Viral Hepatitis

Aswad H. Al.ObeidyFICMS, FICMS GE&Hep

Kirkuk General Hospital

Hepatitis A In 1982, HAV was classified as an enterovirus type

72 belonging to the Picornaviridae family Subsequent determination of the sequence of HAV

nucleotides and amino acids led to questioning of this classification, and a new genus, Hepatovirus, was created for HAV

HAV has an icosahedral shape and lacks an envelope

It measures 27 to 28 nm in diameter Inactivated at 85°C for 1 minute Only one serotype of HAV is known The HAV genome consists of a positive-sense RNA

that is 7.48 kb long, single-stranded, and linear

EPIDEMIOLOGY The epidemiologic risk factors for HAV infection

reported for the U.S. population in 2002 were as follows:

Unknown, 57%; Sexual or household contact with a patient who has

hepatitis A, 12%; International travel, 9%; Male homosexual activity, 8%; Injection drug use, 5%; Child or employee in a daycare center, 1%; Food or waterborne outbreak, 1%; Contact with a daycare child or employee, 3%; Other contact with a patient who has hepatitis, 4%

PATHOGENESIS Once HAV is ingested and survives gastric acid, it

traverses the small intestinal mucosa and reaches the liver via the portal vein

Once the virus reaches the hepatocyte, it starts replicating in the cytoplasm

Once the virus is mature, it reaches the systemic circulation via the hepatic sinusoids and is released into the biliary tree through bile canaliculi, passed into the small intestine, and eventually excreted in the feces

The pathogenesis of HAV-associated hepatocyte injury is not completely defined

Immunologically mediated cell damage is more likely

CLINICAL FEATURES HAV infection usually presents in one of the

following five different clinical patterns: (1) asymptomatic without jaundice (2) symptomatic with jaundice and self-

limited to approximately 8 weeks (3) cholestatic, with jaundice lasting 10

weeks or more (4) relapsing, with two or more bouts of

acute HAV infection occurring over a 6- to 10-week period

(5) FHF

EXTRAHEPATIC MANIFESTATIONS

Consist most commonly of an evanescent rash (14%)

Arthralgias (11%) Less commonly of leukocytoclastic vasculitis Glomerulonephritis Arthritis In rare cases, hepatitis A has been followed

by the development of type 1 AIH

DIAGNOSIS A diagnosis of acute hepatitis A requires

demonstration of IgM anti-HAV in serum The test result is positive from the onset of

symptoms and usually remains positive for approximately 4 months

Some patients may have low levels of detectable IgM anti-HAV for more than a year after the initial infection

IgG anti-HAV is also detectable at the onset of the disease, remains present usually for life, and, after clinical recovery

IgG anti-HAV interpreted as a marker of previous HAV infection

TREATMENT There are no specific medications to treat acute hepatitis A Symptomatic treatment is the rule Attention to sanitation and administration of serum immune

globulin (IG) are the mainstays of preventing HAV infection The availability of excellent HAV vaccines has rendered use

of IG for preexposure prophylaxis unnecessary When IG is used for postexposure prophylaxis, it should be

given within 2 weeks of exposure In these cases, the recommended dose is 0.02 mL/kg, given

by intramuscular injection Although considered safe, IG can cause fever, myalgias,

and pain at the injection site Postexposure prophylaxis with IG can be accompanied

safely at the same time as initiation of active immunization with the vaccine

HEPATITIS B An estimated 400 million persons are carriers of

hepatitis B virus (HBV) in the world today Effective vaccines against HBV have been available

for more than 20 years Hepatitis B is the chief cause of cirrhosis and HCC in

the world today The virus is 100 times as infectious as human

immuno-deficiency virus (HIV) and 10 times as infectious as hepatitis C virus (HCV)

One or more serologic markers of HBV infection were demonstrated in 4.9% of the U.S. population, and the prevalence of chronic infection was 0.2%

Definitions HBV carrier has often been used to refer to persons

persistently infected with HBV who have normal serum aminotransferase levels

Inactive carriers are patients who have evidence of HBV replication on a PCR-based assay only

Long-term follow-up of inactive carriers suggests that the majority of these patients do not have progressive liver disease and do not experience complications

Active carriers, on the other hand, have evidence of HBV replication on non–PCR-based assays for HBV DNA, intermittently or persistently elevated serum aminotransferase levels, and evidence of chronic hepatitis in a liver biopsy specimen

Clinical Sequelae of Acute Hepatitis B Virus Infection The age at which a person becomes infected with

HBV is a principal determinant of the clinical outcome

HBV infection in adults with intact immune systems is likely to cause clinically apparent acute hepatitis B; only 1% to 5% of these persons become chronically infected

By contrast, as many as 95% of infected neonates become chronic HBV carriers because of immunologic tolerance to the virus.

In adults, fulminant liver failure due to acute hepatitis B occurs in less than 1% of cases

The rate of spontaneous survival in acute liver failure due to hepatitis B is only approximately 20%

CLINICAL FEATURES The incubation period of acute hepatitis B varies from a few

weeks to 6 months (average, 60 to 90 days) Acute infections are heralded by a serum sickness–like

prodrome of fever, arthralgias/arthritis, and rash, which is most commonly maculopapular or urticarial, in 10% to 20% of patients

These features generally abate before the manifestations of liver disease and peak serum aminotransferase elevations are observed

Jaundice develops in only about 30% of patients Clinical symptoms and jaundice generally disappear after 1

to 3 months Persistence of HBsAg after six months implies development

of a carrier state Serum aminotransferase levels of 1000 to 2000 U/L are

typical

Extrahepatic Manifestations Arthritis Dermatitis Glomerulonephritis Polyarteritis nodosa Mixed cryoglobulinemia Papular acrodermatitis Polymyalgia rheumatica

DIAGNOSIS HBsAg appears in serum 2 to 10 weeks after exposure to

HBV The disappearance of HBsAg is followed several weeks later

by the appearance of anti-HBs. In most patients, anti-HBs persists for life and provides long-term immunity

Anti-HBc is detectable in acute and chronic HBV infection. During acute infection, anti-HBc is predominantly of the IgM class and is usually detectable for 4 to 6 months after an acute episode of hepatitis

The finding of HBeAg in the serum of an HBsAg carrier indicates greater infectivity, a high level of viral replication, and the need for antiviral therapy

The measurement of serum HBV DNA is commonly employed to evaluate a patient's candidacy for antiviral therapy and to monitor response during treatment

TREATMENT All the guidelines indicate that treatment decisions ideally

should be made in the context of liver histologic findings and that treatment should be directed preferentially to patients with histologically moderate to severe hepatitis

Currently, treatment decisions are not based on specific grading or staging of liver histology

Interferon Advantages Finite duration of treatment. Durable off-treatment response. Loss of HBsAg (5%-8%) Disadvantages Given by injection. Frequent side effects. Expensive. Low response rate with a high level of viremia

Nucleoside analogs Advantages Negligible side effects. Potent inhibition of virus replication. Less expensive than interferon. Disadvantages Oral delivery. Drug resistance. Long or indefinite treatment duration. Low rate of HBsAg disappearance. Moderately expensive when given long term

HEPATITIS D (DELTA) Hepatitis D (delta) virus was discovered by Rizzetto

and associates in 1977 as a unique nuclear antigen in the hepatocytes of patients infected with HBV

At least 5% of HBV carriers worldwide are estimated to be infected with HDV, and therefore, the overall burden of HDV infection is between 15 and 20 million cases

Among the three genotypes of HDV (I to III), genotype I is the most prevalent and is the most common genotype in Mediterranean countries, Africa, Europe, and North America

Genotype II is reported mostly in Japan and Taiwan and is associated with milder liver disease

Genotype III has been isolated from epidemics in South America

PATHOGENESIS The pathogenesis of HD-related liver disease depending

on the interplay of three major factors: (1) HDV-associated factors, such as genotype 2 and the expression of specific HDAg species SHDAg, but not LHDAg, is directly cytotoxic to hepatocytes. (2) Host associated factors, such as the immune response. Several autoantibodies have been described in association with chronic HDV infection. The major LKM-3 antigen appears to be a family of uridine diphosphate-glucuronosyltransferases (UGTs), which are hepatic enzymes involved in phase 2-drug metabolism. (3) Helper virus-associated factors, such as the HBV genotype and the level of HBV replication

CLINICAL FEATURES The clinical and laboratory findings vary with the

type of infection: (1) Coinfection of HBV and HDV results in acute

hepatitis B+D with high incidence of liver failure, the rate of progression to chronic infection is not different from that after classical acute hepatitis B

(2) Superinfection with progression to chronic HDV infection occurs in almost all patients

(3) Helper independent latent infection, which can be rescued by the helper virus at a later time

TREATMENT The management of HDV infection is supportive Liver transplant is the treatment of choice for

fulminant or end stage liver disease The only drug that has been examined in

randomized controlled trials is interferon HBV/HDV coinfection can be prevented by

either preexposure or postexposure prophylaxis for HBV

While prevention of HDV superinfection depends primarily on behavior modification

Hepatitis C HCV is a single-stranded positive-sense RNA virus

that belongs to the Flaviviridae family Hepatitis C virus (HCV) infection is the most

prevalent bloodborne infection in the United States, affecting an estimated 4 million persons

Most patients acutely infected with HCV are asymptomatic and do not clear the infection spontaneously; approximately 85% develop chronic infection

Of patients with chronic infection, 20% to 25% develop cirrhosis over 20 years

Of patients who develop cirrhosis, the risk for hepatocellular carcinoma is approximately 5% per year

DIAGNOSIS The anti-HCV antibody test is the screening test for

at-risk persons A positive test in a person with one of the risk

factors confirms exposure to the virus The HCV RNA test is required to determine active

infection rather than just exposure to the virus In patients with none of the risk factors who have a

positive anti-HCV antibody test and a negative HCV RNA test, the recombinant immunoblot assay (RIBA), which detects antibodies to any of several viral antigens, should be done

A positive RIBA, in the absence of detectable HCV RNA confirms that the patient has been infected with hepatitis C but has spontaneously cleared the infection

TREATMENT Therapy for hepatitis C infection consists of the

combination of pegylated interferon and ribavirin The ideal candidate for therapy is the patient with

detectable virus, some indication of hepatic inflammation (elevated liver tests or inflammation on the biopsy), and no contraindication to therapy

The goal of therapy is to achieve a sustained virologic response, which is defined as undetectable HCV beyond 6 months after the end of treatment

Eleven distinct genotypes of the virus have been identified The most important variable affecting the response rate is

the genotype of the virus Patients who achieve at least a two-log reduction in the

HCV RNA by the twelfth week have a higher likelihood (approximately 66%) of achieving a sustained response

Hepatitis E Hepatitis E is a form of acute, icteric, self-

limited viral hepatitis caused by the hepatitis E virus

The disease was first recognized in the 1980s Its genome was cloned in 1990 and fully

sequenced shortly thereafter It results from fecal-oral transmission Pregnant woman with acute HEV infection

are at greatest risk for developing severe hepatitis or liver failure