Haemochromatosis can be primary (hereditary) or secondary (acquired) and classically presents in white, middle-aged males. Progressive iron deposition and organ damage leads to a clinical spectrum beginning with non-specific symptoms of fatigue, arthralgias, hypogonadism and skin bronzing. Development of further organ dysfunction can lead to complications such as cirrhosis and hepatocellular carcinoma, diabetes mellitus, cardiomyopathy and heart failure.
Classification is based on the mechanism of inheritance. All mechanisms interfere with the process of macrophage-liver communication, leading to decreased activity of hepcidin.
- Type 1: Hereditary (HFE genotype) haemochromatosis
- The cause over 90% of cases
- Autosomal-recessive mutation to HFE gene (chromosome 6)
- Only present in white populations
- Type 2: Juvenile haemochromatosis: Presents in early adulthood (second and third decades) versus classic middle-aged patients of hereditary haemochromatosis.
- Type 2A mutation of the haemojuvelin gene.
- Type 2B mutation of the hepcidin gene A
- Patients often have hypogonadism and cardiomyopathy.
- Type 3: Transferrin receptor 2 haemochromatosis
- Autosomal-recessive mutation in transferrin receptor 2 (chromosome 7)
- Condition mimics HFE haemochromatosis clinically
- Type 4: Ferroportin disease
- Type 4A: low transferrin saturation and macrophage iron deposits
- Type 4B: clinically similar to type 1 (HFE) haemochromatosis- high transferrin saturation and iron deposition in liver.
Other rare forms exist as a result of mutations in the ceruloplasmin gene, transferrin gene, or divalent metal transporter 1 gene.
- Frequent blood transfusions: each new transfusion introduces new iron which is recycled and stored
- Iron supplementation: over-supplementing, particularly with concurrent vitamin C.
- Diseases of erythropoiesis: ineffective erythropoiesis leads to iron accumulation
- The two main mutant alleles are C282Y and H63D.
- Approximately 85-90% of HFE patients are homozygous for the C282Y allele
HFE mutations exhibit low penetrance :
- Estimated 14% penetrance for homozygous males
- Penetrance is even lower for females, attributed to menstruation and genetic variation in HLA subtypes (HFE is a HLA protein)
In addition, the multifactorial nature of the disease complications (such as diabetes, cirrhosis and osteoporosis) may account for the fact that less than half of C282Y homozygotes develop significant clinical problems.
Primary haemochromatosis is due to mutations in the HFE gene, each of which alter the regulatory pathways involved in hepcidin , an acute phase reactant protein that regulates iron stores.
HFE mutation→decreased hepcidin activity→ increased duodenal/jejunal iron absorption and release of iron from bone marrow macrophages → iron deposition in cells → Fenton reaction* and hydroxyl free radicals → DNA, lipid and protein damage → organ dysfunction
- Iron freely undergoes oxidation in cells from Fe2+ to Fe3+ as part of the Fenton reaction
- In this process, hydroxyl free radicals are generated which then cause oxidative damage
- A major mechanism of cell injury is free radical-induced lipid peroxidation which triggers apoptosis
The classic 'bronze' pigmentation is from iron deposition in skin.
Patients can be asymptomatic with an incidental finding of deranged LFTs or raised serum ferritin/ transferrin saturation. Additionally, asymptomatic patients with an affected first-degree relative may present for investigations.
More commonly, patients may present to primary care with non-specific symptoms of lethargy, impotence and arthralgias.
- Joint symptoms are usually a non-inflammatory osteoarthritis presentation in the metacarpophalangeal and proximal interphalangeal joints, but may be present in larger joints such as the hip and shoulder.
The 'classic triad' of cirrhosis, diabetes mellitus and bronze pigmentation is rarely the initial presentation.
- Pigmentation will initially present as skin bronzing but if it has progressed then may be grey or brown.
- Pigmentation most commonly occurs on the face and neck, extensor surfaces of the forearms, dorsum of the hands, lower legs, genitals, and in old scars.
Risk factors for hereditary haemochromatosis
- Male: multifactorial but mainly due to the additional iron loss in menstruation
- Age: most common form of hereditary haemochromatosis rarely establishes before the fourth decade of life
- White ethnicity: approximately 0.4% of Caucasians carry a homozygous C282Y, and 6% heterozygous 
- Family history: the most common form of hereditary haemochromatosis is inherited in an autosomal recessive fashion
- Clinical features of haemochromatosis
- First degree relatives of hereditary haemochromatosis patients:
|Serum ferritin||Raised; >674 picomols/L in men; >449 picomols/L in women|
|Transferrin saturation||> 45%|
|Liver function tests||Raised AST and ALT, likely not more than 2x normal|
|Full blood count||Normal*|
Patients with clinical features, raised transferrin saturation and/or raised serum ferritin should then undergo molecular testing for HFE gene mutation . A C282Y mutation on the HFE gene (chromosome 6) is the most common cause of hereditary haemochromatosis.
Clinical evidence of liver involvement and/or serum ferritin >2247pmol/L must be referred to hepatology for liver biopsy to estimate hepatocyte iron content and assess extent of fibrosis or cirrhosis.
Depending on the presenting complaints, alternative tests include:
- Fasting blood sugar (may be raised in liver/pancreatic involvement)
- ECG (may show arrhythmia or decreased QRS amplitude)
- Echocardiogram (assess iron deposition in conduction pathway and cardiomyopathy)
- Testosterone, FSH, LH (may be low in gonadal/pituitary involvement)
*Note: An FBC should be normal but is useful to rule out alternative diagnoses that could account for non-specific symptoms such as fatigue and arthralgias. For example:
- Low haemoglobin concentration pointing to anaemia
- Raised white cell count and inflammatory markers in infectious/inflammatory conditions
- As an acute phase reactant protein, ferritin is also released in inflammation, infection, malignancy and liver injury
- Dysmetabolic hyperferritinaemia: Normal or low transferrin (<45%)
- Hereditary aceruloplasminaemia: Normal or low transferrin (<45%) with undetectable levels of serum ceruloplasmin. Usually associated with neurological symptoms (such as dementia and cerebellar ataxia).
Patient with deranged LFTs or features of liver disease:
- Hepatitis B : positive Hepatitis B serology and negative genetic testing to rule out a cause of primary haemochromatosis
- Hepatitis C : positive Hepatitis C serology and negative genetic testing to rule out a cause of primary haemochromatosis
- Non-alcoholic fatty liver disease : Features of metabolic syndrome, low/normal
All patients should receive advice on the following:
- Avoid iron and iron-containing supplements
- Avoid vitamin C supplements (which increases the bioavailability of iron for enteric absorption), except in iron chelation therapy where it may increase therapeutic value
- Limit or avoid alcohol
- Consider hepatitis A and B vaccinations if no previous encounter.
Specific management, as per the British Society for Haematology 2018 guidelines, is as follows:
|Stage 0||Normal transferrin saturation and ferritin with no clinical symptoms||Monitoring iron labs and symptoms every 3 years|
|Stage 1||Transferrin saturation > 45%, normal ferritin, no clinical symptoms||Monitoring iron labs and symptoms every 1 year|
|Stage 2, 3, 4||Transferrin saturation > 45%, raised ferritin and/or clinical symptoms||Phlebotomy|
Stage 0 and 1 can be managed in primary care and patients should receive counselling and support for their condition.
Phlebotomy , or venesection, is the process by which blood is removed from the patient to stimulate haematopoiesis, thereby utilising some of the excess iron for haem synthesis. It is performed in two stages:
- Induction: weekly phlebotomy sessions in the secondary care setting to reduce iron levels to <50% transferrin saturation. This should be under the guidance of haematology or hepatology depending on the extent of liver disease). Induction can take several months or even longer depending on the iron burden.
- Maintenance: infrequent (less than monthly) phlebotomy sessions to maintain normal iron levels (<50% transferrin saturation).
- It is encouraged for maintenance phlebotomy to occur at blood donation banks under the NHS Blood & Transplant service if patients are 'fit' and do not have liver disease.
Iron chelation therapy is indicated for stage 2, 3 or 4 patients for whom phlebotomy is contraindicated (such as anaemia, cardiac disease or venous access issues). Both oral agents (Deferasirox) and parenteral agents (Desferrioxamine) are available dependent on the patient's likelihood of compliance and response.
Patients with end-stage cirrhotic liver disease due to haemochromatosis are candidates for liver transplantation. It is important to note that transplant outcomes are worse compared to other causes of cirrhosis.
Direct organ damage complications include:
- Fibrosis or cirrhosis
- Hepatocellular carcinoma: cirrhosis patients have a 100 fold increased risk of developing liver cancer
- The risk is not significantly raised in these patients compared to population but this is due to the overwhelming obesity prevalence rather than iron overload itself not being a risk for progression of diabetes mellitus
- Arrhythmia due to iron deposition in conduction pathway
- Cardiomyopathy: either dilated or dilated-restrictive
- Chronic congestive heart failure
- Hypogonadotrophism can result from iron depositing in the pituitary direct damage to gonads
- Patients without clinical symptoms of organ damage (such as cirrhosis or diabetes mellitus) at the time of diagnosis often have unchanged life expectancy from healthy individuals
- However, large studies put the relative risk at over 2 and the mean survival at 21 years for patients who have cirrhosis at the time of diagnosis
- Cirrhosis at the time of diagnosis increases the risk of life-limiting complications such as hepatocellular carcinoma, diabetes mellitus and cardiac disease
- Liver disease is exacerbated by additional liver injury (for example from alcohol and hepatitis infection).
- Liver transplant is indicated for cirrhosis and cancer development but post-transplant prognosis (1- and 5-year survival) is significantly worse for haemochromatosis compared to other diseases that necessitate liver transplant