World J. Surg. 15, 205-215, 1991

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World Journal of Surgery 9 1991 by the Soci~t6 lnternationale de Chirurgie

Endemic Goiter and Endemic Thyroid Disorders E d u a r d o G a i t a n , M . D . , F . A . C . P . , N o r m a n C. N e l s o n , M . D . , a n d G a l e n V. Poole, M . D . University of Mississippi School of Medicine and Veterans Administration Medical Center, Jackson, Mississippi, U.S.A.

The primary role of iodine deficiencyin goitrogenesis and the prevention and treatment of endemic goiter by iodine supplementation is firmly established. Unfortunately, implementation of iodine prophylaxis programs has met with considerable technical and socioeconomicdifficulties. Besides, lack of knowledge concerning some of the other causative factors of endemic goiter has prevented development of appropriate measures for its complete eradication in those areas where goiter persists in spite of prolonged and adequate iodine supplementation. At present, no less than 5% of the world's population have goiters and associated disorders, resulting in a public health and socioeconomicproblem of major proportions. Seventy-five percent of people with goiter live in less developed countries where iodine deficiencyis prevalent. Goiter prevalence rates of more than 50% and the highest frequency of severe cases of iodine deficiency disorders, namely, cretinism, congenital hypothyroidism, and various degrees of impairment of growth and mental development are found in endemic areas with extreme iodine deficiency.Goiters are usually multinodular and of very large size, producing, on occasion, signs of compression that require surgery. Recurrence rates are as high as 25-30% and second surgery accounts for 16% of all thyroidectomies. Unfortunately, most of these goiters occur in areas with highly restricted medical and surgical facilities. Twenty-fivepercent of people with goiters live in more developed countries where goiter continues to occur in certain areas despite iodine prophylaxis. Iodine-sufficient goiters are associated with autoimmune thyroiditis, hypothyroidism, hyperthyroidism, and thyroid carcinoma. Goiter is of considerable surgical significance in iodine-sufficient endemic areas and, to a lesser degree, in nonendemic areas where it is called "sporadic" goiter. Recurrence rates of iodinesufficientgoiter are 10--19% followingthyroidectomy. Since most 6f these goiters grow by mechanisms other than increased thyrotropin (TSH) stimulation, treatment with suppressive doses of L-thyroxine is inefficient and, because of possible complications, not recommended. Although Graves' hyperthyroidism is not directly related to endemic goiter, it does relate adversely with ingestion or administration of iodine. At present, Graves' disease is treated with ~31Ior antithyroid drugs in more than 90 % of the cases. The incidence rates of papillary, follicular, and anaplastic thyroid carcinomas appear to be related to endemic goiter and iodine supplementation, with surgery being required in essentially all of these cases.

Epidemiology and Clinical Presentation of Endemic Goiter and other Endemic Thyroid Disorders (ETD)

Endemic Goiter as Prototype o f Endemic Disorders Throughout history, goiter has been, perhaps, the most representative of all endemic disorders [1,2]. As early as 2700 B.C., the Chinese were treating goiter with the iodine-rich seaweeds [1], but it was not until the 12th century when the School of Salerno introduced surgery as a way of treatment for this condition [2]. In the 12th and 13th centuries, the School of Salerno became the center of both conservative and operative treatment of goiter. Since then, the surgical approach has been in the frontline among various options for treatment of ETD. In 1960, Kelly and Snedden [3] introduced their findings on the prevalence and geographical distribution of endemic goiter with the following statement: "Goitre, as this survey shows in detail, occurs with varying intensity in almost every country; few countries appear to be entirely free from it. The disease has been observed in the far north, in the tropics, and in the far south; it occurs quite independently of climate, season or weather. Moreover, in its incidence goitre makes no distinction of race, nationality, color, creed or class; the North American, the European, the Chinese, the Himalayan Indian, the Turkoman, and the peoples of Central and South America all suffer from it under certain conditions--some severely, some moderately, some but mildly" (Fig. 1). Although there is great enthusiasm and interest by international agencies (WHO/UNICEF) and the International Council for Control of Iodine Deficiency Disorders (ICCIDD) to help governments throughout the world to implement iodine prophylaxis programs, with few exceptions, the situation 3 decades later remains the same in many of these areas [4-12].

Iodine as a Most Important Variable in Incidence and Clinical Presentation o f ETD Supported by grants from the Veterans Administration Medical Research Service of the United States and the Colombian National Science Foundation (COLCIENCIAS). Reprint requests: Dr. Eduardo Gaitan, Endocrinology Section (151), Veterans AdministrationMedical Center, 1500 Woodrow Wilson Drive, Jackson, Mississippi 39216, U.S.A.

The primary role of iodine deficiency in goitrogenesis and the prevention and treatment of endemic goiter by iodine supplementation are firmly established [4-7]. Unfortunately, implementation of iodine prophylaxis programs has met with considerable technical and socioeconomic difficulties. Besides, lack of knowledge concerning some of the other causative factors of

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World J. Surg. Vol. 15, No. 2, Mar./Apr. 1991

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Fig. 1. Geographical distribution of endemic goiter in the world. Hatching indicates areas where endemic goiter has been reported. Black areas correspond to mountain regions. According to WHO [3]. Reprinted with permission of publisher.

endemic goiter [ 13-15] has prevented development of appropriate measures for its complete eradication in those areas where goiter persists in spite of prolonged and adequate iodine supplementation. At present, no less than 5% of the world's population have goiters and many of these goiters are associated with other disabling disorders which constitute a major public health problem [4-12]. Although 300 million people with goiter live in less developed countries where iodine deficiency is prevalent, 100 million individuals with goiter live in more developed countries where goiter continues to occur in certain areas despite iodine prophylaxis [4]. Although endemic goiter and iodine deficiency are commonly associated with cretinism, congenital hypothyroidism, and various degrees of impairment of growth and mental development (conditions grouped under the name of iodine deficiency disorders or IDD), iodine-sufficient goiters are associated with autoimmune thyroiditis, hypothyroidism, hyperthyroidism, and, probably, thyroid carcinoma. An area is arbitrarily defined as endemic with respect to goiter if more than 10% of the population living in that area have goiter [7]. The term sporadic goiter is used also arbitrarily, whenever the condition occurs in individuals living in nonendemic areas, that is, with less than 10% goiter prevalence. Iodine Deficiency and Endemic Goiter. The criteria for defining a low, adequate, or excess iodine intake have been somewhat arbitrarily set by international agencies, special boards and committees, and different groups of investigators [6, 16]. An extreme iodine deficiency is considered to occur when daily intake is less than 25/xg and moderate when it is 25-50/xg; an adequate intake is defined as 100-200 txg/day, based on the fact that the normal human thyroid gland releases about 65 p~g of hormonal iodine to the circulation per day; and an excess of iodine corresponds to a daily intake of more than 2 mg or

approximately 10-20 times the optimal dose for this nutritional element. Iodine deficiency in endemic areas results in the highest incidence of goiter and associated iodine deficiency disorders (IDD). Goiter prevalence rates of more than 50% and the highest frequency of severe cases of IDD are found in endemic areas with extreme iodine deficiency. Goiters are usually multinodular and of very large size (grade III, WHO classification) [7, 17], producing, on occasion, signs of compression that require surgery. Unfortunately, most of these goiters occur in areas with highly restricted medical and surgical facilities. Besides, the problem in endemic areas is not only that a large segment of the population is affected by a tumor of the neck, but also that most of the individuals affected by IDD are prevented from performing normal and useful functions in their societies. Extreme iodine deficiency is still present in many countries of Africa, Asia, and Latin America [4-7, 10-12]. Moderate to severe iodine deficiency also persists in a number of countries in Europe [5, 8, 9], namely, Italy, Spain, the Federal Republic of Germany, the southwestern German Democratic Republic, Greece, Portugal, Romania, Austria, Hungary, Poland, and Yugoslavia. At present, different methods for massive iodization are being intensively investigated, with attention being directed to those socioeconomic and cultural conditions which are important in each region for the viability of the iodine prophylaxis programs. Iodine deficiency does not always result in endemic goiter. Even in the presence of extreme iodine deficiency, there is unequal geographical distribution of goiter affecting some areas more severely than others [6, 7, 16] (Fig. 1). This observation indicates the existence of factors other than iodine deficiency in the etiology and pathogenesis of endemic goiter [13-15]. For instance, there is epidemiological and experimental evidence that, in the presence of iodine deficiency, the concomitant exposure to a cyanogenic glucoside (linamarin) from Cassava, a

E. Gaitan et ai.: Endemic Thyroid Disorders

staple food in Zaire [15, 18], and to C-glycosylflavones from millet, a staple food in Sudan [15, 19-23], magnifies the severity of the goiter endemia in these 2 places. Severe iodine deficiency significantly alters thyroid gland function. Circulating thyrotropin or thyroid-stimulating hormone (TSH) levels are usually increased [7, 18]; however, this elevation of TSH occurs both in goitrous and nongoitrous individuals living in the same area, or in subjects from some iodine-deficient regions where goiter is not found. Therefore, beside TSH, other environmental and host factors may play a growth-promoting effect on the thyroid for goiter development [13-15, 24--26]. Other alterations of thyroid gland function in severe goiter endemias are: very high 4-hour radioactive iodine uptakes, low-normal or below normal T 4 levels, and normal or elevated serum T 3 levels [18]. Beside iodine deficiency and environmental goitrogens, protein-calorie malnutrition (PCM) also results in various alterations of thyroid gland morphology and function [6, 7]. PCM and endemic goiter frequently coexist, and poor nutrition appears to increase the risk of goiter development in susceptible groups of the population (infants, children, and pregnant women). Studies demonstrate that malnourished individuals have the same thyroid gland abnormalities [27] that have been shown in experimental animals to favor enlargement of the thyroid gland and to enhance the goitrogenic effect of antithyroid agents [28].

Iodine Supplementation, Endemic Goiter, and ETD. Iodine supplementation consistently decreases the incidence of endemic goiter and eradicates IDD. Clear examples are those of the United States of America [3, 29], Denmark, Finland, Iceland, Norway, Sweden, Switzerland, and United Kingdom in Europe [5, 8, 9], and Colombia in Latin America [6, 30-32]; however, iodine supplementation does not always result in complete eradication of goiter, and there are some well-defined instances of clusters or geographical areas where the condition remains endemic. This situation has been documented in various localities of western Colombia [15, 30-36] and Appalachia in eastern Kentucky [6, 29, 35-38]. There is epidemiological and experimental evidence indicating that environmental goitrogens working through the water exposure pathway may be responsible for the persistence of goiter [13-15, 39]. A change in the age distribution of the goitrous population is observed in those endemic areas after iodine supplementation. Goiters develop later in life and they are almost never seen in children under 5 years of age but become apparent during the school age. These goiters of school children and adolescents are of the diffuse type and smaller than those observed in endemic areas with iodine deficiency. While some goiters tend to disappear, others, mainly in women, evolve to the nodular forms which are commonly seen after age 30 [15, 16, 30, 31, 35, 40--42]. The histology of these goiters is not consistent with that of an iodine-deficient gland. Microscopically, diffuse goiters during the prepuberal and puberal years are characterized by areas of focal hyperplasia surrounded by dilated follicles with excessive dense colloid content. After the age of 20, epithelial nodules begin to appear and grow in the glands, later forming a capsule and showing the usual characteristics of follicular adenomas [6, 34, 41-43]. The serum TSH, free-thyroxine-index (FT4I), and triiodothy-

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ronine (T3) values in most of these children are within the normal range with median TSH, FT4I, and T 3 values not significantly different between goitrous and nongoitrous individuals [15, 34-36, 40--42, 44]. Similarly, values of iodine kinetic studies, which are significantly modified according to the degree of TSH activity and of the thyroidal response to exogenous TSH stimulation are normal in these 2 groups; these values being the same as those observed in normal individuals from nonendemic iodine-sufficient areas [11, 34, 41]. Furthermore, administration of suppressive doses of thyroid hormone to goitrous children for a 3-month period did not significantly decrease goiter size when compared to a placebo control group in a double-blind study [34]. Therefore, most goiters occur in these children in the presence of normal parameters of thyroid function. Again, these observations support the concept that beside TSH, thyroid-growth-promoting effects from other factors may also be involved in goitrogenesis [24-26]. The percentage frequency distribution of goiter in endemic areas, whether nutritional iodine deficiency exists [3, 6] or has been corrected [37, 40], is similar for males and females until puberty, but with progression of age it becomes considerably greater in females. Thus, sex is an important factor in the persistence of goiter after the fourth decade of life, when nodular goiters already account for most of them. In endemic areas after iodine supplementation, the follicular adenoma component predominates in these nodular glands (parenchymatous goiters), while the nodular colloid component (colloid goiters) is markedly decreased [6, 43, 45]. Also, the average weight of these goitrous glands is less than at the time of iodine deficiency. These goiters are not only heterogenous morphologically, but also functionally within the same gland [46--48]. Beside the marked regional variability of structure and function among the follicles of these "simple" nodular goiters, as they are also called, insightful observations by Studer and collaborators [47, 48] on the pathogenesis of goiter formation also indicate autonomy and dissociation of follicular growth and function, resulting in "cold" and " h o t " follicles, and eventually, with time, in "toxic adenomas" and overt hyperthyroidism in multinodular goiters (Plummer's disease) [41, 46, 49]. Whenever these "simple" goiters occur in iodine-sufficient "nonendemic" areas (less than 10% goiter prevalence) they are arbitrarily named "sporadic" goiters. These "sporadic" goiters and "solitary" thyroid nodules which, in most instances, are follicular adenomas with the same morphological and functional characteristics of "simple" goiters constitute an important clinical and public health problem in more highly developed countries. In the United States of America, clinically significant thyroid nodules are present in 4-7% of the adult population and are more common in women than in men [50-53]. As in the case of diffuse goiters in children and adolescents in iodine-sufficient endemic areas, the laboratory parameters of thyroid gland function are normal in most of these "simple" nodular goiters [32, 41], again indicating that iodine deficiency and increased TSH stimulation are not the only causes of goiter [7, 13-15, 18, 23, 27, 28, 34, 35, 47, 48]. Plummer's hyperthyroidism evolves very slowly in these goiters and clinical or overt hyperthyroidism is preceded by a stage of functional alterations of the pituitary-thyroid axis which indicate that there is already functional autonomy of the thyroid gland [41, 49, 54-58]. This asymptomatic period of non-TSH dependency has

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[ ] (~ Not Examined [ ] ~D Thyroid Antibodies (TgAb and TMAb) {~ (D Normal(NP) " ~ " ( ~ Deceased ~-~ (~ Goiter (G1- G3) * Subclinical Hyperthyroidism Fig. 2. Pedigree of a family living in the iodine-sufficient endemic area of Appalachia in Eastern Kentucky, U.S.A. *Suppressed S-TSH levels with FT4I values in the upper normal range. S/P: thyroidectomy

been demonstrated by a lack of functional response of the thyroid to the thyroxine-suppression test [41, 49], TSH unresponsiveness to thyrotropin-releasing hormone (TRH) [54], and suppressed or below normal serum TSH levels using a sensitive assay [55, 56]. Figures 2 and 3 illustrate this situation.

Iodine Supplementation and Hyperthyroidism (Thyrotoxicosis). The development of hyperthyroidism or thyrotoxicosis after supplementation of iodine in endemic goiter areas has been repeatedly documented [7, 5%64]. The occurrence of this complication in goiter patients treated with iodine was first described by Coindet in 1821: " I have observed goitrous patients who have been greatly affected by the treatment: acceleration of the pulse, palpitations, dry frequent cough, insomnia, rapid emaciation, loss of strength, in others only swelling of the legs or tremor or a painful hardening of the goitre, sometimes a shrinkage of the breast, remarkable and sustained increase in appetite." Approximately 100 years later, several authors in Switzerland, the United States of America, and Holland cited hyperthyroidism as a consequence of the introduction of iodine prophylaxis programs [7, 65]. More recently, hyperthyroidism was reported to occur in a few cases in New Guinea, Ecuador, Peru, and Brazil after iodized oil was administered [7, 11, 5%63, 66]. An " e p i d e m i c " of thyrotoxicosis, perhaps the best documented, was observed in northern Tasmania after iodized bread was introduced in 1966 [60]. There was a marked and significant increase in the number of cases of thyrotoxicosis seen at the Launceston General Hospital in the 6 months after the onset of the iodization program, when compared with the number of cases observed in the previous 6 years. Similar to what is observed in the Cauca Valley of Colombia, this hyperthyroidism developed primarily in people over 50 years of age with longstanding multinodular goiters [41, 49]. Iodide-induced thyrotoxicosis is known to be more common in iodine deficiency endemic areas affecting not only persons with longstanding multinodular goiters but also patients with Graves' disease who are relatively iodine-deficient and do not express the disease until exposed to adequate amounts of iodine [64, 67]. Although Graves' disease is not directly related to

Fig, 3. Sixty-four-year-old patient with "autonomous" (non-TSH dependent) multinodular goiter from an iodine-sufficient area. No symptoms or signs of hyperthyroidism or visceral compression are evident. RAI scan shows heterogenous distribution of 123I with multiple "hot" areas. S-TSH: <0.05 mU/L (normal: 0.2-5.5), TRH test (500 gg IV): no TSH response, FT4I: 11.1 (normal: 5.0--11.1), T3:3.3 nmol/L (normal: 1.2-3.1), TgAb and TPO (microsomal) Ab: negative, RAI uptake: 6-hr: 13% (normal: 5-15), 24-hr: 23% (normal: 10-35), urinary iodine: 105 /xg/gCr. Treatment with 131I25 mCi twice, 6 months apart.

E. Gaitan et ai.: Endemic Thyroid Disorders

endemic goiter, it does relate with ingestion or administration of iodine. Incidence and rates of recurrence and remission are adversely affected by iodine once treatment with antithyroid drugs is discontinued or after thyroidectomy [64]. Hyperthyroidism is also observed after administration of iodine-containing drugs, such as Amiodarone [68]. Hyperthyroidism was a more frequent (10%) complication of Amiodarone therapy in West Tuscany, Italy, an endemic goiter region with moderately low iodine intake, while hypothyroidism occurred more frequently (22%) in Worcester, United States of America, an area of iodine sufficiency; however, iodine-induced hyperthyroidism has also been described in areas with sufficient iodine intake [64]. Iodine Supplementation and Autoimmune Thyroiditis. There is good circumstantial evidence that iodine supplementation is associated with an increased incidence of lymphocytic autoimmune thyroiditis (LAT) [29, 64, 6%73]. For instance, the incidence of LAT has steadily increased in the United States of America during the past 5 decades and it has been attributed to iodine prophylaxis since 1924 and to excessive iodine intake [29, 6%71]. In western Colombia, where iodine prophylaxis was instituted in 1955, a similar trend has been documented, both in autopsy (195%1972) and surgically (1953-1973) removed thyroid glands [72]; however, lymphocytic infiltration was of high degree in all the glands in the United States series [71] while it was minimal in 71% of the Colombian cases [72]. Urinary iodine excretion values from 1960 to 1974 ranged between 108-633 ~g/gCr in school children and 229-758/~g/gCr in adults living in the areas of western Colombia where the autopsy and surgical materials had been obtained [31, 40--42, 74]. Retrospective studies of this kind have differences in methodology and design which limit the ability to make valid comparisons; however, these differences in degree and frequency of LAT have been confirmed in concomitant studies of 2 populations of school children equally supplemented with iodine, one residing in Kentucky, United States of America, and one residing in Colombia, South America [15, 35, 36, 44]. The prevalence of goiter ranged from 8% to 36% in Kentucky and 5% to 44% in Colombia; however, only in the Kentucky school children was there a significant elevation of antithyroglobulin (TgAb) and antiperoxidase (microsomal) (TPOAb) antibody titers and an association of these elevated titers with goiter and increased serum TSH levels. This was further documented by negative fine-needle aspiration (FNA) cytologies for LAT in the Colombian school children [35, 75, 76]. These studies suggest that, in iodine-sufficient areas only, genetically predisposed individuals exposed to various environmental pollutants develop LAT [15, 35, 36]. It is of interest in this regard, that in Hokkaido, Japan, colloid goiter was the dominant histopathological type of the "endemic coast goiter" attributed to exceedingly high dietary iodide from seaweeds, and that histological findings were not consistent with lymphocytic thyroiditis [6, 77, 78]. Endemic Goiter and Thyroid Carcinoma The concept that thyroid carcinoma occurs more frequently in endemic goiter areas has been held since the beginning of this century [61, 79]. In 1928, Wegelin showed that the frequency of

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thyroid carcinoma in autopsy material was 1.04% for the city of Berne, an endemic goiter area, compared to 0.09% for Berlin, a nonendemic region--a 10-fold difference. Subsequently, the decrease in the incidence of goiter observed after iodine prophylaxis was found to coincide with a decrease in the death rate of thyroid cancer, suggesting a relationship between these 2 entities. Reports from the United States of America [79] and Finland [80] have also supported this concept. Studies carried out in the endemic area of the Cauca Valley in Colombia, 8--14 years after the salt iodization program was established, showed a frequency of thyroid carcinoma of 1% in autopsy material, similar to that found by Wegelin in Berne. The incidence rate for thyroid cancer in the Cauca Valley was up to 10 times higher than those observed in nonendemic areas such as Puerto Rico and the states of New York and Connecticut [6, 81-83]. The mortality rate of this disease in the city of Cali in the Cauca Valley was also significantly higher than that found in Switzerland, Finland, Norway, England, Wales, and the state of New York [82, 83]. As shown in Figure 4, the increase in the incidence rate for thyroid cancer in endemic goiter areas corresponds to cases of the follicular and anaplastic types, while the incidence of papillary carcinoma remains similar to that observed in nonendemic regions. The follicular and anaplastic carcinomas were associated in more than 80% of the cases with the nodular components of the parenchymatous (follicular) type of goiter. These observations indicate that once a nodular goiter is present, iodine supplementation does not prevent the development of thyroid carcinoma. On the other hand, reports from different areas of the world [62, 73, 84, 85] indicate an increased incidence of well-differentiated thyroid carcinomas, particularly papillary carcinoma, a n d a decrease in poorly-differentiated follicular and anaplastic carcinomas after iodine has been supplemented. The direct effect of external irradiation to the thyroid on the subsequent development of thyroid nodules and thyroid cancer is also well documented [86]. Estimated new thyroid cancer cases for 1990 in the United States of America are 12,100, with a 3:1 female to male ratio, corresponding to 112% of all new cancer cases [87]. Surgery of Endemic Goiter and ETD

Goiter in Iodine-Deficient Areas Iodine-deficient diffuse and nodular goiters usually occur in poor areas of the developing world with restricted medical and surgical facilities, and where acceptance of goiter is part of "normal" life. Surgery is mostly restricted to very large (grade III, WHO classification) [7, 17] multinodular goiters producing symptoms and signs of mechanical obstruction and compression, namely, difficulty of breathing, stridor, hoarseness, and dysphagia. Recurrence rates are as high as 25-30% and second surgery accounts for 16% of all thyroidectomies [7]. There are few reliable statistics on the number of thyroidectomies performed in most of these iodine-deficient countries. For instance, in the Shaanxi Province of China, 30,000 goitrous individuals underwent thyroidectomy in a 3-year period (19761979) [88]. More than 85% were very large (grade III, WHO classification) nodular goiters; 53% being goiters of more than 10 years duration. The health care cost expenditures of continuing iodine deft-

World J. Surg. Vol. 15, No. 2, Mar./Apr. 1991

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ciency in the Federal Republic of Germany [89] indicate that social security, private insurance companies, and the government combined spent about 680 million German marks (DM) (1 DM = US $0.53) for in vivo and in vitro procedures for the evaluation and follow-up of ETD in 1986, and it is estimated that 75% of these thyroid disorders are directly related to iodine deficiency. Surgical treatment is often necessary for large nodular goiters, particularly those with compressive manifestations. Some 80,000 subtotal thyroidectomies are performed in the Federal Republic of Germany each year, requiring 650,000 days of hospitalization. When therapy with ]31[ is used to reduce goiter size, patients are hospitalized in special nuclear medicine wards for 7-10 days. The costs for treatment of these inpatients amounted to 200 million DM per year. Besides, surgical treatment involves the risk of complications and their management and, in some 10% of cases, a second thyroidectomy is done because of goiter recurrence. Furthermore, the cost of L-thyroxine suppressive or replacement therapy for goiter or hypothyroidism reached 120 million DM in 1986. Thus, combining the costs for inpatient and outpatient therapy, it was estimated that some 460 million DM per year are spent on medical and surgical treatment of endemic goiter in the Federal Republic of Germany. This means that about 900 million DM per year or 0.4% of the total 250 billion DM spent for medical care in the Federal Republic of Germany in 1986 was allocated for endemic goiter, two-thirds for diagnosis, and one-third for treatment; however, the total costs are substantially more since these figures do not include loss of productivity.

Goiter in Iodine-Sufficient Areas Goiter continues to be of considerable surgical significance in iodine-sufficient endemic areas (Fig. 2), and to a lesser degree in nonendemic areas [6, 48]. Since most of these goiters grow by mechanisms other than increased thyrotropin (TSH) stimulation, treatment with suppressive doses of thyroid hormones is usually doomed to failure and is not recommended [34, 90-93].

Even treatments with L-thyroxine that have been considered successful do not reduce thyroid size by more than 20-30% [94]. Furthermore, L-thyroxine administration can induce thyrotoxicosis in "simple" goiters which are already autonomous or non-TSH dependent [57, 58, 91, 95]. Similarly, most studies agree that routine L-thyroxine treatment following surgery is of no value [57, 58, 92, 96-98]. Thus, L-thyroxine substitution therapy should be restricted to goitrous patients with concomitant hypothyroidism and for those developing this condition following surgery [57, 58, 91, 93]. Surgery of goiter in iodine-sufficient areas has the same indications as in endemic areas with iodine deficiency; however, cosmetic reasons, rapid growth, and suspicion of thyroid cancer become factors more frequently considered for thyroidectomy in the iodine-sufficient more developed countries [99, 100]. In most instances, surgery is performed in "endemic" or "sporadic" euthyroid (nontoxic) as well as in some autonomous (toxic) nodular goiters [57, 58, 92, 96-99]. Most surgical series with follow-up of more than 5 years agree that recurrence rates of goiter are 10-19% following thyroidectomy [92, 99101]. Expertise and the extent of thyroidectomy determine the frequency of complications, namely, hypothyroidism, damage to the recurrent laryngeal nerves, and hypoparathyroidism [96, 99, 100]; however, in some cases, extensive goiter resection aimed at removing all excessively growing foci to prevent recurrence is recommended [48]. Unfortunately, it has been shown that serum thyroglobulin concentrations, studies of TSH-dependency, circulating thyroid autoantibodies (TgAb and TPOAb), and morphological features have poor or no predictive value with special reference to risk of goiter relapse [93,102, 103]. An efficacious alternative to surgery in treatment of nontoxic large multinodular goiters is administration of radioactive iodine (131I, 20-100 mCi) [104]. This approach should probably be used more frequently, particularly in patients with "autonomous" or "toxic" large multinodular goiters which are not causing obstructive symptoms (Fig. 3).

E. Gaitan et al.: Endemic Thyroid Disorders

"Solitary" Thyroid Nodules in Iodine-Sufficient Areas "Solitary" thyroid nodules in iodine-sufficient areas require extensive and costly clinical, laboratory, and other specialized diagnostic procedures, namely, radioactive scans, ultrasonography (US), and fine-needle aspiration (FNA) cytology or needle biopsy to identify those cases of thyroid carcinoma [51, 53]. Radioactive scans and US, although highly sensitive, are of low specificity. Similarly, this is also true of L-thyroxine suppressive therapy as a diagnostic procedure. Thus, the cOsteffectiveness of using these procedures is poor. FNA or needle biopsy have as good a sensitivity and a significantly higher specificity than these other tests and, therefore, FNA is, at present, the recommended diagnostic procedure [51-53]. FNA cytology is excellent for diagnosis of papillary carcinoma, the most frequent type of thyroid cancer in iodine-sufficient areas and of the undifferentiated type, but it is not as good for diagnosis of differentiated follicular carcinoma. In cases of suspicious or indeterminant cytology, those patients showing "cold" or "warm" nodules in radioactive iodine scans should have surgery since at least 20% of these nodules are thyroid carcinomas [53]. Nevertheless, comprehensive evaluation of thyroid nodules is very important to minimize the cost and poor risk/benefit ratio of unnecessary surgery.

Graves' Hyperthyroidism Surveys a,nong thyroidologists in Europe and the United States of America [105, 106] on the management of hyperthyroidism due to Graves' disease indicate that 131I (RAI) and antithyroid drugs are used as the first choice of treatment in more than 90% of cases. Subtotal thyroidectomy used to be the treatment of choice and is still effective therapy whenever indicated [107, 108].

Thyroid Carcinoma Surgery is required in essentially all cases of thyroid carcinoma [53]. The surgical approach will vary depending on the histologic type, and with the size and extent of differentiated (papillary and follicular) thyroid cancer. Small (<2 cm) and intrathyroidal papillary carcinomas in male patients less than 40 years old and female patients less than 50 years old can be treated by lobectomy and isthmectomy. "Berry picking" of enlarged or suspicious lymph nodes is an adequate node dissection, and long-term recurrence rates are not improved by more extensive thyroidectomy or nodal excision [109-ll 1], even though multicentricity can be demonstrated on total thyroidectomy specimens from patients with clinically unilateral neoplasms [112, 113]. Larger and extrathyroidal papillary cancers, and those which occur in older patients are treated best by total thyroidectomy with a dissection of the nodes of the central neck, and a modified neck dissection if extensive node metastases are present. Although small, minimally invasive follicular carcinomas may be managed adequately by less than total thyroidectomy [114]; significant capsular and vascular invasion are important negative prognostic findings in follicular cancer. The presence of these features on frozen section is an indication for a total thyroidectomy. If significant infiltration of the capsule or angio-

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invasion are not detected until permanent histologic sections are reviewed, a completion total thyroidectomy should be done. Follicular carcinoma is more likely to spread to the lungs or bone than to the lymph nodes. Neck dissection is required infrequently, and only if suspicious nodes are present. Hfirthle cell neoplasms are composed of oxyphilic cells and may be a variant of follicular carcinoma. Although the majority of Hfirthle cell tumors are benign, it is difficult to predict the biologic behavior of these tumors on the basis of their histologic appearance. Most of these tumors will have a benign course and are treated adequately by lobectomy [I 15, 116]. Lesions larger than 2 cm and those with capsular or vascular invasion, or nodal metastases should be treated by total thyroidectomy, or completion thyroidectomy if an incomplete resection was performed initially. This approach has been shown to reduce the recurrence rate to 21%, compared to a recurrence rate of 59% in patients who underwent a lesser resection [117]. Since this tumor does not respond to radiotherapy, thyroxine suppression, or chemotherapy [117], early surgical control is mandatory. All patients with differentiated thyroid carcinoma should receive thyroxine postoperatively to suppress TSH secretion. Although the utility of this approach has been questioned [ 118], the results of a large series of patients with papillary cancer support the routine use of thyroxine suppression [53, 119]. Analysis of nuclear DNA content of FNA specimens may provide additional information to AGES (Age, Grade of differentiation, Extension, Size) prognostic factors, and could be used to guide therapy of thyroid carcinomas [120, 121]. Because aneuploid tumors are more aggressive than diploid tumors, a total thyroidectomy might be more appropriate than a lesser resection for an aneuploid but otherwise "good risk" cancer. Until prospective trials are completed, there are insufficient data to determine if this approach would alter long-term outcome. Following total thyroidectomy for well-differentiated thyroid cancer, total body radioiodine scanning should be performed 6--12 weeks after surgery. Any sites of uptake should be ablated with 131I. Ablation should be confirmed with a follow-up scan, and repeated doses of 131I given until residual sites of uptake have disappeared. Scans should be repeated at 1, 3, and 5 years, and then every 5 years to assess for the development of recurrent disease. If metastatic disease develops after an incomplete thyroidectomy, the residual thyroid must be removed surgically or by 131I SO that the metastases can be managed with radioiodine. Metastatic disease that fails to respond to radioiodine may be amenable to surgical excision, even if this involves bone resection with osteosynthesis [122]. An aggressive program of tumor control can significantly reduce recurrence [119] and prolong survival in patients who do develop recurrent differentiated thyroid cancer [122, 123]. An alternative to periodic radioiodine scans to search for metastatic disease in patients who have undergone total thyroidectomy is serum thyroglobulin (Tg) assay [124, 125]. Almost all differentiated thyroid cancers contain immunoreactive Tg, but anaplastic thyroid cancers do not. Elevated serum Tg has also been shown to be a sensitive marker of metastatic thyroid carcinoma in patients who have no residual thyroid gland [125]. Tg is normally present in the serum of adults, and ifTg is to be used as a marker for recurrent thyroid cancer, then

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the thyroid gland must have been completely removed or destroyed by a31I. Anaplastic giant cell carcinoma of the thyroid has a 1-year survival of about 10% and essentially no 5-year survivors. If technically feasible, total thyroidectomy should be part of a multimodality treatment program with external radiotherapy and chemotherapy [126, 127]. Although local control can be achieved and fewer patients will need a tracheostomy, duration of survival has been extended very little by such programs because systemic disease has not been controlled adequately. Beside these types of thyroid cancer which associate with endemic goiter and iodine supplementation, the physician should always keep in mind other, although much less frequent, causes of thyroid enlargement or nodularity, namely, medullary carcinoma, thyroid lymphoma, and cancer metastatic to the thyroid [53]. Diagnosis of these conditions is made also using FNA cytology. R6sum6

Le r61e essentiel de la carence en iode dans la gen~se du goitre et la pr6vention et le traitement du goitre end6mique grace ~t un apport en iode sont 6tablis avec certitude. Cependant, les programmes prophylactiques d'apport en iode ont rencontr6 d'6normes difficult6s et techniques et socio-6conomiques. En outre, le manque de connaissances des autres facteurs qui provoquent le goitre end6mique ont emp6ch6 le d6veloppement des mesures n6cessaires ~ son 6radication totale dans les cas ofl le goitre persiste malgr6 l'apport suppl6mentaire prolong6 et suffisant d'iode. Aujourd'hui, au moins 5% de la population mondiale a un goitre et des d6sordres associ6s provoquant un grave probl~me dans la sant6 publique et en 6conomie sociale. Soixante-quinze pour cent des gens avec goitre vivent dans les pays sous d6velopp6s of1 le manque d'iode est fr6quent. Des taux de goitres d6passant 50% de la population, et la grande fr6quence de cas graves des d6sordres du manque d'iodine, en particulier le cr6tinisme, l'hypothyroidisme cong6nital et les retards de croissance psychomotrice ~t des degr6s divers se rencontrent dans les pays end6miques avec un d6ficit en iode. Les goitres sont en g6n6ral multinodulaires et de grande taille, provoquant h l'occasion des signes de compression qui rel~vent de la chirurgie. Les taux de r6cidive s'61~vent h 25-30% et la chirurgie secondaire compte 16% du nombre total des thyroidectomies. Malheureusement, la plupart de ces goitres surviennent dans des r6gions o~ les possibilit6s m6dicales et chirurgicales sont extr6mement r6duites. Vingt cinq pour cent des patients qui ont un goitre vivent dans des pays plus d6velopp6s oO il continue d'apparaRre en d6pit de l'apport prophylactique suffisant en iode. Les goitres survenant sans d6ficit en iode sont alors fr6qemment associ6s ~t la thyroidite auto-immune, ~t l'hypothyro~die, ~t l'hyperthyroidie et au cancer de la thyroide. Le goitre occupe une place th6rapeutique chirurgicale immense dans les pays d'end6mie o0 l'iode ne manque pas et, hun degr6 moindre, dans les endroits non end6miques oa il est appel6 goitre "sporadique." Le taux de r6cidive des goitres normoiod6s est de 19% apr~s thyroi'dectomie. Puisque la plupart de ces goitres augmentent de volume autrement que par une stimulation accrue de thyrotropine, le traitement avec des doses suppressives de L-thyroxine est inefficace et, en raison des risques de complication, peu indiqu6. Bien que la Maladie de

World J. Surg. Vol. 15, No. 2, Mar./Apr. 1991

Basedow ne soit pas directement en rapport avec le goitre end6mique, elle est en rapport convers6 avec l'ingestion d'iode. Elle se traite aujourd'hui a v e c 131I OU des m6dicaments antithyroidiens dans plus de 90% des cas. L'incidence de cancers papillaires, folliculaires, et anaplasiques semblent 6tre en rapport avec le goitre end6mique et l'augmentation d'iode: la chirurgie est indiqu6e dans pratiquement tous ces cas. Resumen

E1 papel primario de la deficiencia de yodo en la bociog6nesis y en la prevenci6n y tratamiento del bocio end6mico mediante suplemento dietario de yod0, est~i bien establecido. Desafortunadamente los programas profil~icticos mediante suplementaci6n de yodo han encontrado dificultades de carficter t6cnico y socio-econ6mico. Adem~is, la falta de conocimientos relativos a otros factores causales de bocio end6mico ha impedido el desarrollo de medidas adecuadas para lograr su total erradicaci6n en fireas donde el bocio persiste a pesar de una adecuada suplementaci6n de yodo. En la actualidad no menos del 5% de la poblaci6n mundial est~i afectada pot bocio y des6rdenes asociados, lo cual resulta en problemas socio-econ6micos y de salud de proporciones mayores. Setenta y cinco por ciento de las personas afectadas por bocio residen en naciones de menor desarrollo, donde es frecuente la deficiencia de yodo. Tasas de prevalencia de bocio superiores a 50% y la mayor incidencia de casos graves de alteraciones por deficiencia de yodo, tales como cretinismo, hipotiroidismo cong6nito, y desarrollo mental anormal, se presentan en las regiones donde hay deficiencia extrema de yodo; los bocios son generalmente multinodulares y de gran tamafio, capaces de producir comprensi6n mec~inica que demanda cirugfa. Las tasas de recurrencia llegan hasta 25-30%, y la segunda cirugfa representa el 16% de todas las tiroidectomias. Infortunadamente la mayorfa de estos bocios se presentan en ~ireas donde las facilidades m6dicas y quirt~rgicas son restringidas. El 25% de las personas con bocio viven en parses de mayor desarrollo donde el bocio continda present,indose a pesar de la profilaxis mediante suplementaci6n dietaria. Los bocios con suficiencia de yodo se asocian con tiroiditis autoinmune, hipotiroidismo, hipertiroidismo, y carcinoma tiroideo. El bocio es de considerable pertinencia quirdrgica en ~ireas de bocio end6mico con suficiencia de yodo, y e n menor grado en fireas no end6micas, donde el bocio es de tipo "espor~idico." Las tasas de recurrencia del bocio con suficiencia de yodo son de 10-19% despu6s de tiroidectomfa. Puesto que la mayoria de estos bocios se desarrollan pot mecanismos diferentes del estfmulo por tirotropina (TSH) aumentada, el tratamiento con dosis supresoras de L-tiroxina es ineficaz y, por sus potenciales complicaciones, no recomendable. Aunque el hipertiroidismo de Graves no aparece directamente relacionado con el bocio end6mico, si se observan efectos adversos con la ingesti6n o la administraci6n de yodo. En la actualidad la enfermedad de Graves es tratada c o n 131I 0 con drogas antitiroideas en m~is del 90% de los casos. La incidencia de carcinomas tiroideos papilares, foliculares, y anapl~isicos parece estar relacionada con el bocio end6mico y con la suplementaci6n de yodo, y la eirugfa se halla indicada esencialmente en la totalidad de los casos.

E. Gaitan et ai.: Endemic Thyroid Disorders

Acknowledgment

We are most grateful to Mrs. Betty Henderson for her expert secretarial assistance in the preparation of this manuscript. References

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