Page 713 - Clinical Small Animal Internal Medicine

62 Metabolic, Toxic, and Neoplastic Diseases of the Liver 681

Signalment zone 1 (periportal zone) may also become gradually
VetBooks.ir although other breeds can be affected. In cats, the affected. This differs from copper‐associated disease,
Amyloidosis is frequently identified in the shar‐pei dog,
which is the predominant form in all dogs, in which chol-
Siamese, Oriental shorthair, Devon Rex and Burmese are
with copper later accumulating in zones 2 and 3.
predisposed. estasis causes periportal copper accumulation (zone 1),
History and Clinical Signs Copper Storage‐Induced Hepatitis and Cirrhosis
Overt liver dysfunction is rare in amyloidosis, even when in the Bedlington Terrier
the liver is grossly enlarged. Nephrotic syndrome is the Etiology/Pathophysiology
most common finding in these patients due to severe and This disease occurs in Bedlington terriers, resulting in an
prolonged proteinuria resulting from renal amyloidosis. accumulation of copper in the liver, usually due to an
Other possible signs of renal dysfunction are vomiting, autosomal recessive mode of inheritance. In many
anorexia, and polyuria. Spontaneous rupture of the liver affected dogs, the disease is caused by a deletion in the
may occur in severe cases, resulting in acute blood loss, COMMD1 gene, resulting in lack of production of a spe-
shock, and death. cific protein. This protein is an important chaperone for
the copper‐transporting protein ATPase 2, encoded by
Diagnosis the human Wilson disease gene ATP7B, the principal
The deposition of amyloid can only be detected by cyto- hepatocyte exporter of copper into bile. Only homozy-
logic or histologic examination of relevant biopsy mate- gotes become ill; heterozygotes have a normal liver.
rial (liver or kidney). Taking biopsies is not without risk Normally, some of the copper ingested is absorbed in
as the liver may rupture, resulting in severe abdominal the intestine and transported to the liver in the portal
hemorrhage. blood, where it is loosely bound to albumin. Most of this
is taken up by the hepatocytes and excreted in the bile via
Therapy the liver cell lysosomes. A small part is incorporated in
There is no specific treatment available for amyloidosis. ceruloplasmin in the liver, and copper incorporated in
The deposition of amyloid is progressive and in animals this protein is released in the plasma. Copper in cerulo-
with end‐stage disease, the prognosis is very poor. plasmin is used for incorporation in a number of enzymes
and proteins, essential for normal function. Most of the
copper is bound to the protein metallothionein. Copper
Copper Storage Diseases Leading to Chronic
Hepatitis and Cirrhosis then moves to the lysosomes of the hepatocytes and is
excreted into the bile bound to an unidentified protein.
The accumulation of copper in liver tissue has been In this form, it leaves the body in the feces. In Bedlington
described in several breeds of dog. Excessive accumula- terriers with copper storage disease, the hepatocytes are
tion includes that seen in true “copper storage” disease, almost completely unable to excrete copper in the bile
where the primary initiating event is a defect in copper and hence there is an increasing accumulation of copper
excretion leading to secondary hepatocyte damage, and in the liver. The exact nature of the defect is not known,
“copper‐associated” disease, in which copper accumu- but it is a lysosomal disorder. Because the copper accu-
lates secondary to an underlying inflammatory liver mulation begins gradually, the clinical signs usually only
disease. begin to appear after around 4 years of age. The increased
Copper storage diseases probably occur in several copper concentration in the liver can be confirmed after
breeds of dog, although there appear to be differences in 1 year of age; before then, some dogs with the disease
prevalence between countries. Copper storage disease have not yet stored sufficient copper to distinguish them
was suspected in about 30% of all dogs with hepatitis in from normal animals.
one study from The Netherlands, but is relatively uncom- There is a chronic form in which the copper accumula-
mon in the UK. The Bedlington terrier, Labrador tion leads to liver cell necrosis and secondary hepatitis,
retriever, Dalmatian, Anatolian shepherd, Airedale ter- cumulating in cirrhosis. Some dogs also have an acute
rier, and spaniel breeds appear to be predisposed. form of copper storage disease, with a hemolytic crisis.
In primary copper storage disease, copper accumu- The hemolysis is probably the result of a sudden release
lates in the liver when the excretion of excessive copper of a large amount of copper from hepatocytes into the
into the bile is deficient. This is a gradual process and blood. The mechanism for this is not clear. The sudden
usually toxic levels leading to chronic hepatitis and cir- increase in blood copper concentration causes acute
rhosis are reached at an age of 4–7 years. Copper first hemolysis, and because liver function is already reduced,
accumulates in the centrolobular region of the liver (zone this leads to severe icterus. Tubulonephrosis may occur
3 around the central vein); in later stages, zone 2 and and can lead to uremia. The hemolysis in turn results in