Therapeutics in HepatobiliaryDisease

Narelle BrownAnimal Referral Hospital

30/04/10

Section 1Antibiotic 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 2Detoxification/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 3Gastric 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 4Antiemetic 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

Section5Immunosuppressive/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 6Anti-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??

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