J. Endocrinol. Invest. 11: 831 , 1988

SPECIAL LECTURE

Studies on the goiter endemia in Sicilt R. Vigneri Cattedra di Endocrinologia e Patologia Costituzionale dell'Universita di Catania, Ospedale Garibaldi 95123 Catania, Italy ,

INTRODUCTION

children all overthe island, These epidemiological studies covered most of the provinces of Agrigento, Caltanisetta, Catania, Enna, Messina and Palermo, Thyroid enlargement was searched in more than 25,000 schoolchildren and goiter were classified according to the WHO criteria (5). These studies, in addition to definitively demonstrating the high prevalence of goiter in a significant portion of the Sicilian population , also gave the opportunity to identify and examine cases of endemic cretinism (Fig, 1) (6) and of incredibly monstrous goiter (Fig. 2) (7). It was on the basis of these studies that the diffusion of endemic goiter in Sicily and the severity of its complications made the goiter connected diseases to be considered a social problem necessitating public health service intervention, The Sicilian Assembly, therefore, passed a bill to provide funds for the completion of the epidemiological investigations and for the establishment of free outpatient clinics in different towns of the endemic area. These outpatient clinics would be attended by specialized Endocrinologists from the Sicilian Medical Schools in cooperation with local physicians (8), Several thousand patients have been seen in these clinics since 1979 and the studies reported in this lecture are the results of the clinical investigations carried out on the patients of the provinces of Catania, Enna and in part of the province of Messina, More than twenty Fellows, Interns and Researchers from the Cattedra di Endocrinologia of the Catania Medical School actively participated in these studies and their contribution should be considered essential in the collection of clinical and biochemical data and greatly commendable for the commitment and the high quality of their medical and social performance (see acknowledgments) ,

Several evidences and folkloric anectodes suggest that endemic goiter has affected the Sicilian population for many centuries , but the first scientific report of the presence of endemic gOiter in Sicily dates approximately sixty years Qgo. ln 1930 Prof. Coppola published that " ... . in 1926, in the interior of Sicily, between the provinces of Palermo and Catania, I reported the presence of a large area of goiter endemia; in this area, in addition to the widespread presence of goiter, it is also possible to observe cases of typical endemic cretinism " (1). Further reports regarding endemic goiter in Sicily were later published in the early fifties (2) and sixties (3). A systematic study of the epidemiology and the pathophysiology of endemic goiter in Sici ly was started , however; only in the mid sixties, when the Centro di Fisiopatologia Tiroidea was established at the University of Catania Medical School. In a few years a large number of goiter patients were observed, and the diffusion and severity of the gOiter endemia became evident. The studies on the causes and clinical manifestations of endemic goiter in Sicily were greatly promoted by the International Symposium held in Taormina in 1974 with the participation of many Italian and foreign experts in goiter and thyroid pathophysiology (4) . Great advantages were derived from the collaboration with researches who had special experience in the study of goiter endemia, as those in the group directed by Dr. A.M. Ermans from Bruxelles, or with a profound knowledge of iodine metabolism and thyroid physiology, like Dr . S.H. Ingbar from Boston and Dr. Th . LemarchandBeraud from Lausanne. These scientists made a substantial contribution to the design of clinical investigations on the Sicilian goiter endemia. In the late seventies a collaboration was started between t-he three Sicilian Medical Schools in order to perform a systematic epidemiological survey in school-

BIOCHEMICAL STUDIES ON THE ETlOLOG Y OF ENDEMIC GOITER IN SICIL Y The high prevalence and severity of endemic goiter in Sicily is rather surprising since the Sicilian gOiter areas are rather close to the sea. Fish is readily available in these areas and the diet is generally well balanced and varied, The iodine intake, therefore , is not supposed to be very low in these areas , Studies were then undertaken in small samples of adult population to measure the iodine intake in different towns of the endemic area and also in the two major

111al lan Society of En dOCrinol ogy Award Lecture . XXII Nationa l Congres s, Verona , J une 15· 18, 1988.

Key-words. Endemic goiter , thyroid, iodine prophylaxis, iodine deficiency, thyroid

cancer Correspondence: Dr. R. Vlgnerl , Cattedra di Endocrinologia e Patologla COStltUlIOnale, Unlverslta di Catania, P.lla S.M. del Ge se, 95123 Catania, Italy.

831

R. Vigneri

Fig. 1 - Mixedematous cretinism in a 78-yearold woman with severe mental retardation, multinodular goiter, complete deafness and partial mutism. Reproduced, with permission, from ref. 6.

cities of Catania and Messina, which were used as control areas since no goiter endemia was present. Catania (approximately 400,000 inhabitants) and Messina (approximately 270,000 inhabitants) are metropolitan cities, rather different from the smaller and more rural towns in the endemic area . For this reason the towns and villages surrounding the two cities or along the eastern coast of Sicily were included in the control area. People living in the control area have smilar ethnic features, eating habits and ways of life as the people living in the endemic area. Cities from the control area are also well connected with the endemic area by a network of roads and public transports with an average driving distance of approximately one hour. A variety of metabolic investigations was carried out both in the control area and in different zones of the provinces of Catania, Enna and Messina where the epidemiological survery had indicated that endemic goiter was present. The following measurements were collected: a) the iodine content of specimens of 24 h urine collections; b) the 131-lodine uptake by the thyroid 24 h after the oral admini.stration of 10-20 pCi of radioiodine; c) the serum levels of TSH, thyroxine (T 4 ) , triiodothyronine (T 4 ), and thyroglobulin (Tg). The results of these investigations are shown in Tables 1,2 and 3. - Iodine metabolism investigations The results shown in Table 1 demonstrate that the dietary supply of iodine is inadequate in the Sicilian

Fig.2 - A monstruous goiter in a 70-year-old man with neurological cretinism from the endemic area in North-Eastern Sicily (Tortorici). Reproduced, with permission, from ref. 7.

832

Goiter endemia in Sicily

Table 1 - Goiter preva/ence·in schoolchildren and indices of iodine intake in the adult population of different areas of Northeast Sicily,

m ± Sf; number of sUb/ads studied is indicated in parenthesis

% GOiter prevalence in schoolchildren

Inhabitants

Daily urinary iodine excretion (~g/24 h)

13110dine thyroid uptake (% dose at 24 h)

Catania Messina

400,000 270,000

2.2 6.6

(1253) (608)

113.8 ± 8.4 (79) 76.2 ± 16.6 (9)

31.6 ± 1.5 (21) 50.1 ± 2.1 (20)

Bronte Nicosia Traina

22,500 19,700 13,900

36.6 38.5 52.2

(1121 ) (1642) (1200)

43.2± 4.9 (53) 38.5± 6.0 (22) 40.7 ± 2.6 (90)

50.8 ± 2.4 (28) 52.0 ± 2.2 (25) 50.8 ± 2.4 (28)

Maniaci Sant'Angelo Tortorici

3,000 6,400 11,500

66.5 48.7 62.2

(218) (439) (1365)

18,9 ± 4.1 (34) 26.6± 1.7(130) 28.2 ± 5.0 (30)

58.2 ± 3.5 (14) 70.1 ± 2.5 (30)

valence of endemic goiter observed in Bronte and Troina. These considerations prompted us to investigate whether some goitrogenic factors, other than iodine deficiency, might contribute to the severity of goiter endemia. When thiocyanate (SCN), a well known goitrogen whose antithyroid properties are due to both inhibition of iodine transport and iodine organification (10), was measured in the specimens of daily urine collections, values two times higher than control levels were found both in Bronte and Troina. Similarly, high SCN levels were also found in Catania, where no endemic gOiter was present. These observations led us to the conclusion that the balance between iodine and thiocyanate intake is a crucial factor in the etiology of endemic goiter in some of the endemic areas of Sicily. Endemic goiter, in fact, is 'present when the iodine/thiocyanate ratio is low (Table II) since the excess olSCN interferes with the process of thyroid functional adaptation to the iodine deficiency. In contrast, when SCN levels are elevated but the iodine intake is also elevated (as observed in Catania), high iodine/SCN ratio results and no endemic goiter is present (11). The origin of the high SCN levels in the subjects living in some areas of Eastern Sicily is at present unknown.

endemic area as indicated by both iodine urinary excretion and radioiodine thyroid uptake. The severity of iodine deficiency however, varies greatly in different areas of Sicily, being very important in some districts (Maniace, Sant'Angelo,Tortorici), of moderate severity in other towns (Bronte, Nicosia, Troina) and mild in the city of Messina, where no endemic goiter is present. In addition, the severity of iodine deficiency does not parallel the severity of goiter prevalence in schoolchil~ dren.ln some areas witha moderate iodine deficiency, goiter prevalence in schoolchildren was, in fact, very high. In Bronte andTroina, for instance, urinary iodine excretion was below the normal range but only. very little below the level observed in many European coontries where no endemic goiter is present (9). The fact that the iodine deficiency, as evaluated by the urinary iodine excretion, is moderate in these zones is confirmed also by the iodine thyroid uptake measurements. As a matter of fact the values observed in Bronte and Troina are similar to those observed in other areas, both in Sicily (Messina, RAIU = 50.1 ± 2.1 %) and in Europe (Bruxelles, RAIU = 49.4 ± 2.3%) where no endemic goiter is present. Therefore, the iodine deficiency alone can hardly account for the elevated pre-

a

Table 2 - Relationship between goiter prevalence and the daily urinary excretion of iodine and thiocyanate. Urinary excretion

Iodi ne / thiocyanate

% Goiter

Iodine (~g/24 h)

Thiocyanate (mg/24 h)

(~g/mg)

prevalence in SChoolchildren

51.2 ± 5.8 113.8 ± 8.4 76.2 ± 16.6

6.7 ± 1.3 13.1 ± 0.9 8.4 ± 1.9

7.8 8.7 9.1

3.0 2.2 6.6

43.2 ± 4.9 40.7 ± 2.6 26.3 ± 1.7

15.2 ± 1.5 11.0±0.7 7.7 ± 0.3

2.8 3.7 3.4

36.6 52.2 48.7

ratio

Areas without endemic goiter Bruxelles Catania Messina

Areas with endemic goiter Bronte Traina Messina

833

R. Vigneri

One possibility, of course, is that this is the consequence of the large consumption of cabbages, whose thioglucosides can be hydrolyzed to thiocyanate (12). This hypothesis, however, is not very likely since cabbage is also a component of the diet in other areas of Sicily, with or without endemic goiter, where SCN levels are within the normal range. One alternative possibility, is that the elevated SCN levels, seen in the whole area around the vulcano Etna, are in some way connected with the characteristics of the soil in this area, rich in sulphates. In fact, it has been reported that the quality of the soil and its content of various minerals, particularly the sulphate/nitrate ratio, is important in the biosynthesis of glucosinolates by a variety of vegetables, including those of the brassica family (13).

ing the Northern portion of the Simeto and the Alcantara valleys, was an area of severe goiter endemia with the presence of abnormalities in thyroid function of the "healthy" adult population. When the thyroglobulin serum levels were measured in both goitrous patients and non goitrous subjects from the endemic area, they were found significantly higher in the goitrous patients. A similar increase of sBrum Tg levels, however, was also found in patients with a sporadic goiter and not living in the endemic area (14). Therefore, goiter per se, rather than reduced iodine intake, appeared to be the cause of the increased Tg levels. Patients with a large goiter, as a group, had a higher average Tg level than patients with a smaller goiter. However, no significant correlation was found between the Tg levels and goiter size, as well as no correlation between Tg and TSH levels in goitrous patients. As already suggested by Van Herle et al. (15), these findings indicate that factors other than TSH influence the release of Tg in patients with endemic goiter. In euthyroid patients with goiter (both when go it er is due to the low iodine intake or when it is due to an impairment of the hormonogenesis) Tg shows various degree of hypoiodination (16) which may be reflected by the increased T 3fT 4 ratio (14, 17). Hypoiodinated Tg is preferentially hydrolyzed and, therefore, undergoes a more rapid intraglandular turnover. At the same time, the iodine-depleted thyroid is more sensitive to the TSH stimulation (18). It is likely, therefore, that the il'lcreased Tg level observed in goitrous patients is the consequence of an increased Tg turnover to which various factors and mechanisms contribute. These biochemical studies, in addition to the epidemiological and clinical studies, resulted in a better knowledge of the characteristics of endemic goiter in Sicily and of its etiological factors. It became evident that the etiology and the severity of endemic gOiter in Sicily is different in different areas, an observation that must be kept in mind when analyzing the results of the clinical studies reported in the following paragraphs. In the attempt to avoid at least the heterogeneity connected with the severity of iodine deficiency, in these studies

- Investigations on hormone levels in serum As in the findings of iodine supply, the measurements of serum levels of thyroid hormones, TSH and. thyroglobulin (Tg) also gave different results in different zones of the endemic area in Sicily . In most non goitrous adult subjects living in the endemic area, both thyroid hormones and TSH serum levels were within the normal range as compared to the same parameters measured in Catania as the control area. However, the fraction of the population having thyroid hormone levels (particularly T4 serum levels) borderline low was significantly higher in the endemic area. In addition, in some towns like Troina and Sant'Angelo,two areas with a moderate / severe goiter endemia, the average T 4 level in the adult popoluation sample was significant1y lower than in the control area (Table 3). In the area of Maniace and Tortorici, an area of severe goiter endemia where endemic cretinism is present, the average values of both T 3 and T 4 in the adult population sample were significantly lower than in the control area. Also, in this endemic area the average TSH serum levels was abnormally higher than in the control area (Table 3). Therefore, these biochemical datq together with the epidemiological and the clinical observations, indicated that the area of Maniace and Tortorici, located South of the Nebrodi mountains and includ-

Table 3 - Serum levels of TSH, T4 and T3 in "euthyroid" nongoitrous adults in different areas of Sicily. The number of subjects studied is indicated in parentheses. TSH (/.lU/ml) Control area: Catania

3.0

± 0.1

T 4 (l1g/ dl )

(180)

7.4 '::!:: 0.1 (180)

T3 (ng/dl) 167

± 3 (180)

Areas with moderate iodine deficiency: Bronte 3.7 Nicosia 3.9 Troina 3.7

± 0.3 (44) ± 0.2 (36) ± 0.2 (33)

7.2 6.8 6.2

± 0.4 (44) ± 0.3 (36) ± 0.3 (33)

165 ± 9 (44) 154 ± 6 (36) 154 ± 5 (33)

Areas with severe iodine deficiency: Maniace I Tortorici Sant'Angelo

± 0.6 (62) ± 0.2 (49)

6.4 5.9

± 0.4 (62) ± 0.2 (60)

138 ± 4 (62) 145 ± 4 (53)

5.1 2.7

834

Goiter endemia in Sicily

we have subdivided the endemic area ito into two areas, one with a moderate iodine deficiency and a smaller area with a more severe iodine deficiency.

All newborns having a cord serum TSH higher than 50 J.1U 1ml were recalled for further clinical and biochemical thyroid evaluation. At the time of this second examination, average infant age was 32 ± 8 days (m ± SO, range 22-79 days). At this recall examination all infants having a serum TSH higher than 8.0 J.1U/ml and a T4 lower "than 4.5 J.1g1 dl were immediately treated with thyroxine. In contrast, when serum T4 wa.s in the normal range, even in the presence of increased serum TSH levels, infants were not treated but evaluated again after 3-6 weeks. With respect to the control area, serum TSH levels at birth were significantly higher in both the severe (p < 0.001) and the moderate endemic area (p < 0.005) (Table 4). In addition, serum thyroxine levels at birth were significantly lower in newborns from both endemic areas as compared to values observed in newborns from the control area (p < 0.05) (Table 4). When the distribution of TSH and T4 serum levels at birth was investigated, cord TSH values in the endemic area were clearly shifted towards high values and T4 levels towards low values. The percentage of infants with a cord serum TSH higher than 50 J.1U/ml (and therefore the number of newborns that were recalled under suspicion of congenital hypothyroidism) increased from 9 out of 5673 (0.16%) in the control area to 14/2096 (0.67%) in the area of moderate iodine deficiency, and to 18/184 (9.78%) in the area of severe goiter endemia. Also the percentage of newborn with cord TSH values in the range of 30 to 50 J.1U/ml (thus clearly elevated even if lower than the cut-off point) was significantly higher in the endemic areas. In concert with these findings regarding TSH levels at birth, also cord serum T4 levels were shifted towards low values in newborns from the endemic areas. T4 changes, however, were less pronounced than TSH changes. At the time of the recall examination, 3 infants (7.3%) had died during the perinatal period and none of the remaining 38 had clinical evidence of hypothyroidism or goiter. On the basis of serum TSH and T4 values at the recall examination these infants were subdivided into 3 groups:

IODINE DEFICIENCY AND ABNORMALITIES OF THYROID FUNCTION A T BIRTH As already mentioned, in the adult population a moderate iodine deficiency does not cause a relevant change in the thyroid hormone concentrations. Therefore, the large majority of adult subjects living m the Sicilian endemic area is euthyroid. This is not the case for the fetus and the newborn. They are, in fact, in a totally different situation for a variety of different reasons. First of all, the fetal thyroid can receive iodine only through the mother's supply, competing with her thyroid for available iodine. Consequently, when the iodine supply is insufficient, the fetal thyroid finds itself in a situation of severe iodine deficiency. Secondly, in terms of total thyroid iodine content, the newborn thyroid has only 1 % of the iodine content of the adult thyroid (19). Thirdly, the thyroxine requirement and disposal during the first months of life is calculated to be 5" 10 times greater than that of the adult (20). For all these reasons the iodine turnover is much higher in the fetal and neonatal thyroid and a shortage in iodine supply, even if partial or tarnsient, may lead to a severe iodine depletion of the thyroid. The newborn, therefore, is more sensitive than the adult to the effects of iodine deficiency. For these reasons we decided to investigate thyroid function at birth in newborns from the Sicilian areas with endemic goiter. The purpose of the study was to evaluate the frequency of thyroid function abnormalities at birth and the incidence of congenital hypothyroidism in the area of iodine deficiency. In a 30 month period we studied 7953 infants (21): 5673 were from the control area, 2096 from the moderate iodine deficient area and 184 from the area with severe iodine deficiency. No significant difference in gestational age, weight at birfh and cord blood albumin was found among these 3 groups of newborns. Cord serum levels of TSH and T 4 were measured in all infants while T3 levels were measured only in 1255 infants.

Table 4 - Cord serum TSH, T4, and T3 values in newborns from different areas of Sicily with different iodine uptake. TSH values did not have a normal distribution and therefore are presented in different ways. Serum T4 and T3 values are m ± Sf. The numbers of

newborns studied are indicated in parentheses. TSH (t-tU/ml) Areas Studied

Arithmetic mean

Geometric mean

T3 (ng/dl)

Median

± 0.04 (5673) ± 0.06 (2096) 8.3 ± 0.20 (184)

± 1.5 (212) ± 1.1 (939) 83 ± 1.1 (1 04 )

Control

7.8 (5673)

6.8

6.9

10.2

61

Moderate iodine del.

9.5 (2096)

7.9

7.7

9.4

82

21.4 (184)

12.0

10.0

Severe iodine del.

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R. Vigneri many genetic and environmental factors may playa role in determining the time required for thyroid function normalization in each of these infants. 5) No criteria (i.e., severity of hormonaiabnormalities, involvment of both TSH and T4) is available to differentiate between permanent and transient congenital hypothyroidism and no parameter allows a prediction of the duration of transient thyroid deficiency during the neonatal period . Experimental data indicate that irreversible brain damage can follow even from a short period of hypothyroidism occurring during the critical time of early brain development (23). Therefore, screening for congenital hypothyroidism is particularly recommended in the endemic areas. The same criteria as in non endemic areas should be used for recalling infants born in the iodine-deficient areas since neonatal hypothyroidism, irrespective of its etiology, may cause irreversible damage to the central nervous system. Of course, iodine prophylaxis is a necessary and urgent sanitary intervention in the iodine-deficient endem ic areas even in the absence of clinical or biochemical signs of thyroid function impairment in the adult.

- 23 infants had normal TSH and T4 levels and were considered as false positive; - 11 had persistently elevated TSH levels (9.9 - 28.0 I1U 1ml) but normal serum T 4' All of them were from the endemic areas and , as already mentioned, they were not treated but examined again after 3-6 weeks when all had both serum TSH and T 4 within the normal range. These infants were classified, therefore, as newborns with transient hyperthyrotropinemia. - 4 infants in addition to persistently elevated serum TSH (55.0 - 320.0 I1U / ml) also had low serum T4 (1.0 -2.3 I1g / dl). Two of them were from the control area (2/5673 = 0.04%.) and the other two were from the area of severe iodine deficiency (2/184 = 11 %). These infants were considered to have congenital hypothyroidism and were immediately given T4 replacement therapy. At age 10-13 months all4 infants were reevaluated after T4 withdrawal. Congenital hypothyroidism due to thyroid agenesia was confirmed in the two infants from the control area. In contrast, the 2 infants from the area with severe iodine deficiency were found euthyroid and, consequently, they were diagnosed as having transient congenital hypothyroidism. These studies in newbor.ns from the Sicilian endemic areas led to the following conclusions (21) : 1) In an area of moderate iodine deficiency where the adult populaton does nof have any significant impairment of thyroid function , a very clear shift of serum TSH towards high values is found at birth. When the iodine deficiency is more severe and the adult population has minor biochemical signs of thyroid hormone deficiency, an abnormally high serum TSH is very frequent at birth. 2) The severity of thyroid function abnormalities at birth correlates with the severity of iodine deficiency as evaluated on the basis of urinary iodine excretion in the adult population. Under the critical value of 30-40 I1g in daily urine iodine, thyroid function abnormalities in the newborns are very frequent. The minimum iodine requirement, however, is probably an individual variable since genetic and environmental factors may significantly affect this parameter in different newborns. 3) A continuous spectrum of thyroid biochemical abnormalities is present in newborns and infants from the iodine deficient areas. In addition to the classical form of congenital hypothyroidism with high TSH and low T 4, many infants have high TSH with a serum T4 within the normal range, a condition resembling other forms of attenuated hypothyroidism as, for instance, congenital hypothyrodism due to thyroid ectopia or dyshormonogenesis (22). 4) The abnormalities of thyroid function present at birth in newborns from iodine deficient areas are often transient, correcting spontaneously in a few days (so called false positivie) , or a few weeks (newborns with transient hyperthyrotropinemia) or a few months (newborns with transient congenital hypothyroidism). Again,

IODINE DEFICIENCY AND A UTONOMOUSL Y FUNCTIONING THYROID NODULES Iodine is an essential nutrient and a necessary substrate for thyroid hormone synthesis: its deficiency in the diet influences many aspects of thyroid growth and function. The thyroid is able to compensate for a moderate scarcity of iodine. Its enlargement (goiter) is one of the compensatory mechanisms; the changes in in trathyroidal metabolism and turnover is another one. In the presence of iodine deficiency, however, the thyroid is forced to function under non-optimal conditions, therefore becoming more prone to a variety of malfunctions that usually become clinically relevant in the middle or advanced age. Generalized or focal enlargement of the thyroid (i.e. diffuse or nodular goiter) is the most common consequence and the most evident clinical manifestation of iodine deficiency. There are, however, different forms of goiter and of thyroid nodules, and their correlation with iodine deficiency is not always clear. In a survey of the healthy adult population, carried out in both the control area and the area with moderate iodine deficiency in Sicily, we observed that thyroid nodules, as expected, were significantly more frequent in the population sample from the area of endemic goiter (Table 5). Most nodules (nearly 90%) were "cold" at the scan and their frequency was over 2.5 times higher in the endemic area than in the control area. However, also "hot " nodules were significantly more frequent in the adult population of the endemic area. We decided, therefore, to investigate the correlation between iodine deficiency and the frequency as 836

Goiter endemia in Sicily

Table 5 - Morbidity quotient of thyroid nodules in two adjacent areas of Sicily differing for iodine intake. Sample of the "healthy" population (n. subjects)

Average age (yr)

F/M ratio

1253

40.2 ± 14

1683

39.7±15

Thyroid nodules total

"hot"

"cold"

0.98

24 (1.9%)

2 (0.16%)

22 (1.8%)

1.05

86 (5.1%)

9 (0.50%)

77 (4.6%)

Control area Iodine deficient area

well as evolution of solitary autonomously functioning thyroid nodules ("hot" nodules at scan) in the Sicilian endemic area. With this aim we carried a retrospective study reviewing a consecutive series of 31 ,373 patients referred to our Thyroid Clinic in the years 1965-1980 for diagnosis or treatment of either diffuse or nodular thyroid enlargement or hyperthyroidism or hypothyrodism (24). Our Clinic is the only Thyroid Clinic in the provinces of Catania, Enna, Ragusa and Siracusa and more than 85% of all patients with thyroid disorders from this area are referred to it. Most patients (28,590 = 91 .1%) were from the iodine sufficient area including the city of Catania, the surrounding area and the area along the eastern coast of Sicily, but 2,783 patients (8 .9%) were from the already described area of moderate ·iodine deficiency in the highlands of northeastern Sicily. Out of the 31 ,373 patients reviewed, 893 (2.8%) met the criteria for having an autonomously functioning thyroid nodule (AFTN). These criteria included the presence of a solitary thyroid nodule able to concentrate 131 1 more than the surrounding thyroid tissue and that proved to be autonomously functioning by either a TSH test or a T3 suppression test. The prevalence of AFTN was significantly higher in patients from the endemic area (4.4%) than in patients from the control area (2.7%, p < 0.001 at the X2 analysis) in spite of no difference in age or sex distribution between the two groups. Also, the average nodule diameter was not significantly different in patients from the two areas (3.6 ± 0.5 cm in the endemic area vs. 4.2 ± 0.6 cm in the control area, m ± SD).ln.both areas studied, a direct correlation was found between nodule size andpatient age. In addition, a clear correlation was pres~nt between nodule size and hyperthyroidism. A higher prevalence of toxic AFTN was found in patients from the endemic area (1.3%) as compared to the control area (0.9%, p < at the X2 analysis). This higher prevalence of hyperthyrodisim in patients from the endemic area was the result of both an increased number of clinically evident thyrotoxicosis and of subclinical T Ttoxicosis with elevation of only serum T 3 levels in the presence of normal serum T 4 concentrations.

We were able to collect data regarding the evolution of AFTN in 72 patients with a non toxic AFTN (14 from the endemic area and 58 from the control area). During the follow up period (maximum 6 years, average 3.4 years), 57% of the nodules in patients from the endemic area had a substantial change in size and/or function. We found that 4 out of 14 (28.6%) had a diameter increase of more than 1 cm and 4 (28.6%) became toxic. In comparison, during the same period, only 26% of the nodules in patients from the control area had a change in size or function and in particular only 12 out of 58 (20.7%) became toxic . The frequent transformation of nodular goiters into autonomously functioning nodules had been confirmed in another endemic area of Sicily (25).

These results prompted us to suggest the following conclusions: 1. iodine deficiency is one possible factor that favours the development of AFTN; 2. iodine deficiency may also be a factor promoting a more rapid nodule grow1h in patients with an AFTN; 3. in both the iodine deficient and the control areas a larger nodule size and an advanced age are more frequently associated with AFTN toxicity; 4. in the iodine deficient area the progression of non toxic AFTN towards toxicity is more frequent than in the control area. During a short follow-up period , in the endemic area nearly one out of every 3 patients with a non-toxic AFTN became hyperthyroid while, in the same period, only one out of every 5 patients with a non toxic AFTN from the control area became toxic .

IODINE DEFICIENCY AND THYROID CANCER As ' already mentioned and as well established by a series of epidemiological and clinical studies, the prevalence of "cold " nodules is significantly higher in areas of iodine deficiency (Table 5). The most important diagnostic issue in patients with a cold nodule of the thyroid is the possibility that the nodule is of a malignant nature. It is now well documented that the cytologic examination by a fine needle aspirate (FNA) is an accurate and sensitive method to diagnose the malignancy of thyroid 837

R. Vigneri

nodules (26). We, therefore, used this technique to select patients with a "cold" nodule from both the endemic area and the control area for whom surgery was indicated under suspicion of thyroid malignancy. In these patients we studied the prevalence and the characteristics of thyroid tumors in order to evaluate a possible relationship between iodine deficiency and thyroid malignancy. We carried out a cross-sectional study on a consecutive series of 3,718 patients with a "cold" nodule at scan in the period from November 1979 to December 1985 (27). FNA was suggested for all these patients. 2,537 patients (92.5%) from the control area and 911 patients (93.4%) from the endemic area accepted to undergo FNA and the cytologic examination and, therefore, entered the study. Surgery was performed in all patients from the two areas having a thyroid nodule classified as malignant or highly suspicious of malignancy at the cytologic examination (147 patients from the control area and 34 patients from the iodine defi ~ cient area). Surgery was also suggested to all patients with a diagnosis of follicular lesion without clear signs of malignancy at FNA. Among the patients of this group, however, actually underwent surgery 131 patients (= 32.8%) from the control area and 40 (= 28.4%) from the endemic area. In addition, all patients with a negative cytologic examination or with a repeatedly inadequate sample at the FNA, but who also had clinical signs suggesting a possible thyroid malignancy (continuous growth in spite of treatment, induration, recurrent nerve paresis, laterocervical Iymphonodes, recurrence of a hemorragic cyst) were suggested to have surgery. Under this indication , other 44 patients from the control area and 25 patients from the iodine deficient area underwent surgery. Finally, 124 patients with a cold nodule (97 from the control ara and 27 from the endemic area) elected to have the nodule surgically removed in spite of a clinical and cytological diagnosis of a benign lesion. Therefore, as a total , we performed histopathological examinations in 454 patients with a cold nodule, 419 from the control area and 126 from the iodine deficient area , using a selection procedure that, in addition to being similar in the two areas, determined among 3448 patients with a cold nodule all those being at risk of a malignant thyroid tumor (Table 6). Our study, therefore, overcomes some of the criticisms against previous studies on the effect of iodine deficiency on the frequency and characteristics of thyroid cancer. These previous studies, in fact, were carried out by histopathological examination of thyroid glands from patients living in different countries (28, 29). Criticisms on the validity of these 'studies included the different selection criteria, the lack of an adequate control population, the lack of uniform standards for the diagnostic procedure and the possible interference of a variety of different environmental factors other than iodine.

Table 6 - Selection procedure for patients with thyroid cancer. Control area

Iodine deficient area

2743

975

3. FNA & cytology selection of patients at risk for thyroid cancer

2537 (92.5%)

911 (93.4%)

4. Surgery: - patients at high risk - patients with possible risk

419 (100%) (32.8%)

126 (100%) (28.4%)

5. Histopatologyexamination: number of thyroid cancers

139

27

1. Clinical examination: selection of all patients with a thyroid nodule 2. Thyroid scan: selection of patients with a "cold" nodule

Out of the 545 patients who underwent surgery, 166 thyroid carcinomas were identified: 139 in patients from the confrol area and 27 in patients from the iodine deficient area. Therefore, the overall frequency of thyroid cancer among patients with a cold nodule was higher in the control area (139/2,537 = 5.48%) than in tne iodine deficient area (27/911 = 2.96%). However, when these percentages were corrected for the prevalence of "cold" thyroid nodules in the general population from the two areas (Table 5), a significantly higher prevalence of thyroid cancer was calculated in the population from the endemic area (0.127% or 127 cancers per 100,000 inhabitants) as compared to the control area (0.093%, p < 0.001 at the X2 analysis). In addition to being more frequent, thyroid tumors in patients from the iodine deficient area also had different characterstics than in patients from the control area. In particular, follicular carcinomas were nearly 3 times more frequent and anaplastic carcinomas nearly 4 times more frequent in patients from the iodine deficient area (Table 7). No significant difference between the two areas was found as far as papillary carcinomas were concerned (Table 7). Therefore, the ratios of papillary to follicular to anaplastic carcinomas were very different in the two areas (Table 7). In conclusion, these studies suggested the possibility that iodine deficiency is a risk factor for thyroid cancer and particularly for the fOllicular type. Since iodine deficiency may increase TSH levels via a reduced thyroid hormone production, but at the same time a variety of thyroid cell functions may be directly regulated by iodine, (30, 31), it remains to be clarified whether the tumorigenic effect of iodine deficiency is direct, indirect, or both. 838

Goiter endemia in Sicily

Table 7 - Calculated prevalenc e of different thyroid tumors in the population of two areas of Sicily differing for iodine intake. Iodine deficient area

Control area

4,300

1,700

2.9%

5.5%

The requests of iodized salt from the authorities and the people of endemic areas have been insignificant. The commercial distribution chain to promote iodized salt consumption has never been activated, and only a minimal amount of iodized salt has been produced. When in 1977 and 1978 we repeatedly tried to obtain iodized salt to be distributed in the endemic area of Sicily, we failed in spite of the great efforts of the local political and sanitary authorities from some of the towns affected by iodine deficiency. In addition, we considered that the availbility of iodized salt per se was not sufficient for an effective iodine prophylaxis in Sicily where salt is produced locally by a variety of small factories and with. a retail distribution chain independent of all regular distribution networks. Furthermore, the socio-sanitary structure in Sicily is not always adequate for a campaign of information and education oriented to support the consumption of iodized salt. On the basis of the above considerations we envisaged a new method to provide iodine supplementation to the iodine deficient population. This new method entailed the adding of iodine to the drinking water. Water, like salt, is a suitable vehicle for adding iodine to the diet since its consumption is, of course , diffuse to the whole population and is fairly constant in different individuals. We supplemented iodine in the Municipal water supply of Troina, a town of approximately 13,900 inhabitants, located in the area of moderate iodine deficiency in Northeastern Sicily, at an altitude of 1120 m. over sea level (35) . The iodinator is an apparatus designed by Mr. R. Polley (Hydrodine Co., Miami, USA) and consisting of a plastic tank containing crystals of elemental iodine. This apparatus was connec.ted to the main pipe of the municipal water supply by two sets of plastic tubing and valves. One set served as the inlet to the iodinator and the other as the outlet. The inlet was connected to the pipe on the proximal side of a pressure differential regulator. The outlet was connected on the distal side. The pressure differential in the main pipe drove a portion of the water into the iodinator where it became saturated with iodine (approximately 250-300 mgll depending on water temperature and pH) (Fig. 3). The iodine enriched water returning to the main pipe was diluted by the large amount of non iodinated water. By manipulating the inlet and outlet iodinator valves , it was possible to regulate the fraction of the total water flow that went through the iodinator becoming enriched with iodine. By this diluting procedure we were able to achieve an established final concentration of iodine in the water of the distribution network. We diluted the iodine saturated water 1/ 4000 to 1 16000 times in order to obtain a final iodine concentration of approximately 50-75/19 / 1.

Significance (p)

Epidemiologic survey

Prevalence of cold thyroid nodules (105 inhabitants) Histopathologic study

Cancer rate of cold nodules selected by FNAB

Calculated prevalence of thyroid cancer 127 93 (10 5 inhabitants)

- Papillary - Follicular - Anaplastic

52 52 23

69 18 ' 6

< 0.001 NS < 0.001 < 0.001

APPLICA TlON OF A NEW METHOD OF IODINE PROPHYLAXIS THROUGH IODINATION OF DRINKING WA TER It is well known that the prevention of endemic goiter rests primarily on increasing the iodine intake of populations in goitrous regions. Therefore, any method that will provide additional iodine to subjects with dietary iodine deficiency will correct the problem and prevent iodine deficiency related disorders. These methods have now been available for more than 70 years. However, in a very recent meeting, Dr. H. Mahler, General Director of the World Health Organization repeated the statement that " .. .. Iodine deficiency disorders (100) continue to threat the health and well-being, as well as the social and economic productivity and advancement of several hundred million peoplethroughout the developing world ..... The most tragic aspect of the ravages of this nutritional deficiency is that proven techniques have been available for years to combat it. What is more, they are simple , cheap, and fully compatible with the primary health care approach . We have learned, of course , that 100 prevention and control is only in part a medical problem ; the other major dimension is national and international political will needed to overcome the maior geographic, economic, and administrative obstacles" (32). The causes indicated by Dr. Mahler are probably the main reasons why endemic goiter is still a widespread and sometimes severe sanitary problem in Sicily. Similar iodine deficiency related problems are still widespread allover Italy in spite of the industrialization of the country, the availability of iodized salt since 1972 (33) and the special legislation passed in 1977 (34) allowing the distribution of iodized salt in the whole Italian territory. 839

R. Vigneri PRESSURE VALVE P - 5 atmos

P - 3 atmos

~ ~

--.-

OUTLET

(iodine sature solution =iodine -300 mgtl)

Fig. 3 - Lay-out of the water iodination system with its connection to the main pipe of the water distribution network.

creased from 40.7% ± 2.6 (m ± SE) to 85.6 ± 6.5 and the radioiodine thyroid uptake decreased from 50.8 ± 2.4% to 40.7 ± 4.6%. No increase in the frequency of thyrotoxicosis was observed in the Troina population after the water iodination program was initiated and no side effects were reported. The only mild inconvenience occurred when, especially at the beginning of the program, iodine concentration in the water occasionally exceeded 120 /Jg/I. At this concentration, in fact, a mild medicinal odor was perceived, especially in hot or boiling water. I~ conclusion, the iodine supplementation to the municipal water supply resulted in a very effective method of iodine prophylaxis and, in addition, it was safe and easily applicable to the general population . The cost of a water iodination program depends on the initial cost of the apparatus and of setting up the system and also on the rate at which iodine is delivered into the system. When these calculations were carried out in the actual conditions realized in Troina (a water flow of approximately 60 I/person/ day and an iodine concentration in the water of 50 /Jg/I), a cost of approximately 0.04 US dollars/per person/per year was calculated.

Iodination of the Troina Municipal water supply was started in November 1979 but was discontinued at the end of July, 1980 for .15 months, because of a legal dispute between the Sicilian Government (who had authorized water iodination) and the central Italian Government (who had objected to the authorization). The dispute was resolved in favour of the Sicilian Government and the water iodination program was resumed in November 1981. In the following 28 months iodine enrichment of drinking water averaged 46.5 ± 5/Jg/1 (m ± SO). The iodine prophylaxis through iodinated water caused a prompt and dramatic decrease of goiter prevalence in schoolchildren. It decreased from a value of 55% (including an8% prevalence of grade II goiter) to 35% (and only 1.3% of grade II goiter) 3 months after starting water iodination. In the following 3 years the overall prevalence of goiter in Troina schoolchildren decreased to only 6.1% (Table 8). The changes in goiter prevalence observed in Troina schoolchildren did not occur, in the same period, in other endemic areas like Maniace (35). After the water iodination program was started the daily urinary iodine excretion in the adult population sample of Troina in-

Table 8 - Goiter prevalence in Traina schoolchildren. Date 1978

Goiter grade (%)

N. of cases

% Overall gaiter

0

1A

1B

2

942

55.0

45.0

28.5

18.5

8.0

Water iodination started 11 / 1979

1/ 1980

833

42.3

57.7

30.5

9.5

2.3

3/1980

611

35.8

64.2

29.4

4.7

1.3

21 .3 11 .0 7.4 6.1

78.8 89.0 92.6 93.6

19.3 10.3 5.3 5.1

2.0 0.5 1.9 0.9

0.0 0.2 0.2 0.1

Water iodination suspended 8 / 1980 - 11/1981

3/ 1982 6/ 1982 11 / 1982 4/1983

972 900 1002 980

840

Goiter endemia in Sicily

CONCLUSIONS

This cost favourably compares with that of other methods of iodine prophylaxis and would be significantly lower in less developed endemic areas where the pro capite water consumption may be much lower than in Troina. Therefore, the water iodination method fulfills all the requirements for an optimal method of iodoprophylaxis. It is effective, safe, practical and inexpensive. When compared to the iodoprophylaxis with iodized salt, the use of iodinated water shows significant differences (Table 9). The major difference is that is precluded the choice of selective iodine supplementation to diffrent individuals. However, the suppression of the individual choice on whether to receive or not receive iodine supplementation, has proven to be the reason for the success of iodine prophylaxis programs and it does not differ from other public health measures like water chlorination Or mandatory vaccination. An additional advantage of the water iodination method is that it does not require a commercial distribution network and that the iodine concentration in the water may be easily adjusted in different areas or within the same area... according to the different requireme.nts posed by local characteristics (36). More than fifteen years after the availability of iodized salt in Italy and despite its well established efficacy, iodine deficiency diseases persist as a significant public health problem in many areas of Sicily and of Italy. Many different causes have contributed to this delay in eradicating iodine deficiency diseases. We strongly believe that some of these causes may certainly be overcome by providing iodine to the affected population thorough drinking water. We also strongly believe that this method should be immediately used where iodine deficiency is severe and the socio-economic conditions or the sanitary organization do not guarantee the broad use of iodized salt.

Nearly twenty years of clinical research in the endemic area of Sicily have resulted in a better comprehension of some pathophysiological aspects of thyroid diseases and malfunctions related to iodine deficiency. In my opinion, in addition to the scientific accomplishment, these studies have also made a significant contribution to the amelioration of medical care for patients with thyroid diseases in the Sicilian endemic areas. These studies, in addition, have resulted in the decrease or even the eradication of the endemic goiter in some areas of Sicily. These clinical results were a direct consequence of the medical work of the University endocrinologists but also a consequence of the better understanding and care for the iodine deficiency related diseases by patients and local physicians in the endemic area. We believe that these achievements must be regarded as a relevant "side-effect" of our research on the iodine deficient areas of Sicily and as an accomplishment of the educational purpose of our academic commitment.

ACKNOWLEDGMENTS These studies were made possible by the contribution of my coworkers and senior clinical investigators Drs S. Squatrito, v. Pezzino and S. Filetti. They contributed to the planning, the organization and the execution of all these researches. Prof. F. Trimarchi and his coworkers g~ve an essential contribution to the studies performed in the province of Messina. Many interns, fellows and researches, from the Cattedra di Endocrinologia of the University of Catania actively participated to the collection of clinical and laboratory data and to the epidemiological studies. Especially relevant, at this regard, the contribution of Drs. A. Belfiore, E. Lisi, C. Regalbuto, F. Runello and L. Sava. Prof. Polosa, Head of Internal Medicine, contributed with practical and scientific support.

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Table 9 - Common characteristics and specific features of the iodinated water method in comparison to iodized salt for the prophylaxis of endemic goiter.

a) Characteristics that are common to the methods of iodine prophylaxis by iodized salt and iodinated water: - constant consumption - no medical personnel needed - no side-effects - low cost

b) Characteristics that are specific for the water iodination method: - easily distributed - readily adjustable - no individual choice - odor and taste at high iodine concentration

841

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