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 =

WBC =

Segs =

33% (35-54)

11,100/ul (6,-17,000)

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 = 6 mg/dl (6-20)

Creatinine = 0.6 mg/dl (< 2.0)

Cholesterol = 51 mg/dl (120-247)

Glucose = 81 mg/dl (60-120)

Total protein = 5.8 gm/dl (5.5-7.5)

Albumin =

ALT =

1.8 gm/dl (2.5-4.4)

649 IU/L (< 110)

SAP =

Bilirubin =

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


What the clinician needs to know

• Breed predisposition




• Clinical signs

– chronic illness




• Clinical signs

– chronic illness

– asymptomatic dog with lab changes

– acute illness



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




• Clinical signs (or lack there of)

• Absolute necessity of biopsy

WHAT DO YOU DO

AFTER DIAGNOSING

CHRONIC HEPATITIS?

Drugs That Cause Hepatic Disease

Corticosteroids


Corticosteroids

Phenobarbital

Sulfa drugs

Acetaminophen

Primidone

Carprofen


Corticosteroids

Phenobarbital

Sulfa drugs

Amiodarone

Ketoconazole

Doxycycline

Azathioprine

Mibolerone

Mitotane

Mebendazole

Clindamycin

Acetaminophen

Primidone

Carprofen

Itraconazole

Diazepam

Methimazole

Phenytoin

Griseofulvin

Stanozolol

Clavamox

Cimetidine


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

Receiving drugs Not receiving drugs

Proceed with workup

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







Stop drugs


Increased ALT







Stop drugs


Increased ALT







Stop drugs



Copper-associated hepatic disease

• Bedlington terrier

• West Highland white terriers

• Doberman pinschers

• Skye terrier

• Dalmations

• Labrador retrievers


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


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



• 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



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 ...


• 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


• s-adenosyl L-Methionine (SAMe)

– Human studies

• acute intrahepatic cholestasis

• alcoholic liver disease

– Veterinary studies

• healthy animals

• acetaminophen, prednisolone


• Milk thistle (Silymarin)

–

Silybin is the active fraction

– Antioxidant, antifibrotic, anti-inflammatory

– Effective for Amanita , aflatoxin, acetaminophen, ethanol, ischemic damage


Prognosis

• Potentially ominous signs:

– ascites

– icterus

– severe hypoalbuminemia

– apparent cirrhosis

– hepatic encephalopathy


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 with > 99%+ certainty

Owner NOT content 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 =

57 mg/dl (8-29)

2.4 mg/dl (< 2.0)

128 mEq/L (138-148 )

Potassium = 4.9 mEq/L (3.5-5.0)

Total protein = 6.5 gm/dl (5.5-7.0)

Albumin =

ALT =

2.0 gm/dl (2.5-4.4)

72 IU/L (< 130)

SAP =

Bilirubin =

128 IU/L (< 147)

1.6 mg/dl (< 0.8)

GUIDANCE

Hepatic Biopsy

TYPE OF BIOPSY

Blind

Ultrasound

Fine needle aspirate

TAMU # 72927

Sig: 9 yr M(c) Cat

CC: Weight loss & vomiting

6 kg

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”

GUIDANCE

Hepatic Biopsy

TYPE OF BIOPSY

Blind

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

GUIDANCE

Hepatic Biopsy

TYPE OF BIOPSY

Blind

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

CHRONIC HEPATITIS Copper-associated hepatic disease

IMPORTANCE OF THE

WORD “CHRONIC”

WHAT DO YOU DO

AFTER DIAGNOSING