Haemochromatosis describes the state of iron overload. It can be divided into:

HH is one of the most common inherited diseases, with a predominance in Northern Europeans. 90% of HH is due to the C282Y mutation in HFE. The carrier rate of HFE mutation is up to 1 in 10, with 1 in 200 homozygous. However there is low clinical penetrance, especially in pre-menopausal women, due to iron loss with menstruation. For example, 6% of homozygous men will develop cirrhosis, but only 2% of women.


Iron metabolism and pathophysiology

The hormone responsible for control of iron metabolism is hepcidin, which acts to reduce serum iron levels. This is achieved by interaction with ferroportin, an iron transporter, which is present on the basolateral membrane of reticuloendothelial macrophages and enterocytes. Ferroportin permits release of iron from these cells into the blood stream.


The binding of hepcidin to ferroportin causes internalisation and degradation of the transporter. This causes iron to be sequestered in enterocytes, which are then shed during desquamation. HH occurs due to a relative reduction in the action of hepcidin, either due to reduced production or lack of response, analogous to the changes seen in insulin secretion or sensitivity in diabetes mellitus.


The HFE gene product is involved in sensing serum iron levels. It binds to the transferrin receptor to augment release of hepcidin in the presence of high iron levels. Therefore, malfunction of HFE results leads to reduced hepcidin in response to raised serum iron. Mutations in other receptors involved in sensing iron levels can result in more severe forms of haemochromatosis, for example juvenile haemochromatosis due to haemojuvelin mutation.


The natural history of HH involves a period of iron accumulation (0-20 years), followed by a phase of iron overload without tissue damage (20-40 years) and then organ dysfunction may occur after this.


Iron is deposited in the liver, heart, pancreas, joints, skin, pituitary, gonads and adrenals. The tissues most sensitive to damage are the heart, gonads and pituitary. Iron is toxic to hepatocytes and stimulates fibrosis, which can result in cirrhosis. Iron is also mutagenic and HH patients have a high rate of hepatocellular carcinoma.

Presentation and clinical features

Men present at 40-50 years of age, whereas women present roughly 10 years later. Common presentations:

–     Fatigue.

–     Arthralgia.

–     Abnormal liver function tests (LFT).

–     Early onset sexual dysfunction.

–     Type 2 diabetes mellitus in the presence of hepatomegaly or abnormal LFT.


Hepatic features:

–     Hepatomegaly.

–     Cirrhosis.

–     Hepatocellular carcinoma.


Other features:

–     Dilated cardiomyopathy.

–     Diabetes mellitus.

–     Hypogonadism (± testicular atrophy).

–     Panhypopituitarism.

–     Skin pigmentation.

–     Porphyria cutanea tarda.

–     Chondrocalcinosis.

–     Osteoarthritis (OA) – especially in 2nd & 3rd metacarpophalangeal (MCP) joints.


Summary of diagnosing haemochromatosis

Investigations and diagnosis

Transferrin saturation (TS) and serum ferritin are first line investigations.

–     TS >45% suggests iron overload.

–     Ferritin above the upper limit of normal suggests raised circulating iron.

–     However ferritin is an acute phase protein so consider results in the context of concurrent infection or inflammatory processes.


If TS and ferritin suggest iron overload then proceed to genotyping.

–     If the patient is C282Y+/+ then HFE-HH is diagnosed


If genotyping is inconclusive, then a liver biopsy is indicated.

–     Biopsy is the gold standard for diagnosis.

–     The sample is stained for haemosiderin and hepatic iron index is calculated to give a definitive diagnosis.

–     Liver biopsy is also appropriate to assess hepatic damage because if cirrhosis is present then a patient may be considered for liver transplantation.


Other investigations:

–     LFTs may be normal or slightly abnormal.

–     LH and FSH levels may be low.

–     Fasting glucose: for detection of co-existing diabetes.

–     Alpha-fetoprotein (AFP) and ultrasound scan: to assess for hepatocellular carcinoma.


Liver histology of haemochromatosis

A liver biopsy from a patient with haemochromatosis

The image shows part of a liver biopsy taken from a patient with haemochromatosis. The section has been prepared using Prussian blue, which stains haemosiderin deposits blue, seen as intracellular inclusions within many of the hepatocytes [long black and white arrow]. The image also features a portal tract, containing a bile duct [long black arrow], hepatic artery [short black arrow] and a portal vein [short black and white arrow]. The tract is mildly expanded with increased fibrous tissue and an inflammatory infiltrate [asterix] however there is no evidence of cirrhosis (bridging fibrosis or nodules).



Due to the additive effect on liver damage, all alcohol consumption should be stopped. Patients should also be advised to have low-iron diet.


Venesection forms the mainstay of treatment and can be enough to prevent ongoing iron accumulation. One unit (450ml) of blood each 1-3 wks until haemoglobin is at the lower limit of normal, then once each 3-6 months.


Desferrioxamine by intravenous infusion can be used if venesection is not tolerated. It is an iron chelator but less effective than venesection.


Hormone replacement is usually needed to manage the endocrine dysfunction.


Monitor for development of HCC with AFP and ultrasound scan every 3-6 months.


If patients progress to end-stage liver disease then they are candidates for liver transplant according to standard guidelines.


Screening of family members is imperative. Investigation should progress using the tests outlined above.

OSCE examination

OSCE examination findings of a patient with haemochromatosis:

–     ‘Slate-grey’ or unwell appearance. (Bronze skin pigmentation is rare.)

–     Hands: OA, Dupuytren’s contracture, clubbing.

–     Loss of axillary hair.

–     Chest: gynaecomastia, displaced apex beat, murmur of mitral regurgitation, spider naevi (rare).

–     Abdomen: hepatomegaly, splenomegaly.

–     OA of knees.



Image "Liver histology of haemochromatosis" adapted from from: User: Nephron (Own work) [CC-BY-SA-3.0 ( or GFDL (], via Wikimedia Commons. Available at:

Tavill A.S. Diagnosis and Management of Hemochromatosis. Hepatology (2001) 33;5:1321-1328

Pietrangelo A. Hemochromatosis – a new disease paradigm. (Lecture) American Association for the Study of Liver Diseases – The Liver Meeting 2009, State-of-the-Art lectures.

Kumar P., Clark M. Clinical Medicine 7th Edition (2009). Elsevier Saunders

Longmore M., Wilkinson I., et al. Oxford handbook of clinical medicine 8th Edition (2010). Oxford University Press

Bloom S., Webster G. Oxford handbook of gastroenterology and hepatology (2006). Oxford University Press



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