Associations of Fatty Liver Disease and Other Factors Affecting Serum SHBG Concentrations: A Population Based Study on 1657 Subjects

Abstract

Sex hormone binding globulin (SHBG) is a glycoprotein expressed predominantly in the hepatocytes. It regulates the transport of sex steroid hormones in the blood stream to their target tissues. The expression of the SHBG gene is subject to multifactorial regulation including hormonal, metabolic, and nutritional aspects. Against this background, we investigated the effect of fatty liver and metabolic syndrome, together with other parameters, on serum SHBG concentrations in a population-based cohort in Germany. This cross-sectional study included 870 women and 787 men (average age 42.3±12.8 years), who underwent ultrasound screening for fatty liver in addition to providing a complete medical history and undergoing physical and laboratory examination. Fatty liver was diagnosed on ultrasound criteria in 159 women (18.3%) and 287 men (36.5%). Fatty liver was shown to exert a significant influence on serum SHBG concentrations in men and in premenopausal women. Men with grade 1 fatty liver had a 1.96-fold increased risk (95%-confidence interval=1.28–3.02; p=0.0022) and postmenopausal women with grade 1 fatty liver a 2.4-fold risk (95%-confidence interval=1.11–5.27; p=0.0267) for low SHBG concentrations. Among metabolic parameters, HDL-C represented as affecting factor in men (p=0.0058) and premenopausal women (p=0.0002), while cholesterol only showed an association in premenopausal women (p=0.0439) and triglyceride in postmenopausal women (p=0.0436). No association of concentrations of SHBG and metabolic syndrome was observed. Age, BMI and waist-to-hip ratio also influence the SHBG concentration. Based on these findings, we conclude that fat accumulation in the liver influences SHBG concentrations in men and premenopausal women.

Key words

NAFLD - ultrasonography - metabolic syndrome - cross-sectional-study

^* These authors contributed equally to this work.

• References

• 1 Caldwell JD, Jirikowski GF. Sex hormone binding globulin and aging. Horm Metab Res 2009; 41: 173-182
• 2 Pugeat M, Nader N, Hogeveen K. Sex hormone-binding globulin gene expression in the liver: Drugs and the metabolic syndrome. Mol Cell Endocrinol 2010; 316: 53-59
• 3 Tchernof A, Despres JP. Sex steroid hormones, sex hormone-binding globulin, and obesity in men and women. Horm Metab Res 2000; 32: 526-536
• 4 Plymate SR, Matej LA, Jones RE, Friedl KE. Inhibition of sex hormone-binding globulin production in the human hepatoma (hep G2) cell line by insulin and prolactin. J Clin Endocrinol Metab 1988; 67: 460-464
• 5 Selva DM, Hogeveen KN, Innis SM, Hammond GL. Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene. J Clin Invest 2007; 117: 3979-3987
• 6 Bellentani S, Scaglioni F, Marino M. Epidemiology of non-alcoholic fatty liver disease. Dig Dis 2010; 28: 155-161
• 7 Angulo P, Lindor KD. Non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2002; 17: 186-190
• 8 Liu Q, Bengmark S, Qu S. The role of hepatic fat accumulation in pathogenesis of non-alcoholic fatty liver disease (NAFLD). Lipids Health Dis 2010; 9: 42
• 9 Kogiso T, Moriyoshi Y, Nagahara H. Clinical significance of fatty liver associated with metabolic syndrome. Hepatol Res 2007; 37: 711-721
• 10 Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen K, Tuomainen TP, Valkonen VP, Salonen R, Salonen JT. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 2004; 27: 1036-1041
• 11 Rodriguez A, Muller DC, Metter EJ, Maggio M, Harman SM, Blackman MR, Andres R. Aging, androgens, and the metabolic syndrome in a longitudinal study of aging. J Clin Endocrinol Metab 2007; 92: 3568-3572
• 12 Stefan N, Schick F, Haring HU. Sex hormone-binding globulin and risk of type 2 diabetes. N Engl J Med 2009; 361: 2675-2676 author reply 2677–2678
• 13 Peter A, Kantartzis K, Machann J, Schick F, Staiger H, Machicao F, Schleicher E, Fritsche A, Häring HU, Stefan N. Relationships of circulating sex hormone-binding globulin with metabolic traits in humans. Diabetes 2010; 59: 3167-3173
• 14 Carlstrom K, Eriksson S, Rannevik G. Sex steroids and steroid binding proteins in female alcoholic liver disease. Acta Endocrinol (Copenh) 1986; 111: 75-79
• 15 Myking O, Aakvaag A, Digranes O. Androgen-oestrogen imbalance in men with chronic alcoholism and fatty liver. Alcohol Alcohol 1987; 22: 7-15
• 16 Bell H, Frey H, Haug E, Raknerud N. Gonad function in men with alcoholic liver disease. Tidsskr Nor Laegeforen 1990; 110: 1361-1365
• 17 Kaulhausen H, Rohner HG, Siedek M, Lafosse M, Breuer H. Binding capacity of sex hormone binding globulin and corticosteroid binding globulin in serum of male patients with liver cirrhosis (author’s transl). J Clin Chem Clin Biochem 1980; 18: 137-143
• 18 Physical status: The use and interpretation of anthropometry . Report of a WHO expert committee. World Health Organization Technical Report Series 1995; 854: 1-452
• 19 Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499-502
• 20 Saverymuttu SH, Joseph AE, Maxwell JD. Ultrasound scanning in the detection of hepatic fibrosis and steatosis. Br Med Journal (Clin Res Ed) 1986; 292: 13-15
• 21 Hamaguchi M, Kojima T, Itoh Y, Harano Y, Fujii K, Nakajima T, Kato T, Takeda N, Okuda J, Ida K, Kawahito Y, Yoshikawa T, Okanoue T. The severity of ultrasonographic findings in nonalcoholic fatty liver disease reflects the metabolic syndrome and visceral fat accumulation. Am J Gastroenterol 2007; 102: 2708-2715
• 22 Charatcharoenwitthaya P, Lindor KD. Role of radiologic modalities in the management of non-alcoholic steatohepatitis. Clin Liver Dis 2007; 11: 37-54 viii
• 23 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults . Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA 2001; 285: 2486-2497
• 24 Graffigna MN, Belli SH, de Larranaga G, Fainboim H, Estepo C, Peres S, García N, Levalle O. Insulin-like growth factor-binding protein-1: A new biochemical marker of nonalcoholic fatty liver disease?. Acta Gastroenterol Latinoam 2009; 39: 30-37
• 25 Kalme T, Seppala M, Qiao Q, Koistinen R, Nissinen A, Harrela M, Loukovaara M, Leinonen P, Tuomilehto J. Sex hormone-binding globulin and insulin-like growth factor-binding protein-1 as indicators of metabolic syndrome, cardiovascular risk, and mortality in elderly men. J Clin Endocrinol Metab 2005; 90: 1550-1556
• 26 Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen K, Tuomainen TP, Salonen R, Rauramaa R, Salonen JT. Sex hormones, inflammation and the metabolic syndrome: A population-based study. Eur J Endocrinol 2003; 149: 601-608
• 27 American Diabetes Association . Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (Committee Report). Diabetes Care 1997; 20: 1183-1197
• 28 Bonnet F, Cephise FL, Gautier A, Dubois S, Massart C, Camara A, Larifla L, Balkau B, Ducluzeau PH. Role of sex steroids, intra-hepatic fat and liver enzymes in the association between SHBG and metabolic features. Clin Endocrinol (Oxf) 2012; 12089 [Epub ahead of print]
• 29 Fishbein M, Castro F, Cheruku S, Jain S, Webb B, Gleason T, Stevens WR. Hepatic MRI for fat quantitation: Its relationship to fat morphology, diagnosis, and ultrasound. J Clin Gastroenterol 2005; 39: 619-625
• 30 Qayyum A, Chen DM, Breiman RS, Westphalen AC, Yeh BM, Jones KD, Lu Y, Coakley FV, Callen PW. Evaluation of diffuse liver steatosis by ultrasound, computed tomography, and magnetic resonance imaging: Which modality is best?. Clin Imaging 2009; 33: 110-115
• 31 Grant LM, Lisker-Melman M. Nonalcoholic fatty liver disease. Ann Hepatol 2004; 3: 93-99