British Medical Bulletin (1990) Vol. 46, No. 2, pp. 533-547 © The British Council 1990

Clinical presentation of acute viral hepatitis N Mclntyre Academic Department of Medicine, Royal Free Hospital School of Medicine, London, UK

Acute viral hepatitis may be asymptomatic, symptomatic but anicteric, or a classical icteric hepatitis; rarely it is very severe and may be fatal. Different types of illness may be caused by the various hepatitis viruses. This does not help precise diagnosis, which is based on serological tests. This paper describes hepatitis seen with the A, B, C, D and E viruses, and also some of the unusual complications which have been recognized. Serological tests allow precise diagnosis of acute hepatitis A and B, and should be used more widely, because viral hepatitis is often diagnosed when jaundice is caused by other conditions. They also allow diagnosis when viral hepatitis has an atypical presentation, and is thus not considered as the cause of the liver disease. Negative tests suggest the need for further investigation.

The term viral hepatitis is often used as if synonymous with infections caused by the A, B, C, D and E hepatitis viruses, although hepatitis also results from other viral infections, e.g. Epstein Barr or cytomegalovirus. 'Acute' hepatitis due to these viruses may be asymptomatic, symptomatic but anicteric, or it may take the form of classical icteric hepatitis; rarely there is a very severe illness with either a prolonged or fulminant course, both having a high mortality (see Fagan & Williams, this issue). Although the various hepatitis viruses tend to cause similar clinical pictures, there are differences which have only been clearly documented since the introduction of specific diagnostic tests for hepatitis A, B and D; further clarification of these differences is likely to result from the introduction of tests for hepatitis C and E. Differences in the clinical picture are of relatively little value for 0007-1420/90/0046-0533/810.00

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identification of the virus concerned, which is based mainly on the result of serological tests. However, it is important to recognize the different clinical pictures; otherwise, when the presentation is atypical, viral hepatitis may not even be considered in the differential diagnosis. ACUTE HEPATITIS A Hepatitis A is a common illness with a variable symptomatology. The average incubation period, to onset of symptoms, is about 32 days but ranges from 3-6 weeks. It may be possible to pin-point the date of infection in single source epidemics. The 'classical' picture of hepatitis A infection is an acute icteric illness seen in adults and children. The best studies on the symptomatology of hepatitis A have come from relatively recent studies on large scale outbreaks, in which the diagnosis of hepatitis A was confirmed serologically.1'2 Prodromal phase There is usually a prodromal period, lasting several days or more, before the appearance of dark urine or jaundice. Malaise (i.e. weakness, easy fatiguability, and/or tiredness) and anorexia are the commonest symptoms (occurring in well over 75% of patients). Anorexia is sometimes associated with a disturbance of taste, and less often of smell, with aversion to fried foods and meat,3 and to cigarettes (but this is not specific for acute hepatitis). Patients may admit to increased use of salt or sugar, and the taste thresholds for these substances can be elevated.4 Nausea usually follows and may be associated with vomiting, which is usually transient but can be severe. Many complain of epigastric or right upper quadrant discomfort or pain, which may persist for a week or two. Both diarrhoea and constipation are frequent complaints. Fever is common during the prodrome, but is rare in the icteric phase; rigors are uncommon but may occur. In one study about a quarter of patients complained of coryza, sore throat or cough.1 Headache is noted in from 20 to 60% of patients, and myalgia in a smaller proportion. Arthralgia, usually considered a feature of hepatitis B, has been noted in 10-30% of patients with hepatitis A1 (or non-B hepatitis5); it is commoner in older patients and tends to affect the larger joints. Transient exanthematous skin eruptions have been noted, and characterized as

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discrete erythematous, maculopapular, 'measles-like', petechial or urticarial.1 Tenderness in the right upper quadrant, by palpation or percussion, is found late in the prodrome in from 40 to 70% of patients, but hepatomegaly (found by palpation or percussion) was present in only about 14% in two large series; the spleen is palpable, transiently, in from 3-14%.1>2 Icteric phase The appearance of dark urine, due to the presence of bilirubin esters, heralds the icteric phase when the disease is usually recognized. With the onset of jaundice the stools tend to become pale. When jaundice appears most of the prodromal symptoms, including nausea and anorexia, improve rapidly; however, lethargy and tiredness may continue for weeks or months. In severe cases anorexia, nausea and vomiting persist and the weight loss of the prodromal period, due mainly to reduced food intake, may become marked. Mild pruritus is common, but is rarely a problem except in the cholestatic form of hepatitis A (see below). The serum bilirubin may occasionally rise to 400 or 500 |imol/l, but in icteric hepatitis A the median level is about 120 |imol/l. Jaundice usually lasts one to three weeks. At the onset bilirubinuria occurs before jaundice appears; during recovery, however, bilirubin may disappear from urine when serum bilirubin levels are as high as 170 |imol/litre (due to the presence of bili-alb). Before a reliable test for hepatitis A was available there was uncertainty about the frequency of asymptomatic and anicteric cases. In the Holy Cross outbreak there were thought to be twice as many non-icteric as icteric cases;6 however, later testing of the stored sera revealed that only the icteric cases were positive for HAV IgM Ab.7 In two American outbreaks jaundice occurred in 70 and 85% of adults with hepatitis A (proved serologically); in one, 14% of infected patients were asymptomatic,1 while no asymptomatic cases were found in the other outbreak.8 However, in a Chinese study many infections occurred without symptoms or biochemical abnormality (in children and adults) even though virus was isolated from the stool;9 in this study only 20—25% of patients had symptoms, and not all of these were jaundiced. The reasons for these different findings is not known. In acute hepatitis A aminotransferase levels rise sharply during the prodrome; the peak level, usually seen when bilirubinuria

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appears, is characteristically very high (more than 20 x the upper reference limit, i.e. more than 1000 units/1). This is of considerable diagnostic value; normal or low aminotransferase levels early in an illness virtually exclude acute hepatitis A. However levels tend to drop rapidly with the onset of jaundice; if several days elapse before blood is taken the aminotransferase levels may fall to levels which are of little diagnostic value. It is therefore important to take blood samples as early as possible when hepatitis is suspected. The serum alkaline phosphatase is usually either normal or moderately raised,10 but up to 40% of patients may have levels two and a half times the upper reference limit;11 higher levels occur in cholestatic cases (see below). The severity of the illness due to the hepatitis A virus is age related; older adults tend to have worse symptoms than young adults. In an epidemic in Greenland only 1% of children aged less than one year had a clinically recognizable infection, compared with 24% of the 15 year old children;12 similar results have been obtained in many other studies. When symptoms occur in children the prodrome tends to be shorter and milder; vomiting is more common, occurring in about 80%, and they are more likely to complain of abdominal pain.5 Jaundice is less common and tends to be of short duration. Cholestatic hepatitis A In about 5% of patients with hepatitis A infection the clinical picture is cholestatic; the usual clinical features are present but with marked pruritus. Jaundice tends to be deeper and much more prolonged, the alkaline phosphatase higher, and there may be a prolonged prothrombin time correctable by vitamin K.13 Prolonged and relapsing hepatitis A Most cases of acute hepatitis A resolve fairly rapidly over several weeks, with complete clinical and biochemical recovery, but malaise often persists for many months and may be accompanied by depression (often called the 'post-hepatitis syndrome'). In some cases there is a more prolonged, but gradual, return of aminotransferases to normal which usually occurs within 3 months,14 but may take as long as 12 months.15 Hepatitis A may relapse within a few weeks of apparent recovery, even after the aminotransferases have returned to normal;

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there may be return of symptoms and an increase in enzymes, with or without bilirubinuria and jaundice, or the relapse may be asymptomatic with just an increase in aminotransferases.14'16"18 Pruritus may be troublesome during relapses, which may take a cholestatic form.18 The aminotransferases may be higher during the relapse than in the initial phase (when the peak level may have been missed). The relapse tends to be more prolonged than the initial episode (which usually lasts 3-6 weeks), and full recovery may take up to 40 weeks.16"18 Hepatitis A virus RNA is found in the stool during relapses, indicating that hepatitis A rather than another virus is the cause of relapse.19 All patients eventually make a complete recovery from their hepatitis. Three cases have been described with a second relapse, which was asymptomatic but accompanied by very high aminotransferases.20 ACUTE HEPATITIS B In patients with acute hepatitis B the clinical picture is similar to that seen with hepatitis A. The incubation period varies from 4 weeks to 6 months from the time of exposure (but in most cases is from 60 to 110 days). The whole course of acute hepatitis B tends to be more insidious and prolonged than with hepatitis A. The initial symptoms develop less rapidly, and the prodrome is usually longer; in one large study it lasted for more than 16 days in 21 % of patients with hepatitis B, but in only 9% of B negative patients.5 Abdominal discomfort or pain also tends to last longer. Fever, vomiting and diarrhoea are unusual. Arthralgia is common in acute hepatitis A and B, but the duration is longer in hepatitis B. Arthritis, with redness, swelling or effusions, seems to occur only with hepatitis B, and may be a presenting feature causing diagnostic confusion.21'22 It usually appears early in the prodrome, and tends to clear over days or weeks, often before the onset of jaundice. The arthritis affects large joints, and also the small joints of the hands and feet. An erythematous or urticarial rash may precede the arthritis, suggesting a 'serum sickness'-like syndrome. Skin rashes without arthritis are also more common in hepatitis B than A, occurring in over a third of patients in one study.5 As in hepatitis A, symptoms tend to improve with the onset of jaundice. In the icteric phase the serum bilirubin tends to rise less steeply than in hepatitis A, but it reaches higher levels (median 195 umol/1), and jaundice, on average, lasts longer (median dura-

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tion—30 days for hepatitis B, 25 days for non-B hepatitis5), particularly in older patients.23 There is a slower rise in aminotransferase levels,23 which peak much later than in hepatitis A,5 so that relatively high levels are seen a week or two after the onset of jaundice. One problem in acute hepatitis B, not seen in hepatitis A, is that instead of resolving the disease may progress to chronic hepatitis and cirrhosis, with the persistence of HBsAg in serum. It appears that progression to chronic disease is less likely following a florid acute hepatitis. Patients infected with the hepatitis B virus may have an asymptomatic infection and, even in the absence of significant histological evidence of liver disease, can continue to carry HBsAg in the blood ('healthy carriers')- If acute hepatitis due to another virus (or a drug) occurs in such patients, or in those with mild HBsAg positive chronic active hepatitis, an erroneous diagnosis of hepatitis B may be made when the HBsAg is found. Absence of IgM anti-HBc antibody suggests another cause for the hepatitis. DELTA HEPATITIS (see also Monjardino & Saldanha, this issue) The clinical picture resulting from infection with the delta virus depends on the pre-existing hepatitis B status of the patient.24 In a previously healthy person co-infected with HBV and delta, synthesis of the delta virus is dependent on the continuing presence of HBsAntigen, and if the patient clears the hepatitis B infection the delta infection resolves. With co-infection the resulting illness may resemble an attack of acute hepatitis B, although there may a biphasic rise in aminotransferases. If it is a short attack there may be little expression of delta; although delta antigen may be found in the liver the IgM antiD response may be brief (and not detected), and cause no IgG response. If HBsAg production is high and prolonged, then delta synthesis is also increased and the patient may suffer a severe or fulminant illness; with severe necrosis the delta antigen may be released from liver and become detectable in serum. There appears to be a low incidence (about 2%) of chronic liver disease, and of HBsAg carriage, following coinfection. When there is delta superinfection in a 'healthy' carrier there may be a subclinical infection, or an acute hepatitis may result which is easily confused with hepatitis B because of the presence

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in blood of HBsAg. The correct diagnosis of the acute hepatitis is suggested if IgM-antiHBc is absent, and if anti-delta is present, but this requires a high index of suspicion on the part of the clinician. Diagnostic difficulty sometimes results because the delta infection may cause a transient disappearance of HBsAg, and in a small number of patients both the delta virus and HBsAg may disappear permanently. However, chronic active hepatitis develops in most cases of delta superinfection, and the patients become carriers of both HBsAg and delta. When superinfection occurs in an HBsAg positive patient who is already suffering from chronic hepatitis there is usually an exacerbation of the clinical picture, with an increase in bilirubin and aminotransferases. Delta infection should be suspected in patients from Mediterranean and Middle Eastern countries and parts of South America (it is rare in the Far East), and in patients from high risk groups (i.v. drug abusers, haemophiliacs and male homosexuals). Blood transfusion carries a risk of delta infection in HBsAg +ve patients. HEPATITIS C (see Choo et al., this issue) It was recognized over 20 years ago that anicteric hepatitis, detected by elevation of aminotransferases, was much more common after blood transfusion than icteric hepatitis.25'26 Posttransfusion hepatitis B is usually symptomatic, and jaundice appears in most cases. In non-B hepatitis, however, the symptoms are usually of moderate severity (lethargy, anorexia and occasional nausea) and many cases (40-75%) are asymptomatic.27 Jaundice is uncommon (about 10%) and usually mild. The incubation period to rise in aminotransferases is about 6-8 weeks. There may be a single peak of aminotransferases, followed by recovery, but in many cases these enzymes show marked fluctuation over many months, and levels may return to normal between the exacerbations. There is a high rate of progression to chronic hepatitis, and eventually to cirrhosis. Most cases of transfusion related hepatitis appear, on serological grounds, to be due to infection with hepatitis C virus.28-29 There have been similar clinical findings in other groups with a high incidence of parenterally transmitted non-A, non-B hepatitis (i.e. haemophiliacs receiving contaminated Factor VIII and Factor IX concentrates, intravenous drug abusers, and patients on

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haemodialysis), and again hepatitis C virus appears to be the major cause.30 Sporadic cases of hepatitis C also occur and are probably a major cause of 'cryptogenic' cirrhosis. Early identification of hepatitis C infection on clinical grounds is clearly difficult. A normal serum aminotransferase level does not rule out hepatitis C, because of the characteristic fluctuation in enzyme levels; alanine aminotransferase is more likely to be raised than aspartate aminotransferase. The recognition of hepatitis C infection is potentially important because it may clear with interferon therapy. HEPATITIS E (see Bradley, this issue) Water-borne epidemics of acute viral hepatitis, not due to the hepatitis A virus, have occurred in a number of developing countries. The agent responsible is now known as hepatitis E virus. The average incubation period is about 40 days. The highest attack rate is in those aged 15-39 years. The symptoms and signs are similar to those of hepatitis A, with anorexia, lethargy, nausea and vomiting, fever, myalgia, epigastric pain and jaundice, but the illness is generally milder and of shorter duration.31 Biochemical results are also similar to those found with hepatitis A. Cases of fulminant hepatitis are reported, especially in pregnant women in whom the mortality rate is from 10-20%. 32 In Western countries the disease may be seen in those who have recently arrived from places where the disease is endemic or epidemic.33 UNUSUAL COMPLICATIONS OF ACUTE VIRAL HEPATITIS In addition to the classical features of acute hepatitis, other problems may manifest themselves. These include neurological, haematological, dermatological, rheumatological (described above), renal, gastroenterological and cardiopulmonary abnormalities. Neurological The Guillain-Barre syndrome is a rare association with acute hepatitis due to both A and B viruses.34 In hepatitis A neuro-

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logical signs have appeared from 3 days to 2 weeks after headache, fatigue and myalgia signalled the onset of the prodromal period of hepatitis; recovery occurred within 2 or 3 months of the onset. In hepatitis B neurological signs occurred from 3 weeks before to 9 weeks after the onset of the hepatitis, with recovery between 2 and 6 months from onset. With both types of hepatitis there may be residual neurological signs such as facial nerve palsy, ataxia or areflexia. It is not clear whether the Guillain Barre syndrome occurs with the non-A, non-B forms of hepatitis. An aseptic meningitis, meningo-encephalomyelitis, or myelitis can accompany acute viral hepatitis.35'36 Mononeuritis multiplex is common in patients with polyarteritis nodosa who have HBsAg in serum; chronic hepatitis B is usually present. Mononeuritis of various nerves, cranial and peripheral, has been described in patients with acute hepatitis due to A and B viruses.37 It usually occurred from 4 to 21 days after the onset of jaundice, but in one patient with hepatitis B it appeared 40 days before jaundice. The course of the mononeuritis was protracted in most cases. Grand-mal seizures have been reported in 2 patients with acute hepatitis B. 34 Haematological A mild depression of haemoglobin, and white cell and platelet counts is common in patients with acute viral hepatitis, as in other viral infections; it is usually transient.38'39 Marrow aplasia is a rare complication of viral hepatitis, although viral hepatitis is a relatively common cause of aplastic anaemia,40 particularly in the Far East where hepatitis is more prevalent. It is primarily a disorder of younger persons with a median age in one series of 18 years.41 The pathogenesis is poorly understood and there is a high mortality rate. The aplasia usually affects all 3 cell lineages, but pure red cell aplasia,42 and agranulocytosis,43 have also been reported. Cases of aplastic anaemia have occurred following hepatitis A, 44 and hepatitis B, 45 ' 46 but most are a consequence of non-A, non-B infection.40'47-50 Marrow failure usually occurs 2-3 months after hepatitis, which is usually mild, but longer periods have been reported.40'47 A history of transfusion or drug abuse is uncommon, so parenteral

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transmission is an unlikely source of infection; this suggests sporadic non-A, non-B hepatitis as the usual cause. Hepatitis-associated aplastic anaemia recovers spontaneously in some patients. Allogeneic bone marrow transplantation is the treatment of choice in severely affected cases. Acute immune thrombocytopenia has been reported in association with hepatitis A.51>52 Widespread endothelial injury can cause platelet activation with consumption thrombocytopenia, renal failure, microangiopathic haemolytic anaemia and neurological manifestations; this constellation of abnormalities (haemolytic uraemic syndrome or thrombotic thrombocytic purpura) has been reported in association with hepatitis A.53>54 Transient erythrocytosis has been reported early in the course of infectious hepatitis.55 Haemolytic anaemia is common in children with G-6-PD deficiency who develop viral hepatitis.56 Dermatological Some of the dermatological findings in acute hepatitis have been described above. A number of rare dermatological complications of acute hepatitis B have also been described, including Raynaud's syndrome with infarction of the fingertips (occurring early in the prodrome),57 a dermatomyositis-like syndrome,58 and HenochSchonlein purpura,59 (which may also occur with hepatitis A). One distinctive manifestation of acute hepatitis B is the Giannotti-Crosti syndrome, or papular acrodermatitis of childhood. This is characterized by an erythematous papular rash on the face and limbs which clears completely in a few weeks. The accompanying hepatitis is usually anicteric and often asymptomatic; diagnosis rests on correct identification of the skin lesions.60 The syndrome may also be seen with other viral infections.61 Renal Proteinuria is common in acute viral hepatitis. More serious renal abnormalities are rare, except in fulminant hepatitis, but renal failure has been described in otherwise uncomplicated acute viral hepatitis.62'63 Membranous/mesangiocapillary glomerulonephritis, and renal lesions of 'essential' mixed cryoglobulinaemia and polyarteritis nodosa have been described in chronic hepatitis B.

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Gastroenterological Pancreatitis has been seen in fulminant viral hepatitis, and has also been described in a young boy with typical acute hepatitis A, which was confirmed serologically.64 As acute hepatitis is sometimes mistaken for gallstone disease it is worth noting that the gallbladder wall tends to thicken in acute viral hepatitis regardless of the causative agent.65 One dramatic complication of hepatitis B infection, acute and chronic, is a vasculitis closely resembling polyarteritis nodosa. This may affect the arteries to the gut and, rarely, causes mesenteric vascular occlusion with infarction and perforation of the intestine.66 Cardiopulmonary Cardiac complications including prolonged hypotension, progressive cardiomegaly, pulmonary oedema, arrhythmias (atrial fibrillation, ventricular ectopics), other ECG abnormalities and even sudden death have been described in acute viral hepatitis; the hepatitis in these cases is usually fulminant,67 and the heart disease may be due to myocarditis.68 Pericarditis with effusion69'70 has been described in patients who have recovered from acute hepatitis B. Pleural effusion has also been noted during the prodrome or in the early icteric phase of acute viral hepatitis,71'72 particularly in hepatitis B infection.73"75 CONCLUSION Serological tests now allow precise diagnosis of acute hepatitis A and B. It is important that the tests are used when these diagnoses are suspected; in general practice a diagnosis of viral hepatitis is often made when jaundice is caused by other conditions, because other diseases, particularly drug-induced hepatitis, can cause a similar clinical and biochemical picture. It is also sensible to test for hepatitis A and B when other diseases are suspected as the cause of liver disease, as hepatitis can mimic the illness caused by drugs, alcohol, gallstones or tumours. When the currently available hepatitis markers are negative, and the liver disease cannot obviously be explained by a drug, the patient should be referred for investigation as additional diagnostic procedures will be necessary to establish the cause.

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Liver Disease (Proceedings of an International Symposium). New York: Alan R Liss, 1988: p. 154 Shimitzu Y, Kitamoto O. Incidence of viral hepatitis after blood transfusions. Gastroenterology 1963; 44: 740-744 Hampers CL, Prager D, Senior JR. Post-transfusion anicteric hepatitis. N Engl J Med 1964; 271: 747-754 Alter HJ, Purcell RH, Holland PV, Feinstone SM, Morrow AG, Moritsugu Y. Clinical and serological analysis of transfusion-associated hepatitis. Lancet 1975; ii: 838-841 Kuo G, Choo Q-L, Alter HJ, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989; 244: 362-364 Van der Poel CL, Reesink HW, Lelie PN, et al. Anti-hepatitis C antibodies and non-A, non-B post-transfusion hepatitis in the Netherlands. Lancet 1989; ii: 297-298 Estaban JI, Esteban R, Viladomiu L, et al. Hepatitis C virus antibodies among risk groups in Spain. Lancet 1989; ii: 294-296 Molinie C, Saliou P, Roue R, et al. Acute epidemic non-A, non-B hepatitis: study of 38 cases in Chad. In: Zuckerman AJ, ed. Viral Hepatitis and Liver Disease (Proceedings of an International Symposium). New York: Alan R Liss, 1988: p. 154 Bradley DW, Krawczynski K, Cook EH, et al. Enterically transmitted non-A, non-B hepatitis: etiology of the disease and laboratory studies in non-human primates. In: Zuckerman AJ, ed. Viral Hepatitis and Liver Disease (Proceedings of an International Symposium). New York: Alan R Liss, 1988: p. 138 De Cock KM, Bradley DW, Sandford NL, Govindarajan S, Maynard JE, Redeker AG. Epidemic non-A, non-B hepatitis in patients from Pakistan. Ann Intern Med 1987; 106: 227-230 Tabor E. Guillain-Barre syndrome and other neurological syndromes in hepatitis A, B, and non-A, non-B. J Med Virol 1987; 21: 207-216 Apstein MD, Koff E, Koff RS. Neuropsychological dysfunction in acute viral hepatitis. Digestion 1979; 19: 349-358 Bromberg K, Newhall DN, Peter G. Hepatitis A and meningo-encephalomyelitis. J Am Med Assoc 1982; 247: 815 Pelletier G, Elghozi D, Trepo C, Laverdant C, Benhamou J-P. Mononeuritis in acute viral hepatitis. Digestion 1985; 32: 53-56 Firkin FC, Nicholls K, Wheln G. Transient myeloid and erythroid aplasia associated with infectious hepatitis. Br Med J 1978; 2: 1534 Vande-Stouwe RA, Attia AA, Karanas A, Ciavarella D, Grieco MH. Transient agranulocytosis associated with non-A non-B hepatitis. Gastroenterology 1983; 85: 186-189 Zeldis JB, Dienstag JL, Gale RP. Aplastic anaemia and non-A non-B hepatitis. Am J Med 1983; 74: 64-68 Ajlouni K, Doeblin TD. The syndrome of hepatitis and aplastic anaemia. Br J Haematol 1974; 27: 345-355 Iacopino P, Ronco F, Oliva A, Neri A. Pure red cell aplasia and acute viral hepatitis. Case report and review of the literature. Haematologica (Pavia) 1986; 71: 217-220 Nagaraju M, Weitzman S, Baumann G. Viral hepatitis and agranulocytosis. Digest Dis 1973; 18: 247-252 Domenech P, Palomeque A, Martinez-Gutierrez A, Vinolas N, Vela E, Jimenez R. Severe aplastic anaemia following hepatitis A. Acta Haematol (Basel) 1986; 76: 227-229 Kindmark CO, Sjolin J, Nordlinder H, et al. Aplastic anaemia in a case of hepatitis B with a high liter of hepatitis B antigen. Acta Med Scand 1984; 215: 89-92

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