Equine Liver Disease PDF

Objectives Liver Disease in the Horse Scott Austin, DVM, MS, ACVIM VM 654 § Students will list the clinical signs of equine hepatic disease § Students will discuss the pathophysiology of jaundice, hepatic lipidosis, and hyperammonemia § Students will describe the common laboratory abnormalities see...

Objectives Liver Disease in the Horse Scott Austin, DVM, MS, ACVIM VM 654 § Students will list the clinical signs of equine hepatic disease § Students will discuss the pathophysiology of jaundice, hepatic lipidosis, and hyperammonemia § Students will describe the common laboratory abnormalities seen in equine hepatic disease. § Students will identify the tests that detect liver injury versus those that test liver function. Objectives Hepatic Insufficiency § Students will describe appropriate diagnostic testing used to confirm and establish prognosis for equine hepatic disease. § Students will describe common causes of equine hepatic disease and discuss treatment and prognosis of these diseases. § Large functional reserve (80% must be damaged before basic function is impaired) § Clinical signs § Highly variable and non-specific § Dependent upon duration, extent and distribution of damage § Chronic damage may have acute manifestation as functional reserve is exhausted § Hepatic disease may be present without signs of hepatic failure (subclinical) Clinical Signs of Hepatic Insufficiency § § § § § § § Weight loss Anorexia Colic Depression Pyrexia Icterus Hepatoencephalopathy Hepatic Insufficiency: Less common signs § § § § § § § § § § Photosensitization Coagulopathy, hemolysis Ascites, edema Diarrhea Pruritus and seborrhea Endotoxic shock Hypoglycemia Hypoproteinemia Electrolyte abnormalities Bilateral laryngeal paralysis Photo from Veterian Key Icterus (Jaundice) Hepatic Encephalopathy § Yellow discoloration § Abnormal mentation accompanied by hepatic disease § Clinical signs § § § § Sclera Mucous membranes Non-pigmented skin Normal in 10-15% of horses § Hyperbilirubinemia § Deposition of pigment in tissues § Total serum bilirubin = indirect + direct bilirubin § Forebrain disease: depression, head-pressing, circling, hyperactivity, aimless walking, persistent yawning, ataxia, disorientation, and central blindness § Progression to unpredictable aggressive or violent behavior interspersed with somnolence § Diagnosis § Forebrain signs § PE and clinical chemistry findings of hepatic disease § Increased blood ammonia Hepatic Encephalopathy § Severity correlates with degree of hepatocellular damage § Does not predict reversibility!! § Pathophysiology is elusive § Associated with hyperammonemia § Increased in CSF § Increased in serum § Can only determine onsite – keep on ice, determine immediately § Other: false neurotransmitters, inflammation, neurosteroids § Postmortem: develop Alzheimer Type II astrocytes Hepatic Photosensitization Diagnosis of Hepatic Injury – Laboratory § Secondary photosensitivity § Decreased clearance of phylloerythrin § Liver specific § Accumulates in skin where UV light induces free-radical production and cell damage § Most prominent in non-pigmented areas § Sorbitol dehydrogenase (SDH) § Glutamate dehydrogenase (GLDH) § Gamma-glutamyl transferase (GGT) § Tests of liver function § § § § Bile acids (normal 6-10 umol/L) Not affected by short-term fasting Higher values are found in neonates ( up to 20 umol/L) Values in excess of 25 umol/L are associated with poor prognosis in adult horses § Nonspecific labs § Bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) § Ammonia, plasma proteins, hemostatic function, BUN, glucose Roxy § Signalment § 5-year-old § Quarter horse mare § History § Foaled 2 month ago § No history of problems § Vaccinated 30 days before foaling § Given a tetanus toxoid and a tetanus antitoxin at foaling Roxy: Initial Evaluation § TPR § HR – 60 bpm § RR – 24 bpm § Temp – 102.3oF § Sclera– icteric § Mucous membranes § Hyperemic with petechia § CRT > 3 seconds § Prolonged jugular refill time Problem noticed last 2 days • • • • Lethargic Off feed Stumbles Stares into space Roxy § Neurologic examination § § § § Weak Ataxic Head pressing with compulsive circling Appears non visual (PLR intact, menace absent) § Venous blood gas § § § § Glucose: 35 g/dL (low) Lactate: 15 mmol/L (very high) iCa: 0.9 mmol/L (low) pH: 7.298 (low) p Fibrinogen n p Hypofibrinogenemia (91 mg/dL; 129-162) p Ammonia p Serum bile acids n Serum Biochemistry n n n n n GGT 157 U/L (4-20) GLDH 47.7 (1-5) Tbili 24.3 (0.5-2.3) AST 2394 (150-294) Alk Phos 1027 (41-137) n p 274 (15-45) 111.4 (0-20) PT & PTT n 25 (8-15); 56.7 (33-47) Liver-specific Laboratory Abnormalities Liver-specific Laboratory Abnormalities § Glutamate dehydrogenase (GLDH) § Gamma-glutamyl transferase (GGT) § Hepatocellular mitochondrial enzyme § Maker of acute or ongoing hepatocellular necrosis or damage § Short half life; more stable than SDH § Sorbitol dehydrogenase (SDH) § Hepatocellular necrosis § Highly specific § Short half life, acute or ongoing damage Biliary epithelium Marker of cholestasis (biliary disease) Longer half life (17-96 hours) compared to SDH & GLDH Baseline values higher in neonates (<4 weeks of age) and donkeys § Other sources: renal, pancreatic GGT § § § § Specific Tests of Liver Function Nonspecific Laboratory Findings § Bile acids § Bilirubin § Correlates with function reserve of liver § Excellent screen for liver damage § Increased § Hepatocellular damage § Biliary obstruction § Portosystemic shunts § Specific for presence of liver disease not specific for type of disease § Can be NORMAL with liver damage § Indirect (unconjugated) § Increased in acute hepatocellular disease, not specific § Increased with anorexia, hemolysis, & GI disease § Anorexia is one of the most common reasons for elevated bilirubin! § Direct (conjugated) § More reliable indicator of liver disease (values > 25% of total bilirubin) § Cholestasis: > 30 % of total bilirubin, urine positive Nonspecific Laboratory Findings Hyperammonemia § Alkaline phosphatase (ALP) § Ammonia § Chronic or cholestatic liver disease § Pregnancy, hemolysis, GI disease, growing animals § Lactate dehydrogenase (LDH) § Also found in muscle § Isoenzyme (LDH-5) – acute hepatocellular disease § Aspartate aminotransferase (AST) § Hepatocellular damage § Increases more dramatically 2o to muscle damage Diagnosis : Liver Ultrasound § Biproduct of the metabolism of nitrogen-containing compounds § Increases secondary to increased production, decreased delivery, or decreased metabolism § Hyperammonemia § Hepatic disease – liver responsible for clearance of ammonia by urea cycle § Portosystemic shunt § Gastrointestinal disease – increased production § Neurotoxic at elevated concentrations = astrocyte dysfunction § Treatment: aimed at reducing production of ammonia § Lactulose (oral) § Antimicrobials(metronidazole) Liver Biopsy § Useful to evaluate size, shape and position of the liver. § All visible liver may appear normal § Most of the liver is inaccessible: ribs, diaphragm, and lungs obscure view § Older horses frequently have right lobe atrophy § Assess parenchymal changes: abscess, cyst, mass) § Detect dilated bile ducts § Bile ducts are not usually visible § Determine presence of bile stones § Guide liver biopsy Histopathology and microbiology p Coagulation profile performed PRIOR to biopsy p Ultrasound guidance p Right side, 12-14th intercostal space p Diagnosis of Liver Disease § Most useful diagnostics: § § § § § § GLDH (or SDH) GGT Total and direct bilirubin Bile acids Liver US and biopsy ALP, AST, plasma proteins, ammonia, and BUN may useful in specific cases of hepatic disease Treatment of Liver Disease § Goal: adequate support until liver regenerates § § § § § Correct fluid deficits Address acid-base and electrolyte imbalances Address coagulopathies Mineral oil or Biosponge by NGT (bind toxins) Oral antimicrobials § Metronidazole § Neomycin § Nutritional support (high carbs, low protein) § Severe hepatic impairment (fibrosis) carries a poor prognosis Other Therapy Equine Hyperlipidemias § DMSO § 0.5 g/kg as 10% solution IV for 3-5 days § May help dissolve intrabiliary sludge § Pentoxyfylline p p n § 8 mg/kg po q12h § Reduces hepatic fibrosis in people § Silymarin – milk thistle seed extract n p § Chronic liver disease § Hepatoprotective § Horse - < 1% bioavailability n n p Breed: Ponies, miniature horses, donkeys (obese) Stress: illness, late gestation, early lactation Clinical manifestation n § SAMe § Converted to glutathione § Unknown benefit to horses Increased triglyceride concentration Associated with negative energy balance Signs often nonspecific or masked by primary disease Common: reduced water & feed intake, depression Severe: diarrhea, colic, fever, ventral edema, cachexia Definitive diagnosis: increased serum triglycerides Hyperlipidemias: classifications p Mild hypertriglyceridemia n n p n n p p All breeds: TG 100 - 500 mg/dL Not associated with lipemia, fatty infiltrates, clinical signs Gross lipemia in serum p Hyperlipemia with severe hypertriglyceridemia n n n p p p Decreased glucose utilization Promotes gluconeogenesis, glycogenolysis, lipolysis Primary energy reserve is FA stores in adipose tissue Increased activity of Hormone Sensitive Lipase Hormone sensitive lipase p n TG Insulin Glucocorticoids, ACTH Catecholamines _ + Hormone Sensitive Lipase Insulin + Glucocorticoids _ + Insulin Glucocorticoids GLYCOGEN TG Gluconeogenesis LIVER + - Glucocorticoids Insulin p VLDL p p + - Lipoprotein Lipase Glucose Glycerol _ + Insulin Glucocorticoids GLYCOGEN FA TG VLDL Gluconeogenesis LIVER TG (VLDL) tissue uptake ADIPOCYTE TG Physiologic stress exacerbates normal response to negative energy balance n Glucose Glycerol FA Lipoprotein - Lipase Hormone Sensitive Lipase Insulin Hyperlipemia p FA & GLYCEROL + Insulin Glucocorticoids, ACTH Catecholamines Glucocorticoids Lipoprotein lipase p ADIPOCYTE TG metabolism (adipose) _ FA & GLYCEROL Primary energy source Stored in liver as glycogen Stored in adipose as TG (glycerol, FA) 2 Key Hormones n Ponies, miniature horses, donkeys TG > 500 mg/dL Lipemia, fatty infiltrates, clinical signs Negative Energy Balance p n n Adult horses: TG >500 mg/dL Lipemia absent Rare clinical signs & fatty infiltrates TG Glucose n Severe hypertriglyceridemia n ADIPOCYTE Normal Energy Metabolism + Hormone Sensitive Lipase FA & GLYCEROL Insulin + Glucocorticoids Hormone Sensitive Lipase further up-regulated Insulin resistance Obesity = excessive FA mobilization Excessive TG & VLDL production & accumulation in blood Insulin Glucocorticoids, ACTH Catecholamines _ _ + Insulin Glucocorticoids GLYCOGEN TG Gluconeogenesis LIVER Lipoprotein Lipase Glucose Glycerol FA - + - VLDL Glucocorticoids, Insulin Treatment: Hyperlipemia; Hepatic Lipidosis Treatment: Hyperlipemia, Hepatic Lipidosis p Correct primary disease p Correct/prevent negative energy balance Enteral nutrition (palatable feed; enteral feeding tube) n Parenteral nutrition n 5% dextrose supplementation n IVF (balanced electrolytes) n p Inhibit fat mobilization and improve TG uptake by peripheral tissues p Exogenous Insulin p p Suppress Hormone Sensitive Lipase & activate Lipoprotein Lipase Exogenous Heparin p Stimulate Chronic Megalocytic Hepatopathy Lipoprotein Lipase & promote TG metabolism Chronic Megalocytic Hepatopathy Senecio spp pPyrrolizidine alkaloid-containing p Histology plants n n p p (pathognomonic): Megalocytosis Biliary hyperplasia n Fibrosis n Senecio, Crotolaria, Amsinkia Acute toxicity-2% to 5% of body weight n 4 weeks to 12 months after exposure Toxicity: cross-link DNA p Alters cell division p Inhibits protein synthesis p Cell necrosis p Death usually soon after onset of clinical signs Crotalaria Amsinkia Clover Poisoning Clover Poisoning § Trifolium sp § Ultrasonography § Alsike clover § Red clover § Toxic principle not yet identified § Clinical signs § Signs of liver disease § Photodermatitis § Liver enlarged with rounded borders § Progress to small liver with fibrosis § Biopsy § Biliary hyperplasia § Periportal fibrosis § Minimal bile obstruction § Signs within 2 weeks of ingestion of diet >20% clover Cholelithiasis p Biliary calculi Bacterial infection may precipitate Triad of clinical signs: p Diagnosis p p n n n n n n p Icterus, fever, colic Increased: GGT Bilirubin (direct >30% of total) Bile acids and globulins increased Bilirubinuria Ultrasound: dilated bile ducts +/- hyperechoic foci Treatment n n Long-term antimicrobial therapy (until GGT normal) Surgery: choledocholithotripsy, choledochotomy Cholelithiasis Tyzzers disease “Acute serum hepatitis”, “post-vaccination hepatitis” “idiopathic acute hepatic disease” p First described 1919: Africa Horse Sickness vaccine p Clinical signs appear 4-10 weeks after administration of biologic of equine origin n Tetanus antitoxin n Hyper-immune plasma or antiserum/antitoxin: Botulism, anthrax, strangles, WEE, influenza n Vaccinations n Plasma for colloid support Bacterial hepatitis – Clostridium piliforme p Acute, necrotizing hepatitis in foals 7-42 days of age p Nonspecific signs of severe hepatic compromise p Sporadic outbreaks in foals ingesting contaminated feces or soil p Definitive diagnosis: organism identification at post mortem p Highly fatal, grave prognosis in foals p p Theiler’s Disease – Acute Hepatic Necrosis § Clinical signs are variable and nonspecific § Acute onset, rapidly progressive § Lethargy, anorexia, icterus, fever, encephalopathy § Marked increase in liver enzymes § Mortality 50-90% of clinically affected horses § Subclinical horse may have mild increase in liver enzymes only § Histopathology: severe hepatocellular necrosis & degeneration Potential viral association (Parvo virus association) p Roxy: p n TAT administered at foaling n Necropsy Liver: consistent with Theiler's disease Necropsy Brain: Alzheimer Type II Astrocytosis (hepatoencephalopathy) n Newly Discovered Equine Hepatitis Viruses Toxic Hepatopathy (Acute) § Equine parvovirus p § Hepatotropic § Prevalence Centrilobular (lowest O2 tension) or periportal (site of 1st exposure) n p § 13% DNA detection § 15% antibody positive Drugs –hypersensitivity, intrinsic toxicity or idiosyncratic n n § Consistently found in cases of Theiler’s disease n n § Flaviviruses p § Equine hepacivirus – elevated enzymes during active infection § Theiler’s disease-associated virus – not likely cause of disease § Equine pegivirus-high seroprevalence, not associated with disease p p Chronic Active Hepatitis • Idiopathic, chronic, progressive hepatopathy • • • Causes: • Autoimmune • Hypersensitivity • Bacterial – chronic cholangiohepatitis • Viral Insidious onset of progressive liver failure Clinical signs (often intermittent) • • • • • • Lethargy and depression Exercise intolerance Anorexia and weight loss Colic Icterus Rare exfoliative coronary dermatitis Diagnosis of exclusion, history of exposure, or detection of toxin Erythromycin Tetracycline Diazepam Corticosteroids Iron toxicity (Ferrous fumarate): oral administration to foals before ingest colostrum Mycotoxins (Aflatoxin, Fumonisin) Plants (ryegrass, lupine, etc..) Diagnosis of Chronic Active Hepatitis § Liver enzymes • • • • • • Ultrasound: small liver, increased echogenicity (fibrosis) might be seen Systemic inflammation • • • Mild increase GLDH & AST Often marked increase in GGT and ALP Increased bile acids, total protein and bilirubin (esp direct) BUN < 10 Inflammatory leukogram +/- left shift Polyclonal gammopathy Liver biopsy • Histopathology • • • • • Biliary hyperplasia Periportal or biliary inflammation Hepatic necrosis Bridging fibrosis Concurrent culture Chronic Active Hepatitis • Treatment • • • Supportive care Corticosteroid therapy (biopsy shows mononuclear inflammation) Antimicrobial therapy (inflammatory infiltrate or positive culture) • • • Four to 6 weeks Based upon C/S is best Antibiotic that are excreted in bile preferred • • • • Chloramphenicol Ceftiofur Ampicillin Prognosis depends on cause, severity, & duration