Topical ReviewXylitol
Introduction
Xylitol was discovered in the late 19th century; it is also naturally found in low concentrations in a variety of edible plants and mushrooms. Xylitol is a 5-carbon sugar alcohol with many beneficial properties and is primarily used as an artificial sweetener with less than two-thirds the calories of most sugars. Xylitol has many desirable properties for humans including inducing very little insulin release, making it a preferred sugar substitute for individuals intent on consuming low-carbohydrate diets to reduce their glycemic index. Xylitol does not require insulin to enter cells and is antiketogenic, making it an excellent source of energy for diabetics.1 Additionally, xylitol inhibits certain bacterial growth.
The 2 major sources of xylitol exposure are food and dental or medical products. Initially, exposures to xylitol in dogs were from “sugar-free” chewing gums. However, with demands from diabetic patients and particularly with the popularity of Atkins-like “low-carb” diets, many foods now contain xylitol. Many foods for “low-carb” diets, including a wide variety of breads, candies, gums, deserts, etc. have xylitol as the sweetener of choice.2 It is unfortunate that the Food and Drug Administration no longer requires xylitol be listed as an active ingredient on the label of products in which it is incorporated. The Animal Poison Control Center of the American Society for the prevention of cruelty to animals has reported several cases of xylitol toxicity in dogs with a history of eating sugar-free (“low-carb”) food products, including muffins, cupcakes, gum, and cookies.3, 4
Xylitol's antibacterial activity and palatability has made it popular in a variety of preventive dental products.5 It has been added to an expansive list of dental products, particularly high (as much as 35%) in human toothpaste. It has been a problem with dental products where it has been incorporated to increase the palatability of other antimicrobial compounds such as chlorhexidine. Xylitol containing products are safe for cats, and it has been proposed to add it to daily water to prevent feline dental disease; however this would place dogs in the household at risk of a possible life-threatening toxicity.6
Xylitol exposures can occur from a variety of therapeutic sources. It has been used as an energy source in parenteral nutrition recipes. The ability to improve palatability has meant that xylitol has been used by both human and veterinary compounding pharmacies. Significantly, xylitol is not required to be listed on the active ingredients list in either veterinary or human medications. Regional poison centers may be able to supply data relative to xylitol concentrations in human medications.
Section snippets
Toxic Dose
Xylitol has a wide margin of safety in mammals with the exception of dogs. The oral lethal dose 50% levels in mice are approximately 20 g/kg. Oral exposures as low as 0.1 mg/kg have induced hypoglycemia in the dog, and levels of 0.5 mg/kg have resulted in hepatotoxicity in some dogs. Oral dose of 4 mg/kg induced clinical signs but did not cause mortality in one study.7 Hepatotoxicity may depend more on the individual dog rather than the actual dose received.7 The literature reports no cases of
Toxicokinetics
Rapid absorption occurs in the dog when 1-4 gm/kg of xylitol is orally administered. Insulin levels begin to increase at 20 minutes and are maximized at 40 minutes after ingestion.8 Glucose levels began decreasing at 30 minutes and troughed at 60 minutes after ingestion; in this trial, glucose began to rise again at 90 minutes.8 In some cases, the onset of clinical signs of hypoglycemia can be delayed up to 24-48 hours postingestion.
Primary metabolism of xylitol occurs in the liver.9, 10 Xylitol
Mechanism of Toxicity
Xylitol toxicity manifests as 2 clinical syndromes, either as hyperinsulinemia or as hepatic necrosis, or a combination of both. It is postulated that hyperinsulinemia is induced by the liver converting xylitol into metabolites that interfere with normal pentose phosphate pathways affecting regulation of insulin synthesis and release.8 Xylitol itself may directly stimulate pancreatic β cells to release insulin. Elevated insulin then induces dramatic decreases in blood glucose levels.
Hypokalemia
Clinical Signs
Xylitol can induce 2 possible clinical syndromes which are not mutually exclusive. Most dogs exhibit clinical signs consistent with marked hypoglycemia but some have additional clinical signs relative to an acute hepatopathy. There are some that only develop the hepatopathy.
Clinical signs associated with rapid rises in insulin are hypoglycemia, lethargy, weakness, ataxia, vomiting, hypokalemia and possibly seizures, coma, and death.6 Seizures have been seen as early as 30-40 minutes after
Minimum Database
As with all possible toxicosis, pretreatment blood samples should be obtained. Recommended laboratory test include a full serum chemistry profile, complete blood count, and electrolytes. An initial blood glucose level should be recorded while awaiting more complete laboratory results.
Serial blood glucose values should be obtained at entry, 30 minutes, 60 minutes, and then hourly for the next 12 hours in suspected xylitol exposures. If clinical evidence of liver dysfunction becomes apparent,
Confirmatory Test
Xylitol is rapidly absorbed and cleared from the body and is not significantly accumulated in tissues making the probability of successful testing unlikely. Laboratory analysis of foods, baits, or stomach ingesta can be done. Recommendations for appropriate samples, handling, preservation techniques, and possibly legal chain of evidence requirements can be supplied by the diagnostic laboratory. This advice should be solicited before sample submission or shipping.
Treatment
Decontamination techniques are generally avoided in xylitol exposures. There is no evidence that activated charcoal binds xylitol efficiently. Emesis induction should be avoided because the toxin is rapidly absorbed, and depression can be an early sign of toxicosis, which increases the risk of aspiration.
In cases suspected to have an exposure of more than 0.1 g/kg, aggressive treatment is recommended. Delayed treatment, even with no clinical signs, increases the risk for catastrophic hepatic
Prognosis
Dogs with only hypoglycemia and no clinical evidence of hepatic dysfunction have a good prognosis. Dogs with mild elevations in hepatic enzyme values usually return to normal after several days of supportive care. The presence of significant hepatic involvement, particularly with a rising hyperphosphatemia, has a more guarded prognosis. Evidence of fulminant hepatic failure requires a guarded to poor prognosis.4
Differential Diagnosis
Differentials are necessary for both clinical syndromes.
References (12)
Utilization of xylitol in animals and man
The Sweet Miracle of Xylitol
(2003)New findings on the effect of xylitol ingestion in dogs
Vet Med
(2006)Xylitol
Xylitol: a sweet for healthy teeth and more
Altern Complement Ther
(2003)- et al.
Acute hepatic failure and coagulopathy associated with xylitol ingestion in eight dogs
J Am Vet Med Assoc
(2006)
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Xylose and yeasts: A story beyond xylitol production
2022, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :Xylitol is widely used as a sweetener recommended for diabetic patients [5]. Highest yields of xylitol obtained from xylose have been reported for Candida sp. with up to 17 g L−1 [4]. For xylitol to be produced, xylose must be first transported inside the cell, and this represents the first bottleneck for xylose fermentation.
From by- to bioproducts: selection of a nanofiltration membrane for biotechnological xylitol purification and process optimization
2021, Food and Bioproducts ProcessingCitation Excerpt :This sugar alcohol has attracted attention for its health-promoting properties (Dasgupta et al., 2019); it exhibits anticariogenic activity and can be used by individuals with diabetes as a sugar substitute because of its insulin-independent metabolism. Currently, owing to its diverse properties, xylitol is largely used as raw material in the food, pharmaceutical, and dental industries (Peterson, 2013; Irmak et al., 2017; Silva and Chandel, 2012; Ghaffar et al., 2017). On an industrial scale, xylitol is manufactured mainly by chemical synthesis via reduction of high-purity d-xylose in the presence of a nickel catalyst at high pressure and temperature.
Sweeteners as food additives in the XXI century: A review of what is known, and what is to come
2017, Food and Chemical ToxicologyCitation Excerpt :It is estimated that this sweetener has a market of 670 million dollars worldwide, which has been increasing 6% per year, and is expected to continue growing until 2020. These figures, in line with what is happening transversally to all food additives, represent the increasing awareness of naturally derived food additives (Dasgupta et al., 2017; Mitchell, 2006; Peterson, 2013). ( See Fig. 7).
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2017, Pathologic Basis of Veterinary Disease Expert ConsultTransubstantiating commercial mushroom market with ultrasonically ultrasized mushroom powders showcasing higher bioactivity
2016, International Journal of Biological MacromoleculesCitation Excerpt :According to Daglia et al. [57], succinic and malic acids are effective against S.mutans. It is well known that xylitol is reputed for its antibacterial effects against oral pathogens [58,59] This is the reason for its application in various medicines and dental products and gums and mints. Previous studies have indicated that butanoic acid, 1,2-benzenedicarboxylic acid, hexadecanoic acid and octadecanoic acids are potential antimicrobials occurring in mushroom extracts [60].
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