Primary biliary cirrhosis strongly associated with low vitamin D – Nov 2014

Vitamin D in primary biliary cirrhosis, a plausible marker of advanced disease

Immunologic Research, November 2014
Nancy Agmon-Levin, Ron Kopilov, Carlo Selmi, Udi Nussinovitch, María Sánchez-Castañón, Marcos López-Hoyos, Howie Amital, Shaye Kivity, Eric M. Gershwin, Yehuda Shoenfeld

Vitamin D immune-modulating effects were extensively studied, and low levels have been linked with autoimmune diseases. The associations of vitamin D with autoimmune diseases of the liver, and particularly primary biliary cirrhosis (PBC), are yet to be defined. Hence, in this study, serum levels of vitamin D were determined in 79 patients with PBC and 70 age- and sex-matched controls by the LIAISON chemiluminescent immunoassays (DiaSorin—Italy). Clinical and serological parameters of patients were analyzed with respect to vitamin D status. Mean levels of vitamin D were significantly lower among patients with PBC compared with controls (16.8 ± 9 vs. 22.1 ± 9 ng/ml; p = 0.029), and
vitamin D deficiency (≤10 ng/ml) was documented in 33 % of patients with PBC versus 7 % of controls (p < 0.0001).
Vitamin D levels inversely correlated with advanced liver damage and the presence of concomitant autoimmune diseases.
In contrast, higher levels of vitamin D were observed among patients with PBC treated with ursodeoxycholic acid (UDCA).
In conclusion, low vitamin D levels are common among patients with PBC and correlate with advanced disease, lack of UDCA therapy and autoimmune comorbidity. This alludes to the plausible roles of vitamin D as a prognostic marker of PBC severity, and as a potential player in this disease pathogenesis. While further studies are awaited, monitoring vitamin D in patients with PBC and use of supplements may be advisable.

References

1. Selmi C, Bowlus CL, Gershwin ME, Coppel RL. Primary biliary cirrhosis. Lancet. 2011;377(9777):1600–9. doi:10.1016/S0140-6736(10)61965-4. CrossRef
2. Hirschfield GM, Gershwin ME. Primary biliary cirrhosis: one disease with many faces. IMAJ. 2011;13(1):55–9.
3. Agmon-Levin N, Shapira Y, Selmi C, Barzilai O, Ram M, Szyper-Kravitz M, et al. A comprehensive evaluation of serum autoantibodies in primary biliary cirrhosis. J Autoimmun. 2010;34(1):55–8. doi:10.1016/j.jaut.2009.08.009. CrossRef
4. Invernizzi P, Selmi C, Ranftler C, Podda M, Wesierska-Gadek J. Antinuclear antibodies in primary biliary cirrhosis. Semin Liver Dis. 2005;25(3):298–310. doi:10.1055/s-2005-916321. CrossRef
5. Uibo R, Kisand K, Yang CY, Gershwin ME. Primary biliary cirrhosis: a multi-faced interactive disease involving genetics, environment and the immune response. APMIS. 2012;120(11):857–71. doi:10.1111/j.1600-0463.2012.02914.x. CrossRef
6. Kawata K, Tsuda M, Yang GX, Zhang W, Tanaka H, Tsuneyama K, et al. Identification of potential cytokine pathways for therapeutic intervention in murine primary biliary cirrhosis. PLoS ONE. 2013;8(9):e74225. doi:10.1371/journal.pone.0074225. CrossRef
7. Barak V, Selmi C, Schlesinger M, Blank M, Agmon-Levin N, Kalickman I, et al. Serum inflammatory cytokines, complement components, and soluble interleukin 2 receptor in primary biliary cirrhosis. J Autoimmun. 2009;33(3–4):178–82. doi:10.1016/j.jaut.2009.09.010. CrossRef
8. Wang Q, Selmi C, Zhou X, Qiu D, Li Z, Miao Q, et al. Epigenetic considerations and the clinical reevaluation of the overlap syndrome between primary biliary cirrhosis and autoimmune hepatitis. J Autoimmun. 2013;41:140–5. doi:10.1016/j.jaut.2012.10.004. CrossRef
9. Perricone C, Agmon-Levin N, Shoenfeld Y. Novel pebbles in the mosaic of autoimmunity. BMC Med. 2013;11:101. doi:10.1186/1741-7015-11-101. CrossRef
10. Shapira Y, Agmon-Levin N, Renaudineau Y, Porat-Katz BS, Barzilai O, Ram M, et al. Serum markers of infections in patients with primary biliary cirrhosis: evidence of infection burden. Exp Mol Pathol. 2012;93(3):386–90. doi:10.1016/j.yexmp.2012.09.012. CrossRef
11. Leung PS, Wang J, Naiyanetr P, Kenny TP, Lam KS, Kurth MJ, et al. Environment and primary biliary cirrhosis: electrophilic drugs and the induction of AMA. J Autoimmun. 2013;41:79–86. doi:10.1016/j.jaut.2012.12.007. CrossRef
12. Selmi C, Gershwin ME. The role of environmental factors in primary biliary cirrhosis. Trends Immunol. 2009;30(8):415–20. doi:10.1016/j.it.2009.05.006. CrossRef
13. Pludowski P, Holick MF, Pilz S, Wagner CL, Hollis BW, Grant WB, et al. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality-a review of recent evidence. Autoimmun Rev. 2013;12(10):976–89. doi:10.1016/j.autrev.2013.02.004. CrossRef
14. Souberbielle JC, Body JJ, Lappe JM, Plebani M, Shoenfeld Y, Wang TJ, et al. Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: recommendations for clinical practice. Autoimmun Rev. 2010;9(11):709–15. doi:10.1016/j.autrev.2010.06.009. CrossRef
15. Toubi E, Shoenfeld Y. The role of vitamin D in regulating immune responses. IMAJ. 2010;12(3):174–5.
16. Agmon-Levin N, Theodor E, Segal RM, Shoenfeld Y. Vitamin D in systemic and organ-specific autoimmune diseases. Clin Rev Allergy Immunol. 2013;45(2):256–66. doi:10.1007/s12016-012-8342-y. CrossRef
17. Agmon-Levin N, Kivity S, Tzioufas AG, Lopez Hoyos M, Rozman B, Efes I, et al. Low levels of vitamin-D are associated with neuropathy and lymphoma among patients with Sjogren’s syndrome. J Autoimmun. 2012;39(3):234–9. doi:10.1016/j.jaut.2012.05.018. CrossRef
18. Arnson Y, Amital H, Agmon-Levin N, Alon D, Sanchez-Castanon M, Lopez-Hoyos M, et al. Serum 25-OH vitamin D concentrations are linked with various clinical aspects in patients with systemic sclerosis: a retrospective cohort study and review of the literature. Autoimmun Rev. 2011;10(8):490–4. doi:10.1016/j.autrev.2011.02.002. CrossRef
19. Kivity S, Agmon-Levin N, Zisappl M, Shapira Y, Nagy EV, Danko K, et al. Vitamin D and autoimmune thyroid diseases. Cell Mol Immunol. 2011;8(3):243–7. doi:10.1038/cmi.2010.73. CrossRef
20. Agmon-Levin N, Blank M, Zandman-Goddard G, Orbach H, Meroni PL, Tincani A, et al. Vitamin D: an instrumental factor in the anti-phospholipid syndrome by inhibition of tissue factor expression. Ann Rheum Dis. 2011;70(1):145–50. doi:10.1136/ard.2010.134817. CrossRef
21. Hajas A, Sandor J, Csathy L, Csipo I, Barath S, Paragh G, et al. Vitamin D insufficiency in a large MCTD population. Autoimmun Rev. 2011;10(6):317–24. doi:10.1016/j.autrev.2010.11.006. CrossRef
22. Amital H, Szekanecz Z, Szucs G, Danko K, Nagy E, Csepany T, et al. Serum concentrations of 25-OH vitamin D in patients with systemic lupus erythematosus (SLE) are inversely related to disease activity: is it time to routinely supplement patients with SLE with vitamin D? Ann Rheum Dis. 2010;69(6):1155–7. doi:10.1136/ard.2009.120329. CrossRef
23. Arnson Y, Itzhaky D, Mosseri M, Barak V, Tzur B, Agmon-Levin N, et al. Vitamin D inflammatory cytokines and coronary events: a comprehensive review. Clin Rev Allergy Immunol. 2013;45(2):236–47. doi:10.1007/s12016-013-8356-0. CrossRef
24. Kowdley KV, Emond MJ, Sadowski JA, Kaplan MM. Plasma vitamin K1 level is decreased in primary biliary cirrhosis. Am J Gastroenterol. 1997;92(11):2059–61.
25. Herlong HF, Recker RR, Maddrey WC. Bone disease in primary biliary cirrhosis: histologic features and response to 25-hydroxyvitamin D. Gastroenterology. 1982;83(1 Pt 1):103–8.
26. Munoz SJ, Heubi JE, Balistreri WF, Maddrey WC. Vitamin E deficiency in primary biliary cirrhosis: gastrointestinal malabsorption, frequency and relationship to other lipid-soluble vitamins. Hepatology. 1989;9(4):525–31. CrossRef
27. Guanabens N, Pares A, Marinoso L, Brancos MA, Piera C, Serrano S, et al. Factors influencing the development of metabolic bone disease in primary biliary cirrhosis. Am J Gastroenterol. 1990;85(10):1356–62.
28. Phillips JR, Angulo P, Petterson T, Lindor KD. Fat-soluble vitamin levels in patients with primary biliary cirrhosis. Am J Gastroenterol. 2001;96(9):2745–50. doi:10.1111/j.1572-0241.2001.04134.x. CrossRef
29. Selmi C, Meroni PL, Gershwin ME. Primary biliary cirrhosis and Sjogren’s syndrome: autoimmune epithelitis. J Autoimmun. 2012;39(1–2):34–42. doi:10.1016/j.jaut.2011.11.005. CrossRef
30. Polido-Pereira J, Rodrigues AM, Canhao H, Saraiva F, da Silva JA, Fonseca JE. Primary biliary cirrhosis in a rheumatoid arthritis patient treated with rituximab, a case-based review. Clin Rheumatol. 2012;31(2):385–9. doi:10.1007/s10067-011-1879-y. CrossRef
31. Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, et al. Risk factors and comorbidities in primary biliary cirrhosis: a controlled interview-based study of 1032 patients. Hepatology. 2005;42(5):1194–202. doi:10.1002/hep.20907. CrossRef
32. Agmon-Levin N, Damoiseaux J, Kallenberg C, Sack U, Witte T, Herold M, et al. International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. Ann Rheum Dis. 2014;73(1):17–23. doi:10.1136/annrheumdis-2013-203863. CrossRef
33. Ishibashi H, Komori A, Shimoda S, Ambrosini YM, Gershwin ME, Nakamura M. Risk factors and prediction of long-term outcome in primary biliary cirrhosis. Intern Med. 2011;50(1):1–10. CrossRef
34. Pares A, Caballeria L, Rodes J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid. Gastroenterology. 2006;130(3):715–20. doi:10.1053/j.gastro.2005.12.029. CrossRef
35. Corpechot C, Chazouilleres O, Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of long-term outcome. J Hepatol. 2011;55(6):1361–7. doi:10.1016/j.jhep.2011.02.031. CrossRef
36. Kaplan MM, Elta GH, Furie B, Sadowski JA, Russell RM. Fat-soluble vitamin nutriture in primary biliary cirrhosis. Gastroenterology. 1988;95(3):787–92.
37. Petta S, Camma C, Scazzone C, Tripodo C, Di Marco V, 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(4):1158–67. doi:10.1002/hep.23489. CrossRef
38. Fisher L, Fisher A. Vitamin D and parathyroid hormone in outpatients with noncholestatic chronic liver disease. Clin Gastroenterol Hepatol. 2007;5(4):513–20. doi:10.1016/j.cgh.2006.10.015. CrossRef
39. Verma A, Maxwell JD, Ang L, Davis T, Hodges S, Northfield TC, et al. Ursodeoxycholic acid enhances fractional calcium absorption in primary biliary cirrhosis. Osteoporos Int. 2002;13(8):677–82. doi:10.1007/s001980200092. CrossRef
40. Mounach A, Ouzzif Z, Wariaghli G, Achemlal L, Benbaghdadi I, Aouragh A, et al. Primary biliary cirrhosis and osteoporosis: a case-control study. J Bone Miner Metab. 2008;26(4):379–84. doi:10.1007/s00774-007-0833-1. CrossRef

---

See also VitaminDWiki

• Overview Liver and vitamin D
• Important interactions between the liver and vitamin D – May 2013

Click on image for ways of getting vitamin D even if Liver is not functioning well