Joint Effect of Hepatic Steatosis and Alanine Aminotransferase Within the Normal Range on Incident Ischemic Heart Disease: A Prospective Study in Koreans

Figures & data

Figure 1 Flowchart for the selection of study participants.

Table 1 Baseline Characteristics of the Study Population

Variables	Overall (n=16,541)			Group 1	Group 2	Group 3	Group 4	P value*
				Control of ALT (n = 10,700)	Elevated ALT (n=1,100)	Control of ALT + Hepatic Steatosis (n=3,573)	Elevated ALT + Hepatic Steatosis (n=1,168)		Post Hoc**
Age (years)	45.5 ± 10.7		44.3 ± 10.8		45.6 ± 10.5	48.0 ± 10.2	47.9 ± 9.9	< 0.001	a,b,c,d,e
Male sex (%)	48.8		41.6		41.1	69.1	60.5	< 0.001	–
BMI (kg/m^2)	23.1 ± 2.9		22.2 ± 2.6		23.1 ± 2.9	25.0 ± 2.6	25.7 ± 2.8	< 0.001	a,b,c,d,e,f
Systolic BP (mmHg)	121.2 ± 15.4		118.8 ± 15.0		121.2 ± 15.6	126.7 ± 14.7	128.3 ± 14.7	< 0.001	a,b,c,d,e,f
Diastolic BP (mmHg)	75.7 ± 10.1		74.0 ± 9.8		75.4 ± 10.0	79.3 ± 9.6	80.3 ± 9.7	< 0.001	a,b,c,d,e,f
AST (IU/L)	19.6 ± 4.9		18.4 ± 4.0		26.0 ± 5.9	19.5 ± 4.1	25.1 ± 5.4	< 0.001	a,b,c,d,e,f
ALT (IU/L)	18.6 ± 7.4		15.5 ± 5.0		30.5 ± 4.9	19.8 ± 5.4	32.3 ± 4.5	< 0.001	a,b,c,d,e,f
GGT (IU/L)	26.7 ± 23.8		21.7 ± 17.3		40.7 ± 39.2	31.5 ± 22.7	45.0 ± 37.9	< 0.001	a,b,c,d,e,f
FPG (mg/dl)	91.0 ± 9.7		89.3 ± 8.9		90.1 ± 9.9	94.6 ± 9.8	96.1 ± 10.8	< 0.001	a,b,c,d,e,f
Total cholesterol (mg/dl)	188.1 ± 33.0		183.5 ± 31.6		190.2 ± 33.9	196.1 ± 33.2	203.9 ± 34.3	< 0.001	a,b,c,d,e,f
Triglyceride (mg/dl)	117.5 ± 78.0		98.6 ± 51.9		117.7 ± 77.1	156.7 ± 104.1	171.4 ± 109.2	< 0.001	a,b,c,d,e,f
HDL-C (mg/dl)	54.0 ± 12.7		56.5 ± 12.7		55.3 ± 13.7	48.0 ± 10.3	47.9 ± 10.3	< 0.001	a,b,c,d,e
hsCRP (mg/L)	1.3 ± 3.3		1.1 ± 2.7		1.4 ± 4.3	1.6 ± 3.6	2.0 ± 5.7	< 0.001	a,b,c,e,f
Current smoker (%)	23.1		20.5		25.7	28.5	28.6	< 0.001	-
Alcohol drinking (%) ***	42.7		41.5		39.8	46.9	43.8	< 0.001	-
Regular exercise (%) ^#	32.0		32.6		30.6	31.1	30.2	0.151	-
Hypertension (%)	20.4		15.3		20.6	30.1	37.1	< 0.001	-
Hepatic steatosis severity ^##	0.5 ± 1.0		0.0 ± 0.0		0.0 ± 0.0	1.6 ± 1.0	2.2 ± 1.3	< 0.001	b,c,d,e,f
NAFLD by HSI score (%)	14.0	4.2			27.3	23.8	60.5	< 0.001	-

Notes: *P values were calculated using 1-way ANOVA test or Pearson’s chi-square test; **Post hoc analysis with Bonferroni method for mean difference between groups: ^aGroup 1 versus Group 2; ^bGroup 1 versus Group 3, ^cGroup 1 versus Group 4; ^dGroup 2 versus Group 3; ^eGroup 2 versus Group 4, and ^fGroup 3 versus Group 4; ***Alcohol intake ≥ 140 g/week; ^#Moderate intensity physical exercise ≥ three times/week; ^##Average grade of hepatic steatosis via ultrasound.

Abbreviations: BMI, body mass index; BP, blood pressure; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, γ-glutamyltransferase; FPG, fasting plasma glucose; HDL-C, high density-lipoprotein cholesterol; hsCRP, high sensitivity C-reactive protein; NAFLD, nonalcoholic fatty liver disease; HSI, hepatic steatosis index.

Figure 2 Kaplan–Meier plots indicating the cumulative probability of being diagnosed with ischemic heart disease after the baseline survey.

Table 2 Hazard Ratios and 95% Confidence Intervals for New-Onset Ischemic Heart Diseases

		Group 1	Group 2	Group 3	Group 4	P for Trend
		Control of ALT	Elevated ALT	Control of ALT + Hepatic Steatosis	Elevated ALT + Hepatic Steatosis
New cases of ischemic heart disease, n		180	30	109	49
Mean follow-up, years		2.4 ± 1.1	2.4 ± 1.0	2.3 ± 1.1	2.3 ± 1.1
Pearson-years of follow-up		25,435	2,635	8,226	2,638
Incidence rate/1000 person -years		7.0	11.4	13.3	18.6
Model 1	HR (95% CI)	1.00 (reference)	1.64 (1.11–2.42)	1.36 (1.07–1.74)	2.13 (1.55–2.92)	< 0.001
Model 2	HR (95% CI)	1.00 (reference)	1.61 (1.07–2.42)	1.23 (0.93–1.61)	1.81 (1.27–2.59)	0.003
Model 3	HR (95% CI)	1.00 (reference)	1.59 (1.05–2.41)	1.14 (0.86–1.50)	1.68 (1.16–2.42)	0.016

Notes: Model 1, adjusted for age and sex; Model 2, adjusted for age, sex, body mass index, smoking status, alcohol intake, and physical activity; Model 3, adjusted for age, sex, body mass index, smoking status, alcohol intake, physical activity, mean arterial blood pressure, fasting plasma glucose, high density-lipoprotein cholesterol, triglycerides, γ-glutamyltransferase, and high sensitivity C-reactive protein level.

Figure 3 Hazard ratios (95% CIs) for incident ischemic heart disease according to alanine aminotransferase and hepatic steatosis after adjusting for age, sex, body mass index, smoking status, alcohol intake, and physical activity.

Table 3 Hepatic Steatosis with ALT versus ALT Classification and NAFLD by HSI Score for Predicting Ischemic Heart Disease

	Pairwise Comparison of AUC			Ability to Classify IHD
	Difference	95% CI	P value	Sensitivity (%)	Specificity (%)	AUC	P value
Hepatic steatosis with ALT vs ALT classification	0.05	0.02 to 0.07	< 0.001
Hepatic steatosis with ALT vs NAFLD by HSI score	0.07	0.04 to 0.09	< 0.001
ALT classification vs NAFLD by HSI score	0.02	−0.01 to 0.04	0.201
Hepatic steatosis with ALT				51.1	65.1	0.587	< 0.001
ALT classification				21.5	86.5	0.540	< 0.001
NAFLD by HSI score				18.5	86.2	0.523	0.023

Abbreviations: ALT, alanine aminotransferase; NAFLD, nonalcoholic fatty liver disease; HSI, hepatic steatosis index; AUC, area under the receiver operating characteristic curve.

Figure 4 Joint effect of hepatic steatosis and elevated alanine aminotransferase for incident ischemic heart disease. *Age- and sex-adjusted Cox proportional hazards regression model analysis. **P value < 0.001.