Determine the Underlying Reason for Iron Deficiency Anaemia

Dr Sophie Nelson Explores Updated BSG Guidelines on Iron Deficiency Anaemia in Adults, Emphasising the Important Role of Primary Care in Identifying the Cause

Iron deficiency anaemia is a condition that GPs frequently encounter—it is the most common form of anaemia seen in primary care in the UK,¹ and the predominant cause of anaemia worldwide.² In the developed world, iron deficiency anaemia has a point prevalence of between 2% and 5% in adult men and postmenopausal women.¹ The condition is a major cause of morbidity in the UK and worldwide,¹ and expenditure on its management in England totalled £90.6 million in 2017–18.³ Therefore, there is scope to improve the considerable burden of the disease on both patients and the NHS.

In September 2021, the British Society of Gastroenterology (BSG) released its new, much anticipated guidelines for the management of iron deficiency anaemia.¹ The 2021 guidance incorporates the latest evidence to direct the optimal investigation and treatment of people with iron deficiency anaemia, and features some important updates that will be highlighted in this article.

Definition and Causes of Iron Deficiency Anaemia

Definition

The diagnostic criteria for anaemia vary between published studies and between different populations in the UK.¹  In the BSG guidelines, anaemia is defined as a haemoglobin concentration that is less than the lower limit of normal for the relevant population and for the laboratory performing the test.¹  The following lower limits of normal, as defined by the World Health Organization, can be used as a guide:^1,4

• less than 130 g/l in men aged 15 years or older
• less than 120 g/l in nonpregnant women aged 15 years or older
• less than 110 g/l in pregnant women in the second and third trimesters.

Mean cell haemoglobin (MCH; a marker of hypochromia) and mean cell volume (MCV; a marker of microcytosis or abnormally small red blood cells [RBCs]) are both reduced in iron deficiency anaemia, although these markers can be normal in mixed deficiencies, and therefore should not be relied upon.¹ Serum ferritin level, a measure of iron stores in the liver, is the most specific marker of iron deficiency in the absence of inflammation—a level of less than 30 mcg/l is indicative of low body iron stores, whereas less than 15 mcg/l is indicative of absent iron stores. However, ferritin is an acute-phase protein (often raised in the presence of inflammation), so it can be high as a result of inflammation even when a patient is iron deficient.^1,5

Non-anaemic iron deficiency, in which serum ferritin is low but the haemoglobin concentration is normal, is a relatively common scenario.¹ The condition tends to indicate low body iron stores, but not to the extent causing anaemia (although anaemia is likely to occur if the low-iron state persists).¹

Causes

The recognised causes of iron deficiency anaemia include:¹

• chronic blood loss from:
  • the digestive tract (due to, for example, cancer, inflammatory conditions such as peptic ulceration or inflammatory bowel disease [IBD])
  • the genito-urinary tract (due to, for example, haematuria, pathological gynaecological conditions, cancer)
  • the respiratory tract (due to, for example, recurrent epistaxis, haemoptysis)
• malabsorption syndromes (for example, enteropathies such as coeliac disease or Crohn’s disease, gastrointestinal [GI] surgery, genetic disorders)
• chronic disease (for example, chronic heart failure [CHF], chronic kidney disease [CKD], chronic inflammatory disorders).

Menstrual blood loss is a common cause of iron deficiency anaemia in premenopausal women, but in postmenopausal women and adult men the condition is often caused by chronic blood loss from the GI tract, and may indicate an underlying cancer.¹ Between 5% and 10% of cases of iron deficiency anaemia are caused by colon cancer, 5% by gastric cancer, and 1–2% by oesophageal cancer,⁶ so prompt recognition and action are important.

Between 1% and 10% of patients will have more than one cause of their iron deficiency anaemia (for example, significant disease in both the upper and lower GI tract), and this is particularly true in an older population.¹

Investigations in Primary Care

Suspected Iron Deficiency Anaemia

The BSG recommends that suspected iron deficiency should be confirmed by iron studies prior to investigation.¹ A key component is serum ferritin level—a low level of serum ferritin confirms the diagnosis of absolute iron deficiency due to iron deficiency anaemia.¹

Erythrocyte Sedimentation Rate and C-reactive Protein

The BSG also highlights the importance of testing the levels of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).¹ An elevated ESR or CRP can indicate the presence of inflammation,⁷ which can mask iron deficiency anaemia,^1,5 but may also indicate the presence of an underlying cause such as IBD.¹

RBC Changes Related to Iron Deficiency, and Serum Markers

The BSG guidelines also provide details on testing for serum markers of iron deficiency, such as transferrin saturation, and measuring changes in RBCs that accompany iron deficiency anaemia, such as MCH and MCV (see Figure 1 of the BSG guidelines for the complete list of investigations).¹  When MCV is low and iron indices are normal, it may indicate the presence of a haemoglobinopathy.¹

Coeliac Serology

Coeliac disease is present in 3–5% of people with iron deficiency anaemia.¹ The BSG recommends that the condition should be routinely screened for; in primary care, this takes the form of serological screening for a marker such as tissue transglutaminase.¹

Confirmed Iron Deficiency Anaemia

Once iron deficiency anaemia has been confirmed, the BSG recommends that the initial clinical assessment should involve taking a detailed history, which may provide clues as to the cause of the condition.¹ Urinalysis or urine microscopy should be performed to exclude renal pathology, in particular renal carcinoma; however, the BSG states that urine dipstick testing and mid-stream urine analysis have limited sensitivity and specificity for renal tract pathology.¹  

Characteristics such as age, sex, and haemoglobin concentration should be considered as part of a holistic assessment of the risk of GI cancer and, when appropriate, patients should be referred for endoscopic examination of the upper and lower GI tract.¹

Faecal Immunochemical Testing

Faecal immunochemical testing (FIT) detects trace amounts of blood in the stool.¹ FIT is recommended by NICE for determining whether iron deficiency anaemia in people aged less than 60 years warrants an urgent referral for suspected colorectal cancer.⁸ However, the BSG guidelines state that there is currently insufficient evidence to support the use of FIT for risk stratification in iron deficiency anaemia, although it acknowledges this guidance may change in future, as more evidence comes to light.¹

In my opinion, FIT is a useful adjunct to investigation—particularly as the BSG recommends referral of postmenopausal women with iron deficiency anaemia,¹ and menopause is likely to occur before the age of 60 years—although management should not change based on the result.

Referral to Secondary Care

Referral procedures are fairly straightforward—the BSG recommends that all adults with a new diagnosis of iron deficiency anaemia without obvious explanation should be considered for referral to secondary care for GI investigation ‘on an urgent basis’,¹ meaning referral via the suspected cancer (2-week wait) pathway.^8,9 GI investigation normally consists of gastroscopy and colonoscopy (or, for those not suited to colonoscopy, computed tomography [CT] colonography).¹ In a patient with weight loss, a chest, abdomen, and pelvic CT would also usually be performed.

In patients with nonanaemic iron deficiency, the likelihood of an underlying GI cancer is relatively low; however, the guidelines state that clinicians should have a low threshold for referral in men and postmenopausal women, those with a family history of GI pathology, and those with GI symptoms.¹ In symptomatic, premenopausal women with nonanaemic iron deficiency, iron supplementation can usually be initiated without the need for referral to secondary care.¹ However, if there is no response to an initial course of iron replacement therapy, the patient should be referred for investigation.¹

Management of Iron Deficiency Anaemia

The management of iron deficiency anaemia consists of iron replacement therapy.¹ The BSG recommends that iron supplementation should be initiated as soon as iron deficiency anaemia is diagnosed (unless colonoscopy is imminent), so that treatment and investigation can proceed in parallel.¹ Iron replacement therapy generally takes the form of oral iron, a number of different preparations of which are available in the UK.¹ However, parenteral iron is an option in certain patients, such as those with ongoing significant bleeding, malabsorption due to GI disease, issues with administration (for example, severe dysphagia), or compliance, and also in those whose condition has failed to respond to oral iron replacement therapy for reasons such as intolerance or pharmacodynamic failure.¹

Figure 1 below demonstrates the BSG’s approach to iron replacement therapy in patients with iron deficiency anaemia.¹ The most important update in the guidelines is that iron should now be given once daily (as opposed to the traditional two or three times a day). This is because of the action of hepcidin, a hormone that is upregulated after each dose of oral iron and blocks further iron uptake for around 24 hours, rendering additional doses within this period futile.^1,10 Therefore, the frequency of iron supplementation can be reduced to every other day in patients who struggle to tolerate its side effects,¹ which include constipation, nausea, vomiting, and stomach pain.¹¹

The BSG recommends that iron replacement therapy is continued for 2 months after the normalisation of haemoglobin concentration in healthy, almost iron-replete patients to ensure that iron stores are fully replenished.¹  However, in patients with chronic disease, continuing blood loss, impaired absorption, or GI inflammatory disease, a longer period may be required.¹

Monitoring Response to Treatment

After Initiation

The BSG states that there should be a ‘prompt and measurable haematological response’ to iron replacement therapy.¹ Ideally, a full blood count (FBC) should be performed 2 weeks after the initiation of oral iron, at which time a rise in haemoglobin concentration of at least 10 g/l indicates successful treatment. If this is logistically difficult, the BSG advises that a 28-day review is appropriate, at which time a rise in haemoglobin concentration of 20 g/l or into the normal range would indicate an adequate response to treatment.¹

Ongoing Monitoring

Once haemoglobin concentration has reached the normal range, the BSG suggests regular monitoring to ensure a satisfactory response.¹ Therefore, an FBC should be performed every 3 months for 1 year, and thereafter every 6 months for 2–3 years.¹  It is not necessary to monitor serum ferritin each time.¹

Patients who either fail to respond to iron, or whose iron deficiency anaemia recurs once iron replacement therapy has ceased, should be referred for further investigation (in particular, of the small bowel).¹

Other Considerations

There are several scenarios in which a slightly different approach is used to manage iron deficiency anaemia, and these will be covered in the following sections.

Young Women

Iron deficiency anaemia is common in young women—causes include menstrual loss, pregnancy, and poor diet.¹ Underlying GI pathology is uncommon in this population; therefore, excluding screening for coeliac disease, the BSG recommends that further investigation is only warranted if there are additional clinical features of concern, such as red-flag symptoms for cancer or genetic predisposition.¹

Young Men

Iron deficiency anaemia is uncommon in young men, and warrants thorough investigation in the absence of a convincing explanation.¹

Advanced Age

Iron deficiency is common in elderly individuals, and the cause is often multifactorial.¹ Therefore, iron deficiency anaemia in elderly people requires thorough investigation, although the risks and benefits of invasive endoscopic and alternative procedures should be considered, particularly in the presence of comorbidities.¹

Chronic Kidney Disease

Anyone with an estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m² is at risk of anaemia; if eGFR falls to less than 30 ml/min/1.73 m², it becomes very likely.¹  When this occurs, the anaemia is often multifactorial.¹ The BSG advises that decisions about the need for further investigations in a patient with CKD and iron deficiency anaemia are complex, and should ideally be made in conjunction with the nephrologist.¹ However, when the iron deficiency anaemia is newly diagnosed, referral via the 2-week wait pathway is appropriate.¹

Chronic Heart Failure

Anaemia is very common in the presence of CHF—some degree of iron deficiency is present in 40–70% of patients with the condition—and its causes are multifactorial.¹ Boosting the iron levels of these patients with parenteral iron has been shown to be of some prognostic benefit, but oral iron does not improve prognosis and should be avoided in these patients.¹  Decisions about the need for and safety of endoscopic evaluation should be made in conjunction with the patient’s cardiology team.¹ As with CKD, when the iron deficiency anaemia is a new diagnosis, patients should be referred for urgent investigation via the 2-week wait pathway.¹

Inflammatory Bowel Disease

One-third of patients with IBD are thought to have iron deficiency; this may be due to blood loss but can also be caused by other mechanisms, including vitamin B12 and folate deficiency.¹ Because of the presence of chronic inflammation, iron deficiency should be considered if the serum ferritin level of a patient with IBD is less than 100 mg/l.¹ Be aware that these patients may have a reduced ability to absorb oral iron, and therefore often require iron replacement therapy as intravenous infusion.¹

GI Surgery

Iron deficiency anaemia is common following GI surgery as a consequence of reduced nutritional intake and iatrogenic malabsorption.¹ Deficiencies, such as vitamin B12 deficiency, are also relatively common in this group.¹ However, the guidelines state that it is unsafe to attribute iron deficiency anaemia to previous GI surgery without excluding other possibilities and, when the iron deficiency anaemia is a new diagnosis, the patient should be referred for further investigation, as advised for other populations who require a different approach.¹  

Summary

Iron deficiency anaemia is a common presentation in general practice. Most of the investigations to determine its cause are performed using endoscopy in secondary care. However, there are important preliminary investigations that GPs can undertake alongside referral, and treatment with iron therapy should be commenced in primary care as soon as iron deficiency anaemia has been diagnosed. 

Dr Sophie Nelson

GP, Cheshire; GP with a special interest in gastroenterology at Manchester University NHS Foundation Trust; Committee Member for the Primary Care Society for Gastroenterology