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Embee Diagnostics

 

Markers for Viral Hepatitis

Compiled by : Prateek Mittal

Embee Diagnostics Pvt. Ltd.

This article is an attempt to understand the different Hepatitis markers and their significance in diagnosing various viral Hepatitis infections. 

'Hepatitis', the combination of ' Hepatic ' + ' Itis ' means Inflammation of the liver. 

The causes of Hepatitis can be broadly classified into Infectious and Non Infectious. The Infectious causes include Bacteria and more commonly Viruses. The Non-Infectious causes are Alcohol (Alcoholic Hepatitis), Choleatatic, Drugs and Toxic material.

Viral Hepatitis leads to disease like condition which could be non reverse clinical condition. It causes Liver damage/failure and can even lead to death. Correct diagnosis is important for prevention as well as effective treatment. For correct diagnosis, it is important to understand the Host Immune Response (Serological Response), the Disease and Clinical Stage and the types of Viral Hepatitis. 

The recognized types of Viral Hepatitis are :

  • Hepatitis A - Caused by Hepatitis A Virus (HAV)

  • Hepatitis B - Caused by Hepatitis B Virus (HBV)

  • Hepatitis C - Caused by Hepatitis C Virus (HCV)

  • Hepatitis D - Caused by Hepatitis Delta Virus (HDV)

  • Hepatitis E - Caused by Hepatitis E Virus (HEV)

  • Others like Hepatitis G, Hepatitis F, TT Virus and SEN-V are not well recognized

While HAV, HCV, HDV and HEV are all ssRNA viruses (Single stranded), HBV is a dsDNA virus. Two viruses (Hepatitis B and C) are enveloped and two (Hepatitis A and E) are not, whereas the Hepatitis D virus requires an envelope provided by the surface-coat material of Hepatitis B virus for it to propagate. Only Hepatitis B virus integrates into the host DNA. 

Two viruses (Hepatitis A and E) are spread enterically and cause acute illness, whereas three (Hepatitis B, C, D,) are spread parenterally, sexually, parentally and through transfusion too.

Hepatitis B, C and D can cause chronic disease.

 

Clinical Stages

  1. Incubation Period - Asymptomatic

  2. Preicteric Phase - Non specific Symptoms Appearance

  3. Icteric Phase - Jaundice

  4. Convalescence - Period of recovery

 

Hepatitis A

Hepatitis A virus (HAV) is an enterovirus. It has one serotype. The genome is a single strand of positive-sense RNA.. The risk of Hepatitis A in patients with chronic liver disease has been confirmed. Unlike Hepatitis B virus (HBV) transmission by blood via parental routes can occur but is unusual in Hepatitis A infection

Markers : HAV Ag, HAV Ab, HAV IgM

Hepatitis B

Hepatitis B (HBV) is a Hepadnavirus .It is a small enveloped DNA virus containing 3.2 kb. The Hepatitis B virion consists of a surface and a core. The core contains a DNA polymerase and the e antigen. The DNA structure is double stranded and circular. There are four major polypeptide reading frames (genes): the S (surface), the C (core), the P (polymerase) and the X (transcriptional transactivating). Very rarely a mutation may occur in the S gene and may abort the HBsAg with the result that a person may be HbsAg negative but still have virus present as determined by HBV DNA. The C gene is divided into two regions, the pre-core and the core, and codes two different proteins, the Core antigen (HBcAg) and the E antigen (HBeAg)

HBV Mutants

Because HBV uses a reverse transcription mechanism, mutations are fairly common. It is now known that HBV mutates far more frequently than the usual DNA virus but less than rotaviruses. During the last 7 years a series of HBV mutants have been recognized. The most important of these is the so-called pre-core mutation, in which there is a defect in the pre-core region of HBV DNA. This mutation results in the failure to express HBeAg. The pro-core may stop production of HBeAg and these persons will be HBsAg positive, HBV DNA positive, but HBeAg negative. The pre-core mutation has been implicated in the pathogenesis of fulminant hepatitis and may be responsible for severe exacerbations of chronic hepatitis associated with HBV infection. In general, patients with this mutant are more likely to progress to cirrhosis and hepatic insufficiency, compared to infection with wild strains.

To make it even more complex, the HBsAg particles are antigenically complex and these antigenic determinants have been identified. There is a single common determinant designated a, and four sub-determinants designated d, y, w, and r. Thus, the four major determinants are: adr, ayw and ayr.

 

CLINICAL COURSE

Hepatitis B is transmitted by parenteral, congenital and sexual routes. Fulminant disease carries a 1.2% mortality. Up to 10% of patients develop a chronic hepatitis complicated by cirrhosis or hepatocellular carcinoma. Congenital infection brings a high risk of hepatocellular carcinoma.

Markers : HBV DNA, HBsAg, HBeAg, HBcAg, Anti-HBs, Anti-HBe, HBc IgM, HBc IgG

 

Hepatitis C

Ten years have elapsed since identification of the viral agent (Hepatitis C virus [HCV]) responsible for hepatitis was first reported. This remarkable achievement occurred after more than 20 years of intense efforts by investigators worldwide following observation that at least one additional viral agent, other than Hepatitis A and Hepatitis B, was the major cause of post-transfusion hepatitis (Arch RD et al 2000).

HCV is an enveloped, positive stranded RNA virus with a genome that consists of 10,000 nucleotides. The virus is a member of flavivirus family, which also includes other parenenterally spread viruses such as yellow fever and dengue. At least 6 genotypes as well as a number of subtypes have been identified. A correlation seems to exist between the genotype and clinical course of infection and its treatment. For example, genotype1, which is common in the United States, seems to be most virulent of the genotypes and more resistant to treatment. Unfortunately HCV is a very mutagenic virus, a characteristic that enables it to survive the immune defense mechanisms of the host. As a result more than 75%of the adults acquiring acute infection go on to develop chronic Hepatitis C with continuing HCV infection (Widdermann BL 1999).

Markers : HCV RNA Qualitative, HCV RNA Quantitative, anti-HCV

 

Hepatitis D

The Hepatitis D virus (also called delta virus) is a small circular RNA virus. The Hepatitis D virus is replication defective and therefore cannot propagate in the absence of another virus. In humans, Hepatitis D virus infection only occurs in the presence of Hepatitis B infection.

A patient can acquire Hepatitis D virus infection at the same time as she/he is infected with the Hepatitis B virus. This is called co-infection. A patient with Hepatitis B can be infected with Hepatitis D virus at any time after acute Hepatitis B virus infection. This is called super-infection (Desai et al 1990).

 

Hepatitis virus super-infection should be suspected in a patient with chronic Hepatitis B whose condition suddenly worsens. There is usually an obvious history of continued exposure to blood or blood products (e.g. an active intravenous drug user). A particularly aggressive acute Hepatitis B infection could suggest Hepatitis D co-infection. Co-infection or super infection with Hepatitis D virus in a patient with Hepatitis B is diagnosed by the presence of antibodies against the Hepatitis D virus. IgM antibodies indicate acute infection.

Markers : HDV Ag, HDV RNA (PCR), HDV IgG, HDV IgM, HDV Total(IgG+IgM)

 

Hepatitis E

Hepatitis E virus has two main geographically distinct strains, Asian and Mexican; recently, novel isolates from non-endemic areas and a genetically related swine HEV have been described. HEV is responsible for large epidemics of acute hepatitis and a proportion of sporadic hepatitis cases in the Indian subcontinent, Southeast and central Asia, the Middle East, parts of Africa, and Mexico (Khuroo MS et al 1994). Clinical illness is similar to other forms of acute viral hepatitis except for pregnant women, in whom illness is particularly severe with a high mortality rate. Sub-clinical and unapparent infection may occur, however, chronic infection is unknown. No specific treatment is available.  

Hepatitis E virus (HEV) is an important cause of enterically transmitted acute viral hepatitis in several less-developed countries and is transmitted by faecal-oral route. Data on duration of viral excretion and viraemia during HEV infection are limited. An outbreak of Hepatitis E in Lucknow, India provided the authors (Aggarwal et al 2000) with an opportunity to obtain such data. Their data suggest that extended viral excretion and viraemia, particularly those extending beyond the duration of biochemical hepatitis, are distinctly rare. Thus, in disease-endemic areas, individuals who have recovered from acute Hepatitis E are unlikely to serve as a reservoir of HEV infection

Markers : HEV Ag, HEV IgG, HEV IgM, HEV Ab(Total)

 

The following table has been formulated to help understand the importance of various Hepatitis markers in correct and complete diagnosing of Hepatitis :

 
HAV IgG Indicates past infection with HAV and also immunity to HAV
HAV IgM Positive in acute Hepatitis A Infection

Peak at 3-4 weeks from onset of Symptoms

HAV Ab Indicates acute infection when positive with HAV IgM

Remains positive during and after the resolving stage for a long time, falls slowly

HAV Ab is present post vaccination

HBsAg 

(Hep B Surface Ag)

Indicates the patient is infected with the Hepatitis B Virus

First serological marker to appear post infection

Specially important for pre-transfusion diagnosis

Persistence for > 6 months indicates chronic state

HBeAg

(Hep B Envelope Ag)

Indicates active viral replication. Patient is highly infectious.

HBeAg Negative with HBV DNA positive indicates the person is infected with the Precore mutant

HBcAg Extensively surrounded by HBsAg. 

Not freely detectable in the Srum

Anti-HBs Marker of Recovery and Immunity

Appears during convalescence

A level > 10 IU following Hep B Immunization is considered to be protective against HBV Infection

Anti-HBe Reduced Viral Replication

Inactive liver disease(usually)

Reduced Infectious state

Anti-HBc IgM Differentiates between chronic and acute Infection. Anti-HBc IgM. Positive in the acute infection.
Anti-HBc IgG Indicates exposure to HBV

Always detected in HBV Infection

High titer without Anti-HBc IgM indicates persistent Infection

Anti-HCV Indicates past or present HCV infection.

All positive EIA results should be verified using supplemental assay (PCR/W.B.) 

HCV RNA Detects presence or absence of Hepatitis C Virus. Can also help differentiate between Acute, Chronic or past infection
HDV IgM With positive Hepatitis B Infection,  HDV IgM reflects the presence of HDV infection. High titers of HDV IgM are associated with Superinfection

HDV IgM Positive with positive Anti-HBc IgM is associated with Hepatitis D Coinfection

HDV IgG High titers during Hepatitis D chronic Superinfection
HEV IgM Acute HEV Infection

Indicates recent exposure to HEV

HEV IgG Immunity / Old Infection. Performed when HEV IgM is negative

 

Embee Diagnostics now has an entire line of Hepatitis Markers in convenient pack sizes in EIA (Enzyme Immunoassay) Format. Kindly click here to go to our Hepatitis Markers Product list.

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References :

CDC. Recommendations for prevention and control of Hepatitis C Virus (HCV) Infection and HCV -Related Chronic Disease. MMWR 1998;47 (No. RR-19):11

CDC. Prevention of Hepatitis A through active and passive Immunization. MMWR 1996, 45(No. RR-15):2.

Immunization Action Coalition

Hennepin County Community Department Epidemiology

Viral Hepatitis: General Aspects

Amarapurkar DN, Amarapurkar AD, Kriplani AL (2000). Extrahepatic manifestations of viral hepatitis: Hospital based study. J Gastroenterol Hepatol 159 (supplement) S30.

Bzowej NH et al (1999). Viral hepatitis and liver transplantation. J Gastroenterol Hepatol 14 (supplement); S53-S60.

Mondel MJ (2000). Immunopathogenesis of viral hepatitis. Clin Reviews Allergy Immunol 18:141-166.

Ramrakhiani S, Bacon BR (2000). Hepatology in the millennium. Advances in viral hepatitis, hepatic disorders and liver transplantation. Med Clin North Am 84: 1086-1105.

Rosenberg W (1999). Mechanisms of immune escape in viral hepatitis. Gut 44:759-764.

Shaffer EA (2000). The emerging management of viral hepatitis. Can J Gastroenterol 14(suppl B) 4B

Viral Hepatitis: Pathology

Dhillon Amar P (1999). Pathology of viral hepatitis. Liver 19: 261-262.

Huang SN et al (1997). Histopathology and pathobiology of hepatotropic virus-related liver injury. J Gastroenterol Hepatol 12: (supplement) S195-S217.

Koziel MJ (1999). Cytokines in viral hepatitis. Seminars in Liver Disease 19:157-169.

TerBong F et al (2000). A survey of liver pathology in needle biopsies from HBsAg and anti HBe positive individuals. J Clin Pathol 53: 541.

Hepatitis A

Olive G et al (2000). Prevalence of hepatitis A in patients with B and C. Medicina Clinica 115:254-255.

Hepatitis B

Halsey et al (1999). Hepatitis B vaccine and multiple sclerosis. Peditr Infect Dis J 18: 23-24.

Hepatitis C

Alric L et al (2000). Study of host- and viral-related factors associated with spontaneous hepatitis C virus clearance. Tissue Antigens 56:154-158.

Vallisa D et al (1999). Association between hepatitis C virus and non-Hodgkin's lymphoma and effects on viral infection on histologic subtypes and clinical course. Am J Med 106:536-540.

Hepatitis D

Desai Priti R, Banker DD (1990). Hepatitis B and Delta virus in fulminant hepatitis. Indian J Gastroenterol 9:209-210.

Hepatitis E

Aggarwal R, Kini D, Sofat S et al (2000). Duration of viraemia and faecal viral excretion in acute hepatitis E. Lancet 356:1081-1082.

Krawczynski K, Aggarwal R, Kamli S (2000). Hepatitis E. Infect Dis Clin North Am 14:669-687.

Viral Hepatitis; Laboratory Evaluation

MacPharson RA (1994). Laboratory diagnosis of human hepatitis viruses. J Clin Lab Anal 8:369-377.

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