Successful management of suspected acorn (Quercus petraea) toxicity in a dog

Abstract

A 7-year-old neutered male Labrador retriever dog was referred to a tertiary care veterinary hospital because of gastrointestinal signs and icterus. The dog developed a hepatopathy and acute kidney injury after ingesting acorns (Quercus petraea) 4 days prior to referral. The dog required hospitalization in an intensive care unit but made a full clinical recovery and was discharged after 6 days. This report documents that dogs can be affected by this toxicity and highlights the need for veterinarians to consider acorns as a potential cause of acute hepatotoxicity and renal injury. To the authors’ knowledge, this is the first reported case of acorn toxicity in a dog.

Acorns are the nuts produced by oak trees (Quercus spp.). Intoxications are well-documented in large animals and are caused by ingestion of oak buds, leaves, or acorns (1–4). More reports exist for cattle, which may represent species variability in susceptibility to the toxicity (1–3). There may also be variability in susceptibility among individuals (5). The full mechanism of acorn toxicity is unknown; however, the toxicity of oak leaves and acorns is suspected to be due to high concentrations of tannins, including the poisonous metabolites pyrogallol and gallic acid (6). Early effects are due to the ability of these metabolites to form complexes with various compounds in the gastrointestinal tract, including salivary proteins and gastrointestinal mucosal proteins; this causes nitrogen loss and altered enzyme function impairing digestion. Binding with carbohydrates, cellulose, and minerals also occurs, further reducing digestibility of essential nutrients (7–9). Gastrointestinal signs early in the clinical course result from damage to the gastrointestinal mucosa and epithelium, reduced digestibility, and the effects of tannin metabolites on gastrointestinal flora (7,8,10). Gallic acid (released by hydrolysis of tannins) can be absorbed from the intestine, causing acute renal and hepatic damage (7,8). Kidney injury in acorn toxicity is believed to be due to the hydrolyzable metabolites of tannins that cause renal proximal tubular necrosis (11). Gallic acid is metabolized to pyrogallol, which can cause oxidative damage, hepatotoxicity, and induce mutagenesis (11). Pyrogallol causes altered expression of cytochrome p450, glutathione reductase, S-transferase, and peroxidase. A reduction in antioxidant enzymes promotes an oxidative state (12). Lesions that develop can differ among species (11). Monogastric animals are thought to suffer gastrointestinal and hepatic consequences more commonly, whereas in ruminants, renal effects can predominate (11).

In large animals, the time course of progression to liver and kidney injury can vary from a few days after ingestion to over 1 wk (1,13). Ultimately, a common consequence of oak-induced hepato-renal injury is death (1,2,4,7,11,12).

Some herbivores have developed various protective mechanisms against tannins. Tannin-binding proteins in herbivore saliva, such as proline-rich protein, have high affinity for binding to tannins. Tannins bind preferentially with these proteins, preventing their deleterious effects on digestive enzymes and the gastrointestinal mucosa (7). Additional defence mechanisms in some herbivores include increased gastrointestinal mucus production, rapid degradation of tannins by gastrointestinal flora, activation of detoxifying enzymes and an increased capacity of intestinal permeability glycoprotein, which can reduce absorption of the toxin (7,14). Despite these mechanisms, the mortality rate in clinically affected cattle can be as high as 85% (12). Intrinsic resistance to tannins, such as tannin-binding proteins, have not been detected in cats or dogs (7,15).

With only anecdotal reports of suspected acorn toxicity in dogs to date, the objective of this report is to describe clinical course and outcome of the first case of suspected acorn hepatonephrotoxicity in a dog.

Case description

A 7-year-old neutered male Labrador retriever dog weighing 23.4 kg was presented to the emergency department of a referral hospital in the UK for further management of acute onset of vomiting, diarrhea, lethargy, and icterus. Four days before being presented to the primary care veterinarian, the owners documented the dog vomiting 10 to 15 cracked acorns. No acorn material was noted in the feces. The dog had free run on a farm and the owners were questioned on the potential for alternative toxin exposure. Although other toxins could not be ruled out, the owners were sure the vomitus only contained cracked acorns. The dog was up-to-date with his vaccinations, having received a 4-strain leptospirosis booster 52 d before presentation. Two months before presentation, the dog had received 1 injection of meloxicam for an acute onset lameness, with no side effects of the medication noted.

Over 3 d after ingesting the acorns, the dog became lethargic, hyporexic, and continued to vomit. On physical examination at the time of presentation to the referring veterinarian, the dog was lethargic, and the only abnormality detected on physical examination was icteric sclera. In-clinic blood analysis included biochemistry and hematology (without blood smear evaluation). The biochemistry revealed an increase in alkaline phosphatase (ALP), alanine aminotransferase (ALT) activities, and total bilirubin concentration (Table 1). A hematology panel revealed mild thrombocytopenia [platelet count: 103 × 10⁹/L, reference range (RR): 148 to 484 × 10⁹/L]. After 24 h of hospitalization at the primary care practice, the dog was referred for further investigation and management of a hepatopathy.

Table 1.

Progression of blood analysis during hospitalization and post-discharge.

	Primary care veterinarian	Day 1a	Day 3b	Day 6a	2 wk after discharge	1 mo after discharge	10 mo after discharge	Reference rangec
TP	57	49.9	55	56.9	65.3	64		54.9 to 75.3 g/L
Alb	24	25.5		27.1	31.4	31		26.3 to 38.2 g/L
Tbil	144	186.2	195	45.3	17.8	7		0.1 to 4.2 μmol/L
Urea	4.4	6.1		17.8	9.5	6.6		3.1 to 10.1 mmol/L
Creat	89	121	201	161	155	127		20 to 144.5 μmol/L
ALT	289	6490		1907.9	264.6	75		19.8 to 124 U/L
ALP	439	504		500	169	72		0 to 130 U/L
PT	38	64						11.0 to 17.0 s
aPTT	130	Out of range						72 to 102 s
PCV	38.4	41	40	34	43.5	41.6		37 to 55%
Glucosuria		4+		2+			neg
Proteinuria		3+		1+			neg

^aResults from an external referral laboratory.

^bResults obtained on the point-of-care emergency database (ABL800 FLEX, Radiometer).

^cReference ranges are the normal reported for animals according to the referral external laboratory.

TP — Total protein; Alb — Albumin; Tbil — Total bilirubin; Creat — Creatinine; ALT — Alanine aminotransferase; ALP — Alkaline phosphatase; PT — Prothrombin time; aPTT — Activated partial thromboplastin time; PCV — Packed cell volume.

At presentation to the referral hospital, the dog was quiet, alert, and responsive. Cardiac auscultation was unremarkable and heart rate was 80 beats/min, pulses were strong and synchronous. Mucous membranes were tacky, sclerae were icteric, and the capillary refill time was < 1.5 s. The respiratory rate was 16 breaths/min with normal thoracic auscultation. Abdominal palpation was comfortable, but nausea (hypersalivation and lip smacking) was noted at that time. No abnormalities were detected on oral or rectal examination, and rectal temperature was normal (38.3°C). There was no peripheral lymphadenopathy, the body condition score was 4/9, and the dog had a normal muscle condition score. Non-invasive blood pressure (NIBP) doppler measurement was 170 mmHg.

Blood analysis [packed cell volume (PCV) and total solids (TS), blood gas, and electrolytes (ABL800 FLEX; Radiometer, Brønshøj, Denmark), serum biochemistry (AU680; Beckman Coulter, High Wycombe, UK), a complete blood (cell) count (CBC) (Advia 2120i; Siemens, Camberley, UK), coagulation times (Coag Dx; IDEXX, Westbrook, Maine, USA)], and urinalysis were performed. Initial PCV and TS were within normal limits. Blood gas and electrolytes were unremarkable. The CBC revealed a normal neutrophil count with evidence of neutrophil toxicity, mild thrombocytopenia (110 × 10⁹/L; RR: 150 to 900 × 10⁹/L), mild lymphopenia (0.92 × 10⁹/L; RR: 1 to 4.8 × 10⁹/L), and mild monocytosis (1.72 × 10⁹/L; RR: 0.15 to 1.5 × 10⁹/L). On biochemistry, there was mild hypoalbuminemia, moderate hyperbilirubinemia, a marked increase in ALT activity, and a moderate increase in ALP activity (Table 1). The C-reactive protein concentration was 20 mg/L (RR: < 25 mg/L). Coagulation times were abnormal, with significantly prolonged prothrombin time and an out-of-range activated partial thromboplastin time (Table 1). Abdominal point-of-care ultrasound revealed scant peritoneal and moderate retroperitoneal effusion, subjectively edema of the gall bladder wall, cystic lesions on the kidneys, and a small urinary bladder. The thoracic point-of-care ultrasound, however, was unremarkable. Urinalysis, before initiation of intravenous fluid therapy (IVF), revealed a urine specific gravity (USG) of 1.045, glucosuria 4+ (in the presence of normoglycemia), and proteinuria 3+; this was most consistent with acute tubular injury and the sediment examination revealed epithelial cells, granular casts, and bilirubin crystals. Urine culture (cystocentesis sample) was negative.

Full abdominal ultrasonographic examination performed by a Board-certified radiologist, confirmed an abnormal appearance to the liver, gallbladder, and kidneys. The liver parenchyma was diffusely mildly hyperechoic. The gallbladder wall was thickened (4 mm) and had an outer hypoechoic layer. The cranial pole of the left kidney had a well-demarcated, 1.3 × 1.5 cm anechoic round structure, with distal acoustic shadowing. The renal cortex was diffusely hyperechoic, and normal corticomedullary definition was present. The right kidney was similar to the left kidney in appearance and had multiple, variably sized parenchymal cysts. There was a moderate amount of anechoic retroperitoneal fluid streaking between fascial planes. A scant volume of peritoneal fluid was also present. The appearance of the spleen was unremarkable. Cystocentesis of the bladder and fine-needle aspirates (FNA) of spleen and liver were obtained without complication. Spleen FNA was performed to aid in the diagnosis of a possible neoplastic process. Peritoneal fluid was not sampled, as the amount was too small to obtain at the time of scanning. Coagulation times were not rechecked at the time of sampling. Cytology revealed hepatic vacuolar degeneration (glycogen/water type), mild cholestasis, and evidence of mild necrosis with mild hepatocellular atypia. Rhodamine staining revealed only rare hepatocytes containing small amounts of copper. This suggested that the hepatopathy was not associated with copper deposition, and a diagnosis of breed-associated copper storage hepatopathy as a potential cause of the hepatic insult and renal tubular injury was considered unlikely (16). Splenic cytology revealed a predominance of small reactive lymphocytes and presence of plasma cells, most consistent with a reactive spleen and suggestive of strong antigenic stimulation.

Testing for leptospirosis [urine polymerase chain reaction (PCR) and serum microagglutination testing (MAT) (L. australis, L autymnalis, L. ballum, L. brastilava, L. canicola, L. copenhageni, and L. icterohaemorrhagiae) were also submitted] and empiric amoxicillin clavulanic acid (Augmentin; GlaxoSmithKline UK, Uxbridge, UK) 20 mg/kg body weight (BW), intravenous (IV), q8h was initiated while results were pending. Leptospirosis PCR of the urine was negative; however, serum MAT results were positive for L. canicola (MAT antibody titer 1:100) and L. copenhageni (MAT antibody titer 1:100). A convalescent serum MAT was submitted 2 wk after the initial presentation, and the results revealed a MAT antibody titer of 1:100 for L. copenhageni, and negative for other serovars. The diagnosis of leptospirosis was, therefore, considered unlikely. In addition to the above-mentioned diagnostic workup, acorns present on the farm were identified by a biologist (Dr. Elena Suárez-Bonnet), as originating from Quercus petraea, based on photographs of the trees and acorns (Figure 1).

Figure 1.

Acorns from the farm where the dog lives, identified as Quercus petraea (sessile oak).

In addition to antibiotics, treatment included IVF using Hartmann’s (Aqupharm 11; Animalcare, York, UK), 2 mL/kg BW per hour (maintenance fluid rate), omeprazole (Sandoz, Camberley, UK), 1 mg/kg BW, IV, q12h, ondansetron (Demo S.A., Athens, Greece), 0.5 mg/kg BW, IV, q12h, and vitamin K1 (TVM UK Animal Health, Kirtlington, UK), 1 mg/kg BW, IV, q24h. The dog’s NIBP was persistently significantly elevated, 170 to 180 mmHg systolic, and amlodipine (Aurobindo Pharma-Milpharm, South Ruislip, UK), 0.1 mg/kg BW, PO, q24h, was subsequently started.

On Day 2 of hospitalization, repeat blood analysis revealed an increase in creatinine concentration despite adequate IVF and a stable body weight. Total bilirubin concentration had increased further and there were no electrolyte abnormalities. The creatinine concentration continued to rise until Day 3 of hospitalization and the total bilirubin concentration remained high (Table 1). In-clinic urinalysis revealed improvements in both glucosuria and proteinuria. The urine remained concentrated [> 1.030 urine specific gravity (USG)]. S-adenosylmethionine (SAMe) and Silybin (Denamarin; Protexin Veterinary, Somerset, UK), 20 mg/kg BW, PO, q24h and ursodeoxycholic acid (Destolit; Norgine, Harefield, UK) 12.5 mg/kg BW, PO, q24h, were added as empirical hepatoprotectants. At this time, the dog was stable but remained in a critical state. A naso-esophageal feeding tube was placed to provide supplemental nutrition. By the third day of hospitalization, the dog was eating on his own and clinically brighter.

Once the dog was eating 100% of his resting energy requirements, he was discharged after 6 d of hospitalization, with amoxicillin-clavulanic acid (Noroclav; Norbrook Laboratories, Newry, Northern Ireland), 20 mg/kg BW, PO, q12h, for another 7 d as leptospirosis testing was still pending. He was then transitioned to doxycycline (Boehringer Ingelheim Animal Health UK, Bracknell, UK), 10 mg/kg BW, PO, q24h until the convalescent serum MAT was available. Amlodipine (Aurobindo Pharma-Milpharm, South Ruislip, UK), 0.1 mg/kg BW, SAMe (Denamarin; Protexin Veterinary) 20 mg/kg BW, and ursodeoxycholic acid (Destolit, Norgine) 12.5 mg/kg BW all given PO once daily, were continued. Focused serum biochemistry was performed on the day of discharge revealed increased urea, an improvement in bilirubin and creatinine concentrations, static ALP, and a much improved but still increased ALT activity (Table 1).

Improvement continued after discharge and a recheck by the referring veterinarian 2 wk later revealed a continued reduction of liver parameters, but further improvement in total bilirubin concentration (Table 1). On in-clinic CBC without blood smear, there was a mild lymphopenia (3.7 × 10⁹/L, RR: 4.9 to 17.6 × 10⁹/L), with mature neutropenia (neutrophils: 1.78 × 10⁹/L, RR: 2.94 to 12.67 × 10⁹/L), consistent with an ongoing inflammatory process; however, the platelet count was normal (platelets: 283 × 10⁹/L, RR: 143 to 448 × 10⁹/L). Doxycycline was continued until the convalescent MAT leptospirosis results were available, whereas SAMe and ursodeoxycholic acid were continued until liver values normalized. Amlodipine was stopped when hypertension resolved, and the NIBP was monitored following discontinuation, without relapses noted.

A further recheck was performed by the referring veterinarian 1 mo after discharge, and the dog had completely recovered. All values on hematology and biochemistry, performed through an external laboratory, were within normal reference intervals and no further medications were required (Table 1). Ten months after the event, in-clinic urinalysis revealed a USG of 1.046 and resolution of glucosuria, proteinuria, and casts. The dog continues to have a normal life and has no apparent health concerns related to this episode.

Discussion

To the authors’ knowledge, acorn toxicity in dogs has not previously been reported in the veterinary literature. Internet searches of “acorn toxicity in dogs” does, however, reveal multiple veterinary webpages acknowledging acorn toxicity, and veterinary message boards on the Veterinary Information Service (VIN) also discuss a number of anecdotal cases. The Veterinary Poisons Information Service (VPIS) in the UK, has anecdotally reported 105 cases with only oak involvement, indicating numerous suspected intoxications are occurring in this species. Some of these cases presented with gastrointestinal clinical signs, including vomiting, abdominal discomfort, and diarrhea. Of these cases, renal involvement was reported in 2% and hepatic involvement in 5%. There was 1 report in the VPIS database of both hepatic and renal involvement, similar to our patient. Other clinical signs such as muzzle urticaria, edema, and gastrointestinal mechanical obstruction were also reported. According to the VPIS records, only 1 patient died, and another was euthanized.

The dog’s initial clinical signs were gastrointestinal in nature. Vomiting of the cracked acorns was suspected to be due to the disruption of the shell and release of tannins. These signs progressed to lethargy, ongoing vomiting, and diarrhea. Within a few days, the dog suffered acute hepatic injury and acute kidney injury, with no other obvious identifiable cause. The clinical signs in this dog were consistent with signs of gallotoxicity, typically reported in large animals. In the large animal literature, initial clinical signs can vary from localized oral lesions to diffuse gastrointestinal signs (1). This case demonstrated signs of renal injury, as described in the large animal literature, as evidenced by the azotemia with no appreciable pre-renal component based on clinical evaluation and lack of improvement or change in body weight on IVF diuresis, along with the urinalysis results and urine sediment examination (glucosuria without hyperglycaemia and granular casts) (1,17). A USG < 1.030 was not documented during hospitalization. Measurement of USG is often used to help differentiate between pre-renal and renal azotemia (17). Usually, dogs with a USG > 1.030 are considered to have pre-renal azotemia (17–19). Unfortunately, the USG was only checked early in hospitalization, and it was not possible to determine if the dog did lose the ability to concentrate urine. However, the dog had persistent mild azotemia that did not initially improve with IVF diuresis, along with persistent glucosuria (in the face of normoglycemia) and documented granular casts along with acute repeatable hypertension with no other apparent cause that responded to amlodipine. We inferred that these changes were most likely secondary to acute kidney injury (17). Perirenal effusions and increased renal echogenicity, both noted in our patient, have also been associated with acute kidney injury in dogs (20).

In large animals, gross post-mortem findings associated with fatal acorn toxicity include fluid accumulation within body cavities, edema within the subcutaneous, mesenteric, and retroperitoneal spaces (especially peri-renal congestion), erosions and ulcerations of the alimentary tract, and in some cases, hepatocellular degeneration. The kidneys can appear swollen, pale, and can have petechiation of the cortex (13). Evidence of similar fluid accumulation was also seen in this case on initial abdominal imaging, but the volume of fluid present on reassessment was not enough to attempt sampling. Gall bladder wall edema was considered to be secondary to the generalized inflammatory process (21).

Leptospirosis was considered as a differential diagnosis because of the concurrent acute hepatic injury, renal injury, and thrombocytopenia, but was excluded based on a negative urine PCR and serum MAT convalescent testing. The dog had received a single dose of cefuroxime, while hospitalized at the referring veterinarian, 24 h before collection of the urine sample for PCR testing. Although it is generally expected that multiple doses of antibiotics are needed to impact the yield of a urine PCR in this setting, blood PCR may have been a more appropriate choice at this stage (22). Based on the urine PCR combined with the MAT testing, leptospirosis was unlikely (22). Other differentials such as a primary hepatopathy including, but not limited to, cholangiohepatitis, infiltrative neoplasia, and copper storage disease were also considered. The dog did not have signs consistent with an infectious etiology, and an underlying primary hepatopathy was not identified on FNA of the liver. Other hepatotoxins were considered as a possibility (e.g., Amanita mushrooms); however, with the identification of the acorns in the vomitus, concurrent suspected acute kidney injury, absence of any reported mushroom exposure, and complete clinical recovery from hepatotoxicity (uncommon with amatoxin-containing mushrooms such as Amanita phalloides), acorn toxicity was considered the most likely culprit (23).

Further diagnostic steps considered in this case included serum and urine toxicology testing for acorn metabolites. One method for quantitative analysis of pyrogallol and gallic acid in serum and urine in cows has been validated (6,24,25). Unfortunately, no human or veterinary laboratories based in the UK were testing for tannins at the time this case was presented to us, but this could be considered in future similar cases presenting with a suspicion of this condition.

There is no specific treatment for acorn toxicity, and this case responded to supportive care, with treatments including IVF, nutritional support with early enteral feedings, and liver support, including SAMe to address oxidative hepatic injury. Hypertension was treated with amlodipine, and discontinued 2 wk after discharge, with regular monitoring of the blood pressure. The favorable recovery in this dog was at odds with the high mortality rate typical in cattle showing clinical signs (5). It is unknown whether dogs might have intrinsic resistance mechanisms favoring improved clinical outcome, or whether the availability of intensive care in this case made survival more likely. It is also possible that variability in toxicity among acorn types, their maturity at the time of ingestion, and the quantities that dogs are exposed to compared to large animals, could explain discrepancies in expected survival rates between species (8,26,27).

To the authors’ knowledge, this is the first report describing the clinical course and successful treatment of suspected acorn toxicity in a dog. The documented ingestion of cracked acorns resulting in initial gastrointestinal signs with a progression to acute kidney and liver injury in this dog were similar to those reported in other species, including horses and cattle. Hepatic and renal injury due to acorn ingestion appear to be uncommon in dogs. This case report, however, raises the awareness of acorn toxicity as a potential differential diagnosis for concurrent hepato-renal injury in this species. It also describes a favorable outcome with appropriate supportive treatment.