Cytokeratin 18 fragment is associated with steatosis-associated fibrosis estimator score and lipid in patients with steatotic liver disease

doi:10.4254/wjh.v17.i11.110698

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World Journal of Hepatology

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World J Hepatol. Nov 27, 2025; 17(11): 110698
Published online Nov 27, 2025. doi: 10.4254/wjh.v17.i11.110698

Table 1 Clinical factors, n (%)

Cytokeratin 18 fragment (high: > 260 U/L)		Normal	High	P value	Odds ratio/95%CI
Steatotic liver disease	Metabolic dysfunction and alcohol-related liver disease	35 (36.5)	8 (27.6)	0.37810	1
Steatotic liver disease	Metabolic dysfunction-associated steatotic liver disease	61 (63.5)	21 (72.4)	0.37810	1.507/0.726-3.129
Sex	Woman	53 (55.2)	14 (48.3)	0.51180	1
Sex	Man	43 (44.8)	15 (51.7)	0.51180	1.321/0.575-3.035
Age	n	96	29	0.20098	0.975/0.943-1.008
	Median	63.0	59.0
	Q1 (25%)	56.5	48.5
	Q3 (75%)	70.0	69.8
Total bilirubin (normal range, 0.3-1.2 mg/dL)	n	96	29	0.70006	1.482/0.591-3.713
	Median	0.80	0.80
	Q1 (25%)	0.60	0.60
	Q3 (75%)	1.00	1.08
Total protein (6.7-8.3 g/dL)	n	96	29	0.00357	4.828/1.653-14.02
	Median	7.40	7.60
	Q1 (25%)	7.05	7.40
	Q3 (75%)	7.60	7.83
Albumin (3.8-5.2 g/dL)	n	96	29	0.59102	1.553/0.532-4.532
	Median	4.30	4.30
	Q1 (25%)	4.00	4.08
	Q3 (75%)	4.50	4.60
PT (70%-130%)	n	96	29	0.31843	0.99/0.966-1.014
	Median	98.10	92.00
	Q1 (25%)	85.80	83.10
	Q3 (75%)	107.70	102.78
PT international normalized ratio (0.9-1.1)	n	96	29	0.29846	2.701/0.069-105.6
	Median	1.010	1.040
	Q1 (25%)	0.970	0.988
	Q3 (75%)	1.075	1.085
Creatinine (M: 0.61-1.04 mg/dL and W: 0.47-0.79 mg/dL)	n	96	29	0.93705	1.322/0.203-8.593
	Median	0.730	0.750
	Q1 (25%)	0.650	0.648
	Q3 (75%)	0.900	0.873
Body mass index	n	96	29	0.07636	1.057/0.977-1.145
	Median	25.01	26.63
	Q1 (25%)	22.41	23.32
	Q3 (75%)	27.61	30.20
Platelet count (M: [13.1-26.2] × 10⁴/μL and W: [13-36.9] × 10⁴/μL)	n	96	29	0.82183	0.997/0.938-1.059
	Median	18.75	16.80
	Q1 (25%)	15.35	15.50
	Q3 (75%)	21.90	24.03
AST	n	96	29	< 0.00001	1.057/1.033-1.082
	Median	30.0	66.0
	Q1 (25%)	23.0	52.5
	Q3 (75%)	42.5	105.5
ALT	n	96	29	< 0.00001	1.04/1.023-1.058
	Median	29.5	80.0
	Q1 (25%)	20.0	51.3
	Q3 (75%)	51.0	123.5
AST/ALT	n	96	29	0.04739	0.543/0.212-1.391
	Median	1.086	0.837
	Q1 (25%)	0.798	0.651
	Q3 (75%)	1.370	1.165
Alkaline phosphatase (38-113 U/L)	n	96	29	0.81045	1.003/0.99-1.016
	Median	81.5	85.0
	Q1 (25%)	65.5	63.3
	Q3 (75%)	103.5	104.3
γ-glutamyl transpeptidase (M: < 70 U/L and W: < 30 U/L)	n	96	29	0.00269	1.003/1-1.005
	Median	50.5	89.0
	Q1 (25%)	27.0	55.8
	Q3 (75%)	108.0	162.3
Ferritin (M: 39.4-340 ng/mL and W: 3.6-114 ng/mL)	n	85	25	0.00004	1.003/1.001-1.005
	Median	171.2	398.5
	Q1 (25%)	106.9	248.8
	Q3 (75%)	300.3	701.3
IgG (870-1700 mg/dL)	n	76	24	0.42663	1/0.999-1.002
	Median	1285.5	1327.5
	Q1 (25%)	1125.0	1132.0
	Q3 (75%)	1433.5	1582.0
IgM (M: 33-190 mg/dL and W: 46-260 mg/dL)	n	66	22	0.54697	1.003/0.996-1.01
	Median	86.5	90.5
	Q1 (25%)	56.0	58.0
	Q3 (75%)	123.0	134.0
IgA (110-410 mg/dL)	n	69	19	0.18399	1.002/0.999-1.005
	Median	251.0	322.0
	Q1 (25%)	195.5	201.0
	Q3 (75%)	315.8	430.3
Ammonia (30-80 μg/dL)	n	94	29	0.06502	0.976/0.948-1.005
	Median	40.0	37.0
	Q1 (25%)	35.0	29.8
	Q3 (75%)	51.0	43.0
TG (50-149 mg/dL)	n	96	29	0.00117	1.004/1-1.008
	Median	100.5	160.0
	Q1 (25%)	70.5	114.8
	Q3 (75%)	165.5	234.3
LDL (70-139 mg/dL)	n	93	28	0.64258	1.003/0.991-1.015
	Median	109.0	113.0
	Q1 (25%)	91.3	92.0
	Q3 (75%)	139.0	141.0
HDL (M: 40-80 mg/dL and W: 40-90 mg/dL)	n	96	29	0.00340	0.954/0.924-0.985
	Median	63.0	54.0
	Q1 (25%)	52.0	42.8
	Q3 (75%)	74.5	61.8
TG/HDL	n	96	29	0.00041	1.281/1.064-1.544
	Median	1.654	3.260
	Q1 (25%)	1.109	1.764
	Q3 (75%)	3.014	5.545
Small dense LDL (> 35 mg/dL)	n	71	23	0.15677	1.01/0.99-1.031
	Median	35.4	39.6
	Q1 (25%)	20.9	29.8
	Q3 (75%)	48.5	52.0
Hemoglobin A1c (4.8%-6%)	n	93	28	0.02446	1.274/0.883-1.839
	Median	5.8	6.1
	Q1 (25%)	5.5	5.8
	Q3 (75%)	6.2	6.6

The odds ratio and 95% confidence interval were calculated using univariate logistic analysis. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; HDL: High-density lipoprotein; Ig: Immunoglobulin; LDL: Low-density lipoprotein; M: Men; PT: Prothrombin time; Q1: Quartile 1 (25%); Q3: Quartile 3 (75%); TG: Triglyceride; W: Women.

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Table 2 Non-invasive fibrosis testing, n (%)

Cytokeratin 18 fragment (high: > 260 U/L)		Normal	High	P value	Odds ratio/95%CI
Steatotic liver disease	Metabolic dysfunction and alcohol-related liver disease	35 (36.5)	8 (27.6)	0.37810	1
Steatotic liver disease	Metabolic dysfunction-associated steatotic liver disease	61 (63.5)	21 (72.4)	0.37810	1.51/0.73-3.13
Sex	Woman	53 (55.2)	14 (48.3)	0.51180	1
Sex	Man	43 (44.8)	15 (51.7)	0.51180	1.32/0.58-3.04
Age	n	96	29	0.20098	0.98/0.94-1.01
	Median	63.0	59.0
	Q1 (25%)	56.5	48.5
	Q3 (75%)	70.0	69.8
Total bilirubin (normal range 0.3-1.2 mg/dL)	n	96	29	0.70006	1.48/0.59-3.71
	Median	0.80	0.80
	Q1 (25%)	0.60	0.60
	Q3 (75%)	1.00	1.08
Total protein (6.7-8.3 g/dL)	n	96	29	0.00357	4.83/1.65-14.02
	Median	7.40	7.60
	Q1 (25%)	7.05	7.40
	Q3 (75%)	7.60	7.83
Albumin (3.8-5.2 g/dL)	n	96	29	0.59102	1.55/0.53-4.53
	Median	4.30	4.30
	Q1 (25%)	4.00	4.08
	Q3 (75%)	4.50	4.60
PT (70%-130%)	n	96	29	0.31843	0.99/0.97-1.01
	Median	98.10	92.00
	Q1 (25%)	85.80	83.10
	Q3 (75%)	107.70	102.78
PT international normalized ratio (0.9-1.1)	n	96	29	0.29846	2.70/0.07-105.6
	Median	1.010	1.040
	Q1 (25%)	0.970	0.988
	Q3 (75%)	1.075	1.085
Creatinine (M: 0.61-1.04 mg/dL and W: 0.47-0.79 mg/dL)	n	96	29	0.93705	1.32/0.20-8.59
	Median	0.730	0.750
	Q1 (25%)	0.650	0.648
	Q3 (75%)	0.900	0.873
Body mass index	n	96	29	0.07636	1.06/0.98-1.15
	Median	25.01	26.63
	Q1 (25%)	22.41	23.32
	Q3 (75%)	27.61	30.20
Platelet count (M: [13.1-26.2] × 10⁴/μL and W: [13-36.9] × 10⁴/μL)	n	96	29	0.82183	1.00/0.94-1.06
	Median	18.75	16.80
	Q1 (25%)	15.35	15.50
	Q3 (75%)	21.90	24.03
AST (10-40 U/L)	n	96	29	< 0.00001	1.06/1.03-1.08
	Median	30.0	66.0
	Q1 (25%)	23.0	52.5
	Q3 (75%)	42.5	105.5
ALT (5-40 U/L)	n	96	29	< 0.00001	1.04/1.02-1.06
	Median	29.5	80.0
	Q1 (25%)	20.0	51.3
	Q3 (75%)	51.0	123.5
AST/ALT	n	96	29	0.04739	0.54/0.21-1.39
	Median	1.086	0.837
	Q1 (25%)	0.798	0.651
	Q3 (75%)	1.370	1.165
Alkaline phosphatase (38-113 U/L)	n	96	29	0.81045	1.00/0.99-1.02
	Median	81.5	85.0
	Q1 (25%)	65.5	63.3
	Q3 (75%)	103.5	104.3
γ-glutamyl transpeptidase (M: < 70 U/L and W: < 30 U/L)	n	96	29	0.00269	1.00/1-1.01
	Median	50.5	89.0
	Q1 (25%)	27.0	55.8
	Q3 (75%)	108.0	162.3
Ferritin (M: 39.4-340 ng/mL and W: 3.6-114 ng/mL)	n	85	25	0.00004	1.00/1.00-1.01
	Median	171.2	398.5
	Q1 (25%)	106.9	248.8
	Q3 (75%)	300.3	701.3
IgG (870-1700 mg/dL)	n	76	24	0.42663	1.00/1.00-1.00
	Median	1285.5	1327.5
	Q1 (25%)	1125.0	1132.0
	Q3 (75%)	1433.5	1582.0
IgM (M: 33-190 mg/dL and W: 46-260 mg/dL)	n	66	22	0.54697	1.00/1.00-1.01
	Median	86.5	90.5
	Q1 (25%)	56.0	58.0
	Q3 (75%)	123.0	134.0
IgA (110-410 mg/dL)	n	69	19	0.18399	1.00/1.00-1.01
	Median	251.0	322.0
	Q1 (25%)	195.5	201.0
	Q3 (75%)	315.8	430.3
Ammonia (30-80 μg/dL)	n	94	29	0.06502	0.98/0.95-1.01
	Median	40.0	37.0
	Q1 (25%)	35.0	29.8
	Q3 (75%)	51.0	43.0
TG (50-149 mg/dL)	n	96	29	0.00117	1.00/1.00-1.01
	Median	100.5	160.0
	Q1 (25%)	70.5	114.8
	Q3 (75%)	165.5	234.3
LDL (70-139 mg/dL)	n	93	28	0.64258	1.00/0.99-1.02
	Median	109.0	113.0
	Q1 (25%)	91.3	92.0
	Q3 (75%)	139.0	141.0
HDL (M: 40-80 mg/dL and W: 40-90 mg/dL)	n	96	29	0.00340	0.95/0.92-0.99
	Median	63.0	54.0
	Q1 (25%)	52.0	42.8
	Q3 (75%)	74.5	61.8
TG/HDL	n	96	29	0.00041	1.28/1.06-1.54
	Median	1.654	3.260
	Q1 (25%)	1.109	1.764
	Q3 (75%)	3.014	5.545
Small dense LDL (> 35 mg/dL)	n	71	23	0.15677	1.01/0.99-1.03
	Median	35.4	39.6
	Q1 (25%)	20.9	29.8
	Q3 (75%)	48.5	52.0
Hemoglobin A1c (4.8%-6%)	n	93	28	0.02446	1.27/0.88-1.84
	Median	5.8	6.1
	Q1 (25%)	5.5	5.8
	Q3 (75%)	6.2	6.6

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Table 3 Non-invasive test, n (%)

Cytokeratin 18 fragment (high: > 260 U/L)		Normal	High	P value
FIB-4	n	96	29	0.18622
	Median	1.846233758	2.214285714
	Q1 (25%)	1.335421229	1.350050748
	Q3 (75%)	3.034660172	4.838339769
FIB-4 < 1.3	Normal	20 (20.8)	7 (24.1)	0.70470
FIB-4 < 1.3	< 1.3	76 (79.2)	22 (75.9)	0.70470
FIB-4 < 2.67	Normal	66 (68.8)	15 (51.7)	0.09249
FIB-4 < 2.67	< 2.57	30 (31.3)	14 (48.3)	0.09249
SAFE score	n	96	29	0.00038
	Median	106.392705050	180.732578700
	Q1 (25%)	37.891624800	129.469594725
	Q3 (75%)	183.716030000	286.774864650
SAFE low-risk, moderate-risk, and high-risk	Low (< 0)	16 (16.7)	0 (0.0)	0.00696
	Mod (0-100)	30 (31.3)	5 (17.2)
	High (> 100)	50 (52.1)	24 (82.8)
LS	n	86	29	0.05020
	Median	6.1	7.2
	Q1 (25%)	4.1	5.4
	Q3 (75%)	9.3	12.7
LS < 8	LS > 8	32 (37.2)	14 (48.3)	0.29281
LS < 8	LS < 8	54 (62.8)	15 (51.7)	0.29281
LS < 10	LS > 10	19 (22.1)	10 (34.5)	0.18396
LS < 10	LS < 10	67 (77.9)	19 (65.5)	0.18396
Controlled attenuation parameter (dB/m)	n	86	29	0.03146
	Median	283.0	313.0
	Q1 (25%)	250.0	261.3
	Q3 (75%)	318.0	350.3
FAST	n	86	29	< 0.00001
	Median	0.1	0.4
	Q1 (25%)	0.1	0.3
	Q3 (75%)	0.3	0.6
FAST < 0.35	Low	66 (76.7)	12 (41.4)	0.00042
FAST < 0.35	High	20 (23.3)	17 (58.6)	0.00042
Model for end-stage liver disease	n	95	29	0.16863
	Median	7.0	7.0
	Q1 (25%)	6.0	7.0
	Q3 (75%)	8.0	9.0
Albumin bilirubin score	n	96	29	0.96034
	Median	−2.9491	−2.9051
	Q1 (25%)	−3.1863	−3.1601
	Q3 (75%)	−2.6099	−2.7345
Child–Pugh score	n	96	29	0.40759
	Median	5	5
	Q1 (25%)	5	5
	Q3 (75%)	5	5

FAST: FibroScan-aspartate aminotransferase; FIB-4: Fibrosis-4 index; LS: Liver stiffness; Q1: Quartile 1 (25%); Q3: Quartile 3 (75%); SAFE: Steatosis-associated fibrosis estimator.

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Table 4 Complicated metabolic disease, n (%)

Cytokeratin 18 fragment (High: > 260 U/L)		Normal	High	P value
Body mass index (> 23 kg/m²)	Obesity	68 (70.8)	22 (75.9)	0.59711
Body mass index (> 23 kg/m²)	Normal	28 (29.2)	7 (24.1)	0.59711
DM	DM	24 (25.0)	12 (41.4)	0.08782
DM	No	72 (75.0)	17 (58.6)	0.08782
DPP4I	DPP4I	4 (4.2)	2 (6.9)	0.62210
DPP4I	No	92 (95.8)	27 (93.1)	0.62210
SGLT2I	No	86 (89.6)	26 (89.7)	1.00000
SGLT2I	SGLT2I	10 (10.4)	3 (10.3)	1.00000
GLP-1RA	GLP-1RA	3 (3.1)	2 (6.9)	0.32861
GLP-1RA	No	93 (96.9)	27 (93.1)	0.32861
HT	HT	43 (44.8)	15 (51.7)	0.51180
HT	No	53 (55.2)	14 (48.3)	0.51180
ARNII	ARNII	5 (5.2)	0 (0.0)	0.58924
ARNII	No	91 (94.8)	29 (100.0)	0.58924
Triglycerides high	High	32 (33.3)	17 (58.6)	0.01451
Triglycerides high	Normal	64 (66.7)	12 (41.4)	0.01451
High-density lipoprotein low	High	17 (17.7)	11 (37.9)	0.02207
High-density lipoprotein low	Normal	79 (82.3)	18 (62.1)	0.02207
Statin	No	71 (74.0)	20 (69.0)	0.59645
Statin	Statin	25 (26.0)	9 (31.0)	0.59645
Fibrate	Fibrate	5 (5.2)	2 (6.9)	0.66285
Fibrate	No	91 (94.8)	27 (93.1)	0.66285
Cardiometabolic risk factor	n	96	29	0.00814
	Median	2	3
	Quartile 1 (25%)	1.0	1.8
	Quartile 3 (75%)	3.0	4.0

Metabolic disease were as follows: (1) Obesity (body mass index > 23 kg/m²); (2) Diabetes mellites (DM) (DM was defined as patients that were already using therapeutic drugs or had been diagnosed or hemoglobin A1c values > 5.7% or fasting plasma glucose > 100 mg/dL); (3) Hypertension (HT) (HT was defined as patients that were already using therapeutic drugs or had been diagnosed or blood pressure is > 130/85 mmHg); (4) High triglycerides (TG) (TG > 150 mg/dL or lipid lowering drug user); (5) Low high-density lipoprotein (HDL); and (6) HDL < 39 mg/dL in men and < 50 mg/dL in women or lipid lowering drug user. Cardiometabolic risk factor (CMRF) was the total score, with 1 point for obesity, 1 point for DM, 1 point for HT, 1 point for TG high, and 1 point for low HDL. ARNII: Angiotensin receptor neprilysin inhibitor; DM: Diabetes mellites; DPP4I: Dipeptidyl peptidase 4 inhibitor; GLP-1RA: Glucagon-like peptide-1 receptor agonist; HT: Hypertension; SGLT2I: Sodium glucose cotransporter 2 inhibitor.

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Table 5 Correlation of cytokeratin 18 fragment with clinical factors: Clinical factors

	Factors	Total protein	AST	ALT	AST/ALT	γ-glutamyl transpeptidase	Ferritin	TG	HDL	TG/HDL	Hemoglobin A1c
Cytokeratin 18 fragment	R	0.1467	0.4822	0.2819	−0.1157	0.1511	0.3288	0.5594	−0.2406	0.5966	0.1983
	n	123	123	123	123	123	108	123	123	123	119
	P value	0.10258	< 0.00001	0.00145	0.19886	0.09258	0.00045	< 0.00001	0.00689	< 0.00001	0.02923

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; HDL: High-density lipoprotein; TG: Triglyceride; R: Correlation coefficient.

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Table 6 Correlation of cytokeratin 18 fragment with clinical factors: Non-invasive tests

	Factors	CMRF	Modified CMRF	Fibrosis-4 index	Steatosis-associated fibrosis estimator score	Liver stiffness	Controlled attenuation parameter	FibroScan-aspartate aminotransferase
Cytokeratin 18 fragment	R	0.1676	0.2330	0.1090	0.2415	0.1432	0.1963	0.4560
	n	123	123	123	123	113	113	113
	P value	0.06179	0.00891	0.22628	0.00667	0.12676	0.03547	< 0.00001

CMRF: Cardiometabolic risk factor; R: Correlation coefficient.

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Citation: Ichikawa T, Miuma S, Yamashima M, Yamamichi S, Koike M, Nakano Y, Yajima H, Miyazaki O, Ikeda T, Okamura T, Komatsu N, Yoshino M, Miyaaki H. Cytokeratin 18 fragment is associated with steatosis-associated fibrosis estimator score and lipid in patients with steatotic liver disease. World J Hepatol 2025; 17(11): 110698
URL: https://www.wjgnet.com/1948-5182/full/v17/i11/110698.htm
DOI: https://dx.doi.org/10.4254/wjh.v17.i11.110698