Persistent elevation of liver function enzymes within the reference range is associated with increased cardiovascular risk in young adults: the Bogalusa Heart Study

doi:10.1016/j.metabol.2007.01.010

Metabolism

Volume 56, Issue 6, June 2007, Pages 792-798

https://doi.org/10.1016/j.metabol.2007.01.010 Get rights and content

Abstract

Elevations in alanine aminotransferase (ALT) and γ-glutamyl transferase (GGT), markers of liver dysfunction and nonalcoholic fatty liver, are considered as part of the metabolic syndrome and related diseases. However, information is limited regarding the persistence (tracking) in levels of these enzymes over time and their influence on cardiovascular (CV) risk in young adults. The study sample consisted of white and black subjects (N = 489, 40% male, 73% white; baseline age, 18-32 years) followed over a period of 12 years as part of the Bogalusa Heart Study, with repeat measurements of CV risk factor variables and liver enzymes. Both at baseline and follow-up, males vs females had higher ALT (P < .01 to .0001) and GGT (P < .0001); blacks vs whites had higher GGT (P < .0001). With respect to persistence in enzyme levels over time, of those individuals who had ALT and GGT at the top quintile specific for age, race, and sex at baseline, about 50% of them continued to remain so with high values after 12 years. Individuals with levels persistently in the highest quintile vs those in the lowest quintile showed higher (P < .0001) body mass index, waist circumference, triglycerides, low-density lipoprotein cholesterol, glucose, insulin, insulin resistance index, and systolic and diastolic blood pressures; lower (P < .0001) high-density lipoprotein cholesterol; and higher (P < .05 to .001) prevalence of obesity, hypertension, dyslipidemia, metabolic syndrome as defined by the National Cholesterol Education Program Adult Treatment Panel III, positive parental history of type 2 diabetes, and coronary heart disease. In addition, based on a multivariate analysis using 2 separate models for ALT and GGT, baseline levels of both enzymes were independent predictors of follow-up; insulin resistance index and baseline GGT were also predictive of follow-up systolic blood pressure. Elevations in liver enzymes ALT and GGT, within “reference” range, persist over time and relate to clinically relevant adverse CV risk profile in young adults.

Introduction

Nonalcoholic fatty liver (NAFL), a metabolic consequence of obesity, is increasingly being considered as a hepatic expression of metabolic syndrome [1], [2], [3], [4], [5]. Nonalcoholic fatty liver is commonly associated with long-term elevations in liver enzymes such as alanine aminotransferase (ALT) and γ-glutamyl transferase (GGT) [3], [6], [7]. These enzymes are suggested to have substantial clinical and epidemiological significance as useful noninvasive surrogate markers of NAFL and related liver dysfunction [6], [7].

Recent epidemiological and clinical studies have reported a strong association of ALT and GGT with metabolic syndrome and related clinical manifestations including cardiovascular (CV) disease and type 2 diabetes mellitus [8], [9], [10], [11], [12], [13]. However, information is limited regarding the persistence (tracking) of increased levels of these enzymes over time and their effect on CV risk in young adults. As part of the Bogalusa Heart Study, a biracial (black-white) community-based investigation of the early natural history of CV disease [14], the present study examines the tracking of ALT and GGT within “reference” range over time and their association with CV risk in terms of metabolic syndrome and parental histories of coronary heart disease and type 2 diabetes mellitus in apparently healthy young adults.

Section snippets

Study population

Three cross-sectional surveys were performed on young adults during 1985-1986, 1988-1991, and 2000-2001 in the community (65% whites, 35% blacks) of Bogalusa, LA. The study cohort (N = 489; 73% white, 40% male) was selected from those who were fasting and had data on ALT and GGT along with other risk factor variables, and participated in the baseline survey of 1985-1986 or 1988-1991 (baseline age: 25.6 year) as well as the follow-up survey of 2000-2001 (follow-up age, 37.9 years), with a

Results

Mean levels of ALT and GGT at baseline and follow-up are shown in Table 1 by race and sex. At baseline and follow-up, GGT levels were higher in blacks vs whites (P < .0001 to .01) and males vs females (P < .0001), whereas ALT levels were higher only in males vs females (P < .0001 to .01).

Subjects with relatively high/low liver enzyme levels at baseline tended to have retained such levels 12 years later. As shown in Fig. 1, when subjects were grouped into quintiles according to age-, race-, and

Discussion

The present community-based study demonstrates that elevations in enzymes ALT and GGT, biomarkers of liver dysfunction and NAFL, persist over time and relate adversely to metabolic syndrome and its components as well as to parental histories of coronary artery disease and type 2 diabetes mellitus in asymptomatic, healthy young adults. These longitudinal observations in a relatively younger adult cohort are noteworthy in that they strongly support the notion of pathophysiologic link between

Acknowledgments

This study was supported by the National Institutes of Health grant AG-16592 from the National Institute of Aging and grant HL-38844 from the National Heart, Lung, and Blood Institute.

The Bogalusa Heart Study is a joint effort of many investigators and staff members whose contribution is gratefully acknowledged. We especially thank the children and young adults who have participated in this study for many years.

References (46)

H. Cortez-Pinto et al.
Non alcoholic fatty liver: another feature of the metabolic syndrome
Clin Nutr
(1999)
J.M. Clark et al.
The prevalence and etiology of elevated aminotransferase levels in the United States
Am J Gastroenterol
(2003)
S. Liangpunsakul et al.
Unexplained elevations in alanine amino transferase in individuals with the metabolic syndrome: results from the third National Health and Nutrition Survey (NHANES III)
Am J Med Sci
(2005)
W. Bao et al.
Essential hypertension predicted by tracking of elevated blood pressure from childhood to adulthood: the Bogalusa Heart Study
Am J Hypertens
(1995)
A.J. Sanyal et al.
Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities
Gastroenterology
(2001)
A.J. Sanyal et al.
AGA technical review on alcoholic fatty liver disease
Gastroenterology
(2002)
F. Diraison et al.
Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease
Diabetes Metab
(2003)
N.N. Orie et al.
Reactive oxygen species in essential hypertension and non–insulin-dependent diabetes mellitus
Am J Hypertens
(1999)
K.J. Greenlund et al.
Verification of parental history of coronary artery disease and associations with adult offspring risk factors in a community sample: the Bogalusa Heart Study
Am J Med Sci
(1997)
P. Angulo
Non-alcoholic fatty liver disease
N Engl J Med
(2002)

Z.T. Bloomgarden

Non alcoholic fatty liver disease and malignancy as complications of insulin resistance

Metab Syndr Relat Disord

(2005)

G. Marchesini et al.

Nonalcoholic fatty liver disease: a feature of the metabolic syndrome

Diabetes

(2001)

F. Angelico et al.

Non-alcoholic fatty liver syndrome: a hepatic consequence of common metabolic diseases

J Gastroenterol Hepatol

(2003)

J.M. Clark et al.

Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis

JAMA

(2003)

A.J.G. Hanley et al.

Liver markers and development of the metabolic syndrome: the Insulin Resistance Atherosclerosis Study

Diabetes

(2005)

G. Marchesini et al.

Aminotransferase and gamma-glutamyltraspeptidase levels in obesity are associated with insulin resistance and the metabolic syndrome

J Endocrinol Invest

(2005)

M. Nannipieri et al.

Liver enzymes, the metabolic syndrome, and incident diabetes: the Mexico City Diabetes Study

Diabetes Care

(2005)

N. Sattar et al.

Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the West of Scotland Coronary Prevention Study

Diabetes

(2004)

D.H. Lee et al.

Gamma-glutamyltransferase is a predictor of incident diabetes and hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) Study

Clin Chem

(2003)

The Bogalusa Heart Study 20th anniversary symposium

Am J Med Sci

(1995)

S.R. Srinivasan et al.

Serum lipoproteins in children and methods for study

D.R. Matthews et al.

Homeostasis model assessment: insulin resistance and cell function from fasting plasma glucose and insulin concentrations in man

Diabetologia

(1985)

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)

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Persistent elevation of liver function enzymes within the reference range is associated with increased cardiovascular risk in young adults: the Bogalusa Heart Study

Abstract

Introduction

Section snippets

Study population

Results

Discussion

Acknowledgments

Clin Nutr

Am J Gastroenterol

Am J Med Sci

Am J Hypertens

Gastroenterology

Gastroenterology

Diabetes Metab

Am J Hypertens

Am J Med Sci

Non-alcoholic fatty liver disease

N Engl J Med

Non alcoholic fatty liver disease and malignancy as complications of insulin resistance

Metab Syndr Relat Disord

Nonalcoholic fatty liver disease: a feature of the metabolic syndrome

Diabetes

Non-alcoholic fatty liver syndrome: a hepatic consequence of common metabolic diseases

J Gastroenterol Hepatol

Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis

JAMA

Liver markers and development of the metabolic syndrome: the Insulin Resistance Atherosclerosis Study

Diabetes

Aminotransferase and gamma-glutamyltraspeptidase levels in obesity are associated with insulin resistance and the metabolic syndrome

J Endocrinol Invest

Liver enzymes, the metabolic syndrome, and incident diabetes: the Mexico City Diabetes Study

Diabetes Care

Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the West of Scotland Coronary Prevention Study

Diabetes

Gamma-glutamyltransferase is a predictor of incident diabetes and hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) Study

Clin Chem

The Bogalusa Heart Study 20th anniversary symposium

Am J Med Sci

Serum lipoproteins in children and methods for study

Homeostasis model assessment: insulin resistance and cell function from fasting plasma glucose and insulin concentrations in man

Diabetologia

JAMA