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hemochromatosis

An autosomal recessive disorder characterized by an excess accumulation of iron in the liver & other organs. Etiology: 1) genetic defect in HFE protein 2) basic defect may be inappropriately high absorption of iron from the GI tract Epidemiology: 1) heterozygote frequency is 10% 2) 0.5% of white population is homozygous 3) peak incidence between age 40-60 4) iron overload is more common & occurs earlier in men Pathology: 1) increased intestinal absorption 2) decreased excretion of iron 3) preferential deposition of iron in hepatocytes, rather than macrophages 4) progressive iron overload with organ accumulation 5) symptoms generally begin when iron stores exceed 20 g (normal 3-4 g) 6) peroxidative damage enhanced by iron in parenchymal cells leading to fibrosis & organ failure 7) hypogonadotropic hypogonadism [3] 7) cirrhosis is a poor prognostic indicator Genetics: 1) gene linked to HLA-A3 & B15 2) autosomal dominant & autosomal-recessive forms - autosomal recessive [3] 3) defect maps to chromsome 6p (gene for HFE protein) a) C282Y mutation is most common - 0.64% of whites, 0.056% of hispanics, 0.015% of blacks & no Asians homozygous for C282Y mutation [7] - most clinical cases are homozygous for C282Y mutation [19] - C282Y homozygosity associated with hepatic malignancy & death ' among men, but not women [20] b) H63D mutation is second most common c) S65C mutation is third most common d) Asians more likely to have elevated levels of ferritin & transferrin saturation than whites, hispanics or blacks [7] e) low penetrance of disease [4,9] - heterozygotes: rare - homozygotes: 28% of men, 1% of women with clinical disease 45% of men & 8% of women with serum ferritin > 1000 ng/mL 4) defects in SLC40A1 associated with hemochromatosis type 4 5) defects in HFE2 are the cause of hemochromatosis type 2A (juvenile hemochromatosis), autosomal recessive 6) defects in CYBRD1 may be a cause of primary hereditary hemochromatosis 7) associated with defects in TFR2 (transferrin receptor 2); defect maps to 7q22 8) upregulation of UBE2D1 in livers of iron-overloaded patients Clinical manifestations: 1) patients generally present with end-stage disease - case report would suggest otherwise [21] 2) pentads of: a) diabetes b) liver disease, cirrhosis c) heart disease d) hypogonadism, erectile dysfunction e) arthropathy, chondrocalcinosis [22,23] 3) cardiovascular manifestations a) cardiomegaly b) congestive heart failure c) cardiac arrhythmias d) cardiomyopathy - dilated cardiomyopathy more common than restrictive cardiomyopathy [3] e) systolic or diastolic dysfunction f) fatigue 4) other manifestations a) arthropathy (25-50%) 1] chondrocalcinosis 2] calcium pyrophosphate dihydrate (CPPD) crystals 3] osteoarthritis 4] 2nd & 3rd MCP joints are generally 1st to be involved followed by wrist, hip, knee, shoulder, ankle, elbow 5] case report of sacroiliac joint involvement [21] b) hepatomegaly & hepatic failure c) hypogonadism, hypopituitarism, erectile dysfunction d) darkening pigmentation of the skin (brown skin pigmentation) [3] 5) juvenile hemochromatosis onset prior to age 30 Laboratory: 1) serum ferritin a) > 800 ng/mL suggests hemochromatosis b) value of 650 ng/mL used as example in ref [2] c) ref [3] suggests > 1000 mg/mL 2) transferrin saturation > 60% in men (> 50% in women) 3) serum iron 4) total iron binding capacity (TIBC) 5) serum transaminases are generally moderately elevated - HFE C282Y homozygotes generally have lower serum transaminases than non-homozygotes [12] 6) liver biopsy a) MRI obviates need for liver biopsy [3] b) indications [3] - evaluation of fibrosis & cirrhosis place patient at risk for hepatoma & hepatocellular carcinoma c) former indications 1] > 40 years of age* 2] serum ferritin > 1000 ug/L* 3] elevated transferrin saturation, HFE genotype negative 4] formerly standard for diagnosis 5] iron > 10,000 ug/g dry weight 6] hepatic iron index > 2.0 7) HLA typing within a family may help identify susceptible family members 8) screen 1st degree relatives for evidence of iron overload - universal screening not recommended [3] 9) HFE gene mutation: a) HFE gene p.C282Y [3] (most common mutation) - test of choice - HFE gene p.H63D (2nd most common mutation) - HFE gene p.S65C (3rd most common mutation) b) indicated when transferrin saturation > 45% [3] c) a non-diagnostic genotype does not rule out hemochromatosis (obtain liver biopsy) [3] 10) urinary iron following desferrioxamine 11) serum LH & serum FSH may be low [3] 12) cytochrome B reductase in amniotic fluid to evaluate fetus for primary hereditary hemachromatosis 13) see ARUP consult [11] Radiology: - plain radiographs - hook-like osteophytes of 2nd & 3rd metacarpophalangeal joints [3] - asymmetric joint space narrowing - subchondral sclerosis & osteophyte formation in the hips [21] - chondrocalcinosis [3] - magnetic resonance imaging (MRI) of liver - can assess extend of cardiac & hepatic iron overload Differential diagnosis: 1) secondary iron overload 2) acute alcohol abuse 3) advanced liver disease may be associated with elevated serum ferritin but iron saturation is usually normal [3] 4) acromegaly: - absence of liver inflammation - hypertension - change in hand &/or foot size, facial features Complications: 1) cirrhosis 2) increased risk of hepatocellular carcinoma (30% if cirrhosis has developed) 3) increased risk of systemic infections*, including unusual pathogens: a) bacterial infections - Yersinia enterocolitica - Capnocytophaga - Vibrio vulnificus, Vibrio cholerae - Escherichia coli - Listeria monocytogenes b) viral infections - cytomegalovirus - hepatitis B infection - hepatitis C infection - HIV1 infection c) fungal infections - Aspergillys fumigatus - Mucor * iron overload syndromes associated with increased risk of infections with virulence increased by excess iron [3] Management: 1) hereditary hemochromocytosis heterozygous for HFE mutation (C282Y) without symptoms or elevated serum iron & serum ferritin do not need treatment [3] 2) phlebotomy for removal of iron a) indications: - symptomatic patients with evidence of end organ damage - asymptomatic patients with serum ferritin > 1000 ng/mL [3] (MKSAP) - asymptomatic patients with serum ferritin > 800 ng/mL [23] (NEJM) b) removal of 500 mL of blood/week to the point of mild anemia c) maintenance of 4-8 phlebotomies/year required d) if initiated in the pre-cirrhotic stage, phlebotomy can: 1] render the liver normal 2] improve cardiac function 3] improve diabetes e) one unit of blood contains ~ 0.25 g of iron f) target serum ferritin is < 50 ng/mL [3]; (50-100 ng/mL [19]) g) reduce frequency of phlebotomy if anemia develops [22] - effectiveness & cost cited as reasons vs chelation therapy [22] 3) chelation therapy a) deferoxamine (Desferal) IV b) deferasorix (Exjade) PO c) ascorbic acid 4) treatment does NOT: a) reverse arthropathy b) reverse hypogonadism c) reverse the risk of hepatocellular carcinoma if cirrhosis has developed 5) treatment of arthropathy a) NSAIDS b) intra-articular corticosteroids 6) diet: - avoid iron & vitamin C supplements [10] - avoid raw or undercooked seafood, especially oysters (Vibrio vulnificus) [3,17] 7) early detection & treatment prevents complications 8) screening for hepatocellular carcinoma a) patients with fibrosis or cirrhosis b) has not been shown to improve survival [3] 9) USPSTF recommends against routine screening [8] 10) 1st degree relatives of patients with hemochromatosis should be screened with iron studies or genetic studies 11) prognosis: - life expectancy is normal with therapeutic phelbotomy in patients without heart disease or cirrhosis [3]

Interactions

disease interactions

Related

hepatic iron index hepatocellular carcinoma Hereditary hemochromatosis protein; HLA-H (HFE HLAH) iron overload (iron poisoning)

Specific

juvenile hemochromatosis (hemochromatosis type 2B) neonatal hemochromatosis; neonatal giant cell hepatitis

General

cirrhosis disorder of iron metabolism genetic disease of the liver

Database Correlations

OMIM correlations

References

  1. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 365, 374-75
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 322, 338
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2012, 2015, 2018, 2021. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  4. Journal Watch 22(6):48, 2002 Beutler E, Felitti VJ, Koziol JA, Ho NJ, Gelbart T. Penetrance of 845G--> A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet. 2002 Jan 19;359(9302):211-8. PMID: 11812557
  5. Beutler E. Natural history of hemochromatosis. Mayo Clin Proc. 2004 Mar;79(3):305-6. No abstract available. PMID: 1500860
  6. Adams PC. Hemochromatosis. Clin Liver Dis. 2004 Nov;8(4):735-53, vii. Review. PMID: 15464653
  7. Journal Watch 25(10):80, 2005 Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, Dawkins FW, Acton RT, Harris EL, Gordeuk VR, Leiendecker-Foster C, Speechley M, Snively BM, Holup JL, Thomson E, Sholinsky P; Hemochromatosis and Iron Overload Screening (HEIRS) Study Research Investigators. Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med. 2005 Apr 28;352(17):1769-78. PMID: 15858186
  8. Qaseem A, Aronson M, Fitterman N, Snow V, Weiss KB, Owens DK; Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Screening for hereditary hemochromatosis: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2005 Oct 4;143(7):517-21. Summary for patients in: Ann Intern Med. 2005 Oct 4;143(7):I46. PMID: 16204164 (note: corresponding NGC guideline has been withdrawn 12/2010) - US Preventive Services Task Force. Screening for hemochromatosis: Recommendation statement Ann Intern Med 2006, 145:204 PMID: 16880462 (Corresponding NGC guidline withdrawn Jan 2012) - Whitlock EP et al, Screening for hereditary hemochromatosis: A systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2006, 145:209 PMID: 16880463
  9. Allen KJ et al, Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med 2008, 358:221 PMID:
  10. Bacon BR et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011 Jul; 54:328. PMID: 21452290 (corresponding NGC guideline withdrawn Nov 2016)
  11. ARUP Consult: Hemochromatosis The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/hemochromatosis - Hemochromatosis Testing Algorithm https://arupconsult.com/algorithm/hemochromatosis-testing-algorithm
  12. Adams PC et al. Probability of C282Y homozygosity decreases as liver transaminase activities increase in participants with hyperferritinemia in the Hemochromatosis and Iron Overload Screening Study. Hepatology 2012 Jun; 55:1722. PMID: 22183642
  13. Weiss G. Genetic mechanisms and modifying factors in hereditary hemochromatosis. Nat Rev Gastroenterol Hepatol. 2010 Jan;7(1):50-8 PMID: 19918260
  14. Carroll GJ, Breidahl WH, Bulsara MK, Olynyk JK. Hereditary hemochromatosis is characterized by a clinically definable arthropathy that correlates with iron load. Arthritis Rheum. 2011 Jan;63(1):286-94 PMID: 20954257
  15. Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. Gastroenterology. 2010 Aug;139(2):393-408, 408.e1-2 PMID: 20542038
  16. Husar-Memmer E, Stadlmayr A, Datz C, Zwerina J. HFE-related hemochromatosis: an update for the rheumatologist. Curr Rheumatol Rep. 2014 Jan;16(1):393 PMID: 24264720
  17. Khan FA, Fisher MA, Khakoo RA Association of hemochromatosis with infectious diseases: expanding spectrum. Int J Infect Dis. 2007 Nov;11(6):482-7. Epub 2007 Jun 27. PMID: 17600748
  18. Crownover BK, Covey CJ. Hereditary hemochromatosis. Am Fam Physician. 2013 Feb 1;87(3):183-90 PMID: 23418762
  19. Kowdley KV, Brown KE, Ahn J, Sundaram V.. ACG clinical guideline: Hereditary hemochromatosis. Am J Gastroenterol 2019 Aug; 114:1202. PMID: 31335359 https://insights.ovid.com/crossref?an=00000434-201908000-00011
  20. Atkins JL, Pilling LC, Masoli JAH et al Association of Hemochromatosis HFE p.C282Y Homozygosity With Hepatic Malignancy. JAMA. 2020;324(20):2048-2057 PMID: 33231665 https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2020.21566
  21. Sangha S et al A Patient With Back Pain and Morning Stiffness. JAMA. 2020;324(12):1203-1204. August 27. PMID: 32857102 https://jamanetwork.com/journals/jama/fullarticle/2770092
  22. NEJM Knowledge+ Hematology
  23. NEJM Knowledge+ Gastroenterology
  24. Powell LW, Seckington RC, Deugnier Y. Haemochromatosis. Lancet. 2016 Aug 13;388(10045):706-16. PMID: 26975792 Review.
  25. Hemochromatosis https://www.niddk.nih.gov/health-information/liver-disease/hemochromatosis