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Baseline characteristics were similar between the two groups according to the ABI category, except that those with PAD (ABI < 0.90 or > 1.40) were more likely to have higher levels of BMI and WBC than those with the normal range of ABI (0.90–1.40; Table 1). The mean ± SD values for NFS were −1.77 ± 1.13 for all the study patients at baseline, −1.69 ± 1.18 for those with an ABI of < 0.90 or > 1.40, and −1.78 ± 1.12 for those with the normal range of ABI.
Table 1. Baseline characteristics of NAFLD patients according to ABI category
Characteristics ABI P value 0.90–1.40 < 0.90 or > 1.40 Number 1,486 124 Age (years) 58.0 ± 8.0 57.5 ± 8.5 0.51 Men [n (%)] 453 (30.48) 43 (34.68) 0.33 Current smoker [n (%)] 221 (14.87) 21 (16.93) 0.52 Current drinker [n (%)] 40 (3.36) 5 (4.03) 0.39 Hypertension [n (%)] 1,111 (74.81) 85 (68.55) 0.13 Diabetes [n (%)] 494 (33.24) 40 (32.26) 0.82 Physical activity* (MET-h/week) 23.1 (0, 69.3) 23.1 (4.1, 74.2) 0.50 BMI (kg/m2) 27.4 ± 2.9 28.3 ± 3.3 0.002 WC (cm) 88.5 ± 7.6 89.5 ± 8.6 0.15 SBP (mmHg) 146.6 ± 18.9 145.1 ± 19.2 0.40 Diastolic blood pressure (mmHg) 85.7 ± 10.2 86.3 ± 10.6 0.56 Fasting plasma glucose (mmol/L) 6.08 ± 1.96 6.12 ± 2.24 0.81 Triglycerides* (mmol/L) 1.85 (1.35, 2.59) 1.99 (1.41, 2.66) 0.47 Total cholesterol (mmol/L) 5.52 ± 1.10 5.46 ± 1.05 0.59 HDL cholesterol (mmol/L) 1.21 ± 0.26 1.19 ± 0.29 0.37 LDL cholesterol (mmol/L) 3.32 ± 0.91 3.26 ± 0.85 0.44 Albumin (g/L) 49.13 ± 2.23 48.94 ± 2.50 0.35 ALT* (U/L) 23.1 (17.4, 33.3) 24.4 (17.5, 34.8) 0.66 AST* (U/L) 22.3 (19.0, 27.3) 22.5 (18.7, 27.1) 0.86 GGT* (U/L) 28 (20, 44) 31 (21, 41) 0.60 White blood cell (×109/L) 6.13 ± 1.47 6.55 ± 1.46 0.002 HOMA-IR* 2.62 (1.81, 3.84) 2.61 (1.82, 3.63) 0.90 NFS −1.78 ± 1.12 −1.69 ± 1.18 0.40 Note. Data are presented as mean ± SD, median (interquartile range), or number (percentage). P-values were calculated by one-way analysis of variance for continuous variables and chi-square test for categorical variables. *Variables were log-transformed before analysis. Abbreviations: ABI, ankle-brachial index; BMI, body mass index; WC, waist circumference; MET, metabolic equivalent; SBP; systolic blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase; HOMA-IR, homeostasis model assessment of insulin resistance; NAFLD, nonalcoholic fatty liver disease; NFS, NAFLD fibrosis score. -
Table 2 shows the association of PAD with the risk of fibrosis deterioration. The mean ± SD value for NFS at follow-up was −0.91 ± 1.12. Of all the 1,610 NAFLD patients at baseline, 618 (38%) patients developed fibrosis deterioration. When stratified by baseline NFS status, 494 patients progressed from low to intermediate or high and 124 from intermediate to high.
Table 2. Association of PAD with risk of fibrosis deterioration
Fibrosis deterioration PAD No. events / participants Model 1 Model 2 Model 3 OR (95% CI) P OR (95% CI) P OR (95% CI) P Total No 561/1,486 1.00 0.01 1.00 0.003 1.00 0.003 Yes 57/124 1.69 (1.12, 2.56) 1.93 (1.25, 2.98) 1.92 (1.24, 2.98) Intermediate to high No 108/577 1.00 0.03 1.00 0.03 1.00 0.03 Yes 16/52 2.19 (1.10, 4.35) 2.27 (1.06, 4.84) 2.24 (1.05, 4.80) Low to intermediate or high No 453/909 1.00 0.14 1.00 0.04 1.00 0.04 Yes 41/72 1.47 (0.89, 2.44) 1.72 (1.00, 2.94) 1.74 (1.02, 3.00) Note. Data are presented as OR and 95% CI.
Model 1 was adjusted for age, sex, and baseline nonalcoholic fatty liver disease fibrosis score.
Model 2 was further adjusted for central obesity, physical activity, current smoking, current drinking, diabetes, hypertension, triglycerides, HDL cholesterol, LDL cholesterol, and white blood cell based on Model 1.
Model 3 was further adjusted for the homeostasis model assessment of IR based on Model 2.
Abbreviation: PAD, peripheral artery disease; IR, insulin resistance; HDL, high-density lipoprotein; LDL, low-density lipoprotein.As compared with the normal range of ABI, those with an ABI of < 0.90 or > 1.40 were associated with a 69% increased risk of fibrosis deterioration (95% CI: 1.12, 2.56) after adjustments for age, sex, and baseline NFS (Model 1). Further adjusting for conventional metabolic risk factors (Model 2) did not substantially change the results (OR = 1.93, 95% CI: 1.25, 2.98, P = 0.003). To explore whether IR mediated the association, further analysis was performed with adjustments for HOMA-IR (Model 3), and the results slightly decreased but remained significant (OR = 1.92, 95% CI: 1.24, 2.98, P = 0.003).
Then, we grouped the fibrosis deterioration status by baseline NFS category (Table 2). There was a 1.47-fold (95% CI: 0.89, 2.44) increased risk of progression from low to intermediate or high NFS and a 2.19-fold (95% CI: 1.10, 4.35) increased risk of progression from intermediate to high. The results did not change appreciably in Model 2 (low NFS at baseline: OR = 1.72, 95% CI: 1.00, 2.94, P = 0.04; intermediate NFS at baseline: OR = 2.27, 95% CI: 1.06, 4.84, P = 0.03). For further adjustments for HOMA-IR (Model 3), the associations were statistically significant (low NFS at baseline: OR = 1.74, 95% CI: 1.02, 3.00, P = 0.04; intermediate NFS at baseline: OR = 2.24, 95% CI: 1.05, 4.80, P = 0.03).
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In stratified analyses, the risk of fibrosis deterioration with PAD remarkably increased among patients with IR (OR = 3.23, 95% CI: 1.72, 6.04, P = 0.0003), whereas no association was found among those without IR (OR = 1.20, 95% CI: 0.62, 2.32, P = 0.58). There was a significant multiplicative interaction between PAD and IR (P for interaction = 0.03; Figure 2).
Given the observed interaction between PAD and IR, we then explored the joint effect of PAD and IR on fibrosis deterioration (Table 3). Patients with both PAD and IR had a dramatically increased risk of fibrosis deterioration, compared with those with neither PAD nor IR, after adjusting for confounders (OR = 3.85, 95% CI: 2.06, 7.18, P < 0.0001). The similar results were observed among those with progression from low to intermediate or high NFS (OR = 4.20, 95% CI: 1.75, 10.09, P = 0.001) and those with progression from intermediate to high NFS (OR = 2.82, 95% CI: 1.07, 7.42, P = 0.03).
Table 3. Joint effect of PAD and IR on fibrosis deterioration
Deterioration of fibrosis PAD IR OR (95% CI) P No. events/participants Total No No 1.00 246/696 No Yes 1.27 (0.97, 1.65) 0.09 315/790 Yes No 1.16 (0.61, 2.23) 0.65 19/56 Yes Yes 3.85 (2.06, 7.18) < 0.0001 38/68 Intermediate to high No No 1.00 40/233 No Yes 0.86 (0.50, 1.46) 0.57 68/344 Yes No 1.13 (0.30, 4.30) 0.86 4/18 Yes Yes 2.82 (1.07, 7.42) 0.03 12/34 Low to intermediate or high No No 1.00 206/463 No Yes 1.42 (1.04, 1.94) 0.03 247/446 Yes No 1.12 (0.53, 2.37) 0.78 15/38 Yes Yes 4.20 (1.75, 10.09) 0.001 26/34 Note. Data are presented as OR and 95% CI.
P-values were assessed from the logistic regression analyses, after adjustments for age, sex, baseline nonalcoholic fatty liver disease fibrosis score, central obesity, physical activity, current smoking, current drinking, diabetes, hypertension, triglycerides, HDL cholesterol, LDL cholesterol, and white blood cell.
IR: homeostasis model assessment of IR ≥ 2.5 was defined as Yes.
Abbreviation: PAD, peripheral artery disease; IR, insulin resistance; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
doi: 10.3967/bes2020.031
Peripheral Artery Disease and Risk of Fibrosis Deterioration in Nonalcoholic Fatty Liver Disease: A Prospective Investigation
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Abstract:
Objective Liver fibrosis is an important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Peripheral artery disease (PAD) and liver fibrosis share many common metabolic dysfunctions. We aimed to explore the association between PAD and risk of fibrosis deterioration in NAFLD patients. Methods The study recruited 1,610 NAFLD patients aged ≥ 40 years from a well-defined community at baseline in 2010 and followed up between August 2014 and May 2015. Fibrosis deterioration was defined as the NAFLD fibrosis score (NFS) status increased to a higher category at the follow-up visit. PAD was defined as an ankle-brachial index of < 0.90 or > 1.40. Results During an average of 4.3 years’ follow-up, 618 patients progressed to a higher NFS category. PAD was associated with 92% increased risk of fibrosis deterioration [multivariable-adjusted odds ratio (OR): 1.92, 95% confidence interval (CI): 1.24, 2.98]. When stratified by baseline NFS status, the OR for progression from low to intermediate or high NFS was 1.74 (95% CI: 1.02, 3.00), and progression from intermediate to high NFS was 2.24 (95% CI: 1.05, 4.80). There was a significant interaction between PAD and insulin resistance (IR) on fibrosis deterioration (P for interaction = 0.03). As compared with non-PAD and non-IR, the coexistence of PAD and IR was associated with a 3.85-fold (95% CI: 2.06, 7.18) increased risk of fibrosis deterioration. Conclusion PAD is associated with an increased risk of fibrosis deterioration in NAFLD patients, especially in those with IR. The coexistence of PAD and IR may impose an interactive effect on the risk of fibrosis deterioration. -
Figure 2. Stratified analyses of the association between PAD and risk of fibrosis deterioration.
Data are presented as OR and 95% CI. Stratified analyses were adjusted for age, sex, baseline nonalcoholic fatty liver disease fibrosis score, central obesity, physical activity, current smoking, current drinking, hypertension, triglycerides, HDL cholesterol, LDL cholesterol, white blood cell, and HOMA-IR; Model 3, P for interaction was calculated from logistic regression analysis by putting PAD, IR, and IR × PAD in the model simultaneously after the same adjustments as above. *P for interaction < 0.05. Central obesity: WC ≥ 90 cm in men and ≥ 80 cm in women. Abbreviation: PAD, peripheral artery disease; IR, insulin resistance; HDL, high-density lipoprotein; LDL, low-density lipoprotein; HOMA-IR, homeostasismodel assessment of insulin resistance; WC, waist circumference.
Table 1. Baseline characteristics of NAFLD patients according to ABI category
Characteristics ABI P value 0.90–1.40 < 0.90 or > 1.40 Number 1,486 124 Age (years) 58.0 ± 8.0 57.5 ± 8.5 0.51 Men [n (%)] 453 (30.48) 43 (34.68) 0.33 Current smoker [n (%)] 221 (14.87) 21 (16.93) 0.52 Current drinker [n (%)] 40 (3.36) 5 (4.03) 0.39 Hypertension [n (%)] 1,111 (74.81) 85 (68.55) 0.13 Diabetes [n (%)] 494 (33.24) 40 (32.26) 0.82 Physical activity* (MET-h/week) 23.1 (0, 69.3) 23.1 (4.1, 74.2) 0.50 BMI (kg/m2) 27.4 ± 2.9 28.3 ± 3.3 0.002 WC (cm) 88.5 ± 7.6 89.5 ± 8.6 0.15 SBP (mmHg) 146.6 ± 18.9 145.1 ± 19.2 0.40 Diastolic blood pressure (mmHg) 85.7 ± 10.2 86.3 ± 10.6 0.56 Fasting plasma glucose (mmol/L) 6.08 ± 1.96 6.12 ± 2.24 0.81 Triglycerides* (mmol/L) 1.85 (1.35, 2.59) 1.99 (1.41, 2.66) 0.47 Total cholesterol (mmol/L) 5.52 ± 1.10 5.46 ± 1.05 0.59 HDL cholesterol (mmol/L) 1.21 ± 0.26 1.19 ± 0.29 0.37 LDL cholesterol (mmol/L) 3.32 ± 0.91 3.26 ± 0.85 0.44 Albumin (g/L) 49.13 ± 2.23 48.94 ± 2.50 0.35 ALT* (U/L) 23.1 (17.4, 33.3) 24.4 (17.5, 34.8) 0.66 AST* (U/L) 22.3 (19.0, 27.3) 22.5 (18.7, 27.1) 0.86 GGT* (U/L) 28 (20, 44) 31 (21, 41) 0.60 White blood cell (×109/L) 6.13 ± 1.47 6.55 ± 1.46 0.002 HOMA-IR* 2.62 (1.81, 3.84) 2.61 (1.82, 3.63) 0.90 NFS −1.78 ± 1.12 −1.69 ± 1.18 0.40 Note. Data are presented as mean ± SD, median (interquartile range), or number (percentage). P-values were calculated by one-way analysis of variance for continuous variables and chi-square test for categorical variables. *Variables were log-transformed before analysis. Abbreviations: ABI, ankle-brachial index; BMI, body mass index; WC, waist circumference; MET, metabolic equivalent; SBP; systolic blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transpeptidase; HOMA-IR, homeostasis model assessment of insulin resistance; NAFLD, nonalcoholic fatty liver disease; NFS, NAFLD fibrosis score. Table 2. Association of PAD with risk of fibrosis deterioration
Fibrosis deterioration PAD No. events / participants Model 1 Model 2 Model 3 OR (95% CI) P OR (95% CI) P OR (95% CI) P Total No 561/1,486 1.00 0.01 1.00 0.003 1.00 0.003 Yes 57/124 1.69 (1.12, 2.56) 1.93 (1.25, 2.98) 1.92 (1.24, 2.98) Intermediate to high No 108/577 1.00 0.03 1.00 0.03 1.00 0.03 Yes 16/52 2.19 (1.10, 4.35) 2.27 (1.06, 4.84) 2.24 (1.05, 4.80) Low to intermediate or high No 453/909 1.00 0.14 1.00 0.04 1.00 0.04 Yes 41/72 1.47 (0.89, 2.44) 1.72 (1.00, 2.94) 1.74 (1.02, 3.00) Note. Data are presented as OR and 95% CI.
Model 1 was adjusted for age, sex, and baseline nonalcoholic fatty liver disease fibrosis score.
Model 2 was further adjusted for central obesity, physical activity, current smoking, current drinking, diabetes, hypertension, triglycerides, HDL cholesterol, LDL cholesterol, and white blood cell based on Model 1.
Model 3 was further adjusted for the homeostasis model assessment of IR based on Model 2.
Abbreviation: PAD, peripheral artery disease; IR, insulin resistance; HDL, high-density lipoprotein; LDL, low-density lipoprotein.Table 3. Joint effect of PAD and IR on fibrosis deterioration
Deterioration of fibrosis PAD IR OR (95% CI) P No. events/participants Total No No 1.00 246/696 No Yes 1.27 (0.97, 1.65) 0.09 315/790 Yes No 1.16 (0.61, 2.23) 0.65 19/56 Yes Yes 3.85 (2.06, 7.18) < 0.0001 38/68 Intermediate to high No No 1.00 40/233 No Yes 0.86 (0.50, 1.46) 0.57 68/344 Yes No 1.13 (0.30, 4.30) 0.86 4/18 Yes Yes 2.82 (1.07, 7.42) 0.03 12/34 Low to intermediate or high No No 1.00 206/463 No Yes 1.42 (1.04, 1.94) 0.03 247/446 Yes No 1.12 (0.53, 2.37) 0.78 15/38 Yes Yes 4.20 (1.75, 10.09) 0.001 26/34 Note. Data are presented as OR and 95% CI.
P-values were assessed from the logistic regression analyses, after adjustments for age, sex, baseline nonalcoholic fatty liver disease fibrosis score, central obesity, physical activity, current smoking, current drinking, diabetes, hypertension, triglycerides, HDL cholesterol, LDL cholesterol, and white blood cell.
IR: homeostasis model assessment of IR ≥ 2.5 was defined as Yes.
Abbreviation: PAD, peripheral artery disease; IR, insulin resistance; HDL, high-density lipoprotein; LDL, low-density lipoprotein. -
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