Wilson-Conovalov Disease - Treatment

The drug of choice for the treatment of Wilson-Konovalov disease is penicillamine. It binds copper and increases its daily excretion in urine to 1000-3000 mcg. Treatment begins with the oral administration of penicillamine hydrochloride at a dose of 1.5 g / day in 4 doses before meals. Improvement develops slowly; at least 6 months of continuous administration of the drug at this dose is required. If there is no improvement, the dose can be increased to 2 g / day. In 25% of patients with damage to the central nervous system, the condition may initially worsen and only then signs of improvement appear. The Kayser-Fleischer ring decreases or disappears. Speech becomes clearer, tremor and rigidity decrease. Mental status normalizes. Handwriting is restored, which is a good prognostic sign. Biochemical parameters of liver function improve. Biopsy reveals a decrease in the activity of cirrhosis. No improvement is observed in the case of irreversible tissue damage that developed before the start of treatment, or if the patient does not comply with the recommended treatment regimen. Treatment inefficiency can be considered no earlier than after 2 years of regular administration of optimal doses of the drug. This is the minimum period required for adequate initial therapy.

The effectiveness of such therapy is judged by the improvement of the clinical picture, a decrease in the level of free copper in the serum below 1.58 μmol/l (10 μg%) (total amount of copper in the serum minus the amount of copper bound to ceruloplasmin), and a decrease in the copper content in the body tissues, which is judged by a decrease in its daily excretion in the urine to 500 μg or less. Data on whether the copper content in the liver decreases to normal values are contradictory, but even if this happens, it is only after many years of treatment. Accurate determination of the copper content is difficult because it is unevenly distributed in the liver. If the results of initial therapy are positive, the penicillamine dose is reduced to 0.75-1 g/day. To judge the sustainability 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 exacerbation of the disease with a fulminant course.

Treatment of Wilson's disease

• Initial dose of penicillamine 1.5 g/day
• Monitoring of clinical course, serum free copper level, urinary copper level
• Maintenance therapy: reduce the dose to 0.75-1 g/day

Side effects of penicillamine treatment for Wilson's disease occur in approximately 20% of patients. They may appear during the first few weeks of treatment as an allergic reaction with fever and rash, leukopenia, thrombocytopenia, and lymphadenopathy. These effects disappear after discontinuing penicillamine. After resolution of the allergic reaction, penicillamine can be reintroduced in gradually increasing doses in combination with prednisolone. Prednisolone is gradually discontinued after approximately 2 weeks. In addition, penicillamine can also cause proteinuria and a lupus-like syndrome. Serpiginous perforating elastosis and skin laxity (premature skin aging) may develop. The latter complication depends on the dose of the drug taken, so long-term treatment with doses exceeding 1 g/day is not recommended. If severe or persistent side effects of penicillamine develop, it is replaced by another copper chelator, 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; subsequently, the study can be carried out less frequently. At the same time, proteinuria is studied according to the same scheme. Clinical manifestations of pyridoxine deficiency during treatment with penicillamine, although theoretically possible, are extremely rare. When prescribing large doses of penicillamine, pyridoxine can be added to the treatment.

If treatment with penicillamine is not possible, trientine (tetraethylenetetramine hydrochloride) is used, which is less effective than penicillamine in removing copper in the urine, but provides a clinical effect.

Copper absorption in the gastrointestinal tract is inhibited by zinc, administered as acetate 50 mg 3 times daily between meals. Despite the accumulated experience, its clinical efficacy and value in long-term treatment have not been sufficiently studied. Side effects are possible, including gastrointestinal disorders, but these effects are not as pronounced as those of penicillamine. This drug should be used only if long-term use of penicillamine is ineffective or if there is a history of adverse reactions during treatment with penicillamine and trientine.

Physiotherapy can be used to restore gait, writing skills, and general motor activity.

Although a low copper diet is not essential, you should still avoid foods high in copper (chocolate, peanuts, mushrooms, liver, shellfish).

Principles of treatment of Wilson-Konovalov disease

Once the diagnosis is made, the patient should be prescribed a copper-lowering drug. In addition, the patient should avoid foods high in copper, such as red meat, liver, chocolate, nuts, mushrooms, and shellfish. It is important to check the copper content of the patient's primary water source. Patients should be monitored regularly during the first months of treatment to detect side effects of the drug or worsening symptoms. D-penicillamine is most often used to remove copper from the body. Treatment is often started at a dose of 250 mg four times daily. However, in 10-30% of cases, patients who develop neurological manifestations experience a deterioration in the first few months of treatment. This deterioration may be due to an initial increase in serum copper levels due to mobilization of copper stores in the liver and peripheral tissues, which may lead to additional brain damage. Therefore, it is best to start treatment with a lower dose of D-penicillamine - 250 mg 1-2 times a day under control of the content 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 the urine should be maintained at a level of 125 mcg. 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 treatment, the content of copper and ceruloplasmin in the serum, as well as the daily excretion of copper in the urine (to check the regularity of drug intake by the patient) should be regularly monitored. An annual examination of the cornea is performed using a slit lamp to assess the effectiveness of treatment.

Since D-penicillamine is characterized by a high frequency of side effects, it is necessary to conduct a clinical blood test 2-3 times a week during the first month, including reticulocyte count, white blood cell count, platelet count, and at least once a week - urine analysis. D-penicillamine can cause lupus syndrome, dermatitis, stomatitis, lymphadenopathy, thrombocytopenia, agranulocytosis and other complications.

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

Zinc acetate (150 mg/day) is particularly often used in cases of intolerance to D-penicillamine or triene. Zinc acetate is well tolerated, rarely causes side effects, and is effective as a maintenance therapy, but is not recommended for initial treatment. However, zinc acetate can cause gastric irritation, which sometimes makes it necessary 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 with copper in the small intestine, which comes from food or bile, increases the excretion of copper in the feces and, therefore, reduces the degree of its absorption.

Tetrathiomolybdate is also used for initial therapy of patients with severe neurological or mental disorders. Unlike D-penicillamine, it does not carry the risk of increasing 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, many patients still have neurological disorders, such as dysarthria, dystonia, parkinsonism, chorea, or a combination of these. Symptomatic therapy in these cases is the same as for primary extrapyramidal disorders.

Liver transplantation is indicated in the fulminant form of Wilson's disease (which usually leads to death of patients), in the case of ineffectiveness of 2-3 months of penicillamine treatment in young patients with liver cirrhosis with severe hepatocellular failure, or in the case of development of severe liver failure with hemolysis after spontaneous cessation of treatment. Survival at the end of the first year after liver transplantation is 79%. In some, but not all patients, the severity of neurological disorders decreases. Transplantation eliminates the metabolic defect localized in the liver. Before liver transplantation, renal failure can be treated with postdilution and continuous arteriovenous hemofiltration, which removes large amounts of copper in complexes with penicillamine.