-Iodine in biology -Extrathyroidal iodine -Gastric cancer -Atrophic gastritis -Breast cancer -Goitre -Salivary Glands -Oral Health -Immunity -Iodine metabolism -Iodide as an antioxidant -Iodine-prophylaxis -Cretinism -Neuropsycological Pathologies -Evolution -Evolution of Dietary Antioxidants -Vitamin C in Evolution -Selenium: Evolution in Biology

Dr. Sebastiano Venturi via Tre Genghe n. 2;  47864 PENNABILLI (RN) ;  (Italy) Tel : (+39) 0541 928205. E-mail : venturi.sebastiano@gmail.com C.V. Updated March 12, 2011

Published in EUROPEAN EPI-MARKER

Vol. 7, No. 2, April 2003. pagg. 1-7

The Newsletter of the International Center for Studies and Research in Biomedicine, Luxembourg

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IODINE, HELICOBACTER PYLORI, STOMACH CANCER & EVOLUTION

Venturi S, Grossi L*, Marra GA*, Venturi A, Venturi M
Servizio di Igiene, Pennabilli (PU) Italy, and *Ospedale Civile, Novafeltria, ASL n.1 (Pesaro), Regione Marche, Italy.

KEY WORDS:

iodine, antioxidant, evolution, Helicobacter pylori, thyroid, gastritis, stomach cancer

Corresponding address: Dr. Sebastiano Venturi - via Tre Genghe n. 3 ; 46864-PENNABILLI (RN), Italy Tel : (+39) 0541 928205 . Fax : (+39) 0541 928112 .

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SUMMARY

The authors have hypothesized that dietary iodine (I) deficiency or excess are associated with the development of atrophic gastritis and gastric cancer (GC). They report a short review of their own work and general literature on this correlation in three fields: (1) epidemiology, where geographical and temporal correlations between territories with I-deficiency, endemic goitre and high GC-death rate are reported; (2) iodine and atrophic gastritis correlations, and (3) immunology, where the correlations between I-deficiency, immune-deficiency and GC are reported. Thyroid cells phylogenetically and embryologically, derived from primitive I-concentrating gastric cells which, during evolution, migrated and specialized in uptake and storage of iodine, in order to adapt the organisms from I-rich sea to I-deficient land. Stomach and thyroid share an important iodide-concentrating ability and an efficient peroxidase activity, which transfers electrons from iodides to the oxygen of hydrogen peroxide and so protects the cells from peroxidations. Iodide seems to have an ancestral antioxidant function in all iodide-concentrating organisms from primitive algae to more recent vertebrates. In Italy, GC is more frequent in farmers and in I-deficient populations, living in mountainous and hilly areas, than in fishermen. In the last two decades, Italian decrease of GC seems to be correlated more with the higher dietary consumption of I-rich fish rather than with consumption of fruit and vegetables, which indeed has decreased in Italy. In conclusion, iodine deficiency or excess seem to constitute an important risk factors for atrophic gastritis and GC, both by antioxidant activity and regulating gastric trophism and by antagonizing the actions of both Helicobacter pylori and of I-inhibitors, such as nitrates, thiocyanate and salt, well-known risk factors for GC.

FOREWORD

Iodine (I) is the heaviest and richest in electrons of the required elements in the animal diet, and as iodide (I-) enters in the cells. Inorganic iodide is necessary for all living plant and animal cells, but only the vertebrates have the thyroid gland and its iodinated hormones. In humans, the total amount of iodine is about 25-50 mg and about 60-70 % of total iodine is non-hormonal and it is concentrated in extrathyroidal tissues, where its biological role is still unknown. In 1985 (1), we have hypothesized that iodide might have an ancestral antioxidant function in all iodide-concentrating cells from primitive algae to more recent vertebrates (1-3). In these cells iodide acts as an electron donor in the presence of H2O2 and peroxidase, and the remaining iodine atom readily iodinates tyrosine, histidine or certain specific lipids, and so, neutralizes its own oxidant power.

In fact:

2 I- à I2 + 2 e- (electrons) = - 0.54 Volt

and

2 I- + Peroxidase + H2O2 + 2 Tyrosine à 2 Iodo-Tyrosine + H2O + 2 e- (antioxidant)

and

2 e- + H2O2 + 2 H+ (of physiological water-solution) à 2 H2O

Marine algae are also able, by haloperoxidase enzymes, to catalize iodide (I-) incorporation into carbon metabolites producing iodo-methane gas (CH₃I) and other halocarbons in terrestrial atmosphere. According to Petersén et al. (4) and Kuepper et al. (5) this production is a result of the development of photosynthesis and oxygen production and respiration some 3 billion years ago, is due to an adaptation to light in order to reduce the amount of poisonous active oxygen species, such as hydrogen peroxide, superoxide radicals and hydroxyl radicals. Recently, a second pathway for iodine organification has been described, which involves iodine incorporation into specific lipid molecules. Iodine can add to double bonds of some polyunsaturated fatty acids of cellular membranes, making them less reactive to free oxygen radicals (6, 7). Isolated cells of gastric mucosa of mice could produce "in vitro" protein-bound mono-iodotyrosine, di-iodotyrosine and probably some iodolipids (8). These iodolipids have been shown to be regulators of thyroid cells metabolism and proliferation. In particular delta-iodolactone (6-iodo-5-hydroxy-eicosatrienoic acid) has been found to be a potent inhibitor of thyroid cells proliferation ( 9-11) and according to Cann (12) these iodolipids may also play a role in anti-proliferative control of non-thyroidal I-concentrating tissues. In the Mammalia, T4 and reverse-T3 (but not T3) are found to be more effective as antioxidants and inhibitors of lipid peroxidation than vitamin E, glutathione and ascorbic acid. (1,14). Virgili et al. (15) reported that treatment with thyroxine protects from peroxidative intestinal damage, induced by zinc-deficiency in rats. Dietary iodides are also able to defend brain cells from peroxidation in rats (16) and it is helpful in many human chronic diseases (17-19), in cooperation with antioxidant selenium. In fact selenium is present in cellular peroxidases and deiodinases, which are able to extract electrons from iodides, and the latter iodides from iodothyronines.

INTRODUCTION

According to current WHO statistics more than three billion people in the world live in I-deficient countries, including some European Nations, also because of an ineffective I-prophylaxis (20, 21). The urinary iodine excretion (UIE) in these populations examined was less than 100 microgrammes (ug) per day, while the RDA of iodine is 150-200 ug and FAO recommends 400 ug in order to compensate environmental dietary goitrogens (22) . The UIE in Scandinavian countries, thanks to iodized salt, nowadays reaches 250 ug compared to more than 300-400 ug per day in USA (23, 24). The UIE in the Italian populations of the central Apennines is less than 100 ug, and it is lower among older people, farmers and the poorer social classes, who are those more subject to goitre, as well as to gastric cancer (GC) ( 1-3, 25, 27).

IODINE AND EVOLUTION

IODINE and EVOLUTION.
Over three billion years ago, blue-green algae were the first living Prokaryota to produce oxygen in the atmosphere. About 700 million years ago (m/y/a) thyroxine (T4) is present in fibrous exoskeletal scleroproteins of the lowest invertebrates (sponges and corals) without showing any hormonal action. About 500-400 m/y/a some primitive marine fishes started to emerge from the iodine-rich sea (60 ug/L) and transferred to iodine-deficient fresh water (5-0.2 ug/L) and about 400-300 m/y/a these vertebrates evolved in amphibians and reptiles and transferred to I-deficient land. Therefore these vertebrates needed a new follicular organ: the thyroid gland, as reservoir of iodine. These vertebrates started to use its primitive T4 as transporter, into the peripherical cells, of antioxidant iodide and T3. The remaining T3 became the active hormone in the metamorphosis and thermogenesis for a better adaptation to terrestrial environment: fresh water, atmosphere, gravity, temperature and diet.

Over three billion years ago, blue-green algae (Cyanobacteria), which are the most primitive oxygenic photosynthetic organisms, ancestors of multicellular eukaryotic algae that contain the highest amount of iodine, were the first living cells to produce poisonous oxygen in the terrestrial atmosphere. So, algal cells required a protective antioxidant action in which iodides seem to have had this specific role (1-4, 45, 27, 28). In fact iodides are greatly present and available in sea-waters, where algal phytoplankton, the basis of marine food-chain, acts as a biological accumulator of iodides and selenium, and also of n-3 fatty acids. The sea is rich in iodine ( about 60 ug / L) since this is where most of the iodine removed and washed away from the soil accumulated by the glaciations ages. In water the iodine concentration decreases step by step from sea-water to estuary (about 5 ug/ L) and source of rivers (less than 0.26 ug/ L in some Triassic mountain regions of northern Italy), and in parallel, salt-water fishes (herring) contain about 520 ug of iodine per kg compared to fresh-water trouts about 20 ug per kg. Since about 700 million years ago thyroxine (T4) is present in fibrous exoskeletal scleroproteins of the lowest invertebrates (29), without showing any hormonal action. When some primitive marine vertebrates started to emerge from the I-rich sea and transferred to I-deficient fresh water and finally land, their diet became I-deficient and also harboured vegetable I-competitors such as nitrates, nitrites, thiocyanates and some glycosides (28, 30). Hence, about 400-500 million years ago, these animals needed an new efficient follicular organ: the thyroid, as reservoir of iodine. During progressive slow adaptation to terrestrial life, the ancient chordates started to use the primitive, but not antagonized, T4 in order to transport antioxidant iodide into the peripherical cells. The remaining triiodothyronine (T3), the real active hormone, became active in the metamorphosis and thermogenesis for a better adaptation of the organisms to new terrestrial environment ( fresh water, atmosphere, gravity, temperature and diet). The new hormonal action was made possible by the formation of new T3-receptors in the cells of vertebrates. Thyroid cells phylogenetically derived from primitive I-concentrating gastric cells, which are able to form iodo-tyrosines (8), and during evolution migrated and specialized in uptake and storage iodine-compounds in the follicles. Sodium iodide symporter (NIS) is the proteic transmembrane transporter of iodide. Gastric iodide-pump and NIS, more primitive than the thyroidal ones, have lower affinity for iodide and does not respond to more recent TSH (Thyrotropin). For this reason we believe that thyroid cell itself might be less directly damaged by pathologies caused by I-deficiency than other I-concentrating cells, as stomach and probably breast cells (6, 25). In pregnant mouse, fetal gastric mucosa shows iodine-concentrating ability earlier than fetal thyroid (31). In primitive reptilian stomach of lizard radioiodine remains more than 8 days (32); while during human total-body 131-I-scintiscans, the radioiodine remains on the stomach more than 72 hours. Cows have an efficient iodine recycling system in their abomasum, via the gastrointestinal tract, which conserves iodine and can protect them against low dietary iodine (33).

EXTRATHYROIDAL IODIDE-CONCENTRATING ORGANS

Figure 1. Sequence of I-123 total-body scintiscans of a woman after intravenous injection of I-123 (half-life: 13 hours); (from left) respectively at 30 minutes, and at 6, 20 and 48 hours. It is evident the highest and rapid concentration of radioiodide in gastric mucosa of the stomach and high urinary I-excretion. In the thyroid I-concentration is more progressive, as in a reservoir (from 1% to 5.8 % of the total injected dose).

In the Mammalia, several extrathyroidal non-follicular organs share the same gene expression of NIS and particularly stomach mucosa and lactating mammary gland (6, 34). Salivary glands, thymus, epidermis, choroid plexus and articular, arterial and skeletal systems (31) have iodide-concentrating ability too. But what role does iodide play in animal cells? We may chronologically differentiate on the basis of the phylogenesis and embryogenesis three ways of action of iodine :

1) an ancient and direct action, on endodermal fore-gut and stomach and on ectodermal epidermis, where inorganic iodides probably act as antioxidants.

2) a recent and similar direct action, on salivary and mammary glands (6), thymus, ovary and on nervous, arterial and skeletal systems.

3) a more recent and indirect action of the thyroid and its iodinated hormones, on all vertebrate cells, which makes use of specific iodine-compounds: thyroxine (T4) and triiodothyronine (T3), which act in very small quantities and utilize T3-receptors. Indeed thyroid hormones contain less than 1/30 of total iodine amount.

We believe that all these actions of iodine may still take place into the cells of modern vertebrates (3, 28). In fact, Evans et al. (35) reported that 5 mg of potassium iodide (daily injected) acts as 0.25 ug of L-thyroxine in recovering the impaired functions of many organs of thyroidectomized rats.

Furthermore Wolff (30) reported that two patients with goitre and hypothyroidism have been described in whom the ability to concentrate iodide was lost in the thyroid (and in gastric mucosa and salivary gland); both patients were treated with large doses of iodide alone: both responded well (regarding to growth, BMR, cholesterol, etc.). This suggest strongly that while iodides are always necessary, the thyroid hormones are not indispensable for living organisms.

IODINE AND STOMACH: ANATOMY AND PHYSIOLOGY

In the mammal and human, dietary iodine is, by NIS, rapidly adsorbed as iodide (I-) from the small intestine. Iodide is not only concentrated in follicular thyroid but also in the salivary glands, gastric mucosa and its secretions, where there is a concentration of 20-30 % of iodine ( 30, 36, 37) (Fig.1). The gastric cells with iodide-concentrating capacity, are the mucoid cells of the mucosa surface and of the neck of the gastric glands (37).

Cloning and molecular characterization of the human NIS have been recently performed. (38, 39). The gastric mucosa has high and permanent ability to concentrate iodides and to form iodocompounds by gastric peroxidase (8). Inorganic iodine regulates the production of epidermal growth factor (EGF) in the thyroid cells, and controls DNA synthesis and cell proliferation (40); this action might also occur in gastric mucosa and in salivary glands. The fact that mucous cells of some metastases from gastric cancers show I-concentrating ability might be interesting for a possible radiometabolic therapy (41-42).

Iodide-concentration was not observed in the duodenum, jejunum, ileum or colon, whose cancer incidence have different trends, distributions and probably different risk factors from GC. The iodide-concentration and NIS are inhibited by nitrates, nitrites, thiocyanate, some glycosides, salt and also, paradoxically, by an excessive quantity of iodine (43). The peptic and oxyntic cells of gastric mucosa do not have an I-concentrating ability. In fact the concentration and secretion of iodine in gastric juice are independent from chloride-peptic secretion (36). In addition an excess of iodides impairs the iodide pump (NIS) and the cellular trophism of iodide-concentrating tissues, resulting in functional damage including the well-known Wolff-Chaikoff effect, which occurs in the thyroid even with a dosage just in excess of 2 mg (23), as well as degenerative and necrotic lesions in the iodide-concentrating tissues (thyroid, salivary gland and gastric mucosa, but not in the breast) in the case of greater and prolonged quantities (44). In fact the mammary gland has only a temporary ability in concentrating iodides, almost exclusively during pregnancy and lactation, which are considered protective conditions against breast cancer (6). Stomach and thyroid share I-concentrating ability, and many morphological and functional similarities, such as cell polarity and apical microvilli, similar organ-specific antigens and associated autoimmune diseases (1), secretion of similar mucinous glycoproteins (thyroglobulin and mucin) and peptide hormones, the digesting and reabsorbing ability and, lastly, similar ability to form iodotyrosines by peroxidase activity, where iodide acts as optimal electron donor in the presence of H2O2 (8). Gastric peroxidase is an endogenous glycoprotein, which is able to extract electrons from iodides at physiological acid pH of the stomach (46) and scavenges intracellular H2O2 and hydroxyl radical, which are the major causative factor in stress-induced gastric ulceration, inducing lipid peroxidation. (47).

IODINE AND GASTRIC CARCINOGENESIS

Ward and Ohshima (48) and recently the World Cancer Research Found and the American

Institute for Cancer Research (49) reported the role of iodine in carcinogenesis, as tumor promoter, and that dietary iodine deficiency and excess are carcinogens in the thyroid gland.

In early works, Stocks (50) and Spencer (51), reported that iodine-deficient goitre constitute a risk for GC; and Diesing reported, in 1911, an adjuvant therapy of thyroid-extract in some gastric tumours (52). In particular Stocks in 1924, when GC was the most frequent of all malignant tumours in the world, showed a statistical correlation between I-deficient goitre and cancers, and in particular GC, and predicted that I-prophylaxis might result in diminishing cancer mortality, as it is coming true for GC. The fact that 131-I can cause GC in the first generation of exposed pregnant rats, indirectly confirms its action at stomach level (53). Guernsey reported that thyroid hormone is a very powerful co-factor of experimental extrathyroidal carcinogenesis and the mechanism of action may be that of tumor suppressor genes (54). In gastric cancer, recently, Wang et al. (55) reported alterations of thyroid hormone receptor alpha gene and an association with Nm23 protein expression. Li et al. (56) reported that the observation of frequent mechanisms of thyroid hormone receptor (TH-R) beta-1 inactivation suggests a potential role for this gene in the suppression of nonthyroidal primary tumors in early stage cancer, and that thyroid hormone receptor genes (c-erbA, or TR) have been implicated as tumor suppressor genes of GC. Two subtypes of TR genes (TR-alpha and TR-beta) are altered in human gastric cancer.

In previous works (1-3, 25, 45) we attempted to point out the role of iodine in pathophysiology and carcinogenesis of the stomach using data from three different fields:

1) epidemiology; 2) iodine and atrophic gastritis correlations; and 3) immunology.

1. EPIDEMIOLOGY

Iodine is the only trace-element which has a specific clinical marker of prolonged deficiency: goitre, which has been "mapped" and monitored the world over, by means of international epidemiological surveys (Kelly,1946; Kelly and Snedden, 1960; Stanbury and Hetzel, 1980; Hetzel, Dunn and Stanbury, 1987; ICCIDD-WHO, 1995) (57-59). We summarize the results of our previous studies at World and European (Table A), Italian and Regional (Table B) , Provincial level, and of several U.S.L. (Local Health Districts) (Figure 2, 3, 4; from Venturi, 1985, 1990 ).

TABLE. A. Correlation between goitre prevalence (1980-85), iodine intake (1980-85) and gastric cancer mortality rate (1984) in Europe. In endemic goitre nations the gastric cancer mortality is generally higher than in non-endemic countries. Note that Greece and Rumania show endemic goitre only in a small part of their territory

Goitre: 0, practically none; + , < 10%; ++ , 10-30% (or more); +++ , risk of endemic cretinism.
Iodine intake (including iodine-prophylaxis): S, sufficient; B, borderline-sufficient; I, insufficient.
* Data from the European Thyroid Association (1985).
# Data from the World Health Statistics Annuals: a: in 1981; b: in 1980.

Table B. Relation between GC mortality, thyroidectomies and thyroid cancer rates ( from Lampertico, 1982). In both it is evident the north-south decreasing gradient. In Italy there is a significant correlation (p < 0.01) between the incidence of thyroidectomies and thyroid cancers (correlated to iodine-deficiency) and gastric cancer mortality rate (per 100,000). ( From Venturi et al., 1990; 1993).

Statistic Tests of Table B.

Figures 2, 3, 4 . Relation between mountain, plain and sea-coast districts (USL) in Marche, Emilia-Romagna and Tuscany regions and between high and low goitre areas, compared with GC mortality rates (Males + Females, crude rates). ( From Venturi et al.,1985; 1990 ).

In Italy quantitative regional data on I-deficient goitre were not available. So, we used indirect data based on the incidence of thyroidectomies and thyroid cancers, which was reported by a wide study by Lampertico et al. regarding 82 % of the Italian population (60). In fact, the surgical thyroid pathologies, including goitre and tumours, are correlated, even if not exclusively, to I-deficiency (61). In countries where iodized salt has been used in sufficient concentration for many years (not less than 15 mg of potassium iodide (KI) per kg of salt) goitre and gastric cancer have been disappearing almost in parallel (Figure 5; from Venturi, 1990; 1993).

Figure 5. Different national trends of gastric cancer mortality in relation to the beginning (arrows) of iodine prophylaxis (Ip.) and to the percentage of the population in which Ip. is used. Japan and most of Chile and Italy never used iodized salt. In the USA iodized salt has been used since 1920-30 and is the most iodine-concentrated (100 mg of potassium iodide per kg). Canada, Australia and New Zealand show similar trends to the USA, since they have used similar iodized salt during the same period of time. (From Venturi et al. 1990; 1993)

Australia, Canada. New Zealand and USA have used the most iodized salt since 1920-1930 with 100 mg of KI per kg of salt, and have shown similar gastric cancer mortality trends. Also, in Switzerland a relevant drop of gastric cancer mortality was observed after 1970 by the fact that the Swiss government had to double the iodine content of the salt in 1962; the same happened in Finland after 1950. In the 1980’s, investigations have reported large endemic-goitre ares in Italian provinces with the highest mortality rates from GC including Arezzo ( Tuscany), Forlì (E-Romagna) and Pesaro (Marche).We have found an epidemiological, geographic and temporal, correlation between territories with a higher rate of mortality from GC and those with I-deficient goitre (Figure 7,8,9). In the district of Calì, an Andean mountainous territory, in Cauca valley, in Colombia, Correa & Castro (62), and Wahner et al.(63) reported (in 1961 and in 1966) an high endemic goitre area, where in 1976 Correa et al.(64) reported a high mortality from GC.

It was interesting to follow the GC mortality trends in the Italian province of Aosta (110,000 inhabitants), whose population was the only one in Italy to carry out a partial iodine-prophylaxis

( Ip.) from 1930. Goitre had decreased very considerably in the population and UIE was the highest and GC-mortality was the lowest of all the neighbouring provinces of Piemonte region, including Cuneo. From 1975 Ip. was interrupted in Aosta. In contrast, the neighbouring province of Cuneo had never carried out significant Ip., despite the fact that it is an endemic goitre area (1, 25). In Aosta, some years after interrupting the Ip., GC started to reverse and increase its trend

(Figure 6; from Venturi,1993 ).

Figure 6. Gastric cancer rnortality trend in Italy compared with the trends of the near endemic provinces of Cuneo and Aosta (M+F, crude rates). Only Aosta had carried out iodine-prophylaxis since 1930-35, but it was interrupted in 1975. After some years, its trend started to reverse and increase. The same happened in Guatemala after 1976. ( From Venturi et al. 1993).

The same happened in Guatemala where, after a substantial gradual decrease of Ip. between 1965 and 1976, GC mortality increased by 36 % from 5.8 in 1984 (males + females per 100,000), while mortality for all cancers increased from 27.8 to 29.9.

The progressive decrease of GC mortality in Cuneo, in Italy and all over the world, where iodized salt is not used, might have been favoured by greater iodine intake due, in the last decades, to the increased consumption of sea-food and use of dietary iodized additives such as preserving, stabilizing and colouring agents. Other involuntary sources of iodine are drugs, dietary mineral integrators, X-ray contrast media, and indirectly, veterinary iodinated disinfectants and agricultural seaweed fertilizers. According to Doll and Peto (65), dietary additives (many of which contain iodine) have not only caused less than 1 % of the overall cancer death rate in the USA, but they have probably decreased it (with an acceptable interval estimate from -5 to +2 % ) thanks to the potential protecting action of antioxidants, especially with regards to GC.

In previous works (1, 25, 27) we reported that in Italy GC, thyroid cancer and goitre are statistically correlated and more frequent in I-deficient areas, such as in Alpine and Apennines valleys ( 26), and in regions of northern and central Italy compared to southern Italy where the majority of the population lives in sea-side areas. FIGURE 7.

Figure 7. ( Left) Italian map of provincial distribution of GC mortality ( 1975-1977, from Cislaghi et al.).

(Right) Italian map of areas of high endemic goitre (1960-1993, from Costa et al.).

Figure 7.b. World map of prevalence of iodine-deficient goitre before iodine-prophylaxis (Ip.) with Europe in the centre (from WHO, 1960). Some coastal regions of Japan and China have iodine-excess endemic goitre. Oblique lines show areas of iodine-deficient endemic goitre before lp. and shaded areas show chains of mountains. n % of gastric cancer mortality from all cancers (1977). = % as above, in nations where a satisfactory iodine intake has been reached. (From Venturi, 1985)

   In fact Italy has never carried out significant iodine-prophylaxis and, despite the fact that its inland is an endemic goitre area, only less than 3 % of kitchen salt is iodized. GC is more frequent in farmers than in fishermen, whose diet is richer in iodine (66). Recently the Italian National Organization "Istituto Nazionale della Nutrizione", comparing the years 1980 to 1995, found that Italians, whose gastric cancer mortality has decreased, have in fact increased their yearly fish consumption (from 8.7 to 14.4 kg per person) and decreased their consumptions of fruit (from 86.6 to 84.9 kg per person) and vegetables (from 111.4 to 108.2 kg per person) (67). A recent study suggests that, in northern Italy, the consumption of even small amounts of fish, which is rich in iodine, is a favourable indicator of the risk of several cancers, especially of the digestive tract and stomach (68). After the beginning of Ip. in Marche region (1.447.606 inhabitants), in years 1985-88, the percent variation of GC mortality (standardised rates) in years1980-83, compared to years 1992-95, was -33.0 % (Males) and -29.3 % (Females); while the variation of total tumours mortality was -3.0 (Males) and -10.3 (Females) (69). So, in near republic of San Marino (70) the five years survival rates for GC after diagnosis (in years 1989-93) were 35 % (Males) and 55 % (Females) compared to Italian and Torino rates 21 % (Males), and 25 % (Females), and 16-27 % of the mean of Italian cancer registries. On the other hand, an excess of dietary iodine impairs the iodide-pump and NIS and the functions of thyroid and stomach causing degenerative, necrotic and probably also neoplastic lesions, which are well-known in thyroid gland. The fact that the iodine-excess is able to damage the stomach too, should be examined carefully if we consider that the coastal populations of Japan (71) and China (72), which have the highest rate of gastric cancer mortality in the world, frequently eat an excessive and harmful quantity of marine algae (seaweeds), which are very rich in iodine (up to 200 mg /daily / per person).

2) IODINE and ATROPICH GASTRITIS CORRELATIONS:

Is iodide a trophic factor for gastric mucosa?

Previous studies have demonstrated the frequent association between atrophic gastritis and goitre-dysthyroidisms, well known as thyro-gastric syndrome, and between gastric antimucosa and anti-thyroid antibodies (23), which might be attribute to common organ-specific antigens, due to the same embryogenetic derivation. In fact injected anti-thyroid serum can cause experimental gastritis in the stomach (73). Cooking causes losses of 20-50 % of iodine through iodine evaporation and dispersion (23) so, fresh food and fresh vegetables, containing more iodine, are protective against thyroid and gastric cancer (74). We have shown a trophic regulating action of iodine on gastric mucosa similar to the action on the thyroid and we have shown a correlation between iodine-deficiency, goitre and atrophic gastritis (25, 45), by means of gastric biopsies, in three randomized and homogeneous groups of persons having different degrees of iodine-deficiency and goitre: Group C (40 subjects), in which 100 % of the subjects had goitre (as a sample of persons with prolonged a severe iodine-deficiency); Group B (128 subjects), with goitre in 30-40 % of persons (as a sample of persons with less severe iodine-deficiency); and Group A (136 subjects), with goitre in less than 10 %, living in non-iodine-deficient territory. The prevalence of atrophic gastritis in the three groups was significantly correlated to the degree of iodine-deficiency and goitre ( p < 0.001)

( Figure 8).

Figure 8. Groups C and B of iodine-deficient subjects show higher statistically significant prevalence of atrophic gastritis compared to the non-deficient group A ( p < 0.001). ( From Venturi, 1990 ).

We studied the intracellular concentrations of the stomach and we have found that a normal gastric mucosa contains more iodine than that affected by atrophic gastritis (75). Recent studies reported that genetic characterisation and induction of the human NIS gene allows the development of novel gene therapy also for treatment of extrathyroidal and gastric malignancies (76). In fact, targeted expression of functional NIS in undifferentiated cancer cells would enable these cells to concentrate iodine and would therefore offer the possibility of radioiodine therapy. Boland et al. (77) propose to enlarge the therapeutic strategy to non-thyroid tumors by using an adenoviral vector to deliver the NIS gene into the tumor cells for a targeted radiotherapy.(34).

3) IMMUNITY: IODINE, HELICOBACTER PYLORI and STOMACH

The United Nations Nutrition Policy Paper (21), and Food and Nutrition Board and Institute of Medicine (24) have reported that iodine seems to have an important action on the immune system.

The high iodide-concentration of thymus seems to explain this important role of iodine in immune system. Tucker et al (78) reported that immune defences might have an important role in various types of tumours, and perhaps also in GC. We also have reported a significant immune deficiency (79, 80) in our population affected by high gastric cancer, goitre and thyroid cancer. Recently an inhibition of vacuolation toxin activity of Helicobacter pylori by iodine was also reported (81). In vitro studies show that iodine can work with myeloperoxidase from white cell to inactivate bacteria (82). Weetman et al (83) had demonstrated that iodine could increase immunoglobulin-G synthesis in human lymphocytes in vitro. Iodine was and is sometimes used therapeutically in various pathologies where the immune mechanism is known to play a dominant role. It has been administered to patients with tubercular granulomatous, lepromatous, syphilitic and mycotic lesions where it facilitates cure. This effect does not depend on iodine’s direct action on the micro-organism responsible (80). Oral iodine is also very effective therapy in the lymphatic-cutaneous form of sporotrichosis.

In order to establish a relationship between dietary iodine and immune response, 607 schoolchildren residing in our area (Novafeltria-Montefeltro) of high endemic goitre and GC mortality were studied. Their urinary iodine excretion was 47 ug per day. 215 schoolchildren were given Lugol solution (2 mg weekly, by drops, for about 8 months) and 392 not. The immune response was assessed by the skin test method using tetanic toxoid and a clear correlation was shown between this and lymphocyte stimulation and monocytic chemotaxis tests. The test was considered positive when an infiltration of at least 5 mm in diameter was shown after 48 hours (in non I-deficient population of U.S.A. 80% of healthy paediatric cases aged 2-10 years old were positive). A significant difference was noted in the average diameter of the infiltrations after the tetanic toxoid skin test in the two groups considered (P less than 0.001) (79, 80). The results appear to indicate that an adequate iodine intake is necessary for normal retarded immune response (84).

In conclusion, we hypothesized that iodine-deficiency or iodine-excess are risk factors for atrophic gastritis and GC. The antioxidant, immune and trophic action on the gastric mucosa could also provide an interpretation of the pathogenetic mechanism of previously studied risk factors for GC such as nitrates, salt and helicobacter pylori. The knowledge of the antitumour activity of iodide might be useful for helping to prevent GC and also as a novel gene to allow radioiodine therapy to be given to patients with stomach cancer.

Map of the World's Iodine Nutrition ( from ICCIDD, 2003)

Summary of the World's Iodine Nutrition ( from ICCIDD, 2003)

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