Non-Anaemic Iron Deficiency

1. Non-Anaemic Iron Deficiency (NAID) (Causes, Symptoms, and Treatment) ANWER GHANI FIBMS IRAQ

2. Within the body, iron has roles other than haemoglobin synthesis. Iron deficiency (ID) and anaemia are not synonymous; patients with ID can present with symptoms without having anaemia. Therefore iron deficiency without anaemia must be recognised as a clinical diagnosis on its own.

3. . 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 (Hb) level falls. However, problems related to iron depletion can develop before this stage.

4. Non-anaemic iron deficiency (NAID) is sometimes termed 'latent iron deficiency' or 'depleted iron stores. I think that ( Iron Deficiency) is the best term, but it is good to use (NON ANAEMIC IRON DEFICIENCY) for a while to alert people to the problem and that lack of iron does not mean anemia only.

5. Iron depletion may be three times as common as iron deficiency anaemia (IDA), which has a prevalence of 2-5%.

6. Risk factors Non-anaemic Iron Deficiency -Children and adolescents -The elderly -Women of childbearing age ( Iron deficiency may be an under-recognised cause of fatigue in women of childbearing age.) -Obesity (The mechanism is not fully understood, but may involve reduced absorption of iron from the upper GI tract, increased requirements and/or the impact of obesity-related inflammation.

7. Causes of Non-anaemic Iron Deficiency Inadequate intake: Plant-based diets with little meat. Low calorie intake in relation to iron requirement Malabsorption - eg, coeliac disease. Excessive consumption of foods which reduce absorption - eg, cow's milk, tea. Achlorhydria (gastric acid maintains ferric iron in solution, so aids absorption) - eg, from proton pump inhibitors or post-gastrectomy. Helicobacter pylori colonisation (possibly) reduces iron uptake. Excessive loss: (bleedings) Functional iron deficiency: (Chronic diseases) Patients with heart failure should be screened for iron level even if they are not anaemic, as treatment of depletion can improve prognosis[11].

9. Symptoms There may be no symptoms. Fatigue. Poor work productivity. Poor attention and memory. Sore tongue. Poor condition of skin, nails or hair, including hair loss. Delayed skin wound healing. Developmental delay. Restless legs syndrome. Signs There may be no signs. Angular cheilitis or angular stomatitis. Atrophic glossitis. Nails which may show brittleness. Poor condition of skin or hair.

10. Anaemia is a late manifestation of ID

11. Iron deficiency in pregnancy Compared to non-iron-deficient women, gravidas with depleted iron stores at the start of pregnancy are more likely to develop pre- and postnatal ID and have a newborn with a lower birth weight. ID has been associated with mental illness and impaired neurocognitive functions, such as poor memory and slower neural processing, which may be due to ID irrespective of anaemia. Postnatal ID is linked to neonatal iron status and foetal iron loading, and is associated with permanent cognitive and behavioural effects that are measurable until up to 19 years of age, even with postnatal iron repletion. Mothers should be screened and treated for ID before conception. Furthermore, newborns should be screened and treated for ID after birth to avoid permanent neurocognitive damage.

12. DIAGNOSIS Serum ferritin assay has become the standard test for the assessment of iron stores. The WHO defines low ferritin as levels <15 μg/L for adults and <12 μg/L for children. However, in clinical practice, when ferritin levels dip below 30 μg/L, ID can be ascertained. Ferritin is an acute-phase reactant that is increased in serum during chronic inflammation. Cut-off values for ferritin in ID are increased to 100 μg/L in states of chronic inflammation. Transferrin saturation (TSAT) levels below 20% are also diagnostic of ID. In chronic inflammatory conditions when ferritin levels are 100–300 μg/L, TSAT should be used to diagnose ID. Serum iron levels fluctuate throughout the day and should not be used for diagnosis.

13. Interpretation of ferritin levels Ferritin levels reflect body iron stores in otherwise healthy people. However, ferritin levels are unreliable in: Acute or chronic inflammation. CKD. Heart failure. Liver disease. Excessive alcohol intake. Malignancy. Hyperthyroidism. In chronic inflammatory conditionsTSAT should be used to diagnose ID.

15. Other useful tests include Hepcidin, Soluble transferrin receptor (sTFR) and Reticulocyte haemoglobin content (RHC) Although hepcidin is usually low or normal in absolute ID (AID), it helps distinguish AID from functional ID (FID) The sTFR is a valuable indicator of ID as, unlike ferritin, it is unaffected by inflammation. When haemoglobin levels are normal, a low RHC indicates early ID in functional stores and hints at iron need, pre-anaemia and a risk of developing IDA. The distinction between IDA and IDWA relies on the use of strict haemoglobin cut-offs.

16. Pregnancy: 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.

17. Non-anaemic Iron Deficiency management

18. Patients suffering from ID should be treated regardless of whether they are defined as anaemic.

19. NAID should be treated when identified, with a target ferritin of 100 mg/L

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

21. Where diet is a factor, nutritional advice may be helpful. ( Regular consumption of haem iron (eg, red meat, poultry, fish) five times a week along with regular non-haem iron in the form of green vegetables, etc, is recommended.)

22. Iron therapy 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 sulfate may be better tolerated and equally effective. Iron supplements taken every few days may also be effective. Ascorbic acid 250-500 mg twice daily, taken with the iron, enhances absorption. Parenteral iron preparations may be indicated where oral iron is not tolerated or absorbed.

23. Iron therapy Using single doses on alternate days as opposed to multiple doses on consecutive days has been shown to result in higher absorption and better regulation of hepcidin levels in iron-depleted women. The recommended oral dose is 28–50 mg iron daily or 100 mg on alternate days for 25 days. Patients’ haemoglobin, ferritin, and CRP levels in addition to red blood cell indices should be checked 6–8 weeks following the start of treatment to assess treatment response. Once ferritin levels have corrected, patients should be followed up with blood tests every 6–12 months, with replacement reintroduced if necessary.

25. Complications of NAID Iron depletion may cause fatigue and reduced work performance. Iron depletion may affect cognitive or motor development in children. However, the evidence is equivocal. Iron depletion may affect immune function. Iron depletion may increase the risk of developing heart failure, and seems to adversely affect prognosis of existing heart failure. Iron overload can result from excessive replacement, and there can be a secondary haemochromatosis.

26. References Non-anaemic Iron Deficiency (IDA) (Causes, Symptoms, and Treatment) Authored by Dr Mary Harding, Reviewed by Prof Cathy Jackson | Last edited 16 Jul 2018 Iron deficiency without anaemia: a diagnosis that matters Abdulrahman Al-Naseem, medical student,A Abdelrahman Sallam, medical student,A Shamim Choudhury, medical student,A and Jecko Thachil, consultant in haematology Clin Med (Lond). 2021 Mar; 21(2): 107–113.