Thyrotropin receptor expression in Graves' orbital adipose/connective tissues: potential autoantigen in Graves' ophthalmopathy.

It is acknowledged that the TSH receptor (TSHr) on thyroid follicular cells is the autoantigen involved in the hyperthyroidism of Graves' disease. However, whether this receptor is expressed in extrathyroidal tissues, and whether it participates directly in the pathogenesis of Graves' ophthalmopathy (GO) are unclear. We sought to detect the expression of TSHr messenger ribonucleic acid (mRNA) and protein in orbital adipose/connective tissue specimens and in human orbital preadipocyte fibroblast cultures using liquid hybridization analysis and immunohistochemical methods. We demonstrated intact and variant TSHr mRNA transcripts and TSHr-like immunoreactivity in orbital adipose/connective tissue specimens from patients with GO. In addition, TSHr-like immunoreactivity was detected in early passage GO preadipocyte fibroblast cultures that were shown to include some adipose cells. In contrast, neither TSHr mRNA nor protein was detected in normal orbital adipose/connective tissue specimens or in late passage GO orbital fibroblast cultures containing no lipid-laden adipose cells. In conclusion, we showed that TSHr is expressed in the adipose/connective tissue of the diseased orbit in GO. In addition, TSHr is demonstrable in early passage GO preadipocyte orbital fibroblast cultures that contain a subpopulation of adipocytes. Subsequent passaging of these cells results in the loss of both TSHr expression and adipocyte-specific staining. These results suggest that both the expression of this receptor and the accumulation of adipose tissue in the orbit in GO may be induced in vivo by a humoral factor(s) not present in the cell culture environment.

Noninsulinoma pancreatogenous hypoglycemia: a novel syndrome of hyperinsulinemic hypoglycemia in adults independent of mutations in Kir6.2 and SUR1 genes.

In adults, endogenous hyperinsulinemic hypoglycemia is almost invariably due to insulinoma. In these patients with insulinoma, neuroglycopenic episodes exclusively after meal ingestion and negative 72-h fasts are extraordinarily rare. We describe five adults with neuroglycopenic episodes from hyperinsulinemic hypoglycemia within 4 h of meal ingestion and negative 72-h fasts. Each had negative transabdominal ultrasonography, spiral computed tomographic scanning, and celiac axis angiography of the pancreas. However, all showed positive selective arterial calcium stimulation tests indicative of pancreatic beta-cell hyperfunction. At pancreatic exploration, no insulinoma was detected by intraoperative ultrasonography and complete mobilization and palpation of the pancreas. Moreover, the resected pancreata showed islet hypertrophy and nesidioblastosis, but no insulinoma. No definite disease-causing mutation was detected in Kir6.2 and SUR1 genes, which encode the subunits of the pancreatic ATP-sensitive potassium channel responsible for glucose-induced insulin secretion. Four patients who underwent gradient-guided partial pancreatectomy have been free of hypoglycemic symptoms for up to 3 yr follow-up; the other, who underwent a limited distal pancreatectomy, has had brief recurrence of symptoms. The unique clinical features and responses to dynamic testing in these adults with hyperinsulinemic hypoglycemia in the absence of insulinoma may constitute a new syndrome of postprandial hypoglycemia from diffuse beta-cell hyperfunction.

Cytokines in the evolution of Graves' ophthalmopathy.

Infiltration of the retroocular space by inflammatory cells and the accumulation of glycosaminoglycans are histological characteristics of Graves' ophthalmopathy. Various cytokines, released by infiltrating immunocompetent cells and resident connective tissue cells, play a pivotal role in the evolution of this disease. The predominant cytokines secreted by orbital T cells during the course of the disease may govern the activity and stage of the local autoimmune process. Cytokine effects of potential relevance to the pathogenesis of Graves' ophthalmopathy include their ability to stimulate orbital fibroblasts to proliferate and secrete excess quantities of glycosaminoglycans. The edema associated with these hydrophilic macromolecules is directly responsible for many of the characteristic clinical features of the disease. In addition, certain cytokines induce or enhance the expression on orbital fibroblasts of immunomodulatory proteins. We review current evidence supporting the notion that cytokines are central to the development and evolution of Graves' ophthalmopathy.

Noninsulinoma pancreatogenous hypoglycemia syndrome: an update in 10 surgically treated patients.

BACKGROUND: Neuroglycopenia from endogenous hyperinsulinism usually is caused by insulinomas in adults. We recently reported a novel hypoglycemic disorder in 5 patients (patients 1 to 5) with postprandial neuroglycopenia, negative 72-hour fasts, negative perioperative imaging studies, but positive calcium stimulation tests and islet hypertrophy and nesidioblastosis in the gradient-guided resected pancreata. METHODS: In this report we compare our experience with 5 additional patients (patients 6 to 10) with this syndrome to that in the original report. RESULTS: The clinical features of patients 6 to 10 were similar to those of patients 1 to 5. Each had positive calcium stimulation testing that guided the extent of the distal pancreatectomy and histologic evidence of islet cell hypertrophy or nesidioblastosis. All 10 patients are alive from 9 to 50 months after operation, 1 of whom had no amelioration of neuroglycopenia. Minor perioperative complications occurred in 3 patients. One patient has experienced repeated bouts of acute pancreatitis, pseudocyst formation, and exocrine insufficiency. CONCLUSIONS: We have identified adult patients with severe, postprandial hyperinsulinemic hypoglycemia from diffuse islet cell disease, 80% of whom have been well palliated with surgery. The results in 7 men have been better than those in the 3 women for reasons that are not obvious.

The ovine corticotropin-releasing hormone stimulation test in the differential diagnosis of adrenocorticotropic hormone-dependent cushing's syndrome.

OBJECTIVE: To determine the efficacy of the ovine corticotropin-releasing hormone (oCRH) stimulation test in distinguishing between adrenocorticotropic hormone (ACTH)-dependent types of Cushing's syndrome. METHODS: The cortisol and ACTH responses to intravenously administered oCRH were determined in 64 patients with pituitary-dependent Cushing's syndrome and 13 patients with ectopic ACTH production. RESULTS: Of the 64 patients with pituitary-dependent Cushing's syndrome, 57 (89%) had a positive ACTH response to administration of oCRH (an increase of 50% or more above baseline), and 56 (88%) had a positive cortisol response (an increase of 20% or more above baseline). One patient with an ectopic ACTH-secreting tumor had a false-positive cortisol response to administration of oCRH. Two patients with ectopic ACTH-secreting tumors had false-positive responses to both ACTH and cortisol after oCRH was administered. Because both these patients did not have hypercortisolemia at the time of testing, they were excluded from the statistical analysis. When analyzed on the basis of ACTH response alone, oCRH testing yielded a diagnostic sensitivity and specificity for the diagnosis of pituitary-dependent hypercortisolism of 89% and 100%, respectively. The positive predictive value was 100%, and the negative predictive value was 61%. CONCLUSION: oCRH testing distinguished between the ectopic ACTH syndrome and pituitary-dependent hyper-cortisolism in most cases. Therefore, this test is a useful procedure in the diagnostic evaluation of ACTH-dependent forms of Cushing's syndrome.

Evidence-based endocrinology: illustrating its principles in the management of patients with pituitary incidentalomas.

Incidentally discovered pituitary lesions are commonly encountered in the current era of ever-increasing imaging. Individualizing a particular approach implies a thorough analysis of existing evidence and balancing it against different patient expectations. We will illustrate the application of principles of Evidence-Based Medicine to a case of a pituitary incidentaloma by formulating questions that are important to patient care and finding related evidence. Our objective is to reflect the opportunities and the challenges that an evidence-based clinical approach offers to clinicians and patients.

Extracervical fibrosclerosis causing obstruction of a ventriculo-peritoneal shunt in a patient with hydrocephalus and invasive fibrous thyroiditis (Riedel's struma).

The association of invasive fibrous thyroiditis (IFT) with foci of extracervical fibrosclerosis is well recognized. Affected sites include the retroperitoneum, the mediastinum, the biliary tract, and the orbit. The development of subcutaneous fibrosclerosis, however, is extremely rare. We report a patient with known invasive fibrous thyroiditis and hypoparathyroidism who presented with localized subcutaneous fibrosclerosis of the anterior chest wall resulting in compression of his ventriculoperitoneal shunt. The aetiology of IFT has remained unclear. Several histological and serological features, including the presence of mononuclear cells within the fibrosclerotic process, the occurrence of microscopic vasculitis, and the detection of autoantibodies directed against thyroid-specific antigens in a large proportion of patients with IFT, currently support the notion of autoimmune mechanisms playing a role in the pathogenesis of this rare disease.