Digby J. Cullen

A population-based study of the clinical expression of the hemochromatosis gene

BACKGROUND AND METHODS Hereditary hemochromatosis is associated with homozygosity for the C282Y mutation in the hemochromatosis (HFE) gene on chromosome 6, elevated serum transferrin saturation, and excess iron deposits throughout the body. To assess the prevalence and clinical expression of the HFE gene, we conducted a population-based study in Busselton, Australia. In 1994, we obtained blood samples for the determination of serum transferrin saturation and ferritin levels and the presence or absence of the C282Y mutation and the H63D mutation (which may contribute to increased hepatic iron levels) in 3011 unrelated white adults. We evaluated all subjects who had persistently elevated transferrin-saturation values (45 percent or higher) or were homozygous for the C282Y mutation. We recommended liver biopsy for subjects with serum ferritin levels of 300 ng per milliliter or higher. The subjects were followed for up to four years. RESULTS Sixteen of the subjects (0.5 percent) were homozygous for the C282Y mutation, and 424 (14.1 percent) were heterozygous. The serum transferrin saturation was 45 percent or higher in 15 of the 16 who were homozygous; in 1 subject it was 43 percent. Four of the homozygous subjects had previously been given a diagnosis of hemochromatosis, and 12 had not. Seven of these 12 patients had elevated serum ferritin levels in 1994; 6 of the 7 had further increases in 1998, and 1 had a decrease, although the value remained elevated. The serum ferritin levels in the four other homozygous patients remained in the normal range. Eleven of the 16 homozygous subjects underwent liver biopsy; 3 had hepatic fibrosis, and 1, who had a history of excessive alcohol consumption, had cirrhosis and mild microvesicular steatosis. Eight of the 16 homozygous subjects had clinical findings that were consistent with the presence of hereditary hemochromatosis, such as hepatomegaly, skin pigmentation, and arthritis. CONCLUSIONS In a population of white adults of northern European ancestry, 0.5 percent were homozygous for the C282Y mutation in the HFE gene. However, only half of those who were homozygous had clinical features of hemochromatosis, and one quarter had serum ferritin levels that remained normal over a four-year period.

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.

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.

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 HFE 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.

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.

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.

Gastro-oesophageal reflux and respiratory symptoms in Busselton adults: the affects of body weight and sleep apnoea

Background/Aim:  Respiratory symptoms and gastro‐oesophageal reflux disease (GORD) are common within the general population. Although a number of epidemiological studies have addressed their relationship, none has investigated the confounding effects of body mass index (BMI) and obstructive sleep apnoea (OSA), both of which are associated with reflux.