Transcript CHRONIC HEPATITIS Copper-associated hepatic disease

TAMU #81095
Sig: 11 yr M(c) Mixed Labrador
CC: Chronic cough
HPI: Cough and expectoration started 1
week ago
Vet found hypoalbuminemia on
routine blood work
PE: Thin but normal
TAMU #81095
PCV =
33% (35-54)
WBC =
11,100/ul (6,-17,000)
Segs =
9,102/ul (3,-12,000)
Bands =
0/ul (< 500)
Lymphs =
444/ul (1,-5,000)
Platelets =
187,000/ul (200,-500,000)
TAMU #81095
BUN =
Creatinine =
Cholesterol =
Glucose =
Total protein =
Albumin =
ALT =
SAP =
Bilirubin =
6 mg/dl (6-20)
0.6 mg/dl (< 2.0)
51 mg/dl (120-247)
81 mg/dl (60-120)
5.8 gm/dl (5.5-7.5)
1.8 gm/dl (2.5-4.4)
649 IU/L (< 110)
320 IU/L (< 130)
0.1 mg/dl (< 1.0)
TAMU #81095
Abdominal ultrasound:
“No significant findings”
IS IT COST-EFFECTIVE OR
PRACTICAL TO BIOPSY THE
LIVER OF AN ASYMPTOMATIC
DOG JUST BECAUSE IT HAS
INCREASED HEPATIC
ENZYMES?
TAMU #81095
Hepatic biopsy:
SEVERE chronic hepatitis
with marked fibrosis and
scarring; early cirrhotic changes
CHRONIC HEPATITIS
What is it?
• Chronic non-septic inflammatory
disease of the liver which has many
different causes
CHRONIC HEPATITIS
What the clinician needs to know
• Breed predisposition
CHRONIC HEPATITIS
What the clinician needs to know
• Breed predisposition
• Clinical signs
– chronic illness
CHRONIC HEPATITIS
What the clinician needs to know
• Breed predisposition
• Clinical signs
– chronic illness
– asymptomatic dog with lab changes
– acute illness
CHRONIC HEPATITIS
What the clinician needs to know
IMPORTANCE OF THE
WORD “CHRONIC”
One year ago, they found an increased ALT, so
they decided to watch and see what would
happen ...
TAMU #149538
CHRONIC HEPATITIS
What the clinician needs to know
• Breed predisposition
• Clinical signs (or lack there of)
• Absolute necessity of biopsy
WHAT DO YOU DO
AFTER DIAGNOSING
CHRONIC HEPATITIS?
Drugs That Cause Hepatic Disease
Corticosteroids
Drugs That Cause Hepatic Disease
Corticosteroids
Acetaminophen
Phenobarbital
Primidone
Sulfa drugs
Carprofen
Drugs That Cause Hepatic Disease
Corticosteroids
Acetaminophen
Phenobarbital
Primidone
Sulfa drugs
Carprofen
Amiodarone
Itraconazole
Ketoconazole
Diazepam
Doxycycline
Methimazole
Azathioprine
Phenytoin
Mibolerone
Griseofulvin
Mitotane
Stanozolol
Mebendazole
Clavamox
Clindamycin
Cimetidine
CHRONIC HEPATITIS
Causes
• Drugs
– You REALLY want to catch this
BEFORE biopsy
– sometimes easy to establish cause
and effect
– sometimes hard to establish cause
and effect
Increased ALT
Not receiving drugs
Proceed with
workup
Receiving drugs
Patient
significantly ill
Patient not
significantly ill
Drugs cannot
be stopped
Drugs can
be stopped
Stop drugs
Recheck ALT
over next 4 wks
Increased ALT
Not receiving drugs
Proceed with
workup
Receiving drugs
Patient
significantly ill
Patient not
significantly ill
Drugs cannot
be stopped
Drugs can
be stopped
Stop drugs
Recheck ALT
over next 4 wks
Increased ALT
Not receiving drugs
Proceed with
workup
Receiving drugs
Patient
significantly ill
Patient not
significantly ill
Drugs cannot
be stopped
Drugs can
be stopped
Stop drugs
Recheck ALT
over next 4 wks
Increased ALT
Not receiving drugs
Proceed with
workup
Receiving drugs
Patient
significantly ill
Patient not
significantly ill
Drugs cannot
be stopped
Drugs can
be stopped
Stop drugs
Recheck ALT
over next 4 wks
CHRONIC HEPATITIS
Copper-associated hepatic disease
• Bedlington terrier
• West Highland white terriers
• Doberman pinschers
• Skye terrier
• Dalmations
• Labrador retrievers
CHRONIC HEPATITIS
Causes
• Copper intoxication
– primary (causes hepatic disease –
genetic)
• Innocent copper accumulation
– secondary (caused by hepatic disease)
TAMU #170148
Centrilobular (zone 3) deposits of copper
strongly suggest that copper is the cause
of the problem
CHRONIC HEPATITIS
Therapy for inflammation/necrosis
• Remove cause – symptomatic
– Chelate copper with d-Penicillamine
(10-15 mg/kg bid, give with food)
– Do not give zinc when administering
copper chelators
CHRONIC HEPATITIS
Therapy for inflammation/necrosis
• Remove cause – not symptomatic
– Decrease copper absorption with zinc
gluconate (10 mg elemental zinc/kg)
– Administer with tuna fish
– Measure blood zinc levels
• need > 200 mcg/dl to be therapeutic
• > 2,000 mcg/dl may cause hemolysis
CHRONIC HEPATITIS
Therapy for inflammation/necrosis
Decrease the inflammatory response
• Corticosteroids
– prednisolone (not prednisone)
–
budesonide
• Cytotoxic drugs (azathioprine)
• Cyclosporine
HEPATOPROTECTIVE THERAPY
• What this therapy does NOT do ...
• What this therapy does do ...
HEPATOPROTECTIVE THERAPY
• Ursodeoxycholic acid (15 mg/kg qd)
– A hydrophilic bile acid
– Displaces toxic, hydrophobic bile acids
• Hydrophobic bile acids are detergents
– damage hepatocyte & mitochondrial
membrane
– Food enhances bioavailability
HEPATOPROTECTIVE THERAPY
• s-adenosyl L-Methionine (SAMe)
– Human studies
• acute intrahepatic cholestasis
• alcoholic liver disease
– Veterinary studies
• healthy animals
• acetaminophen, prednisolone
HEPATOPROTECTIVE THERAPY
• Milk thistle (Silymarin)
– Silybin is the active fraction
– Antioxidant, antifibrotic, anti-inflammatory
– Effective for Amanita, aflatoxin,
acetaminophen, ethanol, ischemic
damage
CHRONIC HEPATITIS
Prognosis
• Potentially ominous signs:
– ascites
– icterus
– severe hypoalbuminemia
– apparent cirrhosis
– hepatic encephalopathy
CHRONIC HEPATITIS
Prognosis
• < 4 months for those with poor
prognostic signs
• > 1.5 years for others
WHAT ABOUT THE
“NORMAL” DOG THAT HAS
AN INCREASED ALT?
Clinically normal dog with
increased ALT as only abnormality
ALT persistently
> 3-4 X normal
ALT < 3-4 X normal
OR
transiently increased
More likely to be
very important
Often not
real important
Clinically normal dog with
increased ALT as only abnormality
ALT persistently
> 3-4 X normal
ALT < 3-4 X normal
OR
transiently increased
More likely to be
very important
Often not
real important
WHAT ABOUT THE
“NORMAL” DOG THAT JUST
HAS AN INCREASED SAP?
Clinically normal dog with increased
SAP as only significant clinical
pathology abnormality
Look for Hyperadrenocorticism
History/Physical Examination
Look for Tumors/Hepatopathy
Abdominal Ultrasound
Owner content
Owner NOT content
with > 99%+ certainty with > 99%+ certainty
Yearly recheck
Biopsy the liver
Clinically normal dog with increased
SAP as only significant clinical
pathology abnormality
Look for Hyperadrenocorticism
History/Physical Examination
Look for Tumors/Hepatopathy
Abdominal Ultrasound
Owner content
Owner NOT content
with > 99%+ certainty with > 99%+ certainty
Yearly recheck
Biopsy the liver
Clinically normal dog with increased
SAP as only significant clinical
pathology abnormality
Look for Hyperadrenocorticism
History/Physical Examination
Look for Tumors/Hepatopathy
Abdominal Ultrasound
Owner content
Owner NOT content
with > 99%+ certainty with > 99%+ certainty
Yearly recheck
Biopsy the liver
WHAT ABOUT SCOTTISH
TERRIERS?
TAMU #96276
Sig: 4 yr M Cocker Spaniel
CC: Swollen abdomen
HPI: Dark yellow urine and depression
were first noted by owners 2
days ago
Today the dog has an obviously
swollen abdomen
PE: Depressed and has ascites
TAMU #96276
BUN =
Creatinine =
Sodium =
Potassium =
Total protein =
Albumin =
ALT =
SAP =
Bilirubin =
57 mg/dl (8-29)
2.4 mg/dl (< 2.0)
128 mEq/L (138-148)
4.9 mEq/L (3.5-5.0)
6.5 gm/dl (5.5-7.0)
2.0 gm/dl (2.5-4.4)
72 IU/L (< 130)
128 IU/L (< 147)
1.6 mg/dl (< 0.8)
Hepatic Biopsy
GUIDANCE
TYPE OF BIOPSY
Blind
Fine needle aspirate
Ultrasound
TAMU # 72927
Sig: 9 yr M(c) Cat
6 kg
CC: Weight loss & vomiting
HPI: Poor appetite & vomiting bile for
6 weeks; has lost 2.3 kg
ALT = 202 U/L
SAP = 427 U/L
PE:
No significant findings
TAMU # 72927
Cytology of liver (ultrasound guided):
“no cytologic evidence of active
inflammation or neoplasia … mild
hepatic lipidosis”
TAMU # 72927
Histopathology:
“Moderate to severe multifocal
lymphocytic cholangiohepatitis with
cholestasis; mild hepatic lipidosis”
Hepatic Biopsy
GUIDANCE
TYPE OF BIOPSY
Blind
Fine needle aspirate
Ultrasound
Core needle
“Diagnostic Accuracy of Tru Cut
Needle Biopsy Compared to
Wedge Biopsy of the Liver” by
Cole et al, JAVMA 220:1483, 2002
100 dogs and 22 cats
51.6% discordance between results
Hepatic Biopsy
GUIDANCE
TYPE OF BIOPSY
Blind
Fine needle aspirate
Ultrasound
Core needle
Laparoscopy
Wedge
Surgery
TAMU #162500
Abdominal U/S:
“The liver, pancreatic
region, GI tract, kidneys and adrenals
were unremarkable.”
TAMU #139804
Abdominal U/S:
“The liver and spleen
were unremarkable. ... Essentially
normal abdominal ultrasound.”
TAMU #128604
Abdominal U/S:
“A sonographic
examination of the abdomen was
performed and revealed no significant
abnormal findings”
TAMU #168184
Abdominal U/S:
“... sludge within the gall
bladder. This was organizing and probably
the early development of a cholelith. The
remainder of the liver was considered
normal ... Changes in the gall bladder
consistent with sludge and possibly early
cholelith development. Otherwise, normal
abdomen. ”
TAMU #147332
Abdominal U/S:
“The liver appeared to
be of normal size, texture and
echogenicity. ... Essentially normal
abdominal ultrasound.”
Ultrasound and the Liver
• 40% (dog) to 60% (cat) accurate in
diffuse hepatic diseases
• Cannot distinguish benign from
malignant nodules
Modified laparoscopy
JAVMA 187:1032, 1985
Sterile
Not sterile
Sterile towel