Small dense low-density lipoprotein in primary biliary cholangitis: Independent association with metabolic syndrome

Table 1 Baseline characteristics of the study population, n (%)

Number of patients	n = 148
Demographic and anthropometric characteristics
Age (years)	64.15 ± 10.73 (33-88)
BMI	26.76 ± 4.47 (16.51-40.16)
Waist circumference (cm)	89.36 ± 11.27 (60-121)
Gender	Female n = 137 (92.60); Male n = 11 (7.40)
Cardiometabolic comorbidities
Coronary artery disease	4 (2.70)
Acute coronary syndrome	3 (2.00)
History of stroke	7 (4.70)
Peripheral artery disease	2 (1.40)
Treatment
Statin therapy	29 (19.60)
Fibrate therapy	34 (23.00)
UDCA therapy	148 (100.00)
Liver disease characteristics
Complete biochemical response	82 (55.40)
Advanced liver fibrosis F3/F4	32 (21.60)
Metabolic syndrome	58 (39.20)
MASLD	63 (42.60)
CAP (dB/m)	244.87 ± 58.07
TE (kPa)	8.92 ± 8.16
AST × ULN (%)	101.52 ± 60.85
ALT × ULN (%)	87.43 ± 65.42
GGT × ULN (%)	212.10 ± 372.79
ALP × ULN (%)	109.12 ± 84.10
Total bilirubin (µmol/L)	13.71 ± 7.75
Conjugated bilirubin (µmol/L)	3.20 ± 2.75
Metabolic and lipoprotein parameters
Glucose (mmol/L)	5.83 ± 1.87
C-peptide (ng/mL)	2.08 ± 1.2
HOMA-IR	6.37 ± 4.47
Total cholesterol (mmol/L)	5.32 ± 1.26
HDL-C (mmol/L)	1.67 ± 0.44
LDL-C (mmol/L)	3.27 ± 0.92
Triglycerides (mmol/L)	1.30 ± 0.89
Platelets × 109/L	245.29 ± 97.35
sdLDL (mmol/L)	0.09 ± 0.17
largeLDL (mmol/L)	1.29 ± 0.49
sdLDL/LargeLDL	0.08 ± 0.18
ApoB (mg/dL)	43.91 ± 16.87
Lp(a) (mg/dL)	10.75 ± 15.34

ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; ApoB: Apolipoprotein B; AST: Aspartate aminotransferase; BMI: Body mass index; CAP: Controlled attenuation parameter; F3/F4: Advanced liver fibrosis stages 3 and 4; GGT: Gamma-glutamyl transferase; HDL: High-density lipoprotein; HOMA-IR: Homeostasis model assessment of insulin resistance; LDL: Low-density lipoprotein; Lp(a): Lipoprotein a; MASLD: Metabolic dysfunction-associated steatotic liver disease; sdLDL: Small dense low-density lipoprotein; TE: Transient elastography; ULN: Upper limit of normal; UDCA: Ursodeoxycholic acid.

Table 2 Univariable comparison of small dense low-density lipoprotein levels according to metabolic and liver-related factors

Variable	Group	sdLDL (mmol/L), median (IQR)	P value
MetS	Present	0.07 (0.00-0.14)	0.004
	Absent	0.00 (0.00-0.07)
MASLD	Present	0.03 (0.00-0.13)	0.324
	Absent	0.03 (0.00-0.08)
Advanced fibrosis (F3/F4)	Present	0.00 (0.00-0.08)	0.155
	Absent	0.04 (0.00-0.12)
CBR	Present	0.06 (0.00-0.13)	0.017
	Absent	0.00 (0.00-0.07)

CBR: Complete biochemical response; F3/F4: Fibrosis stages 3 and 4; MASLD: Metabolic dysfunction-associated steatotic liver disease; sdLDL: Small dense low-density lipoprotein; IQR: Interquartile range; MetS: Metabolic syndrome.

Table 3 Multivariable linear regression analysis of factors associated with ln-transformed small dense low-density lipoprotein levels

Variable	B (95%CI)	Standardized β	P value
MetS	0.76 (0.26 to 1.26)	0.27	0.003
Age	-0.004 (-0.03 to 0.02)	-0.03	0.750
Female sex	-0.14 (-1.00 to 0.72)	-0.03	0.745
BMI	0.024 (-0.03 to 0.07)	0.08	0.354
Statin therapy	-0.45 (-1.04 to 0.13)	-0.13	0.133
Fibrate therapy	-0.01 (-0.53 to 0.51)	-0.004	0.964
Model statistics: R2 = 0.093 adjusted R2 = 0.054 F = 2.393 P = 0.031

BMI: Body mass index; CI: Confidence interval; MetS: Metabolic syndrome.

Table 4 Sensitivity analysis using waist circumference instead of body mass index in multivariable linear regression

Variable	B (95%CI)	Standardized β	P value
Metabolic syndrome	0.68 (0.17 to 1.18)	0.24	0.010
Age (years)	-0.01 (-0.03 to 0.01)	-0.07	0.421
Female sex	-0.02 (-0.83 to 0.86)	0.00	0.969
Waist circumference (cm)	0.01 (-0.01 to 0.03)	0.08	0.393

CI: Confidence interval.

Table 5 Multivariable logistic regression analysis of factors associated with detectable small dense low-density lipoprotein

Variable	OR (95%CI)	P value
Metabolic syndrome	2.10 (1.02-4.35)	0.045
Age (years)	0.99 (0.96-1.03)	0.731
Female sex	1.43 (0.37-5.49)	0.606
Fibrate therapy	0.92 (0.41-2.04)	0.832
Statin therapy	0.51 (0.21-1.27)	0.149

Model adjusted for age, sex, statin therapy, and fibrate therapy. Hosmer-Lemeshow goodness-of-fit test: χ² = 11.79, df = 8; P = 0.161. OR: Odds ratio; CI: Confidence interval.

Table 6 Lipoprotein subfraction phenotype in primary biliary cholangitis patients with and without metabolic syndrome

Variable	No MetS	MetS	P value
LDL-C (mmol/L)	3.37 ± 0.82	3.08 ± 1.08	0.0211
HDL-C (mmol/L)	1.81 ± 0.38	1.44 ± 0.43	< 0.0011
sdLDL (mmol/L)	0.00 IQR (0.00-0.07)	0.07 IQR (0.00-0.14)	0.0042
largeLDL (mmol/L)	1.27 IQR (1.03-1.78)	1.09 IQR (0.87-1.49)	0.0412
TG (mmol/L)	1.04 IQR (0.82-1.29)	1.31 IQR (1.03-1.78)	< 0.0012
TG/HDL-C ratio	0.60 IQR (0.42-0.79)	1.02 IQR (0.61-1.47)	< 0.0012
sdLDL/LargeLDL ratio	0.00 IQR (0.00-0.05)	0.05 IQR (0.00-0.15)	< 0.0012

¹Independent-samples t-test.

²Mann-Whitney U test.

HDL: High-density lipoprotein cholesterol; LDL: Low-density lipoprotein cholesterol; MetS: Metabolic syndrome; sdLDL: Small dense low-density lipoprotein; IQR: Interquartile range; TG: Triglycerides.

Table 7 Additional lipoprotein-related parameters in primary biliary cholangitis patients with and without metabolic syndrome

Variable	No MetS	MetS	P value
Lp(a) (mg/dL)	3.76 IQR (1.56-13.99)	5.33 IQR (1.65-11.88)	0.8021
ApoB (mg/dL)	39.69 IQR (32.02-52.92)	41.61 IQR (31.60-52.16)	0.5601
ApoB/ApoA-I	0.59 IQR (0.41-0.76)	0.64 IQR (0.47-0.83)	0.0621

¹Mann Whitney U test.

MetS: Metabolic syndrome; Lp(a): Lipoprotein a; ApoA-I: Apolipoprotein A-I; IQR: Interquartile range; ApoB: Apolipoprotein B.

Table 8 Receiver operating characteristic analysis of lipoprotein-related parameters for identification of metabolic syndrome

Variable	AUC (95%CI)	P value	Optimal cut-off	Sensitivity (%)	Specificity (%)	Youden index
sdLDL	0.634 (0.540-0.729)	0.006	0.075	46.6	22.2	0.243
largeLDL	0.400 (0.305-0.495)	0.048	2.290	6.9	97.8	0.047
LDL-C	0.378 (0.283-0.473)	0.013	5.360	6.9	98.9	0.058
sdLDL/LargeLDL ratio	0.650 (0.554-0.745)	0.002	0.034	62.1	70.0	0.321

LDL: Low-density lipoprotein cholesterol; sdLDL: Small dense low-density lipoprotein; AUC: Area under the curve; CI: Confidence interval.