Sonja I. Webb

Distribution of transferrin saturation in an Australian population: relevance to the early diagnosis of hemochromatosis.

BACKGROUND & AIMS An elevated transferrin saturation is the earliest phenotypic abnormality in hereditary hemochromatosis. Determination of transferrin saturation remains the most useful noninvasive screening test for affected individuals, but there is debate as to the appropriate screening level. The aims of this study were to estimate the mean transferrin saturation in hemochromatosis heterozygotes and normal individuals and to evaluate potential transferrin saturation screening levels. METHODS Statistical mixture modeling was applied to data from a survey of asymptomatic Australians to estimate the mean transferrin saturation in hemochromatosis heterozygotes and normal individuals. To evaluate potential transferrin saturation screening levels, modeling results were compared with data from identified hemochromatosis heterozygotes and homozygotes. RESULTS After removal of hemochromatosis homozygotes, two populations of transferrin saturation were identified in asymptomatic Australians (P < 0.01). In men, 88.2% of the truncated sample had a lower mean transferrin saturation of 24.1%, whereas 11.8% had an increased mean transferrin saturation of 37.3%. Similar results were found in women. A transferrin saturation threshold of 45% identified 98% of homozygotes without misidentifying any normal individuals. CONCLUSIONS The results confirm that hemochromatosis heterozygotes form a distinct transferrin saturation subpopulation and support the use of transferrin saturation as an inexpensive screening test for hemochromatosis. In practice, a fasting transferrin saturation of > or = 45% identifies virtually all affected homozygous subjects without necessitating further investigation of unaffected normal individuals.

Analysis of the cost of population screening for haemochromatosis using biochemical and genetic markers

AIMS To estimate the cost of population screening for haemochromatosis in Australia and to compare the cost of alternative screening strategies. METHODS The costs of screening for haemochromatosis were analysed in a hypothetical study using transferrin saturation as the primary screening test, with confirmation of the diagnosis by either liver biopsy or DNA testing for the recently-described haemochromatosis gene. RESULTS Screening, with confirmation of the diagnosis by liver biopsy, would cost between US

A region of primer binding variation at the D6S265 locus associated with HLA-A25 and HLA-A26 antigens

5079 and US

Haemochromatosis and HLA–H

8813 per case detected (excluding administrative costs), depending on the screening strategy (Aust

Cohort Study of Internal Malignancy in Genetic Hemochromatosis and Other Chronic Nonalcoholic Liver Diseases

= US

Localization of the hemochromatosis gene close to D6S105

0.80). If a DNA test were used instead of liver biopsy, the cost would be reduced to an estimated US

Evidence that the ancestral haplotype in Australian hemochromatosis patients may be associated with a common mutation in the gene.

3954-US

Haplotype analysis in Australian hemochromatosis patients : evidence for a predominant ancestral haplotype exclusively associated with hemochromatosis

4410 per case. This would be further reduced to US

Localization of frontotemporal dementia with parkinsonism in an Australian kindred to chromosome 17q21–22

2457 by detection of additional cases by screening family members. The least costly strategy utilised a transferrin saturation threshold of 55% and DNA testing for confirmation of the diagnosis; however, a transferrin saturation threshold of 45% increased the cost only marginally. The initial screening step (transferrin saturation) accounted for 74%-94% of the estimated cost of the screening programme. CONCLUSIONS Screening for haemochromatosis using transferrin saturation involves relatively modest costs which may be recovered if complications of haemochromatosis can be prevented by early detection and treatment. The most cost-effective strategies utilised transferrin saturation for initial screening, followed by DNA testing. Reduction in the cost of transferrin saturation would lead to a significant reduction in total screening costs. Additional benefits of a screening programme include detection of other iron overload disorders and iron deficiency.

Expression of hemochromatosis in homozygous subjects

D6S265 is a polymorphic dinucleotide repeat, mapped within 70 kb centromeric of HLA-A, on chromosome 6p21.3. While genotyping families for genetic linkage analysis, allele non-amplification resulting in apparent non-Mendelian inheritance was observed at the D6S265 locus in 15 individuals, on chromosomes carrying the HLA-A25 and HLA-A26 antigens. The D6S265 locus was sequenced in a variant individual homozygous for allele non-amplification, and in a non-HLA-A25/-A26 individual, homozygous for D6S265 allele 1. Five base changes were identified in the reverse primer binding region of the variant individual, effectively preventing annealing of the 3′ primer to the template.