Postoperative hypoparathyroidism (hypoPT) is one of the predominant and severe complications of thyroid surgery. This condition manifests as suboptimal circulatory levels of parathyroid hormone (PTH), engendering multifaceted systemic perturbations. This comprehensive review elucidates the underlying pathophysiological mechanisms and clinical presentations associated with hypoparathyroidism. Moreover, methodologies for the precise recognition and preservation (naked eye, near-infrared autofluorescence, indocyanine green, carbon nanoparticles, and mitoxantrone hydrochloride) of the parathyroid gland during thyroid surgery have been explored, along with recent therapeutic innovations (palopegteriparatide and parathyroid organoids). Finally, this review prospects and interventions via organoids are contemplated. The aim of the literature is to recapitulate the knowledge and the gaps in this field, increasing awareness of postoperative hypoparathyroidism, and improve the prognosis for patients afflicted with hypoparathyroidism.
managementparathyroid organoidpostoperative hypoparathyroidismpostsurgical hypocalcemiarecombinant PTHthyroid surgerytreatmentThe author(s) declared that financial support was not received for this work and/or its publication.section-at-acceptanceThyroid EndocrinologyIntroduction
Hypoparathyroidism (hypoPT) is the most prevalent complication after thyroid surgery, and understanding its pathogenesis and existing preventive measures will contribute to reducing the incidence of hypoPT. This is an endocrinological disorder typified by insufficient circulating levels of parathyroid hormone (PTH) (1). PTH is instrumental in maintaining mineral ion dynamic equilibrium. In the circulatory system, PTH interacts primarily with G-protein coupled receptors—PTH1 receptor (PTH1R) (2) and PTH-related protein receptor (PPR) (3). These receptors are highly expressed in renal and osseous tissues, leading to diminished renal calcium elimination (4), the promotion of bone resorption, a heightened bone turnover rate, and regulated bone remodeling (5). Furthermore, the synthesis of the bioactive form of vitamin D (1,25-dihydroxyvitamin D) is contingent upon the role of PTH in catalyzing renal 25-hydroxyvitamin D1α-hydroxylase (6). This enzymatic activity indirectly modulates calcium assimilation in the intestines. PTH deficiency culminates in outcomes such as hypocalcemia, hyperphosphatemia, amplified urinary calcium excretion, increased osteoporotic tendencies, and other associated clinical symptoms (Figure 1).
Surgery-induced parathyroid dysfunction resulted in the manifestation of multi-systemic lesions across the body. (a) Surgical injury to the parathyroid gland results in insufficient circulating levels of PTH. (b) Ectodermal dysplasia presents as rough and dry skin, thinning hair, and alopecia areata. (c) Hypercalciuria, urolithiasis, renal calcinosis, chronic renal insufficiency occur and indirectly impact calcium assimilation in the intestines. (d) Osseous anomalies include osteosclerosis, cortical thickening, bone pain, skeletal deformities, fractures, and dental hypoplasia. (e) Ophthalmologically, cataracts and corneal calcification occur. (f) Myocardial and electrocardiographic abnormalities manifest as arrhythmias, prolonged corrected QT intervals, and congestive heart failure. (g) The gastrointestinal system is also affected by chronic constipation. (h) Neurologically and muscularly, symptoms such as tingling, paralysis around the mouth, a positive Chvostek’s sign and a positive Trousseau’s sign can manifest as irritability. Cognitively and psychologically, patients exhibit fatigue, cerebral lethargy (“brain fog”), affective disturbances, and insomnia. Furthermore, there is a significant increase in the risk of ectopic basal ganglia calcification and fungal infections.
Medical illustration showing the systemic effects of reduced parathyroid hormone (PTH) following parathyroidectomy, including ectodermal dysplasia, urinary system disease, osseous anomaly, ophthalmic disease, cardiac abnormalities, gastrointestinal complications, and neuromuscular or psychological disorders, each depicted with relevant anatomical drawings and labeled complications.
The identification and preservation of parathyroid glands during thyroid surgery, along with comprehensive postoperative treatment measures, have been longstanding focal points for surgeons. Addressing permanent hypoparathyroidism poses a challenge, as there is a lack of completely effective corrective methods with limited treatment-associated complications. The recent development of functional parathyroid organoids has emerged as a notable advancement in this field. The main objective of this study was to elucidate postsurgical hypoPT, summarize the efficacy and constraints of related management strategies, anticipate the latest advancements in research, and ultimately enhance the awareness of postoperative hypoparathyroidism.
Clinical manifestations
The symptomatic presentation of hypoPT primarily depends on the rate, extent, and persistence of the decrease in the serum calcium concentration. Calcium and phosphate metabolic disruptions induce a variety of systemic or localized clinical indicators.
Acute hypocalcemia often presents as tetany and is occasionally accompanied by symptoms of laryngospasm, stridor, seizures, and the occurrence of epileptiform activity. When it progresses to chronic hypocalcemia could impairs multiple systems in the body (Figure 1) (7–9). Conventionally, PTH was considered to affect the central nervous system (CNS) mainly by regulating serum blood calcium, but recent studies have confirmed that PTH can cross relatively permeable areas of the blood-brain-barrier (BBB), thereby exerting direct and complex effects on the brain. Studies have confirmed that abnormal PTH levels are directly associated with neuronal calcium dysregulation, hypoperfusion, and disruption of neuronal signaling (10). PTH1R was detected in multiple critical brain regions, including the hypothalamus, hippocampus, cerebral cortex, cerebellum, astrocyte and choroid plexus, provided evidence of the neuroprotective role of PTH (11). The anxiolytic and anti-depressant effects of PTH may be related to its action on PTH receptors in the hypothalamus-pituitary-adrenal (HPA) axis (12). In an Alzheimer’s disease mouse model, PTH treatment was observed to suppresses astrocyte senescence and expression of proinflammatory cytokines, resulting in a decrease in glial cell activation, dystrophic neurites, and amyloid-beta (Aβ) deposition, and ultimately improving the cognitive function (13). Furthermore, in a model of ischemic stroke, PTH increased the expression of trophic and regenerative factors including vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF), facilitated the migration of neuroblasts from the subventricular zone (SVZ), thereby enhanced the neurovascular regeneration and increased the number of newly generated neurons in the peri-infarct cortex (14). Therefore, we can explore PTH analogs capable of effectively crossing the BBB as potential therapeutic agents for mood disorders. The clinical management of patients with hypoPT should emphasize the assessment of their psychiatric symptoms and consider them as the endpoint.
Consequently, patients with hypoPT complain of neuropsychological and cognitive symptoms and show a low quality of life. Patients possibly need pharmacological regimens and recurrent hospital admissions throughout life. Even after prolonged conventional pharmacological therapy, various targeted organ dysfunctions could trouble patients, such as hypercalciuria, urolithiasis, renal calcinosis, and chronic renal insufficiency. All of these factors, in turn, impose a substantial economic burden on the families of patients and markedly decrease their quality of life (15, 16).
Classification
According to the guidelines from the American Thyroid Association Surgical Affairs Committee Statement, hypoPT is classified into distinct categories and can be defined by the following diagnostic metrics: biochemical, clinical, and relative hypoPT (17). Temporal categorizations postsurgery included immediate versus delayed onset, further stratified by duration into transient and permanent conditions (Table 1).
Distinct categories of postoperative hypoparathyroidism based on varying criteria.
Standard
Categorization
Definition
Diagnostic criteria
Biochemical hypoPT
Serum iPTH < 12 pg/ml*,potentially concurrent with hypocalcemia.
Clinical hypoPT
Abnormal biochemical indicators with signs or symptoms of hypocalcemia
Relative hypoPT/ Parathyroid insufficiency
Clinical manifestations of hypocalcemia with normal biochemical indicators
Occurrence time
Immediate hypoPT
Within 24 hours following surgery
Delayed hypoPT
After 24-hour postsurgical window
Transient hypoPT
Within 6 months following surgery
Permanent hypoPT
Beyond 6 months postsurgery without recovery
iPTH, intact PTH. *Intact PTH levels below the lower limit of the laboratory reference range (typically 12 pg/ml).
Risk factors
In the United States, more than 130,000 thyroid surgeries are performed annually (18), and anterior neck surgeries are the most prevalent etiology of this condition, with acquired postoperative hypoPT accounting for approximately 75% of all cases. This encompasses mechanical trauma, thermal injury, surgery [total thyroidectomy (TT) vs. sub-total thyroidectomy (sub-TT) vs. lobectomy (LT)], neck dissection, intentional excision, inadvertent removal, and disruption of the vascular supply (19, 20). Moreover, technique and expertise of surgeon may significantly correlate with incidental parathyroidectomy. The remaining 25% cases of hypoPT may be attributed to genetic factors, autoimmune assaults, pseudohypoparathyroidism, and a minuscule percentage of infiltrative disease (21, 22).
HypoPT is also the most frequent complication following thyroid surgeries (23). The incidence of transient hypoPT ranges from 7.3% to 83%, and that of permanent hypoPT varies from 0% to 12.1% (24–28). With the annual increase in the number of thyroid surgeries, the prevalence is expected to increase. Importantly, once hypoPT manifests, its impact on patients could be profound and potentially lifelong. Therefore, prophylactic measures and therapeutic interventions for hypoPT are of utmost importance (Figure 2).
Options of prevention and treatment for post-operative hypoparathyroidism. (a) Techniques for prophylaxis. Experienced surgeons and use of auxiliary tools to reduce the hypoparathyroidism caused by surgery. NIRAF, near-infrared autofluorescence. ICGF, indocyanine green fluorescence. CNs, carbon nanoparticles. MHI, mitoxantrone hydrochloride. (b) Biochemical supplementation. Supplementation with calcium agents and vitamin D is crucial for treating hypoparathyroidism, Recombinant human PTH(1-84) (Natpara) is approved for adults refractory hypoPT in the US and Europe as a supplement. FDA approved TransCon PTH (Palopegteriparatide) as the first and only long-acting hormone replacement for hypoparathyroidism in adults. (c) Transplantation. Organ or cell transplantation represents a physiological option for managing endocrine disorders, PTautoT is commonly used in surgery, organoids emerge as a new option to replace damaged tissues. PTautoT, parathyroid autotransplantation. Immediate AutoT, immediate autotransplantation. Delayed AutoT, delayed autotransplantation. PTalloT, parathyroid allotransplantation.
Circular infographic divided into three labeled sections: a. Techniques and Tools, listing items such as surgeon, ultrasound, radioactive tracers, angiographic agents, nano-carbon, and FNA-PTH; b. Transplantation, detailing PTAutoT, PTalloT, immediate and delayed autoT, cell transplantation, and organoid transplantation; c. Biochemical Supplementation, referencing calcium and vitamin D, and recombinant PTH. Central illustration depicts a thyroid and pills, representing parathyroid management approaches.Techniques for prophylaxis
Prevention supersedes treatment for patients who undergo surgery. Intraoperative identification of fewer than two PGs is an independent predictor of permanent hypocalcemia following TT (25). Efficient identification, meticulous anatomy and in situ preservation of the glands and their vascular supply are the optimal approaches for ensuring intact parathyroid function (29).
Surgeon technique
The knowledge of normal anatomy and its variation is essential for surgeons. Approximately 85% of superior PGs are situated within a 1 cm radius around the inferior angle of the thyroid cartilage. Inferior PGs and the thymus, which originate from the third pharyngeal pouch, can migrate between the hyoid bone and upper mediastinum, making surgery difficult.
PGs primarily receive blood from two inferior thyroid artery (ITA) and two superior thyroid artery (STA), occasionally from a thyroid ima artery (TIMA) (30). TIMA is an uncommon anatomical variation, usually representing as compensatory for ITA absence (31). These terminal arterial branches lack collateral anastomoses, requiring careful dissection to preserve vascular supply, a safe distance of at least 3 mm from the vessels when energy-based instruments are used to prevent thermal damage, and the use of clamp and tie (CAT) technology to protect arterial branches (32, 33). Moreover, identification of the inferior parathyroid vein aids in preserving the inferior gland in situ. Nonetheless, even if the vascular anatomy remains intact during surgery, postoperative vascular spasms poses a risk for parathyroid dysfunction.
Consequently, owing to the inherent anatomical complexities of PGs, such as their diminutive dimensions (4–6 mm), delicate structure, coloration mimicking adjacent tissues, and variations in glandular location and vascularization, surgeons require extensive fundamental understanding and precise surgical technique. TT performed by high-volume surgeons lead to minimal endocrine-related complication rates about 1.6% and maximal cost effectiveness (34, 35).
Identification technique
Many surgeons rely on the empirical identification of PGs with naked eye (NE) based on anatomical location, and this subjective visual inspections are usually unreliable (36). Utilization of auxiliary technologies significantly improve the accuracy of parathyroid gland identification. The intraoperative application of Near-Infrared Autofluorescence (NIRAF), Indocyanine Green Fluorescence (ICGF), Carbon Nanoparticles (CNs), and Mitoxantrone Hydrochloride (MHI) facilitates the identification and in situ preservation of PGs, thereby reducing the incidence of postoperative complications (37). Therefore, it is imperative to evaluate the advantages and limitations of various methodologies.
Near-infrared Autofluorescence
Under near-infrared light stimulation at wavelength of 760–770nm, PGs emit autofluorescence (AF) at 820–830nm (38, 39). Owing to the inherent cellular structure and low fat density signals, AF intensity of PGs is 2.4- to 8.5-fold stronger compared with the thyroid and background (40.6 ± 26.5 vs. 31.8 ± 22.3 vs. 16.6 ± 15.4). The difference in fluorescence intensity provides a reliable basis for intraoperative real-time identification of the PGs (40, 41).
NIRAF is a high accurate assurance of PGs. In 550 specimens, NIRAF signature is highly consistent with pathologic findings (sensitivity of 98%, specificity of 97%, positive predictive value of 95%, and negative predictive value of 99%) (42). NIRAF can detect an increased number of PGs than NE, probably because the penetration of near-infrared light is more than 3mm, with 98% of PGs could be detected AF, and 46% of PGs could be detectable even when obscured by soft tissue (38). NIRAF used during TT showed the best advantage in reducing the incidence of postoperative early hypocalcemia (from 20.9% to 5.2%), and reducing autotransplantation rate (43).
However, this technique also has certain limitations. NIRAF cannot assess the blood supply of PGs, and is incapable of guiding intraoperative decisions on autotransplantation. Furthermore, commercially available NIRAF devices involve complex operational procedures and lack high-quality consensus.
Indocyanine Green Fluorescence
Indocyanine Green (ICG) is an amphiphilic tricarbocyanine dye rapidly binds to plasma lipoproteins after intravenous injection (44). ICG is taken up by the highly vascularized parathyroid glands, emitting fluorescence with a peak at 832 nm when excited by near-infrared light at wavelength of 800 nm (45). Furthermore, the varying fluorescence intensity positively correlates with the perfusion and functionality, facilitating intraoperative visual assessment of PGs functionlity and determining the in situ preservation. If at least one well vascularized PG is demonstrated by ICGF after surgery, the patient’s postoperative PTH levels could remain within the normal range without treatment (46).
The SUCRA values from a meta-analysis including 29 studies showed that the PGs identification rate of ICGF is significantly higher than that of NE (0.76 vs. 0.04) (47). However, ICGF have the highest autotransplantation rate. This is attributed to the fact that a lack of ICGF intensity—a potential indicator of impaired blood supply—inclined surgeons toward intraoperative autotransplantation. Consequently, the incidence of postoperative hypocalcemia and hypoPT in ICGF group showed no significant difference from that in NE group (47). ICGF has a lower PGs identification rate than NIRAF, as ICG absorption by thyroid glands impedes PGs visualization (44). A randomized controlled trial revealed combining AF with ICGF could reduce the risk of transient postoperative hypocalcemia, facilitate the identification and preservation of PGs, and improve the accuracy of intraoperative PG perfusion assessment (48).
Finally, it should be noted that ICG solution contains sodium iodide and is therefore contraindicated in patients with iodine allergy or renal impairment (49).
Carbon Nanoparticles
CNs—a lymphatic tracing agent with 150 nm diameter—injected into the thyroid accumulate in lymph nodes during thyroidectomy, rapidly staining the thyroid gland and the lymph nodes black while preserving the anatomical color of the PGs and laryngeal nerves (50). According to SUCRA values, CNs have the best advantage in reducing the rate of transient postoperative hypoPT (0.95), followed by AF (0.67), ICGF (0.22), and NE (0.16) (47). Meanwhile, CNs are used for indirect identification of PGs. Compared to direct identification techniques (NIRAF, ICGF), CNs imaging exhibits an extremely high false-negative rate, with PGs identification accuracy only superior to visual inspection (47, 51).
Few side effects related to CNs have been reported. If the injection of CNs is too deep (penetrating the serosal layer) or the dose is excessive during surgery, it may cause dye extravasation. This could stain the surgical field and complicate the protection of the arteries supplying PGs, although this risk can be avoided with carefully administered during surgery (52).
Mitoxantrone Hydrochloride
MHI—a novel lymph nodes tracer—was approved for the first time by the National Medical Products Administration (NMPA) for use in thyroidectomy in 2021. MHI self-assembles into nanocrystals (approximately 100 nm in diameter) in the interstitial spaces of thyroid through noncovalent interactions (53). The gap between capillary lymphatic endothelial cells is 100–500 nm while that between the capillary endothelial cells is only 30–50 nm (51). MHI nanocrystals cannot cross the capillary walls but can enter lymphatic capillaries. They accumulate in lymph nodes via lymphatic drainage and are captured by macrophages, thereby producing a blue tracer effect.
MHI detects PGs indirectly through lymph node negative imagin. Compared to NE, the use of MHI during TT enhances lymph nodes dissection and PGs identification, decreases the rate of inadvertent PGs resection, and reduces the incidence of transient postoperative hypoPT (14.29% vs. 32.5%) (54).
MHI is a safe and effective tracer. No adverse reactions associated with MHI have been observed, and the safe dosage range is 0.2–0.6 ml (55). Furthermore, MHI dye extravasation can be effectively removed by using gauze soaked in saline.
Therapeutic biochemical supplementation
The primary biochemical indicators for diagnosing hypoPT include abnormally low or undetectable serum levels of ionized PTH (iPTH), along with albumin-corrected total serum calcium [corrected calcium = total serum calcium measurement + 0.02 × (40 - albumin measurement)], since 40–45% of serum calcium is protein-bound calcium. Monitoring and ameliorating electrolyte imbalances are crucial for mitigating the risk of hypoPT.
Calcium and vitamin D supplementation
The half-life of PTH is approximately 3–5 minutes, and persistent PTH levels at or above 15 pg/ml for more than 20 minutes postoperatively indicate a low likelihood of postoperative PG dysfunction with no need for intensive serum calcium monitoring or supplementation (17). However, in the event of acute hypocalcemia, prompt calcium and active vitamin D supplementation can improve the chances of restoring PG functionality, reversing permanent dysfunction and keeping the patient alive (56).
Postoperative acute hypocalcemia typically manifests after serum PTH levels decrease, reaching their nadir within 24–72 hours. A serum calcium concentration less than 1.88 mmol/L within 24 hours is indicative of permanent hypocalcemia (57, 58). The “parathyroid splinting” hypothesis suggests that allowing damaged parathyroid tissue to rest after surgery, combined with pharmacological interventions to increase calcium levels, may improve long-term outcomes (59). The panel made a recommendation suggesting conventional therapy as first line therapy, including postoperative supplementation of calcium agents and active vitamin D, correction of abnormal serum magnesium.
Calcium
Oral calcium agents, such as calcium carbonate and calcium citrate, are commonly used for supplementation. Calcium carbonate, which contains 40% elemental calcium, is preferred because of its cost-effectiveness and lower dosage requirements (60). However, its absorption depends on gastric acid, requiring lower doses of meals for those with normal gastric acid. Calcium citrate is an alternative for patients with specific conditions (undergone gastric bypass surgery, take acid-blocking medications, present bloating and constipation side effects of calcium carbonate, elders with reduced gastric acid), requiring approximately double the dose of calcium carbonate due to its 21% elemental calcium (61). Monitoring urinary calcium levels during supplementation is crucial to prevent the renal complication of calcium deposition. Typically, serum calcium levels should be within the lower normal range (8.0–8.5 mg/dl or 2.00–2.12 mmol/l), with urinary calcium levels under 300 mg/day (7.5 mmol/d). Moreover, oral calcium agents can inhibit intestinal levothyroxine absorption, so it is recommended that patients take levothyroxine either 1 hour before or 3 hours after calcium supplementation after thyroidectomy (62, 63). The intravenous administration of 10% calcium gluconate is effective in rapidly increasing blood calcium levels if oral supplements are ineffective, with careful monitoring of the patient’s electrocardiogram for the QT interval and any anomalies, as it poses significant risks especially in patients with cardiac complications. Therefore, it is always safe to offer infusions of 10% calcium gluconate diluted in 150 ml saline instead of direct intravenous administration which should be reserved for emergency conditions like laryngospasms.
Vitamin D
Vitamin D maintains the calcium balance in the bloodstream by promoting calcium absorption in the intestines and bone resorption. There are various formulations of vitamin D, such as ergocalciferol (VD2), cholecalciferol (VD3), dihydrotachysterol, alfacalcidol (1α-OH-D3), and calcitriol [1,25-(OH)2-D3] (55). Calcitriol and alfacalcidol are bioactive forms of vitamin D that undergo 1α-hydroxylation, enhancing their potency by 100–500 times (64). They are commonly used in patients with hypoPT. Therefore, close monitoring of serum calcium levels is essential during drug therapy for hypoPT to prevent hypercalcemia and hypercalciuria caused by vitamin D toxicity (65). Additionally, their relatively short half-lives (4–6 hours) necessitate once- or twice-daily dosing, which improves patient compliance while facilitating timely correction of vitamin D toxicity (6).
However, a concern with vitamin D therapy is the risk of hyperphosphatemia, which can lead to the formation of insoluble calcium phosphate complexes in soft tissues such as the brain, blood vessels, and kidneys. Therefore, it is imperative to monitor phosphorus intake and electrolyte levels and maintain serum phosphate levels within the normal range or a calcium–phosphate product concentration ≤55 mg2/dl (1).
Protocol
Supplementation may be prophylactically administered to patients at risk of postoperative PG dysfunction or on the basis of postoperative blood PTH and calcium level monitoring (Table 2) (66). These medications can assist patients in managing temporary PG dysfunction until normal serum calcium levels are stable. Gradual reduction in drug dosage, monitoring of biochemical markers, and avoidance of complications such as hypercalcemia are essential steps once PG function is restored.
Pharmacological administrations for the treatment of hypoparathyroidism following surgery.
Protocol
Medication
Management in adults
Route
Experientially
Calcium carbonate
0.5-1.25 g of elemental calcium, dividedinto 2-3 doses
50-100 μg q.d. initial dose of 18 μg q.d.increase palopegteriparatide by 3 μg every 7 days
S.C.S.C.
The inability to recover PG function within six months postsurgery indicates permanent dysfunction, requiring lifelong management to maintain normal serum calcium levels, prevent multiorgan complications, and increase patients’ quality of life. Conventional pharmacotherapy can control serum calcium levels but does not correct the underlying PTH deficiency. This deficiency can lead to physiological disturbances, including reduced lomerular filtered of calcium, altered renal calcium reabsorption, and decrease bone turnover.
Thiazide diuretics, along with calcium supplements, can prevent excessive calcium loss (67–69). However, thiazides may cause magnesium loss (<1.6 mg/dl), affecting PTH release, and oral magnesium oxide 400 mg, once or twice daily, is recommended (70). PTH deficiency also affects magnesium reabsorption in the distal convoluted tubules. Concurrently, magnesium deficiency leads to PTH resistance, as magnesium serves as a cofactor for adenylate cyclase. During conventional treatment, patients with hypomagnesemia should receive magnesium supplements to restore normal plasma magnesium levels (71). Additionally, elevated serum magnesium levels reduce the synthesis and secretion of PTH by binding to CaSR, necessitating close monitoring (71).
Recombinant PTH
HypoPT presents a unique challenge in endocrine deficiency disorders, as hormone replacement therapy is avoided previously because of concerns over osteosarcoma development in rat studies (72, 73). However, human trials have not shown this risk. The FDA and EU approved rhPTH(1-84) (Natpara) for adults with refractory hypoPT in the US and Europe as a supplement to conventional therapies that are poorly controlled, require high-dose medications, or severely impact physical and mental health. Recombinant human PTH(1-34) (Teriparatide) is approved for the treatment of osteoporosis, and clinical trials on hypoPT with rhPTH (50–100 μg/day) have been effective in stabilizing renal function, increasing bone turnover, and reducing the use of oral supplements (0 μg/day active vitamin D and ≤500 mg/day calcium) (74). Consequently, in Augest 12, 2024, FDA approved TransCon PTH (Palopegteriparatide, approved under the brand name YORVIPATH® in the EU) as the first and only long-acting hormone replacement for hypoparathyroidism in adults, based on the phase 3 PaTHway trial and phase 2 PaTH Forward trial. This PTH analog is a prodrug of teriparatide that releases PTH(1–34) from carrier through autocleavage of the TransCon linker, administered once-daily subcutaneous injection, with 60-hour apparent half-life and 24-hour sustained release of active PTH (75). In contrast, natpara has a short half-life of 3 hours, once-daily injection leads to wide PTH fluctuations (76). The efficacy is also a critical differences between palopegteriparatide and natpara. In PaTHway, 90% of patients receiving palopegteriparatide independent from conventional therapy by week 26 (77). In contrast with the REPLACE trial, approximately 40% of patients receiving natpara achieved independence (78).
Over time, patients with chronic hypoparathyroidism or managed with conventional therapy can increase the risk of chronic renal complications including nephrocalcinosis and nephrolithiasis. Nevertheless, the effect of natpara on renal calcium remains controversial. It transiently increases the glomerular filtration rate (10–12 h), promoting renal calcium reabsorption and reducing urinary calcium excretion, thereby increasing the risk of long-term renal complications and nephrocalcinosis (79). However, palopegteriparatide treatment is beneficial to individuals, may preserve or improve renal function as observed in trial with a mean increase in estimated glomerrular filtration rate of 9.3ml/min/1.73 m2 (80). Nonetheless, there are adverse reactions related to palopegteriparatide during the 26-week trial with an incidence ≥5% (injection site reaction, headache, unintended changes in calcium levels, orthostatic hypotension, digoxin toxicity with concomitant use of digitalis compounds, etc.), and limited assessments of osteosarcoma beyond 2 years with no recommendation in patients at risk of osteosarcoma. Additionally, this treatment is costly, and further observational studies are needed for widespread application due to the limited clinical data on long-term safety and efficacy.
Transplantation for therapy
For patients with permanent hypoPT, while oral calcium supplements or hormone replacement can compensate for endocrine imbalances, they cannot replicate the complex metabolic interactions of the hormone. Moreover, long-term pharmacotherapy involves various complications, imposing a significant medical burden on patients and physicians. Organ or cell transplantation represents a physiological option for managing endocrine disorders.
Parathyroid autotransplantation
Parathyroid autotransplantation (PTautoT) can significantly reduce the incidence of permanent hypoPT by salvaging unintentionally resected or blood-cessated glands, with success rates ranging from 75% to 100% (81–84). It is supported by the ability of parathyroid tissue to increase vascular endothelial growth factor expression, inducing angiogenesis (85). Vascular growth and functional recovery of the transplanted tissue occur within 10 days to 12 months (86–88).
Immediate autotransplantation
Immediate autotransplantation involves a technique established by Wells et al. (83, 89) The tissue is placed in 4 °C saline or culture medium and sliced into 1*1*2 mm pieces after rapid PTH assays, frozen section pathology and a 30-minute cooling period. The specimens are transplanted into disperse muscle pockets and then closed with metal clips or nonabsorbable sutures. The brachioradialis muscle of the nondominant arm is commonly selected for transplantation because of its abundant blood supply and convenience for subsequent evaluation. The sternocleidomastoid muscle, pectoralis major, thigh muscles, and trapezius on the same side were also utilized. However, the recent meta-analysis and trial sequential analysis showed that PTautoT in the sternocleidomastoid muscle is not associated with a decreased risk of permanent hypoPT, while PTautoT in the brachioradialis muscle does decrease the incidence of permanent hypoPT (90).
Serum PTH levels progressively increase, maintain normal levels by the fourth week, and sustain stabilization for six months without additional supplementation after transplantation (22, 91). Compared with at least one gland autotransplantation without PTH assessment, selective parathyroid autotransplantation with intraoperative PTH <10 ng/l successfully prevents permanent hypoPT and significantly reduces the risk of transient hypoPT (92).
Delayed autotransplantation
Delayed autotransplantation refers to preserving the tissue in liquid nitrogen with 10% dimethyl sulfoxide as a cryoprotectant until six months postsurgery, and there is still no parathyroid function (22, 93). However, tissues are not recommended to freeze for more than two years, as tissue viability decreases over time; for example, the transplantation success rate is only 80% at nine months in rat trials (83).
Indications
In situ identification and preservation of PGs is the optimal strategy to prevent postoperative hypoPT. PTautoT is also a commonly used strategy for preventing and treating postoperative hypoPT. For PGs identified intraoperatively that cannot be preserved in situ, immediate autotransplantation should be performed. For example, immediate autotransplantation should be performed proactively in the following scenarios: - Intraoperative observation of pale PGs indicating complete compromised blood supply - Unintended resection of PGs identified in thyroid, central lymph node, or adipose tissue specimens - Cases where thyroid cancer is tightly adherent to PGs, precluding their preservation - High-risk surgeries (advanced cancer, reoperations) where in situ preservation of all PGs is anticipated to be challenging (82, 94). For extremely high-risk patients, non-preservable PG tissue should be cryopreserved for delayed autotransplantation in case of permanent hypoPT. For example, in cases involving bilateral central zone lymph node dissection or reoperation, multiple (≥2) PGs may be resected or suffer vascular compromise (95). Even if immediate autotransplantation has been performed, cryopreservation may be considered if the number of in situ preserved PGs is extremely limited (≤1) and their function is uncertain (96).
However, some reports refute the effectiveness of autotransplantation in preventing parathyroid dysfunction, as no significant differences were observed in clinical symptoms or calcium and iPTH levels during follow-up, regardless of whether the parathyroid implant was used (97, 98). Because fewer than four glands are retained in situ and the viability is doubted (99–101), the incidence of temporary hypoPT increases with the number of transplants (102–104). A meta-analysis of 18 studies indicated that PTautoT is associated with transient hypoPT but has no effect on the incidence of permanent hypoPT (90).
Parathyroid allotransplantation
Allotransplantation is a potential therapeutic modality for which HLA matching may not be necessary (105). The transplants can come from brain-dead donors, individuals with hyperparathyroidism (transplanting adenomas might induce hyperparathyroidism), or parathyroid-like cells derived from human embryonic stem cells, which are cultured and assessed for viability and functionality (105). Most recipients neither exhibit hypocalcemia nor require long-term immunosuppression (106, 107). However, the survival rate of allografts within 12 months is less than 50%, with the longest reported survival being only three years, necessitating multiple retransplantations (105). Owing to uncertainties about immunosuppressant application, complications, and limited long-term efficacy, further research is needed before widespread clinical application.
Parathyroid cell transplantation
Parathyroid cells cultured in vitro can downregulate MHC-I and MHC-II expression, reducing immunogenicity (108). This process can also control the quantity of implanted cells, regulate the PTH content, cryopreserve and reuse them (108, 109). Proliferative and PTH-secreting cells can be obtained via cell culture passaging, then, alone or in microcapsules, can be implanted into the muscle, abdominal wall, or peritoneum intravenously or subcutaneously, leading to increased serum PTH and calcium concentrations (110). However, cell transplantation has issues such as limited cell duration posttransplantation, restricted cell quantities at transplant sites, rejection in allogeneic cell transplants, and challenges with microencapsulation technology (111, 112). Consequently, the effectiveness of clinical application requires further evaluation.
Transplantation of organoids
Organoids are self-organizing assemblies that feature specific spatial structures and functions that closely resemble the physiological and pathological profiles of human organs; they are formed through in vitro three-dimensional cultures of somatic cells, adult stem cells (including progenitor cells), or pluripotent stem cells (113). Due to their significant advantages over conventional cell and animal models in terms of physiological processes, genetic stability, and ease of operation, organoid technology has presents a novel approach for medical research and is rapidly being implemented in studies on organ development, disease modeling, drug screening, toxicity testing, precision medicine, and regenerative medicine (114–117).
Organoid transplantation
Organoids serve as reserves for transplantation to replace or repair damaged tissues. Researchers have successfully transplanted retinal pigment epithelial cells into patients with age-related macular degeneration. Moreover, liver organoids transplanted into mice integrate functionally within two days and reverse liver failure (118–120). Transplanting intestinal epithelial organoids into a mouse model of ulcerative colitis validated the use of transplantation therapy for refractory ulcerative colitis (121). Thyroid organoids are constructed from induced pluripotent stem cells, which directly simulate key events in development and demonstrate the ability to secrete hormones posttransplantation into mice, advancing regenerative therapies (122).
Parathyroid organoids
Despite early reports of human embryonic stem cells differentiating into parathyroid-like tissues via activin A and Shh proteins (123, 124), research on parathyroid organoids has long been limited because of their small tissue volume, scarce cell numbers, and difficulty in sample acquisition (125). However, a recent breakthrough at the University Medical Center Groningen involved the isolation of stem cells from patients with benign parathyroid hyperplasia to construct parathyroid organoids (126). As demonstrated through hormone secretion monitoring, drug response testing, tracer experiments, and near-infrared autofluorescence properties, these organoids are highly appropriate structured models capable of mimicking functional parathyroid tissues (127). Other researchers have also cultured organoids with intact secretory function from the tissues of 6 patients with benign primary hyperparathyroidism, elucidating the feasibility of using organoids in disease and transplantation research through bioenergetic and metabolic analyses (128). Recently, parathyroid organoids have successfully differentiated from human embryonic stem cells, resulting in an increased differentiation rate and PTH secretion through the overexpression of the GCM2 protein (129). Additionally, researchers generated parathyroid organoids using fibroblast-derived induced pluripotent stem cells and characterized their functional activity and tissue integration potential through in vitro validation and in vivo experiments involving rat transplantation (130). This strategy avoids the ethical concerns associated with embryonic stem cells. Therefore, advanced organoid technology has immense potential for regeneration and offers a viable therapeutic option for treating permanent hypoPT. However, challenges and barriers exist with organoid replacement therapy, including cell diversity, the cultivation environment, the duration of functional maintenance, and immunological rejection.
Conclusion
Hypoparathyroidism remains one of the most common postoperative complications following thyroid surgery. Strategies such as enhancing surgical expertise, perioperative monitoring, supplementation with PTH or calcium and vitamin D, fluorescence technologies, contrast agents, autotransplantation or allotransplantation have been employed for its prevention and treatment. However, the current methodologies are insufficient for completely curing permanent hypoPT, which, once established, impairs quality of life indefinitely. This reality underscores the clinical imperative for a novel, effective treatment modality to manage intractable hypoPT cases, with organoid transplantation emerging as a promising frontier in the quest to address hypoparathyroidism. Palopegteriparatide has been approved for use in patients with hypoparathyroidism as a replacement for PTH therapy. Tracking its long-term clinical efficacy, adverse reactions, and economic impact would be meaningful.
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Correction note
This article has been corrected with minor changes. These changes do not impact the scientific content of the article.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
ReferencesBilezikianJPKhanAPottsJTJr.BrandiMLClarkeBLShobackD.
Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research. J Bone Miner Res. (2011) 26:2317–37. doi: 10.1002/jbmr.483, PMID: 21812031FanYBiRDensmoreMJSatoTKobayashiTYuanQ.
Parathyroid hormone 1 receptor is essential to induce FGF23 production and maintain systemic mineral ion homeostasis. FASEB J. (2016) 30:428–40. doi: 10.1096/fj.15-278184, PMID: 26428657CalviLMSimsNAHunzelmanJLKnightMCGiovannettiASaxtonJM.
Activated parathyroid hormone/parathyroid hormone-related protein receptor in osteoblastic cells differentially affects cortical and trabecular bone. J Clin Invest. (2001) 107:277–86. doi: 10.1172/JCI11296, PMID: 11160151SatoTCourbebaisseMIdeNFanYHanaiJIKaludjerovicJ.
Parathyroid hormone controls paracellular Ca(2+) transport in the thick ascending limb by regulating the tight-junction protein Claudin14. Proc Natl Acad Sci U.S.A. (2017) 114:E3344–53. doi: 10.1073/pnas.1616733114, PMID: 28373577RubinMRDempsterDWZhouHShaneENickolasTSlineyJJr..
Dynamic and structural properties of the skeleton in hypoparathyroidism. J Bone Miner Res. (2008) 23:2018–24. doi: 10.1359/jbmr.080803, PMID: 18684087NeerRMHolickMFDeLucaHFPottsJTJr.
Effects of 1alpha-hydroxy-vitamin D3 and 1,25-dihydroxy-vitamin D3 on calcium and phosphorus metabolism in hypoparathyroidism. Metabolism. (1975) 24:1403–13. doi: 10.1016/0026-0495(75)90055-4, PMID: 1196134CooperMSGittoesNJ.
Diagnosis and management of hypocalcaemia. BMJ. (2008) 336:1298–302. doi: 10.1136/bmj.39582.589433.BE, PMID: 18535072UnderbjergLSikjaerTMosekildeLRejnmarkL.
Postsurgical hypoparathyroidism--risk of fractures, psychiatric diseases, cancer, cataract, and infections. J Bone Miner Res. (2014) 29:2504–10. doi: 10.1002/jbmr.2273, PMID: 24806578GafniRICollinsMT.
Hypoparathyroidism. N Engl J Med. (2019) 380:1738–47. doi: 10.1056/NEJMcp1800213, PMID: 31042826LouridaIThompson-CoonJDickensCMSoniMKuzmaEKosK.
Parathyroid hormone, cognitive function and dementia: a systematic review. PloS One. (2015) 10:e0127574. doi: 10.1371/journal.pone.0127574, PMID: 26010883DettoriCRoncaFScaleseMSaponaroF.
Parathyroid hormone (PTH)-related peptides family: an intriguing role in the central nervous system. J Pers Med. (2023) 13:714. doi: 10.3390/jpm13050714, PMID: 37240884NussdorferGGBahceliogluMNeriGMalendowiczLK.
Secretin, glucagon, gastric inhibitory polypeptide, parathyroid hormone, and related peptides in the regulation of the hypothalamus- pituitary-adrenal axis. Peptides. (2000) 21:309–24. doi: 10.1016/s0196-9781(99)00193-x, PMID: 10764961ChenLXiongLYaoLPanJArzolaEZhuX.
Attenuation of Alzheimer’s brain pathology in 5XFAD mice by PTH(1-34), a peptide of parathyroid hormone. Alzheimers Res Ther. (2023) 15:53. doi: 10.1186/s13195-023-01202-z, PMID: 36918976WangLLChenDLeeJGuXAlaaeddineGLiJ.
Mobilization of endogenous bone marrow derived endothelial progenitor cells and therapeutic potential of parathyroid hormone after ischemic stroke in mice. PloS One. (2014) 9:e87284. doi: 10.1371/journal.pone.0087284, PMID: 24503654FreySFigueresLPattouFLe BrasMCaillardCMathonnetM.
Impact of permanent post-thyroidectomy hypoparathyroidism on self-evaluation of quality of life and voice: results from the national qoL-hypopara study. Ann Surg. (2021) 274:851–8. doi: 10.1097/SLA.0000000000005129, PMID: 34353986VokesT.
Quality of life in hypoparathyroidism. Bone. (2019) 120:542–7. doi: 10.1016/j.bone.2018.09.017, PMID: 30261328OrloffLAWisemanSMBernetVJFaheyTJ3rdShahaARShindoML.
American thyroid association statement on postoperative hypoparathyroidism: diagnosis, prevention, and management in adults. Thyroid. (2018) 28:830–41. doi: 10.1089/thy.2017.0309, PMID: 29848235SosaJAHannaJWRobinsonKALanmanRB.
Increases in thyroid nodule fine-needle aspirations, operations, and diagnoses of thyroid cancer in the United States. Surgery. (2013) 154:1420–6. doi: 10.1016/j.surg.2013.07.006, PMID: 24094448PriviteraFCentonzeDLa VigneraSCondorelliRADistefanoCGiocoR.
Risk factors for hypoparathyroidism after thyroid surgery: A single-center study. J Clin Med. (2023) 12:1956. doi: 10.3390/jcm12051956, PMID: 36902740NingKYuYZhengXLuoZJiaoZLiuX.
Risk factors of transient and permanent hypoparathyroidism after thyroidectomy: a systematic review and meta-analysis. Int J Surg. (2024) 110:5047–62. doi: 10.1097/JS9.0000000000001475, PMID: 38652139ClarkeBLBrownEMCollinsMTJuppnerHLakatosPLevineMA.
Epidemiology and diagnosis of hypoparathyroidism. J Clin Endocrinol Metab. (2016) 101:2284–99. doi: 10.1210/jc.2015-3908, PMID: 26943720KazaureHSSosaJA.
Surgical hypoparathyroidism. Endocrinol Metab Clin North Am. (2018) 47:783–96. doi: 10.1016/j.ecl.2018.07.005, PMID: 30390813BhattacharyyaNFriedMP.
Assessment of the morbidity and complications of total thyroidectomy. Arch Otolaryngol Head Neck Surg. (2002) 128:389–92. doi: 10.1001/archotol.128.4.389, PMID: 11926912EdafeOAntakiaRLaskarNUttleyLBalasubramanianSP.
Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia. Br J Surg. (2014) 101:307–20. doi: 10.1002/bjs.9384, PMID: 24402815ThomuschOMachensASekullaCUkkatJBrauckhoffMDralleH.
The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: a multivariate analysis of 5846 consecutive patients. Surgery. (2003) 133:180–5. doi: 10.1067/msy.2003.61, PMID: 12605179ShobackD.
Clinical practice. Hypoparathyroidism. N Engl J Med. (2008) 359:391–403. doi: 10.1056/NEJMcp0803050, PMID: 18650515KovalevaEVEremkinaAKKrupinovaJAMirnayaSSKimIVKuznetzovNS.
Review of clinical practice guidelines for hypoparathyroidism. Probl Endokrinol (Mosk). (2021) 67:68–83. doi: 10.14341/probl12800, PMID: 34533015PageCStrunskiV.
Parathyroid risk in total thyroidectomy for bilateral, benign, multinodular goitre: report of 351 surgical cases. J Laryngol Otol. (2007) 121:237–41. doi: 10.1017/S0022215106003501, PMID: 17054818Herranz Gonzalez-BotasJLourido PiedrahitaD.
Hypocalcaemia after total thyroidectomy: incidence, control and treatment. Acta Otorrinolaringol Esp. (2013) 64:102–7. doi: 10.1016/j.otorri.2012.09.001, PMID: 23122368BrancaJJVLascialfari BruschiAPiliaAMCarrinoDGuarnieriGGulisanoM.
The thyroid gland: A revision study on its vascularization and surgical implications. Med (Kaunas). (2022) 58:137. doi: 10.3390/medicina58010137, PMID: 35056445MilewskaKZielinskaNLabetowiczPSzewczykBPilewskiDMorysJ.
Morphological variability in thyroid gland vascularisation and its clinical significance. Folia Morphol (Warsz). (2025) 84:848–57. doi: 10.5603/fm.102714, PMID: 40810481JiangHShenHJiangDZhengXZhangWLuL.
Evaluating the safety of the Harmonic Scalpel around the recurrent laryngeal nerve. ANZ J Surg. (2010) 80:822–6. doi: 10.1111/j.1445-2197.2010.05436.x, PMID: 20969691JiangJShenMLuH.
Ultrasonic scalpel with knot tying protects parathyroid function for total thyroidectomy with central neck dissection. Gland Surg. (2020) 9:192–9. doi: 10.21037/gs.2020.01.12, PMID: 32420242AdamMAThomasSYoungwirthLHyslopTReedSDScheriRP.
Is there a minimum number of thyroidectomies a surgeon should perform to optimize patient outcomes? Ann Surg. (2017) 265:402–7. doi: 10.1097/SLA.0000000000001688, PMID: 28059969AnagnostisPPliakosIPanidisSChortiAStelmachVMichalopoulosA.
Should total thyroidectomies be performed by high-volume endocrine surgeons? A cost-effectiveness analysis. Endocrine. (2020) 67:131–5. doi: 10.1007/s12020-019-02087-5, PMID: 31541389HsuHWHuangSHLeeSHLinSTChenMYangRY.
Impact of intraoperative interventions on hypocalcemia post-total thyroidectomy: A meta-analysis. J Otolaryngol Head Neck Surg. (2025) 54:19160216251333355. doi: 10.1177/19160216251333355, PMID: 40285398ChangYKLangBHH.
To identify or not to identify parathyroid glands during total thyroidectomy. Gland Surg. (2017) 6:S20–9. doi: 10.21037/gs.2017.06.13, PMID: 29322019KahramangilBDipFBenmiloudFFalcoJde la FuenteMVernaS.
Detection of parathyroid autofluorescence using near-infrared imaging: A multicenter analysis of concordance between different surgeons. Ann Surg Oncol. (2018) 25:957–62. doi: 10.1245/s10434-018-6364-2, PMID: 29411199TabeiIFukeAFushimiATakeyamaH.
Determination of the optimum excitation wavelength for the parathyroid gland using a near-infrared camera. Front Surg. (2020) 7:619859. doi: 10.3389/fsurg.2020.619859, PMID: 33553239McWadeMAParasCWhiteLMPhayJESolorzanoCCBroomeJT.
Label-free intraoperative parathyroid localization with near-infrared autofluorescence imaging. J Clin Endocrinol Metab. (2014) 99:4574–80. doi: 10.1210/jc.2014-2503, PMID: 25148235FalcoJDipFQuadriPde la FuenteMRosenthalR.
Cutting edge in thyroid surgery: autofluorescence of parathyroid glands. J Am Coll Surg. (2016) 223:374–80. doi: 10.1016/j.jamcollsurg.2016.04.049, PMID: 27212004KoseERudinAVKahramangilBMooreEAydinHDonmezM.
Autofluorescence imaging of parathyroid glands: An assessment of potential indications. Surgery. (2020) 167:173–9. doi: 10.1016/j.surg.2019.04.072, PMID: 31526579BenmiloudFRebaudetSVaroquauxAPenarandaGBannierMDenizotA.
Impact of autofluorescence-based identification of parathyroids during total thyroidectomy on postoperative hypocalcemia: a before and after controlled study. Surgery. (2018) 163:23–30. doi: 10.1016/j.surg.2017.06.022, PMID: 29122325KahramangilBBerberE.
Comparison of indocyanine green fluorescence and parathyroid autofluorescence imaging in the identification of parathyroid glands during thyroidectomy. Gland Surg. (2017) 6:644–8. doi: 10.21037/gs.2017.09.04, PMID: 29302480DesmettreTDevoisselleJMMordonS.
Fluorescence properties and metabolic features of indocyanine green (ICG) as related to angiography. Surv Ophthalmol. (2000) 45:15–27. doi: 10.1016/s0039-6257(00)00123-5, PMID: 10946079Vidal FortunyJBelfontaliVSadowskiSMKarenovicsWGuigardSTriponezF.
Parathyroid gland angiography with indocyanine green fluorescence to predict parathyroid function after thyroid surgery. Br J Surg. (2016) 103:537–43. doi: 10.1002/bjs.10101, PMID: 26864909LuDPanBTangEYinSSunYYuanY.
Intraoperative strategies in identification and functional protection of parathyroid glands for patients with thyroidectomy: a systematic review and network meta-analysis. Int J Surg. (2024) 110:1723–34. doi: 10.1097/JS9.0000000000000991, PMID: 38079585YinSPanBYangZTangMMoHLiY.
Combined use of autofluorescence and indocyanine green fluorescence imaging in the identification and evaluation of parathyroid glands during total thyroidectomy: A randomized controlled trial. Front Endocrinol (Lausanne). (2022) 13:897797. doi: 10.3389/fendo.2022.897797, PMID: 35784544SoundSOkohAYigitbasHYaziciPBerberE.
Utility of indocyanine green fluorescence imaging for intraoperative localization in reoperative parathyroid surgery. Surg Innov. (2019) 26:774–9. doi: 10.1177/1553350615613450, PMID: 26508307SpartalisEGiannakodimosAAthanasiadisDIChrysikosDPaschouSASchizasD.
The potential role of carbon nanoparticles in lymph node tracing, recurrent laryngeal nerve identification and parathyroid preservation during thyroid surgery: A systematic review. Curr Pharm Des. (2021) 27:2505–11. doi: 10.2174/1381612826666200922154824, PMID: 32962609ChenYZhangSMiaoKLiJ.
Evaluating the effectiveness of dual dye combination of indocyanine green and carbon nanoparticles with parathyroid hormone test in preserving parathyroid gland during papillary thyroid cancer surgery: a single-center retrospective cohort study. Updates Surg. (2024) 76:1063–71. doi: 10.1007/s13304-024-01804-8, PMID: 38507176XueSRenPWangPChenG.
Short and long-term potential role of carbon nanoparticles in total thyroidectomy with central lymph node dissection. Sci Rep. (2018) 8:11936. doi: 10.1038/s41598-018-30299-8, PMID: 30093623LiWLiHTangYWuPZhouSSongX.
Application of the novel tracer mitoxantrone hydrochloride in lymph node visualization during lateral neck dissection for thyroid carcinoma. Front Endocrinol (Lausanne). (2025) 16:1712810. doi: 10.3389/fendo.2025.1712810, PMID: 41458548ChengXChenLZangHLiY.
The clinical application of mitoxantrone hydrochloride tracing in endoscopic radical resection of thyroid carcinoma. Sci Rep. (2025) 15:23352. doi: 10.1038/s41598-025-07289-8, PMID: 40603511ChenSHouXHuaSLiuZLiBLiX.
Mitoxantrone hydrochloride injection for tracing helps to decrease parathyroid gland resection and increase lymph node yield in thyroid cancer surgery: a randomized clinical trial. Am J Cancer Res. (2022) 12:4439–47.
Sitges-SerraARuizSGirventMManjonHDuenasJPSanchoJJ.
Outcome of protracted hypoparathyroidism after total thyroidectomy. Br J Surg. (2010) 97:1687–95. doi: 10.1002/bjs.7219, PMID: 20730856Lorente-PochLSanchoJJRuizSSitges-SerraA.
Importance of in situ preservation of parathyroid glands during total thyroidectomy. Br J Surg. (2015) 102:359–67. doi: 10.1002/bjs.9676, PMID: 25605285CiprianiCCianferottiL.
Vitamin D in hypoparathyroidism: insight into pathophysiology and perspectives in clinical practice. Endocrine. (2023) 81:216–22. doi: 10.1007/s12020-023-03354-2, PMID: 37000405Sitges-SerraA.
The PGRIS and parathyroid splinting concepts for the analysis and prognosis of protracted hypoparathyroidism. Gland Surg. (2017) 6:S86–93. doi: 10.21037/gs.2017.07.16, PMID: 29322026GoswamiRMilloTMishraSDasMKapoorMTomarN.
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) 99:1741–8. doi: 10.1210/jc.2013-3863, PMID: 24552219CusanoNERubinMRMcMahonDJZhangCIvesRTulleyA.
Therapy of hypoparathyroidism with PTH(1-84): a prospective four-year investigation of efficacy and safety. J Clin Endocrinol Metab. (2013) 98:137–44. doi: 10.1210/jc.2012-2984, PMID: 23162103MoriniECatalanoALascoAMorabitoNBenvengaS.
L-thyroxine malabsorption due to calcium carbonate impairs blood pressure, total cholesterolemia, and fasting glycemia. Endocrine. (2019) 64:284–92. doi: 10.1007/s12020-018-1798-7, PMID: 30368654SinghNSinghPNHershmanJM.
Effect of calcium carbonate on the absorption of levothyroxine. JAMA. (2000) 283:2822–5. doi: 10.1001/jama.283.21.2822, PMID: 10838651AbergerSSchreiberNPilzSEllerKRosenkranzARKirschAH.
Targeting calcitriol metabolism in acute vitamin D toxicity-A comprehensive review and clinical insight. Int J Mol Sci. (2024) 25:10003. doi: 10.3390/ijms251810003, PMID: 39337491AsifAFarooqN. Vitamin D Toxicity.
StatPearls (2025).
StackBCJr.BimstonDNBodennerDLBrettEMDralleHOrloffLA.
American association of clinical endocrinologists and american college of endocrinology disease state clinical review: postoperative hypoparathyroidism--definitions and management. Endocr Pract. (2015) 21:674–85. doi: 10.4158/EP14462.DSC, PMID: 26135962BrandiMLBilezikianJPShobackDBouillonRClarkeBLThakkerRV.
Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab. (2016) 101:2273–83. doi: 10.1210/jc.2015-3907, PMID: 26943719PorterRHCoxBGHeaneyDHostetterTHStinebaughBJSukiWN.
Treatment of hypoparathyroid patients with chlorthalidone. N Engl J Med. (1978) 298:577–81. doi: 10.1056/NEJM197803162981101, PMID: 628374RyanMP.
Magnesium and potassium-sparing diuretics. Magnesium. (1986) 5:282–92.
NairKSHoldawayIMEvansMCCameronAD.
Influence of magnesium on the secretion and action of parathyroid hormone. J Endocrinol Invest. (1979) 2:267–70. doi: 10.1007/BF03350414, PMID: 231063KhanAAAliDSBilezikianJPBjornsdottirSCollinsMTCusanoNE.
Best practice recommendations for the diagnosis and management of hypoparathyroidism. Metabolism. (2025) 171:156335. doi: 10.1016/j.metabol.2025.156335, PMID: 40581321JoletteJWilkerCESmithSYDoyleNHardistyJFMetcalfeAJ.
Defining a noncarcinogenic dose of recombinant human parathyroid hormone 1–84 in a 2-year study in Fischer 344 rats. Toxicol Pathol. (2006) 34:929–40. doi: 10.1080/01926230601072301, PMID: 17178693VahleJLSatoMLongGGYoungJKFrancisPCEngelhardtJA.
Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety. Toxicol Pathol. (2002) 30:312–21. doi: 10.1080/01926230252929882, PMID: 12051548KhanAARejnmarkLRubinMSchwarzPVokesTClarkeB.
PaTH forward: A randomized, double-blind, placebo-controlled phase 2 trial of transCon PTH in adult hypoparathyroidism. J Clin Endocrinol Metab. (2022) 107:e372–85. doi: 10.1210/clinem/dgab577, PMID: 34347093KarpfDBPihlSMouryaSMortensenEKovoorEMarkovaD.
A randomized double-blind placebo-controlled first-in-human phase 1 trial of transCon PTH in healthy adults. J Bone Miner Res. (2020) 35:1430–40. doi: 10.1002/jbmr.4016, PMID: 32212275ClarkeBLKay BergJFoxJCyranJALagastH.
Pharmacokinetics and pharmacodynamics of subcutaneous recombinant parathyroid hormone (1-84) in patients with hypoparathyroidism: an open-label, single-dose, phase I study. Clin Ther. (2014) 36:722–36. doi: 10.1016/j.clinthera.2014.04.001, PMID: 24802860KhanAARubinMRSchwarzPVokesTShobackDMGagnonC.
Efficacy and safety of parathyroid hormone replacement with transCon PTH in hypoparathyroidism: 26-week results from the phase 3 paTHway trial. J Bone Miner Res. (2023) 38:14–25. doi: 10.1002/jbmr.4726, PMID: 36271471MannstadtMClarkeBLVokesTBrandiMLRanganathLFraserWD.
Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study. Lancet Diabetes Endocrinol. (2013) 1:275–83. doi: 10.1016/S2213-8587(13)70106-2, PMID: 24622413GafniRILangmanCBGuthrieLCBrillanteBAJamesRYovetichNA.
Hypocitraturia is an untoward side effect of synthetic human parathyroid hormone (hPTH) 1–34 therapy in hypoparathyroidism that may increase renal morbidity. J Bone Miner Res. (2022) 37:818. doi: 10.1002/jbmr.4522, PMID: 35238087RejnmarkLGosmanovaEOKhanAAMakitaNImanishiYTakeuchiY.
Palopegteriparatide treatment improves renal function in adults with chronic hypoparathyroidism: 1-year results from the phase 3 paTHway trial. Adv Ther. (2024) 41:2500–18. doi: 10.1007/s12325-024-02843-8, PMID: 38691316ZhangQQuKPWangZSGaoJWZhangYPCaoWJ.
Clinical application of parathyroid autotransplantation in endoscopic radical resection of thyroid carcinoma. Front Oncol. (2022) 12:942488. doi: 10.3389/fonc.2022.942488, PMID: 35992841ChengXLiYChenL.
Efficacy of parathyroid autotransplantation in endoscopic total thyroidectomy with CLND. Front Endocrinol (Lausanne). (2023) 14:1193851. doi: 10.3389/fendo.2023.1193851, PMID: 37441504SenapatiAYoungAE.
Parathyroid autotransplantation. Br J Surg. (1990) 77:1171–4. doi: 10.1002/bjs.1800771027, PMID: 2224467DongZLiuWPengYZhanXSuYDiaoC.
Single inferior parathyroid autotransplantation during total thyroidectomy with bilateral central lymph node dissection for papillary thyroid carcinoma: a retrospective cohort study. World J Surg Oncol. (2023) 21:102. doi: 10.1186/s12957-023-02886-1, PMID: 36959661CarterWBUyKWardMDHoyingJB.
Parathyroid-induced angiogenesis is VEGF-dependent. Surgery. (2000) 128:458–64. doi: 10.1067/msy.2000.107102, PMID: 10965318GiulianiLCarmignaniGBelgranoEPuppoPRepettoUGiustiM.
Parathyroid autotransplantation. Eur Urol. (1981) 7:335–9. doi: 10.1159/000473259, PMID: 6793372WellsSAJr.FarndonJRDaleJKLeightGSDilleyWG.
Long-term evaluation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy and heterotopic autotransplantation. Ann Surg. (1980) 192:451–8. doi: 10.1097/00000658-198010000-00003, PMID: 7425691MalletteLEEisenbergKWilsonHNoonGP.
Generalized primary parathyroid hyperplasia: studies of the evolution of autogenous parathyroid graft function. Surgery. (1983) 93:254–9.
GongWXieYLinYMengZWangY.
Risk factors affecting graft survival after parathyroidectomy and parathyroid autotransplantation in patients on maintenance hemodialysis. Nan Fang Yi Ke Da Xue Xue Bao. (2021) 41:947–52. doi: 10.12122/j.issn.1673-4254.2021.06.20, PMID: 34238750KoimtzisGStefanopoulosLGeropoulosGPapavramidisT.
The outcomes of parathyroid gland autotransplantation during thyroid surgery: a systematic review, meta-analysis and trial sequential analysis. Endocrine. (2025) 87:27–38. doi: 10.1007/s12020-024-04011-y, PMID: 39182014AthanasopoulosPGKyriaziMArkadopoulosNDellaportasDMantaATheodosopoulosT.
Parathyroid autotransplantation in extensive head and neck resections: case series report. World J Surg Oncol. (2011) 9:149. doi: 10.1186/1477-7819-9-149, PMID: 22085420BarczynskiMCichonSKonturekACichonW.
Applicability of intraoperative parathyroid hormone assay during total thyroidectomy as a guide for the surgeon to selective parathyroid tissue autotransplantation. World J Surg. (2008) 32:822–8. doi: 10.1007/s00268-007-9405-8, PMID: 18246390MoffettJMSuliburkJ.
Parathyroid autotransplantation. Endocr Pract. (2011) 17 Suppl 1:83–9. doi: 10.4158/EP10377.RA, PMID: 21324813IorioOPetrozzaVDe GoriABononiMPortaNDe TomaG.
Parathyroid Autotransplantation During thyroid Surgery. Where we are? A Systematic Review on Indications and Results. J Invest Surg. (2019) 32:594–601. doi: 10.1080/08941939.2018.1441344, PMID: 29658811KrauszMMAshkenaziIAlficiR.
Parathyroid autotransplantation in adults and children. Harefuah. (2017) 156:167–70.
HerreraMGrantCvan HeerdenJAFitzpatrickLA.
Parathyroid autotransplantation. Arch Surg. (1992) 127:825–9. doi: 10.1001/archsurg.1992.01420070089017, PMID: 1524483LoCYLamKY.
Postoperative hypocalcemia in patients who did or did not undergo parathyroid autotransplantation during thyroidectomy: a comparative study. Surgery. (1998) 124:1081–6. doi: 10.1067/msy.1998.92560, PMID: 9854587TartagliaFBlasiSGiulianiAMerolaRLivadotiGKrizzukD.
Parathyroid autotransplantation during total thyroidectomy. Results of a retrospective study. Int J Surg. (2016) 28 Suppl 1:S79–83. doi: 10.1016/j.ijsu.2015.05.059, PMID: 26708849YuanHZhongZLiuZYeQ.
Factors influencing the success of cryopreserved parathyroid autotransplantation: A systematic review. Asian J Surg. (2023) 46:3426–3431. doi: 10.1016/j.asjsur.2023.04.032, PMID: 37105818ZhangDGaoLHeGChenJFangL.
Predictors of graft function after parathyroid autotransplantation during thyroid surgery. Head Neck. (2018) 40:2476–81. doi: 10.1002/hed.25371, PMID: 30102831RichardsBAVierkantRADyBMFosterTRMcKenzieTJLydenML.
Intraoperative parathyroid hormone monitoring is of limited usefulness in guiding autotransplantation in reoperative or subtotal parathyroidectomy for primary hyperparathyroidism. Am Surg. (2023), 89:31348231156758. doi: 10.1177/00031348231156758, PMID: 36786277Lorente-PochLSanchoJMunozJLGallego-OtaeguiLMartinez-RuizCSitges-SerraA.
Failure of fragmented parathyroid gland autotransplantation to prevent permanent hypoparathyroidism after total thyroidectomy. Langenbecks Arch Surg. (2017) 402:281–7. doi: 10.1007/s00423-016-1548-3, PMID: 28064342PalazzoFFSywakMSSidhuSBBarracloughBHDelbridgeLW.
Parathyroid autotransplantation during total thyroidectomy--does the number of glands transplanted affect outcome? World J Surg. (2005) 29:629–31. doi: 10.1007/s00268-005-7729-9, PMID: 15827848QiuYFeiYXingZZhuJLuoYSuA.
Does the number of autotransplanted parathyroid glands affect postoperative hypoparathyroidism and serum parathyroid hormone levels? Asian J Surg. (2022) 45:117–24. doi: 10.1016/j.asjsur.2021.03.031, PMID: 33863630MihaiRThakkerRV.
MANAGEMENT OF ENDOCRINE DISEASE: Postsurgical hypoparathyroidism: current treatments and future prospects for parathyroid allotransplantation. Eur J Endocrinol. (2021) 184:R165–75. doi: 10.1530/EJE-20-1367, PMID: 33599211YaoCZIshizukaJTownsendCMJr.ThompsonJC.
Successful intracerebroventricular allotransplantation of parathyroid tissue in rats without immunosuppression. Transplantation. (1993) 55:251–3. doi: 10.1097/00007890-199302000-00003, PMID: 8434371AysanEKilicUGokOAltugBErcanCKesgin TokaC.
Parathyroid allotransplant for persistent hypocalcaemia: A new technique involving short-term culture. Exp Clin Transplant. (2016) 14:238–41. doi: 10.6002/ect.2014.0110, PMID: 25476143NawrotIWozniewiczBTolloczkoTSawickiAGorskiAChudzinskiW.
Allotransplantation of cultured parathyroid progenitor cells without immunosuppression: clinical results. Transplantation. (2007) 83:734–40. doi: 10.1097/01.tp.0000258601.17505.9d, PMID: 17414706LeeMKBaeYH.
Cell transplantation for endocrine disorders. Adv Drug Delivery Rev. (2000) 42:103–20. doi: 10.1016/s0169-409x(00)00056-9, PMID: 10942817NiuZHuangSGaoWYinGGuoWHuangJ.
Promotion of allogeneic parathyroid cell transplantation in rats with hypoparathyroidism. Gland Surg. (2021) 10:3403–14. doi: 10.21037/gs-21-809, PMID: 35070900CabanePGacPAmatJPinedaPRossiRCaviedesR.
Allotransplant of microencapsulated parathyroid tissue in severe postsurgical hypoparathyroidism: a case report. Transplant Proc. (2009) 41:3879–83. doi: 10.1016/j.transproceed.2009.06.211, PMID: 19917405MuruaAPorteroAOriveGHernandezRMde CastroMPedrazJL.
Cell microencapsulation technology: towards clinical application. J Control Release. (2008) 132:76–83. doi: 10.1016/j.jconrel.2008.08.010, PMID: 18789985TakebeTWellsJM.
Organoids by design. Science. (2019) 364:956–9. doi: 10.1126/science.aaw7567, PMID: 31171692NantasantiSde BruinARothuizenJPenningLCSchotanusBA.
Concise review: organoids are a powerful tool for the study of liver disease and personalized treatment design in humans and animals. Stem Cells Transl Med. (2016) 5:325–30. doi: 10.5966/sctm.2015-0152, PMID: 26798060CleversH.
Modeling development and disease with organoids. Cell. (2016) 165:1586–97. doi: 10.1016/j.cell.2016.05.082, PMID: 27315476WaldowABeierLSArndtJSchallenbergSVollbrechtCBischoffP.
cCPE fusion proteins as molecular probes to detect claudins and tight junction dysregulation in gastrointestinal cell lines, tissue explants and patient-derived organoids. Pharmaceutics. (2023) 15:1980. doi: 10.3390/pharmaceutics15071980, PMID: 37514167WuYHChaoHSChiangCLLuoYHChiuCHYenSH.
Personalized cancer avatars for patients with thymic Malignancies: A pilot study with circulating tumor cell-derived organoids. Thorac Cancer. (2023) 14:2591–2600. doi: 10.1111/1759-7714.15039, PMID: 37474689TsuchidaTMurataSMatsukiKMoriAMatsuoMMikamiS.
The regenerative effect of portal vein injection of liver organoids by retrorsine/partial hepatectomy in rats. Int J Mol Sci. (2019) 21:178. doi: 10.3390/ijms21010178, PMID: 31887985ZhangRRKoidoMTadokoroTOuchiRMatsunoTUenoY.
Human iPSC-derived posterior gut progenitors are expandable and capable of forming gut and liver organoids. Stem Cell Rep. (2018) 10:780–93. doi: 10.1016/j.stemcr.2018.01.006, PMID: 29429958RezaHAOkabeRTakebeT.
Organoid transplant approaches for the liver. Transpl Int. (2021) 34:2031–45. doi: 10.1111/tri.14128, PMID: 34614263WatanabeSOgasawaraNKobayashiSKirinoSInoueMHiraguriY.
Organoids transplantation as a new modality to design epithelial signature to create a membrane-protective sulfomucin-enriched segment. J Gastroenterol. (2023) 58:379–93. doi: 10.1007/s00535-023-01959-y, PMID: 36745238KurmannAASerraMHawkinsFRankinSAMoriMAstapovaI.
Regeneration of thyroid function by transplantation of differentiated pluripotent stem cells. Cell Stem Cell. (2015) 17:527–42. doi: 10.1016/j.stem.2015.09.004, PMID: 26593959BinghamELChengSPWoods IgnatoskiKMDohertyGM.
Differentiation of human embryonic stem cells to a parathyroid-like phenotype. Stem Cells Dev. (2009) 18:1071–80. doi: 10.1089/scd.2008.0337, PMID: 19025488JeonSLeeYSOhSRJeongJLeeDHSoKH.
Recent advances in endocrine organoids for therapeutic application. Adv Drug Delivery Rev. (2023) 199:114959. doi: 10.1016/j.addr.2023.114959, PMID: 37301512ChenXSunJLiX.
Adipose derived stem cells to construct parathyroid organoid for hypoparathyroidism. Med Hypotheses. (2021) 149:110540. doi: 10.1016/j.mehy.2021.110540, PMID: 33618246NoltesMESondorpLHJKrachtLAntunesIFWardenaarRKelderW.
Patient-derived parathyroid organoids as a tracer and drug-screening application model. Stem Cell Rep. (2022) 17:2518–30. doi: 10.1016/j.stemcr.2022.09.015, PMID: 36306782BaregamianNSekharKRKrystofiakESVinogradovaMThomasGMannohE.
Engineering functional 3-dimensional patient-derived endocrine organoids for broad multiplatform applications. Surgery. (2023) 173:67–75. doi: 10.1016/j.surg.2022.09.027, PMID: 36400581SekharKRCodreanuSGWilliamsOCRathmellJCRathmellWKMcLeanJA.
Metabolism of parathyroid organoids. Front Endocrinol (Lausanne). (2023) 14:1223312. doi: 10.3389/fendo.2023.1223312, PMID: 37492197WangGDuYCuiXXuTLiHDongM.
Directed differentiation of human embryonic stem cells into parathyroid cells and establishment of parathyroid organoids. Cell Prolif. (2024) 57:e13634. doi: 10.1111/cpr.13634, PMID: 38494923Senkal-TurhanSBulut-OkumusEAydinMBasak TurkmenNTaslidereASahinF.
Induced pluripotent stem cell-derived parathyroid organoids resemble parathyroid morphology and function. Adv Sci (Weinh). (2024) 11:e2407567. doi: 10.1002/advs.202407567, PMID: 39331961
Edited by: Frederic Triponez, Hôpitaux universitaires de Genève (HUG), Switzerland
Reviewed by: Pichit Sittitrai, Chiang Mai University, Thailand
Samuel Frey, Centre Hospitalier Universitaire (CHU) de Nantes, France