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home - Liver - Metabolic Conditions - Wilsons Treatment Written by Dr Sebastian Zeki

Recognises and appropriately investigates patients with auto-immune
liver diseases

Aware of management and complications of autoimmune liver
disease including extra-hepatic manifestations and associations
including malignant complications in PSC

Appreciates and understands that this range of liver disease is
frequently under-diagnosed and may have been inappropriately

Selects appropriate immunomodulatory therapy has awareness of
side effects and may well require specialist care

Responds urgently to the management challenge of these severe and
often acute diseases and involves more specialist services where
Maintains diagnostic vigilance as uncommon metabolic liver diseases
may go unrecognised and so retains awareness of them as
diagnostic possibilities

Recognises the potential need to screen relatives and keeps up to
date with contemporary developments of screening protocols

Liaises with clinical genetic unit where appropriate

Manages patients with steatohepatitis clearly and always

Wilsons Treatment

Cu2+ D-Penicillamine Renally excretedBinds copper via free sulphahydryl group Action Trientine Hypersensitivity reactions and pancytopoenia are rare. Haemorrhagic gastritis, Sideroblastic anemia can occur. Trientine chelates iron; coadministration of iron should be avoided since the trientine iron complex is toxic. It is safe in pregnancy but reduce the dose. Monitoring is done as per penicillamine. Also monitor iron as it chelates it. 5 % can’t tolerate penicillamine so use it as a second line. Caution with a history of renal disease, severe thrombocytopenia, or autoimmune tendency.Crossreactivity to penicillin may occur so use cautiously in those with a penicillin allery. Written by Dr Sebastian Zeki Adverse effects Liver Transplantation It is used if fulminant or not responding to medical therapy.Contraversially it is used with predominant neurological problems. UseIntolerant of penicillamin/ trientesNon-responsive neuropsych diseasePts who have been decopperedAdverse effects —GI upset (best with acetate), also increase amylase and lipase without pancreatitis; Safe in pregnancy Dosing Presence of D-penicillamine in urine by amino acid analysis (stoichiometric binding so accurate copper excretion surrogate)30% have raised ALT despite adequate treatment Wilson’s Disease Treatment Fulminant Hepatic FailureThis is an indication for emergency liver transplantation.Remove copper quickly by plasma exchange with FFP (removes 12mg per session).Haemofiltration and albumin dialysis have also been described as temporizing measures. Prognosis The prognosis in patients with Wilson's disease is excellent in all but those with advanced disease and those who present with rapidly progressive liver failure and haemolysis.The neurologic, psychiatric, and hepatic abnormalities gradually improve with treatment, and liver biochemical tests results usually return to normal.There is no increased HCC risk. Ammonium tetrathiomolybdate This interferes with copper absorption and binds to plasma copper.It is proposed as a more effective treatment for patients with neurologic disease. Treatment MonitoringFBC/Urinalysis/U&E’s monthly for 3/12 then 3/12 for 1 year, then 6 monthly.Measure 24-hour urinary copper excretion (aim for 2000 mcg/day, falling to <500mcg/day at 6 months). Oral zinc This interferes with copper absorption by inducing enterocyte metallothionein (endogenous metal chelator), which has a greater affinity for copper than for zinc; the bound copper is excreted faecally during enterocyte turnover.Dosing comes in several forms: Zinc acetate (50mg tds)/ gluconate/sulfate. Dose: 750-1500mcg/day NH2......NH......NH......NH2 Action Renally excretedBinds copper via free nitrogen group D-Penicillamine Cu2+ Lifetime therapy is required: 2 phasesa)Removing copper ie chelators such as D-penicillamine/ triamterene for the 30% that do not tolerate treatmentb) Preventing reaccumulation. Low dose chelators or zinc (stops copper absorption). Avoid copper containing foods- liver, kidney, shellfish, nuts, dried fruits or beans, peas, unprocessed wheat, chocolate, cocoa, and mushrooms. — Start with incremental doses of 250 to 500 mg/day inc. by 250 mg increments every 4-7d to max 1g-1.5g/d daily in 2-4 divided doses. This regimen may reduce early adverse side effects but doesn’t reduce the incidence of late-onset toxicity eg.nephrotic syndrome. Lower dose (750 to 1000 mg daily in 2 divided doses) sufficient in maintenance phase (usually after 4-6m). Therapeutic response to dose changes takes 6-8w. Paed dose: is 20 mg/kg per day (rounded to the nearest 250 mg) given in 2/3 divided doses. Penicillamine Withold penicillamine if:-WBC< 3000 per cu mm-Neutrophils < 2000 -Platelets < 120,000, -or if a steady decline over three successive tests is observed, even though the counts remain within the normal range.-Proteinuria > 2+ on a dipstick-Red cell or white casts are observed at microscopic examination of the urine, or if more than 10 red cells are seen per hpfUse other treatments if inc toxicity risk eg history of renal disease, severe thrombocytopenia, or an autoimmune tendency. Pharmocakinetics Crossreactivity to penicillin may occurEarly sensitivity reactions (1-3 wks) are characterized by fever, cutaneous eruptions, lymphadenopathy, neutropenia, thrombocytopenia, and proteinuria- discontinue immediately and use alternative.Proteinuria/ renal problems>2g proteinuria may herald nephrotic syndrome so the drug has to be stopper Once stopped, proteinuria may take 1-2 years to resolveCan also get crescentic glomerulonephritis.Goodpasture syndromeMiscellaneous ProblemsBone marrow toxicity including severe thrombocytopenia or total aplasia(may not be reversible)Myasthenia gravis, Polymyositis, Hepatotoxicity, Loss of tasteLupus-like syndrome characterized by hematuria, proteinuria, a +e antinuclear antibody.Dermatological: Elastosis perforans serpiginosa pemphigus, lichen planus, and aphthous stomatitis.GI ProblemsNausea, vomiting, and anorexia are dose-related signs of gastric irritation and improve if the dose is reduced. Neurological problems:Neurology worsens in 10% and can also get new neurology in some necessitating switch to trientineCan also add zinc acetate- but watch Hb as increased risk of sideroblastic anaemia with combination tx.Pyridoxine:Penicillamine inactivates pyridoxine. Thus, small doses of pyridoxine, 25 mg per day, should be given to patients treated with penicillamine to prevent pyridoxal phosphate deficiency. 750-1000mg/day Maintenance Phase-When normal stnthetic function, and near normal ALT, and 24 hour urinary copper is 200-500mcg/day- takes about 5 years to achieve these goals Treatment Phase (4-6 months) max 1000-1500mg/ day 5 days 5 days 5 days 5 days 250mg 250mg t 1/2= 5 hoursAbsorption reduced by 50% by food Asymptomatic patients — Prefer triamterene as relatively side effect freeSymptomatic patients —Use chelator until stable (penicillamine or trientine).Trientine may be preferred, especially in patients with neurologic symptoms, since it appears to be less likely to exacerbate them.Patients presenting with fulminant hepatic failure require liver transplantation.Plasmapheresis, exchange transfusion, hemofiltration, or dialysis may be performed while transplant is being awaited.Special casesPrior to surgery — Reduce dose to 50% of presurgery dose prior to surgery, as penicillamine can impair wound healing. Do not stop altogether.Pregnancy — Reduce to 50% in third trimester as impaired wound healing in C-sectionNo problems with breast feeding on treatment.Wilson’s dose penicillamine causes no teratogenicity, whereas higher doses (for cystinuria) does.Interruption of therapy is associated with a high risk of hemolytic episodes with hepatic insufficiency including maternal fatality.

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