RESUMEN
Primary adrenal insufficiency (PAI) is characterized by impaired production of steroid hormones due to an adrenal cortex defect. This condition incurs a risk of acute insufficiency which may be life-threatening. Today, 80% of pediatric forms of PAI have a genetic origin but 5% have no clear genetic support. Recently discovered mutations in genes relating to oxidative stress have opened the way to research on genes unrelated to the adrenal gland. Identification of causal mutations in a gene responsible for PAI allows genetic counseling, guidance of follow-up and prevention of complications. This is particularly true for stress oxidative anomalies, as extra-adrenal manifestations may occur due to the sensitivity to oxidative stress of other organs such as the heart, thyroid, liver, kidney and pancreas.
Asunto(s)
Insuficiencia Suprarrenal/congénito , Enfermedad de Addison/genética , Glándulas Suprarrenales/anomalías , Glándulas Suprarrenales/embriología , Insuficiencia Suprarrenal/clasificación , Insuficiencia Suprarrenal/genética , Glucocorticoides/deficiencia , Glucocorticoides/genética , Humanos , Mineralocorticoides/deficiencia , Mineralocorticoides/genética , Mutación , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/genética , SíndromeRESUMEN
Context: Mineralocorticoid (MC) replacement therapy in patients with primary adrenal insufficiency (PAI) was introduced more than 60 years ago. Still, there are limited data on how MC substitution should be optimized, because MC dosing regimens have only been systematically investigated in a few studies. We review the management of current standard MC replacement therapy in PAI and its plausible impact on outcome. Design: Using PubMed, we conducted a systematic review of the literature from 1939 to 2017, with the following keywords: adrenal insufficiency, MC deficiency, aldosterone, cardiovascular disease, hypertension, and heart failure. Results: The current standard treatment consists of fludrocortisone (FC) given once daily in the morning, aiming at normotension, normokalemia, and plasma renin activity in the upper normal range. Available data suggest that patients with PAI may be underreplaced with FC as symptoms and signs indicating chronic MC underreplacement, such as salt craving and postural dizziness persist, in many treated patients with PAI. Data acquired from large registry-based studies show that glucocorticoid doses for replacement in PAI are higher than those estimated from endogenous production. Glucocorticoid overreplacement may reduce the need of MC replacement but may also be a consequence of inadequate MC replacement. Conclusions: The commonly used MC replacement in PAI may not be adequate in some patients. Insufficient MC substitution may be responsible for poor cardiometabolic outcome and the failure to restore well-being adequately in patients with PAI. Well-designed studies oriented at optimizing MC replacement therapy are urgently needed.
Asunto(s)
Insuficiencia Suprarrenal/tratamiento farmacológico , Terapia de Reemplazo de Hormonas/métodos , Mineralocorticoides/uso terapéutico , Humanos , Mineralocorticoides/sangre , Mineralocorticoides/deficiencia , Resultado del TratamientoRESUMEN
Classic 3ß-hydroxysteroid dehydrogenase type 2 (3ß-HSD II) deficiency causes congenital adrenal hyperplasia with glucocorticoid, mineralocorticoid, and sex steroid deficiency. We present a female patient with congenital adrenal hyperplasia detected in newborn screening due to elevated 17OH-progesterone. Female external genitalia and non-measurable androgen levels elicited the suspicion of a defect early in the steroid cascade. Two loss-of-function HSD3B2 mutations (1 novel) were detected and confirmed in silico. We argue that in a girl with glucocorticoid and mineralocorticoid deficiency without virilization, 3ß-HSD II deficiency is an important differential diagnosis. 17OH-progesterone may initially be elevated due to placental and peripheral activity of 3ß-HSD I, whereas dehydroepiandrosterone may not be increased.
Asunto(s)
Hiperplasia Suprarrenal Congénita/genética , Progesterona Reductasa/química , 17-alfa-Hidroxiprogesterona/sangre , Hiperplasia Suprarrenal Congénita/sangre , Secuencia de Aminoácidos , Deshidroepiandrosterona/sangre , Femenino , Glucocorticoides/deficiencia , Glucocorticoides/metabolismo , Humanos , Recién Nacido , Mineralocorticoides/deficiencia , Mineralocorticoides/metabolismo , Datos de Secuencia Molecular , Mutación , Progesterona Reductasa/genética , Estructura Secundaria de Proteína , Análisis de Secuencia de Proteína , Virilismo/genética , Virilismo/metabolismoRESUMEN
BACKGROUND: Glucocorticoid deficiency (GD) has been proposed as a key contributor to shock states, but the presence and role of acute mineralocorticoid deficiency may be of equal or greater significance. We sought to analyze the incidence and degree of acute mineralocorticoid deficiency and GD in an animal model of severe hemorrhage and shock. METHODS: Fifty-seven swine underwent 35% volume-controlled hemorrhage followed by aortic cross-clamping for 50 minutes to induce truncal ischemia-reperfusion. Protocol-guided resuscitation was performed. Laboratory analysis included cortisol, aldosterone, and plasma renin activity. The aldosterone-to-renin ratio (ARR) was calculated at each time point, and changes were correlated to markers of perfusion. RESULTS: Mean baseline cortisol levels were 5.8 µg/dL. Following hemorrhage, there was a significant increase in mean cortisol to 9.2 µg/dL (p < 0.001). After 1 hour of reperfusion, there was no change in mean cortisol levels (9.8 µg/dL, p = 0.12). Mean baseline aldosterone was 13.3 pg/mL. Aldosterone levels before cross-clamp removal increased significantly to 115.1 pg/mL (p < 0.001) and then rapidly declined to 49.2 pg/mL (p < 0.001) after 1 hour of reperfusion. Conversely, baseline plasma renin activity was 0.75 ng/mL per hour and increased significantly before cross-clamp removal (1.8) and at 1 hour (8.9, both p < 0.001). The ARR at baseline was 96.1 and increased to 113.5 (p = 0.68) before cross-clamp removal but significantly declined following 1 hour of reperfusion to 7.6 (p < 0.001). Overall, this represented a 93% reduction in mean ARR following reperfusion. The degree of aldosterone deficiency correlated with degree of systemic shock as measured by arterial base deficit (r = 0.47, p = 0.04), while cortisol showed no correlation. CONCLUSION: Hemorrhagic shock with ischemia-reperfusion injury resulted in only modest impact on the glucocorticoid axis, but major dysfunction of the mineralocorticoid axis and severe hyperreninemic hypoaldosteronism. The degree of aldosterone deficiency may provide prognostic information or offer potential targets for pharmacologic intervention. LEVEL OF EVIDENCE: Diagnostic study, level III.
Asunto(s)
Insuficiencia Suprarrenal/metabolismo , Glucocorticoides/deficiencia , Mineralocorticoides/deficiencia , Choque Hemorrágico/metabolismo , Choque Traumático/metabolismo , Animales , Hemodinámica , Daño por Reperfusión/metabolismo , Resucitación/métodos , PorcinosRESUMEN
BACKGROUND: Familial glucocorticoid deficiency (FGD) reflects specific failure of adrenocortical glucocorticoid production in response to adrenocorticotropic hormone (ACTH). Most cases are caused by mutations encoding ACTH-receptor components (MC2R, MRAP) or the general steroidogenesis protein (StAR). Recently, nicotinamide nucleotide transhydrogenase (NNT) mutations were found to cause FGD through a postulated mechanism resulting from decreased detoxification of reactive oxygen species (ROS) in adrenocortical cells. METHODS AND RESULTS: In a consanguineous Palestinian family with combined mineralocorticoid and glucocorticoid deficiency, whole-exome sequencing revealed a novel homozygous NNT_c.598 G>A, p.G200S, mutation. Another affected, unrelated Palestinian child was also homozygous for NNT_p.G200S. Haplotype analysis showed this mutation is ancestral; carrier frequency in ethnically matched controls is 1/200. Assessment of patient fibroblasts for ROS production, ATP content and mitochondrial morphology showed that biallelic NNT mutations result in increased levels of ROS, lower ATP content and morphological mitochondrial defects. CONCLUSIONS: This report of a novel NNT mutation, p.G200S, expands the phenotype of NNT mutations to include mineralocorticoid deficiency. We provide the first patient-based evidence that NNT mutations can cause oxidative stress and both phenotypic and functional mitochondrial defects. These results directly demonstrate the importance of NNT to mitochondrial function in the setting of adrenocortical insufficiency.
Asunto(s)
Glucocorticoides/deficiencia , Mineralocorticoides/deficiencia , Mutación , NADP Transhidrogenasas/genética , Receptores de Mineralocorticoides/metabolismo , Árabes , Consanguinidad , Homocigoto , Humanos , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Estrés Oxidativo/genética , Análisis de Secuencia de ADNRESUMEN
Human Immunodeficiency Virus (HIV) infection is associated with adrenal disorders, which must not be underestimated. Adrenal morphologic changes are primarily related to opportunistic infections, mostly by cytomegalovirus and mycobacteria, and malignant tumours such as non-Hodgkin's lymphoma and Kaposi's sarcoma. The most frequent biological alteration reported to date is the increases in cortisol concentrations which results from a decrease in cortisol metabolism and hyperactivity of the hypothalamo-pituitary-adrenal axis commonly referred to as pseudo-Cushing's syndrome. These modifications can be a consequence of antiretroviral therapy and do not require any investigation or specific treatment. Conversely, adrenal insufficiency, either iatrogenic or secondary to glandular infiltration by neoplasms or infections, needs long-term substitution with hydrocortisone, but at present occurs more rarely and usually at late stages of disease progression. The impact of HIV infection on the other adrenocortical functions has been less reported in the literature although several studies show low levels of adrenal androgens, especially dehydroepiandrostenedione (DHEA). Impairment in mineralocorticoid function appears occasional and remains a subject of debate.
Asunto(s)
Enfermedades de las Glándulas Suprarrenales/etiología , Infecciones por VIH/complicaciones , Enfermedades de las Glándulas Suprarrenales/virología , Neoplasias de las Glándulas Suprarrenales/etiología , Insuficiencia Suprarrenal/etiología , Andrógenos/sangre , Andrógenos/deficiencia , Glucocorticoides/deficiencia , Glucocorticoides/metabolismo , VIH-1/fisiología , Humanos , Mineralocorticoides/deficiencia , Mineralocorticoides/metabolismoRESUMEN
A insuficiência adrenal (IA) consiste em síndrome clínica rara, decorrente da deficiência de glicocorticoides e/ou mineralocorticoides, podendo ser primária. A insuficiência adrenal aguda consiste em emergência endócrina rara, resultante da diminuição súbita do cortisol circulante, ou de aumento significativo da demanda por esse hormônio em pacientes com algum grau de disfunção adrenal, ocorrendo mais frequentemente no contexto da IA primária. O prognóstico da doença depende do reconhecimento e intervenção terapêutica precoces
Adrenal insuficiency (AI) consists of a rare clinical syndrome resulting from glucocorticoids and/or mineralocorticoids deficiency. Adrenal insufficiency may be primary. The acute AI is a rare endocrine emergency resulting from sudden decrease of circulating cortisol or, elevated demand for this hormone in patients with some degree of adrenal disfunction, occuring more frequently in primary AI. The prognosis depends on early recognition and precocious therapeutic intervention
Asunto(s)
Humanos , Masculino , Femenino , Glucocorticoides/deficiencia , Insuficiencia Suprarrenal/diagnóstico , Insuficiencia Suprarrenal/terapia , Mineralocorticoides/deficiencia , Enfermedad Aguda , Corteza Suprarrenal/fisiopatología , Enfermedad de Addison/terapia , Glucocorticoides/administración & dosificación , Hidrocortisona/uso terapéutico , Hormona Adrenocorticotrópica , Mineralocorticoides/administración & dosificación , Sistema Endocrino/fisiopatología , Técnicas de Laboratorio Clínico/métodosRESUMEN
BACKGROUND: In the critically ill, mineralocorticoid deficiency (MD) is associated with greater disease severity, the development of acute renal insufficiency, and increased mortality. We hypothesized that severely injured trauma patients presenting with hemorrhagic shock would demonstrate a high degree of MD. We also hypothesized that MD in these patients would be associated with increased length of stay, hypotension, fluid requirements, and acute kidney injury (AKI). MATERIALS AND METHODS: Thirty-two trauma patients in hemorrhagic shock on admission to the trauma bay (SBP <90 mm Hg × 2) were enrolled. Blood samples were obtained on ICU admission and 8, 16, 24, and 48 hours later. Plasma aldosterone (PA) and renin (PR) were assayed by radioimmunoassay. MD was defined as a ratio of PA/PR ≤2. Demographic data, injury severity score, ICU and hospital length of stay, fluid requirements, mean arterial pressure, serum sodium, hypotension, and risk for AKI were compared for patients with and without MD. RESULTS: At ICU admission, 48% of patients met criteria for MD. Patients with MD were significantly more likely to experience hypotension (MAP ≤60 mm Hg) during the study period. MD patients required significantly more units of blood in 48 h than non-MD patients (13 [7-22] versus 5 [2-7], P = 0.015) and had increased crystalloid requirements (18L [14-23] versus 9L [6-10], P < 0.001). MD patients were at higher risk for AKI according to RIFLE and AKIN criteria. CONCLUSIONS: MD is a common entity in trauma patients presenting in hemorrhagic shock. Patients with MD required a more aggressive resuscitative effort, were more likely to experience hypotension, and had a higher risk of AKI than non-MD patients. Future studies are needed to fully understand the impact of MD following trauma and the potential role for hormonal replacement therapy.
Asunto(s)
Mineralocorticoides/deficiencia , Choque Hemorrágico/metabolismo , Lesión Renal Aguda/etiología , Adulto , Soluciones Cristaloides , Femenino , Humanos , Hipotensión/etiología , Soluciones Isotónicas , Masculino , Persona de Mediana Edad , Heridas y Lesiones/metabolismoRESUMEN
OBJECTIVES: To determine the genetic basis of disordered steroidogenesis in Kuwaiti siblings. STUDY DESIGN: Two siblings (46,XX and 46,XY) had normal female external genitalia and severe glucocorticoid and mineralocorticoid deficiency presenting in the first month of life. Abdominal ultrasonography showed normal size adrenal glands, suggesting cholesterol side chain cleavage enzyme (P450scc) deficiency. The CYP11A1 gene encoding P450scc and the STAR gene encoding the steroidogenic acute regulatory protein (StAR) were directly sequenced from leukocyte DNA. RESULTS: All exons and intron/exon boundaries of the CYP11A1 gene were normal; the STAR gene was homozygous for a novel 14-base deletion/frameshift in exon 4 (g.4643_4656del), so that no functional protein could be produced. Both parents and an unaffected sibling were heterozygous; zygosity was confirmed with a BsmF1 restriction fragment length polymorphism. CONCLUSIONS: Unlike most patients with StAR deficiency, our patients did not have the massive adrenal hyperplasia typical of congenital lipoid adrenal hyperplasia. The distinction between StAR and P450scc deficiency may require gene sequencing.
Asunto(s)
Insuficiencia Suprarrenal/genética , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/deficiencia , Fosfoproteínas/deficiencia , Insuficiencia Suprarrenal/diagnóstico , Enzima de Desdoblamiento de la Cadena Lateral del Colesterol/genética , ADN/metabolismo , Exones , Salud de la Familia , Femenino , Glucocorticoides/deficiencia , Homocigoto , Humanos , Recién Nacido , Intrones , Kuwait , Leucocitos/metabolismo , Mineralocorticoides/deficiencia , Modelos Genéticos , Mutación , Linaje , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
PURPOSE OF REVIEW: Adrenal dysfunction can increase morbidity and mortality among patients with HIV infection. Disorders and medications affecting cortisol, aldosterone or adrenal androgens in patients with HIV infection are reviewed. RECENT FINDINGS: Iatrogenic Cushing's syndrome and hypothalamic-pituitary-adrenal suppression from concomitant use of ritonavir with nonsystemic corticosteroids such as intra-articular triamcinolone in addition to the previously reported interactions with inhaled fluticasone are increasingly recognized in HIV patients. Integrated measure of aldosterone throughout the day is higher in patients with HIV-associated visceral adipose tissue accumulation. SUMMARY: Abnormalities in adrenal function are more common in HIV patients than in the general population. HIV care providers should pursue workup for adrenal dysfunction in HIV patients when symptoms or signs are present, especially in patients with advanced AIDS or receiving medications that can affect adrenal function. The clinical implications of aldosterone elevation in HIV patients with visceral adiposity will need to be examined in future research studies.
Asunto(s)
Glándulas Suprarrenales/fisiopatología , Infecciones por VIH/fisiopatología , Aldosterona/fisiología , Glucocorticoides/deficiencia , Humanos , Hidrocortisona/fisiología , Mineralocorticoides/deficienciaRESUMEN
OBJECTIVE: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Mutations in the ACTH receptor (MC2R) account for approximately 25% of all FGD cases, but since these are usually missense mutations, a degree of receptor function is frequently retained. A recent report, however, suggested that disturbances in the renin-aldosterone axis were seen in some patients with potentially more severe MC2R mutations. Furthermore, MC2R knock out mice have overt aldosterone deficiency and hyperkalaemia despite preservation of a normal zona glomerulosa. We wished to determine whether a group of patients with severe nonsense mutations of the MC2R exhibited evidence of mineralocorticoid deficiency, thereby challenging the conventional diagnostic feature of FGD which might result in diagnostic misclassification. DESIGN: Clinical review of patients with nonsense MC2R mutations. PATIENTS: Between 1993 and 2008, 164 patients with FGD were screened for mutations in the MC2R. Totally 42 patients (34 families) were found to have mutations in the MC2R. Of these, 6 patients (4 families) were found to have homozygous nonsense or frameshift mutations. RESULTS: Mild disturbances in the renin-angiotensin-aldosterone axis were noted in four out of six patients, ranging from slightly elevated plasma renin levels to low aldosterone levels, although frank mineralocorticoid deficiency or electrolyte disturbance were not found. No patient required fludrocortisone replacement. CONCLUSION: Severe nonsense and frameshift MC2R mutations are not associated with clinically significant mineralocorticoid deficiency and are thus unlikely to require long-term mineralocorticoid replacement.
Asunto(s)
Enfermedades de las Glándulas Suprarrenales/genética , Codón sin Sentido , Mutación del Sistema de Lectura , Glucocorticoides/deficiencia , Mineralocorticoides/deficiencia , Receptores de Corticotropina/genética , Adolescente , Enfermedades de las Glándulas Suprarrenales/metabolismo , Enfermedades de las Glándulas Suprarrenales/terapia , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Linaje , Receptores de Corticotropina/metabolismo , Estudios RetrospectivosRESUMEN
BACKGROUND: The hormone deficiencies in Addison's disease (primary adrenal insufficiency) are conventionally treated with oral glucocorticoid and mineralocorticoid replacement but the available therapies do not restore the physiological hormone levels and biorhythm. Despite such treatment these patients self-report impaired health-related quality of life (HRQoL) and recent research has indicated increased mortality. OBJECTIVE/METHODS: We review the literature and recent developments in replacement therapy. RESULTS/CONCLUSION: Patients with Addison's disease require mineralocorticoid replacement, i.e., fludrocortisone 0.05 - 0.20 mg once daily. Starting doses of glucocorticoids should be 15 - 20 mg for hydrocortisone or 20 - 30 mg for cortisone acetate, divided into two or three doses, and preferentially weight-adjusted. There are indications that the synthetic glucocorticoids have undesirable metabolic long-term effects, which make them less suitable as first-line treatment. Timed-release hydrocortisone tablets and continuous subcutaneous hydrocortisone infusion are promising new treatment modalities. Studies of replacement with the adrenal androgen dehydroepiandrosterone (DHEA) in adrenal failure have shown inconsistent benefit on HRQoL. DHEA, or possibly testosterone replacement is likely to be beneficial for selected groups of patients with Addison's disease but this remains to be shown. We here give our opinion of the best treatment and future direction of research in this area.
Asunto(s)
Enfermedad de Addison/tratamiento farmacológico , Andrógenos/administración & dosificación , Glucocorticoides/administración & dosificación , Terapia de Reemplazo de Hormonas , Mineralocorticoides/administración & dosificación , Enfermedad de Addison/sangre , Andrógenos/uso terapéutico , Formas de Dosificación , Vías de Administración de Medicamentos , Esquema de Medicación , Glucocorticoides/efectos adversos , Glucocorticoides/sangre , Glucocorticoides/deficiencia , Humanos , Mineralocorticoides/efectos adversos , Mineralocorticoides/sangre , Mineralocorticoides/deficiencia , Calidad de Vida , Resultado del TratamientoRESUMEN
Acute hyponatremia, following neurosurgery, results from inappropriate antidiuretic hormone secretion (SIADH) or cerebral salt wasting (CSW). CSW is due to abnormally high atrial or brain natriuretic peptides (ANP, BNP), which block all stimulators of zona glomerulosa steroidogenesis, resulting in mineralocorticoid deficiency. A 3 year-old girl presented CSW at day 4, after resection of craniopharyngioma and hypophysectomy. Hyponatremia, hyperkalemia and high natriuresis occurred on day 8, with low renin and aldosterone and elevated BNP 120.3 ng/ml (undetectable before surgery). Fludrocortisone 100 microg/day controlled natriuresis and restored electrolytes within 24 hours. A 5 year-old boy presented CSW at day 6 after partial resection of optic glioma. Fludocortisone 100 microg/day restored electrolytes within 8 hours. ANP was elevated, 60.6 ng/l, aldosterone and renin were low. Fludrocortisone supplementation should be considered in CSW, as excessive natriuresis is controlled, and electrolytes are easily restored, avoiding life-threatening complications of this complex disorder.
Asunto(s)
Cerebro/cirugía , Hiponatremia/diagnóstico , Hiponatremia/etiología , Mineralocorticoides/deficiencia , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Factor Natriurético Atrial/metabolismo , Niño , Preescolar , Craneofaringioma/cirugía , Electrólitos/análisis , Femenino , Fludrocortisona/administración & dosificación , Humanos , Hiperpotasemia/metabolismo , Hiponatremia/metabolismo , Hipofisectomía , Masculino , Péptido Natriurético Encefálico/metabolismo , Neoplasias Hipofisarias/cirugía , Periodo Posoperatorio , Cloruro de Sodio/metabolismoRESUMEN
We report a case of a young hypertensive male who was first seen in 1998 with a right thalamic haemorrhage and uncontrolled hypertension. CT abdomen showed a right adrenal tumour and a hyperplastic left adrenal gland. Laparoscopic adrenalectomy performed followed by histopathological examination confirmed the diagnosis of adrenal adenoma. He subsequently presented to us again a year later with persistent hyperkalaemia and asymptomatic hyponatraemia. Further investigations strongly suggested the presence of isolated mineralocorticoid deficiency with normal cortisol levels. This was confirmed to be due to partial or late-onset congenital adrenal hyperplasia (CAH). We discuss the association of partial CAH and adrenal tumours and the unmasking of the mineralocorticoid deficiency following adrenalectomy.
Asunto(s)
Adenoma/etiología , Neoplasias de las Glándulas Suprarrenales/etiología , Hiperplasia Suprarrenal Congénita/complicaciones , Adenoma/cirugía , Neoplasias de las Glándulas Suprarrenales/cirugía , Adrenalectomía , Humanos , Masculino , Persona de Mediana Edad , Mineralocorticoides/deficiencia , Renina/sangreRESUMEN
CONTEXT: Mutations in DAX1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome gene 1; NR0B1) cause X-linked adrenal hypoplasia congenita, a disease characterized by primary adrenal failure, testicular dysgenesis, and gonadotropin deficiency. Most DAX1 mutations are deletions, nonsense, or frameshift mutations that markedly impair its transcriptional activity. Missense mutations have been restricted to the carboxy-terminal domain and are associated with more variable clinical phenotypes. OBJECTIVE: The objective was to identify novel clinical phenotypes associated with DAX1 missense mutations. PATIENTS AND DESIGN: We investigated the genetic basis of isolated mineralocorticoid deficiency in a patient who carries a unique missense mutation (W105C) in the amino-terminal region of DAX1. RESULTS: The W105C DAX1 mutation in the proband was present in three asymptomatic hemizygous males, but it was not detected in the general population. Using in vitro studies of DAX1 expression and function in transfected cells, we demonstrate that the mutant DAX1 protein exhibits mild loss of function, whether studied for genes it represses or for genes it activates. Structure-function studies suggest that the W105C and other mutations in the aminoterminus are compensated by the presence of repeated LXXLL motifs that mediate DAX1 interactions with other proteins. CONCLUSIONS: We describe the first missense mutation in the aminoterminus of DAX1 and conclude that mutations in this region may be partially compensated by redundant functional domains. Mild DAX1 mutations may be a cause of isolated mineralocorticoid deficiency.
Asunto(s)
Proteínas de Unión al ADN/genética , Mineralocorticoides/deficiencia , Mutación Missense , Receptores de Ácido Retinoico/genética , Proteínas Represoras/genética , Células Cultivadas , Niño , Clonación Molecular , Receptor Nuclear Huérfano DAX-1 , Humanos , Masculino , Modelos Biológicos , Linaje , Estructura Terciaria de Proteína/genética , TransfecciónRESUMEN
Following the discovery of the aquaporin-1 water channel over a decade ago, molecular techniques have been developed to examine the role of renal aquaporin water channels under numerous physiological and pathological conditions. The present article reviews current knowledge regarding the function and dysfunction of renal aquaporins in disorders of water metabolism.
Asunto(s)
Acuaporinas/fisiología , Riñón/metabolismo , Animales , Acuaporinas/metabolismo , Glucocorticoides/deficiencia , Humanos , Hipotiroidismo/patología , Enfermedades Renales/patología , Túbulos Renales Colectores/metabolismo , Mineralocorticoides/deficiencia , Modelos BiológicosRESUMEN
The Authors report two cases of APECED syndrome (Auto-immune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy) revealed by hyponatremia due to isolated mineralocorticoids deficiency. Such cases illustrate the variable endocrine features revealing the syndrome. The mechanisms underlying the auto-immune destruction of the adrenals are discussed.
Asunto(s)
Hiponatremia/etiología , Mineralocorticoides/deficiencia , Poliendocrinopatías Autoinmunes/complicaciones , Poliendocrinopatías Autoinmunes/diagnóstico , Glándulas Suprarrenales/patología , Glándulas Suprarrenales/fisiología , Preescolar , Humanos , Hiponatremia/patología , MasculinoRESUMEN
Mineralocorticoid deficiency is associated with impaired urinary concentration and dilution. The present investigation was undertaken to determine the effects of selective mineralocorticoid deficiency on renal sodium and urea transporters and aquaporin water channels and whether these perturbations can be reversed by maintenance of extracellular fluid volume. Mineralocorticoid deficiency was induced by bilateral adrenalectomies with glucocorticoid replacement. Mineralocorticoid deficient rats receiving plain drinking water (MDW) were compared with mineralocorticoid deficient rats receiving saline-drinking water (MDS) in order to maintain extracellular fluid volume, and with controls (CTL). In MDW rats, there was a significant decrease in renal outer medulla Na-K-2Cl co-transporter and outer medulla Na-K-ATPase as well as an increase in inner medulla aquaporins 2 and 3. There were no significant changes in aquaporin-1, aquaporin-4, or urea transporters. These alterations were reversed with maintenance of extracellular fluid volume in MDS rats. Our findings indicate that mineralocorticoid deficiency in the rat is associated with alterations in factors involved in the countercurrent concentrating mechanism (Na-K-2Cl, Na-K-ATPase) and osmotic water equilibration in the collecting duct (AQP2, AQP3). Maintenance of sodium balance and extracellular fluid volume is associated with normalization of these perturbations.
Asunto(s)
Acuaporinas/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Mineralocorticoides/deficiencia , Simportadores de Cloruro de Sodio-Potasio/metabolismo , Urea/metabolismo , Adrenalectomía , Animales , Transporte Biológico , Hemodinámica , Riñón/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Sodio/análisis , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Equilibrio HidroelectrolíticoRESUMEN
Adrenocortical steroid hormones are importantly involved in the regulation of extracellular fluid volume. The present study was aimed at examining whether aldosterone and/or glucocorticoid regulates the abundance of aquaporin-3 (AQP3), -2, and -1 in rat kidney. In protocol 1, rats were adrenalectomized, followed by aldosterone replacement, dexamethasone replacement, or combined aldosterone and dexamethasone replacement (rats had free access to water but received a fixed amount of food). Protocol 2 was identical to protocol 1, except that all groups received fixed daily food and water intake. In both protocols 1 and 2, aldosterone deficiency was associated with increased fractional Na excretion and severe hyperkalemia. Semiquantitative immunoblotting revealed that aldosterone deficiency was associated with a dramatic downregulation of AQP3 abundance. Consistent with this, immunocytochemistry and immunoelectron microscopy revealed a marked decrease in AQP3 labeling in the basolateral plasma membranes of collecting duct principal cells. In contrast, AQP1 and AQP2 abundance and distribution were unchanged. Glucocorticoid deficiency revealed no changes in AQP3, -2, or -1 abundance. In protocol 3, Na restriction (to increase endogenous aldosterone levels) or exogenous aldosterone infusion in either normal rats or vasopressin-deficient Brattleboro rats was associated with a major increase in AQP3 abundance. In protocol 4, aldosterone levels were clamped by infusion of aldosterone, while Na intake was altered from a low to a high level. Under these circumstances, there were no changes in AQP3 or AQP2 abundance, although the level of the thiazide-sensitive Na-Cl cotransporter was decreased. In conclusion, the results uniformly demonstrate that aldosterone regulates AQP3 abundance independently of Na intake. In contrast, changes in glucocorticoid levels in these models do not influence AQP3 or AQP2 abundance. Therefore, in the collecting duct aldosterone may regulate, at least in part, AQP3 expression in addition to regulating Na and K transport.
Asunto(s)
Acuaporinas/metabolismo , Túbulos Renales Colectores/metabolismo , Mineralocorticoides/farmacología , Adrenalectomía , Aldosterona/farmacología , Animales , Acuaporina 3 , Enfermedades Carenciales/metabolismo , Glucocorticoides/deficiencia , Túbulos Renales Colectores/patología , Masculino , Microscopía Inmunoelectrónica , Mineralocorticoides/deficiencia , Natriuresis , Nitrógeno/orina , Potasio/sangre , Ratas , Ratas Endogámicas , Urea/química , Urea/orina , Uremia/etiología , Vasopresinas/deficiencia , Agua/metabolismoRESUMEN
Adjustment of the mineralocorticoid activity under substitution therapy is of primary importance in Addison's disease. We report the clinical and biological conditions of 2 patients with Addison's disease who developed nephrotic proteinuria during their deficient mineralocorticoid state. Renal biopsy was performed and the specimens processed using conventional histochemistry, Congo red staining, and indirect immunofluorescence. The renal biopsy specimens showed focal segmental glomerular sclerosis and nodular deposits of IgM and C3. Negative for Congo red staining. Serum complement, circulating immune complexes, and anti-DNA and hepatitis B and C and human immunodeficiency virus antibodies were all normal or negative. Absence of vesicoureteral reflux was assessed by X-ray studies. Our observations suggest that deficiency in mineralocorticoid substitution therapy inducing a status of hyperreninemia could play a role in the development of focal segmental glomerulosclerosis in patients with Addison's disease.