Iron overload

Iron overload

Micrograph of haemosiderosis. Liver biopsy. Iron stain.
Classification and external resources
Specialty Hematology
ICD-10 R79.0
ICD-9-CM 275.03
DiseasesDB 5581
MedlinePlus 000327
MeSH D019190

Iron overload, also known as hemochromatosis or haemochromatosis, indicates accumulation of iron in the body from any cause. The most important causes are hereditary haemochromatosis (HHC), a genetic disorder, and transfusional iron overload, which can result from repeated blood transfusions.[1][2]

Signs and symptoms

An explanation of hemochromatosis

Organs commonly affected by haemochromatosis are the liver, heart, and endocrine glands.[3]

Haemochromatosis may present with the following clinical syndromes:[4]

Causes

The causes can be distinguished between primary cases (hereditary or genetically determined) and less frequent secondary cases (acquired during life).[8] People of Celtic (Irish, Scottish, Welsh, Cornish, Breton etc.), English, and Scandinavian origin[9] have a particularly high incidence of whom about 10% are carriers of the C282Y mutation on the HFE gene associated with HLA-A3 and 1% suffer from the condition.

Primary haemochromatosis

Although it was known most of the 20th century that most cases of haemochromatosis were inherited, they were incorrectly assumed to depend on a single gene.[10] The overwhelming majority depend on mutations of the HFE gene discovered in 1996, but since then others have been discovered and sometimes are grouped together as "non-classical hereditary haemochromatosis",[11] "non-HFE related hereditary haemochromatosis",[12] or "non-HFE haemochromatosis".[13]

Description OMIM Mutation
Haemochromatosis type 1: "classical" haemochromatosis 235200 HFE
Haemochromatosis type 2A: juvenile haemochromatosis 602390 Haemojuvelin ("HJV", also known as RGMc and HFE2)
Haemochromatosis type 2B: juvenile haemochromatosis 606464 hepcidin antimicrobial peptide (HAMP) or HFE2B
Haemochromatosis type 3 604250 transferrin receptor-2 (TFR2 or HFE3)
Haemochromatosis type 4/
African iron overload 		604653 ferroportin (SLC11A3/SLC40A1)
Neonatal haemochromatosis 231100 (unknown)
Acaeruloplasminaemia (very rare) 604290 caeruloplasmin
Congenital atransferrinaemia (very rare) 209300 transferrin
GRACILE syndrome (very rare) 603358 BCS1L

Most types of hereditary haemochromatosis have autosomal recessive inheritance, while type 4 has autosomal dominant inheritance.[14]

Secondary haemochromatosis

Diagnosis

Selective iron deposition (blue) in pancreatic islet beta cells(red).

There are several methods available for diagnosing and monitoring iron loading including:

Serum ferritin testing is a low-cost, readily available, and minimally invasive method for assessing body iron stores. However, the major problem with using it as an indicator of iron overload is that it can be elevated in a range of other medical conditions unrelated to iron levels including infection, inflammation, fever, liver disease, renal disease, and cancer. Also, total iron binding capacity may be low, but can also be normal.[15]

The standard of practice in diagnosis of haemochromatosis was recently reviewed by Pietrangelo.[16] Positive HFE analysis confirms the clinical diagnosis of haemochromatosis in asymptomatic individuals with blood tests showing increased iron stores, or for predictive testing of individuals with a family history of haemochromatosis. The alleles evaluated by HFE gene analysis are evident in ~80% of patients with haemochromatosis; a negative report for HFE gene does not rule out haemochromatosis. In a patient with negative HFE gene testing, elevated iron status for no other obvious reason, and family history of liver disease, additional evaluation of liver iron concentration is indicated. In this case, diagnosis of haemochromatosis is based on biochemical analysis and histologic examination of a liver biopsy. Assessment of the hepatic iron index (HII) is considered the "gold standard" for diagnosis of haemochromatosis.

Magnetic resonance imaging (MRI) is emerging as a noninvasive alternative to accurately estimate iron deposition levels in the liver as well as heart, joints, and pituitary gland.,[17][18][19][19]

Screening

Family members of those with primary haemochromatosis should be screened to determine if they are a carrier or if they could develop the disease. This can allow preventive measures to be taken.

Screening the general population is not recommended.[20]

Treatment

Routine treatment in an otherwise-healthy person consists of regularly scheduled phlebotomies (bloodletting). When first diagnosed, the phlebotomies may be fairly frequent, perhaps as often as once a week, until iron levels can be brought to within normal range. Once iron and other markers are within the normal range, phlebotomies may be scheduled every other month or every three months depending upon the patient's rate of iron loading. Each session typically draws from 450 to 500 cc.[21]

For those unable to tolerate routine blood draws, there is a chelating agent available for use.[22] The drug deferoxamine binds with iron in the bloodstream and enhances its elimination in urine and faeces. Typical treatment for chronic iron overload requires subcutaneous injection over a period of 8–12 hours daily. Two newer iron chelating drugs that are licensed for use in patients receiving regular blood transfusions to treat thalassaemia (and, thus, who develop iron overload as a result) are deferasirox and deferiprone.[23][24]

Prognosis

Affected individuals over age 40 or who have high serum ferritin levels are at risk for developing cirrhosis. Iron overload increases the risk of hepatocellular carcinoma.[25] This risk is greater in those with cirrhosis but is still present in those without cirrhosis.[25] Significant problems occur in around one in ten.[20]

Epidemiology

It is most common in certain European populations (such as the Irish and Norwegians) and occurs in 0.6% of the population.[20] Men with the disease are 24 times more likely to experience symptoms than affected women.[20]

Terminology

Historically, the term haemochromatosis (spelled hemochromatosis in American English) was initially used to refer to what is now more specifically called haemochromatosis type 1 (or HFE-related hereditary haemochromatosis). Currently, haemochromatosis (without further specification) is mostly defined as iron overload with a hereditary/primary cause,[26][27] or originating from a metabolic disorder.[28] However, the term is currently also used more broadly to refer to any form of iron overload, thus requiring specification of the cause, for example, hereditary haemochromatosis. Hereditary haemochromatosis is an autosomal recessive disorder with estimated prevalence in the population of 1 in 200 among patients with European ancestry, with lower incidence in other ethnic groups.[29] The gene responsible for hereditary haemochromatosis (known as HFE gene) is located on chromosome 6; the majority of hereditary haemochromatosis patients have mutations in this HFE gene.

Hereditary haemochromatosis is characterized by an accelerated rate of intestinal iron absorption and progressive iron deposition in various tissues. This typically begins to be expressed in the third to fifth decades of life, but may occur in children. The most common presentation is hepatic (liver) cirrhosis in combination with hypopituitarism, cardiomyopathy, diabetes, arthritis, or hyperpigmentation. Because of the severe sequelae of this disorder if left untreated, and recognizing that treatment is relatively simple, early diagnosis before symptoms or signs appear is important.[16][30]

In general, the term haemosiderosis is used to indicate the pathological effect of iron accumulation in any given organ, which mainly occurs in the form of the iron-storage complex haemosiderin.[31][32] Sometimes, the simpler term siderosis is used instead.

Other definitions distinguishing haemochromatosis or haemosiderosis that are occasionally used include:

See also

References

  1. ↑ Hider, Robert C.; Kong, Xiaole (2013). "Chapter 8. Iron: Effect of Overload and Deficiency". In Astrid Sigel, Helmut Sigel and Roland K. O. Sigel. Interrelations between Essential Metal Ions and Human Diseases. Metal Ions in Life Sciences 13. Springer. pp. 229–294. doi:10.1007/978-94-007-7500-8_8.
  2. 1 2 3 Lu JP, Hayashi K. Selective iron deposition in pancreatic islet B cells of transfusional iron-overloaded autopsy cases. Pathol Int. 1994 Mar;44(3):194-9. PubMed PMID 8025661.
  3. ↑ Andrews, Nancy C. (1999). "Disorders of Iron Metabolism". New England Journal of Medicine 341 (26): 1986–95. doi:10.1056/NEJM199912233412607. PMID 10607817.
  4. ↑ John Murtagh (2007). General Practice. McGraw Hill Australia. ISBN 0-07-470436-2.
  5. ↑ Lu JP, Hayashi K. Transferrin receptor distribution and iron deposition in the hepatic lobule of iron-overloaded rats. Pathol Int. 1995 Mar;45(3):202-6. PubMed PMID 7787990.
  6. ↑ Lu JP, Hayashi K. Transferrin receptor distribution and iron deposition in the hepatic lobule of iron-overloaded rats. Pathol Int. 1995 Mar;45(3):202-6. PubMed PMID 7787990.
  7. ↑ http://www.mayoclinic.com/health/hemochromatosis/DS00455/DSECTION=symptoms
  8. ↑ Pietrangelo, A (2003). "Haemochromatosis". Gut 52 (90002): ii23–30. doi:10.1136/gut.52.suppl_2.ii23. PMC 1867747. PMID 12651879.
  9. ↑ The Atlantic: "The Iron in Our Blood That Keeps and Kills Us" by Bradley Wertheim January 10, 2013
  10. ↑ Cam Patterson; Marschall S. Runge (2006). Principles of molecular medicine. Totowa, NJ: Humana Press. p. 567. ISBN 1-58829-202-9.
  11. ↑ Mendes, Ana Isabel; Ferro, Ana; Martins, Rute; Picanço, Isabel; Gomes, Susana; Cerqueira, Rute; Correia, Manuel; Nunes, António Robalo; Esteves, Jorge; Fleming, Rita; Faustino, Paula (2008). "Non-classical hereditary hemochromatosis in Portugal: novel mutations identified in iron metabolism-related genes". Annals of Hematology 88 (3): 229–34. doi:10.1007/s00277-008-0572-y. PMID 18762941.
  12. ↑ Maddrey, Willis C.; Schiff, Eugene R.; Sorrell, Michael F. (2007). Schiff's diseases of the liver. Hagerstwon, MD: Lippincott Williams & Wilkins. p. 1048. ISBN 0-7817-6040-2.
  13. ↑ Pietrangelo, Antonello (2005). "Non-HFE Hemochromatosis". Seminars in Liver Disease 25 (4): 450–60. doi:10.1055/s-2005-923316. PMID 16315138.
  14. ↑ Franchini, Massimo (2006). "Hereditary iron overload: Update on pathophysiology, diagnosis, and treatment". American Journal of Hematology 81 (3): 202–9. doi:10.1002/ajh.20493. PMID 16493621.
  15. ↑ labtestsonline.org > TIBC & UIBC, Transferrin Last reviewed on October 28, 2009.
  16. 1 2 Pietrangelo, Antonello (2010). "Hereditary Hemochromatosis: Pathogenesis, Diagnosis, and Treatment". Gastroenterology 139 (2): 393–408. doi:10.1053/j.gastro.2010.06.013. PMID 20542038.
  17. ↑ Wood JC, Enriquez C, Ghugre N, Tyzka JM, Carson S, Nelson MD. MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients. Blood. Aug 15 2005;106(4):1460-5
  18. ↑ Ghugre NR, Enriquez CM, Gonzalez I, et al. MRI detects myocardial iron in the human heart. Magn Reson Med. Sep 2006;56(3):681-6.
  19. 1 2 Sparacia G, Iaia A, Banco A, D'Angelo P, Lagalla R. Transfusional hemochromatosis: quantitative relation of MR imaging pituitary signal intensity reduction to hypogonadotropic hypogonadism. Radiology. Jun 2000;215(3):818-23
  20. 1 2 3 4 Crownover, BK; Covey, CJ (Feb 1, 2013). "Hereditary hemochromatosis.". American family physician 87 (3): 183–90. PMID 23418762.
  21. ↑ Barton, James C. (1 December 1998). "Management of Hemochromatosis". Annals of Internal Medicine 129 (11_Part_2): 932. doi:10.7326/0003-4819-129-11_Part_2-199812011-00003.
  22. ↑ Miller, Marvin J. (1989-11-01). "Syntheses and therapeutic potential of hydroxamic acid based siderophores and analogs". Chemical Reviews 89 (7): 1563–1579. doi:10.1021/cr00097a011.
  23. ↑ Choudhry VP, Naithani R (2007). "Current status of iron overload and chelation with deferasirox". Indian J Pediatr 74 (8): 759–64. doi:10.1007/s12098-007-0134-7. PMID 17785900.
  24. ↑ Hoffbrand, A. V. (20 March 2003). "Role of deferiprone in chelation therapy for transfusional iron overload". Blood 102 (1): 17–24. doi:10.1182/blood-2002-06-1867.
  25. 1 2 Kowdley, KV (November 2004). "Iron, hemochromatosis, and hepatocellular carcinoma.". Gastroenterology 127 (5 Suppl 1): S79–86. PMID 15508107.
  26. ↑ thefreedictionary.com > hemochromatosis, citing:
    • The American Heritage Medical Dictionary, 2004 by Houghton Mifflin Company
    • McGraw-Hill Concise Dictionary of Modern Medicine. 2002
  27. ↑ Merriam-Webster's Medical Dictionary > hemochromatosis Retrieved on Dec 11, 2009
  28. ↑ thefreedictionary.com, citing:
    • Dorland's Medical Dictionary for Health Consumers, 2007
    • Mosby's Medical Dictionary, 8th edition. 2009
    • Jonas: Mosby's Dictionary of Complementary and Alternative Medicine. 2005.
  29. ↑ "Hemochromatosis".
  30. ↑ Brandhagen, D J; Fairbanks, V F; Batts, K P; Thibodeau, S N (1999). "Update on hereditary hemochromatosis and the HFE gene". Mayo Clinic Proceedings 74 (9): 917–21. doi:10.4065/74.9.917. PMID 10488796.
  31. ↑ Merriam-Webster's Medical Dictionary > hemosideroses Retrieved on Dec 11, 2009
  32. ↑ thefreedictionary.com > hemosiderosis, citing:
    • The American Heritage Medical Dictionary, 2004 by Houghton Mifflin Company
    • Mosby's Medical Dictionary, 8th edition.
  33. ↑ eMedicine Specialties > Radiology > Gastrointestinal > Hemochromatosis Author: Sandor Joffe, MD. Updated: May 8, 2009
  34. ↑ thefreedictionary.com > hemosiderosis, citing:
    • Gale Encyclopedia of Medicine. Copyright 2008
  35. ↑ Notecards on radiology gamuts, diseases, anatomy 2002, Charles E. Kahn, Jr., MD. Medical College of Wisconsin
  36. ↑ thefreedictionary.com > hemosiderosis, citing:
    • Dorland's Medical Dictionary for Health Consumers, 2007
    • Mosby's Dental Dictionary, 2nd edition.
    • Saunders Comprehensive Veterinary Dictionary, 3rd ed. 2007
  37. ↑ The HealthScout Network > Health Encyclopedia > Diseases and Conditions > Hemochromatosis Retrieved on Dec 11, 2009
  38. ↑ thefreedictionary.com > hemosiderosis, citing:
    • McGraw-Hill Concise Dictionary of Modern Medicine. 2002

Further reading

External links

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