Drugs in Liver Disease: All You Need To Know

WSAVA/FECAVA/BSAVA World Congress 2012

Lauren A. T repanier, DVM, PhD, DACVIM, DACVCP
Unive rsity of Wisc onsin - Madison, S c hool of Ve te rinary Me dic ine , Madison, WI, US A

Making a Diagnosis
It is import ant t o perform a liver biopsy whenever possible. Specific biopsy findings
t hat can drive t herapy include: degree of fibrosis (mild, moderat e or severe);
predominant inflammat ory infilt rat es (neut rophils vs. lymphocyt es and plasma cells
vs. pyogranulomat ous); degree of necrosis; presence of cholest asis; and presence of
cirrhosis (dist ort ion of archit ect ure by fibrosis and nodular regenerat ion). The
locat ion of inflammat ion may indicat e t he underlying source. For example, in port al
hepat it is, inflammat ory cells (especially neut rophils) are found around port al areas
wit hout necrosis or fibrosis. This may indicat e inflammat ion secondary t o
ext rahepat ic causes, such as sept icaemia, gast roint est inal neoplasia or inflammat ory
bowel disease. Such cases may not need primary hepat ic t herapy, but inst ead,
at t ent ion t o underlying abdominal disease.
When are Ant imicrobials Indicat ed?
Ant imicrobials are indicat ed for act ive hepat ic or biliary infect ion, ideally based on
result s of cult ure of bile or liver. Bile cult ures can be obt ained from gallbladder
aspirat ion under ult rasound guidance, or from bile fluid obt ained at laparot omy. If you
perform a biopsy of the liver, always culture the bile, and submit bot h aerobic and
anaerobic samples. Bile may be a more sensit ive sit e t o document hepat obiliary
infect ion (versus liver t issue). In almost 250 cases of liver and bile cult ures at t he
Universit y of Wisconsin, 36% of cat s had posit ive bile cult ures (14% posit ive liver)
and 28% of dogs had posit ive bile cult ures (5% posit ive liver). The most common
isolat es were Escherichia coli, Enterococcus spp., Clostridium spp. and
Staphylococcus. The empirical recommended durat ion is 2–4 weeks of t herapy, but
t his has never been evaluat ed.
When are Glucocort icoids Indicat ed?

The rat ionale for glucocort icoids (ant i-inflammat ory, ant i-fibrot ic and choleret ic
effect s) should always be weighed against pot ent ial side effect s in each pat ient .
Consider glucocort icoids for predominant ly lymphocyt ic-plasmacyt ic or eosinophilic
inflammat ory infilt rat es on liver biopsy. Glucocort icoids may be used empirically
(wit hout biopsy) and wit h care if t he owner refuses biopsy, if progressive increases in
alanine aminot ransferase (ALT) are not ed and if infect ious and neoplast ic causes
have been ruled out wit h ult rasonography and serologies. They can, however, be
associat ed wit h severe side effect s in t he animal wit h liver disease (see below).
Prednisolone is preferred in cat s due t o apparent poor conversion of prednisone t o
prednisolone. Budesonide may be less likely t o induce serum alkaline phosphat ase
(ALP) in dogs. It can, however, st ill cause significant polyuria/polydipsia in some dogs,
and leads t o adrenal suppression.
Precaut ions wit h Glucocort icoids
Glucocort icoids are cont raindicat ed in pat ient s wit h uncont rolled hepat ic
encephalopat hy, ascit es, act ive gast roint est inal ulcerat ion, hepat ic lipidosis and
act ive hepat obiliary infect ion. Always st abilise pat ient s and t reat for encephalopat hy
and gast roint est inal ulcers before st art ing glucocort icoids. Add glucocort icoids as a
single change (e.g., 2 weeks aft er ot her support ive care has been st art ed) and
monit or carefully for improvement or decompensat ion. If ascit es is present ,
subst it ut e dexamet hasone (at 1/7 t he dose) for prednisone, since dexamet hasone
has no mineralocort icoid act ivit y.
Immunomodulatory and Ant ioxidant T herapies
Most recommendat ions for t hese agent s are ext rapolat ed from experience in
humans, and are ideally based on a pat ient 's individual liver biopsy findings.
Ursodiol (ursodeoxycholic acid) is a choleret ic bile acid t hat also reduces
hepat ocellular injury and fibrosis in humans and animal models. In pat ient s wit h
moderat e t o severe cholest asis wit hout obst ruct ion, ursodiol is indicat ed as a
choleret ic. It is also t he drug of choice for primary biliary cirrhosis in humans, which
resembles feline cholangit is. Ursodiol is dosed at 10–15 mg/kg/day; t ablet s can be
reformulat ed for cat s and small dogs. Ursodiol should not be used unless bile duct
obst ruct ion has been ruled out (based on normal bilirubin or by ult rasonography).
S-adenosyl-methionine (SAMe) is a modified amino acid, import ant for met hylat ion
react ions in t he liver and elsewhere. SAMe prot ect s membranes from bile salt
damage, and enhances bile excret ion from hepat ocyt es. SAMe is also an indirect
precursor of glut at hione. SAMe administ ered t o dogs helps t o count eract liver
glut at hione deplet ion t hat occurs wit h liver disease or wit h cort icost eroid
administ rat ion. There are no cont rolled clinical t rials of efficacy in dogs wit h nat urally
occurring liver disease, but SAMe has been shown t o prolong survival in alcoholic
cirrhosis in humans. Empirical indicat ions include chronic hepat it is or cholangit is wit h a
significant component of necrosis. Recommended dosing is 18–20 mg/kg on an
empt y st omach, but refer t o individual product s for exact dosing recommendat ions.
Ent eric-coat ed t ablet s should not be broken open.
Milk thistle (silymarin) is anot her hepat oprot ect ive compound, which has been used
for hepat ic disorders since t he t ime of t he ancient Romans. It is t hought t o scavenge
react ive oxygen species, and may have ant i-inflammat ory effect s via inhibit ion of 5-
lipoxygenase. Milk t hist le has been shown experiment ally t o prot ect dogs against
Amanita mushroom hepat ot oxicit y. Milk t hist le may be used in pat ient s wit h
significant inflammat ion and necrosis on biopsy, in addit ion t o, or inst ead of, SAMe.
The empirical dosage is 1.5–8 mg/kg/day. Product formulat ion and pot ency may vary
significant ly from one manufact urer t o anot her.
Vitamin E is a crit ical membrane ant ioxidant t hat prot ect s hepat ocyt es against t he
t oxic effect s of bile acids in vitro. It s use has been advocat ed as empirical t herapy
for any inflammat ory hepat opat hy, especially hepat opat hies wit h significant necrosis.
Vit amin E may be used in addit ion t o SAMe or silymarin, and is empirically dosed at
150–600 IU per dog per day. Overdoses of vit amin E can lead t o a coagulopat hy, and
even modest doses (approximat ely 15 IU/kg in humans) can lead t o subclinical
decreases in t he funct ion of prot hrombin, a vit amin K-dependent coagulat ion fact or.
Alt hough t he exact mechanism is not underst ood, it is hypot hesised t hat high-dose
vit amin E may ant agonise t he effect s of vit amin K. Furt her, vit amin E has been shown
t o exacerbat e t he ant icoagulant effect of warfarin in dogs. Unt il more is known,
vit amin E supplement at ion should be avoided or monit ored carefully in pat ient s wit h
liver disease and coagulopat hy.
Ant ifibrot ics and Decoppering Agent s
Three major ant ifibrot ics are in common use: glucocort icoids, zinc and colchicine.
Glucocorticoids inhibit fibroblast proliferat ion, and may be adequat e for t reat ment
of mild t o moderat e fibrosis accompanied by inflammat ion, part icularly in cat s.
Zinc inhibit s collagen synt hesis and decreases hepat ic fibrosis in animal models. As
a cofact or for superoxide dismut ase, zinc may help t o scavenge superoxide radicals.
Zinc also impairs copper absorpt ion. Zinc may t herefore be useful for dogs wit h
chronic hepat it is wit h moderat e fibrosis, especially if mild t o moderat ely increased
copper is present . The empirical dosage is 15 mg/kg of element al zinc per day. The
goal is for serum zinc levels of 200–500 µg/dl (2–5 µg/ml). Zinc should ideally be
given on an empt y st omach (1 hour before or aft er a meal). I prefer t o add zinc in as a
single drug aft er st abilisat ion of t he dog wit h hepat oprot ect ive agent s and
glucocort icoids (if indicat ed). Formulat ions include: MarinT M: 45 mg of zinc per t ablet
(1–2 mg/kg of element al zinc at label dose); zinc gluconat e (14.3% zinc); and zinc
acet at e (35% zinc; no commercial product but may cause less gast roint est inal upset
t han sulfat e or gluconat e forms). Haemolysis can occur if serum zinc exceeds 1000
µg/dl.
A recent st udy in Labrador Ret rievers in t he Net herlands found t hat zinc did not
increase t he effect iveness of a low copper diet (Royal Canine Hepat ic LS) in reducing
liver copper concent rat ions in dogs wit h copper-associat ed hepat opat hy t hat had
been pret reat ed wit h D-penicillamine. No ot her efficacy st udies have been performed
for zinc.
Colchicine decreases collagen synt hesis. It may be useful in dogs wit h chronic
hepat it is and moderat e t o severe fibrosis, or wit h port al hypert ension and ascit es.
There are however no cont rolled clinical t rials of it s efficacy in dogs. The dosage in
dogs is 0.03 mg/kg orally once daily. Occasional gast roint est inal upset usually
responds t o a 50% dose reduct ion. High dosages can cause leucopenia or peripheral
neuropat hy. Do not use probenecid-cont aining formulat ions, which increase t he risk of
t oxicit y.
D-penicillamine is primarily a copper chelat or, but may also inhibit fibrosis by
prevent ing cross-linking of collagen. It is indicat ed for copper-associat ed
hepat opat hy (Bedlingt on Terriers, some West Highland Whit e Terriers, Dalmat ions,
some Labrador Ret rievers), wit h quant it at ive hepat ic copper levels > 3000 µg/g (dry
mat t er basis). The recommended dosage is 15 mg/kg t wice daily, 30 minut es prior t o
feeding. It may t ake several mont hs for decoppering of liver and improvement s in
ALT. Some clinicians t reat wit h D-penicillamine for 2 mont hs, t hen swit ch t o zinc.
Gast roint est inal upset is also common wit h D-penicillamine.
Ant i-Ulcer T herapy
Empirical ant i-ulcer t herapy is recommended for all acut e and chronic liver disease.
Liver disease is a common predisposing fact or for gast roint est inal ulcerat ion, due t o
impaired mucosal blood flow from port al hypert ension, bile acid st imulat ion of
gast ric acid secret ion and possibly decreased hepat ic clearance of hist amine and
act ive gast rin fragment s. Eit her H2 blockers or pump blockers can be used, alt hough
famot idine (1 mg/kg q12h) has minimal drug int eract ions. The H2 blocker aut horised
for dogs in t he UK is cimet idine.
Management of Hepat ic Encephalopat hy
A checklist for acut e management of hepat ic encephalopat hy includes:
  Lact ulose (orally, or by enema if st upor or seizures).
 No food for 12–24 hours.
 If no response, add met ronidazole (15 mg/kg/day orally).
 If no response, add neomycin orally at 20 mg/kg t hree t imes daily. Provide
int ravenous fluids wit h pot assium (and dext rose for pat ient s wit h
port osyst emic shunt s or severe cirrhosis).
 Add ant i-ulcer t herapy (gast roint est inal bleeding is a prot ein load in hepat ic
encephalopat hy), and add vit amin K1 if jaundiced.
 Wit hhold any glucocort icoids unt il encephalopat hy is resolved!
 Give as much diet ary prot ein as t olerat ed; increase t he lact ulose dosage if
needed.
Management of Ascit es
Spironolactone / hydrochlorthiazide (Aldact izide) is an excellent diuret ic for
hepat ic ascit es. It is more pot ent t han spironolact one alone, but causes less
hypokalaemia and dehydrat ion t han furosemide. The empirical dosage, based on t he
spironolact one component , is 0.5–1.0 mg/kg orally q12h. Furosemide mobilises fluid
well but oft en leads t o hypokalaemia and hypovolaemia.
Therapeut ic abdominocent esis is indicat ed if significant ascit es is impairing mobilit y
or causing respirat ory compromise, and is refract ory t o medical management . I
supplement wit h colloids prior t o cent esis, t o prevent hypovolaemia and worsened
hypoalbuminaemia as fluid shift s back int o t he abdomen. St art an infusion of 10 ml/kg
of Het ast arch over 3 hours, and perform abdominocent esis aft er t he first 30 minut es
of t he infusion. Monit or bodyweight , hydrat ion and abdominal girt h (measure girt h at
level of t he second lumbar vert ebra wit h a measuring t ape) t o document
improvement or progression of ascit es at home.
Assessing Response to T herapy
When using prednisone or prednisolone in dogs, you cannot rely on serum ALP t o
monit or response, since it is induced by glucocort icoids. ALT act ivit y may also
increase wit h prednisone in dogs, but will usually decrease overall as inflammat ion
subsides. ALP and ALT are reliable in cat s, since t hey are not st eroid-inducible. Ot her
paramet ers t o monit or include: albumin and bilirubin; bodyweight , body condit ion
score, abdominal girt h (in dogs); and clinical st at us, t o include appet it e, energy,
resolut ion of vomit ing and diarrhoea, avoidance of severe polyuria/polydipsia and
pant ing.
  
Speaker Information

(click the speaker's name to view other papers and abstracts submitted by this speaker)

Lauren A. Trepanier, DVM, PhD, DACVIM, DACVCP

Universit y of Wisconsin-Madison

School of Vet erinary Medicine

Madison, WI, USA

URL: https ://www.vin.com/doc/?id=5328279