SOUTH AFRICAN LIFESTYLE MEDICINE ASSOCIATION

Running on Empty?

Running on Empty?

By Dr Nyasha Grace Gogoma

There is a medical condition that lurks just beneath the surface, affecting billions of people all over the world, yet often going unrecognized and under-diagnosed. Symptoms such as difficulty concentrating and fatigue are vague and non-specific, leading to dismissal by patients and medical practitioners alike.1,2 In many cases, this condition may be misdiagnosed as depression, burnout, subclinical hypothyroidism or even chronic fatigue syndrome, but the answer lies in careful history-taking and appropriate investigations.1,2

Iron deficiency is the commonest nutritional deficiency worldwide and is an important cause of anaemia.3 Globally, more than 1 billion people have been diagnosed with iron deficiency anaemia (IDA),3 leading to significant functional impairment.4 Due to under-diagnosis, the exact prevalence of iron deficiency without anaemia (IDWA) is unknown, but estimates suggest it is at least twice as prevalent as iron deficiency anaemia.3 Because iron deficiency can produce debilitating symptoms even in the absence of overt anaemia, it is crucial for practitioners to recognize IDWA as a diagnosis in its own right and provide patients with the necessary care.

Iron is a heavy metal that is indispensable for human life. It is vitally important for numerous processes within our bodies, including oxygen transport, cell division and differentiation, and control of gene expression.5 Iron has a storage pool and a functional pool.3 It is stored as ferritin and haemosiderin in the liver, spleen, and bone marrow, and exists in the functional pool in haemoglobin (oxygen-carrying molecules in red blood cells) and myoglobin (oxygen-carrying molecules in heart and skeletal muscle tissue).3 About 70% of our total body iron is found within our red blood cells.5

Iron deficiency occurs when iron stores drop below levels required for adequate cellular functioning.3 Even in the absence of anaemia, iron deficiency causes distressing symptoms due to the following mechanisms. Various enzymes  need iron to work, and without enough of it, cellular respiration, the process by which cells produce energy, is impaired.2,3 This may explain symptoms of iron deficiency such as fatigue, weakness, cognitive dysfunction, poor memory, and exercise intolerance.1,2,3 Reduced iron levels in the brain interfere with production of neurotransmitters, particularly dopamine, which is responsible for motivation, pleasure, and movement control.2,6 This is thought to explain why depression and restless legs may develop – an insatiable desire to move ones legs while resting that is caused by unpleasant sensations in the legs.3,6 Restless legs may contribute significantly to sleep disturbance.3,6

Symptoms such as hair loss, brittle nails, and dry skin occur due to the body selectively allocating this limited resource. Haemoglobin production is prioritized while nerve cells, muscle tissue, and especially the integumentary system are deemphasized.2,3 Other symptoms of iron deficiency include craving and/or eating non-nutritive substances such as ice, soil, or paint (pica), weight gain, cold hands and feet, and general cold intolerance.3,7

The commonest causes of iron deficiency can be grouped into several categories: insufficient dietary consumption, reduced absorption within the digestive tract, increased demand, persistent bleeding, and chronic inflammation.3 Dietary iron exists in two forms: heme and nonheme.5 Heme iron is easily absorbed when consumed, and is found in animal sources, particularly red meat. Nonheme iron is found in plant sources, accounting for up to 90% of total iron acquired through food. However, this form of iron is not as readily absorbed after it is eaten, and thus, people consuming plant-exclusive diets may be at risk of low iron.3,5 Iron is absorbed in the duodenum, and medical conditions such as autoimmune gastritis, bariatric surgery, or frequent use of certain antacids (PPIs) limit its absorption.3

Pregnant women, growing children, and high-performance athletes have increased iron requirements, and are at a higher risk of iron deficiency.3 Women with heavy menstruation, frequent blood donors, and people suffering from cancers of the gastrointestinal tract are also at risk of iron deficiency due to chronic blood loss.3 Finally, persistent inflammatory states such as cancer and inflammatory bowel disease result in increased hepcidin synthesis, and this molecule blocks iron export and absorption, resulting in deficiency.3

After eliciting symptoms suggestive of iron deficiency, clinicians can confirm the diagnosis by ordering blood tests, particularly iron studies. Haemoglobin levels may be normal even in the face of severe iron store depletion, since anaemia is a late sign of iron deficiency.1 Ferritin is indicative of iron stores, and a ferritin blood level of less than 30 μg/L is the most sensitive and specific marker of iron deficiency.1,3 A transferrin saturation level of less than 20% also supports the diagnosis.3 Once iron deficiency without anaemia is diagnosed, further investigation of the root cause is warranted, with prompt initiation of iron replacement therapy.4

Treatment of iron deficiency relies on addressing the cause of the low iron, optimizing dietary intake. and iron supplementation.3,4,5 In cases of diagnosed iron depletion, dietary intake alone is unlikely to correct the deficiency.4,8 Oral iron supplements traditionally exist as ferrous fumarate, ferrous sulphate, and ferrous gluconate. These ferrous salts are preferred due to their affordability and ready absorption, and are best taken on an empty stomach, 1 hour before or 2 hours after a meal.8 Ascorbic acid increases oral iron absorption and is often co-prescribed.5,9 Side effects such as nausea, diarrhoea, and epigastric pain may limit tolerance of oral iron supplements, but these symptoms may be alleviated by alternate-day dosing.4,8 Newer formulations such as Sucrosomial® iron, which consist of ferric pyrophosphate surrounded by a phospholipid and sucrester matrix have superior tolerability, but are often more costly.4

Finally, lifestyle measures can enhance iron absorption. People consuming a whole-food plant-based diet can maintain sufficient iron stores by eating various iron-rich foods such as leafy greens, wholegrains, legumes, dried fruit, nuts and seeds.8 These foods promote a healthy gut microbiome, which further aids in iron absorption.9 Pairing these with foods rich in Vitamin C, such as tomatoes or citrus fruits, also improves absorption.8,9 Calcium and polyphenols inhibit iron absorption, so foods rich in calcium (dairy, fortified plant milks, calcium-set tofu) and polyphenols (green and black tea, coffee, cocoa, and red wine) should not be consumed within the same meal as iron-rich foods.5,8 Additionally, certain plant foods such as spinach and legumes are very iron-rich, but also contain high levels of phytates, which block iron absorption.8 Phytate  in plant foods can be significantly reduced by soaking, sprouting, or fermenting them.9 Other pillars of lifestyle medicine such as stress reduction, regular sleep, and social connection have also been linked with improved iron levels!9

In conclusion, iron deficiency without anaemia is an important but often overlooked diagnosis. Physicians should maintain a high index of suspicion to diagnose it before anaemia develops. Supportive dietary and lifestyle counselling along with oral supplementation are the mainstays of treatment.

References

  1. Soppi ET. Iron deficiency without anemia – a clinical challenge. Clinical Case Reports. 2018;6(6):1082-1086. https://doi.org/10.1002/ccr3.1529
  2. Dr Sermed Mezher. Exhausted for “No Reason”? Check This Result. YouTube. Published online June 10, 2026. Accessed June 11, 2026. https://youtu.be/IX-sXp0dzu0
  3. Al-Naseem A, Sallam A, Choudhury S, Thachil J. Iron deficiency without anaemia: a diagnosis that matters. Clinical Medicine. 2021;21(2):107-113. https://doi.org/10.7861/clinmed.2020-0582
  4. Gómez-Ramírez S, Brilli E, Tarantino G, Domenico Girelli, Muñoz M. Sucrosomial® Iron: An Updated Review of Its Clinical Efficacy for the Treatment of Iron Deficiency. Pharmaceuticals. 2023;16(6):847-847. https://doi.org/10.3390/ph16060847
  5. Piskin E, Cianciosi D, Gulec S, Tomas M, Capanoglu E. Iron Absorption: Factors, Limitations, and Improvement Methods. ACS Omega. 2022;7(24):20441-20456. https://doi.org/10.1021/acsomega.2c01833
  6. Alzaabi FM, Al Tarawneh DJ, Al Tarawneh YJ, et al. Restless Legs and Iron Deficiency: Unraveling the Hidden Link and Unlocking Relief. Cureus. 2025;17(4):e82413. https://doi.org/10.7759/cureus.82413
  7. Muhammet Özbilen, Kaya Y. Beyond anemia: a comprehensive analysis of iron deficiency symptoms in women and their correlation with biomarkers. BMC Women s Health. 2025;25(1). https://doi.org/10.1186/s12905-025-03906-w
  8. Balendran S, Forsyth C. Non-anaemic iron deficiency. Australian Prescriber. 2021;44(6). https://doi.org/10.18773/austprescr.2021.052
  9. Moore S. Lifestyle Strategies to Boost Total Body Iron. American Journal of Lifestyle Medicine. 2022;19(4):611-615. https://doi.org/10.1177/15598276221129218