Weatherly's Woes - Adrenals

THE ADRENAL GLAND

The kidney’s hat

The Adrenal Gland wears many hats. It’s a multifunctional endocrine organ located above the kidneys. There are two major layers.

The Cortex has three sub-layers. They are generally activated by ACTH, although the Zona Glomerulosa also requires Angiotensin II. It’s said that the deeper you go, the sweeter the layer. It goes “salt, sugar, sex.” All Cortex hormones are steroids, which originally started as cholesterol.

The Medulla has only one layer. It’s activated by preganglionic SNS neurons (which release ACh). All Medulla hormones are proteins.

CONGENITAL ADRENAL HYPERPLASIA

Introduction to CAH

Here’s a simplified view of how the Adrenal Cortex makes steroid hormones.

A disease called Congenital Adrenal Hyperplasia (CAH) occurs when one of the three vulnerable enzymes is broken from birth. Keep in mind, if you block one pathway, then the fuel (cholesterol) is funneled down the remaining open pathways. This leads to some wacky symptoms. There are several different kinds of CAH. Here’s a trick for remembering them.

If the enzyme starts with 1, there will be hypertension.

If the enzyme ends with 1, there will be virilization of female genitalia.

In all types of CAH, there will be low Cortisol. Cortisol is the only adrenal product that participates in negative feedback of the HPA axis. Therefore, in CAH there will be high ACTH. That’s important because ACTH stimulates growth of the adrenal glands (hence the name, Adrenal HYPERPLASIA).

21-HYDROXYLASE CONGENITAL ADRENAL HYPERPLASIA

The common CAH

Here is CAH due to 21-Hydroxylase Deficiency. It’s the most common cause of CAH (95%)

Nonclassical 21 CAH is a milder form of CAH that has an adult onset. XX individuals develop symptoms of high androgens like hirsutism, male pattern balding, acne and infertility. XY individuals are typically asymptomatic throughout their lives.

17α-HYDROXYLASE CONGENITAL ADRENAL HYPERPLASIA

The sexual CAH

CAH due to 17a-Hydroxylase Deficiency results in an inability to make Cortisol or Androgens.

11b-HYDROXYLASE CONGENITAL ADRENAL HYPERPLASIA

The other CAH

Here is CAH due to 11b-Hydroxylase Deficiency.

CORTISOL

The stress hormone

Cortisol is the body’s natural corticosteroid. It’s released (a) during stress and (b) right before we wake up (this is our body anticipating a stressful morning). There are many parallels between Cortisol and the sympathetic nervous system. They are both released during stress. While the SNS is short-acting, corticosteroids prefer a slower pace. Without cortisol, repeated stressful situations would literally kill us (Addisonian Crisis). That’s because it has a lot of “stabilizing” properties.

Cortisol puts macronutrients into the blood.

There’s more glucose (↑glycolysis, ↑gluconeogenesis), more fat (↑lipolysis) and more AAs (↑muscle and bone breakdown).

Cortisol is a powerful immunosuppressant*.

It works on many levels. Less prostaglandins (blocks phospholipase a2), less T cell proliferation (blocks IL2), less of all four hypersensitivities, and pacified leukocytes (blocks leukocyte adhesion). Scientists speculate that the purpose of this immunosuppression is to conserve energy. White blood cells are quite energetically demanding, and their importance is negligible compared to the threat of, say, a tiger.

Cortisol raises BP.

(1) It upregulates alpha 1 receptors

(2) It activates the enzyme (PMNT) that converts NorEpi into Epi.

(3) Cortisol has some mineralocorticoid properties (Aldosterone-like), which increases the blood volume.

*Note - Steroids block leukocyte adhesion. That means that neutrophils can’t leave the blood to enter the tissues. So they hang out in the blood instead. On blood work, the WBC will be high (leukocytosis). Although it seems like the patient may be inflamed, they’re actually immunosuppressed!

*Note 2 - One particularly important manifestation of immunosuppression is poor wound healing. Cortisol inhibits every stage of wound healing. It inhibits the early phase (less mast cell degranulation, less edema), the middle phase (less neutrophils) and the late phase (it suppresses fibroblasts and macrophages, which prevents wound closure and scar formation). It also suppresses osteoblasts, delaying fracture healing. These are energetically demanding processes.

*Note 3 - Cortisol suppresses the immune response in the stomach to H. pylori, which can cause stomach ulcers. Perhaps that’s why stress was believed to be the cause of gastritis prior to the discovery of H. pylori.

CUSHING'S SYNDROME

High cortisol

Cushing’s Syndrome means high levels of corticosteroids.

Generally speaking, Cushing’s is caused either by high Cortisol or high ACTH, which then produces Cortisol. The high ACTH type has an additional symptom: hyperpigmentation. Keep in mind that ACTH comes from a precursor molecule called POMC. POMC is cleaved to make three different things: ACTH, Melanin and endorphins. In order to make one ACTH, you also have to make one MSH! That’s why high ACTH leads to dark skin. MSH can cause a general bronze tan, but it first manifests as darkened gums and palmar creases.

Here are the four most common causes of Cushing’s.

Chronic Steroid use is (by far) the most common cause of Cushing’s.

In Cushing’s DISEASE there’s an adenoma in the pituitary making ACTH. It’s the second most common cause.

Adrenal Adenomas are the third most common cause. They secrete Cortisol.

Paraneoplastic ACTH Secretion is the least common cause. They secrete ACTH. It is usually due to a small cell lung carcinoma.

The diagnosis of Cushing’s is a little complicated. Unfortunately, random blood tests for cortisol are unreliable, since it waxes and wanes throughout the day. If you still want to test for cortisol, you should draw the patient's blood at midnight, when people’s endogenous cortisol levels are at their lowest point. Other screening tests include a 24 hour cortisol urine level and a low-dose dexamethasone suppression test. All three of these tests answer the same question -- do they have Cushing’s? Once the diagnosis is confirmed, you should order an ACTH to help pinpoint the cause. If the ACTH is high, you need an additional test -- the high-dose dexamethasone suppression test -- to finally identify the cause. See the diagram above for more information. Treatment options are generally not tested, but options include include surgery (for adenomas/cancers), Meyrapone (steroid blocker), Ketoconazole (adrenal blocker) and Mitotane (adrenal cytotoxin)

Moon facies & Acne

Cushing’s

Violet striae

ADRENAL INSUFFICIENCY

Adrenals done broke

Adrenal Insufficiency is when the adrenal glands stop working. There is a drop in corticosteroids and mineralocorticoids.

ADDISON’S DISEASE is chronic autoimmune primary adrenal insufficiency. The immune system nukes the adrenal glands (all layers). Let's summise the symptoms by working through the layers of the adrenal gland. Patients have low aldosterone, which leads to fluid loss (orthostatic hypotension, tachycardia), metabolic acidosis and hyperkalemia. They have low cortisol, which leads to hypoglycemia and hypotension. They have high ACTH, which leads to high POMC turnover, high MSH and hyperpigmentation. Diagnose with an ACTH Stimulation test -- giving Cosyntropin (ACTH) won’t increase their Cortisol levels. Treatment is simple in theory (give steroids and mineralocorticoids), but in reality this is a tricky complicated disease. Note that the symptoms of Addison’s are very frustrating to spot on an exam vignette! Look for a soft blood pressure and fatigue. Fun fact - former US president JFK went to great lengths to keep his diagnosis of Addison’s disease a secret. However, his health problems were cripplingly severe (spinal fractures, fatigue, ulcers). He was propped up by an unholy diet of steroids, mineralocorticoids, painkillers, vitamins, enzymes, amphetamines, phenobarbital, testosterone and other experimental potions. His youthful Nantucket tan was actually a result of ACTH overproduction!

An ADDISONIAN CRISIS is an acute flare of Addison’s disease. Without cortisol, they are vulnerable to stressful situations (surgery, infection, emotion, trauma), which can cause them to rapidly deteriorate and die. They experience hypotension, tachycardia, dehydration, hypoglycemia, hyponatremia, hyperkalemia, fever, weakness, confusion and - if severe enough - vascular collapse, shock and death. These are all of the normal Addisonian symptoms, but they become magnified during a crisis. Patients with Addisons should wear an ID bracelet, because (a) Addison’s is rare and (b) a crisis can be indistinguishable from septic shock (which is more common). Giving them antibiotics won’t help one bit! Instead they need steroids and mineralocorticoids. Another important concept is steroid dosing. Addisonian patients should take extra doses prior to a stressful situation (surgery). Additionally, if a patient stops taking their steroids, they will go into a sudden crisis.

WATERHOUSE-FRIDERICHSEN SYNDROME is when sepsis from Neisseria meningitidis leads to bilateral adrenal hemorrhage. This will precipitate an Addisonian Crisis, which will worsen their ongoing sepsis (almost always fatal). Note that meningococcal sepsis is also associated with petechiae!

SECONDARY ADRENAL INSUFFICIENCY - a pituitary problem, where less ACTH is being made. Pretty rare. Pretty low yield. Of note, there is no hyperpigmentation (ACTH isn’t being made after all).

TERTIARY ADRENAL INSUFFICIENCY - seen in patients on chronic steroid use who abruptly discontinue their medications, precipitating withdrawal. The prolonged medication use replaced their own adrenal axis, leaving the adrenal glands withered and unable to make cortisol on their own. For that reason, steroids should be sloooowly tapered off.

ADRENAL MEDULLA

Catecholamine factory

The Adrenal Medulla is in the center of the Adrenal Gland. It’s full of Chromaffin Cells (which arise from Neural Crest Cells), When Preganglionic SNS Neurons release ACh, the Chromaffin Cells release NorEpi and Epi. The Medulla only contributes to about 10% of sympathetic tone (so surgical removal is cool).

A PHEOCHROMOCYTOMA is a tumor of Chromaffin Cells in the Medulla. The tumor episodically releases catecholamines, causing 15 minute sympathetic storms with very high blood pressure (200/100), tremors, diaphoresis, anxiety, headache and palpitations. The symptoms are pretty unmistakable. The catecholamines have short half-lives, so they can’t be measured directly, but you can measure their breakdown products in the urine (Vanillylmandelic Acid & Homovanillic Acid). The ultimate treatment is surgical removal. But until surgery is ready, you have to manage their BP. Start with an alpha 1 blocker (Phenoxybenzamine) because alpha 1 is so important in BP. Once you get an alpha 1 blocker on board, you can consider adding on a beta blocker. But avoid giving beta blockers first, because the betas have a more complicated effect on BP (they vasodilate skeletal and splanchnic muscles) and beta blockers can acutely worsen their HTN (killing them). 10% of these are cancerous, bilateral, extra-adrenal, calcified and in kids. Note that the histological samples will stain (+) for Chromogranin, Synaptophysin and NSE.

A NEUROBLASTOMA is a “premature” pheochromocytoma. It’s a cancer of Neural Crest Cells (rather than chromaffin cells) that tends to occur in children. Neuroblastomas are notable because they can secrete catecholamines too (Neuro-BLAST OFF!-oma). The tumor can arise anywhere in the sympathetic chain. It tends to prefer the Medulla though. Medullary masses can lead to large and irregular abdominal masses (may cross the midline). Sympathetic Chain masses can lead to SVC syndrome or Horner’s syndrome. For some reason, patients can get raccoon eyes, opsoclonus-myoclonus (dancing eyes-dancing feet). Although the lab tests are similar to Pheochromocytoma (elevated urine HVA and VMA), kids with Neuroblastoma are less likely to get super high HTN. The tissue stains (+) for Bombesin and Neuron-Specific Enolase. Tumors with an N-myc oncogene overexpression have a worse prognosis.

ALDOSTERONE

The RAAS steroid

Aldosterone is part of RAAS. It adjusts nephron reabsorption in the DCT.

Here are the 3 things it does:

It raises BP

It lowers K+

It alkalinizes the blood

CONN SYNDROME (Primary Hyperaldosteronism) is an adrenal tumor that secretes Aldosterone. Patients get HTN, Hypokalemia, Metabolic Alkalosis and Hypernatremia. Hypokalemia leads to paresthesias, weakness and an EKG U-wave. Their RAAS will shut itself off to limit the Hyperaldosteronism, and you can measure this as a low serum renin. Diagnosis may be made with a CT of the abdomen (showing an adrenal mass). Treatment is surgical or medical. Give Aldosterone blockers (Spironolactone, Eplerenone). Spironolactone is also an Androgen blocker.

SECONDARY HYPERALDOSTERONISM refers to every other kind of high Aldosterone. The renin will be high. A renin-secreting adenoma can cause this. Renal Artery Stenosis can also cause this (it’s tricking the body into thinking it needs more Aldosterone).