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Hemochromatosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]

Synonyms and keywords: Haemochromatosis, Hereditary Hemochromatosis

For patient information click here

Overview

Overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]

Overview

Hemochromatosis is a hereditary disease characterized by improper dietary iron metabolism (making it an iron overload disorder), which causes the accumulation of iron in a number of body tissues. Iron accumulation can eventually cause end organ damage, most importantly in the pancreas manifesting as diabetes, and liver failure. It is estimated that roughly one in every 300-400 people are affected by the disease, primarily of Northern European and Anglo-English descent.

Historical Perspective

The disease was first described in 1865 by Armand Trousseau in an article on diabetes in patients with changing skin color. Trousseau did not connect the diabetes with iron accumulation; instead this was done by Friedrich Daniel von Recklinghausen in 1890. The mutation of human genome to increase iron absorption in people who are exposed to iron deficient diet is evolutionary stand point. Hemocromatosis is also known as Celtic Curse.

Classification

Hemochromatosis is divided on basis of it’s etiology. Hereditary hemochromatosis is caused by defect in gene and secondary hemochromatosis is caused by excess absorption of iron, repeated blood transfusions, or excess oral intake, typically in patients with disorders of erythropoiesis.

Pathophysiology

Hemochromatosis is due to the iron transfer into the bloodstream in the absence of increased erythropoietic needs that can be toxic for the parenchymatous organs. The features of hemochromatosis are due to presence of toxic iron in pro-oxidant form in surroundings of parenchymatous tissue cells of the liver and other organs, where it can cause oxidative damage and lead to cirrhosis, hypogonadism, diabetes, cardiomyopathy, arthropathy, and skin pigmentation.

Causes

Hemochromatosis is due to unchecked transfer of iron into the bloodstream in the absence of increased erythropoietic needs and its toxic effects in parenchymatous organs. It can be primary as genetic or it can be secondary iron over load.

Differentiating Hemochromatosis from other Diseases

Haemochromatosis is notoriously protean, i.e., it presents with symptoms that are often initially attributed to other diseases. It is also true that most people with hereditary hemochromatosis genetics never actually show signs or suffer symptoms of clinical iron overload (i.e., is clinically silent).

Epidemiology and Demographics

Prevalence of hemochromatosis is 6 times higher in white persons than in black persons.It is often described as a “Celtic mutation”–originating in a Celtic population in central Europe and spreading west and north by population movement.

Risk Factors

People who inherit the HFE gene mutation from both parents are at the greatest risk for developing hemochromatosis. Although both men and women can inherit the gene defect, men are more likely to be diagnosed with the effects of hemochromatosis than women.

Screening

Routine screening of the general population for hereditary hemochromatosis, that is, by genetic testing, has been evaluated by the US Preventive Services Task Force (USPSTF), among other groups. In case-finding for hereditary hemochromatosis, serum ferritin and transferrin saturation tests should be performed. Genotyping and liver biopsy is suggested in cases which strongly suggest hemochromatosis due to high levels of serum ferritin and transferrin saturation.

Natural History, Complications and Prognosis

Hemochromatosis is due to unchecked transfer of iron into the bloodstream in the absence of increased erythropoietic needs and its toxic effects in parenchymatous organs.The features of Hemochromatosis are due to presence of toxic iron in pro-oxidant form in surroundings of parenchymatous tissue cells of the liver and other organs, where it can cause oxidative damage and lead to cirrhosis, hypogonadism, diabetes, cardiomyopathy, arthropathy, and skin pigmentation.

Diagnosis

History and Symptoms

Symptoms usually begin in age of 30 years. The involvement of specific organ produces subsequent symptoms. Early symptoms are fatigue and weakness; and as the iron builds up in the body organs, infections and loss of body hair happen. After disease progression, hemochromatosis may cause the following more serious problems such as arthritis, and heart failure.

Physical Examination

Physical examination of hemochromatosis disease depends on the involved organ are: fatigue in heart failure, erectile dysfunction and hypogonadism in gonads involvements, amenorrhea in pitutary, arthritis in joints invovment.

Laboratory Findings

In patients with high suspicion first test ordered is transferrin saturation TS. It is followed by serum ferritin levels. In case of strong evidence of familial history and lab findings patient should go through genotyping which save the need of unnecessary biopsy of liver to check iron index and chemical index to confirm the diagnosis.

ECG

Hemochromatosis can lead to deposition of iron in heart and damage its myocardial tissue as well as conduction tissue. It will cause cardiomyopathy and cardiac arrhythmia.

Ultrasound

On ultrasound the Iron deposits in the liver usually do not alter liver echogenicity. If ultrasonographic liver abnormalities are present, they are usually secondary to cirrhosis.

CT Scan

Clinically the disease may be silent, but characteristic radiological features may point to the diagnosis.

MRI

MRI is not only the most sensitive imaging modality for the diagnosis of haemochromatosis but is also able to estimate iron concentration within the liver, thus forestalling the need for repeated biopsies.

Treatment

The treatment of hemochromatosis depends on levels of iron deposition in body tissues, symptoms and complications due to damaged organs secondary to inflammatory response towards deposition.

References

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Historical Perspective

Historical Perspective

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]

Overview

The disease was first described in 1865 by Armand Trousseau in an article on diabetes in patients with changing skin color.[1] Trousseau did not connect the diabetes with iron accumulation; instead this was done by Friedrich Daniel von Recklinghausen in 1890.[2][3] The mutation of human genome to increase iron absorption in people who are exposed to iron deficient diet is evolutionary stand point. Hemocromatosis is also known as Celtic Curse.

Historical Perspective

Irish people are most commonly affected population and existence of C282Y gene in Irish origin correlates the pathogensis and ethnicity.

The migration of people from Pontic Steppe to the east in prehistory Bronze age era around 4000 years ago led to foundation of Irish population. Genome of men found from that era showed to have carrier of gene mutation C282Y.[4]

  • In 1865, a French internist, Armand Trousseau wrote an article describing hemochromatosis findings as diabetic patient with cirrhosis of the liver that expressed a bronzed skin color.r.[1]
  • In 1929, Strachan, A. S., Scotish pathologist reported 33 cases of hemochromatosis in 1100 autopsies on black subjects in Johannesburg, SA.[5]
  • In 1935 J.H. Sheldon, a British physician, described the hereditary nature of hemochromatosis and it’s pathogensis.[6]
  • In 1937, Widdowson E M, McCance R A, Birtish physicans, explained iron absorption exceeds excretion in two male and female volunteer candidates.[7]
  • In 1942, Balfour WM, U.S. pathologist, showed absorption variability in normal, pregnancy, anemic and hemochromatosis patients. These findings were later concluded by Sheldon to be “data suggest that he was really dealing with deposits of hemosiderin due to hemolysis resulting from parasitic infections-perhaps especially schistosomiasis.” [8]
  • In 1951, Moore A, explained with support of experiment that iron excretion is limited.
  • In 1955, Clement A Finch, a U.S. physician, who published histological findings of hemochroatosis in 707 patients.[9]
  • In 1996, Felder J. N, U.S. geneticist, discovered HEF, a novel MHC class I-like gene which is mutated in patients with hereditary hemochromatosis.[10]

Famous case:

In 1991, the disclosure of medical records confirmed the diagnosis of hemochromatosis in the instance of Ernest Hemingway, an American novelist, short-story writer, and journalist, dating back to the year 1961.[11]

References

  1. ↑ 1.0 1.1 name=Trousseau_1865>Trousseau A (1865). “Glycosurie, diabète sucré”. Clinique médicale de l’Hôtel-Dieu de Paris. 2: 663&ndash, 98.
  2. ↑ 2.0 2.1 von Recklinghausen FD (1890). “Hämochromatose”. Tageblatt der Naturforschenden Versammlung 1889: 324.
  3. ↑ Biography of Daniel von Recklinghausen
  4. ↑ Cassidy, Lara M.; Martiniano, Rui; Murphy, Eileen M.; Teasdale, Matthew D.; Mallory, James; Hartwell, Barrie; Bradley, Daniel G. (2016). “Neolithic and Bronze Age migration to Ireland and establishment of the insular Atlantic genome”. Proceedings of the National Academy of Sciences. 113 (2): 368–373. doi:10.1073/pnas.1518445113. ISSN 0027-8424.
  5. ↑ Lord DK, Dunham I, Campbell RD, Bomford A, Strachan T, Cox TM (1990). “Molecular analysis of the human MHC class I region in hereditary haemochromatosis. A study by pulsed-field gel electrophoresis”. Hum Genet. 85 (5): 531–6. PMID 2227939.
  6. ↑ Bacon BR (1989). “Joseph H. Sheldon and hereditary hemochromatosis: historical highlights”. J Lab Clin Med. 113 (6): 761–2. PMID 2659713.
  7. ↑ Widdowson EM, McCance RA (1937). “The absorption and excretion of iron before, during and after a period of very high intake”. Biochem J. 31 (11): 2029–34. PMC 1267176. PMID 16746545.
  8. ↑ Balfour WM, Hahn PF, Bale WF, Pommerenke WT, Whipple GH (1942). “RADIOACTIVE IRON ABSORPTION IN CLINICAL CONDITIONS: NORMAL, PREGNANCY, ANEMIA, AND HEMOCHROMATOSIS”. J Exp Med. 76 (1): 15–30. PMC 2135296. PMID 19871218.
  9. ↑ Finch CA (1990). “Hemochromatosis–treatment is easy, diagnosis hard”. West J Med. 153 (3): 323–5. PMC 1002547. PMID 2219902.
  10. ↑ Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A; et al. (1996). “A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis”. Nat Genet. 13 (4): 399–408. doi:10.1038/ng0896-399. PMID 8696333.
  11. ↑ Burwell RM. Hemingway: the postwar years and the posthumous novels, 1996

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Classification

Classification

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]

Overview

Hemochromatosis is divided on basis of it’s etiology. Hereditary hemochromatosis is caused by defect in gene and secondary hemochromatosis is caused by excess absorption of iron, repeated blood transfusions, or excess oral intake, typically in patients with disorders of erythropoiesis.

Classification

Hemochromatosis can be classified on basis of mode of entry of iron source:

Entral:

The entral source of hemochromatosis is hereditary hemochromatsis.[1][2]

  • Hereditary hemochromatosis is an autosomal recessive disorder having genetic mutation that affect HFE proteins that limit the entry of iron into the blood by regulating hepcidin, the primary iron regulatory hormone.
  • Following are classes in which hereditary hemochromatosis can be divided:
Description OMIM Mutation Locus
Hemochromatosis type 1: “classical”-hemochromatosis 235200 HFE 6p21.3
Hemochromatosis type 2A: juvenile hemochromatosis 602390 hemojuvelin (“HJV”, also known as HFE2) 1q21
Hemochromatosis type 2B: juvenile hemochromatosis 606464 Hepcidin antimicrobial peptide (HAMP) or HFE2B 19q13
Hemochromatosis type 3 604720 transferrin receptor-2 (TFR2 or HFE3) 7q22
Hemochromatosis type 4 autosomal dominant hemochromatosis (all others are recessive), gene mutation 604653 ferroportin (SLC11A3) 2q32
Paraentral:

Paraentral hemochromatosis refers to patients who get multiple blood transfusions.

Placental:

Placental hemochromatosis/neonatal hemochromatosis to condition in which fetus has deposited iron in it’s hepatic and or extra-hepatic tissue pathologically.[3][4][5]

  • Gestational allo-immune liver disease is cause of fetal liver injury that occurs in all cases of neonatal hemochromatosis.
  • In fetus the level of TFR1, transferrin, and ferritin is found high.
  • It is unclear what is the cause but it is believed that fetal blood extracts more iron from maternal blood.
  • As the fetal liver is damaged, it causes decreased levels of hepcidin.

References

  1. ↑ Liu J, Sun B, Yin H, Liu S (2016). “Hepcidin: A Promising Therapeutic Target for Iron Disorders: A Systematic Review”. Medicine (Baltimore). 95 (14): e3150. doi:10.1097/MD.0000000000003150. PMC 4998755. PMID 27057839.
  2. ↑ Crownover BK, Covey CJ (2013). “Hereditary hemochromatosis”. Am Fam Physician. 87 (3): 183–90. PMID 23418762.
  3. ↑ Feldman AG, Whitington PF (2013). “Neonatal hemochromatosis”. J Clin Exp Hepatol. 3 (4): 313–20. doi:10.1016/j.jceh.2013.10.004. PMC 3940210. PMID 25755519.
  4. ↑ Parkkila S, Waheed A, Britton RS, Bacon BR, Zhou XY, Tomatsu S; et al. (1997). “Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis”. Proc Natl Acad Sci U S A. 94 (24): 13198–202. PMC 24286. PMID 9371823.
  5. ↑ Shimono A, Imoto Y, Sakamoto H, Chiba Y, Matsumoto K, Kawauchi M; et al. (2016). “An immunohistochemical study of placental syncytiotrophoblasts in neonatal hemochromatosis”. Placenta. 48: 49–55. doi:10.1016/j.placenta.2016.10.005. PMID 27871472.

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Pathophysiology

Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]

Overview

Hemochromatosis is due to the iron transfer into the bloodstream in the absence of increased erythropoietic needs that can be toxic for the parenchymatous organs. The features of hemochromatosis are due to presence of toxic iron in pro-oxidant form in surroundings of parenchymatous tissue cells of the liver and other organs, where it can cause oxidative damage and lead to cirrhosis, hypogonadism, diabetes, cardiomyopathy, arthropathy, and skin pigmentation.

Pathophysiology

  • Hemochromatosis is due to the iron transfer into the bloodstream in the absence of increased erythropoietic needs that can be toxic for the parenchymatous organs.
  • The features of hemochromatosis are due to presence of toxic iron in pro-oxidant form in surroundings of parenchymatous tissue cells of the liver and other organs, where it can cause oxidative damage and lead to cirrhosis, hypogonadism, diabetes, cardiomyopathy, arthropathy, and skin pigmentation.
  • Hemochromatosis is a complex genetic disease with strong environmental disease modifiers.
  • In most cases, hemochromatosis is due to partial or total loss of the activity of a small peptide hormone produced by the liver, hepcidin, which normally restrains iron entry into the circulation
  • Normal iron in liver is present at a concentration lower than 20 μmol/g of dry weight.[1]
  • Iron is normally lost in sweat, shed skin cells, and the gastrointestinal tract at a rate of approximately 1 mg/day.
  • Premenopausal adult women lose an additional 0.5 to 1.0 mg/day because of menses.
  • These losses are usually balanced by the absorption of 10 percent of the 10 to 20 mg of iron in the diet in Western societies.
  • For example, HFE is only part of the story, since many patients with mutated HFE do not manifest clinical iron overload, and some patients with iron overload have a normal HFE genotype.[2]
  • Generally, people with abnormal iron regulatory genes do not reduce their absorption of iron in response to increased iron levels in the body.
  • Thus the iron stores of the body increase. As they increase the iron which is initially stored as ferritin is deposited in organs as haemosiderin and this is toxic to tissue, probably at least partially by inducing oxidative stress.[3]

Intestinal crypt enterocytes and iron overload

  • The sensor pathway inside the small bowel enterocyte can be disrupted due to genetic errors in the iron regulatory apparatus.
  • The enterocyte in the small bowel crypt must somehow sense the amount of circulating iron.
  • Depending on this information, the enterocyte cell can regulate the quantity of iron receptors and channel proteins. If there is little iron, the enterocyte cell will express many of these proteins.
  • If there is a lot, the cell will turn off the expression of iron transporters.
  • In haemochromatosis, the enterocyte is somehow constantly fooled into thinking there is iron depletion.
  • As a consequence, it overexpresses the necessary channel proteins, this leading to a massive, and unnecessary iron absorption.
  • These iron transport proteins are named DMT-1 (divalent metal transporter), for the luminal side of the cell, and ferroportin, the only known cellular iron exporter, for the basal side of the cell.

Hepcidin role:

  • In 2000, Hepcidin was discovered which is produced from HAMP gene.[5]
  • Hepcidin is produced in the liver as a 84 amino acid prepropeptide that is processed in a 25 amino acid bio-active circulating form.[6]
  • Hepcidin is hormone produced by liver that is lost genetically in hereditary hemochromatosis.[7]
  • Mutations resulting in modifications in protein that assist hepcicdin are also cause of hereditary hemochromatosis
  • Proteins can be HEF or non-HEF such as transferrin-receptor 2, hemojuvelin, receptor ferroportin.
  • Due to the central pathogenic role of hepcidin, it is anticipated that nongenetic causes of hepcidin loss (eg, end-stage liver disease) can cause acquired forms of hemochromatosis. 
  • Hepcidin is a defensin-like cysteine-rich antimicrobial peptide that likely evolved in humans as part of the innate immune defense. Innate immunity relies on a variety of effector mechanisms to defend against microbial invasion. Among them are the abundant and widely distributed disulfide-linked cationic antimicrobial peptides found in plants, insects, and mammals.[8]
  • Hepcidin is inflammatory responsing agent like to interleukin 6 (IL6) which activates hepcidin transcription through the Jak/STAT3 pathway. [9]
  • Hepcidin is likely also produced in monocytes/macrophages during infection through Toll-like receptors.[10]

Genetics

The regulation of how much iron enters the body from food is complex, and each year brings new discoveries about the numerous factors working in harmony to bring about balance in the metabolism of iron in humans.[11]

  • One of the best-characterized genes that regulates the amount of iron absorbed from food is called HFE.
  • The HFE gene has two common mutations, C282Y and H63D.
  • Inheriting just one of the C282Y mutations (heterozygous) makes a person a carrier who can pass this mutation onward.
  • Carriers of one HFE mutation ordinarily do not manifest with clinically relevant iron accumulation at all.
  • Hepcidin and its receptor ferroportin are the central proteins in hemochromatosis.[12]
  • Loss of HAMP gene or or mutations that hamper the interaction of hepcidin with ferroportin causes hemoochromatosis.[13]
HFE-Hemochromatosis:
  • Most common form of the disease.
  • Homozygosity for the 845G−A polymorphism in HFE that results in Cys282YTyr (C282Y) in the gene product
  • Highly prevalent in whites.
  • The prevalence of C282Y is higher in certain patient groups, such as those with liver disease (5- to 10-fold higher than in the general population) and hepatocellular carcinoma– which is at least twice as frequent among patients with HFE-hemochromatosis compared with those who have other types of liver disease—type 1 diabetes, chondrocalcinosis, or porphyria cutanea tarda.[14]
  • Y231del mutation of HEF gene was found in the Huh-7 hepatoma cell line in Japan population.[15]
  • In the United States, most people with clinically measureable haemochromatosis (i.e., iron overload with or without end organ damage) have inherited two copies of C282Y — one from each parent — and are therefore homozygous for the trait. Mutations of the HFE gene account for 90% of the cases of clinical iron overload. This gene is closely linked to the HLA-A3 locus. Homozygosity for the C282Y mutation is the most prevalent condition resulting in clinical iron accumulation, although heterozygosity for C282Y/H63D mutations, so-called compound heterozygotes, is also known to cause clinical iron overload. So, both homozygotes for C282Y and compound heterozygotes for C282Y/H63D are known to have clinical iron overload and hemochromatosis.[16][17]
  • Most people with two copies of C282Y or one copy each of C282Y/H63D do not manifest clinical hemochromatosis, a phenomenon known as low incomplete penetration. [18] In this condtion penetration differs between different populations.[19]
  • Other genes whose mutations have been associated with iron overload include the autosomal dominant SLC11A3/ferroportin 1 gene and TfR2 (transferrin receptor 2). These mutations, and the iron overload they cause, are much rarer than HFE-haemochromatosis.
Non-HFE Hemochromatosis:
  • The non-HFE−related forms of hemochromatosis are rarer and not restricted to northern European descent.
  • Adult Onset Forms:
  • Are due to TfR2 mutations
  • identified in different ethnicities, including southern Asian populations[20]
  • It is an autosomal dominant hereditary iron loading disorder associated with heterozygote mutations of the ferroportin-1 (FPN) gene and is commonest causes of genetic hyperferritinemia.
  • FPN1 transfers iron from the intestine, macrophages and placenta into the bloodstream. In FD, loss-of-function mutations of FPN1 limit but do not impair iron export in enterocytes, but they do severely affect iron transfer in macrophages. This leads to progressive and preferential iron trapping in tissue macrophages, reduced iron release to serum transferrin (i.e. inappropriately low transferrin saturation) and a tendency towards anemia at menarche or after intense bloodletting.[21]
  • Juvenile Onset Forms:
  • It is due to loss of HAMP.[22]
  • It is due to pathogenic mutations of HJV, with the G320V mutation found in nearly 50% of juvenile hemochromatosis.[23]

Macroscopic Pathology:

The cut surface is seen as golden-brown in color, having a fine, diffuse nodularity, and being extremely firm in consistency

Microscopic Pathology:

Liver biopsy:

In liver biopsy following findings of iron load are seen in microscopic view[24]:

References

  1. ↑ Pietrangelo A (October 2015). “Genetics, Genetic Testing, and Management of Hemochromatosis: 15 Years Since Hepcidin”. Gastroenterology. 149 (5): 1240–1251.e4. doi:10.1053/j.gastro.2015.06.045. PMID 26164493.
  2. ↑ Pietrangelo A (August 2010). “Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment”. Gastroenterology. 139 (2): 393–408, 408.e1–2. doi:10.1053/j.gastro.2010.06.013. PMID 20542038.
  3. ↑ Shizukuda Y, Bolan C, Nguyen T, Botello G, Tripodi D, Yau Y, Waclawiw M, Leitman S, Rosing D (2007). “Oxidative stress in asymptomatic subjects with hereditary hemochromatosis”. Am J Hematol. 82 (3): 249–50. PMID 16955456.
  4. ↑ Pietrangelo A (2010). “Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment”. Gastroenterology. 139 (2): 393–408, 408.e1–2. doi:10.1053/j.gastro.2010.06.013. PMID 20542038.
  5. ↑ Krause A, Neitz S, Mägert HJ, Schulz A, Forssmann WG, Schulz-Knappe P; et al. (2000). “LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity”. FEBS Lett. 480 (2–3): 147–50. PMID 11034317.
  6. ↑ Park CH, Valore EV, Waring AJ, Ganz T (2001). “Hepcidin, a urinary antimicrobial peptide synthesized in the liver”. J Biol Chem. 276 (11): 7806–10. doi:10.1074/jbc.M008922200. PMID 11113131.
  7. ↑ Park CH, Valore EV, Waring AJ, Ganz T (2001). “Hepcidin, a urinary antimicrobial peptide synthesized in the liver”. J Biol Chem. 276 (11): 7806–10. doi:10.1074/jbc.M008922200. PMID 11113131.
  8. ↑ Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P; et al. (2001). “A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload”. J Biol Chem. 276 (11): 7811–9. doi:10.1074/jbc.M008923200. PMID 11113132.
  9. ↑ Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK; et al. (2004). “IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin”. J Clin Invest. 113 (9): 1271–6. doi:10.1172/JCI20945. PMC 398432. PMID 15124018.
  10. ↑ Armitage AE, Eddowes LA, Gileadi U, Cole S, Spottiswoode N, Selvakumar TA; et al. (2011). “Hepcidin regulation by innate immune and infectious stimuli”. Blood. 118 (15): 4129–39. doi:10.1182/blood-2011-04-351957. PMID 21873546.
  11. ↑ Pietrangelo A (August 2010). “Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment”. Gastroenterology. 139 (2): 393–408, 408.e1–2. doi:10.1053/j.gastro.2010.06.013. PMID 20542038.
  12. ↑ Lymboussaki A, Pignatti E, Montosi G, Garuti C, Haile DJ, Pietrangelo A (2003). “The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression”. J Hepatol. 39 (5): 710–5. PMID 14568251.
  13. ↑ Njajou OT, de Jong G, Berghuis B, Vaessen N, Snijders PJ, Goossens JP; et al. (2002). “Dominant hemochromatosis due to N144H mutation of SLC11A3: clinical and biological characteristics”. Blood Cells Mol Dis. 29 (3): 439–43. PMID 12547233.
  14. ↑ Distante S, Robson KJ, Graham-Campbell J, Arnaiz-Villena A, Brissot P, Worwood M (2004). “The origin and spread of the HFE-C282Y haemochromatosis mutation”. Hum Genet. 115 (4): 269–79. doi:10.1007/s00439-004-1152-4. PMID 15290237.
  15. ↑ Takano A, Niimi H, Atarashi Y, Sawasaki T, Terasaki T, Nakabayashi T; et al. (2011). “A novel Y231del mutation of HFE in hereditary haemochromatosis provides in vivo evidence that the Huh-7 is a human haemochromatotic cell line”. Liver Int. 31 (10): 1593–7. doi:10.1111/j.1478-3231.2011.02620.x. PMID 22093335.
  16. ↑ Gochee PA, Powell LW, Cullen DJ, Du Sart D, Rossi E, Olynyk JK (2002). “A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation”. Gastroenterology. 122 (3): 646–51. PMID 11874997.
  17. ↑ Zaloumis SG, Allen KJ, Bertalli NA, Turkovic L, Delatycki MB, Nicoll AJ; et al. (2015). “Natural history of HFE simple heterozygosity for C282Y and H63D: a prospective 12-year study”. J Gastroenterol Hepatol. 30 (4): 719–25. doi:10.1111/jgh.12804. PMC 4782752. PMID 25311314.
  18. ↑ Olynyk J, Cullen D, Aquilia S, Rossi E, Summerville L, Powell L (1999). “A population-based study of the clinical expression of the hemochromatosis gene”. N Engl J Med. 341 (10): 718–24. PMID 10471457.
  19. ↑ Gurrin LC, Bertalli NA, Dalton GW, Osborne NJ, Constantine CC, McLaren CE; et al. (2009). “HFE C282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity”. Hepatology. 50 (1): 94–101. doi:10.1002/hep.22972. PMC 3763940. PMID 19554541.
  20. ↑ Pietrangelo A, Caleffi A, Corradini E (2011). “Non-HFE hepatic iron overload”. Semin Liver Dis. 31 (3): 302–18. doi:10.1055/s-0031-1286061. PMID 21901660.
  21. ↑ Pietrangelo A (2017). “Ferroportin disease: pathogenesis, diagnosis and treatment”. Haematologica. 102 (12): 1972–1984. doi:10.3324/haematol.2017.170720. PMID 29101207.
  22. ↑ PLATTNER HC, NUSSBAUMER T, RYWLIN A (1951). “[Juvenile and familial hemochromatosis with endocrinomyocardiac syndrome]”. Helv Med Acta. 18 (4–5): 499–502. PMID 14873186.
  23. ↑ NUSSBAUMER T, PLATTNER HC, RYWLIN A (1952). “[Juvenile hemochromatosis in three sisters and one brother associated with consanguinity of the parents; anatomo-clinical and genetic study of the endocrino-hepato-myocardial syndrome]”. J Genet Hum. 1 (2): 53–82. PMID 13022939.
  24. ↑ Pigolkin IuI, Osipenkova TK (1998). “[The morphological changes in the internal organs in hemochromatosis]”. Sud Med Ekspert. 41 (2): 20–2. PMID 9608256.
  25. ↑ Lángos J, Bózner A, Vencel P, Tomík F (1974). “[Histological and electron microscopy findings in liver biopsy specimens in hemochromatosis]”. Cesk Gastroenterol Vyz. 28 (4): 253–6. PMID 4846623.

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Causes

Causes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]

Overview

Hemochromatosis is due to the iron transfer into the bloodstream in the absence of increased erythropoietic needs that can be toxic for the parenchymatous organs.

Causes

Hemochromatosis is due to the iron transfer into the bloodstream in the absence of increased erythropoietic needs that can be toxic for the parenchymatous organs.[1][2]

  • Hereditary hemochromatosis can occur when a person inherits two mutated copies of a gene called the HFE gene — one from each parent. Men and women have the same chance of inheriting two copies of this gene.
  • Not everyone who is born with two copies of the mutated HFE gene develops the disease. Scientists do not know what percentage of people who have two copies of the mutated HFE gene develop the disease. Some studies have shown that as few as 1 in 100 people will develop symptoms. Other studies have shown that as many as 50 in 100 people may develop symptoms.
  • A person with only one copy of the mutated HFE gene is usually healthy and is said to be a “carrier” of the genetic condition. Although a carrier usually does not have hemochromatosis, if both a mother and father are carriers, a child may inherit two copies of the mutated gene, one from each parent.

Following are classes which have their respective causes:

Entral:

  • The entral source of hemochromatosis is hereditary hemochromatsis. Genes involved are[3][4]
Description OMIM Mutation Locus
Haemochromatosis type 1: “classical”-haemochromatosis 235200 HFE 6p21.3
Haemochromatosis type 2A: juvenile haemochromatosis 602390 hemojuvelin (“HJV”, also known as HFE2) 1q21
Haemochromatosis type 2B: juvenile haemochromatosis 606464 hepcidin antimicrobial peptide (HAMP) or HFE2B 19q13
Haemochromatosis type 3 604720 transferrin receptor-2 (TFR2 or HFE3) 7q22
Haemochromatosis type 4 autosomal dominant haemochromatosis (all others are recessive), gene mutation 604653 ferroportin (SLC11A3) 2q32

Paraentral:

  • Paraentral haemochromatosis refers to patients who get multiple blood transfusions.

Placental:

  • Placental haemochromatosis/Neonatal hemochromatosis is a condition in which fetus has deposited iron in its hepatic and or extra-hepatic tissue pathologically.[5][6]
  • Gestational allo-immune liver disease is cause of fetal liver injury that occurs in all cases of neonatal hemochromatosis.
  • It is unclear what is the cause but it is believed that fetal blood extracts more iron from maternal blood.
  • As the fetal liver is damaged, it causes decreased levels of hepcidin.

References

  1. ↑ Pietrangelo A (2015). “Genetics, Genetic Testing, and Management of Hemochromatosis: 15 Years Since Hepcidin”. Gastroenterology. 149 (5): 1240–1251.e4. doi:10.1053/j.gastro.2015.06.045. PMID 26164493.
  2. ↑ Salgia RJ, Brown K (2015). “Diagnosis and management of hereditary hemochromatosis”. Clin Liver Dis. 19 (1): 187–98. doi:10.1016/j.cld.2014.09.011. PMID 25454304.
  3. ↑ Crownover BK, Covey CJ (2013). “Hereditary hemochromatosis”. Am Fam Physician. 87 (3): 183–90. PMID 23418762.
  4. ↑ Emanuele D, Tuason I, Edwards QT (2014). “HFE-associated hereditary hemochromatosis: overview of genetics and clinical implications for nurse practitioners in primary care settings”. J Am Assoc Nurse Pract. 26 (3): 113–22. doi:10.1002/2327-6924.12106. PMID 24574363.
  5. ↑ Lopriore E, Mearin ML, Oepkes D, Devlieger R, Whitington PF (2013). “Neonatal hemochromatosis: management, outcome, and prevention”. Prenat Diagn. 33 (13): 1221–5. doi:10.1002/pd.4232. PMID 24030714.
  6. ↑ Korkmaz L, Baştuğ O, Daar G, Doğanay S, Deniz K, Kurtoğlu S (2015). “Neonatal hemochromatosis in monochorionic twins”. J Neonatal Perinatal Med. 8 (4): 413–6. doi:10.3233/NPM-1577113. PMID 26836824.

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Differentiating Hemochromatosis from other Diseases

Differentiating Hemochromatosis from other Diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

Overview

Haemochromatosis should be differentiate from other disorders with iron overload. Iron overload can be sue to iron absorption, or iron overload. Diseases in this category are: hemochromatosis, Thalassemia, chronic liver disease, sideroblastic anemia, african iron overload, and transfusion iron overload.

Differentiating Hemochromatosis from other Diseases

Haemochromatosis should be differentiate from other disorders with iron overload. Iron overload can be sue to iron absorption, or iron overload. Diseases in this category are: hemochromatosis, Thalassemia, chronic liver disease, sideroblastic anemia, african iron overload, and transfusion iron overload.

Different causes of iron overload
Category Disorder Etiology Laboratory abnormalities Physical examination Mechanism
Increased Iron absorption Hemochromatosis[1][2][3][4][5]
Thalassemia[6]
Chronic liver disease[8][9][10][11]
  • Impaired liver function tests with hepatocellular pattern
  • High ferritin
Sideroblastic anemia[12][13][14]
African iron overload[15][16] Insert paragraph Increase iron absorption from intestine
Increased Iron intake Transfusional overload
  • Recurrent blood transfusion for any reason
Hemin infusion

References

  1. ↑ Hemochromatosis-Diagnosis National Digestive Diseases Information Clearinghouse, National Institutes of Health, U.S. Department of Health and Human Services
  2. ↑ Crownover BK, Covey CJ (2013). “Hereditary hemochromatosis”. Am Fam Physician. 87 (3): 183–90. PMID 23418762.
  3. ↑ Nielsen J, Jensen L, Krabbe K (1995). “Hereditary haemochromatosis: a case of iron accumulation in the basal ganglia associated with a parkinsonian syndrome”. J Neurol Neurosurg Psychiatry. 59 (3): 318–21. PMID 7673967.
  4. ↑ Costello D, Walsh S, Harrington H, Walsh C (2004). “Concurrent hereditary haemochromatosis and idiopathic Parkinson’s disease: a case report series”. J Neurol Neurosurg Psychiatry. 75 (4): 631–3. PMID 15026513.
  5. ↑ Salgia RJ, Brown K (2015). “Diagnosis and management of hereditary hemochromatosis”. Clin Liver Dis. 19 (1): 187–98. doi:10.1016/j.cld.2014.09.011. PMID 25454304.
  6. ↑ Gibbons RJ (2012). “α-Thalassemia, mental retardation, and myelodysplastic syndrome”. Cold Spring Harb Perspect Med. 2 (10). doi:10.1101/cshperspect.a011759. PMC 3475406. PMID 23028133.
  7. ↑ Chui DH, Cunningham MJ, Luo HY, Wolfe LC, Neufeld EJ, Steinberg MH (2006). “Screening and counseling for thalassemia”. Blood. 107 (4): 1735–7. doi:10.1182/blood-2005-09-3557. PMC 1895412. PMID 16461765.
  8. ↑ Ceni E, Mello T, Galli A (2014). “Pathogenesis of alcoholic liver disease: role of oxidative metabolism”. World J. Gastroenterol. 20 (47): 17756–72. doi:10.3748/wjg.v20.i47.17756. PMC 4273126. PMID 25548474.
  9. ↑ Mathurin P, Bataller R (2015). “Trends in the management and burden of alcoholic liver disease”. J. Hepatol. 62 (1 Suppl): S38–46. doi:10.1016/j.jhep.2015.03.006. PMC 5013530. PMID 25920088.
  10. ↑ Lucey MR, Mathurin P, Morgan TR (2009). “Alcoholic hepatitis”. N. Engl. J. Med. 360 (26): 2758–69. doi:10.1056/NEJMra0805786. PMID 19553649.
  11. ↑ Datz C, Müller E, Aigner E (June 2017). “Iron overload and non-alcoholic fatty liver disease”. Minerva Endocrinol. 42 (2): 173–183. doi:10.23736/S0391-1977.16.02565-7. PMID 27834478.
  12. ↑ Cazzola M, Invernizzi R (June 2011). “Ring sideroblasts and sideroblastic anemias”. Haematologica. 96 (6): 789–92. doi:10.3324/haematol.2011.044628. PMC 3105636. PMID 21632840.
  13. ↑ Bottomley SS, Fleming MD (August 2014). “Sideroblastic anemia: diagnosis and management”. Hematol. Oncol. Clin. North Am. 28 (4): 653–70, v. doi:10.1016/j.hoc.2014.04.008. PMID 25064706.
  14. ↑ Long Z, Li H, Du Y, Han B (August 2018). “Congenital sideroblastic anemia: Advances in gene mutations and pathophysiology”. Gene. 668: 182–189. doi:10.1016/j.gene.2018.05.074. PMID 29787825.
  15. ↑ Gordeuk VR (October 2002). “African iron overload”. Semin. Hematol. 39 (4): 263–9. PMID 12382201.
  16. ↑ Gordeuk V, Caleffi A, Corradini E, Ferrara F, Jones R, Castro O, Onyekwere O, Kittles R, Pignatti E, Montosi G, Garuti C, Gangaidzo I, Gomo Z, Moyo V, Rouault T, MacPhail P, Pietrangelo A (2003). “Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene”. Blood Cells Mol Dis. 31 (3): 299–304. PMID 14636642.

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Epidemiology and Demographics

Epidemiology and Demographics

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]

Overview

Prevalence of hemochromatosis is 6 times higher in white persons than in black persons.It is often described as a “Celtic mutation”–originating in a Celtic population in central Europe and spreading west and north by population movement.

Epidemiology and Demographics

Hemochromatosis is one of the most common inheritable genetic defects.[1]

Incidence:

  • In 2016, the incidence of C282Y is estimated to be 5400 cases per 100,000.
  • In 2016, the incidence of H63D is estimated to be 13500 cases per 100,000.

Prevalence:

  • In 2017, the prevalence of Hemochromatosis was estimated to be from 500 case in 100000 individuals.
  • The carrier state is estimated to be approximately 10000 in 100000.

Race:

  • Prevalence of hemochromatosis is 6 times higher in white persons than in black persons.
  • C282Y homozygotes account for 82-90% of clinical diagnoses of hereditary hemochromatosis among persons of northern European descent
  • Irish have highest prevalence of hemochromatosis.
  • In 2005, estimated prevalence of C282Y homozygotes was higher in non-Hispanic whites than in Native Americans.[2]
  • Non-Hispanic whites 44000 cases in 100000.
  • Native Americans 11000 cases in 100000.
  • Hispanics 270 cases in 100000
  • Blacks 140 cases in 100000
  • Pacific Islanders cases 120 in 100000
  • Asians less then 1 case in 100000

Countries:

  • It is often described as a “Celtic mutation”–originating in a Celtic population in central Europe and spreading west and north by population movement.
  • The European countries with the highest prevalence include Ireland, France, and Denmark.

References

  1. ↑ Merryweather-Clarke AT, Pointon JJ, Shearman JD, Robson KJ (1997). “Global prevalence of putative haemochromatosis mutations”. J Med Genet. 34 (4): 275–8. PMC 1050911. PMID 9138148.
  2. ↑ Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD; et al. (2005). “Hemochromatosis and iron-overload screening in a racially diverse population”. N Engl J Med. 352 (17): 1769–78. doi:10.1056/NEJMoa041534. PMID 15858186.

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Risk Factors

Risk Factors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]

Overview

People who inherit the HFE gene mutation from both parents are at the greatest risk for developing hemochromatosis. Although both men and women can inherit the gene defect, men are more likely to be diagnosed with the effects of hemochromatosis than women.

Risk Factors

People who inherit the HFE gene mutation from both parents are at the greatest risk for developing hemochromatosis. Although both men and women can inherit the gene defect, men are more likely to be diagnosed with the effects of hemochromatosis than women. Other factors that increase risk are:[1][2]

  • Ethnic Background: White people of northern European descent (for example, families from England, Ireland, Scotland, Denmark, France, and Scandinavia) have a higher chance of having the HFE gene mutation.
  • Family History: People with a close relative (grandparent, mother, father, sibling, niece, nephew) who has hemochromatosis have a higher chance of having the HFE gene mutation.

There are other factors which influence the rate at which iron is absorbed by the body:[3][4][5]

  • Dietary supplements: Taking iron supplements or multivitamins with iron can speed up the rate at which iron builds up in the body. Persons with hemochromatosis should not take pills containing iron. Eating foods that contain iron is fine. Taking vitamin C supplements may cause the body to absorb more iron. Persons with hemochromatosis should not take pills with more than 500 milligrams of vitamin C per day. Eating foods that contain vitamin C is fine.
  • Blood loss: Losing iron by giving blood and losing iron through menstruation and unrecognized bleeding may slow the start of hemochromatosis. Therefore, men at risk for hemochromatosis usually develop the disease and its symptoms at a younger age than women who are at risk.

References

  1. ↑ Benyamin B, Esko T, Ried JS, Radhakrishnan A, Vermeulen SH, Traglia M; et al. (2014). “Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis”. Nat Commun. 5: 4926. doi:10.1038/ncomms5926. PMC 4215164. PMID 25352340.
  2. ↑ Peculis R, Lace B, Putnina A, Nikitina-Zake L, Klovins J (2015). “HFE-related hemochromatosis risk mutations in Latvian population”. Ann Hematol. 94 (2): 343–4. doi:10.1007/s00277-014-2157-2. PMID 25015053.
  3. ↑ Barton JC, Barton JC, Acton RT (2014). “Diabetes in first-degree family members: a predictor of type 2 diabetes in 159 nonscreening Alabama hemochromatosis probands with HFE C282Y homozygosity”. Diabetes Care. 37 (1): 259–66. doi:10.2337/dc13-0713. PMID 23990522.
  4. ↑ Wood MJ, Powell LW, Dixon JL, Ramm GA (2012). “Clinical cofactors and hepatic fibrosis in hereditary hemochromatosis: the role of diabetes mellitus”. Hepatology. 56 (3): 904–11. doi:10.1002/hep.25720. PMID 22422567.
  5. ↑ Fracanzani AL, Piperno A, Valenti L, Fraquelli M, Coletti S, Maraschi A; et al. (2010). “Hemochromatosis in Italy in the last 30 years: role of genetic and acquired factors”. Hepatology. 51 (2): 501–10. doi:10.1002/hep.23333. PMID 20101754.

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Screening

Screening

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]

Overview

Routine screening of the general population for hereditary hemochromatosis, that is, by genetic testing, has been evaluated by the US Preventive Services Task Force (USPSTF), among other groups. In case-finding for hereditary hemochromatosis, serum ferritin and transferrin saturation tests should be performed. Genotyping and liver biopsy is suggested in cases which strongly suggest hemochromatosis due to high levels of serum ferritin and transferrin saturation.

Screening

Screening specifically means looking for a disease in people who have no symptoms. Diagnosis, on the other hand refers to testing people who have symptoms of a disease. Standard diagnostic measures for haemochromatosis, serum transferrin saturation and serum ferritin tests, are not a part of routine medical testing. Screening for hemochromatosis is recommended if the patient has a parent, child or sibling with the disease, or have any of the following signs and symptoms:[1][2]

  • Joint disease
  • Severe fatigue
  • Heart disease
  • Elevated liver enzymes
  • Impotence
  • Diabetes

Routine screening of the general population for hereditary hemochromatosis, that is, by genetic testing, has been evaluated by the US Preventive Services Task Force (USPSTF), among other groups. In case-finding for hereditary hemochromatosis, serum ferritin and transferrin saturation tests should be performed.[3] The USPSTF recommended against doing genetic testing to screen the general population for hereditary hemochromatosis because the likelihood of diagnosing clinically relevant, iron accumulating hereditary hemochromatosis in a treatable patient population approaches less than 1 in 1000 unselected patients. Also, there is no evidence that doing phlebotomy to treat asymptomatic, non-iron overloaded carriers of HFE mutations has any clinical benefit. Also, genetic carriers of the disease may never manifest the symptoms of the disease, so that the potential harm of the attendant surveillance, privacy issues, unnecessary invasive work-up, and anxiety outweigh the potential benefits. [4] [5]

Screening and diagnosis of hemochromatosis.WT, wild type; HII, histologic iron index; CII, chemical iron index; HH, hereditary hemochromatosis[6][7][8][9][10][11][12][13]

 
 
 
 
 
 
 
 
 
 
 
 
Serum Transferin Saturation
TS
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
<50% premenupasal females
<60% men, postmenupasal women
 
 
 
 
 
≥50% premenupasal females
≥60% men, postmenupasal women
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Repeat Transferin Saturation TS
2 Serum Feretin SF
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Repeat testing every 5 year
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TS:<50% premenupasal females
TS: <60% men, postmenupasal women
SF: 20-250μg/L premenupasal females
SF: 10-120μg/L men, postmenupasal women
 
 
 
 
 
 
 
 
TS:≥50% premenupasal females
TS: ≥60% men, postmenupasal women
SF:>200 μg/L premenupasal females
SF:>300 μg/L men, postmenupasal women
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Repeat TS and SF every 2-3 year
 
 
 
 
Serum Feretin<1000 μg/L
 
 
 
 
 
 
Serum Feretin>1000 μg/L
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Geno-typing
 
 
 
 
 
 
 
 
Liver biopsy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WT/WT genotype
 
C282Y/WT genotype
 
 
 
C282Y/H63D genotype
 
C282Y/C282Y genotype
 
 
Histological iron index<0.15
Chemical iron index<2.0
 
Histological iron index>0.15
Chemical iron index>2.0
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Secondray hemochromatosis
 
 
 
 
 
 
 
Phelebotomy to maintain Serum Feretin
 
 
 
 
Repeat TS and SF after 2-3 year
 
Phelebotomy to maintain Serum Feretin
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screen family with Transferin Saturation & Serum Feretin if atypical HH suspected
 
 
 
 
 
 
 
Screen family with genotyping
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Moniter Transferin Saturation & Serum Feretin in subclinical members


References

  1. ↑ Screening and Diagnosis Mayo Foundation for Medical Education and Research (MFMER). Retrieved 18 March, 2007
  2. ↑ [http://www.annals.org/cgi/content/full/143/7/I-46 Screening for Hereditary Hemochromatosis: Recommendations from the American College of Physicians Annals of Internal Medicine (2005) 4 October, Volume 143 Issue 7. (Page I-46). American College of Physicians. Retrieved 18 March, 2007
  3. ↑ Wolthuizen M, Nisselle A, Halliday J, Metcalfe SA, Aitken M, Allen KJ; et al. (2013). “Why do people choose not to have screening for hemochromatosis?”. Genet Test Mol Biomarkers. 17 (1): 21–4. doi:10.1089/gtmb.2012.0247. PMID 23098241.
  4. ↑ “Screening for hemochromatosis: recommendation statement”. Ann. Intern. Med. 145 (3): 204–8. 2006. PMID 16880462.
  5. ↑ Screening for Hemochromatosis U.S. Preventive Services Task Force (2006). Summary of Screening Recommendations and Supporting Documents. Retrieved 18 March, 2007
  6. ↑ Bacon BR (2012). “Hemochromatosis: discovery of the HFE gene”. Mo Med. 109 (2): 133–6. PMID 22675794.
  7. ↑ Asia-Pacific Working Party on Prevention of Hepatocellular Carcinoma (2010). “Prevention of hepatocellular carcinoma in the Asia-Pacific region: consensus statements”. J Gastroenterol Hepatol. 25 (4): 657–63. doi:10.1111/j.1440-1746.2009.06167.x. PMID 20492323.
  8. ↑ Adams PC (2015). “Epidemiology and diagnostic testing for hemochromatosis and iron overload”. Int J Lab Hematol. 37 Suppl 1: 25–30. doi:10.1111/ijlh.12347. PMID 25976957.
  9. ↑ Salgia RJ, Brown K (2015). “Diagnosis and management of hereditary hemochromatosis”. Clin Liver Dis. 19 (1): 187–98. doi:10.1016/j.cld.2014.09.011. PMID 25454304.
  10. ↑ Crownover BK, Covey CJ (2013). “Hereditary hemochromatosis”. Am Fam Physician. 87 (3): 183–90. PMID 23418762.
  11. ↑ Adams PC, Barton JC, Guo H, Alter D, Speechley M (2015). “Serum ferritin is a biomarker for liver mortality in the Hemochromatosis and Iron Overload Screening Study”. Ann Hepatol. 14 (3): 348–53. PMID 25864215.
  12. ↑ Adams PC, McLaren CE, Speechley M, McLaren GD, Barton JC, Eckfeldt JH (2013). “HFE mutations in Caucasian participants of the Hemochromatosis and Iron Overload Screening study with serum ferritin level <1000 µg/L”. Can J Gastroenterol. 27 (7): 390–2. PMC 3956024. PMID 23862168.
  13. ↑ Lim A, Speechley M, Adams PC (2014). “Predicting C282Y homozygote genotype for hemochromatosis using serum ferritin and transferrin saturation values from 44,809 participants of the HEIRS study”. Can J Gastroenterol Hepatol. 28 (9): 502–4. PMC 4205907. PMID 25314357.

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Natural History, Complications and Prognosis

Natural History, Complications and Prognosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sunny Kumar MD [2]

Overview

Hemochromatosis is due to unchecked transfer of iron into the bloodstream in the absence of increased erythropoietic needs and its toxic effects in parenchymatous organs.The features of Hemochromatosis are due to presence of toxic iron in pro-oxidant form in surroundings of parenchymatous tissue cells of the liver and other organs, where it can cause oxidative damage and lead to cirrhosis, hypogonadism, diabetes, cardiomyopathy, arthropathy, and skin pigmentation.

Natural History

Hemochromatosis is due to unchecked transfer of iron into the bloodstream in the absence of increased erythropoietic needs and its toxic effects in parenchymatous organs.The features of Hemochromatosis are due to presence of toxic iron in pro-oxidant form in surroundings of parenchymatous tissue cells of the liver and other organs, where it can cause oxidative damage and lead to cirrhosis, hypogonadism, diabetes, cardiomyopathy, arthropathy, and skin pigmentation.[1]

Complications

End-organ damage Iron is stored in the liver, gonads, joints, brain, pancreas and the heart.[2]

  • Long term effects of haemochromatosis on these organs can be very serious, even fatal when untreated.[3]
  • Cirrhosis: Permanent scarring of the liver. Along with other maladies like long-term alcoholism, haemochromatosis may have an adverse effect on the liver. The liver is a primary storage area for iron and will naturally accumulate excess iron. Over time the liver is likely to be damaged by iron overload. Cirrhosis itself may lead to additional and more serious complications, including bleeding from dilated veins in the esophagus and stomach (varices) and severe fluid retention in the abdomen (ascites). Toxins may accumulate in the blood and eventually affect mental functioning. This can lead to confusion or even coma (hepatic encephalopathy).
  • Liver cancer: Cirrhosis and haemochromatosis together will increase the risk of liver cancer. (Nearly one-third of people with haemochromatosis and cirrhosis eventually develop liver cancer.)
  • Congestive heart failure: If excess iron in the heart interferes with the its ability to circulate enough blood, a number of problems can occur including death. The condition may be reversible when haemochromatosis is treated and excess iron stores reduced.[4]
  • Heart arrhythmias: Arrhythmia or abnormal heart rhythms can cause heart palpitations, chest pain and light-headedness and are occasionally life threatening. This condition can often be reversed with treatment for haemochromatosis.[5]
  • Pigment changes: Deposits of iron in skin cells can turn skin a bronze or gray color.
  • Hypothyroidism: Due to deposition of pro-oxidant iron in thyroid tissue and  damages it level that it is not able to produce thyroid hormone[6]
  • Hypogonadism: Due to damage to pituitary gland.[7]
  • Hypopitutarisum:Due to deposition of pro-oxidant iron in pituitary gland.[8]
  • An increased susceptibility to certain infectious diseases caused by siderophilic microoganisms

Prognosis

References

  1. ↑ Rivers J, Garrahy P, Robinson W, Murphy A (1987). “Reversible cardiac dysfunction in hemochromatosis”. Am Heart J. 113 (1): 216–7. PMID 3799437.
  2. ↑ Hsing AW, McLaughlin JK, Olsen JH, Mellemkjar L, Wacholder S, Fraumeni JF (1995). “Cancer risk following primary hemochromatosis: a population-based cohort study in Denmark”. Int J Cancer. 60 (2): 160–2. PMID 7829208.
  3. ↑ Haemochromatosis Complications
  4. ↑ Miller M, Hutchins GM (1994). “Hemochromatosis, multiorgan hemosiderosis, and coronary artery disease”. JAMA. 272 (3): 231–3. PMID 8022042.
  5. ↑ “Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 31-1994. A 25-year-old man with the recent onset of diabetes mellitus and congestive heart failure”. N Engl J Med. 331 (7): 460–6. 1994. doi:10.1056/NEJM199408183310708. PMID 8035843.
  6. ↑ Walton C, Kelly WF, Laing I, Bu’lock DE (1983). “Endocrine abnormalities in idiopathic haemochromatosis”. Q J Med. 52 (205): 99–110. PMID 6683854.
  7. ↑ Kelly TM, Edwards CQ, Meikle AW, Kushner JP (1984). “Hypogonadism in hemochromatosis: reversal with iron depletion”. Ann Intern Med. 101 (5): 629–32. PMID 6435491.
  8. ↑ Fujisawa I, Morikawa M, Nakano Y, Konishi J (1988). “Hemochromatosis of the pituitary gland: MR imaging”. Radiology. 168 (1): 213–4. doi:10.1148/radiology.168.1.3380960. PMID 3380960.

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Diagnosis

Diagnosis

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