Angie Hardy, DVM; Paula M. Krimer, DVM, DVSc; and Kenneth S. Latimer, DVM, PhD

Class of 2003 (Hardy) and Department of Pathology (Krimer and Latimer), College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7388

Introduction

Although toxic in excessive amounts, zinc is an essential element of the body, required for proper growth and development. It is present in about 200 metalloenzymes, including carbonic anhydrase, alkaline phosphatase, and glutamate, lactate and alcohol dehydrogenases.⁷ Zinc is naturally detectable in every organ system, especially the prostate, liver, pancreas, and kidney, and is at its highest concentration in the tapetum lucidum.¹¹

Zinc toxicosis has been reported in dogs, but it has not been described in cats, most likely due to their more discriminatory eating habits. It is characterized by an intravascular hemolytic anemia, gastrointestinal upset from direct irritation, and, potentially, multiorgan failure. Common sources of zinc contamination include galvanized coating on iron and steel (cages and nails, metal nuts from transport cages, and fencing⁴), automotive parts, batteries, fungicides, and topical medications. There have been reports of dogs that have ingested large amount of zinc oxide ointment, used to combat skin irritation.^2,5 Pennies minted after 1982 are made predominantly of zinc (96-98%) with a copper (2.5%) coating.³ Other sources of zinc include calamine lotion, paints, and shampoos.⁴

Toxicity and Pathophysiology

Of any zinc that is consumed, dietary or accidental, only 50% of it is absorbed in the small intestine.⁴ Approximately 25% is transported by a carrier-mediated mechanism.⁵ The ingested zinc is bound to plasma albumin and beta-2-macroglobulin where it is then carried to hepatocytes. Thirty to forty percent of the protein-bound zinc is extracted by liver and then released in to the blood stream.⁴ Some of the zinc in the blood is deposited in the liver, kidney, prostate, muscle, and pancreas.⁵ Zinc is mainly eliminated through pancreatic secretions and bile into the feces; excretion is slight in the urine (<10%).⁴

In dogs, normal dietary concentrations of zinc are ~80 to 120 ppm on a dry weight basis.³ There is no known minimal toxic dose for metallic zinc. The lowest dose of zinc salts that causes death in 50% of exposed animals exposed (LD₅₀) is approximately 100 mg/kg of body weight in cases of acute toxicity. Chronic toxicosis in cattle has occurred with supplementation over 2000 ppm of zinc.⁵ The amount of zinc absorbed in acute zinc toxicosis varies with each patient. Absorption is increased in acidic environments, and impaired by the simultaneous ingestion of phyates (i.e., inositol hexaphosphate that is present in cereal grains).⁶ Therefore, if the animal ingested a meal before eating a foreign object, the amount of zinc leaching is reduced. Experiments have shown that zinc is easily dissolvable in 1.8 pH hydrochloric acid solution. Copper-coated zinc pennies placed in hydrochloric acid will easily abrade at the mint mark under the date of the coin.⁶

Besides being a direct gastrointestinal irritant, acute zinc toxicity in dogs is associated with a hemolytic anemia and morphological changes of erythrocytes including nucleated erythrocytes, Heinz bodies and spherocytes. However, excess zinc in humans is associated with a nonhemolytic chronic anemia that is unresponsive to iron supplementation.² The underlying mechanism for the hemolytic anemia in zinc toxicosis of dogs is not fully elucidated; however, oxidative damage plays a significant role. Heinz bodies are rarely seen in normal canine erythrocytes, but oxidative damage can result in marked Heinz body formation and subsequent hemolytic anemia (Fig. 1). Heinz bodies are crystallized or denatured hemoglobin that appear as small outpocketings of the red blood cell membrane and are indicators of oxidative damage. These membrane abnormalities may signal the monocyte-macrophage system and result in splenic erythrophagocytosis of the damaged cell.³ Partial phagocytosis results in the formation of spherocytes, another erythrocyte characteristic of zinc toxicosis.² Spherocytes are small red blood cells that lack central pallor and have a small membrane to volume ratio (Fig. 2).

Figure 1. Heinz bodies (red arrows) and nucleated red blood cells (purple arrows) in scattered erythrocytes of a dog with zinc toxicosis (Dog, blood smear, Wright-Leishman stain).	Figure 2. Spherocytes (red arrows) and nucleated red blood cells (purple arrows) in the blood smear of a dog with zinc toxicosis (Dog, blood smear, Wright-Leishman stain).

Zinc may induce oxidative damage through several routes. Zinc has been shown to decrease copper absorption from the intestine, resulting in decreased serum copper. Copper is essential in cerulosplasmin (ferroxidase) activity, an enzyme that controls the rate at which iron (Fe⁺²) is released from the liver and bound to transferrin for transport. Ceruloplasmin is a potent serum antioxidant that scavenges superoxide radicals.⁸ Increased zinc levels also have been shown to decrease intracellular glutathione levels in rat astrocytes.¹² Glutathione is an enzyme present in many cells and is another important inhibitor of oxidative damage.

Clinical signs and diagnosis of zinc toxicosis

Common presenting signs of zinc toxicosis in dogs can be confused with an acute gastrointestinal (GI) episode. These patients may be anorexic and lethargic with vomiting and diarrhea that may or may not be bloody. In one reported case, the primary presenting sign was multiple, generalized seizures⁹, which may be due to the fact that zinc helps in regulating neurotransmission¹². Icterus and anemia are consistent findings and are due to the hemolytic anemia. On abdominal radiographs, one or more metallic dense objects may be seen in the stomach or intestine (Fig. 3 and 4). Some dogs may not have a foreign object on radiographs as they may have vomited the object or passed it in the feces. Topical sources of zinc such as zinc oxide ointment, as well as other ointments or shampoos, will not appear on radiographs. Therefore, a thorough medical history is necessary to identify possible sources of zinc exposure.

Figure 3. Lateral survey radiograph showing stacked pennies in the stomach.

Figure 4. Ventrodorsal survey radiograph of the abdomen of a dog with ingested pennies.

The most consistent hematologic findings in dogs with zinc toxicosis are a regenerative anemia, anisocytosis with nucleated erythrocytes (Fig. 1 and 2), and leukocytosis with a neutrophilia and left shift. The neutrophilia is most likely due to the inflammation caused by the irritated GI tract, multiorgan ischemia, and necrosis. More inconsistent but supportive findings include spherocytes, Heinz bodies in both intact and hemolyzed erythrocytes, and monocytosis.^2,3,9,10 The most common reason for a regenerative anemia with spherocyte formation is an immune-mediated hemolytic anemia, so this disease should be excluded first. Blood parasites also should be excluded.

The most consistent biochemical findings include elevated alkaline phosphatase activity, hyperbilirubinemia, and azotemia with a normal creatinine concentration.^1,2,3,6,9,10 The elevated alkaline phosphatase activity is most likely due to liver necrosis. The elevated blood urea nitrogen concentration in the absence of elevated creatinine concentration may be due to GI hemorrhage. The hyperbilirubinemia (and a hyperbilirubinuria) are due to the intravascular hemolysis. Other biochemical findings can include hyperamylasemia and hyperlipasemia due to pancreatic inflammation, elevated alanine transferase activity, hypokalemia, hypernatremia, and hypochloridemia. Frequent findings on urinalysis include hyperbilirubinuria, proteinuria, isosthenuria, hemoglobinemia, and urinary casts. Disseminated intravascular coagulation (DIC) has been reported to occur during the course of treatment and is marked by prolonged coagulation times with an increase in fibrinogen degradation products and thrombocytopenia.¹⁰

A definitive diagnosis is based on elevated serum zinc levels, which can readily be measured using proper sampling techniques. Most blood tubes will add extraneous amounts of zinc to a sample. For instance, ethylenediaminetetraacetic acid (EDTA) vacuum tubes can contribute up to 5.60 ppm zinc to the sample.² Therefore, Venoject^® tubes, which contribute a mild amount of zinc, are better for sampling. The differentiation of normal versus toxic concentrations should not be affected by the minimal amount of zinc in these tubes.² Normal zinc serum concentration in the dog ranges from 0.70 to 2.0 ppm. Many dogs with zinc toxicosis have serum zinc values > 10 ppm.⁴ Zinc wafer pennies weigh around 2.5 gm,⁶ so an approximate ingested dose can be determined by weighing the penny. However, the total dose of ingested zinc that a patient receives is difficult to determine since a matrix of other salts can replace the zinc that has been leached.²

Treatment

The treatment of zinc toxicosis does not have a specifically defined protocol. However, removal of any ingested source of metal toxicity, either by gastroendoscopy or gastrotomy is absolutely necessary (Fig. 5). Symptomatic and supportive therapy include correcting for and maintaining hydration, acid-base status, and electrolyte balance. Maintaining adequate renal perfusion is essential since renal failure is a potential sequela.¹¹ A blood transfusion should be considered in severely anemic patients, and close monitoring of coagulation status is necessary to detect DIC. Medications to reduce vomiting and diarrhea (such as metaclopramide⁴) and antibiotics may help in preventing deterioration of gastric mucosa and secondary infection. Aminoglycosides should be avoided because of their nephrotoxicity. Chelation therapy with calcium disodium EDTA has been proposed to reduce zinc concentrations.⁵ Calcium disodium EDTA enhances renal excretion of zinc but should be used carefully as it may have toxic renal effects. Daily monitoring of blood chemistry, urinalysis, complete blood count, and serum zinc levels will help determine the success of treatment.

Figures 5A and 5B. Obverse (5A) and reverse (5B) of pennies that were removed from a affected dog with zinc toxicosis. Notice the eroded and pitted surfaces.

If treatment is unsuccessful, several nonspecific postmortem lesions can be found including renal infarcts with tubular necrosis, gastroenteritis with or without ulcerative lesions, and hepatocyte necrosis with hemosiderosis.⁵ One report noted centrilobular hepatocyte vacuolization (fatty change) and cloudy swelling on antemortem liver biopsy. At necropsy, this dog had a pale, firm, friable liver. Histologically, the same centrilobular hepatocyte vacuolization with necrosis of individual cells, bile casts, and hemosiderosis was observed.⁶ Fat necrosis with associated fibrosis may be observed in histologic sections of pancreasl. Reference intervals for zinc concentration (dry weight basis) have been determined in canine liver (normal is 30-70ppm), kidney (16-30ppm), pancreas (22-60ppm), and urine. Zinc toxicosis usually is associated with markedly increased metal concentrations. Interestingly enough, copper and iron concentrations in these organs of dogs with zinc toxicosis may be within reference intervals. ⁹

Summary

Acute zinc toxicosis in dogs, although uncommon, is associated with the ingestion of foreign materials such as galvanized metal and pennies minted after 1982. Zinc toxicosis is more common in dogs that are predisposed to pica and causes gastroenteritis, hemolytic anemia, inflammation, and possible necrosis of liver, kidney, and pancreas. The exact mechanism of zinc toxicity is still unknown, but the prognosis is fair if zinc toxicosis is detected and treated early. Treatment consists of removal of the foreign object(s), alleviating the anemia, supportive fluid therapy, and possibly chelation therapy.

References

1. Torrance A, Fulton R: Zinc-induced hemolytic anemia in a dog. J Am Vet Med Assoc 1987; 191:443-444.

2. Breitschwerdt EB, Armstrong P, Robinette C, Dillman R, Karl M, Lowry E: Three Cases of acute zinc toxicosis in dogs. Vet Hum Toxicol 1986; 28:109-117.

3. Latimer K, Jain A, Inglesby H, Clarkson W, Johnson G: Zinc-induced hemolytic anemia caused by ingestion of pennies by a pup. J Am Vet Med Assoc 1989; 195:77-80.

4. Talcott P, Peterson ME: Zinc Poisoning. In: Small Animal Toxicology. W. B. Saunders, Philadelphia, 2001, pp. 756-761.

5. Osweiler G: Toxicology. Williams and Wilkins, Philadelphia, 1996, pp. 204-205.

6. Meerdink G, Reed R, Perry D, Warfield T: Zinc poisoning from the ingestion of pennies. Proc Am Assoc Vet Lab Diagn 1986; 141-150.

7. Ogden L, Edwards W, Nail N: Zinc intoxication in a dog from the ingestion of copper-clad zinc pennies. Vet Hum Toxicol 1988; 30:577-578.

8. Frieden E: The copper connection. Semin Hematol 1983; 20:114-117.

9. Luttgen P, Whitney M, Wolf A, Scruggs D: Heinz body hemolytic anemia associated with high plasma zinc concentration in a dog. J Am Vet Med Assoc 1990; 197:1347-1350.

10. Meurs KM, Breitschwerdt EB, Baty CJ, Young MA: Postsurgical mortality secondary to zinc toxicity in dogs. Vet Hum Toxicol 1991; 33:579-583.

11. Mineral Tolerance of Domestic Animals. Subcommittee on Mineral Toxicity in Animals, National Academy of Sciences, Washington, D.C., 1980.

12. Ryu JR, Shin CY, Choi J-W, Min HW, Ryu JH, Choi C-R, Ko KH: Depletion of intracellular glutathione mediates zinc-induced cell death in rat primary astrocytes. Exp Brain Res 2002; 143:257-26

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