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Hereditary hemochromatosis(HFE1)

MedGen UID:
140272
Concept ID:
C0392514
Disease or Syndrome
Synonyms: Bronze Diabetes; Bronzed cirrhosis; Familial Hemochromatosis; genetic hemochromatosis; Haemochromatosis; Hemochromatoses; hemochromatosis; HEMOCHROMATOSIS, HEREDITARY; HEMOCHROMATOSIS, TYPE 1; HFE-Associated Hereditary Hemochromatosis; HFE1; Iron storage disorder; Pigmentary cirrhosis; Primary Hemochromatosis; Troisier-Hanot-Chauffard syndrome; Von Recklenhausen-Applebaum disease
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Autosomal recessive inheritance refers to genetic conditions that occur only when mutations are present in both copies of a given gene (i.e., the person is homozygous for a mutation, or carries two different mutations of the same gene, a state referred to as compound heterozygosity).
SNOMED CT: Idiopathic hemochromatosis (399053004); Primary hemochromatosis (399170009); Hereditary hemochromatosis (35400008); Primary hemochromatosis (35400008); Idiopathic hemochromatosis (35400008); Familial hemochromatosis (35400008)
 
Genes: HFE; BMP2
Cytogenetic locations: 20p12.3; 6p22.2
OMIM: 235200

Disease characteristics

Excerpted from the GeneReview: HFE-Associated Hereditary Hemochromatosis
HFE-associated hereditary hemochromatosis (HFE-HH) is characterized by inappropriately high absorption of iron by the gastrointestinal mucosa. The phenotypic spectrum of HFE-HH is now recognized to include Those with clinical HFE-HH, in which manifestations of end-organ damage secondary to iron storage are present; Those with biochemical HFE-HH, in which the only evidence of iron overload is increased transferrin-iron saturation and increased serum ferritin concentration; and Non-expressing p.Cys282Tyr homozygotes in whom neither clinical manifestations of HFE-HH nor iron overload are present. Clinical HFE-HH is characterized by excessive storage of iron in the liver, skin, pancreas, heart, joints, and testes. In untreated individuals: early symptoms may include abdominal pain, weakness, lethargy, and weight loss; the risk of cirrhosis is significantly increased when the serum ferritin is higher than 1,000 ng/mL; other findings may include progressive increase in skin pigmentation, diabetes mellitus, congestive heart failure and/or arrhythmias, arthritis, and hypogonadism. Clinical HFE-HH is more common in men than women. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Description  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
Kris V Kowdley  |  Robin L Bennett  |  Arno G Motulsky   view full author information

Additional descriptions

From OMIM
Hereditary hemochromatosis is an autosomal recessive disorder of iron metabolism wherein the body accumulates excess iron (summary by Feder et al., 1996). Excess iron is deposited in a variety of organs leading to their failure, and resulting in serious illnesses including cirrhosis, hepatomas, diabetes, cardiomyopathy, arthritis, and hypogonadotropic hypogonadism. Severe effects of the disease usually do not appear until after decades of progressive iron loading. Removal of excess iron by therapeutic phlebotomy decreases morbidity and mortality if instituted early in the course of the disease. Classic hemochromatosis (HFE) is most often caused by mutation in a gene designated HFE on chromosome 6p21.3. Adams and Barton (2007) reviewed the clinical features, pathophysiology, and management of hemochromatosis. Genetic Heterogeneity of Hemochromatosis At least 4 additional iron overload disorders labeled hemochromatosis have been identified on the basis of clinical, biochemical, and genetic characteristics. Juvenile hemochromatosis, or hemochromatosis type 2 (HFE2), is autosomal recessive and is divided into 2 forms: HFE2A (602390), caused by mutation in the HJV gene (608374) on chromosome 1q21, and HFE2B (613313), caused by mutation in the HAMP gene (606464) on chromosome 19q13. Hemochromatosis type 3 (HFE3; 604250), an autosomal recessive disorder, is caused by mutation in the TFR2 gene (604720) on chromosome 7q22. Hemochromatosis type 4 (HFE4; 606069), an autosomal dominant disorder, is caused by mutation in the SLC40A1 gene (604653) on chromosome 2q32. Hemochromatosis type 5 (HFE5; 615517) is caused by mutation in the FTH1 gene (134770) on chromosome 11q12.  http://www.omim.org/entry/235200
From GHR
Hemochromatosis is a disorder that causes the body to absorb too much iron from the diet. The excess iron is stored in the body's tissues and organs, particularly the skin, heart, liver, pancreas, and joints. Because humans cannot increase the excretion of iron, excess iron can overload and eventually damage tissues and organs. For this reason, hemochromatosis is also called an iron overload disorder. Early symptoms of hemochromatosis are nonspecific and may include fatigue, joint pain, abdominal pain, and loss of sex drive. Later signs and symptoms can include arthritis, liver disease, diabetes, heart abnormalities, and skin discoloration. The appearance and progression of symptoms can be affected by environmental and lifestyle factors such as the amount of iron in the diet, alcohol use, and infections. Hemochromatosis is classified by type depending on the age of onset and other factors such as genetic cause and mode of inheritance. Hemochromatosis type 1, the most common form of the disorder, and type 4 (also called ferroportin disease) are adult-onset disorders. Men with type 1 or type 4 hemochromatosis typically develop symptoms between the ages of 40 and 60, and women usually develop symptoms after menopause. Type 2 hemochromatosis is a juvenile-onset disorder. Iron accumulation begins early in life, and symptoms may begin to appear in childhood. By age 20, decreased or absent secretion of sex hormones is evident. Females usually begin menstruation in a normal manner, but menses stop after a few years. Males may experience delayed puberty or sex hormone deficiency symptoms such as impotence. If the disorder is untreated, heart disease is evident by age 30. Onset of type 3 hemochromatosis is usually intermediate between types 1 and 2. Symptoms of type 3 hemochromatosis generally begin before age 30. In rare cases, iron overload begins before birth. These cases are called neonatal hemochromatosis. This type of hemochromatosis progresses rapidly and is characterized by liver damage that is apparent at birth or in the first day of life.  http://ghr.nlm.nih.gov/condition/hemochromatosis

Clinical features

Azoospermia
MedGen UID:
504308
Concept ID:
CN000028
Finding
Absence of any measurable level of sperm in his semen.
Testicular atrophy
MedGen UID:
504310
Concept ID:
CN000030
Finding
Wasting (atrophy) of the testicle (the male gonad) manifested by a decrease in size and potentially by a loss of fertility.
Hypogonadotrophic hypogonadism
MedGen UID:
504316
Concept ID:
CN000044
Finding
Hypogonadotropic hypogonadism is characterized by reduced function of the gonads (testes in males or ovaries in females) and results from the absence of the gonadal stimulating pituitary hormones: follicle stimulating hormone (FSH) and luteinizing hormone (LH).
Hypogonadotrophic hypogonadism
MedGen UID:
504316
Concept ID:
CN000044
Finding
Hypogonadotropic hypogonadism is characterized by reduced function of the gonads (testes in males or ovaries in females) and results from the absence of the gonadal stimulating pituitary hormones: follicle stimulating hormone (FSH) and luteinizing hormone (LH).
Diabetes mellitus
MedGen UID:
504609
Concept ID:
CN000766
Finding
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Ascites
MedGen UID:
416
Concept ID:
C0003962
Finding
A disorder characterized by accumulation of serous or hemorrhagic fluid in the peritoneal cavity.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Enlargement of the spleen.
Cirrhosis
MedGen UID:
504826
Concept ID:
CN001275
Finding
A chronic disorder of the `liver` (FMA:7197) in which liver tissue becomes `scarred` (PATO:0001850) and is partially replaced by regenerative nodules and fibrotic tissue resulting in loss of liver function.
Hepatomegaly
MedGen UID:
505165
Concept ID:
CN002031
Finding
Abnormally `increased size` (PATO:0000586) of the `liver` (FMA:7197).
Elevated hepatic transaminases
MedGen UID:
505403
Concept ID:
CN002632
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Alopecia
MedGen UID:
7982
Concept ID:
C0002170
Finding
A disorder characterized by a decrease in density of hair compared to normal for a given individual at a given age and body location.
Hyperpigmentation of the skin
MedGen UID:
504657
Concept ID:
CN000892
Finding
A darkening of the skin related to an increase in melanin production and deposition.
Cardiomegaly
MedGen UID:
5459
Concept ID:
C0018800
Finding
hypertrophy or enlargement of the heart.
Congestive heart failure
MedGen UID:
504881
Concept ID:
CN001488
Finding
The presence of an abnormality of cardiac function that is responsible for the failure of the heart to pump blood at a rate that is commensurate with the needs of the tissues or a state in which abnormally elevated filling pressures are required for the heart to do so. Heart failure is frequently related to a defect in myocardial contraction.
Cardiomyopathy
MedGen UID:
504883
Concept ID:
CN001491
Finding
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Diabetes mellitus
MedGen UID:
504609
Concept ID:
CN000766
Finding
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Abnormal glucose tolerance
MedGen UID:
505023
Concept ID:
CN001766
Finding
An `abnormal` (PATO:0000460) `resistance to` (PATO:0001046) `glucose`(CHEBI:17234), i.e., a reduction in the ability to maintain glucose levels in the blood stream within normal limits following oral or intravenous administration of glucose.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Enlargement of the spleen.

Professional guidelines

PubMed

Stuhrmann M, Gabriel H, Keeney S
Eur J Hum Genet 2010 Sep;18(9) Epub 2010 Feb 3 doi: 10.1038/ejhg.2009.245. [Epub ahead of print] PMID: 20125190Free PMC Article
U.S. Preventive Services Task Force
Ann Intern Med 2006 Aug 1;145(3):204-8. PMID: 16880462

Recent clinical studies

Etiology

Cherfane CE, Hollenbeck RD, Go J, Brown KE
Am J Med 2013 Nov;126(11):1010-5. Epub 2013 Sep 18 doi: 10.1016/j.amjmed.2013.07.013. [Epub ahead of print] PMID: 24054178
Kanwar P, Kowdley KV
Expert Rev Gastroenterol Hepatol 2013 Aug;7(6):517-30. doi: 10.1586/17474124.2013.816114. PMID: 23985001
Crownover BK, Covey CJ
Am Fam Physician 2013 Feb 1;87(3):183-90. PMID: 23418762
Mohammad A, Carey JJ, Storan E, Scarry M, Coughlan RJ, Lee JM
J Clin Gastroenterol 2013 Jul;47(6):559-64. doi: 10.1097/MCG.0b013e31826f7ad7. PMID: 23188073
Trieß C, von Figura G, Stuhrmann M, Butzeck B, Krayenbuehl PA, Strnad P, Kulaksiz H
Dig Dis Sci 2012 Nov;57(11):2988-94. Epub 2012 Jun 7 doi: 10.1007/s10620-012-2243-z. [Epub ahead of print] PMID: 22674401

Diagnosis

Cherfane CE, Hollenbeck RD, Go J, Brown KE
Am J Med 2013 Nov;126(11):1010-5. Epub 2013 Sep 18 doi: 10.1016/j.amjmed.2013.07.013. [Epub ahead of print] PMID: 24054178
Kanwar P, Kowdley KV
Expert Rev Gastroenterol Hepatol 2013 Aug;7(6):517-30. doi: 10.1586/17474124.2013.816114. PMID: 23985001
Karaca H, Güven K, Önal M, Gürsoy Ş, Başkol M, Özkul Y
Turk J Gastroenterol 2013;24(1):43-50. PMID: 23794343
Crownover BK, Covey CJ
Am Fam Physician 2013 Feb 1;87(3):183-90. PMID: 23418762
Trieß C, von Figura G, Stuhrmann M, Butzeck B, Krayenbuehl PA, Strnad P, Kulaksiz H
Dig Dis Sci 2012 Nov;57(11):2988-94. Epub 2012 Jun 7 doi: 10.1007/s10620-012-2243-z. [Epub ahead of print] PMID: 22674401

Therapy

Kanwar P, Kowdley KV
Expert Rev Gastroenterol Hepatol 2013 Aug;7(6):517-30. doi: 10.1586/17474124.2013.816114. PMID: 23985001
Trieß C, von Figura G, Stuhrmann M, Butzeck B, Krayenbuehl PA, Strnad P, Kulaksiz H
Dig Dis Sci 2012 Nov;57(11):2988-94. Epub 2012 Jun 7 doi: 10.1007/s10620-012-2243-z. [Epub ahead of print] PMID: 22674401
Brissot P, Ball S, Rofail D, Cannon H, Jin VW
Transfusion 2011 Jun;51(6):1331-8. Epub 2010 Dec 22 doi: 10.1111/j.1537-2995.2010.02997.x. [Epub ahead of print] PMID: 21175649
Fargion S, Valenti L, Fracanzani AL
Dig Liver Dis 2011 Feb;43(2):89-95. Epub 2010 Aug 24 doi: 10.1016/j.dld.2010.07.006. [Epub ahead of print] PMID: 20739232
Barg A, Elsner A, Hefti D, Hintermann B
Clin Orthop Relat Res 2011 May;469(5):1427-35. Epub 2010 Jul 28 doi: 10.1007/s11999-010-1483-5. [Epub ahead of print] PMID: 20665138Free PMC Article

Prognosis

Kanwar P, Kowdley KV
Expert Rev Gastroenterol Hepatol 2013 Aug;7(6):517-30. doi: 10.1586/17474124.2013.816114. PMID: 23985001
Crownover BK, Covey CJ
Am Fam Physician 2013 Feb 1;87(3):183-90. PMID: 23418762
Shizukuda Y, Smith KP, Tripodi DJ, Arena R, Yau YY, Bolan CD, Waclawiw MA, Leitman SF, Rosing DR
Am J Phys Med Rehabil 2012 May;91(5):418-24. doi: 10.1097/PHM.0b013e3182465f5f. PMID: 22311055Free PMC Article
Shizukuda Y, Tripodi DJ, Zalos G, Bolan CD, Yau YY, Leitman SF, Waclawiw MA, Rosing DR
Am J Cardiol 2012 Mar 15;109(6):856-60. Epub 2011 Dec 22 doi: 10.1016/j.amjcard.2011.11.011. [Epub ahead of print] PMID: 22196777Free PMC Article
Aleman S, Endalib S, Stål P, Lööf L, Lindgren S, Sandberg-Gertzén H, Almer S, Olsson S, Danielsson A, Wallerstedt S, Hultcrantz R
Scand J Gastroenterol 2011 Sep;46(9):1118-26. Epub 2011 Jun 15 doi: 10.3109/00365521.2011.591426. [Epub ahead of print] PMID: 21675821

Clinical prediction guides

Wang J, Zhou X, Zhao J, Li Z, Li X
Genet Mol Res 2013 Dec 4;12(4):6240-8. doi: 10.4238/2013.December.4.11. PMID: 24338419
Kanwar P, Kowdley KV
Expert Rev Gastroenterol Hepatol 2013 Aug;7(6):517-30. doi: 10.1586/17474124.2013.816114. PMID: 23985001
Trieß C, von Figura G, Stuhrmann M, Butzeck B, Krayenbuehl PA, Strnad P, Kulaksiz H
Dig Dis Sci 2012 Nov;57(11):2988-94. Epub 2012 Jun 7 doi: 10.1007/s10620-012-2243-z. [Epub ahead of print] PMID: 22674401
Wood MJ, Powell LW, Dixon JL, Ramm GA
Hepatology 2012 Sep;56(3):904-11. Epub 2012 Jun 19 doi: 10.1002/hep.25720. [Epub ahead of print] PMID: 22422567
Dostalikova-Cimburova M, Kratka K, Balusikova K, Chmelikova J, Hejda V, Hnanicek J, Neubauerova J, Vranova J, Kovar J, Horak J
J Cell Mol Med 2012 Aug;16(8):1816-26. doi: 10.1111/j.1582-4934.2011.01458.x. PMID: 21973163

Recent systematic reviews

Lian J, Xu L, Huang Y, Le Y, Jiang D, Yang X, Xu W, Huang X, Dong C, Ye M, Zhou J, Duan S
Gene 2013 Sep 15;527(1):167-73. Epub 2013 Jun 20 doi: 10.1016/j.gene.2013.06.034. [Epub ahead of print] PMID: 23792061
Picot J, Bryant J, Cooper K, Clegg A, Roderick P, Rosenberg W, Patch C
Genet Test Mol Biomarkers 2009 Feb;13(1):7-14. doi: 10.1089/gtmb.2008.0064. PMID: 19309267
Whitlock EP, Garlitz BA, Harris EL, Beil TL, Smith PR
Ann Intern Med 2006 Aug 1;145(3):209-23. PMID: 16880463
Schmitt B, Golub RM, Green R
Ann Intern Med 2005 Oct 4;143(7):522-36. PMID: 16204165
Qaseem A, Aronson M, Fitterman N, Snow V, Weiss KB, Owens DK; Clinical Efficacy Assessment Subcommittee of the American College of Physicians
Ann Intern Med 2005 Oct 4;143(7):517-21. PMID: 16204164

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