|OMIM||235200 602390 606464 604720 604653|
Haemochromatosis (UK spelling), or hemochromatosis (USA spelling) (pronunciation: he'-mo/kro-mah/to'-sis).
Hemochromatosis ('hemo' from the Greek for haima or blood, 'chroma' from the Greek chroma or color, and 'osis', denoting a morbid or abnormal process) All types of hemochromatosis originate from the same metabolic error: disruption of tendency for consistent circulatory iron levels. It is characterized by improper metabolisis of dietary iron which causes iron to accumulate in a number of body tissues, eventually causing organ dysfunction.
There is a classic or historically consistent group of four manifestations resulting from hemochromatosis. The "tetrad" consists of (1) cirrhosis (scarring of the liver), (2) diabetes mellitus (insulin-sugar metabolism), (3) hyperpigmentation of the skin (bronze colouring), and (4) cardiac failure. Clinical consequences also include hepatocellular carcinoma (liver cancer), impotence, and arthritis. 
Hemochromatosis is most commonly an hereditary disease (the primary or endogenous form), an autosomal recessive genetic anomally of the HFE gene. The less common exogenous form (secondary or acquired form) is caused by metabolic iron overload which may occur in cases of chronic anemia, chronic liver disease and excessive iron supplementation (rare).
Armand Trousseau, in an article on diabetes, first described the disease in 1865 but did not make the association with iron accumulation. Friedrich Daniel von Recklinghausen in 1890 linked the disease with iron accumulation.
Synonyms for hemochromatosis
- Acquired hemochromatosis
- Bronze diabetes
- Classical hemochromatosis
- Genetic iron poisoning
- Genetic hemochromatosis
- Hereditary hemochromatosis (HH or HHC)
- Hepatic iron overload
- Iron overload disease
- Iron deposition disease
- neonatal iron overload
- neonatal hemochromatosis
- Primary hemochromatosis
- Secondary hemochromatosis
Types of Hemochromatosis
There exists two major types of hemochromatosis, hereditary (primary) hemochromatosis and acquired (secondary) hemochromatosis.
A genetic defect in the genes that control iron dietary absorption (HFE genes) is the cause of primary hemochromatosis. This is hereditary hemochromatosis (also known as classical hemochromatosis). The majority of hemochromatosis cases are primary. Primary hemochromatosis occurs with the inheritance of two copies of the abnormal HFE gene, one from each parent (i.e. are homogenous for the genetic defect).
Inheriting one abnormal HFE gene and one normal HFE gene (heterozygous for the genetic defect), results in a condition known as a hemochromatosis “carrier.” Carriers do not usually develop the disease, but they may pass the abnormal gene on to their children. About 1 in 10 people in the USA are believed to be carriers.
Other less common types of abnormal genes have also been linked to hemochromatosis.
Secondary or acquired hemochromatosis is predominantly a result of other diseases or conditions causing iron overload. These include:
- Specific anemias (e.g. thalassemia or aplastic anemia);
- African iron overload, a combination of an inherited disorder and diet;
- Atransferrinemia and aceruloplasminemia, rare inherited diseases:
- Chronic liver disease (e.g. hepatitis, alcoholic liver disease, or nonalcoholic steatohepatitis - fatty hepatitis);
- High iron intake:
- Blood transfusions
- Iron intake (oral iron pills or injected iron)
- Long-term kidney dialysis
Signs and symptoms
Mimicry: Haemochromatosis presents with symptoms that are often initially attributed to other diseases. In other words, the disease is protean in that it mimics other diseases, displaying extensive diversity or variety in appearance, leading to mistaken diagnosis. Conversely, the disease may be insidious, progressing with few or no symptoms. So, some people with the disease never actually show signs or suffer symptoms (i.e. it is clinically silent).
- 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)
- Erectile dysfunction and hypogonadism
- Decreased libido
- Cardiology: Restrictive cardiomyopathy cause congestive heart failure, arrhythmias or pericarditis
- Other symptoms include shortness of breath, fluid accumulation in tissues (edema), abnormal heart rhythms (arrhythmias) and awareness of heartbeats (palpitations).
- Less common are chest pain and fainting (syncope).
- Symptoms commonly occur during exercise since the constricted heart muscles cannot pump enough blood to meet increased need for blood and oxygen.
- Symptoms do not usually occur during rest since the heart can supply the body with enough blood and oxygen during rest.
- Arthritis of the hands (MCP and PIP joints), knee and shoulder joints
- Dyskinesias, including Parkinsonian symptoms  
- Dysfunction of certain endocrine organs:
- Pigmentation changes: A darkish colour to the skin (see pigmentation, hence its name Diabete bronze when it was first described by Armand Trousseau in 1865)
- Increased disease susceptibility: Increased susceptibility to disease may be caused by inhibition of phagocytosis, inhibition of intracellular killing of bacteria, and altered polymorphonuclear cell function.  The increased susceptibility to certain infectious diseases caused by:
Sex differences in diagnostic findings: Males are usually diagnosed after their forties, and women about a decade later, owing to regular iron loss by menstruation (which ceases in menopause), but cases have been found in young children as well.
Hemochromatosis is difficult to diagnose in the early stages. Early signs may mimic other diseases. Stiff joints and fatigue for example are common in haemochromatosis and other maladies.
Serum transferrin saturation: A first step is the measurement of transferrin, the protein which chemically binds to iron and carries it through the blood to the liver, spleen and bone marrow. Measuring transferrin provides a measurement of iron in the blood. Saturation values of 45% are too high.
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.
- Radiographs (X-rays) demonstrate cardiomegaly (enlarged heart) and increased pulmonary vascular markings (visible markings in the blood vessels of the lungs).
- Features of restrictive cardiomyopathy are visible on echocardiograms.
Liver biopsy - Liver biopsies involve taking a sample of tissue from your liver, using a thin needle. The sample is then checked for the presence of iron as well as for evidence of liver damage (particularly cirrhosis: tissue scarring). Formerly, this was the only way to confirm a diagnosis of hemochromatosis but measures of transferrin and ferritin along with a history are considered better options 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 still needs to occur to quantify the amount of accumulated iron. 
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, aren't 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: 
- Joint disease
- Severe fatigue
- Heart disease
- Elevated liver enzymes
Genetic screening does not have any apparent advantages and treatment based on screening results are not demonstrably efficacious. Given that the malady is very rare in the general population, genetic carriers of the disease may never manifest the symptoms of the disease and the potential harm of the attendant surveillance, labeling, unnecessary invasive work-up, anxiety, and, potentially, unnecessary treatments outweigh the potential benefits. 
Hemochromatosis is one of the most common inheritable genetic defects, especially in people of northern European extraction, with about 1 in 10 people carrying the defective gene. The prevalence of haemochromatosis varies in different populations. In Northern Europeans it is of the order of one in 400 persons. A study of 3,011 unrelated white Australians found that 14% were carriers and 0.5% had the genetic condition.
The gene that controls 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. One mutation may lead to slightly excessive iron absorption but usually haemochromatosis does not develop.
In the United States, most people with haemochromatosis have inherited two copies of C282Y — one from each parent — and are homozygous for the trait. Mutations of the HFE gene account for 90% of the cases. This gene is closely linked to the HLA-A3 locus. Homozygosity for the C282Y mutation is the most significant, although hemochromatosis for the heterozygosity for C282Y/H63D mutations is very rare. Carriers of a single copy of either gene also have a very slight risk of haemochromatosis when other factors contribute, but are otherwise healthy.
Other genes that cause haemochromatosis are the autosomal dominant SLC11A3/ferroportin 1 gene and TfR2 (transferrin receptor 2). They are much rarer than HFE-haemochromatosis.
Recently, a classification has been developed (with chromosome locations):
- Haemochromatosis type 1 (Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 235200. World Wide Web URL: http://omim.org/.): "classical" HFE-haemochromatosis (6p21.3).
- Haemochromatosis type 2 (Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 602390. World Wide Web URL: http://omim.org/.): juvenile haemochromatosis :
- Type 2A:(Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 602390. World Wide Web URL: http://omim.org/.): mutations in hemojuvelin ("HJV", also known as HFE2)
- Type 2B (Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 606464. World Wide Web URL: http://omim.org/.): mutation in hepcidin antimicrobial peptide (HAMP) or HFE2B (19q13)
- Haemochromatosis type 3 (Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 604720. World Wide Web URL: http://omim.org/.): transferrin receptor-2 (TFR2 or HFE3, 7q22).
- Haemochromatosis type 4 (Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 604653. World Wide Web URL: http://omim.org/.): autosomal dominant haemochromatosis (all others are recessive), ferroportin (SLC11A3) gene mutation (2q32).
People with the abnormal genes do not have the normal metabolic process to 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 starts to get stored as a breakdown product of ferritin called haemosiderin and this is toxic to tissue, probably at least partially by inducing Oxidative stress.
Early diagnosis is important because the late effects of iron accumulation can be wholly prevented by periodic phlebotomies (extracting blood with a hypodermic needle by venesection) comparable in volume to blood donations. Treatment is initiated when ferritin levels reach 300 micrograms per litre (or 200 in nonpregnant premenopausal women).
Every 450-500 ml) of blood contains 200-250 milligrams of iron. Phlebotomy (or bloodletting) is usually done at a weekly interval until ferritin levels are less than 50 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.)
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. 
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 your blood and eventually affect mental functioning. This can lead to confusion or even coma (hepatic encephalopathy).
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.
In the early stages, the effects of hemochromatosis are reversible and a normal life span and health can be achieved. If left untreated, in advanced stages the complications (e.g. cirrhosis, hepatic carcinoma, restrictive cardiomyopathy, diabetes mellitus) may be irreversible and cause death. The most common causes of death are hepatic failure due to cirrhosis and cirrhosis with liver cancer. 
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- Restrictive Cardiomyopathy Restrictive (or infiltrative) cardiomyopathy: heart disorders in which the walls of the ventricles become stiff, but not necessarily thickened, and resist normal filling with blood between heartbeats. There are a number of types. Examples include (1) scarring in which scar tissue replace cardiac muscle (which takes place in hemochromatosis); (2) Amyloidosis (common in older people): condition in which the protein amyloid (not normally present in the body) accumulates in heart muscle and other tissues; (3) tumors; and (4) granuloma tissue: collections of certain white blood cells (abnormal) that form in response to chronic inflammation (e.g. sarcoidosis)
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