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CORRESPONDENCE

Genetic Manipulations Utilizing Albumin and Alpha-fetoprotein Promoter/Enhancers Affect BothHepatocytes and Oval Cells

To the Editor:

An interesting report by Streetz et al. published in HEPATOLOGY de-scribed the production of hepatocyte conditional gp130 knockout micesubjected to chronic liver injury by repeated carbon tetrachloride (CCl4)treatment.1 Chronic injury induces liver regeneration by recruitment ofcells from a precursor, either from a stem cell or a progenitor cell known asthe oval cell. Numerous mouse studies such as that described by Streetz etal.1 utilize albumin-alpha-fetoprotein (AFP) promoter and/or enhancersequences to achieve hepatocyte specific gene deletions by expressing Crerecombinase.2 The albumin-AFP promoter and/or enhancers are used, asAFP is an early marker of hepatocyte commitment. First detected at 8.5days gestation in hepatoblasts, it is highly expressed in perinatal liver anddiminishes to low or undetectable levels in the adult mouse.3 Albuminproduction commences around 9.5 days gestation and is maintainedthroughout development.4

We have previously shown that the choline-deficient, ethionine-supplemented diet (CDE) induces liver progenitor oval cells in rodentsand that these cells express albumin and AFP.5,6 Oval cells induced byCCl4 will express albumin and AFP.7 We therefore raise the possibilitythat the interpretation of many hepatocyte-specific gene targeting ex-periments may be compromised by this situation. A quiescent pool ofoval cells exists in the liver and will respond to promitogenic signalsinitiated by chronic liver damage. In the study by Streetz et al.,1 re-peated CCl4 treatment may activate oval cell proliferation.7 Therefore,oval cells derived from the endogenous pool will also be deficient forgp130. The protective role of gp130 stimulation as observed by Streetzet al.1 might well be explained by gp130 stimulation of oval cells,which results in cellular proliferation (see below). This phenomenonhas not been considered in the publication. We wish to alert yourreadership that conditional gene targeting utilizing Cre recombinasedriven by the albumin-AFP promoter/enhancer sequences will inacti-vate the gene of interest in hepatocytes and oval cells.

We recently produced novel data implicating the combination ofinterleukin (IL)-6 and its soluble IL-6R (sIL-6R) (hyper IL-6)8 in ovalcell activation (Fig. 1). IL-6 signalling via the sIL-6R requires gp130 toexert its effect. Therefore, in the publication by Streetz et al.,1 it is likelythat the knockout of gp130 in progenitor oval cells may compromisetheir activation during chronic liver injury. Although few oval cells arepresent in normal liver, their presence can confound experiments that

do not involve chronic liver injury. In a mouse model where simianvirus 40 (SV40) large T antigen is overexpressed under the control ofthe albumin promoter, hepatocellular carcinoma occurs9. It is acceptedthat SV40 large T antigen expressed in hepatocytes is responsible forthe hepatocellular carcinoma. Since overexpression of SV40 large Tantigen induces oval cell proliferation and carcinoma, which are posi-tive for the oval cell marker A6,10 it’s possible that the tumorigenicprocess is initiated in an oval cell.

In conclusion, experiments utilizing the albumin and AFP promot-er/enhancers to activate or inactivate genes need to consider that ovalcells as well as hepatocytes may be affected.

VANCE B. MATTHEWS1

STEFAN ROSE-JOHN2

GEORGE C. T. YEOH1

1The University of Western Australia Centre for Medical ResearchWestern Australian Institute for Medical ResearchPerth, AustraliaBiochemistry and Molecular Biology, School of Biomedical and

Chemical SciencesCrawley, Australia2Biochemistry InstituteChristian Albrechts UniversityKiel, Germany

References1. Streetz KL, Tacke F, Leifeld L, Wustefeld T, Graw A, Klein C, et al.

Interleukin 6/gp130-dependent pathways are protective during chronicliver diseases. HEPATOLOGY 2003;38:218–229.

2. Kellendonk C, Opherk C, Anlag K, Schutz G, Tronche F. Hepatocyte-specific expression of Cre recombinase. Genesis 2000;26:151–153.

3. Shiojiri N. Enzymo- and immunocytochemical analyses of the differentiation ofliver cells in the prenatal mouse. J Embryol Exp Morphol 1981;62:139–152.

4. Cascio S, Zaret KS. Hepatocyte differentiation initiates during endoder-mal-mesenchymal interactions prior to liver formation. Development1991;113:217–225.

5. Tian YW, Smith PG, Yeoh GC. The oval-shaped cell as a candidate for a liverstem cell in embryonic, neonatal and precancerous liver: identification basedon morphology and immunohistochemical staining for albumin and pyruvatekinase isoenzyme expression. Histochem Cell Biol 1997;107:243–250.

6. Smith PG, Tee LB, Yeoh GC. Appearance of oval cells in the liver of ratsafter long-term exposure to ethanol. HEPATOLOGY 1996; 23:145–154.

7. Engelhardt NV, Baranov VN, Lazareva MN, Goussev AI. Ultrastructurallocalization of alpha-fetoprotein (AFP) in regenerating mouse liver poi-soned with CCl4. 1. Reexpression of AFP in differentiated hepatocytes.Histochemistry 1984;80:401–407.

8. Fischer M, Goldschmitt J, Peschel C, Kallen KJ, Brakenhoff JPJ, Wollmer A,Grotzinger J, and Rose-John S. A bioactive designer cytokine for human he-matopoietic progenitor cell expansion. Nat Biotechnol 1997;15:142–145.

9. Hino O, Kitagawa T, Nomura K, Ohtake K, Cui L, Furuta Y, Aizawa S.Hepatocarcinogenesis in transgenic mice carrying albumin-promotedSV40 T antigen gene. Jpn J Cancer Res 1991;82:1226–1233.

10. Bennoun M, Rissel M, Engelhardt N, Guillouzo A, Briand P, Weber-Benarous A. Oval cell proliferation in early stages of hepatocarcinogen-esis in simian virus 40 large T transgenic mice. Am J Pathol1993;143:1326–1336.

Copyright © 2004 by the American Association for the Study of Liver Diseases.Published online in Wiley InterScience (www.interscience.wiley.com).DOI 10.1002/hep.20396

Fig. 1. The combination of interleukin (IL)-6 and sIL-6R (hyper IL-6)enhances oval cell activation. (A) Proliferation of a hyper IL-6 (50ng/mL)stimulated immortalized oval cell line as determined by the MTT assay. (B)Male C57BL/6 mice were subjected to the choline-deficient, ethionine-supplemented diet for 2 weeks and injected intraperitoneally every 2 dayswith Hanks Balanced Salt Solution or Hyper IL-6 (4 �g). Livers were excisedand sections stained for the oval cell marker A6. Each data point representsresults from 1 mouse.

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Reply:

In our recent study,1 the contribution of interleukin 6 (IL-6)/gp130–dependent pathways during liver injury was investigated. Weused an ubiquitous (Mx1-promoter, MxCre2,3) and cell-specific (Alf-pCre, alfa-fetoprotein [AFP] �albumin enhancer and albumin-pro-moter4,5) approach to conditionally inactivate gp130 in different livercell types, thereby showing that gp130-deleted mice (either selectivelyin hepatocytes or in all liver cells) had a blunted STAT3 activation andacute-phase response induction after CCl4 treatment. However, gp130deficiency had no effect on the degree of acute CCl4-mediated liverinjury and subsequent hepatocyte proliferation. In contrast, after re-petitive CCl4 injections in 1x-Cre, but not in AlfpCre gp130-deletedmice, a more pronounced fibrosis progression was evident. From theseexperiments we concluded that deletion of gp130 in hepatocytesthrough the AlfpCre construct is not crucial for fibrosis progression inthis model, as the phenotype was evident in mice expressing Cre underthe control of the ubiquitous Mx1-promoter. Therefore, our mainconclusion was that IL-6 acts via gp130 on cells other than hepatocyteswithin or even outside the liver. The interpretation of this observationwould be independent of whether oval cells would also show a deletionof gp130 through the AlfpCre construct.

The body of evidence for an involvement of oval cells duringchronic liver injury is rapidly growing, but the nature of these cellsitself is not yet fully understood. Oval cells have not been specificallyinvestigated in our study, although it is likely that nonactivated ovalcells might be within the pool of Mx1-mediated gp130-deleted cells ofthe liver. Therefore we are thankful for the comment made by Mat-thews et al. about this specific aim. As oval cells are suspected to expressAFP and even albumin, they would be subjected to AlfpCre-mediatedgp130 knockout in our system. This event would occur at the latest atthe time point of their induction by potentially injuring processes. Asthe AlfpCre�/gp130loxP mice did not show any significant pheno-type during acute and chronic CCl4 mediated liver injury, the role ofgp130 in oval cells is most likely not essential under these circum-stances. However, we cannot rule out that nonactivated oval cellsmight initially not express enough AFP/albumin to activate Cre tran-scription.

We are fully aware that ectopic expression of AFP and albumin incells other than hepatocytes has to be taken into consideration espe-cially when using the construct to mediate Cre-recombinase specificgene-inactivation. There is evidence that these genes are activated dur-ing embryonic development in cells of the hepatoblast from theendoderm6 and can even be found within the gut, pancreas, and kid-ney, although at very low levels. To ensure only expression within thehepatic lineage, consideration was taken to limit Cre expression in the

herein-used AlfpCre construct4 by the application of several regulatoryelements (the mouse albumin enhancer, the albumin promoter, and 3mouse AFP enhancers).

Cell type–specific gene expression is always flawed with limitations.This is either due to the fact that most systems for transcriptionalactivation are leaky at some degree or that the achieved expression levelmight be too low to overcome certain barriers. Therefore, better andeven more specific approaches are needed. The specific aim of genedeletion by an AFP/albumin-dependent Cre recombinase in oval cellscannot be successfully answered at this time point. It is, however, aninteresting subject for further studies and should be considered infuture approaches of hepatocyte-specific gene inactivation.

KONRAD L. STREETZ, M.D.TORSTEN WUESTEFELD, PH.D.MICHAEL P. MANNS, M.D.CHRISTIAN TRAUTWEIN, M.D.Department of Gastroenterology, Hepatology & EndocrinologyMedical School of HannoverHannover, Germany

References1. Streetz KL, Tacke F, Leifeld L, Wustefeld T, Graw A, Klein C, Kamino K,

et al. Interleukin 6/gp130-dependent pathways are protective duringchronic liver diseases. HEPATOLOGY 2003;38:218–229.

2. Betz UA, Bloch W, van den Broek M, Yoshida K, Taga T, Kishimoto T, etal. Postnatally induced inactivation of gp130 in mice results in neurolog-ical, cardiac, hematopoietic, immunological, hepatic, and pulmonary de-fects. J Exp Med 1998;188:1955–1965.

3. Wuestefeld T, Klein C, Streetz KL, Betz U, Lauber J, Buer J, et al. Inter-leukin-6/glycoprotein 130-dependent pathways are protective during liverregeneration. J Biol Chem 2003;278:11281–11288. a

4. Kellendonk C, Opherk C, Anlag K, Schutz G, Tronche F. Hepatocyte-specific expression of Cre recombinase. Genesis 2000;26:151–153.

5. Streetz KL, Wustefeld T, Klein C, Kallen KJ, Tronche F, Betz UA, et al.Lack of gp130 expression in hepatocytes promotes liver injury. Gastroen-terology 2003;125:532–543.

6. Soudais C, Bielinska M, Heikinheimo M, MacArthur CA, Narita N, Saf-fitz JE, et al. Targeted mutagenesis of the transcription factor GATA-4gene in mouse embryonic stem cells disrupts visceral endoderm differenti-ation in vitro. Development 1995;121:3877–3888.


Peginterferon Alfa-2a (40 kd) and Ribavirin for Black American Patients With Chronic HCVGenotype 1

To the Editor:

In the recent issue of HEPATOLOGY, Jeffers et al. report the results ofthe prospective study evaluating responses of black patients withchronic hepatitis C to peginterferon alfa-2a and ribavirin.1 We wish tocomment on the role of obesity in interferon resistance in blacks andthe predictability of sustained virological response (SVR) based onearly virological response (EVR).

The black patients in this study were heavier than white pa-tients, a finding that was also observed in a similar study withpeginterferon alpha-2b.2 This fact reinforces a hypothesis that obe-sity might have contributed to poor response to interferon amongblack patients. Obesity-related comorbidities in blacks, such as

diabetes and hypertension, might have contributed to the lowerrate of SVR of 19% in the Muir et al. study compared to 26% in thestudy of Jeffers et al. The apparent lack of body-weight effect in theregression analysis in both studies agrees with earlier observationsthat weight alone is not a reliable parameter to predict response.3 Infact, obesity was found to be an independent negative predictor ofresponse to antiviral treatment only when defined as body massindex greater than 30 kg/m2.3 Obesity presumably diminishes theeffectiveness of interferon by altering its distribution.4 Such a phar-macokinetic difference is supported also by an observation of re-duced incidence of adverse events among black patients found byJeffers et al. Obesity may also induce interferon resistance directlythrough the alteration of immune function.5 Prospective studies are

760 HEPATOLOGY, September 2004

needed to investigate whether weight reduction or higher doses ofinterferon could enhance antiviral responsiveness in black patients.

With regard to the predictability of SVR, Jeffers at al. are correct inpointing out that all patients with a minimum 2-log decrease in viralload should continue antiviral therapy even if the positive predictivevalue of EVR defined as undetectable hepatitis C virus (HCV) RNA atweek 12 is higher. This conclusion is supported by the finding that afair proportion (16%) of the patients who had at least 2-log reductionof HCV-RNA but remained detectable achieved SVR. The authors,however, fail to point out that all such patients with genotype l shouldbe retested with a sensitive qualitative polymerase chain reaction(PCR) assay at week 24. Several authors suggested that if HCV-RNAis detectable at week 24, treatment should be stopped because thelikelihood of achieving SVR is virtually nil.6–10 For example, Davies etal. showed that of those patients who remained PCR positive at week24, only 4% achieved SVR, compared with 33% of those who lostvirus between weeks 12 and 24.6 Furthermore, the probability ofachieving SVR in patients who had 2-log decrease in HCV-RNA butremained PCR positive was about 4 times lower than in those who hadundetectable HCV-RNA after 12 weeks. We are curious why thisinformation was not incorporated in the recent American Associationfor the Study of Liver Disease guidelines.10

MICHAL R. PIJAK, M.D.FRANTISEK GAZDIK, M.D.STEFAN HRUSOVSKY, M.D.Department of Clinical ImmunologySlovak Medical UniversityBratislava, Slovak Republic

References1. Jeffers LJ, Cassidy W, Howell CD, Hu S, Reddy KR. Peginterferon alfa-2a

(40 kd) and ribavirin for black American patients with chronic HCVgenotype 1. HEPATOLOGY 2004;39:1702–1708.

2. Muir AJ, Bornstein JD, Killenberg PG; Atlantic Coast Hepatitis Treat-ment Group. Peginterferon alfa-2b and ribavirin for the treatment ofchronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med2004;350:2265–2271.

3. Bressler BL, Guindi M, Tomlinson G, Heathcote J. High body mass indexis an independent risk factor for nonresponse to antiviral treatment inchronic hepatitis C. HEPATOLOGY 2003;38:639–644.

4. Lam NP, Pitrak D, Speralakis R, Lau AH, Wiley TE, Layden TJ. Effect ofobesity on pharmacokinetics and biologic effect of interferon-alpha inhepatitis C. Dig Dis Sci 1997;42:178–185.

5. Marti A, Marcos A, Martinez JA. Obesity and immune function relation-ships. Obes Rev 2001;2:131–140.

6. Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J.Early virologic response to treatment with peginterferon alfa-2b plus ribavirinin patients with chronic hepatitis C. HEPATOLOGY. 2003;38:645–652.

7. Russo MW, Fried MW. Guidelines for stopping therapy in chronic hepa-titis C. Curr Gastroenterol Rep 2004;6:17–21.

8. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FLJr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virusinfection. N Engl J Med 2002;347:975–982.

9. Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001;345:41–52.

10. Strader DB, Wright T, Thomas DL, Seeff LB; American Association forthe Study of Liver Diseases. Diagnosis, management, and treatment ofhepatitis C. HEPATOLOGY 2004;39:1147–1171.


Reply:

We acknowledge the issues raised by Pijak et al. regarding the role ofobesity in the low response rates to interferon-based therapies of blackpatients with hepatitis C. Indeed, the average weight of black patients washigher than that of white patients in our study,1 as well as in the Muirstudy.2 Although a smaller proportion of black patients with body massindex (BMI) �30 kg/m2 (8 of 35; 23%) achieved sustained virologicalresponse (SVR) than did those with BMI �30 kg/m2 (12 of 42; 29%), therates were not significantly different. Furthermore, the percentages of pa-tients with diabetes (5 of 18; 28%) or hypertension (13 of 43, 30%) whoachieved SVR were similar to that of the whole population. Thus, associ-ations with these two common comorbidities also did not provide anexplanation for the low response rate in blacks.

When BMI �30 kg/m2 was included in the univariate analysis, itfailed to reach statistical significance (odds ratio, 0.74; P � .57) as apredictor for nonresponse. Multivariate analysis that included BMI�30 kg/m2, along with age �40 years, male sex, alanine aminotrans-ferase �3 upper limit of normal, hepatitis C virus (HCV) RNA base-line �800,000 IU/mL, and histologic activity index �10, also failedto show a significant association of BMI �30 kg/m2 with nonresponse(odds ratio, 0.66; P � .479). Thus, the key factors associated with thelow virologic responses of black Americans are not evident from ouranalyses and remain to be elucidated. Finally, Muir et al.2 reported thatonly 19% of black patients achieved SVR, despite the weight-baseddosing of pegylated interferon alfa-2b. Therefore, we surmise thatincreasing the pegylated interferon alfa-2a dose according to weight orBMI is unlikely to override any negative impact of BMI.

With regard to retesting patients with genotype l at week 24, we pointout that in our study, serum HCV RNA was assessed by sensitive testing(�50 IU/mL as measured by the AMPLICOR HCV Test, version 2.0[Roche Diagnostics, Branchburg, NJ]). However, our protocol did notinclude a 24-week stopping rule because other goals of the study were todetermine the differences in viral kinetics over time and to evaluate thehistologic benefits of treatment that may be unique to blacks in compari-son to whites. Our data show that, of 53 black patients with paired biop-sies, 13 (25%) experienced fibrosis improvement, and 36 (68%) showedstabilization. We concluded from our work that although SVR rates werelower, patients with early virological response should continue on treat-ment. Nevertheless, we concur that if patients demonstrate a positiveHCV RNA by a sensitive quantitative assay at 24 weeks, treatment mayreasonably be discontinued.

LENNOX J. JEFFERS, M.D.1

WILLIAM CASSIDY, M.D.2

CHARLES D. HOWELL, M.D.3

SYLVIA HU, PH.D.4

K. RAJENDER REDDY, M.D.51Miami Veterans Affairs Medical Center, Miami, FL2Louisiana State University Health Sciences Center, Baton Rouge, LA3University of Maryland School of Medicine, Baltimore, MD4Roche Laboratories, Inc., Nutley, NJ5University of Pennsylvania, Philadelphia, PA

References

1. Jeffers LJ, Cassidy W, Howell CD, Hu S, Reddy KR. Peginterferon alfa-2a(40 kd) and ribavirin for black American patients with chronic HCVgenotype 1. HEPATOLOGY 2004;39:1702–1708.

2. Muir AJ, Bornstein JD, Killenberg PG; Atlantic Coast Hepatitis Treat-ment Group. Peginterferon alfa-2b and ribavirin for the treatment ofchronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med2004;350:2265–2271.


HEPATOLOGY, Vol. 40, No. 3, 2004 761

No Hepatic Iron Overload 12 Years After Liver Transplantation for Hereditary Hemochromatosis

To the Editor,We read with interest the results from a multinational study reported by

Crawford et al.1 dealing with pathogenesis of hereditary hemochromatosis(HH) using liver transplantation model. They showed that reaccumulation ofliver iron is very unusual 4 years after transplantation and that post–liver trans-plantation survival is reduced in HH (survival at 5 years after orthotopic livertransplantation- [OLT]: 55%). Nevertheless, half of the patients had shownexcessive alcohol consumption before undergoing OLT.

In our institution, 5 male patients underwent OLT for HH (mean age atOLT: 60 years) with a median follow-up of 12 years (Table 1). All patientsunderwent a venesection program before OLT. All were hepatitis B surfaceantigen negative, their alcohol consumption was below 60 g per day, and noadditional cause of liver disease was detected. Three had diabetes mellitus.Indication for OLT was end-stage liver disease with cirrhosis (n � 3) or pri-mary liver cancer (PLC) (n � 3). Two patients (patients 1 and 3) with com-binedhepatocellular-cholangiocarcinomas (HCK)occurringonseptalfibrosiswere treated with chemoembolization before OLT. One patient (patient 5)had a moderately differentiated multifocal hepatocellular carcinoma (6 nod-ules below 3 cm) on cirrhosis. After OLT, all 3 patients with PLC received 9cyclesof chemotherapy including5-fluorouracil andanthracyclines.Histolog-ical iron overload was assessed using Deugnier’s grading system on deparaf-finized liver sections stained with Perls’s stain.2 On explanted native liver,histological iron score and histological hepatic iron index are summarized onTable 1. In the latest liver biopsy post-OLT (mean histological follow up: 105months),weneverobservedanyirondeposit inhepatocytes, sinusoidalcells,orportal tracts. With a longer mean duration of follow-up, our data are in agree-ment with the study of Crawford et al. Furthermore, no patient had eitherabnormal serum iron, or ferritin, or transferring saturation tests after a meanfollow-upperiodof12.2years.However,our survival results arequitedifferentfrom those of Crawford et al. In our series, 4 patients were alive more than 8years after OLT (ranging from 8 to 15.5 years). Moreover, we did not observerecurrence of liver tumor. Nevertheless, all patients developed extrahepaticcancers after OLT: skin cancers (porocarcinoma, basal cell carcinomas, squa-mous carcinomas) surgically resected, ethmoid adenocarcinoma treated withradiotherapy, and a fatal lung adenocarcinoma.

In conclusion, our results showed no evidence of liver iron reaccumu-lation even after a long follow-up period. Although we observed a highincidence of de novo extrahepatic cancers, we emphasize the good survivalafter OLT for HH even when patients had primary liver cancer.

MARIE-PIERRE BRALET, M.D.1

JEAN-CHARLES DUCLOS-VALLEE, M.D.2

DENIS CASTAING, M.D.2

DIDIER SAMUEL, M.D.2

CATHERINE GUETTIER, M.D.11Service d’Anatomie PathologiqueHopital Paul BrousseVillejuif, France2Centre Hepatobiliaire

References1. Crawford DHG, Fletcher LM, Hubscher SG, Stuart KA, Gane E, Angus PW, et

al. Patient and graft survival after liver transplantation for hereditary hemochroma-tosis: implications for pathogenesis. HEPATOLOGY 2004;39:1655–1662.

2. Deugnier YM, Turlin B, Powell LW, Summers KM, Moirand R, FletcherL, et al. Differentiation between heterozygotes and homozygotes in genetichemochromatosis by means of a histological hepatic iron index: a study of192 cases. HEPATOLOGY 1993;17:30–34.


Reply:We were pleased by the comments of Bralet et al.1 relating to our

recent publication in HEPATOLOGY and detailing results from their insti-tution. The findings of the 2 studies are quite similar. Firstly, hereditaryhemochromatosis is an uncommon indication for liver transplantation.Despite not reporting the total number of liver transplants performed intheir institution, it is safe to assume that these 5 patients presented in theircorrespondence represent only a small proportion of their total transplantpopulation. Secondly, the absence of evidence of liver iron reaccumulationafter a lengthy follow-up period (median, 12.2 years) suggests an impor-tant role for the liver in contributing to the pathophysiology of iron over-load in hereditary hemochromatosis.

In contrast to our study, the overall survival of the patients reportedby Bralet et al. is very good. It should be emphasized however, that themost outstanding variable predicting death in our cohort was the pres-ence of a hepatocellular carcinoma outside the Mazzaferro criteria. Thetumor border is not clearly defined in the patients reported by Bralet etal. However, their chemotherapy protocol is deserving of further studyif those tumors were outside the current guidelines regarding trans-plantation in patients with hepatocellular carcinoma.

DARRELL CRAWFORD

LINDA FLETCHER

Gastroenterology and HepatologyPrincess Alexandra Hospital/University of QueenslandBrisbane, Australia

References1. Bralet M-P, Duclos-Vallee J-C, Castaing D, Samuel D, Guettier C. No

hepatic iron overload 12 years after liver transplantation for hereditaryhemochromatosis. HEPATOLOGY 2004;40:762.


Table 1. Characteristics of Patients With Hereditary Hemochromatosis

Haplotype GenotypeDiabetesMellitus

Age at OLT(y) Indication for OLT

Iron Grade(HIS/HHII)Native Liver

Latest LiverBiopsy

(y post-OLT)

Duration ofFollow-Up

(y) (outcome) Complications

1 HLA A3 C282Y�/� No 65 Septal fibrosis � HCK 16/0.24 5 8 (D) Lung ADK2 HLA A3 ND Yes 57 Cirrhosis 27/0.47 10 15.5(A) Skin cancers3 HLA A3 C282Y�/� Yes 64 Septal fibrosis � HCK 4/0.06 7.5 8 (A) Skin cancers4 NA No 58 Cirrhosis 11/0.18 10 14 (A) Skin cancer5 HLA A3 NA Yes 56 Cirrhosis � HCC 9/0.16 12 15.5(A) Ethmoid ADK

Abbreviations: HIS, histological iron score; HHII, histological hepatic iron index; D, deceased; ADK, adenocarcinoma; A, alive; NA, not available; HCC, hepatocellular carcinoma.

762 HEPATOLOGY, September 2004

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