Veterinary Hepatology Chapter 280

Hepatobiliary Disease

Roles of the Liver

• Immunoregulation
• Synthesis of clotting factors
• Storage of vitamins, trace minerals, glycogen, blood, triglycerides
• Detoxification of toxins
• Metabolism of carbs, proteins, lipids
• Liver has remarkable regenerative capacity after loss of functional tissue

Breed Predispositions

• Copper storage diseases: Labrador, Doberman, Dalmatian, Skye Terrier, West Highland White, Bedlington (COMMD1 mutation), Siamese cats
• Idiopathic chronic hepatitis: Labrador, Poodle, Doberman, American and English Cocker Spaniels, English Springer Spaniels
• Amyloidosis: Abyssinian, Oriental, Siamese cats and Shar-Pei dogs
• Congenital extrahepatic portosystemic shunts: Yorkie, Havanese, Pug, Maltese, mini Schnauzer
• Congenital intrahepatic portosystemic shunts: Irish Wolfhound, Labrador, Golden Retriever, Australian Shepherd
• Portal vein hypoplasia or microvascular dysplasia: Maltese, Yorkie, Cairn terrier
• Progressive vacuolar hepatopathy: Scottish Terrier

Physical Examination

• Clinical icterus when the bilirubin is above 3
• Icteric plasma can be noted with bilirubin 0.5-1.0
• Hepatocutaneous syndrome: form of superficial necrolytic dermatitis with hyperkeratosis and crusting of pawpads and mucocutaneous junctions
• Ascites: accumulation of free fluid in the abdomen, often due to portal hypertension or hypoalbuminemia

Portal Hypertension

• Classified based on anatomic location: prehepatic, intrahepatic, posthepatic
• Causes of portal hypertension: increased vascular resistance, obstruction, chronic hepatitis with fibrosis
• Portal hypertension can lead to development of multiple acquired portosystemic shunts (MAPSS)
• Prehepatic and presinusoidal PH result in low protein effusion (< 2.5g/dl), while sinusoidal, postsinusoidal or posthepatic PH have high protein values (> 2.5 g/dl)

Hepatic Encephalopathy

• Multifactorial pathogenesis, occurs when toxins derived from the GI tract accumulate
• Toxins include ammonia, aromatic amino acids, bile acids, endogenous benzodiazepines, gamma aminobutyric acid, glutamine, phenol, short chain fatty acids, tryptophan, and false neurotransmitters
• Acute HE is caused by fulminant liver failure
• Chronic HE is usually caused by MAPSS or congenital portosystemic shunt, less severe in cats
• Cats can develop chronic HE from hepatic lipidosis due to arginine depletion and ammonia accumulation

Laboratory Evaluation

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST): leakage enzymes that can become elevated with damage to hepatocyte membrane
• ALT: specific to liver, half-life 48-60 hours in dogs, 6 hours in cats
• AST: less specific, half-life 22 hours in dogs, 77 minutes in cats
• Alkaline phosphatase (ALP): cholestatic enzyme, attached to membranes by phosphatidylinositol linkages, low specificity for hepatobiliary disease
• Gamma-glutamyl transpeptidase (GGT): cholestatic enzyme, also bound to hepatocyte membrane, largely derived from the liver
• Liver function tests:
  • Hypoglycemia: loss of 75% of liver function, impaired glycogen stores and gluconeogenesis
  • Low blood urea nitrogen: shunting of blood around the liver, or liver failure and acquired shunts
  • Hypoalbuminemia: loss of 70% of liver function
  • Cholestatic disease: hypercholesterolemia
  • Bilirubin:
    • Hyperbilirubinemia: prehepatic (hemolysis), hepatic or posthepatic
    • Hyperbilirubinemia: cholestasis of sepsis, cytokines inhibit expression of hepatocyte transporters necessary for bilirubin transport
    • With bile duct obstruction, conjugated bilirubin in plasma binds irreversibly with albumin (delta bilirubin)
  • Bile acids:
    • Synthesized in the liver from cholesterol, excreted into the biliary tract and stored in the gallbladder
    • Reabsorbed in the ileum and transported back to the liver via the portal vein
    • Efficacy of enterohepatic circulation (EHC) can be estimated by measuring bile acids
  • Ammonia:
    • Accumulates due to action of colonic bacteria on ingested protein
    • Removed by the liver and converted to urea for excretion
    • Increases in ammonia only seen with portosystemic shunting or defects in the urea cycle
  • Coagulation proteins:
    • Liver produces all clotting factors except von Willebrand factor
    • Vitamin K dependent factors: II, VII, IX, X, protein C
    • Cholestasis can lead to impaired vitamin K absorption
    • Splanchnic pooling of blood can lead to thrombocytopenia
    • Diffuse liver disease can lead to hypofibrinogenemia
    • Some liver disease can lead to DIC

Imaging

• Radiography:
  • Liver enlargement if caudal margins extend beyond the ribs
  • Microhepatica if the gastric axis is displaced cranially
• Ultrasound:
  • Hyperechoic hepatomegaly: chronic hepatitis, corticosteroid hepatopathy, fat, vacuolar hepatopathy, toxic insult, lymphoma, phenobarbital
  • Hypoechoic hepatomegaly: acute hepatitis, lymphoma, cholangitis/cholangiohepatitis
  • Useful for assessment of extrahepatic biliary obstruction (EHBDO)
  • Portal vein:Ao ratio less than 0.65, urolithiasis, renomegaly, hepatofugal flow

Sampling

• Fine needle aspiration (FNA):
  • Minimally invasive, low risk of bleeding
  • High frequency of inaccurate results due to low cellularity
  • Useful for diagnosis of hepatic lipidosis
• Biopsy:
  • Can be obtained via needle biopsy, laparoscopically, or surgically
  • Left medial or lateral lobes usually accessible for ultrasound guided Tru Cut
  • Discordant results in 53% of dogs and 50% of cats when comparing ultrasound guided Tru Cut with surgical wedge biopsies

Cytoprotective Agents

• Liver is susceptible to oxidative damage
• Glutathione is an essential antioxidant stored in hepatocytes, synthesized from L-glutamate, L-cysteine, and glycine
• S-adenosyl methionine (SAMe) increases hepatic glutathione, has anti-oxidant and anti-inflammatory properties, and may be antiapoptotic and anti-carcinogenic
• N-acetylcysteine (NAC) helps replenish hepatic cysteine and glutathione levels, used for treatment of acetaminophen toxicity
• Silymarin scavenges free radicals, reduces lipid peroxidation, and may suppress TNFa, IL-1, and NFKB
• Vitamin E protects phospholipids from injury
• Ursodeoxycholic acid (ursodiol) has choleretic, cytoprotective, and immunomodulatory effects, including the suppression of IL-2

Anti-inflammatory and Immunosuppressive Drugs

• Prednisolone is used to treat dogs with severe liver disease, especially in cases of chronic hepatitis
• Autoimmunity may be a common cause of chronic hepatitis in certain breeds (e.g., Doberman, English Springer Spaniel)
• Prednisolone is often used to treat cats with lymphocytic cholangitis and chronic neutrophilic cholangitis
• Azathioprine is a purine analog that can be used in dogs with chronic hepatitis
• Cyclosporine is a T-cell inhibitor that has been used with some success in chronic hepatitis

Medications for Treating Hepatic Copper Accumulation

• D-penicillamine is a chelating agent that combines with copper, allowing it to be mobilized from the liver and excreted in the urine
• Trientine is a chelating agent that causes increased urinary excretion of copper
• Zinc decreases absorption of copper from the GI tract and induces increased synthesis of metallothionein
• Copper accumulation is an important cause of chronic hepatitis in dogs, and sections of liver should be routinely stained for copper

Hepatic Encephalopathy

• Consider a commercial, lower protein diet
• Protein restriction is contraindicated in cats due to high requirement
• Lactulose is an osmotic laxative used to treat hepatic encephalopathy
• Neomycin is a poorly absorbed aminoglycoside antibiotic used to treat hepatic encephalopathy
• Metronidazole is used to treat hepatic encephalopathy

Hepatic Fibrosis

• There are no proven treatments for hepatic fibrosis
• Chronic inflammation leads to activation of myofibroblasts, including hepatic stellate cells and portal fibroblasts
• Treat underlying inflammation to prevent additional fibrosis
• ARB losartan has shown promising antifibrotic effects in rats

Ascites

• Spironolactone is the diuretic of choice, as furosemide can lead to hypovolemia, hypokalemia, and hypochloremic alkalosis, which can precipitate HE

Cytoprotective Agents

• Liver is susceptible to oxidative damage
• Glutathione is an essential antioxidant stored in hepatocytes, synthesized from L-glutamate, L-cysteine, and glycine
• S-adenosyl methionine (SAMe) increases hepatic glutathione, has anti-oxidant and anti-inflammatory properties, and may be antiapoptotic and anti-carcinogenic
• N-acetylcysteine (NAC) helps replenish hepatic cysteine and glutathione levels, used for treatment of acetaminophen toxicity
• Silymarin scavenges free radicals, reduces lipid peroxidation, and may suppress TNFa, IL-1, and NFKB
• Vitamin E protects phospholipids from injury
• Ursodeoxycholic acid (ursodiol) has choleretic, cytoprotective, and immunomodulatory effects, including the suppression of IL-2

Anti-inflammatory and Immunosuppressive Drugs

• Prednisolone is used to treat dogs with severe liver disease, especially in cases of chronic hepatitis
• Autoimmunity may be a common cause of chronic hepatitis in certain breeds (e.g., Doberman, English Springer Spaniel)
• Prednisolone is often used to treat cats with lymphocytic cholangitis and chronic neutrophilic cholangitis
• Azathioprine is a purine analog that can be used in dogs with chronic hepatitis
• Cyclosporine is a T-cell inhibitor that has been used with some success in chronic hepatitis

Medications for Treating Hepatic Copper Accumulation

• D-penicillamine is a chelating agent that combines with copper, allowing it to be mobilized from the liver and excreted in the urine
• Trientine is a chelating agent that causes increased urinary excretion of copper
• Zinc decreases absorption of copper from the GI tract and induces increased synthesis of metallothionein
• Copper accumulation is an important cause of chronic hepatitis in dogs, and sections of liver should be routinely stained for copper

Hepatic Encephalopathy

• Consider a commercial, lower protein diet
• Protein restriction is contraindicated in cats due to high requirement
• Lactulose is an osmotic laxative used to treat hepatic encephalopathy
• Neomycin is a poorly absorbed aminoglycoside antibiotic used to treat hepatic encephalopathy
• Metronidazole is used to treat hepatic encephalopathy

Hepatic Fibrosis

• There are no proven treatments for hepatic fibrosis
• Chronic inflammation leads to activation of myofibroblasts, including hepatic stellate cells and portal fibroblasts
• Treat underlying inflammation to prevent additional fibrosis
• ARB losartan has shown promising antifibrotic effects in rats

Ascites

• Spironolactone is the diuretic of choice, as furosemide can lead to hypovolemia, hypokalemia, and hypochloremic alkalosis, which can precipitate HE