Genetics Northern California

Hereditary Hemochromatosis

Hereditary hemochromatosis (HH) is the most common cause of iron overload. HH is an autosomal recessive disease characterized by excess iron absorption in the small intestine, leading to excessive iron accumulation over many years. Iron deposits in multiple organs leads to end-organ damage. Complications include cirrhosis, liver failure, hepatic cell carcinoma, cardiomyopathy, and arthritis. Early symptoms usually develop in mid-adulthood but there is a wide range in the age of onset and the severity of the condition.  Women who develop medical complications from HH usually have a later on than men, due to the protective effect of menstruation. About 1 in every 400 Caucasians in the United States has the genotype that causes HH. Although the condition is primarily found in Caucasians of Northern European ancestry, a recent study suggests the rate in the Hispanic population is also significant. The carrier frequency among individuals of Northern European descent is thought to be approximately 1 in 10.

Cause
Hereditary hemochromatosis is an autosomal recessive disease. People who carry one normal gene and one abnormal gene are carriers of the disease and most likely have no symptoms. People who have two abnormal genes have the disease, but some may show symptoms of the disease, while others (up to 50%) remain asymptomatic.

Diagnosis
Diagnosis of HH has traditionally been by blood tests that measure iron stores including iron, TIBC (total iron binding capacity), transferrin saturation, and ferritin. These results give a good assessment of whether iron overload is present, but cannot easily tell what genes the person carries. There can be carriers of HH with elevations of transferrin saturation, as well as females who have no evidence of iron overload during the premenopausal years. Iron studies cannot distinguish the asymptomatic carrier from the asymptomatic individual who has two normal genes.  Historically, in order to confirm the diagnosis of HH a liver biopsy was done to show increased hepatic iron.

Molecular testing by DNA analysis of the HFE gene is also available. Two common European mutations have been identified. The C282Y mutation is   more severe than the H63D mutation. DNA testing has a sensitivity of approximately 85%. Approximately 15% of mutated genes cannot be identified in this manner. Therefore, a normal genetic test result cannot absolutely eliminate the possibility of a mutation. If there is a known family history of HH, DNA testing can be very definitive in determining carrier status, particularly if molecular studies are available for an affected relative.

Treatment/Services
Individuals who have two copies of the C282Y mutation have the greatest risk to develop clinical signs/symptoms of hemochromatosis and iron overload. Individuals who have one copy of the severe C282Y mutation and one copy of the mild H63D have about a 2% lifetime risk to develop clinical symptoms. These individuals should have regular iron biochemical testing as recommended by a gastroenterologist or hematologist. These specialists should be able to determine whether to initiate therapeutic phlebotomy and/or make dietary recommendations for management of iron overload. Lifelong therapy by phlebotomy to reduce iron stores can help prevent, improve, or even reverse the serious complications of the disease. It should be noted that if a diagnosis of hereditary hemochromatosis has been made, it is not necessary to wait for symptoms to occur to begin treatment.

 

HFE mutations

Estimated frequency in the European (Caucasian) population

Risk for iron overload

Chance to develop medical problems related to iron overload

TWO MUTATIONS(C282Y/C282Y)

Homozygous C282Y

 

1 in 300

 

Increased risk for iron overload

 


5% (males)
2% (females)

TWO MUTATIONS(C282Y/H63D)

Compound Heterozygous

 

1 in 50

 

Low risk for iron overload

 

2% (males)

TWO MUTATIONS(H63D/H63D)

Homozygous H63D

 

About 1 in 50

 

Very low risk for iron overload

 

Unlikely

ONE MUTATION
(Normal/C282Y)

Heterozygous C282Y

 

1 in 10

 

Iron overload unlikely

 

Unlikely without other risk factors

ONE MUTATION
(Normal/H63D)

Heterozygous H63D 

 

1 in 5

 

Iron overload unlikely

 

Unlikely without other risk factors 

 

RESOURCES

The Hemochromatosis Information Center - A website with general information about hemochromatosis developed  by the Iron Disorders Network.

Genetics Home Reference: Hemochromatosis - A guide to hemochromatosis provided by the U.S. National Library of Health. Includes additional links.

Hereditary Hemochromatosis - Easy-to-read information about HH from FamilyDoctor.org.

References:

  1. Steinberg et al, Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States. JAMA. 2001 May 2;285(17):2216-22.

  2. Beutler  et al, Penetrance of 845G--> A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet. 2002 Jan 19;359(9302):211-8.

  3. Rossi and Jeffrey, Clinical penetrance of C282Y homozygous HFE haemochromatosis. Clin Biochem Rev. 2004 Aug;25(3):183-90.

  4. Gurrin et al,  HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity. Hepatology. 2009 Jul;50(1):94-101.

  5. Gochee et al, A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Gastroenterology. 2002 Mar;122(3):646-51.