1. How the proposed research will contribute to meeting the goals and objectives of the PA: This study proposal will meet several of the goals and objectives of the PA. The core of the project is aimed at exploring the application of a new laboratory method (DNA-based genotyping for the newly discovered hemochromatosis gene) in identifying patients with end-stage liver disease and hereditary hemochromatosis from other patients with end- stage liver disease and hepatic iron overload. Genetic testing for this mutation is already clinically available and being used, but there are limited studies examining the utility and role of genetic testing and clinical practice. The current application will help bring this new laboratory into the clinical setting in an immediate way. The current study will also serve as a pilot study to examine the impact of iron overload on outcome after liver transplantation If increased hepatic iron overload is found to be a predictor of poor outcome after liver transplantation, then the findings of the trial will serve as the basis for a randomized, cooperative group clinical trial of iron reduction prior to liver transplantation. Iron overload is influenced by diet and nutrition, which is described as an area of special interest for this PA. Therefore, this clinical trial meets all the stated goals of the PA. 2.
Specific Aims To determine survival and cause of death in patients with hepatic iron overload undergoing liver transplantation who are homozygous for the C282Y mutation, which is present in most patients with hereditary hemochromatosis. To determine survival and cause of death in patients with hepatic iron overload undergoing liver transplantation who lack the C282Y mutation. To examine the predictive value of serum transferrin-iron saturation and serum ferritin for hepatic iron overload in end-stage liver disease. 3. Rationale for selection of the general methods and approaches to accomplish the specific aims: Although hepatic iron overload is common, most liver transplant centers do not have enough patients with well characterized iron overload and particularly patients with genetically confirmed hereditary hemochromatosis at their individual center to study outcome after liver transplantation in a meaningful. A multi-center study of this type is therefor necessary to enroll an adequate number of patients and achieve an adequate sample size to definitively test the hypotheses and address the specific aims. We have chosen a prospective and retrospective study design intentionally. Subjects who are found to have significant hepatic iron overload at the time of transplant can be retrospectively entered into the study. Subjects with a known diagnosis of hereditary hemochromatosis as defined in the inclusion criteria can be entered prospectively or retrospectively. Subjects who are identified prospectively using serum transferrin-saturation or ferritin will be followed prospectively.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
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Special Emphasis Panel (SRC)
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Robuck, Patricia R
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Ko, Cynthia; Siddaiah, Narendra; Berger, Jose et al. (2007) Prevalence of hepatic iron overload and association with hepatocellular cancer in end-stage liver disease: results from the National Hemochromatosis Transplant Registry. Liver Int 27:1394-401
Alexander, Jacob; Limaye, Ajit P; Ko, Cynthia W et al. (2006) Association of hepatic iron overload with invasive fungal infection in liver transplant recipients. Liver Transpl 12:1799-804
Kowdley, Kris V; Brandhagen, David J; Gish, Robert G et al. (2005) Survival after liver transplantation in patients with hepatic iron overload: the national hemochromatosis transplant registry. Gastroenterology 129:494-503
Kowdley, Kris V (2004) Liver transplantation: an ""in vivo"" model for the pathophysiology of hemochromatosis? Hepatology 39:1495-8
Kowdley, Kris V (2004) Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 127:S79-86