• 1.

    Boal AK, Rosenzweig AC. Structural biology of copper trafficking. Chem Rev. 2009;109(10):47604779. doi:10.1021/cr900104z

  • 2.

    Kim BE, Nevitt T, Thiele DJ. Mechanisms for copper acquisition, distribution and regulation. Nat Chem Biol. 2008;4(3):176185. doi:10.1038/nchembio.72

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Gaetke LM, Chow CK. Copper toxicity, oxidative stress, and antioxidant nutrients. Toxicology. 2003;189(1-2):147163. doi:10.1016/s0300-483x(03)00159-8

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Gaetke LM, Chow-Johnson HS, Chow CK. Copper: toxicological relevance and mechanisms. Arch Toxicol. 2014;88(11):19291938. doi:10.1007/s00204-014-1355-y

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Członkowska A, Litwin T, Dusek P, et al. Wilson disease. Nat Rev Dis Primers. 2018;4(1):21. doi:10.1038/s41572-018-0018-3

  • 6.

    Siaj R, Sauer V, Stöppeler S, et al. Dietary copper triggers onset of fulminant hepatitis in the Long-Evans cinnamon rat model. World J Gastroenterol. 2012;18(39):55425550. doi:10.3748/wjg.v18.i39.5542

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Center SA, Richter KP, Twedt DC, Wakshlag JJ, Watson PJ, Webster CRL. Is it time to reconsider current guidelines for copper content in commercial dog foods? J Am Vet Med Assoc. 2021;258(4):357364. doi:10.2460/javma.258.4.357

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Goldfischer S, Popper H, Sternlieb I. The significance of variations in the distribution of copper in liver disease. Am J Pathol. 1980;99(3):715730.

    • Search Google Scholar
    • Export Citation
  • 9.

    Miyamura H, Nakanuma Y, Kono N. Survey of copper granules in liver biopsy specimens from various liver abnormalities other than Wilson’s disease and biliary diseases. Gastroenterol Jpn. 1988;23(6):633638. doi:10.1007/BF02782948

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Hurwitz BM, Center SA, Randolph JF, et al. Presumed primary and secondary hepatic copper accumulation in cats. J Am Vet Med Assoc. 2014;244(1):6877. doi:10.2460/javma.244.1.68

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Azumi N. Copper and liver injury–experimental studies on the dogs with biliary obstruction and copper loading. Hokkaido Igaku Zasshi. 1982;57(3):331349.

    • Search Google Scholar
    • Export Citation
  • 12.

    Hoefer HL. Gastrointestinal diseases. In: Quesenberry KE, Orcutt CJ, Mans C, Carpenter JW, eds. Ferrets, Rabbits, and Rodents: Clinical Medicine and Surgery. 4th ed. Elsevier; 2020:2738.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    van de Sluis BJ, Breen M, Nanji M, et al. Genetic mapping of the copper toxicosis locus in Bedlington terriers to dog chromosome 10, in a region syntenic to human chromosome region 2p13-p16. Hum Mol Genet. 1999;8(3):501507. doi:10.1093/hmg/8.3.501

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Sarkar B, Roberts EA. The puzzle posed by COMMD1, a newly discovered protein binding Cu(II). Metallomics. 2011;3(1):2027. doi:10.1039/c0mt00031k

  • 15.

    Asada H, Chambers JK, Kojima M, et al. Variations in ATP7B in cats with primary copper-associated hepatopathy. J Feline Med Surg. 2020;22(8):753759. doi:10.1177/1098612X19884763

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Asada H, Kojima M, Nagahara T, et al. Hepatic copper accumulation in a young cat with familial variations in the ATP7B gene. J Vet Intern Med. 2019;33(2):874878. doi:10.1111/jvim.15399

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    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):372380. doi:10.2460/javma.242.3.372

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Fox JG, Zeman DH, Mortimer JD. Copper toxicosis in sibling ferrets. J Am Vet Med Assoc. 1994;205(8):11541156.

  • 19.

    Miller AJ, Center SA, Randolph JF, Friesen CH, Miller AD, Warner KW. Disparities in hepatic copper concentrations determined by atomic absorption spectroscopy, inductively coupled plasma mass spectrometry, and digital image analysis of rhodanine-stained sections in dogs. J Am Vet Med Assoc. 2021;258(4):395406. doi:10.2460/javma.258.4.395

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Setsunan University, Faculty of Pharmaceutical Sciences, Department of Pathology. Wednesday Slide Conference 11, Case III – 2004903384 (AFIP 2937492). Armed Forces Institute of Pathology Department of Veterinary Pathology; 2005:59. Accessed May 30, 2021. https://www.askjpc.org/wsco/wsc/wsc04/04wsc11.pdf.

    • Search Google Scholar
    • Export Citation
  • 21.

    Graham JE, Heinze C, Beamer G, Webster CL. Management of copper toxicosis in a ferret (Mustela putorius furo). Abstract in: Proceedings of the Association of Exotic Mammal Veterinarians. Association of Exotic Mammal Veterinarians; 2016:441.

    • Search Google Scholar
    • Export Citation
  • 22.

    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(6):12741280. doi:10.1111/j.1939-1676.2012.01001.x

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Fieten H, Biourge VC, Watson AL, Leegwater PA, van den Ingh TSGAM, Rothuizen J. Dietary management of Labrador Retrievers with subclinical hepatic copper accumulation. J Vet Intern Med. 2015;29(3):822827. doi:10.1111/jvim.12574

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Strickland JM, Buchweitz JP, Smedley RC, et al. Hepatic copper concentrations in 546 dogs (1982–2015). J Vet Intern Med. 2018;32(6):19431950. doi:10.1111/jvim.15308

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Hoenerhoff M, Williams K. Copper-associated hepatopathy in a Mexican fruit bat (Artibeus jamaicensis) and establishment of a reference range for hepatic copper in bats. J Vet Diagn Invest. 2004;16(6):590593. doi:10.1177/104063870401600619

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Yuschenkoff D, Graham J, Barton BA, Garner MM. Evaluation of the clinical presentation and histologic lesions of hepatic copper accumulation in sugar gliders (Petaurus breviceps). J Exot Pet Med. 2021;39:5156. doi:10.1053/j.jepm.2021.06.007

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    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(12):14741480. doi:10.2460/ajvr.74.12.1474

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Johnston AN, Center SA, McDonough SP, Warner KL. Influence of biopsy specimen size, tissue fixation, and assay variation on copper, iron, and zinc concentrations in canine livers. Am J Vet Res. 2009;70(12):15021511. doi:10.2460/ajvr.70.12.1502

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Pillai S, Center SA, McDonough SP, et al. Ductal plate malformation in the liver of Boxer dogs: clinical and histological features. Vet Pathol. 2016;53(3):602613. doi:10.1177/0300985815610567

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Quaglia A, Burt AD, Ferrell LD, Portmann BC. Systemic disease. In: Burt A, Portmann BC, Ferrell LD, eds. MacSween’s Pathology of the Liver. 6th ed. Churchill Livingston Elsevier; 2012:935986.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Huynh M, Laloi F. Diagnosis of liver disease in domestic ferrets (Mustela putorius). Vet Clin North Am Exot Anim Pract. 2013;16(1):121144. doi:10.1016/j.cvex.2012.10.003

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Morrisey JK, Johnston MS. Ferrets. In: Carpenter JW, Marion CJ, eds. Exotic Animal Formulary. 5th ed. Elsevier; 2018:549550.

  • 33.

    Torkelson MR, Heinze CR, Graham JE. Copper concentration in ten popular commercial ferret diets. Abstract in: Proceedings of the Exotics Conference. 2019;407–408.

    • Search Google Scholar
    • Export Citation
  • 34.

    Hill GM, Shannon MC. Copper and zinc: nutritional issues for agricultural animal production. Biol Trace Elem Res. 2019;188(1):148159. doi:10.1007/s12011-018-1578-5

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Ramirez CJ, Kim DY, Hanks BC, Evans TJ. Copper toxicosis in New Zealand White rabbits (Oryctolagus cuniculus). Vet Pathol. 2013;50(6):11351138. doi:10.1177/0300985813490756

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36.

    Doong G, Keen CL, Rogers Q, Morris J, Rucker RB. Selected features of copper metabolism in the cat. J Nutr. 1983;113(10):19631971. doi:10.1093/jn/113.10.1963

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Committee on Animal Nutrition. In: Nutrient Requirements of Mink and Foxes. 2nd ed. National Academies Press; 1982:717.35. Accessed May 30, 2021. https://doi.org/10.17226/1114.

    • Search Google Scholar
    • Export Citation
  • 38.

    Williams BH, Wyre NR. Neoplasia in ferrets. In: Quesenberry K, Mans C, Orcutt C, eds. Ferrets, Rabbits, and Rodents: Clinical Medicine and Surgery. 4th ed. Elsevier; 2021:102103.

    • Search Google Scholar
    • Export Citation
  • 39.

    Garner MM, Powers L. Diseases of domestic ferrets. In: Proceedings of the Association of Avian Veterinarians Conference. Association of Avian Veterinarians; 2010:209219.

    • Search Google Scholar
    • Export Citation
  • 40.

    van Meer S, de Man RA, van den Berg AP, et al. No increased risk of hepatocellular carcinoma in cirrhosis due to Wilson disease during long-term follow-up. J Gastroenterol Hepatol. 2015;30(3):535539. doi:10.1111/jgh.12716

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41.

    Pfeiffenberger J, Mogler C, Gotthardt DN, et al. Hepatobiliary malignancies in Wilson disease. Liver Int. 2015;35(5):16151622. doi:10.1111/liv.12727

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42.

    Gunjan D, Shalimar DM, Nadda N, et al. Hepatocellular carcinoma: an unusual complication of longstanding Wilson disease. J Clin Exp Hepatol. 2017;7(2):152154. doi:10.1016/j.jceh.2016.09.012

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43.

    Jong-Hon K, Togashi Y, Kasai H, Hosokawa M, Takeichi N. Prevention of spontaneous hepatocellular carcinoma in Long-Evans cinnamon rats with hereditary hepatitis by the administration of D-penicillamine. Hepatology. 1993;18(3):614620.

    • Search Google Scholar
    • Export Citation
  • 44.

    Goussev SA, Center SA, Randolph JF, Kathrani A, Butler BP, McDonough SP. Clinical characteristics of hepatocellular carcinoma in 19 cats from a single institution (1980–2013). J Am Anim Hosp Assoc. 2016;52(1):3641. doi:10.5326/JAAHA-MS-6289

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45.

    Harro CC, Smedley RC, Buchweitz JP, Langlois DK. Hepatic copper and other trace mineral concentrations in dogs with hepatocellular carcinoma. J Vet Intern Med. 2019;33(5):21932199. doi:10.1111/jvim.15619

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46.

    Nair J, Sone H, Nagao M, Barbin A, Bartsch H. Copper-dependent formation of miscoding etheno-DNA adducts in the liver of Long Evans cinnamon (LEC) rats developing hereditary hepatitis and hepatocellular carcinoma. Cancer Res. 1996;56(6):12671271.

    • Search Google Scholar
    • Export Citation
  • 47.

    Rosencrantz RA, LeCompte L, Yusuf Y. Beneath the copper-pediatric Wilson’s disease cirrhosis and hepatocellular carcinoma: a case report with literature review. Semin Liver Dis. 2015;35(4):434438. doi:10.1055/s-0035-1567828

    • Crossref
    • Search Google Scholar
    • Export Citation

Advertisement

Hepatic copper accumulates in ferrets with and without hepatobiliary disease

View More View Less
  • 1 Department of Clinical Sciences, Cummings School of Veterinary Medicine, North Grafton, MA
  • | 2 Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY
  • | 3 Northwest ZooPath, Monroe, WA
  • | 4 Zoo/Exotic Pathology Service, Citrus Heights, CA

Abstract

OBJECTIVE

To determine hepatic copper concentrations and zonal distribution in ferrets with and without hepatobiliary disease, validate rhodanine-based qualitative copper scoring and digital copper quantification in ferret hepatic samples, and ascertain whether clinical features predicted copper accumulation.

ANIMALS

34 ferrets, including 7 with necroinflammatory disease, 5 with hepatocellular carcinoma, 13 with non-necroinflammatory disease, and 9 with no hepatobiliary disease.

PROCEDURES

Rhodanine-based digital copper quantification was validated by use of liver dually measured by atomic absorption spectroscopy and digital scanning (R 2 = 0.98). Clinical features and hepatic copper scores and concentrations (dry weight liver) were compared between groups. Zonal copper distribution was determined.

RESULTS

Hepatic copper concentration was strongly correlated with copper scores (ρ = 0.88). Ferrets with hepatobiliary disease were significantly older and had significantly higher serum alkaline phosphatase and γ-glutamyltransferase activities and creatinine concentrations. Centrilobular copper accumulated in 23 of 34 (64%) ferrets with (n = 15) and without (8) hepatobiliary disease. Median copper concentrations were not significantly different between ferrets with and without hepatobiliary disease but were significantly higher within neoplastic hepatic tissue in ferrets with hepatocellular carcinoma. Hepatic copper concentrations exceeded feline (> 180 µg/g) and canine (> 400 µg/g) reference limits in 19 and 9 ferrets, respectively. Hepatic copper > 1,000 µg/g occurred in 5 ferrets with and 2 without hepatobiliary disease. Clinical features did not predict copper accumulation.

CLINICAL RELEVANCE

Rhodanine-based digital copper quantification and qualitative copper scoring discerned liver copper accumulation in ferrets. Ferrets with and without hepatobiliary disease displayed a propensity for centrilobular hepatic copper accumulation of uncertain clinical importance. Clinical and clinicopathologic features could not exclusively implicate pathologic copper accumulation.

Supplementary Materials

    • Supplementary Table S1 (PDF 156 KB)

Contributor Notes

Corresponding author: Dr. Center (sac6@cornell.edu)