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Canine Chronic Idiopathic Hepatitis

David C. Twedt DVM, DACVIM

§  Problem § Acute Rt rear leg

lameness §  History

§ Probably stepped on by owner’s horse

§ Healthy otherwise § No medications

§  Physical exam § Possible partial ACL

tear § Otherwise normal

Hattie 6 year S/F Mix breed

§  Plan: §  Conservative management §  NSAIDs §  Limit exercise

§  Minimum data base before NSAID therapy §  CBC §  Biochemical profile §  Urinalysis

Hattie 6 year S/F Mix breed

ALT 579 (N< 110) AST 69 (N< 50) ALP 435 (N<140) T. Bili 0.2 Albumin 3.1 BUN 23 Glucose 102 Cholesterol 167

Hattie 6 year S/F Mix breed

§  Plan: §  No NSAID §  Rx Cosequin™ §  Limit exercise §  Go to CSU and see

what they say about liver enzymes

Hattie 6 year S/F Mix breed

Hattie 6 year S/F Mix breed

§  CSU evaluation approximately 1 month later §  No longer lame §  Doing great §  Lab abnormalities:

ALT 687 (N< 110) AST 83 (N< 50) ALP 469 (N<140)

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ABNORMAL LIVER ENZYMES Asymptomatic Symptomatic

Work up the liver

Look for a primary non-hepatic

disease or drug history

Treat primary non-hepatic

disease

Re-evaluate liver

Obvious primary

liver disease

If abnormal

Repeat liver enzymes in 1-2 months and/or

bile acids

Consider antibiotics +/- liver support

Hattie 6 year S/F Mix breed

§  Diagnostics performed: § Bile acids: (N<20) §  pre 48 µmol/L §  post 87 µmol/L

§ US - patchy hyper - hypoechoic liver

§ Coagulation profile-WNL

Hattie 6 year S/F Mix breed §  Laparoscopic Liver biopsy

§  Liver surface had an irregular appearance

4 biopsies taken

Biopsy: Chronic hepatitis

Hattie 6 year S/F Mix breed

Copper 373 µg/g (N<400)

§  Histology §  Hepatitis,

chronic marked and diffuse. Individual cell necrosis and portal fibrosis

Incidence of Liver Disease in 150 Liver Biopsies

Vacuolar hepatopathy

Reactive hepatopathy (usually secondary)

Chronic hepatitis- cirrhosis

Hepatic neoplasia

79% of Biopsies

Acute hepatopathy

Review of 150 Consecutive Liver Biopsies at CSU

ChronicHepatitis -Cirrhosis

n = 3523%

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§ Known etiology: § Copper § Infectious §  Leptospirosis, others? §  ICH adenovirus, others?

§ Drugs (phenobarbital, NSAIDs?) § Genetic

§ Unknown etiology: § Idiopathic (immune-mediated ?)

Chronic Hepatitis Hepatocyte insult: virus, toxin,other

Immune Mediated Mechanism of CH

Injury

Antigen Release

Macrophage Processing

Immunocyte

Cytotoxic Lmphocytes

Antibodies

Breed Predisposition: Doberman pinscher Bedlington terrier Dalmatian West Highland White terrier Labrador retriever Cocker spaniel Standard poodle Scottish terrier? English Springer spaniel

* Andersson JSAP 32: 1991

Chronic Hepatitis Diagnosis of Affected Dogs §  Serum copper - No §  Histochemical stains §  Copper quantitation

§ Normal < 400 µg/g Rhodanine Stain§  3-5 mm fresh sample

§ Place in copper free container

§  Paraffin embedded histo samples §  CSU Diagnostic Lab

Paraffin block

Back to Hattie and Idiopathic CH

Biopsy: Chronic hepatitis

Copper 373 µg/g (N<400)

CH - Clinical Features n=35

§  Age §  4 to 11 years §  Mean 7.5 years

§  Sex

§  Females > males (60/40)

02468

1 2 3 4 5 6 7 8 9 10 11 12 13

# Dogs

Age Distribution n=35

Hattie

6 year S/F

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Laboratory vs Clinical Signs

Severity

Normal Chronic Hepatitis

Cirrhosis EndStage

LaboratoryValues

ClinicalSigns

No Clinical SignsVariation

From Normal

Normal Chronic Hepatitis

Cirrhosis EndStage

ALT / ASTBile Acids

Bilirubin

AlbuminGlucose

BUN

ClottingTimes

Laboratory Progression in CH

ALPGGT

Clinical Signs

NH3

Prognosis for CH §  Early diagnosis

improves prognosis §  Guarded with

secondary complications : § HE § Ascites § GI ulceration § Hypoalbuminemia § Clotting abnormalities

0!

10!

20!

30!

40!

Mon

ths

Cirrhosis CH & Fibrosis

Early CH

Sevelius: JSAP 36:1995 Raffan: JVIM 23:2009

The Four Goals Liver Therapy

Liver Disease

Diet

Specific Therapy

Hepatic Support

Treat 1o Etiology

Hepatic Disease §  Palatability is important §  Meet caloric needs §  Protein restriction

§ Adequate protein is essential, restriction only with protein intolerance

§  Feed balanced moderate protein diet

§  Low copper diets §  RC Hepatic §  Hills l/d

Diet Basis of Therapy

§  Inflammation §  Copper §  Fibrosis §  Cholestasis §  Infection

SpecificTherapy

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Corticosteroids and CH §  Positive benefits

§ Antiinflammatory § Choleretic §  Inhibits fibrosis §  Improves appetite

§  Negative aspects § Steroid hepatopathy § Sodium & water retention § Precipitate early death

Chronic Hepatitis Survival (95 Dogs)

%Alive

Steroid Treated

No Steroids

MonthsStrombeck: JAVMA 193: 1988

Could the ~ 25% having a prolonged survival have immune mediated disease?

0

20

40

60

80

100

120

0 2.5 5 7.5 10 12.5 15 17.5 20 22.5 25

Mean Survival Steroids: 33 months No steroids: 19 months

Glucocorticoid Therapy §  Prednisolone

§ 1 to 2 mg / kg / day § Taper to 1-0.5 mg / kg EOD § >25 kg bw use 25-50 mg/m2/

day §  Many questions:

§ Length of treatment? §  Is therapy effective?

§  Duration ~ 6 months § Re-biopsy § Or stop Rx and evaluate in

ALT 1-2 mos

§  Therapy started § Prednisolone § Ursodiol § Silybin with

vitamin E

Hattie 6 year S/F Mix breed

0 200 400 600 800

1000 1200 1400 1600

Day 1 7 Mos. 11 Mos. 24 Mos

ALP ALT

AST

Hattie 6 year S/F Mix breed

Prednisolone Cyclosporine

UDC Marin

Hattie 6 year S/F Mix breed

Prednisolone

Cyclosporine UDCA

0

400

800

1200

1600

Day 1 7 Mos. 11 Mos. 24 Mos 27 Mos.

ALPALTAST

Silybin

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Hattie 6 year S/F Mix breed

Prednisone Cyclosporine

UDCA

0

400

800

1200

1600

Day1

7Mos.

11Mos.

24Mos

27Mos.

28Mos.

39Mos.

43Mos.

52Mos.

63Mos

ALPALTAST

Silybin

§  Cyclosporine reduced to 5 mg/kg/day then q 48h then off cyclosporine at 50 months

§  Continued on antioxidant therapy

§  Died of unrelated causes at 13 years of age; no active hepatitis

Hattie 11.5 year S/F Mix breed

Cyclosporine Therapy for Chronic Hepatitis (n=13)

§  ALT values decreased by 71% §  7/8 patients with hyperbilirubinemia

and/or ascites prior to treatment – resolved

JVIM 25:704,2011

Cyclosporine 5 mg/kg q12h

Cyclosporine Facts §  Mode of action §  ↓T lymphocyte function

§  Starting dose §  5 mg/kg bid

§  Types (pharmacokinetics) §  AB1= Neoral™= Atopica= modified

generic (microemulsion) §  AB2= Sandimmune™= nonmodified

generic §  Common side effects §  GI signs – try freezing caps §  Gingival hyperplasia

Bile Acids Cause Liver Damage§  Concentrations increase in disease

§ Most are hydrophobic bile acids § Membrane detergents

§ Hydrophilic “good” bile acid § Ursodeoxycholic acid § Ursodiol: §  10-15 mg/kg day

§ Protective properties

Asian Sun Bear

Urosdeoxycholic Acid

Immune modulation Antiinflammatory

Choleresis

Hepatoprotective

Antioxidant

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§  Chronic hepatitis §  Feline cholangitis §  Other cholestatic

liver disease §  Not cholelithiasis §  Mucocele?

Urosdeoxycholic AcidHepatic Copper Chelators

Chelator Renal Excretion

Hepatocyte Copper

Penicillamine10 - 15 mg / kg BID

Kupffer Cell Function In Preventing Portal Derived Infections

§  Kupffer cells clear portal bacteria

§  Altered Kupffer cell function could increase the risk of bacterial colonization

§  ~1/3 liver /bile cultures positive in case series ACVIM Abstract 2005

Antibiotics? §  Amoxicillin §  Amoxicillin clavulanic

acid §  Cephalosporins §  Metronidazole

§  Immunosuppressive activity?

§ Both renal & hepatic metabolism

§  Antibiotics indicated in feline cholangitis 7.5-10 mg/kg BID

Hepatic Fibrosis Stellate Cell

Hepatocyte Sinusoid

Inflammatory Cytokines

Hepatic Fibrosis – Treat the Inflammation

Collagen deposition

Fibrosis becomes a diffusion barrier to normal hepatocyte function

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Hepatic Fibrosis §  Antifibrotic activity?

§ Antiinflammatory Rx § Colchicine ? § Angiotensin II (AT II)

receptor blocker § AT II induces stellate

cells and TGF-β § Losartan (Zestril™

0.25-0.5 mg/kg q 24 h) Hepatology. 2001;34:4, 745.

Hepatic Support §  Provides hepatic protection

and an environment conducive for optimal hepatic and antioxidant function

§  Evidence of possible benefit: § Vitamin E § Silybin § SAMe

Hepatic Support

Hepatitis

2-3 week Antibiotic trial

Good Diet

Anti-inflammatory therapy

Antioxidants: Ursodiol, SAMe &/or

Silybin Vitamin E

Copper chelator therapy