ACTH deficiency arises as a result of decreased or absent production of adrenocorticotropic hormone (ACTH) by the pituitary gland. A decline in the concentration of ACTH in the blood leads to a reduction in the secretion of adrenal hormones, resulting in adrenal insufficiency (hypoadrenalism). Adrenal insufficiency leads to weight loss, lack of appetite (anorexia), weakness, nausea, vomiting, and low blood pressure (hypotension). Because these symptoms are so general, the diagnosis is sometimes delayed or missed entirely. For that reason, some clinicians believe the disorder to be more common than previously thought.
Adrenocorticotropic hormone (ACTH) deficiency (IAD) is a rare disorder that can cause severe hypoglycemia, convulsions, and prolonged cholestatic jaundice. A noncancerous (benign) tumor of the pituitary gland, located at the base of the brain, produces an excess amount of ACTH, which in turn stimulates the adrenal glands to make more cortisol. When this form of the syndrome develops, it’s called Cushing disease.
Adrenal insufficiency can be primary or secondary:
- Primary adrenal insufficiency. This is known as Addison’s disease. It occurs when the adrenal glands are damaged. They don’t make enough of the hormones cortisol and aldosterone. This condition is rare. It may occur at any age.
- Secondary adrenal insufficiency. This starts when the pituitary gland doesn’t make enough of the hormone ACTH (adrenocorticotropin). As a result, the adrenal glands don’t make enough cortisol.
Causes
The exact cause(s) of ACTH deficiency remains unknown. A defect in the brain’s hypothalamus or the pituitary gland may cause the deficiency. Also, there is a congenital (present at birth) form of ACTH deficiency that has been tracked to mutations of the T-box 19 (TBX19) gene (also referred to as TPIT) on the long arm of chromosome one (1q23-q24) and the corticotropin-releasing hormone (CRH) gene on the long arm of chromosome eight (8q13). The inheritance pattern is thought to be autosomal recessive.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, chromosome 1q23-q24 refers to a region on the long arm of chromosome 1 between bands 23 and 24. Similarly, chromosome 8q13 refers to the band numbered 13 on the long arm of chromosome 8. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Genetic diseases are determined by the combination of genes for a particular trait that is on the chromosomes received from the father and the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier of the disease, but usually will not show symptoms.
The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Diagnosis
When ACTH deficiency is suspected, blood samples are taken for analysis, especially of the level of cortisol in the blood. Cortisol is the name of one of the hormones produced by the outer portion (cortex) of the adrenal glands. If the concentration of cortisol is low, it typically indicates a low concentration of ACTH. On occasion, an ACTH stimulation test may be administered.
- Serum cortisol
- Serum adrenocorticotropic hormone (ACTH)
- ACTH stimulation testing
- Central nervous system imaging
Tests to differentiate primary and secondary adrenal insufficiency are discussed under Addison’s disease. Patients with confirmed secondary adrenal insufficiency (see table Confirmatory Serum Testing for Secondary Adrenal Insufficiency) should have CT or MRI of the brain to rule out a pituitary tumor or pituitary atrophy.
Adequacy of the hypothalamic-pituitary-adrenal axis during tapering or after stopping long-term corticosteroid treatment can be determined by injecting cosyntropin 250 mcg IV or IM. After 30 minutes, serum cortisol should be > 20 mcg/dL (> 552 nmol/L); specific levels vary somewhat depending on the laboratory assay in use. An insulin stress test to induce hypoglycemia and a rise in cortisol is the standard for testing the integrity of the hypothalamic-pituitary-adrenal axis in many centers but careful monitoring is required to avoid severe prolonged hypoglycemia.
The corticotropin-releasing hormone (CRH) test can be used to distinguish between hypothalamic and pituitary causes but is rarely used in clinical practice. After administration of CRH 100 mcg (or 1 mcg/kg) IV, the normal response is a rise of plasma ACTH of 30 to 40 pg/mL (6.6 to 8.8 pmol/L); patients with pituitary failure do not respond, whereas those with the hypothalamic disease usually do.
Treatment
Hormone replacement therapy with cortisol is the treatment of choice for this disorder. With such therapy, patients can lead a normal life.
- Hydrocortisone or prednisone
- Fludrocortisone not indicated
- Dose increases during intercurrent illness
Glucocorticoid replacement is similar to that described for Addison disease. Each case varies regarding the type and degree of specific hormone deficiencies. Normally, cortisol is secreted maximally in the early morning and minimally at night. Thus, hydrocortisone (identical to cortisol) is given in 2 or 3 divided doses with a typical total daily dose of 15 to 30 mg. One regimen gives half the total in the morning, and the remaining half split between lunchtime and early evening (eg, 10 mg, 5 mg, 5 mg). Others give two-thirds in the morning and one-third in the evening. Doses immediately before bed should generally be avoided because they may cause insomnia. Alternatively, prednisone 4 to 5 mg orally in the morning and possibly an additional 2.5 mg orally in the evening may be used. During acute febrile illness or after trauma, patients receiving corticosteroids for nonendocrine disorders may require supplemental doses to augment their endogenous hydrocortisone production.
Fludrocortisone is not required because the intact adrenals produce aldosterone.
In panhypopituitarism, other pituitary deficiencies should be treated appropriately.
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Treatment of Chronic Primary Adrenal Insufficiency
1. Glucocorticoid replacement (one of the given regimens):
- Hydrocortisone 15 to 25 mg orally in two or three divided doses (the largest dose is taken early in the morning; typically 10 mg upon awakening in the morning, 5 mg early afternoon, 2.5 mg late afternoon), or
- Prednisone 5 mg (2.5 to 7.5 mg) orally at bedtime, or
- Dexamethasone 0.75 mg (0.25 to 0.75 mg) orally at bedtime
- Monitor clinical symptoms and morning plasma ACTH as needed.
2. Mineralocorticoid replacement:
- Fludrocortisone 0.1 mg (range: 0.05 to 0.2 mg) orally. Hydrocortisone 20 mg and prednisone 50 mg provide a mineralocorticoid effect that is almost equivalent to 0.1 mg of fludrocortisone. Therefore, fludrocortisone replacement (if needed) must be decreased accordingly. Dexamethasone, however, lacks a mineralocorticoid effect and would require a full dose of fludrocortisone.
- Liberal salt intake.
- Monitor supine and standing blood pressure as well as pulse, edema, serum potassium, and plasma renin activity
3. Androgen replacement:
- Dehydroepiandrosterone (DHEA) initially 25 to 50 mg orally (only in women for psychological well-being, if needed, after optimal glucocorticoid and mineralocorticoid replacement).
4. Patient education:
- Educate the patient about the illness, how to manage stress, and inject dexamethasone or other glucocorticoids intramuscularly or subcutaneously.
5. Emergency precautions:
- Patients should have a medical alert bracelet/necklace, an emergency medical information card on their phone or inside their wallet, and prefilled syringes containing 4 mg of dexamethasone in 1 mL saline.
6. Treatment of minor febrile illness or stress:
- Increase glucocorticoid dose two to three times for the few days of illness. Do not change the mineralocorticoid dose (3×3 rule).
- The patient should contact the clinician if the condition worsens or persists for more than three days.
- No extra dose is required for most uncomplicated, outpatient dental procedures under local anesthesia.
- Glucocorticoid supplement for surgical stress:
- Minor: hydrocortisone 25 mg IV (or equivalent) on the day of the procedure
- Moderate: hydrocortisone 50 to 75 mg IV (or equivalent) on day of surgery and postoperative day 1
- Major: hydrocortisone 100 to 150 mg IV (or equivalent) in two or three divided doses on the day of surgery and postoperative days 1 and 2
7. Emergency treatment of severe stress or trauma:
- Each patient should have an injectable as well as vials of sterile 0.9% normal saline and syringes.
Treatment of Adrenal Crisis
Measures to stabilize the patient:
- Intravenous access with one or two large-gauge needles
- Laboratory analysis, including serum electrolytes, glucose, and routine measurement of plasma cortisol and ACTH.
- Infusion of 2 to 3 liters of isotonic saline or 5% dextrose in isotonic saline as urgently as possible. Periodic hemodynamic monitoring and measurement of serum electrolytes.
- Give hydrocortisone 100 mg intravenous bolus, followed by 50 mg intravenously every 6 hours (or 200 mg/24 hours as a continuous intravenous infusion for the first 24 hours). If hydrocortisone is unavailable, alternatives include prednisolone, prednisone, and dexamethasone.
- Correct any ongoing electrolyte abnormalities. Hyponatremia is often corrected by cortisol and volume repletion.
Subacute measures after stabilization of the patient:
- Intravenous isotonic saline infusion at a slower rate for the next 24 to 48 hours.
- Diagnosis and treatment of possible infectious precipitating causes of the adrenal crisis.
- If the patient does not have known adrenal insufficiency, a short ACTH stimulation test should establish the diagnosis and determine its type and cause.
- Tapering of parenteral glucocorticoid over 1 to 3 days to the oral glucocorticoid maintenance dose, if there are no ongoing contraindications.
- Initiating mineralocorticoid replacement with fludrocortisone, 0.1 mg by mouth daily after stopping the saline infusion.
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