Wilson-Konovalov disease: treatment

The drug of choice for the treatment of Wilson-Konovalov's disease is penicillamine. It binds copper and increases its daily excretion in urine to 1000-3000 μg. Treatment begins with the appointment of penicillamine hydrochloride at a dose of 1.5 g / day in 4 meals before meals. Improvement develops slowly; It takes at least 6 months of continuous intake of the drug at this dose. If there is no improvement, the dose can be increased to 2 g / day. In 25% of patients with central nervous system damage, the condition can first worsen and only then there are signs of improvement. The Kaiser-Fleischer ring decreases or disappears. Speech becomes more clear, tremor and stiffness decrease. The mental status is normalized. The handwriting is restored, which is a good prognostic sign. Improved biochemical indicators of liver function. A biopsy shows a decrease in cirrhosis activity. Improvements are not observed with irreversible tissue damage that has developed even before the start of treatment, or if the recommended treatment regimen is not observed. On the ineffectiveness of treatment can be said no earlier than in 2 years with the regular intake of optimal doses of the drug. This is the minimum period necessary for adequate initial therapy.

The effectiveness of such therapy is judged on the improvement of the clinical picture, lowering the level of free copper in the serum below 1.58 μmol / l (10 μg%) (the total amount of copper in the serum minus the amount of copper associated with ceruloplasmin), and also to reduce the copper content in the serum tissues of the body, which is judged by the decrease in daily excretion of it with urine to 500 μg or less. The data on whether the copper content in the liver is falling to normal values is inconsistent, but even if this happens, it is only after many years of treatment. An accurate determination of the copper content is made difficult by the fact that it is unevenly distributed in the liver. With positive results of initial therapy, the dose of penicillamine is reduced to 0.75-1 g / day. To judge the stability of the achieved improvement in patients with a good response to treatment, it is necessary to regularly determine the level of free copper in the serum and daily excretion of copper in the urine. Discontinuation of penicillamine may lead to an aggravation of the disease with fulminant course.

Treatment of Wilson's Disease

• The initial dose of penicillamine is 1.5 g / day
• Observation of clinical course, free copper level in serum, level of copper in urine
• Supportive therapy: dose reduction to 0.75-1 g / day

Side effects in the treatment of Wilson's disease with penicillamine are observed in about 20% of patients. They can appear during the first few weeks of treatment in the form of an allergic reaction with fever and rashes, leukopenia, thrombocytopenia and lymphadenopathy. These phenomena disappear after discontinuation of penicillamine. After resolving the allergic reaction, penicillamine can again be prescribed in gradually increasing doses in combination with prednisolone. Approximately after 2 weeks prednisolone is gradually canceled. In addition, penicillamine can also cause proteinuria and lupus-like syndrome. It is possible to develop serpiginous perforating elastosis and skin sagging (premature aging of the skin). The last complication depends on the dose of the drug taken, so long-term treatment with doses exceeding 1 g / day is not recommended. With the development of severe or persistent side effects of penicillamine it is replaced by another chelator of copper - trientine.

The number of leukocytes and platelets during the first 2 months of treatment with penicillamine is determined 2 times a week, then 1 time per month for 6 months; further research can be conducted less often. At the same time, proteinuria is examined using the same scheme. Clinical manifestations of pyridoxine deficiency in the treatment of penicillamine are theoretically possible, but are extremely rare. When administering large doses of penicillamine, pyridoxine can be added to the treatment.

If penicillamine is not possible, use trientine (tetraethylenetetramine hydrochloride), which is less effective than penicillamine, excretes copper in the urine, but has a clinical effect.

Absorption of copper in the gastrointestinal tract suppresses zinc, administered in the form of acetate 50 mg 3 times a day in between meals. Despite the accumulated experience, its clinical effectiveness and significance in long-term treatment have not been sufficiently studied. There may be side effects, including gastrointestinal disorders, but these effects are not as pronounced as penicillamine. This drug should be used only if the long-term penicillamine intake is ineffective or when referring to adverse reactions in an anamnesis when treated with penicillamine and trentin.

To restore gait, writing skills and general motor activity, you can use physiotherapy.

Although a low-copper diet is not essential, nevertheless, one should refrain from eating foods high in copper (chocolate, peanuts, mushrooms, liver, crustaceans).

Principles of treatment of Wilson-Konovalov's disease

Once the diagnosis is established, the patient should be assigned a drug that reduces the copper content in the body. In addition, the patient should avoid foods high in copper, such as red meat, liver, chocolate, nuts, mushrooms, shellfish and molluscs. It is important to check the copper content in the main source of water that the patient drinks. In the first months of treatment, patients should be examined regularly to see the side effects of the drug or the worsening of symptoms in time. To remove copper from the body, D-penicillamine is most often used. It is often recommended to start treatment with a dose of 250 mg 4 times a day. However, in 10-30% of cases in patients with developed neurological manifestations in the first few months of treatment deterioration develops. This deterioration may be due to the initial increase in serum copper levels due to the mobilization of copper stores in the liver and peripheral tissues, which may lead to additional brain damage. Therefore, it is optimal to start treatment with a lower dose of D-penicillamine 250 mg 1-2 times a day under the control of free copper in the serum and daily excretion of copper in the urine. The drug should be taken 30-60 minutes before meals. Daily excretion of copper in urine should be maintained at 125 μg. Subsequently, the dose of D-penicillamine is increased to 1 g / day, as soon as the level of free copper in the serum and daily excretion of copper in the urine begin to decrease. During the treatment should regularly monitor the content of copper and ceruloplasmin in the serum, as well as daily excretion of copper in the urine (to check the regularity of taking the drug to the patient drug). Annually, the cornea is examined with a slit lamp to evaluate the effectiveness of the treatment.

Since D-penicillamine has a high incidence of side effects, during the first month it is necessary to carry out a clinical blood test 2-3 times a week with counting of reticulocytes, determining the leukocyte formula, the number of platelets and at least 1 time per week - urinalysis. D-penicillamine can cause lupus, dermatitis, stomatitis, lymphadenonathy, thrombocytopenia, agranulocytosis and other complications.

To remove excess copper from the body use also the British antilyuizit, triethylene tetramine (triene, trientine), and to limit the intake of copper in the body - zinc preparations. Dosatriene is usually 1-1.5 g / day. Control during treatment with triene is carried out in the same way as when taking D-penicillamine. The drug can cause kidney dysfunction, bone marrow depression, dermatological complications.

Zinc acetate (150 mg / day) is especially often used when D-penicillamine or triene is intolerant. Zinc acetate is well tolerated, rarely causes side effects and is effective as maintenance therapy, but is not recommended for initial treatment. However, zinc acetate can cause stomach irritation, which sometimes forces you to abandon this drug. The mechanism of action of zinc preparations is associated with the induction of metallothionein in the liver, which, in turn, forms chelates in the small intestine with copper coming from food or bile, increases the excretion of copper with feces and, consequently, reduces its absorption.

For the initial treatment of patients with severe neurological or psychiatric disorders, tetrathiomolybdate is also used, which, unlike D-penicillamine, does not carry the risk of an increase in symptoms. Tetrathiomolybdate blocks the absorption of copper in the intestine (when taken with food), and, penetrating into the blood, forms a non-toxic complex with copper, with which it is excreted from the body.

Despite optimal treatment, neurological disorders persist in many patients, for example, dysarthria, dystonia, parkinsonism, chorea, or a combination of them. Symptomatic therapy in these cases is the same as for primary extrapyramidal disorders.

Liver transplantation is indicated with fulminant form of Wilson's disease (which usually leads to death of patients), with ineffectiveness of 2-3-month penicillamine treatment in young patients with cirrhosis with severe hepatic-cell insufficiency or with the development of severe hepatic failure with hemolysis after self-discontinuation of treatment. Survival by the end of the first year after liver transplantation is 79%. In some, but not all patients, the severity of neurological disorders decreases. The transplantation removes the metabolic defect localized in the liver. Before liver transplantation, renal failure can be treated with post-dilution and continuous arteriovenous haemofiltration, in which large amounts of copper are removed as part of complexes with penicillamine.