Ewa Lundgren

Population-based screening for primary hyperparathyroidism with serum calcium and parathyroid hormone values in menopausal women

BACKGROUND Population-based screenings for primary hyperparathyroidism have failed to systematically use intact parathyroid hormone (PTH) values for diagnosis, to explore prevalence and diagnostic criteria of normocalcemic hyperparathyroidism, and to attempt surgical verification of the disorder. METHODS A total of 5202 women (ages, 55 to 75 years) attending a population-based mammography screening were investigated for primary hyperparathyroidism. In women lacking a family history of hypercalcemia, significant renal impairment, or low urinary calcium excretion hyperparathyroidism was diagnosed on the basis of predetermined criteria encompassing lower intact serum PTH levels in hypercalcemia (serum PTH 25 ng/L or greater; reference range, 12 to 55 ng/L) than in two intervals of normocalcemia (serum PTH 35 or greater, greater than 55 ng/L). RESULTS Prevalence of hyperparathyroidism was 2.1% (n = 109). At diagnosis total serum calcium and serum PTH levels were 2.32 to 3.19 mmol/L and 34 to 300 ng/L, respectively, and 66% of the women exhibited normocalcemia. Repeated examination showed persistent normocalcemia in 30 patients, and all but two of them had normal ionized plasma calcium levels. Significantly higher serum calcium, serum PTH, and urine calcium--but not serum creatinine--levels were found in patients with hyperparathyroidism compared with matched control subjects from the screened population. Within an ongoing stratified treatment program, 59 of 60 patients who underwent operation exhibited pathologic parathyroid tissue (mean weight, 591 mg). CONCLUSIONS Substantial prevalence of sporadic primary hyperparathyroidism is demonstrated in a risk group. Although criteria for hyperparathyroidism recognition included patients with truly mild biochemical derangement, operative findings suggested underdiagnosis of the disorder.

Primary hyperparathyroidism revisited in menopausal women with serum calcium in the upper normal range at population-based screening 8 years ago.

Population-based screening showed 2.1% prevalence of primary hyperparathyroidism (pHPT) in postmenopausal women. Individuals with total serum (s)-calcium levels of 2.55 mmol/L or more at screening were diagnosed with pHPT when subsequent analysis supported inappropriately elevated intact parathormone (PTH) levels in relation to even normal s-calcium levels. The arbitrary diagnostic criteria were validated by parathyroidectomy. Herein we reinvestigated biochemical signs of pHPT in women not diagnosed with pHPT due to s-calcium 2.50 to 2.54 mmol/L (group A, n = 160) at screening or due to appropriate PTH levels on two occasions after screening (group B, n = 70). Altogether, 99 women in group A and 47 in group B underwent reinvestigation 8.8 years after screening when they were 65 to 84 years old. The s-calcium levels averaged 2.56 mmol/L and had increased in group A (mean 0.04 mmol/L) and decreased in group B (mean 0.05 mmol/L). A total of 48 and 18 females (48%, 38%), respectively, met the previously validated criteria of pHPT. Altogether 21% of them were hypercalcemic (range 2.60–3.12 mmol/L). Subgroup analysis showed that PTH had not increased with time (n = 47) and that atherogenic blood lipids, but not glucose levels, were similar in pHPT patients and matched controls (n = 37). Assuming the existence of pHPT already at screening, the prevalence of pHPT could be adjusted to 3.4%. Even the most liberal diagnostic criteria utilized at pHPT screening seemed to underdiagnose the disease by inefficient cutoff limits for s-calcium and PTH. Because one-fifth of the women with pHPT progressed to hypercalcemia, long-term follow-up is advocated for those with s-calcium in the upper normal range.

Normalized dyslipidaemia after parathyroidectomy in mild primary hyperparathyroidism: population‐based study over five years

objective Postmenopausal women are at increased risk of primary hyperparathyroidism (pHPT). Secondary dyslipidaemia in pHPT has attracted little attention, although morbidity and mortality associated with cardiovascular diseases have been reported to be increased in these patients.

Parathyroid Tissue in Normocalcemic and Hypercalcemic Primary Hyperparathyroidism Recruited by Health Screening

Abstract. Parathyroid tissue from 57 women (mean age 65.5 years) with sporadic primary hyperparathyroidism (HPT) was analyzed mainly to clarify its characteristics versus tissue from those with normocalcemia. Patients were recruited by population-based health screening of menopausal women. Analysis of three or four total serum calcium values showed normocalcemia in 16 patients (mean 2.53 mmol/L); 20 and 21 of the women were consistently (mean 2.82 mmol/L) or intermittently (mean 2.59 mmol/L) hypercalcemic, respectively. Parathyroid operation demonstrated a single adenoma in 81% of the individuals, and these lesions were most prevalent and commonly dominated by oxyphil parathyroid cells in the persistently hypercalcemic patients. Chief cell hyperplasia (two or three abnormal glands) of the nodular type was found more often in the normocalcemic patients. Total glandular weight was the smallest (mean 270 mg) among the normocalcemic women and contributed to delicate decisions with regard to the extent of resection. Immunostaining of cryosections with a monoclonal antibody recognizing a putative Ca 2+ sensor demonstrated variably heterogeneous down-regulation of the recognized glycoprotein in the pathologic parathyroid glands from all the individuals. Dose–response relations for PTH release and the cytoplasmic Ca 2+ concentration ([Ca 2+ ] i ) were determined in Ca 2+ 0.5–3.0 mmol/L by examining dispersed cells with radioimmunoassay and microfluorometry after fura-2 loading, respectively. ED 50 for PTH release and [Ca 2+ ] i and the [Ca 2+ ] i concentrations at Ca 2+ 3.0 mmol/L were the least deranged in cells from pathologic glands of the normocalcemic patients. The findings substantiate that the abnormal parathyroid tissue of normocalcemic HPT principally is characterized by the same, albeit less extensive, morphologic and functional derangements, which consistently have been demonstrated in patients with HPT accompanied by hypercalcemia and detected clinically.

Estrogen receptor gene polymorphism in postmenopausal primary hyperparathyroidism

BACKGROUND Estrogen and its receptor play a key role in calcium homeostasis, with implications in both the development and treatment of primary hyperparathyroidism. METHODS Leukocyte DNA was isolated from 101 postmenopausal female patients with primary hyperparathyroidism and age-matched female control subjects (n = 101). Polymorphic estrogen receptor alleles denoted P/p and X/x were detected by polymerase chain reaction and restriction digestion with Pvu II and Xba 1 RESULTS Allelic prevalences were similar in the patients and control subjects. In contrast to normocalcemic control subjects, patients with primary hyperthyroidism homozygous for alleles P and X displayed less elevated serum calcium concentrations (mean, 2.63 and 2.66 mmol/L) versus those with Pp and pp (2.72 mmol/L; p < 0.01) and Xx and xx (2.71; p < 0.05), respectively, as well as trends for higher intact serum parathyroid hormone values (p = 0.09). The PP genotype was accompanied by lower bone mineral density in the lumbar spine (p < 0.05). CONCLUSIONS Estrogen receptor gene polymorphisms are presumably not directly involved in the parathyroid tumorigenesis. However, they seem to interact with the extent of biochemical derangements of primary hyperthyroidism by possible influences on both the peripheral action of parathyroid hormone and calcium regulation of its secretion.

Positive effect of parathyroidectomy on bone mineral density in mild asymptomatic primary hyperparathyroidism

Objectives.  Patients with mild primary hyperparathyroidism (pHPT) often appear asymptomatic, and have previously been regarded as not requiring treatment. However, increased cardiovascular morbidity and dyslipidaemia have also been recognized in mild pHPT, which also seem to be normalized after parathyroidectomy. The present study explores whether postmenopausal women with mild pHPT have decreased bone mineral density (BMD) compared with age‐matched healthy controls, and the effects on BMD of parathyroidectomy.

Double Parathyroid Adenoma, a Clinically Nondistinct Entity of Primary Hyperparathyroidism

Abstract. Double parathyroid adenoma (DA) has been suggested to be a clinically distinct entity of primary hyperparathyroidism (HPT). Altogether 659 patients with sporadic primary HPT were analyzed retrospectively by evaluating consecutive primary operations for more than three decades. Patients with postoperatively persistent HPT and those with incomplete medical, operative, or histologic records were disregarded. The mean age (± SD) at surgery was 60.9 ± 12.7 years; 78% of the patients were female; and the duration of postoperative follow-up averaged 7.8 ± 7.2 years. DA, defined as two enlarged parathyroid glands, was found in 77 patients (12%). Enlargement of a single gland (SA) or three or more glands (MA) occurred in 80% and 8%, respectively. DAs were bilateral in 72% of patients, and the weight of the two glands differed by 317 ± 407 mg. The three histologic subgroups of patients exhibited no significant discrepancy with respect to age, classic symptoms of HPT, proportion of overtly asymptomatic individuals, or parathyroid tissue weight. A lower female predominance and extent of hypercalcemia and higher preoperative serum creatinine level occurred with DA and MA compared to SA. SA and DA differed from MA with respect to variably strong trends to lower postoperative incidences of recurrent HPT and hypoparathyroidism. DA seems to comprise an underrated histologic cause of HPT, which is eligible for a conservative operative approach. Clinical characteristics consistent with a distinct entity of sporadic primary HPT were not seen.

Association of Parathyroid Adenoma and Pregnancy with Preeclampsia

OBJECTIVE Case reports have described associations between calcium metabolism disturbances and primary hyperparathyroidism with preeclampsia, suggesting parathyroid involvement in preeclampsia etiology. This study examines whether parathyroid adenoma, the main cause of hyperparathyroidism, diagnosed and treated before pregnancy is associated with preeclampsia. DESIGN We conducted a register-based study to assess the association between parathyroid adenoma and subsequent preeclampsia. SETTING Births among Swedens general population were studied. POPULATION The study population included 52 women with a diagnosis of parathyroid adenoma and 519 without, all of whom had a subsequent singleton pregnancy between 1973 and 1997. METHODS We performed a conditional logistic regression investigating the association of parathyroid adenoma with subsequent preeclampsia in the first singleton pregnancy with adjustment for potential confounding factors. MAIN OUTCOME MEASURE The main outcome was a diagnosis of preeclampsia that does not include women with prior chronic hypertension. To ensure that treatment of parathyroid adenoma was completed before pregnancy, those with a diagnosis of parathyroid adenoma made less than 2 yr before delivery (and the matched comparison women) were excluded. RESULTS Statistically, parathyroid adenoma prior to delivery is significantly (P < 0.001) associated with preeclampsia, producing an adjusted odds ratio of 6.89 (95% confidence interval, 2.30, 20.58). CONCLUSION A history of parathyroid adenoma should be viewed as a risk for preeclampsia.

Vitamin D Receptor Gene Polymorphism and Parathyroid Calcium Sensor Protein (CAS/gp330) Expression in Primary Hyperparathyroidism

Abstract. Calcitriol, via its receptor (VDR), inhibits parathyroid hormone (PTH) secretion and cell proliferation. Physically linked polymorphic VDR alleles denotedb,a, and T, comprise a novel risk factor for postmenopausal primary hyperparathyroidism (pHPT) by their presumed coupling to reduced VDR expression. This study examines VDR gene polymorphisms, parathyroid calcium-regulated cytoplasmic calcium concentrations ([Ca2+]i) and parathyroid expression of a calcium sensor protein (CAS/gp330). Genomic DNA was obtained from 66 postmenopausal women with pHPT and 66 age-matched female controls. Polymorphic VDR alleles were detected after polymerase chain reaction (PCR) and restriction digestion. Cryosections of pathologic parathyroid glands from 41 of the patients were immunostained with a monoclonal anti-CAS/gp330 antibody. Homozygosity for the VDR alleles b, a, and T was overrepresented in pHPT (p < 0.01–0.05) but did not couple to ED50 for calcium-regulated [Ca2+]i. The enlarged parathyroid glands possessed heterogeneous down-regulation of CAS/gp330. This down-regulation was the least conspicuous in the BBgenotype, and these few patients generally had larger parathyroid lesions (p < 0.05). The VDR haplotype baTis a risk factor for pHPT possibly by hampering the regulatory actions of calcitriol. In contrast the BAt haplotype seems to be underrepresented in pHPT and to couple to larger parathyroid lesions as well as less deranged CAS/gp330 expression and parathyroid cell function. HPT in these individuals may relate to genetic events principally altering the regulation of cell proliferation, rather than calcium sensing of the parathyroid cells.

The NciI polymorphism in the cyclin D1 gene and sporadic primary hyperparathyroidism

Abstract. Correa P, Lundgren E, Rastad J, Åkerström G, Westin G, Carling T (Uppsala University Hospital, Uppsala, Sweden). The NciI polymorphism in the cyclin D1 gene and sporadic primary hyperparathyroidism. J Intern Med 2001; 250: 516–520.