Iron overload

From Wikipedia, the free encyclopedia
Iron overload
Other namesHaemochromatosis or Hemochromatosis
Hemosiderosis high mag.jpg
Micrograph of liver biopsy showing iron deposits due to haemosiderosis. Iron stain.

Iron overload or hemochromatosis (also spelled haemochromatosis in British English) indicates increased total accumulation of iron in the body from any cause and resulting organ damage.[1] The most important causes are hereditary haemochromatosis (HH or HHC), a genetic disorder, and transfusional iron overload, which can result from repeated blood transfusions.[2]

Signs and symptoms[edit]

Organs most commonly affected by hemochromatosis include the liver, heart, and endocrine glands.[3]

Hemochromatosis may present with the following clinical syndromes:

The skin's deep tan color, in concert with insulin insufficiency due to pancreatic damage, is the source of a nickname for this condition: "bronze diabetes" (for more information, see the history of hemochromatosis).[citation needed]


The term hemochromatosis was initially used to refer to what is now more specifically called hemochromatosis type 1 (or HFE-related hereditary hemochromatosis). Currently, hemochromatosis (without further specification) is mostly defined as iron overload with a hereditary or primary cause,[8][9] or originating from a metabolic disorder.[10] 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 hemochromatosis. Hereditary hemochromatosis 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.[11] The gene responsible for hereditary hemochromatosis (known as HFE gene) is located on chromosome 6; the majority of hereditary hemochromatosis patients have mutations in this HFE gene.[1]

Hereditary hemochromatosis is characterized by an accelerated rate of intestinal iron absorption and progressive iron deposition in various tissues. This 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.[12][13]

In general, the term hemosiderosis is used to indicate the pathological effect of iron accumulation in any given organ, which mainly occurs in the form of the iron-storage complex hemosiderin.[14][15] Sometimes, the simpler term siderosis is used instead.

Other definitions distinguishing hemochromatosis or hemosiderosis that are occasionally used include:

  • Hemosiderosis is hemochromatosis caused by excessive blood transfusions, that is, hemosiderosis is a form of secondary hemochromatosis.[16][17]
  • Hemosiderosis is hemosiderin deposition within cells, while hemochromatosis is hemosiderin within cells and interstitium.[18]
  • Hemosiderosis is iron overload that does not cause tissue damage,[19] while hemochromatosis does.[20]
  • Hemosiderosis is arbitrarily differentiated from hemochromatosis by the reversible nature of the iron accumulation in the reticuloendothelial system.[21]

The causes of hemochromatosis broken down into two subcategories: primary cases (hereditary or genetically determined) and less frequent secondary cases (acquired during life).[22] People of Celtic (Irish, Scottish, Welsh, Cornish, Breton etc.), English, and Scandinavian origin[23] 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.[24] This has been recognized in several layman's alternative names such as Celtic curse, Irish illness, British gene, and Scottish sickness.

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 hemochromatosis",[25] "non-HFE related hereditary hemochromatosis",[26] or "non-HFE hemochromatosis".[27]

Description OMIM Mutation
Hemochromatosis type 1: "classical" hemochromatosis 235200 HFE
Hemochromatosis type 2A: juvenile hemochromatosis 602390 Haemojuvelin (HJV, also known as RGMc and HFE2)
Hemochromatosis type 2B: juvenile hemochromatosis 606464 hepcidin antimicrobial peptide (HAMP) or HFE2B
Hemochromatosis type 3 604250 transferrin receptor-2 (TFR2 or HFE3)
Hemochromatosis type 4 / African iron overload 604653 ferroportin (SLC11A3/SLC40A1)
Neonatal hemochromatosis 231100 (unknown)
Acaeruloplasminaemia (very rare) 604290 caeruloplasmin
Congenital atransferrinaemia (very rare) 209300 transferrin
GRACILE syndrome (very rare) 603358 BCS1L

Most types of hereditary hemochromatosis have autosomal recessive inheritance, while type 4 has autosomal dominant inheritance.[28]

Secondary hemochromatosis[edit]


Defects in iron metabolism, specifically involving the iron regulatory protein hepcidin are thought to play an integral role in the pathogenesis of hereditary hemochromatosis.[29] Normally, hepcidin acts to reduce iron levels in the body by inhibiting intestinal iron absorption and inhibiting iron mobilization from stores in the bone marrow and liver.[29] Iron is absorbed from the intestines (mostly in the duodenum) and transported across intestinal enterocytes or mobilized out of storage in liver hepatocytes or from macrophages in the bone marrow by the transmembrane ferroportin transporter.[29] In response to elevated plasma iron levels, hepcidin inhibits the ferroportin transporter leading to decreased iron mobilization from stores and decreased intestinal iron absorption, thus functioning as a negative iron regulatory protein.[29] In hereditary hemochromatosis, mutations in the proteins involved in hepcidin production including HFE (hemostatic iron regulator), hemojuvelin and transferrin receptor 2 lead to a loss or decrease in hepcidin production, which subsequently leads to the loss of the inhibitory signal regulating iron absorption and mobilization, which thus leads to iron overload.[29] In very rare instances, mutations in ferroportin result in ferroportin resistance to hepcidin's negative regulatory effects, and continued intestinal iron absorption and mobilization despite inhibitory signaling from hepcidin.[29] Approximately 95% of cases of hereditary hemochromatosis are due to mutations in the HFE gene.[29]

The resulting iron overload causes iron to deposit in various sites throughout the body, especially the liver and joints, which coupled with oxidative stress leads to organ damage or joint damage and the pathological findings seen in hemochromatosis.[29]


Selective iron deposition (blue) in pancreatic islet beta cells (red)

There are several methods available for diagnosing and monitoring iron loading.

Blood test[edit]

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 variety of other medical conditions including infection, inflammation, fever, liver disease, kidney disease, and cancer. Also, total iron binding capacity may be low, but can also be normal.[30] In males and postmenopausal females, normal range of serum ferritin is between 12 and 300 ng/mL (670 pmol/L) .[31][32][33] In premenopausal females, normal range of serum ferritin is between 12 and 150[31] or 200[32] ng/mL (330 or 440 pmol/L).[33] If the person is showing the symptoms, they may need to be tested more than once throughout their lives as a precaution, most commonly in women after menopause.[citation needed] Transferrin saturation is a more specific test.[citation needed]


DNA/screening: the current standard of practice in diagnosis of hemochromatosis, places emphasis on genetic testing.[12] Positive HFE analysis confirms the clinical diagnosis of hemochromatosis in asymptomatic individuals with blood tests showing increased iron stores, or for predictive testing of individuals with a family history of hemochromatosis. The alleles evaluated by HFE gene analysis are evident in ~80% of patients with hemochromatosis; a negative report for HFE gene does not rule out hemochromatosis. First degree relatives of those with primary hemochromatosis 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.[34]


Histopathology of the liver, showing Kupffer cells with significant hemosiderin deposition (shown next to a hepatocyte with lipofuscin pigment, which is a common normal finding). H&E stain.
Prussian blue iron staining, highlighting the hemosiderin pigment as blue. This finding indicates mesenchymal iron overload (within Kupffer cells and/or portal macrophages) rather than parenchymal iron overload (within hepatocytes).[35]

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 hemochromatosis 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 hemochromatosis.[citation needed]

Magnetic resonance imaging (MRI) is used as a noninvasive method to estimate iron deposition levels in the liver and heart, which may aid in determining a response to treatment or prognosis.[29]



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.[36] The blood drawn is sometimes donated.[37]


A diet low in iron is generally recommended, but has little effect compared to venesection when ferritin levels are exceptionally high. Raw fish and shellfish should be avoided because of increased risk of infections from iron loving pathogens. Alcohol should be limited due to increased iron absorption and compounded liver damage. 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 foods 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. Supplements, cereals, and other fortified foods can also be surprisingly high sources of iron. Numerous popular cereals for example contain about twice the RDA of iron for an adult man (8mg a day) in one serving, and easily surpass the upper tolerable intake (45mg a day) with multiple servings. The RDA for menstruating women is 18mg. A low iron diet can signifcantly reduce need of venesection and in some instances eliminate it altogether. Non-heme iron is not as easily absorbed in the human system and is found in plant-based foods such as grains, beans, vegetables, fruits, nuts, and seeds. Additionally drinking tea with meals has been shown to reduce non-heme iron absorption by up to 70%, and conversely vitamin C and other acids can increase iron absorption. Consequently a mainly non-heme iron diet paired with tea drinking can reduce iron loading significantly. [38] [39] [40] [41] [42] [43] [44]


Medication: For those unable to tolerate routine blood draws, there are chelating agents available for use.[45] 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.[citation needed] 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.[46][47]

Chelating polymers[edit]

A minimally invasive approach to hereditary hemochromatosis treatment is the maintenance therapy with polymeric chelators.[48][49][50] These polymers or particles have a negligible or null systemic biological availability and they are designed to form stable complexes with Fe2+ and Fe3+ in the GIT and thus limiting their uptake and long-term accumulation. Although this method has only a limited efficacy, unlike small-molecular chelators, the approach has virtually no side effects in sub-chronic studies.[50] Interestingly, the simultaneous chelation of Fe2+ and Fe3+ increases the treatment efficacy.[50]


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.[51] The presence of cirrhosis increases the risk of hepatocellular carcinoma.[52] Other risk factors for liver damage in hemochromatosis include alcohol use, diabetes, liver iron levels greater than 2000 μmol/gram and increased aspartate transaminase levels.[29]

The risk of death and liver fibrosis are elevated in males with HFE type hemochromatosis but not in females; this is thought to be due to a protective effect of menstruation and pregnancy seen in females as well as possible hormone related differences in iron absorption.[29]


HHC is most common in certain European populations (such as those of Irish or Scandinavian descent) and occurs in 0.6% of some unspecified population.[34] Men have a 24-fold increased rate of iron-overload disease compared with women.[34]

Stone Age[edit]

Diet and the environment are thought to have had large influence on the mutation of genes related to iron overload. 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 humans who lived at that time were foragers and their diets consisted largely of wild plants, fish, and game. Archaeologists studying dental plaque have found evidence of tubers, nuts, plantains, grasses and other foods rich in iron. Over many generations, the human body became well-adapted to a high level of iron content in the diet.[53]


In the Neolithic era, significant changes are thought to have occurred in both the environment and diet. Some communities of foragers migrated north, leading to changes in lifestyle and environment, with a decrease in temperatures and a change in the landscape which the foragers then needed to adapt to. As people began to develop and advance their tools, they learned new ways of producing food, and farming also slowly developed. These changes would have led to serious stress on the body and a decrease in the consumption of iron-rich foods. This transition is a key factor in the mutation of genes, especially those that regulated dietary iron absorption. Iron, which makes up 70% of red blood cell composition, is a critical micronutrient for effective thermoregulation in the body.[54] Iron deficiency will lead to a drop in the core temperature. In the chilly and damp environments of Northern Europe, supplementary iron from food was necessary to keep temperatures regulated, however, without sufficient iron intake the human body would have started to store iron at higher rates than normal. In theory, the pressures caused by migrating north would have selected for a gene mutation that promoted greater absorption and storage of iron.[55]

Viking hypothesis[edit]

Studies and surveys conducted to determine the frequencies of hemochromatosis help explain how the mutation migrated around the globe. In theory, the disease initially evolved from travelers migrating from the north. Surveys show a particular distribution pattern with large clusters and frequencies of gene mutations along the western European coastline.[56] This led the development of the "Viking Hypothesis".[57] Cluster locations and mapped patterns of this mutation correlate closely to the locations of Viking settlements in Europe established c.700 AD to c.1100 AD. The Vikings originally came from Norway, Sweden and Denmark. Viking ships made their way along the coastline of Europe in search of trade, riches, and land. Genetic studies suggest that the extremely high frequency patterns in some European countries are the result of migrations of Vikings and later Normans, indicating a genetic link between hereditary hemochromatosis and Viking ancestry.[58]

Modern times[edit]

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 bronzed skin color. The term hemochromatosis was first used by German pathologist Friedrich Daniel von Recklinghausen in 1889 when he described an accumulation of iron in body tissues.[59]

Identification of genetic factors[edit]

Although it was known most of the 20th century that most cases of hemochromatosis were inherited, they were incorrectly assumed to depend on a single gene.[60]

In 1935 J.H. Sheldon, a British physician, described the link to iron metabolism for the first time as well as demonstrating its hereditary nature.[59]

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.[59][61] 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.[62]

See also[edit]


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