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Cholestatic Hepatitis, Cutaneous Vasculitis, and Vascular Deposits of Immunoglobulin M and Complement Associated with Hepatitis A Virus Infection MICHAEL

DAN, M.D., RONYANIV,M.D., Ho/on,

/me/

xtrahepatic manifestations of hepatitis A infection are uncommon. These mainly include evanesE cent skin rash in up to 8% of patients and transient arthralgia in about 10% of episodes [l]. Only rarely have other complications been observed: arthritis has been described in three patients, in two of whom concomitant cryoglobulinemia was demonstrated, and one also had cutaneous vasculitis [1,2]. We describe herein a woman with a protracted course of cholestatic hepatitis due to hepatitis A virus infection, in whom maculopapular skin lesions of long duration were observed in association with immunoglobulin M and complement precipitates. CASE REPORT A 31-year-old woman was admitted to the hospital with jaundice and pruritus of 3 weeks’ duration and a skin rash of 2 weeks’ duration. Four weeks before admission, the patient had developed fever, malaise, nausea, and anorexia; these subsided gradually in the following two weeks. Laboratory tests performed 10 days before admission revealed the following values: serum bilirubin, 9.5 mg/dL (normal: 1.0 mg/dL); serum aspartate aminotransferase (AST), 460 U/L (normal: 22 U/L); and alkaline phosphatase, 52 U/L (normal: 85 U/L). The medical history was noncontributory, and no medications had been taken in the preceding months. The patient’s 4-year-old son developed a flu-like illness followed by jaundice 1 week after the patient became sick. Physical examination on admission showed a deeply with no signs of acute distress. An jaundiced woman erythematous papular rash with pruritic lesions was observed mainly over the hips, but also involving the buttocks and arms; an occasional petechial rash was also seen. The remainder of the examination was normal. Laboratory data upon admission included a hemoglobin level of 12.3 g/dL, a white blood cell count of 6,300/mm3 with 66% polymorphonuclears, 2% band forms, 18% lymphocytes, 11% monocytes, and 2% basophils; a platelet count of 408,000/mm3; and an erythrocyte sedimentation rate of 80 mm/hour. Total bilirubin was 18.7 mg/dL, with 12.1 mg/dL direct reacting; AST was 130 IU; serum alanine aminotransferase (ALT) was 40 IU, and alkaline phosphatase was 210 IU. The IgM anti-hepatitis A virus was positive; hepatitis B surface antigen and anti-hepatitis B core antigen were not detected. Serum complement levels were within the normal range. Skin biopsy examination From the Infectious Diseases UN, The E. Wolfson Hospital. Holon, Israel. Requests for reprints should be addressed to Michael Dan, M.D., Infectious Diseases Unit, The E. Wolfson Hospital, Holon 58100, Israel. Manuscript ggitted September 8. 1989, and accepted !n revised form January 10,

showed leukocytoclastic vasculitis. Direct immunofluorescence studies disclosed vascular deposition of IgM (2+) and C3 (l+) (Figure 1). The subsequent clinical course was characterized by rapid resolution of symptoms and gradual regression of skin lesions, jaundice, and liver test abnormalities. The patient was discharged on the seventh hospital day. Eight weeks after the onset of infection, laboratory tests showed a bilirubin of 11.2 mg/dL (with 10.7 mg/dL direct reacting); AST, 100 IU; ALT, 45 IU; and alkaline phosphatase, 60 IU. The clinical and laboratory findings resolved without therapy over the following two weeks with no sequelae. IMMUNOFLUORESCENCE STUDIES Biopsy samples of maculopapular erythematous skin lesions were snap frozen idn liquid nitrogen and stored at -70°C. Sections of about 6 p were cut in a cryostat and stained with fluorescein-conjugated goat

Figure 1. lmmunofluorescent showing granular deposition magnification X 625). July 1990

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antihuman immunoglobulin G, immunoglobulin M, and complement (C,). The sections were then examined with a fluorescent microscope and immunofluorescence was quantified on a scale from 0 to 4. COMMENTS Hepatitis A virus infection has generally been considered to be a benign, self-limited disease, not associated with extrahepatic manifestations and rarely causing hepatic complications [3]. However, new information that has been accumulating in recent years suggests that this widespread perception of hepatitis A virus infection need to be reconsidered. Several recent reports have documented a relapsing form of hepatitis A virus infection [P61, with remissions and exacerbations of both symptoms and liver function abnormalities occurring in about 4% to 8% of affected persons [7,8]. The association of hepatitis A virus infection with cholestatic hepatitis has recently been reaffirmed [9]. Usual features of this entity include pruritus, fever, diarrhea, and weight loss with serum bilirubin levels greater than 10 mg/dL. Arthralgia is reported by 10% of patients during the acute phase of the illness. Frank arthritis was, however, documented in three patients only [1,2]; in two, cryoglobulinemia was detected concomitantly [2]. Skin rash is considered a rare manifestation of hepatitis A virus infection, occurring in about 1% of patients as compared with 5% and 7% in non-A, non-B hepatitis and hepatitis B, respectively [7]. In one outbreak, however, rash was observed in 8% of affected persons [l]. The increased prevalence in this report may be explained by the predilection of some strains to cause eruptions. The evanescent skin rash usually occurs during or immediately before acute illness as discrete erythematous, maculopapular, petechial, or urticarial eruptions. Biopsy-documented cutaneous vasculitis has been previously reported in only one case; concomitant cryoglobulinemia was documented but immunofluorescence studies were not performed PI.

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The role of immune complexes in the formation of cutaneous vasculitis has been well documented in hepatitis B virus infection [lo-121. Evidence for such a mechanism in hepatitis A virus infection was almost nonexistent until now. The association between immune complexes and vasculitis has been shown in marmosets infected with hepatitis A virus [13]. The findings in our patient are the first direct evidence for the possible role of immune phenomena in the pathogenesis of hepatitis A-associated vasculitis in humans. We conclude that the immune response to hepatitis virus infection may be responsible for clinical manifestations not only when hepatitis B virus is the causative agent, but also when hepatitis A virus is involved. REFERENCES 1. Routenberg JA. Dienstaa JL. Harrison WO. et al: Foodborne outbreak of heoatitis A: clinical and laboratory features of acute and protracted illness. Am J Meb Sci 1979: 278: 123-137. 2. lnman RD, Hodge M. Johnston MEA, Wright J. Heathcote J: Arthritis, vasculitis and cryoglobulinemia associated with relapsing hepatitis A virus infection, Ann Intern Med 1986: 105: 7W703. 3. Gocke DJ: Heoatitis A revisited. Ann Intern Med 1986: 105: 960-961. 4. Comu C. Lamy ME, Geubel A, Galanti L: Persistence of immunoglobulin h4 antibody to hepatitis A virus and relapse of hepatitis A infection. Eur J Clin Microbrol 1g&1; 3: 45-46. 6. Jacobson IM. Nath BJ. Dienstag JL: Relapsing viral hepatitis type A. J Med Virol 1985; 16: 163-169. 6. Gruer LD, McKendrick MW. Beechrng NJ, Geddes AM: Relapsing hepatitis associated with hepatitis A virus (letter). Lancet 1982; 2: 163. 7. Bamber M. Thomas HC. Bannister B, Sherlock S: Acute type A, B and non-A. non-B hepatitis in a hospital population in London: clinical and epidemiological features. Gut 1983; 24: 561-564. 8. Weir WR, Mellor JA, Smith H. Tyrell DA: Significance of hepatitisenzyme levels at discharge in acute viral hepatitis. J Infect 1981; 3: 309-315. 9. Gordon SC. Reddy KR, Schiff L. Schiff ER: Prolonged intrahepatic cholestasis secondary to acute hepatitis A. Ann Intern Med 1984; 101: 635-637. 10. Weiss TD. Tsai CC, Baldassare AR, Zuckener J: Skin lesions in viral hepatitis. Histologic and immunofluorescent findings. Am J Med 1978; 64: 269-273. 11. Dienstag JL. Rhodes AR, Bhan AD, Dvorak AM, Mihm MC, Wands JR: Urticaria associated with acute viral hepatitis type B. Studies of pathogenesis. Ann Intern Med 1978; 89: 34-40. 12. Popp JW. Harrist TJ. Dienstag JL. et al: Cutaneous vasculitis associated with acute and chronic heoatitis. Arch Intern Med 1981: 141: 623629. 13. Morita M, Kitajima K. Yoshizawa H, et a/: Glomerulonephritis associated with arthritis in marmosets infected with hepatitis A virus. Br J Exp Pathol 1981; 62: 103-113.