Wilson disease: Histopathological correlations with treatment on follow-up liver biopsies

Table 1 Baseline characteristics of patients who showed progression of the histologic score (progressors) vs those who showed overall improvement or no progression in histology (non-progressors)

	Progressors	Non-progressors
Age at diagnosis (mean ± SD) (yr)	18.0 ± 8.8	16.6 ± 9.8
Phenotype	All hepatic phenotype	4 with hepatic phenotype; 2 with mixed hepatic and neurological phenotype
AST U/L (baseline) (normal range 15-43)	60.0 ± 56.8 (range 18-44) (6)	64.6 ± 51.3 (range 15-129) (6)
AST U/L (time of 2nd biopsy)	45.1 ± 48.2 (range 20-143) (6)	25.5 ± 9.7 (range 13-39) (6)
AST U/L (time of 3rd biopsy)	27.3 ± 10.2 (range 13-44) (6)	28.7 ± 10.8 (range 15-41) (3)
AST U/L (time of 4th biopsy)	24 and 28 (2)
ALT U/L (baseline) (normal range 6-43)	83.5 ± 40.2 (range 45-137) (6)	84.5 ± 60.7 (range 15-164) (6)
ALT U/L (time of 2nd biopsy)	48.5 ± 21.8 (range 24-80) (6)	26.1 ± 12.3 (range 10-46) (6)
ALT U/L (time of 3rd biopsy)	42.0 ± 17.2 (22 and 68) (2)	32.7 ± 17.2 (range 8-48) (3)
ALT U/L (time of 4th biopsy)	47.0 ± 7.0 (42 and 52) (2)
24 h urinary Cu μg/24 h (baseline)	679.7 ± 504.0 (6)	1245.0 ± 1649.0 (6)
Hepatic Cu mg/g dry liver (baseline)	534.4 ± 298.7 (6)	455.0 ± 245.3 (6)
Type of treatment	2 = penicillamine; 4 = zinc	3 = penicillamine; 3 = zinc
	One patient switched to penicillamine during follow up	No change of treatment during follow up

The numbers in brackets represent the number of patients included in the analysis.

Table 2 Histopathology score of serial liver biopsies in WD patients who showed improved or stable hepatic fibrosis

Patient	Biopsy interval (yr)	Biopsy data			Iron staining	Treatment type
		Inflammation	Steatosis	Fibrosis
Group NP
11		0	0	0	None	-
	2	0	0	0	None	Zinc
21		0	2	0	None	-
	5	0	1	0	None	Zinc
3		2	1	2	None	-
	3	0	0	0	None	Zinc
	3	0	0	0	None	Zinc
4		0	1	1	3+, diffuse	-
	2	0	1	0	3+, diffuse	PCA
5		0	0	0	None	-
	4	0	0	0	None	PCA
6		0	2	0	Not done	-
	2	1	1	0	None	PCA
	4	1	1	0	2+, focal	PCA
Group P
7		0	2	0	None	-
	3	1	1	2	None	Zinc
8		1	1	0	Not done	-
	2	1	1	0	None	Zinc
	3	1	1	2	None	Zinc
	2	2	1	2	None	Zinc
9		0	3	1	1+, Kuppfer	-
	3	0	3	1	None	Zinc
	2	1	3	2	None	Zinc
	3	1	3	2	None	Zinc
10		1	0	2	None	Zinc
	12	2	1	3	None	PCA
11		0	0	0	2+	-
	5	1	0	2	None	PCA
12		0	0	1	None	-
	5	1	1	2	None	PCA

Grade of inflammation and steatosis are also described.

¹Indicates the two patients who presented with mixed hepatic and neurological phenotype. NP: Non-progressors; P: Progressors; Zinc: Zinc sulfate; PCA: Penicillamine.

Table 3 Review of the case series describing the evolution of hepatic histology in WD

Grand et al[18], 1975		Treatment: PCA
Interbiopsy interval 2-7 yr		Hepatic copper (μg/g dry weight)		AST/ALT		Histopathology
	Age at diagnosis (yr)	Before	After	Before	After	Before	After
1	24	NA	400	NA	NA	Inflammation 3+; connective tissue 13%; fatty vacuolization 0.5%	Inflammation 1+; connective tissue 7%; fatty vacuolization 0.5%
2	18	NA	80	NA	NA	Inflammation 2+; connective tissue NA; fatty vacuolization NA	Inflammation 2+; connective tissue 3%; fatty vacuolization 2%
3	11	1360	757	NA	NA	Inflammation 3+; connective tissue 17.6%; fatty vacuolization 5%	Inflammation 0/1+; connective tissue 7.6%; fatty vacuolization 3%
4	13.5	1112	90	NA	NA	Inflammation 4+; connective tissue 16%; fatty vacuolization 13%	Inflammation 0; connective tissue 14%; fatty vacuolization 8%
Sternlieb et al[19], 1976		Treatment: PCA
Interbiopsy interval 3-5 yr		Hepatic copper (μg/g dry weight)		AST/ALT		Histopathology
	Age at diagnosis (yr)	Before	After	Before	After	Before	After
1	15	821	109	52/59	39/20	Mild fibrosis; steatosis	Mild fibrosis; marked diminution of steatosis
2	9	1004	945	76/136	20/44	Steatosis	Marked diminution of steatosis
3	12	866	737	180/190	24/26	NA	NA
4	15	1123	239	22/94	16/22	Severe steatosis	Resolution of severe steatosis
5	10	832	453	57/88	53/48	Inflammation; mild fibrosis; steatosis	Resolution of inflammation; mild fibrosis; diminution of steatosis
6	12	1177	1050	65/85	45/43	Inflammation; severe fibrosis and steatosis	Resolution of inflammation; diminution of severe steatosis and fibrosis
7	14	NA	NA	75/82	50/35	Inflammation; steatosis; cirrhosis	Diminution of steatosis and inflammation; persistence of cirrhosis
Shiono et al[20], 2001		Treatment: PCA
Interbiopsy interval 3-8.5 yr		Hepatic copper (mg/g dry weight)		ALT (IU/L)		Histopathology (only stage of fibrosis)
	Age at diagnosis (yr)	Before	After	Before	After	Before	After
1	16	990	319	121	65	Cirrhosis with chronic active hepatitis	Cirrhosis
2	17	1025	200	241	109	Chronic active hepatitis	Chronic inactive hepatitis
3	19	524	190	17	25	Cirrhosis	Cirrhosis
4	23	540	129	19	18	Cirrhosis	Cirrhosis
Marcellini et al[12], 2005		Treatment: zinc sulfate
Interbiopsy interval 10 yr		Hepatic copper (median of 22 pts) (mg/g dry weight)		AST/ALT (mean of 22 pts)		Histopathology summary of 22 pts
		Before	After	Before	After	Before	After
Mean age at diagnosis (yr)		873 (670-982)	690 (600-890)	110/94	21.7/23.7	Inflammation grade 1 in 81% of pts, grade 0 in 19%; steatosis grade 1 in 50%, grade 2 in 22.7%, grade 3-4 in 27.3%; fibrosis stage 1 in 54%, stage 3 in 46%	Resolution of inflammation in all pts; steatosis grade 1 in 90%, grade 2 in 10%; fibrosis stage 1 in 81%, stage 3 in 19%
6.1 ± 2.5
Askari et al[13], 2003		Treatment: trientine + zinc, followed by long-term zinc
Interbiopsy interval 4.4-10 yr		Hepatic copper		Child Pugh score (AST/ALT not available)		Histopathology (only stage of fibrosis)
		Before	After	Before	After	Before	After
Mean age at diagnosis (yr)		NA	NA	9-13	5	Cirrhosis	Fibrosis stage 2-3
25.4 ± 3.9						Cirrhosis	Fibrosis stage 3-4
						Cirrhosis	Fibrosis stage 1
Linn et al[14], 2009		Treatment: zinc
Interbiopsy interval		Hepatic copper (mg/g dry weight)		ALT (U/L)		Histopathology
3-7 yr
	Age at diagnosis (yr)	Before	After	Before	After	Before	After
1	21	NA	NA	59	57	Mild fibrosis	Normal
2	13	1100	270	31	19	Normal	Cirrhosis