13. large animal med- chronic/toxic liver disease and tx

why can chronic liver disease be difficult to diagnose?

due to multiple syndromes being clinically similar

-hard to differentiate on blood tests

-ultrasound helpful, but, biopsy often necessary for diagnosis

what is chronic active hepatitis (CAH)?

chronic, idiopathic hepatic inflammation

characterized by periportal and/or biliary inflammation with variable fibrosis and inflammatory infiltrate (usually lymphocytes and plasma cells)

what pathology does CAH cause to the liver?

inflammatory or infectious insults promote biliary proliferation which may impair bile excretion, destroy hepatocytes, and encourage fibrosis

what are the clinical signs of CAH?

clinical signs of chronic liver disease:

-weight loss, icterus, depression

- +/- behavior changes

-mild colic, intermittent fever

-aseptic vasculitis (rare) causing dermatitis of coronary band

what clinpath changes are seen with CAH?

-mild elevations in AST and SDH

-elevated ALP and GGT during active dz

-elevated serum bile acids (variable)

-elevated bilirubin (conjugated bc cholestasis)

-variable increase in WBCs, fibrinogen, TP

how is CAH diagnosed?

requires biopsy:

-culture the first biopsy sample

-histopathology

what is seen on histopath in patients with CAH?

1. mononuclear infiltrate (lymphocytes, plasma cells, sometimes neutrophils- suggests bacteria)

2. biliary hyperplasia

3. hepatocellular necrosis (bridging lobules or from portal tract to central vein; fibrosis/cirrhosis can eventually occur)

what is the treatment for CAH if due to infection?

antibiotics if fever, CBC, culture, or biopsy suggest infection:

-4 -6 weeks or more

-if culture is negative, choose antibiotic for enteric bacteria (TMS, excede, minocycline)

what is the treatment for CAH if due to lymphocyte infiltration?

corticosteroids (prednisolone, dexamethasone) if lymphoplasmacytic infiltration or fibrosis

what is the prognosis of CAH?

depends on clinical severity and biopsy:

-poor if severe signs or severe fibrosis or cellular disruption on biopsy

-moderate if less chronic or have lymphocytic infiltrate that responds to steroids

**should do serial monitoring of chemistry

what is suppurative cholangiohepatitis?

characterized by neutrophil accumulation within portal tracts and bile ducts

what can suppurative cholangiohepatitis cause?

cholelithiasis

eventual function loss

CAH

what are clinical signs of suppurative cholangiohepatitis?

fever

colic

icterus

weight loss

increased GGT

how is a preliminary diagnosis of suppurative cholangiohepatitis made?

history, clinical signs, and laboratory values:

-elevated enzymes, conjugated bilirubin, inflammatory CBC

how is suppurative cholangiohepatitis diagnosed via ultrasound?

-diffuse increase in echogenicity (cellular infiltrate and fibrosis)

-hepatomegaly (variable)

-mild biliary distension and biliary wall thickening

what is the purpose of doing a liver biopsy for suppurative cholangiohepatitis?

determines severity of disease and degree of fibrosis

shows neutrophilic infiltrate and hepatocyte necrosis

what pathogen are most commonly cultured from liver biopsies in animals with suppurative cholangiohepatitis?

salmonella

e. coli

citrobacter

aeromonas

acinetobacter

what is the treatment for suppurative cholangiohepatitis?

- 4-12 weeks of antibiotics based on culture if possible

-serial measurement of enzymes

-TMS, pen/gent, ampicillin, chloramphenicol, enrofloxacin, ceftiofur

-address gram negatives, possibly anaerobes

what is cholelithiasis?

stones in smaller bile ducts or gallbladder (horses dont have one)

common cause of biliary obstruction in horses (in hepatic parenchyma)

what is choledocholithiasis?

stones in the common bile duct

what is the pathogenesis of cholelithiasis?

ascending inflammation or infection most likely

salmonella, e. coli, citrobacter, group D steptococcus all isolated (unknown if cause or result)

what are equine bile stones composed of?

mix of bile salts, calcium bilirubinate, and cholesterol

what are the clinical signs of cholelithiasis in horses?

triad of clinical signs:

1. intermittent colic

2. fever

3. icterus

often in horses over 5 years old

what do clinical signs of cholelithiasis in horses indicate?

signs indicate multiple stones or occluded bile duct (severe: photosensitization, encephalopathy, weight loss)

obstruction of the common duct can produce severe icterus and profound colic

what clinpath changes are seen with cholelithiasis in horses?

-increased ALP (>7x), GGT (7x), AST (2-4x) and SDH

-increased total bilirubin (>25-30% is direct/conjugated)

-increased serum bile acids, ammonia

-bilirubinuria, prolonged clotting times

-neutrophilia, increased globulins, fibrinogen

how is cholelithiasis diagnosed in horses?

-triad of clinical signs

-increased GGT, ALP, bilirubin

-ultrasound

what ultrasound findings are consistent with cholelithiasis?

-can have hepatomegaly (large with rounded edges)

-dilation and thickening of bile ducts (channel sign “=”)

-diffuse increase in echogenicity (vs spleen)

-choleliths usually in right lobe

-cannot visualize common duct (need gastroscope)

what are differentials for cholelithiasis in horses?

other forms of chronic liver disease

causes of mild recurrent colic (internal abscesses, enteroliths, neoplasia, parasites, sand, verminous arteritis, mesenteric abscesses, urolithiasis)

what is the treatment for cholelithiasis?

long term antibiotics (4-8 weeks) - TMS ideally, chloramphenicol, metronidazole, enrofloxacin, ceftiofur, ampicillin, penicillin-gentamicin

anti-inflammatories - oral phenylbutazone

surgery for choledocholithiasis if severe signs or medical therapy does not succeed

why is the liver so susceptible to toxic diseases?

bc the liver is often the first organ to encounter toxins

substances may be directly hepatotoxic or require biotransformation to toxic metabolites

what are causes of chronic megalocytic hepatopathy?

mycotoxins in ruminants

pyrrolizidine alkaloid containing plants

alfatoxicosis

if pyrrolizidine alkaloid (PA) containing plants are usually unpalatable, how does poisoning occur?

PA poisoning occurs when:

-forage is sparse

-dried plants in hay or silage

-seeds accidentally in ration

-sheep and goats very resistant (can graze)

what are the most common PA-containing plants?

senecio species: tansy ragwort (jacobaea), grounsel

echium species: salvation jane (echium)

lantana

heliotropium (common heliotrope)

how does acute/chronic toxicity occur with PA-containing plant ingestion?

acute toxicity with large consumption in short time period (very rare)

chronic delayed disease is more common (signs can be months to year later) → cumulative effect

what is the pathophysiology of pyrrolizidine alkaloid toxicity?

1. PAs hepatically metabolized to more toxic pyrroles

2. pyrroles crosslink double-stranded DNA (anti-mitotic)--> cells cant divide, and form megalocytes (chronic megalocytic hepatopathy) and cytoplasm increases w/o nuclear division

3. cells die and are replaced by connective tissue (fibrosis disrupts blood flow and prevents regeneration--> marked portal hypertension)

what are the clinical signs of pyrrolizidine alkaloid toxicity in horses?

-weight loss, icterus, encephalopathy

-photosensitization and diarrhea

-abortion with sub-lethal dz

-secondary gastric impaction in ponies

what are the clinical signs of pyrrolizidine alkaloid toxicity in cattle?

-diarrhea, weight loss, tenesmus, prolapsed rectum, ascites

-subtle neuro or behavioral changes

-calves much more susceptible

despite chronic nature, why can pyrrolizidine alkaloid toxicity have abrupt onset of clinical signs?

1. subclinical hepatic damage

2. gradual progression to liver failure with weight loss, anorexia, and mild icterus

3. acute presentation of hepatic failure with sudden onset of photosensitization and HE when hepatic mass reaches critical threshold

how is pyrrolizidine alkaloid toxicosis diagnosed?

-clinical signs, history of exposure to toxic plants

-hepatic enzymes

-serum bile acids (over 50umol/L is a poor prognostic indicator in horses)

how will hepatic enzymes change with pyrrolizidine alkaloid toxicosis?

SDH, LDH, and GLDH elevated during acute hepatocyte destruction, may be normal by the time signs present (this can also reflect decreased hepatic mass)

GGT and ALP consistently elevated (periportal lesion)

what are the classic liver biopsy findings with pyrrolizidine alkaloid toxicosis?

megalocytosis (+/-)

biliary hyperplasia

periportal fibrosis

liver itself will be small, firm and discolored

what is the treatment for pyrrolizidine alkaloid toxicosis?

-supportive, and control of HE

-improvement unlikely if substantial fibrosis present

-horses that retain appetite may survive if protected from further exposure

-death in 5-10 days once obvious signs of failure occur

-serial enzyme/bile acid measurements with serial biopsy helps prognosticate

what does bridging fibrosis seen in pyrrolizidine alkaloid toxicosis indicate?

associated with fatal outcome (very poor prognostic indicator)

how is pyrrolizidine alkaloid toxicosis prevented?

check dried feeds

adequate feed to pastured animals

graze sheep on infested pasture for weed control

what are the principles to treating hepatic disease?

1. eliminate further exposure to causative insult

2. control abnormal behavior

3. protein and clotting factor support

4. treat dehydration, shock, acidosis, electrolytes

5. caloric support

what are the different available treatments for treating hepatic disease?

-antioxidant, anti-inflammatory therapy

-antibiotic therapy if indicated

-B vitamins and fat soluble vitamins

-agents that reduce fibrosis

-agents that reduce ammonia

-surgical intervention if necessary

how is hepatic disease managed?

1. protect from sunlight

2. appropriate diet to stabilize metabolism in recovering or chronic cases

when is treatment for hepatic disease most effective?

therapy is best applied to acute liver failure, like theiler's or cholangiohepatitis

acute liver failure has good prognosis for regeneration

what are poor prognostic indicators of hepatic disease?

-hemolysis, HE, severe acidosis, diarrhea

-bridging necrosis or fibrosis on biopsy samples

-high serum bile acids, long PT, low albumin

how can behavior be controlled with hepatic disease?

-sedation with low dose alpha 2s (xylazine or detomidine, AVOID VALIUM)

-treat hypoglycemia

-reduce blood ammonia (oral neomycin)

how is blood ammonia reduced in horses?

-oral neomycin (1-2 days)

-metronidazole (cautious bc hepatic metabolism)

-lactulose or acetic acid to decrease colonic pH

-mineral oil, epsom salts (do not combine)

how does lactulose/acetic acid decrease colonic pH?

by increasing bacterial assimilation of ammonia and decreases production, traps ammonia in the lumen, and changes microflora

how can fluid therapy be beneficial for managing hepatic disease?

continuous IV fluids with 5% dextrose:

-provides calories and reduces gluconeogenesis

-decreases blood ammonia

-provides hydration and volume support

-improves bile flow

how is severe acidosis treated in animals with hepatic disease?

fluids +/- bicarb

why can adding potassium be beneficial for treating/managing hepatic disease?

hypokalemia enhances renal absorption of ammonia and may enhance intracellular movement of ammonia- by adding potassium into tx you are preventing this

what additional therapy can be used to treat/manage hepatic disease?

-plasma transfusion (coagulopathy/nutrition)

-anti-oxidants (mannitol, vitamin E)

-anti-inflammatories (flunixin)

-pergolide for hyperlipemic PPID ponies

-abortion of late pregnant mares/ponies

-vitamin B1, B9, A, D, E, and K1

when is antibiotic therapy indicated for hepatic disease?

for bacterial cholangitis/cholelithiasis, liver abscesses:

-penicillin and gentamicin (short term)

-ceftiofur, chloramphenicol or enrofloxacin

-TMS or sulfadiazine

-metronidazole (only treats anaerobes)

long term therapy up to 12 wks

how is response to antibiotic therapy for hepatic disease assessed?

monitoring response via fever, appetite, colic signs, and hepatic parameters

what additional therapy can be used in horses with CAH and bridging necrosis w/o evidence of bacterial etiologies?

corticosteroids

-gluconeogenic, stimulates protein catabolism and lipolysis (not desirable in overt liver failure)

which drugs/therapies may decrease hepatic fibrosis?

colchicine

cyclosporine

pentoxyfilline

why is dietary management important in animals with hepatic disease?

important during recovery or for animals with milder disease and good appetite:

-meet energy and protein requirements

-feed small meals frequently to maintain blood glucose and stabilize insulin regulation

what diet changes should be incorporated into patients with hepatic disease?

-palatable feed

-high carbs, moderate protein

-protein source rich in BCAAs (leucine, valine, isoleucine) such as sorghum, milo, beet pulp and bran

what types of feed should be avoided in patients with hepatic disease?

-avoid excessive protein (exacerbates signs of HE)

-avoid alfalfa and legumes

-grazing permissible if high protein spring grasses are avoided

-oat and grass hay preferable