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Canine Chronic Hepatitis


Chronic hepatitis that does not focus on biliary structures is more common in dogs than cats. Several breeds are predisposed, including Bedlington Terriers, Labrador Retrievers, Cocker Spaniels, Doberman Pinschers, Skye Terriers, Standard Poodles, and West Highland White Terriers. Although there is an identifiable etiology for some categories of chronic hepatitis, in most cases the cause remains unidentified. Increased hepatocellular copper and Kupffer cell iron stores are common in dogs with chronic hepatitis. The degree of metal accumulation and its acinar location can assist in determining whether it plays a causal role in the disease process or is secondary to the hepatic injury.

Other associated conditions include infectious canine hepatitis, chronic hepatitis secondary to infectious processes, and chronic exposure to xenobiotics (including certain drugs, biologic toxins, and chemicals). Terminology that reflects specific etiology or breed predilection, such as drug-associated chronic hepatitis, infectious chronic hepatitis, copper-associated hepatitis, etc, is preferred. The term idiopathic chronic hepatitis specifies that an etiology has not been determined.

Histopathologic changes are generally similar in all cases of chronic hepatitis, regardless of the underlying cause, and include a lymphocytic-plasmacytic inflammation with infiltrates extending into hepatic parenchyma, variable single cell or piecemeal necrosis, and in advanced disease, development of bridging fibrosis and nodular regeneration.

Copper-associated Hepatopathy

Copper associated hepatopathy is best characterized in Bedlington Terriers. The condition is caused by an autosomal recessive mutation, and careful breeding programs guided by liver biopsy and genetic testing have remarkably reduced its frequency. Failure to excrete copper through the biliary system leads to chronic hepatitis and cirrhosis. Affected dogs develop high liver copper concentrations by 1 yr of age (normal: <400 μg/g dry liver or 400 ppm). Hepatic copper concentrations increase progressively during the first 6 yr of life, reaching levels as high as 12,000 ppm. Hepatitis is overtly associated with copper concentrations >2,000 ppm.

Three phases of disease have been characterized. Acute hepatic necrosis is characterized in Bedlington Terriers <6 yr old with hepatomegaly, vomiting, lethargy, anorexia, jaundice, copper-associated hemolytic anemia, and hemoglobinuria. Copper-associated hemolytic anemia is only seen concurrent with massive hepatic necrosis (release of large amounts of copper into the systemic circulation). Death usually within 48–72 hr of onset of clinical signs. Untreated survivors suffer recurrent bouts of critical illness induced by stress (eg, whelping). The second clinical presentation is chronic hepatitis with clinical features including chronic weight loss, HE, ascites, and jaundice. Some dogs develop an acquired Fanconi syndrome signaling renal tubular copper toxicity. The third presentation is recognized in young, clinically healthy dogs only showing increased liver enzyme activity (ALT) and increased hepatic copper concentrations on liver biopsy. This presentation may progress to acute hepatic necrosis or chronic hepatitis. Rarely, an affected dog may remain asymptomatic.

Genetic testing is recommended for selection of Bedlington Terrier breeding stock. However, definitive diagnosis of copper storage hepatopathy requires liver biopsy in adult dogs with qualitative copper stains reconciled with the quantitative copper measurements. Rarely, some Bedlington Terriers with apparent copper storage hepatopathy have a unique gene mutation not detected by the current genetic test.

Other purebred dogs also are occasionally diagnosed with an apparent primary copper hepatopathy (especially Labrador Retrievers, Doberman Pinschers, Dalmatians) possibly related to dietary copper supplementation. A genetic cause has not been identified in these breeds.

Treatment of copper storage hepatopathy requires chelation therapy, while concurrently limiting copper intake from dietary and water sources. Dietary copper should be restricted to 0.1 mg copper/100 kcal diet; water should contain not more than 0.1 ppm (0.1 ug copper/liter). Avoid domestically softened water passing through copper pipes which may carry a higher copper load during initial pipe flushing each day.

Administration of antioxidants is important, because copper induces liver damage through oxidative injury. Chelation therapy with d-penicillamine (15 mg/kg, PO, bid, given 30 min before feeding for ≥6 mo) is the gold standard of treatment. Thereafter, chronic therapy may be instituted by reducing the d-penicillamine dosage by half or giving the standard dose every other day. Concurrent administration of pyridoxine (25 mg/day) is advised because d-penicillamine has antipyridoxine (vitamin B6) effects. If d-penicillamine chelation is not tolerated, trientene hydrochloride can be used (5–7 mg/kg, PO, bid, 30 min before feeding) but caution is warranted because trientine has induced acute renal failure in dogs with severe copper storage hepatopathy.

An alternative approach for managing copper storage hepatopathy is to use daily oral zinc acetate supplementation to inhibit copper uptake from the GI tract. Justification of this treatment is to increase dietary options. Zinc therapy must not be given concurrent with chelation therapy, because efficacy of each treatment may be compromised. Information regarding longterm efficacy of zinc supplementation in severely affected dogs is limited. Oral zinc may not be well tolerated, commonly causing vomiting, nausea, and inappetence. If zinc therapy seems more suitable for chronic treatment in a specific dog, a loading phase of elemental zinc at 5–10 mg/kg per day is given in 2 divided doses, 30 min before meals. Plasma zinc concentrations are monitored to ensure that circulating zinc is not nearing toxic values (>800 ppm). After several months, the dosage can be reduced to 2–3 mg/kg/ per day divided bid.

Vitamin E (10 IU/kg/day, PO) and biologically available SAMe (20 mg/kg/day, PO on an empty stomach) are recommended antioxidants that also have anti-inflammatory effects. Vitamin C is contraindicated in copper storage hepatopathy because it may foster injurious transition metal effects.

After chelation therapy, it is essential to limit copper ingestion in both food and water lifelong. Adherence to a copper-restricted diet and water source may obviate the need for continual chelation or zinc therapy. Several commercial prescription diets formulated for dogs with hepatic insufficiency are comparatively copper restricted. These low-protein formulas can be supplemented with protein sources that are low in copper to raise the diet's protein content. Using these diets as the base for a home-prepared ration is preferable to using nonprescription formulations that contain a wide range of copper content.

Severe copper storage hepatopathy was reported in a small number of Dalmatians. Affected dogs were 2–10 yr old and typically were acutely ill. Clinical signs ranged from no abnormalities to jaundice, ascites, HE, and GI signs including progressive inappetence and vomiting (several weeks). Diagnostic features included variable leukocytosis, greater magnitudes of increased ALT and AST than AP, variable hyperbilirubinemia and hypoalbuminemia, and normal glucose and cholesterol concentrations. Renal glucosuria was observed in a few dogs consistent with proximal renal tubular injury (transient Fanconi's syndrome). Liver biopsy disclosed mixed neutrophilic lymphoplasmacytic inflammation and, in some cases, extensive tissue remodeling and necrosis. Tissue lesions were affiliated with diffuse copper retention. The severity of liver injury and advanced state of hepatic failure limited treatment options and survival.

While West Highland White Terriers have been shown to accumulate excessive hepatic copper stores, not all dogs with high hepatic copper concentrations develop hepatitis. Some dogs with severely increased hepatic copper concentrations die of old age without necroinflammatory liver lesions. While West Highland White Terriers with chronic hepatitis usually do have high tissue copper concentrations, they differ from Bedlington Terriers with copper storage hepatopathy in: 1) mode of inheritance has not been determined, 2) maximal copper accumulation occurs by 6 mo of age and may then decline, 3) overall hepatic copper concentrations are lower than in Bedlington Terriers, and 4) hemolytic anemia has not been reported.

Focal hepatitis is seen in early disease, when dogs are asymptomatic. Chronic hepatitis is associated with anorexia, nausea, vomiting, diarrhea, jaundice, and later ascites. Increased liver enzymes develop first with focal disease, followed by increased TSBA concentrations and hyperbilirubinemia. Histopathologic changes include multifocal necroinflammatory hepatitis, necrosis, and cirrhosis. Treatments target copper primarily if an association between inflammation and copper accumulation seems apparent. (For treatment recommendations, see Canine Chronic Hepatitis.)

Idiopathic Chronic Hepatitis

Idiopathic chronic hepatitis is defined as chronic necroinflammatory self-perpetuating liver disease associated with a nonsuppurative inflammatory infiltrate. To qualify as idiopathic, an underlying cause should have been rigorously pursued yet none found. Autoimmune hepatitis is included in this classification. An antinuclear antibody test, endemic infectious disease titers or antigens, drug and toxin exposure, and dietary, environmental, and family history must all be investigated. Middle-aged to older adult dogs are more commonly affected; there is no breed or gender predilection.

Clinical features include variable extremes of anorexia, lethargy, weakness, vomiting, diarrhea, weight loss, jaundice, PU/PD, and in severe or advanced disease, coagulopathies, ascites, and HE. Earliest laboratory findings are persistent or cyclic increases in activity of ALT, AST, AP, and GGT. With advancing disease, increased TSBA concentrations are followed by hyperbilirubinemia. Other findings may include a nonregenerative anemia, leukocytosis, and hyperglobulinemia. In late-stage disease, portal hypertension causes acquired portosystemic shunting and the associated laboratory markers of RBC microcytosis, hypocholesterolemia, hypoalbuminemia, prolonged APTT and/or PT, and ammonium biurate crystalluria. At this stage, signs of overt HE may be recognized. In early disease, liver size is normal and there may be no demonstrable ultrasonographic lesions. In late-stage disease, radiographs may demonstrate a small liver with nodular lesions detected on ultrasound examination.

Definitive diagnosis requires liver biopsy with histopathologic stains to detail inflammatory infiltrates, fibrosis and remodeling, and copper and iron accumulation. Chronic, sustained, unexplained increases in liver enzymes usually indicate liver biopsy. Biopsy specimens should be submitted for both aerobic and anaerobic cultures and quantification of copper, iron, and zinc. Copper stains must be reconciled with quantitative copper measurements. Liver biopsies must be large enough to detail at least 15 contiguous portal triads, and biopsies must be taken from several different liver lobes. Samples collected only from apparent “mass lesions” can lead to erroneous diagnoses.

Supportive care (nutritional, vitamin supplementation) and use of specific therapies to slow inflammation and fibroplasia, and to restore liver antioxidant status, are recommended. Antibiotics are initially prescribed empirically until results of histology and tissue cultures are available, and are continued based on culture results. Additional treatments include ursodeoxycholic acid (15–20 mg/kg, PO, divided bid, given with food), polyunsaturated phosphatidylcholine as an antifibrotic (25–50 mg/kg, PO, with food), vitamin E (10 IU/kg, sid, with food), and SAMe (20–40 mg/kg, PO, on an empty stomach).

Immunosuppressive drugs are used only after careful consideration of infectious or toxic causes, when an active disease process has been characterized by liver biopsy. Prednisolone or prednisone are usually started at a dosage of 1–4 mg/kg, for 7–10 days, and titrated downward to a maintenance level of 0.5–1 mg/kg, given sid or on alternate days, depending on patient response. An additional immunomodulatory agent is also given to reduce the glucocorticoid dosage and adverse effects of each drug, and to achieve multimodal immunosuppression. Adverse effects of glucocorticoids in chronic hepatobiliary disease include sodium and water retention (which can exacerbate or promote ascites), catabolic effects (which can promote HE), GI ulceration and enteric bleeding (which can precipitate HE), pancreatitis, predisposition to secondary infections, glucose intolerance, and iatrogenic hyperadrenocorticism and VH.

Azathioprine is most commonly used at a dosage of 1–2 mg/kg, sid for 3–5 days, then every other day. Beneficial effects may not be seen for up to 8 wk. Because azathioprine can cause bone marrow suppression and gastroenteric toxicity, frequent follow-up assessments are imperative. If azathioprine causes acute bone marrow suppression, treatment is discontinued and restarted after recovery with a 25–50% reduction in dosage. If bone marrow toxicity is identified only after chronic administration, azathioprine should be permanently discontinued. Pancreatitis and idiopathic hepatotoxicity are rare adverse effects that mandate drug discontinuation. Mycophenolate mofetil can be used in dogs that cannot tolerate azathioprine. Recommended dosing is 10–20 mg/kg, PO, bid for 7–10 days, then sid, followed by dosage titration based on patient response. Discontinuation of immunosuppressive therapy is not recommended in dogs with chronic hepatitis.

Complete remission is difficult to evaluate clinically; a follow-up biopsy may be required. Prognosis is widely variable. Some dogs live ≥5 yr after initial diagnosis. Dogs with ascites require dietary sodium restriction and treatment with furosemide and spironolactone (see Portal Hypertension and Ascites in Small Animals). Dogs with HE require dietary protein modification and may benefit from lactulose and administration of low dose metronidazole.

If immune-mediated hepatitis is considered the definitive diagnosis, careful consideration should be given before administration of routine vaccinations. Nonspecific immune stimulation may adversely stimulate hepatitis and cause disease flare.

Breed-specific Chronic Hepatitis

This popular breed is predisposed to chronic hepatitis. Clinical features at diagnosis (in order of highest frequency) include jaundice, inappetence, vomiting, lethargy, and weight loss, with some dogs demonstrating abdominal discomfort, PU/PD, or no signs relevant to hepatitis. Common laboratory features include a normal PCV, leukocytosis, increased ALT (10-fold), increased AP (5-fold), modest or no increases in AST and GGT, increased bilirubin, prolonged APTT, and transient glucosuria. Ultrasonographic imaging usually demonstrates hypoechoic and hyperechoic parenchymal nodules, subjective microhepatica, and less frequently, irregular liver margins and ascites. In some dogs, diffuse hepatocellular copper retention is seen, associated with severe diffuse inflammation.

Treatment is based on liver biopsy interpretation (routine and copper specific stains), and quantification of tissue copper concentrations. Copper chelation and restricted copper intake (food and water) establishes complete remission in dogs lacking a prominent nonsuppurative inflammatory reaction but that have substantial hepatic copper concentrations (>800 μg/g dry weight tissue). Response to treatment is rapid and dramatic if diagnosed early but requires lifelong management of copper-associated hepatopathy (see Copper-associated Hepatopathy). Labrador Retrievers that have a chronic nonsuppurative immune-mediated hepatitis not associated with copper retention are treated lifelong as for idiopathic chronic hepatitis (see above). Response to treatment can be dramatic and is especially effective when diagnosis is early in the disease process.

An idiopathic chronic hepatitis has been reported in Doberman Pinschers. Middle-aged adult female dogs may be predisposed. Copper retention appears to play a role in some dogs and may reflect decreased biliary excretion secondary to disease-induced cholestasis rather than a primary disorder. An immune-mediated nonsuppurative hepatitis also has been characterized.

In dogs with advanced disease, clinical features include cyclic illness involving anorexia, weight loss, vomiting, diarrhea, PU/PD, jaundice, coagulopathies (melena, epistaxis), splenomegaly, microhepatica, ascites, and HE. Laboratory features may include a nonregenerative anemia, leukocytosis, thrombocytopenia, increased AP and ALT activity, hyperbilirubinemia, hypoalbuminemia, prolonged APTT, and a pure or modified transudative abdominal effusion. Ultrasonography may identify nodular lesions in the liver.

Liver biopsy is necessary for definitive diagnosis; some dogs have only an apparent nonsuppurative immune-mediated hepatitis while others have pathologic copper retention with affiliated liver injury.

Treatment in dogs with immune-mediated nonsuppurative hepatitis includes immunomodulation with prednisone (1–2 mg/kg/day for several weeks, slowly titrated to 0.5 mg/kg/day and if possible, to every other day) and antioxidants, with or without azathioprine. In dogs with developing fibrosis, polyunsaturated phosphatidylcholine is also recommended (25–50 mg/kg, PO, with food). Nutritional support depends on the presence of HE and the need for copper restriction. Prognosis is poor for dogs diagnosed with advanced nonsuppurative hepatitis. Dogs diagnosed early can achieve remission for several years. Prognosis for dogs with apparent copper associated hepatopathy can be good if diagnosed early in the disease process.

Chronic hepatitis in Cocker Spaniels is associated with a degenerative vacuolar hepatopathy associated with interface nonsuppurative inflammation. Advanced disease is associated with marked biliary hyperplasia and bridging fibrosis. Common clinical features include abrupt onset of anorexia, weight loss, lethargy, vomiting, variable diarrhea (with or without melena), jaundice, PU/PD, and HE. Baseline laboratory features include mild anemia; leukocytosis; increased ALT, AST, and AP activities; coagulopathy; low BUN; and in fewer dogs, hyperbilirubinemia. Nonjaundiced dogs have high TSBA concentrations. Abdominal effusion is a pure or modified transudate. Grossly, the liver is small and firm with numerous small and large regenerative nodules. Micronodular and macronodular cirrhosis and chronic periportal hepatitis have been characterized. Some dogs have moderate to abundant copper (on copper-specific staining), which is thought to represent copper retention secondary to cholestasis and hepatocellular injury. Positive immunohistochemical staining for α1-antitrypsin within vacuolated hepatocytes is commonly demo-nstrable. It is unclear if a specific genetic defect underlies this liver disorder.

Treatment is supportive and symptomatic using a balanced protocol as described for chronic hepatitis. Early glucocorticoid immunomodulation (before the diagnosis of liver disease, glucocorticoids prescribed for ear or skin disorders) has seemingly prolonged survival in affected dogs. However, in dogs with hypoalbuminemia or ascites, glucocorticoids are poorly tolerated and may cause melena, ascites, HE, etc. If a glucocorticoid trial is undertaken, dexamethasone should be used instead of prednisone to avoid mineralocorticoid affects. Ursodeoxycholic acid, vitamin E, SAMe, polyunsaturated phosphatidylcholine, and individually tailored nutritional support are recommended. A permanent urethrostomy may be necessary in male dogs that develop ammonium biurate calculi. Successful treatment of severely affected dogs has been possible for several years. Need for copper retention treatment is based on specific stains and copper quantification.

Three reports of hepatitis in Skye Terriers, one characterizing disease in 9 related dogs, described no age or gender predilection and clinical signs ranging from asymptomatic to end-stage liver failure at the time of initial diagnosis. Three separate stages of liver disease were described: mild inflammation with no evidence of cirrhosis or copper accumulation to advanced macronodular cirrhosis, cholestasis, and marked copper accumulation.

Last full review/revision March 2012 by Sharon A. Center, DVM, DACVIM

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