Prediction of hepatocellular carcinoma development by aminotransferase to platelet ratio index in primary biliary cholangitis

Table 1 Descriptions of prognostic risk models for primary biliary cholangitis

	Time of evaluation	Definition of suboptimal treatment response
Rotterdam	1 yr	Abnormal bilirubin and/or albumin
Paris I	1 yr	ALP ≥ 3 × ULN or AST ≥ 2 × ULN or bilirubin > 1 mg/dL
Paris II	1 yr	ALP > 1.5 × ULN or AST > 1.5 × ULN or bilirubin > 1 mg/dL
Barcelona	1 yr	ALP > 1 × ULN and decrease in ALP < 40%
Toronto	2 yr	ALP > 1.67 × ULN
APRI	Baseline	AST/ULN of AST/platelet (× 109) × 100
APRI-r1	1 yr	AST/ULN of AST/platelet (× 109) × 100

ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; APRI: AST to platelet ratio index; APRI-r1: APRI at 1-year; AST: Aspartate aminotransferase; PBC: Primary biliary cholangitis; ULN: Upper limit of normal.

Table 2 Baseline characteristics of the study cohort

Variable	Whole cohort,n = 144	Patients with HCC,n = 12	Patients without HCC,n = 132	P value
Age, yr	57.8 (48.7-71.5)	68.1 (56.2-74.6)	57.0 (48.2-70.7)	0.278
Female sex	127 (88.2)	9 (75.0)	118 (89.4)	0.153
Duration of follow-up, yr	6.9 (3.5-10.4)	8.9 (5.2-11.4)	6.8 (3.5-10.1)	0.499
Ursodeoxycholic acid, mg	750 (750-750)	750 (750-750)	750 (750-750)	0.576
Suboptimal treatment response,	61 (42.4)	9 (75.0)	52 (39.4)	0.0173
Rotterdam criteria
Diabetes	29 (20.1)	6 (50.0)	23 (17.4)	0.0163
Smoking1	13 (9.5)	4 (33.3)	9 (6.8)	0.0113
Alcohol1	17 (13.7)	2 (16.7)	15 (11.4)	0.623
Cirrhosis	41 (28.5)	8 (66.7)	33 (25.0)	0.0053
Histological stage 3-42	23 (44.2)	3 (50.0)	20 (43.5)	1.00
Platelet, x 109/L1	216 (152-262)	133 (95-150)	229 (175-266)	< 0.0013
Creatinine, μmol/L1	69 (60-82)	73 (60-79)	68 (60 - 82)	0.0473
Albumin, g/L1	40 (36-42)	24 (14-30)	40 (36-42)	0.087
Bilirubin, μmol/L1	14 (10-26)	30 (19-55)	14 (10-26)	< 0.0013
ALP (U/L)	284 (196-484)	343 (227-362)	273 (196-496)	0.991
ALT, U/L1	74 (54-130)	85 (64-109)	74 (53-133)	0.565
AST, U/L1	68 (51-115)	76 (56-109)	68 (51-115)	0.741
GGT, U/L1	517 (256-771)	626 (353-843)	490 (224-760)	0.285
PT, s	11.3 (10.5-11.7)	11.8 (11.7-12.5)	11.2 (10.5-11.7)	0.0073
AMA positivity	119 (82.6)	8 (66.7)	111 (84.1)	0.223
Globulin, mg/dL1	41 (37-46)	40 (37-44)	41 (37-46)	0.337
IgM, mg/dL1	363 (250-502)	446 (282-579)	359 (250-478)	0.563
Mayo risk score1	4.7 (3.8-5.5)	5.1 (4.8-6.6)	4.6 (3.8-5.4)	0.0223
MELD score	6 (6-8)	8 (6-9)	6 (6-7)	0.097
CP score1	5 (5-6)	6 (5-6)	5 (5-6)	0.125
CP class B/C1	29 (20.1)	2 (16.7)	25 (19.2)	1.00
APRI	1.00 (0.60-1.84)	2.02 (1.05-3.34)	0.97 (0.59-1.72)	0.053
APRI > 0.541	102 (78.5)	9 (90.0)	93 (77.5)	0.689
APRI-r11	0.22 (0.13-0.43)	0.54 (0.31-0.70)	0.20 (0.13-0.38)	0.0023
APRI-r1> 0.541	27 (19.6)	6 (50.0)	21 (16.7)	0.0133

Data are presented as n (%), and all continuous variables are expressed as median (interquartile range).

¹Missing data: smoking (7), alcohol (3), platelet (10), creatinine (1), albumin (2), bilirubin (2), ALT (2), AST (6), GGT (2), globulin (6), IgM (20), Mayo risk score (2), CP score (2), APRI (14), APRI-r1 (6);

²Sixty-two patients had liver biopsies done, with reports available for review for 52;

³P values < 0.05. All continuous variables expressed in median (interquartile range). ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AMA: Anti-mitochondrial antibody; APRI: AST/platelet ratio index; APRI-r1: APRI at 1 year after treatment; AST: Aspartate aminotransferase; CP: Child-Pugh; GGT: Gamma-glutamyl transferase; IgM: Immunoglobulin M; MELD: Model for end-stage liver disease; PT: Prothrombin time.

Table 3 HRs and 95%CIs for the association between hepatocellular carcinoma development and different variables

Variables	Univariate analysis			Multivariate analysis
	HR	95%CI	P value	HR	95%CI	P value
Age, yr	1.06	1.01-1.11	0.0162	1.07	1.02-1.12	0.0042
Male sex	5.22	1.27-21.44	0.0222	3.67	0.69-19.56	0.128
Diabetes mellitus	3.01	0.96-9.44	0.058
Cirrhosis	8.02	2.35-27.29	< 0.0012	4.38	1.06-18.14	0.0412
APRI > 0.54	3.43	0.43-27.19	0.243
APRI-r1 > 0.54	5.10	1.64-15.86	0.0052	3.94	1.04-14.94	0.0432
Creatinine, μmol/L	1.02	0.99-1.05	0.222
Albumin, g/L	0.85	0.75-0.96	0.0072
Bilirubin, µmol/L	1.01	0.98-1.03	0.514
ALP, U/L	0.997	0.994-1.00	0.104
ALT, U/L	0.996	0.987-1.00	0.331
AST, U/L	0.996	0.975-1.01	0.467
GGT, U/L	1.00	0.999-1.001	0.975
PT, s	1.40	0.99-1.98	0.0602
AMA positivity	0.52	0.16-1.75	0.292
Globulin, mg/dL	0.99	0.90-1.08	0.804
IgM, mg/dL	1.00	0.997-1.002	0.830
Suboptimal treatment response, Rotterdam criteria1	5.95	1.59-22.26	0.0082	2.18	0.45-10.58	0.334

¹In the multivariate analyses, albumin was not included as this variable was already included in the Rotterdam criteria.

²P values < 0.05. ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AMA: Anti-mitochondrial antibody; APRI: AST to platelet ratio index; APRI-r1: APRI at 1 year after treatment; AST: Aspartate aminotransferase; CI: Confidence interval; GGT: Gamma-glutamyl transferase; HR: Hazard ratio; IgM: Immunoglobulin M; PT: Prothrombin time.

Table 4 Adjusted HRs and 95%CIs for the association between hepatocellular carcinoma development and different variables

Criteria	HR	95%CI	P value
Rotterdam
Age	1.07	1.02-1.12	0.0041
Male sex	3.67	0.69-19.56	0.128
Cirrhosis	4.38	1.06-18.14	0.0411
APRI-r1 > 0.54	3.94	1.04-14.94	0.0431
Suboptimal treatment response	2.18	0.45-10.58	0.334
Paris I
Age	1.07	1.02-1.12	0.0031
Male sex	3.04	0.54-17.12	0.207
Albumin	0.94	0.80-1.09	0.386
Cirrhosis	4.37	1.07-17.75	0.0391
APRI-r1 > 0.54	3.92	1.06-14.54	0.0411
Suboptimal treatment response	1.7	0.41-7.03	0.466
Barcelona
Age	1.07	1.02-1.12	0.0051
Male sex	3.26	0.56-18.96	0.188
Albumin	0.93	0.80-1.07	0.307
Cirrhosis	4.44	1.06-18.56	0.0411
APRI-r1 > 0.54	4.47	1.26-15.93	0.0211
Suboptimal treatment response	1.22	0.33-4.49	0.768
Toronto
Age	1.07	1.02-1.13	0.0031
Male sex	3.22	0.56-18.50	0.19
Albumin	0.94	0.80-1.09	0.425
Cirrhosis	4.56	1.09-19.17	0.0381
APRI-r1 > 0.54	4.16	1.10-15.69	0.0361
Suboptimal treatment response	1.46	0.31-6.89	0.631

¹P-values < 0.05. The adjusted HR for suboptimal response was derived by multivariate analysis with other significant variables in Table 3 (age, male sex, cirrhosis and albumin) included. Separate multivariate analysis was performed for each criteria in defining suboptimal response. In the multivariate analyses, albumin was not included for the Rotterdam criteria. APRI-r1: AST/platelet ratio index at 1-year; HR: Hazard ratio.

Table 5 Prediction of hepatocellular carcinoma development by APRI-r1 in combination with suboptimal treatment response

Criteria	Univariate analysis					Multivariate analysis1
	HR		95%CI	P value	P trend	HR	95%CI	P value	P trend
Rotterdam
Low-risk	Ref	-		-		Ref	-	-
Intermediate-risk	2.81	0.56-14.01		0.208	< 0.0012	1.54	0.25-9.63	0.644	0.0062
High-risk	10.29	2.55-41.48		0.0012		7.95	1.56-40.45	0.0122
Paris I
Low-risk	Ref	-		-		Ref	-	-
Intermediate-risk	2.81	0.63-12.60		0.177	0.0032	2.34	0.40-13.60	0.345	0.0132
High-risk	8.38	1.99-35.21		0.004		7.28	1.45-36.71	0.0162
Barcelona
Low-risk	Ref	-		-		Ref	-	-
Intermediate-risk	1.28	0.29-5.72		0.75	0.0022	0.53	0.08-3.34	0.496	0.0382
High-risk	10.66	2.85-39.89		< 0.0012		5.54	1.29-23.71	0.0212
Toronto
Low-risk	Ref	-		-		Ref	-	-
Intermediate-risk	3.25	0.81-13.06		0.097	0.052	4.4	0.97-19.90	0.055	0.061
High-risk	4.22	0.85-20.97		0.079		4.77	0.78-29.24	0.091

¹The adjusted HR for suboptimal response was derived by multivariate analysis with other significant variables in Table 3 (age, male sex, cirrhosis and albumin) included;

²P-values < 0.05. Separate multivariate analysis was performed for each criteria in defining suboptimal response. In the multivariate analyses, albumin was not included for the Rotterdam criteria, as this variable was already included in the criteria. APRI-r1: AST/platelet ratio index at 1-year; CI: Confidence interval; HR: Hazard ratio.

Table 6 Predictive performances of prognostic models for hepatocellular carcinoma development

Categorical variable	Rotterdam	Paris I	Barcelona	Toronto	Cirrhosis	Thrombocytopenia, < 150 × 109/L	Hyperbilirubinemia,> 17 mmol/L
AUROC	0.68	0.67	0.64	0.64	0.71	0.75	0.64
(95%CI)	(0.52-0.80)	(0.52-0.81)	(0.48-0.78)	(0.47-0.78)	(0.56-0.86)	(0.58-0.90)	(0.49-0.77)
Sensitivity	75.00%	66.60%	58.30%	63.60%	66.70%	70.00%	66.70%
Specificity	60.60%	66.60%	68.90%	63.60%	75.00%	79.00%	60.80%
PPV	14.80%	15.40%	14.60%	14.00%	19.50%	21.20%	13.60%
NPV	96.40%	95.70%	94.80%	94.90%	96.10%	97.00%	84.90%
Continuous variable	APRI	APRI-r1	Mayo risk score	MELD score	CP score
AUROC	0.68	0.77	0.7	0.63	0.62
(95%CI)	(0.49-0.87)	(0.64-0.88)	(0.54-0.84)	(0.43-0.79)	(0.47-0.76)
Sensitivity	-	-	-	-	-
Specificity	-	-	-	-	-
PPV	-	-	-	-	-
NPV	-	-	-	-	-

APRI: AST to platelet ratio index at baseline; APRI-r1: APRI at 1-year; AUROC: Area under receiver operating curve; CP: Child-Pugh; MELD: Model for end-stage liver disease; NPV: Negative predictive value; PPV: Positive predictive value.