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medsurg3
10/28

dr littman

small animal liver disease

[slide: bedlington terriers - 2/3 of which have liver problems]

remember 
from first year, we talked about liver lobules? Think of the sun and its 
rays....central vein, hepatocytes coming out in rays, then there are the 
triad of hepatic artery, portal vein, and bile duct

blood comes from 
periphery of lobule, percolates through sinusoids, goes out central vein, 
bile comes from hepatocytes and goes out through bile ducts - opposite 
direction. there can be damage near central vein with no icterus; or you 
can have some fibrosis near triad causing cholestasis and icterus.


hypoxia - first affects cells farthest from triad - so centrilobular 
cells are first affected by hypoxia. 

toxins from the GI tract - first 
affect cells near triad - periportal cells get affected first.

first few 
pages of handout are review

remember- albumin is only made in liver, 
half life 2-3 wks. won't drop acutely due to lack of production, but 
could drop due to leakage quickly. if albumin is low, you might be seeing 
peripheral edema, ascites, etc.

coagulation factors are made in liver - 
only factor 8 can also be made outside liver. with liver dz, acute or 
chronic, there will be clotting problems 

globulins are made in immune 
system - liver is part of that. lipoproteins, macroglobulins, also made 
in liver. bile is made only in the liver. liver conjugates fat soluble 
things, making them water soluble for excretion by the kidney.

if animal 
has intrahepatic cholestasis, you may see raised conjugated and 
unconjugated bili. prehepatic jaundice due to IMHA - mostly unconj.
but 
after a few days, both will be raised. posthepatic will be mostly 
conjugated.again, after  a few days, it is harder to tell. generally, if 
bili is really high, think of extrahepatic obstruction - biliary duct, 
etc. or, prehepatic jaundice if anemia. true intrahepatic cases have 
usually low/middle range elevations.

people - get itchy when jaundiced, 
we do not see this in dogs/cats

serum bile acids - assess enterohepatic 
circulation. they are used in small intestine to digest fats and are 
reabsorbed from distal ileum, returned to liver. if that normal 
enterohepatic circulation is not working, due to shunt or whatever 
(congenital or acquired), serum level of bile acids is elevated. shunt 
can be congenital or due to fibrosis or other causes of portal 
hypertension. acquired shunts are multiple shunts. those are harder to 
deal with. 

other liver tasks - protein metabolism: urea cycle occurs in 
liver - takes ammonia from gut (from proetein degradation) to liver, 
where it is converted to NH2NH2 (urea) for excretion by kidney. if there 
is a shunt, blood ammonia is high. hyperammonemia also causes ammonium 
biurate urinary calculi and decreased BUN. these stones may not be 
radioopaque though, so u/s would be required to see them. u/a would 
reveal crystals in urine - they look like ear  mites! they look weird. 
you might have low BUN, pu/pd, hepatoencephalopthy...


hepatoencephalopathy - 3-8 hrs post meal as protein is broken down and 
ammonia is absorbed from colon. if dog is fed only at dinner, may miss 
signs of depression. dog can be manic or depressed - up all night, or 
comatose; disoriented, etc. sometimes seizures. (misdiagnosis = epilepsy 
- then if you start phenobarb you confound dx b/c phenobarb is 
hepatotoxin.

liver also is CHO metabolism factory - storage of glycogen, 
gluconeogenesis..but hypoglycemia is a late change seen in end stage 
fibrosis/cirrhosis; also seen in puppies with congenital shunts and small 
livers. 

detoxification - modification, conjugation of fat-soluble 
stuff...delayed recovery from anesthesia may be first sign.

kupffer 
cells - immune cells lining sinusoids - small livers or shunts present 
may prevent immunologic clearance of blood coming from gut, and animals 
more prone to septicemia

fat metabolism - low cholesterol is poor 
prognostic sign

catabolism of hormones, steroids, proteins...cortisol is 
usually degraded in the liver, so may see hypercortisolemia and signs of 
cushings. other proteins like gastrin - 
cushings animals prone to 
gastric ulcers b/c of
portal hypertension, hypergastrinemia

liver is 
very regenerative. hepatocytes can have mitotic events and regrow. but if 
there is a lot of fibrosis,there will be strange architecture. new 
nodules may not have good blood supply. 

signs of liver dz
icterus

ascites
edema
CNS signs
GI signs - v/d/melena, acholic feces
anorexia
wt 
loss 
fever
bleedinng/ DIC
drug/anest intolerance
pu/pd/amm biurate  
stones

could present with urinary obstruction, vomiting, diarrhea, 
melena - many ways to present. 

in cats, ptyalism (salivation) occurs
in 
dogs,a rare skin lesion - hepatocutaneous syndrome - superficial 
necrolytic dermatitis (tx with zinc) - see crusty paw pads. 

tests to 
screen for liver dz:

* = included in CBC/chem or UA at VHUP

*SALT: 
serum alanine aminotransferase (aka SGPT) - liver specific, half life 2.5 
hrs, intracytoplasmic enzyme which leaks readily w/changes in membrane 
permeability - but would be high after drinking a martini, or getting a 
caparsolate shot. if high, recheck. 

SAST: in lg animals - less liver 
specific in small animals

Arginase - liver specific enzyme

*SAP: serum 
alk phos - not liver specific - three major isoenzymes - one from 
osteoblasts is raised in puppies or with bone tumors; other two are from 
liver - from cholestasis or from steroids in dogs. this alk phos could be 
really high in cushings dog. the cholestasis isoenzyme will be elevated 
early during intra- and extra-hepatic cholestasis.

*GGT: elevated in 
cholestasis, liver specific - but also stimulated by steroids, phenobarb, 
other drugs. 

*SAST: more muscle enzyme in sm animals
*LDH not helpful


*bilirubin - total = conj and unconj. note that bilirubinuria is 
important. in cats there should never be conj bili in urine. if there is, 
it is spilling in from somewhere. means hemolysis,liver problem, 
something. in dogs, it may be a warning flag, but some dogs conjugate 
bili in their renal tubular cells so it may be normal. but in cat, pay 
attention. it shouldn't be in the urine.

*albumin - if low - problem. 
sign of chronic liver dz, or protein losing enteropathy or nephropathy


serum globulins are made not only by liver, so less helpful..
if albumin 
and globulin are both low, consider protein losing enteropathy. renal 
leakage usually will not let globulins out, too big.

*BUN - low levels 
suggest liver disease. could be urea cycle enzyme deficiency (rare), or a 
shunt. look at BUN/creat ratio. should be about 20:1. if you have a low 
BUN:creat ratio, think liver or low protein diet. high ratio might 
suggest high protein meal or GI bleeding.

coagulation tests - PT/PTT - 
bleeding times will be prolonged

*cholesterol can be high due to 
cholestasis (other causes exist too - diabetes, cushing's, hypothyroid...

low cholesterol is bad prognostic sign with liver dz; also a sign of 
lymphangiectasia, chylous effusion

serum bile acids - resting level on 
fasted animal, then 2 hr post feeding level. will detect shunting if 
high.

BG may be low, urine SG may be low, may see amm biurate crystals, 
CBC may show weird looking RBCs - target cells, spur cells, acanthocytes


function tests:

ammonia tolerance test: NH3 from intestine should be 
absorbed into portal blood and converted to urea by liver keeping NH3 
level low in blood. take test at 0 and 30 min fter oral NH4Cl is given. 
do not do to animal with CNS signs. just do resting level. or could just 
feed normal food and test 4 hrs post meal.  put sample on ice immediately 
and keep frozen til assayed or get false positive from degraded plasma 
proteins.

BSP test: a dye that acts like bilirubin (is carried by 
albumin to liver, excreted by bile - test not used anymore

ICG test - 
different dye test, not routine

Abdominal rads - may help assess liver 
size, tumors, ascites, etc. big liver, small liver, etc.

ultrasound - 
more detail - intrahepatic detail - gall bladder, ducts, nodules, veins, 
etc are visible. works even if ascites present. radiolucent ammonium 
biurate stones are visible.

there are also contrast studies you can do - 
contrast enema to see if it gets back to liver or shunts to heart, 
angiography, hepatobiliary scintigraphy, etc.

abdominocentesis - look 
for cell count, bilirubin, can culture, etc. 

liver biopsy - check 
PT/PTT first! bx percutaneously w/u/s guidance, laparoscopically, or 
surgically. if you suspect extrahepatic obstructive dz, use exploratory 
sx. take sample for histopath, cytology, culture, sometimes copper 
content although we have DNA test for bedlingtons now.

titers - lepto, 
toxo, etc. 

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tx for liver dz - specific or symptomatic


recall spaghetti diet - low protein diet - should be well balanced, but 
high CHO, low protein, med/low fat. try to decrease amt of protein in 
diet. if there is no hepatoencephalopathy, try a tolerance test first 
though, b/c you want to keep protein intake normal if the pet can 
tolerate it.

smaller more frequent meals can help. can give lactulose to 
acidify colonic contents and trap ammonia in colonic lumen.  can give as 
enema or orally.

some protein sources are better than others. cottage 
cheese has a good amt of branched chain AAs, fewer aromatics - that is 
good for liver case.
avoid feeding liver to these pets! it contains 
copper and other things bad for liver dz. also avoid salt - probably 
already have edema due to low protein, could make it worse with high salt 
intake. feed normal salt load. ok to feed pretzels, but no salt on them. 


give multivitamins with K+, Ca++ and Zn mineral supplements. Zn 
interferes w/copper absorption, that's good for liver cases. 

if you 
have to transfuse - use FRESH FROZEN PLASMA or fresh blood. not stored 
refrigerated blood! stored blood gets higher ammonia content - this is 
why we have to send in samples on ice, remember? FFP is safest to replace 
albumin. do not use stored blood at all.
if they need red cells, you can 
give fresh blood.

abdominocentesis - may be required to ease dyspnea, 
but do not take all the fluid away b/c by emptying that space you will 
cause hypovolemia - fluid will leave vascular space and refill third 
space and cause a crisis. use diuretics judiciously - K+ sparing. if 
there is pleural effusion, you do want to empty the fluid from the chest, 
though.

antibiotics - these animals are prone to sepsis, remember, so 
you need to give abx for that sometimes, also sometimes to clear gut of 
ammonia producing flora. do not use sulfa or tetracyclines. usually use 
penicillins (amoxi, amp, clavamox, keflex..), sometimes flagyl for 
anaerobes, clostridia, etc. flagyl can be hepatotoxic though. might use 
neomycin/baytril to decrease GI flora; might use specific abx to tx 
cholangiohepatitis if your aerobic/anaerobic culture of liver was 
positive.

H2 blocker - decrease gastric acidity - anti-ulcer tx. moving 
away from tagamet/cimetidine b/c it causes liver probs; ranitidine 
better. tagamet can decrease hepatic arterial perfusion and inhibit p450 
system. also use sucralfate for gastric ulcers

immunosuppressive meds? 
depends what is wrong with liver - if severe inflammatory component - 
some animals put on steroids for chronic active hepatitis (CAH) lived 3x 
longer than those not on steroids...so more and more people are now 
willing to try the pred - may improve appetite, quality of life. can 
cause steroid induced hepatopathy. don't use if infxn present.

actigall: 
helps decrease bile acids. no adverse effects. 
Zn: helps to improve 
crusty footpads and decrease Cu absorption.

antifibrotic - 
d-penicillamine, colchicine - not clear if these improve longterm 
results. study in people with cirrhosis on and off colchicine showed 
liver bx better in colchicine group, but no change in survival time.


chemotherapy for liver cancer

avoid drugs that require hepatic 
inactivation or excretion; be wary and careful with anesthesia, use 
glucose drip, give vitamin K to help make clotting factors if you are 
doing biopsy; for an hour prior to biopsy give FFP to help clotting in 
advance.

types of liver dz:

concepts - VITAMIN D system - 
developmental, anatomical, metabolic, vascular, neoplastic, infection, 
autoimmune, toxic, traumatic....think of all these things that could be 
problems.
consider if congenital or acquired problem, acute vs chronic...

remember foals that got mineral supplement in first few days of life...it 
was high in iron and these normal foals were given this stuff, for a few 
days, and within 2 weeks they were all hepatoencephalopathic. the NBC 
vets figured out that they had a liver problem that was not congenital 
but was due to toxic insult b/c GI tract allowed them to absorb way more 
of the iron than would be expected in an adult, and the iron was toxic to 
their livers. these foals had fibrosis and cirrhosis. the product was 
taken off the market, people were sued, but really to me (hillary, not 
meryl) it sounds like the owner just used it wrong...

acute hepatitis - 
acute hepatocellular degeneration
note that acute hepatitis is caused by 
things that also can cause chronic hepatitis. may be immune mediated dz 
occuring as sequela to acute hepatitis which keeps hepatitis going on, 
too.
causes: often unknown
-hepatotoxins: CCl4, mycotoxins, aflatoxin, 
chlorinated hydrocarbons, heavy metals, acetaminophen, tapazole, 
mebendazole, oxibendazole in filaribits plus, trimethoprim/sulfa, 
phenobarb, diazepam (used to use in cats for behavior stuff,some got 
liver dz over time), methoxyflurane, sulfa in general, caparsolate, 
carprofen  (Rimadyl - this is scary - an NSAID that is  "safer on the 
stomach" and which may be hepatotoxic especially in labradors). if you 
give intranasal kennel cough vaccine subcu by error, it causes liver 
failure.
-organisms: suppurative cholangiohepatitis, ICH (infectious 
canine hepatitis- rare due to vaccine), leptospirosis/new serovars, 
clostridia, e.coli, toxoplasma (cat), FIP, systemic fungi, flukes, 
parasite migration
-acute tissue hypoxia, anemia, circulatory failure.

-acute pancreatitis - may extend and cause cholangiohepatitis
-immune 
mediated response

signs are variable - GI, icterus, anorexia, bleeding, 
DIC
dx: elevated SALT, albumin may not be low yet...liver  bx may help 


Hepatic cirrhosis: a problem that happens with chronicity - fibrosis. 
irreversible change. characterized by diffuse fibrosis and 
architecturally abnormal nodules (regenerative effort), due to 
hepatotoxins, lipidosis, immunological reaction.
signs: ascites, 
peripheral edema, etc.
lab dx: more subtle. SALT/SAP may not be as high 
as with acute b/c fewer hepatocytes are available to leak! function tests 
re more useful with chronic disease.
liver  may look small, may have 
anemia of chronic dz with rbc changes

chronic active hepatitis CAH:

bedlingtons, dobes, WHWT, cocker, skye terrier, lab; swiss cheese liver 
in bernese mt dog. causes as above but w/inflammatory cells

bedlingtons: 
autosomal recessive copper storage dz causes four syndromes
-incidental 
finding of high SALT
-chronic history of vague illness with long term 
progression to liver signs
-acute episodes of anorexia, lethargy, 
vomiting, dehydration
-acute hemolytic anemia and jaundice with high SALT 
due to sudden release of copper from necrotic liver.
dx: old way, wedge 
bx; new way, DNA marker
rx: diet changes, d-penicillamine which chelate 
copper, and zinc.
lab dx of CAH: SALT - recurrent slight/moderate 
increases that do not go away
CAH eventually lead to cirrhosis


infiltrative liver dz:
tumors: cat liver lymphoma often FELV negative. 

metastatic tumors more common than primary liver tumors.
pancreatic 
adenocarcinoma, hemangiosarcoma, etc.
primary :biliary adenocrcinoma
may 
see biliary obstruction
some breed predispositionns: LSA goldens, cat; 
etc.
black and tan breeds seem to get malignant histiocytosis

hepatic 
lipidosis/fatty change
in dogs - diabetes mellitus, cushings
cat - more 
common/important - seen in fat cats that stop eating for some reason and 
then mobilize fat stores. signs vary with presentation. if cat is 
vomiting, we have probs b/c you have to feed them so they stop moving fat 
into liver. may require TPN or jejunostomy tube. 
if lucky, use oral 
feeding - can use PEG or NG tube - nutritional support is most important 
tx. 
sometimes, cat has pancreatitis or cholangiohepatitis with this. 
that's complicated to deal with.

steroid hepatopathy: -in dogs

noninflammatory hepatocellular vacuolation on bx (glycogen, fat 
accumulation)
hepatomegaly (hyperechoic on u/s)
realize - if liver is big 
or alk phos is high, and dog is on steroids don't worry so much about the 
liver stuff, you know it is from the steroid.


cholangitis/cholangiohepatitis: may be suppurative, neutrophilic...tx 
abx, may be seen w/pancreatitis esp in cats which often have IBD and 
pancreatitis w/chlangiohepatitis. 
may be lymphocytic/plasmacytic 
infiltration - viral? immune mediated? 
in cats - periportal lymphocytic 
hepatitis or diffuse lymphosarcoma - weird stuff. see notes. can be hard 
to tell if LSA or not

shar pei- amyloidosis of liver

hyperthyroid cats 
- can have high SALT/alk phos
will resolve when tx hyperthyroid
probably 
due to increased metabolic demands on liver

extrahepatic biliary 
obstruction b/w liver and gut - 
causes - tumors, pancreatitis, foreign 
bodies in gut, duodenal inflammation
usually very icteric, orange, dark 
urine, acholic stool if complete obstruction; very high alk phos


portocaval shunts - congenital
small livers, small glycogen stores, 
hypoglycemia, hepatoencephalopathy, signs of chronic liver 
failure.usually in young dog/cat under a year but sometimes older. 
yorkies, min schnauzer, dobe, gshep overrepresented

therapy - low 
protein diet, lactulose...but really, if surgical candidate (congenital 
single, extrahepatic shunt) try to ligate shunt partially - if you do it 
totally you get acute portal hypertension and pancreatitis. sometimes 
thrombus develops at site of partial ligature and causes the same thing, 
too. this is not risk free but is still best option.try to partly close 
shunt to promote new anastomotic flow to liver.
some animals do not get 
sx, they are managed medically with low protein, lactulose, etc. shorter 
than normal life, though. sometimes btw repeat sx are required.





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