Hemochromatosis: Difference between revisions
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| Haemochromatosis type 4 [[autosomal dominant]] haemochromatosis (all others are [[Recessive gene|recessive]]), gene mutation || {{OMIM2|604653}} || [[ferroportin]] (SLC11A3) || 2q32 | | Haemochromatosis type 4 [[autosomal dominant]] haemochromatosis (all others are [[Recessive gene|recessive]]), gene mutation || {{OMIM2|604653}} || [[ferroportin]] (SLC11A3) || 2q32 | ||
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==End-organ damage== | ==End-organ damage== | ||
Revision as of 12:07, 29 August 2012
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Hemochromatosis Microchapters |
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Hemochromatosis On the Web |
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American Roentgen Ray Society Images of Hemochromatosis |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Haemochromatosis
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
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.[1]
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.
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Haemochromatosis types 1-3 are inherited in an autosomal recessive fashion. -
Haemochromatosis type 4 is inherited in an autosomal dominant fashion.
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.
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. [2] Penetration differs between different populations.
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.
Recently, a classification has been developed (with chromosome locations):
| 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 |
End-organ damage
Iron is stored in the liver, the pancreas and the heart. 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.)
Diabetes: 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). Diabetes is in turn the leading cause of new blindness in adults and may be involved in kidney failure and cardiovascular disease.
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.
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.
Pigment changes: Deposits of iron in skin cells can turn skin a bronze or gray color.
Diagnosis
Haemochromatosis can be difficult to diagnose in the early stages. Early signs may mimic other diseases. Stiff joints, diabetes, and fatigue, for example, are common in haemochromatosis and other maladies.[4]
Signs and symptoms
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).[5] Symptoms may include:[6][7][8]
- Malaise
- Liver cirrhosis (with an increased risk of hepatocellular carcinoma, affecting up to a third of all homozygotes) - this is often preceded by a period of a painfully enlarged liver.
- Insulin resistance (often patients have already been diagnosed with diabetes mellitus type 2) due to pancreatic damage from iron precipitation
- Erectile dysfunction and hypogonadism
- Decreased libido
- Congestive heart failure, arrhythmias or pericarditis
- Arthritis of the hands (especially the MCP and PIP joints), knee and shoulder joints
- Deafness[9]
- Dyskinesias, including Parkinsonian symptoms[10][9][11]
- Dysfunction of certain endocrine organs:
- Pancreatic gland, as above, manifesting as diabetes
- Adrenal gland (leading to adrenal insufficiency)
- Parathyroid gland (leading to hypocalcaemia)
- Pituitary gland
- Testes or ovary (leading to hypogonadism)
- A darkish color to the skin (see pigmentation, hence its name Diabete bronze when it was first described by Armand Trousseau in 1865)
- An increased susceptibility to certain infectious diseases caused by siderophilic microoganisms:
- Vibrio vulnificus infections from eating seafood
- Listeria monocytogenes
- Yersinia enterocolica
- Salmonella enteritidis (serotype Typhymurium)
- Klebsiella pneumoniae
- Escherichia coli
- Rhizopus arrhizus
- Mucor species
Males are usually diagnosed after their forties, and women about a decade later, owing to regular iron loss by menstruation (which ceases in menopause). Cases of iron overload have been found in young children as well.
Imaging features
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 at MR imaging. 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. The arthropathy can therefore be an early clue as to the diagnosis of hemochromatosis. MRI algorithms are available at research institutions to quantify the amount of iron present in the liver, therefore reducing the necessity of a liver biopsy (see below) to measure the liver iron content. As of May, 2007, this technology was only available at a few sites in the USA, but documented reports of radiographic measurements of liver iron content were becoming more common. [12]
Chemistry
Serum transferrin saturation- A first step is the measurement of transferrin saturation, the protein which chemically binds to iron and carries it through the blood to the liver, spleen and bone marrow.[13] Measuring transferrin provides a measurement of iron in the blood. Saturation values of 45% are probably a good cutoff to determine whether a patient is a candidate for further testing. [14] The transferrin saturation is usually expressed as a percentage, and is calculated as the total serum iron level divided by the serum iron transferrin level times 100. Serum Ferritin- Ferritin, the protein which chemically binds to iron and stores it in the body. Measuring ferritin provides a measurement of iron in the whole body. Normal values for males are 12-300 ng/ml (nanograms per milliliter) and for female, 12-150 ng/ml. Low values indicate iron deficiency, which may be attributed to a number of causes. Higher than normal also may indicate other causes including haemochromatosis.[15][16] Other blood tests routinely performed: blood count, renal function, liver enzymes, electrolytes, glucose (and/or an oral glucose tolerance test (OGTT)).
Functional testing
Based on the history, the doctor might consider specific tests to monitor organ dysfunction, such as an echocardiogram for heart failure, or blood glucose monitoring for patients with hemochromatosis diabetes.
Histopathology
Liver biopsy - 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, measured microscopically. Formerly, this was the only way to confirm a diagnosis of hemochromatosis 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, it is debatable whether a liver biopsy is still necessary to quantify the amount of accumulated iron.[17]
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:[18][19]
- 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. 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. [20] [21]
Differential Diagnosis
There exist other causes of excess iron accumulation, which have to be considered before Haemochromatosis is diagnosed.
- African iron overload, formerly known as Bantu siderosis, was first observed among people of African descent in Southern Africa. Originally, this was blamed on ungalvanised barrels used to store home-made beer, which led to increased oxidation and increased iron levels in the beer. Further investigation has shown that only some people drinking this sort of beer get an iron overload syndrome, and that a similar syndrome occurred in people of African descent who have had no contact with this kind of beer (e.g., African Americans). This led investigators to the discovery of a gene polymorphism in the gene for ferroportin which predisposes some people of African descent to iron overload.[22]
- Transfusion hemosiderosis is the accumulation of iron, mainly in the liver, in patients who receive frequent blood transfusions (such as those with thalassemia).
- Dyserythropoeisis, also known as myelodysplastic syndrome is a disorder in the production of red blood cells. This leads to increased iron recycling from the bone marrow and accumulation in the liver.
Treatment
Early diagnosis is important because the late effects of iron accumulation can be wholly prevented by periodic phlebotomies (by venesection) comparable in volume to blood donations.[23] Treatment is initiated when ferritin levels reach 300 micrograms per litre (or 200 in nonpregnant premenopausal women).
Every bag of blood ml) contains 200-250 milligrams of iron. Phlebotomy (or bloodletting) is usually done at a weekly interval until ferritin levels are less than 20 nanograms per millilitre. After that, 1-4 donations per year are usually needed to maintain iron balance.
Other parts of the treatment include:
- Treatment of organ damage (heart failure with diuretics and ACE inhibitor therapy).
- Limiting intake of alcoholic beverages, vitamin C (increases iron absorption in the gut), red meat (high in iron) and potential causes of food poisoning (shellfish, seafood).
- Increasing intake of substances that inhibit iron absorption, such as high-tannin tea, calcium, and foods containing oxalic and phytic acids (these must be consumed at the same time as the iron-containing foods in order to be effective.)
See also
External links
References
- ↑ Hemochromatosis-Causes Mayo Foundation for Medical Education and Research (MFMER) Retrieved March 12, 2007
- ↑ 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.
- ↑ Haemochromatosis Complications
- ↑ Screening and Diagnosis
- ↑ Hemochromatosis-Diagnosis National Digestive Diseases Information Clearinghouse, National Institutes of Health, U.S. Department of Health and Human Services
- ↑ Iron Overload and Hemochromatosis Centers for Disease Control and Prevention
- ↑ Hemochromatosis National Digestive Diseases Information Clearinghouse, National Institutes of Health, U.S. Department of Health and Human Services
- ↑ Hemochromatosis-Signs and Symptoms Mayo Foundation for Medical Education and Research (MFMER)
- ↑ 9.0 9.1 Jones H, Hedley-Whyte E (1983). "Idiopathic hemochromatosis (IHC): dementia and ataxia as presenting signs". Neurology. 33 (11): 1479–83. PMID 6685241.
- ↑ 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.
- ↑ 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.
- ↑ Tanner MA, He T, Westwood MA, Firmin DN, Pennell DJ (2006). "Multi-center validation of the transferability of the magnetic resonance T2* technique for the quantification of tissue iron". Haematologica. 91 (10): 1388–91. PMID 17018390.
- ↑ Transferrin and Iron Transport Physiology
- ↑ Screening and Diagnosis
- ↑ Screening and Diagnosis
- ↑ Ferritin Test Measuring iron in the body
- ↑ Screening and diagnosis Mayo Foundation for Medical Education and Research (MFMER) Retrieved 18 March, 2007
- ↑ Screening and Diagnosis Mayo Foundation for Medical Education and Research (MFMER). Retrieved 18 March, 2007
- ↑ [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
- ↑ "Screening for hemochromatosis: recommendation statement". Ann. Intern. Med. 145 (3): 204–8. 2006. PMID 16880462.
- ↑ Screening for Hemochromatosis U.S. Preventive Services Task Force (2006). Summary of Screening Recommendations and Supporting Documents. Retrieved 18 March, 2007
- ↑ 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.
- ↑ Hemochromatosis - Treatment
de:Hämochromatose it:Emocromatosi he:המוכרומטוזיס nl:Hemochromatose no:Hemokromatose fi:Hemokromatoosi sv:Hemakromotos