July 2000

LIVER DISEASE POTPOURRI

While liver disease in people is very well classified, the hepatic pathology in dogs lacks definitive classification. This impedes our ability to assess the clinical and pathological significance of canine liver disease.

The term "chronic active hepatitis" may be inappropriate in the dog. Chronic progressive hepatitis is the preferred term. True chronic progressive hepatitis is an uncommon disease in dogs, except in Labrador and Golden retrievers.

Pathology is often unevenly distributed throughout the liver and biopsy findings are dependent on the site and type of biopsy:

• True-Cut Type Needle Biopsy. Use a 16-18 gauge needle. Two pieces of representative tissue, ~ 1/2- 3/4 inch long should suffice. Selecting the tissue site is critically important and can be assisted by ultrasound guidance. Focal disease may be easily missed with needle biopsy.

• Wedge Biopsy. Acceptable technique if a large enough wedge of liver is excised. Care is needed with interpretation of pathology in the subcapsular parenchyma. Liver margins can become damaged with aging from episodes of anemia, hypotension, shock, small infarcts, etc., which lead to fibrous tissue deposition. These changes are most likely to be seen in older patients and can be mistakenly interpreted as chronic hepatitis or cirrhosis, especially if only a small piece of liver is biopsied.

• Fine Needle Aspirate. Reasonable technique for first assessment. If cytology findings don’t match clinical suspicions, then true-cut type or wedge biopsy may be required. FNA cytology can determine whether inflammatory cells are present, as can occur with inflammatory bowel disease (IBD), cancer, pancreatitis, and other systemic inflammatory diseases (reactive hepatopathy), leptospirosis, ehrlichiosis, or chronic hepatitis. FNA cytology does not enable a specific diagnosis of chronic, progressive hepatitis. In cats with inflammatory liver disease, the presence of neutrophils (alone or together with lymphocytes and plasma cells) suggests cholangiohepatitis, either due to ascending bacterial infection or secondary to IBD/pancreatitis. If only lymphoid cells are present, lymphoma or lymphocytic portal hepatitis (which has not been associated with IBD/pancreatitis) is more likely.

• The liver often exhibits a variety of non-specific changes in reaction to disease elsewhere in the body (reactive hepatopathy).

• Typically find mild to moderate (2-3 fold), increases in serum ALT (SGPT) and alkaline phosphatase.

• Bile acids are usually normal.

• Can be difficult to distinguish from primary liver disease, even with good quality hepatic biopsies. Cannot distinguish with fine needle aspiration cytology.

• A common finding in dogs older than 6 years.

• Alkaline phosphatase elevation is usually of mild to moderate degree with minimal elevation in ALT (SGPT).

• Bile acids are generally normal, unless hyperplasia is severe (can be elevated to 50-80 ΅mol/L).

• Accurate diagnosis is dependent on quality and site of biopsy samples. The histology can resemble chronic progressive hepatitis depending on where biopsy was obtained. FNA cytology does not enable diagnosis of nodular hyperplasia.

• Vacuolar hepatopathy is most often thought of as a consequence of Cushing’s syndrome, hepatic lipidosis, or corticosteroid exposure. However, vacuolar hepatic change can be seen as a component of a variety of liver diseases including reactive hepatopathy, nodular hyperplasia, toxin exposure and primary inflammatory liver disease. Vacuolar hepatopathy is often idiopathic.

• Idiopathic vacuolar hepatopathy is typically seen in asymptomatic dogs with significantly elevated alkaline phosphatase.

• These dogs do not have Cushing’s syndrome.

• Increases in adrenal sex hormones (androgens or cortisol precursor hormones) have been reported and may be responsible for the vacuolar hepatopathy.

• Liver cultures are not needed routinely as very few are positive. Samples could be frozen or held in transport medium for culture, pending histologic findings.

• In dogs with liver disease, cultures may be useful in patients with suppurative or granulomatous hepatitis, an inflammatory leukogram, or with fever.

• Liver cultures can be useful in cats as E. coli can sometimes be grown from liver biopsies of cats with suppurative hepatitis.

• Tissue in paraffin blocks can be de-paraffinized for elemental (Cu, Zu, and Fe) analysis. Sample size may be a problem here so wedge biopsies are preferred over the True-Cut method.

• Special stains can be substituted for elemental analysis to offer a rough estimate about presence of copper. Normal liver copper is < 400-450 ΅g/g dry weight. Special stains can readily detect copper at > 750 ΅g/g dry weight of liver.

• Other than in West Highland white terriers and Bedlington terriers, copper accumulation in dogs with chronic hepatitis is likely secondary to cholestasis rather than the cause of liver disease. Dalmatians can be presented with hepatitis and hepatic copper accumulation; many also have renal glycosuria.

• Many dogs with chronic hepatitis also have increased liver iron and decreased liver zinc concentrations. The significance of elevated liver iron is uncertain. Zinc is known to have antifibrotic and membrane protective properties.

• For Doberman pinschers with chronic hepatitis, treatment regimens include: anti-inflammatory drugs (steroids), actigall, copper chelator for 6 months or more depending upon results of repeat liver biopsy, and zinc supplementation for life (e.g. 100 mg elemental Zn q 12 h for 3-6 months; 1/2 dose for maintenance).

• SAMe (S-adenosyl-L-methionine). This is a product of body metabolism with several important functions: methylation reactions, maintenance of cell membrane fluidity, antioxidant effects (precursor of glutathione). When given orally, liver concentrations of SAMe and glutathione increase. Although efficacy is unproven, SAMe can be used as adjunctive therapy for patient with acute or chronic liver disease. There are no known side effects. Several products are available over-the-counter but have widely varying potency. One recommended product is Denosyl.™

• Milk Thistle (silymarin). This bioflavonoid has antioxidant properties. It is often used in management of liver disease in people and some benefit has been shown in refereed journal articles. A study in dogs fed hepatotoxic mushrooms showed a protective effect against clinical and pathologic changes when high doses of milk thistle were given at 5 and 12 hours post exposure. Veterinarians have used milk thistle for dogs with chronic liver disease and to ameliorate hepatic effects of anticonvulsants. Doses vary from 50-200 mg q 12-24 hr. Many products are available over-the-counter and potency varies.

References: From Antech consultants conference with Drs. David Twedt and Dennis Meyer; Meyer DJ, Twedt DC, Current Vet Therapy XIII, pp. 668-671, 2000; ACVIM Abstract III, 1999, J Vet Int. Med.