History
A 4-month-old 5.70-kg (12.54-lb) sexually intact female Whippet was evaluated late 1 evening by its primary veterinarian because of recent behavioral changes, including being unsettled, vocalizing (crying), and disinclination to go outdoors. At that initial examination, the dog's mucous membranes were cyanotic and the capillary refill time was 3 seconds. Auscultation of the lungs and heart revealed no abnormalities; there was no evidence of respiratory distress. Rectal temperature was 37.7°C (99.8°F). Initial clinicopathologic analyses did not include hematologic variables; however, results of a basic serum biochemical panel were unremarkable, although it was noted that the collected blood sample appeared dark. Shortly after the evaluation, the dog's right orbital and periocular tissues became swollen, as did the left-sided tissues soon thereafter. The dog was referred to the Ophthalmology Department of the Centre for Small Animal Studies (Animal Health Trust).
Clinical and Clinicopathologic Findings
At the time of referral evaluation the next morning (day 1), the dog was whining and lethargic with cyanosis, tachypnea (40 breaths/min), and tachycardia (200 beats/min). Rectal temperature was 38.7°C (101.7°F). The capillary refill time was unchanged (3 seconds); mucous membranes were cyanotic, and peripheral pulses were considered normal. The dog's face was markedly swollen with distortion of facial features (Figure 1), which prohibited ocular examination. The blood and urine samples that were collected for in-house CBC, serum biochemical analysis, dipstick urinalysis, and blood gas analyses (Table 1) appeared brown.
Photograph of a 4-month-old Whippet that was evaluated initially because of recent behavioral changes, including being unsettled, vocalizing (crying), and disinclination to go outdoors. Notice the diffuse severe facial swelling (edema), with distortion of facial features, and prolapse of the right third eyelid that developed over a period of several hours.
Citation: Journal of the American Veterinary Medical Association 248, 9; 10.2460/javma.248.9.1009
Photograph of a 4-month-old Whippet that was evaluated initially because of recent behavioral changes, including being unsettled, vocalizing (crying), and disinclination to go outdoors. Notice the diffuse severe facial swelling (edema), with distortion of facial features, and prolapse of the right third eyelid that developed over a period of several hours.
Citation: Journal of the American Veterinary Medical Association 248, 9; 10.2460/javma.248.9.1009
Photograph of a 4-month-old Whippet that was evaluated initially because of recent behavioral changes, including being unsettled, vocalizing (crying), and disinclination to go outdoors. Notice the diffuse severe facial swelling (edema), with distortion of facial features, and prolapse of the right third eyelid that developed over a period of several hours.
Citation: Journal of the American Veterinary Medical Association 248, 9; 10.2460/javma.248.9.1009
Relevant findings of an in-house CBC, serum biochemical panel, dipstick urinalysis, and venous blood gas analysis for a 4-month-old Whippet that had facial swelling, cyanosis, and tachycardia.
| Variable | Result | Reference interval |
|---|---|---|
| Hct (%) | 42 | 37–55 |
| Albumin (g/L) | 26 | 21–36 |
| Alkaline phosphatase (U/L) | 173 | 46–337 |
| Alanine aminotransferase (U/L) | 18 | 8–75 |
| Total bilirubin (μmol/L) | 5 | 0–14 |
| Lactate (mmol/L) | 1.62 | 0.50–2.50 |
| Venous blood pH | 7.344 | 7.350–7.450 |
| Base excess (mmol/L) | −7.0 | |
| Bicarbonate (mmol/L) | 17.9 | |
| pCO2 (kPa) | 4.43 | 4.67–6.40 |
| pO2 (kPa) | 3.25 | 11. 1–14.4 |
| Urine specific gravity | 1.012 | > 1.025 |
| Dipstick variables | ||
| Urine protein concentration | 3+ | Negative |
| Urine blood concentration | 3+ | Negative |
| Urine sediment | Nonactive | Nonactive |
Dipstick variables were assessed subjectively on a scale of negative to 3+ (protein, 500 mg/dL) and 4+ (blood, approx 250 erythrocytes/μL). Urine sediment was considered nonactive owing to the absence of inflammatory cells and bacteria.
Formulate differential diagnoses from the history, clinical findings, Figure 1, and Table 1—then turn the page→
Additional Clinical and Clinicopathologic Findings
The presence of cyanosis with a normal Hct, tachypnea (without evidence of altered respiratory effort), and brown blood and urine was compatible with methemoglobinemia. On further questioning of the owner, it was revealed that the dog had accidentally ingested 3 tablets containing 500 mg of acetaminophen and 8 mg of codeine each (ingested dose of approx 265 mg of combined drugs/kg [120.5 mg/lb]). A CBC, including preparation of blood smears, and serum biochemical analyses were performed the next morning (day 2). Evaluation of Wright-Giemsa-stained blood smears revealed moderate anemia (Hct, 28%; reference range, 37% to 55%) and slight poikilocytosis and polychromasia, with moderate numbers of ghost RBCs, few nucleated RBCs, and occasional eccentrocytes (Figure 2). Heinz bodies and basophilic stippling were detected in some RBCs. The RBC changes were indicative of oxidative damage with intravascular hemolysis. Moderate z was present (186 × 109 reticulocytes/L; reference range, < 60 × 109 reticulocytes/L) on day 2, which progressively increased over time. There was concurrent marked thrombocytopenia (47 × 109 platelets/L; reference range, 200 × 109 platelets/L to 500 × 109 platelets/L). Anemia reached a nadir (Hct, 21%) on day 3. Serum biochemical variables were monitored during the dog's hospitalization (duration, 1 week) and were persistently within reference limits.
Photomicrograph of a blood smear preparation obtained from the dog in Figure 1. In this view, ghost cells (g), Heinz bodies (asterisk), an eccentrocyte (e), and a nucleated RBC (arrow) are visible. Wright-Giemsa stain; bar = 6 μm.
Citation: Journal of the American Veterinary Medical Association 248, 9; 10.2460/javma.248.9.1009
Photomicrograph of a blood smear preparation obtained from the dog in Figure 1. In this view, ghost cells (g), Heinz bodies (asterisk), an eccentrocyte (e), and a nucleated RBC (arrow) are visible. Wright-Giemsa stain; bar = 6 μm.
Citation: Journal of the American Veterinary Medical Association 248, 9; 10.2460/javma.248.9.1009
Photomicrograph of a blood smear preparation obtained from the dog in Figure 1. In this view, ghost cells (g), Heinz bodies (asterisk), an eccentrocyte (e), and a nucleated RBC (arrow) are visible. Wright-Giemsa stain; bar = 6 μm.
Citation: Journal of the American Veterinary Medical Association 248, 9; 10.2460/javma.248.9.1009
The day prior to hospital discharge, bilateral keratoconjunctivitis sicca and corneal ulcers developed. For both of the dog's eyes, Schirmer tear test results were 0 mm/min (reference range, > 15 to 20 mm/min) and remained at this level until the time of death 3 months later.
Morphologic Diagnosis and Case Summary
Morphologic diagnosis and case summary: acetaminophen (paracetamol) toxicosis with secondary hemolytic anemia and keratoconjunctivitis sicca in a dog.
Comments
In dogs, acetaminophen toxicosis develops after consumption of the drug at reported ranges from as low as 75 mg/kg (34.1 mg/lb) to 150 to 200 mg/kg (68.2 to 90.9 mg/lb).1,2 Small amounts of acetaminophen are metabolized in dogs and cats to nontoxic sulfate and glucuronide conjugates. However, once these pathways are overwhelmed, production of toxic metabolites, such as N-acetyl para-benzoquinoneimine (NAPQI) and para-aminophenol, occurs.2 Small amounts of NAPQI may be detoxified by glutathione conjugation, and the availability of intracellular glutathione is considered important in forestalling toxic effects.
Dogs exposed to toxic doses of acetaminophen often develop acute hepatic necrosis subsequent to glutathione depletion, NAPQI accumulation, and covalent binding of NAPQI to cysteine groups of hepatocellular proteins. Results of 1 study3 indicated that the source of hematotoxic effects, such as methemoglobinemia, Heinz bodies, and eccentrocytes, all of which more commonly develop in cats, is not NAPQI but rather para-aminophenol, which results in cooxidization and redox recycling with oxyhemoglobin. Para-aminophenol, a minor metabolite, is produced through deacetylation of acetaminophen by hepatic carboxyesterases, and N-acetylation removal of this metabolite is catalyzed by 2 related erythrocyte enzymes, N-acetyltransferase 1 and 2. Dogs have neither enzyme; cats have only N-acetyltransferase 1, potentially allowing for accumulation of this metabolite. Para-aminophenol alone was unlikely to have resulted in the extent of the hematotoxic effects observed in the dog of the present report, and a number of other influences, such as the relatively low number of accessible hemoglobin sulfhydryl groups (n = 4) in canine erythrocytes, compared with the number in feline erythrocytes (8), may have contributed.4 Methemoglobinemia develops after oxidative erythrocyte injury and depletion of methemoglobin reductase (a nicotinamide adenine dinucleotide [reduced form]-dependent enzyme that converts methemoglobin to hemoglobin), and results in a shift of the oxyhemoglobin dissociation curve to the left. The increase of methemoglobin affinity for oxygen decreases the release of oxygen to the tissues leading to cyanosis, as illustrated in the dog of the present report. Visually, blood samples appear dark or brown. If methemoglobinemia exceeds 20%, hemoglobinuria may develop,5 as was observed in this dog. Denaturation of hemoglobin can also occur when the capacity of methemoglobin reductase is overwhelmed, resulting in precipitation of hemoglobin and Heinz body formation. Heinz bodies increase erythrocyte osmotic fragility, with subsequent development of intravascular hemolysis and anemia.
Thrombocytopenia in humans following acetaminophen exposure has been previously reported.6,7 Proposed mechanisms include direct toxic injury to thrombocytes or megakaryocytes7 or drug-induced immune-mediated thrombocytopenia (caused by drug metabolite-enhanced targeting of platelets by antibodies).6 Antibodies enhanced by the metabolite acetaminophen sulfate have been shown to target normal platelets.6 The mechanism responsible for the thrombocytopenia in the dog of the present report is unclear. However, marked thrombopoiesis was evident by day 4 after acetaminophen exposure; therefore, a direct toxic effect on megakaryocytes may be less likely given the exuberant and rapid bone marrow response.
Hepatic necrosis commonly develops in dogs with acetaminophen toxicosis. There are multiple hypotheses as to the cause of hepatic injury in such cases, including mitochondrial dysfunction8 and oxidative stress effects (eg, NAPQI-associated effects)9; however, the pathogenesis remains controversial. Although uncommon, there have been 2 previous individual case reports of dogs with oxidative erythrocyte injury but no signs of hepatic necrosis.10,11 Moreover, the dog of the present report did not develop clinical signs or biochemical indications of hepatic injury.
The pathogenesis of keratoconjunctivitis sicca also has yet to be elucidated. In dogs, direct toxic insult has been considered, perhaps secondary to dogs' reduced ability for acetylation of sulfa moieties, which is the proposed cause of keratoconjunctivitis sicca in association with sulfonamide administration. Following glutathione conjugation, acetaminophen metabolites contain sulfa moieties, which may promote this mechanism of injury.12 Another possible mechanism is reduced tear production following decreased prostaglandin E1 production as a result of acetaminophen's effect on cyclooxygenase (COX)-3, a new COX form identified in dogs in 2002.13 Cyclooxygenase 3 not only appeared to have a role in regulation of prostaglandin E1 production but also was the specific target of acetaminophen.13 In a previous study in rabbits,14 tear production was partly controlled by prostaglandin E1; therefore, decreased amounts of prostaglandin E1 could result in reduced tear production. However, this would not explain the findings of another studya in dogs, which indicated that the return to normal tear production after acetaminophen exposure was idiosyncratic, with some dogs quickly recovering and others failing to recover after more than 5 years. The in vivo importance of COX-3 and its purported effect on prostaglandin E1 production have also been questioned, further undermining these factors as potential contributors to the pathogenesis of acetaminophen-associated keratoconjunctivitis sicca.15 For the dog of the present report, the ophthalmologist recommended to continue palliative topical ocular treatment for a minimum period of 6 months (preferably 9 to 12 months) to allow for recovery, but the owner opted to proceed with parotid duct transplantation at 3.5 months after the initial crisis, and the dog died of cardiac arrest during surgery at the primary clinic.
Although the veterinary medical literature abounds with data related to the toxic effects of acetaminophen in dogs, there remains much to be determined regarding the causes of associated pathological changes, such as thrombocytopenia, hepatic necrosis, and keratoconjunctivitis sicca. Such knowledge may contribute to effective treatment protocols. In atypical cases, such as that described in the present report, it is important to remember that not all cases of intoxication are straightforward, and uncommon effects of poisonings may develop, thereby complicating diagnosis. In atypical cases involving acetaminophen exposure of dogs, identification of key pathological features (eg, methemoglobinemia or oxidative hemolytic anemia) may drive the case investigation.
Footnotes
Feder I, Greentree W, Salisbury MA, et al. Acetaminophen toxicity as a cause of keratoconjunctivitis sicca in dogs (oral presentation). Am Coll Vet Ophthalmol Annu Meet, Hilton Head, SC, October 2011.
References
1. Alwood AJ. Acetaminophen. In: Silverstein K, Hopper K, eds. Small animal critical care medicine. Philadelphia: WB Saunders Co, 2008;334–337.
2. Taylor NS, Dhupa N. Acetaminophen toxicity in cats and dogs. Compend Contin Educ Pract Vet 2000; 22:160–171.
3. McConkey SE, Grant DM, Cribb AE. The role of para-aminophenol in acetaminophen-induced methemoglobinemia in dogs and cats. J Vet Pharmacol Ther 2009; 32:585–595.
4. Aronson LR, Drobatz K. Acetaminophen toxicosis in 17 cats. J Vet Emerg Crit Care 1996; 6:65–69.
5. Kolf-Clauw M, Keck G. Paracetamol poisoning in dogs and cats. Eur J Companion Anim Pract 1994; 4:85–92.
6. Bougie D, Aster R. Immune thrombocytopenia resulting from sensitivity to metabolites of naproxen and acetaminophen. Blood 2001; 97:3846–3850.
7. Fischereder M, Jaffe JP. Thrombocytopenia following acute acetaminophen overdose. Am J Hematol 1994; 45:258–259.
8. Landin JS, Cohen SD, Khairallah EA. Identification of a 54-kDa mitochondrial acetaminophen binding as aldehyde dehydrogenase. Toxicol Appl Pharmacol 1996; 141:299–307.
9. Halmes NC, Hinson JA, Martin BM, et al. Glutamate dehydrogenase covalently binds to a reactive metabolite of acetaminophen. Chem Res Toxicol 1996; 9:541–546.
10. Mariani CL, Fulton RB. Atypical reaction to acetaminophen intoxication in a dog. J Vet Emerg Crit Care 2001; 11:123–126.
11. MacNaughton SM. Acetaminophen toxicosis in a Dalmatian. Can Vet J 2003; 44:142–144.
12. Diehl KJ, Roberts SM. Keratoconjunctivitis sicca in dogs associated with sulfonamide therapy: 16 cases (1980–1990). Prog Vet Comp Ophthalmol 1991; 1:276–282.
13. Chandrasekharan NV, Dai H, Roos KL, et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic / antipyretic drugs: cloning, structure and expression. Proc Natl Acad Sci U SA 2002; 99:13926–13931.
14. Pholpramool C. Secretory effect of prostaglandins on the rabbit lacrimal gland in vivo. Prostaglandins Med 1979; 3:185–192.
15. Kis B, Snipes JA, Busija DW. Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties. J Pharmacol Exp Ther 2005; 315:1–7.
