Year 2018 / Volume 110 / Number 10
Original
Role of the PNPLA3 polymorphism rs738409 on silymarin + vitamin E response in subjects with non-alcoholic fatty liver disease

634-640

DOI: 10.17235/reed.2018.5602/2018

Rocío Aller, Cristina Laserna, Miguel Ángel Rojo, Natalia Mora, Concepción García Sánchez, María Pina, Rebeca Sigüenza, Miguel Durà, David Primo, Olatz Izaola, Daniel de Luis,

Abstract
Background: non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developed countries. Lifestyle changes are the pillar of the treatment, although a pharmacological approach is sometimes required in the case of a failure to respond/adhere to the diet. Objective: the aim of this study was to evaluate the effect of silymarin and the influence of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) variant on the response to treatment in patients with NAFLD in a pilot study. Methods: a total of 54 patients with a NAFLD proven biopsy were enrolled in an open prospective study and were treated with Eurosil 85® (silymarin + vitamin E) for six months. Biochemical parameters and cardiovascular risk factors (diabetes mellitus, dyslipidemia, hypertriglyceridemia, arterial hypertension and HOMA-IR > 2.5) were recorded before and after six months of treatment. Non-invasive indexes (fatty liver index, lipid accumulation product and NAFLD-fibrosis score) were also calculated. The rs738409 PNPLA3 gene polymorphism status was also determined. Results: significant statistical changes from baseline values after six months of treatment were observed in transaminases levels but not in non-invasive index markers. Twenty patients (37.1%) were G allele carriers and had a higher percentage of lobular inflammation and ballooning on the basal liver biopsy. Patients with the G allele had a smaller decrease in transaminases levels after treatment with silymarin + vitamin E than non-G-allele carriers. Conclusions: treatment with silymarin + vitamin E produced a decrease in transaminases after six months of treatment without an accompanying weight loss. PNPLA3 G-allele carriers responded poorly to the treatment.
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References
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9. Chen LZ, Xin YN, Geng N, Jiang M, Zhang DD, Xuan SY. PNPLA3 I148M variant in nonalcoholic fatty liver disease: demographic and ethnic characteristics and the role of the variant in nonalcoholic fatty liver fibrosis. World journal of gastroenterology. 2015;21(3):794-802.
10. Valenti L, Dongiovanni P, Ginanni Corradini S, Burza MA, Romeo S. PNPLA3 I148M variant and hepatocellular carcinoma: a common genetic variant for a rare disease. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2013;45(8):619-24.
11. Bedossa P. Pathology of non-alcoholic fatty liver disease. Liver international : official journal of the International Association for the Study of the Liver. 2017;37 Suppl 1:85-9.
12. Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC gastroenterology. 2006;6:33.
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14. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846-54.
15. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical chemistry. 1972;18(6):499-502.
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18. Centis E, Moscatiello S, Bugianesi E, Bellentani S, Fracanzani AL, Calugi S, et al. Stage of change and motivation to healthier lifestyle in non-alcoholic fatty liver disease. Journal of hepatology. 2013;58(4):771-7.
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20. Hawke RL, Schrieber SJ, Soule TA, Wen Z, Smith PC, Reddy KR, et al. Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. Journal of clinical pharmacology. 2010;50(4):434-49.
21. Trappoliere M, Caligiuri A, Schmid M, Bertolani C, Failli P, Vizzutti F, et al. Silybin, a component of sylimarin, exerts anti-inflammatory and anti-fibrogenic effects on human hepatic stellate cells. Journal of hepatology. 2009;50(6):1102-11.
22. Kim M, Yang SG, Kim JM, Lee JW, Kim YS, Lee JI. Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: analysis of isolated hepatic stellate cells. International journal of molecular medicine. 2012;30(3):473-9.
23. Chan WK, Nik Mustapha NR, Mahadeva S. A Randomized Trial of Silymarin for the Treatment of Nonalcoholic Steatohepatitis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2017.
24. Chan WK, Nik Mustapha NR, Mahadeva S. A Randomized Trial of Silymarin for the Treatment of Non-alcoholic Steatohepatitis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2017.
25. Shaker E, Mahmoud H, Mnaa S. Silymarin, the antioxidant component and Silybum marianum extracts prevent liver damage. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2010;48(3):803-6.
26. de Avelar CR, Pereira EM, de Farias Costa PR, de Jesus RP, de Oliveira LPM. Effect of silymarin on biochemical indicators in patients with liver disease: Systematic review with meta-analysis. World journal of gastroenterology. 2017;23(27):5004-17.
27. Clarke MW, Burnett JR, Croft KD. Vitamin E in human health and disease. Critical reviews in clinical laboratory sciences. 2008;45(5):417-50.
28. Xu R, Tao A, Zhang S, Deng Y, Chen G. Association between vitamin E and non-alcoholic steatohepatitis: a meta-analysis. International journal of clinical and experimental medicine. 2015;8(3):3924-34.
29. Salamone F, Galvano F, Cappello F, Mangiameli A, Barbagallo I, Li Volti G. Silibinin modulates lipid homeostasis and inhibits nuclear factor kappa B activation in experimental nonalcoholic steatohepatitis. Translational research : the journal of laboratory and clinical medicine. 2012;159(6):477-86.
30. Baulande S, Lasnier F, Lucas M, Pairault J. Adiponutrin, a transmembrane protein corresponding to a novel dietary- and obesity-linked mRNA specifically expressed in the adipose lineage. The Journal of biological chemistry. 2001;276(36):33336-44.
31. Wilson PA, Gardner SD, Lambie NM, Commans SA, Crowther DJ. Characterization of the human patatin-like phospholipase family. Journal of lipid research. 2006;47(9):1940-9.
32. Hotta K, Yoneda M, Hyogo H, Ochi H, Mizusawa S, Ueno T, et al. Association of the rs738409 polymorphism in PNPLA3 with liver damage and the development of nonalcoholic fatty liver disease. BMC medical genetics. 2010;11:172.
33. Kawaguchi T, Sumida Y, Umemura A, Matsuo K, Takahashi M, Takamura T, et al. Genetic polymorphisms of the human PNPLA3 gene are strongly associated with severity of non-alcoholic fatty liver disease in Japanese. PloS one. 2012;7(6):e38322.
34. Xu R, Tao A, Zhang S, Deng Y, Chen G. Association between patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and nonalcoholic fatty liver disease: a HuGE review and meta-analysis. Scientific reports. 2015;5:9284.
35. Zhang L, You W, Zhang H, Peng R, Zhu Q, Yao A, et al. PNPLA3 polymorphisms (rs738409) and non-alcoholic fatty liver disease risk and related phenotypes: a meta-analysis. Journal of gastroenterology and hepatology. 2015;30(5):821-9.
36. Miyaaki H, Nakao K. Significance of genetic polymorphisms in patients with nonalcoholic fatty liver disease. Clinical journal of gastroenterology. 2017;10(3):201-7.
1. Wah-Kheong C, Khean-Lee G. Epidemiology of a fast emerging disease in the Asia-Pacific region: non-alcoholic fatty liver disease. Hepatology international. 2013;7(1):65-71.
2. Bellentani S. The epidemiology of non-alcoholic fatty liver disease. Liver international : official journal of the International Association for the Study of the Liver. 2017;37 Suppl 1:81-4.
3. Samuel VT, Shulman GI. Nonalcoholic Fatty Liver Disease as a Nexus of Metabolic and Hepatic Diseases. Cell metabolism. 2017.
4. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015;149(2):367-78.e5; quiz e14-5.
5. Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51(1):121-9.
6. Vilar-Gomez E, Yasells-Garcia A, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, et al. Development and validation of a noninvasive prediction model for nonalcoholic steatohepatitis resolution after lifestyle intervention. Hepatology. 2016;63(6):1875-87.
7. Salameh H, Masadeh M, Al Hanayneh M, Petros V, Maslonka M, Nanda A, et al. PNPLA3 polymorphism increases risk for and severity of chronic hepatitis C liver disease. World J Hepatol. 2016;8(35):1584-92.
8. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nature genetics. 2008;40(12):1461-5.
9. Chen LZ, Xin YN, Geng N, Jiang M, Zhang DD, Xuan SY. PNPLA3 I148M variant in nonalcoholic fatty liver disease: demographic and ethnic characteristics and the role of the variant in nonalcoholic fatty liver fibrosis. World journal of gastroenterology. 2015;21(3):794-802.
10. Valenti L, Dongiovanni P, Ginanni Corradini S, Burza MA, Romeo S. PNPLA3 I148M variant and hepatocellular carcinoma: a common genetic variant for a rare disease. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2013;45(8):619-24.
11. Bedossa P. Pathology of non-alcoholic fatty liver disease. Liver international : official journal of the International Association for the Study of the Liver. 2017;37 Suppl 1:85-9.
12. Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC gastroenterology. 2006;6:33.
13. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical chemistry. 1972;18(6):499-502.
14. Bedogni G, Kahn HS, Bellentani S, Tiribelli C. A simple index of lipid overaccumulation is a good marker of liver steatosis. BMC gastroenterology. 2010;10:98.
15. Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846-54.
16. Vilar-Gomez E, Calzadilla-Bertot L, Friedman SL, Gra-Oramas B, Gonzalez-Fabian L, Villa-Jimenez O, et al. Improvement in liver histology due to lifestyle modification is independently associated with improved kidney function in patients with non-alcoholic steatohepatitis. Alimentary pharmacology & therapeutics. 2017;45(2):332-44.
17. Kenneally S, Sier JH, Moore JB. Efficacy of dietary and physical activity intervention in non-alcoholic fatty liver disease: a systematic review. BMJ open gastroenterology. 2017;4(1):e000139.
18. Centis E, Moscatiello S, Bugianesi E, Bellentani S, Fracanzani AL, Calugi S, et al. Stage of change and motivation to healthier lifestyle in non-alcoholic fatty liver disease. Journal of hepatology. 2013;58(4):771-7.
19. Sorrentino G, Crispino P, Coppola D, De Stefano G. Efficacy of lifestyle changes in subjects with non-alcoholic liver steatosis and metabolic syndrome may be improved with an antioxidant nutraceutical: a controlled clinical study. Drugs in R&D. 2015;15(1):21-5.
20. Hawke RL, Schrieber SJ, Soule TA, Wen Z, Smith PC, Reddy KR, et al. Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. Journal of clinical pharmacology. 2010;50(4):434-49.
21. Trappoliere M, Caligiuri A, Schmid M, Bertolani C, Failli P, Vizzutti F, et al. Silybin, a component of sylimarin, exerts anti-inflammatory and anti-fibrogenic effects on human hepatic stellate cells. Journal of hepatology. 2009;50(6):1102-11.
22. Kim M, Yang SG, Kim JM, Lee JW, Kim YS, Lee JI. Silymarin suppresses hepatic stellate cell activation in a dietary rat model of non-alcoholic steatohepatitis: analysis of isolated hepatic stellate cells. International journal of molecular medicine. 2012;30(3):473-9.
23. Chan WK, Nik Mustapha NR, Mahadeva S. A Randomized Trial of Silymarin for the Treatment of Nonalcoholic Steatohepatitis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2017.
24. Chan WK, Nik Mustapha NR, Mahadeva S. A Randomized Trial of Silymarin for the Treatment of Non-alcoholic Steatohepatitis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2017.
25. Shaker E, Mahmoud H, Mnaa S. Silymarin, the antioxidant component and Silybum marianum extracts prevent liver damage. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2010;48(3):803-6.
26. de Avelar CR, Pereira EM, de Farias Costa PR, de Jesus RP, de Oliveira LPM. Effect of silymarin on biochemical indicators in patients with liver disease: Systematic review with meta-analysis. World journal of gastroenterology. 2017;23(27):5004-17.
27. Clarke MW, Burnett JR, Croft KD. Vitamin E in human health and disease. Critical reviews in clinical laboratory sciences. 2008;45(5):417-50.
28. Xu R, Tao A, Zhang S, Deng Y, Chen G. Association between vitamin E and non-alcoholic steatohepatitis: a meta-analysis. International journal of clinical and experimental medicine. 2015;8(3):3924-34.
29. Salamone F, Galvano F, Cappello F, Mangiameli A, Barbagallo I, Li Volti G. Silibinin modulates lipid homeostasis and inhibits nuclear factor kappa B activation in experimental nonalcoholic steatohepatitis. Translational research : the journal of laboratory and clinical medicine. 2012;159(6):477-86.
30. Baulande S, Lasnier F, Lucas M, Pairault J. Adiponutrin, a transmembrane protein corresponding to a novel dietary- and obesity-linked mRNA specifically expressed in the adipose lineage. The Journal of biological chemistry. 2001;276(36):33336-44.
31. Wilson PA, Gardner SD, Lambie NM, Commans SA, Crowther DJ. Characterization of the human patatin-like phospholipase family. Journal of lipid research. 2006;47(9):1940-9.
32. Hotta K, Yoneda M, Hyogo H, Ochi H, Mizusawa S, Ueno T, et al. Association of the rs738409 polymorphism in PNPLA3 with liver damage and the development of nonalcoholic fatty liver disease. BMC medical genetics. 2010;11:172.
33. Kawaguchi T, Sumida Y, Umemura A, Matsuo K, Takahashi M, Takamura T, et al. Genetic polymorphisms of the human PNPLA3 gene are strongly associated with severity of non-alcoholic fatty liver disease in Japanese. PloS one. 2012;7(6):e38322.
34. Xu R, Tao A, Zhang S, Deng Y, Chen G. Association between patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and nonalcoholic fatty liver disease: a HuGE review and meta-analysis. Scientific reports. 2015;5:9284.
35. Zhang L, You W, Zhang H, Peng R, Zhu Q, Yao A, et al. PNPLA3 polymorphisms (rs738409) and non-alcoholic fatty liver disease risk and related phenotypes: a meta-analysis. Journal of gastroenterology and hepatology. 2015;30(5):821-9.
36. Miyaaki H, Nakao K. Significance of genetic polymorphisms in patients with nonalcoholic fatty liver disease. Clinical journal of gastroenterology. 2017;10(3):201-7.
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Aller R, Laserna C, Rojo M, Mora N, García Sánchez C, Pina M, et all. Role of the PNPLA3 polymorphism rs738409 on silymarin + vitamin E response in subjects with non-alcoholic fatty liver disease . 5602/2018


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Publication history

Received: 15/03/2018

Accepted: 17/05/2018

Online First: 23/07/2018

Published: 01/10/2018

Article revision time: 45 days

Article Online First time: 130 days

Article editing time: 200 days


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