Congenital Adrenal Hyperplasia
decrease aldosterone & cortisol
excess testosterone & DHEA-S
failure to produce all adrenal cortex hormone
Conn’s syndrome/ Aldosteronism
Excess epinephrine & norepinephrine.
General concept for investigation:
1) Establish whether it’s hyper/hyposecretion
Use screening tests :
- Short synacthen (synthetic analogue of ACTH)
- dexamethasone suppression (synthetic analogue of cortisol)
2) Establish the cause of the dysfunction
Use secondary tests :
- ACTH measurement
- long synacthen
- high dose dexamethason
- Na+ increase
- K+ decrease
- Cortisol increase
- Testosterone, andostenedione, DHEA-S increase
- ACTH (may be undetectable / very high – cushing’s disease)
1) Screening test
a. Low-Dose Dexamethasone test
Dexamethasone is a synthetic analogue of cortisol. In normal healthy patient, it inhibits ACTH release by the pituitary (not ectopic) & hence suppresses adrenal cortisol secretion.
However, a patient with Cushing’s, do not usually show cortisol suppression with low doses of dexamethasone. So, over a low dose of dexamethasone given over 2 days, these patients show no suppression of the 24 hours urinary excretion of 17-hydroxycorticosteroids (17-OHCS, breakdown of steroid hormone) and urinary free cortisol.
If there is no suppression, then continue on with a high-dose dexamethasone test.
b. High-Dose Dexamethasone test
This test is done only if there is no suppression of cortisol in low-dose dexamethasone test.
- A high dose of dexamethasone is given over 2 days/as a single bedtime dose. 24-hour urine samples collected before and after dexamethasone dosage given. Measure urinary 17-OHCS & free cortisol. Determine whether there is cortisol suppression.
- A basal lood sample is obtained to detect ACTH level.
- If low dose dexamethasone show suppression
- If low dose & high dose no change (Prob not with pituitary gland)
- Ectopic ACTH suppression (High ACTH level)
- Adrenal adenoma (Normal ACTH level)
- If low dose no change, but high dose suppression (Prob with hyperfunctioning pituitary gland)
- Pituitary Adenoma
- Cushing’s Disease
c. Other laboratory findings
- Slightly increased hemoglobin & hematocrit
- Decreased total lymphocytes, monocytes & eosinophil counts (move out of the circulation into the bone marrow, spleen & lymph nodes)
- Hypokalemia (in ectopic ACTH & adrenocortical carcinoma with increase in cortisol. K+ loss is due to increased GFR and incrased protein catabolism with loss of intracellular K+)
- Increased body pH & HCO3- (metabolic alkalosis)
- Hyperglycemia, glycosuria & decreased GTT (increase gluconeogenesis and decrease glucose uptake)
- Increased urine Ca2+ (decrease renal reabsorption of Ca2+)
Congenital Adrenal Hyperplasia
- Low aldosterone & cortisol
- High testosterone & DHEA-S
- Low glucocorticoid, mineralocorticoid & androgen
1) Diagnostic Tests
a. Estimation of serum electrolyte profile
- Determine serum Na+, K+
- Determine blood markers related to electrolyte balance (eg aldosterone,AVP)
Patient with primary addison’s disease will show low Na+ and elevated K+.
This is due to decreased level of aldosterone production, hence Na+ will not be able to be reabsorbed, and K+ will remain high in the serum.
b. ACTH stimulation test
This is to check whether pituitary gland responds to ACTH.
The test is done first time in the morning when normal cortisol levels are usually highest. Blood is withdrawn from patient to establish a baseline (before given ACTH). Then the patient is given ACTH (Cortrosyn, Cosyntropin, Synacthen) by injection. Blood is drawn 30 minutes later and cortisol level is determined.
If the value is doubled, then the pituitary gland responds to ACTH. If it doesn’t, then the patient does not respond to ACTH and hence have primary addison’s disease, defect is at the adrenal gland itself.
Establish primary/secondary Addisonism
If the short ACTH test (ACTH stimulation test) is abnormal, indicating that the patient has Addison’s disease. Then a long ACTH test to differentiate whether it’s a primary/secondary Addison’s disease.
The patient is given synthetic ACTH (Synacthen) by injection. After 30 mins, 1 hour, 2 hour, 4 hour, 7 hour and 24 hour, plasma cortisol will be measured.
- If plasma cortisol fails to rise
- Primary addisonism
Abnormality due to:
-Destruction of enzymatic (biocatalytic) machinery of the adrenal glands
-Lack of response to ACTH
-no production of cortisol & other adrenal steroids
- If a delayed rise of plasma cortisol is observed
- Secondary addisonism
Abnormality due to:
-No/Low ACTH production by anterior pituitary
-“Functional adrenal cortical atrophy” due to prolonged absence of normal ACTH secretion
-No hyperpigmentation (as seen in primary addisonism) because it is the ACTH that causes the hyperpigmentation, NOT CORTISOL.
c. Insulin Stimulation Test
- Determine whether the pituitary gland can produce ACTH in response to insulin stimulus (hypoglycemia will cause rise in ACTH production)
- Determine the integrity of the messenger pituitary between the hypothalamus, pituitary & adrenal gland.
Upon administration of high dose of insulin, the patient’s blood sugar will be converted to glycogen, and hence will drive the patient into hypoglycemia. Hypoglycemia will stimulate production of ACTH from the anterior pituitary.
Care must be taken to avoid INSULIN SHOCK.
Insulin is injected until the blood glucose level falls below 2.2mmol/L. Then blood is drawn at intervals and serum cortisol will be measured.
- Normal result: increase in cortisol production
- Abnormal result: No/little rise in cortisol production
- Secondary addison’s disease (ACTH production is not stimulated by hypoglycemia, subsequently cortisol will not be produced). Hypothalamic-pituitary-adrenal axis impairment.
d. The overnight Metyrapone test
- An alternative to the insulin stimulation test
- Determine if the pituitary is making ACTH in response to a stimulus
Metyrapone is a drug that blocks the last step of the synthesis of cortisol in the adrenal gland.
The patient will be given metyropone at midnight without food. Blood is then drawn at 8am upon waking up and the levels of cortisol & 11-deoxycortisol (intermediate of cortisol) are measured.
- Normal result:
- Cortisol level decrease
- 11-deoxycortisol level increase
- Abnormal result: Hypothalamic-pitutiary-adrenal axis impairment
- 11-deoxycortisol level no increase
**ALERT: This test can drive a patient into adrenal crisis.
e. CRH Stimulation test
- Determine whether CRH is being produced by the hypothalamus & stimulate the pituitary to make ACTH & hence cortisol by adrenal cortex.
CRH is given to patient by injection & blood is drawn to determine cortisol level.
- ACTH increase but Cortisol remain the same
- Primary Addisonism
- ACTH remain the same
- Secondary Addisonism
- Delayed ACTH response
- Tertiery Addisonism (Pituitary atrophy due to deprived CRH stimulation, not produced by hypothalamus)
- Hyperplastic Adrenal gland
- Aldosterone producing adenoma
- Increase urine/serum aldosterone
- Increase urine K+
- Increase plasma aldosterone:renin ratio
- Increase renin-angiotensin system
- Uninhibited secreteion of aldosterone vs saline infusion
- Fludrocortisone acetate (synthetic mineralocorticoid) suppression test
a. Primary aldosteronism
- Low plasma renin
Problem is with the adrenal gland because aldosterone is secreted without the stimulation of renin.
b. Secondary aldosteronism
- Normal/High plasma renin
Renin causes increase in aldosterone secretion.
c. Other lab findings
- Increased urine K+
- Aldosterone will cause reabsorption of Na+ into the blood, hence Na/K pump will cause K+ to be pumped into the tubules instead. Excess K+ will then be excreted into the urine. Hence, body will experience hypokalemia.
- Decrease plasma K+ (can be normal plasma K+ level as well)
Therefore, in patients with increased aldosterone level, patient will be given increased Na+ intake. Na+ will be constantly reabsorbed, and excess K+ will be excessively excreted. Therefore, there will be excessive K+ in urine, and a significant fall in plasma K+.
K+ depletion will be accompanied by H+ loss (secreted by DCT) as a compensatory mechanism, therefore serum ph will be increased (alkaline) and C02 content will also be increased. The patient will be in metabolic alkalosis. (why?)
- Increase in Epinephrine & Norepinephrine.
- Increase 24 hour urine metanephrines:Creatinine ratio
- Increase in vanillylmandelic acid (VMA)
- Increase in homovanillic acid (HVA)
- Increase in serum NE
- Clonidine HCI does not suppress NE (normally supresses)
- Hyperglycemia, Glycosuria, Overt Diabetes Mellitus, Increased gluconeogenesis, Decreased insulin secretion
Read more on secretions of the adrenal medulla to understand more about it’s actions. Catecholamines will increase glucose production & does not store it as glycogen.
Conditions related with increased Metanephines:
- Extreme stress
- Patients being treated with Rauwolfia Alkaloids/ Methyldopa/ Catecholamines
- Ingestion of foods containing vanilla
- Renal insufficiency (less creatinine in urine, more metanephrine)
Antihypertensives (methlydopa) & other drugs that may produce fluorescence (eg tetracycline & quinine) may give FALSE +VE results.
Clonidine HCI: Inhibitor of NE
——–> For summarised table: Read Prof Chu Wan Loy’s lecture.