Severe Liver Disease Ronald S. Walton DVM, MS Diplomate ACVIM and ACVECC Puget Sound Veterinary Referral Center Tacoma, Washington USA Does this patient have liver disease? Does this patient have liver disease? Does this patient have liver disease? Does this patient have liver disease? Does this patient have liver disease? Does this patient have liver disease? They all do Outline ► Introduction ► Etiology ► Pathogenesis ► Diagnostic Evaluation Plan ► Treatment ► Prognosis ► Focus is Acute Liver Failure (ALF) and injury Introduction ► Liver is the metabolic center piece of normal homeostatic mechanisms in the body ► Pivotal Roles Protein, carbohydrate and fat metabolism Detoxification Formation of most coagulation factors ► Many integral and central actions to normal body function no single test = liver failure ► Large reserve capacity and remarkable regenerative capability Background ► Study of 50 dogs with liver failure 22 breeds Median age was 6 years (1m-13yr) Presenting signs ►Anorexia ►Vomiting ►Polydipsia ►Neurologic signs initial 6/50 Progression to Hepatic Encephalopathy 21/50 ► ACVIM 2011 Background ► Common Clinicopathologic Abnormalities Increased bilirubin 47/48 Increased ALP 45/48 Increased ALT 42/48 Increased PT/aPTT 36/39 Decreased platelets 36/48 Decreased albumin 27/48 ACVIM 2011 Background ► Defined etiology with hepatic biopsy16/32 Neoplasia 12/32 Infarction 2/32 Congenital PSS 1/32 Hepatic Lipidosis 1/32 ► Defined etiology with serology or history Leptospirosis 6/50 Drug toxicity 3/50 Mushroom toxicity 1/50 ACVIM 2011 Background ► Secondary complications Ascites (6/50) DIC (6/50) Renal failure (5/ 50) PTE (2/50) Hemoabdomen (2/50). ACVIM 2011 Background ► Only 7 dogs survived to discharge. ACVIM 2011 Introduction ► Acute Liver failure (True Emergency) rapid functional impairment unable to perform its synthetic and excretory homeostatic roles Often without prior evidence or history of liver disease Clinical outcome of ALF often depends on rapid and aggressive supportive care Introduction ► Chronic Liver Failure associated with irreversible changes that have accumulated over months to years regenerative capacity is often exhausted before clinical signs are evident Introduction ►Basic Premis Regardless of the etiology and pathogenesis: ►Similar supportive/symptomatic therapy is indicated until a final diagnosis can be reached ►The diagnosis and etiology may take several days and require a hepatic biopsy to determine a definitive diagnosis. Etiology ► Infectious Agents Viral (CAV I, FIP) Bacterial (Leptosporosis, Bacillus, Clostridial) Fungal (Histoplasmosis) Protozoal ►(Toxoplasmosis, Cytauxzoonosis) Babesiosis and Etiology ► Chemical and pharmaceutical agents Acetaminophen/ Diazepam – cat Carprofen/ Thiacetarsemide-dog ►Drug induced idiosyncratic reaction primary cause in people ► Infiltrative Disease (Neoplasia , inflammatory cells or lipid) Etiology ► Ischemia and Hypoxic Injury Severe shock, right-sided heart failure, thrombosis, neoplasia, trauma and vascular anomalies ► Metabolic Copper storage disease and hepatic lipidosis ► Anatomic Variants Portosystemic shunting of blood via either congenital or acquired vascular connection(s) ►portal and systemic circulations Pathogenesis ► Hepatic response to injury Hypoxia Free radical exposure or generation Membrane lipid peroxidation, Depletion of essential intracellular compounds Intracellular toxin production Toxin binding to DNA and RNA Cholestatic injury Direct effects on hepatobiliary system ►Endotoxin, viral, parasitic, and immune complexes Pathogenesis ► Hepatic Dysfunction Carbohydrate, lipid , cholesterol, nitrogen and protein metabolism Microsomal enzyme system (P450) Hepatic Encephalopathy (HE) * Cerebral Edema * Coagulopathy * Bilirubin metabolism and jaundice Portal hypertension and ascites Hepatorenal syndrome Diagnostic Evaluation Plan ► History Typically vague and shares a commonality with many disease processes Much of the reserve capacity of the liver lost before signs or symptoms Longstanding but, unrecognized disease process Known hepatotoxins Thermal or traumatic injury Diagnostic Evaluation Plan Clinical Signs and Physical exam General ► ► ► ► ► ► ► ► ► Anorexia Depression Weight loss Small stature for breed Poor hair coat Nausea Vomiting Diarrhea Dehydration Diagnostic Evaluation Plan More specific (not pathognomonic) ►Abdominal enlargement ►Hepatodyna ► Jaundice ► Acholic feces ► Behavioral changes and signs of HE (circling, ataxia, pacing, head pressing, blindness, salivation, tremors, seizures, coma) ► Coagulopathy ► Pu/Pd Diagnostic Evaluation Plan ► Clinpath Findings: Hematology (anemia, microcytosois {PSS}, target cells, acanthocytes, leukocytosis to leukopenia, platelets variable Biochemical Testing: ► Liver Enzymes * ( ALT and AST, ALKP, GGT) ► Hepatic Function Testing (SBA, and ATT) ► Other( TBili, Alb, Glob, BUN, Glucose, Chol, Lytes Urinalysis ► Low USG, Ammonium Biurate/Bilirubin Crystals, Bilirubin, Urobilinogen absence Coagulation Testing ► (PT, APTT, ACT) Diagnostic Evaluation Plan ► Imaging Radiology ►Evaluate liver size and tissue characteristics and to detect abdominal effusion ►Normal to large liver size (acute processes) ►Microhepatica (chronic hepatic disease) Diagnostic Evaluation Plan Ultrasound ►Noninvasively assess focal or generalized parenchymal abnormalities, mass lesions, gallbladder and biliary tract, and vascular lesions Diagnostic Evaluation Plan Additional ►Abdominocentesis ►Serology Diagnostic Evaluation Plan Biopsy (Definitive) ►Fine needle aspirate (FNA): ►Percutaneous needle biopsy ►Laparoscopy ►Exploratory laparotomy Treatment ► Symptomatic ► General Support Major organ systems Fluid, Electrolyte and Acid-Base Balance Hepatoencephalopathy (HE) * Cerebral edema * Hemorrhage and anemia * Ascites * Infection and endotoxemia Nutritional Treatment ► Prevent Formation and Absorption of Enteric Toxins Critical Patient/Hepatic Coma: ► Cleansing enema with warm H2O until clear effluent ► Retention enemas Povidone iodine solution (1:10 dilution with water) leave in 10 minutes then flush with water ► 30% lactulose solution (5-10ml/kg) mixed with neomycin at 22-mg/kg leave for 20-30minutes Treatment ► Prevent formation and absorption of enteric toxins Maintenance therapy: ►Metronidazole (7.5mg/kg q 12hr PO) ►Amoxicillin (22 mg/kg q 12hr PO) ►Neomycin (22mg/kg q 8-12 hr PO) ►Lactulose (0.25 to 0.5 ml/kg q 8-12 hr PO) ►IV Fluids (0.45% NaCl + 2.5% Dextrose) Avoid alkalinizing solutions (esp. lactate) Treatment ► Control GI Hemorrhage Treat GI Ulceration ►Famotidine (0.5-1.0mg/kg q 12-24 hr PO ►Carafate (1g/25kg q 8 hr PO) Correct Coagulopathy ►Vit K1 (1.5-2 mg/kg q 12 hr SC or IM ►Fresh plasma ►Whole blood transfusion ►D/C Glucocorticoids, aspirin and NSAIDs Treatment ► Control Seizures Keppra ( levetiracetam) ► (20 mg/kg IV) ► Oral follow-up 20 mg/kg tid Refractory seizures/status epilepticus ► use general anesthesia with propofol ► mechanical ventilation ► maintain normal PaO2 and PaCO2. Avoid benzodiazepines ► (Flumazenil 0.02 mg/kg?) Treatment ► Decrease cerebral edema Mannitol (0.5-1.0 gm/kg IV) followed by Furosemide (1-2 mg/kg q 12 hr) Treatment ► Nutritional Support Initial NPO for HE Long term management ► Easily digested high carbohydrate diet. Moderate protein restriction on a dry matter basis to 18-22% for dogs and 30-35% for cats. ► Protein source should be dairy or vegetable source High BCAA to AAA ratio ► Sodium restriction ► Multi-vitamin supplement, high in B-vitamins ► Soluble dietary fiber (psyllium mucolloid 1-3 tsp./day) Treatment ► Prevent and Control Hypoglycemia Severe hypoglycemia ►Administer 50% dextrose IV (0.5-1.0ml/kg diluted in sterile water to 20-25% solution ►Add dextrose to IV fluids as needed (2-5%) to maintain adequate blood glucose levels Directed Treatment for Acute Hepatic Injury ► Hepatic Ischemic Injury Ensure adequate volume support Ensure adequate O2 delivery Fresh transfusion with whole blood or packed RBC’s and supplemental oxygen as needed Ensure eugylcemia Glucocorticoids (hydrocortisone sodium succinate 30-100mg/kg) Directed Treatment for Acute Hepatic Injury ► Hepatic Oxidative Injury (Specific Toxin) Acetaminophen toxicity ►N-Acetylcystine (140mg/kg IV loading dose and subsequent doses of 70-140 mg/kg IV or PO q 6 hrs.) ►Cimetidine 5 mg/kg IV or PO for duration of NAcetylcystine Therapy Directed Treatment for Acute Hepatic Injury ► Hepatic Oxidative Injury (Specific Toxin) Amanita Mushroom Intoxication ►Gastric decontamination if acute ingestion ►Dexamethasone (0.3-0.5 mg/kg q 1hr IV) ►Penicillin G 250 mg/kg day Silymarin/Silbinin Legalon® SIL 5mg/kg loading then CRI 20 mg/kg/day (still in clinical trials) Directed Treatment for Acute Hepatic Injury ► Hepatic Oxidative Injury (General or Suspected Toxin non-specific injury) Cimetidine 5 mg/kg IV (only if blocking P-450 enzyme system indicated S-Adenosyl-Methionine SAM-e Denosyl® 20 mg/kg/ day Directed Treatment for Acute Hepatic Injury Silymarin/Silbinin Legalon® SIL 5mg/kg loading then CRI 20 mg/kg/day (still in clinical trials) ?? ►Oral 50-250 mg per day Vitamin E 100-400 IU PO /day Ursodeoxycholic acid (10-15 mg/kg q 24 hr PO) Prognosis ► Variable ► Keys to improvement Rapid recognition Aggressive therapeutic support (HE, Cerebral Edema, Coagulopathy) Degree of damage Remaining regenerative ability ► Acute presentation of CHF uniformly poor ► Biopsy is the key Summary ► Strategies to increase survival in ALF are urgently needed ACVIM 2011 Questions