Elevated serum ferritin

Katie Goot

Simon Hazeldine

Peter Bentley

John Olynyk

Darrell Crawford

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.

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.

Iron metabolism

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

Iron overload

The human body lacks an iron excretion mechanism. Table 2 outlines circumstances in which iron overload can develop.

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

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.

Iron studies

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

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.

Serum ferritin

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.

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

Key points

• 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.

Further information

• Australian Red Cross Blood Service: www.transfusion.com.au/high_ferritin
• Australian Red Cross Blood Service App (which provides real-time processing of referrals and current information regarding patients who do not meet eligibility criteria): http://highferritin.transfusion.com.au
• Haemochromatosis Australia resources for GPs: www.haemochromatosis.org.au/GPResources.htm  
• GESA haemochromatosis clinical practice guidelines: www.gesa.org.au/files/editor_upload/File/Professional/Haemochromatosis.pdf
• FerriScan®: www.resonancehealth.com.

Conflict of interest: none declared.

Acknowledgements

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.

References

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Correspondence afp@racgp.org.au

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