Table 2<\/a> ). The percentage of overweight\/obese PCOS with elevated liver enzymes (> 25 U\/L) was 20.5% (8\/39) for ALT and 15.4% (6\/39) for \u03b3GT, whereas the percentage in overweight\/obese controls was 3% (1\/30) for both ALT and \u03b3GT (ALT: p<0.05, \u03b3-GT: p=0.10). The prevalence of insulin resistance, increased fasting glucose and increased fasting insulin in overweight\/obese PCOS patients was 46.2% (18\/39), 28.2% (11\/39) and 38.5% (15\/39), respectively, and in overweight\/obese control subjects the respective values were 23.3% (18\/39), 0% and 30% (9\/30) (p=0.051, p<0.01 and p=0.46, respectively).<\/p>\nOverweight\/obese PCOS patients had higher values of insulin resistance and exhibited elevated androgens, ALT and \u03b3GT levels when compared to lean PCOS patients [HOMA: 3.4\u00b12.1 vs 1.5\u00b10.6 p<0.001 (unpaired t-test), FAI: 11.4\u00b17.1 vs 7.9\u00b16.6 (unpaired t-test), ALT: 17.7\u00b112.2 vs 12.5\u00b15.8 p<0.01 (Mann-Whitney test), \u03b3GT: 17.9\u00b19.1 vs 11\u00b13 p<0.001 (unpaired t-test)]. Overweight\/obese controls had higher HOMA levels than their lean counterparts [2\u00b11.1 vs 1.1\u00b10.5 p<0.001 (unpaired t-test)] with no difference in the levels of androgens or in liver enzymes.<\/p>\n
In overweight\/obese PCOS patients, \u03b3GT levels correlated with BMI (Pearson\u2019s r=0.35 p<0.05), fasting glucose (Pearson\u2019s r= 0.43 p<0.01), fasting insulin (Pearson\u2019s r=0.61 p<0.001), HOMA (Pearson\u2019s r=0.6 p<0.01) and Trg (Pearson\u2019s r=0.43 p<0.01) levels, while ALT correlated with insulin (Spearman\u2019s r=0.44 p<0.01), HOMA (Spearman\u2019s r=0.42 p<0.05) and Trg (Spearman\u2019s r=0.35 p<0,05). In lean PCOS patients, both \u03b3GT and ALT correlated positively with Trg levels (Pearson\u2019s r=0.31 p<0.05 and Pearson\u2019s r=0.43 p<0.01, respectively). In overweight\/obese PCOS patients and in their respective controls, ALT levels were positively correlated with free androgen index (FAI) (Spearman\u2019s r=0.25 p<0.05 and Pearson\u2019s r=0.77 p<0.05, respectively) and total testosterone levels (Spearman\u2019s r=0.33 p<0.01 and Pearson\u2019s r=0.74 p<0.05, respectively), while SHBG levels were negatively correlated with ALT (Spearman\u2019s r= -0.23 p<0.05 and Pearson\u2019s r=-0.26 p<0.05, respectively) and \u03b3GT(Spearman\u2019s r= -0.28 p<0.05 and Spearman\u2019s r=-0.30 p<0.05, respectively).<\/p>\n
Stepwise multiple regression analysis revealed that BMI and HOMA index have the highest impact on the variability of liver enzymes. The R-Squared statistic indicates that the two predictors explain 35.4 % of the variability for \u03b3GT and 17.7% for ALT, respectively. The equations of the fitted models are [\u03b3GT = 0.693733 + 0.36661 x BMI + 1.65396 x HOMA] (F-ratio=36.58, p<0.001) (BMI: p<0.01, HOMA: p<0.001) and [ALT = 2.39961 + 0.377264 x BMI + 1.59366 x HOMA] (F-ratio=14.39, p<0.001) (BMI: p<0.05, HOMA: p<0.01).<\/p>\n
DISCUSSION<\/strong><\/p>\nIn this cohort of premenopausal women it was demonstrated that overweight\/obese women with PCOS have elevated serum levels of ALT and \u03b3GT as compared with the respective levels in the control groups of comparable age and BMI. However, we did not identify any significant difference in serum liver enzymes between lean PCOS and lean controls and between the total PCOS and total control population. The lean PCOS group exhibited higher insulin resistance expressed by HOMA-IR than the respective control group, but the absolute level of HOMA-IR in lean PCOS is below the accepted cutoff level for insulin resistance. These findings suggest that obesity and the severity of insulin resistance appear to have an additive effect on elevated liver enzymes. This is also shown by the positive correlation of HOMA-IR and BMI with \u03b3GT and ALT and is further supported by the outcome of multiple regression analysis indicating that HOMA-IR and BMI and not the PCOS status appear to be the major determinants of both \u03b3-GT and ALT in our cohort.<\/p>\n
In most previous studies, in which BMI and age matched controls were not included, increased serum aminotransferases, and especially ALT, and an increased prevalence of NAFLD were found in PCOS women.21,22,25<\/sup> Their conclusions, however, of an increased prevalence of hypertransaminasemia and of NAFLD in PCOS were based on comparisons with the respective prevalence rates reported in the general population. The mild metabolic derangement as well as the relatively lower mean BMI in the subjects of our study might account for the lower levels of serum aminotransferases as compared to the previously reported levels in PCOS women.21,22<\/sup> In other words, our patient population consisted of subjects without overt metabolic abnormalities; the triglyceride levels in PCOS women were higher than in controls but still remained within normal limits. In previous studies, lean PCOS patients did not exhibit evidence of NAFLD or elevated liver enzymes in respect to lean controls,23<\/sup> whereas obese PCOS women were shown to have significantly elevated liver enzymes in comparison to controls,24<\/sup> findings that are in agreement with our results, although to a moderate degree since our study population was relatively less obese.<\/p>\nInsulin resistance was present in 41.6% of the overweight\/obese PCOS women and 23.3% in overweight\/obese controls, whereas it was present in 13.6% of the lean PCOS women and in none of the lean controls. The values of hepatic enzymes (\u03b3GT, ALT) in overweight\/obese PCOS women were positively correlated with BMI, HOMA-IR and triglycerides levels, the latter being an indirect indicator of insulin resistance.<\/p>\n
Since ultrasound findings usually precede liver biochemistry abnormalities,25<\/sup> the fact that a previous study in lean PCOS has shown positive u\/s findings compatible with fatty liver with normal liver enzymes should not be considered as contradicting our findings. In that study, normal serum aminotransferases coexisted with u\/s findings compatible with NAFLD in a significant proportion of lean and obese patients with PCOS.25<\/sup> In the same study, patients with PCOS were subdivided into various BMI groups and were investigated for NAFLD, but without a control group. An additional confounder was the fact that 64% of patients were receiving some form of pharmacotherapy, namely metformin and\/or oral contraceptives, at the time of evaluation.25<\/sup> Additionally, subjects included in this and other studies24,25<\/sup> differed from our study population in ethnic composition.<\/p>\nAs mentioned above, all lean patients had a normal lipid profile which was comparable to that in controls, with the exception of serum triglycerides, which nevertheless remained within normal limits. Although fasting serum insulin and glucose levels were higher in lean patients than in lean controls, only 3 out of 38 lean patients had marginal fasting hyperinsulinemia. Moreover, none of the lean PCOS patients had fasting hyperglycemia. This may explain the lack of detectable differences in serum liver enzymes in lean patients in our study compared with their lean controls.<\/p>\n
The positive correlation of ALT with total testosterone and FAI, shown for the first time, may indicate an additional adverse effect of hyperandrogenemia on liver biochemistry30<\/sup> in PCOS. This effect is further demonstrated by the finding that overweight\/obese PCOS patients were more insulin resistant and had higher ALT, \u03b3GT and FAI levels compared with lean PCOS, whereas overweight\/obese controls, despite being more insulin resistant than their lean counterparts, did not exhibit higher liver enzymes. This association between androgen and liver enzyme levels could be an indirect reflection of insulin resistance and compensatory hyperinsulinemia, which may stimulate ovarian androgen production in PCOS women31,32<\/sup> and also inhibit hepatic production of SHBG,33<\/sup> further increasing FAI.<\/p>\nSerum aminotransferase levels should not be considered as accurate diagnostic indicators of NAFLD. The complete histological spectrum of NAFLD was reported in patients with normal ALT activity34<\/sup> and a falsely normal ALT can be seen in 30% of individuals with NASH.35<\/sup> Conversely, increased ALT not associated with fatty liver has been observed in obese subjects.36
\n<\/sup>
\nOn the other hand, numerous studies have shown that NAFLD comprises by far the commonest histological diagnosis in subjects with unexplained elevations of liver enzymes, after excluding known causes of liver dysfunction.37-40<\/sup> In particular, ALT might be a preclinical marker of NAFLD. A slightly increased serum ALT concentration might reflect subclinical (or ultrasonographically undetectable) early fatty changes in the liver (hepatic steatosis), which precedes the overt NAFLD.41<\/sup> In a large healthy, non-diabetic population, increasing ALT concentration, even within the reference range, was an independent predictor of NAFLD assessed by ultrasonography, irrespective of potential confounders, including BMI, alcohol consumption, CRP, HOMA-IR, fasting glucose, lipids and blood pressure.41<\/sup> This relationship remained even after adjustment for diabetes and weight gain.<\/p>\nOur findings in lean and overweight\/obese women with PCOS may have a dual importance. Since overweight\/obese women with PCOS appear to be more prone to develop NAFLD, screening for NAFLD in obese and\/or overweight PCOS women is most likely indicated. Serum liver biochemistry should be determined in these women in combination with ultrasonographic evaluation for the detection of fatty liver infiltration. NAFLD is no longer considered to be devoid of long-term health implications. Although uncomplicated hepatic steatosis (NAFL) may be a benign condition, it has the potential to progress to NASH, which is an established cause of \u2018cryptogenic\u2019 cirrhosis.42<\/sup> Using both liver function tests and ultrasound, NASH may be diagnosed earlier and prompt an early stage approach that could reduce its impact on the patient\u2019s health in conjunction with lifestyle modifications43<\/sup> and\/or insulin-sensitizing agents.44<\/sup> Both NAFLD and elevated serum liver enzymes\u2014independently of NAFLD\u2014emerge as novel components of the metabolic syndrome and may be considered as risk factors for type 2 diabetes and cardiovascular disease. Additionally, neither insulin resistance nor hyperandrogenemia were found to alter the hepatic profile in the subgroup of lean PCOS women. Obesity and insulin resistance appear to be the aggravating factors for disturbed hepatic biochemical profile in women with PCOS compared to controls.
\nIn conclusion, it is advisable to look for NAFLD and abnormal hepatic liver enzymes mainly in overweight\/obese PCOS women since higher \u0392\u039c\u0399 and insulin resistance appear to be the major factors influencing liver enzymes elevation.<\/p>\nREFERENCES<\/strong><\/p>\n1. Diamanti-Kandarakis E, Kouli CR, Bergiele AT, et al, 1999 A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab 84: 4006-4011.
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\n37. Daniel S, Ben-Menachem T, Vasudevan G, Ma CK, Blumenkehl M, 1999 Prospective evaluation of unexplained chronic liver transaminase abnormalities in asymptomatic and symptomatic patients. Am J Gastroenterol 94: 3010-3014.
\n38. Hultcrantz R, Glaumann H, Lindberg G, Nilsson LH, 1986 Liver investigation in 149 asymptomatic patients with moderately elevated activities of serum aminotransferases. Scand J Gastroenterol 21: 109-113.
\n39. Mathiesen UL, Franzen LE, Fryden A, Foberg U, Bodemar G, 1999 The clinical significance of slightly to moderately increased liver transaminase values in asymptomatic patients. Scand J Gastroenterol 34: 85-91.
\n40. Skelly MM, James PD, Ryder SD, 2001 Findings on liver biopsy to investigate abnormal liver function tests in the absence of diagnostic serology. J Hepatol 35: 195-199.
\n41. Chang Y, Ryu S, Sung E, Jang Y, 2007 Higher concentrations of alanine aminotransferase within the reference interval predict nonalcoholic fatty liver disease. Clin Chem 53: 686-692.
\n42. Clark JM, Diehl AM, 2003 Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. JAMA 289: 3000-3004.
\n43. Brown AJ, Tendler DA, McMurray RG, Setji TL, 2005 Polycystic ovary syndrome and severe nonalcoholic steatohepatitis: beneficial effect of modest weight loss and exercise on liver biopsy findings. Endocr Pract 11: 319-324.
\n44. Preiss D, Sattar N, Harborne L, Norman J, Fleming R, 2008 The effects of 8 months of metformin on circulating GGT and ALT levels in obese women with polycystic ovarian syndrome. Int J Clin Pract 62: 1337-1343.<\/p>\n<\/div>\n","protected":false},"excerpt":{"rendered":"
Frangiskos Economou, Xenofon Xyrafis, Sarantis Livadas, Ioannis I. Androulakis, Georgia Argyrakopoulou, Charikleia D.Christakou, Eleni Kandaraki, Eleni Palioura, Evanthia Diamanti-Kandarakis<\/p>\n
Download PDF<\/a><\/div>\nOBJECTIVE: To investigate liver enzymes in a cohort of women with Polycystic Ovary Syndrome (PCOS) and controls divided according to body mass index (BMI) and their association with features of the syndrome. DESIGN: Eighty-three PCOS women and 64 healthy women were studied. Patients and controls were subdivided into two groups …<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[49,2,10],"tags":[398,133,947,948,132],"class_list":["post-1523","post","type-post","status-publish","format-standard","hentry","category-volume-8-issue-3","category-journal-articles","category-volume-8","tag-body-mass-index","tag-insulin-resistance","tag-liver-enzymes","tag-non-alcoholic-fatty-liver-disease","tag-polycystic-ovary-syndrome"],"_links":{"self":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/posts\/1523","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/comments?post=1523"}],"version-history":[{"count":6,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/posts\/1523\/revisions"}],"predecessor-version":[{"id":13685,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/posts\/1523\/revisions\/13685"}],"wp:attachment":[{"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/media?parent=1523"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/categories?post=1523"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/peaceful-mccarthy.213-158-90-25.plesk.page\/index.php\/wp-json\/wp\/v2\/tags?post=1523"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}