Novel triple-drug regimen for preoperative optimization in giant Graves’ disease: a prospective efficacy and safety trial

Introduction

Graves’ disease (GD) is the leading cause of hyperthyroidism worldwide, affecting approximately 2% of women and 0.2% of men (1). Standard therapeutic options include anti-thyroid drugs (ATDs), radioiodine (¹³¹I) therapy, and thyroidectomy. Nearly 25% of patients with GD develop moderate to severe diffuse goiter (2). We have observed that GD patients with marked thyroid enlargement frequently present with severe and refractory hyperthyroidism, airway compression, and a pronounced reduction in quality of life. Given that studies focusing on very large thyroid volumes in GD are scarce and are mainly limited to case reports, we referred to prior literature together with our clinical observations to adopt 100 mL as the threshold for defining “marked” enlargement. In this study, these patients are classified as having “giant” GD. In contrast to typical GD, which is often controlled with ATDs, patients with “giant” GD exhibit persistent difficulty in achieving stable euthyroidism, with recurrent fluctuations between hyperthyroidism and hypothyroidism, inability to discontinue ATDs, and thyrotropin receptor antibody (TRAb) levels consistently exceeding 40 IU/L. Moreover, ATD therapy does not alleviate tracheal compression in these patients. ¹³¹I therapy is also suboptimal, as conventional doses fail to ablate sufficient thyroid tissue and the radiation dose required for efficacy would be excessively high (3). Consequently, thyroidectomy is frequently the definitive and most effective treatment.

Preoperative preparation can effectively reduce the risk of surgery-related complications in patients with GD during the perioperative period (4-6). For patients with typical GD, commonly used pharmacologic strategies include compound iodine solution, ATDs, β-adrenergic blockers, levothyroxine (LT4), and other agents (7-10), each with distinct advantages and limitations when administered alone or in combination. Compound iodine solution plays a central role by inhibiting thyroid peroxidase (TPO), reducing thyroid hormone release through suppression of thyroglobulin (TG) hydrolysis (11), and attenuating the upregulation of genes involved in thyroid hormone synthesis and transport (12). In addition, its use has been associated with reduced intraoperative blood loss through downregulation of vascular endothelial growth factor (VEGF) (13,14). ATDs fundamentally inhibit thyroid hormone synthesis and decrease TRAb production; however, they inevitably lead to elevated thyroid-stimulating hormone (TSH) levels, resulting in thyroid congestion and enlargement, which is unfavorable for surgery (15). The “preoperative preparation method of sequential thyroid defunctionalization”, consisting of ATDs followed by LT4, is designed to nearly abolish thyroid hormone synthesis while suppressing TSH secretion via negative feedback. This approach prevents the transition of follicular epithelial cells from cuboidal to tall columnar morphology and thereby helps reduce surgical difficulty (16).

Compared with typical GD, the thyroid volume in “giant” GD exceeds 100 mL, which is substantially greater than the normal thyroid volume (approximately 14 mL in women and 18 mL in men) (2). The marked enlargement characteristic of “giant” GD poses significant surgical challenges and increases perioperative risk, including difficulty in operative exposure, greater intraoperative blood loss, thyroid storm, cervical hematoma, tracheomalacia, and, in extreme cases, mortality (17,18). However, because of its rarity, “giant” GD has been only sparsely addressed in clinical studies (19), and a comprehensive, standardized preoperative preparation regimen is yet to be established. Building upon prior experience and the concept of sequential thyroid defunctionalization, we have developed a novel triple-drug preoperative regimen for “giant” GD consisting of ATDs, LT4, and compound iodine solution. This strategy is intended to reduce surgical difficulty through a synergistic approach that controls hyperthyroidism, limits further thyroid enlargement, and diminishes thyroidal vascularity. The present prospective clinical study aims to objectively evaluate the safety and efficacy of this regimen in patients with “giant” GD. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-482/rc).

Methods

Patient selection and study design

This prospective, single-arm cohort study recruited patients with “giant” GD who presented to our medical center between July 1, 2021, and December 31, 2024. According to predefined inclusion and exclusion criteria, 13 eligible patients were ultimately enrolled and received the complete “giant GD preoperative triple-drug preparation regimen”, consisting of methimazole (MMI), LT4, and compound iodine solution. Relevant clinical data were collected throughout the entire course of therapy to evaluate the effectiveness of preoperative preparation. This study was conducted in accordance with the STROCSS criteria (20). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Biomedical Ethics Review Committee of West China Hospital, Sichuan University (2023 Review No. 88) and informed consent was obtained from all individual participants. The study was registered in clinicaltrials.gov (ChiCTR2300068267).

Inclusion and exclusion criteria

Because current guidelines do not provide a standardized definition of “giant” GD, we adopted a thyroid volume threshold of ≥100 mL based on institutional experience with severe GD, where this cutoff reliably identified patients with increased surgical complexity and perioperative risk. Owing to the rarity of the condition and the absence of prior data, a formal sample size calculation was not feasible; therefore, all consecutive eligible patients during the study period were prospectively enrolled.

Inclusion criteria were as follows: (I) aged 18 to 80 years; (II) clinically diagnosed GD with thyroid volume ≥100 mL; (III) presence or absence of extrathyroidal manifestations; (IV) contraindication or poor therapeutic response to ATDs or ¹³¹I therapy, with voluntary selection of surgical treatment; (V) good compliance with regular follow-up and willingness to accept appropriate dose adjustments as advised by physicians; (VI) provision of written informed consent. Patients who fulfilled all of the above criteria were enrolled.

Exclusion criteria were as follows: (I) contraindications to surgery; (II) contraindications to study medications, including pregnancy or lactation, or occurrence of severe adverse drug reactions (ADRs) such as serious allergy or bone marrow suppression; (III) use of medications affecting immune function within the previous three months (e.g., glucocorticoids); (IV) participation in another clinical trial during the study period. Patients meeting any exclusion criterion were not enrolled in this study (Figure 1).

Figure 1 A flowchart of this prospective, single-arm clinical study protocol. ATD, anti-thyroid drug; BMR, basal metabolic rate; GD, Graves’ disease; LT4, levothyroxine; PSV, peak systolic velocity.

Triple-drug preparation regimen

The “giant GD preoperative triple-drug preparation regimen” consisted of three sequential stages: (I) MMI preparation period, (II) MMI + LT4 preparation period, and (III) MMI + LT4 + compound iodine solution preparation period. In mainland China, compound iodine solution is the standard preparation for preoperative thyroid surgery, as recommended by the Surgery, 9th edition (People’s Medical Publishing House, 2018). The compound iodine solution used in this study was a licensed hospital-based preparation manufactured in our hospital pharmacy, with stringent quality control and standardized iodine content. The liquid formulation enabled precise dose titration required by our stepwise escalation protocol, which would be difficult to achieve with fixed-dose tablets. The medications and specifications were as follows: MMI (10 mg/tablet), LT4 (50 µg/tablet), and oral compound iodine solution (containing 5 g of iodine and 10 g of potassium iodide per 100 mL; 0.05 mL per drop, corresponding to 5.08 mg of elemental iodine per drop).

MMI preparation period

The aim of this stage was control of hyperthyroidism. Based on thyroid function status and in accordance with current clinical practice guidelines for hyperthyroidism (21), MMI was initiated at 20 mg/day (administered once or twice daily). Thyroid function was reviewed monthly, and the MMI dose was dynamically adjusted as required, with the maximum daily dose increased to 30–40 mg when indicated.

MMI + LT4 preparation period

After initial control of thyroid function [normalization of free thyroxine (FT4) and free triiodothyronine (FT3)], patients with “giant” GD were started on LT4, taken on an empty stomach in the early morning, initially at 25 µg/day. The physiologic LT4 requirement was calculated using thyroid function indices and patient body weight (1.6 µg·kg⁻¹·day⁻¹). The LT4 dose was titrated monthly to gradually replace thyroid hormone production while maintaining normal serum FT4 and FT3 levels. Monthly follow-up and dose adjustments were continued throughout this period.

MMI + LT4 + compound iodine solution preparation period

Once the surgical date had been scheduled, and the doses of MMI and LT4 were kept unchanged, compound iodine solution was added for 14 days. Compound iodine solution was dispensed onto steamed bread using a sterile 2-mL plastic dropper by trained nursing staff, and administration was supervised to ensure accurate timing and dosing. The dosing schedule was three times daily (tid) with identical doses at each administration, beginning at 3 drops/tid and increasing stepwise by 1 drop per dose each day (i.e., 3, 4, 5 … up to 16 drops/tid).

Clinical data collection

Baseline patient characteristics were recorded at enrollment, including sex, age, height, weight, duration of GD, prior GD treatments, and family history. All patients underwent color Doppler ultrasonography of the thyroid and cervical vessels to measure the peak systolic velocity (PSV) data of the bilateral thyroid superior artery (Figure 2). Computed tomography (CT) was used to visualize cervical airway compression caused by “giant” GD (Figure 3). Multiparametric three-dimensional (3D) CT reconstruction provided 3D visualization of the thyroid and associated vasculature through post-processing techniques and enabled precise volumetric assessment of the thyroid gland (Figures 4,5). Basal metabolic rate (BMR) was calculated using Gale’s formula (22), and thyroid hormone levels and relevant antibodies were assessed to determine thyroid functional status. These evaluations were performed repeatedly before and after the preparation regimen to assess treatment effectiveness and determine optimal timing for surgery. Laryngoscopy was conducted by otolaryngologists to evaluate vocal cord mobility and identify potential vocal cord paralysis.

Figure 2 The PSV values of bilateral superior thyroid arteries in a “giant” GD patient at enrollment, after MMI + LT4 preparation, one week after MMI + LT4 + compound iodine solution preparation, and after MMI + LT4 + compound iodine solution preparation were 191.31, 212.78, 137.67 and 86.60 cm/s (A-D) on the left side, respectively; right side: 159.3, 155.65, 142.77, 93.4 cm/s (E-H). GD, Graves’ disease; LT4, levothyroxine; MMI, methimazole; PSV, peak systolic velocity.

Figure 3 Selecting cervical and thoracic CT scans at the hyoid and clavicular planes, the airway of “giant” GD patients is severely compressed. Images A and B, C and D, E and F, and G and H represent paired hyoid and clavicular plane cross-sectional views from four individual patients, respectively. R1=0.78 cm; R2=0.6 cm. R: the diameter of the narrowest point of tracheal compression. CT, computed tomography; GD, Graves’ disease.

Figure 4 Preoperative CT enhanced thyroid imaging and 3D visualization post-processing images of “giant” GD patients show a large thyroid volume and thickening of thyroid arteries and veins. Panels A-F represent the same measurement from 6 individual patients. V: the volume of thyroid, which is labeled in the figure. 3D, three-dimensional; CT, computed tomography; GD, Graves’ disease.

Figure 5 The changes in thyroid volume in “giant” GD patients before and after the application of the “‘giant’ GD preoperative triple drug preparation method” (pre-operative CT thyroid multi parameter 3D visualization post-processing image) (A → B, C → D, E → F). 3D, three-dimensional; CT, computed tomography; GD, Graves’ disease.

Throughout the study, patients were monitored for clinical manifestations of ADRs. Thyroidectomy specimens were photographed, measured, and weighed (net weight recorded). Perioperative data were collected, including intraoperative blood loss, operative time, occurrence of thyroid storm, recurrent laryngeal nerve (RLN) and superior laryngeal nerve (SLN) injury, postoperative parathyroid hormone (PTH) and serum calcium levels, and other relevant indicators.

Surgical procedure

All enrolled patients with “giant” GD underwent total thyroidectomy. A transverse cervical incision of approximately 20 cm was made along a natural skin crease. The strap muscles were transected to achieve adequate operative exposure. The thyroid gland was resected en bloc to avoid excessive bleeding during manipulation of the markedly enlarged and thickened isthmus, rather than sequential lobectomy with delayed isthmusectomy. In addition to standard electrocautery, bipolar coagulation, and ultrasonic scalpel hemostasis, meticulous vessel ligation using conventional techniques played an important role in maintaining intraoperative safety. Intraoperative nerve monitoring (IONM) and parathyroid autotransplantation were routinely performed (23).

Postoperative follow-up and assessment

After surgery, patients were returned to the ward for further continued observation. Beginning on the first postoperative day, patients initiated LT4 replacement therapy, typically at a dose of 100 µg daily. Postoperative serum PTH and calcium levels were routinely assessed the following morning. Oral calcium supplementation (600 mg, two to three times daily) and vitamin D (calcitriol, 0.25 µg, once or twice daily) were administered in cases of symptomatic hypocalcemia or laboratory-confirmed abnormalities (reference ranges: calcium 2.11–2.52 mmol/L; PTH 1.60–6.90 pmol/L). In general, patients were discharged on postoperative day 2. Outpatient follow-up was conducted monthly, with ongoing assessment of extrathyroidal manifestations and recovery of quality of life.

Data and statistical analysis

Statistical analysis was performed using IBM SPSS Statistics, version 26.0. Normally distributed continuous variables are presented as mean ± standard deviation (x¯±s), whereas non-normally distributed variables are reported as median and interquartile range [M (P25, P75)]. For two-group comparisons, paired t tests were applied when normality assumptions were met, and Wilcoxon signed-rank tests were used otherwise. A two-sided P value <0.05 was considered statistically significant. Graphs were generated using GraphPad Prism version 9.0.

Results

The age of enrolled “giant” GD patients ranged from 19 to 78 years, with BMI values ranging from 16.36 to 28.04 kg/m². The disease duration ranged from 1 to 26 years, and all patients had received ATD treatment during the course of diagnosis and management. Three patients had concomitant hyperthyroid heart disease (HHD), among whom 1 patient also presented with Graves’ ophthalmopathy (GO) and pretibial myxedema (PTM), as shown in Table 1. The neck appearance of patients with “giant” GD is illustrated in Figure 6. The duration of the first two preparation stages was individualized based on clinical response, resulting in variable preparation times. The total preparation time for the first two stages had a median duration of 6 months (IQR: 5–7 months).

Figure 6 The appearance of the front and side of the neck in “giant” GD patients; the overall transverse diameter of the thyroid gland can reach 30 cm (C) and the longitudinal diameter can reach 12 cm (D) when measured on the body surface. GD, Graves’ disease.

At enrollment, the mean thyroid volume of “giant” GD patients was 320.13 mL. The PSV of the right superior thyroid artery was 142.77±64.17 cm/s, and that of the left superior thyroid artery was 136.01±69.48 cm/s. Thyroid function testing showed a median FT4 of 26.4 pmol/L, median FT3 of 9.53 pmol/L, suppressed TSH (<0.005 mU/L in all patients), and TRAb levels greater than 40 IU/L in all cases, which represented the upper detection limit of this medical center. All “giant” GD patients completed sequential preparation with MMI alone, followed by MMI plus LT4, and finally MMI + LT4 + compound iodine solution.

At the end of the MMI + LT4 + compound iodine solution preparation period, the mean thyroid volume decreased to 276.44 mL (vs. baseline, P=0.001). The PSV of the right superior thyroid artery decreased to 98.52±53.55 cm/s (vs. baseline, P=0.006), and that of the left superior thyroid artery decreased to 94.73±37.76 cm/s (vs. baseline, P=0.016). Compared with baseline, the maximum reduction in PSV reached 63.64%. Thyroid hormone levels also improved significantly, with FT4 (P=0.001) and FT3 (P<0.001) both being effectively controlled, whereas TRAb levels remained above 40 IU/L throughout. In addition, heart rate decreased from 93–117 to 58–86 beats/min, and BMR decreased from 28–60% to –11% to 16%. Key data and trends of relevant indicators are shown in Table 2 and Figure 7, respectively.

Figure 7 Changes in thyroid function, thyroid volume, and thyroid superior artery PSV during preoperative preparation. 1, 2, 3, 4, and 5 represent the time of enrollment, MMI preparation, MMI + LT4 preparation, and MMI + LT4 + compound iodine solution preparation for 1 and 2 weeks, respectively; median. FT3, free triiodothyronine; FT4, free thyroxine; LT4, levothyroxine; MMI, methimazole; PSV, peak systolic velocity.

During the preoperative preparation period, all 13 “giant” GD patients reported metallic taste as the most prominent discomfort associated with oral administration of the compound iodine solution. One patient developed diarrhea during treatment, which resolved after symptomatic management. No other ADRs were observed.

“Giant” GD also imposes higher technical demands on anesthetic intubation and intraoperative anesthesia management. During thyroidectomy, a thin thyroid fibrous capsule, fragile thyroid tissue, and marked thickening of the superior thyroid arteries were observed (Figure 8). The operative time ranged from 120 to 270 minutes (median, 210 minutes), and intraoperative blood loss ranged from 56.9 to 213.3 mL (median, 77.7 mL). The mass of the resected thyroid gland ranged from 186.4 to 627.0 g (median, 272.9 g), as shown in Figure 9. All patients recovered uneventfully and were discharged from the hospital.

Figure 8 The neck appearance photographed in the preoperative state (A-D) after anesthesia intubation in the operating room. Surgical field of view images (E), the black arrow indicates the left superior thyroid artery (F).

Figure 9 The appearance and weight of specimens from some “giant” GD patients with thyroid resection (627, 325.6, 186.4, 544, 290, and 269.6 g, respectively). This quality data is the net weight of thyroid specimens (calibrated after removing container devices, etc.). GD, Graves’ disease.

Six patients showed a transient postoperative decrease in PTH levels during follow-up on the first day after surgery. Among them, PTH and serum calcium levels returned to normal within one month in five patients, and within three months in one patient. No permanent hypothyroidism occurred. After thyroidectomy, obvious improvements were noted in symptoms related to atrial fibrillation and heart failure, whereas GO and PTM exhibited no significant improvement (Figure 10). Patients reported high satisfaction with surgical outcomes and the consequent improvement in quality of life. During follow-up, neck incision scars gradually faded (Figure 11).

Figure 10 The appearance of GO and PTM (ENV) of “giant” GD patient, these photos were taken at preoperative period (A, E), 1 month after thyroidectomy (B, F), 6 months (C, G) and 1 year postoperatively, respectively (D, H). ENV, elephantiasis nostras verrucosa; GD, Graves’ disease; GO, Graves’ ophthalmopathy; PTM, pretibial myxedema;

Figure 11 The recovery condition of the neck incision appearance of “giant” GD patient, these photos were taken at 1 month, 3 months after thyroidectomy, 6 months and 1 year postoperatively, respectively. GD, Graves’ disease.

Discussion

In previously published clinical studies, the thyroid volumes of GD patients have typically ranged from normal size to several tens of milliliters (24-26); GD with extremely enlarged thyroid glands is rarely reported and is largely limited to sporadic case descriptions due to its low incidence. Clinically, markedly enlarged glands are often accompanied by compressive symptoms such as tracheal deviation or narrowing, dysphagia, and cosmetic deformity, together with substantially impaired quality of life. In addition, patients with very large goiters frequently present with severe and difficult-to-control hyperthyroidism. Conventional treatments have clear limitations in this population. ATDs are associated with a high recurrence rate after withdrawal (approximately 50%) (27,28), and may cause serious adverse reactions (29-31). Prior studies have demonstrated that GD patients with thyroid volumes less than 45.4 mL (32) or even 42 mL (19), are more likely to benefit from ¹³¹I therapy, whereas response is unsatisfactory in markedly enlarged glands. In our cohort, all “giant” GD patients experienced refractory recurrence following ATD withdrawal; 15.38% failed to achieve hypothyroidism after ¹³¹I therapy, and one patient underwent partial thyroidectomy. We describe these cases as “giant” GD based on typical clinical characteristics-severe hyperthyroidism, thyroid volume exceeding 100 mL (extending beyond the posterior border of the sternocleidomastoid muscle and markedly exceeding grade III goiter) (33), evident tracheal compression. For such patients, total thyroidectomy represents an appropriate definitive therapy because of superior efficacy, cost-effectiveness (34), and marked improvement in quality of life (35).

Preoperative preparation is particularly crucial in “giant” GD due to risks of airway obstruction, failed intubation (36,37), massive intraoperative bleeding, and thyroid storm (38,39). ATDs, iodine preparations, β-blockers, and LT4 are commonly used components of preoperative preparation in GD (40-42). In routine clinical practice, conventional GD patients often achieve satisfactory preoperative control with single- or dual-drug regimens. For example, preoperative Lugol’s solution administration has been reported to reduce intraoperative blood loss by 7.4-fold compared with controls (43). Our institution previously developed the ATD + LT4 “Preoperative preparation method of sequential thyroid defunctionalization” protocol (16,44). Initial high-dose ATD therapy controls thyrotoxicosis and typically restores euthyroidism within one to two months while avoiding hypothyroidism. As thyroid function normalizes and trends toward hypothyroidism, LT4 is gradually introduced and co-administered with ATDs to maintain biochemical euthyroidism (normal FT4 and FT3). The underlying rationale is dual suppression: high-dose ATDs such as MMI completely inhibit new thyroid hormone synthesis, whereas concomitant LT4 administration suppresses pituitary TSH secretion through negative feedback. Because TSH is the principal stimulus for thyroid follicular cell proliferation and glandular hypervascularity, this phase aims to transform the hyperemic, friable thyroid characteristic of thyrotoxicosis into a less vascular, surgically favorable gland. Previous work demonstrated that adequate preparation (approximately 2–4 months) significantly reduced intraoperative blood loss (treatment group: 195.74±57.07 mL vs. control: 324.76±163.26 mL, P<0.05), and postoperative histopathology in the treatment group showed features more closely resembling normal thyroid tissue. This regimen has been clinically validated over years of practice and effectively reduces thyroid vascularity, thereby lowering intraoperative bleeding and decreasing the risk of surgical complications and thyroid storm. A notable drawback of this protocol is the relatively long preparation duration, typically 3–5 months. However, because GD is a benign disease, such extended preparation is acceptable when prioritizing surgical safety. Based on our institutional experience, this method is safe, effective, well tolerated by patients, and convenient for clinicians, particularly in hyperthyroid patients with normal-sized thyroid glands.

Patients with “giant” GD frequently experience both physical and psychological impairment caused by the markedly enlarged thyroid gland, including dyspnea, dysphagia, anxiety, depression, and social distress (45-47). Definitive thyroidectomy for GD has been shown to confer greater improvement in overall quality of life and psychosocial functioning compared with other treatment modalities (48-50). Unlike ordinary GD, “giant” GD is characterized by markedly increased thyroid volume, abnormal hypervascularity, and a higher incidence of intraoperative complications attributable to adhesion to adjacent tissues and potential inflammatory changes (51,52). Preoperative preparation is therefore particularly crucial in patients with “giant” GD patients (53). Additionally, T3-predominant GD is frequently observed in patients with large goiters. This regimen is particularly advantageous in T3-predominant “giant” GD, in which elevated type I deiodinase activity accelerates peripheral T4-to-T3 conversion (54). Because the biological half-life of FT3 is considerably shorter than that of FT4, overly aggressive normalization of FT3 before surgery may precipitate transient postoperative hypothyroidism in “giant” GD patients. Exclusive ATD therapy risks rapid postoperative T3 depletion, potentially resulting in transient hypothyroidism, wound or laryngeal edema, and delayed healing (55). Therefore, during preoperative preparation, FT3 should not be excessively suppressed and is preferably maintained slightly below the upper limit of the reference range to avoid the aforementioned scenario. In our ATD + LT4 phase, a stable exogenous T4 reservoir ensures steady peripheral T3 generation, thereby maintaining tissue hormone homeostasis. On this basis, we innovatively proposed the “‘giant’ GD preoperative triple-drug preparation regimen”, consisting of ATDs, LT4, and compound iodine solution, to address practical clinical challenges.

Previous clinical studies most commonly used dedicated thyroid ultrasound to measure linear dimensions and then estimated thyroid volume using an ellipsoid formula (56). This method accounts only for both lobes and neglects the thyroid isthmus, which is inappropriate in “giant” GD, where diffuse enlargement involves the entire gland. To ensure scientific rigor, we employed multiparametric contrast-enhanced CT with 3D thyroid reconstruction to obtain full volumetric data in patients with “giant” GD. Accurate thyroid volume was quantified through 3D visualization post-processing using 3D-Slicer software, enabling true 3D assessment of the thyroid, which is more advanced and precise than conventional approaches. The PSV of the superior thyroid artery plays an important role in the differential diagnosis of thyrotoxicosis (57,58), and a threshold of ≥50 cm/s is widely recognized as an important ultrasound indicator supporting the diagnosis of GD (59,60). A further innovation of the present study lies in the prospective application of PSV as a key index for evaluating preoperative preparation in “giant” GD, in whom hypervascularity is particularly pronounced and bleeding risk is substantially elevated. Serial PSV assessment demonstrated that our triple-drug regimen effectively achieved the intended preparatory objectives. In this study, the FT4 and FT3 levels of 13 patients with “giant” GD were gradually brought under control, after which they underwent total thyroidectomy. Erbil et al. reported that in patients with GD who received 10 drops of Lugol’s solution orally per day for 10 days, thyroid volume decreased from 49±29 to 48.2±29.4 mL (61). In contrast, the effect of the “giant GD preoperative triple-drug preparation method” was more pronounced. Compared with baseline, the median thyroid volume decreased from 307.66 to 283.68 mL, and the PSV of the superior thyroid artery was also reduced, with a maximum reduction of up to 63.64%. Implementation of this triple-drug protocol appeared to optimize the surgical procedure and substantially reduce operative difficulty, with a greater impact than potassium iodide (SSKI) alone. In a previous study, the operative time in ordinary GD patients who received preoperative SSKI was 142 minutes, whereas the median operative time for “giant” GD in the present study was 210 minutes (13). Remarkably, only approximately one additional hour was required to safely remove thyroid glands that were nearly 15-fold larger in volume. In this cohort, the operative duration ranged from 120 to 270 minutes, and the median intraoperative blood loss was 77.7 mL. No perioperative complications occurred, including thyroid storm, recurrent laryngeal nerve or SLN injury, postoperative hemorrhage, or hematoma. Marked improvement was observed in symptoms of severe hyperthyroidism, and some extrathyroidal manifestations showed partial alleviation. While major complications were avoided, attention should also be directed toward technical refinements to further improve patient-reported outcomes. With respect to drain management, a suprasternal exit site was frequently selected in cases with markedly enlarged thyroids to ensure dependent drainage. However, this approach resulted in hypertrophic scarring in one patient (Figure 11). While effective for drainage, alternative exit sites may yield superior cosmetic results; therefore, lateral or superior drain exits will be considered in future practice when feasible.

The safety of the drug regimen is a critical prerequisite for its clinical application and broader implementation. Throughout the administration of the “‘giant’ GD preoperative triple-drug preparation method”, patients were closely monitored, including regular assessment of complete blood counts, liver and kidney function, and surveillance for ADRs. ADRs were classified according to the 2017 U.S. Department of Health and Human Services Common Terminology Criteria for Adverse Events (CTCAE, 5th edition) (62), ranging from Grade 1 (mild; asymptomatic or only detectable clinically or via diagnostic testing, requiring no intervention) to Grade 5 (death related to adverse reactions). In clinical practice, no “giant” GD patient experienced ADRs exceeding Grade 1, including allergic reactions, hepatic or renal dysfunction, vascular edema, or arrhythmia.

In recent decades, the safety of thyroidectomy has improved substantially owing to major advances in surgical and anesthetic techniques. Even in patients with massive goiters or severe thyrotoxicosis, refinements in operative technology have led to a marked reduction in perioperative risk. Modern energy-based hemostatic devices, including bipolar and ultrasonic scalpels, have enhanced vascular control and reduced operative time and intraoperative blood loss. The widespread adoption of IONM has facilitated identification and functional assessment of the recurrent and SLNs, thereby decreasing the incidence of nerve injury (63,64). Meanwhile, developments in preoperative airway evaluation and advanced anesthetic airway management strategies have significantly lowered the risk of difficult intubation and airway-related complications in patients with large goiters. However, despite these technological advances, surgery for “giant” GD remains technically demanding because of extreme gland enlargement, pronounced hypervascularity, adhesions to surrounding tissues, and the metabolic instability associated with severe thyrotoxicosis. These challenges highlight the continuing need for optimized preoperative medical preparation. Rather than questioning these surgical advances, our triple-drug regimen establishes an optimal internal environment characterized by rapid hormonal control and reduced thyroid vascularity, thereby allowing surgeons to take full advantage of contemporary surgical tools. The novelty of this study lies in proposing a standardized medical strategy that synergistically complements operative techniques, emphasizing that comprehensive safety is achieved through the integration of medical optimization and surgical expertise.

The ultimate goal of therapy in “giant” GD is to relieve clinical symptoms and improve quality of life. Classical manifestations of “giant” GD resemble those of ordinary GD, including polyphagia, weight loss, diarrhea, and irritability (65), often accompanied by GO, PTM, and HDD (66,67), but the conditions are more severe. The efficacy of thyroidectomy in treating GD is well established (68), but its impact on associated complications can be variable and unpredictable (69,70). In this study, one patient with concomitant GO, HHD, and elephantiasis nostras verrucosa (ENV) underwent thyroidectomy; while surgical intervention effectively controlled hyperthyroidism, no improvement was observed in the symptoms of GO or PTM. This finding suggests that some extrathyroidal manifestations may be only partially reversible or may require additional targeted therapy beyond control of thyrotoxicosis.

It must also be acknowledged that there are several limitations in this study. First, the relative rarity of “giant” GD inevitably resulted in a small sample size. Establishing a blank control group would not be consistent with the ethical principle of beneficence, because preoperative preparation is already known to improve perioperative outcomes in GD patients. Few clinical studies have specifically investigated preoperative preparation in GD patients with thyroid volumes ≥100 mL. Additionally, the few available case reports focus on surgical or anaesthesia techniques rather than preoperative preparation strategies, lacking detailed protocols and outcome data. Using historical control data from common-volume GD patients would be ethically inadequate, as it would underestimate the true risks in our cohort and potentially compromise patient safety. Consequently, we adopted a single-arm design, which may limit the generalizability of our findings. As a non-controlled study, the results may also be susceptible to selection bias and unmeasured confounding. Potential confounders—including variability in MMI dosing, LT4 titration strategies, disease duration, and prior treatments—may have influenced the observed outcomes. Future multicenter prospective studies are essential to validate these results across diverse referral patterns and clinical settings. In addition, compared with ordinary GD patients who may receive only short-term compound iodine solution as preoperative preparation (typically 1–2 weeks) (7,71), the duration of preparation in “giant” GD is relatively long and requires high patient adherence, which may impose a certain psychological and economic burden. Nevertheless, comprehensive preoperative preparation appears indispensable for patients with “giant” GD and may represent the major current limitation of the “giant GD preoperative triple-drug preparation method”. In the future, studies with larger sample sizes are needed to refine risk stratification in “giant” GD, optimize drug dosing strategies, and determine the optimal timing of surgery.

Conclusions

This first prospective single-arm cohort study demonstrates the feasibility of triple-drug preoperative preparation regimen in “giant” GD and provides preliminary evidence supporting its safety. Definitive conclusions will require validation in larger, controlled clinical studies. In our cohort, thyroid volume and PSV of the thyroid superior artery were significantly decreased, surgical safety and efficiency were improved, total thyroidectomy was successfully completed in all cases, and no serious drug-related adverse events occurred during the preparation period. The “‘giant’ GD preoperative triple-drug preparation regimen” therefore shows promising potential for broader clinical implementation and may benefit a greater number of patients with this rare condition. Continued clinical experience and further studies are warranted to refine and optimize the individualized application of this preoperative strategy.

Acknowledgments

The authors also thank all the patients included in this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-482/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-482/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-482/prf

Funding: This work was supported by the “Qimingxing” Research Fund for Young Talents of West China Hospital (No. HXQMX0105).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-aw-482/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Biomedical Ethics Review Committee of West China Hospital, Sichuan University (2023 Review No. 88) and informed consent was obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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