Jonas Rastad

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.

Intracellular application of horseradish peroxidase and its light and electron microscopical appearance in spinocervical tract cells

Present techniques for the intracellular staining of physiologically identified neurons are not quite satisfactory for ultrastructural investigations. Iontophoretic administration of cobalt chloride for subsequent reaction with ammonium sulphide 12 does not allow fixation before incubation, a disadvantage as regards the ultrastructural preservation. If the injected cobalt chloride is allowed to react with diaminobenzidine 4 the fine structure of the cytoplasm appears to be damaged. This holds true also for iontophoretically injected Procion brown 2. Procion yellow 1~ is not electron dense and ultrastructural identification has to depend on changes of cell organelles9, la. Radioautographic techniques 5 are laborious because ultrastructural interpretation needs statistical analysis since the silver grains are situated at a distance from the source of activity 14. In this study the enzyme horseradish peroxidase (HRP) has been used for intracellular staining. HRP has recently found extensive use as a neuronal marker (for references, see ref. 10) in light and electron microscopical studies. The histochemical staining procedure employed seems not to damage the ultrastructure and the product of enzyme reaction is found in lysosome-like organelles 1°. In the present investigation the enzyme was administered intracellularly in spinocervical tract cells a, neurons previously studied with intracellular injections of Procion yellow 1,s. Cells were identified by monosynaptic excitation from the cutaneous nerves and by antidromic invasion from the dorsolateral funiculus in segment C3 (Fig. 1A-G). An additional criterion was the absence of antidromic invasion from C1 except at a high threshold. A total of 23 spinocervical tract cells were impaled with single barrelled micropipettes with tip diameters of 2-3/~m. The electrodes were filled by pressure with a 15-20 ~o (w/v) solution of HRP (Sigma, type II). In contrast to previous studies, where extracellular iontophoresis of HRP was performed 7,11, solutions in distilled water were initially used. In order to decrease the high electrode resistance by increasing ionic strength, both acid and basic solutions were tested. The best results were obtained

Tissue Distribution of Human gp330/Megalin, a Putative Ca2+-sensing Protein

We used riboprobes and monoclonal antibodies to characterize tissue distribution of the human 550-kD homologue to gp330/megalin, primarily identified in the rat kidney. Human gp330/megalin mRNA and protein are readily identified in human parathyroid cells, placental cytotrophoblasts, kidney proximal tubule cells, and epididymal epithelial cells. The immunoreactivity is found on the surface of the cells and is heterogeneously downregulated in parathyroid hyperplasia and adenomas. Cells of the proximal kidney tubule and epididymis express the protein on their luminal aspect. Moreover, the protein is expressed in Type II pneumocytes, mammary epithelial and thyroid follicular cells, and the ciliary body of the eye. Sequence analysis of cDNA fragments, obtained by RT-PCR, revealed identical nucleotide sequences in parathyroid, kidney, placenta, epididymis, and lung. Immunohistochemistry for parathyroid hormone-related protein (PTHrP) revealed partial co-expression with human gp330/megalin in parathyroid, placenta, and mammary gland. The findings substantiate human gp330/megalin expression in a variety of human tissues expected to possess calcium-sensing functions. It may constitute a protein of utmost importance to adult and fetal calcium homeostasis, although other important functions may also be coupled to this exceptionally large protein with highly restricted tissue distribution. (J Histochem Cytochem 45:383–392, 1997)

Hypocalcemia and parathyroid hormone secretion in critically ill patients.

Objective: To investigate possible causes of hypocalcemia and to assess parathyroid hormone (PTH) secretion in intensive care unit (ICU) patients. Design: Combined cross‐sectional and prospective study. Setting: ICU in a university hospital. Patients: Thirteen patients with sepsis and 13 patients who underwent major surgery. Interventions: None. Measurements and Main Results: Calcium metabolic indices were investigated during the first 24 hrs in the ICU and after 2 days. Eight of the surgical patients and five of the septic patients were subjected to a citrate/calcium infusion on day 1 in the ICU, to study the dynamics of PTH secretion. The blood ionized calcium (Ca2+) concentration was generally low in the septic patients (mean ± SD, 1.03 ± 0.08 mmol/L; reference value, 1.10‐1.30) and increased, but not normalized, after 2 days. Hypocalcemia was only occasionally seen in the surgical patients. In the septic patients, urinary excretion of calcium was low; and, in both patient groups, elevated concentrations of two markers of bone resorption, deoxypyridinoline and ICTP (serum carboxy‐terminal cross‐linked telopeptide of type I collagen), were found. In cases of sepsis, the concentrations of proinflammatory cytokines were high (394 ± 536 pg/mL for tumor necrosis factor‐α and 5676 ± 5190 pg/mL for interleukin‐6, both normally <10‐20). The Ca2+ concentration was inversely related to tumor necrosis factor‐α and interleukin‐6 (r2 = .35 − .42; p < .01), as well as to procalcitonin (r2 = .71; p < .01). Despite normocalcemia in the surgical patients, serum PTH concentrations were elevated in both patient groups (97 and 109 ng/L) (reference value, <55 ng/L), both on day 1 and day 3 in the ICU. The citrate/calcium infusion revealed an increased secretory response of PTH to lowered Ca2+ concentrations in both groups of patients (p < .05), when compared with matched healthy controls. Conclusion: Hypocalcemia was common in septic ICU patients and was not the result of an increased urinary excretion of calcium or of an attenuated bone resorption, but seemed related to the inflammatory response. An increased PTH secretion was found in both patient groups.

Surgery for Asymptomatic Pancreatic Lesion in Multiple Endocrine Neoplasia Type I

Abstract. Patients with multiple endocrine neoplasia (MEN) type I underwent pancreatic surgery at presymptomatic (n = 8, mean age 33 years) or symptomatic (n = 12, mean age 51 years) stages of pancreatic endocrine involvement with the principal aim to evaluate postoperative morbidity, survival, and malignant potential of the pancreatic lesion. Radiologic signs of malignancy were not identified in any patient prior to exploration. All patients displayed multiple tumors with generally complex immunoreactivity. Normal postoperative pancreatic tumor markers were recorded in five of the asymptomatic patients, which became abnormal in three of them at a mean of 3 years after surgery. All patients remained without symptoms for a mean of 6 years after operation. In four symptomatic individuals (33%) metastases were identified at exploration, and two died with tumor; 83% of symptomatic patients displayed persistent or recurrent endocrine morbidity from the pancreatic lesion. Recognizing lead time bias, this limited and uncontrolled patient comparison suggests that exploration at the symptomatic stage of pancreatic involvement in MEN-I patients is unsatisfactory. Rather than to obtain biochemical cure, surgery in asymptomatic patients might be regarded as a means of cancer prevention. The malignancy of the pancreatic lesion may be preceded by several decades of biochemical abnormality. Extensive screening for this lesion allows diagnosis during adolescence and the timely application of primary exploration. Active management of individuals with repeated biochemical analyses followed by selective reintervention could enable satisfactorily maintained pancreatic functions and substantial duration of cancer prevention.

Adrenal lesion in multiple endocrine neoplasia type 1

BACKGROUND Multiple endocrine neoplasia (MEN) type 1 is accompanied by adrenal involvement, but characteristics and clinical handling of this lesion have been insufficiently explored. METHODS Patients with MEN 1 (n = 43) were monitored (mean, 6.3 years) with annual biochemical and radiologic adrenal evaluation. Adrenal specimens were examined by in situ RNA-RNA hybridization for expression of the MEN1 candidate gene phospholipase C beta 3 (PLC beta 3) and immunostaining for insulin-like growth factor-1 receptor. RESULTS Altogether 17 patients (40%) displayed adrenal enlargement, which was limited to the adrenal cortex and showed signs of progression, marked atypia, and cancer development in three of them. Only the carcinoma exhibited adrenocortical hormone excess. PLC beta 3 was expressed in the hyperplastic and adenomatous proliferation but not the carcinoma. Pancreatic endocrine tumors with insulin-proinsulin excess were overrepresented in the patients with adrenocortical involvement, but significant insulin-like growth factor-1 receptor immunoreactivity was restricted to the carcinoma. CONCLUSIONS The prevalent adrenocortical lesion associated with MEN 1 requires regular attention because of malignant potential. It was unrelated to loss of constitution heterozygosity for the MEN1 locus (11q13) and PLC beta 3 expression, except for the cortical carcinoma exhibiting allelic losses involving also the Wiedemann-Beckwith gene at 11p15. Mechanisms for mitogenic relationships between the pancreatic and adrenal lesions of MEN 1 demand further clarification.

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.

Method for Dissection of Mesenteric Metastases in Mid-gut Carcinoid Tumors

With adequate medical management the midgut carcinoid tumor generally is an indolent malignancy associated with substantial life expectancy and appreciable life quality, even in the presence of liver metastases and significant tumor burden. Abdominal complications may occur in this entity of carcinoids owing to entrapment of intestines and encasement of mesenteric vessels by mesenteric metastases and associated marked mesenteric fibrosis. This may be the cause of abdominal pain, disabling diarrhea, weight loss to the extent of malnutrition, and eventually the risk of death with acute or chronic intestinal obstruction or intestinal gangrene. Operative removal of the mesentericointestinal lesion is often indicated to prevent or treat these complications but may be technically difficult when mesenteric metastases extend in the vicinity of major vessels in the mesenteric root. At laparotomy 56 patients with advanced midgut carcinoids underwent removal of the mesenteric tumor with a method for preserving the mesenteric vessels. This was feasible by mobilizing and releasing the right colon and mesenteric root from posterior adhesions, identifying the mesenteric artery below the pancreas, and free-dissecting this artery on the tumor capsule in the mobilized mesentery. Dissection was successful even with tumors initially judged inoperable unless tumor growth completely surrounded the mesenteric vessels or extended retroperitoneally. One patient was subjected to distal intestinal artery bypass. Symptom relief was been substantial and often of long duration after mesenteric tumor removal in patients who prior to surgery often had threatening intestinal ischemia. Patients with advanced midgut carcinoids may benefit markedly from dissectional removal of mesenteric tumors, which (conceivably better than conventional wedge resection) preserves the length of the remaining intestine.

Primary and reoperative parathyroid operations in hyperparathyroidism of multiple endocrine neoplasia type 1

BACKGROUND Operation and reoperation for hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN 1) is controversial regarding surgical strategy, preoperative localization, and biochemical indexes of recurrence. METHODS Fifty patients with MEN 1 with hyperparathyroidism were followed up 2 to 27 years after subtotal (SPX; n = 35) or total parathyroidectomy with forearm autografiing (TPX; n = 15), including 24 who underwent 28 reoperations because of persistent or recurrent hyperparathyroidism. RESULTS Persistent or recurrent hyperparathyroidism was seen in 66% and 20% of patients after SPX involving extirpation of at least 3 glands and TPX, respectively, and 100% after single-gland excision as a primary procedure. After reoperation, hypercalcemia was reversed in 33% of patients by SPX and 61% by intended TPX procedures. All patients received vitamin D substitution after TPX, but restricted thyroid function allowed withdrawal in all but 10 patients (36%). Intact serum parathyroid hormone levels in nongrafted and grafted arms rose with time, but only exceptional ratios localized graft recurrence. Localization of recurrent hyperparathyroidism was achieved with 11C-labeled methionine positron emission tomography. CONCLUSION MEN 1 hyperparathyroidism has a high risk of recurrence, and operation may include primarily SPX of at least 3 glands or TPX, although the latter includes a higher risk of long-term hypoparathyroidism. Reoperation should involve TPX with recognition of the enhanced recurrence rate in individuals with postoperative hyperparathyroidism.

1,25(OH)2D3 inhibits hormone secretion and proliferation but not functional dedifferentiation of cultured bovine parathyroid cells

SummaryIncreasing the extracellular Ca2+ concentration from 0.5 to 3.0 mM induced marked increments in cytoplasmic Ca2+ concentration (Ca2+i) and inhibition of parathyroid hormone (PTH) release of freshly isolated bovine parathyroid cells. 1,25-dihydroxycholecalciferol (1,25(OH)2D3; 0.1–100 ng/ml) did not affect (Ca2+i) and was also without acute effect on the secretion. During 4 days of monolayer culture, the parathyroid cells underwent significant increases in both number and size, and presence of 10–100 ng/ml 1,25(OH)2D3 almost completely inhibited the cell proliferation, whereas the hypertrophy was unaffected. One day of culture with 0.1–100 ng/ml 1,25(OH)2D3 was without effect on PTH release but after 4 days there was a dose-related reduction of recretion. At this time point and irrespective of the culture condition, PTH release was no longer suppressed by high extracellular Ca2+. Furthermore, Ca2+i increased little upon increments in the extracellular Ca2+ concentration as compared with freshly isolated cells. It is concluded that after prolonged exposure to 1,25(OH)2D3, PTH release is inhibited and, at high concentrations, the parathyroid cells cease to proliferate. However, 1,25(OH)2D3 does not affect the development of functional dedifferentiation of parathyroid cells during monolayer culture.