Evolution of untreated hereditary hemochromatosis in the Busselton population: a 17-year study.

OBJECTIVE: To describe the evolution of biochemical and clinical features during a 17-year period in untreated subjects homozygous for the C282Y mutation in the hemochromatosis gene. SUBJECTS AND METHODS: In 1998, 12 subjects from Busselton, Australia, were newly diagnosed as being homozygous for the C282Y mutation. We determined transferrin saturation and ferritin values and retrieved clinical information from the 1981, 1994, and 1998 population surveys for 10 of these subjects. RESULTS: The median age of the 10 subjects in 1981 was 30 years. Between 1981 and 1998, the median transferrin saturation value increased from 42% to 76%. Six subjects with elevated transferrin saturation in 1998 had values less than 45% in 1981. Between 1981 and 1998, the median serum ferritin levels increased from 271 microg/L to 593 microg/L. Serum ferritin levels increased in 4 subjects, remained relatively constant in 4, and decreased in 2. Of 5 subjects with serum ferritin levels lower than 200 microg/L in 1981, 4 had no increase in these levels between 1981 and 1998. Of 4 subjects with persistently elevated serum ferritin levels greater than 500 microg/L, 3 developed stage III or IV fibrosis, based on the METAVIR scoring system. CONCLUSIONS: Untreated C282Y homozygous subjects had progressively increasing transferrin saturation values but marked variation in serum ferritin levels during a 17-year period before diagnosis. A screening threshold for serum transferrin saturation values greater than 45% at an early stage in adult life could fail to detect 60% of C282Y homozygotes who subsequently develop biochemical features of hemochromatosis.

Screening for coeliac disease using anti-tissue transglutaminase antibody assays, and prevalence of the disease in an Australian community.

OBJECTIVES: To determine (i) the prevalence of positive results of anti-tissue transglutaminase (anti-tTG) antibody assays and coeliac disease (CD) in a rural Australian community; and (ii) whether confirmatory testing of a positive assay result with an alternative anti-tTG assay improved the positive predictive value of the test in population screening for CD. DESIGN: Retrospective analysis in December 2004 of stored serum samples taken in 1994-1995 from 3011 subjects in the Busselton Health Study follow-up. Assays for IgA and IgG anti-tTG antibodies were performed, and positive or equivocal samples were retested with a different commercial anti-tTG assay. Available subjects with one or more positive assay results were interviewed, had serum collected for repeat anti-tTG assays and for HLA-DQ2 and HLA-DQ8 haplotyping and, if appropriate, gastroscopy and duodenal biopsy were performed. In unavailable subjects, HLA-DQ2 and -DQ8 haplotyping was performed on stored sera. Total serum IgA levels were assessed in subjects with initially negative assay results. MAIN OUTCOME MEASURE: Prevalence of anti-tTG positivity and biopsy-proven CD. RESULTS: In 47 of 3011 serum samples (1.56%), at least one anti-tTG assay gave positive results: 31 of the subjects who provided these sera were available for clinical review, and 21 were able to have a gastroscopy. Seventeen subjects (0.56%) were diagnosed with definite CD (14 were confirmed at gastroscopy, and three unavailable subjects had three positive results of anti-tTG assays and an HLA haplotype consistent with CD); in a further 12 unavailable subjects, CD status was considered equivocal, with one or more positive anti-tTG assay results and an HLA haplotype consistent with CD. If these subjects were regarded as having CD, the prevalence of CD would be 0.96%. The positive predictive value when all three anti-tTG assays gave positive results was 94%, but fell to 45.2% with only one positive result. CONCLUSIONS: The prevalence of anti-tTG antibodies in this population is 1.56%; the prevalence of CD is at least 0.56%. The utility of a single, positive result of an anti-tTG assay in screening for CD in the community is poor, and repeat and/or collateral assessment with different assays may decrease the need for gastroscopy and distal duodenal biopsy.

Population-based study of the relationship between mutations in the hemochromatosis (HFE) gene and arthritis.

BACKGROUND AND AIM: Mutations in the hemochromatosis (HFE) gene are carried by one in three individuals of British Isles descent and may result in increased iron stores. These increased iron stores could potentially induce or exacerbate diseases, such as arthritis, in which iron has a role in pathogenesis. Although arthritis is a well-known association of clinically overt hereditary hemochromatosis, controversy surrounds the role of mutations in the HFE gene as risk factors for arthritis. The aim of the present study was to determine whether mutations in the HFE gene are associated with an increased prevalence of arthritis. METHODS: A population-based study was conducted in Busselton, Western Australia, of the prevalence of arthritis in 1372 individuals of British Isles descent. Participants completed a questionnaire and general physical examination. Analysis for C282Y and H63D HFE mutations was undertaken. Unadjusted and adjusted odds ratios (OR) were calculated for the relationship between HFE mutations and the prevalence of self-reported, doctor-diagnosed arthritis. RESULTS: There was no association between the presence of HFE mutations and the prevalence of self-reported, doctor-diagnosed arthritis (C282Y/wild type (WT) adjusted OR = 1.041 (95% confidence interval (CI) 0.68-1.61), H63D/WT OR = 0.76 (95% CI 0.53-1.08), C282Y/C282Y OR = 0.39 (95% CI 0.04-3.63), C282Y/H 63D OR = 0.808 (95% CI 0.27-2.42), H63D/H63D OR = 0.419 (95% CI 0.13-1.36)). Overall adjusted OR for arthritis in participants with one or more HFE mutations was 0.81 (95% CI 0.61-1.09). CONCLUSIONS: Mutations of the HFE gene are not risk factors for arthritis in populations of British Isles descent.

Effects of HFE gene mutations and alcohol on iron status, liver biochemistry and morbidity.

BACKGROUND AND AIMS: The aims of the present study were to determine: (i) whether alcohol consumption is greater in individuals with HFE mutations; and (ii) whether common HFE mutations modify the effects of alcohol on serum iron and liver biochemistry or morbidity. METHODS: The residents of the town of Busselton in Western Australia were subject to cross-sectional health surveys between 1966 and 1983. In 1994/1995 all surviving participants of the earlier surveys were invited to take part in a follow-up survey. Logistic, linear and Poisson log-linear regression analyses were performed in 1490 men and 1452 women from the 1994/1995 survey to assess the relationships between HFE mutations, alcohol, iron levels, liver biochemistry and morbidity. RESULTS: Heavy or moderate alcohol consumption was present in 7% or 36% of men and 0.5% or 12% of women, respectively. Alcohol consumption strongly influenced levels of serum ferritin and gamma glutamyl transpeptidase (GGT) and mean cell volume (MCV) in men and women but only alanine aminotransferase (ALT) levels in women. These effects were independent of HFE gene mutations. Hospital admission rates for respiratory disorders were higher in men with the C282Y mutation. CONCLUSIONS: Alcohol consumption strongly influences serum ferritin and GGT levels and MCV in men and women but only ALT levels in women, and these effects are independent of HFE mutations. HFE gene mutations do not predispose to moderate or heavy alcohol consumption. The C282Y mutation is associated with increased respiratory admission rates in men.

A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation.

BACKGROUND & AIMS: Two major mutations are defined within the hemochromatosis gene, HFE. Although the effects of the C282Y mutation have been well characterized, the effects of the H63D mutation remain unclear. We accessed a well-defined population in Busselton, Australia, and determined the frequency of the H63D mutation and its influence on total body iron stores. METHODS: Serum transferrin saturation and ferritin levels were correlated with the H63D mutation in 2531 unrelated white subjects who did not possess the C282Y mutation. RESULTS: Sixty-two subjects (2.1%) were homozygous for the H63D mutation, 711 (23.6%) were heterozygous, and 1758 (58.4%) were wild-type for the H63D mutation. Serum transferrin saturation was significantly increased in male and female H63D homozygotes and heterozygotes compared with wild-types. Serum ferritin levels within each gender were not influenced by H63D genotypes. Elevated transferrin saturation > or = 45% was observed in a greater proportion of male H63D carriers than male wild-types. Male H63D homozygotes (9%) and heterozygotes (3%) were more likely to have both elevated transferrin saturation and elevated ferritin > or = 300 ng/mL than male wild-types (0.7%). Homozygosity for H63D was not associated with the development of clinically significant iron overload. CONCLUSIONS: Presence of the H63D mutation results in a significant increase in serum transferrin saturation but does not result in significant iron overload. In the absence of the C282Y mutation, the H63D mutation is not clinically significant.

Effects of body iron stores and haemochromatosis genotypes on coronary heart disease outcomes in the Busselton health study.

BACKGROUND: Increased iron stores and haemochromatosis gene mutations may be risk factors for coronary heart disease. The aims of this study were to determine in a stable community population whether increased iron stores or haemochromatosis gene mutations were risk factors for coronary heart disease. DESIGN: Cross-sectional and prospective cohort studies. METHODS: We evaluated 1185 men and 1141 women aged 20-79 years of predominantly Anglo-Celtic descent from the 1994-95 assessment of the Busselton population in Western Australia. Subjects underwent haemochromatosis genotyping, serum iron studies, clinical, biochemical and ECG evaluation for coronary heart disease and associated risk factors. Hospital admissions or death from cardiovascular disease were determined by linkage with the Western Australian morbidity and mortality database. The study design was cross-sectional for the 1994-95 cohort comparing coronary heart disease cases with unaffected subjects and unaffected subjects were followed prospectively until December 1998. RESULTS: Cross-sectional and prospective cohort analyses demonstrated that elevated serum iron parameters or possession of either the C282Y or H63D mutations in the gene were not predictive of increased risk for coronary heart disease in men or women. CONCLUSIONS: Increased iron stores or haemochromatosis gene mutations are not significant risk factors for coronary heart disease.