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Quality of Life in Primary Hyperparathyroidism Revisited: Keep Calm and Carry on?

2020; Oxford University Press; Volume: 36; Issue: 1 Linguagem: Inglês

10.1002/jbmr.4225

1523-4681

Marcella D. Walker, Shonni J. Silverberg,

Vitamin D Research Studies

While there is widespread agreement on a surgical approach to the classically symptomatic presentation of primary hyperparathyroidism (PHPT) described by Fuller Albright and others as a "disease of stones, bones, and groans," the same cannot be said for "asymptomatic" or mild disease. Multidisciplinary and international consensus guidelines providing surgical recommendations for the management of asymptomatic PHPT have been issued four times since 1990, with a fifth international consensus conference currently in the early planning stages.(1-4) As new data and tools have emerged, recommendations for the management of PHPT have been revised with additional or refined indications for parathyroidectomy (PTX). Conspicuously absent from all of the serial sets of guidelines has been any indication for surgery to address neuropsychological sequelae or quality of life in "asymptomatic" PHPT. This is not for lack of investigation in this area, which is one of the most hotly debated amongst patients, clinicians, and researchers alike; indeed, there is a large body of literature on the subject. However, much of this literature has been observational and not always controlled. To date, three prior short-term randomized controlled trials (RCTs) assessing quality of life (QOL) and psychological symptoms have been published, one of which includes the 1- and 2-year data from the current report from the Scandinavian Study on Primary Hyperparathyroidism (SIPH).(5-7) Despite overlap in the assessment tools (all used the Short Form 36 Health Survey Questionnaire [SF-36]), the three prior short-term studies indicated inconsistent PTX treatment effects across domains of QOL, some of which did not persist across the full period of follow-up. It was, thus, with great interest and enthusiasm that we read the long-awaited report of Pretorius and colleagues(8) describing the 10-year, end-of-study SIPH results on these outcomes. This multinational RCT of PTX versus observation in patients with mild PHPT (mean calcium 2.65 mmol/L or 10.6 mg/dL) addresses the long-term effect of intervention on QOL and psychological indices. Using two well-validated tools, the SF-36 and the comprehensive psychopathological rating scale (CPRS), the authors report a benefit of PTX compared with observation in some specific QOL domains and no treatment effect on psychological symptoms. In particular, vitality improved after PTX, while social functioning "tended" to get better, though not significantly so. Overall, there was no consistent, global improvement in QOL detected. Further, there was no deterioration in QOL in those who did not undergo surgery. Both surgical and observation groups had improved psychological function on the CPRS, with no treatment effect. The authors conclude that long-term observation of PHPT has no detrimental effect on QOL, and that while PTX led to a modest improvement in some QOL subscales, the magnitude of differences was small and of questionable clinical importance. Although not a prespecified analysis, the authors also add to the literature by describing a trend toward a benefit of PTX on psychological symptoms at 1 year after PTX that is attenuated in subsequent years. They emphasize that these patterns underscore the necessity of control groups and long-term follow-up. Not stated, but perhaps also important to consider, is that such findings mirror 1-year data from numerous short-term studies, suggesting that early postoperative improvements may be more attributable to the nonspecific success of an unblinded surgical intervention, rather than cure of PHPT itself. The study, which is the largest and longest of the RCTs addressing this issue, was rigorously conducted and reported. Further, the authors are aptly measured in their interpretation of the statistical and clinical significance of the small observed improvement in one or two, of numerous, QOL and psychological scores, which were in fact secondary outcomes in a more comprehensive study assessing the effect of PTX or observation on mortality (primary outcome) and other measures such as bone mineral density in PHPT. Although the authors do not make any statement regarding the implications of their findings for subsequent surgical guideline development, the current data provided by this study do not support the inclusion of impaired QOL as a criterion for surgery. A few points that affect the overall conclusions in this regard are, however, worthy of mention. The study originally randomized 191 to treatment (95 to PTX and 96 to observation), but at the end of the study only 129 remained, with 50 (26.2%) withdrawing from the study during follow-up, despite the best efforts of the investigative team. Further 17 (26.6%) in the observation group crossed over to PTX. Although the withdrawal and crossover rates are not unexpected given the length of the study, they do raise some questions. Did those who dropped out, particularly in the observation group, have worse QOL than those who remained in the study, leading to biased estimates of the treatment effect? Did crossover result in low statistical power, such that the true benefit of PTX on some aspects of QOL and psychological symptoms could not be adequately detected? Are those who will accept randomization to surgery versus no surgery different in terms of symptomology and other factors from those who do not, limiting the relevance of findings to real-world patients with PHPT? And might the results have been different had a disease-specific QOL scale (such as the parathyroidectomy assessment of symptoms [PAS] score) been available at the time of study design?(9) It is also important to note, as the authors do, that the study did not investigate cognitive indices, making it impossible to delineate if there is a benefit of PTX on cognition and if it is safe to observe patients long term without surgery in this regard. In summary, the results of this important study suggest it is safe for patients with PHPT lacking biochemical, renal, or skeletal indications for PTX to "keep calm and carry on" with observation without detriment to QOL or psychological symptoms. This study provides the most extensive information available regarding the effects of PHPT and PTX on QOL and psychological symptoms. While some questions remain, it is unclear if further clarification on these issues from future studies will be forthcoming. The arduous and logistically difficult nature of conducting an RCT of PTX versus observation and the availability of data from existing studies make it unlikely that a larger, longer RCT will be performed. As such, clinicians are left with the current evidence, which does not support recommending PTX based on QOL or psychological symptoms alone. It is important to remember, however, that the decision for or against surgery has always relied not only on evidence but also on the availability of expertise as well as individual physician and patient factors and preference. The authors have nothing to disclose. Marcella Walker: Writing-original draft. Shonni J. Silverberg: Writing-review and editing.