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Hepatic Fibrosis Associates With Multiple Cardiometabolic Disease Risk Factors: The Framingham Heart Study
  Hepatology Feb 6 2021 - Michelle T. Long ,1 Xiaoyu Zhang,2 Hanfei Xu,2 Ching-Ti Liu ,2 Kathleen E. Corey ,3 Raymond T. Chung,3 Rohit Loomba ,4 and Emelia J. Benjamin
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We used VCTE (Fibroscan; Echosens, Paris, France) performed by a certified operator to obtain measurements of liver fat (controlled attenuation parameter [CAP]) and liver fibrosis (liver stiffness measurement [LSM]). Participants fasted for >3 hours before examination.
In this large community-based sample of middle-aged and older adults unselected for liver disease, we observed that 8.8% of participants, a substantial minority, exceeded the threshold of potentially clinically significant hepatic fibrosis, defined by LSM ≥ 8.2 kPa. Hepatic fibrosis was associated with multiple obesity-related, glucose-related, vascular-related, and cholesterol-related traits; however, most associations were confounded, at least in part, by general adiposity or hepatic steatosis because the associations were mostly attenuated when BMI or CAP was added to the multivariable model. Notably, hepatic fibrosis remained significantly associated with obesity-related traits, hypertension, low HDL cholesterol, and, most strongly, with diabetes, with 2.5 times increased odds, even after accounting for CAP, which suggests an association between hepatic fibrosis and cardiometabolic disease in addition too the association with hepatic steatosis. Hepatic fibrosis is associated with obesity traits, diabetes, hypertension, and low HDL cholesterol and occurs in approximately 10% of adults in an unselected, community-based sample. Our findings may have implications for screening strategies and also highlight the importance of evaluating for cardiometabolic disease in patients with hepatic fibrosis. Other noninvasive imaging modalities, such as magnetic resonance elastography, are more accurate compared with VCTE(48); however, we choose to perform VCTE because of the lower cost and point-of-care availability. Our study is cross-sectional; we cannot rule out residual confounding or establish causal relations. We examined multiple associations and did not account for multiple testing, and so some of our associations may be falsely positive.
The average BMI was 28.3 ± 5.6 kg/m2, and 32.3% of the sample was obese. A total of 977 participants (28.8%) had hepatic steatosis, regardless of fibrosis stage, and 23.7% overall had hepatic steatosis without advanced fibrosis (CAP ≥ 290 dB/m and LSM < 8.2 kPa). A total of 289 participants, 8.8% of the sample, had LSM ≥ 8.2 kPa consistent with clinically significant fibrosis, and 54 individuals (1.6%) had LSM > 13.6 kPa, consistent with cirrhosis. The prevalence of hepatic fibrosis was 15.7% among participants with obesity and 27.5% among participants with diabetes (Fig. 1).
Correlations Between Hepatic Fibrosis and Cardiometabolic Traits
Hepatic fibrosis, as measured by LSM, demonstrated low-to-moderate correlations with all cardiometabolic variables (Table 2). Higher LSM correlated with higher BMI, waist circumference, CAP, log-ALT, log-AST, fasting glucose, log-hgbA1c, SBP, DBP, and log-triglycerides and lower total cholesterol and HDL cholesterol (P < 0.01 for all). We also observed moderate correlations between BMI and CAP in women and men (0.611 for women, 0.594 for men, 0.610 overall; P < 0.001 for all).
Multivariable-Adjusted Associations Between Hepatic Fibrosis and Dichotomous Cardiometabolic Risk Factors
Hepatic fibrosis (as both a continuous and dichotomous measure) was significantly associated with all dichotomous obesity-related and liver-related traits (Table 4; Fig. 2). Participants with hepatic fibrosis (LSM ≥ 8.2 kPa) had about 3 times the odds of obesity (OR, 3.11; 95% CI, 2.42-4.00), hepatic steatosis (OR, 3.66; 95% CI, 2.84-4.71), severe hepatic steatosis (OR, 3.43; 95% CI, 2.67-4.41), and metabolic syndrome (OR, 2.80; 95% CI, 2.17-3.61) compared with those with LSM < 8.2 kPa. Adjustment for CAP or BMI attenuated the effects; however, LSM ≥ 8.2 kPa continued to be significantly associated with 1.5-2 times increased odds of the obesity-related and liver disease–related traits (Fig. 2).
Background and Aims

NAFLD is increasing in prevalence and will soon be the most common chronic liver disease. Liver stiffness, as assessed by vibration-controlled transient elastography (VCTE), correlates with hepatic fibrosis, an important predictor of liver-related and all-cause mortality. Although liver fat is associated with cardiovascular risk factors, the association between hepatic fibrosis and cardiovascular risk factors is less clear.
Approach and Results
We performed VCTE, assessing controlled attenuation parameter (CAP; measure of steatosis) and liver stiffness measurement (LSM) in 3,276 Framingham Heart Study adult participants (53.9% women, mean age 54.3 ± 9.1 years) presenting for a routine study visit. We performed multivariable-adjusted logistic regression models to determine the association between LSM and obesity-related, vascular-related, glucose-related, and cholesterol-related cardiovascular risk factors.
The prevalence of hepatic steatosis (CAP ≥ 290 dB/m) was 28.8%, and 8.8% had hepatic fibrosis (LSM ≥ 8.2 kPa). Hepatic fibrosis was associated with multiple cardiovascular risk factors, including increased odds of obesity (OR, 1.82; 95% CI, 1.35-2.47), metabolic syndrome (OR, 1.49; 95% CI 1.10-2.01), diabetes (OR, 2.67; 95% CI, 1.21-3.75), hypertension (OR, 1.52; 95% CI, 1.15-1.99), and low high-density lipoprotein cholesterol (OR, 1.47; 95% CI, 1.09-1.98), after adjustment for age, sex, smoking status, alcohol drinks/week, physical activity index, aminotransferases, and CAP.
In our community-based cohort, VCTE-defined hepatic fibrosis was associated with multiple cardiovascular risk factors, including obesity, metabolic syndrome, diabetes, hypertension, and high-density lipoprotein cholesterol, even after accounting for covariates and CAP. Additional longitudinal studies are needed to determine if hepatic fibrosis contributes to incident cardiovascular disease risk factors or events. Multivariable-Adjusted Associations Between Hepatic Fibrosis and Continuous
Cardiometabolic Risk Factors
Hepatic fibrosis (as both a continuous and dichotomous measure) was significantly associated with all obesity-related, liver-related, glucose-related, vascular-related, and cholesterol-related continuous cardiometabolic traits (Table 3). Hepatic fibrosis (LSM ≥ 8.2) was associated with higher BMI, higher waist circumference, higher CAP, higher log-ALT and log-AST, higher fasting glucose, higher log-hgbA1c, higher SBP and DBP, higher log-triglycerides, lower total cholesterol, and lower HDL cholesterol compared with those without hepatic fibrosis. After additionally adjusting for BMI or CAP, most of the associations with hepatic fibrosis were attenuated; however, for total cholesterol, the negative association with hepatic fibrosis was stronger after additionally adjusting for BMI or CAP. Hepatic fibrosis (LSM ≥ 8.2) was no longer associated with DBP or log-triglycerides in CAP-adjusted models.

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