Wilson disease in dogs

Wilson disease in dogs DEFAULT

Wilson disease and canine copper toxicosis

In this article we review the current clinical and research status of Wilson disease and canine copper toxicosis. One of the main clinical challenges in Wilson disease is for clinicians to recognize the possibility of Wilson disease when young patients present with liver disease, psychiatric disease, or a movement-disorder type of neurologic disease. Once the possibility of the disease is recognized, many copper-related tests are available that are quite accurate in making the diagnosis or ruling it out. It is important to remember that this is an inherited disease and that family members at risk should be screened, particularly siblings. The cloning of the Wilson disease gene opened up the possibility that a direct DNA test could be developed, allowing convenient screening of certain patients and family members. However, the large number of mutations already found, with no small set of mutations dominating the picture, have thwarted this approach. Once the diagnosis has been made, a variety of treatments are available. For maintenance therapy, therapy of presymptomatic patients, and therapy of pregnant patients, we use zinc. For initial therapy of patients with liver disease, we use a combination of zinc and trientine. For initial therapy of patients with neurologic disease we use tetrathiomolybdate. Canine copper toxicosis in Bedlington terriers is due to a gene different from the gene for Wilson disease. However, the disease is treatable with the same array of anticopper therapies that work in humans. Recently, we established linkage of the copper toxicosis gene to a microsatellite marker, which has made available a linkage test to breeders of Bedlington terriers.

Sours: https://pubmed.ncbi.nlm.nih.gov/9587157/

Preclinical models of Wilson’s disease, why dogs are catchy alternatives

Abstract

Copper toxicosis is frequently encountered in various dog breeds. A number of differences and similarities occur between Wilson disease and copper toxicosis in Bedlington terriers, caused by a mutation in the COMMD1 gene, and copper toxicosis in Labrador retrievers, caused by mutations in both ATP7A and ATP7B gene. First the specific population structure of dog breeds is explained with reference to its applicability for genetic investigations. The relatively large body size (variable from less than 1 kg to over 50 kg) and life-span (over 10 years) of dogs facilitates preclinical studies on safety on long-term effects of novel procedures. Then copper toxicosis in the two dog breeds is described in detail with an emphasis on the functions of the causative proteins. Some of the advantages of this species for preclinical studies are described with an example of liver stem cell transplantations in COMMD1 deficient dogs. Since the genetic background of copper toxicosis in other dogs’ breeds has not yet been elucidated, it is conceivable that novel copper-related gene products or modifier genes will be discovered. About a century after the Novel prize was awarded to the research on dogs (Pavlov), dogs are in spotlight again as important preclinical model animals.

Sours: https://atm.amegroups.com/article/view/24559
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Preclinical models of Wilson’s disease, why dogs are catchy alternatives

1. Bull PC, Thomas GR, Rommers JM, et al. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene.Nat Genet 1993;5:327-37. 10.1038/ng1293-327 [PubMed] [CrossRef] [Google Scholar]

2. Tanzi RE, Petrukhin K, Chernov I, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene.Nat Genet 1993;5:344-50. 10.1038/ng1293-344 [PubMed] [CrossRef] [Google Scholar]

3. Pierson H, Nuchenditsi A, Byung-Eun K, et al. The function of ATPase copper transporter ATP7B in intestine.Gastroenterology 2018;154:168-80.e5. 10.1053/j.gastro.2017.09.019 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

4. Reed E, Lutsenko S, Bandmann O. Animal models of Wilson disease.J Neurochem 2018;146:356-73. 10.1111/jnc.14323 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

5. Buiakova OI, Xu J, Lutsenko S, et al. Null mutation of the mouse ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation.Hum Mol Genet 1999;8:1665-71. 10.1093/hmg/8.9.1665 [PubMed] [CrossRef] [Google Scholar]

6. Wu J, Forbes JR, Chen H, et al. The LEC rat has a deletion in the copper transporting ATPase gene homologous to the Wilson disease gene.Nat Genet 1994;7:541-5. 10.1038/ng0894-541 [PubMed] [CrossRef] [Google Scholar]

7. Terada K, Nakako T, Yang XL, et al. Restoration of holoceruloplasmin synthesis in LEC rat after infusion of recombinant adenovirus bearing WND cDNA.J Biol Chem 1998;273:1815-20. 10.1074/jbc.273.3.1815 [PubMed] [CrossRef] [Google Scholar]

8. Ferenci P. Phenotype-genotype correlations in patients with Wilson’s disease.Ann N Y Acad Sci 2014;1315:1-5. 10.1111/nyas.12340 [PubMed] [CrossRef] [Google Scholar]

9. Lutsenko S. Modifying factors and phenotypic diversity in Wilson’s disease.Ann N Y Acad Sci 2014;1315:56-63. 10.1111/nyas.12420 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

10. Larson G, Karlsson EK, Perri A, et al. Rethinking dog domestication by integrating genetics, archeology, and biogeography.Proc Natl Acad Sci U S A 2012;109:8878-83. 10.1073/pnas.1203005109 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

11. Parker HG, Shearin AL, Ostrander EA. Man’s best friend becomes biology’s best in show: genome analyses in the domestic dog.Annu Rev Genet 2010;44:309-36. 10.1146/annurev-genet-102808-115200 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

12. Starzl TE, Kaupp HA, Jr, Brock DR, et al. Studies on the rejection of the transplanted homologous dog liver.Surg Gynecol Obstet 1961;112:135-44. [PMC free article] [PubMed] [Google Scholar]

13. Haywood S, Muller T, Muller W, et al. Copper-associated liver disease in north ronaldsay sheep: a possible animal model for non-wilsonian hepatic copper toxicosis of infancy and childhood.J Pathol 2001;195:264-9. 10.1002/path.930 [PubMed] [CrossRef] [Google Scholar]

14. Fuentealba IC, Aburto EM. Animal models of copper-associated liver disease.Comp Hepatol 2003;2:5. 10.1186/1476-5926-2-5 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

15. Twedt DC, Sternlieb I, Gilbertson SR. Clinical, morphologic, and chemical studies on copper toxicosis of Bedlington Terriers.J Am Vet Med Assoc 1979;175:269-75. [PubMed] [Google Scholar]

16. Haywood S, Rutgers HC, Christian MK. Hepatitis and copper accumulation in Skye terriers.Vet Pathol 1988;25:408-14. 10.1177/030098588802500602 [PubMed] [CrossRef] [Google Scholar]

17. Thornburg LP, Rottinghaus G, Dennis G, et al. The relationship between hepatic copper content and morphologic changes in the liver of West Highland White Terriers.Vet Pathol 1996;33:656-61. 10.1177/030098589603300604 [PubMed] [CrossRef] [Google Scholar]

18. Thornburg LP. Histomorphological and immunohistochemical studies of chronic active hepatitis in Doberman Pinschers.Vet Pathol 1998;35:380-5. 10.1177/030098589803500507 [PubMed] [CrossRef] [Google Scholar]

19. Webb CB, Twedt DC, Meyer DJ. Copper-associated liver disease in Dalmatians: a review of 10 dogs (1998-2001).J Vet Intern Med 2002;16:665-8. [PubMed] [Google Scholar]

20. Hoffmann G, van den Ingh TS, Bode P, et al. Copper-associated chronic hepatitis in Labrador Retrievers.J Vet Intern Med 2006;20:856-61. 10.1111/j.1939-1676.2006.tb01798.x [PubMed] [CrossRef] [Google Scholar]

21. 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;8:501-7. 10.1093/hmg/8.3.501 [PubMed] [CrossRef] [Google Scholar]

22. van De Sluis B, Rothuizen J, Pearson PL, et al. Identification of a new copper metabolism gene by positional cloning in a purebred dog population.Hum Mol Genet 2002;11:165-73. 10.1093/hmg/11.2.165 [PubMed] [CrossRef] [Google Scholar]

23. Müller T, van de Sluis B, Zhernakova A, et al. The canine copper toxicosis gene MURR1 does not cause non-Wilsonian hepatic copper toxicosis.J Hepatol 2003;38:164-8. 10.1016/S0168-8278(02)00356-2 [PubMed] [CrossRef] [Google Scholar]

24. Stuehler B, Reichert J, Stremmel W, et al. Analysis of the human homologue of the canine copper toxicosis gene MURR1 in Wilson disease patients.J Mol Med 2004;82:629-34. 10.1007/s00109-004-0557-9 [PubMed] [CrossRef] [Google Scholar]

25. Lovicu M, Dessi V, Lepori MB, et al. The canine copper toxicosis gene MURR1 is not implicated in the pathogenesis of Wilson disease.J Gastroenterol 2006;41:582-7. 10.1007/s00535-006-1807-0 [PubMed] [CrossRef] [Google Scholar]

26. Wu ZY, Zhao GX, Chen WJ, et al. Mutation analysis of 218 Chinese patients with Wilson disease revealed no correlation between the canine copper toxicosis gene MURR1 and Wilson disease.J Mol Med (Berl) 2006;84:438-42. 10.1007/s00109-005-0036-y [PubMed] [CrossRef] [Google Scholar]

27. de Bie P, van de Sluis B, Klomp L, et al. The many faces of the copper metabolism protein MURR1/COMMD1.J Hered 2005;96:803-11. 10.1093/jhered/esi110 [PubMed] [CrossRef] [Google Scholar]

28. Maine GN, Burstein E. COMMD proteins: COMMing to the scene.Cell Mol Life Sci 2007;64:1997-2005. 10.1007/s00018-007-7078-y [PMC free article] [PubMed] [CrossRef] [Google Scholar]

29. Fedoseienko A, Bartuzi P, van de Sluis B. Functional understanding of the versatile protein copper metabolism MURR1 domain 1 (COMMD1) in copper homeostasis.Ann N Y Acad Sci 2014;1314:6-14. 10.1111/nyas.12353 [PubMed] [CrossRef] [Google Scholar]

30. Riera-Romo M. COMMD1: A Multifunctional Regulatory Protein.J Cell Biochem 2018;119:34-51. 10.1002/jcb.26151 [PubMed] [CrossRef] [Google Scholar]

31. Ganesh L, Burstein E, Guha-Niyogi A, et al. The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytes.Nature 2003;426:853-7. 10.1038/nature02171 [PubMed] [CrossRef] [Google Scholar]

32. Spee B, Arends B, van Wees AM, et al. Functional consequences of RNA interference targeting COMMD1 in a canine hepatic cell line in relation to copper toxicosis.Anim Genet 2007;38:168-70. 10.1111/j.1365-2052.2007.01580.x [PubMed] [CrossRef] [Google Scholar]

33. Vonk WI, Bartuzi P, de Bie P, et al. Liver-specific Commd1 knockout mice are susceptible to hepatic copper accumulation.PLoS One 2011;6:e29183. 10.1371/journal.pone.0029183 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

34. de Bie P, van de Sluis B, Burstein E, et al. Distinct Wilson's disease mutations in ATP7B are associated with enhanced binding to COMMD1 and reduced stability of ATP7B.Gastroenterology 2007;133:1316-26. 10.1053/j.gastro.2007.07.020 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

35. Weiss KH, Lozoya JC, Tuma S, et al. Copper-induced translocation of the Wilson disease protein ATP7B independent of Murr1/COMMD1 and Rab7.Am J Pathol 2008;173:1783-94. 10.2353/ajpath.2008.071134 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

36. Vonk WI, de Bie P, Wichers CG, et al. The copper-transporting capacity of ATP7A mutants associated with Menkes disease is ameliorated by COMMD1 as a result of improved protein expression.Cell Mol Life Sci 2012;69:149-63. 10.1007/s00018-011-0743-1 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

37. Favier RP, Spee B, Penning LC, et al. Copper-induced hepatitis: the COMMD1 deficient dog as a translational animal model for human chronic hepatitis.Vet Q 2011;31:49-60. 10.1080/01652176.2011.563146 [PubMed] [CrossRef] [Google Scholar]

38. Favier RP, Spee B, Schotanus BA, et al. COMMD1-deficient dogs accumulate copper in hepatocytes and provide a good model for chronic hepatitis and fibrosis.PLoS One 2012;7:e42158. 10.1371/journal.pone.0042158 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

39. Favier RP, Spee B, Fieten H, et al. Aberrant expression of copper associated genes after copper accumulation in COMMD1-deficient dogs.J Trace Elem Med Biol 2015;29:347-53. 10.1016/j.jtemb.2014.06.007 [PubMed] [CrossRef] [Google Scholar]

40. Fieten H, Hugen S, van den Ingh TS, et al. Urinary excretion of copper, zinc and iron with and without D-penicillamine administration in relation to hepatic copper concentrations in dogs.Vet J 2013;197:468-73. 10.1016/j.tvjl.2013.03.003 [PubMed] [CrossRef] [Google Scholar]

41. Fieten H, Penning LC, Leegwater PA, et al. New canine models of copper toxicosis: diagnosis, treatment, and genetics.Ann N Y Acad Sci 2014;1314:42-8. 10.1111/nyas.12442 [PubMed] [CrossRef] [Google Scholar]

42. Fieten H, Gill Y, Martin AJ, et al. The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders.Dis Model Mech 2016;9:25-38. 10.1242/dmm.020263 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

43. Huch M, Dorrell C, Boj SF, et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration.Nature 2013;494:247-50. 10.1038/nature11826 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

44. Huch M, Gehart H, van Boxtel R, et al. Long-term culture of genome-stable bipotent stem cells from adult human liver.Cell 2015;160:299-312. 10.1016/j.cell.2014.11.050 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

45. Nantasanti S, Spee B, Kruitwagen HS, et al. Disease Modeling and Gene Therapy of Copper Storage Disease in Canine Hepatic Organoids.Stem Cell Reports 2015;5:895-907. 10.1016/j.stemcr.2015.09.002 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

46. Boaru SG, Merle U, Uerlings R, et al. Simultaneous monitoring of cerebral metal accumulation in an experimental model of Wilson's disease by laser ablation inductively coupled plasma mass spectrometry.BMC Neurosci 2014;15:98. 10.1186/1471-2202-15-98 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Sours: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531654/

Diagnosing and treating canine copper-associated hepatopathies

The most consistent laboratory finding is increased alanine transaminase (ALT) activity. Other liver enzyme activities may be increased concurrently, including alkaline phosphatase (ALP), aspartate transaminase (AST), and gamma-

glutamyltransferase (GGT). The relative increase in ALT activity is often much higher than the relative increase in ALP activity, suggesting predominantly hepatocellular rather than cholestatic liver disease. Even mild increases in ALT activity are important and merit more attention than changes in ALP activity. In addition, consider nonhepatic causes of increased ALP activity, particularly if it is the only abnormal parameter.

Hyperbilirubinemia, hypoalbuminemia, hypoglycemia, low blood urea nitrogen (BUN) concentration, or hypocholesterolemia suggests considerable compromise to hepatic function. Elevated bile acid concentrations, ammonia tolerance testing results, or ammonia concentrations can confirm liver dysfunction and may provide prognostic information. However, they do not obviate the need for liver biopsy.

Since copper accumulation in the liver occurs slowly, substantial increase of ALT or AST activity in a previously healthy patient is most suggestive of an acute injury by a noncopper hepatotoxin. Hepatoprotectants, supportive care, and periodic monitoring (every two weeks) of serum chemistry profile results are indicated before liver biopsy is pursued.

Other laboratory abnormalities may include anemia from chronic disease (nonregenerative) or gastrointestinal blood loss (regenerative or nonregenerative). Liver disease predisposes patients to gastrointestinal ulceration because of impaired mucosal blood flow, which is a result of dehydration and portal hypertension and decreased clearance of histamine and gastrin.6 Evidence of gastrointestinal bleeding may include melena, hematochezia, or an increased serum BUN to creatinine ratio. Urinalysis results may reveal bilirubinuria, dilute urine (isosthenuria), or glucosuria.

ULTRASONOGRAPHY

Abdominal ultrasonography is indicated to rule out primary biliary tract disease, especially extrahepatic biliary obstruction, and can provide useful clues about the duration of a patient's liver disease. If the liver appears mottled (mixed echogenicity), small, cirrhotic, or nodular, the liver disease is probably chronic. If the liver appears unremarkable in terms of size and echogenicity in a patient with a one-time-only increase in liver enzyme activities, acute liver injury is more probable.

Figure 1. A laparoscopic photograph showing a nodular and discolored liver. (Photo courtesy of Dr. Mike Willard of Texas A&M University's College of Veterinary Medicine.)

DEFINITIVE DIAGNOSIS

Definitively diagnosing a copper-associated hepatopathy requires obtaining a liver biopsy sample surgically or laparoscopically (Figure 1) for histologic examination and copper quantification. Special stains (rubeanic acid, rhodanine, Timm's) can be used as a qualitative indicator of copper accumulation. Copper-loaded lysosomes can be identified with these stains when hepatic copper concentrations exceed 400 ppm on a dry weight basis (Figure 2).6

Figure 2. A photomicrograph from a liver biopsy demonstrating copper staining of copper-laden lysosomes (rhodanine stain, 400X). (Photo courtesy of Dr. Mike Willard of Texas A&M University's College of Veterinary Medicine.)

Atomic absorption analysis of liver tissue is the only way to accurately assess the hepatic copper concentration. Most laboratories require fresh or freshly frozen liver samples (Table 1). Copper concentrations are reported as µg/g of dry weight, which is the same as parts per million per dry weight (ppm dw).

Table1: Laboratories That Perform Heavy Metal Atomic Absorption Analysis

Copper concentrations > 2,000 ppm dw are thought to be directly hepatotoxic. However, some dogs may accumulate as much as 3,500 ppm dw before liver pathology is evident.1

In non-Bedlington breeds, copper concentrations are often substantially lower; Doberman pinschers with copper concentrations as low as 750 ppm may have morphologic evidence of hepatocellular damage and show improvement with copper chelation therapy.7 This supports the suggestion that the mechanism of copper accumulation may vary with different breeds.

Interpreting the histologic findings in these cases is an essential part of patient diagnosis. Important aspects to identify are the type (suppurative vs. lymphoplasmacytic) and extent of inflammation and the severity of necrosis, fibrosis (bridging is worse than piecemeal), and cholestasis.

TREATMENT

Only treatments for copper-associated hepatopathy are discussed below. In general, provide supportive care as required on a case-by-case basis, and discontinue any drug that is known to be potentially hepatotoxic (e.g. nonsteroidal anti-inflammatory drugs, phenobarbital). See Table 2 for therapy guidelines.

Table 2: Treating Canine Copper Hepatopathy*

Copper-restricted diet

Dogs with copper-associated hepatopathies should not be given soft water from copper pipes.6 Foodstuffs rich in copper, including shellfish, liver, kidney, heart, nuts, mushrooms, cereals, cocoa, and legumes, should also be avoided.6 In addition, these dogs should be fed a copper-restricted diet to slow—but not reverse—hepatic copper accumulation.

For growth and maintenance dog foods, the Association of American Feed Control Officials recommends 7.3 to 250 ppm per dry matter basis (DMB) of copper. Therapeutic veterinary diets designed for patients with liver dysfunction contain 3 to 5 ppm DMB of copper.6 Many of the therapeutic veterinary diets also contain high concentrations of antioxidants and adequate concentrations of high-quality proteins. Protein restriction is only required in dogs with hepatic encephalopathy, which is a rare complication.

Commercially available copper-restricted diets include Prescription Diet Canine l/d (Hill's Pet Nutrition) and Hepatic LS 14 Formula (Royal Canin). If a client prefers a homemade copper-restricted diet, consult a board-certified veterinary nutritionist.

Chelating agents

Copper chelators reduce liver copper content through chelation of copper in plasma and tissue, which is then excreted in the urine. D-penicillamine and trientine are two copper-chelating agents commonly used in veterinary medicine. D-penicillamine is associated with more side effects (e.g. vomiting, nausea, anorexia, lethargy, fever, skin problems) than trientine is, but it may also inhibit fibrosis by preventing cross-linking of collagen and by exerting an immunosuppressive effect by inhibiting T-lymphocyte function.8 Minimal, if any, side effects are associated with trientine use in dogs, but this product may be prohibitively expensive in large-breed dogs. When treating patients with D-penicillamine or trientine, it may take many months to remove excess copper from the liver (at an approximate rate of 900 µg/g dw per year) and for improvement in ALT activity to be appreciated.6,9

Copper chelation is not necessarily a benign treatment. One report in the veterinary literature described iatrogenic copper deficiency associated with long-term copper chelation in a Bedlington terrier.9 Clinical signs associated with copper deficiency can include central nervous system dysfunction, anemia, and abnormal ossification.5

Elemental zinc

Elemental zinc induces synthesis of intestinal mucosal metallothionein, which has a high affinity for copper and, thus, binds dietary copper and limits its absorption.1 The copper bound to the intestinal mucosal metallothionein is eventually excreted in feces as enterocytes are shed.1 Elemental zinc can be supplemented in the acetate, sulfate, gluconate, or methionine forms. Zinc gluconate is the most common formulation and is available over the counter. The dosage listed in Table 2 is for elemental zinc; clients may need help in selecting an appropriate product.

Zinc should be given one to two hours before a meal so the maximum amount of metallothionein will be available to bind copper. If nausea is reported, zinc may be given with a small amount of canned dog food. D-penicillamine and trientine could theoretically chelate zinc, but practically it is not a problem. Staggering the therapy should suffice.9

Ursodiol and glucocorticoids

Most of the information supporting the administration of ursodiol in patients with liver disease comes from studies in people. Ursodiol, or ursodeoxycholic acid, is a hydrophilic bile acid that shifts the bile acid profile toward the less toxic hydrophilic forms by competing with other bile acids for ileal absorption.8 In addition, the choleretic properties of ursodiol may increase copper excretion. Ursodiol may also reduce hepatocellular injury and fibrosis, modulate immune responses, and prevent bile acid-induced peroxidation by acting indirectly as an antioxidant.8

The goal of glucocorticoid therapy in patients with copper-associated hepatopathy is primarily to reduce inflammation. Since prednisolone is the active metabolite of prednisone and prednisone conversion may be impaired in dogs with substantial hepatic dysfunction, we prefer to use prednisolone in patients with liver disease. Prednisone and prednisolone have a 12- to 36-hour duration of action, and alternate-day dosing is ideal.8 Chronic corticosteroid use will increase ALP and GGT activities with minimal increases in hepatocellular leakage enzyme activities (ALT, AST); these changes do not reflect ongoing inflammation from copper-associated damage.

SAMe and vitamin E

S-adenosylmethionine (SAMe), a precursor of the antioxidant glutathione, is used as an antioxidant in liver disease. Also, it is recommended to help combat the oxidative effects of copper in copper-associated hepatopathy.8

Vitamin E is a potent antioxidant commonly used in treating liver disease, particularly copper-associated hepatopathies. Vitamin E is depleted in people with copper storage (Wilson's) disease, and its concentrations are decreased in chronic cholestasis.8 Advise owners to avoid giving their dogs selenium-containing preparations because of possible selenium toxicosis.

MONITORING AND MAINTENANCE THERAPY

Follow-up liver biopsies with copper quantification are required to determine efficacy and duration of chelation therapy. No consensus has been established about when it is appropriate to perform follow-up biopsies in these patients. In our experience, repeating the biopsy after 12 months of chelation therapy is helpful. The decision to perform subsequent biopsies can be based on serial monitoring of hepatic enzyme activities.

After effective chelation therapy, institute maintenance therapy to prevent copper reaccumulation. This therapy usually consists of zinc supplementation along with dietary copper restriction. Intermittent copper chelation therapy may be required to maintain normal hepatic copper concentrations in severely affected individuals.

CONCLUSION

Any patient with evidence of liver disease may have increased hepatic copper concentrations, either as a primary disorder or secondary to hepatocellular dysfunction and cholestasis. If a liver biopsy is performed for histologic analysis, submit a second sample for quantitative copper analysis—especially in known copper hepatopathy-associated breeds—since diagnosis and treatment may mitigate or reverse copper-associated changes.

Brier Bostrum, DVM

Audrey K. Cook, BVM&S, MRCVS, DACVIM, DECVIM-CA

Department of Small Animal Clinical Sciences

College of Veterinary Medicine and Biomedical Sciences

Texas A&M University

College Station, TX 77843

REFERENCES

1. Thornburg LP. A perspective on copper and liver disease in the dog. J Vet Diagn Invest 2000;12(2):101-110.

2. Twedt DC, Sternlieb I, Gilbertson SR. Clinical, morphologic, and chemical studies on copper toxicosis of Bedlington Terriers. J Am Vet Med Assoc 1979;175(3):269-275.

3. van De Sluis B, Rothuizen J, Pearson PL, et al. Identification of a new copper metabolism gene by positional cloning in a purebred dog population. Hum Mol Genet 2002;11(2):165-173.

4. Spee B, Arends B, van den Ingh TS, et al. Copper metabolism and oxidative stress in chronic inflammatory and cholestatic liver diseases in dogs. J Vet Intern Med 2006;20(5):1085-1092.

5. Rolfe DS, Twedt DC. Copper-associated hepatopathies in dogs. Vet Clin North Am Small Anim Pract 1995;25(2):399-417.

6. Guilford WG, Strombeck DR. In: Guilford WG, Center SA, Strombeck DR, et al., eds. Strombeck's small animal gastroenterology. 3rd ed. Philadelphia, Pa: WB Saunders Co, 1996;xiii,978.

7. Mandigers PJ, van den Ingh TS, Bode P, et al. Improvement in liver pathology after 4 months of D-penicillamine in 5 doberman pinschers with subclinical hepatitis. J Vet Intern Med 2005;19(1):40-43.

8. Sartor LL, Trepanier LA. Rational pharmacologic therapy of hepatobiliary disease in dogs and cats. Compend Contin Educ Pract Vet 2003;25:432-447.

9. Seguin MA, Bunch SE. Iatrogenic copper deficiency associated with long-term copper chelation for treatment of copper storage disease in a Bedlington Terrier. J Am Vet Med Assoc 2001;218(10):1593-1597, 1580.

10. Plumb DC. Plumb's veterinary drug handbook. 5th ed. Ames, Iowa: Blackwell Publishing, 2005;929.

Sours: https://www.dvm360.com/view/diagnosing-and-treating-canine-copper-associated-hepatopathies

Disease in dogs wilson

Copper Toxicosis (Menkes and Wilson diseases)

Quick Summary

Copper toxicosis is a metabolic disorder that can cause chronic liver failure and neurological problems that result from deviations in normal levels of copper in the body.

Phenotype: Copper toxicosis is an inherited metabolic disorder that can lead to liver failure when copper levels are higher than normal. The proper amount of copper is very important to normal metabolism and liver function.  If there is a copper deficiency this is known as Menkes disease. On the other hand, when there is an accumulation of excess copper in the body it is referred to as Wilson disease and liver damage results.

Mode of Inheritance: Additive, Sex linked

Alleles:N = normal, 7A = ATP7AMenkes variant, 7B = ATP7B Wilson variant

Breeds appropriate for testing: Labrador Retriever, Labrador Retriever crosses, and potentially Doberman Pinschers and Black Russian Terriers (specifically ATP7B)

Explanation of Results:

ATP7A in females:

  • Female dogs with the N/N genotype do not have the ATP7A variant associated with Menkes disease in canines. Individuals with this genotype will not have altered hepatic copper levels due to this variant.
  • Female dogs with the N/7A genotype have 1 copy of the ATP7A variant detected. The individual may have lower levels of hepatic copper. But this variant is likely not the only variant contributing to low levels of copper in dogs across breeds.  Environmental factors including diet are thought to contribute to the variability in copper levels detected.
  • Female dogs with the 7A/7A genotype have 2 copies of the ATP7A variant detected. The individual may have very low levels of hepatic copper, environmental factors are thought to contribute to the variability in copper levels detected.

ATP7A in males:

  • Male dogs with an N genotype haveno copies of the ATP7A variant. Individuals with this genotype will not have altered hepatic copper levels due to this variant.
  • Male dogs with a 7A genotype have 1 copy of the ATP7A variant. The individual may have very low levels of hepatic copper, environmental factors are thought to contribute to the variability in copper levels detected.

ATP7A may only be relevant in the Labrador Retriever and related crosses.

ATP7B:

  • Dogs with an N/N genotype have no copies of the ATP7B variant associated with Wilson disease in canines. Dogs with this genotype will not have altered hepatic copper levels due to this variant, however other yet unknown variants cannot be ruled out by this genetic test.
  • Dogs with an N/7B genotype have 1 copy of the ATP7B variant. The individual may have moderately elevated levels of hepatic copper, environmental factors such as diet are thought to contribute to the variability in copper levels detected.
  • Dogs with an 7B/7B genotype have 2 copies of the ATP7B variant. Individuals with this genotype may have significantly elevated hepatic copper levels and environmental factors are thought to contribute to the variability in copper levels detected.

ATP7A and ATP7B:

Dogs with variants in both genes ([N/7A, N/7B], [N/7A, 7B/7B], [7A/7A, N/7B], [7A/7A, 7B/7B], [7A, N/7B], [7A, 7B/7B]) appear to have varied hepatic copper levels depending upon the combination of alleles and other environmental contributing factors. However, data suggests affected alleles at both loci have a neutralizing effect on copper level changes and Labrador Retriever dogs with these genotypes will likely be unaffected.  It is not yet known how the presence of 7A by itself or in combination with 7B impacts copper levels in the Doberman.

Results of this test can be submitted to the OFA (Orthopedic Foundation for Animals)

Price

$50 one test per animal
$30 as additional test (same animal)

Additional Details

Normal copper levels within the body are maintained by balancing the rates of copper absorption from the diet and copper excretion through the biliary system (or system that produces and transport the fluid used to break down fats into fatty acids). The balance that is maintained by physiological processes is known as homeostasis. Two proteins, ATP7A for absorption and ATP7B for excretion, act concurrently to maintain appropriate levels of copper. Variants in either of these genes may lead to early-onset, progressive and often-fatal diseases associated with copper deficiency (Menkes) or accumulation (Wilson) in the body. But, combinations of the identified variants in both genes have a neutralizing effect on copper level changes.

The P-type copper-transporting ATPases ATP7A and ATP7B have opposite but crucial roles for copper homeostasis. ATP7A is expressed in intestinal cells, where it is involved in copper absorption and delivery to the liver, where it is stored; ATP7B is expressed in the liver and is involved is excreting excess copper into the bile.

Variants in the ATP7A gene (located on the X chromosome) result in an early-onset and fatal copper-deficiency disorder known as Menkes disease, characterized by brain and cerebellar degeneration, failure to thrive, coarse hair and connective tissue abnormalities. In Labrador Retrievers, Menkes disease is caused by a single nucleotide substitution in the ATP7A gene (c.980C>T)that results in an amino acid substitution from a threonine to an isoleucine at position 327 of the ATP7A protein (p.Thr327Ile).

Wilson disease results from variants in ATP7B, and is associated with copper accumulation in the liver and secondarily in the brain, resulting in hepatic cirrhosis and neuronal degeneration. Age of onset is variable, and disease severity is associated with copper intake levels in the diet. In Labrador Retrievers, Wilson disease is caused by a single nucleotide substitution in the ATP7B gene (c.4358G>A) that causes an amino acid substitution in the C-terminus of the ATP7B protein (p.Arg1453Gln).

Therefore, in Labrador Retrievers, hepatic copper levels depend on the genotypes for both genes. The ATP7B variant leads to increased hepatic copper levels in an additive way. Copper levels are significantly higher in individuals homozygous for the mutation than in heterozygotes, which in turn have higher levels than individuals with no copies of the variant.  Presence of both the ATP7A and ATP7B variants leads to an attenuation of copper accumulation, which appears to be more notable in males.

In Doberman Pinschers, a strong association between excess hepatic copper levels and the ATP7B (c.4358G>A) variant was identified. However, while the ATP7A variant was detected in the Doberman Pinscher study cohort, the sample set did not contain sufficient individuals with ATP7A to conclusively determine the interaction with ATP7B. Therefore, more work is needed to understand the interaction of these loci and any dog testing positive for ATP7A or ATP7B should be clinically evaluated.

Similarly, the ATP7B (c.4358G>A) variant has been detected in Black Russian Terriers with elevated hepatic copper levels.  This research is ongoing.

The VGL offers a DNA test for the ATP7A and ATP7B variants. Test results help breeders make informed breeding decisions, as well as identify dogs to be clinically evaluated to determine copper levels and to manage dietary copper intake of their animals based on their combined genotypes for these two genes. For dogs with either of the variants, veterinarian consultation is recommended to best manage your dog’s health.

Note:This test is specific for the ATP7A and ATP7B copper toxicosis associated variants present in the Labrador Retriever.   The ATP7B variant is also relevant in the Doberman Pinscher and Black Russian Terrier breeds but the role of ATP7A needs further evaluation in the both breeds. This assay does not detect copper- associated liver diseases in the Bedlington Terrier, Dalmatian, West Highland White Terrier, Keeshond, and German Shepherd.

Turnaround Time

At least 15 business days

Results Reported As

ATP7A**

ATP7B

Female Results

N/N

N/N

No copies of the ATP7A and ATP7B variants.

N/7A

N/N

One copy of the ATP7A variant and may have decreased levels of hepatic copper.

7A/7A

N/N

Two copies of the ATP7A Variant and may have very low levels of hepatic copper.

N/N

N/7B

One copy of the ATP7B variant and may have increased levels of hepatic copper.

N/N

7B/7B

Two copies of the ATP7B variant and may have very high levels of hepatic copper.

N/7A

N/7B

One copy each of the ATP7A and ATP7B variants. Hepatic copper levels may be slightly elevated.

N/7A

7B/7B

One copy of the ATP7A variant and two copies of the ATP7B variant. Hepatic copper levels may be elevated.

7A/7A

N/7B

Two copies of the ATP7A variant and one copy of the ATP7B variant. Hepatic copper levels may be slightly decreased.

7A/7A

7B/7B

Two copies each of the ATP7A and ATP7B variants. Hepatic copper levels may be slightly altered from normal ranges.

ATP7A

ATP7B

Male Results

N

N/N

No copies of the ATP7A and ATP7B variants.

7A

N/N

The dog has the ATP7A variant and may have very low levels of hepatic copper.

N

N/7B

One copy of the ATP7B variant and may have increased levels of hepatic copper.

N

7B/7B

Two copies of the ATP7B variant and may have very high levels of hepatic copper.

7A

N/7B

The dog has the ATP7A variant and one ATP7B variant. Hepatic copper levels may be slightly altered from normal ranges.

7A

7B/7B

The dog has the ATP7A variant and two copies of the ATP7B variant. Hepatic copper levels may be elevated.

* Any dog testing positive for 7A, 7B or both should be clinically evaluated.
**ATP7A testing may only be relevant for the Labrador Retriever and related crosses

References

Fieten H., Gill Y., Martin A..J, Concilli M., Dirksen K., van Steenbeek F.G., Spee B., van den Ingh T.S., Martens E.C., Festa P., Chesi G., van de Sluis B., Houwen R.H., Watson A.L., Aulchenko Y.S., Hodgkinson V.L., Zhu S., Petris M.J., Polishchuk R.S., Leegwater P.A., Rothuizen J. (2016) The Menkes and Wilson disease genes counteract in copper toxicosis in Labrador retrievers: a new canine model for copper-metabolism disorders. Dis Model Mech 9(1):25-38. PMID 26747866 DOI: 10.1242/dmm.020263

Hoffmann, G., (2009) Copper-associated liver diseases. Vet Clin Small Animal 39 489-511. Liver Copper Storage Disease.

Wu, X., Mandigers, P.J.J., Watson, A.L., van den Ingh, T.S.G.A.M., Leegwater, P.A.J., Fieten, H. (2019) Association of the canine ATP7A and ATP7B with hepatic copper accumulation in Dobermann dogs. J Vet Intern Med 33:1646-1652, 2019. PMID: 31254371. DOI: 10.1111/jvim.15536.

Sours: https://vgl.ucdavis.edu/test/copper-toxicosis
Wilson Disease - Clinical Presentation

She sat down next to Max, but we were in no hurry to move on. Max took me by the neck and kissed me. He kissed so fucking awkwardly that I really started to flow.

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