Alternative genetic pathways in parathyroid tumorigenesis.

In this study 44 parathyroid tumors from 26 sporadic cases, 10 cases previously given irradiation to the neck, and 8 familial cases were screened for sequence copy number alterations by comparative genomic hybridization. In the sporadic adenomas, commonly occurring minimal regions of loss could be defined to chromosome 11 (38%), 15q15-qter (27%), and 1p34-pter (19%), whereas gains preferentially involved 19p13.2-pter (15%) and 7pter-qter (12%). Multiple aberrations were found in sporadic tumors with a somatic mutation and/or loss of heterozygosity of the MEN1 gene. The irradiation-associated tumors also showed multiple comparative genomic hybridization alterations and frequent losses of 11q (50%), and subsequent analysis of the MEN1 gene demonstrated mutations in 4 of 8 cases (50%). The adenomas from familial cases showed few alterations, and in 3 of these tumors a gain of 19p13.2-pter was seen as the only aberration. In this study numerical copy number alterations were frequently detected in sporadic and irradiation-associated parathyroid adenomas, although these tumors are benign. The majority of these alterations were found in tumors with confirmed involvement of the MEN1 gene locus in agreement with a role of the MEN1 gene in genomic stability. Furthermore, the frequent occurrence of MEN1 mutations (50%) in irradiation-associated parathyroid tumors suggests that inactivation of the MEN1 gene is an important genetic alteration involved in the development of parathyroid tumors in postirradiation patients.

Biochemical hyperparathyroidism and bone mineral status in patients treated long-term with lithium.

Lithium is known to interfere with normal calcium homeostasis, but the long-term effects and possible clinical significance are uncertain. Thus, we measured indices of parathyroid function including intact parathyroid hormone (PTH) and ionized and total calcium levels in 26 patients treated for manic-depressive psychosis with lithium for 10 years or longer (mean +/- SD duration, 15 +/- 6 years). Increased ionized calcium levels were found in 11 patients and increased PTH concentrations in five patients. Altogether, 54% of the patients (14 of 26) had ionized calcium and/or PTH levels above the laboratory reference range. The PTH/ionized calcium relationship of the lithium-treated patients was compared with that of a group of normal subjects (n = 23) and with those of three different groups of patients with abnormal parathyroid function (chronic hypoparathyroidism, n = 21; primary hyperparathyroidism [HPT], n = 50; and tertiary HPT, n = 21). Lithium-treated patients had significantly higher ionized calcium levels (P < .0001) but not significantly higher PTH concentrations (P = .08) than the normal subjects. In comparison to the normal controls, lithium-treated patients had a right-sided shift in their PTH/ionized calcium relationship that was in the same direction but less prominent than in primary or tertiary HPT. Dual-energy x-ray absorptiometry disclosed similar bone mineral densities (BMDs) of lithium-treated patients and age-, sex-, and body mass-matched normal controls in the whole body, lumbar spine, and femoral neck (Z scores: +1.20, +1.22, and +1.02, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Seventeen year follow-up study of bone mass in patients with mild asymptomatic hyperparathyroidism some of whom were operated on.

OBJECTIVE: To compare the effect of operation and observation on bone mineral mass in patients with mild asymptomatic hyperparathyroidism (HPT). DESIGN: A randomised 17-year follow-up study. SETTING: University hospital, Sweden. SUBJECTS: 48 women who had been diagnosed as having asymptomatic HPT during a health screening survey in Stockholm, Sweden during 1971-73. INTERVENTIONS: 26 patients were operated on and 22 were observed. 46 normocalcaemic women served as a reference population. 17 years later, operated on (n = 12), not operated on (n = 8) and control subjects (n = 16) were followed up. MAIN OUTCOME MEASURES: Bone mineral content (BMC) of distal non-dominant forearm, and serum concentrations of calcium and creatinine. RESULTS: On entering the study in 1971-73, the BMC of the distal forearm was 14% lower in the patients with HPT than in age, body mass, and postmenopausal age-matched controls (mean (SD) 1.01 (0.23) compared with 1.18 (0.30) g/cm; p < 0.05). During the first 3 years after operation bone mass increased significantly in the group operated on (n = 26) to 106% of the initial values (95% confidence interval (CI) 100% to 111%), remained unchanged (mean 101%; (97% to 106%)) in the unoperated group (n = 22), and decreased significantly to 94% (92% to 97%) of the initial values in the reference group (n = 46). At follow up 17 years later BMC of distal radius in the operated group (n = 12) and patients treated conservatively (n = 8) showed similar values; that were not significantly lower than those of the controls (difference: -12 (18)%). CONCLUSIONS: Our results suggest that patients with mild asymptomatic HPT have already experienced their major bone loss when diagnosed. Parathyroidectomy had an initial positive effect on bone mineralisation, but we could find no long-term advantage in operative treatments. During the 17 year follow-up period HPT patients who were not operated on showed an improvement in bone mass compared with healthy control subjects.