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Basics ⬇

Outline

BASICS

Definition!!navigator!!

Hyperbilirubinemia is increased bilirubin in the blood.

Pathophysiology!!navigator!!

  • Most bilirubin in the blood of healthy horses originates from the breakdown of hemoglobin by macrophages that have phagocytized aged or damaged erythrocytes
  • Macrophages release water-insoluble, unconjugated (indirect) bilirubin into blood where it binds to albumin. This form of bilirubin does not pass through glomeruli into urine. It enters hepatocytes by a carrier-mediated process. A small amount is refluxed into blood; most is conjugated to a water-soluble form that is excreted into the biliary system. Little conjugated (direct) bilirubin is regurgitated back into systemic circulation
  • Conjugated bilirubin is filtered by glomeruli and bilirubinuria can occur with hyperbilirubinemia
  • Normal horses have higher blood concentrations of bilirubin than many other species
  • Hyperbilirubinemia occurs with decreased food intake, hemolytic anemia, hepatocellular disease, and cholestatic disorders

Systems Affected!!navigator!!

Skin

  • Icterus (yellow discoloration of skin, sclera, or mucous membranes) may be detected when total bilirubin concentrations >2–3 mg/dL. Hyperbilirubinemia can be present without visible icterus
  • Slight yellow discoloration of sclera or mucous membranes occurs in 10–15% of normal horses

Renal/Urologic

Dark-colored urine occurs with bilirubinuria.

Genetics!!navigator!!

N/A

Incidence/Prevalence!!navigator!!

N/A

Geographic Distribution!!navigator!!

N/A

Signalment!!navigator!!

  • All ages and breeds are affected
  • Newborns are at risk for neonatal isoerythrolysis

Signs!!navigator!!

Historical Findings

  • Anorexia
  • Depression
  • Lethargy
  • Weakness
  • Icterus

Physical Examination Findings

  • Hemolytic anemia—pale mucous membranes, tachycardia, and tachypnea
  • Hepatocellular or cholestatic disorders—weight loss, behavioral changes, colic, fever, diarrhea, ascites, edema, hemorrhagic diathesis, photosensitization

Causes!!navigator!!

Prehepatic (Hemolytic) Hyperbilirubinemia

  • Hemolytic disorders cause elevated total bilirubin (primarily unconjugated) when production overwhelms the ability of hepatocytes to uptake, conjugate, and excrete bilirubin
  • Conjugated bilirubin may increase due to increased hepatic production or concurrent hepatobiliary disease
  • Causes for hemolysis include immune-mediated disorders (e.g. neonatal isoerythrolysis, idiopathic, or secondary to drug therapy, infection, neoplasia), infectious diseases (e.g. piroplasmosis, equine infectious anemia), oxidant damage (e.g. red maple leaf intoxication), fragmentation (e.g. disseminated intravascular coagulation), administration of hypotonic fluids and severe hepatic failure

Fasting Hyperbilirubinemia

  • Unconjugated bilirubin predominates with minimal increases in conjugated bilirubin
  • Elevated bilirubin in the blood occurs within 12–15 h of onset of anorexia or fasting
  • Bilirubinemia plateaus after 2–3 days and is usually <8 mg/dL but may be as high as 12 mg/dL
  • The mechanism likely involves impaired bilirubin uptake by hepatocytes
  • Values normalize once food intake resumes

Hepatic Hyperbilirubinemia

  • Hepatocellular disorders increase bilirubin by impairing bilirubin uptake, conjugation, or excretion into biliary canaliculi
  • Unconjugated bilirubin predominates

Cholestatic Hyperbilirubinemia

  • Decreased bilirubin excretion occurs with obstruction of bile flow due to hepatocyte swelling, periportal compression of bile ducts, or extrahepatic blockage of bile ducts
  • Endotoxemia/sepsis may cause functional cholestasis
  • Suspect cholestatic disease when conjugated bilirubin comprises >25% of total bilirubin; conjugated bilirubin rarely exceeds 30–40% of total bilirubin

Risk Factors!!navigator!!

  • Hyperbilirubinemia is common with anorexia
  • Mild hyperbilirubinemia may occur for several days after prolonged exercise
  • Administration of equine biologics (e.g. plasma, tetanus anti-toxin) is associated with Theiler's disease

Diagnosis ⬆ ⬇

Outline

DIAGNOSIS

Differential Diagnosis!!navigator!!

N/A

CBC/Biochemistry/Urinalysis!!navigator!!

  • Total and conjugated bilirubin are measured in serum or heparinized plasma. Unconjugated bilirubin is calculated
  • Exposure to sunlight or fluorescent lighting may decrease bilirubin concentration
  • Separate serum/plasma from cells as soon as possible and protect from light
  • Hemolysis, lipemia, or some drugs may alter bilirubin measurement depending on the methodology used

Prehepatic Hyperbilirubinemia

  • Moderate to severe decreases in RBC count, hematocrit, and hemoglobin
  • Hemoglobinemia and hemoglobinuria occur if hemolysis is intravascular
  • Total protein and albumin concentrations are usually normal
  • Blood smear may reveal morphologic changes supporting hemolysis (e.g. agglutination, spherocytes, Heinz bodies, eccentrocytes, schistocytes, pyknocytes) or organisms
  • Neutrophilia with a left shift may be present
  • The activity of liver enzymes (e.g. AST, SDH) may be normal to slightly elevated due to hypoxia

Fasting Hyperbilirubinemia

  • RBC count, hematocrit, and hemoglobin are normal to slightly decreased if anemia is not part of the disorder causing anorexia
  • Liver enzyme activities are normal if hepatobiliary disease is absent

Hepatic Hyperbilirubinemia

  • RBC count, hematocrit, and hemoglobin concentration are normal to slightly decreased
  • Albumin concentration usually is normal in acute and decreased in chronic hepatocellular disease with loss of function
  • Globulin concentrations are normal to increased
  • Liver enzyme (e.g. AST, SDH, ALP, GGT) activities are significantly increased; the degree of elevation lessens with chronicity
  • With impairment of hepatic function, BUN, glucose, and cholesterol concentrations may decrease. Bile acids and ammonia concentrations increase
  • Elevated triglyceride concentrations occur with hyperlipemia and hepatic lipidosis

Cholestatic Hyperbilirubinemia

  • RBC count, hematocrit, and hemoglobin are normal to slightly decreased
  • Total protein, albumin, BUN, and glucose concentrations usually are normal
  • Activities of enzymes indicative of hepatocellular damage (e.g. AST, SDH) may increase if there is concurrent hepatocyte damage; those indicative of cholestasis (e.g. ALP, GGT) are moderately to markedly increased
  • Serum bile acids are elevated
  • Bilirubinuria is detected

Other Laboratory Tests!!navigator!!

  • Prehepatic hyperbilirubinemia—consider Coggins test, Coombs test, osmotic fragility, serology, or PCR testing to determine the cause of anemia
  • Hepatic hyperbilirubinemia—measure clotting times (prothrombin time, activated partial thromboplastin time) in horses with hemorrhagic diathesis or before surgery to assess risk of hemorrhage

Imaging!!navigator!!

Ultrasonography is useful to evaluate liver size, changes in hepatic parenchyma, and biliary patency.

Other Diagnostic Procedures!!navigator!!

Hepatic biopsy for histopathology and bacterial culture may identify the cause of hepatic disease.

Pathologic Findings!!navigator!!

  • Hepatic disorders associated with hyperbilirubinemia include Theiler's disease, infectious hepatitis, toxic hepatopathies, chronic active hepatitis, amyloidosis, neoplasia, and hepatic lipidosis
  • Cholestatic disorders associated with hyperbilirubinemia include cholangitis, cholelithiasis, hepatitis, neoplasia, fibrosis, large colon displacement, and biliary hyperplasia

Treatment ⬆ ⬇

Outline

TREATMENT

  • Prehepatic hyperbilirubinemia—eliminate the inciting cause of erythrocyte destruction
  • Fasting hyperbilirubinemia—correct the underlying cause for decreased food intake
  • Hepatic or cholestatic hyperbilirubinemia—eliminate the underlying cause and provide supportive care until the liver regenerates

Appropriate Health Care!!navigator!!

  • Medical management is appropriate for most horses
  • Surgery is required in some cases of biliary obstruction

Nursing Care!!navigator!!

  • IV fluid therapy may be required to maintain hydration, tissue perfusion, and electrolyte balance
  • Compatible whole-blood or packed RBC transfusion is rarely required to restore erythrocyte mass in severely anemic horses

Activity!!navigator!!

Restrict activity until underlying abnormalities are corrected.

Diet!!navigator!!

  • Fasting hyperbilirubinemia—offer a high-quality diet; icterus will resolve when food intake resumes
  • Decreased hepatic function—provide a balanced, high-carbohydrate, low-protein diet; oat or grass hay is recommended

Client Education!!navigator!!

N/A

Surgical Considerations!!navigator!!

N/A

Medications ⬆ ⬇

Outline

MEDICATIONS

Drug(s) of Choice!!navigator!!

Prehepatic Hyperbilirubinemia

  • Discontinue any current drugs if suspect drug-induced IMHA
  • Treatment of IMHA includes immunosuppressive doses of corticosteroids (dexamethasone 0.1–0.2 mg/kg IM or IV SID), decreasing gradually once hematocrit stabilizes

Hepatic or Cholestatic Hyperbilirubinemia

  • Bacterial hepatitis or cholangitis are best treated with antibiotics determined by culture and sensitivity results
  • Chronic active (nonsuppurative) hepatitis with a suspected immune-mediated origin may respond to dexamethasone (0.05–0.1 mg/kg) or prednisolone (1 mg/kg) daily for 4–7 days, then gradually decrease over several days
  • Hepatic encephalopathy—neomycin (10–100 mg/kg PO every 6 h for 1 day); lactulose (333 mg/kg PO every 8 h)

Contraindications!!navigator!!

Hepatic or cholestatic hyperbilirubinemia:

  • Avoid drugs known to be hepatotoxic
  • Drugs associated with hepatocellular diseases include phenothiazine and erythromycin
  • Drugs associated with idiosyncratic hepatotoxicity include aspirin, diazepam, halothane, isoniazid, nitrofurantoin, phenobarbital, phenytoin, rifampin (rifampicin), and sulfonamides

Precautions!!navigator!!

Hepatic or cholestatic hyperbilirubinemia:

  • Use drugs cautiously because many require biotransformation or excretion in the liver and dosages may need to be altered
  • Avoid analgesics, anesthetics, and barbiturates if possible

Possible Interactions!!navigator!!

N/A

Alternative Drugs!!navigator!!

N/A

Follow-up ⬆ ⬇

Outline

FOLLOW-UP

Patient Monitoring!!navigator!!

  • Hemolytic hyperbilirubinemia—serial CBCs as indicated by the underlying disease process
  • Hepatic or cholestatic hyperbilirubinemia—regular measurement of liver enzyme activities, albumin, and bilirubin

Prevention/Avoidance!!navigator!!

Dependent on the underlying cause.

Possible Complications!!navigator!!

Dependent on the underlying cause.

Expected Course and Prognosis!!navigator!!

Dependent on the underlying cause.

Miscellaneous ⬆ ⬇

Outline

MISCELLANEOUS

Associated Conditions!!navigator!!

N/A

Age-Related Factors!!navigator!!

Bilirubin often is elevated in neonates because of decreased hepatic function and increased turnover of fetal hemoglobin; values usually decrease to adult concentrations within 1–2 weeks of birth.

Zoonotic Potential!!navigator!!

N/A

Pregnancy/Fertility/Breeding!!navigator!!

N/A

Synonyms!!navigator!!

  • Icterus
  • Jaundice

Abbreviations!!navigator!!

  • ALP = alkaline phosphatase
  • AST = aspartate aminotransferase
  • BUN = blood urea nitrogen
  • GGT = γ-glutamyltransferase
  • IMHA = immune-mediated hemolytic anemia
  • PCR = polymerase chain reaction
  • RBC = red blood cell
  • SDH = sorbitol dehydrogenase

Suggested Reading ⬆ ⬇

Carlson KL. Hepatic diseases in the horse. In: Sprayberry KA, Robinson NE, eds. Robinson's Current Therapy in Equine Medicine, 7e. Philadelphia, PA: WB Saunders, 2015:287–293.

Peek SF. Hemolytic disorders. In: Sprayberry KA, Robinson NE, eds. Robinson's Current Therapy in Equine Medicine, 7e. ST. Louis, MO: WB Saunders, 2015:492–495.

Author(s) ⬆ ⬇

Author: Jennifer S. Thomas

Consulting Editor: Sandra D. Taylor

Additional Further Reading ⬆

Click here for Additional Further Reading