Rational pharmacological management of canine and feline liver diseases is built around removal of the inciting cause, specific therapy (e.g. anti-inflammatory, antifibrotic or anticopper agents) and provision of general liver support. Generally speaking, treatment recommendations are based upon the suspected pathophysiology of the disease or extrapolated from the human medical literature and are not based on veterinary clinical trials.
Rational pharmacological management of canine and feline liver diseases is built around removal of the inciting cause, specific therapy (e.g. anti-inflammatory, antifibrotic or anticopper agents) and provision of general liver support1. Generally speaking, treatment recommendations are based upon the suspected pathophysiology of the disease or extrapolated from the human medical literature and are not based on veterinary clinical trials2.
Anti-inflammatory agents are indicated in the treatment of liver diseases characterized by histological evidence of mononuclear (lymphocytes and plasma cells) inflammation for which no infectious etiology is suspected2. Corticosteroid therapy is generally used for canine chronic hepatitis, feline lymphocytic cholangitis and occasionally feline mixed cholangitis on the assumption that these conditions have an immune-mediated etiology and that control of inflammation is in and of itself beneficial and may delay or prevent fibrosis. In a single retrospective study of 151 dogs with chronic hepatitis, dogs treated with corticosteroids had longer survival compared to untreated dogs1,2. Recently the WSAVA Liver Standardization Group concluded that in the treatment of canine chronic idiopathic hepatitis it is "unethical" not to use glucocorticoids but the group acknowledged that "the supporting evidence is weak"2. Glucocorticoid regimens for canine chronic hepatitis have not been critically evaluated, but treatment recommendations include prednisolone (2.2 mg/kg/day)4 or prednisone (1-2 mg/kg/day)1,5. The response to treatment is ideally monitored via serial liver biopsies and glucocorticoid therapy continued until inflammation and hepatocellular death are resolved histologically5. As this may not be acceptable to owners, glucocorticoids may be tapered to 0.5 mg/kg/day after 6 weeks of treatment or based upon improved clinical signs and liver enzyme activities. Improvement in hepatocellular leakage enzyme activities (i.e. ALT) is expected if the disease process is controlled4. Anecdotally, azathioprine (2 mg/kg q48 hours) or cyclosporine (3-5 mg/kg/day in divided doses) have been used as alternative or adjunctive immunosuppressive agents where glucocorticoids are ineffective or the side effects intolerable4. For treatment of feline lymphocytic cholangitis, prednisolone at an initial dose of 1-2 mg/kg q12 hours and tapered over 6-12 weeks (assuming continued clinical improvement) has been recommended3.
Fibrosis is a potential sequlae of chronic hepatic inflammation2. Inflammatory processes disrupt hepatocellular membranes resulting in the release of mediators such as TNF-alpha which attracts hepatic stellate cells, the major cell type responsible for hepatic fibrosis4. Excessive fibrosis limits the ability of vessels to distend, increases resistance to blood flow, impairs hepatocyte function and causes permanent hepatic distortion and dysfunction4. Prevention of fibrosis is an important treatment goal and is best achieved through controlling inflammation, limiting oxidative damage and, in some cases, administration of specific anti-fibrotic agents. Cholchicine is though to inhibit collagen formation by reversibly inhibiting microtubule assembly. The efficacy of cholchicine as an anti-fibrotic is questionable and veterinary data regarding its anti-fibrotic properties are limited to individual case reports. The recommended canine dose of cholchicine is 0.014-0.03 mg/kg q24 hours6. Its use in the cat has not been described. Gastrointestinal (anorexia, vomiting, diarrhea) side effects are possible. Colchicine administration has also been associated with development of bone marrow necrosis and as such should not be combined with other potentially myelosuppressive agents such as azathioprine, chemotherapeutics, fenbendazole, chloramphenicol or phenylbutazone7. Colchicine is only indicated in canine patients with biopsy confirmed hepatic fibrosis, however given the lack of data on its efficacy and potential for side effects, its use can not be routinely recommended.
Intracellular accumulation of copper causes oxidative damage to hepatocellular membranes and resultant chronic hepatitis. Breeds in which copper storage hepatopathies have been described include the Beddlington Terrier, Labrador Retriever, Doberman Pinscher, West Highland White Terrier, Skye Terrier and Dalmation2. The mechanism, degree and precise role of copper accumulation vary with the breed and the reader is recommended to review the literature pertaining to the breed in question prior to treatment (See reference 4). Normal liver copper concentration generally ranges from 200-400 μg/gm of tissue while liver copper concentrations in affected dogs generally range from 600 to greater than 2200 μg/gm4,8. Using histochemical staining, marked copper staining (5+) with accumulation in hepatocytes and diffusely through the liver and macrophages in areas of inflammation is suggestive of a primary copper storage defect, while slight to moderate (1-2+) centrolobular accumulation in hepatocytes ± within some macrophages is consistent with copper accumulation secondary to cholestasis or inflammation9. Only diseases where copper accumulation is the primary defect require specific anti-copper therapy2. D-Penicillamine chelates copper from tissue, promotes copper excretion in the urine and may have anti-inflammatory and anti-fibrotic effects8. Four months of D-penicillamine treatment (200 mg PO q12 hours) effectively decreased liver copper concentration and improved histological lesions but did not change serum biochemistry results in 5 Doberman Pinschers with chronic hepatitis10. No adverse effects were noted. In a separate study of copper-associated hepatitis in Labrador Retrievers, 3-6 months of D-penicillamine (10-15 mg/kg PO q12 hours) treatment effectively decreased liver copper accumulation11. Gastrointestinal side effects (inappetance, vomiting, diarrhea) were common but were controlled by mixing the drug with food and dividing the total dose throughout the day11. Repeat liver biopsy with copper quantification is recommended every 4-6 months to determine the duration of therapy. D-penicillamine is teratogenic and should not be administered during pregnancy8. Owners should wear gloves when handling the drug, should avoid breaking the tablets whenever possible and pregnant women should not handle the drug8. Trientine hydrochloride may be an alternative copper chelator to D-penicillamine8. Some authors have suggested trientine may be a more effective copper chelator and may be better tolerated2,8. However, veterinary experience with the commercially available form of trientine is lacking. As such, it is generally recommended that D-penicillamine be used as the initial treatment of choice for copper chelation with trientine (10-15 mg/kg PO q12 hours) reserved for dogs that are unresponsive to or intolerant of D-penicillamine2. Oral zinc (100 mg elemental zinc (gluconate or acetate) per dog q12 hours or 10 mg/kg q12 hours) binds and sequesters copper in the intestinal lumen2,8. As such, zinc should be administered 1 hour before each meal2. Zinc does not chelate copper from tissue and as such should not be used as primary anti-copper therapy in dogs where the goal is to decrease liver copper concentration (i.e. moderate to severe copper-associated chronic hepatitis). Ideally, a copper chelator is administered until liver copper concentration is decreased and histologic lesions are improved (generally 3-6 months). Zinc may then be used in place of a chelator to prevent re-accumulation of copper. Zinc may also be effective at preventing copper accumulation when administered to young dogs of predisposed breeds. One author has anecdotally described prevention of clinical copper toxicosis in 70 Beddlington Terriers with subclinical copper toxicosis through chronic administration of zinc gluconate2. However, a recent randomized, controlled clinical trial of 21 Labrador Retrievers related to dogs with copper-associated chronic-hepatitis, demonstrated that dietary copper restriction alone was effective in decreasing liver copper concentration and adjunctive therapy with zinc did not increase the copper lowering effects of dietary restriction12. Side effects may include nausea and vomiting that may be reduced by mixing the drug with a small amount of food8. Copper deficiency has been reported after chronic treatment in humans2. One author suggests plasma zinc concentration be monitored monthly for several months until within a target therapeutic range of at least 200μg/dl (concentration required to suppress copper uptake) but less than 1000μg/dl (concentration where hemolytic anemia will occur)8.
SAMe occurs naturally within hepatocytes. It is a precursor of cysteine, an amino acid required for synthesis of the antioxidant molecule glutathione (GSH)2,13. By trapping excess free radicals, reduced GSH is important for protection of the liver against oxidative damage. SAMe is generated in an enzymatic reaction catalyzed by methionine adenosyl transferase (MAT), the activity of which is decreased in various liver diseases13. Depletion of SAMe stores in liver disease could occur through exhaustion in the face of significant oxidative stress and /or inadequate production due to decreased MAT activity2. Augmentation of hepatic GSH levels is the main therapeutic rationale for exogenous administration of SAMe2,13. Additional benefits of SAMe in hepatobiliary disease may include improved membrane fluidity and inhibit apoptosis in normal cells13. Reduced hepatic GSH concentrations have been documented in canine inflammatory hepatopathies, vacuolar hepatopathy, copper toxicosis and extrahepatic biliary obstruction and feline inflammatory hepatopathies, extrahepatic biliary obstruction and hepatic lipidosis9,14. Exogenous administration of SAMe increases plasma SAMe concentration and hepatic GSH levels in normal dogs and cats15,16. Exogenous administration of SAMe is most likely to be of therapeutic benefit in cholestatic (e.g. gallbladder mucocele, cholecystitis, extrahepatic biliary obstruction) inflammatory (canine acute and chronic hepatitis, feline cholangitis, leptospirosis), metabolic (e.g. vacuolar hepatopathy, copper storage hepatopathy, hepatic lipidosis) and toxic hepatopathies (e.g. Amanita mushroom, acetaminophen, etc.)13. The recommended canine and feline dose is 18 mg/kg (or follow body weight dosing guidelines of commercially available product) once daily given on an empty stomach at least one hour prior to eating7. Tablets should not be crushed or split. Side effects are rare, although post administration vomiting has been reported in cats13. Formulations should be obtained from a reliable commercial source and contain a high percentage of the active S-S isomer.
The main goal in administration of NAC is replenishment of intracellular GSH levels13,17. NAC is metabolized to cysteine, an essential amino acid for GSH synthesis17. NAC is considered the antidote for acetaminophen toxicosis. Acetaminophen toxicosis occurs when glucuronyl transferase activity is overwhelmed and excess acetaminophen is metabolized via cytochrome p450 to N-acetyl-para-benzoquinone-imine (NAPQI)17. NAPQI depletes hepatocyte and erythrocyte GSH levels with resultant hepatotoxicosis, Heinz body formation and methemoglobinmia17. In addition to restoration of GSH, NAC may bind to and inactivate NAPQI and increase the amount of acetaminophen excreted as a harmless sulfate conjugate17. There are published studies to support the use of NAC as antidote to acetaminophen toxicosis in dogs and cats. Given its ability to increase GSG stores, it use can be justified in any acute hepatotoxicity. NAC is administered at a dose of 140 mg/kg IV as a 10% solution diluted at least 1:2 with saline, followed by similarly diluted doses of 70 mg/kg IV every 6 hours for 7 treatments13. It is most effective if given within 16 hours of acetaminophen ingestion13. Adverse effects are uncommon in veterinary patients but could include vomiting, allergic reaction or hypo- or hypertension13.
UCDA is a naturally occurring, hydrophilic bile acid. Synthetic forms of UCDA are widely used in the management of human and veterinary hepatobiliary conditions. Some bile acids, namely those that are hydrophobic, are toxic, especially in the liver where they are most concentrated2,13. The cytoprotective actions of UCDA are incompletely understood but the following potential benefits have been proposed: displacement of the more toxic bile acids from the bile acid pool by constant enrichment of the pool with UCDA, stimulation of increased bile flow (choleresis), immunomodulatory actions, anti-apoptotic effects and increased glutathione production2,13. There are no published studies regarding the clinical efficacy of UCDA therapy in companion animals. However, given its cholerectic effects, its use can be justified in conditions characterised by intra- or extrahepatic cholestasis and absence of complete bile duct obstruction (e.g. canine acute and chronic hepatitis, copper storage hepatopathies, gallbladder sludge, medical management of asymptomatic or minimally symptomatic gallbladder mucocele, post-operative cholecystectomy or other biliary diversion procedure, feline cholangitis, hepatic lipidosis, etc.)13. The recommended canine and feline dose is 15 mg/kg/day and is extrapolated from the human medical literature13.
Silymarin collectively describes the four active ingredients (silybin, isosilybin, silydianin and silychristine) in milk thistle6,13. Silymarin is often used in the management of hepatobiliary diseases for its purported antioxidant, free radical scavenging, antifibrotic, anti-inflammatory, hepatotoxin binding and cholerectic properties2,6,13. Of note, silymarin has been demonstrated to be effective at limiting hepatotoxicosis due to Amanita phalloides ingestion in a canine experimental model6,13. Clinical studies evaluating the efficacy of silymarin in naturally occurring canine and feline liver disease do not exist. Extrapolations from the human medical literature are difficult due to obvious species differences and potential differences in the content of commercially available products. However, silymarin is indicated in the treatment of hepatotoxicosis due to A. phalloides and its use is rational in other oxidative hepatotoxicosis (e.g. acetaminophen) and in canine and feline liver diseases as described for SAM-e, above. There are no studies comparing the hepatoprotective benefits of silymarin, SAME or N-acetylcysteine2. The recommended canine and feline dose is 20-50 mg/kg/day18. Recommended dosing of the veterinary product, Marin (Nutramax Laboratory), is lower (5-10 mg/kg/day) as it contains silybin bound to phosphatidylcholine for improved absorption6.
Vitamin E is an essential vitamin that protects membrane phospholipids from oxidative damage6,13. Vitamin E supplementation was evaluated in a study of 20 dogs with chronic hepatitis19. Dogs fed a diet supplemented with 7 IU alpha tocopherol acetate/kg body weight/day for 3 months demonstrated a decrease in serum ALT activity and an improved GSH to reduced GSH ratio compared to dogs fed a placebo diet19. This suggests Vitamin E supplementation may improve oxidant status and hepatocyte health in dogs with chronic hepatitis19. Doses of 10-15 IU/kg/day of alpha-tocopheral acetate have been recommended for both cats and dogs2,13. Because Vitamin E is a fat soluble vitamin, some authors have recommended higher doses be administered to animals with severe cholestatic disorders while others have recommended alternate anti-oxidants be used in said patients2,13.
Ascites is a common late stage complication of chronic canine liver diseases such as chronic hepatitis, cirrhosis and portal vein hypoplasia2. In dogs with hepatic cirrhosis portal hypertension, hypoalbuminemia and sodium and water retention all contribute to development of ascites1. Cats rarely develop ascites due to chronic liver diseas2. Pooling of blood volume in the splanchnic circulation and underfilling of the systemic arterial circulation with subsequent renal sodium and water retention are purported mechanisms for ascites formation in human patients with cirrhosis. In addition, increased portal pressure favours the development of collateral circulation, or multiple acquired portosystemic shunts, and potential hepatic encephalopathy; the clinical signs of which can be exacerbated by hypokalemia or alkalosis2. Together, this has lead to the recommendation for the potassium sparing, aldosterone antagonist, spironolactone (2-4 mg/kg q12 hours) as the initial diuretic of choice in canine patients with ascites due to chronic liver disease2. Furosemide, alone or in combination with spironolactone, can be administered to patients with normal appetites (consuming sufficient potassium) and without gastrointestinal signs (minimal GI potassium loss) or patients that are non-responsive to spironolactone alone but careful monitoring of serum potassium concentration and blood pH is recommended2.
Lack of dietary intake and decreased absorption of fat soluble vitamins can lead to vitamin K1 deficiency in cats with hepatic lipidosis and cats or dogs with complete extra hepatic biliary obstruction (e.g. cholelithiasis, gall bladder mucocele, stricture, neoplasia, etc). Treatment with 0.5 mg/kg SC q12 hours for 3 doses is recommended, especially prior to any invasive procedures.
Supplementation of water soluble B-vitamins should be considered in cats with hepatic lipidosis as deficiency secondary to concurrent intestinal and/or pancreatic disease is common. Initially, 1-2 mL of B-complex vitamins can added to each litre of intravenous fluids20. Measurement of serum cobalamin and folate levels should be considered as part of the minimum database and chronic supplementation initiated as indicated.
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