Giant cell hepatitis and autoimmune hemolytic anemia after
Giant cell hepatitis and autoimmune hemolytic anemia after
Giant cell hepatitis and autoimmune hemolytic anemia after
Giant cell hepatitis and autoimmune hemolytic anemia after

Giant cell hepatitis and autoimmune hemolytic anemia after

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  • Turk J Gastroenterol 2010; 21 (4): 448-451


    Autoimmune hemolytic anemia (AIHA) is an acu-te, self-limited childhood disease with good res-ponse to treatment. However, on very rare occasi-ons, it is accompanied by giant cell hepatitis(GCH), which is progressive and often fatal (1,2).Giant cell transformation of the liver is commonlyseen during the neonatal and early infantile peri-ods, and it is described in association with autoim-mune disorders, drug reactions and viral infecti-ons (3,4). Coombs-positive hemolytic anemia sup-ports the autoimmune pathogenesis of AIHA withGCH entity, and treatment with immunosuppres-sive drugs may offer beneficial effects and resolu-tion of both diseases (5). Resistance to immuno-suppressant treatment and treatment-associatedcomplications such as infections are the problemsfrequently faced in the management of these pati-ents, and liver transplantation is one of the opti-

    ons that has to be considered in those patients un-responsive to immunosuppressants (6,7). We re-port an infant with GCH and AIHA who failed torespond to treatment and died after a trial ofCD20 monoclonal antibody (rituximab).


    A three-month-old infant was first admitted to alocal hospital with vesicular skin lesions and lossof appetite. Her physical evaluation with a historyof chickenpox-infected brothers at home guidedthe diagnosis of varicella infection. The mother co-uld not clearly define her past vesicular infectionor vaccination. Paleness and scleral jaundice wereobserved on the patients second visit, and she washospitalized with suspected infectious or post-in-fectious complications of the viral disease. Labora-

    Manuscript received: 03.04.2009 Accepted: 01.10.2009

    doi: 10.4318/tjg.2010.0135

    Address for correspondence: Funda ZGENEge niversitesi Tp Fakltesi ocuk Hastanesi, ocuk Gastroenterolojisi Blm, Bornova / zmir, TrkiyePhone: + 90 232 390 10 96 / + 90 232 390 10 01Fax: + 90 232 390 13 57 E-mail:

    Giant cell hepatitis and autoimmune hemolytic anemiaafter chickenpoxSuiei sonras otoimmun hemolitik anemi ve dev hcreli hepatit

    Maflallah BARAN1, Funda ZGEN1, mer BERK1, Demir GKE2, Kaan KAVAKLI3, Funda YILMAZ4, Sait fiEN4, Raflit Vural YACI1

    Departments of, 1Pediatric Gastroenterology, Hepatology and Nutrition, 3Pediatric Hematology, 4Pathology, Ege University Schoolof Medicine, zmirDepartment of 2Pediatrics, Dr. Behcet Uz Children Healt and Disease Hospital, zmir

    Otoimmn hemolitik anemi ile dev hcreli hepatit ocuklardaayr bir klinik tablodur. Bu hastalk genellikle ilerleyici kara-cier hastal ile lmcl seyreder. Geleneksel ilalarla yap-lan immnspresif tedaviye ksmi yant salar, bununla bera-ber bu yant genellikle geicidir. Monoklonal antikorlar ile ya-plan altenatif tedavi sonras hastaln remisyonu rapor edil-mifltir. Biz suiei infeksiyonu sonras otoimmn hemolitikanemi ve dev hcreli hepatit tans alan, standart immunsp-resif ve rituksimab tedavisine direnli bir kz hastay rapor edi-yoruz. Bu ocuk hastada tedaviye ramen remisyon salanama-d ve septik komplikasyondan hasta kaybedildi.

    Anahtar kelimeler: Dev hcreli hepatit, otoimmn hemolitikanemi, rituksimab

    Autoimmune hemolytic anemia with giant cell hepatitis is adistinct entity in children. It is usually fatal with progressive li-ver disease. Immunosuppressive treatment with conventionaldrugs offers some response; however, it is usually only tempo-rary. Alternative therapeutic options with monoclonals have be-en reported with promising remission of the disease. We reporta case with autoimmune hemolytic anemia+giant cell hepatitisafter varicella infection. She was resistant to standard immu-nosuppressive combinations, and rescue therapy with rituxi-mab was used. Remission was not achieved with the drug andthe child died with septic complication.

    Key words: Giant cell hepatitis, autoimmune hemolytic ane-mia, rituximab

  • Giant cell hepatitis and hemolytic anemia after varicella 449

    tory analyses revealed Coombs-positive hemolyticanemia and elevated liver enzymes. Antiviral the-rapy with acyclovir was started during the activedisease with skin rash. She required red blood cell(RBC) transfusions and fresh frozen plasma (FFP)for emerging hemorrhagic diathesis. AIHA was di-agnosed and intravenous immunoglobulin (IVIG)was used to suppress the autoimmune process. So-on after the skin lesions regressed, methylpredni-solone was started (30 mg/kg); however, autoim-mune hemolysis and RBC requirement persisted,and she was referred to our clinic for progressinghepatitis and hepatic synthetic failure.

    Distended abdomen and liver palpable 6 cm belowthe costal margin at the mid-clavicular area werenoted on examination, and laboratory evaluationrevealed marked anemia (6.2 g/dl) with reticulocy-tosis (15%). Her initial alanine and aspartate ami-notransferases, total bilirubin levels and interna-tional normalized ratio (INR) were 800 IU/L, 1200IU/L, 59 mg/dl and 1.2, respectively. As there wasample evidence of hepatitis, diagnosis focused onthe etiology. The viral serology was found negati-ve, including hepatotropic viruses and human im-munodeficiency virus (HIV); inborn errors of me-tabolism were ruled out by extensive metabolicwork-up. Autoimmune antibodies (ANA, AMA,LKM, ASMA) were negative, and plasma alpha 1antitrypsin levels were within normal limits. Por-tal vein Doppler ultrasonography (USG) showedhepatomegaly with normal parenchyma and nor-mal blood flow. Liver biopsy illustrated multinuc-lear GCH, and the diagnosis of GCH with AIHAwas established based on clinical, biochemical andhistopathological findings.

    The immune suppressive therapy was startedwith prednisolone 2 mg/kg and she was also supp-lemented with choleretic ursodeoxycholic acid(UDCA) and vitamins. Red cell consumption andelevation of liver enzymes persisted, so vincristine(1 mg/m2, every week) and cyclosporin (CSA, 2mg/kg/day) were added to the therapy (Figure 1).Evaluation after the second vincristine cycle docu-mented pancytopenia. Drug toxicity-related bonemarrow suppression was suspected, and it wassuccessfully managed after cessation of vincristi-ne. The CSA dosage was adjusted and sustainedin normal therapeutic ranges according to bloodlevels (2-12 mg/kg/d); however, the patient experi-enced hypertension, which was treated with anti-hypertensive treatment. Cardiac and renal toxicside effects of CSA were also monitored by regularrenal function tests and echocardiography. Ade-quate clinical and biochemical response could notbe obtained with different immunosuppressivecombinations and in time, she experienced side ef-fects like bloodstream infections and obesity. Al-ternative immunosuppressive therapies were de-bated due to lack of response. Liver transplantati-on was not decided at first because recurrence ofthe disease in the transplanted liver is high, andAIHA persists unrelated to the liver disease. Afterthe commitment of the local ethical committee andwith written consent of the family, rituximab (375mg/m2, once a week) was started with a treatmentplan of four weeks. Biological efficacy of rituximabwas demonstrated by slope-down of pre- and post-treatment CD20 lymphocyte counts; however, onlypartial clinical and biochemical response could beassessed (Figure 1). She was being followed-up,

    FFiigguurree 11.. Course of hepatic tests and transfusion requirement vs. treatment over time (CS: Corticosteroid, IVIG: Intravenous immu-noglobulin, CSA: Cyclosporin A, RTX: Rituximab).

  • transfused and medicated during outpatient visitswhen she presented with fever, anuria and dehy-dration. Bacterial sepsis was demonstrated withaccompanying acute renal failure (urea: 153mg/dl, creatinine: 5.4 mg/dl) with high cyclosporinlevel (CSA, 593 mcg/dl). Peritoneal dialysis wasattempted with large spectrum antibiotics in theintensive care setting. The child died due to septicshock and adult-type respiratory distress syndro-me (ARDS) on the 10th day of follow-up. Submassi-ve necrosis and fibrosis were demonstrated in theautopsy liver specimen (Figure 2a, 2b). Autopsyspecimen from the kidney revealed interstitial fo-cal microcalcification and cellular vacuolizationin the tubular epithelium, which was attributedto exogenous toxic insult, especially CSA (Figure2c).


    The combination of AIHA with GCH is a rare dis-tinct entity with poor prognosis. GCH is commonlydescribed in infants and is associated with auto-immune disorders, drug reactions and viral infec-tions (3,4). Although the exact cause of the condi-tion is unknown, HIV, hepatitis C and E and her-pes virus are reported to be related with the pre-sumed autoimmune process (3-9). For the currentpatient, drug reactions and autoimmune diseaseswere ruled out and post-infectious autoimmunereaction secondary to chickenpox was suspected.Association of varicella infection with AIHA iswell established; however, there is only one pati-ent with accompanying hepatitis in the literature(10,11). Moreover, histological confirmation high-lighted the nature of the hepatitis in our patient.Although chickenpox is a benign childhood disea-se, the readers attention is drawn once more tothe rare but serious complications of the infection.

    Autoimmune hemolytic anemia (AIHA) is claimedto be a self-limiting illness, unless it presents withearly onset or GCH accompanies the clinical pictu-re (12). The pathogenesis of AIHA mainly relies ondestruction of RBCs by IgG or IgM type auto anti-bodies, and GCH is also suspected to arise from im-mune dysfunction and unrestrained release of cyto-kines (7). Treatment modalities target effectors ofthe immune system for both disease processes.Early institution of steroids has been shown to ha-ve a beneficial effect on both liver function and he-molytic anemia; however, acute varicella infectionsdefined by eruptions prohibited