Associated vitamin D deficiency is a risk factor for the complication of HCV-related liver cirrhosis including hepatic encephalopathy and spontaneous bacterial peritonitis

  • Monkez Moteih Yousif
  • Ayman Magd Eldin Mohammad SadekEmail author
  • Hesham Ahmad Farrag
  • Fayrouz Othman Selim
  • Emad Fawzi Hamed
  • Rasha Ibrahim Salama


The influence of vitamin D, 25-hydroxyvitamin D (25(OH)D), deficiency on hepatitis C virus (HCV)-related cirrhosis had been poorly elucidated especially in patients with hepatic encephalopathy (HE) and spontaneous bacterial peritonitis (SBP). We aimed to investigate the association between vitamin D deficiency and the risk of SBP or HE, including the mortality rate. Serum 25(OH)D levels were prospectively determined in 135 patients. Of them, 45 patients had complications with HE and 45 patients had complications with SBP; 45 cirrhotic patients without complication served as the control group. Vitamin D deficiency was defined as 25(OH)D levels < 20 ng/ml. Receiver operating characteristic (ROC) and Kaplan–Meier method with log-rank test were used in our statistical analysis. Predictors of survival were determined using Cox regression analysis. Serum 25(OH)D levels were significantly (P < 0.05) lower in the HE and SBP groups than in the control group (6.81 ± 2.75, 7.15 ± 2.10, 16.28 ± 6.60, respectively). Moreover, serum 25(OH)D levels were significantly lower in the high HE grade than in the low grade (P < 0.001). Regarding the SBP group, classic SBP was associated with lower 25(OH)D levels compared to other types (P < 0.001). ROC curve revealed that lower 25(OH)D levels less than 7.1 ng/ml and 6.6 ng/ml could predict the mortality in SBP and HE patients, respectively, with high sensitivity and specificity. Serum 25(OH)D levels < 5 ng/ml were associated with significant higher mortality rate (HR = 2.76, P = 0.001). Lower 25(OH)D levels were associated with HE and SBP in cirrhotic patients. In addition, it may be considered a prognostic parameter for the severity of liver cirrhosis.


Vitamin D deficiency Hepatic encephalopathy Spontaneous bacterial peritonitis 



We appreciate Dr. Usama Ragab, the Assistant Lecturer of Internal Medicine, Zagazig University, for the great help in statistics. In addition, we thank Prof. Yossry Elsayed Abo-Elmagd for the great help in laboratory assessment of vitamin D.



Compliance with ethical standards

Conflict of interest

The author(s) declare that they have no conflict of interest.

Statement of human and animal rights

All human rights are preserved according to the declaration of Helsinki guidelines.

Informed consent

Written informed consent was obtained from all individual participants included in the study. For patients with altered sensorium, informed consent was obtained from their first-degree relatives.

Supplementary material

11739_2019_2042_MOESM1_ESM.docx (17 kb)
Supplementary material 1 (DOCX 16 kb)


  1. 1.
    Blach S, Zeuzem S, Manns M, Altraif I, Duberg A-S, Muljono DH et al (2017) Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study. Lancet Gastroenterol Hepatol 2:161–176. CrossRefGoogle Scholar
  2. 2.
    Kouyoumjian SP, Chemaitelly H, Abu-Raddad LJ (2018) Characterizing hepatitis C virus epidemiology in Egypt: systematic reviews, meta-analyses, and meta-regressions. Sci Rep 8:1661. CrossRefGoogle Scholar
  3. 3.
    Byass P (2014) The global burden of liver disease: a challenge for methods and for public health. BMC Med 12:159. CrossRefGoogle Scholar
  4. 4.
    Kung H-C, Hoyert DL, Xu J, Murphy SL (2008) Deaths: final data for 2005. Natl Vital Stat Rep 56:1–120Google Scholar
  5. 5.
    Mokdad AA, Lopez AD, Shahraz S, Lozano R, Mokdad AH, Stanaway J et al (2014) Liver cirrhosis mortality in 187 countries between 1980 and 2010: a systematic analysis. BMC Med 12:145. CrossRefGoogle Scholar
  6. 6.
    Møller S, Bendtsen F (2015) Complications of cirrhosis. A 50 years flashback. Scand J Gastroenterol 50:763–780. Google Scholar
  7. 7.
    Fernández J, Gustot T (2012) Management of bacterial infections in cirrhosis. J Hepatol 56:S1–S12. CrossRefGoogle Scholar
  8. 8.
    Bunchorntavakul C, Chamroonkul N, Chavalitdhamrong D (2016) Bacterial infections in cirrhosis: a critical review and practical guidance. World J Hepatol 8:307. CrossRefGoogle Scholar
  9. 9.
    Ono Y, Watanabe T, Matsumoto K, Ito T, Kunii O, Goldstein E (2004) Opsonophagocytic dysfunction in patients with liver cirrhosis and low responses to tumor necrosis factor-α and lipopolysaccharide in patients’ blood. J Infect Chemother 10:200–207. CrossRefGoogle Scholar
  10. 10.
    Garcia-Tsao G, Wiest R (2004) Gut microflora in the pathogenesis of the complications of cirrhosis. Best Pract Res Clin Gastroenterol 18:353–372. CrossRefGoogle Scholar
  11. 11.
    Wiest R, Lawson M, Geuking M (2014) Pathological bacterial translocation in liver cirrhosis. J Hepatol 60:197–209. CrossRefGoogle Scholar
  12. 12.
    Møller S, Bendtsen F, Henriksen JH (2005) Pathophysiological basis of pharmacotherapy in the hepatorenal syndrome. Scand J Gastroenterol 40:491–500. CrossRefGoogle Scholar
  13. 13.
    European association for the study of the liver (2010) EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 2010(53):397–417. Google Scholar
  14. 14.
    Mortensen C, Jensen JS, Hobolth L, Dam-Larsen S, Madsen BS, Andersen O et al (2014) Association of markers of bacterial translocation with immune activation in decompensated cirrhosis. Eur J Gastroenterol Hepatol 26:1360–1366. CrossRefGoogle Scholar
  15. 15.
    Dam G, Keiding S, Munk OL, Ott P, Vilstrup H, Bak LK et al (2013) Hepatic encephalopathy is associated with decreased cerebral oxygen metabolism and blood flow, not increased ammonia uptake. Hepatology 57:258–265. CrossRefGoogle Scholar
  16. 16.
    Holick MF, Vitamin D (2007) Deficiency. N Engl J Med 357:266–281. CrossRefGoogle Scholar
  17. 17.
    Assa A, Vong L, Pinnell LJ, Avitzur N, Johnson-Henry KC, Sherman PM (2014) Vitamin D deficiency promotes epithelial barrier dysfunction and intestinal inflammation. J Infect Dis 210:1296–1305. CrossRefGoogle Scholar
  18. 18.
    Bitetto D, Fattovich G, Fabris C, Ceriani E, Falleti E, Fornasiere E et al (2011) Complementary role of vitamin D deficiency and the interleukin-28B rs12979860 C/T polymorphism in predicting antiviral response in chronic hepatitis C. Hepatology 53:1118–1126. CrossRefGoogle Scholar
  19. 19.
    Lange CM, Bibert S, Kutalik Z, Burgisser P, Cerny A, Dufour J-F et al (2012) 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 7:e40159. CrossRefGoogle Scholar
  20. 20.
    Backstedt D (2017) 25-Vitamin D levels in chronic hepatitis C infection: association with cirrhosis and sustained virologic response. Ann Gastroenterol. Google Scholar
  21. 21.
    Petta S, Cammà C, Scazzone C, Tripodo C, Di Marco V, Bono A et al (2010) Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology 51:1158–1167. CrossRefGoogle Scholar
  22. 22.
    Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R (1973) Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 60:646–649CrossRefGoogle Scholar
  23. 23.
    Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L et al (1977) Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology 72:573–583Google Scholar
  24. 24.
    Holick MF (2006) High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 81:353–373. CrossRefGoogle Scholar
  25. 25.
    Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B (2006) Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 84:18–28. CrossRefGoogle Scholar
  26. 26.
    Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R (2005) Estimates of optimal vitamin D status. Osteoporos Int 16:713–716. CrossRefGoogle Scholar
  27. 27.
    Thorpe TC, Wilson ML, Turner JE, DiGuiseppi JL, Willert M, Mirrett S et al (1990) BacT/Alert: an automated colorimetric microbial detection system. J Clin Microbiol 28:1608–1612Google Scholar
  28. 28.
    Spanu T, Sanguinetti M, Ciccaglione D, D’Inzeo T, Romano L, Leone F et al (2003) Use of the VITEK 2 system for rapid identification of clinical isolates of Staphylococci from bloodstream infections. J Clin Microbiol 41:4259–4263CrossRefGoogle Scholar
  29. 29.
    Arteh J, Narra S, Nair S (2010) Prevalence of vitamin D deficiency in chronic liver disease. Dig Dis Sci 55:2624–2628. CrossRefGoogle Scholar
  30. 30.
    Guy J, Peters MG (2013) Liver disease in women: the influence of gender on epidemiology, natural history, and patient outcomes. Gastroenterol Hepatol (N Y) 9:633–639Google Scholar
  31. 31.
    Kitson MT, Roberts SK (2012) D-livering the message: the importance of vitamin D status in chronic liver disease. J Hepatol 57:897–909. CrossRefGoogle Scholar
  32. 32.
    Lange CM, Bojunga J, Ramos-Lopez E, von Wagner M, Hassler A, Vermehren J et al (2011) 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 54:887–893. CrossRefGoogle Scholar
  33. 33.
    Trépo E, Ouziel R, Pradat P, Momozawa Y, Quertinmont E, Gervy C et al (2013) Marked 25-hydroxyvitamin D deficiency is associated with poor prognosis in patients with alcoholic liver disease. J Hepatol 59:344–350. CrossRefGoogle Scholar
  34. 34.
    Anty R, Tonohouan M, Ferrari-Panaia P, Piche T, Pariente A, Anstee QM et al (2014) Low levels of 25-hydroxy vitamin D are independently associated with the risk of bacterial infection in cirrhotic patients. Clin Transl Gastroenterol 5:e56. CrossRefGoogle Scholar
  35. 35.
    Finkelmeier F, Kronenberger B, Zeuzem S, Piiper A, Waidmann O (2015) Low 25-hydroxyvitamin D levels are associated with infections and mortality in patients with cirrhosis. PLoS One 10:e0132119. CrossRefGoogle Scholar
  36. 36.
    Baijal R, Amarapurkar D, Praveen Kumar HR, Kulkarni S, Shah N, Doshi S et al (2014) A multicenter prospective study of infections related morbidity and mortality in cirrhosis of liver. Indian J Gastroenterol 33:336–342. CrossRefGoogle Scholar
  37. 37.
    Vidot H, Potter A, Cheng R, Allman-Farinelli M, Shackel N (2017) Serum 25-hydroxyvitamin D deficiency and hepatic encephalopathy in chronic liver disease. World J Hepatol 9:510–518. CrossRefGoogle Scholar
  38. 38.
    Iruzubieta P (2014) Vitamin D deficiency in chronic liver disease. World J Hepatol 6:901. CrossRefGoogle Scholar
  39. 39.
    Zaloga GP (1986) Hypocalcemia in critical illness. JAMA J Am Med Assoc 256:1924. CrossRefGoogle Scholar
  40. 40.
    Kelly A, Levine MA (2013) Hypocalcemia in the critically ill patient. J Intensive Care Med 28:166–177. CrossRefGoogle Scholar
  41. 41.
    Gombart AF (2009) The vitamin D—antimicrobial peptide pathway and its role in protection against infection. Future Microbiol 4:1151–1165. CrossRefGoogle Scholar
  42. 42.
    White JH (2010) Vitamin D as an inducer of cathelicidin antimicrobial peptide expression: past, present and future. J Steroid Biochem Mol Biol 121:234–238. CrossRefGoogle Scholar
  43. 43.
    European Association For The Study Of The Liver (2009) EASL Clinical Practice Guidelines: Management of cholestatic liver diseases. J Hepatol 51:237–267. CrossRefGoogle Scholar
  44. 44.
    Stokes CS, Krawczyk M, Reichel C, Lammert F, Grünhage F (2014) Vitamin D deficiency is associated with mortality in patients with advanced liver cirrhosis. Eur J Clin Invest 44:176–183. CrossRefGoogle Scholar
  45. 45.
    Finkelmeier F, Kronenberger B, Köberle V, Bojunga J, Zeuzem S, Trojan J et al (2014) Severe 25-hydroxyvitamin D deficiency identifies a poor prognosis in patients with hepatocellular carcinoma—a prospective cohort study. Aliment Pharmacol Ther 39:1204–1212. CrossRefGoogle Scholar
  46. 46.
    Zittermann A, Iodice S, Pilz S, Grant WB, Bagnardi V, Gandini S (2012) Vitamin D deficiency and mortality risk in the general population: a meta-analysis of prospective cohort studies. Am J Clin Nutr 95:91–100. CrossRefGoogle Scholar
  47. 47.
    Schöttker B, Ball D, Gellert C, Brenner H (2013) Serum 25-hydroxyvitamin D levels and overall mortality. A systematic review and meta-analysis of prospective cohort studies. Ageing Res Rev 12:708–718. CrossRefGoogle Scholar
  48. 48.
    Rejnmark L, Avenell A, Masud T, Anderson F, Meyer HE, Sanders KM et al (2012) Vitamin D with calcium reduces mortality: patient level pooled analysis of 70,528 patients from eight major vitamin D trials. J Clin Endocrinol Metab 97:2670–2681. CrossRefGoogle Scholar
  49. 49.
    Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I, Reggiardo V et al (1999) Prognostic significance of hepatic encephalopathy in patients with cirrhosis. J Hepatol 30:890–895CrossRefGoogle Scholar
  50. 50.
    Paternostro R, Wagner D, Reiberger T, Mandorfer M, Schwarzer R, Ferlitsch M et al (2017) Low 25-OH-vitamin D levels reflect hepatic dysfunction and are associated with mortality in patients with liver cirrhosis. Wien Klin Wochenschr 129:8–15. CrossRefGoogle Scholar

Copyright information

© Società Italiana di Medicina Interna (SIMI) 2019

Authors and Affiliations

  1. 1.Internal Medicine Department, Faculty of MedicineZagazig University HospitalsZagazigEgypt
  2. 2.Tropical Medicine Department, Faculty of MedicineZagazig University HospitalsZagazigEgypt

Personalised recommendations