Page 623 - Small Animal Internal Medicine, 6th Edition

CHAPTER 36 Hepatobiliary Diseases in the Dog 595

after a challenge to hemostasis, such as liver biopsy; therefore the cause rather than an epiphenomenon of the disease, and
it is very important to evaluate hemostasis before performing accumulation is usually marked, progressive, correlated with
VetBooks.ir liver biopsy. If coagulation times are prolonged, it is worth disease severity, and in zone 3 (perivenous; see Fig. 33.7 for
an explanation of hepatic zonation). Copper chelation is rec-
trying vitamin K1 (phytomenadione) therapy (0.5–1 mg/kg
SC × 3 doses at 12 hour intervals). However, this is much less
copper buildup, whether it is primary or secondary, because
effective in dogs than cats, so administration of fresh or fresh ommended in any dog with chronic hepatitis with significant
frozen plasma may be indicated to replenish depleted clot- copper is a potent oxidizing toxin. Therefore distinguish-
ting factors. A starting dose of 10 mL/kg given slowly is ing primary from secondary copper accumulation may not
recommended; the dose of plasma is titrated on the basis of change treatment recommendations, except for informing
the results of the one stage prothrombin time (OSPT) and a search for an underlying primary cause other than the
activated partial thromboplastin time (APTT). copper.
True copper storage disease likely represents a genetic
defect in copper transport and/or storage. The breed in
COPPER STORAGE DISEASE which this has been best defined is the Bedlington Terrier.

Pathogenesis and Etiology In this breed it is inherited as an autosomal recessive trait,
and up to 60% of Bedlington Terriers in some countries have
Copper storage disease has been recognized as a cause of been affected in the past, although the prevalence is now
acute and chronic hepatitis in several breeds, the best decreasing as a result of selective breeding. The disease is
researched of which is the Bedlington Terrier (see Box 36.1). confined to the liver, and there appears to be a specific defect
Other breeds in which copper storage disease has been in hepatic biliary copper excretion, probably in transport
reported are Dalmatians (in the United States and Canada), from the hepatocyte lysosomes to the biliary tract. Studies
Labrador Retrievers (in the United States and Holland), and have identified at least one genetic defect associated with the
some Doberman Pinschers (in Holland), although individ- disease, a deletion in the MURR1 gene (now COMMD1; Van
ual members of all these breeds have also been reported with de Sluis et al., 2002), which codes for a protein of unknown
chronic hepatitis without copper accumulation. In addition, function. However, Bedlington Terriers with copper storage
copper storage disease has been suspected but not exten- disease but without a COMMD1 deletion have been reported
sively investigated in West Highland White Terriers. The in the United States, United Kingdom, and Australia (Coro-
previously reported copper storage disease in Skye Terriers nado et al., 2003; Haywood, 2006; Hyun et al., 2004), sug-
is now believed to be a congenital ductal plate abnormality gesting that there are additional mutations involved in the
(see later). In one study of several dog breeds in Holland, breed. A recently published study identified an association
hepatitis was ascribed to copper storage disease in 36% and between copper storage disease in Bedlington Terriers and an
was idiopathic and not copper associated in 64% of 101 dogs alternative mutation in metal transporter ABCA 12, which
studied with acute and chronic liver disease (Poldervaart is functionally similar to the ATPase 7B that is mutated in
et al., 2009). It is also possible for seemingly normal dogs humans with Wilson’s disease (Haywood et al., 2016).
without a recognized copper storage disease to develop In Labrador Retrievers, a missense mutation in the
copper-associated chronic hepatitis if fed a diet very high in ATPase 7B gene itself has been associated with copper accu-
copper, such as dry calf feed (Van den Ingh et al., 2007). mulation, whereas a missense mutation in ATPase 7A pro-
Copper is excreted in the bile and can build up as a second- tects against copper accumulation (Fieten et al., 2016).
ary phenomenon in any type of chronic hepatitis associated
with cholestasis. In these cases, the accumulation is usually Clinical Features
mild, often in zone 1 (peribiliary), and the amount of copper Affected Bedlington Terriers can present with acute or
does not correlate with the severity of the disease. An early chronic clinical signs, depending on individual factors, such
study demonstrated that dogs were resistant to copper accu- as the amount of copper in the diet, and other possible
mulation in cholestasis unless they were also copper-loaded factors, including concurrent stress and disease. If there is
in the diet (Azumi, 1982). Copper buildup in the liver is rapid and marked buildup, dogs may present with acute ful-
therefore likely to be an interaction between genetic suscep- minant hepatic necrosis and no previous clinical signs. This
tibility and environment (i.e., dietary copper concentration is usually seen in young to middle-aged dogs and is often
and concurrent biliary stasis). Dietary copper concentration accompanied by acute intravascular hemolytic anemia
heavily affects hepatic copper accumulation in all breeds, not caused by the rapid release of copper into the circulation.
just those predisposed to copper storage disease. An increase The prognosis is poor, and most animals die within a few
in hepatic copper has been observed in dogs since the 1980s, days. Fortunately, this is uncommon; most dogs have a more
and it is hypothesized this is due to the change in formula- chronic, protracted course, with several years of copper
tion of copper added to commercial food to a more bioavail- buildup and persistently high ALT activity, culminating in
able chelate (Gagne et al., 2013). The peribiliary distribution the development of chronic hepatitis with piecemeal necro-
and lack of correlation between amount of copper buildup sis, inflammation, and bridging fibrosis. Clinical signs are
and clinical signs helps distinguish these cases from “true” therefore recognized in these individuals only late in the
copper storage disease, in which the copper accumulation is disease process and are usually those of canine chronic