IMAGES IN LIVER TRANSPLANTATION

An Unusual Occurrence of Giant Cell HepatitisVandana Singh, Madhavi Rudraraju, Elizabeth J. Carey, Thomas J. Byrne, David D. Douglas,Jorge Rakela, and Hugo E. VargasDivision of Hepatology, Mayo Clinic, Scottsdale, AZ

Received October 1, 2007; accepted July 14, 2009.

Giant cell hepatitis is common in neonates but rare inthe adult population. When present in adults, it isknown as postinfantile giant cell hepatitis (PGCH).PGCH is a rare disorder characterized by the presenceof multinucleated cells in the liver as an unusual non-specific tissue reaction to various stimuli, includingtoxins, drugs, and viruses.1-4 The clinical spectrumvaries from mild chronic hepatitis to active cirrhosis. Aconsiderable number of patients exhibit autoimmunefeatures and respond to immunosuppressive ther-apy.5-7

CASE

A 25-year-old woman with a 13-year history of autoim-mune hepatitis was admitted to our hospital for the firsttime with right inner thigh cellulitis. Liver biopsy wasperformed 3 times during the course of her diagnosis,and each biopsy procedure revealed chronic hepatitiswith plasmacyte infiltrates consistent with autoim-mune hepatitis. The last biopsy specimen had beenobtained 5 years prior to this admission and had al-ready demonstrated early nodule formation. A review ofthe laboratory evaluation from the first evaluation thatcould be retrieved showed that she had a negative se-rological workup, except for an elevated antinuclearantibody titer (1:256, speckled) and high immunoglob-ulin G on serum protein electrophoresis. She was main-tained on stable doses of immunosuppressants [pred-nisone (10 mg daily) and mycophenolate mofetil (1 gtwice a day)]. On admission, a laboratory investigationrevealed moderately elevated liver enzymes [alanineaminotransferase (ALT), 96 IU/L; aspartate amino-transferase (AST), 94 IU/L; alkaline phosphatase (ALP),60 IU/L; total bilirubin, 2.1 mg/dL; direct bilirubin, 0.6mg/dL; international normalized ratio, 1.68]. Liver en-

zymes started rising gradually during the hospitaliza-tion.

She was treated with amoxicillin/clavulanate for hercellulitis; there was no significant response after 2days, so she was switched to intravenous vancomycin.Incision and drainage were done for a subcutaneousabscess at the site of infection. She responded very welland was discharged on a 14-day course of cephalexin.

Nine days after discharge, she was readmitted withabdominal pain secondary to Clostridium difficile colitisand was treated with metronidazole. Her liver enzymesduring this admission were further elevated (AST, 1667IU/L; ALT, 1201 IU/L; ALP, 91 IU/L; total bilirubin, 8.4mg/dL; direct bilirubin, 4.9 mg/dL; international nor-malized ratio, 2). She denied any alcohol use. An inpa-tient evaluation for liver transplantation was initiatedand revealed negative serological tests for hepatitis vi-ruses A, B, and C, human immunodeficiency virus,Epstein-Barr virus, and cytomegalovirus. Autoimmunemarkers showed an antinuclear antibody titer of 2.2(negative � 1), whereas antismooth muscle antibodyand antimitochondrial antibody titers were negative.Serum ceruloplasmin, alpha 1-antitrypsin, iron, trans-ferrin, ferritin, and alpha fetoprotein levels were nor-mal. A computerized tomography scan of the abdomenrevealed heterogeneous liver parenchyma and patenthepatic vasculature.

Because of acute decompensation of her liver diseaseafter adequate treatment of the C. difficile colitis, sheunderwent orthotopic liver transplantation. The ex-planted liver revealed micronodular cirrhosis with severefibrosis and scarring (Fig. 1), prominent giant cell change(Fig. 2), and numerous regenerative nodules. Throughoutmost of the liver, there was extensive chronic damage withdense, well-organized fibrosis dissecting the liver intosmall nodules, often less than 1 mm, as well as prominent

Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PGCH, postinfantilegiant cell hepatitis.Address reprint requests to Hugo E. Vargas, M.D., Division of Transplantation Medicine, Mayo Clinic Arizona, 5777 East Mayo Boulevard, Phoenix,AZ 85054. Telephone: 480-342-1094; FAX: 480-342-2324; E-mail: vargas.hugo@mayo.edu

DOI 10.1002/lt.21881Published online in Wiley InterScience (www.interscience.wiley.com).

LIVER TRANSPLANTATION 15:1888-1890, 2009

© 2009 American Association for the Study of Liver Diseases.

pericellular (perisinusoidal) fibrosis. There was severecholestasis with feathery change, prominent giant cellchange, necrosis of giant cells with a neutrophilic reac-tion, and prominent Mallory’s hyaline. (Fig. 3) The histo-logical changes were compatible with the history of auto-immune hepatitis, although there was no prominentinterface activity noted. Although there was severe cho-lestasis, the pattern of fibrosis did not suggest biliarydisease. There was no significant fatty change or evidenceof steatohepatitis.

Her liver enzymes improved significantly after trans-plantation with normalization of AST, but ALT and ALPremained minimally elevated. Her most recent evalua-tion and biopsy at 4 months after transplantationshowed complete normalization of hepatic function andnormal hepatic parenchyma.

DISCUSSION

This report describes the occurrence of PGCH in a pa-tient previously diagnosed with autoimmune hepatitis

without any histological evidence of PGCH in the settingof an acute bacterial infection and recent use of hepa-totoxic medications. Amoxicillin/clavulanate has beenimplicated as a causative agent for drug-induced hep-atitis.8-11 However, in this particular case, the trigger tothe histological conversion may never be found. Thetypical presentation of amoxicillin/clavulanate hepato-toxicity is that of profound cholestasis with occasionalhepatocellular involvement.10 Furthermore, older indi-viduals are generally at higher risk of hepatotoxicity.

PGCH is a rare entity. The natural course is usually afulminant, progressive course to cirrhosis withinmonths, leading to death or a requirement for trans-plantation. Associations with autoimmune disorders,viral infections, and drug reactions and also with con-genital metabolic diseases such as alpha 1-antitrypsindeficiency and hemosiderosis have been described. Inmany cases, no causative event has been found. Thepresence of autoimmune hepatitis in these patientssuggests that there may be an autoimmune componentto the pathogenesis of PGCH in a subgroup of patients.Clinicians need to be aware of this potential change inthe disease as more aggressive management of the pa-tient may be necessary and expedited liver transplan-tation may be in order.

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Figure 1. Explant low power micrograph depicting mi-cronodular cirrhosis with severe fibrosis and scarring.

Figure 2. Explant high power micrograph with giant cellchange.

Figure 3. Explant high power micrograph revealing cholesta-sis with feathery change, prominent giant cell change, necro-sis of giant cells with a neutrophilic reaction, and prominentMallory’s hyaline.

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