Iron overload (also known as haemochromatosis or hemochromatosis) 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 transfusions.
Signs and symptoms
Organs most commonly affected by haemochromatosis are the liver, heart, and endocrine glands.
Haemochromatosis may present with the following clinical syndromes:
- Chronic liver disease and cirrhosis of the liver
- Heart involvement: heart failure, irregular heart rhythm
- Hormonal issues: diabetes (see below) and hypogonadism (insufficiency of the sex hormone producing glands) which leads to low sex drive and/or loss of fertility in men and loss of menstrual cycle in women
Diabetes in people with iron overload occurs as a result of selective iron deposition in islet beta cells in the pancreas leading to functional failure and cell death.
Arthritis, from calcium pyrophosphate deposition in joints leading to joint pains. The most commonly affected joints are those of the hands, particularly the knuckles of the second and third fingers.
Bronzing of the skin. This deep tan color, in concert with insulin insufficiency due to pancreatic damage, is the source of a nickname for this condition: “bronze diabetes”.
Causes and forms
The causes can be distinguished between primary cases (hereditary or genetically determined) and less frequent secondary cases (acquired during life). People of Celtic (Irish, Scottish, Welsh, Cornish, Breton etc.), English, and Scandinavian origin have a particularly high incidence, with about 10% being carriers of the principal genetic variant, the C282Y mutation on the HFE gene, and 1% having the condition. This has been recognised in several alternative names such as Celtic curse, Irish illness, British gene, and Scottish sickness.
Although it was known most of the 20th century that most cases of haemochromatosis were inherited, they were incorrectly assumed to depend on a single gene. The overwhelming majority 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”, “non-HFE related hereditary haemochromatosis”, or “non-HFE haemochromatosis”.
|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/||604653||ferroportin (SLC11A3/SLC40A1)|
|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.
- 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 Diamond–Blackfan 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
Selective iron deposition (blue) in pancreatic islet beta cells(red).
There are several methods available for diagnosing and monitoring iron loading.
Blood tests are usually the first test if there is a clinical suspicion of iron overload. Serum ferritin testing 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, kidney disease, and cancer. Also, total iron binding capacity may be low, but can also be normal. Serum ferritin: In males and postmenopausal females, a serum ferritin value of over 300 ng/mL (670 pmol/L) indicates iron overload. In premenopausal females, a serum ferritin value of over 150 or 200 ng/mL (330 or 440 pmol/L) indicates iron overload. If the person is capable of showing the symptoms, they may need to be tested more than once throughout their lives as a precautionary, most commonly in women after menopause.Transferrin saturation is a more specific test.
DNA/screening: the standard of practice in diagnosis of haemochromatosis places emphasis on genetic testing. 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. First degree relatives of those with primary haemochromatosis should be screened to determine if they are a carrier or if they could develop the disease. This can allow preventive measures to be taken. Screening the general population is not recommended.
Liver biopsy is the removal of small sample in order to be studied and can determine the cause of inflammation or cirrhosis. In someone 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.
Magnetic resonance imaging (MRI) is used as a noninvasive way to accurately estimate iron deposition levels in the liver as well as heart, joints, and pituitary gland.
Phlebotomy/venesection: routine treatment consists of regularly scheduled phlebotomies (bloodletting or erythrocytapheresis). When first diagnosed, the phlebotomies may be performed every week or fortnight, until iron levels can be brought to within normal range. Once the serum ferritin and transferrin saturation are within the normal range, treatments may be scheduled every two to three months depending upon the rate of reabsorption of iron. A phlebotomy session typically draws between 450 and 500 mL of blood.
Diet low in iron is generally recommended, but has little effect compared to venesection. The human diet contains iron in two forms – heme iron and non-heme iron. Heme iron is the most easily absorbed form of iron. People with iron overload may be advised to avoid food that are high in heme iron. Highest in heme iron is red meat such as beef, venison, lamb, buffalo, and fish such as bluefin tuna. A strict low iron diet is usually not necessary. Non-heme iron is not as easily absorbed in the human system and is found in plant-based foods like grains, beans, vegetables, fruits, nuts, and seeds.
Medication: For those unable to tolerate routine blood draws, there are chelating agents available for use. The drug deferoxamine binds with iron in the bloodstream and enhances its elimination in 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.
In general, provided there has been no liver damage, patients should expect a normal life expectancy if adequately treated by venesection. If the serum ferritin is greater than 1000 ug/L at diagnosis there is a risk of liver damage and cirrhosis which may eventually shorten their life. The presence of cirrhosis increases the risk of hepatocellular carcinoma.
It is most common in certain European populations (such as the Irish and Norwegians) and occurs in 0.6% of the population. Men with the disease are 24 times more likely to experience symptoms than affected women.
Two factors are thought to have had large influence on the mutation of genes related to iron overload during the Stone Age: diet and the environment. Starting during the Mesolithic Era, communities of people lived in an environment that was fairly sunny, warm and had the dry climates of the Middle East. Most of the humans who lived at the time were foragers and their diets consisted mostly of hunting game, gathering and even fishing when and if the opportunity arose.
With the archaeologists studying dental plaque and the assumptions of what would have been available to the people due to their environment, leads to the theories of Mesolithic foragers eating substances such as tubers, nuts, plantains, grass and much of the food would have been was very rich in iron. Over hundreds of years and many generations, the body was very well adapted to the high level of iron content in the consumption.
Moving forward in time and studying the Neolithic Era, which was during the end of the Stone Age, we see significant changes in both the environment and diet of the traveling people. During the European Neolithic era, some communities of foragers migrated north. The change in lifestyle and environment, with a decrease in temperatures and a change in the landscape in which the foragers then needed to adapt to. As the people began to develop and advance their use of tools and learn new ways of producing food, hunting and gathering was no longer the main food source, and farming also slowly developed. The change that the travelers encountered would have led to serious stress on the body and a decrease in iron rich consumption. This transition is a key factor in which researchers can start to see the link between the travelers diets, environment and the mutations of genes, especially those that regulated the iron absorption within the body. Iron, which makes of 70% of our red blood cell composition, is a critical micronutrient for effective thermoregulation in the body.
When the body encounters a deficiency of its micronutrients, in this case iron, it will lead to a drop in the core temperature. When the travelers encountered the much more chilly and damp environments of Europe, the supplementary iron from food was a necessity to help keep their temperatures regulated–however, without the iron supplements from the food the human body would have undergone serious stress to make up for the lost iron and would have started to store iron at higher rates than normal. This theory hypothesizes that the pressures caused by the migration would be the initiation to the gene mutation that allowed the body to absorb and store higher amounts of iron.
Many studies and surveys are being conducted in order to determine the frequencies of the disease in countries and also to understand how the mutation migrated around the globe. The theory that this disease initially evolved from travelers migrating north helped to give an understanding of how it may have initially evolved. Through the surveys and counting of affected, there was a very particular distribution pattern of the disease in which there are large clusters and frequencies of the gene mutations found along the coastline of Europe. This is the pattern that has been noticed is what helped lead to the development of the “Viking Hypothesis”. The locations of clusters and mapped patterns of this mutation have a very close correlation to the migration of Vikings and locations of Viking settlements in Europe that occurred around the time of c.700 AD to c.1100 AD. The Vikings originally came from the three countries of Scandinavia (Norway, Sweden and Denmark) and when on land, they had multiple Kingdoms and their way of life mostly evolved around farming and trade. When the Northmen took to the sea they were given the name ‘Vikings’ which was developed from the Old Norse language and meant ‘pirates’. The Viking ships made their way along the coastline of Europe in search for trade, riches, land and the migration of their people. The genetic studies to date along with the extremely high frequency patterns in some European countries lead to the suggestion that the mutation could have been easily spread by Vikings and later by the Normans, indicating a genetic link between hereditary hemochromatosis and Viking ancestry.
In 1865, Armand Trousseau (a French internist) was one of the first to describe many of the symptoms of a diabetic patient with cirrhosis of the liver and had bronzed skin color. The term hemochromatosis was first used by German pathologist named Friedrich Daniel von Recklinghausen in 1890 when he introduced an accumulation of iron in body tissue. In 1935 J.H. Sheldon, a British physician, described the pathophysiology mechanism linked to iron metabolism for the first time.
In 1996 Felder and colleagues identified the hemochromatosis gene, HFE gene. Felder found that the HFE gene has two main mutations, C282Y and H63D, which were the main cause of hereditary hemochromatosis. The next year the CDC and the National Human Genome Research Institute sponsored an examination of hemochromatosis following the discovery of the HFE gene which helped lead to the population screenings and estimates that are still being used today.
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