The Diagnosis and Management of Hereditary Haemochromatosis

Abstract

Hereditary haemochromatosis (HH) is a common genetic disorder of iron metabolism in individuals of Northern European ancestry which leads to inappropriate iron absorption from the intestine and iron overload in susceptible individuals. Iron overload is suggested by elevations in serum ferritin and transferrin saturation. The majority of patients with clinically significant iron overload are homozygous for the C282Y mutation of the HFE gene, however only a minority of C282Y homozygotes fully express the disease clinically. Those with a high serum ferritin (>1000 μg/L) and additional hepatic insults from cofactors are more likely to develop cirrhosis and its complications. The mainstay of treatment is venesection. Those without cirrhosis who undergo appropriate venesection have a normal life expectancy. Family screening is recommended for all first degree relatives of an individual with the disease.

HH refers to a group of inherited disorders that result in progressive iron overload. Mutations of the HFE gene are responsible for the majority of cases of HH,¹ although disease expression is highly variable.² The ready availability of testing for the two clinically relevant mutations: C282Y and H63D, has substantially altered the approach to suspected iron overload in clinical practice. A number of rare but important forms of non-HFE related HH have also been described.³ The other main causes of iron overload are outlined in the Table and include secondary iron overload from iron loading anaemias and also multiple blood transfusions. This review article will concentrate mainly on the approach to HFE-related HH, which is the form predominantly seen in clinical practice.

Table.

Classification of Iron Overload.

HH

HFE related HH

(C282Y/C282Y, C282Y/H63D)

Non-HFE related HH

Juvenile Haemochromatosis

Hemojuvelin related

Hepcidin related

Transferrin receptor-2 related HH

Ferroportin related HH

Secondary Iron Overload

Iron loading anaemia

Thalassaemia major

Sideroblastic anaemia

Chronic haemolytic anaemia

Parenteral iron overload (multiple transfusions)

Others

Metabolic syndrome

Chronic liver disease

Hepatitis C

Alcoholic liver disease

Non-alcoholic steatohepatitis

Porphyria cutanea tarda

African Iron Overload

Acaeruloplasminaemia

Atransferrinaemia

Neonatal iron overload

Clinical Presentation and Phenotypic Expression

The most common symptoms of HH are subjective and non-specific, such as fatigue, lethargy and arthralgia. In cases of significant iron overload, individuals may present with organ specific symptoms such as those related to chronic liver disease. Arthralgia or arthritis related to haemochromatosis typically involves the second and third metacarpo-phalangeal joints. Endocrine dysfunction can take the form of diabetes or hypogonadism. Occasionally the patient may present with symptoms related to cardiomyopathy, either with symptomatic cardiac failure or arrhythmias. It is now quite rare to see the classic triad of bronzed skin, diabetes and cirrhosis, probably because of earlier diagnosis and management.

Commonly, patients are diagnosed with HH subsequent to the discovery of abnormal serum indices suggestive of iron overload as part of standard health checks. Iron overload may be identified as part of the evaluation of an asymptomatic individual with abnormal liver function tests. Additionally, an increasing number of cases are detected as a result of cascade family screening.⁴

There has been much debate regarding the proportion of C282Y homozygotes that clinically express the disease. The definition of disease expression in HH is somewhat difficult and can range from mildly abnormal iron indices to overtly symptomatic disease. A large, middle-aged, population based study from Melbourne, reported an incidence of C282Y homozygosity of 0.68% and compound heterozygosity (C282Y/H63D) of 2.4%.² These rates are similar to studies of white North American populations.^5,6 Disease related to iron overload was defined as documented iron overload and one or more of the following conditions: cirrhosis, liver fibrosis, hepatocellular carcinoma, elevated amino-transferase levels, physician-diagnosed symptomatic haemochromatosis, and arthropathy of the second and third metacarpo-phalangeal joints. The proportion of C282Y homozygotes with documented iron overload related disease was 28.4% (95% confidence interval [CI] 18.8 to 40.2%) for men and 1.2% (95% CI 0.03 to 6.5%) for women. Only one of 719 compound heterozygotes had documented iron overload related disease.

The factors that influence phenotypic expression of HFE-related HH are not clearly defined. It is highly likely that a number of other genetic modifiers are involved. The reduced prevalence of iron overload related disease in female C282Y homozygotes reflects a lower iron burden due to physiological blood loss, but also possibly sex-related disease modifier genes. ⁷

HFE-related haemochromatosis almost always affects individuals with Northern European ancestry. It is a rare cause of iron overload in Asians, Pacific Islanders Australian, African and South American populations.⁸ There is evidence that the C282Y mutation is of Celtic or Scandinavian origin.⁷

Serum Indices of Iron Stores

The appropriate interpretation of transferrin saturation and serum ferritin results is essential in the diagnosis of iron overload. Fasting transferrin saturation (the ratio of serum iron to total iron binding capacity) is the most sensitive initial phenotypic screening test (see Figure).⁴ A cut-off value of ≥45% will detect almost all affected C282Y homozygotes.⁹ A fasting morning sample is recommended as serum iron levels may be misleadingly elevated in the postprandial state and also by circadian rhythm.¹⁰ However one large study has suggested that the use of fasting transferrin saturation had no advantage over the use of random samples in a primary care population.¹¹ Unsaturated iron binding capacity has also been used and is a valid alternative to transferrin saturation.^11–13

Figure.

Algorithm for screening for HFE-associated haemochromatosis. (LFT - liver function test; TS - transferrin saturation.)

This figure was originally published in The Canadian Journal of Gastroenterology 2000;14(2):121-5.

Serum ferritin reflects body iron stores and generally rises later in the progression of iron overload. Iron overload increases the hepatic production and release of ferritin. Interestingly, the role of ferritin in the blood remains unclear. There are a number of confounding causes of hyperferritinaemia that warrant consideration. These include alcohol abuse, the metabolic syndrome, inflammatory states and acute or chronic hepatitis.^14,15 In the absence of these conditions, serum ferritin is a good marker of the degree of iron overload.⁴ High serum ferritin levels greater than 1000 μg/L indicate a greater risk of cirrhosis or advanced fibrosis and have been used, irrespective of age and transaminase levels, as an indication for liver biopsy.¹⁰ The negative predictive value of a normal transferrin saturation and serum ferritin is 97%. In this situation, no further testing is recommended.¹⁰

HFE Gene Mutation Testing

The C282Y mutation is a missense mutation that substitutes a cysteine residue for tyrosine at amino acid position 282 on the HFE protein. The other significant mutation is referred to as H63D which results in the substitution of aspartic acid for histidine at position 63. Testing for these mutations is widely available. Those who have one of each mutation are termed compound heterozygotes. Only those who are homozygous for C282Y and compound heterozygotes have the potential to develop significant iron overload related to HFE gene mutations. Testing for HFE gene mutations is generally indicated in those with an iron overload phenotype and those with a family history of HFE-related HH.⁴

With the advent of genetic testing there has been concern regarding the potential psychological and medical insurance implications of the detection of HFE gene mutations. However studies have shown no adverse psychological effect from HFE genetic testing.^16–18 Furthermore a large study has shown no evidence of discrimination following genetic testing.¹⁹

Genetic testing for other forms of HH is possible. Second line testing for young adults with suspected iron overload without significant HFE gene mutations can include testing for hemojuvelin (HJV), hepcidin (HAMP) and transferrin-2 receptor (TFR2) gene mutations.^3,20 However, these tests are not widely available and often liver biopsy is needed to confirm the diagnosis of haemochromatosis in these cases.

Liver Biopsy

The liver is the most readily accessible tissue with which to formally assess the degree of iron overload by measurement of the hepatic iron content (HIC). However, liver biopsy no longer has a primary role in the diagnosis of haemochromatosis in C282Y homozygotes. The usefulness of liver biopsy in these patients is as a prognostic indicator to establish or exclude the presence of cirrhosis. Liver biopsy is generally recommended as a tool to determine severity of liver disease, particularly when other causes (such as alcohol or viral hepatitis) may be implicated and when HFE gene mutation testing is negative. Those C282Y homozygotes for whom a liver biopsy has been recommended include those aged > 40 years, serum ferritin >1000 μg/L or those with clinical evidence of liver disease, including elevated transaminase levels.^4,10

An assessment of the quantity (HIC) and distribution of hepatic iron should be made when liver biopsy is performed. Perls’ prussian blue staining is used to demonstrate the extent and distribution of iron. In HH there is preferential iron deposition in peri-portal hepatocytes which contrasts with non-HFE forms of HH where the pattern of haemosiderin accumulation is in the sinusoidal lining cells without acinar zone predilection.²¹

Non-invasive Hepatic Iron Quantification

Liver biopsy remains the definitive test for the quantification of hepatic iron concentration. However, there is increasing evidence regarding the use of Magnetic Resonance Imaging (MRI) techniques to accurately estimate HIC.^21,22 Cardiac MRI can be useful to estimate the degree of iron deposition in the heart.

Management of Haemochromatosis

The primary management goal in HH is the removal of excess iron (de-ironing) through venesection. Secondary goals involve management of liver and non-liver complications which requires: (a) the recognition of cirrhosis and its complications; (b) the identification of other contributing causes to liver disease; (c) the clarification of the nature of any genetic cause; and (d) the identification and management of iron deposition in other tissues. These factors influence therapy and have prognostic implications. Finally, consideration should be given to screening of first degree relatives, particularly to detect early disease.

Venesection

Venesection is usually commenced once serum ferritin increases above 200 μg/L in premenopausal women and 300 μg/L in postmenopausal women and men. The mainstay of de-ironing is regular phlebotomy to achieve a serum ferritin level of less than 50 μg/L without anaemia or iron deficiency. One venesection typically removes 250 mg of iron and in the classical presentation with iron overload, removal of 8 to 25 units of blood is usually sufficient to normalise serum ferritin which should be reassessed after each 1–2 g of iron removed.⁴ Once ferritin levels have normalised, venesection frequency can be individualised and may be required once every three to four months.

Desferrioxamine is a subcutaneous chelating agent but is rarely required except in those patients with HH who are intolerant of venesection due to hypotension, anaemia or cardiac failure.²³ An effective oral iron chelating agent has been keenly awaited. Desferasirox (EXJADE®) is effective and available for patients with secondary iron overload, e.g. thalassaemia, but its role in HH is still under investigation.

Liver Related Complications

It is critically important to determine whether a patient with HH has cirrhosis. Traditionally liver biopsy has been performed to determine HIC as a guide to diagnosis and management of HH. Testing for the HFE mutation has now provided an effective substitute test for the majority of patients. The reduction in biopsy however has also reduced valuable histological information about fibrosis and cirrhosis and also diagnostic clarification in non-HFE iron overload.

Certain patient profiles have been found to be correlated to the absence of fibrosis (age <40 years, serum ferritin <1000 μg/L, absence of hepatomegaly and normal liver enzymes).^24,25 The role of non-invasive tests for fibrosis in HH is evolving.

Patients without cirrhosis are not considered to be at increased risk of liver or non-liver related mortality.²⁶ While cirrhosis is irreversible, iron depletion improves portal hypertension as assessed with abdominal ultrasound and upper gastrointestinal endoscopy.²⁷

Non-cirrhotic patients with HH do not appear to have increased risk for hepatocellular carcinoma (HCC) and therefore do not need to undergo screening.^28,29

Cirrhotic patients with HH have increased risk of HCC and should undergo appropriate screening. Patients with cofactors for liver injury such as viral hepatitis, non-alcoholic steatohepatitis and/or alcohol excess have significantly increased risk of more aggressive liver disease and developing HCC. Steatosis has been identified as a cofactor in liver injury in patients with haemochromatosis.³⁰ Fargion and colleagues followed a cohort of 152 patients with HH, homozygous for the C282Y mutation. Ninety-seven patients had cirrhosis and in this group of patients with an age greater than 55, a history of alcohol abuse and positive hepatitis B surface antigen had a relative risk of 150 times that of other cirrhotic homozygotes for development of HCC.²⁸ No patients developed HCC in the non-cirrhotic group. In patients with HH without other liver injury, greater HIC and longer duration of iron overload are associated with HCC.³¹

Liver Transplantation

The effect of HH and iron overload on survival post liver transplantation remains contentious. Poorer outcomes for patients undergoing transplantation with haemochromatosis and/or iron overload were suggested by early studies.^32,33 Results of more recent work with ascertainment of patients that includes the HFE gene mutations have found contrasting results independent of the degree of iron overload - the prognostic implications of which remain debated.^34–36 Successful liver transplantation appears to correct the underlying metabolic defect in the disease.³⁵

Non-liver Related Complications

Iron overload classically may lead to a number of extra-hepatic complications. Cardiomyopathy (both dilated and restrictive) and conduction disturbances are the most common cause of sudden death in HH,^10,37 however they are generally reversible with venesection.³⁸ Impaired cardiac function may necessitate a less aggressive venesection program or the use of chelating agents. Patients should be assessed for cardiac symptoms on history and baseline electrocardiograph should be performed with a low threshold for echocardiography.³⁷

There are numerous endocrine manifestations of iron overload which may present with insidious symptoms of lethargy, weakness, fatigue, loss of libido and impotence.³⁹ Hypogonadotrophic hypogonadism can be assessed by testing serum testosterone in men and follicle stimulating hormone and luteinising hormone levels in women. Osteoporosis may complicate hypogonadism and should be assessed with plain radiographs and bone mineral densitometry.³⁷ Fasting blood glucose and thyroid function tests should be performed to assess for diabetes mellitus and thyroid dysfunction. Arthralgias can be assessed with radiographs and referral for rheumatologic opinion as appropriate. Established hypogonadism, diabetes and arthritis do not reverse with venesection but some improvement may occur.

Screening

Screening is recommended for all first degree relatives of a proband.³⁹ An alternative approach is the testing of the unaffected parent for mutations. The absence of heterozygous state excludes inheritance of HFE mutations that confer increased risk of iron overload (i.e. C282Y homozygous or C282Y/H63D compound heterozygous) in the offspring. There are still no definitive guidelines regarding when to screen for these mutations in the general population. Given the generally progressive nature of iron overload, clinicians can usually defer testing young subjects until 18 to 20 years unless there was history of precocious iron overload which raises concerns of juvenile HH.