Related Terms

• Agalsidase alpha, agalsidase beta, alpha galactosidase, Anderson-Fabry disease, Angiokeratoma corporis diffusum, arginine, bromelain, ceramide trihexosidosis, chymotrypsin, citrulline, cysteine, enzyme deficiency, enzyme replacement therapy, Fabrazyme®, Fabry disease, Gaucher disease, glutaminase-asparaginase, glutamine, lysosomal diseases, Pancrease, Replagal, rutin, serine, thymus extract.

Background

• Enzyme therapy is the use of enzymes to treat deficiencies and other medical conditions in the body. An enzyme is a macromolecule that catalyzes (speeds up) processes in the body. Enzymes help to digest food, break down toxins, cleanse the blood, strengthen the immune system, build protein into muscle, contract muscles, eliminate carbon dioxide from the lungs and reduce stress on the pancreas and other vital organs. Enzyme therapy has a wide variety of proposed medical uses, ranging from the treatment of cystic fibrosis and pancreatic insufficiency, to certain cancers or tumors. The therapy may be systemic or non-systemic, and may be administered via multiple routes of administration, most often orally, topically or intravenously.

• Enzyme replacement therapy, a subdivision of enzyme therapy, is a medical treatment replacing an enzyme in patients in whom that particular enzyme is deficient or absent. Enzyme replacement therapy is usually administered through intravenous (IV) infusion. It is currently available for lysosomal diseases, such as Gaucher disease and Fabry disease.

• Non-specific enzyme therapy, another subtype of the general category of enzyme therapy, does not intend the catalysis(speeding up) of definite steps of metabolism, but claims to stimulate regenerative processes in the body. Initially, non-specific enzyme therapy was considered a promising approach. The growing knowledge in basic research and the lack of evidence for clinical effectiveness rendered the predominantly oral application of enzyme preparations for non-specific treatment outdated by the 1960s. In Germany, however, the absence of strict legal regulations prevented the deregulation of drugs designed for non-specific enzyme therapy, resulting in the continued usage of these therapies.

• Bromelain is one of the most popular enzymes used in enzyme therapy. Bromelain is classified as an herb and contains a photolytic digestive enzyme that comes from the stem and the fruit of the pineapple plant. When taken with meals, bromelain may aid in the digestion of proteins. When taken on an empty stomach, it may act as an anti-inflammatory agent.

• Trypsin, a proteolytic enzyme, is also used in enzyme therapy. When taken orally, it is often used for digestive enzyme supplementation, often in combination with lipase and amylase. It has also been combined with bromelain and rutin to treat osteoarthritis. Trypsin may be used topically to remove necrotic tissue and debris during wound and ulcer cleaning. Trypsin supplements are derived from fungi or bacterial sources, pancreas of livestock or from plant sources. It may be used to remove dead tissue cells that remain after trauma, infection or surgical procedures. This removal allows new skin or tissue cells to grow.

• Chymotrypsin has been used orally to reduce inflammation and edema (swelling) associated with abscesses, ulcers, surgery or trauma. This enzyme is also used as an expectorant in asthma and other pulmonary diseases, and in reducing liver stress. Topically, it is used for inflammatory and infectious disorders. It can also be used as an inhalant, intramuscular injection or opthalmically. It has ingredients that are proteolytic, anti-inflammatory and antioxidant, which are all thought to reduce tissue destruction.

• Pancreatic enzymes were reportedly first used to treat cancer in 1902 by John Beard, a Scottish scientist. In the 1920s, Dr. Edward Howell introduced enzyme therapy to the United States. Howell believed that by eating raw meat, people created an enzyme surplus, which resulted in better health and increased resistance to disease. German researchers later used enzyme therapy to treat patients with multiple sclerosis, cancer and viral infections. Some enzyme mixtures are still commonly used in several European countries.

• Enzyme therapy is a subject of debate in the medical community, as many physicians and other health practitioners do not accept it. There is little or no scientific evidence that enzyme supplements are successful in treating certain diseases, such as cancer. Because enzyme therapies are promoted as dietary supplements (and not as drugs), manufacturers can market them in the United States without proving they are effective, or even safe, as long as they do not claim they can prevent, treat or cure a specific disease. This leads many physicians to believe that enzyme therapy may be an unsafe treatment for patients. Experts question whether enzymes taken as oral supplements can even reach tumors, or other sites of action, through the bloodstream because they are often broken down into amino acids before being absorbed in the digestive tract. Further well-controlled trials are needed to draw any firm recommendations.

Technique

• The technique with which enzyme therapy is administered varies depending on the condition that is being treated. For example, if the enzyme therapy is being used for an enzyme deficiency, generally only the deficient enzyme will be replaced by either oral or intravenous administration of that particular enzyme. If the therapy is being used for debridement of a wound, the enzyme will be applied topically.

• Enzyme supplements are available in pills, capsules, and powders. Supplements often consist of combinations of several different enzymes. Large amounts of supplements are often taken each day. There is currently no established safe or effective dose.

• Patients using enzyme treatment for cancer therapy often take very large doses of multiple enzymes along with vitamin and mineral supplements. The enzymes are generally taken by pill form, and the exact number depends on the individual patient's condition.

• Most pancreatic enzyme preparations that are administered today are porcine (from pigs) in origin and must meet certain standards of quality for human consumption. The quantity of enzymes to be administered depends on the amount of active lipase in the duodenum. An appropriate diet is also important for relieving symptoms of pancreatic insufficiency and improving nutritional status. Patients with chronic pancreatitis display considerable individual variation in their treatment requirements.

Theory/Evidence

• Combinations of hydrolytic enzymes, those that break down a substance using water, have been used in the treatment of a variety of diseases for a long time. Their pharmacology, however, is being recognized only in the last few decades. The following pharmacological effects of combinations of oral hydrolytic enzymes have been reviewed: fibrinolytic (breaks down a certain protein), hemorheologic (changes properties of blood flow), anti-edematous (anti-swelling), anti-inflammatory and immune stimulating. These pharmacological effects are classified on four levels: biochemical, physiological, medical, and immunological. A spectrum of indications of enzyme therapy has been inferred based on the pharmacological effects, including inflammations, traumatological events, surgical interventions, autoimmune and immune complex diseases, rheumatological diseases, viral infections and malignant tumors.

• Despite the success of enzyme therapy for certain conditions, treatment may be limited by the cost of the agent. This makes it important to determine the lowest effective initial and maintenance doses of the enzyme preparation, to define the appropriate clinical indications for treatment, and to establish uniform methods to optimize outcome assessment. The value of treatment for asymptomatic individuals has not been determined. General population screening for affected individuals and for carriers is not appropriate at this time. As a prototype for all rare diseases, the plight of patients with Gaucher disease raises difficult financial and ethical issues.

• Numerous clinical studies have been initiated since the 1960s by the leading producer of enzyme preparations in Germany in hopes to provide the previously missing scientific confirmation. Studies have shown that neither the mechanism of action could be demonstrated, nor the clinical benefit of non-specific enzyme therapy proven on an acceptable level of scientific standards.

• Bromelain: Several preliminary studies suggest that when taken by mouth, bromelain may reduce inflammation or pain caused by inflammation, although better quality studies are needed to confirm these results. It is proposed that bromelain may be a useful addition to other therapies used for sinusitis (such as antibiotics) due to its ability to reduce inflammation and swelling. Studies report mixed results, although overall bromelain appears to be beneficial for reducing swelling and improving breathing in patients with sinusitis. A bromelain-derived debriding agent, Debridase®, has been studied on deep second degree and third degree burns with positive results, but further results are needed to confirm these preliminary results. Moreover, there is not enough information to recommend the use of bromelain in the treatment of cancer, either alone or in addition to other therapies. Although bromelain is an enzyme with the ability to digest proteins, there is little reliable scientific research on whether bromelain is helpful as a digestive aid.

• Pancreatic enzyme therapy: The theory behind pancreatic enzyme therapy is to restore normal gastrointestinal physiology as completely as possible by supplementing deficient pancreatic enzymes. Pancreatic enzyme therapy such as the prescription product Pancrease®, is commonly used to treat pain associated with chronic pancreatitis. However, some studies have found no significant benefit of the therapy to relieve pain associated with chronic pancreatitis. Scientific research suggests that chronic pain may be reduced with other forms of alternative medicine. For example, bromelain, hypnosis and therapeutic touch have been proven to effectively treat symptoms of pain. Although administration of large amounts of proteases as enzyme therapy has provided pain relief in some pancreatitis patients, the rationale for using enzymes to relieve pain in chronic pancreatitis has not been generally accepted. Administered enzymes may be destroyed by gastric acid, resulting in malabsorption of the enzymes. Also, acidic conditions in the duodenum decrease the efficacy of pancreatic enzymes administered with meals. Histamine-H2-receptor antagonists may decrease gastric acidity but there are certain drawbacks to long-term use of these agents. The use of enteric-coated microspheres overcomes many of the problems associated with enzyme destruction. Patients with chronic pancreatitis display considerable individual variation in their treatment requirements. Therapy must be tailored to meet the need for adequate disease control as well as for social and emotional acceptability by the patient. The attending physician and the patient share the responsibility for maintaining appropriate therapy.

• Fabry's disease: Fabry's disease (also known as Anderson-Fabry disease, Angiokeratoma corporis diffusum, and ceramide trihexosidosis) is a rare, X-linked inherited lysosomal storage disease. A deficiency of the enzyme alpha galactosidase causes a glycolipid (ceramide trihexoside) to accumulate in blood vessels and other tissues and organs, impairing their function. Some of the pathological symptoms include skin lesions, episodes of fever and burning in the extremities. The skin lesions present as painless, elevated bumps that appear all over the body. Ocular involvement may also be present. The disease, if untreated, results in death in early adulthood, usually due to renal failure because of proteinuria (protein in the urine) induced hypertension. Enzyme replacement using agalsidase alpha (Replagal®) and agalsidase beta (Fabrazyme®), is now used to treat this disease, but remains problematic due to the cost (about $170,000/year/patient).

• Gaucher disease: Gaucher disease is a common lipid storage disorder caused by a deficiency of the enzyme glucocerebrosidase, leading to an accumulation of its substrate, a fatty substance called glucocerebroside. Symptoms may include enlarged spleen and liver, liver malfunction, skeletal disorders and bone lesions that may cause pain, severe neurological complications, swelling of lymph nodes and occasionally adjacent joints, distended abdomen, a brownish tint to the skin, anemia (low iron), low blood platelets and yellow fatty deposits on the white of the eye (sclera). Enzyme replacement treatment with recombinant glucocerebrosidase enzyme, 60 units/kg, has been given intravenously every two weeks to decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations of the disease.

• Lysosomal storage disorders: Enzyme replacement therapy for the lysosomal storage disorders derives its momentum from the successes achieved in the treatment of Gaucher disease. The development of enzyme replacement therapy for Gaucher disease may possibly be applicable to other lysosomal storage diseases.

• Lymphatic edema: A study evaluating the contribution of proteolytic enzymes used in the treatment of the lymphatic edema (swelling) of the arm after mastectomy and radiotherapy for breast cancer showed that proteolytic enzymes were successfully administered in monotherapy of lymphatic edema as well as supportive therapy.

• Herpes zoster: Herpes zoster is an acute, localized infection that requires an effective, inexpensive form of treatment not only because it impairs quality of life, but also on account of its relatively high incidence and the resulting costs incurred. Given the present situation in the health care sector, the high costs of treatment with the standard drug, acyclovir, often mean that herpes zoster patients do not receive medicinal therapy. In a recent study, over a period of 14 days, two groups of 96 patients each were given acyclovir or an enzyme combination preparation. During the course of the study, the intensity of segmental pain and various skin lesions were investigated. Overall, the enzyme combination preparation showed identical efficacy with acyclovir. Further investigations on the immunomodulatory potency, dosage and effects on pain due to herpes zoster are still required.

• Tumors: The clinical responses to the enzyme L-asparaginase led to renewed interest in other enzymes that might be effective antitumor agents. Biochemical and nutritional studies on animal and human tumors have shown that enzymatic depletion of glutamine, arginine, cysteine, citrulline, and serine could have selective cytotoxicity for some tumors. Several glutaminase-asparaginase enzymes may have antitumor activity in animals and man. These enzymes are currently in phase I trials, and the exact type of tumors they work on is yet to be determined. Arginine-depleting enzymes with suitable properties of therapy have been developed and are in preclinical study. Based on the available research, no enzyme has been found that can adequately deplete circulating levels of cysteine, citrulline, or serine for treatment of cancer

• Wound debridement: Enzyme therapy, the application of microbial proteases in particular, is one way of removing necrotic tissues from purulent, or discharging, wounds. The use of proteolytic enzymes combined with the methods of early closure of granulated wounds considerably may reduce the terms of treatment of patients with purulent wounds.

Dosing/Interactions

• A health professional should always be consulted before starting enzyme therapy. Enzyme therapy may have harmful interactions with other drugs or supplements.

• Bromelain: Interactions have been noted with some antibiotics, blood pressure drugs, anti-cancer drugs, drugs that increase the risk of bleeding (like aspirin, anticoagulants or warfarin (Coumadin®)), anti-platelet drugs (like clopidogrel (Plavix®)), antidepressants, alcohol, non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen (Motrin® or Advil®) or naproxen (Naprosyn® or Aleve®), narcotics (like codeine), potato protein, soybeans, and herbs or supplements with similar effects.

• Human studies suggest that bromelain may increase the absorption of some antibiotics, notably amoxicillin and tetracycline, and increase levels of these drugs in the body. Bromelain may increase the actions of the chemotherapy (anti-cancer) drugs 5-fluorouracil and vincristine, although reliable scientific research in this area is lacking. In theory, use of bromelain with blood pressure medications in the "ACE inhibitor" class such as captopril (Capoten®) or lisinopril (Zestril®) may cause larger drops in blood pressure than expected.

• A typical dose for adults (18 years and older) is 80-1000 milligram tablets up to three times daily. Dosing for children is not determined. There is not enough scientific research to recommend safe use of bromelain in children.

• Some experts suggest that bromelain may cause drowsiness or sedation, and may increase the amount of drowsiness caused by some drugs. Examples include benzodiazepines such as lorazepam (Ativan®) or diazepam (Valium®), barbiturates such as phenobarbital, narcotics such as codeine, some antidepressants, and alcohol. Caution is advised while driving or operating machinery.

• Trypsin: According to current available literature, there are no well-documented interactions. However, this does not mean there are no associated risks. Oral dosage in the combination product Phlogenzym®, which contains rutin 100mg, trypsin 48mg, and bromelain 90mg, has been given as two tablets three times daily for osteoarthritis.

• Chymotrypsin: This enzyme is contraindicated in ocular surgery cases involving congenital cataracts, high vitreous pressure and a gaping incisional wound, or if the patient is twenty years old or younger. Oral dosages in a 6:1 ratio (trypsin: chymostrypsin) in a combined amount of 100,000 units USP four times daily has been used to treat inflammation, edema, and respiratory secretions. The same ratio of 200,000 units USP has been used four times daily for ten days to treat burns.

Safety

• There is very little information available on the safety of enzyme supplements. A physician or other health care professional should be consulted before beginning a new therapy.

• As with all therapies, one should consider possible allergies to the ingredients in the enzyme preparation. Also take caution while pregnant or breastfeeding as most enzyme therapies have little data regarding their usage during these times.

• A case report has shown that a 54 year-old female patient treated for multiple sclerosis with enzyme therapy by a homeopathic physician developed circulatory shock immediately following an injection during the third course of treatment. Other symptoms included tightness, light-headedness and dry mouth. She recovered successfully in hospital.

• Bromelain: Side effects may include abnormal uterine bleeding, diarrhea, difficulty breathing, drowsiness, increased heart rate, increased risk of bleeding, irritation of mucus membranes, menstrual problems, nausea, throat swelling, sedation, stomach upset and vomiting. There are multiple reports of allergic and asthmatic reactions to bromelain products, including throat swelling and difficulty breathing. Allergic reactions to bromelain may occur in individuals allergic to pineapples or other members of the Bromeliaceae family, and in people who are sensitive or allergic to honeybee venom, latex, birch pollen, carrot, celery, fennel, cypress pollen, grass pollen, papain, rye flour, or wheat flour. Few serious side effects have been reported with the use of bromelain at daily doses up to ten grams for each kilogram (2.2 pounds) of body weight. The most common side effects reported are stomach upset and diarrhea.

• In theory, bromelain may increase the risk of bleeding. Caution is advised in people who have bleeding disorders or who are taking drugs that increase the risk of bleeding. Dosing adjustments may be necessary. Bromelain should be used with caution in people with stomach ulcers, active bleeding, a history of bleeding, taking medications that thin the blood, or prior to some dental or surgical procedures. Bromelain may cause heavy/prolonged menstruation.

• Bromelain may increase heart rate at higher doses, and should be used cautiously in people with heart disease. Some experts warn against bromelain use by people with liver or kidney disease, although there is limited scientific information in these areas. Bromelain is not recommended during pregnancy or breastfeeding, as little safety information is available.

• Trypsin: Avoid using trypsin during pregnancy and breastfeeding as there is insufficient available information regarding safety. Adverse reactions of trypsin may include localized pain and transient burning.

• Chymotrypsin: Oral side effects may include anaphylactic reaction characterized by dyspnea, edema, loss of consciousness and death. If hypersensitivity is suspected, a sensitivity test should be given before administration. Chymotrypsin may also lead to increased intraocular pressure and corneal edema in the eye.

Author Information

• This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography

Natural Standard developed the above evidence-based information based on a thorough systematic review of the available scientific articles. For comprehensive information about alternative and complementary therapies on the professional level, go to www.naturalstandard.com. Selected references are listed below.

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