Public health aspects of genetic screening for hereditary haemochromatosis in Australia

Abstract

Hereditary haemochromatosis (HH) is an inherited disorder of iron absorption. It meets several of the key public health principles for population‐based screening and is considered to be a test‐case for public health genetics However, there has been relatively little debate in the public health or wider community regarding the merits of population‐based genetic screening for HH. Genetic susceptibility to HH occurs in about 1:200 people and although mortality is low (age‐standardised rate 2.75/million), there are potentially serious clinical manifestations of iron overload. Regular venesection is a simple and effective treatment for early stage iron overload. DNA‐based testing is available and iron overload may be identified using serum transferrin saturation and ferritin tests. However, there are important gaps in knowledge relevant to screening for HH. The limited data on penetrance of HFE genotypes, and thus the uncertain probability that genetically susceptible individuals will develop clinically significant disease, is a major impediment to population‐based genetic screening. Clinical evidence supports treating early‐stage disease but no randomised controlled trials of the effectiveness of screening in reducing the burden of disease have been conducted. In addition, the natural history of early stages of HH and factors that may modify progression are unclear. Two international consensus panels on HH concluded that there is insufficient evidence for population‐based screening at present. We present recommendations to advance the debate on screening for HH in Australia.

Prevalence of C282Y and H63D mutations in the HFE gene of Brazilian individuals with clinical suspicion of hereditary hemochromatosis

“…2,3,4 It is unquestionable that C282Y is the main mutation responsible for HH in all studied populations, as the majority of published reports worldwide cite its prevalence in more than 80% of individuals with clinical manifestations of HH, 1,[4][5][6]12,15,17,23 thus several other diagnostic guides are based on the result of C282Y mutation genic testing. 2,6,7,15 It is not different for the Brazilian population, as in the paper by Bittencourt et al, 1 homozygous individuals for this mutation present an earlier onset for pathological aspects compared to heterozygous individuals with an onset at an earlier age than the wild allele, 282CC. The allele frequency of 282Y in the present study was 7.9%; a rate considerably greater than other Brazilian studies (2% in general population), 11 indicating a relationship between this mutation and clinical suspicion of HH.…”

“…1,4 These data support clinical findings which report that C282Y mutant homozygotes have a two-fold higher probability of presenting with hepatic diseases. 7,12,13 Most studies identify C282Y as the main mutation responsible for HH, with HH frequencies being influenced by ethnical variables. 2,4,6,8 A transversion from cytidine (C) to guanine (G) in nucleotide 187 reflects in the replacement of histidine (H) by aspartic acid (D) in amino acid 63, thereby determining the H63D mutation, which consequently results in a change in HFE protein conformation minimizing its binding affinity to transferrin.…”

“…Clinical manifestations predominate in men (two to three times more common in men than in women) while the absence of this phenotype is common in women due to monthly blood loss which decreases iron deposits in the body. 2,5,6 HH presents a long term latency 7 and is divided into 3 stages: from 0 to 20 years old, in which there is no iron accumulation; from 20 to 40, in which there is an iron overload, however, with no physiological damage, and over 40, when there is an iron overload and damage to organs, initially with fibrosis and/or hepatic cirrhosis. 8 Generally, clinical manifestations appear between the ages of 40 and 60.…”

Psychological Adjustment and Knowledge About Hereditary Hemochromatosis in a Clinic‐Based Sample: A Prospective Study

“…Because people with hemochromatosis can be identified before symptoms occur and an effective therapy exists, population-based screening has been advocated (Cogswell et al, 1999;McLaren et al, 2003;Nisselle et al, 2004), although whether or not to screen the general population continues to be subject to debate (Allen and Williamson, 1999;Bomford, 2002;Gertig et al, 2002). However, it is accepted clinical practice to genotype patients with symptoms that could be caused by iron overload and relatives of previously identified index cases (cascade testing) (Bomford, 2002).…”

Population genetic screening for hereditary haemochromatosis

“…The key factors in considering population screening of asymptomatic people are whether it will do more benefit than harm and whether it is cost‐effective 7 . International expert opinion has been cautious about population genetic screening for hereditary haemochromatosis, 8 , 9 given the limited population data and possible adverse effects of screening, such as the potential for insurance discrimination in the United States.…”