Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytokines tumor necrosis factor-alpha (TNF alpha), interleukin-1 (IL-1), and IL-6 are secreted at inflammatory sites in tandem and play a crucial role in the inflammatory and wound-healing processes. All three cytokines are potent activators of the hypothalamic-pituitary-adrenal axis, through which they restrain inflammation, whereas IL-6 itself plays a role in the termination of inflammation as well. To test the hypothesis that endogenous glucocorticoids exert a negative tonic effect on the secretion of these cytokines, we studied 17 patients with Cushing's disease and 2 patients with primary adrenal Cushing's syndrome before and after surgery. Plasma TNF alpha, IL-1 beta and IL-6 were measured before surgery, while the patients were hypercortisolemic; on postoperative day 4 or 5, when they were hypocortisolemic; and on postoperative day 9 or 10, when they were receiving glucocorticoid replacement. During severe hypocortisolism, on postoperative day 4 or 5, plasma IL-6 levels rose significantly, compared to the preoperative values (P < 0.001). During the same interval, TNF alpha and IL-1 beta also rose, albeit to a lesser extent. Over the same interval, patients with severe hypocortisolism experienced temperature elevation, fatigue, somnolence, flu-like symptoms, and anorexia, symptoms that have been traditionally attributed to glucocorticoid deficiency; these were also experienced by subjects that received recombinant human IL-6. There was no postoperative increase in any of the cytokines studied in the patients who were not hypocortisolemic after surgery and who also lacked the corresponding symptomatology. Plasma IL-6 concentrations decreased significantly, albeit not to normal levels, in the hypocortisolemic group of patients on postoperative day 9 or 10, when they were receiving glucocorticoid replacement. We conclude that the peripheral levels of IL-6 and to a lesser extent, those of TNF alpha and IL-1 beta are tonically inhibited by basal levels of glucocorticoids. The increased IL-6 production that occurs when cortisol levels fall might explain the symptomatology of acute glucocorticoid deficiency.
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PMID:Acute glucocorticoid deficiency is associated with plasma elevations of interleukin-6: does the latter participate in the symptomatology of the steroid withdrawal syndrome and adrenal insufficiency? 896 68

Patients with familial cortisol resistance have continuously elevated serum cortisol without any clinical manifestations of Cushing's syndrome due to hyposensitivity to cortisol in all tissues including the hypothalamus and the pituitary. Clinical symptoms of the disease are hypertension with hypokalemia and hyporeninemia, virilism in women and mild general fatigue. As the cause of the disease, a defect in glucocorticoid receptor affinity or binding capacity due to mutations in the glucocorticoid receptor gene has been reported. Another cause of the disease is the presence of heat labile glucocorticoid receptor. In 4 of 5 families with cortisol resistance reported so far, mutations of the glucocorticoid receptor gene have been demonstrated.
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PMID:[Familial cortisol resistance and mutations of the glucocorticoid receptor gene]. 970 71

A retrospective analysis of Cushing's syndrome from the retrieved records of 24 out of a total of 27 referred cases over a period of 10 years (January 1985-January 1995) showed confirmation in 16 cases. Fourteen (88%) were females, 9 (56%) were in their third decade. Duration of symptoms before admission was one year or less in eleven (69%) patients. Among symptoms weakness, fatigue and weight gain and among signs moon face, truncal obesity and buffalo hump were found in all patients. Amenorrhea occurred in all the women of childbearing age. Basal urinary 17-hydroxycorticoid (17-OHCS) values were elevated in 9/12 patients and low dose dexamethasone suppression test favoured Cushing's syndrome in 8/9 patients. Definitive treatment consisted of bilateral adrenalectomy in 7 and transfrontal pituitary adenomectomy in 3. Two patients declined surgery; 4 patients were lost to follow up before definitive treatment. Two patients who had bilateral adrenalectomy and two who had transfrontal adenomectomy died subsequently while three remained in good health on corticosteroid replacement therapy. Three of the 7 patients who had bilateral adrenalectomy developed Nelson's syndrome. It is concluded that Cushing's disease is the most frequent cause of Cushing's syndrome in our series. The patients presented with the well-known clinical manifestations of hypercortisolism. However, our laboratory facilities require considerable improvement to serve as a reliable adjunct to clinical evaluation. Since Cushing's syndrome, whatever the cause, is eventually fatal if left untreated, surgical intervention is mandatory after confirmation of the cause with appropriate laboratory tests.
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PMID:Cushing's syndrome: a ten year experience at Tikur Anbassa Hospital. 1021 44

Cortisol resistance (CR) is a rare disease characterized by a generalized reduced sensitivity of end-organs to the actions of glucocorticoids (GCs). GC effects are mediated by the GC receptor (GR). The molecular alterations in CR described thus far were located in the hormone-binding domain of the GR gene. Recent reports of a considerable prevalence of abnormalities in the GR in patients attending the endocrine clinic prompted us to carry out further investigations with respect to GR protein and GR gene in patients attending the endocrine clinic for a broad spectrum of complaints and biochemical evidence suggesting a CR. In the present study, we describe five patients with biochemical and clinical CR. All patients showed a diurnal rhythm of serum cortisol concentrations (albeit at a high level), an insufficient suppression of serum cortisol concentration in reaction to 1 mg dexamethasone (DEX), and variable degrees of androgen overproduction, in the absence of clinical signs and symptoms of Cushing's syndrome. Three of the four female patients presented with complaints of androgen overproduction, two of them in combination with fatigue. The other female patient had severe steroid-resistant asthma. The only male patient and his son were asymptomatic. In four patients, we investigated receptor protein characteristics on mononuclear leukocytes in a whole cell DEX binding assay and studied the ability of DEX to inhibit mitogen-induced cell proliferation in mononuclear leukocytes in vitro. In all patients investigated, we found alterations in receptor number or ligand affinity and/or the ability of DEX to inhibit mitogen-induced cell proliferation. To investigate the molecular defects leading to the clinical and biochemical pictures in these patients, we screened the GR gene using PCR/single-strand conformational polymorphism/sequence analysis. No GR gene alterations were found in these patients. In conclusion, the five patients described had clinical and biochemical evidence of CR, but no abnormalities were demonstrated in the GR gene. Probably, as yet undefined alterations somewhere in the cascade of events starting with ligand binding to the GR protein, and finally resulting in the regulation of the expression of GC responsive genes, or postreceptor defects or interactions with other nuclear factors form the pathophysiologic basis of CR in these patients.
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PMID:Five patients with biochemical and/or clinical generalized glucocorticoid resistance without alterations in the glucocorticoid receptor gene. 130 33

Abnormalities of glucocorticoid receptors were assumed to cause resistance or hypersensitivity to glucocorticoid, while only glucocorticoid resistance has been described clinically. Patients with familial cortisol resistance have continuously elevated serum cortisol without any clinical manifestations of Cushing's syndrome due to hyposensitivity to cortisol in all tissues including the hypothalamus and the pituitary. Clinical symptoms of the disease are characterized by hypertension with hypokalemia and hyporeninemia, virilism in women, isosexual precocity in a boy and mild general fatigue. As the cause of the disease, a defect in glucocorticoid receptor affinity or binding capacity due to mutations in the glucocorticoid receptor gene has been reported. Another cause of the disease is the presence of heat labile glucocorticoid receptor. In 5 of 6 families with cortisol resistance reported so far, mutations of the glucocorticoid receptor gene have been demonstrated.
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PMID:[Disorders caused by abnormalities of glucocorticoid receptors]. 1185 26

We describe a case of multiple pathologic fractures in a woman with Cushing's syndrome during pregnancy. Pathologic fractures were seen in the pubic and ischial bones and in T12 and L1 of the vertebral body. These findings, accompanied by easy fatigue, amenorrhea without nursing, psychological disorder, and premature birth, were retrospectively compatible with those of Cushing's syndrome, not pregnancy-associated osteoporosis. After adrenalectomy, the pain in her groin and back ceased. Plain radiographs showed healing of the fractures and increased mineralization. This case demonstrates the need to be alert to the possible presence of metabolic bone disease, including Cushing's syndrome, when we encounter multiple pathologic fractures with osteoporosis in young patients, even if the patient is pregnant.
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PMID:Case report of a Cushing's syndrome patient with multiple pathologic fractures during pregnancy. 1218 67

This case report describes the diagnosis of Cushing's syndrome due to macronodular adrenal hyperplasia in an elderly woman who presented with fatigue, muscle weakness and oedema, and recent excessive bruising. Long-standing disease and comorbidity precluded adrenalectomy. Despite treatment with metyrapone and diuretics, the patient died after two months hospitalisation. Postmortal examination revealed overexpression of luteinising hormone (LH) receptors in the adrenal glands, suggesting that the postmenopausal rise in LH may have a role in adrenal hyperplasia and hypercortisolism.
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PMID:Macronodular adrenocortical hyperplasia in a postmenopausal woman. 1568 97

We report a case of adrenal black adenoma associated with Cushing's syndrome. A 41-yr-old man presented to our hospital with a 6-yr history of severe hypertension and general fatigue, and a 1-mo history of diabetes mellitus. Physical examination disclosed cushing-oid manifestations. His serum cortisol concentrations ranged from 14.0 to 15.4 microg/dL, with an ACTH level <5 pg/mL. Urinary free cortisol level was increased (125 microg/d). Cortisol was not suppressed on the overnight 1 mg oral dexamethasone suppression test (DST), 2-d low-dose DST, and 2-d high-dose DST. Abdominal computed tomography and magnetic resonance imaging studies revealed a solid round tumor approx 3 cm in diameter, located in the left adrenal gland. Left adrenalectomy was performed; the surgical specimen revealed a black ade-noma consisting of compact cells within numerous pigments that seemed to be lipofuscin in nature.
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PMID:Adrenal black adenoma associated with Cushing's syndrome. 1575 53

A 51-year-old woman with Cushing's syndrome underwent unilateral adrenalectomy for left adrenal adenoma. After 7 years of prednisolone treatment (with some interruptions), followed by 4 years of total withdrawal from prednisolone treatment, she presented with hypotension, weight loss, general fatigue, nausea, hyponatremia and hypoglycemia. These clinical features together with a low response in the rapid adrenocorticotropic hormone test led to the diagnosis of acute adrenal insufficiency. Relatively low serum adrenocorticotropic hormone levels in the face of increased demand for cortisol during adrenal crisis suggested a disordered hypothalamic-pituitary function, indicating secondary adrenal insufficiency. This patient demonstrated the etiology of acute adrenal insufficiency long after unilateral adrenalectomy in association with subsequent glucocorticoid therapy. A reduction in the reserved secretory capacity of cortisol after prolonged prednisolone treatment was considered to have induced secondary adrenal insufficiency, even after 4 years of total withdrawal from prednisolone.
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PMID:Delayed adrenal insufficiency long after unilateral adrenalectomy: prolonged glucocorticoid therapy reduced reserved secretory capacity of cortisol. 1598 81

A 14-year-old female with perinatally acquired HIV on boosted protease inhibitor (PI) therapy with atazanavir and ritonavir rapidly developed cushingoid features with excessive weight gain and moon facies within 2 weeks of receiving inhaled fluticasone/salmeterol for asthma treatment. Soon after discontinuing PIs and inhaled steroid, she required hospitalization for dyspnea, headache, muscle weakness, and extreme fatigue requiring hydrocortisone replacement therapy for presumed adrenal insufficiency. Cushing syndrome and adrenal suppression were very likely caused by elevated steroid systemic concentrations resulting from the cytochrome p450 interaction between the protease inhibitors and fluticasone. The Naranjo probability scale score of 5 suggests that the event was probably drug related. This is the first case report of fluticasone and PI-induced Cushing syndrome and adrenal suppression in a pediatric patient without a history of recent or concomitant treatment with systemic steroid therapy. Additionally, this case is unique as it is the most rapid (<2 weeks) presentation documented, thus far. Health care professionals should be conscious of this important drug-drug interaction in HIV-infected children and adolescents and be aware that rapid onset of hypercortisolism and adrenal suppression are possible.
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PMID:Cushing syndrome and severe adrenal suppression caused by fluticasone and protease inhibitor combination in an HIV-infected adolescent. 1759 45


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