MASTER THESIS

Usefulness of personal counseling in patients with well-differentiated thyroid cancer who follow

a low iodine diet because of treatment with radioactive iodine

Author

R.J. Jagersma1

Student number

1883941

Supervisor

Dr. A.N.A. van der Horst-Schrivers, internist-endocrinologist1

Secondary supervisors

Prof. dr. T.P. Links, internist-endocrinologist1

Mrs. L.G. Swart-Busscher, dietician1

Location 1University Medical Center Groningen, Department of Endocrinology, Groningen, The

Netherlands

Period

January 2015 – June 2015

2

TABLE OF CONTENTS

List of abbreviations ....................................................................................................................3

Abstract ......................................................................................................................................4

Samenvatting ..............................................................................................................................5

Introduction ................................................................................................................................6

Methods .................................................................................................................................... 18

Results ...................................................................................................................................... 22

Discussion ................................................................................................................................. 26

References ................................................................................................................................ 29

Appendices ............................................................................................................................... 32

3

LIST OF ABBREVIATIONS

131I radioactive iodine

AMC academic medical center Amsterdam

DBP diastolic blood pressure

DTC differentiated thyroid cancer

LID low iodine diet

NIS sodium iodide symporter

RAIT radioactive iodine therapy

rhTSH recombinant human thyroid stimulating hormone

RIVM Dutch national institute for public health and the environment

SBP systolic blood pressure

rT3 reverse triiodothyronine

T3 triiodothyronine

T4 thyroxine

Tg thyroglobulin

THW thyroid hormone withdrawal

TSH thyroid stimulating hormone

UIE urinary iodine excretion

UMCG university medical center Groningen

WBS whole body scan

WHO world health organization

4

ABSTRACT

Introduction: Patients with differentiated thyroid cancer (DTC) have to follow an low iodine

diet (LID) before radioactive iodine therapy (RAIT). Several studies investigated the duration

and the strictness of the LID, but none of them studied the optimal way of preparing patients for

the LID. The compliance to the LID differs between patients, as the urinary iodine excretion

(UIE) shows a wide variation in patients who all follow the same diet with the same written

instructions. The aim of this study was to evaluate if personal counseling by a dietician should be

standard care for DTC patients who have to follow an LID.

Methods: In this single-center prospective, non-randomized, unblinded study, all patients with

DTC were asked if they would get personal counseling. The group that received personal

counseling was compared with the group who received written instructions (control group). The

primary endpoint was the percentage of DTC patients who reached the goal of UIE < 50 μg/L

after one week of LID. Secondary endpoints were blood pressure and complaints.

Results: 28 patients were included (counseling group n = 13, control group n = 15). Seven out of

ten patients (70%) in the counseling group reached an UIE 50 < µg/L, compared with nine out of

eleven patients (82%) in the control group (p = 0.64). Mean systolic blood pressure (n = 21)

before diet was 133 ± 17 mmHg compared with 121 ± 15 mmHg at day 7 of the diet (p < 0.001).

Patients in the control group (n = 15) had significantly more complaints of dizziness than the

counseling group (n = 11) (resp. 67% versus 27%, p = 0.047). Conclusion: In patients who have to follow an LID for one week before RAIT, personal

counseling does not have an effect on the UIE, in comparison with standard care.

Key words: differentiated thyroid cancer, low iodine diet, personal dietary counseling, urinary

iodine excretion

5

SAMENVATTING

Inleiding: Patiënten met een gedifferentieerd schildkliercarcinoom (DTC) moeten voorafgaand

aan behandeling met radioactief jodium (RAIT) een jodiumbeperkt dieet volgen (LID). In

verschillende studies is de duur en de striktheid van het LID onderzocht, maar in geen enkele

studie werd gekeken naar de optimale manier van voorbereiding voor het LID. Het blijkt dat de

jodiumexcretie in de urine (UIE) erg uiteen loopt bij patiënten die allemaal op dezelfde manier

worden voorbereid; namelijk middels een voorlichtingsfolder. De UIE weerspiegelt de

jodiuminname en er kan dus worden geconcludeerd dat de therapietrouw erg wisselt. Het doel

van dit onderzoek is om te evalueren of persoonlijke begeleiding door een diëtist standaardzorg

zou moeten zijn voor patiënten met DTC.

Methode: In deze gecentraliseerde, prospectieve, niet-gerandomiseerde, niet-geblindeerde

studie, werden alle patiënten met DTC gevraagd of ze persoonlijke begeleiding wilden. De groep

die persoonlijke begeleiding kreeg, werd vergeleken met de groep die enkel de

voorlichtingsfolder ontving (controlegroep). Het primaire eindpunt was het percentage patiënten

dat een UIE < 50 µg/L bereikte, na een week het LID te hebben gevolgd. Secundaire eindpunten

waren bloeddruk en klachten.

Resultaten: Er werden 28 patiënten geïncludeerd, waarvan dertien in de groep met persoonlijke

begeleiding en vijftien in de controlegroep. In de groep met persoonlijke begeleiding bereikten

zeven van de tien (70%) patiënten een UIE < 50 µg/L in vergelijking met negen van de elf

patiënten (82%) in controlegroep (p = 0.64). De gemiddelde systolische bloeddruk (n = 21) was

133 ± 17 mmHg voor de start van het LID en 121 ± 15 mmHg op dag 7 van het dieet (p < 0.001).

Patiënten in de controlegroep (n = 15) hadden significant meer klachten van duizeligheid

vergeleken met de groep met persoonlijke begeleiding (n = 11) (respectievelijk 67% versus

27%, p = 0.047).

Conclusie: Persoonlijke begeleiding bij patiënten die voorafgaand aan RAIT een week lang een

LID moeten volgen, heeft geen effect op de UIE, vergeleken met voorbereiding middels een

voorlichtingsfolder.

Sleutelwoorden: gedifferentieerd schildkliercarcinoom, jodiumbeperkt dieet, persoonlijke

dieetbegeleiding, jodiumexcretie in de urine

6

INTRODUCTION

Epidemiology

Thyroid cancer is the most common malignant endocrine tumor, although compared to other

malignancies it is a rare disease (1). However, in the Netherlands the incidence of thyroid cancer

has increased over the last decades. In 2014 in total 727 patients were diagnosed with thyroid

cancer, compared with 337 patients in 1990. Women were three times more affected than men

(1).

Fig. 1 shows the incidence of the different types of thyroid cancer over the last 25 years and is

based on data from the website of Integraal Kankercentrum Nederland (2). In this figure, thyroid

cancer is divided into four different types: papillary, follicular, medullary and anaplastic type.

The papillary and follicular types are collectively referred to as well-differentiated thyroid

cancers (DTC) and account for 80% of all thyroid cancers. DTC is the main focus of this thesis.

The medullary and anaplastic type includes the remaining 20% of the thyroid cancers (3).

Fig. 1. Incidence of thyroid cancer in the Netherlands. Integraal Kankercentrum Nederland (2)

Prognosis of thyroid cancer

The overall mortality of thyroid cancer is relatively low and has remained stable over the last 25

years, as shown in Fig. 2 (2). From 1990 until 2013, on average 100 patients died per year. The

crude rate (deaths per 100.000 persons per year) is 0.62.

In the Netherlands, there is no specific death rate reported for the DTC category, nevertheless the

10-year survival rate of DTC is 80-95% (4).

7

Fig. 2. Overall mortality of thyroid cancer in the Netherlands. Integraal Kankercentrum

Nederland (2)

Treatment of DTC

The primary treatment of patients with DTC is near-total thyroidectomy and lymph node

dissection on indication (3). After this near-total thyroidectomy, often there is some thyroid

tissue left and patients receive additional therapy with radioactive iodine (131

I); known as

remnant ablation therapy (5).

The primary goal of remnant ablation therapy is to destroy all residual thyroid cells and thereby

reducing the risk of local and distant tumor recurrence (5).

An additional benefit of this therapy is that ablation facilitates a sensitive tumor marker, namely

thyroglobulin (Tg) (5). Tg is a protein only produced by thyroid cells, both normal and

cancerous, and can be measured in the serum. After thyroidectomy and a successful ablation

therapy, Tg in the serum is undetectable. In case of an unsuccessful procedure, resulting in tumor

progression, Tg levels will increase. Finally, a few days to a week after the remnant ablation

therapy, a sensitive whole body scan (WBS) is obtained to assess for additional sites of 131

I-

uptake. Positive spots on the WBS indicate remained thyroid tissue or metastatic tumor.

After thyroidectomy and remnant ablation therapy, a supra-physiologic dose of thyroid hormone

is administered to cause suppression of the thyroid stimulating hormone (TSH). This is

performed in an effort to decrease the risk of DTC recurrence (6,7).

Follow up

Between six to nine months after ablation therapy, the success of the therapy is evaluated. In

every patient a neck ultrasound is performed and Tg is measured. Depending on the risk

stratification, additional measurements are done: stimulated Tg is measured and/or a WBS is

performed. Stimulated Tg measurement means that there is stimulation of TSH by thyroid

hormone withdrawal (THW) or injections of recombinant human TSH (rhTSH). If there are any

thyroid cells remaining, the Tg will rise under influence of TSH.

8

Worldwide, the ablation success is around 80% (8), although this percentage varies depending on

what definition is used; the success rate depends on the definition of ablation success. Ablation

success according to the Dutch thyroid guidelines (3) is:

1) A negative neck ultrasound

2) No visible uptake on the stimulated WBS

3) Stimulated Tg < 1 ng/ml

When remnant ablation therapy is not successful, the patient receives another subsequent 131

I

treatment. Remnant ablation therapy (first treatment) and subsequent treatments are collectively

referred as radioactive iodine therapy (RAIT).

Preparation for remnant ablation therapy

To maximize the ablation success, there are two important aspects in the preparation for remnant

ablation therapy.

High TSH-level

The first aspect, before starting remnant ablation therapy, is to create a high TSH-level (>25

mU/L), because this causes the stimulation of 131

I uptake in the thyroid cells, by up regulating the

sodium iodide symporter (NIS) (see section ‘Rationale of the LID’) (9).

There are two ways to increase TSH. The first method is endogenous; THW, inducing

hypothyroidism. The second way is the administration of rhTSH. An advantage of this method is

that the patient can continue his/her thyroid medication and does not experience symptoms of

hypothyroidism.

Low iodine diet

Another aspect for the preparation for remnant ablation is the low iodine diet (LID) that is

followed by patients for a certain period of time before RAIT.

Iodine

Iodine is naturally present in some foods and added in others. Dietary iodine is 127

I, the only

stable isotope, in contrast to the not stable 131

I, which is used for radiation therapy. The main

dietary sources of iodine in the Netherlands are dairy products (especially milk), non-alcoholic

beverages, cereals (especially bread) and meat(products) (10).

In the Netherlands, in 1928, iodine was added to salt, because of iodine deficiency in the Dutch

population (11). Nowadays bread contains iodized salt and accounts for approximately 40% of

the total iodine intake in the Dutch population (10).

The World Health Organization (WHO) recommends that the daily intake of iodine should be as

follows (12):

- 90 μg for preschool children (0 to 59 months)

- 120 μg for schoolchildren (6 to 12 years)

- 150 μg for adolescents (>12 years) and adults

- 250 μg for pregnant and lactating women

In 2014 the Dutch National Institute for Public Health and the Environment (RIVM) studied the

iodine intake in 3819 individuals (10). The intake was sufficient since the median intake for men

was between 182 and 256 µg/day and for women between 171 and 211 µg/day.

9

Patients who are prepared for remnant ablation therapy are advised to lower their dietary iodine

intake to a maximum of 50 µg per day.

Physiology of iodine in the thyroid (13,14)

Iodine is an essential component for thyroid hormones, which contain 59-65% of iodine. The

thyroid gland consists of follicular cells that produce Tg under the influence of TSH. Tg is the

precursor of thyroid hormones and is stored in the lumen of the follicle. In the stroma around the

follicles are the C-cells that produce calcitonin, which plays a role in the calcium metabolism.

Around 90% of the hormones produced by the thyroid gland consists of thyroxine (T4), around

9% consists of triiodothyronine (T3) and 1% consists of reverse T3 (rT3).

The synthesis of T4 and T3 occurs in 6 major steps:

1. Active transport of iodine across the basement membrane into the thyroid cell

2. Oxidation of iodine and iodination of tyrosyl residues in Tg

3. Coupling of iodotyrosine molecules within Tg to form T3 and T4

4. Proteolysis of Tg with release of free iodothyronines and iodotyrosines

5. Deiodination of iodotyrosines in the thyroid cell, with conservation and reuse of the free

iodine

6. Under certain circumstances, intrathyroidal conversion of T4 into T3

Figure 3 shows the iodine intake and excretion in a healthy individual. In this figure, as an

example, 500 µg iodine is orally ingested and absorbed by the gastrointestinal tract. In the end,

around 485 µg iodine is excreted via urine and only 15 µg via feces. In this way, the urinary

iodine excretion (UIE) reflects the iodine intake.

Fig. 3. Iodine intake and excretion. Gardner et al. (15)

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Rationale of the LID

The exact mechanism how a LID leads to a higher iodine uptake in the remnant is not known. It

is postulated that the NIS plays a crucial role. Iodine is transported from the serum across the

basement membrane of the thyroid cell by the NIS. In this way the thyroid gland is able to

maintain a concentration of free iodine 30 to 40 times as high as in the serum. The mechanisms

of regulation of NIS, based on animal studies, are the following (16-19):

- TSH binds on the TSH receptor and stimulates NIS transcription

- TSH up regulates Tg and higher values of Tg down regulates NIS-transcription

- High iodine concentrations down regulates NIS-expression

A logical conclusion of the last statement is that a low iodine concentration enhances NIS-

expression, but so far this has not been proved in research setting.

More than 70% of the DTC expresses NIS and greater NIS expression is associated with greater

uptake of 131

I (20).

There are a few studies that have looked at 131

I uptake in the thyroid or metastases after LID, but

a major limitation in all studies is the small number of patients (21-23)

One of the first researchers in the field of the LID, was Barakat et al. (21). Eight patients (four

without thyroid disease and four with thyroid diseases as Graves’ disease and goiter) followed an

LID for three days. On each day they received 20-50 µCi 131

I and underwent several tests. The

LID consisted of milk that had been passed at least three times over an anion exchange column

and therefore contained only 2 µg iodine per 100 ml. On day two of the diet, mannitol was given

to induce osmotic dieresis and to intensify and hasten the iodine depletion. The following results

were significantly different on day three of the LID, compared with one day prior to the LID:

decreased plasma iodine concentration, increased thyroid transfer and clearance rates and

increased 24-hour 131

I uptake.

In 1974, Goslings et al. (22) studied seven patients with metastatic follicular carcinoma and in

each patient the 131

I uptake in metastases was measured for four days. From day 5 until day 12,

the patients followed an LID with a restriction of 20-30 g daily (probably a typo). From day 9,

again the 131

I uptake in metastases was measured for four days. The tumor uptake of 131

I from

day 9-12 increased with a factor of 1.79, compared with the uptake from day 1-4, but no

significance level was given. Since the effective half-life (t½) of 131

I increased by factor 1.19, the

LID resulted in the doubling of the tumor dose (factor 2.13).

Maruca et al. (23) studied in 1984 four patients with metastatic DTC. They all followed an

iodine-depletion-regime for 5 days, which consisted of an LID (< 25 µg iodine daily),

hydrochlorothiazide or furosemide, sodium chloride and 3 liters of water. After this, all patients

received 150 mCi of 131

I. In all four patients the iodine-depletion regime resulted in an increase

in total-body radiation and lesion radiation. The increase in lesion radiation, when corrected for

the increase in total-body radiation, was 46%. Again it is not clear whether this difference was

statistically significant.

Literature about the LID

Since 1980 several studies have investigated the role of the LID (Table 1). Several studies

studied several outcomes: UIE, ablation success and the length of the diet.

11

LID and UIE

Goslings et al. (22) showed that the UIE in 7 patients, who had followed the LID for 4 days,

decreased from 122 µg/day before diet to 30 µg/day on the last day of the diet.

The prospective study of Dobrenic et al. (24) showed that the UIE decreases significantly after 2

weeks LID compared with one day prior to LID.

Last, the prospective studies of Maxon et al. (25) and Lakshmanan et al. (26) showed that the

UIE was significantly lower in patients who follow an LID than in patients with a regular diet.

LID and ablation success

In the following 3 all retrospective studies the intervention was LID and the primary endpoint

was ablation success.

In the study of Morris et al. (27) there was a difference in ablation success between a regular diet

and LID, although this was not statistically significant. The limitations of this study were that in

the diet group the UIE was higher, the control group received higher dosage of 131

I and data

about pre-ablation scintigraphy, Tg and TSH-levels were missing.

Another study, performed by Pluijmen et al. (28), showed significantly higher success rates of

ablation after LID. A major limitation of this study was that the patients in the LID-group with

an UIE > 49.4 µg/day were excluded. Furthermore, a group of before 1992 was compared to a

group of after 1992, inducing a historical bias.

In 2012, Yoo et al. (29) studied if a less strict or very strict diet had influence on the ablation

success. The ablation success was respectively 80 and 76%, but this difference was not

statistically significant.

Sohn et al. (30) also looked retrospectively, but compared patients who were successfully ablated

to those who failed. All patients followed the LID for 2 weeks. In the group of successfully

ablated patients (no visible uptake in the neck on WBS + serum Tg <2 ng/mL) 80.5 % had a

urinary iodine concentration < 66.2 µg/gCr (which is the same as UIE < 150 µg/day (31))

compared with 70.3% in the not successfully ablated patients (no significant difference).

Length of the LID

There is still no worldwide consensus about the question if patients should follow the LID for

one or two weeks. An overview of the conclusions of different studies in this field, is given:

- Park et al. (32), 2004, USA: two weeks LID is necessary in patients who get radioiodine

rhTSH scanning in patients taking levothyroxine.

- Tomoda et al. (33), 2005, Japan: two weeks LID is advised.

- Morsch et al. (34), 2011, Brazil: two weeks LID is sufficient instead of three weeks.

- Kim et al. (35), 2011, South Korea: one week of strict LID is sufficient.

- Lee et al. (36), 2014, South Korea: strict LID for one week is sufficient.

Lee et al. (36) performed a retrospective study with 202 patients and showed that one week of

LID is sufficient for adequate preparation. Patients who had followed the LID strictly, the

median UIE was < 50 µg/L both after one and two weeks. The median UIE values from week 1

and 2 did not differ significantly, they however did not look at ablation success.

Dutch guidelines about the LID

The Dutch guidelines (3) recommend an LID before RAIT, but the length of the diet is not

specified. For this reason, a survey was sent to the nuclear medicine department of 20 hospitals

that perform RAIT. The response rate was 55%. Surprisingly, in one hospital the LID is not

12

recommend. The duration of the LID varies from four to fourteen days before the administration

of 131

I. Patients quit with the LID between one and three days after the administration of 131

I.

In the context of preparation, all hospitals send written dietary instructions to the patients. In five

out of eleven hospitals, the physician additionally explains the LID. In three out of eleven

hospitals patients get information from a specialized nurse and also in three hospitals, patients

have contact details from a dietician. In one hospital, the only way of preparation is written

instructions. In the University Medical Center Groningen patients start the LID one week before

administration of 131

I and they receive written dietary instructions with a sample menu and

contact details of the dietician.

Compliance to the LID

Despite written and/or oral instructions, adherence to the LID may be difficult for patients.

Patients can feel anxious to eat and others think the diet is boring or palatable.

In a previous study of van der Horst-Schrivers et al. (37), fifteen patients, who participated in a

study to investigate the efficacy of rhTSH preparation for remnant ablation therapy, followed the

LID for one week and received written dietary instructions. Those patients showed a wide

variation in UIE values (<39 - 144 μg/L), reflecting the difference in compliance to the LID.

In general (38,39) it is well known that compliance is thought to play an important role in

following a diet and personal counseling by a dietician can increase the compliance.

However, very little is written about LID and compliance. Searches on PubMed with the key

words ‘low iodine diet’ and ‘dietician’, ‘personal counseling’, ‘guidance’, ‘compliance’ or

‘explanation’ give no results. Only Moon et al. (40) wrote about knowledge, self-efficacy and

perceived barriers in the LID among thyroid cancer patients.

In this South Korean study 121 female patients aged between 24 and 66 years old who were

waiting for 131

I-ablation were selected to answer a questionnaire with 33 items related to the LID.

It is not clear how preparation for the LID went (written and/or oral instructions). The main

conclusions were that the knowledge about the LID was poor (mean: 4.51 out of 10 points). A

common misconception (in 88% of the participants) was that an LID is the same as a salt

restricted diet.

Another finding was that the respondents showed low-efficacy in restricting foods that were not

allowed on LID. The most significant barriers perceived by patients were that they had not been

well-informed about how to prepare low-iodine menus and that there is no one to prepare low-

iodine meals for them.

At the end, they looked at correlation and they concluded that interest in cooking and dietary life

and self-assessed cooking skills had more influence on the self-efficacy and perceived barriers

than age or level of education.

Side effects of the LID

Some patients develop a hyponatremia during the LID (41), most likely due to the misconception

that the LID is the same as a salt restricted diet. Other side effects are a decrease in blood

pressure and the manifestation of orthostatic hypotension (42). During the LID, patients mention

complaints as dizziness, headache, nausea, increased need of salt and a change in taste.

13

Preparation and informing patients for the LID

As shown in the additional information of Table 1, patients are informed about the LID in very

different ways. Examples of written instructions are a list with permitted and/or prohibited food

and products (with a wide variation in the extent of this list), a sample menu and the contact

details of a dietician. Oral instructions by a dietician can be given via telephone or face-to-face.

Until now, there have been no studies that compare the different ways of preparation

Aim of this study

In conclusion, an LID is prescribed because of the presumed positive influence on the efficacy of

RAIT. Several studies investigated the duration and the strictness of the LID, but none of them

studied the optimal way of preparing/informing patients for the LID. The compliance to the LID

differs between patients, as the UIE shows a wide variation in patients who all follow the same

diet with the same written instructions.

Therefore, the aim of this study is to evaluate if personal counseling by a dietician for DTC

patients who have to follow an LID should be standard care.

The primary endpoint of this study is the percentage of DTC patients who reach the goal of UIE

< 50 μg/L after one week of LID. The group that received personal counseling will be compared

with patients who receive written instructions (control group). The hypothesis is 80% of the

patients who receive personal counseling will reach this target compared with 33% of the

patients who only receive written instructions.

Secondary endpoints are the following:

- Difference in blood pressure before the LID and on day 7 of the LID

- Presence of orthostatic hypotension on day 7 of the LID

- Complaints as dizziness, nausea, headache and increased need of salt before the LID and

on day 7 of the LID

- Taste on day 7 of the LID, compared with the taste before LID

- Development of hyponatremia during the LID

14

Table 1. Summary of literature about the low iodine diet Author Study design N Intervention Length

of diet

131I dose and

preparation

Primary

outcome

Secondary

outcome

Tertiary

outcome

Exclusion Remarks

Maxon

1983(25) USA

Prospective,

non randomized

40 RD (n =21)

vs LID (n = 19) List

1 week Before

diagnostic scanning, THW

UIE: 347 vs

43 µg/g Cr/day (p<0.001)

- - - LID decreases UIE

Lakshmanan 1988(26) USA

Prospective

5 RD vs simple-to-follow LID

4 weeks Routine whole body 131I scan THW

Mean UIE (µg/g Cr) 209 vs 69 (p<0.01)

- - - 2 UIE values > 300 µg/g Cr were excluded. People got instructions 6 wks before start LID, no differences between hypo/euthyroidism.

Morris 2001(27) USA

Retrospective 94 RD (50; ’90-‘96) vs LID (44: ’97-’99) List en telephone

10-14 days

100-200 mCi THW

Ablation success (% neg WBS) 62 vs 68 (NS)

UIE 1 day prior to beginning and last diet day RD: reduction of 23.6% (498.9 µg/L 381.4

µg/L) LID: reduction of 69% (567.7 173.9) No p-value

Dose-response relationship: no significant difference between RD and LID

Not defined UIE only collected in 14 patients High UIE in LID group, higher dosage of I131 in RD group

Pluijmen 2003(28) Netherlands

Retrospective 120 Regular diet (’86-’91)versus

LID + dietician (’92-’98)

4 days Mean 75 mCi Ablation success (Tg < 2 and neg

WBS) 48% vs 65% (p<0.001)

I131 uptake LID: 5.1% vs 3.1% (p<0.001)

26.6 µg/dag vs 158.8 µg/dag (p <0.001 (part

of exclusion criteria)

296: Non-radical surgery/M1 Additional RTx,

TSH < 25 mE/L, LID + UIE > 49.4 µg/day.

In LID group UIE > 49.4 µg/day were excluded (NOT intention to treat). Administered RAI not

provided.

Prestwich 2005(43) UK

Editorial Revision of British Thyroid Association

guidelines

- - Advice to make LID accurate and as simple as

possible

Erythrosine is more restricted in food in the UK than in the

USA

There’s a limited availability and use of

iodized salt in the UK. Avoiding sea salt is unnecessary

Soy milk is recommended in place of cow’s milk

-

15

Author Study design N Intervention Length

of diet

131I dose and

preparation

Primary

outcome

Secondary

outcome

Tertiary

outcome

Exclusion Remarks

Tomoda 2005(33) Japan

Retrospective 252 Restricted (RID, 220) vs low iodine diet (LID one week:

15, 2 weeks: 17) all lists

1 week RID vs 1 and 2 weeks LID

Therapy and scanning

Median UIE (µg/g Cr) RID 124 1 w LID 130 2 w LID 66

(p <0.01, 1-2 weeks LID))

- - - 2 weeks LID advised: Japan is rich in iodine.

Tala Jury 2010(44) Italy

Retrospective 201 THW (15 days before ablation stop T3) vs rhTSH + T4

4 weeks

30-150 mCi THW and rhTSH

Ablation success (% WBS neg): 82.5 vs 88.2 (NS)

UIE (µg/L) 128 vs 139 (NS) Also no significant difference in UIE between

successfully and non-successfully ablated

Rate of ablation was not significantly different, stratifying UIE

by different cutoff.

Distant metastases

When ablation success = % neg WBS + Tg < 1 the difference in UIE in successfully and non-successfully ablated patients was not significant.

Kim 2010(31) South Korea

Prospective 193 24-h UIE (µg/day) vs spot-urine (simple I in

µg/L) and iodine/Cr ratio in µg/g Cr). Spot-urine was collected in a 8-h fasting state.

1 week strict LID

THW I/Cr ratio showed higher correlation

coefficient with 24-h UIE than simple I I/Cr ratio based on spot-urine

- - Drugs containing iodine 3 months prior to ablation

South Korea is iodine rich. Poor status of iodine restriction was said to be > 150 µg/day = 66.2 µg/g Cr

Dobrenic 2011(24) Croatia

Prospective, no comparison

16 UIE 1 day prior LID and after 2 weeks (before 131I)

LID for 2 weeks (list)

24-150 mCi THW

UIE 153 to 76.6 ug/L (p<0.001)

- - Tg < 2µg/L, pos anti-Tg, pos WBS

-

16

Author Study design N Intervention Length

of diet

131I dose and

preparation

Primary

outcome

Secondary

outcome

Tertiary

outcome

Exclusion Remarks

Yoo 2012(29) South Korea

Retrospective 161 Less strict (71, ’04-‘05) vs very strict (90, ’06-’07) lists)

2 weeks 150 mCi THW

Ablation success (Tg < 2 (no TgAb) and no uptake on WBS)

80% vs 76% (NS)

- Missing M1, rhTSH, dosage not 150 mCi

No difference in ablation success, no UIE available

Sohn 2013(30) South Korea

Retrospective 295 Ablated (no visible uptake in the neck on WBS +

serum Tg <2 ng/mL) vs. non-ablated

LID for 2 weeks

30 mCi THW

Proportion of patients with UIE < 66.2 µg/gCr 80.5% vs

70.3% (p = 0.065)

- - Distant metastases, anti-Tg, peak TSH < 30 mU/L at time of ablation

Only PTC, no FTC

Cr = creatinine, LID = low iodine diet, FTC = follicular thyroid carcinoma, NS = non-significant, PTC = papillary thyroid carcinoma, RD = regular diet, rhTSH = recombinant human thyroid stimulating hormone RID = restricted iodine diet, RTx = radiation therapy, Tg = thyroglobulin, THW = thyroid hormone withdrawal, TSH = thyroid stimulating hormone, UIE = urinary iodine excretion, WBS = whole body scan

17

Additional information Table 1

- Maxon: LID include a list of permitted foods, a sample menu and contact details from the dietician.

- Lakshmanan: Written instructions: use of iodized salt, dairy products, eggs and seafood was restricted, check the label for algae

derivatives, all breads for iodates and avoid all red colored foods and medicine + instruction by a registered dietician.

- Morris: Regular: oral dietary instructions via telephone. Not allowed: salt, multivitamin/mineral preparations that include iodine and

seafood, including sushi, shellfish and other fish. Low iodine diet: diet instructions with an ‘allowed’ and ‘not-allowed’ category via

mail or personal handed

- Pluijmen: LID-group received written LID instructions with an ‘allowed’ and ‘not-allowed’ category and are assisted by a dietician

- Tomoda: RID: avoid seaweed, seaweed soup, iodinated eggs and restaurant foods. LID: as RID + all seafood (including fish and

shellfish), chicken, viscera of animals, food and medications containing red food dyes, convenience food.

- Tala Jury: No specific LID was recommended, but patients were advised not to take any iodine-containing drug or iodine-

supplementing preparation

- Dobrenic: LID was explained to the patients + list was sent home. Avoid the following food: iodized salt, sea salt and salty food,

many prepared and/or cured meat (ham, bacon, sausage), all dairy products (milk, cheese, cream, sour cream, yoghurt, butter, ice

cream), egg yolk, commercial bakery products, chocolate, dried fruit, canned vegetables, beans, sea food and sea products, food

containing red food dyes (candies, liqueurs, cocktails), iodine-containing vitamins and food supplements, medications: Betadine,

Rocaltrol 0.5 µg (use 0.25 instead). Also a list with allowed products.

- Yoo: when ablation success is defined as Tg < 1 and neg WBS the success rates are 71.8% and 67.8% (resp. less strict and very

strict) (p-value 0.579). Less strict: no seafood, iodized salt, egg yolk, dairy products, processed meat, instant prepared meals and

multivitamin allowed. Very strict: as above + rice, freshwater fish, spinach and soybean products

- Sohn: Education by specially trained dieticians, list of not allowed and allowed products, they were given a 3-day sample menu

specially designed for patients living in South Korea and contact information for dietary questions.

Not allowed: iodine-enriched salt, sea salt, all fish and sea products, Kimchi made with sea products, dairy products, canned fruits,

fruit cocktails, canned vegetables, food and drugs containing red food dyes, potatoes, convenience food, restaurant food,

multivitamins.

18

METHODS

Study population

In this single-center prospective, non-randomized, unblinded study, all patients, aged above 18

years, diagnosed with DTC, who had to follow an LID for RAIT, were eligible.

Exclusion criteria were patients with renal impairment (eGFR < 30 ml/min/1,73 m2), the use of

amiodarone and preparation with rhTSH. Patients who did not speak or understand the Dutch

language properly were also excluded.

Approval of the study by the Medical Ethics Committee of the University Medical Center of

Groningen in the Netherlands was requested but waved because the purpose of this study was to

evaluate improved quality of medical care and therefore, according to the Dutch Medical

Research Involving Human Subjects Act, no further Institutional Review Board approval was

required.

Data collection

Identifying patients

Patients were identified by attending the weekly thyroid working group and the weekly

radioiodine planning by the coordinating investigator. In the thyroid working group all patients

who had undergone a near-total thyroidectomy because of a DTC were discussed. When the

diagnosis was follicular or papillary carcinoma, the patient had to receive remnant ablation

therapy and was added to the list of the radioiodine planning.

When a patient was thought to be eligible, the principle doctor was asked for permission to

approach the patient. After checking if the patient had received the letter with detailed

information about the radioiodine procedure and the written dietary instructions (appendix A),

the patient got a call and was asked if he/she wanted to get personal counseling for the LID.

Personal counseling group

Personal dietary counseling was performed by the coordinating investigator (with support from a

dietician) and consisted of the following items. First the patient had to fill in a food frequency list

(appendix B) during two ‘normal’ days and was asked to return this. From this food frequency

list, the coordinating investigator together with the dietician calculated the total iodine intake in

micrograms per day and a personalized advice was composed.

Two to six weeks before the RAIT, the patient visited the outpatient clinic for one hour for

counseling (T0). This was a structured consult, containing the following items: information about

the rationale of the LID, explanation of the sample menu, showing the addendum about water

and fruit/vegetables, explanation about (non)-iodized salt (patient received a non-iodized salt jar

to take home), practice to read nutrition labels, personalized advices and start and stop date of the

diet. Also, the patient was asked about complaints and the blood pressure was measured.

In the end, an appointment for telephonic counseling on day 3 of the diet was made and

instructions for 24-hour urine collection (that would take place on day 7 of the diet) were given.

19

Control group

The control group consisted of patients who did not want to get personal counseling for the LID,

In this group, the moment of telephone contact is T0. Those patients got standard care and only

received written dietary instructions for preparation for the LID. All patients collected 24-hour

urine for determination of the UIE.

Variables at T0

For each patient all the variables were collected in a case record form. Table 2 shows the

variables collected at T0. The following items were collected from Poliplus (the digital patient

information system): gender, age, cardiovascular disease in history (defined as hypertension,

heart failure, myocardial infarction, peripheral vascular disease and cerebrovascular accident),

the use of anti-hypertensive drugs and details about the thyroidectomy (collected from histology

and operation reports).

During counseling, patients were asked who prepared the meals at home, the use of some iodine

containing products and complaints. Also, the blood pressure was measured in standing and

supine position. The patients in the control group didn’t have to answer questions, only the most

recent blood pressure (≤ 6 months before T0) was collected from Poliplus.

Table 2. Variables collected at T0 Collected from Poliplus

Gender

Age

Cardiovascular diseases in history

Use of anti-hypertensive drugs

Details thyroidectomy

- Date of surgery

- Histology: papillary or follicular carcinoma

- TNM stage + risk stratification*

- Details about multifocality and extra nodal growth

Collected during counseling

Who prepares the meals at home? (patient or partner)

Use the following products (yes/no) povidone-iodine (Betadine®) soap or shampoo, tincture of

iodine, cough drops, the candy Stophoest®, multivitamins,

homeopathic products

Complaints (yes/no) dizziness, nausea, headache, increased need of salt

Blood pressure in mmHg, in standing and supine position

*according to the 7th edition of the American Joint Committee in Cancer (appendix C)

Variables at T1

Each patient followed the LID for at least seven days and 24-hour urine samples were collected

on day 7. One day after urine collection, all patients came to the hospital, either to get the RAIT

(100-150 mCi) or the pre therapy scan (1 or 2 mCi). This day is referred as T1.

On T1 the patient delivered the collected urine, got blood tests and went to the endocrinology

ward where the coordinating investigator asked about complaints and taste and measured blood

pressure. An overview of the variables, collected at T1, is given in Table 3.

The reference range for sodium in blood is 135 – 145 mmol/L, so hyponatremia is defined as a

blood sodium level below 135 mmol/L. The sodium in the 24-hour urine is presented in

mmol/24h (reference range 100 – 250 mmol/24h). The total salt intake per day was calculated by

dividing the sodium in the urine (in mmol/24 h) by 17.124. The reference range from iodine in

20

the urine is 39 – 353 µg/L. Another item that was collected at T1, was if the patient had received

remnant ablation therapy or subsequent 131

I treatment.

During intake all patients (counseling and control group) were asked about complaints and their

ability to distinguish different tastes. To evaluate the presence of orthostatic hypotension, the

blood pressure was first measured in standing position and then in supine position. Orthostatic

hypotension is defined as a fall in SBP of at least 20 mmHg and/or a fall in DBP of at least 10

mmHg.

Table 3. Variables collected at T1 Collected from Poliplus

Blood values Sodium (mmol/L)

24-hour urine

Total volume in L

Sodium (mmol/24h)

Iodine (µg/L)

Total salt intake per day

Remnant ablation therapy or subsequent 131I treatment and dose in mCi

Collected during intake

Complaints (yes/no) dizziness, nausea, headaches, increased need of salt

How is your ability to distinguish different tastes?

Blood pressure in mmHg, in standing and supine position

Laboratory

The urine of the patients was sent to the Academic Medical Center (AMC) in Amsterdam, where

the Kolthoff-Sandell reaction with persulfate digestion was used to measure the iodine levels.

Fig. 4 shows the reference range of UIE in µg/L of the AMC, based on the iodine levels in the

urine of 410 persons from 0-70 years. The reference range of UIE for men is <39 – 304 µg/L and

for women this is <39 – 217 µg/L. The lower beam shows the international classification of

iodine nutrition status, based on the article of Pearce (45).

Fig. 4. Reference range of UIE in µg/L, in the Academic Medical Center

The primary endpoint of this study is the percentage of DTC patients who reach moderate iodine

deficiency. The definition of moderate iodine deficiency, according to the WHO classification, is

an UIE < 50 µg/L. As the volume of 24-hour urine varies a lot in patients, the second definition

21

of moderate iodine deficiency we used, was: UIE < 50 µg/L or UIE < 50 µg/day. Patients who

didn’t collect urine, were excluded for final analysis.

Evaluation of the personal counseling and the diet

A few weeks after treatment with radioiodine, patients received a call and were asked to answer

the following questions.

Questions for patients who received personal counseling

1. a. Did you get new information during the personal counseling? Yes / no

b. If yes, what kind of information was the most useful?

2. On a scale of 1 to 10, how useful was the personal counseling for you?

Useless – 1 2 3 4 5 6 7 8 9 10 – Useful

3. Which part of the personal counseling was the most useful?

a. Face-to-face counseling at the outpatient clinic

b. Telephonic counseling on day 3 of the LID

Questions about the diet (for all patients: counseling and control group)

4. Before starting the diet, did you think you would maintain the diet for 1 week?

No – 1 2 3 4 5 6 7 8 9 10 – Yes

5. On a scale of 1 to 10, how easy was it to stick to the diet?

Difficult – 0 1 2 3 4 5 6 7 8 9 10 – Easy

6. a. On a scale of 1 to 10, how much did the LID differ from you normal diet?

Little - 1 2 3 4 5 6 7 8 9 10 – A lot

b. What difference was the most important to you?

7. On a scale of 1 to 10, how was your compliance during the diet?

Low – 1 2 3 4 5 6 7 8 9 10 – High

Statistical analysis

The sample size was based on the difference in rates of moderate iodine deficiency (UIE < 50

µg/L) between the personal counseling group and the control group. We assumed that the rate of

moderate iodine deficiency in the personal counseling group would be 80% and the rate of

moderate iodine deficiency in the control group 33% (based on the UIE values from the study of

van der Horst-Schrivers et al. (37)). We determined that an enrollment of 26 patients with no

missing data would provide a power of 90%, with a two-sided p-value of 0.05.

The following values were used to fill in the formula in Fig. 5: Pa = 0.33, Pb = 0.8, Zα = 1.96

and Zβ = 1.28.

Fig. 5. Formula used to calculate the sample size.

Data are descriptive and presented as number (percentage), mean ± standard deviation in case of

normal distributed variables or median [interquartile range] in case of not normally distributed

variables. Differences between groups were analyzed using t-tests, Mann-Whitney U tests, Chi

square tests, Fisher’s exact tests or McNemar’s tests, depending on the type and the normality of

the data. A p-value of <0.05, was considered to be statistically significant. All data were

analyzed with IBM®

SPSS® Statistics version 22.

22

RESULTS

From February 2015 until May 2015, 36 eligible DTC patients were identified (Fig. 5). Six

patients were excluded: two patients did not want to get personal counseling or collect urine, two

patients were prepared by rhTSH, one patient had no adequate Dutch language proficiency and

one did not want to travel to the hospital again.

Finally, thirty patients participated in the study. Fourteen patients got personal counseling, one

patient forgot to collect urine, so thirteen patients remained. In the control group, which

contained sixteen patients, there was one patient who did not collect urine, so fifteen patients

remained. Due to logistic reasons at the laboratory at the AMC, the UIE was not available in

three patients in the counseling and in four patients in the control group, although all these seven

patients collected 24-hour urine. Therefore 22 patients remained for the final analysis.

Fig. 5. Flow-chart of the eligible DTC patients

23

Patients

Table 4 shows the baseline characteristics of the 22 patients, who were in the final analysis. As

can be deduced from this table, patients in the counseling group had an average age of 57 ± 14

years, compared to 54 ± 19 years for patients in the control group (p = 0.66). As well the

counseling, as the control group consisted of six females (p = 1.00). In the counseling group 5

patients (50.0%) received ablation therapy and 5 (50.0%) received subsequent treatment,

compared with 6 patients (54.5%) and 5 patients (45.5%) in the control group who received

ablation therapy and subsequent treatment respectively (p = 1.00). The histology was papillary

thyroid carcinoma in eight patients (80.0%) in the counseling group and seven patients (63.3%)

in the control group (p = 0.64). Analysis of the risk stratification revealed a significant difference

between the two groups (p = 0.03): in the counseling group, seven out of ten patients (70.0%)

were classified as low risk, where as two out of eleven patients in the control group were

classified as low risk.

Table 4. Baseline characteristics of patients with known UIE values Characteristic Counseling group

(n = 10 )

Control group

(n = 11)

p-value

Age in years 57 ± 14 54 ± 19 0.661

No. of females 6 (60.0) 6 (54.5) 1.002

Purpose of RAIT

Ablation

Subsequent treatment

5 (50.0)

5 (50.0)

6 (54.5)

5 (45.5)

1.002

Histology

Papillary Follicular

8 (80.0) 2 (20.0)

7 (63.3) 4 (36.4)

0.642

Risk stratification

Low

High

7 (70.0)

3 (30.0)

2 (18.2)

9 (81.8)

0.032

Data are presented as mean ± standard deviation or number (percentage). RAIT = radioactive iodine therapy

Urinary iodine excretion

According to the first definition of moderate iodine deficiency (UIE < 50 µg/L) seven out of ten

patients (70.0%) in the counseling group reached this goal, compared with nine out of eleven

patients (81.8%) in the control group (p = 0.64). According to definition 2 of moderate iodine

deficiency (UIE < 50 µg/L or UIE < 50 µg/day) eight out of ten patients (80.0%) in the

counseling group had success, compared with nine out of eleven patients (81.8%) in the control

group (p = 1.000).

The median UIE was 39 [39-48.5] µg/L for all patients. In the counseling group, the median UIE

was 39 [39-56.5] µg/L and in the control group this was 39 [39-40] µg/L (p = 0.61). Table 5

provides an overview of this data.

Table 5. Difference in UIE between the counseling and control group Endpoint Counseling group

(n = 10 )

Control group

(n = 11)

p-value

UIE < 50 µg/L 7 (70.0) 9 (81.8) 0.64

UIE < 50 µg/L or UIE < 50 µg/day 8 (80.0) 9 (81.8) 1.00

UIE in µg/L 39 [39-56.5] 39 [39-40] 0.61

Data are presented as number (percentage) or median [interquartile range]. UIE = urinary iodine excretion

24

Secondary endpoints

Blood pressure

Table 6 shows the data of blood pressure and complaints before the LID (T0) and on day 7 of the

LID (T1). In total, 21 patients had a known blood pressure at T0 and T1 (eleven patients in the

counseling group and ten patients in the control group). Mean systolic blood pressure (SBP) at

T0 was 133 ± 17 mmHg compared with 121 ± 15 mmHg at T1. The mean difference was 12 ± 13

mmHg (p < 0.001). Mean diastolic blood pressure (DBP) at T0 was 80 ± 8 mmHg compared

with 77 ± 9 mmHg at T1 (p = 0.23).

None of the 26 patients, with known standing and supine blood pressure at T1, had orthostatic

hypotension.

Table 6. Blood pressure and complaints on T0 and T1 Endpoint T0 T1 p-value

Blood pressure (n = 21)

SBP in mmHg

DBP in mmHg

133 ± 17

80 ± 8

121 ± 15

77 ± 9

<0.001

0.23

Complaints (n = 11)

Dizziness

Nausea

Headache

Increased need of salt

1 (9.10)

3 (27.3)

-

2 (18.2)

3 (27.3)

4 (36.4)

3 (27.3)

7 (63.6)

0.63

1.00

0.25

0.06

Data are presented as number (percentage) or mean ± standard deviation. T0 = before the low iodine diet, T1 = day 7

of the low iodine diet, SBP = systolic blood pressure, DBP = diastolic blood pressure

Complaints

Complaints at T0 and on T1 were compared in eleven patients of the counseling group and are

presented in Table 6. Dizziness was present in one patient (9.1%) at T0 and three patients

(27.3%) at T1 (p = 0.63). Three out of eleven patients (27.3%) had nausea on T0, compared with

four out of eleven (36.4%) at T1 (p = 1.00). None of the patients complained about headache at

T0, but three patients (27.3%) did on T1 (p = 0.25). On T0, two patients (18.2%) had increased

need of salt, compared with seven patients (63.6%) on T1 (p = 0.06).

We also looked at differences in complaints at T1 between the counseling group (n = 11) and the

control group (n = 15). The patients in the control group had significantly more complaints of

dizziness than the counseling group (ten out of fifteen (66.7%) versus three out of eleven

(27.3%), p = 0.047). Nausea was present in four out of eleven (36.4%) patients in the counseling

group vs. five out of fifteen (33.3%) in the control group (p = 1.00). Three out of eleven (27.3%)

of the counseling group complained about headache, versus four out of fifteen (26.7%) in the

control group, (p = 1.00). At last, seven out of eleven (63.3%) of the patients in the counseling

group had an increased need of salt, compared with six out of fifteen (40.0%) in the control

group (p = 0.23)

There was no significant difference in the salt intake between the two groups. The mean salt

intake in the counseling group was 4.3 ± 1.5 g compared to 3.9 ± 1.4 g in the control group (p =

0.43).

25

On T1, 26 patients answered the question: ‘How is your ability to distinguish different tastes

now, compared with before you have started the LID?’ One patient (3.8%) answered ‘much

worse’, four patients (15.4%) answered ‘worse’, twenty (76.9%) said ‘the same’ and one (3.8%)

said ‘better’.

Development of hyponatremia

Three out of 26 patients (11.5%) had a blood sodium concentration of less than 135 mmol/L at

T1, respectively 132, 132 and 134 mmol/L. Two patients received personal counseling and one

was in the control group. All three (100%) were female compared to twelve out of twenty-three

(52.2%) in group who did not develop a hyponatremia (p = 0.238). All three were aged above 60

years (100%) compared to seven out of twenty-three (30.4%) (p = 0.046).

Evaluation of the personal counseling

Nine patients answered the questions for evaluation of the personal counseling. Seven patients

got new information during the counseling. This is what patients said: ‘There are more

possibilities than I thought there would be’, ‘I got more detailed information about products’, ‘I

received the address of a website that shows the iodine concentrations in several products’, ‘It

was helpful to compose a personal menu, with special focus on the restriction of quantities of

some products’.

Eight patients rated the usefulness of the LID as a 7 or higher (once a 7, four times a 8, twice a 9

and once a 10). One patient gave a 3, because he had already followed the diet twice.

The face-to-face counseling in the outpatient clinic was the most useful part, according to seven

patients. Two patients believed that the usefulness of the face-to-face and the telephonic

counseling is equal.

In total, eighteen patients were asked about the diet (nine patients in the counseling and nine

patients in the control group).

Seventeen patients were confident to maintain the LID for 1 week. One patient was totally not

confident. On the question ‘On a scale of 1 to 10, how easy was it to stick to the diet?’ five

patients answered it was difficult, and thirteen patients thought it was easy (the most given

answer was 8). When we divided the possible answers in a group of 1 to 5 (difficult) and 6 to 10

(easy), there was no significant difference between the counseling and the control group.

The answers on the question ‘On a scale of 1 to 10 (1 is a little and 10 is a lot), how much did the

LID differ from you normal diet?’ were like this: seven patients rated a 5 or below and thought

the two diets differed a little. Eleven patients rated a 6 or higher and the most given answer was 8

(seven times). The most important differences that were mentioned, were: salt less bread, a

restriction in quantities, food tasted faint, the LID is a less varied diet, the need to make pasta

sauce by yourself, not all ready-made food was allowed, not all the vegetables I normally eat, are

allowed, all day I am conscious of what I eat, the products I normally eat (i.e. fish and wine) are

not allowed.

When the patients were asked ‘On a scale of 1 to 10, how was your compliance during the diet?’

all patients answered an 8 or higher, representing a high compliance. The most given answer was

a 10.

26

DISCUSSION

This is the first prospective study that compared two different ways of preparation for the LID.

However, we did not find a significant difference between the counseling and the control group

in the percentage of patients that reached the goal of UIE < 50 ug/L after one week of LID.

Although no other studies have investigated the effect of personal counseling on the UIE in

comparison to written instruction, there are several studies evaluating the UIE after an LID, and

these studies all used different ways of informing patients.

The mean UIE (in µg/L) in our study group was comparable with the results in the study of Kim

et al. (31). In this study 193 DTC patients in South Korea, were educated and encouraged by

specially trained nurses. The patients followed an LID for one week and the median UIE at day 7

of the diet was 40 µg/L.

A slightly higher UIE was found in another study of Kim et al. (35). Nineteen patients received

education by specially trained nurses and dieticians for two hours before the start of the LID.

They also received written dietary instructions with a list of (not) allowed products and a 3-day

sample menu, specially designed for patients living in South Korea. After 1 week of LID, the

mean UIE was 52 µg/L.

In the study of Lee et al. (36) a mean UIE of 28 µg/L in 202 patients who followed the LID for

one week, was found. Preparation was the same as in the previous mentioned studies. Though, it

has to be said that seven patients were excluded because their UIE level was above 479 µg/day

or because they showed an UIE level > 50 µg/L after two weeks of LID, while their UIE level

was < 50 µg/L after one week.

In the study of Morris et al. (27), UIE was determined only in seven patients who had followed

the LID for ten to fourteen days. Preparation consisted of a list with written instructions and the

nuclear medicine department called the patient to clarify the instructions. The mean UIE was 174

µg/L; much higher compared to the patients in our study.

A very low UIE value was found in the study of Pluijmen et al. (28). In total, 416 patients were

treated for DTC and after exclusion, 120 patients were left for statistical analysis. 61 patients had

not received the LID. The remaining 59 patients got written dietary instructions and were

assisted by a dietician, however it was not specified in what way. After 4 days of LID, the mean

UIE was 27 µg/day. However, it should be noted that patients with an UIE > 49.4 µg/day were

excluded for statistical analysis, and it is not clear how many of the 296 excluded patients were

excluded for this reason.

Although it would seem logical to assume that personal counseling leads to a lower UIE after 7

days, we cannot conclude this in the current study. Another hypothesis that came up, is that

personal counseling might be able to shorten the LID. This hypothesis derived from the finding

that one study patient, who followed the LID for only 5 days, had an UIE < 39 µg/L. This patient

was excluded for final analysis because the length of the LID was too short. It remained unclear

at what moment the patient exactly reached an UIE < 39 µg/L. In the study of Kim et al. (35), the

UIE was measured daily. There was seen a major decrease in UIE in the first day: the mean UIE

before starting the LID was 800 µg/L, compared to 200 µg/L on day 1 of the LID. In future

studies the UIE should be measured every day to answer the question if personal counseling

before starting the LID can shorten the length of the diet.

27

We found a significant decrease in the SBP during the diet. This may be caused by a lower

intake of sodium, a phenomenon that is described in the literature (42). The mean salt intake of

the study patients on T1, was lower compared to the known median intake of the Dutch

population, which is 9.8 g/day for men and 7.4 g/day for women (46). Unfortunately, no data of

salt intake of the study patients before start of the LID were available, so no comparison could be

made.

The difference in SBP is more than would be expected from literature (42). This might be caused

by the manual way of measuring. The coordinating investigator could be influenced by the

expectation of a lower blood pressure at T1, compared to T0.

The objective finding of a low mean salt intake on T1, is supported by the finding that patients

experience an increased need of salt on T1, compared to T0.

Furthermore, on T1, we found a lower mean salt intake in the control group than in the

counseling. Possibly, patients in the counseling group are more conscious of the fact that the LID

is not the same as a low salt diet.

Last, patients from the control group had statistically significant more complaints of dizziness

than the counseling group. The lower salt intake in the control group may have contributed to

this finding, although the difference in salt intake was not statistically significant.

In our study, three patients developed a hyponatremia. Al Nozha et al. (41) reviewed various

case reports about hyponatremia after LID and concluded that an older age (> 65 years) is a risk

factor, this is comparable to our findings. Other risk factors that were mentioned, are the use of

thiazide diuretics, the use of SSRI’s, the use of pain medications, prolonged low-sodium diet,

prolonged hypothyroid state and multiple metastases (lung and brain). None of those risk factors

could be evaluated in the current study, because of lacking data.

There are several limitations in this study. First, there might be a bias because of the awareness

of participating in a study. All patients knew the UIE would be measured on day 7 of the diet and

this awareness might have led to a higher compliance to the LID. During evaluation of the diet, it

became clear that all patients thought they were very compliant. Secondly, this study is not

randomized, as the patients have chosen whether they wanted personal counseling or not.

Also, at the time of statistical analysis, not al UIE values were available, so the level of power

we achieved is lower than 90%. Another point of attention is the possibility of inadequate urine

collection and therefore the real UIE values might be a bit higher.

A final limitation has to do with the detection rate of the laboratory. The lower reference

detection limit is 39 µg/L. In all probability, the real values are lower than this. When looking at

the second definition of moderate iodine deficiency (UIE < 50 µg/L or UIE < 50 µg/day) the UIE

per day might as well be lower than calculated in this study.

The findings of this study have several clinical implications. First, in response to the feedback of

the patients, suggestions for improvement of the written dietary instructions have already been

made. A point that has to be clear to patients is that the LID is not the same as a salt restricted

diet. When salt intake remains adequate during LID, this could possibly prevent complaints of

dizziness. In patients over the age of 60 years, physicians should pay attention to the blood

sodium. Based on the findings in this study, personal counseling will not be added to standard

care. Nevertheless, the personal counseling was rated as very useful by the majority of the study

28

patients and almost everybody said they received new information. Thereby, personal counseling

could higher the confidence and thereby improve the quality of life during the LID, although we

did not evaluate the quality of life.

In summary, we conclude that in DTC patients who have to follow an LID for one week before

RAIT, personal counseling does not have an effect on the UIE, in comparison with standard care.

Future randomized studies, that evaluate the effect of personal counseling on the quality of life

during LID and optimal duration, should be performed. For the evaluation of the optimal

duration the UIE should be measured daily.

29

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van Nederlandse kinderen en volwassenen. Resultaten van de voedselconsumptiepeiling 2007-2010. 2012.

(11) Geurts M, Verkaik-Kloosterman J. RIVM Briefrapport 2014-0054. De jodiuminname van de

Nederlandse bevolking na verdere zoutverlaging in brood. 2014.

(12) Assessment of iodine deficiency disorders and monitoring their elimination: a guide for programme

managers.World Health Organization; 2007.

(13) Greenspan F, Strewler G. Basic & Clinical Endocrinology. 5th ed. Stamford: Appleton & Lange; 1997.

(14) Porterfield S, White B. Endocrine Physiology. 3rd ed. Philadelphia: Mosby Elsevier; 2007.

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2011.

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Endocr Rev 2014;35(1):106-149.

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characterization, regulation, and medical significance. Endocr Rev 2003;24(1):48-77.

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symporter in the intestine. Vitam Horm 2015;98:1-31.

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post-transcriptional regulation of the intestinal Na+/I- symporter. J Physiol 2012;590(Pt 23):6013-6026.

(20) Kogai T, Brent GA. The sodium iodide symporter (NIS): regulation and approaches to targeting for cancer

therapeutics. Pharmacol Ther 2012;135(3):355-370.

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patients with differentiated thyroid cancer - initial results. Radiol Oncol 2011;45(3):189-195.

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ablation of thyroid remnants. Clin Nucl Med 1983;8(3):123-126.

(26) Lakshmanan M, Schaffer A, Robbins J, Reynolds J, Norton J. A simplified low iodine diet in I-131 scanning

and therapy of thyroid cancer. Clin Nucl Med 1988;13(12):866-868.

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on ablation rates in radioiodine treatment of thyroid carcinoma. Thyroid 2001;11(8):749-755.

(28) Pluijmen MJ, Eustatia-Rutten C, Goslings BM, Stokkel MP, Arias AM, Diamant M, et al. Effects of low-iodide

diet on postsurgical radioiodide ablation therapy in patients with differentiated thyroid carcinoma. Clin Endocrinol

(Oxf) 2003;58(4):428-435.

(29) Yoo ID, Kim SH, Seo YY, Oh JK, O JH, Chung SK. The success rate of initial (131)i ablation in differentiated

thyroid cancer: comparison between less strict and very strict low iodine diets. Nucl Med Mol Imaging

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(30) Sohn SY, Choi JY, Jang HW, Kim HJ, Jin SM, Kim SW, et al. Association between excessive urinary iodine

excretion and failure of radioactive iodine thyroid ablation in patients with papillary thyroid cancer. Thyroid 2013

;23(6):741-747.

(31) Kim HK, Lee SY, Lee JI, Jang HW, Kim SK, Chung HS, et al. Usefulness of iodine/creatinine ratio from spot-

urine samples to evaluate the effectiveness of low-iodine diet preparation for radioiodine therapy. Clin Endocrinol

(Oxf) 2010;73(1):114-118.

(32) Park JT,2nd, Hennessey JV. Two-week low iodine diet is necessary for adequate outpatient preparation for

radioiodine rhTSH scanning in patients taking levothyroxine. Thyroid 2004;14(1):57-63.

31

(33) Tomoda C, Uruno T, Takamura Y, Ito Y, Miya A, Kobayashi K, et al. Reevaluation of stringent low iodine diet

in outpatient preparation for radioiodine examination and therapy. Endocr J 2005;52(2):237-240.

(34) Morsch EP, Vanacor R, Furlanetto TW, Schmid H. Two weeks of a low-iodine diet are equivalent to 3 weeks

for lowering urinary iodine and increasing thyroid radioactive iodine uptake. Thyroid 2011;21(1):61-67.

(35) Kim HK, Lee SY, Lee JI, Jang HW, Kim SK, Chung HS, et al. Daily urine iodine excretion while consuming a

low-iodine diet in preparation for radioactive iodine therapy in a high iodine intake area. Clin Endocrinol (Oxf) 2011

;75(6):851-856.

(36) Lee M, Lee YK, Jeon TJ, Chang HS, Kim BW, Lee YS, et al. Low iodine diet for one week is sufficient for

adequate preparation of high dose radioactive iodine ablation therapy of differentiated thyroid cancer patients in

iodine-rich areas. Thyroid 2014;24(8):1289-1296.

(37) van der Horst-Schrivers AN, Sluiter WJ, Muller Kobold AC, Wolffenbuttel BH, Plukker JT, Bisschop PH, et al.

Recombinant TSH stimulated remnant ablation therapy in thyroid cancer: the success rate depends on the definition

of ablation success--an observational study. PLoS One 2015;10(3):e0120184.

(38) Glanz K. Dietitians' effectiveness and patient compliance with dietary regimens. A pilot study. J Am Diet

Assoc 1979 Dec;75(6):631-636.

(39) Rosal MC, Ebbeling CB, Lofgren I, Ockene JK, Ockene IS, Hebert JR. Facilitating dietary change: the patient-

centered counseling model. J Am Diet Assoc 2001;101(3):332-341.

(40) Moon JA, Yoo CH, Kim MH, Lee SM, Oh YJ, Ryu YH, et al. Knowledge, Self-Efficacy, and Perceived

Barriers on the Low-Iodine Diet among Thyroid Cancer Patients Preparing for Radioactive Iodine Therapy. Clin

Nutr Res 2012;1(1):13-22.

(41) Al Nozha OM, Vautour L, How J. Life-threatening hyponatremia following a low-iodine diet: a case report and

review of all reported cases. Endocr Pract 2011;17(5):e113-7.

(42) He FJ, Li J, Macgregor GA. Effect of longer-term modest salt reduction on blood pressure. Cochrane Database

Syst Rev 2013;4:CD004937.

(43) Prestwich RJ, Gerrard GE. Low-iodine diet before radioiodine uptake scans or therapy--flawed advice to U.K.

patients. Clin Oncol (R Coll Radiol) 2005;17(2):73-74.

(44) Tala Jury HP, Castagna MG, Fioravanti C, Cipri C, Brianzoni E, Pacini F. Lack of association between urinary

iodine excretion and successful thyroid ablation in thyroid cancer patients. J Clin Endocrinol Metab 2010;95(1):230-

237.

(45) Pearce EN. National trends in iodine nutrition: is everyone getting enough? Thyroid 2007;17(9):823-827.

(46) van Rossum C, Buurma-Rethans E. RIVM Rapport 350050007/2012. Zoutconsumptie van kinderen en

volwassenen in Nederland. Resultaten uit de Voedselconsumptiepeiling 2007-2010. 2012.

32

APPENDICES

A. Written dietary instructions

Inleiding

U wordt (binnenkort) opgenomen voor een behandeling met radioactief jodium. Ter

voorbereiding op uw ziekenhuisopname moet u een aantal dagen een jodiumbeperkt dieet volgen.

Het volgen van dit dieet is noodzakelijk om:

• nauwkeurig te kunnen meten of er, na uw

schildklieroperatie, nog opname is van radioactief jodium door eventueel achtergebleven

schildklier- weefsel en/of tumorweefsel;

• het effect van uw behandeling met radioactief jodium te

verhogen.

Als uw voeding teveel jodium bevat, remt dit de opname van

radioactief jodium.

U begint daarom één week voor uw ziekenhuisopname met het dieet. Tijdens uw verblijf

in het ziekenhuis moet u het dieet nog enkele dagen voortzetten.

Voorafgaand aan het dieet Voordat u met het dieet begint, is het belangrijk dat u weet dat:

• In bijna alle voedingsmiddelen van nature een bepaalde

hoeveelheid jodium zit.

• Er ook voedingsmiddelen zijn, waar in de fabriek jodiumhoudend zout aan is toegevoegd. De

fabrikant is dan wettelijk verplicht dit op de verpakking aan te geven met:

- gejodeerd keukenzout, jodiumhoudend keuken zout of Jozo-zout

­ broodzout, gejodeerd broodzout.

33

Brood bijna altijd gejodeerd zout bevat, ook wel broodzout genoemd. Daarom mag u ook geen brood

van de bakker of uit de supermarkt gebruiken. U mag wel zoutloos brood gebruiken (van

de bakker of zelf gebakken) of zelfgebakken brood van Koopmans broodmix.

Broodzout zit ook in andere producten die de bakker

verkoopt, zoals beschuit, crackers, knäckebröd en koek. Ook deze producten van de bakker mag

u niet gebruiken. Fabrieksmatig bereide beschuit, crackers, knäckebröd en koek mag u wel

gebruiken. Raadpleeg voor de zekerheid steeds de verpakking.

• Zeezout en dieetzouten van nature ook kleine hoeveel­

heden jodium bevatten.

• Ook de rode kleurstof E127 (erythrosine) aan voedings­ middelen kan worden toegevoegd.

Deze rode kleurstof E127 is het enige E­nummer dat jodium bevat. De kleurstof kan onder

andere worden toegevoegd aan rode vruchtenconserven, limonade(siroop), puddingsaus,

vruchten op sap en enkele snoepsoorten.

• Er behalve in voeding ook jodium kan voorkomen in medicijnen, zeep, shampoo, crème en zalf.

Voorbeelden hiervan zijn: betadine zeep, betadine shampoo, jodium­ tinctuur, hoestdrank en

stophoest.

• Als u medicijnen (hieronder vallen ook vitamine­ preparaten, homeopatische­ en

reformproducten) gebruikt, deze mogelijk ook jodium bevatten. Vraagt u dit na bij uw arts of

apotheker. Een multivitamine­

mineralenpreparaat bevat bijvoorbeeld per tablet veel jodium. Tijdens het volgen van het

jodiumbeperkt dieet, mag u dit preparaat dan ook niet gebruiken.

Niet toegestaan tijdens het jodiumbeperkt dieet zijn dan ook:

• Voedingsmiddelen waarin de onderstaande zouten zitten:

- gejodeerd keukenzout;

- jodiumhoudend keukenzout;

­ Jozo­zout;

- broodzout;

- gejodeerd broodzout;

- zeezout;

- dieetzouten.

• Voedingsmiddelen waarin de kleurstof E127 voorkomt. Advies

Lees tijdens het volgen van het jodiumbeperkt dieet op de verpakking welk soort zout en kleurstof aan het

product is toegevoegd. Gebruik bij twijfel het product niet. Bedenk daarbij, dat u het jodiumbeperkt dieet slechts

tijdelijk moet volgen, ongeveer 10 dagen.

34

Overzicht van toegestane voedingmiddelen voor het jodiumbeperkte dieet

In het overzicht ziet u op alfabetische volgorde en per product­ (groep) welke voedingsmiddelen wel zijn

toegestaan. Staat een voedingsmiddel niet in het overzicht, dan is het voedingsmiddel niet toegestaan.

Deze voedingsbeperking geldt ongeveer 10 dagen: namelijk voor de duur van het jodiumbeperkt dieet. Productgroep

Toegestaan

Aardappelen,

(zilvervlies)rijst,

witte macaroni en

witte spaghetti

Gekookte- gebakken- en gefrituurde aardappelen.

Zelfbereide aardappelpuree met Jozo Naturel.

Boter, margarine

en olie

Alle soorten gezouten en ongezouten boter,

margarine, halvarine, olie en bak­en­braad­product. Bouillon, soep Zelfbereide bouillon of soep en de toegestane

soorten groenten, vlees, kruiden en

specerijensoorten en Jozo Naturel. Brood en

broodvervanging

Zelfgebakken brood met ongejodeerd zout (Jozo

Naturel), zelfgebakken brood met Koopmans

broodmix.

Zoutloos brood van de bakker.

Fabrieksmatig bereide beschuit, crackers, knäckebröd,

ontbijtkoek, matses en rijstwafels. Broodbeleg

Kaas Vleeswaren

Zoet en overig beleg

Maximaal 1 plak kaas

(± 20 gram) per dag of één broodbelegging

smeerkaas, alleen de Nederlandse soorten.

Maximaal 1 plak vleeswaren (± 20 gram) per dag. Alle

soorten vleeswaren, zowel van de slager als

voorverpakt.

Uitgezonderd: vleeswaren waar lever in verwerkt is,

zoals leverworst, leverpaté en leverpastei. Alle soorten jam.

Uitgezonderd: jam waar de rode kleurstof E­127 in

verwerkt is.

Vruchtenhagelslag, honing, stroop, appel­ en

perenstroop, kokosbrood, gestapte muisjes.

35

Productgroep

Toegestaan

Dranken Koffie, thee, bouillon, water.

Limonadesiroop .

Uitgezonderd: Limonadesiroop met de kleurstof E­127. Vruchtensap: maximaal 2 glazen, afhankelijk

van het aantal porties vers fruit.

Frisdrank, inclusief light­frisdrank: maximaal

3 glazen (maximaal 500 ml). Bier: maximaal 2 glazen.

Fruit en

vruchtensap

Maximaal 2 porties (200 gram) vers fruit per dag van

de volgende soorten: aardbei, abrikoos, appel, braam,

citroen, druif, framboos, grapefruit, mandarijn, kers,

kruisbes, mango, meloen, peer, perzik, pruim,

sinaasappel. In plaats van 1 portie fruit mag u ook 1 glas vruchten­

sap van de bovengenoemde soorten of 1 portie

vruchtenmoes gebruiken. Groenten

Maximaal 3 opscheplepels zonder saus.

Alleen de volgende soorten, zowel rauw, vers, als uit

blik, glas en diepvries:

aubergine, biet, bleekselderij, bloemkool, Chinese

kool, courgette, doperwten, ijsbergsla, knolselderij,

knoflook, komkommer, koolraap, koolrabi, kropsla,

maïs, paprika, pastinaak, pompoen, prei, rabarber,

rode kool, snijbonen, tomaat, tuinbonen, ui, witte

kool, zuurkool.

36

Productgroep

Toegestaan

Jus en saus Jus en sauzen met de toegestane soorten groente,

vlees, kruiden, specerijen en Jozo Naturel.

Melk en melk-

producten

Melk, karnemelk, sojamelk, yoghurt, yoghurtdrank,

vla en kwark: maximaal 1 glas of schaaltje (± 150 ml)

per dag.

Koffiemelk is toegestaan, maar moet worden

meegerekend bij het maximum van 150 ml melk en

melkproducten.

Uitgezonderd: koffiemelkpoeder en koffiecreamer. Peulvruchten Bruine­ en witte bonen, sojabonen.

Versnaperingen Fabriekskoekjes (verpakt), zoals biscuit, sultana,

jodenkoek, stroopwafel en bitterkoekje.

Fabrieksmatig bereide ontbijtkoek, ouwe wijvenkoek,

reepkoek. Krenten en rozijnen. Hazelnoten, chips.

Kauwgum.

Vlees, vis en

vleesvervangers

Vlees

Maximaal 100 gram vlees (rauw gewogen) met

uitzondering van lever en leverproducten.

Alle soorten kalfs­, paarden­, rund­, varkens­ en

kippenvlees, zowel vers als voorverpakt en/of

gekruid. Vleesvervangers

(vegetarische

producten)

In plaats van vlees, maximaal 100 gram. Alle soorten

op basis van soja, granen, rijst, toegestane groente­

soorten en aardappelen. Tofu, tahoe, tempé.

Zout Jozo­Naturel, niet jodiumhoudend keuken­ of

tafelzout. Diversen Alle verse en gedroogde kruiden en specerijen,

specerijenmengsels, vleeskruiden, aromat, azijn,

mosterd, ketjap, ketchup en tomatenpuree.

Aardappelmeel, maïzena.

Suiker, zoetstof.

37

Voorbeeld van een dagmenu

Ontbijt zoutloos brood of zelfgebakken brood eventueel beschuit, crackers, knäckebröd besmeerd

met gezouten of ongezouten halvarine, margarine of roomboter

beleg: 1 plak vleeswaren

1 x zoet beleg

thee of koffie met/zonder suiker ’s Morgens koffie of thee met/zonder suiker

1 plak ontbijtkoek of biscuits

Warme maaltijd eventueel soep of bouillon

stukje vlees of kip, maximaal 100 gram – rauw gewogen

jus

maximaal 3 groentelepels groente

aardappelen, macaroni, peulvruchten, rijst naar behoefte ’s Middags koffie of thee met/zonder suiker

1 plak ontbijtkoek of biscuits

1 portie fruit of 1 glas vruchtensap

Broodmaaltijd zoutloos brood of zelfgebakken brood eventueel beschuit, cracker, knäckebröd besmeerd met

gezouten of ongezouten halvarine, margarine of roomboter

beleg: 1 plak kaas

1 x zoet beleg

1 beker melk of karnemelk ’s Avonds koffie of thee met/zonder suiker

1 plak ontbijtkoek of biscuits

1 portie fruit of 1 glas vruchtensap

Vragen

Als u na het lezen van deze brochure vragen heeft, kunt u op werkdagen tussen 9.00 ­ 10.00 uur contact

opnemen met één van de diëtistes van sector A, via telefoonnummer (050) 361 29 32.

U kunt ook mailen: dietistsectora@umcg.nl

Patiënteninformatie vlk 039/1412

38

B. Food-frequency list

Datum

Brood en broodvervangers

Brood (per snee of per stuk)

tarwebrood

volkoren, meergranen en speltbrood

volkorenbrood met zonnebloem- of pompoenpitten

witbrood of maisbrood

roggebrood - licht

- donker

bolletje (bruin, wit, meergranen)

krenten-, rozijnen-, suiker- of mueslibrood

krentenbol of mueslibol

croissant

pistoletje, Italiaanse bol, ciabatta of ½ stokbrood

ovenbroodjes (om af te bakken)

Brood vervangers (per stuk of per portie )

beschuit

cracker Vitalu/ cracotte Vital

cracker cream/ matze

knäckebröd

rijstwafel of cracottes naturel

drinkontbijt op fruitbasis per glas

drinkontbijt op melkbasis per glas

ontbijtproducten per eetlepel (cornflakes, cruesli, muesli)

granen ontbijtproduct per eetlepel (Bambix, Brinta, havermout)

Smeersels (per besmeerde boterham)

halvarine

margarine

roomboter

Broodbeleg (per snee brood)

Zoet broodbeleg

jam, honing, (appel)stroop, vruchtenhagelslag of suiker

kokosbrood

Chocoladeproducten

chocolade- of hazelnootpasta

chocolade hagelslag of vlokken melk

chocolade hagelslag of vlokken puur

Hartig broodbeleg

pindakaas

groentespread

komkommerspread

sandwichspread

Kaas (totaal van zowel de broodmaaltijd als tussendoor)

39

Harde kaassoorten (per snee brood of per blokje)

20+ kaas

30+ kaas

40+ kaas

45+ kaas

48+ kaas

Zachte kaassoorten (per snee brood, per 4 toostjes of per 2 crackertjes)

hüttenkäse

strooikaas

verse kaas, light (bv St. môret linesse)

smeerkaas 15-20+

smeerkaas 30-40+

smeerkaas 45+ en hoger

brie

geitenkaas

schapenkaas

Vleeswaren (per snee brood of per 2 toostjes of crackertjes)

soorten dag 1:

soorten dag 2:

Eieren (per stuk)

gekookt ei

gebakken ei

Fruit (per stuk, glas of per schaaltje)

soorten dag 1:

soorten dag 2:

vruchtencompote of –moes

gedroogd fruit

Soep (per bord)

bouillon

heldere soep

gebonden soep

maaltijdsoep

Aardappelen en vervangers (per opscheplepel gekookt/ bereid)

gekookte aardappelen

gebakken aardappelen

aardappelpuree van instantpoeder - bereid met water of bouillon

- bereid met melk

frites

Graanproducten en rijst (per opscheplepel of per stuk)

pasta (macaroni, spaghetti, mie)

rijst - witte rijst

- meergranenrijst of zilvervliesrijst

peulvruchten (bruine of witte bonen, kapucijners, kikkererwten, linzen)

wrap/ taco’s/ tortilla [vulling invullen bij groente en vlees]

40

pannenkoek (per stuk)

Samengestelde gerechten (per opscheplepel)

chili con carne

hartige taart (per punt)

lasagne

pizza (per stuk); soort:

spaghetti bolognese

macaroni met ham/kaas

bami/ nasi

stamppot

kant-en-klare salade(huzaren-, aardappel-, rundvleessalade etc.)

[wanneer u ovenschotels of kant en klaar maaltijden gebruikt probeer deze in te vullen bij voedingsmiddelen in de lijst die erop lijken]

anders, soort:

Groenten (per opscheplepel) gekookt, gestoomd, rauw of gestoofd

soorten dag 1:

soorten dag 2:

Vlees en gevogelte (per 100 gram rauw gewogen)

soorten dag 1:

soorten dag 2:

Vis, schaal- en schelpdieren (per stuk of per 100 gram)

soorten dag1:

soorten dag 2:

Soja(producten) en andere vleesvervangers (per stuk of per portie)

vleesvervangers

soorten dag 1:

soorten dag 2:

Bereidingsvet en olie (per eetlepel)

olie

vloeibare margarine

boter/ margarine in wikkel (hard)

vloeibaar bak en braadvet

bak en braadvet in wikkel (hard)

Jus, dressings en sausen (per eetlepel of sauslepel)

saus

jus

Melk(producten)

Melksoorten, yoghurt, kwark en pap (per beker of per schaaltje)

melk

karnemelk

chocolademelk

sojamelk

Yakult

yoghurt

41

Bulgaarse of Griekse yoghurt

vruchtenyoghurt

vanilleyoghurt

yoghurtdrank

kwark

vruchtenkwark

pap - karnemelkse pap (bloem-,gortpap)

- overig (griesmeel-, havermout-, rijstepap)

indien de pap zelf is bereid, bereid van magere / halfvolle / volle melk

(omcirkel het product dat van toepassing is)

Vla, pudding en mousse (per schaaltje)

vla

pudding - chipolatapudding

- overige soorten

chocolademousse

toetje met room, roomdessert

sojadessert en/of Yofu soja

Koffiemelk en –room (per cupje of per scheutje)

koffiemelk mager of halfvol

koffieroom of volle koffiemelk

koffiecreamer (per zakje of per schepje)

IJs (per stuk of bolletje)

waterijs

roomijs, schepijs, softijs of yoghurtijs (per bolletje)

verpakt ijs, soort:

milkshake

Noten, zaden en snacks

Noten en zaden (per eetlepel)

Japanse mix

noten (divers) en pinda’s

Chips (per zakje à 30 g)

light, Nibbits, ringlings, tortilla chips of Wokkels

overige chips en fritessticks

kroepoek (per schaaltje)

popcorn (per schaaltje)

Snack-a-jacks - mini’s per zakje

- groot per stuk

Toostjes en toostbeleg (per toostje)

toast

(mini of cream) crackers

ei- of vissalade

komkommer-, hamprei, kipkerrie of selderijsalade

paté

zalm, tonijn

[kaasbeleg zie ‘kaas’]

Zoute koekjes (per stuk)

42

zoute biscuits

kaaskoekjes

zoute stokjes

Warme snacks (per stuk)

gefrituurde snacks (bamibal, bitterbal (per 3), frikadel, kroket, nasibal)

kaassoufflé

saucijzen- of worstenbroodje

loempia (1 grote of 2 vietnamese loempia’s)

Gebak, koek, snoep, chocola en suiker

Gebak en koek (geef het aantal producten per groep aan)

soorten dag 1:

soorten dag 2:

Snoep (per stuk, bij benadering)

groep 1: (marshmellow, pepermunt, spekkie, stophoest, winegum, zuurtje)

groep 2: (energiereep, marsepein, mueslireep, 5 toffee’s)

groep 3: drop

groep 4: chocola - bonbon (per stuk),

candybar groot (bounty, mars, snicker, milky way etc.)

- mini candybar

Noem de soorten op beide dagen:

Suiker (toegevoegd aan dranken, desserts of anders)

suiker diverse soorten (per theelepel)

zoetstof (per druppel, theelepel of zoetje)

Dranken

Niet-alcoholische dranken (per glas of per kop)

leidingwater

mineraalwater: soort

thee

koffie

limonade of diksap

frisdrank

vruchtensap - gewoon

multivitaminedrank

vers vruchtensap

groentesap of tomatensap

energie- of sportdrank

Alcoholische dranken (per glas)

bier

wijn

sherry, port of vermouth

likeur

Welk soort zout gebruikt u:

Ruimte voor aanvullende notities

43

C. TNM-classification, according to the 7th edition of the American Joint Committee in

Cancer

Primary tumor

TX Primary tumor cannot be assessed.

T0 No evidence of primary tumor.

T1 Tumor ≤2 cm in greatest dimension limited to the thyroid.

T1a Tumor ≤1 cm, limited to the thyroid.

T1b Tumor >1 cm but ≤2 cm in greatest dimension, limited to the thyroid.

T2 Tumor >2 cm but ≤4 cm in greatest dimension, limited to the thyroid.

T3 Tumor >4 cm in greatest dimension limited to the thyroid or any tumor with minimal

extra thyroidal extension (e.g., extension to sternothyroid muscle or perithyroid soft

tissues).

T4a Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft

tissues, larynx, trachea, oesophagus, or recurrent laryngeal nerve.

T4b Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels.

Regional lymph nodes (cervical or upper mediastinal)

NX Regional lymph nodes cannot be assessed.

N0 No regional lymph node metastasis.

N1 Regional lymph node metastasis.

N1a Metastases to level VI (pretracheal, paratracheal, and prelaryngeal/ Delphian lymph

nodes).

N1b Metastases to unilateral, bilateral, or contralateral cervical (levels I, II, III, IV or V) or

retropharyngeal or superior mediastinal lymph nodes (level VII).

Distant metastases

M0 No distant metastasis.

M1 Distant metastasis.

Risk stratification

Low risk is defined as:

- Primary tumor is classified as T1 or T2.

- No lymph node metastases or lymph node metastases only in level VI without extra nodal

growth.

- No distant metastasis.

High risk is defined as:

- All the other combinations.