Influence of Serum Ferritin and B12 Levels in the Functional Outcomes of Patients with Ruptured and Unruptured Intracranial Aneurysms

Abstract

Introduction Pathological processes in the arterial wall that result in vessel dilation are the cause of intracranial aneurysms (IAs), and the risk factors for their formation and progression are not well established. Ferritin is associated with inflammation and angiogenesis; it has protective antioxidative activity, and controls cell differentiation. Vitamin B12 is related to neurological and hematological disorders; it can be used as differential diagnosis tool, and acts in the control of homocysteinemia, a predictor of worse prognosis. The present article aims to assess the correlation between serum ferritin and B12 levels and the patient's functional outcome.

Materials and Methods In the present cohort study, we assessed the serum levels of ferritin and B12, as well as the scores on the modified Rankin and Glasgow Outcome Scales at 6 months, of 2 groups, one with 19 and the other with 49 individuals, out of 401 patients treated for IA at Universidade de São Paulo from 2018 to 2019. We performed a statistical analysis, using logistic regression, to determine the aforementioned correlation.

Results In the univariable analysis, the serum levels of ferritin showed no significant impact on the functional outcome (odds ratio [OR]: 0.96 for every 100 pg/mL increase; 95% confidence interval [95%CI]: 0.761–1.210; p = 0.732); neither did the serum levels of B12 (OR: 0.998 for every 100 pg/mL increase; 95%CI: 0.826–1.206; p = 0.987). Moreover, no significant impact on the functional outcome was observed in the multivariable analysis regarding the serum levels of B12, age, hypertension, and aneurysm rupture (OR: 1.086 for every 100 pg/mL increase; 95%CI: 0.847–1.392; p = 0.513).

Conclusion We were not able to confirm a statistical correlation regarding the serum levels of ferritin and B12, and functional outcome of IA patients. These variables might be linked to other determinants of the pathophysiology of IAs, like inflammation and homocysteinemia.

Resumo

Introdução Processos patológicos na parede arterial, que resultam em dilatação dos vasos, são a causa dos aneurismas intracranianos (AIs), e os fatores de risco para a sua formação e evolução não estão bem estabelecidos. A ferritina está associada a inflamação e angiogênese, tem atividade antioxidante, e controla diferenciação celular. A vitamina B12 está relacionada a distúrbios neurológicos e hematológicos, é utilizada como ferramenta de diagnóstico, e atua no controle da homocisteinemia. Este artigo visa avaliar a correlação entre os níveis séricos de ferritina e B12 e o desfecho funcional do paciente.

Materiais e Métodos Neste estudo de coorte, analisamos os níveis séricos de ferritina e B12, assim como as pontuações nas escalas de desfechos de Rankin modificada e Glasgow aos 6 meses de 2 grupos, um com 19 e o outro com 49 indivíduos, dos 401 pacientes com AI tratados na Universidade de São Paulo de 2018 a 2019. Para determinar a já mencionada correlação, realizamos análise estatística usando regressão logística.

Resultados Na análise univariada, a ferritina sérica não resultou em impacto significativo sobre o desfecho funcional (razão de possibilidades [RP]: 0,96 para cada aumento de 100 pg/mL; intervalo de confiança de 95% [IC95%]: 0,761–1,210; p = 0,732), nem a B12 sérica (RP: 0,998 para cada aumento de 100 pg/mL; IC95%: 0,826–1,206; p = 0,987). Tampouco observou-se impacto significativo sobre o desfecho na análise multivariada usando B12 sérica, idade, hipertensão e ruptura de aneurisma (RP: 1,086 para cada aumento de 100 pg/mL; IC95%: 0,847–1,392; p = 0,513).

Conclusão Não foi confirmada a correlação estatística entre os níveis séricos de ferritina e de B12 e o desfecho funcional de pacientes com AI. Essas variáveis podem estar ligadas a outros determinantes da fisiopatologia do AI, como inflamação e homocisteinemia.

Keywords

brain aneurysm - ruptured intracranial aneurysm - unruptured intracranial aneurysm - subarachnoid hemorrhage - serum ferritin - serum B12

Palavras-chave

aneurisma cerebral - aneurisma intracraniano rompidoaneurisma intracraniano não rompidohemorragia subaracnóidea - ferritina sérica - B12 sérica

Ethical Standards

The present research project was approved by the Ethics and Research Committee of HCFMUSP (online registration CAPPesq: 15226–approved on 06/20/2016); it is registered on Plataforma Brasil under CAAE number: 61719416.6.0000.0068.

Disclosure

The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in the present article.

Financial Support

The authors declare that they have received no financial support pertaining to the present article.

Originality

The present manuscript is a unique submission and is not being considered for publication in any other source in any medium.

Publication History

Received: 10 January 2022

Accepted: 07 March 2023

Article published online:
17 November 2023

• References

• 1 Korja M, Lehto H, Juvela S, Kaprio J. Incidence of subarachnoid hemorrhage is decreasing together with decreasing smoking rates. Neurology 2016; 87 (11) 1118-1123 DOI: 10.1212/WNL.0000000000003091.
• 2 Korja M, Lehto H, Juvela S. Lifelong rupture risk of intracranial aneurysms depends on risk factors: a prospective Finnish cohort study. Stroke 2014; 45 (07) 1958-1963 DOI: 10.1161/STROKEAHA.114.005318.
• 3 Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol 2009; 8 (07) 635-642 DOI: 10.1016/S1474-4422(09)70126-7.
• 4 Naggara ON, Lecler A, Oppenheim C, Meder JF, Raymond J. Endovascular treatment of intracranial unruptured aneurysms: a systematic review of the literature on safety with emphasis on subgroup analyses. Radiology 2012; 263 (03) 828-835 DOI: 10.1148/radiol.12112114.
• 5 Kotowski M, Naggara O, Darsaut TE. et al. Safety and occlusion rates of surgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis of the literature from 1990 to 2011. J Neurol Neurosurg Psychiatry 2013; 84 (01) 42-48 DOI: 10.1136/jnnp-2011-302068.
• 6 Knovich MA, Storey JA, Coffman LG, Torti SV, Torti FM. Ferritin for the clinician. Blood Rev 2009; 23 (03) 95-104 DOI: 10.1016/j.blre.2008.08.001.
• 7 Arosio P, Elia L, Poli M. Ferritin, cellular iron storage and regulation. IUBMB Life 2017; 69 (06) 414-422 DOI: 10.1002/iub.1621.
• 8 Wang W, Knovich MA, Coffman LG, Torti FM, Torti SV. Serum ferritin: Past, present and future. Biochim Biophys Acta 2010; 1800 (08) 760-769 DOI: 10.1016/j.bbagen.2010.03.011.
• 9 Kitagawa T, Kosuge H, Uchida M. et al. RGD targeting of human ferritin iron oxide nanoparticles enhances in vivo MRI of vascular inflammation and angiogenesis in experimental carotid disease and abdominal aortic aneurysm. J Magn Reson Imaging 2017; 45 (04) 1144-1153 DOI: 10.1002/jmri.25459.
• 10 Petzold A, Worthington V, Appleby I, Kerr ME, Kitchen N, Smith M. Cerebrospinal fluid ferritin level, a sensitive diagnostic test in late-presenting subarachnoid hemorrhage. J Stroke Cerebrovasc Dis 2011; 20 (06) 489-493 DOI: 10.1016/j.jstrokecerebrovasdis.2010.02.021.
• 11 Cunha BA, Pherez FM, Alexiadis V, Gagos M, Strollo S. Adult Kawasaki's disease with myocarditis, splenomegaly, and highly elevated serum ferritin levels. Heart Lung 2010; 39 (02) 164-172 DOI: 10.1016/j.hrtlng.2009.06.007.
• 12 Zulfiqar AA, Andres E, Lorenzo Villalba N. Hipervitaminosis B12. Nuestra experiencia y una revisión. [Hypervitaminosis B12. Our experience and a review]. Medicina (B Aires) 2019; 79 (05) 391-396
• 13 Romain M, Sviri S, Linton DM, Stav I, van Heerden PV. The role of Vitamin B12 in the critically ill–a review. Anaesth Intensive Care 2016; 44 (04) 447-452 . Doi: 10.1177/0310057. Doi: X1604400410
• 14 Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician 2003; 67 (05) 979-986
• 15 Rosi J, Morais BA, Pecorino LS. et al. Hyperhomocysteinemia as a Risk Factor for Intracranial Aneurysms: A Case-Control Study. World Neurosurg 2018; 119: e272-e275 DOI: 10.1016/j.wneu.2018.07.132.
• 16 Garcia-Casal MN, Pasricha SR, Martinez RX, Lopez-Perez L, Peña-Rosas JP. Are Current Serum and Plasma Ferritin Cut-offs for Iron Deficiency and Overload Accurate and Reflecting Iron Status? A Systematic Review. Arch Med Res 2018; 49 (06) 405-417 DOI: 10.1016/j.arcmed.2018.12.005.
• 17 Mwafy SN, Afana WM. Hematological parameters, serum iron and vitamin B₁₂ levels in hospitalized Palestinian adult patients infected with Helicobacter pylori: a case-control study. Hematol Transfus Cell Ther 2018; 40 (02) 160-165 DOI: 10.1016/j.htct.2017.11.010.
• 18 Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington (DC): National Academies Press (US); 1998. . PMID: 23193625
• 19 Gáll T, Balla G, Balla J. Heme, Heme Oxygenase, and Endoplasmic Reticulum Stress-A New Insight into the Pathophysiology of Vascular Diseases. Int J Mol Sci 2019; 20 (15) 3675 DOI: 10.3390/ijms20153675.
• 20 Can A, Lai PMR, Castro VM. et al. Decreased Total Iron Binding Capacity May Correlate with Ruptured Intracranial Aneurysms. Sci Rep 2019; 9 (01) 6054 DOI: 10.1038/s41598-019-42622-y.
• 21 Schwaerzer GK, Kalyanaraman H, Casteel DE. et al. Aortic pathology from protein kinase G activation is prevented by an antioxidant vitamin B₁₂ analog. Nat Commun 2019; 10 (01) 3533 DOI: 10.1038/s41467-01911389-1.
• 22 Peeters AC, van Landeghem BA, Graafsma SJ. et al. Low vitamin B6, and not plasma homocysteine concentration, as risk factor for abdominal aortic aneurysm: a retrospective case-control study. J Vasc Surg 2007; 45 (04) 701-705 DOI: 10.1016/j.jvs.2006.12.019.
• 23 Fu Y, Wang X, Kong W. Hyperhomocysteinaemia and vascular injury: advances in mechanisms and drug targets. Br J Pharmacol 2018; 175 (08) 1173-1189 DOI: 10.1111/bph.13988.
• 24 Warsi AA, Davies B, Morris-Stiff G, Hullin D, Lewis MH. Abdominal aortic aneurysm and its correlation to plasma homocysteine, and vitamins. Eur J Vasc Endovasc Surg 2004; 27 (01) 75-79 DOI: 10.1016/j.ejvs.2003.09.001.
• 25 Roohi J, Kang B, Bernard D, Bedja D, Dietz HC, Brody LC. Moderately Elevated Homocysteine Does Not Contribute to Thoracic Aortic Aneurysm in Mice. J Nutr 2017; 147 (07) 1290-1295 DOI: 10.3945/jn.117.251173.
• 26 Spark JI, Laws P, Fitridge R. The incidence of hyperhomocysteinaemia in vascular patients. Eur J Vasc Endovasc Surg 2003; 26 (05) 558-561 DOI: 10.1016/s1078-5884(03)00381-2.
• 27 Takagi H, Umemoto T. Alice (All-Literature Investigation of Cardiovascular Evidence) group. Vitamins and abdominal aortic aneurysm. Int Angiol 2017; 36 (01) 21-30 DOI: 10.23736/S0392-9590.16.03618-X.
• 28 Czekajło A. Role of diet-related factors in cerebral aneurysm formation and rupture. Rocz Panstw Zakl Hig 2019; 70 (02) 119-126 DOI: 10.32394/rpzh.2019.0061.
• 29 Kumar A, Palfrey HA, Pathak R, Kadowitz PJ, Gettys TW, Murthy SN. The metabolism and significance of homocysteine in nutrition and health. Nutr Metab (Lond) 2017; 14: 78 DOI: 10.1186/s12986-017-0233-z.
• 30 Lindqvist M, Hellström A, Henriksson AE. Abdominal aortic aneurysm and the association with serum levels of Homocysteine, vitamins B6, B12 and Folate. Am J Cardiovasc Dis 2012; 2 (04) 318-322
• 31 Ajiboye N, Chalouhi N, Starke RM, Zanaty M, Bell R. Unruptured Cerebral Aneurysms: Evaluation and Management. ScientificWorldJournal 2015; 2015: 954954 DOI: 10.1155/2015/954954.