwan. These reports indicate that there is a greater likelihood of a fulminant course of HCV in individuals who already have chronic HBV infection. Fulminant HBV infection follows de novo infection in the West but is usually the result of activation of latent infection in the East; the reason for these differences is not known. An increasing cause of ALF due to HBV is reactivation of latent infection in patients undergoing chemotherapy for various malignancies or receiving immune modulating agents of immune diseases. The enteric viruses, hepatitis A virus (HAV) and HEV, cause self-limited disease in most individuals, with only a minority proceeding to ALF. A fulminant course caused by HAV occurs in elderly patients and intravenous drug users. A fulminant course is also more likely to occur when HAV occurs as a superinfection in patients with chronic liver disease. Fulminant HEV infection occurs most commonly in pregnant women, in whom it may be accompanied by hemolysis, elevated liver levels, and low platelet count (HELLP syndrome [hemolysis, elevated liver enzymes, and low platelet count]). Mortality is 20% in the third trimester.

Acute alcoholic hepatitis after heavy or binge drinking may present as acute liver disease and is associated with a high risk of increased short-term mortality. An increasing incidence, especially in women and at a younger age, is reported at least in some parts of the world.

Overdose from acetaminophen, the most widely available analgesic, is the most common cause of fulminant acute failure in the United States and the United Kingdom. Overdose may be intentional or unintentional from self-medication for pain or fever, leading to daily doses exceeding 4 g/day. Susceptible patients have concomitant depression, chronic pain, alcohol or narcotic use, and they may take several preparations simultaneously. Idiosyncratic reactions from common over-the-counter therapeutic drugs, herbal remedies, and dietary supplements cause a significant number of cases of acute hepatitis, some of which may follow a fulminant course. The United States Acute Liver Failure Study Group (ALFSG) found these cases to be the second most common cause of ALF. A comprehensive list of causes of ALF is shown in Table 2.1 .

Clinical Manifestations

Clinical symptoms of ALF reflect pathophysiologic mechanisms associated with rapid arrest of normal hepatic function, and the presentation is marked by the acute onset of hepatic encephalopathy and coagulopathy in a patient without previous history of liver disease. In addition, the acute loss of hepatic function in ALF leads to profound and deleterious effects on all body systems, resulting in acute renal failure, gastrointestinal bleeding, infections, sepsis, respiratory failure, and cardiovascular collapse. Ascites is not common except in cases of ALF caused by acute Budd-Chiari disease.

Encephalopathy and cerebral edema result from the dysregulation of neurotransmission and cerebral blood flow caused by the accumulation of toxic substances such as ammonia and benzodiazepine receptor agonists, which would normally be cleared by a healthy liver. In contrast to cirrhosis, intracranial hypertension and cerebral edema are predominant features of ALF because the brain does not have adequate time to compensate for the abnormal homeostasis.

Bleeding diathesis in patients with ALF is multifactorial and results from decreased production by the liver of coagulation factors II, V, VII, IX, and X; thrombocytopenia; and qualitative platelet functional defects. Concurrent complications such as disseminated intravascular coagulation and sepsis, combined with abnormalities in antithrombin III, protein C, and protein S, further exaggerate the bleeding diathesis. The levels of factor VIII, which is produced by hepatic endothelium, are increased because of endothelial activation. Tests of coagulation including prothrombin time, INR, and levels of factors V and VII are useful parameters for monitoring progression of fulminant hepatic failure; of these, factors V and VII are the most sensitive to changes in hepatic function because they have the shortest serum half-lives of all coagulation factors. Transfusion of fresh-frozen plasma or platelets is generally encouraged only if invasive procedures are indicated, or if platelets are less than 20,000/mm ³ , to avoid false interference with measures of coagulation.

Infectious complications , especially of the respiratory and urinary tracts, occur in about 80% of patients with ALF, and bacteremia is seen in 20% to 26% of patients. The risk of infection derives from reticuloendothelial dysfunction and decreased opsonization of microorganisms. Fungal infections, especially with Candida albicans , occur in a third of patients with ALF and can exclude them from the option of transplantation, thus representing a poor prognostic factor.

Acute renal failure occurs in 40% to 80% of patients with ALF. It is multifactorial, occurring secondary to prerenal azotemia, acute tubular necrosis, hepatorenal syndrome, drug-induced interstitial nephritis caused by contrast material or antibiotics, and sepsis. Patients present with oliguria and increased creatinine levels. Creatinine is preferred over blood urea nitrogen for monitoring kidney function in ALF because the latter is affected by impaired hepatic urea production. Patients with ALF have profound electrolyte and fluid abnormalities ; water retention and hyponatremia are common. Hypokalemia and hypophosphatemia accompany hyponatremia, but in patients with oliguric renal failure, hyperkalemia and hyperphosphatemia may occur. Hypoglycemia is common and occurs because of deficient glycogenolysis and gluconeogenesis by a diseased liver. Cardiorespiratory abnormalities in ALF include systemic vasodilatation, low vascular resistance, increased cardiac output, and abnormal oxygen transport and utilization, leading to hypotension, hypoxia, and lactic acidosis. The laboratory findings in acute liver disease are described in Chapter 3 .

Treatment and Prognosis

Acute liver disease may resolve spontaneously with supportive therapy or progress to ALF or develop into chronic liver disease. Acute autoimmune hepatitis can potentially respond to corticosteroid administration. Short-term mortality associated with severe acute alcoholic hepatitis may be reduced by a short course of corticosteroids. Acute hepatitis B or an acute flare of hepatitis B in a known carrier may respond to antiviral therapy. Drug-induced injury seems to resolve completely following the drug’s withdrawal in less severe cases. Acetaminophen overdose responds well to N -acetylcysteine (NAC) administration, especially if given within 16 hours of acetaminophen exposure. However, despite cessation of the offending agent, chronic liver injury, including cirrhosis, may develop in a small number of cases.