Highlights
Markedly elevated preoperative thyroid-stimulating hormone (TSH) levels, defined as ≥10.0 μIU/mL, were uncommon but clinically meaningful in Graves’ disease patients undergoing total thyroidectomy.
Compared with patients whose TSH was <10.0 μIU/mL, those with TSH ≥10.0 μIU/mL had more intraoperative blood loss, greater thyroid enlargement relative to preadmission status, and longer operations.
After multivariable adjustment, TSH ≥10.0 μIU/mL remained independently associated with greater blood loss and higher enlargement ratios, supporting a link between marked preoperative hypothyrotropinemia and operative difficulty.
The findings suggest that aggressive preoperative preparation that overshoots into iatrogenic hypothyroidism may worsen surgical conditions rather than optimize them.
Background
Graves’ disease is the most common cause of hyperthyroidism in iodine-sufficient regions and remains a frequent indication for definitive thyroid treatment. Although antithyroid drugs, radioiodine, and surgery are all accepted options, total thyroidectomy is often selected in patients with large goiters, compressive symptoms, suspected malignancy, medication intolerance, or a preference for rapid definitive control.
Standard preoperative management aims to reduce the risk of thyrotoxic complications, especially thyroid storm, and to improve intraoperative conditions. This usually includes antithyroid drugs, β-blockers, and short-term iodine. The clinical logic is straightforward: control hormone excess, reduce thyroid vascularity, and stabilize the patient before surgery. Yet this process can become imbalanced. If thyroid hormone synthesis is suppressed too aggressively, especially when combined with iodine, some patients may develop biochemical or overt hypothyroidism before surgery. In that setting, TSH may rise substantially.
Whether this marked TSH elevation is merely a laboratory reflection of treatment intensity or a clinically useful signal of more difficult thyroidectomy has been uncertain. That is a practical question for endocrine surgeons and endocrinologists because preoperative optimization is intended to make surgery safer and easier, not harder. The present study by Sasaki and colleagues directly addresses this gap by examining whether preoperative TSH ≥10.0 μIU/mL is associated with surrogate markers of operative difficulty in Graves’ disease.
Study Design
This was a retrospective cohort study conducted at a single high-volume center. The investigators included consecutive patients with Graves’ disease who underwent total thyroidectomy between 2009 and 2022. The full cohort comprised 1516 patients, and the primary complete-case analysis included 1407 patients.
Patients were grouped according to preoperative TSH level: 48 patients had TSH ≥10.0 μIU/mL and 1359 had TSH <10.0 μIU/mL. Thus, the exposure of interest was relatively uncommon, affecting 3.4% of the analyzed cohort.
The primary outcomes were measures intended to capture operative difficulty: intraoperative blood loss, enlargement ratio (ER), and operative time. ER was defined as estimated preoperative thyroid weight divided by preadmission thyroid weight, providing a dynamic indicator of interval thyroid enlargement during the preoperative treatment period. Secondary outcomes included perioperative complications and resected thyroid weight.
The authors used multivariable linear and logistic regression with prespecified covariates. For rare outcomes, they applied Firth’s penalized logistic regression, an appropriate statistical technique that reduces bias when event counts are low. They also compared preadmission and preoperative TSH values to provide temporal context and further stratified preoperative TSH into four clinically defined categories based on the institutional reference range, recognizing that the broad <10.0 μIU/mL group contains substantial biological heterogeneity.
Key Results
Baseline and exposure frequency
Only a minority of patients had markedly elevated preoperative TSH. Nonetheless, the group with TSH ≥10.0 μIU/mL appeared to represent a clinically distinct subgroup. Preadmission TSH ≥10.0 μIU/mL was more common among these patients than among those with lower preoperative TSH values, at 20.8% versus 3.2%. This suggests that some patients already had a tendency toward TSH elevation before final preoperative preparation, although the study also supports the idea that treatment-related worsening played a role.
Intraoperative blood loss
Blood loss was higher in patients with TSH ≥10.0 μIU/mL. In unadjusted analyses, median blood loss was 52 mL in the TSH ≥10.0 group compared with 34 mL in the TSH <10.0 group, with p < 0.001. In adjusted analysis, the association remained significant: TSH ≥10.0 μIU/mL was associated with an increase in blood loss of 53.03 mL, also with p < 0.001.
Although absolute blood loss volumes may still appear modest in a specialized endocrine surgery setting, the relative increase is clinically meaningful. Thyroidectomy in Graves’ disease is often technically demanding because of vascularity and friability. Even moderate increases in bleeding can impair visualization, complicate recurrent laryngeal nerve identification, and increase surgeon workload.
Thyroid enlargement during preparation
The enlargement ratio was also greater in the markedly elevated TSH group. Unadjusted ER values were 1.137 versus 1.029. After multivariable adjustment, TSH ≥10.0 μIU/mL remained independently associated with a higher ER, with β = 0.12 and p = 0.002.
Dichotomized analysis strengthened the clinical signal. A preoperative TSH ≥10.0 μIU/mL increased the odds of ER ≥1.1, with an adjusted odds ratio of 2.60 and p = 0.004. In other words, marked TSH elevation was associated not just with statistical shifts in average gland size, but with a materially greater chance of interval thyroid enlargement that could influence surgical difficulty.
Operative time
Operations were longer in the high-TSH group. Median operative time was 129 minutes compared with 112 minutes in the lower-TSH group. In dichotomized analysis, TSH ≥10.0 μIU/mL was associated with increased odds of operative time ≥120 minutes, with an adjusted odds ratio of 2.29 and p = 0.018.
Longer operative duration is an important pragmatic endpoint. In thyroid surgery, it often reflects technical complexity, including bleeding, difficult dissection, large goiter volume, and altered tissue planes. The fact that the association persisted after adjustment suggests that marked TSH elevation may be more than a simple bystander biomarker.
Resected thyroid weight and perioperative outcomes
Resected thyroid weight was higher in the TSH ≥10.0 μIU/mL group, with median values of 131.8 g versus 97.0 g. This aligns with the ER findings and supports the possibility that TSH elevation may promote gland growth or reflect a process associated with enlargement.
The abstract does not emphasize a clear increase in perioperative complications, and the study appears primarily powered for operative difficulty metrics rather than rare adverse events. That distinction matters. A more difficult operation does not necessarily translate into more recurrent laryngeal nerve injury, hypoparathyroidism, hematoma, or other complications in a high-volume center, particularly when surgery is performed by experienced endocrine surgeons.
How Might Elevated TSH Increase Operative Difficulty?
The biological explanation is plausible. TSH is a trophic hormone for thyroid follicular cells. In Graves’ disease, the thyroid is already stimulated by TSH receptor antibodies, but endogenous TSH may become less suppressed or even rise during over-treatment with antithyroid drugs and iodine. If TSH climbs markedly, it could contribute to gland enlargement and possibly alter vascularity or tissue characteristics. The observed increase in ER is consistent with this mechanism.
Another possibility is that elevated TSH serves as a marker of a subgroup with more labile thyroid physiology, stronger treatment responses, or different baseline gland architecture. The finding that preadmission TSH ≥10.0 μIU/mL was more common in the exposure group suggests that some predisposition existed before final preoperative intensification. Thus, TSH may be both a biological driver and a clinical marker.
It is also important to consider timing. The interval between preadmission assessment, treatment changes, and operation could influence gland size and vascularity. A short burst of iodine may reduce vascularity in many patients, but prolonged or excessive suppression followed by TSH rebound may have unintended effects. The present study does not fully disentangle these dynamics, but it brings attention to an underappreciated aspect of surgical preparation: overtreatment can be counterproductive.
Clinical Interpretation
For endocrine clinicians, the main takeaway is not that preoperative biochemical normalization should be abandoned. Rather, the study suggests that there may be a therapeutic “sweet spot.” The goal is to avoid uncontrolled thyrotoxicosis while also avoiding marked iatrogenic hypothyroidism. A TSH of ≥10.0 μIU/mL may represent a warning sign that preoperative management has gone too far.
In practice, this may support closer biochemical monitoring during the preoperative period, especially in patients receiving combined antithyroid drugs and iodine. If TSH rises substantially, clinicians may need to reconsider drug dose, timing of surgery, or the duration of iodine exposure. The findings may be particularly relevant in patients with large glands, prior fluctuations in thyroid function, or delayed surgical scheduling.
For surgeons, a markedly elevated TSH may help identify patients at higher likelihood of greater blood loss or prolonged operative time. That information could influence scheduling, staffing, operative planning, and counseling. In a high-volume setting, the effect may be manageable, but in lower-volume environments the impact on technical difficulty may be more consequential.
Strengths of the Study
This analysis has several notable strengths. First, the sample size is large for a surgical Graves’ disease cohort, with more than 1400 patients in the complete-case analysis. Second, the study examines a practical and clinically actionable preoperative biomarker rather than a purely descriptive association. Third, the outcomes are relevant to both operative workflow and patient care: blood loss, operative time, interval gland enlargement, and resected weight.
The statistical approach was also thoughtful. The use of prespecified covariates improves interpretability, and Firth’s penalized logistic regression is appropriate for sparse outcomes. The additional analysis of preadmission TSH adds useful temporal context and guards against a simplistic assumption that all TSH elevation was acutely induced just before surgery.
Limitations and Cautions
As with any retrospective single-center study, residual confounding cannot be excluded. The cohort likely reflects local practice patterns regarding medication regimens, timing of surgery, iodine use, and surgical expertise. That may limit generalizability to centers with different protocols.
The exposure group was small, with only 48 patients having TSH ≥10.0 μIU/mL. While the observed associations were statistically robust for key endpoints, estimates for less common complications may be unstable. In addition, the abstract does not provide the full covariate list, confidence intervals, or detailed complication data, which are important for judging precision and potential confounding.
The use of surrogate markers of operative difficulty is reasonable, but it has limitations. Blood loss and operative time are clinically relevant; however, they can also be influenced by surgeon technique, case sequencing, anesthesia factors, and institutional workflow. ER is innovative, but it depends on thyroid weight estimation methods and assumes consistent measurement quality over time.
Finally, the study demonstrates association, not causation. It is biologically plausible that marked TSH elevation contributes to more difficult surgery, but it remains possible that elevated TSH is partly a marker of more severe or atypical disease rather than a direct driver of operative complexity.
Relation to Existing Evidence and Guidelines
Current practice guidelines for hyperthyroidism and other causes of thyrotoxicosis recommend rendering patients as close to euthyroid as feasible before thyroidectomy, typically using antithyroid drugs and β-blockade, with potassium iodide or Lugol’s solution often added shortly before surgery. These recommendations focus mainly on reducing perioperative thyrotoxic risk and gland vascularity. They do not generally specify an upper TSH ceiling that should trigger concern about overtreatment.
This study suggests that such a ceiling may matter. It does not overturn the principle of preoperative biochemical control, but it adds nuance by indicating that marked TSH elevation may identify a less favorable physiological state for surgery. The work therefore complements, rather than contradicts, existing guideline logic.
Practical Implications for Care Pathways
Several pragmatic messages emerge. First, repeated thyroid function testing before surgery may be more informative than a single “clearance” value, especially when treatment intensity changes quickly. Second, endocrinologists and surgeons should communicate about timing: if TSH is climbing sharply, the choice may be to adjust therapy rather than continue suppressive treatment until the day of operation. Third, patients with very high TSH and enlarging glands may benefit from anticipatory counseling that surgery could be longer or technically more difficult, even when overall complication risk remains acceptable.
These findings may also encourage centers to review their own protocols for preoperative iodine and antithyroid drug use in Graves’ disease. Institutional pathways often emphasize prevention of hyperthyroid complications, but fewer explicitly guard against overshooting into significant hypothyroidism. A balanced protocol may yield better operative conditions.
Conclusion
In this large single-center cohort of patients with Graves’ disease undergoing total thyroidectomy, preoperative TSH ≥10.0 μIU/mL was independently associated with greater intraoperative blood loss and greater thyroid enlargement during preoperative preparation. It was also associated with longer operations in dichotomized analysis and with heavier resected glands. Together, these findings support the clinical impression that marked preoperative TSH elevation may signal a more difficult thyroidectomy.
The central translational message is simple: preoperative preparation should aim for control, not oversuppression. Avoiding iatrogenic hypothyroidism and marked TSH elevation may improve surgical conditions without compromising safety. Prospective multicenter studies are now needed to define optimal biochemical targets and timing strategies before thyroidectomy in Graves’ disease.
Funding and Trial Registration
The abstract provided does not report a funding source or a ClinicalTrials.gov registration number. As this was a retrospective single-center cohort study, prospective trial registration may not have been applicable.
Citation
Sasaki T, Kihara M, Fujishima M, Masuoka H, Higashiyama T, Ito Y, Miya A, Miyauchi A, Akamizu T. Markedly Elevated Preoperative Thyroid-Stimulating Hormone Levels and Greater Operative Difficulty in Graves’ Disease: A Single-Center Cohort Study. Thyroid. 2026-05-13:10507256261449452. PMID: 42126184. URL: https://pubmed.ncbi.nlm.nih.gov/42126184/
Selected References
Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, Rivkees SA, Samuels M, Sosa JA, Stan MN, Walter MA. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016;26(10):1343-1421.
Kahaly GJ, Bartalena L, Hegedüs L, Leenhardt L, Poppe K, Pearce SHS. 2018 European Thyroid Association Guideline for the Management of Graves’ Hyperthyroidism. Eur Thyroid J. 2018;7(4):167-186.
Erbil Y, Ozluk Y, Giriş M, Salmaslioğlu A, Issever H, Barbaros U, Kapran Y, Ozarmağan S, Tezelman S. Effect of Lugol solution on thyroid gland blood flow and microvessel density in the patients with Graves’ disease. J Clin Endocrinol Metab. 2007;92(6):2182-2189.
