When iron reserves are running low

Case Scenario

Vivienne, a 78-year-old patient of yours, recently started an iron supplement for iron deficiency anaemia (IDA) diagnosed by her GP. Her current medicines are irbesartan 150 mg once daily, calcium 600 mg (as carbonate) and colecalciferol 25 microgram once daily and ferrous sulfate 325 mg (105 mg elemental iron) once daily. While chatting, she explains she has been taking the iron an hour before breakfast with her morning cup of tea and her other medicines with breakfast. She seems to be adherent to her medicines, except the iron, which she says upsets her stomach. You also learn that her diet includes limited meat or vegetables. 

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Introduction

Iron is essential for metabolic functions, including oxygen transport, deoxyribonucleic acid (DNA) synthesis and mitochondrial energy generation.¹

A deficiency state occurs when iron stores are insufficient to meet requirements for these functions.^1,2 Iron deficiency has been identified as the most common nutritional deficiency worldwide and is a common cause of anaemia. Iron is crucial in many metabolic functions in the body, and consequences of deficiency can be haematological (anaemia) and non-haematological in nature.^1-4

Pharmacists can identify those who may be at risk and refer for further investigation. They can also advise patients with iron deficiency and iron deficiency anaemia (IDA) on appropriate treatment and dietary options to help manage their condition. 

Clinical features and diagnosis

Iron deficiency with or without anaemia is diagnosed by a medical practitioner and involves clinical assessment and biochemical testing. Biochemical tests may include measurement of serum iron, ferritin, transferrin, transferrin saturation, haemoglobin and mean corpuscular volume (MCV).^4,5

In populations without inflammatory conditions, iron deficiency can usually be confirmed by measuring serum ferritin, which is low during deficiency and reflects iron stores.^3,4

It is important to note that diseases causing inflammation may falsely increase serum ferritin levels and affect reliability. Other biomarkers such as transferrin and transferrin saturation may be utilised to help diagnose iron deficiency in these populations.⁴

Iron deficiency without presence of anaemia is significantly more common than IDA.⁴

Symptoms of iron deficiency include^3-5: 

• fatigue, listlessness 
• poor temperature regulation 
• decreased memory/cognition (particularly children) 
• impaired immune function 
• pica (eating or craving non-food items, e.g. ice, dirt) 
• irritability (infants) 
• restless legs.

Iron deficiency often develops gradually. At an advanced stage of iron depletion, haematopoiesis is compromised, leading to low haemoglobin levels and consequently IDA.⁴ The World Health Organization (WHO) defines anaemia as haemoglobin^1,6:

• <130 g/L adult males (≥15 years of age) 
• <120 g/L adult females (≥15 years of age) 
• <110 g/L adult females (during pregnancy)
• <120 g/L 12–14 years of age 
• <115 g/L children 5–11 years of age.

In iron deficiency without anaemia, haemoglobin levels remain normal.^4,5

IDA causes fatigue, breathlessness, angina, fast heartbeat, claudication, light-headedness, pale skin, brittle nails and poor appetite (especially in children).^3,7

Presence of symptoms may not predict severity. Many patients are asymptomatic with a low haemoglobin, but others experience fatigue with a normal haemoglobin.

Causes

Iron deficiency has three main causes⁴ : 

• blood loss 
• insufficient dietary iron intake 
• inadequate iron absorption.

Blood loss

• This occurs most commonly with menorrhagia in women. 
• Other causes may include gastrointestinal (GI) bleed (e.g. erosions, NSAIDs/aspirin ulcers, bowel cancer), as blood loss means iron loss, chronic enteric infection (e.g. hookworm) and salicylate enteropathy.^3,4

Low dietary iron intake

• This is common in Australia despite accessibility. 
• Can be from insufficient iron in absorbable form (mainly red meat) or plant-based diets in some populations (e.g. vegetarian, vegan).^2,4

Absorption

• Absorption is regulated from dietary iron. This increases when stores are low and decreases when stores are high to prevent iron overload.⁴
• It is compromised in coeliac disease, gastric surgery, inflammatory bowel disease (IBD) and malabsorptive diseases.⁴
• Absorption depends on the dietary iron ingested. Animal foods contain haem iron, which is absorbed 4–5 times more easily than non-haem iron in non-animal foods (e.g. rice, soybeans, wheat).⁴

Risk factors

In Australia, iron deficiency is common. Certain populations can be more at risk, such as women, children, the elderly, recent migrants, Aboriginal and Torres Strait Islander peoples, and institutionalised people.^3,4

Risk also increases during periods of increased demand (e.g. pregnancy, breastfeeding)^3,8 and rapid growth (e.g. toddlers, adolescents).⁴Adolescent girls and women of child-bearing age are particularly vulnerable because menstrual blood loss coincides with a time of rapid growth.²

Other risk factors include^4,9-12:

• haemodialysis for chronic renal failure
• social disadvantage (affordability, poor dietary skills/knowledge)
• medicines (e.g. nonsteroidal antiinflammatory drugs [NSAIDs], proton pump inhibitors, glucocorticoids, anticoagulants, antiplatelets)
• gastric bypass surgery, as food now bypasses the duodenum, where most iron is absorbed.
• bariatric surgery.

Treatment

Before treatment can take place, diagnosis should first be performed by a medical practitioner, as self-diagnosis and treatment can risk incorrect diagnosis and iron toxicity. Other illnesses can also present with similar symptoms.¹³

For both iron deficiency and IDA, the cause should be determined and corrected if possible. ⁵ Management often includes counselling on diet.^5,10

In the case of IDA, increasing dietary iron intake by itself will not be solely sufficient and supplementation is recommended.^3,10 Where supplementation with iron is required, oral medicines are first-line for most patients.¹⁰

Recommended treatment for IDA¹⁰ :

• Adult: 100–200 mg elemental iron orally, daily
• Child: 3–6 mg/kg elemental iron orally (max 100–200 mg), daily. Ferrous salts (sulfate, fumarate, gluconate) are known to have better absorption when compared to iron polymaltose.^3,10 Ferrous salts are best absorbed on an empty stomach 1 hour before food or 2 hours after food. However, they can be recommended to be taken with food if they cause GI upset.¹⁰ Iron polymaltose is best taken with food.¹⁰

Some iron supplements available over the counter (OTC) do not have sufficient elemental iron in line with recommended treatment doses.³

It is important to note that iron deficiency is only one cause of anaemia.⁴ Iron supplementation is contraindicated in cases where anaemia is not caused by iron deficiency.¹⁰ 

There are variations on how long oral supplementation should continue depending on the reference text. For adults with IDA, the Australian Medicines Handbook (AMH) recommends it is continued for at least 3 months after haemoglobin normalises (around 2–3 months in children). Unnecessary longterm use should be avoided.¹⁰

Parenteral iron is considered if oral therapy is inadequate or inappropriate. A blood transfusion may be needed in severe anaemia to increase haemoglobin quickly.¹⁰

Evidence is limited for beneficial effects of iron supplementation in the treatment of iron deficiency without anaemia.⁵ Supplementation may be considered in certain cases to help improve symptoms or for those at risk of developing anaemia.^3,5

Optimising treatment

Some evidence suggests oral iron causes GI upset by increasing methaneproducing microorganisms in the gut.¹⁴

Patients are often non-adherent to oral iron supplementation leading to poor treatment outcomes.⁹ Pharmacists should discuss with the patient if GI side effects are the reason and can suggest ways to optimise tolerability.¹⁰ Iron should be taken for the recommended duration to ensure optimal response to therapy.⁹

Possible measures to enhance tolerability include:

• taking with food (risking reduced efficacy with ferrous salts)¹⁰
• starting with a low dose and increasing gradually after 2–4 weeks¹⁰ 
• using a liquid preparation to split into a divided daily dose (temporarily stains teeth)^9,10,15 
• alternate day dosing.^10,16

Liposomal iron with a phospholipid coat to protect the intestinal mucosa is being investigated to see if it can improve GI tolerability.^9,17

Vitamin C is often recommended to be taken at the same time as iron to enhance absorption.³ A 2020 randomised clinical trial concluded that when compared to iron supplementation alone, iron supplementation with vitamin C produced equivalent results for haemoglobin recovery and iron absorption. Further study is needed.¹⁸

Drinks such as tea and coffee can negatively affect iron absorption. It is recommended to drink tea and coffee between meals when iron intake is marginal and avoid taking with iron supplements.^4,10

Iron can impact absorption of certain medicines in the GI tract or affect their concentration.¹⁰ Absorption of iron can also be affected by some medicines. Separation of iron and the interacting medicine/s is generally recommended; the specific separation time requirement varies depending on the interaction.¹⁰

Some examples of interactions include calcium supplements, quinolones, bisphosphonates, antacids and thyroid hormones.¹⁰

Preventive measures

Optimising dietary iron intake is best achieved by incorporating both haem (found in meat) and non-haem (plantbased) iron in the diet.⁴ For haem iron, iron content is higher in darker (redder) forms of meat.⁴

Non-haem forms of iron are significantly less bioavailable than haem iron. ⁴ It should be considered that some patients do not consume meat and therefore rely on plant-based sources of iron in their diet. Examples of sources of non-haem iron include green leafy vegetables (e.g. spinach, broccoli), dried fruits, seeds, nuts and ironfortified cereals.^4,13

Ensuring a diet rich in iron during pregnancy and introducing suitable solid foods within the recommended timeframe can help prevent iron deficiency in babies less than 12 months of age.¹³

See www.nrv.gov.au/nutrients/iron for the recommended daily iron intake for different life stages and ages in Australia and New Zealand.¹⁹

Knowledge to practice

Pharmacists can help recognise symptoms of iron deficiency in at-risk people and refer for further investigation and diagnosis. Once appropriate diagnosis and recommendation for treatment is made, pharmacists can advise on which OTC oral iron is most appropriate for the individual patient and help optimise ongoing adherence. 

If required, oral iron supplementation is considered first-line in most patients. Ferrous salts are recommended to be taken 1 hour before or 2 hours after food, but if GI adverse effects are reported, allow for co-administration with food to improve adherence. Vitamin C coadministration recommendation remains current, despite unsure benefit.¹⁸

Pharmacists need to be aware of interactions between iron and other medicines and to advise on separating doses when appropriate.^5,10

Conclusion

After diagnosis and investigation of the underlying cause, treatment of iron deficiency with or without IDA may involve dietary interventions and iron supplementation. Given the extended timeframe required for oral iron supplementation to work effectively and potential for adverse effects, adherence can be low. The pharmacist can encourage an iron-rich diet and tailor supplementation use to suit the individual with their intolerances and preferences. Research to provide alternative options is on the horizon and is looking promising to further enhance treatment.

Key Points

• Iron is an essential nutrient required for healthy metabolic function. 
• Iron deficiency can be caused by several factors and can lead to IDA. 
• Treatment can involve investigating and correcting the underlying cause, iron supplementation and/or optimisation of dietary iron intake. Dietary modification alone is not sufficient to treat IDA.

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References

1. Kumar A, Sharma E, Marley A, et al. Iron deficiency anaemia: pathophysiology, assessment, practical management. BMJ Open Gastroenterol. 2022; 9(1):e000759.
2. Abbaspour N, Hurrell R, Kelishadi R. Review on iron and its importance for human health. J Res Med Sci 2014 Feb;19(2):164–74. 
3. Iron deficiency. In eTG complete. Melbourne: Therapeutic Guidelines; 2022.
4. Gastroenterological Society of Australia. Clinical Update: Iron deficiency. Melbourne;GESA; 2015.  At: www.gesa.org.au/public/13/files/Education%20%26%20Resources/Clinical%20Practice%20Resources/Iron%20Deficiency/Iron_Deficiency_2015.pdf
5. Balendran S and Forsyth C. Non-anaemic iron deficiency. Aust Prescr 2021;44:193–6.
6. Aggarwal Al, Aggarwal An, Goyal S, et al. Iron-deficiency anemia among adolescents: a global public health concern. International Journal of Advanced Community Medicine 2020;3(2):35–40.
7. Iron deficiency anemia. Mayo Clinic 2022. At: www.mayoclinic.org/diseases-conditions/iron-deficiency-anemia/symptoms-causes/syc-20355034
8. Haider B, Olofin I, Wang M, et al. Anaemia, prenatal iron use, and risk of adverse pregnancy outcomes: systematic review and meta-analysis. BMJ 2013;346:1–19.
9. Baird-Gunning J, Bromley J. Correcting iron deficiency. Aust Prescr 2016;39:193–9.
10. Rossi S, ed. Australian medicines handbook. Adelaide: Australian Medicines Handbook; 2022.
11. Iron deficiency after gastric bypass surgery. John Hopkins Medicine. At: www.hopkinsmedicine.org/health/wellness-and-prevention/iron-deficiency-after-gastric-bypass-surgery
12. Gowanlock Z, Lezhanska A, Conroy M, et al. Iron deficiency following bariatric surgery: a retrospective cohort study. Blood Adv 2020;4(15):3639–47.
13. Victoria State Government Health and Human Services. Better Health Channel: Iron and iron deficiency. 2021. At: www.betterhealth.vic.gov.au/health/conditionsandtreatments/iron 
14. Bloor S, Schutte R, Hobson A. Oral iron supplementation–gastrointestinal side effects and the impact on the gut microbiota. Microbiol Res 2021;12:490–502.
15. Iron deficiency anaemia. AMH Aged Care Companion. Adelaide: Australian Medicines Handbook; 2022.
16. Stoffel N, Zeder C, Brittenham G, et al. Iron absorption from supplements is greater with alternate day than with consecutive day dosing in iron-deficient anaemic women: a randomised clinical trial. Haematologica 2020;105:1232–9.
17. Pisani A, Riccio E, Sabbatini M, et al. Effect of liposomal iron versus intravenous iron for treatment of iron deficiency anaemia in CKD patients: a randomized trial. Nephrol Dial Transplant 2015;30:645–52.
18. Li N, Zhao G, Wu W, et al. The efficacy and safety of vitamin C for iron supplementation in adult patients with iron deficiency anaemia: a randomized clinical trial. JAMA Netw Open 2020;3:e2023644
19. Australian Government National Medical Research Council. Nutrient Reference Values for Australia and New Zealand. 2014. At: www.nrv.gov.au/nutrients/iron

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