Measurement of blood cortisol levels (cortisolemia) can be helpful in diagnosing conditions of excess cortisol (high cortisol or hypercortisolism) and cortisol deficiency (low cortisol or hypocortisolism). It is important to underline that the dosage of cortisolemia is indicated only in patients in whom the probability of the presence of excess or deficiency of cortisol is increased on the basis of the clinical picture.
Cortisol normal values
THE values of normality of cortisolemia follow a circadian rhythm. In fact, although they can vary from laboratory to laboratory, they are generally between 5 µg / dL and 25 µg / dL (50-250 ng / mL) in the morning, gradually decrease during the day with a small increase in correspondence with meals and are lower at 4.5 µg / dL (45 ng / mL) in the late evening (11.00 pm-midnight).
High cortisol: the dosage of cortisolemia in hypercortisolism
First it is important to remember how blood levels increased by cortisol, which have no pathological significance as such, are present in some physiological conditions such as pregnancy and pathological conditions such as diabetes mellitus, severe obesity, some psychiatric pathologies (e.g. depression), alcoholism, severe psychophysical stress (e.g. strenuous exercise, hospitalization, chronic pain), malnutrition, eating disorders and the use of estrogen.
Therefore, according to the international literature, the indication for the determination of cortisol levels according to the methods indicated below is present in:
- Patients with specific signs and symptoms excess cortisol (red streaks, easy bruising, thin skin, plethoric facies, muscle hypotrophy, hypertrichosis and reduced growth rate in children)
- Patients even without specific symptoms but with suggestive chronic complications (arterial hypertension or diabetes mellitus in the absence of poorly treatable risk and familiarity factors, osteoporosis and / or fragility fractures that cannot be explained on the basis of the patient's characteristics)
- Patients with adrenal or pituitary adenoma of accidental finding (incidentaloma) during radiological examinations carried out for other pathologies.
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It is important to remember that the basal cortisol dosage in the morning has little significance in the suspicion of an excess of cortisol. In fact, as mentioned above, in some subjects cortisolemia can be elevated without representing a pathological state as such.
The test normally used in the screening of hypercortisolism is instead the cortisol dosage in the morning at 08.00-09.00 after taking 1 mg of dexamethasone at 23.00 the previous evening (night suppression test with 1 mg of dexamethasone). This examination has no contraindications or side effects and can be performed on an outpatient basis. In the presence of cortisol levels after night suppression testing with 1 mg dexamethasone equal to or greater than 1.8 µg / dL, the likelihood of hypercortisolism is high (specificity approximately 80%), particularly in subjects with specific clinical symptoms and / or signs of excess cortisol, while in the presence of cortisol levels after night suppression tests with 1 mg dexamethasone below 1.8 µg / dL the probability of hypercortisolism is very low (sensitivity 95%).
As can be seen, therefore, there is about a 20% of subjects who are false positives to this test and a 5% of subjects who are false negatives.
There are some medications (such as phenobarbital, carbamazepine, phenytoin and rifampicin) which can induce an acceleration hepatic metabolism of dexamethasone and thus determine false positives on the test, while others which can induce a slowdown hepatic metabolism (such as fluoxetine, diltiazem and cimetidine) and thus cause false negative test results. For a complete list of drugs that can interfere with cortisol dosage after dexamethasone suppression, please visit http://medicine.iupui.edu/flockhart/table).
Consequently, in the presence of non-suppression of cortisolemia after night suppression test with 1 mg dexamethasone, it is generally necessary to repeat the test eliminating possible interfering factors. To confirm the diagnosis, in some types of patients in whom a state of functional hypercortisolism is suspected (patients with diabetes mellitus, severe obesity, psychiatric pathologies, alcoholism, severe psychophysical stress) it is necessary to carry out the determination of cortisol levels at 09.00 after taking 0.5 mg of dexamethasone every 6 hours in the previous 2 days (8 tablets in total, starting at 09.00 on the first day).
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Conversely, in patients with mild organic hypercortisolism (e.g. with adrenal adenomas with mild cortisol excess) or in some rare forms of cyclic hypercortisolism, cortisolemia after night suppression testing with 1 mg dexamethasone may be borderline or normal . In these cases the first sign of cortisol hypersecretion is the loss of the circadian rhythm. In these forms, therefore, thereference test is cortisol at 23-24. In the presence of blood cortisol levels at 23-24 hours greater than 8 µg / dL (80 ng / mL) hypercortisolism is almost certain (specificity 96%). This method of determining cortisolemia is however difficult and impractical because it requires the patient to be hospitalized.
Once the diagnosis of hypercortisolism has been made, second-level biochemical tests will be performed to determine its adrenal, pituitary or ectopic origin (adrenocorticotropic hormone, ACTH, basal and post stimulus dosage and cortisolemia dosage after night suppression test with 8 mg of dexamethasone ) and radiological (CT scan of the abdomen, pituitary NMR, catheterization of the petrosal sinuses).
Low cortisol: the dosage of cortisolemia in hypocortisolism
The determination of baseline cortisolemia in the suspicion of hypoadrenalism should be performed in subjects with symptoms and / or suggestive signs that cannot be otherwise explained as asthenia, fever, abdominal pain, hypotension, hyponatremia, hyperkalaemia, hypoglycemia and skin hyperpigmentation.
Normal values of cortisol in the morning do not absolutely exclude the presence of hypoadrenalism. Conversely, baseline morning cortisol levels below 5 µg / dL (50 ng / mL) in the presence of frankly elevated ACTH values are considered diagnostic for primary hypo adrenal, although American Society of Endocrinology guidelines always recommend confirmation. diagnostics by determining cortisol levels after stimulus test with ACTH 250 mcg. It should be considered that a cortisolemia lower than 14 μg / dL (140 ng / mL) in the presence of increased ACTH levels is strongly suggestive of hypoadrenalism.
The most used method to diagnose a picture of primary hypoadrenalism is the dosage of cortisolemia after stimulation with ACTH. In fact, cortisol values below 18 µg / dL at 30 or 60 minutes after an ACTH infusion are diagnostic of hypoadrenalism. It is important to remember that in patients with signs or symptoms strongly suggestive of hypoadrenalism and elevated ACTH values, the cortisol response after ACTH test, if normal, should be re-evaluated after a suitable period of time. Some patients with primary adrenal insufficiency of recent onset may in fact maintain a minimum secretory reserve of cortisol but sufficient to give a normal or borderline response to a first stimulus with ACTH (250 μg or 1 μg iv). In case of doubtful response to the ACTH test and, in particular, if associated with elevated ACTH levels, cortisol measurements after insulin hypoglycemia are required to detect the presence of adrenal insufficiency. This can also occur in patients with suspected central hypoadrenalism (due to a deficit of pituitary ACTH secretion), in which obviously the ACTH levels do not help in the diagnosis.
- Nieman LK et al. The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline Journal of Clinical Endocrinology and Metabolism 2008, 93: 1526–1540
- Bornstein SR et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline Journal of Clinical Endocrinology and Metabolism 2016, 101: 364–389
Author: Dr. Iacopo Chiodini, Head of the Diagnosis and Treatment of Endocrine Gland Diseases Service, UOC Endocrinology and Metabolic Diseases, IRCCS Cà Granda Foundation of Milan
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