Liver: acute disease

• Cause: overwhelming toxic insult, infectious or metabolic disease.
• Signs: non-specific; anorexia, vomiting, depression +/- polydipsia/polyuria, jaundice, ascites, bleeding, encephalopathy.
• Diagnosis: biochemistry, hepatic function tests, ultrasonography, hepatic biopsy.
• Treatment: underlying cause if recognized; otherwise supportive and symptomatic.
• Prognosis: depends on severity and treatment of inciting factor.
• See also Liver: chronic disease Liver: chronic disease - overview.

• Anorexia
• Depression.
• Vomiting.

• Diarrhea.
• Polyuria/polydipsia.
• Icterus.
• Abdominal pain.

• Behavioral changes.
• Seizures.
• Coma.
• Bleeding tendency.

• Collapse/coma.
• Dehydrated.
• Seizures.

• Intensive and supportive care can be prolonged and expensive.

• Drugs: acetaminophen (paracetamol Paracetamol ), anesthetics, anticonvulsants, azathioprine Azathioprine , carprofen Carprofen (especially Labradors), ketoconazole Ketoconazole , methoxyflurane Methoxyflurane , sulfonamides Sulfasalazine , tetracycline Tetracycline , thiacetarsamide.
• Chemicals: carbon tetrachloride, chlorinated compounds, heavy metals, selenium, tannic acid.
• Biological substances: aflatoxin, blue-green algae endotoxin Blue-green algae poisoning , bacterial endotoxin.

Infectious/parasitic

• Bacterial: Gram-negative endotoxemia, Leptospira spp Leptospira icterohemorrhagiae , Salmonella spp Salmonella spp , Clostridium spp Clostridia spp ,Bacillus piliformis.
• Viral: adenovirus 1 Canine adenovirus type 1 disease , canine herpesvirus Canine herpesvirus.

Infection

• Mycotic: eg histoplasmosis Histoplasma capsulatum if associated with pulmonary disease.
• Protozoal: toxoplasma Toxoplasmosis.

Metabolic

• Acute pancreatitis Pancreatitis: acute.
• Acute hemolytic anemia Anemia: immune mediated hemolytic.
• Trauma Liver: trauma.
• Heat stroke Heat stroke.
• Secondary to sudden copper release in Bedlington terriers with copper storage disease Copper toxicosis (Bedlington Terrier).
• Hypoxia: cardiorespiratory disease; severe anemia.
• Inflammatory bowel disease Inflammatory bowel disease: overview.

Neoplastic

• Diffuse tumor infiltrate, eg lymphoma Lymphoma.

Specific

• Unvaccinated animals.

• Overwhelming hepatic insult → functional reserve capacity exceeded → failure to perform diverse metabolic functions → clinical signs.

• Hepatic functional reserve large → 70% damage before capacity exhausted → peri-acinar zonal necrosis, infiltration of inflammatory cells due to toxins, living agents and metabolic disease will cause massive damage.
• Local and systemic release of cytokines and other pro-inflammatory mediators → pyrexia, anorexia, depression.
• Decreased production of clotting factors → bleeding tendency.
• Inflammation of biliary system → partial obstruction to biliary flow → icterus.
• Inadequate bile delivery to intestine → impairment of fat digestion → diarrhea.
• Failure to maintain euglycemia →hypoglycemia Blood biochemistry: glucose.
• Decreased production of albumin →hypoalbuminemia Blood biochemistry: albumin.
• Failure to detoxify ammonia and other mercaptans from intestine →hepatic encephalopathy Hepatic encephalopathy.
• Increased resistance to blood flow through liver due to hepatocytes swelling → development of portal hypertension →ascites.
• Portal hypertension → gastrointestinal wall congestion and edema → gastrointestinal ulceration →hematemesis and melena.

• Dependent on etiology, within days of ingestion of toxin, infection.

• Polyuria/polydipsia.
• Icterus.
• Vomiting Vomiting.
• Diarrhea Diarrhea: chronic.
• Seizures Epilepsy: idiopathic.
• Coma.
• Abdominal enlargement.
• Pyrexia.

• Anorexia.
• Depression.
• Vomiting.
• Diarrhea.
• Polydipsia/polyuria.
• Behavioral changes.
• Abdominal enlargement.
• Jaundice.
• Seizures.
• Coma.
• Bleeding tendency.

• Icterus.
• Abdominal pain.
• Ascites.
• Depression.
• Pyrexia.
• Neurological dysfunction related to cerebrum.
• Petechial hemorrhages.
• Bleeding.
• Abdominal pain.

• Further details of investigation can be found in Liver function testing Liver function assessment.

• Serum enzymes- activity may be first indicator of hepatic disease.
• Extent of increased activity does not reflect severity of damage; cannot be used for prognosis. Serum enzyme activity also gives no information about liver function:
  • Alanine aminotransferase (ALT) Blood biochemistry: alanine aminotransferase (SGPT, ALT) - intracellular enzyme released when hepatocellular necrosis occurs.
    Often a marked early increase in acute liver disease. Note also remains high in regeneration so continued elevation does not necessarily equal a poor prognosis.
  • Aspartate aminotransferase (AST) Blood biochemistry: aspartate aminotransferase (AST) - present in both mitochondria and cytoplasm; compared to ALT is released late on and when there is more severe damage. Also present in muscle so use muscle enzymes (creatine kinase) to differentiate source.
  • Alkaline phosphatase (ALP) Blood biochemistry: alkaline phosphatase (ALP) and gamma glutamyltransferase (GGt) Blood biochemistry: gamma glutamyltransferase - increased production due to intrahepatic or biliary cholestasis. Tend not to rise to extent as ALT. Note that GGT is less use in the dog as compared to other species.
• Increases in amylase Blood biochemistry: amylase and lipase Blood biochemistry: lipase may suggest underlying pancreatitis. Other markers of pancreatic disease such as TLI Blood biochemistry: trypsin-like immunoreactivity and cPLI Canine pancreatic lipase immunoreactivity (cPLI) test may also be elevated.
• Plasma proteins:
  • Albumin Blood biochemistry: albumin - usually normal in acute hepatitis.
  • Globulin Blood biochemistry: total globulin - may be increased due to immunoglobulins.
• Ammonia Blood biochemistry: ammonia : produced by intestinal bacteria degraded in liver; increased levels due to hepatic failure or portosystemic shunt.
  Very liable to poor sample handling.
  Samples should be taken into heparin container and stored on ice until analyzed.
• Bilirubin Blood biochemistry: total bilirubin : elevated bilirubin; may analyze conjugated and unconjugated portion to differentiate between prehepatic, hepatic and post-hepatic forms but very unreliable and not recommended.
• Bile acids Blood biochemistry: bile acids : increased resting level and 2 h post-prandial; very good test of hepatic function. A post-prandial sample should always be performed if the resting bile acids are normal. Degree of elevation does not necessarily reflect severity of hepatic damage.
• PT and APTT plus buccal mucosal bleeding time.

• Abdominal examination Ultrasonography: liver to identify pancreatic disease, gall bladder disease .
• Evaluation of hepatic parenchyma  , identification of diffuse or focal lesions.
• Liver normal to enlarged size.

• Liver biopsy to determine etiology if initial tests non-diagnostic - may perform at laparotomy or by ultrasound guided percutaneous biopsy Biopsy: hepatic.
  Check for possible coagulopathy prior to biopsy.
• Fine needle aspiration of limited use in diagnosis of acute liver disease except in lymphoma.

• See abdominal radiography Radiography: abdomen
• Liver normal or enlarged  in acute hepatic failure.
• Little use in an animal with ascites, so proceed to ultrasonography Ultrasonography: liver.

• Microbiology:
  • Blood culture Blood: culture to identify bacteremia.
  • Culture of bile can be very useful in cases of acute bacterial cholangiohepatitis.
• Serology:
  • Adenovirus-1, toxoplasma, leptospirosis Leptospirosis.
• Urinalysis:
  • Dark field examination to identify Leptospira spp.
    This test has a relatively low sensitivity and specificity for the detection of leptospirosis.
  • Bilirubin may be present Blood biochemistry: direct bilirubin.
  • Ammonium urate crystals may be visible, especially in animals with portosystemic shunts.

• Predominant change is moderate/severe hepatic necrosis (centrilobular to massive) - might be prudent to stain for Helicobater spp in cases of hepatobiliary disease.

• Varies with cause, eg mild multifocal to extensive hepato-cellular necrosis, ballooning degeneration, and apoptosis. Bridging necrosis with lobular collapse seen in liver of dogs with carprofen-induced acute hepatic illness.

• Acute toxic insult Liver: toxic hepatitis.
• Other causes of diarrhea Diarrhea: chronic.
• Other causes of icterus, eg hemolysis (most commonly immune-mediated hemolytic anemia Anemia: immune mediated hemolytic ).
• Acute pancreatitis Pancreatitis: acute.
• Acute gastritis Stomach: acute gastritis.
• Other causes of vomiting Vomiting.
• Pyloric obstruction Stomach: pyloric stenosis.
• Small intestinal obstruction.
• End-stage liver disease.
• Systemic infection - bacterial, mycotic, parasitic, protozoal.

• Cage rest to optimize conditions for hepatic regeneration and prevent scarring.
• Intravenous fluids Fluid therapy to maintain fluid balance.
• Intravenous diazepam Diazepam or other anticonvulsants (with care) if seizuring.

• Dextrose added to intravenous fluids if hypoglycemic Fluid therapy.
• Potassium chloride Potassium chloride / gluconate added to intravenous fluids if hypokalemic or anorexic.
• Antibiotics Therapeutics: antimicrobial drug to counter primary and secondary infections and reduce gut ammonia production.
  Use broad spectrum agents safe for use in liver disease (avoid potentiated sulphonamides and tetracyclines).
• If encephalopathy, may use enemas to remove substrates for bacterial metabolism, ampicillin Ampicillin or amoxicillin Amoxicillin and lactulose Lactulose to minimize ammonia and other toxin production.
  Check glucose and potassium level if showing signs of hepatic encephalopathy.
• Discontinue previous medication if possible.
• If hepatotoxicity is due to phenobarbitone Phenobarbital consider changing to potassium bromide Potassium bromide or gabapentin Gabapentin.
• Steroids are generally NOT indicated and may actually worsen clinical signs as they increase water retention (ascites) and risk of gastrointestinal ulceration.
• High quality protein diet if evidence of hepatic encephalopathy Hepatic encephalopathy. Do not limit protein excessively as this will slow hepatic regeneration. Low fat diet if vomiting.
• Treat ascites with spironolactone Spironolactone + - frusemide Furosemide.
• Metoclopramide Metoclopramide if vomiting. This is most effectively administered added to the intravenous fluids and given as a 24 hour infusion.

• Vitamin K Vitamin K if coagulopathy.
• Fresh frozen plasma or whole blood if actively bleeding.
• H2 blockers, eg ranitidine Ranitidine or omeprazole Omeprazole and gastrointestinal protectants, eg sucralfate Sucralfate if gastric bleeding.
• Anti-oxidants such as SAMe or silymarin (milk thistle) especially if toxic cause.
• Ursodeoxycholic acid Ursodeoxycholic acid to remove toxic bile acids. Do not use in complete biliary obstruction (rare to occur in dogs).

• Watch for development of coagulopathy, encephalopathy.
• Check serum glucose Blood biochemistry: glucose in case hypoglycemia develops.
• Check serum potassium Blood biochemistry: potassium - hypokalemia worsens encephalopathy.

Treatment

• Minimize exercise.

Monitoring

• Serum biochemistry weekly.
• If persistent abnormalities, follow-up liver biopsy Biopsy: hepatic.
  Beware that serum enzyme activity, especially ALT, can continue to be raised for several weeks following an acute hepatic insult as they are also increased in hepatic regeneration.

• Depends on severity and elimination of underlying insult.
• Poor if coagulopathy and/or hepatic encephalopathy present.
• Less severe forms may result in complete regeneration.
• Persistent inflammation may result in chronic hepatitis Liver: chronic hepatitis.
• May result in cirrhosis.

• Resolution of vomiting, depression, anorexia, etc within days of treatment initiation.
• Serum biochemistry gradually returns to normal.

• Failure to identify and treat underlying disease/inciting factor.
• Failure to reverse may lead to fibrosis of liver and permanent damage → cirrhosis Liver: cirrhosis.

Refereed papers

• Recent references from PubMed and VetMedResource.
• Watson P J (2004) Chronic hepatitis in dogs: a review of current understanding of the aetiology, progression and treatment. Vet J 167 (3), 228-41 PubMed.
• Toshach K, Jackson M V V & Dubielzig R R (1997) Hepatocellular necrosis associated with SC injection of an intranasal bordetella bronchiseptica - canine parainfluenza vaccine. JAAHA 33 (2), 126-128 PubMed.
• Maddison J E (1992) Hepatic encephalopathy. Vet Intern Med 6 (6), 341-353 PubMed.
• Meyer D J & Williams D A (1992) Diagnosis of hepatic and exocrine pancreatic disorders. Semin Vet Med and Surg 7 (4), 275-284 PubMed.
• Dayrell-Hart B, Steinberg S A, VanWinkle T J & Farnbach G C (1991) Hepatotoxicity of phenobarbital in dogs: 18 cases. JAVMA 199 (8), 1060-1066 PubMed.

Other sources of information

• Scherk M A & Center S A (2005)Toxic, Metabolic, Infectious and Neoplastic Liver diseases.In:Textbook of Veterinary Internal Medicine. 5th edn. Eds: S J Ettinger & E C Feldman. Philadelphia: W B Saunders. pp 1464-1477.
• Watson P J (2005)diseases of the liver.In:BSAVA Manual of Canine and Feline Gastroenterology. 2nd edn. Eds E J Hall, J W Simpson & D A Williams. BSAVA publications. pp 240-268.
• Center S A (1996)Acute hepatic injury: hepatic necrosis and fulminant hepatic failure. In:Strombeck's Small Animal Gastroentererology. Eds W G Guilford. W B Saunders, Philadelphia. pp 654-705.
• Watson T (1996)Nutritional management of canine liver disease.Waltham Symposium, Birmingham. pp 42-46.