Abstract

Lipid peroxidation was shown to be an initiatory cause of cataract development in some cases. It has been established that injection into the vitreous body of the rabbit eye of a suspension of liposomes prepared from phospholipids containing lipid peroxidation products induces the development of posterior subcapsular cataract. Such modelling of cataract is based on a type of clouding of the crystalline lens similar to that observed in cataract resulting from diffusion of toxic lipid peroxidation products from the retina to the lens through the vitreous body on degeneration of the photoreceptors. Saturated liposomes (prepared from dipalmitoylphosphatidylcholine) did not cause clouding of the lens, which demonstrated the peroxide mechanism of the genesis of this form of cataract. Clouding of the lens was accompanied by accumulation of fluorescing lipid peroxidation products in the vitreous body, aqueous humor and the lens and also by a fall in the concentration of reduced glutathione in the lens. The ability of l-carnosine (-alanyl-l-histidine) to interact directly with lipid peroxidation products suggested its anticataract properties. The effect of l-carnosine on inhibiting or reversing the formation of cataract induced by the administration of lipid peroxidation products was discovered. This phenomenon appeared to be related with normalization of the peroxide metabolism parameters in the crystalline lens. In view of the data, an aqueous solution of lcarnosine is physiologically acceptable in effective nonsurgical treatment for cataracts.

Keywords

Lipid peroxidation; Glutathione; l-Carnosine; Histidine; Dipeptide; (Posterior subcapsular cataract)

There are no figures or tables for this document.

Correspondence: M.A. Babizhayev, Abteilung fr Experimentelle Ophthalmologie, Medizinische Einrichtungen der Universitt Bonn, Augenklinik, Sigmund-Freun-Str. 25, D-5300 Bonn., F.R.G. Copyright 1989 Published by Elsevier B.V.

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Cataracts and L-Carnosine

Mar 2, 2011 | By Kay Rockwell

Photo Credit Eye image by slepukhin aleksandr from Fotolia.com The natural lens is a structure in your eye behind the iris. This lens bends the light entering your eye to place it on a specific area of the back of your eye, conducting one of the many steps in creating the visual images you see. As you age, the lens components break down, causing this clear structure to turn cloudy and distort vision. Many people turn to supplements, such as Lcarnosine, to prevent or reverse damage.

L-Carnosine
L-carnosine is a chemical compound that stems from an amino acid and histidine. This product is found in the brain, muscle and other areas of your body where you have high cell content. Lcarnosine has antioxidant properties as well, and this may help protect cells from oxidation, a process that can damage cell structure. In effect, this could help protect the proteins that make up your natural lens, preventing the cells from breaking down and turning the lens cloudy. Sponsored Links Bee Pollen Supplements Pure New Zealand Bee Pollen at low prices. Worldwide delivery! HoneyShop.co.nz

Studies
Some research may validate the potential benefits of L-carnosine for cataracts. In 1994, researchers from the Moscow Helmholtz Research Institute of Eye Diseases linked the antioxidant benefits of this compound to the potential for prevention or partially reversing cataract development. In 2002, some of these same researchers evaluated an eye drop that contained a similar compound, and this drop showed a similar potential. These initial inquiries show promise, but research must continue to evaluate long-term effects.

Treatment
As of 2011, doctors do not have an eye drop or other medication to give you that will dissolve or otherwise treat a cataract. If you have cataracts that affect your vision, your doctor may recommend surgical removal of the cloudy lens. During this procedure, the eye surgeon will replace the cloudy lens with a man-made lens. Most people who have this procedure have excellent vision post surgery.

Considerations
Some manufacturers may market a product as a "miracle cure," but you should discuss these supplements with your doctor before purchasing the product. Your doctor can help you determine if the product has any potential side effects or drug interactions. If the product appears otherwise safe, your doctor may approve of trying the supplement, but she may also warn you that the product is not likely to reverse cataracts. Sponsored Links Scarless Eye Surgery Natural & Long Lasting Results with Quick Recovery. Consult Us Now! doubleeyelid.cosmeticsurgery.sg Cataract Multifocal Lens Fast Painless Phaco Cataract Remova Small Incision Cataract Surgery www.isec.my Cari Dokter Mata di JKT? KMN memiliki dokter spesialis mata yang berpengalaman klinikmatanusantara.com Procurement Reports Download Short Procurement & Purchasing Reports purchasingprocurement-center.com

References

MayoClinic.com; Cataracts; May 2010 SupplementNews.org: Carnosine Introduction "Biochemistry Journal"; L-Carnosine (Beta-alanyl-L-histidine) and Carcinine (Betaalanylhistamine) Act as Natural Antioxidants With Hydroxyl-radial-scavenging and Lipid-peroxidase Activities; M.A. Babizhayev, et al.; December 1994 "Drugs R & D"; Efficacy of N-acetylcarnosine in the Treatment of Cataracts; M.A. Babizhayev; 2002

Article reviewed by Christine Brncik Last updated on: Mar 2, 2011 1-888-997-0112 OUTSIDE USA: 1-561-997-0112 a4m@worldhealth.net

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Senile Cataract & N-acetylcarnosine EyeDrops

Posted on June 23, 2003, 11:51 a.m. in Cataract Senile Cataract & N-acetylcarnosine Eye-Drops By Robert Mason PhD Cataract is the leading cause of blindness and accounts for about 42% of all such cases worldwide, and this is in-spite of the availability of effective surgical treatment. Today we have the appalling situation where more than 17 million people around the world are blind because of cataract and 28,000 new cases are reported everyday. In developing countries, there is simply not a sufficient number of surgeons to perform cataract operations. Cataract surgery is the most commonly performed surgical procedure in people over 65-years of age, and 43% of all visits to ophthalmologists by Medicare patients in the US are directly associated with cataract. Meanwhile, approximately 25% of the population over 65 (and about 50% over 80), have a serious loss of vision due to cataract. Since this is the population that is most susceptible to lens opacification and as this section of the population is expected to increase dramatically, the numbers of individuals with cataract is set to explode! For example, the World Health Organization anticipates that within the next 25-years, that 20% of the population will be 65 or older. Furthermore, the single largest growing section of the population are those over 85 and their actual numbers are expected to quadruple in about the same period. Such a rapidly burgeoning older population can only increase the numbers of individuals suffering from cataract. Of course, there is also the economic impact. Currently 1.35 million cataract operations are performed annually in the United States alone and Medicare estimates the annual cost at $3.5 billion! There's no doubt about it, cataract is a major disease. It is also becoming apparent that it will not be possible to eliminate the overall problems (including blindness), caused by cataract with the current procedures. With so many people presenting the afflictions of maturity onset cataract, it appears not to be possible to train in-time, the necessary numbers of surgeons required. In-fact, as-it-stands, it looks likely that the total number of people with serious eye-disorders because of cataract, will increase dramatically worldwide. Surgical complications There is another aspect to the problem that is rarely discussed. While cataract surgery is generally recognised as being one of the safest operations, there is a significant complication

rate. For example, in the United States 30% to 50% of all patients having cataract extraction, develop opacification of the posterior lens capsule within two years and require further lazer treatment. Since the number of cataract operations is so large, even a small percentage of complications represents a significant number of people. Of the patients having cataract surgery, 0.8% have retinal detachments, 0.6% to 1.3% are hospitalized for corneal edema (or require corneal transplantation), and 0.1% present endophthalmitis. Thus, aside from secondary cataract, about 2% of the 1.35 million (or approximately 27,000 individuals), just in the US each year, develop serious complications as a result of cataract surgery. It is therefore difficult to support the argument that cataract research is unimportant with statistics such as those cited above. The large and growing number of people blind with cataract and the significant complication rate, should be sufficient reason to increase cataract research. The considerable discomfort experienced by patients as their vision diminishes, and the complete loss of accommodation resulting in the removal of the lens should also be recognised. Besides the possible complications, an artificial lens just does not have the overall optical qualities of a natural lens. A medical solution is required that will maintain the transparency of the lens. Even if the development of cataract can be delayed by 10-years, the overall benefits would be highly significant. The development of NALC Over the last decade the scientists at the Helmholtz Institute of Eye Disease in Moscow have tested various forms of carnosine. One in particular, is known as n-alpha acetylcarnosine or abbreviated here to NALC. NALC presents the first major leap forward in the treatment and possible prevention of senile cataract. A particular, proprietary method of producing extremely high purity NALC, has proven itself to be a suitable ophthalmic drug for the non-surgical treatment of age-related cataracts. Yet it also displays high efficacy and physiological tolerance. NALC has a highly statistical and very significant clinical success rate for patients within 3-12 months of treatment. Not surprisingly, NALC now has numerous formula patents, including its use for cataract. It is also interesting to note that NALC eye-drops are patented for use in openangle glaucoma, but as yet, the research for that disorder remains unpublished. Human trials

Carnosine eye-drops were used in a clinical trial to treat 96 patients aged 60 and above. All the patients had senile cataract in various degrees of maturity. The duration of the disease in these patients ranged between 2 and 21 years. Firstly, the researchers stopped the patients use of all other anti-cataract drugs. Then the patients instilled 1 or 2 drops into each eye 3 or 4 times a day, for a period of 3 to 6 months. The level of eyesight improvement and the change of lens transparency was considered as an evaluation index. The results showed that there was a pronounced effect on primary senile cataract, the effective rate was 100% (i.e. all patients experienced an improvement). For the more mature senile cataract (i.e. those who had had the cataract the longest time, in some cases more than 20-years) the effective rate was still an extremely impressive 80%. These are remarkable results, considering that the best that could normally be expected would be a slight improvement, a halt to the progression and under normal (i.e. non-treated) circumstances a continual worsening of the disease. Importantly, it was also noted that there were no side effects noted in any of the cases. Another Russian study was designed to document and quantify the changes in lens clarity over a 6 to 24 month period for 49 volunteers. Their average age was 65 and all suffered from senile cataract of a minimal to advanced opacification. The patients received either a 1% solution of NALC eye-drops or a placebo, as 2-drops twice a day into each eye. The patients were then evaluated at 2 and 6 month periods. The tests consisted of ophthalmoscopy (glare test), stereocinematagraphic (slit-image) and retro-illumination (photography). A computerized digital analysis then displayed the light scattering and absorbing effects of the centers of each lens. At 6-months, 88.9% of all eyes treated with NALC had an improvement of glare sensitivity, (lowest individual score was a 27% improvement, right the way up to a 100% improvement). 41.5% of all eyes treated with NALC had a significant improvement of the transmissivity of the lens, but perhaps most importantly 90% of the eyes treated with NALC showed an improvement in visual acuity. Meanwhile, in the placebo group there was little change in eye quality at 6months and a gradual deterioration at 12 to 24 months. Importantly, this study also showed that at 24-months the NALC treated group, (who already had significant improvement to the quality of their eyesight), sustained these results with continued use of the NALC eye-drops. Once again, no significant side effects were noted in any cases throughout the 2-year period. Another interesting study also evaluated patients between the ages of 48 and 60, who had various degrees of eyesight impairment, but who did not have the symptoms of cataract. After a course of treatment ranging from 2 to 6 months the conclusion was, that the eye-drops alleviated eyetiredness and continued to improve eyesight (i.e. there was more clear vision). The subjects

reported that the treatment brightened and relaxed their eyes. This is an important indicator that the eye-drops have a value both for preventative purposes, as well as medical applications. At this time, it is now believed that carnosine eye-drop treatment has been applied to over one thousand patients with senile cataract in China and Russia, (those countries are home to the principal researchers behind the work). Clear evidence is emerging that NALC eye-drops are a safe, effective treatment and potential preventative against cataract. NALC method of action Cataract is a glycosylation problem. This reaction occurs when proteins became cross-linked (and hence impaired). The result of this reaction leads to the discoloration of the eye-lens to yellow and brown, and hence the impairment of vision. But, carnosine is known to compete on the molecule for the glycating agent and protect cellular structures against aldehydes. Therefore, carnosine can slow and help to prevent proteins from becoming cross-linked, (and in this case from becoming cataract). NALC has been shown to be highly resistant to carnosinase, (the natural enzyme that breaks down L-carnosine into histamine etc.). An experiment on rabbits showed that NALC eye drops allow themselves to be broken down into L-carnosine once inside the eye's aqueous humor, (a process that occurs within 15 to 30 minutes after application of the eye-drops). L-carnosine is an excellent anti-oxidant and is particularly effective against potent free-radicals, especially the Superoxide and the Hydroxyl. It is therefore presumed, that the anti-oxidant role of L-carnosine (within the aqueous humor) is a major factor, in slowing and preventing the appearance of cataract. However, when L-carnosine eye-drops were used there was no presence of L-carnosine in the aqueous humor (even after 30-minutes). This may be because L-carnosine is broken down early into histamine etc., before it reaches the aqueous humor. So, NALC may act as a carrier for Lcarnosine delivering it to where it is needed. The powerful anti-oxidant abilities of carnosine within the eye, and the prevention of crosslinking, helps to explain why NALC is effective at preventing and slowing cataract, perhaps even halting it. But it doesn't explain why NALC has been shown to reverse cataract. But we may already know the answer. For example, it is known that when carnosine is delivered in high doses, that it can reverse protein-aldehyde cross-linking, (this reaction is normally very difficult to reverse). Under these circumstances, carnosine has been shown to have a rejuvenating effect on cultured cells. Cataract develops when anti-oxidant defense is exhausted, leading to the cross-linking of the lens crystallins, (producing a clouded lens, and hence impaired eyesight). We can assume that the regular use of a 1% NALC eye-drop, (as used in the clinical trials), delivers a high-dose of carnosine capable of reversing the lens cross-linking, and hence the reduction and eradication of cataract.

So in conclusion, NALC eye-drops appear to act as a universal anti-oxidant, both in the lipid phase of the cellular lens membranes, and in the aqueous environment. NALC eye-drops reduce and protect the crystalline lens from oxidative stress-induced, cross-linking damage. NALC compared to L-carnosine We may logically ask the question; why have NALC eye-drops been shown to have this action upon cataract, and yet L-carnosine (which is its sister di-peptide) appears to have little benefit? Dr. Mark Babizhayev, one of the principal Russian researchers behind the clinical trials with NALC eye-drops gave us this reply to that very same question: I believe that the application of L-carnosine for the treatment of human cataracts is misleading. This is because L-carnosine readily becomes a substrate for the activity of natural peptidases (i.e. carnosinase) in the aqueous humor. So much so, that there is no sign of L-carnosine in the aqueous humor within 15 minutes after instillation. Furthermore, I consider that L-carnosine eyedrops may even be harmful for eyes because it gradually releases histamine, which, located as it would be in the presence of the eye-lens is a very toxic agent. However, NALC eye-drops are resistant to hydrolysis with natural carnosinase. Therefore, NALC is the only currently known agent which reverses and prevents human cataracts. In conjunction with Dr. Hipkiss and Dr. Kyriazis information, we can conclude that while some of the benefits of oral L-carnosine may derive after carnosinase breaks down into histamine, that in the case of eye-drops, L-carnosine must be avoided. Buyer beware! Dr. Mark Babizhayev also makes it quite clear that ordinary NALC will not be of much use in the treatment of senile-cataract. This is because there are many synthesized carnosines and their biological and medicinal activity strongly varies and depends on the mode of their obtention. For example, if carnosine is extracted from meat muscle substances, the biological and antioxidant activity is very low. This is presumably due to the contamination of the pure carnosine substance by heavy metal salts and proteins and other related impurities. It is very difficult to purify carnosine chromatographically, as the compound chelates divalent metal ions very heavily and the biological and anti-oxidant activities can not be regenerated during the purification procedures. In conclusion, there were many forms of carnosine which were abandoned in the Russian studies because of their lack of anti-cataract and anti-oxidant ability in the human eye.

Cataract is a widespread age-related affliction and NALC eye-drops appear to be a highly efficacious and safe treatment for cataract. As such, I suspect that this supplement is going to become one of the most important new discoveries, and will have a major impact on the way that cataract is controlled.

Copyright 2003. This article may not be reproduced for public broadcast in any form, without the written permission of: www.antiaging-systems.com References 1. Boldyrev AA, Dupin AM, Bunin Aya, Babizhayev MA, Severin SE The antioxidative properties of carnosine, a natural histidine containing di-peptide. Biochem. Inrern., 1987, 15/6, 1105-1113. 2. Babizhayev MA et al N-Acetylcarnosine, a natural histidine-containing di-peptide, as a potent ophthalmic drug in treatment of human cataracts. Peptides (USA) 2001, 22(6): 979-994. 3. Babizhayev MA, Yermakova VN, Deyev Al, Seguin M-C Imidazole-containing peptiomimetic NALCA as a potent drug for the medicinal treatment of age-related cataract in humans. J. Anti-Aging Medicine 2000, 2, 43-62. 4. Babizhayev MA, Yermakova VN, Semiletov yu A, Deyev Al The natural histidinecontaining di-peptide N-acetylcarnosine as an antioxidant for ophthalmic use. Biochemistry (Moscow), 2000, 65, 588-598. 5. Babizhayev MA, Yermakova VN, Sakina NL, Evstigneeva RP, Rozhkova EA, Zheltukhina GA N-Acetycarnosine is a prodrug of L-carnosine in ophthalmic application as antioxidant. Clin. Chim. Acta., 1996, 254, 1-21. 6. Babizhayev MA, Bozzo Costa E Composizioni farmaceutiche contenenti N-acetilcarnosina per il trattamento della cataratta. A61K gruppo 37/00 cap 20122 MI 15.10.1993. Italian patent. 7. Babizhayev MA, Bozzo Costa E Pharmaceutical compositions containing N-Acetylcarnosine for the treatment of cataract. European Patent PCT/EP 94/03340 10.10.1994 Ref. SCB 238 PCT. 8. Babizhayev MA, Seguin M-C, Gueyene J, Evstigneeva RP, Ageyeva EA, Zheltukhina GA Lcarnosine and carcinine act as natural antioxidants with hydroxyl-radical-scavenging and lipid peroxidase activities. Biochem J. 304, 509-516. 9. Babizhayev MA, Antioxidant activity of L-carnosine, a natural histidine-containing dipeptide in crystalline lens. Biochem. Biophys. Acta., 1989, 1004, 363-371. 10. Babizhayev MA, Deyev Al Lens opacity induced by lipid peroxidation products as a model of cataract associated with retinal disease. Biochim. Biophys. Acta., 1989, 1004, 124-133. 11. Babizhayev MA, Deyev Al Free radical oxidation of lipid and thiol groups in genesis of cataract. Biophysics (biofizika), 1986, 31, 119-125, Pergamon Journals Ltd. 12. Kantha S, Wada S, Tanaka H, Takeushi M, Watabe S, Ochi H (1966), Biochem. Biophys. Res. Commun. 223, 278-292. 13. Babizhayev MA, Deyev Al, Linberg LF Lipid peroxidation as a possible cause of cataract. Mech. Ageing Dev. 1988, 44, 69-89. 14. Boldyrev AA, Problems and perspectives in studying the biological role of carnosine International Center for Biotechnology, Department of Biochemistry, Lomonosov, Moscow State University. 15. Hipkiss A, (1998) Int. J. Biochem. Mol. Biol., 30, 863-868. 16. Boldyrev AA, Dupin A, Bunin A, Babizhayev MA, Severin SE (1987), Biochem. Int., 15, 1107-1113. 17. Wang AM, Ma C, Xie H, F Shen Medical application of carnosine Department of Biochemistry and Neurobiology, Harbin Medical University, China.

18. World Health Organisation, Ageing and Health, Website: http://www.who.int/ageing/scope.html

Advanced Glycation Endproducts (AGEs) and Aging Carnosine is a combination of the amino acids beta-alanine and l-histadine. Carnosine is a strong antioxidant but has even greater importance because it blocks the process of glycation. When sugars combine with protein, they may produce damaging substances called advanced glycation endproducts (AGEs). These AGEs interact with adjacent proteins resulting in impaired function, free radical formation and accelerated aging. Carnosine is a very effective inhibitor of glycation. This works by competing with protein for binding sites on sugar molecules. Carnosine is also thought to bind already produced AGEs so they get removed. This process slows aging so it is quite important. Benefits from carnosine therapy include: Restores fibroblasts to connective tissue, which decreases wrinkles, improves damaged skin elasticity, and speeds healing of wounds. Diabetics have more AGEs at an earlier age than non-diabetics. Carnosine may protect against diabetic complications. Prevents cross-linking to beta amyloid in Alzheimers disease, inhibits free radical production in the brain, and protects against lipid peroxidation. May help the body eradicate h. pylori, the ulcer causing bacteria Rejuvenates old cells, extending cell life span, which should benefit longevity (proven in mice). Improves vision in most persons with cataracts. Revitalizes fibroblasts, thus blocking aging of skin (wrinkles). Carnosine is found in health food stores. The total dose is 1000 mg daily taken in divided doses. This should be a valuable supplement for all diabetics and all persons over 50 years of age. N-acetylcarnosine Dissolves Catatarcts A new and valuable therapy for cataracts is N-acetylcarnosine (NAC). This was developed by opthalmologist Dr. Mark Babizhayev in Moscow. Application of a 1% solution of NAC to the eyes has dissolved cataracts. This works by preventing and reversing cross linking of the lens proteins (glycation) that produces opacification and impaired vision. In six months, 90% of patients had improved vision. No side effects or decrease in vision was seen.

Side Effects of Kombu

0 Comments Print Feb 28, 2011 | By Rae Uddin

Kombu, more commonly known as laminaria or kelp, is a type of Japanese seaweed that is used as both a food and medicinal supplement. Traditionally, kombu has been used to induce labor in pregnant women. However, the safety of the use of this natural treatment during pregnancy remains unclear. Discuss the side effects of kombu with your medical provider before using this supplement.

Pregnancy Complications
Kombu has been used to manually dilate a pregnant woman's cervix -- the small opening at the base of the uterus -- and induce labor. Unfortunately, this use of kombu may cause severe pregnancy complications for the mother and baby. Infection, cervical rupture and infant death may occur following treatment with kombu. For this reason, expectant mothers should not use kombu unless otherwise directed by a physician.
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Thyroid Gland Problems

As an iodine-rich supplement, kombu may significantly elevate the levels of iodine in your bloodstream. Iodine stimulates your thyroid gland to produce thyroid hormone. High levels of iodine may result in the overproduction of thyroid hormone, a condition called hyperthyroidism. Symptoms of hyperthyroidism include fatigue, heart rate changes, loose and soft stools, weight loss, and profuse sweating. If you develop any of these symptoms while taking kombu, seek additional care from your doctor.

Medication Interactions
Kombu may interact with certain medications. Avoid using kombu in conjunction with digoxin, ACE inhibitors, potassium supplements, and potassium-sparing diuretics or water pills. Kombu is a high-potassium supplement and may inadvertently elevate your potassium levels to unhealthy levels when used in conjunction with these drugs. In addition, do not take kombu if you are also taking thyroid hormone, because this treatment combination may raise your risk of developing high blood levels of thyroid hormone.

Contraindications

Treatment with kombu is not appropriate for everyone. If you have a pre-existing thyroid gland disease, such as goiter, hypothyroidism or hyperthyroidism, or kidney problems, you should not take kombu. Improper use of kombu may worsen symptoms associated with your health condition.

Read more: http://www.livestrong.com/article/393396-side-effects-of-kombu/#ixzz2I6wwiZyh

Kombu or Laminaria Japonica is large seaweed, which belongs to the brown algae and it is classified in the order of Laminariales. Kombu is an important food source in many Asian cultures, while in occidental it is principally used by vegetarians. Kombu contains:

iodine 8000 mg/100g potassium 6100 mg calcium 710 mg iron 3.9 mg carotene 1100 g vitaminB1 0.48 mg vitaminB2 0.37 mg dietary fiber 27.1g energy 145kcal (per 100gr) glutamic acid

In medicine Kombu is required:

to promote the thyroid gland hormone;

perch ? spiegare

to prevent a rise of blood pressure, cholesterol and blood sugar level; to cure intestinal disorders

As Iodine supply in dietary Iodine deficiency

Since Kombu contains a high iodine contents, it has an effect for thyroid gland. Indeed, iodine is an essential element of thyroid hormones. Thus changes in iodine intake can cause various thyroid disorders. Thyroid hormones, 3,5,3-triiodothyronine (T3) and thyroxine (T4), are implicated in the regulation of metabolism, growth and maturation of a variety of organ systems. The daily requirement of iodine is : ADULT : 150g/die PREGNANT : 250g/die CHILD <2 years 90g/die

Effects of excessive Iodine intake

THE PROBLEM In literature, it is proved that Kombu is used by an increasing number of patient and people. According to the prevailing belief that herbal products are safe owing to their natural origin, most of people use Kombu as dietary supplements. However, many serious and side effects have been recently reported. Kombu has different side effected as toxicity and allergic reactions, moreover Kombu can interact with drugs and other herbs leading to a healthy problems. For example, an excess iodine may induce not only hyperthyroidism but also hypothyroidism, particularly in subjects living in iodine-sufficient area, neonatal or older persons, patients with underlying thyroid disorders such as autoimmune thyroid disease, subacute thyroiditis, thyroidectomy and other. The occurrence of these 2 disparate responses to iodide excess may be due to differences in the sensitivity to iodide-induced turn-off in hormone biosynthesis. Subjects with an elevated sensitivity, such as patients previously treated for Graves' disease with radioactive iodine, subtotal thyroidectomy, antithyroid drugs, or those with chronic autoimmune thyroiditis, have an increased risk to develop hypothyroidism after administration of excessive iodide because of a failure to escape from the acute WolffChaikoff effect . In contrast, in subjects with lowered sensitivity, patients with endemic goiter and iodide deficiency or patients with nodular goiter containing autonomous nodules, iodide excess may result in hyperthyroidism. The Wolff-Chaikoff is an autoregulatory phenomenon, which inhibits formation of thyroid hormones inside of the thyroid follicle, because there is a decrease in sodium/iodide symporter (NIS) and thyroid peroxidase (TPO) due to elevated levels of circulating iodide. NIS and TPO are two proteins, that are involved in synthesis of T4 and T3. In details, NIS transports iodide (I-) across the basolateral membrane into thyroid epithelial cells. TPO is a glycosil protein. Starting from tyreoglobulin, TPO synthetizes T3 and T4 hormones. The expression of NIS and TPO genes is stimulated by thyrotropin (TSH). Wolff-Chaikoff's effect persists in several days (around 10 days), then it is followed by an "escape phenomenon", which is characterized by resumption of normal organification of iodine and normal thyroid peroxidase function. This escape phenomenon in some people could fail and leads to HYPOTHYROIDISM due to excess of iodine. Some researches [1] suggest that NIS and TPO decrease thanks to a transcriptional mechanism. Indeed, these studies report a decrease of NIS and TPO mRNA in Wolff-Chaikoff. In [2] the authors explain the suppression of thyroid function during ingestion of seaweed Kombu in normal Japanese adults. Indeed, most Japanese people eats iodine-rich foods such as seaweed . They demonstrate that the daily ingestion of Kombu over the short term (7-10 days) results in a significant increase in serum TSH with a slight decrease in serum free thyroxine (FT4) and/or free 3,5,3-triiodothyronine (FT3) concentrations. During ingestion of Kombu for long term (5587 days) serum TSH levels are elevated, but FT3 and FT4 concentrations are almost within normal values. FT3 and FT4 concentrations are influenced by various factors such as the degrees of inhibitory effect of iodine on thyroid function, increase of TSH by the negative feedback mechanism, responsiveness and compensatory enlargement of thyroid gland to TSH. The inhibitory action of excess iodine (acute Wolff-Chaikoff effect) is known to be temporary but in this study it is persisted in the patients for three months. This highlights that thyroid

function in normal Japanese adults is suppressed during the ingestion of Kombu, although the suppression is slight and reversible. Recently, some studies have reported that one third of cases of consecutive Hypothyroidism in Japan become euthyroid after iodine restriction. Another study [3] proves that, although iodine supplementation should be implemented to prevent and treat iodine-deficiency disorders, supplementation should be maintained at a safe level. In fact the authors observed an increase in the prevalence of overt hypothyroidism, subclinical hypothyroidism, and autoimmune thyroiditis with increasing iodine intake in China in cohorts from three regions with different levels of iodine intake. They examined the effect of regional differences in iodine intake on the incidence of thyroid disease. Levels that are more than adequate or excessive do not appear to be safe, especially for susceptible populations with either potential autoimmune thyroid disease or iodine deficiency. Supplementation programs should be tailored to the particular region. No iodine supplementation should be provided for regions in which iodine intake is sufficient, whereas in regions in which iodine intake is deficient should be supplemented with iodine according to the degree of iodine deficiency. But in the most cases the not-controlled assumption of Kombu leads to HYPERTHYROIDISM. 1.CASE REPORT:4 A 39-year-old woman (157 cm, 75 kg, body mass index [BMI] 30.4 kg/m2) with enlarged thyroid. The patients medical history and family history were unremarkable. Medical examination confirmed a palpably enlarged thyroid. Normal values of FT3, FT4, and TSH were congruent with the lack of clinical signs of hyper- or hypothyroidism; anti-TPO, antithyroglobuline (TG), and anti-TSH-receptor (TSH-R) antibodies were negative. Normal PARAMETERS: fT4 (ng/dL) fT3 (pg/dL) TSH (mU/L) TPO-AB (kU/L) TG-AB (kU/L) TSH-R-AB (U/L) 0.81.7 210420 0.42.5 <1.9 <0.9 <12 Ultrasonography revealed a multinodular goiter with a total volume of 62 mL. A thyroid 99mTC-pertechnetate scintigraphy showed a homogenous uptake with a moderate autonomy in the right upper lobe, confirmed by a thyroid scan under exogenous TSH suppression with levothyroxine. The patient was informed of the therapeutic options: 1)thyroid resection; 2) routine follow-up clinical visits. She decided against surgery, so that a short-term control visit was arranged. Furthermore, it was pointed out to the patient to avoid the intake of large amounts of iodine, such as iodinated radiocontrast agents or iodine-containing drugs or food. Two months later, the patient was in good general health and endocrine tests revealed thyroid hormones and TSH plasma levels within the normal range. Four months after the initial visit, the patient showed typical signs of hyperthyroidism, including tachycardia (100 beats/min), palpitations, tremor, nervousness, insomnia, fatigue, increased sweating, diarrhea, secondary amenorrhoea, and weight loss. The laboratory analysis revealed

increased levels of FT3 and FT4 as well as a suppressed TSH concentration and anti-thyroid antibodies remained negative. Ultrasonography showed a multinodular goiter with a total volume of 67 mL. The patient did not report any exposure to medications containing iodine, such as iodinated radiocontrast agents or amiodarone. However, on further questioning, the patient reported that for the last 4 weeks she had been consuming a herbal tea, prescribed by a Chinese alternative practitioner to treat her enlarged thyroid. Treatment included kelp, Sargassum weed, and Kombu. Then, the patient was advised to discontinue the consumption of the tea and an antithyroid drug therapy was initiated. Her follow-up visit, 7 months after the diagnosis of hyperthyroidism, revealed normal laboratory values. In another case [5], an excess of iodine can obstruct the therapy: A 55-year-old man had a large mass on the right side of his neck, which was identified in a specimen from a fine-needle aspiration biopsy as papillary thyroid carcinoma . He had a total thyroidectomy and the pathological examination revealed a multifocal, papillary thyroid carcinoma with metastases in 26 of 78 lymph nodes. Ablation with radioiodine was recommended, but the patient had undergone computed tomographic (CT) scanning with an iodine-rich contrast agent 2 months earlier. The level of urinary iodine was elevated and remained elevated after 10 days on furosemide, a diuretic. The patient reported having ingested a large number of supplements, included selenium. The selenium supplement was the source of the excess iodine, which is found in kelp, an inactive ingredient in the supplement. He did not resume taking the supplements and was again placed on a low-iodine diet for 4 weeks and the level of urinary iodine was decreased. Physician who use radioiodine are aware that excess exogenous iodine impairs the efficacy of iodine-131 therapy. In this patient, excessive iodine intake came from an unexpected source (kelp-enriched selenium). The iodine content of kelp is highly variable, and it is likely that the iodine levels in different batches of kelp-enriched selenium are also highly variable. Although it is not routine to assess urinary iodine concentrations in patients receiving radioiodine, it needs for physicians to review patients medications and dietary habits carefully to prevent ingestion hidden sources of iodine. Other researches [6] reported the consequences in neonates born to mothers with excessive iodine intake. These neonates were exposed to elevated quantities of iodine, because their mothers consumed an excessive quantity of Kombu during the pregnancies. This exposure led to transient hypothyroidism. Some of these newborns have required LEVO-thyroxine treatment, because hyperthyrotropinemia was persisted. CONCLUSIONS These researches show that the consumptions of seaweed as Kombu, which are promoted as healthy foods, have to be controlled and have not to exceed the daily limit needed to the person. Particularly patients, which have thyroid disorders, must inform the physician before assuming Kombu. Since most Asian people eat a great deal of Kombu, it is necessary to warn these people against

consuming excessive amounts of seaweed. For instance, in Japan the Ministry of Health, Labour and Welfare recommended an upper intake bound of iodine as 3mg. per day [7]. References 1. Escape from the acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter messenger ribonucleic acid and protein.1999 2.Suppression of thyroid function during ingestion of seaweed Kombu (Laminaria japonica) in normal Japanese adults. Endocrinology Journal (2008); 55 (6): 1103-1108 3.Effect of iodine intake on thyroid disease in China The New England Journal of Medicine (2006); 354: 2783-93 4. Iodine induced thyrotoxicosis after ingestion of kelp containing tea Journal General of Internal Medicine (2006 June); 21(6): C11-C14 5. Excess iodine from an unexpected source The New England Journal of Medicine (2009 January); 360: 4 6. Transient hypothyroidism or persistent hyperthyrotropinemia in neonates born to mothers with excessive iodine intake Thyroid (2004 December); 14(12): 1077-83 7. The Ministry of Health, Labour, and Welfare, Japan (2005) Dietary reference intakes for Japanese (2005) In the Ministry of Health, Labour, and Welfare (ed) Daiichi Shuppan Publishing, Tokyo: 189-193 CHIARA CAMPAGNARO (MATRICOLA 257483)- LAURA CORDERO (MATRICOLA 239608)