To study the relationship between elevated liver tests and high sensitive C-reactive protein (hs-CRP), as potential markers of liver inflammation and non-alcoholic steatohepatitis (NASH), with anthropometric and laboratory parameters in overweight patients, especially the relationship with visceral adipose tissue (VAT).
Patients presenting to the obesity clinic were prospectively included. Detailed anthropometry, computed tomography (CT)-measured VAT, liver tests (aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT)) and hs-CRP were assessed, along with an extended series of biochemical parameters.
All 480 patients (gender distribution male (M)/female (F) (10/90%)) with complete data were included. Mean age was 39±13 years, mean BMI 34.5±6.0 kg m−2. In 37.3% of the patients one or more of the liver tests were elevated. VAT was positively related to AST (r=0.18, P<0.001), ALT (r=0.29, P<0.001), ALP (r=0.16, P<0.01) and GGT (r=0.39, P<0.001). Comparing subjects with high (VAT⩾113 cm2) vs low (VAT<113 cm2) VAT levels, significant differences were noted for AST (26±12 vs 24±12 U l−1, P=0.003), ALT (37±21 vs 31±21 U l−1, P<0.001), ALP (76±20 vs 71±18 U l−1, P=0.008), GGT (33±20 vs 25±15 U l−1, P<0.001) and hs-CRP (0.62±0.43 vs 0.52±0.48 mg dl−1, P<0.001). After correction for BMI the difference in AST and ALP between the high vs low VAT group disappeared. The differences for ALT and GGT remained significant (P=0.008 and P<0.001 respectively). After correction for hs-CRP the four different liver tests remained significantly higher in the high VAT group. A stepwise multiple regression analysis revealed that every single liver test has his own most important determinant; VAT and hs-CRP for AST, insulin resistance calculated with homeostasis model assessment (HOMA-IR) and hs-CRP for ALT and ALP, and triglycerides and VAT for GGT.
In overweight and obese patients, liver tests, especially ALT and GGT, are associated with visceral fat mass. After correction for BMI and hs-CRP, ALT and GGT are significantly higher in patients with increased VAT, thereby supporting evidence for a potential key role of VAT in the pathogenesis of non-alcoholic fatty liver disease (NAFLD).
The worldwide epidemic of obesity has raised the awareness of non-alcoholic fatty liver disease (NAFLD) from a curiosity to a potentially progressive liver disease with risk for non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma.1 In the general population the prevalence of NAFLD is estimated to be approximately 20–30%,2, 3, 4 this may increase up to 75% in an obese population.2
According to Eguchi et al.,5 the severity of fatty liver, evaluated by ultrasonography and computed tomography (CT), was positively correlated with visceral fat accumulation (evaluated by abdominal CT) and insulin resistance in both obese and non-obese subjects suggesting that hepatic fatty infiltration in NAFLD may be influenced by visceral fat accumulation regardless of body mass index (BMI). Insulin resistance is characterized by reductions in whole-body, hepatic and adipose tissue insulin sensitivity. The mechanisms underlying the accumulation of fat in the liver may include excess dietary fat, increased delivery of free fatty acids to the liver, inadequate fatty acid oxidation and increased de novo lipogenesis.6
In addition, it is well accepted that obesity can be regarded as a state of chronic subclinical inflammation,7, 8 and levels of high-sensitive C-reactive protein (hs-CRP), a marker of low-grade inflammation, have been linked to visceral obesity.9, 10, 11, 12, 13 Adipose tissue can induce chronic low-grade inflammation by producing pro-inflammatory cytokines such as leptin, adiponectin and interleukin-6 (IL-6).14 The liver is assumed to be the major source of CRP production, however, it has been suggested that the adipose tissue can also be a direct source of CRP. In severely obese patients with a large amount of body fat, adipose tissue might well significantly contribute to the increased circulating CRP levels.15, 16, 17 This chronic inflammation has a role in the development and progression of cardiovascular disease.18 It still remains unclear whether NAFLD contributes to chronic inflammation, and the resulting increased cardiovascular disease (CVD) risk profile, independent from any effect of visceral adiposity.
In this study we wanted to investigate the possible relationship between elevated liver tests and hs-CRP, as markers of liver inflammation and NASH, with anthropometric and laboratory parameters in a group of overweight and obese subjects, with a particular emphasis on visceral adipose tissue.
Materials and methods
All men and women visiting the weight management clinic of the Antwerp University Hospital for a problem of overweight (BMI ⩾25–29.9 kgm−2)19 or obesity (BMI ⩾30 kgm−2)19 presenting at their own initiative or who were referred by their treating physician and who gave their informed consent underwent a series of metabolic examinations. A number of patients were excluded from the analyses according to the following criteria. Subjects had to be 18 years or older. Both pre- and postmenopausal women were included in the analyses. Menopause was defined using clinical data (no menstruation during the previous year) combined with hormonal data (follicle-stimulating hormone >25 mU ml−1 and estradiol <20 pg ml−1). As diabetes has a specific clinical picture that might substantially influence the obtained results, patients already known to have diabetes or with a de novo diagnosis according to the criteria of the American Diabetes Association were not included in the protocol.20 Other exclusion criteria were Cushing's disease, thyroid illness (thyroid-stimulating hormone >4 or <0.1 μU ml−1), manifest hypertriglyceridemia (>400 mg dl−1) and acute illness. Rather strict criteria concerning alcohol use were applied; by excluding subjects with an intake of one or more alcoholic consumptions per day, also patients with notion of intermittent but important drinking were excluded. Alcohol consumption was self-reported. Patients with hs-CRP levels ⩾2.0 mg dl−1 were excluded from the orginal cohort, as such levels suggest the presence of a major infection.15 If patients showed liver tests fivefold the upper limit value of normal (as set by our hospital lab) they were excluded from further analyses, as well.21 Patients were clinically examined by a physician.
All measurements were carried out in the morning, with patients in fasting conditions and undressed. Height was measured to the nearest 0.5 cm and body weight was measured with a digital scale to the nearest 0.2 kg. BMI was calculated as weight in kilograms over height in meter squared. Waist circumference was measured at the mid-level between the lower rib margin and the iliac crest. Hip circumference was measured at the level of the trochanter major. Waist-to-hip ratio (WHR) was calculated by dividing waist circumference by hip circumference. Body composition was determined by bio-impedance analysis as described by Lukaski et al,22 and fat mass percentage was calculated, using the formula of Deurenberg et al.23 A CT-scan at L4–L5 level was carried out to measure the cross-sectional area of total abdominal adipose tissue (TAT) area, visceral abdominal adipose tissue (VAT) and subcutaneous abdominal adipose tissue (SAT) according to previously described methods.24 First, the total area of abdominal adipose tissue was measured at −190 to −30 Hounsfield Units. Subsequently, the area of VAT was distinguished from SAT by manually tracing the abdominal muscular wall separating the two adipose tissue compartments. The area of VAT was measured and the area of SAT was calculated by subtracting the area of VAT from the total area of TAT. The percentage of visceral fat was derived by the following formula: VAT/TAT × 100.25 Systolic and diastolic blood pressure were determined on the right arm of the patient, after at least 5 min rest, using a mercury sphygmomanometer.
A fasting blood sample was taken from an antecubital vein to determine the fasting levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyltranspeptidase (GGT), hs-CRP, total and high-density lipoprotein cholesterol (HDL-C) and triglycerides. AST:ALT ratio was calculated and low-density lipoprotein cholesterol (LDL-C) was calculated using the Friedewald formula.26 A minimal oral glucose tolerance test was carried out with 75 g of glucose, with blood samples taken to determine glucose and insulin in the fasted state and 2 h after the glucose load. Insulin resistance was estimated using homeostasis model assessment (HOMA) as described by Matthews et al,27 and was calculated as (insulin (mU l−1) × glucose (mmol l−1))/22.5, with 1 as a reference value for normal insulin sensitivity. Plasma glucose, total cholesterol and triglycerides were measured on Vitros 750 XRC (Ortho Clinical Diagnostics, Johnson & Johnson, Buckinghamshire, UK). HDL-C was measured on Hitachi 912 (Roche Diagnostics, Mannheim, Germany). Insulin levels were measured with the Medgenic two-site IRMA assay (BioSource, Nivelles, Belgium). Oestradiol was measured with a RIA assay (DiaSorin, Saluggia, Italy). Follicle-stimulating hormone and thyroid-stimulating hormone were measured using Vitros Immunodiagnostic products (Ortho-Clinical Diagnostics, Johnson & Johnson, UK). AST, ALT, ALP and GGT were all measured by dry chemistry on Vitros Fusion 5.1FS (Ortho Clinical Diagnostics, Beerse, Belgium). The cut-off points, determined according to the laboratory's instructions using control samples, for the different liver tests are 5–40 U l−1 for AST, 7–56 U l−1 for ALT, 36–95 U l−1 for ALP and 11–29 U l−1 for GGT in women and 13–45 U l−1 for GGT in men. Hs-CRP was assayed with nephelometry on BNII (Siemens Healthcare Diagnostics, Brussels, Belgium). The percentage of elevated liver tests in our overweight and obese population was determined according to the cut-off points set by our hospital lab. When one or more of the above mentioned liver tests were above the upper limit value of normal we labeled them as disturbed (AST>40 U l−1 or ALT>56 U l−1 or ALP>95 U l−1 or GGT >29 U l−1). The study was approved by the ethical committee of the Antwerp University Hospital and all patients gave their informed consent.
Statistical calculations were carried out using the statistical package SPSS version 16.0 (SPSS, Chicago, IL, USA). Values are expressed as mean±s.e. (range). Normality of variables was verified with a Kolmogorov–Smirnov test. As most of the variables were not normally distributed, and were not normalized after log or square root transformation, the Spearman's rank correlations were used. Partial correlations were calculated to control for confounding factors. Linear regression analysis with studentized residuals was used to test whether differences were independent of confounding factors. Differences in continuous variables were tested with a Mann–Whitney U-test or Kruskal–Wallis test, as appropriate. Differences in prevalence were determined with the χ2-test. In order to evaluate the most important determinants of the different liver tests, a stepwise multiple regression analysis was carried out. Results were considered significant if P<0.05.
In this study, 480 patients, 367 women (280 pre- and 87 postmenopausal) and 41 men, were included, of whom 120 were overweight and 288 obese. Subjects were predominantly of Caucasian origin. The characteristics of the 408 subjects are shown in Table 1, for men and women separately. Mean age was 39±13 years (range 18–75) with a mean BMI of 34.5±6.0 kgm−2 (range 25.0–52.1). Mean waist was 117.0 cm and 103.0 cm for men and women, respectively, with a mean VAT of 190 cm2 and 121 cm2 for men and women respectively. Normal levels of hs-CRP (<0.3 mg dl−1) were found in 150 of the 408 subjects (36.8%), whereas low-grade inflammation (hs-CRP ⩾0.3 mg dl−1 and <1 mg dl−1) was present in 180 subjects (44.1%). In 37.3% of the subjects one or more of the liver tests was above the upper limit of normality. Regarding glucose tolerance status we identified 19.9% of subjects with isolated impaired glucose tolerance (IGT) and 1.2% of subjects with isolated impaired fasting glucose (IFG).
There was no gender-based difference in BMI. As expected, men had a higher waist, WHR and VAT than women, and a lower fat mass percentage and HDL-C. All liver tests (AST, ALT, ALP and GGT) were significantly higher in men, which explains the higher percentage of elevated liver tests in men compared with women. There was a significant difference in age, triglycerides, fasting glucose, glucose 2-h post load, hs-CRP and systolic blood pressure between men and women.
When pre- and postmenopausal women were compared, after adjustment for age, no significant differences were found in the levels of AST, ALT and GGT. However, ALP remained significantly higher in postmenopausal women even after adjusting for age.
Anthropometry and metabolic variables
Spearman's correlation coefficients between several anthropometric and metabolic variables and the different liver tests (AST, ALT, ALP and GGT) were carried out. The strongest correlations were found for waist, (WHR), VAT, insulin resistance calculated HOMA (HOMA-IR) and HDL-C with ALT and GGT. Relationships with anthropometric and metabolic parameters are consistently stronger with ALT and GGT as compared with AST and ALP.
In our population, 20.1% of the patients had a ‘hypertriglyceridemic waist’ phenotype (waist circumference >90 cm in men and >85 cm in women, along with a plasma triglyceride concentration of ⩾177 mg dl−1).28, 29 Subjects with a hypertriglyceridemic waist had significantly higher levels of the different liver tests (results not shown).
Influence of inflammation on the relationship between VAT and liver tests
Levels of hs-CRP were significantly related to AST, ALP and GGT, as well as to age, BMI, fat mass (%), waist, WHR, TAT, VAT, SAT, HDL-C, triglycerides, fasting insulin and HOMA-IR. The relationships between AST, ALT, ALP and the amount of VAT were no longer significant after correction for hs-CRP (r=0.02; P=0.775, r=0.07; P=0.216, r=0.07; P=0.168 respectively), whereas the relationship between GGT and VAT remained significant (r=0.19; P<0.001).
Comparison between high and low levels of VAT
We divided the sample using the median value of VAT (113 cm2) as the cut-off point and compared the two groups regarding anthropometric and metabolic parameters and analyzed the four different liver tests subsequently (Table 2). A χ2 test for independence (with Yates continuity correction) indicated a significant association between elevated liver tests and VAT (χ2 (1, n=436) =25.18, P<0.001, phi=0.253). Subjects with high levels of visceral fat (⩾113 cm2) had significantly higher liver tests compared with subjects with low levels of visceral fat (<113 cm2); this results in almost twice as much patients with elevated liver tests in the high VAT group compared with the low VAT group. Also BMI and the inflammation marker hs-CRP differed significantly between the low- and high-visceral fat group. After correction for BMI the difference in AST, ALP and hs-CRP disappeared. The differences for ALT and GGT remained significant (P=0.008 and P<0.001, respectively). After correction for hs-CRP the four different liver tests remained significantly higher in the high visceral fat group.
Metabolic and anthropometric determinants of liver tests
To determine the independent determinants of each liver test (AST, ALT, ALP and GGT), we carried out a stepwise multiple regression analysis with liver tests as dependent variables and anthropometric and metabolic variables (age, BMI, VAT, HDL-C, triglycerides and HOMA-IR) as independent variables (Table 3a). The most important independent determinant of AST was VAT. For ALT and ALP, HOMA-IR was the independent determinant and for GGT this was triglycerides.
When hs-CRP was added as an independent determinant, VAT and hs-CRP were the independent determinants of AST, HOMA-IR and hs-CRP were independent determinants of ALT and ALP. For GGT, triglycerides and VAT were the most important determinants (Table 3b).
Categories of ALT and GGT
As ALT and GGT are considered as the most important liver tests related to hepatic steatosis30, 31 we analyzed different levels of ALT and GGT and their possible relationship with VAT, hs-CRP, triglycerides and HOMA-IR.
Subjects were divided in three different categories according to their level of ALT. The upper limit of normality for ALT, as set by the hospital lab, is 56 U l−1. We distinguished three different categories of ALT: ALT less than 41 U l−1 (n=315/77,2%), ALT between 41 and 56 U l−1 (n=59/14,5%) and ALT greater than 56 U l−1 (n=34/8,3%). The cut-off level of 40 U l−1 is based on what is generally accepted as the upper limit of normal in many liver diseases. These three different categories of ALT were compared for anthropometric and laboratory parameters (Figures 1a–c). VAT (P<0.001) was significantly higher in the categories with elevated ALT, this was also the case for BMI but less pronounced (P=0.005). TAT (P=0.059) and SAT (P=0.323) were not significantly different between the groups. The inflammation marker hs-CRP was not significantly different. HOMA-IR as marker of insulin resistance appeared to be significantly higher in the group with elevated ALT (P<0.001). Also the lipid parameters (total cholesterol, HDL-C, triglycerides and LDL-c) differed significantly between the groups. We were particularly interested in comparing the normal values of ALT (<41 U l−1) with the borderline values (41–56 U l−1). For VAT and HOMA-IR the differences were significant between the normal and the borderline values of ALT.
A similar analysis was also carried out for GGT. We distinguished three different categories of GGT: GGT less than 30 U l−1 (n=280/68,6%), GGT between 30 and 58 U l−1 (n=102/25,0%) and GGT greather than 58 U l−1 (n=26/6,4%). The cut-off level of 30 U l−1 is based on what is generally accepted as the upper limit of normal in many liver diseases. These three different categories of GGT were compared for a few anthropometric and laboratory parameters (Figure 2a–c). Differences for BMI (P<0.001), VAT (P<0.001) and TAT (P=0.001) were significant, SAT (P=0.193) was not significantly different between the groups. The inflammation marker hs-CRP was significantly different, as well. HOMA-IR as marker of insulin resistance appeared to be significantly elevated with elevated GGT (P<0.001). Also the lipid parameters (total cholesterol, HDL-C, triglycerides and LDL-c) differed significantly between groups. When comparing the normal values of GGT (<30) with the borderline values (30–56), we found significant differences for VAT, HOMA-IR, triglycerides and hs-CRP.
In this study of overweight and obese non-diabetic women and men, we investigated the possible relationship between liver tests and hs-CRP, as markers of liver inflammation and NAFLD, with anthropometric and laboratory parameters with particular emphasis on the relationship with visceral adipose tissue. The results demonstrate that liver tests, especially ALT and GGT, are associated with VAT. After correction for BMI and hs-CRP, ALT and GGT are still significantly higher in patients with increased visceral adipose tissue. A stepwise multiple regression analysis revealed that every liver test has his own most important determinant, for example VAT, HOMA-IR, hs-CRP or triglycerides. Considering different levels of the most important liver tests ALT and GGT, the relationship of these liver tests with VAT, HOMA-IR, triglycerides and hs-CRP was confirmed.
Previous studies have already addressed that increased levels primarily of ALT and triglycerides, and secondarily of GGT, appear to be the most sensitive biochemical markers of the presence of hepatic steatosis.30, 31, 32 However, these studies did not look at the relationship with between liver tests and visceral fat, as is the case in this study. In our population the relationships of waist, WHR, VAT, HOMA-IR and HDL-C were also consistently stronger with ALT and GGT as compared with AST and ALP. After correction for hs-CRP the relationships of the different liver tests with VAT were no longer significant, except for GGT. In an attempt to determine the relationship between liver tests and visceral fat as assessed by CT-scan, we found higher levels of AST, ALT, ALP and GGT in subjects with higher levels of VAT when compared with subjects with lower levels of VAT independent of BMI and reported increasing levels of ALT by increasing visceral fat. Findings of Stranges et al,33 also support a role for central adiposity independent from BMI in predicting increased levels of hepatic enzymes, in this study abdominal height was used to assess visceral fat accumulation instead of CT-scan. Eguchi et al,5 reported that severity of fatty liver, evaluated by ultrasonography and CT, was positively correlated with VAT (evaluated by abdominal CT) and insulin resistance in both obese and non-obese subjects, thus suggesting that hepatic fatty infiltration in NAFLD may be influenced by visceral fat accumulation regardless of BMI. This conclusion was based on the relationship between fatty liver and VAT on one hand and an association between fatty liver and biochemical data and HOMA-IR on the other hand. In contrast to Eguchi's5 approach, we looked directly at the relationship between VAT and biochemical data.
Analyzing different levels of ALT and GGT and their possible relationship with VAT, hs-CRP, triglycerides and HOMA-IR showed a subtle difference between normal levels and borderline levels of ALT and GGT. This supports the suggestion of Prati et al34 to lower the ALT threshold in the evaluation of persons with specific risk factors for fatty liver, because this would allow earlier recognition of risk and appropriate counseling. We found that the amount of VAT was significantly higher in subjects with borderline normal levels of ALT. These subjects were also more insulin resistant and showed lower HDL-C levels, suggesting the presence of the metabolic syndrome phenotype. We found no significant difference in hs-CRP values between the different categories in accordance with the findings of Prati et al.34
Multiple regression analyses shows that in this study each liver test has its own most important independent determinant(s). For AST this was VAT, for ALT and ALP this was HOMA-IR, for GGT this was triglycerides. Adding hs-CRP to the model showed that besides the metabolic and anthropometric variables, inflammation has an important influence except for GGT were triglycerides and VAT remain the most important determinants. Elevations of liver enzymes are often associated with higher hs-CRP concentrations. Hepatic inflammation secondary to liver steatosis is a potential contributor to the low-grade inflammation associated with the metabolic syndrome.35 Targher et al.36 showed that in non-smoking and non-diabetic men the significant increase of plasma biomarkers of inflammation and endothelial dysfunction in the presence of non-alcoholic hepatic steatosis is largely mediated by abdominal visceral fat accumulation.
In this analysis also HOMA-IR is a determinant for almost every liver test, except for AST. Insulin resistance and hyperinsulinemia may have a role in the development of hepatic steatosis, perceived to be the first stage in the pathogenesis of NASH. Insulin resistance may lead to increased mobilization of fatty acids from adipocytes with greater uptake by the liver. Higher concentrations of intracellular fatty acids may be directly toxic to hepatocytes or may enhance oxidative stress, which may be the second stage in the pathogenesis of NASH leading to inflammation and fibrosis.37 In addition to insulin resistance, systemic inflammation is also of key importance for inducing NAFLD, particularly in apparently healthy non-obese men.38 Very recently van der Poorten et al.39 showed that visceral fat is directly associated with liver inflammation and fibrosis independent of insulin resistance and hepatic steatosis. It has been proposed that the increase in circulating hs-CRP levels could be itself a marker for the presence or absence of NAFLD or of NASH in patients. Our results too show an important role for inflammation, as determined by hs-CRP. Another study, however, indicated that plasma hs-CRP levels are elevated in severely obese patients independent of the presence or absence of metabolic syndrome, diabetes or NASH. This same study therefore stated that plasma hs-CRP levels are not predictive of the diagnosis of NASH in severely obese patients (BMI >40). The liver but also adipose tissue can produce hs-CRP, therefore both tissues might contribute to the elevated plasma hs-CRP levels found in obesity. The large amount of body fat may well produce an important part of the circulating hs-CRP, further limiting its clinical usefulness in the evaluation of NASH in severely obese patients.15, 16, 17 The relationship found between certain liver tests and hs-CRP can therefore be influenced by the visceral fat present in our overweight and obese subjects, and not be associated in the way we would expect. This might explain the inverse relationship found between hs-CRP and AST, and ALT, in the multivariate analyses.
Despite some limitations (no data on viral or autoimmune hepatitis, hemocromatosis, Wilson's disease, α1-antitrypsin deficiency, primary biliary cirrhosis and drug-induced liver disease), we assume that the elevated concentrations of liver enzymes were most likely due to NAFLD. The well-known difficulties in verifying alcohol intake may also limit the reliability of this variable in the context of large epidemiological studies. As we used rather strict criteria for alcohol consumption, we assume that the liver disturbances in our patient group were minimally influenced by alcohol. Another limitation was the inability to evaluate the severity of liver injury, as would be possible in histological studies. On the other hand, histological diagnoses are not feasible in population-based studies, in which most participants are asymptomatic and have no need for liver biopsy. The fact that our sample population was 90% female limits the generalizability of the study results to men.
In conclusion, the results from this preliminary study suggest a plausable relationship between visceral fat accumulation and liver tests, especially ALT and GGT in overweight and obese subjects. It could be hypothesized that there is a link between central obesity with subsequent insulin resistance and liver affection leading to increased hepatic steatosis.
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This work is part of the project ‘Hepatic and adipose tissue and functions in the metabolic syndrome’ (HEPADIP), which is supported by the European Commission as an Integrated Project under the 6th Framework Programme (Contract LSHM-CT-2005–018734).
The authors declare no conflict of interest.
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Verrijken, A., Francque, S., Mertens, I. et al. Visceral adipose tissue and inflammation correlate with elevated liver tests in a cohort of overweight and obese patients. Int J Obes 34, 899–907 (2010). https://doi.org/10.1038/ijo.2010.4
- visceral adipose tissue
- liver tests
- C-reactive protein
- non-alcoholic fatty liver disease
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