What is Hemochromatosis?

Iron overload
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Iron overload

Micrograph of haemosiderosis. Liver biopsy.Iron stain.

ICD-10

R79.0

ICD-9

275.03

DiseasesDB

5581

MedlinePlus

000327

MeSH

D019190

In medicine, iron overload indicates accumulation of iron in the body from any cause. The most important causes are hereditary haemochromatosis(HHC), a genetic disorder, and transfusional iron overload, which can result from repeated blood transfusion.
Contents
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1 Terminology

1.1 Haemochromatosis or haemosiderosis

2 Clinical presentation 3 Causes

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3.1 Primary haemochromatosis 3.2 Secondary haemochromatosis

4 Diagnosis 5 Prognosis 6 Treatment 7 See also 8 Further reading 9 References 10 External links

Terminology[edit]
Haemochromatosis or haemosiderosis[edit]
Historically, the term haemochromatosis (spelled hemochromatosis in American English) was initially used to refer to what is now more specifically called haemochromatosis type 1 (or HFE-related hereditary haemochromatosis). Currently, haemochromatosis (without further specification) is mostly defined as iron overload with a hereditary/primary cause,[1][2] or originating from a metabolic disorder.[3] However, the term is currently also used more broadly to refer to any form of iron overload, thus requiring specification of the cause, for example, hereditary haemochromatosis. Hereditary haemochromatosis is an autosomal recessive disorder with estimated prevalence in the population of 1 in 200 among patients with European ancestry, with lower incidence in other ethnic groups.[4] The gene responsible for hereditary haemochromatosis (known as HFE gene) is located on chromosome 6; the majority of hereditary haemochromatosis patients have mutations in this HFE gene. Hereditary haemochromatosis is characterized by an accelerated rate of intestinal iron absorption and progressive iron deposition in various tissues that typically begins to be expressed in the third to fifth decades of life, but may occur in children. The most common presentation is hepatic cirrhosis in combination with hypopituitarism,cardiomyopathy, diabetes, arthritis, or hyperpigmentation. Because of the severe sequelae of this disorder if left untreated, and recognizing that treatment is relatively simple, early diagnosis before symptoms or signs appear is important.[5][6] In general, the term haemosiderosis is used to indicate the pathological effect of iron accumulation in any given organ, which mainly occurs in the form of haemosiderin.[7][8] Sometimes, the simpler term siderosis is used instead. Other definitions distinguishing haemochromatosis or haemosiderosis that are occasionally used include:

Haemosiderosis is haemochromatosis caused by excessive blood transfusions, that is, haemosiderosis is a form of secondary haemochromatosis.[9][10]

Haemosiderosis is haemosiderin deposition within cells, while haemochromatosis is haemosiderin within cells and interstitium.[11]

Haemosiderosis is iron overload that does not cause tissue damage,[12] while haemochromatosis does.[13] Haemosiderosis is arbitrarily differentiated from haemochromatosis by the reversible nature of the iron accumulation in the reticuloendothelial system.[14]

Clinical presentation[edit]
Organs commonly affected by haemochromatosis are the liver, heart, and endocrine glands.[15] Haemochromatosis may present with the following clinical syndromes:[16]

Cirrhosis of the liver Diabetes due to pancreatic islet cell failure Cardiomyopathy Arthritis (iron deposition in joints) Testicular failure Tanning (bronzing) of the skin Joint pain and bone pain[17]

Causes[edit]
The causes can be distinguished between primary cases (hereditary or genetically determined) and less frequent secondary cases (acquired during life).[18] People of Celtic (Irish, Scottish, Welsh, Cornish, Breton etc.), British, and Scandinavian origin[19] have a particularly high incidence of whom about 10% are carriers of the gene and 1% sufferers from the condition.

Primary haemochromatosis[edit]
The fact that most cases of haemochromatosis were inherited was well known for most of the 20th century, though they were incorrectly assumed to depend on a single gene.[20] The overwhelming majority actually depend on mutations of the HFE gene discovered in 1996, but since then others have been discovered and sometimes are grouped together as "non-classical hereditary haemochromatosis",[21] "non-HFE related hereditary haemochromatosis",[22] or "non-HFE haemochromatosis".[23] Description OMIM Mutation

Haemochromatosis type 1: "classical" haemochromatosis

235200 HFE

Haemochromatosis type 2A: juvenile haemochromatosis 602390

Haemojuvelin ("HJV", also known as RGMc and HFE2)

Haemochromatosis type 2B: juvenile haemochromatosis 606464 hepcidin antimicrobial peptide (HAMP) or HFE2B

Haemochromatosis type 3

604250 transferrin receptor-2 (TFR2 or HFE3)

Haemochromatosis type 4/ African iron overload

604653 ferroportin (SLC11A3/SLC40A1)

Neonatal haemochromatosis

231100 (unknown)

Acaeruloplasminaemia (very rare)

604290 caeruloplasmin

Congenital atransferrinaemia (very rare)

209300 transferrin

GRACILE syndrome (very rare)

603358 BCS1L

Most types of hereditary haemochromatosis have autosomal recessive inheritance, while type 4 has autosomal dominant inheritance.[24]

Secondary haemochromatosis[edit]

Severe chronic haemolysis of any cause, including intravascular haemolysis and ineffective erythropoiesis (haemolysis within the bone marrow)

Multiple frequent blood transfusions (either whole blood or just red blood cells), which are usually needed either by individuals with hereditary anaemias (such as beta-thalassaemia major,sickle cell anaemia, and DiamondBlackfan anaemia) or by older patients with severe acquired anaemias such as in myelodysplastic syndromes

Excess parenteral iron supplements, such as what can acutely happen in iron poisoning Excess dietary iron

Some disorders do not normally cause haemochromatosis on their own, but may do so in the presence of other predisposing factors. These include cirrhosis (especially related to alcohol abuse), steatohepatitis of any cause, porphyria cutanea tarda, prolonged haemodialysis, and post-portacaval shunting.

Diagnosis[edit]
There are several methods available for diagnosing and monitoring iron loading including:

Serum ferritin Liver biopsy HFE MRI

Serum ferritin is a low-cost, readily available, and minimally invasive method for assessing body iron stores. However, the major problem with using it as an indicator of iron overload is that it can be elevated in a range of other medical conditions unrelated to iron levels including infection, inflammation, fever, liver disease, renal disease, and cancer. Also, total iron binding capacity may be low, but can also be normal.[25] The standard of practice in diagnosis of haemochromatosis was recently reviewed by Pietrangelo.[5] Positive HFE analysis confirms the clinical diagnosis of haemochromatosis in asymptomatic individuals with blood tests showing increased iron stores, or for predictive testing of individuals with a family history of haemochromatosis. The alleles evaluated by HFE gene analysis are evident in ~80% of patients with haemochromatosis; a negative report for HFE gene does not rule out haemochromatosis. In a patient with negative HFE gene testing, elevated iron status for no other obvious reason, and family history of liver disease, additional evaluation of liver iron concentration is indicated. In this case, diagnosis of haemochromatosis is based on biochemical analysis and histologic examination of a liver biopsy. Assessment of the hepatic iron index (HII) is considered the "gold standard" for diagnosis of haemochromatosis. MRI is emerging as an alternative to liver biopsy for measuring liver iron loading. For measuring liver iron concentrations, R2-MRI (also known as FerriScan)[26][27] has been extensively validated. More than 11,000 FerriScans have now been conducted in over 120 medical centres across 25 countries. FerriScan is now specifically recommended as a method to measure liver iron concentrations in clinical practice guidelines for thalassaemias,[28][29][30][31][32] sickle cell disease [33][34][35] myelodysplastic syndrome (MDS) [36][37][38] and hereditary haemochromatosis.[39] Family members of those diagnosed with primary haemochromatosis may be advised to be screened genetically to determine if they are a carrier or if they could develop the disease. This can allow preventative measures to be taken.

Prognosis[edit]

A third of those untreated develop hepatocellular carcinoma.[40] Affected individuals over age 40 or have high serum ferritin levels are at risk for developing cirrhosis.

Treatment[edit]
Routine treatment in an otherwise-healthy person consists of regularly scheduled phlebotomies (bloodletting). When first diagnosed, the phlebotomies may be fairly frequent, perhaps as often as once a week, until iron levels can be brought to within normal range. Once iron and other markers are within the normal range, phlebotomies may be scheduled every other month or every three months depending upon the patient's rate of iron loading. For those unable to tolerate routine blood draws, there is a chelating agent available for use. The drug Deferoxamine binds with iron in the bloodstream and enhances its elimination via urine and faeces. Typical treatment for chronic iron overload requires subcutaneous injection over a period of 812 hours daily. Two newer iron chelating drugs that are licensed for use in patients receiving regular blood transfusions to treat thalassaemia (and, thus, who develop iron overload as a result) are deferasirox and deferiprone.