Atypical clinical manifestations of hepatitis A E u g e n e R. S c h i f f
Viral A hepatitis is a self-limited infection occurring predominantly among children usually as an anicteric often subclinical illness. Adults afflicted with this virus are more likeh' to develop icteric hepatitis. This is exemplified in developed countries when a common source outbreak occurs among non-immune adults. Fulminant hepatitis is uncommon in the USA and hepatitis A has never been documented to evolve into chronic hepatitis. However, prolonged cholestasis and relapsing hepatitis are well described. The usual features o f cholestatic viral hepatitis A are pruritus,fever, diarrhoea, and weight loss. Serum bilirubin levels are > 10 mg/dl and the clinical course lasts at least 12 weeks. Cholestasis will spontaneously resolve, although corticosteroids will hasten the resolution but may predispose the patient to develop a relapse o f the hepatitis. A biphasic or relapsing form o f viral hepatitis A occurs in 6 to 10% o f cases. The initial episode lasts 3 to 5 weeks and is followed by a period o f remission characterized by normal liver chemistries lasting 4 to 5 weeks. Relapse may mimic the initial episode o f the acute hepatitis. The full duration o f the illness ranges from 16 to 40 weeks from the onset and immunoglobulin M antibody to hepatitis A virus persists throughout the clinical course. Hepatitis A virus has been recovered from stools during the relapse. Extrahepatic manifestations o f hepatitis A include evanescent skin rash and transient arthralgias. Doeumented cases o f arthritis and cutaneous vasculitis have been associated with cryoglobulinaemia and are rare. Keywords: Hepatitis A; clinical manifestation;cholestasis: relapse: extrahepatic;autoimmune
INTRODUCTION There are at least four well established atypical clinical manifestations of hepatitis A: cholestasis, relapse, extrahepatic and autoimmune trigger. Prolonged intrahepatic cholestasis associated with viral hepatitis has been recognized for > 50 years and was formerly termed 'cholangitic' or 'cholangiolitic' hepatitis ~. CHOLESTASIS Gordon et al. documented six cases of acute cholestatic hepatitis A with serological evidence of immunoglobulin M antibodies to hepatitis A virus (IgM anti-HAV) 2. All of these patients had a serum bilirubin > 10 mg/dl and the duration of jaundice exceeded 12 weeks. This is in contrast to the mean peak serum bilirubin of 10 mg/dl and mean duration of jaundice of ~ 4 weeks noted by Rozen et al. in their study of 347 patients with uncomplicated acute icteric hepatitis 3. After an initial aminotransferase peak early in the course of acute hepatitis, these cholestatic patients characteristically had aminotransferDivision of Hepatology, University of Miami School of Medicine and Veterans Administration Medical Center, Center for Liver Diseases, 1500 N.W. 12th Ave., Suite 1101, Miami, FL 33136, USA
$18
Vaccine, Vol. 10, Suppl. 1, 1992
ase levels < 500 IU/1. There was no evidence ofhaemolysis or renal failure, both of which would have enhanced the hyperbilirubinaemia in any of these six patients. The liver biopsies typically showed marked centrilobular cholestasis with some portal inflammation. The latter histological finding could suggest the appearance of chronic hepatitis which never evolves in hepatitis A. Sciot et al. evaluated the clinical, biochemical and histological characteristics of 13 cases of acute hepatitis A 4. Moderate to severe cholestasis consisting of bile thrombi, cholestatic liver cell rosettes and ductular transformation of hepatocytes was noted in 10 of these patients. These authors postulated that periportal spotty necrosis may play a role in the pathogenesis of the cholestasis by interrupting the continuity of bile flow. In six of the cases, abnormal ductular epithelium was seen resembling the ductular lesions found in septicaemia. Teixeira et al. reviewed the liver biopsies from 17 patients with acute viral hepatitis A and also noted severe centrilobular cholestasis in five of these patients 5. These authors also observed periportal inflammatory reactions which resemble that seen in chronic active hepatitis. The infiltrate was rich in plasma cells. They point out that these lesions may lead to a false impression of impending chronicity which does not occur in type A hepatitis. Fortunately these patients recover completely, although corticosteroid therapy would hasten the resolu0264-410X/92/100S18-03 ~ 1992Butterworth-HeinemannLtd
Atypical clinical manifestations of hepatitis A: E. R. Schiff
tion of the cholestasis 6. A standard regimen utilizes prednisone in a dose of 40 mg/day gradually tapered over, at least, a 4-week period. The serum bilirubin characteristically drops by at least 40% after 4 days of therapy. If corticosteroids are rapidly tapered off, a relapse of the cholestasis may develop. Unfortunately, patients with cholestatic hepatitis serologically proven to be secondary to hepatitis A are often subjected to expensive and invasive evaluations in search of mechanical obstruction. There is frustration, both among physicians and patients, as jaundice and pruritus persist. A favourable response to corticosteroids can quickly resolve this problem. Liver biopsy is unnecessary as are direct forms of cholangiography in the management of most cases. A normal abdominal ultrasound study in the deeply icteric patient should be reassuring. RELAPSE A biphasic or relapsing form of viral hepatitis A occurs in 6-10% of cases 7.8. At times, this may be polyphasic. After an initial episode of typical acute hepatitis, lasting 3-5 weeks, a remission lasting 4-15 weeks follows. The remission is often characterized by normal aminotransferases. Relapse may mimic the initial episode of acute hepatitis and either be less severe or more severe than the initial episode. Typically, aminotransferase levels are > 1000 IU/1 during the relapse. The full duration of the illness lasts from 16-40 weeks and, characteristically, there is a persistence of IgM anti-HAV positivity throughout the entire course. HAV has been recovered from stools during the relapse and HAV RNA has been detected in the serum during the relapse 7.9. Typically, detectable virus in the stool will quickly disappear usually within 30 days of the onset of the illness. More recently, polymerase chain reaction methodology has detected a persistence of HAV RNA for months, but it is not known whether these patients are still infectious. Regardless of this, during the relapse phase viral particles have been detected in the stool by immunoelectron microscopy, molecular hybridization and radioimmunoassay by Sjogren et al 7. They studied seven patients among 17 who relapsed out of 246 patients with acute hepatitis A. The pathogenesis of the relapse is not clear but is undoubtedly immunologically mediated. In the cases reported, there has usually been an absence of an epidemiological suspicion for non-A, non-B or type C hepatitis infection. The prognosis is good and chronic hepatitis does not evolve. EXTRAHEPATIC Extrahepatic manifestations, most often secondary to immune complex disease, are relatively common among patients with hepatitis B. They include urticarial and other cutaneous eruptions and arthritis during acute hepatitis, and polyarteritis and membranous glomerulonephritis associated with chronic hepatitis B. However, extrahepatic manifestations of hepatitis A are relatively rare, although there have been several reports of leucoclastic cutaneous vasculitis and arthritis ~ ~2. Typically in acute hepatitis A, up to 14% of patients have an evanescent rash and up to 1 ! % have arthralgias, both of which are transient u. When the illness becomes protracted however, either as a result of cholestasis or of relapse,
extrahepatic manifestations may be seen. Cutaneous vasculitis appears as an erythematous maculopapular eruption often affecting the lower extremities and buttocks and typically also associated with purpuric lesions. Skin biopsy has demonstrated immune complex phenomena with the presence of IgM anti-HAV and complement in the blood vessel walls. The arthritis also has a predilection for the lower extremities. Both may be associated with cryoglobulinaemia. The cryoglobulin has been demonstrated to contain IgM anti-HAV. Spontaneous resolution occurs, presumably as a result of viral clearance. AUTOIMMUNE
TRIGGER
Finally, a newly recognized atypical manifestation of hepatitis A is the triggering of chronic active autoimmune hepatitis of the type-1 variety. Vento et aL described 13 patients with chronic active autoimmune type1 hepatitis 14. Ten of these 13 patients had serological evidence of hepatitis A in the past. All 13 patients had antibodies to asialoglycoprotein and all had defects in Tcell suppressor-inducer cells that control immune response to these asialoglycoprotein receptors. Fifty-eight first and second degree relatives of these 13 index cases were followed prospectively over 4 years. Fourteen of these relatives had the T-cell suppressor-inducer defect and none had serological evidence of previous hepatitis A infection. However, 38% of the total group of 58 relatives did have serological evidence of a prior infection with hepatitis A. During the prospective follow-up, three subclinical cases of acute hepatitis A developed. Two of these cases were among the 14 patients with the T-cell suppressor-inducer defect for controlling antibodies to asialoglycoprotein receptors. All three patients developed antibodies to asialoglycoprotein receptors, but the two with the T-cell suppressor-inducer defect evolved into clinically apparent icteric autoimmune hepatitis, requiring long-term corticosteroid therapy for control. CONCLUSION Atypical manifestations of hepatitis A include: cholestasis where a rapid serological diagnosis will avoid an unnecessary expensive and invasive evaluation for obstructive jaundice; relapsing hepatitis where there is reappearance of hepatitis A in serum and in stool rendering the patient again potentially infectious; extrahepatic manifestations of leucoclastic cutaneous vasculitis, arthritis and cryoglobulinaemia which are probably related to immune complex phenomena; and finally the triggering of some cases of chronic active autoimmune hepatitis type-l among genetically predisposed individuals. REFERENCES 1 Koff, R.S. Viral hepatitis. In: Diseases of the Liver (Eds Schiff, L. and Schiff, E.R.) 7th Edn, Lippincott, Philadelphia, (in press) 2 Gordon, S.C., Reddy, K.R., Schiff, L. and Schiff, E.R. Prolonged intrahepatic cholestasis secondary to acute hepatitis A. Ann. Intern. Med. 1984, 101,635--637 3 Rozen, P., Kern, R.J. and Zimmerman, H.J. Computer analysis of liver function tests and their interrelation in 347 cases of viral hepatitis. Israel J. Med. Sci. 1970, 6, 67-79 4 Sciot, R., Vandamme, B. and Desmet, V.J. Cholestatic features in hepatitis A. J. Hepatol. 1986, 3, 172-181 5 Teixeira, M.R., Weller, IN.D, Murray, A., Bamber, H.C., Sherlock, T.S.
Vaccine, Vol. 10, Suppl. 1, 1992
$19
A t y p i c a l clinical m a n i f e s t a t i o n s o f hepatitis A. E. R. S c h i f f
6 7 8 9 10
S20
and Scheuer, P.J. The pathology of hepatitis in man. Liver 1982,2, 5360 Williams, R. and Billing, B.H. Action of steroid therapy in jaundice. Lancet 1961, 2, 392-396 Sjogren, M.H., Tanno, H., Fay, O., Sileoni, S., Cohen, D., Burke, D.S. and Feighny, R.J. Hepatitis A virus in stool during clinical relapse. Ann. Intern. Med. 1987, 106, 221-226 Cobden, I. and James. O.F.W. A biphasic illness associated with acute hepatitis A virus infection. J. HepatoL 1986, 2, 19-23 Glikson, M., Galun, E., Oren, R., Tur-Kaspa, R. and Shouval, D. Relapsing hepatitis A: review of 14 cases and literature survey. Medicine 1992, 71, 14-23 Ilan, Y., Hillman, M., Oren, R., Zlotogorski., A. and Shouval, D. Vasculitis and cryoglobulinemia associated with persisting cholestatic hepatitis A virus infection. Am. J. GastroenteroL 1990, 85(5), 586-587
V a c c i n e , Vol. 10, S u p p l . 1, 1992
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Dan, M. and Yaniv, R. Cholestatic hepatitis, cutaneous vasculitis, and vascular deposits of immunoglobulin M and complement associated with hepatitis A virus infection. Am. J. Med. 1990, 89, 103-104 Inman, R.D., Hodge, M, Johnston, ME.A., Wright, J. and Heathcote, J. Arthritis, vasculitis, and cryoglobulinemia associated with relapsing hepatitis A virus infection. Ann. Intern. Med. 1986, 105, 700-703 Routenberg, J.A., Dienstag, J.L., Harrison, W.O., Kilpatrick, M.E., Hopper, RR., Chisari, F.V. et aL Foodborne outbreak of hepatitis A: clinical and laboratory features of acute and protracted illness. Am. J. Med. Sci. 1979, 278, 123-131 Vente, S, Garofano, T., Di Perri, G., Dolci, L., Concia, E. and Bassetti, D. Identification of hepatitis A virus as a trigger for autoimmune chronic hepatitis type 1 in susceptible individuals. Lancet 1991, 337. 1183-1187
Viral A hepatitis is a self-limited infection occurring predominantly among children usually as an anicteric often subclinical illness. Adults afflicted with this virus are more likeh' to develop icteric hepatitis. This is exemplified in developed countries when a common source outbreak occurs among non-immune adults. Fulminant hepatitis is uncommon in the USA and hepatitis A has never been documented to evolve into chronic hepatitis. However, prolonged cholestasis and relapsing hepatitis are well described. The usual features o f cholestatic viral hepatitis A are pruritus,fever, diarrhoea, and weight loss. Serum bilirubin levels are > 10 mg/dl and the clinical course lasts at least 12 weeks. Cholestasis will spontaneously resolve, although corticosteroids will hasten the resolution but may predispose the patient to develop a relapse o f the hepatitis. A biphasic or relapsing form o f viral hepatitis A occurs in 6 to 10% o f cases. The initial episode lasts 3 to 5 weeks and is followed by a period o f remission characterized by normal liver chemistries lasting 4 to 5 weeks. Relapse may mimic the initial episode o f the acute hepatitis. The full duration o f the illness ranges from 16 to 40 weeks from the onset and immunoglobulin M antibody to hepatitis A virus persists throughout the clinical course. Hepatitis A virus has been recovered from stools during the relapse. Extrahepatic manifestations o f hepatitis A include evanescent skin rash and transient arthralgias. Doeumented cases o f arthritis and cutaneous vasculitis have been associated with cryoglobulinaemia and are rare. Keywords: Hepatitis A; clinical manifestation;cholestasis: relapse: extrahepatic;autoimmune
INTRODUCTION There are at least four well established atypical clinical manifestations of hepatitis A: cholestasis, relapse, extrahepatic and autoimmune trigger. Prolonged intrahepatic cholestasis associated with viral hepatitis has been recognized for > 50 years and was formerly termed 'cholangitic' or 'cholangiolitic' hepatitis ~. CHOLESTASIS Gordon et al. documented six cases of acute cholestatic hepatitis A with serological evidence of immunoglobulin M antibodies to hepatitis A virus (IgM anti-HAV) 2. All of these patients had a serum bilirubin > 10 mg/dl and the duration of jaundice exceeded 12 weeks. This is in contrast to the mean peak serum bilirubin of 10 mg/dl and mean duration of jaundice of ~ 4 weeks noted by Rozen et al. in their study of 347 patients with uncomplicated acute icteric hepatitis 3. After an initial aminotransferase peak early in the course of acute hepatitis, these cholestatic patients characteristically had aminotransferDivision of Hepatology, University of Miami School of Medicine and Veterans Administration Medical Center, Center for Liver Diseases, 1500 N.W. 12th Ave., Suite 1101, Miami, FL 33136, USA
$18
Vaccine, Vol. 10, Suppl. 1, 1992
ase levels < 500 IU/1. There was no evidence ofhaemolysis or renal failure, both of which would have enhanced the hyperbilirubinaemia in any of these six patients. The liver biopsies typically showed marked centrilobular cholestasis with some portal inflammation. The latter histological finding could suggest the appearance of chronic hepatitis which never evolves in hepatitis A. Sciot et al. evaluated the clinical, biochemical and histological characteristics of 13 cases of acute hepatitis A 4. Moderate to severe cholestasis consisting of bile thrombi, cholestatic liver cell rosettes and ductular transformation of hepatocytes was noted in 10 of these patients. These authors postulated that periportal spotty necrosis may play a role in the pathogenesis of the cholestasis by interrupting the continuity of bile flow. In six of the cases, abnormal ductular epithelium was seen resembling the ductular lesions found in septicaemia. Teixeira et al. reviewed the liver biopsies from 17 patients with acute viral hepatitis A and also noted severe centrilobular cholestasis in five of these patients 5. These authors also observed periportal inflammatory reactions which resemble that seen in chronic active hepatitis. The infiltrate was rich in plasma cells. They point out that these lesions may lead to a false impression of impending chronicity which does not occur in type A hepatitis. Fortunately these patients recover completely, although corticosteroid therapy would hasten the resolu0264-410X/92/100S18-03 ~ 1992Butterworth-HeinemannLtd
Atypical clinical manifestations of hepatitis A: E. R. Schiff
tion of the cholestasis 6. A standard regimen utilizes prednisone in a dose of 40 mg/day gradually tapered over, at least, a 4-week period. The serum bilirubin characteristically drops by at least 40% after 4 days of therapy. If corticosteroids are rapidly tapered off, a relapse of the cholestasis may develop. Unfortunately, patients with cholestatic hepatitis serologically proven to be secondary to hepatitis A are often subjected to expensive and invasive evaluations in search of mechanical obstruction. There is frustration, both among physicians and patients, as jaundice and pruritus persist. A favourable response to corticosteroids can quickly resolve this problem. Liver biopsy is unnecessary as are direct forms of cholangiography in the management of most cases. A normal abdominal ultrasound study in the deeply icteric patient should be reassuring. RELAPSE A biphasic or relapsing form of viral hepatitis A occurs in 6-10% of cases 7.8. At times, this may be polyphasic. After an initial episode of typical acute hepatitis, lasting 3-5 weeks, a remission lasting 4-15 weeks follows. The remission is often characterized by normal aminotransferases. Relapse may mimic the initial episode of acute hepatitis and either be less severe or more severe than the initial episode. Typically, aminotransferase levels are > 1000 IU/1 during the relapse. The full duration of the illness lasts from 16-40 weeks and, characteristically, there is a persistence of IgM anti-HAV positivity throughout the entire course. HAV has been recovered from stools during the relapse and HAV RNA has been detected in the serum during the relapse 7.9. Typically, detectable virus in the stool will quickly disappear usually within 30 days of the onset of the illness. More recently, polymerase chain reaction methodology has detected a persistence of HAV RNA for months, but it is not known whether these patients are still infectious. Regardless of this, during the relapse phase viral particles have been detected in the stool by immunoelectron microscopy, molecular hybridization and radioimmunoassay by Sjogren et al 7. They studied seven patients among 17 who relapsed out of 246 patients with acute hepatitis A. The pathogenesis of the relapse is not clear but is undoubtedly immunologically mediated. In the cases reported, there has usually been an absence of an epidemiological suspicion for non-A, non-B or type C hepatitis infection. The prognosis is good and chronic hepatitis does not evolve. EXTRAHEPATIC Extrahepatic manifestations, most often secondary to immune complex disease, are relatively common among patients with hepatitis B. They include urticarial and other cutaneous eruptions and arthritis during acute hepatitis, and polyarteritis and membranous glomerulonephritis associated with chronic hepatitis B. However, extrahepatic manifestations of hepatitis A are relatively rare, although there have been several reports of leucoclastic cutaneous vasculitis and arthritis ~ ~2. Typically in acute hepatitis A, up to 14% of patients have an evanescent rash and up to 1 ! % have arthralgias, both of which are transient u. When the illness becomes protracted however, either as a result of cholestasis or of relapse,
extrahepatic manifestations may be seen. Cutaneous vasculitis appears as an erythematous maculopapular eruption often affecting the lower extremities and buttocks and typically also associated with purpuric lesions. Skin biopsy has demonstrated immune complex phenomena with the presence of IgM anti-HAV and complement in the blood vessel walls. The arthritis also has a predilection for the lower extremities. Both may be associated with cryoglobulinaemia. The cryoglobulin has been demonstrated to contain IgM anti-HAV. Spontaneous resolution occurs, presumably as a result of viral clearance. AUTOIMMUNE
TRIGGER
Finally, a newly recognized atypical manifestation of hepatitis A is the triggering of chronic active autoimmune hepatitis of the type-1 variety. Vento et aL described 13 patients with chronic active autoimmune type1 hepatitis 14. Ten of these 13 patients had serological evidence of hepatitis A in the past. All 13 patients had antibodies to asialoglycoprotein and all had defects in Tcell suppressor-inducer cells that control immune response to these asialoglycoprotein receptors. Fifty-eight first and second degree relatives of these 13 index cases were followed prospectively over 4 years. Fourteen of these relatives had the T-cell suppressor-inducer defect and none had serological evidence of previous hepatitis A infection. However, 38% of the total group of 58 relatives did have serological evidence of a prior infection with hepatitis A. During the prospective follow-up, three subclinical cases of acute hepatitis A developed. Two of these cases were among the 14 patients with the T-cell suppressor-inducer defect for controlling antibodies to asialoglycoprotein receptors. All three patients developed antibodies to asialoglycoprotein receptors, but the two with the T-cell suppressor-inducer defect evolved into clinically apparent icteric autoimmune hepatitis, requiring long-term corticosteroid therapy for control. CONCLUSION Atypical manifestations of hepatitis A include: cholestasis where a rapid serological diagnosis will avoid an unnecessary expensive and invasive evaluation for obstructive jaundice; relapsing hepatitis where there is reappearance of hepatitis A in serum and in stool rendering the patient again potentially infectious; extrahepatic manifestations of leucoclastic cutaneous vasculitis, arthritis and cryoglobulinaemia which are probably related to immune complex phenomena; and finally the triggering of some cases of chronic active autoimmune hepatitis type-l among genetically predisposed individuals. REFERENCES 1 Koff, R.S. Viral hepatitis. In: Diseases of the Liver (Eds Schiff, L. and Schiff, E.R.) 7th Edn, Lippincott, Philadelphia, (in press) 2 Gordon, S.C., Reddy, K.R., Schiff, L. and Schiff, E.R. Prolonged intrahepatic cholestasis secondary to acute hepatitis A. Ann. Intern. Med. 1984, 101,635--637 3 Rozen, P., Kern, R.J. and Zimmerman, H.J. Computer analysis of liver function tests and their interrelation in 347 cases of viral hepatitis. Israel J. Med. Sci. 1970, 6, 67-79 4 Sciot, R., Vandamme, B. and Desmet, V.J. Cholestatic features in hepatitis A. J. Hepatol. 1986, 3, 172-181 5 Teixeira, M.R., Weller, IN.D, Murray, A., Bamber, H.C., Sherlock, T.S.
Vaccine, Vol. 10, Suppl. 1, 1992
$19
A t y p i c a l clinical m a n i f e s t a t i o n s o f hepatitis A. E. R. S c h i f f
6 7 8 9 10
S20
and Scheuer, P.J. The pathology of hepatitis in man. Liver 1982,2, 5360 Williams, R. and Billing, B.H. Action of steroid therapy in jaundice. Lancet 1961, 2, 392-396 Sjogren, M.H., Tanno, H., Fay, O., Sileoni, S., Cohen, D., Burke, D.S. and Feighny, R.J. Hepatitis A virus in stool during clinical relapse. Ann. Intern. Med. 1987, 106, 221-226 Cobden, I. and James. O.F.W. A biphasic illness associated with acute hepatitis A virus infection. J. HepatoL 1986, 2, 19-23 Glikson, M., Galun, E., Oren, R., Tur-Kaspa, R. and Shouval, D. Relapsing hepatitis A: review of 14 cases and literature survey. Medicine 1992, 71, 14-23 Ilan, Y., Hillman, M., Oren, R., Zlotogorski., A. and Shouval, D. Vasculitis and cryoglobulinemia associated with persisting cholestatic hepatitis A virus infection. Am. J. GastroenteroL 1990, 85(5), 586-587
V a c c i n e , Vol. 10, S u p p l . 1, 1992
11 12 13
14
Dan, M. and Yaniv, R. Cholestatic hepatitis, cutaneous vasculitis, and vascular deposits of immunoglobulin M and complement associated with hepatitis A virus infection. Am. J. Med. 1990, 89, 103-104 Inman, R.D., Hodge, M, Johnston, ME.A., Wright, J. and Heathcote, J. Arthritis, vasculitis, and cryoglobulinemia associated with relapsing hepatitis A virus infection. Ann. Intern. Med. 1986, 105, 700-703 Routenberg, J.A., Dienstag, J.L., Harrison, W.O., Kilpatrick, M.E., Hopper, RR., Chisari, F.V. et aL Foodborne outbreak of hepatitis A: clinical and laboratory features of acute and protracted illness. Am. J. Med. Sci. 1979, 278, 123-131 Vente, S, Garofano, T., Di Perri, G., Dolci, L., Concia, E. and Bassetti, D. Identification of hepatitis A virus as a trigger for autoimmune chronic hepatitis type 1 in susceptible individuals. Lancet 1991, 337. 1183-1187
