ABSENCE OF RELATIONSHIP BETWEEN SERUM VITAMIN D LEVELS, DEGREE OF HEPATIC FIBROSIS, AND VIROLOGIC RESPONSE TO PEGYLATED INTERFERON AND RIBAVIRIN THERAPY IN PATIENTS WITH CHRONIC HEPATITIS C
Abstract
Introduction: In patients with chronic hepatitis C virus (HCV) infection, 25-hydroxyvitamin D3 [25(OH)D] deficiency has been associated with disease progression and decreased odds of sustained virologic response (SVR) to pegylated interferon and ribavirin combination therapy (PegIFN+RBV). Methods: In this retrospective study, the pretreatment 25(OH)D levels of patients with genotype 1 HCV infection treated with PegIFN + RBV for 48 weeks were measured and correlated with disease stage and periportal necroinflammatory activity (PPA) on liver biopsy, as well as to virologic response at the end of the treatment period. Serum 25(OH)D levels were quantitated by chemiluminescence. Results: Of the 201 patients included, 53% were male and 70% were white, with a mean (SD) age of 46 (±11) years. Subtype 1b was identified in 48% of cases, and 57% of patients had a viral load over 800,000 IU/mL. Overall, 29% of patients had stage 3/4 fibrosis and 40% had grade 3/4 PPA. SVR was achieved in 47% of patients. The mean 25(OH)D concentration was 26.3 (±11.5) ng/mL. Low 25(OH)D levels (<30 ng/dL) were detected in 69% of patients, and were not associated with staging (rS=-0.003; p=0.895) or grading (rS=0.045; p=0.105). There were no significant differences in SVR rate between patients with vs. those without 25(OH)D deficiency (49% vs. 40%, p=0.359). The only variables associated with 25(OH)D insufficiency or deficiency were serum albumin (rS=0.199; p=0.006), female sex (rS=0.249; p=0.002), and age (rS=-0.227; p=0.001). Conclusion: In this sample of patients with chronic HCV infection, vitamin D deficiency was not associated with increased histologic severity, nor with increased likelihood of SVR.
Keywords
References
DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr 2004; 80(6 Suppl): 1689S-96S.
Kitson MT and Roberts SK. D-livering the message: The importance of vitamin D status in chronic liver disease. J Hepatol 2012; 57: 897-909.
Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, et al. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2011; 96: 1911-30.
Atkinson M, Nordin BEC, Sherlock S. Malabsorption and bone disease in prolonged obstructive jaundice. Q J Med 1956; 25: 299-312.
Pongron G, Kennan AL, DeLuca HF. "Activation" of Vitamin D by the Liver. J Clin Invest 1969; 48: 2032-7.
Jung RT, Davie M, Hunter J, Chalmers TM, Lawson DEM. Abnormal vitamin D metabolism in cirrhosis. Gut 1978; 19: 290-3.
Biklej DD, Halloran BP, Gee E, Ryzen E, Haddad JG. Free 25-Hydroxyvitamin D Levels Are Normal in subjects with Liver Disease and Reduced Total 25-Hydroxyvitamin D Levels. J Clin Invest 1986; 78: 748-52.
European Association for Study of Liver. EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. J Hepatol 2014; 60: 392-420.
Minami T, Kishikawa T, Sato M, Tateishi R, Yoshida H, Koike K. Meta-analysis: mortality and serious adverse events of peginterferon plus ribavirin therapy for chronic hepatitis C. J Gastroenterol 2013; 48: 254-68.
Dooley JS, Lok A, Burroughs AK, Heathcote J (eds.). Sherlock’s Diseases of the Liver and Biliary System. 12th ed. Chichester: Wiley-Blackwell; 2011, p. 406-426.
Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 2011; 17: 107-15.
Duarte MPC, Farias MLF, Coelho HSM, Mendonça LMC, Stabnov LMD, Oliveira MC, Lamy RA, et al. Calcium-parathyroid hormone-vitamin D axis and metabolic bone disease in chronic viral liver disease. J Gastroenterol Hepatol 2001; 16: 1022-7.
Barchetta I, Carotti S, Labbadia G, Vespasiani Gentilucci U, Onetti Muda A, Angelico F, et al. Liver VDR, CYP2R1 and CYP27A1 expression: relationship with liver histology and vitamin D3 levels in patients with NASH or HCV hepatitis. Hepatology 2012; 56: 2180-7.
Petta S, Camma C, Scazzone C, Tripodo C, Marco VD, Bono A, et al. Low Vitamin D Serum Level Is Related to Severe Fibrosis and Low Responsiveness to Interferon-Based Therapy in Genotype 1 Chronic Hepatitis C. Hepatology 2010; 51: 1158-67.
Baur K, Mertens JC, Schmitt J, Iwata R, Stieger B, Eloranta JJ, et al. Combined effect of 25-OH vitamin D plasma levels and genetic Vitamin D Receptor (NR 1I1) variants on fibrosis progression rate in HCV patients. Liver Int 2012; 32: 635-43.
Amanzada A, Goralczyk AD, Moriconi F, Thiel DHV, Ramadori G, Mihm S. Vitamin D Status and Serum Ferritin Concentration in Chronic Hepatitis C Virus Type 1 Infection. J Med Virol 2013; 85: 1534-41.
Falleti E, Bitetto D, Fabris C, Fattovich G, Cussigh AR, Cmet S, et al. Vitamin D binding protein gene polymorphisms and baseline vitamin D levels as predictors of antiviral response in chronic hepatitis C. Hepatology 2012; 56: 1641-50.
Lange CM, Bojunga J, Lopez ER, Wagner MV, Hassler A, Vermehren J, et al. Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy. J Hepatol 2011; 54: 887-93.
Kitson MT, Dore GJ, George J, Button P, McCaughan GW, Crawford DHG, Sievert W, et al. Vitamin D status does not predict sustained virologic response or fibrosis stage in chronic hepatitis C genotype 1 infection. J Hepatol 2013; 59: 194-5.
Grammatikos G, Lange C, Susser S, Schwendy S, Dikopoulos N, Buggisch P, Encke J, et al. Vitamin D levels vary during antiviral treatment but are unable to predict treatment outcome in HCV genotype 1 infected patients. PLOS ONE 2014; 9: e87974.
Gayotto LCC. Visão histórica e consenso nacional sobre a classificação das hepatites crônicas. GED 2000; 19: 137-40.
Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, Häussinger D, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975-82.
Hadziyannis SJ, Sette H, Morgan TR, Balan V, Diago M, Marcellin P, Ramadori G, et al. Peginterferon-alpha 2a and ribavirin combination therapy in chronic hepatitis C – a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004 2; 140: 346-55.
Manns MP, Wedemeyer H, Cornberg M. Treating viral hepatitis C: efficacy, side effects, and complications. Gut 2006; 55: 1350-9.
Adinolfi LE, Gambardella M, Andreana A, Tripodi MF, Utili R, Ruggiero G. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology 2001; 33: 1358-64.
Asselah T, Ripault MP, Marcellin P. What does chronic hepatitis C steatosis mean? Gastroenterol Clin Biol 2003; 27: 1073-5.
Mirza S, Siddiqui AR, Hamid S, Umar M, Bashir S. Extent of liver inflammation in predicting response to interferon α & Ribavirin in chronic hepatitis C patients: a cohort study. BMC Gastroenterol 2012; 12: 71.
Lim LY, Chalasani N. Vitamin D deficiency in patients with chronic liver disease and cirrhosis. Curr Gastroenterol Rep 2012; 14: 67-73.
Farrell CJL, Martin S, McWhinney B, Straub I, Williams P, Herrmann M. State-of-the-Art Vitamin D Assays: A Comparison of Automated Immunoassays with Liquid Chromatography–Tandem Mass Spectrometry Methods. Clin Chem 2012; 58: 531-42.
Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N. Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1) naïve patients. World J Gastroenterol 2011; 17: 5184-90.
Atsukawa M, Tsubota A, Shimada N, Abed H, Kondo C, Itokawa N, Nakagawa A, et al. Serum 25(OH)D3 levels affect treatment outcomes for telaprevir/peg-interferon/ribavirin combination therapy in genotype 1b chronic hepatitis C. Dig Liver Dis 2014; 46: 738-43.
Petta S, Grimaudo S, Marco VD, Scazzone C, Macaluso FS, Camma C, Cabibi D, et al. Association of vitamin D serum levels and its common genetic determinants, with severity of liver fibrosis in genotype 1 chronic hepatitis C patients. J Viral Hepat 2013; 20: 486-93.
Corey KE, Zheng H, Navarro JM, Borrego AD, Dienstag JL, Chung RT. Serum Vitamin D Levels Are Not Predictive of the Progression of Chronic Liver Disease in Hepatitis C Patients with Advanced Fibrosis. PLOS ONE 2012; 7: e27144.
Weintraub SJ, Fleckenstein JF, Marion TN, Madey MA, Mahmoudi TM, Schechtman KB. Vitamin D and the racial difference in the genotype 1 chronic hepatitis C treatment response. Am J Clin Nutr 2012; 96: 1025-31.
White DL, Tabasi ST, Kanwal F, Ramsey DJ, Hashmi A, Kuzniarek J, Patel P, et al. The association between serological and dietary vitamin D levels and hepatitis C-related liver disease risk differs in African American and white males. Aliment Pharmacol Ther 2013; 38: 28-37.
Lazaretti-Castro M, Duarte-de-Oliveira MA, Russo EMK, Vieira JGH. Vitamin D receptor alleles and bone density in a normal premenopausal Brazilian female population. Braz J Med Biol Res 1997; 30: 929-32.
Saraiva GL, Cendoroglo MS, Ramos LR, Araújo LM, Vieira JG, Maeda SS, Borba VZ, et al. Prevalence of vitamin D deficiency, insufficiency and secondary hyperparathyroidism in the elderly inpatients and living in the community of the city of São Paulo, Brazil. Arq Bras Endocrinol Metabol 2007; 51: 437-42.
Arantes HP, Kulak CA, Fernandes CE, Zerbini C, Bandeira F, Barbosa IC, Brenol JC, et al. Correlation between 25-hydroxyvitamin D levels and latitude in Brazilian postmenopausal women: from the Arzoxifene Generations Trial. Osteoporos Int 2013; 24: 2707-12.
Rajaraman S, Selvanayagam S, Chidambaram R. Correlation study between total calcium, ionized calcium, serum albumin and their significance with Vitamin D. J Exp Sciences 2011; 2: 17-21.
Lange CM, Bibert S, Kutalik Z, Burgisser P, Cerny A, Dufour JF, Geier A, et al. A Genetic Validation Study Reveals a Role of Vitamin D Metabolism in the Response to Interferon-Alfa-Based Therapy of Chronic Hepatitis C. PLOS ONE 2012; 7: e40159.
Bitetto D, Fabris C, Fornasiere E, Pipan C, Fumolo E, Cussigh A, Bignulin S, et al. Vitamin D supplementation improves response to antiviral treatment for recurrent hepatitis C. Transpl Int 2011; 24: 43-50.
Falleti E, Cmet S, Fabris C, Fattovich G, Cussigh A, Bitetto D, Ceriani E, et al. Genetic Polymorphisms of Vitamin D Pathway Predict Antiviral Treatment Outcome in Slow Responder Naïve Patients with Chronic Hepatitis C. PLOS One 2013; 8: e80764.
Camacho I, Tzu J, Kirsner RS. Regulation of Vitamin D Production Is Independent of Skin Color. J Invest Dermatol 2010; 130: 330.
Diehl JW, Chiu MW. Effects of ambient sunlight and
photoprotection on vitamin D status. Dermatol Ther 2010; 23: 48-60.
Terushkin V, Bender A, Psaty EL, Engelsen O, Wang SQ, Halpern AC. Estimated equivalency of vitamin D production from natural sun exposure versus oral vitamin D supplementation across seasons at two US latitudes. J Am Acad Dermatol 2010; 62: 929.e1-9.
Refbacks
- There are currently no refbacks.
This work is licensed under a Creative Commons Attribution 3.0 License.