Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Doc, does my pet really need all these medications to treat his liver disease? Lisa Carioto, DVM, DVSc, Diplomate ACVIM 1 What prompted me to choose such a title for this presentation? 2 Cody • Treatments Mitotane (Lysodren®) Vitamin E 200 IU per day Vitamin B50 complex 50 mg PO q12h Silymarin (Milk thistle) 175 mg PO q24h SAMe (Denosyl®) 90 mg PO q12h Omega-3 fatty acids 1 capsule PO q24h 3 Objectives • Hepatic disease and the multitude of treatments that exist • Case studies 4 Taz • 3 year old MN Havanese • Referred for Persistent ↑ of ALT ↑ of serum bile acids (SBA) 5 Taz - History • At 1 year of age Pre-anaesthetic blood work ALT: elevated (result not available) • At 2 years, 2 months Ocular discharge and excessive licking of paws ALT: 240 (10 - 100 U/L) 6 Taz - History • At 2 years, 6 months Vomiting and diarrhea / hematochezia ALT : 147 (10 - 100 U/L) Metronidazole x 4 days • 1 month post vomiting and diarrhea episode SBA Pre: Post: 7 2.0 74.0 (0 - 6 umol/L) (0 - 15 umol/L) Taz - History • Presumptive diagnosis of atopy +/or food allergy Severe pruritus, worse during summer Elimination diet initiated 1 week prior to referral Duck and sweet potato Multiple vitamin • Only pet in the house • Vaccines current • No history of medications 8 Interpretation of Laboratory Results • Hepatocellular damage ALT (alanine aminotransferase) ALT (aspartate aminotransferase) • Cholestasis Bilirubine ALP (alcaline phosphatase) GGT (gamma glutamyl transferase) • Induction of ALP due to medications Glucocorticoids, phenobarbital 9 Taz – Physical Exam • 8,3 kg; body condition score 3/5 • BAR, active • No abnormal findings (NAF) other than ptyalism Secondary to nausea due to transportation 10 Taz – Diagnostic Procedures • CBC • Serum biochemical profile • Urinalysis • Abdominal ultrasound 11 Taz – Diagnostic Procedures • CBF: NAF • Serum biochemical profile ALT 64 U/L (4,0 – 62 U/L) • Urinalysis (cystocentesis) pH 8 DU 1,047 12 Taz – Abdominal ultrasound • Moderate microhepatica • Atypical bifurcation of the portal vein adjacent to the hepatic parenchyma? • Excessive panting • Gas in GI tract • CT or spleno-portogram recommended 13 Taz – Recommendations • Active hepatic damage suspected • +/- porto-systemic shunt (PSS) • Owner hesitant to pursue further work-up... • Re-evaluate hepatic profile and SBA in 2-3 months • 6 months later (rDVM) SBA still elevated Pre: Post: 14 3,0 69,0 (0 - 6 umol/L) (0 - 15 umol/L) Taz – 6 months later (FMV) • NAF on PE • Serum biochemical profile ALT 41 U/L (4,0 – 62 U/L) • Partial abdominal ultrasound of liver Moderate microhepathica still present No evidence of PSS • How can one explain the microhepatica? 15 Taz - Differential Diagnoses • Porto-systemic shunt (PSS) Congenital (breed predisposition) Acquired • Hepatic portal venous hypoplasia Previously known as microvascular dysplasia Microscopic shunts (breed predisposition) 16 Taz - Differential Diagnoses • History of an insult Toxic? Viral? Bacterial? Immune-mediated (hepatitis) with 2° fibrosis? Formerly chronic-active/idiopathic hepatitis Familial hepatitis Copper accumulation 17 Taz - Differential Diagnoses • Reactive hepatopathy Extra-hepatic disease responsable of the increased liver enzymes IBD, pyelonephritis, pancreatits, etc. • Others Bone disease, growth (dogs), drugs, etc. 18 Taz - Other diagnostic tests? • CT scan No evidence of a PSS • Aerobic and anaerobic culture: No growth • Copper level: 98 ppm (30-100) • Hepatic biopsy Early stages “lobular dissecting fibrosis” of unknown etiology 19 Taz - Treatment • SAMe 200 mg PO once a day and • Silymarin/silybin 20 – 50 mg/kg PO per day or • Zentonil® Advanced (Vetoquinol) 200 mg PO/day • Denamarin® (Nutramax) in US 20 Treatments for Hepatic Disease 21 21 Immunosuppressive Treatments Prednisone/Prednisolone • Anti-inflammatory • Immunosuppressive agent • Anti-fibrotic • Choleretic • Indication Chronic hepatitis with mononuclear inflammation, without evidence of infection 22 Immunosuppressive Treatments Prednisone/Prednisolone • Cats must metabolise prednisone to prednisolone • Limited oral bioavailability in cats (Center, ACVIM 2010) • Prednisolone at 1-2 mg/kg PO per day (ideal BW) • Gradual weaning q2 weeks • Minimum effective dose (ex. q 48h) for 2-3 months … 23 Immunosuppressive Treatments Prednisone/Prednisolone • Some animals require steroids for 6 months to 1 year or possibly life long, depending upon the underlying cause of the inflammation • Steroids will increase liver enzyme activities in dogs Difficult to determine efficacy of treatment 24 Other Immunosuppressive Agents • Second medication added to prednisone if necessary • Goal Steroid sparing effect 25 Other Immunosuppressive Agents • Azathioprine (Imuran®) – dogs only 2 mg/kg or 50 mg/m2 PO q24h x 7 days, then q48h Gastroenteritis, idiosyncratic hepatotoxicity, pancreatitis, myelosuppression • Chlorambucil (Leukeran®) 1.5 mg/m2 PO q48h (cats) • Cyclosporine 3-5 mg/kg PO q12h • Methotrexate low dose (cats) Efficacy? 26 Treatments - Anti-fibrotics • Prednisone/prednisolone • Silymarin/silybin (Silybum marianum) Milk thistle • S-adenosylmethionine (SAMe) • Zinc • Colchicine 27 Hepatoprotectors • SAMe • Silymarin (milk thistle) • Vitamin E • Taurine • L-carnitine 28 Hepatoprotectors S-adenosylmethionine (SAMe) • Natural metabolite of hepatocytes • Decreased SAMe-synthetase enzyme during liver disease contributes to a decrease in SAMe and glutathion • Precursor of glutathion The most important antioxidant 29 Hepatoprotectors - SAMe • Most important methyl donor of cellular metabolism • Transmethylation Regulates the plasticity of cellular membranes and reinforces their integrity • Transsulfuration Glutathione production 30 Hepatoprotectors - SAMe • Anti-oxydant Helps prevent accumulation of free radicals by increasing hepatic glutathione levels in dogs and cats • Stabilization of the cell membrane function and improves fluidity of hepatocytes Improvement in the conjugation of SBA ↑ flow of bile 31 Hepatoprotectors - SAMe • Modulation of cytokine expression • Improves cellular regeneration • Anti-apoptotic effect in normal cells • Anti-fibrotic? • Anti-neoplastic (hepatocellular carcinoma) Mice, in vitro human hepatic cells 32 Hepatoprotectors - SAMe • Crosses BBB sensation of well being Anti-depressant in humans Treatment of cognitive dysfunction Rème CA et al. Veterinary Therapeutics, summer 2008 - Double blinded study - SAMe (Novifit® - Virbac) was more efficacious than placebo in increasing activity level, interest and therefore quality of life in older dogs 33 Hepatoprotectors - SAMe • Denosyl® SD4 (Nutramax) • Zentonil™ (Vetoquinol) • Do not crush, chew or divide the tablets as will affect bioavailability of product • Question of owner compliance 34 Hepatoprotectors - SAMe • Zentonil™ remplaced by • Zentonil® Plus and Zentonil® Advanced Microencapsulation technology allows one to divide, crush or chew tablets without affecting the bioavailability of SAMe Palatable – meat flavor, vegetable origine Rare side effects Vomiting, cramps, diarrhea 35 Hepatoprotectors - SAMe Zentonil® Plus • SAMe • 200 mg, 400 mg Zentonil® Advanced • SAMe + Silymarin/silybin complexed with phosphatidylcholine • 100 mg + 25 mg • 200 mg + 50 mg • 400 mg + 100 mg 36 Hepatoprotectors – Silymarine/Silybine • Silybum marianum (milk thistle) • Silymarin Collective name of 3 flavonoids that comprise the active ingredients of milk thistle • Silybin The most biologically active of the three flavonoids 37 Hepatoprotectors – Silymarine/Silybine • Hepatoprotective properties of silybin are well documented Anti-oxydant Free radical scavenger Regulator of intracellular concentrations of glutathione Anti-inflammatory Immuno-modulator 38 Hepatoprotectors – Silymarine/Silybine • Modification and reinforcement of external cellular membranes of hepatocytes in order to prevent the entrance of hepatotoxic agents Toxicity studies using Amanita phalloid mushroom and acetaminophen 39 Hepatoprotectors – Silymarine/Silybine • Increased solubility of bile • Anti-fibrotic Inhibits the transformation of Kupffer cells (stellate hepatocytes) into myofibroblasts • Stimulates hepatocyte regeneration Promoter of ribosomal RNA synthesis 40 Hepatoprotectors – Silymarine/Silybine • Oral absorption and bioavailability of silybin are improved significantly when complexed with phosphatidylcholine • No side effects documented 41 Hepatoprotectors – Silymarine/Silybine • Use of human supplements Concerns regarding Quality control Appropriate dose in dogs and cats? • Zentonil® Advanced (Vetoquinol) specifically developped for the veterinary market Therapeutic dose 5-10 mg/kg/day 42 Hepatoprotector - Vitamin E • Alpha-tocopherol • Anti-oxidant • Protect against different types of membrane peroxidation • Anti-inflammatory effect • Anti-fibrotic? • Dogs and cats 10 - 15 UI/kg PO per day 43 Hepatoprotectors • Vitamins B1, B2, B5, B6, B12 Multiple roles in hepatic metabolism Ex.: Cofactors, coenzymes, etc. • Omega-3s Anti-inflammatory AEP: 40 mg/kg/day ADH: 25 mg/kg/day 44 Hepatoprotector Ursodeoxycholic acid (Ursodiol®) • Natural BA • Choleretic Stimulates bile flow Medical management of sludge and mucocoeles • Changes the bile acid pool to a less hepatotoxic form • Anti-apoptosis, anti-oxidant, stabilizes mitochondriae, anti-inflammatory, immune-modulator 45 Hepatoprotector Ursodeoxycholic acid (Ursodiol®) • 10-15 mg/kg PO per day, divided BID (chiens et chats) • Give with food • Contraindication Biliary obstruction • Therapeutic effect of UA is increased by the concurrent administration of SAMe Synergistic vs additive? 46 Treatments – Copper Chelators (dogs) • 2,2,2-tetramine = Trientine HCl (Syprine®) • D-penicillamine • Zinc acetate 47 Treatments - Antibiotics Indications • Biliary infection or hepatic parenchyma Neutrophilic leucocytosis, left shift, toxic/degenerative changes • Fever • Suppurative inflammation on histopathology • Hepatic encephalopathy ↓ the population of colonic bacteria, therefore ↓ ammonia production 48 Treatments - Antibiotics • E. coli, Enterococcus, Clostridium, Staphylococcus, Streptococcus, Klebsiella, Clostridium, Bacteroides • Ampicillin ou amoxicillin • Amoxicillin/clavulanic acid Clavaseptin®, Clavamox® • Metronidazole Decreases anaerobic bacteria Metabolized by the liver, therefore use 25-50% of the standard dose 7,5 mg/kg PO q12h 49 Treatments - Antibiotics • Neomycin Prevents the conversion of glutamine to ammonia by the enterocyte Not systemically absorbed 22 mg/kg PO q12h • Cepalosporins (cephalexin (PO), cefazolin (IV)) • +/- Fluoroquinolone 50 Treatments - Diet One must differentiate between hepatic disease and hepaætic insufficiency 51 Treatments - Diet • Hepatic disease Elevation of enzyme activities, but hepatic function is adequate Urea, albumin, glucose within normal limits It is therefore NOT necessary to use a protein – restricted diet, however high quality protein diet is required >14% of daily caloric requirements, ideally >20% • Protein restriction only if signs of HE 52 Treatments - Diet • Rich in soluble fibre To ↓ the availability and production of ammonia at the level of the intestine To bind noxious bile acids, endotoxins, etc. • Rich in vitamin B complex 53 Treatments - Diet • Supplemented with K+, Zn2+, Ca2+, arginine, taurine, carnitine • Avoid Iron, copper and sodium If ascites is present (<0.5 g Na/1000 kcal) • Small, frequent meals to avoid protein and ammonia overload of the liver 54 Monitoring • Clinical signs • Weight and BCS score • Blood tests Albumin Bilirubin Urea Glucose • Ideally: re-biopsy 55 - ALT - ALP - GGT - Electrolytes Toby • 8 years old, MN Balinese • Intermittent episodes of anorexia, lethargy and fever (40.7°C) x 5 months’ duration • Weight loss • Vomiting and diarrhea of a few days’ duration • Today: depressed and anorexic 56 Toby • Tendency to eat foreign bodies Vomiting episode after ingestion of adhesive tape (August) • Lives with another cat (Persian) • Both live indoors • Vaccines et deworming current 57 Toby • rDVM in October Temperature : 40,4°C Abdominal pain Weight loss since August (approximately 3 months ago) 3.71 kg today vs. 3.41 kg (August) 58 Toby • rDVM in October Treatments Cefovecin (Convenia®) Meloxicam (Metacam®) x 4 days SQ fluids Cyproheptadine (Periactin®) Metronidazole x 14 days Improvement noted, but recurrence 5 days after having discontinued the metronidazole 59 Toby – Physical exam • T: 39,7°C P: 220 bpm R: 28 • Icteric • Prolonged skin tent • Tacky mucous membranes • Abdominal palpation Pain and organomegaly 60 Toby – Problems List • Anorexia • Vomiting • Diarrhea • Icterus • Pyrexia • Abdominal pain and organomegaly • Dehydration estimated at ~ 8% 61 Toby – Differential Diagnoses • Cholangitis/cholangiohepatitis • Pancreatitis • Inflammatory bowel disease • Triaditis • Primary hepatic lipidosis • Neoplasia • FIP 62 Toby – Differential Diagnoses • CBC, serum biochemical profile, urinalysis • Urine culture • FeLV/FIV done at rDVM (negative) • PT/PTT • f PLI • Abdominal radiographs • Abdominal ultrasound 63 Toby - Results • CBC Mild non-regenerative anemia: Hct: 0.25 L/L Moderate neutrophilia: 20.74 x 109/L (2.1-8.3) • Serum biochimie ALT GGT ALP Bilirubin Urea Creatinine 64 profile 435 U/L (normal: 31-105) 18 U/L (normal: 0-6) 200 U/L (normal: 16-113) 45 U/L (normal: 0-3) 20 mmol/L (normal: 6-12) 300 mmol/L (normal: 50-190) Toby - Results • Urinalysis Specific gravity 1.058 Bilirubinuria (3+) Any trace of bilirubinuria in the cat is significant due to high renal threshold for bilirubin • Urine culture No growth 65 Laboratory Interpretation • ALP Dog: half life 66-72 h Cat: half life 6 h No steroid isoenzyme induction Even a mild ↑ is significant An ↑ ALP can go unnoticed due to its very short t½ • ALT Dog: half life 2½ days Cat: half life not documented, ~ 6 h? 66 Laboratory Interpretation • AST Dog: half life 22 h Cat: half life 77 minutes 67 Toby - Results • f PLI: within normal limits • PT/PTT: mildly prolonged • Blood type: A • Abdominal radiographs Hepatomegaly Mild loss of contrast in the left cranial quadrant 68 Toby - Results • Abdominal ultrasound Hepatomegaly Diffuse hyperechogenicity of the liver Prominent portal veins CBD: 3 mm (0-4 mm) 69 Toby - Traitements • Intravenous fluids (IV) • Fresh frozen plasma (coagulation factors) • Vitamin K1 SQ 0.5-1 mg/kg q8-12h 1 to 3 doses prior to performing biopsies • Fine needle aspiration of liver and GB • Hepatic biopsy • Culture and sensitivity of bile and hepatic tissue 70 Toby - Results • Liver cytology Vacuolated hepatocytes Cholestasis • Tru-cut® biopsy Suppurative cholangitis • Culture of bile +ve for E. coli Sensitive against amoxicillin – clavulanic acid (Clavaseptin® 50 mg PO q12h) 71 Toby - Treatments • Feeding via nasoesophagial tube • Ampicillin IV • Analgesics • Anti-emetics Once started eating • Clavaseptin® ~ 8-12 weeks • Ursodiol® q24h • SAMe/silybin (Zentonil® Advanced) q24h 72 Toby - Treatments • Monitoring of hepatic enzymes q4-6 weeks • First re-evaluation (at 4 weeks) BAR Moderate improvement of ALT, ALP and GGT • Clavaseptin® q12h • Ursodiol® q24h • SAMe/silybin (Zentonil® Advanced) q24h 73 Toby - Treatments • 2nd re-evalutaiton (at 8 weeks) BAR, active, eating well ALT very mildly elevated ALP and GGT within normal limits • Clavaseptin® q12h • Ursodiol® PO q48 heures x 1 month • Zentonil® Advanced q24h 74 Toby - Treatments • 3rd re-evaluation (at 12 weeks) ALT, ALP and GGT within normal limits Clavaseptin®: continue an additional 2 weeks Ursodiol®: discontinue Zentonil® Advanced q24h • 4th re-evaluation (at16 weeks) ALT, ALP and GGT within normal limits Clavaseptin®: discontinue Zentonil® Advanced q48h x 2 additional weeks 75 Toby - Treatments • 5th re-evaluation (at 20 weeks) ALT, ALP and GGT within normal limits Discontinue Zentonil® Advanced • Final re-evaluation (at 24 weeks) 4 weeks after discontinuing Zentonil® Advanced ALT, ALP and GGT within normal limits 76 Hepatic Inflammatory Diseases in the Cat • Three types of cholangitis in the cat 1. Neutrophilic Acute (suppurative) Chronic (non-suppurative or mixed) 2. Lymphocytic 3. Cholangitis associated with liver flukes (rare) • There is a considerable overlap of the clinical syndromes of the cholangiohepatitis complex 77 Comparison of neutrophilic and lymphocytic cholangitis Acute neutrophilic cholangitis (suppurative) Chronic neutrophilic cholangitis (non-suppurative) - Ascending infection of CBD by GI bacteria - E. coli often cultured from the liver +/or bile - Other pathogens: Enterobacter Streptococcus Klebsiella Clostridium Bacteroides -Lymphocyticplasmacytic cholangitis - Possibly progresses from the acute form - Possibly secondary to bacteria present in bile ducts 78 Lymphocytic cholangitis - Immune-mediated process Inflammatory Hepatic Diseases in the Cat Treatments Acute neutrophilic cholangitis (suppurative) • IV fluids • Supportive treatment Anti-emetics Appetite stimulants 79 Inflammatory Hepatic Diseases in the Cat Treatments Acute neutrophilic cholangitis (suppurative) • **Antibiotics** Culture and sensitivity (aerobic and anaerobic) Selected against enteric bacteria Excreted in bile Amoxicillin, amoxicillin – clavulanic acid, cephalosporins, enrofloxacin Metronidazole (anaerobes): 7.5 mg/kg PO q12h* Minimum 1 month, often 2 months or more 80 Inflammatory Hepatic Diseases in the Cat Treatments Acute neutrophilic cholangitis (suppurative) • SAMe/silymarin (Zentonil® Advanced) • +/- Ursodiol® **Possible cholelithiasis, +/- obstruction, +/- sx Abdominal ultrasound ideal • +/- Omega-3 fatty acids, vitamin E 81 Inflammatory Hepatic Diseases in the Cat Treatments Chronic neutrophilic cholangitis (non-suppurative) • Ursodiol® • Prednisolone (months) • SAM-e/silymarin (Zentonil® Advanced) • Culture of bile often negative (+/- antibiotics) • +/- Omega-3 fatty acids, vitamin E 82 Inflammatory Hepatic Diseases in the Cat Treatments Lymphocytic cholangitis • Prednisolone (for life?) • Ursodiol® • Antibiotics, if culture +ve • SAMe/silymarin (Zentonil® Advanced) • +/- Omega-3 fatty acids, vitamin E • Methotrexate?, chlorambucil?, cyclosporin? 83 What to do if client are unable to pursue a full work up? 84 84 Plan B • CBC, serum biochemical profile, urinalysis • Don’t run an f PLI or vitamin B12 • Antibiotics Minimum 1 month duration If unable to re-evaluate liver enzyme activities, treat for 2 months 85 Plan B • SAMe/silymarin (Zentonil® Advanced) • +/- Vitamin B12 injection • +/- Anti-emetics • +/- Appetite stimulant • If no, or little improvement noted after 2-4 days… Add prednisolone at an anti-inflammatory dose of 1 mg/kg/day 86 Conclusions • There are a multitude of treatments available for hepatic disease • Adapt a treatment protocol for each individual • Introduce the treatments gradually to avoid overwhelming the patient and client 87