David C. Twedt, DVM, DACVIM
The most important and most common primary liver disease in the dog is chronic hepatitis. Chronic hepatitis is not a single disease but rather the inflammatory changes can be due to many etiologies. I have four general goals in therapy: 1) remove the etiology, 2) provide an adequate diet, 3) give specific therapy, and 4) provide general liver support. First step in the therapy for chronic hepatitis and other liver diseases involves removing the primary etiology if it can be identified. Infectious (leptospirosis), drugs, copper, and immune are common etiologies. Short of treating the primary etiology, all other therapies suggested are unproven in the management of chronic hepatitis in dogs.
Adjusting diet therapy should be considered in all cases; however, only general guidelines should be given. First, palatability is important to ensure adequate energy requirements are met. Next, there is a misconception about diet and liver disease that liver patients should be placed on a protein-restricted diet. Protein restriction should only be instituted in the patient that has clinical evidence of protein intolerance (i.e., hepatic encephalopathy). The goal of dietary therapy is to adjust the quantities and types of nutrients to provide nutrient requirements but to avoid the production of excess nitrogen byproducts associated with liver disease. As a general recommendation, the dietary protein should represent 17 to 22% of digestible kcal. High carbohydrate and moderate fat content is important to supply caloric needs. Mineral supplementation containing high concentrations of both copper and iron should be avoided. Diets low in copper are recommended for the dogs that have copper-associated liver disease based on biopsy. Most formulated "liver diets" have lower copper concentrations and are often supplemented with additional zinc. Vitamins or mineral supplements should not contain copper or iron.
Decreasing inflammation as a specific therapy for chronic hepatitis in the dog or cholangitis in the cat is unproven although the author's clinical impression suggests anti-inflammatory therapy is beneficial in some cases. The treatment of chronic hepatitis is quite controversial and there are as yet no good controlled studies in animals to support corticosteroids use in every case. Anti-inflammatory therapy is indicated in suspected immune-mediated chronic hepatitis. A study by Strombeck found that some dogs with chronic hepatitis tend to have a prolonged survival when treated with corticosteroids. It appears that corticosteroids offer benefit in at least some cases (possibly around 25%). A suggested dose of 1 to 2 mg/kg/day using either prednisone or prednisolone should be instituted. When clinical improvement is suspected or after several weeks, the dose is then gradually tapered eventually to a dose of 0.5 mg/kg/day or every other day. The only accurate way to evaluate a response to any therapy is to re-biopsy the patient in 6 months to 1 year. Alternatively, one could stop steroids and recheck enzymes in 1 to 2 months.
Azathioprine is an effective immunosuppressant drug that has shown to increase survival in man when treated for chronic hepatitis in conjunction with corticosteroids. This therapy may also be beneficial in dogs (don't use in cats) by increasing the immunosuppressive response and enabling a reduction of both steroid dose and their side effects. A dose of 2.2 mg/kg/day is the suggested starting dose and after several weeks given every two days. The level of glucocorticoids can frequently be reduced when using azathioprine. We have more recently been using cyclosporine A in some cases with a good clinical response. Our experience using 5 mg/kg BID or q 24 h (without steroids) has been very encouraging in dogs that are thought to have immune-mediated chronic hepatitis. The veterinary formulation AtopicaTM is a microemulsified preparation. Many dogs will develop gingival hyperplasia at the higher concentrations of cyclosporine. The most common side effect I observe is nausea and vomiting. Often signs resolve after several days, but, if not, try giving the cyclosporine with food or freeze the capsules and give frozen. With evidence of clinical response at 5 mg/kg BID I will often decrease to once-a-day therapy.
If the liver biopsy of a dog with chronic hepatitis indicates significant abnormal hepatic copper accumulation, copper chelators or zinc therapy should be considered. Hepatic copper levels greater than 1000 µg/g dry weight liver require chelator therapy to reduce copper concentrations. Chelators bind with copper either in the blood or the tissues and then promote copper removal through the kidneys. Penicillamine (250-mg capsules) is the most frequent copper chelator recommended for use in dogs. The dose is 10–15 mg/kg BID given on an empty stomach. Side effects include anorexia and vomiting. The length of chelation therapy is variable but based on past experience. As a recommendation, if copper is less than 1000 ppm I generally treat for 3–4 months; if 1000–2000ppm I treat for 6 months; and if greater than 2000 ppm 6–9 months. I monitor ALT levels and if they become normal I often discontinue therapy, maintain on a low-copper diet and will consider zinc supplementation as well. Of course, the ideal recommendation is to obtain repeat liver biopsies measuring hepatic copper.
Zinc given as the acetate, sulfate, gluconate, or other salt has also been proven effective in preventing hepatic copper accumulation by blocking intestinal absorption. Oral causes induction of the intestinal copper-binding protein metallothionein. Dietary copper binds to the metallothionein with a high affinity that prevents transfer from the intestine into the blood. When the intestinal cell dies and is sloughed, the metallothionein-bound copper becomes excreted through the stool. An initial induction dose of 5–10 mg/kg body weight divided BID of elemental zinc. Following one to 3 months of induction the dose can be reduced in approximately half.
Corticosteroids, zinc and penicillamine all have antifibrotic effects. Colchicine is a drug that has been used with chronic hepatitis and other types of liver fibrosis. There is however still the lack of convincing data in humans and dogs with liver disease that colchicine is beneficial. A critical appraisal of colchicine in human liver disease having chronic hepatitis now questions its effectiveness and failed to show benefit in a placebo-controlled metaanalysis. Recently, it was found that angiotensin II inhibitor losartan (0.25–0.5 mg/kg/day) has effects in reducing or preventing fibrosis in humans by affecting the function of stellate (fibrosis-producing) cells.
Decreasing cholestasis has been shown to be of benefit in humans and animals having cholestatic hepatobiliary disease. As serum bile concentrations increase (these are predominately cytotoxic bile acids), they can cause cell membrane permeability changes and fibrogenesis. Ursodeoxycholic acid (ursodiol - 300-mg caps) is a choleretic agent developed to dissolve gallstones but later found to have positive effects in patients with chronic hepatitis. This drug is a synthetic hydrophilic bile acid that essentially changes the bile acid pool from the more toxic hydrophobic bile acids to less toxic hydrophilic bile acids. Ursodeoxycholic acid has been shown to increase bile acid-dependent flow, reduce hepatocellular inflammatory changes, fibrosis, and possibly some immunomodulating effects. The hepatoprotective characteristics makes one believe ursodeoxycholic acid acts as an antioxidant. The dose for ursodeoxycholic acid is 15 mg/kg daily. No toxicity has been observed in dogs and cats at this dose.
Antibiotics are indicated for primary hepatic infections. There may be, however, evidence that bacterial colonization may take place in a diseased liver. Kupffer cell dysfunction could be a reason for secondary bacterial infections. It may be prudent for antibiotic therapy or trial for several weeks in patients having significant hepatic disease (i.e., chronic hepatitis). Amoxicillin, cephalosporin, or metronidazole are suggested. Metronidazole may have some immunosuppressive properties as well as antibacterial mechanisms. For liver disease I would use 7.5–10 mg/kg BID, a much lower dose used for other bacterial infections because of hepatic metabolism of the drug.
Antioxidants in general provide liver support to promote optimal hepatic function. Considerable evidence shows that free radicals are generated in chronic hepatitis and participate in the pathogenesis of oxidative liver injury in dogs and cats. Normally there is an extensive system of cytosolic and membrane-bound enzymatic and non-enzymatic antioxidants which function to prevent oxidative damage by "scavenging" or "quenching" free radicals that are formed. It is reported that close to half the dogs and cats with liver disease have reduced glutathione concentrations in the blood and liver supporting that oxidative damage is present.
Vitamin E, d-alpha tocopherol, functions as a major membrane-bound intracellular antioxidant, protecting membrane phospholipids from peroxidative damage when free radicals are formed. Vitamin E is shown to protect against the effects of copper, bile acids, and other hepatotoxins. In a small study of dogs having chronic hepatitis, we found all dogs had evidence of oxidative damage. In a three-month placebo-controlled study treating only with vitamin E, there was evidence of improvement in the oxidant status of the treated dogs; however, we did not identify changes in clinical, laboratory, or histology during this short treatment period. A suggested vitamin E dose is 50 to 400 IU a day. The d-alpha tocopheryl formulation is much more potent than the most common commercial form (dl-alpha tocopheryl). Since bile acids are required for fat-soluble vitamin E absorption and may be reduced in cholestatic liver disease, a water-soluble formulation is suggested. For a water-soluble form I use TwinLab Liqui-E®. The vitamin E is derived from TPGS (d-alpha tocopheryl polyethylene glycol 1000 succinate) and has a rapid absorption. Because of the potential benefits of vitamin E, the lack of side effects and since the drug is inexpensive, I place most of my liver patients on E therapy.
S-Adenosylmethionine (SAMe) is a naturally occurring molecule found in all living organisms and is involved in a number of metabolic pathways that appear to be beneficial to the liver as well as other tissues. SAMe is involved in three major biochemical pathways. It is involved in cell replication and protein synthesis, has a modulating influence on inflammation, and plays a role as a precursor of the antioxidant glutathione in the hepatocyte. Research has demonstrated that the exogenous administration of SAMe has potential beneficial effects for a number of types of liver damage. I will routinely prescribe SAMe in patients having acute liver toxicity and in many cases having chronic liver disease or other liver disorders. A recommended dose range is 20 mg/kg/day. It should be given on an empty stomach.
Milk thistle has been used for centuries as a natural remedy for diseases of the liver and biliary tract. Silymarin, the active extract, consists of bioflavonolignans that have been reported to work as antioxidants, scavenging free radicals and inhibiting lipid peroxidation. Several recent human clinical trials have assessed the efficacy of silymarin in the treatment of liver disease. The data are somewhat difficult to interpret because of the limited number of patients, poor study design, variable etiologies, lack of standardization of silymarin preparations with different dosing protocols. There is, however, compelling evidence to suggest silymarin has a therapeutic effect in acute viral hepatitis, alcoholic liver disease, patients with cirrhosis, and in toxin- or drug-induced hepatitis. Silybin is the principal active isomer of the silymarin extract. Gastrointestinal absorption is poor and bioavailability is increased by complexing with phosphatidylcholine. We have evaluated a commercially available complex in a preliminary pharmacokinetic study in normal cats and found no clinical outward signs of toxicity giving a dose up to 5 mg/kg and have found improvement in oxidant status in the blood of normal cats and cats having liver disease. A new compound Denamarin® is available containing SAMe and silybin and is available in a chewable formulation. It appears that the combination of both compounds have a good absorption. The Denamarin product appears to be very stable and not oxidized like the other SAMe products. I personally have no experience with other SAMe or milk thistle products.
General Support Therapy
The remainder of the therapy for chronic hepatitis involves treatment of secondary complications. These occur as the disease becomes advanced. Hepatic encephalopathy, GI ulceration, and ascites are common clinical occurrences in advanced hepatitis or cirrhosis. The first step in the management of hepatic encephalopathy includes the use of enemas to clean the colon of both bacteria and protein substrates for ammonia production. Slightly acidic enemas will lower the pH of the colon, thus ionizing ammonia and reducing its absorption. Povidone iodine (betadine) can safely be given by enema as a 10% solution (weak tea color) that will both acidify the colon and have an antiseptic action reducing bacterial numbers. Nonabsorbable intestinal antibiotics are used to alter bowel flora and suppress urease-producing organisms important in the formation of factors causing hepatic encephalopathy. Antibiotic suggestions include oral ampicillin, aminoglycosides (neomycin, kanamycin or gentamicin) or metronidazole. Metronidazole given at 7–10 mg/kg BID has been useful in controlling anaerobic urease-producing bacteria. One should be careful as metronidazole is partially metabolized in the liver and a lower dose range is suggested. A nondigestible disaccharide lactulose (Cephulac® or Chronulac®) given orally acidifies the colon converting ammonia to ammonium that is poorly absorbable, thus trapping ammonia in the colon. The fermentation products of lactulose will also act as an osmotic laxative reducing colonic bacteria and protein substrates. A dose of 1–10 ml orally TID is generally effective. Lactulose is not absorbed systemically and thus considered safe. The dose should be adjusted to cause 3 or 4 soft stools a day. If diarrhea develops, the dose should be reduced. Lactulose can also be given by enema in treating the severe case of hepatic encephalopathy.
Gastrointestinal ulceration not only causes gastrointestinal signs such as vomiting and anorexia but blood loss into the intestinal tract promotes hepatic encephalopathy as blood is an excellent protein source for ammonia production. Gastric ulcers should be treated with the H2 blocker such as ranitidine (2–5 mg/kg BID/TID) and oral sucralfate (Carafate® 1 mg tab/25 kg TID given 1 hour before ranitidine). Cimetidine is to be avoided in liver disease because it is metabolized by the liver and is an enzyme suppressor altering hepatic metabolism of other drugs.
Ascites occurs in chronic hepatitis when portal hypertension, hypoalbuminemia, and renal sodium and water retention work in concert to cause fluid exudation. Diuretics are the major means of managing ascites in small animals. Too rapid removal of ascitic fluid can cause metabolic complications and can precipitate hepatic encephalopathy. The goal of diuretic therapy should be a gentle water diuresis. The two diuretics most commonly used are furosemide and spironolactone. The consensus of most is that spironolactone is more effective with liver disease. The loop diuretic furosemide (Lasix) can, however, cause marked dehydration and loss of potassium. With liver disease, sodium reabsorption at the distal tubule may be great and counter the effects of furosemide due to elevated aldosterone concentrations (reported to occur in some dogs with liver disease). Spironolactone (Aldactone® 1–2 mg/kg/day) is consequently the first-line diuretic. Furosemide can be added later if necessary. If an animal has tense ascites, paracentesis should be performed to decrease the intra-abdominal pressure, relieve compression of the venous circulation, and to increase patient comfort.
References are available upon request.