HFE-associated Haemochromatosis Research Articles

Cost-Effectiveness of Different Population Screening Strategies for Hereditary Haemochromatosis in Australia.

Amongst populations of northern European ancestry, HFE-associated haemochromatosis is a common genetic disorder characterised by iron overload. In the absence of treatment, excess iron is stored in parenchymal tissues, causing morbidity and mortality. Population screening programmes may increase early diagnosis and reduce associated disease. No contemporary health economic evaluation has been published for Australia. The objective of this study was to identify cost-effective screening strategies for haemochromatosis in the Australian setting. A Markov model using probabilistic decision analysis was developed comparing four adult screening strategies: the status quo (cascade and incidental screening), genotyping with blood and buccal samples and transferrin saturation followed by genotyping (TfS). Target populations were males (30 years) and females (45 years) of northern European ancestry. Cost-effectiveness was estimated from the government perspective over a lifetime horizon. All strategies for males were cost-effective compared to the status quo. The incremental costs (standard deviation) associated with genotyping (blood) were AUD7 (56), TfS AUD15 (45) and genotyping (buccal) AUD63 (56), producing ICERs of AUD1673, 4103 and 15,233/quality-adjusted life-year (QALY) gained, respectively. For females, only the TfS strategy was cost-effective, producing an ICER of AUD10,195/QALY gained. Approximately 3% of C282Y homozygotes were estimated to be identified with the status quo approach, compared with 40% with the proposed screening strategies. This model estimated that genotyping and TfS strategies are likely to be more cost-effective screening strategies than the status quo.

Population Screening for Hereditary Haemochromatosis in Australia: Construction and Validation of a State-Transition Cost-Effectiveness Model.

Introduction HFE-associated haemochromatosis, the most common monogenic disorder amongst populations of northern European ancestry, is characterised by iron overload. Excess iron is stored in parenchymal tissues, leading to morbidity and mortality. Population screening programmes are likely to improve early diagnosis, thereby decreasing associated disease. Our aim was to develop and validate a health economics model of screening using utilities and costs from a haemochromatosis cohort.MethodsA state-transition model was developed with Markov states based on disease severity. Australian males (aged 30 years) and females (aged 45 years) of northern European ancestry were the target populations. The screening strategy was the status quo approach in Australia; the model was run over a lifetime horizon. Costs were estimated from the government perspective and reported in 2015 Australian dollars ($A); costs and quality-adjusted life-years (QALYs) were discounted at 5% annually. Model validity was assessed using goodness-of-fit analyses. Second-order Monte-Carlo simulation was used to account for uncertainty in multiple parameters.ResultsFor validity, the model reproduced mortality, life expectancy (LE) and prevalence rates in line with published data. LE for C282Y homozygote males and females were 49.9 and 40.2 years, respectively, slightly lower than population rates. Mean (95% confidence interval) QALYS were 15.7 (7.7–23.7) for males and 14.4 (6.7–22.1) for females. Mean discounted lifetime costs for C282Y homozygotes were $A22,737 (3670–85,793) for males and $A13,840 (1335–67,377) for females. Sensitivity analyses revealed discount rates and prevalence had the greatest impacts on outcomes.ConclusionWe have developed a transparent, validated health economics model of C282Y homozygote haemochromatosis. The model will be useful to decision makers to identify cost-effective screening strategies.

A paradigm shift in the treatment of patients with HFE-associated haemochromatosis

A paradigm shift in the treatment of patients with HFE-associated haemochromatosis

Hfe Acts in Hepatocytes to Prevent Hemochromatosis

Hereditary hemochromatosis (HH) is a prevalent, potentially fatal disorder of iron metabolism hallmarked by intestinal hyperabsorption of iron, hyperferremia, and hepatic iron overload. In both humans and mice, type I HH is associated with mutations in the broadly expressed HFE/Hfe gene. To identify where Hfe acts to prevent HH, we generated mice with tissue-specific Hfe ablations. This work demonstrates that local Hfe expression in hepatocytes serves to maintain physiological iron homeostasis, answering a long-standing question in medicine and explaining earlier clinical observations.

Hepcidin in HFE-associated hemochromatosis: Another piece of the “iron” puzzle

Hepcidin in HFE-associated hemochromatosis: Another piece of the “iron” puzzle

Hepatology

Hepatology

Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis

The mechanisms responsible for disturbed iron homoeostasis in hereditary haemochromatosis are poorly understood. However, results of some studies indicate a link between hepcidin, a liver-derived peptide, and intestinal iron absorption, suggesting that this molecule could play a part in hepatic iron overload. To investigate this possible association, we studied the hepatic expression of the gene for hepcidin (HAMP) and a gene important in iron transport (IREG1) in patients with haemochromatosis, in normal controls, and in Hfe-knockout mice. We extracted total RNA from the liver tissue of 27 patients with HFE-associated haemochromatosis, seven transplant donors (controls), and Hfe-knockout mice. HAMP and IREG1 mRNA concentrations were examined by ribonuclease protection assays and expressed relative to the housekeeping gene GAPD. There was a significant decrease in HAMP expression in untreated patients compared with controls (5.4-fold, 95% CI 3.3-7.5; p<0.0001) despite significantly increased iron loading. Similarly, we noted a decrease in Hamp expression in iron-loaded Hfe-knockout mice. Hepatic IREG1 expression was greatly upregulated in patients with haemochromatosis (1.8-fold, 95% CI 1.5-2.2; p=0.002). There was a significant correlation between hepatic iron concentration and expression of HAMP (r=0.59, p=0.02) and IREG1 (r=0.67, p=0.007) in untreated patients. Lack of HAMP upregulation in HFE-associated haemochromatosis despite significant hepatic iron loading indicates that HFE plays an important part in the regulation of hepcidin expression in response to iron overload. Our results imply that the liver is important in the pathophysiology of HFE-associated haemochromatosis. Furthermore, the increase in hepatic IREG1 expression in haemochromatosis suggests that IREG1 could function to facilitate the removal of excess iron from the liver.

Population screening for HFE-associated haemochromatosis: should we have to pay for our genes?

Haemochromatosis associated with mutations in the HFE gene is the most common inherited disorder in Caucasian populations. Early diagnosis and treatment allows for normal life expectancy, whereas there is considerable morbidity and early mortality in those patients diagnosed late or untreated. Unfortunately, the development of symptoms and signs in haemochromatosis is usually associated with significant iron overload. For this reason, many clinicians and geneticists have advocated population screening. The recent identification of the HFE gene and the availability of a simple DNA-based diagnostic test have led to international debate as to the most cost-effective means of population screening for HFE-associated haemochromatosis. The present paper summarizes the evidence in favour of population screening and analyses the relative advantages of genotypic (DNA test) versus phenotypic (transferrin saturation) testing.