Impact of Low Iodine Diets on Ablation Success in Differentiated Thyroid Cancer

A Mixed-Methods Systematic Review and Meta-Analysis

Georgia Herbert; Clare England; Rachel Perry; Alex Whitmarsh; Theresa Moore; Aidan Searle; Sneha Chotaliya; Andy Ness; Matthew Beasley; Charlotte Atkinson

Disclosures

Clin Endocrinol. 2022;97(6):702-729.

Abstract and Introduction

Abstract

Background: Debate remains regarding whether to recommend a low iodine diet (LID) before radioactive-iodine treatment and its duration and stringency. This mixed-methods review aimed to determine if iodine status affects treatment success, the most effective diet to reduce iodine status, and how LID impacts wellbeing.

Methods: Five electronic databases were searched until February 2021. An effectiveness synthesis (quantitative studies) and views synthesis (qualitative, survey, and experience-based evidence) were conducted individually and then integrated. Quality assessment was undertaken.

Results: Fifty-six quantitative and three qualitative studies were identified. There was greater ablation success for those with an iodine status of <50 mcg/L (or mcg/gCr) compared with ≥250 (odds ratio [OR] = 2.63, 95% confidence interval [CI], 1.18–5.86, n = 283, GRADE certainty of evidence very low). One study compared <50 mcg/L (or mcg/gCr) to 100–199 and showed similar rates of ablation success (OR = 1.59, 95% CI, 0.48–6.15, n = 113; moderate risk of bias). People following a stricter LID before ablation had similar rates of success to a less-strict diet (OR = 0.67, 95% CI, 0.26–1.73, n = 256, GRADE certainty of evidence very low). A stricter LID reduced iodine status more than a less strict (SMD = −0.40, 95% CI, −0.56 to −0.24, n = 816), and reduction was seen after 1 and 2 weeks. The main challenges were a negative impact on psychological health, over restriction, confusion, and difficulty for sub-groups.

Conclusions: Although a LID of 1–2 weeks reduces iodine status, it remains unclear whether iodine status affects treatment success as only a few low-quality studies have examined this. LIDs are challenging for patients. Higher-quality studies are needed to confirm whether a LID is necessary.

Introduction

Differentiated thyroid cancer (DTC) is usually treated with total thyroidectomy, followed by radioactive-iodine treatment (RAIT) with ¹³¹I to destroy any residual thyroid tissue or cancerous tissue left postsurgery (ablation). After ablation, radio-iodine can also be used to treat residual, recurrent or metastatic disease (therapy).^[1] Thyroid-stimulating hormone should be raised to facilitate uptake of ¹³¹I. It has been suggested that high iodine status may interfere with RAIT efficacy as nonradioactive iodine competes with ¹³¹I for uptake by the thyroid.^[2] Furthermore, depleting plasma iodide concentrations may increase the expression of the sodium–iodine symporter gene, increasing the amount of radioactive-iodine uptake in remnant thyroid tissue or DTC cells.^[3] Many international guidelines on the management of thyroid cancer suggest reducing iodine status before RAIT using low iodine diets (LID).^[1,4,5] However, the available evidence for benefit of low iodine status on the efficacy of RAIT for DTC is weak.^[6,7] This has led to inconsistencies both within and between countries regarding recommendations for LID duration and target urinary iodine concentration. In 2015, the Italian Society of Endocrinology recommended that a LID before RAIT was not necessary in countries with mild to moderate iodine deficiency,^[8] and was updated in 2018 to suggest avoiding preserved fish, sushi, and seaweed for 1–2 weeks before RAIT.^[9] The iodine status of the UK falls into this mild to moderate bracket^[10] but British Thyroid Association guidelines state that patients should be advised to follow a LID for 1–2 weeks before RAIT.^[1] A recent survey of practice found that different treatment centres in the UK gave varying LID advice.^[11]

Debate, therefore, remains not only as to whether to recommend a LID or not, but also the duration and stringency. Previous reviews^[6,7] were limited in their searches (e.g., excluded non-English articles, restricted databases), analysis, and descriptions of study quality and additional studies may have been published since the last review in 2016. Furthermore, the impact of the LID on wellbeing has not previously been systematically reviewed. Short-term dietary interventions such as the LID may at first seem achievable but are burdensome.^[12–14]

The aim of this review was to conduct the first mixed-method synthesis in people with DTC receiving RAIT after total thyroidectomy to yield maximum breadth and depth of understanding by addressing the following questions:

Effectiveness synthesis

1. What is the effect of iodine status or LID on ablation and therapy success?

2. What is the effect of iodine status on recurrence of thyroid cancer or cancer-related mortality?

3. What is the effect of LID advice on iodine status before RAIT or whole-body scan?

4. Are there any complications or adverse effects from consuming a LID?

Views synthesis

5. What are the facilitators and barriers of consuming a LID?

1 2 3 4 5

Next Section

Abstract and Introduction
Methods
Results
Discussion
Conclusion
References

Table 1. Characteristics of included studies
Study (year), [abstract/translated], design, country	Total n (n withdrawals/excluded); n analysed; group: n	Age: mean years ± SD (if not otherwise stated)/female: N (%)	Type of DTC: n (%); stage	Diet and groups				Reported outcomes
Study (year), [abstract/translated], design, country	Total n (n withdrawals/excluded); n analysed; group: n		Type of DTC: n (%); stage	Group description(s)	Advised iodine intake (mcg/d)	LID duration; before ablation/DxWBS/therapy	Providers	Impact of LID/IS on ablation success	Impact of LID on UIS	AE/Rec/Mort	F&B/EBE
Randomized controlled trials
Sohaimi (2019), Malaysia	110 (6 excluded: default in therapy); 104 analysed1: Non-specified LID: 492: Strict LID: 55	43.2 ± 13.6; range: 9–77F: 95 (91.3%)	PTC: 84 (80.8%)FTC: 20 (19.2%);Stage I/II: 77 (74%)Stage III/Iva: 13 (13%)Stage IVc: 14 (13%)	1. Written instruction of foods allowed/not allowed 2. Written instruction of foods allowed/not allowed. 7-day sample menu.	1. NR 2. <50	Both 1 wk; DxWBS or ablation	1. NR 2. Nurses or dietitian	X	✓	X/X/X	X/X
Nonrandomized controlled studies
Nonrandomized controlled trials
Gosling (1975), [abstract], Netherlands	15 1. LID: 7 2. LID + ethacrynic acid: 8	NR; F: 4 (57%) in LID group	FTC; Metastatic	1. LID 2. LID + ethacrynic acid (3 doses/d of 50 mg)	20–30 g^a	4 or 9d (unclear); NR	NR	X	✓	X/X/X	X/X
Jagersma (2016), [abstract], Netherlands	27 1. Control: 15 (9 followed LID) 2. Counselling: 12 (7 followed LID)	1. 49 ± 18 2. 53 ± 15 F: 1. 8 (53%) 2. 7 (58%)	NR; NR	1. Control: received standard written instructions 2. Counselling: received structured individualized dietary counseling: 7 followed LID	NR	NR but at least 7 days; NR	NR	X	✓	X/X/X	X/X
Ju (2016), South Korea	92 (78 provided urine samples) 1. Simple guide: 49 2. Intensive education: 43	44.2 ± 11.6 F: 73 (76%)	PTC: 89 (97%) FTC: 3 (3%); Ex: 61 (66.2%) LNI: 46 (50%)	1. 3-page handout on LID with no detailed explanation 2. As group 1 + intensive education program (for a fee): 2.5-h group workshop that included 30 min of LID education.	1 + 2 <100	2 weeks before and until WBS (3 days after ablation)	Nurse and dietitian	X	✓	X/X/X	X/X
Lee (2016a), [abstract], Crossover, Korea	139	NR: NR	PTC; NR	One group underwent 2 diets 1. Seaweed restriction only 2. Conventional LID	NR	1. 1 wk (DxWBS) 2. 2 wks (ablation)	NR	X	✓	X/X/X	X/X
Lee (2016b), [abstract], Crossover Korea	72	NR; F: 53 (74%)	PTC; NR	One group underwent 2 diets. 1. Simplified LID (presumed seaweed restriction only) 2. Stringent LID	NR	1. 8d, 10d; DxWBS 2. 2 wks; therapy	NR	X	✓	X/X/X	X/X
Lim (2015), Korea	108 (7 excluded non-adherence to LID: Restricted iodine diet (RID): 2; LID: 5); 101 analysed 1. RID: 54/56 2. LID: 47/52	52 (23–73) F: 88 (87%)	NR; Stage I/II: 38 (38%) Stage III/Iva: 63 (62%)	1. RID: Diet guidelines (approved, restricted foods); meal plans 2. LID: Stricter diet guidelines (approved, restricted foods) compared to RID; meal plans	1. 50–1002. < 50	4 wks; ablation	Nutrition co-ordinators	X	✓	X/X/X	X/X
Padovani (2015), Brazil	306 (181 excluded due to noncompliance with LID); 125 analysed 1. 15d: 79/153 2. 30d: 46/153	N = 306 Median (range): 37 (20–65) F: 208 (68%)	N = 306 PTC: 235 (77%) FTC: 71 (23%);NR	Instructed to follow a RID and provided with information on allowed/restricted foods: 1. 15days 2. 30 days	<50	1. 15d 2. 30d; DxWBS or therapy	NR	X	✓	X/X/X	X/✓
Roh (2006), South Korea	27 1. Less stringent LID: 14 2. Stringent LID: 13	43.5 ± 10.8; range: 22–60 F: 26 (96%)	PTC (100%); No metastasis	1. Longer timeframe but less information and support on LID 2. Shorter timeframe but more information and support on LID (e.g., specific customized diets)	NR	1. 2 wks 2. 1 wk; ablation	1. NR (not a dietitian) 2. 2. Dietitian	X	✓	X/X/X	X/X
Suzuki (2012), [abstract], Japan	45 1. Self-managed LID: 38 2. Self-managed LID + pre-packaged diet: 7	NR; NR	NR; NR	1. Self-managed LID: explanatory leaflet and advice of healthcare professional 2. Self-managed LID + pre-packaged diet: explanatory leaflet and advice of healthcare professional and a retort pouch diet for last 4d including day of ablation	NR	2 wks; NR	Doctor or dietitian	X	✓	X/X/X	X/X
Tomoda (2005), Japan	252 1. 1 wk restricted iodine diet: 210 2. 1 wk self-managed LID: 15 3. 2 wk self-managed LID: 17	1: 47.1 ± 16; F: 179 (85%) 2: 44.6 ± 15; F: 10 (67%) 3: 47.8 ± 16; F: 14 (82%)	Presumed DTC; NR	For all 3 diets ppts sent home with a simple, 1-page list of dietary recommendations. Foods to avoid for group 1 were less restrictive compared to groups 2 and 3 (who had the same list).	NR	1: 1 wk 2: 1 wk 3: 2 wks; DxWBS	1. 1: NR (explained) 2. 2 + 3: explained then self-managed	X	✓	X/X/X	X/X
Waxman (2000), [abstract], USA	89 1. Unrestricted-avoid high iodine food: 41 2. Rigorous LID: 48	NR; NR	NR; NR	1. Unrestricted diet: avoid high iodine containing foods such as kelp or mineral supplements. 2. Rigorous LID	NR	1. NR; 2. 2 wks; ablation	Dietitian	✓	X	X/X/X	X/X
Single arm prospective studies
Jin (2010), [abstract], Korea	221	46 (22–79); F:167 (76%)	Presumed DTC; NR	One group educated on a stringent LID	NR	2 wks; NR	Specialized nutritionist	X	✓	X/X/X	X/X
Lakshmanan (1988), USA	5 (providing 45 urine samples) 1. Usual diet (5ppts gave 3 samples each = 15 samples) 2. LID (5ppts gave 6 samples each = 30 samples)	30–50 F: 4 (80%)	Assumed DTC because of I-131 scan; NR	One group: instructed by dietitian and a set of written instructions was given to each ppt detailing the foods high in iodine to avoid.	~50	4 wks; NR	Dietitian	X	✓	X/X/X	X/X
Nakada (2016), [abstract], Japan	40	NR; NR	PTC; pT3/pT4, or pN1a/pN1b	One group advised a LID.	NR	7d before to 3d after ablation	Dietitian	X	✓	X/X/X	✓/X
Nakada (2017)[Abstract], PC, Japan	56	27 to 77 F: 36 (64%)	PTC; NR	NR	<100 mcg/d	7 days before to 3 days after RAIT	NR	X	X	✓/X/X	X/X
Nakada (2020),[abstract], Japan	38	61.2 ± 14.2 F: 68%	PTC; Stage II/III	One group advised a LID. Measurements taken	< 100	2 wks (UIS at 1 wk); ablation	Dietitian	X	✓	X/X/X	X/X
Tobey (2018), [abstract], USA	71	42 (median; IQR 32.5, 54.5); NR	NR; intermediate/high risk	One group advised a LID.	NR	2 wks; therapy	X	X	X	X/✓/X	X/X
Cohort studies
Bertolazzi (2010)[abstract], PC, Italy	186 1. THW + LID: 80 2. rhTSH + LID: 106	48; F: 128 (69%)	NR; NR	1. THW (TSH > 40 uU/ml) and LID 2. rhTSH (TSH > 100 uU/ml) and LID	NR	2 wks; DxWBS	NR	X	✓	X	X/X
Choi (2008), [translated], PC, South Korea	67 (16 excluded: missing urine samples); 51 analysed 1. Exposed to contrast agent: 39 2. Not exposed: 12	47.8 ± 11.1 F: 40 (78%)	PTC: 50 (98%) FTC: 1 (2%); Stage I/II: 33 (65%) Stage III/IVA: 15 (29%) Metastatic: 1 (2%)	One group: stringent LID. Three leaflets: allowed and restricted food; iodine in Korean commercial food; example of LID	NR (described as stringent)	2 wks; ablation	Nutritionist/dietitian	X	✓	X/X/X	X/X
Cuenca (2008),[translated], HC, Spain	371 1. General LID: 150 2. Strict LID: 221	47.9 ± 15.2 F: 254 (68%)	PTC: 299 (81%) FTC: 72 (19%); NR	1. General LID recommendations 2. Strict LID: specific information about authorized and prohibited foods	NR	2 wks; DxWBS	NR	X	✓	X/X/X	X/X
Dayrit (2015), [Abstract], PC	59 (50 not reported since these are preliminary results); 9 analysed	39 ± 11 (23–56)F:7	NR	NR	NR	NR	NR	X	X	✓/X/X	X/X
Dobrenic (2011), PC, Croatia	16	Median (range): 55 (43–69) F: 11 (69%)	PTC: 10 (63%) FTC: 6 (37%); Recurrence in 7 (44%): Metastatic: 6LNI: 1	One group advised to adhere to LID. Sent home with a list of dietary recommendations	NR	2 wks; therapy (n = 2) DxWBS (n = 14)	Self-managed	X	✓	X/X/X	X/X
Dobrenic (2017), [abstract] PC, Croatia	77	NR; NR	NR; Biochemically persistent	One group: 2 wk LID initially; ppts who did not achieve "moderate" iodine deficiency after 2 wks advised to follow LID for a further wk (3 wk LID)	NR	2–3 wks;therapy	Self-managed	X	✓	X/X/X	X/X
Ito (2018), PC, Japan	45 (8 used both protocols); 37 analysed 1. Self-managed LID: 25 2. Strict LID: 12	56 (median), 22–76 (range) F: 23 (51%)	PTC; LNI	1. Self-managed LID: Provided with a list of foods which should be avoided 2. Strict LID: Provided ready-made packaged LID	1. NR 2. < 30	2 wks; ablation	Radiologist or nutritionist	✓	✓	X/X/X	X/X
Jang (2011), [abstract] HC, Korea	299	NR; NR	PTC; Ex: 13% LNI: 60%	No information on what diet (if any) they had followed as this was a retrospective review to look at associations between UIE and ablation success.	NR	NR; ablation	NR	✓	X	X/X/X	X/X
Kang (2018), PC, South Korea	100 (5 in group 1 and 1 in group 2 did not collect urine samples); 94 analysed 1. Thyroxine withdrawal: 45 2. rhTSH: 49	1. 43.2 ± 9.8 2. 41.6 ± 8.3 F: 86 (91%)	PTC: 87 (92%) FTC: 5 (5%) Other: (2%); Stage I: 60 (64%) Stage III/Iva: 34 (36%)	1. Thyroxine withdrawal 2. rhTSH Both groups given same information on allowed and restricted foods.	^b I/Cr ratio < 100 (mcg/gCr)	2 wks; ablation	NR	X	✓	X/X/X	X/X
Kim (2011), PC, South Korea	20 (1 excluded non-adherence to LID); 19 analysed	39.7 ± 10.5 F: 13 (68%)	PTC: 18 (95%) FTC: 1 (5%); Stage I: 14 (74%) Stage III: 5 (26%)	One group: Educated for 2hrs before start of LID. Ppts could ask questions to HCP during LID.	^b<66mcg/gCr or 150mcg/L	2 wks; NR	Specially trained HCP	X	✓	X/X/X	X/X
Kim (2017), HC, South Korea	326	49.3 ± 12.3 F: 248 55.8 ± 15.9 F:11	NR	NR	NR	23.9 ± 2.8 days	NR	X	X	✓/X/X	X/X
Lee (2014), PC, South Korea	202 (7 excluded: non-adherence to LID); 195 analysed	44 ± 11.08 F: 149 (76%)	PTC; T1–3N0M0: 49 (25%) T1–3N1M0: 146 (75%)	One group: Educated for 90-minutes on LID. Hotline to answer questions on LID.	<50	2 wks; ablation	Specially trained HCP	✓	✓	X/X/X	X/✓
Lee (2014), HC, South Korea	2241 (12 excluded due to missing data); 2229 analysed	47.0 ± 11.0 F: 1701 (76.3%)	PTC: 97%; Lung metastasis: 1.0%	NR	NR	2 wks	NR	X	X	✓/X/X	X/X
Li (2017), [abstract], HC, USA	207	49 F: 72%	NR: NR	One group advised a LID.	NR	2 wks; ablation	NR	X	X	X/✓/X	X/X
Maxon (1983), PC, USA	40 1. Usual diet: 21 2. LID: 19	NR; NR	NR; Residual disease: 9 Metastasis: 10	1. Regular diet 2. LID: detailed diet sheets (listing permitted foods with serving sizes), alternate foods, dietary pattern and sample menu.	50	1 wk; DxWBS	Dietician	X	✓	✓/X/X	X/✓
Markovic (2015), [abstract], HC, Croatia	135 1. Regular diet: 34 2. Advice only: 30 3. Written strict LID: 71	Median (range): 54 (19–79) F: 107 (79%)	DTC (100%); Stage 1	1. Regular diet 2. LID advice only 3. Written instructions, strict LID	NR	NR; ablation	NR	✓	X	X/X/X	X/X
Morris (2001), HC, USA	140 1. Regular diet (RD): 50 (+ 7 healthy controls) 2. LID: 44 (7/44 thyroid cancer gave UI measurement) 3. 3. Control: 39 (all healthy)	NR; NR	NR; LNI: 27 Metastasis: 3	1. Advised not to eat iodinated foods (salt, multivitamins and seafood). 2. Copy of LID diet in pre-ablation instructions mailed/given in person	NR	10–14 days; ablation	NR	✓	✓	X/X/X	X/✓
Nakano (2020),[abstract], HC, Japan	24	NR; NR	PTC	One group advised a self-managed LID	NR	1 wk; ablation	NR	✓	✓	X/X/X	X/X
Park (2004), HC and PC, USA	45 (PC, all had rhTSH) 1. 1 wk LID: 212. 2 wk LID: 24(Of these, previously prepared with THW and followed 2wk LID: 15)	NR; F: PC: 80% H: --	NR; Residual and recurrent	LID explained at visit. Ppts sent home with a simple 1-pg list of dietary recommendations to limit iodine intake.	<50	1. 1 wk 2. 2 wks; DxWBS	NR (not a dietitian)	X	✓	X/X/X	X/X
Pluijmen (2003), HC, Netherlands	120 1. Controls: 61 2. LID: 59	43 ± 15; F: 94 (78%)	PTC: 101 (84%) FTC: 19 (16%); LNI: 32	1. Controls: no diet 2. LID: written instructions; assisted by dietitian.	NR	4 days; ablation	Dietitian	✓	X	X/X/X	X/X
Passero (2002),[abstract], HC, USA	59	NR; NR	NR; NR	One group advised a LID	<50	NR; ablation	NR	✓	X	X/X/X	X/X
Sohn (2013), HC, South Korea	295	45.8 ± 9.5 F: 246 (83.4%)	PTC; Ex: 250 (85%) LNI: 179 (61%)	One group advised a LID. Advised on foods and drugs that were allowed/not allowed. Given a 3-day sample menu tailored for Korean people and contact details for dietary questions.	NR	2 wks; ablation	Dietitian	✓	X	X/X/X	X/X
Sun (2015), [abstract] HC, China	95 1. Moderate-severe LID: 30 2. Mild iodine deficient: 26 3. Adequate iodine: 39	NR; NR	PTC; Intermediate risk	1. 2–4wks of moderate to severe LID 2. 2–4 weeks of mild LID 3. 2–4 weeks of adequate LID	NR	2–4 wks; ablation	NR	✓	X	X/X/X	X/X
Tala Jury (2010), HC, Italy	201 1. THW: 125 2. rhTSH: 76	44.0 ± 15.2 F: 164 (81.6%)	PTC: 182 (90.5%) FTC: 19 (9.5%); T1-T3N0M0: 144 (72%) T1-T3N1M0: 57 (28%)	Specific LID not recommended; advised not to take any iodine containing drug or iodine-supplementing preparation.	NR	4 wks; ablation	NR	✓	✓	X/X/X	X/X
Tamura (2016), [translated], HC and survey, Japan	39 (1 urine sample not collected before conducting LID); 38	57.0 ± 2.3 F: 24 (61.5%)	PCT (100%); pT3 or pT4a	One group received: handbook for the LID (food prohibited; allowed in limited amounts; allowed freely); a LID menu for 2wks; individualised advice (consultations 15–30 min long)	<100	10 d (1 wk before; 3 days after); ablation, DxWBS	Nutritionists/dietitians	X	✓	✓/X/X	✓/X
Yoo (2012), HC, South Korea	161 1. Less strict LID: 71 2. Very strict LID: 90	47.8 ± 11.2 F: 133 (82.6%)	NR; Capsular invasion: 109 (68%) Ex: 58 (36%)	1. Guidelines including restricted and allowed items. 2. Further food items were restricted.	NR	1 and 2: 2 wks (at least); ablation	Nuclear medicine physicians	✓	X	X/X/X	✓/X
Case reports/case series
Al Asiri (2012) Saudi Arabia	1	62: F	PTC	NR	NR	3 wks	NR	X	X	✓/X/X	X/X
Al Nozha (2011), Saudi Arabia	1	66: F	PTC	NR	NR	4 wks	Dietitian	X	X	✓/X/X	X/X
Hinds (2008), USA	1	21: F	PTC; LNI	LID	NR	4 wks; DxWBS	Endocrinologist	X	✓	X/X/X	X/X
Ju (2015), South Korea	3	P1: 53: F P2: 48: F P3: 59: F	PTC; Stage II or III	Education program: 2.5-h group workshop that included 30 min of LID education.	< 100	2 wks; ablation	MDT including dietitian	X	✓	X/X/X	X/X
Kim (2014), South Korea	2	P1: 70: F P2: 68: F	PTC	NR	NR	2 wks	NR	X	X	✓/X/X	X/X
Krishnamurthy (2007), USA	2	P1: 70: M P2: 81: F	PTC	P1: NRP2: Booklet produced by ThyCa.org containing LID advice	NR	P1: 2 wks P2: NR	NR	X	X	✓/X/X	X/X
Maruca (1984), USA	3 (4 cases, 1 ppt counted twice)	P1: 66: F P2: 31: F P3: 33: F	NR: Metastasis	Whilst in hospital ppts put on a controlled iodine-depletion regimen	<25	5d; therapy	Nutritionist	X	✓	X/X/X	X/X
Nozu (2011), Japan	1	77: F	PTC	NR	NR	2 wks	NR	X	X	✓/X/X	X/X
Shakir (2008), USA	5	P1: 87: F P2: 66: F P3: 77: F P4: 68: M P5: 71: F	P1: FTC P2: PTC P3: PTC P4: PTC P5: FTC	NR	NR	P1: 10d/5wks P2: 6 wks P3: 1 wk P4: 10 d P5: 2 wks	NR	X	X	✓/X/X	X/X
Roopnarinesingh (2011), [abstract], case study, USA.	1	81, F	PTC	NR	NR	2 wks	NR	X	X	✓/X/X	X/X
Surveys
England (2020), Survey (including freetext box), UK	56 (completed by personnel at 47 treatment centres; no patients surveyed)	NA	NA	Described current practice regarding the LID.	NA	NA	NA	X	X	X/X/X	✓/X
Moon (2012), survey, South Korea	121 patients surveyed (4 incomplete surveys excluded); 117 analysed	41.5 (24–66);F: 117 (100%)	Assumed DTC; NR	Survey assessed: Dietary life and cooking skills; knowledge of LID; self-efficacy; personal and environmental barriers	NA	NA;2–4 wks before therapy	NR	X	X	X/X/X	✓/X
Qualitative studies
Herbert (2020), interviews, UK	28	51 (24–80) F: 19 (68%)	NR; NR	Ppts recruited from three centres which offered different advice: Site 1 advised a LID for 2 wks before treatment, and 48 h after; Site 2 advised a LID for 1 wk before treatment; and Site 3 did not advise a LID.				X	X	X/X/X	✓/X
Lee (2016), interviews, Korea	5	28–58; F: 4 (80%)	NR; Stage 1: 1; Stage 3: 3; Stage 4: 1	Iodine restricted diet beginning 2 wks before RAI therapy. Ppts were going through the last two weeks of hormone withdrawal before high-dose radiation therapy (100–150mCi) to remove any remaining thyroid tissue.				X	X	X/X/X	✓/X
Stajduhar (2000), focus groups/interview/field notes, Canada	27	38 (18–80) F: 22 (81%)	NR; NR	NA				X	X	X/X/X	✓/X

Abbreviations: AE, adverse effects; d, days; DTC, Differentiated Thyroid Cancer; DxWBS, Diagnostic Whole-Body Scan; EBE, Experience based evidence; Ex, extrathyroidal invasion; F, female; F&B, facilitators and barriers; FTC, follicular thyroid cancer; HCP, healthcare professional; HC, historical cohort study; I/Cr, iodine/creatine; IQR, interquartile range; LID, low iodine diet; LNI, lymph node involvement; mcg, micrograms; mcg/gCr, urinary iodine-to-creatinine ratio; mCi, millicurie; mort, mortality; Na, serum sodium; NA, not applicable; NR, not reported; pN1a, Cancer has spread to the lymph nodes around the thyroid; pN1b, Cancer has spread beyond the central compartment; pT3, The tumour is larger than 4 cm, but the tumour does not extend beyond the thyroid gland; pT4, The tumour is any size and has extended beyond the thyroid; PC, prospective cohort study; ppts, participants; PTC, papillary thyroid cancer; RAI, radioactive iodine; RAIT, radioactive-iodine treatment; rhTSH, recombinant human thyroid-stimulating hormone; Rec, recurrence; SD, standard deviation; THW, thyroid hormone withdrawal; TSH, thyroid-stimulating hormone; UIC, urine iodine concentration; UIE, urine iodine excretion; UIS, urinary iodine status; WBS, whole-body scan; wk(s), weeks; yr(s), years; --: Uninterpretable.
^aExpected misprint; probably, mcg/d.
^bNot iodine intake: advised UIC or I/Cr ratio.

Table 2. Facilitators and barriers to consuming a LID.
Themes^a	Subthemes	Study (year), evidence type (1st or 2nd OC^b)	Supporting evidence	Recommendation for intervention
Self-perception	+ Strong belief: Understandable rationale/clear coherence	Herbert (2020) Qualitative (1st oc)	It's easily understandable why you have to go on that diet. Without it, the treatment isn't as effective, so I'd rather the treatment be effective and try and get cured than eat stuff that I'm normally eating.	Education: rationale for LID explained
		Lee (2016) Qualitative (2nd oc)	They understood the importance of the LID treatment enough that they demonstrated a strong will to remain focused on it.
		Moon (2012) Survey	Perceived barrier related to LID practice: I do not believe that LID is helpful for my treatment (1 strongly disagree – 7 strongly agree): 1.93 ± 1.24.
	+ Active role in treatment/sense of control	Herbert (2020) Qualitative (1st oc)	I wanted to make sure that I was really strict, because at the end of the day, that is something that I can kind of control. As long as I have a LID, then I have done everything I can to make sure that the treatment works.	Empowering patients to reduce their iodine intake (to take control in their treatment)
		Lee (2016) Qualitative (1st oc)	I also checked and kept a daily record of what I ate.
		England (2019) Qualitative (2nd oc)	…clinicians also said that there were people who liked feeling in control of a part of their cancer treatment.
Changes to health	+ Other health benefits	Herbert (2020) Qualitative (2nd oc)	+…some stated that it helped them to lose weight and feel healthier.	No recommendation
	+ Other health benefits	England (2019) Qualitative (2nd oc)	+…clinicians also said that there were people…who experienced other health benefits from thinking about what they were eating.	No recommendation
	+/− Reduction in energy intake	Herbert (2020) Qualitative (2nd oc)	+…some stated that it helped them to lose weight	Education: food recommendation and clear length and level of restriction
		Ju et al (2016) Quantitative	+/− The mean level of energy intake during the LID period was 1325 kcal, which was 446 kcal lower than the intake during the usual diet (1771 kcal).
		Maxon (1983) EBE	+/− Participants were informed that the LID did not meet recommended daily calories (i.e., 1400 kcal).
	- Negative impact on psychological health (guilt over relapses, blame, anxiety, depression boredom, overwhelming, early unsettled feelings) and physical health (fatigue, hunger, loss of appetite, nutrient content)	Herbert (2020) Qualitative (1st oc)	Then when I went in, I explained that I'd messed up, so they had to look into it. I think they went to see Doctor [Name] then to see if it was okay to continue, which it was at that time.	Ongoing support
		Lee (2016) Qualitative (1st oc)	I had some food I wasn't allowed to eat in the first treatment. I regret and feel sorry for my body because it's due my carelessness that I am going through this second treatment.
		England (2019) Qualitative (2nd oc)	The diet was identified as being a source of anxiety for some people…
		Stajduhar (2000), Qualitative (2nd oc)	Yet, little nutritional consultation was offered to assist them in understanding what constituted a low-iodine diet. As a result, many participants did their own research, yet some continued to be unclear and worried that this might have affected their treatment.
		Ju et al (2016) Quantitative	The intake levels of most nutrients, were significantly lower during LID compared to the usual diet.
		Lee (2014) EBE	In our experience, a LID could be a source of anxiety because the patients feel that the variety of foods that could be eaten safely is low.
		Maxon (1983) EBE	They did complain that the diet was boring.
		Morris (2001) EBE	Others found it "overwhelming" to maintain the diet while adapting to a new diagnosis of cancer and withdrawing from medications.
Dietary adaptation	+/− Cancer treatment context + Easy compared to other cancer journeys; short time frame. - Dealing with other treatment and medication side effects	Herbert (2020) Qualitative (1st oc)	+ I mean compared to having chemotherapy or radiotherapy, anything like that, if this can sort it out and it means me not on anything else, it's far easier on me and my family than anything else. - …when you are already experiencing… Your emotions are all over the place because you have just been told you have got cancer. You have just had surgery or whatever and now you have got to take more treatment that you don't know is definitely going to work and then you have got to go and do this [referring to the LID], it is a lot.	Support
		England (2019) Survey	+/− 31 of the 56 clinicians (53%) indicated that they thought people coped very well with the diet
		Lee (2016) Qualitative (2nd oc)	- As time went on and the hormone deficiency grew more severe while the LID aggravated nutrition deficiencies, patients became more worn out from the physical symptoms they experienced.
		Morris (2001) EBE	- Others found it "overwhelming" to maintain the diet while adapting to a new diagnosis of cancer and withdrawing from medications.
	- Greater difficulty for sub-groups:^c e.g. older people, diabetics, vegetarians, those culturally consuming diets higher in iodine	Lee (2016) Qualitative (1st oc)	It was difficult to refrain from what I wanted to eat. I am going to have kimchi when the treatment is over.	Education: food recommendations adapted for sub-groups
		Herbert (2020) Qualitative (1st oc)	I am vegetarian so I did find the diet very hard.
		England (2019) Qualitative (2nd oc)	…some groups of people were more likely to find the diet difficult, specifically, people with diabetes, vegans/vegetarians, older people and people from non-British backgrounds
		Nakada (2016) Quantitative	Practice of LID may be difficult in older patients or patients with higher UIC under routine diet. Since risk of failure of LID increases in such group, it is recommended LID plan for rh-TSH aided remnant tissue ablation should be applied on a patient-to-patient basis taking patients' personal characteristics into consideration.
		Moon (2012) Survey	Perceived barrier related to LID practice: I enjoy foods with high iodine content (1 strongly disagree – 7 strongly agree): 4.53 ± 1.48.
		Ju (2015) EBE	Maintaining the LID is challenging for Korean patients, whose regular diet consists of foods with very high iodine content, such as seaweeds, seafoods, soy sauce, soybean pastes, and salted vegetables such as kimchi.
	- Unable to moderate: Over restriction in terms of time on the diet and dietary choices (especially for those on a LID for recurrence).	Herbert (2020) Qualitative (1st oc)	Sometimes you may eat something that you think, Oh my gosh, that might have had dairy in or iodine. Literally once I find something that hasn't got any iodine or low iodine in, this time I was living on a jacket potato.	Education: clear length and level of restriction
		Lee (2016) Qualitative (1st oc)	Because there isn't much I am allowed to eat, I cannot eat regularly. I would eat only once a day, when I felt like I was starving.
		England (2019) Qualitative (2nd oc)	…and there were comments that some people were more restrictive than advised and attempted to follow no- iodine diets, rather than reduced iodine.
		Moon (2012) Survey	Knowledge questionnaire item – "I have to practice LID after radioactive iodine treatment" Almost half (46.2%) thought this statement was true when the answer was false.
Behavioural strategies	+ Substituting high for low iodine products	Herbert (2020) Qualitative (2nd oc)	Substitutions for milk were discussed by most people particularly because of its importance in tea, coffee and cereal. Participants reported trying non-dairy substitutes for milk such as soya, oat, rice and coconut…Other substitutions included swapping milk for dark chocolate, butter for dairy-free spreads and consuming gluten-free products.	Education and behaviour modification: food recommendation - substitution of high for low iodine products
	+ Substituting high for low iodine products	Lee (2016) Qualitative (1st oc)	I love sweets! But since I couldn't have them, I had apples and pears instead.
	+/− Information seeking: Checking products are low in iodine (on ingredients lists/with companies)	Herbert (2020) Qualitative (1st oc)	+ Also, it got me checking the labels on the ingredients a little bit more thoroughly just so I could prep a couple of days before going on the diet and then also during the diet, I'd look and see, "This is okay or not". - Just going to the supermarket, taking so long to check products that haven't got iodine in, that's the only hard part is identifying the products you can't have…	Education: food recommendation – food labelling
		Lee (2016) Qualitative (2nd oc)	+ They were interested in everything about their diets and proactively searched online to get information about the regimen.
		Stajduhar (2000) Qualitative (2nd oc)	- Yet, little nutritional consultation was offered to assist them in understanding what constituted a low-iodine diet. As a result, many participants did their own research, yet some continued to be unclear and worried that this might have affected their treatment.
		Moon (2012) Survey	- Perceived barrier related to LID practice: I cannot distinguish foods high in iodine from those low in iodine (1 strongly disagree – 7 strongly agree): 4.79 ± 1.81.
	+/− Preparing low iodine meals	Lee (2016) Qualitative (1st oc)	+ From two weeks before the RAI treatment, I started to freeze what I could eat. I also checked and kept a daily record of what I ate.	Education: food recommendation – food provision
		Herbert (2020) Qualitative (1st and 2nd oc)	- A few participants discussed repeatedly eating the same meal due to a lack of time to prepare and organise a LID meal: "I was back at work, so I just used to have jam sandwiches, usually".
		Yoo (2012) Quantitative	+ We thought that those who work and thus cannot cook every meal according to the LID might have a lower radioactive iodine ablation success rate, but there was no difference between actively working patients and stay-at-home patients.
		Moon (2012) Survey	- Item: I am not knowledgeable about how to prepare low-iodine menus (1 strongly disagree – 7 strongly agree): 5.51 ± 1.72.
		Tamura (2016) Survey	- Response of patients to questionnaire survey. Have you had any difficulties in preparing LID? 60% said yes.
Information provision	+ Clear advice about the LID UK LID working group diet sheet and HCP	Herbert (2020) Qualitative (1st oc)	I used to keep that [referring to the 'diet sheet'] in my bag, so when I went shopping, I could look at the list and then look at what was in it…because I kept forgetting.	Education: clear education/food recommendation/level of restriction
		England (2019) Survey	There was good awareness and usage of the UK LID-WG diet sheet (66% reported using it) and only four centres indicated that they were unaware of it.
	- Confusion Lack of clear advice, limited knowledge of acceptable foods. Led to skipping meals, repetition of same meals and feelings of limited food choice.	Herbert (2020) Qualitative (1st oc)	I did get a bit confused about the whole thing, so I just really limited my diet to a few recipes and I just repeated them over and over again. At the end of it, I was, kind of, getting a bit desperate for food.
		Lee (2016) Qualitative (1st oc)	I would cook a porridge with rice crust. I skipped lunch at work because I was so concerned with what I was not allowed to eat.
		Stajduhar (2000) Qualitative (2nd oc)	Participants were concerned about the lack of information about dietary considerations associated with treatment. Participants explained that they must be on a LID six weeks before treatment and approximately 24–48 h posttreatment. Yet, little nutritional consultation was offered to assist them in understanding what constituted a LID.
		Moon (2012) Survey	The respondents also possessed little knowledge of the foods restricted in LID, such as soybean paste, soy sauce, multi-vitamins, processed meats, milk, and dairy products. The item 'LID is a low-salt diet (false)' presented the lowest percentage of correct answers (12%).
		England (2019) Survey	For some questionnaire items, different responses were provided by different clinicians from the same centre.
		Morris (2001) EBE	Since 1997 some patients submitted feedback on the LID. Some suggested the diet was difficult to understand and confusing.
		Lee (2014) EBE	In our experience, a LID could be a source of anxiety because the patients feel that the variety of foods that could be eaten safely is low.
Environment	+ Positive and effective reinforcement e.g., practical and emotional support and responsive HCP	Herbert (2020) Qualitative (1st oc)	… my parents, obviously, were here as well, so they've just reminded me not to have milk and stuff.	Ongoing support
		Lee (2016) Qualitative (2nd oc)	…they wanted emotional support to maintain a temperate lifestyle and to remain disciplined.
		Moon (2012) Survey	Perceived barrier related to LID practice: I do not have someone who will prepare low-iodine menus for myself (1 strongly disagree – 7 strongly agree): 4.86 ± 2.14.

Abbreviations: +, facilitating factor to consuming a LID; −, challenge/barrier to consuming a LID; EBE, experience-based evidence; HCP, health care professional; kcal, kilocalories; LID, low iodine diet; LID-WG, low iodine diet working group; OC, order construct; UIC, urinary iodine concentration; rhTSH, recombinant human thyroid-stimulating hormone; RAI, radio-active iodine.
^aThe synthesis of both first and second order constructs, into 3rd order constructs (interpretations of the review authors).
^b1st and 2nd order constructs relevant for qualitative studies: 1st order constructs are those that reflect participants' understandings, as reported in the included studies (usually found in the results); 2nd order constructs are interpretations of participants' understandings made by authors of these studies (usually found in the discussion/conclusion).
^cWho experience existing dietary restriction for other health or lifestyle reasons.

Table 3. Matrix of effectiveness synthesis studies use of intervention recommendations identified in the views synthesis.
Study (year)	Type of LID	Clear length of restriction	Education													Overall intervention investment for educator and level of ppt empower-ment to follow a LID^a	Post IS mean (SD) (unit)
			Support				Food recommendations
			Inclusion of family/friends	Relationship with HCP			Food recommendations
				Number of contact sessions/Format: In or Gr	HCP	Ongoing support (e.g., phone)	Delivery and amount of detail on LID		List of foods to avoid/restrict	List of allowed foods	Food labelling/food composit-ion	Meal plan/sample menu	Food provision	Adapted for sub-groups	Advised iodine intake (mcg/d)
				Number of contact sessions/Format: In or Gr	HCP	Ongoing support (e.g., phone)	Written	Face-to-face (length)	List of foods to avoid/restrict	List of allowed foods	Food labelling/food composit-ion	Meal plan/sample menu	Food provision	Adapted for sub-groups	Advised iodine intake (mcg/d)
Choi (2008)	LID	2wks	X	1/In	Nu/DN	X	✓	✓ (NR)	✓	✓	✓	✓	X	✓	NR	Medium	85 (85) (24 h; mcg/d)
Dobrenic (2011)	LID	2wks	X	1/In	NR	X	✓	NR	✓	✓	X	X	X	X	NR	Low	76.6 (9.0) (spot; mcg/L)
Ito (2018)	LS- LID	2wks	X	1/In	Radiol/Nu	X	✓	✓ (NR)	✓	X	X	X	X	X	NR	Low	_ _
Ito (2018)	S- LID	2wks	X	NR	NR	X	NR	NR	X	X	X	✓	✓	X	<30	Low	_ _
Ju (2016)	LS- LID	2wks and 3 days	X	1/In	Nurse	X	✓	✓ (10–15 min)^b	✓	✓	X	X	X	X	<100	Low	82.7 (57.3) (3 day diet records; mcg/d)
Ju (2016)	S- LID	2wks and 3 days	X	1/In and Gr	DN + other HCP	X	✓	✓ (In: 10–15 min; Gr: 2.5 h)^c	✓	✓	X	✓	X	X	<100	High	68.1 (28.8) (3 day diet records; mcg/d)
Kang (2018)	LID	2wks	X	NR	NR	X	✓	NR	✓	✓	X	X	X	X	<100 (μg/gCr]	Low	THW: 23.8 (19.9) rhTSH: 47.4 (18.4) (spot I/Cr; mcg/gCR)
Kim (2011)	LID	2wks	X	Multiple^d/In	Nurses/DNs	✓	✓	✓ (2 hrs)	✓	✓	X	✓	X	✓	<150	High	19.5 (8.8) (spot I/Cr; mcg/gCr)
Lakshma-nan (1988)	LID	4wks	X	1/In	DN	X	✓	✓ (NR)	✓	X	✓	X	X	✓	~50	Medium	69 (14) (spot; mcg/gCr)
Lee (2014)	LID	2wks	X	Multiple/In	Nurses	✓ (hotline)	✓	✓ (90 min)	✓	✓	X	✓	X	✓	<50	High	22.62 (15.48) (spot UI; mcg/L)
Lim (2015)	LS- LID	2wks	X	1/In	NC	X	✓	✓ (NR)	✓	✓	X	✓	X	✓	<50	Medium	35.8 (35.2) (24 h I/Cr; mcg/gCr)
Lim (2015)	S- LID	2wks	X	1/In	NC	X	✓	✓ (NR)	✓	✓	X	✓	X	✓	50 – 100	Medium	28.6 (23.6) (24 h I/Cr; mcg/gCr)
Maxon (1983)	LID	1wk	X	Multiple^e/In	DN	X	✓	✓ (NR)	✓	✓	X	✓	X	✓	<50	High	42.8 (49.3) (24 h I/Cr; mcg/gCr)
Padovani (2015)	LID	15d/30 d	X	1/In	NR	X	✓	NR	✓	✓	X	X	X	X	< 50	Low	2 wks: 76 (NR) 4 wks: 63 (NR) (24 h UI; mcg/L)
Park (2004)	LID	1wk/2wks	X	1/In	NR	X	✓	✓ (NR)	✓	X	X	✓	X	X	< 50	Medium	1 wk: 199.87 (169.53) 2wks: 84.69 (44.03)(spot I/Cr; mcg/gCr)
Roh (2006)	LS- LID	2wks	X	1/In	NR (not a DN)	X	✓	NR	✓	X	X	X	X	X	NR	Low	289.75 (188.24) (spot I/Cr; mcg/gCr)
Roh (2006)	S-LID	1wk	X	1/In	DN	X	✓	✓ (NR)	✓	✓	X	✓	X	✓	NR	Medium	127.87 ± 78.52 (spot I/Cr; mcg/gCr)
Sohaimi (2019)	LS-LID	1wk	X	1/In	NR	X	✓	✓ (NR)	✓	✓	X	X	X	NR	NR	Low	63.82 (51.21) (spot UI; mcg/L)
Sohaimi (2019)	S-LID	1wk	X	1/In	DN/nurse	X	✓	✓ (NR)	✓	X	X	✓	X	✓	<50	Medium	56.85 (50.07) (spot UI; mcg/L)
Tamura (2016)	LID	1wk and 3d	X	1/In	NU/DNs	X	✓	✓ (15–30 min)	✓	✓	X	✓	X	✓	<100	High	119.2 (49.7) (spot; mcg/gCr)
Tomoda (2005)	LS- LID	1wk	X	1/In	NR	X	✓	NR	✓	X	X	X	X	X	NR	Low	182.2 (161.59) (spot I/Cr; mcg/gCr)
Tomoda (2005)	S- LID	1wk/2 wks	X	1/In	NR	X	✓	NR	✓	X	X	X	X	X	NR	Low	1wk:119.4 (62.27) 2wks: 63.1 (40.58) (spot I/Cr; mcg/gCr)

Abbreviations: Cr, creatinine ratio; d, days; DN, dietitian; g, gram; Gr, group; HCP, healthcare professional; hr(s), hour(s); In, individual; I/Cr, iodine/creatine; IS, iodine status; L, litre; LID, low iodine diet; LS, less-strict; mcg, microgram; NC, Nutrition co-ordinators; NU, Nutritionist; NR, not-reported; ppt, participant; Radiol, Radiologist; RAIT, radioactive-iodine treatment; SD, standard deviation; S-LID, stricter low iodine diet; rhTSH, recombinant human TSH; THW, thyroid hormone withdrawal; UI, urinary iodine; wk(s), weeks; --, uninterpretable.
^aLow: provision of a leaflet; medium: provision of a leaflet + 1 face-to-face contact; high: intensive food recommendations, face-to-face contact >1, ongoing support, possible food provision.
^bexplaining RAIT - minimal time on LID.
^c30 min on LID.
^dCompliance regularly checked and reinforced.
^eFree access.

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Impact of Low Iodine Diets on Ablation Success in Differentiated Thyroid Cancer

A Mixed-Methods Systematic Review and Meta-Analysis

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