Central Obesity and Elevated Liver Enzymes
Lam, Gregory M
Nonalcoholic fatty liver disease is commonly associated with obesity, a growing epidemic worldwide. A new large, population-based investigation has shown a statistically significant association between central adiposity and elevated liver enzymes. This finding adds to the growing research specifically linking central adiposity, and more specifically, visceral adiposity, with adverse health effects.
Key words: obesity, liver enzymes, fatty liver, nonalcoholic fatty liver disease, adipose tissue, central adiposity, visceral adiposity
© 2004 International Life Sciences Institute
Nonalcoholic fatty liver disease (NAFLD), currently defined as fat accumulation in the liver exceeding 5% to 10% by weight,1 is estimated to affect 10% to 24% of the general population.2 The term refers to a wide range of liver damage, from steatosis to steahepatitis, advanced fibrosis, and cirrhosis. Requiring alcohol consumption to be less than 14 units/week or 20 g/day,1 NAFLD is still the most common etiology of abnormal liver test results among adults in the United States.2 NAFLD is a syndrome with a multifactorial etiology, with which obesity is most commonly associated.3 Obesity is a growing worldwide epidemic with links to numerous medical conditions such as diabetes, cardiovascular disease, ischemic stroke, hypertension, obstructive sleep apnea, gout, osteoarthritis, and a higher incidence of some cancers. Steatosis is found in more than two-thirds of the obese population and in more than 90% of the morbidly obese.2 Steatohepatitis affects 3% of the lean population, 19% of the obese population, and almost half of the morbidly obese population.2 A recent study by Stranges et al.4 evaluated the relationship between central fat accumulation, body mass index (BMI, kg/m^sup 2^), and the liver enzymes alanine aminotransferase (ALT), aspartate ami-* notransferase (AST), and γ-glutamyltransferase (GGT). It is the first large, population-based investigation to do so, and the findings seem to support a role of central adiposity independent of overall adiposity in predicting increased liver enzymes and potential liver damage.
The study by Stranges et al.4 was based on data obtained from a sample of residents of Erie and Niagara Counties in New York State from September 1995 to May 2001; 6837 people were identified and 4065 agreed to participate. Exclusion criteria were: a self-reported history of chronic or acute hepatitis, cirrhosis, or noncirrhotic liver disease; coronary artery disease; missing anthropometric measurements; missing data on education, smoking, and drinking habits; and missing blood determination of liver enzymes. Of the total population, 2704 were included in the analysis-1519 women and 1185 men. Participants were then invited for an interview regarding their health conditions and lifestyle habits, especially alcohol intake. Participants also had a physical examination consisting of measurements of abdominal height, waist and hip circumference, height, and weight. Abdominal height, or the sagittal (anteroposterior) abdominal diameter, was measured to the nearest 0.1 cm using the Holtain-Kahn abdominal caliper. This measurement has been shown to be correlated with the volume of visceral fat.4 All three readings were repeated until they were within 0.5 cm of each other. Waist circumference was determined by measuring the smallest circumference between the bottom of the rib cage and the top of the iliac crest. Hip circumference (while standing) was determined by measuring the largest circumference between the iliac crest and crotch for women or iliac crest and head of the femur for men. Height was determined using a mounted vertical board, and weight by a balance-beam scale calibrated to the nearest one-tenth of a pound. The morning after an 8- to 12-hour fast, a blood sample was taken that measured ALT, AST, and GGT levels.
To analyze the data, the liver enzyme distribution was normalized using natural log transformation. The other continuous variables were not significantly skewed so they were not log transformed. Differences by gender and menopausal status were compared with independentsample Student t tests for continuous variables and chi-square tests for categorical variables. It was found that there was interaction between anthropometric measures, menopausal status, and all three hepatic enzymes. Therefore, women were stratified by menopausal status.
Pearson linear correlations were used to test the bivariate associations between the anthropometric measurements. All anthropometric variables were correlated to some degree. Abdominal height and waist circumference were more correlated with BMI on a scale of 0.840 to 0.910 among premenopausal women, postmenopausal women, and men than waist-to-hip ratio, which was correlated less strongly at a range of 0.335 to 0.415. Premenopausal women consistently showed higher correlation coefficients than men or postmenopausal women, although the difference was only approximately 0.07 and 0.05, respectively.
Partial correlation coefficients between anthropometric variables and liver enzymes were examined. In premenopausal women, waist circumference and abdominal height showed slightly higher correlation with ALT (0.371, 0.360) and GGT (0.370, 0.387) than both BMI (0.340, 0.352) and waist-to-hip ratio (0.250, 0.273). For men and postmenopausal women, abdominal height was the strongest correlate of ALT and GGT, but was only 0.227 and 0.205, respectively, for men and 0.181 and 0.211, respectively, for postmenopausal women. AST levels were not consistently correlated with anthropometric measurements, ranging from -0.077 to 0.204. Because the associations between anthropometric measurements and liver enzymes tended to be stronger in the premenopausal group, Stranges et al.4 hypothesized that the contribution of excess weight or visceral obesity may be more predictive at an earlier age or that hormonal changes may have played a role in the observed differences. Although statistically significant, the overall associations with anthropometric measurements were small (approximately -0.054 to 0.387).
Multiple linear regression analysis was used to investigate the association between anthropometric indices and hepatic enzymes, with ALT and GGT as the dependent variables and abdominal height and BMI as the independent variables. When this analysis was done for ALT without abdominal height as a variable in premenopausal women, the variable coefficient R^sup 2^ was 0.132; this increased to 0.145 when abdominal height was added in. For postmenopausal women, the R^sup 2^ value changed from 0.039 to 0.046; for men the R^sup 2^ went from 0.138 to 0.152. For the analyses of GGT, the variable coefficient changed from 0.213 to 0.229 for premenopausal women, 0.061 to 0.076 for post-menopausal women, and 0.087 to 0.102 for men.
Although the associations that Stranges et al.4 found were somewhat small, they were statistically significant. This was the first large, population-based investigation to evaluate the relationship of overall adiposity, visceral fat distribution, and three common liver function tests. The findings support the role of visceral adiposity as a predictor of increased levels of hepatic liver enzymes, and add to the growing literature on the adverse health effects of central obesity and the importance of clinical indicators other than BMI to measure risk.
Accumulating evidence is suggesting that central deposition of body fat plays a role in health risk independently from the degree of obesity. Hayashi et al.5 published a prospective study with a 10- to 11-year follow-up of 300 Japanese Americans with a systolic blood pressure less than 140 mm Hg and a diastolic blood pressure less than 90 mm Hg. Exclusion criteria also required that the patient was not on antihypertensive medications, oral hypoglycemic medications, or insulin at study entry. Investigators calculated BMI with weight and height measurements and used CT scans of the thorax, abdomen, and mid-thigh to measure visceral adiposity from the intra-abdominal fat area. Subcutaneous fat was calculated as the sum of subcutaneous thoracic and abdominal fat areas plus twice the right thigh subcutaneous area. Total fat was the addition of subcutaneous plus intra-abdominal fat. Waist circumference was measured at the level of the umbilicus. The investigators found that greater visceral adiposity was associated with a higher risk for incident hypertension independently of plasma insulin level, 2-hour plasma glucose level, age, sex, alcohol consumption, smoking status, energy expenditure through exercise, and other measures of total and regional adiposity. They also found that greater visceral adiposity was associated with hypertension independent of plasma insulin level, suggesting that visceral adiposity may affect hypertension through a mechanism unrelated to insulin level or sensitivity. Other studies examining the relation between hypertension and CT-measured intra-abdominal fat have been cross-sectional studies that have made drawing conclusions about cause-and-effect relationships difficult. The results have also been inconsistent. This new study by Hayashi et al.5 did demonstrate that visceral adiposity is a significant risk factor in the development of hypertension in this select population subsample.
Omagari et al.6 examined a Japanese population of 3432 patients between January and December of 2000. Total body fat was measured by bipedal impedance, and diagnosis of fatty liver was made by ultrasound. Although ultrasonography was cited as 89% to 95% sensitive and 84% to 93% specific for steatosis, and 57% to 77% sensitive and 85% to 89% specific for fibrosis, liver biopsies were not performed to confirm the liver diagnoses. Abdominal height was not measured. Fatty liver was seen most often in men and overweight individuals. Multivariate analysis was performed using logistic regression analysis, which demonstrated BMI, ALT, and triglycerides as independent predictors of fatty liver in both sexes, while fasting blood glucose, uric acid, percentage body fat, and total cholesterol were independent predictors in men only. Interestingly, 141 patients with fatty liver were classified as non-alcohol drinkers and non-overweight. Of these patients, 27.2% of men had a body fat percentage >25%, and 59.2% of women had >30% body fat. This differed from the non-overweight, non-alcohol-drinking group, in which only 7.7% of men and 20.2% of women had excess body fat. Omagari et al.6 argued that those participants with a normal BMI but increased body fat can be assumed to have central body fat distribution.
Quetelet originally proposed the concept of the BMI back in 1835. In the early 20th century, the life insurance industry identified central adiposity as a risk factor for death based on height and weight tables. With the classification scheme cutoffs established for BMI, it is the most widely used schema for identifying at-risk patients. However, BMI does not account for the wide variation in body fat distribution, and has considerable limitations in predicting intra-abdominal fat accumulation. For example, Janssen et al.7 analyzed 14,924 participants in the National Health and Nutrition Examination Survey. When waist circumference was used as a continuous variable, it accounted for cardiovascular disease more so than when it was dichotomized into normal or high risk, as it is today. For a given waist circumference value, people categorized as overweight to obese and normal weight had comparable health risks. Although BMI predicted more variance in health risk than waist circumference alone, Janssen et al.7 argued that if waist circumference were risk stratified into five or more categories like BMI, it may be possible to use waist circumference alone as a health indicator. In the study by Stranges et al.4 there was a significant relationship between waist circumference and ALT and GGT, although it was diminished in comparison with abdominal height and BMI.
Chan et al.8 examined 59 white men with wide-ranging BMIs. MRIs were obtained, and abdominal fat was divided into subcutaneous abdominal adipose tissue, intraperitoneal adipose tissue, and retroperitoneal adipose tissue using a computer software program. Waist circumference predicted intraperitoneal, retroperitoneal, and anterior subcutaneous adipose tissue mass better than BMI or waist-to-hip ratio. Abdominal height was not measured. The authors admitted that only 60% of the regional adipose tissue mass could be accounted for using their indices. Their study size was small and did not include women, children, or other racial groups.
Although the study by Stranges et al.4 consistently showed abdominal height to be the strongest predictor of ALT and GGT levels, there was a high co-linearity between anthropomorphic indices.
Omagari et al.6 found that percentage body fat was an independent predictor of fatty liver in nonalcoholic and non-overweight participants. Percentage body fat was an independent predictor of fatty liver only in men. BMI was an independent predictor of fatty liver in both sexes. The study by Stranges et al.4 did not include a measurement of body fat percentage. Lonardo and Trande9 attempted to examine sex differences and body fat distribution in 199 patients and found that BMI was an independent predictor of fatty liver diagnosed by ultrasound. Central adiposity reflected by increased waist-to-hip ratio was observed in women with fatty liver disease but not in men, seemingly contradicting the results of Omagari.6 Stranges et al. found correlations among the 1519 women and 1185 men with elevated ALT and GGT compared with abdominal height, waist circumference, and waist-to-hip ratio.
The progression of NAFLD to more advanced stages is poorly understood. The prevailing theory is that NAFLD starts with fat accumulation in hepatocytes via lipolysis and hyperinsulinemia.3 Dietary triglycerides and excess carbohydrates transformed into free fatty acids reach the liver through the portal vein and are partially released into the bloodstream.3 Abdominal fat may more easily release lipids, thus promoting a direct flow to the liver through the portal vein.3 In rat models, large amounts of visceral fat are strictly related to the onset of insulin resistance in the liver and muscle tissue, and visceral fat removal decreases hepatic insulin resistance.10 Hepatic fat accumulation is associated with reduced insulin-mediated suppression of endogenous glucose production. Free fatty acid (FFA) breakdown in mitochondria increases the production of reactive oxygen species, which may be responsible for insulin resistance involving a protein kinase-C-related pathway. It may be a source of oxidative stress to which the cell adapts, but may also become more vulnerable to environmental or genetic damage. Chronic oxidative stress leads to significant depletion of natural antioxidants such as glutathione and vitamin E and of excess reactive oxygen species. In the adipocyte, insulin promotes lipolysis and causes increased FFA delivery to the liver. In the hepatocyte, insulin stimulates synthesis and inhibits oxidation of FFAs. Degradation of apolipoprotein B100 is enhanced in hyperinsulinemia, as shown in animal models,3 and it reduces the release of triglycerides from the liver. Therefore, there is increased flow of FFAs and decreased production or secretion of very-low-density lipoproteins. In addition, increased levels of FFAs can be directly toxic to hepatocytes. It is thought that increased flux of FFAs through the liver during peripheral lipolysis may play a role in injury.
The metabolic syndrome, characterized by excess body fat stores, diabetes, hypertension, and/or altered lipid metabolism, is associated with a threefold increased risk of nonalcoholic steatohepatitis among NAFLD subjects after correcting for sex, age, and body mass.3 Insulin resistance is the most reproducible factor in the development of NAFLD,3 and much of the focus in studying the pathogenesis of liver damage focuses on the metabolic alterations involved in insulin resistance.
Several mediators have been identified as regulating insulin sensitivity. Tumor necrosis factor alpha (TNF-α) is activated by excess reactive oxygen species; it stimulates lipogenesis in hepatocytes, increases FFA release from adipocytes, and modifies the activity of several mitochondrial enzymes. It may also directly induce hepatocyte apoptosis. TNF-α activates inhibitor kinase beta (IKK-β), which activates nuclear factor kappa beta (NKκβ), which induces the synthesis of TNF-α. Therefore, this mechanism initiates a positive feedback mechanism or a vicious cycle that induces insulin resistance and perpetuates TNF-α production.
Leptin, a satiety hormone synthesized by adipose tissue, is elevated in nonalcoholic steatohepatitis patients and may play a role in regulating the partitioning of fat between mitochondrial β-oxidation and triglyceride synthesis. Leptin may exert an anti-steatotic effect. In animal studies in which obesity was induced by excessive caloric intake, serum leptin levels were increased.3 Initially, storage of fat is stimulated in adipose tissue only. Afterwards, leptin resistance develops and fat is deposited in vital organs such as the liver, pancreas, and heart.
Adiponectin is an anti-inflammatory protein exclusively secreted by adipose tissue; it is known to modulate insulin effects. Adiponectin increases FFA oxidation in rodent muscle, antagonizes TNF, and is negatively correlated with ALT and GGT levels.11 It is suppressed in states of insulin resistance and obesity. Recombinant adiponectin has been shown to alleviate both alcohol-induced fatty liver and NAFLD in mice.10
In biopsy-proven nonalcoholic steatohepatitis patients, a single missense mutation of the PPAR-α gene has been observed,3 which could support a genetic predisposition to this disease. This receptor modulates lipid oxidation in the mitochondria, peroxisomes, and microsomes, and simulates the synthesis of protein-2. An increased expression of UCP-2, an inner mitochondrial membrane protein involved in oxidative phosphorylation, has been documented in fatty ob/ob mice.
P53 has also been shown to be involved in the molecular mechanisms of injury associated with steatosis. Yahagi et al.12 examined the ob/ob mouse model, which is deficient in leptin and develops obesity, insulin resistance, and glucose intolerance. Lipogenesis of the liver is increased in ob/ob mice. The ob/ob liver had higher levels of p53 than the wild-type liver. The expression of p21 mRNA, a p53-regulated gene, was also elevated in ob/ob livers. Ob/ob mice were crossed with p53-null mice to create six male mice deficient in both leptin and p53. These mice had decreased p21 mRNA expression. P53 deficiency in ob/ob mice resulted in marked improvements in plasma ALT levels, implicating p53 as being involved in the mechanism of hepatocellular injury.12
Samuel et al.13 showed a causal relationship between hepatic fat accumulation and hepatic insulin resistance. Rats were subjected to 3 days of high-fat feeding versus controls and then a 12-hour fast before they underwent continuous infusion of U13C glucose. Animal tissues were harvested after the experiment and stored at -80°C. High fat-fed rats had tripled hepatic triglycerides and fatty acyl CoA content, which was not evident in skeletal muscle. Plasma glucose concentration and endogenous glucose production were not affected. Insulin-stimulated whole-body glucose utilization was similar to controls. However, endogenous glucose production was suppressed by 74% in the control group but only by 8% in the fat-fed group. This study supports the role of hepatic insulin resistance developing independently of adipose tissue insulin resistance.
The results of Samuel et al.13 showed that several steps in the insulin signal pathway were affected, suggesting impaired insulin signaling in fat-fed animals. Insulin-stimulated IRS-1 and IRS-2 tyrosine phosphorylalion were blunted in fat-fed animals. There was also impaired insulin activation of AKT2 and impaired inactivation of GSK3. This defect in the insulin-signaling pathway ultimately led to decreased activation of glycogen synthase activity, which diminishes the ability of the liver to store glycogen. Using the mitochondrial uncoupler 2,4-dinitrophenol, the investigators were able to prevent the accumulation of fat and fatty acid metabolites within the liver in fat-fed rats with improved hepatic insulin responsiveness. The addition of 2,4-dinitrophenol preserved AKT2 activation and GSK3 inactivation.
Novel protein kinase C has been implicated in the pathogenesis of skeletal muscle insulin resistance in rodents and humans. Lam et al.14 raised plasma fatty acid levels with intralipid+heparin-infused rats and caused both peripheral and hepatic insulin resistance compared with saline controls. Of all of the isoforms assayed, PKC-δ was the only one activated. This was implicated as a possible mediator for fat-induced hepatic insulin resistance. Samuel et al.13 did not find increased activity of PKC-δ after subjecting rats to 3 days of high-fat feedings, instead they found increased levels of another novel PKC, PKC-ε. JNK-1 levels were increased in fat-fed rats, and may play a key role in fat-induced insulin resistance, although the target proteins for this kinase remain unknown.
A 2004 study by Klein et al.15 examined the effect of large abdominal liposuction on metabolic risk factors for coronary heart disease in women with abdominal obesity. They evaluated 15 obese women before and 10 to 12 weeks after abdominal liposuction. Eight had normal glucose tolerance but moderate insulin resistance and seven had type 2 diabetes. Liposuction decreased the volume of abdominal adipose tissue on average by 44% in subjects with normal glucose tolerance with 9.1 ± 3.7 kg of fat. Abdominal adipose tissue was decreased by 28% in those with diabetes with an average of 10.5 ± 3.3 kg fat loss. Plasma glucose, insulin, leptin, lipid, c-reactive protein, adiponectin, interleukin-6, and TNF-α were measured prior to liposuction and 10 to 12 weeks afterward. There was a considerable loss in body weight, waist circumference, and leptin levels, but not the other risk factors of coronary heart disease, namely markers of inflammation and insulin resistance. The investigators point out that the induction of a negative energy balance, not simply a decrease in the mass of adipose tissue, is essential for achieving the metabolic benefits of weight loss.15
Weight loss decreases visceral fat mass, intramyocellular fat, intrahepatic fat, fat cell size, and the rate of release of fatty acids from adipose tissue. While liposuction reduces the total number of body fat cells, it does not alter the visceral fat mass or size of the remaining fat cells, intramyocellular fat, or intrahepatic fat.15 Visceral adiposity is more strongly associated with insulin resistance, so it is unclear whether removal of visceral adipose tissue may have yielded a different outcome. In rat models, the surgical resection of visceral adipose tissue yielded immediate improvements in insulin resistance, whereas removal of equivalent amounts of subcutaneous adipose tissue had little effect.10 Perhaps the removal of visceral fat in humans would affect other known adipose tissue-secreted hormones such as TNP-α, interleukin-6, and adiponectin.
Kissebah et al.16 examined 34 moderately obese women without diabetes, hypertension, or clinically recognizable heart disease, and separated them into groups of predominantly upper body obesity or predominantly lower body obesity. Upper segment obesity was considered to be when the measured brachial-to-femoral adipose ratio was > 1 and lower segment obesity was when the ratio was
Brown fat is present in cervical, axillary, perirenal, and periadrenal deposits in human fetuses and newborns and disappears soon after birth in humans.17 It is present throughout the life cycle of rodents. Brown adipose tissue expresses uncoupling protein 1 (UCP1), which is a 32-kd protein expressed on the inner membrane of mitochondria. UCP1 allows the dissipation of the proton electrochemical gradient generated by the respiratory chain by uncoupling oxygen consumption and ATP synthesis to promote energy dissipation as heat. Cold exposure activates the sympathetic nervous system to stimulate brown fat cells to dissipate heat. This contributes to the maintenance of temperature in hibernating animals. Thermogenesis can also be induced by diet in rats and may control energy efficiency of food.18 Mice that have ablation of their brown fat tissue using a toxigene approach develop decreased adjustment of food intake in relation to ambient temperature. The metabolic phenotype of these mice resembled syndrome X in humans. At 16 days, the transgenic mice had a 68% reduction in uncoupling protein content of interscapular brown fat depot, accompanied by moderate obesity. At 22 to 26 weeks, marked obesity developed in association with increased levels of glucose, insulin, and triglycerides, and was worsened by a high-fat diet. Cittadini et al.19 analyzed 12-week-old transgenic mice with echocardiography, aortic catheterization, and isolated whole heart studies. Body weights in the transgenic mice were increased by 77% compared with controls. Insulin and serum leptin levels were increased by 18 and 16 times, respectively. The average increase of mean blood pressure was 29%. Left ventricular mass was increased by 135%. Cardiac output was increased by 130%. White adipose tissue controls the supply of energy to the body by releasing fatty acids during periods of energy deficit; it comprises the majority of fat found in humans. The same tissue expresses UCPl mRNA at very low levels.20
One of the distinguishing features of brown adipose tissue is the expression of UCP1. UCP1 biosynthesis is mainly controlled at the transcriptional level. Peroxisome proliferator-activated receptor gamma (PPARγ) and PPARy coactivator 1-alpha (PGC-1α) are two enhancers in DNA that have been shown to induce UCP1 gene transcription. Tiraby et al.17 produced a PGC-1α human adenovirus (serotype 5) from full-length human PGC-1α parent plasmid consisting of a green fluorescent protein gene and PGC-1α cDNA downstream of cytomegalovirus promoters (the generation of this adenovirus is described elsewhere21). PGC-1α adenoviral-mediated expression of human PGC-1α increased the expression of UCP1, respiratory chain proteins, and fatty acid oxidation enzymes in human adipocytes, demonstrating that human white adipocytes can acquire the characteristics of brown fat cells. This is an area that may yield new strategies for dealing with obesity.
The new study by Stranges et al.4 corroborates evidence of the adverse effects of central obesity, and more specifically, visceral adipose deposition. As our understanding of the specific mechanisms on how obesity adversely affects health increases, so do our strategic options on how to best treat this all-too-common problem.
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15. Klein S, Fontana L, Young VL, et al. Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. N Engl J Med. 2004;350:2549-2557.
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20. Oberkofler H, Dallinger G, Liu YM, Hell E, Krempler F, Patsch W. Uncoupling protein gene: quantification of expression levels in adipose tissues of obese and non-obese humans. J Lipid Res. 1997;38: 2125-2133.
21. He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B. A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA. 1998;95:2509-2514.
Gregory M. Lam, DO, and Sohrab Mobarhan, MD
Dr. Lam is with the Department of Internal Medicine and Dr. Mobarhan is with the Department of Internal Medicine and Division of Gastroenterology, Hepatology, and Nutrition, Loyola University Medical Center, Maywood, Illinois.
Please address correspondence to: Gregory M. Lam, DO, Division of Internal Medicine, Loyola University Medical Center, 2160 S. First Ave., Maywood, IL 60153; Phone: 708-216-9468; Fax: 708-216-9456; e-mail: email@example.com.
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