Asthenia and hypochondria — possible masks of hidden iron deficiency

Background. Asthenia is usually considered not as a disease, but as a syndrome characterized, on the one hand, by fatigue and weakness, decreased physical and mental performance, and, on the other hand, by abnormally easy excitability with excessively rapid exhaustion of nervous functions. This process is always pathological, not directly related to or dependent solely on overwork. Symptoms of asthenia are found in 45-90% of patients with serious somatic diseases, being an independent reason for seeking medical attention in 30% of cases. Hypochondria is considered to be an unfounded or exaggerated fear for one's health, which in modern interpretation has been given a special name – anxiety disorder associated with illness. The prevalence of this condition among the adult population is estimated to range from 2.1% to 13.1%, and among patients receiving medical care, it can reach 19.9%. Health anxiety has a significant impact on patients suffering from it, worsening their quality of life. Currently, there is growing evidence that conditions associated with fatigue and anxiety (especially chronic ones), such as apathy and hypochondriacal disorders, may occur or be associated with iron deficiency.

Results. The article reviews current understanding of the manifestations, causes, pathogenesis, and approaches to treating conditions such as asthenia and hypochondria, as well as the problem of their possible connection with iron deficiency. An overview of current literature on research into the combination of these conditions is presented. The role of iron deficiency in the formation of congenital and acquired diseases of the nervous system and pathologies of psycho-emotional development is considered separately. Examples of successful treatment of a number of mental and neurological diseases are given, and the role of iron preparations in the effective correction of mood disorders, anxiety, and other pathological manifestations of asthenia and hypochondria is described.

1. Demyanovskaya E. G., Vasilyev A. S., Shmyrev V. I. Asthenia. A modern concept. Lechaschi Vrach. 2023; 10 (26): 18-23. https://doi.org/10.51793/OS.2023.26.10.003. (In Russ.)

2. Chutko L. S., Surushkina S. Yu. Asthenic disorders. History and modernity. Zhurnal nevrologii i psikhiatrii im. S. S. Korsakova 2020; 120 (6): 131-136. https://doi.org/10.17116/jnevro2020120061131. (In Russ.)

3. Vasenina E. E., Gankina O. A., Levin O. S. Stress, asthenia, and cognitive disorders. Zhurnal nevrologii i psikhiatrii im. S. S. Korsakova. 2022; 122 (5): 23-29. https://doi.org/10.17116/jnevro202212205123. (In Russ.)

4. Young P., Finn B. C., Bruetman J., Pellegrini D., Kremer A. Enfoque del syndrome de astenia crónica [The chronic asthenia syndrome: a clinical approach]. Medicina (B Aires). 2010; 70 (3): 284-292.

5. Akarachkova E. S. Chronic fatigue and approaches to its treatment. Zhurnal nevrologii i psikhiatrii im. S. S. Korsakova. 2010; 1 (2): 48-54. (In Russ.)

6. Mackay A. A. Paradigm for Post-Covid-19 Fatigue Syndrome Analogous to ME/ CFS. Front Neurol. 2021; 12: 701419. DOI: 10.3389/fneur.2021.701419.

7. Froestl W., Muhs A., Pfeifer A. Cognitive enhancers (nootropics). Part 1: drugs interacting with receptors. J Alzheimers Dis. 2012; 4 (32): 793-887. DOI: 10.3233/JAD-2012-121186.

8. Fedin A. I., et al. Treatment of asthenic syndrome in patients with chronic cerebral ischemia (results of the TRIUMF non-interventional observational program). Zhurnal nevrologii i psikhiatrii im. S. S. Korsakova. 2014; 12 (114): 104-111. (In Russ.)

9. Kikas K., et al. Illness anxiety disorder: a review of the current research and future directions. Current Psychiatry Reports. 2024. DOI: 10.1007/s11920-024-01507-2.

10. Sunderland M., Newby J. M., Andrews G. Health anxiety in Australia: prevalence, comorbidity, disability and service use. Br J Psychiatry. 2013; 202 (1): 56-61. https://doi.org/10.1192/bjp.bp.111.103960.

11. Weck F., Richtberg S., MB Neng J. Epidemiology of hypochondriasis and health anxiety: comparison of different diagnostic criteria. Curr Psychiatry Rev. 2014; 10 (1): 14-23. https://doi.org/10.2174/1573400509666131119004444.

12. Pandey S., Parikh M., Brahmbhatt M., Vankar G. K. Clinical study of illness anxiety disorder in medical outpatients. Arch Psychiatry Psychother. 2017; 4: 32-41. https://doi.org/10.12740/APP/76932.

13. Tyrer P., Cooper S., Crawford M., Dupont S., Green J., Murphy D., et al. Prevalence of health anxiety problems in medical clinics. J Psychosom Res. 2011; 71 (6): 392-394. https://doi.org/10.1016/j.jpsychores.2011.07.004.

14. Newby J. M., Hobbs M. J., Mahoney A. E. J., Wong S., Andrews G. DSM-5 illness anxiety disorder and somatic symptom disorder: comorbidity, correlates, and overlap with DSM-IV hypochondriasis. J Psychosom Res. 2017; 101: 31-37.

15. Newby J. M., Smith J., Uppal S., Mason E., Mahoney A. E. J., Andrews G. Internet-based cognitive behavioral therapy versus psychoeducation control for illness anxiety disorder and somatic symptom disorder: A randomized controlled trial. J Consult Clin Psychol. 2018; 86 (1): 89-98. https://doi.org/10.1037/ccp0000248.

16. Salkovskis P. M., Warwick H. M. C. Meaning, misinterpretations, and medicine: a cognitive-behavioral approach to understanding health anxiety and hypochondriasis. In: Starcevic V., Lipsitt D. R., editors. Hypochondriasis: Modern perspectives on an ancient malady. New York (US): Oxford University Press; 2001. P. 202–222.

17. Mier D., Josef B., Julia O., Tobias K., Vera Z., Fred R., et al. Neural correlates of an attentional bias to health-threatening stimuli in individuals with pathological health anxiety. J Psychiatry Neurosci. 2017; 42 (3): 200. https://doi.org/10.1503/jpn.160081.

18. Yan Z., Witthöft M., Bailer J., Diener C., Mier D. Scary symptoms? Functional magnetic resonance imaging evidence for symptom interpretation bias in pathological health anxiety. Eur Arch Psychiatry Clin Neurosci. 2019; 269 (2): 195-207. https://doi.org/10.1007/s00406-017-0832-8.

19. Axelsson E., Hedman-Lagerlöf E. Cognitive behavior therapy for health anxiety: systematic review and meta-analysis of clinical efficacy and health economic outcomes. Expert Rev Pharmacoecon Outcomes Res. 2019; 19 (6): 663-676. https://doi.org/10.1080/14737167.2019.1703182.

20. Greeven A., van Balkom A. J., Visser S., Merkelbach J. W., van Rood Y. R., van Dyck R., et al. Cognitive behavior therapy and paroxetine in the treatment of hypochondriasis: a randomized controlled trial. Am J Psychiatry. 2007; 164 (1): 91-99. https://doi.org/10.1176/ajp.2007.164.1.91.

21. Shestakova R. A., Kinkulkina M. A., Goncharova E. M., Goncharova S. A., Avdeeva T. I., Ivanets N. N. Psychopharmacotherapy of hypochondriacal disorders in late adulthood: frequency of use and effectiveness of drugs. Zhurnal nevrologii i psikhiatrii im. S. S. Korsakova. 2022; 122 (1): 91-97. https://doi.org/10.17116/jnevro202212201191. (In Russ.)

22. Drapkina O. M., Martynov A. I., Baida A. P., Balan V. E., Baranov I. I., Vlasova E. E., Vorobev P. A., Volkova S. A., Gaiduk I. Yu., Gornostaeva Zh. A., Grigoreva N. Yu., Dobrokhotova Yu. E., Dvoretsky L. I., Dikke G. B., Dolgushina V. F., Dunicheva O. V., Eliseeva E. V., Ivanova E. V., Koryagina N. A., Kunyaeva T. A., Kupaev V. I., Mitina T. A., Mozheiko M. E., Oboskalova T. A., Orlova S. V., Pestrikova T. Yu., Sanina N. P., Sas E. I., Safuanova G. Sh., Sokolova T. M., Stuklov N. I., Tov N. L., Tribuntseva L. V., Umarova Z. A., Fatkullina L. S., Fendrikova A. V., Khlynova O. V., Shavkuta G. V., Sharapova Yu. A., Shikh E. V., Shepel R. N., Kaburova A. N. Resolution of the Expert Council "Current Issues of Iron Deficiency in the Russian Federation." Kardiovaskuliarnaia terapiya i profilaktika. 2020; 19 (5): 2700. DOI: 10.15829/1728-8800-2020-2700. (In Russ.)

23. Fairweather-Tait S. Iron requirements and prevalence of iron deficiency in adolescents. An overview. In: Iron nutrition in health and disease. Hallberg L., Asp N. G., eds. London: Libbey and Co, 1996. Р. 137-148.

24. Beard J. L. Iron requirements in adolescent females. J Nutr. 2000; 130 (2S, Suppl.): 440S-442S.

25. Stevens G. A., Finucane M. M., De-Regil L. M., Paciorek C. J., Flaxman S. R., Branca F., Peña-Rosas J. P., Bhutta Z. A., Ezzati M; Nutrition Impact Model Study Group (Anaemia). Global, regional, and national trends in haemoglobin concentration and prevalence of total and severe anaemia in children and pregnant and non-pregnant women for 1995-2011: a systematic analysis of population-representative data. Lancet Glob Health. 2013; 1 (1): e16-25. DOI: 10.1016/S2214-109X(13)70001-9.

26. Human vitamin and mineral requirements. Report of a joint FAO/WHO expert consultation Bangkok, Thailand. Food and Agriculture Organization of the United Nations, World Health Organization. Rome; 2002. Available at: http://www.fao.org/docrep/004/Y2809E/y2809e00.htm.

27. McCann S., Perapoch Amadó M., Moore S. E. The Role of Iron in Brain Development: A Systematic Review. Nutrients. 2020; 12 (7): 2001. DOI: 10.3390/nu12072001.

28. Stuklov N. I., Kovalchuk M. S., Gurkina A. A., Vareha N. V. The Ferritin 2023 program for studying population indicators of serum ferritin in women in the Moscow agglomeration (2023-2024). Akusherstvo i ginekologiia: novosti, mneniia, obuchenie. 2024; 3 (12): 94-101. DOI: https://doi.org/10.33029/2303-9698-2024-12-3-94-101. (In Russ.)

29. Varekha N. V., Stuklov N. I., Gordienko K. V., et al. Development of a method for the differential diagnosis of iron deficiency anemia and anemia of chronic diseases based on demographic data and routine laboratory test results using machine learning technologies. Onkogematologiia. 2025; 20 (1): 171-181. DOI: https://doi.org/10.17650/181883462025201171-181. (In Russ.)

30. Textbook on Hematology. N. I. Stuklov, N. D. Kisloy. 2nd ed., rev. and expanded. Moscow: Prakticheskaia meditsina, 2022. 350 p.: ill. ISBN 978-5-98811-687-5: 800.00. (In Russ.)

31. Stuklov N. I., Levakov S. A., Sushinskaya T. V., Mitchenkova A. A., Kovalchuk M. O. Prevention and treatment of anemia in women of reproductive age with gynecological diseases. Akusherstvo i ginekologiia. 2020; 3: 218-226. https://dx.doi.org/10.18565/aig.2020.3.218-226/. (In Russ.)

32. Wurzinger B., Eisenmangel K. P. Müdigkeit und Restless-Legs-Syndrom. Wien Med Wochenschr. 2016; 166: 447-452. https://doi.org/10.1007/s10354016-0497-3.

33. Van der Vinnea N., Vollebregta M. A., van Puttenc M. J. A. M. Frontal alpha asymmetry as a diagnostic marker in depression: Frontal alpha asymmetry as a diagnostic marker in depression: Fact or fiction? A meta-analysis. NeuroImage: Clinical. 2017; 16: 79-87. https://doi.org/10.1016/j.nicl.2017.07.006.

34. Kim J., Wessling-Resnick M. Iron and mechanisms of emotional behavior. J Nutr Biochem. 2014; 25 (11): 1101-1107. DOI: 10.1016/j.jnutbio.2014.07.003.

35. De Andraca I., Castillo M., Walter T. Psychomotor development and behavior in iron-deficient anemic infants. Nutr Rev. 1997; 55 (4): 125-132. DOI: 10.1111/j.1753-4887.1997.tb06463.x.

36. Connor J. R., Menzies S. L. Relationship of iron to oligondendrocytes and myelination. 1996; 2 (17): 83-93. https://doi.org/10.1002/(SICI)10981136(199606)17:2<83::AID-GLIA1>3.0.CO;2-7.

37. Li Y., Kim J., Buckett P. D., Böhlke M., Maher T. J., Wessling-Resnick M. Severe postnatal iron deficiency alters emotional behavior and dopamine levels in the prefrontal cortex of young male rats. J Nutr. 2011; 141 (12): 2133-2138. DOI: 10.3945/jn.111.145946.

38. Ward K. L., Tkac I., Jing Y., Felt B., Beard J., Connor J., Schallert T., Georgieff M. K., Rao R. Gestational and lactational iron deficiency alters the developing striatal metabolome and associated behaviors in young rats. J Nutr. 2007; 137 (4): 1043-1049. DOI: 10.1093/jn/137.4.1043.

39. Kim J., Wessling-Resnick M. Iron and mechanisms of emotional behavior. J Nutr Biochem. 2014; 25 (11): 1101-1107. DOI: 10.1016/j.jnutbio.2014.07.003.

40. Youdim M. B. H., Green A. R. Iron deficiency and neurotransmitter synthesis and function. Proceedings of the Nutrition Society. 1978; 37 (2): 173-179. doi:10.1079/PNS19780022.

41. Batra J., Seth P. K. Effect of iron deficiency on developing rat brain. Indian J Clin Biochem. 2002; 17: 108-114. https://doi.org/10.1007/BF02867982.

42. Hill J. M. Iron concentration reduced in ventral pallidum, globus pallidus, and substantia nigra by GABA-transaminase inhibitor, gamma-vinyl GABA. Brain Research. 1985; 1 (342): 18-25. https://doi.org/10.1016/0006-8993(85)91348-4.

43. Felt B. T., Beard J. L., Schallert T., Shao J., Aldridge J. W., Connor J. R., Georgieff M. K., Lozoff B. Persistent neurochemical and behavioral abnormalities in adulthood despite early iron supplementation for perinatal iron deficiency anemia in rats. Behav Brain Res. 2006; 171 (2): 261-270. DOI: 10.1016/j.bbr.2006.04.001.

44. Burhans M. S., Dailey C., Beard Z., Wiesinger J., Murray-Kolb L., Jones B. C., Beard J. L. Iron deficiency: differential effects on monoamine transporters. Nutr Neurosci. 2005; 8 (1): 31-38. 10.1080/10284150500047070.

45. Anderson J. G., Fordahl S. C., Cooney P. T., Weaver T. L., Colyer C. L., Erikson K. M. Extracellular norepinephrine, norepinephrine receptor and transporter protein and mRNA levels are differentially altered in the developing rat brain due to dietary iron deficiency and manganese exposure. Brain Res. 2009; 1281: 1-14.

46. Erikson K. M., Syversen T., Steinnes E., Aschner M. Globus pallidus: a target brain region for divalent metal accumulation associated with dietary iron deficiency. J Nutr Biochem. 2004; 15 (6): 335-341. 10.1016/j.jnutbio.2003.12.006.

47. Shukla A., Agarwal K. N., Chansuria J. P., Taneja V. Effect of latent iron deficiency on 5-hydroxytryptamine metabolism in rat brain. J Neurochem. 1989; 52 (3): 730-735. 10.1111/j.1471-4159.1989.tb02515.x.

48. https://jamanetwork.com/journals/jamapediatrics/fullarticle/485884.

49. Dziembowska I., Kwapisz J., Izdebski P. Mild iron deficiency may affect female endurance and behavior. Physiology & Behavior. 2019; 205: 44-50. https://doi.org/10.1016/j.physbeh.2018.09.012.

50. Kassebaum N. J., Lozano R., et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood.Volume. 2014; 30 (123), Issue 5: 615-624. https://doi.org/10.1182/blood-2013-06-508325.

51. Yokoi K., Konomi A. Iron deficiency without anaemia is a potential cause of fatigue: meta-analyses of randomised controlled trials and cross-sectional studies. British Journal of Nutrition. 2017; 117 (10): 1422-1431. doi:10.1017/S0007114517001349.

52. Chen, et al. Association between psychiatric disorders and iron deficiency anemia among children and adolescents: a nationwide population-based study. Su1BMC Psychiatry. 2013; 13: 161. http://www.biomedcentral.com/1471-244X/13/161.

53. Cortese S., Azoulay R., Castellanos F. X., Chalard F., Lecendreux M., Chechin D., Delorme R., Sebag G., Sbarbati A., Mouren M. C. Brain iron levels in attentiondeficit/hyperactivity disorder: A pilot MRI study. World J Biol Psychiatry. 2012; 13 (3): 223-231. 10.3109/15622975.2011.570376.

54. Muldaeva G., Rukaber N., Arystan L., Haydargalieva L., Kenzhetaeva Z. [irondeficiency anemia as a factor of development of asthenia syndrome]. Georgian Med News. 2016; (256-257): 72-76. Russian. PMID: 27661280.

55. A rshad H., Arshad A., Hafiz M. Y., Muhammad G., Khatri S., Arain F. Psychiatric manifestations of iron deficiency anemia-a literature review. Eur Psychiatry. 2023; 66 (Suppl 1): S243-S244. DOI: 10.1192/j.eurpsy.2023.560.

56. Vaucher P., Druais P. L., Waldvogel S., Favrat B. Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial. CMAJ. 2012; 184 (11): 1247-1254. DOI: 10.1503/cmaj.110950.

57. Houston B. L., Hurrie D., Graham J., Perija B., Rimmer E., Rabbani R., Bernstein C. N., Turgeon A. F., Fergusson D. A., Houston D. S., Abou-Setta A. M., Zarychanski R. Efficacy of iron supplementation on fatigue and physical capacity in non-anaemic iron-deficient adults: a systematic review of randomised controlled trials. BMJ Open. 2018; 8 (4): e019240. DOI: 10.1136/bmjopen-2017-019240.

58. Wurzinger B., König P. Eisenmangel, Müdigkeit und Restless-Legs-Syndrom. Wien Med Wochenschr. 2016; 166: 447-452. https://doi.org/10.1007/s10354016-0497-3.