Pheochromocytoma and paraganglioma: Clinical feature based disease probability in relation to catecholamine biochemistry and reason for disease suspicion

OBJECTIVE Hypertension and symptoms of catecholamine excess are features of pheochromocytomas and paragangliomas (PPGLs). This prospective observational cohort study assessed whether differences in presenting features in patients tested for PPGLs might assist establishing likelihood of disease. DESIGN AND METHODS Patients were tested for PPGLs because of signs and symptoms, an incidental mass on imaging or routine surveillance due to previous history or hereditary risk. Patients with (n=245) compared to without (n=1820) PPGLs were identified on follow-up. Differences in presenting features were then examined to assess probability of disease and relationships to catecholamine excess. RESULTS Hyperhidrosis, palpitations, pallor, tremor and nausea were 30-90% more prevalent (P<0.001) among patients with than without PPGLs, whereas headache, flushing and other symptoms showed little or no differences. Although heart rates were higher (P<0.0001) in patients with than without PPGLs, blood pressures were not higher and were positively correlated to body mass index (BMI), which was lower (P<0.0001) in patients with than without PPGLs. From these differences in clinical features, a score system was established that indicated a 5.8-fold higher probability of PPGLs in patients with high than low scores. Higher scores among patients with PPGLs were associated, independently of tumor size, with higher biochemical indices of catecholamine excess. CONCLUSIONS This study identifies a complex of five signs and symptoms combined with lower BMI and elevated heart rate as key features in patients with PPGLs. Prevalences of these features, which reflect variable tumoral catecholamine production, may be used to triage patients according to likelihood of disease

STAT3-Ser/Hes3 signaling: a new molecular component of the neuroendocrine system?

The endocrine system involves communication among different tissues in distinct organs, including the pancreas and components of the Hypothalamic- Pituitary-Adrenal Axis. The molecular mechanisms underlying these complex interactions are a subject of intense study as they may hold clues for the progression and treatment of a variety of metabolic and degenerative diseases. A plethora of signaling pathways, activated by hormones and other endocrine factors have been implicated in this communication. Recent advances in the stem cell field introduce a new level of complexity: adult progenitor cells appear to utilize distinct signaling pathways than the more mature cells in the tissue they co-reside. It is therefore important to elucidate the signal transduction requirements of adult progenitor cells in addition to those of mature cells. Recent evidence suggests that a common non-canonical signaling pathway regulates adult progenitors in several different tissues, rendering it as a potentially valuable starting point to explore their biology. The STAT3- Ser/Hes3 Signaling Axis was first identified as a major regulator of neural stem cells and, subsequently, cancer stem cells. In the endocrine/neuroendocrine system, this pathway operates on several levels, regulating other types of plastic cells: (a) it regulates pancreatic islet cell function and insulin release; (b) insulin in turn activates the pathway in broadly distributed neural progenitors and possibly also hypothalamic tanycytes, cells with important roles in the control of the adrenal gland; (c) adrenal progenitors themselves operate this pathway. The STAT3-Ser/Hes3 Signaling Axis therefore deserves additional research in the context of endocrinology

Biochemical Diagnosis of Chromaffin Cell Tumors in Patients at High and Low Risk of Disease: Plasma versus Urinary Free or Deconjugated -Methylated Catecholamine Metabolites

BACKGROUND Measurements of plasma or urinary metanephrines are recommended for diagnosis of pheochromocytoma and paraganglioma (PPGL). What test offers optimal diagnostic accuracy for patients at high and low risk of disease, whether urinary free metanephrines offer advantages over deconjugated metanephrines, and what advantages are offered by including methoxytyramine in panels all remain unclear. METHODS A population of 2056 patients with suspected PPGLs underwent prospective screening for disease using mass spectrometric-based measurements of plasma free, urinary deconjugated, and urinary free metanephrines and methoxytyramine. PPGLs were confirmed in 236 patients and were excluded in others on follow-up evaluation. RESULTS Measurements of plasma free metabolites offered higher ( < 0.01) diagnostic sensitivity (97.9%) than urinary free (93.4%) and deconjugated (92.9%) metabolites at identical specificities for plasma and urinary free metabolites (94.2%) but at a lower ( < 0.005) specificity for deconjugated metabolites (92.1%). The addition of methoxytyramine offered little value for urinary panels but provided higher ( < 0.005) diagnostic performance for plasma measurements than either urinary panel according to areas under ROC curves (0.991 vs 0.972 and 0.964). Diagnostic performance of urinary and plasma tests was similar for patients at low risk of disease, whereas plasma measurements were superior to both urinary panels for high-risk patients. CONCLUSIONS Diagnosis of PPGLs using plasma or urinary free metabolites provides advantages of fewer false-positive results compared with commonly measured deconjugated metabolites. The plasma panel offers better diagnostic performance than either urinary panel for patients at high risk of disease and, with appropriate preanalytics, provides the test of choice. Measurements of methoxytyramine in urine show limited diagnostic utility compared with plasma

PTBP1 Is Required for Embryonic Development before Gastrulation

Polypyrimidine-tract binding protein 1 (PTBP1) is an important cellular regulator of messenger RNAs influencing the alternative splicing profile of a cell as well as its mRNA stability, location and translation. In addition, it is diverted by some viruses to facilitate their replication. Here, we used a novel PTBP1 knockout mouse to analyse the tissue expression pattern of PTBP1 as well as the effect of its complete removal during development. We found evidence of strong PTBP1 expression in embryonic stem cells and throughout embryonic development, especially in the developing brain and spinal cord, the olfactory and auditory systems, the heart, the liver, the kidney, the brown fat and cartilage primordia. This widespread distribution points towards a role of PTBP1 during embryonic development. Homozygous offspring, identified by PCR and immunofluorescence, were able to implant but were arrested or retarded in growth. At day 7.5 of embryonic development (E7.5) the null mutants were about 5x smaller than the control littermates and the gap in body size widened with time. At mid-gestation, all homozygous embryos were resorbed/degraded. No homozygous mice were genotyped at E12 and the age of weaning. Embryos lacking PTBP1 did not display differentiation into the 3 germ layers and cavitation of the epiblast, which are hallmarks of gastrulation. In addition, homozygous mutants displayed malformed ectoplacental cones and yolk sacs, both early supportive structure of the embryo proper. We conclude that PTBP1 is not required for the earliest isovolumetric divisions and differentiation steps of the zygote up to the formation of the blastocyst. However, further post-implantation development requires PTBP1 and stalls in homozygous null animals with a phenotype of dramatically reduced size and aberration in embryonic and extra-embryonic structures

Expression of the transcription factor Hes3 in the mouse and human ocular surface, and in pterygium

Purpose: In this work we examined the presence of the neural stem cell biomarker Hairy and Enhancer of Split 3 (Hes3) in the anterior eye segment and in the aberrant growth condition of the conjunctiva pterygium. Further, we studied the response of Hes3 to irradiation. Materials and methods: Adult mouse and human corneoscleral junction and conjunctiva, as well as human pterygium were prepared for immunohistochemical detection of Hes3 and other markers. Total body irradiation was used to study the changes in the pattern of Hes3 expression. Results: The adult rodent and human eye as well as pterygium, contain a population of cells expressing Hes3. In the human eye, Hes3-expressing (Hes3+) cells are found predominantly in the subconjunctival space spanning over the limbus where they physically associate with blood vessels. The cytoarchitecture of Hes3 + cells is similar to those previously observed in the adult central nervous system. Furthermore, irradiation reduces the number of Hes3 + cells in the subconjunctival space. In contrast, irradiation strongly promotes the nuclear localization of Hes3 in the ciliary body epithelium. Conclusions: Our results suggest that a recently identified signal transduction pathway that regulates neural stem cells and glioblastoma cancer stem cells also operates in the ocular surface, ciliary body, and in pterygium

Hypertensive crisis in pregnancy due to a metamorphosing pheochromocytoma with postdelivery Cushing's syndrome

Pheochromocytomas in pregnancy are rare but potentially lethal. Even rarer is the combination of pheochromocytoma in pregnancy with subsequent development of ectopic Cushing's syndrome. We report a 36-year-old woman, previously diagnosed with essential hypertension, who developed severe hypertension in pregnancy complicated by insulin-dependent gestational diabetes. A cesarean section was performed at 32 weeks following a hypertensive crisis after routine administration of betamethasone. Postnatal persistence of signs and symptoms of catecholamine excess led to the diagnosis of a left adrenal pheochromocytoma. Between diagnosis and planned tumor removal, the patient developed signs and symptoms of Cushing's syndrome (facial edema and hirsutism, myopathy and fatigue). Biochemical testing confirmed hypercortisolism with extremely elevated levels of plasma adrenocorticotropin, urinary cortisol and multiple steroids of a plasma panel that were all normal at previous testing. The previously noradrenergic tumor also started producing epinephrine. Histopathological examination confirmed the pheochromocytoma, which was also immunohistochemically positive for adrenocorticotropin. Full post-surgical recovery was sustained with normal blood pressure and biochemical findings after one year. This report not only underlines the chameleon behavior of pheochromocytoma but also illustrates its potential for a metamorphosing presentation. Corticosteroid administration in pregnancy requires a cautious approach in patients with hypertension

Pheochromocytoma and paraganglioma: clinical feature-based disease probability in relation to catecholamine biochemistry and reason for disease suspicion

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Biochemical Diagnosis of Chromaffin Cell Tumors in Patients at High and Low Risk of Disease: Plasma versus Urinary Free or Deconjugated O-Methylated Catecholamine Metabolites

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Reference intervals for plasma concentrations of adrenal steroids measured by LC-MS/MS: Impact of gender, age, oral contraceptives, body mass index and blood pressure status

Contains fulltext : 174653.pdf (Publisher’s version ) (Open Access)BACKGROUND: Mass spectrometric-based measurements of the steroid metabolome have been introduced to diagnose disorders featuring abnormal steroidogenesis. Defined reference intervals are important for interpreting such data. METHODS: Liquid chromatography-tandem mass spectrometry was used to establish reference intervals for 16 steroids (pregnenolone, progesterone, 11-deoxycorticosterone, corticosterone, aldosterone, 18-oxocortisol, 18-hydroxycortisol, 17-hydroxyprogesterone, 21-deoxycortisol, 11-deoxycortisol, cortisol, cortisone, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androstenedione, testosterone) measured in plasma from 525 volunteers with (n=227) and without (n=298) hypertension, including 68 women on oral contraceptives. RESULTS: Women showed variable plasma concentrations of several steroids associated with menstrual cycle phase, menopause and oral contraceptive use. Progesterone was higher in females than males, but most other steroids were higher in males than females and almost all declined with advancing age. Using models that corrected for age and gender, body mass index showed weak negative relationships with corticosterone, 21-deoxycortisol, cortisol, cortisone, testosterone, progesterone, 17-hydroxyprogesterone and 11-deoxycorticosterone, but a positive relationship with 18-hydroxycortisol. Hypertensives and normotensives showed negligible differences in plasma concentrations of steroids. CONCLUSION: Age and gender are the most important variables for plasma steroid reference intervals, which have been established here according to those variables for a panel of 16 steroids primarily useful for diagnosis and subtyping of patients with endocrine hypertension

Improved Diagnostic Accuracy of Clonidine Suppression Testing Using an Age-Related Cutoff for Plasma Normetanephrine

BACKGROUND Moderately elevated plasma normetanephrine (NMN) levels are frequent among patients with suspected pheochromocytoma and paraganglioma (PPGL). Clonidine suppression testing (CST) is recommended to distinguish patients with from those without PPGL. We aimed at evaluating the diagnostic outcome of CST in patients with moderate NMN elevations. METHODS Data from patients participating in the PMT study (Prospective Monoamine-Producing Tumor) and the ENSAT (European Network for the Study of Adrenal Tumours) registry in 6 European reference centers were analyzed retrospectively. Eighty-nine patients with suspected PPGL and moderate NMN elevations upon screening were included. During follow-up, PPGL was confirmed in 16 and excluded in 73 cases. Plasma NMN was measured by liquid chromatography tandem mass spectrometry before and 180 minutes after oral clonidine. Receiver operating characteristic analysis was performed to identify optimal cutoffs. RESULTS If published diagnostic criteria for CST (ie, NMN ≥112 ng/L and NMN suppression <40%) were applied, a sensitivity of 88% (CI, 61%-98%) and a specificity of 97% (CI, 90%-100%) were observed. An improved cutoff for plasma NMN 180 minutes after clonidine was established at 80% of the age-related upper limit of normal, resulting in a sensitivity of 94% and a specificity of 97%. False-negative CST results occurred in 2 patients with small PPGL. CONCLUSIONS This study, involving one of the largest cohorts of patients with suspected PPGL and moderately elevated NMN, confirmed the diagnostic accuracy of CST. The application of an adapted cutoff further improved sensitivity