Therapeutics in Hepatobiliary
Disease
Narelle Brown
Animal Referral Hospital
30/04/10
Section 1
Antibiotic Therapy
When To Consider Antibiotic Therapy?
• Increased risk of infection
– EHBDO
– Chronic liver Dz with portal hypertension
– Compromised hepatic perfusion /bile flow
– Enteric Bacterial Translocation
• Bowel Dz
• Bacterial dysbiosis
• Splanchnic Hypoperfusion
Hepatobiliary Infections
• Considerations:
• primary Vs secondary infections
– “innocent Bystander”
• effects on antibiotic metabolism (dose and dosing
frequency)
• bacteria found in bile/liver/GB :enteric origin
– E Coli, Clostridium, Enterococcus sp
• anaerobic and gm neg bacteria
• ideally based on culture and sensitivity
Samples for culture
• Cholecystocentesis
– Not advised if EHBDO or US changes necrotizing
cholecystitis
– Transhepatic approach
• Limits bile extravasation
–
–
–
–
Drain as much of the bile as possible
Submit sample in culture bottle
US guidance (22G spinal needle)
Recheck US 24-48hrs later
Samples for culture:Liver Abscess
• Ultrasound guided
• May be only therapy required if complete drainage
• Generally better to surgically explore once stable as
often associated with necrotic center (neoplasia) or
migrating FB
Samples for Culture:Liver Biopsy
• surgically
• Tru-Cut (ultrasound guided) ,
• laproscopy
• Sample liver tissue for culture (into sterile , sealed
container)
• Assess patients ability to clot
BEFORE you do the biopsy
General guidelines
• In the absence of C+S:
– Cover aerobic and anaerobic enteric orgs
– B lactamase resistance penicillin OR
metronidazole OR clindamycin
–
PLUS
– Aminoglycoside or fluorinated quinolone
– Start treatment BEFORE sx if EHBDO or known
infection
Antibiotics
• Antibiotics that achieve therapeutic concentrations in
liver and bile, renal excretion:
– Amoxicillin 11-20mg/kg PO,IV,IM BID
– Cephalexin 15mg/kg PO, SQ, IV BID-TID
– Ticarcillin 50mg/kg IV TID
– Enrofloxacin 2.5-5mg/kg PO, SQ BID
Metronidazole
•
•
•
•
•
Dose: 7.5mg/kg PO , IV, rectal BID-TID
High bioavailability
Wide tissue distribution (bone/bile/CSF,brain/prostate/ascites)
Note “Liver “dose
Important action against many urease producers (decrease
ammonia production)
• Immunosuppressive activity
• Overdose: cerebellar/central vestibular signs/seizures
Neomycin
• Can be used alone or is synergistic with lactulose in
effects on gut flora (decrease ammonia production)
• Not systemically absorbed
• Beware if concurrent IBD as may be absorbed
• May improve portal hypertension
• 22mg/kg Po BID-TID
Chloramphenicol
•
•
•
•
????
If you have to use it use a low dose :
11mg/kg PO, SQ, IV BID
Inactivates mixed function oxidases in liver>>>>>
adverse drug reactions
• Anorexia / Erythroid hypoplasia
• Bone marrow injury in humans
Antibiotics to Avoid
•
•
•
•
•
Tetracyclines
Lincomycin
Erythromycin
Trimethoprim-Sulphonamides
Either inactivated by liver, require hepatic
metabolism or can injure liver
REMEMBER
• Hepatobilary disease can influence the clearance
and volume of distribution of drugs
• See table in Greenes
Infectious diseases
Section 2
Detoxification/Removal Intestinal Toxins
Lactulose
–
–
–
–
–
–
–
Decrease intestinal ammonia production
Decrease ammonia absorption
Antiendotoxin effect
Indicated for treatment hepatic encephalopathy
Works synergistically with neomycin
0.25-1.0 ml PO per 5kg
Adjust dose to achieve 2-3 soft stools /day
Enemas
• Perform a “mechanical enema
“ first to flush faecal contents from colon
• Retention enemas for a prolonged effect
– Lactulose: 5-15ml diluted 1:3 with water:
– retain 20-30 mins . If faecal pH >6 repeat
– Activated charcoal
– Vinegar :dilute 1:10 with water BID-TID
– Betadine :dilute 1:10 in water :flush out
– after 10-15 mins :BID-TID
Section 3
Gastric Protectants
Gastric protectants
• Animals with chronic major bile duct obstruction at an increased
risk gastroduodenal ulceration/perforation
– H2 Receptor antagonists
• Cimetidine (??)
• Suppression cytochrome P450 oxidases
– Most cases increases pharmacologic effects or toxicity of
concomitant drugs
• 5mg/kg IM, IV, PO BID-TID
• Famotidine
• 20-30x more potent than cimetidine
• 0.4-0.7mg/kg PO, IV (SID if PO , BID if IV)
Proton Pump Inhibitors
• Omeprazole
– 5-10 fold more potent than cimetidine
– Inhibits p450 cytochrome oxidases similar to
cimetidine
– 0.7-2mg/kg PO SID (dogs)
– Limited experience with this drug in cats
Gastric Cytoprotection
• Sucralfate
– Direct action on mucosal prostoglandin E production
– Binds to surface mucosal ulcers/protective barrier
– Inhibits pepsin activity
– Does NOT require an acid environment to be effective (no
need to stagger dose with antacid) ?
– Will interfere with absorption of drugs orally administered
– It inactivates fluoroquinolones
– May promote constipation
Sulcralfate
•
•
•
•
•
DOSE:
Large dogs: 1g, PO BID-QID
Medium dogs: 0.5gm PO BID-QID
Small Dogs/Cats: 0.12-0.25g PO BID-QID
May cause oesophageal impaction so best mixed
with water and given via syringe
Section 4
Antiemetic Therapy
Metoclopramide (Maxalon)
– Impaired hepatic function decreases plasma
clearance by 25%
– Normal dose: 0.2-0.4mg/kg PO TID-QID
• 1-2mg/kg/24hours CRI
– 25% reduced dose: 0.13-0.3mg/kg PO TID -QID
• 0.75-1.5mg/kg/24hours CRI IV
Ondansetron (Zofran)
• Good anti-emetic effect in patients with poor
responsive to maxalon
• $$$$
• Dose:
• 0.1-1.0mg/kg PO q12hours(use low end dose range
with liver dz as eliminated by hepatic metabolism)
• Cats: 0.1-0.5mg/kg PO BID-SID
Maropitant (Cerenia)
• NK1 antagonist
• Good anti-emetic
• Dose:1mg/kg s/c SID or 2mg/kg PO SID
Section5
Immunosuppressive/Immunomodulatory Therapy
Immunosuppressant/Immunomodulatory
Therapy
• Glucocorticoids
• Azathioprine
• Ursodeoxycholic Acid
Glucocorticoids
• Indications
• Antifibrotic (weak)
• Non septic active
inflammation
• Immunologic Injury
• Promote bile flow
• Appetite stimulant
•
•
•
•
Side Effects
Sodium/water retention
Catabolic
Increased susceptibility
infection
• GI ulceration
Glucocorticoids
• If ascites or oedema are a problem-use
glucocorticoids that lack mineralocorticoid activity
– Dexamethasone (try for every three day dosing to
avoid excessive suppression P-A axis)
– Taper dose to lowest effective level
Azathioprine
•
•
•
•
Immunosuppression
More expensive than prednisolone
Steroid sparing
Side Effects
– Bone marrow suppression
– Hepatopathy
– Pancreatitis
– Toxic to humans
Ursodeoxycholic Acid (UDCA)
•
•
•
•
•
Non Toxic hydrophilic bile acid
Choleretic
Decreases proportion toxic bile acids
Reduces the immune response
Increased production glutathione (GSH) and metallothionein in
hepatocytes
• Contraindicated EHBDO
• 15mg/kg/day divided in 2 doses
• Indicated in cholestatic disorders (not PSS or HL)
Section 6
Anti-Oxidant Therapy
Anti-Oxidants
•
•
•
•
•
•
•
Vitamin C (can be pro-oxidant)
S-Adenosyl-L-Methionine (SAMe)
Vitamin E
Silymarin
N-Acetlcysteine
Zinc*
UDCA*
S-Adenosyl-L-Methione (SAMe)
• Precursor of cysteine:one of AA that makes up glutathione
(GSH)
• GSH is a defense mechanism against oxidative stress.
Depletion GSH:oxidative stress
• Helps to restore depleted GSH in
hepatocytes
• 20mg/kg PO SID (empty stomach).
• Do not split tabs
• 2 isomers:ss and rs (the ss is the active form)
Silymarin
• Extracted from milk thistle
• Free radical scavenger
• Increases cellular SOD (main defense against oxidative
damage)
• Choleretic/anti-inflammatory
• Indicated where main damage to liver is oxidative
– Amanita mushroom intoxication
– Paracetamol intoxication
– 20-50mg/kg/day divided q6-8hr PO
• No side effects
Vitamin E
•
•
•
•
Dose:10-15 IU/kg /day PO
Indicated in liver dz associated with oxidative injury
Anti-inflammatory
Especially important in fat malabsorption (bile duct
obstruction)
– Copper toxicity
– Paracetamol toxicity
• No side Effects
N-Acetylcysteine
• Cytoprotective (along with SAMe, UDCA, Silymarin,
Vit E)
• Anti-oxidant (increases GSH)
• Anti-Inflammatory
• Improves hepatic circulation
• Improves tissue O2 delivery
• 140mg/kg IV once then 70mg/kg IV q6hr
AntiFibrotic Drugs
• Fibrosis end result of chronic inflammation
• A lot of research into drugs to limit fibrosis/cirrhosis :all
experimental at this stage
• Colchicine:
– Stimulates collagenase
– Side Effects
• HE, BM suppression, renal injury, neuropathy
– 0.025-0.3mg/kg SID few days then EOD
– NO evidence that it helps
– Don’t use it (?if fibrosis is primary lesion)
Anti Copper Medications
• Free intracellular copper causes oxidative damage
– Genetic disease
•
•
•
•
•
•
•
Bedlington Terriers
Skye Terriers
West Highland White Terriers
Dalmatians
Labradors
Dobermans
DNA test (don’t need a liver biopsy anymore)
– Secondary to decreased bile excretion
Anti-Copper Medications
• Chelating Agents
– Bind free extracellular copper ….excreted in
urine….movement copper from intracellular space
to extracellular space…decreases intracellular
toxic pool
– D Penacillamine (preferred)
– Trientine (more potent)
– 10-15mg/kg BID with food
Anti-copper Medications(cont)
• Zinc (gluconate or acetate)
– Induces metallothionein in enterocytes-binds cu sequestered in senescent enterocytes -sloughed..excreted
– Give 1 hour Before meals
– Don’t use chelators and zinc together
– 10mg elemental zinc /kg BID
– Watch for haemolytic anaemia (excess zinc) or iron
deficiency
Ascites
• Rare in cats with liver dz
• Portal hypertension w/o hypoalbuminaemia will only
cause ascites RARELY (ie: A-V fistula, complete
thrombosis portal vein)
• Sodium restriction
• Cage rest
• Sodium wasting diuretics
Ascites with Hepatobiliary Disease
•
•
•
•
Measure BW, abdominal girth, PCV, TS, BUN
Spironolactone 0.5-1.0mg/kg PO BID 3-4d
Frusemide 1.0mg/kg PO BID -4d
If respond :taper drugs to lowest effective dose
Ascites With Hepatobiliary Disease
•
•
•
•
•
If no response:(and PCV/TS/BUN stable)
Spironolactone 2mg/kg PO BID 4d
If still no response (and PCV etc stable)
Frusemide 2mg/kg PO BID
Watch:
– Hypokalemia
– Dehydation
Ascites (cont) :If still no response
• Colloid Administration
– Expand the ECF compartment:promote diuresis
– Plasma preferred ($$$)
Therapeutic Abdominocentesis
• 18 or 16g catheter or open ended tom cat catheter through 14g
teflon catheter
• Remove over 1 hour
• Can improve efficiency of diuretics
• Risks:
– Infection
– Bleeding
– Continued seroma formation at puncture site (lateral body
wall)
– Loss albumin
– Hypotension (unlikely)
Vitamin K
• Deficiency possible with reduced hepatic function or
cholestasis
• Major Bile Duct Obstruction
– 5-15mg (sm-lg dog) IM x3 doses q 12hours
– OR
– 0.5-1.5mg/kg IM 3 doses q 12 hrs
– Then every 7-28d as needed (PIVKA test, PT,
PTT)
– Don’t give it IV (anaphylactic reactions)
Vitamin K
• CATS:
– 5mg or 0.5-1.5mg/kg IM -3 doses q12 hours then
1-2x weekly PO until recovery
– Watch for heinz body hemolytic anaemia
– Monitor PCV/RBC morphology
Summary
• SAMe:
– Necroinflammatory hepatopathies
– Metabolic Hepatopathies (FHL)
– Cholestatic Hepatopathies
– Paracetamol Toxicity
Summary
• N-Acetylcysteine
– Paracetamol Toxicity
– Acute Liver Failure
• Ursodeoxycholic Acid
– Cholestatic Hepatopathies
– Necro-inflammatory Hepatopathies
– Metabolic Hepatopathies
– Immune-Mediated Hepatopathies
Summary
• Silymarin
– Amanita Mushroom Toxicity
– Hepatotoxicity
– Cholestatic Hepatopathies
– Necro-Inflammatory hepatopathies
• Vitamin E
– Cholestatic hepatopathies
– Necro-Inflammatory Hepatopathies
Case Study
• 13 yr FS Chihuahua
• 9 day hx lethargy ,
inappetance
• PU/PD
• Orange Urine
• Vomited once
Clinical Pathology
• CBC: Hct 57% WBC 13 N’phil 9.2 L’cyte 2.6 M’cyte
1.0 Plt 318
• Chemistry:Alt 4359 Alkp 6320 Tbil 288 Chol 19.1 Alb
38 Glu 2.8 BUN 6.1
• Treated Amoxyclav 4 days
Physical Examination
•
•
•
•
•
Mildly Dehydrated
T 39.3C
Icteric mm
Mild cranial abdominal discomfort, hepatomegaly
BCS 6/9
Ultrasound Findings
•
•
•
•
•
•
Intrahepatic bile ducts markedly distended
Common Bile duct distended (1.7cm)
Gall bladder distended
R Adrenal Mass
L Adrenal Mass
Multiple Splenic Masses
• Consistent with EHBDO
Thoracic Radiographs
• Unremarkable
Exploratory Laparotomy
• CBD obstructed by choleliths and inflammatory
debris
• Flushed CBD via enterotomy
• Splenectomy
• Intestinal polypoid mass resection
Pathology
• Bile Culture: no growth
• Splenic Masses: Nodular hyperplasia/myelolipomas
• Intestinal leimyosarcoma (low grade:completely
resected)
• Liver: vacuolar change
Treatment
•
•
•
•
•
Timentin
enrofloxacin
Esomeprazole
Methadone
IV Fluids
Outcome
•
•
•
•
Bright, eating, resolution of icterus
Treatment with Clavulox/Baytril for 6 weeks
Ursodeoxycholic Acid indefinitely
Bilateral adrenalectomy??
•