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-thalassemia require red-cell transfusions to survive beyond the first decade of life. Although this intervention clearly prolongs survival,1 it also results in the accumulation of iron in tissue, which is itself fatal without iron-chelating therapy2. Before the introduction of deferoxamine, iron-induced cardiac dysfunction was a predictable outcome in thalassemia,3 and it is still the leading cause of death, followed in incidence by hepatic disease1. Despite the successes with deferoxamine,4,5,6,7 many patients still have serious complications, because of either advanced age at the start of therapy or erratic compliance8,9,10,11,12,13,14. To date, the treatment of complications has been supportive, with high mortality after the onset of cardiac disease15. We report here the treatment of cardiac and hepatic failure in a patient with thalassemia by transplantation of the heart and liver from a single cadaveric donor. Two years after this procedure, our patient's hepatic and cardiac function was normal. Although he remained dependent on transfusion and chelation, biopsy specimens of the allograft heart showed no iron deposits, with only mild iron deposits demonstrable in the transplanted liver.
Case Report
The patient was born in 1965. Homozygous -thalassemia was diagnosed when he was two years old. DNA studies confirmed heterozygosity in the -globin gene for the frame-shift mutation at codon 39 and for the G-to-A mutation in intron 1 at position 110,16 and an 
-globin genotype of -3.7/-3.7. Red-cell transfusions were begun when the patient was four years old. Over a 10-year period, the mean hemoglobin value before transfusion was 8.0 g per deciliter. The patient underwent splenectomy at the age of 11, and the hemoglobin level was subsequently maintained above 10.0 g per deciliter. In 1978, subcutaneous deferoxamine therapy was initiated; compliance was erratic, and the serum ferritin concentration consistently exceeded 2000 ng per milliliter (range, 2590 to 16,000).
Cardiac failure developed at the age of 17, and the patient began treatment with digoxin and diuretics; subsequent ventricular tachycardia was treated with amiodarone. In 1990, cardiac magnetic resonance imaging (MRI)17 demonstrated a loss of signal consistent with heavy iron deposition; cardiac angiography showed a left ventricular ejection fraction of 21 percent, with no increase with exercise. An endomyocardial-biopsy specimen revealed heavy iron deposits and fibrosis.
Insulin-dependent diabetes mellitus was diagnosed in 1987. The patient remained prepubertal; stimulation testing with gonadotropin-releasing hormone in 1989 produced a prepubertal response,7 whereas MRI showed marked iron loading in the anterior pituitary.
Continuous ambulatory intravenous deferoxamine therapy18 was begun in 1990. Despite the patient's improved compliance, over the subsequent year the prothrombin time was repeatedly prolonged (to more than three seconds longer than the control value), the serum albumin level was depressed (to 3.3 g per deciliter; normal, >3.8), and the serum aspartate and alanine aminotransferases were consistently elevated (to three and five times normal, respectively). A firm, enlarged liver and moderate abdominal ascites were noted in 1991; a liver biopsy showed heavy iron loading and portal fibrosis with patchy cirrhosis. The patient tested positive for antibody to hepatitis C in October 1990; a test for hepatitis B antigen was negative.
Combined cardiac and liver transplantation was carried out in 1991. Both donor and recipient were O-positive, and their HLA genotypes were matched. Technical details of the 20-hour operation are reported elsewhere (unpublished data).
Results
Light-microscopical analysis of the excised heart demonstrated extensive fibrosis and iron in the cardiac-muscle fibers, endothelial cells, and macrophages (Figure 1A). The iron content was 5.8 mg per gram of dry-tissue weight. Eighteen months after transplantation, the donor heart showed no stainable iron (Figure 1B); the iron content was determined to be less than 0.5 mg per gram of dry-tissue weight.
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Discussion
There are few therapeutic options for patients with end-stage iron-induced cardiac and hepatic failure; reversal of this condition is unpredictable even with aggressive chelation therapy, and the five-year survival is low1,15. For several reasons, combined cardiac and liver transplantation rather than cardiac transplantation alone was considered to be indicated in this patient. Serial liver biopsies had shown worsening histologic features, including patchy cirrhosis not expected to improve with chelation therapy. In parallel fashion, deterioration in hepatic synthetic function, evidenced by abnormalities in prothrombin time and serum albumin levels, was believed to reflect an insufficient hepatocellular reserve for cardiac transplantation, considering both that azathioprine after transplantation may be problematic in the presence of hepatic injury and that the high cardiac output of cirrhosis might compromise a cardiac allograft. Moreover, studies in animals have demonstrated that when the liver or the spleen is transplanted together with a kidney, the heart, or a lung from the same donor, the recipient has fewer and less severe episodes of rejection19,20.
Combined human heart and liver transplantation has, however, been performed too infrequently to indicate whether the outcome is superior to that of single-organ transplantation. Three successful and two unsuccessful combined procedures have been reported,19,20,21,22,23 including one that included lung transplantation23. Cardiac transplantation alone has been performed in one patient with thalassemia without cirrhosis; hepatic synthetic function was not reported in this patient24. Cardiac transplantation alone may be indicated in patients with irreversible cardiac dysfunction in whom hepatic fibrosis has not progressed to cirrhosis24.
Before transplantation, the patient's hepatic iron concentration was grossly elevated -- to more than four times the median value (6.8 mg per gram of tissue) measured in 75 patients with thalassemia over the past year (unpublished data). On the basis of the weight and iron content of the organs excised at transplantation, the body iron load removed was approximately 64 g, or 1 g per kilogram, a lethal amount of iron25. Given the presence of markedly reduced hepatic and cardiac iron concentrations after transplantation, the patient's elevated serum ferritin concentration probably does not reflect the total-body iron load but instead reflects postoperative inflammatory complications.
Because the genetic defect in this patient was unchanged and regular transfusions remained necessary, the present finding of reduced tissue levels of iron did not necessarily predict a good long-term outcome. However, in the light of reports of substantial hepatic iron accumulation in children with thalassemia after only three years of transfusions26 and of liver biopsies demonstrating iron-induced hepatic fibrosis in patients with thalassemia after only two years of transfusions,27 the presence of such markedly reduced tissue iron stores at this time was certainly encouraging. Clearly, however, continued strict adherence to a regimen of chelation therapy was required for the maintenance of low tissue iron levels; the patient's compliance improved as a result of weekly home nursing visits, increased maturity on the part of the patient, and improved ease of intravenous deferoxamine administration18.
Clearly, a substantial cohort of patients may be considered for combined organ transplantation. Although virtually all patients with thalassemia in developed countries begin chelation before the age of 10,2 there remains an older cohort who received transfusions for years without chelation therapy. Since the time of the procedure in our patient, two patients in our clinic who had iron-induced cardiac and liver dysfunction died, despite intensive treatment with deferoxamine, before a suitable donor became available. This outcome highlights the importance of the early identification of an inexorable downhill course of cardiac and hepatic failure. We would consider combined organ transplantation for any patient with iron loading and severe cardiac dysfunction associated with biopsy-demonstrated hepatic cirrhosis. At present, this may be the only option for patients with end-stage iron-induced cardiac and liver disease.
Dr. Olivieri is a Career Scientist of the Ontario Ministry of Health.
We are indebted to Drs. Tirone David, Chris Feindel, and Gary Levy and to Ms. Beverley Tyler, B.Sc.N., for participation in the follow-up of the patient.
Source Information
From the Hospital for Sick Children (N.F.O., G.D.S., P.J.M., A.F.C.) and the Toronto Hospital (N.F.O., P.P.L., P.A.D., P.D.G., W.H.F., D.M.T., J.B.), Toronto.
Address reprint requests to Dr. Butany at the Department of Pathology, Toronto Hospital, 200 Elizabeth St., Toronto, ON M5G 2C4, Canada.
References
-thalassemia major. N Engl J Med 1990;323:713-719. [Abstract]
-thalassaemia patients receiving regular transfusion and iron chelation: reversal by intensified chelation. Acta Haematol 1990;84:113-117. [Medline]
-thalassemia major treated with deferoxamine. J Pediatr 1991;118:540-545. [CrossRef][Medline]
thalassemia (HBT). Blood 1993;82:Suppl 1:359a-359a.abstract
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