Chronic Canine Liver Disease PDF VCS 846-1_2024

2/23/2024 Nolie Parnell, DVM, DACVIM VCS 84601 G132 [email protected]   Frequently encountered problem in practice Divided into several categories  Circulatory disorders  Congenital vascular disorders  Disorders associated with portal hypertension  Arteriovenous fistulas  Biliary Disorders...

2/23/2024 Nolie Parnell, DVM, DACVIM VCS 84601 G132 [email protected]   Frequently encountered problem in practice Divided into several categories  Circulatory disorders  Congenital vascular disorders  Disorders associated with portal hypertension  Arteriovenous fistulas  Biliary Disorders  Inflammation (cholangitis and cholangiohepatitis)  Biliary cystic disease  Diseases of the gallbladder 1 2/23/2024  Parenchymal Diseases  Reversible Injury  Vacuolar change  Steroid-induced hepatopathy (excessive glycogen accumulation)  Hepatic lipidosis      Acute and chronic hepatitis Hepatic abscesses and granulomas Hepatic metabolic storage disorders Liver is recipient of splanchnic venous outflow Exposed to inflammatory cytokines and endotoxin circulated from GI viscera  May culminate in mild hepatic injury associated with mild-modest infiltrates in portal, lobular, and centrilobular regions  No hepatocyte death  This condition is termed nonspecific reactive hepatopathy to systemic disease  It is not chronic hepatitis 2 2/23/2024  Is characterized by: hepatocellular apoptosis or necrosis  Variable mononuclear or mixed inflammatory infiltrate  Regeneration  Fibrosis    Activity of disease determined by amount of inflammation Stage of disease (and possibly prognosis) determined by extent of fibrosis and architectural distortion Pyogranulomatous inflammation (aggregates of macrophages and diffuse infiltration of neutrophils) Vet Clin NASAP 2009;39(3) Webster et al. JVIM 2019: (33);3 pp 113-1560 3 2/23/2024   Chronic hepatitis can occur in any breed or mixed breed but breed, age, and sex predispositions are considered risk factors Clinical signs in early CH are vague and nonspecific   ALT can be elevated for years prior to overt signs When overt signs develop, the often represent later stages  Common Clinical Signs         Decreased appetite Lethargy Icterus Ascites PU/PD Vomiting Diarrhea Hepatic encephalopathy 4 2/23/2024  Doberman Pinscher  Incidence 4-6% of doberman pinschers  Suggests genetic link  Begins in young dogs  1-3 years  Only  ALT    Clinical signs appear 4-7 y Cocker Spaniels Any breed can develop CH 5 2/23/2024   7 yr FS Cocker Spaniel Hx of intermittent inappetence and lethargy Owner brought Molly into office because lasted longer than 2 days   Increased ALT, ALP, and GGT Can wax and wane reflecting disease activity 600 500 mg/ dl  400 300 200 100 ALT ALP GGT 0 6 2/23/2024 Abdominal radiographs Microhepatica, ascites Can have normal hepatic size Abdominal Ultrasound Can be normal but the majority of exams are not Irregular surface margins, regenerative nodules, hyperechogenicity, acquired portosystemic shunts 7 2/23/2024  Sampling     The larger the sample the more accurate   Ultrasound-guided Laparoscopy Laparotomy May not be possible Characterization Mixed inflammatory cell infiltrates  Possible necrosis  Some degree of regeneration  If fibrosis present  Indicative of more severe, progressive disease  IMMUNE-MODULATING     Prednisone/prednisolone Cyclosporine Mycophenolate Azathioprine  HEPATIC SUPPORT     Denosyl Marin Marin Plus Denamarin Use with caution 8 2/23/2024 ANTI-FIBROTIC     Colchicine Prednisone Penicillamine Zinc MISCELLANEOUS   Vitamin E Ursodeoxycholic acid Cholerectic  Changes the bile acid pool  Possible antioxidant since has hepatoprotective effects    Antibiotics Diet 9 2/23/2024  Liver      Primary recipient of Cu Highest stored Cu content Delivers Cu in proteinbound form to other tissues Principal organ of excessive Cu elimination Occurs secondary to excessive Cu accumulation     uptake of Cu Primary defects in hepatic Cu metabolism Altered biliary excretion of Cu  2° inflammation  Toxicity is related to   Total concentration of Cu Hepatocellular location of molecules 10 2/23/2024  West Highland White Terriers Clinical signs appear between 3-7 years  Variable hepatic Cu accumulation   Not correlated with clinical signs  Affected dogs produced affected offspring DALMATIAN  All presented with GI signs  ALT >> ALP  Hepatic Cu concentrations similar to Bedlingtons LABRADOR RETRIEVER  Females most commonly affected  Diagnosis between 2-7 yrs  Seen within families 11 2/23/2024 DIAGNOSTIC CRITERIA    Histological evidence of CH associated with Cu accumulation centrilobular area Histochemical staining showing Cu accumulation in centrilobular areas Hepatic copper quantification > 1000 ug/g dry weigh liver CHALLENGES IN DX OF CUCH      Lobe to lobe variation Regenerative nodules have ↓ Cu accumulation Presence of significant fibrotic tissue ↓ Cu concentration Later stage changes + inexperienced pathologist “Gray Zone”: hepatic Cu concentrations 600-1000 ug/g dry weight liver Need biopsy FNA not adequate Differentiates chronic hepatitis from other chronic hepatopathies Documents the presence, severity and location of inflammation and necrosis Semiquantitative evaluation of Cu concentrations using rubeanic acidstained tissues 12 2/23/2024  Multimodal Approach     Dietary copper restriction Removal of Cu from the liver by chelation Antioxidant treatment Treatment response is highly patient dependent  Earlier the diagnosis better the prognosis  D-penicillamine  Cuprimine®  Greater affinity for tissue copper  GI intolerance- vomiting if given on empty stomach  Give with a small amount of food  Shown to effectively reduce hepatic Cu concentrations  Trientine dihydrochloride  Greater affinity for serum copper  Better GI tolerance Hoffman. JVIM 2006 13 2/23/2024  Copper-restricted diets    Challenge is finding a diet which is copperrestricted Do NOT restrict dietary protein unless the dog is encephalopathic     Has been shown to be effective in  hepatic copper concentrations Hyperammonemic Overt signs of dysfunction (ascites, hypoalbuminemic) Restricting protein prematurely will cause catabolism and prevent liver from regeneration If dietary protein restriction is not clinically indicated and restricted copper is…. Add protein to diet when using a prescription hepatic diet 14 2/23/2024  Dependent upon Stage of disease at time of diagnosis  Ascites negative prognostic indicator  Patient’s response to therapy   Survival times with a diagnosis of cirrhosis or lobular dissecting hepatitis is short   1-2 months (average, some patients do live much longer) Factors associated with poor prognosis Hyperbilirubinemia Prolonged PT and PTT  Hypoalbuminemia  Presence of ascites (either portal hypertension or ↓ colloid)  Degree of fibrosis on histopathology   15