70 Infectious Hepatitis

Hepatitis literally refers to any inflammation of the liver. Even when restricted by the term “infectious,” it has many causes, including malaria and many vi­ruses including that of yellow fever.

Even the distinction between infectious and non- infectious hepatitis is a problem. Autoimmune chronic active hepatitis will not be considered here, although there is evidence of viral involvement in triggering the autoimmune reaction. Liver cancer will be included as a late consequence of infection with hepatitis B virus, because that seems to be the main cause. Other clinically similar diseases that are not covered here are cirrhosis due to toxins such as alcohol, and jaundice due to physical obstruction of the bile duct.

History

Until the mid-1900s, hepatitis was frequently equated with jaundice, although jaundice is only a sign of a failure to clear normal breakdown products from the blood. Under this terminology, hepatitis and other liver diseases played a very important role in early medical writings, but it is difficult to deter­mine which references relate to hepatitis as we now know it, and which refer to the various other causes of jaundice. It is even more difficult to distinguish one type of hepatitis from another in the early refer­ences. Hippocrates identified at least four kinds of jaundice, one of which he considered epidemic and thus, by implication, infectious. Another was “au­tumnal hepatitis”; this condition, which appeared after an interval appropriate to the incubation pe­riod following the dry Mediterranean summer when water supplies would have shrunk, could have been hepatitis A.

Postclassical writers continued to have difficulty in distinguishing infectious forms from noninfectious forms of jaundice because of the long and variable incubation periods of the infectious diseases. Clear recognition of the infectivity of hepatitis is usually ascribed to Pope Zacarias (St. Zachary), who in the eighth century advocated a quarantine of cases. This had little effect on general thinking, however, be­cause of the variety of circumstances that were associ­ated with different outbreaks. Many cases seemed to be sporadic, but epidemics of what must have been hepatitis A, or enterically transmitted non-A, non-B, were known from the early seventeenth century to be common in troops under campaign conditions. An epi­demic Ofhepatitis B, associated with one lot of small­pox vaccine of human origin, was well described by A. Liirman in 1885. In spite of this, as late as 1908, the dominant medical opinion held that all hepatitis was due to obstruction of the bile duct. The picture did not really begin to clear until the middle of the twentieth century.

Hepatitis A

Etiology

Hepatitis A is caused by an RNA virus 27 nano­meters in diameter. It is very similar to poliovirus in general structure and also in its ability to spread through fecal contamination of food and water. The virus is very fastidious in its host range. It is known to infect only humans, apes, and marmosets, and it replicates in vitro only in a few primate cell lines.

Geography and Epidemiology

The virus of hepatitis A is essentially worldwide in its distribution, but it is very much commoner where drinking water is unsafe and sanitation inadequate. Like poliomyelitis, however, the prevalence of dis­ease is often inversely related to the prevalence of virus. In the less developed countries most people become immune through infection in childhood, of­ten with no apparent illness.

Clinical Manifestations

Hepatitis A is manifested by general malaise, loss of appetite, and often, jaundice. Definitive diagnosis of hepatitis requires the demonstration of elevated blood levels Ofbilirubin and of certain enzymes. Spe­cific diagnosis can be confirmed only by electron microscopic examination of the feces or, more practi­cally, by demonstration of specific antibodies. The disease is seldom fatal when uncomplicated by other conditions, and rarely leaves sequelae. Recovery nor­mally occurs in 4 to 8 weeks.

History

As noted above, although the existence of a hepatitis transmitted by conventional infectious routes could be inferred from the early literature, specific identifi­cation of hepatitis A was not accomplished until the late 1960s and 1970s. Then, the development of methods for recognizing hepatitis B, and Saul Krugman’s (1967) demonstration of two distinct agents in his studies of children in a home for the retarded, made its existence apparent. The agent of this disease remained enigmatic because it could not be propagated, except in humans. S. M. Feinstone, A. Z. Kapikian, and R. A. Purcell identified the virus in feces in 1973. F. W. Deinhardt and others showed in 1972 that the marmoset was susceptible. Finally, in 1979, P. J. Provost and M. R. Hilleman found a tissue culture line that could be used to grow the virus. An attenuated vaccine has been produced and successfully tested, but not marketed because of con­tinuing production problems.

Hepatitis B

Etiology

The cause of hepatitis B is a very unusual virus. Most important, it is unusually stable and can with­stand boiling temperatures and drying without inac­tivation.

Geography and Epidemiology

The stability of hepatitis B virus means that it can persist on any article that is contaminated with blood, most significantly, used needles and surgical instruments. In developed countries it has usually been transmitted in this way. Disposable needles, and tests to make certain that blood for transfusion is free of the virus, have reduced the incidence of this dis­ease in most of the population, but it continues to be a serious problem among intravenous drug abusers.

Hepatitis B can also be sexually transmitted. It is excreted in the semen and transmitted from male to female and from male to male in this way. Because the heterosexual transmission does not form a com­plete cycle, this has been less of a problem among heterosexuals than in the male homosexual commu­nities of Europe and North America.

The ability of the virus to remain infectious when dried means that it can persist on sharp stones and thorns along paths and, perhaps, also on the probos­cises of mosquitos. This provides a particularly im­portant mode of spread in primitive societies, where shoes are not worn and scant clothing is used. There, hepatitis B attains very high prevalence levels through gradual exposure over a lifetime.

The most serious pattern of hepatitis B infection is seen in South Asia and sub-Saharan Africa, where transmission from mother to child is common.

Clinical Manifestations and Prevention Infection with hepatitis B can have a variety of out­comes. It may be inapparent, or it may cause a dis­ease indistinguishable from that caused by hepatitis A. It may also, however, cause chronic active hepati­tis with or without cirrhosis. Any of these forms may lead to a chronic carrier state in which large quanti­ties of surface antigen, and sometimes infectious whole virus, circulate in the blood. This may damage the kidneys or, as described above, lead to cancer. Thus, although uncomplicated hepatitis B is not of­ten fatal in the acute phase, the total mortality that it causes can be great.

A good vaccine is available. It was proven effective in an extraordinary trial, published by Wolf Szmu- ness and others in 1980, which was carried out with the help of the New York male homosexual commu­nity. Thousands participated, either as vaccine re­cipients or as part of a placebo group. Because of the high homosexual transmission rate, the incidence of disease in the unvaccinated group was high enough to provide a good level of significance in the results. The first vaccine was produced by purifying hepati­tis B antigen from the blood of carriers. This method was efficient, and never proved unsafe, but it left open the possibility that some other disease might be transmitted with the vaccine. Bacterial clones have now been developed that carry the gene for the virus antigen, and the product of these clones has now replaced blood as a source of antigen in the United States.

It must be remembered that the vaccine only pre­vents infection. There is as yet no way to cure the disease or abort the carrier state. A person who becomes a carrier is likely to remain so for many years. This means that many people already infected are still doomed to liver cancer, and it emphasizes the need for vaccination of health workers who may be exposed frequently.

History

Although it had been clear for many years that blood products could transmit hepatitis, the full import of this fact did not register on the medical profession. Normal human serum continued to be used to pre­vent measles in children and to stabilize vaccines. In 1942, a new yellow fever vaccine, mixed with human serum, was administered to U.S. troops headed over­seas: Of those vaccinated, 28,000 developed hepati­tis, and many died.

The discovery of hepatitis B virus followed an un­usual course. In the early 1960s, Baruch Blumberg was studying blood groups in diverse populations and found a new antigen in the blood of Australian aborigines. Later, he found that one of his staff, who worked with the blood samples, had acquired the “Australia antigen,” and he recognized that it was infectious. Ultimately, it turned out that this anti­gen was the surface protein of the hepatitis B virus.

Hepatitis C

Etiology

The virus of hepatitis C has neither been seen nor cultured to the time of writing. However, in 1989, a 3,000-kiloDalton strand of RNA from the blood of an experimentally infected chimpanzee was transcribed into DNA by Qui-Lim Choo and his associates. Propa­gated into a bacterial clone, this DNA codes for an antigen that crossreacts with the agent of an impor­tant transfusion-transmitted hepatitis virus. The dis­coverers suggested that this “hepatitis C Virus” might be structurally similar to the virus of yellow fever or equine encephalitis. This implies that the virus genetic material was the original RNA strand, not DNA. Hepatitis C is inactivated by chloroform, showing that, unlike the viruses Ofhepatitis A or B, it has a lipid-containing envelope. The agent of some other transfusion-transmitted non-A, non-B hepati­tis is resistant to chloroform, indicating the existence of at least one more unidentified agent of this disease.

Geography and Epidemiology

Wherever hepatitis A and B have been distin­guished, a residuum of non-A, non-B cases have re­mained. Some of these cases are associated with blood transfusions, whereas others, as described be­low, are not. Hepatitis C is the most common transfusion-transmitted non-A, non-B in the United States, but its role in the rest of the world is un­known. Although it is important as a cause of posttransfusion hepatitis, this is not its main mode of transmission, and it is encountered sporadically in untransfused persons. Transmission by intrave­nous drug use is more frequent, and sexual transmis­sion seems also to occur.

Clinical Manifestations

Hepatitis C is a serious disease in that a high propor­tion of cases develop permanent liver damage. In spite of the paucity of our knowledge about this disease, it is almost unique among viral infections in being treatable. Alpha interferon results in dra­matic improvement of hepatitis C liver disease. Un­fortunately, the disease often recurs when treatment stops, and the treatment is both expensive and ac­companied by unpleasant side effects.

Hepatitis Associated with Delta Agent

Etiology

A fourth hepatitis virus, the delta agent, is unable to grow independently; it grows only in cells that are also infected with hepatitis B. Its defect is an inabil­ity to make coat protein, and it must, therefore, wrap itself in the surface protein of another virus to become infectious. As has been noted, hepatitis B produces large quantities of coat protein; in this way, delta can attain very high titers in the blood. Envel­opment in the other’s coat also gives delta the advan­tage of hepatitis B virus’s freedom from immune attack, and the fact that hepatitis B is commonly persistent in infected persons gives delta a reason­ably large field in which to forage. Like hepatitis A, but not B, delta virus has an RNA genome. It does produce one distinctive protein that permits sero­logic identification of the infection. Wrapped in the hepatitis B coat, it is intermediate in size between A and B, at 36 nanometers.

Geography and Epidemiology

Delta virus has been found in most countries of Eu­rope and North America as well as in much of the rest of the world. Its distribution, however, seems to be more spotty than that of the A or B virus. Al­though there is no evidence that delta shares the unusual stability of hepatitis B virus, they are often transmitted together by parenteral injection.

Clinical Manifestations

Infection with delta virus, which is always superim­posed on an underlying hepatitis B infection, has the highest acute fatality rate of all the hepatitides. Outbreaks of unusually severe hepatitis have often proven to have been caused by it. Otherwise, the symptoms caused by delta are not distinctive.

History

The antigen of delta virus was first recognized in Italy in 1977. Since that time, there has been a number of studies of its distribution and its molecu­lar characteristics. No vaccine is available as yet.

Enterically Transmitted Non-A, Non-B Hepatitis (ET-NANBH)

Etiology

ET-NANBH is a virus structurally similar to but immunologically distinct from hepatitis A. It has recently been associated with a number of previ­ously inexplicable hepatitis epidemics. As yet the virus has not been grown in culture, but it can be serially passed through monkeys and has been iden­tified by electron microscopy. Biochemical character­ization remains to be done.

Geography and Epidemiology

Most epidemics attributed to ET-NANBH have oc­curred in less developed countries at times when even the normally limited sanitation procedures have bro­ken down. Most of these have been in South Asia, but there have also been epidemics in the southern former Soviet Union, in refugee camps in Somaliland, and in Mexican villages, where water supplies be­came grossly contaminated. All ages are commonly affected, but there may actually be a preponderance of adult cases. These circumstances suggest that ET- NANBH virus is less infectious than hepatitis A and that, even in conditions of generally poor sanitation, most people remain only minimally susceptible.

Clinical Manifestations

ET-NANBH usually causes a hepatitis that is indis­tinguishable from that caused by hepatitis A or B. However, infected pregnant women have an unusu­ally high mortality rate, which may reach 20 percent.

History

A major epidemic of ET-NANBH occurred in New Delhi in 1955. The New Delhi sewage emptied into the Ganges River a little below the point of a water supply intake. In that year there was a drought, the river became low, and the sewage began to flow upstream. Alert water technicians recognized the problem and raised chlorination levels, so that there was no unusual outbreak of bacterial disease. How­ever, a month or so later, 68 percent of the exposed population developed jaundice, and more than 10 percent of the affected pregnant women died. Care­ful investigations were made at the time, but the cause of the epidemic remained undetermined until recently, when Daniel Bradley and his associates developed a test based on reactions (observed in the electron microscope) of immune sera and virus from feces of patients in a more recent Burmese epidemic.

Francis L. Black

Bibliography

Alter, Marion J., and R. F. Sampliner. 1989. Hepatitis C: And miles to go before we sleep. New England Journal OfMedicine 321: 1538-9.

Beasley, R. Palmer, et al. 1981. Hepatocellular carcinoma and hepatitis B virus, a prospective study of 27,707 men in Taiwan. Lancet 2: 1129-33.

Blumberg, Baruch S., et al. 1967. A serum antigen (Aus­tralia antigen) in Down’s syndrome, leukemia and hepatitis. Annals OfInternal Medicine 66: 924—31.

Bonino, Ferrucio, et al. 1984. Delta hepatitis agent: Struc­tural and antigenic properties of the delta-associated particle. Infection and Immunity 43: 1000—5.

Bradley, Daniel W., and James E. Maynard. 1986. Etiology and natural history of post-transfusion and enter- ically transmitted non-A, non-B hepatitis. Seminars in Liver Disease 6: 56—66.

Deinhardt, F. W., et al. 1972. Viral hepatitis in nonhuman primates. Canadian Medical Association Journal 106 (Supplement): 468—72.

Feinstone, S. M., A. Z. Kapikian, and R. A. Purcell. 1973. Hepatitis A: Detection by immune electron micros­copy of a viruslike antigen associated with acute ill­ness. Science 182: 1026-8.

Hadler, S. C., and H. S. Margolis. 1989. Viral hepatitis. In Viral infections of humans, ed. Alfred S. Evans. New York.

Hilleman, Maurice, R. 1984. Immunologic prevention of human hepatitis. Perspectives in Biology and Medi­cine 27: 54357.

Krugman, Saul. 1967. Infectious hepatitis: Evidence for two distinctive clinical, epidemiological and immuno­logical types of infection. Journal of the American Medical Association 200: 365-73.

Krugman, Saul, and Joan P. Giles. 1970. Viral hepatitis. Journal of the American Medical Association 212: 1019-29.

Lurman, A. 1885. Eine Icterusepidemie. Berliner klinische Wochenschrift 22: 20-3.

Murray, K. 1987. A molecular biologist’s view of viral hepatitis. Proceedings of the Royal Society of Medi­cine, Biology 230: 107-46.

Provost, P. J., and M. R. Hilleman. 1979. Propagation of human hepatitis A virus in cell culture in vitro. Pro­ceedings of the Society for Experimental Biology and Medicine. 160: 213-21.

Szmuness, Wolf, et al. 1980. Hepatitis B vaccine demon­stration of efficacy in a controlled clinical trial in a high risk population. New England Journal of Medi­cine 303: 833-41.

Vyas, Girish H., and Jay H. Hoofhagle, eds. 1984. Viral hepatitis and liver disease. Orlando.

Zuckerman, Arie J. 1975. Human viral hepatitis. Amster­dam.