Quality of life in patients with hypoparathyroidism receiving standard treatment: an updated systematic review

Purpose Hypoparathyroidism is defined by hypocalcemia with inappropriately normal or low parathyroid hormone levels. The current standard treatment consists of lifelong calcium and/ or vitamin D supplementation. Even while on stable treatment regimens, hypoparathyroid patients might still suffer from symptoms that can negatively impact their quality of life. Methods A systematic literature review to identify the current knowledge regarding quality of life in patients with hypoparathyroidism receiving standard treatment was performed on November 1st, 2023. PubMed as well as Web of Science were searched. The systematic review is registered in PROSPERO (#CRD42023470924). Results After removal of duplicates, 398 studies remained for title and abstract screening, after which 30 were included for full-text screening. After exclusion of seven studies with five studies lacking a control population, one using a non-validated questionnaire, and one being a subsample of the larger included study, 23 studies were included in this systematic review. The majority of the included studies used a guideline-conform definition of hypoparathyroidism, and the SF-36 was the most often applied tool. Almost all studies (87%) reported statistically significantly lower scores in at least one quality of life domain compared to a norm population or controls. Conclusion Patients with hypoparathyroidism receiving standard treatment report impairments in quality of life. The reasons for these impairments are probably multifaceted, making regular monitoring and the inclusion of various professionals necessary.


Introduction
Hypoparathyroidism (hypoPT) is a rare endocrine disorder defined by hypocalcaemia with inappropriately normal or low parathyroid hormone (PTH) levels [1][2][3].For approximately 75% of cases, thyroid or parathyroid surgery is the main cause for hypoPT [4].Other causes of hypoPT can be autoimmune disease or genetic variations, but the causes for a considerable proportion of the non-surgical cases remain unclear and are considered as idiopathic [5,6].The prevalence of hypoPT lies between 5.3-40.0 per 100,000 individuals, with differences between countries [5,[7][8][9][10][11][12].The standard treatment consists of lifelong calcium and/or vitamin D supplementation with regular monitoring [13], but this treatment does not restore the regular calcium/phosphorus homeostasis [2,10].Patients with hypoPT suffer from a variety of symptoms such as tingling, cramps, and gastrointestinal problems even long after diagnosis.These symptoms can have an impact on hypoPT patients' quality of life (QoL) [10,14,15].The importance of QoL is also highlighted in the European [13] und North-American [16] guidelines for the management of hypoPT, stating that treatment should be personalized and focused on overall well-being and QoL.Especially with new treatments emerging within the last years, the focus on QoL is becoming more important [17][18][19][20][21].
To better understand the relationship of hypoPT with QoL, we had conducted a systematic review in 2016 [22].Since that time, new studies have been published, warranting an update of this overview.
The aim of this updated systematic review is to give an overview of hypoPT patients' QoL receiving standard treatment and to provide information on the definition of hypoPT and questionnaires used in the respective studies.

Search strategy
On November 1st, 2023, a systematic literature search in PubMed and Web of science was performed.This systematic review was performed in accordance with the PRISMA statement [23].The search terms were the same as in the previous systematic review, namely "hypoparathyroidism" or "hypocalcemia" or "hypocalcaemia" in combination with the terms "quality of life" or "qol" or "well-being" within the title or abstract.Grey literature and references of all selected publications were checked.No further restrictions were applied.The systematic review is registered in PROSPERO (#CRD42023470924).

Eligibility criteria
The following inclusion criteria were applied (a) adult patients with a diagnosis of hypoPT for more than 6 months, (b) QoL had to be measured with a validated instrument, (c) patients needed to be on current conventional treatment consisting of calcium and/or vitamin d, (d) QoL outcome measure needed to be compared to a reference population or controls.Exclusion criteria were: (a) pediatric patients, (b) patients with untreated hypoPT, (c) case reports, (d) and review papers.

Manuscript screening and data abstraction
All titles and abstracts were screened by two independent reviewers (MB and KT) using Covidence [24].Full texts of all eligible studies were acquired and evaluated by the two independent reviewers.If disagreement regarding inclusion of a study occurred, this was solved by discussion between the two reviewers resulting in a consensual decision.Extracted data was stored in an electronic file including: authors, year of publication, journal name, study design, sample population, reference population, and QOL instruments used.For intervention studies investigating new treatments in patients with hypoPT, QoL at baseline was extracted for the impact of standard treatment on QoL.When available, QoL scores were extracted as well.QoL scores available only in figures were not extracted.

Quality assessment
Quality assessment of the studies was carried out by using the Newcastle-Ottawa Quality assessment scale for crosssectional studies as proposed by Herzog et al. [25].Using this assessment tool, studies can score a total of ten stars, indicating the highest quality.The scoring can be subdivided into three domains consisting of selection (maximum five stars), comparability (maximum two stars), and outcome (maximum three stars) [25].Seven studies were not of cross-sectional origin but were considered crosssectional as only information on baseline comparisons was extracted for this systematic review.

Study selection
The literature search resulted in 398 papers (after removal of 836 duplicates).After title and abstract screening, 30 studies remained for full-text review.Of these, five were removed because they lacked a control population, one was removed because QoL was assessed using a non-validated questionnaire and one was removed because its data was used in a larger study included in this analysis, leaving 23 studies eligible for data extraction.The full literature screening process is presented in Fig.  assessments of all included studies can be found in Table 1; no studies were excluded based on their quality.Regarding the control population, 11 studies [5,14,17,19,20,[26][27][28][29][30][31] used norm population data for comparison while 12 studies used controls [32][33][34][35][36][37][38][39][40][41][42][43].Information on the hypoPT group and comparison group for each study can be found in Table 2.

Diagnosis of hypoPT
In most studies (18 of 23) [5, 17, 19, 20, 26-29, 32, 33, 35-37, 39-43], the hypoPT diagnosis was confirmed by laboratory parameters, namely low or inappropriately low PTH levels in combination with hypocalcemia or low calcium levels for at least six months.Two studies [30,34] reported that hypoPT was confirmed by the treating physician without further information on the diagnostic criteria, and two studies [14,31] relied on a self-reported diagnosis from the patient.Hillary et al. [38] used a combined study population for their analysis, including patients with a confirmed diagnosis of low PTH in combination with hypocalcemia or low calcium levels as well as patients with a self-reported diagnosis enrolled from self-help organizations.

Quality of life compared to norm populations
Of the eleven studies comparing hypoPT patients' QoL to norm populations, eight studies [5,14,19,26,[28][29][30][31] found at least one QoL-related domain where hypoPT patients reported statistically significantly lower scores compared to the norm population.Vokes et al. [20] reported lower SF-36 baseline scores for the hypoPT patients compared to the norm population but the differences were small.In the two studies by Khan et al. [17,27], the PCS of the SF-36 was lower compared to the norm population without any reporting of statistical tests.Three studies [19,26,30] reported statistically significantly lower SF-36 scores across all domains compared to a norm population.Two of those studies [19,26] had mixed hypoPT populations (post-surgical and non-surgical hypoPT), and the study of Underbjerg et al. [30] only looked at non-surgical hypoPT.In Astor et al. [5]

Quality of life compared to controls
Four [35,37,40,43]  of the eight SF-36 domains [39].Using the SCL-90R, GBB-24, and B-L Zerssen, Arlt et al. [32] showed that 25 women with postsurgical hypoPT compared to 25 women without hypoPT matched for age and time since surgery reported significantly higher global complaint scores for the three questionnaires used.Two studies [34,41] solely included patients with and without hypoPT after treatment for thyroid cancer.Büttner et al. [34] analyzed data from the development of thyroid cancer-specific EORTC thyroid module (EORTC QLQ-THY34) [51].Seventeen patients with hypoPT at least nine months after treatment for thyroid cancer were compared to 72 controls without hypoPT at least 9 months after treatment for thyroid cancer using the EORTC QLQ-C30.HypoPT patients had statistically significantly lower scores compared to the controls in five (global quality of life (hypoPT: 51.0; controls: 68.5; p = 0.03), physical functioning (hypoPT: 66.7; controls: 82.7; p = 0.01), role functioning (hypoPT: 66.7; controls: 82.7; p = 0.02), emotional functioning (hypoPT: 56.9; controls: 80.0; p < 0.01), and social functioning (hypoPT: 69.6; controls: 86.0; p = 0.04),) of the six functioning domains [34].In Mazoni et al. [41], 89 hypoPT patients after treatment for differentiated thyroid cancer were compared to 89 controls without hypoPT using the SF-36, resulting in statistically significantly lower scores in physical functioning, general health, role functioning related to emotional problems, PCS and MCS for the hypoPT patients.The study be Sikjaer et al. [42] is the only one that used more than one control population: 22 postsurgical hypoPT patients with well-substituted hypothyroidism were compare to 22 postsurgical patients with well-substituted hypothyroidism but without hypoPT and with 22 controls.Groups were matched for age, gender and time since surgery (not for the healthy controls).Compared to the postsurgical controls, the hypoPT patients reported statistically significantly lower scores in the physical health and role functioning related to physical health domains of the SF-36, while compared to the healthy controls they scored statistically significantly lower in seven (all except role functioning related to emotional problems) of the eight SF-36 domains.

Discussion
This updated systematic review summarizes more evidence for the association of QoL with hypoPT in patients receiving standard treatment and provides an overview regarding the definition of hypoPT used in the studies, the QoL instruments used.
The majority of studies included in this systematic review used a definition of hypoPT as it is stated in the guidelines, namely low calcium and an inappropriately low PTH for at least 6 months [13,16].An accurate and comprehensible diagnosis of hypoPT is crucial in order to provide the best treatment to the patient.Two systematic reviews [52,53] have investigated different definitions of hypoPT used in studies.In 2010, Mehanna et al. [53] conducted a systematic review in order to identify different definitions of hypoPT used in the literature and to apply them to their cohort of 202 patients undergoing total or hemithyroidectomy.The ten main different definitions identified in this review resulted in a cumulative incidence of post-surgical hypoPT ranging from 0 to 46% showing the high heterogeneity among the different definitions.Harslof et al. [52] conducted a systemic review in 2019 looking at 89 studies and their definition of hypoPT.They identified 20 different definitions and 16 studies not reporting any information on the definition of hypoPT.Four of the studies in our systematic review did not provide a clear definition of hypoPT, but two studies enrolled their participants from hypoPT self-help organizations with extensive questions regarding their diagnosis of hypoPT within the used surveys.Therefore, we are confident that only patients with a clear diagnosis of hypoPT were included.The two other studies did not report a clear definition of hypoPT, but patients were diagnosed in a hospital setting by their treating physician ensuring an appropriate hypoPT diagnosis.
Only four studies (17%) in our systematic review used hypoPT-specific QoL instruments while the rest used generic or cancer-specific instruments.The problem with generic QoL instruments is that they might miss symptoms or QoL impairments of the specific disease [54,55].Even though the majority of studies reported impairments in QoL in hypoPT, some did not or only for very few domains [17,20,27], leaving the question open as to whether a disease-specific tool might have found more or different impairments or improvements.This may well be the case, as studies have identified hypoPT symptom burden to be associated with impairments in QoL [41,56].Because the hypoPT-specific questionnaires only have been recently developed [31,50], the included studies cannot be criticized for not applying them.For future studies, it is important to use a tool which covers generic QoL domains as well as the hypoPT-specific symptoms or domains.
HypoPT patients receiving standard treatment report impairments in QoL compared to norm populations or matched controls.HypoPT patients report QoL scores comparable to patients with chronic heart disease or diabetes [57], or worse compared to patients with other chronic diseases such as Addison's disease or congenital adrenal hyperplasia [58,59].There are various possible explanations for the impairments in QoL.The lack of PTH itself might negatively impact QoL as PTH receptors have been found in muscle cells, the central nervous system, and several brain regions [60][61][62][63][64]. Song et al. [43] found a potential association of current PTH levels and QoL, but this finding was not confirmed by Hepsen et al. [37].Studies investigating new treatments using synthetic PTH have shown promising results also in relation to QoL [17,18,21,29].Another potential factor influencing QoL in hypoPT patients is the occurrence and severity of hypoPT symptoms (e.g., cramps, tingling, gastrointestinal symptoms) [15].Studies have shown that a higher symptom burden is associated with lower QoL in hypoPT patients [41,56].Hillary et al. [38] reported that patients with hypoPT had significantly more symptoms using the HcSS compared to the control population.In Büttner et al. [14] patients with hypoPT had the highest symptom burden in loss of vitality, pain and cramps, and numbness and tingling sensations using the HPQ-28.The effect of current calcium levels and symptoms or QoL are controversially discussed within the literature.In the studies included in our systematic review 18 studies [5,17,19,20,26,28,29,32,33,[35][36][37][38][39][40][41][42][43] reported calcium levels of their study sample.While five studies [17,19,20,40,41] reported mean or median calcium levels within the reference range eleven studies [5, 26, 28, 29, 33, 35-37, 39, 42, 43] reported values below the reference range.Arlt et al. [32] stated that 18 of their 25 hypoPT had serum calcium levels within the accepted therapeutic range and in Hillary et al. [38] 43% of the participants stated that their calcium was in the normal range, while 44% had low or very low values and 3% had high values.An association between calcium levels and QoL was only observed in Hepsen et al. [37] with calcium levels being associated with general health and vitality of the SF-36.In the other included studies which investigated the association between calcium levels and QoL no association was found [5,10,19,27,32,33,35,41,43].Addressing this, the European Society of Endocrinology clinical guideline [13] states that "Symptoms of hypocalcemia do not translate directly into serum calcium levels.Sudden fluctuations in serum calcium levels may cause symptoms, even if calcium levels are (almost) normal.".HypoPT and its long-term conventional treatment might also lead to additional co-morbidities such as renal stones, cardiovascular disease, or calcifications, which might have a negative impact on QoL [3,10].Patients with hypoPT have reported that they have the feeling their disease is not understood [15,65,66] or that it is challenging to find an expert treating their disease [65].This psychological burden might lead to a higher risk for anxiety and depression compared to norm populations [33,65,[67][68][69], which might in turn influence QoL.In a study of 264 hypoPT patients, 16.3% of the patients reported that they had made use of at least one psychological service (e.g., psychologist, psychotherapist) due to their disease [65], with this share being the same or even higher compared to cancer patients [70,71].One aspect seldom assessed when the QoL of hypoPT patients is discussed is their ability of work.Büttner et al. [56] have shown that being unable to work due to the disease was associated with higher odds of reporting impairments of clinical importance for physical functioning, role functioning, and social functioning using the EORTC QLQ-C30.In the study by Astor et al. [5], it was stated that 40% of the hypoPT patients were receiving permanent or temporary social security benefits, while the proportion among the general Norwegian population is about 10% for permanent social security benefits and four percent for temporary benefits.In another study, 30% of the hypoPT who were working before their diagnosis stated the hypoPT had had an impact on their working situation ranging from reducing working hours to early retirement, or even being fired [65].Among hypoPT patients, being hospitalized because of hypocalcemia is not uncommon.Proportions of hypoPT patients with at least one hospitalization because of hypocalcemia range from 5-44% between studies [65,[72][73][74][75][76][77].Anaforoğlu et al. [72] found an association between hospitalizations or emergency department visits in hypoPT patients and QoL, making the fear or burden of hospitalization due to hypocalcemia another potential factor influencing QoL.As studies have shown an effect of hypothyroidism on QoL [78], one might question whether this was also present in the studies included in this systematic review and might explain some of the QoL impairments.Studies included in this systematic review could not find an association between thyroid stimulating hormone (TSH) levels and QoL in hypoPT patients [36,42].Additionally, the studies in postsurgical hypoPT populations had often matched controls who had also had total thyroidectomy, so that patients in both groups had to take medication for hypothyroidism [32,34,36,41,42].Lastly, as thyroid cancer patients report impairments in QoL, the possibility exists that some of the impairments in postsurgical hypoPT patients might be attributable to the thyroid cancer itself and not hypoPT.Büttner et al. [34] and Mazoni et al. [41] only included thyroid cancer patients with and without hypoPT in their analysis and still found profound differences in QoL between hypoPT and non-hypoPT patients.While two studies [38,42] stated that thyroid cancer might have an impact on QoL, other studies could not find an association between thyroid cancer and QoL in their hypoPT populations [36,37,56].With longer disease duration it might be assumed that patients develop coping strategies or have accepted their disease resulting in fewer QoL impairments.Of the included studies six [26,29,33,35,38,43] did not find an association between disease duration and QoL while three [14,19,37] studies found an association and the remaining studies did not include disease duration in their analysis.Hepsen et al. [37] and Tabacco et al. [19] found a correlation between disease duration and QoL in vitality and mental health respectively PCS using the SF-36.Using the disease specific HPQ-28 Büttner et al. [14] found a significant association between disease duration and various domains (neurovegetative symptoms, loss of vitality, depression and anxiety, rapid heartbeat, and depressive symptoms).

Conclusion
Compared to norm populations or clinical controls, patients with hypoPT on standard treatment report impairments in QoL in various domains.The potential factors influencing QoL are most likely multifaceted and require regular monitoring as well as the inclusion of different professions.
this work.Katherine Taylor has no relevant financial or non-financial interests to disclose.
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Fig. 1
Fig. 1 Flow chart of the literature selection process Star (*) represents whether a study fulfills the respective criteria.In total are the sum of all stars Endocrine (2024) 85:80-90 1.The quality