Effect of aluminium on the development of hyperparathyroidism and bone disease in the azotaemic rat

Aluminium toxicity in dialysis patients is associated with arelative parathyroid hormone (PTH) deficiency as well as osteomalacia.In-vitro studies of parathyroid cells have shown that aluminiuminhibits PTH secretion. However, only limited data are availableon how aluminium affects the development of hyperparathyroidismin the azotaemic animal. Four groups of azotaemic rats werestudied; in each group, renal failure was induced by a two-stage5/6 nephrectomy, after which rats were studied for 40 days.In three groups hyperparathyroidism was stimulated by the useof a high phosphorus (1.2%) diet (HPD). The four groups were(1) HPD; (2) HPD+high-dose aluminium (HDAL)—1.5 mg ofaluminium was adminis tered intraperitoneally (IP) 5 days perweek; (3) HPD+low-dose aluminium (LDAL)—0.5 mg of aluminiumwas administered IP 5 days per week; and (4) moderate phosphorus(0.6%) diet (MPD); the MPD group was used to control hyperparathyroidismand thus provide a comparison of PTH levels and azota emic bonedisease. After 40 days, the serum PTH level was higher (P<0.05)in the HPD+HDAL group (37±2pmol/l) than the HPD, HPD+LDAL,and MPD groups (24±3, 28±4, and 6±1 pmol/lrespect ively). The correlation between serum PTH and calcium,serum PTH and phosphorus, and serum calcium and phosphorus wassignificant for the four groups (P<0.02); however, the relationshipbetween serum PTH and calcium, and between serum calcium andphosphorus was altered in the HPD+HDAL group (serum aluminium30.8±2µmol/l). Aluminium administration induceda decrease (P<0.05) in the bone formation rate and the adjustedapposition rate, and an increase (P<0.05) in osteoid volumeand the min eralization lag time. Despite aluminium administration,diet-induced hyperparathyroidism resulted in an increase (P<0.05)in the osteoblast surface. In conclusion, in the azotaemic rat(1) aluminium did not slow the development nor decrease themagnitude of hyper parathyroidism; (2) aluminium appeared toalter the relationship between serum PTH and calcium, and betweenserum calcium and phosphorus; (3) hyperpara thyroidism changedthe expression of aluminium-induced bone disease and may affordthe bone some protection against the toxic effects of aluminium.     

Different effects of calcitriol and parathyroidectomy on the PTH--calcium curve in dialysis patients with severe hyperparathyroidism

BACKGROUND: The PTH–calcium sigmoidal curve is shifted to the right,the slope of the curve is steeper, and the set point of calciumis increased in dialysis patients with secondary hyperparathyroidism,compared to patients with low-turnover bone disease. These findingscould be related to increased parathyroid cell mass and increasedsensitivity of parathyroid cells to serum calcium variationsin these patients. Calcitriol therapy has been documented toreduce PTH levels by shifting the curve to the left and downward.The effect of a surgical reduction of parathyroid gland masson the PTH-calcium curve has not yet been investigated. In thisstudy we compared the effects of calcitriol and subtotal parathyroidectomy(PTH) on the dynamics of PTH secretion in response to acutechanges of serum calcium in two groups of dialysis patientswith severe hyperparathyroidism. METHODS: Fourteen dialysis patients treated for 6 months with high-dosei.v. calcitriol (1–2 µg thrice weekly), and 10 dialysispatients who underwent subtotal PTx were studied. The PTH–calciumrelationship obtained by inducing hypo- and hypercalcaemia bymeans of low and high calcium dialysis was evaluated beforeand 2–6 months after treatment. RESULTS: Both calcitriol and subtotal PTx significantly decreased PTH(respectively from 797±595 to 380±244 and from1036±250 to 70±34 pg/ml), as well as maximal PTHresponse to hypocalcaemia (PTHmax), and maximal PTH suppressionduring hypercalcaemia (PTHmin). When the PTH–calcium curveswere constructed using PTHmax as 100% to factor for differencesin absolute PTH levels and to provide an assessment of individualparathyroid cell function, a shift of the sigmoidal curve tothe left and downward, and a significant decrease in the setpoint of ionized calcium (from 1.31±0.05 to 1.26±0.05and from 1.36±0.09 to 1.22±0.07 mmol/1) was documentedwith both treatments. However, the slope of the PTH–calciumcurve increased after subtotal PTx indicating that the sensitivityof the parathyroid cell to serum calcium changes increased withPTx, while on the contrary it decreased with calcitriol. CONCLUSIONS: PTH secretion decreases proportionally more with calcitriolthan with surgery for a given decrease in the functional massof parathyroid cells. The change in the PTH–ICa sigmoidalcurve induced by subtotal PTx is due to the removal of a largemass of parathyroid tissue with advanced hyperplasia.     

Cinacalcet HCl Suppresses <Emphasis Type="Italic">Cyclin D1</Emphasis> Oncogene-Derived Parathyroid Cell Proliferation in a Murine Model for Primary Hyperparathyroidism

Cinacalcet HCl (cinacalcet) is a calcimimetic compound, which suppresses parathyroid (PTH) hormone secretion from parathyroid glands in both primary hyperparathyroidism (PHPT) and secondary hyperparathyroidism (SHPT). We previously reported the suppressive effect of cinacalcet on PTH secretion in vivo in a PHPT model mouse, in which parathyroid-targeted overexpression of the cyclin D1 oncogene caused chronic biochemical hyperparathyroidism and parathyroid cell hyperplasia. Although cinacalcet suppressed parathyroid cell proliferation in SHPT in 5/6-nephrectomized uremic rats, its effect on PHPT has not yet been determined. In this study, the effect of cinacalcet on parathyroid cell proliferation was analyzed in PHPT mice. Cinacalcet (1 mg/g) was mixed into the rodent diet and orally administrated to 80-week-old PHPT mice for 10 days before death. 5-Bromo-2′-deoxyuridine (BrdU, 6 mg/day) was infused by an osmotic pump for 5 days before death, followed by immunostaining of the thyroid–parathyroid complex using an anti-BrdU antibody to estimate parathyroid cell proliferation. Compared to untreated PHPT mice, cinacalcet significantly suppressed both serum calcium and PTH. The proportion of BrdU-positive cells to the total cell number in the parathyroid glands increased considerably in untreated PHPT mice (9.5 ± 3.1%) compared to wild-type mice (0.7 ± 0.1%) and was significantly suppressed by cinacalcet (1.2 ± 0.2%). Cinacalcet did not affect apoptosis in the parathyroid cells of PHPT mice. These data suggest that cinacalcet suppressed both serum PTH levels and parathyroid cell proliferation in vivo in PHPT.     

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

Background

Hypoparathyroidism, the most common complication after thyroid surgery, leads to hypocalcaemia and significant medical problems. An RCT was undertaken to determine whether intraoperative parathyroid gland angiography with indocyanine green (ICG) could predict postoperative hypoparathyroidism, and obviate the need for systematic blood tests and oral calcium supplementation.

Methods

Between September 2014 and February 2016, patients who had at least one well perfused parathyroid gland on ICG angiography were randomized to receive standard follow‐up (measurement of calcium and parathyroid hormone (PTH) on postoperative day (POD) 1 and systematic supplementation with calcium and vitamin D; control group) or no supplementation and no blood test on POD 1 (intervention group). In all patients, calcium and PTH levels were measured 10–15 days after thyroidectomy. The primary endpoint was hypocalcaemia on POD 10–15.

Results

A total of 196 patients underwent ICG angiography during thyroid surgery, of whom 146 had at least one well perfused parathyroid gland on ICG angiography and were randomized. None of these patients presented with hypoparathyroidism, including those who did not receive calcium supplementation. The intervention group was statistically non‐inferior to the control group (exact 95 per cent c.i. of the difference in proportion of patients with hypocalcaemia –0·053 to 0·053; P = 0·012). Eleven of the 50 excluded 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, which was significantly different from the findings in randomized patients (P = 0·007).

Conclusion

ICG angiography reliably predicts the vascularization 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. Registration number: NCT02249780 ( http://www.clinicaltrials.gov ).     

Calcium homeostasis and bone pathology in magnesium deficient rats

Summary Calcium homeostasis and bone pathology were studied in weanling rats fed a low (70 ppm) magnesium diet for 2–21 days. The rats developed significant, progressive hypercalcemia after 6 days on the diet. The increase in blood calcium was accompanied by progressive hypoactivity of the parathyroid gland (PTG), as determined by histologic and morphometric analyses. Thus hyperactivity of the PTG could not have been responsible for the hypercalcemia observed. Histologic examination of femora and humeri from magnesium-deficient rats showed progressive subperiosteal hyperplasia, consisting of undifferentiated osteoprogenitor cells and fibrous tissue, after 7 days of deficiency. The presence of unmineralized osteoid tissue in the metaphyses indicated that mineralization was not proceeding normally. The alterations in differentiation of osteoprogenitor cells, together with the failure of mineralization, resulted in significantly lower rates of bone formation (as measured by fluorochrome labeling) in the magnesium-deficient rats. Basophilic cementing lines and inactive osteocytes in the cortices of bones from magnesium-deficient rats indicated that bone resorption was also severely reduced in magnesium deficiency. We postulate that bone magnesium depletion (66% by day 21) has a direct negative effect on osteoblastic and osteocytic activity, and may explain, in part, the decreased responsiveness of bone to parathyroid hormone (PTH) that has been observed in magnesium-deficient animals.     

Calcimimetic NPS R-568 prevents parathyroid hyperplasia in rats with severe secondary hyperparathyroidism

Calcimimetic NPS R-568 prevents parathyroid hyperplasia in rats with severe secondary hyperparathyroidism. BACKGROUND: Secondary hyperparathyroidism (secondary HPT) in chronic renal insufficiency (CRI) is characterized by multiglandular hyperplasia. METHODS: In this study, we investigated the effects of the calcimimetic NPS R-568 on the parathyroid gland in rats with CRI induced by ligation of the renal arteries and severe secondary HPT induced by dietary phosphorus loading. Six days after surgery, high-phosphorus diet feeding was started, and NPS R-568 was administered to the rats for 56 days either by daily gavage (30 or 100 micromol/kg) or by continuous subcutaneous infusion (20 micromol/kg. day). RESULTS: After 54 days, serum PTH levels in vehicle-treated CRI rats were 1019 vs. 104 pg/mL in sham-operated controls. Infusion of NPS R-568 maintained serum PTH at levels comparable with those of sham-operated controls, whereas daily gavage also prevented much of the increase in CRI controls and decreased PTH levels intermittently in a dose-dependent fashion. Parathyroid gland enlargement was caused predominantly by hyperplasia. Total cell number per kg body wt was 3.5-fold higher in vehicle-treated CRI rats than in sham-operated controls. Both infusion and high-dose gavage of NPS R-568 completely prevented the increase in parathyroid cell number. CONCLUSION: These results demonstrate that the calcimimetic compound NPS R-568 can prevent both the increase in serum PTH levels and parathyroid hyperplasia in rats with CRI and severe secondary HPT. Moreover, these changes occurred despite decreases in serum 1, 25(OH)2D3 and increases in serum phosphate, suggesting a dominant role for the calcium receptor in regulating parathyroid cell proliferation.     

近红外自体荧光显像技术在甲状腺肿瘤手术中辅助识别甲状旁腺有效性分析

目的 探讨分析近红外自体荧光显像（NIRAF）技术在甲状腺肿瘤手术中辅助识别甲状旁腺的有效性。方法 回顾性分析中国人民解放军总医院第一医学中心2020-04-01-2020-10-20应用NIRAF技术实施甲状腺肿瘤手术的53例病例临床资料,设为辅助组。同时对同中心同期完成的甲状腺肿瘤手术病例资料经过倾向性评分匹配后选取53例作为对照组,与辅助组进行匹配。对比分析两组术后甲状旁腺保护情况。结果 辅助组术中识别确切甲状旁腺数目多于对照组,差异有统计学意义（P<0.05）。辅助组术后甲状旁腺激素（PTH）水平和血清钙离子浓度高于对照组,差异有统计学意义（P<0.05）。行双侧甲状腺切除的病例中,辅助组术后PTH水平和血清钙离子浓度高于对照组,差异有统计学意义（P<0.05）。通过甲状腺切除后标本观察证实,补救2枚遗漏甲状旁腺,予以重新种植。结论 NIRAF技术能够有效辅助识别甲状旁腺,进而提示外科医生对其有效保护,起到功能保护的作用,进一步提高了甲状腺手术的安全性。     

Sevelamer hydrochloride reverses parathyroid gland enlargement via regression of cell hypertrophy but not apoptosis in rats with chronic renal insufficiency.

BACKGROUND: Dietary phosphate restriction suppresses parathyroid hormone (PTH) secretion, synthesis, and parathyroid cell proliferation in experimental animals with chronic renal insufficiency (CRI), independently of serum calcium and 1,25(OH)2D3 levels. This study was conducted to examine whether sevelamer hydrochloride (sevelamer), a metal-free phosphate binder, could regress an advanced parathyroid gland (PTG) hyperplasia and enlargement in rats with CRI. METHODS: Male Sprague-Dawley rats were fed a diet containing adenine for 6 weeks to establish CRI. Normal rats and adenine-treated rats were sacrificed to obtain the PTG (baseline group). The adenine diet was changed to a normal diet or diet containing 1 or 3% sevelamer for another 4 weeks. Time course changes of serum levels of calcium, phosphorus, and PTH were measured. At the end of the study, the PTG was weighed and examined histologically. RESULTS: Adenine-treated rats developed severe CRI with marked elevation of serum phosphorus and PTH. The PTG weight markedly increased with enlarged cell volume (i.e. cell hypertrophy) at baseline. Sevelamer treatment rapidly lowered serum phosphorus and PTH levels within 6 days, and after 4 weeks, reduced the PTG weight by 38% compared to adenine-treated rats at baseline. The reduction in PTG weight was due to regression of cell hypertrophy, but not to decreased cell number by apoptosis. Decreased expression of calcium receptor in the PTG at baseline was partially recovered by the sevelamer treatment. CONCLUSIONS: The sevelamer treatment can reduce the PTG weight with a reduction in serum PTH levels via regression of cell hypertrophy but not apoptosis in rats with CRI. Reduced PTG function might contribute to the regression of cell hypertrophy.     

Parathyroid hormone modulates the release of atrial natriuretic peptide during acute volume expansion.

In this study we investigated the effect of volume expansion on plasma and atrial concentrations of atrial natriuretic peptide (ANP) in the presence and absence of the parathyroid gland and under normocalcemic and hypocalcemic conditions. After volume expansion ANP concentration in plasma was significantly (p < 0.001) higher in intact (702 +/- 86 pg/ml) than in hypocalcemic parathyroidectomized (PTX) (271 +/- 38 pg/ml) rats. Plasma ANP of PTX rats rendered normocalcemic with oral calcium supplementation increased to 402 +/- 85 pg/ml after volume expansion. Results from this study suggest that parathyroid hormone (PTH) is required for augmented ANP secretion in response to acute volume loading and alterations of extracellular calcium may modulate volume-induced ANP release in PTX rats. We would discuss that a parathyroid gland-cardiac atria interaction exists and that changes in serum level of PTH may play a role in the regulation of fluid homeostasis via ANP secretion.     

Parathormone response to thyroid surgery

BACKGROUND: Confident determination of adequate residual parathyroid function early after thyroid surgery could facilitate the discharge of patients soon after their operation without the need for subsequent serum calcium monitoring and/or calcium and vitamin D supplementation. METHODS: Thirty-one patients who underwent 33 thyroid operations (22 unilateral lobectomies and 11 bilateral thyroid resections) were prospectively studied. Parathormone (PTH) levels were measured intraoperatively, and serum calcium was monitored before and after surgery to determine PTH and calcium homeostatic response to thyroid surgery. RESULTS: A significant decrease in circulating PTH occurred during 27 procedures, most markedly after specimen mobilization. Intraoperative PTH and postoperative calcium levels were lowest in those who underwent bilateral operations. Patients who underwent unilateral procedures experienced significant decreases in PTH but not postoperative calcium levels. A PTH level >50% of baseline predicted normocalcemia by postoperative day 3. However, PTH level did not accurately triage other patients' risk for postoperative hypocalcemia. CONCLUSIONS: A decrease in PTH levels intraoperatively is a common event during both unilateral and bilateral thyroid operations. Although normal PTH levels at the end of surgery ensure normocalcemia after surgery, patients with low final PTH measurements may not develop significant hypocalcemia after surgery.     

Endoscopic Lateral Approach Thyroid Lobectomy: Safe Evolution from Endoscopic Parathyroidectomy

Introduction Endoscopic thyroid surgery has been shown to be feasible. Most minimal access procedures have been performed via a midline approach. Based on our experience of more than 500 endoscopic parathyroidectomies via a lateral approach we have used the same method for thyroid lobectomy. Methods We present our experience of endoscopic thyroid lobectomy via a lateral approach (ETLA) and review of the results over a 1-year period (2004). Inclusion criteria for ETLA were (1) solitary nodule with atypical/suspicious fine–needle biopsy (FNB) or solitary toxic nodule; (2) lesions with a diameter of <3 cm. Patients with a history of previous neck surgery or radiation exposure were excluded. All patients underwent postoperative vocal cord checks and plasma calcium evaluation. Results A total of 742 thyroid procedures were performed during 2004. Among them, 38 patients (5.1%) underwent ETLA. Indications for surgery were suspicious FNB results (36 patients) and a toxic nodule (2 patients). Mean nodule size was 19.2 mm. Mean ± SD operating time was 102 ± 27 minutes. All recurrent laryngeal nerves were identified (including one that was nonrecurrent). Of the 38 patients, the superior parathyroid gland was identified in 36 and the inferior parathyroid gland in 33. There were two conversions due to difficulty with the dissection. Two operations were converted because malignancy was diagnosed on frozen section examination. Two patients underwent a delayed completion thyroidectomy when definitive histology necessitated it. There were no permanent operative complications, and all patients were discharged on the first postoperative day. Conclusions ETLA offers excellent intraoperative visualization of the vital structures and is a safe alternative to conventional thyroid lobectomy in selected cases.     

Effect of endothelin receptor antagonist on parathyroid gland growth, PTH values and cell proliferation in azotemic rats.

BACKGROUND: A variety of stimuli are involved in the pathogenesis of parathyroid gland hyperplasia in renal failure. Recently, it was shown that blocking the signal from the endothelin-1 (ET-1) receptor (ET(A)R/ET(B)R) by a non-selective receptor antagonist, bosentan, reduced parathyroid cell proliferation, parathyroid gland hyperplasia and parathyroid hormone (PTH) levels in normal rats on a calcium deficient diet. Our goal was to determine whether in 5/6 nephrectomized (NPX) rats with developing or established hyperparathyroidism, the endothelin receptor blocker, bosentan, reduced the increase in parathyroid cell proliferation, parathyroid gland hyperplasia and PTH values. METHODS: High (HPD, 1.2%) or normal phosphorus diets (PD) (NPD, 0.6%) were given to 5/6 NPX rats for 15 days (NPX(15)). In each dietary group, one-half the rats were given bosentan (B) i.p. 100 mg/kg/day. The four groups of rats were: (1) NPX(15)-1.2% P; (2) NPX(15)-1.2% P+B; (3) NPX(15)-0.6% P; and (4) NPX(15)-0.6% P+B. In a second study in which hyperparathyroidism was already established in 5/6 NPX rats fed a HPD for 15 days, rats were divided into two groups in which one group was maintained on a HPD and the other group was changed to very low PD (VLPD, <0.05%) for an additional 15 days. In each dietary group, one-half the rats were given bosentan i.p. 100 mg/kg-day. The four groups of rats were: (1) NPX(30)-1.2% P; (2) NPX(30)-1.2% P+B; (3) NPX(30)-0.05% P and (4) NPX(30)-0.05% P+B. Parathyroid cell proliferation was measured by proliferating cell nuclear antigen (PCNA) staining and ET-1 expression by immunohistochemical techniques. RESULTS: In the study of developing hyperparathyroidism, bosentan reduced ET-1 expression in the parathyroid glands of rats on the NPD and HPD (P<0.05). But only in rats on the NPD did bosentan result in a reduced increase in parathyroid gland weight (P<0.05). In the study of established hyperparathyroidism, in which 5/6 NPX rats were given a HPD for 15 days, bosentan started on day 15 reduced (P<0.05) ET-1 expression in rats maintained for 15 additional days on the HPD or the VLPD. On the VLPD, parathyroid gland weight was less (P<0.05) than that in rats on the HPD sacrificed at 15 or 30 days. Bosentan did not reduce parathyroid cell proliferation or parathyroid gland weight in rats maintained on the HPD or further reduce these parameters beyond that obtained with dietary phosphorus restriction. PTH values were lowest in the VLPD group, intermediate in the NPD group, and highest in the HPD group, but in none of the three groups did bosentan decrease PTH values. CONCLUSIONS: In azotemic rats with developing hyperparathyroidism, bosentan resulted in a reduced increase in parathyroid gland weight when dietary phosphorus content was normal. Despite a reduction in ET-1 expression in rats on a HPD with developing or established hyperparathyroidism, bosentan did not reduce the increase in parathyroid cell proliferation, parathyroid gland growth or PTH values. Thus, ET-1 blockade with bosentan did not prevent parathyroid gland growth in the azotemic rat.     

Hemithyroidectomy: long-term effects on parathyroid function--preliminary report

Early hypocalcemia after thyroid surgery has frequently been reported, whereas data regarding long-term effects on calcium homeostasis are scarce. We have previously studied patients after hemithyroidectomy with an oral calcium load test and found normal parathyroid hormone (PTH) suppression. However, the 1,25-dihydroxyvitamin D concentration was decreased and the phosphate concentration increased, implying parathyroid insufficiency. We therefore proceeded to investigate PTH secretion and suppression in 10 euthyroid patients subjected to hemithyroidectomy due to benign thyroid disease before and at 1 year after surgery. In addition, biochemical variables known to influence calcium homeostasis were analyzed. Basal, maximal, and total PTH secretion were unaltered 1 year postoperatively. However, maximal PTH secretion was reached at a lower serum level of ionized calcium, and there was a tendency toward increased parathyroid sensitivity to ionized calcium. Furthermore, compared to preoperative, total serum calcium, 1,25-dihydroxyvitamin D, and free thyroxine (T4) concentrations were decreased at follow-up. Total serum calcium and 1,25-dihydoxyvitamin D concentrations were decreased 1 year after hemithyroidectomy. These changes were not due to parathyroid insufficiency. Instead, our results imply increased parathyroid sensitivity to calcium and possibly reduced peripheral sensitivity to PTH.     

Low parathyroid hormone levels after thyroid surgery: a feasible predictor of hypocalcemia

BACKGROUND: Selecting patients with a low risk of hypocalcemia is mandatory if patients are to be discharged on the first day after bilateral thyroidectomy. This study investigated the predictive value of intraoperative parathyroid hormone (PTH). METHODS: Thirty-eight patients underwent total or near-total thyroidectomy. Patients with or without biochemical and symptomatic hypocalcemia were compared regarding intraoperative PTH levels and previously suggested risk factors. The accuracy of intraoperative PTH to predict patients at risk for postoperative hypocalcemia was compared with a calcium concentration of less than 2.00 mmol/L (8.0 mg/dL) on the first postoperative day. RESULTS: PTH levels after resection of the second lobe, age, and number of parathyroid glands identified intraoperatively were independently associated with the reduction in serum calcium concentration measured at nadir on the first or second postoperative day. PTH levels after resection of the second lobe were lower among patients who developed biochemical (P <.001) and symptomatic hypocalcemia (P <.01) compared with those who did not. Low levels of intraoperative PTH identified the 3 patients who required intravenous calcium during the first 24 postoperative hours. An intraoperative PTH level below reference range and a calcium concentration of less than 2.00 mmol/L measured 1 day postoperatively both predicted biochemical hypocalcemia with a similar sensitivity (90% vs 90%) and specificity (75% vs 82%). Intraoperative PTH was slightly better than a serum calcium concentration of less than 2.00 mmol/L on postoperative day 1 to predict symptomatic hypocalcemia, with a sensitivity of 71% vs 52% and a specificity of 81% vs 76%, respectively. CONCLUSIONS: Parathyroid gland insufficiency is the main determinant of transient hypocalcemia after bilateral thyroid surgery. Low intraoperative PTH levels during thyroid surgery are therefore a feasible predictor of postoperative hypocalcemia.     

Calcium deficiency reduces circulating levels of FGF23

Fibroblast growth factor (FGF) 23 inhibits calcitriol production, which could exacerbate calcium deficiency or hypocalcemia unless calcium itself modulates FGF23 in this setting. In Wistar rats with normal renal function fed a diet low in both calcium and vitamin D, the resulting hypocalcemia was associated with low FGF23 despite high parathyroid hormone (PTH) and high calcitriol levels. FGF23 correlated positively with calcium and negatively with PTH. Addition of high dietary phosphorus to this diet increased FGF23 except in rats with hypocalcemia despite high PTH levels. In parathyroidectomized rats, an increase in dietary calcium for 10 days increased serum calcium, with an associated increase in FGF23, decrease in calcitriol, and no change in phosphorus. Also in parathyroidectomized rats, FGF23 increased significantly 6 hours after administration of calcium gluconate. Taken together, these results suggest that hypocalcemia reduces the circulating concentrations of FGF23. This decrease in FGF23 could be a response to avoid a subsequent reduction in calcitriol, which could exacerbate hypocalcemia.     

Accuracy of PTH assay and corrected calcium in early prediction of hypoparathyroidism after thyroid surgery.

OBJECTIVE: To evaluate the accuracy of the intraoperative parathyroid hormone (ioPTH) and 6-hour PTH (6hPTH) assay in predicting transient hypoparathyroidism after thyroidectomy. STUDY DESIGN: A nonrandomized prospective study was conducted on patients undergoing thyroid surgery. SUBJECTS AND METHODS: Of 138 patients undergoing thyroid surgery, intraoperative PTH was measured 10 minutes after gland removal. Serum calcium, magnesium, inorganic phosphorus, albumin, and PTH levels were assayed 6 and 16 hours after surgery and daily until patient discharge. RESULTS: The development of postoperative hypocalcemia was associated with low ioPTH (P < 0.0001) and 6hPTH (P < 0.0001) values, and the decline of PTH from baseline (P < 0.0001). The cutoff for percentage decline of ioPTH and 6hPTH (55.7% and 379%, respectively) was more accurate than an absolute value. Accuracy, and positive and negative predictive values were 88 percent, 63 percent, and 100 percent for ioPTH and 75 percent, 46 percent, and 100 percent for 6hPTH, respectively. CONCLUSION: With the use of ioPTH decline in association with 16-hour corrected calcium, it is possible to distinguish early normocalcemic patients from hypocalcemic ones in most cases.     

Effect of Roux-en Y Gastric Bypass on Bone Metabolism in Patients with Morbid Obesity: Mansoura Experiences

Background  Roux-en-Y gastric bypass (RYGBP) has been found to be the most efficient way to lose weight and maintain the weight loss in morbid obesity. However, with the formation of a new stomach and the modification of intestinal anatomy, there are significant changes on bone metabolism. The objectives of this study were to evaluate effects of weight loss on bone metabolism after Roux-en Y gastric bypass in patients with morbid obesity. Methods  Our study included 70 patients with morbid obesity; RYGB was done for all patients. Daily postoperative oral supplementation with 1,000 mg of calcium and 800 IU of vitamin D was done for each patient. Body weight (BW), body mass index (BMI), total body fat, total lean tissue mass, bone mineral content (BMC), bone mineral density (BMD), total bone area (TBA; using dual energy X-ray absorptiometry), serum calcium, parathyroid hormone (PTH), 25-OH vitamin D, 24-h urinary calcium, and bone-specific alkaline phosphatase (BSAP) were assessed preoperatively and 1 year after surgery. Results  In our study, females comprised 70% of cases. The mean age was 35 ± 8.8 years. One year after RYGB, BW decreased significantly from 132.8 ± 26.5 to 90.3 ± 17.3 kg (p = 0.001). BMI decreased significantly from 48 ± 7.3 to 32.6 ± 4.1 kg/m² (p = 0.001). BMC decreased significantly from 2,968.6 ± 71.4 to 2,700.8 ± 45.4 g (p = 0.001). BMD decreased significantly from 1.026 ± 0.03 to 1.22 ± 0.015 g/cm² (p = 0.001). TBA decreased significantly from 2,356.2 ± 35.4 to 2,216.3 ± 43.5 cm² (p = 0.001). Serum calcium, 24-h urinary calcium, and BSAP were not significantly decreased while 25-OH vitamin D and PTH were not significantly increased after surgery. Conclusions  From this study, it is shown that RYGBP operation gives very good results as regards reduction of body weight in morbidly obese patients. Postoperative supplementation with calcium and vitamin D partially corrects osteoporosis. Thus, these patients need periodic follow-up for BMD, PTH, calcium, serum vitamin D, and markers of bone resorption and formation specially postmenopausal female.     

Hyperplasia of the parathyroid gland without secondary hyperparathyroidism

BACKGROUND: Low dietary phosphorus (P) prevents parathyroid gland (PTG) hyperplasia and the development of secondary hyperparathyroidism (SH) in uremic rats. The present study explores the effects of P restriction on parathyroid hormone (PTH) synthesis and secretion and PT cell growth in rats with established SH and PTG hyperplasia. METHODS: Normal and 5/6 nephrectomized rats were fed a high P (0.8%) diet. After two weeks, the normal rats and half of the uremic rats were sacrificed (U-HP) while the remaining uremic rats were switched to a low P (0.2%) diet (U-HP-LP). RESULTS: High dietary P induced a significant increase in serum P, PTH, and PTG weight, but not ionized calcium compared to normal animals fed the same diet (N-HP). P restriction returned serum P and PTH to normal levels by one week. In contrast, PTG size did not regress and glands remained enlarged for up to eight weeks with no evidence of apoptosis. Ribonuclease protection assay and metabolic labeling studies demonstrated similar PTH/actin mRNA ratios and 35S-labeled PTH among the three groups. Intracellular intact PTH was higher in U-HP and U-HP-LP rats compared to N-HP animals with no differences between the two uremic groups. PTG-PTH content correlated only with PTG weight, and serum PTH only with serum P. The PTG secretory response to calcium remained intact. CONCLUSIONS: In established chief-cell hyperplasia, P restriction restores normal serum PTH levels without affecting PTG hyperplasia, PTH synthesis, PTG cytosolic PTH or the PTH secretory response to calcium, suggesting an impaired exocytosis of PTH.     

Pancreastatin Plasma Levels in Patients with Primary Hyperparathyroidism

Pancreastatin, a C-terminally amidated peptide derived from chromogranin A, is known to inhibit insulin secretion, pancreatic enzyme release, and gastric acid secretion. It also inhibits parathyroid hormone (PTH) secretion in animals. The physiologic and clinical relevance of pancreastatin in humans, however, is not known. Because pancreastatin has been found in parathyroid adenomas, we investigated the plasma levels in patients with primary hyperparathyroidism (pHPT). Thirteen patients operated on for solitary parathyroid adenoma were investigated. Plasma levels of pancreastatin and serum levels of ionized calcium and intact PTH were measured before and 6 weeks after operation. In 10 patients the levels were also monitored before and 60 minutes after adenoma excision. The adenomas were investigated for pancreastatin immunoreactivity by immunocytochemistry. The median weight of the excised parathyroid adenoma was 0.64 g (range 0.07–2.00 g). Cells displaying pancreastatin immunoreactivity were present in all adenomas examined and varied in number and immunostaining intensity among and within the adenomas. Intraoperatively, after adenoma excision the levels of PTH and pancreastatin declined (p < 0.01), whereas the levels of ionized calcium did not change (p= 0.96). At the 6-week follow-up the levels of ionized calcium and PTH had decreased compared to the preoperative levels (p < 0.01), and all patients were normocalcemic. In contrast, the pancreastatin levels were not changed (14.5 ± 6.1 pmol/L preoperatively vs. 12.8 ± 11.2 pmol/L 6 weeks postoperatively; p= 0.12). In patients with pHPT, pancreastatin is likely to be produced by the parathyroid adenoma. The changes in pancreastatin levels immediately after surgery warrant further investigation.     

Maintenance of normocalcemia by continuous infusion of the synthetic bovine parathyroid hormone (1–34) in parathyroidectomized rats

Summary This work was conducted to estimate the replacement dose of the synthetic bovine parathyroid hormone [PTH(1–34)] that is required for maintenance of serum calcium (Ca) in parathyroidectomized (PTX) rats. Male rats were PTX and used in this study only if serum Ca was reduced to at least 7 mg/dl. We found that a solution of 2% cysteine, 150 mM NaCl, and 1 mM HCl was superior to 20 mM acetic acid for maintenance of biological activity of PTH (1–34) in situ during the period of hormone infusion studied. The PTH dose—calcemic response relationship was investigated using PTH in doses of 0.6, 1, and 3 U/h. The infusion of 1 U PTH per hour raised Ca to the normal level, whereas rats infused with 0.6 U/h were hypocalcemic and 3 U/h resulted in marked hypercalcemia. To extend this observation we carried out an infusion of 1 U PTH per hour for 14 days. We found that this infusion rate of bovine PTH (1–34) provided a relatively stable level of serum calcium with modest fluctuation from normocalcemic to somewhat hypercalcemic levels for the entire 14-day period of PTH infusion. Serum calcitonin was also elevated during the infusion period and then returned to the initial level when PTH treatment was stopped. After the minipumps containing PTH were removed, the serum Ca dropped rapidly to 5 mg/dl, which was significantly lower than the control (vehicle-infused) or initial values of serum Ca (7 mg/dl). Infusion of PTH at 3 U/h for 4 days did not produce this rebound hypocalcemia after the pumps were removed. Serum Ca in those experiments returned to the initial level after hormone treatment was discontinued.