Toxicology Brief: Too much of a good thing: Zinc toxicosis in dogs
Drs. Grigsby and Medici offer an in-depth look at how to recognize possible zinc exposure in dogs and properly treat patients for toxicosis.
Is zinc toxicosis on your radar? Overexposure to this essential mineral can result in a variety of clinical signs and laboratory findings including hallmarks such as hemolytic anemia, bilirubinemia, and pigmenturia. Thus, zinc toxicosis can be misdiagnosed as immune-mediated hemolytic anemia (IMHA), revealing the necessity for imaging in all suspected IMHA cases. Prompt recognition of possible zinc exposure and treatment will provide the best outcome for these patients.
ZINC AS A NECESSARY TRACE ELEMENT
Zinc is an essential trace element with many important functions. More than 200 metalloenzymes require zinc for normal carbohydrate, protein, lipid, and DNA metabolism. Some of these enzymes include carbonic anhydrase, alkaline phosphatase, and urea cycle enzymes.1-3 These metalloenzymes are involved in gene expression, cell membrane structure and function, cell signaling, modulation of the cell's redox state, and cellular respiration.3-5
Ingestion of pennies minted after 1982 is a common source of zinc exposure in dogs.
About 25% of ingested zinc is absorbed by the intestine. Once absorbed, 60% of the zinc is bound to plasma albumin, 30% is bound to alpha2-macroglobulin, and 10% is bound to transferrin ceruloplasmin.6 About 90% of zinc in whole blood is found within red blood cells (RBCs) in the metalloenzymes carbonic anhydrase and copper-zinc superoxide dismutase.1
Zinc is excreted from the body via biliary and pancreatic secretions. Small amounts are excreted by the kidneys into the urine, but most is excreted in the feces.7 Studies have demonstrated that the tissues that contain the highest zinc concentrations in healthy animals are the uveal tract, prostate, bone, skin, muscle, liver, pancreas, and kidney.8 However, extreme excesses of zinc have a deleterious effect on almost every organ system.
SOURCES OF ZINC
Dietary sources of zinc include meat, eggs, dairy products, nuts, seeds, legumes, and cereals. Additional sources of zinc for people can include vitamin and mineral supplements (e.g. multivitamins), cold remedy lozenges, zinc oxide creams and ointments, and acne medications. Zinc chloride-containing products (soldering flux), which are used in stained glass work and can also be found in old window frames, have been reported to cause toxicosis in the human literature.9
Common sources animals are exposed to include pennies minted after 1982, nuts and bolts (galvanized steel) from pet transport cages, zinc oxide creams and ointments, tacks, and clothing and luggage zippers, although any time a metallic foreign body is seen, zinc toxicosis must be a differential.
INCIDENCE AND ABSORPTION
Zinc toxicosis has been reported in domesticated and wild animals, including cattle,10 horses,11 pigs,12 sheep,13,14 dogs,8,15-20 birds,21 ferrets,22 and other wildlife.23 In 2010, the ASPCA Animal Poison Control Center (APCC) reported 4,660 cases of zinc exposure in dogs and 250 cases in cats. Most of these reported sources of zinc were from metallic objects, multivitamins, and zinc oxide creams and ointments.24
To date, multiple case reports and a retrospective study have been published documenting the various clinical manifestations of zinc toxicosis.2,7,8,15-20,25,26 Most of these reports involve ingestion of metallic objects, in particular pennies. A retrospective case series of 19 patients documented that small-breed dogs were overrepresented.15 This overrepresentation may have been due to dose-related effect or because metallic objects could not pass through the pylorus due to small patient size.15 Zinc chloride ingestion has also been reported in the human literature. Symptoms reported included burns of the oral mucosa, pharynx, trachea, esophagus, and stomach; central nervous system depression; nephritis; hemolysis; and pancreatitis.19
Most of the toxic effects of zinc occur when free zinc is released by the stomach's acidic environment. Free zinc forms zinc salts, which are caustic to the intestinal mucosa and absorbed.7 Thus, the longer the object sits in the stomach's acidic environment, the more zinc is absorbed systemically.7 For example, when zinc oxide ointment is ingested in large amounts, it interacts with hydrochloric acid within the stomach to form zinc chloride. The formation of zinc chloride produces irritation and corrosion of the gastric and duodenal mucosa. Thus, vomiting has been reported in dogs that have ingested tubes of zinc oxide ointments or creams.18 In these patients, hemolytic anemia is unlikely since decontamination through spontaneous emesis has occurred. But chronic ingestion of zinc oxide-containing products applied to a patient's skin can be a source of toxicosis as a result of low-dose chronic ingestion over a few days or longer.18
The toxic dose has not been established in dogs. However, normal zinc serum concentrations in dogs are between 0.7 and 2 μg/ml.25
Zinc toxicosis can cause intravascular hemolysis, pancreatitis, coagulopathies, acute renal failure, and neurotoxicity (scan the QR code to the right or go to dvm360.com/ZincEffects to see the important ways zinc toxicosis can cause adverse effects). Most patients begin to exhibit clinical signs within a few days of zinc ingestion. The severity of the clinical signs is usually positively correlated to the dose ingested. Clinical signs can range from mild vomiting to death. For example, reversible cytopenias (anemia and neutropenia) have been documented in people with chronic oversupplementation of zinc.27 Early clinical signs of toxicoses can include vomiting and anorexia, diarrhea, and melena. This is due to zinc-induced gastric irritation.7
Pigmenturia, lethargy, and weakness can occur from intravascular hemolysis.8,15,18,19,20,25 Port wine-colored, pink, or brown urine is commonly noted. Gastric and duodenal ulceration, hepatic dysfunction, pancreatitis, acute renal failure, seizures, coagulopathies, and disseminated intravascular coagulation (DIC) may also occur as a result of zinc toxicosis.8,15-20
PHYSICAL AND NEUROLOGIC EXAMINATION FINDINGS
Physical examination findings often include pale mucous membranes, tachycardia, a heart murmur (secondary to anemia), dehydration, icterus (Figure 1), and abdominal pain.15 Tachypnea, lameness, polyuria, and polydipsia have also been documented.9,15
1. Icteric mucous membranes are evident in this dog secondary to zinc toxicosis.
Neurologic abnormalites can vary from mild lethargy to severe depression. Weakness can be noted. Seizures are possible. Severe neurologic disease (i.e. seizures, vocalizing) is rarely documented in cases of zinc toxicosis. Continuous howling was documented in a puppy that died after ingestion of fragment of a zinc-containing heating pipe.9
For a patient that is presented for evaluation of pigmenturia and anemia, a complete blood count, a serum chemistry profile, a urinalysis, a direct Coombs test, a saline agglutination test (SAT), and abdominal and thoracic radiography may be indicated.
Complete blood count
Clinical pathologic findings on a complete blood count can include regenerative anemia, thrombocytopenia, and leukocytosis with a mature neutrophilia. Heinz bodies were reported in 33% of canine patients in a retrospective study of zinc toxicosis.15 The presence of spherocytes is also an inconsistent finding in zinc-related hemolysis.15 In one study, 20% of dogs with zinc-induced hemolytic anemia had mild spherocytosis.15
Serum chemistry profile
Abnormalities that may be seen on a serum chemistry profile include hyperbilirubinemia, hyperproteinemia (not often seen), azotemia, and elevated amylase, lipase, and hepatic enzyme activities.15 Also, a disproportionate elevation in blood urea nitrogen (BUN) concentration compared with creatinine concentration may be seen due to dehydration or gastrointestinal (GI) blood loss.
Urinalysis may reveal proteinuria and pigmenturia from increased bilirubinuria or hemoglobinuria.15 Proteinuria and casts are often seen.18 To differentiate hematuria from hemoglobinuria, simply centrifuge the urine. Unlike blood cells in the case of hematuria, hemoglobin will not settle out but will remain in the supernatant.
Direct Coombs test
Direct Coombs testing, which is a direct antiglobulin test, is used to diagnose primary or secondary immune disorders causing hemolytic anemia. This test documents complement fixation or antibodies on the surface of RBCs. A positive result can be seen with zinc toxicosis. This can occur because serum proteins are damaged by RBC injury or zinc may interact with proteins on the surface of RBCs and induce an immune response.2
Saline agglutination test
An SAT is an easy in-house assessment of intravascular auto-agglutination of RBCs. Most cases of zinc-induced hemolytic anemia will have negative SAT results. However, because of the possibility that an immune response can be mounted in some cases of zinc toxicosis, the test result may occasionally be positive. Thus, the test is helpful in differentiating IMHA from zinc-induced hemolytic anemia but is not foolproof.
To perform this test, apply a drop of saline solution to a small drop of blood on a glass slide, and assess for agglutination via microscopy (Figure 2). Rouleaux are stacks of RBCs that can be a normal finding and should not be mistaken for agglutination.
2. This figure represents rouleaux vs. microagglutination. Rouleaux appears as stacks of RBCs like coins. Agglutination appears as clusters of RBCs.
Blood coagulation profiles
Activated clotting times, prothrombin times, and partial thromboplastin times may be prolonged due to direct or indirect effects of zinc on specific clotting factors and because the liver fails to synthesize these factors.2
Serum zinc concentration
In many cases, determining the serum zinc concentration is unnecessary to diagnose zinc toxicosis if a zinc-containing object or known source of zinc toxicity is found. Definitive diagnosis of zinc toxicosis is obtained by assessing serum zinc concentrations. Normal serum zinc concentrations in dogs and cats are 0.7 to 2 μg/ml.25 The exact toxic serum concentration of zinc is unknown. Avoid zinc contamination of serum samples by using royal blue top, trace element-free collection tubes.2,3
Radiographic identification of a metallic foreign object within the GI tract is highly suggestive of zinc toxicosis in a patient with hemolytic anemia. They are usually found within the stomach (Figures 3 & 4) but can be found anywhere along the GI tract. The absence of a metallic object does not rule out the possibility of zinc toxicosis. Obtaining serum zinc concentrations may also be indicated.
3 & 4. Abdominal radiographs revealed a metallic object, a penny, within the stomach of a dog.
Necropsy findings can vary based on the wide variety of clinical derangements caused by zinc toxicosis. A zinc-containing object may be found within the GI tract along with catarrhal gastritis or enteritis and edema or ulceration of the mucosa. The liver may contain centrilobular to diffuse hepatocellular vacuolar degeneration and necrosis. Pancreatic necrosis and fibrosis may be noted. The kidneys may have diffuse tubular degeneration and epithleial necrosis. The brain's grey matter may display shrunken neuronal cells that become triangular with pyknotic nuclei and dark-red cytoplasm. The white matter can develop edema, astrocytosis, and astrogliosis.2,16,19
Treatment is largely based on supportive care and the removal of the zinc source. Initial goals are to treat dehydration, shock, and electrolyte abnormalities and to enhance diuresis.2,3 Most patients will require fluid therapy at a rate of at least twice maintenance with a balanced electrolyte solution. If the animal is not producing appropriate amounts of urine, the fluid rate will need to be adjusted.
Foreign body removal
If a zinc-containing foreign object is found in the GI tract, it must be removed once the patient is stable.2,3,15 Removal can be performed by endoscopy if the object is within the stomach. During endoscopy the mucosa can be assessed for irritation and ulcerations caused by zinc. Once the object has passed into the small intestine, a laparotomy will be necessary.
Blood products (packed RBCs, whole blood) are often needed to treat the hemolytic anemia.2,3,15 If a patient is anemic, it may benefit from the administration of blood products. Plasma is routinely used to treat coagulopathies and may also be used to treat pancreatitis.28 Plasma contains alpha2-macroglobulin, which is a scavenger protein for activated proteases. Protease activity is inhibited by alpha2-macroglobulin. Also, plasma contains some albumin and coagulation factors, thus reducing the potential for DIC, and provides oncotic support in a patient with severe pancreatitis.28 Blood products and plasma also provide colloidal support, which helps maintain blood pressure and, thus, organ perfusion.
Other therapeutic interventions
It is important to initiate treatment with proton-pump inhibitors, such as omeprazole, or H2 blockers to reduce gastric acid production since it will decrease systemic absorption of zinc salts from the GI tract.2,3,15 Gastroprotectants, such as sucralfate, are indicated at normal doses for gastric irritation and ulceration. Antiemetics may be necessary to treat continued nausea from GI ulceration, pancreatitis, and renal failure. Opioids are indicated for pain from pancreatitis.
The use of chelation therapy is controversial. With appropriate supportive care, chelation therapy may not be necessary. Chelation will increase the renal excretion of zinc, but it can also increase intestinal absorption.2,3,15 There have been no published studies to document the benefit of chelation therapy.2,3,15
Chelation therapy has been attempted with calcium disodium EDTA, D-penicillamine, and dimercaprol. Calcium EDTA is a heavy metal chelator used for lead or zinc intoxication. It is contraindicated in patients with anuric renal failure. Adverse effects include renal tubular necrosis, vomiting, diarrhea, and depression.2,3,15 The typical doses given are 100 mg/kg divided into four subcutaneous doses per day diluted in 5% dextrose-containing fluids until zinc concentrations normalize.
D-penicillamine is used primarily in dogs for copper storage hepatopathies, but it chelates a variety of heavy metals including copper, lead, iron, mercury, and zinc. Side effects include vomiting, nausea, and depression. The recommended dose is 110 mg/kg/day given orally divided every six to eight hours, 30 minutes before feeding, for one to two weeks.2
Attention to patient history should alert you to the potential for exposure to zinc-containing products. Physical and neurologic examinations, laboratory testing, and imaging should also help attain the diagnosis. Complications of zinc toxicosis include the development of pancreatitis, acute renal failure, coagulopathies, and hepatic dysfunction, most of which are reversible with appropriate recognition and care. Many dogs that develop zinc toxicosis can recover quickly if diagnosis and therapy are initiated in a timely manner. It is important to stabilize the patient first and then remove the source of zinc exposure (e.g. removal of metallic object from the GI tract).
Laura Grigsby, DVM, VCA Mission Animal Referral and Emergency Center, 5914 Johnson Drive, Mission, KS 66202.
Emily Medici, DVM, DACVIM, Sugar Land Veterinary Specialists, 1515 Lake Pointe Parkway, Sugar Land, TX 77478.
To view the references for this article, visit dvm360.com/ZincToxRefs.