1. Therapeutics in Hepatobiliary Disease
Narelle Brown
Animal Referral Hospital
30/04/10

3. Section 1
Antibiotic Therapy

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. Antibiotics to Avoid Tetracyclines Lincomycin Erythromycin
Trimethoprim-Sulphonamides
Either inactivated by liver, require hepatic metabolism or can injure liver

15. REMEMBER
Hepatobilary disease can influence the clearance and volume of distribution of drugs
See table in Greenes
Infectious diseases

16. Section 2
Detoxification/Removal Intestinal Toxins

17. Lactulose Decrease intestinal ammonia production
Decrease ammonia absorption
Antiendotoxin effect
Indicated for treatment hepatic encephalopathy
Works synergistically with neomycin
ml PO per 5kg
Adjust dose to achieve 2-3 soft stools /day

18. 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 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 mins :BID-TID

19. Section 3
Gastric Protectants

20. 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
mg/kg PO, IV (SID if PO , BID if IV)

21. 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

22. 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

23. Sulcralfate DOSE: Large dogs: 1g, PO BID-QID
Medium dogs: 0.5gm PO BID-QID
Small Dogs/Cats: g PO BID-QID
May cause oesophageal impaction so best mixed with water and given via syringe

24. Section 4
Antiemetic Therapy

25. Metoclopramide (Maxalon)
Impaired hepatic function decreases plasma clearance by 25%
Normal dose: mg/kg PO TID-QID
1-2mg/kg/24hours CRI
25% reduced dose: mg/kg PO TID -QID
mg/kg/24hours CRI IV

26. Ondansetron (Zofran)
Good anti-emetic effect in patients with poor responsive to maxalon
$$$$
Dose:
mg/kg PO q12hours(use low end dose range with liver dz as eliminated by hepatic metabolism)
Cats: mg/kg PO BID-SID

27. Maropitant (Cerenia) NK1 antagonist Good anti-emetic
Dose:1mg/kg s/c SID or 2mg/kg PO SID

28. Section5
Immunosuppressive/Immunomodulatory Therapy

29. Immunosuppressant/Immunomodulatory Therapy
Glucocorticoids
Azathioprine
Ursodeoxycholic Acid

30. 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

31. 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

32. Azathioprine Immunosuppression More expensive than prednisolone
Steroid sparing
Side Effects
Bone marrow suppression
Hepatopathy
Pancreatitis
Toxic to humans

33. 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)

34. Section 6
Anti-Oxidant Therapy

35. Anti-Oxidants Vitamin C (can be pro-oxidant)
S-Adenosyl-L-Methionine (SAMe)
Vitamin E
Silymarin
N-Acetlcysteine
Zinc*
UDCA*

36. 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)

37. 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

38. 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

39. 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

40. 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
mg/kg SID few days then EOD
NO evidence that it helps
Don’t use it (?if fibrosis is primary lesion)

41. 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

42. 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

43. 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

44. 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

45. Ascites with Hepatobiliary Disease
Measure BW, abdominal girth, PCV, TS, BUN
Spironolactone mg/kg PO BID 3-4d
Frusemide 1.0mg/kg PO BID -4d
If respond :taper drugs to lowest effective dose

46. 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

47. Ascites (cont) :If still no response
Colloid Administration
Expand the ECF compartment:promote diuresis
Plasma preferred ($$$)

48. 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)

49. 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
mg/kg IM 3 doses q 12 hrs
Then every 7-28d as needed (PIVKA test, PT, PTT)
Don’t give it IV (anaphylactic reactions)

50. Vitamin K
CATS:
5mg or mg/kg IM -3 doses q12 hours then 1-2x weekly PO until recovery
Watch for heinz body hemolytic anaemia
Monitor PCV/RBC morphology

51. Summary SAMe: Necroinflammatory hepatopathies
Metabolic Hepatopathies (FHL)
Cholestatic Hepatopathies
Paracetamol Toxicity

52. Summary N-Acetylcysteine Paracetamol Toxicity Acute Liver Failure
Ursodeoxycholic Acid
Cholestatic Hepatopathies
Necro-inflammatory Hepatopathies
Metabolic Hepatopathies
Immune-Mediated Hepatopathies

53. Summary Silymarin Amanita Mushroom Toxicity Hepatotoxicity
Cholestatic Hepatopathies
Necro-Inflammatory hepatopathies
Vitamin E
Cholestatic hepatopathies
Necro-Inflammatory Hepatopathies

54. Case Study 13 yr FS Chihuahua 9 day hx lethargy , inappetance PU/PD
Orange Urine
Vomited once

55. 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

56. Physical Examination Mildly Dehydrated T 39.3C Icteric mm
Mild cranial abdominal discomfort, hepatomegaly
BCS 6/9

57. 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

58. Thoracic Radiographs
Unremarkable

59. Exploratory Laparotomy
CBD obstructed by choleliths and inflammatory debris
Flushed CBD via enterotomy
Splenectomy
Intestinal polypoid mass resection

60. Pathology Bile Culture: no growth
Splenic Masses: Nodular hyperplasia/myelolipomas
Intestinal leimyosarcoma (low grade:completely resected)
Liver: vacuolar change

61. Treatment
Timentin
enrofloxacin
Esomeprazole
Methadone
IV Fluids

62. Outcome Bright, eating, resolution of icterus
Treatment with Clavulox/Baytril for 6 weeks
Ursodeoxycholic Acid indefinitely
Bilateral adrenalectomy??

63.