NAFLD in Polycystic Ovary Syndrome: Association with PNPLA3 and Metabolic Features
Abstract
:1. Introduction
2. Materials and Methods
2.1. Ethical Aspects
2.2. Study Design and Population
2.3. Exclusion Criteria
2.4. Diagnosis of NAFLD and Assessment of the Degree of Liver Fibrosis
2.5. Extraction of Genomic DNA
2.6. Variables Evaluated in the Study
2.7. Statistical Analysis
3. Results
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Chalasani, N.; Younossi, Z.; Lavine, J.E.; Diehl, A.M.; Brunt, E.M.; Cusi, K.; Charlton, M.; Sanyal, A.J. The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012, 142, 1592–1609. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Younossi, Z.M.; Golabi, P.; de Avila, L.; Paik, J.M.; Srishord, M.; Fukui, N.; Qiu, Y.; Burns, L.; Afendy, A.; Nader, F. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J. Hepatol. 2019, 71, 793–801. [Google Scholar] [CrossRef] [PubMed]
- Romeo, S.; Kozlitina, J.; Xing, C.; Pertsemlidis, A.; Cox, D.; Pennacchio, L.A.; Boerwinkle, E.; Cohen, J.C.; Hobbs, H.H. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 2008, 40, 1461–1465. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tai, C.M.; Huang, C.K.; Tu, H.P.; Hwang, J.C.; Yeh, M.L.; Huang, C.F.; Huang, J.F.; Dai, C.Y.; Chuang, W.L.; Yu, M.L. Interactions of a PPARGC1A Variant and a PNPLA3 Variant Affect Nonalcoholic Steatohepatitis in Severely Obese Taiwanese Patients. Medicine 2016, 95, e3120. [Google Scholar] [CrossRef]
- Sookoian, S.; Castaño, G.O.; Burgueño, A.L.; Gianotti, T.F.; Rosselli, M.S.; Pirola, C.J. A nonsynonymous gene variant in the adiponutrin gene is associated with nonalcoholic fatty liver disease severity. J. Lipid Res. 2009, 50, 2111–2116. [Google Scholar] [CrossRef] [Green Version]
- Paschou, S.A.; Polyzos, S.A.; Anagnostis, P.; Goulis, D.G.; Kanaka-Gantenbein, C.; Lambrinoudaki, I.; Georgopoulos, N.A.; Vryonidou, A. Nonalcoholic fatty liver disease in women with polycystic ovary syndrome. Endocrine 2020, 67, 1–8. [Google Scholar] [CrossRef]
- Macut, D.; Božić-Antić, I.; Bjekić-Macut, J.; Tziomalos, K. MANAGEMENT OF ENDOCRINE DISEASE: Polycystic ovary syndrome and nonalcoholic fatty liver disease. Eur. J. Endocrinol. 2017, 177, R145–R158. [Google Scholar] [CrossRef] [Green Version]
- Wang, J.Z.; Cao, H.X.; Chen, J.N.; Pan, Q. PNPLA3 rs738409 underlies treatment response in nonalcoholic fatty liver disease. World J. Clin. Cases 2018, 6, 167–175. [Google Scholar] [CrossRef]
- The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil. Steril. 2004, 81, 19–25. [Google Scholar] [CrossRef]
- Azziz, R.; Carmina, E.; Chen, Z.; Dunaif, A.; Laven, J.S.; Legro, R.S.; Lizneva, D.; Natterson-Horowtiz, B.; Teede, H.J.; Yildiz, B.O. Polycystic ovary syndrome. Nat. Rev. Dis. Prim. 2016, 2, 16057. [Google Scholar] [CrossRef]
- de Lédinghen, V.; Vergniol, J. Transient elastography for the diagnosis of liver fibrosis. Expert Rev. Med. Devices 2010, 7, 811–823. [Google Scholar] [CrossRef] [PubMed]
- Sasso, M.; Beaugrand, M.; de Ledinghen, V.; Douvin, C.; Marcellin, P.; Poupon, R.; Sandrin, L.; Miette, V. Controlled attenuation parameter (CAP): A novel VCTE™ guided ultrasonic attenuation measurement for the evaluation of hepatic steatosis: Preliminary study and validation in a cohort of patients with chronic liver disease from various causes. Ultrasound Med. Biol. 2010, 36, 1825–1835. [Google Scholar] [CrossRef] [PubMed]
- Consultation WHO. Obesity: Preventing and managing the global epidemic. World Health Organ. Tech. Rep. Ser. 2000, 894, 1–253. [Google Scholar]
- Sterling, R.K.; Lissen, E.; Clumeck, N.; Sola, R.; Correa, M.C.; Montaner, J.; Sulkowski, M.S.; Torriani, F.J.; Dieterich, D.T.; Thomas, D.L.; et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology 2006, 43, 1317–1325. [Google Scholar] [CrossRef]
- Angulo, P.; Hui, J.M.; Marchesini, G.; Bugianesi, E.; George, J.; Farrell, G.C.; Enders, F.; Saksena, S.; Burt, A.D.; Bida, J.P.; et al. The NAFLD fibrosis score: A noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007, 45, 846–854. [Google Scholar] [CrossRef]
- Handelsman, Y.; Bloomgarden, Z.T.; Grunberger, G.; Umpierrez, G.; Zimmerman, R.S.; Bailey, T.S.; Blonde, L.; Bray, G.A.; Cohen, A.J.; Dagogo-Jack, S.; et al. American association of clinical endocrinologists and american college of endocrinology—Clinical practice guidelines for developing a diabetes mellitus comprehensive care plan-2015. Endocr. Pract. 2015, 21, 1–87. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Whelton, P.K.; Carey, R.M.; Aronow, W.S.; Casey, D.E.; Collins, K.J.; Dennison Himmelfarb, C.; DePalma, S.M.; Gidding, S.; Jamerson, K.A.; Jones, D.W.; et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 2017, 71, e127–e248. [Google Scholar]
- Matthews, D.R.; Hosker, J.P.; Rudenski, A.S.; Naylor, B.A.; Treacher, D.F.; Turner, R.C. Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985, 28, 412–419. [Google Scholar] [CrossRef] [Green Version]
- Vasques, A.C.; Rosado, L.E.; Cássia GAlfenas, R.; Geloneze, B. Critical analysis on the use of the homeostasis model assessment (HOMA) indexes in the evaluation of the insulin resistance and the pancreatic beta cells functional capacity. Arq. Bras. Endocrinol. Metabol. 2008, 52, 32–39. [Google Scholar] [CrossRef] [Green Version]
- Grundy, S.M.; Cleeman, J.I.; Daniels, S.R.; Donato, K.A.; Eckel, R.H.; Franklin, B.A.; Gordon, D.J.; Krauss, R.M.; Savage, P.J.; Smith, S.C.; et al. Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005, 112, 2735–2752. [Google Scholar] [CrossRef] [Green Version]
- Oliveira, A.I.N.; Malta, F.M.; Zitelli, P.M.Y.; Salles, A.P.M.; Gomes-Gouvea, M.S.; Nastri, A.C.S.; Pinho, J.R.R.; Carrilho, F.J.; Oliveira, C.P.; Mendes-Corrêa, M.C.; et al. The role of PNPLA3 and TM6SF2 polymorphisms on liver fibrosis and metabolic abnormalities in Brazilian patients with chronic hepatitis C. BMC Gastroenterol. 2021, 21, 81. [Google Scholar] [CrossRef] [PubMed]
- Macut, D.; Tziomalos, K.; Božić-Antić, I.; Bjekić-Macut, J.; Katsikis, I.; Papadakis, E.; Andrić, Z.; Panidis, D. Non-alcoholic fatty liver disease is associated with insulin resistance and lipid accumulation product in women with polycystic ovary syndrome. Hum. Reprod. 2016, 31, 1347–1353. [Google Scholar] [CrossRef] [PubMed]
- Armandi, A.; Rosso, C.; Caviglia, G.P.; Bugianesi, E. Insulin Resistance across the Spectrum of Nonalcoholic Fatty Liver Disease. Metabolites 2021, 11, 155. [Google Scholar] [CrossRef] [PubMed]
- Ramezani-Binabaj, M.; Motalebi, M.; Karimi-Sari, H.; Rezaee-Zavareh, M.S.; Alavian, S.M. Are women with polycystic ovarian syndrome at a high risk of non-alcoholic Fatty liver disease; a meta-analysis. Hepat. Mon. 2014, 14, e23235. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Stender, S.; Kozlitina, J.; Nordestgaard, B.G.; Tybjærg-Hansen, A.; Hobbs, H.H.; Cohen, J.C. Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat. Genet. 2017, 49, 842–847. [Google Scholar] [CrossRef]
- Rocha, A.L.L.; Faria, L.C.; Guimarães, T.C.M.; Moreira, G.V.; Cândido, A.L.; Couto, C.A.; Reis, F.M. Non-alcoholic fatty liver disease in women with polycystic ovary syndrome: Systematic review and meta-analysis. J. Endocrinol. Investig. 2017, 40, 1279–1288. [Google Scholar] [CrossRef] [PubMed]
- Szczuko, M.; Zapałowska-Chwyć, M.; Drozd, A.; Maciejewska, D.; Starczewski, A.; Stachowska, E. Metabolic pathways of oleic and palmitic acid are intensified in PCOS patients with normal androgen levels. Prostaglandins Leukot. Essent. Fat. Acids 2017, 126, 105–111. [Google Scholar] [CrossRef]
- Maciejewska, D.; Drozd, A.; Ossowski, P.; Ryterska, K.; Jamioł-Milc, D.; Banaszczak, M.; Raszeja-Wyszomirska, J.; Kaczorowska, M.; Sabinicz, A.; Stachowska, E. Fatty acid changes help to better understand regression of nonalcoholic fatty liver disease. World J. Gastroenterol. 2015, 21, 301–310. [Google Scholar] [CrossRef]
- Trojak, A.; Waluś-Miarka, M.; Woźniakiewicz, E.; Małecki, M.T.; Idzior-Waluś, B. Nonalcoholic fatty liver disease is associated with low HDL cholesterol and coronary angioplasty in patients with type 2 diabetes. Med. Sci. Monit. 2013, 19, 1167–1172. [Google Scholar]
- Zhang, J.; Hu, J.; Zhang, C.; Jiao, Y.; Kong, X.; Wang, W. Analyses of risk factors for polycystic ovary syndrome complicated with non-alcoholic fatty liver disease. Exp. Ther. Med. 2018, 15, 4259–4264. [Google Scholar] [CrossRef] [Green Version]
- Brzozowska, M.M.; Ostapowicz, G.; Weltman, M.D. An association between non-alcoholic fatty liver disease and polycystic ovarian syndrome. J. Gastroenterol. Hepatol. 2009, 24, 243–247. [Google Scholar] [CrossRef] [PubMed]
- Setji, T.L.; Holland, N.D.; Sanders, L.L.; Pereira, K.C.; Diehl, A.M.; Brown, A.J. Nonalcoholic steatohepatitis and nonalcoholic Fatty liver disease in young women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 2006, 91, 1741–1747. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Falcetta, P.; Benelli, E.; Molinaro, A.; Di Cosmo, C.; Bagattini, B.; Del Ghianda, S.; Salvetti, G.; Fiore, E.; Pucci, E.; Fruzzetti, F.; et al. Effect of aging on clinical features and metabolic complications of women with polycystic ovary syndrome. J. Endocrinol. Investig. 2021, 44, 2725–2733. [Google Scholar] [CrossRef]
- Hossain, N.; Stepanova, M.; Afendy, A.; Nader, F.; Younossi, Y.; Rafiq, N.; Goodman, Z.; Younossi, Z.M. Non-alcoholic steatohepatitis (NASH) in patients with polycystic ovarian syndrome (PCOS). Scand. J. Gastroenterol. 2011, 46, 479–484. [Google Scholar] [CrossRef] [PubMed]
- Teede, H.J.; Misso, M.L.; Costello, M.F.; Dokras, A.; Laven, J.; Moran, L.; Piltonen, T.; Norman, R.J.; Network, I.P. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil. Steril. 2018, 110, 364–379. [Google Scholar] [CrossRef] [Green Version]
- Kanwar, P.; Nelson, J.E.; Yates, K.; Kleiner, D.E.; Unalp-Arida, A.; Kowdley, K.V. Association between metabolic syndrome and liver histology among NAFLD patients without diabetes. BMJ Open Gastroenterol. 2016, 3, e000114. [Google Scholar] [CrossRef] [Green Version]
- Huang, C.; Seah, J.J.; Tan, C.K.; Kam, J.W.; Tan, J.; Teo, E.K.; Kwek, A.; Wong, Y.J.; Tan, M.; Ang, T.L.; et al. Modified AST to platelet ratio index improves APRI and better predicts advanced fibrosis and liver cirrhosis in patients with non-alcoholic fatty liver disease. Clin. Res. Hepatol. Gastroenterol. 2021, 45, 101528. [Google Scholar] [CrossRef]
- Cotter, T.G.; Rinella, M. Nonalcoholic Fatty Liver Disease 2020: The State of the Disease. Gastroenterology 2020, 158, 1851–1864. [Google Scholar] [CrossRef]
- Wong, G.L.; Chan, H.L.; Choi, P.C.; Chan, A.W.; Lo, A.O.; Chim, A.M.; Wong, V.W. Association between anthropometric parameters and measurements of liver stiffness by transient elastography. Clin. Gastroenterol. Hepatol. 2013, 11, e295–302.e3. [Google Scholar] [CrossRef]
- Wong, V.W.; Irles, M.; Wong, G.L.; Shili, S.; Chan, A.W.; Merrouche, W.; Shu, S.S.; Foucher, J.; Le Bail, B.; Chan, W.K.; et al. Unified interpretation of liver stiffness measurement by M and XL probes in non-alcoholic fatty liver disease. Gut 2019, 68, 2057–2064. [Google Scholar] [CrossRef]
- Legro, R.S.; Arslanian, S.A.; Ehrmann, D.A.; Hoeger, K.M.; Murad, M.H.; Pasquali, R.; Welt, C.K.; Society, E. Diagnosis and treatment of polycystic ovary syndrome: An Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 2013, 98, 4565–4592. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dokras, A.; Saini, S.; Gibson-Helm, M.; Schulkin, J.; Cooney, L.; Teede, H. Gaps in knowledge among physicians regarding diagnostic criteria and management of polycystic ovary syndrome. Fertil. Steril. 2017, 107, 1380–1386.e1. [Google Scholar] [CrossRef] [PubMed]
% (n) or Mean ± SD | |
---|---|
Age, y | 32.5 ± 8.1 |
NAFLD | 72.4% (118) |
PNPLA3 polymorphism | |
CC | 50.3% (82) |
CG | 41.7% (68) |
GG | 8.0% (13) |
CAP, dB/m * | |
<231 | 6.8% (8) |
231–267 | 22.0% (26) |
268–300 | 19.5% (23) |
>300 | 51.7% (61) |
LSM, kPa * | |
<5.8 | 54.2% (64) |
5.8–6.9 | 22.0% (26) |
7.0–8.6 | 11.9% (14) |
8.7–11.4 | 10.2% (12) |
>11.4 | 1.7% (2) |
AST, U/L | 20.0 ± 9.0 |
ALT, U/L | 25.0 ± 16.0 |
GGT, U/L | 30.0 ± 22.0 |
Ferritin, ng/mL | 112.6 ± 103.4 |
PCOM | 82.4% (131) |
HA | 95.7% (156) |
Irregular menstrual cycles | 95.7% (156) |
PCOS phenotype | |
A | 73.8% (118) |
B | 16.9% (27) |
C | 5.0% (8) |
D | 4.4% (7) |
Total testosterone, ng/dL | 59.1 ± 37.1 |
Free testosterone, ng/dL | 36.0 ± 24.0 |
Androstenedione, ng/dL | 2.4 ± 4.7 |
DHEA-S, ng/mL | 2130.0 ± 1376.0 |
Glycemic profile | |
Normal | 19.8% (32) |
IR without diabetes or prediabetes | 50% (81) |
Prediabetes | 17.3% (28) |
Diabetes | 13% (21) |
Fasting insulin, µU/mL | 27.2 ± 27.5 |
Fasting glucose, mg/dL | 94.0 ± 35.0 |
HOMA-IR | 6.6 ± 6.9 |
HOMA-IR ≥ 2.5 | 75% (120) |
Metformin use | 33.7% (55) |
Metabolic syndrome | 42.6% (69) |
SAH | 18.4% (30) |
Total cholesterol, mg/dL | 182.0 ± 36.0 |
LDL, mg/dL | 107.0 ± 30.0 |
HDL, mg/dL | 49.0 ± 12.0 |
Triglycerides, mg/dL | 151.0 ± 98.0 |
Smoking status | |
Current smoker | 5.5% (9) |
Former smoker | 4.9% (8) |
Weight classification by BMI | |
Normal | 12.3% (20) |
Overweight | 22.7% (37) |
Obesity class I | 26.4% (43) |
Obesity class II | 25.1% (41) |
Obesity class III | 13.5% (22) |
Waist circumference, cm | 99.7 ± 17.0 |
WHR | 0.9 ± 0.1 |
B | Standard Error | p-Value | Odds Ratio | 95% CI | |
---|---|---|---|---|---|
Age > 32 years | 1.344 | 0.495 | 0.007 * | 3.833 | 1.454–10.106 |
Polymorphism CG/GG | −0.564 | 0.782 | 0.471 | 0.569 | 0.123–2.632 |
HDL ≥ 50 mg/dL | −1.440 | 0.476 | 0.003 * | 0.237 | 0.093–0.603 |
HOMA-IR ≥ 2.5 | 1.462 | 0.639 | 0.022 * | 4.313 | 1.234–15.075 |
Polymorphism CG/GG * HOMA-IR | 2.501 | 1.049 | 0.017 * | 12.198 | 1.562–95.243 |
B | Standard Error | p-Value | Odds Ratio | 95% CI | |
---|---|---|---|---|---|
Polymorphism CG/GG | 0.947 | 0.768 | 0.205 | 2.640 | 0.588–11.947 |
Metabolic syndrome | 2.603 | 1.117 | 0.020 * | 13.050 | 1.511–120.625 |
AST > 32 U/L | 2.202 | 0.848 | 0.009 * | 9.039 | 1.715–47.640 |
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Recuero, A.M.; Gomes, L.G.; Maciel, G.A.R.; de Mello Malta, F.; Salles, A.P.M.; Vezozzo, D.C.P.; Baracat, E.C.; Pinho, J.R.R.; Carrilho, F.J.; Stefano, J.T.; et al. NAFLD in Polycystic Ovary Syndrome: Association with PNPLA3 and Metabolic Features. Biomedicines 2022, 10, 2719. https://doi.org/10.3390/biomedicines10112719
Recuero AM, Gomes LG, Maciel GAR, de Mello Malta F, Salles APM, Vezozzo DCP, Baracat EC, Pinho JRR, Carrilho FJ, Stefano JT, et al. NAFLD in Polycystic Ovary Syndrome: Association with PNPLA3 and Metabolic Features. Biomedicines. 2022; 10(11):2719. https://doi.org/10.3390/biomedicines10112719
Chicago/Turabian StyleRecuero, Amanda Medeiros, Larissa Garcia Gomes, Gustavo Arantes Rosa Maciel, Fernanda de Mello Malta, Ana Paula Moreira Salles, Denise Cerqueira Paranaguá Vezozzo, Edmund Chada Baracat, João Renato Rebello Pinho, Flair José Carrilho, José Tadeu Stefano, and et al. 2022. "NAFLD in Polycystic Ovary Syndrome: Association with PNPLA3 and Metabolic Features" Biomedicines 10, no. 11: 2719. https://doi.org/10.3390/biomedicines10112719
APA StyleRecuero, A. M., Gomes, L. G., Maciel, G. A. R., de Mello Malta, F., Salles, A. P. M., Vezozzo, D. C. P., Baracat, E. C., Pinho, J. R. R., Carrilho, F. J., Stefano, J. T., & Oliveira, C. P. (2022). NAFLD in Polycystic Ovary Syndrome: Association with PNPLA3 and Metabolic Features. Biomedicines, 10(11), 2719. https://doi.org/10.3390/biomedicines10112719