Esteban Mezey
Hepatitis
Hepatitis is an inflammatory condition that may be localized in the liver or may be part of a generalized systemic process. Acute hepatitis is usually a self-limited disease. The principal causes of acute hepatitis are viruses, drugs, and alcohol. Chronic hepatitis is unresolved hepatitis that has persisted for longer than 6 months. Cirrhosis is often the principal consequence of chronic hepatitis.
Acute Hepatitis
Viral Hepatitis
Viral hepatitis is a systemic infection whose principal manifestations are hepatic. The four types of viral hepatitis that are well-defined, separate entities are designated type A, B, C, and E. Delta hepatitis (hepatitis D virus [HDV]) is infection by a defective virus-like particle that is dependent on persisting or concomitant infection with type B virus.
Table 47.1 shows the characteristic features of types A, B, C, and E hepatitis. Type A hepatitis, previously known as infectious hepatitis, is more common than the other types. It is usually transmitted by the fecal-oral route and has a particularly high incidence wherever people come in close contact under poor hygienic conditions. A number of epidemics have been described after fecal contamination of the water or food supply. Ingestion of contaminated shellfish has been associated with both sporadic cases and epidemics.
Type B hepatitis, previously called serum hepatitis, is usually transmitted by the parenteral route from blood, blood products, or contaminated needles. It is also commonly transmitted by sexual contact and from the mother to the fetus. HDV is transmitted by the same routes as type B hepatitis (1). Its incubation period ranges from 3 to 13 weeks. Infection with the δ agent may become manifest as a biphasic pattern of hepatitis when there is simultaneous infection with hepatitis B virus (HBV), or as a clinical exacerbation of hepatitis in patients who are carriers of HBC with or without chronic liver disease. HDV has been implicated in cases of fulminant hepatitis and in worsening of chronic liver disease with more rapid progression to cirrhosis. However, the incidence of HDV is unknown.
Hepatitis C virus (HCV) accounts for most cases of hepatitis acquired by blood transfusion, although it is now more commonly transmitted by other routes. In the West, 4% of cases of HCV are acquired by blood transfusion, 38% by parenteral use of illicit drugs, 10% by sexual or household exposure to people who have had hepatitis or multiple partners, 2% by occupational exposure to infected blood, and 1% by dialysis (2). The principal sources of HCV infection in health care workers are accidental needle sticks; the risk of becoming infected with HCV by needle stick from a patient already infected with HCV is approximately 3%. Skin tattoos are also a risk factor. Ear piercing in men and intranasal cocaine use have been found to be more common in blood donors infected with HCV than in noninfected donors (3). The source of infection in approximately 45% of cases is unknown; a large proportion of these patients are in a low socioeconomic level.
Hepatitis E virus (HEV) is a common cause of hepatitis epidemics in developing countries, but it can also occur sporadically in developed countries. The virus is transmitted by the fecal-oral route, usually by ingestion of contaminated water. It is associated with a high mortality rate in pregnant women (4).
Hepatitis G virus (HGV) is a single-stranded ribonucleic acid (RNA) virus that has a genomic sequence similar to HCV. It is present in 1.8% of healthy blood donors and often is found in the blood of patients with HCV infection. In a few cases HGV is the only virus identified in patients with hepatitis, and in most of these cases the hepatitis is mild. However, definitive proof is lacking to implicate HGV as a causative agent of hepatitis.
Clinical Presentation
The symptoms of the various types of hepatitis are similar. However, in contrast to the other types of viral hepatitis, acute viral HCV is usually a mild illness that is very likely to persist and develop into chronic hepatitis. Most cases of hepatitis are anicteric; patients have a few nonspecific symptoms, such as fatigue and nausea, and the disease is often misdiagnosed as a flu-like illness. The correct diagnosis, if suspected, is made by demonstrating bilirubin in
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the urine and an increase in the level of serum aminotransferases. In icteric disease, the symptoms that usually precede jaundice are anorexia, fatigue, abdominal discomfort, and nausea. Erythematous skin rashes, urticaria, arthralgias, and low-grade fever may also appear. These initial symptoms are followed within 10 days by the appearance of dark urine, often pruritus, and jaundice. It is at this stage that most patients seek medical attention. On physical examination, a tender, palpable liver is found in approximately 70% of the patients. Posterior cervical lymphadenopathy and splenomegaly may also be present. Jaundice usually increases in intensity during the first few days and then begins to decrease, disappearing completely by 2 to 8 weeks after onset.
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TABLE 47.1 Comparison of Selected Characteristics of Various Types of Viral Hepatitis |
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Laboratory Features
A mild degree of transient anemia, granulocytopenia, lymphocytosis with the appearance of atypical lymphocytes, and mild hemolytic anemia, with an increase in the reticulocyte count, are commonly found in patients with acute viral hepatitis. Both the direct (conjugated) and the total fraction of serum bilirubin rise; the height reached by the total bilirubin is an indication of the severity of the disease. However, total serum bilirubin concentrations higher than 30 mg/dL are almost invariably caused by complicating hemolysis. The serum aminotransferases usually rise before the onset of detectable jaundice, may reach levels as high as several thousand units, and may remain elevated for several weeks. The height reached by the aminotransferases in the serum provides only a rough estimate of the degree of hepatocellular injury and is of no prognostic value. However, a rapid fall in aminotransferases from a high peak to normal in less than 1 week may be an indication of fulminant hepatitis with massive necrosis and collapse of liver parenchyma. The serum alkaline phosphatase usually rises in the early, cholestatic phase of hepatitis, remains elevated throughout the illness, and is often the last serum enzyme to return to normal levels after clinical recovery. The concentration of serum albumin is normal in acute hepatitis. Serum gammaglobulins often are transiently elevated. The prothrombin time is usually normal and, if prolonged, is usually responsive to the administration of vitamin K, typically 10 to 15 mg given by subcutaneous injection. Prolongation of the prothrombin time with no response to vitamin K administration suggests severe hepatitis; if the prolongation increases, it is indicative of fulminant hepatitis.
Imaging Studies
Imaging of the liver by either ultrasonography or computed tomography (CT) scanning is not useful in the diagnosis or management of acute viral hepatitis. However, ultrasonography is useful to confirm a decrease in liver size in hospitalized patients with severe necrosis and fulminant hepatitis in whom the liver cannot be palpated.
Virologic Features
Hepatitis A is caused by an RNA virus. In acute type A hepatitis, fecal excretion of hepatitis A antigen (HAAg) can be demonstrated a few days before the increase in serum aminotransferases, rises to a peak during maximal serum aminotransferase elevation, and then falls as jaundice appears. Anti hepatitis A (anti-HA, predominantly immunoglobulin M [IgM]), appears in the serum at approximately the same time as HAAg disappears from the stool. Anti-HA then rises rapidly to high levels and gradually becomes undetectable over 10 to 12 months. Anti-HA IgG remains detectable for at least 10 years, indicative of
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immunity against reinfection. Because HA infection is very common, many healthy people have detectable anti-HA in the serum. The prevalence of positive anti-HA is approximately 30% to 40% in the United States and as high as 90% in certain areas of Latin America and Asia (5). Hence, identification of an acute episode of hepatitis as type A requires a high titer of anti-HA of the IgM class or the appearance of or a rise in anti-HA titer in the serum collected during the convalescent stage compared with the acute stage of hepatitis.
The HBV by electron microscopy appears as a double-shelled, 42-nm spherical particle, originally called the Dane particle. The outer shell of this particle is hepatitis B surface antigen (HBsAg), and the inner core contains an antigen that has been designated the hepatitis B core antigen (HBcAg). The inner core also contains double-stranded deoxyribonucleic acid (DNA) and DNA polymerase activity. In acute type B viral hepatitis, HBsAg first appears in the blood 1 to 2 weeks before and usually disappears by 2 to 3 months after the onset of clinical symptoms (Fig. 47.1). Hepatitis B core antibody (anti-HBc) appears in the serum at the onset of clinical symptoms, reaches a peak soon after the maximal level of serum aminotransferase is reached, and then falls gradually, becoming undetectable 1 to 2 years after the infection. Antibody to the hepatitis B surface antigen (anti-HBs) usually appears during the convalescence, when HBsAg is no longer detectable, and then persists for many years. The presence of HBsAg or IgM anti-HBc during the acute illness is evidence that the hepatitis is caused by the HBV (6). Persistence of HBsAg in the serum beyond 3 months after the infection suggests that the patient has become a chronic carrier of the HBV (7). The presence of high titers of anti-HBc but absent anti-HBs is usually found in association with HBsAg in the carrier state. The presence of anti-HBs indicates that the patient has had a prior infection with type B hepatitis and now is immune to reinfection. Another antigen, the so-called e antigen, is detectable in some HBsAg-positive sera. The hepatits B e antigen (HBeAg), although associated only with type B hepatitis, is immunologically distinct from HBsAg and HBcAg. HBeAg appears transiently in the serum during the early phase of acute type B hepatitis. In chronic carriers of HBsAg, the presence of HBeAg is a marker of active virus replication and correlates with infectivity of the carrier (8) and, some studies suggest, correlates also with the risk of progression of acute HBV to chronic hepatitis or cirrhosis. Appearance of anti-HBe (and disappearance of HBeAg) usually indicates remission of the disease. However, some patients develop chronic anti-HBeAg hepatitis (without detectable HBeAg) because of a HBV precore or core mutation that abolishes the production of HBeAg (9). Hepatitis B DNA detection (HBV DNA) is used to detect the HBV and to obtain information on viral load.
HDV is a defective virus-like particle that is composed of a small RNA genome surrounded by hepatitis D antigen (HDAg) and a coat of HBsAg. Acute HDV infection (1) is associated with a brief rise in HDAg that lasts approximately
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10 days and is followed by the appearance of hepatitis D virus antibody (anti-HDV). Initially the antibody is of IgM type, lasting 10 to 20 days; this is followed by the appearance of IgG anti-HD. A characteristic of HDV infection is a lowering of HBsAg titers; probably HDV requires HBV for its replication.
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FIGURE 47.1. Pattern of appearance of hepatitis B surface antigen (HbsAg) and antibodies to hepatitis B surface antigen (anti-HBs) and to hepatitis B core antigen (anti-HBc) in acute hepatitis B infection. AST, aspartate aminotransferase. (From Mezey, E. Specific liver diseases. In: Halsted JH, Halsted CH, eds. The laboratory in clinical medicine. 2nd ed. Philadelphia: WB Saunders, 1981. ) |
HCV is caused by a single-stranded RNA virus. There are at least six major genotypes of the HCV, which have different geographic distributions and influences on the clinical course of the disease and its response to therapy (10). Hepatitis C virus RNA (HCV RNA) is detectable within 10 days after infection and persists during the development of acute and chronic hepatitis. Anti-HC becomes detectable 5 to 15 weeks after infection. In most cases, it persists in the blood regardless of the outcome of the disease (11).
HEV is also caused by a single-stranded RNA virus. Acute HEV infection is associated with rises of IgM and IgG anti-HEV antibodies. IgM anti-HEV is found in more than 90% of patients 1 week to 2 months after the onset of the illness. IgG anti-HEV appears after the IgM antibody response, and its titer rises after the acute illness, remaining detectable for 1 to 4.5 years. HEV infection in the serum and stool can be detected by reverse transcriptase-polymerase chain reaction (RT-PCR) measurement of HEV RNA (4).
At present, the practical usefulness of the immunologic markers for hepatitis is as follows. Acute HAV infection is confirmed by the demonstration of anti-HA of the IgM class (IgM anti-HAV). Infection with HBV is usually confirmed by the presence of HBsAg, but if the antigen is absent and it is clinically indicated, the diagnosis can be confirmed by demonstrating IgM anti-HBc. The determination of anti-HBs is useful to find out whether a person is immune to HBV or whether that person is a candidate for prophylaxis (see Prevention and Prophylaxis of Viral Hepatitis). HBV DNA is useful in monitoring the virologic response of chronic HBV to treatment. Acute HCV infection is diagnosed by the detection of HCV RNA, whereas chronic HCV is diagnosed by detection of HCV RNA or by anti-HC 6 months or longer after the onset of illness. The false-positive detection of anti-HC is less than 10% and occurs principally in chronic autoimmune hepatitis (see later discussion). HDV, as a cause of fulminant hepatitis or recurrent type B hepatitis, is diagnosed by the presence of HDAg or IgM anti-HD. Hepatitis E is diagnosed by showing initially the presence of IgM anti-HEV in the serum, or later in the course of the infection the appearance of IgG anti-HEV.
Management
Acute viral hepatitis usually resolves completely in 1 to 3 months. There is no specific therapy. Rest often alleviates the symptoms, but there is no evidence that it changes the overall course of the illness (12). As the patient's symptoms improve, a gradual increase in activity is allowed as tolerated by the patient. Intake of a normal-calorie, normal-protein (50 to 70 g protein per day) diet should be encouraged, although it is often difficult for the patient to eat because of nausea and anorexia. However, these symptoms are usually minimal in the morning, so the patient should be encouraged to eat a large breakfast. Strict isolation of the patient to his or her own room and bathroom is often impractical and probably unnecessary. General hygienic measures, such as washing the hands after contact with the patient and careful handling of stool and blood samples, are mandatory (see Prevention and Prophylaxis of Viral Hepatitis).
Hospitalization is indicated for patients in whom the diagnosis is uncertain and for those who have severe symptoms of nausea and vomiting, changes in mental status, or a prothrombin time that is prolonged more than 4 seconds above the control value. Patients with very high levels of serum bilirubin (greater than 30 mg/dL), who most likely have severe hemolysis complicating their hepatitis, should be hospitalized. By contrast, the magnitude of elevation of serum aminotransferase by itself, is not an indication for hospitalization. In addition, it is advisable to admit to the hospital patients who do not have somebody at home who can observe and help them.
Nausea can be controlled with oral diphenhydramine, 25 mg three times a day, or by prochlorperazine, 10 mg two to four times a day, without danger of central nervous system depression. Acetaminophen, 500 mg four times a day, can be safely given for abdominal discomfort (the risk of hepatotoxicity occurs at much higher dosages). No sedatives should be given, because they may precipitate hepatic encephalopathy. Corticosteroids are of no value in the treatment of acute viral hepatitis.
Patients should be monitored at intervals varying from 1 to 3 weeks and should not be discharged from ambulatory care until all symptoms have disappeared and all laboratory tests have returned to normal. Patients are advised not to ingest alcoholic beverages until 1 month after all laboratory tests have returned to normal. Patients who develop chronic hepatitis should avoid alcohol indefinitely.
Patients with acute viral hepatitis who are asymptomatic can return to light work despite abnormal liver tests such as hyperbilirubinemia and elevations of the serum aminotransferases and alkaline phosphatase. Patients whose serum bilirubin is high enough to cause jaundice can also return to work but may need a note of their condition to their employer to avoid concern on the part of coworkers. The exception are food handlers with HAV or HEV, as noted in the section Prevention of Viral Hepatitis.
In patients with HBV, HBsAg should be measured after 6 months. If HBsAg is still detectable at that time, a hepatologist should be consulted for further management. In patients with HCV, chronicity is defined as elevations
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of serum aminotransferases that persist for longer than 6 months. It is not necessary to continue to measure HCV RNA, except to monitor virologic response to therapy (see later discussion).
Liver Biopsy
A liver biopsy is indicated only if the diagnosis is uncertain or the clinical course of the disease is prolonged beyond 6 months. A specialist in liver disease should be consulted to evaluate the patient and to perform the liver biopsy.
In patients who do not require hospitalization for another reason, liver biopsies are performed as outpatient procedures in a hospital. The patient should have a history of normal hemostasis, a prothrombin time less than 4 seconds above control, and a platelet count greater than 80,000 per cubic millimeter. A liver biopsy is contraindicated if there is an infiltrate in the right lower lung or a right-sided pleural effusion, absent hepatic dullness to percussion, suspected liver hemangioma or abscess, massive ascites, extrahepatic obstruction, severe anemia (hemoglobin less than 10 g/dL), or significantly impaired hemostasis (see above).
Patient Experience.
After application of local anesthesia, the liver biopsy is performed by the intercostal right subcutaneous route using suction with a needle 1.6 mm in diameter. It entails minimal risk when done by a skilled operator. The most common complication is pleuritic pain lasting a few hours after the biopsy, which is noted in approximately 5% of the cases. The most serious complications are bleeding and bile peritonitis, which occur in fewer than 1% of cases. The risk of mortality from liver biopsy is 0.2%. After the procedure, patients are observed for approximately 4 hours and then, if no complications have occurred, are sent home accompanied by a friend or relative.
Prognosis
Most patients with acute HAV, HBV, or HEV recover from their illness without any sequelae. The mortality rate from all types of hepatitis is less than 0.1%. The principal cause of death is the development of fulminant hepatitis, which is more common in type B hepatitis. Fulminant hepatitis usually overcomes the patient within 10 days after the onset of the symptoms of hepatitis. Older patients and patients with other medical illnesses, such as diabetes mellitus, are more likely to have a prolonged course and a higher mortality rate. Type E hepatitis, transmitted by the fecal-oral route, results in a high mortality rate in pregnant women. Indications of a poor prognosis are changes in mental status, a nonpalpable liver that is also small on hepatic imaging, a liver that decreases rapidly in size, or a prothrombin time (PT) that is prolonged more than 4 seconds above normal.
Chronic hepatitis occurs in approximately 85% of untreated patients with HCV, and 15% to 20% of those patients eventually develop cirrhosis. Chronic hepatitis occurs in 3% to 5% of patients with type B hepatitis, of whom 6% to 20% develop cirrhosis within 5 years. Chronic hepatitis and cirrhosis do not occur after type A or type E hepatitis. These complications should be suspected in patients with HBV or HCV who continue to have clinical and laboratory evidence of liver disease 6 months after the onset of acute hepatitis (13). Most patients clear the HBsAg from their serum within 3 months of the onset of the illness. Approximately 10% of patients with type B hepatitis become chronic carriers of HBsAg. Chronic carriers of HBsAg with abnormal levels of serum aminotransferases should be evaluated for the development of chronic active hepatitis by liver biopsy. An increased incidence of hepatocellular carcinoma has been found in carriers of HBsAg or HCV RNA.
Differential Diagnosis
A number of other viruses have been reported to cause hepatitis. Cytomegalovirus (CMV), usually clinically inapparent in adults, can present with manifestations of hepatitis in patients being administered immunosuppressive therapy, in those who have diseases characterized by immunosuppression (see Chapter 39), or after blood transfusions in healthy subjects. The diagnosis is made by the demonstration of IgM CMV antibody and by examination of biopsy specimens for intranuclear inclusions and detection of the virus in tissue with specific antibodies. Mononucleosis (caused by the Epstein-Barr virus, [EBV]) is often associated with hepatocellular dysfunction with mild transient jaundice in 5% to 10% of patients. It is diagnosed by the presence in the serum of a heterophil antibody that is not absorbed by guinea pig kidney or by a positive mononucleosis spot test. Demonstration of IgM EBV antibodies specific for EBV confirms the diagnosis (see Chapter 58).
Hepatitis caused by leptospirosis should be suspected in patients who have been in close contact with rodents or with food, water, soil, or other material contaminated with the urine of rodents; the diagnosis is established by recovery of Leptospira in culture of the blood or by a rise in antibodies in the course of the disease. Drug-induced hepatitis (see later discussion) manifests with clinical features that are indistinguishable from those of viral hepatitis, and a history of drug intake is a most important clue in suspecting the diagnosis. Alcoholic hepatitis (discussed later) usually develops after recent heavy alcohol ingestion; the serum aminotransferases are rarely elevated more than 10 times above normal, and the elevation is primarily in the serum aspartate aminotransferase (AST). In patients with marked cholestasis—as evidenced by persistent elevation of the bilirubin, high serum alkaline phosphatase,
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and pruritus in association with persistently dark urine and light stools—the diagnosis of extrahepatic biliary obstruction should be entertained. An abnormal sonogram may provide a clue to extrahepatic obstruction if the biliary ducts are found to be dilated, and the patient should then be referred to a specialist in liver diseases for further evaluation.
Prevention and Prophylaxis of Viral Hepatitis
General hygienic measures, such as washing the hands after contact with the patient, are the most effective means of preventing the spread of hepatitis from the patient to others. In cases of HAV and HEV, which are principally acquired by the oral route, the patient's dishes and eating utensils can be shared by other people only if they have been cleaned and heated to more than 120°F (48.8°C) for 15 to 20 minutes in a dishwasher after the patient has used them. Assignment of the patient to a separate bathroom is ideal but often impractical. The viruses can be present in feces, blood, and other body fluids of the patient; any of these materials should be handled with care. Because the virus appears in the stool during the prodromal period of hepatitis, the precautions mentioned should be taken routinely in environments where there is a high risk of development of hepatitis, such as in institutions for the mentally retarded.
The screening of blood for HBsAg and anti-hepatitis C before transfusion has markedly decreased the risk of posttransfusion infection by HBV and HCV to 1 in 63,000 and 1 in 100,000 units transfused, respectively (14). Other sources of type B and type C hepatitis that can easily be controlled are contaminated needles, pins used to test sensation, and dental and surgical instruments. All used needles or pins should be discarded in specially labeled bottles containing 40% formalin, which is known to inactivate the hepatitis viruses. The preferred method for cleaning surgical and dental instruments is by heat sterilization. The risk that most health care workers who are HBsAg-positive pose to their patients is minimal if high standards of hygiene are maintained. The exceptions are dentists and surgeons (15), who often develop cuts on their hands while operating. Dentists are urged to wear gloves regardless of whether they are HBsAg-positive, to protect themselves and their patients. Patients who have had HBV or HCV and have apparently recovered (clinically and serologically) may still be infectious for many years and therefore should not be allowed to donate blood. Spouses of patients with HBV should receive HBV vaccine. Unvaccinated sexual partners of patients who have recovered from HBV may be at risk. Sexual partners of patients with chronic HCV who are in monogamous relationships have virtually no risk of infection (0% to 0.6%). Therefore, those in long-term monogamous relationships need not change their sexual practices (16). Food handlers with HAV infection should not return to their work with food until 4 months after the onset of symptoms, because HAV can be detected in the stool for that long.
Standardimmune serum globulin (ISG) is known to prevent the clinical manifestations of HAV in 80% to 90% of persons when administered within 2 weeks after exposure. However, it does not prevent subclinical infection. The recommended dosage of standard ISG is 0.02 mg/kg, given by intramuscular injection. Hepatitis A vaccine is indicated for close personal contacts of patients with known HAV, inmates of institutions during an epidemic of HAV, and travelers to areas where hepatitis is endemic. It is not indicated for casual acquaintances or coworkers of the patient or for people who are known to have anti-HA antibody in their serum. To obtain immediate and long-term protection in people recently exposed to HAV, the vaccine is combined with the administration of ISG. The HAV vaccine results in the development of protective anti-HA antibody 2 weeks after its administration, a protection that lasts approximately 6 months, at which time a booster dose is given to extend the protection for up to 10 years. The vaccination (Havrix or Vaqta) is given as an injection of 0.5 mL to children and adolescents aged 2 to 17 years and as a 1-mL injection to adults (17).
The role of standard ISG in the prevention of type B hepatitis is uncertain. Hepatitis B immune globulin (containing a high titer of anti-HBs) prevents approximately 75% of cases of type B hepatitis (if given immediately after exposure) in people who have been stuck with needles contaminated by HBsAg-positive patients, in sexual partners of HBsAg-positive patients, in newborns of HBsAg-positive mothers, and in staff personnel of dialysis units (18). It is not indicated for casual or work contacts of patients with type B hepatitis or for patients who have been demonstrated to have anti-HBs. Testing for anti-HBs should be done routinely before administration of HBV immune globulin, provided that the results of the tests can be obtained within 1 week after exposure to the virus.
Chapter 18 contains details regarding indications, dosages, and schedules for primary prevention of HBV with hepatitis B vaccine, postexposure prophylaxis for adults and newborn infants exposed to people who have active HBV or are known HBsAg carriers, and postexposure prophylaxis for adults exposed to people whose HBsAg status is unknown.
There have been insufficient studies to know whether the incidence of posttransfusion HCV or HEV is decreased by the administration of standard ISG. No vaccines are currently available for the prevention of HCV or HEV.
Drug-Induced Hepatitis
The liver is the principal organ concerned with drug metabolism; hence, it is not surprising that it is also a principal target for drug toxicity. Every drug has the potential
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for producing hepatocellular damage. Drug-induced hepatitis results from either direct hepatotoxicity or from an idiosyncratic reaction (host hypersensitivity). Hepatotoxic reactions caused by direct toxins such as carbon tetrachloride and inorganic phosphorus are dose dependent and reproducible with a brief interval after exposure to the drug. Idiosyncratic reactions are the more common response to drugs. Characteristically, they are not dose dependent, occur in only a small number of people who are exposed, and are preceded by a sensitizing period of 1 to 4 weeks of exposure or a history of exposure. Drug reactions may be cholestatic, may simulate viral hepatitis, or may combine features of both processes.
Cholestatic Reactions
Cholestasis is caused by a direct dose-related effect of the administration of anabolic steroids and oral contraceptives. Cholestasis occurs in 1% to 2% of patients receiving anabolic steroids but less often after the ingestion of oral contraceptive drugs. Jaundice and pruritus are prominent symptoms. The elevated serum bilirubin is composed principally of the direct conjugated fraction. Serum alkaline phosphatase and cholesterol are elevated, whereas serum aminotransferases are normal or only slightly elevated. Cholestasis disappears soon after withdrawal of the offending drug.
A much larger number of drugs cause cholestasis through hypersensitivity. Examples are phenothiazine derivatives such as chlorpromazine, antibiotics such as erythromycin, antithyroid drugs such as propylthiouracil and methimazole, hypoglycemic agents such as tolbutamide and chlorpropamide, immunosuppressant drugs such as azathioprine, and alkylating agents such as chlorambucil. Common clinical features of these drug reactions are fever, right upper quadrant abdominal pain, pruritus, skin rash, and eosinophilia. Serum aminotransferases are moderately elevated (less than 10 times normal). The clinical and laboratory abnormalities usually subside between 2 and 4 weeks after discontinuation of the drug, although on occasion cholestasis persists for months to years. Severe pruritus is treated with cholestyramine (Questran) given in a dosage of 4 g three times a day before meals. Relief of pruritus is obtained in 4 to 7 days after starting this medication. Patients with cholestasis should be hospitalized whenever the jaundice persists unchanged or increases 2 to 4 weeks after discontinuation of the drug, to investigate the possibility of other causes of cholestasis (see Chapter 96).
Hepatocellular Reactions
Most agents that produce direct hepatocellular damage are toxins rather than drugs. Acetaminophen, however, is a drug that produces hepatic necrosis in all people if ingested in a large dose (greater than 10 g), usually in a suicide attempt. Alcoholics and patients taking drugs such as phenobarbital, which are inducers of microsomal enzymes, are at risk for development of hepatic necrosis after the ingestion of lower doses of acetaminophen. Shortly after ingestion the patient develops nausea and vomiting, but evidence of hepatocellular damage often does not become apparent until 48 hours later, when serum aminotransferases rise and the prothrombin time becomes prolonged. The patient's condition then deteriorates; jaundice appears and central nervous system depression may occur. The mortality rate of patients who took an overdose of acetaminophen was found to be 3.5% in one large study (19). Therefore, patients who are known or suspected to have ingested toxic amounts of acetaminophen should be hospitalized for support and treatment (ordinarily with N-acetylcysteine).
There has been a marked increase in the use of herbal medications in the Western world in recent years (20). Some of these products, the ingredients of which are often poorly defined, are hepatotoxic. A history of taking herbal medicines should be sought in any patient with unexplained liver disease.
Idiosyncratic hepatocellular reactions have been reported after the administration of a number of drugs, the most common of which are isoniazid, α-methyldopa, nitrofurantoin, ketoconazole, sulfonamides, terbinafine (Lamisil), β-hydroxy-beta-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), troglitazone, phenylbutazone, and halothane. Asymptomatic increases in serum aminotransferases, which subside despite continued administration of the drug, have been reported in 5% to 10% of patients taking isoniazid or α-methyldopa. Because of the often transient nature of the serum aminotransferase elevations, there is no need to monitor these tests in asymptomatic patients. However, the development of symptoms of fatigue and anorexia or of nausea and general malaise is an indication for the determination of serum aminotransferase concentrations; if aminotransferase activity is increased, the drug should be discontinued immediately, because this often heralds the onset of severe hepatocellular damage. In some cases rifampin, an occasional cause of hepatotoxicity itself, potentiates the hepatotoxic effects of isoniazid. The incidence of acute hepatitis in patients taking these latter two drugs is 0.1% to 0.3%. Women and older patients are more likely to be affected. The onset of the reaction is between 1 and 10 weeks after the start of therapy. The symptoms, laboratory tests, and findings on liver biopsy are indistinguishable from those of viral hepatitis (see earlier section Acute Hepatitis), so serologic tests to rule out viral hepatitis are often obtained. The hepatitis usually resolves within a few weeks after the drug is discontinued. However, a mortality rate as high as 12% has been reported for severe hepatitis caused by isoniazid. Moreover, chronic active liver disease can develop if the drug responsible for the hepatitis is continued.
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Administration of corticosteroids is not indicated in drug-induced hepatitis of any type.
Alcoholic Hepatitis
This condition is seen most often after prolonged heavy alcohol intake. Women are more susceptible to alcoholic liver disease than men are, and it usually does not develop in men who drink less than 40 g of ethanol per day or in women who drink less than 20 g per day (equivalent to 4 and 2 ounces [120 and 60 mL] of 86 proof whiskey, 48 and 24 ounces of beer, and 400 to 200 mL of wine, respectively). Many of the presenting clinical characteristics of patients with alcoholic hepatitis (e.g., anorexia, significant fatigue, jaundice, tender hepatomegaly) are indistinguishable from those of viral hepatitis. However, patients with alcoholic hepatitis are more likely to have fever and leukocytosis. The elevation of the serum aminotransferases is rarely 10 times above normal, and often there is a prolongation of the PT. The elevation of AST is characteristically greater than that of alanine aminotransferase (ALT). Patients with alcoholic hepatitis and jaundice should be admitted to the hospital and have a definite diagnosis established by liver biopsy, if not contraindicated by abnormal hemostatic function. Liver biopsy differentiates alcoholic hepatitis from drug-induced hepatitis and viral hepatitis and gives an indication of any underlying chronic liver disease. The illness is often more severe than in patients with viral hepatitis, and decompensation with hepatic encephalopathy and death can occur. Patients with severe alcoholic hepatitis, manifested by jaundice and prolongation of the PT >4 seconds above control and/or encephalopathy, should be hospitalized and considered for treatment with either corticosteroids or pentoxifylline. Approximately one third of patients with alcoholic hepatitis have been shown to progress to cirrhosis, often within 6 months (21). However, if patients can abstain from further drinking of alcohol (see Chapter 28), approximately one-third recover completely, both clinically and histologically, usually within 1 month.
Chronic Hepatitis
Chronic hepatitis is inflammation of the liver detected by abnormal liver tests or abnormal liver histology that has persisted for longer than 6 months. The spectrum of chronic hepatitis varies from a benign, reversible process to an unrelenting process that often progresses to cirrhosis. Liver biopsy is essential both for the diagnosis and to establish the severity of the disease and the need for treatment. The liver histology is graded semiquantitatively according to the degree of necrosis and inflammation (minimal, mild, moderate, or severe activity) and staged for the amount of fibrosis and the presence of cirrhosis (22).
The principal causes of chronic hepatitis are infection with a hepatitis virus (type B or C), autoimmune disease (formerly called lupoid hepatitis), and drugs such as isoniazid, α-methyldopa, and nitrofurantoin. In addition, patients with Wilson disease, a1-antitrypsin deficiency, or primary biliary cirrhosis may present with clinical and histologic features of chronic hepatitis.
The onset of chronic hepatitis is usually insidious. The patient may be asymptomatic, with liver disease detected by aminotransferase elevations on routine testing, or there may be symptoms of general malaise, fatigue, abdominal discomfort, anorexia, and jaundice. In approximately one third of the patients, the disease evolves from a clinically overt episode of acute hepatitis. Physical examination in patients with chronic hepatitis often reveals hepatomegaly and sometimes, when the disease is more advanced, splenomegaly, spider angiomas, palmar erythema, and gynecomastia. Elevations of serum aminotransferases may be the only laboratory abnormality, but elevations of bilirubin and globulins are also common. Decreases in serum albumin and prolongation of the PT reflect loss of hepatocellular function and a poor prognosis. Older male patients are more likely to have HBsAg in the serum and to present with an acute onset of illness. Patients with chronic hepatitis caused by HCV may have arthralgias, vasculitis, palpable purpura, and peripheral neuropathy caused by type II cryoglobulinemia. Often these patients have false-negative test results for hepatitis C antibody (anti-HCV) and undetectable HCV RNA because these factors are concentrated in the cryoprecipitates (23).
Patients with autoimmune hepatitis are more likely to be women and to present with acne, amenorrhea, arthralgia and arthritis, pleurisy, or intermittent fever (24). Additionally, they may have associated thyroiditis, Sjögren syndrome, ulcerative colitis, glomerulonephritis, or hemolytic anemia. Laboratory tests on these patients show evidence of immunologic hyperactivity: serum γ-globulin is often markedly elevated, and there is elevation in the titers of antinuclear antibodies and smooth muscle antibodies. A small subgroup of patients with chronic autoimmune hepatitis have normal titers of antinuclear antibodies but elevated liver–kidney microsomal (anti-LKM) antibodies. Additionally, antimitochondrial antibodies are found in 15% of these patients.
The diagnosis of Wilson disease (which affects approximately 1 in 1 million people) should be considered in all patients, particularly those younger than 25 years of age, who have clinical and laboratory features of otherwise unexplained chronic hepatitis (25). Wilson disease is discussed in more detail in the section Cirrhosis later in this chapter. The diagnosis of chronic hepatitis caused by α1-antitrypsin deficiency(which affects 1 in 1,000 people) is suggested by the finding of an absent or low alpha-1-globulin on serum protein electrophoresis (26). The diagnosis is established by demonstrating a low value of α1-antitrypsin in the serum by quantitative measurement and by protease inhibitor (Pi) typing (26). The common allele is
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PiM; liver disease occurs in approximately 20% of people who are homozygous for the allele PiZ. Liver biopsy reveals periodic acid–Schiff (PAS)–positive cytoplasmic inclusions that are resistant to diastase in both homozygous and heterozygous patients for the allele PiZ. There is no known medical therapy for this deficiency, which is transmitted by codominant inheritance. The diagnostic characteristics of primary biliary cirrhosis are discussed later in the section Cirrhosis. The diagnosis of drug-induced chronic hepatitis (see Drug-Induced Hepatitis) depends on a careful history and the demonstration of improvement of the patient after discontinuation of drugs that are known to produce this illness. In most cases, chronic active hepatitis caused by drugs reverts to normal after discontinuation of the offending drug.
The clinical course of patients with chronic active hepatitis is variable. Patients can be asymptomatic for a long time, have periods of intermittent worsening and remission, or have a progressive course to cirrhosis and death if untreated. HDV is associated with clinical exacerbation of chronic HBV and more rapid progression to cirrhosis (1).
Therapy
Autoimmune Hepatitis
Corticosteroids are beneficial for symptomatic patients with chronic autoimmune hepatitis. Clinical, biochemical, and histologic improvement and even remission have been observed, and mortality rates have been reduced after therapy with corticosteroids (24). Prednisone or prednisolone, 40 to 60 mg, is given initially to suppress the activity of the disease and then is tapered slowly, usually over 1 to 3 months, to a maintenance dosage of 10 to 20 mg. Symptomatic improvement followed by a fall in serum aminotransferases occurs during the first few weeks. Treatment with corticosteroids is decreased to the smallest dosage possible to maintain normal or minimally increased values of the serum aminotransferases. Discontinuation of the corticosteroid therapy often results in a relapse. Azathioprine at an initial dosage of 100 mg/day in combination with prednisone is often effective in maintaining a remission (24). Asymptomatic patients with chronic hepatitis are usually treated only if they have persistent elevations of serum aminotransferases, histologic evidence of at least a mild grade of activity, and evidence of early fibrosis. Administration of corticosteroids to patients with chronic viral hepatitis is contraindicated because it appears to favor replication of hepatitis viruses, resulting in a higher morbidity and mortality (27).
Hepatitis B
Interferon α-2b therapy is effective in eliminating evidence of viral replication (HBeAg) and in normalizing serum aminotransferases in more than one third of patients with type B hepatitis (28). Higher dosages and prolonged administration of interferon α-2b result in improvement in 15% to 25% of patients with chronic HDV (14). Pegylated interferon α-2a (Pegasys) in a dose of 180 µg once a week for 6 months was recently found to result in a greater drop in HBV DNA levels than conventional interferon and in HBeAg seroconversion in 37% of patients at 6 months of followup (29).
Lamivudine, a nucleoside analog, in an oral dose of 100 mg/day, results in a decrease in HBV DNA to undetectable levels in 95% of patients after 6 months of treatment, and in a normalization of ALT levels in 52% at 6 months and 70% at 1 year (30). These effects are associated with improvement in liver histology in 75% of patients. After 6 to 8 months of therapy, however, viral mutants that are resistant to the therapy begin to appear; in these cases after discontinuation of the therapy the HBV DNA and ALT return to pretreatment levels as the virus returns to the wild type. Approximately 30% of patients receiving lamivudine for 1 year who experience a loss of HBeAg remain in remission for 6 months after the therapy (31). Adefovir, another nucleoside analogue, in an oral dose of 10 mg/day is equally effective in decreasing HBV DNA and normalization of serum aminotransferases, and up to the present time has the advantage of a much lower development of resistant viral mutants (32).
Pegylated interferon α-2a, lamivudine, and adefovir (33) have each been shown to result in biochemical and virological improvement in HBeAg negative chronic HBV; in one comparative study, treatment for 48 weeks with pegylated interferon α-2a was superior to lamivudine in the response during treatment and in the sustained suppression of HBV DNA after 24 weeks of treatment (10). Entecavir is the newest nucleoside analogue that shows potent antiviral effect against HBV (34).
Hepatitis C
Pegylated interferons are more effective and have replaced conventional interferon in the treatment of chronic HCV. The two pegylated interferons presently available are PegInterferon α-2a (Pegasys) and PegInterferon α-2b (Peg Intron). These pegylated interferons are administered by subcutaneous injection once a week (180 µg of PegInterferon α-2a or 1.5 µg/kg body weight for PegInterferon α-2b) together with ribavirin in a daily oral dose of 1,000 mg (if <75 kg body weight) or 1,200 mg (if >75 kg body weight). The treatment outcomes and side effects are similar for these two types of pegylated interferons. Patients with genotypes 1 and 4 are treated for 48 weeks, while those with genotypes 2 and 3 are treated for 24 weeks. Early virologic response defined as a decrease in HCV RNA levels by 2 logs at 12 weeks of treatment occurs in approximately 86% of cases (35). The early virologic response is usually associated with a fall or normalization of the serum aminotransferases. The lack of an early virologic response usually predicts a failure to achieve a sustained viral response
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(SVR) after treatment. The overall end of treatment viral response (HCV RNA undetectable) is 69%. SVR at 2 years after the end of the treatment are 42% to 46% for genotype 1 and 76% to 82% for genotypes 2 and 3 (35). Decisions about the use of interferon, lamivudine, adefovir, ribavirin, and newer agents should be made in consultation with a hepatologist.
No specific therapy exists for type E hepatitis.
Unexplained Elevations of Liver Enzymes in the Serum
Elevations of serum aminotransferases and alkaline phosphatase are occasionally found in normal subjects or in patients without suspected liver disease. In such a situation the abnormality should first be confirmed by repeat testing. Next, it is important to remember that elevated serum aminotransferases and alkaline phosphatase do not necessarily originate from the liver. For example, elevated serum aminotransferases can be caused by injury to the heart and striated muscle; if the source of the serum aminotransferases is muscle, the more specific creatine kinase will also be elevated. Elevation of serum γ-glutamyl transpeptidase (GGTP) is useful to confirm the hepatic origin of elevated serum aminotransferases, because, unlike the latter enzymes, it does not originate from damaged muscle. Elevation of GGPT alone, however, should not be used as an indication of liver damage, because GGPT is a microsomal enzyme and elevations may occur as a result of ingestion of drugs that are microsomal enzyme inducers, such as phenytoin (Dilantin), phenobarbital, and ethanol. An isolated increase of serum alkaline phosphatase can originate from liver or bone. The hepatic origin of alkaline phosphatase can be confirmed by demonstration of an elevated 5′-nucleotidase value; unlike alkaline phosphatase, this enzyme is present only in the liver and in the epithelium of the bile ducts. By contrast, an elevated serum alkaline phosphatase accompanied by a normal serum 5′-nucleotidase value is almost invariably caused by bone disease; a common cause of such an occurrence is Paget disease of bone. A common cause of elevations of serum aminotransferases is nonalcoholic steatohepatitis (see later discussion). Any persistent elevation of serum aminotransferases for longer than 6 months that remains unexplained is an indication for liver biopsy to rule out chronic hepatitis. A persistent elevation of serum alkaline phosphatase in the absence of an elevated serum bilirubin can occur in patients with fatty liver, which is common in diabetic and obese patients, or it can be the result of space-occupying lesions, such as granulomas or metastatic carcinoma. A CT scan with intravenous contrast of the liver, or an magnetic resonance imaging (MRI), if the patient is allergic to the contrast, is recommended in these cases to rule out primary hepatic or metastatic carcinoma. Liver biopsy is indicated if the CT scan or MRI shows a space-occupying lesion or if there is clinical suspicion of diseases such as tuberculosis or sarcoidosis that may result in hepatic granulomas.
Alcoholic Fatty Liver
Alcoholic fatty liver results from alterations of lipid metabolism caused by alcohol and therefore occurs in all persons who ingest alcohol in excessive amounts. It is manifested mainly by a feeling of abdominal fullness caused by hepatomegaly and mild elevation of the serum aminotransferases (rarely more than twice normal). On occasion, marked fatty infiltration is associated with symptoms of malaise, weakness, anorexia, tender hepatomegaly, and even jaundice. These symptomatic patients require further evaluation, occasionally including liver biopsy, to distinguish fatty liver from alcoholic hepatitis and cirrhosis. The treatment of fatty liver consists of abstinence from alcohol. With abstinence, the abnormal accumulation of fat disappears within 4 to 6 weeks. As the patient's condition improves, the liver decreases in size and becomes nontender. Serum bilirubin and aminotransferase values promptly return to normal. Recurrent episodes of symptomatic fatty liver are common after heavy alcohol ingestion, but there is no evidence that this lesion itself leads to cirrhosis.
Nonalcoholic Steatohepatitis
Nonalcoholic steatohepatitis is a chronic disease of unknown origin characterized by fatty infiltration and hepatocellular damage with inflammation in patients who lack a history of significant alcohol ingestion (36). It is a very common cause of elevated serum aminotransferases. It is more common in women. Obesity, defined as a body mass index (the weight in kilograms divided by square of the height in meters) greater than 30, is found in at least 30% of patients, and type 2 diabetes is found in 34% to 75% of patients (36, 37). Hyperlipidemia is also common. Most of the patients are asymptomatic and liver disease is discovered by finding elevated serum aminotransferases. The principal symptoms, when present, are fatigue and right upper abdominal discomfort. Hepatomegaly is a finding in 90% of the patients, but splenomegaly is rare. The serum ALT level is usually higher than the serum AST, which helps in differentiating nonalcoholic from alcoholic steatohepatitis. The serum ferritin and transferrin saturation values are often elevated, but few of these patients are homozygous for the hemochromatosis gene. If the diagnosis is in doubt, fatty infiltration can be confirmed by ultrasonography. Liver biopsy is indicated in symptomatic patients with serum aminotransferase elevations of more than 6 months’ duration. Patients with evidence of moderate to severe fibrosis on liver biopsy have at least a 5%
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risk of progressing to cirrhosis. Weight reduction by intake of a calorie-restricted, low-fat diet often results in a decrease in fatty infiltration, improvement of symptoms, a decrease in liver size, a fall in serum triglycerides, and a fall in serum aminotransferases (38).
Cirrhosis
Cirrhosis is a chronic diffuse liver disease characterized by widespread hepatic fibrosis and nodule formation. The fibrosis is the result of extensive destruction of liver cells, and the nodularity represents regeneration. For clinical purposes, cirrhosis can be classified into the following major categories: alcoholic, viral (HBV and HBC), cardiac, and biliary cirrhosis; Wilson disease; hemochromatosis; and schistosomiasis. The onset of cirrhosis is usually insidious and is associated with nonspecific symptoms such as fatigue, anorexia, weight loss, nausea, and abdominal discomfort. As the disease progresses, signs of hepatocellular failure become prominent: jaundice, edema, ascites, electrolyte abnormalities, bleeding tendencies, spider angiomas, palmar erythema, gynecomastia, impotence, and loss of axillary and pubic hair. Hepatomegaly and portal hypertension resulting in splenomegaly and a venous collateral circulation are common. The most severe complications of cirrhosis are hepatic encephalopathy, bleeding from esophageal and/or gastric varices, infection (e.g., spontaneous bacterial peritonitis), and hepatorenal syndrome. Patients with alcoholic cirrhosis often have recurring episodes of hepatocellular failure, precipitated by superimposed alcoholic hepatitis and fatty infiltration induced by alcohol ingestion. Clinical improvement often occurs after abstinence from alcohol and after rest and optimal nutrition. Rapid deterioration of patients with cirrhosis should raise the suspicion of a complicating hepatocellular carcinoma. Common laboratory findings in patients with cirrhosis include anemia, a normal or slightly decreased leukocyte count, and moderate thrombocytopenia. The most common abnormal liver tests are hyperbilirubinemia, a depressed serum albumin, elevated serum globulins, and a prolonged prothrombin time.
Differential Diagnosis
The diagnostic characteristics of some of the other types of cirrhosis are as follows.
Cardiac Cirrhosis
Cardiac cirrhosis develops only after prolonged and severe cardiac failure, usually in patients with right heart failure or constrictive pericarditis. Jaundice, hepatomegaly, and ascites are prominent features, but the diagnosis can be established with certainty only by liver biopsy. Treatment of cardiac failure—for example, treatment of constrictive pericarditis by pericardiectomy—results in improvement of liver function.
Primary Biliary Cirrhosis
Primary biliary cirrhosis (39) is a chronic disease of unknown cause that is characterized by progressive intrahepatic cholestasis and is most often seen in middle-aged women. The principal manifestations are jaundice with pruritus, hepatomegaly, hypercholesterolemia with the formation of xanthomas and xanthelasmas, and steatorrhea caused by the decreased delivery of bile acids to the intestine. Antimitochondrial antibodies are found in 95% of these patients, and their presence is virtually diagnostic. Liver biopsy in the early stages reveals injury to the septal and large intralobular bile ducts with surrounding accumulation of inflammatory plasma cells and lymphocytes and with granuloma formation. In the end stages of the disease, cirrhosis develops that is almost indistinguishable from other causes of nonalcoholic cirrhosis. Treatment with ursodeoxycholic acid (10 to 15 mg/kg/day) has been found to reduce serum bilirubin and aminotransferases, delay clinical progression of the disease, and increase survival (40).
Primary Sclerosing Cholangitis
Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease of unknown etiology caused by inflammation and obstruction of the bile ducts. It has a prevalence of 1 to 7 cases per 100,000 population and is more common in men. There is a strong association between PSC and inflammatory bowel disease, both ulcerative colitis and Crohn disease, with a prevalence greater than 50% in most studies (41). The patients may initially be asymptomatic and present with laboratory values indicating cholestasis, such as elevations of serum bilirubin and alkaline phosphatase, or they may be symptomatic and present with abdominal pain, pruritus, jaundice, or fever. Hepatomegaly is common. Perinuclear antineutrophil cytoplasmic antibodies (pANCA) are found in approximately 80% of patients, but this test is not very specific. Low-titer antimitochondrial antibodies are present in approximately 5% of patients. Dilated bile ducts may be seen by sonography, but visualization of the bile ducts by endoscopic retrograde cholangiopancreatography (ERCP) or by magnetic resonance cholangiopancreatography (MRCP) is essential to establish the diagnosis. It usually demonstrates multiple strictures and beading of the intrahepatic and extrahepatic biliary tree. Liver biopsy typically shows portal and periportal inflammation and fibrosis, initially often concentric around bile ductules. The disease often progresses to cirrhosis. The most serious complications in patients with PSC are cholangiocarcinoma in 7% to 15% of patients and
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cancer of the colon in those patients with associated inflammatory bowel disease. High doses of ursodeoxycholic acid (20 to 25 mg/kg/day) improve liver tests and survival in patients with primary sclerosing cholangitis (42). There is no proven medical therapy for PSC. Major dominant bile duct obstructions, resulting often in bacterial cholangitis, are treated with ballooning, stenting of the bile ducts, and antibiotics. The development of permanent jaundice is an indication for liver transplantation (see Chronic Hepatitis).
Wilson Disease
Wilson disease is a rare disorder of copper metabolism that is inherited as an autosomal recessive disorder (25). Its symptoms result from hepatic and neurologic dysfunction. In children the principal symptoms are caused by liver involvement, whereas in adults neurologic symptoms tend to predominate. The diagnosis should be suspected in all children or young adults who develop cirrhosis, because treatment with copper-chelating agents can arrest the disease and alleviate all symptoms. A characteristic finding that is virtually diagnostic is the presence of Kayser–Fleischer rings, which are greenish-brown rings found on the posterior surface and in the periphery of the cornea. Because these rings cannot often be seen by the naked eye, it is important to refer all suspected patients to an ophthalmologist for slit-lamp examination of the cornea. Serum ceruloplasmin, the copper-binding protein, is reduced in most, but not all, cases. Histologic examination of a liver biopsy is not diagnostic. However, quantitative determination of copper with a finding of more than 250 µg/g of dry liver weight or the urinary excretion of more than 50 µg copper in 24 hours is diagnostic. Treatment of Wilson disease with D-penicillamine or trientine, chelating agents with potential toxicity, is best done by a hepatologist.
Hemochromatosis
Hemochromatosis is an inherited disorder of iron metabolism that results in excessive body iron; it is characterized principally by cirrhosis, diabetes mellitus, and grayish pigmentation of the skin. Other symptoms are cardiac failure and arrhythmias, peripheral neuritis, arthritis, and testicular atrophy. The iron overload appears to be caused by an increased absorption of dietary iron, and the mode of inheritance is autosomal recessive. The hemochromatosis gene has been identified. The primary mutation in the gene is C282Y (substitution of cysteine by tyrosine). Another mutation is H63D (substitution of histidine by aspartate). The homozygous C282Y/C282Y mutation is responsible for 61% to 92% of the cases of hemochromatosis around the world. Compound heterozygotes (C282Y/H63D) have a fourfold increased risk of hemochromatosis, compared with the general population. Homozygous genotype H63D/H63D is not associated with increased iron deposition (43). The disease usually appears in people older than 40 years of age, and it develops earlier in men, probably because of the menstrual loss of iron in women. The diagnosis is made by demonstrating a high serum iron concentration (greater than 150 µg/dL), a high saturation of iron-binding protein (greater than 50%), and increased serum ferritin, usually in a patient with a positive family history (44). The finding of the genotype C282Y/C282Y confirms the diagnosis of hemochromatosis. Therapy consists of removal of excess iron by repeated phlebotomy (1 to 2 units weekly) with the goal of achieving a serum ferritin concentration between 25 and 50 nanograms per milliliter.
Schistosomiasis
Hepatic schistosomiasis may occur in people from tropical areas who have been infected by schistosome cercariae while swimming or walking in infested water. The liver disease is caused by the deposition of ova of Schistosoma mansoni in the portal areas, with the development of an inflammatory reaction, often with granuloma formation and periportal fibrosis. Jaundice is uncommon in these patients at presentation. The most common laboratory abnormalities are increases in serum alkaline phosphatase and mild elevations of serum bilirubin and aminotransferases. The diagnosis of active infection is made by demonstrating motile Schistosoma ova on fresh examination of rectal biopsy, and the diagnosis of liver involvement is made by showing the presence of ova capsules on liver biopsy. Praziquantel is an effective drug for the treatment of hepatic schistosomiasis as well as other clinical forms of schistosomiasis (45).
Management
The treatment of uncomplicated cirrhosis consists of voluntary restriction of activity if the patient has weakness and fatigue, a diet that is high in protein but low in salt, and abstinence from alcohol (see Chapter 28). This regimen almost invariably results in improvement of hepatocellular function in patients with alcoholic cirrhosis and occasionally in patients with nonalcoholic cirrhosis. Tranquilizers and sedatives should be avoided. Infection and gastrointestinal bleeding, which in addition to alcohol ingestion are common precipitating factors of decompensation, should be sought and treated. Vitamin K, 10 mg subcutaneously, may improve prolongation of the prothrombin time. Multivitamins and folic acid, 1 mg/day, may be given if the patient's dietary intake appears to be inadequate or if there is evidence of vitamin deficiencies. Potassium deficiency is common and may contribute to the precipitation of hepatic encephalopathy, but its extent is difficult to assess because serum potassium concentration
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is a poor reflection of the total body potassium. However, when the serum potassium concentration falls below 3.5 mEq/L, the deficit often can be replaced by giving 30 mL of 10% potassium chloride orally two or three times a day, if tolerated, or K-Dur tablets, 20 mEq, two or three times daily.
Fluid retention is treated with sodium restriction (500 mg of sodium chloride per day) and diuretics. The induced diuresis should be slow and should result in a loss of no more than 2.27 kg (5 lb) of weight per week because of the danger of precipitating electrolyte depletion, especially hypokalemia. Diuresis can be initiated by spironolactone, 100 mg/day, and the dosage can be increased gradually to 200 mg/day to obtain a diuresis. A loop diuretic (e.g., furosemide) is added to the regimen gradually if diuresis is inadequate. The dosage of the diuretics is decreased or their use is discontinued if the patient develops hyponatremia or impaired renal function. Patients with ascites that is unresponsive to sodium restriction and high dosages of diuretics should be referred to a hepatologist for management by either therapeutic paracentesis or transjugular intrahepatic portosystemic stent shunt (TIPS). The development of acute hepatic encephalopathy manifested by asterixis or changes in mental status is an indication that the patient should be hospitalized for evaluation and treatment. Acute and chronic gastrointestinal bleeding is also an indication for hospitalization.
Lactulose is the principal therapy for hepatic encephalopathy. Lactulose is a nonabsorbable synthetic disaccharide that reduces blood ammonia and improves encephalopathy in more than 80% of patients when administered in dosages of 20 to 30 g (30 to 45 mL) three to four times a day. Lactulose usually is effective only when it also increases the frequency of bowel movements. Other than producing mild abdominal cramps and flatulence, lactulose is devoid of side effects. The mechanism of its action is not well defined, but its effectiveness is related to its ability to trap nitrogen in the stool and decrease ammonia production. Some of the decrease in ammonia production may be caused by a decrease in contact time of the stool with colonic bacteria. Patients with cirrhosis should be prescribed a normal protein diet of 50 to 70 g/day, which is sufficient to maintain an anabolic state. Higher amounts of protein are of no benefit and can result in the development of encephalopathy. If encephalopathy develops while the patient is on a normal protein diet, it is initially controlled with lactulose therapy with minimal or no reduction of the intake of protein. However, oral protein may need to be restricted if the encephalopathy is not controlled by lactulose. If adequate protein intake cannot be achieved because of worsening hepatic encephalopathy, then oral or enteral formulas of casein hydrolysates (Ensure) are indicated. The administration of adequate protein, which results in a positive nitrogen balance, decreases muscle wasting, and improves serum albumin and hepatic encephalopathy (21). A change from animal protein to a vegetable protein diet may also improve hepatic encephalopathy. The exact mechanism whereby vegetable protein is better tolerated is unknown. However, vegetable protein contains smaller amounts of ammonia, methionine, and aromatic acids, and it also results in alterations of small intestinal and colonic bacterial flora so that the excretion of fecal nitrogen is increased (46). The beneficial effects of a vegetable protein diet and lactulose on hepatic encephalopathy are additive. Patients with decompensated cirrhosis who are not responding to therapy should be considered for liver transplantation and should be referred to a hepatologist for evaluation.
Liver Transplantation
Liver transplantation has become an important option for some patients with end-stage liver disease. In general, patients should be referred to a transplantation center for consideration of liver transplantation if they have fulminant hepatitis or if they have developed cirrhosis with impaired hepatic synthetic function, hyperbilirubinemia, ascites, bleeding esophageal or gastric varices, and/or encephalopathy. Results in patients who do undergo transplantation are excellent compared with patients who do not. For example, in patients with HCV and end-stage liver disease, the 5-year survival rate is approximately 70%, compared with less than 50% in untransplanted patients with comparable disease (47)—this, despite the almost universal recurrence of HCV in the allograft (48). Results in patients with other causes of cirrhosis are comparable.
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
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