Key messages
- Tests that measure the level of ferritin in the blood may be reasonably accurate for diagnosing iron deficiency (low iron levels) in people:
- seeking medical care; and
- whose doctors suspect iron deficiency.
- The accuracy of ferritin blood tests for diagnosing iron overload (high iron levels) is unclear, due to a lack of robust evidence.
- To strengthen the evidence, we need future studies to:
- investigate a wider range of populations; and
- identify the levels of ferritin in the blood that are the best indicators of iron deficiency and overload.
Why is it important to diagnose iron deficiency and overload?
Iron is a mineral found in every cell of the body. It comes from iron-rich foods like red meat, beans and fortified cereal (to which iron has been added artificially), among others, or from supplements (iron tablets, micronutrient powders, drops or syrups). The body needs iron to make:
- red blood cells; and
- haemoglobin, a protein in blood that carries oxygen from the lungs to the rest of the body.
An iron test can show if someone has too little iron (iron deficiency) or too much iron (iron overload). It is important to test iron levels because:
- iron deficiency can cause anaemia (low levels of red blood cells or haemoglobin), tiredness and weakness. It can be a sign that someone has a serious health problem, such as internal bleeding; while
- iron overload can damage the liver, heart and other organs permanently.
What tests can be used to diagnose iron deficiency and overload?
There are several different tests available to check the level of iron in the body. The most accurate tests involve using a needle to collect a small sample of:
- bone marrow fluid (to diagnose iron deficiency); or
- tissue from the liver (to diagnose iron overload).
However, these tests are expensive and can be risky for people in poor health.
A simpler test involves measuring the level of ferritin (a protein that stores iron) in the blood, to estimate the amount of iron in the body.
What did we want to find out?
We wanted to find out if ferritin blood tests accurately diagnose iron deficiency and iron overload.
What did we do?
We searched for studies that compared ferritin blood tests against:
- tests of iron levels in the bone marrow, to diagnose iron deficiency; and
- tests of iron levels in the liver, to diagnose iron overload.
We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors like study methods and sizes.
What did we find?
We included 72 studies of 6059 people investigating the ability of ferritin blood tests to diagnose:
- iron deficiency in people who sought medical care and whose doctor suspected iron deficiency (70 studies, 5709 people);
- iron deficiency in people without any sign of disease (five studies, 350 people); and
- iron overload suspected by a doctor (36 studies, 1927 people).
Evidence suggests that ferritin blood tests may be reasonably accurate for diagnosing iron deficiency in people seeking medical care. For example, in studies where people with fewer than 30 micrograms of ferritin in one litre of blood were diagnosed with iron deficiency, ferritin blood tests correctly identified:
- iron deficiency in four out of five people who did have iron deficiency; and
- no iron deficiency in 19 out of 20 people who had normal levels of iron.
The evidence was not robust enough to determine if ferritin blood tests accurately diagnose:
- iron deficiency in people without any sign of disease; or
- iron overload suspected by a doctor.
What are the limitations of the evidence?
The studies were:
- small;
- conducted in ways that may have introduced errors into their results; and
- focused on specific populations (like children, young people and pregnant women).
For these reasons, we have limited confidence in the evidence.
How up-to-date is this evidence?
The evidence is up-to-date to June 2020.
At a threshold of 30 micrograms/L, there is low-certainty evidence that blood ferritin concentration is reasonably sensitive and a very specific test for iron deficiency in people presenting for medical care. There is very low certainty that high concentrations of ferritin provide a sensitive test for iron overload in people where this condition is suspected. There is insufficient evidence to know whether ferritin concentration performs similarly when screening asymptomatic people for iron deficiency or overload.
Reference standard indices of iron deficiency and iron overload are generally invasive, expensive, and can be unpleasant or occasionally risky. Ferritin is an iron storage protein and its concentration in the plasma or serum reflects iron stores; low ferritin indicates iron deficiency, while elevated ferritin reflects risk of iron overload. However, ferritin is also an acute-phase protein and its levels are elevated in inflammation and infection. The use of ferritin as a diagnostic test of iron deficiency and overload is a common clinical practice.
To determine the diagnostic accuracy of ferritin concentrations (serum or plasma) for detecting iron deficiency and risk of iron overload in primary and secondary iron-loading syndromes.
We searched the following databases (10 June 2020): DARE (Cochrane Library) Issue 2 of 4 2015, HTA (Cochrane Library) Issue 4 of 4 2016, CENTRAL (Cochrane Library) Issue 6 of 12 2020, MEDLINE (OVID) 1946 to 9 June 2020, Embase (OVID) 1947 to week 23 2020, CINAHL (Ebsco) 1982 to June 2020, Web of Science (ISI) SCI, SSCI, CPCI-exp & CPCI-SSH to June 2020, POPLINE 16/8/18, Open Grey (10/6/20), TRoPHI (10/6/20), Bibliomap (10/6/20), IBECS (10/6/20), SCIELO (10/6/20), Global Index Medicus (10/6/20) AIM, IMSEAR, WPRIM, IMEMR, LILACS (10/6/20), PAHO (10/6/20), WHOLIS 10/6/20, IndMED (16/8/18) and Native Health Research Database (10/6/20). We also searched two trials registers and contacted relevant organisations for unpublished studies.
We included all study designs seeking to evaluate serum or plasma ferritin concentrations measured by any current or previously available quantitative assay as an index of iron status in individuals of any age, sex, clinical and physiological status from any country.
We followed standard Cochrane methods. We designed the data extraction form to record results for ferritin concentration as the index test, and bone marrow iron content for iron deficiency and liver iron content for iron overload as the reference standards. Two other authors further extracted and validated the number of true positive, true negative, false positive, false negative cases, and extracted or derived the sensitivity, specificity, positive and negative predictive values for each threshold presented for iron deficiency and iron overload in included studies.
We assessed risk of bias and applicability using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 tool. We used GRADE assessment to enable the quality of evidence and hence strength of evidence for our conclusions.
Our search was conducted initially in 2014 and updated in 2017, 2018 and 2020 (10 June). We identified 21,217 records and screened 14,244 records after duplicates were removed. We assessed 316 records in full text. We excluded 190 studies (193 records) with reasons and included 108 studies (111 records) in the qualitative and quantitative analysis. There were 11 studies (12 records) that we screened from the last search update and appeared eligible for a future analysis. We decided to enter these as awaiting classification.
We stratified the analysis first by participant clinical status: apparently healthy and non-healthy populations. We then stratified by age and pregnancy status as: infants and children, adolescents, pregnant women, and adults.
Iron deficiency
We included 72 studies (75 records) involving 6059 participants.
Apparently healthy populations
Five studies screened for iron deficiency in people without apparent illness. In the general adult population, three studies reported sensitivities of 63% to 100% at the optimum cutoff for ferritin, with corresponding specificities of 92% to 98%, but the ferritin cutoffs varied between studies. One study in healthy children reported a sensitivity of 74% and a specificity of 77%. One study in pregnant women reported a sensitivity of 88% and a specificity of 100%. Overall confidence in these estimates was very low because of potential bias, indirectness, and sparse and heterogenous evidence. No studies screened for iron overload in apparently healthy people.
People presenting for medical care
There were 63 studies among adults presenting for medical care (5042 participants). For a sample of 1000 subjects with a 35% prevalence of iron deficiency (of the included studies in this category) and supposing a 85% specificity, there would be 315 iron-deficient subjects correctly classified as having iron deficiency and 35 iron-deficient subjects incorrectly classified as not having iron deficiency, leading to a 90% sensitivity. Thresholds proposed by the authors of the included studies ranged between 12 to 200 µg/L. The estimated diagnostic odds ratio was 50.
Among non-healthy adults using a fixed threshold of 30 μg/L (nine studies, 512 participants, low-certainty evidence), the pooled estimate for sensitivity was 79% with a 95% confidence interval of (58%, 91%) and specificity of 98%, with a 95% confidence interval of (91%, 100%). The estimated diagnostic odds ratio was 140, a relatively highly informative test.
Iron overload
We included 36 studies (36 records) involving 1927 participants. All studies concerned non-healthy populations. There were no studies targeting either infants, children, or pregnant women.
Among all populations (one threshold for males and females; 36 studies, 1927 participants, very low-certainty evidence): for a sample of 1000 subjects with a 42% prevalence of iron overload (of the included studies in this category) and supposing a 65% specificity, there would be 332 iron-overloaded subjects correctly classified as having iron overload and 85 iron-overloaded subjects incorrectly classified as not having iron overload, leading to a 80% sensitivity. The estimated diagnostic odds ratio was 8.