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Turk J Gastroenterol 2010; 21 (4): 448-451 INTRODUCTION 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 commonly seen 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 with GCH 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-associated complications such as infections are the problems frequently 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 to respond to treatment and died after a trial of CD20 monoclonal antibody (rituximab). CASE REPORT A three-month-old infant was first admitted to a local hospital with vesicular skin lesions and loss of appetite. Her physical evaluation with a history of chickenpox-infected brothers at home guided the diagnosis of varicella infection. The mother co- uld not clearly define her past vesicular infection or vaccination. Paleness and scleral jaundice were observed on the patient’s second visit, and she was hospitalized 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 ÖZGENÇ Ege Üniversitesi T›p Fakültesi Çocuk Hastanesi, Çocuk Gastroenterolojisi Bölümü, Bornova / ‹zmir, Türkiye Phone: + 90 232 390 10 96 / + 90 232 390 10 01 Fax: + 90 232 390 13 57 • E-mail: [email protected] Giant cell hepatitis and autoimmune hemolytic anemia after chickenpox Suçiçe¤i sonras› otoimmun hemolitik anemi ve dev hücreli hepatit Maflallah BARAN 1 , Funda ÖZGENÇ 1 , Ömer BERK 1 , Demir GÖKÇE 2 , Kaan KAVAKLI 3 , Funda YILMAZ 4 , Sait fiEN 4 , Raflit Vural YA⁄CI 1 Departments of, 1 Pediatric Gastroenterology, Hepatology and Nutrition, 3 Pediatric Hematology, 4 Pathology, Ege University School of Medicine, ‹zmir Department of 2 Pediatric’s, Dr. Behcet Uz Children Healt and Disease Hospital, ‹zmir Otoimmün hemolitik anemi ile dev hücreli hepatit çocuklarda ayr› bir klinik tablodur. Bu hastal›k genellikle ilerleyici kara- ci¤er hastal›¤› ile ölümcül seyreder. Geleneksel ilaçlarla yap›- lan immünsüpresif tedaviye k›smi yan›t sa¤lar, bununla bera- ber bu yan›t genellikle geçicidir. Monoklonal antikorlar ile ya- p›lan altenatif tedavi sonras› hastal›¤›n remisyonu rapor edil- mifltir. Biz suçiçe¤i infeksiyonu sonras› otoimmün hemolitik anemi ve dev hücreli hepatit tan›s› alan, standart immunsüp- resif ve rituksimab tedavisine dirençli bir k›z hastay› rapor edi- yoruz. Bu çocuk hastada tedaviye ra¤men remisyon sa¤lanama- d› ve septik komplikasyondan hasta kaybedildi. Anahtar kelimeler: Dev hücreli hepatit, otoimmün hemolitik anemi, rituksimab Autoimmune hemolytic anemia with giant cell hepatitis is a distinct entity in children. It is usually fatal with progressive li- ver disease. Immunosuppressive treatment with conventional drugs 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 report a case with autoimmune hemolytic anemia+giant cell hepatitis after 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 and the child died with septic complication. Key words: Giant cell hepatitis, autoimmune hemolytic ane- mia, rituximab

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

INTRODUCTION

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).

CASE REPORT

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 patient’s 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 ÖZGENÇEge Üniversitesi T›p Fakültesi Çocuk Hastanesi, Çocuk Gastroenterolojisi Bölümü, Bornova / ‹zmir, TürkiyePhone: + 90 232 390 10 96 / + 90 232 390 10 01Fax: + 90 232 390 13 57 • E-mail: [email protected]

Giant cell hepatitis and autoimmune hemolytic anemiaafter chickenpoxSuçiçe¤i sonras› otoimmun hemolitik anemi ve dev hücreli hepatit

Maflallah BARAN1, Funda ÖZGENÇ1, Ömer BERK1, Demir GÖKÇE2, Kaan KAVAKLI3, Funda YILMAZ4, Sait fiEN4, Raflit Vural YA⁄CI1

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

Otoimmün hemolitik anemi ile dev hücreli hepatit çocuklardaayr› bir klinik tablodur. Bu hastal›k genellikle ilerleyici kara-ci¤er hastal›¤› ile ölümcül seyreder. Geleneksel ilaçlarla yap›-lan immünsüpresif tedaviye k›smi yan›t sa¤lar, bununla bera-ber bu yan›t genellikle geçicidir. Monoklonal antikorlar ile ya-p›lan altenatif tedavi sonras› hastal›¤›n remisyonu rapor edil-mifltir. Biz suçiçe¤i infeksiyonu sonras› otoimmün hemolitikanemi ve dev hücreli hepatit tan›s› alan, standart immunsüp-resif ve rituksimab tedavisine dirençli bir k›z hastay› rapor edi-yoruz. Bu çocuk hastada tedaviye ra¤men remisyon sa¤lanama-d› ve septik komplikasyondan hasta kaybedildi.

Anahtar kelimeler: Dev hücreli hepatit, otoimmün 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).

DISCUSSION

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 early and promptimmunosuppressant use in our patient. IVIG was

BARAN et al.450

FFiigguurree 22aa.. Autopsy specimen of the liver. Hepatocytes had be-en lost and replaced by fibrosis. Hepatocyte rosettes and choles-tasis were established (HE X400).

FFiigguurree 22bb.. Autopsy specimen of the liver. The striking fibrosisand submassive hepatocellular loss are prominent (Masson’strichrome X100).

FFiigguurree 22cc.. Autopsy specimen of the kidney. Interstitial focalmicrocalcification and cellular vacuolization in the tubular epit-helium are shown (HE X100).

Giant cell hepatitis and hemolytic anemia after varicella 451

preferred, and after the skin lesions regressed, im-munosuppressives were started in the secondmonth from the initial presentation of hemolysisand hepatitis. The patient received conventionalimmunosuppressive drug combinations due to lackof adequate response. Since the clinical progressionof a refractory GCH is aggressive and fatal, thechild was considered eligible for innovative thera-pies. Liver transplantation was not taken into con-sideration, because disease recurrence has occur-red in most of the transplanted cases (6,7,13).

Rituximab is an anti-CD 20 monoclonal antibody;it inhibits B cell proliferation and antibody pro-duction. It has been successfully used for AIHA(14). Gorelik et al. (2) first used rituximab for ref-ractory AIHA with GCH and documented resoluti-on of hemolysis and hepatitis. Soon after Gorelik’sexperience, Miloh et al. (14) also tried rituximabas a rescue therapy for decompensated liver disea-se. The monoclonal was well tolerated without anymajor side effects in both cases. Transfusion requ-irement was decreased and suppression of liverenzyme levels was achieved with rituximab in ourpatient; however, from the aspect of response eva-luation, remission was not achieved. The patientwas faced with long-term threats of immunosup-

pressants and died due to septic complication.Postmortem evaluation of the liver verified the cli-nical non-response. Although rituximab is repor-ted to be effective as a rescue therapy for liver di-sease, non-response in our patient may be attribu-table to the delayed use of the drug (14). It is wellknown that early and prompt use of steroids is as-sociated with a better response in cases with OI-HA+GCH, and it may also be the same for alterna-tive therapies with monoclonals.

In summary, GCH with AIHA is a rare and dis-tinct entity during infancy. It usually has a fataloutcome with progressive liver disease. Immuno-suppressive treatment with conventional drugs of-fers some response; however, it is usually onlytemporary. Alternative therapeutic options withmonoclonals have been reported with promisingremission of the disease. We report a case withpost-varicella AIHA+GCH who was resistant tostandard immunosuppressive combinations, andresponse could also not be achieved with rituxi-mab. We conclude that alternative treatmentswith monoclonals must be taken into considerati-on in the management of these patients; timing ofthese therapies may also have an impact on remis-sion induction.

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hepatitis with autoimmune hemolytic anemia in earlychildhood. J Pediatr 1981; 99: 704-11.

2. Gorelik M, Debski R, Frangoul H. Autoimmune hemolyticanemia with giant cell hepatitis: case report and review ofthe literature. J Pediatr Hematol Oncol 2004; 26: 837-9.

3. Moreno A, Moreno A, Pérez-El›ías MJ, et al. Syncytial giantcell hepatitis in human immunodeficiency virus-infectedpatients with chronic hepatitis C: 2 cases and review of theliterature. Hum Pathol 2006; 37: 1344-9.

4. Devaney K, Goodman ZD, Ishak KG. Postinfantile giant-cell transformation in hepatitis. Hepatology 1992; 16: 327-33.

5. Vajro P, Migliaro F, Ruggeri C, et al. Life saving cyclop-hosphamide treatment in a girl with giant cell hepatitisand autoimmune haemolytic anaemia: case report and up-to-date on therapeutical options. Dig Liver Dis 2006; 38:846-50.

6. Akyildiz M, Karasu Z, Arikan C, et al. Successful livertransplantation for giant cell hepatitis and Coombs-positi-ve hemolytic anemia: a case report. Pediatr Transplant2005; 9: 630-3.

7. Melendez HV, Rela M, Baker AJ, et al. Liver transplant forgiant cell hepatitis with autoimmune haemolytic anaemia.Arch Dis Child 1997; 77: 249-51.

8. Harmanci O, Onal IK, Ersoy O, et al. Postinfantile giantcell hepatitis due to hepatitis E virus along with the pre-sence of autoantibodies. Dig Dis Sci 2007; 52: 3521-3.

9. Domiati-Saad R, Dawson DB, Margraf LR, et al. Cytome-galovirus and human herpesvirus 6, but not human papil-lomavirus, are present in neonatal giant cell hepatitis andextrahepatic biliary atresia. Pediatr Dev Pathol 2000; 3:367-73.

10. Terada K, Tanaka H, Mori R, et al. Hemolytic anemia as-sociated with cold agglutinin during chickenpox and a revi-ew of the literature. J Pediatr Hematol Oncol 1998; 20:149-51.

11. Apak H, Karaman S, Do¤an Y, et al. Varicella-induced he-molytic anemia with hepatitis. Ann Hematol 2006; 85: 64-5.

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