Gastroenterology Hepatology

Hepatitis A and E

How can I be sure that the patient has hepatitis A or E?

Both hepatitis A and E present with nonspecific symptoms. Prodromal symptoms include fatigue, malaise, nausea, vomiting, anorexia, fever, abdominal pain, myalgia and arthralgia. These symptoms typically last a week, and in patients who will develop jaundice, dark-colored urine and acholic stools evolve. All symptoms subside with the onset of jaundice. The incubation period lasts from 15 to 60 days for both diseases, and symptoms usually begin 30 to 40 days following exposure.

Presentations range from asymptomatic to acute self-limiting icteric hepatitis to fulminant hepatic failure (FHF). Only 20% of children under the age of 6 may develop symptoms and jaundice with hepatitis A infection, whereas 80% of older children and adults present with icterus.

Both hepatitides are responsible for epidemic and sporadic disease. The primary means of transmission is via the fecal-oral route, and water-borne and food-borne epidemics are commonly described. Sporadic hepatitis E infections in developed countries, including the U.S., are associated with ingestion of undercooked pork products, wild boar, venison, and fish. Studies have demonstrated that in rare instances, hepatitis A and E may be transmitted through blood product transfusions, wherein the donors were viremic at the time of blood collection. Hepatitis E has been transmitted vertically and is associated with a high neonatal mortality rate, while no such data exists concerning hepatitis A.

A tabular or chart listing of features and signs and symptoms

There are no pathognomonic or characteristic features for hepatitis A and E.

Some less common clinical presentations?

Hepatitis A and E may occasionally present as prolonged cholestasis. Cholestatic phases are associated with marked jaundice, pruritus, fever, and weight loss. Bilirubin levels may exceed 10 mg/dL and alkaline phosphatase is elevated disproportionately to aminotransferases. The jaundice may persist for many weeks but eventually resolves. Short courses of steroids and ursodiol may be of some benefit in cholestatic hepatitis A.

Three to twenty percent of hepatitis A infections may manifest as relapsing illness with one or more bouts. The initial flare will typically last from 3 to 6 weeks and remissions between flares last from 4 to 15 weeks. Relapses are either entirely biochemical or associated with mild symptoms. Anti-HAV IgM titers persist in these individuals and HAV-RNA is detectable in stool during relapses. The relapsing form of illness may last from 3 to 9 months.

Extrahepatic manifestations of hepatitis A most commonly include arthralgias (14%) and an evanescent rash (11%). Isolated cases of vasculitis, cryoglobulinemia, arthritis, optic neuritis, transverse myelitis, Guillain-Barre syndrome, interstitial nephritis, agranulocytosis, and red cell aplasia have also been described.

What other diseases and conditions might mimic the signs, symptoms, or clinical features of hepatities A and E?

Other viral hepatitides (B and C). Survey HBsAg, anti-HBc IgM, anti-HCV, and HCV-RNA.

Autoimmune hepatitis (AIH). ANA, antismooth muscle, IgG, and liver biopsy: occasionally, type 1 AIH can develop following hepatitis A infection in genetically susceptible individuals.

Drug-induced hepatitis. There is a temporary association between the initiation of drug and biochemical evidence of liver injury. Cessation of the suspected medication results in improved liver function tests. In developed countries, 21% to 28% of those meeting criteria for drug-induced hepatitis were found to have a sporadic hepatitis E infection.

Ischemic hepatitis.Evidence of a significant hypotensive episode.

Alcoholic hepatitis.History of heavy alcohol use; AST is typically less than 500, ALT is less that 200 and AST /ALT ration is often greater than 2.

Acetaminophen overdose. History of significant acetaminophen intake and disproportionately high aminotransferases in the range of thousands.

How can I confirm the diagnosis?

The diagnosis of hepatitis A is based on detecting IgM antibodies to hepatitis A virus in serum. The antibodies are measurable at the time symptoms develop and remain so for approximately 3 to 6 months following the primary infection (up to 1 year in 25% of individuals), and persists in cases of relapsing disease.

HAV RNA may be found in serum, feces, and liver biopsy tissue. Stool becomes positive 1 week prior to initial presentation and remains so for 2 weeks. In neonates the stool may remain positive for several months. HAV RNA is not routinely available and is thus used in the context of research.

AST and ALT may be elevated in the range of 1000 to 10000 IU/mL where ALT levels are higher than AST levels. Bilirubin elevations follow those of the aminotransferases and remain high for up to 3 months beyond which bilirubin excess represents cholestatic hepatitis A. IgG HAV antibodies appear shortly after IgM antibodies and confer lifelong immunity to hepatitis A, although rare cases of re-infection 20 years after the initial one have been described. The presence of IgG antibodies indicates either past infection or prior vaccination.

The current available tests in the US for hepatitis E are HEV IgM and HEV IgG. The pattern of viremia and antibody formation is similar to that of hepatitis A. A combination of anti-HEV IgM, HEV-RNA in serum/stool, and rising titers of IgG can be used to diagnose acute hepatitis E infection.

IgM HEV antibodies are present at the onset of symptoms and remain detectable for up to 3 months. HEV-RNA is present in serum from 2 weeks prior to the onset of symptoms to 7 weeks thereafter. False negative IgM results were associated with re-infection, while false positive IgM results were found in polyclonal immune activation due to some other virus or in conjunction with high rheumatoid factor levels.

IgG appears shortly after IgM but requires a period of 6 months to mature. Thus, IgG avidity index has been studied in order to distinguish past from primary infection. This test is based on the strength with which IgG attaches to the antigen. An index of less than 40% is consistent with an acute infection, and an index of greater than 60% is consistent with prior infection. A similar index was studied in hepatitis A and was found to be of particular utility in elderly patients. The levels of IgG antibodies deemed protective have not been established, and negative seroconvert ion has been associated with re-infection. Patients with chronic hepatitis E infection have persistently elevated HEV-RNA in serum and stool.

Liver biopsy has little role to play in acute hepatitis A and E.

What other diseases, conditions, or complications should I look for in patients with hepatitis A and E?

Both hepatitis A and E can lead to FHF and death in patients with underlying liver disease. Studies have reported FHF occurring in patients with chronic hepatitis C or B, with and without cirrhosis. In patients with chronic liver disease, hepatitis E increases mortality up to 70%.

Another well-known complication is the increased mortality (up to 20%) in pregnant women with hepatitis E infection. Immune alterations during pregnancy were suspected to be the underlying mechanism, but the exact pathophysiology is still not known.

In comparison to hepatitis A infection, which does not lead to chronic infection, hepatitis E can lead to chronic infection in immunosuppressed persons and especially in solid organ transplant recipients. All reports have involved the genotype 3 virus. Liver transplant, short time after transplantation, lower liver enzyme levels, lower serum creatinine, lower platelet counts, and tacrolimus-based immunosuppressive regimens rather than cyclosporine are all risk factors associated with chronic hepatitis E infection. Serial liver biopsies in patients with persistent hepatitis E infection demonstrated progressive fibrosis and suggested the possible development of cirrhosis.

What is the right therapy for the patient with hepatitis A or E?

Treatment for acute hepatitis A and E is largely supportive. Children usually have milder symptoms and do not require hospitalization. Adults with dehydration must be hospitalized for intravenous fluid administration. Antiemetics, antidiarrheals, and acetaminophen, not exceeding 2 g per day, are recommended. There are no specific dietary restrictions; however, patients should avoid alcohol and hepatotoxic medications. All patients with signs of FHF (hepatic encephalopathy, increasing PT, decreasing albumin) should be transferred to a center where liver transplant surgery is available.

Treatment of chronic hepatitis E in patients post solid organ transplantation is currently under investigation. Approximately one-third achieve viral clearance after reduction of immunosuppression. Case reports have shown clearance of the infection with pegylated interferon alfa-2a or alfa-2b for 3 months or with ribavirin monotherapy for 3 months in patients following kidney transplant.

Prevention

Two types of inactivated hepatitis A vaccines are currently licensed in the U.S.A.: HAVRIX and Vaqta. Twinrix is a combined vaccine containing hepatitis A and hepatitis B antigens. Hepatitis A vaccine is recommended for all children at the age of 1 year; for persons at increased risk for complications from hepatitis A (e.g., persons who have chronic liver disease); those who are at increased risk for infection (e.g., people traveling to countries with high or intermediate rates of hepatitis A); men who have sex with men; intravenous drug users; and persons with clotting factor disorders. Most studies demonstrate a 100% seroconversion rate (IgG anti-HAV >20 IU/ml) after a complete vaccination course. Duration of immunity can last for up to 25 years in adults and at least 14 to20 years in children and young adults.

The tolerability of hepatitis A vaccine in compensated chronic liver disease is satisfactory, and adequate protective titers are usually achieved. In comparison, patients with advanced cirrhosis seroconvert in only 48% of cases following vaccination. Due to the lower response rates seen in these patients, IgG levels should be monitored after the vaccination course is completed, although there are no standard recommendations concerning this. Furthermore, early vaccination for hepatitis A is recommended in patients with chronic hepatitis B and C infection.

Prevaccination testing for IgG anti-HAV is cost effective and recommended only for persons born in areas with high or intermediate prevalence of hepatitis A, groups with a high prevalence of infection (e.g., injection drug users), and certain ethnic groups (Hispanics, Indians, Alaska natives).

Before traveling to destinations with a high or intermediate prevalence, the Advisory Committee on Immunization Practices (ACIP) recommends one dose of hepatitis A vaccine any time before departure. Older, immunosuppressed persons with chronic liver disease who are planning to travel in less than 2 weeks should receive the initial dose of vaccine with concurrent immunoglobulin (0.02 mL/kg) at separate injection sites.

Two separate vaccines for hepatitis E completed phase III trials, but neither one has reached the market yet. There is no comparative data on the immunogenicity or safety of two vaccines.

What is the most effective initial therapy?

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Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

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A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

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Listing of these, including any guidelines for monitoring side effects.

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How should I monitor the patient with hepatitis A and E?

Hepatitis A does not lead to chronic infection, has an excellent prognosis, and results in the development of antibodies that confer long-term immunity to subsequent re-challenge. Hepatitis E, however, may evolve into chronic hepatitis in organ transplant recipients and immunosuppressed individuals and requires longer term follow up to assess the outcome of infection.

What is the Evidence?

Acharya, SK, Panda, SK. "Hepatitis E: water, water everywhere—now a global disease". J Hepatol. vol. 54. 2011. pp. 9-11.

Aggarwal, R. "Hepatitis E: historical, contemporary and future perspectives". J Gastroenterol Hepatol. vol. 26. 2011. pp. 82-72.

Huang, S, Zhang, S, Jiang, H. "Profile of acute infectious markers in sporadic hepatitis E". PloS One. vol. 21. 2010. pp. e13560.

Kamar, N, Garrouste, C, Haaqsma, EB. "Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants". Gastroenterology. vol. 140. 2011. pp. 1481-9.

Kamar, N, Rostaing, L, Abravanel, F. "Ribavirin therapy inhibits viral replication on patients with chronic hepatitits E viral infection". Gastroenterology. vol. 139. 2010. pp. 1612-8.

Haaqsma, EB, Riezebos-Brilman, A, van den Berq, AP. "Treatment of chronic hepatitis E in liver transplant recipients with pegylated interferon alpha-2b". Liver Transpl. vol. 16. 2010. pp. 474-7.

Kamar, N, Rostaing, L, Abravanel, F. "Pegylated interferon alpha for treating chronic hepatitis E virus infection after liver transplantation". Clin Infect Dis. vol. 50. 2010. pp. e30-3.

Sarin, SK, Kumar, M. "A vaccine for hepatitis E: has it finally arrived?". Gastroenterology. vol. 140. 2011. pp. 1349-52.

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