Does adjunctive near-infrared autofluorescence and indocyanine green angiography improve long-term rates of postoperative hypoparathyroidism?

Near-infrared autofluorescence (NIRAF) and indocyanine green angiography (ICGA) have emerged as valuable intraoperative adjuncts during thyroid and parathyroid surgery (1-3). NIRAF leverages an intrinsic property of parathyroid tissue to emit autofluorescence when exposed to near-infrared light (4), which has led to improved rates of parathyroid gland (PG) identification and decreased reliance on pathologic frozen sections (5,6). Separately, ICGA assesses in situ PG perfusion and viability, allowing for real-time evaluation of parathyroid vascularity and to potentially guide decisions with autotransplantation (7,8). Both techniques have certain technical limitations, as NIRAF alone cannot discern vascularized from nonviable PGs (2,4), and ICGA is unable to distinguish parathyroid tissue from surrounding structures (3).

The use of NIRAF with or without ICGA has demonstrated promise in mitigating the risk of hypoparathyroidism, a known complication after total and completion thyroidectomy. Some centers report permanent rates as high as 12.5–16.6% (9,10), although most studies cite less than 5% (11). NIRAF appears to reduce postoperative hypoparathyroidism, particularly in patients who also underwent central lymph node dissection (12-14). ICGA may similarly decrease subnormal parathyroid levels postoperatively when at least one well perfused PG is identified (15-17). When both adjunctive modalities are combined, the synergistic effects often lead to improved results (18-21).

While recent NIRAF and ICGA studies consistently demonstrate improvements in transient hypoparathyroidism in the early postoperative period, long-term outcomes data are very limited (14,15,18). Few studies have specifically assessed NIRAF with concomitant ICGA, with most applying ICGA mapping after thyroid resection (18-21). Moreover, definitions of “permanent” hypoparathyroidism have been inconsistent, although recent joint societal efforts have been made for standardized reporting (22).

Michaelsen and colleagues have attempted to bridge this knowledge gap, offering the largest study to date to evaluate the application of NIRAF and pre-resection ICGA in patients undergoing total or completion thyroidectomy (23). This single-center cohort study compares 154 prospectively identified intervention (i.e., NIRAF + pre-resection ICGA) patients with 462 controls from a retrospective registry matched for several preoperative factors, including surgical indication and procedure type. The incidence of permanent hypoparathyroidism was primarily assessed, which was defined as treatment with an activated vitamin D analogue (AVDA) 12 months after surgery in alignment with Danish national documentation requirements and European expert consensus (24). In this analysis, rates of permanent hypoparathyroidism were decreased in the intervention group (6.5%) compared to controls (12.3%). Furthermore, while the unadjusted odds ratio (OR) for permanent hypoparathyroidism in the NIRAF + ICGA group was 0.50 [95% confidence interval (CI): 0.25–0.996, P=0.049], the risk was significantly reduced further when accounting for potential confounders (OR: 0.16, 95% CI: 0.05–0.56, P=0.004).

The authors provide compelling evidence for the use of NIRAF and ICGA in preventing long-term postoperative hypoparathyroidism while expanding upon known limitations from existing literature (i.e., evaluating both techniques, use of pre-resection ICGA, consistent definition of permanent hypoparathyroidism). In a series of 120 patients, Moreno-Llorente et al. retrospectively observed AVDA supplementation at 12 months in none who underwent ICGA pre- and post-thyroid resection compared to 12% of controls (P=0.03), but NIRAF use was not evaluated (15). Di Lorenzo et al. also observed no permanent hypoparathyroidism (defined as persistently low intact parathyroid hormone levels at six months) in patients who received intervention (NIRAF + ICGA) compared to 8.5% of controls, though this did not reach statistical significance (P=0.09) (18). In both studies, central lymph node dissections were pursued in all cases (15,18). However, Michaelsen’s analysis implements a non-rigid study protocol that involved patients with benign and malignant thyroid indications, inclusion of high-volume (defined as ≥10 total/completion thyroidectomies annually) and low-volume surgeons (inclusive of cases by surgical trainees), matching variables that included cervical nodal dissections, and an intention-to-treat approach that did not exclude patients with low vitamin D and serum calcium levels preoperatively, all of which is more akin to real-world surgical practices (23).

Apart from hypoparathyroidism, several other outcomes were observed in the study that are worth mentioning. Application of NIRAF resulted in increased PG detection and decreased inadvertent PG resection on histopathology, a finding that has remained relatively consistent across the literature (14,17-21,25), though specific rates may change based on a surgeon expertise (25). In contrast, rates of PG autotransplantation were similar between intervention and control groups (11% vs. 9%, P=0.5), which is consistent with some data (19,21) but conflicts with the 10% absolute reduction reported by the PARAFLUO trial (17). Unique to Michaelsen’s analysis was the improvement in time spent on intraoperative ICGA, which significantly decreased over the study period. The total number of minutes spent using both NIRAF and ICGA averaged 6 to 9 minutes, which are marginal increases to operating time when considering the potential to reduce permanent hypoparathyroidism rates.

The study satisfactorily addresses its chief limitation, the use of a control cohort based on retrospective data, by drawing parallels to other prospective (but similarly designed) trial data (26). A separate key critique was the use of a treatment-based definition of AVDA use at one year as a surrogate for diminished parathyroid function. Patients may continue receiving AVDA (e.g., calcitriol, alfacalcidol) despite parathyroid recovery, which can overestimate the true prevalence of hypoparathyroidism (27,28). While follow-up with the institution’s oncology and endocrinology departments is mentioned, it is unclear whether attempts at AVDA weaning were attempted, and the control arm specifically had incomplete biochemical data. This is especially relevant as contemporary consensus guidelines, sponsored by both regional and international endocrine surgery associations, now recommend biochemical confirmation of hypoparathyroidism at one year as well as documented efforts at ceasing supplementation to assure a proper diagnosis (22).

We applaud the authors for this excellent study that augments the growing literature on the long-term benefits of adjunctive NIRAF and ICGA. This study uniquely investigated the bimodal use of each technique, with specific attention to pre-resection ICGA, to reduce rates of permanent hypoparathyroidism. While the results should be interpreted prudently in the context of AVDA use in lieu of a biochemical definition of hypoparathyroidism, the methodological strengths (matched cohort, adequately powered study) and non-exclusion of real-world clinical variables such as surgeon experience reinforce the study’s overall findings. Further prospective and randomized clinical trials, particularly in the context of how recent consensus statements have defined permanent hypoparathyroidism, are ultimately needed to confirm the potential benefits of NIRAF and ICGA.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Thyroid. The article has undergone external peer review.

Peer Review File: Available at https://aot.amegroups.com/article/view/10.21037/aot-2026-1-0011/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aot.amegroups.com/article/view/10.21037/aot-2026-1-0011/coif). G.R.V. has received consulting fees from Veracyte, Inc. The other 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.

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