[4] Humans, like most animals, have no mechanism to regulate excess iron, simply losing a limited amount through various means like sweating or menstruating.

The unaffected carrier parents play an integral role in transmitting one copy of the mutated gene to their child, who ultimately develops the disease.

Still, in most cases, they remain asymptomatic throughout their lives unless other genetic or environmental factors contribute to excessive iron accumulation within their bodies.

[12] Haemochromatosis is protean in its manifestations, i.e., often presenting with signs or symptoms suggestive of other diagnoses that affect specific organ systems.

Also, juvenile form of primary haemochromatosis (Hemochromatosis type 2) present in childhood with the same consequences of iron overload.

Toxins may accumulate in the blood and eventually affect mental functioning due to increased risk of hepatic encephalopathy.

One of the better-characterized genes responsible for hereditary haemochromatosis is HFE[26] on chromosome 6, which codes for a transmembrane protein involved in the induction of hepcidin expression upon high iron load.

This makes them compound heterozygous for haemochromatosis and puts them greatly at risk of storing excess iron in the body.

[44] As about the people with one copy of the H63D alteration (heterozygous carriers), this genotype is very unlikely to cause a clinical presentation, there is no predictable risk of iron overload.

As such, the degree to which the liver and other organs are affected is highly variable and is dependent on these factors and co-morbidities, as well as age at which they are studied for manifestations of disease.

[citation needed] Since the regulation of iron metabolism is still poorly understood, a clear model of how haemochromatosis operates is still not available.

A working model describes the defect in the HFE gene, where a mutation puts the intestinal absorption of iron into overdrive.

As they increase, the iron which is initially stored as ferritin is deposited in organs as haemosiderin and this is toxic to tissue, probably at least partially by inducing oxidative stress.

Fasting transferrin saturation values in excess of 45%, and the serum ferritin more than 250 ug/L in males and 200 ug/L in females are recognized as a threshold for further evaluation of haemochromatosis.

Examples of causes for raised serum ferritin include but are not limited to: infection, chronic alcohol consumption (mainly >20g/day), liver disease, cancer, porphyria, Hemophagocytic lymphohistiocytosis, hyperthyroidism, obesity, metabolic syndrome, diabetes, several blood transfusions, too many iron supplements, aceruloplasminemia, atransferrinemia, hyperferritinemia cataract syndrome and others.

The amount of iron in the sample is then quantified and compared to normal, and evidence of liver damage, especially cirrhosis, is measured microscopically.

Formerly, this was the only way to confirm a diagnosis of haemochromatosis, but measures of transferrin and ferritin along with a history are considered adequate in determining the presence of the malady.

Now, when a history and measures of transferrin or ferritin point to haemochromatosis, whether a liver biopsy is still necessary to quantify the amount of accumulated iron is debatable.

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 in MRI scans.

Early diagnosis is vital, as the late effects of iron accumulation can be wholly prevented by periodic phlebotomies (by venesection) comparable in volume to blood donations.

For example, one serving of several popular cereals, such as Cheerios or Grape Nuts, has about two times the RDA of iron for a man or non menstruating woman.

[69][70][71] 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 the uptake of these ions and their long-term accumulation.

Although this method has only a limited efficacy, unlike small-molecular chelators, such an approach has virtually no side effects in sub-chronic studies.

[71] Persons with symptomatic haemochromatosis have somewhat reduced life expectancy compared to the general population, mainly due to excess mortality from cirrhosis and liver cancer.

[9] Genetics studies suggest the original haemochromatosis mutation arose in a single person, possibly of Celtic ethnicity, who lived 60–70 generations ago.

In some cases, however, a condition that was thought to be due to diet or environment was later linked to a genetic polymorphism, as in African iron overload.

[citation needed] In 1847, Virchow described a golden brown granular pigment that was soluble in sulfuric acid and produced red ash on ignition.

[85] During this period of time, other investigators reported additional evidence suggesting that a genetic factor could play a central role in the absorption of iron in people with haemochromatosis.

[83] Finally, in 1976, Marcel Simon and his collaborators confirmed that haemochromatosis is an autosomal recessive disorder that has a link to the human leukocyte antigen (HLA) region of the genome.

[32][83][84] Finally, several groups reported their findings in a series of patients with haemmochromatosis where they discovered the existence of the C282Y mutation in about 85-90% of the cases.