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Feature Article Gastroenterology
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Haemochromatosis – a clinician’s guide

James J. Chen, John K. Olynyk
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Haemochromatosis is common in Australia and causes significant morbidity and mortality. Advances in the past few decades include improved understanding of its pathogenesis and a test for the most common genetic cause. Timely assessment through family screening and evaluation of individuals with suggestive biochemical or clinical features will enable early diagnosis and treatment.

Key Points
    • Haemochromatosis is a common condition that presents in general practice, especially in patients of European descent.
    • Although several genetic mutations may cause haemochromatosis, homozygosity for the C282Y mutation in the HFE gene accounts for almost all clinically significant cases of hereditary haemochromatosis.
    • The most common clinical manifestations of haemochromatosis are liver disease and arthritis; rates of dementia and malignancy, including hepatocellular carcinoma, cholangiocarcinoma and colorectal and breast cancer, are also increased.
    • Identification of symptoms, family history and measurement of serum transferrin saturation and ferritin levels are the foundations of initial assessment for haemochromatosis.
    • The cornerstone of management is regular phlebotomy to reduce the serum ferritin level to 50 to 100 mcg/L.
    • Effective management is fundamental to normalising quality of life and survival, as well as regression of complications such as liver fibrosis.

Haemochromatosis describes a group of inherited disorders most often marked by reduced levels of the iron regulatory hormone hepcidin, which can result in iron overload. It is distinct from the secondary iron overload that occurs in conditions such as haemoglobinopathies (e.g. thalassaemia, sickle cell disease) and after repeated blood transfusions. Haemochromatosis is common in Australia. Significant advances over the past few decades include an understanding of the variable clinical expression of this condition and the crucial role of hepcidin, along with the ready availability of a genetic test for the principal cause, mutations in the HFE gene.

Nevertheless, haemochromatosis continues to be a significant cause of morbidity and premature death. Although the establishment of effective management can restore normal life expectancy, the nonspecific clinical and biochemical features of haemochromatosis are a challenge for diagnosis.

This article describes the most common form of haemochromatosis, HFE-related haemochromatosis (HH). It outlines a framework for GPs to identify and manage patients in their practice with this condition.


Genetic basis of HH

Although several genetic mutations can cause HH, at least 95% of cases are due to a homozygous mutation in the HFE gene, termed C282Y.1-4 This is a point substitution that results in the replacement of cysteine with tyrosine at position 282 of the resulting protein. This principal cause of HH is inherited in an autosomal recessive fashion. Other mutations in the HFE gene, including the point substitution H63D, are of little clinical consequence.

Epidemiology of HH

Haemochromatosis is marked by ethnic variability, with the highest rates of C282Y homozygosity affecting about one in every 150 to 220 individuals of European descent.2,4-7 Simple heterozygosity for C282Y or the more minor H63D variant in the HFE gene affects one in seven and one in three individuals, respectively, and does not cause any significant clinical disease. Likewise, heterozygosity for both the C282Y and H63D genotypes (‘compound heterozygosity’) represents an extremely low risk for clinical disease.2,4,8

According to the 2021 national census, 57% of the Australian population have European ancestry, suggesting that about 73,000 individuals in our community have HH.9

Pathogenesis of HH

Iron is an important element for physiological function. Iron is absorbed by the enterocytes of the small intestine, predominantly in the duodenum and first section of the jejunum. It is most readily bioavailable from heme-containing sources (e.g. red meat). It is exported from enterocytes into the blood via the iron-export protein ferroportin. About 80 to 85% of absorbed iron is transported by transferrin for either storage in the liver or bone marrow or incorporation into haemoglobin or other proteins.10

The liver is an important organ in iron metabolism; it is not only the principal site of iron storage but also the key organ regulating iron absorption through the synthesis of the regulatory hormone, hepcidin (Figure).11 Increasing iron stores normally result in increased synthesis of hepcidin, which acts as a negative regulator, decreasing both iron absorption from the gastrointestinal tract and release of iron into the circulation from bone marrow stores through inhibition of ferroportin. Conversely, reduced iron stores result in lower hepcidin production, leading to increased iron absorption from the gastrointestinal tract and increased iron release from the bone marrow, as exemplified by the physiological response to iron-deficiency anaemia.

In patients with HH, the homozygous C282Y mutation abolishes the production of HFE protein. This protein is a key component of the regulatory pathway of hepcidin production, and its absence results in inappropriately low serum hepcidin levels. This leads to inappropriate increases in iron absorption from the intestine and iron release from the bone marrow, and substantially elevated total body iron stores in up to 40% of affected individuals.12 Other factors that can alter hepcidin expression and iron availability include infection, inflammation and hypoxia.13

Iron overload leads to oxidative stress-related tissue injury. This is responsible for the manifestations of HH at the organ level, including in the liver, heart and possibly joints.2,14

Clinical manifestations of HH

A major challenge in the diagnosis of HH relates to the variability of its biochemical and clinical manifestations. Further, these manifestations may not be progressive, which makes diagnosis and management challenging.4-7 The variable biochemical and clinical penetrance is most likely due to multiple genetic and environmental modifiers.15 Men are at higher risk than women, probably because of the protective effects of menstruation and pregnancy in reducing iron overload in women.16


Symptoms of HH are nonspecific and often have equal prevalence in individuals with and without HH.6,7 The most common symptom is fatigue, which is observed mainly in men with serum ferritin levels raised over 1000 mcg/L.6 The most frequent clinical morbidities are liver disease (advanced liver fibrosis or cirrhosis and primary liver cancer) and arthritis.3,8,17-19

Liver disease

Advanced liver fibrosis, cirrhosis and primary liver cancer (hepatocellular carcinoma [HCC] and cholangiocarcinoma) are the most significant liver disorders associated with HH.11 Advanced liver fibrosis or cirrhosis are rare under the age of 45 years in the absence of other liver comorbidities; they occur in about 8% of women and 25% of men with HH.1,3,4,17,20,21 Risk factors for advanced fibrosis include excess alcohol consumption, diabetes mellitus, arthritis, serum ferritin levels greater than 1000 mcg/L, platelet levels less than 200 × 109 cells/L, elevated aspartate aminotransferase (AST) levels, a liver iron concentration greater than 200 mcmol/g and total mobilisable iron stores by therapeutic phlebotomy of greater than 9.6 g.21-26 The risk of liver fibrosis also correlates with the duration of haemochromatosis and extent of total body iron levels. HH presenting with cirrhosis is uncommon; however, HH should always be considered in individuals of European descent with a new diagnosis of cirrhosis.

The risk of primary liver cancer is substantially increased in men, but not women, with HH; men with HH have a 12-fold increased lifetime risk of primary liver cancer of 7.2% compared with 0.6% in those without HFE mutations.27 The risk of primary liver cancer is greatest in people with advanced hepatic fibrosis or cirrhosis.18,19,28 These individuals should be recommended to undergo routine cancer surveillance with six-monthly liver ultrasound examination. Surveillance is generally continued lifelong as the risk of HCC remains while cirrhosis persists.2,3,8,17

Regression of advanced liver fibrosis has been associated with a significant reduction in the long-term risk of HCC, although cirrhosis persists after treatment in most cases.28 When regression is proven, clinicians may consider cessation of surveillance for HCC.


Arthritis is common in people with HH, affecting at least 24% of individuals, and is a major cause of disability and reduced quality of life.29,30 HH-associated arthritis presents similarly to degenerative osteoarthritis, with noninflammatory arthritis manifestations. Indeed, degenerative arthritis findings such as Heberden’s and Bouchard’s nodes with prominent involvement of the interphalangeal, knee and great toe metatarsophalangeal joints have similar frequency in people with HH as in people without the disorder.30 A helpful differentiating factor is the location of arthropathy; HH-associated arthritis affects the second to fifth metacarpophalangeal joints or bilateral large joints (radiocarpal, elbow, hip, knee and ankle joints) eight times more often than other types of arthritis.30

There is significant heterogeneity in the clinical manifestations of HH-associated arthritis; an unpredictable subset of patients are predisposed to arthritis, and it can occur at any point in the course of HH despite appropriate treatment.3,30 Risk factors for the development of arthritis include increasing age, advanced liver fibrosis, serum ferritin levels greater than 1000 mcg/L, and serum transferrin saturation greater than 50% for at least six years.31,32

Liver disease and arthritis tend to occur concomitantly, with arthritis more likely with a higher iron load or more advanced liver disease.33,34 A study found that 84% of participants with advanced liver fibrosis had arthritis, and 34% of those with HH and arthritis had advanced liver fibrosis, compared with 5% of those without arthritis. Thus, the absence of arthritis had a 95% negative predictive value for advanced liver fibrosis, making it a simple clinical tool for ascertaining the risk of significant liver disease.22


Other clinical manifestations of HH

Other conditions that have been reported predominantly in men with HH include dementia, osteoporosis, diabetes mellitus, hypogonadotrophic hypogonadism, pneumonia and cardiomyopathy.2,3,17,35,36 These conditions are usually managed as per the standard of care and in addition to the treatment of iron overload. There is also a twofold increased rate of colorectal cancer in both sexes and a twofold increased risk of breast cancer in women.35,37

Diagnostic approach

Screening for HH

General population screening for haemochromatosis has not been recommended because of variable and incomplete penetrance of the mutation and lack of proof of a resulting survival advantage.3,17,38,39 However, the recent report of significantly increased mortality in men who are homozygous for C282Y compared with those without HFE variants in the UK Biobank study supports re-examination of the utility of screening in susceptible male populations.27 Screening is indicated in first-degree relatives of probands, as discussed below.3,17

Recommended approach to clinical assessment

Common patient presentations to GPs requiring assessment for HH include:

  • asymptomatic patients with a family history of HH
  • asymptomatic patients with abnormal iron test results (elevated serum transferrin saturation, ferritin or aminotransferase levels)
  • patients with symptoms of HH.2,3,17

Algorithms for the assessment and diagnosis of these three groups are outlined in Flowchart 1, Flowchart 2 and Flowchart 3. The general principles of assessment for HH are:

  • assess for a genetic mutation likely to result in clinically significant iron overload
  • stratify the risk of end-organ pathology, particularly advanced liver disease and arthritis.

Asymptomatic patients with a family history of HH

For individuals under the age of 18 years with a family history of HH, the optimal approach is to determine the genotype of both parents as disease onset is extremely rare before 18 years (Flowchart 1).3,17,40 If one of the parents does not have the C282Y mutation then there is no risk of C282Y homozygosity in the offspring.3,40,41 If the H63D mutation is found in one parent (without C282Y), there is no strong recommendation to follow up the patient as compound heterozygosity for C282Y plus H63D carries an extremely low risk for development of iron overload.

Patients for whom genotyping of the other parent is not available and those who are over the age of 18 years should undergo HFE genetic testing at the earliest convenience. This is to assess for:

  • C282Y homozygosity (high risk of iron overload)
  • compound heterozygosity for C282Y and H63D (very low risk of iron overload)
  • simple heterozygosity for C282Y or H63D (no increased risk of iron overload).

Serum transferrin saturation and ferritin levels should be measured in those who are homozygous for C282Y or compound heterozygous for C282Y and H63D. Patients with elevated transferrin saturation or serum ferritin levels (as defined in the Table) should undergo further work up as for those with HH symptoms (see below).42,43 If serum ferritin levels are not elevated then measurement of serum ferritin levels should be repeated after one to five years to assess for disease progression.3,17

In individuals who are homozygous for C282Y and aged 55 years or older and whose serum ferritin levels are within the reference range, surveillance can cease as it is highly unlikely that iron overload will ever evolve.44 In women, serum ferritin levels generally plateau 10 to 20 years after menopause at no greater than 400 mcg/L, a level too low to result in disease.16


Individuals who are homozygous for C282Y should be advised about family screening of first-degree relatives and standard-of-care colorectal and breast cancer surveillance.37,40

Asymptomatic patients with elevated serum transferrin saturation, ferritin or liver biochemistry results

Elevated serum transferrin saturation or ferritin or aminotransferase levels are common in the general population. Elevated serum transferrin saturation or ferritin levels as defined in the Table are found in up to 6% of adults.4-7,42 An elevated serum alanine aminotransferase (ALT) level is seen in up to 14% of adults.45,46 Most people with this abnormality do not have HH. However, individuals with an abnormal ALT level should have serum transferrin saturation and ferritin levels measured (Flowchart 2).

If serum transferrin saturation and ferritin levels are elevated, the most appropriate investigation for those with European ancestry is testing for the HFE C282Y mutation. Those who are not of European ancestry and those found to be homozygous for C282Y should be evaluated as for patients with HH symptoms (see below).

Clinically significant iron overload is rare in people of European ancestry who are not homozygous for C282Y, even in the presence of elevated serum transferrin saturation or ferritin levels.47 An elevated serum ferritin level is thus not diagnostic on its own and requires confirmation with another method before iron overload is diagnosed, as described below (Quantification of Liver Iron).

For those whose serum transferrin saturation and ferritin level are not elevated, HH is unlikely. Alternative causes of ALT derangement should be sought.

Patients with HH symptoms

Patients who have symptoms consistent with HH should undergo clinical assessment to determine the risk of end-organ damage, especially liver disease and arthritis (Flowchart 3). The risks of arthritis, advanced liver fibrosis, cirrhosis and the subsequent development of primary liver cancer increase with progressive iron loading, particularly when the serum ferritin level exceeds 1000 mcg/L. HH arthritis is a useful clinical predictor for advanced liver fibrosis, as described above.22,33,34 The presence of additional risk cofactors for liver disease in people who are homozygous for C282Y may warrant assessment of liver disease at lower ferritin levels.3,17

Key components of the assessment of severity of liver disease are quantification of liver iron concentration and assessment of the liver fibrosis stage. These assessments should be routine in all patients with arthritis or serum ferritin levels greater than 1000 mcg/L and in those at risk because of additional cofactors, including unexplained hepatomegaly or elevated serum aminotransferase levels.

Quantification of liver iron

Increasing liver iron concentration is associated with an increased risk of advanced liver fibrosis and the development of cirrhosis. There are three ways to quantify liver iron concentration:

  • invasively via liver biopsy, which is now rarely performed as more reliable methods of noninvasive measurement are available3,8,17,23,48
  • retrospective calculation of iron removed based on the number and volume of therapeutic phlebotomies undertaken to reduce the serum ferritin level to 50 to 100 mcg/L17
  • MRI quantification of the liver iron concentration.

Allowing for substantial heterogeneity in iron deposition within the liver and the attendant limitations of comparing biopsy with imaging methods, MRI provides good clinical utility for quantifying iron overload and thus is the preferred method.3,49-52 MRI is also accurate for quantifying myocardial iron deposition.53 In Australia, an automated system for MRI quantification of liver iron concentration (FerriSmart) has been approved by the TGA.51

Assessment of liver fibrosis

Assessment of the stage of liver fibrosis is crucial to management and prognostication for patients with HH. Further, in patients with cirrhosis, the finding of regression of advanced fibrosis with phlebotomy therapy can guide the requirement for ongoing HCC surveillance.24

Methods to assess liver fibrosis include:

  • liver biopsy - although previously considered a gold standard, biopsy is now used less often because of its invasive nature and the development of validated noninvasive serum biomarker panels
  • noninvasive serum biomarker panels
    – AST-to-platelet ratio index  (APRI = [AST/AST upper limit  of normal] × [100/platelet concentration])
    – fibrosis-4 index  (Fib4 = [age x AST]/[platelets × √ALT])
  • transient elastography.54,55

Detection of advanced liver fibrosis and cirrhosis is crucial for defining prognosis and the risk of HCC. The noninvasive scores APRI and Fib4 accurately detect liver biopsy-diagnosed advanced liver fibrosis in patients with HH with an accuracy of over 80%, with APRI also useful for monitoring fibrosis regression during treatment.54 The Hepascore (an algorithm based on age, sex and serum levels of bilirubin, alpha2-macroglobulin, hyaluronic acid, gamma-glutamyl transferase) and transient elastography were shown in a recent study to be more limited in their clinical utility as they may underdiagnose advanced liver fibrosis.55

Individuals with noninvasive marker values consistent with advanced liver fibrosis may be recommended to undergo liver biopsy for definitive diagnosis when clinically appropriate.3,17 All individuals with advanced liver fibrosis or cirrhosis are at high risk of primary liver cancer and require cancer surveillance.3,8,17,18,28


The aim of management in patients with HH is to return total body iron stores to the low-normal range and to minimise or reverse clinical complications of HH. All patients with HH and elevated serum ferritin levels should be treated, as this has been shown to result in clinical improvement.3,17,56 Disease manifestations of HH should also be managed as per the standard of care for the particular problem.

Dietary treatment

Individuals with HH should adopt a healthy lifestyle, including maintaining normal body weight and limiting alcohol consumption.57 Dietary iron intake does not need to be restricted, as this has little or no proven benefit in routine management.3,8,17,58 However, iron supplements should be avoided.


Phlebotomy is the mainstay of treatment for patients with HH. Phlebotomy is recommended in all those who are homozygous for C282Y and have elevated serum ferritin levels. There is no good evidence supporting phlebotomy treatment for individuals with unexplained elevated ferritin levels caused by other conditions, such as fatty liver disease, or where iron overload has not been definitively proven by confirmatory testing as described above (Quantification of Liver Iron).59,60

Patients with HH and serum ferritin levels greater than 1000 mcg/L have a markedly increased risk of advanced liver fibrosis or cirrhosis. Treatment with phlebotomoy improves fatigue, cognition and liver fibrosis.24,28,54,56,61 Improvements in liver fibrosis occur across the spectrum of fibrosis.24,28,54,61 Cirrhosis regresses with adequate phlebotomy therapy in up to 23% of individuals; 18% regressing to levels below the threshold associated with the long-term risk of primary liver cancer.28

Although phlebotomy is an effective and safe therapy, some HH individuals find it difficult to comply for reasons such as lack of motivation, needle phobia and difficult venous access.62 Further, some patients have symptoms caused by hypovolaemia after phlebotomy or problems such as cardiac morbidity, hypoproteinaemia and thrombocytopenia.63 In these situations, alternative approaches including erythrocytapheresis or chelation therapy may be considered.

Erythrocytapheresis is a method of red blood cell removal where whole blood is drawn from the patient, centrifuged to separate it into plasma and red cells, and the plasma is returned to the patient. Compared with phlebotomy, erythrocytapheresis can reduce the time to achieve acceptable serum ferritin levels and reduce symptoms of hypovolaemia. It requires specialised equipment and is, therefore, more costly and less accessible than phlebotomy.64-66 It should be considered by specialists in patients with contraindications or difficulties with phlebotomy.


Chelation therapy, most commonly oral deferasirox, may be considered for patients with HH who cannot tolerate other iron removal therapies.67

Phlebotomy treatment has two distinct phases:

  • induction, which has a target serum ferritin level of 50 to 100 mcg/L
  • maintenance, which aims to maintain serum ferritin levels at  50 to 100 mcg/L.

An electronic referral tool for phlebotomy, confirming eligibility and prescribing the frequency of therapy is the standard of care in Australia and available at the website of the Australian Red Cross Lifeblood service ( Blood products prepared from individuals with HH can be safely used for transfusion purposes.

An unexplained reduction in the need for phlebotomy should be investigated as it may be due to occult blood loss. On occasion, no explanation for the reduced need can be identified suggesting there may be variation in phenotypic expression of the genetic mutation within individuals.68

Induction phase

Treatment in the induction phase usually involves weekly phlebotomy until an endpoint serum ferritin level of 50 to 100 mcg/L is reached.3,17 Less frequent phlebotomy therapy may be necessary in some patients who cannot tolerate weekly treatments. Measurement of haemoglobin is recommended at each phlebotomy, whereas serum ferritin level can be measured at every fourth phlebotomy during the early induction phase, increasing to every phlebotomy when the serum ferritin level reaches 200 mcg/L.

Maintenance phase

After the target serum ferritin level has been achieved, the maintenance phase commences to stabilise the level. This most often involves three-monthly phlebotomy, but the required frequency is highly variable and needs to be individualised and titrated to target serum ferritin levels. Serum ferritin levels may need to be monitored only once or twice yearly after the phlebotomy requirements are stabilised. Noncompliance with venesection is more common in the maintenance phase, and noncompliant patients are at risk of reaccumulating iron and associated complications.62


Recent population studies have shown that men, but not women, homozygous for C282Y have a significantly increased mean risk of death by the age of 75 years of 19.5% compared with 15.1% for the control group.27 The development of chronic liver disease further reduces long-term survival. Early phlebotomy treatment before the onset of cirrhosis results in normal survival compared with subjects matched for age and sex. Given the potential for reversal of advanced hepatic fibrosis and cirrhosis with phlebotomy, survival in these individuals is also likely to be substantially improved by treatment.


HH is a common disorder with variable clinical expression in men and women, which if left untreated can lead to significantly increased morbidity and mortality. Timely assessment through family screening and evaluation of individuals with suggestive biochemical or clinical features will detect disease at the earliest opportunity. Men have greater mortality and morbidity than women; the main clinical issues are liver disease, arthritis and dementia. All individuals with HH and elevated serum ferritin levels should receive treatment. All adults with HH should be informed of their increased risk of breast and colorectal cancer and receive appropriate screening. Long-term follow-up is best managed by community-based GPs in partnership with the patient, and in conjunction with supporting specialists to ensure optimal patient outcomes. Individuals with elevated serum ferritin levels who do not have HH or another proven iron-overload disorder do not need monitoring of serum ferritin levels or phlebotomy treatment.  MT


COMPETING INTERESTS: Professor Olynyk is Chief Medical Officer for Resonance Health, a  TGA-approved provider of MRI measurement of liver  iron levels (FerriSmart) and received travel support  from Resonance Health to attend a conference.  He provides GP education talks for AstraZeneca, Pfizer and Pharmacosmos and medical advice to AstraZeneca, Australian Red Cross Lifeblood and Haemochromatosis Australia.  Dr Chen: None.



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