ACTH (Adrenocorticotropic Hormone), Cushing’s Syndrome
- The Patient’s plasma is needed.
- Place blood immediately in ice water and freeze plasma in 15 min.
- The sample should be collected in a prechilled plastic test tube with EDTA or heparin.
- For the diagnosis of Cushing’s syndrome, the sample should be taken between 6 to 11 pm.
- Centrifuge the sample at 4 °C and store at -20 °C immediately within 15 minutes of collection.
- A stressful collection of the blood will raise the level.
- Avoid physical activity 10 to 12 hours prior to taking the sample.
- Stop medication like corticosteroids 48 hours before this test.
- Collect the sample in a chilled plastic vial with EDTA or Heparin.
- ACTH is very labile and requires antiprotease in the collecting vial.
- In the routine, the ACTH level is not measured because it degrades in the plasma.
- Put the patient on a low carbohydrate diet.
Purpose of the test (Indications)
- This hormone is estimated in various conditions like Adrenal insufficiency, in Cushing’s syndrome and Acromegaly, etc.
- For the diagnosis of Addison’s disease (level is>1000 pg /ml).
- Its level decreases in Secondary Adrenocortical Insufficiency, Adrenal carcinoma, and adenoma.
- This is the test of the anterior pituitary gland.
- Adrenocortical hormone (ACTH) is produced by the anterior pituitary lobe.
- ACTH is a 39 amino acid peptide hormone secreted by the anterior pituitary gland.
- The anterior pituitary gland is considered as the master gland due to many hormones secreted by this gland.
- The hormones secreted are TSH (Thyrotropin), ACTH, reproductive hormones like FSH, and LH and many others.
- The anterior hormones are produced in a pulsatile pattern.
- Anterior pituitary hormones are either tropic means their action is specific for another endocrine gland or are direct effectors because they act directly on the peripheral tissue.
- Corticotropin-releasing-hormone (CRH) is made and released from the hypothalamus and gives rise to the release of ACTH from the pituitary glands.
- CRH stimulates ACTH production in the anterior pituitary gland.
- Now ACTH sends signals to the adrenal gland (cortex) which secretes steroids (cortisol, androgen, and aldosterone).
- The rising level of cortisol acts as a negative feedback mechanism and stop the production of CRH and ACTH.
- There are two peaks:
- ACTH is released in a burst so its level can vary from minute to minute.
- Highest between 6 to 8 AM.
- The lowest level between 9 to 10 PM.
- During sleep is the normal level.
- Pregnancy, menstrual cycle, and stress increase the secretion.
- ACTH is released in response to many stresses.
- ACTH is advised for investigating disorders of the hypothalamic, pituitary, and renal system.
- ACTH is secreted by the anterior pituitary gland that signals the adrenal gland to produce steroids (androgens, cortisol, and aldosterone). These are needed for the normal functioning of the body.
- With adrenal insufficiency, the pituitary gland release proopiomelanocortin and ACTH are increased.
- ACTH is unstable in the blood. Most commercial RIA kits are insensitive and nonspecific to measure ACTH.
- 6 to 8 a.m = < 80 pg / mL or <18 pmol /L (SI units).
- 6 to 11 p.m = < 50 pg /mL or <11 pmol /L (SI units).
- or less than 120 pg/ml
Another reference gives the following values:
- 8 AM ( unrestricted activity) = <120 pg/mL
- 4 to 8 PM <85 pg/mL
- Cord blood = 50 to 570 pg/mL
- Newborn = 10 to 185 pg/mL
- Cushing’s syndrome is named after the name of Dr. Harvey Cushing who was the surgeon.
- Causes of Cushing’s syndrome:
- As a result of treatment with corticosteroids, this is the nonadrenal cause.
- Secondary to a benign hormone-secreting pituitary adenoma. These are ACTH secreting adenomas (68%).
- Cortisol production from the adrenal tumors or nodules (17%).
- Excess ACTH ectopic production (15%). Mostly there are malignant tumors.
- Chronic alcoholism, stress, and obesity.
- Clinical presentation:
- This may be a form of Hyperadrenalism or Hypercortisolism with common clinical presentations.
- These patients have similarities like diabetes mellitus type1 (insulin resistant).
- There are 4 times increased mortality even after successful treatment.
- Patients have cardiovascular diseases. There is left ventricular hypertrophy.
- There are changes in the ECG and nocturnal hypotension.
- Blood pressure changes were seen in 85 to 90%.
- Central obesity is seen in 90%.
- Glucose intolerance is seen in 80%.
- Hirsutism is seen in 65%.
- There are abnormal menses by 60%.
- There may be muscle weakness in 60%.
- Untreated cases have a 50% mortality for 5 years.
- The abnormal Overnight Dexamethasone suppression test and 24 hours urinary cortisol test are diagnostic of Cushing’s Syndrome.
- Free urinary cortisol level (24 hours sample) is most sensitive, 95 to 100% and specificity of 98%.
- Random plasma cortisol level is of little value for the diagnosis of Cushing’s syndrome.
- There is a loss of diurnal rhythm because late-night values remain high.
- The ideal time for the collection of ACTH and cortisol are between 11.00 p.m and 12.00 a.m.
- A single midnight serum sample concentration >7.5 µg/dL is diagnostic of Cushing’s syndrome with a sensitivity of 90 to 96% and specificity of 100%.
- Saliva cortisol level at 11.00 p.m, when combined with 8.00 a.m salivary cortisol concentration after the 1 mg overnight dexamethasone suppression test, had sensitivity and specificity of 100%.
- Radiological work-up:
- Adrenal gland CT distinguishes the hyperplasia vs tumor.
- Adrenal MRI distinguishes the carcinoma.
- Pituitary CT diagnoses 85% of the microadenoma.
- CT scan finds the ectopic source of ACTH like bronchial adenoma, medullary thyroid carcinoma, and squamous cell carcinoma.
- When Cushing’s syndrome is due to Pituitary or ectopic source then the ACTH level is high.
- When the source is the Adrenal gland, the ACTH is low.
Table for differentiation of Cushing’s syndrome and Addison’s disease:
|Disease||ACTH value||Cortisol value|
|ACTH- producing Pituitary tumor||Raised||Raised|
|Ectopic ACTH (Lung cancer)||Raised||Raised|
|Adrenal gland failure ( Infarction, Haemorrhage)||Raised||Low|
|Congenital adrenal hyperplasia||Raised||Low|
Increased ACTH level is seen in:
- Addison disease (primary adrenal insufficiency).
- Ectopic ACTH syndrome.
- Cushing’s syndrome. This is dependent upon the adrenal hyperplasia due to the pituitary gland.
Decreased ACTH level is seen in:
- Secondary adrenal insufficiency is due to pituitary insufficiency.
- Adrenal adenoma or cancer.
- Exogenous steroid administration.
Test value for the Layman:
- This test is advised if the patient has diabetes mellitus, reduced glucose tolerance, and muscle wasting to rule out Cushing syndrome.
- If there are truncal obesity and thin extremity.
- In case of abnormal lipid metabolism.