Transcript Advanced - Vetoquinol

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