Does this patient have pheochromocytoma? A systematic review of clinical signs and symptoms.

CONTEXT: Pheochromocytoma is a rare disease but with high mortality if it is not being diagnosed early. Several biochemical tests with high accuracy have been obtained, but the clinical threshold for request of these tests is not determined clearly. OBJECTIVES: To determine the Likelihood Ratios of clinical symptoms and signs in diagnosing pheochromocytoma. And also meta-analysis of their sensitivity in this disease. DATA SOURCES: MEDLINE was searched for relevant English-language articles dated 1960 to February 2014. Bibliographies were searched to find additional articles. STUDY SELECTION: We included original studies describing the sensitivity and/or likelihood ratios of signs and symptoms in clinical suspicion of pheochromocytoma. Their method of diagnosis should have been based on pathology. We excluded specific subtypes or syndromes related to pheochromocytoma, or specific ages or gender. Also we excluded studies before 1993 (JNC5) which no definition of hypertension was presented. 37 articles were chosen finally. DATA EXTRACTION: Two authors reviewed data from articles independently and gave discrepancies to third author for decision. The aim was extraction of raw numbers of patients having defined signs or symptoms, and draw 2 × 2 tables if data available. We meta-analyzed sensitivities by Statsdirect and Likelihood Ratios by Meta-disc soft wares. Because our data was heterogeneous based on I(2) > 50 % (except negative Likelihood ratio of hypertension), we used random effect model for doing meta-analysis. We checked publication bias by drawing Funnel plot for each sign/symptom, and also Egger test. DATA SYNTHESIS: The most prevalent signs and symptoms reported were hypertension (pooled sensitivity of 80.7 %), headache (pooled sensitivity of 60.4 %), palpitation (pooled sensitivity of 59.3 %) and diaphoresis (pooled sensitivity of 52.4 %). The definition of orthostatic hypotension was different among studies. The sensitivity was 23-50 %. Paroxysmal hypertension, chest pain, flushing, and weakness were the signs/symptoms which had publication bias based on Funnel plot and Egger test (P value < 0.05). Seven of the articles had control group, and could be used for calculating LR of signs/symptoms. Diaphoresis (LR+ 2.2, LR- 0.45), Palpitation (LR+ 1.9, LR- 0.52) and headache (LR+ 1.6, LR- 0.24) were significant symptoms in clinical diagnosis of pheochromocytoma. Other signs and symptoms had been reported in only one study and could not have been meta-analyzed. Classic triad of headache, palpitation and diaphoresis in hypertensive patients had the LR+ 6.312 (95 % CI 0.217-183.217) and LR- 0.139 (95 % CI 0.059-0.331). Surprisingly, hypertension was not important in clinical suspicion of pheochromocytoma, and even normotension increased the probability of the disease. CONCLUSIONS: By available data, there is no single clinical finding that has significant value in diagnosis or excluding pheochromocytoma. Combination of certain symptoms, signs and para-clinical exams is more valuable for physicians. Further studies should be done, to specify the value of clinical findings. Until that time the process of diagnosis will be based on clinical suspicion and lab tests followed by related imaging.

Type 1 11beta -hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets.

Metabolic transformation of glucocorticoid hormones constitutes a determinant of their cell-specific effects. The most important reaction for this class of steroids is the reversible C11 keto/beta-hydroxyl conversion between receptor-binding 11beta-OH steroids and the nonbinding 11-oxo compounds, carried out by 11beta-hydroxysteroid dehydrogenases (11beta-HSDs). In this study, we determined the role of glucocorticoid conversion by 11beta-HSD in pancreatic islets and its function in the regulation of insulin release. Pancreatic islets isolated from ob/ob mice display type 1 11beta-hydroxysteroid dehydrogenase activity, i.e. in intact cells the reductive reaction prevails, leading from dehydrocorticosterone to corticosterone. Expression of type 1 11beta-HSD mRNA was detected by reverse transcriptase-polymerase chain reaction in islets isolated from ob/ob mice and also from human tissue. Incubation of beta-cells in the presence of 11-dehydrocorticosterone leads to a dose-dependent inhibition of insulin release, indicating cellular activation of 11-dehydrocorticosterone to the receptor ligand, further confirmed by reporter gene assays. Inhibition of 11beta-HSD activity by carbenoxolone reverses inhibition of insulin release. The presence of 11beta-HSD in islets supports the concept that reactivation of inert circulating hormone precursors in a cell-specific manner plays a major role in glucocorticoid physiology in rodents and man.

p57Kip2, a glucocorticoid-induced inhibitor of cell cycle progression in HeLa cells.

Glucocorticoids exert antiproliferative effects on a number of cell types, including the HeLa cervical carcinoma cell line. However, the mechanism responsible for the antiproliferative effect is poorly understood. In this report we have investigated the role of the recently identified cyclin-dependent kinase inhibitor (CDI) p57Kip2 in the antiproliferative effect conferred by glucocorticoids. When HeLa cells were treated with the synthetic glucocorticoid dexamethasone (DEX), the doubling time of exponentially growing cells increased 2-fold. Within 11 h of DEX treatment, this was accompanied by an accumulation of cells in the G1 phase of the cell cycle with a corresponding decreased proportion of cells in the S phase and decreased CDK2 activity. DEX treatment of the HeLa cells dramatically induced the protein and mRNA expression of the CDI p57Kip2. This induction was seen within 4 h of DEX treatment, preceding a major DEX-induced accumulation of cells in the G1 phase. DEX-induced mRNA expression of p57Kip2 did not require de novo protein synthesis, and the transcription of the p57Kip2 gene was increased as determined by a run-on transcription assay. Furthermore, DEX induction of p57Kip2 was not a consequence of the cell cycle arrest, since other growth inhibition signals did not result in strong p57Kip2 induction. Overexpression of p57Kip2 using HeLa cells stably transfected with a tetracycline-inducible vector showed that p57Kip2 is sufficient to reconstitute an antiproliferative effect similar to that seen in DEX-treated cells. Selective p57Kip2 expression by the tetracycline analog doxycycline to levels comparable to those observed on DEX induction resulted in a 1.7-fold increase in the doubling time and a shift of HeLa cells to the G1 phase as well as a decrease in CDK2 activity. Taken together, these results suggest that glucocorticoid treatment directly induces transcription of the p57Kip2 gene and that the p57Kip2 protein is involved in the glucocorticoid-induced antiproliferative effect.

Increased glucocorticoid sensitivity in islet beta-cells: effects on glucose 6-phosphatase, glucose cycling and insulin release.

Glucose-6-phosphatase (G6Pase) activity and the rate of glucose cycling are increased in islets from animal models of Type II (non-insulin-dependent) diabetes mellitus. Glucocorticoid treatment further stimulates these processes and inhibits glucose-induced insulin release. To determine whether these effects result from a direct action of glucocorticoids on the beta-cells, we used isolated islets. The islets were from transgenic mice overexpressing the glucocorticoid receptor in their beta-cells to increase the cells' sensitivity to glucocorticoid. Islets from transgenic and non-transgenic control mice utilized and oxidized the same amount of glucose. In contrast, islet G6Pase activity was 70 % higher, glucose cycling was increased threefold and insulin release was 30 % lower in islets from transgenic mice. Hepatic G6Pase activity was the same in transgenic and control mice. Dexamethasone administration increased G6Pase activity and glucose cycling and decreased insulin release in both transgenic and control mouse islets. We conclude that glucocorticoids stimulate islet G6Pase activity and glucose cycling by acting directly on the beta-cell. That activity may be linked to the inhibition of insulin release.

Pancreatic beta cells are important targets for the diabetogenic effects of glucocorticoids.

Abnormalities contributing to the pathogenesis of non-insulin-dependent diabetes mellitus include impaired beta cell function, peripheral insulin resistance, and increased hepatic glucose production. Glucocorticoids are diabetogenic hormones because they decrease glucose uptake and increase hepatic glucose production. In addition, they may directly inhibit insulin release. To evaluate that possible role of glucocorticoids in beta cell function independent of their other effects, transgenic mice with an increased glucocorticoid sensitivity restricted to their beta cells were generated by overexpressing the glucocorticoid receptor (GR) under the control of the insulin promoter. Intravenous glucose tolerance tests showed that the GR transgenic mice had normal fasting and postabsorptive blood glucose levels but exhibited a reduced glucose tolerance compared with their control littermates. Measurement of plasma insulin levels 5 min after intravenous glucose load demonstrated a dramatic decrease in acute insulin response in the GR transgenic mice. These results show that glucocorticoids directly inhibit insulin release in vivo and identify the pancreatic beta cell as an important target for the diabetogenic action of glucocorticoids.