Hereditary haemochromatosis

Hereditary haemochromatosis is an autosomal recessive disorder that results in iron overload.

Hereditary haemochromatosis (HH) is one of the most common genetic disorders seen in Northern European populations. The disease is most commonly related to genetic variants (i.e. mutations) in the HFE gene that has an important role in iron regulation, although other genes have been identified.

The disease is characterised by a state of iron overload that most commonly affects the liver, heart, joints, pancreas, and pituitary gland. Classically, it was termed ‘bronzed diabetes’ due to the typical skin pigmentation and development of diabetes mellitus from iron overload. The main manifestation of untreated HH is liver cirrhosis.

Haemochromatosis broadly refers to an abnormal accumulation of iron that can lead to organ dysfunction.

Haemochromatosis is a state of iron overload that may be broadly divided into hereditary or acquired.

• Hereditary (primary): due to an underlying genetic variant (i.e. mutation) that lead to iron accumulation
• Acquired (secondary): a state of chronic iron overload often due to frequent red blood cells transfusions (e.g. in patients with thalassaemia or sickle cell disease) or from excessive intake of dietary iron.

Hereditary haemochromatosis is common amongst Northern Europeans.

Across Europe, the prevalence of having at least one copy (i.e. heterozygous) of the most common variant within the HFE gene (known as C282Y) is 6.2% (EASL), but this varies greatly depending on the population. The condition is rare in East Asia.

The presence of two abnormal copies of the HFE gene (i.e. homozygous) is thought to affect 1 in 150 to 1 in 300 people in certain white populations. However, the condition is a low penetrance disorder so not all patients who have abnormal copies of the gene will develop the clinical disease haemochromatosis (see aetiology for details on penetrance).

HH is an autosomal recessive disorder most commonly due to an underlying genetic variant in the HFE gene.

More than 90% of cases of HH are due to a genetic variant in the HFE gene. The remaining cases are related to a series of other genes involved in iron regulation, but these are rare. To represent these genetic differences, HH s broadly divided into:

• HFE-haemachromatosis
• Non-HFE-haemochromastosis

HFE-haemochromatosis

The HFE gene is involved in iron regulation, but the exact mechanism is incompletely understood. The HFE gene, located on chromosome 6, encodes a transmembrane glycoprotein that interacts with other receptors to regulate iron within the body. Variants in the HFE gene lead to excess iron absorption by enterocytes and ultimately iron overload.

There are two main variants of the HFE gene

• C282Y: the amino acid cysteine is converted to tyrosine at position 282 in the protein
• H63D: the amino acid aspartate is converted to histidine at position 63 in the protein

As hereditary haemochromatosis is an autosomal recessive condition, two abnormal copies of the gene are needed to develop the condition. There are some important terms to note:

• Heterozygous: single abnormal copy (e.g. C282Y/wildtype – normal)
• Homozygous: two abnormal copies (e.g. C282Y/C282Y)
• Compound heterozygous: two different, but abnormal copies (e.g. C282Y/H63D)

The most common inheritance pattern is two abnormal C282Y variants that occur in >80% of cases. A small proportion of cases are compound heterozygous, which means they have one abnormal C282Y variant and one abnormal H63D variant (or another abnormal recessive allele).

Rarer HFE mutations can occur.

Non-HFE haemochromatosis

Rare genetic variants in non-HFE genes can lead to hereditary haemochromatosis. These other genetic variants generally occur in genes also involved in iron metabolism. These very rare conditions tend to cause haemochromatosis at a younger age.

Other terms may be used such as ‘juvenile haemochromatosis’ or ‘types 2-4 HH’.

Penetrance

This is a very important concept to understand hereditary haemochromatosis, which is a low penetrance condition.

Penetrance essentially refers to the probability of a person with an abnormal gene that causes disease actually developing the condition. For example, a gene with 100% penetrance means every person with the abnormal gene copy will develop the disease. If a gene has a 10% penetrance, only 1 in 10 people with the abnormal copy will develop the disease.

Iron levels may be raised in 80% of males and 50% of females with HFE-haemochromatosis. However, the penetrance in patients with homozygous C282Y variants in the HFE gene may be as low as 1% in women and 28% in men. This means the vast majority of patients with the abnormal gene will not develop HH.

Patients with HH develop progressive organ dysfunction due to iron overload, most notably in the liver.

Iron is primarily absorbed from the upper gastrointestinal tract by a tightly regulated process. There is no regulatory pathway to excrete iron, but it may be lost through the desquamation of gastrointestinal cells, menstruation or blood loss. The latter is because blood is a major store of iron.

Disruption to the regulatory pathway involved in iron absorption is seen in hereditary haemochromatosis.

Iron metabolism

In total, the body contains approximately 4 g of iron. The majority (3 g) is stored within the haemoglobin of red blood cells.

Around 1 mg of iron is lost from the desquamation of gastrointestinal cells each day and 15-40 mg with each menstrual cycle. We require ~1-2 mg/day of dietary iron to maintain normal levels.

Iron is absorbed from the upper gastrointestinal tract and enters the body via the ferroportin receptor on the basolateral surface. It is then transferred within the body by carrier protein transferrin. Transferrin is able to transport iron from body stores to tissues by interacting with the transferrin receptor. Once in tissue, iron is stored as ferritin that is a readily available soluble iron store. A small amount of ferritin is found within the serum and can be measured. Many immune cells of the reticuloendothelial system can also store large sums of iron in the form of ferritin.

This process is regulated by the protein hepcidin. Hepcidin, made in the liver, inhibits the efflux of iron from enterocytes and the reticuloendothelial system by inducing degradation of ferroportin. The levels of hepcidin are regulated by the HFE protein that interacts with several other receptors (e.g. transferrin receptor) primarily on hepatocytes, intestinal cells and immune cells. Genetic variants in the HFE gene lead to reduced levels of hepcidin that enables the increased efflux of iron (up to 2-4 mg / day).

Iron overload state

In HH, variants in the HFE gene enable increased levels of iron to accumulate within the body. This leads to increased stores of iron, which raises the level of measured serum ferritin (a marker of total body stores). However, many conditions can cause an increase in serum ferritin, which is an acute phase reactant. This means levels go up as part of the inflammatory response.

Other features of iron overload in haemochromatosis include a rise in transferrin saturation. In health, the protein transferrin is estimated to be 30% saturated with iron. In HH, this increases and levels >50% in men and >40% in women are supportive of the condition.

The problem with excess iron within the body is that it leads to deposition in key organs and causes major dysfunction. However, this occurs over a long period of time so the disease does not become clinically apparent until later in adult life. The primary organs affected by iron overload include the liver, heart, pituitary gland, pancreas, and joints.

A variety of symptoms can occur in HH depending on the extent of organ dysfunction.

The clinical manifestations of HH are very broad and depend on the extent of iron deposition in different organs over time. The condition is classically termed ‘bronzed diabetes’ due to the presence of diabetes mellitus and skin hyperpigmentation due to deposition in the pancreas and skin, respectively.

Liver

Chronic iron deposition can lead to fibrosis and cirrhosis (fixed irreversible scarring). For more information on clinical features see our notes on Chronic liver disease.

Heart

Deposition of iron in the heart can lead to cardiomyopathy (i.e. heart muscle disease) that results in heart failure. In addition, patients are at risk of conduction defects. For more information on clinical features see our notes on Heart failure.

Pituitary gland

Accumulation of iron in the pituitary gland can lead to dysfunction and reduced release of key hormones such as sex hormones (FH/TSH) and thyroid-stimulating hormone (TSH). This can lead to features of hypogonadism and hypothyroidism.

• Secondary hypogonadism: in men, low testosterone can lead to impotence and reduced sexual libido. In women, reduced sexual hormones may lead to amenorrhoea.
• Secondary hypothyroidism: weakness, fatigue, cold intolerance, constipation, and weight gain amongst others.

Pancreas

Infiltration of iron in the pancreas causes toxicity to beta cells that can result in reduced insulin secretion and the development of type 2 diabetes mellitus. This may affect >50% of symptomatic patients with HH.

• Polyuria
• Polydipsia
• Weight loss

Joints

Iron deposition in joints can lead to chronic arthropathy, particularly in the small joints of the hand. The most commonly affected joints are the second and third metacarpophalangeal (MCP) joints. The findings are indistinguishable from pseudogout with the deposition of calcium pyrophosphate.

Skin

Deposition of iron and melanin in the skin causes hyperpigmentation and gives the skin a bronzed colour leading to the term ‘bronzed diabetes’ to describe the classic presentation of HH.

Genetic testing is needed to confirm the presence of abnormal variants in the HFE (or non-HFE) genes.

Due to the low penetrance of the condition, screening unselected populations for an abnormal HFE gene is not recommended. This is because even if the abnormal gene copies are identified, the majority of patients will not develop clinical haemochromatosis. Therefore, suspected cases are first investigated with iron studies before proceeding to genetic testing.

Suspected cases

Any patient with features suggestive of haemochromatosis (e.g. early onset arthropathy, liver disease) should undergo a series of basic investigations to screen for haemochromatosis.

• Full blood count
• Liver function tests
• Serum ferritin
• Serum iron
• Transferrin saturation

In addition, these tests should be offered to family members (i.e. first-degree relatives – parents, siblings, children) after a diagnosis of HH is made in a patient.

Iron studies

Serum ferritin, serum iron and transferrin saturation form a series of investigations that are collectively known as ‘iron studies’. Serum ferritin and transferrin saturation are essential to determine who is at risk of HH and should undergo genetic testing.

• Serum ferritin: raised in 80% of men and 50% of women with HH. May be raised for many other reasons as an acute phase reactant (i.e. goes up with inflammation).
• Transferrin saturation: the ratio of serum iron and total iron-binding capacity. Expressed as a percentage and will go up with excess iron as occurs in HH.

The likelihood of a patient being homozygous for the C282Y HFE variant can be estimated based on the serum ferritin and transferrin saturation and this should guide offering genetic testing.

• Men: a 19% likelihood if serum ferritin > 300 ug/L and transferrin saturation >50%
• Women: a 16% likelihood if serum ferritin > 200 ug/L and transferrin saturation >40%

Genetic testing

Patients with an unexplained raised serum ferritin and random transferrin saturation (>300 ug/L and >50% males; >200 ug/L and >40% females) should be offered genetic testing for HFE variants. This includes patients who are asymptomatic and have raised levels detected for another clinical reason, or during routine testing as part of family screening.

Patients are initially screened for common HFE variants (i.e. C282Y, H63D). If these variants are not detected and there is clear evidence of significant iron overload (e.g. iron loading on liver MRI), testing for rarer genetic variants should take place.

Organ dysfunction

Iron overload can lead to organ dysfunction as discussed in clinical features. Investigations should be directed towards the organ affected. For example, joint x-rays for arthropathy or HbA1c for suspected diabetes mellitus.

Liver disease is a major concern and patients should have liver function tests checked. Patients with abnormal liver function tests or serum ferritin >1000 ug/L should be referred to Hepatology for fibrosis assessment and further management of liver disease.

An MRI liver can be requested to assess the degree of iron loading in uncertain cases. A liver biopsy is an alternative.

The principal treatment of HH is venesection, which involves removal of blood to reduce serum ferritin levels.

Venesection is the process of removing blood from the body. It is commonly completed during blood donation. All fit patients with evidence of biochemical iron overload (i.e. raised levels of iron on blood tests) should be referred for venesection, if appropriate, with or without clinical features.

Venesection

The decision to proceed with venesection should take into account a patients’ age, co-morbidities, degree of iron overload, and presence of organ dysfunction.

Those fit to undergo venesection should have weekly removal of blood (~450-500 mL) with regular monitoring. This amount of blood equates to around 200-250 mg of iron. The rate of venesection should reduce if anaemia develops. Monitoring should include:

• Full blood count: weekly
• Serum ferritin: monthly
• Transferrin saturation: 1-3 monthly

Venesection continues until the serum ferritin is 20-30 ug/L and transferrin saturation <50%. After this period, the patient can enter a maintenance phase of treatment. The aim is to keep the serum ferritin <50 ug/L with less frequent venesection and this can continue, preferably, at blood donation centres (if eligible).

Iron-chelation

Alternative options for people who are unable to undergo venesection include iron chelation therapy. Chelators such as deferasirox bind to iron and form a stable complex that can be excreted in the kidneys.

Organ dysfunction

Patients who develop organ dysfunction secondary to iron overload require input from the relevant specialist team. The most important complication is cirrhosis and any patient with abnormal elevated LFTs or significantly elevated serum ferritin need assessment by a hepatologist. Patients with cirrhosis will need management of their condition that includes surveillance ultrasound every 6 months due to the increased risk of hepatocellular carcinoma.

For more information on the management of cirrhosis see our notes on Chronic liver disease.

The major complication of HH is liver cirrhosis, which is irreversible once established.

The aim of treatment is to reduce the state of iron overload before irreversible organ damage. Complications secondary to iron overload include:

• Cirrhosis
• Hypopituitarism
• Arthropathy
• Diabetes mellitus
• Heart failure