Zinc toxicosis — Associated hemolytic anemia and pancreatic disease in 2 dogs

Abstract

Two cases of canine zinc toxicosis with pancreatic disease are reported. Both dogs had pigmenturia, pallor, regenerative anemia, an inflammatory leukogram, hyperbilirubinemia, hyperamylasemia, and hyperlipasemia. Zinc toxicosis was diagnosed post-mortem in patient 1 based on the discovery of a metallic gastric foreign object, pancreatic necrosis, nephrosis, and high tissue zinc concentrations. Survey radiographs of patient 2 allowed identification and prompt removal of coins from the stomach with resolution of anemia, hyperamylasemia, and hyperlipasemia 3 days post-gastroscopy. Plasma zinc concentration was markedly elevated in patient 2. Zinc toxicosis should be considered in dogs with concurrent hemolytic anemia and pancreatic disease.

Zinc toxicosis in dogs is commonly associated with ingestion of zinc-containing foreign objects (1). Such objects are typically radiodense and when diagnosed and removed early, the prognosis is excellent (2). However, diagnosis can be delayed due to the non-specific nature of the initial clinical signs (3) especially if ingestion of the object was not witnessed. Continued absorption of zinc leads to hemolytic anemia with or without Heinz body formation (2). In some cases, spherocytes may also be present (2), which can lead to a misdiagnosis of primary immune-mediated hemolytic anemia (4). Pancreatic disease associated with zinc toxicosis has been reported less frequently (5–7) and veterinary clinicians may not be aware of this potential complication. These cases serve as a reminder to consider zinc toxicosis when presented with cases of hemolytic anemia and to pursue survey radiographs to ensure early identification and removal of zinc sources. These cases also highlight the effect of zinc on the pancreas and the rapidity with which pancreatic enzyme activity declines following removal of the zinc source.

Case description

Patient 1

A 4-month-old intact female 3.6-kg miniature Australian shepherd dog was presented at the Cornwall Veterinary Clinic, Prince Edward Island with a history of vomiting for 48 h (day 1). No significant abnormalities were noted on physical examination and diagnostic tests were declined. Symptomatic treatment with maropitant citrate (Cerenia 16 mg; Zoetis, Kirkland, Quebec), 1/2 tablet PO, q24h was initiated. The puppy returned 4 days later (day 5) as an after-hours emergency with continued vomiting, lethargy, anorexia, diarrhea of 1-day duration, and acute onset of pigmenturia. The owner mentioned the possibility of anticoagulant rodenticide exposure but had not witnessed ingestion of this substance. Due to unavailability of complete diagnostic laboratory service on that day and financial concerns, no blood analyses were initially performed. Supportive treatment was initiated including fluids (Sodium Chloride 0.9%; Baxter, Mississauga, Ontario), 50 mL SQ, q12h, vitamin K1 (Vitamin K1 injection 10 mg/mL; Vétoquinol, Lavaltrie, Quebec), 15 mg initial dose, PO, followed by 2.5 mg/kg body weight (BW), PO, q12h, and amoxicillin/clavulanic acid (Aventiclav 62.5 mg; Aventix, Burlington, Ontario), 1 tablet, PO, q12h. The following morning (day 6), the puppy was depressed, weak, tachycardic, and hypothermic. She was ~7% to 10% dehydrated with pale mucous membranes and displayed mild cranial abdominal discomfort. Hematemesis was suspected based on the presence of blood-tinged fluid on bedding. Intravenous fluid therapy (Lactated Ringer’s Injection; Baxter), 22 mL/h, ampicillin (Ampicillin Sodium 100 mg/mL; Novopharm, Toronto, Ontario), 22 mg/kg BW, IV, q8h, maropitant citrate (Cerenia 10 mg/mL; Zoetis), 1.0 mg/kg BW, SQ, q24h, and sucralfate (Sulcrate 1 g/5 mL; Aptalis, Mont Saint-Hilaire, Quebec), 0.5 g, PO, q12h were initiated. Blood was submitted for a complete blood (cell) count (CBC), serum biochemical panel, prothrombin time (PT), and partial thromboplastin time (PTT). Evaluation of the CBC revealed a marked macrocytic, hypochromic anemia [hematocrit (HCT): 0.08 L/L; reference interval (RI): 0.40 to 0.56 L/L] which was markedly regenerative (reticulocyte count: 484 × 10⁹/L; RI: < 85 × 10⁹/L). Blood smear evaluation revealed high numbers of nucleated red blood cells (nRBCs) [34/100 white blood cells (WBCs); RI: 0 to 2/100 WBCs], marked polychromasia, moderate anisocytosis, and mild macrocytosis. Results were consistent with blood loss and/or hemolysis of at least 3 to 4 d duration (8). Mild leukocytosis (corrected WBC count: 24.7 × 10⁹/L; RI: 5.4 to 14.3 × 10⁹/L) characterized by a mild neutrophilia (segmented neutrophil count: 16.5 × 10⁹/L; RI: 2.8 to 10.1 × 10⁹/L), mild left shift (band neutrophil count: 1.7 × 10⁹/L; RI: 0.0 to 0.3 × 10⁹/L), and mild monocytosis (monocyte count: 2.7 × 10⁹/L; RI: 0.1 to 1.4 × 10⁹/L) were also present indicating inflammation (8). Mild toxic change of neutrophils was observed on blood smear evaluation. Serum biochemical results are outlined in Table 1. Notable abnormalities consisted of mild panhypoproteinemia, moderate azotemia, mild to moderate decreases in concentrations of sodium, potassium, and chloride and mild elevation in bilirubin concentration. Activities of alkaline phosphatase (ALP) and aspartate transaminase (AST) were mildly to moderately increased and marked elevations in activities of amylase and lipase were present.

Table 1.

Initial serum biochemistry results for patients 1 and 2 (Roche Cobas 6000).

Test	Units	Patient 1 Day 1	Patient 2 Day 1	Reference intervala
Total protein	g/L	48	64	56 to 71
Albumin	g/L	25	23	30 to 36
Globulin	g/L	23	41	25 to 38
CK	U/L	675	400	44 to 249
AST	U/L	431	291	18 to 55
ALT	U/L	33	22	13 to 69
ALP	U/L	266	237	18 to 113
GGT	U/L	2	0	0 to 7
Total bilirubin	μmol/L	12	25	0 to 4
Urea	mmol/L	53.3	15.5	2.8 to 9.8
Creatinine	μmol/L	139	72	54 to 122
Phosphorus	mmol/L	3.04	2.03	0.84 to 1.83
Glucose	mmol/L	6.7	4.9	4.0 to 6.3
Sodium	mmol/L	141	146	144 to 151
Potassium	mmol/L	2.9	3.2	3.9 to 5.3
Chloride	mmol/L	96	108	105 to 117
Cholesterol	mmol/L	3.58	4.27	3.87 to 8.39
Amylase	U/L	9653	3260	324 to 1005
Lipase	U/L	8190	2661	78 to 583

^aAdult reference intervals.

CK — creatine kinase; AST — aspartate transaminase; ALT — alanine transaminase; ALP — alkaline phosphatase; GGT — gamma glutamyltransferase.

A slightly prolonged PT (8.4 s; RI: 6.1 to 8.0 s) and moderately prolonged PTT (31.5 s; RI: 8.8 to 14.8 s) supported a coagulopathy (8). Referral for a blood transfusion and further diagnostic testing was declined. The puppy failed to respond to supportive treatment and was euthanized 3 d later. Gross findings on post-mortem examination included pallor, pale yellow-green discoloration of the kidneys, a nodular appearing pancreas, and a metallic gastric foreign object (Figure 1).

Figure 1.

Gross findings on necropsy in patient 1: A — Abdominal and thoracic viscera showing pale lungs that failed to collapse when the thorax was opened. The kidney (K) is slightly swollen and has a green discoloration and the pancreas (P) is pale and edematous. B — Pallor of oral mucosa. C — Metal object found in the stomach. The object measured 2 cm × 2 cm × 0.02 cm and weighed 3.4 g.

Significant microscopic findings were restricted to the pancreas (Figure 2) and kidneys. The pancreatic interstitium was distended with edematous fluid and there was mild multifocal interstitial fibrosis. Acinar epithelial cells were at different stages of degeneration or necrosis with multifocal loss of zymogen granules or shrunken cells with karyorrhectic nuclei. Peripancreatic blood vessels were multifocally infiltrated with lymphocytes and macrophages. Both kidneys had tubular degenerative changes. Renal tubular epithelial cells contained numerous small eosinophilic cytoplasmic droplets with multifocal mineralization or exfoliation. Multifocal intraluminal hyaline casts were present within medullary tubules. The liver had minimal lesions consisting of scattered foci of extramedullary hematopoiesis and mild generalized edema with separation of the spaces of Disse.

Figure 2.

Photomicrograph of tissue section of pancreas in patient 1. Hematoxylin and eosin stain. A — Loss of pancreatic acini with interstitial fibrosis and edema (Bar 100 μm). B — Higher magnification of pancreatic acinar cells showing loss of zymogen granules, pyknosis and karyorrhexis (Bar 20 μm).

Liver, kidney, and pancreatic tissues were evaluated for lead and zinc concentrations. Lead concentrations were low (< 0.035 ppm wet weight for all 3 tissues; RI: < 0.1 ppm wet weight for liver and kidney (9); RI not available for pancreas). Tissue zinc concentrations were high (217 ppm, 291 ppm, and 304 ppm wet weight, for liver, kidney, and pancreas, respectively; RI: 30 to 70 ppm, 16 to 30 ppm, and 22 to 60 ppm wet weight, respectively) (1,9). These results confirmed zinc toxicosis.

Patient 2

A 1-year-old intact female, 4.5-kg Lhasa apso dog was presented at the Atlantic Veterinary College, University of Prince Edward Island (day 1) with acute weakness and pigmenturia. Physical examination findings included depression, pallor, delayed palpebral and menace responses, tachycardia, dehydration (~7%), hypertension, thready pulses, and a grade IV/VI systolic heart murmur. A penny had been removed from the dog’s mouth the previous day. Hematologic evaluation revealed a moderate macrocytic, hypochromic moderately regenerative anemia (HCT: 0.18 L/L; RI: 0.40 to 0.56 L/L, reticulocyte count: 239 × 10⁹/L; RI: < 85 × 10⁹/L) consistent with blood loss and/or hemolysis of at least 3 to 4 d duration (8). Blood smear evaluation revealed high numbers of nRBCs (28/100 WBCs; RI: 0 to 2/100 WBCs), spherocytes, and Heinz bodies. Marked anisocytosis and polychromasia were present. Moderate eccentrocytosis and mild macrocytosis were seen along with low numbers of ghost cells. Moderate leukocytosis (corrected WBC count: 38.9 × 10⁹/L; RI: 5.4 to 14.3 × 10⁹/L) characterized by a moderate neutrophilia (segmented neutrophil count: 23.7 × 10⁹/L; RI: 2.8 to 10.1 × 10⁹/L) with a moderate left shift (band neutrophil count: 9.7 × 10⁹/L; RI: 0.0 to 0.3 × 10⁹/L), and mild monocytosis (monocyte count: 1.9 × 10⁹/L; RI: 0.1 to 1.4 × 10⁹/L) were present, consistent with inflammation (8). Blood smear evaluation revealed moderate toxic change in neutrophils. Mild thrombocytosis was also present (platelet count: 585 × 10⁹/L; RI: 218 to 470 × 10⁹/L). Serum biochemical results are outlined in Table 1. Most notable changes included moderate hyperbilirubinemia and hypoalbuminemia, moderately increased activities of amylase, lipase, and AST, and mildly increased urea concentration and ALP activity. Coagulation test results were within normal limits (PT: 7.3 s; RI: 6.1 to 8.0 s, PTT: 13.4 s; RI: 8.8 to 14.8 s).

A radiodense circular object was identified in the stomach on examination of abdominal radiographs. Treatment consisted of IV fluid support (Plasmalyte 148 with 25 mEq KCl/L; Baxter), a blood transfusion (DEA 1.1 + packed red blood cells), and endoscopic removal of 2 gastric foreign bodies (an eroded American penny and a Canadian quarter). During endoscopy, focal mucosal ulceration was visualized at the site of adherence of the coins to the gastric wall. Examination of post-endoscopy radiographs confirmed removal of all radiodense objects. Intravenous fluids were continued and treatment for gastrointestinal ulceration was instituted. Medications included pantoprazole (Pantoprazole Sodium 4 mg/mL; Sandoz Canada, Boucherville, Quebec), 1 mg/kg BW, IV, q8h, famotidine (Famotidine 10 mg/mL; Omega, Montreal, Quebec), 0.5 mg/kg BW, IV, q12h, sucralfate (Sulcrate 1 g/5 mL; Aptalis), 2.5 mL, PO, q8h, buprenorphine HCl (Vetergesic 0.3 mg/mL; Champion Alstoe Animal Health, York, UK), 0.01 mg/kg BW, IV, q8h, and ampicillin (Novo-Ampicillin 100 mg/mL; Novopharm), 22 mg/kg BW, IV, q8h. Following the development of hypoglycemia, IV fluids were supplemented with dextrose (Dextrose 500 mg/mL; Vétoquinol) to achieve a final concentration of 50 mg/mL.

Results of another CBC and serum biochemical panel were evaluated on day 2. Resolution of the thrombocytosis, anemia, spherocytosis, Heinz bodies, eccentrocytosis, and ghost cells was seen (Table 2). Reticulocytes and nRBCs were still increased (Table 2) but to a lesser degree compared with the initial CBC. The inflammatory leukogram persisted (Table 2) but with a milder degree of neutrophilia compared to day 1 values. Notable abnormalities on the serum biochemistry panel included marked hyperbilirubinemia, moderate hypoglycemia, mild to moderate panhypoproteinemia, moderately increased ALP and AST activities and mildly increased urea concentration (Table 3). Serum activities of amylase and lipase remained moderately elevated (Table 3) but were slightly lower than day 1 values.

Table 2.

Sequential hemogram results for Patient 2 (Sysmex XT2000iV).

Test	Units	Day 2	Day 4	Day 19	Reference interval
HCT	L/L	0.49	0.52	0.41	0.40 to 0.56
RBC	×1012/L	7.9	8.0	6.1	5.7 to 8.4
HgB	g/L	184	185	139	135 to 198
MCV	fL	62	65	68	64 to 75
MCHC	g/L	374	354	337	334 to 357
Reticulocytes	× 109/L	197	270	63	< 85
WBC	× 109/L	31.6	20.4	11.2	5.4 to 14.3
Corrected WBC	× 109/L	29.0	20.2	11.1	5.4 to 14.3
Neutrophils	× 109/L	16.2	13.5	6.3	2.8 to 10.1
Bands	× 109/L	8.7	0.8	0.0	0.0 to 0.3
Lymphocytes	× 109/L	2.0	4.0	3.3	0.9 to 4.6
Monocytes	× 109/L	2.0	1.8	0.7	0.1 to 1.4
Eosinophils	× 109/L	0.0	0.0	0.8	0.0 to 1.5
Basophils	× 109/L	0.0	0.0	0.0	0.0 to 0.1
nRBC	/100 WBC	9	1	1	0 to 2
Platelets	× 109/L	264	305	406	218 to 470
Toxic change		3+	n/d	n/d
RBC morphology
Anisocytosis		1+	1+	n/d
Polychromasia		1+	1+	n/d
Howell Jolly bodies		slight	n/d	n/d

Blood transfusion and removal of zinc-containing object occurred on Day 1.

HCT — hematocrit; RBC — red blood cell; HgB — hemoglobin; MCV — mean cell volume; MCHC — mean cell hemoglobin concentration; WBC — white blood cell; nRBC — nucleated RBC; n/d — not detected.

Table 3.

Sequential biochemistry results for Patient 2 (Roche Cobas 6000).

Test	Units	Day 2	Day 4	Day 19	Reference interval
Total protein	g/L	41	48	54	56 to 71
Albumin	g/L	23	25	31	30 to 36
Globulin	g/L	18	23	23	25 to 38
CK	U/L	846	759	119	44 to 249
AST	U/L	283	41	23	18 to 55
ALT	U/L	40	41	23	13 to 69
ALP	U/L	628	586	86	18 to 113
GGT	U/L	0	3	3	0 to 7
Total bilirubin	μmol/L	257	22	3	0 to 4
Urea	mmol/L	15.1	4.3	8.9	2.8 to 9.8
Creatinine	μmol/L	101	68	67	54 to 122
Phosphorus	mmol/L	1.96	1.74	1.59	0.84 to 1.83
Glucose	mmol/L	2.6	3.4	5.5	4.0 to 6.3
Sodium	mmol/L	146	145	143	144 to 151
Potassium	mmol/L	3.4	4.8	4.6	3.9 to 5.3
Chloride	mmol/L	106	106	108	105 to 117
Cholesterol	mmol/L	3.17	3.35	5.53	3.87 to 8.39
Amylase	U/L	2367	992	730	324 to 1005
Lipase	U/L	2100	263	109	78 to 583

Blood transfusion and removal of zinc-containing object occurred on Day 1.

CK — creatine kinase; AST — aspartate transaminase; ALT — alanine transaminase; ALP — alkaline phosphatase; GGT — gamma glutamyltransferase.

Over the next 2 d (days 2 and 3), the dog remained depressed and anorexic and developed abdominal discomfort unresponsive to opioid pain medications. These included buprenorphine (Vetergesic; Champion Alstoe Animal Health), initially q8h and subsequently q4h and fentanyl citrate (Fentanyl 50 μg/mL; Sandoz Canada), 3.5 μg/kg BW per hour, IV, constant rate infusion (CRI). Pain control was achieved with a combination of fentanyl citrate (Fentanyl 50 μg/mL; Sandoz Canada), 2.5 μg/kg BW per hour, lidocaine (Lidocaine 20 mg/mL; Vétoquinol), 1.5 mg/kg BW per hour, and ketamine (Narketan 100 mg/mL; Vetoquinol), 0.6 mg/kg BW per hour diluted in saline (0.9% Sodium Chloride; Baxter) administered at 1 mL/h, IV, CRI. Maropitant citrate (Cerenia 10 mg/mL; Zoetis), 1 mg/kg BW, SQ, q24h was also administered.

Abdominal ultrasonography was performed on day 4 (3 d after removal of the coins) to investigate the abdominal discomfort and delayed clinical improvement. A mildly hyperechoic right renal cortex with decreased corticomedullary distinction was evident. Evaluation of a CBC on day 4 showed changes consistent with ongoing mild inflammation (8) and persistent reticulocytosis despite resolution of anemia (Table 2). Notable biochemical changes included persistent but less severe panhypoproteinemia, hyperbilirubinemia, hypoglycemia, and elevated ALP activity (Table 3). The dog improved clinically over the next 24 h and was discharged on day 5. On day 19, the patient returned for evaluation. Hematologic values were within reference limits (Table 2) and serum biochemical abnormalities were restricted to mildly low concentrations of sodium and total protein associated with mild hypoglobulinemia (Table 3).

Retrospective analysis of the initial plasma sample collected on day 1 before removal of the coins revealed a zinc concentration of 27.28 ppm (RI: < 2.00 ppm) (9), confirming zinc toxicosis.

Discussion

Zinc toxicosis has been reported in many animal species and is most often due to ingestion of zinc-containing foreign objects (1). Although the exact mechanism of toxicity is not clearly defined, zinc affects several organ systems, including the gastrointestinal tract, kidneys, pancreas, liver, and erythrocytes (1). The earliest clinical signs are related to the direct caustic effect of zinc on the gastrointestinal tract; these include vomiting, diarrhea, anorexia, and lethargy (3). These clinical signs are non-specific and ingestion of foreign objects often goes unnoticed. This can delay diagnosis increasing the risk of a fatal outcome, particularly if imaging is not pursued at initial presentation. This was clearly demonstrated in patient 1 of this report.

Duodenal absorption of zinc (10) follows the formation of soluble zinc salts through interaction with gastric acid (11). Gastric retention of a zinc-containing object promotes continued zinc absorption (11) and rapid development of toxic blood zinc concentrations (10) causing hemolytic anemia (1). Continuing absorption underscores the importance of early diagnosis and removal of the zinc source. In patient 2, the discovery of gastric radiodense objects coupled with the hematologic findings allowed early intervention and a successful outcome. The zinc source was presumed to be the eroded American penny. Although the minting year was not recorded, American pennies minted after 1982 are mainly composed of zinc with a copper coating (12). The eroded surface allowed interaction of the zinc metal with gastric acid and subsequent duodenal absorption of zinc salt (11). Early recognition of a metallic gastric foreign object was not achieved for patient 1 due to financial restrictions and a misleading history. The prolonged absorption of zinc resulted in a fatal outcome and a post-mortem diagnosis.

Although hemolytic anemia is commonly reported in cases of zinc toxicosis (2), the pathophysiology is incompletely understood and multiple mechanisms have been proposed including oxidative injury (13), hapten-induced immune destruction (4), and direct damage to erythrocyte membranes (4). Oxidative injury indicated by the presence of Heinz bodies has been reported to occur in only ~33% of cases of zinc toxicity (2). This hematologic finding should prompt consideration of toxin ingestion including zinc. Finding numerous Heinz bodies and the history of having had a penny removed from the mouth of patient 2 raised suspicion of zinc toxicosis. This led to prompt treatment and an excellent outcome. Patient 2 also had mild spherocytosis which has been reported to occur in ~20% of cases of zinc toxicosis. This can erroneously lead to a presumptive diagnosis of primary immune-mediated hemolytic anemia (4). If further diagnostic evaluation is delayed, inappropriate treatment can lead to a potentially fatal outcome (4). Therefore, it is critical to consider zinc toxicosis as a differential diagnosis in patients with these hematologic findings.

In contrast, although patient 1 had a regenerative anemia with hyperbilirubinemia, no Heinz bodies or eccentrocytes were seen to provide evidence of oxidant–induced hemolytic anemia. The panhypoproteinemia could have been attributed to other causes including young age as only adult reference intervals were available (8). However, the combination of panhypoproteinemia, suspected hematuria, and a history of possible rodenticide ingestion made anticoagulant rodenticide toxicosis a top differential diagnosis. Although the mildly prolonged PT and moderately prolonged PTT were not typical of vitamin K deficiency (8), prior administration of vitamin K1 could have altered these results making interpretation difficult (14). The coagulation test results, and the young age of the patient also raised the possibility of an inherited intrinsic coagulation factor deficiency (8). These factors contributed to misdirected treatment and a fatal outcome. Prolonged PTT values with or without mildly prolonged PT values have been reported in cases of zinc toxicity (2,4). It has been speculated that zinc may inhibit intrinsic pathway coagulation factors (2) which could explain the prolonged PTT in patient 1. Mild disseminated intravascular coagulation (DIC) is another consideration for these findings given the post-mortem pancreatic lesions in this puppy.

Pancreatic secretion via the gastrointestinal tract is a major route of systemic zinc excretion (3,15). However, biochemical support for pancreatic disease in dogs with zinc toxicity has been sporadically reported (5–7,16,17). Reports of cases with histologic confirmation of pancreatic disease are even less common (7,16,17). Histologic changes include early degeneration and necrosis of acinar cells followed by acinar atrophy and fibrosis (18). Similar histologic changes were seen in patient 1 and can explain the hyperamylasemia and hyperlipasemia. Although not confirmed histologically and canine pancreatic lipase concentration was not measured, pancreatic disease was supported in patient 2. Elevations in serum amylase and lipase activities were potentially supportive of pancreatic disease, although decreased renal clearance due to dehydration could be completely or partly responsible (8). Further support for pancreatic disease included persistence of an inflammatory leukogram and development of severe abdominal pain warranting multimodal analgesia following removal of the foreign bodies. While gastric ulceration could also explain these findings, the lack of response to opioid pain medication is considered unusual with pain due to focal ulceration. Although ultrasonographic evidence of pancreatitis was lacking, this diagnostic modality does not have 100% sensitivity for pancreatitis (18). Due to an unavoidable delay, abdominal ultrasonography was not performed on patient 2 until day 4 which coincided with normalization of serum amylase and lipase activities and clinical improvement.

Renal clearance plays a role in zinc homeostasis and acute renal failure has been reported in several cases of zinc toxicosis in dogs (4,16,19,20). Renal tubular epithelial degeneration indicating acute tubular injury (21) was present in patient 1, a finding previously described in cases of canine zinc toxicosis (19). Although renal damage could not be confirmed in patient 2, the increased serum concentrations of urea and phosphorus along with ultrasonographic findings of a mildly hyperechoic right renal cortex and decreased corticomedullary distinction could be associated with acute renal injury (20). However, these ultrasonographic findings are not specific for acute renal injury and could instead be incidental findings. Furthermore, the increased serum concentrations of urea and phosphorus could be due to pre-renal azotemia (8). Azotemia is considered likely in this patient despite the normal serum creatinine concentration as low muscle mass could have concurrently lowered it (8). Unfortunately, a concurrent urine specific gravity was not available. Upper gastrointestinal bleeding associated with gastric ulceration could also have been contributing to the increased serum urea concentration in this patient (8). Disparity between concentrations of urea and creatinine have commonly been reported in cases of zinc toxicosis (2,4,5,12). Proposed causes include dehydration or gastrointestinal tract hemorrhage (2).

Zinc toxicosis has been reported to cause hepatic necrosis and fibrosis (22). However, microscopic hepatic lesions in patient 1 instead consisted of mild non-specific edema and extramedullary hematopoiesis. These mild changes were unexpected given the high hepatic zinc concentration. There was also no histologic evidence of cholestasis and the hyperbilirubinemia was instead attributed to hemolysis (8). In patient 2, ALT activity remained within the reference interval over the course of the illness providing no support for hepatocellular injury. The increased AST activity noted on day 1 was attributed to muscle enzyme leakage as creatine kinase activity was also increased (8). The increase in ALP activity could have been due to cholestasis, but endogenous corticosteroid induction due to stress was also a consideration (8).

Treatment of zinc toxicosis requires removal of the zinc source along with blood transfusions and supportive treatment including IV fluid therapy, pain management, and gastroprotectants (1). If removal of the zinc source cannot be carried out promptly, treatment with an H₂-receptor antagonist or a proton pump inhibitor can increase gastric pH and potentially reduce zinc absorption (11). The use of chelating agents such as calcium disodium EDTA and D-penicillamine in cases of zinc toxicosis has been reported (2,6,23). However, it is unclear whether chelation alters clinical course. Treated dogs had prolonged hospitalization (5 to 15 d) compared with the median hospitalization of 2 d reported in dogs not treated with chelating agents in another report (2). Chelating agents may also increase gastrointestinal absorption of zinc if given before removal of the zinc source and may promote drug- or zinc-induced nephrotoxicity (3). Given these risks and the rapid decline in serum zinc concentration following removal of the zinc source (12,24), chelation therapy is not routinely warranted. Chelation therapy was not considered for patient 2 since the lack of Heinz bodies and eccentrocytes on day 2 indicated no ongoing oxidative damage.

In summary, these 2 classic cases of hemolytic anemia secondary to zinc toxicosis serve as a reminder to consider zinc toxicosis in dogs with hemolytic anemia. The index of suspicion for zinc toxicosis should be particularly high when there is evidence of oxidant damage to erythrocytes, spherocytosis, or both. However, these are not consistent findings and their absence should not exclude zinc toxicosis from the list of differential diagnoses for hemolytic anemia. Furthermore, the toxic effect of zinc on the pancreas can erroneously lead to a presumptive diagnosis of primary pancreatitis. These cases clearly demonstrate the importance of performing abdominal radiography on any dog with vomiting or abdominal discomfort, especially in the presence of hemolytic anemia.