Acute Autoimmune Hepatitis Presenting WithCentrizonal Liver Disease: Case Report and Reviewof the LiteratureRanvir Singh, M.D., Satheesh Nair, M.D., Gist Farr, M.D., Andrew Mason, M.B.B.S., andRobert Perrillo, M.D.Sections of Gastroenterology and Hepatology and Pathology, Ochsner Clinic Foundation, New Orleans,Louisiana

ABSTRACTRelatively little is known about the histological appearanceof autoimmune hepatitis during the early stage of disease.We describe a case of autoimmune hepatitis in a 20-yr-oldwoman in which the initial liver biopsy was characterized bya marked predominance of centrizonal injury. Over thecourse of several months, the histological appearanceevolved to what is more commonly associated with chronicautoimmune hepatitis. A review of the literature on thisinteresting entity is presented. (Am J Gastroenterol 2002;97:2670–2673. © 2002 by Am. Coll. of Gastroenterology)

INTRODUCTION

In about 20–30% of cases of autoimmune hepatitis, thepresentation is acute, and the clinical features may be in-distinguishable from viral hepatitis (1, 2). The diagnosis isusually suggested by the finding of a positive test for anti-nuclear, antismooth muscle, or antiliver/kidney microsomalantibodies as well as negative tests for hepatitis viruses.Relatively little is known about the histological appearanceduring the acute phase of the disease, but during the chronicphase, the most common histological features are piecemealnecrosis, lobular inflammation, portal and periportal inflam-mation with lymphocytes and plasma cells, as well as pa-renchymal infiltrates (3, 4). We describe a case of acuteautoimmune hepatitis in a 20-yr-old woman where the ini-tial liver biopsy revealed a predominance of centrizonalinjury and no significant changes in the portal and periportalareas. Over the course of several months, the histologicalappearance evolved to what is more commonly associatedwith chronic autoimmune hepatitis. A review of the litera-ture on this interesting entity is presented.

CASE REPORT

A 20-yr-old woman presented with an 8-month history ofabnormal liver function tests. She was apparently well untilSeptember 2000 when she was seen by her physician for theacute onset of jaundice. She denied any preceding or ongo-

ing fever, flu-like illness, abdominal pain, anorexia, vomit-ing, joint pain, or skin rash. She had no significant pastmedical history and denied previous blood transfusion,i.v.drug abuse, nasal cocaine, or intake of potential hepatotoxicdrugs or other agents. There was a questionable familyhistory of hepatitis in her aunt. She admitted to taking oralcontraceptives during the preceding 5 yr, but this was dis-continued when her jaundice became apparent. She deniedthe use of minocycline.

On physical examination, the patient was jaundiced, butthere was no organomegaly, ascites, or spider nevi. Thelaboratory data revealed an AST level of 241 IU/L, an ALTof 374 IU/L, total bilirubin of 7.1 mg/dl, and serum albuminof 3.4 g/dl (Table 1). An acute hepatitis profile for hepatitisA, B, and C was negative as was an abdominal ultrasound.Approximately 4 wk later, AST had decreased to 71 IU/L,ALT to 126 IU/L, and serum bilirubin was 1.5 mg/dl.Testing for hepatitis C virus RNA by polymerase chainreaction was negative 2 months into her illness. A liverbiopsy done at an outside hospital 1 month after the onset ofher illness revealed centrizonal hepatocyte dissolution andprominent congestion (Fig. 1). The portal tracts revealedminimal if any inflammation, and there were no features oflobular inflammation. The patient continued to demonstratepersistent elevations in serum aminotransferase levels inassociation with a mild elevation of serum bilirubin. Anti-liver/kidney microsomal, smooth muscle, and liver solubleantigen antibodies were found to be negative. Antinuclearantibody was 30 IU/ml (�7.5 reported as normal for thelaboratory). A Doppler ultrasound revealed no disturbancein blood flow pattern. The patient was not started on im-munosuppressive treatment.

When the patient presented to the Ochsner Clinic Foun-dation 8 months after the onset of illness, she complainedof fatigue, menstrual abnormalities, and marked worsen-ing of facial acne. She denied joint pain and dry eyes.Physical examination was essentially unremarkable ex-cept for severe cystic acne in the facial area. There wasno ascites detectable on clinical examination. ALT andAST remained elevated (114 and 86 IU/L, respectively),

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serum albumin was 3.3 g/dl, and PT was 11.5 s. Becauseof the initial biopsy interpretation and the long-term useof contraceptives, a diagnosis of chronic hepatic veno-occlusive disease was initially entertained. Tests for pro-

tein C, protein S, antithrombin III, and factor V Leidenwere all negative. The antinuclear antibody was repeat-ably positive (1:320), and an IgG level was elevated(1635 mg/dl, upper range of normal 1475 mg/dl). A

Figure 1. (A) Centrizonal congestion with surrounding hepatocyte loss observed in the initial biopsy, taken 2 months after the acute onsetof illness. Note the absence of parenchymal inflammation. (B) Representative findings in portal triads in initial liver biopsy. Note that thereis minimal mononuclear inflammatory infiltrate, no interface hepatitis, and no parenchymal inflammation. (C) Centrizonal area from secondliver biopsy obtained 8 months later. There is now prominent parenchymal inflammation with acidophilic bodies (arrow). The central veinarea demonstrates a persistent loss of hepatocytes and accumulation of mononuclear cells. (D) Marked expansion of the portal triads bymononuclear cells in the second biopsy. There is conspicuous interface hepatitis, and bridging inflammation is evident between a portaltriad (lower arrow) and inflamed central vein area (upper arrow).

Table 1. Serial Liver Function Testing in Our Case of Autoimmune Hepatitis

DateAST

(IU/L)ALT

(IU/L)

TotalBilirubin(mg/dl)

Albumin(g/dl)

ALP(IU/L)

PT(s)

9/18/00 241 374 7.1 3.4 12510/09/00 71 126 1.5 3.3 8712/01/00 105 164 2.2 3.6 1071/30/01 178 215 1.2 3.6 835/02/01 86 114 1 3.3 109 11.57/10/01 291 293 4.1 3.4 198 137/17/01* 301 243 3.8 3.4 184 12.57/31/01 20 30 1.5 3.5 120 129/25/01 15 14 0.9 4.4 86 12.5

* Prednisone and azathioprine started on day of second liver biopsy.

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repeat Doppler ultrasound revealed hepatopedal flow, andultrasonography revealed a normal sized liver. In July, 9months after the onset of illness, a liver biopsy was donebecause of persistent elevations in the serum aminotrans-ferases and bilirubin levels (Table 1). A liver chemistryprofile obtained on the day of biopsy revealed an ALT of243 IU/L, an AST of 301 IU/L, total bilirubin of 3.8mg/dl, and serum albumin of 3.4 g/dl. It was believed thather age, sex, and antinuclear antibody results were con-sistent with autoimmune hepatitis. Accordingly, thepatient was started on azathioprine 75 mg and prednisone30 mg daily immediately after the second biopsy. Therepeat liver biopsy revealed moderate-to-severe portaltriaditis with central venous inflammation, hepatocellularloss, and bridging inflammation. She had a marked ben-eficial response to immunosuppressive treatment whenseen 2 wk later (Table 1). Her fatigue and her acne hadimproved considerably. The liver function tests had com-pletely normalized except for a persistent mild elevationof serum bilirubin (1.5 mg/dl). Her prednisone was de-creased to 20 mg, and repeat liver profile testing 2 wklater (4 wk after initiation of treatment) was completelynormal.

DISCUSSION

Limited information exists with respect to the histologicalappearance of acute autoimmune hepatitis. This is an im-portant consideration because approximately 30% of pa-tients with autoimmune hepatitis present in an acute fashion,and failure to recognize the peculiar histological features atthis time can lead to mistaken diagnosis and inappropriatetherapy. There are only a few previous reports on the his-tological appearance of acute autoimmune hepatitis (5–8).Pratt et al. first described a predominance of centrilobularnecrosis in five patients with steroid-responsive autoim-mune hepatitis (5). In two patients who were not promptlytreated because of the uncertainity of the diagnosis, thehistological appearance was shown to evolve from centri-lobular necrosis to the periportal infiltrates more typicallyassociated with chronic autoimmune hepatitis. This transi-tion was also well documented in our patient. Of note, in thecases described by Pratt et al. (5), follow-up biopsies aftertreatment revealed either marked improvement or completeresolution of the centrilobular injury. Subsequent to thedescription of this entity, a histological variant of autoim-mune hepatitis associated with prominent centrilobular ne-crosis was also described in a 39-yr-old woman (6). Thispatient had a strongly positive antinuclear antibody(1:2560), and the most conspicuous finding was lytic ne-crosis in all centrilobular areas and total sparing of the portaltracts. This patient, too, responded very well to corticoste-roid treatment. Taken together, our case and the case de-scriptions in the literature suggest that the pattern of pre-dominant centrilobular injury may be an earlyrepresentation of autoimmune hepatitis. It is perplexing,

however, why this pattern of injury has not been demon-strated in other case series of acute autoimmune hepatitis inwhich liver biopsies were available (7, 8). An explantationfor these discrepant findings is not clear, but it may relate tothe particular sensitivity of some individuals, perhaps ge-netically determined, to have endothelial injury with centri-zonal necrosis.

A murine model of autoimmune hepatitis immunizedintraperitoneally with syngeneic liver homogenates providessome interesting observations (9). In animals treated withS-100 protein in complete Freund’s adjuvant, an evolvingpattern of liver injury was observed. The initial lesions(within 20 days) were characterized by infiltrates of poly-morphonuclear leukocytes with some lymphocytes localizedmainly in the centrilobular and portal areas. As the hepatitisprogressed and peaked at 4 wk, focal necrosis with a denseinflammatory polymorphonuclear and lymphocytic infiltratewas found preferentially around the central vein. Threemonths after injection of the S-100 protein, infiltration oflymphocytes remained most dense around the central veinand in the vascular sinusoids, but biopsies obtained a fewmonths later demonstrated subsidence of the perivascularinfiltrate. It is currently unknown if these findings haverelevance to the human condition.

In summary, acute autoimmune hepatitis may presentwith histopathological features of centrizonal necroin-flammation and congestion. With time, the more typicallesion of chronic hepatitis becomes predominant. Thelength of time required for this evolution cannot be de-termined from the literature nor can it be understood whythis lesion has not been seen in all cases of acute auto-immune hepatitis. Nonetheless, a failure to appreciate thesignificance of the early perivenular findings observed inautoimmune hepatitis of short duration has the potentialto lead to mistaken diagnosis and delay in treatment.Further studies in humans and animal models need to bedone to evaluate the pathogenesis and pattern of injury inthe early stages of autoimmune hepatitis.

Reprint requests and correspondence: Robert P. Perrillo, M.D.,Head, Section of Gastroenterology and Hepatology, OchsnerClinic Foundation, 1514 Jefferson Highway, New Orleans, LA70121.

Received Feb. 6, 2002; accepted May 30, 2002.

REFERENCES

1. Bearn AG, Kunkel HG, Slater RJ. The problem of chronic liverdisease in young women. Am J Med 1956;21:3–15.

2. Soloway RD, Summerskill WH, Schoenfield LJ. Clinical, bio-chemical and histological remission of severe chronic liverdisease: A controlled study of treatments and early prognosis.Gastroenterology 1972;63:820–33.

3. Bach N, Thung SN, Schaffner F. The histological features ofchronic hepatitis C and autoimmune chronic hepatitis: A com-parative analysis. Hepatology 1992;15:572–7.

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4. Czaja AJ, Carpenter HA. Sensitivity, specificity and predict-ability of biopsy interpretations in chronic hepatitis. Gastroen-terology 1993;105:1824–32.

5. Pratt DS, Fawaz KA, Kaplan MM. A novel histologic lesion inautoimmune chronic active hepatitis. Hepatology 1994;20:144A (abstract).

6. Te HS, Koukoulis G, Ganger DR. Autoimmune hepatitis: Ahistological variant associated with prominent centrilobular ne-crosis. Gut 1997;41:269–71.

7. Burgart LJ, Batts KP, Ludwig J, et al. Recent-onset autoim-mune hepatitis biopsy findings and clinical correlations. Am JSurg Pathol 1995;19:699–708.

8. Nikias GA, Batts KP, Czaja AJ. The nature and prognosticimplications of autoimmune hepatitis with an acute presenta-tion. J Hepatol 1994;21:866–71.

9. Lohse AW, Manns M, Dienes HP, et al. Experimental autoim-mune hepatitis: Disease induction, time course and T cell re-activity. Hepatology 1990;11:24–30.

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