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- Acute Viral Hepatitis
- Symptoms and Signs
- Key Points
- Fulminant Hepatitis
- Resources In This Article
Acute Viral Hepatitis
Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed by anorexia, nausea, and often fever or right upper quadrant pain. Jaundice often develops, typically as other symptoms begin to resolve. Most cases resolve spontaneously, but some progress to chronic hepatitis. Occasionally, acute viral hepatitis progresses to acute liver failure (indicating fulminant hepatitis). Diagnosis is by liver function tests and serologic tests to identify the virus. Good hygiene and universal precautions can prevent acute viral hepatitis. Depending on the specific virus, preexposure and postexposure prophylaxis may be possible using vaccines or serum globulins. Treatment is usually supportive.
(For neonatal hepatitis B, see Neonatal Hepatitis B Virus Infection.)
Acute viral hepatitis is a common, worldwide disease that has different causes; each type shares clinical, biochemical, and morphologic features. Liver infections caused by nonhepatitis viruses (eg, Epstein-Barr virus, yellow fever virus, cytomegalovirus) generally are not termed acute viral hepatitis.
At least 5 specific viruses appear to be responsible (see Table: Characteristics of Hepatitis Viruses). Other unidentified viruses probably also cause acute viral hepatitis.
HAV is a single-stranded RNA picornavirus. It is the most common cause of acute viral hepatitis and is particularly common among children and young adults. In some countries, > 75% of adults have been exposed. HAV spreads primarily by fecal-oral contact and thus may occur in areas of poor hygiene. Waterborne and food-borne epidemics occur, especially in underdeveloped countries. Eating contaminated raw shellfish is sometimes responsible. Sporadic cases are also common, usually as a result of person-to-person contact.
Fecal shedding of the virus occurs before symptoms develop and usually ceases a few days after symptoms begin; thus, infectivity often has already ceased when hepatitis becomes clinically evident. HAV has no known chronic carrier state and does not cause chronic hepatitis or cirrhosis.
HBV is the most thoroughly characterized and complex hepatitis virus. The infective particle consists of a viral core plus an outer surface coat. The core contains circular double-stranded DNA and DNA polymerase, and it replicates within the nuclei of infected hepatocytes. A surface coat is added in the cytoplasm and, for unknown reasons, is produced in great excess.
HBV is the 2nd most common cause of acute viral hepatitis. Prior unrecognized infection is common but is much less widespread than that with HAV. HBV is often transmitted parenterally, typically by contaminated blood or blood products. Routine screening of donor blood for hepatitis B surface antigen (HBsAg) has nearly eliminated the previously common posttransfusion transmission, but transmission through needles shared by drug users remains common. Risk of HBV is increased for patients in renal dialysis and oncology units and for hospital personnel in contact with blood. The virus may be spread through contact with other body fluids (eg, between sex partners, both heterosexual and homosexual; in closed institutions, such as mental health institutions and prisons), but infectivity is far lower than that of HAV, and the means of transmission is often unknown. The role of insect bites in transmission is unclear. Many cases of acute hepatitis B occur sporadically without a known source.
HBV, for unknown reasons, is sometimes associated with several primarily extrahepatic disorders, including polyarteritis nodosa, other connective tissue diseases, membranous glomerulonephritis, and essential mixed cryoglobulinemia. The pathogenic role of HBV in these disorders is unclear, but autoimmune mechanisms are suggested.
Chronic HBV carriers provide a worldwide reservoir of infection. Prevalence varies widely according to several factors, including geography (eg, < 0.5% in North America and northern Europe, > 10% in some regions of the Far East and Africa). Vertical transmission from mother to infant is common (see Neonatal Hepatitis B Virus Infection) unless the neonate is treated with hepatitis B immune globulin (HBIG) and is vaccinated immediately after delivery (see Pregnancy Complicated by Disease:Acute viral hepatitis).
HCV is a single-stranded RNA flavivirus. Six major HCV subtypes exist with varying amino acid sequences (genotypes); these subtypes vary geographically and in virulence and response to therapy. HCV can also alter its amino acid pattern over time in an infected person, producing quasispecies.
Infection is most commonly transmitted through blood, primarily when parenteral drug users share needles, but also through tattoos or body piercing. Sexual transmission and vertical transmission from mother to infant are relatively rare. Transmission through blood transfusion has become very rare since the advent of screening tests for donated blood. Some sporadic cases occur in patients without apparent risk factors. HCV prevalence varies with geography and other risk factors.
HCV infection sometimes occurs simultaneously with specific systemic disorders, including essential mixed cryoglobulinemia, porphyria cutanea tarda (about 60 to 80% of porphyria patients have HCV infection, but only a few patients infected with HCV develop porphyria), and glomerulonephritis; the mechanisms are uncertain. In addition, up to 20% of patients with alcoholic liver disease harbor HCV. The reasons for this high association are unclear because concomitant alcohol and drug use accounts for only a portion of cases. In these patients, HCV and alcohol act synergistically to worsen liver inflammation and fibrosis.
HDV, or delta agent, is a defective RNA virus that can replicate only in the presence of HBV. It occurs uncommonly as a coinfection with acute hepatitis B or as a superinfection in chronic hepatitis B. Infected hepatocytes contain delta particles coated with HBsAg. Prevalence of HDV varies widely geographically, with endemic pockets in several countries. Parenteral drug users are at relatively high risk, but HDV (unlike HBV) has not widely permeated the homosexual community.
HEV is an enterically transmitted RNA virus. Outbreaks of acute HEV infection, often waterborne and linked to fecal contamination of the water supply, have occurred in China, India, Mexico, Pakistan, Peru, Russia, and central and northern Africa. These outbreaks have epidemiologic characteristics similar to HAV epidemics. Sporadic cases also occur. No outbreaks have occurred in the US or in Western Europe. HEV was not originally thought to cause chronic hepatitis, cirrhosis or chronic carrier state; however reports document chronic hepatitis E, exclusively in immunocompromised patients (including organ-transplant recipients, patients receiving cancer chemotherapy, and HIV-infected patients).
Characteristics of Hepatitis Viruses
Acute infection tends to develop in predictable phases:
Incubation period: The virus multiplies and spreads without causing symptoms (see Table: Characteristics of Hepatitis Viruses).
Prodromal (pre-icteric) phase: Nonspecific symptoms occur; they include profound anorexia, malaise, nausea and vomiting, a newly developed distaste for cigarettes (in smokers), and often fever or right upper quadrant abdominal pain. Urticaria and arthralgias occasionally occur, especially in HBV infection.
Icteric phase: After 3 to 10 days, the urine darkens, followed by jaundice. Systemic symptoms often regress, and patients feel better despite worsening jaundice. The liver is usually enlarged and tender, but the edge of the liver remains soft and smooth. Mild splenomegaly occurs in 15 to 20% of patients. Jaundice usually peaks within 1 to 2 wk.
Recovery phase: During this 2- to 4-wk period, jaundice fades.
Appetite usually returns after the first week of symptoms. Acute viral hepatitis usually resolves spontaneously 4 to 8 wk after symptom onset.
Sometimes anicteric hepatitis, a minor flu-like illness without jaundice, is the only manifestation. It occurs more often than icteric hepatitis in patients with HCV infection and in children with HAV infection.
Recrudescent hepatitis occurs in a few patients and is characterized by recurrent manifestations during the recovery phase. Manifestations of cholestasis may develop during the icteric phase (called cholestatic hepatitis) but usually resolve. When they persist, they cause prolonged jaundice, elevated alkaline phosphatase, and pruritus, despite general regression of inflammation.
HAV often does not cause jaundice and may not cause any symptoms. It almost invariably resolves after the acute infection, although there can be early recrudescence.
HBV causes a wide spectrum of liver diseases, from a subclinical carrier state to severe hepatitis or acute liver failure, particularly in the elderly, in whom mortality can reach 10 to 15%. Five to 10% of all patients with HBV develop chronic hepatitis or become inactive carriers. Cirrhosis can develop. Hepatocellular carcinoma can ultimately develop in chronic HBV infection, even without being preceded by cirrhosis.
HCV may be asymptomatic during the acute infection. Its severity often fluctuates, sometimes with recrudescent hepatitis and roller-coaster aminotransferase levels for many years or even decades. HCV has the highest rate of chronicity (about 75%). The resultant chronic hepatitis is usually asymptomatic or benign but progresses to cirrhosis in 20 to 30% of patients; cirrhosis often takes decades to appear. Hepatocellular carcinoma can result from HCV-induced cirrhosis but results only rarely from chronic infection without cirrhosis (unlike in HBV infection).
Acute HDV infection typically manifests as unusually severe acute HBV infection (coinfection), an acute exacerbation in chronic HBV carriers (superinfection), or a relatively aggressive course of chronic HBV infection.
HEV may be severe, especially in pregnant women.
Acute hepatitis must first be differentiated from other disorders that cause similar symptoms. In the prodromal phase, hepatitis mimics various nonspecific viral illnesses and is difficult to diagnose. Anicteric patients suspected of having hepatitis based on risk factors are tested initially with nonspecific liver function tests, including aminotransferases, bilirubin, and alkaline phosphatase. Usually, acute hepatitis is suspected only during the icteric phase. Thus, acute hepatitis should be differentiated from other disorders causing jaundice (see Figure: Simplified diagnostic approach to possible acute viral hepatitis. and Jaundice).
Acute hepatitis can usually be differentiated from other causes of jaundice by its marked elevations of AST and ALT (typically ≥ 400 IU/L). ALT is typically higher than AST, but absolute levels correlate poorly with clinical severity. Values increase early in the prodromal phase, peak before jaundice is maximal, and fall slowly during the recovery phase. Urinary bilirubin usually precedes jaundice. Hyperbilirubinemia in acute viral hepatitis varies in severity, and fractionation has no clinical value. Alkaline phosphatase is usually only moderately elevated; marked elevation suggests extrahepatic cholestasis and prompts imaging tests (eg, ultrasonography). Liver biopsy is usually not needed unless the diagnosis is uncertain. If laboratory results suggest acute hepatitis, particularly if ALT and AST are>1000 IU/L, PT is measured. Manifestations of portosystemic encephalopathy, bleeding diathesis, or prolongation of INR suggest acute liver failure, indicating fulminant hepatitis (see Fulminant Hepatitis).
If acute hepatitis is suspected, efforts are next directed toward identifying its cause. A history of exposure may provide the only clue of drug-induced or toxic hepatitis. The history should also elicit risk factors for viral hepatitis. Prodromal sore throat and diffuse adenopathy suggest infectious mononucleosis rather than viral hepatitis. Alcoholic hepatitis is suggested by a history of drinking, more gradual onset of symptoms, and presence of vascular spiders or signs of chronic alcohol use or chronic liver disease (see also Alcoholic Liver Disease); aminotransferase levels rarely exceed 300 IU/L, even in severe cases. Also, unlike in viral hepatitis, AST is typically higher than ALT, although this difference by itself does not reliably differentiate the two. In uncertain cases, liver biopsy usually distinguishes alcoholic from viral hepatitis.
In patients with findings suggesting acute viral hepatitis, the following studies are done to screen for hepatitis viruses A, B, and C:
If any are positive, further serologic testing may be necessary to differentiate acute from past or chronic infection (see Table: Hepatitis A Serology, Hepatitis B Serology*, and Hepatitis C Serology). If serology suggests hepatitis B, testing for hepatitis B e antigen (HBeAg) and antibody to hepatitis B e antigen (anti-HBe) is usually done to help determine the prognosis and to guide antiviral therapy. If serologically confirmed HBV infection is severe, anti-HDV is measured. If the patient has recently traveled to an endemic area, IgM antibody to HEV (IgM anti-HEV) should be measured if the test is available.
Hepatitis B Serology*
HAV is present in serum only during acute infection and cannot be detected by clinically available tests. IgM antibody typically develops early in the infection and peaks about 1 to 2 wk after the development of jaundice. It diminishes within several weeks, followed by the development of protective IgG antibody (IgG anti-HAV), which persists usually for life. Thus, IgM antibody is a marker of acute infection, whereas IgG anti-HAV indicates only previous exposure to HAV and immunity to recurrent infection.
HBV has at least 3 distinct antigen-antibody systems that can be tested:
HBV-DNA can also be tested. HBV surface coat can be detected in serum as HBsAg.
HBsAg characteristically appears during the incubation period, usually 1 to 6 wk before clinical or biochemical illness develops, and implies infectivity of the blood. It disappears during convalescence. However, HBsAg is occasionally transient. The corresponding protective antibody (anti-HBs) appears weeks or months later, after clinical recovery, and usually persists for life; thus, its detection indicates past HBV infection and relative immunity. In 5 to 10% of patients, HBsAg persists and antibodies do not develop; these patients become asymptomatic carriers of the virus or develop chronic hepatitis.
HBcAg reflects the viral core. It is detectable in infected liver cells but not in serum except by special techniques. Antibody to HBcAg (anti-HBc) usually appears at the onset of clinical illness; thereafter, titers gradually diminish, usually over years or life. Its presence with anti-HBs indicates recovery from previous HBV infection. Anti-HBc is also present in chronic HBsAg carriers, who do not mount an anti-HBs response. In acute infection, anti-HBc is mainly of the IgM class, whereas in chronic infection, IgG anti-HBc predominates. IgM anti-HBc is a sensitive marker of acute HBV infection and occasionally is the only marker of recent infection, reflecting a window between disappearance of HBsAg and appearance of anti-HBs.
HBeAg is a protein derived from the viral core (not to be confused with hepatitis E virus). Present only in HBsAg-positive serum, HBeAg tends to suggest more active viral replication and greater infectivity. In contrast, presence of the corresponding antibody (anti-HBe) suggests lower infectivity. Thus, e antigen markers are more helpful in prognosis than in diagnosis. Chronic liver disease develops more often among patients with HBeAg and less often among patients with anti-HBe.
In patients with active HBV infection, HBV-DNA can be detected in the serum with special testing, although this testing is not routinely available.
In HCV , serum antibody to HCV (anti-HCV) almost always implies active infection; it is not protective. Anti-HCV usually appears within 2 wk of acute infection but is sometimes delayed; however, HCV-RNA is positive. In a small proportion of patients, anti-HCV merely reflects prior exposure with clearance of the virus rather than active infection. In such cases, ALT and AST levels are usually normal. In unclear cases, HCV-RNA is measured.
In HDV , anti-HDV implies active infection. It may not be detectable until weeks after the acute illness.
In HEV , the test for IgM anti-HEV is not routinely available. In a patient with endemic exposure and compatible clinical findings, anti-HEV suggests acute HEV infection.
Biopsy is usually unnecessary but, if done, usually reveals similar histopathology regardless of the specific virus: patchy cell dropout, acidophilic hepatocellular necrosis, mononuclear inflammatory infiltrate, histologic evidence of regeneration, and preservation of the reticulin framework. HBV infection can occasionally be diagnosed based on the presence of ground-glass hepatocytes (caused by HBsAg-packed cytoplasm) and using special immunologic stains for the viral components. However, these findings are unusual in acute HBV infection and are much more common in chronic HBV infection. HCV causation can sometimes be inferred from subtle morphologic clues.
Liver biopsy may help predict prognosis in acute hepatitis but is rarely done solely for this purpose. Complete histologic recovery occurs unless extensive necrosis bridges entire acini (bridging necrosis). Most patients with bridging necrosis recover fully. However, some cases progress to chronic hepatitis.
No treatments attenuate acute viral hepatitis except, occasionally, postexposure immunoprophylaxis. Alcohol should be avoided because it can increase liver damage. Restrictions on diet or activity, including commonly prescribed bed rest, have no scientific basis. Most patients may safely return to work after jaundice resolves, even if AST or ALT levels are slightly elevated. For cholestatic hepatitis, cholestyramine 8 g po once/day or bid can relieve itching. Viral hepatitis should be reported to the local or state health department.
Because treatments have limited efficacy, prevention of viral hepatitis is very important. Good personal hygiene helps prevent transmission, particularly fecal-oral transmission, as occurs with HAV and HEV. Blood and other body fluids (eg, saliva, semen) of patients with acute HBV and HCV infection and stool of patients with HAV infection are considered infectious. Barrier protection is recommended, but isolation of patients does little to prevent spread of HAV and is of no value in HBV or HCV infection. Posttransfusion infection is minimized by avoiding unnecessary transfusions and screening all donors for HBsAg and anti-HCV. Screening has decreased the incidence of posttransfusion hepatitis, probably to about 1/100,000 units of blood component transfused.
Immunoprophylaxis can involve active immunization using vaccines and passive immunization.
Preexposure HAV prophylaxis should be provided for travelers to highly endemic areas. It is also indicated for diagnostic laboratory workers and, because they have an increased risk of fulminant hepatitis from HAV, patients with chronic liver disorders (including chronic hepatitis C). It can be considered for day-care center employees and for military personnel. Several vaccines against HAV are available, each with different doses and schedules; they are safe, provide protection within about 4 wk, and provide prolonged protection (probably for > 20 yr).
For postexposure prophylaxis, standard immune globulin, formerly immune serum globulin, prevents or decreases the severity of HAV infection and should be given to family members and close contacts of patients; 0.02 mL/kg IM is generally recommended, but some experts advise 0.06 mL/kg (3 to 5 mL for adults).
Vaccination in endemic areas has dramatically reduced local prevalence. Preexposure immunization has long been recommended for people at high risk. However, selective vaccination of high-risk groups in the US and other nonendemic areas has not substantially decreased the incidence of HBV infection; thus, vaccination is now recommended for all US residents < 18 beginning at birth. Universal worldwide vaccination is desirable but is too expensive to be feasible.
Two recombinant vaccines are available; both are safe, even during pregnancy. Three IM deltoid injections are given: at baseline, at 1 mo, and at 6 mo. Children are given lower doses, and immunosuppressed patients and patients receiving hemodialysis are given higher doses.
After vaccination, levels of anti-HBs remain protective for 5 yr in 80 to 90% of immunocompetent recipients and for 10 yr in 60 to 80%. Booster doses of vaccine are recommended for patients receiving hemodialysis and immunosuppressed patients whose anti-HBs is < 10 mIU/mL.
HBV postexposure immunoprophylaxis combines vaccination with hepatitis B immune globulin (HBIG), a product with high titers of anti-HBs. HBIG probably does not prevent infection but prevents or attenuates clinical illness. For infants born to HBsAg-positive mothers, an initial dose of vaccine plus 0.5 mL of HBIG is given IM in the thigh immediately after birth. For anyone having sexual contact with an HBsAg-positive person or percutaneous or mucous membrane exposure to HBsAg-positive blood, 0.06 mL/kg of HBIG is given IM within days, along with vaccine. Any previously vaccinated patient sustaining a percutaneous HBsAg-positive exposure is tested for anti-HBs; if titers are < 10 mIU/mL, a booster dose of vaccine is given.
A vaccine is now available for hepatitis E; it appears to have about 95% efficacy in preventing symptomatic infection in males and is safe. Efficacy in other groups, duration of protection, and efficacy in preventing asymptomatic infection are unknown.
No product exists for immunoprophylaxis of HCV or HDV. However, prevention of HBV infection prevents HDV infection. The propensity of HCV for changing its genome hampers vaccine development.
Transmission is the fecal-oral route for hepatitis A and parenterally or via blood for hepatitis B and C.
Hepatitis B and C, unlike hepatitis A, predispose to chronic hepatitis and liver cancer.
Patients with acute viral hepatitis may be anicteric or even asymptomatic.
Do viral serologic testing (IgM anti-HAV, HBsAg, anti-HCV) if clinical findings are consistent with acute viral hepatitis and AST and ALT are elevated out of proportion to alkaline phosphatase.
Treat patients supportively.
Vaccinate as many people against hepatitis B as possible, and vaccinate selected people against hepatitis A and E.
Fulminant hepatitis is a rare syndrome of massive necrosis of liver parenchyma and a decrease in liver size (acute yellow atrophy) that usually occurs after infection with certain hepatitis viruses, exposure to toxic agents, or drug-induced injury.
HBV is sometimes responsible, and up to 50% of cases of fulminant hepatitis B involve HDV coinfection. Fulminant hepatitis with HAV is rare but may be more likely in people with preexisting liver disorders. The role of HCV remains uncertain.
Patients rapidly deteriorate because portosystemic encephalopathy develops, progressing to coma and cerebral edema over a period of several days to several weeks. Coagulopathy commonly results from liver failure or disseminated intravascular coagulation, and functional renal failure (hepatorenal syndrome—see Renal and Electrolyte Abnormalities) may develop. Increasing PT or INR, portosystemic encephalopathy, and particularly renal failure are ominous.
Meticulous nursing care and aggressive treatment of complications improve the outcome. If fulminant hepatitis results from hepatitis B, treatment with oral nucleoside or nucleotide analogs can increase the likelihood of survival. However, emergency liver transplantation provides the best hope for survival. Survival in adults is uncommon without transplantation; children tend to do better. Patients who survive usually recover fully.
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