FormalPara Key Points for Decision Makers

Study findings suggest that patients with hypoparathyroidism experience a substantial burden of illness, both with respect to the range and severity of symptoms associated with the condition.

A validated disease-specific composite measure of symptoms in individual patients would be useful and help standardize the language used to describe the severity of the clinical syndrome in individual patients.

The validation-ready HPES-Symptom is intended to be a brief useful tool for assessing symptoms of hypoparathyroidism from the patient perspective, and for use in future studies that evaluate disease burden or treatment efficacy relating to symptom improvement among adults with hypoparathyroidism.

1 Background

Hypoparathyroidism (HP) is a rare endocrine disorder characterized by absent or inappropriately low levels of circulating parathyroid hormone (PTH) [1, 2]. Parathyroid hormone is important in the homeostasis of calcium and phosphate in the body, the former within a narrow physiological range [1, 3]. Parathyroid hormone is also a key hormone maintaining bone turnover [4,5,6]. Low levels or the absence of PTH circulating in the bloodstream can lead to hypocalcemia, hyperphosphatemia, hypercalciuria, and over-mineralized bone [1, 3].

The prevalence of HP in the USA is estimated to be between 70,000 and 115,000 patients [1, 7,8,9], or up to 37 per 100,000 residents. A paucity of data exists on the global prevalence of this condition, but estimates available for other countries have been lower, ranging from approximately 25 per 100,000 residents in Denmark, to 10 per 100,000 residents in Norway, and 5.9 per 100,000 residents in Italy [1, 10]. The most common source of HP is post-surgical, accounting for approximately 75% of cases [2, 9]. It occurs when the parathyroid glands are irreversibly damaged or inadvertently removed, or their blood supply is damaged during anterior neck surgery [2, 9]. The next most common etiology is auto-immune [2], characterized by the autoimmune destruction of the parathyroid glands leading to the loss of PTH secretion [11]. Idiopathic hypoparathyroidism occurs for unknown reasons [2]. Other etiologies include genetic mutations, severe and prolonged hypomagnesemia, hemochromatosis, Wilson disease, metastasis, and radiation-induced damage/fibrosis [1, 12,13,14].

Conventional treatment of HP, often referred to as standard of care (SoC), includes oral calcium and vitamin D supplements, often in large doses, with the goal of normalizing serum calcium levels [1,2,3, 14]. Parathyroid hormone [1–84] replacement therapy has also been approved by the US Food and Drug Administration for the treatment of HP in adults who cannot be well controlled with SoC [1, 15].

Hypoparathyroidism is associated with significant physical and cognitive symptoms [1]. Prior studies have found that patients with HP more frequently report experiencing symptoms such as fatigue, muscle spasms, paresthesia, and cognitive dysfunction, compared with either the general population [16, 17] or matched case controls [18, 19]. In a web-based survey of 374 adult patients with HP, over half reported experiencing the following symptoms over the previous 12 months despite taking medications: fatigue, muscle pain/cramping, paresthesia, tetany, joint or bone pain, heaviness or weakness in the extremities, “brain fog”, inability to focus or concentrate, forgetfulness, sleep disturbances, anxiety, and feeling sad or depressed [20]. More severe symptoms of HP include laryngospasm (spasm of the voice box), bronchospasm (spasm of the muscles that line the airways), cardiac arrhythmias, and seizures [1, 2]. Additionally, there may be complications associated with the long-term use of calcium and vitamin D supplements, including premature cataracts, pseudotumor cerebri, soft-tissue calcifications, kidney stones, renal failure, and Parkinson’s disease resulting from basal ganglia calcifications [1, 2, 9, 14].

Research indicates that patients with HP receiving SoC and/or PTH replacement therapy may have a reduced health-related quality of life (HRQOL) [1, 17, 21,22,23]. While several studies have used validated questionnaires to explore this, these questionnaires were not disease specific, and did not assess a number of symptoms associated with this condition, including cognitive deficits, fatigue, or decreased muscle strength [21, 24]. Moreover, because most patients with post-surgical HP also have post-surgical hypothyroidism, limited data are available on the extent to which reduced HRQOL is due to HP or the combination of HP and hypothyroidism [18]. Thus, there is a need to better understand, from the patient’s perspective, the signs and symptoms experienced with HP.

The purpose of this study was to develop a new disease-specific measure of the signs and symptoms of HP, the Hypoparathyroidism Patient Experience Scale-Symptom (HPES-Symptom), and provide evidence for the content validity of items in the measure based on rigorous qualitative research methodologies for patient-reported outcome (PRO) development. In addition, the study aimed to develop a preliminary theoretical model to identify relationships between signs and symptoms and their impacts on HRQOL related to the new PRO measure and inform future studies using the measure. Compared with generic measures, condition-specific instruments should have greater face validity, be more responsive to change over time, and be more useful to both clinicians and researchers to assess the impact of treatment on patients with HP.

2 Methods

The HPES-Symptom was developed in accordance with the Food and Drug Administration guidance [25] and best research practices for PRO measure development [26,27,28,29]. Concept elicitation (CE) interviews with clinical experts and people with HP were used to inform the structure and content of the measure and to develop the preliminary theoretical model. Cognitive interviews were then conducted to ensure that instructions and items were clear, relevant, and inoffensive, and that the recall period and response options and scales were appropriate.

2.1 Concept Elicitation

Individual CE interviews were conducted by telephone with clinical experts and people with HP to identify key concepts of relevance and importance to the target population to inform the development of the PRO measure [28]. The key concepts of interest were the signs and symptoms of HP. Clinical experts and patient participants were also asked about how these signs and symptoms affected HRQOL (to be reported in a separate publication). The current literature on HP was used to inform the development of the semi-structured interview guides, which included open-ended questions and probes. The patient participant interview guide was further developed based on input from the clinical expert interviews, and included questions asking not only what types of signs, symptoms, and impacts they experienced, but how bothersome these were and how frequently they were experienced.

Clinical expert interviews were conducted with physicians in the USA and Denmark who were recruited through a key opinion leader. Eligible clinical experts were well-established physicians currently practicing endocrinology and providing care to adult patients with HP.

Patient participants with HP were recruited via a national hypoparathyroidism organization and required to verify their eligibility by answering screening questions over the telephone and providing documentation of their diagnosis. Because of the low prevalence of people with HP, it was necessary to recruit participants throughout the USA, which in turn required that participants be interviewed by telephone because travel to each participant’s location was unfeasible. However, studies have shown telephone interviews [30,31,32] to be a valid qualitative research method and a rich source of data.

Eligible participants needed to be at least 18 years old; be able to read, write, and speak English; have a diagnosis of HP of either at least 6 months (post-surgical), or at least 12 months (auto-immune or idiopathic); and be stable on SoC (oral calcium and vitamin D supplements) and/or short-acting PTH replacement therapy for at least 3 months. Stable was defined as experiencing infrequent severe hypo- or hypercalcemia requiring infusion treatment no more than one or two times in the past 3 months. Exclusion criteria were having HP due to a CASR mutation or pseudohypoparathyroidism; another condition that may affect calcium or phosphate metabolism; impaired renal dysfunction, defined as having Chronic Kidney Disease Stage 4 or 5 (estimated glomerular filtration rate ≤ 30 mL/min/1.73 m2); or a cognitive impairment or other medical condition, including psychiatric disorders, that would impact an individual’s ability to participate in a telephone interview.

The individual interviews with clinical experts and patient participants were completed by trained qualitative research interviewers familiar with HP. Interviews lasted approximately 1 h and were conducted in an open-ended conversational style, generally following the semi-structured interview guides, but also responding to participants’ thoughts. Thus, while the interviews were not identical, each followed the general themes and scope of the guides. Completed interviews were also used to guide and inform subsequent interviews as emergent issues that were raised by experts and patient participants in earlier interviews were further explored. Interviews were audio-recorded and transcribed verbatim. Clinical expert and patient participant names were replaced with unique ID numbers in the transcripts prior to analysis.

The study was approved by the Copernicus Group Institutional Review Board (tracking #420180290). Informed consent was obtained from all patient interview participants.

2.2 Qualitative Data Analysis

Data were qualitatively analyzed through an adapted grounded theory approach, entailing developing and refining a theory based on concepts derived during the research process [33]. This involved iteratively analyzing the participant and clinical expert interview transcripts for content by theme using Dedoose (http://www.dedoose.com), a qualitative analysis software program. For the portion of the study related to the development of the HPES-Symptoms measure, the overarching theme was the signs and symptoms associated with HP, and the key concepts within these were the specific signs and symptoms that patient participants reported experiencing and/or clinicians reported observing in their patients. Following the completion of the interviews, a preliminary code list of themes and concepts was created based on the interview guides. Next, each transcript was read once, initially coded, and then reviewed multiple times. Within each study population (patient and physician), transcripts were coded in chronological order by when the interviews were conducted. Throughout the coding process, emerging concepts (signs and symptoms) were added to the coding scheme as they arose, and earlier transcripts were re-evaluated for the new concepts. Concepts were also iteratively reviewed to assess whether any redundancies among them existed, or whether any concept categories appeared to encompass multiple discrete concepts that needed to be separated from one another. Finally, the coded concepts were organized into larger categories of major themes (the signs and symptoms domains) for each study population, refining the preliminary themes based on the analysis and internal deliberations and consensus among the research team. Thematic saturation, defined as that point in time when no new major themes or concepts emerged, [34] was evaluated through the development of a saturation grid populated with the key concepts that were discussed in each participant interview.

To address the question raised in the literature about the extent to which impaired HRQOL may be due to HP as a stand-alone condition vs. HP combined with hypothyroidism, comparative frequencies for the overall endorsement rates (the percentage of participants who spontaneously reported or affirmed in response to interview probing) of physical and cognitive symptoms were examined based on the proportions of participants with vs. without hypothyroidism. Differences of at least 20% in the proportions of participant endorsement rates between these subgroups were considered to be potentially meaningful. Given that the meaningful difference was not explored in the interviews, the 20% threshold cannot be considered a clinically meaningful difference.

2.3 Item Generation

A 3-day, in-person, item generation meeting was held by the project research team. In accordance with Food and Drug Administration guidelines and good practices for PRO measure development, the team established criteria to identify signs and symptoms of importance and relevance to patients, including patients with differing demographic characteristics and disease severity levels [25,26,27,28,29]. Minimum percentages were included for CE participant endorsement of items, with some exceptions, to ensure the relevance of items to the target population and to avoid floor effects in the measure. The final agreed-upon criteria for the consideration of signs and symptoms as major included:

  1. 1.

    Endorsement by at least 30% of patient participants (including both participants who spontaneously reported experiencing a particular sign or symptom and those who affirmed experiencing it in response to interview probing), or by 20–29% if warranted by additional justification (e.g., if considered to be extremely bothersome by participants who reported these signs and symptoms);

  2. 2.

    For concepts that appeared to include overlapping but potentially multiple distinct issues, such as muscle spasms vs. muscle twitching, each issue would be provisionally categorized as major, even if the endorsement rates fell below 20%, pending results of the cognitive debriefing (CD) interviews; items found to be distinct conceptually and endorsed as both relevant and bothersome by a majority of CD participants would be retained as major concepts;

  3. 3.

    Must be clearly linked to the burden of illness rather than the burden of treatment;

  4. 4.

    Considered as bothersome to participants; and

  5. 5.

    Must be proximal. Proximal symptoms were considered more immediate (e.g., muscle cramping), while distal symptoms were considered longer term (e.g., poorer overall health).

All issues not fulfilling these criteria were categorized as minor, distal, or a modifier. The criteria for categorizing concepts as minor included:

  1. 1.

    Endorsement of at least 10% but less than 20% of participants; and

  2. 2.

    Endorsement of 20–29% of participants with no additional justification for inclusion as a major issue.

Based on decisions regarding major and minor symptoms, a theoretical model was developed for the relationships among the key concepts of interest and to identify potential modifying factors [26]. Based on the qualitative analysis, the major signs and symptoms identified, and the preliminary theoretical model, the team then generated the preliminary measure items and created an item definition table, which specified each item’s intent and acceptable synonyms, using the language of the participants as closely as possible for each item.

2.4 Cognitive Debriefing Interviews

Following item generation, CD interviews were conducted to reach a consensus on the appropriate format and structure of the measure; ensure that items, response options, and instructions were clear and relevant; confirm that the recall period was reasonable; and ensure that the content was comprehensive [26, 29]. The interviews were conducted in an independent sample of patients with HP who met the same eligibility criteria as the CE sample. Participants were emailed the HPES-Symptom in advance and asked to complete it 24–48 h prior to their interview, and to have it with them for the interview.

A semi-structured interview guide with relevant probes was used to direct the cognitive interview process. Interview questions focused primarily on participants’ comprehension and perceptions of each item and the instructions, and also addressed issues of formatting, wording, content, recall period, response options, and relevance, using verbal probing techniques as needed. Individual interviews were conducted in blocks of four respondents each and edits were made in between blocks based on participants’ comments. This process continued until a determination was made that the readability and relevance were acceptable based on a consensus agreement among the participants in the final block. Once the final block of cognitive interviews was completed, a validation-ready version of the measure was produced, and the preliminary theoretical model was updated to incorporate findings from the cognitive interviews.

3 Results

3.1 Concept Elicitation

3.1.1 Sample Description

A total of five expert interviews were conducted with well-established metabolic bone disease-specialist endocrinologists whose practices were located in the USA (n = 3, 60%) and in Denmark (n = 2, 40%). On average, the physicians had been treating patients with HP for 16 (range 5–30) years. Physicians reported seeing an average of 12 (range 1–40) patients with HP of all ages per month and having an average of 60 (range 2–140) adult patients with HP in their practice. Three physicians worked in academic medical centers (60%) and two worked at university hospitals (40%).

A total of 43 adults participated in the telephone interviews; however, one participant was excluded from the data analysis because her childhood polio had an impact on her physical and daily life functioning. Thus, 42 participants were included in the data analysis. The majority were female (n = 35, 83%), and the average age was 53 (range 26–76) years. The majority (n = 36, n = 86%) identified the source of their HP as post-surgical while 14% (n = 6) reported the source as idiopathic. On average, participants had HP for 14 (range 1–49) years. Participants reported having an average of five (median 4, range 0–20) comorbidities in addition to their HP, including hypothyroidism (n = 30, 71%), osteoarthritis (n = 16, 38%), and depression (n = 12, 29%). Nearly all participants reported currently using vitamin D (n = 41, 98%) or calcium supplements (n = 40, 95%), and more than half reported currently using magnesium supplements (n = 24, 57%) or PTH replacement therapy (n = 22, 52%) to manage their HP. Table 1 presents the demographics and health characteristics of the study participants.

Table 1 Concept elicitation participant demographic and health characteristics
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3.1.2 Qualitative Analysis

Thematic and conceptual saturation was assessed for the 42 participant interviews in the order in which they occurred. A total of 67 concepts (including all signs and symptoms that were reported by at least one participant) of HP emerged from the interviews. After the 17th interview, 75% of signs and symptoms had been discussed, and by the 39th interview, 95% were covered.

Participants and clinical experts reported a total of 51 physical signs and symptoms, as shown in Table 2. The most frequently reported signs and symptoms included tingling/numbness/paresthesia (n = 37, 88%), muscle cramping (n = 36, 86%), physical fatigue (n = 35, 83%), pain (n = 32, 74%), sleep issues (n = 21, 50%), muscle spasms/twitching (n = 20, 48%), muscle weakness/fatigue/decreased stamina (n = 17, 40%), heat intolerance (n = 14, 33%), and cardiovascular symptoms (n = 14, 33%).

Table 2 Patient- and clinician-reported physical signs and symptomsa
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Participants and clinicians reported a total of 13 cognitive signs and symptoms, as shown in Table 3. The most frequently reported cognitive signs and symptoms included memory impairment/forgetfulness (n = 24, 57%), conversation/speech issues (n = 21, 50%), lack of concentration/focus (n = 18, 43%), unable to think clearly/“fuzzy thinking” (n = 13, 31%), and impaired ability to understand information (n = 11, 26%). The vast majority of participants who reported experiencing cognitive symptoms (32/36, 89%) also used the term “brain fog” or affirmed experiencing “brain fog” when queried about it during the interviews. Based on the analysis, it appears that participants used this phrase as a catch-all umbrella term to encompass cognitive impairments, rather than as its own discrete symptom.

Table 3 Cognitive signs and symptoms
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Overall, there were no differences in the proportions of participants who reported experiencing the major physical and cognitive symptoms based on comorbidity status. However, there were a few differences in endorsement rates for the minor symptoms. A higher proportion of participants with hypothyroidism reported experiencing kidney problems (9/31, 29%) than those without this comorbidity (1/11, 9%). Conversely, a lower proportion of participants with hypothyroidism (2/31, 6%) reported experiencing impaired decision-making ability than those without this comorbidity (3/11, 27%).

3.1.3 Preliminary Theoretical Model

Based on the qualitative data analysis results, a preliminary theoretical model of the signs and symptoms of HP was developed (Fig. 1). The model illustrates the hypothesized relationships among the major and minor physical signs and symptoms, proximal impacts, and distal consequences along with potential mediators and modifiers. Potential modifiers and mediators that may mitigate or amplify the impacts experienced by individuals with HP include treatment status, comorbidities, disease severity, age, time with HP, disease etiology, and access to medical care. The model is considered preliminary in nature, as it may require modification based on the psychometric validation of the measure.

Fig. 1
figure 1

Preliminary theoretical model of the signs and symptoms of hypoparathyroidism

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3.2 Item Generation

Items were generated for the major signs and symptoms while minor signs and symptoms, as well as proximal or distal impacts, were excluded from the measure. Based on the criteria outlined above, 17 signs and symptoms were categorized as major, including muscle cramps, muscle spasms, muscle twitching, muscle weakness, tingling with numbness, tingling without numbness, pain, sensitivity to heat, feeling tired, trouble sleeping, heart problems, low energy, trouble remembering, trouble finding the right words, trouble concentrating, and trouble thinking clearly.

Items were worded as closely as possible to the language used by participants. For each item generated, the qualitative analysis findings were reviewed to confirm that the item reflected a concept considered to be important and bothersome by a majority of the participants who reported experiencing it.

3.3 Cognitive Debriefing

A total of 16 adults participated in CD interviews. As with the CE sample, the majority (n = 12, 75%) were female, and had post-surgical HP (n = 11, 69%). The average age was 47 (range 20–63) years. On average, participants had HP for 12 (range 2–50) years. Participants reported an average of three (median two, range zero to nine) comorbidities in addition to their HP, including depression (n = 4, 25%), chronic back pain (n = 4, 25%), and hypothyroidism (n = 3, 18%). The majority reported currently using calcium (n = 14, 88%) and/or vitamin D (n = 12, 75%) supplements to manage their HP. Half reported currently using magnesium supplements or PTH replacement therapy.

After the first block of interviews, findings were reviewed, and a decision was made as to whether any changes to the HPES-Symptom were necessary. This process continued in blocks of four participants until a determination was made that the readability, clarity, and relevance of all instructions and items, including response options and response scale format, were acceptable based on consensus agreements among respondents in an entire block. A total of four blocks were necessary to refine the HPES-Symptom items in terms of readability and relevance.

The CD resulted in the validation-ready HPES-Symptom tool, which is made up of 17 items using the same stem and response options. For example, respondents are asked, “In the past two weeks, because of your hypoparathyroidism, how often did you experience muscle cramping?” Response options are based on a five-point Likert-type scale, chosen to ensure that meaningful distinctions could be made among responses for analysis while minimizing the cognitive burden for respondents completing the instrument [35]. Response options included “Never”, “Occasionally (1–25% of the time)”, “Sometimes (26–50% of the time)”, “Often (51–75% of the time)”, and “Very Often/Always (76–100% of the time)”. A numeric scale was provided for each response option greater than “Never” as a result of feedback from the first block of CD participants, who suggested that this additional quantitative specificity was needed for clarification. The 2-week recall was used to allow for the daily variability of symptoms, which is common for this condition. The appropriateness and ability to answer for a 2-week recall period was examined in the CD interviews. Participants understood and were able to answer in that timeframe. Participants reported taking an average of 4 min to complete the HPES-Symptom measure and did not consider this to be burdensome.

Table 4 presents representative quotes for each of the 17 HPES-Symptom items.

Table 4 Exemplary quotes for the items in the Hypoparathyroidism Patient Experience Scale-Symptom (HPES-Symptom)
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4 Discussion

Study findings suggest that patients with HP experience a substantial burden of illness, both with respect to the range and severity of symptoms associated with the condition. The vast majority of CE and CD participants reported experiencing both physical and cognitive signs and symptoms. Very few potentially meaningful differences based on hypothyroidism comorbidity status were identified in the analysis. Based on these findings, this study provides evidence for the content validity of the signs and symptoms captured in the HPES-Symptom.

Prior research suggests that the signs and symptoms associated with HP may also impact patient HRQOL [19,20,21,22,23, 36]. In this study, impacts associated with HP symptoms were reported across four HRQOL domains: physical functioning, daily life, psychological well-being, and social life and relationships. In addition to developing the HPES-Symptom measure, the findings on impacts were used to develop a separate disease-specific, patient-reported impact measure on how HP affects daily functioning and well-being (to be reported separately). The symptoms identified in this study are similar to those included in a recently developed symptom diary for this condition, lending support to the validity of our findings [37].

Having access to a brief disease-specific measure of the signs and symptoms of HP experienced by patients has the potential to enhance their clinical care. A validated disease-specific composite measure of symptoms and their effects on HRQOL would be useful and help standardize the language used to describe the severity of the clinical syndrome in individual patients. Although HP is seldom immediately life threatening, it imposes a substantial HRQOL burden on many patients [1, 17, 21,22,23]. However, some patients with HP are minimally symptomatic or completely asymptomatic. At present, there is no easily applied, convenient method to classify such patients for ease of communication and to help place into context the potential risks and benefits of various therapies for HP. The goal is for the HPES-Symptom to be a brief useful tool for assessing symptoms of HP from the patient perspective, and to use the HPES-Symptom in future studies that evaluate disease burden or treatment efficacy relating to symptom improvement.

As with all research, this study has limitations. While efforts were made to recruit a diverse sample of study participants, the majority were female and had post-surgical HP, which is similar to the sample compositions in other studies of patients with HP [17, 20, 38]. In addition, most participants were White/Caucasian, and it was a US-based population. However, the clinical experts from Denmark reported observing similar signs and symptoms among their patients, and studies describing patients with HP in Canada, India, and multiple European countries provide evidence that the measure may also be appropriate for assessments in other populations [17, 19, 36, 39, 40]. Cultural and linguistic validation of the measure would be required for use in non-US populations. This study was also limited to an adult population. Additional CE research would be required to explore whether signs and symptoms differ for children and adolescents.

Given the sample sizes within each CE subgroup and the differences in the numbers of participants within the hypothyroidism vs. non-hypothyroidism subgroups (n = 30 vs. n = 11), study findings based on subgroups should be interpreted with caution. There were also variations within each subgroup that may affect the burden of illness, such as other comorbidities, duration of time with HP, and a high proportion of participants without hypothyroidism who were taking PTH replacement therapy (8/11, 73%). A quantitative survey study would be appropriate to further explore variations among subgroups based on treatment status, comorbidities, and other potential modifiers such as sex, age, disease etiology, and length of time with the condition.

5 Conclusions

The study findings provide evidence of content validity for the validation-ready HPES-Symptom measure, which includes 17 items across two domains of signs and symptoms: Physical and Cognitive. The identification of the major patient-reported signs and symptoms of HP can provide the basis for a validated PRO measure to enable clinicians and researchers to assess the impact of treatments for this condition, including examining the differences between treatments, and assessment of the treatment risk/benefit ratio. Additional research is needed to validate the HPES-Symptom measure in patients with HP to determine whether it is a reliable measure. Factor analysis will be performed in the validation study to confirm the measurement properties and factor structure of the measure. While the preliminary theoretical model may be used to inform future research using the HPES-Symptom measure, modifications to the model may be required.