ORIGINAL ARTICLE

Postoperative Chronic Hypoparathyroidism and Quality

of Life After Total Thyroidectomy
Camilla Uhre Jørgensen,1,2 Preben Homøe,1,3 Morten Dahl,3,4 and Mette Friberg Hitz2,3
1
Department of Otorhinolaryngology and Maxillofacial Surgery, Zealand University Hospital (ZUH), Køge, Denmark
2
Department of Medical Endocrinology, Zealand University Hospital (ZUH), Køge, Denmark
3
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
4
Department of Clinical Biochemistry, Zealand University Hospital (ZUH), Køge, Denmark

ABSTRACT
Chronic hypoparathyroidism (HypoPT) is a common complication after total thyroidectomy and it impacts affected patients’ quality
of life (QoL). This study aimed to assess the QoL in patients with chronic HypoPT independently from their concurrent hypothyroidism
and other comorbidities. For this purpose a follow-up study was performed, including 14 patients who developed chronic HypoPT
after total thyroidectomy and 28 age- and sex-matched patients who had intact parathyroid function after total thyroidectomy.
We used the RAND Short Form 36 Health Survey (SF-36) to compare the QoL between patients with or without chronic HypoPT.
Chronic HypoPT patients had lower QoL scores in all domains of the RAND-SF-36 questionnaire and significant impairment in six
of eight domains after adjustment for relevant confounders. They were more often operated because of a toxic diagnosis (p = .01),
often being Graves disease. Additionally adjusting for surgical indications resulted in three of eight domains being significant
affected. Chronic HypoPT is associated with significantly impairment of QoL, independently of the concurrent disease of hypothy-
roidism, comorbidities, and prospective values of TSH and serum (se)-ionized-Ca++. There is a need for more focus and better treat-
ment of patients experiencing chronic HypoPT after surgery. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on
behalf of American Society for Bone and Mineral Research.

KEY WORDS: CALCIUM; PARATHYROIDEA; QoL; RAND-36; THYROIDECTOMY

Introduction contributing to hypercalciuria and hyperphosphatemia.

These changes are associated with severe long-term
complications, (1,7–9) particularly in the renal, neuropsychiat-
P ostoperative hypoparathyroidism (HypoPT) is an endocrine
disorder caused by iatrogenic injury to the parathyroid
glands during thyroid surgery. HypoPT is characterized by an
ric, and musculoskeletal organ systems, resulting in
impaired health-related quality of life (QoL) in patients with
inappropriately low level of circulating parathyroid hormone chronic HypoPT. (1,9–11)
(PTH), resulting in hypocalcemia.(1) It is noteworthy, that all patients with chronic HypoPT due to
The reported incidence of postoperative chronic HypoPT total thyroidectomy (TT) are also suffering from a concurrent
6 months after thyroidectomy is highly variable, ranging from hypothyroidism. This condition has previously been shown to
0% to 17%, depending on the methods used to define HypoPT independently affect the QoL,(12) and its unclear whether QoL
in the specific studies.(2–6) impairment in chronic HypoPT is due to insufficient production
Chronic HypoPT is a complex condition to treat. Current treat- of PTH, thyroid hormones, or a combination. A few other stud-
ment involves supplementation with calcium and active vitamin
ies(11,13) have sought to address this, but their results have been
D analogues, which makes chronic HypoPT the only remaining
inconclusive.
endocrine disorder where standard treatment does not consist
The aim of this study is to test whether QoL is reduced in
of replacing the missing hormone.(1,7,8)
patients with chronic HypoPT independently from comorbid
In order to obtain normocalcemic levels in blood,
patients with chronic HypoPT need lifelong medication. hypothyroidism. For this purpose we compared QoL scores in
Despite this, patients often experience calcium fluctuations patients with postoperative chronic HypoPT after TT versus
because of lack of direct and indirect actions of PTH, patients with intact parathyroid function after TT.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
Received in original form October 27, 2020; revised form February 2, 2021; accepted February 13, 2021. Accepted manuscript online February 18, 2021.
Address correspondence to: Camilla Uhre, Jørgensen, Department of Otorhinolaryngology and Maxillofacial Surgery, ZUH, Køge, Nyvej 14, 1850, Copenhagen,
Denmark. E-mail: [email protected]
JBMR® Plus (WOA), Vol. 5, No. 4, April 2021, e10479.
DOI: 10.1002/jbm4.10479
© 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

1 of 6 n
Patients and Methods Outcome measures and data collection

Study subjects All included patients were invited to clinical evaluations at the
department of Medical Endocrinology ZUH Køge, where pro-
For this follow-up study, we identified all patients who under- spective data collection took place. Two patients completed
went TT due to a benign thyroid disorder at Zealand University the data collection from home.
Hospital (ZUH), Køge (Denmark) from 2013 to 2018.(6) Data on
year and type of surgery was drawn from the national Thykir Primary outcome
database, which contains information regarding all thyroid pro-
cedures in Denmark since 2001, and supplemented by proce- QoL
dure codes (KBAA60 and KBAA60A). In our department, this We used the RAND Short Form 36 Health Survey (SF-36)(14) to
also included completion thyroidectomy. measure and compare QoL in patients with and without chronic
We invited all patients identified with postoperative chronic HypoPT. The RAND SF-36 consists of 36 questions and covers
HypoPT at 6 months after TT, and of the 25 patients invited, eight concepts of physical and mental health: physical function-
14 (56%) accepted the invitation to participate in this study. ing (PF), role physical (RP), bodily pain (BP), general health (GH),
Those who declined to participate were more often males vitality (VT), social functioning (SF), role emotional (RE), and men-
(54%), but did not differ in either geographical living area, year tal health (MH). By the RAND algorithm, the scores were recalcu-
of surgery, or preoperative health status from the participants lated and expressed into a 0 to 100 scale. Higher score indicates
included in the study. For each patient with chronic HypoPT, more favorable QoL. The validated Danish version of the RAND
we invited two age- and gender-matched patients from the SF-36 is a self-reported questionnaire to be completed
same study population, but without any postoperative distur- electronically.
bances in calcium homeostasis (without chronic HypoPT).
Median duration since surgery was 41.5 months (range, 12–70).
In accordance with the European Society of Endocrinology
Secondary outcomes
Clinical Guideline,(1) HypoPT was defined as hypocalcemia and Prospective biochemistry
inappropriately low serum (se)-PTH due to insufficient produc-
tion of PTH. Chronic HypoPT was confirmed if the condition per- Se-ionized-Ca++, PTH, 25-Hydroxyvitamin D, phosphate, thyroid
sisted ≥6 months and/or if the patient needed continuous status (TSH, T4, T3), renal status (creatinine, eGFR), and liver sta-
treatment with an active vitamin D to maintain normocalcemia. tus (alanine aminotransferase [ALAT], bilirubin, lactate dehydro-
Hypocalcemia was defined as se-ionized-Ca++ <1.16 mmol/L in genase [LDH], basic phosphatase) were measured by standard
two consecutive measurements, in accordance with the lower hospital assays. All biochemical samples were taken after patient
limit of the local hospital laboratory. inclusion and measured from May 1, 2019 to September 1, 2019.
Se-ionized-Ca++ was measured at latest the first day postoper-
atively after TT and then three times daily until stabilization or Medicine
normal values were obtained. Patients in continuous need of All patients informed us of their daily medication consumption,
treatment with an active vitamin D were followed up by endocri- which was verified in the individual patient health records.
nologists. Attempts to reduce doses or stop treatment were stan-
dard procedure.
Comorbidity
We further retrieved preoperative and postoperative se-TSH,
medical prescriptions for active vitamin D analogues, and data Age-adjusted Charlson Comorbidity Index (ACCI) score was cal-
on the indication for surgery (toxic vs nontoxic diagnosis) from culated to account for competing concurrent diseases, aside
the patient health records. Surgical indications were most often from the primary disease of interest. ACCI is a method of catego-
pressure symptoms (including globus and respiratory com- rizing comorbidities based on a patient interview and the Inter-
plaints), and dysphagia due to either a toxic or nontoxic disease. national Classification of Diseases (ICD). Each comorbidity was
Some patients being hyperthyroid preoperatively had surgery scored from 1 to 6 and for each decade >50 years, a score of
due to multiple relapse of toxicity and few were non-tolerant 1 was added. In case of cancer or metastasis, points were only
to medicine. assigned if present ≤5 years.

Ethical statement
Inclusion/exclusion criteria
We performed the study in accordance with the Declaration of
Patients with and without chronic HypoPT met the same inclu- Helsinki II. All participants provided written informed consent
sion and exclusion criteria. Inclusion criteria: patients before any procedures took place. The study was approved by
(i) undergoing TT or completion thyroidectomy for a benign dis- The Danish Data Protection Agency (REG-015-2019) and The Eth-
order performed at the Department of Otorhinolaryngology and ical Committee of Central Denmark (No. 66792).
Maxillofacial Surgery, ZUH Køge in the period June 1, 2013 to
September 30; 2018, (ii) ≥18 years at the time of inclusion; and
Statistics
(iii) able to provide written informed consent to the study invita-
tion. Exclusion criteria: patients with (i) a diagnosis of thyroid Statistical analyses were conducted using R-studio v. 1.2.1335
cancer; (ii) prior parathyroid disease; (iii) prior disturbances in cal- (R Foundation for Statistical Computing, Vienna, Austria;
cium homeostasis, for example, hypocalcemia or estimated glo- https://www.r-project.org/). The level of significance was
merular filtration rate (eGFR) <30 mL/min, or plasma creatinine defined as p < .05. Results are reported as n (%) or as median
>200 μmol/L; (vi) sarcoidosis; or (v) transient HypoPT distur- with range, as indicated. Comparison of groups was assessed
bances lasting <6 months (transient HypoPT). by chi-square test or Fisher’s exact test for categorical variables,

n 2 of 6 JØRGENSEN ET AL. JBMR Plus (WOA)

Table 1. Clinical Characteristics of Patients With Chronic Hypoparathyroidism After Total Thyroidectomy
Characteristic No chronic HypoPT (n = 28) Chronic HypoPT (n = 14) p
Females, n (%) 28 (100) 14 (100) NA
Age (years), median (range) 53 (27–74) 44 (34–72) NA
Indication for surgery, n (%) .01
Toxic 7 (25) 9 (64.3)
Nontoxic 21 (75) 5 (35.7)
Medical treatment
Levothyroxine, n (%) 27 (96.4) 14 (100) 1.00
Dose (μg/day), median (range) 129 (0–300) 168 (50–300) .11
Alfacalcidol, n (%) 0 13 (93) NA
Dose (μg/day), median (range) 0 1.5 (0–6) NA
Calcium supplement, n (%) 14 (50) 14 (100) .001
Dose (mg/day), median (range) 80 (0–800) 1400 (400–3700) <.001
Vitamin D3 supplements, n (%) 18 (64.3) 13 (93) .06
Dose (μg/day), median (range) 10 (0–76) 49 (0–114) .001
ACCI score, n (%) .01
0 9 (32) 10 (72)
1 14 (50) 1 (7)
≥2 5 (18) 3 (21)
Values are n (%) or median (range). Bold values are significant at p < .05. Values of p by two-sample t test, Mann-Whitney U test, chi-square test, or Fisher’s
excact as appropriate.Abbreviations: ACCI, age-adjusted comorbidity score; HypoPT, hypoparathyroidism; NA, not applicable.

Table 2. Biochemical Characteristics of Patients With Chronic Hypoparathyroidism After Total Thyroidectomy
Characteristic No chronic HypoPT (n = 28) Chronic HypoPT (n = 14) p
Preoperative
TSH (mIU/L) 0.77 (0.005–6.2) 0.58 (0.005–2.0) .83
Prospective
Calcium, ionized (mmol/L) 1.28 (1.17–1.35) 1.27 (0.89–1.40) .18
PTH (pmol/L) 5.3 (2.3–9.6) 1.6 (0.50–3.4) <.001
25-Hydroxyvitamin D (nmol/L) 62 (29–125) 101 (34–146) <.01
Phosphate (mmol/L) 1.06 (0.70–1.36) 1.13 (0.79–1.60) <.05
Magnesium (mmol/L) 0.90 (0.79–0.99) 0.93 (0.73–1.00) .68
eGFR (mL/min) 90 (65->90) 90 (55 to >90) .70
TSH (mIU/L) 0.70 (0.005–19) 0.55 (0.005–17) .94
Values are median (range). Bold values are significant at p < .05. Values of p by two-sample t test or Mann-Whitney U test. Prospective values were taken
from May 1, 2019 to September 1, 2019.Abbreviations: eGFR, estimated glomerular filtration rate; HypoPT, hypoparathyroidism; PTH, parathyroid hor-
mone; TSH, thyroid-stimulating hormone.

and two-sample t test or Mann-Whitney U test for continuous consumption were significantly higher among patients with
variables. chronic HypoPT. In addition, all of them, except one, received
When assessing QoL score, we adjusted for age, ACCI, se-TSH, daily supplementation with an active vitamin D analogue in
se-ionized-Ca++, and/or indication for surgery using the analysis terms of Alfacalcidol (mean 1.7 μg/day) and all patients in both
of covariance (ANCOVA). ACCI was transformed into a categorical groups received standard levothyroxine for their hypothyroid-
variable consisting of integers (0 to ≥2). ism except one group who received desiccated thyroid
extract.
ACCI was higher among patients without chronic
Results HypoPT (p = .01).
Patients with chronic HypoPT had significantly lower serum
Characteristics
PTH level, higher levels of serum 25-hydroxyvitamin D and serum
All 42 patients included were women (Table 1). Patients with phosphate (Table 2). Some patients with chronic HypoPT were
chronic HypoPT had more often a toxic indication for surgery seen to have a minor residual parathyroid function (s-PTH 1.6
when compared to patients without chronic HypoPT (p = .01). pmol/L [range, 0.50–3.4 pmol/L]). These patients also presented
Among patients with a toxic indication for surgery, 87.5% had with more irregular levels of se-ionized-Ca++, as indicated by
Graves disease (data not shown). the lower minimum value, as compared with patients without
Patients with chronic HypoPT used more often daily calcium chronic HypoPT (range, 0.89–1.40 mmol/L vs. 1.17–1.35 mmol/
(100% vs 50%) and vitamin D3 supplements (93% vs. 64%) L, lower limit of reference interval = 1.16 mmol/L).
compared with patients without chronic HypoPT (Table 1). Preoperative TSH was significantly lower (p < .01) in patients
The median doses of daily calcium and vitamin D3 with a toxic surgical indication, compared with nontoxic (median

JBMR® Plus POSTOPERATIVE CHRONIC HYPOPARATHYROIDISM AND QOL 3 of 6 n

Figure 1. Unadjusted QoL scores by RAND SF-36 questionnaire in patients with chronic hypoparathyroidism. QoL, quality of life; SF-36, Short Form
36 Health Survey.

Table 3. Adjusted QoL Scores by RAND-SF-36 Questionnaire in Patients With Chronic HypoPT
SF-36 variables No chronic HypoPT (n = 28) Chronic HypoPT (n = 14) Adjusted model 1a
Physical functioning 81.9  3.7 66.7  5.5 0.03
Role physical 80.8  6.0 48.2  12.1 0.02
Bodily pain 77.3  5.0 54.9  9.0 0.04
General health 46.9  2.4 33.2  3.3 <0.01
Role emotional 85.8  5.9 61.9  12.4 0.11
Vitality 58.2  3.6 31.7  7.4 <0.01
Social functioning 85.8  3.6 70.9  7.2 0.08
Mental health 77.3  2.8 63.1  4.4 0.02
Values are mean  SD. Differences in QoL score were assessed using ANCOVA.Abbreviations: ACCI, age-adjusted Charlson Comorbidity Index; ANCOVA,
analysis of covariance; HypoPT, hypoparathyroidism; QoL, quality of life; SD, standard deviation; SF-36, Short Form 36 Health Survey; TSH, thyroid-
stimulating hormone.
a
Adjusted for age, ACCI, TSH, and ionized calcium.

0.045 mIU/L [range, 0.005–2.00 mIU/L] vs. 0.87 mIU/L [range, not shown). Comparing chronic HypoPT patients with a minor
0.02–6.2 mIU/L]). Results not shown in table 2. residual parathyroid function (s-PTH >0.5 pmol/L; n = 9) to
chronic HypoPT with no residual function (n = 4), 3 of 8 QoL
domains were significantly affected in both groups, when com-
QoL paring with patients without chronic HypoPT (Supplementary
The scores for the eight QoL RAND-SF-36 measures were higher Table S1.)
in patients with chronic HypoPT compared with patients without
chronic HypoPT although not all comparisons reached statistical Discussion
significance (Figure 1). After adjustment for age, comorbidities
(ACCI), TSH and se-ionized-Ca++ patients with chronic HypoPT Patients with postsurgical HypoPT have an inappropriately low
had significantly lower scores in the QoL domains: physical func- level of circulating parathyroid hormone (PTH). The chronic con-
tioning (PF), role physical (RP), bodily pain (BP), general health dition results in disturbances in calcium-phosphate homeostasis,
(GH), vitality (VT), and mental health (MH) (Table 3). After addi- where patients often experience severe long-term complica-
tionally adjusting for surgical indications, chronic HypoPT tions, including lower QoL. This study is one of the few to high-
patients were significantly affected in three of eight domains: light the impact of chronic HypoPT on QoL, taking the surgical
role physical (RP), general health (GH), and vitality (VT) (data indication and comorbidities into account, in patients receiving

n 4 of 6 JØRGENSEN ET AL. JBMR Plus (WOA)

conventional treatment after TT compared to patients without patients also suffer from a state of concurrent hypothyroidism.
evidence of any parathyroid disturbances after TT. Hypothyroidism has been shown previously to affect QoL,
We find in this study that patients who suffer from chronic despite being euthyroid on levothyroxine treatment.(12) The
HypoPT had lower QoL scores in all domains of the RAND-SF-36 influence of TSH on QoL in patients suffering from chronic
questionnaire. Although not all comparisons reached statistical HypoPT have previously been investigated,(11,16) but the results
significance, our data suggests significant lower scores of QoL still remain inconsistent.
in six of eight domains among patients suffering from chronic In this study, all patients suffered from hypothyroidism and
HypoPT, compared with matched and clinically relevant patients were receiving some kind of thyroid hormone supplement, most
without chronic HypoPT. These reductions are considerably often being levothyroxine (97.6%).
higher than the minimal clinically important difference of pro- We could not report an association between prospective TSH
posed for RAND-SF-36 scores in clinical trials.(15) After adjustment and the impact of QoL. Patients with dysregulated TSH were pre-
for patients’ surgical indication (toxic/nontoxic diagnosis) signifi- sent in both groups (p = .94), and results did not change after
cantly lower scores were observed only for the RP, GH, and VT adjusting for TSH (model 1). Because this study has no control
domains; however, the trend remained the same, that all QoL group of healthy individuals we could not examine whether
domains were more reduced in patients with chronic HypoPT hypothyroidism itself has an impact on QoL. However, this study
compared to patients without chronic HypoPT. Additionally, we implies a combination of HypoPT and hypothyroidism to have a
compared chronic HypoPT patients with a minor residual para- greater impact on QoL than HypoPT itself in accordance with
thyroid function (s-PTH >0.5 pmol/L), to chronic HypoPT patients comparable studies.(11,13) Furthermore, despite a higher comor-
with no residual function, showing impairment of QoL in three of bidity score among the patients without chronic HypoPT, their
eight domains in both groups. Considering the small sample size QoL scores were less affected. This indicated a strong impor-
(n = 9 and n = 5), we could not conclude any difference in QoL tance of HypoPT disease on QoL in this study population.
pattern regarding a residual parathyroid function.
Other studies using a SF-36 questionnaire in the investigation
of QoL present impairment in all eight domains,(7,16) whereas Biochemical fluctuations
others reflect our result, only showing significant impairment in
Maintaining se-ionized-Ca++ within the therapeutic range
some domains, including PF, RP, BP, GH, VT, and SF,(11,17–19)
remains a challenge in these patients.(9) Previous authors have
roughly in accordance with our results. The studies reporting
failed to find a correlation between biochemical markers such
impairment in all eight domains compared their HypoPT patients
as calcium levels and QoL scores.(16,19,21) As a result of the con-
to a general population and not to well-matched controls. Other
ventional treatment with calcium, vitamin D3 and active
questionnaires (SCL-90-R and GBB-24), as used by Arlt and
vitamin D, most of our chronic HypoPT patients presented with
colleagues,(13) confirm the same pattern.
se-ionized-Ca++ levels within the normal range (mean
Compared to other chronic diseases, a Norwegian study(16)
1.27 mmol/L).
reported QoL in HypoPT patients to be significantly lower than
Despite large amounts of supplements, we could confirm an
in patients with Addison’s disease, and a systematic review(17)
insufficient effect on the physiological calcium homeostasis in
reported an effect to the same extent as patients suffering from
the group of chronic HypoPT patients, because large variations
diabetes or heart diseases.
and fluctuations were seen (range, 0.89–1.40 mmol/L). The one
This study has not investigated the QoL score in the healthy
patient not receiving active vitamin D presented with the lowest
Danish population. However, another Danish study(11) also using
ionized-Ca++ (0.89 mmol/L). Our findings could not report a rela-
the SF-36 questionnaire reported significantly lower scores in
tion between calcium fluctuations and QoL outcome (Table 3).
seven of eight domains, when comparing HypoPT patients with
healthy controls.
Lack of parathyroid hormone
Preoperative toxicity
Some authors have suggested the impairment of QoL to be a
Patients with and without chronic HypoPT were generally well direct result of the lack of stimulation by parathyroid
matched and all had previously undergone TT, but chronic hormone,(13,17,22) because receptors are expressed in numerous
HypoPT patients were more often operated because of a toxic brain regions as well as in muscle tissue. This correlates with
diagnosis. Patients with a toxic indication for surgery suffered the impairment seen in the physical domains. The hypothesis
mainly from Graves disease (87.5%). Among surgeons, it is well has been studied in several clinical trials, investigating the effi-
known that TT due to Graves diseases can be troublesome due cacy of replacement therapy with recombinant human parathy-
to hypervascularization and inflammation of the gland, which roid hormone (rhPTH(1-84)) on QoL. Some authors have
makes it difficult to find the parathyroid glands and to preserve reported an association between the number of treatment years
their blood supply.(20) with rhPTH(1-84), a reduction of symptoms, and increasing QoL
The observed overrepresentation of preoperative toxic thy- in the SF-36 questionnaire.(19,23,24)
roid diseases could explain some of the QoL impairment we Other studies have not been able to prove any significant ben-
report in chronic HypoPT patients. As expected, preoperative eficial effects.(18) There is, however, an agreement between
level of TSH was significantly lower in these patients, compared researchers that rhPTH(1-84) therapy seems to stabilize the se-
with nontoxic patients, which might affect the QoL itself. ionized-Ca++ level and lower the need for supplemental calcium
and vitamin D, when compared to conventional treatment.(25)
Whether the reported improvement in QoL is due to a more
Concurrent hypothyroidism
stable se-ionized-Ca++ level, a reduction in supplemental treat-
Because chronic HypoPT in these patients is a result of unin- ment, or a direct effect of parathyroid hormone still remains
tended damage to the parathyroid glands during TT, these uncertain.

JBMR® Plus POSTOPERATIVE CHRONIC HYPOPARATHYROIDISM AND QOL 5 of 6 n

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Preben Homøe: Conceptualization; supervision; validation. quality of life in hypoparathyroidism: results from a randomized con-
Morten Dahl: Data curation; supervision; validation. Mette trolled trial. Osteoporos Int. 2014;25(6):1717-1726.
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