Review
Copyright ©The Author(s) 2021.
World J Hepatol. Nov 27, 2021; 13(11): 1552-1567
Published online Nov 27, 2021. doi: 10.4254/wjh.v13.i11.1552
Table 1 Adverse effects of copper chelating drugs
Name of the drug
Side effects
D-PenicillamineEarly (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
TrientineParadoxical neurological worsening (10%-50%), sideroblastic anemia, bone marrow suppression, gastritis, skin rash, arthralgia, myalgia, hirsutism
Ammonium tetra thiomolybdateNeurological 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 diseaseUCu > 500 μg/dNCC > 15 μg/dL
Inadequate doseUCu < 200 μg/dNCC > 15 μg/dL
Over-treatmentUCu < 200 μg/dNCC < 5 μg/dL
Table 3 Pediatric studies of chelation in liver diseases
Ref.
Disease
Drug
Follow up duration
Response
Adverse effects
Dhawan et al[60]WDDPA (n = 32)Median:11.78 (1.45-34.2) yr20/32 (62.5%)Minor- 6.3%; Major- 21.9%
Wang et al[106]WDDPA/TA (n = 9)Mean: 5.1 4.1 yrAll respondedNot mentioned
Das et al[50]WDDPA (n = 65), TA(n = 4)Median: 3.6 (0.8-12) yrDPA (42/65) 64.6%, TA (3/4) 75%DPA 10.8%
Arnon et al[107]WDTA (n = 10)Treatment duration: 18 mo. Follow up:12-60 moAll responded1/10 (10%) reported hepatotoxicity
Taylor et al[108]WDTA (n = 16)6.4 (0.78-18.6) yr14/16 (87.5%)1 had allergic reaction
Santos Silva et al[59]WDAll decompensated liver diseaseDPA (n = 1)TA (n = 4)18-60 moAll responded one still had raised transaminase3/4 (75%) on DPA developed cytopenia
Bavdekar et al[73]ICCDPA (n = 68)3.5 (1-7) yr29/68 (42.6%) alive after follow up5 children had proteinuria
Tomar et al[75]ICCDPA (n = 60)12 mo duration13/17 (76.5%) of grade III survived11.8% drug rash, 5.9% fever
Tanner et al[74]ICC (15 children treated with DPA in both trials together)DPA (n = 15)6 yrTrial I: 1/15 (6.7%) survived in 6 yr, Trial II: 5/10 (50%) survived in 6 yrNot mentioned
Horselen et al[77]Case report CACC (age 7 yr)DPA19 moHepatic copper normalizednone
Maggiore et al[78]Case report CACC (age 10 yr)DPA24 moNo improvementNot mentioned
Rodeck et al[109]CACC (age 6 and 10 mo)DPA18 mo, other child deteriorated immediately following DPA initiationOne child improved and other developed acute liver failure requiring liver transplantationNone
Flynn et al[83]2002NHDFO (n = 5) with antioxidantFollow up at 48 mo2/5 (40%) survived without transplantationNot mentioned
Rodrigues et al[84] 2005NHDFO with antioxidant (n = 9)Follow up 3-9.8 yr1/9 (11.1%) survived without transplantationNot mentioned
Sigurrdson et al[85] 1998NHDFO with antioxidant (n = 8)Not mentionedNone survived without transplantationNot mentioned
Masera et al[110] 2013HJV hemochromatosis Case report (7/F)DFX12 mo of treatmentIron indices improved on 12 mo treatmentNot mentioned
Table 4 Properties of iron-chelators
Properties
Deferoxamine (DFO)
Deferasirox (DFX)
Deferiprone (DFP)
Chelator: Iron ratio1:12:13:1
Plasma t1/230 min12-16 h2-3 h
Usual dose20-50 mg/kg per day over 8-24 h20-40 mg/kg per day once daily75-100 mg/kg per day in 3 divided doses
Route of administrationSubcutaneous, intravenousOralOral
ClearanceRenal, hepaticHepaticRenal
Efficacy in removing liver iron storesGoodGoodModerate
Efficacy in removing cardiac ironModerateModerateGood
AdvantagesLong safety data available, strongest chelator on molar basisOral once daily dose is sufficientOral, effective in removing cardiac iron
Adverse effectsLocal reactionsGastric intoleranceNausea
Sensorineural hearing lossRashVomiting
Bone abnormalitiesDiarrheaDiarrhea
RetinopathyElevation in creatinineArthralgia
Pulmonary diseaseElevation in transaminasesElevated liver enzymes
Allergic reactionPeptic ulcerAgranulocytosis
Bacterial infections (e.g., Listeria, Klebsiella)Renal dysfunction
Hepatic dysfunction