Goiter and Other Iodine Deficiency Disorders: A Systematic Review of Epidemiological Studies to Deconstruct the Complex Web

Archives of Medical Research 38 (2007) 1e14

REVIEW ARTICLE

Goiter and Other Iodine Deficiency Disorders: A Systematic Review of Epidemiological Studies to Deconstruct the Complex Web Atul Kotwal,a,b Ritu Priya,b and Imrana Qadeerb a

Management Information Systems Organization, Integrated HQ Min of Defence (Army), New Delhi, India Center for Social Medicine and Community Health, School of Social Sciences, Jawaharlal Nehru University, New Delhi, India

b

Received for publication May 6, 2006; accepted August 21, 2006 (ARCMED-D-06-00185).

A systematic review of the available literature on goiter and other iodine deficiency disorders (IDDs) was carried out with the aim of analyzing available evidence and providing inputs to the policy makers and program formulators regarding the entire issue. The findings point to major issues such as the following: methodological issues in epidemiology of goiter and other iodine deficiency disorders (IDDs); lacunae in causal linkages; inadequate attention to multicausality; flawed assessment of the impact of intervention, i.e., iodized salt; and harmful effects of iodine not given due cognizance. Most of the research to date has been unidirectional and does not provide comprehensive data on all aspects of IDDs. To further compound the issue, many independent researchers, on finding something different from the existing dominant paradigm (iodized salt as panacea for goiter) have tended to ignore these in their final conclusions and recommendations. Thus, evidence from this systematic review demonstrates enough basis to start a debate on the entire issue, recognizing opposing research findings while continuing with the present strategy. This imposes specific problems and necessitates area-specific solutions instead of a universal solution, which apart from being less effective may be harmful in the long run. Ó 2007 IMSS. Published by Elsevier Inc. Key Words: Goiter, Iodine deficiency disorders, Iodized salt, Micronutrient, Health policy.

Introduction Goiter and other iodine deficiency disorders (IDDs) have been known since antiquity and much has been written about the subject. The existence of endemic goiter in an extensive belt along the southern slopes of the Himalayas, Alps and Andes has long been described. The early pioneers in the study of endemic goiter included Sir Robert McCarrison (1,2) and Stott (3). Both pointed to the complex etiology of goiter and commented on various causative factors. The role of iodine in the causation of goiter was elucidated by various researchers working in these areas. The results from different geographical areas and few studies formed the basis of control and prevention activities of goiter (4,5). As per a recent review ‘‘Sustainable eliminaAddress reprint requests to: (Lt Col) Atul Kotwal, MD, Classified Specialist, Preventive and Social Medicine and Epidemiologist, Joint Director (Medical and Health), Management Information Systems Organization, Integrated HQ Min of Defence (Army), West Block-III, RK Puram, New Delhi-110066, India; E-mails: [email protected] and [email protected]

tion of IDD is within reach and would constitute an unprecedented global success story in the field of noncommunicable diseases, but continuing vigorous action is required to attain this goal (6).’’ Across the world, some countries have resorted to universalization of iodized salt (USI), whereas others have not done so and instead focused on making it available as a community choice. Although the Government of India initiated the National Goiter Control Programme (NGCP) in 1962, the program, however, faltered on many accounts and various reviews of the program specified different aspects and reasons for not achieving the aim. Whatever the strategies adopted for the control of goiter and other IDDs, the problem has increased rather than showing any decline, as shown in Table 1 (7,8). The scientific backbone of universal iodization has also been challenged by pointing out the weaknesses in the science and politics of the intervention to control IDDs. Few papers have also challenged the research forming the basis of the information on the magnitude of the problem and effectiveness of the intervention (9,10).

0188-4409/06 $esee front matter. Copyright Ó 2007 IMSS. Published by Elsevier Inc. doi: 10.1016/j.arcmed.2006.08.006

Kotwal et al./ Archives of Medical Research 38 (2007) 1e14

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Table 1. Total goiter prevalence in various regions of World Health Organization over a period of time Total goiter prevalence (%) WHO region

1993

1997

2004

Percentage change between 1993 and 2004

Africa Americas Southeast Asia Europe Eastern Mediterranean Western Pacific Total

15.6 08.7 13.0 11.4 22.9 09.0 12.0

20.0 05.0 12.0 15.0 32.0 08.0 13.0

28.3 04.7 15.4 20.6 37.3 06.1 15.8

þ81.4 46.0 þ18.5 þ80.7 þ62.9 32.2 þ31.7

Adapted from WHO documents (7,8).

This prompted us to carry out a systematic review of the available literature with the aim of initiating a healthy debate and providing input for a mid-course correction. The objectives were to highlight the lacunae in research on etiology; efficacy/effectiveness of the intervention; evaluation strategy adopted; the direction in which the program is progressing; the problems when one solution is supposed to be a panacea for all regions/communities rather than giving due recognition to multicausality while planning any intervention; and the contrasting views of organizations/ individuals involved in various aspects of IDDs control over a period of time. This review in no way tries to belittle the importance of iodization in preventing the spread or reducing the problem and of the research carried out on various aspects of IDDs. Because rational measures for the prevention and control of any disease depend upon the adequacy of knowledge about its etiology and pathogenesis, the availability of an effective intervention, appropriate conceptualization, implementation and subsequent evaluation and feedback/review of the program, as the acolytes of evidence-based medicine, we must take steps to prevent our medical successors, using the long lens of history, from judging us as harshly as we might judge the early history of prevention and control of IDDs. As per available evidence, the issues related to IDDs can be classified into four main groups: 1) magnitude of the problem and evidence for multicausality, 2) evidence for benefit of iodized salt, 3) assessment of intervention, and 4) harmful effects of iodine.

Methodology of the Review More than 120 studies (1906 to the present) from various parts of the world were reviewed. These included published as well as unpublished works from various journals, internet sites, institutions/organizations and governmental sources. We searched the following from inception to May 2005: MedLine, EMBASE, Index Medicus, Cochrane controlled trials register, and the Nursing and Allied Health

Collection. In addition, we searched for unpublished and on-going studies and also publications of International Council for Control of Iodine Deficiency Disorders (ICCIDD). All available studies were included in this review. None of the available studies was excluded as we wanted to capture the diversity of methodology and interpretations being used in research on goiter and IDDs. Due to the heterogeneity of the study methodologies in this review it was not possible to apply the meta-analysis techniques; thus, a systematic review was conducted. The studies were classified based on their study design (community based/hospital based, cross sectional/longitudinal, nonexperimental/ experimental) and also the focus (assessment of the problem, assessment of program, intervention) to assess the four major issues mentioned above. The Indian scenario was analyzed in detail in the overall global context.

Magnitude of the Problem and Evidence for Multicausality Issues in Epidemiology of Goiter and Other IDDs The problems encountered by epidemiological studies of thyroid disorders are those of misclassification (e.g., overt and subclinical hypothyroidism); mode of sampling in populations; various confounders (age, gender, environmental factors, etc); different classifications (Perez, WHO, Stanbury, etc.) used for the measurement of thyroid size; difficulty in carrying out certain tests leading to lack of data on thyroid function; and focus on monocausality or ignoring multicausality on finding. Thus, results of epidemiological surveys carried out in various states, countries and over a period of time within the same community or country are often difficult to compare. This is further compounded by different methods to present the results and investigators’ interpretation of classification criteria in their own way. Criteria for Identifying Goiter Estimation of breadth, volume, palpability or visibility of a thyroid gland is subjective as it depends on many factors: certain characteristic of subjects (shape of neck, thickness of subcutaneous fat, disposition of SCM muscle, etc.); investigators approach (interpretation of classification criteria, experience, fatigue, etc); and on the circumstances of examination (illumination of the subject’s neck, position of neck in relation to investigators eye, time devoted to examination, etc.). Furthermore, goiter measurements are hampered by the fact that soft glands are fairly common and any estimate will depend on the finger pressure (11). The most important factors affecting the accuracy of estimation of goiter frequency are intra- and inter-observer variability, and studies have shown different levels of concordance or discordance among observers and in an observer over-repeated measurements. It has been shown

A Systematic Review of Goiter and Other Iodine Deficiency Disorders

that observation variation is greatest in deciding whether a thyroid that is palpable but not visible is normal or enlarged (12). There was also considerable overlap between the various grades when compared with thyroid volume estimated by ultrasonography (USG), which increased the sensitivity of the test because 30% of individuals were found positive by USG but only 14.6% by conventional methods (13,14). USG also increased the correlation and agreement between observers (15); however, USG has not been extensively used in field studies. It is therefore important to know the estimates of variability before embarking on any tests of statistical significance. Classifications have also changed over a period of time with each one having its characteristics, e.g., difficulty in Perez et al. classification was in defining at which degree of enlargement one considers a sufficient pathological alteration of the gland in order to classify as goiter (16,17). Even after modification, the distinction between grade 0 and I was unsettled for a long time. The Caracas, WHO/FAO group tried to resolve some of the issues and concluded that some of the small thyroid hypertrophies do not have sufficient pathological significance to be classified as goiter but should also not be classified as normal. Thus, two subgrades, 0a and 0b, were defined, creating more confusion during community surveys and when comparing historical data. Figures 1 and 2 depict the total goiter prevalence (TGP) along with 95% confidence intervals as per few of the Indian studies carried out in various states of India prior to the USI (18e28). Most of these studies reported a high proportion of goiter in lower categories that are subject to

3 Mean 95% CI Upper 95% CI Lower Total Goiter Prevalence

70

60

50

40

30

20

10

0 l1

De

l2

De

j1

Gu

j2

Gu

j3

Gu

j4

Gu

j5 ar1 ar2 h1 ri1 ri2 ild O O H H Ma Ch tal o T

Gu

Area of study Figure 2. Total goiter prevalence: pre-iodization studies among children in various states of India. Del, Delhi; Guj, Gujarat; Har, Haryana; Mah, Maharashtra; Ori, Orissa.

biases as discussed earlier. Figure 3 depicts a few of the studies from other countries (29e33). Criteria for Identifying Regions Endemic for Iodine-Deficiency Disorders

80

Mean 95% CI Upper 95% CI Lower Total Goiter Prevalence

60

The classification of endemias according to severity has been done with the premise that goiter is physiological in about 5% of young girls at puberty. Therefore, arbitrarily a population having a prevalence of 10% of any grade is considered endemic (34). It has been estimated that goiter and endemic cretinism prevalence in India have been overestimated by a multiplicatory factor somewhere between 3 and 6 due to bias in the mathematical model used (35).

40

Etiology of Goiter and Other IDDs 20

0 Assam Guj1 Guj2 Guj3 Guj4 Guj5 Mah1 Mah2 Mah3 Total adults

Area of study Figure 1. Total goiter prevalence: pre-iodization studies among adults in various states of India. Guj, Gujarat; Mah, Maharashtra.

Etiology of endemic goiter is complex and not fully elucidated. The fact that goiter persists in many areas despite iodine supplementation for prolonged periods reiterates the importance of doing so. After studying goiter in Chitral and Gilgit valleys in the then undivided India, McCarrison showed the association of goiter prevalence with contaminated water supplies in a trial in Himachal Pradesh (one of the Northern states of India) where prevalence of goiter among school children decreased by changing the water supply from contaminated to uncontaminated, the other factors (iodine content of water, soil, etc.) being unchanged (1,2).

Kotwal et al./ Archives of Medical Research 38 (2007) 1e14

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Mean 95% CI Upper 95% CI Lower Total Goiter Prevalence

70

60

50

40

30

20

10

0 l1

De

l2

De

j1

Gu

j2

Gu

j3

Gu

j4

Gu

j5 ar1 ar2 h1 ri1 ri2 ild O O H H Ma Ch tal o T

Gu

Area of study Figure 3. Total goiter prevalence: studies from a few countries. Del, Delhi; Guj, Gujarat; Har, Haryana; Mah, Maharashtra; Ori, Orissa.

A majority of the initial studies tried to assess the issue of causality along with assessing the extent of the problem. A few hospital/community-based studies on causality are shown in Table 2 (4,5,36e42), whereas others have been described in text. A high TGP, with a high proportion of grade 0b goiter (subject to classification bias), was found among a tribal population in a coastal area on the Eastern coast of India, which either shatters the myth of iodine deficiency as a causal factor in goiter as marine fauna is rich in iodine or it is an inflated figure due to lack of internal validity of the study (43). Similar results have also been found from other coastal areas, pointing to some effect modifier or confounder in the entire issue of iodine as a causal factor of goiter. This lack of correlation between iodine and goiter was also found in a study where a majority of the children with growth failure had dysgenetic thyroid gland, showing that factors other than pure iodine deficiency are at play in goitrogenesis and hypothyroidism (36). Another study found no correlation between grade of goiter and urinary iodine in pregnant women (37). Goiter was found to be more prevalent among the poorest, field laborers and cultivators, after rains, after food famines, and among those consuming water with high levels of calcium in the then United Provinces of India, and no association was found between goiter and diet and iodine content of water (3). In other goiter prevalence studies in different areas, no association was found with iodine intake. The researchers also did not find any association of goiter with cretinism, deaf mutism, and other aspects of physical and mental growth retardation (19,22). This association of

goiter with socioeconomic and life style factors has also been demonstrated in Denmark (44). There are innumerable descriptions of goiter attributed to drinking water. Microorganisms contaminating water supplies have been implicated as a causative factor in few endemias. Studies supporting similar findings were done in India in the 1970s and 1980s but were not given due recognition and thus were not repeated later. Antithyroid activity has been shown in cultures of E. coli isolated from polluted streams of highly endemic areas. Organic compounds with antithyroid activity have also been isolated from water. A similar association of goiter with contaminated drinking water, low literacy and socioeconomic levels was found in many studies in different geographic areas across India (18,19,21e23,26). Few of these areas were free of goiter until about 10 years prior to the study period. An important change during this period was the introduction of new water sources in the form of tube wells and other types of wells. The role of pollutants in water has also been demonstrated in the U.S. where goiter prevalence was higher in children whose homes obtained water from dug wells as compared to children whose homes were served by piped water supply ( p !0.025). The majority of the dug wells were polluted and the iodine content was adequate in both populations (45). Worldwide, there are several endemias attributed to environmental goitrogens—Tasmania, Finland, Nigeria, Chile, West Virginia, etc. The vehicle for goitrogens in the majority was water and milk. Environmental factors other than nutritional iodine deficiency are responsible for the persistence and development of new cases in certain endemias and also for the differences observed in goiter prevalence among communities with similar iodine intake. Iodine deficiency must act in conjunction with other goitrogenic factors to produce a goiter endemia. Environmental goitrogens when low in concentration may normally be ineffective but may become significant when iodine supply is restricted. In other situations they may be sufficiently potent in themselves to cause goiter despite an abundance of iodine. Adequate iodine intake of 75e300 mg/day does not always eradicate goiter because 6e40% prevalence existed in certain areas despite these intakes (46). The goitrogenic action of calcium has been well established under experimental conditions but the evidence for calcium in drinking water and food having practical importance for the development of endemic goiter is conflicting (47). The increase in prevalence of goiter in Papua New Guinea, subsequent to economic recession despite a well-implemented intervention by iodized oil (48), shows that multicausality has been ignored for IDDs. Similar studies on multicausality have also been reported from Denmark (49,50). Studies are also available showing high goiter rates despite lack of iodine deficiency (51,52). A survey in the U.S. in Tecumseh, MI indicated relatively high goiter prevalence without convincing evidence of iodine deficiency. Similar results were obtained during studies in

Table 2. Results and comments on studies regarding causal linkages of goiter and other iodine deficiency disorders Serial no. Ref (year) 1

4 (1961)

Study area Punjab (I)

Ie12e16

Bihar (II) Bihar (III) India

IIe8e12 IIIe12e15 All goitrous in I and II Non-goitrous in III All euthyroid Goitrous controls (case-control)

5 (1973)

UP, India

3

36 (1989)

Delhi, India

Patients of thyroid clinic from 1983e88 (case series)

37 (1990)

Ie33 IIe43 IIIe18

5

38 (1977)

Delhi, India

7

39 (1982)

40 (1984)

Hypo

Goiterþ Goiter Iodine deficiency

479

Iodized saltþ Iodized salt Odds ratio 5 p 5 0.411 I TCR

Goitrous and nongoitrous children (Case/Control)

UP Delhi

Goiter

9 106 1.73

17 347 (0.69e4.26)

UI !50 3 30 1.84

UI O50 23 423 (0.41e6.97)

TSH

646

23.33 21.675 0.7 T4 mg/dl

14.6 9.8 0.01

p5 Neonates

UP

Goiterþ

I RCR

15.5

No association between goiter and iodized salt; urinary iodine excretion and iodized salt

UI

AIU

0.0695 0.1372 0.01 T3 ng/dl

20.0 76.4 0.001 rT3 ng/dl

2.532 1.646 0.05

96.34 59.78 0.001

168.42 174.3 NS

Hypo

5.75

No correlation found with iodine deficiency

30 0 19

PII

4.28 6.41 NS T4

Wide and overlapping 95% CI, invalid controls

Euthy

10 0 0

88.39 22.2 0.001 TSH mIU/L 20 89

Hyper

19 98 3

Iodized saltþ Iodized salt Odds ratio 5 Goitrous 27.3% p 5 0.193

Neonates

UP, India Delhi, India UP, Delhi, Kerala, India

TSHebetween grades p !0.05; linear relation with grade of goiter p !0.02; compared with controls p !0.001

46 Hypo 117

Cases Controls p5 6

Overinterpretation of causality based on a cross-sectional study

Ie62.5% IIe62.9% IIIe39.05%

26

Municipal Pregnant women of Hospitals, low socioeconomic Maharashtra, strata attending ANC India in a 3-month period

Cross-sectional

Remarks

PBI uptake

Hyper 10 Euthy 30

4

Results

T4

5

Number of cases and controls not provided

A Systematic Review of Goiter and Other Iodine Deficiency Disorders

2

n

Study population and design

No correlation found between goiter and cretinism

T4 higher in Kerala, rT3 not used

6.09 5

(Continued)

41 (1987)

42 (1994)

8

9

118.2 109.8 Controls

London, UK

Matching controls (case-control)

National register of children with CH compared with

Maharashtra, India

Cohort

361 315

97.5 109.1

TSH 427 575 12407 Delhi Kerala All neonates

Cases !42.8 Cases O42.8

TSH O30 TSH !30 T4

12057 CHþ 5 0 Mean IQ (manual)

302 CHe 345 12057 Mean IQ (non manual) 107.6 115.5

48

Mild hypothyroidism in CH showed no significant difference in IQ levels

Incidence 28/1000 as per TSH values used by Kochupillai et al. but 0.4 per thousand after follow-up 8.5 8.7

!30

30e80

1

8.3 7.57 O80

Remarks Results n Study population and design Study area Serial no. Ref (year)

Table 2. Continued

I TCR, radioactive iodine thyroidal clearance rate (mL/min); I RCR, radioactive iodine renal clearance rate (mL/min); PII, plasma inorganic iodide levels (mg%); AIU, absolute iodine uptake rates (mg/h); UI, urinary iodine (mg/g); CH, congenital hypothyroidism; WI, iodine content of watermg/L; T3, in nmol/L; T4, in nmol/L; TSH, mIU/L; TGP, total goiter prevalence; CI, 95% confidence interval; PBI, protein bound iodine.

Kotwal et al./ Archives of Medical Research 38 (2007) 1e14

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Kentucky. Dietary iodine deficiency (corrected for age and gender, as well as analysis of iodine in daily food samples) could not be implicated. Goiter was found even in those households that had been consuming iodized salt for more than 20 years. All water samples were polluted and there were no goitrogens in the diet (53). Many other studies in different areas of the U.S. yielded similar results. In Mexico, studies concluded that iodine deficiency may be the main but not the only cause of goiter. Also, no correlation was found between the average iodine intake and prevalence of goiter (54). The prevalence of goiter in Greece was 40e60% in 1966 and 21% in 1996. This decrease was despite not having a program of IDD control and was due to changes in food habits, etc. An interesting observation was that increased urinary iodine levels were associated with antithyroid antibodies in children, which may lead to autoimmune thyroiditis. This might be the reason for residual goiter especially among children with sufficient iodine intake (55). Even experimental and clinical studies have suggested a link between the level of iodine intake and the development of autoimmune thyroid disease (56). In India, a nationwide survey was conducted to assess the problem before Universal Salt Iodization (57). Thus, the goal of universal iodization was already formulated a priori. The states and districts were purposely selected, i.e., those where information was already available about high prevalence of goiter. The results thus might have been valid for the particular districts but neither generalizable to the states from which the districts were selected nor to other parts of the country. The question raised is why probability sampling techniques were not used in a nationwide survey. Despite this purposeful sampling, overall total prevalence was only 21.1%. The report mentions probable underreporting of 0b, thus accepting an observer or other bias at play, raising the issue that there could have been an overreporting of 0b. Many 0a were classified as 0b due to the ultimate goal of USI being validated by the survey. Water samples were also drawn without any sampling procedure and were tested only for iodine but not for other pollutants (organic and inorganic) or other possible goitrogens. Urine samples were collected but not analyzed (possibly due to transportation problems or other administrative challenges), which reflects operational failure of the survey. These failures also might have affected other areas like training, quality assurance, etc., thus questioning the internal validity of the survey. Whatever the possible flaws, the survey clearly shows that goiter and cretinism were not correlated, e.g., prevalence of goiter in two of the northeast states of India (65.8 and 19.8%, respectively) did not correlate with prevalence of cretinism (2.2 and 6.1%, respectively). Cretinism also was not apparent in areas where iodine deficiency was supposedly more prevalent. Many researchers have compared different aspects of endemic and nonendemic areas. In one such study, higher uptake of iodine was shown in school children with visible goiter. However, the sample size was small in each group,

Table 3. Details of studies on assessment of intervention for control of goiter and other iodine deficiency disorders Results n

Population studied; study design; year; class used Serial no.

Ref. (year)

1

84 (1987)

2

85 (1993)

3

86 (1994)

Area/region/ year of iodination

4

90 (1998)

Coastal area

5

91 (1998)

6

95 (1995)

Island group in Bay of Bengal Northern state Dist A 1966 Dist B 1966 Dist C 1960 Dist D 1966 Dist E 1986 Dist F 1966 Dist G 1966 Northern state 1980 Eastern state 1976 Dist A Dist B Northern state 1976 Northern state 1976

7

96 (1996)

8

97 (1997)

9

98 (1998)

10

99 (1997)

11

100 (1997)

Delhi

General population; CS; 1978 General population; CS; 1970 General population; CS; 1970

Present study

Previous

Present

Previous study (TGP%)

TGP (%)

General population; CS

5573

3248

68.6

72.5 (cretinism 3%)

General population CS; WHO General population; CS; Perez (Iae75.9, Ib-20.5, IIe3.0, IIIe0.55)

NA

4375

17

NA

11523

Children 6e11 years age; CS Children 7e18 years; CS General population; CS 1930 1930 1860 1965 1973 1930 1930 General population; CS; 1980 General population

Children 5e15 years age; CS; 1956 General population; CS; 1954 School children 10e21 years; CS; 1980

UI !10 (%)

IS !15 (%)

38.38 TGP

23.32 20.4 20.3 20.8 2.6l

24.1 81.9

7.5

NA

2065

City A 7.3 City B 7.3 City C 13.2 NA

NA

900

NA

16.5

5000

40.0 3.7 23.2 39.7 65.0 3.7 40.0 60

21.9 18.7 23.6 16.3 31.2 19.1 24.3 50.3

57.2 64.5 41.2

12.8 10.4 8.8

49.3 48.8 32.8

26.7 34.2 10.8 23.4

General population: CS 1988 1966 1969 1969 1989 1989 1974 General population; CS

NA

Children 6e12 years age; CS

NA

NA

69

NA

Children 8e10 years age;

NA

662 666 6897

School children 8e10 years age; CS; WHO School children, 10e14 years; CS;

NA

1358

41.2

5.8

23.7

3200

1684

55.0

20.5

24.9

A Systematic Review of Goiter and Other Iodine Deficiency Disorders

Northeastern state 1978 Northeastern state 1987 Northeastern state 1987

Previous study

Present study

CS, cross-sectional; UI, urinary iodine (mg/gm); IS !15eproportion of salt samples having !15 ppm of iodine; TGP, total goiter prevalence; Dist, District. 7

8

Kotwal et al./ Archives of Medical Research 38 (2007) 1e14

increasing the possibility of chance error. Moreover, goitrous children from endemic areas were compared with adults from non-endemic areas. They also found lower protein-bound iodine (PBI) in goitrous children as compared to nongoitrous children. Contrasting results of no difference in ankle jerk reflex as well as PBI in goitrous as compared to nongoitrous children were found by another group (58). Higher TSH levels were actually compared with controls in England. However, when T4 levels were found to be higher in Indian cases as compared to English controls, this was dismissed as controls being from a different country. Moreover, the higher value of T3 in cases was not assigned any importance. The subgroup analysis with small numbers in each group increased the chance error in the estimates. Thus, an inference of convenience was drawn and many studies in later years quoted this study as a milestone and a basis for the problem of goiter in the Himalayas (5). Another study found decreased iodine excretion, increased TSH values, decreased T4 and increased T3 in endemic as compared to non-endemic areas (29). However, both areas differed in many other factors like geophysical characteristics, dietary patterns, etc. A conclusion of cretinism in Zaire due to severe iodine and selenium deficiency was made based only on cross-sectional data in a study dealing with neonatal hypothyroidism and comparing biochemical parameters between neonates from Zaire and Malawi. The results of Zaire neonates were compared with Belgian neonates, whose number is also not provided. However, the authors somehow conclude that etiopathogenesis of goiter is multifactorial (59). A hospital-based case-control study presumed hospital and home diets to be similar. An interesting finding was a positive iodine balance among all cases. Despite this, iodine deficiency was being reported as a major cause of goiter. The researchers mention this towards the end of their discussion but do not give due recognition to this important finding (38). Multiple regression analysis in two studies (r2 5 0.57 and 0.51, respectively) showed that goiter size depends on iodine uptake, age and vitamin A and thus inferred that vitamin A nutrition is as important as iodine status. Decreased vitamin A stores play a causal role in goitrogenesis, and iodine itself contributes to goiter formation due to indiscrete iodine intake (60,61). Experimental studies have consistently shown the role of other factors in the causality. Experiments on rats showed that environmental goitrogens (thiocyanates, etc.) might be significant determinants in the etiology/prevalence of endemic goiters (62). In another study, it was shown that apart from or along with iodine deficiency the goitrogens present in staple foods may be important contributory factors (63). Goiter, Congenital Hypothyroidism and Endemic Cretinism Despite the well-researched and accepted linkage, the evidence in favor of maternal hypothyroidism and infantile

cretinism is conflicting. Some studies have shown more stillbirths, infant deaths and endemic cretinism among offspring of women showing biochemical evidence of iodine deficiency (decreased T4 and T3, increased TSH) but without clinical evidence of hypothyroidism (64). Against the maternal hypothyroidism hypothesis is the fact that thyroid hormone transfer across the placenta is minimal and thyroidepituitary feedback mechanisms are autonomous in mother and fetus. A literature review of pregnancies in hypothyroid women indicated an excess of congenital anomalies but no case in which deaf mutism, diplegia or congenital hypothyroidism (CH) was present (65,66). A group of researchers found pockets of endemic cretinism in Himalayas with prevalence of 1e4% (67), but another study found prevalence to be !1% in many areas of the Himalayas (68). In the newer areas of goiter endemias, e.g., Delhi (India) (25), endemic cretinism is not seen at all but reference is made to subclinical cretinism. The methodology adopted for proving this new hypothesis involves development and intelligence testing. In one such study, children of goitrous mothers and controls were compared by Gessel development score. It was concluded that development quotient (DQ) and language development were lower in children of goitrous mothers (69). The mean DQ for controls was 98.4 as compared to 94.4 in other groups; this small difference was shown as statistically significant and profound conclusions were drawn. This approach is highly controversial and has been riddled with a priori assumptions, conscious fraud and politics, so that its very value and scientific objectivity have been questioned (9). Studies assessing causality and studying other factors like CH have used statistical significance on an as-required basis apparently to fit into their hypothesis and taking very low cutoff values for CH. No statistically significant difference in rT3 and T4 in cord blood samples among neonates in one of the endemic districts of Bihar (India) and Delhi (India) was found, but inference was still drawn that all values in children of endemic areas were several fold higher as compared to Delhi children (nonendemic area) (39). Incidence of CH is another area of dispute. By using TSH as a marker, one group found incidence of CH as 4% in endemic areas and 0.1% in nonendemic areas and tried to find a correlation between goiter prevalence and congenital hypothyroidism (40). However, studies by the same researchers showed that endemic areas had a goiter prevalence of 64% as compared to 52% in nonendemic areas. The authors discussed the importance of rT3 in their previous study in the same areas and inferred that rT3 levels faithfully reflect thyroid status of newborns in endemic area (53) but did not use that in this study. Although prevalence of goiter was shown to be much less in Kerala (India) as compared to other areas, the mean value of T4 was less in Kerala as compared to Delhi, thus raising doubts on the validity of using biochemical parameters in these studies. In Bangladesh as well, no association was found between cretinism (0.5%) and goiter (47%), despite

A Systematic Review of Goiter and Other Iodine Deficiency Disorders

a high prevalence of the latter. This is contrary to assumptions by researchers in India, as per which the cretinism prevalence in that area would be O2% (30). Hospital-based studies in a coastal city in India showed that positive predictive value of using 50 mIU/L of TSH as cut-off for CH was quite low and leads to overestimation of the problem. A 2.81% incidence of CH was initially found, which dropped considerably (0.000403% or 1:2481) after 2 years of follow-up with neonates having TSH O250, only eventually developing hypothyroidism. The study also raised another important issue of some other factors responsible for TSH surge in newborns (41). Thus, previous studies (52,53) did not take transient neonatal hypothyroidism into account while studying TSH values for CH. The same authors referred to transient neonatal hypothyroidism in one of their later papers and mentioned that it could be an important issue in iodine-deficient areas (70). However, starting thyroxine for babies based on a single result of a high TSH is unethical, as European as well as Indian studies have shown this phenomenon of transient neonatal hypothyroidism (29). Welldesigned follow-up studies need to be carried out in areas already studied to determine the real incidence of CH. Work has been done in this direction by a few groups of scientists who have shown evidence for the role of maternal thyroid hormone on early brain development (71,72). However, the entire issue needs to be revisited because the findings of one study question the benefit of screening and early treatment as screening reduces but does not eliminate neurological impairment (42). To sum it up, lack of an experimental model, lack of a similar clinical picture in children of hypothyroid mothers in non-iodine deficient countries, and lack of a similar clinical picture in syndromes of resistance to thyroid hormones are paradoxical and require further investigation to understand the mechanism of neurological cretinism using a holistic approach. Until that time, present efforts need to continue to prevent CH. Evidence for Benefits of Iodized Salt Even in this area the evidence from trials and other studies is conflicting as most of the studies showed only a marginal decrease in prevalence of goiter despite so-called universal salt iodization. Some of the possible reasons for this lack of effectiveness were commented by some researchers but studied by none. These included poor implementation of the program, iodine losses during cooking, increased goitrogens in environment/diet/water, decrease in goiter due to economic development, iatrogenic goiter/anemia, etc. There is a definite lack of cohort studies at present. There have been very few community-based intervention studies and two of these were conducted in the present Himachal Pradesh (India) (2,73). The first one showed no evidence of the role of iodine in goiter whereas the other has provided the only evidence of effectiveness of iodized salt in the prevention and control of goiter. The two communities provided

9

with iodized salt showed decreased prevalence in all groups as compared to the third community. However, the assessment was not blinded and inter- and intra-observer variability in classification of goiter was neither commented upon nor shown in the results. Thus, subjective interpretation might have affected grade b of the classification used in the study, with more in this grade before iodization and less after iodization in the intervention areas. Moreover, only those participants were studied who were available at home during the time of the survey. The prevalence of goiter among the general population at baseline was higher in the control area as compared to both intervention areas and this was statistically significant. The difference among school children after 12 years of follow-up was reduced significantly (74). The residual difference was in grade b goiter, which suffers from subjective classification. In a trial in one of the southern states of India, the blocks were provided with double-fortified (iodine and iron) or only iron-fortified salt or only iodized salt. However, the blocks were not comparable at baseline. The results of the third arm of the intervention group, which was supplied with iodized salt, have not been provided in the paper for reasons best known to the investigators. The question that needs to be answered is whether these showed any negative effects or did not show any benefit. Although urinary iodine excretion increased among the double-fortified salt (DFS) group as well as the iodized salt group, the mean hemoglobin levels decreased in both groups. A significantly higher proportion of girls ( p !0.001) showed a decrease in hemoglobin levels in the iodized salt group as compared to the DFS group (75). In another trial, iodine supplementation alone was shown to raise levels of urinary iodine, T4 and iron status, whereas iron and iodine supplementation in combination did not lead to any significant changes in these parameters (76). These results raise an important issue of whether iodized salt is hampering, in any manner, the absorption or utilization of iron. Could the present high prevalence of irondeficiency anemia in India be contributed to by iodine in salt? The issue needs to be understood well before any changes are implemented in the programs for correction of these deficiencies, especially in countries with high levels of irondeficiency anemia. Decreased incidence of CH in one of the northern states of India post-iodization was concluded to demonstrate the effectiveness of USI (77) despite surveys in UP in the 1990s, showing a high continued usage of noniodized salt. Was it iodized salt, iodine from other sources (improved nutrition/dietary practices), or increased iodine availability due to lack of goitrogens (improved water supply, dietary) that played a role in decreased CH?

Assessment of Intervention As with other aspects, assessment of intervention, i.e., iodized salt/oil also suffers from various drawbacks. We

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Kotwal et al./ Archives of Medical Research 38 (2007) 1e14

highlight a few: lack of temporal comparability due to use of different classifications, methodologies, techniques and study population; confounders not studied adequately in available cohort studies; inadequate data on other factors affecting absorption/utilization of iodine; and inadequate studies on lack of correlation between iodine nutrition and TGP. In the U.S., a high prevalence was found in 1924, but subsequent surveys in 1951 (consequent to iodization of table salt in 1924) found a low prevalence of goiter, from 38.6% to 1.4%. Whereas 20% were still using uniodized salt only, 75% of households were using iodized salt only and 4% were using both. Thus, the decrease in goiter prevalence was largely due to iodization of table salt but changes in the processing and distribution of food as well as in food habits, which also occurred during the same period of time, contributed to this decrease. However, from 1955 onwards, the iodine intake increased tremendously (O600% of U.S. RDA) due to other sources like greater utilization of iodine in food technology, sanitation and in the chemical industry. Still the goiter persisted! Thus a hypothesis was generated that this persistent goiter was not related to iodine deficiency (53). The decision of the Indian government to implement USI by 1990, 20 years after inception of NGCP, was severely criticized by researchers presently spearheading the campaign of USI (78,79). According to these researchers, iodine deficiency was a place-specific problem and hence necessitated area-specific solutions. They clearly stated that ‘‘USI besides introducing a fresh economic burden would also magnify the already extensive chain of participating agencies out of proportion. All this might lead to a delay in the supply of iodated salt to hyperendemic areas. Thus, priority should be to consolidate the existing infrastructure, strengthen weak links and prioritize the distribution of salt. Only after meeting the needs of endemic areas, one may subsequently plan for USI’’. They also commented on the methodological issues like classification of goiter, need for uniform sampling procedures and use of median for urinary iodine excretion instead of mean values due to skewed values. However, as the available evidence indicates, none of the subsequent studies/surveys addressed these issues satisfactorily. Even when the prevalence was shown to have increased after a period of iodization and banning plain salt in a particular area, only salt iodization was being targeted for review without making any attempt to study the situation in its entirety. None of the researchers ever thought about whether the problem was with the program implementation or with the entire concept of salt iodization or were there other factors operating/interfering with availability/assimilation of iodine? A detailed analysis of available studies reveals that various researchers have used different classifications. Some have used Perez, some WHO, others Stanbury and in one paper a new improvised

classification of only two categories (0 and 1) was also seen. The other major drawbacks noticed were different age groups being studied and piecemeal evaluation of the program. In India, salt and goiter are being targeted during evaluations. No effort is being made to study the changes in diets, etc. to correlate with the present prevalence. Many of the studies have only looked at the process, i.e., proportion of salt sample having adequate amount of iodine with utter disregard to outcome, thus conducting a biased exercise with predetermined notion of efficacy and effectiveness of the intervention (80e83). Increase in goiter post-iodination has been shown in some northeastern states of India (84e87). However, none of these studied possible reasons for this high prevalence despite IDD control program. Was it failure of the program or other factors affecting the absorption and utilization of iodine provided by salt? A high prevalence was found among adolescents in slums of a coastal city despite iodination of salt. Another important finding was that difference in urinary iodine excretion levels was statistically nonsignificant among various grades of goiter (88,89). Thus, raising the issue whether this high prevalence is due to excess iodine as shown by studies from China (31,32) or some goitrogens in water/diet are behind this high prevalence? In another coastal area, where no survey was done earlier or there was a ban on noniodized salt, survey prevalence included children of 6e11 years of age, whereas the same researchers had been studying children of only 8e10 years of age for evaluation surveys in other areas. Without any explanation being given for this differential methodological choice, one is left wondering whether a deliberate effort is being made towards some unstated objective. Even then, TGP was only 2.6%, which clearly pointed to the fact of non-existence of goiter even in the absence of iodized salt. In fact, no further attempt was evident from discussion to evaluate any reasons for this low prevalence of goiter (90). A similar study in Andaman and Nicobar islands (Bay of Bengal) found TGP of 16.5% despite 93% salt samples having O15 ppm of iodine (91). The tribal population of these islands was found to consume a great amount of seafood, which is rich in iodine. However, iodized salt was introduced to this island, which most probably resulted in iodine excess goiter. Iodine is a volatile substance and how much iodine in salt is lost during cooking? In India, substantial losses of iodine during cooking have been shown (92). Countries like the U.S. introduced iodine only in table salt (added to cooked food) but as per the current Indian policy, iodine is added to all types of salt, thus wasting a lot of iodine due to the addition of salt prior to cooking. It has been shown that iodine content of raw food was significantly higher than that of a mixed cooked diet due to appreciable iodine losses during cooking (range 37.4e69.7% loss) (93). However, iodine losses during cooking have not been adequately studied.

A Systematic Review of Goiter and Other Iodine Deficiency Disorders

Low levels of TGP were found 7 years after the Delhi government banned sale of non-iodized salt despite 41% of families consuming salt with !15 ppm (94). However, only 8- to 10-year-old children were studied instead of all children. This kind of variance makes comparison difficult with other studies that included children 5e15 years of age. Moreover, during prevalence surveys that formed the basis of USI, all children (especially 5e15 years old) were studied, including adolescents with a high probability of having a physiological goiter, but in evaluation surveys the majority of studies include only children between 8 and 10 years of age! Other studies regarding evaluation are depicted in Table 3 (84e86,90,91,95e100). In a well-designed multicentric study to assess iodinedeficiency disorders, children (6e!12 years old) from 15 districts of ten states in India were studied during 1997e2000. What the results show is really quite disturbing. The prevalence of goiter in one of the districts of UP was maximum (31.02%), though median urinary iodine excretion (UIE) value was sufficient (127 mg/L), and O82% salt samples had adequate iodine content. The next in order of prevalence of goiter (12.95%) was another district with adequate median UIE value (115 mg/L) but adequate iodine content in only 4.7% of the salt samples. A district in Bihar, with insufficient median UIE value of 90 mg/L and only 2.9% of the salt samples having adequate iodine content, showed prevalence of only 0.2% goiter. The investigators just cursorily mentioned this lack of correlation between the three parameters of iodine deficiency at the end of their paper, without giving it due importance (101). In fact, the findings clearly call for a revisit of the entire debate of iodine-deficiency disorders—magnitude of the problem, causality and control strategy. A similar lack of correlation between adequate iodine nutrition and TGP has also been shown by WHO in many countries worldwide, to mention a few: Bangladesh (49.9%) and Australia (19.4%) with different TGPs but classified as having mild iodine deficiency, and Eritrea (36.7%) and India (17.9) both shown as having optimal iodine nutrition (8). Similar results of ineffectiveness of iodized salt in the reduction of goiter were available since 1980, raising the hypothesis that after a certain level the prevalence of goiter does not decrease by iodination alone due to the role of other factors such as goitrogens in food, pollutants in water, etc. Definite identification of the active agents and knowledge of their biological and physicochemical properties may permit public health officials to develop procedures for eliminating these compounds at the community level and eradicating goiter from endemic areas (102).

Harmful Effects of Iodine Studies are available on the possible link of increased iodine intake leading to increased hypothyroidism/hyperthyroid-

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ism. Many researchers have commented on toxicity of iodine but other harmful effects, e.g., hypothyroidism, autoimmune thyroiditis, etc. at smaller dosage have not been studied adequately. None of the researchers have studied this problem, especially among the higher socioeconomic group, and what level of iodine is optimal to avoid the consequences of iodine deficiency while preventing side effects. Studies in China showed that goiter might be caused by excess iodine intake. All subjects were clinically euthyroid but biochemical tests suggested a spectrum of thyroid dysfunction from subclinical to overt hypothyroidism (31). Studies showing similar results have been done in Japan (103) and China (32,104,105). In one of these community-based surveys in China (32) among people from all ages in two villages, it was found that goiter due to iodine excess affected all ages in different geographical locations. These findings strengthen the association between iodine excess and goiter and hypothyroidism probably due to some autoimmune mechanism and have also been corroborated by pioneers of research in goiter and IDDs (106). Studies done in a few countries to analyze the current status of morphological and functional thyroid abnormalities in a previously iodine-deficient area have shown a number of thyroid disorders in previously iodine-deficient regions. This clearly points to the need for further studies to investigate the change of thyroid disorders during iodine supplementation programs. A study in Laos to assess the impact of salt iodination program found a higher median value of urinary iodine but almost similar goiter prevalence after introduction of iodized salt as compared to an earlier period (107). A review of IDD found that in areas with relatively high iodine intake, the incidence rate of hypothyroidism is several fold higher than that of hyperthyroidism (108). Even experimental studies show that iodine appeared to have a direct toxic effect on thyroid epithelial cells of rats by showing that a high intake of iodine accelerated the development of lymphocytic thyroiditis in BB/W rats (109,110). Conclusions and Future Perspectives Evidence from this scientific, systematic review of empirical studies provides enough basis to question the current dominant paradigm and reveals that opposing research findings were ignored. The studies available provide enough evidence to start a fresh debate on evidence about iodine as the sole factor in causality; magnitude of the problem as a major public health problem universally; effectiveness of universal iodization of salt as a measure that leads to decreasing goiter and other IDDs by itself; and possible negative impacts on health itself like increase in hyperthyroidism, goiter and interaction with other minerals like iron. The problem of IDDs has increased in many parts of the world (refer to Table1), and the use of iodization as a strategy can at best claim to prevent further increase than present prevalence. This review shows that wherever endemic IDD

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Kotwal et al./ Archives of Medical Research 38 (2007) 1e14

does exist it is a problem with socioeconomic, developmental and ecological causes. Rarely has it been tackled successfully through iodine supplementation alone. Iodine deficiency of soil is related to flooding, deforestation and soil degradation. Changes in dietary patterns could be significant factors. Changing exposure to bacterial flora could be another issue. Lack of food exchanges is also important in the causation of endemic goiter. These factors could be interacting at different levels in various regions and so local factors of significance need to be identified. A program to combat iodine deficiency should essentially tackle these issues for a long-term and sustainable solution rather than looking at a single intervention of iodized salt alone. Development and ecology thus should be the key areas of focus to reduce IDD. The problem of goitrogens in food, water and synthetic chemicals and the role of polluted water need to be understood and taken care of rather than just pushing iodized salt as a panacea for the prevention and control of IDD. The ethics of public health demands that the possible negative consequences of interfering with iron metabolism and thereby enhancing anemia and the increase in goiter due to excess iodine need to be investigated under diverse conditions before a program for universal iodization of salt can be initiated. We propose use of iodized salt in populations where iodine deficiency is convincingly found to be a major public health problem after other causes have been ruled out, and leaving people the choice in other regions. The proponents of USI say a ban in just the severely affected regions has proved unsuccessful without analyzing the reasons for this failure. There are optional approaches available to deal with the problem in highly affected areas. Participatory community programs of iodization of salt or water at a local level is one that has been tried successfully in countries such as Thailand. Supplying subsidized iodized salt in these areas so that it is cheaper than non-iodized salt is another option, which directly addresses the problem without adding the negative health consequences of the intervention and adhering to the concept of ‘primum non nocere’. Acknowledgments The authors are extremely grateful to Dr. Monica Agrawal and Ms. Parul for collection of various references from libraries and organizations spread all over the vast city of New Delhi; Dr. (Lt Col) Jyoti Kotwal for her patient reading of several drafts of this review and providing insightful comments.

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