Etiology and Pathophysiology of Hypoparathyroidism: A Narrative Review

Etiology of Hypoparathyroidism

Postsurgical

Autoimmune

Autoimmune polyglandular syndrome‐1

Isolated autoimmune hypoparathyroidism

Infiltrative

Granulomatous disease

Sarcoidosis

Amyloidosis

Metastatic cancer

Riedel struma

HIV

Destructive

Radiation—external beam and ionizing radiation

Metal deposition

Wilson's disease (copper)

Hemochromatosis (iron)

Transfusion dependence (iron)

Aluminum toxicity

Metabolic causes

Hypermagnesemia

Magnesium deficiency

Burn injury

Fetal exposure to retinoids, alcohol or hyperglycemia or maternal hypercalcemia

Toxic agents^a

Genetic disorders of isolated or syndromic hypoparathyroidism^b

Mitochondrial disorders^c

Idiopathic^d

Asparaginase, Ethiofos, immune checkpoint inhibitors (eg, nivolumab).

Isolated parathyroid hypoplasia or PTH hyposecretion including mutations in PTH, CASR, GNA11; DiGeorge Sequence; TBX; CHARGE syndrome; Hypoparathyroidism, Deafness, Renal anomaly (HDR) syndrome (Barakat syndrome); Sanjad‐Sakati syndrome, and Kenny‐Caffey syndrome; Smith‐Lemli‐Opitz syndrome.

Kearns‐Sayre syndrome; Pearson Marrow‐Pancreas syndrome; MELAS syndrome; Long‐chain 3‐hydroxy‐acyl‐coenzyme A dehydrogenase (LCHAD) deficiency; medium‐chain acyl‐CoA dehydrogenase deficiency (MCADD).

No etiology determined after extensive workup completed.

This systematic review was prepared in consultation with an experienced medical librarian who executed a comprehensive search in PubMed and Embase. The complete search strings are supplied in Fig. 1. All articles from the database search were added to a reference manager, and duplicates were removed. Inclusion and exclusion criteria were developed to screen articles by abstract using two independent reviewers (KW and CY). Inclusion criteria included articles with publication dates from 1980 to 2020, in the English language, and with primary data and a focus on etiology and pathophysiology of hypoparathyroidism. Exclusion criteria included any article not primarily focusing on the etiology or pathophysiology of hypoparathyroidism, and those with a primary focus on genetic etiologies of hypoparathyroidism were excluded because that topic is covered elsewhere. Conference abstracts, opinion pieces, commentaries, letters, and case reports were excluded. The full text of articles selected by title and abstract screening were reviewed using the same criteria and methods. Articles retained for analysis underwent cited reference searching. Articles from cited reference searching and those recommended by experts were included if they met the above inclusion and exclusion criteria. Results are presented in a Preferred Reporting Items for Systematic reviews and Meta‐Analyses (PRISMA) flow diagram and articles were further categorized according to subtopic (Fig. 1). A meta‐analysis was not performed given the noninterventional nature of the data collected. Risk‐of‐bias (RoB) and quality assessment were not performed given the nature of the question and data collected.

Fig. 1

PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only. The search was executed with the following approach: *PubMed Search Terms. (“Hypoparathyroidism/etiology”[Majr] OR “Hypoparathyroidism/pathology”[Majr] OR ((hypoparathyroidism[ti] OR hypoparathyroidism[ot]) AND (etiology OR pathophysiology OR physiopathology OR pathology))) AND (random* OR control* OR cohort OR case–control OR “clinical trial” OR review[pt] OR systematic[sb]) NOT (letter[pt] OR editorial[pt] OR case reports[pt]) AND ((1980:3000/12/12[pdat]). **Embase Search Terms. ((‘hypoparathyroidism’/exp OR hypoparathyroidism) AND (‘pathophysiology’/exp OR pathophysiology OR ‘etiology’/exp OR etiology) AND [humans]/lim AND [english]/lim AND (‘case control study’/de OR ‘clinical article’/de OR ‘clinical study’/de OR ‘clinical trial’/de OR ‘cohort analysis’/de OR ‘comparative study’/de OR ‘controlled clinical trial’/de OR ‘controlled study’/de OR ‘cross sectional study’/de OR ‘human experiment’/de OR ‘longitudinal study’/de OR ‘major clinical study’/de OR ‘multicenter study’/de OR ‘observational study’/de OR ‘prospective study’/de OR ‘randomized controlled trial’/de OR ‘randomized controlled trial topic’/de OR ‘retrospective study’/de OR ‘systematic review’/de) AND [1980–2021]/py) AND (‘article’/it OR ‘article in press’/it). From: Page and colleagues.⁽⁵⁾ For more information, visit: http://www.prisma‐statement.org/.

Etiology of Hypoparathyroidism

Postsurgical hypoparathyroidism

Postsurgical hypoparathyroidism occurs after inadvertent removal or devascularization of the parathyroid glands during surgery. Routine deliberate removal of glands for autotransplantation has also been associated with a higher risk of postsurgical hypoparathyroidism.⁽⁶^,⁷⁾ Postoperative hypocalcemia is the most common complication following bilateral thyroid surgery, reoperative thyroid and parathyroid surgeries, and extensive neck dissections. The estimated prevalence of temporary and permanent hypoparathyroidism varies widely from 14% to 43% and 1% to 25%, respectively.⁽^6,8‐13⁾ Much of the variation stems from the lack of a single definition of postsurgical hypoparathyroidism, variable timing of biochemical monitoring, incomplete follow‐up, different postoperative policies for Ca and vitamin D supplementation, single institutional/surgeon retrospective series, and lack of corroborating intact PTH (iPTH) values.⁽^14‐16⁾ Growing evidence from large population cohorts and national audits indicate that permanent hypoparathyroidism is a significant clinical problem.

Crosslinking data from the Swedish Drug Register and all patients who underwent bilateral thyroidectomy for benign disease, Anneback and colleagues⁽⁹⁾ estimated that 12.5% of patients remained hypoparathyroid 1 year following surgery. Utilizing National Surgical Quality Improvement Program (NSQIP) data, Kazaure and colleagues⁽¹⁷⁾ found that 5.8% (428/7366) of patients experienced severe hypocalcemia post‐thyroidectomy (defined as readmission, utilization of intravenous Ca, or emergent postoperative clinic visits within 30 days of the index operation), illustrating the magnitude of this problem and lack of standardized guidelines for management of post‐thyroidectomy hypocalcemia. Emerging data indicate that this surgical complication has significant long‐term morbidity and mortality affecting renal, cardiovascular, and potentially cancer events,⁽^18‐20⁾ the details of which are discussed by Task Force 1.⁽²¹⁾ These data underscore the importance of proactive preservation of the parathyroid glands and their vascular supply during thyroid and parathyroid surgery.

Definition of postsurgical hypoparathyroidism

Immediate postsurgical hypoparathyroidism is defined as a serum albumin‐adjusted calcium (s‐Ca) level that is <2 mmol/L (8.0 mg/dL), with or without symptoms. It occurs frequently in patients following thyroid surgery and is usually transient (>85% to 90% of the time). A patient's s‐Ca and serum P (s‐P) should be monitored within the first 6 hours postoperatively and treatment initiated prior to the onset of symptoms.⁽²²⁾ Symptomatic patients and patients in whom postsurgical parathyroid failure is suspected should receive therapy with Ca salts and activated vitamin D metabolites prior to discharge. Patients who undergo parathyroid/thyroid surgery should have normal serum concentrations of 25(OH) vitamin D (>50 nmol/L or 20 ng/mL) and receive supplementation if levels are lower than this. The surgical procedure and the number of glands remaining in situ can predict the likelihood of immediate, protracted and permanent postoperative parathyroid failure.⁽¹¹^,²³⁾ A rising s‐P in conjunction with a declining s‐Ca following a total thyroidectomy suggests inadequate PTH secretion and is a simple, cost‐effective screening tool in lieu of intact PTH (iPTH) measurements, to delineate those at risk of developing hypocalcemia.⁽²²⁾ Many centers utilize iPTH measurements within 6 hours postoperatively or prior to discharge and institute calcium and activated vitamin D metabolite therapy if iPTH drops below 10 pg/mL (1.06pM)⁽^4,11,24‐27⁾ (Fig. 2) to prevent both biochemical and clinical hypocalcemia. Although some authors and guidelines advocate for routine Ca supplementation as a cost‐effective strategy in all postoperative patients,⁽^23,28‐30⁾ in a recent Cochrane review, there was no high‐quality evidence to support this approach,⁽³¹⁾ and numerous reports have illustrated the danger of unchecked Ca supplementation, poor patient compliance, and medication side‐effects.⁽¹⁷^,³⁰^,³²⁾

Fig. 2

An algorithm for management strategies for the evaluation and treatment of postoperative parathyroid gland insufficiency following total thyroidectomy with or without lymph node dissection.

Resolution of parathyroid insufficiency occurs in the majority (70% to 80%) of patients within 1 month following surgery.⁽¹¹^,²⁴^,³³⁾ Patients who still require supplement therapy due to persistently low or absent iPTH after 1 month are considered to have protracted postsurgical hypoparathyroidism. The prevalence of protracted postsurgical hypoparathyroidism varies from 13% to 44%.⁽¹¹^,¹⁴^,¹⁶^,³⁴⁾ Others have demonstrated that the rate of protracted postsurgical hypoparathyroidism depends on the number of glands left in situ, ranging from 13% to 15% when all four glands remain in situ, to 40% to 44% when two or fewer remain in situ.⁽¹¹^,²³⁾ The probability of recovering parathyroid function over the next 12 months is approximately 75%.

There is lack of consensus on the definition of permanent postsurgical hypoparathyroidism.⁽²^,⁸^,¹⁶⁾ Most investigators and guidelines use the need for Ca salts and active vitamin D therapy at 6 or 12 months.⁽³⁵⁾ Permanent postsurgical hypoparathyroidism includes three distinct subcategories (Table 2). Approximately 10% to 15% of cases recover after 1 year.⁽¹⁴^,²⁴⁾

Table 2

Subclassification of Permanent Surgical Hypoparathyroidism

Subcategory of permanent surgical hypoparathyroidism	Biochemical diagnosis	Treatment
Hypoparathyroidism	Low or undetectable iPTH Hypocalcemia +/− High serum phosphorus	Elemental calcium 2 to 4 g/day or more^a Calcitriol 0.5 to 2 μg/day or more^a PTH replacement^b Thiazide diuretic
Parathyroid insufficiency	Low iPTH Elevated serum phosphorus Normal or only slightly reduced serum calcium	Elemental calcium titrated Maintain vitamin D sufficiency with vitamin D3 or D2
Relative parathyroid insufficiency	Normal iPTH level but insufficient to maintain serum phosphorus and/or calcium within normal limits	Address any impaired absorption issues or drugs that lower serum calcium^c Maintain serum calcium levels with elemental calcium supplements

Subcategory of permanent surgical hypoparathyroidism	Biochemical diagnosis	Treatment
Hypoparathyroidism	Low or undetectable iPTH Hypocalcemia +/− High serum phosphorus	Elemental calcium 2 to 4 g/day or more^a Calcitriol 0.5 to 2 μg/day or more^a PTH replacement^b Thiazide diuretic
Parathyroid insufficiency	Low iPTH Elevated serum phosphorus Normal or only slightly reduced serum calcium	Elemental calcium titrated Maintain vitamin D sufficiency with vitamin D3 or D2
Relative parathyroid insufficiency	Normal iPTH level but insufficient to maintain serum phosphorus and/or calcium within normal limits	Address any impaired absorption issues or drugs that lower serum calcium^c Maintain serum calcium levels with elemental calcium supplements

Abbreviation: iPTH = intact parathyroid hormone.

These are average calcium and calcitriol doses and can be higher and lower depending on individual patient needs.

Available as recombinant human PTH⁽^1‐4,6‐84⁾ in certain countries.

Malabsorption syndromes and diseases, short gut, gastric bypass, bisphosphonate or denosumab therapy. Minimize use of thiazide diuretics and/or proton‐pump inhibitors. All of these mitigating issues can make chronic hypoparathyroidism worse.

Table 2

Subclassification of Permanent Surgical Hypoparathyroidism

Subcategory of permanent surgical hypoparathyroidism	Biochemical diagnosis	Treatment
Hypoparathyroidism	Low or undetectable iPTH Hypocalcemia +/− High serum phosphorus	Elemental calcium 2 to 4 g/day or more^a Calcitriol 0.5 to 2 μg/day or more^a PTH replacement^b Thiazide diuretic
Parathyroid insufficiency	Low iPTH Elevated serum phosphorus Normal or only slightly reduced serum calcium	Elemental calcium titrated Maintain vitamin D sufficiency with vitamin D3 or D2
Relative parathyroid insufficiency	Normal iPTH level but insufficient to maintain serum phosphorus and/or calcium within normal limits	Address any impaired absorption issues or drugs that lower serum calcium^c Maintain serum calcium levels with elemental calcium supplements

Subcategory of permanent surgical hypoparathyroidism	Biochemical diagnosis	Treatment
Hypoparathyroidism	Low or undetectable iPTH Hypocalcemia +/− High serum phosphorus	Elemental calcium 2 to 4 g/day or more^a Calcitriol 0.5 to 2 μg/day or more^a PTH replacement^b Thiazide diuretic
Parathyroid insufficiency	Low iPTH Elevated serum phosphorus Normal or only slightly reduced serum calcium	Elemental calcium titrated Maintain vitamin D sufficiency with vitamin D3 or D2
Relative parathyroid insufficiency	Normal iPTH level but insufficient to maintain serum phosphorus and/or calcium within normal limits	Address any impaired absorption issues or drugs that lower serum calcium^c Maintain serum calcium levels with elemental calcium supplements

Abbreviation: iPTH = intact parathyroid hormone.

These are average calcium and calcitriol doses and can be higher and lower depending on individual patient needs.

Available as recombinant human PTH⁽^1‐4,6‐84⁾ in certain countries.

Risk factors for surgical hypoparathyroidism

The parathyroid glands are at risk during thyroid surgery due to their small size, close proximity to the thyroid gland, and delicate blood supply. Devascularization and/or resection of these glands increase the risk of both transient and permanent postsurgical hypoparathyroidism (odds ratio [OR] 2.79, OR 4.62, respectively).⁽³⁶⁾ Hypoparathyroidism can lead to acute postoperative complications (Table 3), hospital readmission,⁽¹⁷^,³⁷^,³⁸⁾ significant long‐term morbidity, and increased mortality (adjusted hazard ratio [HR] 2.09).⁽¹⁸^,²⁰⁾ Risk factors for the development of hypoparathyroidism can be divided into patient, disease, and operative factors (Table 4).

Table 3

Symptoms of Acute Hypocalcemia Postoperatively^a

Mild	Severe
Neuromuscular
Chvostek's sign (facial nerve excitability)	Confusion
Trousseau's sign (carpal spasm)	Seizures
Paresthesia (perioral and extremity)	Tetany
Muscle cramps	Laryngospasm
Headache	Bronchospasm
Cardiac
Prolonged QTc interval	Congestive heart failure
T‐wave inversion	Ventricular tachycardia Torsades de pointes Other arrhythmias

Mild	Severe
Neuromuscular
Chvostek's sign (facial nerve excitability)	Confusion
Trousseau's sign (carpal spasm)	Seizures
Paresthesia (perioral and extremity)	Tetany
Muscle cramps	Laryngospasm
Headache	Bronchospasm
Cardiac
Prolonged QTc interval	Congestive heart failure
T‐wave inversion	Ventricular tachycardia Torsades de pointes Other arrhythmias

These signs and symptoms noted may be present during hypocalcemic episodes in the patient with chronic hypocalcemia or hypoparathyroidism of any etiology.

Table 3

Symptoms of Acute Hypocalcemia Postoperatively^a

Mild	Severe
Neuromuscular
Chvostek's sign (facial nerve excitability)	Confusion
Trousseau's sign (carpal spasm)	Seizures
Paresthesia (perioral and extremity)	Tetany
Muscle cramps	Laryngospasm
Headache	Bronchospasm
Cardiac
Prolonged QTc interval	Congestive heart failure
T‐wave inversion	Ventricular tachycardia Torsades de pointes Other arrhythmias

Mild	Severe
Neuromuscular
Chvostek's sign (facial nerve excitability)	Confusion
Trousseau's sign (carpal spasm)	Seizures
Paresthesia (perioral and extremity)	Tetany
Muscle cramps	Laryngospasm
Headache	Bronchospasm
Cardiac
Prolonged QTc interval	Congestive heart failure
T‐wave inversion	Ventricular tachycardia Torsades de pointes Other arrhythmias

These signs and symptoms noted may be present during hypocalcemic episodes in the patient with chronic hypocalcemia or hypoparathyroidism of any etiology.

Table 4

Risk Factors for Postsurgical Hypocalcemia

Factors	Risk of hypoparathyroidism or incidental parathyroidectomy	Highest level of evidence
Patient factors
Obesity BMI >40 kg/m²	OR 1.94⁽³⁷^,³⁸⁾	National registry multivariate analysis (n = 8381)
Vitamin D deficiency	RR 1.92–2.45⁽⁸⁵⁾	Meta‐analysis of 39 prospective/retrospective studies
Pediatric	7.3% to 22%⁽⁴²^,⁴³^,⁸⁶⁾ CLND OR 16.18⁽⁴²^,⁴⁵⁾	National registry (n = 740)
Disease factors
Graves' disease	Transient rate 70.5%, permanent rate 27.3%. OR 1.75 to 4.40⁽⁶^,¹²^,⁸⁷⁾	Meta‐analysis of 115 observational studies
Malignancy	RR 1.60⁽³⁹⁾	Meta‐analysis 35 retrospective studies
Concomitant thyroid/parathyroid surgery	OR 2.38 to 7.23⁽⁸⁸⁾	Single institution (n = 1065)
Operative factors
Central lymph node Level VI dissection	OR 1.48 to 4.44⁽¹⁰^,³⁶^,³⁸^,⁴¹⁾	Prospectively maintained national registry (n = 8672)
Reoperative surgery	OR 1.44⁽⁴¹⁾	Prospectively maintained national registry (n = 8672)
Transoral approach	Transient OR 0.96, permanent OR 0.32⁽⁸⁹⁾	Meta‐analysis 6 retrospective studies
Surgical time >3 hours	OR 2.63⁽³⁷⁾	National registry multivariate analysis (n = 8381)
Low surgeon volume	OR 2.94⁽³⁶⁾	Single center (n = 1114)
Incidental parathyroidectomy	12.4%⁽³⁹⁾	Meta‐analysis 35 cohort studies

Factors	Risk of hypoparathyroidism or incidental parathyroidectomy	Highest level of evidence
Patient factors
Obesity BMI >40 kg/m²	OR 1.94⁽³⁷^,³⁸⁾	National registry multivariate analysis (n = 8381)
Vitamin D deficiency	RR 1.92–2.45⁽⁸⁵⁾	Meta‐analysis of 39 prospective/retrospective studies
Pediatric	7.3% to 22%⁽⁴²^,⁴³^,⁸⁶⁾ CLND OR 16.18⁽⁴²^,⁴⁵⁾	National registry (n = 740)
Disease factors
Graves' disease	Transient rate 70.5%, permanent rate 27.3%. OR 1.75 to 4.40⁽⁶^,¹²^,⁸⁷⁾	Meta‐analysis of 115 observational studies
Malignancy	RR 1.60⁽³⁹⁾	Meta‐analysis 35 retrospective studies
Concomitant thyroid/parathyroid surgery	OR 2.38 to 7.23⁽⁸⁸⁾	Single institution (n = 1065)
Operative factors
Central lymph node Level VI dissection	OR 1.48 to 4.44⁽¹⁰^,³⁶^,³⁸^,⁴¹⁾	Prospectively maintained national registry (n = 8672)
Reoperative surgery	OR 1.44⁽⁴¹⁾	Prospectively maintained national registry (n = 8672)
Transoral approach	Transient OR 0.96, permanent OR 0.32⁽⁸⁹⁾	Meta‐analysis 6 retrospective studies
Surgical time >3 hours	OR 2.63⁽³⁷⁾	National registry multivariate analysis (n = 8381)
Low surgeon volume	OR 2.94⁽³⁶⁾	Single center (n = 1114)
Incidental parathyroidectomy	12.4%⁽³⁹⁾	Meta‐analysis 35 cohort studies

Table 4

Risk Factors for Postsurgical Hypocalcemia

Factors	Risk of hypoparathyroidism or incidental parathyroidectomy	Highest level of evidence
Patient factors
Obesity BMI >40 kg/m²	OR 1.94⁽³⁷^,³⁸⁾	National registry multivariate analysis (n = 8381)
Vitamin D deficiency	RR 1.92–2.45⁽⁸⁵⁾	Meta‐analysis of 39 prospective/retrospective studies
Pediatric	7.3% to 22%⁽⁴²^,⁴³^,⁸⁶⁾ CLND OR 16.18⁽⁴²^,⁴⁵⁾	National registry (n = 740)
Disease factors
Graves' disease	Transient rate 70.5%, permanent rate 27.3%. OR 1.75 to 4.40⁽⁶^,¹²^,⁸⁷⁾	Meta‐analysis of 115 observational studies
Malignancy	RR 1.60⁽³⁹⁾	Meta‐analysis 35 retrospective studies
Concomitant thyroid/parathyroid surgery	OR 2.38 to 7.23⁽⁸⁸⁾	Single institution (n = 1065)
Operative factors
Central lymph node Level VI dissection	OR 1.48 to 4.44⁽¹⁰^,³⁶^,³⁸^,⁴¹⁾	Prospectively maintained national registry (n = 8672)
Reoperative surgery	OR 1.44⁽⁴¹⁾	Prospectively maintained national registry (n = 8672)
Transoral approach	Transient OR 0.96, permanent OR 0.32⁽⁸⁹⁾	Meta‐analysis 6 retrospective studies
Surgical time >3 hours	OR 2.63⁽³⁷⁾	National registry multivariate analysis (n = 8381)
Low surgeon volume	OR 2.94⁽³⁶⁾	Single center (n = 1114)
Incidental parathyroidectomy	12.4%⁽³⁹⁾	Meta‐analysis 35 cohort studies

Factors	Risk of hypoparathyroidism or incidental parathyroidectomy	Highest level of evidence
Patient factors
Obesity BMI >40 kg/m²	OR 1.94⁽³⁷^,³⁸⁾	National registry multivariate analysis (n = 8381)
Vitamin D deficiency	RR 1.92–2.45⁽⁸⁵⁾	Meta‐analysis of 39 prospective/retrospective studies
Pediatric	7.3% to 22%⁽⁴²^,⁴³^,⁸⁶⁾ CLND OR 16.18⁽⁴²^,⁴⁵⁾	National registry (n = 740)
Disease factors
Graves' disease	Transient rate 70.5%, permanent rate 27.3%. OR 1.75 to 4.40⁽⁶^,¹²^,⁸⁷⁾	Meta‐analysis of 115 observational studies
Malignancy	RR 1.60⁽³⁹⁾	Meta‐analysis 35 retrospective studies
Concomitant thyroid/parathyroid surgery	OR 2.38 to 7.23⁽⁸⁸⁾	Single institution (n = 1065)
Operative factors
Central lymph node Level VI dissection	OR 1.48 to 4.44⁽¹⁰^,³⁶^,³⁸^,⁴¹⁾	Prospectively maintained national registry (n = 8672)
Reoperative surgery	OR 1.44⁽⁴¹⁾	Prospectively maintained national registry (n = 8672)
Transoral approach	Transient OR 0.96, permanent OR 0.32⁽⁸⁹⁾	Meta‐analysis 6 retrospective studies
Surgical time >3 hours	OR 2.63⁽³⁷⁾	National registry multivariate analysis (n = 8381)
Low surgeon volume	OR 2.94⁽³⁶⁾	Single center (n = 1114)
Incidental parathyroidectomy	12.4%⁽³⁹⁾	Meta‐analysis 35 cohort studies

A meta‐analysis of 115 observational studies identified preoperative vitamin D deficiency, Graves' disease (OR 1.75), and inadvertent parathyroidectomy (parathyroids found in the pathology specimen not intended to be removed during surgery) (OR 1.90) as risk factors for postoperative hypocalcemia.⁽⁶⁾ Bai and colleagues⁽³⁹⁾ found an average rate of incidental parathyroidectomy of 12.4%. Risk factors for incidental parathyroidectomy include central neck dissection (relative risk [RR] 2.35), reoperation (RR 1.81), malignancy (RR 1.60), and total thyroidectomy (RR 1.42). Incidental parathyroidectomy increases the risk of symptomatic hypocalcemia (RR 1.54), with permanent hypoparathyroidism occurring at a rate 6.7% in patients with versus 2.2% in those without incidental parathyroidectomy (RR 3.10).

Surgical experience, expertise and technique play key roles in determining the risk of hypoparathyroidism.⁽⁶^,¹⁰^,³⁶^,⁴⁰^,⁴¹⁾ A recent single‐center study of >1000 thyroidectomies identified an average inadvertent parathyroidectomy rate of 22.4% (range, 16.9% to 43.6%) directly correlating with surgeon volume (R² = 0.77 for thyroidectomies and R² = 0.93 for central neck dissection).⁽³⁶⁾ In their multivariate analysis, low‐volume surgeon (OR 2.94), extrathyroidal extension of the tumor (OR 3.13), and prophylactic (OR 2.68) or therapeutic central neck dissection (OR 4.44) were associated with incidental parathyroidectomy.

Surgical risk factors for hypoparathyroidism in children are less well known, due to the small number of studies and cohort sizes, but they are similar to those in adults.⁽^42‐45⁾ Pediatric patients present unique challenges for the surgeon due to small gland size and appearance of brown fat, thymus, and lymph nodes.

Role of parathyroid autotransplantation

Autotransplantation of parathyroid glands initially gained popularity in the treatment of parathyroid hyperplasia following total parathyroidectomy.⁽^46‐48⁾ This evolved into routine autotransplantation of normal parathyroid glands during thyroid surgery in an attempt to reduce postsurgical hypoparathyroidism.⁽⁴⁷^,⁴⁸⁾ Several authors have demonstrated biochemical graft uptake in 83% to 90% of patients, even when normal parathyroid glands were left in situ.⁽⁴⁹^,⁵⁰⁾ This led some surgeons to recommend routine or liberal autotransplantation of at least one parathyroid gland during thyroid surgery.⁽^51‐53⁾ However, a recent meta‐analysis of 25 studies showed an increased risk of postsurgical hypoparathyroidism in thyroidectomy patients who underwent parathyroid autotransplantation, and the number of autotransplanted glands correlated positively with the rate of postsurgical hypoparathyroidism.⁽⁷⁾ This analysis included both liberal autotransplantation and its use only after incidental parathyroidectomy. Thus, autotransplantation is likely not the dominant risk factor for postsurgical hypoparathyroidism, but rather the direct result of removal and/or devascularization of the gland(s).

Lorente‐Poch and colleagues⁽²³⁾ followed 657 total thyroidectomy patients and demonstrated that the rates of immediate, protracted, and permanent postsurgical hypoparathyroidism were significantly lower in those patients in whom all four parathyroid glands were left in situ, compared to those with three or fewer glands in situ, illustrating the importance of in situ preservation of all the glands.⁽²³⁾ Autotransplantation should only be utilized when inadvertent parathyroidectomy has occurred, and every effort should be made to preserve the parathyroid glands in situ.⁽¹¹^,²³^,⁵⁴^,⁵⁵⁾

Studies have shown that intraoperative identification of parathyroid glands results in a lower incidence of inadvertent parathyroidectomy.⁽¹¹^,²³^,⁵⁶^,⁵⁷⁾ Discoloration of three or more glands is predictive of transient hypoparathyroidism, but challenges remain in determining the viability of glands that appear normal to the eye.⁽⁵⁸^,⁵⁹⁾ Macroscopic appearance of the parathyroid gland has a sensitivity of only 78% for predicting postoperative hypocalcemia.⁽³⁰⁾ Even those glands that appear abnormal may retain function. Rudin and colleagues⁽⁶⁰⁾ demonstrated that visual inspection overestimated parathyroid ischemia compared to indocyanine green (ICG)‐labeled blood‐flow, illustrating in many cases autotransplantation would remove functioning glands if based solely on the gross appearance of the gland.

Emerging technology and intraoperative assessment of parathyroid viability

ICG is a water‐soluble, low molecular weight, cyanine‐based dye that is rapidly bound to plasma proteins after intravenous injection. ICG has recently been utilized to assess the viability of parathyroid glands. In a randomized trial of 146 patients with least one ICG well‐perfused parathyroid gland demonstrated at the time of surgery, postoperative normocalcemia could be predicted.⁽⁶¹^,⁶²⁾ In addition to ICG, other technologies such as Laser Speckle Contrast Imaging,⁽⁶³⁾ have been proposed to help assess the parathyroids. Near‐infrared autofluorescence, which does not require injected dye for parathyroid visualization, is also considered an evolving technology in this field.⁽⁶⁴⁾ However, surgical technique is the main factor preventing the devascularization of the glands or incidental parathyroidectomy. Although several imaging modalities have been studied to help prevent incidental parathyroidectomy, few have evaluated clinically relevant end‐points such as surgical hypoparathyroidism.⁽^65‐69⁾

iPTH for diagnosis and management of acute surgical hypoparathyroidism

The optimal strategy for identifying patients who will develop postsurgical hypoparathyroidism has yet to be defined.⁽³⁰⁾ Same‐day discharge and limited healthcare resources have resulted in a variety of Ca management strategies following thyroidectomy.⁽⁷⁰⁾ Kazaure and colleagues⁽¹⁷⁾ found that 6% of thyroidectomy patients in the United States developed severe hypocalcemia following discharge, illustrating the need for standardized guidelines and policies for postoperative hypocalcemia management. The utility of iPTH‐based protocols is evolving and should be utilized to identify those patients at risk for developing parathyroid insufficiency prior to discharge from hospital,⁽⁷¹⁾ keeping in mind that studies have found the utilization of iPTH criteria are not as reliable in vitamin D–deficient patients⁽⁷²^,⁷³⁾ (Fig. 2).

There is no consensus regarding the timing or cutoff values for iPTH measurements in postoperative stratification of patients following thyroidectomy. Some authors obtain iPTH while closing the skin,⁽⁷⁴^,⁷⁵⁾ others at 4 hours⁽^25‐27^,⁷⁶^,⁷⁷⁾ to select patients for early replacement therapy and safe same‐day discharge strategies, and others the following morning.⁽⁷⁶⁾ Surgeons need to adopt a consistent algorithmic strategy for management of patients following total thyroidectomy that is in keeping with their health resources and discharge and follow‐up practice (Fig. 2). In general, medical therapy (2 to 3 g of elemental Ca per day and 0.5 to 1.5 μg calcitriol per day) should be started if iPTH concentrations drop below 10 pg/mL (1.06pM) or decline by more than 70% of the preoperative values at 4 hours after surgery.⁽^25‐27^,⁷⁶⁾

Between 70% to 80% of cases of postoperative parathyroid failure will recover within 1 month after thyroidectomy.⁽¹¹^,⁷⁸⁾ Serum Ca, P, and iPTH should be checked within 2 weeks to determine whether parathyroid function has recovered and replacement therapy can be terminated. The chances of parathyroid recovery are dependent on the number of parathyroid glands remaining in situ and s‐Ca and iPTH levels. Detectable iPTH, four glands left in situ, and serum Ca >2.25 mmol/L (9.00 mg/dL) at 1 month after surgery are favorable predictors of recovery.⁽^{11,23,78‐81}⁾

Follow‐up strategies beyond 1 postoperative month of protracted hypoparathyroidism are important, as many patients will recover over the course of the year (75%), and up to 12% beyond 1 year.⁽¹⁴^,²³^,²⁴^,⁸²⁾ Monthly iPTH and s‐Ca measurements for at least 12 months are suggested, to diagnose persistence of hypoparathyroidism or recovery of the parathyroid function.

Nonsurgical etiologies of hypoparathyroidism

Approximately 25% of adults with hypoparathyroidism have a developmental, genetic, autoimmune, metabolic, or environmental condition that impairs either the secretion or action of PTH or alters parathyroid gland mass (Table 1).⁽¹^,³^,⁸³⁾ Medical hypoparathyroidism is particularly important in pediatric patients. Functional hypoparathyroidism can be broadly categorized as a condition in which hypocalcemia and hyperphosphatemia are the consequence of a disorder that (i) impairs development or survival of parathyroid glands, (ii) decreases secretion of biologically active PTH, or (iii) reduces target organ responsiveness to PTH (pseudohypoparathyroidism).

Genetic disorders

The genetic disorders that are associated with hypoparathyroidism are discussed more fully elsewhere (see manuscript for Task Force 3⁽³⁵⁾).

Autoimmune hypoparathyroidism

Autoimmune hypoparathyroidism can occur as an isolated endocrinopathy or as a part of the autoimmune polyglandular syndrome type I (APS‐1), a genetic disorder caused by mutations in the autoimmune regulator (AIRE) gene. APS‐1 is also known as autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED).⁽^84,90‐92⁾

In APS‐1, tissue‐specific autoantibodies targeted against the parathyroid, thyroid, and adrenal glands have been identified and support an autoimmune etiology. Key studies have identified anticytokine antibodies that are highly specific and sensitive markers for APS‐1, including autoantibodies directed against interferon (IFN)‐ω, IFN‐α2A, interleukin (IL)‐17F, and IL‐22.⁽⁹³⁾ NACHT leucine‐rich repeat protein 5 (NALP5) has been identified as a target antigen for autoimmune attack in the parathyroid cells, leading to tissue destruction. Isolated autoimmune hypoparathyroidism has also been described in adult patients who develop circulating antibodies targeted against the extracellular domain of the calcium‐sensing receptor (CaSR).⁽⁹³⁾ These antibodies activate the receptor and thereby inhibit PTH secretion.⁽^94‐96⁾ Patients with noncytotoxic anti‐CaSR antibodies may recover from hypoparathyroidism over time as antibody titers decrease.

Radiation, toxins, and medications

Ionizing radiation can have dichotomous effects on parathyroid tissue. High‐dose radioactive iodine that is administered for the treatment of thyroid cancer has been associated with hypoparathyroidism,⁽⁹⁷^,⁹⁸⁾ but this is a rare event. Similarly, high‐dose external beam radiation has been linked to parathyroid damage. At lower levels of exposure, ionizing radiation has also been shown to induce parathyroid adenomas and primary hyperparathyroidism. Deposition of iron, copper, or aluminum in parathyroid tissue, as can be seen in hemochromatosis or transfusion dependence, Wilson's disease, or renal dysfunction (with use of aluminum‐containing phosphate binders), can lead to destruction of the glands.⁽¹^,³^,⁸³⁾ In addition, invasion of the parathyroid glands by neoplastic, granulomatous, or inflammatory cells (eg, sarcoidosis, Riedel struma, or human immunodeficiency virus [HIV]) or infiltration by amyloid protein can also damage the parathyroid glands.⁽⁸³^,⁹⁹⁾

Very few medications or toxins can damage the parathyroid glands. Most notable are l‐asparaginase, which is used in the treatment of leukemia,⁽¹⁰⁰⁾ and nivolumab, an anti‐PD‐1 immune checkpoint inhibitor that has been associated with development of activating autoantibodies against the CaSR.⁽¹⁰¹⁾ In addition, fetal exposure to retinoids, alcohol, or hyperglycemia via poorly controlled gestational diabetes are associated with a DiGeorge‐like syndrome and parathyroid dysgenesis without an obvious genetic deletion, although clinical hypoparathyroidism is uncommon.⁽¹⁰²⁾

Metabolic disorders

Children with severe burns can develop hypocalcemia within days after burn injury, irrespective of parenteral Ca supplementation, and urinary Ca excretion is typically elevated. Serum concentrations of PTH are inappropriately low for the blood Ca levels, indicating that children with burns have not only hypocalcemia and hypercalciuria but also hypoparathyroidism.⁽¹⁰³⁾ Although these children have severe magnesium (Mg) depletion, replacement with supplemental Mg does not reverse the parathyroid defect, which has been attributed to upregulation of the CASR through an as yet unknown mechanism.⁽¹⁰⁴⁾ An increase in circulating levels of IL‐1β and IL‐6 have been proposed, as in vitro studies have shown that these cytokines are capable of upregulating the parathyroid gland CASR.

Hypoparathyroidism can also be caused by either hypermagnesemia or hypomagnesemia. Hypomagnesemia is associated with impaired release of PTH from the parathyroid cell, likely through a disturbance in the stimulus‐secretion coupling mechanism.⁽¹⁰⁵⁾ Because both Mg and Ca activate the CaSR and reduce PTH synthesis and secretion,⁽¹⁰⁶⁾ albeit with different potencies, elevated levels of extracellular Mg can lead to functional hypoparathyroidism. Hypomagnesemia can also cause PTH resistance and functional hypoparathyroidism.⁽^{105,107‐109}⁾

Maternal hypercalcemia

Infants exposed in utero to maternal hypercalcemia (eg, in the context of maternal primary hyperparathyroidism, vitamin D disorders, or maternal familial hypocalciuric hypercalcemia with a nonaffected fetus) are at risk of suppression of parathyroid function and postnatal hypocalcemia. Additional risks to the developing fetus include intrauterine growth retardation, preterm delivery, and intrauterine fetal death if the hyperparathyroidism in the mother remains untreated.⁽^110‐112⁾

Idiopathic

Hypoparathyroidism is considered to be idiopathic when extensive evaluation of all potential causes of hypoparathyroidism fail to disclose an etiology.⁽¹¹³⁾ It is conceivable that many patients with early‐onset or congenital hypoparathyroidism will have underlying genetic etiologies that may require the application of unbiased molecular genetic technologies, such as whole‐exome sequencing or whole‐genome sequencing, to diagnose. In contrast, individuals with late‐onset hypoparathyroidism may have an underlying autoimmune etiology. In the absence of a clear etiology for hypoparathyroidism, these subjects should be monitored closely for the development of additional disorders.

Pathophysiology of the Disease and Selected Complications

Renal manifestations

The kidney is a target organ often damaged in patients with hypoparathyroidism. Under normal conditions, PTH is critical to sustain renal distal tubular reabsorption of filtered Ca and, therefore, to maintain the extracellular Ca concentrations. When PTH is absent, less Ca is reabsorbed, and the extracellular Ca level is not maintained within the normal range. However, the absolute amount of urinary Ca is not usually high because there is a reduced filtered load in untreated patients. Similarly, insufficient PTH secretion causes a larger proximal tubular reabsorption of filtered P resulting in hyperphosphatemia. Lack of PTH action impairs 1,25‐(OH)₂ D production. Low 1,25‐(OH)₂ D contributes to reduced distal tubular Ca reabsorption and intestinal Ca and P absorption, as suggested by animal studies.⁽¹¹⁴⁾

Conversely, renal complications are found in patients with hypoparathyroidism treated with active vitamin D and/or Ca. Three main complications have been reported: nephrolithiasis, nephrocalcinosis, and chronic kidney disease (CKD).⁽¹¹⁵⁾ Because the activation of the CaSR inhibits distal tubular Ca reabsorption and enhances urinary Ca excretion, these problems are especially frequent in patients with autosomal dominant hypocalcemia 1 caused by activating mutations in CASR.⁽¹¹⁶⁾ Nephrolithiasis is reported to be a complication in up to 36% of patients with hypoparathyroidism.⁽^117‐121⁾ Nephrocalcinosis is reported to complicate the course of hypoparathyroidism in up to 38% of patients, depending on the population and assessment methods.⁽^118‐121⁾ Some studies do not allow one to distinguish between nephrolithiasis and nephrocalcinosis, the rate of which ranged from 19% to 31%.⁽^122‐125⁾ The rates of CKD range from 2.5% to 41%, depending on definition (estimated GFR lower than 60 mL/min/1.73 m², International Classification of Diseases [ICD] codes or self‐report).⁽^{115,117‐119,121,122,124‐129}⁾ The risk of CKD progression is higher in patients with chronic hypoparathyroidism.⁽¹³⁰⁾ Various factors were found to be associated with the rate of CKD development: age, duration of disease, proportion of time with relative hypercalcemia, number of hypercalcemic episodes, increased Ca × P product, and fractional excretion of P.⁽¹¹⁸^,¹²²^,¹²⁶^,¹³¹⁾

Other renal manifestations can also complicate the course of hypoparathyroidism, such as acute dehydration during episodes of acute hypercalcemia; however, this has not been clearly reported in the medical literature.

Skeletal manifestations

The principal skeletal manifestation of hypoparathyroidism is a generalized increase in bone mass in both cortical and cancellous compartments. This can be demonstrated by dual‐energy X‐ray absorptiometry (DXA) and high‐resolution peripheral quantitative computed tomography (HR‐pQCT).⁽^132‐135⁾ Iliac crest bone biopsies in patients with hypoparathyroidism reveal increased cortical thickness and cancellous bone volume (Figs. 3 and 4). The increase in the latter is due to increased trabecular thickness with normal trabecular number and separation.⁽¹³⁶^,¹³⁸⁾ Despite the higher bone mass and these structural changes in hypoparathyroidism, the effect on fracture risk in the axial and appendicular skeleton has not yet been firmly established.⁽¹³⁹^,¹⁴⁰⁾

Fig. 3

Iliac crest bone biopsies from a control subject (left) and a hypoparathyroid subject (right), Goldner trichrome stain. Note the higher cortical thickness and cancellous bone volume in the hypoparathyroid subject. Reproduced with permission from Rubin and colleagues.⁽¹³⁶⁾

Fig. 4

Microcomputed tomographic images of cancellous bone from a hypoparathyroid subject (left) and a control subject (right). Note the higher cancellous bone volume and dense trabecular structure in hypoparathyroidism. Reproduced with permission from Dempster.⁽¹³⁷⁾

Biochemical markers and bone histomorphometry show that the structural changes in the hypoparathyroid skeleton are associated with a profound reduction in the bone remodeling rate (Fig. 5).⁽¹³⁶^,¹³⁸^,¹⁴¹⁾ In the first histomorphometric study of bone from hypoparathyroid patients, mineralizing surface, bone formation rate, and remodeling activation frequency were all significantly reduced by 58%, 80%, and 54%, respectively, compared to age‐ and sex‐matched controls.⁽¹⁴²⁾ Figure 6 shows the reconstructed remodeling cycles from hypoparathyroid and control subjects in this study. Resorption depth was reduced, and the total resorption period was increased from 26 to 80 days. There was a slightly positive bone balance of approximately 5 μm between the resorption depth and wall thickness of cancellous bone packets in the hypoparathyroid subjects compared to the controls. Thus, slightly more bone was being replaced than was removed in each remodeling cycle. However, this is unlikely to account for the magnitude of the observed increases in bone mass, especially since turnover is so low.

Fig. 5

Tetracycline labels in a hypoparathyroid (left) and control subject (right). Note reduction in tetracycline uptake in the hypoparathyroid subject reflecting reduced bone turnover. Reproduced with permission from Rubin and colleagues.⁽¹³⁶⁾

Fig. 6

Bone remodeling cycles in hypoparathyroid (upper) and normal (lower) subjects. All phases of the remodeling cycle are elongated in hypoparathyroidism. Reproduced with permission from Langdahl and colleagues.⁽¹⁴²⁾

One plausible explanation for the elevated bone mass in hypoparathyroidism has been proposed by Christen and colleagues.⁽¹⁴³⁾ The authors used a load adaptive bone modeling and remodeling simulation model to predict changes in microarchitecture due to changes in mechanical loading or cellular activity. The model predicted that, in addition to lowering turnover, the hypoparathyroid state must also cause increased mechanosensitivity of the a normal level of mechanosensitivity (panel a, 100%) osteocytes leading to a marked increase in bone formation during the first year after the onset of the disease (Fig. 7).

Fig. 7

Bone formation and resorption in a simulation of the onset of hypoparathyroidism. In the left panel (A), osteocyte mechnaosensitivity is set to 100%. In the panel on the right (B), osteocyte mechanosensitivity is set to 140%. As shown in panel (B), a net greater increase in bone mass will occur under these conditions. Repoduced with permission from Christen and colleagues.⁽¹⁴³⁾

. https://doi.org/10.1136/bmj.n71.

Neurologic, psychiatric, and neuromuscular manifestations

Tetany, muscle stiffness, and seizures are common presenting features in 40% to 60% of patients with hypoparathyroidism.⁽¹⁴⁴⁾ These symptoms recur when calcemic control is disturbed, as with noncompliance with therapy, intercurrent acute infections, or gastritis or diarrhea. Seizures are common in young patients, especially if the etiology of the hypoparathyroidism is nonsurgical. Eighty percent (80%) of the time these seizures are generalized tonic clonic with diffuse slow‐wave activity on electroencephalogram, but petit mal, partial, or atonic seizures can also occur.⁽¹⁴⁵⁾ Seizure frequency varies from occasional to daily and has been managed with valproate in 40%, carbamazepine in 27%, and levetiracetam in 13% of cases in a series of 70 patients with idiopathic hypoparathyroidism.⁽¹⁴⁵⁾ Extracellular and intracellular Ca are important for normal neuronal function and muscle contraction. The possible mechanisms underlying the paradox of increased neuromuscular excitability in the hypocalcemic state has been explained by inhibition of CaSRs in brain cells in a hypocalcemic milieu.⁽¹⁴⁶^,¹⁴⁷⁾ Inhibited CaSRs modulate neuronal “Na leak” and “Ca‐activated K” channels. This leads to an inward flow of Na⁺ and a decrease in the outflow of K⁺ in the neurons triggering early depolarization and neuronal excitability. Reduced stimulation of CaSRs in the hypocalcemic state can also release excitatory glutamate neurotransmitter leading to postsynaptic excitability.⁽¹⁴⁸⁾

Basal ganglia calcification (BGC) is a common sign in patients with hypoparathyroidism with a prevalence of 60% to 90%.⁽¹²⁹^,¹⁴⁴^,¹⁴⁹⁾ Sachs and colleagues⁽¹⁴⁹⁾ observed a 93% prevalence of BGC in patients with hypoparathyroidism when the duration of illness was over two decades. These calcifications are most commonly seen in globus pallidus (69%), followed by putamen (56%), caudate nucleus (55%), gray‐white junction (40%), cerebellar parenchyma (31%), thalamus (29%), and dentate nuclei (25%).⁽¹⁴⁴⁾ The cortical gray surface of the brain is spared from calcification. The predisposition of the basal ganglia region for calcification has been explained by a “two‐hit mechanism.”⁽¹⁵⁰^,¹⁵¹⁾ The “first‐hit” is increased expression of several pro‐osteogenic molecules (osteonectin, β‐catenin, klotho, frizzled‐4, ecto‐5′‐nucleotidase, low‐density lipoprotein receptor‐related protein 5 [LRP5], Wnt3A, and type 1 collagen) and the presence of neuroprogenitor cells in the basal ganglia.⁽¹⁵¹⁾ Hyperphosphatemia, resulting from the lack of PTH, constitutes the “second‐hit” leading to BGC in hypoparathyroidism. The second‐hit acts by decreasing expression of osteoclast carbonic anhydrase‐II enzyme and inducing neuro‐osteoprogenitor cell differentiation.⁽¹⁵⁰^,¹⁵¹⁾ The severity of hyperphosphatemia is also a significant predictor of increases in volume of BGC and spread of calcifications to other intracranial regions when followed over time.⁽¹⁴⁴⁾

Neuropsychological complications are sometimes linked to BGC. Aggarwal and colleagues⁽¹⁵²⁾ assessed 62 hypoparathyroid patients and observed extrapyramidal features (mask‐like face, rigidity, reduced arm swing, and micrographia) in 15% and cerebellar signs (impaired tandem walk and abnormal heel‐shin/finger nose coordination) in 19%. Despite extensive calcification in several patients, Parkinson's disease requiring levodopa therapy occurred in only two patients. Similarly, cases of chorea, hemiballism, dementia, peripheral neuropathy, and cranial nerve palsies due to raised intracranial pressure can occur, but only occasionally in patients with hypoparathyroidism.⁽¹⁵²⁾ Somatic concern (26%), anxiety (47%), guilt (18%), tension (55%), odd mannerism (10%), depressive mood (40%), hostility and suspiciousness (31%) are other manifestations that have been associated with hypoparathyroidism.⁽¹⁵²⁾ These neuropsychological dysfunctions do not correlate with the volume of BGC.⁽¹⁵²⁾ Rarity of clinical parkinsonism and lack of correlation between cognitive disturbance and BGC could be explained by the presence of relatively intact glucose metabolism and dopaminergic transporters in calcified basal ganglia region in hypoparathyroidism.⁽¹⁵³⁾ These observations raise the possibility that mechanical destruction of the surfaces of the corticostriatal tracts where they pass through calcified basal ganglia or alteration in Ca²⁺‐dependent enzymes might contribute to the pathogenesis of neuropsychological symptoms in hypoparathyroidism.⁽¹⁵⁴⁾

Ocular manifestations

Patients with chronic hypoparathyroidism have a twofold to fourfold higher risk of developing cataracts and requiring surgery at an average age of 35 years.⁽¹²⁸^,¹⁵⁵^,¹⁵⁶⁾ Pohjola⁽¹⁵⁷⁾ reported cataract, papilledema, corneal changes, and loss of eyebrows in 58%, 11%, 10%, and 7% of 118 cases of hypoparathyroidism, respectively. Most cataracts were subcapsular but could be rosette and punctate. Recently, Saha and colleagues⁽¹⁵⁵⁾ described a 46% prevalence of cataracts in 151 cases of idiopathic hypoparathyroidism, which increased to 68% after 8 years of follow‐up. Posterior capsular opacification (75%) and decentralization of the lens (25%) are unique long‐term complications observed following cataract surgery in patients with idiopathic hypoparathyroidism.⁽¹⁵⁵⁾ Cataracts are associated with intracranial calcification, but not with nephrocalcinosis, suggesting different mechanisms for calcification.⁽¹³¹⁾ The mechanisms of cataract development in hypoparathyroidism are not clear but could involve the hypocalcemic environment per se. Cataracts can be induced in an experimental model in vitamin D–deficient rats.⁽¹⁵⁸⁾ In this model, reduction of s‐Ca led to decreased Ca content of the aqueous humor and increased Na content of the lens. Clark⁽¹⁵⁹⁾ showed decreased deposition of Ca in the lens extracted from pigs, after they were immersed in CaCl₂ solution along with PTH. Therefore, cataracts in hypoparathyroidism could also possibly be due to lack of PTH leading to increased deposition of Ca in the lens.⁽¹⁵⁹⁾

Quality of life

Chronic hypoparathyroidism negatively impacts quality of life (QOL).⁽^{120,127,160‐163}⁾ Patients and caregivers carry a substantial burden of illness.⁽¹⁶⁴^,¹⁶⁵⁾ Impact on QOL has been assessed in cohorts around the world that include postsurgical patients⁽^{120,127,160‐163}⁾ and patients with nonsurgical hypoparathyroidism.⁽¹²⁷^,¹⁵²^,¹⁶¹⁾ Detailed review of QOL studies in patients with hypoparathyroidism is included in elsewhere.⁽²¹⁾

Future directions, unanswered questions, and research agenda

There are several unanswered questions, and further studies are necessary.

For example, hypocalcemia has been reported in patients with viral infection with such as severe acute respiratory syndrome‐coronavirus‐2 (SARS‐CoV‐2), SARS‐CoV, and Ebolavirus.⁽¹⁶⁶⁾ However, the mechanism and the natural course of this hypocalcemia has not been well characterized.

The mechanism underlying the profound increase in bone mass in hypoparathyroidism is not clearly understood.

PTH treatment improves several symptoms and QOL in patients with hypoparathyroidism.⁽^167‐170⁾ However, it is not completely understood whether this improvement is caused by direct actions of PTH on various tissues or by a better control of s‐Ca levels. It is not clear what the optimal s‐Ca levels are for a given patient, because some patients complain of symptoms even when s‐Ca is normal. It is possible that the lack of PTH accounts for such problems.

Many etiologies for hypoparathyroidism have been identified, but the pathogenesis is unexplained in a large number of patients. The term idiopathic or primary hypoparathyroidism is still used in the literature because it is difficult to determine the etiologies in all cases of hypoparathyroidism. Future research should address as yet unknown causes of this disease.

The value of emerging technologies and intraoperative assessment of parathyroid viability on the functionality of the parathyroid glands after surgical manipulation merits further assessment.

Acknowledgments

We acknowledge unrestricted financial support from: Amolyt, Ascendis, Calcilytix, and Takeda. They had no input into the planning or design of the project, the conduct of the reviews, evaluation of the data, writing or review of the manuscript, its content, conclusions, or recommendations contained herein.

Authors’ roles: Conceptualization, Visualization: DMS, JLP, KW, CTY. Data Curation, Formal Analysis, Investigation, Methodology, Validation, Software: DMS, JLP, KW, CTY. Project Administration, Funding Acquisition, Resources: DMS, JLP. Supervision: DMS, JLP. Writing‐ original draft: DMS, JLP, SC, DD, SF, RG, PH, MAL, KW, CTY, JP, AS. Writing‐ review & editing: DMS, JLP, SC, DD, SF, RG, PH, MAL, KW, JP, CTY, AS, NDP.

Author Contributions

Janice L Pasieka: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; writing – original draft; writing – review and editing. Kelly Wentworth: Conceptualization; data curation; formal analysis; investigation; methodology; writing – original draft; writing – review and editing. Caitlin T Yeo: Conceptualization; data curation; formal analysis; investigation; methodology; writing – original draft; writing – review and editing. Serge Cremers: Writing – original draft; writing – review and editing. David W Dempster: Writing – original draft; writing – review and editing. Seiji Fukumoto: Writing – original draft; writing – review and editing. Ravinder Goswami: Writing – original draft; writing – review and editing. Pascal Houillier: Writing – original draft; writing – review and editing. Michael A Levine: Writing – original draft; writing – review and editing. Jesse D. Pasternak: Writing – original draft; writing – review and editing. Nancy D Perrier: Writing – review and editing. Antonio Sitges‐Serra: Writing – original draft; writing – review and editing. Dolores Shoback: Conceptualization; data curation; formal analysis; investigation; methodology; project administration; writing – original draft; writing – review and editing.

Conflicts of Interest

PH: consultant to Shire/Takeda and Kyowa Kirin, speaker for Shire/Takeda and received research grants from Shire. MAL: consultant to Shire/Takeda and clinical trials investigator for Shire. SC, DD, SF, RG, JLP, NDP, JDP, DMS, AS‐S, KW, and CTYeo: nothing to disclose.

Ethical Statement

These papers are retrospective reviews and did not require ethics committee approval.

Peer Review

The peer review history for this article is available at https://publons.com/publon/10.1002/jbmr.4714.

Data Availability Statement

The data that support the findings in this study are openly available in PubMed, MEDLINE, EMBASE, and the Cochrane databases.

References

Gafni

Collins

Hypoparathyroidism

N Engl J Med

2019

;

380

(

1738

‐

1747

Sitges‐Serra

Etiology and diagnosis of permanent hypoparathyroidism after total thyroidectomy

J Clin Med

2021

;

(

543

Bilezikian

Hypoparathyroidism

J Clin Endocrinol Metab

2020

;

105

(

1722

‐

1736

Kazaure

Sosa

Surgical hypoparathyroidism

Endocrinol Metab Clin North Am

2018

;

(

783

‐

796

Page

McKenzie

Bossuyt

, et al. .

The PRISMA 2020 statement: an updated guideline for reporting systematic reviews

BMJ

2021

;

372

n71

. https://doi.org/10.1097/SLA.0000000000003800.

Edafe

Antakia

Laskar

Uttley

Balasubramanian

Systematic review and meta‐analysis of predictors of post‐thyroidectomy hypocalcaemia

Br J Surg

2014

;

101

(

307

‐

320

Wang

Zhu

Liu

The effectiveness of parathyroid gland autotransplantation in preserving parathyroid function during thyroid surgery for thyroid neoplasms: a meta‐analysis

PLoS One

2019

;

(

e0221173

Chadwick

Kinsman

Walton

. The British Association of Endocrine and Thyroid Surgeons: Fifth National Audit Report 2017. https://www.baets.org.uk/wp-content/uploads/BAETS-Audit-National-Report-2017.pdf

Annebäck

Hedberg

Almquist

Stålberg

Norlén

Risk of permanent hypoparathyroidism after total thyroidectomy for benign disease: a nationwide population‐based cohort study from Sweden

Ann Surg

2021

;

274

(

e1202

‐

e1208

Díez

Anda

Sastre

, et al. .

Prevalence and risk factors for hypoparathyroidism following total thyroidectomy in Spain: a multicentric and nation‐wide retrospective analysis

Endocrine

2019

;

(

405

‐

415

Ponce de León‐Ballesteros

Velázquez‐Fernández

Hernández‐Calderón

, et al. .

Hypoparathyroidism after total thyroidectomy: importance of the intraoperative management of the parathyroid glands

World J Surg

2019

;

(

1728

‐

1735

Jørgensen

Homøe

Dahl

Hitz

High incidence of chronic hypoparathyroidism secondary to total thyroidectomy

Dan Med J

2020

;

(

A11190647

Powers

Joy

Ruscio

Lagast

Prevalence and incidence of hypoparathyroidism in the United States using a large claims database

J Bone Miner Res

2013

;

(

2570

‐

2576

Lorente‐Poch

Sancho

Muñoz‐Nova

Sánchez‐Velázquez

Sitges‐Serra

Defining the syndromes of parathyroid failure after total thyroidectomy

Gland Surg

2015

;

(

‐

Jessie

Harrison

Hypocalcemia after thyroidectomy: the need for improved definitions

World J Endocrine Surgery

2010

;

(

‐

. https://doi.org/10.1097/SLA.0000000000003725.

Mehanna

Jain

Randeva

Watkinson

Shaha

Postoperative hypocalcemia—the difference a definition makes

Head Neck

2010

;

(

279

‐

283

Kazaure

Zambeli‐Ljepovic

Oyekunle

, et al. .

Severe hypocalcemia after thyroidectomy: an analysis of 7366 patients

Ann Surg

2021

;

274

(

e1014

‐

e1021

Bergenfelz

Nordenström

Almquist

Morbidity in patients with permanent hypoparathyroidism after total thyroidectomy

Surgery

2020

;

167

(

124

‐

128

Ponce de León‐Ballesteros

Bonilla‐Ramírez

Hernández‐Calderón

, et al. .

Mid‐term and long‐term impact of permanent hypoparathyroidism after total thyroidectomy

World J Surg

2020

;

(

2692

‐

2698

Almquist

Ivarsson

Nordenström

Bergenfelz

Mortality in patients with permanent hypoparathyroidism after total thyroidectomy

Br J Surg

2018

;

105

(

1313

‐

1318

Bjornsdottir

Ing

Mitchell

, et al. .

Epidemiology and financial burden of adult chronic hypoparathyroidism

J Bone Miner Res

. 2022;

(

2602

‐

2614

. https://doi.org/10.1002/jbmr.4675.

Sam

Dhillo

Donaldson

, et al. .

Serum phosphate predicts temporary hypocalcaemia following thyroidectomy

Clin Endocrinol (Oxf)

2011

;

(

388

‐

393

Lorente‐Poch

Sancho

Ruiz

Sitges‐Serra

Importance of in situ preservation of parathyroid glands during total thyroidectomy

Br J Surg

2015

;

102

(

359

‐

367

Sitges‐Serra

Gómez

Barczynski

Lorente‐Poch

Iacobone

Sancho

A nomogram to predict the likelihood of permanent hypoparathyroidism after total thyroidectomy based on delayed serum calcium and iPTH measurements

Gland Surg

2017

;

(

Suppl 1

S11

‐

S19

Cayo

Yen

Misustin

, et al. .

Predicting the need for calcium and calcitriol supplementation after total thyroidectomy: results of a prospective, randomized study

Surgery

2012

;

152

(

1059

‐

1067

Carr

Yen

Fareau

, et al. .

A single parathyroid hormone level obtained 4 hours after total thyroidectomy predicts the need for postoperative calcium supplementation

J Am Coll Surg

2014

;

219

(

757

‐

764

Lecerf

Orry

Perrodeau

, et al. .

Parathyroid hormone decline 4 hours after total thyroidectomy accurately predicts hypocalcemia

Surgery

2012

;

152

(

863

‐

868

Wang

Cheung

Roman

Sosa

To supplement or not to supplement: a cost‐utility analysis of calcium and vitamin D repletion in patients after thyroidectomy

Ann Surg Oncol

2001

;

(

1293

‐

1299

Ross

Burch

Cooper

, et al. .

2016 American Thyroid Association guidelines for diagnosis and Management of Hyperthyroidism and Other Causes of thyrotoxicosis

Thyroid

2016

;

(

1343

‐

1421

Orloff

Wiseman

Bernet

, et al. .

American Thyroid Association statement on postoperative hypoparathyroidism: diagnosis, prevention, and management in adults

Thyroid

2018

;

(

830

‐

841

Edafe

Mech

Balasubramanian

Calcium, vitamin D or recombinant parathyroid hormone for managing post‐thyroidectomy hypoparathyroidism

Cochrane Database Syst Rev

2019

;

(

CD012845

Stack

Jr,

Bimston

Bodenner

, et al. .

American Association of Clinical Endocrinologists and American College of endocrinology disease state clinical review: postoperative hypoparathyroidism‐definitions and management

Endocr Pract

2015

;

(

674

‐

685

Shoback

Bilezikian

Costa

, et al. .

Presentation of hypoparathyroidism: etiologies and clinical features

J Clin Endocrinol Metab

2016

;

101

(

2300

‐

2312

Hallgrimsson

Nordenström

Almquist

Bergenfelz

Risk factors for medically treated hypocalcemia after surgery for Graves' disease: a Swedish multicenter study of 1,157 patients

World J Surg

2012

;

(

1933

‐

1942

Mannstadt

Cianferotti

Gafni

, et al. .

Hypoparathyroidism: genetics and diagnosis

J Bone Miner Res

. 2022. Online ahead of print. https://doi.org/10.1002/jbmr.4667.

Barrios

Shafqat

Alam

, et al. .

Incidental parathyroidectomy in thyroidectomy and central neck dissection

Surgery

2021

;

169

(

1145

‐

1151

Taye

Inabnet

3rd,

Pan

, et al. .

Post‐thyroidectomy emergency room visits and readmissions: assessment from the collaborative endocrine surgery quality improvement program (CESQIP)

Am J Surg

2020

;

220

(

813

‐

820

Torabi

Avery

Salehi

Lee

Risk factors and effects of hypocalcemia prior to discharge following thyroidectomy

Am J Otolaryngol

2020

;

(

102420

Bai

Chen

Risk factors and outcomes of incidental parathyroidectomy in thyroidectomy: a systematic review and meta‐analysis

PLoS One

2018

;

(

e0207088

Sitges‐Serra

Gallego‐Otaegui

Suárez

Lorente‐Poch

Munné

Sancho

Inadvertent parathyroidectomy during total thyroidectomy and central neck dissection for papillary thyroid carcinoma

Surgery

2017

;

161

(

712

‐

719

Chadwick

Hypocalcaemia and permanent hypoparathyroidism after total/bilateral thyroidectomy in the BAETS registry

Gland Surg

2017

;

(

Suppl 1

S69

‐

S74

Demidchik

Reiners

, et al. .

Comprehensive clinical assessment of 740 cases of surgically treated thyroid cancer in children of Belarus

Ann Surg

2006

;

243

(

525

‐

532

Nordenström

Bergenfelz

Almquist

Permanent hypoparathyroidism after total thyroidectomy in children: results from a national registry

World J Surg

2018

;

(

2858

‐

2863

de Jong

Lorente‐Poch

Sancho‐Insenser

, et al. .

Late recovery of parathyroid function after total thyroidectomy in children and adults: is there a difference?

Horm Res Paediatr

2020

;

(

9‐10

539

‐

547

Chiang

Fisher

, et al. .

Risks of hypoparathyroidism after total thyroidectomy in children: a 21‐year experience in a high‐volume cancer center

World J Surg

2020

;

(

442

‐

451

Wells

Jr,

Ellis

Gunnells

Schneider

Sherwood

Parathyroid autotransplantation in primary parathyroid hyperplasia

N Engl J Med

1976

;

295

(

‐

Olson

Jr,

DeBenedetti

Baumann

Wells

Jr.

Parathyroid autotransplantation during thyroidectomy. Results of long‐term follow‐up

Ann Surg

1996

;

223

(

472

‐

478

Iorio

Petrozza

De Gori

, et al. .

Parathyroid autotransplantation during thyroid surgery. Where we are? A systematic review on indications and results

J Investig Surg

2019

;

(

594

‐

601

Sierra

Herrera

Herrero

, et al. .

Prospective biochemical and scintigraphic evaluation of autografted normal parathyroid glands in patients undergoing thyroid operations

Surgery

1998

;

124

(

1005

‐

1010

Cavallaro

Iorio

Centanni

, et al. .

Parathyroid reimplantation with PR‐FaST technique in unselected patients during thyroidectomy. A case series with long term follow up confirming graft vitality and parathormone production

Int J Surg

2017

;

202

‐

205

Zedenius

Wadstrom

Delbridge

Routine autotransplantation of at least one parathyroid gland during total thyroidectomy may reduce permanent hypoparathyroidism to zero

Aust N Z J Surg

1999

;

(

794

‐

797

Ahmed

Aurangzeb

Muslim

Zarin

Routine parathyroid autotransplantation during total thyroidectomy: a procedure with predictable outcome

J Pak Med Assoc

2013

;

(

190

‐

193

Wei

Jin

, et al. .

Autotransplantation of inferior parathyroid glands during central neck dissection for papillary thyroid carcinoma: a retrospective cohort study

Int J Surg

2014

;

(

1286

‐

1290

Lorente‐Poch

Sancho

Muñoz

, et al. .

Failure of fragmented parathyroid gland autotransplantation to prevent permanent hypoparathyroidism after total thyroidectomy

Langenbecks Arch Surg

2017

;

402

(

281

‐

287

Tartaglia

Blasi

Giuliani

, et al. .

Parathyroid autotransplantation during total thyroidectomy. Results of a retrospective study

Int J Surg

2016

;

(

Suppl 1

S79

‐

S83

Applewhite

White

Xiong

, et al. .

Incidence, risk factors, and clinical outcomes of incidental parathyroidectomy during thyroid surgery

Ann Surg Oncol

2016

;

(

4310

‐

4315

Park

Rhu

Woo

Choi

Kim

Preserving parathyroid gland vasculature to reduce post‐thyroidectomy hypocalcemia

World J Surg

2016

;

(

1382

‐

1389

Lang

Chan

Chow

Wong

Chang

The association of discolored parathyroid glands and hypoparathyroidism following total thyroidectomy

World J Surg

2016

;

(

1611

‐

1617

Sung

Lee

Yoon

Chung

Hong

Importance of the intraoperative appearance of preserved parathyroid glands after total thyroidectomy

Surg Today

2016

;

(

356

‐

362

Rudin

McKenzie

Thompson

Farley

Lyden

Evaluation of parathyroid glands with indocyanine green fluorescence angiography after thyroidectomy

World J Surg

2019

;

(

1538

‐

1543

Vidal Fortuny

Belfontali

Sadowski

Karenovics

Guigard

Triponez

Parathyroid gland angiography with indocyanine green fluorescence to predict parathyroid function after thyroid surgery

Br J Surg

2016

;

103

537

‐

543

Vidal Fortuny

Sadowski

Belfontali

, et al. .

Randomized clinical trial of intraoperative parathyroid gland angiography with indocyanine green fluorescence predicting parathyroid function after thyroid surgery

Br J Surg

2018

;

105

(

350

‐

357

Mannoh

Thomas

Solórzano

Mahadevan‐Jansen

Intraoperative assessment of parathyroid viability using laser speckle contrast imaging

Sci Rep

2017

;

(

14798

Di Marco

Palazzo

Near‐infrared autofluorescence in thyroid and parathyroid surgery

Gland Surg

2020

;

(

Suppl 2

S136

‐

S146

Kim

Song

Lee

, et al. .

Intraoperative real‐time localization of normal parathyroid glands with autofluorescence imaging

J Clin Endocrinol Metab

2016

;

101

(

4646

‐

4652

Benmiloud

Rebaudet

Varoquaux

Penaranda

Bannier

Denizot

Impact of autofluorescence‐based identification of parathyroids during total thyroidectomy on postoperative hypocalcemia: a before and after controlled study

Surgery

2018

;

163

(

‐

Kahramangil

Berber

ASO author reflections: parathyroid autofluorescence and near‐infrared imaging

Ann Surg Oncol

2018

;

(

876

‐

877

. https://doi.org/10.1002/lary.29297.

DiMarco

Chotalia

Bloxham

McIntyre

Tolley

Palazzo

Does fluoroscopy prevent inadvertent parathyroidectomy in thyroid surgery?

Ann R Coll Surg Engl

2019

;

101

(

508

‐

513

Barbieri

Indelicato

Vinciguerra

, et al. .

Autofluorescence and indocyanine green in thyroid surgery: a systematic review and meta‐analysis

Laryngoscope

2021

;

131

(

1683

‐

1692

Caglià

Puglisi

Buffone

, et al. .

Post‐thyroidectomy hypoparathyroidism, what should we keep in mind

Ann Ital Chir

2017

;

371

‐

381

Lee

Hinson

Siegel

Steelman

Bodenner

Stack

Jr.

Comparison of intraoperative versus postoperative parathyroid hormone levels to predict hypocalcemia earlier after total thyroidectomy

Otolaryngol Head Neck Surg

2015

;

153

(

343

‐

349

Sam

Dhillo

Donaldson

Meeran

Tolley

Palazzo

Serum parathyroid hormone is not an accurate predictor of postthyroidectomy hypocalcemia in vitamin D‐deficient patients: a pilot study

Clin Chem

2011

;

(

1206

‐

1207

Pradeep

Ramalingam

Postoperative PTH measurement is not a reliable predictor for hypocalcemia after total thyroidectomy in vitamin D deficiency: prospective study of 203 cases

World J Surg

2014

;

(

564

‐

567

Roh

Park

Intraoperative parathyroid hormone assay for management of patients undergoing total thyroidectomy

Head Neck

2006

;

(

990

‐

997

Lang

Wong

Hung

Wong

Mak

Indocyanine green fluorescence angiography for quantitative evaluation of in situ parathyroid gland perfusion and function after total thyroidectomy

Surgery

2017

;

161

‐

Barczyński

Cichoń

Konturek

Which criterion of intraoperative iPTH assay is the most accurate in prediction of true serum calcium levels after thyroid surgery?

Langenbecks Arch Surg

2007

;

392

(

693

‐

698

Chang

Park

Jung

Liu

Kim

Koo

The most reliable time point for intact parathyroid hormone measurement to predict hypoparathyroidism after total thyroidectomy with central neck dissection to treat papillary thyroid carcinoma: a prospective cohort study

Eur Arch Otorhinolaryngol

2020

;

277

(

549

‐

558

Sitges‐Serra

The PGRIS and parathyroid splinting concepts for the analysis and prognosis of protracted hypoparathyroidism

Gland Surg

2017

;

(

Suppl 1

S86

‐

S93

Pattou

Combemale

Fabre

, et al. .

Hypocalcemia following thyroid surgery: incidence and prediction of outcome

World J Surg

1998

;

(

718

‐

724

Kihara

Miyauchi

Kontani

Yamauchi

Yokomise

Recovery of parathyroid function after total thyroidectomy: long‐term follow‐up study

ANZ J Surg

2005

;

(

532

‐

536

Sitges‐Serra

Ruiz

Girvent

Manjón

Dueñas

Sancho

Outcome of protracted hypoparathyroidism after total thyroidectomy

Br J Surg

2010

;

(

1687

‐

1695

Villarroya‐Marquina

Sancho

Lorente‐Poch

Gallego‐Otaegui

Sitges‐Serra

Time to parathyroid function recovery in patients with protracted hypoparathyroidism after total thyroidectomy

Eur J Endocrinol

2018

;

178

(

105

‐

113

Mannstadt

Bilezikian

Thakker

, et al. .

Hypoparathyroidism

Nat Rev Dis Primers

2017

;

17080

Gylling

Kääriäinen

Väisänen

, et al. .

The hypoparathyroidism of autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy protective effect of male sex

J Clin Endocrinol Metab

2003

;

(

4602

‐

4608

Vaitsi

Anagnostis

Veneti

Papavramidis

Goulis

Preoperative vitamin D deficiency is a risk factor for postthyroidectomy hypoparathyroidism: a systematic review and meta‐analysis of observational studies

J Clin Endocrinol Metab

2021

;

106

(

1209

‐

1224

de Jong

Nounou

Rozalén García

, et al. .

Children are at a high risk of hypocalcaemia and hypoparathyroidism after total thyroidectomy

J Pediatr Surg

2020

;

(

1260

‐

1264

Al Qubaisi

Haigh

Hypocalcemia after total thyroidectomy in Graves disease

Perm J

2019

;

‐

188

Riss

Kammer

Selberherr

Scheuba

Niederle

Morbidity associated with concomitant thyroid surgery in patients with primary hyperparathyroidism

Ann Surg Oncol

2015

;

(

2707

‐

2713

Wang

Zhou

Liu

, et al. .

Transoral endoscopic thyroidectomy vestibular approach vs conventional open thyroidectomy: meta‐analysis

Head Neck

2021

;

(

345

‐

353

Lankisch

Jaeckel

Strassburg

The autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy or autoimmune polyglandular syndrome type 1

Semin Liver Dis

2009

;

(

307

‐

314

Finnish‐German APECED Consortium

An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD‐type zinc‐finger domains

Nat Genet

1997

;

(

399

‐

403

Husebye

Anderson

Kämpe

Autoimmune polyendocrine syndromes

N Engl J Med

2018

;

378

(

2543

‐

2544

Song

Rais

, et al. .

Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism

J Clin Invest

1996

;

(

910

‐

914

Goswami

Brown

Kochupillai

, et al. .

Prevalence of calcium sensing receptor autoantibodies in patients with sporadic idiopathic hypoparathyroidism

Eur J Endocrinol

2004

;

150

(

‐

Kemp

Gavalas

Krohn

Brown

Watson

Weetman

Activating autoantibodies against the calcium‐sensing receptor detected in two patients with autoimmune polyendocrine syndrome type 1

J Clin Endocrinol Metab

2009

;

(

4749

‐

4756

Brown

Anti‐parathyroid and anti‐calcium sensing receptor antibodies in autoimmune hypoparathyroidism

Endocrinol Metab Clin North Am

2009

;

(

437

‐

445

Glazebrook

Effect of decicurie doses of radioactive iodine 131 on parathyroid function

Am J Surg

1987

;

154

(

368

‐

373

Winslow

Meyers

Hypocalcemia as a complication of radioiodine therapy

Am J Otolaryngol

1998

;

(

401

‐

403

Chopra

Wool

Crosson

Sawin

Riedel's struma associated with subacute thyroiditis, hypothyroidism, and hypoparathyroidism

J Clin Endocrinol Metab

1978

;

(

869

‐

871

Chisari

Hochstein

Kirschstein

Seligmann

Parathyroid necrosis and hypocalcemic tetany induced in rabbits by L‐asparaginase

Am J Pathol

1972

;

(

461

‐

468

Piranavan

Brown

Kemp

Trivedi

Immune checkpoint inhibitor‐induced hypoparathyroidism associated with calcium‐sensing receptor‐activating autoantibodies

J Clin Endocrinol Metab

2019

;

104

(

550

‐

556

Davies

Immunodeficiency in DiGeorge syndrome and options for treating cases with complete athymia

Front Immunol

2013

;

322

Schryver

Klein

Herndon

Suman

Branski

Sousse

Bone metabolism in pediatric burned patients: a review

Burns

2018

;

(

1863

‐

1869

Santa Maria

Cheng

, et al. .

Interplay between CaSR and PTH1R signaling in skeletal development and osteoanabolism

Semin Cell Dev Biol

2016

;

‐

Khan

Sbayi

Shlingmann

. Magnesium homeostasis. In

Bilezikian

, ed.

Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism

. Hoboken, New Jersey:

John Wiley & Sons

;

2019

Google Preview

Vetter

Lohse

Magnesium and the parathyroid

Curr Opin Nephrol Hypertens

2002

;

(

403

‐

410

Mune

Yasuda

Ishii

Matsunaga

Miura

Tetany due to hypomagnesemia induced by cisplatin and doxorubicin treatment for synovial sarcoma

Intern Med

1993

;

(

434

‐

437

Mori

Harada

Okazaki

Inoue

Matsumoto

Ogata

Hypomagnesemia with increased metabolism of parathyroid hormone and reduced responsiveness to calcitropic hormones

Intern Med

1992

;

(

820

‐

824

Mihara

Kamikubo

Hiramatsu

Itaya

Ogawa

Sakata

Renal refractoriness to phosphaturic action of parathyroid hormone in a patient with hypomagnesemia

Intern Med

1995

;

(

666

‐

669

Schnatz

Curry

Primary hyperparathyroidism in pregnancy: evidence‐based management

Obstet Gynecol Surv

2002

;

(

365

‐

376

Truong

Lalakea

Robbins

Friduss

Primary hyperparathyroidism in pregnancy: a case series and review

Laryngoscope

2008

;

118

(

1966

‐

1969

Khan

Clarke

Rejnmark

Brandi

Management of endocrine disease: hypoparathyroidism in pregnancy: review and evidence‐based recommendations for management

Eur J Endocrinol

2019

;

180

(

R37

‐

R44

Wang

Nie

Wang

, et al. .

Genetic screening in a large Chinese cohort of childhood onset hypoparathyroidism by next‐generation sequencing combined with TBX1‐MLPA

J Bone Miner Res

2019

;

(

2254

‐

2263

Haussler

Livingston

Sabir

Haussler

Jurutka

Vitamin D receptor mediates a myriad of biological actions dependent on its 1,25‐dihydroxyvitamin D ligand: distinct regulatory themes revealed by induction of klotho and fibroblast growth factor 23

JBMR Plus

2020

;

(

e10432

Gosmanova

Houillier

Rejnmark

Marelli

Bilezikian

Renal complications in patients with chronic hypoparathyroidism on conventional therapy: a systematic literature review: renal disease in chronic hypoparathyroidism

Rev Endocr Metab Disord

2021

;

(

297

‐

316

Pearce

Williamson

Kifor

, et al. .

A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium‐sensing receptor

N Engl J Med

1996

;

335

(

1115

‐

1122

Underbjerg

Sikjaer

Mosekilde

Rejnmark

Cardiovascular and renal complications to postsurgical hypoparathyroidism: a Danish nationwide controlled historic follow‐up study

J Bone Miner Res

2013

;

(

2277

‐

2285

Levy

Licht

Daneman

Sochett

Harrington

The impact of hypoparathyroidism treatment on the kidney in children: long‐term retrospective follow‐up study

J Clin Endocrinol Metab

2015

;

100

(

4106

‐

4113

Hadker

Egan

Sanders

Lagast

Clarke

Understanding the burden of illness associated with hypoparathyroidism reported among patients in the PARADOX study

Endocr Pract

2014

;

(

671

‐

679

Arlt

Fremerey

Callies

, et al. .

Well‐being, mood and calcium homeostasis in patients with hypoparathyroidism receiving standard treatment with calcium and vitamin D

Eur J Endocrinol

2002

;

146

(

215

‐

222

Meola

Vignali

Matrone

Cetani

Marcocci

Efficacy and safety of long‐term management of patients with chronic post‐surgical hypoparathyroidism

J Endocrinol Investig

2018

;

(

1221

‐

1226

Mitchell

Regan

Cooley

, et al. .

Long‐term follow‐up of patients with hypoparathyroidism

J Clin Endocrinol Metab

2012

;

(

4507

‐

4514

Kim

Shin

Yang

, et al. .

Diverse genetic aetiologies and clinical outcomes of paediatric hypoparathyroidism

Clin Endocrinol (Oxf).

2015

;

(

790

‐

796

Lopes

Kliemann

Bini

, et al. .

Hypoparathyroidism and pseudohypoparathyroidism: etiology, laboratory features and complications

Arch Endocrinol Metab

2016

;

(

532

‐

536

Leidig‐Bruckner

Bruckner

Raue

Frank‐Raue

Long‐term follow‐up and treatment of postoperative permanent hypoparathyroidism in patients with medullary thyroid carcinoma: differences in complete and partial disease

Horm Metab Res

2016

;

(

806

‐

813

. https://doi.org/10.1007/s12020-021-02629-w.

Underbjerg

Sikjaer

Rejnmark

Long‐term complications in patients with hypoparathyroidism evaluated by biochemical findings: a case‐control study

J Bone Miner Res

2018

;

(

822

‐

831

Astor

Løvås

Debowska

, et al. .

Epidemiology and health‐related quality of life in hypoparathyroidism in Norway

J Clin Endocrinol Metab

2016

;

101

(

3045

‐

3053

Vadiveloo

Donnan

Leese

Abraham

Leese

Increased mortality and morbidity in patients with chronic hypoparathyroidism: a population‐based study

Clin Endocrinol (Oxf)

2019

;

(

285

‐

292

Khan

Abu Alrob

Punthakee

, et al. .

Canadian national hypoparathyroidism registry: an overview of hypoparathyroidism in Canada

Endocrine

2021

;

(

553

‐

561

Gosmanova

Chen

Rejnmark

, et al. .

Risk of chronic kidney disease and estimated glomerular filtration rate decline in patients with chronic hypoparathyroidism: a retrospective cohort study

Adv Ther

2021

;

(

1876

‐

1888

Saha

Kandasamy

Sharma

Bal

Sreenivas

Goswami

Nephrocalcinosis, renal dysfunction, and calculi in patients with primary hypoparathyroidism on long‐term conventional therapy

J Clin Endocrinol Metab

2020

;

105

(

dgz319

Seeman

Wahner

Offord

Kumar

Johnson

Riggs

Differential effects of endocrine dysfunction on the axial and the appendicular skeleton

J Clin Invest

1982

;

(

1302

‐

1309

Abugassa

Nordenström

Eriksson

Sjödén

Bone mineral density in patients with chronic hypoparathyroidism

J Clin Endocrinol Metab

1993

;

(

1617

‐

1621

Chen

Kaji

, et al. .

Effects of an excess and a deficiency of endogenous parathyroid hormone on volumetric bone mineral density and bone geometry determined by peripheral quantitative computed tomography in female subjects

J Clin Endocrinol Metab

2003

;

(

4655

‐

4658

Silva

Rubin

Cusano

Bilezikian

Bone imaging in hypoparathyroidism

Osteoporos Int

2017

;

(

463

‐

471

Rubin

Dempster

Zhou

, et al. .

Dynamic and structural properties of the skeleton in hypoparathyroidism

J Bone Miner Res

2008

;

2018

‐

2024

Dempster

. Bone histomorphometry in hypoparathyroidism. In

Brandi

Brown

, eds.

Hypoparathyroidism

Milan

Springer

;

2015

287

‐

296

Rubin

Dempster

Kohler

, et al. .

Three dimensional cancellous bone structure in hypoparathyroidism

Bone

2010

;

190

‐

195

Rubin

Skeletal manifestations of hypoparathyroidism

Bone

2019

;

120

548

‐

555

Formenti

Tecilazich

Giubbini

Giustina

Risk of vertebral fractures in hypoparathyroidism

Rev Endocr Metab Disord

2019

;

(

295

‐

302

Cusano

Bilezikian

Update on hypoparathyroidism

Curr Opin Rheumatol

2019

;

(

381

‐

387

Langdahl

Mortensen

Vesterby

Eriksen

Charles

Bone histomorphometry in hypoparathyroid patients treated with vitamin D

Bone

1996

;

103

‐

108

Christen

Ito

Müller

, et al. .

Patient‐specific bone modelling and remodelling simulation of hypoparathyroidism based on human iliac crest biopsies

J Biomech

2012

;

2411

‐

2416

Goswami

Sharma

Sreenivas

Gupta

Ganapathy

Das

Prevalence and progression of basal ganglia calcification and its pathogenic mechanism in patients with idiopathic hypoparathyroidism

Clin Endocrinol (Oxf)

2012

;

(

200

‐

206

Modi

Tripathi

Saha

Goswami

Seizures in patients with idiopathic hypoparathyroidism: effect of antiepileptic drug withdrawal on recurrence of seizures and serum calcium control

Eur J Endocrinol

2014

;

170

(

777

‐

783

Han

Trinidad

Shi

Hypocalcemia‐induced seizure: demystifying the calcium paradox

ASN Neuro

2015

;

(

1759091415578050

Giudice

Mihalik

Dinnyés

Kobolák

The nervous system relevance of the calcium sensing receptor in health and disease

Molecules

2019

;

(

2546

Phillips

Harnett

Chen

Smith

Calcium‐sensing receptor activation depresses synaptic transmission

J Neurosci

2008

;

(

12062

‐

12070

Sachs

Sjöberg

Ericson

Basal ganglia calcifications on CT: relation to hypoparathyroidism

Neurology

1982

;

(

779

‐

782

Goswami

Millo

Mishra

, et al. .

Expression of osteogenic molecules in the caudate nucleus and gray matter and their potential relevance for basal ganglia calcification in hypoparathyroidism

J Clin Endocrinol Metab

2014

;

(

1741

‐

1748

Kar

Millo

Saha

Mahtab

Agarwal

Goswami

Osteogenic mechanisms of basal ganglia calcification and its ex‐vivo model in hypoparathyroid milieu

Endocrinology

2021

;

162

(

bqab024

Aggarwal

Kailash

Sagar

, et al. .

Neuropsychological dysfunction in idiopathic hypoparathyroidism and its relationship with intracranial calcification and serum total calcium

Eur J Endocrinol

2013

;

168

(

895

‐

903

Modi

Arora

Bal

, et al. .

Effect of basal ganglia calcification on its glucose metabolism and dopaminergic function in idiopathic hypoparathyroidism

Clin Endocrinol (Oxf)

2015

;

(

563

‐

571

Nestler

Walaas

Greengard

Neuronal phosphoproteins: physiological and clinical implications

Science

1984

;

225

1357

‐

1364

Saha

Gantyala

Aggarwal

Sreenivas

Tandon

Goswami

Long‐term outcome of cataract surgery in patients with idiopathic hypoparathyroidism and its relationship with their calcemic status

J Bone Miner Metab

2017

;

(

405

‐

411

Kim

Rhee

Kim

, et al. .

Prevalence and complications of nonsurgical hypoparathyroidism in Korea: a nationwide cohort study

PLoS One

2020

;

(

e0232842

Pohjola

Ocular manifestations of idiopathic hypoparathyroidism

Acta Ophthalmol

1962

;

255

‐

265

Takahashi

Ca(2+)‐ATPase activity in the hypocalcemic cataract

Nippon Ganka Gakkai Zasshi

1994

;

(

142

‐

149

Clark

The effect of parathyroid hormone on the permeability of the lens capsule to calcium

Am J Phys

1939

;

126

136

‐

141