Indian Journal of Medical Sciences Medknow Publications on behalf of Indian Journal of Medical Sciences Trust ISSN: 0019-5359 EISSN: 1998-3654 Vol. 57, Num. 11, 2003, pp. 511-517

Indian Journal of Medical Sciences, Volume 57, Number 11, November 2003, pp. 511-517

Practitioners Section

VIRAL HEPATITIS (Part - IV)

D D Banker

Correspondence: D. D. Banker Consultant Pathologist, Mumbai, India.

Accepted Date: 01-07-2003

Code Number: ms03042

Hepatitis D (HD)
HDV infection was discovered by Rizzetto, et al in Italy in 1977.¹ The HD virus was formerly called delta antigen or delta virus. It is found within certain HBsAg particles. Although closely associated with HBV it is distinct from the known antigens of HBV. In blood HDV is surrounded by an envelope of HBsAg. So far only one serotype of HDV is recognized all over the world.

Epidemiology
The epidemiology of HD closely parallels that of HBV, HD has infected more than 10 million people worldwide who are also infected with HBV, HD is endemic in many parts of the developing world, and is an important problem all over the world in terms of morbidity and mortality. HB and HD may also occur among homosexual men. Transmission of HDV is thought to occur by person-to-person contact where HDV is highly endemic, whereas it mainly occurs through parental exposure to blood or body fluids in areas of low endemicity such as many developed countries. Transmission of HDV may accur through

1. Direct percutaneous exposure to contaminated blood through the parenteral use of drugs or through blood and blood product transfusion,

2. Horizontal non-parenteral transmission of siblings, specially between household members who are HBsAg carriers,

3. Sexual contact,

4. Through open skin lessons, needlestick injury or environmental contamination. Perinatal transmission is uncommon.

HD associated hepatitis is generally more severe than HB alone. Persistent carriers of HBV are at high risk of acquiring HD in-infection (superinfection) and progressive liver disease.

Natural History
HD infection is found throughout the world with highest prevalence reported from Italy, West Asia, Africa and South America (the Amazon basin). It has also been reported from certain parts of India, including Mumbai.² Mode of transmission is similar to that of HBV, namely blood transfusion, hemodialysis injectable drug abuse and sexual intercourse. HD may also occur in explosive outbreaks involving localised pockets of HB carriers. HD may occur as coinfection along with HB or may give rise to superinfection on a pre-existing HB infection. HB vaccine, by preventing HB infection also provides protection against HD, because HDV needs presence of HBV for replication. However vaccination does not protect HB carriers from superinfection by HDV.

Clinical Features
In a study reported from Mumbai (Bombay) out of 331 cease of hepatitis B, 148 patients had also evidence of HD infection. Fulminant hepatitis developed in 39 patients, 32 of whom had hepatitis B and 20 (63%) also had HD. Patients infected with HDV are much more likely to develop fulminant hepatitis than in the case of other patients. Coinfection with HBV and HDV intensifies the symptoms of acute hepatitis and enhances the progress of chronic hepatitis.³

Diagnosis
This is carried out by detection of HDV antigen and antibodies by serologic tests such as ELISA and PCR (Polymerase chain reaction).¹

Pathology and Microbiology
HDV is found only in the cells of patients who are HBsAg positive. It is a viral parasite and cannot reproduce or infect in the absence of HBV. HDV causes liver injury by cytopathic mechanisms. HDV resides in hepatocytes, HDV genome is made up of RNA fragment and a delta protein antigen (HDAg) quite distinct from HBV genome. Presence of HDV carries increased risk of severe liver disease. In patients simultaneously co-infected with HBV and HDV, the disease is self-limiting in most cases with only 2% progressing to chronic infection. Fulminant hepatic failure (FHF) occurs in less than 10% of cases of co-infection. In HBV carriers subsequently superinfected with HDV the clinical course may be quite different. Approximately 80% of the cases result in chronic HDV carrier state, often with acute liver disease, FHF may occur in upto 20% cases of superinfection.

Since HDV is a defective virus and depends on HBV for replication, it occurs only in patients positive for HBsAg. HD usually occurs in intravenous drug abusers. In drug addicts anti-delta may occur without severe disease. Anti-delta in asymptomatic HBsAg carriers increases their risk of underlying liver disease four times.^4-6

Prevention
Active immunization against hepatitis B effectively prevents spread of HD.

Hepatitis E (HE)
HE like HA is an acute, resolving infection. It is caused by a small non-enveloped virus spread by the fecal-oral route. Waterborne epidemics have been described in the Indian subcontinent and elsewhere with subsequent exclusion of HA by serology. HE has a restricted geographical distribution. Clinically severe cases occur in young to middle-aged adults with unusually high mortality of about 20% in the third trimester of pregnancy.⁷

Epidemiology
The availability of a specific diagnostic assay enabled a retrospective confirmation of the fact that HEV was indeed the cause of hepatitis which occurred in Delhi after contamination of the city's water supply. Similarly, the HEV was the cause of epidemics in Kashmir Valley, India and the central Asian republics of the former USSR.^8.9

HEV was identified in 1983 by Balayan⁸ in Russia as an anti-genically distinct entity out of the group originally classified as NANB hepatitis. It may occur in sporadic form or in epidemic form, specially in developing countries where water supply may be contaminated by sewage or feces. It is mostly transmitted by feco-oral route, The latest outbreak to be reported from India and the largest so far recorded occurred in Kanpur affecting an estimated 79,091 persons. HE is endemic in a zone stretching from Morocco to Hong Kong and outbreaks have bean reported in Somalia, Ethiopia, Egypt, Pakistan, Myanmar (Burma), China, and Americas (central and south America). In central Mumbai a small epidemic of hepatitis occurred in a crowded housing society during 1996 Investigation revealed the cause to be HE due to contamination of water storage tank by fecal matter.^10-18

Clinical Features
Incubation period is 15 to 60 days. Clinical illness resembles other forms of acute viral hepatitis. Only acute forms are recognized. Asymptomatic and anicteric infections may occur in a significant number of cases. The incidence rate is highest among young adults. The mortality rate is usually low, about 0.1 to 0.6%.¹⁰

Viremia and virus shedding occurs in the pre-icteric phase and lasts upto 10 days into the clinical phase. There is no carrier state associated with HEV.^19-20

Pathology
The changes are typical of viral hepatitis. However, cholestasis is a predominant feature in 20 per cent of the patients. About half of the patients have distinctive morphological changes of cholestatic viral hepatitis. The changes include absence of diffuse lobular degeneration and inflammation, predominance of focal necrosis, marked intrahepatic and intracanalicular cholestasis with characteristic bile plugs in the lobules. HEV replicates in hepatocytes.¹¹

Laboratory Diagnosis
ELISA is available for detection of Ig and IgM antibodies against HEV. IgM is the marker of choice for diagnosis of acute disease. IgM anti HEV remains positive for upto 6 months. IgG may persist for several years. Transmission of HEV may sometimes also occur parenterally. Direct person to person transmission is rare. There is no active immunization available so far. When threatened by an outbreak of HE, passive immunization may be tried with normal human immunoglobulin.

Isolation of a swine virus resembling human HEV has raised the possibility that zoonotic HEV infection may occur in areas where animal hosts are abundant, including some pig-farming regions of USA. Travellers to regions where HE is endemic may acquire HEV infection.

Prevention
The same sanitary and hygienic measures as for prevention of HA should be followed. Water for drinking and washing should be pure and food should be well cooked. Water storage tanks should be periodically inspected for any dirt or filth and treated with hypochlorite as required to stop an epidemic.

Other Contender Viruses
There are still about 10% of the cases suspected to be viral hepatitis which may be considered non A to non E. During the 1990s viruses F and G and transfusion transmitted virus (TTV) were described but they have not been accepted as true hepatotrophic viruses. However, recently SEN virus has been described which is claimed to be genuine and is under investigation in many parts of the world.

SPECIAL ISSUES

Role of Liver Biopsy in Viral Hepatitis
Infection with three viruses namely HBV, HCV and HDV of the currently recognized hepatitis viruses is associated with progress to chronic liver disease. Liver biopsy has an important role in management of patients with chronic hepatitis. It confirms the diagnosis, mainly for HBV to exclude another diagnosis, but its important role is to determine the degree of liver disease- fibrosis or cirrhosis- which has crucial prognostic significance. The risk of major complication from liver biopsy is less than 1 in 1000. Since the pathologic biopsy features of HC are nonspecific, liver biopsy is not important to establish the diagnosis of HC.

Histologic Scoring
Ranging from milder forms, previously labelled chronic persistent or chronic lobular hepatitis, to the more severe form, formerely labelled chronic active hepatitis, a composite classification scheme has been developed combining clinical, serologic and histologic variables with demonstrated prognostic significance. The classification is based on etiology (viral, toxic, autoimmune, cryptogenic), histologic activity or grade (degree of inflammation and necrosis) and the stage (degree of fibrosis) of liver disease. In the case of HB, HC and HD confirmation of cirrhosis is not only important in assessing the potential for development of liver failure but also in the risk of development of HCC.

Role of Liver Transplantation for Viral Hepatitis
Both HB and HC are important causes of liver failure requiring liver transplantation. It is estimated that HB accounts for about 5% and HC about 20% of all transplant cases in developed countries. The probability of HB recurrence after liver transplantation is very high without therapy. HBIg improves short term survival. In HB the role of nucleoside therapy is being evaluated and lamivudine therapy has given promising results. In patients with chronic HC, post-transplantation recurrence of viremia is almost universal. Although usually mild, aggressive and progressive hepatitis with cirrhosis occurs in approximately 10% of the patients. Combination therapy with interferon alpha-2b and ribavirin may help.

Screening for Hepatocellular Carcinoma (HCC)
The risk of this complication is less for those who have been successfully treated. The screening procedure commonly employed for all patients with HB and in cirrhotic patients with HB as also in cirrhotic patients with HC is alpha-feto-protein (AFP) estimation in serum and liver ultrasound every 6 to 12 months.

Treatment of Chronic Hepatitis
Three hepatitis virus infections HB, HC and HD may progress to chronic hepatitis. For HB, treatment should be carried out with interferon alpha-2b and lamivudine. For patients with decompensated cirrhosis and HB, lamusidine is the drug of choice. In chronic HC interferon and ribavirin combination is helpful. Antantidine non-steroidal anti-inflammatory drugs, quinoline etc. have also been tried. In chronic HD, the mainstay is interferon though relapses are common.

Management Issues in Pregnancy and Birth
The clinical findings and histologic changes of hepatitis in pregnant and nonpregnant patients are the same, except in HEV infection in which maternal and fetal mortality rates are considerably increased in the third trimester of pregnancy. The management rests mostly on prevention. HBV cases in infants usually occur during the first year due to vertical transmission from infected mothers. Vertical transmission rate in viremic mothers can be as high as 90%. HCV can be transmitted perinatally, parenterally and sexually. History of IV drug use is the most common risk factor in HCV infection in pregnancy. The rate of cholestasis in pregnant women is higher in anti-HCV positive compared with anti-HCV negative women. All children born to women who are infected with HCV should be screened for HCV. In the case of HD, although perinatal transmission does occur it is rare. In developing countries HEV infection is common and in pregnancy high fatality rate upto 20% may occur in the third trimester of pregnancy as stated above. Although intrafamilial spread of HEV appears to be negligible, vertical transmission of HEV can occur at high rates with significant perinatal morbidity and mortality.

Management of Hemodialysis Patients
Patients on chronic dialysis are at increased risk for acquisition of HB, HC, or HD, through parenteral or nosocomial routes of transmission. Routine use of HB vaccine can reduce the risk of HB as well as HD by as much as 70%. Lack of response in hemodialysis patients can be overcome by increasing the vaccine dose. HCV outbreaks have also occurred in plamapheresis centres, and should be prevented by adequate sterilization techniques.

Transplantation Recipients
Transplantation from an HBsAg positive or HCV positive donor must be avoided. In bone marrow transplantation, abnormal ALT levels in donors are a predictor of potentially lethal liver complications in HBsAg positive patients. Likewise anti-HBc positive donors should not be used for liver transplantation even if HBsAg negative. But they may be considered for nonhepatic transplants. Liver transplantation into an HBsAg positive patient is performed for end-stage liver failure secondary to HBV infection. These transplants are carried out with intermittent HBIg prophylaxis which is costly but effective. Immunosuppression and interferon treatment may be required. In HCV positive recipient, along with transplantation interferonribavirin combination therapy should be simultaneously carried out to avoid graft rejection. All potential transplant recipients should be vaccinated against HAV and HBV before transplant. All donors for solid organs, bone marrow and even of bone ligament and tendon allografts should be tested for presence of HBsAg and HCV infection.

Immunocompromised Patients
The therapeutic effect of most immunosuppressive agents is nonspecific and therefore often result in an increased risk of infection by viral, bacterial or fungal organisms as well as an increased incident of malignant neoplasms. Repeated HB vaccine would be required because immunity may not easily develop. HCV infection progresses faster in immunocompromised patients and cases with hypoglobulinemia have a potential for cholestatic course and poor prognosis. However, early treatment with high doses of alpha interferon may help clear HCV.

Managing Hepatitis Patients with HIV
Liver disease is a common cause of admission and death in HIV patients, specially if they are infected with HCV. The problem is great in hemophiliac, thalassemic and IV drug users who may be co-infected with HIV, HBV, HCV, and HDV and also with multiple genotypes of HCV. Concomitant HIV infection may alter the course of HBV and HCV infection and viceversa through effect of one virus on the replication and immunopathology of the other. In co-infected patients, a low CDU T-cell count, high alcohol consumption rate, and increased age at the time of acquisition of HCV infection are associated with a higher rate progression to liver fibrosis. HBV infection, either active or prior is particularly frequent in HIV positive IV drug users. In the era of highly active Antiretroviral therapy (HAART) an upgrading of immune function may theoretically increase liver damage due to immunopathology from HBV or HCV. Lamivudine in antiretroviral combinations would have an impact on HBV against which it is effective. Response to HBV vaccine is suboptimal (30 to 40%) in HIV infected patients with immune dysfunction but it should still be given. In patients chronically infected with HCV co-infection with HIV may be associated with increased HCV viremia. The frequency of HCV transmission to sexual partners is 5 times higher when HIV is also transmitted. Infants of mothers with an HCV and HIV co-infection or with a high HCV-RNA titre are at high risk of HCV infection and about 80% of them may progress to chronic infection. Caution should be exercised before discontinuation of lamivudine in patients with concomitant HBV and HIV. All patients of hepatitis with suggestive history should be tested for presence of HIV and so also all HIV positive patients he shacked for HBV HCV and HDV markers.

Alcohol and Viral Hepatitis
Alcoholic liver disease is increasing in developing countries. Oxygen supply to liver is reduced in alcoholic liver disease. Alcohol has adverse effect on chronic HB or HC. The three independent factors associated with increased progression are age more than 40 years, alcohol consumption more than 50 g/day and male sex. Alcohol has direct hepatotoxic effects and leads to higher levels of viremia. Patients with viral hepatitis should be counseled against intake of alcohol.

Autoimmune Hepatitis
It differs from systemic lupus erythematosus by the absence of antibodies to double stranded DNA, which is observed in rare drug induced liver injuries. Autoimmune chronic hepatitis is frequent in postmenopausal women. The cellular infiltrate in liver is mainly T lymphocytes with predominance of helper cells. It may rarely progress to HCC.

Portal Cirrhosis
Large regenerative modules may form which resemble HCC even on ultrasonography (usg), encouraging surgical exploration. Alterations of DNA content of hepatocytes determined by microspectrophotography suggest high risk of malignant transformation. In cirrhosis in young adults, adolescent onset of alcoholism and heroin addiction should be suspected.

Hepatocellular Carcinoma (HCC)
In HCC there are three stages - initiation, promotion and progression. In initiation chemical carcinogens may play a part. Clinically important HCC markers are alphafetoprotein (AFP), carcino-embryonic antigen (CEA) and ferritin which shows increase on histopathology.

REFERENCES

1. Hadziyannis SJ. Review: hepatitis delta. J Gastroentero Hepatol 1997;12:289-98.

2. Mehta SH, Cox A, Hoover DR, et al. Protection against persistence of hepatitis C. Lancet 2002;359:1478-83.

3. Govindrajan S, Chin KP, Redkar AG, Peter RL. Fulminant B viral hepatitis. Role of delta agent. Gastroenterol 1984;84:1417-20.

4. Govindrajan S, Valinluck B, Peter RL. Relapse of acute B viral hepatitis, role of delta agent. GUT 1986;27:19-27.

5. Cassidy EM, Govindrajan S, Gupta S, Valinluck B, Redkar AG. Influence of HIV on chronic hepatitis B & D infection, Hepatology 1989;10:690.

6. Khuroo MS. Study of an epidemic of non-A non-B hepatitis. Possibility of another human hepatitis virus distinct from post-transfusion non-A non-B type. Amer J Med 1980;68:818-24.

7. Balayan MS., Andzhaparidze AG, Savinskaya, et al. Evidence for a virus in non-A non-B hepatitis transmitted via the fecal oral route. Intervirology 1983;20:23-31.

8. Ramalingaswami V, Purcell RH. Waterborne Non-A non-B hepatitis. Lancet 1988;1:570-3.

9. Krawczynski K. Hepatitis E. Hepatology 1993;17:932-41.

10. Vishwanathan R. Infectious hepatitis in Delhi (1955-56). A critical study; epidemiology. Indian J Med Res 1997;45(Supp 1):1-29.

11. Khuroo MS. Hepatitis E. Enterically transmitted non-A non-B hepatitis, Gastroenterology 1991;10:96-100.

12. Naik SR, Aggarwal R, Salunke PN, et al. A large waterborne viral hepatitis E epidemic in Kanpur, India. Bull, WHO. 1992;70:597-604.

13. Shah SR. Community based prospective study of hepatitis E virus infection, in A Review of Scientific Performance 1974 to 2002. Mumbai: Sir HN Medical research Society; pp. 72.

14. Bradley DW. Hepatitis E: Epidemiology, etiology and molecular biology. Rev Med Viral 1992;2: 19-28.

15. Arankalle VA, Chadha MS, Banerjee K, Sreenivasan MA, Chobe LP. Hepatitis E: virus infection in pregnant rhesus monkey. India J Med Res 1993;97:4-8.

16. Khuroo MS, Rustgi VK, Dawson GJ, et al. Spectrum of hepatitis E virus infection in India. J Med Virolo 1994;43:281-6.

17. Aggrawal R, Naik SR. Hepatitis E: intrafamilial transmission versus water-borne spread. J Hepatol 1994;21:718-23.

18. Nanda SK, Yalcinkya K, Panigrahi AK, et al. Etiological role of hepatitis E virus in sporadic fulminant hepatitis. J Med Viral 1994;42:133-7.

19. Aggrawal R, Naik SR. Epidemiology of hepatitis E, past, present and future. Trop Gastroenterol 1997;18:49-56.

20. Aggrawal R, Naik SR. Hepatitis E: epidemiology, Gastroenterology today 1999;3:92-8.

Copyright 2003 - Indian Journal of Medical Sciences.