A Review of Parathyroid Surgery for Primary Hyperparathyroidism from the United Kingdom Registry of Endocrine and Thyroid Surgery (UKRETS)

Background The United Kingdom Registry of Endocrine and Thyroid Surgeons is a national database holding details on > 28,000 parathyroidectomies. Methods An extract (2004–2017) of the database was analysed to investigate the reported efficacy, safety and use of intra-operative surgical adjuncts in targeted parathyroidectomy (tPTx) and bilateral neck exploration (BNE) for adult, first-time primary hyperparathyroidism (PHPT). Results 50.9% of 21,738 cases underwent tPTx. Excellent short-term (median follow-up 35 days) post-operative normocalcaemia rates were reported overall (tPTx 96.6%, BNE 94.5%, p < 0.05) and in image-positive cases (tPTx 96.7%, BNE 96%, p < 0.05). Intra-operative PTH improved overall normocalcaemia rates (tPTx 97.8% vs 96.3%, BNE 95% vs 94.4%: both p < 0.05). Intra-operative nerve monitoring reduced vocal cord (VC) dysfunction in image-positive tPTx, but not in BNE (97.8% vs 93.2%, p < 0.05). Complications were higher following BNE (7.4% vs 3.8%, p < 0.05), especially hypocalcaemia (5.3% vs 2%, p < 0.05). There was no difference in rates of subjective dysphonia following tPTx or BNE (2.4% vs 2.3%, p > 0.05), nor any difference in VC dysfunction when formally examined (4.9% vs 4.1%, p > 0.05). Conclusions In image-positive, first time, adult PHPT cases, tPTx is as safe and effective as BNE, with both achieving excellent short-term results with minimal complications.


Introduction
The United Kingdom Registry of Endocrine and Thyroid Surgery (UKRETS) is a multi-centre, multi-disciplinary (General, Otolaryngology, Oral and Maxillofacial, Transplant and Vascular surgeons) database. It is the world's largest endocrine surgery database and is maintained by the British Association of Endocrine and Thyroid Surgeons (BAETS) members.
UKRETS has recognised potential deficiencies in care, including under-diagnosis and heterogeneous practise across the United Kingdom (UK). Therefore, the National Institute for Health and Care Excellence (NICE) have published guidelines on the management of primary hyperparathyroidism (PHPT) in the UK [1].
Targeted parathyroidectomy (tPTx) in selected patients, with pre-operative localisation and intra-operative parathyroid hormone (ioPTH), have led to well-documented reductions in operating time and post-operative complications (especially hypocalcaemia) [2][3][4][5]. However, there is the potential to miss multiglandular disease (MGD) [6,7], leading to recurrences. ioPTH during tPTx may mitigate this risk, but its benefit in first-time parathyroidectomy remains debatable due to its cost, only moderately high specificity in identifying those cases with remaining abnormal tissue following adenoma excision [8], and marginal improvement in cure [5]. A literature review by Morris et al. [9] demonstrated that in a case of localised PHPT, ioPTH increased the success rate of tPTx from 96.3 to 98.8%, whilst incurring an approximate additional cost of 4% to the procedure. However, the authors did also conclude that there were institution specific factors that influenced the value of ioPTH.
With this in mind, a review of parathyroid surgery recorded in the UKRETS was undertaken.

Aims
This study investigated the recorded efficacy and safety of tPTx and bilateral neck exploration (BNE) with and without surgical adjuncts in first-time PHPT cases from the UKRETS.

Material and methods
Access to UKRETS was granted through the BAETS executive committee in February 2018, for data from 2004 to 2017. Patient consent is obtained by surgeons to collect and anonymously analyse data in UKRETS along General Data Protection Regulation requirements. Clinical data are uploaded by surgeons, but the dataset has not been externally validated. The data fields for parathyroid surgery are available in the appendix of the Fifth National Report [9]. The lead author (HI) analysed the database.
Adults (C 18 years old) undergoing first-time parathyroidectomy for sporadic PHPT between 2004 and 2017 were included. Cases with illogical/inaccurate data (e.g. age [ 100 years old) and cases not specified as first-time surgeries were excluded. Cases with incomplete outcome data were excluded from specific sub-analyses to prevent skewing of interpretation. Missing data rates varied across outcomes, so the denominator (total number of cases analysed) varied depending on the outcome in question.
The recorded surgical technique (tPTx or BNE), adjuncts and number of glands removed were analysed. tPTx cases converted to BNE were analysed as BNE.
Complication rates and their nature were analysed. The method (US, indirect or direct laryngoscopy) by which formal vocal cord (VC) function was examined is not specified in UKRETS.
UKRETS does not record operating centre or operative findings, therefore, it was not possible to explain why (failure to identify adenoma, identifying two ipsilateral adenomas, or failure of ioPTH to fall below 50% of baseline) some tPTx cases were converted to BNE. Neither does it record decision-making on ioPTH or ioNM use, availability of ioPTH/ioNM or operative approach (tPTx or upfront BNE). Therefore, no comments or inferences on these topics were made.
Definitions BAETS [8] defines tPTx as ''surgery that may include mini-incision open techniques, endoscopic methods or even unilateral neck exploration (UNE)'', but UKRETS does not distinguish between these techniques.
''Image-positive''cases where pre-operative localisation modalities (ultrasonography (US) and/or nuclear medicine (NM) and/or computed tomography (CT)/magnetic resonance imaging (MRI)) identified target gland(s). UKRETS does not record of the number or location(s) of the target gland(s).
''Normocalcaemia'' was defined as the absence of hypocalcaemia and persistent hypercalcaemia at the first post-operative visit.
''Subjective dysphonia'' the subjective (assessed by the surgeon) presence of voice change at the first post-operative visit.

Statistical analysis
Descriptive statistics are reported as medians with interquartile ranges (IQR; 25-75%), unless stated otherwise. Medians were used to avoid central tendencies being affected by outlying values.
Differences between groups and categorical variables were calculated with the Mann-Whitney U and Fisher's exact test, respectively. P-values of \ 0.05 were considered statistically significant.
Image-positive BNE had higher complication rates than image-positive tPTx (4.9%; 274/5570 vs 3.5%; 376/10,850) (p \ 0.05). Wound infection and hypocalcaemia rates were lower following image-positive tPTx compared to image-positive BNE ( Table 6). Analysis of image-positive cases where only one gland was removed Values in parentheses are percentages
Despite positive pre-operative localisation, 52% of patients underwent BNE. 8% of these (867/10,676) were initially treated as tPTx then converted to BNE, inferring NS not significant, NOS not otherwise specified, RTT return to theatre  [2]. The UKRETS does not currently collect data on long-term (more than six months) follow-up data. Normocalcaemia rates for image-positive cases suggestive of single gland disease managed by tPTx and BNE (96.7% vs 96.0%), although statistically significant, were marginal and so of questionable clinical importance. This supports the recommendation of discussing both operative approaches in image-positive patients [1].
Normocalcaemia rates following tPTx were excellent with (97.8%) or without (96.4%) ioPTH. These figures underestimate the benefit of ioPTH, as cases converted from tPTx to BNE, possibly due to failure of ioPTH to fall below 50% of baseline, were analysed as BNE, and so not included in the analysis of tPTx. Ishii et al. [14] reported overall cure at six months was higher (99.3% vs 98.1%, p \ 0.05) and recurrence lower (0.2% vs 1.5%, p \ 0.05) when ioPTH was utilised with minimally invasive parathyroidectomy. They found ioPTH was less likely to be utilised in image concordant (versus image discordant) cases. The low record of ioPTH in UKRETS suggests it is still not being routinely used. However, the database demonstrated that the rate of ioPTH was at its highest in 2017. NICE [1] does not recommend routine use of ioPTH in first-time surgery, which seems justified, given the extra cost, for only marginal improvements in normocalcaemia rates. Neither NICE or AAES currently recommend routine use of ioNM [1,2]. UKRETS demonstrated, in a small subset of cases (6%) which reported ioNM use with a documented post-operative VC assessment outcome, there were fewer abnormal VC function following tPTx, but not BNE. It is unclear why ioNM should be beneficial in tPTx but not BNE, though limited dissection during tPTx may compromise a satisfactory view of the recurrent laryngeal nerve. ioNM was used more frequently in tPTx than BNE, probably due to increasing popularity of tPTx coinciding with increasing availability of ioNM. Given the small proportion of cases with reported ioNM use, these results may not be representative of or applicable to overall care. However, UKRETS demonstrated an association between ioNM in tPTx and improved rates of post-operative normal VC function.
It was not possible to ascertain if hypocalcaemia was temporary or permanent or if there was a cause such as hungry bone syndrome. Hypocalcaemia rates were significantly higher following BNE than tPTx, but this study found that more glands were excised during BNE, so this higher rate is expected.
Abnormal VC function following tPTx (4.9%) was higher than Jinih et al.'s [12] and Ishii et al.'s [14] numbers. The high rate of missing data for VC function meant it was difficult to draw any definitive conclusions. Subjective dysphonia rate was 2.4% (no difference between techniques). However, subjective assessment is inaccurate, variable and may potentially underestimate actual VC dysfunction [15,16]. Rates of formally assessed post-operative abnormal VC function were 4.9% following tPTx and 4.1% following BNE (p [ 0.05), but it is not fair to compare these figures against subjective dysphonia rates as there may be other reasons for dysphonia (injury to external branch of superior laryngeal nerve, vocal cord oedema, surgical scar tissue, etc.).
BAETS do not endorse same-day discharge following thyroidectomy due to potential airway obstruction secondary to post-operative haematoma [17]. This has influenced parathyroidectomy practise and may explain the similar proportion of overnight stays following tPTx and BNE. BNEs had longer post-operative stays which may be partially explained by the higher hypocalcaemia rate in this group, where normalising calcium may have required intravenous replacements, delaying discharge.

Strengths and limitations
Registries are useful to answer certain questions that are not suitable for randomized clinical trials. This registry study provides the best insight into parathyroidectomy outcomes across the UK. Multi-disciplinary surgeons have contributed from both small and large volume centres, reducing the risk of skewed data, and allowing comparison with recognised guidelines [1,2]. The large number of cases reduces the risk of bias/errors that are inherent from small sample sizes, and highlights statistically significant differences between groups with similar clinical outcomes. It is important to consider these results carefully, as the World J Surg (2021) 45:782-789 787 number of patients needed to treat to achieve comparable results may not justify expensive interventions for only marginal benefits. Limitations include the significant amount of missing data, design flaws of data collection, potential self-reporting bias, coding errors, voluntary nature of uploading cases and lack of external validation (though this is currently being addressed). The results only allowed a median follow-up of 35 days, meaning long-term outcomes (cure, persistent disease and recurrence rates) were not recorded, limiting its use when comparing techniques. ''Targeted parathyroidectomy'' as per UKRETS, encompasses various surgical techniques, which may affect outcomes. Selection criteria for surgery, symptoms, complications or severity of PHPT are not recorded and therefore not assessed.
An example of potential coding errors is highlighted in the number of glands removed by operative technique. An average of 1.07 glands was excised during tPTx, most likely because UNEs are coded as tPTx in UKRETS. It is not possible to explain why 3, 3.5 or 4 glands were excised during tPTx, as UKRETS does not record pre-operative findings or histology of excised glands, though presumably these may be coding errors.
Factors confounding the interpretation of results include the fact that only selected patients underwent tPTx, therefore the incidence of MGD is likely to be higher in cases undergoing BNE, where more glands were excised. This affects comparisons of normocalcaemia and hypocalcaemia rates between tPTx and BNE. However, this study did demonstrate that in image-positive cases where only one gland was removed, BNE had a higher rate of postoperative hypocalcaemia than tPTx.
Interpretation of localisation results are limited. The number anatomical location of pathological glands or whether the results corresponded to operative findings are not recorded. Hence any inferences about the concordance or discordance of localisation modalities cannot be made.
This study has highlighted areas of the registry that can be updated to improve data collection and analysis.

Conclusions
This study has reported on the largest parathyroid registry in the world; 21,738 cases of first-time primary hyperparathyroidism treated between 2004 and 2017. This study has demonstrated that in image-positive cases, tPTx is as safe and effective as BNE, with both achieving excellent results with minimal complications.

Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
Ethical approval There were no ethical or Institutional Review Board (IRB) considerations applicable to this study.
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