Primary hyperparathyroidism. Aspects on pathophysiology, symptoms, and treatment.
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Calcium Channels↗
Biomedical subjects
J Rastad
Publications and source records attributed to J Rastad.
Disturbance of basal and stimulated serum levels of intact parathyroid hormone in primary hyperparathyroidism.
In patients with primary hyperparathyroidism, measurements were made of basal and stimulated levels of intact parathyroid hormone (PTH). The basal PTH values were elevated in all but six of 89 patients and provided clear separation towards normal individuals (n = 75) and patients with hypercalcemia of other origin (n = 34). The PTH value correlated with the serum calcium concentration in hyperparathyroidism and with the weight of excised parathyroid adenomas but not with that of chief cell hyperplasias. A constant ethylenediaminetetraacetic acid infusion during 60 minutes of induced essentially linear reductions of plasma-ionized calcium concentrations, averaging 0.02 mmol/L/10 minutes, which were associated with swift, curvilinear, elevations of PTH levels that reached a plateau after 10 to 20 minutes. The increment in serum PTH level correlated with the basal PTH value both in patients with hyperparathyroidism and controls. However, in proportion to the much greater glandular mass in the patients with hyperparathyroidism, the secretion of PTH was relatively reduced. The findings support the value of the intact PTH assay in the differential diagnosis of hypercalcemia and show that PTH secretion in vivo is extremely sensitive to hypocalcemic stimulation, that the pathological parathyroid tissue in hyperparathyroidism is characterized by a reduction of hormone release per unit weight, and that the hormone secretion in hyperparathyroidism operates closer to its maximal capacity than under normal circumstances.
Adult↗
Distribution of monoclonal antiparathyroid antibody E11 in mice grafted with human parathyroid adenoma and carcinoma.
One hundred six immunoincompetent mice grafted with human parathyroid adenoma or carcinoma were used to evaluate distribution of the murine monoclonal antibody E11, which recognizes a calcium sensor of high molecular weight on the parathyroid cell surface. The subcutaneous parathyroid grafts were infiltrated with murine fibrous tissue, which seemed to increase with the duration of transplantation and the size of inserted tissue pieces. Intraperitoneal injection of biotinylated or 125I-labeled E11 antibody indicated time- and dose-dependent antibody accumulation, as well as the presence of unoccupied binding sites in the transplanted parathyroid tissue. The iodinated intact immunoglobulin G and Fab fragment of the E11 antibody demonstrated low radioactivity in the lung, liver, spleen, kidney, and intestine for up to 14 days, except for the Fab fragment, which was rapidly accumulated and cleared from the kidney. The peak radioactivity ratio in the adenoma tissue versus blood averaged 2.8 for the intact antibody and 5.3 for the Fab fragment, whereas the corresponding values for the carcinoma tissue were 8.6 and 8.8, respectively. These ratios increased considerably, especially for the adenoma specimens, when weights of the excised grafts were adjusted for the calculated content of parathyroid tissue. The results support that the E11 antibody may localize even minute amounts of human parathyroid adenoma and carcinoma tissue.
Adenoma↗
500-Kilodalton calcium sensor regulating cytoplasmic Ca2+ in cytotrophoblast cells of human placenta.
Two monoclonal IgG antibodies E11 and G11, which react with parathyroid and kidney tubule cells, are in the present communication demonstrated to immunostain the surface of cytotrophoblast cells in human placenta. The G11 but not the E11 antibody has earlier been found to interfere with the sensing and gating of extracellular calcium in parathyroid cells. Microfluorometric measurement of the cytoplasmic calcium (Ca2+i) concentration was performed on suspended placental cells loaded with fura-2. The E11-positive placental cells displayed biphasic and parathyroid-like increases in Ca2+i in response to extracellular Ca2+. This increase was blocked by the G11 antibody and absent in the E11-negative placental cells. A sandwich enzyme-linked immunosorbent assay was constructed in which the G11 and E11 antibodies were shown to react with the same molecule. This calcium sensor was isolated and found to consist of a single, glycosylated polypeptide of approximately 500 kDa.
Antibodies, Monoclonal↗
Expression of platelet-derived growth factor beta-receptors on stromal tissue cells in human carcinoid tumors.
Carcinoid tumors of the midgut type are slowly growing neoplasms which often present clinically and histologically pronounced fibrosis around the tumors. Cryosections from 41 neuroendocrine tumors (31 midgut carcinoid tumors, 8 endocrine pancreatic carcinomas, 1 parathyroid carcinoma, and 1 pheochromocytoma) and 22 nonneuroendocrine carcinomas were examined for the presence of platelet-derived growth factor (PDGF) beta-receptor by immunohistochemistry using the monoclonal antibody PDGFR-B2. Twenty midgut carcinoid tumor tissues (66%) and 4 endocrine pancreatic carcinomas (50%) and the parathyroid carcinoma stained positively with the antibody. In contrast, only 2 nonneuroendocrine tumor tissues (10%) were stained, and the staining in these cases was weak. The immunoreaction in the carcinoid tumors was observed in connective tissue cells adjacent to tumor cell clusters but not in the tumor cells themselves. The degree of positive PDGF beta-receptor expression in the carcinoid tissues seems to correlate positively with the presence of macrophages as determined by the monoclonal antibody anti-Leu-M5, but not with other infiltrated lymphocytes identified with the monoclonal antibody anti-Leu-4, or with anti-HLA-DR antibodies. Stromal cells adjacent to tumor cells, including small capillaries, stained more strongly than the stromal cells which were distant from tumor cell clusters. Furthermore, carcinoid tumor metastases from lymph nodes as well as from liver showed stronger immunoreactivity in the stromal cells with the PDGF beta-receptor antibody than the corresponding primary tumors. Our data suggest that carcinoid tumor cells may directly or indirectly induce expression of PDGF beta-receptor on adjacent stromal cells in the tumor tissue, which may contribute to the fibrosis that is often seen around carcinoid tumors.
Aged↗
Light microscopical study of dendrites and perikarya of interneurones mediating la reciprocal inhibition of cat lumbar alpha-motoneurones.
Interneurones which mediate disynaptic inhibition from la muscle spindle afferents of the quadriceps nerve to lumbar alpha-motoneurones were stained with intracellular injection of horseradish peroxidase. Seven best stained and most satisfactorily preserved cells were selected for analysis, and the light microscopic morphology of their cell bodies and dendrites were quantitatively investigated in parasagittal sections. The perikarya were located dorsal or dorso-medial to the motoneurones; they had mean diameters of 51 x 27 microns and a mean volume of 35,820 microns 3. The cells had 3 to 7 dendrites, which were arranged asymmetrically around the parent somata. The dendrites extended mainly in the dorso-ventral direction, in which the mean tip to tip distance for each cell was 1742 microns. The dendrites had few spines and they branched almost only in bifurcations. On the average, each process divided 3.5 times and in each cell they gave rise to 14.9 branching points as well as a total combined length of more than 7000 microns. Primary dendrites had a mean length of 193 microns which was generally shorter than the lengths of the branches of higher order. A more detailed analysis of two cells revealed the mean width of primary dendrites to be 5.6 microns while that of the 5th order processes was 1.5 microns. The mean tapering of individual dendritic branches per unit length was 17%, being somewhat more pronounced for the distally located segments, while at branching points the sum of daughter processes approximately equalled the diameter of the parent process.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Monoclonal antiparathyroid antibodies--tools for studies of the regulation of cytoplasmic calcium and function of parathyroid and other antibody-reactive cells.
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Animals↗
Medical aspects on surgery in Graves' disease. Clinical review.
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Adult↗
Clinical and experimental advances in sporadic primary hyperparathyroidism.
Primary hyperparathyroidism (HPT) has shown prevalence of up to 3% among elderly women in Nordic health screening surveys, and is increasingly diagnosed in patients with diffuse neuromuscular or psychiatric symptoms. Primary HPT, even with mild hypercalcemia, is associated with increased mortality risk, mainly from cardiovascular disease. Despite the efficacy of new methods, reliable histopathologic distinction between adenomatous and hyperplastic parathyroid disease may still be difficult, and indeed circumstantial evidence suggests that adenoma and chief cell hyperplasia are not always distinctly separate pathophysiologic entities. Irrespective of symptoms, the hyperplasia is associated mainly with mild to moderate hypercalcemia, and may thus constitute an early form of HPT. A more liberal attitude to surgery in primary HPT would increasingly extend treatment to less clear-cut cases. The demonstration by monoclonal antiparathyroid antibodies of a specialized calcium receptor mechanism on the surface of parathyroid cells and its reduced expression in pathologic parathyroid tissue seems to explain defective parathyroid cell function and ensuing hypercalcemia in HPT. These antibodies appear to offer new prospects in parathyroid histopathology and research.
Antibodies, Monoclonal↗
Adrenocortical carcinoma. A retrospective study of a rare tumor with a poor prognosis.
A retrospective study was performed on 54 patients diagnosed as having adrenocortical carcinoma during 1974-1983. The initial symptoms were often diffuse: abdominal pain, weight loss, or fever, and more than 60% of the patients showed no evidence of overproduction of hormone. The median tumor diameter was 13 cm and almost half of the tumors had metastasized at diagnosis. A radical tumor resection could be performed in less than 50% of the patients, and at histopathological re-examination some tumors were not conclusively verified as malignant. Capsular invasion, nuclear pleomorphism and mitoses were found more commonly in patients who succumbed to the disease. Seven of 29 patients treated with chemotherapy showed an objective response and two of them are still alive and free of disease. The overall 5-year-survival rate was 19%, compared with 45% for patients with radically resected tumors. Patients with no biochemical signs of overproduction of adrenocortical hormone appeared to have a better prognosis than those with hormone excess. Together with increased use of ultrasound and computed tomography, a urinary steroid profile might hopefully contribute to earlier discovery of these often clinically silent tumors. However, it remains to be determined whether these diagnostic improvements, together with more aggressive surgery and adrenolytic chemotherapy, can improve the poor prognosis.
Adolescent↗
Clinical characteristics and surgical treatment of sporadic primary hyperparathyroidism with emphasis on chief cell hyperplasia.
In 570 patients with sporadic primary hyperparathyroidism, the age, sex, symptoms, and preoperative serum calcium values were related to the histopathologic diagnoses, operative findings, and the extent and outcome of parathyroid surgery. Renal stone formation was especially prevalent in younger patients with slight hypercalcemia and parathyroid chief cell hyperplasia, whereas neuromuscular and psychiatric disturbances were overrepresented among older women with higher serum calcium values. Serum calcium concentration was inversely correlated to the proportional incidence of chief cell hyperplasia and positively correlated to the glandular weight of both adenomas and hyperplasias. Glandular size was markedly irregular in chief cell hyperplasia, with increased gland weights of no more than two glands in 78% of patients. During follow-up, for as long as 27 years, normocalcemia was obtained in 91% of patients with adenomas, with failures mainly depending on difficulties in identifying the parathyroid glands. The rate of normocalcemia was lower (80%) among patients with hyperplasia, but an inability to visualize the glands was not a major cause of failure. In patients with hyperplasia with asymmetric and more markedly enlarged glands, it appeared sufficient to remove only the enlarged glands, whereas the findings advocated a subtotal 3- to 3.5-gland resection in patients with more symmetrically or less enlarged hyperplastic glands.
Adenoma↗
[Hypercalcemia and skeletal engagement in malignancy--development and therapeutic possibilities].
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Bone Neoplasms↗
Muscle function in patients with primary hyperparathyroidism.
The muscle contraction of the anterior tibial muscle was investigated by measurements of electrically stimulated and computer-analyzed muscle twitches in 18 unselected patients with primary hyperparathyroidism (HPT) and in 20 healthy control persons. The HPT patients had a lower muscle twitch tension (TT) at single stimulation, compared with the control group [76 +/- 24 N (SD) and 99 +/- 33 N respectively, P less than 0.05]. At high-frequency stimulation the difference in muscle force increased, and at 20 Hz stimulation the force in the HPT patients was 73% of that in the controls (P less than 0.01). There were no differences between the HPT patients and the control persons in neither contraction time nor half relaxation time at single muscle twitch nor in twitch potentiation after 20 and 90 seconds maximal voluntary contraction. The results indicate that patients with primary HPT have an impaired muscle function of probable importance for their symptoms of weakness and generalized fatigue.
Adult↗
Interaction of monoclonal antiparathyroid antibody with Ca2+ agonistic actions of Mn2+ in normal human parathyroid cells.
Effects of the monoclonal antiparathyroid antibodies G11 and E11 on Mn2+ interaction with individual normal human parathyroid cells were studied. At 0.5mM Ca2+, 3mM Mn2+ induced a rapid transient increase in cytoplasmic Ca2+ [Ca2+i] followed by quenching of the fluorescence from the Ca2+ indicator fura-2 as Mn2+ entered into the cells. Whereas the antibody E11 had no effects, treatment with G11 abolished the Ca2+i transient and considerably delayed the entry of Mn2+. The results support the presence of a cation-sensitive receptor mechanism on parathyroid cells and indicate that the antibody G11 not only blocks the interaction between Ca2+ and this receptor mechanism but also that of Mn2+.
Antibodies, Monoclonal↗
Microfluorometric measurements of cytoplasmic calcium in chief and oxyphil parathyroid cells of adenomatous and hyperplastic glands and of normal-sized glands associated with adenomas.
The effects of extracellular calcium on the cytoplasmic Ca2+ concentration (Ca2+i) were studied by dual-wavelength microfluorometry in individual human parathyroid cells obtained from adenomatous glands and normal-sized glands associated with adenomas in hypercalcemic hyperparathyroidism (HPT), as well as from enlarged glands of patients with uremia with HPT. In comparison with the normal parathyroid tissue, chief cells of the adenomatous and hyperplastic glands showed significantly lower Ca2+, and also right-shifted responses of Ca2+i to increases in the extracellular calcium concentration within the 0.5 to 3.0 mmol/L range. This pathophysiologic disturbance apparently was independent of the cell size. Oxyphil cells of nodules from the hyperplastic glands had lower Ca2+i and responded less to increments in extracellular Ca2+ than the chief cells from the surrounding parts of the same glands. Also the chief cells from the normal-sized glands associated with single adenomas exhibited a disturbance of the regulation of Ca2+i, which was less pronounced than that in the cells of the adenomas. These findings support the presence of relative calcium insensitivity of Ca2+i in chief and oxyphil parathyroid cells from adenomatous and hyperplastic glands. This derangement may also be found in all parathyroid glands of individuals with adenomatous HPT.
Adenoma↗
Parathyroid histology and cytology with monoclonal antibodies recognizing a calcium sensor of parathyroid cells.
Two monoclonal antibodies reacting with surface structures on exclusively parathyroid cells and proximal kidney tubule cells were evaluated in the microscopic diagnosis of parathyroid disease. Immunostained cryosections of adenomatous and hyperplastic parathyroid glands from 30 hypercalcemic patients with primary or uremic hyperparathroidism (HPT) showed a reduced and heterogeneous staining with the antibodies. This contrasted with the intense and even staining of normal and suppressed human parathyroid glands, as well as lymph node metastases of parathyroid carcinoma. Fine-needle aspiration biopsies and imprints of the parathyroid glands showed a conspicuous antibody staining that enabled the identification of parathyroid cells. The antibodies seem to provide new means for histologic and cytologic identification of normal and pathologic parathyroid tissue, in conjunction with their highly restricted tissue reactivity. Because one of the antibodies interacts with a surface receptor mechanism of the parathyroid cells that is involved in the sensing and gating of calcium and, thereby, also with the regulation of parathyroid hormone release, the unequivocal demonstration of reduced staining of the adenomatous and hyperplastic parathyroid tissue suggests that HPT is associated with reduced expression of the calcium sensoring mechanism of the pathologic parathyroid tissue.
Adenoma↗
Self-rated psychiatric symptoms in patients operated on because of primary hyperparathyroidism and in patients with long-standing mild hypercalcemia.
Self-rated psychiatric symptoms were investigated in 30 patients referred for surgery because of primary hyperparathyroidism (HPT) (serum calcium, 2.87 +/- 0.21 mmol/L) in 38 subjects detected in a health screening, with 15 years of mild hypercalcemia and probable HPT (serum calcium, 2.66 +/- 0.09 mmol/L), and in 38 normocalcemic control subjects. The psychiatric symptomatology was evaluated by use of the Hopkins Symptom Checklist (HSCL-56), a self-rating symptom scale. The patients with verified HPT had the highest mean HSCL score, 89.1 +/- 20.1 before surgery, compared with 76.6 +/- 17.0 (p less than 0.01) in the health survey hypercalcemic patients and 73.8 +/- 16.0 (p less than 0.001) in the controls. The factors for anxiety, depression, and cognitive symptoms were the most pronounced in the HPT patients and were also increased among the mildly hypercalcemic persons of the health survey, compared with the controls. Somatic symptoms such as headache, back pain, chest pain, and weakness were equally common in HPT and in the controls, and measurements of isometric muscle strength of knee extension did not demonstrate reduction of muscle strength in the health survey hypercalcemic patients. Follow-up of the HPT patients 1 year after parathyroid surgery revealed a marked improvement in mental health (HSCL score 73.2 +/- 13.7, p less than 0.001). In the health survey hypercalcemic patients, neither the psychiatric symptomatology nor the muscle strength were influenced by 6 months of oral vitamin D therapy (alphacalcidol). The results demonstrate that psychiatric symptoms are experienced frequently by patients with HPT and minimum to moderate increases in the serum calcium level and that these disturbances are reversed by parathyroid surgery.
Adult↗
Kinetic evidence for cytoplasmic calcium as an inhibitory messenger in parathyroid hormone release.
A sudden change of extracellular Ca2+ from 0.5 to 3.0 mM resulted in a transient rise of the cytoplasmic Ca2+ concentration (Ca2+i) followed by a sustained increase in parathyroid cells loaded with the Ca2+-indicator fura-2. The initial transient could be eliminated by increasing the Ca2+ buffering capacity of the cytoplasm. Under such conditions the rise of Ca2+i exhibited kinetics reminiscent of those for 45Ca uptake and cell depolarization. Addition of 0.5 mM Mn2+ mimicked the effect of raising the extracellular Ca2+ concentration, since there was an initial Ca2+i transient followed by a slower entry of Mn2+ into the cells. This reaction pattern was different from that of pancreatic alpha 2-cells in which there was no substantial influx of Mn2+ before depolarization with arginine. When measuring the kinetics of parathyroid hormone (PTH) release it was apparent that Ca2+ inhibition of secretion followed Ca2+i and thus became substantially delayed after eliminating the initial transient. The results support the concept of a depolarizing Ca2+ permeability in the parathyroid cell membrane which can be activated by external Ca2+, and indicate that Ca2+i is an inhibitory messenger of importance for the physiological regulation of PTH release.
Animals↗