Canine Chronic Idiopathic Hepatitis David C. Twedt DVM, DACVIM Problem Acute Rt rear leg lameness History Probably stepped on by owner s horse Healthy otherwise No medications Physical exam Possible partial ACL tear Otherwise normal Plan: Conservative management NSAIDs Limit exercise Minimum data base before NSAID therapy CBC Biochemical profile Urinalysis ALT 579 (N< 11) AST 69 (N< 5) ALP 435 (N<14) T. Bili.2 Albumin 3.1 BUN 23 Glucose 12 Cholesterol 167 Plan: No NSAID Rx Cosequin Limit exercise Go to CSU and see what they say about liver enzymes CSU evaluation approximately 1 month later No longer lame Doing great Lab abnormalities: ALT 687 (N< 11) AST 83 (N< 5) ALP 469 (N<14) 1
ABNORMAL LIVER ENZYMES Asymptomatic Consider antibiotics +/- liver support Repeat liver enzymes in 1-2 months and/or bile acids If abnormal Look for a primary non-hepatic disease or drug history Re-evaluate liver Treat primary non-hepatic disease Symptomatic Obvious primary liver disease Work up the liver Diagnostics performed: Bile acids: (N<2) pre 48 µmol/l post 87 µmol/l US - patchy hyper - hypoechoic liver Coagulation profile-wnl Laparoscopic Liver biopsy Liver surface had an irregular appearance 4 biopsies taken Biopsy: Chronic hepatitis Copper 373 µg/g (N<4) Histology Hepatitis, chronic marked and diffuse. Individual cell necrosis and portal fibrosis Incidence of Liver Disease in 15 Liver Biopsies Acute hepatopathy Vacuolar hepatopathy Reactive hepatopathy (usually secondary) Chronic hepatitiscirrhosis Hepatic neoplasia 79% of Biopsies Review of 15 Consecutive Liver Biopsies at CSU 23% Chronic Hepatitis - Cirrhosis n = 35 2
22/9/15 Immune Mediated Mechanism of CH Chronic Hepatitis Known etiology: Hepatocyte insult: virus, toxin,other Cytotoxic Lmphocytes Copper Infectious Leptospirosis, others? ICH adenovirus, others? Drugs (phenobarbital, NSAIDs?) Genetic Unknown etiology: Idiopathic (immune-mediated?) Chronic Hepatitis Breed Predisposition: Doberman pinscher Bedlington terrier Dalmatian West Highland White terrier Labrador retriever Cocker spaniel Standard poodle Scottish terrier? English Springer spaniel Antibodies Injury Immunocyte Antigen Release Macrophage Processing Diagnosis of Affected Dogs Serum copper - No Histochemical stains Copper quantitation Normal < 4 µg/g Rhodanine Stain 3-5 mm fresh sample Place in copper free container Paraffin embedded histo samples CSU Diagnostic Lab Paraffin block * Andersson JSAP 32: 1991 Back to Hattie and Idiopathic CH Biopsy: Chronic hepatitis Copper 373 µg/g (N<4) CH - Clinical Features n=35 Age # 4 to 11 years Dogs Mean 7.5 years 8 6 4 2 Sex Females > males (6/4) 1 2 3 4 5 6 7 8 9 1 11 12 13 Age Distribution n=35 Hattie 6 year S/F 3
Laboratory vs Clinical Signs Severity Normal No Clinical Signs Laboratory Values Clinical Signs Chronic Hepatitis Cirrhosis End Stage Laboratory Progression in CH Variation From Normal Clinical Signs Normal Bile Acids ALT / AST Bilirubin Clotting ALP Times GGT NH3 Albumin Chronic Hepatitis Cirrhosis End Stage Glucose BUN Prognosis for CH Early diagnosis improves prognosis Guarded with secondary 4! complications : 3! 2! HE 1! Ascites! GI ulceration Hypoalbuminemia Clotting abnormalities Months Cirrhosis Sevelius: JSAP 36:1995 Raffan: JVIM 23:29 CH & Fibrosis Early CH The Four Goals Liver Therapy Treat 1 o Etiology Specific Therapy Liver Disease Diet Hepatic Support Hepatic Disease Palatability is important Meet caloric needs Protein restriction Adequate protein is essential, restriction only with protein intolerance Feed balanced moderate protein diet Low copper diets RC Hepatic Hills l/d Diet Specific Therapy Basis of Therapy Inflammation Copper Fibrosis Cholestasis Infection 4
Corticosteroids and CH Positive benefits Antiinflammatory Choleretic Inhibits fibrosis Improves appetite Negative aspects Steroid hepatopathy Sodium & water retention Precipitate early death Chronic Hepatitis Survival (95 Dogs) % Alive 12 1 8 6 Mean Survival Steroids: 33 months No steroids: 19 months Could the ~ 25% having a prolonged survival have immune mediated disease? 4 Steroid Treated 2 No Steroids 2.5 5 7.5 1 12.5 15 17.5 2 22.5 25 Strombeck: JAVMA 193: 1988 Months Glucocorticoid Therapy Prednisolone 1 to 2 mg / kg / day Taper to 1-.5 mg / kg EOD >25 kg bw use 25-5 mg/m 2 / day Many questions: Length of treatment? Is therapy effective? Duration ~ 6 months Re-biopsy Or stop Rx and evaluate in ALT 1-2 mos Therapy started Prednisolone Ursodiol Silybin with vitamin E 16 14 12 1 8 6 4 2 ALP AST Day 1 7 11 24 Mos Prednisolone UDC Marin Cyclosporine ALT 16 12 8 4 Day 1 7 11 24 Mos 27 Prednisolone Cyclosporine UDCA Silybin ALP ALT AST 5
16 12 8 4 Prednisone Cyclosporine UDCA Silybin Day 1 7 11 24 Mos 27 28 39 43 ALP ALT AST 52 63 Mos Hattie 11.5 year S/F Mix breed Cyclosporine reduced to 5 mg/kg/day then q 48h then off cyclosporine at 5 months Continued on antioxidant therapy Died of unrelated causes at 13 years of age; no active hepatitis Cyclosporine Therapy for Chronic Hepatitis (n=13) ALT values decreased by 71% 7/8 patients with hyperbilirubinemia and/or ascites prior to treatment resolved JVIM 25:74,211 Cyclosporine 5 mg/kg q12h Cyclosporine Facts Mode of action T lymphocyte function Starting dose 5 mg/kg bid Types (pharmacokinetics) AB1= Neoral = Atopica= modified generic (microemulsion) AB2= Sandimmune = nonmodified generic Common side effects GI signs try freezing caps Gingival hyperplasia Bile Acids Cause Liver Damage Concentrations increase in disease Most are hydrophobic bile acids Membrane detergents Hydrophilic good bile acid Ursodeoxycholic acid Ursodiol: 1-15 mg/kg day Protective properties Asian Sun Bear Urosdeoxycholic Acid Hepatoprotective Antioxidant Choleresis Antiinflammatory Immune modulation 6
Urosdeoxycholic Acid Chronic hepatitis Feline cholangitis Other cholestatic liver disease Not cholelithiasis Mucocele? Hepatic Copper Chelators Chelator Penicillamine 1-15 mg / kg BID Renal Excretion Hepatocyte Copper Kupffer Cell Function In Preventing Portal Derived Infections Kupffer cells clear portal bacteria Altered Kupffer cell function could increase the risk of bacterial colonization ~1/3 liver /bile cultures positive in case series ACVIM Abstract 25 Antibiotics? Amoxicillin Amoxicillin clavulanic acid Cephalosporins Metronidazole Immunosuppressive activity? Both renal & hepatic metabolism Antibiotics indicated in feline cholangitis 7.5-1 mg/kg BID Hepatic Fibrosis Hepatic Fibrosis Treat the Inflammation Stellate Cell Inflammatory Cytokines Collagen deposition Sinusoid Hepatocyte Fibrosis becomes a diffusion barrier to normal hepatocyte function 7
Hepatic Fibrosis Antifibrotic activity? Antiinflammatory Rx Colchicine? Angiotensin II (AT II) receptor blocker AT II induces stellate cells and TGF-β Losartan (Zestril.25-.5 mg/kg q 24 h) Hepatology. 21;34:4, 745. Hepatic Support Hepatic Support Provides hepatic protection and an environment conducive for optimal hepatic and antioxidant function Evidence of possible benefit: Vitamin E Silybin SAMe Copper chelator therapy Anti-inflammatory therapy Good Diet Hepatitis Vitamin E 2-3 week Antibiotic trial Antioxidants: Ursodiol, SAMe &/or Silybin 8