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Sample

  1. The Patient’s plasma is needed. 
    1. Place blood immediately in ice water and freeze plasma in 15 min.
  2. The sample should be collected in a prechilled plastic test tube with EDTA or heparin.
  3. For the diagnosis of Cushing's syndrome, the sample should be taken between 6 to 11 pm.
  4. Centrifuge the sample at 4 °C and store at -20 °C immediately within 15 minutes of collection.

Precaution

  1. A stressful collection of the blood will raise the level.
  2. Avoid physical activity 10 to 12 hours prior to taking the sample.
  3. Stop medication like corticosteroids 48 hours before this test.
  4. Collect the sample in a chilled plastic vial with EDTA or Heparin.
  5. ACTH is very labile and requires antiprotease in the collecting vial.
  6. In the routine, the ACTH level is not measured because it degrades in the plasma.
  7. Put the patient on a low carbohydrate diet.

Purpose of the test (Indications)

  1. This hormone is estimated in various conditions like Adrenal insufficiency, in Cushing's syndrome and Acromegaly etc.
  2. For the diagnosis of Addison’s disease (level is>1000 pg /ml).
  3. Its level decreases in Secondary Adrenocortical Insufficiency, Adrenal carcinoma, and adenoma.
  4. This is the test of the anterior pituitary gland.

Pathophysiology

  1. Adrenocortical hormone (ACTH) is produced by the anterior pituitary lobe.
    1. ACTH is 39 amino acid peptide hormone secreted by the anterior pituitary gland.
    2. The anterior pituitary gland is considered as the master gland due to many hormones secreted by this gland.
      1. The hormones secreted are TSH (Thyrotropin), ACTH, reproductive hormones like FSH, and LH and many others.
    3. The anterior hormones are produced in a pulsatile pattern.
    4. 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.

  1. Corticotropin-releasing-hormone (CRH) is made and released from the hypothalamus and give rise to release of ACTH from the pituitary glands.
    1. CRH stimulates ACTH production in the anterior pituitary gland.
    2. Now ACTH sends signals to the adrenal gland (cortex) which secretes steroids (cortisol, androgen, and aldosterone).     
    3.  The rising level of cortisol acts as a negative feedback mechanism and stop production of CRH and ACTH.                                                                                                       

  1. There are two peaks:
    1. ACTH is released in a burst so its level can vary from minute to minute.
    1. Highest between 6 to 8 AM.
    2. The lowest level between 9 to 10 PM.
    3. During sleep is the normal level.
  2. Pregnancy, menstrual cycle and stress increase the secretion.
    1. ACTH is released in response to many stresses.
  3. ACTH is advised for investigating disorders of the hypothalamic, pituitary and renal system.
  4. 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.
  5. With adrenal insufficiency, the pituitary gland release proopiomelanocortin and ACTH are increased.
  6. ACTH is unstable in the blood. Most commercial RIA kits are insensitive and nonspecific to measure ACTH.

Normal ACTH

Source 2

Another reference gives the following values:

Cushing’s Syndrome

  1. Cushing's syndrome is named after the name of Dr. Harvey Cushing who was the surgeon.
  2. Causes of Cushing's syndrome:
    1. As a result of treatment with corticosteroids, this is the nonadrenal cause.
    2. Secondary to a benign hormone-secreting pituitary adenoma. These are ACTH secreting adenomas (68%).
      1. Cortisol production from the adrenal tumors or nodules (17%).
      2. Excess ACTH ectopic production (15%). Mostly there are malignant tumors.
    3. Chronic alcoholism, stress, and obesity.
  3. Clinical presentation:
    1. This may be a form of Hyperadrenalism or Hypercortisolism with common clinical presentations.
    2. These patients have similarity like diabetes mellitus  type1 (insulin resistant).
    3. There are 4 times increased mortality even after successful treatment.
    4. Patients have cardiovascular diseases. There is left ventricular hypertrophy. 
      1. There are changes in the ECG and nocturnal hypotension.
      2. Blood pressure changes were seen in 85 to 90%.
      3. Central obesity is seen in 90%.
      4. Glucose intolerance is seen in 80%.
      5. Hirsutism is seen in 65%.
      6. There are abnormal menses in 60%.
      7. There may be muscle weakness in 60%.
    5. Untreated cases have 50% mortality for 5 years.
  4. Diagnosis:
    1. The abnormal Overnight Dexamethasone suppression test and 24 hours urinary cortisol test are diagnostic of Cushing’s Syndrome.
    2. Free urinary cortisol level (24 hours sample) is most sensitive,  95 to 100% and specificity of 98%.
      1. Random plasma cortisol level is of little value for the diagnosis of Cushing's syndrome.
      2. There is a loss of diurnal rhythm because late night values remain high.
        1. The ideal time for the collection of ACTH and cortisol is between 11.00 p.m and 12.00 a.m.
        2. 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%. 
      3. 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%.
    3. Radiological work-up:
      1. Adrenal gland CT distinguishes the hyperplasia vs tumor.
      2. Adrenal MRI distinguishes the carcinoma.
      3. Pituitary CT diagnoses 85% of the microadenoma.
      4. CT scan finds the ectopic source of ACTH like bronchial adenoma, medullary thyroid carcinoma, and squamous cell carcinoma.
    4. When Cushing’s syndrome is due to Pituitary or ectopic source then ACTH level is high.
    5. 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
Cushing’ syndrome Increased/low  Increased
Adrenal adenoma Low Raised
Adrenal cancer low Raised
ACTH- producing Pituitary tumor Raised Raised
Ectopic ACTH (Lung cancer) Raised Raised
Addison disease    
Adrenal gland failure ( Infarction, Haemorrhage) Raised Low
Congenital adrenal hyperplasia Raised Low
Hypopituitarism Low Low

Increased ACTH level is seen in:

  1. Addison disease (primary adrenal insufficiency).
  2. Ectopic ACTH syndrome.
  3. Cushing’s syndrome. This is dependent upon the adrenal hyperplasia due to the pituitary gland.
  4. Stress.

Decreased ACTH level is seen in:

  1. Hypopituitarism.
  2. Secondary adrenal insufficiency, this is due to pituitary insufficiency.
  3. Adrenal adenoma or cancer.
  4. Exogenous steroid administration.

Test value for the Layman:

  1. This test is advised if the patient has diabetes mellitus, reduced glucose tolerance, and muscle wasting to rule out Cushing syndrome.
  2. If there are truncal obesity and thin extremity.
  3. In case of abnormal lipid metabolism.

Possible References Used

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