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Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Mutations of CYP11B1 include a 5′-base duplication (Skinner and Rumsby 1994), cluster of mutations in exons 6–8 (Curnow et al. 1993), and splice donor site mutations (Chabre et al. 2000). Defects in CYP11B1 are the cause of adrenal hyperplasia type 4, which is a form of congenital adrenal hyperplasia, a common recessive disease attributed to defective synthesis of cortisol. Congenital adrenal hyperplasia is characterized by androgen excess leading to ambiguous genitalia in affected females, rapid somatic growth during childhood in both sexes with premature closure of the epiphyses, and short adult stature. Patients with adrenal hyperplasia type 4 usually have hypertension. Defects in CYP11B1 are a cause of familial hyperaldosteronism type 1. It is a disorder characterized by hypertension, variable hyperaldosteronism, and abnormal adrenal steroid production, including 18-oxocortisol and 18-hydroxycortisol.
Primary aldosteronism
Published in Demetrius Pertsemlidis, William B. Inabnet III, Michel Gagner, Endocrine Surgery, 2017
Mihail Zilbermint, Constantine A. Stratakis
FH type I or GRA is a rare, mostly autosomal dominant (occasionally sporadic) disorder, causing less than 1% of PA (Table 30.1) [85]. The key finding is early onset of severe and resistant hypertension, sometimes accompanied by hemorrhagic strokes [86, 87]. The GRA can be excluded with a 4-day dexamethasone suppression test (0.5 mg administered every 6 hours). Plasma aldosterone and renin are measured at baseline, at days 2 and 4. Non-GRA patients respond with decreased levels of aldosterone by approximately 50% and return to baseline levels by day 4. In the case of GRA, aldosterone levels remain suppressed. Urinary levels of 18-hydroxycortisol (>100 nmol/L) and 18-oxocortisol may also be elevated, although sometimes this is misleading [3, 88]. Most cases of GRA are caused by a fusion of the ACTH-dependent 11β-hydroxylase gene (CYP11B1) promoter to the coding sequence of the aldosterone-producing gene (CYP11B2), allowing for ACTH to exclusively control aldosterone secretion [5–10]. Genetic testing via polymerase chain reaction techniques is widely available and should be considered the first step in the confirmatory workup of the selected population [13, 86, 87].
The adrenal cortex
Published in Martin Andrew Crook, Clinical Biochemistry & Metabolic Medicine, 2013
The majority of cases of PH are due to adrenal aldosterone-producing adenomas (APAs), which produce 18-oxocortisol and 18-hydroxycortisol steroids in excess, although 45 per cent of cases may be due to bilateral idiopathic adrenal hyperplasia (IAH). There is also a genetic–familial variety of PH. Type 1 familial PH is glucocorticoid remediable aldosteronism (GRA), in which the associated hypertension responds to small doses of glucocorticoids in addition to antihypertensives. This condition is due to a chimeric gene product that combines the promoter of the 11-β-hydroxylase gene with the coding region of the aldosterone synthetase gene and is associated with haemorrhagic stroke.
Hypertensive crisis in pregnancy due to a metamorphosing pheochromocytoma with postdelivery Cushing's syndrome
Published in Gynecological Endocrinology, 2018
Katharina Langton, Matthias Gruber, Jimmy Masjkur, Charlotte Steenblock, Mirko Peitzsch, Jörn Meinel, Jacques Lenders, Stefan Bornstein, Graeme Eisenhofer
Steroid profiling revealed a normal profile at the time of initial diagnosis of pheochromocytoma (Table 1). Most steroids (particularly 11-deoxycortisol and 11-deoxycorticosterone) showed elevations at presentation of Cushing’s syndrome, with post-operative normalization at 4 weeks after surgery. For several steroids (dehydroepiandrosterone, dehydroepiandrosterone-sulfate, pregnenolone, corticosterone and 18-hydroxycortisol) concentrations were reduced to below the lower cutoffs four weeks post-operatively, returning to within reference limits later. Postoperative hydrocortisone replacement therapy and treatment with antihypertensive agents was discontinued at 5 months postoperatively. One year after surgery, all biochemical parameters had normalized (Table 1) and 24-h ambulatory blood pressure monitoring revealed normotensive blood pressure.
Macrolides for KCNJ5–mutated aldosterone-producing adenoma (MAPA): design of a study for personalized diagnosis of primary aldosteronism
Published in Blood Pressure, 2018
Giuseppe Maiolino, Giulio Ceolotto, Michele Battistel, Giulio Barbiero, Maurizio Cesari, Laurence Amar, Brasilina Caroccia, Roberto Padrini, Michel Azizi, Gian Paolo Rossi
For Study B, the primary endpoint will be the within-patient changes from baseline of plasma aldosterone concentration in peripheral blood. Secondary endpoints will be the changes of direct renin active concentration and serum K+, 18-oxocortisol, 18-hydroxycortisol, 11-deoxycorticosterone, corticosterone, cortisol, blood pressure values and tolerability and safety (QTc interval).