Iron overload

Source: Wikipedia, the free encyclopedia.
(Redirected from
Hemochromatosis
)
Iron overload
Other namesHaemochromatosis or Hemochromatosis
Micrograph of liver
Iron stain.
SpecialtyHematology, gastroenterology/hepatology

Iron overload (also haemochromatosis (

blood transfusions.[2]

Signs and symptoms

Organs most commonly affected by hemochromatosis include the liver, heart, and endocrine glands.[3]

Hemochromatosis may present with the following clinical syndromes:

Hemochromatosis leading to secondary diabetes (through iron deposition in the insulin secreting beta cells of the pancreas), when combined with a bronzing or darkening of the skin, is sometimes known as "bronze diabetes".[9]

Causes

The term hemochromatosis was initially used to refer to what is now more specifically called

hemochromatosis type 1 (or HFE-related hereditary hemochromatosis). Currently, hemochromatosis (without further specification) is mostly defined as iron overload with a hereditary or primary cause,[10][11] or originating from a metabolic disorder.[12]
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 hemochromatosis.

Primary hemochromatosis and hemosiderosis

Hereditary hemochromatosis

Hereditary hemochromatosis 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.

transferrin receptor-2 and ferroportin.[6]

Hereditary hemochromatosis 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 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.[14][15]

Hemosiderosis

In general, the term

hemosiderin.[16][17] Sometimes, the simpler term siderosis
is used instead.

Other definitions distinguishing hemochromatosis or hemosiderosis that are occasionally used include:

The causes of hemochromatosis broken down into two subcategories: primary cases (hereditary or genetically determined) and less frequent secondary cases (acquired during life).[24] People of Northern European descent, including Celtic (Irish, Scottish, Welsh, Cornish, Breton etc.), English, and Scandinavian origin[25] have a particularly high incidence, with about 10% being carriers of the principal genetic variant, the C282Y mutation on the HFE gene, and 1% having the condition.[26]

Non-classical hereditary hemochromatosis

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 hemochromatosis",[27] "non-HFE related hereditary hemochromatosis",[28] or "non-HFE hemochromatosis".[29]

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

Most types of hereditary hemochromatosis have

autosomal dominant inheritance.[30]

Secondary hemochromatosis

Pathophysiology

Defects in iron metabolism, specifically involving the iron regulatory protein hepcidin are thought to play an integral role in the pathogenesis of hereditary hemochromatosis.[6]

Normally, hepcidin acts to reduce iron levels in the body by inhibiting intestinal iron absorption and inhibiting iron mobilization from stores in the bone marrow and liver.[6] Iron is absorbed from the intestines (mostly in the duodenum) and transported across intestinal enterocytes or mobilized out of storage in liver hepatocytes or from macrophages in the bone marrow by the transmembrane ferroportin transporter.[6] In response to elevated plasma iron levels, hepcidin inhibits the ferroportin transporter leading to decreased iron mobilization from stores and decreased intestinal iron absorption, thus functioning as a negative iron regulatory protein.[6]

In hereditary hemochromatosis, mutations in the proteins involved in hepcidin production including HFE (hemostatic iron regulator), hemojuvelin and transferrin receptor 2 lead to a loss or decrease in hepcidin production, which subsequently leads to the loss of the inhibitory signal regulating iron absorption and mobilization and thus leads to iron overload.[6] In very rare instances, mutations in ferroportin result in ferroportin resistance to hepcidin's negative regulatory effects, and continued intestinal iron absorption and mobilization despite inhibitory signaling from hepcidin.[6] Approximately 95% of cases of hereditary hemochromatosis are due to mutations in the HFE gene.[6]

The resulting iron overload causes iron to deposit in various sites throughout the body, especially the liver and joints, which coupled with oxidative stress leads to organ damage or joint damage and the pathological findings seen in hemochromatosis.[6]

Diagnosis

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

There are several methods available for diagnosing and monitoring iron overload.

Blood test

Blood tests are usually the initial test if there is a clinical suspicion of iron overload. Serum

postmenopausal females, normal range of serum ferritin is between 12 and 300 ng/mL (670 pmol/L) .[33][34][35] In premenopausal females, normal range of serum ferritin is between 12 and 150[33] or 200[34] ng/mL (330 or 440 pmol/L).[35] In those with hemochromatosis, the serum ferritin level correlates with the degree of iron overload.[6] Ferritin levels are usually monitored serially in those with hemochromatosis to assess response to treatment.[6]

Elevations in serum levels of the iron transporter protein

Total iron binding capacity may be low in hemochromatosis, but can also be normal.[36]

Genetics

General screening for hemochromatosis is not recommended, however

first-degree relatives of those affected should be screened.[6][37][38][39]

Once iron overload has been established,

HFE gene mutation genetic testing for hereditary causes of iron overload is indicated.[38][14] The presence of HFE gene mutations in addition to iron overload confirms the clinical diagnosis of hereditary hemochromatosis.[38] The alleles evaluated by HFE gene analysis are evident in ~80% of patients with hemochromatosis; a negative report for HFE gene does not rule out hemochromatosis.[citation needed
]

Biopsy

Histopathology of the liver, showing Kupffer cells with significant hemosiderin deposition (shown next to a hepatocyte with lipofuscin pigment, which is a common normal finding). H&E stain.
Prussian blue iron staining, highlighting the hemosiderin pigment as blue. This finding indicates mesenchymal iron overload (within Kupffer cells and/or portal macrophages) rather than parenchymal iron overload (within hepatocytes).[40]

Liver biopsy is the removal of small sample in order to be studied and can determine the cause of inflammation or cirrhosis. In someone 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 hemochromatosis 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 hemochromatosis.[citation needed]

Imaging

Magnetic resonance imaging (MRI) is used as a noninvasive method to estimate iron deposition levels in the liver and heart, which may aid in determining a response to treatment or prognosis.[6] Liver elastography has limited utility in detecting liver fibrosis in hemochromatosis.[6]

Treatment

Phlebotomy

venesection is the mainstay of treatment in iron overload, consisting of regularly scheduled blood draws to remove red blood cells (and iron) from the body.[6] Upon initial diagnosis of iron overload, the phlebotomies may be performed weekly or twice weekly, until iron levels are normalized. Once the serum ferritin and transferrin saturation are within the normal range, maintenance phlebotomies may be needed in some (depending upon the rate of reabsorption of iron), scheduled at varying frequencies to keep iron stores within normal range.[38] A phlebotomy session typically draws between 450 and 500 mL of blood.[41] Routine phlebotomy may reverse liver fibrosis and alleviate some symptoms of hemochromatosis, but chronic arthritis is usually not responsive to treatment.[6] In those with hemochromatosis; the blood drawn during phlebotomy is safe to be donated.[42][38]

Phlebotomy is associated with improved survival if it is initiated before the onset of cirrhosis or diabetes.[38]

Diet

The human diet contains iron in two forms: heme iron and non-heme iron. Heme iron is usually found in red meat, whereas non-heme iron is found in plant based sources. Heme iron is the most easily absorbed form of iron. In those with hemochromatosis undergoing phlebotomy for treatment; restriction of dietary iron is not required.[38][39][6] However, those who do restrict dietary iron usually require less blood needing to be phlebotomized (about 0.5-1.5 liters of blood less per year).[43] Vitamin C and iron supplementation should be avoided as vitamin C accelerates intestinal absorption of iron and mobilization of body iron stores.[38][39] Raw seafood should be avoided because of increased risk of infections from iron loving pathogens such as Vibrio vulnificus.[6][44] Alcohol consumption should be avoided due to the risk of compounded liver damage with iron overload.[6]

Medication

Medications are used for those unable to tolerate routine blood draws, there are

thalassaemia (and, thus, who develop iron overload as a result) are deferasirox and deferiprone.[46][47]

Chelating polymers

A minimally invasive approach to hereditary hemochromatosis treatment is the maintenance therapy with polymeric chelators.[48][49][50] These polymers or particles have a negligible or null systemic biological availability and they are designed to form stable complexes with Fe2+ and Fe3+ in the GIT and thus limiting their uptake and long-term accumulation. Although this method has only a limited efficacy, unlike small-molecular chelators, the approach has virtually no side effects in sub-chronic studies.[50] Interestingly, the simultaneous chelation of Fe2+ and Fe3+ increases the treatment efficacy.[50]

Prognosis

In general, provided there has been no liver damage, patients should expect a normal life expectancy if adequately treated by venesection. If the serum ferritin is greater than 1,000 µg/L at diagnosis there is a risk of liver damage and cirrhosis which may eventually shorten their life.[51] The presence of cirrhosis increases the risk of hepatocellular carcinoma.[52] Other risk factors for liver damage in hemochromatosis include alcohol use, diabetes, liver iron levels greater than 2,000 μmol/gram and increased aspartate transaminase levels.[6]

The risk of death and liver fibrosis are elevated in males with HFE type hemochromatosis but not in females; this is thought to be due to a protective effect of menstruation and pregnancy seen in females as well as possible hormone-related differences in iron absorption.[6]

Epidemiology

HHC is most common in certain European populations (such as those of Irish or Scandinavian descent) and occurs in 0.6% of some unspecified population.[37] Men have a 24-fold increased rate of iron-overload disease compared with women.[37]

Stone Age

Diet and the environment are thought to have had large influence on the mutation of genes related to iron overload. Starting during the

Mesolithic era, communities of people lived in an environment that was fairly sunny, warm and had the dry climates of the Middle East. Most humans who lived at that time were foragers and their diets consisted largely of wild plants, fish, and game. Archaeologists studying dental plaque have found evidence of tubers, nuts, plantains, grasses and other foods rich in iron. Over many generations, the human body became well-adapted to a high level of iron content in the diet.[53]

Neolithic

In the

gene mutation that promoted greater absorption and storage of iron.[55]

Viking hypothesis

Studies and surveys conducted to determine the frequencies of hemochromatosis help explain how the mutation migrated around the globe. In theory, the disease initially evolved from travelers migrating from the north. Surveys show a particular distribution pattern with large clusters and frequencies of gene mutations along the western European coastline.

Viking ships made their way along the coastline of Europe in search of trade, riches, and land. Genetic studies suggest that the extremely high frequency patterns in some European countries are the result of migrations of Vikings and later Normans, indicating a genetic link between hereditary hemochromatosis and Viking ancestry.[58]

Modern times

In 1865, Armand Trousseau (a French internist) was one of the first to describe many of the symptoms of a diabetic patient with cirrhosis of the liver and bronzed skin color. The term hemochromatosis was first used by German pathologist Friedrich Daniel von Recklinghausen in 1889 when he described an accumulation of iron in body tissues.[59]

Identification of genetic factors

Although it was known most of the 20th century that most cases of hemochromatosis were inherited, they were incorrectly assumed to depend on a single gene.[60]

In 1935 J.H. Sheldon, a British physician, described the link to iron metabolism for the first time as well as demonstrating its hereditary nature.[59]

In 1996 Felder and colleagues identified the hemochromatosis gene, HFE gene. Felder found that the HFE gene has two main mutations, causing amino acid substitutions C282Y and H63D, which were the main cause of hereditary hemochromatosis.[59][61] The next year the CDC and the National Human Genome Research Institute sponsored an examination of hemochromatosis following the discovery of the HFE gene, which helped lead to the population screenings and estimates that are still being used today.[62]

See also

References

  1. ^
    PMID 35699322
    .
  2. PMID 24470094
    .
  3. PMID 10607817
    .
  4. ^
    ISBN 978-0-07-470436-3.[page needed
    ]
  5. ^
    S2CID 25357672
    .
  6. ^
    S2CID 254432917
    .
  7. ^ a b Bruce R Bacon, Stanley L Schrier. "Patient information: Hemochromatosis (hereditary iron overload) (Beyond the Basics)". UpToDate. Retrieved 2016-07-14. Literature review current through: Jun 2016. | This topic last updated: Apr 14, 2015.
  8. PMID 29620054
    .
  9. ^ "Haemochromatosis and diabetes". Diabetes UK.
  10. ^ thefreedictionary.com > hemochromatosis, citing:
    • The American Heritage Medical Dictionary, 2004 by Houghton Mifflin Company
    • McGraw-Hill Concise Dictionary of Modern Medicine. 2002
  11. ^ Merriam-Webster's Medical Dictionary > hemochromatosis Retrieved on December 11, 2009
  12. ^ 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.
  13. ^ "Hemochromatosis". Archived from the original on 2007-03-18. Retrieved 2012-10-05.
  14. ^
    PMID 20542038
    .
  15. PMID 10488796
    .
  16. ^ Merriam-Webster's Medical Dictionary > hemosideroses Retrieved on December 11, 2009
  17. ^ thefreedictionary.com > hemosiderosis, citing:
    • The American Heritage Medical Dictionary, 2004 by Houghton Mifflin Company
    • Mosby's Medical Dictionary, 8th edition.
  18. ^ eMedicine Specialties > Radiology > Gastrointestinal > Hemochromatosis Author: Sandor Joffe, MD. Updated: May 8, 2009
  19. ^ thefreedictionary.com > hemosiderosis, citing:
    • Gale Encyclopedia of Medicine. Copyright 2008
  20. ^ Notecards on radiology gamuts, diseases, anatomy Archived 2010-07-21 at the Wayback Machine 2002, Charles E. Kahn, Jr., MD. Medical College of Wisconsin
  21. ^ 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
  22. ^ The HealthScout Network > Health Encyclopedia > Diseases and Conditions > Hemochromatosis Archived 2010-02-09 at the Wayback Machine Retrieved on December 11, 2009
  23. ^ thefreedictionary.com > hemosiderosis, citing:
    • McGraw-Hill Concise Dictionary of Modern Medicine. 2002
  24. PMID 12651879
    .
  25. ^ The Atlantic: "The Iron in Our Blood That Keeps and Kills Us" by Bradley Wertheim January 10, 2013
  26. ^ "Hemachromatosis". Encyclopædia Britannica.com. Retrieved 17 April 2017.
  27. S2CID 23206256
    .
  28. ISBN 978-0-7817-6040-9
    .
  29. S2CID 260320984
    .
  30. PMID 16493621
    .
  31. PMID 18025154
    .
  32. S2CID 44923011
    .
  33. ^ a b Ferritin by: Mark Levin, MD, Hematologist and Oncologist, Newark, NJ. Review provided by VeriMed Healthcare Network
  34. ^ a b Andrea Duchini. "Hemochromatosis Workup". Medscape. Retrieved 2016-07-14. Updated: Jan 02, 2016
  35. ^ a b Molar concentration is derived from mass value using molar mass of 450,000 g•mol−1 for ferritin
  36. ^ labtestsonline.org TIBC & UIBC, Transferrin Last reviewed on October 28, 2009.
  37. ^
    PMID 23418762
    .
  38. ^
    S2CID 9311604
    .
  39. ^
    S2CID 198192589
    .
  40. PMID 17729397
    .
  41. S2CID 53087679
    .
  42. ^ NIH blood bank. "Hemochromatosis Donor Program".
  43. PMID 23803887
    .
  44. PMID 1872665
    .
  45. doi:10.1021/cr00097a011
    .
  46. S2CID 19930076
    .
  47. PMID 12637334
    .
  48. PMID 16283713
    .
  49. PMID 35610854
    .
  50. ^
    S2CID 221827050
    .
  51. PMID 18199861
    .
  52. PMID 15508107
    .
  53. ^ "The Evolution of Diet". National Geographic. Retrieved 2018-04-11.
  54. PMID 10198751
    .
  55. ^ Heath KM, Axton JH, McCullough JM, Harris N (May 2016). "The evolutionary adaptation of the C282Y mutation to culture and climate during the European Neolithic". American Journal of Physical Anthropology. 160 (1): 86–101.
    PMID 26799452
    .
  56. ^ "Clinical Penetrance of HFE Hereditary Hemochromatosis, Serum Ferritin Levels, and Screening Implications: Can We Iron This Out?". www.hematology.org. 2008-05-01. Archived from the original on 2018-06-15. Retrieved 2018-04-11.
  57. PMID 21766093
    .
  58. ^ "Videos: Hereditary Hemochromatosis | Canadian Hemochromatosis Society". www.toomuchiron.ca. Retrieved 2018-04-11.
  59. ^
    PMID 29663319
    .
  60. ISBN 978-1-58829-202-5
    .
  61. S2CID 26239768
    .
  62. PMID 9669792
    .

External links

Wikimedia Commons has media related to Hemochromatosis.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Iron_overload&oldid=1217166751"