Novel nomogram for differential diagnosis of UGT1A1 gene mutation-associated unconjugated hyperbilirubinemia with hemolytic diseases

doi:10.4254/wjh.v18.i4.117456

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Apr 27, 2026 (publication date) through Apr 22, 2026

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World Journal of Hepatology

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Hepatol. Apr 27, 2026; 18(4): 117456
Published online Apr 27, 2026. doi: 10.4254/wjh.v18.i4.117456

Table 1 Comparison of clinical characteristics between patients with uridine diphosphate glucuronosyltransferase 1A1-associated and hemolytic disease-associated unconjugated hyperbilirubinemia in the training and internal validation cohorts, n (%)/median (interquartile range)

Variables	Total (n = 379)	UGT1A1 mutation group (n = 317)	Hemolysis group (n = 62)	Statistic	P value
Age (years)	39.00 (31.00, 51.00)	39.00 (32.00, 52.00)	36.00 (21.25, 48.00)	Z = -2.11	0.035
Sex, male	260 (68.60)	219 (69.09)	41 (66.13)	χ² = 0.21	0.646
Cholelithiasis	58 (15.30)	21 (6.62)	37 (59.68)	χ² = 112.61	< 0.001
Splenomegaly	76 (20.05)	23 (7.26)	53 (85.48)	χ² = 197.95	< 0.001
WBC (× 10⁹/L)	5.57 (4.71, 6.53)	5.56 (4.70, 6.50)	5.67 (4.76, 6.72)	Z = -0.66	0.510
PLT (× 10⁹/L)	209.00 (172.00, 243.00)	211.00 (176.00, 244.00)	185.00 (150.25, 235.00)	Z = -2.63	0.009
RBC (× 10¹²/L)	4.81 (4.38, 5.21)	4.93 (4.55, 5.25)	3.44 (2.96, 4.15)	Z = -9.49	< 0.001
HGB (g/L)	147.00 (134.00, 160.00)	151.00 (139.00, 162.00)	111.00 (93.25, 135.75)	Z = -9.07	< 0.001
HCT (%)	43.30 (39.30, 46.50)	44.40 (41.40, 46.90)	31.55 (27.55, 38.15)	Z = -9.92	< 0.001
MCV (fL)	90.60 (88.10, 93.20)	90.30 (87.90, 92.40)	93.80 (90.08, 99.20)	Z = -5.26	< 0.001
MCH (pg)	30.90 (30.00, 31.85)	30.70 (29.90, 31.60)	32.80 (31.02, 34.40)	Z = -6.63	< 0.001
MCHC (g/L)	340.00 (334.00, 348.00)	339.00 (333.00, 346.00)	349.00 (339.00, 358.50)	Z = -4.18	< 0.001
RDW (%)	12.40 (12.00, 13.00)	12.24 (11.90, 12.60)	17.30 (14.93, 21.32)	Z = -10.98	< 0.001
RDWSD (fL)	40.90 (39.40, 43.40)	40.40 (39.00, 41.90)	56.30 (49.92, 68.20)	Z = -11.15	< 0.001
RET (× 10⁹/L)	68.80 (57.60, 94.45)	66.60 (55.60, 78.70)	225.05 (147.75, 364.07)	Z = -11.98	< 0.001
RET percentage (%)	1.43 (1.19, 1.96)	1.37 (1.14, 1.58)	7.04 (4.19, 11.25)	Z = -12.12	< 0.001
ALT (U/L)	20.00 (15.00, 28.00)	20.00 (15.00, 28.00)	17.50 (12.00, 37.12)	Z = -1.07	0.285
AST (U/L)	23.00 (18.50, 28.85)	23.00 (19.00, 28.00)	21.50 (17.00, 31.00)	Z = -0.10	0.924
TBiL (μmol/L)	40.00 (30.10, 59.10)	35.80 (28.60, 47.10)	94.10 (78.95, 131.02)	Z = -10.59	< 0.001
DBiL (μmol/L)	11.30 (8.75, 14.75)	10.80 (8.50, 13.90)	14.75 (10.00, 20.00)	Z = -4.94	< 0.001
IBiL (μmol/L)	27.10 (20.30, 43.15)	24.90 (19.70, 32.90)	82.05 (54.78, 115.62)	Z = -10.33	< 0.001
IBiL/TBiL ratio (%)	0.70 (0.65, 0.76)	0.69 (0.65, 0.74)	0.86 (0.74, 0.91)	Z = -7.11	< 0.001
ALB (g/L)	46.50 (44.60, 48.30)	46.60 (44.90, 48.30)	45.56 (42.17, 48.20)	Z = -2.61	0.009
GLB (g/L)	27.20 (25.10, 29.20)	27.30 (25.60, 29.55)	25.05 (23.07, 27.48)	Z = -4.57	< 0.001
ALP (U/L)	70.83 (58.00, 86.65)	70.00 (58.00, 85.00)	71.95 (58.00, 96.27)	Z = -0.77	0.439
GGT (U/L)	17.00 (13.00, 24.72)	17.00 (13.00, 23.23)	20.50 (12.25, 40.50)	Z = -1.61	0.108
TBA (μmol/L)	3.60 (2.30, 6.00)	3.31 (2.20, 5.30)	5.80 (3.95, 10.85)	Z = -5.45	< 0.001
BUN (mmol/L)	5.00 (4.25, 5.76)	5.01 (4.24, 5.76)	4.86 (4.26, 5.99)	Z = -0.11	0.911
CR (μmol/L)	64.00 (55.00, 72.21)	66.00 (56.00, 73.00)	55.50 (49.18, 65.86)	Z = -3.96	< 0.001
GFR [mL/(minute × 1.73 m²)]	112.61 (103.25, 121.85)	111.50 (102.80, 119.60)	120.70 (109.67, 134.77)	Z = -4.30	< 0.001
UA (μmol/L)	348.00 (288.57, 402.50)	337.00 (285.00, 393.00)	411.89 (330.75, 485.00)	Z = -5.21	< 0.001
GLU (mmol/L)	5.20 (4.96, 5.46)	5.21 (4.99, 5.48)	5.10 (4.78, 5.44)	Z = -2.08	0.038
TG (mmol/L)	1.00 (0.78, 1.40)	0.96 (0.77, 1.32)	1.27 (0.89, 1.75)	Z = -3.31	< 0.001
TC (mmol/L)	4.17 (3.63, 4.88)	4.32 (3.87, 5.03)	3.00 (2.66, 3.38)	Z = -9.39	< 0.001
HDL (mmol/L)	1.20 (1.00, 1.49)	1.28 (1.11, 1.52)	0.82 (0.73, 1.02)	Z = -9.48	< 0.001
LDL (mmol/L)	2.44 (1.85, 3.09)	2.58 (2.12, 3.21)	1.46 (1.20, 1.69)	Z = -9.28	< 0.001
Spleen wide (mm)	33.55 (30.87, 39.00)	32.57 (30.00, 35.02)	49.04 (41.48, 59.75)	Z = -10.74	< 0.001
CAP (dB/m)	236.02 (206.39, 265.35)	237.00 (207.00, 263.00)	235.28 (205.75, 265.68)	Z = -0.27	0.789
LSM (kPa)	5.10 (4.40, 6.10)	5.00 (4.30, 5.90)	6.52 (5.06, 8.57)	Z = -5.27	< 0.001
COOMBS				χ² = 10.78	0.001
Negative	352 (92.88)	301 (94.95)	51 (82.26)
Positive	27 (7.12)	16 (5.05)	11 (17.74)
Abnormal peripheral blood smear				χ² = 183.42	< 0.001
Normal	338 (89.18)	313 (98.74)	25 (40.32)
Abnormal	41 (10.82)	4 (1.26)	37 (59.68)

UGT1A1: Uridine diphosphate glucuronosyltransferase 1A1; Z: Mann-Whitney test, WBC: White blood counts; PLT: Platelet; RBC: Red blood cell; HGB: Hemoglobin; HCT: Hematocrit; MCV: Mean corpuscular volume; MCH: Mean corpuscular hemoglobin; MCHC: Mean corpuscular hemoglobin concentration; RDW: Red cell distribution width; RDWSD: Red cell distribution width - standard deviation; RET: Reticulocyte; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; TBiL: Total bilirubin; DBiL: Direct bilirubin; IBiL: Indirect bilirubin; ALB: Albumin; GLB: Globulin; ALP: Alkaline phosphatase; GGT: Gamma-glutamyl transferase; TBA: Total bile acid; BUN: Blood urea nitrogen; CR: Creatinine; GFR: Glomerular filtration rate; UA: Uric acid; GLU: Glucose; TC: Total cholesterol; TG: Triglycerides; HDL: High-density lipoprotein; LDL: Low-density lipoprotein; CAP: Controlled attenuation parameter; LSM: Liver stiffness measurement; COOMBS: Coombs test.

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Table 2 Determination of optimal diagnostic cutoff values for variables selected by least absolute shrinkage and selection operator regression using receiver operating characteristic curve analysis

	AUC (95%CI)	Accuracy (95%CI)	Sensitivity (95%CI)	Specificity (95%CI)	PPV (95%CI)	NPV (95%CI)	Cut off
HCT	0.903 (0.839-0.966)	0.826 (0.776-0.867)	0.872 (0.748-0.940)	0.817 (0.760-0.862)	0.506 (0.400-0.612)	0.967 (0.931-0.985)	40.152
RDWSD	0.953 (0.910-0.997)	0.955 (0.923-0.974)	0.872 (0.748-0.940)	0.972 (0.941-0.987)	0.872 (0.748-0.940)	0.972 (0.941-0.987)	45.55
RET percentage	0.986 (0.971-1.00)	0.936 (0.899-0.962)	0.957 (0.858-0.988)	0.931 (0.890-0.958)	0.750 (0.628-0.842)	0.990 (0.965- 0.997)	2.095
IBiL/TBiL ratio	0.776 (0.673-0.857)	0.830 (0.780-0.871)	0.660 (0.517-0.778)	0.867 (0.815- 0.906)	0.517 (0.393-0.638)	0.922 (0.877-0.951)	0.776

AUC: Area under the receiver operating characteristic; CI: Confidence interval; PPV: Positive predictive value; NPV: Negative predictive value; HCT: Hematocrit; RDWSD: Red cell distribution width-standard deviation; RET: Reticulocyte; IBiL: Indirect bilirubin; TBiL: Total bilirubin.

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Table 3 Univariate and multivariable logistic regression analysis to identify factor for differential diagnosis (backward stepwise regression)

Variables	Univariate analysis					Multivariate analysis
Variables	β	SE	Z	P value	OR (95%CI)	β	SE	Z	P value	OR (95%CI)
Splenomegaly
No					1.00 (reference)
Yes	4.28	0.49	8.82	< 0.001	72.14 (27.88-186.68)
Peripheral blood smear
Normal					1.00 (reference)					1.00 (reference)
Abnormal	4.66	0.65	7.14	< 0.001	105.61 (29.37-379.76)	4.12	1.74	2.37	0.018	61.73 (2.05-1854.84)
RDWSD
< 45.55 fL					1.00 (reference)					1.00 (reference)
≥ 45.55 fL	5.49	0.6	9.11	< 0.001	241.44 (74.19-785.72)	3.43	1.24	2.76	0.006	30.72 (2.71-348.77)
RET percentage
< 2.1%					1.00 (reference)					1.00 (reference)
≥ 2.1%	5.72	0.77	7.42	< 0.001	304.50 (67.25-1378.84)	4.43	1.21	3.65	< 0.001	84.27 (7.82-908.54)
HCT
< 40.15%					1.00 (reference)					1.00 (reference)
≥ 40.15%	-3.41	0.47	-7.25	< 0.001	0.03 (0.01-0.08)	-2.16	1.07	-2.02	0.043	0.11 (0.01-0.94)
IBiL/TBiL ratio	10.2	1.67	6.09	< 0.001	26851.06 (1009.96-713868.82)	7.81	4.68	1.67	0.095	2457.55 (0.25-23737621.41)

OR: Odds ratio; CI: Confidence interval; RDWSD: Red cell distribution width-standard deviation; RET: Reticulocyte; HCT: Hematocrit; IBiL: Indirect bilirubin; TBiL: Total bilirubin.

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Citation: Yu HT, Li MH, Tang S, Liang C, Sheng DC, Jiang H, Dong JX, Hou W, Zheng SJ. Novel nomogram for differential diagnosis of UGT1A1 gene mutation-associated unconjugated hyperbilirubinemia with hemolytic diseases. World J Hepatol 2026; 18(4): 117456
URL: https://www.wjgnet.com/1948-5182/full/v18/i4/117456.htm
DOI: https://dx.doi.org/10.4254/wjh.v18.i4.117456