Cause Of Adrenal Insufficiency Research Articles

Modern approach to corticosteroid replacement therapy

The therapeutic index of corticosteroids for adrenal insufficiency is narrowing with recognition of the adverse consequences from even minor overtreatment. As in endogenous Cushing syndrome, chronically excessive glucocorticoid dosage can produce weight gain, hypertension, hypercholesterolemia, glucose intolerance, and bone demineralization. By contrast, deficient replacement leads to the constitutional and other symptoms of adrenal insufficiency and can induce lifethreatening shock, particularly during major stress. Optimum therapy depends on the cause of adrenal insufficiency. Primary and secondary adrenal insufficiency, congenital adrenal hyperplasia, and Nelson syndrome each present unique problems that require specific approaches to treatment. The clinician's major challenge is to adjust mineralocorticoid and glucocorticoid doses so as to meet physiologic requirements without inducing corticosteroid excess. Herein, we review the patho-physiology of adrenal insufficiency, outline a stepwise approach to adrenal hormone replacement, and discuss literature relevant to current issues of corticosteroid replacement therapy.

Mutation R96W in cytochrome P450c17 gene causes combined 17 alpha-hydroxylase/17-20-lyase deficiency in two French Canadian patients.

Congenital adrenal hyperplasia (CAH) is the most frequent cause of adrenal insufficiency and ambiguous genitalia in newborn children. In contrast to CAH caused by 21 alpha-hydroxylase and 11 beta-hydroxylase deficiencies, which impairs steroid formation in the adrenal exclusively, 17 alpha-hydroxylase/17,20-lyase deficiency impairs steroid biosynthesis in the adrenals and gonads. The sequence of CYP17 gene was determined by direct sequencing of asymmetric PCR products in two French-Canadian 46,XY pseudohermaphrodite siblings suffering from combined 17 alpha-hydroxylase/17,20-lyase deficiency. The two patients are homozygous for the novel missense mutation R96W caused by a C to T transition converting codon Arg96 (CGG) into a Trp (TGG) in exon 1. The both parents are heterozygous for this missense mutation. We assessed the effect of the R96W mutation on 17 alpha-hydroxylase/17,20-lyase activity by analysis of mutant enzyme, generated by site-directed mutagenesis, expressed in COS-1 cells. The presence of R96W substitution almost completely abolished the activity of the mutant protein. The present findings provide a molecular explanation for the signs and symptoms of combined 17 alpha-hydroxylase/17,20-lyase deficiency in these two patients and provide useful information on the structure-activity relationships of the P450c17, enzyme.

Diagnosis of X-linked Adrenal Hypoplasia Congenita by Mutation Analysis of the DAX1 Gene

To develop a rapid diagnostic approach to individuals with the X-linked cytomegalic form of adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH) due to mutations in DAX1, a new member of the nuclear hormone receptor gene superfamily. Molecular genetic diagnostic investigations of individuals with AHC and their relatives included polymerase chain reaction amplification of DAX1 for identification of intragenic mutations and fluorescence in situ hybridization with a cosmid containing the DAX1 gene for evaluation of larger deletions. Families that had males affected with AHC were evaluated for mutations involving the DAX1 gene. DAX1 mutations were identified in four families that had males affected with AHC. Two apparently independent pedigrees had an identical frame-shift mutation due to a single base pair deletion, and a third had a larger deletion involving the entire DAX1 locus. The fourth family was evaluated by fluorescence in situ hybridization for prenatal diagnosis, and both the DAX1 locus and the contiguous glycerol kinase region were deleted. Molecular genetic and molecular cytogenetic techniques represent rapid and complementary approaches to the diagnosis of mutations in the DAX1 gene responsible for AHC and the associated HH. Specific diagnosis of the cause of adrenal insufficiency in these boys permits anticipatory management of the HH and prenatal counseling for parents of the affected child and other members of their families.

Adrenal insufficiency in a man with non-classical 21-hydroxylase deficiency: Consequence or coincidence?

Deficiency of the adrenal enzyme 21-hydroxylase, which is required for cortisol synthesis, appears in two forms: a rare classical variant with severe enzyme deficiency, usually presenting in neonates with ambiguous genitalia (from androgen overproduction) or adrenal crisis (from glucocorticoid and mineralocorticoid underproduction), and a common (1% of the general population) non-classical variant with mild enzyme deficiency, usually presenting in young adults with findings of androgen excess but without clinical evidence of decreased steroid hormone production. We describe a 22-year-old man who had clinical and biochemical findings consistent with adrenal insufficiency, including a favorable response to hydrocortisone replacement, in whom elevated serum levels of the cortisol precursor 17-hydroxyprogesterone were diagnostic of non-classical 21-hydroxylase deficiency and in whom no other cause of adrenal insufficiency could be identified. These findings raise the possibility that non-classical 21-hydroxylase deficiency, an extremely frequent disorder which is generally thought to be without significant morbidity, might cause or contribute to adrenal insufficiency in adults.

Normal newborn 17-hydroxyprogesterone level in an infant with congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Introduction: Neonatal screening with filter paper 17-hydroxyprogesterone (17-OHP) levels has improved detection of infants with adrenal 21-hydroxylase deficiency. The occurrence of false-negative 17-OHP screening results for classical 21-hydroxylase deficiency is extremely rare. Results: We report a case of a 7-week-old male infant whose clinical presentation was suggestive of 21-hydroxylase deficiency. Because his neonatal 17-OHP screening levels were normal, additional hormone levels were measured. Elevated deoxycortisol and deoxycorticosterone levels led to the diagnosis of 11β-hydroxylase deficiency. Discussion: When confronted with adrenal insufficiency in a neonate in whom 17-OHP neonatal screening results are normal, other causes of adrenal insufficiency should be considered.

X-linked adrenoleukodystrophy in patients with idiopathic Addison disease.

The two main causes of primary adrenal disease are tuberculosis and auto-immune adrenal destruction. The latter is responsible for about 70% of the cases of primary adrenal insufficiency (Addison disease). Commonly referred to as a rare cause of adrenal failure is X-linked adrenoleukodystrophy (ALD), a demyelinating peroxisomal disorder affecting 1: 20,000 Caucasian males. Albeit primary adrenal insufficiency is a rare entity per se, we decided to study patients with idiopathic Addison disease and establish the frequency of ALD as a cause of adrenal insufficiency. The biochemical defect of ALD was found in 5 out of 24 patients. The small number of cases in our series led us to include in our analysis the published results of two other groups of investigators. This analysis indicates that the proportion of cases in which Addison disease is attributable to ALD is age dependent. It is highest when the adrenal insufficiency manifests before 15 years. This study clearly demonstrates that the proportion of ALD in patients presenting primary adrenal insufficiency has been under-estimated. Addison disease manifesting during the first decade of life has a high likelihood of being the first sign of X-linked adrenoleukodystrophy.

Molecular basis of congenital adrenal hyperplasia due to 3 beta-hydroxysteroid dehydrogenase deficiency.

Congenital adrenal hyperplasia is the most frequent cause of adrenal insufficiency and ambiguous genitalia in newborn children. In contrast to congenital adrenal hyperplasia due to 21-hydroxylase and 11 beta-hydroxylase deficiencies, which impair steroid formation in the adrenal cortex, exclusively, classical 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency affects steroid biosynthesis in the gonads as well as in the adrenals. The structures of the highly homologous type I and II 3 beta-HSD genes have been analyzed in three male pseudohermaphrodite 3 beta-HSD deficient patients from unrelated families in order to elucidate the molecular basis of classical 3 beta-HSD deficiency from patients exhibiting various degrees of severity of salt losing. The nucleotide sequence of DNA fragments generated by selective polymerase chain reaction amplification that span the four exons, the exon-intron boundaries, as well as the 5'-flanking region of each of the two 3 beta-HSD genes have been determined in the three male patients. The five point mutations characterized were all detected in the type II 3 beta-HSD gene, which is the gene predominantly expressed in the adrenals and gonads, while no mutation was detected in the type I 3 beta-HSD gene, predominantly expressed in the placenta and peripheral tissues. The two male patients suffering from severe salt-losing 3 beta-HSD deficiency are compound heterozygotes, one bearing the frame-shift mutation 186/insC/187 and the missense mutation Y253N, while the other bears the nonsense mutation W171X and the missense mutation E142K. The influence of the detected missense mutations on enzymatic activity was assessed by in vitro expression analysis of mutant recombinant enzymes generated by site-directed mutagenesis in heterologous mammalian cells. Recombinant mutant type II 3 beta-HSD enzymes carrying Y253N or E142K substitutions exhibit no detectable activity. On the other hand, the nonsalt-losing patient is homozygous for the missense mutation A245P. This mutation decreases 3 beta-HSD activity by approximately 90%. The present findings, describing the first missense mutations in the human type II 3 beta-HSD gene, provide unique information on the structure-activity relationships of the 3 beta-HSD superfamily. Moreover, the present findings provide a molecular explanation for the enzymatic heterogeneity responsible for the severe salt-losing form to the clinically inapparent salt-wasting form of classical 3 beta-HSD deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Insufficiency From Bilateral Adrenal Hemorrhage

Bilateral adrenal hemorrhage is a rare cause of adrenal insufficiency in adults. Because of the nonspecific manifestations of adrenal insufficiency, antemortem diagnosis is difficult. Serial computed tomographic scans of the abdomen are a valuable adjunct in confirming the diagnosis of bilateral adrenal hemorrhage, which manifests as round or oval adrenal masses of high density that subsequently decrease in both size and density. The diagnosis should be suspected in any complex highly stressful illness, in the postoperative period, or in the presence of a coagulopathy in conjunction with hypotension, fever, or electrolyte disturbances. Herein we describe five patients in whom the computed tomographic scans suggested or confirmed the presence of bilateral adrenal hemorrhage. In three of the five patients, the presence of a circulating lupus anticoagulant was demonstrated. Once the diagnosis of adrenal hemorrhage is suspected, steroid replacement therapy should be initiated promptly.

Adrenal function in patients with active tuberculosis.

Although tuberculosis is a recognised cause of adrenal insufficiency, little is known about adrenal function in patients with active tuberculosis. Ninety Melanesian adults with active tuberculosis (30 pulmonary, 30 miliary, 30 extrapulmonary) had adrenal function assessed prospectively before and three to four weeks after starting antituberculous chemotherapy. Basal serum cortisol concentrations were normal in 55 (61%) and raised in 35 (39%) of the subjects. No patient had a low basal cortisol concentration. After Synacthen stimulation, cortisol responses were normal in 81 (92%) of the patients and subnormal in seven (8%). After antituberculous chemotherapy the response to Synacthen stimulation was normal in all but one patient. It is concluded that adrenal dysfunction is an uncommon problem in patients with active tuberculosis, and that, contrary to recent reports, antituberculous chemotherapy regimens that include rifampicin do not have an adverse effect on adrenal function.

Clinical Clues to the Cause of Addison’s Disease

Abstract Tuberculosis and other potentially treatable diseases remain important causes of adrenal insufficiency. Knowledge of the cause of adrenal destruction, although often difficult to ascertain clinically, is necessary for appropriate management. Clinical data are reviewed In eight patients with Addison's disease who underwent computed tomographic scanning and in 31 additional patients with Addison's disease in whom autopsy was performed. Seven of eight patients (87 percent) with tuberculous Addison's disease of no greater than two years' duration had enlarged glands whereas patients with longer duration of disease had smaller or normal-sized glands. Adrenal enlargement was also found in five of six (87 percent) subjects with carcinomatous replacement of the adrenal glands. The adrenal glands were small or undetectable in each of 16 patients with idiopathic Addison's disease. Adrenal calcification was found in nine of 17 (53 percent) tuberculous patients and was not found in any of the 22 other patients. Duration of adrenal disease, adrenal size on computed tomographic scanning, and presence of adrenal calcification were useful clues to the cause of Addison's disease.

Clinical clues to the cause of Addison's disease

Tuberculosis and other potentially treatable diseases remain important causes of adrenal insufficiency. Knowledge of the cause of adrenal destruction, although often difficult to ascertain clinically, is necessary for appropriate management. Clinical data are reviewed In eight patients with Addison's disease who underwent computed tomographic scanning and in 31 additional patients with Addison's disease in whom autopsy was performed. Seven of eight patients (87 percent) with tuberculous Addison's disease of no greater than two years' duration had enlarged glands whereas patients with longer duration of disease had smaller or normal-sized glands. Adrenal enlargement was also found in five of six (87 percent) subjects with carcinomatous replacement of the adrenal glands. The adrenal glands were small or undetectable in each of 16 patients with idiopathic Addison's disease. Adrenal calcification was found in nine of 17 (53 percent) tuberculous patients and was not found in any of the 22 other patients. Duration of adrenal disease, adrenal size on computed tomographic scanning, and presence of adrenal calcification were useful clues to the cause of Addison's disease.

The corticotropin-releasing hormone stimulation test: a possible aid in the evaluation of patients with adrenal insufficiency.

Ten patients with adrenal insufficiency receiving chronic glucocorticoid therapy were studied. All had subnormal plasma cortisol responses to ovine corticotropin-releasing hormone ( CRH ) (1 microgram/kg as an iv bolus) 12-60 h after discontinuation of steroid treatment. Plasma ACTH responses to CRH fell into three different patterns. The first three patients with primary adrenal insufficiency had high basal ACTH levels and augmented ACTH responses to CRH . A fourth such patient, however, treated with pharmacologic doses of prednisone, had a low normal ACTH response. Patients with secondary adrenal insufficiency had either low basal ACTH levels and diminished responses to CRH or low basal ACTH values but prolonged and augmented plasma ACTH responses to CRH with a delayed peak. We postulate that the group of patients with the former pattern have pituitary gland destruction whereas the patients with the latter pattern have hypothalamic CRH deficiency. Thus, CRH may be useful in differentiating between hypothalamic and pituitary causes of adrenal insufficiency.

Laboratory Tests in the Diagnosis and Investigation of Endocrine Function

Material prepared from taped lectures by more than 30 clinicians for a University of California postgraduate course forms the basis of this compact handbook of endocrinology. Updated ten years after the original publication, the second edition outlines methods of testing various functions of each organ, including appropriate indications and interpretations. Since the contributors in many cases summarize their own research work, the chapters cover the biochemical principles both accurately and authoritatively. The practical applications for diagnostic investigation provide essential expertise for a well-rounded internist, and apply to every specialty field in which he consults, but are often too complex for the general practitioner. One must understand the feedback systems operating in normal pituitary and adrenal function before he may assess the pathological changes in disease. Unfortunately, the most common cause of adrenal insufficiency, exogenous corticoid administration for therapeutic purposes, is hardly mentioned. The academic professors would render both patients and

Arenal cortical insufficiency associated with paracoccidioidomycosis (South American blastomycosis). Report of four patients.

Involvement of the adrenal glands is shown at autopsy in approximately 50% of patients with disseminated paracoccidioidomycosis. However, medical literature reveals only 7 proved cases of Addison's disease and 12 with low adrenal reserve associated with this mycosis. We report here 4 patients with adrenal cortical hypofunction and paracoccidioidomycosis. Stress is laid on the possibility that in Venezuela paracoccidioidomycosis constitutes an important cause of adrenal insufficiency.

Teaching a Patient to Live with Adrenal Insufficiency

Whatever the cause of adrenal insufficiency may be—and there are many causes—its successful therapy requires the cooperation of a wellinformed patient. This is particularly important when the patient is at home and more or less responsible for regulating the dosages of his prescribed hormonal-replacement medications according to signs and symptoms which he must be able to recognize. Nurses and physicians at the Clinical Research Center, Peter Bent Brigham Hospital, Boston, recognizing the need for a structured program to teach patients such a complicated subject as hormone therapy, developed the detailed teaching guide described here.

Histoplasmosis and torulosis as causes of adrenal insufficiency: Arnold J. Rawson, Leon H. Collins, Jr., and Joseph L. Grant, Am. J. M. Sc. 215: 363–371, April, 1948

Histoplasmosis and torulosis as causes of adrenal insufficiency: Arnold J. Rawson, Leon H. Collins, Jr., and Joseph L. Grant, Am. J. M. Sc. 215: 363–371, April, 1948

SOME EFFECTS OF CONSTANT INTRAVENOUS INJECTION OF POTASSIUM CHLORIDE SOLUTIONS INTO NORMAL CONSCIOUS DOGS

THE MAJORITY of workers are in disagreement as to the nature of the fundamental I cause or causes of adrenal insufficiency. The most widely held theory is that the syndrome is due to some defect in salt and water metabolism. Some have suggested that defective sodium metabolism is the primary cause (I, 2, 3); others, that it is a failure of the blood-diluting mechanism (4, 5, 6, but see also 7); and still others, that the syndrome is due to hyperpotassemia (8, 9, 10). Various workers have induced some of the symptoms of adrenal insufficiency by KCl administration, but the majority of the authors have not examined their animals or experimental subjects on more than a few of the facets of the problem. Zwemer and Trusskowski (11) present the most comprehensive report to date, but their report lacks details of experimental technic and treats only subjectively of the symptoms of adrenal insufficiency.