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Haemochromatosis is usually a hereditary condition, characterised by increased iron absorption leading to iron deposition
in tissues and ultimately organ damage. Iron is an essential mineral in the diet. It is a key constituent of haemoglobin
and helps regulate a number of biological processes involved in the immune response, oxygen transport and the function
of various enzymes in the body, including the hepatic cytochrome enzymes. The average person has around three to four
grams of iron in their body.1 As there is no control mechanism for iron excretion in humans, iron stores in
the body are regulated by controlling iron absorption; a key hormone involved is hepcidin, which is released by the liver
and acts on duodenal cells to inhibit iron absorption.
In 1996 it was discovered that approximately 80% – 85% of cases of hereditary haemochromatosis are caused by common
variants of the HFE gene.2, 3 Although the molecular mechanism is not clear, these common variants increase
the chances of low hepatic production of hepcidin, leading to increased iron absorption. People with this form of haemochromatosis
are referred to as having HFE hereditary haemochromatosis (HFE-HH). However, the condition is recessive and people who
inherit only one copy of identified genetic risk factors will not develop clinical disease. Iron accumulation in people
with HFE-HH is usually not evident until adulthood.
The prevalence of hereditary haemochromatosis in New Zealand is unknown, but a study of over 1000 people in Christchurch
(predominantly Caucasian) found that 38.4% of the population had at least one copy of a risk allele; however, only 0.28%,
or one in 355, had haemochromatosis requiring treatment.4
Who is most at risk?
A patient’s ethnicity is a key feature to consider when assessing their risk of hereditary haemochromatosis, and sex
is a risk factor for developing clinical complications.
European ethnicity
Caucasian ethnicity is a risk factor for hereditary haemochromatosis, but people
of other ethnicities may still develop the condition.
The highest prevalence of genetic risk alleles occurs in people of European descent, with prevalence in Asian and Pacific
peoples one-third or less of that seen in Caucasians (see: “Genetic terminology and haemochromatosis”,
for a description of risk alleles).5 There is no direct data available on the prevalence of risk alleles for
haemochromatosis in Māori.
Males are at greater risk of developing iron overload and clinical complications
Females show much lower rates of progression to symptomatic disease resulting
from iron deposition.
There is no sex difference in the inheritance of haemochromatosis alleles, but males are more likely to develop iron
overload and progress to clinical disease. This is assumed to result from females having greater iron loss than
males, due to menstruation. The prevalence of iron overload-related complications (e.g. cirrhosis, hepatocellular
carcinoma, biochemical evidence of liver damage, arthropathy) in people who are homozygous for C282Y is reported
to be 28% in males and 1% in females (see: “Genetic terminology and haemochromatosis”, for an explanation
of genetic terms).6
Who to test and what to look for
Early symptoms of haemochromatosis are non-specific
In the early stages of haemochromatosis, patients may experience vague, non-specific symptoms, such as lethargy or gastrointestinal
symptoms. In more advanced haemochromatosis, symptoms arise as a result of iron overload causing damage to specific organs.
Patients may experience:2, 6, 7
- Early, non-specific symptoms
- Lethargy, apathy, malaise
- Weight loss
- Gastrointestinal symptoms, abdominal pain
- Symptoms arising from clinical consequences:
- Arthalgias (from joint effects; hand and knee joints are most commonly involved8, 9)
- Loss of libido, erectile dysfunction, amenorrhea (from reproductive system effects)
- Chest pain, shortness of breath (from cardiac effects)
- Weight loss, frequent urination and symptoms of diabetes (from effects on the pancreas); consider assessing ferritin
and transferrin saturation in adult patients with a new presentation of type 1 diabetes
- Sensitivity to cold, weight gain (from thyroid effects, e.g. hypothyroidism)
Signs to specifically look for on clinical examination include:2, 6, 7
- Liver tenderness, hepatomegaly and other signs of liver disease (e.g. cutaneous signs of chronic liver disease)
- Skin pigmentation or nail changes, porphyria cutanea tarda (discolouration or lesions on light-exposed skin such
as the back of the hands), koilonychia (spoon-shaped nails)
- Oedema and signs of congestive heart failure
- Testicular atrophy and gynaecomastia in males
- Loss of body hair
- Early osteoarthritis
Biochemical testing of high iron stores
The key laboratory tests for the evaluation of body iron stores in patients with suspicious signs or symptoms are:
- Ferritin levels: increased hepatic iron stores causes elevated ferritin levels, but elevations may be due to other
non-specific causes
- Transferrin saturation: transferrin binds iron in the circulation. Transferrin saturation is calculated by measuring
serum iron levels and iron binding capacity.10
N.B. A fasting sample may improve the accuracy of results if there is uncertainty about an abnormal result.2
Haemochromatosis is likely in patients with elevated ferritin (> 300 micrograms/L in males or > 200 micrograms/L
in females) or transferrin saturation (> 45%) levels which cannot be explained by other reasons. Elevated ferritin
is a less specific marker for haemochromatosis as there are a number of clinical scenarios which can result in abnormal
test results. Clinical guidelines differ as to whether elevations in both ferritin and transferrin saturation are necessary,
or one alone is sufficient, for further follow-up for haemochromatosis.2, 6, 11 Table 1 offers guidance on
appropriate follow-up of ferritin and transferrin saturation results. Clinicians should only request genetic testing
in a patient with biochemical evidence of abnormal iron metabolism*.
Other possible reasons a patient may have elevated ferritin include:6, 12
*Or if performed as part of family screening. However, screening of asymptomatic family members is not
recommended unless performed under the advice of a clinician with relevant genetic experience or after discussion with
a genetic counsellor, see: “Screening of first degree relatives”.
- Acute illness or inflammation: the inflammation associated with an infection, or chronic inflammatory conditions,
causes increased ferritin. Measuring CRP can help distinguish these patients. Evaluation of iron metabolism should be
repeated or delayed until after the acute illness has resolved.
- Alcohol intake: alcohol increases ferritin levels. Patients should be questioned about their alcohol consumption
and, if indicated, liver function tests requested.
- Other forms of liver disease: patients with non-alcohol fatty liver disease, hepatitis or alcoholic liver disease
can have elevated ferritin levels.
- Iatrogenic: people who receive blood or iron transfusions may have elevated iron levels following a transfusion
- Cancer: some tumours and tissue necrosis can lead to elevated ferritin10
- Excessive dietary intake of iron or vitamin C through supplementation
Although initial biochemical testing is performed to establish a diagnosis, it may also reveal information of prognostic
importance about the presence of organ damage due to iron overload, e.g. ferritin levels > 1000 micrograms/L can indicate
iron-overload induced cirrhosis.
Patients with biochemical results suggestive of haemochromatosis which cannot be explained by other diagnoses should
undergo genetic testing, particularly if they have a family history or symptoms and signs of haemochromatosis.2 Requests
for haemochromatosis gene testing can be made according to local guidelines. Clinicians can contact Genetic Health Services
New Zealand for advice, or refer patients to the service, if there are questions that are specifically related to family
risk they cannot answer.
Further information and contact details for Genetic Health Services New Zealand
is available on their website: https://www.tewhatuora.govt.nz/health-services-and-programmes/genetic-health-service-nz/
For more about Genetic Health Services New Zealand, see:
www.bpac.org.nz/BT/2014/November/ghsnz.aspx and www.bpac.org.nz/BT/2014/November/genetic-tests.aspx
Incidental discovery of asymptomatic patients
Asymptomatic patients with haemochromatosis may be identified during investigation for other conditions. The finding
of abnormally high iron levels in a patient, particularly if associated with abnormal liver function tests, should be
considered as suspicious for haemochromatosis.2 These findings should be followed up by biochemical testing
for abnormal iron metabolism, particularly in patients with a first degree relative with hereditary haemochromatosis.
A radiologist may also suggest that a patient be assessed for iron overload due to suspicious signs on radiological examinations
for other conditions, e.g. chondrocalcinosis often occurs in patients with hereditary haemochromatosis.9
Table 1: When to request genetic testing in a patient with
biochemical evidence of abnormal iron metabolism 2, 6, 11
|
Ferritin normal |
Ferritin elevated |
| Transferrin saturation < 45% |
Haemochromatosis highly unlikely; other reasons for any signs or symptoms should be investigated |
Haemochromatosis possible; investigate other reasons for elevated ferritin and if other causes ruled out (and
elevated ferritin persists), proceed to genetic testing |
| Transferrin saturation > 45% |
Proceed to genetic testing for haemochromatosis |
Proceed to genetic testing for haemochromatosis |
Genetic terminology and haemochromatosis
Alleles versus mutations and genetic testing for haemochromatosis:
Mutations are changes in the genetic code which are rare in the population (with a prevalence of <1%)
Alleles are differing versions of a gene which are common in the population. For any gene there are
usually at least two relatively common alleles in the population.
Alleles of the HFE gene which contribute to the development of haemochromatosis are common. For example,
in a study in Christchurch, 38.4% had at least one risk allele (out of 1064 people).
Most cases of haemochromatosis are due to common risk alleles of the HFE gene and these are assessed
in routine genetic testing for haemochromatosis. However, some patients may develop haemochromatosis due to other mutations
in genes involved in iron metabolism. Further genetic testing would be required to identify underlying genetic causes
of haemochromatosis in these patients.
Haemochromatosis allele terminology
There are two main alleles of interest for the investigation of haemochromatosis: C282Y and H63D. In laboratory test
results or clinical correspondence, these alleles may be written in different ways but are all synonymous:
- C282Y allele: may also be referred to as Cys282Tyr or Cys → Tyr 282
- H63D allele: may also be referred to as His63Asp or His → Asp 63
Homozygous and heterozygous:This refers to how many copies of a mutation or allele a person has. Someone
who is heterozygous has one copy, someone who is homozygous has two. Most cases of haemochromatosis are due to people
being homozygous for the C282Y allele.
Recessive versus dominant:In genetic conditions which are dominant, patients only need to have one
copy of an allele or mutation to develop a clinical condition. Hereditary haemochromatosis is recessive, so that a person
who has one copy of a risk allele is not at risk of developing complications from iron overload; two copies are necessary.
Penetrance: This term describes how likely it is that someone with a specific genotype will develop
a clinical condition. The risk alleles for hereditary haemochromatosis show low penetrance: only 10% of people homozygous
for haemochromatosis risk alleles develop the clinical effects of haemochromatosis. For this reason, genetic screening
of the general population is not recommended.2
In summary, many people in the population have at least one risk allele for haemochromatosis. However,
a person would need two copies of common risk alleles to be at risk of developing haemochromatosis (or have other rare
dominant mutations). Even with two copies of common risk alleles not all people will develop symptoms or biochemical evidence
of abnormal iron metabolism.
Genetic testing for hereditary haemochromatosis
Standard genetic testing for haemochromatosis assesses whether a patient has
common risk alleles and how many copies they have.
A diagnosis of HFE hereditary haemochromatosis can be made on the basis of biochemical signs of iron overload (increased
ferritin and/or transferrin saturation) and the presence of risk alleles.
Most cases of hereditary haemochromatosis (approximately 80%) are due to a patient inheriting a C282Y allele of the
HFE gene from both parents (homozygous for the C282Y HFE allele).2 This C282Y allele is known as the major
risk allele. Another risk allele is H63D; this is more prevalent in the population but less likely to cause haemochromatosis
and is referred to as a minor risk allele. Approximately 5% of cases are due to inheriting one copy each of the C282Y
and H63D alleles (referred to as “compound heterozygous”).3
The most important findings from genetic testing for the diagnosis and management of patients are identifying those
with:
- Two C282Y alleles, i.e. homozygous for the major risk allele. These patients are most likely to develop
iron overload and clinical complications
- One C282Y allele and another minor risk allele (e.g. a C282Y/H63D genotype). People with this genotype
may also develop haemochromatosis although are less likely to do so than people homozygous for two C282Y alleles. Particular
attention should be paid to excluding other causes of elevated ferritin before establishing a diagnosis of haemochromatosis
in these patients.
- Variant genotype.Biochemical evidence of iron overload or even elevated iron stores on liver biopsy
but with a genotype other than those above (e.g. patients with a H63D/H63D genotype with elevated ferritin).2, 13 These
patients do not develop sufficient iron deposition to progress to clinical disease and can be reassured that they do
not need treatment.2
Genetic testing forms part of the diagnostic process and can provide some prognostic information, however, clinical
management and treatment is the same for all individuals with hereditary haemochromatosis who develop iron overload, regardless
of their underlying genotype.
Screening of first degree relatives
Upon learning they have a condition with a strong genetic component, patients may enquire about genetic testing of family
members or relatives. In general, the evaluation of family members should follow the same diagnostic process described
here: family members with symptoms or signs that may be suggestive of haemochromatosis should have ferritin and transferrin
saturation tests performed to establish whether they have biochemical evidence of abnormal iron metabolism, and if so,
be followed up with genetic testing.
Hereditary haemochromatosis is an adult onset disorder, so testing children in affected families is not indicated.
Once children reach adulthood, the family diagnosis can be discussed with them and if patients without symptoms or biochemical
evidence of altered iron metabolism wish to undergo genetic testing they should first be referred to a genetic counsellor;
Genetic Health Services New Zealand recommends that genetic testing of asymptomatic adult family members of an affected
individual should only be undertaken following the recommendation of a clinician with relevant genetic experience or after
discussion with a genetic counsellor. It is important to note that people can be genetically at risk, with one of the
above combinations of haemochromatosis alleles, but not progress to develop haemochromatosis. Therefore, genetic testing
of asymptomatic family members may identify people who are genetically at risk but without biochemical evidence of abnormal
iron metabolism or suspicious symptoms and signs. If this is the case, these family members should have serum transferrin
and ferritin levels measured annually to monitor the potential development of iron overload.6
For further information, see: “Possible patterns of inheritance
of haemochromatosis alleles”.
Non-HFE hereditary haemochromatosis and other diagnoses
Patients with unexplained elevated ferritin or transferrin saturation, or clinical signs suggestive of haemochromatosis
but without identified HFE risk alleles after referral to genetic testing services should be followed up, particularly
if aged 20 years and under (see “Other forms of haemochromatosis”). Referral to a haematologist
is recommended.
Some patients, with a family history of the condition, develop haemochromatosis but without identifiable risk alleles
or mutations in the HFE gene, and are classified as having non-HFE hereditary haemochromatosis. These patients are uncommon,
making up approximately 5% of all people with hereditary haemochromatosis.2 Risk alleles or mutations in other
genes involved in iron homeostasis may be the underlying cause of their condition. Standard genetic testing for haemochromatosis
assesses the presence of common risk alleles and screening for other alleles or mutations would only be performed if there
were indications for doing so.
Patients with unexplained biochemical evidence or signs of iron overload may require investigation for rare diagnoses:
ineffective erythropoiesis, such as in β-thalassemia, can cause inappropriately high iron levels; patients may show signs
such as splenomegaly or jaundice or have biochemical evidence of microcytosis and hypochromia.1, 14
Following diagnosis: treatment and prevention of complications
Following a diagnosis, the most important clinical steps are to investigate patients for the presence of haemochromatosis
complications and initiate treatment. Patients should be assessed for the presence of complications arising from iron
overload and treated, such as diabetes mellitus, joint disease, endocrine disturbances (hypothyroidism and hypogonadism),
cardiac disease, porphyria cutanea tarda and osteoporosis.6
The key clinical intervention for treating haemochromatosis is venesection (phlebotomy) to reduce iron stores. Clinical
guidelines recommend that all patients with haemochromatosis are offered venesection to normalise ferritin levels. Some
patients with hereditary haemochromatosis may maintain mildly elevated iron stores without progressing to clinical complications,
such as liver disease, arthropathy, heart problems or other conditions resulting from iron overload. For these patients
venesection may represent a form of overtreatment. However, as there is no reliable method of predicting which patients
will develop complications, and venesection is a low-risk procedure, clinical guidelines recommend offering venesection
to all patients with elevated ferritin levels.2 Where venesection is not initiated, patients should be monitored
for worsening of biochemical measures of iron overload or the development of clinical complications, and to report if
suspicious symptoms develop.2
Table 2: Key practice points for venesection in hereditary haemochromatosis2
| How often should venesection be performed? |
How much blood should be removed? |
Measures during treatment |
Measurement targets |
| Analyte |
When to measure |
| Initially every one to two weeks until ferritin normalises |
500 mL (one unit) per session |
Haematocrit
Haemoglobin |
Baseline and before each session |
Within 80% of baseline values – delay venesection if values fall below 80% |
|
|
Ferritin |
Baseline and check after four venesections |
50 – 100 micrograms/L |
Referral for ultrasound and liver biopsy
Patients with haemochromatosis and ferritin levels > 1000 micrograms/L have been found to have a prevalence of cirrhosis
ranging from 20 to 45%.2 As raised liver enzymes may also indicate cirrhosis, it is recommended that:2
- Patients with ferritin > 1000 micrograms/L undergo an ultrasound and liver biopsy
- Patients with ferritin < 1,000 micrograms/L and with altered liver enzymes (AST, ALT) undergo an ultrasound and
liver biopsy
It has been reported that a study of 670 patients with two haemochromatosis risk alleles found that ferritin levels > 1000
micrograms/L had a 100% sensitivity and 70% specificity for identifying cirrhosis, and conversely, no patients with cirrhosis
had a ferritin level < 1000 micrograms/L. See “Monitoring clinical complications”, for further information.
Liver biopsy is the gold standard technique for the assessment of liver complications in patients with haemochromatosis,
as it allows for the histological assessment of the degree of liver damage and direct measurement of hepatic iron content.2 Liver
biopsy can be prone to sampling error, and ultrasound assessment of the liver allows a wider assessment of the distribution
of cirrhotic or fibrotic liver tissue.15
Venesection normalises ferritin levels
Venesection to reduce iron stores may be performed under the guidance of a haematologist or a general practitioner.
For patients unable to tolerate venesection or where it is contraindicated, referral to a haematologist is recommended;
treatment with deferoxamine mesilate (subcutaneous infusion for iron overload) in a hospital setting may be an option.
The aim is to reduce ferritin levels to 50 – 100 micrograms/L by having patients undergo venesection every one to two
weeks, removing 500 mL of blood each time, until this treatment target is reached. This amount of blood would typically
contain 200 – 250 mg of iron.2 Targeting treatment below 50 micrograms/L has been found to cause a paradoxical
increase in iron absorption.2 Table 2 shows treatment and monitoring information for patients undergoing venesection.
There is a high degree of individual variability in the rate of iron accumulation after venesection ceases, and little
evidence to guide subsequent monitoring and treatment.2, 6 Current practice is for patients to be monitored
for changes in serum ferritin and transferrin saturation to guide when or whether to re-initiate venesection.
Adverse effects and patient experiences of venesection
Patients often experience adverse effects with venesection treatment and these are similar to the adverse effects of
blood donation. Most commonly these include tiredness, loss of appetite and pain or discomfort at the needle site.16 Light-headedness
and fainting during or after the procedure is also possible.
In one survey of over 200 patients, 50% reported experiencing adverse effects during most or all venesection treatments.
In addition, the time burden of attending regular venesection sessions was rated as influencing their work or daily routine
“most of the time” or “all of the time” by 50% of patients. However, there was an overall high level of acceptance of
venesection, with 87% of patients regarding treatment as worthwhile and only 16% reporting that they would opt out of
venesection if another treatment was available.16
Patient guides and resources:
- Leukaemia and Blood Cancer New Zealand: a patient guide to haemochromatosis and venesection record book are available
at: www.leukaemia.org.nz/page/387
- Since 2011 haemochromatosis patient support has been available from Leukaemia and Blood Cancer New Zealand, which
was formerly provided by IRONZ, the New Zealand Haemochromatosis Support & Awareness Group:
www.leukaemia.org.nz
Treatment improves some symptoms and complications, but not others
Patients undergoing venesection often experience improvement in subjective symptoms of lethargy and abdominal pain,
and changes in skin pigmentation. Biochemical measures of liver function and diabetes control (if present) generally improve,
and liver fibrosis has been shown to reverse in 30% of cases.10 However, venesection does not reverse all the
characteristic symptoms and sequelae of iron overload: liver cirrhosis, arthropathy, testicular atrophy or thyroid dysfunction,
and the symptoms patients experience as a result of these complications, usually do not improve with treatment.10 Consultation
with, or referral to, an appropriate specialist is recommended for the management of complications due to haemochromatosis.
Studies suggest that patients with haemochromatosis who are adequately treated, and do not have liver cirrhosis or diabetes,
have the same life expectancy as the general population.6
Dietary advice
Given that haemochromatosis involves increased iron absorption in the gut, restricting dietary iron would appear at
face value to be an intuitive treatment. However, there is limited evidence to support a change in diet. Patients with
haemochromatosis should avoid dietary supplements containing iron, and also avoid supplements with vitamin C.3, 6,
10 Since people with haemochromatosis are already at risk of liver disease, it is recommended that patients are
advised to limit alcohol intake.
A systematic review published in 2013 found that no randomised controlled trials had assessed dietary iron reduction
and its effects on haemochromatosis management.17 However, from available limited evidence the authors estimated
that dietary iron reduction could reduce the need for venesection by one to three sessions per year, depending on patient
characteristics. Therefore, dietary iron reduction may reduce clinical burden but there is no data on the longer-term
effects of dietary iron reduction on prognosis.
Monitoring clinical complications
The range of complications and other conditions which can arise from iron overload is diverse. Particular attention
should be paid to the potential development of liver disease. Clinicians should also ensure that patients with haemochromatosis
have up to date hepatitis A and B vaccinations to reduce the risk of liver damage.
Haemochromatosis can result in a wide range of complications due to the deposition of iron in tissues around the body.
There are no specific guidelines for monitoring all of these complications. In general, clinicians should be aware that
patients with haemochromatosis may present with a variety of symptoms, and have a lower threshold for investigating other
conditions. During ongoing management clinicians should be alert for the development of symptoms and signs suggestive
of complications related to iron overload.
Patients with haemochromatosis are at increased risk of liver disease
The development of liver disease is one of the most pressing concerns in the management of patients with haemochromatosis.
Patients are at greatly increased risk of hepatic fibrosis and cirrhosis, as well as hepatocellular carcinoma. Key points
include:
- The absolute risk of liver disease in people with two C282Y risk alleles is approximately 5% for males and 1% for
females3
- People with haemochromatosis and cirrhosis have a reduced life expectancy6
- Hepatocellular carcinoma is reported to account for 30% of deaths in people with haemochromatosis (very rarely without
cirrhosis10
- Patients with hereditary haemochromatosis and cirrhosis should be screened for the development of hepatocellular
carcinoma by ultrasound every six to twelve months,10 or an alternative screening strategy discussed with
a haematologist or oncologist.
Possible patterns of inheritance of haemochromatosis alleles*
|
Genetic risk of haemochromatosis for offspring ** |
Two C282Y heterozygote parents |
Parents |
One in four homozygous for C282Y, at risk of hereditary haemochromatosis
Two in four heterozygous for C282Y, not at risk of hereditary haemochromatosis but may pass risk to their own offspring
One in four without C282Y risk alleles |
|
 C282Y / –
(other allele not associated with haemochromatosis) |
 C282Y / –
|
Offspring
 C282Y / C282Y
 C282Y / –
– / C282Y
– / – |
One C282Y heterozygote parent
+
one C282Y homozygote parent |
Parents |
One in two homozygous for C282Y, at risk of hereditary haemochromatosis
One in two heterozygous for C282Y, not at risk of hereditary haemochromatosis but may pass risk to their own offspring |
 C282Y / C282Y
|
C282Y / – |
Offspring
C282Y / C282Y
C282Y / C282Y
C282Y / –
C282Y / – |
One C282Y heterozygote parent
+
one H63D heterozygote parent |
Parents |
One in four with “compound heterozygote” genotype C282Y/H63D. At risk of hereditary haemochromatosis,
but risk is lower than C282Y/C282Y genotype
Two in four heterozygous for C282Y or H63D. Not at risk of haemochromatosis but may pass risk to their own offspring
One in four without risk alleles |
C282Y / – |
H63D / – |
Offspring
C282Y / H63D
C282Y / –
– / H63D
– / – |
One heterozygous parent
+
one parent without risk alleles |
Parents |
Since condition is recessive no offspring are at risk, although two in four may pass risk to their
own offspring |
C282Y / – |
– / – |
Offspring
C282Y / –
C282Y / –
– / –
– / – |
* The purpose of this table is to highlight common scenarios. Other combinations of parental genotypes
are possible, e.g, in the rare circumstance that both parents are homozygous for risk alleles, all offspring will be genetically
at risk for haemochromatosis.
** These figures represent theoretical mathematical averages. It is possible in clinical practice to find
a family where siblings have a distribution of risk alleles which differs from that shown here.
Acknowledgement
Thank you to Dr Joanne Dixon, National Clinical Director, Genetic Health Service New Zealand for expert review of this article.
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