Deficiency Iodine

Ag

e

e

l

eunidirectional and does not provide comprehensive data on all aspects of IDDs. To furthercompound the issue,many independent researchers, on finding something different from theexisting dominant paradigm (iodized salt as panacea for goiter) have tended to ignore thesein their final conclusions and recommendations. Thus, evidence from this systematic reviewdemonstrates enough basis to start a debate on the entire issue, recognizing opposing re-search findings while continuing with the present strategy. This imposes specific problemsand necessitates area-specific solutions instead of a universal solution, which apart from be-ing less effectivemay be harmful in the long run. 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) havebeen known since antiquity and much has been writtenabout the subject. The existence of endemic goiter in an ex-tensive belt along the southern slopes of the Himalayas,Alps and Andes has long been described. The early pio-neers in the study of endemic goiter included Sir RobertMcCarrison (1,2) and Stott (3). Both pointed to the complexetiology of goiter and commented on various causative fac-tors. The role of iodine in the causation of goiter was elu-cidated by various researchers working in these areas.The results from different geographical areas and few stud-ies formed the basis of control and prevention activities ofgoiter (4,5). As per a recent review Sustainable elimina-

tion of IDD is within reach and would constitute anunprecedented global success story in the field of noncom-municable diseases, but continuing vigorous action isrequired to attain this goal (6).

Across the world, some countries have resorted to uni-versalization of iodized salt (USI), whereas others havenot done so and instead focused on making it available asa community choice. Although the Government of Indiainitiated the National Goiter Control Programme (NGCP)in 1962, the program, however, faltered on many accountsand various reviews of the program specified different as-pects and reasons for not achieving the aim. Whatever thestrategies 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 uni-versal iodization has also been challenged by pointing outthe weaknesses in the science and politics of the interven-tion to control IDDs. Few papers have also challenged the

Address reprint requests to: (Lt Col) Atul Kotwal, MD, Classified

Specialist, Preventive and Social Medicine and Epidemiologist, Joint Di-

rector (Medical and Health), Management Information Systems Organiza-REVIEW

Goiter and Other Iodine DeficiencyEpidemiological Studies to D

Atul Kotwal,a,b Ritu PriyaManagement Information Systems Organization, Inte

bCenter for Social Medicine and Community Health, School of S

Received for publication May 6, 2006; accept

A systematic review of the available literaturders (IDDs) was carried out with the aim of anputs to the policy makers and program formupoint tomajor issues such as the following:meand other iodine deficiency disorders (IDDs);tion tomulticausality; flawed assessment of thharmful effects of iodine not given due cogni

Archives of Medical Retion, Integrated HQ Min of Defence (Army), West Block-III, RK Puram,

New Delhi-110066, India; E-mails: [email protected] and

[email protected]

0188-4409/06 $esee front matter. Copyright 2007 IMSS. Published by Elsdoi: 10.1016/j.arcmed.2006.08.006RTICLE

Disorders: A Systematic Review ofeconstruct the Complex Web

a,b and Imrana Qadeerb

rated HQ Min of Defence (Army), New Delhi, India

ocial Sciences, Jawaharlal Nehru University, New Delhi, India

d August 21, 2006 (ARCMED-D-06-00185).

on goiter and other iodine deficiency disor-alyzing available evidence and providing in-ators regarding the entire issue. The findingsthodological issues in epidemiology of goiterlacunae in causal linkages; inadequate atten-impact of intervention, i.e., iodized salt; and

zance. Most of the research to date has been

search 38 (2007) 1e14research forming the basis of the information on the magni-tude of the problem and effectiveness of the intervention(9,10).

evier Inc.

2 Kotwal et al./ Archives of Medical Research 38 (2007) 1e14This prompted us to carry out a systematic review of theavailable literature with the aim of initiating a healthydebate and providing input for a mid-course correction.The objectives were to highlight the lacunae in researchon etiology; efficacy/effectiveness of the intervention; eval-uation strategy adopted; the direction in which the programis progressing; the problems when one solution is supposedto be a panacea for all regions/communities rather than giv-ing due recognition to multicausality while planning any in-tervention; and the contrasting views of organizations/individuals involved in various aspects of IDDs control overa period of time. This review in no way tries to belittle theimportance of iodization in preventing the spread orreducing the problem and of the research carried out on var-ious aspects of IDDs. Because rational measures for theprevention and control of any disease depend upon theadequacy of knowledge about its etiology and pathogenesis,the availability of an effective intervention, appropriateconceptualization, implementation and subsequent evalua-tion and feedback/review of the program, as the acolytesof evidence-based medicine, we must take steps to preventour medical successors, using the long lens of history, fromjudging us as harshly as we might judge the early history ofprevention and control of IDDs.

As per available evidence, the issues related to IDDs canbe classified into four main groups: 1) magnitude of theproblem and evidence for multicausality, 2) evidence forbenefit of iodized salt, 3) assessment of intervention, and4) harmful effects of iodine.

Methodology of the Review

More than 120 studies (1906 to the present) from variousparts of the world were reviewed. These included publishedas well as unpublished works from various journals, inter-net sites, institutions/organizations and governmental sour-ces. We searched the following from inception to May2005: MedLine, EMBASE, Index Medicus, Cochrane con-trolled trials register, and the Nursing and Allied Health

Table 1. Total goiter prevalence in various regions of World Health

Organization over a period of time

WHO region

Total goiter prevalence (%) Percentage change

between 1993

and 20041993 1997 2004

Africa 15.6 20.0 28.3 81.4Americas 08.7 05.0 04.7 46.0Southeast Asia 13.0 12.0 15.4 18.5Europe 11.4 15.0 20.6 80.7Eastern Mediterranean 22.9 32.0 37.3 62.9Western Pacific 09.0 08.0 06.1 32.2Total 12.0 13.0 15.8 31.7

Adapted from WHO documents (7,8).Collection. In addition, we searched for unpublished andon-going studies and also publications of InternationalCouncil for Control of Iodine Deficiency Disorders (IC-CIDD). All available studies were included in this review.None of the available studies was excluded as we wantedto capture the diversity of methodology and interpretationsbeing used in research on goiter and IDDs. Due to the het-erogeneity of the study methodologies in this review it wasnot possible to apply the meta-analysis techniques; thus,a systematic review was conducted. The studies were clas-sified based on their study design (community based/hospi-tal based, cross sectional/longitudinal, nonexperimental/experimental) and also the focus (assessment of the prob-lem, assessment of program, intervention) to assess the fourmajor issues mentioned above. The Indian scenario wasanalyzed in detail in the overall global context.

Magnitude of the Problem and Evidencefor Multicausality

Issues in Epidemiology of Goiter and Other IDDs

The problems encountered by epidemiological studies ofthyroid disorders are those of misclassification (e.g., overtand subclinical hypothyroidism); mode of sampling in pop-ulations; various confounders (age, gender, environmentalfactors, etc); different classifications (Perez, WHO, Stan-bury, etc.) used for the measurement of thyroid size; diffi-culty in carrying out certain tests leading to lack of dataon thyroid function; and focus on monocausality or ignor-ing multicausality on finding. Thus, results of epidemiolog-ical surveys carried out in various states, countries and overa period of time within the same community or country areoften difficult to compare. This is further compounded bydifferent methods to present the results and investigatorsinterpretation of classification criteria in their own way.

Criteria for Identifying Goiter

Estimation of breadth, volume, palpability or visibility ofa thyroid gland is subjective as it depends on many factors:certain characteristic of subjects (shape of neck, thicknessof subcutaneous fat, disposition of SCM muscle, etc.); in-vestigators approach (interpretation of classification crite-ria, experience, fatigue, etc); and on the circumstances ofexamination (illumination of the subjects neck, positionof neck in relation to investigators eye, time devoted toexamination, etc.). Furthermore, goiter measurements arehampered by the fact that soft glands are fairly commonand any estimate will depend on the finger pressure (11).The most important factors affecting the accuracy ofestimation of goiter frequency are intra- and inter-observervariability, and studies have shown different levels of con-cordance or discordance among observers and in anobserver over-repeated measurements. It has been shown

3A Systematic Review of Goiter and Other Iodine Deficiency Disordersthat observation variation is greatest in deciding whethera thyroid that is palpable but not visible is normal or en-larged (12). There was also considerable overlap betweenthe various grades when compared with thyroid volume es-timated by ultrasonography (USG), which increased thesensitivity of the test because 30% of individuals werefound positive by USG but only 14.6% by conventionalmethods (13,14). USG also increased the correlation andagreement between observers (15); however, USG has notbeen extensively used in field studies. It is therefore impor-tant to know the estimates of variability before embarkingon any tests of statistical significance.

Classifications have also changed over a period of timewith each one having its characteristics, e.g., difficulty inPerez et al. classification was in defining at which degreeof enlargement one considers a sufficient pathological alter-ation of the gland in order to classify as goiter (16,17). Evenafter modification, the distinction between grade 0 and I wasunsettled for a long time. The Caracas, WHO/FAO grouptried to resolve some of the issues and concluded that someof the small thyroid hypertrophies do not have sufficient path-ological significance to be classified as goiter but should alsonot be classified as normal. Thus, two subgrades, 0a and 0b,were defined, creating more confusion during communitysurveys 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 In-dian studies carried out in various states of India prior tothe USI (18e28). Most of these studies reported a high pro-portion of goiter in lower categories that are subject to

80

60

40

20

0

Assam Guj1 Guj2 Guj3 Guj4 Guj5 Mah1 Mah2 Mah3 Totaladults

Mean95% CI Upper95% CI LowerTotal Goiter Prevalence

Area of study

Figure 1. Total goiter prevalence: pre-iodization studies among adults in

various states of India. Guj, Gujarat; Mah, Maharashtra.biases as discussed earlier. Figure 3 depicts a few of thestudies from other countries (29e33).

Criteria for Identifying Regions Endemicfor Iodine-Deficiency Disorders

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

Etiology of Goiter and Other IDDs

Etiology of endemic goiter is complex and not fully eluci-dated. The fact that goiter persists in many areas despite io-dine supplementation for prolonged periods reiterates theimportance of doing so. After studying goiter in Chitraland Gilgit valleys in the then undivided India, McCarrisonshowed the association of goiter prevalence with contami-nated water supplies in a trial in Himachal Pradesh (one ofthe Northern states of India) where prevalence of goiteramong school children decreased by changing the water sup-ply from contaminated to uncontaminated, the other factors(iodine content of water, soil, etc.) being unchanged (1,2).


70

60

50

40

30

20

10

0

Area of study

Del1

Del2

Guj1

Guj2

Guj3

Guj4

Guj5

Har1

Har2

Mah1 Ori

1Ori

2

Total C

hild

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.

4 Kotwal et al./ Archives of Medical Research 38 (2007) 1e14A majority of the initial studies tried to assess the issue ofcausality along with assessing the extent of the problem.

A few hospital/community-based studies on causalityare shown in Table 2 (4,5,36e42), whereas others havebeen described in text. A high TGP, with a high proportionof grade 0b goiter (subject to classification bias), was foundamong a tribal population in a coastal area on the Easterncoast of India, which either shatters the myth of iodinedeficiency as a causal factor in goiter as marine fauna isrich in iodine or it is an inflated figure due to lack of inter-nal validity of the study (43). Similar results have also beenfound from other coastal areas, pointing to some effectmodifier or confounder in the entire issue of iodine asa causal factor of goiter. This lack of correlation betweeniodine and goiter was also found in a study where a majorityof the children with growth failure had dysgenetic thyroidgland, showing that factors other than pure iodine defi-ciency are at play in goitrogenesis and hypothyroidism(36). Another study found no correlation between gradeof goiter and urinary iodine in pregnant women (37).

Goiter was found to be more prevalent among the poor-est, field laborers and cultivators, after rains, after food fam-ines, and among those consuming water with high levels ofcalcium in the then United Provinces of India, and no asso-ciation was found between goiter and diet and iodine con-tent of water (3). In other goiter prevalence studies indifferent areas, no association was found with iodine intake.The researchers also did not find any association of goiterwith cretinism, deaf mutism, and other aspects of physicaland mental growth retardation (19,22). This association of


70

60

50

40

30

20

10

0

Area of study

Del1

Del2

Guj1

Guj2

Guj3

Guj4

Guj5

Har1

Har2

Mah1 Ori

1Ori

2

Total C

hild

Figure 3. Total goiter prevalence: studies from a few countries. Del, Delhi;

Guj, Gujarat; Har, Haryana; Mah, Maharashtra; Ori, Orissa.goiter with socioeconomic and life style factors has alsobeen demonstrated in Denmark (44).

There are innumerable descriptions of goiter attributed todrinking water. Microorganisms contaminating water sup-plies have been implicated as a causative factor in few ende-mias. Studies supporting similar findings were done in Indiain the 1970s and 1980s but were not given due recognitionand thus were not repeated later. Antithyroid activity hasbeen shown in cultures of E. coli isolated from pollutedstreams of highly endemic areas. Organic compounds withantithyroid activity have also been isolated from water. Asimilar association of goiter with contaminated drinking wa-ter, low literacy and socioeconomic levels was found inmanystudies in different geographic areas across India(18,19,21e23,26). Fewof these areaswere free of goiter untilabout 10 years prior to the study period. An important changeduring this period was the introduction of new water sourcesin the form of tube wells and other types of wells. The role ofpollutants in water has also been demonstrated in the U.S.where goiter prevalence was higher in children whose homesobtained water from dug wells as compared to childrenwhose homes were served by piped water supply ( p!0.025). The majority of the dug wells were polluted andthe iodine content was adequate in both populations (45).

Worldwide, there are several endemias attributed toenvironmental goitrogensTasmania, Finland, Nigeria,Chile, West Virginia, etc. The vehicle for goitrogens inthe majority was water and milk. Environmental factorsother than nutritional iodine deficiency are responsible forthe persistence and development of new cases in certainendemias and also for the differences observed in goiterprevalence among communities with similar iodine intake.Iodine deficiency must act in conjunction with other goitro-genic factors to produce a goiter endemia. Environmentalgoitrogens when low in concentration may normally be in-effective but may become significant when iodine supply isrestricted. In other situations they may be sufficiently po-tent in themselves to cause goiter despite an abundanceof iodine. Adequate iodine intake of 75e300 mg/day doesnot always eradicate goiter because 6e40% prevalenceexisted in certain areas despite these intakes (46). The goi-trogenic action of calcium has been well established underexperimental conditions but the evidence for calcium indrinking water and food having practical importance forthe development of endemic goiter is conflicting (47).The increase in prevalence of goiter in Papua New Guinea,subsequent to economic recession despite a well-imple-mented intervention by iodized oil (48), shows that multi-causality has been ignored for IDDs. Similar studies onmulticausality have also been reported from Denmark(49,50). Studies are also available showing high goiter ratesdespite lack of iodine deficiency (51,52).

A survey in the U.S. in Tecumseh, MI indicated relativelyhigh goiter prevalencewithout convincing evidence of iodinedeficiency. Similar results were obtained during studies in

Table 2. Results and comments on studies regarding causal linkages of goiter and other iodine deficiency disorders

Remarks

Overinterpretation of causality

based on a cross-sectional study

de Wide and overlapping 95% CI,

invalid controls

No correlation found with iodine

deficiency

No association between goiter

and iodized salt; urinary iodine

excretion and iodized salt

I AIU Number of cases and

controls not provided

.0 2.532

.4 1.646

.001 0.05

g/dl No correlation found between

goiter and cretinism

.42

.3

S

T4 higher in Kerala, rT3 not used

.09

(Continued) 5ASystem

aticReview

ofGoiter

andOther

IodineDeficiency

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

1 4 (1961) Punjab (I) Ie12e16 PBI uptake

Bihar (II) IIe8e12 Ie33 Ie62.5%

Bihar (III) IIIe12e15 IIe43 IIe62.9%

India All goitrous in I and II IIIe18 IIIe39.05%Non-goitrous in III

All euthyroid

2 5 (1973) UP, India Goitrous controls

(case-control)

26 TSHebetween grades p !0.05; linear relation with graof goiter p !0.02; compared with controls p !0.001

46

3 36 (1989) Delhi, India Patients of thyroid

clinic from 1983e88(case series)

Hypo 117 Hypo Hyper Euthy

Hyper 10 Goiter 19 10 30Euthy 30 Goiter 98 0 0

Iodine

deficiency

3 0 19

4 37 (1990) Municipal

Hospitals,

Maharashtra,

India

Pregnant women of

low socioeconomic

strata attending ANC

in a 3-month period

479 Goiter Goiter

Iodized salt 9 17Iodized salt 106 347Odds ratio 5 1.73 (0.69e4.26)

Cross-sectional Goitrous 27.3% p 5 0.193

UI !50 UI O50Iodized salt 3 23Iodized salt 30 423Odds ratio 5

p 5 0.411

1.84 (0.41e6.97)

5 38 (1977) Delhi, India Goitrous and

nongoitrous children

(Case/Control)

I TCR I RCR PII U

Cases 88.39 23.33 0.0695 20

Controls 22.2 21.675 0.1372 76

p 5 0.001 0.7 0.01 0

6 39 (1982) Neonates TSH mIU/L T4 mg/dl T3 ng/dl rT3 n

UP 20 14.6 4.28 96.34 168

UP, India Delhi 89 9.8 6.41 59.78 174

Delhi, India p 5 0.01 NS 0.001 N

7 40 (1984) UP, Delhi,

Kerala,

India

Neonates TSH T4 Hypo T4

UP 646 15.5 5.75 5 6

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

Table2.Continued

Serialno.

Ref

(year)

Studyarea

Studypopulationanddesign

nResults

Rem

arks

Delhi

427

8.7

8.5

18.3

Kerala

575

7.57

841(1987)

Maharashtra,

India

Allneonates

12407

TSH

!30

30e80

O80

Incidence

28/1000

asper

TSH

values

usedbyKochupillai

etal.but0.4

per

thousandafter

follow

-up

Cohort

12057

302

48

CH

CHe

TSHO30

5345

TSH!30

012057

942(1994)

National

registerofchildren

withCH

compared

with

T4

MeanIQ

(manual)

MeanIQ

(non

manual)

Mildhypothyroidism

inCH

show

ednosignificant

difference

inIQ

levels

361

Cases!42.8

97.5

107.6

London,UK

Matchingcontrols

(case-control)

315

CasesO42.8

109.1

115.5

Controls

109.8

118.2

ITCR,radioactive

iodinethyroidalclearance

rate(m

L/m

in);IRCR,radioactive

iodinerenalclearance

rate(m

L/m

in);PII,plasm

ainorganiciodidelevels(mg%);AIU

,absoluteiodineuptakerates(mg/h);

UI,urinaryiodine(mg/g);CH,congenitalhypothyroidism;WI,iodinecontentofwaterm

g/L;T3,in

nmol/L;T4,in

nmol/L;TSH,mIU

/L;TGP,totalgoiter

prevalence;CI,95%

confidence

interval;PBI,

protein

boundiodine.Kentucky. Dietary iodine deficiency (corrected for age andgender, as well as analysis of iodine in daily food samples)could not be implicated. Goiter was found even in thosehouseholds that had been consuming iodized salt for morethan 20 years. All water samples were polluted and therewere no goitrogens in the diet (53).Many other studies in dif-ferent areas of the U.S. yielded similar results. In Mexico,studies concluded that iodine deficiency may be the mainbut not the only cause of goiter. Also, no correlation wasfound between the average iodine intake and prevalence ofgoiter (54). The prevalence of goiter in Greece was40e60% in 1966 and 21% in 1996. This decreasewas despitenot having a program of IDD control and was due to changesin food habits, etc. An interesting observation was thatincreased urinary iodine levels were associated with antithy-roid antibodies in children, which may lead to autoimmunethyroiditis. This might be the reason for residual goiter espe-cially among childrenwith sufficient iodine intake (55). Evenexperimental and clinical studies have suggested a linkbetween the level of iodine intake and the development ofautoimmune thyroid disease (56).

In India, a nationwide survey was conducted to assess theproblem before Universal Salt Iodization (57). Thus, the goalof universal iodization was already formulated a priori. Thestates and districts were purposely selected, i.e., those whereinformation was already available about high prevalence ofgoiter. The results thus might have been valid for the partic-ular districts but neither generalizable to the states fromwhich the districts were selected nor to other parts of thecountry. The question raised is why probability samplingtechniques were not used in a nationwide survey. Despite thispurposeful sampling, overall total prevalence was only21.1%. The report mentions probable underreporting of 0b,thus accepting an observer or other bias at play, raising the is-sue that there could have been an overreporting of 0b. Many0a were classified as 0b due to the ultimate goal of USI beingvalidated by the survey.Water sampleswere also drawnwith-out any sampling procedure and were tested only for iodinebut not for other pollutants (organic and inorganic) or otherpossible goitrogens. Urine samples were collected but notanalyzed (possibly due to transportation problems or otheradministrative challenges), which reflects operational failureof the survey. These failures also might have affected otherareas like training, quality assurance, etc., thus questioningthe internal validity of the survey. Whatever the possibleflaws, the survey clearly shows that goiter and cretinismwerenot correlated, e.g., prevalence of goiter in two of the north-east states of India (65.8 and 19.8%, respectively) did notcorrelate with prevalence of cretinism (2.2 and 6.1%, respec-tively). Cretinism alsowas not apparent in areaswhere iodinedeficiency was supposedly more prevalent.

Many researchers have compared different aspects ofendemic and nonendemic areas. In one such study, higheruptake of iodine was shown in school children with visiblegoiter. However, the sample size was small in each group,

Results

Present study

TGP (%) UI !10 (%) IS !15 (%)

72.5 (cretinism 3%)

38.38

TGP

23.32

20.4

20.3

20.8

2.6l 24.1 69

16.5 81.9 7.5

21.9

18.7

23.6

16.3

31.2

19.1

24.3

50.3

12.8 49.3 26.7

10.4 48.8 34.2

8.8 32.8 10.8

5.8 23.7 23.4

20.5 24.9

District.

7ASystem

aticReview

ofGoiter

andOther

IodineDeficiency

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

Serial

no.

Ref.

(year)

Area/region/ year

of iodination

Population studied; study design; year; class used n

Previous study Present study Previous Present Previous study (TGP%)

1 84 (1987) Northeastern

state 1978

General population;

CS; 1978

General population; CS 5573 3248 68.6


state 1987

General population;

CS; 1970

General population

CS; WHO

NA 4375 17


state 1987

General population;

CS; 1970

General population; CS;

Perez (Iae75.9,

Ib-20.5, IIe3.0,

IIIe0.55)

NA 11523

City A 7.3

City B 7.3

City C 13.2

4 90 (1998) Coastal area Children 6e11 years

age; CS

NA 2065 NA

5 91 (1998) Island group

in Bay of Bengal

Children 7e18 years; CS NA 900 NA

6 95 (1995) Northern state General population; CS General population: CS NA NA

Dist A 1966 1930 1988 40.0

Dist B 1966 1930 1966 3.7

Dist C 1960 1860 1969 23.2

Dist D 1966 1965 1969 39.7

Dist E 1986 1973 1989 65.0

Dist F 1966 1930 1989 3.7

Dist G 1966 1930 1974 40.0

7 96 (1996) Northern

state 1980

General population;

CS; 1980

General population; CS NA 5000 60

8 97 (1997) Eastern

state 1976

General population Children 6e12 yearsage; CS

NA

Dist A 662 57.2

Dist B 666 64.5

9 98 (1998) Northern state

1976

Children 5e15 years

age; CS; 1956

Children 8e10 years age; NA 6897 41.2

10 99 (1997) Northern state

1976

General population;

CS; 1954

School children

8e10 years age;CS; WHO

NA 1358 41.2

11 100 (1997) Delhi School children

10e21 years; CS;

1980

School children,

10e14 years; CS;

3200 1684 55.0

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

8 Kotwal et al./ Archives of Medical Research 38 (2007) 1e14increasing the possibility of chance error. Moreover,goitrous children from endemic areas were compared withadults from non-endemic areas. They also found lower pro-tein-bound iodine (PBI) in goitrous children as compared tonongoitrous children. Contrasting results of no difference inankle jerk reflex as well as PBI in goitrous as compared tonongoitrous children were found by another group (58).Higher TSH levels were actually compared with controlsin England. However, when T4 levels were found to behigher in Indian cases as compared to English controls, thiswas dismissed as controls being from a different country.Moreover, the higher value of T3 in cases was not assignedany importance. The subgroup analysis with small numbersin each group increased the chance error in the estimates.Thus, an inference of convenience was drawn and manystudies in later years quoted this study as a milestone anda basis for the problem of goiter in the Himalayas (5).

Another study found decreased iodine excretion, increasedTSH values, decreased T4 and increased T3 in endemic ascompared to non-endemic areas (29). However, both areasdiffered in many other factors like geophysical characteris-tics, dietary patterns, etc. A conclusion of cretinism in Zairedue to severe iodine and selenium deficiency was made basedonly on cross-sectional data in a study dealing with neonatalhypothyroidism and comparing biochemical parametersbetween neonates from Zaire and Malawi. The results ofZaire neonates were compared with Belgian neonates, whosenumber is also not provided. However, the authors somehowconclude that etiopathogenesis of goiter is multifactorial (59).

A hospital-based case-control study presumed hospitaland home diets to be similar. An interesting finding wasa positive iodine balance among all cases. Despite this,iodine deficiency was being reported as a major cause ofgoiter. The researchers mention this towards the end of theirdiscussion but do not give due recognition to this importantfinding (38). Multiple regression analysis in two studies(r2 5 0.57 and 0.51, respectively) showed that goiter sizedepends on iodine uptake, age and vitamin A and thusinferred that vitamin A nutrition is as important as iodinestatus. Decreased vitamin A stores play a causal role in goi-trogenesis, and iodine itself contributes to goiter formationdue to indiscrete iodine intake (60,61).

Experimental studies have consistently shown the role ofother factors in the causality. Experiments on rats showedthat environmental goitrogens (thiocyanates, etc.) mightbe significant determinants in the etiology/prevalence of en-demic goiters (62). In another study, it was shown that apartfrom or along with iodine deficiency the goitrogens presentin staple foods may be important contributory factors (63).

Goiter, Congenital Hypothyroidism andEndemic Cretinism

Despite the well-researched and accepted linkage, theevidence in favor of maternal hypothyroidism and infantilecretinism is conflicting. Some studies have shown morestillbirths, infant deaths and endemic cretinism among off-spring of women showing biochemical evidence of iodinedeficiency (decreased T4 and T3, increased TSH) but with-out clinical evidence of hypothyroidism (64). Againstthe maternal hypothyroidism hypothesis is the fact thatthyroid hormone transfer across the placenta is minimal andthyroidepituitary feedback mechanisms are autonomous inmother and fetus. A literature review of pregnancies inhypothyroid women indicated an excess of congenitalanomalies but no case in which deaf mutism, diplegia orcongenital hypothyroidism (CH) was present (65,66).

A group of researchers found pockets of endemic cretin-ism in Himalayas with prevalence of 1e4% (67), but anotherstudy found prevalence to be!1% in many areas of the Hi-malayas (68). In the newer areas of goiter endemias, e.g.,Delhi (India) (25), endemic cretinism is not seen at all but ref-erence is made to subclinical cretinism. The methodologyadopted for proving this new hypothesis involves develop-ment and intelligence testing. In one such study, children ofgoitrous mothers and controls were compared by Gessel de-velopment score. It was concluded that development quotient(DQ) and language development were lower in children ofgoitrous mothers (69). The mean DQ for controls was 98.4as compared to 94.4 in other groups; this small differencewas shown as statistically significant and profound conclu-sions were drawn. This approach is highly controversialand has been riddled with a priori assumptions, consciousfraud and politics, so that its very value and scientificobjectivity have been questioned (9).

Studies assessing causality and studying other factors likeCH have used statistical significance on an as-required basisapparently to fit into their hypothesis and taking very low cut-off values for CH. No statistically significant difference inrT3 and T4 in cord blood samples among neonates in oneof the endemic districts of Bihar (India) and Delhi (India)was found, but inference was still drawn that all values inchildren of endemic areas were several fold higher as com-pared to Delhi children (nonendemic area) (39). Incidenceof CH is another area of dispute. By using TSH as a marker,one group found incidence of CH as 4% in endemic areas and0.1% in nonendemic areas and tried to find a correlation be-tween goiter prevalence and congenital hypothyroidism (40).However, studies by the same researchers showed that en-demic areas had a goiter prevalence of 64% as compared to52% in nonendemic areas. The authors discussed the impor-tance of rT3 in their previous study in the same areas and in-ferred that rT3 levels faithfully reflect thyroid status ofnewborns in endemic area (53) but did not use that in thisstudy. Although prevalence of goiter was shown to be muchless in Kerala (India) as compared to other areas, the meanvalue of T4was less inKerala as compared toDelhi, thus rais-ing doubts on the validity of using biochemical parameters inthese studies. In Bangladesh as well, no association wasfound between cretinism (0.5%) and goiter (47%), despite

9A Systematic Review of Goiter and Other Iodine Deficiency Disordersa high prevalence of the latter. This is contrary to assumptionsby researchers in India, as per which the cretinism prevalencein that area would beO2% (30).

Hospital-based studies in a coastal city in India showedthat positive predictive value of using 50 mIU/L of TSH ascut-off for CH was quite low and leads to overestimation ofthe problem. A 2.81% incidence of CH was initially found,which dropped considerably (0.000403% or 1:2481) after 2years of follow-up with neonates having TSH O250, onlyeventually developing hypothyroidism. The study also raisedanother important issue of some other factors responsible forTSH surge in newborns (41). Thus, previous studies (52,53)did not take transient neonatal hypothyroidism into accountwhile studying TSH values for CH. The same authorsreferred to transient neonatal hypothyroidism in one of theirlater papers andmentioned that it could be an important issuein iodine-deficient areas (70). However, starting thyroxinefor babies based on a single result of a high TSH is unethical,as European as well as Indian studies have shown this phe-nomenon of transient neonatal hypothyroidism (29). Well-designed follow-up studies need to be carried out in areasalready studied to determine the real incidence of CH.

Work has been done in this direction by a few groups ofscientists who have shown evidence for the role of maternalthyroid hormone on early brain development (71,72). How-ever, the entire issue needs to be revisited because the find-ings of one study question the benefit of screening andearly treatment as screening reduces but does not eliminateneurological impairment (42). To sum it up, lack of an exper-imental model, lack of a similar clinical picture in children ofhypothyroid mothers in non-iodine deficient countries, andlack of a similar clinical picture in syndromes of resistanceto thyroid hormones are paradoxical and require further in-vestigation to understand the mechanism of neurologicalcretinism using a holistic approach. Until that time, presentefforts need to continue to prevent CH.

Evidence for Benefits of Iodized Salt

Even in this area the evidence from trials and other studiesis conflicting as most of the studies showed only a marginaldecrease in prevalence of goiter despite so-called universalsalt iodization. Some of the possible reasons for this lack ofeffectiveness were commented by some researchers butstudied by none. These included poor implementation ofthe program, iodine losses during cooking, increased goi-trogens in environment/diet/water, decrease in goiter dueto economic development, iatrogenic goiter/anemia, etc.There is a definite lack of cohort studies at present.

There have been very few community-based interventionstudies and two of thesewere conducted in the present Hima-chal Pradesh (India) (2,73). The first one showed no evidenceof the role of iodine in goiter whereas the other has providedthe only evidence of effectiveness of iodized salt in the pre-vention and control of goiter. The two communities providedwith iodized salt showed decreased prevalence in all groupsas compared to the third community. However, the assess-ment was not blinded and inter- and intra-observer variabilityin classification of goiter was neither commented upon norshown in the results. Thus, subjective interpretation mighthave affected grade b of the classification used in the study,with more in this grade before iodization and less after iod-ization in the intervention areas.Moreover, only those partic-ipants were studied who were available at home during thetime of the survey. The prevalence of goiter among the gen-eral population at baseline was higher in the control area ascompared to both intervention areas and this was statisticallysignificant. The difference among school children after 12years of follow-up was reduced significantly (74). The resid-ual difference was in grade b goiter, which suffers fromsubjective classification.

In a trial in one of the southern states of India, the blockswere provided with double-fortified (iodine and iron) or onlyiron-fortified salt or only iodized salt. However, the blockswere not comparable at baseline. The results of the thirdarm of the intervention group, which was supplied withiodized salt, have not been provided in the paper for reasonsbest known to the investigators. The question that needs to beanswered is whether these showed any negative effects or didnot show any benefit. Although urinary iodine excretion in-creased among the double-fortified salt (DFS) group as wellas the iodized salt group, the mean hemoglobin levels de-creased in both groups. A significantly higher proportion ofgirls ( p !0.001) showed a decrease in hemoglobin levelsin the iodized salt group as compared to the DFS group(75). In another trial, iodine supplementation alone wasshown to raise levels of urinary iodine, T4 and iron status,whereas iron and iodine supplementation in combinationdid not lead to any significant changes in these parameters(76). These results raise an important issue of whetheriodized salt is hampering, in any manner, the absorption orutilization of iron. Could the present high prevalence of iron-deficiency anemia in India be contributed to by iodine in salt?The issue needs to be understoodwell before any changes areimplemented in the programs for correction of these defi-ciencies, especially in countries with high levels of iron-deficiency anemia. Decreased incidence of CH in one ofthe northern states of India post-iodization was concludedto demonstrate the effectiveness of USI (77) despite surveysin UP in the 1990s, showing a high continued usage of non-iodized salt. Was it iodized salt, iodine from other sources(improved nutrition/dietary practices), or increased iodineavailability due to lack of goitrogens (improvedwater 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

10 Kotwal et al./ Archives of Medical Research 38 (2007) 1e14highlight a few: lack of temporal comparability due to useof different classifications, methodologies, techniques andstudy population; confounders not studied adequately inavailable cohort studies; inadequate data on other factorsaffecting absorption/utilization of iodine; and inadequatestudies on lack of correlation between iodine nutritionand TGP.

In the U.S., a high prevalence was found in 1924, butsubsequent surveys in 1951 (consequent to iodization of ta-ble salt in 1924) found a low prevalence of goiter, from38.6% to 1.4%. Whereas 20% were still using uniodized saltonly, 75% of households were using iodized salt only and4% were using both. Thus, the decrease in goiter prevalencewas largely due to iodization of table salt but changes in theprocessing and distribution of food as well as in food habits,which also occurred during the same period of time, con-tributed to this decrease. However, from 1955 onwards,the iodine intake increased tremendously (O600% ofU.S. RDA) due to other sources like greater utilization ofiodine in food technology, sanitation and in the chemicalindustry. Still the goiter persisted! Thus a hypothesis wasgenerated that this persistent goiter was not related toiodine deficiency (53).

The decision of the Indian government to implementUSI by 1990, 20 years after inception of NGCP, was se-verely criticized by researchers presently spearheading thecampaign of USI (78,79). According to these researchers,iodine deficiency was a place-specific problem and hencenecessitated area-specific solutions. They clearly stated thatUSI besides introducing a fresh economic burden wouldalso magnify the already extensive chain of participatingagencies out of proportion. All this might lead to a delayin 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 maysubsequently plan for USI. They also commented on themethodological issues like classification of goiter, needfor uniform sampling procedures and use of median for uri-nary iodine excretion instead of mean values due to skewedvalues.

However, as the available evidence indicates, none of thesubsequent studies/surveys addressed these issues satisfac-torily. Even when the prevalence was shown to have in-creased after a period of iodization and banning plain saltin a particular area, only salt iodization was being targetedfor review without making any attempt to study the situa-tion in its entirety. None of the researchers ever thoughtabout whether the problem was with the program imple-mentation or with the entire concept of salt iodization orwere there other factors operating/interfering with avail-ability/assimilation of iodine? A detailed analysis of avail-able studies reveals that various researchers have useddifferent classifications. Some have used Perez, someWHO, others Stanbury and in one paper a new improvisedclassification of only two categories (0 and 1) was alsoseen. The other major drawbacks noticed were differentage groups being studied and piecemeal evaluation of theprogram. In India, salt and goiter are being targeted duringevaluations. No effort is being made to study the changes indiets, etc. to correlate with the present prevalence. Many ofthe studies have only looked at the process, i.e., proportionof salt sample having adequate amount of iodine with utterdisregard to outcome, thus conducting a biased exercisewith predetermined notion of efficacy and effectiveness ofthe intervention (80e83).

Increase in goiter post-iodination has been shown insome northeastern states of India (84e87). However, noneof these studied possible reasons for this high prevalencedespite IDD control program. Was it failure of the programor other factors affecting the absorption and utilization ofiodine provided by salt? A high prevalence was foundamong adolescents in slums of a coastal city despite iodin-ation of salt. Another important finding was that differencein urinary iodine excretion levels was statistically nonsig-nificant among various grades of goiter (88,89). Thus, rais-ing the issue whether this high prevalence is due to excessiodine as shown by studies from China (31,32) or somegoitrogens in water/diet are behind this high prevalence?

In another coastal area, where no survey was done ear-lier or there was a ban on noniodized salt, survey preva-lence included children of 6e11 years of age, whereasthe same researchers had been studying children of only8e10 years of age for evaluation surveys in other areas.Without any explanation being given for this differentialmethodological choice, one is left wondering whether a de-liberate effort is being made towards some unstated objec-tive. Even then, TGP was only 2.6%, which clearly pointedto the fact of non-existence of goiter even in the absence ofiodized salt. In fact, no further attempt was evident fromdiscussion to evaluate any reasons for this low prevalenceof goiter (90). A similar study in Andaman and Nicobar is-lands (Bay of Bengal) found TGP of 16.5% despite 93%salt samples having O15 ppm of iodine (91). The tribalpopulation of these islands was found to consume a greatamount of seafood, which is rich in iodine. However,iodized salt was introduced to this island, which mostprobably resulted in iodine excess goiter.

Iodine is a volatile substance and how much iodine insalt is lost during cooking? In India, substantial losses of io-dine during cooking have been shown (92). Countries likethe U.S. introduced iodine only in table salt (added tocooked food) but as per the current Indian policy, iodineis added to all types of salt, thus wasting a lot of iodinedue to the addition of salt prior to cooking. It has beenshown that iodine content of raw food was significantlyhigher than that of a mixed cooked diet due to appreciableiodine losses during cooking (range 37.4e69.7% loss) (93).However, iodine losses during cooking have not beenadequately studied.

11A Systematic Review of Goiter and Other Iodine Deficiency DisordersLow levels of TGP were found 7 years after the Delhigovernment 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 allchildren. This kind of variance makes comparison difficultwith other studies that included children 5e15 years of age.Moreover, during prevalence surveys that formed the basisof USI, all children (especially 5e15 years old) were stud-ied, including adolescents with a high probability of havinga physiological goiter, but in evaluation surveys the major-ity of studies include only children between 8 and 10 yearsof age! Other studies regarding evaluation are depicted inTable 3 (84e86,90,91,95e100).

In a well-designed multicentric study to assess iodine-deficiency disorders, children (6e!12 years old) from 15districts of ten states in India were studied during1997e2000. What the results show is really quite disturb-ing. The prevalence of goiter in one of the districts of UPwas maximum (31.02%), though median urinary iodine ex-cretion (UIE) value was sufficient (127 mg/L), and O82%salt samples had adequate iodine content. The next in orderof prevalence of goiter (12.95%) was another district withadequate median UIE value (115 mg/L) but adequate iodinecontent in only 4.7% of the salt samples. A district in Bihar,with insufficient median UIE value of 90 mg/L and only2.9% of the salt samples having adequate iodine content,showed prevalence of only 0.2% goiter. The investigatorsjust cursorily mentioned this lack of correlation betweenthe three parameters of iodine deficiency at the end of theirpaper, without giving it due importance (101). In fact, thefindings clearly call for a revisit of the entire debate ofiodine-deficiency disordersmagnitude of the problem,causality and control strategy. A similar lack of correlationbetween adequate iodine nutrition and TGP has also beenshown by WHO in many countries worldwide, to mentiona few: Bangladesh (49.9%) and Australia (19.4%) with dif-ferent TGPs but classified as having mild iodine deficiency,and Eritrea (36.7%) and India (17.9) both shown as havingoptimal iodine nutrition (8).

Similar results of ineffectiveness of iodized salt in thereduction of goiter were available since 1980, raising thehypothesis that after a certain level the prevalence of goiterdoes not decrease by iodination alone due to the role ofother factors such as goitrogens in food, pollutants in water,etc. Definite identification of the active agents and knowl-edge of their biological and physicochemical propertiesmay permit public health officials to develop proceduresfor eliminating these compounds at the community leveland eradicating goiter from endemic areas (102).

Harmful Effects of Iodine

Studies are available on the possible link of increased iodineintake leading to increased hypothyroidism/hyperthyroid-ism. Many researchers have commented on toxicity ofiodine but other harmful effects, e.g., hypothyroidism, auto-immune thyroiditis, etc. at smaller dosage have not beenstudied adequately. None of the researchers have studied thisproblem, especially among the higher socioeconomic group,and what level of iodine is optimal to avoid the conse-quences of iodine deficiency while preventing side effects.

Studies in China showed that goiter might be caused byexcess iodine intake. All subjects were clinically euthyroidbut biochemical tests suggested a spectrum of thyroid dys-function 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 commu-nity-based surveys in China (32) among people from allages in two villages, it was found that goiter due to iodineexcess affected all ages in different geographical locations.These findings strengthen the association between iodineexcess and goiter and hypothyroidism probably due to someautoimmune mechanism and have also been corroboratedby pioneers of research in goiter and IDDs (106).

Studies done in a few countries to analyze the current sta-tus of morphological and functional thyroid abnormalities ina previously iodine-deficient area have shown a number ofthyroid disorders in previously iodine-deficient regions. Thisclearly points to the need for further studies to investigate thechange of thyroid disorders during iodine supplementationprograms. A study in Laos to assess the impact of salt iodin-ation program found a higher median value of urinary iodinebut almost similar goiter prevalence after introduction of io-dized salt as compared to an earlier period (107). A review ofIDD found that in areas with relatively high iodine intake, theincidence rate of hypothyroidism is several fold higher thanthat of hyperthyroidism (108). Even experimental studiesshow that iodine appeared to have a direct toxic effect on thy-roid epithelial cells of rats by showing that a high intake ofiodine accelerated the development of lymphocytic thyroid-itis in BB/W rats (109,110).

Conclusions and Future Perspectives

Evidence from this scientific, systematic review of empiri-cal studies provides enough basis to question the currentdominant paradigm and reveals that opposing research find-ings were ignored. The studies available provide enoughevidence to start a fresh debate on evidence about iodineas the sole factor in causality; magnitude of the problemas a major public health problem universally; effectivenessof universal iodization of salt as a measure that leads todecreasing goiter and other IDDs by itself; and possiblenegative impacts on health itself like increase in hyperthy-roidism, goiter and interaction with other minerals like iron.

The problem of IDDs has increased in many parts of theworld (refer to Table1), and the use of iodization as a strategycan at best claim to prevent further increase than presentprevalence. This review shows that wherever endemic IDD

12 Kotwal et al./ Archives of Medical Research 38 (2007) 1e14does exist it is a problemwith socioeconomic, developmentaland ecological causes. Rarely has it been tackled successfullythrough iodine supplementation alone. Iodine deficiency ofsoil 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 ofendemic goiter. These factors could be interacting at differentlevels in various regions and so local factors of significanceneed to be identified. A program to combat iodine deficiencyshould essentially tackle these issues for a long-term and sus-tainable solution rather than looking at a single interventionof iodized salt alone. Development and ecology thus shouldbe the key areas of focus to reduce IDD. The problem of goi-trogens in food, water and synthetic chemicals and the role ofpolluted water need to be understood and taken care of ratherthan just pushing iodized salt as a panacea for the preventionand control of IDD. The ethics of public health demands thatthe possible negative consequences of interfering with ironmetabolism and thereby enhancing anemia and the increasein goiter due to excess iodine need to be investigated underdiverse conditions before a program for universal iodizationof salt can be initiated.

We propose use of iodized salt in populations where io-dine deficiency is convincingly found to be a major publichealth problem after other causes have been ruled out, andleaving people the choice in other regions. The proponentsof USI say a ban in just the severely affected regions hasproved unsuccessful without analyzing the reasons for thisfailure. There are optional approaches available to deal withthe problem in highly affected areas. Participatory commu-nity programs of iodization of salt or water at a local levelis one that has been tried successfully in countries such asThailand. Supplying subsidized iodized salt in these areasso that it is cheaper than non-iodized salt is another option,which directly addresses the problem without adding thenegative health consequences of the intervention and adher-ing to the concept of primum non nocere.

AcknowledgmentsThe authors are extremely grateful to Dr. Monica Agrawal andMs. Parul for collection of various references from libraries andorganizations spread all over the vast city of New Delhi; Dr. (LtCol) Jyoti Kotwal for her patient reading of several drafts of thisreview and providing insightful comments.

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Goiter and Other Iodine Deficiency Disorders: A Systematic Review of Epidemiological Studies to Deconstruct the Complex WebIntroductionMethodology of the ReviewMagnitude of the Problem and Evidence for MulticausalityIssues in Epidemiology of Goiter and Other IDDsCriteria for Identifying GoiterCriteria for Identifying Regions Endemic for Iodine-Deficiency Disorders

Etiology of Goiter and Other IDDsGoiter, Congenital Hypothyroidism and Endemic Cretinism

Evidence for Benefits of Iodized SaltAssessment of InterventionHarmful Effects of IodineConclusions and Future PerspectivesAcknowledgmentsReferences

Deficiency Iodine

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