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, anti-

fibrotic, 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?