Hepatic Steatosis, Obesity and the Metabolic Syndrome Are Independently and Additively Associated With Increased Systemic Inflammation

Abstract

Objective

To assess the independent and collective associations of hepatic steatosis, obesity, and the metabolic syndrome with elevated high-sensitivity CRP (hs-CRP) levels.

Methods and Results

We evaluated 2,388 individuals without clinical cardiovascular disease between December 2004 and December 2006. Hepatic steatosis was diagnosed by ultrasound, and the metabolic syndrome was defined using NHLBI criteria. The cutpoint of ≥ 3 mg/L was used to define “high” hs-CRP. Multivariate logistic regression was used to assess the independent and collective associations of hepatic steatosis, obesity, and the metabolic syndrome with high hs-CRP. Steatosis was detected in 32% of participants, 23% met criteria for metabolic syndrome, and 17% of individuals were obese. After multivariate regression, hepatic steatosis (OR 2.07; 95% CI: 1.68-2.56), obesity (OR 3.00; 95% CI: 2.39-3.80), and the metabolic syndrome (2.39; 95% CI: 1.88-3.04) were all independently associated with high hs-CRP. Combinations of these factors were associated with an additive increase in the odds of high hs-CRP, with individuals with 1, 2, and 3 factors having ORs for high hs-CRP of 1.92 (1.49-2.48), 3.38 (2.50-4.57) and 4.53 (3.23-6.35), respectively.

Conclusion

Hepatic steatosis, obesity, and the metabolic syndrome are independently and additively associated with increased odds of high hs-CRP levels.

There is growing evidence that hepatic steatosis is associated with increased cardiovascular disease (CVD) risk. Hepatic steatosis has been associated with a greater degree of subclinical atherosclerosis among asymptomatic men¹. In cross-sectional epidemiologic studies, hepatic steatosis has also been associated with an increased prevalence of CVD, independent of traditional risk factors². Elevations of serum levels of liver enzymes have been shown to independently predict future CVD in prospective epidemiologic studies³. Furthermore, in a case control study of 2,103 patients with type II diabetes mellitus, hepatic steatosis diagnosed by ultrasound was associated with an increased risk of future CVD, despite adjustment for obesity, components of the metabolic syndrome and other traditional cardiovascular risk factors⁴. However, the mechanisms underlying the relationship between hepatic steatosis and CVD remain unclear.

One mechanism that may explain part of the link between hepatic steatosis and CVD is chronic inflammation. Inflammation is central to all stages of atherosclerosis, including fatty streak development, formation of the atherosclerotic plaque, and plaque rupture with associated thrombosis⁵. Circulating markers of systemic inflammation, measured in the serum, have been shown to predict future cardiovascular disease in apparently healthy individuals⁶. Of these, Creactive protein (CRP) is the most reliable and robust predictor of adverse cardiovascular outcomes⁷. Elevated levels of CRP, measured in asymptomatic individuals, are strongly and independently predictive of the future development of peripheral artery disease, stroke, and myocardial infarction^7-9.

In patients with non-alcoholic fatty liver disease (NAFLD), the progression from simple steatosis to steatohepatitis and cirrhosis is characterized by cellular injury from oxidative stress and cytokine-driven intra-hepatic inflammation¹⁰. Some studies have suggested that the intra-hepatic inflammation associated with NAFLD may also be linked to systemic elevations in inflammatory biomarkers, such as CRP^11-13. However, previous studies investigating the relationship between hepatic steatosis and systemic inflammation have either been relatively small, have used select patient populations, or have used abnormal liver function tests, a much less sensitive marker of steatosis than abdominal imaging¹⁴.

Hepatic steatosis is also closely linked with obesity and the metabolic syndrome¹⁵, which are both well established as pro-inflammatory conditions. It is therefore important to assess the independent relationship between hepatic steatosis and systemic inflammatory markers, and to determine the collective impact of combinations of these conditions on systemic inflammation. In this cross-sectional study of a large, community-based cohort of diabetic and non-diabetic men and women, we investigated the relationship between hepatic steatosis, as identified by ultrasound, and systemic levels of CRP, measured with a high-sensitivity assay (hs-CRP). We further sought to assess the independent and collective associations of hepatic steatosis, obesity and the metabolic syndrome with systemic inflammation.

METHODS

We evaluated a group of asymptomatic men and women, free of coronary heart disease, who submitted to an obligatory clinical and laboratory health evaluation paid for by their employers from December 2004 to December 2006 at the Preventive Medicine Center of the Albert Einstein Hospital in São Paulo, Brazil. The exam protocol consisted of a clinical consultation, laboratory evaluation and an ultrasonographic abdominal scan. All individuals provided details of their demographics, medical history, quantitative alcohol consumption, smoking status and medication usage at the time of their clinical consultation. We included all individuals for whom full information was available for all of the covariates of interest. We excluded individuals with a known history of liver disease from this analysis, as well as those individuals drinking over 20 grams of alcohol per day.

Information regarding medical history was obtained via questionnaire. Smoking status was defined as current smoker versus current non-smoker. Diabetes was identified by previous physician diagnosis or by the use of glucose lowering medication. Hypertension and dyslipidemia were ascertained by a previous history of these conditions or the use of blood pressure or lipid lowering medications; those individuals with systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg at the clinical evaluation were also labeled as having hypertension. During physical examinations, blood pressure was measured with a mercury sphygmomanometer using the method recommended by the American Heart Association¹⁶. Waist circumference was measured at the smallest diameter between the iliac crest and the costal margin using a plastic anthropometric tape held parallel to the floor.

Blood specimens were collected after an overnight fast. Plasma lipid, glucose and liver transaminase levels were measured by standardized automated laboratory tests using a Vitros platform (Johnson & Johnson Clinical Diagnostics). Alanine aminotranferase (ALT) levels were considered elevated if concentrations were greater than the 90^th distribution percentile for the population according to gender. High-sensitivity CRP (hs-CRP) levels were determined by immuno-nephelometry (Dade-Behring, US). The previously established cutpoint of > 3mg/L, a level associated with increased cardiovascular risk in prospective studies, was used to define “high” hs-CRP levels in our analysis. All tests were performed at the Central Laboratory of the Albert Einstein Hospital.

Hepatic steatosis was diagnosed after at least a 6 hour fast using an ACUSON XP-10 device (Mountain View, CA,USA), and was identified by the presence of an ultrasonographic pattern of a bright liver, with evident contrast between hepatic and renal parenchyma, as has been previously described¹⁷. All hepatic ultrasounds were read by board certified radiologists. Obesity was defined as a body mass index of greater than 30 kg/m². The metabolic syndrome was defined using criteria from the AHA/NHLBI scientific statement on the metabolic syndrome¹⁸. Patients with ≥ 3 of the following metabolic risk factors were determined to have the metabolic syndrome: truncal obesity (≥ 102 cm or 40 inches for men, and ≥ 88 cm or 36 inches for women), high blood pressure (blood pressure ≥ 130/85mmHg, or the use of antihypertensive medications), hyperglycemia (fasting blood glucose ≥100 mg/dl), low HDL-C (≤ 40mg/dl for men, and ≤ 50 mg/dL for women), and hypertriglyceridemia (≥ 150mg/dl). This study was approved by the local IRB and a waiver for informed consent was obtained.

Baseline characteristics of individuals with and without hepatic steatosis were compared using Wilcoxon’s t test for continuous variables and the Pearson’s chi squared test for categorical variables. Because of the skewed distribution of hs-CRP, median values of hs-CRP were used in comparisons of groups of individuals with and without hepatic steatosis, elevated ALT, obesity and the metabolic syndrome, using the nonparametric Kruskal Wallis test. In multivariate linear regression analyses, we assessed the associations of hepatic steatosis, elevated ALT, obesity and the metabolic syndrome with continuous levels of natural log-transformed hs-CRP (ln hs-CRP). Multivariate logistic regression was used to evaluate associations of hepatic steatosis, elevated ALT, obesity and the metabolic syndrome with hs-CRP levels > 3 mg/L (“high” hs-CRP). For all regression analyses, a hierarchical model approach was utilized, adjusting first for traditional risk factors (age, gender, diabetes mellitus, LDL-C, lipid lowering therapy, smoking, and physical activity), and then simultaneously adjusting for other independent predictors of hs-CRP levels in the multivariate model. Sub-analysis testing was performed to estimate the odds of high hs-CRP associated with hepatic steatosis among those with and without other independent predictors of high hs-CRP. To assess the combined effects of hepatic steatosis, obesity and the metabolic syndrome on systemic inflammation, multivariate logistic regression was utilized to assess the effect of having any one, two or all three of these conditions on the odds of having a high hs-CRP level. All statistical analyses were performed using STATA version 9.

RESULTS

Twenty individuals were excluded from the analysis for missing covariates of interest, sixty-one individuals for positive hepatitis serologies, and ten individuals for alcohol use of ≥20 grams per day, leaving a study population of 2,388 individuals. The characteristics of the study population, stratified by the presence or absence of hepatic steatosis, are displayed in Table 1. In our study population, hepatic steatosis was detected in 32% of study participants. Participants with hepatic steatosis were older (46 vs 43 years, p<0.0001) and much more likely to be male (94 vs 72%, p<0.0001) than those without steatosis. Hepatic steatosis was also associated with a worse risk factor profile: individuals with hepatic steatosis had higher systolic blood pressure, LDL-C, triglycerides, fasting glucose, BMI and waist circumference, and lower HDL-C, than participants without steatosis. Hepatic steatosis was associated with a higher burden of diabetes (35% vs 12%, p<0.0001) and hypertension (24 vs 9%, p<0.0001), and increased use of medications to treat these conditions.

Table 1.

Baseline Characteristics of Study Population

Variables	Hepatic Steatosis Present (n=767)	Hepatic Steatosis Absent (n=1621)	P value
Age, in years (SD)	46±9	43±9	<0.0001
Percent Male	723 (94%)	1172 (72%)	<0.0001
Mean Systolic Blood Pressure, in mmHg (SD)	130±14	120±14	<0.0001
Percent with Hypertension	184 (24%)	146 (9%)	<0.0001
Mean LDL-C, in mg/dl (SD)	129±35	121±34	<0.0001
Mean HDL-C, in mg/dl (SD)	41±10	49±12	<0.0001
Median triglycerides, in mg/dl (Interquartile Range)	143 (106-196)	96 (73-128)	<0.0001
Mean Waist Circumference, in cm (SD)	100±11	87±12	<0.0001
Mean Fasting Glucose, in mg/dl (SD)	99±21	90±11	<0.0001
Percent with Diabetes Mellitus	267 (35%)	187 (12%)	<0.0001
Percent with Metabolic Syndrome	363 (47%)	178 (11%)	<0.0001
Mean BMI, in kg/m2 (SD)	29±4	25±4	<0.0001
Percent with Obesity (BMI≥ 30 Kg/m2)	288 (38%)	123 (8%)	<0.0001
Median ALT, in U/L (Interquartile Range)	51 (41-47)	40 (33-48)	0.0001
Median ALT/AST ratio (Interquartile Range)	1.76 (1.53-2.04)	1.54 (1.33-1.76)	0.0001
Median hs-CRP, in mg/L (Interquartile Range)	2.0 (1.1-3.8)	1.2 (0.6-2.4)	0.0001
Percent with high hs-CRP (≥3 mg/dl)	271 (35%)	326 (20%)	<0.0001
Percent Using Lipid Lowering Medications	75 (10%)	120 (7%)	0.048
Percent Using Anti-Hypertensive Medications	168 (22%)	130 (8%)	<0.0001
Percent Using Hypoglycemic Medications	28 (4%)	9 (0.6%)	<0.0001

Overall, those with hepatic steatosis were more likely to have the metabolic syndrome (47% vs. 11%, p<0.0001), obesity (38% vs. 8%, p<0.0001), and elevated ALT (19% vs. 6%, p<0.0001) than those without steatosis. The median (inter-quartile range) of hs-CRP was 2.0 mg/L (1.1-3.8 mg/dl) among those with hepatic steatosis as compared to 1.2 mg/L (0.6-2.5 mg/L) among those without steatosis (p=0.0001). In a similar fashion, higher hs-CRP levels were noted among those with high ALT versus normal ALT [1.9 mg/L (1.0-3.6 mg/L) vs. 1.4 mg/L (0.7-2.9 mg/dl), p=0.0002], among those with versus those without the metabolic syndrome [2.4 mg/L (1.2-4.2 mg/dl) vs. 1.3 mg/L (0.6-2.5 mg/L), p=0.0001], and among those with versus those without obesity [2.7 mg/L (1.5-4.4 mg/L) vs. 1.8 mg/dl (0.9-3.1 mg/L), p=0.0001]. As Figure 1 demonstrates, participants with steatosis, elevated ALT, the metabolic syndrome or obesity also had a higher prevalence of “high” hs-CRP levels (≥ 3 mg/L) than those without those conditions.

Figure 1.

Prevalence of High hs-CRP (≥ 3 mg/dl) Associated With High ALT, Hepatic Steatosis, the Metabolic Syndrome and Obesity.

Tables 2 and 3 compare the associations of hepatic steatosis, elevated ALT, the metabolic syndrome and obesity with hs-CRP, both as a continuous variable (ln hs-CRP) and as a categorical variable (“high” hs-CRP), in unadjusted and adjusted analysis. Hepatic steatosis, the metabolic syndrome, obesity, and elevated ALT were each associated with higher levels of ln hs-CRP after controlling for traditional cardiovascular risk factors, with obesity demonstrating the strongest association. After additionally adjusting for the other predictors of increased ln hs-CRP (obesity, elevated ALT, and metabolic syndrome components, including abdominal obesity) in our full regression model, the presence of hepatic steatosis was associated with an increase in ln hs-CRP of 0.24 (95% CI: 0.14-0.33), which corresponds to a 27% higher average hs-CRP level among those with hepatic steatosis. In our full regression model, the metabolic syndrome was also independently associated with an increase in ln hs-CRP of 0.24, and obesity was associated with an increase in ln hs-CRP of 0.42, or 52% higher average hs-CRP levels. Elevated ALT did not demonstrate an independent association with ln hs-CRP (table 2).

Table 2.

Comparison of Hepatic Steatosis, High ALT, MS & Obesity with Continuous ln hs-CRP in Multivariate Linear Regression Analyses

	High ALT	Hepatic Steatosis	Metabolic Syndrome	Obesity (BMI≥ 30 Kg/m2)
	B Coefficients (95% CI)	B Coefficients (95% CI)	B Coefficients (95% CI)	B Coefficients (95% CI)
Model 1*	0.27 (0.13, 0.41)	0.47 (0.37, 0.56)	0.57 (0.47, 0.67)	0.67 (0.56, 0.78)
Model 2†	0.23 (0.10, 0.37)	0.41 (0.32, 0.50)	0.50 (0.39, 0.61)	0.62 (0.51, 0.73)
Model 3‡	0.03 (-0.10, 0.16)	0.24 (0.14, 0.33)	0.24 (0.12, 0.36)	0.42 (0.31, 0.55)

^*Model 1: unadjusted

^†Model 2 variables: age, gender, presence of diabetes-mellitus, LDL-cholesterol, smoking status (current smoker or non-smoker), use of lipid lowering medication, and physical activity (assessed by the International Physical Activity Questionnaire as low, moderate or high physical activity)

^‡Model 3 variables: Model 2 variables + hepatic steatosis, high ALT, metabolic syndrome components (abdominal obesity, fasting hyperglycemia, low HDL, hypertriglyceridemia and hypertension/anti-hypertensive medication use) and obesity

Table 3.

Associations of High ALT, Hepatic Steatosis, Metabolic syndrome and Obesity with “High” CRP (≥3 mg/L) in Multivariate Logistic Regression Analyses.

	High ALT	Hepatic Steatosis	Metabolic Syndrome	Obesity (BMI ≥ 30kg/m2)
	Odds Ratio (95% CI)	Odds Ratio (95% CI)	Odds Ratio (95% CI)	Odds Ratio (95% CI)
Model 1*	1.56 (1.17-2.07)	2.17 (1.79-2.63)	2.64 (2.15-3.25)	3.23 (2.58-4.04)
Model 2†	1.50 (1.12-2.00)	2.07 (1.68-2.56)	2.39 (1.88-3.04)	3.00 (2.39-3.80)
Model 3‡	1.07 (0.84-1.34)	1.49 (1.18-1.88)	1.48 (1.12-1.94)	2.21 (1.70-2.89)

^*Model 1: unadjusted

^†Model 2 variables: age, gender, presence of diabetes-mellitus, LDL-cholesterol, smoking status (current smoker or non-smoker), use of lipid lowering medication, and physical activity (assessed by the International Physical Activity Questionnaire as low, moderate or high physical activity)

^‡Model 3 variables: Model 2 variables + hepatic steatosis, high ALT, metabolic syndrome components (abdominal obesity, fasting hyperglycemia, low HDL, hypertriglyceridemia and hypertension/anti-hypertensive medication use) and obesity

Similarly, after adjustment for traditional cardiovascular risk factors, independent associations with “high” hs-CRP levels were found for hepatic steatosis (OR 2.07; 95% CI: 1.68-2.56), the metabolic syndrome (OR 2.39; 95% CI: 1.88-3.04), obesity (OR 3.00; 95% CI: 2.39-3.80), and elevated ALT (OR 1.50; 95% CI: 1.12-2.00). However, these relationships were attenuated when all of the above predictors of increased hs-CRP were added to our regression model, with significant associations with high hs-CRP only remaining for hepatic steatosis (OR 1.49 [95% CI: 1.18-1.88]), the metabolic syndrome (OR 1.48 [95% CI: 1.12-1.94]) and obesity (OR 2.21 [95% CI: 1.70-2.89)) (Table 3). When using the metabolic syndrome criteria for abdominal obesity rather than the BMI-based definition of obesity, we found similar associations with ln hs-CRP 0.45 (0.34-0.57) and high hs-CRP (OR 2.36 [95% CI: 1.81-3.09]) in our full regression model.

In sub-analyses, we demonstrated that the presence of steatosis was associated with high hs-CRP levels among individuals with and without the metabolic syndrome, as well as among those with and without obesity, even after controlling for traditional cardiovascular risk factors. Among participants with the metabolic syndrome, the OR for high hs-CRP associated with hepatic steatosis was 1.83 (1.40-2.40), whereas the respective OR was 1.67 (1.13-2.46) in the absence of the metabolic syndrome. In a similar fashion, the ORs for high hs-CRP associated with steatosis were 1.61 (1.11-2.32) and 1.79 (1.21-2.65) among obese and non obese individuals, respectively. The interaction of gender and hepatic steatosis for high hs-CRP was not significant (p=0.80), indicating similar associations among men and women. In multivariate analyses, the association of hepatic steatosis with high hs-CRP was similar among individuals with high ALT (OR 1.53 [95% CI: 1.20-1.92]) and those without elevated liver enzymes (OR 1.52 [95% CI: 1.20-1.93]).

Since hepatic steatosis, the metabolic syndrome and obesity were independent predictors of elevated hs-CRP, we also assessed whether a combination of these factors was associated with a higher burden of inflammation. In our study, 58% of participants were unaffected by hepatic steatosis, the metabolic syndrome or obesity, whereas 22%, 12% and 9% had 1, 2 or all 3 of these independent predictors of increased hs-CRP. Among those with none of these independent predictors, elevated CRP was noted in only 17% of study participants. A linear increase in the likelihood of elevated hs-CRP was noted with increasing numbers of the above predictors, with 48% of those individuals with hepatic steatosis, obesity and the metabolic syndrome having high hs-CRP (Figure 2). After taking into account traditional risk factors, as compared to those with neither hepatic steatosis, the metabolic syndrome nor obesity, the likelihood of high hs-CRP increased from an OR of 1.9 with one of these conditions to an OR of 4.5 with the presence of all three predictors (Table 4).

Figure 2.

Prevalence of High hs-CRP (≥ 3 mg/dl) Associated With Combinations of Hepatic Steatosis, Metabolic Syndrome and Obesity. The presence of a greater number of factors was associated with a higher prevalence of elevated hs-CRP levels.

*Factors: Hepatic Steatosis, Metabolic Syndrome and Obesity

Table 4.

Associations of Combined Presence of Hepatic Steatosis, Metabolic Syndrome and Obesity with High hs-CRP (≥3 mg/L) in Multivariate Logistic Regression Analyses

Number of Conditions Present	Model 1* Odds Ratio (95% CI)	Model 2† Odds Ratio (95% CI)
None	Ref group‡	Ref group‡
1	1.80 (1.42-2.29)	1.92 (1.49-2.48)
2	3.29 (2.50-4.34)	3.38 (2.50-4.57)
3	4.44 (3.27-6.01)	4.53 (3.23-6.35)

^*Model 1: unadjusted

^†Model 2: adjusted for age, gender, diabetes mellitus, LDL-cholesterol, smoking status (current smoker or non-smoker), use of lipid lowering medication, and physical activity (assessed by the International Physical Activity Questionnaire as low, moderate or high physical activity)

^‡Reference Group: No hepatic steatosis, metabolic syndrome or obesity.

DISCUSSION

In this study of 2,388 diabetic and non-diabetic men and women without known CHD, we found a significant association between hepatic steatosis identified by ultrasound and elevated hs-CRP levels. Hepatic steatosis was associated with higher hs-CRP levels among obese and non-obese individuals, and among those with and without the metabolic syndrome. As expected, obesity and the metabolic syndrome were also independently associated with increased hs-CRP levels; after adjusting for these and other traditional risk factors, an independent association persisted between hepatic steatosis and elevated hs-CRP levels. The combined presence of hepatic steatosis, obesity and the metabolic syndrome was associated with an additive increase in the likelihood of high hs-CRP levels, with individuals with all three conditions having a 4.5 times higher odds of hs-CRP ≥ 3 mg/dl than those without any of them.

Our findings support the concept of an independent association between hepatic steatosis and systemic inflammation, beyond what is explained by the presence of obesity and the metabolic syndrome. This elevation in hs-CRP among patients with hepatic steatosis may serve as a marker of long term cardiovascular risk, and may explain some of the previously observed associations between hepatic steatosis and CVD. Some small studies have found a relationship between NAFLD and increased levels of inflammatory biomarkers. In one study of 77 patients, those with biopsy proven fatty liver disease had higher serum levels of the inflammatory cytokines CCL2/MCP-1 and CCL 19 than healthy controls, after adjusting for age, sex, and BMI¹¹. Similarly, in another study of 135 middle aged men, those with hepatic steatosis and steatohepatitis had higher levels of hs-CRP and other inflammatory biomarkers than age and obesity matched controls after multivariate regression analysis¹⁹. In a larger study of 1,740 individuals, abnormal liver function tests were associated with elevated hs-CRP independent of cardiometabolic risk factors¹². Additionally, in a study of 832 Chilean subjects, increased hs-CRP was one of the variables independently associated with ultrasound-diagnosed hepatic steatosis²⁰. This study extends these findings in a large, community-based cohort of middle-aged asymptomatic men and women, among whom hepatic steatosis was identified via abdominal imaging.

The epidemiologic association between hepatic steatosis and increased hs-CRP levels found in this study does not prove a causal relationship. However, excess triglyceride accumulation in hepatocytes is known to be associated with impaired fatty acid oxidation, increased oxidative stress, and local inflammation that can fuel a transition from simple steatosis to steatohepatitis¹⁰. It is also noteworthy that the liver is the primary source of CRP production, and previous studies indicate that the degree of hepatic steatosis and inflammation by histology correlates with systemic levels of inflammatory biomarkers. In one study of 85 patients, increasing grades of hepatic steatosis, necroinflammation, and fibrosis on biopsy samples were each associated with sequentially increasing hs-CRP levels, well into the “high risk” range¹³. Other studies have found a direct association between NAFLD severity and hepatocyte expression of inflammatory mediators²¹.

Abdominal obesity and the metabolic syndrome predispose to hepatic steatosis, both via increased delivery of free fatty acids to the liver and through increases in hepatic lipogenesis associated with hyperinsulinemia¹⁰. In turn, the worsening insulin resistance associated with hepatic steatosis may also exacerbate the metabolic syndrome. The close associations among hepatic steatosis, obesity, and cardiometabolic risk factors have led to the suggestion that hepatic steatosis may be a novel component of the metabolic syndrome²². However, even among patients with obesity and those with the metabolic syndrome as currently defined, the presence of hepatic steatosis in this study was associated with higher levels of hs-CRP. This suggests that in these already high risk populations, the finding of hepatic steatosis could be a marker for an even greater degree of systemic inflammation. Furthermore, combinations of hepatic steatosis, obesity and the metabolic syndrome were associated with an increasing likelihood of elevated hs-CRP in our analysis. Given their physiologic inter-relatedness, it is certainly conceivable that these conditions could be reinforcing each other in an inflammatory cascade that predisposes to increased cardiovascular risk.

This study has some limitations. While ultrasound is a very useful non-invasive tool for identifying hepatic steatosis, its sensitivity for detecting fatty changes within the liver is reduced when the steatosis is less than moderate in severity²³. Therefore, it is likely that some cases of hepatic steatosis, particularly of mild severity, were not detected in this cohort. Additionally, more direct measures of visceral adiposity, such as computed tomography, may be even more accurate than anthropometric measurements in assessing and controlling for the impact of abdominal obesity on inflammatory biomarkers. Because this is an observational study, there is always the possibility of residual bias. Finally, as this is a cohort of Brazilian men and women, the extent to which these findings can be generalized to other populations is unclear.

Strengths of the present study include a large number of participants from both genders, each of whom had undergone extensive cardiovascular risk factor assessment. This allowed for adjustment for potentially confounding risk factors in assessing the associations of hepatic steatosis, obesity and the metabolic syndrome with high hs-CRP levels. The broadly representative cohort also allowed for evaluation of the relationship between hepatic steatosis and hs-CRP within demographic and clinical subgroups. The use of abdominal imaging to identify steatosis is also a strength of this study, as abnormal liver function tests – which have been used in previous analyses – are known to have poor sensitivity for the detection of NAFLD¹⁴. Finally, our use of individuals without known CVD may help make this data most relevant, as hs-CRP measurement is most commonly performed as part of a primary prevention strategy.

In summary, this study demonstrated an association between hepatic steatosis and elevated hs-CRP levels among asymptomatic men and women, independent of obesity, the metabolic syndrome, and other cardiovascular risk factors. The combined presence of hepatic steatosis, obesity and the metabolic syndrome was associated with an additive increase in the odds of high hs-CRP. Additional research is needed to further elucidate the mechanisms underlying the interrelationships among hepatic steatosis, obesity, the metabolic syndrome and systemic inflammation, and to determine the impact of these associations on cardiovascular risk.