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, West Highland White Terriers, Springer Spaniels, Chihuahuas, and Maltese. 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 help determine its relevance to tissue 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 indicates 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. The acinar zone of involvement varies with the underlying cause.
Copper-associated hepatopathy is a leading cause of chronic hepatitis in dogs, increasing in prevalence since 1997 when copper supplements in commercial dog foods were modified to a more bioavailable form. Retrospective evaluation of liver biopsies from Labrador Retrievers and Doberman Pinschers from 1980 to 2013 indicated that dogs of these breeds, with and without chronic hepatitis, had significantly higher hepatic copper concentrations in the last 10 yr of the study. Management of body copper homeostasis relies on numerous copper transporters, chaperones, and binding proteins, as well as biliary canalicular egress. Copper-associated hepatopathy is best characterized in Bedlington Terriers, which have a mutation (deletion of exon 2) of the COMMD1 copper transporter protein. Careful breeding programs guided by liver biopsy and genetic testing (PCR gene mutation test) have remarkably reduced disease frequency in Bedlington Terriers. However, some Bedlington Terriers with biopsy-confirmed copper-associated hepatopathy lack this specific gene mutation.
Failure to excrete copper into bile leads to chronic hepatitis and, eventually, cirrhosis and liver failure. Affected dogs develop high liver copper concentrations by 1 yr of age (normal: <400 mcg/g dry liver or 400 ppm), which progressively increase during the first 6 yr of life (values may be > 12,000 ppm). Liver injury is reflected by increased ALT activity and has been shown in dogs with hepatic copper as low as 600 ppm.
Three disease phases were historically characterized in Bedlington Terriers. Acute hepatic necrosis occurred in dogs <6 yr old, presenting with hepatomegaly, vomiting, lethargy, anorexia, jaundice, copper-induced hemolytic anemia, and hemoglobinuria. Copper-associated hemolytic anemia occurs only with massive hepatic necrosis, which releases large amounts of copper into the systemic circulation. Death usually occurs within 48–72 hr of onset of clinical signs. In this group of dogs, untreated survivors suffered recurrent bouts of critical illness induced by stress (eg, whelping, attending dog shows, traveling). Another clinical presentation involves chronic hepatitis associated with clinical features, including chronic weight loss, HE, ascites, and jaundice. Some dogs develop an acquired Fanconi syndrome (glucosuria, aminoaciduria, metabolic acidosis, inappropriately alkaline urine pH), signaling renal tubular copper toxicity. The last clinical presentation was recognized in young, clinically healthy dogs, simply demonstrating increased ALT activity and increased hepatic copper concentrations (on liver biopsy). This presentation progresses to acute hepatic necrosis or chronic hepatitis. Rarely, an affected dog remained asymptomatic until another disease process caused liver injury augmented by excessive hepatic copper stores.
Genetic testing is recommended for selection of Bedlington Terrier breeding stock. However, definitive diagnosis of copper-associated hepatopathy requires liver biopsy in adult dogs with qualitative copper stains reconciled with quantitative copper measurements.
Many other purebred and mixed-breed dogs of all ages also may develop copper-associated hepatopathy. More commonly and perhaps more severely affected are Labrador Retrievers; whether the high breed popularity influences this observation remains unclear. Doberman Pinschers, West Highland White Terriers, and some dogs related to Dalmatians also may develop profoundly increased hepatic copper concentrations accompanied by severe liver injury. A genetic cause has not been identified in any of these breeds. It is important to emphasize that copper-associated hepatopathy can be the primary cause of hepatitis in any dog (purebred or mixed breed) and can be definitively diagnosed only by liver biopsy. There is no recognized gender predisposition.
Histologic features of copper-associated hepatopathy include a focus on the centrilobular region (zone 3), finding eosinophilic granules within the cytosolic compartment of hepatocytes and within macrophages in areas of single cell necrosis. Small granulomas develop subsequent to hepatocyte necrosis and release of copper granules into the surrounding parenchyma. Zone 3 lesional–associated parenchymal collapse is verified with reticulin staining (centrilobular collapse) and fibrillar collagen deposition with Masson trichrome staining (centrilobular connective tissue deposition). With advanced injury, regenerative nodules and regions of parenchymal extinction are seen. The prominent role of copper in driving tissue injury is verified by finding copper granules (rhodanine staining) in nearly every hepatocyte within regenerative nodules.
Treatment of copper-associated hepatopathy requires copper chelation with concurrent restriction of copper intake from dietary and water sources. Dietary copper restriction can be achieved by feeding a prescription diet formulated for dogs with HE (delivering 2.2–2.5 g of protein/kg body wt). These low-protein formulas can be supplemented with protein sources low in copper to raise the dietary protein intake to 3.5 g of protein/kg body wt. Supplementary protein sources are selected using the USDA food tables (sort based on copper concentration), with feeding amounts of selected foods calculated using the Nutritional Analysis Tool 2.0 (http://archive.myfoodrecord.com/ human nutrition). Copper in water should contain <0.1 ppm (0.1 mcg copper/L); if copper pipes transport water, flushing the system for 5 min will eliminate any leached copper.
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 ≥4-–6 mo) is the gold standard treatment. Thereafter, chronic therapy may be instituted by reducing the d-penicillamine dosage by half and administering the drug every other day while maintaining dietary copper restriction. Alternatively, the dog may be treated with zinc acetate (see below). Concurrent administration of pyridoxine (25 mg/day) is advised during d-penicillamine treatment, because this drug has antipyridoxine (vitamin B6) effects. If d-penicillamine chelation is not tolerated, trientene hydrochloride can be used (5–7 mg/kg, PO, bid, given 30 min before feeding). Caution is warranted with trientine used at the originally higher recommended dose, because this has induced acute renal failure in dogs with severe copper storage hepatopathy.
An alternative approach to manage copper storage hepatopathy is daily administration of oral zinc (acetate, gluconate, sulfate) to inhibit copper uptake from the GI tract (zinc induces enterocyte metallotheinine, which irreversibly binds copper and prohibits its absorption; copper is subsequently eliminated with effete enterocytes in feces). Although zinc treatment theoretically increases dietary options, study of the efficacy of zinc treatment in people with Wilson disease confirms unreliable control of dietary copper uptake. Zinc therapy must not be given concurrent with chelation therapy, because this will thwart efficacy of each treatment. Oral zinc is not well tolerated by some dogs, 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/day is given in two 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/day divided bid, but without study of radiolabelled copper uptake the efficacy of treatment in an individual dog remains unknown.
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 and potentially antifibrotic effects. Vitamin C is contraindicated in copper storage hepatopathy, because it may foster injurious transition metal effects.
After chelation therapy, it is essential to continue to limit copper ingestion in food and water lifelong. Adherence to a copper-restricted diet and water source may obviate the need for continual chelation or zinc therapy.
Although West Highland White Terriers have been shown to accumulate excessive hepatic copper, 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. Although West Highland White Terriers with chronic hepatitis usually do have high tissue copper concentrations, they differ from Bedlington Terriers with copper storage hepatopathy in that: 1) the 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 may be seen in asymptomatic young adult dogs. 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 then hyperbilirubinemia as the severity of liver injury advances. Histopathologic changes include multifocal necroinflammatory hepatitis with typical copper-affiliated granulomas and single cell necrosis, with advanced disease culminating in cirrhosis. Treatments target copper primarily if an association between inflammation and copper accumulation is histologically verified. (For treatment recommendations, see copper-associated hepatitis, Copper-associated Hepatopathy, and canine chronic hepatitis, Canine Chronic Hepatitis.)
Idiopathic chronic hepatitis is defined as chronic necroinflammatory self-perpetuating liver disease associated with a nonsuppurative inflammatory infiltrate. To qualify as an idiopathic syndrome, an underlying cause should have been rigorously pursued yet not discovered. Autoimmune hepatitis is included in this classification. An antinuclear antibody test, testing for endemic infectious diseases (titer or antigen tests), and investigation of drug and toxin exposure, along with dietary, environmental, and family history, must be undertaken. Middle-aged to older adult dogs are more commonly affected; there are no breed or gender predilections.
Clinical features include variable anorexia or hyporexia, 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, ALP, 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 development of APSSs and the associated laboratory markers of RBC microcytosis, hypocholesterolemia, hypoalbuminemia, prolonged APTT and/or PT, and ammonium biurate crystalluria. At this stage, overt signs of HE may manifest. 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. Ultrasonographic evaluations also may disclose ascites and APSSs in dogs with advanced liver injury.
Definitive diagnosis requires liver biopsy to detail acinal distribution of liver injury, the type of inflammatory infiltrates, the presence of lobular remodeling and fibrosis, and accumulation of copper and/or iron. Chronic, sustained, unexplained increases in liver enzymes usually indicate liver biopsy. Biopsy specimens should be submitted for both aerobic and anaerobic bacterial cultures and quantification of copper, iron, and zinc. Copper stains must be reconciled with quantitative copper measurements to avoid erroneous interpretations. 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. Application of special stains will disclose the acinar location of liver injury (reticulin staining); presence of collagen deposition of fibrosis (Masson's trichrome staining); extent of iron accumulation in macrophages, Kupffer cells, and hepatocytes (Prussian blue staining); and the extent and location of hepatocellular copper accumulation (rhodanine staining).
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 the biopsy and tissue cultures become available, and then adjusted or discontinued based on culture results. Additional treatments include ursodeoxycholic acid as a hepatoprotectant and anti-inflammatory choleretic (15–20 mg/kg, PO, divided bid, given with food), polyunsaturated phosphatidylcholine as an antifibrotic (PhosChol® [the specific source used containing 52% of the active antifibrotic component dilinoleoylphosphatidylcholine] 25–50 mg/kg/day, given PO with food), vitamin E as an antifibrotic and antioxidant (10 IU/kg/day, given with food), and bioavailable SAMe as an antioxidant (20–40 mg/kg/day, PO, on an empty stomach).
Immunosuppressive drugs are used only after careful consideration and exclusion of infectious or toxic causes and when an active disease process (nonsuppurative or pyogranulomatous inflammation) is characterized on liver biopsy. Prednisolone or prednisone is usually started at a dosage of 2–4 mg/kg/day, for 7–10 days and titrated downward to a maintenance level of 0.5–1 mg/kg, given every 24 hr or on alternate days, depending on patient response. In the presence of ascites or APSSs, dexamethasone is used instead of prednisone or prednisolone, because it is a synthetic glucocorticoid lacking mineralocorticoid effects. The dose is adjusted considering its longer biologic half-life (72–96 hrs) and higher potency (7–10 fold more than prednisolone or prednisone) such that dexamethasone is used at 0.1–0.2 mg/kg, PO, given every 3 days after a daily loading dose for 3 days. An immunomodulatory agent additional to the glucocorticoid is used to enable titration of the glucocorticoid dosage to the lowest effective dose. This reduces the dose of each immunosuppressive drug, reducing their adverse effects and achieving a multimodal immunosuppressive effect. 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 (glycogen-like VH).
Azathioprine is most commonly used at a dosage of 1–2 mg/kg/day 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, pancreatic, and rarely liver toxicity, frequent follow-up assessments are imperative. If azathioprine causes acute bone marrow suppression (within 1 mo), treatment is discontinued until recovery, then restarted with a 25%–50% reduction in dosage. If bone marrow toxicity is identified only after chronic administration (months), azathioprine should be permanently discontinued. Pancreatitis and idiopathic hepatotoxicity are rare adverse effects that also mandate drug discontinuation. Mycophenolate mofetil is used in dogs that cannot tolerate azathioprine or, alternatively, as an initial immunosuppressant. Recommended dosing is 10–20 mg/kg, PO, bid for 7–10 days, then every 24 hr, followed by dosage titration based on patient response. Cyclosporin is another alternative immunosuppressant used in combination therapy. Some dogs previously managed well on azathioprine have lost remission on conversion to cyclosporin. Other dogs started on cyclosporin as their primary immunosuppressant have responded well. In the absence of placebo-controlled clinical trials for treatment of canine immune-mediated hepatitis, treatment is individualized to each dog based on sequential monitoring and, sometimes, follow-up liver biopsy. Discontinuation of immunosuppressive therapy is not recommended in dogs with chronic hepatitis; if drugs are discontinued, they should be withdrawn gradually, with close monitoring (serum biochemical profiles).
Because complete remission is difficult to evaluate clinically, a follow-up biopsy may be required. In most cases, serum ALT activity serves as a surrogate marker of disease activity. 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.
This popular breed is predisposed to chronic hepatitis that is commonly associated with pathologic accumulation of hepatocellular copper (see copper-associated hepatitis, Copper-associated Hepatopathy). However, this breed also can develop a primary lymphoplasmacytic hepatitis that appears to involve immune-mediated mechanisms. 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 ALP (5-fold), modest or no increases in AST and GGT, hyperbilirubinemia, prolonged APTT, and transient glucosuria if severe copper-associated hepatopathy is a concurrent problem. Ultrasonographic imaging often demonstrates hypoechoic and hyperechoic parenchymal nodules, subjective microhepatica, and less frequently, irregular liver margins and ascites. A lymphocytic-plasmacytic hepatitis with single cell necrosis and remodeling may focus on the portal tract or be diffusely disseminated. If pathologic copper accumulation is a leading cause of the liver injury, inflammatory responses are focused in the centrilobular region. When both disorders coexist, marked lymphoplasmacytic infiltrates are seen within sinusoids of all acinar zones. Copper-associated hepatopathy is not typically associated with a marked lymphoplasmacytic infiltrate. In dogs with coexistent lesions, it remains unclear whether sensitization to epitopes on hepatocytes damaged from copper toxicity is the primary underlying etiopathogenesis of the immune-mediated response.
Treatment decisions are based on liver biopsy findings with routine and special liver stains and tissue copper quantification. Copper chelation and restricted copper intake (food and water) establishes complete remission in dogs with overt copper overload (>800 mcg/g dry weight tissue but lacking a nonsuppurative inflammatory reaction). Response to treatment is rapid and dramatic if diagnosed early but lifelong management of copper-associated hepatopathy (see Copper-associated Hepatopathy) is required. Labrador Retrievers with chronic nonsuppurative immune-mediated hepatitis not associated with hepatic 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 made early in the disease process.
An idiopathic, chronic, immune-mediated hepatitis recognized in Doberman Pinschers in the mid 1980s predominantly involved middle-aged adult female dogs. Copper retention appears to play a role in some dogs, which currently contributes to hepatitis seen in this breed.
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 ALP and ALT activities, hyperbilirubinemia, hypoalbuminemia, prolonged APTT, and a pure or modified transudative abdominal effusion. Ultrasonography may identify nodular liver lesions.
Liver biopsy is necessary for definitive diagnosis and treatment recommendations.
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, PhosChol® 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 with prednisone, vitamin E, antioxidants, and ursodeoxycholic acid. Prognosis for dogs with apparent copper-associated hepatopathy can be good if diagnosed early in the disease process (see copper-associated hepatitis, Copper-associated Hepatopathy).
Chronic Cocker Spaniel hepatopathy is associated with a degenerative vacuolar hepatopathy (glycogen, lipid, and hydropic degeneration) associated with low-grade nonsuppurative inflammation and sinusoidal myofibrocyte activation that leads to sinusoidal deposition of fine tendrils of fibrillar collagen. Disease is typically advanced at initial presentation. Definitive diagnosis by liver biopsy demonstrates regenerative nodules and marked distortion of the hepatic architecture consistent with micronodular and macronodular cirrhosis. There is no gender predisposition, and most dogs are diagnosed as young adults (4–4.6 yr, range 2–11 yr). Most dogs lack signs of liver disease antecedent to development of portal hypertension, ascites (pure or modified transudate), hypoalbuminemia, abrupt onset of HE, and APSSs. Clinical signs at presentation may include (in declining frequency) inappetence, lethargy, diarrhea, weight loss, melena, vomiting, and amaurosis. In some dogs, hepatopathy is discovered during abdominal ultrasonography for another health problem. Clinicopathologic features include modestly increased to normal liver enzyme activity, hypoalbuminemia, hypocholesterolemia, and increased TSBAs in the absence of hyperbilirubinemia. Normal fibrinogen, clotting times, normal or increased C-reactive protein, and subnormal antithrombin activity argue for a lack of acute phase marker induction and an inflammatory phenotype. Some dogs have moderate to abundant copper (on copper-specific staining), which may represent copper retention secondary to cholestasis (mild copper retention) or a more primary copper-associated injury (copper >800 ppm). In the latter dogs, foci of hepatocellular damage coordinate with regions of dense copper retention.
Strong sinusoidal staining with alpha-smooth muscle actin confirms transformation of resting stellate cells (Ito cells) that normally store retinoic acid (vitamin A) into activated myofibrocytes. Although the lesion has been labeled “lobular dissecting hepatitis” and Cocker Spaniel “hepatitis,” the minimal inflammation and necrosis and lack of clinicopathologic markers of inflammation suggest that “hepatopathy” is better terminology. Chronic Cocker Spaniel hepatopathy studied in Sweden nearly 20 yr ago investigated whether a genetic abnormality causing alpha1-antitrypsin (AAT) deficiency was involved. AAT is an important serum protease inhibitor synthesized in the liver and exported to the systemic circulation. Study of plasma AAT protein configuration and immunohistochemistry of AAT in canine liver biopsies implicated a unique enzyme phenotype associated with AAT globules evident in hepatocytes of some but not all Cocker Spaniels. Unfortunately, retention of AAT in damaged or dysfunctional hepatocytes may also occur as an epiphenomenon of compromised protein transcription consequent to hepatocellular injury (but usually not retention of globules) as demonstrated in affected dogs. Yet it remains unknown whether AAT plays a role in this breed-related syndrome. In people, treatment for AAT deficiency is liver transplant.
Treatment is supportive and symptomatic using a balanced protocol as described for chronic hepatitis. Early glucocorticoid immunomodulation (eg, 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 effects. Ursodeoxycholic acid, vitamin E, SAMe, polyunsaturated phosphatidylcholine (PhosChol®), 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 chelation is based on specific stains and copper quantification. Management of HE (dietary modification, lactulose, low-dose metronidazole, or nonabsorbable orally administered antimicrobials), and management of ascites (sodium restriction, diuretics, judicious therapeutic abdominocentesis) as described previously are recommended. Dogs receiving glucocorticoids as treatment for antecedent health issues before hepatopathy diagnosis and dogs treated with glucocorticoids with or without azathioprine after diagnosis may have improved survival. Additional supportive treatments reported include ursodeoxycholic acid, antioxidants, and antifibrotics. Although there was no correction of hypoalbuminemia in most dogs, survival beyond 3 yr of diagnosis was documented.
Three reports of hepatitis in Skye Terriers, one characterizing disease in nine related dogs, described no age or gender predilection and clinical signs ranging from asymptomatic to end-stage liver failure at time of initial diagnosis. Three separate liver disorders were described: mild inflammation with no evidence of cirrhosis or copper accumulation, advanced macronodular cirrhosis with cholestasis, and marked copper accumulation. Treatment is based on liver biopsy, as described previously for these disorders.
Maltese dogs have a high prevalence of congenital hepatic vascular malformations (MVD, PSVAs). Dogs with MVD vastly outnumber those with PSVAs. Within kindreds, finding high TSBAs in 60%–90% of dogs confirms high trait prevalence. Clinicians and breed enthusiasts have been confused by a published article proposing that TSBA quantification in Maltese dogs is confounded by interfering analytes. Liver biopsies from Maltese dogs with increased TSBA concentrations strongly refute that supposition, with >250 studied cases (60% lacking PSVAs) demonstrating lesions of portal hypoperfusion. An inflammatory and degenerative zone 3 (centrilobular) hepatic lesion develops in a subset of dogs with the MVD/PSVA trait; the lesion often coexists with marked persistent or cyclic increases of serum ALT activity. Histologic lesions vary in severity and may be progressive, eventually culminating in cirrhosis. This hepatopathy is often associated with concurrent inflammatory bowel disease and may derive from splanchnic delivery of inflammatory cytokines and inflammatory cells. Histologic lesions in dogs with increased serum ALT and high TSBA concentrations typically consist of a lymphoplasmacytic infiltrate with or without eosinophils adjacent to and sheathing hepatic venules (centrilobular, zone 3). Dogs develop a degenerative hepatopathy with lipogranulomas (foamy macrophage aggregates) located adjacent to hepatic venules that appear to partially or completely obscure vascular lumen. A spectrum of histologic severities exists within biopsy sections from an individual dog. Severe lesions provoke postsinusoidal intrahepatic portal hypertension and development of APSSs. Although cirrhosis has been confirmed in a small subset of dogs, ascites is detected clinically in nearly 75% of those affected. In dogs with ascites, ultrasonography usually discloses hepatic parenchymal nodules, a nodular liver surface contour consistent with hepatic remodeling, and narrowing of hepatic venules on color-flow vascular interrogation. A small subset of dogs may have copper-associated hepatopathy (rhodanine staining and quantified tissue copper > 1,200 ppm). Dogs with zone 3 degenerative hepatopathy concurrent with a PSVA usually respond poorly to surgical or ameroid shunt attenuation.
Treatment focuses on management of associated inflammatory bowel disease (hypoallergenic diets, home-cooked nutritionist-formulated or commercially available diets), metronidazole (7.5 mg/kg, PO, bid [low dose because of portal hypoperfusion]), and glucocorticoids avoiding use of drugs with mineralocorticoid effects (eg, dexamethasone, every 3 days, anti-inflammatory dose). Vitamin E (10 IU/kg/day) and SAMe (20 mg/kg/day) are recommended for antioxidant and antifibrotic benefits. Because a subset of severely affected dogs have developed thromboemboli involving hepatic venules and/or portal veins, minidose aspirin (0.5 mg/kg, PO, once to twice daily) has been prescribed for some dogs until inflammation abates (assumed based on decline in liver enzyme activity with maintained synthetic markers). Inflammation also has been successfully managed with budesonide in some dogs. In dogs treated with glucocorticoids, dosage is titrated to response (enzymes, clinical features) to minimize undesirable adverse effects. Some dogs require combined immunomodulation to achieve control of inflammation or because of unacceptable glucocorticoid effects. In these, azathioprine or cyclosporine are used in combination with or to replace glucocorticoids. Ascites is managed with sodium restriction and combined furosemide and spironolactone administration. A loading dose of spironolactone (2–4 mg/kg, PO, given once) followed by 1–2 mg/kg, PO, bid. Furosemide is dosed at 1 mg/kg, PO, once to twice daily. Diuretic treatment is suspended when ascites is in remission and reinstituted on recurrence, with continued sodium restriction.