History

Along with outlining the presenting complaint and its severity and sequelae, the history should also initiate a search for the source of exposure (eg, overseas travel, lack of immunization, intravenous [IV] drug use) and attempt to exclude other possible causes of acute hepatitis (eg, accidental acetaminophen overdose). The incubation period is 2-6 weeks (mean, 4 wk). Shorter incubation periods may result from higher total dose of viral inoculum. Discussion focusing on excluding other potential causes should be undertaken early in order to guide further investigation. Not every patient with fever, hepatomegaly, and jaundice has hepatitis A virus (HAV) infection. Some of the important differential diagnoses for acute hepatitis warrant early and specific management.

Prodrome
In the prodrome, patients may have mild flulike symptoms of anorexia, nausea and vomiting, fatigue, malaise, low-grade fever (usually < 39.5C), myalgia, and mild headache. Smokers often lose their taste for tobacco, like persons presenting with appendicitis.

Icteric phase
In the icteric phase, dark urine appears first (bilirubinuria). Pale stool soon follows, although this is not universal. Jaundice occurs in most (70-85%) adults with acute HAV infection; it is less likely in children and is uncommon in infants. The degree of icterus also increases with age. Abdominal pain occurs in approximately 40% of patients. Itch (pruritus), although less common than jaundice, is generally accompanied by jaundice. Arthralgias and skin rash, although also associated with acute HAV infection, are less frequent than the above symptoms. Rash more often occurs on the lower limbs and may have a vasculitic appearance.

Relapsing hepatitis A
Relapsing hepatitis A is an uncommon sequela of acute infection, is more common in elderly persons, and is characterized by a protracted course of symptoms of the disease and a relapse of symptoms and signs following apparent resolution (see Complications).

Physical Examination
The physical examination focuses on detecting features that support a diagnosis of acute hepatitis and should include assessment for features of chronic liver disease or, similarly, assessment for evidence of decompensation. Hepatomegaly is common. Jaundice or scleral icterus may occur. Patients may have a fever with temperatures of up to 40C.

Complications

Prolonged cholestasis may follow the acute infection. The frequency at which this occurs increases with age. Prolonged cholestasis is characterized by a protracted period of jaundice (>3 mo) and resolves without intervention. Corticosteroids and ursodeoxycholic acid may shorten the period of cholestasis. The usual features of cholestatic viral hepatitis A are pruritus, fever, diarrhea, and weight loss, with serum bilirubin levels higher than 10 mg/dL. Some investigators believe that the use of corticosteroids may predispose patients to developing relapsing hepatitis A. Good data to support this hypothesis are lacking. Acute renal failure, interstitial nephritis, pancreatitis, red blood cell aplasia, agranulocytosis, bone marrow aplasia, transient heart block, Guillain-Barr syndrome, acute arthritis, Still disease, lupuslike syndrome, and Sjgren syndrome have been reported in association with HAV. These complications are all rare. Autoimmune hepatitis after HAV infection has received substantial discussion in the literature. A postulated mechanism involves molecular mimicry and genetic susceptibility. With this condition, as with traditional autoimmune hepatitis, steroid therapy has been associated with good clinical response and improvement in biochemical and clinical parameters. However, these findings are confined to isolated case reports, and the results of larger clinical trials are not available. Relapsing HAV infection occurs in 3-20% of patients with acute HAV infection and uncommonly takes the form of multiple relapses. After a typical acute course of HAV infection, a remission phase occurs, with partial or complete resolution of clinical and biochemical manifestations. The initial flare usually lasts 3-6 weeks; relapse occurs after a short period (usually < 3 wk) and mimics the initial presentation, although it usually is clinically milder. A tendency to greater cholestasis exists in these patients. Vasculitic skin rashes and nephritis may be additional clinical clues to this syndrome. During relapses, shedding of virus can be detected. IgM antibody test findings are positive. The clinical course is toward resolution, with lengthening periods between flares. The total duration is 3-9 months. Liver transplantation has been performed in patients with this condition when signs of significant decompensation have occurred. Corticosteroid treatment has been shown to improve the clinical course, although the course is generally benign without treatment.

Diagnostic Considerations
The main condition to be considered in the differential diagnosis for acute hepatitis A virus (HAV) infection is acute hepatitis E virus (HEV) infection. The 2 viruses have a similar clinical presentation and the same mode of transmission, and both are common in developing countries. Dual infection is believed to occur. Data on this implication (ie, prognosis, disease course) are not available. See the following for more information:

Alcoholic Hepatitis

Autoimmune Hepatitis Dermatologic Manifestations of Hepatitis C Hepatitis B Hepatitis C Hepatitis D Hepatitis E Hepatitis in Pregnancy Pediatric Hepatitis A Pediatric Hepatitis B Pediatric Hepatitis C Viral Hepatitis

Other problems to be considered include the following:

Acute drug-induced liver injury (eg, acetaminophen, Ecstasy) Acute HIV infection[13] Drug-induced hypersensitivity reactions (eg, sulfasalazine hypersensitivity)

Differentials

Budd-Chiari Syndrome Cytomegalovirus Hepatitis, Viral

Approach Considerations
Central to the prevention of any legal problem is establishing the correct diagnosis, which comes from a combination of careful history and subsequent examination. Appearances may be deceiving; therefore, always exclude drugs, particularly acetaminophen, as a cause of acute liver injury. After establishing a diagnosis of hepatitis A virus (HAV) infection, tracing contacts and notifying local public health authorities are important steps for preventing further cases. Omitting these measures may place the practitioner in a vulnerable situation. One important note is that the most common reason for misdiagnosis of hepatitis A is misinterpreting the serology tests.

Complete Blood Count and Coagulation Study

Complete blood count
Mild lymphocytosis is not uncommon. Pure red cell aplasia and pancytopenia may rarely accompany infection. Indices of low-grade hemolysis are not uncommon.

Prothrombin time

The prothrombin time (PT) usually remains within or near the reference range. Significant rises should raise concern and support closer monitoring. In the presence of encephalopathy, an elevated PT has ominous implications (eg, fulminant hepatic failure [FHF]).

Serologic Tests
Anti-hepatitis A virus immunoglobulin M
The diagnosis of acute HAV infection is based on serologic testing for immunoglobulin M (IgM) antibody to HAV. Test results for anti-HAV IgM are positive at the time of onset of symptoms and usually accompany the first rise in the alanine aminotransferase (ALT) level. This test is sensitive and specific, and the results remain positive for 3-6 months after the primary infection and for as long as 12 months in 25% of patients. In patients with relapsing hepatitis, IgM persists for the duration of this pattern of disease. False-positive results are uncommon and should be considered in the event that anti-HAV IgM persists.

Anti-hepatitis A virus immunoglobulin G

Anti-HAV immunoglobulin G (IgG) appears soon after IgM and generally persists for many years. The presence of anti-HAV IgG in the absence of IgM indicates past infection or vaccination rather than acute infection. IgG provides protective immunity.

Liver Function Tests

Liver enzymes
Rises in the levels of ALT and aspartate aminotransferase (AST) are sensitive for hepatitis A. levels may exceed 10,000 mIU/mL, with ALT levels generally greater than AST levels. levels usually return to reference ranges over 5-20 weeks. Rises in alkaline phosphatase accompany the acute disease and may progress during the cholestatic phase of the illness following the rises in transaminase levels.

Hepatic synthetic function

Bilirubin level rises soon after the onset of bilirubinuria and follows rises in ALT and AST levels. levels may be impressively high and can remain elevated for several months; persistence beyond 3 months indicates cholestatic HAV infection. Older individuals have higher bilirubin levels. Both direct and indirect fractions increase because of hemolysis, which often occurs in acute HAV infection. Modest falls in serum albumin level may accompany the illness.

Ultrasonography

Imaging studies are usually not indicated in HAV infection. However, ultrasonography may be required when alternative diagnoses must be excluded. The goals should be to assess vessel patency and to evaluate any evidence supporting the presence of unsuspected underlying chronic liver disease. Ultrasound scanning is essential in patients with FHF.

Other Tests
Liver biopsy has a minimal role in acute HAV infection. It may play a part in chronic relapsing HAV infection or in situations where the diagnosis is uncertain. Other investigations (eg, serum acetaminophen) may be necessary, depending on findings from the history and clinical examination. Molecular diagnostic techniques performed on blood and feces for HAV RNA are purely research tools at present.

Histologic Findings
Histopathology reveals pronounced portal inflammation early in the illness, which is consistent with viral hepatitis. Focal necrosis and acidophilic bodies are less pronounced than with infections of hepatitis B virus (HBV) and hepatitis C virus (HCV). In FHF, biopsy findings may show extensive cell loss with ballooning in many of the remaining hepatocytes. Immunofluorescent stains for HAV antigen yield positive results.

Supportive Care
For acute cases of HAV infection, therapy is generally supportive, with no specific treatment of acute uncomplicated illness. Locating the primary source and preventing further outbreaks are paramount. Initial therapy often consists of bed rest. The patient should probably not work during the acute phase of the illness. Nausea and vomiting are treated with antiemetics. Dehydration may be managed with hospital admission and intravenous (IV) fluids. In most instances, hospitalization is unnecessary. The majority of children have minimal symptoms; adults are more likely to require more intensive care, including hospitalization. About 3-8% of cases of FHF are caused by HAV; however, only 1-2% of HAV infections in adults lead to FHF. Refer patients with FHF to facilities with expertise in liver transplantation. Acetaminophen may be cautiously administered but is strictly limited to a maximum dose of 3-4 g/day in adults. Other treatments are directed by specific complications.

Liver Transplantation
Patients with FHF are considered for liver transplantation. Recurrent disease after liver transplantation has not been reported. Patient selection for liver transplantation may be

difficult, in that 60% of patients recover from FHF without needing the transplant (much as with acetaminophen toxicity), and predicting who needs this life-saving procedure is difficult. Late referral has ominous implications, with the accompanying comorbidities (eg, renal failure, coagulopathy, cerebral edema) and waiting times contributing to poor outcomes. Liver transplantation for chronic relapsing HAV infection has occurred in the context of decompensation with good results; however, there is a report of clinical recurrence after liver transplantation.

Postexposure Prophylaxis
Passive immunization with Gammagard reduces infection when administered within 14 days of exposure (ie, postexposure prophylaxis). Recommendations for providing postexposure prophylaxis are developed on the basis of risk. Postexposure prophylaxis is recommended for nonimmunized close contacts of those recently diagnosed with acute HAV infection. The appropriate public health authority should be notified after diagnosis of HAV infection, and the process of contact tracing should be initiated. In the United States, as many as 10% of cases of acute HAV infection are seen in commercial food handlers. In any suspected food handler transmission, it is imperative that health department officials be notified immediately. In many instances, preexposure prophylaxis has been somewhat replaced by immunization (see Immunization). For travelers, cost-benefit analysis suggests that vaccination is preferred over gamma globulin when an extended stay in the area of risk (ie, high endemicity) is longer than 3 months or when repeat travel to the area (ie, >2 visits outside a 3-mo period) is likely.

Immunization
Vaccination is highly effective at preventing HAV disease. The efficacy of the hepatitis A vaccine ranges from 80% to 100% after 1-2 doses compared to placebo. Current dosing recommendations are available (see Medication). Immunization is indicated for individuals traveling to areas of high endemicity who have less than 2 weeks before departure. Both the vaccination and intramuscular (IM) immunoglobulin should be administered to provide long-term immunity, particularly in persons who intend to travel to these areas repeatedly. People with chronic liver disease of any cause should consider hepatitis A vaccination. Response rates in patients with advanced liver disease and in those on immunosuppressive therapies are likely to be lower. The potentially disastrous outcome of acute HAV infection in this group cannot be overemphasized. Hepatitis A vaccination in some low-risk groups who are potential sources of larger outbreaks of infection (eg, food handlers) has been implemented by some employers, although cost-benefit analysis for the employer does not seem to support such measures.

Epidemiologic studies of current and historical information related to hepatitis A infection patterns and risk factors show strong associations between socioeconomic improvement, increased water and sanitation, and decreasing HAV infection rates.[15, 16] Areas in which a transition of epidemic hepatitis A (childhood acquisition very high) to endemic hepatitis A is occurring will likely lead to an increase in adult acquired infections and the morbidity associated with this in the absence of vaccination programs. An excellent illustration of why this is likely is that the most prevalent risk factor for HAV acquisition in the United States is international travel.[17] This study also lends further support to the importance of vaccination for international travelers. Hepatitis A is the most frequent vaccine-preventable disease in travelers, and it has the highest mortality and morbidity rates for any vaccine-preventable infection in travelers.[18, 19, 20] The global burden of acute cases of hepatitis A is changing and certainly is decreasing in Western societies.[15] In the United States, vaccination programs targeting children during urban outbreaks have demonstrated significant benefits.[21, 22] Immunization programs applied to high-risk groups show morbidity and cost benefits. Approximately 20% of individuals with acute HAV infection may require hospitalization. Global immunization appears to be prohibitively expensive. The hepatitis A vaccine is not yet licensed for use in persons younger than 2 years.

Diet and Activity

Encourage an adequate diet. Patients should avoid alcohol and medications that may accumulate in liver disease. Otherwise, no specific dietary restrictions are necessary. Bed rest during the acute illness may be important, although data to support this practice are lacking. Restricting transmission is important, especially in the early phases of the illness. Returning to work should probably be delayed for 10 days after the onset of jaundice.

Prevention
Control at the source, with treatment of contacts to prevent further cases of disease is the primary goal. Long-term secondary goals include immunization, which increases herd immunity and reduces the likelihood of further outbreaks in high-risk communities. Education about transmission and prevention of transmission (eg, hand washing, safe food sources) is also important.

Medication Summary
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Agents used include analgesics, antiemetics, vaccines, and immunoglobulins. Although acetaminophen may be safely used to treat some of the symptoms associated with hepatitis A virus (HAV) infection, the dosage should be no higher than 4 g/day.

Analgesic agents
Class Summary
Pain control is essential to quality patient care. Acetaminophen is useful for pain and/or fever. View full drug information

Acetaminophen (Tylenol, Tempra, Feverall)

Acetaminophen reduces fever by acting directly on hypothalamic heat-regulating centers, thereby increasing dissipation of body heat via vasodilation and sweating. It relieves mild to moderate pain.

Antiemetics
Class Summary
Antiemetic agents are used to treat nausea and vomiting. View full drug information

Metoclopramide (Reglan)

Metoclopramide is a dopamine antagonist that stimulates acetylcholine release in the myenteric plexus. It acts centrally on chemoreceptor triggers in the floor of the fourth ventricle, and this action provides important antiemetic activity.

Vaccines, viral, prevention

Class Summary
Hepatitis A vaccine is used for active immunization against disease caused by HAV. View full drug information

Hepatitis A vaccine, inactivated, and hepatitis B vaccine (Twinrix)

This combined hepatitis Ahepatitis B vaccine is used for active immunization of persons older than 18 years against disease caused by HAV and infection by all known subtypes of hepatitis B virus (HBV).

View full drug information

Hepatitis A vaccine, inactivated (Havrix, Vaqta)

Hepatitis A vaccine may be administered with immunoglobulin injections without affecting efficacy.

Immune globulins
Class Summary
Hepatitis A vaccine may be administered with immunoglobulin injections without affecting efficacy. View full drug information

Immune globulin IM (Gamunex, Octagam, Gammaplex)

Immune globulin IM neutralizes circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including interferon-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks the complement cascade; promotes remyelination; and may increase cerebrospinal fluid immunoglobulin G (10%). It is effective when administered within 14 days of exposure. If the patient is likely to be returning to areas of high endemicity, concurrent vaccination is recommended. For situations in which exposure is likely to occur before vaccination would be effective, both agents may be administered without reducing the efficacy of the HAV vaccine.