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Basics ⬇

Basics

Definition

Increased total bilirubin concentration causing yellow tissue discoloration

Pathophysiology

  • Bilirubin-derived from degradation of heme-containing proteins; most (80%) from senescent erythrocytes; remainder from other heme-containing proteins (e.g., P450 cytochromes, myoglobin).
  • Unconjugated bilirubin-transported in plasma bound to albumin; diglucuronide conjugated after hepatocellular uptake.
  • Conjugated bilirubin-transported in bile and expelled into the intestines where most is converted to other products: e.g., urobilinogen can undergo enterohepatic circulation, stercobilin colors feces brown.
  • Hyperbilirubinemia-caused by increased bilirubin production (increased RBC destruction; hemolytic jaundice); heme exceeding the hepatic capacity for uptake, conjugation, or biliary excretion (hepatic jaundice), or interrupted biliary elimination (post-hepatic jaundice).
  • Non-hemolytic jaundice is caused by hepatobiliary disease or bile peritonitis.

Systems Affected

  • Skin/Exocrine-skin discoloration (jaundice) reflects serum bilirubin >2.5 mg/dL.
  • Hepatobiliary-retained bile acids and markedly increased bilirubin may contribute to hepatocellular injury.
  • Renal/Urologic-extreme hyperbilirubinemia may cause renal tubular injury.
  • Nervous-extreme unconjugated hyperbilirubinemia may cause degenerative brain lesions (rare, kernicterus).

Signalment

Species

Dog and cat

Mean Age and Range

  • Most causes-diseases of adult animals
  • Young, unvaccinated dogs-at risk for infectious canine hepatitis

Predominant Sex

Adult female pure-bred dogs-at risk for immune-mediated hemolytic anemia

Signs

Historical Findings

Increased Formation-Hemolysis

  • Vague signs: lethargy, weakness
  • Gastrointestinal signs: anorexia, constipation, vomiting, weight loss
  • Jaundice
  • Recent blood transfusion
  • Severe trauma: bleeding into muscle, abdomen, or hematoma formation
  • Rhabdomyolysis (rare cause)

Decreased Elimination-Cholestasis

  • Vague GI signs: anorexia, vomiting, diarrhea, change in fecal color: non-obstructive jaundice is green, orange; obstructed jaundice is acholic.
  • Jaundice.
  • Change in urine color: orange.
  • Abdominal enlargement: if ascites.
  • Polyuria and polydipsia.
  • Altered mentation: if HE.

Physical Examination Findings

Increased Formation-Hemolysis

  • Pallor, tachycardia, tachypnea, weakness, bounding femoral pulses, anemic heart murmur
  • Jaundice
  • Hepatomegaly/Splenomegaly: EMH, RE hyperplasia
  • Lymphadenopathy
  • Bleeding tendencies-if thrombocytopenic
  • Orange feces
  • Fever
  • “Gelatinous” feel to skin (vasculopathy)
  • Rhabdomyolysis: weakness, pain

Decreased Elimination-Cholestasis

  • Weight loss
  • Jaundice
  • Hepatomegaly/Splenomegaly
  • Abdominal effusion/Mass/Pain
  • Melenic, Orange, Green, or Acholic feces
  • Fever

Causes

Prehepatic Jaundice

  • Hemolytic disorders: immune-mediated hemolysis; certain drugs (propylene glycol carriers in cats, trimethoprim sulfa); SLE; infectious disorders; toxins (e.g. oxidative injury: zinc, onions; phenols); severe hypophosphatemia
  • Incompatible blood transfusion
  • Infections-FeLV; Mycoplasma haemofelis; heartworm; Babesia; Ehrlichia; Cytauxzoon
  • Large volume blood resorption-hematomas, body cavities (e.g. hemangiosarcoma, warfarin)

Hepatic Jaundice

  • Chronic idiopathic or familial hepatitis
  • Adverse drug reactions-e.g., anticonvulsants; acetaminophen; trimethoprim sulfate; carprofen; stanozolol (cats); benzodiazepines (cats) (see Hepatotoxins)
  • Cholangitis/cholangiohepatitis
  • Infiltrative neoplasia-lymphoma
  • Cirrhosis (dogs)
  • Hepatic lipidosis (cats)
  • Massive liver necrosis: e.g., aflatoxin, cycad, NSAIDs (carprofen), copper associated injury
  • Systemic illnesses with hepatic involvement-leptospirosis (dogs); histoplasmosis; FIP; hyperthyroidism (cats); toxoplasmosis (cats)
  • Bacterial sepsis-originating anywhere in the body; may elaborate bacterial products that impair hepatic bilirubin processing/elimination.

Posthepatic Jaundice

Transient or persistent mechanical bile duct obstruction: (1) pancreatitis (transient obstruction); (2) neoplasia-bile duct, pancreas, duodenum; (3) intraluminal duct occlusion-cholelithiasis, sludged bile, liver flukes (cats), immune-mediated duct destruction (sclerosing cholangitis in cats), GB mucocele (dogs); (4) ruptured biliary tree causing bile peritonitis.

Risk Factors

  • Young unvaccinated dogs-infectious disease, canine infectious hepatitis.
  • Breed predisposition for familial hepatic disease-Labrador retriever, Doberman pinscher, Bedlington terrier, Cocker spaniel, Dalmatian
  • Middle-aged, obese dogs-pancreatitis
  • Anorectic, obese cats-hepatic lipidosis
  • Hepatotoxic drugs
  • Blunt abdominal trauma, chronic biliary tract disease, gallbladder mucocele-bile peritonitis
  • Hemolytic anemia

Diagnosis ⬆ ⬇

Diagnosis

Differential Diagnosis

  • Prehepatic jaundice-usually abrupt onset; mucous membrane pallor; mild to moderate jaundice; weakness; tachypnea; cardiac murmur with severe anemia.
  • Hepatic jaundice-breed risk for familial hepatitis; variable jaundice; otherwise normal mucous membranes; alteration in liver size (large or small); abdominal effusion (pure or modified transudate); polyuria and polydipsia; behavioral abnormalities of HE; coagulopathy.
  • Posthepatic jaundice-chronic and/or recurrent bouts of apparent GI signs or pancreatitis with cholelithiasis; moderate or marked jaundice; otherwise normal mucous membranes; diffuse or cranial abdominal pain; cranial abdominal mass; abdominal effusion (septic, nonseptic, or bile peritonitis); bleeding tendencies; acholic feces unless melena.

Laboratory Findings

Disorders That May Alter Laboratory Results

  • Bilirubin assay-based on the diazo reaction; assesses direct-reacting and total serum bilirubin; most yield reasonable total bilirubin results; values for direct bilirubin vary.
  • Higher readings in heparinized plasma.
  • Sample management-important; total bilirubin may decrease by 50% per hour with direct exposure to sunlight or artificial lighting.
  • Hemolysis-variable effects on total bilirubin measured by spectrophotometry.
  • Lipemia-falsely increases total bilirubin values measured by endpoint assays.
  • Fractionation into conjugated and unconjugated-unable to define causes of jaundice, contrary to dogma.

CBC/Biochemistry/Urinalysis

Prehepatic Jaundice

  • CBC-severe anemia (usually regenerative); blood smear may reveal autoagglutination, spherocytes, Heinz bodies, or parasites; hemoglobinemia with intravascular hemolysis, normal to low platelets, and normal to high WBCs, with a left shift.
  • Biochemistry-normal to high ALT and ALP activity and BUN concentration; normal to low albumin; normal to high globulin; normal glucose and cholesterol; high bilirubin.

Hepatic Jaundice

  • CBC-mild nonregenerative anemia; low MCV with chronic liver disease and portosystemic shunting; variable WBC count.
  • Biochemistry-mildly to markedly high ALT ± ALP; normal to low albumin, BUN, glucose, and cholesterol.
  • Urinalysis-normal to dilute urine; bilirubinuria precedes hyperbilirubinemia; bilirubinuria is important in cats.

Posthepatic Jaundice

  • CBC-± mild nonregenerative anemia; variable WBC count.
  • Biochemistry-increased ALT and moderate to markedly increased ALP; usually normal albumin, BUN, and glucose concentrations; normal to high cholesterol,

Other Laboratory Tests

  • In-Saline autoagglutination slide test-with suspected RBC agglutination; may have reported high MCV.
  • Direct Coombs' test-submit if no evidence of autoagglutination.
  • Osmotic fragility test-detects likelihood of RBC hemolysis tonicity challenge.
  • Blood smears-hemoparasites, spherocytes, schistocytes, anisocytosis (regenerative).
  • Plasma zinc-if hemolytic anemia.
  • ANA-with hemolytic anemia.
  • Serum bile acids-redundant if nonhemolytic jaundice already suspected.
  • Serology-for infectious diseases (e.g., FeLV, leptospirosis, mycoses) with signs of multisystemic illness and hepatic jaundice.
  • Abdominal effusion-characterize cell and protein content.
  • Coagulation tests-prolonged values, especially PIVKA and PT, with bile duct occlusion; vitamin K1 responsive.
  • Microbial culture and sensitivity-blood ± other specimens if inflammatory leukon and suspected bacterial infection (e.g., urinary tract, biliary tract, liver).

Imaging

  • Abdominal radiography-obscured by effusion; may reveal hepatomegaly, mass effect, mineral or gas interface in liver (emphysematous cholecystitis, choleliths); splenomegaly (hemolytic anemia, portal hypertension, abdominal neoplasia); metallic foreign body with zinc-induced hemolysis.
  • Thoracic radiography-may reveal metastatic disease; sternal lymphadenopathy (reflecting abdominal disease); general lymphadenopathy (lymphosarcoma, systemic infection [fungal]).
  • Abdominal ultrasonography-may distinguish parenchymal liver disease from extrahepatic biliary obstruction; characterizes hepatic parenchymal lesions; may disclose abdominal neoplasia; may determine cause of abdominal effusion; used to target lesions, fluid, or cystocentesis sampling (aspirates or needle biopsy).

Other Diagnostic Procedures

  • Fine-needle aspiration-cytology of mass, lymph node, hepatic parenchyma, bile.
  • Liver biopsy-bacterial culture of liver, bile, and other specimens obtained via celiotomy, blind percutaneous, keyhole, laparoscopic, or ultrasound-guided techniques.
  • Surgical intervention-required for diagnosis and treatment of posthepatic disorders.

Treatment ⬆ ⬇

Treatment

Medications ⬆ ⬇

Medications

Drug(s)

  • Prehepatic jaundice-eliminate inciting cause; see Anemia, Immune-Mediated; whole blood transfusion for life-threatening anemia.
  • Hepatic/Posthepatic jaundice-treat specific disorders based on imaging, biopsy, and culture.

Contraindications

  • Avoid known hepatotoxic drugs.
  • Avoid tetracyclines unless clearly indicated-suppress hepatic protein synthesis, promote hepatic lipidosis.
  • Avoid analgesics, anesthetics, barbiturates-with hepatic failure.

Precautions

  • Sedatives-may precipitate HE.
  • Corticosteroids-for nonseptic inflammation; increases risk for infection; may aggravate ascites (water and sodium retention), promotes VH (dogs) and hepatic lipidosis (cats).

Possible Interactions

Consider influence of altered hepatic metabolism on drug therapy; hypoalbuminemia influences potency of protein-bound drugs, enhancing effects (may lead to toxicity).

Follow-Up ⬆ ⬇

Follow-Up

Patient Monitoring

  • Prehepatic jaundice-recheck PCV and blood smears as needed; may require repeat transfusions; taper immunosuppressive drugs.
  • Hepatic and posthepatic jaundice-recheck serum biochemical profile as dictated by underlying disease; continue symptomatic and specific treatments until remission, varies with disease process.

Miscellaneous ⬆

Miscellaneous

Associated Conditions

  • Patients with immune-mediated hemolysis treated with immunosuppressive doses of corticosteroids are predisposed to thromboembolism, gastrointestinal ulcers, and infection.
  • Patients in hepatic failure: are susceptible to infections, enteric bleeding, and ascites.
  • Patients with reconstructive biliary surgery have risk for recurrent bacterial cholangitis.

Synonym

Jaundice

Abbreviations

  • ALP = alkaline phosphatase
  • ALT = alanine aminotransferase
  • ANA = antinuclear antibodies
  • BUN = blood urea nitrogen
  • EMH = extramedullary hematopoiesis
  • FeLV = feline leukemia virus
  • FIP = feline infectious peritonitis
  • HE = hepatic encephalopathy
  • MCV = mean corpuscular volume
  • PCV = packed cell volume
  • PIVKA = proteins invoked by vitamin K absence or antagonism
  • PT = prothrombin time
  • RBC = red blood cell
  • RE = reticuloendothelial
  • SLE = systemic lupus erythematosus
  • VH = vacuolar hepatopathy
  • WBC = white blood cell

Suggested Reading

Willard MD, Twedt DC: Gastrointestinal, pancreatic, and hepatic disorders. In: Small Animal Clinical Diagnosis by Laboratory Methods; 5th ed. St Louis, MO: Saunders, 2012, pp. 212–214.

Author Sharon A. Center

Consulting Editor Sharon A. Center

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