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Hereditary hemochromatosis: recent advances in molecular genetics and clinical management
1Dipartimento di Scienze Biomediche e Oncologia Umana, Azienda Ospedaliera S. Luigi, Orbassano, CNR CIOS Turin, Italy. camaschella@csivms.csi.it
Insights
Hereditary hemochromatosis (HC) is an iron overload disorder. Early diagnosis and phlebotomy prevent severe symptoms, offering a normal life expectancy. Genetic screening is now possible for better disease control.
Area of Science:
- Genetics
- Metabolic Disorders
- Hematology
Background:
- Hereditary hemochromatosis (HC) is an inherited iron metabolism disorder causing progressive iron overload.
- Advances in understanding HC pathogenesis and management necessitate a review of current knowledge.
Purpose of the Study:
- To review recent advances in the pathogenesis and management of hereditary hemochromatosis.
- To discuss diagnostic approaches and the role of genetic factors in HC.
Main Methods:
- Literature review of articles and abstracts from Science Citation Index and Medline.
- Inclusion of authors' extensive research experience and cited publications in the field.
Main Results:
- HC is a late-onset, autosomal recessive condition, prevalent in Caucasians.
- Early diagnosis via transferrin saturation and liver biopsy is crucial; phlebotomy normalizes life expectancy.
- A candidate gene, HLA-H, has been identified on chromosome 6 and found mutated in many patients, enabling molecular screening.
Conclusions:
- Early diagnosis and treatment of HC prevent severe organ damage and ensure normal life expectancy.
- Liver biopsy remains essential for HC diagnosis and prognosis, despite advances in genetic testing.
- Identification and mutation analysis of the HLA-H gene represent a significant step towards better control and understanding of hereditary hemochromatosis.
Background And Objective:
Hereditary hemochromatosis (HC) is an inborn error of iron metabolism leading to increased intestinal iron absorption and progressive iron overload. There have been definite advances in our knowledge of the pathogenesis and management of idiopathic hemochromatosis in recent years, which prompted us to review this subject.
Information Sources:
The material examined in the present review includes articles and abstracts published in the journals covered by the Science Citation Index and Medline. In addition, both authors have been working in this field for several years and have contributed twelve of the papers cited in the references.
State Of Art And Perspectives:
The disease is a late onset autosomic recessive condition, especially frequent in Caucasians. If unrecognized, severe clinical symptoms develop in mid-life related to organ failure. Early diagnosis prevents complications, since an intensive phlebotomy course removes excess iron and offers patients a normal life expectancy. Transferrin saturation is the first examination step, but liver biopsy is still essential for diagnosis and prognosis of HC. The biochemical defect is unknown. Positional cloning of the HC gene has led to the isolation of all the candidate region on the short arm of chromosome 6, telomeric to HLA-A. Recently a putative HC gene has been cloned from this region and found to be mutated in a large proportion of patients. The gene, known as HLA-H, is an atypical MHC class I gene. Although its biological function remains unknown, HLA-H is the first strong HC candidate gene. Molecular screening of patients and carriers is now possible in a significant portion of cases, thereby permitting better control of the disease. If it is unequivocally confirmed that the HLA-H gene is responsible for the disease, understanding of its biological function will provide information on the type and activity of the involved protein, revealing new insights into iron uptake and metabolism in humans.