Non-anaemic Iron Deficiency

Iron deficiency is a reduced content of total body iron. Iron deficiency anaemia (IDA) occurs when the iron deficiency is sufficient to reduce erythropoiesis and therefore the haemoglobin level falls. However, problems related to iron deficiency can develop before this stage.

Note that most of the literature on this topic deals with iron deficiency anaemia, and there is less information on iron deficiency with normal haemoglobin levels.

Non-anaemic iron deficiency is sometimes termed 'latent iron deficiency' or 'depleted iron stores'.¹

Iron deficiency is common. For example, in the UK, iron deficiency occurs in about 20% of girls and women aged 11-64.² Non-anaemic iron deficiency may be three times as common as IDA.³ Iron deficiency is more common in the developing world.

• Iron balance is regulated by absorption of iron rather than by excretion, because humans cannot actively excrete iron. Iron is absorbed from the small intestine.
• The regulation of iron absorption and transport is complex; there seems to be an important role for hepcidin, a hormone secreted by the liver.
• Iron is lost from the body through sloughed skin cells and sloughed enterocytes from the gut, and through any form of blood loss.
• A mature fetus has iron stores, which are required because breastfeeding does not meet the infant's iron requirements. Low birthweight babies lack this store.
• Iron requirements increase at times of growth (early childhood and adolescence); during pregnancy and with menstruation.
• Dietary iron is in two forms, haem iron (the organic form, mainly found in meat) and non-haem iron (the inorganic form, mainly from plants). Haem iron is much better absorbed. Non-haem iron absorption can be improved by meat and ascorbic acid (vitamin C). Absorption is inhibited by calcium, phytates (in some plant foods) and polyphenols (in tea and coffee).
• Iron is present in many foods, so iron intake is partly related to calorie intake.

Inadequate intake (nutritional iron deficiency):

• Monotonous plant-based diets with little meat
• Low calorie intake in relation to iron requirement, e.g. growing children, pregnant women and the elderly.

Inadequate absorption:

• Malabsorption, e.g. coeliac disease.
• Excessive consumption of foods which reduce absorption, e.g. cows' milk, tea.
• Achlorhydria (gastric acid maintains ferric iron in solution, so aids absorption), e.g. from proton pump inhibitors or post-gastrectomy.
• Possibly, Helicobacter pylori colonisation reduces iron uptake.

Excessive loss:

• Menorrhagia.
• Gastrointestinal (GI) losses:
  • Gastric ulcers, erosions, oesophagitis.
  • GI malignancy (although this tends to cause iron deficiency with anaemia³).
  • Inflammatory bowel disease.
  • NSAIDs.
  • Other GI losses, e.g. recurrent bleeding from haemorrhoids, dental bleeding or epistaxis.
  • Intestinal parasites, e.g. hookworms are a common cause of IDA worldwide.
• Exfoliating skin conditions.
• Haematuria.
• Blood donation.
• Intravascular haemolysis (rarely).
• Endurance athletes may be at risk of iron deficiency from increased losses,⁴ but iron supplementation for athletes is debated and indiscriminate supplements could be harmful.⁵

Functional iron deficiency:

• This is inadequate iron supply to the bone marrow, while storage iron is present in the reticulo-endothelial cells. It can occur in renal failure.³

Symptoms

There may be no symptoms until significant anaemia develops. However, symptoms which may be linked to iron deficiency are:²

• Fatigue⁶
• Poor work productivity
• Poor attention and memory
• Sore tongue
• Poor condition of skin, nails or hair, including hair loss
• Pica (there has been debate as to whether pica is the cause or the result of iron and zinc deficiency)⁷
• Developmental delay (see Complications below)
• Restless legs syndrome⁸

Signs

There may be no signs. Possible signs of irons deficiency are:

• Angular cheilitis or angular stomatitis
• Atrophic glossitis
• Nails may show brittleness, ridging or koilonychia (spoon-shaped nails)⁹
• Poor condition of skin or hair.

Initial investigation of iron status¹⁰

A full blood count and serum ferritin are the most useful initial tests for iron deficiency.

Full blood count may show:

• Microcytosis - reduced mean cell volume (MCV) - and hypochromia - reduced mean cell haemoglobin (MCH). MCH is the more reliable of these two. Note that MCH and MCV are affected by vitamin B12 or folate deficiency.
• Increased red cell distribution width (RDW).
• Haemoglobin level is required to rule out anaemia.

Further investigation of iron status^10,15

Where the diagnosis is unclear, the following may be helpful:

• Blood film.
• Discussion with haematologist.
• Vitamin B12 and folate levels.
• Tests for other causes of fatigue, microcytosis, etc:
  • Hb electrophoresis (for haemoglobinopathies)
  • Thyroid function tests
  • Liver and renal function
  • Inflammatory markers (ESR and CRP)
• Other tests of iron status:¹
  • Reticulocyte haemoglobin content - an early indicator of iron deficiency, but not always available; gives false normal values in some situations, e.g. thalassaemia and high MCV.
  • Other serum markers of iron deficiency are: low serum iron, low transferrin saturation, high transferrin receptor levels¹⁴, raised iron-binding capacity, raised red cell protoporphyrin.
  • In chronic disease, a more helpful measure may be the ratio of serum transferrin receptors/log 10 serum ferritin.³
  • Bone marrow biopsy - can assess iron status and look for other causes of abnormal blood picture, e.g. myelodysplasia.
  • Therapeutic trial of iron. If iron deficiency is likely but is difficult to confirm, e.g. in the presence of chronic disease, it may be appropriate to try iron therapy and repeat blood tests after a few weeks.
• Pregnancy:⁹
  • The MCV may naturally increase by approximately 4 fL
  • In the 2nd-3rd trimester, if iron levels need to be assessed, the most helpful indicators are erythrocyte protoporphyrin levels or transferrin receptors. Ferritin levels, serum iron and transferrin are not useful in this scenario.
• Chronic kidney disease:
  • There are separate guidelines for assessment of iron status in chronic kidney disease (CKD).¹³

Investigating the cause of iron imbalance

With iron-deficiency anaemia, patients are normally investigated for GI causes (unless the cause is obvious, e.g. menorrhagia). With non-anaemic iron deficiency, it is less certain who needs investigating, but the following information may be relevant:

• Coeliac disease is common and easily missed. Current UK guidelines recommend coeliac serology testing in patients with IDA.¹⁶ Some authors state that coeliac disease may also manifest as non-anaemic iron deficiency.¹⁷
• The British Society for Gastroenterology guidelines comment that, on current evidence, the prevalence of gastro-intestinal malignancy is low in patients with non-anaemic iron deficiency. They suggest that, from the available evidence, only post-menopausal women and men >50 years require gastrointestinal investigation for non-anaemic iron deficiency.³
• Diets which are borderline low in iron are common.
• If the blood picture does not improve with treatment, e.g. a trial of iron therapy - see below under Iron therapy, then evaluate further.

Other causes of a similar blood picture (microcytosis and hypochromia) are:

• Haemoglobinopathies
• Hypothyroidism
• Anaemia of chronic disease (but iron-deficiency can co-exist)²
• Myelodysplastic disorders

The aims of treatment are to restore red cell indices to normal, to replace iron stores and to treat any underlying cause.

Iron therapy^3,18

• Ferrous iron salts:
  • Ferrous sulphate 200 mg twice daily is simple and inexpensive.
  • Ferrous fumarate, ferrous gluconate or iron suspensions may be better tolerated than ferrous sulphate.
  • Common side-effects are nausea and epigastric pain. These may be reduced by taking the iron with meals or reducing the dose. Constipation or diarrhoea may also occur.
  • Lower doses of ferrous sulphate may be better tolerated and equally effective.
  • Iron supplements taken every few days may also be effective.²
  • Keep iron preparations out of children's reach.
• Ascorbic acid 250-500 mg twice daily, taken with the iron, enhances absorption.
• Parenteral iron preparations are rarely indicated. Side-effects and serious adverse reactions are possible.
• There are separate guidelines for treating iron deficiency in CKD.¹³

Duration of treatment and follow-up

For IDA, guidelines suggest:³

• Oral iron should be continued until 3 months after the deficiency has been corrected, so that iron stores are replenished.
• Once the red cell indices are normal, repeat the blood count at 3-monthly intervals for one year, then annually. If the results are not clear then repeat the ferritin level.
• Treat the cause of iron deficiency, if possible.
• If the haemoglobin or red cell indices are not maintained, consider further investigation.

• Non-anaemic iron deficiency may cause fatigue⁶ and reduced work performance.
• Possibly, iron deficiency and IDA affect cognitive or motor development in children. However, the evidence is equivocal.
• Anaemic schoolchildren have reduced motor activity and school performance, but it is not clear whether this is due to anaemia or lack of iron.
• Iron deficiency may affect immune function.
• The risk of chronic lead poisoning may be increased by iron deficiency.

Iron therapy should resolve the symptoms, signs and blood picture, unless there is a serious underlying cause. The deficiency is likely to recur unless the cause is addressed.

• Adequate diet. This may be augmented by:
  • Taking vitamin C (or foods rich in it) with meals.
  • Avoiding excess consumption of foods inhibiting iron absorption, e.g. tea and coffee, cows' milk.
  • For babies, breastfeeding and a suitable weaning diet.¹⁹
• Treatment of intestinal parasite infections.
• Routine iron supplementation or fortification of foods is feasible. However, untargeted iron supplementation may have adverse effects; its benefits and harms are debated.^2,20
• Screening programmes for high-risk groups have been used. For example, routine blood counts are performed during antenatal care. In the 1970s, infants and toddlers in the USA were screened for IDA.²¹