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Basics ⬇

Basics

Definition

Positive, semiquantitative urine heme (also reported as occult blood) concentration detected via routine laboratory tests (e.g., reagent test strip).

Pathophysiology

  • Hemoglobin released from RBC during intravascular hemolysis (hemoglobinemia) is bound (high-affinity) to haptoglobin, thereby inhibiting oxidative tissue destruction. Hemoglobin-haptoglobin complexes are too large to pass through normal glomerular capillaries and are removed by the reticuloendothelial system, mainly in the spleen. Haptoglobin becomes saturated when hemoglobin concentration is high; free hemoglobin (4 heme-containing chains, 64,000 daltons) rapidly dissociates into unstable dimers (32,000 daltons) small enough to pass through glomerular capillaries, resulting in hemoglobinuria (red discoloration). Free hemoglobin undergoes fluid-phase endocytosis (via megalin and tubulin receptors expressed at the apical membrane) in renal tubular epithelial cells. Globin is degraded while free heme is catabolized by heme oxygenase, resulting in lipid peroxidation and Fe deposition. In addition, an acidic intratubular environment favors hemoglobin precipitation, cast formation, and tubular obstruction. Methemoglobinemia causes an analogous disease process.
  • In contrast, myoglobin, a single heme-containing chain (approximately 17,500 daltons), is released from muscle following decreased energy supply or injury. Interaction of heme with the protein portion (globin) allows myoglobin to carry oxygen without oxidation of ferrous (Fe2+) to ferric (Fe3+) iron. Myoglobin is freely and rapidly cleared by passing through the glomerular barrier (small size, no carrier protein) and plasma remains colorless. However, myoglobin accumulation in urine causes brown discoloration while an acidic environment favors precipitation, cast formation, and tubular obstruction. In addition, myoglobin enters proximal renal tubular epithelial cells via megalin and tubulin receptors, where it causes lipid peroxidation without release of free iron (via redox cycling of the heme center). Alkaline conditions prevent myoglobin-induced lipid peroxidation by (1) stabilizing the reactive ferryl myoglobin complex and (2) decreasing myoglobin precipitation in renal tubules.

Systems Affected

Renal/Urologic-hemoglobin, methemoglobin, and myoglobin are nephrotoxic, especially when decreased renal perfusion and acidic conditions are present.

Signalment

  • Bedlington terrier-inherited copper toxicosis can cause hemolysis due to copper release from the liver into the blood. Although copper-associated liver disease has been reported in other breeds of dogs, only Bedlington terriers have been reported to have a hemolytic outcome.
  • English springer spaniel, American cocker spaniel, English cocker spaniel, cocker spaniel-inherited phosphofructokinase deficiency may cause intravascular hemolysis with hemoglobinuria and myopathy.
  • Racing sled dogs and greyhounds-exertional myopathy can result in myoglobinuria.
  • Old English sheepdog-exertional lactic acidosis with hemoglobinuria.
  • Neonatal isoerythrolysis in cats-(blood type B queen with type A or AB kittens) British shorthair, Cornish Rex, Devon Rex, Abyssinian, Birman, Himalayan, Persian, Scottish fold, and Somalia breeds; neonates die within 2 days.

Signs

General Comments

A diversity of clinical signs may be associated with specific causes; see “Causes.”

Historical Findings

Breed and drug treatment history are particularly important; see “Causes.”

Physical Examination Findings

  • Signs associated with anemia (pale mucous membranes, tachycardia, lethargy, icterus).
  • Signs associated with muscle damage (tenderness, bruising).

Causes

Hemoglobinuria

  • Oxidative damage-drugs (acetaminophen, benzocaine, vitamin K3, new methylene blue, phenacetin, phenazopyridine, monensin sodium); food (onions, garlic); heavy metals (copper, zinc).
  • Physical agents-burns, heat stroke, crush injury, electric shock, IV hypotonic fluid administration, microangiopathy (e.g., disseminated intravascular coagulopathy, D. immitis caval syndrome).
  • Toxins (loss of membrane integrity)-snake (e.g., Eastern diamondback, Eastern coral) or spider (e.g., brown recluse) venom.
  • Infectious agents-babesiosis (e.g., B. canis), leptospirosis (e.g., L. icterohemorrhagica), cytauxzoonosis (e.g., C. felis), mycoplasmosis (e.g., M. hemofelis).
  • Immune-mediated-idiopathic immune-mediated hemolytic anemia, incompatible blood transfusion, isoerythrolysis (e.g., type B queen with type A or AB kittens).
  • Deficiencies-hypophosphatemia (e.g., following insulin treatment in diabetes mellitus patients).
  • Genetic associated-PFK deficiency, copper toxicity.
  • Other-retroperitoneal hemorrhage.

Myoglobinuria

  • Myositis-infectious (e.g., toxoplasmosis, neosporosis), eosinophilic (German shepherd dog, other breeds), immune-mediated.
  • Genetic-associated-X-linked muscular dystrophy (e.g., golden retriever, Weimaraner, rottweiler, Samoyed, Groenendael shepherd, miniature schnauzer); glycogenoses (storage diseases)-Type II (spitz), Type III (German shepherd dog), Type VII (springer spaniel colony, one American cocker spaniel); mitochondrial abnormalities (Clumber spaniel, Sussex spaniel, possibly Old English sheepdog).
  • Toxins (loss of membrane integrity)-snake (e.g., coral) or spider (e.g., brown) venom.
  • Physical-ischemia, crush injury, compartment syndrome.
  • Excessive body temperature (e.g., heat stroke, prolonged seizures).
  • Extreme exercise.

Risk Factors

  • Genetic predisposition (see “Signalment”)
  • Exposure to specific drugs or toxins
  • Certain infectious agents
  • Extreme physical exertion
  • Heat stroke
  • Snake or spider venom

Diagnosis ⬆ ⬇

Diagnosis

Differential Diagnosis

  • Urine reagent test strip heme (occult blood) pads detect RBC, hemoglobin (or methemoglobin), and myoglobin; the following assist with differentiation:
    • Clear plasma/serum with RBC or RBC ghost cells in urine sediment suggests hematuria.
    • Hemolyzed plasma/serum (not related to collection) suggests hemoglobinuria.
    • Chocolate-colored whole blood suggests methemoglobinuria.
    • Clear plasma/serum with an increased CK concentration and clinical evidence of muscle damage suggests myoglobinuria.
    • False-positive results (see “Laboratory Findings”).

Laboratory Findings

Drugs That May Alter Laboratory Results

  • Vitamin C (ascorbic acid) administration may cause false-negative reagent test strip results.
  • Hemoglobin-based oxygen carriers (Oxyglobin) administration causes positive reagent test strip results.

Disorders That May Alter Laboratory Results

  • Hyposthenuria (low urine specific gravity) may cause in vitro RBC lysis (no intact RBC in sediment) with a positive reaction.
  • Bacteriuria may cause a false-positive result (bacterial peroxidase).
  • Oxidizing reagents (e.g., from disinfectants) may cause a false-positive result.
  • Free hemoglobin from transfused blood or blood products may cause a positive reaction.
  • Formalin causes false-negative results.

Valid if Run in Human Laboratory?

Yes

CBC/Biochemistry/Urinalysis

  • Proteinuria.
  • Intravascular hemolysis-decreasing PCV (may be accompanied by leukocytosis), blood smear abnormalities (RBC parasites, Heinz bodies, RBC ghost cells [complement mediated]), bilirubinemia, increased ALT activity, bilirubinuria.
  • Rhabdomyolysis-increased CK and AST activities.

Other Laboratory Tests

  • Ammonium sulfate precipitation test-mix 5 mL urine with 2.8 g ammonium sulfate and centrifuge; hemoglobin precipitates, myoglobin remains in solution. Dark precipitate is suggestive for hemoglobinuria, dark supernatant is suggestive of myoglobinuria, and if both are dark, hemoglobin and myoglobin are present.
  • New methylene blue stained blood smear to detect Heinz bodies.
  • Methemoglobin detection confirms toxin as oxidant.
  • Haptoglobin concentration is decreased with intravascular hemolysis.
  • Increased serum copper or zinc concentration.
  • DNA test for PFK deficiency.

Imaging

Abdominal radiography or ultrasonography-coins, hardware or other metal objects in the gastrointestinal tract; abnormal liver size in patients with copper-associated hepatopathy.

Diagnostic Procedures

  • Liver biopsy to measure copper concentration
  • Forced exercise (e.g., Old English sheepdog)

Treatment ⬆ ⬇

Treatment

Medications ⬆ ⬇

Medications

Drug(s) Of Choice

Vary with underlying cause.

Contraindications

See list of causes for contraindicated drugs.

Alternative Drug(s)

N/A

Follow-Up ⬆ ⬇

Follow-Up

Patient Monitoring

PCV, pO2, urinalysis, serum creatinine, ALT (copper-associated), CK (myopathy-associated).

Possible Complications

Renal damage (failure) may develop.

Miscellaneous ⬆

Miscellaneous

Age-Related Factors

Neonatal isoerythrolysis

Zoonotic Potential

  • Leptospirosis
  • Toxoplasmosis

Pregnancy/Fertility/Breeding

N/A

Synonyms

Pigmenturia

See Also

See “Causes”

Abbreviations

  • ALT = alanine aminotransferase
  • AST = aspartate aminotransferase
  • CK = creatine kinase
  • PCV = packed cell volume
  • PFK = phosphofructokinase
  • RBC = red blood cell

Suggested Reading

Bartges JW. Hematuria and other conditions causing discolored urine. In: Ettinger SJ, Feldman EC, eds., Textbook of Veterinary Internal Medicine, 7th ed. St. Louis, MO: Elsevier, 2010, pp. 164–168.

Harvey JW. Pathogenesis, laboratory diagnosis, and clinical implications of erythrocyte enzyme deficiencies in dogs, cats, and horses. Vet Clin Pathol 2006, 35:144–156.

Mitchell K, Kruth S. Immune-mediated hemolytic anemaia and other regenerative. In: Ettinger SJ, Feldman EC, eds., Textbook of Veterinary Internal Medicine, 7th ed. St. Louis, MO: Elsevier, 2010, pp. 761–772.

Osborne CA, Stevens JB. Biochemical analysis of urine: Indications, methods, interpretation. In: Urinalysis: A Compassionate Guide to Patient Care. Shawnee, KS: Bayer, 1999, pp. 86–124.

Shelton DG. Rhabdomyolysis, myoglobinuria, and necrotizing myopathies. Vet Clin North Am Small Anim Pract 2004, 34:1469–1482.

Singh D, Chander V, Chopra K. Rhabdomyolysis. Methods Find Exp Clin Pharmacol 2005, 27:39–48.

Authors Cheryl L. Swenson, Carl A. Osborne and Eugene E. Nwaokorie

Consulting Editor Carl A. Osborne

Acknowledgment The authors and editors acknowledge the prior contributions of Frederic Jacob and Leslie Sharkey.