Hereditary hemochromatosis (HH) is an autosomal recessive disorder that results most often from mutations in the HFE
which regulates iron absorption. HH caused by functional mutations in the HFE
gene is commonly referred to as HH type 1. Mutations in the HFE
gene place the individual at an increased risk for developing symptomatic HH, an iron metabolism disorder that leads to excess iron absorption from the diet, particularly in males. Since the body lacks a natural way to rid itself of the excess iron, it accumulates over time, resulting in organ damage, particularly in the heart, liver, and pancreas. In extreme cases, hemochromatosis can even lead to death, usually due to heart or liver failure.
Early detection of the disorder, and thus earlier treatment by phlebotomy (repeated blood draws), can greatly mitigate its effects and allow HH patients to live normal, healthy lives.4 HFE
testing in combination with a patient's family history and physical health record can provide guidance for clinical interventions or lifestyle changes that a patient would not have without genetic testing. Testing for the presence of HFE
gene mutations can also help physicians to identify patients experiencing characteristic symptoms of the disorder, clarify their diagnosis, and sometimes prevent irreversible organ damage.
HH is a candidate for genetic screening for many reasons. First, the mutations associated with HH are present at birth, whereas characteristic symptoms of hemochromatosis as a disease usually do not develop until mid-adulthood, beginning in an individual's 40s and 50s. In addition, the variability and non-specific nature of symptoms can make diagnosis difficult, raising the possibility that patients, especially those with no family history, may be diagnosed too late. Therefore, an early, specific diagnosis allows for an effective treatment plan. Secondly, unlike some hereditary disorders, a limited number of genes are associated with HH that can be tested for mutations to determine a patient's risk. Finally, HH is among the most common recessive genetic traits in some populations of Northern European descent, resulting in a relatively high carrier frequency. Between 1 in 200 and 1 in 400 people of Northern European descent, or 0.5% of this population, is homozygous for the HFE
mutation and thus at high risk of developing clinical hemochromatosis.5
The estimated carrier frequency of HFE
mutation is 1 in every 8 to 10 individuals of Northern European ancestry.6
The reason for higher population frequency in Northern Europe is not known. One intriguing, but still speculative, theory posits a survival advantage among those with HH mutations in resisting infections causing plague and other diseases prevalent in Europe.7
Another hypothesis, which is not incompatible, is co-selection of hemochromatosis and certain major histocompatibility loci involved in immune function.8
Despite this, universal genetic screening has not been recommended for several reasons. First, presence of the mutation does not mean that the individual will develop HH. While testing may assist physicians in diagnosing HH when a patient is presenting characteristic symptoms, presence of the mutation merely indicates one's susceptibility to iron overload and not the certainty of disease for those who are asymptomatic. The symptoms of HH are highly variable among homozygotes (those in whom both chromosomal copies of the HFE
gene have hemochromatosis-associated mutations). Some are completely asymptomatic, others are severely affected. Several studies provide evidence that the penetrance of the HFE
mutations, or the chance that those with the mutations will have HH symptoms, is lower than first estimated and highly variable.3
The disease is also rarer in non-white populations. Homozygous mutation levels are 0.27 homozygotes per 1,000 Hispanic individuals, less than .0001 homozygotes per 1,000 Asian American individuals, 0.12 homozygotes per 1,000 in Pacific Islanders, and an estimated .14 homozygotes per 1,000 in African–American individuals.9
The American College of Physicians does not recommend genetic or phenotypic (using biochemical tests) screening for HH in the asymptomatic general population.5
The U.S. Preventive Services Task Force (USPTF) similarly found insufficient evidence to support broad population genetic screening.9
Finally, the current price of the genetic diagnostic tests also makes their use as an initial screening procedure for HH prohibitive. Current practice is to identify symptomatic individuals utilizing non-genetic tests that measure iron overload, followed by genetic testing for specific diagnosis and to detect cases in families once an HH proband is identified.
Hereditary hemochromatosis is a natural case study for studying the impact of intellectual property (IP) on patient access to genetic testing. Patents exist on the HFE
gene, its related protein, genetic screening test methods, and related testing kits (see Appendix A
). Additional genes linked to rarer forms of HH are also patented.
The impact of these patents and their licensing on access to testing for HH type 1 is complicated by the generally subordinate role of clinical genetic testing in hemochromatosis, but also by the complex history of ownership of these patents. Despite an initial controversy about patenting, HFE genetic testing appears to have been adopted in clinical practice and much of the heat may have drained from the public debate. The path to the current state, however, involved transitional periods of turbulence that centered on exclusive licensing of a genetic diagnostic test.
One distinctive feature of this case is how HFE testing has evolved over time. HFE genetic testing illustrates how patent ownership and use by different patent-holders can affect licensing. HFE patent rights were transferred many times, and use and licensing policies changed over time. A 2002 Nature article, written when the licensing schema was based on exclusive licensing and a single-provider model, judged that HFE genetic testing “failed the test” of socially optimal access. In 2007 and 2008, compared to 2002, we found little controversy surrounding HFE genetic testing, and the licensing model has evolved to include several providers and sublicensing for use on different platform technologies. The past licensing practices of SmithKline Beecham Clinical Laboratories (SBCL) (exclusive licensing model) were controversial, but the current owner of patent rights, Bio-Rad Ltd., appears to have adopted a broad sub-licensing model that has resulted in broader clinical and patient access and less public conflict.
HFE genetic testing in the context of HH also shows how genetic testing is part of a larger set of diagnostic tools addressing a clinical syndrome. The clinical utility of those tools, including genetic testing, evolves over time. Growing knowledge about the uncertain penetrance of HFE mutations required additional research to determine the clinical significance of different HFE mutations, and other factors influencing expression of disease. These studies demonstrated a much lower clinical penetrance of HFE mutations than first expected, suggesting that the mutations alone were poor predictors of developing clinically significant hemochromatosis. Population screening was more likely to be pursued, if at all, by chemical or protein assays rather than genetic testing—with genetic tests finding more limited use in confirmatory diagnosis and family risk assessment once an index case is found. This most likely had a significant impact on interest in investing in patent enforcement, since the market for HFE genetic testing became much smaller when general population use seemed highly unlikely.