Hereditary haemochromatosis (or hemochromatosis) is a genetic disorder characterized by excessive intestinal absorption of dietary iron, resulting in a pathological increase in total body iron stores. Humans, like most animals, have no means to excrete excess iron. Excess iron accumulates in tissues and organs, disrupting their normal function. The most susceptible organs include the liver, adrenal glands, heart, skin, gonads, joints, and the pancreas; patients can present with cirrhosis, polyarthropathy, adrenal insufficiency, heart failure, or diabetes. The hereditary form of the disease is most common among those of Northern European ancestry, in particular those of Celtic descent. The disease is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but do not show signs and symptoms of the condition.
Haemochromatosis is protean in its manifestations, i.e., often presenting with signs or symptoms suggestive of other diagnoses that affect specific organ systems. Many of the signs and symptoms below are uncommon, and most patients with the hereditary form of haemochromatosis do not show any overt signs of disease nor do they suffer premature morbidity, if they are diagnosed early, but more often than not, diagnosis occurs in the autopsy 
Presently, the classic triad of cirrhosis, bronze skin, and diabetes is less common because of earlier diagnosis.
Less common findings including:
Males are usually diagnosed after their forties and fifties, and women several decades later, owing to the fact that symptoms mimic those of menopause. Most people display symptoms in their 30s but due to the lack of knowledge surrounding haemochromatosis, they are diagnosed years later. The severity of clinical disease in the hereditary form varies considerably. Some evidence suggests that hereditary haemochromatosis patients affected with other liver ailments such as hepatitis or alcoholic liver disease suffer worse liver disease than those with either condition alone. Also, juvenile forms of hereditary haemochromatosis present in childhood with the same consequences of iron overload.
Iron is stored in the liver, pancreas, and heart. Long-term effects of haemochromatosis on these organs can be very serious, even fatal when untreated. For example, similar to alcoholism, haemochromatosis can cause cirrhosis of the liver. The liver is a primary storage area for iron and naturally accumulates 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 (esophageal varices) and stomach (gastric 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).
Cirrhosis and haemochromatosis together can increase the risk of liver cancer. (Nearly one-third of people with haemochromatosis and cirrhosis eventually develop liver cancer.)
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.
If excess iron in the heart interferes with its ability to circulate enough blood, a number of problems can occur, such as congestive heart failure and death. The condition may be reversible when haemochromatosis is treated and excess iron stores are reduced.
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.
Bronze or grey coloration of the skin pigmentation is caused primarily by increased melanin deposition, with iron deposition playing a lesser role.
The regulation of dietary iron absorption is complex and understanding is incomplete. One of the better-characterized genes responsible for hereditary haemochromatosis is HFE on chromosome 6, which codes for a protein that participates in the regulation of iron absorption. The HFE gene has three common mutations, C282Y, H63D and S65C. The C282Y allele is a transition point mutation from guanine to adenine at nucleotide 845 in HFE, resulting in a missense mutation that replaces the cysteine residue at position 282 with a tyrosine amino acid. Heterozygotes for either allele can manifest clinical iron overload, if they have two of any alleles. This makes them compound heterozygous for haemochromatosis and puts them greatly at risk of storing excess iron in the body.
Mutations of the HFE gene account for 90% of the cases of nontransfusional iron overload. This gene is closely linked to the HLA-A3 locus. Homozygosity for the C282Y mutation is the most common genotype responsible for clinical iron accumulation, though heterozygosity for C282Y/H63D mutations, so-called compound heterozygotes, results in clinically evident iron overload. Considerable debate exists regarding the penetrance—the probability of clinical expression of the trait given the genotype— for clinical disease in homozygotes. Most, if not all, males homozygous for HFE C282Y show manifestations of liver dysfunction such as elevated liver-specific enzymes such as serum gamma glutamyltransferase by late middle age.
Each patient with the susceptible genotype accumulates iron at different rates depending on iron intake, the exact nature of the mutation, and the presence of other insults to the liver, such as alcohol and viral disease. 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. Penetrance differs between populations.
Individuals with the relevant mutations may never develop iron overload. Phenotypic expression is present in 70% of C282Y homozygotes with less than 10% going on to experience severe iron overload and organ damage.
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. Normally, HFE facilitates the binding of transferrin, which is iron's carrier protein in the blood. Transferrin levels are typically elevated at times of iron depletion (low ferritin stimulates the release of transferrin from the liver). When transferrin is high, HFE works to increase the intestinal release of iron into the blood. When HFE is mutated, the intestines perpetually interpret a strong transferrin signal as if the body were deficient in iron. This leads to maximal iron absorption from ingested foods and iron overload in the tissues. However, HFE is only part of the story, since many patients with mutated HFE do not manifest clinical iron overload, and some patients with iron overload have a normal HFE genotype. A possible explanation is the fact that HFE' normally plays a role in the production of hepcidin in the liver, a function that is impaired in HFE mutations.
People with abnormal iron regulatory genes do not 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 is deposited in organs as haemosiderin and this is toxic to tissue, probably at least partially by inducing oxidative stress. Iron is a pro-oxidant. Thus, haemochromatosis shares common symptomology (e.g., cirrhosis and dyskinetic symptoms) with other "pro-oxidant" diseases such as Wilson's disease, chronic manganese poisoning, and hyperuricaemic syndrome in Dalmatian dogs. The latter also experience "bronzing".
The diagnosis of haemochromatosis is often made following the incidental finding on routine blood screening of elevated serum liver enzymes or elevation of the transferrin saturation. Arthropathy with stiff joints, diabetes, or fatigue, may be the presenting complaint.
Serum transferrin and transferrin saturation are commonly used as screening for haemochromatosis. Transferrin binds iron and is responsible for iron transport in the blood. Measuring transferrin provides a crude measure of iron stores in the body. Fasting transferrin saturation values in excess of 45% for males or 35% in premenopausal women (i.e. 300 ng/l in males and 200 ng/l in females) are recognized as a threshold for further evaluation of haemochromatosis. Transferrin saturation greater than 62% is suggestive of homozygosity for mutations in the HFE gene.
Ferritin, a protein synthesized by the liver, is the primary form of iron storage within cells and tissues. Measuring ferritin provides another crude estimate of whole-body iron stores, though many conditions, particularly inflammation (but also chronic alcohol consumption, nonalcoholic fatty liver disease, and others), can elevate serum ferritin, which can account for up to 90% of cases where elevated levels are observed. Normal values for males are 12–300 ng/ml and for female, 12–150 ng/ml. Serum ferritin in excess of 1000 ng/ml of blood is almost always attributable to haemochromatosis.
Other blood tests routinely performed include blood count, renal function, liver enzymes, electrolytes, and glucose (and/or an oral glucose tolerance test).
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, 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. Risks of biopsy include bruising, bleeding, and infection. 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.
MRI-based testing is a noninvasive and accurate alternative to measure liver iron concentrations.
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 in MRI scans. 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 haemochromatosis.
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 haemochromatosis diabetes.
The American Association for the Study of Liver Diseases suggests the following three stages for the condition (identified by the European Association for the Study of Liver Diseases):
Individuals at each stage do not necessarily progress on to the next stage, and end stage disease is more common in males.
Other causes of excess iron accumulation exist, which have to be considered before haemochromatosis is diagnosed.
Standard diagnostic measures for haemochromatosis, transferrin saturation and ferritin tests, are not a part of routine medical testing. Screening for haemochromatosis is recommended if the patient has a parent, child, or sibling with the disease.
Routine screening of the general population for hereditary haemochromatosis is generally not done. Mass genetic screening has been evaluated by the U.S. Preventive Services Task Force, among other groups, which recommended against genetic screening of the general population for hereditary haemochromatosis because the likelihood of discovering an undiagnosed patient with clinically relevant iron overload is less than one in 1,000. Although strong evidence shows that treatment of iron overload can save lives in patients with transfusional iron overload, no clinical study has shown that for asymptomatic carriers of hereditary haemochromatosis treatment with venesection (phlebotomy) provides any clinical benefit. Recently, patients are suggested to be screened for iron overload using serum ferritin as a marker. If serum ferritin exceeds 1000 ng/ml, iron overload is very likely the cause.
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. Initiation of treatment is recommended when ferritin levels reach 500 μg/l.
Phlebotomy (or bloodletting) is usually done at a weekly interval until ferritin levels are less than 50 μg/l. To prevent iron reaccumulation, subsequent phlebotomies are normally carried out about once every three to four months for males, and twice a year for females.
Where venesection is not possible, long-term administration of desferrioxamine mesylate is useful. Desferrioxamine is an iron-chelating compound, and excretion induced by desferrioxamine is enhanced by administration of vitamin C. It cannot be used during pregnancy or breast-feeding due to risk of defects in the child.
Persons with symptomatic haemochromatosis have somewhat reduced life expectancy compared to the general population, mainly due to excess mortality from cirrhosis and liver cancer. Patients who were treated with phlebotomy lived longer than those who were not. Patients without liver disease or diabetes had similar survival rate to the general population.
Haemochromatosis is one of the most common heritable genetic conditions in people of Northern European extraction, with a prevalence of one in 200. The disease has a variable penetration, and about one in 10 people of this demographic carry a mutation in one of the genes regulating iron metabolism, the most common allele being the C282Y allele in the HFE gene. The prevalence of mutations in iron-metabolism genes varies in different populations. A study of 3,011 unrelated white Australians found that 14% were heterozygous carriers of an HFE mutation, 0.5% were homozygous for an HFE mutation, and only 0.25% of the study population had clinically relevant iron overload. Most patients who are homozygous for HFE mutations do not manifest clinically relevant haemochromatosis (see Genetics above). Other populations have a lower prevalence of both the genetic mutation and the clinical disease.
Genetics studies suggest the original haemochromatosis mutation arose in a single person, possibly of Celtic ethnicity, who lived 60–70 generations ago. At that time, when dietary iron may have been scarcer than today, the presence of the mutant allele may have provided an evolutionary or natural selection reproductive advantage by maintaining higher iron levels in the blood.
The term "haemochromatosis" is used by different sources in many different ways.
It is often used to imply an association with the HFE gene. For many years, HFE was the only known gene associated with haemochromatosis, and the term "hereditary haemochromatosis" was used to describe haemochromatosis type 1. However, many different genetic associations with this condition are now known. The older the text, or the more general the audience, the more likely that HFE is implied.
"Haemochromatosis" has also been used in contexts where a genetic cause for iron accumulation had not been known. 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.
The disease was first described in 1865 by Armand Trousseau in a report on diabetes in patients presenting with a bronze pigmentation of their skin. Trousseau did not associate diabetes with iron accumulation; the recognition that infiltration of the pancreas with iron might disrupt endocrine function resulting in diabetes was made by Friedrich Daniel von Recklinghausen in 1890.