Article Text

Download PDFPDF
Daily supplementation with 5 mg of folic acid in Brazilian patients with hereditary spherocytosis
  1. Clóvis Paniz1,
  2. Maylla Rodrigues Lucena2,
  3. Juliano Felix Bertinato1,
  4. Felipe Rebello Lourenço3,
  5. Bruna Cipriano A Barros2,
  6. Guilherme Wataru Gomes1,
  7. Maria Stella Figueiredo2,
  8. Rodolfo Delfini Cançado4,
  9. Vera Lúcia Nascimento Blaia-D Avila5,
  10. Christine M Pfeiffer6,
  11. Zia Fazili6,
  12. Ralph Green7,
  13. Valdemir Melechco Carvalho8,
  14. Elvira Maria Guerra-Shinohara1,2
  1. 1 Análises Clínicas e Toxicológicas, Universidade de São Paulo, São Paulo, Brazil
  2. 2 Disciplina de Hematologia e Hemoterapia, Universidade Federal de São Paulo, São Paulo, Brazil
  3. 3 Farmácia, Universidade de São Paulo, São Paulo, Brazil
  4. 4 Seção de Hematologia e Oncologia, Faculdade de Medicina da Santa Casa de São Paulo, São Paulo, Brazil
  5. 5 Divisão de Hematologia, Pontificia Universidade Católica de São Paulo, Sorocaba, Brazil
  6. 6 CDC, National Center for Environment Health, Atlanta, Georgia, USA
  7. 7 Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, California, USA
  8. 8 Grupo Fleury, São Paulo, Brazil
  1. Correspondence to Dr Clóvis Paniz, Análises Clínicas e Toxicológicas, Universidade de São Paulo, São Paulo 05508-000, Brazil; clovis.paniz{at}


Patients with hereditary spherocytosis (HS) have increased rates of erythropoiesis and higher folate requirements. In a case-control study of patients with HS, we evaluated the associations between the use of 5 mg folic acid (FA) daily and serum concentrations of folate, unmetabolized folic acid (UMFA), interleukin (IL)-6, IL-8, IL-10, interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α); and mRNA expression of dihydrofolate reductase (DHFR), methylene tetrahydrofolate reductase (MTHFR), IL8, IFNG and TNFA genes. Total serum folate and folate forms were measured in 27 patients with HS (21 users [HS-U] and 6 non-users [HS-NU] of supplemental FA) and 54 healthy controls not consuming 5 mg/day supplemental FA. Each patient was matched to two controls based on age, sex and body mass index. The mononuclear leucocyte mRNA expression of relevant genes and their products were determined. Serum folate, UMFA, 5-methyl-tetrahydrofolate (5-methyl-THF) and tetrahydrofolate (THF) concentrations were significantly higher in HS-U compared with matched healthy controls (p<0.001, n=42). HS-NU had lower serum folate concentrations than matched healthy controls (p=0.044, n=12). HS-U and HS-NU presented similar hematological and biochemical markers profiles. No differences were found between HS-U and HS-NU for cytokine serum concentrations and mRNA expression genes. DHFR mRNA expression was higher in HS-U than in HS-NU. The use of high daily doses of FA for treatment of patients with HS may be excessive and is associated with elevated serum UMFA and elevated DHFR mRNA expression. It is not known whether long-term high-dose FA use by patients with HS might have adverse health effects.

  • folic acid
  • cytokines

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


  • Contributors CP designed the research study, collected the samples and data, performed the laboratorial determinations, analyzed the data and wrote the paper. MRL and JFB collected the samples and data, performed the laboratorial determinations and analyzed the data. FRL performed statistical analysis and analyzed the data. BCAG and VMC performed MMA determinations and analyzed the data. GWG performed the laboratorial determinations and reviewed the paper. MSF, RC, VLBD included the patients and performed collect of clinical data. CMP and ZF performed UMFA and folate forms by LC/MS and reviewer the paper. RG designed the research study and did an expert review of the paper. EMG designed the research study, analyzed the data, performed statistical analysis and wrote the paper.

  • Funding This study was financially supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2012/12912-1) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 4826412012-6 and 401586/2014-6), and in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001, Brazil. JFB, MSF and EMGS have fellowships from CNPq, and MRL has a fellowship from CAPES.

  • Competing interests None declared.

  • Ethics approval The Institutional Ethics Committee approved this study (CNS 466/12, CAEE 04389512.2.000.0067).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent for publication Not required.