Treatment of hepatobiliary disease in dogs and cats (Proceedings)

In ideal cases, treatment of hepatobiliary cases is based on biopsy, when indicated. Although not all clients will be willing to follow this diagnostic test, I think it is important to make this recommendation. Of course, there are exceptions. A patient must be stable before considering any invasive test.

What's in a biopsy?

·         Only ~44% correlation between liver aspirate cytology and liver biopsy histopathology

·         Only ~40% correlation between 18-gauge needle biopsy and wedge biopsy of liver

·         collect.Biopsy sample via exploratory laparotomy, key-hole approach or laparoscopically possible

·         Although it is less invasive to have an ultrasound-guided liver biopsy performed, the quality of the sample is not typically good enough to be able to definitely diagnose the underlying problem.

·         In most cases, I would rather manage a case WITHOUT a needle (Tru-cut) liver biopsy then with one. In those cases I use my clinical skills to decide the most likely differentials and treatment.

·         DO NOT be hesitant to recommend a liver biopsy in a healthy, asymptomatic patient with elevations in ALT, AST, bile acids or with evidence of liver dysfunction. As long as an owner is willing to accept that the results may be normal or non-diagnostic, it is a good idea.

·         Many animals do not develop clinical illness until end-stage disease is present.

·         One of the few times to ‘treat' the test results

What can be treated?

Infection

Culture of bile and/or liver tissue for both aerobic and anaerobic organisms is recommended. Culture of bile has a higher yield. Antimicrobial therapy should be based on culture and susceptibility results when possible. If these are unavailable, antibiotics should possess activity against enteric organisms and obtain therapeutic levels in the hepatobiliary system. Reasonable options to start with, pending culture include amoxicillin-clavulonic acid, clindamycin, 2nd or 3rd generation cephalosporin +/- metronidazole.

In cats with acute neutrophilic cholangitis E. coli is most often cultured from either the bile or liver. Other organisms include Enterococcus, Bacteroides spp, Enterobacter, Staphylococcus, Streptococcus, Klebsiella, Pseudomonas, Salmonella, and occasionally anaerobes such as Clostridium.

Inflammation

Neutrophilic inflammation usually indicates bacterial involvement, and administration of an appropriate antibiotic (see above) for a minimum of 2 weeks with acute disease and ~4 weeks for chronic disease, is recommended. If lymphocytic or lymphoplasmacytic inflammation is present, then administration of prednisolone (or prednisone) may be beneficial (0.5- 1 mg/kg PO q 12 h in dogs; in cats 1-2 mg/kg q 12h is an appropriate starting dose). If treatment is needed and a histological diagnosis is not available, then a combination of an antibiotic and steroids is appropriate. If the patient is stable with mild to moderate signs, I administer 1-2 weeks of antibiotics prior to initiating steroid therapy. I continue antibiotics for another ~2 weeks. Monitoring the patient based on history, physical exam findings and monitoring liver enzymes and/or liver function values every 1-2 weeks initially is recommended. If there is a positive response to treatment, I gradually taper the steroid dose over about a 2-3 month period. Some cats may require long term steroid therapy. Cyclosporine is another immunosuppressant that can be used, but AVOID azathioprine in cats.

Canine patients that have clinical and biochemical improvement with glucocorticoid therapy, but have unacceptable side effects, can be administered azathioprine at ~1 mg/kg/day; after 1-2 weeks, I decrease to Q 48 hours then taper to lowest effective dose. Although azathioprine has been associated with hepatotoxicity, it is also successfully used to manage autoimmune hepatitis in people. Cyclosporine at 5-10 mg/kg initially, then taper to lowest effective dose.

Cholestasis

Treatment for intrahepatic cholestasis should be focused on the primary histopathologic abnormality (inflammation, infection, etc), but additional supportive care may be beneficial. Ursodiol or ursodeoxycholate (Actigall®) is a hydrophilic bile acid. Beneficial properties of ursodiol include 1) displacement of less hydrophilic bile acids which accumulate with cholestasis and cause hepatocyte injury 2) enhanced bile flow, which may promote biliary excretion of potentially toxic agents 4) anti-oxidant, anti-apoptotic and immunomodulating effects.

It has been proven to be effective in the management of several hepatobiliary disorders in people including: primary biliary cirrhosis, sclerosing cholangitis, active hepatitis, etc. Controlled studies are lacking in veterinary medicine, but ursodiol may be beneficial in dogs and cats with any cause of intrahepatic cholestasis. As it increases bile flow, its use with complete extrahepatic biliary obstruction is contraindicated. Typical dose is 10-15 mg/kg PO q 24 hours. Side effects are uncommon but may include decreased appetite or vomiting. Giving with food or dividing dose may decrease risk of side effects.

Fibrosis

There are no drugs known to reverse fibrosis. Medications used to inhibit further development of fibrosis include: colchicine, prednisone, azathioprine, silymarin.

Colchicine has two basic therapeutic effects that are of benefit in the treatment of liver disease. Colchicine has anti-inflammatory effects mediated primarily through inhibition of neutrophil and mononuclear cell migration to the sites of inflammation and by inhibition of neutrophil degranulation inflammatory responses. It is also an anti-fibrotic drug. Colchicine inhibits secretion of procollagen molecules that are necessary components for the microtubular assembly of collagen. The drug also suppresses release of mediators of fibrogenesis from inflammatory cells and macrophages, and increases activity of collagenases. Colchicine also appears to have a direct hepatoprotective effect by stabilizing hepatocellular membranes and recently has been determined to facilitate copper excretion. Because of a narrow therapeutic index, I do not prescribe colchicines without biopsy confirmation of fibrosis.

The primary beneficial effects of corticosteroids in the treatment of liver disease are anti-inflammatory effects, choleretic action, and anti-fibrotic effects. Suppression of immune response and inflammatory activity in the liver controls a major stimulus of fibrogenesis in the liver. Corticosteroids also have direct anti-fibrotic effects.

The dose of prednisone most commonly recommended is 1 - 2 mg/kg/day initially, gradually tapered to 0.5 mg/kg alternate-day-therapy. Evaluation of response to corticosteroids is complicated in the dog by steroid-induction of liver enzymes activities. Both ALT and ALP activities are predictably and significantly increased by corticosteroids, particularly in dogs with existing hepatic pathology. Resolution of clinical signs, resolution of hyperbilirubinemia and improvement in serum albumin are good indicators of hepatic functional improvement. In addition to the predictable systemic side-effects from corticosteroids, dogs with significant hepatic dysfunction are particularly at risk for gastrointestinal ulceration and hemorrhage, hepatic encephalopathy, and severe muscle wasting when treated with corticosteroids.

Azathioprine is an anti-metabolite that has immune modulating effects. It is metabolized in the liver to the active 6-mercaptopurine which competes with purines in the synthesis of nucleic acids, thereby disrupting nucleic acid synthesis. It also disrupts mitosis, with the net effect to inhibit proliferation of rapidly dividing cells. T-lymphocyte functions such as cell-mediated immunity and T-cell dependent antibody synthesis are particularly diminished.

Combination therapy using azathioprine and corticosteroids is recommended especially for long-term treatment of dogs with chronic hepatitis. Initially, the dose of azathioprine is 1 mg/kg/day in combination with prednisone at 0.5 - 1.0 mg/kg/day. If possible, both drugs should be tapered to alternate day dosages (prednisone on days 1,3,5 and azathioprine on days 2,4,6 etc).The primary adverse effect of azathioprine is reversible bone marrow suppression. However, when used on an alternate day basis, this does not seem to be a common problem in the dog.

Copper accumulation

The decision to treat dogs with copper accumulation is based on the location and amount of hepatic copper. It is recommended that copper levels be measured in every patient undergoing a liver biopsy AND that copper stains of the biopsy sample be performed. The amount and location of copper helps determine if therapy is indicated. Excess copper levels can be treated by feeding a copper restricted food, administering zinc to inhibit copper absorption from the gut, or by administering a copper chelator. Dietary copper restriction alone will not decrease hepatic copper enough to be clinically significant.

Penicillamine (10-15mg/kg BID PO) chelates copper from tissues and promotes copper excretion in urine. Penicillamine inhibits collagen synthesis by disrupting disulfide bonds and inducing collagenase activity, subsequently decreasing fibrosis associated with chronic liver disease. Adverse effects include inappetence, vomiting, and diarrhea. These can be minimized by mixing the drug with food, and dividing the dosage in more frequent administrations per day.

Clinical improvement from penicillamine treatment might take months, and there occur large inter-individual variations with respect to the effectiveness of the drug. Follow-up liver biopsies are required to determine the length of penicillamine therapy. Once chelation therapy has been started, hepatic histopathology and copper concentrations should be evaluated at least once yearly. In general, Bedlington terriers will require life-long treatment, whereas dogs presumed might only need to be on a chelator for 8 - 12 months. If normal hepatic copper concentration is achieved with chelation treatment, dietary copper restriction and zinc supplementation should be continued

Elemental zinc acetate administered at a dose of 10 mg/kg PO q 12 h for 1-2 months then 5 mg/kg PO q 12 h as a maintenance dose is appropriate in dogs with a predisposition to copper-associated hepatitis. Ideally, serum zinc levels are monitored in order to avoid toxicity, including hemolytic anemia. A therapeutic level of < 300 mcg/ml of zinc is recommended. If monitoring serum zinc levels is cost prohibitive, then monitoring PCV or HCT is indicated.

Antioxidants/ nutraceuticals

 Increased production of free radicals has been implicated as a mechanism of liver damage induced experimentally by various drugs, copper, iron, ischemia-reperfusion injury, etc.  Dogs with chronic hepatitis have been determined to have increased concentration of markers of hepatic oxidant injury. Oxidant injury to hepatic mitochondria occurs in Bedlington terriers with copper toxicosis. These oxidants are thought to contribute to hepatocyte injury. Some studies indicate that antioxidant therapy may be beneficial in some types of chronic hepatitis. For this reason, treatment with an antioxidant drugs to scavenge free radicals might be protective against oxidant injury to hepatocytes, particularly in patients with copper accumulation.

S-Adenosylmethionine (SAMe) is an indirect precursor to glutathione, a major cellular antioxidant. It has special importance in hepatocytes that play a pivotal role in intermediary metabolism. It is important in pathways that influence cell repair, tissue regeneration, inflammatory cascades, DNA synthesis, and cell senescence/apoptosis. Cirrhosis is associated with abnormal methionine metabolism due to down regulation of SAMe synthetase. This leads to increased risk of damage due to oxidant injury imposed by liver disease.  SAMe is labile and the veterinary product is an enterically coated tablet with confirmed bioavailability when given on an empty stomach (followed by a 2-hr fast), and maximal plasma concentrations within 4 to 8 hrs.  A chewable form is on the market. One veterinary product is Denosyl®. SAMe may interact with tricyclic antidepressants (imipramine, mirtazepine, clomipramine, etc).

-Milk thistle (silymarin, silybin) reduces the extent of hepatic fibrosis, acts as a free radical scavenger, detoxifies xenobiotic radicals, increases intracellular glutathione levels, promotes hepatocyte regeneration, and diminishes entry of some hepatotoxins. It may also induce choleresis. Its use is recommended for Amanita mushroom hepatotoxicity. Side effects are rare.  Marin® is one veterinary product.

Denamarin® incorporates both SAMe and silybin. One study showed that administration decreased liver enzyme activity in dogs receiving lomustine (CCNU) for treatment of neoplasia.

Ascites

Abdominal fluid may develop in patients with liver disease due to decreased oncotic pressure from hypoalbuminemia and/or portal hypertension due to hepatic fibrosis. In many patients ascites does not greatly impact quality of life. If such a patient has a decreased appetite, increased respiratory effort, restlessness or abdominal discomfort, medical intervention is recommended. Centesis and fluid removal is typically reserved for patients with respiratory compromise.  Furosemide at the lowest effective dose is frequently effective in decreasing ascites. I usually start with a dose of 1 mg/kg twice daily and quickly taper.

Hepatic encephalopathy (HE)

(HE) is typically effectively managed with oral antibiotics (amoxicillin, neomycin or metronidazole) which decrease the number of ammonia producing bacteria in the gut. Lactulose is a synthetic disaccharide that is neither metabolized nor absorbed in the small intestine. In the colon bacteria ferment it to acid metabolites which lower intraluminal pH. NH3 is converted to NH4+ which is not readily absorbed. Lower colonic pH also inhibits bacterial growth. Byproducts of lactulose fermentation also increase colonic luminal osmolality, causing osmotic diarrhea and subsequent reduction of colonic bacteria. The starting dose is 0.5-1.0 ml/kg Q8-12 and should be adjusted to produce soft but formed stool. A protein-restricted diet, such as Hill's L/D will decrease the nitrogenous wastes originating from the diet.