OVERVIEW

Introduction

Bromelain is a concentrated mixture of proteins and enzymes made from the stems and fruit of the pineapple plant (Ananas comosus) that has antiinflammatory and digestive properties, and is used topically to treat wounds and burns and orally for digestive problems and sinusitis. Bromelain is generally recognized as safe (GRAS) and has not been linked to serum aminotransferase elevations nor to instances of clinically apparent liver injury.

Background

Bromelain is a concentrated mixture of proteolytic enzymes made from the stems and fruit of the pineapple plant (Ananas comosus) that has antiinflammatory and digestive properties, and is used topically to treat wounds and burns or orally for digestive complaints and sinusitis. Bromelain is typically concentrated, but only partially purified because its proteolytic enzymes can be inactivated by purification techniques. The major compounds in bromelain are enzymes such as is endopeptidases, phosphatases, glucosidases, peroxidases and cellulases and various glycoproteins. Applied topically, the proteolytic enzymes may help in wound debridement and burn management. In cooking, bromelain is used as a meat tenderizer. Orally, the enzymes and proteins of bromelain are absorbed intact to some degree and may possibly be helpful for digestive complains, infections and even metabolic problems. Bromelain has been used to treat symptoms of indigestion, nausea and abdominal pain as well as medical conditions including sinusitis, osteoarthritis, rheumatoid arthritis, prostatitis, inflammatory bowel disease, and multiple sclerosis. However, bromelain has not been proven to be of convincing benefit for any condition and is not formally approved for use for any medical disease in the United States. Nevertheless, it is used orally in dietary supplements and topically to help in wound healing and debridement of dead tissue. Bromelain is approved in Europe for topical use in wound and burn management. Bromelain is available in many commercial herbal preparations alone and as a part of multiingredient dietary supplements. The dose varies by source and medical use between 200 and 2000 mg daily. Bromelain is generally recognized as safe (GRAS, according to the FDA definition), and side effects are uncommon and typically are mild degrees of abdominal discomfort and nausea. Hypersensitivity reactions including urticaria and rash have been reported but are usually mild and resolve rapidly with discontinuation. Rare instances of anaphylaxis have been described with its use.

Hepatotoxicity

Oral bromelain has been evaluated in more than 100 clinical trials for conditions such as sinusitis, osteoarthritis, and rheumatoid arthritis, and is usually described as well tolerated and without significant side effects or adverse events. These studies have rarely reported results of liver enzyme testing, and most studies were for short term use only (3 to 6 days) and included a limited number of subjects. Nevertheless, despite widespread use, there have been no reports of liver injury, jaundice or hepatotoxicity associated with oral or topical use of bromelain. In large case series, systematic reviews, and reports from pharmacovigilance registries on liver injury due to botanical products, bromelain has not been mentioned or listed.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

Other Names: Bromelins, Ananas comosus, Pineapple extract

Drug Class: Herbal and Dietary Supplements

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Bromelain – Generic

DRUG CLASS

Herbal and Dietary Supplements

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 10 February 2024

Abbreviations: DSHEA, Dietary Supplement Health and Education Act; HDS, herbal and dietary supplements.

  • Zimmerman HJ. Unconventional drugs. Miscellaneous drugs and diagnostic chemicals. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott,1999: pp. 731-4.
    (Expert review of hepatotoxicity published in 1999; several herbal medications linked to liver injury are discussed, but bromelain is not mentioned).
  • Seeff L, Stickel F, Navarro VJ. Hepatotoxicity of herbals and dietary supplements. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 631-58.
    (Review of hepatotoxicity of herbals does not mention bromelain).
  • Bromelain. PDR for Herbal Medicines. 4th ed. Montvale, New Jersey: Thomson Healthcare Inc. 2007; pp 945-8.
    (Compilation of short monographs on herbal medications and dietary supplements).
  • Taub SJ. The use of bromelains in sinusitis: a double-blind clinical evaluation. Eye Ear Nose Throat Mon. 1967;46:361-2. [PubMed: 5342723]
    (Among 59 adults with acute or chronic sinusitis treated with bromelain or placebo four times daily for 6 days concurrently with antibiotics and decongestants, an excellent response was reported in 69% on bromelain vs 23% on placebo, and although there were no differences in improvements in headache and pain, there were also no “toxic manifestations”).
  • Seltzer AP. Adjunctive use of bromelains in sinusitis: a controlled study. Eye Ear Nose Throat Mon. 1967;46:1281-8. [PubMed: 4864820]
    (Among 49 patients with symptoms of sinusitis treated for 6 days, good to excellent responses occurred in 80% of patients on bromelain treatment vs 50% on placebo, although rates of improvements in headache and pain were not different in the two groups; “side effects were not encountered”).
  • 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;23:410-5. [PubMed: 15278753]
    (Among 103 patients with painful osteoarthritis of the knee treated with bromelain or diclofenac orally for 6 weeks, improvements in symptom scores were similar in the two groups as were adverse event rates [28% vs 23%] and while median values of ALT, AST and GGT decreased with bromelain, they increased with diclofenac; rates of abnormal values were not reported).
  • 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;38:431-5. [PMC free article: PMC1724873] [PubMed: 15273178]
    (Among 674 patients with acute unilateral ankle sprain treated with 7 different combinations of hydrolytic enzymes [bromelain, rutoside, and trypsin] or placebo 3 times daily for 10 days, decreases in pain, ankle volume, and range of motion were similar in the 8 different groups while adverse events were more frequent with enzyme therapy, although there was only one serious adverse event [thrombosis in the calf judged to be unrelated to the therapy]; no mention of ALT elevations or hepatotoxicity).
  • Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. [PubMed: 15390328]
    (Among ~50,000 liver transplants reported to UNOS between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, including 7 [5%] for herbal medications, none were specifically attributed to a product containing bromelain).
  • Braun JM, Schneider B, Beuth HJ. Therapeutic use, efficiency and safety of the proteolytic pineapple enzyme Bromelain-POS in children with acute sinusitis in Germany. In Vivo. 2005;19:417-21. [PubMed: 15796206]
    (Among 116 children with sinusitis treated with bromelain, standard therapy alone, or the combination of the two, duration of symptoms was 6.7 vs 8.0 days vs 9.1 days, while side effects were rare, although one child with pineapple allergies developed a mild, self-limiting allergic reaction; no mention of ALT elevations or hepatotoxicity).
  • Guo R, Canter PH, Ernst E. Herbal medicines for the treatment of rhinosinusitis: a systematic review. Otolaryngol Head Neck Surg. 2006;135:496-506. [PubMed: 17011407]
    (A systematic review of the literature on use of herbal products in sinusitis identified 10 randomized controlled trials, 3 of which evaluated bromelain, all reported positive findings without any serious adverse events and either no or only mild side effects with similar rates compared to placebo controls).
  • García-Cortés M, Borraz Y, Lucena MI, Peláez G, Salmerón J, Diago M, Martínez-Sierra MC, et al. [Liver injury induced by "natural remedies": an analysis of cases submitted to the Spanish Liver Toxicity Registry]. Rev Esp Enferm Dig 2008; 100: 688-95. Spanish. [PubMed: 19159172]
    (Among 521 cases of drug induced liver injury submitted to Spanish registry, 13 [2%] were due to herbals, but none were attributed to bromelain).
  • Navarro VJ. Herbal and dietary supplement hepatotoxicity. Semin Liver Dis 2009; 29: 373-82. [PubMed: 19826971]
    (Review of the problems of causality assessment in herbal and dietary supplement [HDS] associated liver disease, including the variable clinical presentations, the complexity and lack of information on their components, absence of controlled trials demonstrating safety and efficacy, the possibility of contamination or incorrect labeling, and the frequent underreporting of herbal use by patients. Regulation of HDS is under DSHEA, which requires manufacturers to determine safety and prohibits claims of efficacy in treating specific diseases. The US Pharmacopeia sets standards for food and drugs and includes HDS; HDS induced liver injury is a growing problem and currently accounts for at least 10% of cases of acute liver injury due to medications).
  • Jacobsson I, Jönsson AK, Gerdén B, Hägg S. Spontaneously reported adverse reactions in association with complementary and alternative medicine substances in Sweden. Pharmacoepidemiol Drug Saf 2009; 18: 1039-47. [PubMed: 19650152]
    (Review of 778 spontaneous reports of adverse reactions to herbal products to a Swedish Registry does not list or mention bromelain).
  • Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]
    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 [11%] were attributed to drug induced liver injury of which 12 [9%] were due to herbals, but none were attributed to bromelain).
  • Bromelain. Monograph. Altern Med Rev. 2010;15:361-8. [PubMed: 21194252]
    (Summary of purported biologic effects and clinical uses of bromelain in multiple conditions including antibiotic potentiation, diarrhea and intestinal infections, cardiovascular diseases, inflammatory bowel disease, multiple sclerosis, musculoskeletal injuries, osteoarthritis, prostatitis, renal disease, respiratory conditions, rheumatoid arthritis, and wound debridement, discusses side effects but does not mention ALT elevations or hepatotoxicity).
  • Teschke R, Wolff A, Frenzel C, Schulze J, Eickhoff A. Herbal hepatotoxicity: a tabular compilation of reported cases. Liver Int 2012; 32: 1543-56. [PubMed: 22928722]
    (A systematic compilation of all publications on the hepatotoxicity of specific herbals identified 185 publications on 60 different herbs, herbal drugs and supplements, but bromelain was not listed or mentioned).
  • Navarro VJ, Barnhart H, Bonkovsky HL, Davern T, Fontana RJ, Grant L, Reddy KR, et al. Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network. Hepatology 2014; 60: 1399-408. [PMC free article: PMC4293199] [PubMed: 25043597]
    (Among 85 cases of HDS associated liver injury [not due to anabolic steroids] enrolled in a US prospective study between 2004 and 2013, none were attributed to a product containing bromelain).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a prospective database between 2004 and 2012, HDS were implicated in 145 [16%], the single major herbal cause being green tea and none were attributed to bromelain [see also Navarro et al Hepatology 2014]).
  • García-Cortés M, Robles-Díaz M, Ortega-Alonso A, Medina-Caliz I, Andrade RJ. Hepatotoxicity by dietary supplements: A tabular listing and clinical characteristics. Int J Mol Sci 2016; 17: 537. [PMC free article: PMC4848993] [PubMed: 27070596]
    (Listing of published cases of liver injury from HDS products, but does not mention or list bromelain).
  • Brown AC. An overview of herb and dietary supplement efficacy, safety and government regulations in the United States with suggested improvements. Part 1 of 5 series. Food Chem Toxicol 2017; 107: 449-71. [PubMed: 27818322]
    (Summary of the US regulations on safety and efficacy of herbal and dietary supplements).
  • Brown AC. Liver toxicity related to herbs and dietary supplements: Online table of case reports. Part 2 of 5 series. Food Chem Toxicol 2017; 107: 472-501. [PubMed: 27402097]
    (Description of an online compendium of cases of liver toxicity attributed to HDS products, does not mention or list bromelain).
  • Navarro VJ, Khan I, Björnsson E, Seeff LB, Serrano J, Hoofnagle JH. Liver injury from herbal and dietary supplements. Hepatology 2017; 65: 363-73. [PMC free article: PMC5502701] [PubMed: 27677775]
    (Review of the problems of liver injury and HDS products, mentions that multiingredient dietary supplements account for the major of cases, but does not mention a product with bromelain as a component).
  • Ballotin VR, Bigarella LG, Brandão ABM, Balbinot RA, Balbinot SS, Soldera J. Herb-induced liver injury: Systematic review and meta-analysis. World J Clin Cases. 2021;9:5490-5513. [PMC free article: PMC8281430] [PubMed: 34307603]
    (Systematic review of the literature on herb induced liver injury identified 446 references describing 936 cases due to 79 different herbal products, the most common being He Shou Wu [91], green tea [90] Herbalife products [64], kava kava [62] and greater celandine [48]; bromelain was not among the 79 implicated products).
  • Bessone F, García-Cortés M, Medina-Caliz I, Hernandez N, Parana R, Mendizabal M, Schinoni MI, et al. Herbal and dietary supplements-induced liver injury in Latin America: experience from the LATINDILI Network. Clin Gastroenterol Hepatol. 2022;20:e548-e563. [PubMed: 33434654]
    (Among 367 cases of hepatotoxicity enrolled in the Latin American DILI Network between 2011 and 2019, 29 [8%] were attributed to herbal products, the most frequent being green tea [n=7], Herbalife products [n=5] and garcinia [n=3], while bromelain is not mentioned).
  • Kumar V, Mangla B, Javed S, Ahsan W, Kumar P, Garg V, Dureja H. Bromelain: a review of its mechanisms, pharmacological effects and potential applications. Food Funct. 2023;14:8101-8128. [PubMed: 37650738]
    (Extensive review of the source, chemical components, method of preparation, pharmacologic activities, mechanism of action, safety, and clinical efficacy of bromelain mentions side effects of allergic reactions including anaphylaxis, digestive complains of nausea, vomiting, diarrhea and abdominal discomfort, potential anticoagulant activity, but concludes that it is generally safety in usual doses and allergic reactions are rare; no mention of hepatotoxicity or ALT elevations).
  • Shoham Y, Gasteratos K, Singer AJ, Krieger Y, Silberstein E, Goverman J. Bromelain-based enzymatic burn debridement: A systematic review of clinical studies on patient safety, efficacy and long-term outcomes. Int Wound J. 2023;20:4364-4383. [PMC free article: PMC10681521] [PubMed: 37455553]
    (Systematic review of the literature on the use of bromelain for enzymatic burn debridement identified 34 clinical studies and concluded that bromelain has positive effects on functional and cosmetic outcomes of major burns, and that there is no strong evidence of adverse events such as infections or hemorrhage).