Surgery is the only curable treatment in patients with PHPT [15]. Furthermore, it is known that commonly QoL in PHPT is deteriorated [25] and patients may experience diverse and often non-specific symptoms [4, 26, 27]. Thus, evaluation of benefits of PTX from patient’s perspective in terms of improving QoL and symptoms is of importance. In addition, as far as the clinical picture of PHPT has changed over the last decades, mainly due to the early detection of hypercalcemia and often occurs as an “asymptomatic” or a mildly “symptomatic” disease [1], the information about the impact of different types of PHPT on QoL might be helpful in decision making. In this single-center prospective observational study we have analyzed comprehensively the impact of PHPT on QoL and investigated the trajectory of changes in PROs during 24 months after successful surgery.
We demonstrated high disease burden in terms of PROs in PHPT patients before surgery using the battery of generic and disease specific QoL questionnaires, namely SF-36 and PHPQoL as well as symptom assessment tool PAS. Patient’s QoL was significantly lower as compared to healthy controls, namely, role physical and role emotional functioning, physical functioning, vitality, social functioning and mental health were decreased. Almost 40% of patients had poor or very poor QoL measured by disease specific PHPQoL questionnaire. This points to the fact that before surgery disease specific areas of QoL in PHPT patients are compromised. Furthermore, symptom profile was analyzed using PAS, the tool developed to assess symptoms of PHPT. The vast majority of patients experienced common PHPT symptoms. Of importance, half of the patients had moderate-to-severe (≥ 40 scores) nonspecific symptoms, such as tiredness, weakness, joint pains, forgetfulness and mood changes. In general, the more symptoms experienced by a patient, the worse his QoL. Impaired QoL in PHPT patients was reported in previous studies [6, 7, 10]. To note, those studies had limitations regarding insufficient patients numbers, lack of control population, insufficient assessment of cognitive areas, and the use of non-specific questionnaires. In our study comprehensive PRO assessment was performed which allowed to illustrate from patient’s perspective full-on disease burden before surgery. The use of generic QoL questionnaire SF-36 which assesses overall health and well-being as well as disease-specific PHPQoL, which measures the impact in two areas important to PHPT patients, physical and emotional/neuropsychological functions, along with symptom assessment tool PAS, sounds worthy to describe patient’s functioning before treatment.
Another important outcome of our study is that using the battery of PRO measures we demonstrated differences in QoL deterioration and symptom burden in patients with “symptomatic” and “asymptomatic” disease. We found that patients with “symptomatic” PHPT had worse QoL and more pronounced psychological problems than patients with “asymptomatic” disease. In general, similar findings have been discussed by other researchers before [6, 7]. However, apart from other studies, we found that differences between “symptomatic” and “asymptomatic” PHPT were mostly in psychosocial domain. Thus, patients with “symptomatic” disease had lower vitality, social functioning, mental health, and role physical functioning by SF-36 as well as lower mental component by PHPT as compared to patients with “asymptomatic” PHPT. As for symptoms, we demonstrated that only mood changes and feeling ‘‘blue’’ were more pronounced in patients with “symptomatic” PHPT as compared to “asymptomatic”. The severity of other symptoms was similar in both groups. These data may confirm that patients with “asymptomatic” PHPT have similar symptom profile in patients with symptomatic PHPT, excluding psychological problems, which more pronounced in the latter ones.
For decades, researchers have attempted to understand the factors associated with the reduction and/or maintenance of QoL in PHPT [7, 8, 11, 13, 28, 29]. We found no significant effect of disease-related factors, such as level of preoperative Ca2+, preoperative p-PTH and disease duration on QoL subcategories. These results confirm the data obtained in the studies by E.M. Ryhanen et al. [7], S.M. Webb et al. [11], and Tsukahara K et al. [12], apart from the results by Ejlsmark-Svensson H. et al. [8], Tzikos G. et al. [28], Mohan B. et al. [29]. Our findings demonstrate that patients with PHPT experience various systemic and neuropsychological symptoms which attribute to reduction of QoL and may be considered as a nonclassical manifestation of PHPT which cannot be inferred from the biochemical and other biomedical parameters used for patient evaluation.
Taking into account that at present QoL assessment has become increasingly important in PHPT patients undergoing PTX to evaluate the effect of surgery, the main goal of our study was to analyze trajectory of changes in generic and disease-specific QoL aspects in PHPT patients at different terms of follow-up after surgery, and to explore the predictive significance of preoperative parameters in terms of meaningful QoL improvement after PTX. In those patients who had successful surgery we demonstrated distinct noticeable positive changes in QoL already at 3 months after PTX. The most remarkable improvement was revealed for psychological and social aspects of QoL measured by generic questionnaire SF-36. As for PHPT-specific QoL questionnaire we revealed similar trajectory of improvement for both physical and psychological components of QoL after surgery. Also we found that the severity of the most frequent and severe preoperative symptoms – tiredness, weakness, mood changes and forgetfulness decreased significantly at 3 months after surgery. Noteworthy, positive QoL and symptom changes sustained over 24 months after PTX. The results obtained are in accordance with our preliminary data analysis [30] and support valuable changes of PROs after surgery. Improvement of QoL after PTX was reported in other studies [6–10, 25] but only in a few of them there were several study time-points after surgery and long-term follow-up was performed. On the contrary, in our study PROs were measured at 3, 12 and 24 months which allowed to trace the dynamics of QoL and symptoms at different time-points after surgery and to confirm sustained QoL improvement and symptom alleviation at long-term follow-up.
It is remarkable that more than half of the operated patients (61.1%) had clinically meaningful QoL improvement, namely were QoL responders. Here it is worthy to emphasize that small differences in QoL may be statistically significant yet clinically unimportant. The concept of clinically meaningful change in QoL, namely minimal clinically important difference, has been proposed to refer to the smallest difference in a score that is considered to be worthwhile or important [31]. We used the difference of at least 9 points between the baseline and any follow-up time-point PHPQoL total score based on the reports by the PHPQoL developers [11]. Thus, the patients with improvement in PHPQoL total score after surgery by at least 9 points were considered as QoL responders. To note, the proportion of QoL responders was similar in patients with “symptomatic” or “asymptomatic” PHPT. Moreover, no differences in the proportion of QoL responders were observed between patient’s subgroups depending on the level of preoperative hypercalcemia. This finding may be viewed as the evidence of similar benefit of PTX in terms of PROs in patients with “symptomatic” and “asymptomatic” PHPT as well as in patients with different level of preoperative hypercalcemia. Thus, preoperative QoL and its changes after surgery are not dependent on clinical parameters, but are mostly related with neurocognitive problems and psychological symptoms, experienced by the patient due to disease.
The data on predictors of surgery success in PHPT patients are till limited and studies aimed to reveal what preoperative variables may be predictive of QoL improvement along with normalization of disease-related biochemical parameters is worthwhile. To explore the nature of relationship between meaningful QoL improvement and preoperative variables in PHPT patients the regression analysis was applied. The list of baseline independent variables involved those clinically relevant, including type of PHPT, preoperative Ca2+, p-PTH, disease duration, presence of comorbidities as well as patient’s age and education along with patient-reported outcomes, such as baseline QoL by disease-specific questionnaire and severity of most pronounced PHPT symptoms by PAS. Along with results of E.M. Ryhanen et al. [7], we detected that preoperative QoL is predicting for QoL improvement. On contrary to Ryhanen data, education was not predictive for meaningful QoL improvement in our study. Also all disease-related parameters included in the analysis did not demonstrate their predictive significance for QoL improvement after surgery. Moreover, only mental component of QoL was significantly predicting meaningful QoL improvement after PTX in the final regression model. In other words, the worse psychological condition of patient, the higher probability of meaningful QoL improvement over time after surgery. This finding suggests that the derangement of mental health may be considered as an individual indication for surgery.
Our study has several limitations. First, sufficient number of patients were lost during follow-up because of electronic administration of PRO measures, which may bias the results. Taking into account commonly high withdrawal rate in prospective QoL studies and taking into consideration CONSORT PRO Guidelines for handling missing data in order to minimize bias we performed GEE for comparisons. Second, the levels of Ca2+, p-PTH, 25OHD and other biochemical parameters were not controlled after surgery due to the study design. Among other study limitations the lack of a control group of non-operated PHPT patients may be mentioned.
In this paper, we examined preoperative PROs in a comprehensive way and analyzed their changes during 24 months after surgery. Future studies should address follow up for more than 24 months after PTX with sufficient number of patients. Also it is of importance to provide comparison of QoL in PHPT patients at long-time follow-up after surgery with healthy controls.