Why do Wilson's disease patients have high copper levels with nonadherence to treatment?

From the Guidelines

Wilson's disease patients have high copper levels with nonadherence to treatment because they have a genetic defect that impairs copper excretion from the body, leading to accumulation of copper in the liver, brain, and other tissues, and causing toxicity. Wilson's disease is caused by mutations in the ATP7B gene, which normally helps transport excess copper into bile for elimination 1. Without proper treatment, copper accumulates in the liver, brain, and other tissues, leading to toxicity. The main treatments include chelating agents like penicillamine (typical dose 250-500 mg four times daily), trientine (250-500 mg three times daily), or zinc acetate (50 mg three times daily), which either bind copper for excretion or block its absorption 1. When patients stop taking these medications, the underlying genetic defect remains uncorrected, allowing copper to build up again. This accumulation happens gradually but steadily, eventually causing liver damage, neurological symptoms, psychiatric disturbances, and the characteristic Kayser-Fleischer rings in the eyes. Some key points to consider in the management of Wilson's disease include:

• Monitoring of 24-hour urinary copper excretion to assess treatment efficacy, with values ranging from 200-500 µg (3-8 µmol) per day on treatment 1
• Measurement of non-ceruloplasmin bound copper to estimate the concentration of copper not bound to ceruloplasmin in the blood, which is usually elevated above 25 µg/dL (250 µg/L) in untreated patients 1
• Dietary copper restriction, avoiding foods like shellfish, nuts, chocolate, and liver, to minimize copper intake
• Lifelong treatment adherence, as the genetic defect cannot be cured, only managed through consistent medication use and dietary restriction. It is essential to note that nonadherence to treatment can lead to significant progression of liver disease and liver failure within 1-12 months following discontinuation of treatment, resulting in death or necessitating liver transplantation 1.

From the FDA Drug Label

Wilson's disease (hepatolenticular degeneration) is an autosomal recessive metabolic defect in hepatic excretion of copper in the bile, resulting in accumulation of excess copper in the liver, and subsequently in other organs, including the brain, kidneys, eyes, bone, and muscles In this disease, hepatocytes store excess copper, but when their capacity is exceeded copper is released into the blood and is taken up in extrahepatic sites, such as the brain, resulting in motor disorders (ataxia, tremors, speech difficulties) and psychiatric manifestations (irritability, depression, deterioration of work performance) Redistribution of excess copper in hepatocytes leads to hepatocellular injury, inflammation, necrosis, and eventual cirrhosis.

The copper level would be high with nonadherence to treatment for Wilson's disease patients because the metabolic defect in the disease leads to an accumulation of excess copper in the liver and other organs. When treatment is not adhered to, the excess copper is not effectively removed from the body, resulting in high copper levels. The treatment, such as zinc acetate or penicillamine, works by either blocking the intestinal absorption of copper or promoting the excretion of copper deposited in tissues 2, 3. Nonadherence to treatment would lead to a decrease in the effectiveness of these mechanisms, resulting in an increase in copper levels. Key points include:

• Accumulation of excess copper in the liver and other organs
• Ineffective removal of excess copper with nonadherence to treatment
• High copper levels as a result of nonadherence to treatment
• Importance of adherence to treatment to manage Wilson's disease.

From the Research

Copper Levels in Wilson's Disease Patients with Nonadherence to Treatment

• Wilson's disease is a genetic disorder characterized by excess accumulation of copper, leading to liver or brain injury due to accumulation of copper 4, 5, 6.
• Nonadherence to treatment can lead to high copper levels in Wilson's disease patients, as the goal of therapy is to reduce copper accumulation either by enhancing its urinary excretion or by decreasing its intestinal absorption 4, 5.
• Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein, leading to disturbed cellular homeostasis of copper 6.
• Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury, which can result in high copper levels 6.
• Poor compliance with treatment is a major problem, especially in adolescents and patients with psychiatric disorders, which can lead to high copper levels and worsening of symptoms 4.
• Regular monitoring of copper metabolism is necessary to prevent copper deficiency or excess, which can cause neurological and hematological symptoms 7.

Monitoring Copper Levels

• Copper concentration in CSF appears to be a valuable parameter for diagnosis and monitoring therapy in patients with cerebral manifestation of Wilson's disease 8.
• Urinary copper excretion, serum copper concentration, and ceruloplasmin levels are also important parameters for monitoring therapy and diagnosing Wilson's disease 4, 5, 8.
• Early diagnosis and correct treatment are crucial to prevent long-term complications and improve quality of life in Wilson's disease patients 4, 5, 6.