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My name is Fernando Florido (also known as Juan Fernando Florido Santana), a GP in the UK. In this episode, I will go through the guideline by the British Society for Haematology on the laboratory diagnosis of iron deficiency in adults (excluding pregnancy) and children, focusing on what is relevant in Primary Care only.

In the coming episodes, I will also cover the recommendations by the British Society for haematology on:

·      The assessment of raised ferritin

·      The concept of functional iron deficiency

I am not giving medical advice; this video is intended for health care professionals, it is only my summary and my interpretation of the guidelines and you must use your clinical judgement.  

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The link to the new guideline by the British Society for Haematology on the laboratory diagnosis of iron deficiency can be found here:

·      https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.17900

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Transcript

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Hello and welcome, I am Fernando, a GP in the UK. Today, we will go through the guideline by the British Society for Haematology on the laboratory diagnosis of iron deficiency, focusing on what is relevant in Primary Care only.

In the coming episodes, I will also cover their recommendations on:

·      The assessment of raised ferritin

·      The concept of functional iron deficiency

So, stay tuned for those!

Right, let’s jump into it.

The British Society for Haematology produces Good Practice Papers to recommend good practice in areas where there is limited evidence but where a degree of consensus is likely to be beneficial to patient care.

The laboratory diagnosis of iron deficiency is difficult, because iron homeostasis is dynamic and no single test can provide an accurate assessment of iron absorption, transport, storage, and utilisation.

Iron metabolism in adults and children can be considered equivalent, and these recommendations are applicable to both paediatric and adult practice, but it does not include pregnancy.

Let’s start by saying that iron deficiency is the most common cause of anaemia worldwide. In the UK, the prevalence of iron deficiency anaemia can go up to 6% depending on age and sex, with higher rates in certain groups like menstruating women and those aged over 85 years.

The prevalence of iron deficiency without anaemia, however, is not well documented.

In this episode we are just focusing on the laboratory assessment of iron status and not the full guidance on iron deficiency anaemia which requires a detailed history, clinical examination and the review of, for example, national gastrointestinal and gynaecology guidelines as well as other local pathways.

The British Society for Haematology has suggested an algorithm for the laboratory investigation of iron deficiency anaemia which we will review at the end. But first, let’s look at the different laboratory parameters that we will need to consider.

As you may already be aware, the main diagnostic tests in iron deficiency anaemia are a full blood count and ferritin.

So let’s now start with the red cell parameters in a full blood count. Anaemia will be confirmed if haemoglobin or Hb is below the reference range. But Hb alone does not indicate iron status and at population level, there’s considerable overlap in Hb levels between iron-replete and iron-deficient people.

Iron deficiency is typically associated with microcytic hypochromic anaemia.

But low MCV, MCH, or MCHC can also appear in other conditions, especially the thalassaemias.

Interestingly, MCV can be normal in up to 40% of iron-deficient patients, and also in cases of mixed haematinic deficiency.

There are other advanced parameters like percentage of hypochromic cells (%HRC) and reticulocyte mean Hb content which can help evaluate iron availability further.

Given that Erythrocytes contain about half of the body’s iron at any one time,

a high percentage of hypochromic cells or low reticulocyte Hb content — without thalassaemia — suggests that iron is not adequately reaching newly formed red cells, which could be due to iron deficiency or iron restriction.

Morphological changes appear in iron deficiency and generally, anisocytosis precedes hypochromia and microcytosis but blood cell morphology is not diagnostic

So, in summary, in respect of full blood counts, it is recommended that:

• If thalassaemia is not present, any of MCV, MCH, or MCHC result which is below normal could suggest iron deficiency,
• On the other hand, normal red cell indices do not exclude iron deficiency as a cause of anaemia. Further investigation may still be required if there is high clinical suspicion.
• Mean reticulocyte Hb content of <29 pg can support the diagnosis of iron deficiency if initial tests are inconclusive and finally, although not diagnostic,
• Inspection of a peripheral blood film should be performed when the diagnosis is unclear.

Let’s now move onto ferritin.

Ferritin reflects iron stores and levels <15 µg/L strongly suggest iron deficiency.

Levels up to 30 µg/L can still be consistent with deficiency but are less specific.

Ferritin acts as an acute phase protein, meaning it rises with inflammation, kidney disease, liver disease, and malignancy and, because of this, interpreting ferritin in inflammatory states can be challenging.

Formulas to correct ferritin with CRP or ESR have been proposed, but the evidence isn’t robust enough for clinical use.

So, in summary, the recommendations are that:

• In children over 5 and adults a ferritin <15 µg/L is indicative of iron deficiency.
• For children under 5 the threshold is a ferritin <12 µg/L. However,
• A ferritin level within the normal range does not exclude iron deficiency if there’s inflammation or chronic disease and further investigation is often needed.

And this is where iron studies come into play. They should not be done routinely but they should be considered when:

• FBC shows microcytic or hypochromic anaemia
• Ferritin is borderline or normal but there's suspicion of iron deficiency e.g., in chronic inflammation or
• There's a need to differentiate iron deficiency from other causes of anaemia (like thalassaemia)

Iron studies include primarily: serum iron, total iron binding capacity (TIBC) and transferrin saturation (TSAT).

Let’s break this down.

Serum Iron only measures ferric iron bound to transferrin, not the iron in haemoglobin. Someone with iron deficiency will usually exhibit a low concentration of serum iron, but it is a dynamic parameter with well-established day-to-day variability. Consequently, measuring serum iron in isolation is not helpful but its measurement is required to allow calculation of percentage TSAT.

ON the other hand, TIBC and Transferrin rise in iron deficiency. Transferrin is a negative acute phase protein so its concentration may be reduced in inflammation. Although TIBC and transferrin have less variability than serum iron, their specificity remains poor so they are not really that useful for diagnostic purposes.

Finally, transferrin Saturation (TSAT) is calculated as the ratio of serum iron to TIBC or transferrin.

It reflects how much transferrin is carrying iron, but like serum iron, it’s variable and diurnal fluctuations can be up to 70%. Also conditions like malnutrition and chronic illness affect its accuracy.

A diagnostic threshold for TSAT has not been well established, but it has been suggested a target of <16% as a screening threshold.

So, in summary,

• Serum iron, TIBC and transferrin should not be used alone in diagnosing iron deficiency but a
• TSAT <16% can support the diagnosis if other tests are inconclusive.

As promised, let’s look at the algorithm proposed in this paper by the British Society for Haematology.

The first line tests for the investigation of iron deficiency anaemia are a FBC, ferritin and CRP. Based on the results, we have three main scenarios.

The simplest one is when haemoglobin is normal and no anaemia is identified.

In these cases, if ferritin is below 15, we should still suspect iron deficiency and investigations into the cause of the iron deficiency may still be required.

The other two scenarios is when there is anaemia.

And according to WHO criteria, anaemia is when Haemoglobin is:

Below 130 in adult males

Below 120 in non-pregnant females or

Below their age and gender specific reference range in children

So, if there is anaemia but no signs of inflammation, that is, CRP is normal,

But ferritin is below 15

Then this is a case of iron deficiency anaemia

However, if ferritin is 15 or higher,

Then iron deficiency is unlikely and we should consider other causes of anaemia

If there is anaemia but also signs of acute or chronic inflammation, that is, when the CRP is high

If ferritin is below 15

We should also regard this as iron deficiency anaemia.

If ferritin is higher than 150,

Then iron deficiency is also unlikely and we should consider other causes of anaemia

But if ferritin is between 15 and 150 in the context of a high CRP

Then further tests will be required, including a blood film and iron studies.

Blood film morphology will help us exclude alternative diagnoses and

We are likely to consider a diagnosis or iron deficiency anaemia if TSAT is <16% or mean reticulocyte haemoglobin content is less than 29 pg

In summary, we have summarised the current investigations for iron deficiency but this should be used alongside clinical guidelines, for example like in suspected gastrointestinal bleeding.

So that is it, a review of the laboratory investigations of iron deficiency.

We have come to the end of this episode. Remember that this is not medical advice but only my summary and my interpretation of the guidelines. You must always use your clinical judgement.

Thank you for listening and goodbye.