Scientific Name(s): Ananas comosus (L.) Merr. Family: Bromeliaceae
Common Name(s): Pineapple , bromelain , Phlogenzym , Debridase
Few well-controlled clinical trials have been published to support the wide range of therapeutic claims for bromelain, a crude, aqueous extract of pineapple. Evidence exists primarily for the use of bromelain in debridement of burns and as an anti-inflammatory agent.
Two slices of pineapple contain approximately 100 mg of ascorbic acid (vitamin C). The usual dosage of bromelain is 40 mg taken 3 or 4 times daily. Pineapple products are available commercially in liquid, tablet, and capsule doseforms. Most products contain bromelain 500 mg; manufacturers suggest a dose of 500 to 1,000 mg daily.
Hypersensitivity to any of the components in pineapple. Cross-reaction with honeybee venom, olive tree pollen, celery, cypress pollen, bromelain, and papain have been reported.
Information regarding safety and efficacy in pregnancy and lactation is lacking. Data is lacking to support the historical use of pineapple as an emmenagogue and abortifacient.
Potentiation of amoxicillin and tetracycline because of increased volume of distribution by bromelain has been documented.
The juice from unripe pineapples can act as a violent purgative. Bromelain ingestion is associated with a low incidence of adverse reactions, including diarrhea, menorrhagia, nausea, skin rash, and vomiting. Angular stomatitis/cheilitis can result from eating large amounts of the fruit.
Bromelain has very low toxicity.
The well-known pineapple fruit is actually a complex flower head that forms around the stem. Each of the eyes on the surface is the dried base of a small flower. The pineapple is the only cultivated fruit whose main stem runs completely through it. 1 , 2 The top crown of leaves contains a bud that, when mature, indicates that the fruit is ready for cutting. The crowns from the top of the fruit are usually used for propagation because pineapples contain no viable seeds; occasionally, slips from the base of the fruit or suckers are used if planting material is in short supply. 3 The plant grows to a height of 1 m; the first crop is ready for harvesting approximately 18 months after planting. Because the plant is xerophytic and uses water very efficiently, pineapple may be grown in areas of relatively low rainfall (50 to 200 cm). 3
The pineapple is native to South America and was brought to Europe by Spanish explorers. Planting began on a large scale in Hawaii early in the 19th century. Growth of the industry peaked in the 1950s, then declined slowly under the pressure of international competition. 3 Today, the bulk of the world's pineapple crop comes from Thailand, the Philippines, and Brazil. Traditional uses include the brewing of pineapple wine, production of fiber, and medicinal use as an emmenagogue, abortifacient, antiamebic, and vermifuge.
Pineapple is rich in citric and malic acids; citric acid concentrations in some cultivars exceed 8%. 4 The fruit also contains moderate amounts of ascorbic acid; 2 slices of pineapple contain ascorbic acid 100 mg. 5 A steroidal component of the leaves possesses estrogenic activity, 4 and a variety of aromatic compounds are found in the essential oil. The residue left after juice extraction contains large quantities of vitamin A and is used as a component of livestock feed. A crude aqueous extract of pineapple known as bromelain is obtained from the stems and immature fruits; stem and fruit bromelains are distinguishable from one another. 6
Bromelain comprises a complex mixture of sulfhydryl-containing proteolytic enzymes in addition to a number of nonspecific components, such as phosphatases, glucosidases, peroxidases, cellulases, glycoproteins, and carbohydrates. The extract also contains a proteinase inhibitor consisting of isoinhibitors. 6 Each isoinhibitor has a 2-chain structure, 7 and the amino acid sequence has been determined. 8 In an aqueous solution, bromelain rapidly deteriorates through self-digestion. 9 Commercial bromelain preparations are evaluated according to their proteolytic activity.
Clinical trials have assessed the effectiveness of bromelain in commercial preparations of differing complexes of proteolytic enzymes and concentrations of bromelain.
Uses and Pharmacology
Various studies have investigated the anti-edematous effects of bromelain in animal models. 9 , 10 , 12 The efficacy of bromelain has been compared with the anti-inflammatory effect of prednisone, etodolac, indomethacin, acetylsalicylic acid, and oxyphenbutazone. Oral and intraperitoneal routes have been investigated. The anti-edematous action may be the result of increased tissue permeability by fibrinolysis and the reabsorption of edema fluids into the circulatory system. 9Clinical data
Clinical trials have employed a variety of preparations including bromelain in combination with trypsin/rutin (as Phlogenzym ) compared with diclofenac or placebo. Outcomes are equivocal, 9 with older trials suggesting anti-inflammatory and analgesic effects. 13 , 14 , 15
In moderate to severe osteoarthritis during 12 weeks of administration of bromelain 800 mg daily, there was no change in total Western Ontario and McMaster Universities osteoarthritis index (WOMAC) score compared with placebo. 16 A trial comparing 6 weeks of a combination of bromelain and trypsin/rutin with diclofenac 100 mg daily in osteoarthritis of the hip found no difference in total WOMAC scores, but showed the combination to be equivalent to diclofenac. 17
In a review of the efficacy of bromelain on edema, bruising, pain, and healing time after surgery or trauma, a reduction in total analgesic intake and swelling after surgical correction of long bone fractures and decreased pain following dental surgery was recorded. 18 Conflicting results were noted with regard to rhinoplasty surgery. In a large multicenter trial (N = 721), no effect of a combination of bromelain and trypsin/rutin was found compared with placebo in ankle ligament injury. 19 No effect in managing muscle soreness after unaccustomed exercise was found for the combination preparation compared with placebo. 20Antimicrobial
Bromelain has been shown to prevent intestinal fluid secretion caused by Vibrio cholerae and Escherichia coli enterotoxins in rabbit ileum in vitro. 21 Strong antifungal activity has been documented against Trichoderma viride . 22 In addition, antihelminthic action has been documented. 23 , 24Animal data
A reduced incidence of diarrhea associated with K88-positive enterotoxigenic E. coli was found in newly weaned piglets that received bromelain for 10 days. 25 One day after starting therapy, the piglets received a 7-day challenge with K88-positive enterotoxigenic E. coli . Bromelain-treated piglets had significantly lower disease scores than untreated piglets ( P < 0.05), as well as significantly increased weight gain compared with controls ( P < 0.05).Clinical data
Clinical trials are lacking.Burns
Escharase is a nonproteolytic component in bromelain thought to be important in the action of topical bromelain. 11 Topical preparations typically contain 35% of a bromelain-derived enzyme mixture extracted from pineapple stems in a lipid base ( Debridase ). 9Animal data
Topical application of pineapple-derived enzymes has been shown to separate burned tissue or eschar from living tissue in animal models. 9 , 10 , 26 , 27 Complete debridement of experimental burns in rats was achieved in 2 days, with no damage to adjacent tissues. 9 , 26
In pigs with experimentally-induced circumferential burns, topical application of Debridase relieved burn-induced compartment syndrome within 30 minutes and did not cause any adverse local or systemic effects or affect healthy, unburned tissue. 27Clinical data
A prospective, noncomparative clinical study examined the efficacy of Debridase in 130 patients with deep second- and third-degree burns. The topical bromelain preparation was applied for 4 hours under an occlusive dressing. Application of the preparation was repeated as necessary, with the majority (72.6%) of patients requiring only 1 application. Percentage of debridement was 89% (standard deviation [SD] = 21%) for a single application, 77% (SD = 27%) for 2 applications, and 62% (SD = 27%) for 3 applications. 28 Topical bromelain has also been studied for eschar removal in frostbite. 9Ear, nose, throat/acute sinusitis
In a clinical trial (N = 116), decreased duration of symptoms was demonstrated in children with acute sinusitis with oral bromelain administration over standard therapy. 29 Similar results were reported in a clinical trial (N = 48) evaluating bromelain against standard therapy in acute sinusitis. 10Immunomodulation
Because bromelain modulates immune responses, the possibility of clinical use has been suggested. In vitro studies 30 , 31 , 32 have shown that bromelain modulates T- and B-cell immune responses, 30 blocks activation of extracellular regulated kinase-2 T cells, 31 and activates murine macrophages and natural killer cells. 32 In vivo, mice treated with bromelain had increased B-cells and reduced interleukin-2, indicating an enhanced antibody response. 30Clinical data
Bromelain has been investigated for use in pityriasis lichenoides chronica, an uncommon rash of unknown origin. In a small study (N = 8), complete clinical response was reported following 3 months of oral bromelain therapy. No adverse reactions were reported. Anti-inflammatory, immunomodulatory, and antiviral actions of bromelain may have been responsible for the effect. 33Malignant disease
Pineapple juice reduces the mutagenic activity of carcinogens in the Ames Salmonella typhimurium assay by approximately 50%. In vitro studies have demonstrated concentration-dependent inhibition of tumor-cell proliferation by bromelain. 9 However, a study investigating the effects of pineapple on the growth of HepG2 human liver cancer cells in vitro found no antiproliferative activity. 34 Bromelain reversibly reduced glioma cell adhesion, migration, and invasion without affecting cell viability in vitro.Animal data
Bromelain also reduced local tumor weight but did not reduce lung colonization in a murine tumor growth model. 35 , 36 Mouse melanoma cells, preincubated in vitro with bromelain, reduced lung metastatic tumor weight. However, no survival benefit was found. 9Clinical data
Ingestion of pineapple resulted in the inhibition of endogenous nitrosation in human volunteers, suggesting that the ascorbic acid content of the fruit can limit the formation of potentially toxic digestive by-products. 37 Anecdotal reports of the beneficial effects of high-dose oral bromelain therapy in cancer patients have been published. 38 Bromelain also has been used in combination with chemotherapeutic agents, such as fluorouracil and vincristine. 9 , 10
Bromelain stimulated monocytic cytotoxicity in breast cancer patients in vitro. Sixteen breast cancer patients and healthy volunteers received oral bromelain 3,000 mg/day for 10 days. Cytotoxic activity also increased. Bromelain was less effective in stimulating the cytotoxicity of monocytes from healthy donors. 39Other effects
Esophageal meat impaction
An in vitro experiment suggests fresh (or frozen/thawed), but not processed, pineapple juice is effective at 4.5 hours in moving impacted esophageal meat bolus. 40 Caution is advised when using proteolytic enzymes for this purpose because of the risk of complications, such as hemorrhagic pulmonary edema or aspiration pneumonia. 41Multiple sclerosis
In a large, multicenter clinical trial, bromelain with trypsin/rutin had no effect on neurological symptoms over placebo. 42Nutrition
Positive nutritional effects have been shown in bedridden, tube-fed, nursing home patients who received a supplementary digestive aid containing bromelain plus an extract of Aspergillus niger . Total protein concentration improved significantly with the supplement ( P < 0.02), which was reversed after withdrawal. 43Sepsis
Phlogenzym (an oral enzyme formulation of rutoside, bromelain, and trypsin) showed efficacy as an adjuvant for early improvement in children with sepsis in a double-blind, randomized, controlled trial (N = 60). Fever, hemodynamic support, results from the Glasgow Coma Scale, and oral feeding improved 1 to 2 days earlier for the Phlogenzym -treated patients compared with placebo. 44Ulcerative colitis
Case reports detailing the successful use of bromelain in the treatment of mild ulcerative colitis have been published. 45 Patients took bromelain in addition to their usual drug regimen and experienced rapid improvement of symptoms, confirmed by endoscopy.
Two slices of pineapple contain approximately 100 mg of ascorbic acid (vitamin C), approximately the recommended daily adult intake. Commercially available bromelain supplements contain predominately stem bromelain, as compared with fruit bromelain 50
The usual dosage of bromelain is 40 mg 3 or 4 times daily. However, because bromelain is regarded as being relatively nontoxic, doses of up to 2,000 mg/day have been used. 9 Most commercial products contain bromelain 500 mg; manufacturers suggest a dosage regimen of 500 to 1,000 mg daily.
Confusion may arise with bromelain dosage because bromelain activity is defined in a number of ways, including rorer units, gelatin-dissolving units, milk-clotting units, 51 and Fédération Internationale Pharmaceutique standards. 9
Information regarding safety and efficacy in pregnancy and lactation is lacking. A lack of clinical evidence exists to support the historical use of pineapple as an emmenagogue and abortifacient. Previously, bromelain/trypsin (as Kimotab ) was investigated for use in breast engorgement during lactation. 52
Bromelain increases blood and urine levels of certain antibiotics in humans by increasing the volume of distribution of tetracycline and amoxicillin. The mechanism may be associated with enhanced absorption and increased permeability into diseased tissue, thus enhancing antibiotic access to the infection site. 10
Repeated exposure of pineapple cutters to bromelain can result in the obliteration of fingerprints, and the hooked margins of the leaves can cause painful mechanical injury.
Ethyl acrylate, an aromatic component of the juice, can produce dermal sensitization. Allergy to pineapple is documented. Cross-reactivity studies with bromelain indicate an immunoglobulin E (IgE)–mediated reaction. Cross-reaction with honeybee venom, olive tree pollen, celery, cypress pollen, and papain have been reported. Sensitization to enzymes may follow inhalation (through occupational or other exposure; some reviews show up to 50% occurrence) or ingestion (rare). An unusual case report describes delayed allergic contact cheilitis caused by a bromelain-containing mouthwash. 10 , 53 , 54
The juice from unripe pineapples can act as a violent purgative. Bromelain ingestion is associated with a low incidence of adverse reactions, including diarrhea, menorrhagia, nausea, skin rash, and vomiting. Angular stomatitis/cheilitis can result from eating large amounts of the fruit. 1 , 11
Bromelain has very low toxicity. Lethal intraperitoneal doses (LD 50 ) of bromelain have been determined as 37 and 85 mg/kg in mice and rats, respectively. No immediate toxic effects were observed. These doses far exceed those normally administered to humans. No effects in human clinical tests were documented with bromelain supplementation up to 460 mg; however, doses of up to 1,840 mg increased heart rate. 9 , 10
Bibliography1. Ananas comosus (L.) Merr. USDA, NRCS. 2007. The PLANTS Database ( http://plants.usda.gov June, 2008). National Plant Data Center, Baton Rouge, LA 70874-4490 USA.
2. Morton JF. Major Medicinal Plants . Springfield, IL: Thomas; 1977.
3. Department of Tropical Plant and Soil Sciences. Pineapple in Hawaii . Available at: http://www.tpss.hawaii.edu/pineapple/pinehaw.htm . Accessed June 12, 2006.
4. Duke JA. CRC Handbook of Medicinal Herbs . Boca Raton, FL: CRC Press; 1985.
5. Szeto YT, Tomlinson B, Benzie IF. Total antioxidant and ascorbic acid content of fresh fruits and vegetables: implications for dietary planning and food preservation. Br J Nutr . 2002;87(1):55-59.
6. Leung AY. Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics . New York, NY: Wiley; 1980.
7. Sawano Y, Muramatsu T, Hatano K, Nagata K, Tanokura M. Characterization of genomic sequence coding for bromelain inhibitors in pineapple and expression of its recombinant isoform. J Biol Chem . 2002;277(31):28222-28227.
8. Lenarcic B, Ritonja A, Turk B, Dolenc I, Turk V. Characterization and structure of pineapple stem inhibitor of cysteine proteinases. Biol Chem Hoppe Seyler . 1992;373(7):459-464.
9. Maurer HR. Bromelain: biochemistry, pharmacology and medical use. Cell Mol Life Sci . 2001;58(9):1234-1245.
10. Kelly GS. Bromelain: A literature review and discussion of its therapeutic applications. Altern Med Rev . 1996;1:243-257.
11. Hale LP, Greer PK, Trinh CT, James CL. Proteinase activity and stability of natural bromelain preparations. Int Immunopharmacol . 2005;5(4):783-793.
12. Leipner J, Iten F, Saller R. Therapy with proteolytic enzymes in rheumatic disorders. BioDrugs . 2001;15(12):779-789.
13. Brien S, Lewith G, Walker A, Hicks SM, Middleton D. Bromelain as a Treatment for Osteoarthritis: a Review of Clinical Studies. Evid Based Complement Alternat Med . 2004;1(3):251-257.
14. Klein G, Kullich W. Short-term treatment of painful osteoarthritis of the knee with oral enzymes. A randomised, double-blind study versus diclofenac. Clin Drug Invest . 2000;19:15-23.
15. Akhtar NM, Naseer R, Farooqi AZ, Aziz W, Nazir M. Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee--a double-blind prospective randomized study. Clin Rheumatol . 2004;23(5):410-415.
16. Brien S, Lewith G, Walker AF, Middleton R, Prescott P, Bundy R. Bromelain as an adjunctive treatment for moderate-to-severe osteoarthritis of the knee: a randomized placebo-controlled pilot study. QJM . 2006;99(12):841-850.
17. Klein G, Kullich W, Schnitker J, Schwann H. Efficacy and tolerance of an oral enzyme combination in painful osteoarthritis of the hip. A double-blind, randomised study comparing oral enzymes with non-steroidal anti-inflammatory drugs. Clin Exp Rheumatol . 2006;24(1):25-30.
18. MacKay D, Miller AL. Nutritional support for wound healing. Altern Med Rev . 2003;8(4):359-377.
19. Kerkhoffs GM, Struijs PA, de Wit C, Rahlfs VW, Zwipp H, van Dijk CN. A double blind, randomised, parallel group study on the efficacy and safety of treating acute lateral ankle sprain with oral hydrolytic enzymes. Br J Sports Med . 2004;38(4):431-435.
20. Stone MB, Merrick MA, Ingersoll CD, Edwards JE. Preliminary comparison of bromelain and Ibuprofen for delayed onset muscle soreness management. Clin J Sport Med . 2002;12(6):373-378.
21. Mynott TL, Guandalini S, Raimondi F, Fasano A. Bromelain prevents secretion caused by Vibrio cholerae and Escherichia coli enterotoxins in rabbit ileum in vitro. Gastroenterology . 1997;113(1):175-184. Erratum in: Gastroenterology . 1997;113(4):1425.
22. Taira T, Ohdomari A, Nakama N, Shimoji M, Ishihara M. Characterization and antifungal activity of gazyumaru ( Ficus microcarpa ) latex chitinases: both the chitin-binding and the antifungal activities of class I chitinase are reinforced with increasing ionic strength. Biosci Biotechnol Biochem . 2005;69(4):811-818.
23. Stepek G, Lowe AE, Buttle DJ, Duce IR, Behnke JM. In vitro and in vivo anthelmintic efficacy of plant cysteine proteinases against the rodent gastrointestinal nematode, Trichuris muris. Parasitology . 2006;132(Pt 5):681-689.
24. Stepek G, Buttle DJ, Duce IR, Lowe A, Behnke JM. Assessment of the anthelmintic effect of natural plant cysteine proteinases against the gastrointestinal nematode, Heligmosomoides polygyrus , in vitro. Parasitology . 2005;130(Pt 2):203-211.
25. Edenharder R, John K, Ivo-Boor H. Antimutagenic activity of vegetable and fruit extracts against in-vitro benzo(a)pyrene [in German]. Z Gesamte Hyg . 1990;36(3):144-147.
26. Rowan AD, Christopher CW, Kelley SF, Buttle DJ, Ehrlich HP. Debridement of experimental full-thickness skin burns of rats with enzyme fractions derived from pineapple stem. Burns . 1990;16(4):243-246.
27. Krieger Y, Rosenberg L, Lapid O, et al. Escharotomy using an enzymatic debridement agent for treating experimental burn-induced compartment syndrome in an animal model. J Trauma . 2005;58(6):1259-1264.
28. Rosenberg L, Lapid O, Bogdanov-Berezovsky A, et al. Safety and efficacy of a proteolytic enzyme for enzymatic burn debridement: a preliminary report. Burns . 2004;30(8):843-850.
29. Karkos PD, Leong SC, Arya AK, Papouliakos SM, Apostolidou MT, Issing WJ. Complementary ENT: a systematic review of commonly used supplements. J Laryngol Otol . 2007;121(8):779-782.
30. Engwerda CR, Andrew D, Ladhams A, Mynott TL. Bromelain modulates T cell and B cell immune responses in vitro and in vivo. Cell Immunol . 2001;210(1):66-75.
31. Mynott TL, Ladhams A, Scarmato P, Engwerda CR. Bromelain, from pineapple stems, proteolytically blocks activation of extracellular regulated kinase-2 in T cells. J Immunol . 1999;163(5):2568-2575.
32. Engwerda CR, Andrew D, Murphy M, Mynott TL. Bromelain activates murine macrophages and natural killer cells in vitro. Cell Immunol . 2001;210(1):5-10.
33. Massimiliano R, Pietro R, Paolo S, Sara P, Michele F. Role of bromelain in the treatment of patients with pityriasis lichenoides chronica. J Dermatolog Treat . 2007;18(4):219-222.
34. Sun J, Chu YF, Wu X, Liu RH. Antioxidant and antiproliferative activities of common fruits. J Agric Food Chem . 2002;50(25):7449-7454.
35. Tysnes BB, Maurer HR, Porwol T, Probst B, Bjerkvig R, Hoover F. Bromelain reversibly inhibits invasive properties of glioma cells. Neoplasia . 2001;3(6):469-479.
36. Beuth J, Braun JM. Modulation of murine tumor growth and colonization by bromelaine, an extract of the pineapple plant ( Ananas comosum L.). In Vivo . 2005;19(2):483-485.
37. Helser MA, Hotchkiss JH, Roe DA. Influence of fruit and vegetable juices on the endogenous formation of N-nitrosoproline and N-nitrosothiazolidine-4-carboxylic acid in humans on controlled diets. Carcinogenesis . 1992;13(12):2277-2280.
38. Michael A, Hedayati B, Dalgleish AG. Disease regression in malignant melanoma: spontaneous resolution or a result of treatment with antioxidants, green tea, and pineapple cores? A case report. Integr Cancer Ther . 2007;6(1):77-79.
39. Eckert K, Grabowska E, Stange R, Schneider U, Eschmann K, Maurer HR. Effects of oral bromelain administration on the impaired immunocytotoxicity of mononuclear cells from mammary tumor patients. Oncol Rep . 1999;6(6):1191-1199.
40. Thomas L, Low C, Webb C, Ramos E, Panarese A, Clarke R. Naturally occurring fruit juices dislodge meat bolus obstruction in vitro. Clin Otolaryngol Allied Sci . 2004;29(6):694-697.
41. Lee J, Anderson R. Best evidence topic report. Proteolytic enzymes for oesophageal meat impaction. Emerg Med J . 2005;22(2):122-123.
42. Baumhackl U, Kappos L, Radue EW, et al. A randomized, double-blind, placebo-controlled study of oral hydrolytic enzymes in relapsing multiple sclerosis. Mult Scler . 2005;11(2):166-168.
43. Glade MJ, Kendra D, Kaminski MV Jr. Improvement in protein utilization in nursing-home patients on tube feeding supplemented with an enzyme product derived from Aspergillus niger and bromelain. Nutrition . 2001;17(4):348-350.
44. Shahid SK, Turakhia NH, Kundra M, Shanbag P, Daftary GV, Schiess W. Efficacy and safety of phlogenzym--a protease formulation, in sepsis in children. J Assoc Physicians India . 2002;50:527-531.
45. Kane S, Goldberg MJ. Use of bromelain for mild ulcerative colitis. Ann Intern Med . 2000;132(8):680.
46. Sripanidkulchai B, Wongpanich V, Laupattarakasem P, Suwansaksri J, Jirakulsomchok D. Diuretic effects of selected Thai indigenous medicinal plants in rats. J Ethnopharmacol . 2001;75(2-3):185-190.
47. Xie W, Xing D, Sun H, Wang W, Ding Y, Du L. The effects of Ananas comosus L. leaves on diabetic-dyslipidemic rats induced by alloxan and a high-fat/high-cholesterol diet. Am J Chin Med . 2005;33(1):95-105.
48. Sebeková K, Dämmrich J, Krivosíková Z, Heidland A. The effect of oral protease administration in the rat remnant kidney model. Res Exp Med (Berl) . 1999;199(3):177-188.
49. Gläser D, Hilberg T. The influence of bromelain on platelet count and platelet activity in vitro. Platelets . 2006;17(1):37-41.
50. Hale LP, Greer PK, Trinh CT, James CL. Proteinase activity and stability of natural bromelain preparations. Int Immunopharmacol . 2005;5(4):783-793.
51. Bromelain. Altern Med Rev . 1998;3(4):302-305.
52. Snowden HM, Renfrew MJ, Woolridge MW. Treatments for breast engorgement during lactation. Cochrane Database Syst Rev . 2001;(2):CD000046.
53. Nettis E, Napoli G, Ferrannini A, Tursi A. IgE-mediated allergy to bromelain. Allergy . 2001;56(3):257-258.
54. Raison-Peyron N, Roulet A, Guillot B, Guilhou JJ. Bromelain: an unusual cause of allergic contact cheilitis. Contact Dermatitis . 2003;49(4):218-219.
Copyright © 2009 Wolters Kluwer Health