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: 2.0 (0 - 6 umol/L) Post: 74.0 (0 - 15 umol/L)

7

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

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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

20

Treatments for Hepatic Disease

2121

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

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

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

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

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?

8484

• 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

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