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Living-donor parathyroid allotransplantation for therapy-refractory postsurgical persistent hypoparathyroidism in a nontransplant recipient – three year results: a case report
© The Author(s). 2016
Received: 15 February 2016
Accepted: 22 July 2016
Published: 3 August 2016
Therapy-refractory persistent hypoparathyroidism after extensive neck surgery is a rare but severe complication. Parathyroid allotransplantation may represent a definitive treatment option.
A 32-year old female was referred to our hospital with intractable persistent hypocalcemia after neck surgery for papillary thyroid cancer. Despite optimal medical treatment including calcium and vitamin D supplementation and even hormonal replacement therapy hypocalcemic symptoms failed to improve. The quality of life was considered very low. In light of the unsuccessful medical therapy and the young age of the patient parathyroid allotransplantation seemed an attractive treatment option to restore normal calcium homeostasis despite of the need for immunosuppressive therapy after the procedure. Therefore, we performed living-donor allotransplantation of two healthy parathyroid glands to the recipient’s left forearm. The surgical intervention was successful. Neither the donor nor the recipient showed any complications. In the postoperative course clinical symptoms of hypocalcemia significantly improved whereas serum calcium and parathyroid hormone (PTH) levels progressively increased into the normal range. Former intense replacement therapy could be discontinued completely in a stepwise fashion. To date, nearly three years after transplantation, the patient remains asymptomatic with normal serum levels of calcium and PTH.
Successful living-donor parathyroid allotransplantation for postsurgical hypoparathyroidism represents an innovative therapeutic strategy that could provide the definitive treatment in those patients in which the disease is therapy-refractory. The procedure can be justified even in nontransplant recipients. Retrieval of parathyroid glands from healthy donors is feasible and safe.
KeywordsHypoparathyroidism Hypocalcemia Living-donor parathyroid allotransplantation Immunosuppression
Postsurgical hypoparathyroidism with symptomatic hypocalcemia after neck surgery is a common but usually transient complication. However, if hypocalcemia persists for more than six months even with medical replacement therapy and cryopreserved autologous parathyroid tissue is not available, permanent hypoparathyroidism can lead to dependence on high doses of calcium and vitamin D supplementation [1–4]. Chronic hypocalcemia is significantly associated with longterm risks of multiorgan calcinosis and renal failure. Symptoms related to hypocalcemia can even be life-threatening (e.g. laryngeal spasm, refractory heart failure). Importantly, in rare cases hypocalcemia cannot be controlled despite of aggressive oral supplementation of calcium and vitamin D and frequent additional intravenous (i.v.) administration of calcium may be required seriously affecting the quality of life . Recently, novel synthetic PTH-replacement therapies have been approved showing promising results for patients who do not respond well to treatment with calcium and active forms of vitamin D alone. However, long-term hormonal treatment may be limited because of the potential risk of bone cancer [6, 7].
Allotransplantation of parathyroid cells could be an ideal therapeutic option to establish physiologic treatment for patients with persistent hypoparathyroidism. Successful allotransplantation of parathyroid tissue from deceased and living donors has been described sporadically in recent years. However, most of these procedures were performed in kidney transplant recipients with ongoing immunosuppression [8–11].
We present - to the best of our knowledge – the first successful case of living-related allotransplantation of parathyroid glands obtained from a healthy donor in a nontransplant patient suffering from therapy-refractory postsurgical hypoparathyroidism.
Serum calcium levels of the donor
Months after transplant
PTH values and serum calcium levels posttransplant (recipient)
Months after transplant
Surgery for thyroid or parathyroid disease is the leading cause of hypoparathyroidism due to damage or (accidental) removal of parathyroid glands [2, 3, 13, 14]. In most cases resulting hypocalcemia and corresponding hypocalcemic symptoms can easily be controlled by oral calcium and vitamin D supplementation. However, in less frequent cases (0,4 – 33 %) the usually transitory postsurgical hypoparathyroidism persists for more than six months causing serious metabolic disorders with long-term risks of multiorgan calcinosis and renal failure . Moreover, acute fall in serum calcium levels can even cause life-threatenig symptoms. Affected patients may frequently require i.v. calcium administration in addition to high doses of oral calcium and vitamin D supplements. Intractable hypocalcemic symptoms and repeated hospitalizations significantly reduce the quality of life in these patients . Recently, novel synthetic PTH replacement therapies became available as a promising treatment option for patients who do not respond well to calcium and vitamin D supplementation alone. PTH (1–84) (Natpara; whole molecule) and PTH (1–34) (Forteo; active amino terminal portion) are injectable formulations (subcutaneous injection) [6, 7]. However, animal studies in rats showed that prolonged treatment with PTH (1–84) and PTH (1–34) is associated with the development of bone tumors (osteosarcoma) . Although to date this response has not been observed in humans long-term therapy may be limited [16, 17]. Moreover, PTH (1–34) was approved by the Food and Drug Administration (FDA) only for therapy of osteoporosis. Therefore, treatment for hypoparathyroidism requires off label use. High monthly costs and an adequate patient compliance (inconvenient daily injections) are further aspects that have to be taken into account before starting a hormonal replacement therapy with either PTH (1–84) or PTH (1–34) .
The most physiological and potentially definitive therapy for persistent hypoparathyroidism would be a restoration of parathyroid tissue in order to re-establish calcium homeostasis. In this context parathyroid tissue allotransplantation from deceased or living donors has been performed sporadically over the past decades [8–11, 18]. Importantly, to avoid rejection of the graft lifelong immunosuppressive therapy of the recipient is necessary and therefore adverse effects of immunosuppression (e.g. impaired kidney function, opportunist infections, cancer) have to be carefully considered. However, searching the literature several authors reported on alternative experimental strategies to restore parathyroid tissue without the need for immunosuppressive therapy, e.g. by using cultured cells [8, 19], cryopreserved tissue [20, 21] or magnetic microspheres depletion of major histocompatibility complex (MHC) of cells from parathyroid adenoma . Microencapsulation of parathyroid tissue constitutes another innovative concept aiming to exclude parathyroid cells from a host-versus-graft reaction. While the transplants are isolated from the immune system nutrients and hormones may pass the semipermeable membrane of the microcapsule. Initial results were encouraging showing normal PTH levels from the third week after transplantation  or graft survival up to 8 months . However, Bohrer et al. recently could demonstrate that the promising results of microencapsulation of allogeneic parathyroid tissue are not due to the protection of the graft from the immune system, but rather derive from delaying immunization of the host . Therefore, long-term effectiveness of this method may be limited.
The first successful parathyroid gland allotransplantation was published in 1973 by Growth et al. in a recipient who developed severe hypocalcemia after kidney transplantation . The donor was a patient with parathyroid hyperplasia. As the recipient was already under immunosuppression and the donor needed surgical excision of parathyroid adenoma living donor allotransplantation seemed an attractive and justified therapy. The parathyroid graft survived 21 months. Since then several authors have described this procedure achieving various results concerning graft function [9, 25, 26]. Interestingly, Alfrey et al. published a case of a renal transplant patient with normocalcemia even 13 years after additional successful parathyroid allotransplantation . The first report of a healthy patient who donated two parathyroid glands was published in 1975 by Wells et al. . The recipient was a renal failure patient requiring total parathyroidectomy after kidney transplantation resulting in hypoparathyroidism. The father of the patient who previously had been his renal transplant donor additionally donated two healthy parathyroid glands resulting in successful treatment of hypocalcemia and associated symptoms of the recipient. The parathyroid grafts showed a good function for more than one year. Another similar report of a healthy patient donating one parathyroid gland to a family member who previously had undergone kidney transplantation shows a good functionig graft two years after parathyroid allotransplantation (normal PTH levels, oral calcium supplementation 1 g/day) . Only recently, Garcia-Roca published the first successful case of simultaneous living donor kidney and pararthyroid allotransplantation (healthy family member donated kidney and one parathyroid gland) . Nine months after transplantation the recipient remains asymptomatic with normal renal function and PTH levels (oral calcium supplementation 2 g/day). The authors conclude that parathyroid allograft transplantation can be justified in recipients who receive immunosuppressive therapy for another organ. However, for successful and potentially definitive treatment of debilitating hypocalcemia that is otherwise not controllable parathyroid gland allotransplantion might as well be a reasonable option for patients without immunosuppression because of previous transplantation of another organ. In this context Hermosillo-Sandoval et al. recently performed five parathyroid allografts in patients with iatrogenic hypoparathyroidism . The living donors were patients with primary or secondary hyperparathyroidism requiring surgical excision. Four of the grafts are functioning two years after allotransplantation but calcium supplementation at a lower dose than before the procedure is necessary. No adverse effects of immunosuppression have been observed. In our case study the recipient also suffered from iatrogenic (postsurgical) hypoparathyroidism. The patient was otherwise healthy not receiving immunosuppressive therapy due to previous transplantation of another organ. Nevertheless parathyroid allotransplantation seemed a very attractive therapeutic option in light of the unsuccessful medical treatment including hormonal replacement therapy. To date the graft shows excellent function without the need for additional calcium supplementation. Furthermore, so far no adverse effects of the immunosuppressive drugs occurred and the patient significantly gained in quality of life. Therefore, in our opinion parathyroid gland allotransplantation can be justified also in nontransplant recipients. However, prevention or early detection and treatment of potential adverse effects of immunosuppression is the only acceptable posttransplant strategy. An adequate patient compliance and close long-term follow-up have to be guaranteed. Moreover, as the procedure is elective and ischemia time is the shortest living donation seems most advantageous. Against this background willing healthy individuals (not requiring surgery for parathyroid disease) might also be considered as donors. Although identification and removal of parathyroid tissue from a normocalcemic healthy donor may be challenging due to small size of the parathyroid glands, it is generally considered as a safe procedure. Importantly, in the light of improved preoperative localization of parathyroid glands by innovative diagnostic tools (Technetium-sestamibi scintigraphy, contrast-enhanced ultrasonography) focused minimally invasive organ retrieval causing only minimal trauma and excellent cosmetic results has become standard.
Parathyroid gland allotransplantation is a valuable and potentially definitive therapeutic option for patients with intractable persistent hypoparathyroidism. Provided that the well informed patient is willing to undergo transplantation despite of potential adverse effects of immunosuppressive therapy parathyroid allotransplantation can even be justified in nontransplant recipients. Living donation from healthy donors is a safe procedure that can be performed in minimally invasive technique.
CEUS, contrast-enhanced ultrasonography; FDA, food and drug administration; i.v., intravenous; MHC, Major histocompatibility complex; PTH, parathyroid hormone.
The authors thank Prof. Dr. Henning Dralle (Department of Surgery, University Hospital Halle (Saale), Germany) for excellent technical advice and essential contribution to this study.
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article.
AA is the first author of the manuscript, proposed the technique, performed the surgical procedure and treated the patient after surgery. MNS, CM, and HJS treated the patient after surgery, substantially contributed to the draft of the manuscript and revised the manuscript. TK and CG revised the manuscript, treated the patient after surgery and collected data during the follow-up period. FE performed pathohistological examination and revised the manuscript. EMJ performed contrast-enhanced ultrasonography and revised the manuscript. AS proposed the technique, treated the patient after surgery and revised the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Written informed consent was obtained from the patients for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Ethics approval and consent to participate
Living-donor parathyroid allotransplantation was approved by the University Hospital Regensburg Ethics Committee and the Universtiy Hospital Regensburg Living-Donation Committee. Consent to participate was obtained from the living-donor and the recipient.
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