Interpreting Raised Serum Ferritin Levels • Link to This Article Online for CPD/CME Credits Marianna Koperdanova, Jonathan O Cullis
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EDUCATION PRACTICE EDUCATION PRACTICE RATIONAL TESTING Interpreting raised serum ferritin levels • Link to this article online for CPD/CME credits Marianna Koperdanova, Jonathan O Cullis Salisbury District Hospital, Salisbury A 60 year old businessman attended his general practi- Raised ferritin due to iron overload SP2 8BJ, UK tioner after an insurance medical examination at which Iron overload occurs when there is increased absorption Correspondence to: J O Cullis abnormal liver function tests had been noted (alanine of dietary iron, or after administration of iron or via blood [email protected] aminotransferase 70 IU/L (normal range 10-40 IU/L) transfusion. Cite this as: BMJ 2015;351:h3692 doi: 10.1136/bmj.h3692 and γ-glutamyltransferase 120 IU/L (normal range 0-37 Secondary iron overload—This may follow repeated IU/L)). He was otherwise fit and well and not taking blood transfusions, multiple infusions of intravenous iron This series of occasional articles regular medication. His general practitioner noted that (such as in people with renal failure and cancer patients provides an update on the best use of key diagnostic tests in the his full blood count and renal function were normal, and who have been treated with repeated parenteral iron), or initial investigation of common or requested hepatitis B and C serology (which were nega- prolonged ingestion of iron supplements. It may occur in important clinical presentations. tive) and serum ferritin level, which was 567 µg/L (nor- chronic anaemias with ineffective erythropoeisis (such The series advisers are Steve Atkin, professor of medicine, Weill mal range 24-300 µg/L). as thalassaemia intermedia, sideroblastic anaemias, and Cornell Medical College Qatar; chronic haemolytic anaemias). In such cases, those who and Eric Kilpatrick, honorary What is the next investigation? have received >20 transfusions (for example, patients with professor, department of clinical biochemistry, Hull Royal Infirmary, Ferritin is an intracellular iron storage protein and a sickle cell disease, β thalassaemia major, aplastic anae- Hull York Medical School. To marker of iron stores. Normal serum ferritin levels vary mia, or myelodysplasia) are at risk of iron overload and in suggest a topic for this series, between laboratories but generally concentrations the long term may develop cardiac, hepatic, or endocrine please email us at [email protected]. >300 µg/L in men and postmenopausal women and dysfunction. Secondary iron overload may also be due to >200 µg/L in premenopausal women are regarded as porphyria cutanea tarda, a hepatic porphyria presenting elevated.1 Low ferritin values provide absolute evidence with cutaneous photosensitivity and liver dysfunction due of iron deficiency.2 Raised levels often indicate iron to hepatic iron deposition. overload, but they are not specific, as ferritin is an acute Primary iron overload (hereditary haemochromatosis)— phase protein and is also released from damaged hepato- This is iron accumulation due to inheritance of mutations cytes; thus levels are elevated in inflammatory disorders, in the HFE gene on chromosome 6. This autosomal reces- liver disease, alcohol excess, or malignancy.3 4 Raised sive disorder is the commonest single gene disorder in ferritin levels therefore require further investigation in northern European populations (estimated prevalence primary care to determine if they truly represent iron 0.4%), but is far less common in other populations.6 It overload. It is critical to consider two broad categories causes excessive absorption of dietary iron, but is often of causes: asymptomatic and unrecognised in primary care.9 10 • Raised ferritin without iron overload Associated morbidities (hepatic, endocrine, cardiac) are • Raised ferritin due to iron overload. serious and preventable: timely diagnosis and treatment These can usually be distinguished through clinical are important. assessment and measurement of serum transferrin saturation.5 Clinical assessment in primary care Initial clinical assessment of any patient with hyperfer- Raised ferritin without iron overload ritinaemia should first consider reactive causes (box 2); Most patients (90%) with hyperferritinaemia will not have if these are clearly present, further investigation may iron overload.6 7 Many conditions are associated with “reac- be unnecessary. An alcohol history is mandatory, as is tive” high ferritin levels (box 1), and these may coexist assessment for liver disease. Check body mass index and (such as inflammation and hepatitis).8 blood pressure, as elevated ferritin levels in absence of THE BOTTOM LINE Box 1 | Causes of high ferritin without iron overload • Elevated ferritin levels are usually due to causes such as acute or chronic Common inflammation, chronic alcohol consumption, liver disease, renal failure, • Liver disease (such as non-alcoholic steatohepatitis or viral metabolic syndrome, or malignancy rather than iron overload hepatitis) • Exclude these causes clinically or with initial tests such as full blood count, • Alcohol excess liver and renal function, and inflammatory markers (C reactive protein or • Acute and chronic inflammatory conditions erythrocyte sedimentation rate) • Infections • A normal serum transferrin saturation (ideally fasting) usually excludes iron • Malignancy overload (where it is raised) and suggests a reactive cause for raised ferritin • Renal failure • Unexplained serum ferritin values >1000 μg/L warrant referral for further • Metabolic syndrome investigation Less common • Consider HFE mutation screen for hereditary haemochromatosis in individuals • Thyrotoxicosis with elevated ferritin and a raised transferrin saturation >45% • Acute myocardial infarction the bmj | 8 August 2015 31 EDUCATION PRACTICE iron overload are increasingly recognised in patients with thebmj.com Box 2 | Causes to be considered at first encounter with a Previous articles in this metabolic syndrome (obesity, type 2 diabetes, dyslipidae- 11 12 patient with raised ferritin series mia, and hypertension). Box 2 outlines other causes • Tests to predict to be excluded. Causes without iron overload imminent delivery in • Recent illness (such as acute infection) threatened preterm First line tests • Alcohol intake These include: labour • Abnormal liver function, chronic liver disease, cirrhosis— • Blood count and inflammatory markers (C reactive (BMJ 2015;350:h2183) Check liver function tests, consider liver ultrasound scan protein or erythrocyte sedimentation rate) to detect • Viral hepatitis—Serology for hepatitis B and C • Investigating occult inflammatory disorders • Acute or chronic inflammatory conditions—Erythrocyte intracerebral Serum creatinine and electrolytes for renal function • sedimentation rate or C reactive protein, or both haemorrhage • Liver function tests—Abnormal results should • Metabolic syndrome (obesity, type 2 diabetes, (BMJ 2015;350:h2484) prompt consideration of viral hepatitis screening and dyslipidaemia, hypertension)—Check body mass index, Screening tests for • abdominal ultrasonography blood pressure, blood glucose, lipid studies tuberculosis before Blood glucose and lipid studies. • • Renal failure—Check renal function starting biological • Malignancy (for example, weight loss, anorexia)—Imaging Transferrin saturation therapy as appropriate (BMJ 2015;350:h1060) If the cause of hyperferritinaemia is unclear, the most use- • Investigating young ful test to aid differentiation of true iron overload from Causes with iron overload adults with chronic other causes is the serum transferrin saturation. • Iron supplements, intravenous iron, transfusion history diarrhoea in primary care • Anaemia or known haematological conditions—Full blood (BMJ 2015;350:h573) Normal transferrin saturation count, blood film, haemoglobinopathy studies • Investigating sepsis In patients with unexplained hyperferritinaemia, normal • Hereditary haemochromatosis (fatigue, lethargy, transferrin saturation (<45% in females, <50% in males) with biomarkers arthralgia, diabetes, loss of libido, impotence, usually excludes conditions of iron overload, and reac- amenorrhoea, right upper quadrant abdominal pain, (BMJ 2015;350:h254) 1 4 tive causes should be reconsidered. Ideally, transfer- hepatomegaly, cirrhosis, chondrocalcinosis, skin rin saturation should be measured on a fasting morning hyperpigmentation, heart failure) sample, as serum iron levels undergo diurnal variation, • Family history of iron overload and may rise with recent food ingestion, temporarily • Porphyria cutanea tarda (cutaneous photosensitivity) increasing transferrin saturation.13 Patients should also not be tested during acute illness, when iron levels may – Refer to a hepatologist, as this degree of elevation fall and misleadingly lower transferrin saturation. is more likely to be due to serious underlying pathology.8 Elevated transferrin saturation • Patients with positive HFE mutation results In healthy adults, transferrin saturation >45% has a sen- – Refer for further assessment and therapy. sitivity of 94% and a positive predictive value of 6% for Venesection is the mainstay of management hereditary haemochromatosis.6 If the elevation is slight, in patients with iron overload, aiming to reach consider repeating measurement on a fasting sample to and maintain ferritin concentrations <50 µg/L.14 eliminate effects of recent food. Generally, genetic muta- Combined genetic testing and iron studies would tion screening (for C282Y and H63D polymorphisms) also be offered to siblings.15