What is Canine Chronic Hepatitis?

• ‘Chronic hepatitis’ = hepatic mononuclear or mixed inflammatory infiltrate with piecemeal necrosis and varying degrees of fibrosis. Fibrosis tends to progress to cirrhosis, but not inevitably.
• Cirrhosis describes progressive bridging fibrosis, inflammation, and nodular regeneration which has classically been considered end stage and irreversible.

What Isn’t Chronic Hepatitis?

In addition, it is important to rule out secondary hepatopathies which are a much commoner cause of increased liver enzymes than primary liver disease. This differentiation is usually achieved through careful interpretation of clinical examination, history, clinicopathological tests, and diagnostic imaging. Secondary hepatopathies are usually not clinically significant in their own right and resolve when the underlying cause is treated.

Causes of Canine Chronic Hepatitis

Chronic hepatitis frustratingly usually remains a non-specific diagnosis in dogs and the cause is generally unknown. The potential causes of canine chronic hepatitis are reviewed in. They include copper storage disease and autoimmune disease in some dogs particularly English Springer Spaniels.

• Recognised in wide variety of dog breeds including cross breeds.
• Consistently increased incidences in certain specific breeds: middle aged dogs of a number of breeds including English Springer Spaniels; American and English Cocker Spaniels (males more than females), West Highland White Terriers (no apparent sex predisposition), Dobermans (strong female predisposition) and Labrador Retrievers (female bias). Skye Terrier hepatitis is now believed to be a congenital ductal plate abnormality.
• Suggests a genetic basis for the disease but so far studies in dogs failed to elucidate specific genetic mechanisms apart from DLA associations in English Springer Spaniels and Dobermans.
• Some cases are associated with primary or secondary increases in copper.
• Some cases may be autoimmune, but not all. The most likely breeds to have autoimmune hepatitis on current evidence are Cocker Spaniels, English Springer Spaniels and some Dobermans.
• Potential low-grade infections such as atypical leptospira could also potentially be involved but, again, these causes are not well investigated in dogs. Chronic bacterial infections are typically associated with more of a granulomatous inflammatory response (- neutrophils and macrophages) and eubacterial fluorescent in-situ hybridisation should be considered in these cases.

Treatment of Canine Chronic Hepatitis

The aims of treatment of any dog with chronic hepatitis are:

• To treat the underlying cause, if this can be identified.
• To try to slow progression of the disease even if the cause if not identified.
• To support liver function as long as possible and support the dog in positive calorie and nitrogen balance.
• To treat the complications of liver disease which affect quality and length of life.

The aim in all cases is to try to prevent the progression of disease to the end stage i.e., cirrhosis. Cirrhosis is often accompanied by the development of portal hypertension, where increased resistance to flow through the hepatic vasculature raises portal pressure resulting in splanchnic congestion, development of ascites and often acquired portosystemic shunts and hepatic encephalopathy (HE). It is, however, very important to remember that fibrosis of the liver is not inevitably progressive in one direction and that even early cirrhosis can be reversible if the underlying cause is removed, as has been clearly demonstrated in humans with alcoholic and viral hepatitis. The aim in treating canine CH should, therefore, be to identify and treat the cause wherever possible.

The clinician should use all the information available to them to optimise treatment for an individual case. On the clinical examination, blood results, and imaging, the clinician needs to assess the degree of loss of liver function and identify signs of biliary stasis, portal hypertension, acquired portosystemic shunts, ascites, gastrointestinal oedema or ulceration or protein- calorie malnutrition. On the liver biopsy if available, the clinician should assess the amount and distribution of inflammation and the types of inflammatory cells involved, the degree and distribution of fibrosis and the presence of any obvious cause including buildup of copper. Combining all this information allows optimal treatment of the patient. It is not possible - and indeed is potentially dangerous - to give specific treatments for CH (such as copper chelators and steroid or other immunosuppressive therapy) without biopsy confirmation of disease.

Treating the Cause of the Disease

If a significant amount of copper is found in the biopsy, in proportion to the severity of the disease, copper storage disease should be strongly suspected and treated with chelation and dietary therapy. If copper storage disease is ruled out, the type and distribution of inflammation present may suggest a cause for the disease. There are more details in the liver biopsy lecture tomorrow.

Steroids should never be used without a liver biopsy because they are not indicated in non-inflammatory fibrosis and cirrhosis: if used in these cases in the presence of portal hypertension they have no clear benefit and conversely, they increase the risk of serious consequences including increased water retention and gastrointestinal ulceration. None-the-less, corticosteroid therapy should offer the best chance of survival in dogs with true autoimmune CH so should not be withheld if the clinician and pathologist believe on the basis of liver biopsies that this is the most likely cause of disease in a particular dog. There are also some promising results from a study in the USA using cyclosporine for dogs with suspected immune-mediated chronic hepatitis.

Treating Clinical Signs and Supportive Therapy

Treating the clinical signs of disease non-specifically is a very worthwhile aim in CH because it improves the quality of life of the patient. Ultimately, most dogs with CH die because the owners request euthanasia due to poor quality of life, so improving the quality of life should also improve life expectancy in these patients.

The factors to consider and treat are:

• Ascites: if present, this should be treated with spironolactone as the primary diuretic and addition of loop diuretics as necessary.
• Vomiting, diarrhoea, and evidence of GI ulceration: these are common in animals with portal hypertension and should be treated predominantly by careful little and often feeding to provide nutrition for gut wall healing and avoidance of potentially ulcerogenic drugs such as steroids. H2 antagonists such as ranitidine or proton pump inhibitors such as omeprazole could be used, together with sucralfate, although evidence for their efficacy in ulceration due to portal hypertension is lacking.
• Jaundice: when pre-hepatic causes and post hepatic obstruction have been ruled out, this should be treated with ursodeoxycholic acid and anti-oxidants. Ursodeoxycholic acid has a large number of potential benefits in animals with CH including choleresis, displacement of toxic bile acids and anti-oxidant properties. There are no contraindications to its use but, like all other therapies in canine CH, the evidence for its efficacy is very sparse. However, it makes logical sense to use it. It also makes sense to use anti-oxidants in this circumstance since refluxed bile damages mitochrondrial membranes and is a strong oxidant toxin. A combination of S-adenosyl methionine, silybin, and vitamin E is advised. The clinician should try to choose neutraceuticals with proven bioavailability in dogs.
• Hepatic encephalopathy (HE): this is not as prominent or easily recognised in dogs with CH as it is in young dogs with congenital portosystemic shunt. None-the-less, it can be an important cause of confusion and unusual behaviour in these animals due to the development of acquired portosystemic shunts secondary to portal hypertension. It should be treated carefully: marked protein restriction is not indicated in these dogs, as they are likely to be suffering from protein-calorie malnutrition already. HE can be addressed by treating any underlying inflammatory trigger and also any precipitating gastrointestinal bleeding and giving a highly digestible, high quality diet little and often. Antibiotic and lactulose therapy may also be considered. Dietary protein restriction is very rarely necessary in these cases.
• Treatment of protein-calorie malnutrition: many dogs with CH present in negative nitrogen balance. They are often thin with partial anorexia and vomiting and diarrhoea which contribute to nutrient malabsorption. It is, therefore, very important to prioritise nutrition in the treatment of these patients. Ideally, they should be fed a highly digestible, high quality diet little and often and this diet should not be protein-restricted.