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Home , Hepatomegaly

Practical Disease Wendy Blount, DVM Primary vs Secondary Liver Disease • One of the most difficult tasks of dealing with liver disease is to distinguish one from another • Primary Liver disease must be treated at it’s cause, if we are to do anything but palliate • Secondary Liver Disease just distracts us from the primary problem, whether liver disease, and/or something else • Secondary Liver Disease = Reactive Hepatopathy • However, as the liver acts as an innocent bystander, it can suffer collateral damage, which we should mediate Primary vs Secondary Liver Disease Signs of Primary Liver Disease – The Liver Is Sick! • Change in liver size or shape – Hepatomegaly – Microhepatia – Liver mass – Irregular liver margins – Radiographs the best test for liver size – the best test for liver shape and to find masses • Icterus without anemia • Hepatic encephalopathy Primary vs Secondary Liver Disease Signs of Primary Liver Disease – The Liver Is Sick! • Acholic feces • Superficial necrolytic hyperkeratosis – aka hepatocutaneous syndrome Primary vs Secondary Liver Disease Signs of Primary Liver Disease • Coagulopathy – The Liver Is Very Sick!! – GI hemorrhage death spiral 1. Increased stomach acidity – Decreased hepatic clearance of gastrin, decreased mucus, mucosal ischemia – Increased bile acids further stimulate HCl secretion 2. Clotting factor’s, AT3 not produced adequately by failing liver – Poor clotting and thromboembolic disease 3. DIC – more AT3 consumption – more • Positive Feedback Loop #1 - GI Bleeding exacerbates hepatic encephalopathy • Positive Feedback Loop #2 - Large bleed can cause depletion coagulopathy Primary vs Secondary Liver Disease Signs of Primary Liver Disease • Coagulopathy – The Liver Is Very Sick!! – GI hemorrhage death spiral 4. Cholestasis Vit K absorption – Vit K needed to make factors 2,7,9,10 – Long term antimicrobial Tx inhibits Vit K production

– Hemorrhage elsewhere only when near death • Petechiae, bruising, bleeding into cavities Normal Liver Size • Look at the gastric axis!! (fundus to pylorus) • Normal gastric axis range: • From: perpendicular to the spine; To: parallel to the ribs. Hepatomegaly • Look at the gastric axis!! (fundus to pylorus) • Gastric axis more acute angle with the spine Hepatomegaly • Focal hepatomegaly is often, but not always neoplasia • Gallbladder mass can be mistaken for liver mass or even normal liver if filled with amorphous sludge Hepatomegaly • Focal hepatomegaly is often, but not always neoplasia • Gallbladder mass can be mistaken for liver mass or even normal liver if filled with amorphous sludge Hepatomegaly • Focal hepatomegaly is often, but not always neoplasia • Gallbladder mass can be mistaken for liver mass or even normal liver if filled with amorphous sludge Hepatomegaly • Focal hepatomegaly is often, but not always neoplasia • Gallbladder mass can be mistaken for liver mass or even normal liver if filled with amorphous sludge • Glycogen vacuolar hepatopathy can be focal • Nodular hyperplasia is a benign process causing liver masses • Generalized hepatomegaly • Primary or secondary liver disease • Toxic exposure and swelling of the liver – hypoechoic large liver with smooth borders and rounded margins • Steroid hepatopathy – hyperechoic large liver with smooth borders and normal margins • Any generally large liver with rounded margins can be neoplastic, regardless of echotexture and relative echogenicity – LSA, MCT, Microhepatia - Microhepatica • Look at the gastric axis!! (fundus to pylorus) • Gastric axis more obtuse angle with the spine Microhepatia - Microhepatica Differential Diagnosis: 1. Atrophy • Portasystemic shunt – any age, chronic disease • AV fistula – usually less than 2 yrs old (rare) • Often normal panel, but elevated bile acids + ammonias Microhepatiacirrhosis - Microhepatica scites Differential Diagnosis: iver 1. Atrophy – Small, maybe hyperechoic liver • Portasystemic shunt – any age, chronic disease • AV fistula – usually less than 2 yrs old (rare) • Often normal panel, but elevated bile acids + ammonias 2. • history of chronic inflammatory disease • History of massive hepatic necrosis • History of untreated PSS for years • Usually middle aged to older patients • Liver enzymes usually but not always elevated, bile acids elevated, albumin may be low • is common Microhepatia - Microhepatica Differential Diagnosis: 3. Congenital small size – diagnosis of exclusion • Imaging – no lumps, normal appearing margins, normal echotexture (just small) • All liver blood tests normal, except changes due to secondary liver disease • Liver biopsy normal • Splenic portagram normal Problems Causing Reactive Hepatopathy

• Any systemic or – Occult - urinary tract, metritis, prostatitis, dental disease, etc. • Disease of organ drained by portal vein – Gut, spleen, pancreas (ultrasound the best test) • Hyperthyroidism in cats • Severe muscle disease • Untreated Cushing’s Disease or diabetes mellitus • Hypoxia, passive congestion – , respiratory disease, severe anemia – hypotension • Drugs causing liver enzyme induction • VARYING DEGREES OF COLLATERAL DAMAGE Diagnostics for Liver Disease First Tier Tests: • CBC, panel, urinalysis • Fecal flotation, direct smear, cytology • HWAg in the dog, FeLV/FIV in the cat

Second Tier Tests: • Bile Acids • Complete Abdominal Ultrasound (not focused liver/GB and not GlobalFAST®) • Liver sampling & spleen FNA – after BMBT • FNA – 25-50% diagnostic • Ultrasound guided biopsy – 50% diagnostic • Wedge biopsy – more likely to be diagnostic Diagnostics for Liver Disease Third Tier Tests: • if Bile Acids are equivocal and PSS is suspected – Ammonia tolerance test – Splenic portagram • Coagulation tests if significantly systemically ill, severe liver disease is suspected, or liver sampling will be done • Hunt for causes of secondary liver disease • Imaging – thoracic rads and ultrasound • Testing for infectious disease and Cushing’s Disease • Diagnostic , MRI/CT Pattern Recognition - Liver Disease • High liver enzymes – ALT – hepatocellular disease (hepatocellular membrane) – ALKP, GGT – more sensitive indicator of cholestasis than bilirubin (from biliary epithelium) • Low albumin – low alb indicates severe disease (90% loss of hepatic function) – Beware human labs (falsely low values) - Abaxxis • Low fasting glucose (70% loss of hepatic function) • High prost-prandial glucose • Low BUN • Abnormal cholesterol, triglycerides ALT Gems The enzyme formerly known as SGPT • RBC & skeletal muscle contain small amts of ALT – Hemolysis and muscle damage cause moderate elevations in ALT (2-3x)

• ALT - t1/2 – 1-2 days – the first to improve – Starts improving within 1-2 weeks of liver disease resolution – remains elevated during hepatic regeneration • DDx hepatocellular turnover – Hepatocellular disease – Poor perfusion – hypotension, passive congestion, anemia • Marker for anaphylaxis, along with increased PTT and AFAST sonogram – Trauma – surgery, trauma, peritonitis – Toxicity ALKP Gems • Bone disease can also cause ALKP elevation – Neoplasia, osteomyelitis, hyperPTH, growth & healing • DDx cholestasis: – Gallbladder disease • Intramural - Gallbladder sludge, mucocoele, stones, infection • Mural - Gallbladder wall polyps, masses, infection • Extramural – Pancreatitis, , duodenal foreign body, diaphragmatic • Gallbladder trauma or rupture – Liver Disease • microscopic cholestatic disease (infectious, inflammatory, toxic), liver trauma, neoplasia, lipidosis ALKP Gems • DDx cholestasis: – Systemic cholestatic disease • Endocrine – diabetes mellitus, hyperadrenocorticism, chronic stress, hyperthyroidism • Passive congestion – RHF, pericardial disease • Systemic infection/inflammation – especially sepsis, rickettsial disease, protozoal disease, fungal disease GGT Gems • less influenced by secondary liver disease or acute hepatic necrosis than ALKP • Not confounded by bone disease as ALKP • more useful in cats to identify fatty liver • More useful in dogs to identify biliary disease • Otherwise, follows ALKP

Hepatotoxic Drugs

• Drug induced ALKP does not necessarily indicate hepatic – Assess with bile acids if concerned – Phenobarbital can also cause hepatotoxicity, but glucocorticoids almost never do • GGT increases markedly with corticosteroid enzyme induction in dogs • Drug induced ALKP takes weeks to months to resolve after stopping the drug • Glucocorticoids almost always elevate ALKP (and ALT) in dogs, but almost never in cats Hepatotoxic Drugs

• Drugs that increase ALT are more likely to cause hepatic damage if continued • At a marked increase in ALT, the offending drug should ideally be stopped, and ALT rechecked in 30 days • Lomustine - missing from the chart, but can cause potentially life threatening hepatotoxicity indicated first by increased ALT and then decreased albumin • Use of any drug on either chart indicates monitoring of liver nz + bile acids, albumin Elevated Liver Enzymes in the Cat Cats are not little dogs – Thumb Rules • Cats with persistently elevated enzymes should be worked up

– T1/2 of liver enzymes is hours in the cat, not days as in the dog – cats have 1/3 the liver ALKP compared to dogs • Cats with significant cholangiohepatitis can have normal liver enzymes, though that problem often causes very high ALT • GGT in cats has higher sensitivity but lower specificity for biliary disease • If a cat has biliary disease, GGT is likely high • If cat does not have biliary disease, GGT can still sometimes be high Elevated Liver Enzymes in the Cat Cats are not little dogs – Thumb Rules • ALKP elevation significantly exceeds GGT elevation only in hepatic lipidosis • High bile acids in the cat indicate liver disease nearly 100% of the time • Most common causes of ALKP elevation in the cat – Cholangiohepatitis, cholangitis – Hyperthyroidism – Fatty liver, diabetes mellitus (not hyperadrenocorticism alone) – (, Pancreatitis) Elevated Liver Enzymes in Well Dogs Grrrr… Reactive Hepatopathy or Liver Disease? 1. Expect ALKP to be high in growing dogs (2x) 2. Explore the history & exam for untreated problems that might cause reactive hepatopathy  treat 3. Treat empirically for common things first • Treat subclinical cholangiohepatitis – Amoxicillin 10 mg/lb PO BID x 3 weeks • Supplement to curtail hepatic inflammation – Denosyl®, Denamarin® – dosage chart in package • Now available in chewables (Denosyl®, Denamarin®) – Be careful of SAMe supplements not in foil packages – Milk thistle (Marin®) – Combination antioxidants (VetriScience Cell Advance®) Elevated Liver Enzymes in the Well Pet

Milk Thistle • Dried herb: 15-20mg/lb SID (1.5-3% silymarin) • Standardized Concentrated Extract: 2-5 mg/lb BID (70-80% silymarin) • concentrated extract: 2-5 mg/lb BID- TID (70-80% silymarin)

NOTE: some extracts are whole herb extracts, and these are hard to dose high enough to be effective Elevated Liver Enzymes in Well Dogs 4. Recheck Liver enzymes in 30 days 5. Proceed with further diagnostics for liver disease if still significantly elevated (2-3x), or trending up – Assess liver function with bile acids – Abdominal ultrasound and liver/spleen cytology – ACTH stim or Low Dose Dex if signs of Cushing’s 6. If Step 4 reveals no significant problems, Proceed to 3 Tier Liver Diagnostics – ammonia tolerance test, coag tests – testing for hyperadrenocorticism & infectious dz – splenic portagram, thoracic/advanced imaging – liver biopsy, diagnostic surgery Pattern Recognition Canine Liver Enzymes • ALT is highest with: – Acute hepatic necrosis – Primary hepatic neoplasia (except lymphoma) – Chronic inflammatory • Cushing’s Disease without elevated liver enzymes is rare, especially ALKP • GGT increases before ALKP in cholestasis • Scotties can have very high liver enzymes with no identifiable pathology Pattern Recognition Canine Liver Enzymes • Most common causes of increased ALKP – Hepatobiliary disease – Glucocorticoids (Cushing’s, iatrogenic or stress) – (Barbiturate anticonvulsant ) • Other Causes: – Cholestasis causing hepatotoxicity – Systemic Causes of increased ALKP • Sepsis, toxemia • Vacuolar Hepatopathy – glycogen or corticosteroid • Systemic inflammation or infection Pattern Recognition Canine Liver Enzymes • GGT in dogs is less sensitive but more specific than ALKP for biliary disease in dogs – If GGT is high, the dog probably has biliary disease – If GGT is normal, the dog still might have biliary dz • Albumin and BUN most often low with – chronic inflammatory hepatitis – PSS – cirrhosis Significant Liver Disease that may show Normal ALT & SAP

• End stage liver disease (cirrhosis) • Hepatic Lymphoma ** • Metastatic neoplasia • Portasystemic shunt (especially if advanced) • Feline Cholangiohepatitis • FIP** • Feline pancreatitis** • Histoplasma** **Not uncommon to cause icterus without elevated liver enzymes, in cats Diego 5 yr male Chihuahua – 4.4 lbs • Problems for 1-2 weeks • Acting weird - won’t go up and down the stairs, or through doors • Starts wandering, then falls over with tremors • Treated with Tramadol and Rimadyl by another vet – Gets “wired” after tramadol • Had a generalized seizure yesterday – Lasted 45-60 seconds – Several hours before back to normal • Has always been thin, and a very picky eater Diego Neurologic exam – declines referral to neurologist • Tongue deviates to the right – lower brain stem • CP deficits all 4 – L worse than R – R brain/upper neck • Seizures, dull mental state – cerebrum • Blind (PLR, eyes normal, + dazzle) – forebrain (cortical blindness) • Open fontanelle

Lesion Localization - Multifocal CNS Disease

Likely not an epileptic – neuro deficits between episodes Diego DDx – multifocal CNS Disease • Large or Metastatic neoplasia • Rickettsial, fungal, protozoal meningoencephalitis • Granulomatous meningoencephalitis • Hepatic encephalopathy • CDV, rabies unlikely • Could be compounded by hydrocephalus

Diagnostic Plan: • CBC, panel, lytes, UA, HW Test • Thoracic radiographs, abdominal ultrasound • Fasting and post-prandial bile acids Check Bile acids in any small dog with neurologic dz Diego CBC, panel, lytes – ALT 160 U/L UA – SG 1.008 Thoracic rads, abdominal US – NSAF BMBT – 1 min 30 sec

Treatment Plan pending bile acids, and cytologies of liver and spleen: • Levetiracetam (Keppra®) 40 mg (0.2cc) PO TID • 2.5 mg PO x 3d, then 1.25 mg PO x 3d, then 1.25 mg PO QOD x 3 doses, then as directed • Doxycycline 20 mg PO BID x 3 weeks • 50cc LRS SC BID Diego 3 days later – Recheck: • No seizures • Trouble seeing only at night • Improving every day, eating better • Still stumbles some – left side is still weaker • “Personality coming back in little doses”

Neuro exam • Tongue is straight, more alert • Little change in CP deficits

Bile Acids – fasting 74, 2 hour post-prandial 177 Diego Immediate Treatment Plan: • Metronidazole 20 mg PO BID – Will eventually transition to neomycin • Lactulose 1 cc PO TID – Can gradually increase, to effect for HE – Reduce if stools get too soft • Continue Keppra® • Diet –L/D • Silymarin 80% (milk thistle) 15 mg PO BID

Referral to Specialist for: • Splenic portagram – nuclear scintigraphy • Corrective or Diagnostic surgery, if indicated Splenic or Rectal Portagram • Splenic is often preferred to rectal portagram 1. Radioactive isotope put into the rectum or injected into the spleen 2. Put dog on the camera 3. See which lights up first – heart or liver • Liver first = normal • Heart first = PSS

Hospitalized for 1-3 days Diego Splenic portagram: • Scintigraphy shows mild shunting • No single extrahepatic vessel visualized on scintigraphy or ultrasound • Surgery to explore for single shunt recommended – If found, ameroid constrictor will be placed • If no single shunt found, liver biopsy for cause of HE • Big hubbub about whether to neuter him at the same time

3 weeks later: • Diego is feeling & eating better than he ever has • Finished with doxycycline, off prednisone • On silymarin, neomycin, lactulose, L/D, and Keppra® Diego Surgery: • No shunt found • Histopath revealed microvascular dysplasia • He was not neutered

Outcome: • Eventually weaned off neomycin/lactulose and did very well on Keppra®, silymarin & multiple small meals of L/D • Gained one pound in one month • Bile acids 6 months later 0.9 fasting, 50 post-prandial • 12 months – episode of HE responded to therapy • 20 months – HE unresponsive to treatment for 2 weeks – owners elected euthanasia Diego At the time of euthanasia: • CBC, panel, lytes normal

• 2 weeks prior to euthanasia, Diego was at the deer lease, and grabbed a chocolate chip pancake and downed it before they could get it away from him • He had seizures all night, fell into HE and never came out of it • A liver patient’s final episode is often precipitated by a stressful event – Anesthesia – Dietary indiscretion (high protein) Diego Lessons from Diego: • PSS dogs are not always diagnosed prior to 1-2 years of age – single intrahepatic shunts tend to present sooner – The milder the shunt, the older onset of symptoms • Some dogs with severe liver disease can do very well with medical/nutritional therapy for several years • Always check bile acids in small dogs with multifocal neurologic disease, cerebral signs, or seizures – Keep PSS on the differential diagnosis list • Euthanasia in PSS dogs is most often due to refractory hepatic encephalopathy Portasystemic Shunt

Hyperechoic, Small Liver Hypoechoic spleen Portasystemic Shunt Congenital 1. Single extrahepatic in small dogs • Yorkie, schnauzer, poodle, dachshund • Corrected with ameroid constrictor over 4-5 weeks Pattern Recognition – PSS • Signalment & History – usually but not always a young dog who has been a poor doer and intermittently ill with any symptoms of hepatic disease • may not have done well after first surgery – Most common symptom in cats with PSS: • • Other common signs – hepatic encephalopathy, GI upset • CBC – low MCV (Microcytosis) • Serum panel – usually a liver pattern, but could possibly be normal – Advanced PSS more likely to be normal than early PSS – Almost never icteric Pattern Recognition – PSS • Urinalysis – ammonium biurate crystals or stones are 33- 50% sensitive for PSS • Bile acids – usually markedly elevated – possible but unlikely to have intermittently normal bile acids • Ammonia – almost always elevated • Imaging – small liver + hyperechoic – Congenital – fails to receive trophic factors (80%) – Acquired – fibrosis and cirrhosis (20%) • Splenic Portagram – Extrahepatic and Intrahepatic shunts will show shunting which can be measured – Sometimes single shunts, if large, can be visualized on the scan – Microvascular dysplasia will give variable scan results, but often normal Hepatic Microvascular Dysplasia aka HMD aka MVD (microvascular dysplasia) aka portal vein hypoplasia aka microscopic portasystemic shunt • Portal veins branch normally, but they are hypoplastic • Portal venules travel right through the liver, instead of breaking down to capillaries to be detoxified by the hepatocytes • All of the portal venules are dilated, and do small scale shunting • Yorkshire, Cairn Terriers predisposed Hepatic Encephalopathy Abnormal mental status in patients with severe hepatic insufficiency • Caused by neurotoxins that bypass a failing liver into systemic circulation and hypoglycemia • Severity of HE does not always correlate with severity of liver disease Hepatic Encephalopathy Things that can precipitate an HE episode: • Increased protein intake, GI hemorrhage • Dehydration, diuretic therapy • Barbiturates, benzodiazepines and other sedatives Do not give diazepam or phenobarbital to HE dogs Keppra is the anticonvulsant of choice • Uremia • Infection, endotoxemia, , increased anaerobes in the colon • Increased methionine intake Progression of Hepatic Encephalopathy

1. Mildest form – and lethargy 2. May progress to weight loss, retarded growth, subtle behavior changes, inability to train, loss of training 3. Neurologic abnormalities – Ataxia – Confusion, stupor, loss/lack of training – Pacing and wandering – Twitching progressing to seizures 4. , 5. Severe neurologic problems – **Temporary blindness** – Dementia, seizures, coma – Multifocal deficits on neurologic exam Treatment of Hepatic Encephalopathy • IV fluids • Avoid drugs that exacerbate HE – Benzodiazepines (diazepam, lorazepam, midazolam, etc.) – CNS depressants – opiates, barbiturates, etc. – Drugs metabolized by the liver • Consider ammonia trapping when significantly low albumin, even if no HE – ammonia prevents release of albumin from the hepatocytes • Ammonia trapping – Lactulose metabolized by colonic bacteria to lower colon pH + – Ammonia (NH3) is converted to ammonium (NH4 ) + – NH4 is less lipid soluble and trapped in the colon Treatment of Hepatic Encephalopathy • Cleansing enemas to decrease bacterial numbers – Moves bacteria that make ammonia out of the colon – Warm soapy water 20-25 ml/kg up to q2hrs – Can add low dose Gentocin® to kill urease producing bacteria (0.45 mg/lb daily) • Retention enema after the cleansing enema • Anticonvulsants only if severe generalized seizures – Often needed only for managing the crisis – Keppra® first choice 20-60mg/kg IV, PO TID – Then zonisamide 5-10 mg/kg PO BID – Bromide likely won’t act fast enough to help, but can be used for long term control if Keppra® and zonisamide are not possible – Phenobarbital should be avoided due to hepatotoxicity Treatment of Hepatic Encephalopathy • Lactulose also an osmotic cathartic – Moves bacteria that make ammonia out of the colon – 0.5 ml/kg PO TID (up to q 2-4 hrs in HE crisis) – Titrate up until stools soft – Give as a retention enema if stupor prevents PO meds • Food Fast until crisis resolves – Avoid proteins if feeding L/D precipitates HE • Oral antibiotics – Anaerobes and gram negatives (gut flora) make ammonia – Metronidazole 3-5 mg/lb BID-TID – Neomycin 9 mg/lb PO TID (not absorbed systemically) – Beta lactam if gram negative spectrum needed – Add quinolone if severe HE • Eat L/D long term Bile Acids

1. 12 hour fast – red top tube 2. Feed 1-2 Tablespoons a/d (not low fat – need gallbladder contraction) 3. 2 hour post prandial red top tube Overfeeding can induce HE • If not fasted, doing only the post-prandial can be a screen for liver insufficiency • Can’t run bile acids on a lipemic sample • Don’t bother checking bile acids in an icteric animal – they are high Bile Acids • Things that decrease bile acids: – Severe disease or resection of the ileum – Prolonged anorexia – Delayed gastric emptying and intestinal hypomotility (delayed delivery to the ileum) – Intestinal malabsorption • Ursodiol increases bile acids • Gallbladder removal makes bile acid assays inaccurate • “Backwards” bile acids (post-prandial higher) due to blocked enterohepatic circulation or dysbiosis Urine Bile Acid:Creatinine Ratio (UBAC) • Better than a single bile acid value, if you can’t keep the patient for 2 hours, or can’t make a fractious animal eat • Treatment with ursodiol does not interfere • Hematuria and hemoglobinuria my interfere Protein C • Plasma anticoagulant works at endothelial cell surface • Vitamin K dependent – drops prior to PT, PTT with anticoagulant rodenticides • Low value identifies hypercoagulable state – Indicates need for Plavix® in chronic liver patients • May help distinguish PSS from MVD – <70% for PSS – >70% for MVD • Rise in Protein C after shunt surgery can mean hepatic flow was re-established • Low in dogs with aflatoxin poisoning • Cornell – Do Not Confuse with C Reactive Protein Pockets 12 year old F Yorkie: CC - GI upset while out of town • Bloodwork showed elevated liver enzymes – owners wants work-up • Regular vet said she was too small to spay • A+++ owner

Exam: 3lbs 11 ounces (ideal 5 lbs), BCS 3.5/5 • Has always been a very picky eater • 3 mammary nodules all < 2cm, mammary hyperplasia • Immature cataracts OU • G3 dental disease Pockets CBC, panel, lytes, UA - NSAF HWTest, fecal, current

Thoracic Rads: NSAF Abdominal US: Pockets CBC, panel, lytes, UA - NSAF HWTest, fecal, vaccines current

Thoracic Rads: NSAF Abdominal US:

Right kidney Pockets CBC, panel, lytes, UA - NSAF HWTest, fecal, vaccines current

Thoracic Rads: NSAF Abdominal US: hyperechoic liver, liver mottled in echotexture, mild sludge in gall bladder

Bile Acids: Fasting normal, post prandial 55 Liver Cytology: Mild suppurative cholangiohepatitis, with cholestasis. No etiologic agents seen. None of the hepatocytes show the atypia associated with neoplasia. Mammary Mass Cytology: mammary cells with mild atypia Inguinal Lymph node Cytology: reactive lymph node Pockets Tx • Denamarin® daily • Metronidazole 20mg PO BID x 4 weeks 2 weeks - OHE, remove MGT, liver biopsy, then dental Liver histopath: moderate portal fibrosis, mild hepatic vacuolar degeneration with cholestasis. Copper stains subjectively normal – no quantitation indicated. COMMENT: The lesions are mild. Moderate fibrosis is observed particularly in one portal area. Minimal numbers of inflammatory cells are observed within portal areas. My interpretation: chronic inflammatory hepatitis MGT histopath: mixed mammary tumors, completely excised Pockets 4 week recheck: • Feeling better than she has in years • Appetite has improved • Gained 0.5 pounds • Owner notes Denamarin® pills whole in the feces • Bile acids – fasting normal, 2 hour post prandial 62 • Change to Denamarin® chewable • ursodiol 15 mg PO BID

Refer for splenic portagram – no shunt Pockets 60 days later: • Serum panel still normal • Bile acids – normal • Mammary gland hyperplasia has resolved • Another mammary tumor <1cm • 3 views thorax rads – NSAF • Lymph node cytology - NSAF MGT removed • histopath – mammary adenocarcinoma, completely excised Pockets 6 months later (regular vet): • Doing very well • Weaned off of liver meds • CBC, panel, lytes - NSAF • bile acids – post prandial >100 Tx (regular vet) • Denamarin® chewable, Metronidazole again

Recheck 3 weeks: • bile acids – fasting 105, post prandial 180 • Referred back to me for re-evaluation Pockets • Now PU-PD with stranguria • UA – USG 1.005 • Urine culture – Staph • Thoracic rads – NSAF • Abdominal US – liver mottled in echotexture, no sludge in gall gladder, kidneys and bladder NSAF • Liver cytology – suppurative cholangiohepatitis • Inguinal LN cytology - NSAF Tx • Clavamox 31mg PO BID x 2 weeks • Continue Denamarin® chewable for now, re-evaluate liver when UTI resolved Pockets • Clavamox made her vomit unmercifully • cephalexin 50 mg PO BID x 2 weeks Recheck 1 week after stopping antibiotics • PU-PD and stranguria resolved • UA – USG 1.020, sediment quiet • Urine culture – Klebsiella spp • NSAID panel - NSAF Tx - • Ampicillin 50 mg PO BID x 4 weeks Pockets Recheck 1 week after stopping Antibiotics • UA – USG 1.022, sediment quiet • Urine culture – negative • NSAID panel – NSAF • Bile acids - pre 1.6, post 114.1 Tx - • milk thistle 50 mg PO BID, ursodiol 15mg PO BID • Recheck urine culture in 30 days, 60 days after that, 90 days after that and then twice yearly • Yearly dental due (G2) – when bile acids improved Pockets 60 days later • 30 day urine culture was negative • NSAID panel – NSAF • Bile acids - pre 2.1, post 73 • 60 day urine culture – negative Tx - • milk thistle and ursodiol, probably forever • Start L/D diet • Recheck urine culture in 90 days and then twice yearly • Dental went well, with antibiotics 1 week before and 1 week after (amoxicillin > metronidazole) • Extra UA and urine culture 1 week after antibiotics Pockets 90 days recheck • UA – bacteria (rods) on sediment w/ minimal inflammation, USG 1.018 • NSAID panel – NSAF • Bile acids - pre 2, post 62 (unchanged) • Abd US - unchanged

Tx - Continue milk thistle, ursodiol, L/D • Start serial urine culture recheck schedule again • 1 week, 30 days, 60 days, 90 days, semi-annual • Start over at any positive culture • Increase antibiotic therapy to 6-8 weeks if needed • Start bedtime antibiotics or midTx culture if stubborn Pockets Rechecks • Pockets now 14 years old • Many UTIs and dental • she is deaf and has nearly mature cataracts • is overweight at 5 pounds 12 ounces • Liver enzymes, albumin, bile acids normal to almost normal for the rest of her life • Cleaned her teeth 3 times a year, with amoxicillin Developed CRF at 15 years of age Euthanized due to metastatic nasal melanoma at 16 • Died with almost no teeth in her head Lessons from Pockets • Never underestimate the importance of controlling bacterial infections in chronic liver patients • Bacterial infection can cause decompensation • Always assume UTIs in patients are complicated, and can be silent • Never underestimate the importance of serial follow-up urine cultures in resolving complicated urinary tract infections, and dental antibiotics for liver patients • Early intervention can prevent cirrhosis • Significant liver disease can be present in the face of normal liver enzymes DDx Chronic Inflammatory Liver Dz the disease formerly known as Chronic Active Hepatitis

Infectious Canine Hepatitis (CAV2) Chronic GI Disease (Leaky Gut) Autoimmune Disease In many cases, etiology can not be determined, and does not affect treatment choices Early detection and treatment are essential, to prevent cirrhosis DDx Chronic Inflammatory Liver Dz the disease formerly known as Chronic Active Hepatitis Copper Storage Disease Fungal Hepatitis • Histoplasma, Blastomyces, Coccidiodes Parasitic/Protozoal Hepatitis Heterobilharzia, Platynosomum, Pisthorcis, Amphimerus, Metorchis, Clonorchis, Capillaria Many rickettsial and protozoon disease Determining etiology is important to treating these causes Chronic Inflammatory Liver Dz Histopathology • Inflammation starts at the portal triads • Then extends to the hepatic lobule • Eventual necrosis and bridging fibrosis between adjacent portal areas • Then nodular hyperplasia • Then cirrhosis Other frequent characteristics: • Inflammation predominantly mononuclear – prednisone • Suppurative inflammation suggests bacteria • hyperplasia (reduplication) and cholestasis – Treat with ursodiol • Secondary copper accumulation can accelerate disease Antibiotics for Liver Dz without HE Dogs with chronic inflammatory liver disease are prone to bacterial hepatitis and sepsis (chicken/egg) » Kuppfer cells and hepatic reticuloepithelial system remove pathogens from portal blood – If septic, start with IV antibiotics for a few days, then SC/IM, then PO when not vomiting – Gut bacteria are the offenders » gram negatives and anaerobes » Amoxicillin, metronidazole or both x 3 weeks » If severe disease, add a quinilone x 3 weeks – Use antibiotics aggressively in liver patients Tx Chronic Inflammatory Liver Dz

Antioxidants - Very important part of therapy, as free radical positive feedback is a problem with this disease. – (Vitamin E – 7 U/lb PO BID) – Milk thistle – raises glutathione levels – SAMe – also raises glutathione levels » Glutathione is depleted in about 50% of canine hepatopathies » 9 mg/lb PO divided BID » Absorption is best given on an empty stomach, but less vomiting when given with food » Should not be used if there is hepatic encephalopathy, because it contains methionine, which precipitates HE Tx Chronic Inflammatory Liver Dz Ursodiol = (Actigall®) – if cholestasis or sludge in the gall bladder – Bile acid with anti-inflammatory properties – Dissolves gall stones at 1mm per month » Works best if stone < 2cm – Colorrhetic, for bile sludging – 6-7 mg/lb/day, can divide BID – Once mucocoele is organized, it is there to stay – Trade name $$$ 300mg caps - generic 250mg tabs affordable Tx Chronic Inflammatory Liver Dz Immunosuppression – Studies show mixed results in dogs – More effective in cats – Prednisolone (rather than prednisone) » Liver converts prednisone to prednisolone » Start at 0.5-1 mg/lb/day for 3-4 weeks » Wean down to 0.2 mg/lb/day » Then wean to lowest effective dose – (Imuran®) » 50 mg/m2 PO SID x 2 weeks, then QOD » Then wean to lowest effective dose Tx Chronic Inflammatory Liver Dz Surgical correction of biliary obstruction if present (remove the gallbladder) – Obstructive mucocoele – Cholecystoliths – Gall bladder rupture or near rupture from Bacterial Cholangiohepatitis • Acute > chronic – cats • Chronic > acute - dogs • Leptospirosis (acute, chronic) – dogs • Secondary to GI disease (leaky gut) or other infected abdominal organs which drain into the portal vein

• GI signs, elevated liver enzymes + bile acids

• Ultrasound – thickened gallbladder wall & sludge, mottled liver echotexture Bacterial Cholangiohepatitis • Acute > chronic – cats • Chronic > acute - dogs • Leptospirosis (acute, chronic) – dogs • Secondary to GI disease (leaky gut) or other infected abdominal organs which drain into the portal vein

• GI signs, elevated liver enzymes + bile acids

• Ultrasound – thickened gallbladder wall & sludge, mottled liver echotexture

• Acute bacterial cholangiohepatitis often associated with in dogs and cats Liver Aspiration Cytology • Most helpful for: – Hepatic lipidosis – Histoplasma & other fungi, Cytauxzoon & other protozoa – Cholangiohepatitis – inflammation & cholestasis • Can do bacterial culture & sensitivity if bacterial seen (cat) – Some neoplasias • Good for histiocytic, aggressive carcinoma, MCT, • OK for LSA , moderate grade carcinoma • Not good for hepatoma, low grade carcinoma, HSA • Least helpful for Fibrosis, PSS Liver Aspiration Cytology

fatty liver (steroid vacuolar Hepatopathy)

normal hepatocytes

histoplasmosis, fatty liver hepatic carcinoma Liver Aspiration Cytology

bacterial cholangiohepatitis

hepatic lymphocytes Liver Aspiration Cytology

metastatic sarcoma

histiocytic sarcoma

hepatic lymphoma Liver Aspiration Cytology

Glycogen vacuolar hepatopathy

hepatic mast cell tumor Feline Cholangiohepatitis Forms: • Lymphocytic-plasmacytic – immune mediated • Eosinophilic – immune mediated, parasitic (deworm!) • Suppurative - bacterial • End stage – biliary cirrhosis (rare) Concurrent Problems: • Triaditis – pancreatitis, IBD • Bile duct obstructions, cholelithiasis • Sepsis Feline Cholangiohepatitis Treatment: • antioxidants • Antibiotics x 1-3 months or more as needed – use C&S to guide as necessary • corticosteroids if indicated by cytology or histopath • Ursodiol if bile sludging or cholestasis • Surgery to correct biliary obstruction/rupture, hepatic abscesses or necrotic gall bladder • Tube feeding for prolonged anorexia • Antiemetics as needed Popcorn Treatment for cirrhosis with ascites • Hetastarch 20 ml/kg IV over 30 min • Abdominocentesis to help breathing • Amoxicillin 40 mg PO BID x 3 wks • Denamarin according to label dose • Furosemide 4.125 mg PO BID • Later added spironolactone • 0.014 mg/lb daily • If GI side effects, reduce dose by 25% • Gradually change diet to L/D over 5-7 days • Watch for signs of HE and treat • Repeat abdominocentesis and Hetastarch as needed Popcorn

Popcorn did well for 8 months • She eventually did not respond as well to therapy, and was euthanized • She never developed HE • We did used lactulose for ammonia trapping • Euthanized due to uncontrollable ascites that resulted in dyspnea Popcorn Lessons from Popcorn • Patients with chronic liver disease often seem to become ill over a short period of time • When liver disease progresses to cirrhosis, pursuing the original etiology is seldom fruitful or helpful • Long term prognosis of cirrhosis is dismal • Short term prognosis (1 year or so) is variable • Some crashing patients continue to crash and die • Some respond to supportive therapy up to several times Max • 7 year old male Doberman • Hx - Anorexia, weight loss 1 month in duration • Exam – ascites, • CBC – PCV 31% • Chemistries • ALT 789 U/L, ALP 1122 U/L • Albumin 1.9 g/dl, globulins normal • Cholesterol 85 mg/dl • Glucose 81 mg/dl • Bile Acids – fasting 88, 2 hour post-prandial – 144 • Urine P:C Ratio – 0.56 Max • Tap • 12cc whole blood • PCV 30% - aspirated fluid • Abdominal Ultrasound Max • Tap Abdomen • 12cc whole blood • PCV 30% • Abdominal Ultrasound

Gall bladder Max • Tap Abdomen • 12cc whole blood • PCV 30% • Abdominal Ultrasound • Free fluid in the abdomen • Large spleen, hypoechoic • Liver – mixed echogenicity, multiple hyperechoic foci 1-2cm, irregular margins • Diagnostic Laparotomy Max • Tap Abdomen • 12cc whole blood • PCV 30% • Abdominal Ultrasound • Free fluid in the abdomen • Large spleen, hypoechoic • Liver – mixed echogenicity, multiple hyperechoic foci 1-2cm, irregular margins • Diagnostic Laparotomy Max • Liver Histopathology • Chronic inflammatory hepatitis with fibrosis • Cirrhotic areas • Spleen Histopathology • Passive congestion • Outcome • Max suffered hepatic encephalopathy after surgery • Owner elected euthanasia Lessons from Max • If you get blood tapping the abdomen on the left, consider that you may have hit the spleen • Especially if it is big – tap on right (HR site) • Ultrasound guidance or assistance into the fluid • Liver biopsy on end stage liver can cause decompensation • Portal hypertension can cause splenomegaly due to passive congestion • Nodules in the liver are not always neoplastic • Liver dz can be asymptomatic until end stage Gall Bladder Sludge When is it clinically significant? Gravity dependent (free falling) sludge is likely insignificant, unless: – Clinical signs (abdominal pain, GI signs) – Abnormal gall bladder wall – Abnormal liver enzymes and/or bile acids – Cholestasis on cytology or histopath Gall Bladder Sludge When is it medically treatable? – Gravity dependent (free falling) – amorphous texture (is not yet organized into a mucocoele) – Not extensive and not highly organized – decreases in response to therapy – Treatable underlying disease » Hyperlipidemia » Hypothyroidism » Cushing’s Disease » Bacterial Cholangiohepatitis » Pancreatitis Gall Bladder Sludge When is it surgically treatable? – Sludge organizes into a mucocoele – Symptoms stop responding to therapy in a way that is satisfactory to the owner – fluid around GB on ultrasound signals impending or recent rupture – Bile peritonitis from GB rupture is a life threatening immediate emergency » bili in ascites >> serum » Fluid analysis chart Gall Bladder Sludge Treatment: • Amoxicillin 10 mg/lb PO BID x 3 weeks • Or based on C&S • Actigall® 15 mg/kg PO divided BID • Wedgewood Rx has reasonable 250mg quad tabs • Denamarin® (milk thistle, SAMe) • Pain meds • Low fat diet • Treat underlying cause Amorphous unorganized sludge Organizing sludge Organized GB sludge, localized edema – impending rupture

Gall Bladder Aspiration • The only indication is culture and sensitivity – For chronic bacterial cholangiohepatitis/cholangitis • Easily performed with ultrasound guidance if gall bladder is enlarged • Deep sedation or short general anesthesia is required – To prevent gall bladder rupture – Rupture can happen even if all goes well – Rupture requires emergency surgery repair – Risky in practices without 24-hour care Dottie

Gall bladder sludge before treatment with Vetoryl® and Ursodiol® Dottie

Gall bladder sludge after treatment with Vetoryl® and Ursodiol® Steroid Hepatopathy Pattern Recognition • Hyperechoic hepatomegaly • Normal liver margins • Liver enzymes almost always elevated (ALKP > ALT) • Bile acids rarely elevated, almost never icteric • Albumin normal • Liver FNA – steroid vacuolar hepatopathy • Adrenal US – mass(es) or both enlarged • Hypercoagulable rather than increased bleeding • Gallbladder sludge not uncommon • Symptoms often resolve when treated Poppie • 6 yr F Miniature Pinscher • CC: urine has been dark • Urinalysis: 4+ bilirubin, USG 1.024 • CBC, panel: ALT 322, SAP 633, bili 1.8 • Abdominal US: Poppie • 6 yr F Miniature Pinscher • CC: urine has been dark • Urinalysis: 4+ bilirubin, USG 1.024 • CBC, panel: ALT 322, SAP 633, bili 1.8 • Abdominal US: hyperechoic liver • BMBT: 1 minute 5 seconds • Liver Cytology: mild cholestasis • Tx: amoxicillin x 3 weeks, milk thistle, recheck 30 days Poppie Recheck 2 weeks: urine cleared up, now dark again • Appetite has been a little off • Mild icterus noted on exam CBC, panel: ALT 752, SAP1433, bili 2.1 BMBT: 1 minute 10 seconds Abdominal US: Poppie Recheck 2 weeks: urine cleared up, now dark again • Appetite has been a little off • Mild icterus noted on exam CBC, panel: ALT 752, SAP1433, bili 2.1 BMBT: 1 minute 10 seconds Abdominal US: Poppie Recheck: urine seemed to clear up, now dark again • Appetite has been a little off • Mild icterus noted on exam CBC, panel: ALT 752, SAP1433, bili 2.1 BMBT: 1 minute 10 seconds Abdominal US: many nodules 1-30mm, rounded and bumpy liver margins Liver Cytology: histiocytic sarcoma • Poppie’s dam died of the same tumor, at the same age • Litter mate showed a similar sonogram recently Lessons from Poppie • Never hesitate to repeat the ultrasound, to check for progression of disease • Repeat FNA as well, even if no sonographic change • Recheck as soon as 14-30 days if looking for neoplasia Scooter • 10 yr old SF Boxer • CC: anorexia, lethargy • over 30 days or so • Exam: no clinically significant abnormalities • CBC: mild neutrophilia 15,000/ul • Profile: ALT 532, ALP 986 • Abdominal Ultrasound Scooter • 10 yr old SF Boxer • CC: anorexia, lethargy • over 30 days or so • Exam: no clinically significant abnormalities • CBC: mild neutrophilia 15,000/ul • Profile: ALT 532, ALP 986 • Abdominal Ultrasound

Mottled echotexture liver, hypoechoic liver masses, liver hyperechoic to fat Scooter • 10 yr old SF Boxer • CC: anorexia, lethargy • over 30 days or so • Exam: no clinically significant abnormalities • CBC: mild neutrophilia 15,000/ul • Profile: ALT 532, ALP 986 • Abdominal Ultrasound

Mixed echogenicity liver, *huge* gall bladder, hypoechoic liver masses, local ascites between liver and right kidney Scooter • 10 yr old SF Boxer • CC: anorexia, lethargy • over 30 days or so • Exam: no clinically significant abnormalities • CBC: mild neutrophilia 15,000/ul • Profile: ALT 532, ALP 986 • Abdominal Ultrasound

Mottled echotexture liver at hepatic vein, liver hyperechoic to fat Scooter • 10 yr old SF Boxer • CC: anorexia, lethargy • over 30 days or so • Exam: no clinically significant abnormalities • CBC: mild neutrophilia 15,000/ul • Profile: ALT 532, ALP 986 • Abdominal Ultrasound

Mixed echogenicity liver, hyperechoic liver mass; tail of the spleen normal echogenicity but enlarged, pleural effusion. Scooter • 10 yr old SF Boxer • CC: anorexia, lethargy • over 30 days or so • Exam: no clinically significant abnormalities • CBC: mild neutrophilia 15,000/ul • Profile: ALT 532, ALP 986 • Abdominal Ultrasound

Mixed echogenicity liver with cystic lesion at stomach Scooter • 10 yr old SF Boxer • CC: anorexia, lethargy • over 30 days or so • Exam: no clinically significant abnormalities • CBC: mild neutrophilia 15,000/ul • Profile: ALT 532, ALP 986 • Abdominal Ultrasound

Liver mottled in echotexture; hypoechoic spleen (cranial body) Scooter • 10 yr old SF Boxer • CC: anorexia, lethargy • over 30 days or so • Exam: no clinically significant abnormalities • CBC: mild neutrophilia 15,000/ul • Profile: ALT 532, ALP 986 • Abdominal Ultrasound

Transverse - Large hepatic mass mixed echogenicity Scooter • Client declined further diagnostics • Treatment: • (Carprofen) & Yunnan Pai Yao daily for life • Amoxicillin 500 mg PO BID x 2 weeks • Outcome: • Good response to therapy, returned to normal • Scooter had 3 more similar episodes over a one year period of time • Response to therapy was good for all but the last episode, at which time owner elected euthanasia Lessons from Scooter • FNA of cystic liver tumors • Propensity to bleed • NSAIDs are probably a better choice then prednisone for palliative treatment of unresectable liver carcinomas/other cancers • Presence of metastatic cancer does not necessarily mean death will come soon • Sometimes there is a poor response to palliative therapy & survival is short • Sometimes the pets return to good quality of life, and survival is as long as1-2 years Detecting Icterus

• Bilirubinuria • Mild to moderate bilirubinuria can be normal in the dog • Never normal in the cat – Cats have higher renal threshold for bili than dogs – Can be used to monitor cholestatic disease at home Detecting Icterus

• Icterus on exam – 2.0-3.0 mg/dl – Can be seen at lower bili if cholestasis – More delta bilirubin that is not cleared by the kidneys – gets stored in SC/peripheral fat • Most common cause of icterus in the cat – Feline Cholangiohepatitis (bacterial) • Most common cause of icterus in the dog – canine inflammatory hepatitis (immune mediated) DDx Icterus

1. Pre-Hepatic (hemolysis) – RBC destroyed at a high rate, faster than the liver can process the Hb & conjugate the bili (PCV <20%) 2. Hepatic (hepatocellular disease) – Liver cells cannot conjugate the bili to be excreted by the gall bladder – Happens when <10% of liver function remains 3. Post-Hepatic (bile duct obstruction) – Bile duct obstructed – cannot excrete bili into the duodenum DDx Icterus

Hepatic and post-hepatic icterus are difficult to separate • Bile acids retained by obstruction are hepatotoxic • Ultrasound is the best test to determine cause of hepatic and/or post-hepatic icterus DDx Hepatic Icterus

• Cats 1. Hepatic Lipidosis (30%) 2. Cholangiohepatitis – bacterial, fungal (20%) 3. Lymphoma (20%) – FIP – Drug toxicity (methimazole, diazepam) – Sepsis – Protozoal – Cytauxzoon spp DDx Hepatic Icterus

• Dogs – DDx acute hepatic failure – Sepsis – pyometra, prostatitis, GI obstruction, fight wounds, pneumonia, pyelonephritis, etc. – Leptospirosis – Acute hepatic necrosis – idiopathic, toxins, pancreatitis, sepsis, hypoxia/ischemia/trauma – Toxicity (next slide) – Exacerbation of chronic liver disease, leaky gut – Viral – infectious canine hepatitis (CAV2) – SIRS Hepatotoxins • Acetaminophen • Itraconazole • Aflatoxins • Kava Kava • Anabolic Steroids • Ketoconazole • Anticonvulsants • Mebendazole • Antineoplastics • Mitotane • Arsenicals • Mushrooms (Amanita) • Blue Green Algae • Oxabendazole • Carprofen • Phenols (Lysol®) • Castor Beans (Ricin) • Sago Palm (seeds) • Diazepam • Sulfonamides • Diethylcarbamazine • Thiabendazole • Griseofulvin • TMPS • Iron – chronic overdose • Xylitol Benzer 5 year old male GSD • Benzer was fine yesterday • Ate his dinner last night – then shared French fries from owner’s dinner, fine at bedtime • Early this morning, Benzer was weak an unable to rise, vomited bile found nearby • Immediately taken to the vet on call • Elevated liver enzymes & HCT, azotemia • Vomiting and bloody diarrhea today • No response to IV fluids, ampicillin, enrofloxacin today Benzer Exam • Injected mucous membranes • T- 103.1F, P – 168, R – panting • Bounding pulses, CRT 3 sec, tacky mucous membranes • Laterally recumbent • Bloody diarrhea on fecal loop • Rectal exam – prostate normal size, shape and non-painful Benzer CBC: neutrophils 15,000/ul, platelets 85,000/ul Panel: ALT 2100, SAP 1753, bili 8.3, TCO2 15 glucose 61, BUN 93, creat 3.0, phos 7.3 Lytes: normal UA: USG 1.012 (after fluid therapy) Fecal, HW test – negative Coags – PT 16 sec (normal 3-7), PTT 21 sec (normal 10-17), ACT normal, AT3 70%, FDPs normal Benzer Suspected Acute Liver Failure, pancreatitis or both: ALT 2100, SAP 1753, bili 8.3, neutrophils 15,000/ul, glucose 61 DDx – sepsis, gall bladder dz, other post-hepatic obstruction

DIC: platelets 85,000/ul, PT 16 sec, PTT 21 sec, AT3 70%

Possible Acute Renal Failure: BUN 73, creat 3.0, phos 7.3, USG 1.012 DDx – blood in gut + dehydration/hypovolemic shock + fluid therapy Benzer Diagnostic Plan: • Thoracic x-rays - NSAF • Abd ultrasound – diffusely hypoechoic liver Benzer Diagnostic Plan: • Thoracic x-rays - NSAF • Abd ultrasound – diffusely hypoechoic liver – Liver cytology - suppurative inflammation, cholestasis, no bacteria seen after antibiotics • cPLI –normal • Leptospirosis titers – negative • Urine culture - negative

Dx – azotemia, acute hepatic necrosis, DIC Benzer Treatment Plan: • LRS + 5% dextrose + 20 mEq/L KCl 2x maint (calculator, K sliding scale) • IV ampicillin TID and enrofloxacin SID • Heparin 75 U/kg SC TID • Weigh BID Dx – azotemia, acute hepatic necrosis, DIC The next morning: • Benzer is laterally recumbent and breathing really hard, minimally responsive • T 99.9F, P 120, R 80, mm pink and moist, CRT 1-2 sec, pulses normal, stools no longer bloody Benzer Diagnostic Plan: • CBC –neutrophils 22,000/ul22,000/ul, platelets 145,000 • Panel/lytes – ALT 987, SAPSAP 1311,1311, bilibili 2323, BUN 43, creat

& phos normal, TCO2 99, glucose 153 Why is Benzer worse when many tests are better? • The only vital sign not improved is RR Benzer Diagnostic Plan: • CBC –neutrophils 22,000/ul22,000/ul, platelets 145,000 • Panel/lytes – ALT 987, SAPSAP 1311,1311, bilibili 2323, BUN 43, creat

& phos normal, TCO2 99, glucose 153 Why is Benzer worse when many tests are better? • The only vital sign not improved is RR • Bicarbonate therapy may keep him alive over the next day or two while his liver continues to get better over the coming week or two Benzer Treatment Plan: • Discontinue heparin – platelets normal • Continue IV fluids, antibiotics, weigh BID – Reduce dextrose to 2.5% (glucose 153) – Prevent bilirubin uremia (bili 23, BUN 43) • Bicarbonate therapy – 25% of base deficit over 20 min Outcome: • Benzer was sternal within 30 minutes with RR 30, and able to stand that afternoon • Walked outside to eliminate the next morning • gradually recovered during a 10 day stay in ICU • Died 5 years later of complications from megaesophagus Lessons from Benzer • Acute hepatic necrosis has a guarded short term prognosis, but an excellent long term prognosis if survived • Acute hepatic necrosis often has no identifiable cause • Panting in a severely ill animal can indicate acidosis – a clue to check acid-base status • Bicarbonate therapy can be a life saving game changer in fulminant acidosis • DIC can be reversible if the cause can be reversed • Liver failure patients are usually yellow when they go home – urine clears  then serum  then tissues – Delta bilirubin (conjugated) is not cleared by the kidneys – Values improve in this order – ALT  SAP  bilirubin DDx Post-Hepatic Icterus

Most common: 1. Pancreatitis (15%) - #1 2. Gall bladder mucocoele, cholecystitis – dogs #2 3. Neoplasia (10%) – liver, bile duct, pancreas, duodenum – cats #2 DDx Post-Hepatic Icterus

Less common causes of post-hepatic icterus • Pancreatic abscess, neoplasia or granuloma • Liver, Bile Duct, Duodenal Abscess or Granuloma, severe IBD • Cholelithiasis or inspissated bile plugs • Duodenal foreign body • parasite migration, pancreatic or liver flukes Icterus Work-Up

1. MDB - CBC, panel – Anemia, icterus  pursue hemolysis • <20% in the cat, <25% in the dog – No anemia – pursue liver dz, bile obstruction – Remember that icteric cats can have ACID (non- regenerative – need a retic count to be sure) 2. Imaging - Abdominal rads & ultrasound – liver, pancreas 3. Sample the liver + bile – Cytology, histopathology, culture/sensitivity 4. Syndrome specific diagnostics Icterus Thumb Rules

• Danger value for bili >20 mg/dl for dogs (cats unknown) – kernicterus brain toxicity, renal toxicity) • Steroid hepatopathy and PSS patients are almost never icteric • Slight elevations in bili are rarely clinically significant • Lipemia & hemolysis falsely elevate bili • Measurement of direct (conjugated) and indirect (unconjugated) fractions is not useful because hemolytic, hepatic an biliary tract diseases have unpredictable variation in each fraction Treatment of Icterus

• IV fluid therapy • Supportive treatment for underlying hepatic and post- hepatic disease • Protect kidneys & brain from bilirubin toxicity • Exposure to UV light reduces bilirubin by as much as 50% per hour • treat underlying cause • Hemolysis • Hepatic/post-hepatic disease What Can You Do for the Bleeding Liver Patient? • Fresh whole blood or plasma • Heparinized plasma if DIC?? • Vit K 5 mg/kg the first day and then 2.5 mg/kg/day, especially if cholestasis • Heparin 75 U/kg SC TID if DIC • Treat GI ulceration (see vomiting section) • Don’t do surgery or liver aspirates until controlled • Treat the liver problem before it is too late Why Liver Patients Crash • Something precipitates HE • Sepsis due to overwhelmed RE system • Overwhelming toxicity of hepatic necrosis, hepatic abscess rupture or gall bladder rupture • due to low oncotic pressure • Albumin <1.0 in most or <1.5 if CHF • Bleeding • SIRS (Systemic Inflammatory Response Syndrome) Hepatic Lipidosis A significant problem for cats rather than dogs Etiologies • Starvation or anorexia • Predispositions: • Carnitine deficiency • Obesity • Diabetes mellitus • Cholangiohepatitis – bacterial endotoxins • Hypoxic injury • Triaditis – especially pancreatitis Hepatic Lipidosis Diagnosis • Usually anorectic, unless recovering • Often Icteric or at least bilirubinuric • Hepatomegaly on abdominal palpation • Liver aspiration cytology often diagnostic • Liver enzymes • ALT, SAP, GGT often all elevated • Only in hepatic lipidosis does ALKP elevation significantly exceed GGT elevation. • Ultrasound • Large, hyperechoic liver relative to fat Hepatic Lipidosis Diagnosis • Usually anorectic, unless recovering • Often Icteric or at least bilirubinuric • Hepatomegaly on abdominal palpation • Liver aspiration cytology often diagnostic • Liver enzymes • ALT, SAP, GGT often all elevated • Only in hepatic lipidosis does SAP elevation significantly exceed GGT elevation. • Ultrasound • Large, hyperechoic liver relative to fat Hepatic Lipidosis Treatment – feed the cat • Appetite stimulants – cyproheptadine, mirtazapine, low dose propofol (0.5 mg/kg IV) • Usually requires a feeding tube • High protein, low carb diet • Add carnitine, use antiemetics • Short term prognosis guarded • Long term prognosis can be excellent, if survives and no co-morbidities • If feeding precipitates hepatic encephalopathy, prognosis is poor Summary

PowerPoints - .pptx, .pdfs – 1 and 6 slides per page Vet Handouts • Blount - Bicarbonate administration • Blount - Fluid analysis diagnostic chart • Blount - IV potassium supplementation • Blount – Adrenal Testing • Blount – Liver FNA • Idexx – SNAP Bile Acids

Articles – Liver Cytology Summary

Vet Handouts • Willard – Algorithm for Increased ALT • Willard – Algorithm for increased ALKP • Willard – Algorithm for increased Bili • Willard – Algorithm for abnormal liver size • Willard – Algorithm for low albumin

Cornell Comparative Coag Lab – submission form, blood collection guidelines, electronic payment form, sample labels, shipping guidelines, test price list, supply form Summary

Client Handouts Excel Calculators • Cholangiohepatitis • IV Fluid Rate Calculator • Chronic Liver Disease • Percent Calories • Cytauxzoon Calculator • Fatty Liver • Icterus • Infectious Canine Hepatitis • Portasystemic Shunt Summary

Client Drug Handouts • Amoxicillin • Leviteracetam • Spironolactone • Azathioprine • Maropitant • Taurine • Carnitine • Metronidazole • Ursodiol • Colchicine • Milk Thistle • Yunnan Bai Yao • Cyproheptadine • Mirtazapine • Zonisamide • Doxycycline • Neomycin • Furosemide • Phenobarbital • Hetastarch • Prednisone • Lactulose • SAMe Summary

Sponsor Materials • Denosyl® - Brochure, package insert • Denosyl® Chewable - package insert • Denamarin® - brochure, package insert • Denamarin® Chewable – package insert Acknowledgments

• Dr. Adam Honeckman, ACVIM. “Icteric Cats – More than Just Lipidosis.” Mobile Veterinary Diagnostics, Orlando, FL.

• DeNovo RC, Chapter 5, “Diseases of the Stomach,” in Todd R Tams Small Animal Gastroenterology, 2nd Edition.

• Richter KP, Chapter 9, “Diseases of the Liver and Hepatobiliary System,” in Todd R Tams Small Animal • Gastroenterology, 2nd Edition. Acknowledgments

• Stacy Simmonds, DVM, DACVECC • Emergency Animal Hospital of Northwest Austin

• Michael Connolly, DVM • Connolly Animal Clinic, Nacogdoches TX

• Tam Garland, DVM, PhD, DABVTT • Toxicology Consultant

• Adam Honeckman, DACVIM • Mobile Veterinary Diagnostics, Orlando FL Acknowledgments

• Margie Scherck, DABVP, VIN Consultant

• Willard MD and Tvedten H. Small Animal Clinical Diagnosis by Laboratory Methods, 5th ed. Chapter 7 – Gastrointestinal, Pancreatic and Hepatic Disorders. Eds Willard MD and Tvedten H. 2014. Acknowledgements

Teleah Grand, DVM Animal Care Center at Stonebridge Ranch Radiographs of Gall Bladder Mass Connolly Animal Clinic Nacogdoches TX Multiple Cases – Pockets, Max, Popcorn Eastex Veterinary Clinic Nacogdoches TX Multiple Cases – Teaching Material, Jim Wilson, DVM The Ole Stirrin’ Stick God Bless His Soul Case - Popcorn