We report an unusual liver disease which may occur after bone marrow transplantation, i.e. the collapse of hepatic lobuli followed by regenerative islets: the resulting clinical picture may mimic GvHD or a viral disease, but histology is diagnostic, showing nodular regeneration in the absence of inflammation or fibrosis

De Rosa G

Lucania A

Muretto P

Pezzullo L

PICARDI, MARCO

Rotoli B.

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669Haematologica vol. 85(6):June 2000scientific correspondence237-40.4. Hunt DM, Higgs DR, Winichagoon P, Clegg JB,Weatherall DJ. Haemoglobin Cs Sp has an unstable αchain messenger RNA. Br J Haematol 1982; 51:405-13.5. Harteveld CL, Traeger-Synodinos J, Ragusa A, et al.Multicentric origin of Hb Constant Spring [α2 codon142 TAA-CAA]. Br J Haematol 1998; 102:50.6. Pootrakul P, Winichagoon P, Fucharoen S, Pravat-muang P, Piankijagum A, Wasi P. Homozygous hemo-globin Constant Spring: a need for revision of con-cept. Hum Genet 1981; 59:250-5.7. Schrier SL, Bunyaratvej A, Khuhapinant A, et al. Theunusual pathobiology of hemoglobin Constant Springred blood cells. Blood 1997; 89:1762-9.Liver nodular regenerative hyperplasia afterbone marrow transplantWe report an unusual liver disease which mayoccur after bone marrow transplantation, i.e. thecollapse of hepatic lobuli followed by regenerativeislets: the resulting clinical picture may mimic GvHDor a viral disease, but histology is diagnostic, show-ing nodular regeneration in the absence of inflam-mation or fibrosis.Sir,Liver abnormalities are frequently detected afterbone marrow transplantation (BMT). Early after thetransplant they may be due to drug toxicity, less fre-quently to venocclusive disease (VOD), viral or septicinfection. Late liver impairment is often related tochronic graft-versus-host disease (GvHD), and less fre-quently to viral reactivation or drug toxicity. Persistingdisorders are also to be expected in patients who sur-vive a VOD.1 A rarer post-transplant liver disorder isnodular regenerative hyperplasia (NRH), which is charac-terized by the formation of intrahepatic nodules ofregenerating hepatocytes, with moderate or no fibro-sis. This disorder has been associated with a numberof clinical conditions of  autoimmune (rheumatoidarthritis; Sjögren's, CREST or Felty's syndrome), hema-tologic (myelo-and lymphoproliferative disorders), orendocrine (diabetes mellitus) origin,2 or even after pro-longed administration of immunosuppressive3 or con-tracceptive drugs. We report the case of a patient whohad NRH nine months after an allogeneic BMT.A 35-year old male with chronic myeloid leukemiain chronic phase received a bone marrow transplantfrom his HLA-identical brother in March 1998. Theconditioning regimen was BuCy2; he was infused with1.6×108/kg. GvHD prophylaxis was a short course ofcyclosporin A and methotrexate (MTX). On day +2,after the first dose of MTX, the patient developedweight gain, painful hepatomegaly, decreased  diure-sis and increased  bilirubin, transaminases and PAI-1.With the suspicion of an impending VOD, we discon-tinued MTX and all signs and symptoms disappeared.On day +33, a grade IV acute cutaneous GvHDoccurred, successfully treated with high dose pred-nisone. At +5 months the patient presented withincreased ALT, AST, γ-GT, ALP and bilirubin, in theabsence of markers of viral infection. The patient wasthought to have hepatic GvHD, so she underwent liv-er biopsy, which showed  liver injury probably due todrug toxicity. All drugs were discontinued, and all liv-er function parameters improved; however, threemonths later a new wave of hepatic cytolysis andcholestasis  occurred (Figure 1). A repeat  liver biopsyshowed hepatocyte nodular regeneration with com-pression of the surrounding tissue, in the absence ofinflammatory cells even in portal areas and virtually nofibrosis. This picture is typical of  NRH (Figure 2 ). Notreatment was planned; liver enzymes are checkedevery month and continue to fluctuate. Seven monthsafter the diagnosis of NRH, no sign of portal hyper-tension has appeared. The pathogenesis of NRH is not well understood.Probably it results from sinusoidal lesions causinglocal hypoperfusion with regenerative hyperplasia inthe normally perfused surrounding areas.4 Clinically,NRH may be confused with liver cirrhosis.5 Fifty percent of patients with NRH develop portal hyperten-sion.4 Hepatic failure, rupture of the liver, malignanttransformation and gastric antral vascular ectasiasyndrome are described complications of NRH.6,7It is possible that post-transplant NRH is more fre-quent than reported, since several cases could havebeen clinically misdiagnosed as VOD, GvHD or drugtoxicity.8 Since no clinical or laboratory findings arespecific to NRH, an informative liver biopsy is theonly key to a correct diagnosis.9 In addition, since theliver may be sequentially involved by a number of dif-ferent events in the post-transplant period, repeat liv-er biopsies may be necessary to identify all the dam-aging mechanisms.Luca Pezzullo, Pietro Muretto, Gennaro De Rosa,Marco Picardi, Anna Lucania, Bruno RotoliDivision of Hematology, Federico II Univeristy, Naples,and Pathology Service, S. Salvatore Hospital, Pesaro, Italy.Key wordsNRH, BMT, GvHD, Liver Biopsy, LMCCorrespondenceBruno Rotoli, M.D., via S. Pansini 5, 80131 Napoli, Italy.Phone: international+39-081-7462068 – Fax: interna-tional+39-081-7462165Figure 1. Post-transplant time course of liver enzymes.References1. Richardson PG, Elias AD, Krishnan A, et al.Treatmentof severe veno occlusive disease with defribotide: com-passionate use results in efficacy without significanttoxicity in high risk population. Blood 1997; 90(Sup-pl 1):252a.2. Thung SN, Gerber MA, Bodenheimer HC Jr. Nodularregenerative hyperplasia of the liver in a patient withdiabetes mellitus. Cancer 1982; 49:543-6.3. Duvoux C, Kracht M, Lang P, Vernant JP, Zafrani ES,Dhumeaux D. Nodular regenerative hyperplasia of theliver associated with azathioprine therapy. Gastroen-terol Clin Biol 1991; 15:968-73.4. Ueno S, Tanabe G, Sueyoshi K, et al. Hepatic hemo-dynamics in a patient with nodular regenerative hyper-plasia. Am J Gastroenterol 1996; 91:1012-5.5. Connolly CE, O'Brien MJ. Nodular transformation ofthe liver: report of a case. Hum Pathol 1977; 8:350-2.6. Stromeyer FW, Ishak KG. Nodular transformation(nodular "regenerative" hyperplasia) of the liver. Aclinicopathologic study of 30 cases. Hum Pathol1981; 12:60-71.7. Cales P, Voigt JJ, Payen JL, et al. Diffuse vascular ecta-sia of the antrum, duodenum, and jejunum in apatient with nodular regenerative hyperplasia. Lack ofresponse to portosystemic shunt or gastrectomy. Gut1993; 34:558-61.8. Snover DC, Weisdorf S, Bloomer J, McGlave P, Weis-dorf D. Nodular regenerative hyperplasia of the liverfollowing bone marrow transplantation. Hepatology1989; 9:443-8.9. Wanless IR. Micronodular transformation (nodularregenerative hyperplasia) of the liver: a report of 64cases among 2.500 autopsies and a new classificationof benign hepatocellular nodules. Hepatology 1990;11:787-97.Incidence of factor v leiden and prothrombinG20210A in patients submitted to stem celltransplantationFactor V Leiden (FVL) and prothrombin G20210Aare the most common defects associated withthrombophilia. The purpose of our study was todefine the incidence FVL and prothrombin 20210Ain a population of patients with hematologic malig-nancies submitted to high dose chemotherapy andstem cell transplantation and verify the role of thesemutations in the development of thrombotic com-plications during and after transplantationSir,Factor V Leiden (FVL) and prothrombin G20210Aare the most frequent mutations associated withinherited thrombophilia. They are fairly common inthe general population and exert a substantial risk ofdevelopment of thromboses during a subject’s lifes-pan. The prevalences of FVL and prothrombinG20210A are 5% and 2%, respectively, in Caucasians1and 1.8% and 2.8%, respectively, in the general Italianpopulation.2,3 The relevance of these mutationsprompted us to investigate their prevalence and sig-nificance in thrombotic complications after stem celltransplantation (SCT) in patients with hematologicmalignancies.Sixty-nine consecutive patients referred to ourTransplant Unit were screened for FVL and pro-thrombin G20210A mutation. Protein C, S and ATI-II deficiency, and antiphospholipid antibodies wereexcluded in this series of patients. The patients’ char-acteristics are shown in Table 1. Donor-recipientpairs were studied before allogeneic SCT in order toavoid bias from post-transplantation chimerism.4Fifty-four patients are alive after a median follow-up of 31 months (range 10-69). Two out of 69patients (2.9%) were heterozygotes for these throm-bophilic mutations, one for FVL (1.4%) and one for670Haematologica vol. 85(6):June 2000scientific correspondenceFigure 2. Post-transplant liver nodular regenerative hyper-plasia. A: Two regenerative nodules compressing hepato-cytes. A portal area (bottom  right) shows moderate fibro-sis. (HE, 400x). B: Note the absence of inflammatory cellson the boundary between regenerating and compressedhepatocytes. (HE 1000x). C: Reticular fibrosis in the com-pressed areas, revealed by the Gomori’s staining (400x).

Liver nodular regenerative hyperplasia after bone marrow transplant.

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