Thyroid I - Endemic Goiter
| Introduction | |
| Current Status | |
| Etiology | |
| Natural History and Pathophysiology | |
| Diagnosis | |
| Prevention and Medical Treatment | |
| Indications for Surgery | |
| Thyroidectomy | |
| Conclusions and comments | |
| Recommendations |
| References |
| Questions |
| Clinical Cases |
Iodine deficiency disorders (IDD) is the collective name of endemic goiter and endemic cretinism. It is a major worldwide problem, especially during pregnancy and childhood (1). It is a threat to the social and economic development of countries. The most devastating outcomes of iodine deficiency are increased perinatal mortality and mental retardation. Iodine deficiency is the main preventable cause of brain damage in children and constitutes a universal public-health concern (2). This was the primary motivation in the current worldwide drive to eliminate IDD (3). Although cretinism is the most extreme manifestation, the more subtle degrees of mental impairment leading to poor school performance, reduced intellectual ability and impaired work capacity are of considerably greater significance (3;4). Estimates suggest that 2 billion people globally have insufficient iodine intake according to data quoted from the WHO Global Database on Iodine Deficiency, 2004, by Andersson et al (3). The virtual elimination of IDD by the year 2000, as pledged by most world governments and International organizations during the World Summit for Children in 1990, has not yet been achieved (3;5). Dunn, in 1996 described seven major errors that occur during iodine supplementation programs and offered suggestions for their avoidance. Unreliable assessment of iodine deficiency, poor iodine supplementation plan, exclusion of relevant stakeholders, inadequate education, insufficient monitoring, inattention to cost and nonsustainability are the seven ‘deadly sins’ to be avoided in order to achieve the goal of sustainable elimination of iodine deficiency (6). Toteja in a multicentric study in India, showed a significant decrease in IDD between 1997 and 2000, following iodine supplementation programs (5).
Goiter is conveniently referred to as endemic when it occurs in more than 10% of the population in a defined area (7). It is the chief consequence of iodine deficiency, resulting from either low iodine intake or ingestion of goitrogens. A total goiter rate (TGR) of 5% or more is now recommended as the cut-off point to indicate a public health problem as per the decision made by the key international bodies concerned (UNICEF/ICCIDD/WHO, 1992). This recommendation is based on the observation that goiter prevalence rates between 5% and 10% may be associated with a range of abnormalities including inadequate urinary iodine(UI) excretion or subnormal levels among adults, children and neonates (8).WHO recommends that iodine deficiency surveys examine school-age children ( 6-12 years) because of their high physiologic vulnerability and their accessibility through school for studies in baseline health parameters (9). The WHO cut-off points applied for classifying iodine nutrition into different degrees of public health significance are shown in Table 1:
Table
1. Epidemiological criteria for assessing iodine nutrition based on
median UI concentrations in school-age children |
||
| Median UI(µg) | Iodine intake | Iodine nutrition |
| <20 | insufficient | Severe iodine deficiency |
| 20-49 | insufficient | Moderate iodine deficiency |
| 50-99 | insufficient | Mild iodine deficiency |
| 100-199 | Adequate | Optimal iodine nutrition |
| 200-299 | More than adequate | Risk of iodine-induced hyperthyroidism within 5 - 10 years following introduction of iodized salt in susceptible groups |
| =300 | Excessive | Risk of adverse health consequences (iodine induced hyperthyroidism, auto-immune thyroid diseases) |
| Source: WHO Global Database on Iodine Deficiency | ||
Data on urinary iodine (UI) collected between 1993 and 2003 by the WHO Global Database on Iodine Deficiency were available from 126 countries of the 192 member states. Sixty-six have no data on UI. In 54 countries the population has insufficient iodine intake as indicated by a median UI below 100 micrograms/l. The lowest prevalence of iodine deficiency is found in the American Region, where 90% of households consume iodized salt, the highest in the world. In contrast the highest prevalence of iodine deficiency is in the European Region where only 27% of households consume iodized salt (3). Some authorities in this region have been reluctant to implement the salt iodization policy due to perceived or real complications of iodine administration (10).
During the same period data on total goiter prevalence (TGP) were available from 100 countries. Globally, the TGP in the general population is estimated to be 15.8%, varying between 4.7% in the Americas to 28.3% in Africa. When comparing current levels to the 1993 estimates, TGP has increased by 31.7% worldwide. This is inconsistent with current iodine status based on UI. Several explanations have been suggested including time lag from implementation of salt iodization programs, and poor assessment methods of TGP by palpation. The introduction of ultrasonography in recent years has increased the TGR detection when compared to initial surveys done by palpation only (3;11). A total of 36.5 % (285 million) school-age children were estimated to have an insufficient iodine intake. Iodine intake was more than adequate or excessive in 29 countries (3).
The world’s natural supply of iodine is mostly from the ocean in the form of iodide. The commonly quoted historical areas of goiter include the Himalayan slopes, the Andean region of South America, the European Alps and the mountainous areas of China. The Rift valley regions of East and Central Africa are also endemic areas. Low lands with heavy rains or floods are usually prone to iodine deficiency.
Despite the established benefits of iodine supplementation in the prevention of endemic goiter, IDD is still a major problem in developing countries (12;13). The geographic isolation and the socioeconomic, cultural, and political factors in these communities contribute to the technical difficulty in implementing iodine prophylaxis programs (14). To be successful, control programs for iodine deficiency disorders also need assessment of the salt trade, monitoring, education and occasional targeted interventions with iodized oil or other supplements (15-17).
In severely iodine deficient areas, goiter appears at an early age, and the prevalence increases markedly during childhood and attains its peak at puberty. From the age of 10 years, the prevalence is higher in girls than in boys (18), probably because of the difference in metabolism of iodine during adolescent growth. In both sexes, goiter prevalence decreases during adulthood but the decline is sharper in men than in women (19).
Low supply of dietary iodine is the main cause of endemic goiter. The normal human thyroid gland releases 65 micrograms of hormonal iodine to the circulation per day which represents the minimum daily requirements of iodine. Iodine requirements increase during puberty, pregnancy and lactation. The adequacy of dietary iodine is usually determined by the measurement of urinary excretion of iodine (20). In non-endemic areas, the urinary iodine level is at least 100 micrograms per liter. Mild to severe iodine deficiency is reflected in gradually decreasing levels of urinary iodine. The prevalence of endemic goiter varies with the severity of iodine deficiency (3;21).
The global salt iodization program has resulted in a reduction in goiter prevalence. The persistence of goiter in some areas with adequate iodine prophylaxis and the unequal geographic distribution of goiter in iodine deficient areas suggest the existence of other goitrogenic factors (22;23). Cyanoglucosides are naturally occurring goitrogens found in several staple foods in the tropics, namely cassava, maize, bamboo shoots, and sweet potatoes (13;24). The brassica family of vegetables is a famous example producing thioglycosides. Flavonoides from millet, a staple food in Sudan are also known to have antithyroid activity (25). Millet consumption in Sudan and Cassava in the Democratic Republic of Congo (DRC) was found to aggravate the goiter endemism in these places (26).Natural History and Pathophysiology
Thyroid hormone synthesis is impaired when the iodine intake is low. This impairment leads to an increased thyroid clearance of iodide from the plasma and decreased urinary clearance of iodide, an adaptation towards iodine conservation. The synthesis of T3 is increased because it is 3-4 times more potent than T4 and contains only ¾ as much iodide. Peripheral conversion of T4 to T3 also takes place. Clinical euthyroidism is thus maintained, but biochemically the pattern of low T4, elevated TSH and normal or elevated T3 levels is often found (27). In endemic cretinism, where thyroid failure is severe, serum T3 and T4 levels are low and serum TSH concentration is markedly elevated. In less severe situations, serum T3 and T4 levels may remain normal. The serum TSH may also be normal or only moderately elevated.
In endemic areas, a wide variation in the level of TSH has been observed in normal and goitrous individuals. Such dissociation between goiter size and biochemical findings suggests the possible role of circulating thyroid growth factors, such as epidermal growth factors, or an autoimmune process in the pathogenesis of goiter (28).
The physiologic changes to iodine deficiency discussed above, are usually accompanied by an increase in the size of the thyroid gland (8;9). Generalized epithelial hyperplasia occurs, with cellular hypertrophy and reduction in follicular spaces. In chronic iodine deficiency, the follicles become inactive and distended with colloid accumulation. These changes persist into adulthood, and focal nodular hyperplasia may develop, leading to nodular formation. Some of these nodules retain the ability to secrete thyroxine and form functioning thyroid nodules (29). Others do not retain this ability, become inactive and form cold nodules. Necrosis and scarring result in fibrous septae, which contribute to the formation of multinodular goiter (30).
Classification of goiter in general is according to the size of the thyroid
gland on physical examination and the grading system recommended by the WHO
in 1960 and modified in 1994 (31):
• Grade 0: No palpable or visible goiter
• Grade 1: Mass consistent with enlarged thyroid that
is palpable but not visible when the neck is in the neutral position; it also
moves upwards in the neck as the subject swallows.
• Grade 2: Swelling visible in a neutral position of
neck and is consistent with an enlarged thyroid when the neck is palpated
The simplicity of this of this assessment allows for easy training of field
staff in public health surveys (32). Goiter volume can be
assessed precisely with ultrasonography and is a useful guide in the assessment
of response of goiter shrinkage under medical treatment. However this is mainly
used in a clinical setting and ill adapted to use in mass surveys in developing
countries (11).
A diffuse thyroid enlargement is the most common from of goiter in small children. The finding of a small solitary, palpable nodule in adolescence is common as nodularity could occur at a young age. Some diffuse goiters persist into adulthood, or most of the gland may become replaced by nodules that form a multinodular goiter.
The individual often remains clinically euthyroid despite biochemical evidence of hypothyroidism, with low or normal serum T4 levels and minimally elevated TSH levels. Hyperthyroidism may be precipitated by iodination and cause what is referred to as iodine induced hyperthyroidism (IIH) (33;34). This phenomenon, which was reported to have increased during iodine supplementation programs in the mid nineteen nineties in various African countries (35;36), caused concern to thyroidologists and the WHO, who started to pay more attention to this previously rare occurrence. Azizi et al in multicentric surveys in Iran, have shown that IIH is not of major concern in properly implemented iodization programs and occurred only with high intake of iodine (34).
Endemic cretinism is a sequel of severe iodine deficiency in which intrauterine growth is affected by the deficiency of maternal T4 and dietary iodine (37). The infant is born with mental retardation and either a predominantly neurological syndrome of hearing and speech defects and varying degrees of characteristic stance and gait disorders or predominant hypothyroidism and stunted growth (1). These changes are preventable with iodine prophylaxis but are not curable once they have occurred (38).
Pressure symptoms with tracheal deviation and compression often arise in patients with huge goiters. These symptoms are worse in cases of retrosternal or intrathoracic extension as venous compression, leading to the superior vena cava syndrome, can occur. This is clinically obvious from the presence of collateral venous circulation on the chest wall. Surgery is always indicated in such patients.
The presence of hard nodules suggests possible malignancy. Although an increase in the incidence of thyroid cancers in endemic goiters remains controversial, studies done in afflicted areas of Nigeria seem to support this (39). Anaplastic and follicular carcinomas are more common in endemic goiter areas. The diagnosis is often delayed in such patients because goiters are so common in iodine-deficient areas. Fine needle biopsy, helps select patients for thyroidectomy, although its sensitivity varies with the experience and training of the cytopathologist.
Prevention and Medical Treatment
The supply of adequate iodine in the diet and the elimination of goitrogens are the means used to prevent endemic goiter. However, there is increasing evidence endemic goiter could be provoked by genetic (40) as well as environmental factors including emotional stress, smoking and infections. There are on-going case-controlled studies to examine this aspect (22;41)
Global iodization of salt has been successfully introduced with remarkable results in the last 80 years after its initial successful introduction in Switzerland and the state of Michigan in the early part of the 20th century. The technology of iodination is simple, and its production is easy to regulate. This is the preferred method of prophylaxis because salt consumption is consistent and universal. Unfortunately, legislation is usually required to iodize salt and many countries are still reluctant to introduce iodized salt because of resistance by lobby groups worried about the development of hyperthyroidism in their populations. Up to 1999 only 28% of the European population had access to iodized salt, making it the worst in the world. Globally 68% of the world population had access to iodized salt at that time (7). Recent cross-sectional data on urinary iodine (UI) and total goiter prevalence (TGP) in school-age children from the WHO Global data base on iodine deficiency indicate a marked improvement in the worldwide iodine deficiency disorders (IDD) situation. Nevertheless, IDD is still a cause for concern. It is still a public health problem in 54 WHO member countries, in spite of previous optimism that it would be eliminated by the year 2000 (3).
Iodine in the form of potassium iodide is added to table salt in varying amounts ranging from 1 part in 10000 of salt to 1 part in 200000, depending on local factors such as customary consumption of salt. Potassium iodide is preferred in humans because of its increased stability. Although surveys have confirmed the dramatic reduction in the prevalence of goiter and gradual disappearance of cretinism within a few years of introduction of iodized salt (42), compliance by manufacturers of salt has been a subject of recent debate. The tendency has been to supply less iodine than what is recommended in the health legislation (43;44). Difficulties in implementation occur in countries where locally inexpensive salt is available and government programs to increase iodine consumption are lacking (6). Benede et al. did a cross-sectional study and found iodine deficiency of moderate severity in a rural community in KwaZulu Natal with no iodine supplementation program, in spite of the fact that South Africa was considered officially iodine sufficient (45). This happens in spite of the low cost of the salt iodization process. Iodination of vegetable oil is also in use in areas where salt consumption is not common either due to geographical barriers or cultural factors. It has also been helpful for initiating the start-up phase of prevention programs using iodized salt awaiting approvals or health legislation (14).
There have been concerns about the increase in cases of iodine induced hyperthyroidism (IIH) after implementation of iodization programs. This has been shown to be rare following well executed iodine supplementation programs (34). The cause was attributed to the presence of autonomous nodules or underlying hyperthyroidism present in persons with long-standing endemic goiters. The enormous benefits of correcting iodine deficiency far outweigh the occurrence of thyrotoxicosis in iodine deficient regions. Overall, it abolishes endemic goiter and reduces the incidence of toxic nodular goiters in the long run. At the World Summit for Children in 1990 attended by 71 heads of state, it was decided to eliminate IDD by the year 2000. This was to be accomplished by universal salt iodination by 1995. So far all the 192 WHO member states have signed the declaration (3). Unfortunately, IDDs were not eliminated by the year 2000 as projected but significant progress was made as per the findings of the WHO Global Database on Iodine Deficiency of 2004 in which 126 member countries participated representing 92.1% of the world’s school-age children (3).
The cost of salt iodination is currently estimated at 5 US cents per person per year. There are concerted efforts and campaigns in affected countries to convince governments, salt producers and relevant organizations of the cost effectiveness of salt iodination. Funding has been provided to analyze the existence and the severity of the problem as well as to start the programs in developing countries.
In established hypothyroidism and endemic goiter, the functional and neurological changes are irreversible (46). It is reported however, that supplementation in the first 6 months of life prevents some neurological problems. Iodination also causes regression in the size of the endemic goiter in young children and adolescents.
In the adult population, thyroxine therapy causes involution of the hyperplasic tissue in large, diffuse or nodular goiters by the suppression of TSH in over 50% of the patients. 20% decrease in the goiter size has been reported. This has not been the case in our experience, where most patients are seen at the stage of cystic degeneration. Combinations of L-thyroxine and iodine are frequently used with good results in diffuse goiters (47). Mirmiran in Iran used iodized oil injections (1ml equivalent to 480mg iodine) in school children aged 8-14 years and achieved a reduction in goiter size and normalization of thyroid function for up to 3 years after injection (48). As mentioned earlier, this is an excellent method of reversing the effects of IDD, prior to the implementation of salt iodization programs which tend to be slow because of the need of legislation from the governments and reluctance by salt manufacturers to comply.
Surgery is indicated for:
1. Increase in size while on TSH suppression
2. Pressure Symptoms
3. Toxic changes
4. Suspected or proven malignancy
5. Cosmetic reasons
A full discussion on thyroidectomy will be the subject matter of another
review. However, general comments on the techniques and controversies in the
surgical management of endemic will be included.
Partial, subtotal, near-total and total thyroidectomy are all accepted and
practiced procedures for endemic goiter when surgery is indicated.
The tendency is towards total thyroidectomy in various centers in endemic
regions (49). Difficulties with the management of recurrences
are usually quoted as the reason for this drastic measure, and the subsequent
dependence on permanent thyroxine replacement is not considered a major set
back. Complications rates are also reported to be comparable to near-total
thyroidectomy in major endocrine surgical centers. I concur with writers like
Acun (50), who advocate near-total thyroidectomy (read partial)
for thyroid disease in endemic areas. It is effective and safe, especially
in third world countries where there are few specialized centers. This would
minimize disabling complications like hypoparathyroidism and permanent recurrent
laryngeal nerve palsies. Our patients are also either naturally averse to
taking permanent medications for life or cannot afford the cost of the drugs.
The recurrences that do occur after partial thyroidectomies do not warrant
an across the board total thyroidectomy with all its complications and need
for permanent medications in patients with benign goiters. This is more pertinent
in our set-up in the third world.
Our technique for thyroidectomy in patients with non-toxic multinodular goiters entails a sequential complete exposure of both lobes. The amount of thyroid tissue excised depends on the extent of involvement of the lobe. In most patients there is usually a false capsule of normal compressed thyroid tissue surrounding the nodular and cystic areas, especially on the posterior aspect. It is possible to preserve this tissue after removing all the affected parts and achieve a euthyroid state post-operatively in the majority of patients. In fact the decision to do a near-total, sub-total or partial thyroidectomy is decided intraoperatively depending on the findings. It is also our opinion that the difference between partial, sub-total and near-total thyroidectomy for endemic goiter is purely academic. This is because the amount of residual thyroid tissue is not decided by the surgeon but by what macroscopically appears normal at exploration. Experience and discretion would guide the surgeon as to what is normal and how much should be retained. As long as there is residual thyroid tissue left behind, it would be reasonable to use the term partial thyroidectomy. Probably the terms near-total thyroidectomy should be reserved for the relevant malignancies and sub-total thyroidectomy for operations on toxic goiters.
Post-operative thyroxine is only given when there is evidence of compensated or overt hypothyroidism three months after thyroidectomy or when the amount of residual thyroid tissue at surgery is deemed too small to avoid post-operative hypothyroidism. The question of suppressive or substitutive doses of thyroxine in patients with normal thyroid function post-operatively, as advocated by Miccoli and others are rarely considered. Annual follow-ups are used to monitor thyroid function and recurrences. Post-operative compensated hypothyroidism is an indication for thyroid replacement therapy as such goiters would inevitably recur because of the TSH overstimulation. However, if a patient remains euthyroid with a TSH level in the mid-range, thyroxine is not given. Salt iodization is adequate and closely monitored in our region. In fact, the 2004 WHO Data Base for Iodine Deficiency indicated Kenya as sufficient in iodine nutrition with adequate UI levels of 100-199 micrograms in school children (3).
The malignancies of the thyroid in endemic areas are predominantly in young women and follicular in nature as described by Lawal in an endemic region in Nigeria (39). We have similar experiences in Kenya. Development of differentiated thyroid cancer in a long standing endemic goiter is very rare, but anaplastic cancers do occur (51;52). The malignancies we see are mostly solitary nodules arising from a grossly normal thyroid gland (52). The diagnosis is more often than not made after a hemithyroidectomy, due to the known difficulties of differentiating follicular lesions with FNAC, especially in inexperienced hands. Chen made a comparative study of the use and indications of FNAC in two endocrine centers; one in Britain and the other in the US and found different indications but similar diagnostic results (53). Papillary malignancies are often reported to be commoner than follicular in the western literature (54). This fact leads to some sceptism, during international forums, about the accuracy of histopathological diagnosis from other parts of the world, especially the third world.
Endemic Goiter is a preventable disease and is a common world-wide problem
since more than 12% of the world’s population is affected (WHO). Iodization
is cost effective, and although it results in a transient increase in hyperthyroidism,
overall the benefits outweigh the risks. Thyroid hormone treatment is used
in established cases of goiter before cystic degeneration sets in to decrease
the size of the goiter or arrest its further growth.
However, thyroidectomy is usually required for complications, documented or
suspected malignant change and cosmetic reasons. The type of thyroidectomy
for benign nodular goiter is controversial, but we believe it should be less
radical in poor countries where trained and experienced thyroid surgeons are
few. This would reduce major complications and also minimize unaffordable
life-long dependence on replacement therapy.
Hopefully this review would stimulate discussions and create awareness on
this important public health issue.
1. Iodization of salt is the commonest supplementation program for IDD, but
IM injections of iodized oil or oral iodine is used in areas with severe deficiencies.
2. Endemic goiter can be reversed with iodide and/or thyroxine in the early
stages. Response is generally poor or negligible after the formation of nodules
and onset of cystic degeneration.
3. Prudent selection of patients for thyroidectomy in endemic goiter areas
to avoid unnecessary surgery. What might be considered cosmetically unacceptable
in a young urban girl does not apply to an elderly woman in the country side.
4. Thyroidectomies should be performed by qualified and experienced surgeons
or under their supervision.
5. Surgery for endemic goiter, when indicated, should be less radical than
what is generally recommended in the literature; to avoid disabling complications
and dependence on replacement therapy. The African patient has a phobia for
life-long medications, even when they could afford them.
6. Compensated or overt hypothyroidism 3 months after surgery must be treated
with thyroxine replacement therapy.
John Adwok
Associate Professor of Surgery
Faculty of Medicine, University of Nairobi
P.O.Box 21274,
00505, Nairobi
Kenya
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