Pediatric Wilson disease presenting as acute liver failure: Prognostic indices

doi:10.12998/wjcc.v9.i14.3273

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World Journal of Clinical Cases

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World J Clin Cases. May 16, 2021; 9(14): 3273-3286
Published online May 16, 2021. doi: 10.12998/wjcc.v9.i14.3273

Table 1 Results of ATP7B sequencing in patients with Wilson disease with acute liver failure

Patient No.	*ATP7B* variants		Category of variants	Outcome
1	c.314C>A, p.Ser105X²	c.3700delG, p.Val1234Leufs*96²	Biallelic severe	Liver transplant
2	c.2333G>T, p.Arg778Leu/c.2310C>G, p.Leu770Leu¹	c.3517G>A, p.Glu1173Lys	Non-severe	Liver transplant
3	c.2333G>T, p.Arg778Leu/c.2310C>G, p.Leu770Leu¹	c.3089Gly>A, p.Gly1030Asp³	Non-severe	Survival
4	c.2975C>T, p.Pro992Leu	c.2975C>T, p.Pro992Leu	Non-severe	Survival
5	c.994G>T, p.Glu332X	c.1529T>C, p.Leu510Pro³	Monoallelic severe	Survival
6	c.2455C>T, p.Gln819X³	c.1842_1845delins23³	Biallelic severe	Survival
7	c.2975C>T, p.Pro992Leu	c.2975C>T, p.Pro992Leu	Non-severe	Survival
8	c.994G>T, p.Glu332X	c.994G>T, p.Glu332X	Biallelic severe	Survival
9	c.2621C>T, p.Ala874Val/c.4072delG, p.Ala1358Profs*35¹^,²	c.2975C>T, p.Pro992Leu²	Monoallelic severe	Death
11	c.2333G>T, p.Arg778Leu	c.3182G>A, p.Gly1061Glu	Non-severe	Survival
12	c.2333G>T, p.Arg778Leu	c.2621C>T, p.Ala874Val	Non-severe	Death
13	c.2975C>T, p.Por992Leu²	c.3443T>C, p.Ile1148Thr²	Non-severe	Survival
14	c.2333G>T, p.Arg778Leu/c.2310C>G, p.Leu770Leua	c.1708-5T>G,	Monoallelic severe	Survival
15	c.3517G>A, p.Glu1173Lys	c.3884C>T, p.Ala1295Val	Non-severe	Liver transplant
16	c.2356-2A>G	c.2333G>T, p.Arg778Leu/c.2310C>G, p.Leu770Leu¹	Monoallelic severe	Survival
17	c.2333G>T, p.Arg778Leu/c.2310C>G, p.Leu770Leu¹	c.2975C>T, p.Pro992Leu	Non-severe	Survival
18	c.2333G>T, p.Arg778Leu/c.2310C>G, p.Leu770Leu¹	c.3809A>G, p.Asn1207Ser	Non-severe	Survival
21	c.2932_2933insG, pVal978Glyfs*50²^,³	c.2333G>T, p.Arg778Leu²	Monoallelic severe	Survival
22	c.1708-1G>C	c.2333G>T,p.Arg778Leu	Monoallelic severe	Survival
23	c.1708-1G>C	c.2333G>T,p.Arg778Leu	Monoallelic severe	Survival
24	c.2528G>A, p.Gly843Glu³	c.2975C>T,p.Pro992Leu	Non-severe	Survival
25	c.2975C>T, p.Pro992Leu	c.2975C>T, p.Pro992Leu	Non-severe	Survival
26	c.2543dupG, p.Asn849Glnfs*5²^,³	c.2924C>A, p.Ser975Tyr²	Monoallelic severe	Survival
27	c.2333G>T, p.Arg778Leu	c.2975C>T, p.Pro992Leu	Non-severe	Survival
28	c.2975C>T, p.Pro992Leu	c.2668G>A, p.Val890Met	Non-severe	Survival
29	c.2924C>A, p.Ser975Tyr	c.2128G>A, p.Gly710Ser	Non-severe	Survival
30	c.2620G>C, p.Ala847Pro²	c.2621C>T, p.Ala874Val²	Non-severe	Survival
31	c.2939G>A, p.Cys980Tyr	c.2333G>T, p.Arg778Leu	Non-severe	Survival
32	c.2719C>T, p.Gln907X⁴	c.2924C>A, p.Ser957Tyr²	Non-severe	Survival
34	c.1168A>G, p.Ile390Val	c.2975C>T, p.Pro992Leu, /c.1708-1G>C	Non-severe	Survival
35	c.2157>A, p.Tyr719X	c.3452G>A, p.Arg1151His	Non-severe	Survival
38	c.2333G>T, p.Arg778Leu	c.2333G>T, p.Arg778Leu	Non-severe	Survival
39	c.314C>A, p.Ser105X	c.2620G>C,p.Asn874Pro	Non-severe	Survival
40	c.2333G>T, p.Arg778Leu/c.2310C>G, p.Leu770Leu¹^,²	c.3809A>G,p.Asn1270Ser²	Non-severe	Survival
41	c.3836A>G, p.Asp1279Gly²	c.2333G>T, p.Arg778Leu²	Non-severe	Survival

¹c.2333G>T, p.Arg778Leu is a confirmed disease-causing variant. c.2310C>G, p.Leu770Leu is a single nucleotide polymorphism variant linked to c.2333G>T, p.Arg778Leu. c.2621C>T, p.Ala874Val and c.4072delG, p.Ala1358Profs*35, both of which are confirmed disease-causing variants, are also linked.

²Parental origins confirmed. Variants in left panel, paternal; in right panel, maternal. Patients 4, 7, 8, 25, and 38 were homozygotes. Patient 34 harbored three different variants, without parental origin confirmation. Patient 10, 19, 33, 36 and 37 were not assessed by ATP7B sequencing.

³Novel.

⁴de novo. ATP7B variants were categorized as either severe, including frameshift, nonsense, and classical splice-site variants, or non-severe (all others).

Table 2 Demographics and baseline clinical characteristics in patients with Wilson disease with acute liver failure with non-transplanted survival (n = 35), poor outcome (n = 6; 3 dying, 3 surviving after liver transplantation), and dying (n = 3)

	Poor outcome group	Survival group	P value	Dying group	Survival group	P value
	n = 6 (14.63%)	n = 35 (85.37%)	P value	n = 3 (7.89%)	n = 35 (92.10%)	P value
Males (%)	2 (33.33%)	20 (57.14%)	0.390	1 (33.33%)	20 (57.14%)	0.577
Age (yr)	9.82 ± 2.16	10.54 ± 2.60	0.685	11.28 ± 2.17	10.54 ± 2.64	0.465
Jaundice	6 (100%)	26 (74.29%)	0.309	3 (100%)	26 (74.29%)	1.000
Hepatomegaly	2 (33.33%)	8 (22.86%)	0.622	1 (33.33%)	8 (22.86%)	1.000
Splenomegaly	2 (33.33%)	13 (37.14%)	1.000	1 (33.33%)	13 (37.14%)	1.000
Encephalopathy	4 (66.67%)	3 (8.57%)	0.005^a	2 (66.67%)	3 (8.57%)	0.040^a
Total bilirubin (μmol/L)	452.22 ± 294.19	129.20 ± 175.64	0.007^a	395.03 ± 187.16	129.20 ± 175.64	0.021^a
Direct bilirubin (μmol/L)	251.27 ± 157.76	75.79 ± 108.91	0.008^a	229.77 ± 115.63	75.79 ± 108.91	0.025^a
Bile acid (μmol/L)	103.80 ± 96.52	88.61 ± 46.64	0.650	128.87 ± 129.41	88.61 ± 46.64	0.976
ALT (IU/L)	48.67 ± 43.32	61.68 ± 49.13	0.519	74.67 ± 47.44	61.68 ± 49.13	0.432
AST (IU/L)	89.00 ± 26.01	131.24 ± 105.11	0.555	111.67 ± 12.22	131.24 ± 105.11	0.607
GGT (IU/L)	89.67 ± 56.39	159.63 ± 76.06	0.035^a	51.00 ± 37.27	159.63 ± 76.06	0.019^a
ALP (IU/L)	155.33 ± 147.72	224.19 ± 150.24	0.285	220.67 ± 188.32	224.19 ± 150.24	0.935
Albumin (g/L)	26.93 ± 6.67	25.74 ± 4.23	0.658	28.80 ± 9.20	25.74 ± 4.23	0.343
Total protein (g/L)	56.10 ± 7.80	60.81 ± 7.93	0.249	52.50 ± 5.75	60.81 ± 7.93	0.095
Ammonia (μmol/L)	96.33 ± 26.96	62.65 ± 27.94	0.011^a	114.33 ± 25.58	62.65 ± 27.94	0.015^a
Serum creatinine (μmol/L)	55.00 ± 47.44	42.24 ± 13.45	0.791	26.33 ± 1.53	42.24 ± 13.45	0.030^a
Serum urea nitrogen (mmol/L)	7.75 ± 5.96	3.94 ± 1.20	0.076	4.43 ± 0.95	3.94 ± 1.20	0.386
PT (s)	39.00 ± 15.36	27.04 ± 7.06	0.011^a	48.4 ± 17.84	27.04 ± 7.06	0.009^a
INR	4.12 ± 2.20	2.53 ± 0.89	0.012^a	5.46 ± 2.57	2.53 ± 0.89	0.009^a
APTT (s)	74.17 ± 27.70	55.85 ± 12.80	0.042^a	90.00 ± 34.01	55.85 ± 12.80	0.028^a
Fibrinogen (g/L)	1.03 ± 0.40	1.40 ± 0.41	0.080	0.733 ± 0.23	1.40 ± 0.41	0.014^a
WCC × 10⁹/L	11.40 ± 6.54	8.15 ± 4.67	0.203	6.40 ± 2.36	8.15 ± 4.67	0.626
Hemoglobin (g/L)	85.47 ± 19.42	106.41 ± 22.89	0.027^a	94.73 ± 19.40	106.41 ± 22.89	0.316
Reticulocyte %	7.78 ± 3.81	4.38 ± 2.72	0.080	7.05 ± 4.10	4.38 ± 2.72	0.136
Platelet count × 10⁹/L	100.33 ± 41.32	109.66 ± 48.01	0.796	69.33 ± 11.59	109.66 ± 48.01	0.129
Serum sodium (mmol/L)	133.83 ± 2.48	136.28 ± 3.28	0.073	132.00 ± 2.00	136.28 ± 3.28	0.029^a
Ceruloplasmin (g/L)	0.080 ± 0.002	0.068 ± 0.029	0.082	0.079 ± 0.00	0.068 ± 0.029	0.281
24 h urine copper (μg/24 h)	2563 ± 1915	2083 ± 1964	NA	582.00 ± NA	2083 ± 1964	NA
KCHC	12.00 ± 1.67	8.43 ± 3.42	0.020^a	11.33 ± 0.58	8.43 ± 3.42	0.157
MELD/PELD score	31.67 ± 9.87	19.00 ± 7.65	0.007^a	38.00 ± 7.00	19.00 ± 7.65	0.006^a
LIU-PT score	223.33 ± 63.49	115.77 ± 54.29	0.002^a	221.67 ± 45.18	115.77 ± 54.29	0.016^a
LIU-INR score	390.67 ± 89.19	217.49 ± 95.36	0.002^a	424.33 ± 110.21	217.49 ± 95.36	0.019^a
aLIU-PT score	338.50 ± 114.04	160.31 ± 79.75	0.003^a	353.00 ± 35.38	160.31 ± 79.75	0.010^a
aLIU-INR score	428.17 ± 147.81	189.74 ± 101.95	0.002^a	467.00 ± 61.25	189.74 ± 101.95	0.009^a
Devarbhavi model score	32.13 ± 18.64	8.59 ± 11.62	0.007^a	30.47 ± 10.00	8.59 ± 11.62	0.014^a

^aP value < 0.05. aLIU: Admission to Liver Injury Unit; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; APTT: Active partial thromboplastin times; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transpeptidase; INR: International normalized ratio; KCHC: King’s College Hospital Criteria; LIU: Liver Injury Unit; MELD/PELD: Model for end-stage liver disease/pediatric end-stage liver disease; NA: Not available; PT: Prothrombin time; WCC: White cell count.

Table 3 Area under the curve and its related indices for comparison of different models predicting mortality in pediatric Wilson disease with acute liver failure

Model	AUC	95%CI			Sensitivity	Specificity	Cutoff value
KCHC	0.748	0.604	-	0.892	1.000	0.714	11.0
MELD/PELD	0.981	0.939	-	1.000	1.000	0.943	31.0
LIU-PT	0.924	0.830	-	1.000	1.000	0.857	175
LIU-INR	0.914	0.795	-	1.000	1.000	0.800	300
aLIU-PT	0.952	0.884	-	1.000	1.000	0.943	290
aLIU-INR	0.962	0.900	-	1.000	1.000	0.943	374
Devarbhavi model	0.933	0.851	-	1.000	1.000	0.914	23.0

AUC: Area under the curve; aLIU: Admission to Liver Injury Unit; KCHC: King’s College Hospital Criteria; LIU: Liver Injury Unit; MELD/PELD: Model for end-stage liver disease/pediatric end-stage liver disease.

Table 4 Sensitivity, specificity, and positive and negative predictive values of different mortality-predicting models using their original cutoff values in our pediatric patients with Wilson disease with acute liver failure

	KCHC			MELD/PELD			LIU-PT			LIU-INR			aLIU-PT			aLIU-INR			Devarbhavi model
Cutoff values	< 11	≥ 11	P	< 30	≥ 30	P	< 153	≥ 153	P	< 297	≥ 297	P	< 173	≥ 173	P	< 212	≥ 212	P	< 10.4	≥ 10.4	P
Death (n)	0	3	0.034^a	0	3	0.004^a	0	3	0.013^a	0	3	0.013^a	0	3	0.04^a	0	3	0.031^a	0	3	0.02^a
Survival (n)	25	10	0.034^a	31	4	0.004^a	29	7	0.013^a	29	7	0.013^a	25	11	0.04^a	26	10	0.031^a	27	8	0.02^a
Sensitivity			1.000			1.000			1.000			1.000			1.000			1.000			1.000
Specificity			0.714			0.886			0.806			0.806			0.694			0.722			0.771
PPV			0.231			0.429			0.300			0.300			0.214			0.231			0.273
NPV			1.000			1.000			1.000			1.000			1.000			1.000			1.000

^aP value < 0.05. aLIU: Admission to Liver Injury Unit; KCHC: King’s College Hospital Criteria; LIU: Liver Injury Unit; MELD/PELD: Model for end-stage liver disease/pediatric end-stage liver disease; NPV: Negative predictive value; PPV: Positive predictive value.

Citation: Fang WY, Abuduxikuer K, Shi P, Qiu YL, Zhao J, Li YC, Zhang XY, Wang NL, Xie XB, Lu Y, Knisely AS, Wang JS. Pediatric Wilson disease presenting as acute liver failure: Prognostic indices. World J Clin Cases 2021; 9(14): 3273-3286
URL: https://www.wjgnet.com/2307-8960/full/v9/i14/3273.htm
DOI: https://dx.doi.org/10.12998/wjcc.v9.i14.3273