Polycystic Ovary Syndrome (PCOS) Is Associated With NASH Severity and Advanced Fibrosis

Monika Sarkar; Norah Terrault; Wesley Chan; Marcelle I. Cedars; Heather G. Huddleston; Caroline C. Duwaerts; Dana Balitzer; Ryan M. Gill

Disclosures

Liver International. 2020;40(2):355-359. 

In This Article

Discussion

Polycystic ovary syndrome is a recognized risk group for imaging-confirmed NAFLD,[6] although less is known about its association with the more clinically relevant manifestation of NASH. In the current study of reproductive-aged women with biopsy-confirmed NAFLD, PCOS was independently associated with more severe NASH and advanced fibrosis. Among women with advanced fibrosis, those with PCOS were also five years younger than those without PCOS, suggesting a potential 'head start' in NASH progression.

We found that over one third of women with biopsy-confirmed NAFLD carried a diagnosis of PCOS, which is higher than the ~10% estimate of PCOS prevalence in the general population.[1] Our findings likely relate to shared metabolic risk factors for PCOS and NAFLD, as insulin resistance is a hallmark feature of PCOS, with a twofold higher rate of progression from insulin resistance to frank diabetes than age-matched women without PCOS.[10] Other NAFLD risk factors are also more common in women with PCOS, including higher prevalence of obesity and dyslipidaemia than age-matched non-PCOS controls.[11] This adverse metabolic profile likely sets the stage for early onset NAFLD, which is seen in 40%-55% of these young women.[4,5] The current study expands upon our existing knowledge of NAFLD in women with PCOS by further demonstrating their increased risk for more severe NASH histology.

Beyond concurrent metabolic risk factors, the high testosterone state of PCOS may further promote NAFLD/NASH in these young women. We have previously shown higher levels of testosterone in women to confer an increased risk of imaging-confirmed NAFLD, independent of insulin resistance, obesity and dyslipidaemia.[3] Interestingly, visceral adiposity appears to be an important mediator of this relationship between testosterone and NAFLD in women.[3] Likewise, a recent study from the United Kingdom included over 63 000 women with PCOS as well as non-PCOS controls, and found the high testosterone phenotype of PCOS to confer a more than twofold higher odds of prevalent NAFLD.[12] Given the potential role of testosterone in NAFLD, we also conducted a sensitivity analysis among women with hyperandrogenic PCOS. We did find an even more pronounced association of hyperandrogenic PCOS with advanced fibrosis, although given smaller sample size, confidence intervals were wide. Our findings do lend credence to prior publications supporting a role of testosterone in the pathogenesis of NAFLD in PCOS, and the need for larger studies evaluating the potential mechanism linking testosterone to NASH histology in women.

There have been limited prior studies of histologically-confirmed NASH, or biomarkers of NASH in women with PCOS. In a study by Hossain et al, 25 women with PCOS and biopsy-confirmed NAFLD were matched to 25 non-PCOS controls, and NASH was identified in twice as many women with PCOS (44% vs 21%, P = .08).[13] Additional histologic features were not reported in that study. In the current study a statistically similar proportion of women had NASH, present in 76% of women with PCOS and 66% of non-PCOS controls, which may relate to differences in study settings, as our sample derived from a tertiary care centre. Interestingly, our study sample was younger, although baseline alanine aminotransferase levels were ~70I U/mL compared to median of 40 IU/mL in the study by Hossain et al, suggesting more severe disease in our population. The proportion of women with diabetes was similar, although our cohort did have higher triglyceride levels. Two prior studies have reported caspase-cleaved fragment cytokeratin 18 (CK18) levels as a biomarker of NASH in women with PCOS. In a smaller, uncontrolled study of women with PCOS and without known liver disease, ALT and/or CK18 levels were elevated in ~20% of women.[14] In a controlled study including 192 women with PCOS and 73 age-matched controls, CK18 levels were significantly higher in women with PCOS, independent of BMI, suggesting their higher risk for NASH.[15] The current study supports these findings by confirming the increased risk for histologically significant liver injury and fibrosis in women with PCOS.

There are some notable limitations as well as strengths of our study. Given the modest sample size, we were unable to adjust for comprehensive metabolic covariates beyond age and BMI, although only these two variables were significantly different between groups. Insulin resistance is a hallmark feature of PCOS, and we lacked fasting insulin and glucose levels to assess for insulin resistance, which may be an important driver of our findings. There was a numerically higher proportion of PCOS patients with advanced fibrosis among those with metformin use, which likely reflects a surrogate of insulin resistance. Our study was also conducted at a tertiary care centre with a dedicated PCOS clinic, therefore, the high proportion of women with PCOS (36%) could reflect referral bias. Nonetheless, having a study population enriched with PCOS increased our power detect important histologic differences between groups. Additional strengths of our study include independent slide review by two pathologists blinded to PCOS status, as well as with expertise in NAFLD pathology to facilitate the calculation of NAFLD Activity Scores and comprehensive histologic features of NAFLD. Inclusion of a non-PCOS control population also lends confidence to our findings. Although our sample was modest, this is the largest study to date characterizing histologic features of NAFLD in women with PCOS.

In summary, women with PCOS and fatty liver have more severe NASH histology than women without PCOS, as well as more advanced disease at a younger age. PCOS appears to represent a distinct at-risk group, not only for imaging-confirmed steatosis but also for more severe histologic manifestations of NAFLD. Consequently, NASH treatment studies should consider this metabolically and hormonally distinct group of young women, who appear at early risk for disease progression. Hepatologists should also inquire about irregular menses and hirsutism in their evaluation of reproductive-aged women with suspected NAFLD, given the potential implications of PCOS on long-term liver health.

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