Treatment of Wilson disease

 What is the aim of treatment of Wilson disease?

Removal or copper deposited in various organ and

Prevention of reaccumulating.

Along with the pharmacological therapy people with Wilson disease should reduce the consumption of Copper containing food items.

 For Clinical features and diagnosis of Wilson Disease 

First introduced in 1956 AD and still the standard of treatment.

How does it act?

The sulfhydryl group in d-penicillamine chelates copper removes the copper from the tissue and out of the body via urinary excretion.

It can also induce the endogenous hepatic metallothionein, a cytosolic metal-binding protein, which sequesters copper and thereby limiting damage to the liver.

 

How penicillamine is absorbed?

Its absorption is decreased by as much as 50 percent when taken with food. Thus, it should be taken 1 hour before or 2 hours after meal.

What is the dose of D-penicillamine?

The drug is introduced at a dose of 250 to 500 mg/day and then increased by 250 mg every 4 to 7 days to a maximum of 1000 to 1500 mg daily in two to four divided doses.

For children and adults who weigh less than 45 kg, start with 250 mg daily with a maximum total daily dose of 20 mg per kg (rounded to the nearest 250 mg) or approximately 1000 mg in two or three divided doses.

What are the adverse effects of D-penicillamine?

Worsening of neurological symptoms or new onset neurological symptoms

Fever, arthralgia, cutaneous eruptions, thrombocytopenia, neutropenia

Nephrotic syndrome, Nephritic syndrome

Cutaneous manifestations like:

Elastosis perforans serpiginosa,

cutis laxa,

pemphigus,

lichen planus, and aphthous stomatitis

It also lowers pyridoxine thus supplementation at low doses is necessary.

How D-penicillamine can worsen CNS symptoms?             

It is postulated that - Mobilization of hepatic copper stores leading to increased brain copper exposure, or the development of intracellular copper complexes can result in worsening neurological symptoms.

Triethylene tetramine hydrochloride                                                                                                                                       

First introduced in 1969 AD as a second line agent for copper chelation.

It also acts by copper chelation and then urinary excretion.

More copper is bound by D-penicillamine than Trientine.

Food and Trientine.

It should be given 1 hour prior or 2-3 hours after meal.

What are the adverse effects of Trientine?

Hypersensitivity reaction

Reversible sideroblastic anemia

Neurological worsening.

All these adverse effects are less common than D-penicillamine

Zinc salts are being increasingly used as first-line therapy for the treatment of presymptomatic patients and for maintenance therapy after initial decoppering with a chelator, but the efficacy of zinc monotherapy in symptomatic patients with liver disease is still under debate.

What is the mode of action of zinc?         

 It interferes with the absorption of copper. Metallothionein (an endogenous chelator of metals) in enterocytes is induced by zinc causing it to bind luminal copper and thereby preventing its entry into the circulation. This metallothionein bound copper is excreted fecally during normal turnover of enterocytes.

It may also induce hepatic metallothionein production.

What are the formulations for zinc?         

Zinc acetate – best absorption

Zinc gluconate – good alternative and better than Zinc sulphate – in terms of GI tolerability

Dosing of zinc-

Adults and children > 50 kg = 150 mg in 2 or 3 divided doses. Single daily dose is not effective

In case of children below 50 kg – 75 mg/day in 2 or 3 divided doses.