Copper Storage Disease in Dogs



Copper Toxicity/Chronic Active Hepatitis


The trace mineral Copper (Cu) is incorporated into several
enzymes which catalyze important

reactions in the body. Cu is mainly stored in the liver, but is
also found in the skeletal system (bone marrow) as well as in
muscle, brain and spleen tissue. While unavailable dietary Cu is
excreted in the feces, via bile, approximately 40-60% of dietary
(ingested) Cu is absorbed into the blood by the mucosa of the
small intestine. The serum proteins albumin and transcuprein then
transport Cu in the blood to the liver, which is the site of
synthesis of the iron-containing protein ceruloplasmin (CEP).
CEP transports Cu to target tissues in the body, then returns to
the liver. In the liver, CEP is degraded, resulting in Cu being
lost in bile salts, which is a main route of excretion. Blockage
of the bile ducts will lead to an accumulation of copper in the
liver tissue. (Class notes, ANSC 604, Spring 1997).


Other copper-containing enzymes synthesized in the liver are:
cytochrome oxidase, which
functions in muscles and other tissues to reduce oxygen to water;
superoxide dismutase (SOD) which degrades superoxide to yield
peroxide and oxygen, also in muscles; and metallothionein.
Metallothionein contains many cysteine residues which have
sulfhydryl groups that allow it to bind heavy metals, especially
copper and zinc. Copper bound to metallothionein is sequestered,
thereby decreasing its absorption. Zinc intake regulates the
synthesis of metallothionein, and therefore also the absorption
rate of copper. Bile salts also inhibit absorption of Cu.
Copper-containing enzymes in other parts of the body include
dopamine- -hydroxylase in the brain, and lysyl oxidase in the
connective tissue (Linder 1991).

Deficiency of copper causes multiple symptoms in animals,
including depigmentation, bone problems, spinal cord paralysis
and ataxia, cardiac failure, connective tissue abnormalities, and
anemia. Deficiencies are more commonly seen than toxicities;
however, toxicity of copper also has serious implications for the
affected animal. In humans, Wilson's disease has been studied; in
dogs, the analogous disease group is chronic active hepatitis
(CAH). Both diseases affect the liver, the site of copper
storage. The focus of this paper is the role of copper toxicosis
in canine CAH.

Levels of copper and other metals stored in the body generally
tend to be higher in newborns, decreasing as the individual
matures. However, in some animals such as sheep, cattle, and
dogs, this trend is not seen. Normal newborn canine hepatic
copper concentrations are higher than those seen in mature
humans, mice and rats (Keen 1981), and remain fairly constant
over the lifetime of the individual (Thornburg 1985), unless the
individual is suffering from CAH or some form of toxicosis. Mean
concentrations of copper in the liver of normal dogs of any breed
is 200-400 parts per million (ppm) on a dry weight (DW) basis
(Keen 1984). Dogs with CAH may exhibit concentrations up to
10,000 ppm, with levels of 2,000 generally accepted as being
toxic (Thornburg 1985).

There is some speculation as to why canine hepatic copper
concentrations are so different from other species. Most likely,
this is due to the fact that copper metabolism in dogs is
different from other species, with regards to copper-binding
proteins. Cu in the liver of dogs is associated not with
metallothionein, as it is in other animals, but with other
similarly-weighted proteins that have low cysteine concentrations
(Keen 1981), making them less likely to bind copper. It has also
been found that albumin in canine serum lacks the specific
characteristic preferential binding site for Cu(II) that is found
in human, bovine, and rat serum albumin (Appleton 1971). Since in
other mammalian species albumin transports Cu, the reduced
ability of canine albumin to do so presents a possible
explanation for the dog's unusual metabolism of Cu. Although the
dog has adaptive mechanisms --Cu is transported via gamma
globulin in serum-- they may not be sufficient to maintain the
efficiency of copper transport afforded by albumin (Appleton
1971).

The defined copper storage diseases that are known, are Wilson's
disease in humans, and a similar disorder in Bedlington Terriers.
The term "defined" in this case means that copper concentrations
are increased up to fifty times normal (Crawford 1985). It is
arguable whether other breeds of dogs suffer a storage disorder,
such that copper toxicosis is the cause of CAH, or rather if the
copper accumulation is a result of the CAH. In Bedlingtons, it is
said that dietary copper accumulates in the liver until reaching
toxic levels, at which time pathologic changes then develop. The
belief is that a genetic defect in the hepatic lysosomal
mechanism for copper excretion is responsible for the disease
(Crawford 1985). Similarly, in Dobermans, it is suggested that
copper toxicosis is a cause rather than a result of liver
disease, but not the primary cause, since one of the cases
presented demonstrated no copper accumulation at all (Franklin
1988).

CAH is actually a group of hepatic diseases with similar
characteristics but different causes. It most often affects
certain breeds of dogs, and has been well studied in Bedlington
Terriers, West Highland White Terriers, and Doberman Pinschers.
In some breeds, CAH is an inherited defect of metabolism
involving biliary excretion (Bedlingtons), while in others the
cause is not known to be linked to genetics but is thought to be
related to a storage defect, perhaps influenced by diet
(Dobermans). In Bedlingtons and West Highland White Terriers, an
autosomal recessive copper-toxicosis (CT) gene has been linked to
the Cu metabolism disorder. A test was developed to assist owners
and breeders in identifying carriers of the CT gene earlier in
life and without invasive measures. The test involves
administering an intravenous dose of the 64Cu radioisotope, and
measuring 64Cu excreted in the feces after 48 hours. The method,
while not perfect, has been found effective and has enabled
diagnosis and preventive treatment to begin before the dog
becomes ill, when treatment is most effective (Brewer 1992).

In Dobermans, females of middle-age (approximately 7 years) are
by far the most often affected, but the disease is also seen in
males. One study suggested a genetic basis due to the high
percentage of one breed affected with CAH, in the hospital
population (Crawford 1985). Another author concurs, stating that
a high frequency of CAH in one breed suggests a genetic basis
(Johnson 1982). Further support of this theory is offered, in
that the wide range of age of onset (2.5 to 11 years) may
indicate the involvement of an environmental agent playing a role
in the genetically predetermined host response (Johnson 1982).

Other reported possible causes of CAH in dogs are leptospire
infections, adenovirus infections, and primidone therapy
(Crawford 1985). A further proposed cause is an immune-mediated
reaction from the infectious canine hepatitis virus (Franklin
1988).




Opinions regarding the influence of diet on copper accumulation
are varied. One study purported that no evidence of dietary
explanation of increased hepatic copper was found (Thornburg
1988). The same author in an earlier paper stated that "the
disease is independent of diet; affected dogs accumulate copper
when fed a diet that would not result in copper accumulation in a
normal dog" (Thornburg 1985). This seems to contradict his
previous assertion that "most cases of toxicosis are due to
excess copper in the diet" (Thornburg 1983). He also reported
that in cases where the dog is suspected to be genetically
predisposed to Cu toxicosis, normal dietary levels of copper
cannot be tolerated (Thornburg 1983). Su et al speculate that
perhaps "commercial dog chows are so laden with copper that dogs
are sequestering a continuous overdosage in their livers" (Su
1982).

Although the cause has not been definitively determined, CAH has
been studied and much has been learned about its diagnosis and
treatment. The disease is progressive, with copper accumulating
in the hepatocellular lysosomes as the dog ages, reaching levels
that are toxic, and resulting in damage to and eventual failure
of the liver (Dill-Macky 1995).

There are three progressive stages of copper toxicosis. During
Stage 1, the dog is not clinically ill, but copper levels are
accumulating in the liver; values have been reported as high as
1,500 ppm DW (Thornburg 1985). Regardless of breed, the
accumulation begins very early in the dog's life. The
accumulation progresses at different rates in different breeds,
and even differs among individuals within breeds. The copper
begins to accumulate in the centrilobular hepatocytes in
granules, with the band of granules gradually widening until the
midzonal hepatocytes begin to fill as well (Thornburg 1985). The
livers of dogs in Stage 1 present no clinical abnormalities, and
biopsy at this time will indicate that things are normal.
However, if liver tissue is stained, using the methods developed
by Thornburg et al. (1985), increased levels of copper are
revealed.

Stage 2 begins when the hepatic copper concentration reaches
2,000 ppm DW (Thornburg 1985). The dog is still not clinically
ill, but a biopsy at this point will reveal hepatitis, and is the
only reliable method of diagnosis. Biochemical and toxicologic
findings including elevated serum enzyme levels (Alanine
Aminotransferase [ALAT] and Alkaline Phosphatase [AP]) may be
seen, but do not specifically indicate copper toxicosis: "Dogs
with hepatitis only will have elevated ALAT, but hepatitis never
causes clinical disease. The ALAT elevation merely reflects liver
damage and is neither characteristic nor diagnostic of inherited
copper toxicosis. Hepatitis does not alter the liver function
tests" (Thornburg 1988). High ALAT and AP values indicate an
episode of necrosis (Thornburg 1984). In a study of Dobermans
with CAH, mean ALAT levels of 549 IU/L were seen, with normal
being 15 to 50 IU/L, while AP levels were reported at a mean of
661 IU/L, with normal being 20 to 60 IU/L (Crawford 1985). A
slightly earlier study, also with Dobermans, reported even higher
values for these enzymes: ALAT of 3,045 IU/L (normal 18 to 70
IU/L); and AP of 2,650 IU/L (normal 12 to 70 IU/L) (Thornburg
1984). Increased bilirubin, hypoalbuminemia, anemia, prolonged
prothrombin time, low platelet count, increased resting blood
ammonia concentrations, raised serum copper content, and
increases of both iron and copper content in the liver and kidney
tissue were other findings noted in Dobermans, as well as thyroid
abnormalities, abdominal effusion, microhepatica, and pleural
effusion (Crawford 1985).

Finally, in Stage 3, the dog becomes clinically ill, and may have
anorexia, depression, vomiting, abdominal pain, polydipsia,
polyuria, icterus, jaundice, ascites, and encephalopathy
(Dill-Macky 1995, Franklin 1988). Weight loss is the predominant
indicator, and in some dogs, is the only sign. The clinical signs
are usually the result of liver necrosis, triggered when copper
concentrations exceed 2,000 ppm DW, causing centrilobular
hepatocytes to die off and lyse (Thornburg 1985). This event in
turn may cause connective-tissue stroma to collapse, leading to
formation of ascites (Thornburg 1985). ALAT values are elevated,
but then rapidly decrease following necrosis (Thornburg 1985).
Bilirubin concentration, and amylase and lipase activities may
also be elevated (Dill-Macky 1995).

Interestingly, the concentration of copper in the liver actually
decreases after necrosis and repair occur. The cells that die
during necrosis are the same ones that are the first to
accumulate copper -- the centriolobular hepatocytes. As the cells
die, copper is released into the blood and excreted in the urine.
As hepatocytes are regenerated, and scar tissue is formed, the
overall ppm DW concentration of copper is decreased, since
neither of these new cell types contains copper stores (Thornburg
1986).

Because of the progressive nature of the disease, most affected
animals are not presented for diagnosis and treatment until the
late stages, when clinical symptoms appear. Treatment is mainly
supportive, and prognosis is complicated by the fact that
diagnosis and treatment come so late in the progression of the
disease. One study revealed that dogs with lower blood glucose
levels and prolonged prothrombin time lived less than one week
from examination and diagnosis (Dill-Macky 1995). Some
Bedlingtons died after one episode of acute necrosis (Thornburg
1985) while most reported cases in Dobermans lived only a few
months before succumbing to cirrhosis and liver failure
(Cornelius 1989).

In instances where the copper accumulation was detected early on,
when the dog was asymptomatic, and treatment began early on,
affected individuals seemed to recover and live longer (Cornelius
1989). Some Bedlingtons are routinely biopsied and screened for
copper accumulation, with biochemical profiles done annually
(Thornburg 1984). Biochemical screening and liver biopsy may
permit diagnosis and allow treatment to begin before irreversible
damage has occurred (Johnson 1982).

Treatment of CAH may be dietary, medical, or a combination of
these methods. Some treatment regimens for Bedlingtons involve a
higher-level, "cleansing" dosage of medicine, or a routine,
lower-level "maintenance" dosage, in an effort to rid the liver
of excess copper and allow the dog a better chance of remaining
symptom free (Thornburg 1984). In contrast to these findings,
Franklin reported that in Dobermans, prognosis is very poor,
since usual methods of medical treatment do not stop disease
progression (Franklin 1988). The literature indicates that
dietary methods have proved more successful in extending the
lives of CAH dogs of this breed.

Dietary modifications suggested for management of dogs with CAH
include providing a high quality protein source while lowering
the overall level of protein fed. This will act to minimize
hyperammonemia and abnormal amino acid ratios; however, if
protein restriction is too excessive, it may impair hepatocyte
regeneration (Dill-Macky 1995). Suggested protein sources include
cottage cheese, eggs, and lean meat (Strombeck 1976, Franklin
1988). Other dietary modifications include providing an easily
digestible source of carbohydrates, both to provide calories and
to prevent catabolism (Dill-Macky 1995). It is further
recommended that dietary fat intake be restricted, to reduce
short-chain fatty acids which could contribute to encephalopathy
(Hardy 1986).

Dietary supplementation recommended for long-term management of
dogs with CAH includes providing a daily balanced vitamin
(Dill-Macky 1995), to counteract the pyridoxine deficiency known
to be caused by a commonly used drug treatment for CAH
[penicillamine] (Thornburg 1984), and supplementation with
vitamin C (ascorbic acid) which may help promote copper excretion
in the urine (Cornelius 1989). Also, since ascorbic acid is
poorly synthesized in dogs with CAH, additional vitamin C in the
diet may help to prevent a deficiency (Cornelius 1989). Zinc
supplements, in the form of zinc gluconate, may also help to
reduce absorption of copper in the intestine (Cornelius 1989) by
inducing the synthesis of metallothionein (Schilsky 1993) which
would in turn act to bind copper, preventing its absorption. One
report mentioned the use of vitamin K as part of the dietary
therapy used to treat the most severely affected of the dogs in
the study group (Crawford 1985), presumably to help counteract
the prolonged thromoboplastin time seen in these dogs (all
Doberman Pinschers, a breed prone to bleeding disorders). Another
study of CAH in Doberman Pinschers reported the use of a treament
consisting of amino acid supplements and vitamin B12, but did not
elaborate as to the reasoning for this particular supplementation
(Franklin 1988). Presumably the amino acids would help to
stabilize and correct the abnormal rations mentioned by
Dill-Macky, while vitamin B12 would help to counteract the
drug-induced vitamin deficiency mentioned above.

Medical treatments have two goals: to reduce absorption of
copper, perhaps by sequestering it; and to enhance excretion of
copper. To this end, chelating agents are commonly used. Chelates
are a complex of an organic ligand (electron donor) and a metal
(electron acceptor), in a ring structure formed by the
positive-negative attraction of the electrons. Certain metals
form stronger chelates than others, with Cu forming the
strongest, and magnesium the weakest (Class notes, ANSC 604,
Spring 1997). Chelates are important in the transport and storage
of mineral elements in the body. Therapeutic use of chelating
agents has been successful in detoxifying metals from target
organs and bones. The chelating agent competes with binding sites
in the body for complexing the metals, producing a water-soluble
complex which is then excreted in the urine or bile (Kratzner
1986).

The most commonly used chelating agent in the treatment of canine
CAH is d-penicillamine, which in addition to mobilizing copper
from tissues and promoting its excretion in the urine, seems to
increase the synthesis of metallothionein (Schilsky 1993).
D-penicillamine also reportedly has anti-inflammatory,
immunosuppressive, and antifibrotic effects (Cornelius 1989).
Other chelating agents that have been used successfully in the
treatment of CAH are trientine (Schilsky 1993) and
2,3,2-tetramine (Dill-Macky 1995).

Aside from chelating agents, CAH is sometimes treated with drugs
aimed at reducing the inflammation and resolving hepatic
fibrosis. Some commonly used drugs in the treatment of CAH in
dogs include glucocorticoids, and corticosteroids, such as
prednisone or prednisolone, which can have catabolic and
immunosuppressive effects. However, despite the potentially
harmful side effects, it has been reported that
corticosteroid-treated dogs have a greater long-term survival
than untreated dogs (Dill-Macky 1995). Liver enzyme levels may be
altered by increasing or decreasing dosages of prednisone, but
these results are not conclusive (Crawford 1985) since they are
not necessarily indicative of high copper concentrations. Liver
copper concentrations fluctuate as a result of the use of steroid
drugs such as prednisone; concentrations first decrease
dramatically in response to the drug --with greater decreases
observed at higher dosages-- then increase again as liver failure
develops (Crawford 1985).

Another drug with antifibrotic and anti-inflammatory properties
is colchicine. Colchicine may play a role in collagen
degradation, yet its benefit has been shown in dogs affected with
liver problems. One study reported improvement in a dog treated
with colchicine, when earlier treatments with diet modification
and prednisolone had failed to produce a favorable response
(Dill-Macky 1995).

In summary, while trace amounts of copper are necessary to
maintain proper body function, excesses can contribute to the
development of CAH in dogs and humans. The exact role of copper
cause and effect, i.e. does excess Cu cause CAH, or is excess Cu
a result of CAH, remains an unresolved and debated question in
the literature. However, most of the studies indicate that CAH
is a result of copper accumulation in liver cells. CAH progresses
through three stages, culminating in clinical symptoms and
usually eventual death of the affected dog. Because diagnosis is
usually made in the late stages of the disease, when symptoms
finally appear, treatments have a limited efficacy. Treatments
center around providing dietary modification and supplementation,
in addition to medical methods for removing excess copper from
the body. Chelating agents and steroids are commonly used to
assist the body in excreting excess copper while fighting
inflammation and fibrosis of the liver. CAH cannot be cured;
however, if detected in the early stages, treatment may begin
immediately, affording the best opportunity to extend the dog's
life significantly.

REFERENCES:


Animal Science 604: Regulation of Micro-Nutrient Metabolism, Dr.
J. Soares, Jr., Spring 1997 (Class
Notes) University of Maryland, College Park.

Appleton, David W.; Sarkar, Bibudhendra, The Absence of Specific
Copper (II)-binding Site in Dog
Albumin, Jrnl Biol Chem, vol 246, no 16, Aug 25, 1971, 5040-5045.

Brewer, George J.; Schall, William; Dick, Robert;
Yuzbasiayan-Gurkan, Vilma; Thomas, Michael;
Padgett, George; Use of 64Copper Measurements to Diagnose Canine
Copper Toxicosis, Jrnl
Vet Internal Med, vol 6, 1992, 41-43.

Cornelius, Larry M., Chronic Weight Loss; The Case of a Doberman
Pinscher, Vet Med Rep, vol 1,
no 3, 1989, 351-357.

Crawford, M.A.; Schall, W.D.; Jensen, R.K.; Tasker, J.B., Chronic
Active Hepatitis in 26 Doberman
Pinschers, Jrnl Am Vet Med Assoc, vol 187, no 12, Dec 15, 1985,
1343-1349.

Dill-Macky, Elizabeth, Chronic Hepatitis in Dogs, Vet Clinics of
N Amer: Sm An Practice, vol 25,
no 2, March 1995, 387-397.

Franklin, John E.; Saunders, Geoffrey K.; Chronic Active
Hepatitis in Doberman Pinschers,
Compendium Sm An, vol 10, no 11, November 1988, 1247-1254.

Hardy, R.M., Chronic Hepatitis in Dogs: A Syndrome, Compend
Contin Educ Pract Vet, vol 8,
1986, 904-914.

Johnson, Gerald F.; Zawie, Dennis A.; Gilbertson, Steven R.;
Sternlieb, Irmin; Chronic Active
Hepatitis in Doberman Pinschers, Jrnl Amer Vet Med Assoc, vol
180, no 12, June 15, 1982,
1438-1442.

Keen, Carl L; Lonnerdal, Bo; Fisher, Gerald L.; Age-Related
Variations in Hepatic Iron, Copper,
Zinc, and Selenium Concentrations in Beagles, Am Jrnl Vet Res,
vol 42, no 11, Nov 1981,
1884-1887.

Kratzner, Chelates in Metal Detoxification and Therapeutics,
Chelates in Nutrition, 1986, chapter 12, pp 141-151.

Linder, Maria C., Nutritional Biochemistry and Metabolism with
Clinical Applications, 2nd ed,
Appleton and Lange, Norwalk, Ct., 1991, p. 233.

Schilsky, Michael L.; Sternlieb, Irmin; Animal Models of Copper
Toxicosis, Advances in Vet Sci and
Comparative Med, vol 37, 1993, 357-373.

Strombeck, Donald R.; Rogers, William; Gribble, David; Chronic
Active Hepatic Disease in a Dog,
Jrnl Amer Vet Med Assoc, vol 169, no 8, Oct 15, 1976, 802-804.

Su, Le-Chu; Owen, Charles A.; Zollman, Paul E.; Hardy, Robert M.;
A Defect of Biliary Excretion
of Copper in Copper-Laden Bedlington Terriers, Amer Jrnl Physiol
243 (Gastrointest. Liver
Physiol. 6) 1982, G231-G236.

Thornburg, Larry P.; Rottinghaus, George; Koch, John; Hause,
Wayne R.; High Liver Copper Levels
in Two Doberman Pinschers with Subacute Hepatitis, Jrnl of the
Amer An Hosp Assoc, vol
20, Nov/Dec 1984, 1003-1005.

Thornburg, L.P.; Polley, D.; Dimmitt, R.; The Diagnosis and
Treatment of Copper Toxicosis in
Dogs, Canine Practice, vol. 11, no. 5, Sept/Oct 1984, 36-39.

Thornburg, L.P.; Dennis, G.L.; Olwin, D.B.; McLaughlin, C. David;
Gulbas, Nita K.; Copper
Toxicosis in Dogs Part 2: The Pathogenesis of Copper-Associated
Liver Disease in Dogs,
Canine Practice, vol. 12, no. 5, Sept/Oct 1985, 33-37.

Thornburg, L.P.; Rottinghaus, G.; Gage, H.; Chronic Liver Disease
Associated with High Hepatic
Copper Concentration in a Dog, Jrnl Amer Vet Med Assoc, vol. 188,
no. 10, May 15, 1986,
1190-1191.

Thornburg, Larry P., A Study of Canine Hepatobiliary Diseases
Part 4: Copper and Liver Disease,
Companion An Practice, vol. 2, no. 7, July 1988, 3-6.


This article written by J. Boniface, (c) copyright 1997, all
rights reserved.

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