Parathyroid

The treatment of surgically acquired and idiopathic hypoparathyroidism requires life-long treatment with vitamin D and oral calcium supplementation. This is not, however, a perfect physiologic replacement because, although it sufficiently regulates blood calcium and phosphate levels, it does not reverse the lowered urinary calcium reabsorption and excessive urinary calcium excretion, which may result in renal stones.25 Owing to the complexity of parathyroid hormone's metabolic interactions, clinical hypoparathyroidism is one of the most difficult of all endocrine disorders to treat. Autotransplantation of parathyroid tissue in humans is well established and widely practiced.37"41 Although parathyroid allotransplantation is well established in animal models, it is rarely performed in humans and has rarely been used clinically because its advantages have been outweighed by the need for immunosuppression. Allotransplantation of parathyroid tissue in humans may be desirable, however, for treating long-term hypoparathyroidism (e.g., after inadvertent removal of parathyroid glands during thyroid surgery). Studies have attempted to reduce the immunogenicity of parathyroid tissue similarly to thyroid tissue. Microencapsulation, as noted before, is a technique that was first attempted in islet cell transplantation. Hasse and colleagues have been able to achieve long-term success in a rat model.42 After isolation and tissue culture, tissue pieces from parathyroid glands of 280 Lewis rats were encapsulated in barium alginate and grafted into hypocalcemic DA rats. From the 7th to the 90th day after transplantation, the recipient rats (DA rats) showed a normal serum calcium concentration, demonstrating the successful long-term survival and function of microencapsulated allotransplanted parathyroid tissue.

This group subsequently evaluated the feasibility of parathyroid xenotransplantation.43 In this study, human parathyroid tissue was microencapsulated and transplanted into the rat and the effect of this microencapsulation on xenotransplanted human parathyroid tissue was evaluated over a 30-week course. Functionally human parathyroid tissue was able to replace that of the rat. All animals that had received the microencapsulated parathyroid tissue were normocalcemic for 16 weeks and 27 of 40 animals were normocalcemic at the end of the study. In contrast, serum calcium concentrations dropped to postparathyroidectomy levels within 4 weeks in the animals that had received native tissue only. Histologic evaluation of the explanted, functionally successful xenografts showed vital parathyroid tissue inside intact microcapsules surrounded by a small rim of fibroblasts. Fibrotic nonfunctioning parathyroid remnants were demonstrated in animals with nonencapsulated parathyroid tissue. These authors established the feasibility of microencapsulation of human parathyroid tissue and ability to preserve its viability over long periods in vivo, even with xenotransplanted tissue. Thus, transplantation of human parathyroid tissue and maintenance of its physiologic function were achieved without postoperative systemic immunosuppression in a xenotransplant model.44'45 The group validated this model with an amitogenic alginate, and this technique has now been used clinically where parathyroid transplantation was performed without immunosuppression (Fig. 77-2).46

j Weeks

Transplantation j Weeks

Transplantation

FIGURE 77-2. Calcium and intact parathyroid hormone (iPTH) concentrations before and after parathyroid allotransplantation. Hasse and colleagues46 succeeded in parathyroid allotransplantation in two human subjects without immunosuppression. The donor for the patients was an ABO-compatible, human leukocyte antigen (HLA)-mismatched patient with parathyroid hyperplasia caused by secondary hyperparathyroidism. After parathyroidectomy, the tissue was cut into 1-mm3 pieces and immersed in amitogenic 2% sodium alginate. The suspension was passed through a spray nozzle for encapsulation with a constant flow of 6.5 L/min. The microencapsulated parathyroid cells were cultured and 20 microcapsules were transplanted into the brachioradialis muscle of the nondominant forearm of the patients. After transplantation, the recipients had normal levels of calcium and iPTH without immunosuppression. (From Lee MK, Bae YH. Cell transplantation for endocrine disorders. Adv Drug Deliv Rev 2000;42:103.)

Prior to these techniques utilizing immunoisolation, other investigators also studied parathyroid allotransplantation using other techniques47"49 leading to attempts at parathyroid allotransplants in humans.50 Duarte and coauthors reported on a 25-year-old woman with idiopathic hypoparathyroidism that had been diagnosed when the patient was 4 years of age.51 Long-term medical management with vitamin D and oral calcium supplementation was complicated by multiorgan calcinosis and renal failure. At the age of 21 years, the patient received a successful cadaveric renal allograft; however, 4 years later, she developed calcinosis cutis with widespread skin necrosis. Medical control of calcium and phosphate metabolism was unsatisfactory, and the skin necrosis became progressive and life threatening. A parathyroid allograft that was performed with tissue from a parathyroid adenoma resulted in normalization of the serum calcium and phosphorus levels with arrest and subsequent healing of the skin necrosis. Later failure of the parathyroid allograft was followed by successful retransplantation of normal parathyroid tissue from a cadaveric organ donor.51 In addition, Tolloczko and colleagues reported on patients with postoperative hypoparathyroidism (after thyroid operations) who were treated with cultured, hormonally active, living and ABO-compatible parathyroid cells.52"54 Tissue was harvested from two patients with secondary hyperparathyroidism. In these studies, hormonal activity of the graft was variable but lasted up to 14 months. Others have also attempted parathyroid allotransplantation to treat intractable hypoparathyroidism.55'56

Similar to the immunoisolation provided by encapsulation, other methods to avoid long-term immunosuppression such as immunomodulation have been employed in order that parathyroid allotransplantation be feasible. Pretransplantation treatment of the graft to eliminate passenger cells is one such method. An alternative approach is short-term treatment of the recipients with cyclosporine. Bloom and associates cultured parathyroid glands from Lewis X Brown Norway rats for 1 week and treated them with antiserum directed against class II MHC antigens.57 Treated glands were then transplanted into hypocalcemic Wistar-Furth recipients that previously received 30 mg/kg cyclosporine once a day for 3 days before transplantation. At 280 days after transplantation, 67% of the recipients had functional parathyroid allografts. Control rats (no cyclosporine; fresh, untreated glands) rejected these grafts within 28 days. Control rats given 3 days of cyclosporine and transplanted with fresh, untreated glands had functional grafts for greater than 56 days (median survival, 80.5 days). The authors concluded that prolongation of allograft survival with short-term, preoperative cyclosporine demonstrates the efficacy of immunosuppression given at the time of antigen presentation. This course of cyclosporine was even more effective when the recipient received a graft whose passenger cells were eliminated.

Some sites in the body may also be immunoprivileged. The lateral ventricle of the brain has been investigated as a potential immunoprivileged site for viable parathyroid allografts.58,59 Yao and colleagues allotransplanted parathyroid tissue from histoincompatible rats that survived and remained functional for more than 3 months in the cerebral ventricles of recipient F344 rats. Microscopic examination proved that the allotransplanted parathyroid tissues retained normal histologic features. In contrast, when the parathyroid was placed beneath the renal capsule, the allografted parathyroid tissue uniformly lost its capacity to liberate parathyroid hormone within 1 month, and only residual scar tissue remained at the transplantation site. After allotransplantation of parathyroid tissue into the cerebroventricle, the serum concentrations of both Ca2+ and parathyroid hormone were maintained at levels similar to those before parathyroidectomy, until the time of sacrifice. The thymus has also been reported as an immunoprivileged site for parathyroid auto transplants.60

As noted, parathyroid autotransplantation is a well-defined clinical entity with an interesting history37 39 and is most often performed for a parathyroid inadvertently removed during thyroid surgery or when it cannot be preserved on its vascular supply. Autotransplantation may also be performed in the management of the patient with parathyroid hyperplasia or secondary hyperparathyroidism. As this is the technique most commonly performed by the endocrine surgeon, the technique of autotransplantation is reviewed here.

Parathyroid tissue to be autotransplanted is temporarily stored in iced saline solution. A muscle pocket is created (generally in the sternocleidomastoid or the forearm, although the subcutaneous space has also been used). It is important to avoid bleeding in the pocket as hematoma formation prevents subsequent vascularization of the autograft; thus, packing the pocket for several minutes to ensure hemostasis is advised. Multiple pockets may also be created, and we do so to maximize subsequent autotransplant success and decrease the risk of loss related to hematoma. The parathyroid tissue (approximately 1- x 1-mm pieces) is placed into the pocket(s). The pocket may be closed with a Prolene suture, clip, or both, to mark the transplant site as hyperparathyroidism may develop after autotransplantation of histologically normal parathyroid tissue. For this reason, it is important to mark the site of the parathyroid autotransplant.61 In addition to the immediate transplantation of fresh tissue, cryopreserved tissue may be autotransplanted in this manner. The specific techniques of cryopreservation have been described in detail and are widely used.62'63

Thus, although parathyroid autotransplantation is well established clinically, allotransplantation may hold promise for the future. Cultured fetal parathyroid gland cells have been used in treating patients with hypoparathyroidism.64 Whether these techniques or stem cell technology will have utility in the treatment of hypoparathyroid patients will require further elucidation.

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