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Indian Journal of Medical Sciences, Volume 57, Number 9, September 2003, pp. 415-424 VIRAL HEPATITIS (Part - II) D D Banker* Correspondence: D. D. Banker Consultant Pathologist, Mumbai, India. Accepted Date: 01-07-2003. Code Number: ms03026 Hepatitis B (HB) Hepatitis B virus HB was formerly called serum hepatitis. It occurs worldwide, more than 2000 million people having already been infected with HB virus (HBV). Sub clinical infection are common. An icteric infection is four times the icteric episode. Besides causing acute hepatitis the disease tends to chronic and often causes carrier state, subacute hepatitis, cirrhosis and primary hepatocellular carcinoma (HCC). HBV is an important cause of HCC, which is one of the commonest cancers in the world. Hundreds of thousands of persons die of this type of cancer each year. Hepatitis B infection accounts for 60 to 80% of primary liver cancer worldwide. HB is upto 100 times more infectious than HIV and HB is second only to tobacco as cause of major cancer in humans. The chance discovery of Australia antigen now known as HBsAg revolutionized the study and control of HBV infection. The pathological and clinical manifestation of HBV infection are a result of cellular and immune response of the host.1-5 HBV possesses three important antigens : one on surface is termed HBsAg, the other associated with envelope is HBeAg And the third present in the core is called HBcAg. HbsAg persists in the blood of chronic hepatitis cases and its determination reveals the carrier rate and thus the prevalence of the infection among a population. HBsAg is a complex antigen. Each particle contains a group _ specific antigen a, as also two pairs of subdeterminants d/y and w/r thus for phenotypes of HBsAg are known : adw,ayw,adr and ayr.6 In the year 2000, there were an estimated 5.2 million cases of HB infection and over 5,20,000 deaths due to hepatitis B related diseases, 4,70,000 from cirrhosis and cancer, and about 50,000 from acute hepatitis B. About one third of the world's population, around 2 billion people as stated earlier, are believed to have been infected with the virus at some time during their lifetime, many of them in developing countries. Primary liver cancer is the main cause of cancer deaths among men in Sub-Saharan Africa and much of Asia and an important cause of cancer deaths among women worldwide. Mother-to-child and child-to-child transmission accounts for the majority of infections and carriers. Although young children rarely develop the acute form of the disease, at least one in four of those infected before the age of seven will become long term carriers with no sign of illness until much later in life. The disease is also transmitted through the use of contaminated needles or other medical equipment, blood transfusion, unprotected sex, cultural practices which involves skin piercing such as tattooing and among injecting drug users. The `invisibility' of the chronic form of the disease is one of the reasons why the disease has been neglected for so long in developing countries. Today HB vaccine is one of the three priority vaccines which is made available cheaply to the poorest countries since 1997 through the Vaccine Fund. In 2002 developing countries eligible to buy this vaccine through UNICEF could get it for about us $ 0.35 (Rs.16/-) for a 10 dose vial. GSK (Glaxo Smith Kline) have now produced a pentavalent vaccine for infants containing DPT + Polio + HB which is being introduced in USA. By the end of 2001, 142 countries were using HB vaccine in routine immunization schedules. Over 40 of the least developed countries are currently being helped by the Vaccine Fund for the introduction of HB vaccine routine schedules. There are more than 350 million chronic carriers all over the world, most of them infected at birth or during childhood. Twenty-five per cent of the carriers develop chronic hepatitis. Many of these will prematurely die of chronic liver damage. In some countries such as China, Korea, Taiwan and in a few countries in Africa the carrier rate in 1990s used to be as high as 20 to 30 per cent but is now dropping with active immunization of newborn infants on a large scale. In India the carrier rate is a moderate 2 percent among the general population. In most of the developed countries the carrier rate is about one percent or less. Clinical Features The incubation period is 42 to 161 days. The clinical symptoms of acute are typical of viral hepatitis and include nausea, anorexia, fatigue and malaise followed by jaundice. Elevations in serum transaminase precede the onset of jaundice. Rarely patient with acute HB present with pancreatitis. Upto 30 percent of patients have raised amylase activity and autopsy examination in patients dying of fulminant HB shows histologic changes of the pancreatitis in upto 50%. Myocarditis, pericarditis, pleural effusion, arthritis, aplastic anemia, encephalitis and polyneuritis have all been reported in patients with hepatitis B. In common with other types of hepatitis myalgia, nausea, vomiting, fatigue and malaise, right upper abdominal pain, photophobia, headache, diarrhea and itching may also be present. Hepatomegaly occurs in about 10%, splenomegaly in 5%. A few cases of acute hepatitis develop a profound cholestatic illness. Leucopenia is common, anemia and thrombocytopenia occur in severe cases. In most of the adults, about 75%, HBV infection is subclinical. Approximately 10% of adults develop a chronic infection manifested by persistence of HBsAg in serum along with production of other viral antigens and HBV DNA. The risk of becoming a chronic carrier of HBsAg depends on i) the mode of acquisition of initial infection ii) age and iii) immune status of the patient at the time of infection. Children infected during the first few months of life almost invariably develop chronic infection. Patient with chronic HBV infection may be separated into those with high replication (detectable HBeAg and HBV _ DNA) and abnormal liver histology, those who are so-called "healthy carriers" with inactive carriers state who have normal or almost liver histology without symptoms of chronic liver disease, very low viral replication i.e. undetectable HBeAg and HBV DNA by hybridization method and normal liver blood tests.2,3 Healthy carriers rarely transmit the infection to others and usually do not have progressive liver disease. For those patients with high level of viral replication, chronic hepatitis with progression to liver failure, cirrhosis and HCC is common. Persistent necroinflammatory changes in liver markedly increase the risk of death. Patients with chronic hepatitis have fatigue as the leading symptom. Serology Transaminases may be elevated in the early period. After the onset of acute infection the first detectable virologic marker is the envelope protein surface antigen HBsAg, It persists indefinitely in chronic carriers, In most adult cases HBsAg becomes undetectable 1 to 2 months following the onset of jaundice, rarely persisting beyond 6 months, unless the disease becomes chronic. After HBsAg disappears antibody to HBsAg (anti HBs) appears in serum and persists indefinitely. There may be lag period (window period) between the disappearance of HBsAg and the appearance of antiHBs during which time patients with HBV infection may not be identified by routine serologic testing. The HBV core antigen HBcAg itself is sequestrated inside an HBsAg coat and is not usually detectable in the serum of HBV-infected patients. Anti HBcIgM, however, may be detectable and can be used to identify acute HBV infection during the silent window period. The infection can also be detected by polymerase chain reaction (PCR) for HB DNA. In acute HB the various serological markers appear in the following sequences a) HBsAg, b) HB DNA, c) HBeAg, d) HBc IgM and IgG, and e) antiHBs.7 Quantitative determination of HBsAg, particularly in a serial manner, assists in prognosis. It is highest in hemodialysis patients and lowest in blood donors. It disappears in fulminant hepatitis, even in the presence of IgM anti-core. Its visualization in liver speaks against acute hepatitis B but rather for an underlying chronic HB infection, with the acute episode often due to some other virus. Antibodies to surface antigen (anti HBs) are not significant, in serologic diagnosis and also in pathogenesis. They indicate HB vaccination and protection. Monoclonal antibodies to HBsAg are more sensitive and detect hidden HBV antigens. They provide "fingerprints" to many subdivisions of subtypes which allow identification of the specific variants in different geographic regions or in families and are useful in epidemiology. The e antigen is either free or IgG bound, the latter reflecting a less favourable prognosis; e and c antigens are coded by the same gene with e apparently being part of c. Determination of HBV DNA is important in certain circumstances, e.g. in needle stick injury it indicates infectivity. It is present in serum not only in acute and chronic liver disease but also in biopsy-proven asymptomatic HBsAg carriers and in a number of patients with HCC. Normally DNA parallels e antigen in serum. There are some cases where HBV DNA is found along with anti-e which may be associated with severe liver disease. The absence of HBV DNA along with c in liver and serum may reflect defective virus particle formation, Sometimes HBV DNA is present in serum in the absence of HBsAg or other serologic markers in serum or liver. This happens in alcoholics either because of impaired host immune response or variations in the expression of genes. HBV DNA has been demonstrated in saliva, urine and seminal fluid of e-antigen positive carriers, through the urine appears to contain relatively little, while its presence in integrated form in spermatozoa raises the possibility of a vertical transmission via the germ line.8 Hepatic HBV DNA By southern blot hybridization HBV DNA has been found in liver, free (episomal) and integrated into host chromosomal DNA and then presumably no more infectious.4 Epidemiology A quantity of blood as small as 0.05ml or of plasma as little as 0.0001ml is enough to transmit HBV infection. Transmission of HBV is chiefly parenteral through transfusion of virus infected blood or blood products such as fibrinogen or factor VIII or dialysis fluids, or by use of improperly sterilized syringes or needles as happens among drug addicts and in substandard medical clinics. The virus may also be spread by unsterile instruments used for tattooing, shaving or body piercing. Contact with blood may also lead to infection. HBV is highly infectious about 100 times more than HIV as stated earlier. Laboratory personnel and health care workers handling specimens from HB patients are particularly at risk and should follow safe practices including wearing of gloves and proper disposal/disinfection of all instruments.9 Another important route of transmission is close intimate contact which occurs during sexual intercourse specially with IV drug users. Body fluids such as saliva, semen and vaginal fluid contain the virus. Horizontal transmission occurs among infants and small children in some areas. Vertical transmission is also common among newborn infants born to HBV infected mothers, specially to those possessing the infective HBeAg, This occurs as perinatal infection during or soon after birth. HBsAg positive asymptomatic carrier mothers with anti HBe antibodies and HBeAg negative may transmit infection less frequently. As HBV normally does not cross placenta, transplacental transmission is rare. Shaving razors and common tooth brushes may also transmit HBV infection. Engorged mosquitoes and bedbugs may transmit the virus under suitable circumstances. Cases of hepatitis B usually occur sporadically. However an epidemic of icteric hepatitis in 1942 involving nearly 50,000 US army personnel was linked to specific lots of yellow fever vaccine stabilized with human serum. This was ultimately proved to be due to HBV, because screening in 1985 of 597 veterans who had been in the army showed presence of HBs antibodies (anti HBs) in 97 percent of the group. Infection occurs in young adults because of lifestyle or occupational exposure. Transfusion associated HB has become rare in developed countries where routine screening of blood is practiced.10 Geographic Distribution of HBsAg Surveillance of HBsAg gives the carrier rate. It varies according to regions. High prevalence areas (10-20%) are Sub-Saharan Africa, China, East Asia, South-east Asia and Pacific Islands. Medium prevalence areas (2 to 10%) are former USSR, Indian subcontinent Northern Africa, Southern Europe parts of South and Central America, and Japan. Low prevalence areas (less than 2%) are Australia, New Zealand, Canada, Western Europe, UK and USA.7 Prevention Preventive measures include improvement of life style, avoidance of multiple sex partners, and sexual exposure with known or suspected HBsAg carrier, rigorous testing of blood used for transfusion and of blood and organ donors, scrupulous cleaning and sterilization of piercing instruments, adoption of safe practice by laboratory and health care personnel and active immunization of all susceptible persons in high risk areas, professions and countries and of infants born to HBsAg positive mothers. HB must now be considered a preventable disease because it can be effectively eliminated by due care and active and passive immunization. The following rules should be observed for control of HB : a) Persons with a history of Jaundice must not donate blood or organ. Avoid professional donors. Active Immunization Vaccine against hepatitis B not only prevents acute and chronic hepatitis but also HCC and hepatitis delta virus (HDV) infection because HDV needs HBV for its replication. Immunity to HBV infection can be produced by injection of HBsAg alone. The priorities for immunization against HB are not the same for all geographical regions, countries or population groups. However the following indications are applicable for active immunization with HB vaccines. i) All persons residing in endemic areas, Perinatal Prevention Interruption in the chain of MV infections is particularly important in newborns of infected mothers, not only to protect the child but also to reduce horizontal and further vertical infection. The problem is particularly severe in the Far East, but this is being tackled for the last few years by large scale and regular HB vaccination of the susceptible subjects. Comparison between blood samples of mother and infant suggests that viral antigens or particles pass through the placenta perinatally giving sufficient time for preventive measures before infection occurs. In such cases immunoglobulin may also have to be used at the same time. In some areas in West Africa, however, most HBV infections occur in infancy rather than perinatally and in such cases Ig for vaccination is not required. Breast fed infants of positive mothers are at higher risk than formula fed ones. Vaccines i) Genetically engineered recombinant DNA vaccine is preferred in most parts of the world. In India several manufactures produce such vaccine. Among these are: a) Glaxo Smith Kline (GSK) where yeast Streptomyces cerevisae is used as the vector, The competition bas reduced the price from Rs. 300/- per dose a few years ago to Rs. 100/-. All the varieties are equally effective. Three doses of 1 ml each subcutaneously are required at 0, 1 and 6 months. Some clinical trials have shown that 0.1 ml. intradermally in three doses also produce good antibody response. The HB vaccine bas been successfully combined with DPT vaccine and with HA vaccine. ii) Plasma-Derived This vaccine is prepared from pooled plasma of hepatitis B carriers rich in HBsAg. This was the vaccine originally used for active immunization but now has been replaced by genetically engineered DNA vaccine. The advantages of plasma-derived vaccine are that it is easier to prepare and cheaper.11 Some developing countries still use this type of vaccine. Plasma-derived vaccine is no longer available in India. Adult Patients Some adult patients may have suboptimal response to vaccine e.g. hemodialysis patients, alcoholics, immunosuppressed patients, elderly and diabetics. These may require more frequent booster doses. Indications HB vaccine should be given to all those at high risk homosexuals, IV drug abusers, those having multiple sexual partners, patients in hemodialysis, those receiving multiple blood transfusions, newborn infants of infected mothers, medical and healthcare personnel and laboratory workers handling blood. Mass vaccination of infants and children in hyperendemic areas such as China and Taiwan has been effective in preventing them from becoming carriers. Contraindications to HB Vaccines These are hypersensitivity to any component of the vaccine, severe febrile infection and pregnancy. Passive Immunizations This is achieved by administration of hepatitis B immunoglobulin (HBIg). Indications are postexposure within 14 days to accidental needle stick injury, or mucosal contact or sexual contact with persons harbouring HBsAg and neonates born to carrier mothers. Specific HBIg is effective in a single dose of 0.06 ml/kg intramuscularly. If specific Ig is not available, normal Ig may be tried. In liver transplant cases in which HBIg is given intravenously. For passive immunization HBIg should be given within 48 to 72 hours after exposure for best results. Simultaneous Active and Passive Immunization This procedure may be used in newborn children of HBsAg positive mothers to prevent perinatal infection within 12 hours of birth. HBIg 0.5 ml is given in one limb and HB vaccine in another limb. The vaccine should be repeated 1 and 6 months later. This procedure may be required also for post-exposure prophylaxis within 2 weeks, for example in sexual exposure to HBsAg positive person and needle -stick injuries containing HBsAg positive blood. Combined HA and HB Vaccine This is now available and is highly effective. The adult dose is 1ml. ready for use containing 720 ELISA units of inactivated HAV, 20 Ug of HBsAg aluminium salt and neomycin. The course is of 3 injections at 0, 1 and 6 months in deltoid region. The protection is, expected to last about 15 years. Combined vaccine is indicated for those at high risk of both HAV and HBV infections which include health care workers, staff and residents of prisons and institutions, foreign travellers, IV drug abusers, and liver transplant patients. It is expected that HB with diphteria, pertussis and tetanus vaccine for use in infants and children will soon become available in many countries. Hepatitis G Hepatitis G virus (HGV) HGV also referred to as GBV-C) is a novel viral agent transmitted mainly through blood and blood products.12 It frequently occurs as a coinfection with HBV, HCV or other hepatitis viruses due to common modes of transmission. However the data presently available do not indicate a major role for this virus in causing liver disease. Prevention Prevention of HB and HD are both based on universal precautions adequate sanitation and disinfection of medical equipment and environmental surfaces. Because HDV replication is completely dependent on HBV help, HDV will be automatically prevented by effective HB vaccination. Diagnosis As stated earlier, diagnosis of viral hepatitis is a complex multistage procedure. Clinical symptomatology, serologic tests such as abnormalities in bilirubin, serum transamineses and presence of characteristic antibodies as well as histologic pathology of liver are to be considered in both acute and chronic hepatitis regardless of etiology. Quantitation of these markers often has prognostic and clinical value and many of these tests can be used to evaluate patient response to therapy.7,10,13 The traditional markers to be investigated are HBsAg and HBcAg. The serologic diagnosis of HBV infection is established by detecting either antibodies and /or their respective antigens, (i.e. HBsAg, anti HBs, HBcAg - anti HBc, and HBcAg - anti HBc). Either RIA or ELISA may be used for the serology. HBV DNA The presence of HBV DNA (the viral genome) indicates active viral replication. HBV DNA is assayed by polymerase chain reaction (PCR) methods, branched-chain DNA (b DNA) methods and by nucleic acid hybridization methods. PCR is more sensitive but b DNA and hybridization - based assays may provide more specificity. All of these methods detect HBV DNA in serum and are important in monitoring the effect of antiviral therapy on HB replication. It has been found that some HB Patients from endemic areas may be HBsAg positive, HBeAg negative but HBV-DNA positive. These so-called "precore mutants" are unable to secrete HBeAg but may have more aggressive disease. Chronic Hepatitis Some 10% of HB patients progress into chronic hepatitis, which is defined as viremia and Hepatic inflammation continuing more than 6 months following subclinical or clinical HBV infection. Persistence of ALT is characteristic of chronic hepatitis. The two basic histologic changes in chronic hepatitis are: chronic persistent hepatitis and chronic active hepatitis probably due to failure to develop immunity and also due to auto-immune mechanism. Chronic HB infection is the cause of 80% of primary HCC usually after a latent period of 10 to 30 years. Symptoms of chronic hepatitis include frequent bouts of ill-health, and fatigue pain in the liver area. Fatigue is a predominant symptom in chronic hepatitis. The patient would be a carrier and react positive with high ALT level and presence of HBsAg and or other markers. Reactivation of chronic hepatitis is relatively frequent and is associated with reappearance of serum markers of replication such as HBV DNA and e antigen. Some of these episodes are indistinguishable from acute hepatitis and there may also be superinfection by HAV, HCV or HDV. Age over 40, bilirubin level above 1.5 mg / dl and particularly ascites and spider nevi point to a grave prognosis. In chronic hepatitis in children, HBV DNA is cleared rapidly with aggressive evolution, but there is a subgroup in which even after six years replication markers persist. HBsAg carriers are particularly frequent in some countries of Africa and far East and among Eskimos.14,15 Fulminant Hepatic Failure (FHF) Or Acute Liver Failure Death in hepatitis is usually due to fulminant hepatic failure. It is a rare, devastating complication of acute viral hepatitis. As the term fulminant implies it is of explosive, sudden onset and very serious It is defined by development of hepatic encephalopathy occurring less than 8 weeks of symptoms or within 2 weeks afar onset of jaundice in a patient without pre-existing liver disease. The primary clinical features of acute liver failure are jaundice with raised bilirubin level and encephalopathy. Jaundice almost always precedes encephalopathy in acute liver failure. It is characterized by delayed coagulation due to lack of synthesis of liver derived factors and prolongation of prothrombin time. Usually the patient dies within 10 days in coma due to rapid destruction of infected hepatocytes by cytotoxic T cells. Hypoglycemia is seen only in fulminant liver disease and can be severe. Serum albumin is decreased. Prolonged prothrombia time in acute hepatitis, even if the patient is clinically well without signs of encephalopathy, should be regarded as sinister and the patient must be closely monitored. The risk of developing fulminant disease is low but there are groups with higher risks. The risk of development of liver failure in hepatitis A increases with age while fulminant hepatitis B is seen in adult infection and specially when there is co-infection or superinfection with hepatitis D virus. Pregnant women with hepatitis E are also at special risk, about 20% during the third trimester. The peak of alanine transaminase level does not corelate with the risk of developing liver failure. However the likelihood of progression to FHF varies according to the etiologic agent, e.g. acute HAV 0.1% HBV 1 to 2%. HBV + HDV 5 to 20%, HCV about 2% and HEV in pregnant woman 20% during the third trimester. Viral hepatitis remains the major cause of FHF worldwide. FHF can also occur in multiple virus infection, e.g. HBV with HDV, HAV and herpes. In about one third of cases of presumed viral FHF no specific agent can be identified. Recently parvovirus 19 has been reported to cause FHF in children. Once the diagnosis of FHF has been established by presence of encephalopathy, jaundice and coagulopathy such as disseminated intravascular coagulation (DIC), prognosis is extremely poor and survival is usually a matter of days or weeks only. Further clinical symptoms include multiorgan failure secondary to tissue hepoxia, endotoxemia, cytokine release and macrophage activation. Intensive care and support of hemodynamic, septic and cerebral complications are essential. Liver transplantation should be considered in patients with severe FHF. The early identifiction of patients unlikely to survive without liver transplantation is important. Survival rate is about 75% after transplantation. Treatment Acute Hepatitis B This infection is usually self-limited. Most patients will clear the virus completely. Sexual and close household contacts should receive active immunization. Patients should be monitored to ensure that fulminant liver failure does not develop. Serologic testing should be repeated 3 months after infection to check that the virus is cleared from blood. About 5 to 10 percent of patients will remain positive for HBsAg at 3 months and a smaller percentage will have ongoing viral replication indicated by positive e antigen or positive PCR DNA test. All such patients require close follow-up for development of chronic hepatitis. Chronic Hepatitis Treatment options at present include three drug classes: 1) Interferons, synthetically produced versions of the naturally occurring cytokine, Interferons Alfa-interferons are a family of naturally occurring proteins that are secreted by many mammalian cells. Of the 20 or more subtypes only 5 forms have been successfully evaluated and found to be effective in large controlled trials. There are interferon alfa 2b, interferon alfa 2a, interferon alfa n-3, alfa con-1 and alfa n-1. Interferons interfere with viral replication by an as yet unknown mechanism. In addition to antiviral activity they possess immunoregulatory and anti-inflammatory properties. The potency of most alfar interferon products is indirectly determined by measuring activity in biologic assays relative to an international reference standard expressed in million units (MU). In contrast the potency of interferon alfo con-1 is standardized in micrograms. Many alfa interferon treatment regimens for HB, HC and HD have been explored and the one to be used depends on physician's preference and experience. Long term sustained response rates for interferon monotherapy are disappointing and range from 15 to 45 % for HBV. A number of side effects have been described with alfa interferons. Common side effects include fever, myalgia, headache, fatigue and arthralgia which together are described as flu-like syndrome. A serious side effect may be neuropsychiatric complication such as depression including suicidal thoughts, irritablity and anxiety. Emergence of depressive symptoms appears to be related to duration and intensity of interferon therapy. The clinician should pay particular attention to changes in mood, behaviour and cognitive performance of patients during interferon therapy. Neuropsychiatric symptoms may or may not respond to drug withdrawal or dose adjustment but in refractory cases antidepressant therapy may be useful. Another major side effect commonly observed is suppression of bone marrow with resulting granulocytopenia, thrombocytopenia, anemia and alopecia. It is usually dose related. In about 5% of the cases auto-immune thyroid disease may be induced. Contraindications for interferon include hepatic decompensation, severe chromic obstructive pulmonary disease, severe myelosuppression, severe cardiovascular disease or pre-existing psychiatric disease such as major depression. For chronic HB combination of alfa interferon and lamivudine helps. References
Copyright 2003 - Indian Journal of Medical Sciences. |
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