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Basics ⬇

Basics

Definition

  • Severe hepatic accumulation of copper (Cu) causes acute or chronic hepatitis leading to cirrhosis or death from liver failure.
  • Mild to moderate hepatic Cu accumulation augments oxidative injury and increases risk for liver disease by other hepatobiliary insults, notably, hepatotoxicity from NSAIDs.
  • Primary Copper Associated Hepatopathy (Cu-AH) depicts copper accumulation in the absence of other liver disorders or as the major cause of liver injury.
  • Secondary Cu-AH depicts Cu accumulation caused by severe chronic cholestasis in cats (not dogs) or fulminant hepatic failure (rare).
  • Genetic-Primary Cu-AH: only proven in the Bedlington terrier.
  • Acquired-Primary Cu-AH: Most common canine cause of Cu-AH, reflects dietary Cu availability in commercial dog food that exceeds an individual's ability to maintain a neutral Cu balance.
  • Congenital Primary Cu-AH: (no gene mutation characterized) is comparatively rare in cats.
  • Some animals with primary Cu-AH accumulate Cu without histologic evidence of liver damage despite vacillating liver enzyme activity (ALT most common).

Pathophysiology

  • Hepatic Cu homeostasis depends on a complex regulatory system that includes: protein transporters, chaperones, membrane receptors, intracellular binding-proteins, and canalicular egress pumps. Cu is absorbed from the small intestine, stored in the liver, with excess excreted in bile.
  • A single gene mutation in dogs (COMMD1) is proven to cause genetic-primary Cu-AH in Bedlington terriers.
  • More commonly, canine hepatic Cu accumulation reflects Cu intake exceeding capacity to maintain neutral Cu balance; this likely reflects complex transporter differences between individual dogs and may reflect genetic drift associated with development of breed standards.
  • Secondary Cu-AH reflects reduced canalicular Cu egress secondary to severe cholestasis (cats only) or severe panlobular liver injury (fulminant hepatic failure, rare).
  • In primary Cu-AH: cytosolic hepatocellular Cu first accumulates in zone 3 (centrilobular region).
  • In secondary Cu-AH (cats): cytosolic hepatocellular Cu accumulates in zone 1 (periportal) or adjacent to injured regions.
  • Hepatic Cu concentrations are widely variable. Primary Cu-AH may range from 500 to >10,000 µg/g dry weight liver (DWL) whereas secondary Cu-AH rarely exceeds 1,000 µg/g DWL.
  • Cu accumulation causes hepatocellular injury due to oxidative membrane and mitochondrial injury.
  • Focal hepatitis progresses to chronic hepatitis and eventually cirrhosis and may initiated an immune-mediated process.
  • Rarely, acute severe hepatic necrosis releases Cu into the systemic circulation causing hemolysis and/or an acute-onset acquired Fanconi syndrome (proximal renal tubular injury causing euglycemic glucosuria).

Systems Affected

  • Hepatobiliary-focal hepatitis, chronic hepatitis, eventual cirrhosis.
  • Hemic/Lymphatic-hemolytic anemia a rare sequel to acute hepatic necrosis in dogs with high hepatic Cu concentrations (e.g., Bedlington terrier) in which large amounts of Cu are suddenly released into the systemic circulation.
  • Renal-rare reversible Fanconi syndrome causing euglycemic glycosuria, granular casts, with or without clinicopathologic evidence of reduced renal function.

Genetics

  • Autosomal recessive COMMD1 mutation in Bedlington terriers reduces biliary Cu excretion.
  • Gene mutations remain unproven in other breeds and in cats.
  • Predisposition to Cu-AH is recognized in Labrador retrievers, West Highland white terriers, Doberman pinschers, and other breeds likely reflecting pharmacogenetic differences in Cu regulatory proteins or processes selected during breed development.

Incidence/Prevalence

  • Bedlington terrier-at one time up to 2/3 of dogs carried the COMMD1 mutation; incidence significantly declined with genetic testing.
  • Prevalence of excess hepatic Cu remains high in West Highland white terriers, Labrador retrievers, Doberman pinschers and other breeds; historical account in Skye terriers.
  • Cu-AH is currently the most common cause of chronically increased ALT activity in dogs (since the mid 1990s), likely linked wtih altered Cu supplements in dog foods.
  • Cu-AH currently comprises 20% of liver biopsy submissions for abnormal enzyme activity in dogs. High hepatic Cu concentration (>400 µg/g DWB) is not always associated with histologic evidence of liver injury.
  • Primary-congenital Cu-AH occurs in cats but is comparatively rare.

Geographic Distribution

Reported worldwide

Signalment

Species

Dog and cat; more common in dogs

Breed Predilections

Bedlington terrier, West Highland white terrier, Labrador retriever, Doberman pinscher, Dalmatian, Welsh Corgi, Keeshonds, Staffordshire terrier observed to have increased incidence of high hepatic Cu concentrations. No canine breed is exempt.

Mean Age and Range

  • Bedlington terrier-Cu slowly accumulates to a maximum at ∼ 6 years of age; dogs can be clinically affected at any age, most present as middle-aged to older dogs with chronic hepatitis.
  • West Highland white terrier-maximum Cu accumulation observed by 12 months of age; clinical disease may occur at any time; some dogs with high hepatic Cu live to old age (15 y) without evidence of liver injury.
  • Labrador retrievers, Dalmatians, other breeds with apparent increased risk-young adult to middle-aged at diagnosis for chronic hepatitis.
  • Doberman pinschers-may begin to develop hepatitis with ALT increases and Cu accumulation at 1–3 years of age; clinical signs of liver disease often occur after 7 years of age.
  • Skye terrier-all ages can be affected.

Predominant Sex

None

Signs

Historical Findings

  • Primary Cu-AH: 4 categories (1) no clinical signs, (2) subclinical disease, (3) acute disease (uncommon) associated with severe acute hepatic necrosis, or (4) chronic progressive hepatitis (middle-aged to older dogs), progressive to cirrhosis.
  • Secondary Cu-AH accompanies feline necroinflammatory cholestatic liver disease (cholangiohepatitis) or rarely, in dogs with fulminant liver necrosis.
  • Acute signs-sudden onset lethargy, anorexia, vomiting; may have a rapid course, with dogs succumbing despite intensive supportive care.
  • Chronic signs-variable, intermittent lethargy, hyporexia, weight loss, vomiting, diarrhea, polydipsia and polyuria. Later signs may include: abdominal distention (ascites), jaundice, bleeding tendencies, and HE.

Physical Examination Findings

  • Acute signs-lethargy, weakness, jaundice, pallor (anemia), vomiting, diarrhea, and dark urine (bilirubinuria; rare hemoglobinuria).
  • Chronic signs-weight loss, ascites, jaundice, and nodular microhepatia. Melena and petechial hemorrhage in animals with diffuse panlobular injury.

Causes

  • Genetic Cu-AH-single gene mutation in Bedlington terriers.
  • Primary Cu-AH: either Bedlington mutation or suspected pharmacogenetic differences in other dog breeds involving regulatory pathways influencing Cu homeostasis making them intolerant to current levels of dietary Cu supplementation.
  • Secondary Cu-AH-necroinflammatory chronic cholestatic liver disease in cats or diffuse severe panlobular injury in dogs or cats (rare) impairing Cu regulatory pathways.

Risk Factors

  • Primary-feeding diets or providing water with Cu concentrations exceeding an individual dog's ability to maintain a neutral Cu balance.
  • Stress may precipitate acute disease.
  • Asymptomatic dogs with primary Cu-AH may become symptomatic when additional disease processes or toxicities (e.g., NSAID administration; CCNU chemotherapy) impose oxidative challenge or another primary liver abnormality develops (e.g., immune-mediated hepatitis, severe glycogen-type vacuolar hepatopathy, cholangiohepatitis).

Diagnosis ⬆ ⬇

Diagnosis

Differential Diagnoses

  • Acute diseases-infectious diseases (e.g., infectious canine hepatitis, leptospirosis, septicemia), acute hepatic necrosis, hepatic abscess, drug- or toxin-induced hepatic injury, acute pancreatitis, hepatic lymphoma, autoimmune hemolytic anemia, or zinc toxicity.
  • Chronic diseases-chronic hepatitis; cholangiohepatitis of inflammatory or immune-mediated origin, drug- or toxin-induced liver injury, severe diffuse glycogen-type vacuolar hepatopathy (dogs), infectious hepatitis, chronic obstructive biliary disease, chronic fibrosing pancreatitis, congenital portosystemic shunt, hepatic neoplasia, or metastatic neoplasia.

CBC/Biochemistry/Urinalysis

  • CBC-may be normal. Regenerative anemia, leukocytosis, neutrophilia in some animals with acute Cu-associated hemolysis. Microcytic or normocytic, normochromic non-regenerative anemia in some dogs with chronic progressive disease. RBC microcytosis may reflect acquired portosystemic shunting (APSS).
  • Biochemistry-increased liver enzymes (ALT, AST, GGT and ALP; transaminase increases prominent with fold increase in ALT > ALP; hyperbilirubinemia notable in dogs with severe liver injury. Increased ALT without clinical signs increases suspicion for early or cyclic Cu-AH necrosis.
  • As hepatic function deteriorates, hypoalbuminemia, ± hyperglobulinemia, low BUN, rare hypoglycemia, and hypocholesterolemia develop.
  • Urinalysis-usually normal or positive for bilirubinuria; later dilute urine, ammonium biurate crystalluria may appear in dogs with APSS which reflect sinusoidal hypertension (remodeling and fibrosis). Rarely, acquired Fanconi syndrome reflects proximal renal tubule Cu toxicity.

Other Laboratory Tests

  • High fasting or postprandial TSBA values.
  • Prolonged PT, APTT, ACT, and mucosal bleeding time in advanced cases.
  • Rare increase in serum Cu concentrations in dogs with acute severe Cu-AH liver necrosis; otherwise serum Cu does not reflect liver Cu concentrations; a low yield screening test.
  • Hepatic Cu measurements must be reconciled with histopathologic findings.
  • Genetic marker testing in Bedlington terriers: microsatellite markers or specific COMMD1 mutation. However, kindreds of Bedlington terriers with Cu-AH have had negative PCR-based gene tests (suspected additional gene mutation).

Imaging

  • Radiography-unremarkable in most dogs; small liver in chronic hepatic injury, poor abdominal detail if ascites.
  • Ultrasonography-early: normal hepatic echogenicity; later: hyperechoic to mixed nodular echogenicity; abdominal effusion if ascites.

Diagnostic Procedures

  • Liver biopsy-confirms and characterizes liver injury.
  • Routine H&E staining-can overlook pathologic Cu accumulation.
  • Cu-specific staining-rhodanine (preferred) or rubeanic acid stains needed to identify and confirm Cu-protein aggregates and detail zonal distribution and association with liver injury.
  • Semiquantitative scoring system-estimates severity of Cu accumulation.
  • Cu measurements-can be completed on: fresh, frozen, formalin fixed liver, or liver tissue extracted from paraffin blocks.
  • Distribution of hepatocytes with cytosolic Cu granules and quantification of Cu should be reconciled-areas of dense fibrosis, parenchymal extinction, regenerative nodules contain lower Cu concentrations than unremodeled liver tissue. This phenomenon causes discordance between measured and assessed Cu accumulation.

Cu Measurement

  • Atomic absorption spectroscopy-gold standard method of Cu determination.
  • Cu must be expressed per DWL.
  • Hepatic Cu determination (atomic absorption spectroscopy)-requires at least a full needle biopsy ( 16 g) sample.
  • Digital scanning of rhodanine-stained biopsy sections-validated against atomic absorption spectroscopy; accurately measures liver Cu (Cornell University) on biopsy reconciling histologic change with Cu; routine diagnostic assessment (Cornell University).

Hepatic Cu Concentrations (DWL)

  • Normal hepatic Cu: 400 µg/g.
  • Hepatic Cu concentration in dogs with primary Cu-AH (µg/g DWL):
    • Bedlington terriers: 850–12,000
    • West Highland white terriers: up to 3,500
    • Labrador retrievers: 400-9,000
    • Doberman pinschers: 1,000–10,000
    • Dalmatians: 750-8400
    • Cats: 700-8,000
  • Avoid analytic methods “estimating” sample hydration or reporting Cu on a wet weight basis.

Pathologic Findings

  • Cu accumulates in lysosomes in Zone 3 (centrilobular) hepatocytes in dogs.
  • Histochemical Cu staining (e.g., rhodanine) confirms affiliation of Cu with histologic injury.
  • Histologic features commonly include formation of “copper granulomas” in areas of hepatocellular necrosis.
  • Oxidative injury-mechanism of hepatocellular injury.
  • In some cases, an apparent immune-mediated hepatitis accompanies the Cu-AH lesions, reflecting response to neoepitope formation.
  • Chronic untreated necroinflammatory injury progresses to chronic hepatitis, parenchymal extinction, liver fibrosis, and eventually to cirrhosis with splanchnic hypertension, and formation of APSS.
  • Cu-AH causing necroinflammatory liver injury leads to development of microhepatia with nodules reflecting regenerative nodules, and a fibrotic “firm” texture.

Treatment ⬆ ⬇

Treatment

Appropriate Health Care

  • Outpatient for most dogs.
  • Inpatient evaluation and treatment for dogs with signs of hepatic failure.
  • See Hepatitis, Chronic Active and Cirrhosis and Fibrosis of the Liver for detailed management of liver disease.

Nursing Care

  • Animals in liver failure require fluid and electrolyte correction; treatment for HE; may require treatment for coagulopathy; and should be treated with IV N-acetylcysteine (NAC) for oxidative injury, with d-penicillamine chelation started as soon as oral treatment is possible.
  • Dogs demonstrating hemolytic anemia may require whole or packed RBC transfusion and IV NAC.
  • Dogs demonstrating acquired Fanconi syndrome require IV fluid therapy to protect against acute renal failure and IV NAC.

Activity

Normal; rest if signs of severe necrosis.

Diet

  • Feed Cu-restricted diets to all affected dogs for their lifetime.
  • Prescription liver diets deliver 2.2–2.5 g protein/kg body weight when fed for maintenance energy requirements.
  • Dietary protein content should only be reduced for dogs exhibiting signs of nitrogen intolerance, e.g., HE or developing ammonium biurate crystalluria (reflects hyperammonemia and APSS formation).
  • Supplemental protein is added to the base “liver” diet to increase protein intake by 0.5 g up to 1.5 g protein/kg body weight using low Cu–containing foods.
  • Select supplemental low Cu–containing protein sources using the USDA food tables (available on internet).
  • Determine the amount for selected foods to feed using the Nutritional Analysis Tool-2 (free web software, site maintained by the Illinois School of Human Nutrition).
  • Balanced homemade diets avoiding Cu-rich foods (e.g., organ meats, nuts, certain grains) may also be formulated, but these should be recommended by a Veterinary Clinical Nutritionist. Such diets are frequently not feasible for large-breed dogs where commercial diets are often the better option as a baseline meal, as described above.
  • Prescription type liver diets contain the lowest Cu content (approximately 4 mg/kg of diet) formulated originally to maintain neutral Cu balance in Cu-AH affected Bedlington terriers.
  • Chelation therapy in conjunction with commercial diets can successfully manage affected dogs.
  • All affected dogs must have lifetime dietary/water Cu restriction.
  • Measure waterborne Cu and restrict access to water with Cu >0.2 ppm.
  • Avoid mineral supplements containing Cu.
  • Supplement water-soluble vitamins but avoid ascorbate (vitamin C supplements during Cu hepatotoxicity: may augment oxidative injury).

Client Education

  • Educate all Bedlington terrier owners about the genetic basis of Cu-AH in this breed and appropriate genetic testing.
  • Other breeds should be monitored for increased ALT activity and Cu should be specifically stained for in liver biopsies.
  • Dogs receiving NSAIDs with associated increase in ALT activity should be investigated for potential “silent” hepatic Cu accumulation.
  • Dietary management and chronic intermittent chelation or zinc administration are needed for life in most dogs.

Surgical Considerations

  • Animals with hepatic failure are surgical and anesthetic risks.
  • Hypoxia encountered during anesthesia or surgery can provoke Cu-driven oxidative injury.

Medications ⬆ ⬇

Medications

Drug(s)

See other liver topics for other specific treatments of chronic hepatitis and cirrhosis.

Chelation

d-penicillamine

  • 10–15 mg/kg PO q12h.
  • Chelates Cu, promotes urinary excretion of Cu, and suspected to have other Cu-protective effects.
  • Initiate treatment in dogs with increased ALT activity and biopsy confirmed centrilobular Cu accumulation affecting >25% centrilobular hepatocytes or reconciling with lobular injury/remodeling (reticulin and Masson's trichrome staining assessment).
  • Hepatic Cu as low as 600 µg/g DWL may require chelation and chronic management.
  • Dogs with hepatic Cu <1,500 µg/g DWL are usually easily cleared with 6 months of d-penicillamine chelation (biopsy proven).
  • Dogs with hepatic Cu >3,000 µg/g may require >9–12 months of chelation.
  • Administer drug 1 h before feeding.
  • Drug-associated vomiting or hyporexia may be abated with low dose prednisone.
  • Following a course of therapy (6 months–1 year) re-biopsy to monitor treatment efficacy is optimal, but following ALT is an alternative method of monitoring.
  • Expect substantial decline in ALT by 8 weeks of chelation.
  • Successful chelation results in remarkable histologic improvement and resolution of ALT activity.

Trientine hydrochloride

  • 5–15 mg/kg PO q12h; alternative Cu chelator; as effective as d-penicillamine with similar guidelines.
  • Administer 1 h before meals.
  • Acute renal failure has been observed in some dogs given higher dosing of trientine.
  • Trientine is currently restrictively expensive.
  • Trientine is not more effective than d-penicillamine in humans with Wilson's disease; results are interchangeable.

Zinc-Blocking Enteric Cu Uptake

  • Zinc therapy may assist in chronic control of Cu-AH. Use of zinc is predicated on study of 6 dogs (see Suggested Reading).
  • Zinc reduced intestinal absorption of Cu; study demonstrated reduced hepatic Cu concentrations with 2 years of therapy in a few Bedlington (n=3) and West Highland white terriers (n=3).
  • 100 mg of elemental zinc PO q12h as loading dose for 2 months, then 25–50 mg PO q12h for Bedlington- terrier-sized dog; zinc acetate is best tolerated.
  • In humans with Wilson's disease, zinc dosing is optimized with Cu-isotope uptake studies.
  • In humans, zinc therapy is less effective than chelation for chronic management (see Suggested Reading).
  • Administer zinc 1 h before feeding.
  • May be beneficial in earlier stages or dogs with lower hepatic Cu concentrations (generally <1,000 µg/g DW).
  • Zinc may lack efficacy in dogs with high Cu concentrations and hepatitis where chelation therapy is preferred.
  • Coadministration of zinc and Cu chelators requires careful staggered dosing; direct physical interaction makes treatment ineffective.
  • Vomiting, inappetence, gastritis-frequent side effects.
  • Low concentrations of zinc given in a low Cu diet in previously chelated Labrador retrievers was found to be no better than feeding a Cu-restricted diet (see Suggested Reading).

Antioxidants

  • d--tocopherol (vitamin E)-10 U/kg q24h PO may protect the liver from oxidative damage imposed by Cu.
  • S-Adenosylmethionine (SAMe), use product with proven bioavailability that increases hepatic GSH-20 mg/kg q24h, enteric-coated tablets given on an empty stomach.

Hepatoprotectants

  • Silibinin (milk thistle extract, use form bound to PPC for best bioavailability)-5 mg/kg PO q24h; utility in Cu storage hepatopathy undetermined.
  • Ursodeoxycholic acid-10–15 mg/kg PO divided BID given with food for best bioavailability; recommended if chronic hepatitis (see Hepatitis, Chronic Active) and high serum bile acid concentrations.

Contraindications

  • Ascorbic acid (vitamin C) may augment Cu hepatotoxicity.
  • Avoid treatment with NSAID in affected dogs as these may cause centrilobular toxic adduct–related liver injury.

Possible Interactions

Penicillamine or trientine may not be effective if given concurrently zinc therapy.

Precautions

  • Remain aware of altered drug metabolism related to reduced first-pass extraction if APSS develop or altered hepatic metabolism/biotransformation in dogs with severe centrilobular necrosis and remodeling.
  • Avoid NSAID administration-metabolized by p450 cytochromes in centrilobular region where toxin adducts with oxidative injury augmented by Cu accumulation.

Follow-Up ⬆ ⬇

Follow-Up

Patient Monitoring

  • Liver enzymes q3–6 months; evaluate body weight and condition.
  • Examine hepatic biopsy and measure hepatic Cu concentration within 1 year of initiated treatment as optimal follow-up assessment.
  • If using zinc therapy-assess serum zinc concentrations initially, then during first 2–3 weeks and until stable to assure values increase but remain within the non-toxic range (200–500 µg/dL), then q6 months.

Possible Complications

  • d-Penicillamine can cause anorexia and vomiting. Start at the low end of the dose range for the first week; give 1 h before meals; small amount of food may reduce nausea but may reduce treatment efficacy when given with meals.
  • d-Penicillamine side effects: glomerulonephritis, polyarthritis, drug-associated hepatopathy, or an autoimmune-like vesicular disease of the mucocutaneous junctions that resolves on drug withdrawal.
  • Excess zinc (oral dose of >200 mg/day or blood concentration of >800 µg/dL) can cause hemolytic anemia.

Prevention/Avoidance

Breed only Bedlington terriers that do not carry the COMMD1 mutation. A liver registry is available for Bedlington terriers proven unaffected on the basis of hepatic Cu concentration <400 µg/g DW at 1 year of age or gene testing. Other breeds have unknown kindred predispositions.

Expected Course and Prognosis

  • Prognosis is poor in acutely affected young dogs with fulminant hepatic failure or older dogs with cirrhosis; however, some of these respond to acute supportive care and chelation, as described.
  • Dogs with mild to moderate acute hepatic injury usually respond to chelation therapy (prognosis is good).
  • Even dogs with nodular hepatopathy and microhepatia and ascites can respond remarkably well to the described treatment protocol with resolution of many histologic lesions (including fibrosis).
  • A good prognosis is warranted if Cu-AH is detected before liver remodeling or development of hepatitis (liver biopsy pursued based on high ALT activity and high index of suspicion for Cu hepatotoxicity) in dogs treated as described above.

Miscellaneous ⬆

Miscellaneous

Associated Conditions

Age-Related Factors

  • Health evaluations that include ALT measurement helps identify at-risk dogs.
  • Important to evaluate ALT in any dog placed on chronic NSAIDs where Cu retention appears to augment centrilobular hepatotoxicity; measure ALT before and 2–4 weeks after NSAID initiation or sooner if patient demonstrates inappetence, vomiting, lethargy.

Pregnancy/Fertility/Breeding

Do not breed affected Bedlington terriers or carriers; genetics of other suspected breeds has not been determined.

Synonyms

  • Bedlington hepatitis
  • Chronic active hepatitis
  • Chronic Cu toxicity
  • Cu toxicosis

See Also

Abbreviations

  • APSS = acquired portosystemic shunt
  • Cu = Copper
  • Cu-AH = copper associated hepatopathy
  • DWL = dry weight liver
  • GSH = glutathione
  • HE = hepatic encephalopathy
  • NAC = N-acetylcysteine
  • TSBA = total serum bile acids

Internet Resources

www.vetgen.com for genetic screening in Bedlington terriers

Suggested Reading

Center SA, McDonough SP, Bogdanovic L. Digital image analysis of rhodanine-stained liver biopsy specimens for calculation of hepatic copper concentrations in dogs. Am J Vet Res 2013, 74:1474–1480.

Fieten H, Hooijer-Nouwens BD, Biourge VC, et al. Association of dietary copper and zinc levels with hepatic copper and zinc concentration in Labrador Retrievers. J Vet Intern Med 2012, 26:1274–1280.

Hoffmann G, van den Ingh TS, Bode , P, et al. Cu-associated chronic hepatitis in Labrador Retrievers. J Vet Intern Med 2006, 20(4): 856–861.

Johnston AN, Center SA, McDonough SP, Wakshlag JJ, Warner KL. Hepatic copper concentrations in Labrador Retrievers with and without chronic hepatitis: 72 cases (1980–2010). J Am Vet Med Assoc 2013, 242(3):372–380.

Mandigers PJ, van den Ingh TS, Bode P, et al. Association between liver Cu concentration and subclinical hepatitis in Doberman Pinschers. J Vet Intern Med 2004, 18(5):647–650.

Weiss KH, Gotthardt DN, Klemm D, et al. Zinc monotherapy is not as effective as chelating agents in treatment of Wilson disease. Gastroenterology 2011, 140:1189–1198.

Authors Sharon A. Center and Sean P. McDonough

Consulting Editor Sharon A. Center

Client Education Handout Available Online