Noninvasive fatty liver markers predict liver disease mortality in the U.S. population

Abstract

Nonalcoholic fatty liver disease (NAFLD) contributes to premature death along with obesity, diabetes, and cardiovascular disease (CVD). We examined whether hepatic steatosis (HS) on ultrasound and liver enzyme activities were associated with increased liver disease mortality in the U.S. National Health and Nutrition Examination Survey (NHANES), 1988-1994, with up to 23 years of linked-mortality data. Survey-linked National Death Index records were analyzed among 14,527 adult participants who were negative for viral hepatitis B and C and iron overload. HS on ultrasound was categorized as normal, mild, moderate, or severe. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) elevation was defined as the highest sex-specific decile. Cumulative mortality was 36.2% from all causes, including 16.3% from CVD, 10.8% from cancer, 5.4% from diabetes, and 1.1% from liver disease. Severe HS was associated with increased liver disease mortality in both age-adjusted (hazard ratio [HR]: 3.92; 95% confidence interval [CI]: 1.49-10.27; P for trend: 0.011) and multivariate-adjusted analyses (HR, 2.68; 95% CI: 1.02-7.03; P for trend: 0.072). HS was not independently associated with mortality from all causes, CVD, cancer, or diabetes. Higher liver disease mortality was found with elevated ALT (HR, 4.08; 95% CI: 1.99-8.33), AST (HR, 4.33; 95% CI: 2.18-8.59), and GGT (HR, 7.91; 95% CI: 3.06-20.46). GGT elevation was associated with increased overall mortality (HR, 1.45; 95% CI: 1.21-1.74). Liver enzymes were otherwise unrelated to overall or cause-specific mortality.

Conclusions: In the U.S. population, severe hepatic steatosis on ultrasound and liver enzyme elevation were associated with increased liver disease mortality, but were not independently associated with mortality from all causes (except for GGT), CVD, cancer, or diabetes.

Figure 1

Derivation of NHANES III sample for analysis of noninvasive fatty liver markers and mortality. NHANES III, third National Health and Nutrition Examination Survey; HBV sAg+, hepatic B virus surface antigen positive; HCV Ab+, hepatitis C virus antibody positive; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyltransferase.

Figure 2

(A) Multivariate-adjusted hazard ratios and 95% confidence intervals for all-cause mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (B) Multivariate-adjusted hazard ratios and 95% confidence intervals for cardiovascular disease mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (C) Multivariate-adjusted hazard ratios and 95% confidence intervals for cancer mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (D) Multivariate-adjusted hazard ratios and 95% confidence intervals for diabetes mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (E) Multivariate-adjusted hazard ratios and 95% confidence intervals for liver disease mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. Footnotes for Figure 2: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyltransferase. For hepatic steatosis, N=7,729 with normal liver and 1,657 with mild, 1,908 with moderate, and 922 with severe steatosis. For ALT, N=4,627 in deciles 1-3, 8,343 in deciles 4-9, and 1,462 in decile 10. Cut-points were 13 and 34 IU/L for men and 9 and 22 IU/L for women. For AST, N=4,375 in deciles 1-3, 8,428 in deciles 4-9, and 1,629 in decile 10. Cut-points were 18 and 30 IU/L for men and 15 and 26 IU/L for women. For GGT, N=9,804 in deciles 1-9 and 1,460 in decile 10. Cut-points were 58 IU/L for men and 40 IU/L for women. Hazard ratios were estimated using Cox proportional hazards regression analysis and adjusted for age, sex, race-ethnicity, education, alcohol intake, cigarette smoking, caffeine intake from beverages, physical activity, BMI, waist-to-hip ratio, diabetes, total and HDL cholesterol, systolic and diastolic blood pressure, C-reactive protein, and estimated glomerular filtration rate.

Figure 2

(A) Multivariate-adjusted hazard ratios and 95% confidence intervals for all-cause mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (B) Multivariate-adjusted hazard ratios and 95% confidence intervals for cardiovascular disease mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (C) Multivariate-adjusted hazard ratios and 95% confidence intervals for cancer mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (D) Multivariate-adjusted hazard ratios and 95% confidence intervals for diabetes mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (E) Multivariate-adjusted hazard ratios and 95% confidence intervals for liver disease mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. Footnotes for Figure 2: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyltransferase. For hepatic steatosis, N=7,729 with normal liver and 1,657 with mild, 1,908 with moderate, and 922 with severe steatosis. For ALT, N=4,627 in deciles 1-3, 8,343 in deciles 4-9, and 1,462 in decile 10. Cut-points were 13 and 34 IU/L for men and 9 and 22 IU/L for women. For AST, N=4,375 in deciles 1-3, 8,428 in deciles 4-9, and 1,629 in decile 10. Cut-points were 18 and 30 IU/L for men and 15 and 26 IU/L for women. For GGT, N=9,804 in deciles 1-9 and 1,460 in decile 10. Cut-points were 58 IU/L for men and 40 IU/L for women. Hazard ratios were estimated using Cox proportional hazards regression analysis and adjusted for age, sex, race-ethnicity, education, alcohol intake, cigarette smoking, caffeine intake from beverages, physical activity, BMI, waist-to-hip ratio, diabetes, total and HDL cholesterol, systolic and diastolic blood pressure, C-reactive protein, and estimated glomerular filtration rate.

Figure 2

(A) Multivariate-adjusted hazard ratios and 95% confidence intervals for all-cause mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (B) Multivariate-adjusted hazard ratios and 95% confidence intervals for cardiovascular disease mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (C) Multivariate-adjusted hazard ratios and 95% confidence intervals for cancer mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (D) Multivariate-adjusted hazard ratios and 95% confidence intervals for diabetes mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (E) Multivariate-adjusted hazard ratios and 95% confidence intervals for liver disease mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. Footnotes for Figure 2: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyltransferase. For hepatic steatosis, N=7,729 with normal liver and 1,657 with mild, 1,908 with moderate, and 922 with severe steatosis. For ALT, N=4,627 in deciles 1-3, 8,343 in deciles 4-9, and 1,462 in decile 10. Cut-points were 13 and 34 IU/L for men and 9 and 22 IU/L for women. For AST, N=4,375 in deciles 1-3, 8,428 in deciles 4-9, and 1,629 in decile 10. Cut-points were 18 and 30 IU/L for men and 15 and 26 IU/L for women. For GGT, N=9,804 in deciles 1-9 and 1,460 in decile 10. Cut-points were 58 IU/L for men and 40 IU/L for women. Hazard ratios were estimated using Cox proportional hazards regression analysis and adjusted for age, sex, race-ethnicity, education, alcohol intake, cigarette smoking, caffeine intake from beverages, physical activity, BMI, waist-to-hip ratio, diabetes, total and HDL cholesterol, systolic and diastolic blood pressure, C-reactive protein, and estimated glomerular filtration rate.

Figure 2

(A) Multivariate-adjusted hazard ratios and 95% confidence intervals for all-cause mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (B) Multivariate-adjusted hazard ratios and 95% confidence intervals for cardiovascular disease mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (C) Multivariate-adjusted hazard ratios and 95% confidence intervals for cancer mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (D) Multivariate-adjusted hazard ratios and 95% confidence intervals for diabetes mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (E) Multivariate-adjusted hazard ratios and 95% confidence intervals for liver disease mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. Footnotes for Figure 2: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyltransferase. For hepatic steatosis, N=7,729 with normal liver and 1,657 with mild, 1,908 with moderate, and 922 with severe steatosis. For ALT, N=4,627 in deciles 1-3, 8,343 in deciles 4-9, and 1,462 in decile 10. Cut-points were 13 and 34 IU/L for men and 9 and 22 IU/L for women. For AST, N=4,375 in deciles 1-3, 8,428 in deciles 4-9, and 1,629 in decile 10. Cut-points were 18 and 30 IU/L for men and 15 and 26 IU/L for women. For GGT, N=9,804 in deciles 1-9 and 1,460 in decile 10. Cut-points were 58 IU/L for men and 40 IU/L for women. Hazard ratios were estimated using Cox proportional hazards regression analysis and adjusted for age, sex, race-ethnicity, education, alcohol intake, cigarette smoking, caffeine intake from beverages, physical activity, BMI, waist-to-hip ratio, diabetes, total and HDL cholesterol, systolic and diastolic blood pressure, C-reactive protein, and estimated glomerular filtration rate.

Figure 2

(A) Multivariate-adjusted hazard ratios and 95% confidence intervals for all-cause mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (B) Multivariate-adjusted hazard ratios and 95% confidence intervals for cardiovascular disease mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (C) Multivariate-adjusted hazard ratios and 95% confidence intervals for cancer mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (D) Multivariate-adjusted hazard ratios and 95% confidence intervals for diabetes mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. (E) Multivariate-adjusted hazard ratios and 95% confidence intervals for liver disease mortality by category of hepatic steatosis on ultrasound or AST, ALT or GGT decile, United States, 1988-2011. Footnotes for Figure 2: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyltransferase. For hepatic steatosis, N=7,729 with normal liver and 1,657 with mild, 1,908 with moderate, and 922 with severe steatosis. For ALT, N=4,627 in deciles 1-3, 8,343 in deciles 4-9, and 1,462 in decile 10. Cut-points were 13 and 34 IU/L for men and 9 and 22 IU/L for women. For AST, N=4,375 in deciles 1-3, 8,428 in deciles 4-9, and 1,629 in decile 10. Cut-points were 18 and 30 IU/L for men and 15 and 26 IU/L for women. For GGT, N=9,804 in deciles 1-9 and 1,460 in decile 10. Cut-points were 58 IU/L for men and 40 IU/L for women. Hazard ratios were estimated using Cox proportional hazards regression analysis and adjusted for age, sex, race-ethnicity, education, alcohol intake, cigarette smoking, caffeine intake from beverages, physical activity, BMI, waist-to-hip ratio, diabetes, total and HDL cholesterol, systolic and diastolic blood pressure, C-reactive protein, and estimated glomerular filtration rate.

Figure 3

Hazard ratios and 95% confidence intervals for the relationship of hepatic steatosis on ultrasound with all-cause, cardiovascular disease, or liver disease mortality adjusted for risk factors, United States, 1988-2011 (N=11,715). WHR, waist-to-hip ratio; HDL, high-density lipoprotein. Hepatic steatosis was included in models as an ordinal variable with 4 levels, i.e., normal, mild, moderate, and severe. Hazard ratios were estimated using Cox proportional hazards regression analysis. Multivariate-adjusted hazard ratios were adjusted for age, sex, race-ethnicity, education, alcohol intake, cigarette smoking, caffeine intake from beverages, physical activity, BMI, waist-to-hip ratio, diabetes, total and HDL cholesterol, systolic and diastolic blood pressure, and C-reactive protein.