Investigating microcytic anaemiaBMJ 2013; 346 doi: https://doi.org/10.1136/bmj.f3154 (Published 07 June 2013) Cite this as: BMJ 2013;346:f3154
- Correspondence to: J Uprichard
Iron deficiency anaemia and thalassaemia trait are the commonest causes of microcytic anaemia, but they may coexist
Serum ferritin and haemoglobin A2 quantitation are the two most important investigations to distinguish between iron deficiency anaemia and thalassaemia trait
Failure of iron deficiency anaemia to respond to oral iron supplementation may be due to poor adherence, malabsorption, continued blood loss, or the presence of a concurrent disorder such as thalassaemia trait or anaemia of chronic disease
A 27 year old Pakistani housewife presented with tiredness. She attributed some of this to looking after her 18 month old twins, born in Pakistan where she had received her antenatal care, but wondered if there might be another cause. She consumed a mixed diet, took no drugs or supplements, and had no anorexia, weight loss, gastrointestinal symptoms, or menorrhagia. A physical examination revealed pallor of the conjunctivae, but the findings were otherwise unremarkable. Anaemia was suspected.
A full blood count showed haemoglobin 86 g/L (reference range 110-140 g/L), mean cell volume 68 fL (76-96 fL), mean cell haemoglobin 22 pg (27-32 pg), white cell count 8×109/L (4-11×109/L), and platelet count 460×109/L (150-400×109/L).
What are the causes of microcytic anaemia?
Anaemia with a reduced mean cell volume is usually due to iron deficiency (table 1⇓) or in certain ethnic groups, thalassaemia trait1 (table 2⇓). Less commonly it may be due to sideroblastic anaemia or to anaemia of chronic disease (a hypoproliferative anaemia, often with raised inflammatory markers and occurring in response to infection, inflammation, or malignancy).2 Different anaemias, with distinguishing features, may coexist (table 3⇓).
The type of anaemia and the underlying cause should be identified, although this is not always possible, especially in elderly patients.7
Iron deficiency anaemia usually occurs as a result of blood loss through the gastrointestinal tract or through menstruation.10 The likely cause varies according to patient group (table 1). It should be noted that use of non-steroidal anti-inflammatory drugs and aspirin account for 10-15% of iron deficiency anaemia in the United Kingdom.11 Worldwide, especially where there is poverty and shortage of food, insufficient iron in the diet is a common contributory factor.5The prevalence of gastrointestinal cancer as a cause of iron deficiency anaemia increases with age, reaching a peak of 35% in men aged more than 70 years.12 Hookworm infestation is a common cause of iron deficiency anaemia in developing countries.13
Menorrhagia (a loss of ≥80 mL of blood per menstrual cycle) may result in iron deficiency anaemia, but menstrual loss is difficult to estimate. Only about 1 mg of the 10-15 mg iron in the daily Western diet is absorbed.14 Thus a regular loss of 60 mL of blood, which contains 20-30 mg iron, risks the development of iron deficiency anaemia.
Thalassaemias are inherited disorders resulting from mutations in globin genes, leading to reduced rates of globin chain synthesis (commonly α globin or β globin). They cause anaemia in the carrier state (trait) but people are usually only symptomatic when both parents are affected (thalassaemia major).
What is the next investigation?
Repeat the full blood count to confirm the initial blood count and establish if the abnormal results are stable or progressive. How urgently the full blood count needs to be repeated depends on the severity of the anaemia. If the results are abnormal request an examination of a peripheral blood film (this is not always carried out, table 4⇓). Rather than provide a definitive diagnosis, the blood film more often suggests a differential diagnosis and may thus indicate which further tests are appropriate.15 As was the case with this patient, a large retrospective study16 showed that 13% of adults with iron deficiency anaemia had mild thrombocytosis, possibly due to increased production of endogenous erythropoietin.17
Table 3 shows the tests to differentiate the causes of microcytic anaemias. If these tests do not result in a diagnosis, then a reticulocyte count should be requested to differentiate anaemia due to underproduction (low in untreated iron deficiency anaemia) from that due to red blood cell loss or destruction (raised in haemolysis, bleeding, and during treatment for iron deficiency). In patients aged over 65, a carefully controlled trial of iron supplementation may be useful to confirm and treat iron deficiency anaemia.19 This, however, needs close follow-up, as confirmation requires evaluation for a possible gastrointestinal source, such as carcinoma.20
If iron deficiency anaemia is confirmed
There may be more than one contributory factor to iron deficiency anaemia, so which tests are subsequently performed depends on the pretest probability of the underlying cause. This will depend on age, sex, diet, menopausal status, ethnicity, use of drugs, geographical location, and socioeconomic status (see table 1). For example, extensive investigation may not be appropriate in a teenage female with rapid body growth, heavy periods, and poor diet. A woman with menorrhagia will require pelvic ultrasonography. Consider upper and lower gastrointestinal investigations in other patients without a history of important overt non-gastrointestinal blood loss.11 In a prospective case series of 96 patients aged over 70 years with iron deficiency anaemia, 66% had a gastrointestinal lesion with the potential to cause chronic blood loss. In 16% of the 96 patients this was a gastrointestinal malignancy. Of the 73 patients with a benign upper gastrointestinal lesion, 17 (23%) also had a colonic lesion, which was a carcinoma in seven (10%).20
Men and postmenopausal women need investigation of the upper and lower gastrointestinal tract unless there is bleeding from a non-gastrointestinal source. Premenopausal women with gastrointestinal symptoms and iron deficiency anaemia require investigation. All premenopausal women should be screened for coeliac disease; however even those found to be positive for the condition who are aged more than 50 or have a family history of colon cancer, need investigation of the lower gastrointestinal tract.11 Those found to be negative for coeliac disease with no other obvious cause for iron deficiency anaemia, such as aspirin ingestion, poor diet, or blood donation, merit a therapeutic trial of iron supplements for three weeks. Failure to respond requires further gastrointestinal investigation.11
In a third of cases of iron deficiency anaemia, endoscopy of the upper and lower gastrointestinal tract fails to establish a cause.21 Further investigations should then include screening for coeliac disease (anti-tissue transglutaminase antibodies), autoimmune gastritis (gastrin and parietal cell antibodies), and Helicobacter pylori (urea breath test) owing to a possible association with reduced iron absorption.21
Test the urine of all patients for blood as about 1% of patients with iron deficiency anaemia have renal tract malignancy.12
When to refer
Unless patients with iron deficiency anaemia have overt non-gastrointestinal and non-gynaecological bleeding:
Refer patients to the gastrointestinal department whether or not they have gastrointestinal symptoms
Refer women to a gynaecologist if there is a structural abnormality on pelvic ultrasonography, menorrhagia unresponsive to medical management, or postmenopausal bleeding
Refer patients to a haematology service when the type of anaemia is in doubt, laboratory findings suggest iron deficiency anaemia but there has been a poor response to oral iron supplements, or when further haematological investigations, such as bone marrow examination or an investigation of bleeding state, cannot be carried out in primary care.
The patient was found to have a microcytic, hypochromic blood film and a serum ferritin concentration of 4 μg/L (range 10-420 μg/L). Given her Pakistani origin, haemoglobin electrophoresis was requested and showed the presence of haemoglobin A and haemoglobin A2; quantitation showed the haemoglobin A2 concentration to be 3.4% (normal <3.5%). These findings were consistent with iron deficiency anaemia. To correct the anaemia and replace body stores, iron supplementation is given orally unless the patient is intolerant or fails to respond. Ferrous sulphate 200 mg three times daily is effective,22 although ferrous fumarate may be cheaper. In cases of poor response or intolerance, intravenous iron is reasonably well tolerated and safe.10 Assess response by measuring haemoglobin after three weeks, as either form of treatment should result in an increase in haemoglobin concentration of 20 g/L over that time.22 Lack of response may be due to poor adherence, malabsorption, continued blood loss, or the coexistence of a disorder such as thalassaemia trait or anaemia of chronic disease.23 Expert opinion suggests that treatment should be continued for three months after iron deficiency has been corrected, to replenish iron stores.11
This patient was started on oral iron supplements but her increase in haemoglobin level was less than expected after three weeks. She denied non-compliance with her treatment. Haemoglobin A2 quantitation was repeated and her haemoglobin A2 concentration increased to 3.7%, consistent with the unmasking of β thalassaemia trait by iron therapy. DNA sequencing to confirm diagnosis is not necessary and is only available in specialised laboratories.
She was diagnosed as having both iron deficiency anaemia and β thalassaemia trait. Most patients with β thalassaemia trait are asymptomatic and do not have any abnormal physical findings apart from mild pallor. Although antenatal screening for sickle cell disease and thalassaemia has been carried out routinely in the United Kingdom since 2005,24 it is not performed in some parts of the world.
In patients of appropriate ethnic origin, thalassaemia trait may coexist with iron deficiency anaemia and should be considered (by repeating haemoglobin A2 quantitation) when a microcytic anaemia fails to respond to iron supplementation. In the presence of iron deficiency, the haemoglobin A2 concentration may be reduced and the diagnosis of β thalassaemia trait may be missed.25 To avoid iron overload in patients receiving long term treatment, monitor serum ferritin levels only when there is a dual cause for anaemia (as in iron deficiency anaemia with thalassaemia trait or with anaemia of chronic disease).21
Cite this as: BMJ 2013;346:f3154
This series of occasional articles provides an update on the best use of key diagnostic tests in the initial investigation of common or important clinical presentations. The series advisers are Steve Atkin, professor, head of department of academic endocrinology, diabetes, and metabolism, Hull York Medical School; and Eric Kilpatrick, honorary professor, department of clinical biochemistry, Hull Royal Infirmary, Hull York Medical School. To suggest a topic for this series, please email us at email@example.com
Contributors: Both authors contributed to the case history, preparation, and editing of the manuscript. JU is the guarantor.
Competing interests: Both authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
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