MANAGEMENT OF ENDOCRINE DISEASE: Postsurgical hypoparathyroidism: current treatments and future prospects for parathyroid allotransplantation

in European Journal of Endocrinology
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  • 1 Department of Endocrine Surgery, Churchill Cancer Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, Oxfordshire, UK
  • 2 Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK

Correspondence should be addressed to R Mihai; Email: radumihai@doctors.org.uk

Background

Permanent postsurgical hypoparathyroidism (POSH) is a major complication of anterior neck surgery in general and of thyroid surgery in particular. Depending on diagnostic criteria, up to 10% of patients undergoing bilateral thyroid surgery develop POSH. This leads to a multitude of symptoms that decrease the quality of life and burden the healthcare provision through complex needs for medication and treatment of specific complications, such as seizures and laryngospasm.

Methods

Narrative review of current medical treatments for POSH and of the experience accumulated with parathyroid allotransplantation.

Results

In most patients, POSH is controlled with regular use of calcium supplements and active vitamin D analogues but a significant proportion of patients continue to experience severe symptoms requiring repeated emergency admissions. Replacement therapy with synthetic PTH compounds (PTH1-34, Natpara® and PTH1-84, teriparatide, Forsteo®) has been assessed in multicentre trials, but the use of this medication is restricted by costs and concerns related to the risk of development of osteosarcoma. Based on recent case reports of successful allotransplantation of parathyroid tissue between siblings, there is renewed interest in this technique. Data on selection of donors, parathyroid cell preparation before allotransplantation, site and timing of transplantation, need for immunosuppression and long-term outcomes are reviewed.

Conclusion

A prospective trial to assess the efficacy of parathyroid allotransplantation in patients with severely symptomatic protracted post-surgical hypoparathyroidism is warranted.

Abstract

Background

Permanent postsurgical hypoparathyroidism (POSH) is a major complication of anterior neck surgery in general and of thyroid surgery in particular. Depending on diagnostic criteria, up to 10% of patients undergoing bilateral thyroid surgery develop POSH. This leads to a multitude of symptoms that decrease the quality of life and burden the healthcare provision through complex needs for medication and treatment of specific complications, such as seizures and laryngospasm.

Methods

Narrative review of current medical treatments for POSH and of the experience accumulated with parathyroid allotransplantation.

Results

In most patients, POSH is controlled with regular use of calcium supplements and active vitamin D analogues but a significant proportion of patients continue to experience severe symptoms requiring repeated emergency admissions. Replacement therapy with synthetic PTH compounds (PTH1-34, Natpara® and PTH1-84, teriparatide, Forsteo®) has been assessed in multicentre trials, but the use of this medication is restricted by costs and concerns related to the risk of development of osteosarcoma. Based on recent case reports of successful allotransplantation of parathyroid tissue between siblings, there is renewed interest in this technique. Data on selection of donors, parathyroid cell preparation before allotransplantation, site and timing of transplantation, need for immunosuppression and long-term outcomes are reviewed.

Conclusion

A prospective trial to assess the efficacy of parathyroid allotransplantation in patients with severely symptomatic protracted post-surgical hypoparathyroidism is warranted.

Introduction

When Albert, a 34 years old man with multiple recent fractures, was admitted under the care of Dr Felix Mandle in Vienna in early 1920s, the initial working diagnosis was an insufficiency of the parathyroid gland function. A victim of a tram accident was used as donor, and Albert received the first recorded allotransplant of parathyroid glands. When it became apparent that this procedure had no clinical impact, Dr Mandle decided to explore Albert’s neck and this first successful parathyroidectomy started the history of parathyroid surgery (1). Currently, parathyroid surgery for primary hyperparathyroidism is one of the most common endocrine operations. It could be that in a further decade parathyroid allotransplantation (PTalloT) will become part of the surgical practice.

This paper is a narrative review of current therapeutic options for hypoparathyroidism and aims to create the background for a potential clinical trial exploring the role of allotransplantation in patients with severely symptomatic refractory hypoparathyroidism.

Causes of postsurgical hypoparathyroidism (hypoPT)

Hypoparathyroidism (hypoPT) is defined as low serum calcium levels in the presence of inappropriately low/absent PTH levels. The condition is divided into primary hypoPT due to intrinsic genetic and autoimmune defects within the parathyroid glands, and the much more common secondary/acquired hypoPT due to impaired parathyroid function.

The vast majority of cases of secondary hypoPT are represented by postsurgical hypoPT (POSH), caused by intraoperative injury to the parathyroid glands through compromising vascular supply, thermic injury or inadvertent excision. It is rare to encounter patients with secondary hypoPT caused by rare infiltrative disorders (e.g. iron/copper overload) or by ionising radiation exposure (2).

Bilateral thyroid surgery is the cause of POSH in over 80% of patients. About 10–15% of POSH cases occur after parathyroid surgery. Radical resection of laryngeal tumours is a rare cause of POSH (under 5% of cases). The risk of POSH after thyroid surgery is influenced by several operative factors. High surgical volume (3, 4), routine parathyroid identification and in situ preservation of parathyroid glands (5) are all reducing the risk of POSH. In contrast, longer operations, reoperation for bleeding, the need for associated central compartment lymph node dissection and the routine use of parathyroid autotransplantation (6) increase the risk of POSH. It is expected that the intraoperative use of (auto)fluorescence for identification of parathyroid glands and for assessment of their vascular supply can reduce the risk of POSH (7).

Epidemiology of postsurgical hypoPT

The reported incidence of POSH varies widely because different definitions are used (e.g. calcium levels under the lower limit of the normal range, or symptomatic hypocalcaemia, or low PTH levels within 4 h or within 24 h after the operation). Similarly, permanent hypoPT is diagnosed after full biochemical reassessment at 6 or 12 months after the operation, and patients who take calcium/vitamin D supplements for other indications (e.g. osteoporosis) are not always excluded in large population studies.

Transient POSH is estimated to occur in 25–80% of patients after neck surgery, whereas permanent POSH, defined as lasting more than 6 months, is estimated to occur in up to 5% of cases (discussed in (2)). The most recent report on the incidence of POSH is based on analysis of 7852 patients who underwent a total thyroidectomy in Sweden from 2005 to 2015. Permanent hypoPT was defined as treatment with calcium and/or active vitamin D for more than 1 year after surgery and based on this definition, 938 patients (12.5%) developed POSH. In a multivariable analysis, there was a higher risk of POSH among women, patients over the age of 60 years, patients who underwent parathyroid autotransplantation and those operated in centers with a volume of <100 thyroidectomies per year. Surgeons might not be aware of most of these cases as their self-reported data from the quality register only identified 178 of these 938 patients with POSH (4).

Using data from the Danish National Patient Registry, the prevalence of POSH was estimated as 22/100 000 (discussed in (2)). On the background of the constantly increasing number of thyroid operations performed worldwide, the prevalence of POSH is likely to increase in future decades.

Consequences of postsurgical hypoPT

Recently, the Hypoparathyroidism Patient Experience Scale-Symptom has been developed as a specific tool for patient-reported outcomes in hypoPT (8). One hundred per cent of the concept elicitation patient group experienced physical symptoms attributed to hypoPT, such as tingling, numbness and paresthesia (88%), muscle cramps (86%), physical fatigue (83%), cognitive dysfunction (86%), impaired memory (57%), impaired ability to have a conversation (50%), and a lack of concentration/focus (43%). A total of 17 major signs and symptoms were identified during item generation and these led to the 17-item scoring system (8). The validity of this questionnaire should now be tested in large cohorts.

In our own survey of 252 members of the HypoPara UK (now ParathyroidUK) patient support group, the highest scores for severity of symptoms were 4.8 ± 1.8 for fatigue, and 4.5 ± 1.9 for low sense of well-being. Only 4% of patients never experienced fatigue or numbness/tingling sensations, while 30–35% experienced these symptoms almost all the time. In addition, 149 patients listed a myriad of associated symptoms rarely described in literature (9).

The burden of the disease on individual patients extends to their carers, and this amplifies the impact on health services. In a study of 398 patients with chronic hypoPT not adequately controlled on conventional therapy and 207 caregivers, caregivers’ burden increased with patients’ self-rated symptom severity (10).

Interestingly, the majority of patients are still experiencing symptomatic hypocalcaemia despite regular use of medication and this impacts even more on their quality of life (9). A recent population study of 374 adult patients with hypoPT showed that 75% of sufferers experienced symptoms despite treatment and 79% had required emergency department or hospital admissions (11). This mirrors the results of our survey of HypoPara UK patients, where 93% of responders reported that they required emergency admission to hospital within the last 6 months (9).

In addition to their impaired QoL, patients with hypoPT experience significant long-term morbidity including cataracts, epilepsy and soft tissue calcification. A study of 239 patients with permanent hypoPT identified from the Scandinavian Quality Register for Thyroid, Parathyroid, and Adrenal Surgery found that after a mean follow-up of 4.5 years they had an increased risk for renal insufficiency (HR: 4.88), for any malignancy (HR: 2.15) and for cardiovascular events (HR: 1.88) (12). Using the same registry data it was found that the risk of death was significantly higher among patients with permanent hypoPT after total thyroidectomy (HR: 2.09, 95% CI: 1.04–4.20) (13).

Current management of post-surgical hypoPT

In the short term, the goals of medical therapy are to reduce symptoms, hospital stay and readmissions, while in the long term, the treatment aims to improve the QoL and reduce the morbidity. Recent European guidelines highlight some of the difficulties in the management of these patients (14). Several medical therapeutic options exist:

1. Oral calcium and vitamin D supplementation represent the standard treatment of hypoPT. The most cost-effective approach is to prescribe routine calcium supplements to all patients for 4–6 weeks after bilateral thyroid surgery before reassessing parathyroid function and decide on long-term management. In a meta-analysis of 15 studies with 3037 patients, routine supplementation with calcium + vitamin D3 offered a lower risk of symptomatic (risk difference (RD) −0.25) and biochemical (RD -0.24) hypocalcaemia than treatment based on measurement of calcium levels. The number needed to treat was 4 (95% CI: 3–6) for symptomatic hypocalcaemia (15). This strategy has been labelled as ‘parathyroid splinting’ by researchers in Barcelona, who hypothesised that the recovery of parathyroid function is more likely after a period of intense medical treatment (16).

Historically, most surgeons preferred to monitor calcium levels during in-hospital admission and to select patients who are given calcium supplements based on their symptoms, their slope of calcium changes and/or the dynamic of their PTH levels. Currently, early measurement of PTH in the postoperative period is widely accepted as the best way to identify patients at risk of hypocalcemia following total thyroidectomy (reviewed in (6)). In this way prophylactic calcium and Vitamin D replacement can be initiated early in the postoperative period, reducing the incidence of symptomatic hypocalcemia and avoiding prolonged length of hospital stay.

Daily doses of up to 1200–2000 mg calcium are recommended and this requires regular calcium measurements. Alfacalcidol (1-Alpha-Hydroxycholecalciferol), a vitamin D analogue, is routinely included in the medication of patients with POSH in a dose of 1–3 µg/day. Calcitriol (Rocaltrol®, 1,25(OH)2 vitamin D), is the synthetic physiologically-active analogue of vitamin D, and is administered orally at an initial dose of 250 ng daily, and then adjusted up to the usual dose of 0.5–1 µg/day. While Alfacalcidol is used more in the UK, Rocaltrol is used more widely in the USA.

2. Synthetic PTH would be the ideal replacement for a hormonal failure, but this medication is not widely available nor routinely used. The drug was accepted for use by the Food and Drug Administration (FDA), USA in 2015 and in the EU in 2017. Both PTH(1-34) or PTH(1-84) improve the bone-remodelling dynamics (17) and the physical and mental functioning (18).

Importantly, PTH(1-34) cannot be discontinued abruptly, as this could lead to severe hypocalcemia and patients have to be slowly weaned over several weeks (19). A further downside of PTH replacement is that it requires daily injections. PTH(1-34) delivered by insulin pump, represents an important advance in the management of hypoPT that has been used in adults and children and proven to achieve a physiological biochemical profile (20, 21).

Two recent developments in this field might make this treatment more ‘user-friendly’. The first is the possibility of delivering teriparatide orally, using nanoemulsion (22). The second is the use of a chemical derivative (TransCon PTH) that is a sustained-release, essentially inactive prodrug transiently bound to an inert carrier, designed to release PTH(1-34). In a phase 1, randomised, placebo-controlled study TransCon PTH administered to healthy adults was generally well tolerated and free PTH demonstrated an effective half-life of approximately 60 h. Based on these data the drug will advance into phase 2 clinical development (23).

The long-term benefits of synthetic PTH have not yet been demonstrated and its safety profile is not fully established. A risk of osteosarcoma was reported in rats but, thus far, skeletal malignancies have not been described by clinical trials in humans (24). Nevertheless, the most recent guidance on FORTEO® (teriparatide) from FDA, USA (August 2013, https://www.fda.gov/media/77492/download) informs healthcare providers of the 2-year maximum lifetime duration of treatment and prohibits its use in children and young adults whose bones are still growing. Furthermore, the FDA Adverse Event Reporting System listed cutaneous calcification and calciphylaxis (https://www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/january-march-2019-potential-signals-serious-risksnew-safety-information-identified-fda-adverse).

Cost analysis of current medication regimes

In a population-based study from Minnesota, USA the yearly cost of medical care for patients with hypoPT was estimated to be about three times that for healthy patients (2). This however might be a significant underestimate, as the study did not quantify the costs related to utilisation of outpatient clinics, hospitals, emergency departments, or pharmacies, nor the likely costs related to hospitalisation for acute complications of hypoPT.

As a simplified financial model some calculate only the costs related to daily medication. Calcium supplements are cheap and can be bought over the counter. Calchichew (1 gr calcium carbonate two-three times daily for 4 weeks) is approx. £10. Vitamin D supplements (alfacalcidol: 1 µg/day for 1 month) costs under £10. Average retail price for calcitriol (100 capsules, 250 µg) in USA is $35. PTH 1-34 (teriparatide, Forsteo®) is not licensed for use in hypoPT but could be obtained on named patient basis. It is dispensed as a 2.4 mL pre-filled pen (equivalent of 20 µg/day) and it costs £326. PTH 1-84 (Natpara®) is currently used in the ‘BALANCE’ study (https://clinicaltrials.gov/ct2/show/NCT03324880) and is available as multiple-dose cartridge containing different dosage strengths (25–100 µg/dose). The cost of the drug in UK is not available, but the price on the European continent is in the region of £6500 for 28 doses.

Parathyroid transplantation

As part of routine surgical practice, parathyroid glands that are recognised to have been inadvertently removed are reimplanted during the same procedure into a muscle pocket, with the expectation that they will regain vascular supply and subsequently will maintain their secretory function. The procedure is called autotransplantation, as the patient’s own tissue is transplanted.

In contrast, when discussing other procedures of replacing a deficient organ, such as a kidney transplant or a heart-lung transplant, one refers to using an organ retrieved from another individual (the donor) being reimplanted surgically in a patient (the recipient). The term used to describe this process is allotransplantation. This relies on using a potentially large source of transplantable organs through a rigorous selection process of the donors followed by strict matching with the recipient, based on HLA and blood-groups. The main downside of allotransplantation is the need for life-long immunosuppression medication.

Parathyroid autotransplantation

One of pioneers of thyroid surgery, Dr Frank Lahey, first performed parathyroid autotransplantation during a thyroidectomy in 1926.

When one (or more) parathyroid gland(s) are inadvertently removed with the thyroid specimen, the need/benefit of autotransplantation is easily accepted. A more difficult scenario is to decide on autotransplantation of a gland deemed devascularised. With increasing surgical experience, one expects to be able to recognise when the blood supply has been compromised and the gland is nonviable, hence the decision of autotransplanting could be justified. More recently, the intraoperative use of autofluorescence with ICG (indocyanine green) has been to assess perfusion of parathyroid glands at the end of the operation. In a study including 196 patients, 11 of the 50 patients in whom no well-perfused parathyroid gland could be identified by angiography, presented with hypoparathyroidism on POD 1, and six on POD 10–15 (7). In their experience, ICG angiography reliably predicts the vascularisation of the parathyroid glands and obviates the need for postoperative measurement of calcium and PTH, and supplementation with calcium in patients with at least one well-perfused parathyroid gland. Whether these findings from the enthusiastic group in Geneva who were early-adopters of this technology could be replicated in other units remains to be determined in future years.

The preferred site for autotransplantation is the sternocleidomastoid muscle. Similar outcomes are expected if re-implantation is performed in the forearm as this has the added benefit of easier monitoring of graft function.

The technique used for autotransplantation is based on personal experience, with a choice between reimplanting 10–20 small slices/fragments of the gland (as described by Wells (25)) or injection of a suspension of parathyroid tissue in buffered saline (26). When performed, it is thought to be associated with a transient hypoPT but a subsequent reduction in rates of permanent hypoPT (26).

Parathyroid allotransplantation

Recently, parathyroid allotransplantation (PTalloT) has been increasingly discussed as a possible treatment for patients with POSH, after hopes were raised by a case report of a 32-year-old female with intractable hypoPT who underwent successful PTalloT (27).

There are no registered clinical trials involving PTalloT. The topics explored by recent and ongoing trials on hypoPT are summarised in Table 1. Intriguingly, the PARADIGM study from University of California (Pancreatic Islets and Parathyroid Gland Co-transplantation for Treatment of Type 1 Diabetes, ClinicalTrials.gov Identifier: NCT03977662, registered in 2019), aims to assess the effectiveness of co-transplantation of allogeneic parathyroid cells with adult pancreatic islets. The hypothesis explored is that the parathyroid glands, a richly vascularised organ that can be transplanted routinely in the muscle, can provide the CD34+ vascular endothelial progenitor cells that reside within PTG, and such cells will induce neoangiogenesis and promote islet engraftment and survival when co-transplanted with the pancreatic islets.

Table 1

Topics addressed by studies on hypoparathyroidism identified on clinicaltrials.gov registry (accessed on 1 May 2020).

TopicNumber of studies
Epidemiology of hypoPT5
Use of synthetic PTH as treatment for hypoPT26
Techniques for reducing the incidence of post-thyroidectomy hypoPT14
Care of patients with genetic syndromes associated with hypoPT30

Several factors have to be considered when planning PTalloT:

1. Selection of donors of parathyroid tissue

  • Living donors: A case report from the Regensburg, Germany, described a 32-year-old female who underwent a living-donor allotransplantation of two healthy parathyroid glands from her brother (27). Similarly, parathyroid tissue was retrieved as a simultaneous additional surgical procedure during donor nephrectomy and transplanted into the same patient (28, 29).
  • Brain-dead donors: A single case report from Antwerp, Belgium, described a woman with terminal renal failure and a previous total parathyroidectomy who underwent combined kidney/parathyroid transplantation from a brain-dead donor (30).
  • Hyperplastic gland(s) from patients with secondary hyperparathyroidism is the most common source of viable parathyroid tissue for transplantation reported to date. Because multigland hyperplasia is a physiological response to the biochemical abnormalities triggered by chronic renal failure, it is postulated that such glands should return to normal function once successfully transplanted in a patient with normal renal function.
  • Adenomatous glands from patients with primary hyperparathyroidism (PHPT): The first case report was published over three decades ago (31). This option is attractive, because of the large number of potential donors. Many patients with PHPT have minimally raised calcium levels and their set-point for the calcium-PTH curve is only minimally shifted to the right by the monoclonal expansion of parathyroid cells with abnormal expression of the calcium-sensing receptor (CaSR). Such cells could represent a reasonable source of cells if the donor had an adenoma with a setpoint close to upper range of normal calcium levels. Reassuringly, xenografts from parathyroid adenomas into rabbits showed no histological changes during follow-up without any reported malignant transformation (32) but such data is yet to be published for allografts.This approach raises concerns that a successful allotransplantation could induce hyperparathyroidism (and its associated morbidity) in a patient previously suffering with hypoparathyroidism. This has not been reported and the risk could be mitigated by using parathyroid adenomas with a calcium threshold close to normal (i.e. donors with calcium levels just above normal range). Furthermore, if hyperparathyroidism becomes more distressing than the initial hypoparathyroidism, patients could have the graft removed.
  • Parathyroid-like cells derived from human embryonic stem cell lines would be optimal for cellular replacement, as each cell contains the complete functions of the organ, and parathyroid cells do not have requirement for an architectural structure for their function (33). Future progress in this field could make allotransplantation a very attractive option but at this point such cells are not available.

2. Parathyroid cell preparation before allotransplantation

Critical to preserving parathyroid function after PTalloT is ensuring a reasonable cell yield and maintaining the viability of the cells. Several solutions have been explored.

University Of Wisconsin solution is commonly used. For example, some reported successful transplantation with cold ischemia time of 14 h (30).

Parathyroid transport solution reported from Bezmialem Vakif University, Istanbul, Turkey, was designed specifically for parathyroid tissue transplantation. This has a pending patent and is reported to support cellular viability and PTH release and to protect CaSR functionality for up to 24 h of cold ischaemia (34).

Microencapsulation of parathyroid tissue is a technique based on protecting the tissue to be transplanted from the immunologic response by coating it with a semipermeable membrane. This could allow allotransplantation without immunosuppression (35).

In a report from the University of Chile, commercial sodium alginate was used for microencapsulation and the graft functioned for at least 20 months (36). At the Bezmialem Vakif University, Istanbul, Turkey, microencapsulation of cultured parathyroid cells was performed with ultrapure alginate and spheroids were generated with calcium chloride. Microencapsulated parathyroid cells showed the functionality for more than 1 year (37). At the University of Wurzburg, Germany, tissue particles and single cells/cell clusters were microencapsulated with amitogenic Ba(2+) alginate. Preoperative evaluation of microencapsulated parathyroid tissue revealed differences in function and thus facilitated selection of the optimal bioartifical graft for human PTalloT (38).

Thermoreversible gel made of polyethyleneglycol-polyalanine-co-phenylalanine (PEG-PAF) (sol form at 4°C, gel form at 37°C) was manufactured by researchers at the Hallym University, Chuncheon, Korea. On day 70, the PTH level was restored by just over 50% and histology confirmed the successful transplantation of parathyroid tissues (39).

Macrocapsule containing 20–30 × 106 parathyroid cells was constructed by researchers in Minsk, Belarus using polyvinylidine difluoride and implanted into the deep femoral artery followed by at least 3 months of functional activity (40). No other group has replicated this technique.

3. Site of transplantation

The commonly used method is injection into the left deltoid muscles (41) and forearm muscles (27), but some centres used laparoscopic transplantation in the omental tissue (37). In animal models, the thymus (42) and the adrenal glands (43) appear to be a privileged sites for PTalloT, but these experimental data would have limited clinical applicability.

4. Timing of transplantation

The initial paper, published in 1996 from the Medical Academy, Warsaw, Poland, described allotransplantation after culturing of cells (44). In that report, 85 patients underwent 116 allotransplantations of cultured parathyroid cells. After 6 weeks of cultivation and freezing, the parathyroid cells decreased their normal HLA (HLA) class I ABC expression and were free of HLA class II positive cells. The viability of cultured cells was 95%. In 64 patients the allografts retained their endocrine function for more than 2 months (45).

In a more recent report, the parathyroid glands resected from the living donors with secondary hyperparathyroidism were fragmented quickly in the operation room before being injected into the left deltoid muscles of the two recipients (41).

5. Impact of HLA typing on success of parathyroid allotransplantation

Surprisingly, HLA-matching might not be significant for successful PTalloT. Only one study evaluated the role of extensive immunological tests before PTalloT. Four unrelated recipients whose grafts functioned 1–4 years and one living donor were evaluated for HLA-typing, PRA (panel reactive antibodies), and CXM tests (compatibility test Xmatch). Two out four patients were negative for de novo donor specific antibodies and three out of four of the recipients remained negative for PRA (37).

6. Use of immunosuppression after parathyroid allotransplantation

Some centres have not used immunosuppression after PTalloT (46). Metylprednisolone as a short course (2 days postop) has been used in two successful allotransplants with a rapid return to normal calcium levels within 1 month and lasting over 1 year (41, 47). Similarly, in another report methylprednisolone was used for 1 month after allotransplantation (48).

Tacrolimus, mycophenolate mofetil and steroids were used by a group in Cleveland, USA, for allotransplantation of cryopreserved parathyroid tissue in a kidney transplant recipient (49). When an immunosuppressive regimen of 6 months was used by researchers from Guadalajara, México, none of the patients had immunosuppression side effects and four out of five grafts maintained PTH secretion for 2 years (50).

7. Expected long-term outcomes after parathyroid allotransplantation

The longest survival reported to date is from the University Hospital Regensburg, Germany, where a 32-year-old female had a living-donor allotransplantation and remains with normal calcium/PTH levels 3 years later (27).

A recent systematic literature review summarised the evidence from five studies and reported a mean allograft survival of 47% (95% CI 24–71%) when patients were followed-up for < 6 months and 41% (2.3–80%) when followed-up for up to 1-year. In further five studies, patients were followed up > 12 months and the mean graft survival was 46% (95% CI 11–80%) (51).

8. Symptomatic benefits after allotransplantation

The recent systematic review found that only two studies reported the impact on symptoms related to POSH (51). Chvostek and Trousseau’s signs disappeared in over 90% of patients and most could carry out basic daily activities without having signs of hypocalcaemia, which was not possible before transplantation (51).

Final comments

Permanent hypoparathyroidism is currently the most common and debilitating complication of thyroid surgery. In parallel with efforts to improve its medical management, there is growing pressure to reduce its incidence by ensuring such operations are done in high volume units. In 2019, the European Society of Endocrine Surgeons reviewed the evidence for volume-outcome correlation in thyroid surgery and reported that the incidence of complications (recurrent laryngeal nerve injury and hypocalcaemia/hypoparathyroidism) is lower when the surgeon performs more than 30 operations yearly. The ESES recommends therefore that routine thyroid cases should be operated in centres performing at least 25/year and surgery for thyroid cancer should be centralised in units performing at least 50 thyroid operations/year (52). Similar recommendations are expected soon in the United Kingdom after completion of a national review of service delivery for endocrine surgery under the acronym GIRFT (get it right first time).

The options available for patients with severely symptomatic hypoPT are summarised in Table 2. Though the clinical need for a new effective treatment in patients with poorly controlled hypoPT is very high, data available so far regarding long-term outcome of allotransplantation are deemed as unconvincing and therefore PTalloT has remained restricted to a very small number of units.

Table 2

Comparisons of current medical therapy for permanent hypoparathyroidism.

AdvantagesDisadvantages
Oral calcium and vitamin D supplementsCheap, easily availableNeed for regular blood tests
SafeIneffective in many patients
Synthetic PTHIdeal hormonal replacementExpensive
Very effective when administered with a pumpLong term unknown
Not suitable for needle-phobic patients
Restricted use up to 2 years due to concerns regarding development of osteosarcoma
AutotransplantationEasy to performNeed for cryopreservation facilities
No need for immunosuppressionUnpredictable survival or preserved tissue
AllotransplantationPotentially unlimited source of donor cellsAlleged need for immunosuppression
Could be repeatedCost of HLA matching and the surgical procedure
Need for graft monitoring

Patients’ expectations remain disproportionate compared with the enthusiasm of clinicians to consider this as a viable therapeutic option. Is likely that a mean transplant survival of 12 months is unlikely to be a compelling prospect for patients. There is, therefore, a need to define better the benefits and the limitations of PTalloT.

At this point, PTalloT should be offered only for patients who remain severely symptomatic despite intense medical therapy. This approach can only be assessed in a prospective multicenter study that should build on the experience of single centers. Until its effectiveness is convincingly demonstrated in a study with 3–5 years follow-up, PTalloT will remain as an experimental procedure restricted to a small number of units who showed enthusiasm with the technique.

Based on the data available, our view is that the source of parathyroid cells should be adenomas from patients with mild hyperparathyroidism or hyperplastic glands from patients with secondary hyperparathyroidism because the pool of donors would be large enough. Cells from the resected parathyroid adenomas could be cultured and assessed in the laboratory for viability and function for a short period of 1–2 days, before transplantation into a forearm muscle pocket.

The need and extent of immune suppression should be explored prospectively in a randomised fashion. It is encouraging that some reported successful allotransplantation without long-term immunosuppression as it remains likely that daily medication with standard immunosupressants (tacrolimus, everolimus) or even the new co-stimulation blocker iscalimab (Novartis) might trigger side effects that could outweigh the benefits of avoiding/reducing the use of calcium-vitamin D supplements.

Recruitment of patients into such a trial and the proposed design of such a trial are outlined in Figs 1 and 2, respectively. In our recent paper investigating the views of members of HypoPara UK group, at least 40% of 252 respondents expressed an interest participating in a clinical trial that would explore the feasibility and benefits of PTalloT (9). In addition to analysing biochemical parameters, such a study should determine if the improvement in quality of life becomes apparent and is sustainable.

Figure 1
Figure 1

Proposed strategy for recruitment into a prospective trial of parathyroid allotransplantation for patients with severe hypoparathyroidism.

Citation: European Journal of Endocrinology 184, 5; 10.1530/EJE-20-1367

Figure 2
Figure 2

Proposed design for a randomised trial of parathyroid allotransplantation.

Citation: European Journal of Endocrinology 184, 5; 10.1530/EJE-20-1367

A prospective cohort trial, rather than more case reports, should be the next step in this process and such collaboration between endocrinologists and thyroid surgeons could make a significant impact on the care of a group of patients with a debilitating chronic condition.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC) Programme (to R V T).

Author contribution statement

Both authors have contributed to the planning and writing of this review.

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    Anneback M, Hedberg J, Almquist M, Stalberg P & Norlen O Risk of permanent hypoparathyroidism After total thyroidectomy for benign disease: a nationwide population-based cohort study From Sweden. Annals of Surgery 2020 In press. (https://doi.org/10.1097/SLA.0000000000003800)

    • Search Google Scholar
    • Export Citation
  • 5

    Lorente-Poch L, Sancho JJ, Ruiz S & Sitges-Serra A Importance of in situ preservation of parathyroid glands during total thyroidectomy. British Journal of Surgery 2015 102 359367. (https://doi.org/10.1002/bjs.9676)

    • Search Google Scholar
    • Export Citation
  • 6

    Edafe O, Antakia R, Laskar N, Uttley L & Balasubramanian SP Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia. British Journal of Surgery 2014 101 307320. (https://doi.org/10.1002/bjs.9384)

    • Search Google Scholar
    • Export Citation
  • 7

    Vidal Fortuny J, Sadowski SM, Belfontali V, Guigard S, Poncet A, Ris F, Karenovics W & Triponez F Randomized clinical trial of intraoperative parathyroid gland angiography with indocyanine green fluorescence predicting parathyroid function after thyroid surgery. British Journal of Surgery 2018 105 350357. (https://doi.org/10.1002/bjs.10783)

    • Search Google Scholar
    • Export Citation
  • 8

    Brod M, Waldman LT, Smith A & Karpf D Assessing the patient experience of hypoparathyroidism symptoms: development of the hypoparathyroidism patient experience scale-symptom (HPES-symptom). Patient 2020 13 151162. (https://doi.org/10.1007/s40271-019-00388-5)

    • Search Google Scholar
    • Export Citation
  • 9

    Stevenson A & Mihai R Patients’ views about parathyroid transplantation for post-thyroidectomy hypoparathyroidism. Langenbeck’s Archives of Surgery 2018 403 623629. (https://doi.org/10.1007/s00423-018-1693-y)

    • Search Google Scholar
    • Export Citation
  • 10

    Siggelkow H, Clarke BL, Germak J, Marelli C, Chen K, Dahl-Hansen H, Glenister E, Bent-Ennakhil N, Judge D & Mycock K et al. Burden of illness in not adequately controlled chronic hypoparathyroidism: findings from a 13-country patient and caregiver survey. Clinical Endocrinology 2020 92 159168. (https://doi.org/10.1111/cen.14128)

    • Search Google Scholar
    • Export Citation
  • 11

    Hadker N, Egan J, Sanders J, Lagast H & Clarke BL Understanding the burden of illness associated with hypoparathyroidism reported among patients in the PARADOX study. Endocrine Practice 2014 20 671679. (https://doi.org/10.4158/EP13328.OR)

    • Search Google Scholar
    • Export Citation
  • 12

    Bergenfelz A, Nordenstrom E & Almquist M Morbidity in patients with permanent hypoparathyroidism after total thyroidectomy. Surgery 2020 167 124128. (https://doi.org/10.1016/j.surg.2019.06.056)

    • Search Google Scholar
    • Export Citation
  • 13

    Almquist M, Ivarsson K, Nordenstrom E & Bergenfelz A Mortality in patients with permanent hypoparathyroidism after total thyroidectomy. British Journal of Surgery 2018 105 13131318. (https://doi.org/10.1002/bjs.10843)

    • Search Google Scholar
    • Export Citation
  • 14

    Bollerslev J, Rejnmark L, Marcocci C, Shoback DM, Sitges-Serra A, van Biesen W, Dekkers OMEuropean Society of Endocrinology. European Society of Endocrinology Clinical Guideline: treatment of chronic hypoparathyroidism in adults. European Journal of Endocrinology 2015 173 G1G 20. (https://doi.org/10.1530/EJE-15-0628)

    • Search Google Scholar
    • Export Citation
  • 15

    Sanabria A, Rojas A & Arevalo J Meta-analysis of routine calcium/vitamin D3 supplementation versus serum calcium level-based strategy to prevent postoperative hypocalcaemia after thyroidectomy. British Journal of Surgery 2019 106 11261137. (https://doi.org/10.1002/bjs.11216)

    • Search Google Scholar
    • Export Citation
  • 16

    Sitges-Serra A The PGRIS and parathyroid splinting concepts for the analysis and prognosis of protracted hypoparathyroidism. Gland Surgery 2017 6 S86S93. (https://doi.org/10.21037/gs.2017.07.16)

    • Search Google Scholar
    • Export Citation
  • 17

    Cusano NE, Rubin MR, McMahon DJ, Zhang C, Ives R, Tulley A, Sliney Jr J, Cremers SC & Bilezikian JP Therapy of hypoparathyroidism with PTH(1–84): a prospective four-year investigation of efficacy and safety. Journal of Clinical Endocrinology and Metabolism 2013 98 137144. (https://doi.org/10.1210/jc.2012-2984)

    • Search Google Scholar
    • Export Citation
  • 18

    Cusano NE, Rubin MR, McMahon DJ, Irani D, Tulley A, Sliney Jr J & Bilezikian JP The effect of PTH(1–84) on quality of life in hypoparathyroidism. Journal of Clinical Endocrinology and Metabolism 2013 98 23562361. (https://doi.org/10.1210/jc.2013-1239)

    • Search Google Scholar
    • Export Citation
  • 19

    Gafni RI, Guthrie LC, Kelly MH, Brillante BA, Christie CM, Reynolds JC, Yovetich NA, James R & Collins MT Transient increased calcium and calcitriol requirements After discontinuation of human synthetic parathyroid hormone 1–34 (hPTH 1–34) replacement therapy in hypoparathyroidism. Journal of Bone and Mineral Research 2015 30 21122118. (https://doi.org/10.1002/jbmr.2555)

    • Search Google Scholar
    • Export Citation
  • 20

    Winer KK, Fulton KA, Albert PS & Cutler Jr GB Effects of pump versus twice-daily injection delivery of synthetic parathyroid hormone 1–34 in children with severe congenital hypoparathyroidism. Jurnalul Pediatrului 2014 165 556.e1563.e1.

    • Search Google Scholar
    • Export Citation
  • 21

    Winer KK, Sinaii N, Reynolds J, Peterson D, Dowdy K & Cutler Jr GB Long-term treatment of 12 children with chronic hypoparathyroidism: a randomized trial comparing synthetic human parathyroid hormone 1–34 versus calcitriol and calcium. Journal of Clinical Endocrinology and Metabolism 2010 95 26802688. (https://doi.org/10.1210/jc.2009-2464)

    • Search Google Scholar
    • Export Citation
  • 22

    Altaani BM, Almaaytah AM, Dadou S, Alkhamis K, Daradka MH & Hananeh W Oral delivery of teriparatide using a nanoemulsion system: design, in vitro and in vivo evaluation. Pharmaceutical Research 2020 37 80. (https://doi.org/10.1007/s11095-020-02793-0)

    • Search Google Scholar
    • Export Citation
  • 23

    Karpf DB, Pihl S, Mourya S, Mortensen E, Kovoor E, Markova D & Leff JA A randomized double-blind placebo-controlled first-in-human Phase 1 trial of TransCon PTH in healthy adults. Journal of Bone and Mineral Research 2020 35 14301440. (https://doi.org/10.1002/jbmr.4016)

    • Search Google Scholar
    • Export Citation
  • 24

    Marcucci G, Della Pepa G & Brandi ML Drug safety evaluation of parathyroid hormone for hypocalcemia in patients with hypoparathyroidism. Expert Opinion on Drug Safety 2017 16 617625. (https://doi.org/10.1080/14740338.2017.1311322)

    • Search Google Scholar
    • Export Citation
  • 25

    Wells Jr SA, Gunnells JC, Shelburne JD, Schneider AB & Sherwood LM Transplantation of the parathyroid glands in man: clinical indications and results. Surgery 1975 78 3444.

    • Search Google Scholar
    • Export Citation
  • 26

    Hicks G, George R & Sywak M Short and long-term impact of parathyroid autotransplantation on parathyroid function after total thyroidectomy. Gland Surgery 2017 6 S75S85. (https://doi.org/10.21037/gs.2017.09.15)

    • Search Google Scholar
    • Export Citation
  • 27

    Agha A, Scherer MN, Moser C, Karrasch T, Girlich C, Eder F, Jung EM, Schlitt HJ & Schaeffler A Living-donor parathyroid allotransplantation for therapy-refractory postsurgical persistent hypoparathyroidism in a nontransplant recipient – three year results: a case report. BMC Surgery 2016 16 51. (https://doi.org/10.1186/s12893-016-0165-y)

    • Search Google Scholar
    • Export Citation
  • 28

    Garcia-Roca R, Garcia-Aroz S, Tzvetanov IG, Giulianotti PC, Campara M, Oberholzer J & Benedetti E Simultaneous living donor kidney and parathyroid allotransplantation: first case report and review of literature. Transplantation 2016 100 13181321. (https://doi.org/10.1097/TP.0000000000001042)

    • Search Google Scholar
    • Export Citation
  • 29

    Giulianotti PC, D’Amico G, Tzvetanov I & Benedetti E Living donor parathyroid allotransplantation with robotic transaxillary procurement in a kidney transplant recipient. Transplant International 2014 27 e43e 45. (https://doi.org/10.1111/tri.12269)

    • Search Google Scholar
    • Export Citation
  • 30

    Chapelle T, Meuris K, Roeyen G, De Greef K, Van Beeumen G, Bosmans JL & Ysebaert D Simultaneous kidney-parathyroid allotransplantation from a single donor after 20 years of tetany: a case report. Transplantation Proceedings 2009 41 599600. (https://doi.org/10.1016/j.transproceed.2008.12.026)

    • Search Google Scholar
    • Export Citation
  • 31

    Duarte B, Mozes MF, John E, Aronson I, Pollak R & Jonasson O Parathyroid allotransplantation in the treatment of complicated idiopathic primary hypoparathyroidism. Surgery 1985 98 10721076.

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    Aysan E, Duzkoylu Y, Can i & Buyukpinarbasili N Xenotransplantation of human cryopreserved parathyroid tissue isolated from parathyroid adenomas to normocalcemic rabbits. Turkish Journal of Surgery 2017 33 9195. (https://doi.org/10.5152/turkjsurg.2017.3427)

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    Bingham EL, Cheng SP, Woods Ignatoski KM & Doherty GM Differentiation of human embryonic stem cells to a parathyroid-like phenotype. Stem Cells and Development 2009 18 10711080. (https://doi.org/10.1089/scd.2008.0337)

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  • 34

    Goncu B, Yucesan E, Ozdemir B, Basoglu H, Kandas NO, Akbas F & Aysan E A new transport solution for parathyroid allotransplantation: effects on cell viability and calcium-sensing receptors. Biopreservation and Biobanking 2018 16 278284. (https://doi.org/10.1089/bio.2018.0008)

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  • 35

    Hasse C, Bohrer T, Barth P, Stinner B, Cohen R, Cramer H, Zimmermann U & Rothmund M Parathyroid xenotransplantation without immunosuppression in experimental hypoparathyroidism: long-term in vivo function following microencapsulation with a clinically suitable alginate. World Journal of Surgery 2000 24 13611366. (https://doi.org/10.1007/s002680010225)

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  • 36

    Cabane P, Gac P, Amat J, Pineda P, Rossi R, Caviedes R & Caviedes P Allotransplant of microencapsulated parathyroid tissue in severe postsurgical hypoparathyroidism: a case report. Transplantation Proceedings 2009 41 38793883. (https://doi.org/10.1016/j.transproceed.2009.06.211)

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  • 37

    Yucesan E, Goncu B, Ozdemir B, Idiz O, Ersoy YE & Aysan E Importance of HLA typing, PRA and DSA tests for successful parathyroid allotransplantation. Immunobiology 2019 224 485489. (https://doi.org/10.1016/j.imbio.2019.05.007)

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  • 38

    Moskalenko V, Ulrichs K, Kerscher A, Blind E, Otto C, Hamelmann W, Demidchik Y & Timm S Preoperative evaluation of microencapsulated human parathyroid tissue aids selection of the optimal bioartificial graft for human parathyroid allotransplantation. Transplant International 2007 20 688696. (https://doi.org/10.1111/j.1432-2277.2007.00496.x)

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    Park HS, Jung SY, Kim HY, Ko DY, Chung SM, Jeong B & Kim HS Feasibility of injectable thermoreversible gels for use in intramuscular injection of parathyroid autotransplantation. European Archives of Oto-Rhino-Laryngology 2016 273 38273834. (https://doi.org/10.1007/s00405-016-3990-9)

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    Khryshchanovich V & Ghoussein Y Allotransplantation of macroencapsulated parathyroid cells as a treatment of severe postsurgical hypoparathyroidism: case report. Annals of Saudi Medicine 2016 36 143147. (https://doi.org/10.5144/0256-4947.2016.21.3.1130)

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  • 41

    Yucesan E, Goncu B, Basoglu H, Ozten Kandas N, Ersoy YE, Akbas F & Aysan E Fresh tissue parathyroid allotransplantation with short-term immunosuppression: 1-year follow-up. Clinical Transplantation 2017 31 e13086. (https://doi.org/10.1111/ctr.13086)

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    Gao Z, Xing Z & Zhu Y Preliminary observation of the thymus as a privileged site for parathyroid gland allotransplantation in rats. Chinese Medical Sciences Journal 1993 8 246247.

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    Kukreja SC, Johnson PA, Ayala G, Bowser EN & Williams GA Allotransplantation of rat parathyroid glands: effects of organ culture and transplantation into the adrenal gland. Experientia 1979 35 559560. (https://doi.org/10.1007/BF01922771)

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    Wozniewicz B, Migaj M, Giera B, Prokurat A, Tolloczko T, Sawicki A, Nawrot I, Gorski A, Zabitkowska T & Kossakowska AE Cell culture preparation of human parathyroid cells for allotransplantation without immunosuppression. Transplantation Proceedings 1996 28 35423544.

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    Nawrot I, Wozniewicz B, Tolloczko T, Sawicki A, Gorski A, Chudzinski W, Wojtaszek M, Grzesiuk W, Sladowski D & Karwacki J et al. Allotransplantation of cultured parathyroid progenitor cells without immunosuppression: clinical results. Transplantation 2007 83 734740. (https://doi.org/10.1097/01.tp.0000258601.17505.9d)

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    Kunori T, Tsuchiya T, Itoh J, Watabe S, Arai M, Satomi T, Takakura K & Yamaguchi H Improvement of postoperative hypocalcemia by repeated allotransplantation of parathyroid tissue without anti-rejection therapy. Tohoku Journal of Experimental Medicine 1991 165 3340. (https://doi.org/10.1620/tjem.165.33)

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    Aysan E, Yucesan E, Idiz UO & Goncu B Discharging a patient treated with parathyroid allotransplantation after having been hospitalized for 3.5 years with permanent hypoparathyroidism: a case report. Transplantation Proceedings 2019 51 31863188. (https://doi.org/10.1016/j.transproceed.2019.03.036)

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    Flechner SM, Berber E, Askar M, Stephany B, Agarwal A & Milas M Allotransplantation of cryopreserved parathyroid tissue for severe hypocalcemia in a renal transplant recipient. American Journal of Transplantation 2010 10 20612065. (https://doi.org/10.1111/j.1600-6143.2010.03234.x)

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    Hermosillo-Sandoval JM, Leonher-Ruezga KL, Jimenez-Gomez JA, Fuentes-Orozco C, Gonzalez-Ojeda A & Ramirez-Gonzalez LR Allogeneic parathyroid: 2-year follow-up. Cirugia y Cirujanos 2015 83 188192. (https://doi.org/10.1016/j.circir.2015.05.002)

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  • 51

    Parameswaran R, Samuel M, Satish RL, Kripesh A, Moorthy V, Vajjhala R, Ng XL, Yip GW, Voon FCT & Chandran M Parathyroid allotransplantation to treat post-thyroidectomy hypoparathyroidism: a review of case studies. Surgeon 2020. (https://doi.org/10.1016/j.surge.2020.06.008)

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  • 52

    Lorenz K, Raffaeli M, Barczynski M, Lorente-Poch L & Sancho J Volume, outcomes, and quality standards in thyroid surgery: an evidence-based analysis-European Society of Endocrine Surgeons (ESES) positional statement. Langenbeck’s Archives of Surgery 2020 405 401425. (https://doi.org/10.1007/s00423-020-01907-x)

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    Proposed strategy for recruitment into a prospective trial of parathyroid allotransplantation for patients with severe hypoparathyroidism.

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    Proposed design for a randomised trial of parathyroid allotransplantation.

  • 1

    Niederle BE, Schmidt G, Organ CH & Niederle B Albert J and his surgeon: a historical reevaluation of the first parathyroidectomy. Journal of the American College of Surgeons 2006 202 181190. (https://doi.org/10.1016/j.jamcollsurg.2005.03.036)

    • Search Google Scholar
    • Export Citation
  • 2

    Clarke BL, Brown EM, Collins MT, Juppner H, Lakatos P, Levine MA, Mannstadt MM, Bilezikian JP, Romanischen AF & Thakker RV Epidemiology and diagnosis of hypoparathyroidism. Journal of Clinical Endocrinology and Metabolism 2016 101 22842299. (https://doi.org/10.1210/jc.2015-3908)

    • Search Google Scholar
    • Export Citation
  • 3

    Thomusch O, Machens A, Sekulla C, Ukkat J, Brauckhoff M & Dralle H The impact of surgical technique on postoperative hypoparathyroidism in bilateral thyroid surgery: a multivariate analysis of 5846 consecutive patients. Surgery 2003 133 180185. (https://doi.org/10.1067/msy.2003.61)

    • Search Google Scholar
    • Export Citation
  • 4

    Anneback M, Hedberg J, Almquist M, Stalberg P & Norlen O Risk of permanent hypoparathyroidism After total thyroidectomy for benign disease: a nationwide population-based cohort study From Sweden. Annals of Surgery 2020 In press. (https://doi.org/10.1097/SLA.0000000000003800)

    • Search Google Scholar
    • Export Citation
  • 5

    Lorente-Poch L, Sancho JJ, Ruiz S & Sitges-Serra A Importance of in situ preservation of parathyroid glands during total thyroidectomy. British Journal of Surgery 2015 102 359367. (https://doi.org/10.1002/bjs.9676)

    • Search Google Scholar
    • Export Citation
  • 6

    Edafe O, Antakia R, Laskar N, Uttley L & Balasubramanian SP Systematic review and meta-analysis of predictors of post-thyroidectomy hypocalcaemia. British Journal of Surgery 2014 101 307320. (https://doi.org/10.1002/bjs.9384)

    • Search Google Scholar
    • Export Citation
  • 7

    Vidal Fortuny J, Sadowski SM, Belfontali V, Guigard S, Poncet A, Ris F, Karenovics W & Triponez F Randomized clinical trial of intraoperative parathyroid gland angiography with indocyanine green fluorescence predicting parathyroid function after thyroid surgery. British Journal of Surgery 2018 105 350357. (https://doi.org/10.1002/bjs.10783)

    • Search Google Scholar
    • Export Citation
  • 8

    Brod M, Waldman LT, Smith A & Karpf D Assessing the patient experience of hypoparathyroidism symptoms: development of the hypoparathyroidism patient experience scale-symptom (HPES-symptom). Patient 2020 13 151162. (https://doi.org/10.1007/s40271-019-00388-5)

    • Search Google Scholar
    • Export Citation
  • 9

    Stevenson A & Mihai R Patients’ views about parathyroid transplantation for post-thyroidectomy hypoparathyroidism. Langenbeck’s Archives of Surgery 2018 403 623629. (https://doi.org/10.1007/s00423-018-1693-y)

    • Search Google Scholar
    • Export Citation
  • 10

    Siggelkow H, Clarke BL, Germak J, Marelli C, Chen K, Dahl-Hansen H, Glenister E, Bent-Ennakhil N, Judge D & Mycock K et al. Burden of illness in not adequately controlled chronic hypoparathyroidism: findings from a 13-country patient and caregiver survey. Clinical Endocrinology 2020 92 159168. (https://doi.org/10.1111/cen.14128)

    • Search Google Scholar
    • Export Citation
  • 11

    Hadker N, Egan J, Sanders J, Lagast H & Clarke BL Understanding the burden of illness associated with hypoparathyroidism reported among patients in the PARADOX study. Endocrine Practice 2014 20 671679. (https://doi.org/10.4158/EP13328.OR)

    • Search Google Scholar
    • Export Citation
  • 12

    Bergenfelz A, Nordenstrom E & Almquist M Morbidity in patients with permanent hypoparathyroidism after total thyroidectomy. Surgery 2020 167 124128. (https://doi.org/10.1016/j.surg.2019.06.056)

    • Search Google Scholar
    • Export Citation
  • 13

    Almquist M, Ivarsson K, Nordenstrom E & Bergenfelz A Mortality in patients with permanent hypoparathyroidism after total thyroidectomy. British Journal of Surgery 2018 105 13131318. (https://doi.org/10.1002/bjs.10843)

    • Search Google Scholar
    • Export Citation
  • 14

    Bollerslev J, Rejnmark L, Marcocci C, Shoback DM, Sitges-Serra A, van Biesen W, Dekkers OMEuropean Society of Endocrinology. European Society of Endocrinology Clinical Guideline: treatment of chronic hypoparathyroidism in adults. European Journal of Endocrinology 2015 173 G1G 20. (https://doi.org/10.1530/EJE-15-0628)

    • Search Google Scholar
    • Export Citation
  • 15

    Sanabria A, Rojas A & Arevalo J Meta-analysis of routine calcium/vitamin D3 supplementation versus serum calcium level-based strategy to prevent postoperative hypocalcaemia after thyroidectomy. British Journal of Surgery 2019 106 11261137. (https://doi.org/10.1002/bjs.11216)

    • Search Google Scholar
    • Export Citation
  • 16

    Sitges-Serra A The PGRIS and parathyroid splinting concepts for the analysis and prognosis of protracted hypoparathyroidism. Gland Surgery 2017 6 S86S93. (https://doi.org/10.21037/gs.2017.07.16)

    • Search Google Scholar
    • Export Citation
  • 17

    Cusano NE, Rubin MR, McMahon DJ, Zhang C, Ives R, Tulley A, Sliney Jr J, Cremers SC & Bilezikian JP Therapy of hypoparathyroidism with PTH(1–84): a prospective four-year investigation of efficacy and safety. Journal of Clinical Endocrinology and Metabolism 2013 98 137144. (https://doi.org/10.1210/jc.2012-2984)

    • Search Google Scholar
    • Export Citation
  • 18

    Cusano NE, Rubin MR, McMahon DJ, Irani D, Tulley A, Sliney Jr J & Bilezikian JP The effect of PTH(1–84) on quality of life in hypoparathyroidism. Journal of Clinical Endocrinology and Metabolism 2013 98 23562361. (https://doi.org/10.1210/jc.2013-1239)

    • Search Google Scholar
    • Export Citation
  • 19

    Gafni RI, Guthrie LC, Kelly MH, Brillante BA, Christie CM, Reynolds JC, Yovetich NA, James R & Collins MT Transient increased calcium and calcitriol requirements After discontinuation of human synthetic parathyroid hormone 1–34 (hPTH 1–34) replacement therapy in hypoparathyroidism. Journal of Bone and Mineral Research 2015 30 21122118. (https://doi.org/10.1002/jbmr.2555)

    • Search Google Scholar
    • Export Citation
  • 20

    Winer KK, Fulton KA, Albert PS & Cutler Jr GB Effects of pump versus twice-daily injection delivery of synthetic parathyroid hormone 1–34 in children with severe congenital hypoparathyroidism. Jurnalul Pediatrului 2014 165 556.e1563.e1.

    • Search Google Scholar
    • Export Citation
  • 21

    Winer KK, Sinaii N, Reynolds J, Peterson D, Dowdy K & Cutler Jr GB Long-term treatment of 12 children with chronic hypoparathyroidism: a randomized trial comparing synthetic human parathyroid hormone 1–34 versus calcitriol and calcium. Journal of Clinical Endocrinology and Metabolism 2010 95 26802688. (https://doi.org/10.1210/jc.2009-2464)

    • Search Google Scholar
    • Export Citation
  • 22

    Altaani BM, Almaaytah AM, Dadou S, Alkhamis K, Daradka MH & Hananeh W Oral delivery of teriparatide using a nanoemulsion system: design, in vitro and in vivo evaluation. Pharmaceutical Research 2020 37 80. (https://doi.org/10.1007/s11095-020-02793-0)

    • Search Google Scholar
    • Export Citation
  • 23

    Karpf DB, Pihl S, Mourya S, Mortensen E, Kovoor E, Markova D & Leff JA A randomized double-blind placebo-controlled first-in-human Phase 1 trial of TransCon PTH in healthy adults. Journal of Bone and Mineral Research 2020 35 14301440. (https://doi.org/10.1002/jbmr.4016)

    • Search Google Scholar
    • Export Citation
  • 24

    Marcucci G, Della Pepa G & Brandi ML Drug safety evaluation of parathyroid hormone for hypocalcemia in patients with hypoparathyroidism. Expert Opinion on Drug Safety 2017 16 617625. (https://doi.org/10.1080/14740338.2017.1311322)

    • Search Google Scholar
    • Export Citation
  • 25

    Wells Jr SA, Gunnells JC, Shelburne JD, Schneider AB & Sherwood LM Transplantation of the parathyroid glands in man: clinical indications and results. Surgery 1975 78 3444.

    • Search Google Scholar
    • Export Citation
  • 26

    Hicks G, George R & Sywak M Short and long-term impact of parathyroid autotransplantation on parathyroid function after total thyroidectomy. Gland Surgery 2017 6 S75S85. (https://doi.org/10.21037/gs.2017.09.15)

    • Search Google Scholar
    • Export Citation
  • 27

    Agha A, Scherer MN, Moser C, Karrasch T, Girlich C, Eder F, Jung EM, Schlitt HJ & Schaeffler A Living-donor parathyroid allotransplantation for therapy-refractory postsurgical persistent hypoparathyroidism in a nontransplant recipient – three year results: a case report. BMC Surgery 2016 16 51. (https://doi.org/10.1186/s12893-016-0165-y)

    • Search Google Scholar
    • Export Citation
  • 28

    Garcia-Roca R, Garcia-Aroz S, Tzvetanov IG, Giulianotti PC, Campara M, Oberholzer J & Benedetti E Simultaneous living donor kidney and parathyroid allotransplantation: first case report and review of literature. Transplantation 2016 100 13181321. (https://doi.org/10.1097/TP.0000000000001042)

    • Search Google Scholar
    • Export Citation
  • 29

    Giulianotti PC, D’Amico G, Tzvetanov I & Benedetti E Living donor parathyroid allotransplantation with robotic transaxillary procurement in a kidney transplant recipient. Transplant International 2014 27 e43e 45. (https://doi.org/10.1111/tri.12269)

    • Search Google Scholar
    • Export Citation
  • 30

    Chapelle T, Meuris K, Roeyen G, De Greef K, Van Beeumen G, Bosmans JL & Ysebaert D Simultaneous kidney-parathyroid allotransplantation from a single donor after 20 years of tetany: a case report. Transplantation Proceedings 2009 41 599600. (https://doi.org/10.1016/j.transproceed.2008.12.026)

    • Search Google Scholar
    • Export Citation
  • 31

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