Chelation therapy in liver diseases of childhood: Current status and response

Table 1 Adverse effects of copper chelating drugs

Name of the drug	Side effects
D-Penicillamine	Early (1-3 wk): Fever, rash, arthralgia, cytopenia, proteinuriaLate: (1) Skin: degenerative dermatoses elastosis perforans serpingosa, cutis laxa, pseudoxanthoma elasticum, bullous dermatoses, psoriasiform dermatoses, lichen planus, seborrheic dermatitis alopecia, aphthous ulcerations, hair loss; (2) Connective tissue disorders: Lupus like syndrome, arthralgia, Rheumatoid arthritis, polymyositis; (3) Renal: proteinuria, hematuria, glomerulonephritis, nephrotic syndrome, renal vasculitis, Goodpasture’s syndrome; (4) Nervous system: paradoxical neurological worsening, neuropathies, myasthenia, hearing abnormalities, serous retinitis; (5) Gastrointestinal: Nausea, vomiting, diarrhea, elevated transaminases, cholestasis, hepatic siderosis; (6) Respiratory: pneumonitis, pulmonary fibrosis, pleural effusion; (7) Hematological: cytopenia, agranulocytosis, aplastic anemia, hemolytic anemia; and (8) Others: Immunoglobulin deficiency, breast enlargement, pyridoxine deficiency
Trientine	Paradoxical neurological worsening (10%-50%), sideroblastic anemia, bone marrow suppression, gastritis, skin rash, arthralgia, myalgia, hirsutism
Ammonium tetra thiomolybdate	Neurological dysfunction (rare), hepatotoxicity, bone marrow suppression

Table 2 Twenty-four hours urine copper and non-ceruloplasmin copper in various stages of Wilson’s disease treatment

Early stages of treatment (< 1 yr)	UCu > 500 μg/dNCC > 25 μg/dL
Good control (treatment > 1 yr)	UCu 200-500 μg/dNCC < 15 μg/dL
Poor compliance/uncontrolled disease	UCu > 500 μg/dNCC > 15 μg/dL
Inadequate dose	UCu < 200 μg/dNCC > 15 μg/dL
Over-treatment	UCu < 200 μg/dNCC < 5 μg/dL

UCu: Twenty-four hours urinary copper; NCC: Non ceruloplasmin copper.

Table 3 Pediatric studies of chelation in liver diseases

Ref.	Disease	Drug	Follow up duration	Response	Adverse effects
Dhawan et al[60]	WD	DPA (n = 32)	Median:11.78 (1.45-34.2) yr	20/32 (62.5%)	Minor- 6.3%; Major- 21.9%
Wang et al[106]	WD	DPA/TA (n = 9)	Mean: 5.1 4.1 yr	All responded	Not mentioned
Das et al[50]	WD	DPA (n = 65), TA(n = 4)	Median: 3.6 (0.8-12) yr	DPA (42/65) 64.6%, TA (3/4) 75%	DPA 10.8%
Arnon et al[107]	WD	TA (n = 10)	Treatment duration: 18 mo. Follow up:12-60 mo	All responded	1/10 (10%) reported hepatotoxicity
Taylor et al[108]	WD	TA (n = 16)	6.4 (0.78-18.6) yr	14/16 (87.5%)	1 had allergic reaction
Santos Silva et al[59]	WDAll decompensated liver disease	DPA (n = 1)TA (n = 4)	18-60 mo	All responded one still had raised transaminase	3/4 (75%) on DPA developed cytopenia
Bavdekar et al[73]	ICC	DPA (n = 68)	3.5 (1-7) yr	29/68 (42.6%) alive after follow up	5 children had proteinuria
Tomar et al[75]	ICC	DPA (n = 60)	12 mo duration	13/17 (76.5%) of grade III survived	11.8% drug rash, 5.9% fever
Tanner et al[74]	ICC (15 children treated with DPA in both trials together)	DPA (n = 15)	6 yr	Trial I: 1/15 (6.7%) survived in 6 yr, Trial II: 5/10 (50%) survived in 6 yr	Not mentioned
Horselen et al[77]	Case report CACC (age 7 yr)	DPA	19 mo	Hepatic copper normalized	none
Maggiore et al[78]	Case report CACC (age 10 yr)	DPA	24 mo	No improvement	Not mentioned
Rodeck et al[109]	CACC (age 6 and 10 mo)	DPA	18 mo, other child deteriorated immediately following DPA initiation	One child improved and other developed acute liver failure requiring liver transplantation	None
Flynn et al[83]2002	NH	DFO (n = 5) with antioxidant	Follow up at 48 mo	2/5 (40%) survived without transplantation	Not mentioned
Rodrigues et al[84] 2005	NH	DFO with antioxidant (n = 9)	Follow up 3-9.8 yr	1/9 (11.1%) survived without transplantation	Not mentioned
Sigurrdson et al[85] 1998	NH	DFO with antioxidant (n = 8)	Not mentioned	None survived without transplantation	Not mentioned
Masera et al[110] 2013	HJV hemochromatosis Case report (7/F)	DFX	12 mo of treatment	Iron indices improved on 12 mo treatment	Not mentioned

DPA: D-Penicillamine; TA: Trientine; WD: Wilson’s disease; ICC: Indian childhood cirrhosis; NH: Neonatal Hemochromatosis; DFO: Deferoxamine; DFX: Deferasirox; CACC: Copper associated childhood cirrhosis.

Table 4 Properties of iron-chelators

Properties	Deferoxamine (DFO)	Deferasirox (DFX)	Deferiprone (DFP)
Chelator: Iron ratio	1:1	2:1	3:1
Plasma t1/2	30 min	12-16 h	2-3 h
Usual dose	20-50 mg/kg per day over 8-24 h	20-40 mg/kg per day once daily	75-100 mg/kg per day in 3 divided doses
Route of administration	Subcutaneous, intravenous	Oral	Oral
Clearance	Renal, hepatic	Hepatic	Renal
Efficacy in removing liver iron stores	Good	Good	Moderate
Efficacy in removing cardiac iron	Moderate	Moderate	Good
Advantages	Long safety data available, strongest chelator on molar basis	Oral once daily dose is sufficient	Oral, effective in removing cardiac iron
Adverse effects	Local reactions	Gastric intolerance	Nausea
	Sensorineural hearing loss	Rash	Vomiting
	Bone abnormalities	Diarrhea	Diarrhea
	Retinopathy	Elevation in creatinine	Arthralgia
	Pulmonary disease	Elevation in transaminases	Elevated liver enzymes
	Allergic reaction	Peptic ulcer	Agranulocytosis
	Bacterial infections (e.g., Listeria, Klebsiella)	Renal dysfunction
		Hepatic dysfunction