Red Maple Leaf Toxicosis in Horses
ACVIM 2008
Ashley Alward, DVM, DACVIM
Scottsdale, AZ, USA

Introduction

Ingestion of dried or wilted Red Maple (Acer rubrum) leaves by equids and camelids may result in oxidative damage to erythrocyte cell membranes and hemoglobin, resulting in intra- or extra-vascular hemolysis, Heinz body formation and/or methemoglobinemia.1-4 Clinical signs of Red Maple Toxicosis (RMT), are reflective of hemolysis and tissue hypoxia. Treatment is directed towards inhibiting further toxin absorption, restoring tissue perfusion and oxygenation, reducing inflammation and providing analgesia.

Etiology

Red Maple trees grow extensively throughout the entire eastern United States (generally east of the Mississippi River) and Canada. The trees are of medium size, with 2 to 4 inch long leaves consisting of 3 to 5 lobes with serrated margins, relatively shallow sinuses, light green top surfaces and a slightly silvery underside. In the spring, the trees develop bright red flowers, followed by new leaves and small clusters of fruit. During the fall, the leaves may become vibrant red, orange or yellow.5

Horses ingesting dried or wilted red maple leaves begin to display clinical signs within 12-48 hours, and death often occurs within 3 to 6 days of intoxication (however, death may occur peracutely).1

Pathogenesis

Acer rubrum toxicosis may result in two clinical syndromes characterized by hemolytic anemia and methemoglobinemia, which may occur independently or concurrently. 1,6 Experimental studies have resulted in the discovery of two toxic compounds present in red maple leaves capable of inducing methemoglobin formation and hemolysis in equine erythrocytes: gallic acid and a second, as yet unidentified oxidizing compound.7 These compounds are not unique to Acer rubrum, suggesting that ingestion of leaves from other maple species (e.g., Acer saccharum and Acer saccharinum) may result in clinical signs similar to RMT.

Oxidative damage to hemoglobin results in denaturation and subsequent precipitation of the protein. The precipitated protein form spherical, refractile Heinz bodies that attach to erythrocyte membranes, resulting in damage to the RBC, hyperpermeability, loss of normal intracellular tonicity and subsequent intravascular hemolysis. Direct oxidative damage to the erythrocyte cell membrane may result in decreased deformability of the cell membrane, premature removal of the RBC by the spleen and extravascular hemolysis.6

Methemoglobin is a form of the oxygen-carrying protein hemoglobin, in which the iron in the heme group is in the ferric Fe3+ state, not the ferrous Fe2+ of normal hemoglobin. The ferric iron in methemoglobin does not bind oxygen; therefore erythrocytes containing methemoglobin are unable to carry oxygen to tissue.8 The NADH-dependent enzyme methemoglobin reductase is responsible for converting methemoglobin back to hemoglobin. Horses have a much slower rate of methemoglobin reductase activity than other mammalian species, as well as a relatively inefficient lactate-dependent pathway of methemoglobin reduction.9 These two factors result in an inability of equids to rapidly reduce methemoglobin in the face of continued oxidative stress, subsequent accumulation of clinically significant concentrations of methemoglobin, and resultant tissue hypoxia.

Clinical Signs and Clinicopathologic Findings

Clinical signs of RMT vary depending upon the severity and rapidity of hemolysis, degree of methemoglobinemia, efficacy of tissue perfusion and severity of hypoxia. Animals with mild cases of RMT may display no detectable clinical signs, or show only slight depression, lethargy, and inappetence. Common clinical signs and physical examination abnormalities associated with RMT include: colic, pigmenturia, tachycardia, tachypnea, dyspnea, fever, discolored ("chocolate", "muddy", or icteric) mucous membranes, weakness, depression and ataxia. There have been reports of abortion and sudden death associated with red maple leaf toxicosis in horses.

Hematologic abnormalities in horses with RMT may include anemia (which can be quite marked), Heinz body formation, eccentrocytosis, poikilocytosis, anisocytosis, increased RBC fragility and agglutination, increased mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC), increased free plasma hemoglobin, methemoglobinemia, leukocytosis (most commonly due to a neutrophilia) and rarely neutropenia. Methemoglobin (metHgb) concentrations, percent methemoglobin and corrected hemoglobin (total Hgb-metHgb) levels may be normal to markedly elevated.

Biochemical abnormalities may include azotemia (increased serum creatinine and blood urea nitrogen concentrations); elevated creatine kinase (CK) and aspartate aminotransferase (AST) activities; elevated gamma glutamyl transpeptidase (GGT), alkaline phosphatase (ALP) and sorbitol dehydrogenase (SDH) activities; increased total, direct and indirect bilirubin levels; hyperglycemia; hypercalcemia and metabolic acidosis. Gross hemolysis may prevent colorimetric assays on many biochemistry analyzers.

Urine obtained from horses with RMT is often dark brown to black, with hematuria, hemoglobinuria, methemoglobinuria, proteinuria, bilirubinuria and occasional casts. Horses with RMT-induced acute renal failure may be oliguric, anuric and isosthenuric.

Diagnosis

A diagnosis of RMT is based upon historic exposure of animals to toxic leaves; clinicopathologic evidence of acute hemolytic anemia, Heinz body anemia and/or methemoglobinemia; and ruling out other causes of hemolytic crisis. Differential diagnoses for acute hemolytic anemia in the horse include immune-mediated hemolytic anemia (e.g., drug-induced, neoplastic, idiopathic), infectious anemia (e.g., Equine Infectious Anemia, piroplasmosis), administration of hypertonic or hypotonic solutions, snake envenomation, hepatic failure and RMT.10,11 Methemoglobinemia in the horse has been attributed to RMT, phenothiazine toxicosis, onion (Allium spp) ingestion, congenital methemoglobinemia and flavin adenine dinucleotide (FAD) deficiency.10-12 A detailed history often elicits information to support the diagnosis of maple toxicity.

Treatment

There is no specific antidote for red maple toxicosis. Therapy in horses is largely supportive, and directed towards improving tissue oxygenation, promoting perfusion, reducing inflammation and providing analgesia. Activated charcoal and mineral oil administered via nasogastric intubation may be beneficial in the acute stages after ingestion to reduce toxin absorption. Ascorbic acid (30-50mg/kg IV twice daily diluted in 5-10L crystalloid fluids) has been suggested to promote non-enzymatic reduction of methemoglobin.9 Tissue oxygenation may be improved by a combination of enhancing perfusion via crystalloid fluids, as well as administering whole blood transfusions or hemoglobin-based oxygen carriers (Oxyglobin®). Non-steroidal anti-inflammatory medications must be used judiciously, as many horses with RMT develop renal insufficiency secondary to hypoxia, hypoperfusion and hemoglobin / pigment nephrotoxicity.

Complications and Prognosis

The published mortality rates associated with natural and experimentally-induced red maple toxicosis range from 60-65%. In one retrospective study, there were no clinicopathologic variables upon admission that accurately predicted survival.13 Acute renal failure is commonly seen in horses with RMT; this is presumed to be due to a combination of inadequate renal perfusion / oxygenation and pigment nephropathy. Colic signs may develop secondarily to enterocyte ischemia, impaired motility and secondary impactions (particularly cecal). Severe systemic inflammation, hypoxia and poor perfusion may result in the development of laminitis.

Summary

Ingestion of dried or wilted maple leaves may result in hemolytic and/or methemoglobinemic crises in equids and camelids. Even with aggressive supportive care, mortality rates of horses with maple toxicosis can be quite high (approximately 60%). The best treatment for RMT in horses is prevention of exposure and ingestion.

References

1.  George LW, et al. Vet Pathol 1982; 19:521-533.

2.  Divers TJ, et al. J Am Vet Med Assoc 1982;180:300-302.

3.  Weber M, Miller RE. J Zoo Wildl Med 1997;28:105-108.

4.  Dewitt SF, et al. J Am Vet Med Assoc 2004;225:539, 578-583.

5.  vanGelderen DM, et al. Maples of the World. Portland OR: Timber Press; 1994: 320-323.

6.  Tennant B, et al. J am Vet Med Assoc 1981;179:143-150.

7.  Boyer JD, et al. Am J Vet Res 2002;63:604-610.

8.  Mansouri A, Lurie AA. Am J Hematol 1993;42:7-12.

9.  McConnico RS, Robwin CF. Cornell Vet 1992;82:293-300.

10. Corriher CA, et al. Compend Contin Educ Pract Vet 1999;21:74-80.

11. Sellon DC. Equine Internal Medicine 2nd ed. Philadelphia PA: WB Saunders; 2004: 727-735.

12. Harvey, et al. Vet Path 2003;40:632-642.

13. Alward AL, et al. J Vet Int Med 2006;20:1197-1201.

Speaker Information
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Ashley Alward, DVM, DACVIM
Phoenix, AZ


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