Investigating the Role of Serum Hepcidin and Interleukin-6 in Non-Anemic Women with Acute Ischemic Stroke

Zahir Hussain

 
For citation: Hussain Z. Investigating the Role of Serum Hepcidin and Interleukin-6 in Non-Anemic Women with Acute Ischemic Stroke. International Journal of Biomedicine. 2024;14(2):260-264. doi:10.21103/Article14(2)_OA3
 
Originally published June 5, 2024
 

Abstract: 

Background: Hepcidin (HP) is an important regulator of iron homeostasis. Iron status and IL-6 have been shown to regulate the expression of HP. Serum iron (SI), HP, and IL-6 have a highly significant role in inflammation since inflammation elevates the levels of HP for expressing the ischemic condition. The present study was carried out to investigate the impact of an interactive association between HP, SI, and IL-6 in non-anemic women with acute ischemic stroke (AIS).
Methods and Results: The present case-control, descriptive study comprised 25 non-anemic women with AIS and 25 healthy non-anemic women controls. The age range of AIS and control subjects was 50 to 54 years. Non-anemic AIS women within 8 hours after AIS onset (AIS<8 hrs) and 72 hours after onset of AIS (AIS-72 hours) were examined. The patients underwent assessment of traditional risk factors, physical examination, CBC, blood biochemistry test, 12-lead ECG, CT scans, MRI, CT or MR angiogram, carotid ultrasound of the arteries, transcranial doppler ultrasound, and EEG. Office blood pressure was measured using a mercury sphygmomanometer. Significantly increased values were obtained for systolic blood pressure and diastolic blood pressure in AIS women, compared to the control subjects: 137.44±12.35 vs. 130.88±7.30 mmHg (P=0.0267) and 86.72± 8.48 vs. 81.80± 5.42 mmHg (P=0.0183), respectively. Serum CRP and LDL-C levels in AIS were significantly higher than in healthy control women (P<0.0001).
A significant increase in serum HP, SI, and IL-6 for AIS<8 hrs was found, compared to AIS-72 hrs (P<0.001 in all cases). Comparison for AIS<8 hrs vs. controls showed a highly significant increase in serum HP, SI, and IL-6 for AIS<8 hrs (P<0.001 in all cases). On the other hand, AIS-72 hrs vs. controls indicated a significant increase in SI (P=0.0028) and IL-6 (P=0.0065) but a non-significant increase in serum HP (P>0.05) in AIS-72 hrs. Linear regression expressed a high strength of the relationship between serum HP and SI for AIS<8 hrs (R2=0.82, P<0.0001) and AIS-72 hrs (R2=0.73, P<0.0001), but a negligible linear association for controls (R2=0.01, P=0.5990). There was a high relationship between HP and IL-6 for AIS<8 hrs (R2=0.67, P<0.0001) and AIS-72 hrs (R2=0.67, P<0.0001), but a small linear association for controls (R2=0.28, P=0.0063). The R2 value of 0.47 (P<0.0002) and 0.42 (P<0.0004) was found between SI and IL-6 for AIS<8 hrs and AIS-72 hrs, and a negligible linear association (R2=0.006, P=0.7250) for controls.
Conclusion: The present study provides evidence of the association of AIS in non-anemic women with increased hepcidin. The interactive pathophysiological role of HP, IL-6, and SI in non-anemic women with AIS has also been shown.

Keywords: 
acute ischemic stroke • non-anemic women • hepcidin • serum iron • interleukin-6
References: 
  1. Krishnamurthi RV, Ikeda T, Feigin VL. Global, Regional and Country-Specific Burden of Ischaemic Stroke, Intracerebral Haemorrhage and Subarachnoid Haemorrhage: A Systematic Analysis of the Global Burden of Disease Study 2017. Neuroepidemiology. 2020;54(2):171-179. doi: 10.1159/000506396.
  2. Holmqvist L, Boström KB, Kahan T, Schiöler L, Hasselström J, Hjerpe P, et al. Cardiovascular outcome in treatment-resistant hypertension: results from the Swedish Primary Care Cardiovascular Database (SPCCD). J Hypertens. 2018 Feb;36(2):402-409. doi: 10.1097/HJH.0000000000001561.
  3. Patlolla SH, Lee HC, Noseworthy PA, Wysokinski WE, Hodge DO, Greene EL, Gersh BJ, Melduni RM. Impact of Diabetes Mellitus on Stroke and Survival in Patients With Atrial Fibrillation. Am J Cardiol. 2020 Sep 15;131:33-39. doi: 10.1016/j.amjcard.2020.06.049. Epub 2020 Jun 30. PMID: 32723556.
  4. Almutairi MMA, Xu G, Shi H. Iron Pathophysiology in Stroke. Adv Exp Med Biol. 2019;1173:105-123. doi: 10.1007/978-981-13-9589-5_6.
  5. Hajar R. Risk Factors for Coronary Artery Disease: Historical Perspectives. Heart Views. 2017 Jul-Sep;18(3):109-114. doi: 10.4103/HEARTVIEWS.HEARTVIEWS_106_17.
  6. Musuka TD, Wilton SB, Traboulsi M, Hill MD. Diagnosis and management of acute ischemic stroke: speed is critical. CMAJ. 2015 Sep 8;187(12):887-93. doi: 10.1503/cmaj.140355. Epub 2015 Aug 4.
  7. Simmatis LER, Scott SH, Jin AY. The Impact of Transient Ischemic Attack (TIA) on Brain and Behavior. Front Behav Neurosci. 2019 Mar 11;13:44. doi: 10.3389/fnbeh.2019.00044.
  8. Boehme AK, Esenwa C, Elkind MS. Stroke Risk Factors, Genetics, and Prevention. Circ Res. 2017 Feb 3;120(3):472-495. doi: 10.1161/CIRCRESAHA.116.308398.
  9. Chopra VK, Anker SD. Anaemia, iron deficiency and heart failure in 2020: facts and numbers. ESC Heart Fail. 2020 Oct;7(5):2007-2011. doi: 10.1002/ehf2.12797.
  10. Barandiarán Aizpurua A, Sanders-van Wijk S, Brunner-La Rocca HP, Henkens MTHM, Weerts J, Spanjers MHA, et al. Iron deficiency impacts prognosis but less exercise capacity in heart failure with preserved ejection fraction. ESC Heart Fail. 2021 Apr;8(2):1304-1313. doi: 10.1002/ehf2.13204.
  11. Guedes M, Muenz D, Zee J, Lopes MB, Waechter S, Stengel B, et al. Serum biomarkers of iron stores are associated with worse physical health-related quality of life in nondialysis-dependent chronic kidney disease patients with or without anemia. Nephrol Dial Transplant. 2021 Aug 27;36(9):1694-1703. doi: 10.1093/ndt/gfab050.
  12. Neidlein S, Wirth R, Pourhassan M. Iron deficiency, fatigue and muscle strength and function in older hospitalized patients. Eur J Clin Nutr. 2021 Mar;75(3):456-463. doi: 10.1038/s41430-020-00742-z.
  13. Kemna EH, Tjalsma H, Willems HL, Swinkels DW. Hepcidin: from discovery to differential diagnosis. Haematologica. 2008 Jan;93(1):90-7. doi: 10.3324/haematol.11705.
  14. Mabjeesh NJ, Escuin D, LaVallee TM, Pribluda VS, Swartz GM, Johnson MS, et al. 2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF. Cancer Cell. 2003 Apr;3(4):363-75. doi: 10.1016/s1535-6108(03)00077-1.
  15. Chamorro Á. Neuroprotectants in the Era of Reperfusion Therapy. J Stroke. 2018 May;20(2):197-207. doi: 10.5853/jos.2017.02901.
  16. Wilkinson DA, Pandey AS, Thompson BG, Keep RF, Hua Y, Xi G. Injury mechanisms in acute intracerebral hemorrhage. Neuropharmacology. 2018 May 15;134(Pt B):240-248. doi: 10.1016/j.neuropharm.2017.09.033.
  17. Petrova JJ, Manolov VE, Hadjidekova SP, Hadjiev EA, Bogov BI, Marinov BM, et al. Is There a Link Between Changes in Levels of Hepcidin and Stroke? Clin Lab. 2015;61(12):1935-9. doi: 10.7754/clin.lab.2015.150522.
  18. Słomka A, Świtońska M, Żekanowska E. Hepcidin Levels Are Increased in Patients with Acute Ischemic Stroke: Preliminary Report. J Stroke Cerebrovasc Dis. 2015 Jul;24(7):1570-6. doi: 10.1016/j.jstrokecerebrovasdis.2015.03.031.
  19. Khan NI, Naz L, Mushtaq S, Rukh L, Ali S, Hussain Z. Ischemic stroke: prevalence of modifiable risk factors in male and female patients in Pakistan. Pak J Pharm Sci. 2009 Jan;22(1):62-7.
  20. Harakeh S, Kalamegam G, Pushparaj PN, Al-Hejin A, Alfadul SM, Al Amri T, et al. Chemokines and their association with body mass index among healthy Saudis. Saudi J Biol Sci. 2020 Jan;27(1):6-11. doi: 10.1016/j.sjbs.2019.03.006. Epub 2019 Mar 20.
  21. Nuttall FQ. Body Mass Index: Obesity, BMI, and Health: A Critical Review. Nutr Today. 2015 May;50(3):117-128. doi: 10.1097/NT.0000000000000092. Epub 2015 Apr 7. PMID: 27340299; PMCID: PMC4890841.
  22. Moliner P, Jankowska EA, van Veldhuisen DJ, Farre N, Rozentryt P, Enjuanes C, et al. Clinical correlates and prognostic impact of impaired iron storage versus impaired iron transport in an international cohort of 1821 patients with chronic heart failure. Int J Cardiol. 2017 Sep 15;243:360-366. doi: 10.1016/j.ijcard.2017.04.110.
  23. Beutler E, Waalen J. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration? Blood. 2006 Mar 1;107(5):1747-50. doi: 10.1182/blood-2005-07-3046.
  24. von Haehling S, Ebner N, Evertz R, Ponikowski P, Anker SD. Iron Deficiency in Heart Failure: An Overview. JACC Heart Fail. 2019 Jan;7(1):36-46. doi: 10.1016/j.jchf.2018.07.015.
  25. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018 May 15;71(19):e127-e248. doi: 10.1016/j.jacc.2017.11.006. Epub 2017 Nov 13. Erratum in: J Am Coll Cardiol. 2018 May 15;71(19):2275-2279. PMID: 29146535.
  26. Oh SY, Ryue J, Hsieh CH, Bell DE. Eggs enriched in omega-3 fatty acids and alterations in lipid concentrations in plasma and lipoproteins and in blood pressure. Am J Clin Nutr. 1991 Oct;54(4):689-95. doi: 10.1093/ajcn/54.4.689.
  27. Warnick GR, Nguyen T, Albers AA. Comparison of improved precipitation methods for quantification of high-density lipoprotein cholesterol. Clin Chem. 1985 Feb;31(2):217-22.
  28. Tremblay AJ, Morrissette H, Gagné JM, Bergeron J, Gagné C, Couture P. Validation of the Friedewald formula for the determination of low-density lipoprotein cholesterol compared with beta-quantification in a large population. Clin Biochem. 2004 Sep;37(9):785-90. doi: 10.1016/j.clinbiochem.2004.03.008.
  29. Zahir H, Javaid A, Rehman R, Hussain Z. Statistical concepts in biology and health sciences. J Ayub Med Coll Abbottabad. 2014 Jan-Mar;26(1):95-7. PMID: 25358229.
  30. Ding H, Yan CZ, Shi H, Zhao YS, Chang SY, Yu P, et al. Hepcidin is involved in iron regulation in the ischemic brain. PLoS One. 2011;6(9):e25324. doi: 10.1371/journal.pone.0025324.
  31. Chen Z, Gao C, Hua Y, Keep RF, Muraszko K, Xi G. Role of iron in brain injury after intraventricular hemorrhage. Stroke. 2011 Feb;42(2):465-70. doi: 10.1161/STROKEAHA.110.602755.
  32. Chi SI, Wang CK, Chen JJ, Chau LY, Lin TN. Differential regulation of H- and L-ferritin messenger RNA subunits, ferritin protein and iron following focal cerebral ischemia-reperfusion. Neuroscience. 2000;100(3):475-84. doi: 10.1016/s0306-4522(00)00317-1.
  33. Rouault TA, Cooperman S. Brain iron metabolism. Semin Pediatr Neurol. 2006 Sep;13(3):142-8. doi: 10.1016/j.spen.2006.08.002. PMID: 17101452.
  34. Adibhatla RM, Hatcher JF. Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2010 Jan;12(1):125-69. doi: 10.1089/ars.2009.2668.
  35. Rehu M, Punnonen K, Ostland V, Heinonen S, Westerman M, Pulkki K, et al. Maternal serum hepcidin is low at term and independent of cord blood iron status. Eur J Haematol. 2010 Oct;85(4):345-52. doi: 10.1111/j.1600-0609.2010.01479.x.
  36. Choi HS, Song SH, Lee JH, Kim HJ, Yang HR. Serum hepcidin levels and iron parameters in children with iron deficiency. Korean J Hematol. 2012 Dec;47(4):286-92. doi: 10.5045/kjh.2012.47.4.286.
  37. Tan G, Liu L, He Z, Sun J, Xing W, Sun X. Role of hepcidin and its downstream proteins in early brain injury after experimental subarachnoid hemorrhage in rats. Mol Cell Biochem.2016 Jul;418(1-2):31-8.doi: 10.1007/s11010-016-2730-1.

Download Article
Received March 29, 2024.
Accepted April 14, 2024.
©2024 International Medical Research and Development Corporation.