A New Public Health Assessment of the Disease Burden of Hereditary Hemochromatosis: How Clinically Actionable is C282Y Homozygosity?

This blog post is based on a recent paper by Grosse, Gurrin, Bertalli, and Allen in Genetics in Medicine.

Hereditary hemochromatosis (HH) attributable to mutations in the HFE gene is the most common autosomal recessive disorder among adults of northern European origin. It occurs in 1 in 300 non-Hispanic whites in the United States. Approximately 80–90% of HH cases are due to homozygosity for the C282Y allele in the HFE gene. Iron overload can result in life-threatening clinical complications, most notably severe liver disease such as cirrhosis or hepatocellular carcinoma (HCC). These complications are readily preventable in presymptomatic patients through minimally invasive interventions. Specifically, clinical guidelines recommend that individuals with HH with SF above the reference range undergo periodic phlebotomy until a target SF concentration is reached

Despite the lack of definitive, randomized trial evidence of treatment efficacy, population screening of asymptomatic adults to detect the signs of HH to allow for preventative measures has been proposed by some clinical experts. By contrast, experts in population screening have not been supportive of screening for HH, largely because severe clinical disease is widely believed to be relatively uncommon among people with HFE genotypes associated with HH despite the high frequency of these alleles.

In particular, in 2006, the US Preventive Services Task Force (USPSTF) recommended against routine genetic screening of the general adult population for HFE mutations because “clinically important disease due to HH appears to be rare.” Several other US groups have concurred with the USPSTF stance on universal testing, but have endorsed genetic counseling and cascade testing for first-degree relatives of patients with HFE hemochromatosis.

Skeptics of the clinical utility of genetic testing have cited the allegedly low clinical penetrance of HFE genotypes: “Variants in the HFE gene were once considered so informative they could be used to screen the general population; when the gene was studied in large populations, the chance that carriers expressed hemochromatosis was revised from more than 80% to less than 1%.”

In the recent paper, Grosse and coauthors reviewed the epidemiologic evidence from population-based studies on the clinical penetrance of HFE C282Y homozygosity in males in terms of the cumulative risk of severe liver disease. They excluded studies of clinic-based samples of HH patients and family-history-based samples of relatives of HH patients. Ascertainment bias from such samples for other conditions has been shown to result in overestimates of penetrance. For example, older estimates of the cumulative incidence to age 70 of colorectal cancer among male carriers of MLH1/MSH2 mutations in the range 65–82% have been supplanted by unbiased estimates of 41–48% based on representative samples.

The lifetime incidence of severe liver disease alone appears to be approximately 9% (95% confidence interval: 2.6–15.3%) of male HFE C282Y homozygotes of European ancestry based on data from prospective cohort studies. This is a lower-bound point estimate; because of the lack of systematic liver biopsies, studies potentially under ascertain the frequency of occurrence of severe liver disease. Furthermore, not all subjects in those studies were followed to at least 60 years of age, let alone age 70.

A longer follow-up would be needed to accurately establish the lifetime cumulative incidence.

The implication of the finding that almost 1 in 10 male C282Y homozygotes is likely to develop severe liver disease in the absence of presymptomatic detection is that widespread detection could avert considerable numbers of premature deaths in populations of predominantly European ancestry.

A newly published cost-effectiveness model of population screening strategies for HH on which Lyle Gurrin collaborated has supported the argument that routine genotyping at age 30 in Australian males of northern European ancestry would be highly cost-effective. The authors calculated that routine genetic screening of such males at age 30 and females at age 45 could identify 40% of all homozygotes in Australia, compared with the detection of roughly 3% of homozygotes using current testing strategies.

However, an evidence-based case for population screening for HH still needs to be established. In particular, HH homozygotes are not underrepresented among the elderly, and hence they do not have a shorter life expectancy. Similarly, all-cause mortality is no higher for C282Y homozygotes, who on average have significantly reduced low-density lipoprotein cholesterol levels. Therefore, it is unclear whether the identification and management of homozygotes will extend life overall.

Another approach, besides cascade screening, to achieving more preclinical detection of adult HFE homozygotes is the incorporation of the HFE C282Y variant in lists of medically actionable gene variants. This is because the threshold of benefit required to justify the return of a known variant when a patient undergoes gene sequencing is lower than for population screening.

In 2013, the American College of Medical Genetics and Genomics (ACMG) established a list of 56 genes for which “incidental” findings of gene sequencing could be recommended to be reported to patients. In 2016, the renamed ACMG Secondary Findings list was expanded to include 59 genes considered to be medically actionable. A systematic framework was recently proposed to evaluate clinical actionability on the basis of four scored criteria (severity, likelihood of disease, effectiveness of interventions, and how risky, medically burdensome, or intensive an intervention would be) and the knowledge base. The authors assessed the 59 variants in version 2.0 of the ACMG Secondary Findings and found that 20 of the variants had a score of 9 or less on a 12-point scale. Applying those criteria to HFE C282Y would yield a score of 10 (a reasonable possibility of death or major morbidity, a 5–39% chance of a serious outcome, and highly effective and low-risk intervention). This score would appear to warrant its inclusion in the ACMG Secondary Findings list—more so than some variants currently included.

Additional research on the long-term health outcomes of cohorts of individuals genotyped for HFE variants could yield more precise estimates of clinical penetrance, which could further inform decisions on ways to lessen the population health impact of hereditary hemochromatosis.