Chronic hepatitis that does not focus on biliary structures is more common in dogs than cats. Certain breeds have been noted to be predisposed to chronic hepatitis. An important issue contributing to chronic hepatitis is the pathological accumulation of copper. Since dietary adjustments of the type of copper used in commercial pet foods (nonbioavailable copper oxides replaced by bioavailable copper chelates) ~1997, copper-associated hepatopathy has escalated in prevalence and is now the dominant cause of chronic necroinflammatory liver disease in dogs in North America.
While several breeds are notably affected (Bedlington Terriers, Labrador Retrievers, Doberman Pinschers, Dalmatians, West Highland White Terriers, Welsh Corgis, Keeshonds, and others), no breed is free of this devastating toxicity. Because copper accumulation in hepatocytes fosters oxidative injury, its presence escalates hepatocyte damage initiated by other processes. Until dietary recommendations are modified and enacted, this will be a continuing canine problem.
Excluding copper-associated hepatopathy, conditions that may initiate chronic hepatitis include chronic hepatitis secondary to infectious processes (ie, bacterial, fungal, protozoal, rarely viral), drug-induced liver injury (DILI), and injury initiated by certain biologic, environmental, or chemical toxins. Terminology that reflects the presumed etiology or breed predilection, such as drug-associated chronic hepatitis, infectious chronic hepatitis, or copper-associated hepatitis, is preferred. Idiopathic chronic hepatitis denotes an unknown etiology.
Histopathologic changes are generally similar in all cases of chronic hepatitis, regardless of the underlying cause. This involves lymphocytic-plasmacytic and macrophage-mediated inflammation with particular zonal tropisms, variable single-cell necrosis or apoptosis, and in advanced disease, development of sinusoidal dissecting fibrosis, bridging fibrosis, and regenerative nodules. Identification of lymphocytic satellitosis implicates cytotoxic lymphocyte targeting. However, absence of this observation does not discount lymphocyte-mediated cellular injury. The acinar zone of involvement varies somewhat with the underlying cause.
Chronic Hepatitis With or Without Increased Hepatic Copper in West Highland White Terriers
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 the following ways:
the mode of inheritance has not been determined
maximal copper accumulation occurs by 6 months and may then decline
overall hepatic copper concentrations are lower than in Bedlington Terriers
hemolytic anemia has not been reported
Focal hepatitis may be seen in clinically normal 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 total serum bile acid (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.
Idiopathic 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 sex predilections.
Clinical features include variable anorexia or hyporexia, lethargy, weakness, vomiting, diarrhea, weight loss, jaundice, polyuria/polydipsia (PU/PD), and in severe or advanced disease, coagulopathies, ascites, and hepatic encephalopathy (HE).
Earliest laboratory findings are persistent or cyclic increases in activity of ALT, AST, alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT). With advancing disease, increased total serum bile acid (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 acquired portosystemic shunts (APSSs) and the associated laboratory markers of RBC microcytosis, hypocholesterolemia, hypoalbuminemia, activated partial thromboplastin time (aPTT) and prolonged prothrombin time (PT), and ammonium biurate crystalluria.
At this stage, overt clinical 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 ultrasonography. Ultrasonographic evaluations also may disclose ascites and APSSs in dogs with advanced liver injury.
Definitive diagnosis requires liver biopsy to detail acinar distribution of liver injury, the type of inflammatory infiltrates, the presence of lobular remodeling and fibrosis, and accumulation of copper 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 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 treatments to slow inflammation and fibroplasia and to restore liver antioxidant status are recommended. Antimicrobials 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 the following:
ursodeoxycholic acid (ursodiol) as a hepatoprotectant and anti-inflammatory choleretic (10–15 mg/kg/day, PO with food, every 24 hours or divided every 12 hours)
polyunsaturated phosphatidylcholine as an antifibrotic (the specific source used containing 52% of the active antifibrotic component dilinoleoylphosphatidylcholine; 25–50 mg/kg, PO with food, every 24 hours)
vitamin E as an antifibrotic and antioxidant (10 U/kg, PO with food, every 24 hours)
bioavailable S-adenosylmethionine (SAMe) as an antioxidant (20–40 mg/kg, PO, on an empty stomach, every 24 hours)
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, PO, every 24 hours for 7–10 days, and titrated downward to a maintenance level of 0.5–1 mg/kg, PO, every 24 hours 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 hours) and higher potency (7- to 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 decreases 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 vacuolar hepatopathy).
Azathioprine is most commonly used at a dosage of 1–2 mg/kg, PO, every 24 hours for 3–5 days, then every 48 hours. Beneficial effects may not be seen for up to 8 weeks. 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 month), treatment is discontinued until recovery, then restarted with a 25%–50% decrease in dosage. If bone marrow toxic effects are 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, every 12 hours for 7–10 days, then every 24 hours, followed by dosage titration based on patient response.
Cyclosporine is another alternative immunosuppressant used in combination treatment. Some dogs that previously managed well on azathioprine have lost remission on conversion to cyclosporine. Other dogs started on cyclosporine 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 years after initial diagnosis. Dogs with ascites Portal Hypertension and Ascites in Small Animals Ascites develops secondary to portal hypertension, with or without hypoalbuminemia. Liver disorders associated with ascites trigger physiologic responses that sustain euvolemia and splanchnic... read more require dietary sodium restriction and treatment with furosemide and spironolactone. 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
Labrador Retrievers and Chronic Hepatitis
Labrador Retrievers are predisposed to chronic hepatitis that is commonly associated with pathological accumulation of hepatocellular copper. 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 clinical 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 pathological 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 present 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 toxicosis 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) establish 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; however, lifelong management of 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 Idiopathic Chronic Hepatitis Canine chronic hepatitis is a syndrome of chronic inflammation of the liver. Chronic hepatitis that does not focus on biliary structures is more common in dogs than cats. Certain breeds have... read more . Response to treatment can be dramatic and is especially effective when diagnosis is made early in the disease process.
Doberman Pinschers and Chronic Hepatitis
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 and 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, PO, every 24 hours for several weeks, slowly titrated to 0.5 mg/kg, PO, every 24 hours and, if possible, to every 48 hours) 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 with advanced nonsuppurative hepatitis. Dogs can achieve remission for several years with early diagnosis and treatment 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.
Cocker Spaniel Hepatopathy and Chronic Hepatitis
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 evaluation.
Definitive diagnosis by liver biopsy demonstrates regenerative nodules and marked distortion of the hepatic architecture consistent with micronodular and macronodular cirrhosis. There is no sex predisposition, and most dogs are diagnosed as young adults (4–4.6 years; range, 2–11 years).
Most dogs lack clinical signs of liver disease antecedent to development of portal hypertension, ascites (pure or modified transudate), hypoalbuminemia, abrupt onset of HE, and APSSs. Clinical signs 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), which 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 years 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 humans, treatment for AAT deficiency is liver transplant.
Treatment is supportive 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 time 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, 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 of ascites (sodium restriction, diuretics, judicious therapeutic abdominocentesis) as described previously is 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 years of diagnosis was documented.
Skye Terriers and Chronic Hepatitis
Three reports of chronic hepatitis in Skye Terriers, one characterizing disease in nine related dogs, described no age or sex predilection and clinical signs ranging from clinically normal 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.
Based on results of liver biopsy, treatment is as described for the underlying disorder.
Maltese Dog Zone 3 (Centrilobular) Hepatopathy and Chronic Hepatitis
Maltese dogs have a high prevalence of congenital hepatic vascular malformations (microvascular dysplasia [MVD], portosystemic vascular anomalies [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, every 12 hours [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 U/kg, PO, every 24 hours) and SAMe (20 mg/kg, PO, every 24 hours) 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 is 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, administered once) is followed by 1–2 mg/kg, PO, every 12 hours. 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.