A 16-year-old boy is brought to the office by his parents due to tremors and difficulty walking. Over the past year, his school performance has declined, and he has been moodier and more impulsive. His parents also note that he has been sleeping more than usual and has had a poor appetite for the past 2 months. Approximately 3 weeks ago, the patient developed a tremor in both hands that is most prominent when he reaches for an object or tries to write. The tremor has worsened significantly over the past week, and he has developed an unsteady, broad-based gait. Laboratory studies reveal elevated serum transaminases and 24-hour urinary copper excretion. The patient is prescribed penicillamine therapy. This medication primarily works through which of the following mechanisms?

Question

A 16-year-old boy is brought to the office by his parents due to tremors and difficulty walking.  Over the past year, his school performance has declined, and he has been moodier and more impulsive.  His parents also note that he has been sleeping more than usual and has had a poor appetite for the past 2 months.  Approximately 3 weeks ago, the patient developed a tremor in both hands that is most prominent when he reaches for an object or tries to write.  The tremor has worsened significantly over the past week, and he has developed an unsteady, broad-based gait.  Laboratory studies reveal elevated serum transaminases and 24-hour urinary copper excretion.  The patient is prescribed penicillamine therapy.  This medication primarily works through which of the following mechanisms?

Quizplus · Accepted Answer

11ec160b_3bd6_d8c2_9249_51efeebe2529_MD0001_00 This patient has Wilson disease, an autosomal recessive disorder characterized by excessive copper deposition in the liver, basal ganglia, and cornea. Copper is an essential nutrient that is absorbed in the intestines, metabolized by hepatocytes, and excreted in the bile. Pathogenesis of Wilson disease involves impaired hepatocellular copper transport, which results in decreased biliary excretion of copper. The resultant increase in intracellular copper causes oxidative stress and apoptosis of hepatocytes, which leads to liver dysfunction (eg, elevated transaminases, liver failure). Excess copper is then released into the bloodstream and deposited into extrahepatic tissues, causing neurologic (eg, tremor, ataxia) and psychiatric symptoms (eg, impulsivity, depressive symptoms). Although renal excretion of copper in healthy patients is extremely low, the relative increase in serum copper in Wilson disease results in increased urinary excretion of copper, as seen in this patient. First-line treatment of Wilson disease is with penicillamine, a copper chelating agent. Penicillamine binds free copper as well as reduces copper bound to other proteins. This reduction preferentially increases affinity of copper to the chelating agent. The chelator-copper complex is soluble, thereby increasing urinary copper excretion. (Choice A) Zinc decreases intestinal absorption of copper and can be used in conjunction with penicillamine to treat Wilson disease. (Choice C) Acetaminophen overdose causes hepatotoxicity via depletion of intracellular glutathione, which can be reversed with N-acetylcysteine treatment. (Choices D and E) Gene therapy could theoretically improve or cure Wilson disease by transferring a functional copper transport protein gene into hepatocytes. This would restore their ability to transport excess copper into secretory vesicles, promoting exocytosis of copper into the bile canaliculi. Educational objective: Penicillamine, a first-line treatment for Wilson disease, is a copper chelating agent that increases the urinary excretion of copper. __________ References: Clinical management of Wilson disease. (http://www.ncbi.nlm.nih.gov/pubmed/31179303)

A 16-Year-Old Boy Is Brought to the Office by His