Early Diagnosis Of Hemochromatosis Phenotyping Vs Genotyping

Early diagnosis of hemochromatosis permits treatment of iron overload and thereby prevents premature death due to hepatic cirrhosis (and primary liver cancer) and diabetes mellitus complications.1-1,2-1 Preventing iron overload may also reduce the frequency or severity of arthropathy, hypogonadotrophic hypogonadism and other endocrinopathic disorders, and cardiac abnormalities.[1,2]

The cornerstone of case detection in medical care and in population screening has been the measurement of serum transferrin saturation.[1] The severity of iron overload is estimated by quantification of the serum ferritin concentration, and by measurement of iron stores in liver biopsy specimens. An estimate of excess body iron stores can also be determined after the completion of iron depletion by therapeutic phlebotomy, although this does not provide data useful in prospective case ascertainment.

After the cloning of HFE and observations from early reports of significant associations of the mutations C282Y and H63D with hemochromatosis in Caucasians, there was hope that HFE genotyping could be used to identify persons at risk for developing iron overload. This would allow early intervention that could prevent or reduce the morbid conditions that often develop in persons with severe iron overload. Although genotyping is useful to detect hemochromatosis in western Caucasian ethnic groups and family members of affected individuals,[24] there are still too many unanswered questions regarding factors that affect clinical penetrance to recommend universal population genotypic screening. However, HFE genotyping is a useful test that can augment phenotyping with serum transferrin saturation and serum ferritin levels.

With the recent discovery of mutations in genes associated with other forms of hemochromatosis there is now the possibility that these mutations when present with HFE mutations can enhance or modify the risk for ''classical'' hemochromatosis (Table 3). In addition to ''classical'' hemochromatosis three other forms of hemochromatosis have been described. Juvenile hemochromatosis (OMIM #602390) is a relatively rare severe autosomal recessive disorder with an early age of onset.[25] Clinical symptoms usually appear in the second to third decade of life. There may be two forms of this disorder. Mutations in HAMP, a gene located on chromosome 19q13 (OMIM #606464) that codes for hepcidin, have been observed associated with one form of severe juvenile hemochroma-tosis in Italian families and in individuals with, ''altered indicators of iron status.''[26,27] Mutations in HAMP have been observed in subjects with iron overload who are also heterozygous for C282Y or S65C.[27-29] These data suggest that the onset or severity of iron overload may be ''modified'' by the presence of HAMP mutations in C282Y homozygous or heterozygous individuals.

The other form of juvenile hemochromatosis is linked to a gene on chromosome 1q21 (OMIM #608374). Mutations in the transcript unit LOC148738 now referred to as HJV have been reported associated with juvenile hemochromatosis in several families.[30] This gene appears to modulate hepcidin expression.

Mutations in TFR2, which maps to 7q22 and codes for transferrin receptor 2, have also been reported associated

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