small animal med- hepatobiliary diseases part 2 (pages 15-36)

what is canine chronic hepatitis most often due to?

damage from copper (copper associated hepatitis -CAH)

copper is an essential trace element, but excess amounts can cause disease

what occurs when the amount of copper within a hepatocyte exceeds whats needed for normal physiologic processes?

cell damage occurs, resulting in focal necrosis, chronic hepatitis, and cirrhosis

-copper pigment granulomas are common sequelae

-acute hepatic necrosis from copper leading to hemolytic anemia can occur, but is rare

what breeds have genetic mutations which affect copper handling?

bedlington terriers

labs

doberman pinschers

westies

sky terriers

dalmations

how do copper pigment granulomas develop?

copper accumulates in the centrilobular regions--> increases hepatocellular necrosis, inflammation, and macrophages fill with copper --> pigment granulomas develop

what are the semiquantitative copper scores used with histology when evaluating evidence of chronic hepatitis and cirrhosis?

grade 0: no copper seen

grade 1: solitary hepatocytes in the centrilobular area have positive granules

grade 2: small groups of hepatocytes in centrilobular region have small to moderate granules

grade 3: centrilobular and some macrophages have moderate granules

grade 4: centrilobular and midzonal hepatocytes and macrophages affected

grade 5: panlobular or diffuse hepatocytes and macrophages

grades 3-5 consistent with CAH

are copper levels higher in CAH (copper associated hepatitis) or ICH (immune-mediated chronic hepatitis)?

copper levels higher in CAH

what are the copper levels in healthy dogs?

can be up to 400ppm

can cats get CAH?

they can, but it is uncommon

how else can CAH occur?

with cholestatic disease:

copper excreted thru bile, if bile is not moving, it will accumulate in hepatocytes and kupffer cells

almost always associated with inflammation

what are causes of immune-mediated chronic hepatitis (ICH)?

toxins and drug exposure

idiopathic

what are the histo findings associated with ICH?

-hepatocellular apoptosis

-hepatocellular necrosis

-mononuclear or mixed inflammatory infiltrates

-hepatocellular regeneration

-fibrosis

-cirrhosis

does severity of lesions with ICH correlate with clinical progression?

not necessarily

exception: cirrhosis --> end stage phenomenon

what occurs to hepatocytes when inflammation and necrosis is present?

free radicals are generated, leading to oxidant injury

how can immune-mediated chronic hepaitis (ICH) lead to copper accumulation in the liver?

ICH causes hepatitis or cholestasis, leading to copper accumulation

how can interface help differentiate ICH from CAH?

interface hepatitis is the death of hepatocytes at the interface of parenchyma and newly formed connective tissue- this is seen with ICH

what are the clinical signs of canine chronic hepatitis?

weight loss

anorexia

vomiting

lethargy

PU/PD

weakness

ascites

rarely: icterus, bleeding, seizures, fever

what physical exam findings may be seen with canine chronic hepatitis?

can be unremarkable

may occur: distended abdomen, poor BCS, icterus (rare)

what CBC changes are seen with canine chronic hepatitis?

-anemia of chronic disease

-thrombocytopenia if DIC present (uncommon)

what chemistry panel changes are seen with canine chronic hepatitis?

variable liver enzymes (usually ALT elevated first, then ALP. as functional mass decreases, so does ability to make liver enzymes, so both ALT and ALP eventually decrease

globulins are normal, but can be increased with chronic inflammation

may have abnormal bile acids and serum ammonia

what chem panel changes are seen with advanced chronic hepatits (synthetic failure)?

decreased BUN

decreased cholesterol

decreased albumin

decreased clotting factors

decreased glucose (poor prognosis)

what does increased PT and PTT indicate with canine chronic hepatitis?

guarded prognosis

what type of effusion is the ascetic fluid in canine chronic hepatitis?

can be a transudate or a modified transudate secondary to fibrosis and cirrhosis

what radiographic changes are seen in dogs with canine chronic hepatitis?

microhepatica

ascites causing decreased abdominal detail

what changes are seen on ultrasound in dogs with canine chronic hepatitis?

hyperechoic liver parenchyma

nodules

microhepatica

ascites

extrahepatic shunting (rare)

how is canine chronic hepatitis diagnosed?

biopsy

how is canine chronic hepatitis treated?

ICH: cyclosprine, mycophenolate, budenoside (a better glucocorticoid option)

-dietary protein restriction not recommended

CAH:

-primary tx with chelators and low copper diet

-ursodiol (cholorectic in some animals with increased bilirubin)

-antioxidants (SAMe, silybin, vit.E)

what is the prognosis of canine chronic hepatitis?

variable

recent report of ICH and CAH in 29 dogs showed 90% remission on biopsies taken 6 months later

copper levels should decrease to <400ppm

how is granulomatous hepatitis differentiated from granulomatous hepatitis in dogs?

granulomatous hepatitis has large numbers of macrophages that are typically seen as multifocal lesions

may also see lymphoma, histiocytosis, and intersitial lymphangectasia

what organisms are associated with granulomatous hepatitis?

Nocardia spp.

Mycobacterium spp.

Rhodococcus

Borrelia burgdorferi

Bartonella spp.

Histoplasma capsulatum

Coccidioides immitis

Hepatozoon canis

Heterobilharzia americanum

when is immunosuppressive therapy recommended for granulomatous hepatitis?

because infectious organisms are implicated in many cases, immunosuppressive therapy only recommended when infection is ruled out

what is acute liver injury characterized by?

characterized by inflammation, hepatocellular apoptosis, necrosis, and variable regeneration

may be self limiting, or can initiate chronic inflammation

what is acute liver failure?

refers to severe liver dysfunction requiring >75% loss of functional mass

often includes coagulopathy, increased bilirubin, hypoglycemia, and encephalopathy

which liver conditions can cause liver failure in dogs and cats?

drug toxicity, diffuse liver cancer, and hepatic lipidosis

what are the clinical signs of liver failure?

anorexia

depression

lethargy

vomiting with abdominal pain

jaundice

hepatic encephalopathy

-> hemorrhage may occur from depleted clotting factors or DIC

--> septicemia can occur from GI translocation

what clin path changes are seen with acute liver injury?

-moderate/marked elevation in transminases

-increase in cholestatic enzymes with time

-elevated bilirubin

-depending on extent of damage synthetic function may be abnormal (BUN, albumin, glucose, cholesterol)

-increased ammonia

how is acute liver failure treated?

treat underlying disease and supportive care

may need to supplement vitamin K1 in cases of cholestatic disease until clotting times normalize

what are some infectious causes of acute liver disease?

-infectious diseases (and some toxins): will see multifocal necrosis

-bacterial and protozoal diseases: neutrophils with necrosis

-viral causes: lymphocytes (or no inflammation)

-fungal/mycobacteria species: macrophages (+/- neutrophils)

why may severe, chronic liver damage be minimal?

due to the liver having an immense regenerative capacity

what are some infectious agents causing acute liver injury?

theres a lot, a few are:

-CAV-1

-canine and feline herpes virus

-lepto

-toxoplasma gondii

-neospora caninum

-brucella

-septicemia

-heartworm

-ehrlichia

-rickettsia

t or f: lepto is a common cause of acute liver disease

true

lepto is most commonly associated with acute renal and hepatic injury in dogs

liver damage is suspected to be immune mediated

what histologic changes of the liver are seen in animals with lepto?

edema

sinusoidal congestion

mild neutrophilic/eosinophilic infiltrates found in early disease

what are 4 clinically relevant lepto serovars which result in liver disease?

1. L. bratislava

2. L. autumnalis

3. L. grippotyphosa (causes chronic hepatitis)

4. L. Pomona

what is the treatment for lepto causing liver disease in animals?

supportive care for acute hepatitis

penicillins (amoxicillin, ampicillin) clear bacteremia, tetracyclines (doxycycline) to completely eliminate infection

^^lepto spp. have shown susceptibility to penicillins and tetracyclines

what enteric organism can cause hepatotoxicity?

clostridium sp.

what other bacteria (like from food poisoning) can cause hepatotoxicity?

staphylococci, e.coli, salmonella, bacillus cereus

why is the liver susceptible to drug induced injury?

the liver receives blood from the GIT so any ingested toxins or drugs enters portal circulation and can cause damage directly

metabolism by the liver in phase 1 reactions and conjugation via phase 2 reactions may damage the liver

drugs then circulate systemically and the liver can be repeatedly exposed via return thru hepatic arterial blood flow

what is the difference between dose-dependent and idiosyncratic liver injury?

dose-dependent: may resolve with dose reduction. more common and predictable

idiosyncratic: problematic regardless of the doss

what type of injury occurs with dose-dependent hepatotoxicity?

either cytotoxic or cholestatic

cholestatic injury results from inhibition of bile transporters, mitochondrial damage, or intrahepatic cholestasis

what are examples of drugs causing dose-dependent hepatic injury?

acetaminophen

antifungal azoles

lomustine

phenobarbital

amiodarone

azithropine

what are examples of drugs causing idiosyncratic hepatic injury?

NSAIDs

methimazole

trimethoprim-sulfa

diazepam

what is the MOA of acetaminophen causing hepatic injury in dogs and cats?

toxicity most common in cats, but hepatotoxicity can occur in dogs (never give to cats)

induces cytochrome p450 and impairs hepatic glutathione

what is the treatment for acetaminophen toxicity?

supportive care and anti-oxidants such as n-acetylcysteine and SAMe

cimetidine inhibits CYP450 and decreases production of toxic metabolites

how do antifungal azoles cause hepatotoxicity in cats and dogs?

hepatotoxicity is due to oxidative damage, glutathione depletion and mitochondrial damage

will see increased ALT in dogs and cats, but rarely liver failure

-elevations of ALT and ALP can correlate with dose

which antifungal azoles are most and least hepatotoxic?

-greatest damage occurs with ketoconazole and posaconazole

-followed by itraconazole and voriconazole

-fluconazole is the least hepatotoxic

monitoring patients on antifungal azoles longer than ___ weeks is recommended

2 weeks

glutathione precursors (SAMe) can be given to help prevent damage

what is lomustine? how does is cause hepatotoxicity?

an alkylating agent commonly used for neoplastic disorders

has a dose-dependent cumulative hepatotoxicity. portal hypertension and liver failure can occur months after d/c of drug

what hepatic histo changes are seen in animals given lomustine?

inflammation, portal vein abnormalities, biliary epithelial cell atypia, and fibrosis

what should be done before each lomustine dose in dogs?

evaluate liver enzymes and bile acids before each lomustine dose, and discontinue if there is a 4-5 fold increase in either

what is phenobarbital? which animals are at risk of hepatotoxocity with use?

a common first line anticonvulsant in dogs and cats, but cats do not have an inducible CYP450 so they are not at risk

what is the MOA of phenobarbital causing hepatotoxicity?

mechanism of toxicity unknown, but possible that inducing CYP450 makes them more susceptible to injury from other substances using this pathway

toxicity is both dose and duration dependent

what are concerns for significant damage caused by phenobarbital use?

-signs of hepatic encephalopathy

-if ALT>ALP

-increased bilirubin

-decreased albumin

-increased bile acids (should monitor bile acids every 6-12 months)

what is azathioprine? what are its affects in cats and dogs?

a purine metabolism inhibitor used for immune disorders

cats: not used bc of extreme susceptibility to bone marrow depression

dogs: causes dose dependent hepatotoxicity

what liver enzyme elevations are seen with azathioprine use?

increases in ALT and ALP occur, most commonly within first month of treatment

liver failure is rare

increases in liver values over 4-5 fold, increases in bilirubin, or other signs of hepatic failure should prompt dose reduction of d/c

what is idiosyncratic hepatic injury thought to involve?

immune mediated mechanisms that activate certain surface cell death receptors, signal apoptosis, signal necrosis, or cause hapten or neopitope formation on hepatocytes

most idiosyncratic injuries commonly cause centrilobular necrosis

what can happen if oral diazepam is given to cats?

can cause severe hepatotoxocity within days of administration to cats that can progress to fulminant liver failure (why diazepam is avoided in cats)

what can occur within the first month of methimazole administration in cats?

can cause cholestatic hepatotoxicity

-causes increased liver enzymes and jaundice

-injury typically reversible with discontinuation

what are the clinical presentations of acute liver injury?

-asymptomatic

-increased liver enzymes

-hepatic failure (BUN, glucose, albumin, cholesterol)

-anorexia

-vomiting/diarrhea

-coagulopathy

-renal failure (lepto, acute copper hepatopathy)

-abdominal pain

what is the treatment for acute ingestion (<8 hours) toxicities?

-induce vomiting (apomorphine in dogs, dexmed in cats)

-gastric lavage

-activated charcoal

-enemas

-cholestyramine (prevents enterohepatic recirc)

-antioxidants (SAMe, silymarin, vit.E)

-lipid emulsion for fat soluble toxins

do not induce vomiting if unconscious or ingested caustic substances

what is the treatment for fulminant (severe) hepatic failure due to toxicity?

-plasma and vitamin K to replace clotting factors

-dextrose for hypoglycemic patient

-fluids (promotes biliary and urinary elimination, also circulatory support)

-avoid protein bound drugs if toxin is highly protin bound

-nutritional support

what is the prevalence of cholangitis in cats?

second most common feline liver disease (most common is hepatic lipidosis)

no breed or sex predilection

what is cholangitis?

inflammation of the limiting plate (limiting plate=single layer of hepatocytes)

infiltrate can be suppurative (neutrophils) or lymphocytic cholangiohepatitis/cholangitis (lymphocytes)

what is cholangiohepatitis?

inflammation extending beyond the limiting plate

what diseases in cats is cholangitis associated with?

pancreatitis and IBD

other causes: trematode infection, extra-hepatic biliary obstruction, cholelithiasis, cholecystitis, ductal plate abnormalities, infections

what is ductopenia pathognomic for in cats?

destructive cholangitis

what is suppurative cholangitis?

neutrophilic inflammation in bile ducts +/- macrophages, lymphocytes, plasma cells

inflammation can extend to portal areas (cholangiohepatitis), will see periportal necrosis, biliary duct necrosis, degeneration, vacuolation, pyknosis (shrunken nucleus)

what is the pathogenesis of suppurative cholangitis?

ascending biliary infection

bacteria from intestine via portal circulation or hematogenous spread

what age of cats is suppurative cholangitis more common in?

middle aged/older cats

what are clinical signs of suppurative cholangitis in cats?

anorexia

lethargy

weight loss

fever

vomiting

jaundice

abdominal pain

what clin path changes are seen with suppurative cholangitis in cats?

-increased ALT , bilirubin, GGT, bile acids

-CBC: leukocytosis with left shift

-increased clotting times

how can diagnostic imaging be used to diagnose suppurative cholangitis in cats?

rads: unremarkable changes

ultrasound: gallbladder distension, prominent bile duct, choleliths, patchy echotexture, thickened gallbladder wall

what is needed to achieve a definitive diagnosis of suppurative cholangitis in cats?

histopath needed for definitive diagnosis

-FNA of gallbladder (may see neutrophils)

-submit bile and liver samples for aerobic/anaerobic culture and sensitivity

how is suppurative cholangitis in cats treated?

-supportive care

-antibiotics based on culture

-glucocorticoids (for short term anti-inflammatory and to increase bile flow, not for long term use)

-ursodiol if no extrahepatic biliary obstruction

-antioxidants

-vitamin K (give 36-48 hours prior to biopsy if coagulopathy present)

what antibiotics are used to treat suppurative cholangitis?

based on culture:

-amoxicillin, clavamox, cephalexin, metronidazole

-fluoroquinolones (esp. pradofloxacin) to get thru bile

how is suppurative cholangitis treated surgically?

1. cholecystectomy (removing gallbladder): if inspissated bile or choleliths

2. cholecystoduodenostomy (connects gallbladder and duodenum if common bile duct blocked): if complete biliary obstruction

3. choledochal stenting (relieves common bile duct obstruction)

what is the prognosis for suppurative cholangitis in cats?

-good with medical management

-poor if cholecystoduodenostomy

-cats with IBD/pancreatitis need additional therapy

what is non-suppurative cholangitis/cholangiohepatitis?

characterized by a lymphocytic or lymphoplasmacytic infiltrate in the area of the bile ducts

bile duct epithelium is invaded and biliary cells become dysplastic and degenerative, as well as bile duct hypertrophy and hyperplasia

with chronicity, fibrosis occurs that may bridge portal tracts

what is ductopenia?

more severe form of non-suppurative cholangitis where the bile ducts are destroyed and missing

ductopenia has a poorer prognosis

what is lymphocytic portal hepatitis?

cases of non-suppurative cholangitis where inflammation is only in the portal areas

is non-suppurative cholangitis more common in younger or older cats?

more common in younger cats

what are the clinical signs of non-suppurative cholangitis?

similar to chronic enteropathy:

-weight loss

-poor apetite

-vomiting

less common: icterus, ascites, polyphagia, hepatomegaly

what clin path changes are seen with non-suppurative cholangitis?

-increased/decreased liver enzymes

-increased bile acids

-GGT less often elevated than in suppurative

-hyperglobulinemia (from chronic inflammation)

what changes are seen on ultrasound with non-suppurative cholangitis?

-heterogenous liver with irregular margins

-dilated biliary tree

-hyperechoic liver if fibrosis present

how is non-suppurative cholangitis diagnosed?

histopath is required

biopsy:

-U/S guided tru-cut, laparoscopic, or surgical

-bile culture to r/o neutrophilic/suppurative dz

how is non-suppurative cholangitis treated?

-treat concurrent disease (IBD, pancreatitis)

-immunosuppression (prednisolone, budesonide)

-supportive (ursodiol, antioxidants, nutritional support)

what is the prognosis of non-suppurative cholangitis?

good for the short term, guarded for long term

destructive form (ductopenia) has poor prognosis

is extra-hepatic biliary duct obstruction (EHBDO) more common in cats or dogs?

more common in cats (cats pancreatic duct joins common bile duct and small intestine)

what are the most common causes of EHBDO?

fibrosis

inflammation

choleliths

neoplasia (biliary tree or duodenal papilla)

severe IBD

dilated/tortuous ducts w/o obstruction

how is EHBDO diagnosed?

abdominal ultrasound/CT

timeline of dilation after obstruction:

-gallbladder and cystic ducts= 24 hrs

-common bile duct= 24-48 hrs

-peripheral bile ducts= 5-7 days

what is the treatment for EHBDO?

-manage underlying dz (IBD, pancreatitis)

-surgery (if cholelith, neoplasia)

-stenting (if from inflammation, stricture)

what can EHBDO predispose to?

biliary infection (considered an emergency)