Overall Bottom Line

HH is an autosomal recessive disease caused by mutations in the HFE gene leading to increased iron absorption and deposition of iron in various organs, including the liver.
It is the most common hereditary disorder in White people with a prevalence as high as 1 in 140 individuals in some studies although phenotypic expression is much less common.
It typically presents as asymptomatic elevation in iron studies but can present in middle age with abnormal liver enzymes and hepatomegaly as well as arthralgias, loss of libido, diabetes and heart failure due to iron deposition in other organs.
The diagnosis relies on demonstration of elevated body iron stores with a high iron saturation and ferritin. Testing for HFE gene mutations and hepatic iron content on liver biopsy can also be helpful.
Treatment is based on depletion of iron through phlebotomy and improves survival and can even reverse cirrhosis in selected patients.

Section 1: Background

Definition of disease

There is no universally accepted definition of HH but it is essentially an inherited condition leading to increased total body iron.

Disease classification

The disease can be classified into stages:
- Stage 1: patients with the genetic disorder (positive HFE gene test) but normal iron stores.
- Stage 2: patients with the genetic disorder and elevated iron stores but no tissue/organ damage.
- Stage 3: patients with the genetic disorder with iron overload and tissue/organ damage.
In addition, iron overload can be classified according to whether it is an inherited disorder (as in HH) or one of the many causes of secondary iron overload.

Incidence/prevalence

The prevalence of HH defined by HFE gene polymorphisms varies according to population but is as high as 1 in 140 for C282Y homozygosity in people of Northern European ancestry and 1 in 330 in a racially mixed population.
The frequency of the C282Y allele is as high as 12.5% in Ireland.
C282Y homozygosity accounts for approximately 80% of inherited iron overload syndromes, with 5% accounted for by C282Y and H63D heterozygosity. The remaining 15% likely have mutations in other genes involved in iron absorption and metabolism.

Economic impact

The economic impact of HH is unclear. Despite the high prevalence of the disorder, the low phenotypic expression and simplicity of treatment would suggest a minimal economic impact compared with other causes of chronic liver disease.

Etiology

There are several genetic defects that have been identified in HH.
The commonest genetic defect is closely linked to the HLA-A3 locus on the short arm of chromosome 6. In 1996, two missense mutations were identified on a candidate gene and termed the HLA-H or HFE gene.
Substitution of tyrosine for cysteine at amino acid position 282 (C282Y) of the HFE gene product is the commonest with C282Y homozygotes accounting for 80–85% of all HH patients. Substitution of histidine for aspartate at position 63 (H63D) and serine substituted for cysteine at position 65 (S65C) make up the other two commonly identified mutations but are rarely seen in iron overload unless associated with C282Y in a compound heterozygote.
Several other mutations in genes encoding for a variety of other proteins involved in iron regulation (hepcidin, ferroportin, hemojuvelin, and transferrin receptor 2, ceruloplasmin) probably play a role in HH in the absence of HFE gene mutations.

Pathology/pathogenesis

In normal individuals, 1 mg of iron is lost daily through skin, sweat and the gastrointestinal tract and is replaced by 1 mg absorbed through duodenal enterocytes, a process regulated by iron stores.
In HH, failure of this regulatory mechanism leads to absorption of several milligrams of iron daily which overcomes the normal iron loss. After the increased need for iron in childhood and adolescence abates, iron stores gradually increase at a rate of approximately 1 g a year (less in women due to menstruation, pregnancy and lactation). By middle age 20–30 g of excess iron has been deposited in several organs leading to the clinical manifestations.
Liver damage in HH is thought to be related to iron-dependent oxidative processes which damage several cell functions initiating a cascade of cytokines that ultimately lead to fibrosis.
The function of the HFE gene protein is still unclear but it is structurally similar to major histocompatibility complex class-1 proteins and can bind to transferrin receptors (1 and 2). The resulting complex may have a role in sensing iron on the hepatocyte cell membrane and/or affecting hepcidin expression, and may be involved in iron uptake by duodenal enterocytes.
Hepcidin appears to be the most important peptide in iron regulation. It is made in hepatocytes and secreted into the circulation where it encounters ferroportin on macrophages and enterocytes. The hepcidin binds to ferroportin which is internalized and inhibits iron release. Excess iron induces hepcidin expression while iron deficiency decreases it.
HFE gene mutations decrease hepcidin expression leading to up-regulation of ferroportin levels in enterocytes and an increase in intestinal iron absorption.

Section 2: Prevention

Clinical Pearls

No interventions have been demonstrated to prevent the development of the disease.
By definition, HH is a genetic disease so cannot be prevented. However, treatment ideally should be started in asymptomatic patients prior to clinical evidence of the disease.

Screening

Screening tests for HH depend on the patient population being investigated.
Despite the high prevalence of HFE gene mutations, the low disease penetrance means that routine screening of the general population is not recommended.
Patients with abnormal liver enzymes or clinical evidence of liver disease should be screened for HH.
Patients with a family history of HH should be screened.
The initial screening test for HH should include serum iron studies: transferrin saturation and ferritin.
If the transferrin saturation is greater than 45% or the ferritin is above the normal range, genetic testing for HFE mutations is recommended.
In patients with a first degree relative with HH, iron studies and HFE genetic testing is recommended.

Section 3: Diagnosis

Clinical Pearls

Due to the increased awareness of HH and the availability of genetic testing, approximately 75% of patients are asymptomatic at presentation.
When present symptoms include generalized weakness and fatigue, skin changes (hyperpigmentation), loss of libido and arthralgias.
Examination findings can include cardiomegaly, hepatomegaly, testicular atrophy, skin pigmentation and arthritis.
Laboratory testing for HH is usually prompted by the finding of abnormal liver enzymes. The initial evaluation includes demonstration of elevated iron stores based on an iron saturation of greater than 45% and an elevated ferritin.
HFE gene testing is appropriate for patients with elevated iron studies.
Liver biopsy and hepatic iron content are helpful in certain cases where the diagnosis is in doubt and to assess the degree of fibrosis.
Imaging can be helpful if cirrhosis is suspected and newer MRI techniques can demonstrate increased hepatic iron content.