Polycystic ovary syndrome (PCOS) affects 5–11% of women at their reproductive age and is considered the most common endocrinopathy in premenopausal women 1. It is characterized by both reproductive and metabolic abnormalities including irregular menstrual cycles and laboratory and/or clinical evidence of hyperandrogenism. Several significant metabolic abnormalities have been associated with PCOS including insulin resistance (IR), type 2 diabetes mellitus (DM), dyslipidemia, and hypertension (HTN) 2–6. There are, at least, three recognized disorders commonly associated with PCOS including simple, hyperinsulinemic, nonhyperandrogenic obesity. Typical PCOS is characterized by steroidogenic enzyme hyperactivity, but without hyperinsulinemia 7–9. Insulin-resistant PCOS has the highest metabolic, renal, and cardiovascular risks 9, resulting from gene abnormalities involved in the secretion and action of insulin. Approximately 50% of patients with PCOS have IR and fulfill the criteria of metabolic syndrome 10.
Nonalcoholic fatty liver disease (NAFLD) has a diverse spectrum of manifestations including steatosis alone and/or with nonspecific inflammation, NASH, and cirrhosis. NAFLD is characterized by fat accumulation in the hepatocytes after excluding alcohol consumption and accounts for up to 70% of cryptogenic chronic hepatitis.
NAFLD is now considered as the hepatic manifestation of the metabolic syndrome, where IR plays a crucial role in its development 7,11,12.
Considering the fact that IR is a common feature in both NAFLD and PCOS, it is very likely that both entities would coexist simultaneously in the same patient. Thus, for an accurate clinical management for such patients, verification of hepatic involvement would be essential. In this work, we aimed to study the prevalence and characteristics of NAFLD in young adult Egyptian women with PCOS during the study period.
Patients and methods
Sixty-three consecutive young adult nontreated women with PCOS, ranging in age from 23 to 37 years, attending the Infertility Out-Patient Clinic, Gynecology Department, Mansoura University Hospital, during 2009–2011 were enrolled after providing well-informed consent. Patients with PCOS were divided into two groups: (a) the first group included 46 overweight-obese patients with BMI greater than 25 kg/m2 and (b) the second group included 17 lean patients with BMI less than 25 kg/m2.
Exclusion criteria: patients were excluded if they had other causes of irregular menstrual cycles or androgenic excess including hyperprolactinemia, uncontrolled thyroid disease, congenital adrenal hyperplasia, premature ovarian failure, Cushing’s syndrome, androgen-secreting tumor, or pregnancy. We also excluded pregnant women, smokers, and those with a history suggestive of chronic viral hepatitis, hemochromatosis, Wilson disease, other metabolic or autoimmune chronic liver diseases, alcohol intake, or those taking ovulatory drugs or other known hepatotoxic agents.
Our study protocol included assessment of detailed medical history including age, diagnosis of DM and HTN, and their medications, if any, history of alcohol consumption and physical examination. Anthropometric measurements included height, weight, and BMI. Obesity was defined in women with BMI greater than 30 kg/m2, overweight BMI greater than 25 kg/m2, and less than 30 kg/m213. Fatty liver was determined by abdominal ultrasound using standardized criteria in a qualitative manner using accepted criteria including a bright hepatic echo pattern (compared with the right kidney), a homogeneous or a coarse echo pattern, increased attenuation of the ultrasound beam, and loss of intrahepatic architectural details 14. PCOS was defined according to the Rotterdam criteria, after the exclusion of other related disorders, according to two of the following features: (1) oligo-ovulation or anovulation, (2) clinical and/or biochemical signs of hyperandrogenism, or (3) polycystic ovaries 15. Patients were included in this study if they had a history of irregular menstrual cycles and evidence of androgenic excess, including hirsutism, acne, male pattern hair loss, or an elevated testosterone level. Patients’ medical records were revised and provided us with many clinical and laboratory data including fasting glucose serum levels and insulin, oral glucose tolerance test, 2 h glucose and insulin, fasting cholesterol [total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL)], triglycerides, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transferase (γ-GT) levels. None of the enrolled patients with elevated ALT levels agreed to undergo liver biopsy. The homeostasis model assessment of insulin resistance (HOMA-IR) was calculated=insulin (IU/ml)×fasting plasma glucose (mmol/l)/22.5 16. In this study, IR was diagnosed if HOMA-IR greater than 2.6 17.
Student’s t-test and χ2 tests were used to compare data as appropriate. A P value less than 0.05 was considered to indicate statistical significance. Statistical analyses were carried out using statistical software (Statistical Package for Social Sciences (SPSS), version 15.0; SPSS Inc., Chicago, Illinois, USA). Multivariate logistic regression analysis was used to detect data predictability.
During a 3-year study period, 63 consecutive nonpregnant, nontreated young adult women with PCOS ranging in age from 23 to 37 years fulfilled our inclusion criteria and were enrolled. Participants were divided into two groups: (a) overweight-obese group (46 patients) and (b) lean group (17 patients); their clinical and biochemical characteristics are shown in Table 1. A significant increase in ALT, total cholesterol, and triglyceride LDL and decrease in HDL in group 1 compared with that in the group 2 (P<0.001) was observed. The fasting glucose and fasting insulin and HOMA-IR in obese PCOS were highly significantly increased compared with that of the lean group (P<0.001 and P<0.05, respectively), indicating that obese women with PCOS had more IR than lean women.
Table 2 shows the clinical and biochemical characteristics of patients with PCOS with and without NAFLD, where women with PCOS women and NAFLD had a significantly higher BMI, systolic and diastolic blood pressure, ALT level, total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, fasting blood glucose, and HOMA-IR (P<0.001).
IR was diagnosed in 28/46 (60.8%) of the obese group and in 4/17 (23.52%) of the lean group, whereas NAFLD was confirmed in 24/46 women (52.17%) of the obese group and 3/17 women (17.6%) of the lean group.
Stepwise multivariate logistic regression analysis showed that HOMA-IR. (P<0.001), fasting glucose (P=0.001), and total cholesterol (P=0.002) were the most predictive for NAFLD development in the women with PCOS studied.
In terms of the metabolic features of our patients with PCOS studied, a significantly higher prevalence of NAFLD 24/46 (52.17%) in the obese group than lean women 3/17 (17.6%) (P<0.001), and elevated ALT in 14/46 obese women (30.4%) when compared with 2/17 (11.7%) (P<0.05) lean patients was found, indicating more steatosis in the obese group. A higher prevalence of HOMA-IR 28/46 (60.8%) in the obese group than in lean patients 4/17 (23.52%) (P<0.001), and more incidences of DM 15/46 (32.6%) in the first group than in lean group 3/17 (17.6%) (P<0.05) were noted, indicating a more significant IR in obese group. Also, HTN was more common in the obese group 10.46 (21.7%) than in the lean group 1/17 (5.88%) (P<0.05) as shown in Table 3.
NAFLD is currently recognized as the most common form of chronic liver disease in the USA and in many parts of the world, where IR plays a pivotal role in its development. Moreover, many women with PCOS, whether obese or nonobese, have IR in common 10. Thus, IR is a remarkably common and key feature in both NAFLD 18,19 and PCOS 20–22.
Our work aimed at studying the frequency of NAFLD in both obese and lean women with PCOS and assessing their clinical and biochemical characteristics.
In this study, 52.17% of the obese women with PCOS and 17.6% of women in the lean group had ultrasonographic features of NAFLD, with higher IR (P<0.001) in the obese group.
Similarly, Gambarin-Gelwan et al.23 found that fatty liver was identified in 55% of women with PCOS and ∼40% of them were lean. Also, Zheng and Ding found that the occurrence of IR and NAFLD was [63% (38/60), 42% (25/60), respectively] in his PCOS case series 24. Interestingly, Clark et al. 25 and Cristiàn et al.26 found that the estimated prevalence of NAFLD in patients with PCOS was 41.7 and 41.5%, respectively compared with Clark and colleagues, who estimated the prevalence of NAFLD among general population samples as 6–14% 27. Our higher results, in comparison to the previous prevalence reports, may be attributed to the fact that we studied a special group (women with PCOS), not the general population, with certain different features including the remarkable IR.
In this study, when comparing women with PCOS with and without NAFLD, we found that BMI, fasting blood glucose, and HOMA-IR were highly significantly elevated in patients with PCOS with NAFLD than without NAFLD (P<0.001), which clarifies a pathogenetic role of IR in patients with PCOS with a high BMI and may also explain the different NAFLD findings in obese (52.17%) and lean (17.6%) PCOS participants. Gambarin-Gelwan et al.23 and Cristiàn et al.26 reported results that were in agreement with our findings; they reported that the presence of steatosis was associated with a high BMI and HOMA-IR. Also, Zheng and Ding 24 found that patients with PCOS with NAFLD had significantly increased BMI (P<0.001), fasting insulin, and HOMA-IR (P<0.001) than non-NAFLD patients with PCOS, and similar results were obtained when comparing lean patients with PCOS with and without NAFLD, where the NAFLD lean group showed a significantly increased fasting blood glucose and HOMA-IR (P<0.001). It can thus be concluded that IR would be the reasonable underlying mechanism of NAFLD in both lean and obese patients with PCOS.
Although NAFLD is a histological diagnosis, elevated liver enzymes have been used as a noninvasive surrogate marker of NAFLD, provided that other traditional potential causes of liver disease have been excluded 25.
In this work, ALT levels were highly significantly elevated in NAFLD women with PCOS than in those without NAFLD (P<0.001), and in obese PCOS with NAFLD (31.25%) than in the lean women without NAFLD (9%). Our results may be attributed to the presence of multiple risk factors of elevated ALT levels in women with PCOS including obesity, IR, dyslipidemia, hyperandrogenemia, and the greater likelihood of the development of NASH. The latter notion is in agreement with Cristiàn et al.26, who found increased liver enzyme (ALT) in 51% of their steatotic PCOS case series and the presence of NASH was the accepted explanation. In all case series, ALT levels and IR were more significantly elevated in obese patients with PCOS, suggesting a higher incidence of NASH and probably explaining the observed results in obese women with PCOS than the lean women. This is in agreement with the result of Gambarin-Gelwan et al.23, who noted that the presence of steatosis was associated with a greater BMI (P=0.005) and HOMA-IR (P=0.033) and the development of NASH was related more to the severity of IR rather than increased BMI.
In our study, findings suggested that the prevalence of NAFLD was associated with high HOMA-IR, total cholesterol, LDL, and triglycerides, consistent with the findings of Setji et al.27.
Although most patients with NASH would have elevated serum levels of transaminases, liver biochemistry may occasionally be normal 28. Moreover, an increased ALT level, to the upper limit of normal, without overt hypertransaminasemia is a proposed independent predictor of imminent NAFLD 29. In addition, more data have shown that increased ALT and γ-GT, but still within normal limits, would predict future development of type 2 DM, and other cardiovascular events, independent of other known risk factors 9,30–32. Thus, relying on the appearance of persistently significant ALT elevation in this setting could be too delayed to detect a probably serious hepatic histopathological injury of NASH. All of these data would merit increased clinicians’ awareness and anticipation of liver disease even in young women with PCOS.
NASH is typically diagnosed in individuals older than 40 years of age and liver biopsy has been recommended previously for patients with radiographic evidence of NAFLD if they are older than 45 years of age or have obesity and/or diabetes 33,34. In addition, considering the reversibility of steatosis 35–38, steatohepatitis 36,38, and possibly liver fibrosis with appropriate measures and the presence of significantly elevated ALT in our young adult participants, it may be prudent to suggest earlier evaluation of women with PCOS for liver disease, especially those with abnormal lipogram and proven IR as suggested by Setji et al.27.
In conclusion, our data showed a significant association between NAFLD and PCOS, where IR is strongly blamed. Increased clinicians’ awareness, anticipation, and early recognition are of paramount prognostic and therapeutic importance.
Conflicts of interest
There are no conflicts of interest.
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