ACUTE VIRAL HEPATITIS

ACUTE VIRAL HEPATITIS

Acute viral hepatitis is a systemic infection affecting the liver predominantly.Almost all cases of acute viral hepatitis are caused by one of five viral agents: hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), the HBV-associated delta agent or hepatitis D virus (HDV), and hepatitis E virus (HEV).All these human hepatitis viruses are RNA viruses, except for hepatitis B, which is a DNA virus.

Hepatitis A Virology and Etiology

Hepatitis A virus is a nonenveloped 27-nm, heat-, acid-, and ether-resistant RNA virus in the Hepatovirus genus of the picornavirus family 

•Hepatitis A has an incubation period of 4 weeks.• Its replication is limited to the liver, but the virus is present in the liver, bile, stools, and blood during the late incubation period and acute preicteric phase of illness.•Despite persistence of virus in the liver, viral shedding in feces, viremia, and infectivity diminish rapidly once jaundice becomes apparent.•HAV can be cultivated reproducible in vitro.

SEROLOGY OF HEPATITIS A

•Antibodies to HAV (anti-HAV) can be detected during acute illness when serum aminotransferase activity is elevated and fecal HAV shedding is still occurring.

• This early antibody response is predominantly of the IgM class and persists for several months, rarely for 6–12 months.

During convalescence, however, anti-HAV of the IgG class becomes the predominant antibody.

•Therefore, the diagnosis of hepatitis A is made during acute illness by demonstrating anti-HAV of the IgM class.

• After acute illness, anti-HAV of the IgG class remains detectable indefinitely, and patients with serum anti-HAV are immune to reinfection

Hepatitis B virus is a DNA virus with a remarkably compact genomic structure; despite its small, circular, 3200-bp size, HBV DNA codes for four sets of viral products with a complex, multiparticle structure

Serologic and Virologic Markers

•After a person is infected with HBV, the first virologic marker detectable in serum within 1–12 weeks, usually between 8–12 weeks, is HBsAg

• Circulating HBsAg precedes elevations of serum aminotransferase activity and clinical symptoms by 2–6 weeks and remains detectable during the entire icteric or symptomatic phase of acute hepatitis B and beyond.

• In typical cases, HBsAg becomes undetectable 1–2 months after the onset of jaundice and rarely persists beyond 6 months.

•After HBsAg disappears, antibody to HBsAg (anti-HBs) becomes detectable in serum and remains detectable indefinitely thereafter.

•HBcAg is intracellular and, when in the serum, sequestered within an HBsAg coat, naked core particles do not circulate in serum• HBcAg is not detectable routinely in the serum of patients with HBV infection.
•anti-HBc is readily demonstrable in serum, beginning within the first 1–2 weeks after the appearance of HBsAg and preceding detectable levels of anti-HBs by weeks to months.Because variability exists in the time of appearance of anti-HBs after HBV infection, occasionally a gap of several weeks or longer may separate the disappearance of HBsAg and the appearance of anti-HBs. 

•During this "gap" or "window" period, anti-HBc may represent the only serologic evidence of current or recent HBV infection, and blood containing anti-HBc in the absence of HBsAg and anti-HBs has been implicated in the development of transfusion-associated hepatitis B.
• In part because the sensitivity of immunoassays for HBsAg and anti-HBs has increased, however, this window period is rarely encountered. In some persons, years after HBV infection, anti-HBc maypersist in the circulation longer than anti-HBs. 

Scheme of typical laboratory features of wild-type chronic hepatitis B

•HBeAg and HBV DNA can be detected in serum during the replicative phase of chronic infection, which is associated with infectivity and liver injury.

•Seroconversion from the replicative phase to the nonreplicative phase occurs at a rate of 10% per year and is heralded by an acute hepatitis- like elevation of ALT activity; during the nonreplicative phase, infectivity and liver injury are limited.

•In HBeAg-negative chronic hepatitis B associated with mutations in the precore region of the HBV genome, replicative chronic hepatitis B occurs in the absence of HBeAg.

•Recent and remote HBV infections can be distinguished by determination of the immunoglobulin class of anti-HBc. Anti-HBc of the IgM class (IgM anti-HBc) predominates during the first six months after acute infection

•whereas IgG anti-HBc is the predominant class of anti-HBc beyond six months.

•Therefore, patients with current or recent acute hepatitis B, including those in the anti-HBc window, have IgM anti-HBc in their serum.

•In patients who have recovered from hepatitis B in the remote past as well as those with chronic HBV infection, anti-HBc is predominantly of the IgG class.

•Infrequently, in 1–5% of patients with acute HBV infection, levels of HBsAg are too low to be detected; in such cases, the presence of IgM anti-HBc establishes the diagnosis of acute hepatitis B.

•Generally, in persons who have recovered from hepatitis B, anti-HBs and anti-HBc persist indefinitely.

Hepatitis D

•The delta hepatitis agent, or HDV, the only member of the genus Deltavirus, is a defective RNA virus that coinfects with and requires the helper function of HBV (or other hepadnaviruses) for its replication and expression

•HDV can either infect a person simultaneously with HBV (co-infection) or superinfect a person already infected with HBV (super-infection); when HDV infection is transmitted from a donor with one HBsAg subtype to an HBsAg-positive recipient with a different subtype, the HDV agent assumes the HBsAg subtype of the recipient, rather than the donor.

•Because HDV relies absolutely on HBV, the duration of HDV infection is determined by the duration of (and cannot outlast) HBV infection. HDV antigen is expressed primarily in hepatocyte nuclei and is occasionally detectable in serum.

•During acute HDV infection, anti-HDV of the IgM class predominates, and 30–40 days may elapse after symptoms appear before anti-HDV can be detected.

•In self-limited infection, anti-HDV is low-titer and transient, rarely remaining detectable beyond the clearance of HBsAg and HDV antigen.

•In chronic HDV infection, anti-HDV circulates in high titer, and both IgM and IgG anti-HDV can be detected.

Organization of the hepatitis C virus

•The three structural genes at the 5' end are the core region,

•C, which codes for the nucleocapsid,

•envelope regions, E1 and E2, which code for envelope glycoproteins.

• Adjacent to the structural proteins is p7, a membrane protein that appears to function as an ion channel.

• At the 3' end are six nonstructural (NS) regions, NS2, which codes for a cysteineprotease; NS3, which codes for a serine protease and an RNA helicase; NS4 and NS4B; NS5A; and NS5B, which codes for an RNA-dependent RNA polymerase.

• After translation of the entire polyprotein, individual proteins are cleaved by both host and viral proteases .

•Currently available, third-generation immunoassays, which incorporate proteins from the core, NS3, and NS5 regions, detect anti-HCV antibodies during acute infection.

• The most sensitive indicator of HCV infection is the presence of HCV RNA, which requires molecular amplification by PCR or transcription-mediated amplification (TMA)

• To allow standardization of the quantification of HCV RNA among laboratories and commercial assays, HCV RNA is reported as international units (IUs) per milliliter

• quantitative assays are available that allow detection of HCV RNA with a sensitivity as low as 5 IU/mL.

•HCV RNA can be detected within a few days of exposure to HCV—well before the appearance of anti-HCV— and tends to persist for the duration of HCV infection .

Hepatitis E

•epidemic or enterically transmitted non-A, non-B hepatitis, HEV is an enterically transmitted virus that occurs primarily in India, Asia, Africa, and Central America; in those geographic areas, HEV is the most common cause of acute hepatitis

Pathogenesis

•For HBV, the existence of inactive hepatitis B carriers with normal liver histology and function suggests that the virus is not directly cytopathic.

•The fact that patients with defects in cellular immune competence are more likely to remain chronically infected rather than to clear HBV supports the role of cellular immune responses in the pathogenesis of hepatitis B–related liver injury

•Nucleocapsid proteins (HBcAg and possibly HBeAg), present on the cell membrane in minute quantities, are the viral target antigens that, with host antigens, invite cytolytic T cells to destroy HBV-infected hepatocytes

•An important distinction should be drawn between HBV infection acquired at birth, common in endemic areas, such as the Far East, and infection acquired in adulthood, common in the west.

• Infection in the neonatal period is associated with the acquisition of immunologic tolerance to HBV, absence of an acute hepatitis illness, but the almost invariable establishment of chronic, often lifelong infection. Neonatally acquired HBV infection can culminate decades later in cirrhosis and hepatocellular carcinoma.

•In contrast, when HBV infection is acquired during adolescence or early adulthood, the host immune response to HBV infected hepatocytes tends to be robust, an acute hepatitis-like illness is the rule, and failure to recover is the exception.

• After adulthood acquired infection, chronicity is uncommon, and the risk of hepatocellular carcinoma is very low.

•Based on these observations, some authorities categorize HBV infection into an "immunotolerant" phase, an "immunoreactive" phase, and an "inactive" phase.

•This somewhat simplistic formulation does not apply at all to the typical adult in the west with self-limited acute hepatitis B, in whom no period of immunologic tolerance occurs.

HEPATITIS C 

•Cell-mediated immune responses and elaboration by T cells of antiviral cytokines contribute to the containment of infection and pathogenesis of liver injury associated with hepatitis C.

• cross-reactivity between viral antigens (HCV NS3 and NS5A) and host autoantigens (cytochrome P450 2D6) has been invoked to explain the association between hepatitis C and a subset of patients with autoimmune hepatitis and antibodies to liver-kidney microsomal (LKM) antigen (anti-LKM)

Extrahepatic Manifestations

•Immune complex–mediated tissue damage appears to play a pathogenetic role in the extrahepatic manifestations of acute hepatitis B.

•serum sickness–like syndrome observed in acute hepatitis B appears to be related to the deposition in tissue blood vessel walls of HBsAg-anti-HBs circulating immune complexes, leading to activation of the complement system and depressed serum complement levels.

•In patients with chronic hepatitis B

•Glomerulonephritis with the nephrotic syndrome.

•Generalized vasculitis (polyarteritis nodosa)

•Essential mixed cryoglobulinemia (EMC), was reported initially to be associated with hepatitis B. 

Clinical and Laboratory Features

Symptoms and Signs

The prodromal symptoms

•Constitutional symptoms of anorexia, nausea and vomiting, fatigue, malaise, arthralgias, myalgias, headache, photophobia, pharyngitis, cough, and coryza may precede the onset of jaundice by 1–2 weeks.

•The nausea, vomiting, and anorexia are frequently associated with alterations in olfaction and taste.

•A low-grade fever between 38° and 39°C (100°–102°F) is more often present in hepatitis A and E than in hepatitis B or C, except when hepatitis B is heralded by a serum sickness–like syndrome; rarely, a fever of 39.5°–40°C (103°–104°F) may accompany the constitutional symptoms.

•Dark urine and clay-colored stools may be noticed by the patient from 1–5 days before the onset of clinical jaundice.

clinical jaundice

•the constitutional prodromal symptoms usually diminish, but in some patients mild weight loss (2.5–5 kg) is common and may continue during the entire icteric phase.

•The liver becomes enlarged and tender and may be associated with right upper quadrant pain and discomfort.

•Infrequently, patients present with a cholestatic picture, suggesting extrahepatic biliary obstruction.

•Splenomegaly and cervical adenopathy are present in 10–20% of patients with acute hepatitis.

•Rarely, a few spider angiomas appear during the icteric phase and disappear during convalescence

recovery phase

•some liver enlargement and abnormalities in liver biochemical tests are still evident.

•Complete clinical and biochemical recovery is to be expected 1–2 months after all cases of hepatitis A and E and 3–4 months after the onset of jaundice in three-quarters of uncomplicated, self-limited cases of hepatitis B and C (among healthy adults, acute hepatitis B is self-limited in 95–99% while hepatitis C is self-limited in only 15%).

•In the remainder, biochemical recovery may be delayed.

•The duration of the posticteric phase is variable, ranging 2–12 weeks, and is usually more prolonged in acute hepatitis B and C.