Wikipedia

Hereditary haemochromatosis

This article is about hereditary haemochromatosis (HHC) associated with the HFE gene. For other causes of haemochromatosis, see Iron overload.

Hereditary haemochromatosis type 1 (HFE-related haemochromatosis)[3] is a genetic disorder characterized by excessive intestinal absorption of dietary iron, resulting in a pathological increase in total body iron stores.[4] Humans, like most animals, have no mechanism to regulate excess iron, simply losing a limited amount through various means like sweating or menstruating.[5][6][7]

Haemochromatosis type 1
Other namesHFE hereditary haemochromatosis[1] HFE-related hereditary haemochromatosis[2]
Iron accumulation demonstrated by Prussian blue staining in a patient with homozygous genetic haemochromatosis (microscopy, 10x magnified): Parts of normal pink tissue are scarcely present.
SpecialtyEndocrinology, hepatology Edit this on Wikidata
Differential diagnosis

Excess iron accumulates in tissues and organs, disrupting their normal function. The most susceptible organs include the liver, heart, pancreas, skin, joints, gonads, thyroid and pituitary gland; patients can present with cirrhosis, polyarthropathy, hypogonadism, heart failure, or diabetes.[8]

There are five types of hereditary hemochromatosis: type 1, 2 (2A, 2B), 3, 4[9] and 5,[10] all caused by mutated genes. Hereditary hemochromatosis type 1 is the most frequent, and uniquely related to the HFE gene. It is most common among those of Northern European ancestry, in particular those of Celtic descent.[11]

The disease follows an autosomal recessive pattern of inheritance, meaning that an individual must inherit two copies of the mutated gene involved in each cell to develop the condition.[12] In most cases, when a person has this autosomal recessive condition, their parents act as carriers. Carriers possess one copy of the mutated gene but do not manifest any signs or symptoms associated with the disease, and are referred to as carriers. The unaffected carrier parents play an integral role in transmitting one copy of the mutated gene to their child, who ultimately develops the disease. However, carriers may experience iron overload themselves at a later stage if certain factors come into play. Still, in most cases, they remain asymptomatic throughout their lives unless other genetic or environmental factors contribute to excessive iron accumulation within their bodies.[12]

Signs and symptoms

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Haemochromatosis is protean in its manifestations, i.e., often presenting with signs or symptoms suggestive of other diagnoses that affect specific organ systems. Many of the signs and symptoms below are uncommon, and most patients with the hereditary form of haemochromatosis do not show any overt signs of disease nor do they have premature morbidity, if they are diagnosed early, but, more often than not, the condition is diagnosed only at autopsy.[13]

Presently, the classic triad of cirrhosis, bronze skin, and diabetes is less common because of earlier diagnosis.[14]

The more common clinical manifestations include:[8][14][15][16]

Less common findings including:

In the hereditary hemochromatosis (HH or HHC), males are usually diagnosed after their forties and fifties, and women some decades later, during menopause. The severity of clinical disease varies considerably. Some evidence suggests that hereditary haemochromatosis patients affected with other liver ailments such as hepatitis or alcoholic liver disease have worse liver disease than those with either condition alone. Also, juvenile form of primary haemochromatosis (Hemochromatosis type 2) present in childhood with the same consequences of iron overload.[citation needed]

End-organ damage

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Iron is stored in the liver, pancreas and heart. Long-term effects of haemochromatosis on these organs can be serious, even fatal when untreated.[22]

Since the liver is a primary storage area for iron and naturally accumulates excess iron over time, it is likely to be damaged by iron overload. Toxins may accumulate in the blood and eventually affect mental functioning due to increased risk of hepatic encephalopathy. Together, they can increase the risk of liver cancer to one in three persons.

If excess iron in the heart interferes with its ability to circulate enough blood, a number of problems can occur, including (potentially fatal) congestive heart failure. The condition may be reversible when haemochromatosis is treated and excess iron stores are reduced. Arrhythmia or abnormal heart rhythm can cause heart palpitations, chest pain, and light-headedness, and is occasionally life-threatening. This condition can often be reversed with treatment.[citation needed]

The pancreas, which also stores iron, is very important in the body's mechanisms for sugar metabolism. Diabetes affects the way the body uses blood sugar (glucose), and diabetes is, in turn, the leading cause of new blindness in adults and may be involved in kidney failure.[23]

Haemochromatosis may lead to cirrhosis and its complications, including bleeding from dilated veins in the esophagus (esophageal varices) and stomach (gastric varices) and severe fluid retention in the abdomen (ascites). Severity of periodontal disease is associated with high transferrin saturation in haemochromatosis patients.[24][25]

Genetics

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The regulation of dietary iron absorption is complex and understanding is incomplete. One of the better-characterized genes responsible for hereditary haemochromatosis is HFE[26] on chromosome 6, which codes for a transmembrane protein involved in the induction of hepcidin expression upon high iron load. The HFE gene has three often observed genetic variants:[27][28]

  • rs1799945, c.187C>G, p.His63Asp (H63D);
  • rs1800562, c.845G>A, p. Cys282Tyr (C282Y);
  • rs1800730, c.193A>T, p.Ser65Cys (S65C).

The worldwide prevalence rates for H63D, C282Y and S65C (minor allele frequencies) are 10%, 3% and 1% respectively.[29][30][31]

The C282Y allele is a transition point mutation from guanine to adenine at nucleotide 845 in HFE, resulting in a missense mutation that replaces the cysteine residue at position 282 with a tyrosine amino acid.[32] Heterozygotes for either allele can manifest clinical iron overload, if they have two of any alleles. This makes them compound heterozygous for haemochromatosis and puts them greatly at risk of storing excess iron in the body.[33][34][35][36] Homozygosity for the C282Y genetic variant is the most common genotype responsible for clinical iron accumulation, though heterozygosity for C282Y/H63D variants, so-called compound heterozygotes, results in clinically evident iron overload.[37] Considerable debate exists regarding the penetrance—the probability of clinical expression of the trait given the genotype— for clinical disease in homozygotes.[38] Most males homozygous for HFE C282Y show at least one manifestation of iron-storage disease by middle age.[39] Individuals with the relevant genetic variants may never develop iron overload. Phenotypic expression is present in 70% of C282Y homozygotes with less than 10% going on to experience severe iron overload and organ damage.[40]

The H63D variant is just a gene polymorphism, and if there are no other changes, it may not have clinical significance.[41][42][43] In a 2014 study, H63D homozygosity was associated with an elevated mean ferritin level, but only 6.7% had documented iron overload at follow-up.[44] As about the people with one copy of the H63D alteration (heterozygous carriers), this genotype is very unlikely to cause a clinical presentation, there is no predictable risk of iron overload.[45] Besides that, two 2020 studies revealed that the frequency of homozygous or heterozygous H63D variant is significantly higher in elite endurance athletes comparing to ethnically matched controls, and is associated with high V̇O2max in male athletes.[46][47]

Each patient with the susceptible genotype accumulates iron at different rates depending on iron intake, the exact nature of the genetic variant, and the presence of other insults to the liver, such as alcohol and viral disease. As such, the degree to which the liver and other organs are affected is highly variable and is dependent on these factors and co-morbidities, as well as age at which they are studied for manifestations of disease.[48] Penetrance differs between populations.

Disease-causing genetic variants of the HFE gene account for 90% of the cases of non-transfusion iron overload.[medical citation needed]

This gene is closely linked to the HLA-A3 locus.[citation needed]

Pathophysiology

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The normal distribution of body iron stores

Since the regulation of iron metabolism is still poorly understood, a clear model of how haemochromatosis operates is still not available. A working model describes the defect in the HFE gene, where a mutation puts the intestinal absorption of iron into overdrive. Normally, HFE facilitates the binding of transferrin, which is iron's carrier protein in the blood. Transferrin levels are typically elevated at times of iron depletion (low ferritin stimulates the release of transferrin from the liver). When transferrin is high, HFE works to increase the intestinal release of iron into the blood. When HFE is mutated, the intestines perpetually interpret a strong transferrin signal as if the body were deficient in iron. This leads to maximal iron absorption from ingested foods and iron overload in the tissues. However, 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. A possible explanation is the fact that HFE normally plays a role in the production of hepcidin in the liver, a function that is impaired in HFE mutations.[49]

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.[50] Iron is a pro-oxidant. Thus, haemochromatosis shares common symptomology (e.g., cirrhosis and dyskinetic symptoms) with other "pro-oxidant" diseases such as Wilson's disease, chronic manganese poisoning, and hyperuricaemic syndrome in Dalmatian dogs. The latter also experience "bronzing".[citation needed]

Diagnosis

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The diagnosis of haemochromatosis is often made following the incidental finding on routine blood screening of elevated serum liver enzymes or elevation of the transferrin saturation or elevated serum ferritin. Arthropathy with stiff joints, diabetes, or fatigue, may be the presenting complaint.[51]

Blood tests

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Serum ferritin and fasting transferrin saturation are commonly used as screening for haemochromatosis. Transferrin binds iron and is responsible for iron transport in the blood.[52] Measuring ferritin provides a crude measure of iron stores in the body. Fasting transferrin saturation values in excess of 45%, and the serum ferritin more than 250 ug/L in males and 200 ug/L in females are recognized as a threshold for further evaluation of haemochromatosis.[53] Other source says that the normal values for males are 12-300 ng/mL and for female, 12-150 ng/mL.[54] Fasting transferrin saturation is a better test to detect HH.[14][55] Transferrin saturation greater than 62% is suggestive of homozygosity for mutations in the HFE gene.[56]

Ferritin, a protein synthesized by the liver, is the primary form of iron storage within cells and tissues. Measuring ferritin provides a crude estimate of whole-body iron stores, though is raised in many conditions, particularly inflammatory conditions. Examples of causes for raised serum ferritin include but are not limited to: infection, chronic alcohol consumption (mainly >20g/day), liver disease, cancer, porphyria, Hemophagocytic lymphohistiocytosis, hyperthyroidism, obesity, metabolic syndrome, diabetes, several blood transfusions, too many iron supplements, aceruloplasminemia, atransferrinemia, hyperferritinemia cataract syndrome and others. Proinflammatory states account for up to 90% of raised ferritin.[57][58][4] Serum ferritin in excess of 1000 ng/mL of blood is almost always attributable to haemochromatosis.[citation needed]

Other blood tests routinely performed include blood count, renal function, liver enzymes, electrolytes, and glucose (and/or an oral glucose tolerance test).[citation needed]

Liver biopsy

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Liver biopsies involve taking a sample of tissue from the liver, using a thin needle. The amount of iron in the sample is then quantified and compared to normal, and evidence of liver damage, especially cirrhosis, is measured microscopically. Formerly, this was the only way to confirm a diagnosis of haemochromatosis, but measures of transferrin and ferritin along with a history are considered adequate in determining the presence of the malady. Risks of biopsy include bruising, bleeding, and infection. Now, when a history and measures of transferrin or ferritin point to haemochromatosis, whether a liver biopsy is still necessary to quantify the amount of accumulated iron is debatable.[51]

MRI

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MRI-based testing is a noninvasive and accurate alternative to measure liver iron concentrations.[59]

Other imaging

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Clinically, the disease may be silent, but characteristic radiological features may point to the diagnosis. The increased iron stores in the organs involved, especially in the liver and pancreas, result in characteristic findings on unenhanced CT and a decreased signal intensity in MRI scans. Haemochromatosis arthropathy includes degenerative osteoarthritis and chondrocalcinosis. The distribution of the arthropathy is distinctive, but not unique, frequently affecting the second and third metacarpophalangeal joints of the hand.[60] The arthropathy can, therefore, be an early clue as to the diagnosis of haemochromatosis.[citation needed]

Functional testing

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Based on the history, a physician might consider specific tests to monitor organ dysfunction, such as an echocardiogram for heart failure, or blood glucose monitoring for patients with haemochromatosis diabetes.[citation needed]

Stages

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The American Association for the Study of Liver Diseases suggests the following three stages for the condition (identified by the European Association for the Study of Liver Diseases):[40]

  1. Genetic susceptibility but no iron overload. Individuals who have the genetic disorder only.
  2. Iron overload but no organ or tissue damage.
  3. Organ or tissue damage as a result of iron deposition.

Individuals at each stage do not necessarily progress on to the next stage, and end stage disease is more common in males.

Differential diagnosis

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Other causes of excess iron accumulation exist, which have to be considered before haemochromatosis type 1 is diagnosed.

Screening

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Standard diagnostic measures for haemochromatosis, transferrin saturation and ferritin tests, are not a part of routine medical testing. Screening for haemochromatosis is recommended if the patient has a parent, child, or sibling with the disease.[62]

Routine screening of the general population for hereditary haemochromatosis is generally not done. Mass genetic screening has been evaluated by the U.S. Preventive Services Task Force, among other groups, which recommended against genetic screening of the general population for hereditary haemochromatosis because the likelihood of discovering an undiagnosed patient with clinically relevant iron overload is less than one in 1,000. Although strong evidence shows that treatment of iron overload can save lives in patients with transfusional iron overload, no clinical study has shown that for asymptomatic carriers of hereditary haemochromatosis treatment with venesection (phlebotomy) provides any clinical benefit.[63][64] Recently, patients are suggested to be screened for iron overload using serum ferritin as a marker. If serum ferritin exceeds 1000 ng/mL, iron overload is very likely the cause.

Treatment

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Phlebotomy

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Early diagnosis is vital, as the late effects of iron accumulation can be wholly prevented by periodic phlebotomies (by venesection) comparable in volume to blood donations.[65][66]

Phlebotomy (or bloodletting) is usually done at a weekly or each two weeks interval until ferritin levels are 50 μg/L or less. To prevent iron reaccumulation, subsequent phlebotomies are normally carried out about once every three to four months for males, and twice a year for females to keep the serum ferritin between 50 and 100 ug/L[67]

Iron chelation therapy

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Where venesection is not possible, long-term administration of an iron chelator as Deferoxamine (or Desferrioxamine), Deferasirox and Deferiprone is useful. Deferoxamine is an iron-chelating compound, and excretion induced by deferoxamine is enhanced by administration of vitamin C. It cannot be used during pregnancy or breast-feeding due to risk of defects in the child.[citation needed]

Organ damage

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Diet

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Diet can be a powerful but understudied and utilized tool in prevention of iron overload. It can strongly affect the incidence of disease and treatment. Especially in the Western world where many foods are fortified and animal protein (heme iron) is relatively convenient and inexpensive, it is very common for people to eat more than the Recommended Dietary Allowance of iron even in a single meal. For example, one serving of several popular cereals, such as Cheerios or Grape Nuts, has about two times the RDA of iron for a man or non menstruating woman. Menstruating women have roughly twice the iron requirements of a man or non menstruating woman. For this reason, it can very helpful for those recently diagnosed to track their iron and vitamin C consumption for a time and comparing it to the RDA.

Chelating polymers

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A novel experimental approach to the hereditary haemochromatosis treatment is the maintenance therapy with polymeric chelators.[69][70][71] 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 the uptake of these ions and their long-term accumulation. Although this method has only a limited efficacy, unlike small-molecular chelators, such an approach has virtually no side effects in sub-chronic studies.[71] Interestingly, the simultaneous chelation of Fe2+ and Fe3+ increases the treatment efficacy.[71]

Prognosis

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Persons with symptomatic haemochromatosis have somewhat reduced life expectancy compared to the general population, mainly due to excess mortality from cirrhosis and liver cancer. Patients who were treated with phlebotomy lived longer than those who were not.[72][73] Patients without liver disease or diabetes had similar survival rate to the general population.

Epidemiology

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Haemochromatosis is one of the most common heritable genetic conditions in people of Northern Europe, with a prevalence of 1:200.[74] The disease has a variable penetration, and about one in 10 people of this demographic carry a mutation in one of the genes regulating iron metabolism.[75] In the U.S., the frequency of the C282Y and H63D mutations is 5.4% and 13.5%, respectively. Whereas, the worldwide frequency of the C282Y and H63D mutations is about 1.9% and 8.1%, respectively, so mutation in H63D allele are more than C282Y allele.[74] The prevalence of mutations in iron-metabolism genes varies in different populations. A study of 3,011 unrelated white Australians found that 14% were heterozygous carriers of an HFE mutation, 0.5% were homozygous for an HFE mutation, and only 0.25% of the study population had clinically relevant iron overload. Most patients who are homozygous for HFE mutations do not manifest clinically relevant haemochromatosis (see Genetics above).[48] Other populations have a lower prevalence of both the genetic mutation and the clinical disease. It is the most frequent genetic disease in the U.S. with a prevalence of 1:300 in the non-Hispanic white population,[8][76] It is 2-3 times more common in males.[9]

Genetics studies suggest the original haemochromatosis mutation arose in a single person, possibly of Celtic ethnicity, who lived 60–70 generations ago.[77] At that time, when dietary iron may have been scarcer than today, the presence of the mutant allele may have provided an evolutionary advantage by maintaining higher iron levels in the blood.[citation needed]

The distribution of the C282Y variant was noted in various countries. Non-HFE associated hemochromatosis, as Haemochromatosis type 2, Haemochromatosis type 3, Haemochromatosis type 4 and Haemochromatosis type 5,[10] were discovered in Mediterranean countries. On the other side, Northern European ancestry is closely linked to hereditary hemochromatosis disease (HFE). In one study, over 93% of Irish patients with HFE C282Y mutation were homozygotic. The G320V mutation in the HJV gene, which produces hemojuvelin protein, is widely distributed in central Europe and Greece.[74]

Terminology

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The term "haemochromatosis" is used by different sources in many different ways.

It is often used to imply an association with the HFE gene. For many years, HFE was the only known gene associated with haemochromatosis, and the term "hereditary haemochromatosis" was used to describe haemochromatosis type 1. However, many different genetic associations with this condition are now known. The older the text, or the more general the audience, the more likely that HFE is implied. "Haemochromatosis" has also been used in contexts where a genetic cause for iron accumulation had not been known. In some cases, however, a condition that was thought to be due to diet or environment was later linked to a genetic polymorphism, as in African iron overload.[citation needed]

History

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In 1847, Virchow described a golden brown granular pigment that was soluble in sulfuric acid and produced red ash on ignition.[78] The disease was first described in 1865 by Armand Trousseau in a report on diabetes in patients presenting with a bronze pigmentation of their skin.[79] Two years later, Perls developed the first practical method for the analysis of iron in tissue. Despite Trousseau not associating diabetes with iron accumulation, the recognition that infiltration of the pancreas with iron might disrupt endocrine function resulting in diabetes was made by Friedrich Daniel von Recklinghausen in 1890.[80][81] In 1935, English gerontologist Joseph Sheldon described the cases of haemochromatosis. He established this as the name of the disorder and his detailed monograph. Despite lacking the modern molecular techniques accessible today, he came to accurate conclusions that describe haemochromatosis disease as an inborn error of metabolism where this inherited disorder can increase the absorption of iron and thus cause tissue damage due to iron deposition. Moreover, he rejected theories that alcohol, drug, and other factors contribute to the disorder.[82][83][84]

The clinical case series from 1935 to 1955 indicated that haemochromatosis was more common than had been acknowledged.[78] During the 1960s, MacDonald, a pathologist at Boston City Hospital, diverted attention away from the true cause of haemochromatosis. He believed that haemochromatosis was a nutritional condition because he observed many drunken patients of Irish ancestry.[85] During this period of time, other investigators reported additional evidence suggesting that a genetic factor could play a central role in the absorption of iron in people with haemochromatosis. However, alcohol consumption is known to increase the risk of liver injury in haemochromatosis. This finding is consistent with the concept that excess iron metabolism is a primary cause of haemochromatosis disease.[83]

Finally, in 1976, Marcel Simon and his collaborators confirmed that haemochromatosis is an autosomal recessive disorder that has a link to the human leukocyte antigen (HLA) region of the genome. It took 20 years for researchers at Mercator Genetics to effectively identify and clone the haemochromatosis genes using a positional cloning approach.[86]

In 1996, Feder et al. identified HFE, which is a major histocompatibility complex (MHC) gene. They found that 83% of patients have homozygosity for a missense mutation (C282Y) in the HFE gene.[32][83][84] Finally, several groups reported their findings in a series of patients with haemmochromatosis where they discovered the existence of the C282Y mutation in about 85-90% of the cases. The discovery has led to improved clinical medicine and liver disease evaluation.[83]

References

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  1. ^ Allen KJ, Gurrin LC, Constantine CC, et al. (January 2008). "Iron-overload-related disease in HFE hereditary hemochromatosis" (PDF). N. Engl. J. Med. 358 (3): 221–30. doi:10.1056/NEJMoa073286. PMID 18199861. Archived (PDF) from the original on 28 August 2021. Retrieved 10 June 2019.
  2. ^ Jacobs EM, Verbeek AL, Kreeftenberg HG, et al. (December 2007). "Changing aspects of HFE-related hereditary haemochromatosis and endeavours to early diagnosis". Neth J Med. 65 (11): 419–24. PMID 18079564. Archived from the original on 6 May 2021.
  3. ^ Franchini M (March 2006). "Hereditary iron overload: update on pathophysiology, diagnosis, and treatment". Am. J. Hematol. 81 (3): 202–9. doi:10.1002/ajh.20493. PMID 16493621. S2CID 40950367.
  4. ^ a b St John A (June 2011). "Testing for HFE-related haemochromatosis" (PDF). Australian Prescriber. 34 (34): 73–6. doi:10.18773/austprescr.2011.046. Retrieved 3 June 2011.[permanent dead link‍]
  5. ^ Janet RH (June 2009). "Body iron excretion by healthy men and women". The American Journal of Clinical Nutrition. 89 (6): 1792–1798. doi:10.3945/ajcn.2009.27439. PMID 19386738.
  6. ^ "The interaction of iron and erythropoietin". sickle.bwh.harvard.edu. Archived from the original on 13 December 2022. Retrieved 25 July 2022.
  7. ^ Ofojekwu MJ, Nnanna OU, Okolie CE, Odewumi LA, Isiguzoro IO, Lugos MD (2013). "Hemoglobin and Serum Iron Concentrations in Menstruating Nulliparous Women in Jos, Nigeria". Laboratory Medicine. 44 (2): 121–124. doi:10.1309/LMM7A0F0QBXEYSSI. S2CID 73154256.
  8. ^ a b c "Hereditary Hemochromatosis". www.cdc.gov. Centers for Disease Control and Prevention. Archived from the original on 2 June 2021.
  9. ^ a b Porter JL, Rawla P (2021). "Hemochromatosis". StatPearls. StatPearls. PMID 28613612. Archived from the original on 27 January 2022. Retrieved 22 May 2021.
  10. ^ a b c "FTH1-related iron overload - About the Disease". Genetic and Rare Diseases Information Center. Archived from the original on 13 December 2022. Retrieved 24 May 2021.
  11. ^ Messmer J (16 March 2005). "The Medical Minute: Hemochromatosis -- the Celtic curse". news.psu.edu. Penn State University. Archived from the original on 17 December 2023.
  12. ^ a b Reference GH. "Hereditary hemochromatosis". Genetics Home Reference. Archived from the original on 16 August 2019. Retrieved 22 July 2019.
  13. ^ Hemochromatosis-Diagnosis Archived 18 March 2007 at the Wayback Machine National Digestive Diseases Information Clearinghouse, National Institutes of Health, U.S. Department of Health and Human Services
  14. ^ a b c Pietrangelo A (June 2004). "Hereditary hemochromatosis—a new look at an old disease". N. Engl. J. Med. 350 (23): 2383–97. doi:10.1056/NEJMra031573. PMID 15175440.
  15. ^ Hemochromatosis Archived 18 March 2007 at the Wayback Machine National Digestive Diseases Information Clearinghouse, National Institutes of Health, U.S. Department of Health and Human Services
  16. ^ "Hemochromatosis: Symptoms". Mayo Foundation for Medical Education and Research (MFMER). Archived from the original on 30 April 2008. Retrieved 17 March 2007.
  17. ^ a b Jones H, Hedley-Whyte E (1983). "Idiopathic hemochromatosis (IHC): dementia and ataxia as presenting signs". Neurology. 33 (11): 1479–83. doi:10.1212/WNL.33.11.1479. PMID 6685241. S2CID 26103887.
  18. ^ 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. doi:10.1136/jnnp.2003.027441. PMC 1739011. PMID 15026513.
  19. ^ 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. doi:10.1136/jnnp.59.3.318. PMC 486041. PMID 7673967.
  20. ^ Barton JC, Acton RT (April 2009). "Hemochromatosis and Vibrio vulnificus Wound Infections". J. Clin. Gastroenterol. 43 (9): 890–893. doi:10.1097/MCG.0b013e31819069c1. PMID 19349902. S2CID 35800188.
  21. ^ Jolivet-Gougeon A, Loréal O, Ingels A, et al. (October 2008). "Serum transferrin saturation increase is associated with decrease of antibacterial activity of serum in patients with HFE-related genetic hemochromatosis". Am. J. Gastroenterol. 103 (10): 2502–8. doi:10.1111/j.1572-0241.2008.02036.x. PMID 18684194. S2CID 23383278.
  22. ^ "Hemochromatosis: Complications". Mayo Foundation for Medical Education and Research (MFMER). Archived from the original on 7 March 2008. Retrieved 17 March 2007.
  23. ^ Hong J, Surapaneni A, Daya N, Selvin E, Coresh J, Grams ME, Ballew SH (7 July 2021). "Retinopathy and Risk of Kidney Disease in Persons With Diabetes". Kidney Medicine. 3 (5): 808–815.e1. doi:10.1016/j.xkme.2021.04.018. ISSN 2590-0595. PMC 8515075. PMID 34693260.
  24. ^ Meuric V, Lainé F, Boyer E, Le Gall-David S, Oger E, Bourgeois D, Bouchard P, Bardou-Jacquet E, Turmel V, Bonnaure-Mallet M, Deugnier Y (September 2017). "Periodontal status and serum biomarker levels in HFE haemochromatosis patients. A case-series study" (PDF). Journal of Clinical Periodontology. 44 (9): 892–897. doi:10.1111/jcpe.12760. PMID 28586532. S2CID 35455901. Archived (PDF) from the original on 20 July 2018. Retrieved 22 May 2020.
  25. ^ Boyer E, Le Gall-David S, Martin B, Fong SB, Loréal O, Deugnier Y, Bonnaure-Mallet M, Meuric V (December 2018). "Increased transferrin saturation is associated with subgingival microbiota dysbiosis and severe periodontitis in genetic haemochromatosis". Scientific Reports. 8 (1): 15532. Bibcode:2018NatSR...815532B. doi:10.1038/s41598-018-33813-0. PMC 6195524. PMID 30341355.
  26. ^ Olynyk JK, Trinder D, Ramm GA, Britton RS, Bacon BR (September 2008). "Hereditary hemochromatosis in the post-HFE era". Hepatology. 48 (3): 991–1001. doi:10.1002/hep.22507. PMC 2548289. PMID 18752323.
  27. ^ "Hemochromatosis". Mayo Foundation for Medical Education and Research (MFMER). Archived from the original on 31 May 2013. Retrieved 30 November 2020.
  28. ^ den Dunnen JT, Dalgleish R, Maglott DR, Hart RK, Greenblatt MS, McGowan-Jordan J, Roux AF, Smith T, Antonarakis SE, Taschner PE (June 2016). "HGVS Recommendations for the Description of Sequence Variants: 2016 Update". Human Mutation. 37 (6): 564–9. doi:10.1002/humu.22981. hdl:2381/37207. PMID 26931183. S2CID 205923146.
  29. ^ "Reference SNP (rs) Report rs1799945 Allele Frequency". National Center for Biotechnology Information. Archived from the original on 10 September 2019. Retrieved 30 November 2020.
  30. ^ "Reference SNP (rs) Report rs1800562 Allele Frequency". National Center for Biotechnology Information. Archived from the original on 9 March 2021. Retrieved 30 November 2020.
  31. ^ "Reference SNP (rs) Report rs1800730 Allele Frequency". National Center for Biotechnology Information. Archived from the original on 13 September 2019. Retrieved 30 November 2020.
  32. ^ a b Feder JN, Gnirke A, Thomas W, et al. (1996). "A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis". Nature Genetics. 13 (4): 399–408. doi:10.1038/ng0896-399. PMID 8696333. S2CID 26239768.
  33. ^ Aranda N, Viteri FE, Montserrat C, Arija V (August 2010). "Effects of C282Y, H63D, and S65C HFE gene mutations, diet, and life-style factors on iron status in a general Mediterranean population from Tarragona, Spain". Ann Hematol. 89 (8): 767–73. doi:10.1007/s00277-010-0901-9. PMC 2887936. PMID 20107990.
  34. ^ Spínola C, Brehm A, Spínola H (January 2011). "Prevalence of H63D, S65C, and C282Y hereditary hemochromatosis gene variants in Madeira Island (Portugal)". Ann Hematol. 90 (1): 29–32. doi:10.1007/s00277-010-1034-x. PMID 20714725. S2CID 20788219. Archived from the original on 2 February 2024. Retrieved 2 February 2024.
  35. ^ Axelrod EV, Mironov KO, Dunaeva EA, Shipulin GA (2016). "[The comparison of three molecular genetic techniques for identifying major mutations in gene HFE related to development of inherent hemochromatosis.]". Klin Lab Diagn (in Russian). 61 (5): 316–320. doi:10.18821/0869-2084-2016-61-5-316-320 (inactive 1 November 2024). PMID 31529915.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
  36. ^ Madani HA, Afify RA, Abd El-Aal AA, Salama N, Ramy N (June 2011). "Role of HFE gene mutations on developing iron overload in beta-thalassaemia carriers in Egypt". East Mediterr Health J. 17 (6): 546–51. doi:10.26719/2011.17.6.546. PMID 21796974.
  37. ^ Hsu CC, Senussi NH, Fertrin KY, Kowdley KV (June 2022). "Iron overload disorders". Hepatol Commun. 6 (8): 1842–1854. doi:10.1002/hep4.2012. PMC 9315134. PMID 35699322. S2CID 249644289.
  38. ^ Cooper DN, Krawczak M, Polychronakos C, Tyler-Smith C, Kehrer-Sawatzki H (October 2013). "Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease". Hum Genet. 132 (10): 1077–130. doi:10.1007/s00439-013-1331-2. PMC 3778950. PMID 23820649.
  39. ^ David A. Warrell, Edward J. Benz Jr., Timothy M. Cox, John D. Firth (2003). Oxford Textbook of Medicine. Vol. 1. Oxford University Press. p. 92. ISBN 978-0-19-262922-7. Most patients with the disease develop symptoms at, or above, the age of 40 years. [...] Most middle-aged male C282Y homozygous appear to express at least one clinical manifestation of iron-storage disease.
  40. ^ a b Bacon BR, Adams PC, Kowdley KV, Powell LW, Tavill AS (July 2011). "Diagnosis and management of hemochromatosis: 2011 Practice Guideline by the American Association for the Study of Liver Diseases". Hepatology. 54 (1): 328–343. doi:10.1002/hep.24330. PMC 3149125. PMID 21452290.
  41. ^ Bacon BR, Olynyk JK, Brunt EM, Britton RS, Wolff RK (June 1999). "HFE genotype in patients with hemochromatosis and other liver diseases". Annals of Internal Medicine. 130 (12): 953–62. doi:10.7326/0003-4819-130-12-199906150-00002. PMID 10383365. S2CID 9764782.
  42. ^ Gochee PA, Powell LW, Cullen DJ, Du Sart D, Rossi E, Olynyk JK (March 2002). "A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation". Gastroenterology. 122 (3): 646–51. doi:10.1016/s0016-5085(02)80116-0. PMID 11874997.
  43. ^ Jackson HA, Carter K, Darke C, Guttridge MG, Ravine D, Hutton RD, Napier JA, Worwood M (August 2001). "HFE mutations, iron deficiency and overload in 10,500 blood donors". British Journal of Haematology. 114 (2): 474–84. doi:10.1046/j.1365-2141.2001.02949.x. PMID 11529872. S2CID 4800162.
  44. ^ Kelley M, Joshi N, Xie Y, Borgaonkar M (April 2014). "Iron overload is rare in patients homozygous for the H63D mutation". Canadian Journal of Gastroenterology & Hepatology. 28 (4): 198–202. doi:10.1155/2014/468521. PMC 4071918. PMID 24729993.
  45. ^ "Heterozygous for p.H63D". Archived from the original on 17 October 2020. Retrieved 16 October 2020.
  46. ^ Semenova EA, Miyamoto-Mikami E, Akimov EB, Al-Khelaifi F, Murakami H, Zempo H, Kostryukova ES, Kulemin NA, Larin AK, Borisov OV, Miyachi M, Popov DV, Boulygina EA, Takaragawa M, Kumagai H, Naito H, Pushkarev VP, Dyatlov DA, Lekontsev EV, Pushkareva YE, Andryushchenko LB, Elrayess MA, Generozov EV, Fuku N, Ahmetov II (March 2020). "The association of HFE gene H63D polymorphism with endurance athlete status and aerobic capacity: novel findings and a meta-analysis". European Journal of Applied Physiology. 120 (3): 665–673. doi:10.1007/s00421-020-04306-8. PMC 7042188. PMID 31970519.
  47. ^ Thakkar D, Sicova M, Guest N, Garcia-Bailo B, El-Sohemy A (December 2020). "HFE Genotype and Endurance Performance in Competitive Male Athletes". Medicine and Science in Sports and Exercise. 53 (7): 1385–1390. doi:10.1249/MSS.0000000000002595. PMID 33433155. S2CID 231585184.
  48. ^ a b 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" (PDF). N Engl J Med. 341 (10): 718–24. doi:10.1056/NEJM199909023411002. PMID 10471457. Archived (PDF) from the original on 10 August 2017. Retrieved 5 April 2019.
  49. ^ Vujić Spasić M, Kiss J, Herrmann T, et al. (2008). "Hfe acts in hepatocytes to prevent hemochromatosis". Cell Metab. 7 (2): 173–8. doi:10.1016/j.cmet.2007.11.014. PMID 18249176.
  50. ^ 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. doi:10.1002/ajh.20743. PMID 16955456. S2CID 12068224.
  51. ^ a b "Hemochromatosis: Tests and diagnosis". Mayo Foundation for Medical Education and Research (MFMER). Archived from the original on 31 May 2013. Retrieved 20 April 2009.
  52. ^ "Iron Transport and Cellular Uptake: Transferrin/Iron Physiology". sickle.bwh.harvard.edu. Archived from the original on 7 March 2007. Retrieved 17 March 2007.
  53. ^ "Hereditary Hemochromatosis - Hematology and Oncology". Merck Manuals Professional Edition. Archived from the original on 2 June 2021. Retrieved 31 May 2021.
  54. ^ MedlinePlus Encyclopedia: Ferritin Test
  55. ^ 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 (28 April 2005). "Hemochromatosis and iron-overload screening in a racially diverse population" (PDF). The New England Journal of Medicine. 352 (17): 1769–1778. doi:10.1056/nejmoa041534. PMID 15858186. Archived (PDF) from the original on 22 July 2018. Retrieved 2 February 2024.
  56. ^ Dadone MM, Kushner JP, Edwards CQ, Bishop DT, Skolnick MH (August 1982). "Hereditary hemochromatosis. Analysis of laboratory expression of the disease by genotype in 18 pedigrees". American Journal of Clinical Pathology. 78 (2): 196–207. doi:10.1093/ajcp/78.2.196. PMID 7102818.
  57. ^ "Ferritin test - Mayo Clinic". Mayo Clinic. Archived from the original on 8 March 2024. Retrieved 21 May 2021.
  58. ^ https://webmd.com/a-to-z-guides/ferritin-blood-test Archived 21 May 2021 at the Wayback Machine. Reviewed 21 May 2021.
  59. ^ St Pierre, Clark PR, Chua-Anusorn W, Fleming AJ, Jeffrey GP, Olynyk JK, Pootrakul P, Robins E, Lindeman R (2005). "Non-invasive measurement and imaging of liver iron concentrations using proton magnetic resonance". Blood. 105 (2): 855–61. doi:10.1182/blood-2004-01-0177. PMID 15256427.
  60. ^ Hirsch JH, Killien FC, Troupin RH (March 1976). "The arthropathy of hemochromatosis". Radiology. 118 (3): 591–596. doi:10.1148/118.3.591. ISSN 0033-8419. PMID 175396.
  61. ^ 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. doi:10.1016/S1079-9796(03)00164-5. PMID 14636642.
  62. ^ "Summaries for patients. Screening for hereditary hemochromatosis: recommendations from the American College of Physicians". Ann. Intern. Med. 143 (7): I-46. 2005. doi:10.7326/0003-4819-143-7-200510040-00004. PMID 16204158. S2CID 53088428. Archived from the original on 16 March 2007. Retrieved 17 March 2007.
  63. ^ U.S. Preventive Services Task Force (2006). "Screening for haemochromatosis: recommendation statement". Ann. Intern. Med. 145 (3): 204–8. doi:10.7326/0003-4819-145-3-200608010-00008. PMID 16880462.
  64. ^ Screening for Hemochromatosis Archived 6 February 2007 at the Wayback Machine U.S. Preventive Services Task Force (2006). Summary of Screening Recommendations and Supporting Documents. Retrieved 18 March 2007
  65. ^ "Hemochromatosis: Treatments and drugs". Mayo Foundation for Medical Education and Research (MFMER). Archived from the original on 7 March 2008. Retrieved 17 March 2007.
  66. ^ European Association For The Study Of The Liver. (2010). "EASL clinical practice guidelines for HFE hemochromatosis". Journal of Hepatology. 53 (1): 3–22. doi:10.1016/j.jhep.2010.03.001. PMID 20471131. Archived from the original on 28 August 2021. Retrieved 25 May 2015.
  67. ^ Kowdley KV, Bennett RL, Motulsky AG, Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean L, Bird TD, Dolan CR, Fong CT, Smith R, Stephens K (1993). "HFE Hemochromatosis". HFE-Associated Hereditary Hemochromatosis. University of Washington, Seattle. PMID 20301613. Archived from the original on 18 January 2017. Retrieved 25 May 2015.
  68. ^ Plaut D, McLellan W (2009). "Hereditary hemochromatosis". Journal of Continuing Education Topics & Issues. 11 (1). Archived from the original on 11 October 2016. Retrieved 11 October 2016.
  69. ^ Polomoscanik SC, Cannon CP, Neenan TX, Holmes-Farley SR, Mandeville WH, Dhal PK (November 2005). "Hydroxamic Acid-Containing Hydrogels for Nonabsorbed Iron Chelation Therapy: Synthesis, Characterization, and Biological Evaluation". Biomacromolecules. 6 (6): 2946–2953. doi:10.1021/bm050036p. PMID 16283713.
  70. ^ Qian J, Sullivan BP, Peterson SJ, Berkland C (18 April 2017). "Nonabsorbable Iron Binding Polymers Prevent Dietary Iron Absorption for the Treatment of Iron Overload". ACS Macro Letters. 6 (4): 350–353. doi:10.1021/acsmacrolett.6b00945. PMID 35610854.
  71. ^ a b c Groborz O, Poláková L, Kolouchová K, Švec P, Loukotová L, Miriyala VM, Francová P, Kučka J, Krijt J, Páral P, Báječný M, Heizer T, Pohl R, Dunlop D, Czernek J, Šefc L, Beneš J, Štěpánek P, Hobza P, Hrubý M (December 2020). "Chelating Polymers for Hereditary Hemochromatosis Treatment". Macromolecular Bioscience. 20 (12): 2000254. doi:10.1002/mabi.202000254. PMID 32954629. S2CID 221827050.
  72. ^ Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G (14 November 1985). "Survival and Causes of Death in Cirrhotic and in Noncirrhotic Patients with Primary Hemochromatosis". New England Journal of Medicine. 313 (20): 1256–1262. doi:10.1056/NEJM198511143132004. PMID 4058506.
  73. ^ Bokhoven MA, Deursen CT, Swinkels DW (19 January 2011). "Diagnosis and management of hereditary haemochromatosis". BMJ. 342 (jan19 2): c7251. doi:10.1136/bmj.c7251. hdl:2066/95805. PMID 21248018. S2CID 5291764. Archived from the original on 8 March 2024. Retrieved 17 September 2021.
  74. ^ a b c "Hemochromatosis". Medscape. 14 June 2021. Archived from the original on 22 May 2023. Retrieved 20 November 2021.
  75. ^ Mendes AI, Ferro A, Martins R, et al. (March 2009). "Non-classical hereditary hemochromatosis in Portugal: novel mutations identified in iron metabolism-related genes" (PDF). Ann. Hematol. 88 (3): 229–34. doi:10.1007/s00277-008-0572-y. PMID 18762941. S2CID 23206256. Archived (PDF) from the original on 29 August 2019. Retrieved 29 August 2019.
  76. ^ McLaren GD, Gordeuk VR (January 2009). "Hereditary hemochromatosis: insights from the Hemochromatosis and Iron Overload Screening (HEIRS) Study". Hematology. 2009 (1): 195–206. doi:10.1182/asheducation-2009.1.195. PMC 3829617. PMID 20008199.
  77. ^ Lucotte G (31 October 1998). "Celtic Origin of the C282Y Mutation of Hemochromatosis" (PDF). Blood Cells, Molecules and Diseases. 24 (20): 433–438. doi:10.1006/bcmd.1998.0212. ISSN 1079-9796. PMID 9851897. Archived from the original (PDF) on 2 December 2008. Retrieved 7 January 2014.
  78. ^ a b Barton JC, Edwards CQ, eds. (2000). Hemochromatosis: Genetics, Pathophysiology, Diagnosis and Treatment. Cambridge University Press. ISBN 978-0-521-59380-9. Archived from the original on 2 July 2022. Retrieved 2 July 2022.
  79. ^ Trousseau A (1865). "Glycosurie, diabète sucré". Clinique Médicale de l'Hôtel-Dieu de Paris. 2: 663–98.
  80. ^ von Recklinghausen FD (1890). "Hämochromatose". Tageblatt der Naturforschenden Versammlung 1889: 324.
  81. ^ "Friedrich Daniel von Recklinghausen". www.whonamedit.com. Archived from the original on 16 November 2018. Retrieved 24 March 2004.
  82. ^ Sheldon JH (1935). "Haemochromatosis". London: Oxford University Press.
  83. ^ a b c d Bacon BR (2012). "Hemochromatosis: Discovery of the HFE Gene". Missouri Medicine. 109 (2): 133–136. ISSN 0026-6620. PMC 6181731. PMID 22675794.
  84. ^ a b Brissot P (June 2003). "The discovery of the new haemochromatosis gene: Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis [Nat Genet 1996;13:399–408]". Journal of Hepatology. 38 (6): 704–709. doi:10.1016/S0168-8278(03)00142-9. ISSN 0168-8278. PMID 12763361. Archived from the original on 8 March 2024. Retrieved 20 November 2021.
  85. ^ MacDonald RA (1964). Hemochromatosis and Hemosiderosis. Springfield, IL: Charles C Thomas.
  86. ^ Simon M, Bourel M, Fauchet R, Genetet B (1976). "Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis". Gut. 17 (5): 332–334. doi:10.1136/gut.17.5.332. PMC 1411133. PMID 1278715.
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