INTRODUCTION
Hypoparathyroidism is a disease characterized by chronic hypocalcemia associated with low or inappropriately normal levels of parathyroid hormone (PTH).[1] The main cause of hypoparathyroidism is total thyroidectomy (TT), described in approximately 75% of the cases. The leading cause of TT is nodular thyroid disease, of which the main etiology is thyroid cancer. The incidence rate of hypoparathyroidism after TT reported internationally is close to 8%, however, around 75% of cases are transient. On the other hand, the development of permanent hypoparathyroidism is described in 1% to 5% of patients with TT.[2,3] This can often be prevented with partial thyroidectomy (PT). Based on this fact, several international guidelines, including those of the American Thyroid Association, include PT as a therapeutic alternative in the management of differentiated thyroid cancer (DTC) to reduce the risk of hypoparathyroidism in selected patients.[4,5] Furthermore, the rate of post-surgical hypoparathyroidism is considered an indicator of quality associated with neck surgery, and the preservation of the function of the parathyroid glands is considered a primordial objective.[6]
Chronic PTH deficiency results in decreased intestinal absorption and renal reabsorption of calcium, decreased bone resorption, and increased renal reabsorption of phosphorus, manifesting as hypocalcemia and hyperphosphatemia. Clinically, hypoparathyroidism manifests with neuromuscular symptoms such as paresthesia, cramps, seizures, and laryngospasm, among others.[7] The goals of treatment in hypoparathyroidism include the relief of symptoms of hypocalcemia, maintaining calcemia within the low-normal range and phosphorous in normal range, and to prevent hypercalciuria. To achieve these goals, conventional treatment is based on the use of calcium and active vitamin D supplements, and in some cases, thiazide diuretics if hypercalciuria develops with treatment.[8]
Chronic hypoparathyroidism is associated with complications such as renal failure, urolithiasis, cardiovascular disease, impaired cognitive function, and cataracts, among others.[1,9] In addition, when it develops as a post-surgical complication, it has been associated with prolonged hospital stays and increased health costs.[10] Given the irreversible nature of this condition, patients must continue with medical therapy and biochemical monitoring throughout life.
Given the multiple complications associated with post-surgical hypoparathyroidism, relevant efforts have been made in recent years to quantify and characterize the deterioration in quality of life (QOL). The SF-36v2 survey is a QOL survey used for undifferentiated scenarios, which has been described as decreased in patients with hypoparathyroidism despite optimal levels of calcium and phosphorus.[11-15] Furthermore, specific QOL surveys for hypoparathyroidism are under development,[16-19] which have not been thoroughly validated or recommended by clinical guidelines, a scenario that could change in the coming years. Despite these efforts, an underestimation of the impact of hypoparathyroidism on the QOL of patients by health personnel has been described,[20] highlighting the importance of characterizing and quantifying this condition in our population.
To date, limited data on the impact on QOL in patients with post-surgical hypoparathyroidism is available in the South American region. The goal of our study is to characterize QOL, clinical manifestations, and adherence to therapy in Chilean patients with post-surgical hypoparathyroidism compared to a valid control group, to provide useful data to guide the best decision regarding surgical decisions for DTC.
METHODS
1. Patients and study design
We conducted a case-control study. Subjects 18 years or older with the diagnosis of post-surgical permanent hypoparathyroidism, defined as hypocalcemia and low or normal PTH on more than one occasion at least 6 months after a TT for DTC, were included (Group 1, cases). Patients who underwent TT for DTC without the development of post-surgical hypoparathyroidism (Group 2, controls) were included as a control group. For the identification of cases and controls, clinical records between January 2019 and July 2021 that met the aforementioned criteria were reviewed and all patients with postoperative hypoparathyroidism were included. Patients for the control group were randomly selected by a computerized system. A sample size of at least 34 patients per group was estimated to find significant differences between study groups, based on the SF-36v2 values reported by Astor et al. [12] (median difference per domain of 17 standard deviation [SD], ±27). A sample size of control group was increased to improve statistical power. Patients were contacted by telephone to obtain informed consent. Demographic data, medical history, symptom questionnaire, and record of therapies received were obtained. Laboratory tests included the last serum calcium, phosphorus, albumin, and alkaline phosphatases. Pathology report after TT and the use of radioiodine I-131 (RAI) were analyzed.
The study was carried out in accordance with the ethical standards and the protection of patient confidentiality established in the Declaration of Helsinki. The study was approved by the ethics committee of our institution (No. 200813012).
2. Evaluation of QOL
Two surveys were applied: SF-36v2 and a survey designed by the research team.
The SF-36v2 survey was applied to Groups 1 and 2. It consists of thirty-five items from eight dimensions of health-related QOL and is divided into two components: Physical Health (Physical Component Summary [PCS]) and Mental Health (Mental Component Summary [MCS]). The PCS includes the dimensions: Physical Functioning (PF), Role Physical (RP), Bodily Pain, and General Health (GH), while the MCS contains: Vitality (VT), Social Function (SF), Role Emotional (RE), and Mental Health (MH). A high score indicates better health-related QOL. As in the user’s manual for the SF-36v2, the results of the survey were transformed into normalized values (−NBS), each one with a mean of 50 and a SD of 10 points.[21]
The structured survey designed by the research team was applied by a phone interview to Group 1 and measured symptoms associated with hypoparathyroidism, adherence to therapy, economic costs, and adverse effects of therapy, adapting it to local reality. This survey was based on elements of previous specific QOL surveys for hypoparathyroidism that are under development.[16-19] An item referring to the periodicity of six symptoms was included, using the following categories: never, less than once a month, 1 to 3 times a month, weekly, and daily. Symptoms included muscle cramps, tingling or numbness, fatigue or tiredness, muscle weakness, short-term memory problems, and short-term concentration problems. Adherence to therapy was evaluated with the question “Of the last 10 doses of the prescribed drug, how many did you actually take?”. The question was applied to the use of calcium supplements with or without vitamin D and to the use of calcitriol. “Out-of-pocket cost” was also evaluated, that is, direct payments by people to finance their health needs. Patients were asked in Chilean pesos (1 USD=approximately 850 Chilean pesos or CLP) “How much money do you spend out of pocket per month on average on medical consultations and tests related to hypoparathyroidism?”. In addition, the same question was asked for out-of-pocket spending on drugs for hypoparathyroidism, both questions with the following alternatives: Less than 10,000 CLP (12 USD), 10,001-50,000 CLP (12-60 USD), 50,001-100,000 CLP (60-121 USD), 100,001-250,000 CLP (121-303 USD), more than 250,000 CLP (303 USD), and not applicable. Finally, an open question was included for the report of adverse effects attributed to drugs for the management of hypoparathyroidism. The answers were later grouped into constipation, abdominal pain, dizziness, and other gastrointestinal symptoms.
3. Statistical analysis
NBS of each domain of SF-36v2 were compared between Groups 1 and 2. First, the results of our study group were compared with the worldwide normal values and it was referred as “general population” in the manuscript. The results were analyzed in two different and validated ways: (1) subjects’ individuals score, considered significantly lower than the general population with a score of <45, expressed as the proportions of individuals under these threshold per group; (2) groups’ averages scores considered significantly lower than the general population with a score of <47, expressed as the average score per group. Missing data were replaced by the mean scores of the completed items in the same dimension if at least half of the items were answered. Second, the results of our study were also compared with the prior Chilean SF-36v2 validation study,[22] and it was referred to as “Chilean population” in the manuscript. These results were illustrated in a radar chart.
Categorical variables were described in percentages and compared between the study groups with χ2. Numerical variables normally distributed were described as mean and SD and non-categorical variables were described as medians and interquartile range (IQR). Numerical variables were compared between study groups with the Student,s t-test or the Mann-Whitney test as appropriate. Multivariable logistic regressions were performed to compare the results in each of the domains of the SF-36v2 survey, as an independent variable, between Groups 1 and 2, adjusted for sex, age, and use of RAI, expressed as adjusted odds ratio (aOR). A significance level of 5% (P<0.05) was used for all comparisons. Data was analyzed with the SPSS statistics (version 25; SPSS Inc., Chicago, IL, USA).
RESULTS
1. Baseline characteristics
One hundred and six subjects were included, of whom 93 (88%) were female. Forty-one subjects were in Group 1 (post-surgical hypoparathyroidism, cases) and 65 subjects in Group 2 (patients without hypoparathyroidism, control group). The median age was 38 years in Group 1 (IQR, 30-46) and 44 years in Group 2 (IQR, 36-54), P<0.017. Group 1 presented more frequent lymph node dissection compared to Group 2 (70.7% vs. 35.4%; P<0.001). Consistently, the use of RAI was more frequent in Group 1 than in Group 2 (82.9% vs. 53.8%; P=0.002). A complete demographic description, treatment received, histology, and biochemical parameters are included in Table 1.
2. QOL in SF-36v2 survey
The mean results of patients of Group 1 had worse QOL than the SF-36v2 general population in the MCS, RP-NBS, GH-NBS, VT-NBS, SF-NBS, RE-NBS, and MH-NBS components. In addition, patients in Group 1 presented significantly worse QOL in the PF-NBS component compared to Group 2 (P<0.05). The rest of the results of the SF-36v2 survey is detailed in Table 2 and Figure 1.
Thirty-four percent of the patients in Group 1 and 15% of the patients in Group 2 had worse QOL compared to the general population in the PF-NBS component, this difference being statistically significant between groups (P=0.025). In addition, multivariable analysis showed an aOR of 3.8 (95% CI, 1.2-11.7) for Group 1 contrasted with Group 2 for impairment of QOL in the PF-NBS, adjusted for sex, age, and RAI.
Results of each domain in SF-36v2 among Group 1, Group 2, and the Chilean population are presented in Figure 2. Of note, Group 1 had worse QOL in most of the domains compared to the Chilean population of the SF-36v2 validation study.
3. Report of symptoms in the structured survey
Table 3 shows the frequency of reported symptoms in Group 1. Seventy-one percent of the patients in Group 1 reported paresthesias ≥1 time per month, 34% reported daily fatigue, and 51% memory disturbances ≥1 time per month.
4. Treatment and adherence report
Ninety-seven percent of the patients in Group 1 were users of calcium supplements, with a median daily elemental calcium of 950 mg/day (IQR, 500-1,500). Ninety percent of them used calcium carbonate and only 7.3% used calcium citrate. Also, 85.7% of the patients in Group 1 used calcitriol, with a median dose of 0.5 mcg per day (IQR, 0.5-1.0). Thiazides were used in 7.3% of patients with hypoparathyroidism. Among patients of Group 1, those using higher doses of calcium supplements (>1,000 mg/day) had more frequently impaired QOL in the PCS domain, compared to lower doses (P=0.033). This impairment in QOL was also seen in patients using calcitriol, compared to those without calcitriol (P=0.026).
Regarding adherence to therapy in Group 1, only 56.2% and 71.4% of patients reported 100% adherence to the last 10 indicated doses of calcium and calcitriol, respectively. On the other hand, 23% and 9.6% of patients reported an intake of 50% or less of the last 10 indicated doses of calcium and calcitriol, respectively.
The frequency of consumption of at least two dairy units per day was 40.0% and 27.6% for Groups 1 and 2, respectively, with an average consumption of 1.47 dairy products/day and 1.09 dairy products/day respectively.
5. Adverse effects to therapy and associated costs
In Group 1, at least one adverse effect of hypoparathyroidism therapy was reported in 24% of patients. The most common symptoms were gastrointestinal discomfort (12.2%), followed by constipation (9.8%), abdominal pain (2.4%), and dizziness (2.4%). Fifty-eight % of patients in Group 1 reported out-of-pocket costs of drugs between 10,001 to 50,000 CLP/month (12-60 USD), and 12.5% >100,000 CLP/month (121 USD). In relation to the out-of-pocket cost of medical check-ups, 31.7% reported an expense of 10,001-50,000 CLP/month (12-60 USD), 25.8% <10,000 CLP/month (<12 USD) and only 12.2% had expenses greater than 250,000 CLP/month (>303 USD).
DISCUSSION
Patients with post-surgical hypoparathyroidism displayed impaired QOL, high frequency of persistent symptoms associated with the disease, limited adherence to medical therapy, and high associated economic costs. This characterization of impaired QOL will provide relevant information to optimize therapeutic decision-making in patients undergoing thyroid surgery, considering that this disease can be prevented, in many cases, with more conservative surgical approaches. There is increasing evidence that selected patients may opt for PT or follow-up for the management of nodular thyroid disease which could prevent hypoparathyroidism.[4,5,23,24] However, the decision must always be considered in the context of other fundamental variables such as the oncologic criteria of the tumor, the expertise of the surgical team, centers with a high volume of thyroid surgery, among others.
Impaired QOL in patients with hypoparathyroidism has been described in the literature. However, to the best of our knowledge, this is the first report in Latin America.[25] Physical Function scores in Group 1 compared to Group 2 had an OR of 3.8 (95% CI, 1.2-11.7), showing around 4 times more risk in that dimension. This could translate in impaired physical activities such as lifting and carrying groceries, climbing stairs, bending, kneeling, or stooping, and performing self-care activities. Also, Group 1 presented lower scores in several components compared to the general and Chilean populations. Thus, involvement of QOL is evidenced when compared with the national and international reference population, even though most of our studied subjects fulfilled the goals of treatment proposed by the latest international guidelines.[8] This highlights the need for new and more effective treatment options for patients with hypoparathyroidism.
In the present study, we evaluated conventional treatment in patients with hypoparathyroidism. A median dose of 2,048 mg/day of calcium and 0.5 mcg/day of calcitriol has been reported in the North American population.[26] In contrast, European cohorts have described a lower median dose 1,000 mg/day of calcium and a somewhat higher dose 0.75 mcg/day of calcitriol.[12] These differences are highlighted in international guidelines, where an optimum calcium-to-calcitriol proportion of supplementation is still lacking.[8] In our study, we observed a median calcium intake of 950 mg/day and calcitriol of 0.5 mcg/day. These findings could be explained by limited access to calcitriol given its relatively elevated cost in Chile. Regarding thiazide prescription, reports in the United States have described that 20% of patients with hypoparathyroidism are using these medications, in contrast to our study in which only 7.3% of patients were using thiazides.[26] Considering the wide availability of thiazides in Chile, the low prescriptions of these medications observed may be associated with a lack of awareness by physicians of its clinical utility.
Despite achieving optimal therapeutic goals of calcium and phosphorus, it is described in patients with hypoparathyroidism persistence of symptoms such as cramps, paresthesias, impaired memory, concentration, and mood changes.[1] In our study, we found that a high percentage of patients remained symptomatic despite serum calcium and phosphate levels within the therapeutic target, consistent with what is described in the literature (Table 3). The presence of paresthesias at least once a month occurred in 70% of the patients, and the presence of more non-specific symptoms such as fatigue, memory, and concentration alterations were also frequent. In addition, 1 out of 4 patients reported adverse effects to therapy, and complete adherence to medication was low. These elements support the complexity of the medical management of the disease and highlight the limited efficacy and tolerability of first-line therapeutic alternatives in hypoparathyroidism.
Our study presents strengths and limitations. We show results consistent with international literature in a previously unevaluated Latin American population. In addition, an internationally validated survey and a second survey of specific symptoms of hypoparathyroidism were used, given the lack of specific validated surveys for hypoparathyroidism to date. We included the adverse effects of therapy and associated costs. Also, we had a valid control group. In contrast, we did not consider plasma levels of thyrotropin or tumor, node, and metastasis stage at the time of evaluation and it could influence the results. Also, we did not apply the structured survey to measure hypoparathyroidism symptoms in Group 2 and it could be a potential bias. Our study group with hypoparathyroidism was significantly younger, with more history of lymph node dissection, and more frequent use of RAI when compared to control group, suggesting they had a more aggressive disease and more aggressive treatments. Nevertheless, we adjust our analysis for these possible confounding variables. The results of our study are in patients with post-surgical hypoparathyroidism due to treatment of thyroid cancer, so this might not be necessary extrapolated to hypoparathyroidism due to other causes.
It is essential to validate in different populations the new QOL surveys that are under study in hypoparathyroidism. In addition, new therapies to treat this condition are needed, such as recombinant human PTH (rhPTH [1-84]), long-acting PTH analogs, TransCon PTH, and calcilytics, among others. Preliminary results with some of these agents have demonstrated benefits in QOL surveys.[27] In addition to achieving the therapeutic biochemical goals, it is essential to improve the well-being of patients, adverse effects and better adherence in this chronic pathology.
In conclusion, Chilean patients with post-surgical hypoparathyroidism presented a high frequency of disease-associated symptoms, poor adherence to therapy, high drug costs, and lower QOL. This possible complication of TT must be considered between all variables when deciding the best surgical alternative for DTC.
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