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  • Author: Göran Åkerström x
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Lars Benson, Leif Wide, Göran Åkerström and Sverker Ljunghall

Abstract. Experimental studies have suggested that in primary hyperparathyroidism (HPT) the cells of the hyperfunctioning parathyroid tissue retain some capacity for stimulation and that an increase in secretion of parathyroid hormone (PTH) can occur when the extracellular calcium concentration is lowered within the hypercalcaemic range.

We have tested this hypothesis in 23 patients with HPT, 10 patients with hypercalcaemia of other origin (7 of whom had disseminated malignant disease) and 17 normal subjects.

In all three groups a single injection of 100 MRC units of salmon calcitonin caused a reduction in serum calcium of approximately 3 to 5%. In the hypercalcaemic patients this reduction was correlated to the basal calcium level (r = −0.57, P < 0.01). In the patients with HPT, although they all remained hypercalcaemic, the decrease in serum calcium was associated with a mean increase in serum PTH of 10%. Only in 2 patients did such an increase fail to occur despite an adequate decrease in serum calcium. These 2 patients had high basal PTH levels and the lack of response might have been due to a high degree of autonomous parathyroid function. Calcitonin also reduced serum calcium and increased serum PTH in normal subjects.

None of the patients with hypercalcaemia of other origin than primary HPT displayed a secretory PTH response to serum calcium reduction.

Thus, this test could be of practical clinical value, particularly in patients with borderline PTH values. A calcitonin-induced rise in PTH while serum calcium is lowered within the hypercalcaemic range strongly suggests primary HPT.

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Lars Benson, Jonas Rastad, Sverker Ljunghall, Claes Rudberg and Göran Åkerström

Abstract. Hyperparathyroidism (HPT) in the syndrome of multiple endocrine neoplasia type 1 (MEN-1) exhibits a different picture regarding its propensity for recurrence compared with sporadic primary HPT. In order to shed further light on the MEN-1 syndrome an investigation in vitro was made of parathyroid hormone (PTH) release of dispersed parathyroid cell from 11 patients with parathyroid hyperplasia associated with MEN-1, 10 patients with single parathyroid adenomas, and 10 preparations of normal bovine parathyroid glands. The two patient groups had the same average serum calcium value prior to surgery. Immunoreactive concentrations of PTH were measured after 2-h incubations at extracellular calcium concentrations of 0.5–3.0 mmol/l. Compared with the normal bovine parathyroid cells, the cells of the MEN-1 patients had a reduced calcium sensitivity of the PTH release and secreted smaller amounts of hormone at both low and high extracellular calcium concentrations. A similar abnormality of the PTH release was found for the cells of the hyperplastic and adenomatous parathyroid glands. Although individual parathyroid glands were investigated in only three MEN-1 patients, the results suggested the secretory regulation to be less defective in the small glands of each patient. It is concluded that in patient groups matched for serum calcium, the parathyroid tissue of MEN-1 patients has an abnormality of the PTH release similar to that of parathyroid adenomas.

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Lars Benson, Jonas Rastad, Leif Wide, Göran Åkerström and Sverker Ljunghall

Abstract. A constant EDTA infusion of 24 mg/kg/h during 60–120 min was given to 26 patients with primary hyperparathyroidism (HPT), 8 patients with hypercalcaemia of other origin and 10 healthy control subjects. PTH and ionized calcium concentrations were measured at 5–10 min intervals. In all three groups the infusion caused a linear decrease in plasma ionized calcium. In both the HPT patients and the healthy subjects there was a prompt increase in the serum levels of parathyroid hormone (PTH) until a plateau was reached. The PTH response of the HPT patients appeared already within the hypercalcaemic range and the plateau value was attained at higher levels of PTH and ionized calcium than in the healthy subjects. The enhanced response distinguished half of the HPT patients with basal PTH values within the reference range from the healthy controls. The patients with nonhyperparathyroid hypercalcaemia displayed no increase in PTH values until the ionized calcium concentration was reduced far into or below the reference range. Thus the EDTA infusion permitted a complete differentiation between HPT and other causes of hypercalcaemia. In most cases an infusion over 30 min was sufficient for this purpose.

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Sverker Ljunghall, Göran Åkerström, Claes Rudberg, Orjan Selking, Henry Johansson and Leif Wide

Abstract.

Treatment with cimetidine (1000 mg daily in four divided doses) was given for 3–20 weeks to 10 patients with primary hyperparathyoidism (HPT). All patients had hypercalcaemia and raised serum concentrations of parathyroid hormone (PTH). During treatment no consistent effects were noted on either serum calcium or PTH and normalization did not occur in any case. Hypergastrinaemia was demonstrated in 6 patients and was also unaffected by therapy while in the 4 patients with normal pre-treatment gastrin values a slight increase was seen.

This study does not support the view that cimetidine can be of use for the treatment of primary HPT.

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Claes Rudberg, Göran Åkerström, Henry Johansson, Sverker Ljunghall, Jan Malmaeus and Leif Wide

Abstract. The effects of 125-dihydroxycholecalciferol (1,25-(OH)2D3) and 24,25-dihydroxycholecalciferol (24,25-(OH)2D3) on parathyroid hormone (PTH) release from human parathyroid cells were investigated using an in vitro system of dispersed cells. The cells were obtained from 7 patients with primary hyperparathyroidism (HPT) and adenoma, 4 patients with primary HPT due to hyperplasia and 2 patients with parathyroid hyperplasia secondary to chronic renal failure.

The dispersed cells were incubated in tissue culture medium at low, normal and high external calcium concentrations for 2–16 h. There was a gradual suppression of PTH release (5–55%) when the calcium concentration in the medium was increased from 0.5 to 3.0 mM, thus indicating retained regulation of hormone release. The addition of 1,25-(OH)2D3 in concentrations of 0.1 and 1 ng/ml and of 24,25-(OH)2D3 in concentrations of 1.0 and 10 ng/ml during the incubations did not further affect the amount of PTH released by the cells. The concentrations of the different vitamin D metabolites tested closely correspond to levels observed under normal physiological conditions and during treatment with high doses of vitamin D in vivo.

Thus, the findings contradict the idea of any direct short-term regulatory effect of either 1,25-(OH)2D3 or 24,25-(OH)2D3 on the secretion of PTH from hyperfunctioning human parathyroid tissue.

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Lars Lind, Bo Wengle, Ole Helmer Sørensen, Leif Wide, Göran Åkerström and Sverker Ljunghall

Abstract. The parathyroid gland possesses receptors for 1,25-dihydroxyvitamin D3, the active metabolite of the vitamin D system, and in vitro experiments have shown that 1,25-dihydroxyvitamin D3 can inhibit the secretion of PTH. In this study 31 subjects who had displayed persistent mild hypercalcemia for 14 years and presumably had mild primary hyperparathyroidism (HPT) were challenged with 1.0 μg alphacalcidol (1α-(OH)-vitamin D3) over 6 months in a double-blind, placebo-controlled study. Before initiation of therapy, the hyperparathyroid subjects showed lower serum levels of 1,25-dihydroxyvitamin D in relation to PTH or calcium when compared with age- and sex-matched controls. Treatment induced a slight rise in serum calcium (0.05 mmol/l), but no significant decrease of the PTH levels. Eighteen of the subjects thereafter entered an open study with a higher dose of alphacalcidol (2.0 μg) over 1 year. Although this high dose induced a marked rise in serum calcium (0.17 mmol/l), there was only a transient reduction of the PTH levels. Thus, during long-term condition there was an escape from the suppressive action of the elevated calcium concentrations and no evidence of a specific inhibition of PTH secretion by a small oral dose of active vitamin D.

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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.

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Henrik Joborn, Rolf Larsson, Jonas Rastad, Peter Nygren, Göran Åkerström and Sverker Ljunghall

Abstract.

Influence of vasoactive intestinal polypeptide, neuropeptide Y, calcitonin gene-related peptide, and substance P was investigated on dispersed parathyroid cells of adult cattle. At a physiological concentration of extracellular calcium, vasoactive intestinal polypeptide stimulated the parathyroid hormone release in a dose-dependent manner, whereas no effects were noted for the other peptides. The dependency of PTH secretion upon extracellular calcium was shifted to the right by vasoactive intestinal polypeptide at 10−6 mol/l, with a tendency for greater effects at low (0.5 mmol/l) than high concentrations (2.0-3.0 mmol/l) of the cation. Vasoactive intestinal polypeptide significantly enhanced cAMP release of the parathyroid cells, whereas no influence was noted on cytoplasmic calcium or pH within the cells. The results suggest that vasoactive intestinal polypeptide stimulates the PTH release by interaction with cAMP production of the parathyroid cells. This effect may contribute to the development of hypercalcemia in patients with neuroendocrine tumours secreting vasoactive intestinal polypeptide.

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Claes Rudberg, Henry Johansson, Göran Åkerström, Torsten Tuvemo and F Anders Karlsson

Rudberg C, Johansson H, Å&#x212B; G, Tuvemo T, Karlsson FA. Graves' disease in children and adolescents. Late results of surgical treatment. Eur J Endocrinol 1996;134:710–5. ISSN0804–4643

All children and adolescents with Graves' disease in the county of Uppsala (catchment area population 250000) treated between 1970 and 1994 were evaluated in a retrospective study. The material comprised 31 patients with a mean age of 11 years (range 4–16), 29 (94%) of whom were girls, and four (13%) of the patients had Down's syndrome. Treatment was primarily conservative and surgery was considered if prolonged medical treatment failed. Lasting remission after antithyroid drug therapy (median 6.5 years; range 4.5–8 years) was noted in 6/31 patients (19%), three (10%) of whom subsequently developed hypothyroidism. Twenty-four of the remaining patients (77%) ultimately underwent subtotal (N=20) or total thyroidectomy (N=4) after experiencing one or more episodes of recurrent hyperthyroidism during medical treatment (median 6 years; range 0.5–11 years). After surgery one patient developed permanent hypocalcemia requiring low-dose vitamin D supplementation. During a postoperative follow-up period of 12.2 years (median: range 1–17 years), there were two cases of recurrent thyrotoxicosis, 1 and 10 years after surgery. The results underline that gender and Down's syndrome are risk factors of juvenile Graves' disease and that the disorder often is difficult to control by long-term medical therapy. In such cases thyroid surgery offers a safe and prompt reversal of the thyrotoxicosis. A proportion of the patients may ultimately develop hypothyroidism, substantiating a need for long-term follow-up of persons afflicted with Graves' disease early in life.

F Anders Karlsson, Department of Medicine, University Hospital, S-751 85 Uppsala. Sweden

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Brita Winsa, Jonas Rastad, Göran Åkerström, Henry Johansson, Kerstin Westermark and F Anders Karlsson

Winsa B, Rastad J, Åkerström G, Johansson H, Westermark K, Karlsson FA. Retrospective evaluation of subtotal and total thyroidectomy in Graves' disease with and without endocrine ophthalmopathy. Eur J Endocrinol 1995;132:406–12. ISSN 0804–4643

A retrospective analysis was performed in 173 consecutive patients with Graves' disease (GD) with the principal aim of evaluating the influences of subtotal (N = 157) and total (N = 19) thyroidectomy on postoperative recurrence rates, endocrine ophthalmopathy (EO) and thyrotropin receptor antibody (TSH-R-ab) titres. Postoperatively recurrent disease, identified by increased thyroid hormone levels, occurred in 32 patients (20%) who underwent subtotal resection. These recurrences were associated with over-representation of preoperative EO (p < 0.001) as well as high TSH-R-ab levels post-operatively (p < 0.05–0.01). Subtotal and total resections were followed by an aggravation of preoperative EO in nine (16%) and one (6%), and by a development of EO in two and none of the patients, respectively. Persistently elevated TSH-R-ab titers during thyrostatic therapy became close to normalized in seven (32%) and 15 (88%) of the patients undergoing subtotal or total thyroidectomies, respectively, which illustrates a thyroid tissue dependency of the autoantibody production. Among the total material of 173 patients, altogether 75 cases exhibited persistent or progressive EO and/or TSH-R-ab elevation after more than 1 year of preoperative thyrostatic treatment. In this group, recurrent GD or aggravated EO occurred in 23 (39%) of those operated with subtotal resection and in one (6%) of those undergoing total thyroidectomy (p < 0.05). The results thus indicate that EO, particularly at the time of surgery, and prevailing TSH-R-ab titers are associated with an increased risk of recurrent GD and suggest that patients exhibiting these characteristics should benefit from total rather than subtotal thyroidectomy.

Brita Winsa, Department of Internal Medicine, University Hospital, S-751 85 Uppsala, Sweden