Micrograph of haemosiderosis. Liver biopsy. Iron stain. |
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| ICD-10 | R79.0 |
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| ICD-9 | xxx |
| DiseasesDB | 5581 |
| 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 disease, and transfusional iron overload, which can result from repeated blood transfusion.
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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 disease with estimated prevalence in the population of 2 in 1,000 among patients with European ancestry, with lower incidence in other ethnic groups. 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 disease if left untreated, and recognizing that treatment is relatively simple, early diagnosis before symptoms or signs appear is important.[4][5]
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.[6][7] Sometimes, the simpler term siderosis is used instead.
Other definitions distinguishing haemochromatosis or haemosiderosis that are occasionally used include:
Organs commonly affected by haemochromatosis are the liver, heart, and endocrine glands.[14]
Haemochromatosis may present with the following clinical syndromes:[15]
The causes can be distinguished between primary cases (hereditary or genetically determined) and less frequent secondary cases (acquired during life).[16] People of Celtic (Irish, Scottish, Welsh) origin have a particularly high incidence of whom about 10% are carriers of the gene and 1% sufferers from the condition.
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.[17] 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",[18] "non-HFE related hereditary haemochromatosis",[19] or "non-HFE haemochromatosis".[20]
| 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.[21]
There are several methods available for diagnosing and monitoring iron loading including:
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.[22]
The standard of practice in diagnosis of haemochromatosis was recently reviewed by Pietrangelo.[4] 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) [2][23] 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,[24][25][26][27][28] sickle cell disease [29][30][31] myelodysplastic syndrome (MDS) [32][33][34] and hereditary haemochromatosis.[35]
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.
A third of those untreated develop hepatocellular carcinoma.[36]
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 8–12 hours daily. Two newer iron chelating drugs that are licensed for use in patients receiving regular blood transfusions to treat thalassaemia (and, thus, who develop iron overload as a result) are deferasirox and deferiprone.
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