Primary hyperparathyroidism due to parathyroid carcinoma

OBJECTIVES: Our aim was to determine whether tissue factor pathway inhibitor (TFPI), a physiologically important natural anticoagulant that acts by inhibiting the extrinsic pathway, concentrations decrease as liver disease progresses, and, second, whether TFPI has an etiologic role in portal vein thrombosis in cirrhotics. METHODS: After taking their informed consent, we determined TFPI concentrations in the plasma of healthy subjects (group I) (n = 15) (average age, 45.1 = 11.8 yr), cirrhotics (group II) (n = 16) (average age, 43.6 +/- 9.8 yr), and cirrhotics with portal vein thrombosis (group III) (n = 12) (average age, 42.6 +/- 10.7 yr). Mean and median TFPI values and interquartile ratios were determined for groups I, II, and III. Then group II and III were further divided according to the Child classes A, B, or C, and mean and median TFPI values and interquartile ratios were determined for these classes as well. Using the Man-Whitney U test, we compared the results. RESULTS: Statistically important differences were documented (p = 0.005) between the median TFPI levels of healthy adults and Child C cirrhotics (concentration lower in Child C) and between normal subjects and cirrhotics with portal vein thrombosis (p = 0.02) (TFPI concentration being lower in the latter group again). CONCLUSIONS: TFPI concentration decreases in advanced liver disease, and this may be a contributory factor for portal vein thrombosis in at least some cases of cirrhotics.     

A measles epidemic controlled by immunisation

AIM: In 1997, an immunisation campaign, using measles-mumps-rubella vaccine, was planned for children aged 2-10 years to prevent a measles epidemic predicted by mathematical modelling. The epidemic started before the campaign and is described here. METHOD: Measles hospitalisation, notification and laboratory data were combined. RESULTS: The epidemic started in April 1997 and was largely over by January 1998. No deaths were identified and only one hospitalisation was coded as measles encephalitis, compared to seven deaths and ten cases of measles encephalitis in the 1991 epidemic. For the 12 months from 1 March 1997 there were 2,169 (60 per 100,000) measles cases identified, 314 (9 per 100,000) of whom were hospitalised. Two-thirds of hospitalised cases were notified. The age-standardised measles incidence rates were 33, 34, and 174 per 100,000 for Europeans, Maori and Pacific people, respectively. The respective age-standardised hospitalisation rates were 4, 9 and 32 per 100,000. Measles incidence was highest for under one-year-olds (904 per 100,000) and low for 11-16 year-olds (27 per 100,000)--the cohort previously offered a second vaccine dose. Most cases were aged 10 years and under, and this group were the main drivers of virus transmission. CONCLUSIONS: The immunisation campaign prevented 90-95% of predicted cases. The campaign was appropriately targeted at children aged 10 years and under.     

The management of malignant hypercalcaemia

Malignant hypercalcaemia is a common problem for cancer clinicians. However, the management of this condition has altered substantially over the last 10 years and the condition is usually amenable to modern treatment. A number of effective pharmacological agents are available in current practice. Bisphosphonate drugs, particularly clodronate and pamidronate, are confirmed as the mainstay of modern management. Bisphosphonates are effective and well tolerated when given intravenously. Many aspects of the actions of bisphosphonates are not well understood, and knowledge of their pharmacokinetics is limited.     

Metastatic parathyroid carcinoma in the MEN2A syndrome

We report a patient with a metastatic parathyroid carcinoma and medullary carcinoma of the thyroid. This patient represents a variation of the multiple endocrine neoplasia syndrome (MEN) type 2A. There was no evidence of a phaeochromocytoma. The case illustrates the difficulties that may be encountered in localising the source of PTH secretion; the patient underwent four unsuccessful exploratory operations of the neck and mediastinum before further investigations revealed a single metastatic deposit of parathyroid carcinoma involving the first thoracic vertebra. PCR amplification and sequencing of the RET oncogene from the metastatic parathyroid carcinoma and genomic DNA revealed a heterozygous mutation (Cys634Tyr) in exon 11, as has previously been described to occur in MEN 2A. In addition, loss of tumour heterozygosity was demonstrated at loci from chromosomes 1, 2, 3p, 13q and 16p. This represents the first report of a parathyroid carcinoma in a MEN2A patient, in which the multiple allelic deletions are consistent with the generalised losses observed in aggressive tumours.     

Secretion of parathyroid hormone by abnormal human parathyroid glands in vitro

Radiation survival curves for Lewis lung tumours in the lungs ranging in size from 0-5 to 20 mm3 have been obtained, and a size-dependent variation in hypoxic fraction was found. Cell-survival studies following treatment of various sizes of s.c. tumours indicated that the effects of 60Co gamma-rays and the chemotherapeutic agents 1,3-bas(2-chloroethyl)-1-nitrosourea (BCNU) and cyclophosphamide are all size-dependent. Large pulmonary nodules which had regressed but had not been cured by cyclophosphamide regrew with a radiosensitivity that was characteristic of previously untreated tumours. The results give additional experimental support to the clinical interest in early adjuvant therapy of micrometastases, and sequential combined modality therapy for larger tumours.     

Regulation of parathyroid hormone-related protein expression in MCF-7 breast carcinoma cells by estrogen and antiestrogens

Expression of parathyroid hormone-related protein (PTHrP) in breast carcinoma is a frequent cause of the paraneoplastic syndrome of hypercalcemia. In response to treatment with estrogen or tamoxifen, some breast cancer patients also develop a transient hypercalcemia. Therefore, the effect of 17beta-estradiol (E2), tamoxifen, or its more potent metabolite, 4-hydroxytamoxifen (OH-tamoxifen), on PTHrP expression in an estrogen receptor (ER)-positive breast carcinoma cell line (MCF-7) was evaluated. E2 increased PTHrP mRNA levels in MCF-7 cells and stimulated PTHrP(1-86) release in a dose-dependent fashion (10(-10)-10(-6) M). Tamoxifen and OH-tamoxifen also stimulated PTHrP release in a concentration-dependent fashion that paralleled their relative ER binding affinities (10(-6) or 10(-8)-10(-6) M, respectively). Combined treatment with the partial estrogen agonist, OH-tamoxifen, and E2 decreased E2-stimulated PTHrP secretion in MCF-7 cells to the levels seen with OH-tamoxifen treatment alone. These results suggest that transient estrogen- or tamoxifen-induced hypercalcemia in patients with breast carcinoma may be a PTHrP-mediated effect that is a marker of ER positivity.     

Primary hyperparathyroidism secondary to parathyroid carcinoma: report of a case

Distinguishing parathyroid carcinoma from benign hyperparathyroidism is often difficult. Clinical features most commonly associated with parathyroid carcinoma, such as palpable cervical mass, markedly higher serum calcium, high parathyroid hormone immunoassay, and evidence of bone disease may not be present. Therefore, intraoperative recognition is essential. We report a case in which the presenting symptoms, physical examination, and laboratory analysis were consistent with benign disease. During surgery, the finding of an enlarged firm gland with surrounding inflammatory reaction altered the approach to include the possibility of parathyroid carcinoma. The gland and surrounding tissue were removed, and pathologic examination led to the diagnosis of carcinoma. At 18-month follow-up, the patient was free from recurrence. Any parathyroid gland with a gray appearance, firm texture, and surrounding inflammatory reaction should be treated as carcinoma. Initial intraoperative recognition offers the best chance for cure, since local recurrences are rarely curable.     

Cortisol stimulation of parathyroid hormone secretion by rat parathyroid glands in organ culture

Addition of cortisol (10(-6) to 10(-8) M) and related glucocorticoid congeners to cultures of rat parathyroid glands stimulated dose-related increases in parathyroid hormone secretion; the addition of deoxycorticosterone or cortexolone was without effect. Cortexolone, however, inhibited the stimulatory activity of cortisol when both were added to the culture medium. This direct stimulatory effect of cortisol on parathyroid gland secretion may account in part for the increased concentration of parathyroid hormone in the serum of cortisol-treated animals.     

Surgical and medical management of patients with pulmonary metastasis from parathyroid carcinoma

BACKGROUND: The aim of this study was to characterize patients with pulmonary metastasis of parathyroid carcinoma and to evaluate the long-term effect of surgical and medical therapy. METHODS: Seven patients with pulmonary metastasis of parathyroid carcinoma were treated between 1980 and 1992. Six patients underwent resection of pulmonary metastases, and one patient has had long-term bisphosphonate therapy alone. Bisphosphonate was also given before or after operation to three patients. RESULTS: Two patients underwent a unilateral thoracotomy for a single pulmonary lesion, and four other patients with multiple lesions underwent staged bilateral thoracotomies. The postoperative serum calcium level returned to normal after each thoracotomy in three patients who were alive and well 3, 8, and 12 years after the first thoracotomy. Hypercalcemia persisted in the other three patients. In two of the patients, bisphosphonate therapy was also unable to control hypercalcemia. In one patient the serum calcium level has been maintained in the 13 mg/dl range by bimonthly bisphosphonate therapy alone for 3 years. CONCLUSIONS: The aggressive surgical approach to pulmonary metastasis of parathyroid carcinoma was shown to be effective for palliation in selected patients. Bisphosphonate therapy is an alternative to resection but has only a temporary calcium-lowering effect.     

Identification of a parathyroid adenoma by operative ultrasonography

During surgery, real-time ultrasound scanning accurately localized a parathyroid adenoma posterior to be the superior pole of the right thyroid lobe. This was made feasible because of the ultrasound features of parathyroid tissue and current developments in ultrasound instrumentation.     

Proliferative effect of parathyroid hormone-related protein on the hypercalcemic Walker 256 carcinoma cell line

The rat Walker 256 carcinoma is an animal model for humoral hypercalcemia of malignancy. This tumor produces and secretes parathyroid hormone (PTH)-related protein (PTHrP), a likely mediator for this syndrome. In this study, we investigated the effect of PTHrP on Walker 256 tumor cell proliferation. We found that [Tyr36]human (h)PTHrP (1-36)NH2 and hPTHrP (1-86), unlike hPTHrP (38-64)NH2, stimulate DNA synthesis dose-dependently in these cells. A similar mitogenic effect was also observed with bovine (b)PTH (1-34) or (Nle8.18, Tyr34)bPTH (3-34)NH2. Moreover, addition of anti-hPTHrP (1-34) neutralizing antibodies decreased tumor cell growth. Conversely, 10(-4)M dibutyryl cAMP or Sp-cDBIMPS (a cAMP analogue) inhibited DNA synthesis in these cells, being incompetent at lower doses. PTHrP or PTH failed to stimulate cAMP production, but they induced a cytosolic calcium transient increase in these cells. These findings support an autocrine role of PTHrP in the regulation of this tumor growth.     

Prevalence of hypercalcaemia in a health screening in Stockholm

A free health check, offered to 21417 20-63-year-old employees of the Stockholm City and County Council in 1971-73, was accepted by 15903 persons. The examination included a multichannel chemical analysis of a single blood sample. Serum calcium levels greater than or equal to 11.0 mg/100 ml (2.75 mmol/l) and greater than or equal to 11.1 mg/100 ml (2.78 mmol/l) were encountered in 3.9% and 1.1% of the population, respectively. Among subjects below 50 years of age, the calcium concentration was significantly higher in males than in females. This difference disappeared in older subjects, essentially because the calcium level decreased with advancing age in the men. To a further investigation were invited 178 subjects with a single serum calcium registration greater than or equal to 11.1 mg/100 ml (2.78 mmol/l). Of this group, 95 persons (53.4%) exhibited hypercalcaemia (HC) on repeated testing. Twelve had been operated on prior to the actural follow-up and found to have parathyroid adenomata. Twenty subjects were on continuous treatment with diuretics of the thiazide type and seven had diseases that might induce HC (two had hyperthyroidism, two hypothyroidism, one sarcoidosis, one hypernephroma and one mammary carcinoma). In 56 patients the laboratory and physical examinations did not reveal any obvious cause for the HC except possible hyperparathyoidism (HPT). Eighty (84.2%) of the 95 HC subjects were women, mostly over 50 years. The 95 persons constituted 6% of the total number of health-screened persons. The highest prevalence, 13%, was recorded for women aged 60-63. The prevalence of HPT in the total material was 3.6%, which is higher than that found in several other studies. This is based on surgical findings to date.     

High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro

Phosphate retention plays an important role in the pathogenesis of secondary hyperparathyroidism in patients with renal failure. In in vitro studies, high extracellular phosphate levels directly stimulate PTH secretion in rat and bovine parathyroid tissue. The present study evaluates the effect of high phosphate levels on the secretion of PTH and the production of prepro PTH mRNA in human hyperplastic parathyroid glands. The study includes parathyroid glands obtained from patients with primary adenomas and from hemodialysis and kidney-transplant patients with diffuse and nodular secondary hyperplasia. The experiments were performed in vitro using small pieces of parathyroid tissue. The ability of high calcium levels to decrease PTH secretion was less in adenomas than in secondary hyperplasia; among the secondary hyperplasia, nodular was less responsive to an increase in calcium than diffuse hyperplasia. In diffuse hyperplasia, PTH secretion was increased in response to 3 and 4 mM phosphate compared with 2 mM phosphate, despite a high calcium concentration in the medium; prepro PTH mRNA levels increased after incubation in 4 mM phosphate. Similar results were obtained with nodular hyperplasia, except that the elevation of PTH secretion in response to 3 mM phosphate did not attain statistical significance. In adenomas, high calcium concentrations (1.5 mM) did not result in inhibition of PTH secretion, independent of the phosphate concentration, and the prepro PTH mRNA was not significantly increased by high phosphate levels. In conclusion, first, the PTH secretory response to an increase in calcium concentration is less in nodular than diffuse hyperplasia; second, high phosphate levels directly affect PTH secretion and gene expression in patients with advanced secondary hyperparathyroidism.     

Proliferation of parathyroid cells negatively correlates with expression of parathyroid hormone-related protein in secondary parathyroid hyperplasia

BACKGROUND: Parathyroid hormone-related protein (PTHrP) is now suspected to act as an autocrine or paracrine regulator of cell growth or differentiation, although it was originally reported as a hypercalcemic substance in malignancies. This study was performed to assess the relationship between PTHrP expression and cell proliferation in human parathyroid glands. METHODS: The localization of PTH and PTHrP was studied in 42 samples of hyperplastic parathyroid from 14 long-term hemodialysis cases with immunohistochemistry and in situ hybridization. Results were compared with proliferative activity (proliferating cell nuclear antigen index: counts of proliferating cell nuclear antigen-positive cells/100 cells). The localization of the PTH/PTHrP receptor was also examined. Ten normal glands were studied as controls. RESULTS: In hyperplasia, cells positive for PTH, PTHrP, or both were observed immunohistochemically. The areas expressing PTHrP mRNA completely coincided with those positive for PTHrP immunohistochemically. Oxyphilic or transitional oxyphilic cells were consistently positive for PTHrP. PTH/PTHrP receptors were located in the cytoplasmic membrane in most parathyroid cells. Proliferating cell nuclear antigen-positive cells were rare in normal glands with an index of 0. 22 +/- 0.09 (mean +/- sem). They were significantly increased in hyperplastic cases but less for PTHrP-positive than for -negative cells (1.25 +/- 0.16 as compared with 7.80 +/- 0.52; P < 0.0001). CONCLUSION: The observed low level of proliferation of PTHrP-positive cells suggests a functional role for PTHrP as a possible growth suppressor in the human parathyroid.     

The parathyroid hormone/parathyroid hormone-related peptide receptor coordinates endochondral bone development by directly controlling chondrocyte differentiation

During vertebrate limb development, growth plate chondrocytes undergo temporally and spatially coordinated differentiation that is necessary for proper morphogenesis. Parathyroid hormone-related peptide (PTHrP), its receptor, the PTH/PTHrP receptor, and Indian hedgehog are implicated in the regulation of chondrocyte differentiation, but the specific cellular targets of these molecules and specific cellular interactions involved have not been defined. Here we generated chimeric mice containing both wild-type and PTH/PTHrP receptor (-/-) cells, and analyzed cell-cell interactions in the growth plate in vivo. Abnormal differentiation of mutant cells shows that PTHrP directly signals to the PTH/PTHrP receptor on proliferating chondrocytes to slow their differentiation. The presence of ectopically differentiated mutant chondrocytes activates the Indian hedgehog/PTHrP axis and slows differentiation of wild-type chondrocytes. Moreover, abnormal chondrocyte differentiation affects mineralization of cartilaginous matrix in a non-cell autonomous fashion; matrix mineralization requires a critical mass of adjacent ectopic hypertrophic chondrocytes. Further, ectopic hypertrophic chondrocytes are associated with ectopic bone collars in adjacent perichondrium. Thus, the PTH/PTHrP receptor directly controls the pace and synchrony of chondrocyte differentiation and thereby coordinates development of the growth plate and adjacent bone.     

Intra-operative parathyroid hormone assay for simplified localization of parathyroid adenomas

Lack of success in parathyroid surgery is usually due to failure to identify the abnormal parathyroid gland correctly at operation. The surgeon may be helped by rapid parathyroid hormone (PTH) assay in peripheral blood after removal of a suspected adenoma, and by frozen section histology, but these are not true localization techniques. We have adapted a non-isotopic immunoassay for rapid measurement of PTH in samples from the upper, middle and lower thyroid veins taken at operation, before exploration begins. Fifteen patients with primary hyperparathyroidism were operated on. In 10 the parathyroid adenoma was located easily, and was associated with high local venous PTH levels. In four patients the abnormal parathyroid was not immediately apparent but the assay indicated its location, which was confirmed after further exploration. In one patient there was no difference in PTH levels in the six venous samples. An ectopic adenomatous gland was successfully identified behind the thymus. The operation was successful in all patients as shown by a fall in the plasma calcium to the normal range. We conclude that intra-operative selective venous sampling and rapid PTH assay facilitates operative localization of parathyroid adenomas.