Boron for Better Teeth, Bones, Thyroid and Parathyroid

“It has been suggested that boron is to the parathyroids what iodine is to the thyroid gland.”

~ Content Source

Boron is a mineral or trace element that is found in food and the environment. It has an atomic weight of 10.81 and symbol B. 

Boron is a tough element, very hard, second only to carbon (diamond).

Boron is an essential nutrient for all green plants and is present in all plants and unprocessed foods.

Boron compounds such as borax (sodium tetraborate, Na2B4O7.10H2O) have been known and used by ancient cultures for thousands of years. Borax is a white powder consisting of soft colourless crystals that dissolve easily in water. The name ‘borax’ is derived from the Arabic buraq, meaning white. 

Boron is an indispensable element in NIB (Neodymium-Iron-Boron) magnets, invented in the early 1980s, which are used in computers, mobile (cell) phones etc.

Health Effects of Boron

Borax and boric acid have basically the same health effects with good antiseptic, antifungal and antiviral properties, but only mild antibacterial action.

Boron is essential for the integrity and function of cell walls and for the way signals are transmitted across membranes. It is distributed throughout the body with the highest concentration in the parathyroid glands followed by bones and dental enamel. It is essential for healthy bone and joint function, regulating the absorption and metabolism of calcium, magnesium and phosphorus through its influence on the parathyroid glands. It has been suggested that boron is to the parathyroids what iodine is to the thyroid gland.

The parathyroid glands are small endocrine glands in the neck that produce parathyroid hormone. Humans usually have four parathyroid glands which are located on the rear surface of the thyroid gland. The parathyroid glands control the amount of calcium in the blood and within the bones. The main function is to maintain the body’s calcium levels within a very narrow range, so that the nervous and muscular systems can function properly. Parathyroid hormone controls calcium and phosphate homeostasis, as well as bone physiology.

Boron deficiency causes the parathyroid glands to become overactive, releasing too much parathyroid hormone which raises the blood levels of calcium by releasing calcium from bones and teeth. This then leads to arthritis, osteoporosis and tooth decay.

Boron also affects the metabolism of steroid hormones, and especially the metabolism of sex hormones. It increases low testosterone levels in men and oestrogen levels in menopausal women. It also has a role in converting vitamin D to its active form, thus increasing calcium uptake and deposition into bone. It is also said to improve thinking skills and muscular coordination.

Dietary Sources of Boron

Boron occurs in various forms in fruits (especially dried), vegetables, legumes and nuts. The actual amount varies, linked to the soil content of boron. The amount of boron is rather low, so that it is relatively easy to develop deficiency of boron. Foods with the highest content of boron (from www.algaecal.com/boron) include:

   
Food Boron (mg/100g)
   
Almond 2.82
Apricots (dried) 2.11
Avocado 2.06
Beans (red kidney) 1.40
Brazil Nuts 1.72
Cashew Nuts 1.15
Chick Peas 0.71
Dates 1.08
Hazel Nuts 2.77
Lentils 0.74
Prunes 1.18
Raisins 4.51
Walnut 1.63

Boron and Bone Health

Boron plays an important part in supporting healthy bones since it is involved with calcium and magnesium metabolism and vitamin D.

In a study of postmenopausal women, a boron-deficient diet was consumed for 119 days, followed by 48 days of boron supplementation. On the boron-depleted diet (0.25mg boron/day), the participants demonstrated increased urinary loss of both calcium and magnesium. On the boron-supplemented diet (3mg boron/day) however, they showed less urinary excretion of calcium and magnesium, as well as increased levels of two hormones associated with healthy bone mass.

From this study, adequate boron intake is essential to preserve the body’s stores of bone-building calcium and magnesium.

The researchers also studied the women during periods of both adequate magnesium intake and magnesium deficiency. Boron helped to preserve the essential stores of calcium and magnesium in the body. While the magnesium-depleted diet was associated with an increased loss of calcium in the urine, boron supplementation significantly reduced urinary loss of both calcium and magnesium. The researchers observed that boron deprivation produced changes similar to those seen in osteoporosis, and adequate boron status helped prevent calcium loss and bone demineralisation in postmenopausal women.

(Nielsen, F.H et al. Journal of Federation of American Societies for Experimental Biology (FASEB-J) 1987 Nov:1(5):394-7)

Thus boron has important applications in helping women preserve bone mass and in preventing osteoporosis following menopause.

Boron may help to alleviate the detrimental effects of vitamin D deficiency on calcium metabolism. Vitamin D is crucial to bone health because it helps to support calcium absorption.

People in an environment that is boron rich and who consume boron-rich foods have been shown to have less joint disorders. It is suggested that deficiencies of boron could contribute to the development of osteoarthritis.

Dosage of Boron

Ideally, boron should be obtained from the foods listed above.

If taken as a supplement, 3mg-6 mg of boron daily is recommended for bone health. A higher dose, up to 9mg per day, is suggested in the management of osteoarthritis. Commercial supplies generally come in 3 mg capsules (eg those from iherb.com).

Boron is often combined with a calcium supplement.

The following is an economical way of obtaining a therapeutic source of boron:

Dissolve a teaspoonful of borax (5-6 grams) in one litre of water. This is your stock solution. A standard dose is one teaspoonful (5ml) of stock solution. This contains 25-30mg of borax and provides about 3mg of boron. Take one dose daily with drink or food.

Up to 10mg of boron daily is considered safe. Toxic effects appear at an intake of about 100mg. My personal regimen contains about 165mg of boron per day with no toxic effects. However I did build up to that slowly over a 6 month period.

*Copyright 2012: The Huntly Centre.

Disclaimer: All material in the huntlycentre.com.au website is provided for informational or educational purposes only. Consult a health professional regarding the applicability of any opinions or recommendations expressed herein, with respect to your symptoms or medical condition.

~Further Reading – Nothing Boring About Boron

Study Finds New Iodine Mouthwash May Impact LDL Cholesterol

~ Content Source

SAN ANTONIO–(BUSINESS WIRE)–Cleaning your mouth and cleaning your arteries could be as simple as a once-a-day oral rinse if additional studies confirm preliminary findings about a new product.

“We didn’t expect to see any difference in LDL cholesterol”

Biomedical Development Corporation (BDC) on April 23 will present data to the American Academy of Oral Medicine showing that its oral rinse was safe and effective at fighting gingivitis in a recent clinical trial.  But the most surprising finding of the study was that users of the oral rinse showed significantly lower LDL cholesterol levels than the placebo group.

“We didn’t expect to see any difference in LDL cholesterol,” said Dr. Charles Gauntt, the study’s principal investigator. “We expected to see improvements in oral health, and we did.  But we also monitored a number of biological markers for inflammation. The results showed the oral rinse had no adverse effects and users exhibited lower levels of LDL, or what many people know as bad cholesterol.  This definitely merits further study.”

The three-month, phase II trial was funded by the National Heart, Lung and Blood Institute (NHLBI).  The trial was preceded by a phase I clinical trial for safety and a phase II pilot efficacy clinical trial.  Another, longer phase II trial is now under way and will evaluate gingivitis patients over a six-month period.  This new trial, conducted by the Center for Oral Health Research at the University of Kentucky, will monitor gingivitis and LDL cholesterol levels as the previous trial did.  The NHLBI is funding the research, which is also supported by the Kentucky SBIR/STTR Matching Funds Program.

BDC’s product is designed as a once-daily, 30-second oral rinse.  The active ingredient is a proprietary formula based on iodine.  The National Institutes of Health Office of Dietary Supplements fact sheet on iodine addresses a variety of important roles for iodine in the human body, from helping the thyroid function properly to appearing to play a part in the body’s immune response system.  About 40 percent of the world’s population is thought to be at risk of iodine deficiency.

Gauntt also notes that iodine is known to be effective in inactivating viruses, bacteria and funguses. He is intrigued by recent clinical studies showing what appears to be a closer link between oral health and cardiovascular health. Although scientists cannot yet fully explain how the two are connected, there is ample statistical evidence to suggest that gum disease and heart disease are closely related.  According to the American Academy of Periodontology, people with periodontal disease (gum disease) are almost twice as likely to have coronary artery disease.  The academy also notes that one study showed stroke victims were more likely than the general population to also have oral infections.

Gauntt believes that future research might make it much clearer that a healthy mouth, free of gum disease and its associated toxins and bacteria, is critical to a healthy cardiovascular system.  Although further study is required, he adds, he believes BDC’s oral rinse may eventually prove to be an important tool in keeping both mouths and cardiovascular systems healthy, in addition to proper nutrition and exercise.

Phyllis Siegel, CEO of BDC, said that while results of its ongoing clinical trials are pending, a specific formulation of the product called iCLEAN®, designed for general mouth cleaning, will soon be available. For more information, visit www.iCLEANmouths.com.

Lugol’s solution and other iodide preparations: perspectives and research directions in Graves’ disease

~ Content Source

Abstract

Lugol’s solution and other preparations containing iodide have for almost a century been used as an adjuvant treatment in patients with Graves’ disease planned for thyroidectomy. Iodide has been shown to decrease thyroid hormone levels and reduce blood flow within the thyroid gland. An escape phenomenon has been feared as the iodide effect has been claimed to only be temporary. Lugol’s solution has many additional effects and is used in other settings beside the thyroid. Still, there are questions of its mode of action, which doses should be deployed, if it should be used preoperative in all thyroidectomies or only in a few selected ones if at all, what is its use in other forms of thyrotoxicosis besides Graves’ disease, and what is the mechanism acting on the vasculature and if these effects are confined only to arterial vessels supporting the thyroid or not. This review aims to collate current available data about Lugol’s solution and other iodide preparations in the management of Graves’ disease and give some suggestions where more research is needed.

Keywords: Hyperthyroidism, Thyroidectomy, Iodide, Adjuvant treatment, Escape

Introduction

Lugol’s solution (LS) was developed 1829 by the French physician Jean Guillaume August Lugol, initially as a cure for tuberculosis. It is a solution of elemental iodine (5%) and potassium iodide (KI, 10%) together with distilled water. It has been used as a disinfectant, a reagent for starch detection in organic compounds, in histologic preparations, in dental procedures and in diagnosis of cervical cell alterations, the Schiller´s test (Table 1). Already in the 1920s LS was given as a pre-treatment to thyroid surgery []. By that time LS became the standard pre-operative treatment in patients with Graves’ disease (GD). Iodide treatment could also be given as a saturated solution of potassium iodide (SSKI) or tablets. Radiopaque cholecystographic agents such as iopanic acid containing iodide has also been used previously, although nowadays their use is restricted []. These agents are also potent inhibitors of type 1 and type 2 deiodinases, blocking the conversion of T4 to T3 and rT3 to T2 [].

Table 1

Examples of usage of Lugol’s solution and other iodine preparations

Graves’ disease
Disinfectant
Sterilisation
Foot ulcers
Dental procedures
Histopathology
 Schiller´s test
Water purification
Radiation emergency
Iodine deficiency/ cretinism
Protection from goiter

Iodide is the ion state of iodine which is the result when elemental iodine (which is corrosive) binds to e.g. potassium and in this state can be more easily consumed or applied topically. However, often the terms iodide and iodine are used interchangeably. With the development of pharmacologic agents such as antithyroid drugs and with radioiodine therapy, LS is not routine anymore in many countries [], although it is still advocated in current American Thyroid Association guidelines [], although this has recently been challenged [].

GD is a common autoimmune disease, with typical symptoms as weight loss, heat intolerance, tachycardia and mental disturbances as tiredness and restlessness. There is a female preponderance (4:1 in a first episode of hyperthyroidism) with a peak incidence at 40–69 years []. Antithyroid drugs are often chosen since these are mostly well-tolerated, and can induce cure in around 50% after 12–18 months of treatment []. These pharmacologic compounds, propylthiouracil, methimazole or carbimazole, block the thyroid hormone synthesis by inhibiting thyroid peroxidase. In cases of large goiters, intolerance to medication or recurrent disease, surgery or radioiodine treatment could be alternative treatment. Radioiodine therapy, inducing life-long hypothyroidism, has been the preferred first option in most US centers [], while in European centers antithyroid drugs are preferred []. Surgery is often a secondary option performed with subtotal (<2 g), near total or total thyroidectomy to minimize the risk of recurrence. To diminish the risk of vascular complications hyperthyroidism should be pre-treated before operation []. This could be by beta-blockers alone, or together with antithyroid drugs, with or without adding LS. Moreover, LS could also be used when there is a need to control GD promptly to avoid serious consequences [].

The aims of this review are to provide a summary of currently available knowledge of LS including other iodide preparations in the treatment of GD and give some suggestions in areas where more research is needed.

Iodide effects in healthy man and in rats

Iodide (I) is essential for the synthesis of thyroid hormones, T4 and T3. The primary source is food, often salt fortified with iodine. The recommended daily intake is 150 μg in adults, with a preferred increase in pregnant and lactating females []. Iodide is transported across the basement membrane by the Na+/I transporter where it is rapidly oxidized by H2O2 to iodine, catalyzed by thyroid peroxidase and is then incorporated into thyroglobulin. In healthy humans who are not predisposed to thyrotoxicosis, increased thyroid hormone synthesis can be induced by high doses of iodine such as iodine containing contrast agents, and after a long-time use of antiseptics such as povidone–iodine swabs [], in dietary supplements as kelp, and secondary to iodine containing medications such as amiodarone. Radiographic contrast media and amiodarone can contain much more iodine than daily requirements, 75 mg and 320–370 mg, respectively. The thyroid had been estimated to tolerate up to 1100 μg/iodine/day []. By an iodide overload hyperthyroidism could ensue as a consequence [], the Jod-Basedow effect, which is more frequent in iodine deficient areas, and in patients with multinodular goiter. Iodine excess can also lead to other untoward thyroid complications, such as iodide goiter, iodide-induced hypothyroidism, and iodide-induced subacute thyroiditis []. These pathologic consequences will disappear when iodine is withdrawn []. Symptom relief from iodine induced thyrotoxicosis can be achieved with beta-blockers and in severe cases with high doses of antithyroid drugs [].

Mechanisms of iodide on the thyroid gland and the escape phenomenon

In the short term LS reduces the thyroid hormones, T4 and T3 by increasing iodine uptake and inhibiting the enzyme thyroid peroxidase [], thus attenuating oxidation and organification of thyroid hormones []. Moreover, the release of thyroid hormones is also blocked []. The mechanism could partly be explained by activation of substances as iodolactones and iodoaldehydes as these have been shown to inhibit nicotinamide adenine, dinucleotide phosphate oxidase, thyroid peroxidase, and TSH-induced cyclic adenosine monophosphate (cAMP) formation in the thyroid [].

Wolff-Chaikoff is the effect of iodide in normal mice which lead to an increase of intrathyroidal iodine concentration within 24–48 h and a subsequent decrease of thyroid hormone synthesis []. In healthy subjects there is an adaption to iodine excess by an autoregulatory mechanism within the thyroid, which serves as a defense against fluctuations in the supply of iodine and permits escape from the paradoxical inhibition of hormone synthesis that a very large quantity of iodine induces. Defective or absent autoregulation can occur in predisposed patients, as in those with euthyroid Hashimoto’s thyroiditis and in GD-patients treated with radioiodine or subtotal thyroidectomy []. Thus, these are more prone to develop hypothyroidism secondary to an iodine overload. Hyperthyroidism more commonly occurrs in iodine deficent subjects, and in patients with multinodular goiter.

The escape from acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter causing a reduction in intrathyroidal iodide concentration []. There is also a form of escape following iodide therapy in GD which has been described as common []. Thus, in treating patients with hyperthyroidism with LS an exacerbation of thyroid hormone levels could be a consequence after a period of blocking the thyroid, as the gland has become loaded of iodine substrate for hormone synthesis [].

However, in the investigation by Takata et al. a combination of iodide solution was used together with methimazole for up to 8 weeks []. Iodide was discontinued when patients showed normal free T4. Eleven patients (25%) escaped from the Wolff-Chaikoff effect, and 3 derived no benefit at all. Moreover, in another study including patients with mild GD who received primary treatment with LS (50–100 mg daily), control of hyperthyroidism after 12 months was comparable with that seen in patients receiving low-dose methimazole treatment []. How often and how early escape occurs is not clear, but in an observational study from Japan long-term treatment with LS alone or in combination with antithyroid drugs has been used, with 29/44 (66%) being well-controlled on 100 mg LS daily alone for 7 years []. In another study of 21 patients with hyperthyroidism given iodide daily, hormone levels started to increase again after 3 weeks in some, but others remained euthyroid even after 6 weeks []. Reactivation of thyrotoxicosis could to some extent be explained by a stimulation of the immune system as elevation of TSH receptor antibodies has been noted in euthyroid patients preoperatively with 60 mg iodide twice daily for 10 days []. However, in long-term treatment with iodide these antibodies has been reported to decline [].

Vascular effects

Plummer observed a 75% decrease in mortality associated with thyroidectomy when LS was introduced []. At that time metabolic rate decreased as well as symptoms. As a complement to effect on T4 and T3 reductions vascular effects has been of interest and already in 1925 intrathyroid blood vessel compression was described after LS therapy []. Reduced blood flow has since then been described as an effect of LS in GD patients with different methods. In 9 subjects with GD uptake of thallium was decreased with a third after 10 days of LS (0.5 ml tds) [], and the authors speculated that this could be a result of decreased perfusion, as the amount of colloid had increased. A reduction in vascularity measured with 99mTC-pertechnetate after LS has also been shown []. In a number of investigations of euthyroid individuals with GD LS has reported to decrease the rate of blood flow, thyroid vascularity, and intraoperative blood loss during thyroidectomy [].

In a recent randomized control trial in patients receiving LS median blood losses (50 vs. 140 mL), and operative times (138 vs. 150 min), were also significantly less compared to controls []. The reduced blood loss is associated with both a 60% reduction in systemic angiogenic factor (VEGF) and with 50% of interleukin-16 []. If other angiogenic mediators also are involved is unknown. Furthermore, microvessel density, calculated with ultrasound, displayed decreased blood flow after 10 days of 10 drops iodide (74.7 vs. 54.4, mL/min), decreased blood loss (128.6 vs. 108.7 mL) and less expression of CD34 measured with immunohistochemistry []. On the other hand, another study demonstrated no difference in blood loss or time of surgical procedure comparing 13 patients on iodide vs. 24 on antithyroid drugs [].

Treatment with LS

LS tastes bitter and is also corrosive, and this should be disguised by taking it with a sweet drink such as apple juice. The applied doses come from experience rather than by prospective randomized controlled trials (Table 2). Historically Plummer used 80–320 mg iodide daily and this was established as a pre-treatment before thyroidectomy in GD []. However, the efficacy of much smaller doses has also been investigated in the late 1920s to 1960, also in long-term treatment. Thomson et al. found that 6 mg daily iodine induced euthyroidism in most patients [], and as low doses as 1 mg has also been effective []. Reports on escape and the development of antithyroid drugs and radioactive therapy then discouraged physicians from this route of treatment.

Table 2

Examples of different applied doses of iodide and preparations in treatment of Graves’ disease in different publications

Publication Lugol’s solution 5–8 mg/drop SSKI 50 mg/drop Tablet KI Iodide mg/day Treatment duration Number of patients with iodide
Plummer [] 10 drops od to qid 80–320 10 days 600
Feek 1980 [] 60 mg tds ? 10 days 10
Roti 1988 [] 6 drops bd 456 10 days 8
Kaur 1988 [] 0.4 ml tds 15 10 days 24
Tan 1989 [] 0.5 ml daily 50 10 days 10
Philippou 1992 [] 10 drops tds 114 3–7 weeks 21
Erbil 2007 [] 10 drops tds 114 10 days 17
Takata 2010 [] 50 mg daily 38.2 4.9 ± 3.8 weeks 32
6.2 ± 3.1 weeksa 37
Uchida 2014 [] 50–100 mg daily 35–75 1 year 30
Okamura 2014 [] 50 mg daily 10–800 Years 44
Sato 2015 [] 50 mg daily 38.2 up to 90 days 161
Yilmaz 2016 [] 0.8 mg/kg 56b 10 days 20
Fischli 2016 [] 13 drops tds 243.75 10–14 days 10
Calissendorff 2017 [] 5 drops tds 100.5 7–10 days 27
Ross 2016 [] 5–7 drops tds 40–56 10 days
(ATA Guidelines) 1–2 drops tds 50–100

SSKI saturated solution of potassium iodide

a With addition of 30 or 15 mg methimazole daily, longer iodide treatment in the group receiving low dose methimazole

b Dose in a 70 kg man

Takata et al. demonstrated that normalisation of free T4 was more rapid with a combination of LS and antithyroid drugs, than methimazole alone, however, remission did not differ during a 4–5 year follow-up []. In another Japanese study the combination also resulted in a higher propotion of normalized thyroid hormones at 30 and 60 days compared to antithyroid drugs alone []. In both these investigations iodide was stopped when free T4 had normalized. In the ATA guidelines 5–7 drops thrice daily of LS or 1–2 drops of SSKI (50–100 mg iodide) 10 days before thyroidectomy is recommended. SSKI contain 1 g of potassium iodide per ml. An iodide dose of 5 drops LS thrice daily is equivalent to 100.5 mg iodide daily []. Yilmaz et al. used twice as high dose in their study []. Other doses of iodide have also been applied such as 150 or 375 mg daily [], all with good effect in reducing free T4 and free T3. Lower doses as 50 mg KI have also been applied (equivalent to 38.2 mg of iodide) []. In long-term treatment 10–400 mg iodide has been used, with 40% experienced remission on iodide alone during a follow-up of 17.6 years (range 8.6–28.4) []. Thus, the doses used vary considerably and which dose has the most favourable vascular effects are unknown.

In uncontrolled GD, or if adverse effects of antithyroid drugs develops such as agranulocytosis or liver failure, rescue treatment with LS is one option. Radioactive iodine could also be deployed but the fear of thyroid storm if thyroid function exacerbates by this therapy could make LS followed by thyroidectomy a reasonable choice. We recently demonstrated that LS in this setting was effective and decreased both thyroid hormone levels and heart rate with few side effects []. In a Swiss investigation, patients with high free T4 and free T3 were pretreated before surgery with betablockers, 2 mg dexamethasone (to inhibit peripheral conversion to T3) and 13 drops LS thrice daily (243.75 mg of iodide daily) for 10–14 days, and acquired almost normalization of thyroid hormones [].

Iodide compounds and iodine content

There are several iodide compounds available. Classically LS is prescribed in a dose of 5–10 drops thrice daily with each drop containing 5–8 mg/drop [], or 1–2 drops SSKI, 50 mg/drop thrice daily. Higher doses of SSKI has also been used []. Iodide tablets, if available, containing 60 mg has been given as three times daily []. In Japan, tablets with 50 mg potassium iodide (KI) have been used []. When examining the iodide content in 5% dental solution (iodine and iodide potassium) the iodide content was 6.7 mg/drop equivalent to LS []. Lower doses have been subscribed when long-term treatment is planned, rather than as a pre-operative adjunct [].

Adverse effects

LS and other iodide preparations seem to have low frequency of adverse effects. In doses of 1000 times the normal nutritional need, side effects may include: acne, loss of appetite, or upset stomach. More severe side effects are fever, weakness, unusual tiredness, swelling in the neck or throat, mouth sores, skin rash, nausea, vomiting, stomach pains, irregular heartbeat, numbness or tingling of the hands or feet, or a metallic taste in the mouth. (www.medicinenet.com/potassium_iodide-oral/article.htm Accessed 10 August 2017). In the study by Sato et al. adverse effects with a combination of methimazole 15 mg and inorganic iodine (KI tablets) at dose of 38.2 mg per day were less common than in a group of patients treated with methimazole alone with 30 mg daily []. We found that 15% of our patients treated with LS experienced mild adverse effects, mostly in form of rash []. Okamura et al. studied patients with GD with adverse effects to antithyroid drugs who were switched to KI tablets instead []. The only adverse effects found were a transient increase in TSH receptor antibodies and hypothyroidism in a few patients. However, an anaphylactic-like reaction has been reported when using LS in diagnosis of cervical cell alterations (Schiller’s test) []. Other adverse effects such as iodide-associated sialadenitis (iodide mumps) after iv iodide contrast [], and esophageal ulcers have also been described. Allergic reactions to iodine compounds are possible, and LS treatment in patients with dermatitits herpetiformis should be performed with caution as this is linked to iodine sensitivity (www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM080542.pdf Accessed 10 August 2017).

Future research directions

Most studies on LS therapy have been retrospective and often with few participants. Recently the issues on blood loss and vasculature effects were questioned due to the lack of proper randomized trials []. However, we have here made a comprehensive review of the literature on iodide therapy, doses to be applied, on effects on the vasculature, and on short and long-term treatment, also discussing the escape phenomenon, reviewing limitations and current insights.

There is a need for future prospective investigations with a sufficient number of participants but also randomized control trials as well as in patients with mild vs. severe GD. This would enable us to draw firm conclusions if LS, alone or in combination with antithyroid drugs, do affect operative time, blood loss, and surgical complications such as hypocalcemia and damage of the recurrent laryngeal nerve. The efficacy of long-term treatment with LS needs also to be further explored. It is not proven if the iodine background, ethnicity or other factors make the relatively low number of patients escaping from iodide blocking in Japan a phenomenon which should not be feared to the same extent as it has in the past. To explore this investigations in areas with different iodine backgrounds have to be performed with focus on control of GD, degree of escape from therapy and adverse effects. Adverse events need to be better recorded, both in the short and long-term use of LS therapy. The optimal dose of LS also needs to be clarified. Moreover, the mechanisms of LS, especially on the vasculature are intriguing and merit further research. It is fascinating that almost 200 years since this compound was invented, and 100 years since it became a treatment in GD, we still do not fully understand how the effects on the vasculature are mediated. We also do not know if the vasculature effects in GD are present in other thyroidal diseases such as goiter or multinodular diseases, or in other vascular beds in the body.

Conclusion

LS has been advocated for almost 100 years in the treatment of GD. It has effects in decreasing thyroid hormones, and possibly in reducing blood flow during thyroidectomy. LS is used both in combination with antithyroid drugs preoperatively in planned thyroidectomies in certain centers routinely, and alone as a rescue therapy if severe side effects to antithyroid drugs have occurred. These effects, especially on the vasculature have to explored further, together with investigations on how common there is an escape from LS-blocking, the mechanisms of action, which doses that should be applied, and registration of side effects.

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Consequences of Excess Iodine

~ Content Source

Abstract

Iodine is a micronutrient that is essential for the production of thyroid hormones. The primary source of iodine is the diet via consumption of foods that have been fortified with iodine, including salt, dairy products and bread, or that are naturally abundant in the micronutrient, such as seafood. Recommended daily iodine intake is 150 μg in adults who are not pregnant or lactating. Ingestion of iodine or exposure above this threshold is generally well-tolerated. However, in certain susceptible individuals, including those with pre-existing thyroid disease, the elderly, fetuses and neonates, or patients with other risk factors, the risk of developing iodine-induced thyroid dysfunction might be increased. Hypothyroidism or hyperthyroidism as a result of supraphysiologic iodine exposure might be either subclinical or overt, and the source of the excess iodine might not be readily apparent.

Introduction

Iodine (atomic weight 126.9 g per atom) is a micronutrient that is required for the synthesis of the thyroid hormones. It is a trace element in Earth’s upper crust and is found primarily in or near coastal areas. For adults who are not lactating or pregnant, the US Institute of Medicine, and jointly by the WHO, United Nations Children’s Fund (UNICEF) and the International Council for the Control of Iodine Deficiency Disorders (ICCIDD), recommend a daily iodine intake of 150 μg and state a tolerable upper level (the approximate threshold below which notable adverse effects are unlikely to occur in the healthy population) of 1,100 μg per day in adults.,

However, iodine is present in concentrations up to several thousand-fold higher than these amounts in medications, supplements and in the iodinated contrast agents used for radiologic studies (Box 1). In some susceptible individuals, the use of these iodine-containing substances can result in thyroid dysfunction as a result of the high iodine load. In certain circumstances, iodine excess can result in adverse thyroidal effects after only a single exposure to an iodine-rich substance.

Box 1

Sources of iodine exposure and potential excess

Diet

  • Kelp (per g): 16–8,165 μg
  • Bread (per slice): 2.2–587.4 μg
  • Milk (per 8 oz): 88–168 μg
  • Fish fillet (per g, dry weight): 0.73 μg
  • Iodized salt: Variable

Other sources

  • Vitamins (prenatal, labelled content per daily serving): 75–200 μg
  • Amiodarone (per 200 mg): 75,000 μg
  • Iodinated contrast (free iodine content, per CT scan): 13,500 μg
  • Topical iodine (povidone iodine): variable, usually 1–5%
  • Expectorants, mouthwashes, vaginal douches: variable
  • Saturated solution of potassium iodide (per drop): 50,000 μg

Measures of iodine excess

Overall iodine levels cannot be reliably measured in individuals given the considerable day-to-day variation in iodine intake. Instead, median urinary iodine concentrations (UIC) have been widely used as a biomarker of population iodine intake, with levels >300 μg/l considered excessive in children and adults and levels >500 μg/l considered excessive in pregnant women.

In dried blood spots from children, the concentration of thyroglobulin correlates with iodine exposure and could be a novel marker for monitoring population iodine status in this age group. In 2006, the international reference range of 4–40 μg/l for this assay was developed as a measure that indicates iodine sufficiency in children 5–14 years old. This standard has since been adopted and recommended by the WHO, UNICEF and the ICCIDD as a method of assessing iodine nutrition in school-aged children (≥6 years old). One study demonstrated that the mean concentration of thyroglobulin in dried blood spots was statistically significantly higher in healthy children aged 6–12 years in whom the median UIC was >300 μg/l than in those with lower UICs. These findings suggest that levels of thyroglobulin in dried blood spots could be developed as a sensitive marker of iodine excess in this population.

Thyroidal adaptation to excess iodine

The acute Wolff–Chaikoff effect was described in 1948 by Drs Jan Wolff and Israel Lyon Chaikoff at the University of California Berkeley, USA. Wolff and Chaikoff observed a transient reduction (lasting ~24 h) in the synthesis of thyroid hormones in rats exposed to high amounts of iodide administered intraperitoneally. The mechanism for the acute Wolff–Chaikoff effect is not completely understood, but is thought to be at least partially explained by the generation of several inhibitory substances (such as intrathyroidal iodolactones, iodoaldehydes and/or iodolipids) on thyroid peroxidase activity. Reduced intrathyroidal deiodinase activity as a result of the increased iodine load might also contribute to decreased synthesis of thyroid hormones.

In most individuals, the decreased production of thyroid hormones is only transient and resumes after adaptation to the acute Wolff–Chaikoff effect. In rats, this adaptation is associated with a marked decrease in expression of the sodium–iodide symporter (NIS) that is present on the basolateral membrane of thyroid follicular cells. NIS is a 13-transmembrane glycoprotein that mediates the active transport of iodine from the circulation into the thyroid. The decrease in expression of the NIS occurs by 24 h after exposure to excess iodine and results in reduced intrathyroidal iodine concentrations. In turn, the reduced iodine levels lead to a decrease in levels of the iodinated substances that inhibit synthesis of thyroid hormones, which results in the resumption of normal production of thyroid hormone (Figure 1).

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The Wolff–Chaikoff effect. a | The proposed mechanism for the acute Wolff–Chaikoff effect. During initial iodine exposure, excess iodine is transported into the thyroid gland by the sodium–iodide symporter. This transport results in transient inhibition of TPO and a decrease in the synthesis of thyroid hormone. b | The mechanism by which adaptation to the acute Wolff–Chaikoff effect occurs. A decrease in the expression of the sodium–iodide symporter results in reduced iodine transport, which enables the synthesis of thyroid hormone to resume. Abbreviations: DIT, diiodotyrosine; I, iodide; MIT, monoiodotyrosine; TPO, thyroid peroxidase. Permission obtained from Massachusetts Medical Society © Pramyothin, P. et al. N. Engl. J. Med365, 2123–2127 (2011).

In individuals with dysregulation of the thyroid follicular cell, excess iodine exposure can induce thyroid dysfunction, which might be transient or permanent.

Iodine-induced hypothyroidism

Vulnerable patients with specific risk factors might have an increased risk of failing to adapt to the acute Wolff–Chaikoff effect. Susceptible patients include those with autoimmune thyroid disease; a previous history of surgery, 131I or antithyroid drug therapy for Graves disease; subacute thyroiditis; postpartum thyroiditis; type 2 amiodarone-induced thyrotoxicosis (AIT); hemithyroidectomy; IFNα therapy; and concomitant use of potential goitrogens, such as lithium. Failure to escape from the acute Wolff–Chaikoff effect might also be more likely during fetal development, a period when the hypothalamic–pituitary–thyroid axis is still immature, and during neonatal life.

The underlying mechanism of iodine-induced hypothyroidism remains unclear, but could be attributable to failure to adapt to the acute Wolff–Chaikoff effect, probably because of a damaged thyroid as a result of previous pathological insults. Exposure to high concentrations of iodine might also decrease the release of thyroid hormone, as reported in several small studies that show mild decreases in serum levels of thyroid hormone and increases in the serum level of TSH to the upper limit of the normal range. Administration of iodine to patients with severe hyperthyroidism or thyroid storm is efficacious, as it results in an acute decrease in the release of thyroid hormones.

Iodine-induced hyperthyroidism

In some susceptible patients, an excess iodine load provides a rich substrate for increased production of thyroid hormones. Iodine-induced hyperthyroidism (the Jod–Basedow phenomenon) was first described in the early 1800s, when thyrotoxicosis was observed to be more common among patients with endemic goiter treated with iodine supplementation than in individuals without goiter.Iodine-induced hyperthyroidism might be transient or permanent, and risk factors include nontoxic or diffuse nodular goiter, latent Graves disease and long standing iodine deficiency. In addition, iodine-induced hyperthyroidism in euthyroid patients with nodular goiter in iodine-sufficient areas has also been reported when iodine supplementation is excessive.

Sources of iodine excess

Iodine supplementation

Globally, iodine supplementation has been the primary method over the past century to decrease iodine deficiency, which is the leading cause of preventable mental retardation. Iodine has been administrated as iodized oil orally and intramuscularly, introduced into the water supply, used in crop irrigation, incorporated into animal fodder and introduced into food through salt iodization, bread iodophors and other products. Fortified micronutrient biscuits have also been successfully used to raise the median UICs of schoolgirls (aged 10–15 years) in India.

Although iodine supplementation has decreased the number of people at risk of iodine deficiency and its associated sequelae, particularly in the past few decades, the use of iodine has also led to concerns of excessive iodine exposure in some individuals. A study published in 2012 reported that the median UIC (730 μg/l) of the populations of two Somali refugee camps in Kenya who were receiving iodine supplementation were in the range consistent with excessive iodine intake. In a study of >200 Chinese adults, subclinical hypothyroidism was more common in those supplemented with a 400 μg iodine tablet than in those given placebo.These findings are similar to the results of other studies in Denmark and New Zealand, which also showed an increased prevalence of transient hyperthyroidism. The incidence of thyrotoxicosis was increased following periods of mandatory salt iodization, compared with when supplementation was not required, in both Spain and Zimbabwe. Another iodine supplementation programme in Bangladesh has shown no increased risk of thyroid dysfunction.

Iodine supplementation also affects other aspects of thyroid health. For example, high iodine intake seems to increase the prevalence of autoimmune thyroiditis in the Bio Breeding/Worcester rat model and in humans., The number of reported cases of thyroid cancer, particularly papillary thyroid cancer, has also increased following iodine supplementation in some studies, including a nearly 20-year study in northeastern China and a >50-year study in Denmark.

Diet

The diet is the main way of achieving adequate iodine nutrition. Dairy products (due to the use of iodophor cleaners for milk cans and teats), some breads (due to the use of iodate bread conditioners), seaweed and other seafood and iodized salt are the most common iodine-containing foods. In children from the USA aged 6–12 years, dairy intake is a particularly good source of adequate iodine, probably due to the abundance of dairy content in the diet of children in this age range.Australia introduced iodization of bread in 2009, which resulted in a modest increase in the median UIC of a small group of pregnant women. The amount of iodine that can be obtained from plant-based food is minimal and is dependent on the local environment (that is, iodine levels in the soil, groundwater used for irrigation, crop fertilizers and livestock feed).

The many varieties of seaweed are a unique potential source of excess ingestion of iodine. Seaweed is a popular food item in many parts of the world, particularly in Japan and other Asian countries, where ingestion of seaweed soup is common in the everyday diet and is a frequent practice during the postpartum period.However, the iodine content of seaweed can vary widely. Cases of kelp-induced thyrotoxicosis have been widely reported, including one woman who drank kelp-containing tea for 4 weeks and another patient who had a long-standing history of using kelp-containing dietary supplements. In other reports, chronic seaweed ingestion has also been reported to be associated with a modest increase in serum levels of TSH without overt thyroid dysfunction.,

The iodine-rich content of the Japanese diet is unique and demonstrates how chronic exposure to excess iodine could result in several adaptive mechanisms. A 2013 paper reported a case of delayed onset congenital hypothyroidism in an infant with a mutation in the gene that encodes dual oxidase (DUOX2), an enzyme known to be associated with transient congenital hypothyroidism, that was exacerbated by the infant’s mother ingesting large amounts of seaweed during pregnancy. Among Japanese schoolchildren (aged 6–12 years old), high UIC are associated with smaller thyroid glands than are found in children living in other iodine-sufficient areas. A comparison of individuals with negative thyroid antibody titres living in coastal regions versus noncoastal areas of Japan showed that people from areas in which iodine-rich seaweed is abundant have an increased prevalence of hypothyroidism (12.1% versus 2.3%). Finally, a small study in Japan found that consumption of seaweed was positively associated with an increased risk of papillary thyroid cancers in postmenopausal women (HR 1.71, 95% CI 1.01–2.90). The high iodine intake in Japan has probably reduced the adverse effects of the 2011 Fukushima reactor accident on thyroid function and radiation-induced thyroid cancer, as the uptake of radioactive iodine is inversely proportional to the ambient iodine intake.

Salt iodization is viewed as one of the safest and most effective methods of achieving iodine sufficiency across a population. Iodine fortification of all food-grade salt is mandated in ~120 countries, although the enforcement and degree of implementation of these efforts in individual countries are unknown. Although salt iodization is not obligatory in the USA and the FDA does not require that iodine content is listed on food labels, it is reassuring that >90% of households in the USA have access to iodized salt. Salt is not generally considered to be a source of excess iodine, although it is one of the most widely available iodine-containing foods.

Vitamins and supplements

The iodine content of multivitamins is not uniform. Supplements in the USA are not regulated by the FDA to the same rigorous standards as FDA-approved medications; therefore, their actual contents might not match the labelled content. In a US study published in 2009, iodine (as potassium iodide or kelp) was a labelled ingredient in only 51% of 223 prenatal nonprescription and prescription multivitamins. However, among the 25 brands containing iodine derived from kelp, measured values (33–610 μg per daily dose) were frequently discordant with the labelled values (75–300 μg per daily dose), including 13 brands with a >50% discrepancy between the measured and labelled values. Thus, potassium iodide, and not kelp, should be used in vitamin preparations.

Several cases of congenital hypothyroidism caused by ingestion of excess maternal iodine tablets during pregnancy have been reported. Similarly, hypothyroidism in neonates born to mothers who ingested excessive amounts of seaweed or seaweed soup during both pregnancy and lactation have been reported., Given the risks of potential iodine-induced thyroid dysfunction, the American Thyroid Association recommends against ingestion of an iodine or kelp daily supplement containing >500 μg iodine for all individuals, except for certain medical indications.

Medications

Amiodarone, an iodine-rich medication used in the management of ventricular and supraventricular tachyarrhythmias, is probably the most important and common source of medication-induced thyroid dysfunction. Amiodarone is 37% iodine by weight and has some structural resemblance to the thyroid hormones T3 and T4. Thus, one 200 mg tablet of amiodarone contains 75 mg iodine, which is several hundred-fold higher than the recommended daily intake of 150 μg in adults. The drug has a long half-life of ~100 days, is very lipophilic and accumulates in various tissues, including adipose tissue, liver and the lungs. As a result of its high iodine content, use of amiodarone is associated with thyrotoxicosis in 9.6% of patients with low ambient iodine intake, and hypothyroidism in 22.0% of patients with normal ambient iodine intake. Overall, amiodarone-induced hyperthyroidism is more common in iodine-deficient areas, whilst amiodarone-induced hypothyroidism is more common in iodine-sufficient areas.

Two types of AIT have been described: type 1 AIT is associated with increased synthesis of thyroid hormones, whereas type 2 AIT is characterized by destructive thyroiditis. Both occur approximately three times more frequently in men than in women, which is in contrast to amiodarone-induced hypothyroidism. A comprehensive update on this topic was published in 2012. Type 1 AIT is a form of the Jod–Basedow phenomenon, in which excess iodine exposure results in thyroid autonomy as a result of altered thyroid function regulation. Type 1 AIT is treated with thionamides, β-blockers, and if available, perchlorate; corticosteroids could also be used if the initial treatment is not rapidly effective. By contrast, type 2 AIT is characterized by parts of the thyroid gland being destroyed, which results in thyroid hormones leaking into the circulation. Type 2 AIT is usually managed with corticosteroids; one trial has demonstrated that treatment with perchlorate did not improve the likelihood of restoring euthyroidism. In severe cases of AIT, thyroidectomy might be required, with the use of iopanoic acid, if available, for the rapid control of hyperthyroidism before the surgery. The discontinuation of amiodarone might be considered, if this strategy is tolerated by the patient and in collaborative discussion with the patient’s cardiologist.

Some patients present with a mixed form of AIT, displaying features of both type 1 AIT and type 2 AIT. Differentiating between type 1 AIT and type 2 AIT can be difficult, but the use of radioiodine uptake and colour flow Doppler ultrasonography has been proposed. Finally, the risk of AIT might be further increased in some patients who are concomitantly treated with warfarin, due to a variety of mechanisms that can occur in patients who receive amiodarone that result in the potentiation of the effects of warfarin.

Radiologic studies

Use of iodinated contrast agents in diagnostic radiologic studies is a common source of excess iodine exposure in many patients. A single dose of iodinated contrast can contain up to 13,500 μg of free iodine and 15–60 g of bound iodine (which is more than several thousand times above the recommended daily intake). Following exposure to an iodinated contrast agent, iodine stores in the body remain raised and provide a continuous pool that can potentially induce thyroid dysfunction. In euthyroid, healthy adults from the USA without previous thyroid or renal disease, UIC did not return to baseline in a study with a small number of participants until a median of 43 days following exposure to the contrast agent. In another study of patients with athyreosis in Brazil, UICs did not normalize until 1 month after receiving a single intravenous contrast dose given for a CT scan.

Several case reports have demonstrated the effects of thyroid dysfunction arising after use of an iodinated contrast agent. For example, a 53-year-old woman in the USA developed thyroid storm and cardiopulmonary arrest immediately after undergoing an iodinated radiologic study. Two studies in Germany and the USA showed that a small proportion of patients who received either coronary angiography or an iodinated CT scan developed subclinical hypothyroidism ~1 week after the exam., A Turkish study of 101 patients who underwent coronary angiography found a small increased risk of subclinical hyperthyroidism at up to 8 weeks after the iodine exposure. However, one small study showed that intravenous administration of an iodine contrast agent during pregnancy did not result in a notably increased incidence of fetal thyroid dysfunction. Finally, we have reported the occurrence of iodine-induced hypothyroidism in three neonates who received intravenous contrast agents to evaluate congenital cardiac defects.

One of the most rigorous studies that has examined the association between iodinated contrast use and thyroid dysfunction was a large case–control study that used medical records from two hospitals in Boston, USA, over a 20-year period.In this study, patients without pre-existing hypothyroidism or hyperthyroidism who received a single iodinated contrast dose had a 2–3-fold increased risk of developing either incident hyperthyroidism (including overt hyperthyroidism) or overt hypothyroidism at a median of 9 months following exposure, compared with patients who did not receive the high iodine load.

Iodine-induced thyroid dysfunction is a potential consequence in patients with nodular goiters and/or elderly patients., Guidelines from the Contrast Media Safety Committee of the European Society of Urogenital Radiology advocate that high-risk patients are monitored for thyroid dysfunction following iodinated contrast use. No guidelines are currently available for screening or follow-up of at-risk patients receiving iodinated contrast in the USA.

Topical iodine

The use of transdermal iodine and thyroid dysfunction associated with this practice is often seen in hospitalized neonates. A study in Israel reported significantly higher serum levels of TSH in preterm neonates on whom topical iodinated antiseptic cleansers had been used than in preterm neonates on whom alcohol-based topical cleansers had been used (15.4 mIU/l versus 7.8 mIU/l, P<0.01).Iodine is also frequently used as a topical antiseptic in many surgical settings and for burn victims, whose ability to absorb topical iodine might be increased.Iodine-induced thyrotoxicosis has been described in a paraplegic woman in the USA who had applied topical povidone-iodine prior to urinary self-catheterization several times daily for many years.

Other sources of excess iodine exposure

Other sources of potential excess iodine exposure include various expectorants, food preservatives, prescribed medications, parenteral nutrition preparations, mouthwashes and vaginal douches. Reversible increases in serum levels of TSH have been observed among US astronauts drinking iodinated water as purified drinking water and individuals ingesting water purified with iodinated tablets.In the 1990s, due to the use of a faulty iodine-based water filtration system, small increases in serum levels of TSH were detected in American Peace Corp workers in Niger; these changes resolved when the iodinated water source was no longer used.

Indications for supraphysiologic iodine

Administration of supraphysiologic levels of iodine is medically appropriate in some very specific settings. A saturated solution of potassium iodide, of which the US generic formulation contains 1,000 mg potassium iodide per ml, can be used for the rapid treatment of hyperthyroidism, usually in patients with thyroid storm or in the preoperative period in patients with Graves disease, in conjunction with antithyroid drugs and other therapies. In such patients, pharmacologic doses of iodine should be administered after a thionamide has been given to block excess synthesis of thyroid hormones. Finally, individuals in the vicinity of a nuclear power plant can be directed to take potassium iodide in the event of a nuclear accident to prevent uptake of radioactive iodine into the thyroid, as was carried out in Poland following the Chernobyl nuclear accident.

Conclusions

Iodine is required for the production of thyroid hormones. Iodine is primarily taken in through the diet, with the recommended amount at 150 μg per day in adults who are not pregnant or lactating. Although excess iodine exposure generally does not result in any apparent clinical consequences, thyroid dysfunction can occur in vulnerable patients with specific risk factors, including those with pre-existing thyroid disease, the elderly, fetuses and neonates. As iodine-induced hypothyroidism or hyperthyroidism might be either subclinical or overt, excess iodine exposure should be suspected if the aetiology of thyroid dysfunction is not discernible.

The Iodine Deficiency Disorders

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Creswell J Eastman, M.D. and Michael B Zimmermann, M.D.

ABSTRACT

This chapter provides an overview of the disorders caused by iodine deficiency. Extensively referenced, it includes data on dietary sources of iodine, goitrogens, the effects of iodine deficiency throughout the lifecycle, the pathophysiology of iodine deficiency, as well as strategies for control and monitoring of the iodine deficiency disorders, such as iodized salt and iodized oil. It emphasizes the role of iodine deficiency in the development of brain damage and neurocognitive impairment, assessment of the iodine status of a population, the potential side effects of excessive iodine intake and current worldwide epidemiological data.

INTRODUCTION

This chapter provides a global overview of the disorders caused by iodine deficiency. Special emphasis will be put on recent developments such as the role of iodine deficiency in the development of brain damage and neurocognitive impairment, assessment of the iodine status of a population, strategies for control and monitoring of the iodine deficiency disorders (IDD), as well as side effects of iodine. Up to date information on IDD can be obtained by visiting the website of the Iodine Global Network (IGN) http://www.ign.org.

ETIOLOGY

Iodine (atomic weight 126.9 g/atom) is an essential component of the hormones produced by the thyroid gland. Thyroid hormones, and therefore iodine, are essential for mammalian life. Iodine (as iodide) is widely but unevenly distributed in the earth’s environment. Most iodide is found in the oceans (≈50 μg/L), and iodide ions in seawater are oxidized to elemental iodine, which volatilizes into the atmosphere and is returned to the soil by rain, completing the cycle. However, iodine cycling in many regions is slow and incomplete, and soils and ground water become deficient in iodine. Crops grown in these soils will be low in iodine, and humans and animals consuming food grown in these soils become iodine deficient (1). In plant foods grown in deficient soils, iodine concentration may be as low as 10 μg/kg dry weight, compared to ≈1 mg/kg in plants from iodine-sufficient soils. Iodine deficient soils are most common in inland regions, mountainous areas and areas of frequent flooding, but can also occur in coastal regions (2). This arises from the distant past through glaciation, compounded by the leaching effects of snow, water and heavy rainfall, which removes iodine from the soil. The mountainous regions of Europe, the Northern Indian Subcontinent, the extensive mountain ranges of China, the Andean region in South America and the lesser ranges of Africa are all iodine deficient. Also, the Ganges Valley in India, the Irawaddy Valley in Burma, and the Songkala valley in Northern China are also areas of endemic iodine deficiency. Iodine deficiency in populations residing in these areas will persist until iodine enters the food chain through addition of iodine to foods (e.g. iodization of salt) or dietary diversification introduces foods produced in iodine-sufficient areas.

Complete text including charts and citations.

Health Consequences of Iodine Deficiency

Abstract

Iodine Deficiency Disorders (IDD) are one of the biggest worldwide public health problem of today. Their effect is hidden and profoundly affects the quality of human life. Iodine deficiency occurs when the soil is poor in iodine, causing a low concentration in food products and insufficient iodine intake in the population. When iodine requirements are not met, the thyroid may no longer be able to synthesize sufficient amounts of thyroid hormone. The resulting low-level of thyroid hormones in the blood is the principal factor responsible for the series of functional and developmental abnormalities, collectively referred to as IDD. Iodine deficiency is a significant cause of mental developmental problems in children, including implications on reproductive functions and lowering of IQ levels in school-aged children. The consequence of iodine deficiency during pregnancy is impaired synthesis of thyroid hormones by the mother and the foetus. An insufficient supply of thyroid hormones to the developing brain may result in mental retardation. Brain damage and irreversible mental retardation are the most important disorders induced by iodine deficiency. Daily consumption of salt fortified with iodine is a proven effective strategy for prevention of IDD.

Keywords: Iodine, Cretinism, Mental Retardation

Iodine is a trace element essential for the synthesis of thyroid hormones, triodothyronine (T3) and thyroxine (T4). These hormones regulate the metabolic pattern of most cells and play a vital role in the process of early growth and development of most organs, especially the brain. In humans, the early development of the brain occurs during foetal and early postnatal life. Inadequate intake of iodine leads to insufficient production of these hormones, which adversely affect the muscle, heart, liver, kidney and the developing brain. This results in the disease states collectively known as Iodine Deficiency Disorders (IDD).

MAGNITUDE OF IDD

Iodine Deficiency Disorders are known to be a significant public health problem in 118 countries. At least 1,572 million people worldwide are estimated to be at risk of IDD i.e. those who live in areas where iodine deficiency is prevalent (total goiter rates above 5%), and at least 655 million of these are considered to be affected by goiter. Most of these are in developing countries in Africa, Asia, and Latin America, but large parts of Europe are also vulnerable.

PHYSIOLOGICAL FUNCTIONS OF IODINE

Iodine is an essential dietary element which is required for the synthesis of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3). The T4 and T3, which are iodinated molecules of the essential amino acid tyrosine, regulate cellular oxidation and hence affect calorigenesis, thermoregulation, and intermediary metabolism. These hormones are necessary for protein synthesis. They also promote nitrogen retention, glycogenolysis, intestinal absorption of glucose and galactose, as well as lipolysis, and the uptake of glucose by adipocytes.

The healthy human body contains 15–20 mg of iodine, of which about 70–80% is present in the thyroid gland. In a day, 60 μg of circulating iodine needs to be trapped by the thyroid for the adequate supply of T3 and T4. To extract this amount of iodine from the circulation, the thyroid daily clears several hundred litres of plasma of its iodine. This work can increase several times over in severely iodine deficient environments. To cope with this increased workload, the thyroid enlarges in size, under the influence of the Thyroid Stimulating Hormone (TSH), secreted from the pituitary gland. This compensatory mechanism, triggered by the hypothalamus to increase TSH secretion from the pituitary, causes remarkable enlargement of the thyroid gland (goiter).

An inadequate dietary intake of iodine leads to insufficient production of thyroid hormones, which affects many parts of the body, particularly muscle, heart, liver, kidney and the developing brain. Inadequate hormone production adversely affects these tissues, resulting in the disease states known collectively as iodine deficiency disorders, or IDD. Dietary iodine deficiency stimulates TSH secretion, which results in thyroid hypertrophy. The enlargement of the thyroid gland due to dietary iodine deficiency is called endemic goiter. Iodine intakes consistently lower than 50 μg/day usually result in goiter. Severe and prolonged iodine deficiency, may lead to a deficient supply of thyroid hormones. This condition is referred to as hypothyroidism.

ETIOLOGY OF IDD

Iodine is one of the essential elements required for normal human growth and development. Its daily per capita requirement is 150 micrograms [Table 1]. Soils from mountain ranges, such as the Himalayas, Alps, and Andes and from areas with frequent flooding, are particularly likely to be iodine deficient. The problem is aggravated by accelerated deforestation and soil erosion. The food grown in iodine deficient regions can never provide enough iodine to the population and live-stock living there. Unlike nutrients such as iron, calcium or vitamins, iodine does not occur naturally in specific foods; rather, it is present in the soil and is ingested through foods grown on that soil. Iodine deficiency results when there is lack of iodine on the earth’s crust. Living on the sea coast does not guarantee iodine sufficiency and significant pockets of iodine deficiency have been reported from costal regions in different parts of the world.

Table 1:

The Daily Reference Intakes (DRI) for Iodine

Life Stage Iodine mcg
Infants
0–6 Months 110
7–12 Months 130

Children
1–8 Years 90

Males
9–13 Years 120
14–70 Years 150
> 70 Years 150

Females
9–13 Years 120
14–18 Years 150
19–70 Years 150
> 70 Years 150

Pregnancy
< 18 – 50 Years 220

Lactation
< 18 Years 290
19–30 Years 290
31–50 Years 290

Iodine deficiency thus results mainly from geological rather than social and economic conditions. It cannot be eliminated by changing dietary habits or by eating specific kinds of foods grown in the same area. Besides nutritional iodine deficiency, a variety of other environmental, socio-cultural and economic factors operate to aggravate iodine deficiency and related thyroid dysfunctions. These include poverty related protein-energy malnutrition, ingestion of goitrogens through unusual diets (particularly by the poor), bacteriologically contaminated drinking water, as well as bulky, high residue diets, which interfere with the intestinal absorption of iodine.

Several environmental and genetic factors interfere with the processes of thyroxin synthesis leading to goiter formation. The genetic factors, which are rare, mainly affect the enzymes involved in thyroxin synthesis. Environmental factors are amongst the most common factors that interfere in thyroxin synthesis and lead to goiter formation. The most important environmental factors are (i) environmental iodine deficiency and (ii) goitrogens. The most frequent cause of goiter in India and other countries is environmental iodine deficiency. However, there is emerging evidence in different countries of world that goitrogens may play a secondary role in several endemic foci. Goitrogens are chemical substances that occur primarily in plant food. They can occasionally be present in contaminated drinking water. Goitrogens interfere in thyroxin synthesis by inhibiting the enzymes involved in the synthesis of thyroxin.

There is also evidence to show that intensive cropping, resulting in large scale removal of biomass from the soil, as well as widespread use of alkaline fertilizers, rapidly deplete the soil of its iodine content. Since both intensive cropping and use of alkaline fertilizers are widely practiced in almost all developing the countries, it is not surprising that nutritional iodine deficiency and endemic goiter are seen wherever they are looked for in these regions. The relationship between dietary iodine intake and severity of IDD is shown in Table 2.

Table 2:

The Spectrum of Iodine Deficiency Disorders

Foetus Abortions
Stillbirths
Congenital Anomalies
Increased Perinatal Mortality
Increased Infant Mortality
Neurological Cretinism
  Mental deficiency
  Deaf-mutism
  Spastic diplegia
  Squint
Myxedematous Cretinism
  Mental deficiency
  Dwarfism
  Psychomotor Defects

Neonate Neonatal goiter
Neonatal hypothyroidism

Child and Adolescent Goiter
Juvenile hypothyroidism
Impaired mental function
Retarded physical development
Adult Goiter with complications

Hypothyroidism
Impaired mental function

METABOLISM OF IODINE IN THE THYROID

Iodine enters the body in the form of iodate or iodide in the water we drink or food we eat; the iodate is converted to iodide in the stomach. The thyroid gland traps and concentrates iodide and uses it in the synthesis and storage of thyroid hormones [Figure 1]. The minimum daily iodine intake needed to maintain normal thyroid function in adults is about 150μg/dl. Iodide is rapidly absorbed from the gastrointestinal tract and distributed to extracellular fluids. But the concentration of iodide in the extracellular fluid is usually low because of the rapid uptake by the thyroid gland and renal clearance. It is estimated that 75% of the iodide taken into the body each day enters the thyroid by active transport. About two-thirds of that is used in hormone synthesis, with the remaining amount released back into the extra cellular fluid. The thyroid gland contains the body’s largest pool of iodide, about 8 to 10 mg. Most of this iodide is associated with thyroglobulin, a thyroid hormone precursor and a source of hormone and iodinated tyrosines.

The thyroid produces thyroxine (T4) and triiodothyronine (T3). Iodine is an essential component of both T3 and T4. These hormones regulate the rate of metabolism and affect physical and mental growth and the rate of function of many other systems in the body. The thyroid is controlled by the hypothalamus and the pituitary gland.

The production of thyroxine and triiodothyronine is regulated by the thyroid-stimulating hormone (TSH), released by the anterior pituitary. TSH production is suppressed when the T4 levels are high, and vice versa. The TSH production itself is modulated by the thyrotropin-releasing hormone (TRH), which is produced by the hypothalamus.

SOURCES OF DIETARY IODINE

About 90% of iodine intake is obtained from food consumed and the remainder from water. Iodine is available in traces in water, food and common salts. It is very low in the foods grown at high altitudes. Iodine found in sea-water is 0.2 mg per litre. Sea weeds and spongy shells are rich in iodine. The iodine content of common food items is given in Table 3. Rich sources are sea fish, green vegetables and leaves like spinach grown on iodine rich soil. Common sources are milk, meat, and cereals. Common salt fortified with small quantities of sodium or potassium iodate is now compulsorily made available in the market as iodized salt to check goiter. Certain vegetables like cabbage, cauliflower and radish contain glucosinolates (thiogluosides) which are potential goitrogens. Eating too much of these foods inhibits the availability of iodine to the body from the food and thus leads to the development of goiter.

Table 3:

Iodine content of food

Food Iodine (μg)
Salt, iodized, 1 teaspoonful 400
Haddock, 75g 104 – 145
Bread, regular process, 1 slice 35
Cheese, cottage, 2% fat, 1/2 cup 26 – 71
Shrimp, 75g 21 – 37
Egg, 1 18 – 26
Cheese, cheddar, 30g 5 – 23
Ground beef, 75g, cooked 8

THE DAILY REFERENCE INTAKES OF IODINE

HEALTH CONSEQUENCES OF IODINE DEFICIENCY

Iodine deficiency remains the single greatest cause of preventable brain damage and mental retardation worldwide. Eliminating iodine deficiency is recognized as one of the most achievable of the goals that the 1990 World Summit for Children set for the year 2000.

The most important biological role played by thyroxin is in the early foetal stage of life. It ensures the growth, differentiation and maturation of different organs of the body, and particularly the brain. Iodine deficiency has been identified as the world’s major cause of preventable mental retardation. Its severity can vary from mild intellectual blunting to frank cretinism, a condition that includes gross mental retardation, deaf-mutism, short stature and various other defects. In areas of severe iodine deficiency, the majority of individuals risk some degree of mental impairment. The damage to the developing brain results in individuals poorly equipped to fight disease, learn, work effectively, or reproduce satisfactorily. The spectrum of disorders caused due to iodine deficiency affects all the stages of life, from foetus to adult age [Table 3].

If pregnant women’s diets do not contain adequate iodine, the foetus cannot produce enough thyroxin and foetal growth is retarded. Hypothyroid foetuses often perish in the womb and many infants die within a week of birth. The current data on the embryology of the brain suggest that the critical time for the effect of iodine deficiency is mid the second trimester i.e. 14–18 weeks of pregnancy. At this time, neurons of the cerebral cortex and basal ganglia are formed. It is also the time of formation of the cochlea (10–18 weeks), which is also severely effected in endemic cretinism. A deficit in iodine or thyroid hormones occurring during this critical period of life results in the slowing down of the metabolic activities of all the cells of the foetus and irreversible alterations in the development of brain. The growth and differentiation of the central nervous system are closely related to the presence of iodine and thyroid hormones. Hypothyroidism may lead to cellular hypoplasia and reduced dendritic ramification gemmules and interneuronal connections. Hypothyroid children are intellectually subnormal and may also suffer physical impairment. They lack the aptitudes of normal children of similar age, and are often incapable of completing school. Studies have documented that in areas with an incidence of mild to moderate IDD, IQs of school children are, on average, 10 –12 points below those of children living in areas where there is no iodine deficiency.

ENDEMIC CRETINISM

Endemic cretinism is the extreme clinical manifestation of severe hypothyroidism during foetal, neonatal and childhood stages of development. It is characterised by severe and irreversible mental retardation, short stature, deaf-mutism, spastic dysplegia and squints. In early eighties, in many seriously endemic Tarai districts of north India, an average prevalence of 1–2% of cretinism was seen. The situation has improved significantly with the supply of iodized salt and cretins are no longer born.

Cretinism seen in severe endemic areas is predominantly of two types (a) neurological cretinism, where the neurological manifestations of thyroxin deficiency early in life, i.e. hypothyroidism, were confined to the in-utero or neonatal stages. (b) Myxedematous cretinism, where besides having mental retardation, sufferers also have myxoedema and dwarfism. This variant of cretinism is presumably because of continuing hypothyroidism through all phases of life.

CRETINOIDS

Besides the few children who manifest as cretins in an endemic goiter area, a large number of individuals with lesser degrees of mental retardation, speech and hearing defects, psychomotor retardation, as well as gait defects may be seen. Such individuals are known as cretinoids. The prevalence of cretinoids in severely endemic regions may be ten-fold greater or more than fully manifested cretins.

OTHER SYNDROMES DUE TO FOETAL IODINE DEFICIENCY

There is preliminary scientific evidence suggesting that severe iodine deficiency can lead to foetal wastage such as abortion, still births and congenital abnormalities; however, hard evidence available in this regard is limited.

NEONATAL AND CHILDHOOD HYPOTHYROIDISM

Studies have documented that more than 30% of the goitrous subjects in endemic areas are functionally decompensated and hypothyroid despite the ‘adaptive’ enlargement of the thyroid. Research studies on screening the cord blood of over 20,000 newborns discovered that one out of every 10 newborns from the Tarai regions of Uttar Pradesh were hypothyroid at birth.

ADULT HYPOTHYROIDISM

A large number of goitrous adults in an endemic region can have varying degrees of hypothyroidism leading to a variety of clinical symptomatologies and complications related to hypo-metabolic states. This symptomatology can seriously hamper human energy and work capacity with resultant erosion of the economic productivity of endemic regions.

SITUATION OF IDD IN OMAN AND THE GULF

A study conducted in Oman which included 3,061 school children in the 9–12 years age group revealed that 10% of the population showed signs of goiter grades 1a, 1b and 2. Cases of grade 3 were not seen, and 88.1% of the children did not show goiter.

A study conducted amongst 2,996 children in Bahrain aged 8–11.99 years during 1993–94, revealed that the total prevalence of goiter was 10 % (9.6 % grade I and 0.4 % Grade II), the median urinary iodine excretion levels was 91 μg per liter.Another national study in Oman conducted in 2004 amongst non-pregnant women (sample size 338, age group 15–49.99 years) revealed that the median urinary iodine excretion levels was 223 μg per liter.

SITUATION OF IODIZATION OF SALT IN OMAN

Presently, there is no national programme for the control of iodine deficiency disorders in Oman; however, since 1995, there has been legislation/Royal decree, for universal salt iodization in the country.

The percentage of households consuming iodized salt was 61% as per the MOH/UNICEF survey in 1998.

CONCLUSION

Today, iodine deficiency is claimed to be the world’s single most significant preventable cause of brain damage and mental retardation. The detrimental effect of iodine deficiency on the mental and physical development of children as well as on the productivity of adults has been recognized. The neurological sequelae of iodine deficiency are mediated by thyroid hormone deficiency. All the basic processes of neurogenesis: cellular proliferation, differentiation, migration and selective cell death are impaired during the major period of brain growth.

In Oman, for the prevention of IDD, there is a need to undertake regular cyclic surveys, every 3 – 5 years, to assess the urinary iodine excretion amongst the school age children along with the level of iodization in salt consumed by them. This data can provide the current status of iodine nutriture and status of universal salt iodization in the country. Also, there is a need to enforce strictly the decree of universal iodization of salt in the country so that the population can have access only to iodized salt.

Table 4:

Relationship between Iodine intake and IDD

Nutritional Status Daily Iodine intake (μg)
Associated with cretinism 20 or less
Associated with goiter 20 – 50
Marginal 50 – 100
Normal 100 – 300
More than normal 300 and above

CME QUIZ

  1. What are the three sociocultural and ecological factors that aggravate iodine deficiency in a population?

    1. …………………………………………………………………..
    2. …………………………………………………………………..
    3. …………………………………………………………………..
  2. Mention some clinical conditions that are induced by iodine deficiency.

    1. …………………………………………………………………..
    2. …………………………………………………………………..
    3. …………………………………………………………………..
  3. What are physiological mechanisms behind the clinical observation that, in spite of severe iodine deficiency in certain individuals, they have no signs or symptoms of goiter or cretinism?

    1. …………………………………………………………………..
    2. …………………………………………………………………..
    3. …………………………………………………………………..
  4. What is the duration of transient neonatal hypothyroidism in relation to the severity of iodine deficiency and what factors determine the persistence of hypothyroids in the postnatal period?

    1. …………………………………………………………………..
    2. …………………………………………………………………..
    3. …………………………………………………………………..
  5. What are therapeutic strategies for the different iodine deficiency disorders?

    1. …………………………………………………………………..
    2. …………………………………………………………………..
    3. …………………………………………………………………..

REFERENCES

1. Bernal J, Nunez J. Thyroid hormone action and brain development. Trends Endocrinol Metab. 2000;133:390–398.
4. A guide for programme managers. 2nd ed. WHO Press; Geneva: 2001. Assessment of Iodine Deficiency Disorders and Monitoring their Elimination; pp. 7–9. ICCIDD/UNCF/WHO.
5. Hetzel BS. SOS for a billion – the nature and magnitude of iodine deficiency disorders. In: Hetzel BS, Pandav CV, editors. SOS for a billion – the conquest of iodine deficiency disorders. 2nd Ed. New Delhi: Oxford University Press; 1997. pp. 1–29.
6. Stanbury JB. The iodine deficiency disorders: Introduction and general aspects. In: Hetzel BS, Dunn JT, Stanbury JB, editors. The prevention and control of iodine deficiency disorders. Amsterdam: Elsevier Science Publishers; 1987. pp. 35–48.
7. World Health Organization. Geneva: WHO Press; 1994. Indicators for assessing Iodine Deficiency Disorders and their control through salt iodization; pp. 12–16. WHO-UNICEF-ICCIDD.
8. Dunn JT. Endemic goitre and cretinism. An updated on iodine status. J Pediatr Endocrinol Metab. 2001;14:1469–1473. [PubMed]
9. Markou K, Georgopolous N, Kyriazopoulou V, Vagenakis GA. Iodine induced hypothyroidism. Thyroid. 2001;11:501–507. [PubMed]
10. Delange FM, Fisher DA. Thyroid hormone and iodine requirements in man during brain development. In: Stannbury JB, Delange F, Dunn JT, Pandav CS, editors. Iodine in pregnancy. Delhi: Oxford University Press; 1998. pp. 1–27.
11. WHO . Trace elements in human nutrition and health. Geneva: Macmillan; 1996. Iodine; pp. 49–71.
12. Kochupillai N, Godbole MM, Pandav CS, Karmarkar MG, Ahuja MMS. Neonatal thyroid status in iodine deficient environments of the SubHimalayan region. Indian J Med Res. 1984;80:293–299. [PubMed]
13. Ministry of Health(Oman),WHO, UNICEF, Sultan Qaboos University . Sultanate of Oman National Study on Prevalence of Iodine Deficiency Disorders (IDD) Muscat: Ministry of Health; 1994.
14. Moosa K, Abdul Wahab AWM, Al-Sayyad J, Baig BZH. National study on the prevalence of iodine deficiency disorders among schoolchildren 8–12 years of age in Bahrain. East Mediterr Health J. 2001;7:609–616. [PubMed]
15. Vitamin and Mineral Nutrition Information System (VMNIS), WHO Global Database on Iodine Deficiency, WHO Press. Geneva: World Health Organisation; 2006.
16. Monitoring of Universal salt iodization: a collaborative project of MOH/UNICEF. Ministry of Health; Muscat: 1998.

Iodine in autism spectrum disorders

Abstract

OBJECTIVE:

The aim of our study was to assess the iodine status of Polish boys with severe autism compared to their healthy peers and evaluate the relationship between urinary iodine, thyroid hormones, body mass index and Autism Spectrum Disorder (ASD) symptomatology.

SUBJECTS AND METHODS:

Tests were performed in 40 boys with ASD and 40 healthy boys, aged 2-17 from the same geographic region in Poland. Urinary iodine (UI), free triiodothyronine (fT3), free thyroxine (fT4), thyroid stimulating hormone (TSH), BMI, and individual symptoms measured by the Childhood Autism Rating Scale (CARS) were correlated. Validated ion chromatography method with pulsed amperometric detection was applied for the determination of urinary iodine after optimized alkaline digestion in a closed system assisted with microwaves.

RESULTS:

19 out of 40 children with ASD had mild to moderate iodine deficiency. Statistically significant lower levels of UI, fT3 and fT4 and higher levels of TSH were found in the autistic group when compared with the control group. Concentration of iodine in urine was negatively associated with clinician’s general impression for children between 11 and 17 years. Emotional response, adaptation to environmental change, near receptor responsiveness, verbal communication, activity level, and intellectual functioning are more associated with UI than other symptoms listed in CARS.

CONCLUSION:

The severity of certain symptoms in autism is associated with iodine status in maturing boys. Thyroid hormones were within normal reference ranges in both groups while urinary iodine was significantly lower in autistic boys suggesting that further studies into the non-hormonal role of iodine in autism are required.

Properties and Therapeutic Application of Bromelain: A Review

~ Content Source

Abstract

Bromelain belongs to a group of protein digesting enzymes obtained commercially from the fruit or stem of pineapple. Fruit bromelain and stem bromelainare prepared differently and they contain different enzymatic composition. “Bromelain” refers usually to the “stem bromelain.” Bromelain is a mixture of different thiol endopeptidases and other components like phosphatase, glucosidase, peroxidase, cellulase, escharase, and several protease inhibitors. In vitro and in vivo studies demonstrate that bromelain exhibits various fibrinolytic, antiedematous, antithrombotic, and anti-inflammatory activities. Bromelain is considerably absorbable in the body without losing its proteolytic activity and without producing any major side effects. Bromelain accounts for many therapeutic benefits like the treatment of angina pectoris, bronchitis, sinusitis, surgical trauma, and thrombophlebitis, debridement of wounds, and enhanced absorption of drugs, particularly antibiotics. It also relieves osteoarthritis, diarrhea, and various cardiovascular disorders. Bromelain also possesses some anticancerous activities and promotes apoptotic cell death. This paper reviews the important properties and therapeutic applications of bromelain, along with the possible mode of action.

1. Introduction

Pineapple is the common name of Ananas comosus (syns. A. sativus, Ananassa sativa, Bromelia ananas, B. comosa). Pineapple is the leading edible member of the family Bromeliaceae, grown in several tropical and subtropical countries including Philippines, Thailand, Indonesia, Malaysia, Kenya, India, and China. It has been used as a medicinal plant in several native cultures [1] and these medicinal qualities of pineapple are attributed to bromelain (EC 3.4.22.32), which is a crude extract from pineapple that contains, among other compounds, various closely related proteinases, exhibiting various fibrinolytic, antiedematous, antithrombotic, and anti-inflammatory activities in vitro and in vivo. Bromelain has been chemically known since 1875 and is used as a phytomedical compound [2]. Bromelain concentration is high in pineapple stem, thus necessitating its extraction because, unlike the pineapple fruit which is normally used as food, the stem is a waste byproduct and thus inexpensive [3]. A wide range of therapeutic benefits have been claimed for bromelain, such as reversible inhibition of platelet aggregation, sinusitis, surgical traumas [4], thrombophlebitis, pyelonephriti angina pectoris, bronchitis [5], and enhanced absorption of drugs, particularly of antibiotics [67]. Several studies have been carried out indicating that bromelain has useful phytomedical application. However, these results are yet to be amalgamated and critically compared so as to make out whether bromelain will gain wide acceptance as a phytomedical supplement [8]. Bromelain acts on fibrinogen giving products that are similar, at least in effect, to those formed by plasmin [9]. Experiment in mice showed that antacids such as sodium bicarbonate preserve the proteolytic activity of bromelain in the gastrointestinal tract [10]. Bromelain is considered as a food supplement and is freely available to the general public in health food stores and pharmacies in the USA and Europe [11]. Existing evidence indicates that bromelain can be a promising candidate for the development of future oral enzyme therapies for oncology patients [12]. Bromelain can be absorbed in human intestines without degradation and without losing its biological activity [1213].

2. Biochemical Properties

The crude aqueous extract from stem and fruit of pineapple is known as bromelain. It is a mixture of different thiol endopeptidases and other components like phosphatases, glucosidase, peroxidases, cellulases, glycoproteins, carbohydrates, and several protease inhibitors [14]. Stem bromelain (EC.3.4.22.32) is different from fruit bromelain (EC.3.4.22.33) [15]. The enzymatic activities of bromelain comprise a wide spectrum with pH range of 5.5 to 8.0 [16]. Different protein fractions were obtained by mean of various “biochemical techniques as sodium dodecyl sulphate polyacrylamide gel electrophoresis” (SDS-PAGE), isoelectric focusing (IEF), and multicathodal-PAGE [1718]. Nowadays, bromelain is prepared from cooled pineapple juice by centrifugation, ultrafiltration, and lyophilization. The process yields a yellowish powder, the enzyme activity of which is determined with different substrates such as casein (FIP unit), gelatin (gelatin digestion units), or chromogenic tripeptides [7171920].

3. Absorption and Bioavailability

The body can absorb significant amount of bromelain; about 12 gm/day of bromelain can be consumed without any major side effects [13]. Bromelain is absorbed from the gastrointestinal tract in a functionally intact form; approximately 40% of labeled bromelain is absorbed from intestine in high molecular form [21]. In a study carried out by Castell et al. [13] bromelain was detected to retain its proteolytic activity in plasma and was also found linked with alpha 2-macroglobulin and alpha1-antichymotrypsin, the two antiproteinases of blood. In a recent study, it was demonstrated that 3.66 mg/mL of bromelain was stable in artificial stomach juice after 4 hrs of reaction and also 2.44 mg/mL of bromelain remained in artificial blood after 4 hrs of reaction [22].

4. Medicinal Uses

Clinical studies have shown that bromelain may help in the treatment of several disorders.

4.1. Effects of Bromelain on Cardiovascular and Circulation

Bromelain prevents or minimizes the severity of angina pectoris and transient ischemic attack (TIA). It is useful in the prevention and treatment of thrombophlebitis. It may also break down cholesterol plaques and exerts a potent fibrinolytic activity. A combination of bromelain and other nutrients protect against ischemia/reperfusion injury in skeletal muscle [23]. Cardiovascular diseases (CVDs) include disorders of the blood vessels and heart, coronary heart disease (heart attacks), cerebrovascular disease (stroke), raised blood pressure (hypertension), peripheral artery disease, rheumatic heart disease, heart failure, and congenital heart disease [24]. Stroke and heart disease are the main cause of death, about 65% of people with diabetes die from stroke or heart disease. Bromelain has been effective in the treatment of CVDs as it is an inhibitor of blood platelet aggregation, thus minimizing the risk of arterial thrombosis and embolism [25]. King et al. [26] reported that administration of medication use to control the symptoms of diabetes, hypertension, and hypercholesteromia increased by 121% from 1988–1994 to 2001–2006 (P < 0.05) and was greater for patients with fewer healthy lifestyle habits. Bromelain supplement could reduce any of risk factors that contribute to the development of cardiovascular disease. In a recent research, Bromelain was found to attenuate development of allergic airway disease (AAD), while altering CD4+ to CD8+T lymphocyte populations. From this reduction in AAD outcomes it was suggested that bromelain may have similar effects in the treatment of human asthma and hypersensitivity disorders [27]. In another study, carried out by Juhasz et al., Bromelain was proved to exhibit the ability of inducing cardioprotection against ischemia-reperfusion injury through Akt/Foxo pathway in rat myocardium [28].

4.2. Bromelain Relieves Osteoarthritis

Osteoarthritis is the most common form of arthritis in Western countries; in USA prevalence of osteoarthritis ranges from 3.2 to 33% dependent on the joint [29]. A combination of bromelain, trypsin, and rutin was compared to diclofenac in 103 patients with osteoarthritis of the knee. After six weeks, both treatments resulted in significant and similar reduction in the pain and inflammation [30]. Bromelain is a food supplement that may provide an alternative treatment to nonsteroidal anti-inflammatory drug (NSAIDs) [31]. It plays an important role in the pathogenesis of arthritis [32]. Bromelain has analgesic properties which are thought to be the result of its direct influence on pain mediators such as bradykinin [3334]. The earliest reported studies investigating bromelain were a series of case reports on 28 patients, with moderate or severe rheumatoid or osteoarthritis [35].

4.3. Effect of Bromelain on Immunogenicity

Bromelain has been recommended as an adjuvant therapeutic approach in the treatment of chronic inflammatory, malignant, and autoimmune diseases [36]. In vitro experiments have shown that Bromelain has the ability to modulate surface adhesion molecules on T cells, macrophages, and natural killer cells and also induce the secretion of IL-1β, IL-6, and tumour necrosis factor α (TNFα) by peripheral blood mononuclear cells (PBMCs) [3743]. Bromelain can block the Raf-1/extracellular-regulated-kinase- (ERK-) 2 pathways by inhibiting the T cell signal transduction [44]. Treatment of cells with bromelain decreases the activation of CD4 (+) T cells and reduce the expression of CD25 [45]. Moreover, there is evidence that oral therapy with bromelain produces certain analgesic and anti-inflammatory effects in patients with rheumatoid arthritis, which is one of the most common autoimmune diseases [46].

4.4. Effect of Bromelain on Blood Coagulation and Fibrinolysis

Bromelain influences blood coagulation by increasing the serum fibrinolytic ability and by inhibiting the synthesis of fibrin, a protein involved in blood clotting [47]. In rats, the reduction of serum fibrinogen level by bromelain is dose dependent. At a higher concentration of bromelain, both prothrombin time (PT) and activated partial thromboplastin time (APTT) are markedly prolonged [48]. In vitro and in vivostudies have suggested that bromelain is an effective fibrinolytic agent as it stimulates the conversion of plasminogen to plasmin, resulting in increased fibrinolysis by degrading fibrin [4950].

4.5. Effects of Bromelain on Diarrhea

Evidence has suggested that bromelain counteracts some of the effects of certain intestinal pathogens like Vibrio cholera and Escherichia coli, whose enterotoxin causes diarrhoea in animals. Bromelain appears to exhibit this effect by interacting with intestinal secretory signaling pathways, including adenosine 3′ : 5′-cyclic monophosphatase, guanosine 3′ : 5′-cyclic monophosphatase, and calcium-dependent signaling cascades [51]. Other studies suggest a different mechanism of action. In E. coli infection, an active supplementation with bromelain leads to some antiadhesion effects which prevent the bacteria from attaching to specific glycoprotein receptors located on the intestinal mucosa by proteolytically modifying the receptor attachment sites [5253].

4.6. Effect of Bromelain on Cancer Cells

Recent studies have shown that bromelain has the capacity to modify key pathways that support malignancy. Presumably, the anticancerous activity of bromelain is due to its direct impact on cancer cells and their microenvironment, as well as on the modulation of immune, inflammatory, and haemostatic systems [12]. Most of the in vitro and in vivo studies on anticancer activity of bromelain are concentrated on mouse and human cells, both cancerous and normal, treated with bromelain preparations. In an experiment conducted by Beez et al chemically induced mouse skin papillomas were treated with bromelain and they observed that it reduced tumor formation, tumor volume and caused apoptotic cell death [54]. In one study related to bromelain treatment of gastric carcinoma Kato III cell lines, significant reduction of cell growth was observed [55] while in another study bromelain reduced the invasive capacity of glioblastoma cells and reduced de novo protein synthesis [56]. Bromelain is found to increase the expression of p53 and Bax in mouse skin, the well-known activators of apoptosis [54]. Bromelain also decreases the activity of cell survival regulators such as Akt and Erk, thus promoting apoptotic cell death in tumours. Different studies have demonstrated the role of NF-κB, Cox-2, and PGE2 as promoters of cancer progression. Evidence shows that the signaling and overexpression of NF-κB plays an important part in many types of cancers [5758]. Cox-2, a multiple target gene of NF-κB, facilitates the conversion of arachidonic acid into PGE2 and thus promotes tumour angiogenesis and progression [5960]. It is considered that inhibiting NF-κB, Cox-2, and PGE2 activity has potential as a treatment of cancer. Bromelain was found to downregulate NF-κB and Cox-2 expression in mouse papillomas [54] and in models of skin tumourigenesis [61]. Bromelain was also shown to inhibit bacterial endotoxin (LPS)-induced NF-κB activity as well as the expression of PGE2 and Cox-2 in human monocytic leukemia and murine microglial cell lines [6263]. Bromelain markedly has in vivo antitumoural activity for the following cell lines: P-388 leukemia, sarcoma (S-37), Ehrlich ascetic tumour, Lewis lung carcinoma, and ADC-755 mammary adenocarcinoma. In these studies, intraperitoneal administration of bromelain after 24 hours of tumour cell inoculation resulted in tumour regression [54].

4.7. Role of Bromelain in Surgery

Administration of bromelain before a surgery can reduce the average number of days for complete disappearance of pain and postsurgery inflammation [6465]. Trials indicate that bromelain might be effective in reducing swelling, bruising, and pain in women having episiotomy [66]. Nowadays, bromelain is used for treating acute inflammation and sports injuries [31].

4.8. Role of Bromelain in Debridement Burns

The removal of damaged tissue from wounds or second/third degree burns is termed as debridement. Bromelain applied as a cream (35% bromelain in a lipid base) can be beneficial for debridement of necrotic tissue and acceleration of healing. Bromelain contains escharase which is responsible for this effect. Escharase is nonproteolytic and has no hydrolytic enzyme activity against normal protein substrate or various glycosaminoglycan substrates. Its activity varies greatly with different preparations [67]. In two different enzymatic debridement studies carried out in porcine model, using different bromelain-based agents, namely, Debriding Gel Dressing (DGD) and Debrase Gel Dressing showed rapid removal of the necrotic layer of the dermis with preservation of the unburned tissues [6869]. In another study on Chinese landrace pigs, enzymatic debridement using topical bromelain in incised wound tracks accelerated the recovery of blood perfusion, pO2in wound tissue, controlled the expression of TNF-α, and raised the expression of TGT-β [70]. Enzymatic debridement using bromelain is better than surgical debridement as surgical incision is painful, nonselective and exposes the patients to the risk of repeated anaesthesia and significant bleeding [7174].

4.9. Toxicity of Bromelain

According to Taussig et al. [75] bromelain has very low toxicity with an LD50(lethal doses) greater than 10 g/kg in mice, rates, and rabbits. Toxicity tests on dogs, with increasing level of bromelain up to 750 mg/kg administered daily, showed no toxic effects after six months. Dosages of 1500 mg/kg per day when administered to rats showed no carcinogenic or teratogenic effects and did not provoke any alteration in food intake, histology of heart, growth, spleen, kidney, or hematological parameters [76]. Eckert et al. [41] after giving bromelain (3000 FIP unit/day) to human over a period of ten days found no significant changes in blood coagulation parameters.

5. Conclusion

Bromelain has a wide range of therapeutic benefits, but the mode of its action is not properly understood. It is proved that bromelain is well absorbed in body after oral administration and it has no major side effects, even after prolonged use. All the evidences reviewed in this paper suggest that bromelain can be used as an effective health supplement to prevent cancer, diabetes, and various cardiovascular diseases in the long run.

6. Future Trends and Perspectives

Bromelain can be a promising candidate for the development of oral enzyme therapies for oncology patients. It is clear from this paper that bromelain is a multiaction enzyme; however, more research is required to understand the proper mechanism of action of bromelain so that the multiaction activities of bromelain can be harnessed efficiently.

Acknowledgments

The authors are grateful to DEAN, Department of Biotechnology, IBMER, Mangalayatan University, Aligarh, India, for providing necessary facilities and encouragement. They are also thankful to all faculty members of the Institute of Biomedical Education and Research, Mangalayatan University, Aligarh, India, for their generous help and suggestions during the paper preparation.

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Properties and Therapeutic Application of Bromelain(Pineapple):A Review

~ Content Source

Abstract

Bromelain belongs to a group of protein digesting enzymes obtained commercially from the fruit or stem of pineapple. Fruit bromelain and stem bromelainare prepared differently and they contain different enzymatic composition. “Bromelain” refers usually to the “stem bromelain.” Bromelain is a mixture of different thiol endopeptidases and other components like phosphatase, glucosidase, peroxidase, cellulase, escharase, and several protease inhibitors. In vitro and in vivo studies demonstrate that bromelain exhibits various fibrinolytic, antiedematous, antithrombotic, and anti-inflammatory activities. Bromelain is considerably absorbable in the body without losing its proteolytic activity and without producing any major side effects. Bromelain accounts for many therapeutic benefits like the treatment of angina pectoris, bronchitis, sinusitis, surgical trauma, and thrombophlebitis, debridement of wounds, and enhanced absorption of drugs, particularly antibiotics. It also relieves osteoarthritis, diarrhea, and various cardiovascular disorders. Bromelain also possesses some anticancerous activities and promotes apoptotic cell death. This paper reviews the important properties and therapeutic applications of bromelain, along with the possible mode of action.

1. Introduction

Pineapple is the common name of Ananas comosus (syns. A. sativus, Ananassa sativa, Bromelia ananas, B. comosa). Pineapple is the leading edible member of the family Bromeliaceae, grown in several tropical and subtropical countries including Philippines, Thailand, Indonesia, Malaysia, Kenya, India, and China. It has been used as a medicinal plant in several native cultures [] and these medicinal qualities of pineapple are attributed to bromelain (EC 3.4.22.32), which is a crude extract from pineapple that contains, among other compounds, various closely related proteinases, exhibiting various fibrinolytic, antiedematous, antithrombotic, and anti-inflammatory activities in vitro and in vivo. Bromelain has been chemically known since 1875 and is used as a phytomedical compound []. Bromelain concentration is high in pineapple stem, thus necessitating its extraction because, unlike the pineapple fruit which is normally used as food, the stem is a waste byproduct and thus inexpensive []. A wide range of therapeutic benefits have been claimed for bromelain, such as reversible inhibition of platelet aggregation, sinusitis, surgical traumas [], thrombophlebitis, pyelonephriti angina pectoris, bronchitis [], and enhanced absorption of drugs, particularly of antibiotics []. Several studies have been carried out indicating that bromelain has useful phytomedical application. However, these results are yet to be amalgamated and critically compared so as to make out whether bromelain will gain wide acceptance as a phytomedical supplement []. Bromelain acts on fibrinogen giving products that are similar, at least in effect, to those formed by plasmin []. Experiment in mice showed that antacids such as sodium bicarbonate preserve the proteolytic activity of bromelain in the gastrointestinal tract []. Bromelain is considered as a food supplement and is freely available to the general public in health food stores and pharmacies in the USA and Europe []. Existing evidence indicates that bromelain can be a promising candidate for the development of future oral enzyme therapies for oncology patients []. Bromelain can be absorbed in human intestines without degradation and without losing its biological activity [].

2. Biochemical Properties

The crude aqueous extract from stem and fruit of pineapple is known as bromelain. It is a mixture of different thiol endopeptidases and other components like phosphatases, glucosidase, peroxidases, cellulases, glycoproteins, carbohydrates, and several protease inhibitors []. Stem bromelain (EC.3.4.22.32) is different from fruit bromelain (EC.3.4.22.33) []. The enzymatic activities of bromelain comprise a wide spectrum with pH range of 5.5 to 8.0 []. Different protein fractions were obtained by mean of various “biochemical techniques as sodium dodecyl sulphate polyacrylamide gel electrophoresis” (SDS-PAGE), isoelectric focusing (IEF), and multicathodal-PAGE []. Nowadays, bromelain is prepared from cooled pineapple juice by centrifugation, ultrafiltration, and lyophilization. The process yields a yellowish powder, the enzyme activity of which is determined with different substrates such as casein (FIP unit), gelatin (gelatin digestion units), or chromogenic tripeptides [].

3. Absorption and Bioavailability

The body can absorb significant amount of bromelain; about 12 gm/day of bromelain can be consumed without any major side effects []. Bromelain is absorbed from the gastrointestinal tract in a functionally intact form; approximately 40% of labeled bromelain is absorbed from intestine in high molecular form []. In a study carried out by Castell et al. [] bromelain was detected to retain its proteolytic activity in plasma and was also found linked with alpha 2-macroglobulin and alpha1-antichymotrypsin, the two antiproteinases of blood. In a recent study, it was demonstrated that 3.66 mg/mL of bromelain was stable in artificial stomach juice after 4 hrs of reaction and also 2.44 mg/mL of bromelain remained in artificial blood after 4 hrs of reaction [].

4. Medicinal Uses

Clinical studies have shown that bromelain may help in the treatment of several disorders.

4.1. Effects of Bromelain on Cardiovascular and Circulation

Bromelain prevents or minimizes the severity of angina pectoris and transient ischemic attack (TIA). It is useful in the prevention and treatment of thrombophlebitis. It may also break down cholesterol plaques and exerts a potent fibrinolytic activity. A combination of bromelain and other nutrients protect against ischemia/reperfusion injury in skeletal muscle []. Cardiovascular diseases (CVDs) include disorders of the blood vessels and heart, coronary heart disease (heart attacks), cerebrovascular disease (stroke), raised blood pressure (hypertension), peripheral artery disease, rheumatic heart disease, heart failure, and congenital heart disease []. Stroke and heart disease are the main cause of death, about 65% of people with diabetes die from stroke or heart disease. Bromelain has been effective in the treatment of CVDs as it is an inhibitor of blood platelet aggregation, thus minimizing the risk of arterial thrombosis and embolism []. King et al. [] reported that administration of medication use to control the symptoms of diabetes, hypertension, and hypercholesteromia increased by 121% from 1988–1994 to 2001–2006 (P < 0.05) and was greater for patients with fewer healthy lifestyle habits. Bromelain supplement could reduce any of risk factors that contribute to the development of cardiovascular disease. In a recent research, Bromelain was found to attenuate development of allergic airway disease (AAD), while altering CD4+ to CD8+T lymphocyte populations. From this reduction in AAD outcomes it was suggested that bromelain may have similar effects in the treatment of human asthma and hypersensitivity disorders []. In another study, carried out by Juhasz et al., Bromelain was proved to exhibit the ability of inducing cardioprotection against ischemia-reperfusion injury through Akt/Foxo pathway in rat myocardium [].

4.2. Bromelain Relieves Osteoarthritis

Osteoarthritis is the most common form of arthritis in Western countries; in USA prevalence of osteoarthritis ranges from 3.2 to 33% dependent on the joint []. A combination of bromelain, trypsin, and rutin was compared to diclofenac in 103 patients with osteoarthritis of the knee. After six weeks, both treatments resulted in significant and similar reduction in the pain and inflammation []. Bromelain is a food supplement that may provide an alternative treatment to nonsteroidal anti-inflammatory drug (NSAIDs) []. It plays an important role in the pathogenesis of arthritis []. Bromelain has analgesic properties which are thought to be the result of its direct influence on pain mediators such as bradykinin []. The earliest reported studies investigating bromelain were a series of case reports on 28 patients, with moderate or severe rheumatoid or osteoarthritis [].

4.3. Effect of Bromelain on Immunogenicity

Bromelain has been recommended as an adjuvant therapeutic approach in the treatment of chronic inflammatory, malignant, and autoimmune diseases []. In vitro experiments have shown that Bromelain has the ability to modulate surface adhesion molecules on T cells, macrophages, and natural killer cells and also induce the secretion of IL-1β, IL-6, and tumour necrosis factor α (TNFα) by peripheral blood mononuclear cells (PBMCs) []. Bromelain can block the Raf-1/extracellular-regulated-kinase- (ERK-) 2 pathways by inhibiting the T cell signal transduction []. Treatment of cells with bromelain decreases the activation of CD4 (+) T cells and reduce the expression of CD25 []. Moreover, there is evidence that oral therapy with bromelain produces certain analgesic and anti-inflammatory effects in patients with rheumatoid arthritis, which is one of the most common autoimmune diseases [].

4.4. Effect of Bromelain on Blood Coagulation and Fibrinolysis

Bromelain influences blood coagulation by increasing the serum fibrinolytic ability and by inhibiting the synthesis of fibrin, a protein involved in blood clotting []. In rats, the reduction of serum fibrinogen level by bromelain is dose dependent. At a higher concentration of bromelain, both prothrombin time (PT) and activated partial thromboplastin time (APTT) are markedly prolonged []. In vitro and in vivostudies have suggested that bromelain is an effective fibrinolytic agent as it stimulates the conversion of plasminogen to plasmin, resulting in increased fibrinolysis by degrading fibrin [].

4.5. Effects of Bromelain on Diarrhea

Evidence has suggested that bromelain counteracts some of the effects of certain intestinal pathogens like Vibrio cholera and Escherichia coli, whose enterotoxin causes diarrhoea in animals. Bromelain appears to exhibit this effect by interacting with intestinal secretory signaling pathways, including adenosine 3′ : 5′-cyclic monophosphatase, guanosine 3′ : 5′-cyclic monophosphatase, and calcium-dependent signaling cascades []. Other studies suggest a different mechanism of action. In E. coli infection, an active supplementation with bromelain leads to some antiadhesion effects which prevent the bacteria from attaching to specific glycoprotein receptors located on the intestinal mucosa by proteolytically modifying the receptor attachment sites [].

4.6. Effect of Bromelain on Cancer Cells

Recent studies have shown that bromelain has the capacity to modify key pathways that support malignancy. Presumably, the anticancerous activity of bromelain is due to its direct impact on cancer cells and their microenvironment, as well as on the modulation of immune, inflammatory, and haemostatic systems []. Most of the in vitro and in vivo studies on anticancer activity of bromelain are concentrated on mouse and human cells, both cancerous and normal, treated with bromelain preparations. In an experiment conducted by Beez et al chemically induced mouse skin papillomas were treated with bromelain and they observed that it reduced tumor formation, tumor volume and caused apoptotic cell death []. In one study related to bromelain treatment of gastric carcinoma Kato III cell lines, significant reduction of cell growth was observed [] while in another study bromelain reduced the invasive capacity of glioblastoma cells and reduced de novo protein synthesis []. Bromelain is found to increase the expression of p53 and Bax in mouse skin, the well-known activators of apoptosis []. Bromelain also decreases the activity of cell survival regulators such as Akt and Erk, thus promoting apoptotic cell death in tumours. Different studies have demonstrated the role of NF-κB, Cox-2, and PGE2 as promoters of cancer progression. Evidence shows that the signaling and overexpression of NF-κB plays an important part in many types of cancers []. Cox-2, a multiple target gene of NF-κB, facilitates the conversion of arachidonic acid into PGE2 and thus promotes tumour angiogenesis and progression []. It is considered that inhibiting NF-κB, Cox-2, and PGE2 activity has potential as a treatment of cancer. Bromelain was found to downregulate NF-κB and Cox-2 expression in mouse papillomas [] and in models of skin tumourigenesis []. Bromelain was also shown to inhibit bacterial endotoxin (LPS)-induced NF-κB activity as well as the expression of PGE2 and Cox-2 in human monocytic leukemia and murine microglial cell lines []. Bromelain markedly has in vivo antitumoural activity for the following cell lines: P-388 leukemia, sarcoma (S-37), Ehrlich ascetic tumour, Lewis lung carcinoma, and ADC-755 mammary adenocarcinoma. In these studies, intraperitoneal administration of bromelain after 24 hours of tumour cell inoculation resulted in tumour regression [].

4.7. Role of Bromelain in Surgery

Administration of bromelain before a surgery can reduce the average number of days for complete disappearance of pain and postsurgery inflammation []. Trials indicate that bromelain might be effective in reducing swelling, bruising, and pain in women having episiotomy []. Nowadays, bromelain is used for treating acute inflammation and sports injuries [].

4.8. Role of Bromelain in Debridement Burns

The removal of damaged tissue from wounds or second/third degree burns is termed as debridement. Bromelain applied as a cream (35% bromelain in a lipid base) can be beneficial for debridement of necrotic tissue and acceleration of healing. Bromelain contains escharase which is responsible for this effect. Escharase is nonproteolytic and has no hydrolytic enzyme activity against normal protein substrate or various glycosaminoglycan substrates. Its activity varies greatly with different preparations []. In two different enzymatic debridement studies carried out in porcine model, using different bromelain-based agents, namely, Debriding Gel Dressing (DGD) and Debrase Gel Dressing showed rapid removal of the necrotic layer of the dermis with preservation of the unburned tissues []. In another study on Chinese landrace pigs, enzymatic debridement using topical bromelain in incised wound tracks accelerated the recovery of blood perfusion, pO2in wound tissue, controlled the expression of TNF-α, and raised the expression of TGT-β []. Enzymatic debridement using bromelain is better than surgical debridement as surgical incision is painful, nonselective and exposes the patients to the risk of repeated anaesthesia and significant bleeding [].

4.9. Toxicity of Bromelain

According to Taussig et al. [] bromelain has very low toxicity with an LD50(lethal doses) greater than 10 g/kg in mice, rates, and rabbits. Toxicity tests on dogs, with increasing level of bromelain up to 750 mg/kg administered daily, showed no toxic effects after six months. Dosages of 1500 mg/kg per day when administered to rats showed no carcinogenic or teratogenic effects and did not provoke any alteration in food intake, histology of heart, growth, spleen, kidney, or hematological parameters []. Eckert et al. [] after giving bromelain (3000 FIP unit/day) to human over a period of ten days found no significant changes in blood coagulation parameters.

5. Conclusion

Bromelain has a wide range of therapeutic benefits, but the mode of its action is not properly understood. It is proved that bromelain is well absorbed in body after oral administration and it has no major side effects, even after prolonged use. All the evidences reviewed in this paper suggest that bromelain can be used as an effective health supplement to prevent cancer, diabetes, and various cardiovascular diseases in the long run.

6. Future Trends and Perspectives

Bromelain can be a promising candidate for the development of oral enzyme therapies for oncology patients. It is clear from this paper that bromelain is a multiaction enzyme; however, more research is required to understand the proper mechanism of action of bromelain so that the multiaction activities of bromelain can be harnessed efficiently.

Acknowledgments

The authors are grateful to DEAN, Department of Biotechnology, IBMER, Mangalayatan University, Aligarh, India, for providing necessary facilities and encouragement. They are also thankful to all faculty members of the Institute of Biomedical Education and Research, Mangalayatan University, Aligarh, India, for their generous help and suggestions during the paper preparation.

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