Hepatopathies in the Dog Jinelle Webb DVM, DVSc, Dipl ACVIM
MOVEH WOOF WALK 2017
Canine Hepatopathies l Vacuolar hepatopathy/nodular hyperplasia/aging change l Toxin/drug induced l Idiopathic chronic hepatitis / copper storage disease l Infections, including leptospirosis and bacterial cholangiohepatitis l Vascular disorders l Neoplasia
Pattern Recognition l Yorkshire Terrier puppy l Young Doberman l Geriatric Beagle l Mature Bernese Mountain Dog
Diagnostics for the Liver l History l Physical Examination l Blood Work and Urinalysis l Additional Laboratory Work l Radiographs l Ultrasound l Advanced Imaging l Aspirate/Biopsy
History l Many dogs will have no symptoms l PSS l Chronic hepatitis l Sometimes symptoms are subtle l Changes in behaviour after eating l Mild lethargy, increased urination and drinking interpreted as an aging change l Distended abdomen interpreted as weight gain
Physical Examination l Many dogs will have a normal PE l Sometimes changes are subtle l Distended abdomen l Loss of muscle l Abnormal mentation l Mild icterus
Blood Work l Hepatocellular leakage/necrosis l ALT, AST l Cholestasis l ALP, GGT, bilirubin, bile acids l Decreased hepatic function l Bilirubin, bile acids, albumin, urea, cholesterol, clotting factors, ammonia l Electrolytes depending on symptoms l CBC depending on cause
Bile acids l Will be elevated if hyperbilirubinemia present l Not often performed if bilirubin elevated l Post prandial most useful, random less useful l Good assessment of liver function l Expect significant elevation with: l Vascular liver disorder l Cirrhotic liver l Severe, acute hepatic necrosis
Additional testing l Ammonia l Biggest issue is volatility and ability to get a rapid, reliable result l Similar use to bile acids; if reliable result, can perform in hospital at some clinics l Ammonia tolerance test l Should not be used with hepatic encephalopathy l Can have false positives l Urea cycle enzyme deficiencies l Breed related (Irish Wolfhound puppies, etc)
Hepatic enzymes l Vacuolar hepatopathy/nodular hyperplasia/ aging change l Increased ALP, can be marked l Occasional mild increase in ALT l Idiopathic chronic hepatitis / copper storage l Increased ALT is hallmark, sometimes fluctuating l Often have increased ALP, not all cases l If progressed to end stage, can see evidence of decreased function ( urea/albumin, bilirubin)
Hepatic enzymes l Infections, including leptospirosis and bacterial cholangiohepatitis l Variable increase in ALT, ALP, bilirubin, often marked increase in ALT in leptospirosis l Can also have reduction in urea, albumin l Toxin/drug induced l Variable increase in ALT, ALP, bilirubin, however often marked increase in ALT l Can also have reduction in urea, albumin
Hepatic enzymes l Neoplasia l Normal l Increased ALP, ALT l Increased bilirubin usually only with primary hepatic neoplasia l Reduced urea, albumin paraneoplastic? l Vascular disorders l Increased bile acids l +/- Increased ALT and ALP l +/- Low urea and albumin
Urinalysis l Can be normal l Low urine specific gravity l Occasional isosthenuria l Ammonium biurate crystalluria, about 50% of dogs with PSS l Presence of bilirubin (can be normal in some pets, esp if urine is concentrated)
Coagulation Parameters l All clotting factors made in liver other than a subtype of factor VIII l Prolongation of PT/PTT seen if factors <30% l Can happen quickly (acute hepatic necrosis) l In one study, 57% of dogs with liver disease had prolongation of PT and/or PTT l May or may not result in clinical hemorrhage l Coagulation status not correlated with post biopsy hemorrhage in one study
Radiographs l Canine and feline liver should come slightly beyond the costal arch (breed dependent) l Feline liver often lifted dorsally due to falciform fat, and often more right-sided l Useful test to assess hepatomegaly, and somewhat microhepatica l Can sometimes see masses, choleliths, diaphragmatic hernia, etc
Ultrasound l Smooth margins, not rounded l Homogeneous, uniform texture, medium level echogenicity (spleen>liver>kidney) l Radiographs may be superior for size assessment l Presence of nodules, masses, abscesses, ascites l Assessment of gall bladder and bile duct l Assessment of pancreas and duodenal papilla l Assessment of anomalous vasculature l One study showed 40% of PSS are not seen with U/S l Acquired shunts can be very difficult to see
Advanced Imaging l CT / MRI l Suspected portosystemic shunt cases l 5.5 times more likely to visualize PSS than U/S l Recent evidence that multiple branches can be present in PSS l Hepatic masses prior to resection l Assess ability to resect l 94% successful in differentiating benign from malignant l Non-surgical visualization of acquired shunts l Challenging cases
Advanced Imaging l Angiography l Intraoperative portography l Ultrasound guided splenic portography l Infrequently utilized due to other imaging modalities l Scintigraphy l Per-rectum evaluate whether heart is imaged prior to liver (shunt fraction high in PSS) l Trans-splenic visualization of shunting vessels l Require facility able to house radioactive material l Results may be equivocal
Ultrasound-Guided Aspirate l Useful to diagnose lymphoma, some solid tumours and ~vacuolar change l Less invasive and lower cost than biopsy l Less risk of hemorrhage l Dogs with friable livers l Dogs with ascites l Cannot diagnose hepatitis versus toxic versus bacterial l No architectural information
Ultrasound-Guided Aspirate l 30-61% correlation to hepatic biopsy l 60% sensitivity for vacuolar change l 52% sensitivity for neoplasia l Usually will detect lymphoma and primary/ metastatic carcinoma l Likely correct if diagnosis of neoplasia, however lack of neoplastic cells does not rule out neoplasia
Liver Biopsy l Ultrasound-guided l Diffuse disease, ideally multiple biopsies l Diagnosis of a focal mass but risk for hemorrhage l Consider size of patient l Rarely recommended when ascites present l Laparoscopic l Diffuse or focal disease l Sample will be peripheral, less useful for a dorsal, central mass l Minimally invasive
Liver Biopsy l Key hole laparotomy l Obtain a relatively large sample, can be from more than one lobe l Quantitative copper levels l Often a day procedure l Exploratory laparotomy l Most invasive option l Best evaluation of liver, biliary system +/- entire abdomen, samples of other organs l Resection of masses
Mature dogs with ALP Should we ignore the ALP??? l Nodular hyperplasia l Idiopathic vacuolar hepatopathy l Hepatoma l Hyperadrenocorticism
Treatment
Anti-bacterials l Broad spectrum for possible bacterial cholangiohepatitis l BAM - Enrofloxacin, amoxicillin, metronidazole l Clavamox and metronidazole l Convenia less ideal l Ideally always based on culture results, however some cases are culture negative
Immunosuppression l Glucocorticoids l Most frequently used type l Prednisone/prednisolone drug of choice l 2 mg/kg q 24 hours x 2-4 weeks, then taper slowly l Give with food, and gastroprotection at high dose l Prednisolone if end stage liver disease l Typical side effects l Dexamethasone can also be used (0.25 mg/kg q 24 hours starting dose), remission in refractory cases? l Minimal data in veterinary literature
Immunosuppression l Budesonide - Locally acting nonhalogenated corticosteroid l High hepatic clearance, resulting in high local and low systemic activity l Useful in cases that are very sensitive to prednisone, or contraindications l Highly effective in some cases, other cases have little to no response l 0.5 3 mg PER DOG q 24-48 hours, usually not tapered
Immunosuppression l Cyclosporine l Induces cell mediated immunosuppression l Some cases have a better response to cyclosporine than glucocorticoids l Side effects in up to 50% l Vomiting, inappetence, diarrhea, alopecia, gingival hyperplasia, idiosyncratic hepatopathy, opportunistic infectious disease l 5 mg/kg PO q 12-24 hours l Expensive l Should avoid certain formulations
Ursodiol l Synthetic hydrophilic bile acid l Increase biliary flow, anti-inflammatory, antifibrotic, possible immunomodulation l 10-15 mg/kg once daily PO with food, gradually increase dose to full amount to improve tolerance l Only FDA approved drug for human biliary cirrhosis l Limited veterinary data
Antioxidants l same l Several veterinary products l Antioxidative, anti-inflammatory and possible immunomodulatory l Some evidence of efficacy but limited data l Vitamin E l Antioxidative l 50 to 400 IU per day l One study showed less oxidative damage but no change in biochemical or histologic parameters
Antioxidants l Silymarin (Milk thistle) l Anti-oxidant l Problems with human studies due to small study sizes, lack of standardization of silymarin, and conflicting results l Minimal veterinary data, one study showed improvement in Amanita cases l Silybin is an extract of silymarin, which is used in some products l Overall, minimal veterinary data
Antioxidants l N-acetylcysteine l Anti-oxidant l Given IV, usually causes vomiting if given PO l For acute hepatic injury l Conflicting results in the literature l Improved markers of hepatic circulation and oxidation with canine bile duct ligation l No beneficial effect in canine model of ischemic liver injury l Current recommendations are to use short term in acute hepatic injury, transition to oral same as soon as possible
Hepatic encephalopathy l Lactulose l Osmotic laxative, acidifies colon which causes ammonia to move from blood to colon l Orally or enema l Neomycin l Poorly absorbed aminoglycoside antibiotic l Reduces ammonia-producing bacteria in colon l Metronidazole l Also used to modify bacterial population l Caution due to neurotoxicity and hepatic clearance
Ascites l Spironolactone l Aldosterone receptor antagonist l Furosemide l Loop diuretic l Can lead to dehydration, hypovolemia, hypokalemia, metabolic hypochloremic alkalosis l These can precipitate hepatic encephalopathy l Low salt diet l Abdominocentesis avoided if possible, due to potential for worsening hypoalbuminemia
Diet l Vegetable based protein better than meat l Significant protein restriction in cases with liver failure or hepatic encephalopathy l Hill s l/d l Dry egg, soybean, pork l Canned soybean, egg l RC Hepatic l Dry soybean l Canned chicken and pork
Diet l Cases without hepatic failure or hepatic encephalopathy do not need hepatic diet l Some degree of protein restriction l 17-22% protein l Could consider vegetable based diet, less information available for these cases l Palatability and appetite are first concern
Benign liver changes l Nodular hyperplasia l Idiopathic vacuolar hepatopathy l Breed-related such as Scottish Terrier l Relationship to endocrine disease in some cases (such as hyperadrenocorticism) l Incidental finding in some? l How much to investigate an older dog with increased ALP, no symptoms, and hepatic nodules?
Toxin/drug induced TOXINS l Mycotoxins, aflatoxins l Blue green algae l Amanita mushrooms l Xylitol (sugar substitute) l Organic solvents l Alpha lipoic acid DRUGS l Carprofen l Acetaminophen l TMS l Azathioprine l Amiodarone l Mitotane
Toxin/drug induced l Clinical onset sudden and varied l Marked increase in ALT/ALP, may or may not have elevation in bilirubin l Definitive diagnosis only obtained if exposure is known l Treatment is usually supportive, plus N- acetylcysteine in most cases l Prognosis varied, but often poor, especially in reported cases of Amanita intoxication
Infections of the Liver l Bacterial cholangiohepatitis is this a rare disease? l VERY limited data in veterinary literature l Enteric bacteria: Escherichia coli, Enterococcus spp., Bacteroides spp., Streptococcus spp., Clostridium spp. l 1/3 to ½ caused by >1 organism l Ideally antibiotic choice should be based on culture (pool samples from liver and gall bladder), but not always realistic
Leptospirosis l From wildlife reservoirs (and cats?) l Serovar specific for damage to liver l Necrosis, cholestasis, acute hepatitis l Diagnostic options: PCR, ELISA and MAT l Treatment: doxycycline (start with ampicillin if IV route needed), along with supportive care l Good prognosis if survive first few days l VACCINATE
Chronic hepatitis l Immune-mediated / Copper-associated l Middle aged dogs (3-7 yo) l Breed predisposition (Doberman Pinscher, Bedlington Terrier, Labrador Retriever, etc) l CH is a slow, insidious process with typically no clinical signs until late-stage l Ascites, hypoproteinemia, cachexia l Intermittent elevation in ALT long term l 90% have ALT 5-18 times normal
Chronic hepatitis l Liver biopsy with aerobic/anaerobic culture and copper quantification l Ultrasound-guided l Surgical (keyhole approach) l Laparoscopy l Can be difficult to convince owners to perform biopsy due to cost/invasiveness l Need to counsel owners about sequelae in untreated cases l cirrhosis, acquired shunts, ascites, cachexia
Chronic hepatitis - treatment l Early stage l anti-inflammatory (glucocorticoid, ~cyclosporine) l choleretic and anti-inflammatory (ursodiol) l anti-oxidant (same) l +/- copper-chelating agent l Late stage l diuretic (spironolactone) l +/- anti-fibrotic (colchicine) l supportive (antiemetic, appetite stimulant, etc) l low protein diet
Vascular disorders l Portosystemic shunt l Extrahepatic and intrahepatic l PSS are congenital, usually small breed dogs (other than intrahepatic shunts) l Many have no symptoms increased ALT found on pre-anesthetic blood work l Increased bile acids in almost all cases l There is an increased use of contrast CT/MRI over U/S
Vascular disorders l Surgery for extrahepatic PSS l Complication rate of 7-20% l Mortality rate of 0-17% l 94% of dogs have a good outcome l Medical management MST of 10 months l Microvascular dysplasia l Requires a biopsy for diagnosis l Supportive care such as anti-oxidant therapy l Usually a good long term prognosis
Neoplasia l Diffuse or multifocal l Lymphoma, histiocytic sarcoma l Solitary l Hepatoma l Hepatocellular carcinoma l Cholangiocarcinoma l Diffuse or solitary l Hemangiosarcoma
Neoplasia l Hepatoma surgery, excellent Px l Lymphoma chemotherapy, variable Px l Histiocytic sarcoma chemotherapy, poor Px l Hepatocellular carcinoma surgery and chemotherapy, very variable Px l Cholangiocarcinoma surgery and chemotherapy, poor Px l Hemangiosarcoma surgery and chemotherapy, poor Px
Questions?