- Hepatitis A: Old and New
The clinical features of viral hepatitis, once symptoms commence, are similar regardless of the specific hepatotrophic alphabet virus involved. Extrahepatic manifestations and complications may differ quantitatively, but qualitatively they also are common. There are unique aspects of clinical hepatitis A, however, because of the different patient populations in which the disease is observed. Thus, hepatitis A can be sporadic, endemic, or epidemic.
Sporadic Hepatitis A
Cockayne was the first observer to recognize that the sporadic form of the disease (at that time referred to as catarrhal jaundice) was identical to the epidemic form of the disease 46. He cites Rolleston 211 as thinking that the febrile cases of sporadic jaundice were the same as the epidemic cases, although few in number. In contrast, Cockayne pointed out that the geographic range, age, seasonal incidence, symptoms, physical signs, variable prevalence ("a peculiarity of all infectious diseases"), occurrence of prolonged jaundice, and relapses were comparable in the sporadic and epidemic cases. He concluded that "Sporadic and epidemic catarrhal jaundice are found somewhat in the same way as sporadic and epidemic poliomyelitis, except that jaundice is more common in the sporadic form and met with more often and over a wider area in the epidemic form."
Endemic Hepatitis A
The endemic form of the disease is more difficult to recognize because of the high incidence of asymptomatic and anicteric cases when the disease is acquired in early childhood. Passive transmission of maternal antibody protects the neonate, but protection wanes during infancy, and young children are ideal fecal-oral transmitters of infection. In the developing world, where sanitation is limited or absent, infection remains almost universal. In Egyptian children 1 to 3 years old, the seroprevalence rate was 100% 58, remaining at this level until age 67. Similarly, 2- to 4-year-old Nicaraguan children have a seroprevalence rate of 73% 194, and in Pune, India, virtually 100% of children are infected by late childhood 17. Immigrants and travelers from areas of low disease rates are therefore at high risk of infection when residing in countries where infection is endemic.
Cameron, who reported on epidemic hepatitis among British troops in Palestine during World War II, recognized the existence of endemic infection in the region 42. He wrote that "a large number of [indigent] children acquire the disease in a mild form and are immune for life, thus reducing the incidence in the adult native population. With each new immigration of settlers [from Germany, for example], a new non-immune child population is added, and this accounts for epidemics. ... The arrival of British troops represents another immigration."
The immunity of Indian and Maori troops to epidemic hepatitis during World War II and the relative incidence (10:1) in white and nonwhite American troops 266 can be explained by differences in childhood exposure rates. Similarly, the observation that officers in the British Army and flying personnel in the Royal Air Force had a fourfold-higher rate of infection than ordinary ranks and ground staff 266, a difference not seen in U.S. forces, is also understandable by differences in childhood exposure rates secondary to socioeconomic disparities.
Epidemic Hepatitis A
Long before the advent of serologic testing for hepatitis A and before the development of quantitative tests of hepatocellular necrosis, large series of epidemic jaundice cases were carefully observed and the manifestations were reported. Epidemics of jaundice from HAV (infectious hepatitis) usually commenced early in the fall and peaked in winter, waning then until the next yearly cycle started. This seasonal pattern is unexplained. The clinical picture was and is remarkably similar in all epidemics, with little change despite major differences in age and geography. The cases manifesting specific symptoms and signs in three series are shown in Tables 2 and 3. The cases in these epidemics varied in age as well as place of infection. Of 194 cases reported in Detroit between November 1937 and March 1938, only 27 involved persons more than 14 years old 173. In the military epidemics of World War II, the cases reflected the ages of the troops, with the majority ranging from 19 to 40 years old 102, 113.
Epidemic Hepatitis and War
Epidemics of jaundice are common in military medical history. Blumer reported that the first known epidemic in the United States was in conjunction with the War of 1812 33. In "The Medical and Surgical History of the War of the Rebellion" (the Civil War), Smart recorded 71,691 cases of jaundice in Federal troops 224. Details in the individual histories are consistent with infectious hepatitis (hepatitis A). The peak incidence occurred in the fall and winter of 1863, also suggestive of the seasonal occurrence of hepatitis A. Cockayne quoted different statistics: 22,569 cases of epidemic jaundice with 161 deaths among 2,218,599 Federal troops during the war between the North and the South (10% infection rate, 0.7% case fatality rate) 46. I have not found an original source for these latter statistics, but based on my assessment of Cockayne (from his published analysis of jaundice, which included 142 references), I consider that they are likely to be more accurate.
In World War I, British, French, and other Allied forces reported epidemics of jaundice starting in 1915 and continuing intermittently 14, 161, 262. The Mesopotamian epidemic is curious in that Indian and British troops were equally affected, and Willcox reported that there was little evidence of person-to-person contact 263. One possible explanation is that hepatitis E accounted for some or all of the cases. Hepatitis A is endemic in India, whereas hepatitis E is more often associated with large epidemics. Furthermore, in hepatitis E, there is less person-to-person spread. Purcell likewise suggests that at least some of the epidemics of hepatitis in Europe in past centuries may have been due to hepatitis E infection in that they predominantly affected young adults and fulminant hepatitis occurred in pregnant women 202. In two recent studies, there was cooccurrence of HAV and HEV as causes of acute hepatitis. Interestingly, in both reports, the hepatitis E cases occurred in the indigent or native population (Nepalese in one instance, Djibouti natives in the other), whereas hepatitis A was found in nonnatives (tourists in Nepal, French troops in Djibouti) 44, 52. The United States escaped most of the epidemics in World War I by late entry into the conflict. Paul and Gardner consider this one of the reasons for U.S. military unpreparedness for the impact of hepatitis epidemics on troops during World War II, since plans for dealing with infectious disease were developed based on experience in the previous war 188.
Campaign jaundice was of major military importance in World War II. Epidemics occurred in British troops in Palestine in 1940 to 1941 42 and in Allied forces in North Africa in 1942 to 1943 102, 113, 188, 266; every theater of military operations was affected by the end of hostilities 188. The large numbers of active servicemen involved are illustrated in the El Alamein campaign. At the peak of the epidemic in November 1942, the number of men hospitalized with jaundice (1,861 for the month) was only exceeded by those hospitalized with battle casualties (3,602). Overall, there were ~200,000 recognized cases of hepatitis in the U.S. Army alone 188, with a total in the millions likely in the combined Allied forces. In Germany, the situation was identical or even worse, with 190,000 cases in September 1941, 5 to 6 million cases in their armed forces over a 3-year period, and more than 10 million estimated military and civilian cases during the war 98.
The scientific thinking about hepatitis was further complicated in this era by the recognition of sporadic and epidemic forms of a long-incubation hepatitis (see above). Appreciating the military importance of the disease, the U.S. Army sponsored research that investigated experimental transmission of hepatitis, characterized the features of short-incubation and long-incubation disease, and examined prevention strategies 188. The success of the latter initiative is reported below, and some of the transmission and clinical studies are specifically referenced herein.
Common Clinical Features
After an incubation phase of 15 to 50 days (mean, 30 days), most infected persons developed nonspecific constitutional symptoms followed by gastrointestinal symptoms (Table 2). This preicteric or prodromal period averaged 5 to 7 days but varied in length from 1 day to more than 2 weeks 102, 113, 173. In approximately 15% of cases, however, there was no obvious prodrome before the appearance of jaundice. The findings resemble other viral prodromes and are indistinguishable from them. Less common manifestations than those tabulated included chills, myalgias and arthralgias, cough and upper respiratory symptoms, constipation, diarrhea, pruritus, and urticaria. The nonspecificity of symptoms is such that the diagnosis of an anicteric case of infectious hepatitis cannot be made with certainty unless modern testing is used. This is illustrated in a retrospective analysis of an outbreak of hepatitis affecting the Holy Cross football team in 1969. The epidemic was considered on clinical grounds to have involved almost all members of the team. However, when anti-HAV antibody was measured in stored sera, the attack rate was only 33% 85. Only the icteric cases were truly infected; all the supposedly anicteric cases were not. The Holy Cross outbreak is unusual in this regard. In other outbreaks of hepatitis A among adults, the percentage with jaundice varies between 40 and 70% 144, 214. One potential explanation for the finding of jaundice in 100% of true hepatitis A cases in the Holy Cross outbreak is that there are strain-related differences in disease severity; there is no supportive evidence for this explanation. Alternatively, another systemic infection may have occurred simultaneously with the hepatitis A. This explanation could account for not only the gastrointestinal symptoms in the non-HAV cases but also the increase in jaundiced cases if the additional infection were associated with an increase in bilirubin load (hemolysis) or another mechanism of interference with bilirubin transport or excretion.
The onset of the icteric phase is heralded by dark urine (conjugated bilirubinuria) before jaundice becomes apparent. The nonspecific and gastrointestinal symptoms often subside but may persist. The duration of jaundice is quite variable. In the Detroit series, the mean length was 7 days, with a range of 4 to >22 days 173. In contrast, the modal length reported by Havens was 20 to 29 days 102. Actual quantitation of bilirubin (in milligrams per deciliter rather than the earlier "icterus index") was not performed routinely until the 1950s, and consequently precise levels from the older epidemics are sparse. The maximum bilirubin in 60 patients from Havens' series was 10.8 mg/dl 102. In the series from the Rockefeller Institute Hospital in New York 113, the average was 6.7 mg/dl. Since all patients in these case series were icteric, they form a more homogeneous group than later series, in which infections could be identified by biochemical, serologic, or virologic means. Abnormal physical examination findings apart from jaundice occurred in approximately half the patients or fewer (Table 3).
Disease duration, not unexpectedly, varied with the duration of jaundice. In Detroit, the mean length was 15 days. This relatively short duration may reflect their younger age. In Havens' cases, hospitalization length averaged 30 days, ranging from 7 to 87 days. Patients recovered uneventfully; relapse and other complications were uncommon in most series. Three relapses among 200 patients were observed by Havens 102 although Hoagland and Shank reported retention of sulfobromophthalein, an organic anion transported like bilirubin, in 18.5% of cases after initial normalization 113, indicating a decrease in hepatic function during relapse. The military burden, however, was quite considerable because of the large numbers of men involved and the length of time before return to full duty.
Anicteric and Asymptomatic Hepatitis
The accurate diagnosis of anicteric hepatitis and recognition of the existence of asymptomatic hepatitis required the development of an objective measurement of hepatic injury as indirect evidence of acute hepatitis. In 1955, Wróblewski and LaDue reported their work on the release of GOT with liver injury 267. They measured SGOT activity in 10 patients with jaundice from parenterally transmitted hepatitis and in 5 patients with jaundice without any recognized parenteral risk factors. SGOT levels were elevated in all patients and returned to normal with recovery from the acute illness. Using measurement of SGOT, Krugman and colleagues demonstrated the existence of asymptomatic infection with HAV following ingestion of infectious material 140. Serum collected at the time of modest elevation of SGOT transmitted infection to additional recipients, demonstrating a temporal relationship between the elevated SGOT levels and infectivity. In addition, measurement of SGOT levels permitted the unequivocal detection of anicteric cases of both hepatitis A and hepatitis B 138.
Careful analysis of a food-borne outbreak of hepatitis A at a naval facility in San Diego demonstrated that 14% of patients were asymptomatic and that 30% were not jaundiced 214. This study used aminotransferase levels in case finding and also confirmed etiology by demonstrating rising titers of anti-HAV antibodies. Common symptoms and signs in this outbreak occurred less frequently than in the epidemics from the late 1930s and early 1940s but were qualitatively similar, with few exceptions (Tables 4 and 5). Arthralgias were noted in 10% and a rash in 14%, symptoms that are more often associated with acute hepatitis B. A recent review of 59 patients hospitalized in Pasadena, Calif., for sporadic hepatitis A between 1985 and 1994 reveals virtually identical findings (Table 6) 246. Arthralgias (19%) and rash (7%) were also observed in this cohort. Findings on physical examination were qualitatively similar for both epidemic and sporadic hepatitis A to those reported in earlier outbreaks.
The ratio of anicteric to icteric cases (1:3.5) in the San Diego epidemic likely reflects the ages of the individuals. In young children, the fraction of inapparent infections can be much higher. In an outbreak of hepatitis A in a religious community, where all diagnosed patients were under 20 years old, a limited household serosurvey detected IgM anti-HAV in 15 individuals, only 2 of whom developed jaundice, a ratio of 7.5:1 191. Clinically obvious disease, however, can occur even in infancy. In a series of six infants aged 2 weeks to 8 months reported by Linder et al., bilirubin levels were 5 to 12 mg/dl and the alkaline phosphatase was strikingly elevated (mean, 5.9-fold; range, 1.2 to 12.1-fold) 153. This may represent a cholestatic form of hepatitis A in infancy.
The attack rate in members of households exposed to infection is consistent with asymptomatic disease in young children 84. Thus, Ford observed that the rate of clinically apparent disease was much lower in children under 5 years of age (2 of 73 [3%] compared with 20 of 72 [28%] for 5- to 10-year-old children and 18 of 66 [27%] for 10- to 15-year-old children) despite apparently identical risks of infection. The low attack rate in adults (8 of 438 [2%]) almost certainly reflects immunity rather than inapparent infection 84. In 1937, Hugh Barber correctly predicted the natural history of hepatitis A infections based on his own observations and a review of the literature. He wrote, "If infective hepatic jaundice is due to a virus, which sets up acute hepatitis; if it is highly infectious in children, but well resisted by them; if most adults have acquired immunity, but those who become infected have a liver less capable of regeneration than the child, the natural history of epidemic and sporadic cases may be explained" 24.
Laboratory Investigations of Acute Hepatitis A
As with the clinical symptoms and signs, there are no pathognomonic findings in the laboratory investigations that distinguish HAV from other hepatotrophic viruses. The maximum elevation of alanine aminotransferase and aspartate aminotransferase can be substantially higher than that observed in acute hepatitis B, but there is a wide range. In general the degree of aminotransferase elevation roughly correlates with the severity of the acute hepatitis A in that asymptomatic cases have lower aminotransferase levels. The overall severity of the infection, however, is demonstrated by the bilirubin level as well as the prothrombin time. Most cases of hepatitis A have a bilirubin of 10 mg/dl in the absence of hemolysis, an indication that hepatitis A is usually not severe.
Relapsing, Prolonged, and Cholestatic Hepatitis A
Relapses in the course of hepatitis A occur in some patients 45, 46, 91, 102, 129, 240, 246. For example, Cockayne wrote that "Relapse may occur after it has completely disappeared ..." 46. However, the cases that he documents are difficult to distinguish from second infections with a different etiologic agent without the availability of specific diagnostic tests. Similar criticisms can be applied to most reports of relapse prior to the isolation of HAV and development of specific assays for the virus. Demonstration of HAV in stool during relapse 223 provides the best evidence of causality. The techniques of immune electron microscopy, RIA, and molecular hybridization were used, indicating that both protein and nucleic acid components of the virus were present and thus suggesting continued infectivity.
The rate of hepatitis A relapse varies: 3 of 200 (1.5%) in Havens' case series, 17 of 256 (6.6%) in Argentina, and 7 of 59 (11.9%) patients hospitalized in Pasadena, Calif., in the 10 years between 1985 and 1994 102, 223, 246. The severity of symptoms and biochemical abnormalities during the second phase are essentially the same as observed during the initial illness except for a tendency to greater cholestasis 91, 240. A relapse necessarily lengthens the course, and the overall duration of disease is similar to those with a prolonged (but not biphasic) illness 240.
In some individuals, the course of hepatitis A is unusually prolonged. Havens observed jaundice for up to 120 days (17 weeks) in his series, for example 102. Complete follow-up of almost all the cases in the San Diego naval outbreak revealed a prolonged course (abnormal aminotransferase levels after 14 weeks) in 11 of 130 cases (8.5%). Liver biopsies performed at that time demonstrated portal inflammation with piecemeal necrosis, periportal fibrosis, and lobular hepatitis. All biochemical abnormalities eventually resolved by 5 months. Since prolonged excretion of virus (i.e., viral nucleic acid detected by RT-PCR) may occur in patients with persistent elevation of alanine aminotransferase 269, any patient with either relapse or a prolonged course should be regarded as potentially infectious. Fatigue may persist after resolution of biochemical abnormalities in some patients. When patients were questioned up to 30 months postinfection, fatigue was more frequent in those hospitalized for hepatitis A or B than in those hospitalized with other infections 28. Most patients, however, recover completely in 6 months or less 246.
The occurrence of "cholangiolytic" or cholestatic variants of acute hepatitis A was described in 1984 95 after the advent of specific diagnostic testing that permitted identification of the etiologic agent. Previous accounts of this variant (reviewed in reference 95) did not have the benefit of such tests. Severe pruritus, diarrhea, weight loss, and malabsorption may accompany the cholestasis. Although resolution occurred in all patients, symptomatic relief was obtained with corticosteroids in some patients without untoward sequelae 95. However, the report of persistent aminotransferase elevation and viral excretion with progressive hepatic fibrosis in one patient treated with corticosteroids 166 is cautionary when considering treating what is otherwise a relatively benign variant.
Fulminant Hepatitis A
Like hepatitis B, delta hepatitis, and hepatitis E, hepatitis A can cause acute hepatic failure. Fulminant hepatitis A was diagnosed in 20 of 295 patients in a recent retrospective study of acute hepatic failure in the United States, less frequent than acetaminophen toxicity (60 of 295) and hepatitis B (30 of 295) 217. The fatality rate for hepatitis A is generally low, quoted as 115. Between 1983 and 1987, 381 deaths due to hepatitis A were reported to the CDC 147. With ~30,000 reported cases yearly, this gives an estimated fatality rate of 1.3%, likely a maximum rate because of relative underreporting of nonfatal disease. Fulminant disease occurs more frequently in adults than children 264 but can occur in childhood 62. The spontaneous recovery rate for patients with fulminant acute hepatitis A in the recent retrospective U.S. study, which included all age groups, was 35%, whereas it was 39% in a French pediatric population 62. Other patients may survive following liver transplantation 62, 217. Occasionally, hepatitis A infection recurs following transplantation 75, 86.
In the largest recent epidemic, in Shanghai, where 292,301 cases were reported between January and March 1988, there were 32 deaths 100, a minuscule fatality rate of 0.01%. In contrast, five deaths were associated with a large urban epidemic in Tennessee in 1994 and 1995. Of 256 patients hospitalized in Tennessee for severe disease, 3 developed classic fulminant hepatic failure, of whom 2 died. One patient with underlying chronic liver disease also died. Two cases of prolonged illness were classified as autoimmune hepatitis on the basis of positive antinuclear antibody (titer, >1:640) and liver biopsy samples consistent with that diagnosis. These patients also died. Factors that contributed to mortality in those with severe disease included age of >40 years (deaths of 3 of 53 hospitalized patients who were older than 40 years) and other comorbid conditions (e.g., chronic hepatitis C).
Chronic Liver Disease and Acute Hepatitis A
The risk of fulminant hepatitis is increased in patients with underlying chronic liver disease who develop acute viral hepatitis, regardless of etiology 133, and patients without prior exposure should be vaccinated 13. However, the report from Italy of an unexpectedly high rate of fulminant hepatitis A in patients with underlying chronic hepatitis C (7 of 17 [41%]) but not chronic hepatitis B (0 of 10) 253 has not been confirmed by other investigators 22, 108.
The classic teaching for many years has been that hepatitis A infection does not cause chronic liver disease and that there is no chronic carrier state. With the advent of highly sensitive assays for HAV detection, it has become clear that in rare patients, viral nucleic acids can be detected in stool for many weeks after the onset of infection, even when hepatic enzymes have returned to normal 269. Does this represent chronic infection or one end of the normal spectrum? One patient had HAV RNA in stool (by RT-PCR) 11 months after onset of illness, at which time he also had persistent aminotransferase elevation and detectable anti-HAV of the IgM class 126. A liver biopsy at that time showed portal inflammation and interface hepatitis. The patient developed esophageal varices at 25 months, and aminotransferase elevations and IgM anti-HAV were still present after 31 months. Although reported as chronic hepatitis A, it may represent two separate diseases, prolonged hepatitis A and a second, unidentified cause of chronic liver disease.
Similarly, a case report of chronic hepatitis A with persistent IgM class anti-HAV antibody and progressive liver disease 165 may represent observations that are true but unrelated. In the absence of chronic liver disease, low-level IgM anti-HAV can be detected up to 32 months after acute infection 220. Furthermore, the titer of IgM anti-HAV is normally such that early in the course of infection samples are diluted 1:4,000 before assaying to avoid a false-negative prozone effect. IgM class antibodies may therefore be detectable, albeit at a lower level, for many months as the titer gradually declines. Thus, it would seem that persistence of detectable IgM class anti-HAV antibody does not prove persistent infection.
Chronic liver disease can appear to follow acute hepatitis A but lack a direct etiologic relationship 120, 204, 252. The triggering of autoimmune hepatitis by HAV infection in two subjects was reported in 1991 in a prospective study of relatives of patients with autoimmune chronic active hepatitis 252. With the overwhelming advantage of a prospective evaluation and the observation of autoimmune hepatitis occurring in two study subjects, these data are difficult to refute. Similarly, when aminotransferase levels are normal before HAV infection and the illness is characterized as steroid-responsive liver disease that recurs on steroid withdrawal 204, the assumption that HAV infection is triggering or unmasking autoimmune hepatitis seems reasonable. However, when the diagnosis of autoimmune hepatitis is made in persons with concurrent HAV infection, it is quite problematic, since viral hepatitis is associated with antinuclear antibody positivity and the features on liver biopsy are sufficiently similar to preclude absolute diagnoses.
A variety of extrahepatic manifestations can be observed in patients with acute hepatitis A. In order of frequency, as seen in 256 patients hospitalized in Tennessee in 1994 to 1995, these include hemolysis (10 patients), acalculous cholecystitis (10 patients), acute renal failure (3 patients), and pleural or pericardial effusion, acute reactive arthritis, and pancreatitis (1 patient each) 264. Neurologic manifestations, although not reported in this particular series, may also be seen.
Hemolysis is precipitated by viral hepatitis, including hepatitis A, in patients with glucose-6-phosphate dehydrogenase deficiency 119, 219. In addition, red cell survival in the absence of an underlying red cell abnormality can be shortened by acute infectious hepatitis (presumptive hepatitis A) 132. Hemolysis may be autoimmune in nature, associated with antibodies to triosephosphate isomerase 208, 209, and can be severe 156, 244. Other hematologic abnormalities include aplastic anemia 73, autoimmune thrombocytopenic purpura 47, and pure red cell aplasia 221.
Acute cholecystitis and acute pancreatitis may complicate hepatitis A. The exact pathogenesis of acute cholecystitis is uncertain. In one patient, HAV antigen was detected in bile duct epithelium and the gallbladder wall, suggesting a direct effect of viral infection rather than a secondary phenomenon 176. Most cases of acute pancreatitis complicating viral hepatitis occur in fulminant hepatitis (reviewed in reference 61). Occasionally, however, pancreatitis may be encountered in nonfulminant disease 61, 264.
Occasionally, patients with HAV infection manifest symptoms consistent with circulating immune complex formation. These include cutaneous vasculitis, arthritis, and cryoglobulinemia 57, 122, 123. Either IgM or IgG anti-HAV is detected in the cryoglobulins 122, 123. The symptoms resolve spontaneously with resolution of the hepatitis A.
Interstitial nephritis 90, renal failure with proteinuria and hypocomplementemia suggesting immune complex disease 43, immune complex mesangial proliferative glomerulonephritis 164, 271, and acute tubular necrosis 76, 152 occur in the absence of fulminant hepatitis. The lack of severe liver disease precludes a missed diagnosis of hepatorenal syndrome. The exact mechanism(s) involved has not been defined. Immune complex formation may be an important etiologic factor.
Mononeuritis 193, mononeuritis multiplex 215, Guillain-Barré syndrome 239, postviral encephalitis 60, 243, and transverse myelitis 39 have been described in patients with acute hepatitis A. The etiology of these findings is uncertain; they may be caused by vasculitis.
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