Chronic autoimmune thyroiditis and C-cell hyperplasia. Study of calcitonin secretion in 24 patients

Serum calcitonin (CT) was determined by radioimmunoassay, using two monoclonal antisera, in 22 women and two men, who had Hashimoto's thyroiditis as confirmed by echographic, immunological or cytological criteria; in 23 patients, serum CT levels were measured after intravenous infusion of pentagastrin (Pg). In 21 cases, basal and Pg stimulated serum CT concentrations were normal. A 61-year-old woman and a 63-year-old man, both euthyroid, had high serum basal CT: 12 pg/ml and 35 pg/ml; infusion of Pg resulted in abnormal increases in serum CT levels: respectively 64 pg/ml and 115 pg/ml. Another patient, a 65-year-old woman with primary hypothyroidism had high serum basal CT: 90 pg/ml (the Pg stimulation test was not done because of ischemic heart disease). Each of these 3 patients had a total thyroidectomy. Pathological examination of the thyroid showed typical features of Hashimoto's thyroiditis and extensive C-cell hyperplasia. After surgery, serum CT levels fell to normal. Therefore, a high serum CT can be observed as the consequence of C-cell hyperplasia in Hashimoto's thyroiditis.     

Frequency of RET proto-oncogene mutations in patients with normal and with moderately elevated pentagastrin-stimulated serum concentrations of calcitonin.

The possibility of germline mutations of the RET proto-oncogene (exons 10, 11, 13, 14, and 16) was investigated in 75 patients (57 men, 18 women) with a negative family history for medullary thyroid carcinoma (MTC), elevated (> 10 pg/mL) basal serum concentrations of human calcitonin (hCT) and a pentagastrin (PG)-stimulated serum hCT ranging from 50-100 pg/mL. Seventy patients (50 men, 20 women) with basal serum calcitonin concentrations in the normal range served as controls. Among the 75 patients with elevated basal serum hCT concentrations we identified 1 man with the mutation S649L and 2 patients (1 man and 1 woman) with the mutation Y791F. Among the 70 individuals with normal basal calcitonin 1 man and 1 woman presented with the mutation Y791F. No other mutations (such as those in codons 618 or 634, considered to be of greater clinical relevance) were identified in either group. On the other hand, the RET proto-oncogene mutation Y791F, characterized by a low penetrance, occurs comparatively frequently among patients with normal serum calcitonin concentrations. To preselect patients for RET screening by moderately (50-100 pg/mL) pentagastrin stimulation hCT concentrations does not increase the number of identified cases of familial MTC.     

Supravalvular aortic stenosis with parafollicular cell (C-cell) hyperplasia

Autopsy examination of a patient with well-documented supravalvular aortic stenosis and other characteristic features of the idiopathic infantile hypercalcemia syndrome revealed previously unreported hyperplasia of parafollicular cells (C cells). Immunohistochemical analysis demonstrated up to 30 calcitonin-containing cells per high power field, whereas normal glands contain only 4 to 10 cells per low power field in areas of highest concentration. The parathyroid glands were found to be normal both grossly and microscopically, whereas the bones showed thickened trabeculas, normal Haversian canals and no apparent increase in osteoblast or osteoclast activity, suggesting normal parathyroid hormone, but increased thyrocalcitonin activity. We suggest that C-cell hyperplasia has occurred in response to a persistent, rather than transient, elevation in serum calcium levels and that thyrocalcitonin function is augmented, rather than impaired in this disorder. The primary biochemical defect promoting hypercalcemia remains to be clarified, as well as the role, if any, such a defect plays in producing significant pathology in the central nervous system and in the cardiovascular, renal and skeletal systems.     

Inhibitory effect of galanin on basal and pentagastrin-stimulated gastric acid secretion in rats.

The dose-dependent effects of galanin on basal and pentagastrin-stimulated gastric acid secretion in pentobarbital-anesthetized rats were examined. Intravenous infusion of galanin at doses of 0.31, 0.62, 1.25, 1.87, 3.11, and 6.22 nmol/kg-1/h-1 into pentagastrin-stimulated rats produced a diminution in gastric acid secretion which was maximal (54.7%) at the level of the 1.87 nmol/kg-1/h-1 dose. Furthermore, the effect was biphasic, since both lower and higher doses of peptide were less effective. At the optimum concentration of 1.87 nmol/kg-1/h-1 galanin also inhibited basal gastric acid secretion. We conclude that endogenous galanin might be involved in the physiologic regulation of gastric acid secretion.     

Differential expression of galectin-3 in medullary thyroid carcinoma and C-cell hyperplasia

OBJECTIVE AND DESIGN: Galectin-3 is a beta-galactoside-binding protein that plays a role in cell adhesion and tumour progression. It was shown recently to diagnose malignant follicular thyroid lesions accurately. The reliability of this marker in the differential diagnosis between medullary thyroid carcinoma and C-cell hyperplasia was studied by immunohistochemistry. PATIENTS: Tissue specimens were obtained from 34 patients belonging to families with medullary thyroid carcinoma who underwent prophylactic thyroidectomy for RET gene mutation and/or abnormally increased plasma calcitonin levels. RESULTS: Galectin-3 was expressed in 23 of 25 cases of medullary thyroid carcinoma and in none of the nine cases of C-cell hyperplasia only, giving a sensitivity of 92% and a specificity of 100% for the diagnosis of carcinoma. A significant association was found between higher galectin-3 expression and occurrence of lymph node metastases (P < 0.05). CONCLUSIONS: Galectin-3 is a reliable diagnostic marker of medullary thyroid carcinoma, and its use may provide relevant information for prognosis and therapy.     

Plasma calcitonin in primary hyperparathyroidism: failure of C-cell response to sustained hypercalcemia

An acute increase in serum calcium stimulates calcitonin (CT) secretion, but the effects of chronic hypercalcemia are controversial. Histopathological studies have shown C-cell hyperplasia in primary hyperparathyroidism (1 degree HPT), although circulating levels of CT have been variously reported to be normal, elevated, or depressed. We reexamined this relationship using CT RIA in conjunction with a silica extraction technique that conveys improved sensitivity and specificity for monomeric CT. Nine men and seven women with surgically documented 1 degree HPT were studied preoperatively before and after a short calcium infusion (2 mg Ca/kg, for 5 min), as were 72 normal men and 76 normal women. Basal whole plasma immunoreactive CT and silica-extractable CT concentrations in 1 degree HPT were indistinguishable from normal, regardless of sex. In addition, the whole plasma and silica-extractable CT responses to calcium stimulation were normal or blunted in patients with 1 degree HPT. We conclude that hypercalcemia resulting from 1 degree HPT is not associated with augmented CT secretion in response to an iv calcium infusion.     

Predictive value of pentagastrin test for preoperative differential diagnosis between C‐cell hyperplasia and medullary thyroid carcinoma in patients with moderately elevated basal calcitonin levels

Background and Objectives Medullary thyroid carcinoma (MTC) is a calcitonin (CT)‐secreting neuroendocrine tumour originating from thyroid C cells. Serum CT concentrations are helpful in the early detection of MTC, while it is still unclear whether they can be used also for the differential diagnosis between MTC and C‐cell hyperplasia (CCH), a precancerous condition in familial MTCs but with unclear clinical significance in sporadic MTCs. Nowadays, surgery is recommended in all patients with basal or pentagastrin (PG)‐stimulated CT value of 100 pg/ml or more, without discriminating if they are affected with MTC or CCH only. The objective of this study was to investigate the utility of the PG test for CT in distinguishing CCH from MTC before surgery. Patients and Methods Sixteen of 20 patients with thyroid nodules and basal CT levels between 15 and 100 ng/l had a positive PG test (>100 ng/l PG CT peak) and form the basis of the data analysis. A diagnosis of MTC was histologically proved on surgical samples in seven patients and of CCH in nine other patients. Four patients with neither FNAB nor PG test consistent with a diagnosis of MTC did not undergo thyroidectomy. Results A peak of CT of 275 ng/l after PG was able to significantly distinguish patients with MTC from patients with CCH, with 100% sensitivity and 89% specificity (P = 0·002). PG‐stimulated calcitonin levels >275 ng/l had a positive predictive value (PPV) value for diagnosis of MTC of 100%, and PG‐stimulated calcitonin levels <275 had a PPV for the diagnosis of CCH of 89%. Conclusions A CT cut‐off after PG of 275 ng/l is suggested to be highly predictive in distinguishing CCH from MTC before surgery, and this may be helpful in selecting patients for thyroid surgery.     

Survival in patients with heart failure and normal basal systolic wall motion

To assess the prognostic effect of preserved systolic function in patients with congestive heart failure (CHF), the authors analyzed survival curves in 91 nonselected adult patients with CHF. Patients were assigned to one of two groups on the basis of fractional shortening. The first group consisted of 44 patients with a normal fractional shortening (greater than 0.17), and the second group, of 47 patients with a fractional shortening of 0.17 or less. The two groups were similar in respect to all historical and physical findings. Median survival was eleven months for patients with a decreased fractional shortening and twenty-six months for patients with a normal fractional shortening. Patients with a decreased fractional shortening had a significantly shorter survival (p = 0.01). The authors conclude that congestive heart failure with preserved systolic function is common and is associated with a better prognosis, and the literature suggests it may require nonstandard therapy. Their data also suggest, however, that CHF patients with preserved systolic function cannot be reliably distinguished at the bedside. Rather, echocardiography or other tests of systolic wall motion are needed to make the diagnosis.     

Inhibition of pentagastrin-stimulated gastric secretion by duodenal acidification or administration of fat in normal subjects and in patients with duodenal ulcer

The inhibitory effect of duodenal acidification and intraduodenal fat infusion on pentagastrin-stimulated gastric secretion in normal subjects and in patients with duodenal ulcer was studied. Intraduodenal infusion of acid resulted in inhibition of HCl secretion found to be significant only in ulcer patients. Pepsin output, although lower during the first 15 minutes of duodenal acidification, later increased. Intraduodenal infusion of olive oil resulted in significant inhibition of HCl and pepsin output in both groups of patients, which was maximal 45–60 minutes after the beginning of fat infusion. Gastric secretion was more readily inhibited in ulcer patients than in normal subjects; this difference was particularly evident in inhibition of pepsin secretion. In addition, decrease in concentration of HCl and pepsin was observed to be significant only in ulcer patients. Mechanisms by which duodenal acidification and fat inhibit gastric secretion are discussed. The results obtained suggest that secretin, which is probably responsible for inhibition after duodenal acidification, is not the inhibitor during inhibition by fat. The ulcer patients were found to have unimpaired mechanisms of inhibition by acid and fat.     

Aspects of the effect of metiamide on pentagastrin-stimulated and basal gastric secretion of acid and pepsin in man.

This study has examined the inhibition produced by metiamide on the gastric secretion of acid and pepsin in 13 patients with duodenal and three with gastric ulcer. The effect of metiamide on the response to a range of doses of pentagastrin in three normal individuals was determined, as was the interaction of metiamide and atropine on prolonged basal secretion. Metiamide inhibited the secretion of acid more than pepsin and the gastric secretion of patients with gastric ulcer more than duodenal ulcer. Metiamide inhibited both the maximal secretory response attainable with pentagastrin and decreased the sensitivity to pentagastrin. Atropine augmented and prolonged the action of metiamide.     

Small intestinal nodular lymphoid hyperplasia in patients with giardiasis and normal serum immunoglobulins

Nodular lymphoid hyperplasia of the upper small intestine was demonstrated in 25 patients with giardiasis. All had normal serum immunoglobulin levels and seven patients initially presented with clinical findings suggestive of an abdominal lymphoma. In only two, however, was the diagnosis of primary jejunal lymphoma confirmed. It is possible that an aetiological relationship exists between recurrent parasitic infestation and nodular lymphoid hyperplasia of the upper small intestine.     

Suppression of basal insulin secretion by adrenalin in normal man and in patients with insulinomas

Summary Basal insulin secretion has been thought to be via a different mechanism from stimulated insulin secretion, partly because it is not similarly suppressed by adrenalin. However, adrenalin normally causes hyperglycaemia, but if it is infused while the plasma glucose is kept constant there is marked suppression of insulin secretion. Sympathetic stimulation modulates basal insulin secretion, and alpha adrenergic blockade impaired the suppression of insulin secretion in response to hypoglycaemia. Four of five benign insulinomas had marked suppression of insulin secretion by adrenalin, but one malignant and one benign insulinoma had little suppression. Both had a raised proportion of their basal plasma insulin as proinsulin, and the impaired suppression of secretion by adrenalin probably signified an undifferentiated tumour.     

Synthetic salmon calcitonin is not diabetogenic in patients with normal or impaired glucose metabolism

The effects of short term administration of 200 MRC U of synthetic salmon calcitonin (sCT) daily on carbohydrate metabolism were investigated in 10 patients with various bone diseases, 3 of whom had type II diabetes mellitus and 3 of whom had impaired glucose tolerance. Blood glucose levels during the nocturnal postabsorptive period, blood glucose and blood insulin (IRI) levels and the ratio of the area under the insulin curve to the area under the glucose curve (AI/AG) after a mixed meal were determined before and after 15 days of treatment. The values before and after sCT treatment were not significantly different, suggesting that high doses of sCT are not diabetogenic and can be given to patients with impaired glucose tolerance or to diabetics, without any risk of deteriorating metabolic control.     

The effect of beta-adrenergic blockade upon basal and pentagastrin-stimulated gastric acid secretion and upon gastrin response to food.

Beta-adrenergic blockade with 10 mg of propanolol had no significant effect upon the spontaneous gastric acid secretion, while the maximum (pentagastrin) acid secretion was depressed in healthy subjects and patients with duodenal ulcer. The gastrin response to food was significantly higher during beta-adrenergic blockade. It is suggested that a minor part of the maximum acid secretion may be due to activation of beta-receptors, while the gastrin response to food is probably not related to activation of beta-receptors.     

Prevalence of normal serum amylase levels in patients with acute alcoholic pancreatitis

Acute alcoholic pancreatitis is uncommonly diagnosed when the serum amylase level is normal. We defined acute alcoholic pancreatitis as a clinical syndrome in which hyperamylasemia was not a necessary component and sought support for the diagnosis by ultrasonography and computed tomography of the pancreas. In 68 episodes of acute alcoholic pancreatitis identified in a one-year period, the serum amylase level was normal at the time of hospital admission in 32%. In 40 episodes, we performed ultrasonography and computed tomography within 48 hr of admission. The diagnosis was supported by ultrasonography in 43%, by computed tomography in 68%. Ultrasonography and computed tomography supported the diagnosis as frequently in patients with normal serum amylase levels as in patients with hyperamylasemia. We conclude that patients with acute alcoholic pancreatitis frequently have normal serum amylase levels. The widespread clinical practice of relying solely on hyperamylasemia to establish the diagnosis of acute alcoholic pancreatitis is unjustified and should be abandoned.