Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus.

The purpose of this review is to assess the most recent evidence in the management of primary hyperparathyroidism (PHPT) and provide updated recommendations for its evaluation, diagnosis and treatment. A Medline search of "Hyperparathyroidism. Primary" was conducted and the literature with the highest levels of evidence were reviewed and used to formulate recommendations. PHPT is a common endocrine disorder usually discovered by routine biochemical screening. PHPT is defined as hypercalcemia with increased or inappropriately normal plasma parathyroid hormone (PTH). It is most commonly seen after the age of 50 years, with women predominating by three to fourfold. In countries with routine multichannel screening, PHPT is identified earlier and may be asymptomatic. Where biochemical testing is not routine, PHPT is more likely to present with skeletal complications, or nephrolithiasis. Parathyroidectomy (PTx) is indicated for those with symptomatic disease. For asymptomatic patients, recent guidelines have recommended criteria for surgery, however PTx can also be considered in those who do not meet criteria, and prefer surgery. Non-surgical therapies are available when surgery is not appropriate. This review presents the current state of the art in the diagnosis and management of PHPT and updates the Canadian Position paper on PHPT. An overview of the impact of PHPT on the skeleton and other target organs is presented with international consensus. Differences in the international presentation of this condition are also summarized.

Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop.

OBJECTIVE: Asymptomatic primary hyperparathyroidism (PHPT) is a common clinical problem. The purpose of this report is to guide the use of diagnostic tests for this condition in clinical practice. PARTICIPANTS: Interested professional societies selected a representative for the consensus committee and provided funding for a one-day meeting. A subgroup of this committee set the program and developed key questions for review. Consensus was established at a closed meeting that followed. The conclusions were then circulated to the participating professional societies. EVIDENCE: Each question was addressed by a relevant literature search (on PubMed), and the data were presented for discussion at the group meeting. CONSENSUS PROCESS: Consensus was achieved by a group meeting. Statements were prepared by all authors, with comments relating to accuracy from the diagnosis subgroup and by representatives from the participating professional societies. CONCLUSIONS: We conclude that: 1) reference ranges should be established for serum PTH in vitamin D-replete healthy individuals; 2) second- and third-generation PTH assays are both helpful in the diagnosis of PHPT; 3) DNA sequence testing can be useful in familial hyperparathyroidism or hypercalcemia; 4) normocalcemic PHPT is a variant of the more common presentation of PHPT with hypercalcemia; 5) serum 25-hydroxyvitamin D levels should be measured and, if vitamin D insufficiency is present, it should be treated as part of any management course; and 6) the estimated glomerular filtration rate should be used to determine the level of kidney function in PHPT: an estimated glomerular filtration rate of less than 60 ml/min.1.73 m2 should be a benchmark for decisions about surgery in established asymptomatic PHPT.

Circulating PTH molecular forms: what we know and what we don't.

Circulating parathyroid hormone (PTH) molecular forms have been identified by three generations of PTH assays after gel chromatography or high-performance liquid chromatography fractionation of serum. Carboxyl-terminal (C) fragments missing the amino-terminal (N) structure of PTH(1-84) were identified first. They represent 80% of circulating PTH in normal individuals and up to 95% in renal failure patients. They are regulated by calcium (Ca) slightly differently than PTH(1-84), occurring in a relatively smaller proportion relative to the latter in hypocalcemia but in a much larger proportion in hypercalcemia. Synthetic C-PTH fragments do not bind to the PTH/PTHrP type I receptor and are not implicated in the classical biological effect of PTH(1-84). They bind to a different C-PTH receptor and exert biological actions on bone that are opposite to those of PTH(1-84). The integrity of the distal C-structure appears to be important for these biological effects, and it is uncertain if all C-PTH fragments are intact up to position 84. A second category of C-PTH fragment has a partially preserved N-structure. They are called non-(1-84) PTH or N-truncated fragments. They react in Intact (I)-PTH assays but not in PTH assays with a 1-4 epitope. They are acutely regulated by Ca(2+) concentration. They also exert similar hypocalcemic and antiresorptive effects but have 10-fold greater affinity for the C-PTH receptor compared to other C-PTH fragments. Even if they represent only 10% of all C-PTH fragments, they could be as relevant biologically. An N form of PTH other than PTH(1-84) has been identified in the circulation. It reacts very well in PTH assays with a 1-4 epitope but poorly in I-PTH assay with a 12-18 epitope. It is oversecreted in severe primary and secondary hyperparathyroidism and in parathyroid cancers. Its biological activity is still unknown. Overall, these studies suggest that PTH(1-84) and C-PTH fragments are regulated differently to exert opposite biological effects on bone via two different receptors. This may serve to control bone turnover and Ca concentration more efficiently.

Origin of parathyroid hormone (PTH) fragments detected by intact-PTH assays.

BACKGROUND: Intact parathyroid hormone (I-PTH) assays react with non-(1-84)PTH, large carboxyl-terminal (C) fragments with a partially preserved amino-terminal (N) structure. They account for up to 50% of I-PTH in renal failure and may be implicated in PTH resistance. We wanted to know if they were secreted by the parathyroid glands and generated by peripheral metabolism of PTH(1-84). METHODS: Anesthetized normal and nephrectomized (NPX) rats were injected i.v. with 1.5 microg human (h) PTH(1-84). Blood was obtained from 8 rats at 2, 4, 6, 8, 12, 24, 48 and 96 min. I-PTH (Allegro I-PTH) was measured in all samples. Pools of serum were fractionated by HPLC at each time point and the fractions assayed to quantitate hPTH(1-84) and non-(1-84)PTH. Secretion studies were performed with dispersed cells from 5 parathyroid adenomas. The serum of 10 patients with primary hyperparathyroidism and cell supernatants were fractionated by HPLC and were analyzed as described. RESULTS: hPTH(1-84) disappeared from serum biexponentially. The half-life of the first exponential was similar in normal (2.08 min) and NPX (1.94 min) rats, while that of the second was longer in NPX rats (32.4 vs 20.9 min). The residual quantity of hPTH(1-84) under the curve was greater in NPX (6964+/-2392 pmol) than in normal rats (3229+/-561 pmol; P<0.001). Non-(1-84)PTH concentration was maximal at 8 min in both groups and was higher in NPX (92.8+/-13.8 pmol/l) than in normal rats (38.8+/-7.2 pmol/l; P<0.01). The area under the curve of non-(1-84)PTH was also greater in NPX (1904+/-405 pmol) than in normal rats (664+/-168 pmol; P<0.001). All parathyroid adenomas secreted non-(1-84)PTH. It represented 21.1+/-3.9% of secreted and 32.5+/-1.3% of circulating I-PTH in primary hyperparathyroidism. CONCLUSIONS: Non-(1-84)PTH, like other C-PTH fragments, originates from both the peripheral metabolism of hPTH(1-84) and from parathyroid gland secretion. Renal failure influences its concentration by increasing the amount of substrate available and by reducing non-(1-84)PTH clearance. Its higher proportion in serum relative to cell supernatants in primary hyperparathyroidism reflects the added role of peripheral metabolism and the longer half-life of fragments.

Aberrant membrane hormone receptors in incidentally discovered bilateral macronodular adrenal hyperplasia with subclinical Cushing's syndrome.

Cortisol secretion in adrenal Cushing's syndrome can be regulated by the aberrant adrenal expression of receptors for gastric inhibitory polypeptide, vasopressin, catecholamines, LH/human CG (LH/hCG), or serotonin. Four patients with incidentally discovered bilateral macronodular adrenal hyperplasia without clinical Cushing's syndrome were evaluated for the possible presence of aberrant adrenocortical hormone receptors. Urinary free cortisol levels were within normal limits, but plasma cortisol levels were slightly elevated at nighttime and suppressed incompletely after dexamethasone administration. Plasma ACTH was partially suppressed basally but increased after administration of ovine CRH. A 51-yr-old woman had ACTH-independent increases of plasma cortisol after 10 IU AVP im (292%), 100 microg GnRH iv (184%), or 10 mg cisapride orally (310%); cortisol also increased after administration of NaCl (3%), hCG, human LH, and metoclopramide. In a 61-yr-old man, cortisol was increased by AVP (349%), GnRH (155%), hCG (252%), and metoclopramide (191%). Another 53-yr-old male increased plasma cortisol after AVP (171%) and cisapride (142%). Cortisol secretion was also stimulated by vasopressin in a 54-yr-old female. This study demonstrates that subclinical secretion of cortisol can be regulated via the aberrant function of at least V1-vasopressin, LH/hCG, or 5-HT4 receptors in incidentally identified bilateral macronodular adrenal hyperplasia.

Normal parathyroid function with decreased bone mineral density in treated celiac disease.

Decreased bone mineral density (BMD) has been reported in patients with celiac disease in association with secondary hyperparathyroidism. The present study investigated whether basal parathyroid hormone (PTH) remained elevated and whether abnormalities of parathyroid function were still present in celiac disease patients treated with a gluten-free diet. Basal seric measurements of calcium and phosphate homeostasis and BMD were obtained in 17 biopsy-proven patients under treatment for a mean period of 5.7+/-3.7 years (range 1.1 to 15.9). In addition, parathyroid function was studied with calcium chloride and sodium citrate infusions in seven patients. Basal measurements of patients were compared with those of 26 normal individuals, while parathyroid function results were compared with those of seven sex- and age-matched controls. Basal results were similar in patients and controls except for intact PTH (I-PTH) (3.77+/-0.88 pmol/L versus 2.28+/-0.63 pmol/L, P<0.001), which was higher in the former group but still within normal limits. Mean 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D values were normal in patients. Parathyroid function results were also found to be similar in both groups. Compared with a reference population of the same age (Z score), patients had significantly lower BMDs of the hip (-0.60+/-0.96 SDs, P<0.05) and lumbar spine (-0.76+/-1.15 SDs, P<0.05). T scores were also decreased for the hip (-1.3+/-0.9 SDs, P<0.0001) and lumbar spine (-1.4+/-1.35 SDs, P<0.0001), with two to three patients being osteoporotic (T score less than -2.5 SDs) and seven to eight osteopenic (T score less than -1 SDs but greater than or equal to -2.5 SDs) in at least one site. Height and weight were the only important determinants of BMD values by multivariate or logistical regression analysis in these patients. The results show higher basal I-PTH values with normal parathyroid function in treated celiac disease. Height and weight values are, but I-PTH values are not, an important determinant of the actual bone mass of patients. Normal parathyroid function in treated patients suggests a lack of previous severe secondary hyperparathyroidism and/or complete adaptation to prior changes in parathyroid function.

Synthetic carboxyl-terminal fragments of parathyroid hormone (PTH) decrease ionized calcium concentration in rats by acting on a receptor different from the PTH/PTH-related peptide receptor.

Even if the carboxyl-terminal (C-) fragments/intact (I-) PTH ratio is tightly regulated by the ionized calcium (Ca(2+)) concentration in humans and animals, in health and in disease, the physiological roles of C-PTH fragments and of the C-PTH receptor remain elusive. To explore these issues, we studied the influence of synthetic C-PTH peptides of various lengths on Ca(2+) concentration and on the calcemic response to human (h) PTH-(1-34) and hPTH-(1-84) in anesthetized thyroparathyroidectomized (TPTX) rats. We also looked at the capacity of these PTH preparations to react with the PTH/PTHrP receptor and with a receptor for the carboxyl (C)-terminal portion of PTH (C-PTH receptor) in rat osteosarcoma cells, ROS 17/2.8. The Ca(2+) concentration was reduced by 0.19 +/- 0.03 mmol/liter over 2 h in all TPTX groups. Infusion of solvent over 2 more h had no further effect on the Ca(2+) concentration (-0.01 +/- 0.01 mmol/liter), whereas infusion of hPTH-(7-84) or a fragment mixture [10% hPTH-(7-84) and 45% each of hPTH-(39-84) and hPTH-(53-84)] 10 nmol/h further decreased the Ca(2+) concentration by 0.18 +/- 0.02 (P<0.001) and 0.07+/-0.04 mmol/liter (P< 0.001), respectively. Infusion of hPTH-(1-84) or hPTH-(1-34) (1 nmol/h) increased the Ca(2+) concentration by 0.16 +/- 0.03 (P < 0.001) and 0.19 +/- 0.03 mmol/liter (P < 0.001), respectively. Adding hPTH-(7-84) (10 nmol/h) to these preparations prevented the calcemic response and maintained Ca(2+) concentrations equal to or below levels observed in TPTX animals infused with solvent alone. Adding the fragment mixture (10 nmol/h) to hPTH-(1-84) did not prevent a normal calcemic response, but partially blocked the response to hPTH-(1-34), and more than 3 nmol/h hPTH-(7-84) prevented it. Both hPTH-(1-84) and hPTH-(1-34) stimulated cAMP production in ROS 17/2.8 clonal cells, whereas hPTH-(7-84) was ineffective in this respect. Both hPTH-(1-84) and hPTH-(1-34) displaced (125)I-[Nle(8,18),Tyr(34)]hPTH-(1-34) amide from the PTH/PTHrP receptor, whereas hPTH-(7-84) had no such influence. Both hPTH-(1-84) and hPTH-(7-84) displaced (125)I-[Tyr(34)]hPTH-(19-84) from the C-PTH receptor, the former preparation being more potent on a molar basis, whereas hPTH-(1-34) had no effect. These results suggest that C-PTH fragments, particularly hPTH-(7-84), can influence the Ca(2+) concentration negatively in vivo and limit in such a way the calcemic responses to hPTH-(1-84) and hPTH-(1-34) by interacting with a receptor different from the PTH/PTHrP receptor, possibly a C-PTH receptor.

Hypocalcemia induced during major and minor abdominal surgery in humans.

Hypocalcemia has only been rarely reported during surgical procedures not involving massive blood transfusions. The frequent observation in our hospital of a low serum ionized calcium level during surgery in nonacutely ill patients prompted us to investigate the calcium-PTH axis in three groups of subjects undergoing major (hepatectomy; n = 10), moderately severe, or minor surgery under general anesthesia (colectomy; n = 7, herniorrhaphy; n = 9) compared to that in one group of minor surgery cases under epidural anesthesia (herniorrhaphy; n = 15). Serum samples were obtained before anesthesia, after anesthesia but before surgery, and 40 and 120 min after the beginning of surgery in all groups of patients and for up to 3 days in major and moderately severe cases. Significant falls (P < 0.01), always proportional to the severity of the surgical/anesthesia procedure, were observed for ionized calcium (6-20%), total calcium (8-19%), and albumin (8-23%) accompanied by increases in intact PTH (105-635%). The decrease in ionized and total calcium correlated with a decrease in albumin (P < 0.001). Phosphorus, pH, and magnesium levels remained within the normal range. Adjustment of ionized calcium for variation in albumin revealed that 50-100% of the variation in ionized calcium could be attributed to a fall in albumin resulting from fluid administration to patients before admission to the surgery ward and between the onset of anesthesia and the end of surgery (1.2-5.6 L). Albumin- and pH-independent residual ionized calcium decreases of 12.2% in the hepatectomy group, 4.6% in the group of moderately severe and minor cases under general anesthesia, and 3.7% in the control group reflected the severity of the surgical/anesthesia procedure.

Functional evidence for two types of parathyroid adenoma.

OBJECTIVE: The carboxyterminal parathyroid hormone (C-PTH)/intact (I-) PTH ratio is influenced by serum calcium concentrations in man, increasing to a maximum value in hypercalcaemia and decreasing to a minimum value in hypocalcaemia. We decided to use this ratio to screen for parathyroid tumour with a normal sensitivity to calcium, symptomatic mainly through a mass effect. DESIGN AND SUBJECTS: Nineteen patients with hypercalcaemia and elevated or inappropriate PTH, were studied in the basal state and during CaCl2 and Na2EDTA infusion and compared with 26 normal individuals. They all had one parathyroid adenoma removed surgically, and two remained hypercalcaemic. RESULTS: In the basal state, the patients were hypercalcaemic (ionized calcium 1.44 +/- 0.12 vs. 1.23 +/- 0.03 mmol/l, P < 0.001) and had elevated PTH levels (I-PTH: 10.8 +/- 8.0 vs. 2.3 +/- 0.6 pmol/l, P < 0.001; C-PTH: 31.6 +/- 38.9 vs. 5.25 +/- 1.11 pmol/l, P < 0.001) when compared with normals. Their mean C-PTH/I-PTH ratio was similar to normals (2.7 +/- 1.3 vs. 2.4 +/- 0.6, NS) but, when individual values were considered, three patients had elevated values at 4.9, 5.3 and 5.8 (normal = 1.2-3.6). The regression line between basal C- and I-PTH revealed a significantly higher slope in these patients (P < 0.0001). The 16 patients with a normal basal C-PTH/I-PTH ratio had, as a group, an increased set point of I- or C-PTH stimulation by calcium and increased values of stimulated and non-suppressible I- and C-PTH, but these abnormalities were not all present in the smaller tumours (< or = 200 mg). Only three tumours in that group were larger than 1000 mg. Serum calcium concentration was related to the increased set point and non-suppressible fraction of I-PTH in these patients (r2 = 0.797). The three patients with a high basal C-PTH/I-PTH ratio had large tumours (2346, 4364 and 17,300 mg) and were more difficult to study, requiring a larger decrease in calcium concentration to achieve maximal stimulation. In the basal state, they were already expressing a non-suppressible level of I- or C-PTH and already had a maximal C-PTH/I-PTH ratio. Our data further suggest a normal set point of I- and C-PTH stimulation in the two patients who achieved sufficient hypocalcaemia and a normal set point of C-PTH/I-PTH ratio modulation in these three patients. Their hypercalcaemia was essentially related to the non-suppressible fraction of PTH. Furthermore, larger tumours were less active than smaller ones and produced less stimulated I-PTH/100 mg of tissue. CONCLUSIONS: These data indicate two types of parathyroid tumours when calcium sensitivity is considered: (1) a majority of small tumours with abnormal sensitivity to calcium, symptomatic through an abnormal set point and an increased non-suppressible fraction and (2) a smaller number of larger tumours, with normal sensitivity to calcium and an increased non-suppressible fraction, of PTH.

Adaptation of parathyroid function to intravenous 1,25-dihydroxyvitamin D3 or partial parathyroidectomy in normal dogs.

Parathyroid function was studied in 14 normal dogs 1 month before and after daily i.v. administration of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) (eight dogs), or about 50% parathyroidectomy (six dogs), to test the hypothesis that degradation of newly synthesized intact parathyroid hormone (I-PTH) is involved in parathyroid gland adjustment to a modified demand for I-PTH. Parathyroid function was studied through i.v. infusions of Na2EDTA and CaCl2 and measurement of ionized calcium (Ca2+), I-PTH and carboxyl-terminal PTH (C-PTH) at various time points. The C-PTH/I-PTH ratio was used as an index for change in the relative proportion of circulating C-PTH vs I-PTH, 1 month prior to and following each intervention. This ratio was further validated by looking at the HPLC profile of I- and C-PTH in hypo- and hypercalcemia under experimental conditions. Basal Ca2+ was unaltered 1 month after surgery, and was maintained constant in the 1,25-(OH)2D3-treated group by gradually decreasing 1,25-(OH)2D3 doses over time from 0.25 to 0.13 microgram twice daily during the last week of the experimental protocol. In this same group, basal 1,25-(OH)2D3 was increased by 65% (P < 0.0001) and basal I-PTH was decreased by 40% (P < 0.05), while basal C-PTH and the C-PTH/I-PTH ratio remained unchanged. Stimulated and non-suppressible I- and C-PTH followed the same pattern with, this time, an increase of stimulated and non-suppressible C-PTH/I-PTH ratio of 60% (P < 0.05) and 85% (P < 0.05) respectively. There was no change in basal I-PTH, C-PTH, or C-PTH/I-PTH ratio after surgery. However, stimulated I- and C-PTH were decreased by 45% (P < 0.005) and 65% (P < 0.005) respectively, with a 30% (P < 0.005) decrease of stimulated C-PTH/I-PTH ratio. There was no change in non-suppressible I-PTH, while non-suppressible C-PTH decreased by 55% (P < 0.005), with a 55% (P < 0.05) decrease in non-suppressible C-PTH/I-PTH ratio. The HPLC profiles of I- and C-PTH obtained in hypo- and hypercalcemia disclosed a similar distribution of the immuno-reactivity into peaks before and after i.v. administration of 1,25-(OH)2D3 as well as partial parathyroidectomy. This indicated that C-PTH/I-PTH ratio changes were related to different circulating levels of I- and C-PTH rather than to a different composition of I- and C-PTH. These data indicate a shift in the circulating PTH profile toward more PTH carboxyl-terminal fragments after 1 month of i.v. 1,25-(OH)2D3, but toward more intact PTH 1 month after about 50% parathyroidectomy, possibly reflecting adjustments in PTH degradation induced by a modified demand for I-PTH. Although these changes are most likely modulated at the parathyroid gland level, we cannot formally eliminate participation of the hormone's peripheral metabolism.

Screening for thyroid disease at the menopausal clinic.

The prevalence of hypothyroidism has been reported to increase with age and to attain up to 10% in older women. We wanted to verify whether routine screening for thyroid disease could be justified in a specific sub-population of aging women, those consulting for the first time at a menopausal clinic. Standard thyroid profiles (Total T4, T3 uptake, calculated free thyroxine index (FTI), and sensitive thyroid stimulating hormone (TSH)) were obtained in 500 consecutive patients seen at such a clinic over 18 months. Thyroid microsomal and thyroglobulin antibody titers were also obtained in over half of them. Twenty-three carefully selected, age-matched, peri-menopausal hospital employees served as a reference group for the TRH response test. Thirteen women (2.6%) had previously diagnosed hypothyroidism but 4 of them were found to be sub-optimally treated. Fifty other subjects (10%) had out-of-range screening TSH levels, 7 below and 43 over the assay reference range. In the former, 3 (0.6%) were found to be hyperthyroid while in the latter 8 (1.6%) were found to be overtly hypothyroid based on TSH levels over 10 mU/L and accompanying signs and symptoms. Twelve other subjects (2.4%) were found to have sub-clinical hypothyroidism based on a positive TRH response test and a significantly increased prevalence of goiter and positive antibody titers. The remaining 23 patients had a normal TRH response test, although their mean TSH level at 30-min post-TRH and the prevalence of positive antibody titers were significantly higher than those of the control group and normal subjects respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of 1,25(OH)2D production by hypercalcemia in osteitis fibrosa cystica: influence on parathyroid hormone secretion and hungry bone disease.

Primary hyperparathyroidism is usually associated with normal or elevated serum 1,25-dihydroxyvitamin D [1,25(OH)2D] levels. We report a 63-year-old patient with extreme hypercalcemia (ionized serum calcium, 2.51 mmol/l; normal range, 1.19-1.36), very high serum concentrations of intact immunoreactive parathyroid hormone (iPTH) (145 pmol/l; normal range, 1-6.8), radiological lesions of osteitis fibrosa cystica, only mildly impaired renal function (creatinine clearance, 69 ml/min/m2) and very low serum levels of 1,25(OH)2D (28.8 pmol/l; normal range, 72-120). Presurgery normalization of the calcemia with normal saline, salmon calcitonin and pamidronate caused an increase in 1,25(OH)2D serum concentration to 228.3 pmol/l. A negative correlation could be established between ionized calcium and 1,25(OH)2D levels during that period (r2 = 0.80, P < 0.04). While serum calcium decreased with treatment, serum iPTH also decreased to 48.6 pmol/l, suggesting some 1,25(OH)2D inhibition of parathyroid adenoma function. Serum alkaline phosphatase also rose from 309 to 390 units/l (normal range, 25-97), suggesting the beginning of resolution of her osteitis fibrosa cystica prior to surgery. Surgical removal of a parathyroid adenoma was associated with a decrease in serum calcium and iPTH levels. To our surprise, the hypocalcemia could be managed easily with 1500 mg of oral calcium carbonate daily, even if the hungry bone disease became more active with an increase in alkaline phosphatase to 486 units/l. This was explained by the very high levels of serum 1,25(OH)2D (> 200 pmol/l) which prevailed in the postsurgery period and were probably related to decreased bone resorption and increased bone formation. This case illustrates that normalizing serum calcium prior to surgery in patients with primary hyperparathyroidism and osteitis fibrosa cystica can be highly beneficial.

Tc-99m sestamibi and other agents in the detection of metastatic medullary carcinoma of the thyroid.

The 10-year survival rate for medullary carcinoma of the thyroid (MCT) is 50%; thus, good tumor-seeking radiopharmaceuticals are needed to localize foci of recurrence and metastasis during follow-up. Two patients with metastatic MCT were studied with Tl-201, I-131 MIBG, Tc-99m (V)-DMSA, and Tc-99m MIBI. A SPECT study with the latter agent allowed the visualization and precise localization of a metastatic mediastinal lymph node. More studies need to be done to evaluate the role of Tc-99m MIBI in the detection of recurrence and metastases of MCT.

Effects of passive immunization against parathyroid hormone (PTH)-like peptide and PTH in hypercalcemic tumor-bearing rats and normocalcemic controls.

Passive immunization using antisera raised against rat PTH-like peptide [PLP-(1-34)] and rat PTH-(1-84) was used to assess and compare the roles played by PLP and PTH in modulating mineral metabolism in hypercalcemic rats bearing the Rice-500 Leydig cell tumor and in normocalcemic control animals. After immunization, plasma calcium in the tumor-bearing animals rapidly normalized and remained within the normal range for several days, plasma phosphate rose, and urinary phosphate and cAMP fell. These changes were associated with increased longevity of the tumor-bearing rats. Reduction of plasma calcium was shown to be a function of early (5 h) neutralization of PLP bioactivity in the kidney, whereas the effect of immunoneutralization of PLP in bone appeared later (24-48 h) and was more prolonged. Immunization against PTH in normocalcemic animals resulted in a hypocalcemic episode of smaller magnitude and shorter duration than that achieved in hypercalcemic animals immunized against PLP and appeared to be unassociated with neutralization of distal tubular effects. Neutralization of proximal tubular and skeletal actions of PTH appeared to occur in a manner analogous to that seen for PLP in tumor-bearing animals, but were of shorter duration. These studies suggest that in normal animals the action of PTH in the skeleton and/or on vitamin D metabolism contributes considerably more than renal transport activity to the maintenance of normocalcemia and that compensatory mechanisms rapidly restore homeostasis. PTH appears to be the major modulator of calcium homeostasis in normal rats, with PLP playing a minor role, if any. In tumor-bearing rats, mechanisms to restore calcium levels to baseline are delayed after PLP immunoneutralization, and PLP appears to be both necessary and sufficient for the hypercalcemic state.

Suppression of T4 secretion in a metastatic follicular carcinoma.

Despite total thyroidectomy, a patient with metastatic follicular carcinoma of the thyroid remained biologically euthyroid three months after stopping thyroxine (T4) therapy. Thyroid hormone production was investigated by means of a modified tri-iodothyronine (T3) suppression test, in which serum T4 was used as a suppression marker. After three weeks of oral T3 (Cytomel) therapy (50 micrograms/day), the serum T4 decreased from normal (108 nmol/L) to undetectable values. However, even though suppressive therapy was effective in preventing TSH dependent hormone secretion by the tumor, it did not prevent tumor growth and the eventual death of the patient.

Elective total parathyroidectomy without autotransplant in end-stage renal disease.

Ten patients are reported following parathyroidectomy (PTX). In 9 all identifiable parathyroid tissue in the neck was deliberately removed, and in the tenth (operated 14 years ago) the remnant which had been left probably did not function. Their post-operative course resembled that of patients treated conventionally, and their subsequent course was likewise uneventful with disappearance of all symptoms associated with their osteodystrophy. All patients required oral calcium supplementation but none were given vitamin D compounds after the initial period of repletion following surgery. Mean serum values were (before PTX and current) for calcium 2.63 +/- 0.14 and 2.33 +/- 0.08 mmol/liter, P = NS, for phosphorus 1.96 +/- 0.13 and 1.38 +/- 0.09 mmol/liter, P less than 0.01, and for alkaline phosphatase 713 +/- 191 and 101 +/- 14 IU, P less than 0.05. Evidence for residual parathyroid tissue was present in each case; one patient remained mildly hyperparathyroid and several were mildly hypoparathyroid by the IRMA PTH assay. Bone histomorphometry in five subjects post-PTX showed either normal or low turnover. Radiologically, striking remineralization was seen with disappearance of all erosive changes. We suggest that residual areas of parathyroid tissue are stimulated and continue to secrete hormone even when all the discrete glands have been removed. It is recommended that when indicated, and in the absence of aluminum excess, total PTX without autotransplant should be the preferred form of therapy for long-term dialysis patients.

Estrogen replacement decreases the set point of parathyroid hormone stimulation by calcium in normal postmenopausal women.

Estrogens decrease serum total and ionized calcium (Ca) concentrations in postmenopausal women with or without primary hyperparathyroidism, but cause little or no increase in serum PTH suggesting a modification of the relationship between the two. In order to define this relationship, we studied the effect of conjugated estrogens on total and ionized serum Ca and serum PTH concentrations in five normal postmenopausal women, before and after 3, 11, and 23 weeks of therapy. Dynamic tests of parathyroid gland function, based on 2-h iv infusions of CaCl2 and NaEDTA, were performed at each time. Total and ionized serum Ca and carboxylterminal PTH were measured every 15 min during the infusions, and parathyroid function was evaluated by a nonlinear 4-parameter mathematical model. Estrogen therapy caused decreases in serum total [2.36 +/- 0.04 (SD) mmol/L, baseline vs. 2.19 +/- 0.05 mmol/L, 23 weeks, P less than 0.005) and ionized calcium (1.27 +/- 0.01 mmol/L, baseline vs. 1.21 +/- 0.02 mmol/L, 23 weeks, P less than 0.005]; the decreases were evident at 3 weeks and persisted for the duration of the study. Serum PTH concentrations did not change (8.94 +/- 1.84 pmol/L, baseline vs. 8.98 +/- 2.38 pmol/L, 23 weeks). Three parameters of the parathyroid function, the maximal response to hypocalcemic stimulation, the nonsuppressible fraction of circulating PTH, and the slope of PTH on calcium at the set point were not affected by estrogen treatment. The fourth parameter, the set point of PTH stimulation by serum total calcium (2.16 +/- 0.04 mmol/L, baseline vs. 1.97 +/- 0.07 mmol/L, 23 weeks, P less than 0.0166) or by serum ionized Ca (1.19 +/- 0.04 mmol/L, baseline vs. 1.12 +/- 0.03 mmol/L, 23 weeks, P less than 0.01), was decreased by estrogen treatment. This was evident at the earliest time point studied and persisted thereafter. The decrease in ionized Ca set point only explained 40% of the decrease in total calcium set point, the remaining 60% being related to hemodilution of plasma protein during therapy. We conclude that estrogen replacement can influence parathyroid function in postmenopausal women by resetting the set point of PTH stimulation by ionized Ca. This in turn could contribute to the estrogen-induced changes in their Ca balance.

Reversible cerebral lesions associated with tiazofurin usage: MR demonstration.

Tiazofurin is an experimental chemotherapeutic agent currently undergoing clinical evaluation. We report our results with magnetic resonance (MR) in demonstrating reversible cerebral abnormalities concurrent with the use of this drug. The abnormalities on MR were correlated with findings on CT as well as with cerebral angiography. The utility of MR in the evaluation of patients receiving this new agent is illustrated.

Premenopausal bone mineral content relates to height, weight and calcium intake during early adulthood.

The influence of dietary and anthropometric factors on bone mineral content was studied in 183 healthy premenopausal French-Canadian women aged between 40 and 50 years and living in the same area. Dietary evaluation of their calcium (Ca), caffeine and alcohol intake since the age of 20 was performed in all cases. Age, height, weight, exercise level, cigarette smoking, parity and estrogen were also recorded. Bone mineral content of the L2 to L4 vertebrae (BMCL, n = 183) and forearm (BMCF, n = 137) were measured respectively by dual and single photon absorptiometry. While stepwise regression analysis showed a significant relationship between total BMCL and height, weight and Ca intake, this only occurred with weight and Ca intake when BMCL was corrected for height of L2-L4 (BMCL/cm) or for bone scan area of L2-L4 (BMCL/cm2). BMCF expressed per unit of length correlated to height only. When subjects were divided into three groups according to their Ca intake (less than 500 mg/day, between 500 and 1000 mg/day and greater than 1000 mg/day), the mean BMC adjusted for significant covariables (height and weight) was statistically different for the low and high intake groups at both sites (BMCF, F = 3.9, P = 0.02; BMCL, F = 4.2, P less than 0.02; BMCL/cm, F = 6.1, P less than 0.005; BMCL/cm2, F = 4.4, P less than 0.02). These findings indicate that, of the variables considered, Ca intake, height and weight were the only significant factors related to bone mass in our homogeneous population. It is therefore suggested that Ca intake in early adulthood influences the axial and appendicular bone mass in premenopausal women.