Hereditary haemochromatosis is caused by iron overload resulting from unregulated entry of iron into the circulation and its toxic accumulation in tissues including the heart, liver, pancreas, gonads, articular cartilage and skin. Iron stores are regulated by controlling its uptake; the body cannot eliminate iron except by blood loss. Iron enters the body via the small intestine, and its transport and storage is regulated by a circulating protein known as hepcidin. About 80% of cases of hereditary haemochromatosis are due to polymorphisms in the HFE gene, which codes for a protein involved in iron transport into cells. 1:200 - 300 people of Northern European descent are homozygous for the major HFE polymorphism. Iron accumulation is slow in the classic form of the disease, which presents between 30-50 years of age in men and later in women, probably because of menstrual blood loss. Iron deposition causes low grade inflammation and fibrosis, and its deposition causes cardiomyopathy, hepatic cirrhosis and/or arthritis together with diabetes and hypogonadism. Its accumulation in the skin causes a slate-grey or bronzed appearance, hence the term “bronzed diabetes”. Treatment is by repeated venesection.
Pigmentation of the liver and pancreas due to iron stainingThe first description of hereditary haemochromatosis was by Armand Trousseau, who described a patient with diabetes of bronzed appearance whose liver was also pigmented at autopsy. The term “haemochromatosis” was proposed by von Recklinghausen in 1889. The condition was recognised as an inborn error of iron metabolism in the 1930s, and was first treated by blood letting in the 1950s. In 1975 haemochromatosis was shown to be an autosomal recessive HLA-linked condition – the gene does not form part of the HLA system but is located on the same region of chromosome 6. The landmark discovery was identification of the HFE gene by Feder and colleagues in 1996, since when other genes involved in iron metabolism have been found in juvenile and intermediate forms of hereditary haemochromatosis.
As the name implies, hereditary haemochromatosis is the term used to describe inherited syndromes of iron overload. Iron overload may also occur as the result of repeated blood transfusions, or disorders of erythropoeisis in which red cell formation and breakdown are accelerated, as in thalassaemias, sideroblastic or sickle cell anaemia. Excessive iron intake may predispose, as may alcohol abuse, fatty liver, porphyria and haemodialysis. These acquired syndromes are sometimes referred to as secondary haemochromatosis or haemosiderosis, and differ from hereditary haemochromatosis in some of their consequences, although they also predispose to diabetes.
The prevalence of hereditary haemochromatosis reflects the frequency of the C282Y variant of HFE, which is found mainly in populations of Northern European descent but is less frequent elsewhere. Homozygosity of this variant is present in 1:200 to 1:300 in high-risk populations of Celtic or Northern European descent. The C282Y polymorphism in HFE is about 10 times as common as the most frequent mutation which causes cystic fibrosis, and appears to predispose to other forms of liver disease, which is 5-10 times as common in those with the polymorphism as compared with the general population. Penetrance is relatively low, and the gene is thus a marker of susceptibility rather than disease; it has been estimated that only 10-33% of carriers will develop haemochromatosis-associated morbidity. A second variant of HFE, _H63D _, is less common but may present in a similar way.
Penetrance of HFE mutations is much lower in women than in men, which is assumed to be due to the protective effect of menstrual blood loss. Conversely, penetrance is increased by alcohol consumption and possibly by other diseases or risk factors, as noted above.
Other genetic variants influencing iron storage account for around 20% of cases. All these result in unregulated iron absorption, with essentially similar pathological consequences. Juvenile hereditary haemochromatosis represents an accelerated version of the syndrome due to more rapid build up of iron stores.
The classic triad is hepatic cirrhosis, diabetes and skin pigmentation, now rarely seen owing to greater awareness of the condition and earlier diagnosis. A more typical presentation is with fatigue, malaise, arthralgia and hepatomegaly. Other features include cardiomyopathy (which may present with signs of right heart failure) diabetes, and hypogonadism.
The typical patient with HFE hemochromatosis is male, of European origin, aged 40-50 years, and presents with fatigue, skin pigmentation, arthralgia and/or hepatomegaly.
Physiology of iron absorption
We consume 15 to 20 mg of elemental iron daily, but only 1-2m are actually absorbed in the gut. In health, iron balance is maintained by control of absorption.
Iron is taken up by enterocytes and enters the circulation, where it binds to transferrin, a carrier protein which maintains it in a non-toxic state whilst in the circulation. The transferrin-iron complex binds to receptors on the surface of target cells such as liver or red blood cells and is transported into the cell. Here it enters enterosomes which retrieve the iron, whereas the transferrin molecule is recycled back into the circulation.
The regulation of iron transport and storage is incompletely understood. Transgenic mouse studies suggest that hepcidin regulates export of iron from the enterocyte into the circulation, and that it does so by binding to a transmembrane transporter protein known as FPN which is expressed in enterocytes, liver cells and reticuloendothelial macrophages.
When circulating hepcidin binds to FPN, the transporter is internalized, thus reducing movement of iron into the circulation. Hepcidin production appears to be regulated by signals from the bone marrow, and is reduced in response to iron deficiency or anaemia. This negative feedback loop provides an inbuilt brake which protects against iron overload. Hepcidin secretion also forms part of the innate immune response, probably because its action reduces the availability of iron needed by invading micro-organisms.
The HFE protein is a 348 residue type 1 transmembrane protein related to class 1 light chain beta2-microglobulin. This does not bind transferrin directly, but interacts with a transferrin receptor in the cell membrane. Hepcidin binds to this receptor complex, potentially reducing its affinity for iron-bearing transferrin and thus acting as a brake upon the entry of iron into the cell. This control is lost if the function of HFE is impaired. A number of other proteins are also involved in iron uptake and metabolism, and abnormalities in the genes coding for these proteins are responsible for the rarer forms of hereditary haemochromatosis.
Pathology of Haemochromatosis
Free iron is toxic to cells as it acts as a catalyst in the formation of free radicals from reactive oxygen species via the Fenton reaction. It is therefore stored in a non-toxic form by binding to ferritin, a protein involved in intracellular iron storage and iron transport.
Hereditary haemochromatosis is characterized by iron deposition in tissues leading to oxidative damage and fibrosis. In the liver, signs of iron deposition are maximal in the periportal areas and diminish towards the centrilobular regions. Cirrhosis develops but is rarely associated with portal hypertension or liver failure; the incidence of hepatocellular carcinoma is increased about two-fold.
Pancreatic fibrosis leads to loss of both endocrine and exocrine function, iron deposition in the articular cartilage leads to arthralgia and arthritis, and it deposition in the testis and ovaries leads to hypogonadism.
In the endocrine pancreas iron deposits are usually restricted to beta cells and are, in diabetic patients, associated with loss of granulation and a decreased beta cell mass.
A number of rare opportunistic infections are more likely to develop in individuals with iron overload.
Diagnosis of Hereditary Haemochromatosis
Circulating ferritin levels reflect total body iron stores. A normal ferritin level thus excludes the diagnosis of haemochromatosis. Ferritin is however an acute phase protein which rises in response to infection and inflammation, so a raised ferritin level does not in itself indicate an iron storage disorder.
Transferrin saturation (TS) is normally measured at the same time as ferritin. IF TS and ferritin are both elevated, people of European extraction should progress to HFE gene testing. Identification of C282Y homozygosity is considered to confirm the diagnosis. HFE mutations are much less common in people of non-European descent, and a liver biopsy may be required to confirm or exclude haemochromatosis1.
Treatment is by venesection. Although there are no evidence-based guidelines, weekly removal of one unit of blood is normally performed until serum ferritin has fallen to 20-50 µg/L, and TS has fallen below 30%. Once this has been achieved, which may take 1-2 years (each venesection removes 200-250 mg of iron), and 3-4 venesections per year thereafter are usually sufficient to maintain this level.
Generally resembles that of the background population when the condition is detected early. Established tissue damage resulting in cirrhosis, insulin dependent diabetes and joint damage is only partially reversible by iron depletion, but symptoms such as weakness and fatigue improve, as do liver function tests. Hepatocellular carcinoma is a potential late complication.
HFE haemochromatosis is transmitted as an autosomal recessive trait, and family members should therefore be tested. Other groups with a high prevalence of the polymorphism (liver disease, porphyria cutanea tarda) should also be tested. Routine testing for ferritin/TS has not been proposed in type 2 diabetes, but there should be a high threshold of suspicion, especially when liver function tests are abnormal.
Haemochromatosis and Diabetes
The prevalence of diabetes in hereditary haemochromatosis has been estimated at between 20-50%; the prevalence appears to be falling as genetic testing becomes more widely available and the diagnosis is increasingly made before substantial pancreatic damage has occurred.
Conversely, several studies have examined the prevalence of the HFE gene in people with diabetes, with inconsistent results. This may reflect the incomplete penetrance of the gene and the high frequency of diabetes in the populations tested. In consequence, routine genetic screening is not formally recommended in diabetes.
Although haemochromatosis is most commonly confused with type 2 diabetes, it may also masquerade as late onset type 1. A Danish study found 9 cases among 716 patients diagnosed with type 1 diabetes over the age of 30 (1.26%) vs 23 cases among 9146 population controls (0.25%)
The pathophysiology of diabetes in hereditary hemochromatosis is considered to originate in beta cell dysfunction and decreased insulin secretory capacity rather than increased insulin resistance, and patients tend to be insulin-dependent; insulin requirements often fall during venesection but the need for insulin persists.
Although haemochromatosis is often listed among the causes of chronic pancreatitis, there have been few studies of exocrine function in this condition, and malabsorption does not form part of the clinical spectrum.
Susceptibility to hereditary haemochromatosis is common in European populations, but the fully expressed clinical syndrome has become increasingly rare due to greater awareness and access to genetic testing. Diabetes tends to be irreversible, generally requires insulin, but is often relatively easy to control. Early diagnosis can prevent or limit end-organ damage, and clinicians should always be alert to this diagnosis in people with diabetes.
^ Pietrangelo A. Hereditary hemochromatosis: pathogenesis, diagnosis and treatment. Gastroenterology 2010;139:393-408
^ Feder JN et al. A novel MHC class 1-like gene is mutated in patients with hereditary hemochromatosis. Nat Genet 1996;13:399-408
^ Whitlock EP et al. Screening for hereditary hemochromatosis: a systematic review for the US Preventive Services Task Force. Ann Int Med 2006;145:209-223
^ Rahier J, Loozen S, Goebbels RM, Abraham M. The haemochromatotic human pancreas: a quantitative immunohistochemical and ultrastructural study. Diabetologia 30:5-12, 1987.
^ Utzschneider KM, Kowdley K. Hereditary hemochromatosis and diabetes mellitus: implications for clinical practice. Nature Rev Endocrinol 2010;6:26-33
^ Ellervik C et al. Prevalence of hereditary haemochromatosis in late-onset type 1 diabetes mellitus: a retrospective study. Lancet 2001;358:1405-9