Multiorgan dysfunction syndrome secondary to joint supplement overdosage in a dog

Abstract

A 5-year-old spayed female Bernese mountain dog, with a chief complaint of vomiting and melena ingested approximately 200 nutritional joint supplement tablets. Despite aggressive therapy, the patient developed a coagulopathy, pancreatitis, peritonitis, acute kidney injury, and was euthanized. Postmortem examination revealed myocardial necrosis, pneumonia, centrilobular hemorrhage and necrosis of the liver, vasculitis, and acute tubular necrosis.

Supplements containing glucosamine and chondroitin are routinely used alone or in conjunction with anti-inflammatory drugs and weight loss to combat degenerative joint disease in dogs and humans. Despite the widespread dogma that nutritional joint health products are universally safe, hepatotoxicity associated with joint supplement overdosage in dogs has been previously reported (1). Furthermore, recent literature in human and veterinary medicine suggests that joint supplements containing glucosamine and chondroitin result in liver damage (2–6). These reports suggest that the safety of these products should be reevaluated. The purposes of this case report are to increase awareness of hepatotoxicity associated with joint supplement overdosage and to provide veterinary professionals with the clinicopathologic and histologic changes observed in cases of joint supplement overdosage in dogs (1).

Case description

A 5-year-old, spayed female, Bernese mountain dog ingested approximately 200 joint supplement chews (Joint MAX Triple Strength; Pet Health Solutions, Union City, California, USA). The estimated doses of glucosamine and chondroitin sulfate ingested were 2173 mg/kg body weight (BW) and 217 mg/kg BW, respectively. The patient was presented to the veterinarian approximately 10 h after ingestion with a chief complaint of vomiting, inappetence, and lethargy. On examination, the patient was quiet but responsive, cardiothoracic auscultation was normal, and abdominal palpation was unremarkable. Melena was present on rectal examination. Body condition score was 6/9. Blood tests showed markedly elevated hepatocellular enzymes and moderately elevated bilirubin levels.

Upon presentation to the critical care service, approximately 16 h after ingestion, the patient’s physical examination findings were unchanged. Diagnostic tests included a complete blood (cell) count (CBC), serum biochemistry, coagulation parameters, abdominal radiographs, and urinalysis. The CBC abnormalities included moderate hemoconcentration at 59% [reference range (RR): 37% to 55%], mild neutrophilia at 13.88 × 10³/μL (RR: 2.0 to 12.0 × 10³/μL), mild basophilia at 0.10 × 10³/μL (RR: 0.00 to 0.10 × 10³/μL), and a decreased mean corpuscular hemoglobin concentration at 293 g/L (RR: 300 to 375 g/L). Serum chemistry abnormalities included moderately elevated alkaline phosphatase (ALKP = 509 U/L; RR: 23 to 212 U/L), mildly elevated total bilirubin (tBil) at 30.8 μmol/L (RR: 0.0 to 15.4 μmol/L), and mildly elevated lipase at 1997 U/L (RR: 200 to 1800 U/L). A blood sample sent to a reference laboratory showed the alanine aminotransferase (ALT) markedly elevated at 14 950 U/L (RR: 12 to 118 U/L), prolonged prothrombin time (PT) of 18.5 s (RR: 5.5 to 12 s), and a normal activated partial thromboplastin time (aPTT) of 22.5 s (RR: 10 to 25 s). Urinalysis revealed a urine specific gravity (USG) of 1.033, a pH of 7.5, proteinuria (3+), bilirubinuria (3+), and hematuria (2+). A sediment was not evaluated. The most significant abdominal radiographic finding was generalized loss of serosal detail. An abdominal ultrasound was recommended but declined.

A consulting veterinarian at the ASPCA Animal Poison Control Center (APCC) was contacted and indicated several cases of liver failure had been associated with joint supplement overdosage in recent years. The most common side effects of acute joint supplement toxicity included moderate to severe gastroenteritis, elevated liver enzymes, and prolonged clotting times. Treatment recommendations made by the APCC included intravenous fluid therapy with vitamin B complex supplementation, anti-emetics, abdominal pain control, N-acetylcysteine or S-adenosylmethionine (SAM-E) if the patient was not vomiting.

The dog was treated with intravenous fluids containing vitamin B complex (Vitamin B complex; Phoenix Pharmaceutical, St. Joseph, Missouri, USA), 2 mL/L, and a crystalloid (Normosol R; Hospira, Lake Forest, Illinois, USA) bolus of 65 mL/kg body weight (BW) followed by a rate of 5.4 mL/kg BW per hour. The following medications were administered: S-adenosylmethionine with silybin (Denamarin; Nutramax Laboratories, Lancaster, South Carolina, USA), 20 mg/kg BW, PO, q24h, famotidine (Famotidine; APP Pharmaceuticals, Shaumburg, Illinois, USA), 1 mg/kg BW, IV, q24h, maropitant (Maropitant citrate; Zoetis, New York, New York, USA), 1 mg/kg BW, SC, q24h, vitamin K₁ (Vitamin K1; Phoenix Pharmaceutical), 3 mg/kg BW, SC, q12h, and ampicillin sodium/sublactam sodium (Ampicillin sodium/sublactam sodium; AuroMedics Pharma, Dayton, New Jersey, USA), 22 mg/kg BW, IV, q8h.

The following morning, the patient had peripheral edema, icteric mucous membranes, abdominal pain, and prominently enlarged popliteal lymph nodes. The patient’s heart rate remained elevated at 160 beats/min, and occasional runs of ventricular premature contractions were noted on continuous electrocardiography. The patient was transitioned to oral famotidine (Famotidine; TEVA Pharmaceuticals, Sellerville, Pennsylvania, USA), 1 mg/kg BW, PO, q24h, vitamin K₁ (Vitamin K; Bimeda, Le Sueur, Minnesota, USA), 2.3 mg/kg BW, PO, q12h, and amoxicillin with clavulanic acid (Clavamox; Zoetis), 18.75 mg/kg BW, PO, q12h. Treatment with S-adenosylmethionine with silybin, maropitant, and crystalloids was continued as previously described. A coagulation panel submitted to a reference laboratory showed prolongation of PT (39 s) and APTT (41 s). The serum biochemical profile revealed mild hypoproteinemia (48 g/L; RR: 50 to 74 g/L), mild hypoalbuminemia (22 g/L; RR: 27 to 44 g/L), markedly elevated aspartate aminotransferase (AST) (4389 U/L; RR: 15 to 66 U/L), markedly elevated ALT (14 343 U/L), moderately elevated ALKP (345 U/L), moderately elevated gamma glutamyltransferase (GGT) (19 U/L; RR: 1 to 12 U/L), moderately elevated tBil (58.1 μmol/L; RR: 1.7 to 5.1 μmol/L), and mild hypocalcemia (2.17 mmol/L; RR: 2.23 to 2.85 mmol/L).

On day 3 of hospitalization, the patient tolerated oral medications but remained lethargic and icteric. The serum chemistry showed progressive worsening of liver values including mild hypoalbuminemia (22 g/L), markedly elevated but improved AST (2580 U/L), moderately elevated ALP (431 U/L), markedly elevated but improved ALT levels (12 848 U/L), severe elevation in GTP (22 U/L); markedly elevated tBil (94.1 μmol/L; RR: 1.7 to 5.1 μmol/L) and mild hypocalcemia (2.1 mmol/L).

On day 4 of hospitalization, the patient developed abdominal distention with a palpable fluid wave. Serum chemistry showed persistent abnormalities in liver values, with worsening hyperbilirubinemia (119.7 μmol/L), and moderately elevated creatinine phosphokinase (1189 U/L; RR: 59 to 895 U/L).

By day 5 of hospitalization, the patient remained anorexic and depressed and failed to show any clinical improvement. The most significant changes on the serum chemistry included a markedly elevated total bilirubin (183 μmol/L), moderate azotemia [blood urea nitrogen (BUN), 23.2 mmol/L, serum creatinine 221 mmol/L], mild hyponatremia (serum sodium 137 mmol/L; RR: 139 to 154 mmol/L), mild hyperkalemia (serum potassium 5.8 mmol/L; RR: 3.6 to 5.5 mmol/L), and highly elevated creatinine phosphokinase (2080 U/L; RR: 59 to 895 U/L). An abdominal ultrasound showed a moderate amount of anechoic fluid, hyperechoic liver, loss of corticomedullary distinction in both kidneys, and markedly hyperechoic omentum and mesentery. An abdominocentesis was performed and approximately 2 L of clear fluid were removed from the abdomen. The abdominal fluid was not submitted for analysis but, based on appearance, was suspected to be a transudate or modified transudate. Due to lack of response to therapy, worsening condition and poor prognosis, the owner elected euthanasia.

The patient’s body was submitted for necropsy. Grossly, the integument and subcutaneous fat were yellow and edematous. The peritoneal cavity contained 2 L of serosanguinous fluid. Multifocal to coalescing petechial and ecchymotic hemorrhages were present throughout the diaphragm and epicardium. The right auricle and atrioventricular valves were thickened. The tracheobronchial lymph nodes were enlarged. Two firm, circumscribed masses were observed in the right middle lung lobe. The liver was diffusely enlarged, friable, and had a prominent reticular pattern. Macroscopic and microscopic areas of hemorrhage were present in the pancreas and the cortex of the kidneys. The final histologic diagnosis was diffuse hemorrhagic myocardial necrosis characterized by necrotizing vasculitis, pancreatitis, marked hepatic centrilobular necrosis with mild chronic periportal fibrosis, membranoproliferative glomerulonephropathy, acute tubular necrosis, histiocytic to lymphoplasmacytic pneumonia and a malignant pulmonary fibrous histocytoma of the right middle lung lobe. There was no evidence of metastasis.

A postmortem toxicology panel performed on a wet-weight basis showed elevated levels of iron and manganese in the liver. The liver had mildly elevated iron values at 514 ppm (RR: 100 to 500 ppm) and the manganese levels were above the reference range at 13.4 ppm (RR: 1.00 to 5.00 ppm). The arsenic, copper, cadmium, lead, thallium, and zinc levels in the kidney and liver were not elevated.

Discussion

Decades ago joint supplements containing glucosamine, chondroitin, vitamins, and trace minerals became a mainstay for the adjunct treatment of osteoarthritis in human and veterinary medicine. Joint supplements are generally viewed as a benign based on the high LD₅₀ values of glucosamine and chondroitin and lack of reported side effects associated with their use (7). Yet, strong evidence supporting the efficacy and more importantly the safety of these products is lacking (7). Joint supplements are not regulated by the United States Food and Drug Administration (FDA) and are not subject to rigorous regulatory mandates and quality control. Thus, in light of recent literature in human and veterinary medicine, suggesting joint supplements have been associated with liver damage in dogs and humans, acute and long-term safety of these products should be reevaluated (1–6).

In cases of hepatoxicity reported secondary to glucosamine containing supplements in humans, typically it has been associated with individuals taking a recommended dosage over a period of weeks rather than an acute overdosage (2–4). The major clinical signs reported with suspected toxicity included vomiting, diarrhea, inappetence, and jaundice (2–4). The clinical outcome in most cases was resolution of hepatocellular enzyme elevation with discontinuation of supplement. However, 1 individual developed chronic hepatitis and another developed fulminant liver failure resulting in death (2).

On the contrary, hepatotoxicity secondary to joint supplements in dogs has only been reported with large overdoses (1). In a letter to the editor in 2010, toxicologists at the ASPCA documented acute hepatic failure secondary to joint supplement toxicosis in 21 dogs reported to the ASPCA during 2008–2009 (1). The major clinical signs in the present case mirror those previously reported and include vomiting, diarrhea, lethargy, and acute hepatotoxicity (1). Postmortem findings previously reported in 1 patient included centrilobular liver necrosis, acute tubular necrosis, vascular thrombosis in the kidneys, and necrosis of the pancreas and myocardium (1). These necropsy findings were almost identical to the necropsy findings herein.

Joint supplements are marketed primarily for the reported effects of glucosamine and chondroitin on joint health but contain other major and minor ingredients. Ingredients found in the joint supplement ingested in this case included glucosamine hydrochloride, chondroitin, dimethyl sulfone, creatinine monohydrate, docosahexanoic acid, eicosapentaenoic acid, ascorbic acid, vitamin E, vitamin C, grape seed extract, L-glutathione, thioctic acid, citrus bioflavonoids, selenium, zinc, and manganese. Minor ingredients were marine lipid concentrates, natural meat flavors (non-bovine origin), bioflavanol, sucrose, soybean oil, and magnesium stearate. Safety studies documenting species-specific toxicities are available for some, but not all, of the aforementioned ingredients (7–13).

The 4 main ingredients listed on the label of the supplement ingested in this case were dimethyl sulfone, creatinine monohydrate, glucosamine, and chondroitin sulfate. Dimethyl sulfone has been shown to be safe in rats at an acute oral dose of 2 g/kg BW and at a chronic dose of 1.5 g/kg BW but safety has not been reported in dogs (11). Dietary creatinine monohydrate toxicology studies are limited to mice in which they cause inflammatory hepatic lesions (10). In an animal risk assessment, the oral LD₅₀ of glucosamine hydrochloride was > 5000 mg/kg BW while the “no observed adverse effect level” in dogs was 2149 mg/kg BW (7,8). Studies establishing an oral LD₅₀ for chondroitin in dogs are lacking but in mice it is > 10 000 mg/kg BW (9).

Additional ingredients present in lesser quantities were docosahexanoic acid, eicosapentaenoic acid, ascorbic acid, vitamin E, vitamin C, grape seed extract, L-glutathione, thioctic acid, citrus bioflavonoids, selenium, zinc, and manganese. None of these ingredients were considered to be the cause of the hepatoxicity, given the amounts ingested. However, it should be noted that thiotic acid, also known as alpha lipoic acid, has a maximum tolerated dose of 126 mg/kg BW and an oral LD₅₀ of 400 to 500 mg/kg BW in the dog (12,14). In 1 case series, 2 dogs ingesting large amounts of alpha lipoic acid developed hypoglycemia and hepatic dysfunction (15). The patient in this report ingested a dose of 0.454 mg/kg BW which is unlikely to have resulted in any abnormalities.

The etiologic agent responsible for the hepatotoxicity associated with joint supplement overdosage in dogs has been difficult to elucidate for several reasons including use of multiple ingredients, lack of quality control, lack of quantity control in regards to the amount listed on the label compared with that in the product and the possible presence of contaminants such as heavy metals or pesticides. With the lack of safety regulation by the FDA, the potential for use of contaminated ingredients or unknown ingredients is of the utmost concern. Unfortunately, the regulatory mandates that are implemented by the FDA for drugs does not apply to dietary or nutritional supplements (6,16). The FDA considers these products to be of lower priority and relies upon State governments to ensure that products adhere to the guidelines provided by the Association of American Feed Control Officials (AFFCO) (16), which reviews the supplement label but only to ensure that the product contains approved ingredients as outlined in the AAFCO guidelines.

In this case, the pathology report, and specifically the finding of centrilobular necrosis in the liver, suggested heavy metal toxicosis as the underlying cause of hepatic necrosis but the toxicology report failed to show elevated levels of heavy metals in the liver. The lack of evidence in the toxicology report does not negate the possibility of heavy metal toxicosis. The levels of toxins present in tissues at the time of death are unlikely to be the same as the acute exposure level because of biotransformation by the liver and excretion by the kidneys.

The elevated manganese levels found in the liver could suggest it as a possible cause of hepatotoxicity. The calculated dose of manganese ingested in this case was 4.5 mg/kg BW, which is much lower than the reported intravenous toxic dose of 16 mg/kg BW per day that caused periportal hepatic necrosis in dogs (13). However, the pattern of necrosis in this case was centrilobular and not consistent with the distribution of necrosis reported with manganese administration in dogs (13). Therefore, it is unlikely that manganese played a role in the hepatotoxicity in this case.

The elevated iron levels found in the liver were not thought to be the cause of hepatoxicity. Based on the ingredients listed, the joint supplement did not contain iron nor did the patient receive any treatment with iron. The elevated iron levels found in the liver were most likely due to inflammation associated with occult hepatic disease and impaired hepatic metabolism.

Periportal fibrosis was present in the liver of this dog. The fibrosis was presumably a result of occult chronic liver disease. Yet, the patient had no reported clinical signs or clinicopathologic changes suggestive of liver disease prior to the joint supplement overdosage. It is unknown whether or not the underlying liver disease played a role in this case.

When evaluating cases of acute hepatopathy suspected secondary to toxin ingestion or exposure, the clinician should obtain a thorough medical history, timeline of events, product information, and should attempt to quantify the dose ingested. In cases of new or emerging toxicosis, veterinarians should consult with a veterinary toxicologist. Differential diagnoses that should be considered for acute hepatic insult secondary to toxin ingestion include acetaminophen, aflatoxins, sago palm, hepatotoxic mushrooms, blue-green algae, xylitol, iron, non-steroidal anti-inflammatory drugs, and joint supplements.

The underlying mechanism, by which joint supplements cause hepatotoxicity is unknown. Proposed theories for joint supplement induced hepatoxicity include heavy metal contamination, pesticide contamination, misformulation of product, pre-existing liver disease, synergistic effects of multiple ingredients, or toxic metabolite formation following ingestion. Given that not all dogs experience liver failure and some make a complete recovery, a dose-dependent toxicity to one of the aforementioned label ingredients or an unrecognized toxin are potential sources.

Dogs with a history of joint supplement overdosage should be evaluated and monitored for acute liver failure, coagulopathy, and acute kidney injury. Veterinarians recommending treatment with joint supplements should warn clients of the potential side effects reported. The ASPCA APCC recommends decontamination if the ingestion occurred within 2 h of presentation. Fluid diuresis, charcoal administration, and gastroprotectants are recommended following decontamination. Hepatoprotective medications (SAM-E, N-acetylcysteine, silymarin) are also recommended though their efficacy has not been determined. CVJ