, Volume 51, Issue 2, pp 211–221 | Cite as

Evidence that non-alcoholic fatty liver disease and polycystic ovary syndrome are associated by necessity rather than chance: a novel hepato-ovarian axis?

  • Giovanni TargherEmail author
  • Maurizio Rossini
  • Amedeo Lonardo


Increasing evidence suggests that non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) are associated with obesity, insulin resistance, metabolic syndrome, cardiovascular disease, cirrhosis, and liver tumors. On these grounds, we have hypothesized that NAFLD and PCOS occur more frequently than expected by chance alone. We have tested this hypothesis by reviewing the clinical and biological evidence that supports a significant association between NAFLD and PCOS. PubMed was extensively searched for articles published through March 2015 using the keywords “nonalcoholic fatty liver disease” or “fatty liver” combined with “PCOS.” Several cross-sectional and case–control studies have consistently demonstrated that the prevalence of NAFLD is remarkably increased in young women with PCOS, independent of overweight/obesity and other coexisting metabolic syndrome features, and that these women are more likely to have the more severe forms of NAFLD (non-alcoholic steatohepatitis, advanced fibrosis, and cirrhosis). Accumulating evidence suggests that NAFLD, especially its necro-inflammatory form, may exacerbate hepatic and systemic insulin resistance and releases multiple pro-inflammatory, pro-coagulant, and pro-fibrogenic mediators that may play important roles in the pathophysiology of PCOS. These findings call for more active and systematic search for NAFLD among women with PCOS. Conversely, gastroenterologists/hepatologists need to be aware of the presence of PCOS among female patients with NAFLD and compatible clinical features. Finally, all these patients should undergo regular follow-up not only for liver-related complications but also for cardio-metabolic diseases.


Non-alcoholic fatty liver disease Polycystic ovary syndrome PCOS Metabolic syndrome Review 


Conflict of interest

Nothing to declare.


  1. 1.
    F. Nascimbeni, R. Pais, S. Bellentani, C.P. Day, V. Ratziu, P. Loria, A. Lonardo, From NAFLD in clinical practice to answers from guidelines. J. Hepatol. 59, 859–871 (2013)CrossRefPubMedGoogle Scholar
  2. 2.
    N. Chalasani, Z. Younossi, J.E. Lavine, A.M. Diehl, E.M. Brunt, K. Cusi, M. Charlton, A.J. Sanyal, American Association for the Study of Liver Diseases; American College of Gastroenterology; American Gastroenterological Association. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Am. J. Gastroenterol. 107, 811–826 (2012)CrossRefPubMedGoogle Scholar
  3. 3.
    Q.M. Anstee, G. Targher, C.P. Day, Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat. Rev. Gastroenterol. Hepatol. 10, 330–344 (2013)CrossRefPubMedGoogle Scholar
  4. 4.
    G. Targher, C.P. Day, E. Bonora, Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N. Engl. J. Med. 363, 1341–1350 (2010)CrossRefPubMedGoogle Scholar
  5. 5.
    G. Targher, C.D. Byrne, Diagnosis and management of nonalcoholic fatty liver disease and its hemostatic/thrombotic and vascular complications. Semin. Thromb. Hemost. 39, 214–228 (2013)CrossRefPubMedGoogle Scholar
  6. 6.
    A. Lonardo, S. Ballestri, G. Targher, P. Loria, Diagnosis and management of cardiovascular risk in nonalcoholic fatty liver disease. Expert Rev. Gastroenterol. Hepatol. 9, 629–650 (2015)CrossRefPubMedGoogle Scholar
  7. 7.
    A. Lonardo, S. Ballestri, G. Marchesini, P. Angulo, P. Loria, NAFLD a precursor of the metabolic syndrome. Dig. Liver Dis. 47, 181–190 (2015)CrossRefPubMedGoogle Scholar
  8. 8.
    A. Lonardo, C. Carani, N. Carulli, P. Loria, ‘Endocrine NAFLD’a hormonocentric perspective of nonalcoholic fatty liver disease pathogenesis. J. Hepatol. 44, 1196–1207 (2006)CrossRefPubMedGoogle Scholar
  9. 9.
    Y. Yilmaz, Z.M. Younossi, Obesity-associated nonalcoholic fatty liver disease. Clin. Liver Dis. 18, 19–31 (2014)CrossRefPubMedGoogle Scholar
  10. 10.
    M. Machado, P. Marques-Vidal, H. Cortez-Pinto, Hepatic histology in obese patients undergoing bariatric surgery. J. Hepatol. 45, 600–606 (2006)CrossRefPubMedGoogle Scholar
  11. 11.
    P. Loria, L. Carulli, M. Bertolotti, A. Lonardo, Endocrine and liver interaction: the role of endocrine pathways in NASH. Nat. Rev. Gastroenterol. Hepatol. 6, 236–247 (2009)CrossRefPubMedGoogle Scholar
  12. 12.
    G. Targher, G. Zoppini, E. Bonora, P. Moghetti, Hemostatic and fibrinolytic abnormalities in polycystic ovary syndrome. Semin. Thromb. Hemost. 40, 600–618 (2014)CrossRefPubMedGoogle Scholar
  13. 13.
    C.E. Kelley, A.J. Brown, A.M. Diehl, T.L. Setji, Review of nonalcoholic fatty liver disease in women with polycystic ovary syndrome. World J. Gastroenterol. 20, 14172–14184 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    G. Daskalopoulos, A. Karkanaki, A. Piouka, N. Prapas, D. Panidis, P. Gkeleris, V.G. Athyros, Excess metabolic and cardiovascular risk is not manifested in all phenotypes of polycystic ovary syndrome: implications for diagnosis and treatment. Curr. Vasc. Pharmacol 14(1), 109–119 (2015)Google Scholar
  15. 15.
    F. Nascimbeni, S. Ballestri, L. Di Tommaso, M. Piccoli, A. Lonardo, Inflammatory hepatocellular adenomatosis, metabolic syndrome, polycystic ovary syndrome and non-alcoholic steatohepatitis: chance tetrad or association by necessity? Dig. Liver Dis. 46, 288–289 (2014)CrossRefPubMedGoogle Scholar
  16. 16.
    J.D. Yang, M.F. Abdelmalek, H. Pang, C.D. Guy, A.D. Smith, A.M. Diehl, A. Suzuki, Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatology 59, 1406–1414 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    H. Tomiyama, A. Yamashina, T. Arai, K. Hirose, Y. Koji, T. Chikamori, S. Hori, Y. Yamamoto, N. Doba, S. Hinohara, Influences of age and gender on results of noninvasive brachial-ankle pulse wave velocity measurement: a survey of 12517 subjects. Atherosclerosis 166, 303–309 (2003)CrossRefPubMedGoogle Scholar
  18. 18.
    D. Roulot, J.L. Costes, J.F. Buyck, U. Warzocha, N. Gambier, S. Czernichow, H. Le Clesiau, M. Beaugrand, Transient elastography as a screening tool for liver fibrosis and cirrhosis in a community-based population aged over 45 years. Gut 60, 977–984 (2011)CrossRefPubMedGoogle Scholar
  19. 19.
    C. Bunchorntavakul, R. Bahirwani, D. Drazek, M.C. Soulen, E.S. Siegelman, E.E. Furth, K. Olthoff, A. Shaked, K.R. Reddy, Clinical features and natural history of hepatocellular adenomas: the impact of obesity. Aliment Pharmacol. Ther. 34, 664–674 (2011)CrossRefPubMedGoogle Scholar
  20. 20.
    P. Loria, L.E. Adinolfi, S. Bellentani, E. Bugianesi, A. Grieco, S. Fargion, A. Gasbarrini, C. Loguercio, A. Lonardo, G. Marchesini, F. Marra, M. Persico, D. Prati, Baroni GS; NAFLD Expert Committee of the Associazione Italiana per lo Studio del Fegato. Practice guidelines for the diagnosis and management of nonalcoholic fatty liver disease. A decalogue from the Italian Association for the Study of the Liver (AISF) Expert Committee. Dig. Liver Dis. 42, 272–282 (2010)CrossRefPubMedGoogle Scholar
  21. 21.
    R.S. Legro, S.A. Arslanian, D.A. Ehrmann, K.M. Hoeger, M.H. Murad, R. Pasquali, C.K. Welt, Endocrine Society, Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 98, 4565–4592 (2013)CrossRefPubMedGoogle Scholar
  22. 22.
    T.L. Setji, N.D. Holland, L.L. Sanders, K.C. Pereira, A.M. Diehl, A.J. Brown, Nonalcoholic steatohepatitis and nonalcoholic fatty liver disease in young women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 91, 1741–1747 (2006)CrossRefPubMedGoogle Scholar
  23. 23.
    M. Gambarin-Gelwan, S.V. Kinkhabwala, T.D. Schiano, C. Bodian, H.C. Yeh, W. Futterweit, Prevalence of nonalcoholic fatty liver disease in women with polycystic ovary syndrome. Clin. Gastroenterol. Hepatol. 5, 496–501 (2007)CrossRefPubMedGoogle Scholar
  24. 24.
    C. Cerda, R.M. Pérez-Ayuso, A. Riquelme, A. Soza, P. Villaseca, T. Sir-Petermann, M. Espinoza, M. Pizarro, N. Solis, J.F. Miquel, M. Arrese, Nonalcoholic fatty liver disease in women with polycystic ovary syndrome. J. Hepatol. 47, 412–417 (2007)CrossRefPubMedGoogle Scholar
  25. 25.
    A.J. Cussons, G.F. Watts, T.A. Mori, B.G. Stuckey, Omega-3 fatty acid supplementation decreases liver fat content in polycystic ovary syndrome: a randomized controlled trial employing proton magnetic resonance spectroscopy. J. Clin. Endocrinol. Metab. 94, 3842–3848 (2009)CrossRefPubMedGoogle Scholar
  26. 26.
    E. Vassilatou, S. Lafoyianni, A. Vryonidou, D. Ioannidis, L. Kosma, K. Katsoulis, E. Papavassiliou, I. Tzavara, Increased androgen bioavailability is associated with non-alcoholic fatty liver disease in women with polycystic ovary syndrome. Hum. Reprod. 25, 212–220 (2010)CrossRefPubMedGoogle Scholar
  27. 27.
    M.M. Brzozowska, G. Ostapowicz, M.D. Weltman, An association between non-alcoholic fatty liver disease and polycystic ovarian syndrome. J. Gastroenterol. Hepatol. 24, 243–247 (2009)CrossRefPubMedGoogle Scholar
  28. 28.
    Y. Gutierrez-Grobe, G. Ponciano-Rodríguez, M.H. Ramos, M. Uribe, N. Méndez-Sánchez, Prevalence of nonalcoholic fatty liver disease in premenopausal, postmenopausal and polycystic ovary syndrome women: the role of estrogens. Ann. Hepatol. 9, 402–409 (2010)PubMedGoogle Scholar
  29. 29.
    A. Markou, I.I. Androulakis, C. Mourmouris, A. Tsikkini, C. Samara, S. Sougioultzis, G. Piaditis, G. Kaltsas, Hepatic steatosis in young lean insulin resistant women with polycystic ovary syndrome. Fertil. Steril. 93, 1220–1226 (2010)CrossRefPubMedGoogle Scholar
  30. 30.
    N. Hossain, M. Stepanova, A. Afendy, F. Nader, Y. Younossi, N. Rafiq, Z. Goodman, Z.M. Younossi, Non-alcoholic steatohepatitis (NASH) in patients with polycystic ovarian syndrome (PCOS). Scand. J. Gastroenterol. 46, 479–484 (2011)CrossRefPubMedGoogle Scholar
  31. 31.
    R.C. Ma, K.H. Liu, P.M. Lam, L.P. Cheung, W.H. Tam, G.T. Ko, M.H. Chan, C.S. Ho, C.W. Lam, W.C. Chu, P.C. Tong, W.Y. So, J.C. Chan, C.C. Chow, Sonographic measurement of mesenteric fat predicts presence of fatty liver among subjects with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 96, 799–807 (2011)CrossRefPubMedGoogle Scholar
  32. 32.
    M.F. Gangale, L. Miele, A. Lanzone, F. Sagnella, D. Martinez, A. Tropea, F. Moro, A. Morciano, A. Ciardulli, C. Palla, M. Pompili, C. Cefalo, A. Grieco, R. Apa, Long-term metformin treatment is able to reduce the prevalence of metabolic syndrome and its hepatic involvement in young hyper insulinaemic overweight patients with polycystic ovarian syndrome. Clin. Endocrinol. (Oxf). 75, 520–527 (2011)CrossRefPubMedGoogle Scholar
  33. 33.
    H. Jones, V.S. Sprung, C.J. Pugh, C. Daousi, A. Irwin, N. Aziz, V.L. Adams, E.L. Thomas, J.D. Bell, G.J. Kemp, D.J. Cuthbertson, Polycystic ovary syndrome with hyperandrogenism is characterized by an increased risk of hepatic steatosis compared to nonhyperandrogenic PCOS phenotypes and healthy controls, independent of obesity and insulin resistance. J. Clin. Endocrinol. Metab. 97, 3709–3716 (2012)CrossRefPubMedGoogle Scholar
  34. 34.
    L.F. Zueff, W.P. Martins, C.S. Vieira, R.A. Ferriani, Ultrasonographic and laboratory markers of metabolic and cardiovascular disease risk in obese women with polycystic ovary syndrome. Ultrasound Obstet. Gynecol. 39, 341–347 (2012)CrossRefPubMedGoogle Scholar
  35. 35.
    S. Borruel, E. Fernández-Durán, M. Alpañés, D. Martí, F. Alvarez-Blasco, M. Luque-Ramírez, H.F. Escobar-Morreale, Global adiposity and thickness of intraperitoneal and mesenteric adipose tissue depots are increased in women with polycystic ovary syndrome (PCOS). J. Clin. Endocrinol. Metab. 98, 1254–1263 (2013)CrossRefPubMedGoogle Scholar
  36. 36.
    R. Karoli, J. Fatima, A. Chandra, U. Gupta, F.U. Islam, G. Singh, Prevalence of hepatic steatosis in women with polycystic ovary syndrome. J. Hum. Reprod. Sci. 6, 9–14 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Z. Qu, Y. Zhu, J. Jiang, Y. Shi, Z. Chen, The clinical characteristics and etiological study of nonalcoholic fatty liver disease in Chinese women with PCOS. Iran J. Reprod. Med. 11, 725–732 (2013)PubMedPubMedCentralGoogle Scholar
  38. 38.
    A.J. Dawson, T. Sathyapalan, J.A. Smithson, R.V. Vince, A.M. Coady, R. Ajjan, E.S. Kilpatrick, S.L. Atkin, A comparison of cardiovascular risk indices in patients with polycystic ovary syndrome with and without coexisting nonalcoholic fatty liver disease. Clin. Endocrinol. (Oxf). 80, 843–849 (2014)CrossRefPubMedGoogle Scholar
  39. 39.
    C. Toso, L. Rubbia-Brandt, F. Negro, P. Morel, G. Mentha, Hepatocellular adenoma and polycystic ovary syndrome. Liver Int. 23, 35–37 (2003)CrossRefPubMedGoogle Scholar
  40. 40.
    T.C. Liu, N. Vachharajani, W.C. Chapman, E.M. Brunt, Noncirrhotic hepatocellular carcinoma: derivation from hepatocellular adenoma? Clinico-pathologic analysis. Mod. Pathol. 27, 420–432 (2014)PubMedGoogle Scholar
  41. 41.
    H.F. Escobar-Morreale, M. Luque-Ramírez, F. González, Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and meta-analysis. Fertil. Steril. 95, 1048–1058 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    F. González, Inflammation in polycystic ovary syndrome: underpinning of insulin resistance and ovarian dysfunction. Steroids 77, 300–305 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    S. Palomba, A. Falbo, G. Chiossi, F. Orio, A. Tolino, A. Colao, G.B. La Sala, F. Zullo, Low-grade chronic inflammation in pregnant women with polycystic ovary syndrome: a prospective controlled clinical study. J. Clin. Endocrinol. Metab. 99, 2942–2951 (2014)CrossRefPubMedGoogle Scholar
  44. 44.
    M. Ramezani-Binabaj, M. Motalebi, H. Karimi-sari, M.S. Rezaee-Zavareh, S.M. Alavian, Are women with polycystic ovarian syndrome at a high risk of nonalcoholic fatty liver disease? A meta-analysis. Hepat. Mon. 14, e23235 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    R. Azziz, D.A. Dumesic, M.O. Goodarzi, Polycystic ovary syndrome: an ancient disorder? Fertil. Steril. 95, 1544–1548 (2011)CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    M.A. Brower, M.R. Jones, J.I. Rotter, R.M. Krauss, R.S. Legro, R. Azziz, M.O. Goodarzi, Further investigation in Europeans of susceptibility variants for polycystic ovary syndrome discovered in genome-wide association studies of Chinese individuals. J. Clin. Endocrinol. Metab. 100, E182–E186 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    G. Targher, C.D. Byrne, Clinical review: nonalcoholic fatty liver disease: a novel cardiometabolic risk factor for type 2 diabetes and its complications. J. Clin. Endocrinol. Metab. 98, 483–495 (2013)CrossRefPubMedGoogle Scholar
  48. 48.
    A. Lonardo, S. Lombardini, F. Scaglioni, L. Carulli, M. Ricchi, D. Ganazzi, L.E. Adinolfi, G. Ruggiero, N. Carulli, P. Loria, Hepatic steatosis and insulin resistance: does etiology make a difference? J. Hepatol. 44, 190–196 (2006)CrossRefPubMedGoogle Scholar
  49. 49.
    A.L. Birkenfeld, G.I. Shulman, Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology 59, 713–723 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    K. Kobaly, P. Vellanki, R.K. Sisk, L. Armstrong, J.Y. Lee, J. Lee, M.G. Hayes, M. Urbanek, R.S. Legro, A. Dunaif, Parent-of-origin effects on glucose homeostasis in polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 99, 2961–2966 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    E. Deligeoroglou, N. Vrachnis, N. Athanasopoulos, Z. Iliodromiti, S. Sifakis, S. Iliodromiti, C. Siristatidis, G. Creatsas, Mediators of chronic inflammation in polycystic ovarian syndrome. Gynecol. Endocrinol. 28, 974–978 (2012)CrossRefPubMedGoogle Scholar
  52. 52.
    M.J. Armstrong, L.A. Adams, A. Canbay, W.K. Syn, Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology 59, 1174–1197 (2014)CrossRefPubMedGoogle Scholar
  53. 53.
    K. Kantartzis, A. Peter, F. Machicao, J. Machann, S. Wagner, I. Königsrainer, A. Königsrainer, F. Schick, A. Fritsche, H.U. Häring, N. Stefan, Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene. Diabetes 58, 2616–2623 (2009)CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    A. Amaro, E. Fabbrini, M. Kars, P. Yue, K. Schechtman, G. Schonfeld, S. Klein, Dissociation between intrahepatic triglyceride content and insulin resistance in familial hypobetalipoproteinemia. Gastroenterology 139, 149–153 (2010)CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    R.J. Perry, V.T. Samuel, K.F. Petersen, G.I. Shulman, The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510, 84–91 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    F. Tosi, R. Dorizzi, R. Castello, C. Maffeis, G. Spiazzi, G. Zoppini, M. Muggeo, P. Moghetti, Body fat and insulin resistance independently predict increased serum C-reactive protein in hyperandrogenic women with polycystic ovary syndrome. Eur. J. Endocrinol. 161, 737–745 (2009)CrossRefPubMedGoogle Scholar
  57. 57.
    F. Tosi, D. Di Sarra, J.M. Kaufman, C. Bonin, R. Moretta, E. Bonora, E. Zanolin, P. Moghetti, Total body fat and central fat mass independently predict insulin resistance but not hyperandrogenemia in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 100, 661–669 (2015)CrossRefPubMedGoogle Scholar
  58. 58.
    J.J. Kim, Y.M. Choi, Dyslipidemia in women with polycystic ovary syndrome. Obstet. Gynecol. Sci. 56, 137–142 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    R.L. Rosenfield, Clinical review: adolescent anovulation: maturational mechanisms and implications. J. Clin. Endocrinol. Metab. 98, 3572–3583 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    F. González, C.L. Sia, D.M. Bearson, H.E. Blair, Hyperandrogenism induces a proinflammatory TNFα response to glucose ingestion in a receptor-dependent fashion. J. Clin. Endocrinol. Metab. 99, E848–E854 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    M.W. O’Reilly, A.E. Taylor, N.J. Crabtree, B.A. Hughes, F. Capper, R.K. Crowley, P.M. Stewart, J.W. Tomlinson, W. Arlt, Hyperandrogenemia predicts metabolic phenotype in polycystic ovary syndrome: the utility of serum androstenedione. J. Clin. Endocrinol. Metab. 99, 1027–1036 (2014)PubMedPubMedCentralGoogle Scholar
  62. 62.
    M. Lazo, I. Zeb, K. Nasir, R.P. Tracy, M.J. Budoff, P. Ouyang, D. Vaidya, Association between endogenous sex hormones and liver fat in a multi-ethnic study of atherosclerosis. Clin. Gastroenterol. Hepatol. (2015). doi: 10.1016/j.cgh.2014.12.033 PubMedPubMedCentralGoogle Scholar
  63. 63.
    G. Targher, L. Bertolini, L. Zenari, Hypoadiponectinemia is closely associated with nonalcoholic hepatic steatosis in obese subjects. Diabetes Care 27, 2085–2086 (2004)CrossRefPubMedGoogle Scholar
  64. 64.
    G. Targher, L. Bertolini, L. Scala, F. Poli, L. Zenari, G. Falezza, Decreased plasma adiponectin concentrations are closely associated with nonalcoholic hepatic steatosis in obese individuals. Clin. Endocrinol. (Oxf). 61, 700–703 (2004)CrossRefPubMedGoogle Scholar
  65. 65.
    G. Targher, L. Bertolini, S. Rodella, G. Zoppini, L. Scala, L. Zenari, G. Falezza, Associations between plasma adiponectin concentrations and liver histology in patients with nonalcoholic fatty liver disease. Clin. Endocrinol. (Oxf). 64, 679–683 (2006)CrossRefPubMedGoogle Scholar
  66. 66.
    S. Francque, A. Verrijken, S. Caron, J. Prawitt, R. Paumelle, B. Derudas, P. Lefebvre, M.R. Taskinen, W. Van Hul, I. Mertens, G. Hubens, E. Van Marck, P. Michielsen, L. Van Gaal, B. Staels, PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. J. Hepatol. (2015). doi: 10.1016/j.jhep.2015.02.019 Google Scholar
  67. 67.
    S. Cankaya, B. Demir, S.E. Aksakal, B. Dilbaz, C. Demirtas, U. Goktolga, Insulin resistance and its relationship with high molecular weight adiponectin in adolescents with polycystic ovary syndrome and a maternal history of polycystic ovary syndrome. Fertil. Steril. 102, 826–830 (2014)CrossRefPubMedGoogle Scholar
  68. 68.
    T.P. Ciaraldi, V. Aroda, S.R. Mudaliar, R.R. Henry, Inflammatory cytokines and chemokines, skeletal muscle and polycystic ovary syndrome: effects of pioglitazone and metformin treatment. Metabolism 62, 1587–1596 (2013)CrossRefPubMedGoogle Scholar
  69. 69.
    C.J. Weston, E.L. Shepherd, L.C. Claridge, P. Rantakari, S.M. Curbishley, J.W. Tomlinson, S.G. Hubscher, G.M. Reynolds, K. Aalto, Q.M. Anstee, S. Jalkanen, M. Salmi, D.J. Smith, C.P. Day, D.H. Adams, Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis. J. Clin. Invest. 125, 501–520 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    K.M. Seow, C.C. Juan, P.H. Wang, L.T. Ho, J.L. Hwang, Expression levels of vascular cell adhesion molecule-1 in young and nonobese women with polycystic ovary syndrome. Gynecol. Obstet. Invest. 73, 236–241 (2012)CrossRefPubMedGoogle Scholar
  71. 71.
    A. Rohatgi, A. Khera, J.D. Berry, E.G. Givens, C.R. Ayers, K.E. Wedin, I.J. Neeland, I.S. Yuhanna, D.R. Rader, J.A. de Lemos, P.W. Shaul, HDL cholesterol efflux capacity and incident cardiovascular events. N. Engl. J. Med. 371, 2383–2393 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    A. Roe, J. Hillman, S. Butts, M. Smith, D. Rader, M. Playford, N.N. Mehta, A. Dokras, Decreased cholesterol efflux capacity and atherogenic lipid profile in young women with PCOS. J. Clin. Endocrinol. Metab. 99, E841–E847 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    S. Ballestri, A. Lonardo, S. Bonapace, C.D. Byrne, P. Loria, G. Targher, Risk of cardiovascular, cardiac and arrhythmic complications in patients with non-alcoholic fatty liver disease. World J. Gastroenterol. 20, 1724–1745 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    A. Lonardo, S. Lombardini, F. Scaglioni, S. Ballestri, A.M. Verrone, M. Bertolotti, L. Carulli, D. Ganazzi, N. Carulli, P. Loria, Fatty liver, carotid disease and gallstones: a study of age-related associations. World J. Gastroenterol. 12, 5826–5833 (2006)CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    A.L. Fracanzani, L. Valenti, M. Russello, L. Miele, C. Bertelli, A. Bellia, C. Masetti, C. Cefalo, A. Grieco, G. Marchesini, S. Fargion, Gallstone disease is associated with more severe liver damage in patients with non-alcoholic fatty liver disease. PLoS One 7, e41183 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    A.R. Moschen, S. Kaser, H. Tilg, Non-alcoholic steatohepatitis: a microbiota-driven disease. Trends Endocrinol. Metab. 24, 537–545 (2013)CrossRefPubMedGoogle Scholar
  77. 77.
    C.E. Ruhl, J.E. Everhart, Relationship of non-alcoholic fatty liver disease with cholecystectomy in the US population. Am. J. Gastroenterol. 108, 952–958 (2013)CrossRefPubMedGoogle Scholar
  78. 78.
    M.V. Machado, H. Cortez-Pinto, Gut microbiota and nonalcoholic fatty liver disease. Ann. Hepatol. 11, 440–449 (2012)PubMedGoogle Scholar
  79. 79.
    K. Tremellen, K. Pearce, Dysbiosis of Gut Microbiota (DOGMA): a novel theory for the development of polycystic ovarian syndrome. Med. Hypotheses 79, 104–112 (2012)CrossRefPubMedGoogle Scholar
  80. 80.
    A.B. Sopher, G. Grigoriev, D. Laura, T. Cameo, J.P. Lerner, R.J. Chang, D.J. McMahon, S.E. Oberfield, Anti-Mullerian hormone may be a useful adjunct in the diagnosis of polycystic ovary syndrome in nonobese adolescents. J. Pediatr. Endocrinol. Metab. 27, 1175–1179 (2014)PubMedPubMedCentralGoogle Scholar
  81. 81.
    A. Köninger, L. Koch, P. Edimiris, A. Enekwe, J. Nagarajah, S. Kasimir-Bauer, R. Kimmig, T. Strowitzki, B. Schmidt, Anti-Mullerian hormone: an indicator for the severity of polycystic ovarian syndrome. Arch. Gynecol. Obstet. 290, 1023–1030 (2014)CrossRefPubMedGoogle Scholar
  82. 82.
    S. Ballestri, A. Lonardo, D. Romagnoli, L. Carulli, L. Losi, C.P. Day, P. Loria, Ultrasonographic fatty liver indicator, a novel score which rules out NASH and is correlated with metabolic parameters in NAFLD. Liver Int. 32, 1242–1252 (2012)CrossRefPubMedGoogle Scholar
  83. 83.
    L. Castera, V. Vilgrain, P. Angulo, Noninvasive evaluation of NAFLD. Nat. Rev. Gastroenterol. Hepatol. 10, 666–675 (2013)CrossRefPubMedGoogle Scholar
  84. 84.
    S. Ballestri, D. Romagnoli, F. Nascimbeni, G. Francica, A. Lonardo, Role of ultrasound in the diagnosis and treatment of NAFLD and its complications. Expert Rev. Gastroenterol. Hepatol. 19, 1–25 (2015)Google Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Giovanni Targher
    • 1
    Email author
  • Maurizio Rossini
    • 2
  • Amedeo Lonardo
    • 3
  1. 1.Section of Endocrinology, Diabetes and Metabolism, Department of MedicineUniversity and Azienda Ospedaliera Universitaria Integrata of VeronaVeronaItaly
  2. 2.Section of Rheumatology, Department of MedicineUniversity and Azienda Ospedaliera Universitaria Integrata of VeronaVeronaItaly
  3. 3.Outpatient Liver Clinic and Division of Internal Medicine – Department of Biomedical, Metabolic and Neural Sciences, NOCSAE, Baggiovara, Azienda USLUniversity of Modena and Reggio EmiliaModenaItaly

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