HFE-Associated Hereditary Hemochromatosis

Clinical Diagnosis

It is increasingly unusual for individuals with HFE-associated hereditary hemochromatosis (HFE-HHC) to present with advanced "clinical" HFE-HHC (i.e., with end-organ damage secondary to iron storage). More typically, individuals with HFE-HHC are diagnosed with "biochemical" HFE-HHC after evaluation of transferrin-iron saturation and serum ferritin concentration reveals evidence of iron overload (see Testing below). Occasionally, individuals with HFE-HHC present either with early clinical findings of hereditary hemochromatosis such as elevated serum liver enzymes or vague nonspecific symptoms such as abdominal pain, fatigue, arthralgia, and/or decreased libido.

HFE-HHC should be suspected in any individual presenting with clinical signs of advanced iron overload, including:

• Hepatomegaly

• Hepatic cirrhosis

• Hepatocellular carcinoma

• Diabetes mellitus

• Cardiomyopathy

• Hypogonadism

• Arthritis (especially involving the metacarpophalangeal joints)

• Progressive increase in skin pigmentation

Testing

Molecular Genetic Testing

Gene.   All individuals affected with HFE-HHC have mutations in the HFE gene.

Molecular genetic testing: Clinical uses

• Confirmatory diagnostic testing

• Predictive testing for at-risk relatives

• Carrier testing (for the identification of heterozygotes)

• Prenatal diagnosis (technically available but rarely performed)

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular genetic testing: Clinical methods

• Targeted mutation analysis.  Targeted mutation analysis for the two known disease-causing alleles in the HFE gene (p.C282Y and p.H63D) is available on a clinical basis [Feder et al 1996]. About 87% of individuals of European origin with HFE-HHC are either homozygotes for the p.C282Y mutation or compound heterozygotes for the p.C282Y and p.H63D mutations.

  Note: Most clinical laboratories do not routinely test for the S65C allele because it appears to account for only 1% of individuals affected clinically [Mura et al 1999] and its clinical significance is currently unclear.

• Sequence analysis.   Testing to identify other mutant alleles associated with HFE-HHC is available in a limited number of clinical and research laboratories [Barton et al 1999].

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in HFE-HHC

Test Method	Mutations Detected	Mutation Detection Rate		Test Availability
		% of Individuals with HHC  1,  2	Genotype
Targeted mutation analysis	HFE mutations: p.C282Y, p.H63D	~60%-90%	p.C282Y/p.C282Y	Clinical
		3%-8%	p.C282Y/p.H63D
		~1%	p.H63D/p.H63D  3
Sequence analysis	HFE sequence alterations	Unknown	Unknown  4

From Ramrakhiani & Bacon (1998)
1. In populations of European origin
2. Morrison et al 2003
3. There is no evidence that p.H63D/p.H63D is associated with a hemochromatosis phenotype in the absence of another cause of iron overload.
4. A few individuals who are compound heterozygotes for the p.C282Y allele and one of a small number of rare HFE mutations have the hemochromatosis phenotype.

Interpretation of test results

• For issues to consider in interpretation of sequence anlysis results, click here.

• Up to 5% of individuals with phenotypic hemochromatosis are p.C282Y heterozygotes. They likely have other mutations in HFE or mutations in other iron-related genes.

Testing Strategy for a Proband

Figure 1. Testing strategy to establish the diagnosis (more...)

Figure 1. Testing strategy to establish the diagnosis of HFE-HHC

Figure 1

• Individuals homozygous for the p.C282Y mutation or compound heterozygous for the p.C282Y and p.H63D mutations can be diagnosed as having the genetic make-up to develop HFE-HHC.

• Individuals who are not p.C282Y homozygotes generally represent a heterogeneous group, many of whom either have liver disease unrelated to HFE-HHC or have other metabolic syndromes — although rare cases may have primary iron overload in a pattern identical to HFE-HHC. Therefore, liver biopsy with assessment of histology and measurement of hepatic iron concentration is the next diagnostic step for these individuals [Morrison & Kowdley 2000, Whittington & Kowdley 2002].

Genetically Related (Allelic) Disorders

Although numerous studies have examined the relationship between HFE mutations and other diseases, no other phenotypes are known to be associated with mutations in HFE [DuBois et al 2004].

Natural History

Individuals with HFE-associated hereditary hemochromatosis (HFE-HHC) who express the phenotype clinically have inappropriately high absorption of iron from a normal diet by the gastrointestinal mucosa, resulting in excessive parenchymal storage of iron, which may result in damage in a number of end-organs and, potentially, organ failure. Although previous reports have suggested that males are ten times more likely than females to have symptoms of organ failure resulting from HFE-HHC, recent studies show that, among individuals with HFE-HHC, women are half as likely as men to develop complications of end-stage organ failure [Moirand et al 1997].

Affected individuals may be identified because of signs and symptoms related to iron overload; most frequently, however, they are identified before symptoms develop, either through detection of abnormal iron-related studies or by evaluation as family members at risk for HFE-HHC.

Symptoms related to iron overload usually appear between age 40 and 60 years in males and after menopause in females. Occasionally, HFE-HHC manifests at an earlier age, but hepatic fibrosis or cirrhosis is rare before age 40 years. Often the first signs of clinically expressed HFE-HHC are hepatomegaly, arthropathy involving the metacarpophalangeal joints, a progressive increase in skin pigmentation resulting from deposits of melanin and iron, diabetes mellitus resulting from pancreatic iron deposits, and cardiomyopathy resulting from cardiac parenchymal iron stores. By the time cirrhosis or liver failure is recognized, about 50% of individuals have diabetes mellitus and 15% have congestive heart failure or arrhythmias.

Hepatomegaly may or may not be present early in the disease; however, asymptomatic individuals can occasionally have hepatomegaly on physical examination. With progression of the disease, liver cirrhosis may develop and be complicated by portal hypertension, hepatocellular carcinoma, and end-stage liver disease [Kowdley et al 2005].

Other common symptoms early in the disease are joint stiffness and pain. Males may have impotence from pituitary dysfunction. Abdominal pain, weakness, lethargy, and weight loss are common, but nonspecific, findings.

When individuals with HFE-HHC are identified through iron studies or screening of at-risk family members, most (75%-90%) are asymptomatic. Normal serum ferritin level at diagnosis is usually associated with lack of symptom development [Yamashita & Adams 2003]. Clinical disease appears to be more common among at-risk sibs of clinically affected individuals.

Liver biopsy can be helpful to determine prognosis.

• Individuals diagnosed and treated prior to the development of cirrhosis appear to have normal life expectancy, but a large fraction of such individuals most likely have the (usually non-penetrant) p.C282Y/p.C282Y genotype, and thus never would have developed any clinical signs of the disease regardless of treatment.

• Those identified after the development of cirrhosis have a decreased life expectancy even with iron depletion therapy [Adams et al 2004].

• Individuals with cirrhosis who are treated have a better outcome than those who are not; however, treatment does not eliminate the 10%-30% risk for hepatocellular carcinoma (HCC) and cholangiocarcinoma years after successful iron depletion.

Failure to deplete iron stores after 18 months of treatment is a poor prognostic sign. With iron depletion, dysfunction of some affected organs (liver and heart) can improve; however, endocrine abnormalities and arthropathy improve in only 20% of those treated.

Alcohol consumption causes worsening of symptoms in HFE-HHC [Scotet et al 2003]. In addition, cirrhosis is much more common among p.C282Y homozygotes who consume excessive amounts of alcohol [Fletcher et al 2002].

Death in clinically affected individuals with HFE-HHC is usually caused by liver failure, cancer, congestive heart failure, or arrhythmia. However, many p.C282Y homozygotes identified via screening studies survive to old age. Some studies have reported that p.C282Y homozygotes are under-represented among older populations [Rossi et al 2004], whereas others have shown no such reduction [Willis et al 2003].

Heterozygotes.   Although some heterozygotes tend to have elevated concentrations of serum iron and ferritin and transferrin-saturation values that exceed normal, they do not develop complications of iron overload [Bulaj et al 1996].

Genotype-Phenotype Correlations

Probands.  Homozygotes for p.C282Y show greater iron overload than do p.C282Y/p.H63D compound heterozgotes.

Individuals ascertained in population-based studies.  In the interpretation of population studies aimed at examining the morbidity related to hemochromatosis, the critical difference between the expression of biochemical versus clinical manifestations of iron excess must be understood.

Several large-scale screening studies in the general population have demonstrated that most individuals identified to be homozygous for the p.C282Y mutation do not have evidence of significant end-organ damage, such as advanced cirrhosis, cardiac failure, skin pigment changes, or diabetes (see Penetrance).

However, a significant proportion of homozygotes for p.C282Y (especially males) have elevated serum TS as well as elevated serum ferritin concentrations. Controversy among experts is ongoing as to whether such individuals, who have biochemical expression of iron overload in the absence of overt end-organ damage,f are at increased risk for subsequent development of complications, or whether phlebotomy treatment should be instituted in such cases. Prospective follow-up of a few individuals in some of these studies has been inconclusive as to whether progressive iron overload occurs in these persons. The evidence at present suggests that although serum ferritin concentration may rise in these individuals over time, end-organ damage is rare [Yamashita & Adams 2003, Andersen et al 2004, Olynyk et al 2004].

Penetrance

Penetrance in HFE-HHC refers to the percentage of adults (males and females separately) homozygous or compound heterozygous for HFE mutations who exhibit a specifically defined manifestation of hemochromatosis, i.e., either biochemically defined abnormalities (elevated transferrin-iron saturation and serum ferritin concentration) or the characteristic clinical endpoints (i.e., diabetes mellitus, cirrhosis, and liver carcinoma).

• Homozygosity for p.C282Y/p.C282Y.  Penetrance for biochemically defined abnormalities among p.C282Y/p.C282Y homozygotes is relatively high, but not 100%. In contrast, accumulating data suggest that penetrance for the characteristic clinical endpoints is quite low. In the absence of unbiased data, a definitive value for penetrance of clinical endpoints cannot yet be determined for p.C282Y homozygotes, but was as low as 2% in the large study by Beutler et al (2002). Currently, no test can predict whether a p.C282Y homozygote will develop clinical signs and symptoms.

• Compound heterozygosity for p.C282Y/p.H63D.  The p.C282Y/p.H63D genotype has low penetrance; only about 0.5%-2.0% of such individuals develop clinical evidence of iron overload. Many p.C282Y/p.H63D compound heterozygotes who develop clinical evidence of iron overload appear to have a complicating factor leading to iron overload such as fatty liver or viral hepatitis.

• Homozygosity for p.H63D/p.H63D.  The p.H63D/p.H63D genotype has an even lower penetrance than the p.C282Y/p.H63D genotype. Although biochemically defined abnormalities may be present, characteristic clinical endpoints are rare [Gochee et al 2002].

Nomenclature

HFE-HHC has been variably described in the past as hereditary hemochromatosis, primary hemochromatosis, genetic hemochromatosis and "bronze diabetes."

More recently, after the identification of other forms of iron overload associated with mutations in other iron-related genes, HFE-HHC has been described as HFE-hemochromatosis or type 1 hemochromatosis.

Prevalence

Heterozygote prevalence is about 11% of the general Caucasian population, based on a carrier rate between 1/8 and 1/10 [Worwood 1994].

The prevalence of individuals with two p.C282Y HFE alleles is about 3:1000 to 5:1000, or 1:200 to 1:400 [Adams et al 2005].

• The frequency of homozygotes for hemochromatosis among African Americans is rare (1:7000) with 2.3% of that population being heterozygotes.

• Homozygotes for the p.C282Y variant are extremely rare among Asians and heterozygotes have a frequency of only about 1:1000.

• Hispanics have homozygote and heterozygote frequencies of 0.027% and 3.0%, respectively.

• The p.H63D variant rarely causes clinical problems in the homozygous or compound heterozygous (p.C282Y/p.H63D) state and is relatively common in the heterozygous state in most populations (Caucasians: 25%; Hispanics: 18%; African Americans: 6%; Asians: 8.5%).

• Considering the high frequency of heterozygotes for the p.C282Y and p.H63D alleles, about one-third of the Caucasian population is heterozygous for either one or the other of these two variant alleles.

Evaluations at Initial Diagnosis to Establish the Extent of Disease

Figure 2. (LFT = Liver function tests) Use of serum (more...)

Figure 2. (LFT = Liver function tests) Use of serum ferritin concentration to help direct management

Figure 2

For p.C282Y homozygotes: If serum ferritin concentration exceeds 1000 ng/mL, liver biopsy is indicated to determine if cirrhosis is present.

Note: p.C282Y homozygotes with serum ferritin concentration below 1000 ng/mL need not undergo biopsy [Tavill 2001, Morrison et al 2003].

Treatment of Manifestations

Absence of characteristic clinical endpoints.  Current data suggest that even though serum ferritin concentration may rise over time, subsequent development of end-organ damage from iron storage is rare. Consequently, there is no general agreement that phlebotomy treatment is indicated in the presence of biochemically defined abnormalities (i.e., elevated transferrin-iron saturation and elevated serum ferritin concentration) in the absence of characteristic clinical endpoints (i.e., diabetes mellitus, cirrhosis, and liver carcinoma). More long-term studies are required.

Since the long-term clinical course appear benign in the majority of those who have abnormal laboratory tests only, phlebotomy may be deferred; biannual follow-up testing for increasingly abnormal serum ferritin concentration and transferrin-iron saturation levels is recommended. Because of the absence of definitive prognostic knowledge, many clinicians recommend initiation of phlebotomies or at least frequent blood donations to avoid potential clinical harm. Both physicians and at-risk individuals should realize, however, that the chance of clinical disease developing is small when there is only biochemical evidence of increased iron storage.

Presence of characteristic clinical endpoints.  Treatment by phlebotomy is clearly indicated when clinical symptoms of hemochromatosis are present.

Therapeutic phlebotomy

• The usual therapy is removal of the excess iron by weekly phlebotomy (i.e., removal of a unit of blood) until the serum ferritin concentration is 50 ng/mL or lower. Twice-weekly phlebotomy may be occasionally useful to accelerate iron depletion.

• Weekly phlebotomy is carried out until the hematocrit is 75% of the baseline hematocrit.

• At this point, if the serum ferritin concentration is 50 ng/mL or higher despite a significant reduction in hematocrit, phlebotomies need to be spaced further apart. In all affected individuals, serum ferritin concentrations should be quantified after each additional one or two treatments once the serum ferritin concentration is 100 ng/mL or lower [Barton et al 1998].

• The serum ferritin concentration is the most reliable and inexpensive way to monitor therapeutic phlebotomy.

• Maintenance therapy is aimed at maintaining serum ferritin concentration below 50 ng/mL and transferrin-iron saturation below 50%. On average, men require removal of twice as many units of blood as women. Subsequent phlebotomies can be carried out to prevent reaccumulation of iron about every three to four months for men and once or twice a year for women.

Treatment of iron overload

• Periodic phlebotomy is a simple, inexpensive, safe, and effective treatment. Each unit of blood (400-500 mL) with a hematocrit of 40% contains about 160-200 mg of iron. Each mL of packed red blood cells contains 1 mg of iron.

• Iron chelation therapy is not recommended unless an individual has an elevated serum ferritin concentration and concomitant anemia that makes therapeutic phlebotomy impossible. However, this is uncommon in individuals with HFE-HHC.

Orthotopic liver transplantation.  Orthotopic liver transplantation is the only treatment for end-stage liver disease from decompensated cirrhosis. However, the post-transplant survival among untreated individuals with HFE-HHC is poor [Crawford et al 2004, Kowdley et al 2005].

Prevention of Primary Manifestations

See 'Absence of characteristic clinical endpoints' and 'Presence of characteristic clinical endpoints' in Treatment of Manifestations.

Prevention of Secondary Complications

Individuals with iron overload should be advised against ingestion of shellfish or raw fish.

Vaccination against hepatitis A and B is advised [Tavill 2001].

Surveillance

If the serum ferritin concentration is less than 50 ng/mL initially or at the time that therapeutic phlebotomy reduces the hematocrit to 75% of that at presentation, routine monitoring of serum ferritin concentration every three to four months is adequate.

Individuals homozygous for the p.C282Y mutation who have not developed elevated serum ferritin concentrations should be monitored with measurement of serum ferritin concentrations at yearly intervals starting in early adulthood. Therapeutic phlebotomy may be initiated in men when serum ferritin concentrations are elevated when compared to a control population of the same age and gender.

Individuals who have cirrhosis should undergo routine screening for hepatocellular cancer (HCC) [Tavill 2001]. The cost-effectiveness of screening for HCC among individuals with cirrhosis continues to be debated. Nevertheless, most hepatologists advocate biannual abdominal ultrasound examiniation and/or CT scan and measurement of serum AFP concentration.

Agents/Circumstances to Avoid

Dietary management includes avoidance of medicinal iron, mineral supplements, excess vitamin C, and uncooked seafood.

Those with hepatic involvement are advised to avoid alcohol consumption.

Testing of Relatives at Risk

Adults.  The following strategy is appropriate:

• 1

  Offer molecular genetic testing to the adult sibs of a proband homozygous for p.C282Y/p.C282Y.

• 2

  Perform iron studies on those sibs who are p.C282Y/p.C282Y homozygotes.

• 3

  Begin phlebotomy therapy if the iron studies are abnormal and the proband had clinically expressed hemochromatosis. (Such individuals appear to have a higher risk of developing clinical hemochromatosis than individuals with identical laboratory results whose relatives are not clinically affected.)

During childhood.  No guidelines exist. However, screening in this population is not advised because expression of symptomatic disease is very rare.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

HFE-associated hereditary hemochromatosis (HFE-HHC) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• Most parents of individuals with HFE-HHC are heterozygotes and therefore carry a single copy of the mutant HFE gene. Heterozygotes do not develop iron overload but may occasionally have abnormal serum iron studies [Bulaj et al 1996].

• On occasion, one parent who has two variant HFE alleles may have clinical findings of HFE-HHC. The occurrence of an autosomal recessive disorder in two generations of a family without consanguinity (called "pseudodominance") is attributed to the high carrier frequency for a mutant HFE allele in persons of European origin (11% of the population or one in every nine persons). Thus, it is appropriate to evaluate the parents of an individual with HFE-HHC using mutation analysis of the HFE gene if the two variant HFE alleles have been identified in the proband or using serum iron studies if two abnormal alleles have not been identified in the proband.

Sibs of a proband

• When both parents are heterozygous, each sib of an individual with HFE-HHC has, at conception, a 25% chance of inheriting both mutated HFE alleles, a 50% chance of inheriting one mutated HFE allele, and a 25% chance of inheriting both normal HFE alleles.

• When one parent of an individual with HFE-HHC has HFE-HHC because of homozygosity for p.C282Y and the other parent is a heterozygote, each sib of an individual with HFE-HHC has a 50% chance of inheriting both mutated HFE alleles and a 50% chance of inheriting one mutated HFE allele.

Offspring of a proband

• Individuals with HFE-HHC are usually fertile. Affected homozygotes transmit one mutant allele to each child.

• Because of the high carrier rate for HFE mutant alleles in the general Caucasian population, the risk that a Caucasian partner of an individual with HFE-HHC is heterozygous for the p.C282Y allele is approximately 1/9. Thus, the risk to the offspring of a proband of being homozygous for this allele is about 5% (i.e., 1/9 x 1/2 = 1/18). HFE targeted mutation analysis can be offered to the reproductive partner of a person with HFE-HHC to determine if their offspring are at risk of having a genotype with the potential for HFE-HHC manifestations.

• It is appropriate to evaluate adult offspring with HFE mutation analysis and to proceed with serum iron studies if two abnormal disease-causing alleles are present.

Other family members of a proband.  Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

If both HFE alleles are identified in a proband, molecular genetic testing can be used to determine the carrier status of at-risk family members.

In genetic testing of reproductive partners, if molecular genetic testing is not performed, it is reasonable to measure serum transferrin-iron saturation at least once in adult obligate heterozygotes given that they may be unrecognized compound heterozygotes [El-Serag et al 2000]. However, the penetrance in compound heterozygotes is very low.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adults.   Evaluation of sibs and offspring of affected individuals can be either by biochemical phenotype (i.e., serum iron studies) or by genotype (i.e., HFE mutation analysis) if the two abnormal alleles have been identified in the proband. Genotype-based testing has been found to be more cost-effective in most individuals because it has excellent negative predictive value. However, genotype-based testing has a low positive predictive value because many individuals who are p.C282Y homozygotes and compound heterozygotes will not express the disease [El-Serag et al 2000, Beutler et al 2002].

Testing of at-risk asymptomatic children.   Consensus holds that children at risk for adult-onset disorders should not have testing in the absence of symptoms (See the National Society of Genetic Counselors statement on genetic testing of children.)

Family planning.  The optimal time for determination of genetic risk and clarification of carrier status is before pregnancy; however, family planning is rarely an issue in hemochromatosis.

DNA banking.  DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations and diseases will improve in the future, consideration should be given to banking DNA. DNA banking is particularly important in conditions with low penetrance because modifying genes may be identified to predict which homozygotes will develop clinical symptomotology. See DNA Banking for a list of laboratories offering this service.

Population Screening

Population screening has been considered because of the high prevalence of HFE-HHC, the lack of clinical findings early in the course of the disease, the lack of specificity of clinical findings once they appear, the low cost of diagnosis, the relatively simple and effective early treatment, and the high cost and low success rate of treatment when the diagnosis is established late. However, since the clinical penetrance of the genotype appears low and the natural history of untreated individuals cannot be predicted, no uniform recommendations for population-based screening have been adopted. Furthermore, the psychological and social implications* of identifying individuals with a non-expressing "disease" need to be considered [Burt et al 1998; McDonnell et al 1998; Phatak et al 1998; Beutler et al 2002; Imperatore et al 2003].

* Including unwarranted loss of health insurance; for example, p.C282 homozygotes rarely develop clinical manifestations and can be readily treated successfully with phlebotomy.

In a study commissioned by the Annals of Internal Medicine to develop clinical practice guidelines for general population screening for hereditary hemochromatosis, Qaseem et al (2005) and Schmitt et al (2005) concluded that current knowledge:

• Leads to varied definitions of "hemochromatosis"

• Provides insufficient evidence to recommend for or against screening in the general population

Specifically, the authors cited a lack of prospective data on the frequency of diabetes mellitus, cirrhosis, and other clinical manifestations in p.C282Y homozygotes. More long-term research is recommended to help with the development of uniform diagnostic criteria, a definition of natural history, and indications for treatment.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for HFE-HHC is rarely requested, though technically possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing alleles must be identified in an affected family member or both parents before prenatal testing can be performed.

Note: It is the policy of GeneReviews to include information on prenatal testing that is available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of its use by the author(s), editor(s), or reviewer(s).

Requests for prenatal testing for adult-onset conditions such as HFE-HHC that do not affect intellect or life span and have treatment available are very uncommon. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

Author Information

Dr. Kowdley’s Web site: www.uwgi.org/hemochromatosis

Revision History

• 4 December 2006 (me) Comprehensive update posted to live Web site

• 13 July 2005 (kk) Revision: sequence analysis of entire coding region clinically available

• 13 September 2004 (kk) Author revisions

• 7 October 2003 (me) Comprehensive update posted to live Web site

• 3 April 2000 (me) Review posted to live Web site

• October 1998 (kk) Original submission