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. Saturday 8 June 1985

GOITRE AND IODINE DEFICIENCY IN EUROPE

Report of the Subcommittee for the Study of Endemic Goitre andIodine Deficiency of the European Thyroid Association*

"The scientific community has an obligation to contribute to the eradicationof endemic goitre and iodine deficiency in Europe. With the availableknowledge it is an anachronism that endemic goitre still exists in Europe"-A. QUERIDO, 1981.

Summary The prevalence of endemic iodine-deficiencygoitre in Europe has been reduced in many

areas by the introduction of iodination programmes. Recentreports, however, show that goitre remains a significantproblem and that its prevalence has not decreased in a

number of European countries. Hetzel1 has pointed out thatthe high global prevalence of iodine-deficiency disorderscould be eradicated within 5-10 years by introduction ofan iodised salt programme. The current World Health

Organisation recommendations for iodine intake are between150 and 300 µg/day.2

Methods

The European Thyroid Association (ETA) Subcommittee for theStudy of Endemic Goitre and Iodine Intake in Europe has

documented, as far as possible, prevalence of goitre and iodinestatus in all European countries. This has been done by evaluatingprevious epidemiological studies, by obtaining reports fromindividuals, and by questionnaire. Such methods are subject to anumber of limitations and the following points should be borne inmind in relation to the data reported:

*Subcommittee members: Prof P. C. Scriba, Lubeck (Chairman); Prof C.Beckers, Brussels; Prof H. Bürgi, Solothurn; Prof F. Escobar Del Rey,Madrid; Prof M. Gembicki, Poznan; Prof D. A. Koutras, Athens; Prof B. A.Lamberg, Helsinki; Prof P. Langer, Bratislava; Dr J. H. Lazarus, Cardiff; ProfA. Querido, Leiden; Dr C. Thilly, Brussels; Dr R. Vigneri, Catania.

(a) There is little reliable epidemiological data on the prevalenceof goitre in many European countries; although regional data areavailable these do not necessarily reflect the situation throughoutthe country from which they originate.(b) Most studies have used the standard classification of goitre size

which is associated with a small but significant risk of

overestimation, especially in children.2 Sonographic volumetry hasshown that clinical evaluation by experienced physicians gives afalse-positive rate of thyroid enlargement of approximately 4%.3

(c) Daily urine iodine excretion (widely accepted as a satisfactoryindex of iodine intake) is generally closely correlated with the urineiodine/creatinine ratio. This ratio has been widely used but may beunreliable in areas where protein malnutrition leads to reducedcreatinine excretion.4

(d) Most studies ignore the possible effects of dietarygoitrogens.5,6

Results

Information from each country was reviewed.’°8 Somecountries did not supply any information, while data wasscanty or largely historical from others.Prevalence of goitre (fig 1) is based mainly on regional

figures in specific areas of the various countries; samplenumbers from which these figures are derived range from afew hundred to several hundred thousand. Regionalprevalence is high in the Federal Republic of Germany, Italy,Greece, Turkey, Bulgaria, and Spain. The four Scandinaviancountries have little or no endemic goitre. There is someassociation between high regional prevalence figures and low(<100 g iodine/g creatinine) urine iodine excretion (fig 2);urine iodine excretion is much lower in the Federal Republicof Germany than in Scandinavia. There is no information oniodine prophylaxis in many areas and regional iodinationprogrammes are only in force in some countries. Table Ishows the variation in goitre prevalence and iodine

prophylaxis. Information on goitre prevalence and iodinesupply is given for selected countries below.

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Fig 1-Goitre prevalence.

[ ] denotes regional values.

Austria.-Iodine prophylaxis has been mandatory since 1967.Goitre prevalence has fallen in the northern Tyrol (from 50 to 35%of the entire population and from 46 to 12% of schoolchildren);9 9prevalence in army recruits is 3’3%. Urine iodine excretion,however, remains low in the Tyrol,9 Salzburg," Graz,12 andVienna.13 Thus goitre persists, and the prevalence is unlikely tochange further until the potassium iodide content of the salt isincreased from its present level of 10 mg KI/kg.Belgium.-A low overall prevalence of goitre (1 .8%) has been

noted in over 50 000 male army recruits. 14 Nevertheless, there areregional variations, and surveys have shown marginally low iodineintakes7,15-18 and reduced urine iodine excretion in severalareas.19-23Bulgaria. -Overall prevalence of goitre in 1957 was 19. 2% in a

study of 1 million schoolchildren. Regional prevalence of goitre hassubsequently fallen from 55 to 12% with elimination of goitre inchildren under 15 years.8 The salt is iodinated to a level of 20 mgKI/kg.Czechoslovakia.-Mandatory iodine prophylaxis was introduced

in 1953; goitre prevalence before that time was 50% in males and70% in females,8 with considerable regional variation.24,25 Effectsof low iodine intake were compounded by thiocyanate ingestionfrom brassica plants.26 Goitre prevalence has decreased sharplysince 1953. Nevertheless, cessation of prophylaxis in two districtsfor 7 years (1967-1973, inclusive) led to a 70% fall in urine iodineexcretion and an increase in mean thyrotropin concentration inthose areas.27-29Federal Republic of Germany.-A study of 5.4 million military

recruits showed a high overall goitre prevalence of 15%30 and iodinedeficiency has been found in populations of children and adults.23Level of iodination of salt was variable before 1981 but has now beenstandardised at 20 mg iodine/kg salt.31Finland.-Prevalence of goitre has fallen to less than 6% as the

result of voluntary use of iodised salt (25 mg Nal/kg salt).32,33German Democratic Republic.--Overall goitre prevalence of 12%

has been found in military recruits and low urine iodineconcentrations have been shown in schoolchildren. It is understoodthat mandatory iodine prophylaxis will be introduced in the nearfuture.34Greece.-Endemic goitre remains common with prevalence

figures as high as 50% in some rural areas. Iodised salts areavailable but are more expensive than non-iodised preparations;they are used more by the urban than by the rural population. Urineiodine excretion in Athenians has increased by over 100% sinceiodised salts became available.35,36

Fig 2-Urine iodine excretion.

Values for Belgium and France were derived in part from R. Lagasse, et al(personal communication 1976). Values are Ilg/day or g/g creatinine. f 1denotes regional values.

7/y.&mdash;Many studies have shown a high prevalence of goitre inItaly. 7,34-44 High prevalence figures have been reported fromSicily (25-80% ofschoolchildren), Tuscany (63% ofschoolchildrenand 83% of adults), the Alto Adige, Lazio, Calabria, and theAppenines. Iodised salt is available in some regions although its useremains limited. A very successful water iodination programme hasbeen carried out in Troina (Sicily) with almost complete eradicationof goitre.41The Netherlands.-Endemic goitre is still present in some regions

although iodination programmes have decreased goitre prevalence.(J. W. F. Elte, D. van der Heide, B. M. Goslings, and A. Querido,personal communication, 1983). Iodine prophylaxis is believed tobe inadequate and an increase in the potassium iodide content ofbread salt from 46 to 60 mg KIlkg has been recommended, to give20 lig of iodine in each slice of bread.45 It has also been suggestedthat all household salt should contain 26-2 2 mg KI/kg. Thesemeasures should give a daily iodine intake in the optimum range ofbetween 150 and 300 lAg.Portugal.-Most of the population lives near the coast and there is

no endemic goitre in these areas. However, a high prevalence ofgoitre has been reported from the inland towns of Castel Branco(35% of adult males and 51% of schoolchildren, decreasing to 9%after introduction of iodised salt),46,47 and Portalegre and the twosouthern regions of Baixo Alentejo and Algarve.

4,7,4Spain.-Goitre is endemic in several provinces. A recentsurvey shows a goitre prevalence of 86% in schoolchildren in theLas Hurdes region (south-west of Salamanca) and cretinism alsopersists in this area. Prophylaxis with iodised oil has now beenintroduced in this region49 but a significant problem remains inother areas.Switzerland.-Iodination of salt is mandatory in Switzerland and

the potassium iodide content of salt has been increased

progressively over the last two decades to 20 mg KI/kg. A 1975survey showed a goitre prevalence of 20% in adults aged 20-39 andof 60% in the 60-79 age group; the higher figures in the elderlyreflect inadequate iodination of salt before 1980.’ A recentsurvey of 19-year-old male army recruits showed a goitre prevalenceof 1%. (B. Selz and H. Burgi, personal communication.)

United Kingdom.-Regional prevalence data are insufficient topermit generalised conclusions 55 but there is little evidence thatmajor areas of endemic goitre persist.56,57 The average British dietprovides 323 g iodine a day; milk is the most important individualsource of iodine but is also the most variable. 58

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Discussion

Inevitably the data in this survey are not uniform; somevariations between countries clearly representmethodological differences, incomplete information and, insome instances, failure to use the generally acceptedclassification of thyroid size. Nevertheless, the reportsummarises the status of endemic goitre and iodine intake inEurope up to 1983 and shows that goitre remains a significantproblem. The various European countries fall into four

categories.No Endemic Goitre

This group consists of Norway, Sweden, and Finland(where a highly effective goitre prophylaxis programme hasbeen established) and probably Denmark, Iceland, theUnited Kingdom, and Ireland. These countries define thegoal which could and should be achieved elsewhere in

Europe.

Intermediate

This group comprises Bulgaria, Czechoslovakia, TheNetherlands, and Switzerland. All these countries have hadmajor problems with endemic goitre in the past but haveintroduced effective goitre prevention programmes andiodine intake is now adequate. Epidemiological surveys have

TABLE I-GOITRE, IODINE DEFICIENCY, AND PROPHYLAXIS IN EUROPE

I 1 I 1

Goitre: 0=practically none; + =10%; + + = 10-30% (or more); + + + = riskof endemic cretinism; - = no information.Iodine intake (including prophylaxis): s= sufficient; b=borderline sufficient;i =insufficient; - =no information.Iodine prophylaxis: m=mandatory (or v >90%); v=voluntary; n=none;- =no information.

TABLE 11-IODINE CONTENT OF SALT FROM 17 EUROPEAN COUNTRIES

*As Nal or KI.

shown that goitre persists in some adults in these countriesbut that it is seldom seen in children. Belgium probablybelongs in this group because iodine prophylaxis is voluntaryand urine iodine excretion and balance studies indicate thatiodine -intake is not adequate in all regions. These data,however, are incomplete and further goitre surveys arerequired.Endemic Goitre Persists

It is disturbing that this group contains 12 countries-50%of those in this survey.

Iodine prophylaxis mandatory.-This sub-group consists ofAustria, Hungary, Poland, and Yugoslavia; substantial areasof high goitre prevalence persist despite iodine prophylaxis.Dietary iodine intake remains borderline and analysis of theiodine content of salt from three of these countries gave values

ranging from 4 to 12 mg of iodine/kg salt (see table II).Experience from other countries in which iodine prophylaxisis mandatory has shown that iodine content of salt must be atleast 20 mg/kg to meet the WHO recommended iodine intake(150-300 lig/day) in areas where there is little iodine in othercomponents of the diet.Iodine prophylaxis not mandatory.- This large group consistsof the Federal German Republic, German DemocraticRepublic, Greece, Italy, Portugal, Romania, Spain, andTurkey. Goitre continues to be a major problem in thesecountries, either nationally or regionally, and iodine intakesare so low in some regions that the risk of cretinism persists.Iodine prophylaxis programmes are urgently required inthese countries.

Adequate Information UnobtainableCountries in this group are Albania, France, and the

USSR.

The overall results of this survey give grounds for concernrather than complacency, and point to the need for moreepidemiological studies (including studies of other

goitrogenic mechanisms) and comprehensive iodination

programmes. Such programmes must also be monitored foreffectiveness and to ensure that any iodine-induced

hyperthyroidism receives adequate attention. The qualityand standardisation of iodised salt preparations must also bechecked carefully. In a recent study (H. Biirgi, personal

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communication) the iodine content of 104 commercial saltsamples from 19 European countries was analysed. Theresults showed (table II) that iodine content was significantly(>30%) lower than that intended by the manufacturer inapproximately 30% of samples. Of special relevance to iodinedeficiency, data from the European Society for PaediatricEndocrinology and ETA on iodine deficiency in thenewborn59,6o show transient effects on thyroid function andincreased susceptibility to the toxic effects of acute iodineloads. The increased frequency of elevated thyrotropin levelsin neonatal screening programmes may also be regarded as asensitive index for iodine deficiency.Considerable sums are spent on the diagnosis and

treatment of thyroid diseases by public health systems orinsurance companies in many countries-eg, DM 380 millionon outpatient diagnosis and medical treatment of thyroiddisorders in 1979 in the Federal Republic of Germany.61Much of this money was spent on endemic goitre and itssequelae; prevention is straightforward and cheap.

The Committee gratefully acknowledges the help of Dr W. G. Wood,Lubeck and Dr D. C. Evered, London, in the preparation of this report.

The ETA Subcommittee is grateful for personal communications andreports of work in press to: N. Cabassa, Bolzano; A. Costa, Torino; F. Delange,Brussels; E. Duren, Istanbul; J. W. F. Elte, Leiden; G. Fenzi, Pisa; H. Frey,Oslo; G. Galvan, Salzburg; R. Goebel, Graz; B. M. Goslings, Leiden;R. Gutekunst, Lubeck; G. Hennemann, Rotterdam; F. A. Horster,Dusseldorf; R. Islambekov, Moscow; M. H. Jonckheer, Brussels; P.

Lampertico, Milan; P. Laurberg, Aarhus; E. Limbert, Lisbon; W. Meng,Greifswald; S. M. Milcu, Bucharest; T. Munkner, Copenhagen; F. Peter,Budapest; D. I. W. Phillips, Southampton; A. Pinchera, Pisa; J. Podoba,Bratislava. G. Riccabona, Innsbruck; B. Selz, Solothurn; K. H. Sjoberg,Oskarshamn; P. Smyth, Dublin; L. G. Sobrinho, Lisbon; G. Szilagyi,Budapest; Z. Szybinski, Cracow; I. Urgancioglou, Istanbul; D. van der Heide,Leiden; W. Waldhausl, Vienna.

Correspondence should be addressed to Dr David C. Evered, Secretary-Treasurer ETA, The Ciba Foundation, 41 Portland Place, London WIN4BN.

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ABSENT FACTOR VIII RESPONSE TOSYNTHETIC VASOPRESSIN ANALOGUE

(DDAVP) IN NEPHROGENIC DIABETESINSIPIDUS

NATHAN L. KOBRINSKY

ESTHER D. ISRAELSMARY S. CHEANG

JOHN J. DOYLEJEREMY S. D. WINTERROBERT D. WALKER

AGNES J. BISHOP

Department of Pediatrics and Child Health and the ComputerDepartment for the Health Sciences, Faculty of Medicine,

University of Manitoba, and the Manitoba Cancer Treatment andResearch Foundation, Winnipeg, Manitoba, Canada

Summary To study the effect of 1-deamino-8D-

arginine vasopressin (DDAVP) on the factorVIII response in nephrogenic diabetes insipidus (NDI),0&middot;30 &micro;g/kg DDAVP was given to 2 unrelated NDI patients, 3obligate carriers, and 20 controls. Factor VIII coagulantactivity (FVIIIC) and factor VIII related antigen (FVIIIR:Ag)responses were absent in both NDI patients and weredecreased by approximately 50% in the carriers bycomparison with controls. These results show that the

vasopressin receptor defect in NDI is not confined to thekidney but is equally expressed in other tissues including the,vascular endothelium and hepatic sinusoids, the respectivesites of FVIIIR:Ag and FVIIIC production. A decreasedfactor VIII response may help in identifying carriers infamilies at risk.

Introduction

NEPHROGENIC diabetes insipidus (NDI) is an X-linkeddisorder characterised by resistance of renal tubules to theactions of vasopressin;l if this resistance is due to a more

general defect of the vasopressin receptor, then other end-organ responses may be absent. 1-deamino-8D-argininevasopressin (DDAVP), a synthetic vasopressin analogue,stimulates the release of factor VIII related antigen(FVIIIR:Ag) from vascular endothelium and factor VIIIcoagulant activity (FVIIIC) from liver and other unidentifiedsites in normal subjects.2-4 Therefore, if NDI is due to a moregeneral defect of the vasopressin receptor, the factor VIIIresponse to DDAVP may be absent in NDI patients anddecreased in obligate carriers. To investigate this possibility,FVIIIR:Ag and FVIIIC responses to intravenous DDAVPwere studied in NDI patients and carriers and compared toresponses of healthy control subjects.

Patients and Methods

Patients

2 male patients with NDI, 3 obligate female carriers, and 20healthy female controls were studied. Obligate carriers were

diagnosed by the following criteria: an affected father; an affectedson and at least one other affected relative; or an affected relative andan abnormal water deprivation test.5 Patients and carriers werefrom two unrelated families.

Family A.-Patient 1, a 3-year-old boy of Scottish andUkrainian/Polish descent, presented at 13 months of age with

hypernatraemic dehydration and failure to concentrate urine

(osmolality 62-85 mosmol/kg). He had a lifelong history ofpolyuria, polydipsia, and failure to thrive (weight less than 5thcentile). Diagnosis of NDI was confirmed by inability to

concentrate urine despite a 5% weight loss and increasing serumosmolality during a 5-hour water-deprivation test,’ inability toconcentrate urine after 5 ug of intranasal DDAVP (0 - 05 ml), andabsence of renal tubular acidosis, aminoaciduria, hypercalcaemia,and hypokalaemia. Although the family history for fully expressedNDI was negative, the boy’s otherwise healthy 30-year-old mother(carrier 1) also had a history of polyuria and polydipsia and wasunable to concentrate urine after a 12-hour water-deprivation test(maximum urine osmolality 400 mosmol/kg).Family B.-Patient 2, a 59-year-old French Canadian man, had a

lifelong history of polyuria and polydipsia. He had an extensivefamily history of NDI: 8 male family members over threegenerations were affected. Diagnosis was confirmed by inability toconcentrate urine after 20 lAg of intravenous DDAVP and absence ofother renal or metabolic disorders (see above). His 26-year-olddaughter (carrier 2), although an obligate carrier, was symptom-free. His sister’s 32-year-old daughter (carrier 3) was also symptom-free but had an affected son.Controls.-20 healthy female controls (mean age 29-O-hl6-7 7

years, range 11-57 years) were studied and have been reportedpreviously. 7Approval for the study was obtained from the Committee for the

Use of Human Subjects in Research of the Faculty of Medicine,University of Manitoba. All subjects or their guardians were awareof the experimental nature of the investigations and gave informedconsent in accordance with the Declaration of Helsinki.

Methods

DDA VP infusion.-DDAVP (0 - 30 lAg/kg, maximum dose 24 lAg)was diluted to a final concentration of 0 - 5 5 g/ml in physiologicalsaline and infused intravenously over 20 min. Facial flushing andmild light-headedness were observed in controls and carriers but notin either NDI patient.Blood collection and plasma preparation.-Blood samples were

collected by venepuncture (21-gauge needle) immediately beforeand 1 h after the infusion. Nine parts blood were added to plastictubes containing one part acid citrate (two parts citric acid0’ 1 mmol/1 and three parts equimolar sodium citrate). Platelet-poorplasma was obtained after centrifugation at 2000 g for 10 min at4&deg;C and used fresh or kept frozen at -20&deg;C until tested.Assay methods.-FVIIIR:Ag was assayed by quantitative

immunoelectrophoresis with a commercial monospecific antiserum(’Clottimune’ AHG-associated protein, Behringwerke, Marburg,West Germany).8 FVIIIC was assayed in fresh samples by a one-stage method based on the partial thromboplastin time, in whichfactor VIII-deficient plasma (Pacific Hemostasis, Bakersfield,California) was used as substrate.9 9