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Transcript of Doc, does my pet really need all these medications to treat his liver disease? Lisa Carioto, DVM,...
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Doc, does my pet really need all these medications to treat his liver disease?
Lisa Carioto, DVM, DVSc, Diplomate ACVIM
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What prompted me to choose such a title for this presentation?
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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
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Objectives
• Hepatic disease and the multitude of treatments that exist
• Case studies
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Taz
• 3 year old MN Havanese
• Referred for Persistent ↑ of ALT ↑ of serum bile acids (SBA)
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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)
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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: 2.0 (0 - 6 umol/L) Post: 74.0 (0 - 15 umol/L)
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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
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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
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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
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Taz – Diagnostic Procedures
• CBC
• Serum biochemical profile
• Urinalysis
• Abdominal ultrasound
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Taz – Diagnostic Procedures
• CBF: NAF
• Serum biochemical profile ALT 64 U/L (4,0 – 62 U/L)
• Urinalysis (cystocentesis) pH 8 DU 1,047
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Taz – Abdominal ultrasound
• Moderate microhepatica
• Atypical bifurcation of theportal vein adjacent to thehepatic parenchyma?
• Excessive panting
• Gas in GI tract
• CT or spleno-portogram recommended
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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: 3,0 (0 - 6 umol/L) Post: 69,0 (0 - 15 umol/L)
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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?
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Taz - Differential Diagnoses
• Porto-systemic shunt (PSS) Congenital (breed predisposition) Acquired
• Hepatic portal venous hypoplasia Previously known as microvascular dysplasia Microscopic shunts (breed predisposition)
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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
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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.
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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
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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
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Treatments for Hepatic Disease
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Immunosuppressive Treatments Prednisone/Prednisolone
• Anti-inflammatory
• Immunosuppressive agent
• Anti-fibrotic
• Choleretic
• IndicationChronic hepatitis with mononuclear inflammation,
without evidence of infection
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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 …
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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
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Other Immunosuppressive Agents
• Second medication added to prednisone if necessary
• Goal Steroid sparing effect
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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?
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Treatments - Anti-fibrotics
• Prednisone/prednisolone
• Silymarin/silybin (Silybum marianum) Milk thistle
• S-adenosylmethionine (SAMe)
• Zinc
• Colchicine
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Hepatoprotectors
• SAMe
• Silymarin (milk thistle)
• Vitamin E
• Taurine
• L-carnitine
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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
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Hepatoprotectors - SAMe
• Most important methyl donor of cellular metabolism
• Transmethylation Regulates the plasticity of cellular membranes and reinforces
their integrity
• Transsulfuration Glutathione production
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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
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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
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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
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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
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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
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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 mg36
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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
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• Hepatoprotective properties of silybin are well documented Anti-oxydant
Free radical scavenger Regulator of intracellular
concentrations of glutathione Anti-inflammatory
Immuno-modulator
Hepatoprotectors – Silymarine/Silybine
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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
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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
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Hepatoprotectors – Silymarine/Silybine
• Oral absorption and bioavailability of silybin are improved significantly when complexed with phosphatidylcholine
• No side effects documented
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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
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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
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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
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HepatoprotectorUrsodeoxycholic 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
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HepatoprotectorUrsodeoxycholic 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?
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Treatments – Copper Chelators (dogs)
• 2,2,2-tetramine = Trientine HCl (Syprine®)
• D-penicillamine
• Zinc acetate
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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
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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
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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
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Treatments - Diet
One must differentiate between hepatic disease and hepaætic insufficiency
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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
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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
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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
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Monitoring
• Clinical signs
• Weight and BCS score
• Blood tests Albumin - ALT Bilirubin - ALP Urea - GGT Glucose - Electrolytes
• Ideally: re-biopsy
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• 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
Toby
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• 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
Toby
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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)
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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
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Toby – Physical exam
• T: 39,7°C P: 220 bpm R: 28
• Icteric
• Prolonged skin tent
• Tacky mucous membranes
• Abdominal palpation Pain and organomegaly
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Toby – Problems List
• Anorexia
• Vomiting
• Diarrhea
• Icterus
• Pyrexia
• Abdominal pain and organomegaly
• Dehydration estimated at ~ 8%
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Toby – Differential Diagnoses
• Cholangitis/cholangiohepatitis
• Pancreatitis
• Inflammatory bowel disease
• Triaditis
• Primary hepatic lipidosis
• Neoplasia
• FIP
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Toby – Differential Diagnoses
• CBC, serum biochemical profile, urinalysis
• Urine culture
• FeLV/FIV done at rDVM (negative)
• PT/PTT
• f PLI
• Abdominal radiographs
• Abdominal ultrasound
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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 profile ALT 435 U/L (normal: 31-105) GGT 18 U/L (normal: 0-6) ALP 200 U/L (normal: 16-113) Bilirubin 45 U/L (normal: 0-3) Urea 20 mmol/L (normal: 6-12) Creatinine 300 mmol/L (normal: 50-190)
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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
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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?
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Laboratory Interpretation
• AST Dog: half life 22 h Cat: half life 77 minutes
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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
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Toby - Results
• Abdominal ultrasound Hepatomegaly Diffuse hyperechogenicity
of the liver Prominent portal veins CBD: 3 mm (0-4 mm)
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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 tissue70
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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)
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Toby - Treatments
• Feeding via nasoesophagial tube
• Ampicillin IV
• Analgesics
• Anti-emetics
Once started eating
• Clavaseptin® ~ 8-12 weeks
• Ursodiol® q24h
• SAMe/silybin (Zentonil® Advanced) q24h72
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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
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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
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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
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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
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Hepatic Inflammatory Diseases in the Cat
• Three types of cholangitis in the cat1. 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
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Comparison of neutrophilic and lymphocytic cholangitis
Acute neutrophilic cholangitis (suppurative)
Chronic neutrophilic cholangitis (non-suppurative)
Lymphocytic cholangitis
- Ascending infection of CBD by GI bacteria- E. coli often cultured from the liver +/or bile- Other pathogens: EnterobacterStreptococcusKlebsiellaClostridiumBacteroides
-Lymphocytic-plasmacytic cholangitis- Possibly progresses from the acute form- Possibly secondary to bacteria present in bile ducts
- Immune-mediated process
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Inflammatory Hepatic Diseases in the Cat Treatments
Acute neutrophilic cholangitis (suppurative)
• IV fluids
• Supportive treatment Anti-emetics Appetite stimulants
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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
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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
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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
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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?
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What to do if client are unable to pursue a full work up?
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• 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
Plan B
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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
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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
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