Normal liver enzymes are correlated with severity of metabolic syndrome in a large population based cohort

Key features of the metabolic syndrome are insulin resistance and diabetes. The liver as central metabolic organ is not only affected by the metabolic syndrome as non-alcoholic fatty liver disease (NAFLD), but may contribute to insulin resistance and metabolic alterations. We aimed to identify potential associations between liver injury markers and diabetes in the population-based Heinz Nixdorf RECALL Study. Demographic and laboratory data were analyzed in participants (n = 4814, age 45 to 75y). ALT and AST values were significantly higher in males than in females. Mean BMI was 27.9 kg/m2 and type-2-diabetes (known and unkown) was present in 656 participants (13.7%). Adiponectin and vitamin D both correlated inversely with BMI. ALT, AST, and GGT correlated with BMI, CRP and HbA1c and inversely correlated with adiponectin levels. Logistic regression models using HbA1c and adiponectin or HbA1c and BMI were able to predict diabetes with high accuracy. Transaminase levels within normal ranges were closely associated with the BMI and diabetes risk. Transaminase levels and adiponectin were inversely associated. Re-assessment of current normal range limits should be considered, to provide a more exact indicator for chronic metabolic liver injury, in particular to reflect the situation in diabetic or obese individuals.

[1]  M. Stepanova,et al.  Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. , 2011, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[2]  G. Gerken,et al.  Vitamin D counteracts fibrogenic TGF-β signalling in human hepatic stellate cells both receptor-dependently and independently , 2014, Gut.

[3]  J. Everhart,et al.  Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. , 2003, Gastroenterology.

[4]  A. Kaya,et al.  Relationship between cerebral arterial pulsatility and carotid intima media thickness in diabetic and non-diabetic patients with non-alcoholic fatty liver disease , 2009, Journal of endocrinological investigation.

[5]  M. Blachier,et al.  Report Title: The burden of liver disease in Europe: a review of available epidemiological data , 2013 .

[6]  T. Saibara,et al.  7. 非アルコール性脂肪肝炎 (NASH) の診断と治療 , 2006 .

[7]  A. Sanyal,et al.  Abnormalities of lipid metabolism in nonalcoholic fatty liver disease. , 2008, Seminars in liver disease.

[8]  Guido Gerken,et al.  The interaction of hepatic lipid and glucose metabolism in liver diseases. , 2012, Journal of hepatology.

[9]  A. Abdo,et al.  Revising the Upper Limit of Normal for Levels of Serum Alanine Aminotransferase in a Middle Eastern Population with Normal Liver Histology , 2013, Digestive Diseases and Sciences.

[10]  K. Cusi,et al.  Relationship of vitamin D with insulin resistance and disease severity in non-alcoholic steatohepatitis. , 2015, Journal of hepatology.

[11]  C. Hellerbrand,et al.  Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. , 2014, Best practice & research. Clinical gastroenterology.

[12]  P. Scherer,et al.  The adipocyte-secreted protein Acrp30 enhances hepatic insulin action , 2001, Nature Medicine.

[13]  Z. Younossi,et al.  Nonalcoholic fatty liver disease: a manifestation of the metabolic syndrome. , 2008, Cleveland Clinic journal of medicine.

[14]  J. Cantley The control of insulin secretion by adipokines: current evidence for adipocyte-beta cell endocrine signalling in metabolic homeostasis , 2014, Mammalian Genome.

[15]  Ahmad Esmaillzadeh,et al.  Calcium-vitamin D cosupplementation influences circulating inflammatory biomarkers and adipocytokines in vitamin D-insufficient diabetics: a randomized controlled clinical trial. , 2014, The Journal of clinical endocrinology and metabolism.

[16]  D. Hoffmann,et al.  Novel Algorithm for Non-Invasive Assessment of Fibrosis in NAFLD , 2013, PloS one.

[17]  R. Luben,et al.  Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies , 2012, Diabetologia.

[18]  W. Rathmann,et al.  Type 2 diabetes: prevalence and relevance of genetic and acquired factors for its prediction. , 2013, Deutsches Arzteblatt international.

[19]  Trevor Hastie,et al.  LOCAL CASE-CONTROL SAMPLING: EFFICIENT SUBSAMPLING IN IMBALANCED DATA SETS. , 2013, Annals of statistics.

[20]  M. Vidali,et al.  Review article: role of oxidative stress in the progression of non‐alcoholic steatosis , 2005, Alimentary pharmacology & therapeutics.

[21]  J. Walley,et al.  Liver aminotransferases and risk of incident type 2 diabetes: a systematic review and meta-analysis. , 2013, American journal of epidemiology.

[22]  J. Mitri,et al.  Vitamin D and type 2 diabetes: a systematic review , 2011, European Journal of Clinical Nutrition.

[23]  A. Sanyal,et al.  Association between high-normal levels of alanine aminotransferase and risk factors for atherogenesis. , 2013, Gastroenterology.

[24]  S. Sharp,et al.  Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation study , 2015, The lancet. Diabetes & endocrinology.

[25]  C. Day From fat to inflammation. , 2006, Gastroenterology.

[26]  C. Mantzoros,et al.  Circulating alanine transaminase (ALT) and γ-glutamyl transferase (GGT), but not fetuin-A, are associated with metabolic risk factors, at baseline and at two-year follow-up: the prospective Cyprus Metabolism Study. , 2014, Metabolism: clinical and experimental.

[27]  S. Sookoian,et al.  Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. , 2008, Journal of hepatology.

[28]  Y. Terauchi,et al.  The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity , 2001, Nature Medicine.

[29]  W. Rathmann,et al.  Regional and neighborhood disparities in the odds of type 2 diabetes: results from 5 population-based studies in Germany (DIAB-CORE consortium). , 2013, American journal of epidemiology.

[30]  C. Bogardus,et al.  Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans. , 2002, Diabetes.

[31]  S. Rhee,et al.  Upper normal threshold of serum alanine aminotransferase in identifying individuals at risk for chronic liver disease , 2012, Liver international : official journal of the International Association for the Study of the Liver.

[32]  R. Evans,et al.  A Vitamin D Receptor/SMAD Genomic Circuit Gates Hepatic Fibrotic Response , 2013, Cell.

[33]  D. Jacobs,et al.  Associations between γ-glutamyltransferase (GGT) and biomarkers of atherosclerosis: the Multi-ethnic Study of Atherosclerosis (MESA). , 2014, Atherosclerosis.

[34]  Dominik Heider,et al.  Non-Invasive Separation of Alcoholic and Non-Alcoholic Liver Disease with Predictive Modeling , 2014, PloS one.

[35]  D. Torres,et al.  NAFLD: Predictive value of ALT levels for NASH and advanced fibrosis , 2013, Nature Reviews Gastroenterology &Hepatology.

[36]  C. Apovian,et al.  Serum 25‐hydroxyvitamin D levels and metabolic health status in extremely obese individuals , 2014, Obesity.

[37]  S. Moebus,et al.  Baseline recruitment and analyses of nonresponse of the Heinz Nixdorf recall study: Identifiability of phone numbers as the major determinant of response , 2005, European Journal of Epidemiology.

[38]  B. Cheung,et al.  Hypoadiponectinemia as an independent predictor for the progression of carotid atherosclerosis: a 5-year prospective study. , 2014, Metabolic syndrome and related disorders.

[39]  E. DeLong,et al.  Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. , 1988, Biometrics.

[40]  F. Schaffner,et al.  Nonalcoholic fatty liver disease. , 1986, Progress in liver diseases.

[41]  H. Kolb,et al.  Serum adipokines as biomarkers of beta‐cell function in patients with type 1 diabetes: positive association with leptin and resistin and negative association with adiponectin , 2013, Diabetes/metabolism research and reviews.

[42]  S. Verma,et al.  Predictive value of ALT levels for non‐alcoholic steatohepatitis (NASH) and advanced fibrosis in non‐alcoholic fatty liver disease (NAFLD) , 2013, Liver international : official journal of the International Association for the Study of the Liver.

[43]  W. D. van Marken Lichtenbelt,et al.  Body composition changes in bodybuilders: a method comparison. , 2004, Medicine and science in sports and exercise.

[44]  Jeanne M Clark,et al.  Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. , 2003, JAMA.

[45]  S. Friedman,et al.  Glucokinase links Krüppel‐like factor 6 to the regulation of hepatic insulin sensitivity in nonalcoholic fatty liver disease , 2012, Hepatology.

[46]  Dominik Heider,et al.  A Combination of α-Fetoprotein and Des-γ-Carboxy Prothrombin Is Superior in Detection of Hepatocellular Carcinoma , 2013, Digestion.

[47]  M. Rosenbaum,et al.  Alanine transferase: An independent indicator of adiposity related comorbidity risk in youth , 2015, Journal of diabetes.

[48]  A. Wree,et al.  Adipocyte cell size, free fatty acids and apolipoproteins are associated with non-alcoholic liver injury progression in severely obese patients. , 2014, Metabolism: clinical and experimental.

[49]  A. McCullough,et al.  Hypovitaminosis D is associated with increased whole body fat mass and greater severity of non‐alcoholic fatty liver disease , 2014, Liver international : official journal of the International Association for the Study of the Liver.

[50]  A. Hevener,et al.  Strength fitness and body weight status on markers of cardiometabolic health. , 2015, Medicine and science in sports and exercise.

[51]  Miranda E. Kroehl,et al.  Association between vitamin D metabolism gene polymorphisms and risk of islet autoimmunity and progression to type 1 diabetes: the diabetes autoimmunity study in the young (DAISY). , 2013, The Journal of clinical endocrinology and metabolism.

[52]  S. Friedman,et al.  Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid‐induced liver injury in superobese patients with nonalcoholic steatohepatitis , 2013, Hepatology.

[53]  Katsutoshi Tokushige,et al.  Hepatocellular carcinoma in non‐alcoholic steatohepatitis: Growing evidence of an epidemic? , 2012, Hepatology research : the official journal of the Japan Society of Hepatology.

[54]  G. Svegliati-Baroni,et al.  From the metabolic syndrome to NAFLD or vice versa? , 2010, Digestive and Liver Disease.

[55]  G. Norman,et al.  SAFETY study: alanine aminotransferase cutoff values are set too high for reliable detection of pediatric chronic liver disease. , 2010, Gastroenterology.