Dietary evaluation of a low-iodine diet in Korean thyroid cancer patients preparing for radioactive iodine therapy in an iodine-rich region.

BACKGROUND/
OBJECTIVES: Despite the importance of a low-iodine diet (LID) for thyroid cancer patients preparing for radioactive iodine (RAI) therapy, few studies have evaluated dietary intake during LID. This study evaluated the amount of dietary iodine intake and its major food sources during a typical diet and during LID periods for thyroid cancer patients preparing for RAI therapy, and examined how the type of nutrition education of LID affects iodine intake. SUBJECTS/
METHODS: A total of 92 differentiated thyroid cancer patients with total thyroidectomy were enrolled from Seoul National University Hospital. All subjects completed three days of dietary records during usual and low-iodine diets before (131)I administration.
RESULTS: The median iodine intake was 290 µg/day on the usual diet and 63.2 µg/day on the LID. The major food groups during the usual diet were seaweed, salted vegetables, fish, milk, and dairy products and the consumption of these foods decreased significantly during LID. The mean energy intake on the LID was 1,325 kcal, which was 446 kcal lower than on the usual diet (1,771 kcal). By avoiding iodine, the intake of most other nutrients, including sodium, was significantly reduced during LID (P < 0.005). Regarding nutritional education, intensive education was more effective than a simple education at reducing iodine intake.
CONCLUSION: Iodine intake for thyroid cancer patients was significantly reduced during LID and was within the recommended amount. However, the intake of most other nutrients and calories was also reduced. Future studies are needed to develop a practical dietary protocol for a LID in Korean patients.

INTRODUCTION

The incidence of thyroid cancer in Korea increased by about 22.3% per year between 1993 and 2012 [1]. Many studies have focused on the initial management of differentiated thyroid cancer (DTC); radioactive iodine (RAI) therapy eliminates microscopic residual tissues after thyroidectomy and decreases the recurrence of thyroid cancer [23]. For successful RAI therapy in DTC patients following a total thyroidectomy, patients must increase their thyroid-stimulating hormone (TSH) levels and deplete the whole body iodine pool through a low-iodine diet (LID)[4].

Regarding dietary iodine guidelines for LID, the American Thyroid Association recommends restricting dietary iodine intake to less than 50 µg daily for 1-2 weeks before RAI therapy [2], while the Korean Thyroid Association recommends restricting intake to less than 100 µg daily due to the iodine-rich diet commonly eaten in Korea [5].

According to a recent systematic review of RAI therapy [6], the most commonly recommended dietary iodine intake was 50 µg per day, with the duration ranging widely from 5 days to 4 weeks. Most studies have estimated the dietary iodine levels using urinary iodine measurements because urinary iodine excretion is considered a marker of recent iodine intake [7] and have analyzed studies conducted in different countries.

According to a report on global and regional iodine status, iodine intake levels differ by region. Koreans were classified as having 'more than adequate' iodine intake [8]. Since Korea is a peninsula surrounded by sea on three sides, the consumption of seafood and seaweed is high, and the Korean population is presumed to have an iodine-rich diet [9]. Based on recent studies of dietary iodine intake, the median iodine level in Korean adults was as high as 375.4 µg per day, and that 65.6% of the iodine came from seaweed, 18.0% from salted vegetables, and 4.8% from fish [10]. Compared to other countries, the median dietary iodine intake from two 24-h dietary records was 123 µg per day (25th-75th percentile, 27-211) for UK women [11], and the average iodine intake for US adults ranged from 138 to 353 µg/day [12]. Both of the latter studies reported that milk, eggs, and dairy products were the major sources of dietary iodine. This indicates that iodine intake and its dietary sources vary by region.

Besides, the recommended dietary iodine levels or duration of LID differ by region. Even within one region such as Korea, the protocol for LID differs across hospitals. Only a few studies have reported compliance with a LID with RAI outcomes. Sohn et al. [13] reported that excessive urinary iodine (> 250 µg/gCr) was associated with poor RAI ablation outcomes [13]. Yoo et al. [14] reported little difference between a less strict LID and a very strict LID. The less strict LID restricted seafood, iodized salt, egg yolk, dairy products, processed meat, instant prepared meals, and multi-vitamins. In addition to these foods, the very strict LID restricted rice, freshwater fish, spinach, and soybean products. Although the efforts to improve compliance have been made, no studies examined the type of nutrition education for LID.

It may be very challenging to restrict iodine intake for a LID in iodine-rich areas. Korean thyroid cancer patients often have difficulty maintaining a LID. According to Moon et al. [15] , patients often misunderstand that LID is a low-salt diet because foods containing sea salt and seasonings are restricted. Therefore, nutrition education is important to improve compliance with LID.

Along with nutrition education, a more practical dietary strategy would be helpful. To develop practical dietary guidelines for LID, it is necessary to quantify dietary iodine intake levels or its major food sources. It is very difficult to assess the usual iodine intake due to considerable day-to-day variation. The majority of studies have based iodine intake on food-frequency questionnaires containing certain food items [1617], but these studies are limited in their ability to quantify dietary intake [7]. Imaeda et al. [18] reported the usual iodine intake and the major food sources of iodine using 7 days of weighed dietary records from Japanese adults.

In order to elucidate the appropriate dietary iodine levels and duration of LID for the Korean population, a thorough examination of dietary iodine levels and its major food sources in the Korean population and an evaluation of ablation efficacy by dietary iodine intake levels are needed. This study evaluated the amount of dietary iodine intake and its major food sources during a typical diet and during LID periods for thyroid cancer patients preparing for RAI therapy, and examined how the type of nutrition education of LID affects iodine intake.

SUBJECTS AND METHODS

Subjects and study design

Ninety-six patients with DTC preparing for their first round of RAI therapy (low-RAI dose, 1.1 GBq) were prospectively enrolled between October 2013 and February 2015 at Seoul National University Hospital. Patients who met the inclusion criteria of this study were aged 20 years or older, had newly diagnosed DTC, and had recently undergone total or near-total thyroidectomy. The study excluded patients who had been treated with contrast agents within the previous 2 months, alcoholics, drug addicts, and patients who were receiving dialysis treatment or who had any of the following diseases: psychotic depression, bipolar disorder, schizophrenia, liver failure, liver cirrhosis, and chronic renal failure. Out of 96 eligible subjects, three withdrew consent, and one did not complete any dietary records, so the final sample size was 92 patients (19 men and 73 women). For treatment, 77 patients stopped levothyroxine (LT4) therapy four weeks prior to RAI, then received liothyronine (T3) for two weeks, followed by T3 withdrawal before 131I-wholebody scintigraphy (WBS). The other 15 patients continued LT4 replacement therapy, and rhTSH (Thyrogen™) was injected twice: two days and one day before 131I administration. All patients maintained a LID two weeks before 131I administration and until WBS. WBS was performed after three days. A low dose of radioiodine (1.1 GBq) was used for remnant ablation due to the diminished chance of side effects.

The Institutional Review Board (IRB) of Seoul National University College of Medicine reviewed and approved the protocol for this study (H-1308-066-513). Research participants gave signed, informed consent, which was confirmed by the IRB, after receiving an explanation of the study purpose.

Low-iodine diet (LID) and education type

The LID was implemented with the goal of limiting iodine intake to less than 100 µg day, corresponding to the Korean Thyroid Association guidelines. Once a subject decided to undergo RAI therapy, a nurse provided general education for RAI, which consisted of an introduction to RAI and information about LID; this took 10 to 15 minutes and used a leaflet. As most information on the LID is given in a 3-page handout with no detailed explanation, we labeled this group the 'simple guide' group.

The patients were also able to choose an additional intensive education program for a fee. This consisted of a 2.5-hour group workshop that included 30 minutes of LID education by a clinical dietician. We labeled this group the 'intensive education' group. The scheme of the education program is presented in Table 1.

Table 1

A comparison of the dietary guideline for low-iodine diet (LID) to prepare the radioactive iodine (RAI) therapy

The dietary guidelines for the LID used in this study are presented in Table 2.

Table 2

Dietary guidelines for a low-iodine diet for Korean thyroid cancer patients preparing for radioactive iodine therapy

Dietary assessment

To assess the patients' diets during usual and LID periods, three-day diet records were collected. The diet records included two weekdays and one weekend day. The food record booklet was designed to be entirely self-administered, and contained written instructions to help the patient record the relevant details of all foods and beverages consumed, as well as an example of a correctly completed record.

Energy and nutrient intakes, except for iodine, were estimated using a Diet Evaluation System (DES) [19]. Iodine intake was calculated using the database recently established by Han et al. [10] and modified for this study. In total, 813 food items appeared in this study. Among those items, 282 items matched the analytical values in the database, values for 368 items were imputed to substituted or calculated values, and 163 items were assigned a value of zero. The coverage of iodine intake in this study was 93.8%.

Urinary iodine excretion

For urinary iodine analysis, spot urine was collected twice. The first sample was collected at a regular medical check-up during the usual diet period, and the second sample was collected prior to 131I administration after two weeks of LID. Urinary iodine concentration was analyzed by the Sandell-Kolthoff method using an ammonium persulfate digestion, creatinine was measured using the Jaffe method, and both were analyzed using a microplate reader (Beckman Coulter AU 5800). The results are expressed as iodine/creatinine (µg/gCr). Only 78 patients provided both urine samples.

Assessment of other variables

Height and weight were measured during the usual diet period at a regular medical check-up, and again after two weeks of LID, prior to 131I administration. Body Mass Index (BMI) was calculated as the ratio of weight (kg) divided by height squared (m2). Age at diagnosis, sex, surgery method, histopathologic information, and the method of TSH elevation were obtained from medical records.

Statistical analysis

All statistical analyses were conducted using SAS software, version 9.4 (SAS Institute, Cary, North Carolina, USA). Categorical variables were tested by the χ2 test, and continuous variables were tested by the t-test. A paired t-test was conducted to examine the differences in dietary intake between the usual diet and LID in the same individual. Iodine intake during the LID period was compared using a generalized linear model (GLM) by the type of nutritional education received after adjusting for age, sex, and energy intake. All statistical tests were two-sided, and P-values of < 0.05 were considered significant.

RESULTS

Patient characteristics

Patient characteristics are summarized in Table 2. Data from a total of 92 patients (19 men, 73 women, age 44.2 ± 11.6 years) were analyzed; 96.7% had papillary carcinomas, and 50% had lymph node metastases at initial presentation. All patients received a low-dose (1.1 GBq) of 131I ablation after TSH stimulation by thyroid hormone withdrawal (n = 77) or injection of rhTSH (n = 15) with 2 weeks of LID. Aside from sex differences, patient characteristics did not differ between simple and intensive education groups as illustrated in Table 3.

Table 3

General characteristics of the Korean thyroid cancer patients

Data are expressed as the Mean ± SD.

*P-value was obtained by t-test for continuous variables and χ2 test for categorical variables.

BMI, body mass index; BRAF, B-Raf proto-oncogene serine/threonine kinase; TSH, thyroid-stimulating hormone; rhTSH, recombinant human thyroid-stimulating hormone

Iodine intake and urinary concentration

Fig. 1 shows the iodine intake and iodine/creatinine ratio in spot urine samples for the usual and low-iodine diets. Iodine intake was significantly lower during the LID period than during the usual intake period (P < 0.001). The median iodine intake levels for usual diet and LID were 290 and 63.2 µg/day, respectively. Due to reduced dietary intake, the urinary iodine/creatinine ratio was significantly lower during LID than during the usual diet. A total of 73 out of 92 (79.3%) patients met the guidelines established by the Korean Thyroid Association (iodine intake < 100 µg/day during the LID period).

Fig. 1

The iodine intake and urinary iodine during usual and low-iodine diet periods among Korean thyroid cancer patients.

(a) Iodine intake, (b) Urinary iodine/Creatinine ratio in spot-urine. Q1: 25th percentile, Q3: 75th percentile, Box: Q3-Q1 (Inter-quartile range), ⋄: mean, ▪: extreme value. ▪: 2 extreme values are clipped on the box plot (a). ▪: 3 extreme values are clipped on the box plot (b). †P-value obtained using a paired t-test to compare the usual and low-iodine diets.

Food and iodine intake according to food groups

Table 4 shows the intake of food and iodine according to food groups. Seaweed was the largest contributor to iodine intake during the usual diet period, followed by salted vegetables, fish, and milk. Although the daily intake of vegetables, fruits, and beverages were more than 100 g, the iodine content of these was low (as little as 5.5, 12.3 and 4.1 µg per day). The iodine intake from seasonings including salt, soy sauce, soy paste and red pepper paste was only 2.4 µg per day, and their degree of contribution to total iodine intake was very low. In accordance with the guidelines, fewer subjects consumed sugars, legumes, salted vegetables, egg yolks, fish, seaweeds, milk, processed foods, and beverages including alcohol during the LID compared to the usual diet. By contrast, more consumed mushrooms, egg whites, and others (including oral nutrition supplements). Compared to usual intake, the intake of grains, sugar, sweets, legumes, salted vegetables, meat, eggs, fish, milk and dairy products, seasonings, and processed foods was reduced during the LID period. Although the intake of potatoes, vegetables, mushrooms, fruits, egg whites, and others significantly increased during LID, the iodine intake from these sources was less than 10 µg.

Table 4

Iodine intake from food groups during the usual and low-iodine diet (LID) periods using 3-day dietary records of Korean thyroid cancer patients

The total number of subjects was 92.

Data are expressed as the Mean ± SD.

*P-value was obtained from a χ2 test between usual and low-iodine diet.

†P-value was obtained from a paired t-test between usual and low-iodine diet.

Energy and nutrient intake

The changes in energy and nutrient intake between usual and low-iodine diet were assessed. Table 5 shows the intake of energy and nutrients during usual and low-iodine diets. The mean level of energy intake during the LID period was 1,325 kcal, which was 446 kcal lower than the intake during the usual diet (1,771 kcal). The intake levels of most nutrients, including sodium, were significantly lower during LID compared to the usual diet (P < 0.005). Potassium and vitamin A intake did not differ between the two diet periods, but vitamin C intake was higher during LID than during the usual diet (P < 0.001). During the LID period, the percentage of energy from carbohydrates significantly increased, whereas intake from proteins and fats significantly decreased compared to the usual diet period.

Table 5

Nutrient intake based on three days of dietary records during usual and low-iodine diet periods among Korean thyroid cancer patients

Data are expressed as the Mean ± SD.

*Mean values were tested using a paired t-test between usual and low-iodine diets

Iodine intake by type of nutrition education during low-iodine diet

The energy and nutrient intake during LID was also compared between the two educational groups. After adjusting for age, sex, method of TSH elevation, and energy intake, the intake of energy and all nutrients except iodine were not different between groups. Iodine intake was significantly lower in the intensive education group (P = 0.040) (Table 6).

Table 6

Comparison of iodine intake by the type of education for the low-iodine diet period among Korean thyroid cancer patients

†Mean values were tested using the GLM model after adjusting for age, sex, method of TSH elevation, and energy intake between simple and intensive education groups.

†Distribution was tested using the χ2 test between simple guide and intensive education groups.

DISCUSSION

We evaluated iodine intake and its major food sources during the usual diet and LID for 92 patients who had undergone thyroidectomy and were receiving RAI therapy.

In this study, the median iodine intake was 290.4 µg per day on the usual diet, which was reduced considerably during the LID diet to 63.2 µg, which met the Korean Thyroid Association recommendations of less than 100 µg per day. We also measured the urinary iodine excretion as a secondary measure of dietary iodine in a subpopulation. The median urinary iodine/creatinine ratio of the 78 patients with urine samples was reduced to 21 µg/gCr per day during LID, and 68 patients (88.5%) achieved levels lower than the recommended 100 µg/gCr (data not shown).

In terms of urinary iodine levels, previous studies [2021] have suggested that an acceptable reduction of the urinary iodine concentration is less than 100 µg/gCr, and this was achieved in 71% and 70% of the patients during the 2-week LID in both studies. Compared to these results, the patients in this study successfully restricted dietary iodine intake. When comparing the dietary iodine intake with Japanese adults who are regarded as having similar iodine intake levels, the median iodine intake in Japan was 312 µg for men and 413 µg for women, values that were slightly higher than our results for Koreans (290 µg per day). Considering that the patients in our study had thyroid cancer, the dietary iodine intake values seem comparable.

Despite the importance of LID for RAI therapy, it is very difficult to restrict dietary iodine intake for LID, particularly in iodine-rich areas such as Korea. Moon et al. [15] reported that thyroid cancer patients are able to successfully select foods low in iodine and avoid foods high in iodine, but that patients are much less able to prepare low-iodine meals. Although condiments containing refined slat instead of sea salt are allowed, patients avoid using main seasonings such as soy sauce, soybean paste, and red pepper paste.

By avoiding dietary iodine intake, most patients also end up reducing their intake of other nutrients and energy. Our study also showed that energy and nutrient intake decreased during LID compared to a usual diet. Moreover, BMI decreased significantly after two weeks of LID (data not shown). These results indicate that more practical dietary strategies that maintain the intake of other nutrients while reducing iodine intake should be explored for Korean patients.

The most interesting finding of this study was that intensive nutrition education was more effective compared to a simple guide at increasing compliance with a LID. Choi et al. [22] reported that most patients could achieve iodine levels below recommendations after two weeks of stringent LID and advice from a specialized nutritionist. Chung [23] suggested that if patients are adequately educated, and if their compliance is regularly monitored, one week of LID may be sufficient prior to RAI therapy, even in an iodine-rich areas.

Due to a lack of relevant data for the Korean population, there is no standard LID protocol in Korea. Regarding food group consumption during LID, subjects increased their consumption of potatoes, nuts, vegetables, fruits, and egg whites. These findings agree with the results of Moon et al. [15] , who also found that self-efficacy related to consuming various fruits and vegetables, to choosing potatoes and sweet potatoes for snacks, and restricting the consumption of eggs, milk, milk products, and processed foods was rated highly.

Our results also showed that patients avoided foods with high iodine contents. All the patients in our study tried to use refined salt instead of sea salt in accordance with the LID guidelines. In addition, the patients consumed various vegetables, and sought fruit, baked potatoes and sweet potatoes for snacks. Using these foods with simple recipes showed high self-efficacy. By contrast, the significant reduction in the intake of sodium, sugar, oils and seasonings implies that the patients cooked less frequently than they did during their usual diets. Difficulties related to cooking, and misunderstanding LID as a low-sodium diet, may cause patients to stop cooking. To counteract this, clinical dieticians should educate patients on how to cook while complying with a LID, and what seasonings to use.

In this study, the contribution of seasonings for usual iodine intake was very low (only 2.4 µg per day), so limiting sea salt and seasonings containing sea salt would have very little effect on overall iodine intake. This result may be useful for the development of more practical dietary guidelines for LID, including the practical strategy of avoiding consuming stock made by stewing anchovies or kelp, which contributes much more to iodine intake than seasonings.

Our study has several limitations. First, the iodine database for common Korean foods is still incomplete. Our iodine database was mainly based on analytical values determined by the Korean Food and Drug Administration (KFDA). These values, for a total of 455 foods, were determined through inductively coupled plasma mass spectrometry (ICP-MS) [24]. However, for seasonings such as soybean paste and red pepper paste, the type of salt was not specified, and only mean iodine content of sea salt, soy sauce, soybean paste, and red pepper paste were reported. The values for iodine content per 100 g for these foods are 1.83, 1.80, 14.4, and 8.03 µg, respectively. Since the type of salt is very important for thyroid cancer patients, the iodine database should be updated. Second, iodine intake was assessed using three days of dietary records. Since dietary intake was self-administered, nutrient intake, including iodine, may have been underestimated due to the high burden of keeping dietary records. Third, we measured urinary iodine levels, although not in all patients. In addition, the time period of dietary assessment was not matched to the urinary assessment, because they reported 3-day dietary records. Therefore, we used urinary iodine levels as a secondary measurement. Fourth, the type of nutrition education for LID could not be randomized because the patients paid for the intensive education. Finally, the side effects of LID, including hyponatremia were not investigated. Previous studies have reported cases of severe hyponatremia associated with hypothyroidism induced by pretreatment of 131I therapy, such as LID and withdrawal of thyroid hormones [25262728].

Nevertheless, to our knowledge, this study was the first study to examine iodine intake during LID in a Korean population, and we were able to identify the major foods that contribute to iodine intake, which may be useful for developing future LID guidelines specifically for Korean thyroid cancer patients.

In conclusion, iodine intake was significantly reduced during LID, but the intake of almost all other nutrients also decreased due to the difficulties associated with maintaining a LID. Future studies are needed to develop a practical protocol for LID in order to maintain the intake of other nutrients while reducing iodine intake.