Insulinomas in MEN-I patients: early detection and treatment of insulinomas in patients with the multiple endocrine neoplasia syndrome type-I.

In the multiple endocrine neoplasia syndrome type I (MEN-I syndrome), periodic screening of patients and their close relatives may improve prognosis and life expectancy. Although there is diffuse involvement of the pancreas with microadenomatosis, insulinomas in the MEN-I syndrome usually occur as single tumours. This is illustrated here by two patients with insulinomas and the MEN-I syndrome. Preoperative localization of the tumours was achieved accurately by digital subtraction angiography combined with dynamic computerized tomography after a bolus injection of contrast medium. At present, two and three years after elective surgery both patients are asymptomatic. The early detection and treatment of insulinomas is extremely important because of the high risk of cerebral damage associated with late diagnosis. Periodic investigation of MEN-I family members can promote the early diagnosis and treatment of insulinomas, especially in young patients, whose life expectancy and quality of life may be improved.

Evolutionary pathways of the calcitonin (CALC) genes.

Recombinant DNA techniques have made it possible to establish the structure of various genes encoding polypeptide hormones. Comparison of nucleotide sequences of the calcitonin (CALC) genes in man has revealed surprising similarities and variations. These findings and the homologies among the sequences in different species offered an opportunity for speculation about relationships between these genes and about their evolutionary origin. The first gene (CALC-I) directing the synthesis of calcitonin (CT) or CT gene-related peptide (CGRP) comprises six exons and gives rise to two mRNAs by an alternative RNA-processing mechanism. The homology between CGRP and CT reflects their common origin. The human genome contains a second gene (CALC-II) that is structurally related to the CALC-I gene. The CALC-II RNA transcripts do not appear to be differentially processed, as only preproCGRP-II mRNA and not preproCT-II is detected. The first and second CT/CGRP genes probably have evolved from a common ancestor gene early in evolution. Meanwhile, a third genomic locus containing nucleotide sequences highly homologous to exons 2 and 3 of both CALC genes was detected and probably generated by duplication of a part of CALC-II. This locus is not likely to encode a CT- or CGRP-related polypeptide hormone. The CALC genes and this last (pseudo) gene are located on the short arm of chromosome 11. Recently, islet- or insulinoma-amyloid polypeptide (IAPP) was isolated as a major constituent of amyloid present in human insulinoma and in pancreatic islet amyloid in noninsulin-dependent diabetes mellitus. IAPP shows 46% amino acid sequence homology with human CGRP-II.(ABSTRACT TRUNCATED AT 250 WORDS)

Evolutionary pathways of the calcitonin genes.

Since the development of molecular biology, knowledge about polypeptide hormones has increased rapidly. Recombinant DNA techniques have made it possible to establish the structure of genes encoding polypeptide hormones. The results have provided insight into the mechanisms underlying the increasing diversity of polypeptide hormones. Comparison of nucleotide sequences of various genes has revealed surprising similarities and variations. The calcitonin (CT) genes offered an opportunity for speculation about the evolutionary origin on one hand and relationships between these genes on the other.

Investigation of the zinc status of surgical patients--II. Influence of vascular reconstruction on the zinc status.

Patients admitted for major vascular reconstruction operations received an i.v. dose of 65Zn. From the increased whole-body retention of 65Zn and the findings on other parameters it was concluded that the was concluded that the post-operative zinc metabolism of these patients differed from that of the control subjects. Unexpectedly, this difference persisted for several months. These patients can probably serve as controls in studies of patients who have undergone surgery of the intestinal tract. Increase of whole-body retention of 65Zn may be a sensitive indicator for subclinical zinc deficiency, but application in practice is hampered by the long duration of the period required for the measurement. From the present results it seems likely that measurement of the retention of 65Zn in the forearm as a function of time yields the same information but in a considerably shorter time.

Investigation of the zinc status of surgical patients.

Zn kinetics were studied in two surgical patients and compared with the findings in three controls. One patient had malabsorption following resection of part of the small intestine, the other was suffering from malabsorption due to radiation enteropathy incurred more than 10 years earlier. Whole-body retention of i.v. administered 65Zn, measured with a simple linear scanner, showed a sharp initial drop in the first patient, followed by an increased retention. This was explained by large initial intestinal losses of Zn leading to a state of Zn deficiency. In the second patient, who had developed Zn deficiency over a period of years, the whole-body retention was increased from the beginning. Compared with other parameters, whole-body retention seems to be a good indicator for the Zn status of patients, although of limited clinical use because the measurements take too much time.

Fluoride in serum and bone during treatment of osteoporosis with sodium fluoride, calcium and vitamin D.

Thirteen patients with primary osteoporosis were treated for two years with sodium fluoride (NaF), calcium and dihydrotachysterol (group A). The dose of NaF was modified according to the serum fluoride concentration, which was kept as constant as possible between 0.20 and 0.25 microgram/ml. In patients with bone fluoride content greater than or equal to 0.20% a significant increase in the volumetric density and in the surface percentage covered with osteoid and with osteoblasts was observed. A second group of 7 patients with primary osteoporosis was also treated for 2 years with calcium and dihydrotachysterol, but without fluoride (group B). In these patients no significant change in the volumetric density or in the surface percentage covered with osteoid or osteoblasts was found. Patients in group A with a bone fluoride content less than 0.20% could not be distinguished from the patients in group B. Based on the available data an advice was given for the dosage of NaF in patients with osteoporosis. Regular assessment of the serum fluoride concentration remains advisable.

Bilateral occurrence of pheochromocytoma in patients with the multiple endocrine neoplasia syndrome type 2A (Sipple's syndrome).

Two kindreds with the multiple endocrine neoplasia type 2A syndrome were studied. Of one of these we examined 150 members, 20 of whom were treated with thyroidectomy for medullary carcinoma and nine with bilateral adrenalectomy for pheochromocytoma. Of the second kindred 50 members were examined, seven of whom were thyroidectomized and seven treated with bilateral adrenalectomy. Pheochromocytomas were invariably found on both sides, even in four cases in which the adrenals on one side appeared to be completely normal, not only at preoperative roentgenologic examination but also on inspection during the operation. The microscopic finding of micronodules and a cluster of abnormal medullary cells identical with those found in pheochromocytomas in one of the apparently normal adrenals represents a first stage in the development of diffuse medullary hyperplasia as well as nodular hyperplasia. This is in accordance with the fact that in the MEN type 2A syndrome pheochromocytomas are always multicentric and multiple in origin. On the basis of these findings we conclude that all patients with the MEN 2A syndrome who show symptoms and signs of active pheochromocytoma should be subjected to bilateral adrenalectomy, even when one or both of the adrenals appear to be normal at roentgenologic investigation.

The use of hydroxy-DL-proline-2-(14)C in the investigation of hydroxyproline metabolism in normal subjects and in patients with renal insufficiency.

The metabolism of hydroxyproline was investigated in six healthy subjects and four patients with chronic renal insufficiency (creatinine clearances respectively 40, 10, 7, 2 1/2 ml/min). For this purpose hydroxy-DL-proline-2-(14)C was administered intravenously and the excretion patterns of radio-activity in plasma, urine and expired air (14CO2) were determined. A separation procedure (using thin layer chromatography followed by oxidation with D-amino acid oxidase) made it possible to determine the concentration of hydroxy-L-proline-2-(14)C in the presence of the D-isomer and the degradation products of both. Although the use of a racemic mixture as tracer made conclusions more difficult, it could be shown that in uremic patients the concentration of hydroxy-DL-proline -2-(14)C remained high in the blood for a longer period, the metabolites appeared in the urine later, and the peak respiratory 14CO2 excretion was reached later and was lower than in the healthy subjects. On this basis it was concluded that the metabolism of hydroxyproline is diminished in patients with renal insufficiency.