Diseases of the Adrenal Glands (PEARLS): Adrenal insufficiency & Cushing’s syndrome (Smarty PANCE)
3 types of adrenal insufficiency?
1. Primary (problem w/ adrenal gland itself) 2. Secondary (steroid withdrawal or pituitary issue) 3. Tertiary (hypothalamus)
What is adrenocorticotropic hormone (ACTH) and where does it come from?
Adrenocorticotropic hormone ACTH) is a hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. It stimulates the adrenal cortex to secrete cortisol (glucocorticoids)
Another option for the initial diagnosis of Cushing syndrome?
Another option is also the dexamethasone suppression test, which is when a person is given a low dose of dexamethasone, which is an exogenous steroid that suppresses ACTH production in the pituitary gland. Normally that should cause a decrease in serum cortisol levels, but if Cushing syndrome is caused by endogenous cortisol production, then the serum cortisol levels should remain unchanged. If that test is positive, the next step is to determine the exact cause of endogenous cortisol production, and ACTH plasma levels can be checked.
Test to differentiate between secondary and tertiary adrenal insufficiency?
CRH Stimulation Test: the differentiation between secondary and tertiary adrenal insufficiency can be made by the administration of corticotropin-releasing hormone (CRH) ● Secondary (pituitary) - low ACTH and low cortisol - there is little or no ACTH response in patients with secondary (pituitary-related) adrenal insufficiency ● Tertiary (hypothalamic) - low ACTH and low cortisol - patients with tertiary disease due to lack of CRH from the hypothalamus usually have an exaggerated and prolonged ACTH response
What are the clinical manifestations of Cushing syndrome?
Central obesity, moon facies, dewlap (under chin), dorsocervical and supraclavicular fat pad thickening Thin extremities with muscle wasting and proximal muscle weakness Thin skin, facial plethora, violaceous striae, easy bruising, slow wound healing Hyperglycemia and glucose intolerance Psychological problems (irritability, depression, psychosis, mania, anxiety, and insomnia) Osteoporosis (vertebral compression fractures, aseptic necrosis, hypercalciuria, and renal calculi) Immune suppression, cutaneous fungal infections, lymphopenia, decreased eosinophils Hyperpigmentation, lymphopenia, decreased eosinophils (if ACTH-dependent Cushing syndrome)
Cushing's is all about an increase in what?
Cortisol (glucocorticoid)
Describe exogenous vs. endogenous Cushing's?
Cushing syndrome can happen because of exogenous cortisol meaning that it comes from "outside" usually in the form of medications, or because of endogenous cortisol - meaning that the excess cortisol is made by the body.
Does Cushing disease present with hypokalemia or hyperkalemia?
Cushing's causes increased levels of cortisol. Cortisol, at high levels, acts like a mineralocorticoid (aldosterone), stimulating absorption of sodium and excretion of potassium at the collecting tubules. Hence, any disorder involving an excess of mineralocorticoids will cause hypokalemia.
Most common initial diagnosis of Cushing syndrome?
Diagnosis of Cushing syndrome is initially based on measuring the free, or unbound cortisol in a 24-hour urine sample, in order to assess the total amount of cortisol excreted in the urine over a 24-hour period. Alternatively, blood or saliva tests late at night can help check if there's a normal daily rise and fall of cortisol levels.
How does excess cortisol affect glucose and insulin levels in the blood?
Excess cortisol leads to elevated blood glucose levels, and that leads to high insulin levels
How does excess cortisol affect muscle, bone and skin?
Excess cortisol leads to severe muscle, bone and skin breakdown which are the major protein stores of the body
What are some additional clinical features in acute adrenal crisis?
Fever, abdominal pain, orthostatic hypotension, hypovolemia, hypotension, shock, confusion, and coma
Evaluation of patients with possible adrenal insufficiency?
For most patients measuring 8 AM serum cortisol and plasma ACTH, and a high-dose 250 mcg ACTH stimulation test
Is cortisol higher or lower in the morning?
Free cortisol in the blood is involved in a number of things and it's part of the circadian rhythm. Cortisol levels peak in the morning, when the body knows we need to "get up and go" and then drop in the evening, when we're preparing for sleep
Is most cortisol free or bound?
Glucocorticoids are not soluble in water, so most cortisol in the blood is bound to a special carrier protein, called cortisol-binding globulin, and only about 5% is unbound or free. Only this small fraction of free cortisol is biologically active, and its levels are carefully controlled. Excess free cortisol is filtered in kidneys and dumped into the urine.
Why does excess cortisol cause hypertension?
High cortisol levels cause hypertension for two reasons. First, it amplifies the effect of catecholamines on blood vessels. Second, cortisol starts cross-reacting with mineralocorticoid receptors, which normally only binds a related steroid hormone (mineralocorticoids are secreted from the zona glomerulosa layer of the adrenal cortex). Because the cortisol is structurally similar to mineralocorticoid it can bind to that receptor and it can trigger the mineralocorticoid effect - which is mainly to increase blood pressure by retaining fluid through sodium reabsorption and potassium excretion
Describe adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent Cushing's syndrome?
Hyperfunction of the adrenal cortex can be adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent ACTH-dependent hyperfunction may result from ● Hypersecretion of ACTH by the pituitary gland (Cushing disease) ● Secretion of ACTH by a nonpituitary tumor, such as small cell carcinoma of the lung or a carcinoid tumor (ectopic ACTH syndrome) ● Administration of exogenous ACTH ACTH-independent hyperfunction usually results from ● Therapeutic administration of corticosteroids ● Adrenal adenomas or carcinomas
What is the mechanism of hyperpigmentation?
Hypocortisolemia causes increased secretion of ACTH and other proopiomelanocortin -derived peptides such as MSH. These peptides stimulate melanin production, resulting in hyperpigmentation.
What is the most common cause of Cushing syndrome?
Iatrogenic administration of exogenous corticosteroids (including intra-articular injections and dermatologic preparations) is the most common cause of Cushing syndrome.
How do cortisol levels which increase in times of stress affect gluconeogenesis?
In times of stress, the body needs to have plenty of energy substrates around, so cortisol increases gluconeogenesis, which is the synthesis of new glucose molecules, proteolysis, which is the breakdown of protein and lipolysis, which is the breakdown of fat.
How should patients adjust their medications for when under stress (illness/surgery)?
Increase glucocorticoid dose 2- to 3-fold during periods of minor illness; intravenous high-dose glucocorticoids during severe illness or major surgery
What is symptom of Cushing's is related to elevated insulin levels?
Insulin, among its many actions, targets adipocytes or fat cells in the center of the body - around the waist and buttocks. In those cells, the insulin activates lipoprotein lipase, which is an enzyme that helps those adipocytes accumulate more fat molecules. The result is central obesity (a core symptom of Cushing's syndrome)
What 2 screening tests are used to confirm hypercortisolism?
Low-dose dexamethasone suppression test (administered at 11 PM, with an 8 AM serum cortisol the next day) and 24-hour urinary free cortisol test
What is the radiographic test of choice for identifying suspected pituitary adenomas?
MRI of the sella turcica, with and without gadolinium (though up to 50% of adenomas may not be seen)
What is a drug used in Cushing syndrome that inhibits 11-beta-hydroxylase, thereby inhibiting glucocorticoid synthesis?
Metyrapone is a drug used in Cushing syndrome as it inhibits 11-beta-hydroxylase, thereby inhibiting glucocorticoid synthesis.
What are the etiologies of primary adrenal insufficiency?
Most commonly from autoimmune destruction of the adrenal cortex. Plasma ACTH is high and serum cortisol levels are low. ● Autoimmune destruction (most common as Addison disease) ● Tuberculosis (leading cause where TB is prevalent) ● Adrenal hemorrhage (i.e., sepsis, anticoagulation therapy, antiphospholipid antibody syndrome) ● Congenital
What is a feature of Cushing syndrome due to cortisol-mediated break down of muscle to produce amino acids for gluconeogenesis.
Muscle weakness is a feature of Cushing syndrome due to cortisol-mediated break down of muscle to produce amino acids for gluconeogenesis.
What are the clinical features of adrenal insufficiency?
Nausea, vomiting, weakness, fatigue, lethargy, weight loss, anorexia, and hyperpigmentation
What is corticotropin-releasing hormone (CRH) and where does it come from?
Normally, the hypothalamus, which is located at the base of the brain, secretes corticotropin-releasing hormone, known as CRH, which stimulates the pituitary gland to secrete adrenocorticotropic hormone, known as ACTH. ACTH, then, travels to the pair of adrenal glands, on top of each kidney, where it specifically targets cells in the adrenal cortex.
How will cortisol levels respond to a dexamethasone suppression test in patients with Cushing syndrome caused by cortisol-producing adrenal tumor?
Patients with Cushing syndrome caused by cortisol-producing adrenal tumor will show no change in cortisol levels following a dexamethasone suppression test.
What form of adrenal insufficiency is associated with an elevated ACTH?
Primary
Primary? Secondary? Tertiary?
Primary = adrenal (ACTH high and cortisol low) Secondary = pituitary (ACTH low and cortisol low) Tertiary = hypothalamic (ACTH and cortisol low with exaggerated and prolonged ACTH response with administration of CRH - corticotropin releasing hormone test)
Which form of adrenal insufficiency is associated with hyperpigmentation?
Primary adrenocortical insufficiency (Addison's disease)
↑ ACTH (from pituitary hypersecretion) + ↓ Cortisol (failure of the adrenal cortex) + ↓ Aldosterone
Primary adrenocortical insufficiency (Addison's disease)
Does primary adrenocortical insufficiency from a pituitary tumor present with hypokalemia or hyperkalemia?
Primary adrenocortical insufficiency (Addison's disease) results in ↑ ACTH (from pituitary hypersecretion) + ↓ Cortisol (failure of the adrenal cortex) + ↓ mineralocorticoid (aldosterone). Aldosterone normally causes absorption of sodium and excretion of potassium at the collecting tubules. Hence, any disorder involving a decrease in mineralocorticoids will cause hyperkalemia.
What is the usual presentation of ectopic ACTH production?
Rather than the typical Cushingoid habitus, ectopic ACTH production tends to present with rapidly progressive hypokalemia, metabolic alkalosis, hyperpigmentation, hypertension, edema, and weakness.
What is the treatment for primary adrenal insufficiency?
Replacement therapy with a combination of glucocorticoids and mineralocorticoids. Hydrocortisone is the glucocorticoid of choice. Mineralocorticoid replacement (fludrocortisone) and increased dietary salt intake. Adjustments in dosage are made according to the clinical response. A proper dose usually results in a normal WBC count differential
What is secondary adrenal insufficiency?
Secondary adrenal insufficiency is adrenal hypofunction due to a deficient secretion of ACTH by the pituitary gland which may be isolated or occur in conjunction with other pituitary hormone deficiencies. ACTH and cortisol levels both are low.
↓ Cortisol, ↓ ACTH, normal aldosterone, with little or no ACTH response during corticotropin-releasing hormone test
Secondary adrenocortical insufficiency
What forms of adrenal insufficiency are associated with a low ACTH?
Secondary and tertiary
In which forms of adrenal insufficiency is mineralocorticoid (aldosterone) secretion intact?
Secondary and tertiary. The adrenal cortex maintains responsiveness to the renin-angiotensin system
↓ Cortisol, ↓ ACTH, and normal aldosterone
Secondary or tertiary
What are the causes of ectopic ACTH secretion?
Small cell lung cancer (50%), pancreatic islet cell carcinoma, thymoma, carcinoid tumors, medullary thyroid carcinoma, and pheochromocytoma
What type of lung tumors can cause excessive ACTH production and Cushing syndrome?
Small cell lung cancer and carcinoid tumors may produce Cushing syndrome due to paraneoplastic adrenocorticotropic hormone (ACTH) secretion
What is the treatment for Cushing syndrome secondary to adrenal adenomas and carcinomas?
Surgical resection of the tumor. Adrenal carcinomas may also require mitotane therapy, although this is controversial. Adrenal enzyme inhibitors can be used to control refractory Cushing syndrome.
What is the treatment for Cushing disease?
TSS (transsphenoidal surgery)
What is the cause of tertiary adrenal insufficiency?
Tertiary adrenal insufficiency refers to impaired hypothalamic release of corticotropin-releasing hormone (CRH) with resulting decreased production of ACTH by the pituitary. The most common causes of tertiary adrenal insufficiency, also suppress corticotropin (ACTH) secretion: ● Abrupt cessation of high-dose glucocorticoid therapy ● Correction (cure) of hypercortisolism (Cushing's syndrome)
↓ Cortisol, ↓ ACTH, normal aldosterone, with exaggerated and prolonged ACTH response (↑ ACTH) with the administration of CRH corticotropin-releasing hormone test
Tertiary adrenocortical insufficiency (HPA suppression)
Describe the adrenal cortex and it's layers?
The adrenal cortex is the outer part of the adrenal gland and is subdivided into three layers- the zona glomerulosa, the zona fasciculata, and the zona reticularis
The body uses negative feedback, which means that high levels of cortisol tell the hypothalamus and pituitary gland to (decrease or increase) their secretion of CRH and ACTH?
The body uses negative feedback, which means that high levels of cortisol tell the hypothalamus and pituitary gland to decrease their secretion of CRH (hypothalamus) and ACTH (pituitary)
What test is used diagnostically to identify the underlying cause of non-iatrogenic Cushing syndrome.
The dexamethasone suppression test is used diagnostically to identify the underlying cause of non-iatrogenic Cushing syndrome.
Is the majority of Cushing's syndrome exogenous or endogenous cause?
The majority of cases of Cushing syndrome occur in individuals using exogenous steroid medications over a long period of time - often to treat autoimmune and inflammatory disorders, like asthma or rheumatoid arthritis. Because the molecular structure of exogenous steroid medications is so similar to cortisol they mimic its actions on various tissues. Exogenous steroid medications can also cause negative feedback on the hypothalamus and the pituitary gland. This causes a decrease in CRH and ACTH, which in turn, shuts down endogenous cortisol production from the zona fasciculata.
What is the most common cause of endogenous Cushing's?
The most common reason for increased levels of endogenous cortisol is excess ACTH caused by a pituitary adenoma, which is a benign tumor of the pituitary gland - and this is called Cushing disease
A 24-hour urine free cortisol is elevated, a late night salivary cortisol is elevated, and/or there is an inadequate suppression on 1 mg overnight dexamethasone test in a patient suspected of Cushing syndrome. What is the next diagnostic step?
The next step would be to measure adrenocorticotropic hormone (ACTH).
ACTH specifically stimulates cells in which zone to secrete what substance, which belongs to a class of steroids, called glucocorticoids?
The zona fasciculata is the middle zone and also the widest zone and it takes up the majority of the volume of the whole adrenal gland. ACTH (secreted by the pituitary) stimulates cells in this zone to secrete cortisol, which belongs to a class of steroids, called glucocorticoids
What is acute and chronic adrenocortical insufficiency?
● Acute adrenocortical insufficiency (adrenal crisis) is an emergency caused by insufficient cortisol ● Chronic adrenocortical insufficiency or primary adrenal insufficiency (Addison disease) is caused by dysfunction or absence of the adrenal cortices
Cushing's syndrome vs. Cushing's disease?
● Cushing's Syndrome: symptoms from chronic ↑ cortisol levels and doesn't specify cause or source of excess ● Cushing's Disease is Cushing's syndrome that results from excess pituitary production of adrenocorticotropic hormone (ACTH), generally secondary to a pituitary adenoma. Cushing disease accounts for about 40% of Cushing syndrome cases
What are causes of secondary adrenal insufficiency?
● Iatrogenic (adrenal suppression from prolonged steroid use) ● Pituitary or hypothalamic adenoma ● Long-term glucocorticoid therapy ● Sheehan syndrome (severe low blood pressure during or after childbirth) ● Traumatic brain injury ● Subarachnoid hemorrhage
What are causes of adrenal crisis?
● Stress (e.g., trauma, surgery, infection, hyperthyroidism, or prolonged fasting) in a patient with latent or treated adrenal insufficiency ● Sudden withdrawal of adrenocortical hormone in a patient with chronic insufficiency or temporary insufficiency (suppression by exogenous corticosteroids) ● Bilateral adrenalectomy or removal of a functioning adrenal tumor that suppressed the other adrenal ● Sudden destruction of the pituitary gland (pituitary necrosis) ● Injury to both adrenals (e.g., trauma, hemorrhage, anticoagulant therapy, thrombosis, infection, or metastatic carcinoma) ● Administration of etomidate (rapid anesthesia induction or intubation).
What are common laboratory findings associated with adrenocortical insufficiency?
● WBC count with moderate neutropenia, lymphocytosis, and total eosinophil count over 300/μL ● Low serum Na+ (due to low aldosterone) ● Elevated K+ (due to low aldosterone) ● Low fasting blood glucose (due to lack of cortisol)
