Kakizoe, S

Pillay, P

Starzl, TE

Tzakis, AG

Tzoracoleftherakis, E

Van Thiel, DH

English

PubMed

D-Scholarship@Pitt

II!I Orthotopic Liver Transplantation for Hemochromatosis P. Pillay, E. Tzoracoleftherakis, A.G. Tzakis, S. Kakizoe, D.H. Van Thiel, and T.E. Starzl WE report here the use of orthotopic liver transplan-tation (OL T) at the University of Pittsburgh for the treatment of hereditary hemochromatosis (He) in adults. An association between iron overload and clinical diabetes mellitus. hyperpigmentation and cirrhosis of the liver has been recognized since 1871 1; since then. cardiomyopathy has been identified as another lethal complication. In 1935. Sheldon postulated that this disease. referred to as idio-pathic hemochromatosis. was an inborn error of iron metabolism. 2 With the development of percutaneous liver biopsy techniques and the ability to easily measure serum iron and ferritin levels. premortem diagnosis became pos-sible before the development of the lethal hepatic and extrahepatic complications. HLA typing has permitted discriminating genetic studies of the disease. and the term idiopathic hemochromatosis has been replaced with the terms primary hemochromatosis or hereditary hemochro-matosis (He). The availability of these tests has also delineated a wide variety of other hepatic disorders (sec-ondary hemochromatosis or hemosiderosis). J These latter conditions include transfusional iron overload in cases with thalassemia or hereditary spherocytosis. chronic ex-cessive iron intake. cirrhosis of any cause associated with portal systemic shunting and iron overload. and. particu-larly. Laennec's (alcoholic) cirrhosis . The gene frequency for hereditary hemochromatosis (He) is estimated to be I per 200 individuals with 10% of the white population thought to carry the gene.4 which is on chromosome 6. adjacent to the locus for the HLA antigens. H A transferrin saturation index (TSI) of >62% can accurately predict 92% of homozygous cases .7 HLA antigens A3. 87. and 814 have been shown to be closely associated with the gene for He. 4 Five of six of our cases were of this variety. The classical complications of diabe-tes mellitus. bronze pigmentation. arthralgia. pseudogout. cardiomyopathy. and cirrhosis often can be forestalled by therapeutic phlebotomy if the diagnosis is made early. However. once hepatic fibrosis develops. the long-term prognosis is poor because of progressive liver failure and the frequent development of hepatocellular carcinoma.1I MATERIALS AND METHODS A total of 14 adult patients were identified who had OLT between I January 1982 and J I December 1988 because of hemochroma· tosis. Biochemical studies ~ieK serum iron. serum ferritin. trans· ferrin saturation index. total iron binding capacity) and histologic studies suggested excessive iron overload. The amount of his-tologic iron deposition was graded on a scale of grade I to IV as described by Scheurer et aI.9 Hepatic iron was quantitated by atomic absorption spectrometry. Chronic phlebotomy therapy had been tried in all cases prior to referral for transplantation. Eight of the 14 patients were excluded from further study because the foregoing tests. and the clinical histories suggested that the iron overload was secondary to either chronic viral hepatitis ~O examples). postnecrotic cirrhosis (2). alcoholic cirril<>-sis (2). or hemolytic disease (2). I n the other 6. the combination of clinical data. liver function tests. iron studies of serum and liver. HLA typing data. and hepatic histology were consistent with a diagnosis of hereditary hemochromatosis. All of these adults had prolonged treatment with phlebotomy and/or desferoxamine. These six patients were among 1429 liver recipienis treated over the 7·year period. They were all males (Table I). Each had classic He with a chronic course. Variceal bleeding was the commonest symptom while ascites and jaundice were the most frequent signs. Two additional infants with perinatal acute hemochromotosis are being reponed separately. Five of the 6 patients with HC had the H LA antigens associated with HC (AJB7). HLA typing was not available for the sixth who had diabetes mellitus and clinically significant arthropathy despite a number of venesections over a IO-year period (Table I) . The mean duration of monthly phlebotomy therapy was 7 years (range of 3 to 12 years). One of these six patients had a hepatocellular carcinoma. RESULTS One of the six patients died soon after OLT as the result of a hepatic artery thrombosis despite an attempt at retrans-plantation 19 days after the initi~l OLT. The five survivors are well with follow-ups ranging from 6 months to 5'12 years (Table D. All five have normal liver function. Posttransplant biopsies from 6 months to 5 years . after transplantation have not shown any evidence of iron reaccumulation. DISCUSSION With He. the excess iron in tissue is distributed widely. Iron deposition occurs in the parenchyma of the liver. pancreas. other endocrine glands. and heart. Such iron deposition leads to cellular injury and the classical clinical findings of diabetes mellitus. cardiomyopathy. hyperpig-From the Departments of Surgery. Medicine and Pathology, University Health Center of Pittsburgh, University of Pittsburgh. Pittsburgh, Pennsylvania. Supported by research grants from the Veterans Administration and Project Grant No. OK 29961 from the National InsliMes of Health. Bethesda. M8l'fIand. Address reprint requests to Thomas E. Starzl. MD. PhD. FACS, Department of Surgery. 3601 Fifth Avenue, Falk Clinic SC. Pitts-burgh. PA 15213. (l 1991 by Appleton & Lange 0041-1345191/$3.001 + 0 1888 Transplantation Proceedings, Vol 23. No 2 (April). 1991: pp 1888-1889 OL T FOR HEMOCHROMATOSIS 1889 Tlble 1. Clinical Feltures Ind Outcome of PatIents WHh Hemochromatosis Age HLA Serum Iron (Years) Sex C~nk:al SymptornsiSigns Status SlUdies 41 M Diabetes. jaundice, variceal A3B7 bleeding 44 M Variceal bleeding, jaundice A3B7 61 M Liver failure, hepatocellular A3B7 CA 52 M Diabetes, pigmentation ND' 45 M Chronic liver failure, en· A3B7 cephalopathy, varices. arthropathy 44 M Variceal bleeding, ascrtes, A3B7 liver failure 'NO g nol done. mentation. and hepatic failure. Appropriate therapy con-sisting of phlebotomy can be effective if instituted early. before the development of many of these sequelae. The commonest subtype of congenital hemochromato-~isK hereditary hemochromatosis (HO. is an autosomal recessive disorder of iron metabolism with an HLA association , ~ All six of our:cases were of this variety and all were male. The precise metabolic error in HC is not established. An abnormaliiy either in the control of gas-trointestinal abso'l'tion of iron or hepatic uptake of iron are candidate possibilities . 10 An incorrect affinity for iron contained in transferrin. II or a defect in the processing of iron by the reticuloendothelial system of the liver. I! have also been considered. Most of these speculations l ) have concerned the adult HLA-linked disorder from which five of our six patients suffered. The exact way in which iron damages cells also is hypothetical. I) Although we have previously mentioned our experience of OL T for HC . '4 this is our first formal report on this indication for liver replacement. The observations suggest that this poorly understood defect in iron metabolism is either corrected with liver transplantation or effectively palliated for a long period. until enough iron reaccumula-lion can occur to injure tissues. Even if there is a recurrence and. at present. there is no evidence to suspect that this should be anticipated. death from causes other Grade or Iron Ouralion of FoIlow·Up Staining Venesection Outcome Period 4 7y Alive 4,5 y 4 12 Y Alive 4.3 y 4 By Rejection, died 19 days after re-GLT 2 lOy Alive 5y 4 3y Alive 4 y 4 6y Alive 0.6 y than HC is likely to occur before the latter eventuality is reached. Based upon this experience. liver transplantation probably will play a larger role in the future in the treatment of both classical HC as well as the fulminant pediatric disorder. REFERENCES I. Troiser M: Bull Soc Anat Paris 44:23 I. 1971 2. Sheldon JH : Haemochromatosis . London , Q,.;ford Univer-sity Press. 1935 3. Powell LW: Postgrad Med J 46:200. 1970 4, Bassett ML. Halliday JW. Powell LW: Semin Liver Dis 4:217. 1984 5. Simon M. Ale,.;andre JL. Farchet R, et al : Prog Med Genet 4: 135. 1980 6. Milder MS. Cook 10. Stray S. et al : Medicine 59:34, 1980 7. Edwards CO. Griffen LM . Goldgar D. et al : New Eng! J Med 318:1355. 1988 8. Niederau C. Fischer R. Sonnenberg A, et al : New Engl J Med 313:1256. 1985 9. Scheuer PJ. Williams R. Muir AR: J Pathol Bact 84:53. 1962 10. Hahn PF, Bale WF, Ross JF. et al : J E,.;p Med 78: 169. 1943 II. Co,.; TM, Peters TJ : Lancet I: 123. 1978 12. Batey RG. Pettet JE. Nicholas AW. et al: Gastroenterology 75 :856. 1978 13. Powell LW, Bassett ML. Halbday JW : Gastroenterology 78:374. 1980 14. StaIZI TE. Demetris AJ. Van Thiel DH: New Engl J Med 321 :1014.1989 

Orthotopic liver transplantation for hemochromatosis

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Orthotopic liver transplantation for hemochromatosis

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