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Emil Hagström, Ewa Lundgren, Jonas Rastad, and Per Hellman

Objective: Dyslipidemia, hypertension, diabetes mellitus and also primary hyperparathyroidism (pHPT) are associated with an increased risk of cardiovascular diseases. Metabolic abnormalities in mild pHPT have been reported, but never in cases with normal calcium and high parathyroid hormone (PTH) levels, i.e. suffering from ‘normocalcemic pHPT’. Our aim was to explore the occurrence of these metabolic abnormalities in individuals with normocalcemic pHPT identified in a population-based screening, and the effects of parathyroidectomy vs conservative treatment on metabolic variables.

Design and methods: A population-based screening of 5202 post-menopausal women identified 30 patients with normal calcium, inappropriately high PTH and normal creatinine. A 5-year follow-up included 15 parathyroidectomized (PTx) and nine conservatively followed cases, in a non-randomized setting, together with age-matched controls. Biochemical variables and body mass index (BMI) were investigated.

Results: At study entry, cases had higher calcium, PTH, glucose, low-density lipoprotein (LDL)/high-density lipoprotein (HDL)-cholesterol, very low-density lipoprotein (VLDL)-cholesterol, total triglycerides, and BMI compared to controls (P = < 0.0001–0.035). The cases had a lower HDL-cholesterol value (P = 0.013) and one third of the cases had hypertriglyceridemia. During follow-up, the PTx cases decreased in calcium, PTH, LDL/HDL-cholesterol, total and LDL-cholesterol (P = 0.0076–0.022). Investigated biochemical variables remained adverse in conservatively followed cases during follow-up except a decreased LDL-cholesterol value. All surgically treated patients had parathyroid adenoma.

Conclusions: Cases with normocalcemic pHPT have increased proatherogenic lipoprotein levels, BMI and glucose levels compared to age-matched controls. Parathyroidectomy has positive effects on some of these variables and reverses them to the same level as the controls, while conservative treatment fails to normalize the investigated metabolic variables.

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Peter Ridefelt, Peter Nygren, Per Hellman, Rolf Larsson, Jonas Rastad, Göran Åkerström, and Erik Gylfe

Effects of the protein kinase C activating phorbol ester 12-O-tetradecanoyl phorbol 13-acetate and the inhibitor 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine (H-7) on parathyroid hormone (PTH) release were studied in normal bovine and pathological human parathyroid cells. An increase of extracellular Ca2+ from 0.5 to 3.0 mmol/l inhibited PTH release by 60% in the bovine cells with half maximal effect (ED50) at 1.31 mmol/l. This inhibition reached less than 50% in the cells from patients with primary and uremic hyperparathyroidism, and the ED50 values were 1.49 and 1.42 mmol/l, respectively. The phorbol ester (0.1 μmol/l) made secretion insensitive to changes of extracellular Ca2+, an action counteracted by H-7 (50 μmol/l) in the bovine cells, whereas H-7 alone had no effects. The phorbol ester and H-7 had opposite actions on regulation of PTH release also from cells from patients with hyperparathyroidism. However, in pathological cells H-7 alone improved Ca2+ inhibition of secretion by stimulating release in low Ca2+ concentrations and decreasing the ED50 values. The magnitude of changes in ED50 values by H-7 increased with the severity of the secretory disturbance of the pathological cells. The results indicate that increased protein kinase C activity may be a factor of importance in the pathophysiology of hyperparathyroidism.

Free access

Samuel Backman, Duska Bajic, Joakim Crona, Per Hellman, Britt Skogseid, and Peter Stålberg

Objective

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome usually caused by loss-of-function mutations in the MEN1 gene. However, a minority of patients who fulfill the criteria for MEN1 are not found to harbor MEN1 mutations. Besides, some of these individuals, present with a subtly different phenotype suggestive of sporadic disease. The aim of the present study was to investigate the genetic architecture of mutation-negative MEN1.

Design

Fourteen patients with a clinical diagnosis (n = 13) or suspicion (n = 1) of MEN1 who had negative genetic screening of the MEN1 gene were included.

Methods

Constitutional DNA from the included patients, as well as tumor DNA from six of the patients, was subjected to whole genome sequencing. Constitutional variants were filtered against population databases and somatic variants were studied under a tumor-suppressor model.

Results

Three patients carried pathogenic variants (two splice-site variants, one missense variant) in MEN1 that had not been detected during routine clinical sequencing, one patient carried a pathogenic variant in CASR and one patient carried a gross deletion on chromosome 1q which included the CDC73 gene. Analysis of matched tumor DNA from six patients without mutations did not detect any recurrent genes fulfilling Knudson’s two-hit model.

Conclusion

These results highlight the possibility of germline mutations being missed in routine screening, the importance of considering phenocopies in atypical or mutation-negative cases. The absence of apparent disease-causing mutations suggests that a fraction of MEN1 mutation-negative MEN1 cases may be due to the chance occurrence of several endocrine tumors in one patient.