PRACTITIONERS SECTION |
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| Year : 2003 | Volume
: 57
| Issue : 8 | Page : 363-8 |
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Viral hepatitis (Part-I).
DD Banker
Consultant Pathologist, Mumbai, India
Correspondence Address:
Consultant Pathologist, Mumbai, India
How to cite this article:
Banker D D. Viral hepatitis (Part-I). Indian J Med Sci 2003;57:363 |
| ¤ Historical | |  |
During the first half of 20th century viral etiology of hepatitis was established. Viral hepatitis causes a set of typical clinical biochemical and histological changes with or without icterus resulting from hepatic cell damage. It may be acute or chronic. It is a global disease of major public health importance. At a current estimate more than 300 million people worldwide suffer from viral hepatitis. Nearly 300 deaths per year attributed to fulminant acute disease and some 15,000 persons succumb each year to chronic liver disease. The acute form causes considerable morbidity and mortality and the chronic sequelae may play a havoc resulting in liver cirrhosis and hepatocellular carcinoma (HCC). Viral hepatitisis thus a major public health problem in all parts of the world. The disease has an enormous impact on health and national economy of many countries including India.[1],[2],[3]
At least five etiological agents alphabetically named A, B, C, D and E have definitely been recognized while putative agents F and G have also been described. Candidate virus F is no longer accepted as hepatotrophic. However it has been associated with some sporadic and parenteral acute cases and may give rise to fulminant hepatitis with liver failure requiring transplantation.[4],[6] Hepatitis G virus (HGV) is widely distributed among people who have received multiple transfusions and among IV drug abusers. It is also found in association with HBV and HCV.[5],[6],[7],[8] Recently TTV (Transfusion Transmitted Virus) and SEN virus have been incriminated with some cases of viral hepatitis.[9],[10],[11],[12],[13] Other viruses causing hepatitis are those of yellow fever, infectious mononucleosis, cytomegalovirus, parvovirus B 19, herpes simplex and rubella, the last two particularly in the newborn.[5],[13],[14] These are not considered to be 'hepatitis viruses' because the infection is not confined only to liver. Infectious mononucleosis also called glandular fever is due to Epstein-Barr virus, a member of herpes group. It is characterized by acute fever, sore throat, generalized lymphadenopathy splenomegaly and sometimes hepatitis. Epstein Barr (EB) virus causes rise in liver enzymes in almost all cases of acute infection, but it is uncommon for the liver injury to be sufficiently severe to cause jaundice. When jaundice does occur in EB virus infection it may be prolonged with a large cholestatic element. Diagnosis can be made by typical symptoms and specific serologic tests. Cytomegalovirus infection may also cause acute hepatitis. This is uncommon, rarely severe and runs a chronic course only in immuno-compromised patients. [5],[14]
Epidemic infective jaundice has been a major problem for centuries, particularly in military campaigns. It was long thought to be due to catarrhal inflammation of bile ducts. Its viral origin had been suspected in the 1930s but was not proved until during and after the Second World War by studies in human volunteers. The previous catarrhal jaundice was then named viral hepatitis A (HA). By then a second category of infective hepatitis was identified, particularly following serum administration and also in diabetic and venereal clinics. Initially termed homologous serum jaundice in 1943, it later became known as viral hepatitis B (HB). The causal role of inadequately sterilized syringes was first appreciated by British Scientist F. O. MacCallum in the same year. The next big forward step was the discovery in 1965 by Blumberg in USA of the so-called Australia Antigen, now known as hepatitis B surface antigen (HBsAg). It was a pure basic scientific study leading on to findings of major practical and clinical importance. An antigen found in the blood of an Australian aborigine being investigated for leukemia was found to be linked with hepatitis B but not with hepatitis A. this discovery was followed by electron-microscopic identification of viral particles in the blood of hepatitis patients by Bayer in 1968 in USA. At that time a third clinical category of non A- non B hepatitis was formed which included those cases where no cause could be detected. Research continued into epidemiological background of viral hepatitis and in successful transmission of virus into chimpangees. Vaccines against hepatitis B and later against hepatitis A were developed. Viruses C, D and E were identified which reduced the number of hepatitis cases of unknown etiology to only about 10 percent. Candidate viruses which are being investigated for this are F, G, SEN viruses and TTV, as stated earlier.
| ¤ Clinical Features | | |
Acute viral hepatitis is a systemic infection that predominantly affects liver. In most cases the virus does not damage hepatocytes, liver damage and subsequent clinical symptoms are generally due to host's response to infection. The clinical features of infection with various hepatitis viruses are similar and laboratory investigations are required to identify the responsible virus. From asymptomatic and subclinical infection, the symptoms may present anicteric form of disease, acute illness with jaundice, severe prolonged jaundice, subacute or chronic hepatitis and acute fulminant hepatitis. Besides chronic hepatitis, the sequelae include liver cirrhosis and primary hepatocellular carcinoma (HCC), particularly with hepatitis B, C, and D viruses.[5],[14],[15]
The chief serological manifestation in acute hepatitis is elevated level of the enzyme alanine aminotransferasse (ALT or formerly called SGTP). Sometimes the ALT activity may be 100 times normal. For specific diagnosis other serological markers are needed, as described below for each virus.
Acute hepatitis is defined as one in which clinical and biochemical abnormalities are present for up to 6 months. The viral infection produces severe inflammation of liver and in acute stage, symptoms include anorexia, nausea, vomiting, tremendous weakness and fatique, abdominal pain, mild fever, jaundice, dark urine and clay coloured stools. Signs include yellow discolouration of sclera, enlarged tender liver and often splenomegaly. Hepatitis A and E viruses are cleared from the body within 6 months, while B, C, and D may persist longer, leading to chronic hepatitis, liver cirrhosis and HCC. In the last 50 years liver biopsies and better epidemiological and virological methods have helped to establish the different types of liver diseases. Types A, B, and D can already be prevented by use of vaccines. Development of vaccines against types C and E will greatly improve preventive measures against these infections.[5],[7],[16]
| ¤ Pathological Features of Acute Viral Hepatitis | | |
Acute injury to liver shows similar morphology whatever may be the etiology. There is two-fold mechanism involved in causing damage
i) The virus may have direct cytopathogenic effect on liver parenchyma,
ii) Immunological attack on liver cells by cytotoxic T cells. Hepatomegaly is due to swelling of liver cells, portal tract expansion and infiltration by inflammatory cells. The three basic histological features are: hepatocellular injury, inflammatory cell infiltrate chiefly by mononuclear cells and hepatocyte regeneration. In mild cases there may only be focal necrosis of liver cells while in severe cases there may be widespread destruction of liver cells. Hepatocyte regeneration occurs early in infection and hyperplasia and hypertrophy are seen in surviving cells. The liver quickly recovers from the acute injury.[5],[14],[15]
| ¤ Hepatitis A (HA) | | |
This infection is present worldwide and is inversely proportional to the levels of environmental sanitation and personal hygiene. In developing countries like India where sanitation and hygiene are unsatisfactory specially among those belonging to lower socioeconomic group, nearly 100 per cent of the population is infected as shown by presence of antibodies in early life and manifest infection in adults is rare. In developed countries e.g. USA only about 40% of population have antibodies and are thus susceptible to HAV infection.[5],[14]
| ¤ Clinical Features | | |
HAV is classified under the genus Hepatovirus within the picornaviridae family. HAV produces liver cell damage by direct cytopathic effect. Many infections are silent especially in young children. Usually the course is mild. The incubation period is 14 to 42 days. HAV first multiplies in intestines and then enters liver where it causes necrosis. Viremia precedes clinical symptoms and during this incubation period feces and blood are potentially infectious. If jaundice is severe it may be accompanied by itching. Mortality in young adults is upto 1% but it increases with age. Death is due to fulminant hepatic necrosis. The important features of HA are:
i) Chronic hepatitis is rare
ii) Infection with HAV confers lifelong immunity. [5],[14],[15]
The HA infection formerly called infectious hepatitis is benign. Many children have a mild or subclinical infection without jaundice. The mortality rate in children is less than 0.1 percent, the disease is self-limited and does not become chronic. In developed countries the disease with jaundice may occur in young adults who lack immunity and who are not careful about food and water, when they travel to endemic areas. Only one serotype of HAV is known. HA viremia is relatively brief with maximal infectivity occurring prior to clinical symptoms. Severity of HA varies with age of the patient. Fulminant (i.e. sudden explosive) hepatitis is rare and also age dependent, occurring more frequently in older patients. The incidence also varies, being 0.1% in USA and about 4.0% in France. Mild to moderate tenderness over an enlarged liver can usually be detected. In about 80% of cases the duration of jaundice is less than two weeks. In the majority of adults the infection is cleared within 6 months. Relapse and prolonged cholestasis are rare. Normally HA is an acute infection and is not prolonged. However in rare cases superimposition of HAV infection on cirrhosis has bean observed.[5],[14],[15]
| ¤ Serology | | |
Serum alanine aminotransferase (ALT or SGPT) and asparate aminotransferase (AST or SGOT) rise rapidly during the prodromal period, whereas serum bilirubin levels reach their peak later and decline less rapidly than aminotransferases. Specific immunoglobulin M (IgM) antibodies appear during the acute phase and are present in high liter by the time jaundice appears. These decline after 6 months. During recovery IgG antibodies to HAV develop and persist indefinitely. The presence of anti-HAV IgG antibodies confers immunity to reinfection.[5],[14],[15]
| ¤ Treatment | | |
This is mainly symptomatic and the disease is usually self-limiting. During acute phase bed-rest is advisable. Diet should be light and nourishing. Oily and spicy food should be avoided. Plenty of glucose should be given by mouth or glucose-saline infusion to support the diseased liver. In severe cases ribavirin, an oral antiviral agent has been found beneficial in developing countries in a dose of 400 mg. three times a day.[15]
| ¤ Epidemiology | | |
HA is spread principally by feco-oral route due to contaminated food or water or from person to person. HAV survives for long periods in water and wet environment. Important factors in transmission of HAV infection are personal sanitation e.g. handwashing after visiting toilet, availability of clean drinking water and proper sewage disposal. Hence prevalence is high among developing countries, where 80% of the people have evidence of infection by the age of 20 years and 100% by the age of 50, compared to about 40% in developed countries. Large quantities of virus are excreted in feces for several days, before and after the onset of jaundice, but after one week of clinical illness the patient's stools may be considered non-infectious. Both endemic and epidemic forms occur; some of the latter have been traced to ingestion of infected shellfish. HA can be acquired by swimming in contaminated water. HA is the third most important foreign travel-associated infection after diarrhea and malaria. There is no evidence of vertical transmission from mother to child. Parenteral transmission of HAV may occur but it is rare due to the short period of viremia during the initial period of illness.[5],[14]
Outbreaks have occurred in day care centres. Nosocomial infections have been reported in nurseries as well as among adults in institutions. Post transfusion HA has developed in neonatal intensive care unit. HA may relapse and develop prolonged intrahepatic cholestasis. Superinfection on hepatic cirrhosis may also occur.[17],[18]
Several outbreaks have occurred due to consumption of raw oysters or improperly cooked clams obtained from sewage polluted waters. Sudden, large epidemics of HA usually result from fecal contamination of a single source such as drinking water, food or milk. The largest ever recorded outbreak of HAV infection occurred in Shanghai in 1988 involving 2,90,000 people and was traced to consumption of raw clams. Outbreaks by person to person spread commonly occur among families, institutions and troops. Very rarely HAV may be transmitted by the use of contaminated syringes, needles, clotting factor concentrates or blood transfusion because there is a short period of viremia in infected persons. However, transplacental transmission is not common in infected persons.[14]
| ¤ Prevention | | |
From consideration of epidemiology it is obvious that prevention of HA is primarily through sanitation. Clean water for drinking and cooking is essential. Waste disposal must be separate from water supply. Hand washing, boiling of water, thorough cooking of food and peeling of vegetables and fruits should be practiced HAV is inactivated by chlorination, ultraviolet radiation and boiling of water for 20 minutes. Stable and uncooked food should be avoided. Salad should be properly washed in running water before consumption. Segregation or isolation of patient from family member is not imperative, but soiled clothing & should be boiled and washed separately.[14],[19]
| ¤ Active Immunization | | |
HAV was propagated in cell culture in 1979 and molecular cloning of the genome was carried out in 1983. This enabled development of various types of vaccines in different countries. A single dose of inactivated vaccine generates protective antibodies that last for several years. A booster dose given between 6 and 12 months after the first dose extends the duration of protection by a decade or more. The two inactivated vaccines approved for use in the USA have been well tolerated. The most common adverse reaction reported is mild transient soreness at the site of injection. Immunization with inactivated HA vaccine is a safe and effective method for susceptible children, adults and travellers to endemic areas.[20] HA vaccine can be successfully combined with HB vaccine, specially for infant's.[21] Live attennated oral vaccine is also developed of which two doses are to be taken two weeks apart.
| ¤ Indications For HA Vaccines | | |
These are Children, institutionalized adults, travellers to endemic areas, prison inmates, asylums, military personnel certain ethnic groups with high rates of HA such as Native Americans, Native Alaskans, persons engaging in high risk sexual activity, IV drug users and those with occupational exposure like laboratory and health personnel. Future widespread immunization of children would reduce overall prevalence and ultimately help eradication of the disease, though at present this is not required in countries like India.[22]
| ¤ Passive Immunization | | |
Human immunoglobulin (Ig) prepared from large pools of normal adult plasma gives useful passive protection when administered within two weeks before or after exposure to HAV. The protection lasts for about 4 months, and could be used by travellers to endemic areas if active immunization is not possible. Ig may be given concomitantly with inactivated vaccine in persons requiring both immediate and long term protection, with care taken to use different limbs for injection to minimise interference by passive antibodies. In such patients a vaccine booster dose may be required sooner than usual.
| ¤ Diagnosis | | |
Acute infection is diagnosed by positive anti-HAV IgM in serum taken during the early illness. Antibody titres reach a peak within a few weeks of onset of symptoms and then rapidly decline in 6 to 12 months. Third generation radio-immunoassay (RIA) and enzyme-linked lmmunoassay (ELISA) are most commonly used. Established immunity to HAV or prior infection is determined by the presence of total antibodies (IgM + IgG) to HAV.
| ¤ Pediatric Infections of HA | | |
These account for more than one third of the recognized cases of HA. Children generally experience subclinical infection or a milder clinical course than adults and clinical manifestations may often go unnoticed. Once HA, infection sets in, treatment is similar to that described for adults, namely adequate bed rest, hydration and nutritional support.
| ¤ Pregnancy | | |
During pregnancy also HA infection is self-limiting and does not carry a different prognosis than that in non-pregnant patients. No teratogenic effects of acute HAV infection during pregnancy have been noted. Transmission to the neonate from an infected mother can occur by the usual feco-oral route during delivery and the postpartum period. Intrauterine transmission is, however, extremely rare. HA vaccine should be used during pregnancy only when clearly indicated. Newborn infants of HAV infected mothers whose symptoms first manifested between 2 weeks before and 9 weeks after delivery should receive specific HA immunoglobulin.
| ¤ References | | |
| 1. | Hollinger FB. Viral Hepatitis. Practice of Pediatrics 1979;1-2.  |
| 2. | Zuckerman AJ. The chronicle of viral hepatitis. Abstracts of Hygiene, 1979;54:1113-31. |
| 3. | Zuckerman AJ, Howard CR. The history of viral hepatitis in Hepatitis Viruses of Man. London: Academic Press; 1979. pp. 1-18. |
| 4. | Editorial. The A to F of viral hepatitis. Lancet 1990;336:1158-60. |
| 5. | Deodhare SG. General Pathology and Pathology of Systems. 6th edn. Mumbai: Popular Prakashan; 2002. pp. 1111-30. |
| 6. | Zuckerman AJ. Alphabet of hepatitis viruses. Lancet 1996;347:558-9. [PUBMED] |
| 7. | Editorial. Hepatitis G and F. Lancet 1996;347:558-9. |
| 8. | Chakravarti A, Berry N, Mittal N. Hepatitis G virus, Indian J Med Microbiol 1998;16:96-100. |
| 9. | Muller C. The hepatitis alphabet- hepatitis A-G and TTV Wien Chin Wochenschr 1999;111:461-8. [PUBMED] |
| 10. | Primi D, Sottini A. Identification and characterization of SEN virus, a family of novel DNA viruses, Antiviral Therapy, 2000;5(Suppl 1)G-7. |
| 11. | Umemura T, Yeo AET, Sottini et al. SEN virus infection and its relationship to transfusion associated hepatitis. Hepatology 2001;33:1303-11. |
| 12. | Forrester L, Zou S, Giullivi A. SEN virus and the rapid response surveillance system, Canada Communicable Dis Report, 2001;27 S3:1-4. |
| 13. | Shibata M, Wang RY, Yushiba M. et al. The presence of a newly identified infectious agent (SEN virus) in patients with liver disease and in blood donors in Japan. J Infect Dis 2001;184:400-4. |
| 14. | Banker DD. Modem Practice in Immunization. 4th edn. Mumbai: Universal Publishing Corporation; 1999. pp. 423. |
| 15. | Ryder SD, Beckingham IJ. Acute hepatitis. BMJ 2001;322:251-3. |
| 16. | Etienne MS, Melchior M, Cornu C. et al. Acute parvovirus B 19 infection associated with fulminant hepatitis of favourable prognosis in young children. Lancet 1998;352:1739-41. |
| 17. | Popper H. Progress in liver diseases. West Germany and New York: Falk Foundation ev; 1985. pp. 60. |
| 18. | Youno ssi Z, editor. Viral hepatitis guide for practicing physicians, Cleve Clin J Med 2000;67 (Suppl):SL3-48. |
| 19. | Feinstone SM. Hepatitis A epidemiology and prevention. Eur J Gastroentrol Hepatol 1996;8:300-5. [PUBMED] |
| 20. | Koff RS. Preventing hepatitis A infection in travelers to endemic areas, Amer J Trop Med Hyg 1995;53:586-90. [PUBMED] |
| 21. | Ramonet M, da Silveira TR, Melman ML, et al. A two-dose combined vaccine against hepatitis A and hepatitis B. in healthy children and adolescents compared to the corresponding monovalent vaccines, Arch Med Res 2002;33:67-73. |
| 22. | Batra Y, Bhatkal B, Ojha B, et al. Vaccination against HA virus may not be required for school children in northern India: results of a seroepidemiological survey. Bull. WHO 2002;80:728-31. [PUBMED] [FULLTEXT] |
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