Copper Chelator Therapy

Chapter 143


Copper Chelator Therapy





Pathophysiology of Copper-Associated Liver Disease


Copper is an essential component of metalloenzymes used in many metabolic functions, and the liver is central in regulating copper body stores. Copper enters the body through the diet, with approximately 30% to 60% absorbed in the small intestine, and the rest passing out through the feces. After hepatic uptake, it is complexed with the transport protein ceruloplasmin, incorporated into hepatic cellular pathways, or bound to hepatic metallothioneins. Metallothioneins are cytosolic proteins that store copper, thereby protecting the surrounding cell from its toxic effects. Biliary excretion is the major determinant of copper homeostasis, with about 80% of absorbed copper excreted in bile.


When copper concentrations exceed hepatic metallothionein–complexing capabilities, hepatic injury results from free radical–induced hepatocellular necrosis or apoptosis. Abnormal accumulation of hepatic copper can be caused by a metabolic defect of copper metabolism, secondarily from cholestatic or hepatocellular disease resulting in decreased biliary excretion of copper, or from increased dietary intake of copper.


Reduction of hepatic copper levels is fundamental to treatment of copper-associated hepatic disease. The mainstay of treatment for primary copper hepatopathy is typically a chelating agent, which is a ligand (or drug) that binds to a metal ion for the purpose of removing the metal from the body, generally by renal excretion. Adjunctive therapies include zinc, antioxidants, hepatoprotectants, and dietary restriction of copper intake.



Copper Chelating Agents



Indications for Chelating Agents


Therapy is indicated in cases with significant increases in hepatic copper concentrations. Ideally, quantification of hepatic copper should be performed; normal canine concentrations range from 200 to 400 µg/g of dry weight liver. A semiquantitative histochemical grading scheme estimating the amount of hepatic copper also has been described, with the amount of copper accumulation graded on a scale of 0 to 5+. The scoring system tends to approximate the magnitude of copper concentration in the liver.


Chelation therapy given to patients incorrectly diagnosed with copper-associated liver disease is detrimental. Therefore it is important to determine whether the hepatic copper accumulation is a primary condition leading to liver damage or secondary to cholestasis. Secondary hepatic copper accumulation using histochemical staining is located predominantly in zone 1 (periportal), whereas in dogs with primary copper hepatoxicity it is found in zone 3 (centrilobular). Generally, copper concentrations from cholestatic or hepatocellular disease are lower (e.g., <1000 µg/g or a grade of +2 or less) and located in zone 1 (Spee, Arends, and van den Ingh, 2006). The authors believe that most cases having secondary hepatic copper accumulation may not require chelator therapy, but rather treatment is directed at the primary liver disease and prevention of hepatic copper accumulation. However, the authors and others recommend chelation therapy if copper concentrations exceed 1500 µg/g regardless of the cause, believing concentrations at that level are hepatotoxic.


Dogs having primary copper-associated liver disease based on breed, hepatic copper concentrations (e.g., >750 to 1000 µg/g or >3+ grade), and location (zone 3) should have chelation therapy directed at lowering hepatic copper. If the suspected primary copper deposition is mild, other therapies, such as oral zinc supplementation and low-copper diets, may be sufficient.



Commonly Used Chelators


Penicillamine is the treatment of choice for humans with Wilson’s disease, a primary metabolic disease associated with abnormal hepatic copper accumulation (Wiggelinkhuizen et al, 2009). Given the available veterinary data and experience, it should also be the first-line treatment for dogs with primary copper storage disease. Penicillamine is a thiol, a compound with a sulfhydryl (SH) group, making the molecule an active metal chelating agent with a high affinity for copper. It forms a stable water-soluble complex with copper that is then excreted through the kidneys. Additional mechanisms of action may include formation of a nontoxic hepatic chelate; induction of synthesis of metallothionein, which will bind to free copper; weak antifibrotic activity via interference with procollagen cross-linking; and immunomodulatory effects. The latter two mechanisms may be of additional benefit in chronic hepatitis.


The recommended initial dosage of penicillamine is 10 to 15 mg/kg q12h PO. It should be given on an empty stomach at least 1 hour before or 2 hours after meals to maximize absorption and reduce inactivation by chelating substances within the gastrointestinal tract. The most common side effect in dogs is nausea and vomiting, which is observed in about 30% of patients. The side effects often can be avoided by either reducing the dose or giving the medication with a small amount of food until the patient becomes accustomed to the medication. Dermatologic reactions have been observed occasionally in the dog. Penicillamine is reported to cause depletion of vitamin B6 in people. Although not reported in dogs, B vitamin supplementation with long-term use may be advisable. Because penicillamine is related to penicillin, patients with a known penicillin allergy should not be treated with this chelator. Finally, because of potential teratogenic effects, penicillamine should not be given to pregnant animals, and pregnant women should avoid contact with the drug. Penicillamine is relatively expensive, and using less-expensive compounding pharmacies is appealing; however, the purity and efficacy of the drug cannot be ensured.


Trientine is a triethylene tetramine or 2,2,2-tetramine used as an alternative copper chelator in humans that do not tolerate penicillamine. Similarly, it may be an alternative in dogs that do not tolerate penicillamine. The exact mechanism of trientine is poorly understood, but it appears to have a copper-lowering effect similar to that of penicillamine when given to affected Bedlington terriers and normal dogs. Because it may lower serum copper levels more rapidly it is the preferred treatment in cases of hemolysis resulting from copper toxicity.


The recommended dosage in dogs is 10 to 15 mg/kg q12h PO given on an empty stomach. Trientine appears to be well-tolerated by dogs, with rare cases of renal toxicity and vomiting being uncommon. Trientine also should be regarded as a potential teratogen.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Copper Chelator Therapy
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