Chronic Primary Adrenal Insufficiency Research Articles

Non-invasive assessment of tissue sodium content in patients with primary adrenal insufficiency

ObjectiveReplacement therapy in primary adrenal insufficiency (PAI) with corticosteroids modulates sodium homeostasis. Serum sodium is, however, prone to osmotic shifts induced by several additional factors besides corticosteroids and does not always reliably reflect treatment quality. Non-osmotic tissue storage can be visualized by sodium MRI (23Na-MRI) and might better reflect corticosteroid activity.DesignLongitudinal study of 8 patients with newly diagnosed PAI and cross-sectional study in 22 patients with chronic PAI is reported here. Comparison was made with matched healthy controls.MethodsUsing a 23Na-MRI protocol on a 3T scanner, relative sodium signal intensities (rSSI) to signal intensities of the reference vial with 100 mmol/L of sodium were determined in the muscle and skin of the lower calf.ResultsIn newly diagnosed patients, tissue rSSI (median, range) were reduced and significantly increased after treatment initiation reaching levels similar to healthy controls (muscle: from 0.15 (0.08, 0.18) to 0.18 (0.14, 0.27), P = 0.02; skin: from 0.12 (0.09, 0.18) to 0.18 (0.14, 0.28), P < 0.01). Muscle rSSI was significantly higher in patients with chronic PAI compared to controls (0.19 (0.14, 0.27) vs 0.16 (0.12, 0.20), P < 0.01). In chronic PAI, skin rSSI significantly correlated with plasma renin concentration.Conclusion 23Na-MRI provides an additional insight into sodium homeostasis, and thus the quality of replacement therapy in PAI, as tissue sodium significantly changes once therapy is initiated. The increased tissue sodium in patients with chronic PAI might be an indication of over-replacement.

ЗНАЧЕНИЕ АНТИТЕЛ К 21-ГИДРОКСИЛАЗЕ ДЛЯ ДИАГНОСТИКИ, ДИФФЕРЕНЦИАЛЬНОЙ ДИАГНОСТИКИ И ПРОГНОЗИРОВАНИЯ АУТОИММУННОЙ ПЕРВИЧНОЙ ХРОНИЧЕСКОЙ НАДПОЧЕЧНИКОВОЙ НЕДОСТАТОЧНОСТИ

21-hydroxylase (21-OH) is the main antigen of the adrenal cortex, so the determination of antibodies (Ab) to 21-OH can help in the diagnosis and prognosis of chronic primary adrenal insufficiency (CPAI). Purpose of the study: evaluation of the relevance of Ab to 21-OH for the diagnosis and prediction of autoimmune CPAI. Materials and methods of research: the study consisted of three blocks: 1) assessment of the specificity and sensitivity, as well as the prognostic potential of Ab to 21-OH in patients with polyglandular autoimmune syndrome (APS) – individuals with APS type 1 with and without CPAI (n=106); 2) assessment of the dynamics of the level of Ab to 21-OH – patients with autoimmune CPAI were included (n=41); 3) assessment of the significance of Ab data for the differential diagnosis of various forms of CPAI, including patients with CPAI and APS type 1 exclusion (n=30). The study of Ab to 21-hydroxylase was performed using enzymelinked immunosorbent assay (BioVendor kits, Czech Republic). Results: statistically significant differences were obtained in the frequency of detection of Ab to 21-OH in patients with or without PCNI (p&lt;0,001). The sensitivity of the method was 96%, specificity was 75%, a positive predictive value was 90%, and the negative predictive value was 89%. In 83% of patients, the level of Ab decreased with time (median size decreases – 20,4%/year). An inverse relationship was also found between the level of Ab and the duration of the course of CPAI (R=–0,460, p&lt;0,001). In a group of 30 patients with CPAI and with exclusion of APS type 1, 21 were found to have Ab to 21-OH, only one of them had a monogenic non-autoimmune cause of CPAI (a mutation in the MC2R gene). Monogenic forms of CPAI were found in another 7 patients (mutations were found in the DAX1 and ABCD1 genes), among them an increase in Ab to 21-OH was not detected. Conclusion: determination of Ab to 21-OH is a specific and sensitive method for the diagnosis of autoimmune CPAI. An increase in Ab to 21-OH is a risk marker of autoimmune CPAI development.

SAT-219 Allgrove Syndrome: How to Suspect a Problem?

Background: Allgrove syndrome (triple A syndrome) is a rare autosomal recessive multisystem disease characterized by adrenal insufficiency, alacrimia and achalasia. It is caused by a mutation in the AAAS gene (12q13) encoding the protein ALADIN (1). This syndrome is often associated with neurological dysfunction disorders, amyotrophy, in such cases, it is named 4A and 5A syndrome, but sometimes there is also 2A syndrome. Prevalence:<1/1000000. The first description was in 1978. Clinical case: A 18-year patient A. complained of fatigue, weakness, darkening of the skin. From anamnesis of life: born from the first pregnancy without complications, weight 3200g. Parents often turned to the pediatrician with complaints: lethargy, frequent regurgitation, ARVI up to 6–7 times a year. Slow weight gain, dyspeptic syndrome (nausea, vomiting) was noted objectively. At the age of 3, the boy entered the surgical department with acute abdomen, fever, vomiting. Achalasia was revealed, reconstructive surgery was carried out. In the diagnostic search for the causes of body weight loss he was directed to the endocrinologist. There were an increase in ACTH 470 pg/ml (0,0-46 pg/ml), cortisol 0.05 µg/DL. Diagnosis: primary chronic adrenal insufficiency; the dose of hydrocortisone 10 mg/day did not change with age. An in-depth anamnesis found: the patient never cried with tears. Objectively: asthenic body type, BMI 16.5 kg/m2, hyperpigmentation of the palms, armpits; weakness in the proximal muscles of the limbs. Laboratory studies: ACTH 95 PG/ml, cortisol 0.1 µg/DL (3.7–19.4 µg/DL). The secretion of mineralocorticoids was evaluated: plasma aldosterone and renin levels were within the reference values. Ophthalmologist: injected conjunctiva, sclera. Schirmer’s test: mild alacrimia. It allowed to make the diagnosis: “Primary chronic adrenal insufficiency. Condition after surgery for achalasia (1997). Alacrimia. Allgrove Syndrome.” The dose of hydrocortisone was increased to 17.5 mg/day. In 2019, the patient complained of a sharp deterioration of health, darkening of the skin. The dose of hydrocortisone was increased to 25 mg/day (15 mg at 8.00, 10 mg in the afternoon). The ophthalmologist noted an increase in the severity of alacrimia, artificial tear drops was recommended. The diagnosis was confirmed by pathogenic mutation c.43C>T of the AAAS gene. Discussion: Despite the full clinical picture, the right diagnosis was made only after 14 years. We shown the difficulty of diagnosis is due to the lack of awareness of clinicians about the disease, the importance of interdisciplinary interaction, as well as the need for follow-up of such patients. Reference: (1) Handschug K, Sperling S, Yoon SJ, et al. Triple A syndrome is caused by mutations in AAAS, a new WD-repeat protein gene. Human Molecular Genetics. 2001;10:283–290.

SAT-386 Assessment Of Tissue Sodium Content By23Na-MRI In Patients With Adrenal Insufficiency

Patients with chronic primary adrenal insufficiency (PAI) depend on lifelong replacement therapy with gluco- (GC) and mineralocorticoids (MC). Monitoring is based on clinical parameters assessing hemodynamic stability, electrolyte status and plasma renin concentration (PRC). Reduced subjective well-being is however often described by these patients in absence of objectifiable abnormalities, thus suggesting a gap between the concept of adequate hormone substitution and physiological requirements. This study investigated the potential role of 23Na-MRI for noninvasive assessment of sodium status in PAI. Tissue sodium was initially analyzed both in the calf muscle and in the skin of 16 patients with chronic PAI and 16 sex-, age- and BMI-matched controls. Patients were classified into 3 groups (optimal/subtherapeutic/supraphysiological) according to the quality of GC and MC substitution assessed separately by clinical scores based on subjective wellbeing and clinical/laboratory parameters. We additionally performed a longitudinal analysis in 8 patients with newly diagnosed PAI. Muscle and skin sodium content (Muscle-SC, Skin-SC) were determined using a 23NA-MRI protocol on a 3T scanner implementing a 3D sequence. A vial with 100mmol/L of sodium was scanned with every participant. Tissue sodium is presented as the ratio of tissue sodium signal intensity to sodium signal intensity of the reference vial. Muscle-SC was significantly higher in patients with chronic PAI compared to controls (19.1 vs. 16.0, p<0.05), whereas Skin-SC was similar between the two groups (16.1 vs. 17.1). These results were replicated in the subgroups classified as receiving optimal GC and MC replacement, respectively. Skin-SC was significantly correlated with 24h-urine sodium level in the whole cohort. When comparing Muscle-SC and Skin-SC with obtained clinical scores a trend from lower SC for low scores to higher SC for higher scores was observed. The longitudinal analysis of 8 patients with newly diagnosed PAI revealed that Skin-SC was significantly lower at primary diagnosis compared to sex-, age- and BMI-matched controls (12.1 vs. 15.8, p=0.05), whereas the difference in Muscle-SC was less pronounced (14 vs. 16.1, p=0.18). A significant increase in both Muscle- and Skin-SC at follow-up compared to first diagnosis was detected (19.4 vs. 14, p<0.05 and 19.3 vs. 12.1, p<0.05), consistent with a significant decrease in PRC (200 vs. 31.2 ng/l, p<0.05). Interestingly, patients with chronic PAI under replacement therapy exhibited significantly higher Muscle-SC compared to controls. The agreement between tissue SC and clinical scores as well as the significant increase in tissue SC under replacement therapy in newly diagnosed patients indicate that 23Na-MRI might be a quantitative method to assess steroid replacement. Further studies on a larger cohort are, however, needed to prove these initial findings.

The first case of a rare form of isolated glucocorticoid insufficiency associated with to NNT gene mutation reported in the Russian Federation

Familial glucocorticoid deficiency (FGD, MIM*202200) is a rare form of primary chronic adrenal insufficiency characterized by resistance of the adrenal cortex to ACTH, decrease in secretion of glucocorticoids and adrenal androgens, and increase in plasma ACTH level. Currently, at least 7 genes whose mutations lead to the development of FGD have been described. These are MC2R, MRAP, STAR, CYP11A1, NNT, TXNRD2, and AAAS. E. Meimaridou and J. Kowalczyk were the first who described NNT gene mutation in 2012 in one patient who underwent molecular genetic examination and 9 patients with clinical presentation of familial glucocorticoid deficiency. Understanding of the exact cause of primary chronic adrenal insufficiency enables adjusting the treatment, predicting the development of possible complications and related dysfunctions of other organs, as well as the need for medical and genetic counseling of the family.

Addison Disease: The First Presentation of the Condition May be at Autopsy.

Addison disease is chronic primary adrenal insufficiency, which, in developed countries, is most commonly due to autoimmune destruction of the cortex (termed autoimmune or idiopathic Addison disease). Although the disease process has some classic features, such as increased pigmentation, salt craving, and signs and symptoms related to decreased blood pressure, the initial clinical presentation may be vague and/or insidious. Following an acute stressor such as a gastrointestinal (GI) infection, the patient may experience an adrenal crisis, which can cause sudden death. As such, knowledge of this disease process and the diagnostic criteria in the postmortem period is essential for the practicing forensic pathologist. The diagnosis of autoimmune Addison disease at autopsy is aided by several factors including 1) history, including salt craving, features consistent with orthostatic hypotension, and GI complaints including nausea, vomiting and pain, 2) physical examination findings of increased pigmentation and small or unidentifiable adrenal glands, 3) serologic testing for 21-hydroxylase antibodies, 4) serum cortisol concentrations, and 5) vitreous electrolyte testing. While the listed historical information, the increased pigmentation, decreased serum cortisol concentrations, and evidence of hyponatremia may be found in all forms of Addison disease, small or unidentifiable adrenal glands and 21-hydroxylase antibodies are found exclusively in the autoimmune form of Addison disease. While other causes of Addison disease, such as tuberculosis, metastatic tumor, or other infiltrative processes would have enlarged adrenal glands, these diseases would lack 21-hydroxylase antibodies. The purpose of this paper is to focus on the diagnosis of autoimmune Addison disease.

Addison’s disease in a child: a case report

Addison's disease is chronic primary adrenal insufficiency, a rare disorder which is characterized by adrenocortical insufficiency. The sign and symptom in Addison's disease is nonspecific. This paper is to report Addison’s disease in a child focusing in diagnostic approach. Method is case report. Girl, 4 years old suffered from general weakness without paresthesia, fatigue, salt craving and hyperpigmentation including skin, lips, gum, buccal mucosa, hard palate and plantar creases. Tanner stage was prepubertal condition. Basal cortisol plasma level in the morning was 94.8 (50-250) µg/mL and 14.5 (25-125) µg/mL in the evening. This patient was performed ACTH stimulation test. The result revealed declining cortisol plasma level before (20.83) and 30’, 120’ after the test (16.53, 5.91, respectively). Free T4 was 17.31 (9-20) pmol/L; TSH 2.48 (0.25-5) uIU/mL. Adrenal ultrasound revealed no classification nor hemorrhage. Primary adrenal insufficiency was established. Tuberculosis is frequently reported in Addison. In our patient the Tuberculin skin test revealed negative. Treatment planned to be given were oral hydrocortisone 15 mg/m2 and oral fludrocortisone. Based on anamnesis, physical examination and laboratory findings, addison disease was established. As conclusion, beware of generalized weakness and hyperpigmentation in a child, it may be the symptom of adrenal insufficiency. Careful diagnosis procedure is very important. Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Müdigkeit, Hyperpigmentierung, Gewichtsverlust, Nausea und Erbrechen

In this patient with tiredness, hyperpigmentation, weight loss, nausea and vomiting, chronic primary adrenal insufficiency (M. Addison) was diagnosed based on the clinical features, the typical electrolyte abnormalities and the reduced morning cortisol together with increased adrenocorticotropic hormone. The detection of autoantibodies against adrenal tissue and 21-hydroxylase revealed an auto-immune adrenalitis as the cause. The additional primary hypothyroidism (with positive thyreoperoxidase-anti-bodies, anti-TPO-antibodies) and the coeliac disease argued for a polyglandular autoimmune syndrome type 2. Treatment with hydrocortisone and with mineralocorticoid and thyroxine later on showed a rapid improvement of clinical symptoms. In patients with Morbus Addison, a screening for associated endocrine disorders is warranted.

The etiology and pathogenesis of primary chronic adrenal insufficiency: Current aspects

Primary chronic adrenal insufficiency is a relatively rare disease. To date, according to various authors, the prevalence of Primary chronic adrenal insufficiency in the world varies significantly.

Современные аспекты этиологии и патогенеза первичной хронической надпочечниковой недостаточности

Primary chronic adrenal insufficiency is a relatively rare disease. To date, according to various authors, the prevalence of Primary chronic adrenal insufficiency in the world varies significantly.

Addison's disease

Addison's disease, or primary adrenal insufficiency, results in glucocorticoid and mineralocorticoid deficiency. Orthostatic hypotension, fever, and hypoglycemia characterize acute adrenal crisis, whereas chronic primary adrenal insufficiency presents with a more insidious history of malaise, anorexia, diarrhea, weight loss, joint, and back pain. The cutaneous manifestations include darkening of the skin especially in sun-exposed areas and hyperpigmentation of the palmar creases, frictional surfaces, vermilion border, recent scars, genital skin, and oral mucosa. Measurement of basal plasma cortisol is an insensitive screening test. Synthetic adrenocorticotropin 1-24 at a dose of 250 μg works well as a dynamic test. Elevated plasma levels of adrenocorticotropin and renin confirm the diagnosis. Treatment involves replacement of the deficient hormones.

Recent Advances in the Diagnosis and Therapy of Primary Adrenal Insufficiency

Primary adrenal insufficiency (PAI) is the consequence of the bilateral destruction or impaired function of the adrenal cortex. The reduction of adrenocortical cell mass is responsible for a deficiency of glucocorticoids and, in some cases, of mineralocorticoids and adrenal androgens. Over the past few decades, new data on the prevalence of PAI, advances in the procedure for the clinical testing of the adrenal function, and the development of novel genetic and molecular biology techniques have improved our understanding of the physiopathological mechanisms involved in the process of adrenal dysfunction and its genetic background. The estimated prevalence of PAI is 110-120 subjects per million individuals, being slightly higher among females than among males. The diagnosis of PAI is made in the presence of the typical symptoms and signs accompanied by reduced levels of serum cortisol and elevated levels of plasmatic ACTH. The intravenous injection of synthetic ACTH (250 μg) (HDT) is helpful for testing cortisol response in patients with suspected PAI. Recently, we have demonstrated that the intravenous injection of very low doses of synthetic ACTH (1 μg) (LDT) has a high diagnostic sensitivity and specificity for PAI, and this test could be proposed as an accurate way to identify subjects with adrenal dysfunction. The presence of a mineralocorticoid deficiency can be tested by measuring plasmatic or urinary aldosterone levels, which can be low in PAI, and plasma renin activity, which is elevated. Adrenal androgen deficiency (i.e. DHEA) can be assessed by specific radioimmunoassays, but they are not usually performed in routine clinical practice. The clinical spectrum of Addisons disease has expanded dramatically, and a long series of additional causative mechanisms has been identified. In Western countries, up to 70% of cases of PAI is the consequence of the autoimmune destruction of adrenocortical cells. The enzyme steroid 21-hydroxylase (21OH) is the major adrenal autoantigen in autoimmune PAI and the appearance of adrenal cell autoantibodies (ACA) and 21OH antibodies (21OHAb) is considered a sensitive and specific immune marker of this condition. The genetic risk for autoimmune PAI is associated with HLA-DR3-DQ2 and with allele 5.1 of the MHC class I chain-related A (MICA) gene. Chronic PAI may also result from targeting of the adrenal gland by Mycobacterium tuberculosis, fungal agents, Cytomegalovirus infection during AIDS or coagulative diseases and bilateral metastasis. Many genetic disorders, such as X-linked adrenoleukodystrophy (ALD), adrenal hypoplasia congenita (AHC) and ACTH resistance syndrome, can cause PAI in children, and sometimes also in adult subjects. ALD is a hereditary peroxisomal disorder characterized by demyelination of the nervous system and PAI; the detection of increased plasmatic levels of VLCFA is the biochemical marker of this disease. AHC is another X-linked disorder, in which affected males present with hypogonadotropic hypogonadism and PAI; the gene involved is known as DAX-1 and is located in the long arm of chromosome X. Familial ACTH resistance syndrome is characterized by high levels of ACTH and adrenal insufficiency due to mutations of the ACTH receptor gene, located on chromosome 18p11. This clinical form should be differentiated from triple A syndrome (achalasia, alacrimia, adrenal insufficiency), which is caused by a recently identified gene located on chromosome 12q13. This wide range of forms of PAI suggests that identification of the etiologic cause of PAI in the individual patient is an important diagnostic step, due to the different clinical management. The treatment of PAI is based on hormone-replacement therapy. Cortisol deficiency can be compensated by oral administration of hydrocortisone or cortisone acetate twice or three times a day. The mineralocorticoid drug used for aldosterone replacement is 9-alpha-fluoro-cortisol, administered orally every day or on alternate days. Recent clinical studies have shown that the administration of DHEA is beneficial in PAI patients, and for this reason it has been proposed that treatment with DHEA could be a useful supplement to the replacement therapy for PAI.

The daily rhythm of secretion of adrenocorticotropic hormone in assessing the adequacy of replacement therapy for primary chronic adrenal insufficiency

Plasma level о] АС 1Н was radioimmunoassayed every 4 hours for 24 h in three groups of patients in order to evaluate the possibility of using circadian rhythm of ACTH secretion for assessment of the efficacy of substitute glucocorticoid therapy for primary chronic adrenal insufficiency (CAI-1, Addison’s disease). In group 1 (n = 14) patients with CAI-1 were treated with prednisolone (5 mg at 9.00 and 2.5 mg at 14.00), in group 2 dexamethasone (0.5 mg at 23.00) and prednisolone (2.5 mg at 14.00). In addition, all patients with CAI-1 were administered 9a-fluorocortisol in a daily dose of0.005-0.01 mg. Control group consisted of 14 healthy volunteers.&#x0D; The level of A CTH varied within a wide range in both variants of substitute therapy in comparison with the norm. The areas under the curve reflecting ACTH concentrations within 24h differed negligibly in groups 1 and 2 and in group 2 and control. The area under ACTH curve in group 1 was significantly larger than in the control. The mean concentrations of ACTH in group I at 7.00 and 11.00 were significantly higher than in the two other groups. In general, circadian rhythms of ACTH secretion were closer to the norm in the patients treated with dexamethasone. According to our clinical experience, dexamethasone had to be discontinued because of the overdosage syndrome (body weight excess, high appetite and insomnia) in at least 2/3 of patients initially prescribed this agent, and therefore we conclude that the clinical picture and data on the 24-h rhythm of A CTH secretion disagree. Evaluating the results of substitute therapy for CAI-1, one should remember that normal rhythm of ACTH secretion during 24 h does not rule out overdosage of glucocorticoids, and therefore the results of laboratory tests should be interpreted with due consideration for the clinical picture.

Coma hiponatrêmico como manifestação de doença de Addison

OBJETIVO: alertar sobre a importância de distúrbio hidroeletrolítico grave devido a doença crônica não previamente diagnosticada. MÉTODO: relato de um caso de coma hiponatrêmico devido a crise adrenal em criança portadora de doença de Addison não diagnosticada previamente, apesar de história clínica sugestiva desta doença há cerca de quatro anos. RESULTADO: Após atendimento inicial à emergência, com correção da hiponatremia grave com hipovolemia discreta, hipernatriúria e hiperpotassemia, o diagnóstico diferencial deste distúrbio hidroeletrolítico revelou tratar-se de uma crise adrenal secundária a uma insuficiência adrenal primária crônica. O tratamento com hidrocortisona oral possibilitou alta hospitalar com correção total dos distúrbios metabólicos. CONCLUSÃO: é importante manter um alto grau de suspeita de doença de Addison para evitar as graves conseqüências de seu diagnóstico tardio, como distúrbios hidroeletrolíticos graves, além de atraso de crescimento e desenvolvimento.

Hyponatremic coma as a manifestation of Addisońs disease

OBJECTIVE: To show the importance of severe hydroelectrolytic disorder as a consequence of previously undiagnosed chronic disease. DESCRIPTION: Case report of hyponatremic coma caused by adrenal crisis in a child with previously undiagnosed Addisońs disease despite suggestive clinical findings of this disease in the last four years. After correction of severe hyponatremia, mild hypovolemia, hypernatriuria and hyperkalemia, the differential diagnosis of this hydroelectrolytic disorder revealed an adrenal crisis resulting from a primary chronic adrenal insufficiency. Oral treatment with hydrocortisone was efficient in correcting the metabolic disorder and the patient was then discharged. COMMENTS: It is very important to highly suspect of Addisońs disease in order to avoid the dangerous consequences of late diagnosis such as severe hydroelectrolytic disorders and retarded growth and development.

Adrenal Insufficiency in Critically Ill Patients

Patients with adrenal insufficiency in the critical care setting may present with a spectrum of disease severity ranging from life-threatening adrenal crisis to mild organ dysfunction. The recognition of adrenal insufficiency is made more difficult in the critically ill patient because of the unavailability of a reliable history, delay in reporting of diagnostic laboratory results, and the comorbidities that obscure a definitive diagnosis. The present discussion will illustrate how the classic presentations of adrenal insufficiency are modified in critically ill patients and how appropriate diagnosis and management can be achieved in the critical care setting. CLASSICAL PRESENTATIONS OF ADRENAL INSUFFICIENCY Adrenal insufficiency can be subdivided into three broad categories: ( 1 ) Chronic primary adrenal insufficiency, also called Addison’s disease, is a result of destruction of the adrenal cortex. The most common causes include autoimmune disease (about 70 to 80%), tuberculosis (about 20%), adrenal hemorrhage, adrenal metastases, and AIDS in association with cytomegalovirus (CMV), other pathogens, or ketoconazole treatment (1). ( 2 ) Chronic secondary adrenal insufficiency occurs when insufficient adrenocorticotropic hormone (ACTH) is available to stimulate the adrenal cortex. Most commonly it is due to exogenous glucocorticoid therapy, but it can also be the result of generalized hypopituitarism (usually from pituitary or hypothalamic tumors) or isolated ACTH deficiency (probably autoimmune in nature). ( 3 ) Acute adrenal crisis may result from stress in patients with chronic adrenal insufficiency who are not adequately replaced, but it also occurs in patients with acute adrenal hemorrhage or pituitary apoplexy. Both chronic primary and chronic secondary adrenal insufficiency lead to glucocorticoid deficiency and occasionally androgen deficiency (in women). The clinical features common to both primary and secondary adrenal insufficiency include hypotension, weakness, fatigue, anorexia, weight loss, nausea, and vomiting. Eosinophilia and normocytic anemia are common and occasionally one may see hypercalcemia. Hypoglycemia may be present particularly in children with primary adrenal insufficiency and in patients with secondary adrenal insufficiency in the context of panhypopituitarism when growth hormone is also missing. Chronic primary adrenal insufficiency may be accompanied by other autoimmune disorders (polyglandular failure), the most common being autoimmune thyroid disease (Grave’s or Hashimoto’s). Rarely, autoimmune hypoparathyroidism is present and such patients would be hypocalcemic. Two features distinguish primary and secondary adrenal insufficiency. First, mineralocorticoid deficiency is present in primary but absent in secondary (ACTH does not play a major role in regulation of aldosterone). For this reason, hyperkalemia is usually present in primary insufficiency but absent in secondary. Hyponatremia is a feature of both, but in primary insufficiency it is associated with volume contraction resulting in an elevated blood urea nitrogen (BUN) and creatinine. Hyponatremia in secondary adrenal insufficiency is dilutional because of decreased ability to excrete a water load and increased vasopressin levels. A second distinguishing feature is the high concentrations of ACTH and other propiomelanocortin (POMC)-derived peptides in primary insufficiency and the low or normal concentrations of these peptides in secondary insufficiency. This would typically lead to hyperpigmentation in primary insufficiency (from melanocyte-stimulating activity of POMC-derived peptides) and lack of hyperpigmentation, and occasionally pallor, in secondary insufficiency. Acute adrenal crisis is characterized by hypotension and shock, fever, confusion, nausea, and vomiting. In the setting of acute adrenal hemorrhage, many patients will also have abdominal, flank, or back pain. Pituitary apoplexy is usually associated with severe headache and frequently ophthalmoplegia. Laboratory abnormalities include azotemia and eosinophilia.

Primary adrenal insufficiency replacement therapy

Adrenal insufficiency is a clinical syndrome caused by insufficient secretion of hormones by the adrenal cortex, which is the result of a malfunction of one or more parts of the hypothalamic-pituitary-adrenal system [2]. Primary chronic adrenal insufficiency (1-CNI) develops as a result of the destruction of more than 90% of the cortex of both adrenal glands by a pathological process. The main causes of 1-CNN are currently autoimmune (80–85%) and tuberculosis (5–10%) destruction of the adrenal cortex [2, 3]. 1-CNN of the indicated etiology is better known as "Addison's disease." 1-CNN is a relatively rare disease (40-110 new cases per 1 million people per year) [2, 3], but it is of considerable importance in the practice of endocrinology. Without exception, all patients with a diagnosis of 1-chronic heart failure need lifelong replacement therapy with corticosteroids (CS), which will be discussed in this work.

Bone mineral density in patients with primary chronic adrenal insufficiency

Forty-four patients (11 men and 33 women) with primary chronic adrenal insufficiency (CAI) treated by substitute synthetic glucocorticoids (GC) prednisolone and dexamethasone and 9a-fluorohydrocortisone (cortineff) were examined in order to investigate the effects of various factors on changes in mineral compactness of bone tissue (MCB). In men the disease duration was 10.33±1.4 years, in women 11.64±3.49 years. Twenty (60%) women were postmenopausal, ten of these (50%) for more than ten years. None of these women was treated by estrogens. Bi-energy x-ray absorptiometry (BRA) of forearm bones was carried out in all 44 patients and quantitative computer-aided tomography (CAT) of L2, L3, and L4 vertebrae was carried out in 25 patients. Plasma levels of dihydroepiandrosterone sulfates (DEA-S) were measured; in men plasma testosterone was measured. A decrease of MCB to less than —1 SD by the T index was detected by BRA in 72.7±13.4 men and in only 42.4±8.6%o women, and by the Z index in 45.5±15.01 men and 33.3±8.2% women. CAT of the spine showed MCB decrease by the T index in 83.3±15.23% men and 63.15±11.07%o women and by the Z index in 16.7±15.23%o men and 26.3±10.1 women. Despite an appreciably high incidence of osteopenia and osteoporosis in men, the difference between men and women by these parameters is insignificant. Among women at least 80% osteopenias and osteoporosis occurred in postmenopausal women. In women with decreased MCB (Z&lt;—1) the duration of the postmenopause was significantly (p&lt;0.05) higher than in women with normal MCB. No significant differences in the disease duration, patients’ age, and plasma levels of DEA-S and testosterone between groups with normal and decreased MCB were observed in both men and women. Analysis of correlations of the results of both osteodensitometry methods showed a strong inverse correlation between MCB and duration of postmenopause. In four men CAT of the spine revealed a strong positive correlation between MCB and testosterone level. Hence, a characteristic feature of the osteopenic syndrome in patients with CAI treated by substitute synthetic GC is its increased incidence in men, compatible to that in women; the duration of postmenopause is a significant factor of risk of osteopenia in women with CAI.

Антитела к ферментам надпочечникового стероидогенеза и ферменту отщепления боковой цепи при хронической надпочечниковой недостаточности

The significance of circulating antibodies to adrenal steroidogenesis enzymes P450c21, P450cl7, and P450scc in the etiological diagnosis of primary chronic adrenal insufficiency (1-CAI) and autoimmune polyglandular syndromes (APS) was evaluated by immunoblotting with recombinant homologous enzymes. Sera from 54 patients were tested: from 6 patients with tuberculous 1-CAI, 23 with isolated autoimmune 1-CAI, 15 with 1-CAI within the framework of type 2 APS (APS-1), 6 with 1-CAI within the framework of type 1 APS (APS-1, candido-polyendocrine syndrome), 3 with A PS-2 without 1-CAI, and from 1 patient with autoimmune oophoritis. The above antibodies were not detected in patients with tuberculous 1-CAI and with APS-2 without 1-CAI, or in the patient with autoimmune oophoritis. Antibodies to P450c21 were detected in 17 out of 23 (74%)) patients with isolated autoimmune 1-CAI, 12 out of 15 (80%o) patients with APS-2, and in 5 out of 6 (83%) patients with APS-1. No antibodies to P450cl7 were detected in patients with isolated 1-CAI; these antibodies were detected in only 1 out of 15 (6.6%) patient with APS-2 and in 4 out of 6 (67%)) patients with APS-2. Antibodies to P450scc were detected in 4 out of 23 (17.4%o) patients with isolated 1-CAI, 1 patient with APS-2, and in 4 out of 6 (67%o) patients with APS-1. Analysis of the results for groups with autoimmune 1-CAI and APS-2 (38 patients) showed that in the subgroup with 1-CAI lasting less than 15 years antibodies to P450c21 were detected in 86.2+6.4% cases, while in patients with 1-CAI duration of 15years or longer they were detected in 44.4±16.56%o cases (t=2.35; p<0.05). Hence, testing of antibodies to P450c21 is a valuable instrument for the etiological diagnosis of 1-CAI, specifically, for the differential diagnosis of autoimmune and tuberculous 1-CAI.

Etiological and clinical structure of primary chronic adrenal insufficiency: retrospective analysis of 426 cases

A retrospective analysis of case histories of 426 patients with primary chronic adrenal insufficiency (1-AI), followed up at Endocrinology Research Center, Russian Academy of Medical Sciences, and/or Endocrinology Clinic of I. M. Setchenov Moscow Medical Academy in 1954-1977, was carried out in order to assess the etiological and clinical structure of this disease. The idiopathic form of Addison 's disease prevailed over its tuberculous form (70 and 30%), respectively); dynamic assessment of morbidity over the above period showed a progressive predominance of the idiopathic form. 1-AI is more than 2 times more incident in women, and the incidence of the disease in women vs. men is ever growing. There are at least 2.5 times more women than men among patients with idiopathic Addison's disease, while for the tuberculous form the ratio is 1:1. The mean age of 1-AI manifestation is 34.3 ± 0.46 years. The peak of clinical manifestation of idiopathic Addison's disease occurs between 20 and 40 years (at the age of 32.8 years on average), while for the tuberculous form this age is 30-50 years (37.4), which indicates a later manifestation of this form (p &lt; 0.01). In 28%) cases idiopathic Addison's disease coursed in the presence of autoimmune polyglandular syndromes (APS): type 1 in 3%o and type II in 25% cases. Dynamic assessment of the ratio of the incidence of 1-AI alone to that in the presence of APS showed that from the thirties to the fifties, idiopathic Addison's disease was a component of APS in 13 % cases and by the eighties and nineties this values increased to 34%), which permits a conclusion about pathomorphism of 1-AI, consisting in gradual transfer of this disease into APS. Many patients with 1-AI develop concomitant autoimmune diseases; analysis of family history of such patients reveals autoimmune diseases in close relatives in many cases, while the majority of patients with the tuberculous form of Addison 5 disease have a family history of tuberculosis.