Nonalcoholic Fatty Liver Disease and Polycystic Ovary Syndrome

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States. There are two stages: 1) steatosis (usually benign and often reversible, with increased fat in the hepatocytes) and 2) a more severe stage called nonalcoholic steatohepatitis (NASH). The latter may develop with further obesity and features of the metabolic syndrome, particularly insulin resistance as well as type 2 diabetes mellitus. NASH may lead to cirrhosis (~30%), hepatic failure and sometimes hepatocellular carcinoma. Clinically liver biopsy is the only definitive procedure to make a diagnosis of NASH, since liver ultrasonography can not distinguish between NAFLD and NASH.

In view of the increased prevalence of obesity (mostly USA) and the metabolic syndrome (MS) in polycystic ovary syndrome (PCOS) with 40-50% of reproductive aged women with PCOS having the MS, it appeared that a study of NAFLD in PCOS may be a good indicator of the presence of the MS or the presence of some of its components. Since PCOS was the most common cause of the metabolic syndrome in younger women it was of interest and not surprising that NAFLD was very common in this syndrome. Dr. Kinkhabwala, a fellow at the Mount Sinai School of Medicine, presented an abstract at the Endocrine Society Conference on this subject in 2005. These findings which were later published in 2007 by Gambarin-Gelwan et al support the finding that 55% of such women with PCOS presented with NAFLD. Many had a central fat distribution, and 39% of lean women had NAFLD. Only one other series to date has studied the association of PCOS and NAFLD, with the prevalence in PCOS in Cerda’s group in Chile reporting a prevalence of 41%.

Our presentation is the result of a Mount Sinai School of Medicine retrospective study of 88 consecutive nondiabetic reproductive-aged women with PCOS with a view to note the associated factors that may be observed with NAFLD.

All women were studied with abdominal ultrasonography and graded 1-3, with the latter demonstrating very significant signs of more severe hepatic steatosis and 1) as mild, and 2) as moderate NAFLD. At the time of the study there were 22 non-obese controls and since publication a total of 39 non-obese reproductive aged controls were obtained. The diagnosis of PCOS was made using the National Institutes of Health Consensus Conference in Bethesda as criteria for inclusion. Women with regular menses were excluded from the study. The women were grouped into “lean”, “overweight” and “obese” on the basis of the BMI and the homeostasis model assessment of insulin resistance (HOMA-IR) (fasting insulin (mIU/L x fasting glucose (mg.dL)/405) was performed on all subjects.

43% of the PCOS study population was lean, 15% overweight and 42% obese.
48%/88 subjects had NAFLD.

The greater the BMI the more frequent the presence of steatosis. 70% of obese women had NAFLD (similar to the data of Schwimmer et al).

The lean group had a prevalence of NAFLD of 39%, while the overweight women had a prevalence of 54%.

Homa-IR and HDL cholesterol levels were significantly abnormal, with the former showing a more significant prevalence of NAFLD on ultrasonography as the HOMA-IR increased.

Elevated aminotransferase (ALT) and glutamyltransferase (GGT) levels were found in 15% of the 88 subjects (Schwimmer et al found an incidence of 30%).
NAFLD was found on ultrasonographic in 9 of 39 controls (23%).

Unlike a number of world-wide studies indicating the presence of 3-16% of NAFLD in world-wide studies including China, Italy, Japan, and Korea, our study reports a 39% incidence in lean women with PCOS. The HOMA-IR score was also significantly increased in NALD women with PCOS, indicative of insulin resistance.

The additive effect of a high BMI appears to augment the insulin resistance and thus this demonstrates a 70% incidence of NAFLD in obese subjects. Furthermore, the relatively low incidences of liver chemistry abnormalities of 15% indicate that it is not generally a useful marker in predicting more advanced liver disease. The report by Setji et al, however, indicate that performing liver biopsies in young women with PCOS with elevated enzymes, demonstrated evidence of NASH. Further studies to define early transition to a more severe state of liver pathology are essential to prevent potential serious complications that NASH may engender. The use of liver biopsies with normal liver chemistries remains controversial and associated with clinical risks.

References:

References:

Marchinese G, Brizi M, Bianchi G, Tomasetti S, Bugianesi E, et al. Non-alcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 2001;50:1844-50.

Gambarin-Gelwan M, Kinkhabwala SV, Schiano TD, Bodian C, Yeh HC, Futterweit W. Prevalence of nonalcoholic fatty liver disease in women with polycystic ovary syndrome. Clin Gastroenterol Hepatol 2007;5:496-01

Angelico F, Del Ben M, Conti R, Francioso S, Feol K et al. Insulin resistance, the metabolic syndrome, and non-alcoholic liver disease. J Clin Endocrinol Metab 2005;90:1578-82.

Schwimmer JB, Khorram O, Chiu V, Schwimmer WB. Abnormal aminotransferase activity in women with polycystic ovary syndrome. Fert Steril 2005;83:494-97.

Setji TL, Holland ND, Sanders LL, Pereira KC, Diehl AM, Brown AJ. Nonalcoholic steatohepatitis and nonalcoholic fatty liver disease in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:1741-7.

Cerda C, Perez-Ayuso RM, Riquelme A, Soza A, Villasca P et al. Nonalcoholic fatty liver disease in women with polycystic ovary syndrome. J He`patol 2007;47:412-7.

Carmina E. Need for liver evaluation in polycystic ovary syndrome. J Hepatol 2007;47:313-5.