Elevated serum ferritin is commonly encountered in general practice. Ninety percent of elevated serum ferritin is due to noniron overload conditions, where venesection therapy is not the treatment of choice.
This article aims to outline the role of the Australian Red Cross Blood Service Therapeutic Venesection program, to clarify the interpretation of the HFE gene test and iron studies, and to describe the steps in evaluating a patient with elevated serum ferritin.
After exclusion of hereditary haemochromatosis, investigation of elevated serum ferritin involves identifying alcohol consumption, metabolic syndrome, obesity, diabetes, liver disease, malignancy, infection or inflammation as causative factors. Referral to a gastroenterologist, haematologist or physician with an interest in iron overload is appropriate if serum ferritin is >1000 µg/L or if the cause of elevated serum ferritin is still unclear.
The Australian Red Cross Blood Service has experienced a growing number of referrals from general practitioners for therapeutic venesection for patients with elevated serum ferritin (SF) who do not meet the eligibility criteria of two HFE mutations or documented iron overload. Thirty-six percent of referrals to the Australian Red Cross Blood Service Therapeutic Venesection program in an 8 month period in 2011 were for patients with elevated SF and an HFE genotype not associated with iron overload.1 Venesection therapy, while the mainstay of treatment for iron overload due to hereditary haemochromatosis (HH), does not address the underlying reasons for elevated SF in patients without true iron overload.2
While there is interest in iron reduction therapy for cancer risk reduction,3 improvement of insulin sensitivity in metabolic syndrome4 and management of fatty liver disease not responding to lifestyle changes,5 the Australian Red Cross Blood Service Therapeutic Venesection program is currently restricted to patients meeting the criteria listed in Table 1, and who also meet the general eligibility criteria for volunteer blood donation.
Table 1. Eligibility criteria for Australian Red Cross Blood Service Therapeutic Venesection program
- Evidence of hereditary haemochromatosis:
- C282Y homozygosity
- C282Y/H63D compound heterozygosity
- Clinical iron overload supported by FerriScan ® MRI or liver biopsy
- Polycythaemia rubra vera
- Porphyria cutanea tarda
Patients meeting therapeutic venesection criteria with contraindications to volunteer blood donation (eg. comorbid angina, hepatitis C, cerebrovascular disease) need to be referred elsewhere for therapeutic venesection. Options include private pathology providers, public hospitals, haematologists and some GPs.
In the absence of contraindications, patients with elevated SF who do not meet eligibility criteria for therapeutic venesection may become volunteer whole-blood donors every 12 weeks.
Potential harms of frequent venesection therapy for a person without true iron overload include development of iron deficiency anaemia, reinforcement of a suboptimal management strategy for a biochemical abnormality, perpetuation of the myth that a genetic condition affecting family members exists, and the general venesection risks of venous scarring, phlebitis and vasovagal episodes.
Approximately 75% of the body's 3–4 g total iron is found within haemoglobin in red blood cells, 10–20% is stored in the protein ferritin and the remainder is found in the iron transport protein transferrin, as well as in myoglobin, cytochromes and as unbound serum iron.6
Synthesised by the liver, the hormone hepcidin regulates total body iron levels by controlling intestinal iron absorption.7 Under the strict control of hepcidin, daily iron losses of 1–2 mg from sloughed mucosal, gastrointestinal and skin cells are accurately offset by daily absorption of 1–2 mg from dietary sources. Only 10% of daily dietary iron intake is absorbed.2
The human body lacks an iron excretion mechanism. Table 2 outlines circumstances in which iron overload can develop.
Table 2. Causes of iron overload
|Mechanism of iron overload||Example|
|Inappropriately increased intestinal iron absorption
- Hereditary haemochromatosis
- Type 1: HFE mutation (HFE gene)
- Non-HFE haemochromatosis (rare)
- type 2A: haemojuvelin mutation (HJV gene)
- type 2B: hepcidin mutation (HAMP gene)
- type 3: transferrin receptor 2 mutation (TfR2 gene)
- type 4: ferroportin mutation (FPN1 gene)
|Transfusional iron overload
1 unit packed red cells ≈250 mg iron
- Multiple transfusions to treat anaemia due to:
- red cell aplasia (congenital or acquired)
- myelodysplastic syndrome, leukaemia
- cancer or chemotherapy for cancer
- severe haemorrhage in haemophilia/surgery/trauma
- Chronic haemolytic anaemias
- Congenital sideroblastic anaemia
- Congenital dyserythropoietic anaemia
|Hepatocellular chronic liver disease
- Alcoholic liver disease
- Hepatitis B or C
- Nonalcoholic steatohepatitis
|Excess parenteral iron
Assessment of iron overload relies on surrogate markers, including serum tests (transferrin saturation, serum ferritin), noninvasive magnetic resonance imaging (MRI) scans for hepatic iron concentration (FerriScan®), liver biopsy and quantitative phlebotomy.2,6
Whole blood contains 250 mg iron per 500 mL.
In HH, total body iron stores can be calculated from the volume of blood removed during weekly venesections. Removal of 4 g or more of iron (16 weekly venesections) without developing iron deficiency anaemia indicates iron overload.6
Hereditary haemochromatosis is an autosomal recessive condition of progressive iron overload, usually due to homozygosity for the C282Y mutation in the HFE gene. This mutation causes inappropriately increased intestinal iron absorption at a rate 2–3 times greater than normal.8 Similar to type 1 diabetes being a metabolic condition of glucose homeostasis due to insulin deficiency, HH is a metabolic condition of iron homeostasis due to hepcidin deficiency.9
Approximately 1 in 200 people of Caucasian race are homozygous for the C282Y mutation. This mutation has much higher penetrance than the H63D mutation. C282Y homozygotes are at highest risk of developing total body iron overload whereas C282Y/H63D compound heterozygotes have much lower risk.8,10 Even if H63D homozygotes develop elevated serum iron indices, they are unlikely to develop total body iron overload.10,11
C282Y homozygosity confers risk of the multi-organ consequences of iron overload, including liver fibrosis, liver cirrhosis, hepatocellular carcinoma, cardiac arrhythmias, cardiomyopathy, diabetes, arthropathy, hypogonadism and skin hyperpigmentation. Organ damage can be averted with early diagnosis and appropriate venesection therapy, but this is challenging due to the variable, subtle and nonspecific symptoms in early disease.
Whereas the HFE gene test indicates the risk of eventually developing iron overload, iron studies indicate if iron overload is currently present. The HFE gene test is performed once, whereas iron studies are performed every time an assessment of current iron overload is required (Table 3). A typical schedule of venesections for a patient with HH and iron overload is presented in Table 4.
Table 3. Advice based on HFE genotype and serum ferritin
|Genotype||Prevalence in Caucasian Australians11,12||Advice if serum ferritin is normal||Advice if serum ferritin is elevated|
|High risk HFE genotypes|
|1 in 188
- Increased risk of future iron overload
- Check iron studies every 1–5 years
- Family members need testing13
- Begin venesections – candidate for therapeutic venesection
- Family members need testing13
- SF >1000 μg/L: refer to gastroenterologist, haematologist or physician with an interest in iron overload
C282Y/H63D compound heterozygous
|1 in 46
|Low risk HFE genotypes|
||1 in 49
- Check iron studies every 1–5 years
- Not a candidate for therapeutic venesection but can become a volunteer blood donor if no contraindications exist
- Look for another cause of elevated SF apart from HH, especially alcohol consumption, metabolic syndrome, obesity, liver disease and inflammation
- Consider non-HFE haemochromatosis
- Family members don't need testing13
- SF >1000 μg/L: refer to gastroenterologist, haematologist or physician with an interest in iron overload
|1 in 8
1 in 4
3 in 5
- No further follow up needed13
Table 4. Venesection schedule
|Iron unloading phase, target serum ferritin ~50 μg/L|
- Weekly venesection of ~7 mL/kg (maximum 550 mL) whole blood
- Ensure pre-venesection haemoglobin >120 g/L
- Monitor Hb and SF
- Hb: is it safe to remove more blood? Delay for 1 week if pre-venesection Hb <120 g/L
- SF: is it safe to remove more iron? Monitor SF every 4–6 venesections, more often as SF approaches
- It may take many months or even years to unload excess iron
- Oral vitamin B12 and folate supplements support erythropoiesis during frequent venesections
|Lifelong maintenance phase, target SF ~50–100 μg/L|
- Venesections to maintain SF ~50–100 μg/L
- Highly variable between individuals, often in the range 2–6 venesections per year
- Monitor SF at least every 12 months
Accurate diagnosis of a patient's total body iron stores requires careful interpretation of iron studies (Table 5). Serum iron exhibits diurnal variation14 and the ideal specimen for iron studies is a fasting morning sample where oral iron supplementation has been withheld for at least 24 hours before testing.13
Table 5. Interpretation of iron studies
|Iron study test name||Explanation||Iron as an analogy to money||Abnormal values|
(vary from laboratory-to-laboratory)
|Suggestive of low iron stores||Suggestive of high iron stores|
||Unbound serum iron
||'Loose change in your pocket'
|Total iron binding capacity
||Ability to bind even more iron
||'Greediness for more money'
- Iron absorbed from duodenum bound to a transport protein
- One molecule of transferrin binds two atoms of iron
|'Money kept in your wallet'
- Iron within a storage protein
- One molecule of ferritin binds 4500 atoms of iron
|'The savings you have in your bank'
- >200 μg/L pre-menopausal women
- >300 μg/L men and postmenopausal women
- >1000 μg/L refer to gastroenterologist, haematologist or physician with an interest in iron overload
The most useful tests in the evaluation of iron overload due to HH are transferrin saturation and serum ferritin.15 Transferrin saturation >45% is sensitive and fairly specific for diagnosing HH, with increasing specificity when the threshold is increased to >55%. Serum ferritin is most useful in monitoring venesection requirement and venesection response in patients already diagnosed with HH.
While low SF is a sensitive and specific indicator of low total body iron stores, elevated SF is sensitive but very nonspecific for iron overload. While a normal SF rules out iron overload, only 10% of cases of elevated SF are due to iron overload (Figure 1). Chronic alcohol consumption, metabolic syndrome, obesity, diabetes, malignancy, infection and inflammatory conditions explain 90% of causes of elevated SF.6,16
Figure 1. Algorithm for the investigation and management of elevated serum ferritin in general practice
Elevations of SF in the range 300–1000 μg/L are common, and often reflect the presence of the previously listed conditions. Mild elevations below 1000 μg/L are 'tolerable'6 and in the absence of HH, the risk of hepatic iron overload is exceedingly low.17
Australian studies have shown a link between alcohol consumption and elevated SF, with beer more so than spirits or wine causing increases in ferritin secretion by the liver.18 Chronic daily consumption of two or more standard drinks might explain elevated SF.19 Repeat SF testing after a period of alcohol abstinence can clarify the contribution of a patient's alcohol intake on their elevated SF.
There exists a well-established link between elevated SF, metabolic syndrome and fatty liver.20,21 With the Australian prevalence of metabolic syndrome being 1 in 3,22 the high pre-test probability of 'metabolic hyperferritinaemia' is important to consider when evaluating patients with elevated SF. Features which may discriminate elevated SF due to HH from metabolic hyperferritinaemia are listed in Table 6.
Table 6. Comparison between elevated serum ferritin in haemochromatosis and in metabolic syndrome
|Feature||Elevated serum ferritin due to hereditary haemochromatosis||Metabolic hyperferritinaemia due to metabolic syndrome/fatty liver/insulin resistance/diabetes/obesity|
||Not C282Y homozygous
||Usually normal (20–45%)
(not commercially available)
|Reduced hepcidin levels
||Normal or elevated hepcidin levels
|Serum ferritin over time
||Progressively more elevated
||Fluctuations from one test to another
|Total body iron levels
|Response to weekly 500 mL venesections
||Patient tolerates >16 weekly venesections without becoming anaemic
||Patient becomes anaemic after <16 weekly venesections
|Hepatic iron concentration
(FerriScan ® MRI or liver biopsy )
|Pattern of iron deposition on liver biopsy
||Parenchymal deposition in hepatocytes
||Nonparenchymal deposition in sinusoidal and Kupffer cells
- Iron depletion
- iron chelation therapy
- Lifestyle modifications
- weight control
- correction of insulin resistance
Liver disease is a cause of elevated SF. Injured hepatocytes leak ferritin into the serum, so in liver disease, SF can be considered as another type of liver function test (LFT), along with the transaminases (alanine transaminase [ALT], aspartate aminotransferase [AST]) and gamma-glutamyl transferase (GGT). Some causes of liver disease are associated with increased hepatic iron concentration (hepatitis B, hepatitis C, alcoholic liver disease, HH) so elevated SF with abnormal LFTs usually requires further investigation.23
Malignancy, infection and inflammatory conditions may all cause elevated SF. Normal screening tests for C-reative protein (CRP), erythrocyte sedimenation rate (ESR) and antinuclear antibody (ANA) can help exclude the presence of these conditions.
Specialist review is mandatory if SF exceeds 1000 μg/L due to the increased risk of fibrosis and cirrhosis above this threshold. However, in the absence of C282Y homozygosity, hepatic iron concentration is usually normal or only mildly elevated and fatty liver, hepatitis B, hepatitis C and alcoholic liver disease may be found.17,24
- Of all HFE genotypes, only C282Y homozygotes have a high risk of hepatic iron overload.
- Once HH has been excluded in a patient with elevated SF, assess for potential causes including chronic alcohol consumption, metabolic syndrome, obesity, diabetes, liver disease, malignancy, infection and inflammation.
- If SF >1000 μg/L, refer to a gastroenterologist, haematologist or physician with an interest in iron overload.
- If SF <1000 μg/L, address reversible causes and repeat iron studies.
- Encourage voluntary blood donation every 12 weeks.
Conflict of interest: none declared.
The authors thank Dr Barbara Bell, National Medical Services Manager, Australian Red Cross Blood Service for her assistance in providing referral data. Australian governments fully fund the Australian Red Cross Blood Service for the provision of blood products and services to the Australian community.
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- Zacharski LR, Chow BK, Howes PS, et al. Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial. J Natl Cancer Inst 2008;100:996–1002.
- Houschyar KS, Ludtke R, Dobos GJ, et al. Effects of phlebotomy-induced reduction of body iron stores on metabolic syndrome: results from a randomized clinical trial. BMC Med 2012;10:54.
- Valenti L, Moscatiello S, Vanni E, et al. Venesection for non-alcoholic fatty liver disease unresponsive to lifestyle counselling: a propensity score-adjusted observational study. QJM 2011;104:141–9.
- Adams PC, Barton JC. A diagnostic approach to hyperferritinemia with a non-elevated transferrin saturation. J Hepatol 2011;55:453–8.
- Bridle KR, Frazer DM, Wilkins SJ, et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 2003;361:669–73.
- Allen K. Hereditary haemochromatosis – diagnosis and management. Aust Fam Physician 2010;39:938–41.
- Pietrangelo A. Hemochromatosis: an endocrine liver disease. Hepatology 2007;46:1291–301.
- Gurrin LC, Bertalli NA, Dalton GW, et al. HFEC282Y/H63D compound heterozygotes are at low risk of hemochromatosis-related morbidity. Hepatology 2009;50:94–101.
- Gochee PA, Powell LW, Cullen DJ, Du Sart D, Rossi E, Olynyk JK. A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Gastroenterology 2002;122:646–51.
- Olynyk JK, Cullen DJ, Aquilia S, Rossi E, Summerville L, Powell LW. A population-based study of the clinical expression of the hemochromatosis gene. N Engl J Med 1999;341:718–24.
- Centers for Disease Control and Prevention. Hemochromatosis for health care professionals. Available at www.cdc.gov/ncbddd/ hemochromatosis/training/pdf/hemochromatosis_ course.pdf [Accessed 11 July 2012].
- Dale JC, Burritt MF, Zinsmeister AR. Diurnal variation of serum iron, iron-binding capacity, transferrin saturation, and ferritin levels. Am J Clin Pathol 2002;117:802–8.
- EASL clinical practice guidelines for HFE hemochromatosis. J Hepatol 2010;53:3–22.
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- Rossi E, Bulsara MK, Olynyk JK, Cullen DJ, Summerville L, Powell LW. Effect of hemochromatosis genotype and lifestyle factors on iron and red cell indices in a community population. Clin Chem 2001;47:202–8.
- Brudevold R, Hole T, Hammerstrom J. Hyperferritinemia is associated with insulin resistance and fatty liver in patients without iron overload. PLoS One 2008;3:e3547.
- Trombini P, Piperno A. Ferritin, metabolic syndrome and NAFLD: elective attractions and dangerous liaisons. J Hepatol 2007;46:549–52.
- Chew GT, Gan SK, Watts GF. Revisiting the metabolic syndrome. Med J Aust 2006;185:445–9.
- Pietrangelo A. Iron in NASH, chronic liver diseases and HCC: How much iron is too much? J Hepatol 2009;50:249–51.
- Wong K, Adams PC. The diversity of liver diseases among outpatient referrals for an elevated serum ferritin. Can J Gastroenterol 2006;20:467–70.