Interpreting iron studies - University of Glasgow

1 RATIONAL TESTINGI nterpreting iron studiesAlison U Kelly specialty registrar in chemical pathology 1, Stephen T McSorley clinical researchfellow 2, Prinesh Patel general practitioner 3, Dinesh Talwar consultant clinical scientist 11 Department of Biochemistry, Glasgow Royal Infirmary, Glasgow , UK; 2 Academic Unit of Surgery, School of Medicine, University of Glasgow , Glasgow Royal Infirmary, Glasgow , UK; 3 Alva Medical Practice, Alva, Stirlingshire, UKA 63 year old woman visits her doctor with a three month historyof fatigue and generalised joint pains. Her medical history isunremarkable and she reports no recent stress, infection, orweight loss.

2 There are no abnormalities on clinical , creatinine, and electrolytes, liver enzymes,glucose, inflammatory markers, and thyroid function tests arenormal. Ferritin, iron , transferrin, and transferrin saturation arealso article discusses some situations in which ferritin and ironstudies might be helpful and how to avoid common pitfalls intheir are the next investigations?The doctor in this case requested iron studies to investigate thepossibility of iron overload and to screen for studies are also commonly indicated in clinical practice toinvestigate iron deficiency, or to monitor response to treatmentfor these conditions (box 1).

3 Conventional laboratory tests of iron status are often referredto as iron studies . They include tests for serum ferritin, iron ,transferrin, or total iron binding capacity (TIBC), and is a key component of haemoglobin in red blood cells,myoglobin in muscle, and many metalloproteins and is essential for uptake of oxygen and its delivery to tissues,utilisation of oxygen by muscle cells, and mitochondrial Normal iron metabolism and regulation is outlinedin Figure 1 . The adult male body contains 3-5 g of iron . Lessthan of total body iron stores circulate in plasma.

4 DietaryFe3+ is reduced to Fe2+ and transported into the enterocyte bythe divalent metal transporter DMT1. iron is exported acrossthe basolateral membrane via the iron export protein ferroportin1 or stored as ferritin. Transferrin bound iron binds to transferrinreceptor 1 (TFR1) and is taken up into the cell via receptormediated endocytosis. Expression of TFR1 is regulated locallyby the iron demands of the cell, via binding of iron regulatoryproteins. Old or damaged erythrocytes are removed from thecirculation by splenic macrophages. iron is removed from haemby haem oxygenase 1, and either stored as ferritin or releasedinto the of iron release at a systemic level is mediated by thepeptide hormone hepcidin (produced predominantly byhepatocytes) and has an inhibitory effect on iron release fromcells and dietary iron absorption.

5 Expression is controlled bycomplex signalling is included in iron studies ?Ferritin is the intracellular storage form of iron . A very smallamount is found in serum. In inflammation, liver disease , andmalignancy, ferritin levels can rise because ferritin is an acutephase In these patients, ferritin can appear either falselyhigh or normal, when in reality stores are iron refers to ferric ions (Fe3+) bound to serumtransferrin. Serum iron concentration is highly variable and isaffected by dietary iron intake, inflammation, and is the principal iron transport protein in increases in iron deficiency to maximise utilisation ofavailable Total iron binding capacity is an alternative testto transferrin.

6 TIBC reflects the availability of iron binding siteson transferrin. Values increase in iron deficiency and decreasein iron overload. Some laboratories measure unsaturated ironbinding capacity (UIBC) and calculate TIBC by adding serumiron to saturation is calculated from serum iron and eitherTIBC or transferrin measurements. Typically, transferrin is 30%saturated with Transferrin saturation rises in iron overloadand falls in iron deficiency, but does not quantitatively reflectiron A rise in serum iron due to dietary iron intake cancause raised transferrin to A U Kelly personal use only: See rights and reprints : 2017.

7 357:j2513 doi: (Published 2017 June 15)Page 1 of 6 PracticePRACTICEWhat you need to know I ron overload typically results in a high ferritin and transferrin saturation I ron deficiency is best assessed using serum ferritin, which is low in the absence of inflammation F erritin levels can be elevated by inflammatory processes and can mask iron deficiencyBox 1: Suggested indications for iron studiesInvestigation of iron overload (haemochromatosis)1o at early stages can be asymptomatic or present with vague symptoms such as fatigue, weakness, or generalised joint painso later manifestations might include deranged liver enzymes, cirrhosis, erectile dysfunction, arthritis, or cardiomyopathyo suspected iron overdose/toxicity iron deficiency2o investigating aetiology of low haemoglobino symptoms of anaemia such as lethargy, shortness of breath, palpitations, pallor, headache, atrophic glossitis, angular occult blood loss in males and post menopausal females eg.

8 Peptic ulcer diseaseo menorrhagiao iron malabsorption eg, investigation of unintentional weight loss or chronic diarrhoea, or secondary to existing conditions such ascoeliac diseaseo Anaemia in pregnancy (increased iron demands)o investigation of poor growth in infantso distinguishing low iron stores from functional iron deficiency eg, in chronic kidney disease response to medical treatmento monitoring patients who require repeated transfusions or venesectiono monitoring response to iron chelatorso assessing response to iron therapyInterpretationInterpretation of iron studies can be challenging because thedifficulties listed above affect almost all markers of iron , iron studies play an important role in clinicalassessment (table 1 ).

9 Reference intervals are quoted; however,these can vary by laboratory and must be confirmed overloadTesting for iron overload (increased total body iron stores withor without organ dysfunction) can be triggered by clinicalfeatures such as those listed in box 1. Primary iron overloadincludes inherited mutations in iron regulatory genes (causingiron loading syndromes such as haemochromatosis). Secondaryiron overload is associated with other conditions or iatrogenicfactors (box 2).Hereditary haemochromatosis (an autosomal recessive geneticcondition caused by mutation of the HFE gene) is the mostcommon inherited cause of iron overload.

10 Homozygosity forthe C282Y polymorphism affects 1 in 200 people of northernEuropean descent and accounts for more than 80% of clinicallyrecognised cases. Clinical penetrance varies widely (1%-28%of C282Y homozygotes in population studies ).7 In an unselectedpopulation, raised serum ferritin (>200 g/L for premenopausalwomen or >300 g/L for men and postmenopausal women) andtransferrin saturation >50% diagnosed C282Y homozygositywith a sensitivity of 90% in men and 75% in Anapproach to hyperferritinaemia has previously been techniques for assessing iron overload include liverbiopsy, magnetic resonance imaging, and superconductingquantum interference device susceptometry, a non-invasivetechnique that measures the amount of in vivo magnetisationcaused by hepatic Indications for these tests can includemarked hyperferritinaemia (>1000 g/L) or further assessmentwhen the diagnosis of iron overload is in doubt.