[Clinical characteristics of adult-onset primary hypoparathyroidism: a retrospective analysis of 200 cases].

Objective: To study the clinical characteristics of primary hypoparathyroidism in adults. Methods: The clinical data of 200 cases with adult-onset primary hypoparathyroidism in Peking Union Medical College Hospital during December 1987 to December 2015 were collected and analyzed retrospectively. Among them, 128 cases were followed up for a median period of 3 years. Results: The major manifestations at their first visits were tetany and numbness in the distal extremities(81.5%, 163/200 and 62.0%, 124/200). Thirty-two percent of the cases (62 cases) had history of seizures, and 60.9%(98/161) and 74.4%(96/129) of them were with intracerebral calcifications and cataracts, respectively.Most of subjects(155/200)had more than one year delay in diagnosis. Hypercalciuria occurred in 67.2%(86/128) of the cases during the follow-up. No significant differences in the clinical characteristics and biochemical markers between the hypercalciuria subjects and the non-hypercalciuria subjects. Renal nephrocalcinosis or stones were found in 6.5%(5/77) of the cases, and kidney function decreased in 6.6%(6/91) of the patients. Kidney function was negatively associated with age and duration of disease. Conclusions: The predominant manifestations of primary hypoparathyroidism in adults included tetany and numbness in the distal extremities and seizures. It is often misdiagnosed. Calcium supplement combined with vitamin D or its metabolites effectively relieve clinical symptoms and signs. The serum and urinary calcium levels should be monitored frequently to reduce renal complications.

Therapy of Hypoparathyroidism With PTH(1-84): A Prospective Six Year Investigation of Efficacy and Safety.

CONTEXT: Human recombinant (rh)PTH(1-84) was recently approved for the treatment of refractory hypoparathyroidism, based upon a short-term phase 3 clinical trial. Long-term data are needed, because no time limit was placed on the treatment period. OBJECTIVE: We studied the effect of long-term rhPTH(1-84) treatment in hypoparathyroidism for up to 6 years. DESIGN: Prospective open-label study. SETTING: Referral center. PATIENTS: A total of 33 subjects with hypoparathyroidism. INTERVENTIONS: rhPTH(1-84) treatment was initiated at a starting dose of 100 µg every other day for 6 years. Due to the availability of new dosages during the 6-year time period of the study, the dose could be and was adjusted for most patients to a daily dosing regimen. MAIN OUTCOME MEASURES: Supplemental calcium and vitamin D requirements, serum and urinary calcium (monthly for 6 mo and then biannually), serum phosphorus, bone turnover markers, and bone mineral density (BMD) biannually. RESULTS: Treatment with rhPTH(1-84) progressively reduced supplemental calcium requirements over 6 years by 53% (P < .0001) and 1,25-dihydroxyvitamin D requirements by 67% (P < .0001). Sixteen subjects (48%) were able to eliminate 1,25-dihydroxyvitamin D supplementation completely. Serum calcium concentration remained stable, and urinary calcium excretion fell. Lumbar spine BMD increased (3.8 ± 1%, P = .004) as did total hip BMD (2.4 ± 1%, P = .02), whereas femoral neck BMD remained stable and the distal one third radius decreased (-4.4 ±1%, P < .0001). Bone turnover markers increased significantly, reaching a 3-fold peak above baseline values at 1 year and subsequently declining but remaining higher than pretreatment values. Hypercalcemia was uncommon (12 episodes over 6 y; 2.5% of all values). CONCLUSIONS: Long-term, continuous therapy of hypoparathyroidism for 6 years with rhPTH(1-84) is associated with reductions in supplemental calcium and calcitriol requirements, stable serum calcium concentration, and reduced urinary calcium excretion. The safety profile remains good. These data represent the longest experience with the therapeutic use of PTH for any condition and demonstrate its long-term efficacy and safety in hypoparathyroidism.

Effects of once versus twice-daily parathyroid hormone 1-34 therapy in children with hypoparathyroidism.

CONTEXT: Hypoparathyroidism is among the few hormonal insufficiency states not treated with replacement of the missing hormone. Long-term conventional therapy with vitamin D and analogs may lead to nephrocalcinosis and renal insufficiency. OBJECTIVE: Our objective was to compare the response of once-daily vs. twice-daily PTH 1-34 treatment in children with hypoparathyroidism. SETTING: The study was conducted at a clinical research center. SUBJECTS: Fourteen children ages 4-17 yr with chronic hypoparathyroidism were studied. STUDY DESIGN: This was a randomized cross-over trial, lasting 28 wk, which compared two dose regimens, once-daily vs. twice-daily PTH1-34. Each 14-wk study arm was divided into a 2-wk inpatient dose-adjustment phase and a 12-wk outpatient phase. RESULTS: Mean predose serum calcium was maintained at levels just below the normal range. Repeated serum measures over a 24-h period showed that twice-daily PTH 1-34 increased serum calcium and magnesium levels more effectively than a once-daily dose. This was especially evident during the second half of the day (12-24 h). PTH 1-34 normalized mean 24-h urine calcium excretion on both treatment schedules. This was achieved with half the PTH 1-34 dose during the twice-daily regimen compared with the once-daily regimen (twice-daily, 25 +/-15 microg/d vs. once-daily, 58 +/- 28 microg/d; P < 0.001). CONCLUSIONS: We conclude that a twice-daily PTH 1-34 regimen provides a more effective treatment of hypoparathyroidism compared with once-daily treatment because it reduces the variation in serum calcium levels and accomplishes this at a lower total daily PTH 1-34 dose. The results showed, as in the previous study of adult patients with hypoparathyroidism, that a twice-daily regimen produced significantly improved metabolic control compared with once-daily PTH 1-34.

Sporadic hypoparathyroidism treated with teriparatide: a case report and literature review.

Herein we describe the case of a 64-year-old woman with hypoparathyroidism diagnosed at the age of 40, after an acute episode of tetany and seizures due to severe hypocalcemia. She was treated for more than 20 years with calcitriol and calcium supplementation but she presented with marked hypercalciuria and recently nephrolithiasis, although serum calcium was maintained at levels below normal range. Provided that any attempt to increase the recommended dose of calcitriol was leading to an exacerbation of hypercalciuria, we decided to enroll an alternative tool in the treatment strategy. In order to avoid further deterioration of renal function she was administered once-daily a subcutaneous (sc) injection of synthetic human parathyroid hormone (PTH 1-34) while doses of calcium and calcitriol were gradually decreased depending on the response of calcium metabolism in serum and urine samples taken periodically. Within two months of administration, PTH (1-34) significantly reduced the level of urine calcium excretion compared with calcitriol therapy and maintained serum calcium in the normal range. The relevant literature is reviewed in light of this alternative therapeutic approach in long-standing hypoparathyroidism, illustrating the potential benefits and the unresolved issues in parathyroid hormone replacement.

Effect of parathyroid hormone administration in a patient with severe hypoparathyroidism caused by gain-of-function mutation of calcium-sensing receptor.

Hypoparathyroidism caused by gain-of-function mutations of the calcium-sensing receptor (CaR) in the transmembrane domain is usually severe and difficult to manage. A patient with severe hypoparathyroidism, caused by CaR activating mutation F821L, was treated for 3 days (Day 1 to Day 3) with synthetic human parathyroid hormone 1-34 (teriparatide, PTH). An Ellsworth-Howard test of the patient revealed normal responses of urine phosphate and cyclic AMP excretion, indicating that the patient's renal tubules normally responded to extrinsic PTH. On Day 1 to Day 3, 0.9 microg/kg/day of PTH was administered subcutaneously twice daily at 0800 and 2000. On Day 1, the serum calcium level that was 1.8 mmol/l before PTH administration increased to 2.1 mmol/l at 1200, and gradually decreased to 1.8 mmol/l at 2000. On Days 2 and 3, the maximum calcium levels were 2.5 and 2.4 mmol/l, respectively, at 1200. At 2000, they returned to or below basal levels at 0800. On Day 4 without PTH administration, the calcium levels were maintained at the basal levels at Day 0. The urine calcium/creatinine (Ca/Cr) ratio that was high (>0.4) before PTH injection decreased after PTH administration (0.4>). Changes in the ionized calcium levels were almost parallel with the total calcium levels. The serum inorganic phosphate (IP) level decreased to 2.4 mmol/l at 1000, but gradually increased before the second PTH injection to the level at 0800 on Day 1. The minimum IP level on Days 2 and 3 was 2.1 mmol/l and 2.0 mmol/l, respectively. In contrast to the remarkable changes in the serum calcium level by PTH treatment, the serum magnesium levels showed few changes. These results indicate that PTH therapy could be effective in correcting serum and urine calcium and the phosphate levels in hypoparathyroidism caused by activating mutation of CaR.

Synthetic human parathyroid hormone 1-34 vs calcitriol and calcium in the treatment of hypoparathyroidism.

OBJECTIVE: To test the hypothesis that treatment with human parathyroid hormone 1-34 (PTH 1-34) can maintain normal serum calcium without hypercalciuria in patients with hypoparathyroidism. DESIGN: Randomized crossover trial lasting 20 weeks. Each 10-week arm consisted of a 2-week inpatient dose-adjustment phase followed by an 8-week outpatient phase. SETTING: Tertiary care center. PATIENTS: A total of 10 patients with hypoparathyroidism were enrolled consecutively over a 15-month period. Half of the patients were prior National Institutes of Health patients, and the other 5 patients were referred from outside physicians. INTERVENTIONS: A dose of PTH 1-34 was administered each morning by subcutaneous injection. Calcitriol was given orally twice daily with supplemental calcium carbonate. MAIN OUTCOME MEASURES: Serum and urine calcium and phosphorus levels. RESULTS: Once-daily treatment with PTH 1-34 maintained serum calcium in the normal range with decreased urine calcium excretion (P<.05 at 2 weeks and P<.Ol at 10 weeks) compared with calcitriol treatment. Biochemical markers of bone turnover increased significantly (P<.Ol at 10 weeks) during PTH 1-34 treatment. CONCLUSIONS: Treatment of hypoparathyroidism with PTH 1-34 reduces urine calcium excretion compared with treatment with calcitriol and calcium.

Hypercalciuria in parathyroid disorders: effect of dietary sodium control.

Moderate dietary Na restriction (80 mmol/d for 7 days) during constant Ca intake can reduce high urinary Ca excretion to normal levels in idiopathic hypercalciuria (IH). A similar protocol was used to test its effect in primary hyperparathyroidism (PHPT) and also in hypoparathyroid subjects (HOPT) during treatment with dihydrotachysterol (DHT). Nine subjects with PHPT, 10 with HOPT, and one with pseudo-HOPT were evaluated after Na-restricted (80 mmol/d) and Na-supplemented (200 mmol/d) diets for 7 days each with dietary Ca constant. Na restriction resulted in a decrease in mean urinary 24-hour Ca excretion in PHPT subjects (10.6 v 7.6 mmol/d [424 v 304 mg], P less than 0.0001) and in one pseudo-HOPT subject, similar to the pattern seen previously in IH subjects. In contrast, Na restriction was not accompanied by significant change in Ca excretion in HOPT. There was no change in serum immunoreactive PTH (iPTH) or 1,25(OH)2 vitamin D levels in either group when Na intake was altered. Thus, the presence of parathyroid hormone (PTH) is necessary for sodium-related alterations in urinary Ca to occur. The effect of PTH appears to be "permissive" rather than "active." Dietary Na restriction may have a role in the management of hypercalciuria in mild PHPT cases when parathyroidectomy is contraindicated.

Use of thiazide diuretics to reduce the hypercalciuria of hypoparathyroidism during pregnancy.

A pregnant patient with idiopathic hypoparathyroidism is presented. Her hypomagnesemic hypocalcemia was unresponsive to conventional therapy, or magnesium supplementation. Sodium restriction with thiazide therapy successfully reduced her renal calcium wastage to control her symptoms and raise her serum calcium levels.

Urinary calcium excretion in familial hypocalciuric hypercalcemia. Persistence of relative hypocalciuria after induction of hypoparathyroidism.

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant trait comprising hypercalcemia, hypophosphatemia, parathyroid hyperplasia, and unusually low renal clearance of calcium. We evaluated the role of parathyroid hormone in the relative hypocalciuria of FHH and characterized the renal transport of calcium in this disorder using three previously hypercalcemic FHH patients with surgical hypoparathyroidism and three controls with surgical hypoparathyroidism. Intravenous infusion of calcium chloride in two patients with FHH and in three controls increased serum calcium from a mean basal of 5.0 to a mean peak of 6.8 meq/liter in two FHH patients and from 4.2 to 5.7 in three control subjects. Urinary calcium in a third FHH patient was studied without calcium infusion during recovery from hypercalcemia of vitamin D intoxication. At all serum concentrations of calcium, calcium clearance was lower in FHH than in controls; at base-line serum calcium, the ratio of calcium clearance to inulin clearance (C(Ca)/C(IN)) in FHH subjects was 32% of that in controls and decreased to 19% during hypercalcemia. Calcium infusion increased the ratio of sodium clearance to inulin clearance in controls from a base line of 0.020 to 0.053 at peak concentrations of calcium in serum, but did not affect this parameter in FHH (0.017 at base-line serum calcium vs. 0.019 at peak). When calcium infusion studies were performed (in two patients with FHH and one control) during administration of acetazolamide, a drug whose principal renal action causes inhibition of proximal transport of solute, C(Ca)/C(IN) in the patients with FHH was 29 and 7% of that of the control at base-line and peak serum calcium, respectively. In contrast, ethacrynic acid, a diuretic that acts in the ascending limb of the loop of Henle, increased C(Ca)/C(IN) more in the FHH patients than in the control subject; C(Ca)/C(IN) was 65% at base-line and 47% at peak serum calcium, compared with that of the control subject. The greater calciuric response to ethacrynic acid than to acetazolamide or calcium infusion alone in FHH indicates that a major renal locus of abnormal calcium transport in this disorder may be the ascending limb of the loop of Henle.Decreased clearance of calcium in patients with FHH and hypoparathyroidism when compared with hypoparathyroid controls indicates that relative hypocalciuria in FHH is not dependent on hyperparathyroidism. Since the parathyroid glands in FHH are not appropriately suppressed by calcium, this implies that FHH represents a disorder of abnormal transport of, and/or response to, extracellular calcium in at least two organs, parathyroid gland and kidney.

Parathyroid function tests with EDTA infusions in infancy and childhood.

To determine the functional capabilities of the parathyroid glands, 17 EDTA infusions were given to 11 children (ages 1 month to 12 years) and to two mothers of four of the children. Serum ionized Ca fell from 4.1 mg/dl to 3.4 mg/dl. Excessive parathyroid hormone responses were elicited during seven of nine EDTA infusions in five children and in one adult with hypophosphatemic rickets, during the active phase of rickets. In four of five subjects with problems related to hypercalcemia, borderline low or undetectable PTH responses were elicited. Three relatively normal PTH responses were obtained, two in an infant after phosphate-induced hypocalcemic tetany was corrected, and one in a child with a malabsorption syndrome. The renal tubular reabsorption of phosphate was inversely related and the urinary cyclic AMP excretion was positively related to the PTH response. Thus EDTA infusions in infants and children might be useful in the identification of hyper-, normo-, or hypoparathyroid states and would be of value in defining the functional condition of the parathyroid glands in children with deranged Ca or P metabolism.

The acute effect of chlorothiazide on serum-ionized calcium. Evidence for a parathyroid hormone-dependent mechanism.

The acute effects of chlorothiazide (CTZ) on total (TSCA) and ionized (SCA-plus 2) serum calcium concentrations were studied in three groups of people: (a) eight subjects with normal parathyroid function; (b) six patients with hypoparathyroidism; and (c) two patients with hyperparathyroidism. Most subjects were studied on four occasions; at least 3 days intervened between studies on an individual subject. During each experiment the subject received an i.v. influsion of 5% dextrose in water at 1 ml/min from 8 a.m. to 4 p.m. Additions to the infusions were (a) none; (b) CTZ to deliver 3.33 mg/kg/h; (c) parathyroid extract to deliver 1 U/kg/h; or (d) both CTZ and parathyroid extract at the rates previously indicated. CTZ, when used, was added to the infusion at 10 a.m., parathyroid extract at 8 a.m. When CTZ was infused, the diuretic-induced losses of Na and water were replaced by i.v. infusion. In normal subjects 2 h after the start of CTZ infusion, there was a transient increase in SCA-plus 2 which coincided in time of day with a transient decrease in SCA-plus 2 in control experiments. At that time of day SCA-plus 2 was 4.18 plus or minus 0.12 mg/100 ml in control experiments and 4.56 plus or minus 0.08 in experiments with CTZ, P smaller than 0.025. The corresponding values for (TSCA) were 9.32 plus or minus 0.15 and 9.80 plus or minus 0.30, P smaller than 0.01. Such differences were not observed in the group with hypoparathyroidism. In the two patients with hyperparathyroidism, CTZ produced sustained increases in TSCA and SCA-plus 2. In normal subjects and those with hypoparathyroidism, CTZ plus parathyroid extract infusion resulted in sustained increases in both SCA-plus 2 and TSCA throughout the periods of observation when compared to experiments in which only parathyroid extract was infused, P smaller than 0.01 in all instances. The results suggest that the acute hypercalcemic action of CTZ requires the presence of circulating parathyroid hormone.