Management of Hepatitis

Jules L. Dienstag

Viral and nonviral forms of hepatitis are more common than generally thought. More than 50,000 cases of viral hepatitis in the United States are reported to the Centers for Disease Control and Prevention each year, although the actual number is estimated to be 10 times as high. Hepatitis B accounts for 30% to 35% of cases of acute viral hepatitis, hepatitis A for 45% to 50%, and hepatitis C for 15% to 20%; both hepatitis D and especially E are very rare in the United States, and a few percent of cases cannot be attributed to any known hepatitis virus. In addition, a proportion of patients with acute hepatitis B, C, and D progress to chronic infection. Some become inactive carriers; others have chronic hepatitis, which is associated with an increased risk of cirrhosis and death. Approximately 25% to 40% of chronic liver disease in the United States and Europe derives from chronic hepatitis C infection and 10% to 15% from hepatitis B. Other important causes of chronic liver disease include alcohol-associated liver injury, hemochromatosis, autoimmune hepatitis, and nonalcoholic steatohepatitis (NASH). In about 15% to 20% of cases, the cause is unknown (“cryptogenic”).

The primary physician needs to be skilled in the management of both viral and nonviral forms of hepatitis, because these are illnesses usually encountered in the outpatient setting. Effective outpatient management requires knowledge of diagnosis (see Chapter 57), natural history, and treatment options. Immunosuppressive therapy for nonviral disease, interferon and direct antiviral agents (e.g., nucleoside analogues, protease inhibitors) for viral disease, and transplantation for end-stage liver disease have widened the therapeutic options substantially. Although many treatment decisions require subspecialty consultation, especially in persons with advanced disease, the primary physician retains responsibility for long-term management and follow-up, working in conjunction with the liver specialist. This charge requires knowing the indications and contraindications for the various treatment options and the best means of monitoring clinical course and therapeutic interventions.

CLINICAL PRESENTATION AND NATURAL HISTORY (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16)

Acute Viral Hepatitis

In most instances, acute viral hepatitis is a self-limited illness; on the order of 85% of hospitalized patients and more than 95% of outpatients recover completely and uneventfully within 3 months (except in the case of hepatitis C—see later discussion). Most persons with acute viral hepatitis never become jaundiced; their illness is labeled mistakenly as a nonspecific viral syndrome unless liver biochemical tests, such as aminotransferase levels, are ordered. A large proportion of patients remain asymptomatic, especially children. In elderly or immunologically compromised patients, the prognosis is more guarded, with an increased risk of severe and protracted disease.

Prodromal symptoms occur after an incubation period of 2 to 4 (rarely 6) weeks for hepatitis A, 2 to 8 weeks for hepatitis E, 4 to 24 weeks for hepatitis B (with or without simultaneous acute hepatitis D infection), and 3 to 15 weeks (80% within 5 to 10 weeks) for hepatitis C. Characteristically, prodromal symptoms consist of 1 to 2 weeks of malaise, anorexia, nausea, vomiting, change in senses of taste and smell, low-grade fever, right upper quadrant or midepigastric abdominal discomfort, and fatigue.
Aminotransferase elevations may precede or coincide with the onset of prodromal symptoms.

If jaundice develops, it usually does so as the prodromal complaints begin to subside, although the persistence of prodromal symptoms is observed in more severe cases. By the time 6 to 8 weeks have elapsed, most patients are well on their way to full recovery. Occasionally, isolated mild aminotransferase elevations persist after clinical recovery. If these biochemical abnormalities resolve within 3 to 6 months, the mild elevations have no prognostic significance.

Fulminant Acute Hepatitis

This is the most ominous form of acute hepatitis, characterized by overwhelming hepatocellular necrosis and signs of liver failure—encephalopathy, ascites, progressive jaundice, and coagulopathy. This complication is seen more often in cases of hepatitis B (especially with simultaneous hepatitis D infection) than in those of hepatitis A or C, although the frequency is particularly high among pregnant women with hepatitis E (see Chapter 57). Before the availability of liver transplantation, the mortality of fulminant hepatitis approached 80%, despite the most meticulous intensive medical care.

Other Variants of Acute Hepatitis

In 5% to 10% of cases of acute hepatitis B, the prodromal phase of the illness may be characterized as a serum sicknesslike syndrome, with urticaria, arthralgias, fever, and polyarticular arthritis. Some patients with acute viral hepatitis, especially those with hepatitis A or E, have a cholestatic illness, with marked jaundice, elevation of serum alkaline phosphatase activity, and pruritus lasting 1 to several months.

Approximately 5% to 10% of patients with acute viral hepatitis experience mild clinical and biochemical relapses during convalescence. These occur in approximately 10% of patients with acute hepatitis A and are associated with a return of virus excretion in stools and infectivity. In patients with acute hepatitis B, what appears clinically as a relapse may represent the clinical expression of simultaneous hepatitis D infection. Episodic swings in aminotransferase levels are common during acute and chronic hepatitis C, attributable to the emergence of viral variants (“quasispecies”) that evade host immunologic containment; in some instances, these recurrent aminotransferase elevations are accompanied by clinical “relapses.”

Progression to Chronic Hepatitis

The risk of progression varies among the several types of viral hepatitis. Although an occasional case of hepatitis A may be slow to resolve and last more than 6 months, no cases of chronic hepatitis have been linked to hepatitis A infection. Similarly, hepatitis E does not progress to chronic infection in immunologically competent persons. In patients with hepatitis B, the persistence of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) increases the risk of chronic hepatitis, although the early presence of either has no predictive value. In fact, no reliable predictors of chronicity have been identified in patients with acute hepatitis B. In patients with acute hepatitis C, the host IL28B genotype C/C is associated with more than 50% likelihood of spontaneous recovery, which is much less likely (<30%) in patients with IL28B genotype C/T or T/T. Clinical manifestations of progression to chronic viral hepatitis may be subtle, with little more than a persistence of mild symptoms and biochemical abnormalities for 6 or more months. Many patients remain asymptomatic, and almost all remain anicteric.

Hepatitis B.

Hepatitis B can progress to chronic hepatitis but usually at a very low rate (˜1%) when clinically apparent acute infection occurs among immunocompetent adults. Classification of the relative severity of chronic hepatitis B is based on liver histologic grade (necroinflammatory activity) and stage (fibrosis). Patients with negligible virus replication—HBV DNA levels ≤10³ to 10⁴ international units (IU) per milliliter—and aminotransferase and histologic activity are inactive HBsAg carriers.

The likelihood of chronic HBV infection is higher, approaching 90%, when acute infection occurs at birth or in early childhood or when acute infection occurs in an immunocompromised host. Most patients who present with chronic hepatitis B acquired their acute infection subclinically and have no history of having experienced an acute hepatitis-like clinical illness. Among those infected at birth, as is common in Asian countries, the early decades of life are characterized by a period of relatively high immunologic tolerance to HBV, with high-level HBV DNA but negligible liver injury (normal to near-normal aminotransferase levels); during the middle decades, the level of immunologic tolerance to HBV is relatively lower, as reflected clinically by activation of liver injury (elevated aminotransferase and histologic activity) and progressive hepatic fibrosis (histologic stage). In patients with simultaneous acute hepatitis B and D, the likelihood of chronicity is not increased, but the severity of acute and chronic hepatitis is amplified.

Although most inactive hepatitis B carriers are asymptomatic and have a nonprogressive course, a small proportion may actually have subtle and insidious progression to chronic liver disease. Rarely, acute hepatitis-like exacerbations can occur. Such events may represent superimposed infection with another hepatitis virus (A, C, D) or reactivation of hepatitis B. Occasionally, an acute hepatitis-like elevation of aminotransferase activity represents a successful spontaneous seroconversion from highly replicative, HBeAg-positive, high-level HBV DNA infection to relatively nonreplicative, anti-HBe-positive, lowlevel HBV DNA infection; when such seroconversions occur (spontaneously or as a result of antiviral therapy, see below), chronic liver injury gives way to an inactive carrier state. With early-generation clinical assays for HBV DNA, the level of HBV DNA in “nonreplicative” carriers fell below the detection threshold (10⁵ to 10⁶ IU/mL), but with exquisitely sensitive amplification techniques such as polymerase chain reaction assays, HBV DNA can be detected in inactive carriers, albeit at a threshold of ≤10³ to 10⁴ IU/mL.

Another important category of chronic hepatitis B has been recognized, HBeAg-negative chronic hepatitis B. Such patients have mutations in the C gene of HBV. The C gene, which codes for the nucleocapsid core protein (HBcAg), also codes for HBeAg; HBeAg production requires an intact precore gene sequence. When one of several precore or core promoter mutations prevents elaboration of HBeAg, HBcAg and intact virus particles can still be synthesized, leading to highly replicative hepatitis B, in the absence of HBeAg. Patients with such mutations in the precore region have levels of HBV DNA greater than or equal to 10⁵ IU/mL (but lower than levels observed in HBeAg-positive patients, 10⁶ to 10⁹ IU/mL) and substantial liver injury, despite the absence of HBeAg, the conventional marker for high-level HBV replication and infectivity. Also characteristic in this subset of patients are fluctuating, even intermittently normal, aminotransferase levels. Often, these HBeAg-negative variants emerge after many years of HBeAg-reactive chronic hepatitis B or even after years of inactive carriage. HBeAg-negative chronic hepatitis B does respond to antiviral therapy, but virologic relapse is the rule after discontinuation of therapy (see below).

Patients with chronic hepatitis B, especially those with infection acquired early in life, are at a markedly increased risk of progression to cirrhosis and hepatocellular carcinoma.

Hepatitis C.

In hepatitis C, 50% to 60% of patients experience elevations in aminotransferase that persist for more than 1 year after acute infection, and almost all of these go on to
have long-standing chronic hepatitis. Moreover, even among patients in whom aminotransferase elevations appear to resolve within the first 6 months, chronic viremia persists in the vast majority. Between the 50% to 60% with chronic hepatitis after acute hepatitis C virus (HCV) infection and the remainder with chronic viremia, chronicity of HCV infection occurs in more than 85% of acutely infected persons. What is more, patients with chronic viremia remain at risk for the development of chronic hepatitis.

Among patients with chronic hepatitis C, cirrhosis develops in 20% of cases within 10 to 20 years after the onset of acute infection. Most have little clinically apparent effect of their disease for many decades, but in patients with moderate to severe chronic hepatitis on liver biopsy, the risk of progression to cirrhosis over 10 to 20 years is high. Among those with compensated cirrhosis, 10-year survival is very good, approximately 80%; once hepatic decompensation begins, the 10-year survival is diminished to less than 50%. In compensated cirrhotic patients with chronic hepatitis C, hepatic decompensation occurs in approximately 4%/year, death in approximately 2%/year, and hepatocellular carcinoma (rare during the first three decades of infection and in the absence of advanced fibrosis) in approximately 1% to 4%/year.

Toxic and Drug-Induced Hepatitis

Drugs can trigger hepatocellular injury through a direct toxic effect or by means of an idiosyncratic reaction, which, usually, reflects individual genetic differences in drug metabolism and corresponding differences in generation of toxic drug metabolites. Some agents are associated with a cholestatic reaction, either as part of an idiosyncratic process or independent of it. The severity of drug-induced hepatitis can range from an asymptomatic increase in liver enzymes to life-threatening illness. Prompt cessation of the drug is essential to limiting further hepatic injury; rechallenge may lead to an exaggerated reaction. Most cases are self-limited, provided that severe injury has not already occurred. Acetaminophen hepatotoxicity, one of the more commonly encountered forms of drug-induced hepatitis, is managed by the administration of N-acetylcysteine (see later discussion).

Direct Toxins

Directly toxic reactions are dose-related and predictable in all patients treated and cause characteristic and reproducible histologic patterns of liver injury. The latency period is short, and manifestations suggestive of a hypersensitivity reaction are absent. Acetaminophen is the most commonly used drug that is directly hepatotoxic, although only when taken in massive doses.

Idiosyncratic Reactions

Idiosyncratic drug reactions, once believed to be immunologically mediated but now recognized to result primarily from the hepatotoxic effects of drug metabolites, are less predictable than those from direct toxins. They occur in only a small proportion of treated persons and cause variable histologic patterns of liver injury. As noted above, susceptibility to this type of drug hepatotoxicity appears to result from genetic differences from person to person in the generation of toxic drug metabolites. In the idiosyncratic type of drug hepatotoxicity, latency is variable, and liver injury is not dose-dependent. In about 25% of patients, extrahepatic manifestations suggestive of a hypersensitivity reaction (e.g., fever, rash, arthralgias, eosinophilia) occur. Hepatitis resulting from halothane, isoniazid, methyldopa, valproic acid, and trimethoprim/sulfamethoxazole follows an idiosyncratic pattern.

Cholestatic Reactions

Two predominant types of cholestatic reactions occur: bland cholestasis, with little evidence of hepatitis, and inflammatory cholestasis. As is the case for other types of drug hepatotoxicity, some categories of cholestatic drug injury appear to represent predictable, dose-dependent, direct toxicity and others unpredictable, non-dose-dependent, idiosyncratic reactions. Oral contraceptives cause bland cholestasis, and the reaction is dose dependent and variable in onset. Erythromycin (especially the estolate preparation, but also other forms) and chlorpromazine are capable of causing idiosyncratic cholestasis with hepatitis, as are other phenothiazines, amoxicillin-clavulanic acid, and oxacillin. Anabolic steroids (17α-substituted androgens) also can cause cholestasis, often accompanied by a mild degree of hepatocellular injury. Other drugs cause a clinical picture reminiscent of sclerosing cholangitis, with inflammatory destruction of intrahepatic bile ducts (e.g., the chemotherapeutic agent floxuridine), whereas others (e.g., carbamazepine, chlorpromazine, tricyclic antidepressant agents) can result in the disappearance of bile ducts—“ductopenic” cholestasis—reminiscent of chronic rejection after liver transplantation.

Drug-Induced Steatosis

Although liver biopsy is the best means of detecting fibrosis and cirrhosis, a number of formulas based on blood-test results have proven moderately predictive (positive likelihood ratios of 5 to 10) for clinically significant fibrosis or cirrhosis in HCV-infected persons. Parameters incorporated into a these formulas include age, platelet count, AST, ALT, haptoglobin, GGT, apolipoprotein, total bilirubin, and alpha2 macroglobulin.

Macrovesicular or microvesicular steatosis or fatty infiltration with accompanying hepatitis (steatohepatitis) complicates therapy with several drugs. Among patients treated with antiretroviral drugs for HIV infection, severe steatohepatitis, a reflection of mitochondrial toxicity, has been observed in association with the use of reverse transcriptase inhibitors such as zidovudine and didanosine and with protease inhibitors such as indinavir and ritonavir.

Chronic Hepatitis

Classification by Grade and Stage

The prognostic distinctions between what used to be labeled “chronic persistent” and “chronic active” hepatitis are no longer recognized as valid, and these terms have been phased out of clinical use. Chronic persistent hepatitis, which now is called minimal or mild chronic hepatitis, referred to more indolent disease, whereas chronic active hepatitis was the designation for more progressive disease that is now labeled as moderate to severe chronic hepatitis. The obsolete distinctions have been replaced by assessments of relative inflammatory activity (grade) and fibrosis (stage). In clinical trials of chronic hepatitis, especially of chronic viral hepatitis, a numerical histologic index is used to assess severity (grade) and progression (stage). The histologic activity index includes numeric scores for periportal necrosis (including piecemeal and bridging necrosis), intralobular necrosis (focal and confluent), portal inflammation, and fibrosis.

Mild Chronic Hepatitis.

In mild chronic hepatitis, mononuclearcell inflammation is confined to the portal tract, the limiting plate of periportal hepatocytes is not eroded, hepatocellular necrosis and inflammation do not extend into the lobule, and fibrosis is absent or very limited. This mild category of chronic hepatitis was believed in the past to be predictive of a good prognosis and limited progression; however, although the benignity of mild chronic hepatitis tends to persist, the prognostic value of this designation
is now recognized to be more limited and does not preclude progression to more severe chronic hepatitis or even cirrhosis.

Moderate to Severe Chronic Hepatitis.

Moderate to severe chronic hepatitis is characterized histologically by a mononuclear-cell portal infiltrate that not only expands portal zones but also extends beyond the portal tract into the adjacent periportal lobular area with erosion of the limiting plate of periportal hepatocytes (piecemeal necrosis or interface hepatitis). Fibrous septa extending into the lobule are also characteristic, fibrosis can range from mild to severe, and a proportion of such patients may have cirrhosis on their initial liver biopsies. A more severe form of this lesion includes bridging necrosis, in which confluent necrosis and cell dropout span lobules (bridging portal tract to portal tract or portal tract to central vein).

Chronic Viral Hepatitis

In the chronic forms of viral hepatitis, the level of virus replication and the histologic pattern appear to be the most important determinants of progression. In patients with chronic hepatitis B, one fourth of patients with mild chronic hepatitis B can still become cirrhotic. Similarly, in patients with histologically mild chronic hepatitis C, 20% can progress to cirrhosis over one to two decades. Superinfection with hepatitis D can cause progression to more severe liver disease among persons with mild chronic hepatitis B.

Hepatitis B.

The 15-year survival of histologically mild chronic hepatitis B exceeds 95%, that of moderately severe chronic hepatitis B is about 85%, and that of the most histologically severe forms of chronic hepatitis B with cirrhosis is about 40%. Progression to cirrhosis has been noted in 13% of patients with mild chronic hepatitis B, in 16% of patients with moderate chronic hepatitis B (without bridging necrosis), and in 88% of those with severe chronic hepatitis B (with bridging necrosis).

The determinant of prognosis that underlies histology in chronic hepatitis B is virus replication. Level of virus replication (as measured by serum concentration of HBV DNA and the presence of HBeAg) is probably the most important determinant of progression to cirrhosis in patients with chronic hepatitis B. For example, in one study, cirrhosis developed in 53% of those with persistent, high-level HBV DNA but in none of those with HBV DNA undetectable by hybridization assays (≤10⁵ to 10⁶ IU/mL). In patients with chronic hepatitis B, conversion from HBeAg to anti-HBe may signal an improvement in liver histology, whereas superinfection with hepatitis D is usually associated with deterioration in histology in up to one third of patients and an acceleration of the disease process.

In sum, although histologic appearance is important, liver biopsy provides only a measure of disease at one point in time. In chronic hepatitis B, the degree of virus replication activity may be the best predictor of prognosis. Lifelong infection with HBV, such as occurs primarily among those infected at or shortly after birth, is associated with an increased risk of hepatocellular carcinoma, whether cirrhosis is present or not. In this subset of patients with early-life acquisition of HBV infection, during the early decades of life, high-level HBV replication tends to be dissociated from liver injury (a period of relatively high immunologic tolerance to HBV); the correlation between virus replication and liver injury is restored during middle decades of life (a period of relatively lower immunologic tolerance to HBV).

Hepatitis C.

Episodic bursts of inflammatory activity often punctuate the clinical course of patients whose liver biopsies show mild chronic hepatitis C. As with hepatitis B, histologic features of chronic hepatitis C can change, and even patients with clinically and histologically mild chronic hepatitis C can progress insidiously and slowly to cirrhosis. Chronic hepatitis C is commonly associated with erosion of the limiting plate of periportal hepatocytes (piecemeal necrosis, interface hepatitis) but rarely with clinical or histologic criteria for severe chronic hepatitis (10-fold elevation of aminotransferase activity, disabling symptoms, multilobular collapse). Still, despite this apparent relative benignity, chronic hepatitis C may progress insidiously, even in the absence of symptoms or marked elevations in aminotransferase activity, and cirrhosis may occur in 20% of cases within 10 to 20 years. Although a wide range of frequencies of progression to cirrhosis has been reported, and although most patients with chronic hepatitis C do very well with limited clinical consequences over several decades, patients with long-standing chronic infection often demonstrate histologic progression. In contrast to the correlation between HBV replication and disease progression, a similar correlation between HCV replication and disease progression cannot be demonstrated invariably. Among the several variables associated with progression in chronic hepatitis C, duration of infection is important; however, the best clinical predictor of progression may be histologic stage and grade. Mild inflammation and necrosis and mild fibrosis characterize a cohort of patients with an excellent prognosis and limited progression to cirrhosis over time, whereas moderate to severe necrosis/inflammation and/or fibrosis in the absence of successful therapeutic intervention (see later discussion) portends progression to cirrhosis almost invariably over one to two decades. Histologic progression in chronic hepatitis C can be accelerated by concomitant excessive alcohol use, by obesity (and hepatic steatosis), and by concomitant HIV infection.

Nonviral (Autoimmune, Idiopathic) Chronic Hepatitis

An autoimmune mechanism is believed to account for many cases of nonviral chronic hepatitis. The severity of histologic change may have a degree of prognostic value. Like other autoimmune diseases, the condition predominates in women between the ages of 20 and 40 years and was first labeled “lupoid hepatitis.” An acute form with severe fatigue, jaundice, fever, amenorrhea, and anorexia sometimes occurs, but many patients present asymptomatically. Extrahepatic manifestations, including arthritis, rash, and thyroiditis, are common, whereas others, such as glomerulonephritis and pleuropericarditis, occur only rarely. Asymptomatic patients are typically discovered when an incidental modest elevation in aminotransferase levels is noted on routine testing. Marked elevation in gamma globulin (more than two times normal) is characteristic, as are high titers of antinuclear antibody and antibody to smooth muscle. Enzyme immunoassays for antibody to hepatitis C may yield false-positive readings in such patients; therefore, in patients with what appears to be autoimmune hepatitis, if screening tests for anti-HCV are reactive, a confirmatory test, such as a test for HCV RNA, should be done. The bilirubin may be higher than in viral hepatitis. Histology and disease activity are important determinants of prognosis for nonviral chronic hepatitis.

Untreated severe autoimmune hepatitis (defined by disabling symptoms, sustained aminotransferase elevations more than 10 times normal, gamma globulin levels twice normal, and bridging or multilobular collapse on biopsy) may progress to cirrhosis and eventual death. The 6-month fatality rate in the absence of therapy is 40% in patients with these findings. Bridging or multilobular necrosis on liver biopsy is associated with cirrhosis in 40% and death in 20% of patients after 5 years. In contrast, patients with less severe disease (piecemeal necrosis alone, minimal symptoms) are usually not at substantial risk for death, and progression to cirrhosis is rare (3% to 10%).

Mild autoimmune chronic hepatitis has a good prognosis in most cases but is not uniformly benign. This lesion has been documented to deteriorate to more severe chronic hepatitis and to progress to cirrhosis in certain patients, such as those with an initial histologic diagnosis of severe hepatitis whose liver biopsies improve with therapy and immunosuppressed patients with a histologic diagnosis of mild chronic hepatitis.

Nonalcoholic Fatty Liver Disease

Fatty liver accounts for approximately 20% of patients referred to specialists for the evaluation of abnormal liver biochemical tests. Among this group, a large majority have simple fatty infiltration of the liver, but a small proportion have fatty infiltration accompanied by necrosis and inflammation (NASH) including neutrophilic infiltration and the presence of Mallory hyaline, reminiscent of alcohol-associated liver injury. Simple fatty infiltration tends to be entirely benign and even responds to weight reduction; however, NASH can be progressive and accompanied by fibrosis. According to current estimates, NASH culminates in cirrhosis in approximately 15% of cases, and NASH is believed to be the most common cause of the so-called “cryptogenic” cirrhosis. NASH is associated with insulin resistance and the “metabolic syndrome” and occurs in as many as 50% of patients with diabetes mellitus and of obese persons and is almost universal in the morbidly obese; however, steatosis can occur in the absence of obesity. Liver biopsy is the only reliable method for establishing a diagnosis of nonalcoholic fatty liver disease and for distinguishing between simple fatty infiltration and NASH. The likelihood of NASH is increased in patients with a basal metabolic index exceeding 30, type 2 diabetes, age greater than 45 years, and a ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) exceeding 1.

PRINCIPLES OF MANAGEMENT (7,12,16,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 and 60)

Screening and Prophylaxis (see Chapter 57)

Management of Acute Viral Hepatitis

As a generally benign and self-limited illness, acute viral hepatitis can be managed in most cases on an outpatient basis. Hospitalization should be reserved for high-risk patients (e.g., elderly or immunocompromised patients, patients with difficult-to-manage underlying chronic diseases) and those with signs of severe hepatocellular injury (e.g., marked prothrombin time prolongation, encephalopathy, ascites and edema, hypoglycemia, or hypoalbuminemia) and/or with inability to maintain oral intake. Other than specific antiviral therapy (for hepatitis B and C, see later discussion), specific therapy for acute viral hepatitis is not available or necessary to accelerate convalescence or prevent sequelae. The usual goals of care are to maintain adequate nutrition and patient comfort, to avoid additional hepatocellular insults from hepatotoxic medications and alcohol, and to prevent the spread of infection to others.

Specific dietary manipulations, corticosteroids, and strict bed rest have no beneficial effect on the course or prognosis of acute uncomplicated or acute severe viral hepatitis. Oral contraceptives do not necessarily need to be stopped, but alcohol intake should cease, and the use of other drugs known to cause liver injury should be discontinued or monitored carefully. Exercise does not interfere with recovery; patients should be encouraged to engage in as much physical activity as they can tolerate without discomfort or undue fatigue.

Symptoms may range from mild to incapacitating. Nausea and vomiting can be controlled by the cautious use of antiemetics; however, because phenothiazines cause cholestatic hepatitis in approximately 1% of patients, nonphenothiazine antiemetics, such as trimethobenzamide, should be used. Small frequent feedings, especially in the morning when nausea is at a low ebb, can ensure adequate calorie intake. No specific foods need to be restricted, although some patients with acute hepatitis cannot tolerate fatty foods. In patients with cholestasis and pruritus, the bile-sequestering resin cholestyramine usually provides relief. The identification of a patient with acute viral hepatitis should prompt consideration of prophylactic measures to limit the spread of infection to contacts (see Chapter 57).

Hepatitis A and E

Therapy for acute hepatitis A and E is not available; instead, management relies on the nonspecific measures reviewed previously.

Hepatitis B

Because patients with clinically apparent acute hepatitis B almost always recover, specific antiviral therapy is not indicated. For the unfortunate 1% to 2% of immunologically competent patients with clinically apparent acute hepatitis who remain chronically infected, antiviral therapy can be instituted once chronicity has been documented. In patients with severe, rapidly progressive, or fulminant acute hepatitis B, the use of one of the oral polymerase inhibitors has been reported to be effective and is now recommended; although data from formal controlled trials are limited, such patients, left untreated, often require liver transplantation, and most authorities would use one of the two first-line drugs, entecavir or tenofovir (see later discussion).

Hepatitis C

For patients with acute hepatitis C, antiviral therapy during early acute hepatitis has been shown to reduce the frequency of chronicity and is recommended (see later discussion). Most authorities recommend treatment for at least 6 months with standard doses of pegylated interferon once a week plus ribavirin daily in patients with acute hepatitis C; however, the optimal doses and duration of therapy have not been determined; the role of recently approved protease inhibitors (see below) in the treatment of acute hepatitis C has not been evaluated. In clinical practice, such acute cases are encountered primarily among health workers who sustain accidental needle sticks or other percutaneous exposures (rare) and among active injection drug users (common).

Monitoring and Follow-Up

The patient is monitored clinically by observing symptoms and checking liver biochemical tests, especially those that reflect hepatocellular injury and function. An aminotransferase level obtained weekly at the outset and then monthly is useful for judging the presence of ongoing inflammation, although the absolute level is not a particularly sensitive determinant of disease severity in the acute phase of illness. Prothrombin time is a good measure of hepatocellular synthetic function and should be checked when the patient presents initially and when worsening is suspected. The half-life of prothrombin is 18 hours to 3 days; therefore, impaired hepatic synthetic function is reflected rapidly by changes in prothrombin time. Serum bilirubin, a marker of hepatic excretory function, also correlates with severity. A fall in serum albumin indicates reduced hepatocellular synthetic function, but because its half-life is approximately
20 days, this change does not become apparent until late in the acute illness.

An office visit 1 to 2 weeks after the first presentation is often helpful to be sure that worsening has not occurred and that the patient is managing satisfactorily. Thereafter, follow-up depends on how well the patient feels. At 3 months, to ascertain disease activity, severity, and virologic status, a repeat aminotransferase, bilirubin, albumin, and prothrombin time should be obtained; in cases of acute hepatitis B, HBsAg and HBeAg determinations should be performed; and in cases of acute hepatitis C, HCV RNA should be repeated.

If symptoms and laboratory evidence of activity persist after 3 months, repeat evaluations at monthly intervals are helpful in monitoring for recovery. Liver biopsy is not indicated in patients with acute viral hepatitis unless clinical suspicion of chronic hepatitis is present and/or the information obtained has the potential to influence management decisions.

Fulminant Acute Hepatitis

In those rare instances when follow-up reveals the rapid development of fulminant acute viral hepatitis, corticosteroid therapy has been shown not only to be ineffective but also to be detrimental and should not be used. In most cases, specific medical therapy has not been shown to be effective. The best approach involves meticulous attention to the details of the multisystem dysfunction that accompanies acute liver failure. Such patients should be admitted to an intensive care unit and considered for early referral to a transplantation center. Liver transplantation is the only intervention that has truly lifesaving potential. With timely transplantation, survival rates exceeding 60% are possible. Recurrent viral hepatitis may occur in the new liver, but not invariably, and antiviral therapy for hepatitis B and C can be used after transplantation to reduce the impact of reinfection. Experimental trials have been done to assess a variety of hepatic assist devices, but, to date, none has been proven effective. As noted, reversal of acute fulminant hepatitis B has been observed anecdotally with the early administration of a nucleoside analogue polymerase inhibitor, as reported with the use of lamivudine and entecavir; one of the two first-line agents, entecavir or tenofovir, is recommended, and treatment should be continued for a minimum of 3 months after HBsAg-to-anti-HBs seroconversion or for 6 months after HBeAg-to-anti-HBe seroconversion (see later discussion).

Drug-Induced Hepatitis (2, 3 and 4,12)

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