Introduction

The liver is a unique organ that has regulatory function for detoxification and metabolism. Consequently, it is a target for multiple metabolic and endocrine disorders, including hypertension, type 2 diabetes, obesity, hyperlipidemia, hypothyroidism, hyperthyroidism, adrenal dysfunction, autoimmune disease, excess alcohol or heavy metal consumption, substance and/or drug abuse, and polycystic ovary syndrome (PCOS) .

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in Western industrialized countries (affecting 20–40% of the general population) and with a growing prevalence in Asian countries (12–29% in the population subgroups according to different age, ethnicity, gender, and location) . According to the longitudinal studies conducted in east Asia, the prevalence of NAFLD has almost doubled in the most recent 12-year period . There is strong evidence that the presence of NAFLD increases in parallel with the prevalence of obesity, type 2 diabetes, and metabolic syndrome . NAFLD has become an emerging problem in the Asia-Pacific region and also an endemic disorder worldwide . NAFLD includes a spectrum of hepatic manifestations, ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), according to the severity. The characteristic features of NASH include hepatocellular ballooning, mixed acute and chronic lobular inflammation, and perisinusoidal fibrosis, which is indistinguishable from alcoholic steatohepatitis, excluding a history of alcohol consumption . The general impression is that most individuals with NAFLD are unlikely to develop significant hepatic decompression. Although rare, the natural history of NASH can progress to more progressive complications (cirrhosis and hepatocellular carcinoma) . NAFLD can also progress to severe complications in not only Western countries but also a region in Japan with a low prevalence of obesity . A cohort study conducted in a Japanese population reported 36% with advanced hepatic fibrosis, 20% with a 5-year cumulative incidence of hepatocellular carcinoma, and a 2.4% mortality rate due to liver-related complications, such as variceal bleeding, ascites and hepatic encephalopathy among patients diagnosed with NAFLD . The elevated liver enzymes have been proposed as a biomarker that correlates with the occurrence of diabetes and cardiovascular disease and an increased risk of mortality from liver disease after a long-term follow-up . Because NAFLD is also common in children and adolescents, clarifying the potential risk factors in a young population might be helpful in an effort to prevent liver damage progression at an early age .

PCOS is one of the most common endocrinopathies among women of early reproductive age, and it is characterized by chronic anovulation (oligomenorrhea or amenorrhea), clinical and/or biochemical hyperandrogenism, and the presence of polycystic ovaries . The phenotypic characteristics of women with PCOS, including hyperandrogenism, polycystic ovaries, and anovulation, are apparent at a young age and may disappear with aging ; however, the metabolic disturbances persist and deteriorate with aging . Therefore, further investigation of the potential metabolic dysfunction with early intervention in young women might help prevent disease. Women with PCOS are well known to have a higher prevalence of infertility, insulin resistance, obesity, dyslipidemia , hypertension , and disturbed metabolic profile that may lead to subsequent cardiometabolic diseases than women without PCOS. Recently, there has been growing evidence demonstrating a strong association among PCOS, NAFLD, and NASH . Most of the endocrine and metabolic characteristics of women with PCOS, including elevated androgen levels, insulin resistance, dyslipidemia, and elevated low-grade inflammation levels, are thought to contribute to the presence and progression of NAFLD . Women with PCOS have been reported to have a higher prevalence of NAFLD and NASH diagnosed by liver biopsy , magnetic resonance spectroscopy , computed tomography , and abdominal ultrasonography . In addition, common treatments of women with PCOS include oral contraceptives, antiandrogens, and insulin sensitizers, which may have diverse effects on liver function . In this review, we discuss all the hepatic manifestations that might be related to the phenotypic characteristics and treatments of women with PCOS ( Table 1 and Fig. 1 ).

Schematic presentation of the association between PCOS phenotypes and non-alcoholic fatty liver disease/nonalcoholic steatohepatitis.

Obesity and metabolic syndrome in relation to NAFLD and PCOS

The link between metabolic syndrome and PCOS has been greatly emphasized because insulin resistance and visceral obesity are characteristic features of women with PCOS . The prevalence of metabolic syndrome in women with PCOS is 40–50%, which is approximately seven times the female population of similar age in the US ; however, even in regions in which metabolic syndrome is less common than the USA, such as Italy and Taiwan [25], metabolic syndrome is still four and two times more common than similar-aged young women, respectively. In the Multi-ethnic Study of Atherosclerosis (MESA), more patients with NAFLD have metabolic syndrome than the NAFLD-free subjects (31.9% vs. 6.6%, P < 0.001) . NAFLD is widely considered as a hepatic manifestation of metabolic syndrome . In fact, NAFLD has a prevalence of 75–95% in the morbidly obese population, with 20–47% having NASH . Due to the characteristics of PCOS, including obesity, insulin resistance, and metabolic syndrome, women with liver biopsy- or ultrasound-proven NAFLD were shown to have a higher prevalence of PCOS . Indeed, it has been reported that modest weight loss and exercise can improve NASH in women with PCOS by liver biopsy documentation . A study conducted in the USA reported that intrahepatic fat is more closely related to the metabolic complications of obesity than visceral fat . Furthermore, a number of studies have shown that the prevalence of NAFLD is increased in young women with PCOS, independent of the coexisting metabolic features and obesity . Such findings suggest a close relationship between NAFLD and PCOS, rather than sharing risk factors of obesity and metabolic syndrome ( Fig.1 ).

Obesity and metabolic syndrome in relation to NAFLD and PCOS

The link between metabolic syndrome and PCOS has been greatly emphasized because insulin resistance and visceral obesity are characteristic features of women with PCOS . The prevalence of metabolic syndrome in women with PCOS is 40–50%, which is approximately seven times the female population of similar age in the US ; however, even in regions in which metabolic syndrome is less common than the USA, such as Italy and Taiwan [25], metabolic syndrome is still four and two times more common than similar-aged young women, respectively. In the Multi-ethnic Study of Atherosclerosis (MESA), more patients with NAFLD have metabolic syndrome than the NAFLD-free subjects (31.9% vs. 6.6%, P < 0.001) . NAFLD is widely considered as a hepatic manifestation of metabolic syndrome . In fact, NAFLD has a prevalence of 75–95% in the morbidly obese population, with 20–47% having NASH . Due to the characteristics of PCOS, including obesity, insulin resistance, and metabolic syndrome, women with liver biopsy- or ultrasound-proven NAFLD were shown to have a higher prevalence of PCOS . Indeed, it has been reported that modest weight loss and exercise can improve NASH in women with PCOS by liver biopsy documentation . A study conducted in the USA reported that intrahepatic fat is more closely related to the metabolic complications of obesity than visceral fat . Furthermore, a number of studies have shown that the prevalence of NAFLD is increased in young women with PCOS, independent of the coexisting metabolic features and obesity . Such findings suggest a close relationship between NAFLD and PCOS, rather than sharing risk factors of obesity and metabolic syndrome ( Fig.1 ).

Insulin resistance and insulin sensitizer

Women with PCOS are known to have a higher level of insulin resistance than age- and body mass index (BMI)-matched women without PCOS . Insulin resistance and hyperinsulinemia in women with PCOS might reflect a genetic origin, obesity, diet, and sedentary lifestyle. Insulin resistance and hyperinsulinemia are considered major causes, other than obesity, contributing to the pathogenesis of PCOS . Insulin sensitizers, such as metformin and thiazolidinedione (TZD), have been reported to be effective in increasing insulin sensitivity, improving glucose intolerance, and restoring menstrual regularity in women with PCOS . Metformin has been reported to improve liver enzyme activity, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), but has no significant impact on liver histology, and therefore has not been recommended as a specific treatment for NASH . TZDs are recommended in the treatment of biopsy-proven NASH, even though the safety of long-term treatment is still of concern .

Surrogate markers to predict liver injury in PCOS

Women with PCOS have been reported to have a higher prevalence of NAFLD and NASH diagnosed by liver biopsy , magnetic resonance (MR) spectroscopy , computed tomography (CT) , and abdominal ultrasonography . Liver enzymes, such as ALT and AST, are cytosolic enzymes and are thought to be specific markers of liver damage ; however, ALT levels can be normal in patients with NAFLD . A previous study demonstrated that 48 of 88 women (55%) with PCOS had NAFLD proven by ultrasonography, but only seven (15%) had elevated aminotransferase levels . Therefore, the elevated ALT levels in women with PCOS may represent a higher severity of liver cell injuries . Not only aminotransferase levels but also some innovative markers, such as the caspase 3-cleaved fragment of cytokeratin 18 , have been shown to represent progressive hepatocyte injury in women with PCOS. Other noninvasive surrogate markers, such as the formulated index of the NAFLD liver fat score (LFS), which has been reported to have a good prediction rate of MR spectroscopy-detected NAFLD , have not yet been validated in other populations, like women with PCOS. Central obesity represents visceral adiposity and could better represent the severity of insulin resistance than the BMI among women with PCOS and NAFLD. By contrast, the presence and severity of NAFLD is currently considered one of the anthropometric measurements, such as BMI, waist circumference (WC), waist-to-hip ratio (WHR), CT scan, and MR imaging of fat distribution, to reflect body adiposity and used in the assessment of the related disease risk . Endogenous sex hormones , disturbed lipid profiles , adipocytokines , and pro-inflammatory cytokines and chemokines might represent the severity of low-grade inflammation and oxidative stress and have been reported to correlate with the presence of NAFLD and NASH in women with and without PCOS.

Dyslipidemia and statins

Among all the components of metabolic syndrome, dyslipidemia has a greater impact than the other defined metabolic features of metabolic syndrome on NAFLD and PCOS. Low HDL (high-density lipoprotein) cholesterol and/or high triglyceride levels are found in >75% of patients with NAFLD and 65.1% of young women with PCOS . In addition, the disturbed process of lipid metabolism and the severity of dyslipoproteinemia in obese young adolescents with PCOS are associated with liver fat . Adiponectin, an adipose-secreted cytokine, is known to have antiatherogenic properties . Low levels of adiponectin in women with PCOS are independently correlated with the severity of dyslipidemia from the coexistence of obesity and insulin resistance . Patients with NAFLD also exhibit lower levels of adiponectin, while the adiponectin levels are not significantly different in patients with simple steatosis and steatohepatitis . Not only adiponectin, but other adipocytokines (leptin, ghrelin, resistin, and visfatin) have been reported to be involved in the pathogenesis of hepatic steatosis, steatohepatitis, and dyslipidemia and are predictive of metabolic alterations in women with PCOS . Statin, a lipid-lowering agent, is effective in reducing chronic inflammation, lipid profiles, and biochemical hyperandrogenemia in women with PCOS . A meta-analysis revealed that statins might improve the serum liver enzyme activity (aminotransferases) as well as ultrasound findings in patients with NAFLD and NASH ; however, there are no studies regarding the beneficial effects of statins on histologic changes or liver-related morbidity and mortality in patients with NAFLD and women with PCOS .

Low-grade inflammation and hepatocyte-secreted acute-phase proteins in women with PCOS

Whether or not PCOS is an inflammatory disease is debatable, yet there is abundant evidence to support the presence of chronic low-grade inflammation in women with PCOS . Various inflammatory markers, including a number of pro-inflammatory cytokines and chemokines (interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 [MIP-1], and IL-18), have been reported to be specifically elevated in women with PCOS and may contribute to endothelial cell damage and the presence of atherosclerosis in women with PCOS . Most studies reported that the presence of elevated pro-inflammatory cytokines and chemokines represent the status of chronic low-grade inflammation in women with PCOS and might be due to the higher coexisting prevalence of obesity and insulin resistance . Because NAFLD and NASH are well-known diseases with hepatocyte inflammation, the low-grade inflammation status of women with PCOS might contribute to or reflect some degree of hepatic cell injury.

Apart from obesity and insulin resistance, it is presumed that PCOS-specific characteristics (hyperandrogenism and chronic anovulation) might also directly contribute to the low-grade inflammatory status in women with PCOS. Specific proteins secreted primarily from hepatocytes in response to inflammation (C-reactive protein (CRP), follistatin, and ferritin) have been reported to be higher in women with PCOS than women without PCOS . Increased body iron stores represented by elevated ferritin, iron, and other iron-binding protein levels have been reported to be associated with the severity of oligomenorrhea in women with PCOS and in the general population with diabetes and nonalcoholic hepatic steatohepatitis . The iron-promoted generation of reactive oxygen species in the liver may lead to tissue injury and organ failure. Follistatin, another hepatocyte-secreted protein, is also derived from the brain, ovaries, endothelial cells, and skeletal muscle. Follistatin has various functions, including anti-inflammation, ovulatory function, insulin resistance, and lean muscle mass metabolism, and is regulated by androgen levels in women with PCOS . The levels of CRP, another hepatocyte-secreted acute phase protein, are positively correlated with the levels of follistatin in women with PCOS . The levels of CRP, ferritin, and follistatin are elevated and decreased in women with PCOS who are prescribed oral contraceptives and metformin, respectively .

Hyperandrogenism in relationship with liver injury in women with PCOS

Advanced liver damage and hepatocyte injury disturb the metabolism of sex steroid hormones and endogenous circulating sex hormones (testosterone, sex-hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEAS), and estradiol) and are highly associated with obesity, glucose and lipid metabolism, and liver fat . Women with PCOS are characterized as having elevated ovarian or adrenal androgens levels, including decreased SHBG levels, increased testosterone, and/or DHEAS levels.

Testosterone, free testosterone, and SHBG

Higher levels of testosterone are associated with a lower prevalence of metabolic syndrome, obesity, and diabetes in men , but not in postmenopausal women . For women with PCOS and adolescent girls who are characterized by having higher androgen levels, the higher levels of testosterone are reported to contribute to the coexisting higher prevalence of obesity, metabolic syndrome, and dyslipidemia. In addition, androgens and androgen receptors are known to be involved in hepatic carcinogenesis and considered to be a therapeutic target for hepatocellular carcinoma, fatty liver, cirrhosis, and virus-related hepatitis . The characteristic hyperandrogenemia in women with PCOS is known to contribute to the high prevalence of hepatic steatosis, as confirmed by MR spectroscopy and elevated liver enzymes independent of obesity, dyslipidemia, and insulin resistance.

SHBG is a blood transport protein for testosterone and estradiol derived primarily from the liver . A low SHBG level is associated with higher levels of bioavailable testosterone levels, a higher degree of low-grade inflammation, insulin resistance, and metabolic syndrome in women with PCOS . It has been reported that lower SHBG levels are associated with a higher risk of NAFLD in men , postmenopausal women , and women with PCOS ; however, because the circulating SHBG is exclusively of liver origin, the SHBG levels will increase in the extreme status of the liver injury and can be used as a pre-diagnostic risk marker to predict the presence of cirrhosis and subsequent hepatocellular carcinoma occurrence .