Lauren A. Trepanier, DVM, PhD, DACVIM, DACVCP
University of Wisconsin - Madison, School of Veterinary Medicine, Madison, WI, USA
Making a Diagnosis
It is important to perform a liver biopsy whenever possible. Specific biopsy findings that can drive therapy include: degree of fibrosis (mild, moderate or severe); predominant inflammatory infiltrates (neutrophils vs. lymphocytes and plasma cells vs. pyogranulomatous); degree of necrosis; presence of cholestasis; and presence of cirrhosis (distortion of architecture by fibrosis and nodular regeneration). The location of inflammation may indicate the underlying source. For example, in portal hepatitis, inflammatory cells (especially neutrophils) are found around portal areas without necrosis or fibrosis. This may indicate inflammation secondary to extrahepatic causes, such as septicaemia, gastrointestinal neoplasia or inflammatory bowel disease. Such cases may not need primary hepatic therapy, but instead, attention to underlying abdominal disease.
When are Antimicrobials Indicated?
Antimicrobials are indicated for active hepatic or biliary infection, ideally based on results of culture of bile or liver. Bile cultures can be obtained from gallbladder aspiration under ultrasound guidance, or from bile fluid obtained at laparotomy. If you perform a biopsy of the liver, always culture the bile, and submit both aerobic and anaerobic samples. Bile may be a more sensitive site to document hepatobiliary infection (versus liver tissue). In almost 250 cases of liver and bile cultures at the University of Wisconsin, 36% of cats had positive bile cultures (14% positive liver) and 28% of dogs had positive bile cultures (5% positive liver). The most common isolates were Escherichia coli, Enterococcus spp., Clostridium spp. and Staphylococcus. The empirical recommended duration is 2–4 weeks of therapy, but this has never been evaluated.
When are Glucocorticoids Indicated?
The rationale for glucocorticoids (anti-inflammatory, anti-fibrotic and choleretic effects) should always be weighed against potential side effects in each patient. Consider glucocorticoids for predominantly lymphocytic-plasmacytic or eosinophilic inflammatory infiltrates on liver biopsy. Glucocorticoids may be used empirically (without biopsy) and with care if the owner refuses biopsy, if progressive increases in alanine aminotransferase (ALT) are noted and if infectious and neoplastic causes have been ruled out with ultrasonography and serologies. They can, however, be associated with severe side effects in the animal with liver disease (see below). Prednisolone is preferred in cats due to apparent poor conversion of prednisone to prednisolone. Budesonide may be less likely to induce serum alkaline phosphatase (ALP) in dogs. It can, however, still cause significant polyuria/polydipsia in some dogs, and leads to adrenal suppression.
Precautions with Glucocorticoids
Glucocorticoids are contraindicated in patients with uncontrolled hepatic encephalopathy, ascites, active gastrointestinal ulceration, hepatic lipidosis and active hepatobiliary infection. Always stabilise patients and treat for encephalopathy and gastrointestinal ulcers before starting glucocorticoids. Add glucocorticoids as a single change (e.g., 2 weeks after other supportive care has been started) and monitor carefully for improvement or decompensation. If ascites is present, substitute dexamethasone (at 1/7 the dose) for prednisone, since dexamethasone has no mineralocorticoid activity.
Immunomodulatory and Antioxidant Therapies
Most recommendations for these agents are extrapolated from experience in humans, and are ideally based on a patient's individual liver biopsy findings.
Ursodiol (ursodeoxycholic acid) is a choleretic bile acid that also reduces hepatocellular injury and fibrosis in humans and animal models. In patients with moderate to severe cholestasis without obstruction, ursodiol is indicated as a choleretic. It is also the drug of choice for primary biliary cirrhosis in humans, which resembles feline cholangitis. Ursodiol is dosed at 10–15 mg/kg/day; tablets can be reformulated for cats and small dogs. Ursodiol should not be used unless bile duct obstruction has been ruled out (based on normal bilirubin or by ultrasonography).
S-adenosyl-methionine (SAMe) is a modified amino acid, important for methylation reactions in the liver and elsewhere. SAMe protects membranes from bile salt damage, and enhances bile excretion from hepatocytes. SAMe is also an indirect precursor of glutathione. SAMe administered to dogs helps to counteract liver glutathione depletion that occurs with liver disease or with corticosteroid administration. There are no controlled clinical trials of efficacy in dogs with naturally occurring liver disease, but SAMe has been shown to prolong survival in alcoholic cirrhosis in humans. Empirical indications include chronic hepatitis or cholangitis with a significant component of necrosis. Recommended dosing is 18–20 mg/kg on an empty stomach, but refer to individual products for exact dosing recommendations. Enteric-coated tablets should not be broken open.
Milk thistle (silymarin) is another hepatoprotective compound, which has been used for hepatic disorders since the time of the ancient Romans. It is thought to scavenge reactive oxygen species, and may have anti-inflammatory effects via inhibition of 5-lipoxygenase. Milk thistle has been shown experimentally to protect dogs against Amanita mushroom hepatotoxicity. Milk thistle may be used in patients with significant inflammation and necrosis on biopsy, in addition to, or instead of, SAMe. The empirical dosage is 1.5–8 mg/kg/day. Product formulation and potency may vary significantly from one manufacturer to another.
Vitamin E is a critical membrane antioxidant that protects hepatocytes against the toxic effects of bile acids in vitro. Its use has been advocated as empirical therapy for any inflammatory hepatopathy, especially hepatopathies with significant necrosis. Vitamin E may be used in addition to SAMe or silymarin, and is empirically dosed at 150–600 IU per dog per day. Overdoses of vitamin E can lead to a coagulopathy, and even modest doses (approximately 15 IU/kg in humans) can lead to subclinical decreases in the function of prothrombin, a vitamin K-dependent coagulation factor. Although the exact mechanism is not understood, it is hypothesised that high-dose vitamin E may antagonise the effects of vitamin K. Further, vitamin E has been shown to exacerbate the anticoagulant effect of warfarin in dogs. Until more is known, vitamin E supplementation should be avoided or monitored carefully in patients with liver disease and coagulopathy.
Antifibrotics and Decoppering Agents
Three major antifibrotics are in common use: glucocorticoids, zinc and colchicine.
Glucocorticoids inhibit fibroblast proliferation, and may be adequate for treatment of mild to moderate fibrosis accompanied by inflammation, particularly in cats.
Zinc inhibits collagen synthesis and decreases hepatic fibrosis in animal models. As a cofactor for superoxide dismutase, zinc may help to scavenge superoxide radicals. Zinc also impairs copper absorption. Zinc may therefore be useful for dogs with chronic hepatitis with moderate fibrosis, especially if mild to moderately increased copper is present. The empirical dosage is 15 mg/kg of elemental zinc per day. The goal is for serum zinc levels of 200–500 µg/dl (2–5 µg/ml). Zinc should ideally be given on an empty stomach (1 hour before or after a meal). I prefer to add zinc in as a single drug after stabilisation of the dog with hepatoprotective agents and glucocorticoids (if indicated). Formulations include: MarinTM: 45 mg of zinc per tablet (1–2 mg/kg of elemental zinc at label dose); zinc gluconate (14.3% zinc); and zinc acetate (35% zinc; no commercial product but may cause less gastrointestinal upset than sulfate or gluconate forms). Haemolysis can occur if serum zinc exceeds 1000 µg/dl.
A recent study in Labrador Retrievers in the Netherlands found that zinc did not increase the effectiveness of a low copper diet (Royal Canine Hepatic LS) in reducing liver copper concentrations in dogs with copper-associated hepatopathy that had been pretreated with D-penicillamine. No other efficacy studies have been performed for zinc.
Colchicine decreases collagen synthesis. It may be useful in dogs with chronic hepatitis and moderate to severe fibrosis, or with portal hypertension and ascites. There are however no controlled clinical trials of its efficacy in dogs. The dosage in dogs is 0.03 mg/kg orally once daily. Occasional gastrointestinal upset usually responds to a 50% dose reduction. High dosages can cause leucopenia or peripheral neuropathy. Do not use probenecid-containing formulations, which increase the risk of toxicity.
D-penicillamine is primarily a copper chelator, but may also inhibit fibrosis by preventing cross-linking of collagen. It is indicated for copper-associated hepatopathy (Bedlington Terriers, some West Highland White Terriers, Dalmations, some Labrador Retrievers), with quantitative hepatic copper levels > 3000 µg/g (dry matter basis). The recommended dosage is 15 mg/kg twice daily, 30 minutes prior to feeding. It may take several months for decoppering of liver and improvements in ALT. Some clinicians treat with D-penicillamine for 2 months, then switch to zinc. Gastrointestinal upset is also common with D-penicillamine.
Empirical anti-ulcer therapy is recommended for all acute and chronic liver disease. Liver disease is a common predisposing factor for gastrointestinal ulceration, due to impaired mucosal blood flow from portal hypertension, bile acid stimulation of gastric acid secretion and possibly decreased hepatic clearance of histamine and active gastrin fragments. Either H2 blockers or pump blockers can be used, although famotidine (1 mg/kg q12h) has minimal drug interactions. The H2 blocker authorised for dogs in the UK is cimetidine.
Management of Hepatic Encephalopathy
A checklist for acute management of hepatic encephalopathy includes:
Lactulose (orally, or by enema if stupor or seizures).
No food for 12–24 hours.
If no response, add metronidazole (15 mg/kg/day orally).
If no response, add neomycin orally at 20 mg/kg three times daily. Provide intravenous fluids with potassium (and dextrose for patients with portosystemic shunts or severe cirrhosis).
Add anti-ulcer therapy (gastrointestinal bleeding is a protein load in hepatic encephalopathy), and add vitamin K1 if jaundiced.
Withhold any glucocorticoids until encephalopathy is resolved!
Give as much dietary protein as tolerated; increase the lactulose dosage if needed.
Management of Ascites
Spironolactone / hydrochlorthiazide (Aldactizide) is an excellent diuretic for hepatic ascites. It is more potent than spironolactone alone, but causes less hypokalaemia and dehydration than furosemide. The empirical dosage, based on the spironolactone component, is 0.5–1.0 mg/kg orally q12h. Furosemide mobilises fluid well but often leads to hypokalaemia and hypovolaemia.
Therapeutic abdominocentesis is indicated if significant ascites is impairing mobility or causing respiratory compromise, and is refractory to medical management. I supplement with colloids prior to centesis, to prevent hypovolaemia and worsened hypoalbuminaemia as fluid shifts back into the abdomen. Start an infusion of 10 ml/kg of Hetastarch over 3 hours, and perform abdominocentesis after the first 30 minutes of the infusion. Monitor bodyweight, hydration and abdominal girth (measure girth at level of the second lumbar vertebra with a measuring tape) to document improvement or progression of ascites at home.
Assessing Response to Therapy
When using prednisone or prednisolone in dogs, you cannot rely on serum ALP to monitor response, since it is induced by glucocorticoids. ALT activity may also increase with prednisone in dogs, but will usually decrease overall as inflammation subsides. ALP and ALT are reliable in cats, since they are not steroid-inducible. Other parameters to monitor include: albumin and bilirubin; bodyweight, body condition score, abdominal girth (in dogs); and clinical status, to include appetite, energy, resolution of vomiting and diarrhoea, avoidance of severe polyuria/polydipsia and panting.