Read the German translation: Chronische Hepatitis beim Hund (R/U)
Diseases and inflammation of the liver occur frequently in dogs. In many cases the etiology remains unknown, although recent studies suggest that copper plays an important role in more cases than previously suspected.
Nonspecific, Reactive Hepatitis
Reactive hepatitis represents a non-specific response to a variety of extrahepatic disease processes, previous or ongoing febrile illnesses and/or inflammation somewhere in the splanchnic area. The inflammatory infiltrate is mostly localized in the portal area during this non-specific reaction of the liver.1
Acute Hepatitis
Acute hepatitis is characterized morphologically by a combination of inflammation, hepatocellular apoptosis and necrosis, and, in some instances, regeneration. The distinction from chronic hepatitis is not the duration of the disease but the absence of fibrosis (which is by definition present in chronic hepatitis).
In cases of known infectious causes of hepatitis treatment should be initiated against the diagnosed or suspected organism. However, clinically most cases of acute hepatitis are idiopathic, and therefore no causal therapy is possible. Prednisolone is contraindicated in acute hepatitis! Although no controlled studies confirm the effectiveness, the author would use ursodeoxycholic acid (ursochol, 7,5mg/kg BID PO for 3 months) for a suspected anti-inflammatory and "hepatoprotective" effect. Control biopsies are recommended after 6-8 weeks will reveal (self) recovery in most cases. Unfortunately some patients progress into chronic hepatitis and require prednisolone treatment to avoid fibrosis of the liver.
Chronic Hepatitis / Cirrhosis
Chronic hepatitis can only be diagnosed histologically, and is characterized by hepatocellular apoptosis or necrosis, a variable inflammatory infiltrate, regeneration and fibrosis. Cirrhosis is the end-stage of chronic hepatitis with distortion of the lobular architecture from fibrosis.
Treatment: in cases of chronic hepatitis from unknown reason the 'gold standard' for treatment is prednisolone (1mg/kg once daily, for at least 6 weeks). However, a recent retrospective study suggested that prednisolone might not have a good long-term effect, and copper accumulation might be involved in many cases.2
Copper-Associated Chronic Hepatitis
Progressive chronic hepatitis from accumulation of copper occurs as a breed related disease in Bedlington terriers,3 Labrador retrievers,4 Doberman Pinchers,5 West Highland White terriers,6 and Dalmatians.7 Copper continuously accumulates in hepatocytes, starting in the centrolobular regions, and with progressive accumulation results in hepatocellular necrosis, inflammation with copper-laden macrophages and finally chronic hepatitis and cirrhosis.
Healthy dogs with normal livers may have copper levels up to 400 micrograms per gram dry weight. Hepatic copper levels in breeds with primary copper storage disease vary between individual animals and between breeds from 600-2,200 micrograms per gram.
Bedlington Terriers
Hepatic copper toxicity was first identified in Bedlington Terriers in 1975. It was subsequently shown that affected Bedlington Terriers have an inherited autosomal recessive defect of the MURR1 gene, which was renamed to COMMD1 (copper metabolism murr1 domain--containing protein 1). The extent of hepatic damage tends to parallel the increasing hepatic Cu concentrations. The morphological changes extend from focal necrosis to chronic hepatitis that may ultimately lead to cirrhosis. In some cases, acute hepatic necrosis and Cu associated hemolytic anemia and acute liver failure may occur.
Samples for analysis of quantitative copper should be placed in a Cu free container (such as a serum blood tube) for analysis. Normal canine hepatic Cu concentrations are less than 400 µg/g dry weight liver. The concentration at which abnormal hepatic Cu contributes to hepatic damage is unknown. It is possible to take adequate size biopsy sample embedded in paraffin for histology and de-paraffinize the sample to obtain a quantitation of copper. Morphologic evidence of inflammatory hepatic injury in Bedlington Terriers begins when concentrations reach approximately 2,000 µg/g dry weight. Homozygous affected dogs have increased copper concentrations but should not be biopsied before they are older than one year of age. This is because the heterozygous carrier dogs normally may have copper concentrations out of the normal range until around 6-9 months of age before concentrations fall back into the normal range. Genetic testing is available for Bedlington Terriers.3
Doberman Pinscher
The disease begins in young dogs (1-3 years) with increased ALT concentrations and sub-clinical hepatitis. Clinical evidence of liver disease usually begins around 4-7 years of age with chronic hepatitis and cirrhosis. Copper appears to be associated with the disease and recent studies suggest that copper is often increased prior to development of clinical hepatitis.5
West Highland White Terriers
The "Westie" breed has been associated with liver disease and hepatic copper accumulation. Twenty-four dogs described ranged from 3-7 years of age. Some dogs in this report had high copper concentrations but no evidence of liver disease while others did.6 While the Bedlington Terrier tends to accumulate Cu with age it was not apparent in this group of dogs.
Dalmatians
A retrospective study summarizes 10 Dalmatians suspected of having hepatic copper toxicosis. Two of the dogs were related and all presented for gastrointestinal clinical signs, had elevated liver enzymes and necroinflammatory hepatic changes. In 5 of these 9 dogs, hepatic copper concentrations exceeded 2,000 µg/g dry weight liver with several dogs having copper levels as high as those observed in Bedlington Terriers.7
Labrador Retriever
Chronic hepatitis is reported to be common in this breed and associated copper accumulation is found in about 75% of cases. Females are more commonly affected and the diagnosis is generally made around 7 years of age (range 2-10 years). Affected dogs show non-specific clinical symptoms like anorexia, vomiting, and weight loss. Hepatic copper concentrations generally range between 650 to 3000 µg/g dry weight liver (histologically above 2+ using rubeanic acid stain). The centrilobular histological location of the Cu suggests that Cu elevation is primary and not secondary to cholestasis.
Penicillamine treatment (10-15mg/kg BID PO for 6-12 weeks), followed by dietary management with a diet low in copper (hepatic from Royal Canin) were effective against the disease in double blinded, placebo-controlled trials performed at the Veterinary Faculty in Utrecht.8,9
Other Breeds
The Skye Terrier, Anatolian Shepherd, and possibly the Keeshond as well as other breeds have also been reported with liver disease and increased copper accumulation. The exact mechanism or extensive description in specific breeds is lacking.
Secondary Copper Accumulation
Copper may also concentrate in the liver secondary to cholestatic liver diseases. Because copper is excreted via the bile, cholestatic liver diseases often results in copper accumulation in another regions of the liver lobule (the periportal areas). The magnitude of Cu concentrations from cholestasis is not as high as those found in the breeds described to have a genetic basis for copper accumulation. In a Review of 17 liver biopsies from breeds not yet identified to have inherited Cu copper associated liver disease (including 2 Standard Poodles, 2 Cocker Spaniels, 5 mixed breeds and the remainder single dogs of different breeds), the mean copper concentration was 984 µg/g dry weight liver.
References
1. Ingh vd., In: WSAVA Standards for Clinical and Histological Diagnosis of Canine and Feline Liver Diseases
2. Poldervaart, et al. Primary hepatitis in dogs. A retrospective review JVIM (2009) 23(1) 72-80.
3. Brewer GJ, et al. J Am Vet Assoc. 1992; 201(4):5644.
4. Hoffmann, et al. Copper-associated chronic hepatitis in Labrador retrievers, J Vet Intern Med 2006; 20(4) 856-861.
5. Mandigers PJJ, Ingh vd, Bode, Rothuizen. J Vet Intern Med 2005; 19(1): 40-43.
6. Thornburg LP, Shaw, Dolan, et al. Hereditary copper toxicosis in West Highland white terriers. Vet Pathol 1986; 23:148-154.
7. Webb CB, Twedt, Meyer. J Vet Intern Med 2002; 16(6):665-8.
8. Hoffmann, et al. Double-blind, placebo-controlled treatment with D-penicillamine against hepatic copper accumulation in Labrador retrievers, J Vet Intern Med (2008).
9. Hoffmann, et al. Dietary management of hepatic copper accumulation in Labrador retrievers. J Vet Intern Med (2009) 23(5): 957-963.