Upload
hadan
View
217
Download
1
Embed Size (px)
Citation preview
22/09/15
1
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)
22/09/15
2
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%
22/09/15
3
§ 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
22/09/15
4
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
22/09/15
5
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
22/09/15
6
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
22/09/15
7
§ 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
22/09/15
8
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