In the latest in our series from Pulse Live talks, Dr Kevin Fernando discusses how GPs can treat the person and not the number when it comes to abnormal blood tests
The use of inflammatory markers (ESR & CRP) in primary care
Inflammatory markers such as C-reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR) are commonly requested in primary care for the diagnosis and monitoring of inflammatory and autoimmune conditions and to help exclude infection and cancer.
There has been a steady increase in requests for these blood tests over the last 10 years [1]. We often encounter false-positive results when checking inflammatory markers, which leads to further investigations and possible referrals.
Two large observational studies recently published in the BJGP [1, 2] compared the diagnostic accuracies of CRP and ESR and considered whether checking both together improved accuracy.
The studies found little difference between the accuracy of CRP and ESR. CRP had slightly superior diagnostic accuracy for infections but the two tests were equivalent for autoimmune conditions and cancers. The authors felt that CRP should generally be our first-line inflammatory marker test.
The authors also found that testing multiple inflammatory markers simultaneously did not increase the ability to rule out disease. Unsurprisingly, testing multiple inflammatory markers was associated with more abnormal and discordant results and increased costs. Interestingly, the negative predictive value of a single inflammatory marker test was similar to that of multiple tests, so testing both ESR and CRP adds little value.
Overall, the authors concluded that inflammatory markers have low accuracy for disease outcomes (except for polymyalgia rheumatica) and should not be used as rule-out tests. The authors also quantified the impact of over-requesting of inflammatory markers: for every 1,000 inflammatory marker tests performed, anticipate 236 false positive results generating an additional 710 GP appointments, 229 phlebotomy appointments and 24 referrals in the next 6 months.
Interpreting iron studies in primary care
Iron studies are also commonly requested in primary care to investigate iron deficiency and the possibility of iron overload. This can be both primary iron overload such as haemochromatosis and secondary iron overload as a result of a chronic haemolytic anaemia.
Ferritin
Ferritin is the intracellular storage form of iron and is the best investigation for suspected iron-deficient anaemia. It should be noted that ferritin is an acute phase protein so can be falsely elevated or normal in inflammatory disorders, liver disease, alcohol excess, and malignancy when iron stores are low.
A normal or high serum ferritin can be secondary to infection, inflammation, liver disease or cancer and therefore can mask underlying iron deficiency. It is useful to check CRP in this context to exclude underlying inflammation
Transferrin
Transferrin is the main iron transport protein that controls the level of free iron. It increases in iron-deficient anaemia to maximise use of available iron and reduces in iron overload.
Transferrin saturation is the proportion of iron-binding sites of transferrin occupied by iron. A high transferrin saturation (>50%) is a sensitive and specific test for iron overload (for example haemochromatosis), whereas low values are poorly specific for iron deficiency. Pregnancy, COCP use and chronic illness all lower transferrin saturation without iron deficiency.
Serum iron
Serum iron is the level of circulating iron bound to transferrin. Serum iron levels are highly variable and affected by dietary intake, inflammation, infection, and malignancy. An isolated low serum iron level has poor diagnostic specificity for iron deficiency.
Iron studies should be measured on a fasting morning sample, as serum iron levels undergo diurnal variation and may rise after eating, temporarily increasing transferrin saturation. People should not be tested during acute illness, when iron levels may fall and artificially lower transferrin saturation.
Importantly, do not assume all microcytic anaemias are iron-deficient anaemias – check ferritin levels. Other causes of microcytic anaemic include thalassaemias, anaemic of chronic disease and rarely lead poisoning.
A low ferritin level is diagnostic of an iron-deficient anaemia but a normal or high ferritin level does not exclude iron deficiency. If unsure, check serum iron and transferrin on a fasting sample: low serum iron and transferrin ≥3g/l are then diagnostic of iron-deficient anaemia.
Finally, if the cause of a high ferritin is unclear, the most useful test to differentiate true iron overload from other causes is transferrin saturation. However, most people with high ferritin levels will not have iron overload. Most of these are reactive high ferritin levels secondary to conditions such as liver disease, alcohol excess, malignancy, and chronic kidney disease. Consider referral for further investigation if there is a persistent unexplained serum ferritin level of more than 1000mcg/L.
References
1: Watson J, Jones HE, Banks J et al (2019). Use of multiple inflammatory markers tests in primary care: using Clinical Practice Research Datalink to evaluate accuracy. BJGP 69(684):e462-469
2: Watson J, Salisbury C, Whiting P et al (2019). Added value and cascade effects of inflammatory marker tests in UK primary care: a cohort study from the Clinical Practice Research Datalink BJGP 69(684):e470-478
Dr Kevin Fernando is a GP partner at North Berwick Health Centre. If you want to hear more from Dr Fernando, he is speaking at Pulse Live Birmingham on 6 June 2023. You can register here
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READERS' COMMENTS [1]
Please note, only GPs are permitted to add comments to articles
There was a useful review of inflammatory markers in the BMJ in 2012 which I still direct trainees to.
In effect it said:
If you know what diagnosis you’re testing for (PMR, inflammatory arthritis, IBD) then use them.
If you just want to know “if there’s something worrying going on” they add little to clinical judgement.