Soluble forms of extracellular cytokeratin 18 may differentiate simple steatosis from nonalcoholic steatohepatitis

doi:10.3748/wjg.v13.i6.837

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Feb 14, 2007 (publication date) through Feb 11, 2025

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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World J Gastroenterol. Feb 14, 2007; 13(6): 837-844
Published online Feb 14, 2007. doi: 10.3748/wjg.v13.i6.837

Table 1 General and biochemical characteristics of patients with suspected NAFLD

Characteristic	Entire cohort(n = 83)	Definitive NASH(n = 45)	Borderline NASH(n = 24)	Simple steatosis(n = 9)	Normal tissue(n = 5)
Male gender	54.2%	62.2%	50.0%	44.4%	20.0%
Age (yr)	48.9 ± 9.1	47.8 ± 8.8	48.7 ± 6.2	53.1 ± 10.1	52.4 ± 19.2
Body mass index (kg/m²)	30.3 ± 4.8	30.2 ± 4.1	31.1 ± 6.5	29.5 ± 3.7	28.0 ± 3.0
Waist circumference (cm)	99 ± 9	101 ± 8	100 ± 9	94 ± 10	93 ± 11
Waist/hip ratio	0.93 (0.01-1.08)	0.95 (0.09-1.08)	0.93 (0.09-1.02)	0.8 (0.74-1.05)	0.86 (0.01-0.87)
Hypertension	33.7%	28.9%	50%	22.2%	20%
Systolic blood pressure (mmHg)	122 ± 13	124 ± 13	121 ± 13	121 ± 16	115 ± 11
Diastolic blood pressure (mmHg)	77 ± 10	80 ± 9	76 ± 11	71 ± 10	72 ± 9
Diabetes mellitus	14.5%	13.3%	16.7%	22.2%	0%
Fasting glucose (mg/dL)	103 ± 22	102 ± 21	105 ± 25	109 ± 25	93 ± 7
Fasting insulin (μU/mL)¹	24 (1-298)	34 (3-298)	21 (1-281)	20 (1-110)	11 (1-16)
HOMA index	3.0 (0.2-16.5)	3.1 (0.3-16.5)	2.9 (0.3-8.1)	2.6 (0.2-4.9)	2.3 (1.6-3.8)
Hyperlipidemia history	83.1%	80.0%	91.7%	77.8%	80%
Total cholesterol (mg/dL)	213 ± 40	213 ± 44	224 ± 31	190 ± 27	199 ± 49
Triglycerides (mg/dL)¹	149 (38-424)	151 (38-424)	164 (90-398)	102 (49-286)	149 (44-182)
Metabolic syndrome	34.9%	37.8%	33.3%	33.3%	20.0%
Lp(a) (mg/dL)¹	10 (2-157)	9 (2-98)	20 (2-157)	6 (2-68)	19 (5-32)
Microalbuminuria (μg/mL)¹	1.0 (0.2-48.4)	4.2 (0.2-48.4)	0.7 (0.2-3.8)	0.65 (0.3-8.9)	0.4 (0.2-1.0)
AST (IU/L)¹	42 (16-102)	44 (18-95)	33 (16-102)	32 (17-65)	28 (19-91)
ALT (IU/L)¹	60 (10-184)	68 (23-184)	47 (12-146)	47 (19-84)	35 (10-149)
AST/ALT ratio	0.68 (0.34-1.90)	0.65 (0.34-0.95)	0.71 (0.45-1.42)	0.77 (0.59-1.21)	0.8 (0.6-1.9)
ALP (UI/L)¹	82 (19-154)	84 (44-152)	85 (43-132)	94 (19-154)	76 (61-131)
GGT (UI/L)¹	47 (15-526)	52 (16-526)	29 (15-199)	65 (22-164)	73 (17-124)
LDH (UI/L)¹	196 (132-379)	198 (143-375)	193 (132-295)	184 (163-379)	171 (152-340)
Total Bilirubin (mg/dL)¹	0.7 (0.1-2.5)	0.7 (0.1-2.5)	0.6 (0.1-1.7)	0.5 (0.1-0.8)	0.8 (0.4-2.1)
HbA1c	5.6 (4.6-9.9)%	5.7 (4.7-9.9)%	5.5 (4.6-7.7)%	5.6 (5.1-7.4)%	5.5 (5.4-6.2)%
Transferrin saturation	19 (2-48)%	20 (2-48)%	17 (5-29)%	23.5 (11-44)%	18 (8-28)%
Ferritin (ng/mL)¹	77 (6-406)	93 (6-399)	69 (12-297)	96 (10-406)	23 (9-61)
Positive ANA	21.6%	23.9%	20.8%	0%	40.0%
Positive AMA	1.2%	2.1%	0%	0%	0%
Positive ASMA	7.2%	4.3%	4.4%	0%	20.0%
Positive LKM-1	0%	0%	0%	0%	0%

¹Data expressed as median (minimum-maximum); HOMA: homeostasis model assessment; HDL: high-density lipoprotein; Lp(a): lipoprotein(a); AST: aspartate aminotransferase; ALT: alanine aminotransferase; ALP: alkaline phosphatase; GGT: gamma glutamyl transpeptidase; LDH: lactate dehydrogenase; HbA1c: glycated hemoglobin; ANA: antinuclear antibodies; AMA: antimitochondrial antibodies; ASMA: anti-smooth muscle antibody; LKM-1, liver-kidney microsomal antigen.

Table 2 Histological findings in 83 patients with suspected NAFLD

Variable	Definition	Score	Entire cohort(n = 83) (%)	Definitive NASH(n = 45) (%)	Borderline NASH(n = 24) (%)	Simple steatosis(n = 9) (%)	Normal tissue(n = 5) (%)
Steatosis	< 5%	0	8.40	0	8.30	0	100
	5%-33%	1	39.80	13.30	75.00	100	0
	> 33%-66%	2	30.10	46.70	16.70	0	0
	> 66%	3	21.70	40.00	0	0	0
Lobular inflammation (foci per 200 × field)	No foci	0	15.70	0	0	88.90	100
	< 2 foci	1	26.50	8.90	70.80	11.10	0
	2-4 foci	2	43.40	64.40	29.20	0	0
	> 4 foci	3	14.50	26.70	0	0	0
Ballooning	None	0	12	0	0	55.60	100
	Few balloon cells	1	24.10	6.70	70.90	44.40	0
	Many cells/prominent ballooning	2	63.90	93.30	29.10	0	0
Fibrosis stage	None	0	54.20	33.30	66.70	100	100
	Mild, zone 3, perisinusoidal	1A	8.40	11.10	8.30	0	0
	Moderate, zone 3, perisinusoidal	1B	3.60	6.70	0	0	0
	Portal/periportal	1C	13.30	15.60	16.60	0	0
	Perisinusoidal and portal/periportal	2	13.30	22.20	4.20	0	0
	Bridging fibrosis	3	7.20	11.10	4.20	0	0
	Cirrhosis	4	0	0	0	0	0

Table 3 Imaging findings in 83 patients with suspected NAFLD

Steatosis		Entire cohort(n = 83)	Definitive NASH(n = 45)	Borderline NASH(n = 24)	Simple steatosis(n = 9)	Normal tissue(n = 5)
Sonographic grade of hepatosteatosis	Mild	44.00%	27.50%	50.00%	77.80%	100.00%
	Moderate	40.00%	55%	31.80%	11.10%	0%
	Severe	16.00%	17.50%	18.20%	11.10%	0%
Liver attenuation on CT (HU)		43.8 ± 14.6	36.9 ± 11.9	49.5 ± 15.1	55.2 ± 6.2	64.1 ± 3.3

Table 4 Concentrations of serum M30-antigen and M65-antigen in the study groups

Biomarker	Definitive NASH(n = 45)	Borderline NASH(n = 24)	Simple steatosis(n = 9)	Normal tissue(n = 5)	Healthy volunteers(n = 49)	No-NASH(n = 38)	¹P
M30-antigen (IU/L)	200.4 ± 183.1	69.8 ± 37.1	60.1 ± 36.8	81.0 ± 17.5	43.3 ± 45.9	69.0 ± 34.9	< 0.001
²P	Reference category	< 0.001	< 0.01	NS	< 0.001	< 0.001
M65-antigen (IU/L)	362.8 ± 178.7	210.6 ± 59.6	215.3 ± 78.2	207.0 ± 47.4	150.9 ± 44.1	211.2 ± 61.5	< 0.001
²P	Reference category	< 0.001	< 0.01	< 0.05	< 0.001	< 0.001

¹P value calculated using Kruskal-Wallis test.

²Comparisons between definitive NASH patients and other patient groups were performed by Mann-Whitney U Test.

Table 5 Diagnostic performance of serum M30-antigen and M65-antigen levels for the diagnosis of definitive NASH

Patientcategory	Serumbiomarker	Cut-off value¹(IU/L)	Sensitivity(95% CI)	Specificity(95% CI)	Positive predictivevalue (%)	Negative predictivevalue (%)	Negativelikelihood ratio	Area under theROC curve (95% CI)
Borderline NASH	M30-antigen	121.6	60 (44.3-74.3)	95.8 (78.8-99.3)	96.40	56.10	0.42	0.783 (0.668-0.783)
	M65-antigen	241.34	68.9 (53.3-81.8)	83.3 (62.6-95.2)	88.60	58.80	0.37	0.809 (0.697-0.894)
Simple steatosis	M30-antigen	109.64	62.2 (46.5-76.2)	100 (66.2-100.0)	100.00	34.60	0.38	0.83 (0.703-0.918)
	M65-antigen	186.77	93.3 (81.7-98.5)	66.7 (30.1-92.1)	93.30	66.70	0.10	0.807 (0.677-0.902)
Normal tissue	M30-antigen	96.5	64.4 (48.8-78.1)	100 (48.0-100.0)	100.00	23.80	0.36	0.724 (0.508-0.841)
	M65-antigen	227.18	73.3 (58.1-85.4)	80 (28.8-96.7)	97.10	25.00	0.33	0.809 (0.673-0.906)
Healthy controls	M30-antigen	82.52	75.6 (60.5-87.1)	85.7 (72.7-94.0)	82.90	79.20	0.29	0.881 (0.798-0.938)
	M65-antigen	189.64	91.4 (77.6-98.6)	68.1 (36.1-94.2)	92.00	68.20	0.18	0.94 (0.839-0.980)
No-NASH	M30-antigen	121.6	60 (44.3-74.3)	97.4 (86.1-99.6)	96.40	67.30	0.41	0.787 (0.683-0.869)
	M65-antigen	243.82	68.9 (53.3-81.8)	81.6 (65.7-92.2)	81.60	68.90	0.38	0.809 (0.708-0.887)

¹Cut-off value corresponding to the highest accuracy value (minimal false negative and false positive results).

Table 6 Diagnostic performance of serum M30-antigen and M65-antigen levels in discriminating NAFLD patients with severe fibrosis from subjects with early fibrosis

	Cut-off value¹(IU/L)	Sensitivity(95% CI) (%)	Specificity(95% CI) (%)	Positive predictivevalue (%)	Negative predictivevalue (%)	Negativelikelihood ratio	Area under thecurve (95% CI)
M30-antigen	121.6	64.7 (38.4-85.7)	77.3 (65.3-86.7)	42.30	89.50	0.46	0.733 (0.624-0.824)
M65-antigen	243.82	70.6 (44.1-89.6)	71.2 (58.7-81.7)	38.70	90.40	0.41	0.742 (0.635-0.832)

¹Cut-off value corresponding to the highest accuracy value (minimal false negative and false positive results).

Table 7 Diagnostic value of serum biomarkers in combination with CT scans for the diagnosis of definitive NASH according to multivariate regression analysis

		P	Odds ratio	95% CI	Sensitivity(%)	Specificity(%)	Positive predictivevalue (%)	Negative predictivevalue (%)	Accuracy(%)
Combination	CT	0.001	0.891	0.831-0.955	86.10	83.30	86.10	83.30	84.80
	M30-antigen	0.002	1.029	1.011-1.048
Combination	CT	0.003	0.916	0.865-0.971	83.30	83.30	85.70	86.60	83.30
	M65-antigen	0.003	1.015	1.005-1.025

Citation: Yilmaz Y, Dolar E, Ulukaya E, Akgoz S, Keskin M, Kiyici M, Aker S, Yilmaztepe A, Gurel S, Gulten M, Nak SG. Soluble forms of extracellular cytokeratin 18 may differentiate simple steatosis from nonalcoholic steatohepatitis. World J Gastroenterol 2007; 13(6): 837-844
URL: https://www.wjgnet.com/1007-9327/full/v13/i6/837.htm
DOI: https://dx.doi.org/10.3748/wjg.v13.i6.837