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International journal of endocrinology 1 (73) 2016

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Subclinical Hypercorticism: the Necessity of Diagnostic Search

Authors: Kvacheniuk А.N. - Institute of Endocrinology and Metabolism named after V.P. Komisarenko of NAMS, Kyiv; Lutsenko L.А. - Kyiv Municipal Clinical Endocrinological Center, Kyiv, Ukraine

Categories: Endocrinology

Sections: Specialist manual

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Summary

С учетом определенных трудностей в диагностике субклинического гиперкортицизма целью данной работы было сфокусировать внимание врачей различных специальностей на необходимости тщательного обследования пациентов с патологическими состояниями, которые могут быть проявлениями синдрома Кушинга (артериальная гипертензия, ожирение, нарушения углеводного обмена, остеопороз). Инструментом для раннего выявления субклинического гиперкортицизма является лабораторная диагностика.

З урахуванням певних труднощів у діагностиці субклінічного гіперкортицизму метою даної роботи було сфокусувати увагу лікарів різних спеціальностей на необхідності ретельного обстеження пацієнтів із патологічними станами, що можуть бути проявами синдрому Кушинга (артеріальна гіпертензія, ожиріння, порушення вуглеводного обміну, остеопороз). Інструментом для раннього виявлення субклінічного гіперкортицизму є лабораторна діагностика.

Considering certain difficulties in subclinical hypercorticism diagnosis, the object of this work is to focus attention of doctors in different areas on the necessity of thorough examination of patients with pathological conditions that may be the manifestation of Cushing’s syndrome (arterial hypertension, obesity, impaired carbohydrate metabolism and osteoporosis). The laboratory diagnosis is the instrument for early subclinical hypercorticism detection.


Keywords

гиперкортицизм, ожирение, сахарный диабет, артериальная гипертензия, кортизол слюны.

гіперкортицизм, ожиріння, цукровий діабет, артеріальна гіпертензія, кортизол слини.

hypercorticism, obesity, diabetes mellitus, arterial hypertension, saliva cortisol.

Recently doctors have paid more and more attention to the problem of early diagnosis of subclinical forms of endocrinological diseases. One of such problems is early diagnosis of subclinical Cushing syndrome (CS).

Cushing syndrome means a clinical syndrome caused by lasting glucocorticoids hypersecretion. Clinical manifestation of hypercorticism syndrome results from the presence of glucocorticoids receptors in different target-organs. It includes numerous symptoms which can be divided into specific ones and less specific ones. Specific symptoms include definitive changes in skin (red and violet striae, dryness, petechial and widespread hemorrhages and folliculitis), proximal myopathy and plethora. But according to the range of publications one should consider the possibility of hypercorticism presence without specific clinical symptoms. At least two thirds of patients with CS have osteoporosis and the manifestations of metabolic syndrome. The prevalence rate of subclinical hypercorticism among patients with arterial hypertension is 0.5-2%. The detection and elimination of hypercorticism as a causative factor of arterial hypertension result, as a rule, in the decrease in arterial tension of 75% of patients after several weeks or a year. According to different researches the prevalence rate of CS among the patients with uncontrolled diabetes is 1-9.4%. Patients have “cushingoid” type of diabetes being formed. However, in case of subclinical hypercorticism there may be the absence of the specific body fat distribution. According to different researchers the prevalence rate of subclinical hypercorticism among patients with obesity may be 8.7%. The osteoporosis intensity in case of CS depends on the hypercorticism duration and often (in 25-50% of patients) comes with pathological fractures (as a rule, compression) of vertebral bodies. According to I. Chiodini and his co-authors’ research 10.8% of patients with symptom-free vertebral fractures are diagnosed with subclinical CS.

The detection of the states mentioned above shall determine diagnostic focus of the doctor in any area. Diabetes mellitus of the second type and other carbohydrate metabolism disorder, arterial hypertension, obesity and osteoporosis may be the consequences of the chronic little cortisol surplus, however, the connection between these states and subclinical cortisol hypersecretion is not expressly proven [19]. The intensity of clinical symptoms is likely to be connected with the intensity of cortisol hypersecretion [20].

Thus, arterial hypertension, osteoporosis, obesity and carbohydrate metabolism disorder should be the most alarming symptoms as for the excluding subclinical hypercorticism. Multidisciplinary approach, i.e. the participation of the specialists in different areas, is necessary for early hypercorticism diagnosis.

Laboratory diagnosis becomes primary in the diagnosis of subclinical CS.

In accordance with the international recommendations “The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline” 1-mg dexamethasone suppressive test, the detection of daily excretion of cortisol with urine and night detection of cortisol in saliva are used for the CS diagnosis.

Night suppressive test with 1-mg dexamethasone is based on the suppression of ACTH with the subsequent decrease in cortisol secretion. The ambulatory conducting of this examination is possible without patient needing preliminary preparation. The level of cortisol in blood less than 1.8 mcg/dl (50nmol/l) allows excluding patient’s hypercorticism. Sensitivity and specificity of 1-mg dexamethasone suppressive probe using minimum limit for cortisol of 1.8 mcg/dl (50 nmol/l) are 75-100% and 72-82% accordingly. The detection of cortisol in daily urine also has rather high sensitivity and specificity. Considering the possibility of the result of cortisol within referential values in 9% of patients in case of a single examination of daily urine, such examination should be conducted twice.

The night detection of cortisol in saliva that reflects the concentration of free (not connected with proteins) and excludes the impact of circadian rhythm of cortisol on the result is the most valuable test for hypercorticism detection. The amount of cortisol in saliva does not depend on the saliva volume and is thermally stable at indoor temperature. The advantages of the detection of cortisol in saliva include: painlessness and noninvasiveness of the methodology, the absence of necessity of hospitalization, participation of middle medical staff and pharmacological interference.

Thus, considering the possibility of the subclinical CS diagnosis as causative factor in patients with widespread in the population arterial hypertension, obesity, carbohydrate metabolism disorder and osteoporosis, such patients are subject to examination for cortisol hypersecretion detection. Modern laboratory researches (saliva cortisol, daily urine cortisol) unveil the opportunities for early subclinical CS diagnosis before the development of symptomatic clinical picture.


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1.      Melmed S. Williams textbook of endocrinology. – 12th ed./S.Melmed [et al]. Philadelphia, 2012. 1920 р.

2.      Findling JW, Raff H. Screening and diagnosis of Cushing’s syndrome. Endocrinol. Metab. Clin. North Am. 2005.;34:385-402.

3.      Nieman L. Cushing’s syndrome: update on signs, symptoms and biochemical screening. Eur. J. Endocrinol. 2015; 173:33-38, doi: 10.1530/EJE-15-0464.

4.      Chanson P, Salenave S. Metabolic syndrome in Cushing’s syndrome. Neuroendocrinology. 2010; 92(suppl 1): 96-101.

5.      Anderson G, Blakeman N, Streeten DH.. The effect of age on prevalence of secondary forms of hypertension in 4,429 consecutively referred patients. J. Hypertens. 1994;12: 609-615.

6.      Omura M. Prospective study on the prevalence of secondary hypertension among hypertensive patients visiting a general outpatient clinic in Japan. Hypertens. Res. 2004; 27: 193-202.

7.      Faggiano A. Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission. J. Clin. Endocrinol. Metab. 2003; 88: 2527-2533.

8.      Fallo F. Effect of surgical treatment on hypertension in Cushing’s syndrome. Am. J.Hypertens. 1996; 9: 77-80.

9.      Giordano R. Metabolic and cardiovascular outcomes in patients with Cushing’s syndrome of different etiologies during active disease and 1 year after remission. Clin. Endocrinol. (Oxf). 2011; 75: 354-360.

10.  Catargi B. Occult Cushing’s syndrome in type-2 diabetes. J. Clin. Endocrinol. Metab. 2003; 88: 5808-5813.

11.  Reimondo G. Screening of Cushing’s syndrome in adult patients with newly diagnosed diabetes mellitus. Clin Endocrinol (Oxf). 2007; 67: 225-229.

12.  Chiodini I. Association of subclinical hypercortisolism with type 2 diabetes mellitus: a case-control study in hospitalized patients. Eur. J. Endocrinol. 2005; 153: 837-844.

13.   Praveen EP. Morning cortisol is lower in obese individuals with normal glucose tolerance. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2011; 4: 347-352.

14.  Basu R. Obesity and Type 2 Diabetes Do Not Alter Splanchnic Cortisol Production in Humans. J. Clin. Endocrinol. Metab. 2005; 90: 3919-3926.

15.  Ness-Abramof R. Overnight dexamethasone suppression test: a reliable screen for Cushing’s syndrome in the obese. Obes. Res. 2002; 10: 1217-1221.

16.  Tiryakioglu O. Screening for Cushing’s syndrome in obese patients. Clinics (Sao Paulo). 2010; 65: 9-13.

17.  Otdalennyie rezultatyi hirurgicheskogo lecheniya sindroma Kushinga, obuslovlennogo kortikosteromoy // Materialyi 9-go (11-go) Ros.simpoziuma po hirurgicheskoy endokrinologii [«Sovremennyie aspektyi hirurgicheskoy endokrinologii»] – Chelyabinsk, 2000. – S. 180 – 185.

18.  Chiodini I. Subclinical hypercortisolism among outpatients referred for osteoporosis. Ann. Intern. Med. 2007; 147: 541-548.

19.  Zografos GN, Perysinakis I, Vassilatou E. Subclinical Cushing's syndrome: current concepts and trends. Hormones (Athens). 2014;13 (3): 323-337.

20.  Gatta B. Reevaluation of the combined dexamethasone suppression-corticotropin-releasing hormone test for differentiation of mild Cushing’s disease from pseudoCushing’s syndrome. J. Clin. Endocrinol. Metab. 2007; 92(11): 4290-4293.

21.  Nieman LK. The Diagnosis of Cushing's syndrome: аn endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 2008; 93: 1526-1540.

22.  Terzolo M, Pia A, Reimondo G. Subclinical Cushing’s syndrome: definition and management. Clinical Endocrinology. 2012; 76:12-18.

23.  Zeiger MA. American association of clinical endocrinologists and American association of endocrine surgeons medical guidelines for the management of adrenal incidentaloma. Endocrine practice. 2009;15: 1-20.

24.   Ob'emnyie obrazovaniya nadpochechnikov (diagnostika i differentsialnaya diagnostika): metodicheskie rekomendatsii dlya vrachey, okazyivayuschih spetsializirovannuyu meditsinskuyu pomosch / E. A. Troshina [i dr.]. Pod red. I. I. Dedova, G. A. Melnichenko // Consilium Medicum. 2009; 11, # 12. – S. 76-94.

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