Rhubarb and Oxalosis (Rheum Species)

Rhubarb and Oxalosis (Rheum Species)

Rhubarb and Oxalosis (Rheum Species) Donald G. Barceloux, MD History Although the petioles of rhubarb leaves have been a food source in modern times, ...

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Rhubarb and Oxalosis (Rheum Species) Donald G. Barceloux, MD History Although the petioles of rhubarb leaves have been a food source in modern times, the dried root or rhizome has been used as a medicinal herb since the third millennium BC. Chinese rhubarb is a traditional herb used as a purgative and bacteriocidal agent for dysentery.1 In the 16th and 17th centuries, Chinese rhubarb was coveted as a medicinal remedy that was superior to European varieties. During this time, Russian sources (the Commerce Collegium in St. Petersburg, the Rhubarb Commission on the Mongolian border) and the British East India Company supplied Europe with large quantities of rhubarb.2 This popular laxative was the “All Bran of the Age of Reason.” Although the Russian explorer, Nikolai Mikhailovich Przheval’skii, obtained rhubarb seeds from the major Chinese production center (Sining) in the late 1800s, European growing conditions could not duplicate the luxuriant growth of rhubarb cultivated in China. In the early 1900s, the anthraquinone compounds responsible for the purgative action of rhubarb were separated from powdered rhubarb root at the Wellcome Research Laboratories (Beckenham, Kent, UK). Consumption of rhubarb leaves as a food substitute for spinach was encouraged in England during World War I until several deaths were attributed to the ingestion of cooked leaves.3

Botanical Description Species in the oxalate-containing genus Rheum include Rheum officinale Baillon (Chinese rhubarb), Rheum palmatum L. (Turkey rhubarb), Rheum rhabarbarum L. (garden rhubarb), and Rheum rhaponticum L. (false rhubarb). Other plant species that contain substantial quantities of oxalate include Halogeton glomeratus (Bieb.) C. A. Mey. (barilla, This article was published in: Barceloux DG. Medical Toxicology of Natural Substances: Foods, Fungi, Medicinal Herbs, Toxic Plants, and Venomous Animals. Hoboken, NJ: John Wiley & Sons, 2008. pp. 84-88. Copyright © 2008 by John Wiley & Sons, Inc. Reprinted with permission of John Wiley & Sons, Inc. Dis Mon 2009;55:403-411 0011-5029/2009 $36.00 ⫹ 0 doi:10.1016/j.disamonth.2009.03.011 DM, June 2009


saltlover), Oxalis caerulea (Small) R. Knuth (blue woodsorrel), Oxalis corniculata L. (creeping oxalis, creeping woodsorrel, yellow oxalis), Portulaca oleracea L. (common purslane, duckweed), Rumex acetosa L. (garden sorrel), Rumex crispus L. (curley dock, yellow dock),4 and Tetragonia tetragonioides (Pallas) Kuntze (New Zealand spinach). Common Name: Garden rhubarb Scientific Name: Rheum rhabarbarum L. Botanical Family: Polygonaceae (buckwheat) Physical Description: A garden vegetable plant with large, leathery, heart-shaped leaves and a reddish color. Distribution and Ecology: R. rhabarbarum L. is an introduced, perennial plant that inhabits Alaska, the Rocky Mountain States, Georgia, and the northeastern United States.

Exposure The leaf petioles (stalks) are used as a vegetable and a constituent of pies. The dried roots have been used medicinally as a cathartic and as a tonic.5,6 In traditional Chinese medicine, official rhubarb (dahuang) is a purgative and detoxicant used to treat fever, constipation, cancer, abdominal distention and obstruction, jaundice, hematemesis, appendicitis, amenorrhea, skin lesions, food poisoning, inflammation, hypertension, and renal failure.7,8 The official Chinese herbal medicine contains dried rhizome and root of R. palmatum L., R. tanguticum Maxim. ex Balf., and R. officinale Baillon. The Japanese version of Rhei Rhizoma (rhubarb) also contains R. coreanum Nakai.

Principal Toxins Structure and Properties Salts of oxalic acid are the main toxic constituents in rhubarb. This chemical is the simplest dicarboxylic acid [(COOH)2] and oxalic acid forms soluble (iron, lithium, potassium, sodium) and insoluble (calcium, magnesium) salts. Boiling spinach for 1 minute removes only about 10% of the insoluble oxalate salts compared with 47% of the soluble oxalate salts.9 Cooking does not substantially alter the oxalate concentration in rhubarb. Roots of some species of rhubarb (R. palmatum L.) contain up to 2% anthraquinone glycoside derivatives similar in structure to the sennosides, which also possess laxative properties.7 The major active components of the herbs derived from rhubarb (eg, dahuang) are hydroxyanthraquinone compounds including rhein, emodin, aloe-emodin, 404

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FIG 1. Hydroxyanthraquinone compounds in rhubarb.

and chrysophanol.10 Figure 1 displays the structure of some hydroxyanthraquinone compounds in herbs derived from the Chinese rhubarb (Rheum officinale). Emodin is a naturally occurring anthraquinone present in the rhubarb as well as the roots and bark of numerous plants of the genus Rhamnus including buckthorn (Rhamnus cathartica L.), senna (Senna alexandrina Mill.), cascara (Frangula purshiana (DC) J.G. Cooper), and aloe (Aloe ferox Mill.). This hydroxyanthraquinone compound is a common constituent of herb-based stimulant laxatives that produce mild nephrotoxicity in some rodents following the administration of very high doses (ie, about 1 g emodin/kg body weight daily for 2 years).11

Poisonous Parts Oxalate occurs in most plant tissues and the amount depends on growing conditions, season, and plant part. The average Western diet contains about 50-150 mg oxalate/d with vegetarian diets somewhat higher (ie, 150 mg/d).12 Spinach contains oxalate compounds divided into approximately 55% soluble oxalate and 45% calcium oxalate, whereas rhubarb contains primarily calcium oxalate.13 The most toxic part of the rhubarb plant is the leaf, which contains ⬍1% fresh weight soluble oxalates.14 The petioles of rhubarb leaves are edible because of the low oxalate content. Food sources beside rhubarb that contain substantial amounts of oxalate include sugar beets, chocolate, coconut, peanuts, DM, June 2009


TABLE 1. Oxalate content of some foods Food Group


Soluble Oxalatea

Total Oxalatea

Apple Banana Orange Strawberry

0.3-1.8 0.1-2.2 0.2 0.6-1.9

0.4-5.8 0.5-23.9 1.8 1.5-4.3

0.5-1.1 1.5 8.8-18.9 380 33.3-168 2.5-4.5

1.8-3.1 13.9 8.8-35.3 570-1900 100-627 3.7-13.7


Vegetables Asparagusb Beans Potatoesb Rhubarb Spinachb Tomato Bread Rye White

0.9 4.9-8.6

Beer Black tea Chocolate Cocoa Coffee Coke Iced tea

1.7-1.8 2.5-6.2 7.1


154-980 0.5-0.7 0.05 0.46-1.72


Source: Adapted from Ref. 18. a mg oxalate/100 g food. b Cooked.

spinach, strawberries, wheat bran, and tea.15,16 Table 1 lists the oxalate content of some common foods. The major bioactive constituents of herbal preparations of rhubarb are phenolic compounds (sennosides, anthraquinone glycosides, glucose gallates, naphthalenes, catechins).17 These concentrations and types of phenolic compounds (eg, sennosides, anthraquinone glycosides) vary between different species of Rheum.

Mechanism of Toxicity The ingestion of rhubarb causes oxalate poisoning that is associated with local corrosive effects and renal damage from the excretion of oxalate crystals.5 The formation of large amounts of calcium oxalate crystals in the body may produce hypocalcemia as well as renal dysfunction, renal calculi, and electrolyte imbalance.18 The deposition of calcium oxalate crystals in the myocardium of patients with renal failure may occur without the presence of oxalate poisoning.19 Pathological changes associated with fatal oxalate ingestions include corrosive effects on the gastrointestinal tract, cloudy swelling and hyalin degeneration of 406

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the renal tubules, glomerulosclerosis, and birefringent crystals in vascular walls throughout the body.20

Dose Response The ingestion of small amounts of plant parts containing oxalates usually causes only mild gastrointestinal irritation. Serious intoxication from the ingestion of rhubarb leaf is not well-documented in the modern medical literature. Fatalities associated with the ingestion of rhubarb probably involved other agents, toxins, or etiologies. The intravenous injection of 20 mg sodium oxalate/kg produced profound hypocalcemia and cardiac arrest.21

Toxicokinetics Gastrointestinal absorption of oxalate occurs in the small intestine by active transport and by passive diffusion along the small intestine and the colon. The bioavailability of oxalate is low (⬍2-6% as total oxalate) and varies with plant species.15 In a study of volunteers, the average bioavailability of oxalate in sugar beets and spinach was 0.7% and 4.5%, respectively.22 The mean bioavailability of a solution of sodium (soluble) oxalate in the same study was 6.2%. Endogenous intermediary metabolism in humans produces oxalate as a result of glycine, ascorbic acid, and glycolate metabolism. As end-products of metabolism, oxalates are excreted by the kidney rather than metabolized. Most renal excretion of oxalate absorbed from the diet occurs within 8-12 hours.13 In a study of 12 volunteers, the elimination half-life of the hydroxyanthraquinone compound, rhein, derived from the Chinese rhubarb was 3.38 ⫾ 0.35 hours.23

Clinical Response Most casual exposures of children to the rhubarb plant produce mild gastrointestinal symptoms (vomiting, diarrhea) that resolve within a few hours.24 The initial symptoms of oxalate intoxication result from irritation of the oropharynx and the gastrointestinal tract manifest by sore throat, dysphagia, nausea, vomiting, anorexia, diarrhea, abdominal pain, and occasionally hematemesis. Symptoms typically begin within 2-12 hours after ingestion.14 Serious oxalate toxicity produces renal dysfunction and electrolyte imbalance that develops after signs of gastrointestinal distress. The presence of paresthesias, tetany, hyperreflexia, muscle twitches, and muscle cramps suggest hypocalcemia. Seizures may complicate the clinical course as a result of hypocalcemia.25 Other sources of oxalosis include excessive oxalate formation as a result pyridoxine deficiency,26 DM, June 2009


primary hyperoxaluria with glycolic aciduria or L-glyceric aciduria,27 increased oxalate intake from the diet, toxins (ethylene glycol, glycolate), renal failure, and fungal infections.28,29 Rarely, case reports associate exposure to rhubarb with the development of vesiculobullous, photosensitivity dermatitis.30 Another case report associated acute renal failure, atrophy of the renal tubules, and interstitial renal fibrosis with the chronic ingestion of the nonsteroidal antiinflammatory drug, diclofenac, and a slimming pill that contained anthraquinone derivatives extracted from Rhizoma Rhei (rhubarb).31

Diagnostic Testing Analytical Methods Methods for detecting anthraquinone derivatives in rhubarb include thin layer chromatography,32 capillary electrophoresis,33 high performance liquid chromatography (HPLC),34 high speed counter-current chromatography,10 high performance liquid chromatography with ultraviolet detection and mass spectrometry,35 and HPLC coupled with electrospray ionization mass spectrometry.17 HPLC with mobile phase gradient conditions and UV detection (280 nm) can detect at least 30 compounds in rhubarb at detection limits ranging from 0.05-2 ␮g/mL.36 These compounds include anthraquinones, anthraquinone glucosides, dianthrones, phenylbutanones, stilbenes, galloylglucoses, acylglucoses, flavan-3-ols, procyanidins, and gallic acid.

Biomarkers Normal values of oxalate in the serum range from approximately 60-230 ␮g/dL.37 The concentration of urinary oxalate depends on urine volume and electrolytes as well as diet. In a study of 20 men with recurrent calcium containing kidney stones, the upper ranges of urine oxalate concentrations for daily urine volumes of 1, 2, and 3 L were 46 mg, 55 mg, and 63 mg, respectively.38 Women excreted slightly lower daily amounts of urine oxalate.

Abnormalities The definition of hyperoxaluria is the urinary excretion of ⬎0.5 mmol oxalate/1.73 m2 body surface area daily. Electrolyte imbalance (eg, hypocalcemia) complicates serious cases of oxalate poisoning. Laboratory evidence of renal dysfunction includes the presence of anuria, oliguria, proteinuria, hematuria, and oxaluria. Microscopic examination of urine sediment may demonstrate red blood cells, leukocytes, or 408

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birefringent crystals of calcium oxalate as either needle-like or envelopeshaped dimorphic forms.

Treatment Decontamination Decontamination is not usually necessary following the ingestion of oxalate-containing plant parts. Symptomatic treatment for pharyngeal irritation includes demulcents (milk, chipped ice) and antihistamines. For serious oxalate ingestions, lavage with 0.15% calcium hydroxide (lime water) to precipitate insoluble calcium oxalate in the gastrointestinal tract was a previously recommended treatment for patients presenting to a health care facility within 1 hour of ingestion, but there are no clinical data to substantiate the efficacy or safety of this therapeutic modality.

Supplemental Care For symptomatic patients, generous fluid replacement (⬎2 L/m2/d) should be administered to promote the excretion of calcium oxalate crystals from the kidney tubules. The treatment of patients with chronic secondary oxalosis includes the use of sodium citrate (0.15 g/kg/d) to inhibit calcium oxalate crystallization in the kidneys,39 but there are few clinical data on the use of sodium citrate following the acute ingestion of calcium oxalate-containing plants. Symptomatic patients should receive a complete blood count, serum electrolytes including serum calcium, and kidney function tests (serum creatinine and BUN [blood urea nitrogen], urinalysis). Kidney function may deteriorate over the first week and careful management of fluid and electrolyte balance may be necessary. Intravenous calcium is not usually required to reverse the oxalate-induced hypocalcemia unless the patient is symptomatic. The initial adult treatment for symptomatic hypocalcemia is 10 mL of 10% calcium gluconate intravenously with cardiac monitoring over a 10-minute period and repeated if symptoms, signs, and electrocardiogram (ECG) evidence (eg, shortened QT interval) persist. Hemodialysis easily removes oxalate from the blood with most elimination within the first 2 hours.40


Butler AR. The Fifth Haldane Tait Lecture. The coming of rhubarb. Rep Proc Scott Soc Hist Med 1994;96:52-5. Foust CM. Mysteries of rhubarb: Chinese medicinal rhubarb through the ages. Pharm His 1994;36:155-9. Robb HF. Death from rhubarb leaves due to oxalic acid poisoning. JAMA 1919; 73:627-62.

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4. 5. 6.


8. 9. 10.


12. 13. 14. 15.

16. 17.

18. 19. 20. 21. 22.

23. 24. 410

Farre M, Xirgu J, Salgado A, et al. Fatal oxalic acid poisoning from sorrel soup. Lancet 1989;2:1524. Jacobziner H, Raybin HW. Rhubarb poisoning. NY J Med 1962;62:1676-8. Harima S, Matsuda H, Kuo M. Study of various rhubarbs regarding the cathartic effect and endotoxin-induced disseminated intravascular coagulation. Biol Pharm Bull 1994;17:1522-5. Wojcikowski K, Johnson DW, Gobe G. Medicinal herbal extracts — renal friend or foe: Part two: Herbal extracts with potential renal benefits. Nephrol 2004;9: 400-5. Peigen X, Liyi H, Liwei W. Ethnopharmacologic study of Chinese rhubarb. J Ethnopharmacol 1984;10:275-93. Ohkawa H. Gas chromatographic determination of oxalic acid in foods. J Assoc Off Anal Chem 1985;68:108-11. Liu R, Li A, Sun A. Preparative isolation and purification of hydroxyanthraquinones and cinnamic acid from the Chinese medicinal herb Rheum officinale Baill. by high-speed counter-current chromatography. J Chromatogr A 2004;1052:217-21. National Toxicology Program. NTP toxicology and carcinogenesis studies of EMODIN (CAS NO. 518-82-1) feed studies in F344/N rats and B6C3F1 mice. Natl Toxicol Program Tech Rep Ser 2001;493:1-278. Siener R, Ebert D, Nicolay C, et al. Dietary risk factors for hyperoxaluria in calcium oxalate stone formers. Kidney Int 2003;63:1037-43. Prenen JAC, Boer P, Dorhout Mees EJ. Absorption kinetics of oxalate from oxalate-rich food in man. Am J Clin Nutr 1984;40:1007-10. Tallqvist H, Vaananen I. Death of a child from oxalic acid poisoning due to eating rhubarb leaves. Ann Paediatr Fenn 1960;6:144-7. Massey LK, Roman-Smith H, Sutton RA. Effect of dietary oxalate and calcium on urinary oxalate and risk of formation of calcium oxalate kidney stones. J Am Diet Assoc 1993;93:901-6. Finch AM, Kasidas GP, Rose GA. Urine composition in normal subjects after oral ingestion of oxalate-rich foods. Clin Sci (London) 1981;60:411-8. Ye M, Han J, Chen H, et al. Analysis of phenolic compounds in rhubarbs using liquid chromatography coupled with electrospray ionization mass spectrometry. J Am Soc Mass Spectrom 2007;18:82-91. Hoppe B, Leumann E, von Unruh G, et al. Diagnostic and therapeutic approaches in patients with secondary hyperoxaluria. Front Biosci 2003;8:e437-43. Salyer WR, Hutchins GM. Cardiac lesions in secondary oxalosis. Arch Intern Med 1974;134:250-2. Sanz P, Reig R. Clinical and pathological findings in fatal plant oxalosis. Am J Forensic Med Pathol 1992;13:342-5. Dvorackova I. [Fatal poisoning following intravenous administration of sodium oxalate]. Arch Toxikol 1966;22:63-7 [German]. Hanson CF, Frankos VH, Thompson WO. Bioavailability of oxalic acid from spinach, sugar beet fibre and a solution of sodium oxalate consumed by female volunteers. Food Chem Toxicol 1989;27:181-4. Lee J-H, Kim JM, Kim C. Pharmacokinetic analysis of rhein in Rheum undulatum L. J Ethnopharmacol 2003;84:5-9. Lamminpää A, Kinos M. Plant poisonings in children. Hum Exp Toxicol 1996; 15:245-9. DM, June 2009

25. 26. 27. 28. 29. 30. 31.






37. 38. 39. 40.

Kaliiala H, Kauste O. Ingestion of rhubarb leaves as cause of oxalic acid poisoning. Ann Paediatr Fenn 1964;10:228-31. Williams HE, Smith LH Jr. Disorders of oxalate metabolism. Am J Med 1968; 45:715-35. Kuiper JJ. Initial manifestation of primary hyperoxaluria type I in adults: recognition, diagnosis, and management. West J Med 1996;164:42-53. Nime FA, Hutchins GM. Oxalosis caused by Aspergillus infection. Johns Hopkins Med J 1973;133:183-94. Weiner ES, Hutchins GM. Localized endotracheal oxalosis probably secondary to aspiration of rhubarb. Arch Intern Med 1979;139:602. Diffey BL, Lawlor EF, Hindson TC. Photoallergic contact dermatitis to rhubarb wine. Photodermatology 1984;1:43-4. Kwan TH, Tong MK, Leung KT, et al. Acute renal failure associated with prolonged intake of slimming pills containing anthraquinones. Hong Kong Med J 2006;12:394-7. Zhang HX, Liu MC. Separation procedures for the pharmacologically active components of rhubarb. J Chromatogr B Analyt Technol Biomed Life Sci 2004; 812:175-81. Koyama J, Morita I, Kobayashi N. Simultaneous determination of anthraquinones in rhubarb by high-performance liquid chromatography and capillary electrophoresis. J Chromatogr A 2007;1145:183-9. Zhang YZ, Lu YH, Wei DZ, et al. Preparative isolation and purification of hydroxyanthraquinones from Rheum tanguticum Maxim. on normal phase silica gel: using a Flash Master Personal system. Prep Biochem Biotechnol 2007;37:185-193. Lin CC, Wu CI, Lin TC, et al: Determination of 19 rhubarb constituents by high-performance liquid chromatography-ultraviolet-mass spectrometry. J Sep Sci 2006;29:2584-93. Komatsu K, Nagayama Y, Tanaka K, et al. Development of a high performance liquid chromatographic method for systematic quantitative analysis of chemical constituents in rhubarb. Chem Pharm Bull 2006;54:941-7. Hodgkinson A, Zarembski PM. Oxalic acid metabolism in man: a review. Calcif Tissue Res 1968;2:115-32. Oreopoulos DG, Husdan H, Leung M, et al. Urine oxalic acid: relation to urine flow. Ann Intern Med 1976;85:617-8. Leumann E, Hoppe B, Neuhaus T, et al. Efficacy of oral citrate administration in primary hyperoxaluria. Nephrol Dial Transplant 1995;10(suppl 8):14-6. Langman CB. The optimal approach to the patient with oxalosis. Adv Renal Replace Ther 2001;8:214-22.

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