Adrenal and RAAS

Question 1

The right adrenal gland is wedged between . . .

Answer 1

The right adrenal gland is wedged between the liver, the right kidney, the inferior vena cava, and the crus of the diaphragm and can therefore be more challenging to fully visualize on imaging

Question 2

The left adrenal gland is surrounded by . . .

Answer 2

The left adrenal gland is surrounded by the left kidney, the pancreas, and the aorta, but because of the absence of compression by the liver and the fact that the adrenals are surrounded by adipose tissue (Gerota’s fascia), the left adrenal gland is usually easily visualized.

Question 3

Embryonic origins and roles of the adrenal cortex and medulla

Answer 3

The cortex stems from mesenchymal tissue and functions primarily to produce steroids,

whereas the medulla arises from neural crest cells and functions primarily to synthesize catecholamines.

Question 4

The 3 histologic layers of the adrenal cortex

Answer 4

the zona glomerulosa (ZG), zona fasciculata (ZF), and zona reticularis (ZR)

Question 5

Adrenals on CT

Answer 5

Question 6

Steroidogenesis and structure in the adrenal cortex

Answer 6

Unique p450 enzymes involved in steroidogenesis are expressed in each layer of the cortex. ACTH stimulates uptake of cholesterol and synthesis of these hormones. Angiotensin II and hyperkalemia stimulate just aldosterone synthesis.

Cortisol is synthesized in the ZF,

aldosterone in the ZG,

and DHEA (dehydroepiandrosterone) and androsterone are synthesized in the ZR.

Question 7

Cortisol is both . . .

Answer 7

. . . a glucocorticoid and a mineralocorticoid

Question 8

Glucocorticoid signaling

Answer 8

The GR is expressed in virtually every cell in the body. Activation of the GR does many things, including raising blood glucose, increasing blood pressure by inducing expression of adrenergic receptors, suppressing immune activity/inflammation, increasing appetite, regulating mood and behavior, and also plays a key role in organogenesis, development, and parturition.

Cortisol is essential to almost every vital function of the body and a key requirement for vitality

Question 9

Mineralocorticoid signaling

Answer 9

The MR is classically expressed in the distal nephron of the kidney, but is also in the heart, vasculature, and other organs. At the distal nephron, it facilitates sodium and water reabsorption via stimulating ENaC, and promotes potassium excretion.

Question 10

11β-hydroxysteroid dehydrogenase

Answer 10

Classically co-expressed with the renal-MR and functions to convert cortisol to the inactive cortisone. Inactivates the majority of cortisol before it can bind to and activate the renal MR.

This mechanism of cortisol inactivation permits aldosterone, which circulates in much lower concentrations than cortisol, to play the role of the primary mineralocorticoid in human physiology.

Question 11

phenylethanolamine N-methyltransferase

Answer 11

Enzyme that converts norepinephrine to epinephrine. Only expressed in the adrenal medulla.

Question 12

Effects of endocrine norepinephrine

Answer 12

Norepinephrine can activate the α1 and β1 adrenergic receptors and thus induce arterial vasoconstriction to raise blood pressure, tachycardia, increased cardiac conduction velocity, and increased inotropy to increase cardiac output.

Question 13

Effects of endocrine epinephrine

Answer 13

Epinephrine can activate α1, α2, β1, β2 adrenergic receptors. Thereby, it has most of the effects of norepinephrine, and also results in skeletal muscle arteriolar vasodilation and mobilizes glucose.

Question 14

ACTH is derived from . . .

Answer 14

POMC! The peptide endocrine poly-hormone precursor that must be cleaved to release all of its hormone bits, including endorphins, melanocyte-stimulating hormone, and others.

Question 15

Dominant secretogogues of aldosterone

Answer 15

1. Angiotensin II
2. Potassium

Question 16

Summary of cortisol and aldosterone regulation

Answer 16

Question 17

“Adrenal insufficiency” is ___.

Answer 17

“Adrenal insufficiency” is relative.

It is an insufficiency relative to the current physiologic demand of the body.

Question 18

Pathophysiology of Addison’s Disease / Primary Adrenal Insufficiency

Answer 18

Insufficient secretion of cortisol, aldosterone, and adrenal androgens. The absence of negative feedback from cortisol, the hypothalamus and pituitary augment secretion of CRH, POMC, and as a result ACTH and melanocyte stimulating hormone (MSH).

Question 19

Presentation of Adrenal Insufficiency (primary or secondary)

Answer 19

• Typically present very sick or critically ill
• General malaise and feelings of being unwell, gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain), weight loss, and in severe cases, hypoglycemia
• In the absence of aldosterone, renal sodium retention decreases and patients develop intravascular depletion. This presents as lightheadedness and orthostasis, weight loss, and hypotension (often circulatory shock)
• Diffuse hyperpigmentation of skin and mucous membranes if primary (due to MSH)
• On blood labs, hyponatremia, hyperkalemia, and a markedly elevated renin

Question 20

Diagnosing adrenal insufficiency

Answer 20

• Screen for primary adrenal insufficiency by measuring a cortisol and ACTH simultaneously
• Blood labs show hyponatremia, hyperkalemia, and a markedly elevated renin
• Cosyntropin stimulation: Challenge with cosyntropin (ACTH mimetic) and measure response via cortisol. If there is a failure to produce cortisol, the diagnosis is confirmed.

Question 21

Diagnosing secondary adrenal insufficiency

Answer 21

• Screen for primary adrenal insufficiency by measuring a cortisol and ACTH simultaneously. In contrast to primary, both cortisol and ACTH will be low.
• Blood labs show hyponatremia, hyperkalemia, and a markedly elevated renin
• Cosyntropin stimulation: Can be used to rule out primary adrenal insufficiency. Challenge with cosyntropin (ACTH mimetic) and measure response via cortisol. If cortisol responds on a background of cortisol and ACTH deficiency, then the diagnosis is confirmed.
  
  • A robust response indicates that the disease has been acute in course, since the adrenals have not atrophied. A mild response indicates chronic course, as the adrenals have partially atrophied.

Question 22

The most common cause of primary adrenal insufficiency, particularly in developed parts of the world, is . . .

Answer 22

Autoimmune adrenalitis

This may occur in isolation, or as part of an autoimmune polyglandular syndrome

Question 23

Autoimmune polyglandular syndromes

Answer 23

Question 24

Major causes of primary adrenal insufficiency

Answer 24

• Autoimmune
• Bilateral infiltrative infection
• Bilateral adrenal hemorrhage
• Infiltrative malignancies
• Bilateral surgical adrenalectomy and lack of proper hormone replacement
• Medications

Question 25

Medications that are known to occasionally interfere with steroid hormone synthesis

Answer 25

* Anti-fungals (especially triazoles) * Etomidate (a short-acting IV anesthetic) * Heparin (rarely)

Question 26

Major causes of *secondary* adrenal insufficiency

Answer 26

* **Iatrogenic****​** * Not what you typically think of for iatrogenic. Surgery is usually fine, the real problem is **chronic glucocorticoids**. These lead to **atrophy of the corticotropes.** * Primary or metastatic tumors * Infection * Hemorrhage * **Opioid medications** can suppress ACTH (uncommon)

Question 27

Treatment of *primary* adrenal insufficiency

Answer 27

* **Hormone replacement** with **hydrocortisone or prednisone** (as a glucocorticoid) and **fludrocortisone** (as a mineralocorticoid). * Patients are **at risk of salt wasting and intra-vascular depletion** and should therefore be **instructed to consume sufficient dietary sodium and water** (or electrolyte rich fluids), **especially on warmer days** when insensible loses of water and salt can be greater.

Question 28

Treatment of *secondary* adrenal insufficiency

Answer 28

* **Hormone replacement** with **hydrocortisone or prednisone** (as a glucocorticoid). No need for mineralocorticoid replacement. * Patients are **usually not at risk for salt wasting**, but you can check their electrolytes to make sure. If so, you may consider a mineralocorticoid, but this is very rare. * If cause was iatrogenic glucocorticoid administration, then the goal of therapy should be to **gradually taper the glucocorticoid down** in hopes that the **endogenous hypothalamic-pituitary-adrenal axis will revive** and resume normal function.

Question 29

Pathophysiology of primary aldosteronism

Answer 29

* May be unilateral or bilateral * Unilateral primarily due to an **adenocarcinoma secreting aldosterone, aka Conn's tumor**, or smaller hyperplasias with similar effects * Bilateral due to bilateral hyperplasia or microscopic foci of activity * **May be heritable**, with numerous possible genetic etiologies, but this is still rare * Familial Aldosteronism Type I, aka glucocorticoid remediable aldosteronism or **GRA**, is a heritable translocation of **aldosterone under the 11β-hydroxylase promoter.** Thus, there is **ACTH-dependent aldosterone synthesis**.

Question 30

Treatment of glucocorticoid remediable aldosteronism

Answer 30

As the name suggests, since aldosterone is now effectively under the control of ACTH, it may be treated by giving glucocorticoids to suppress ACTH production.

Question 31

Presetation of primary aldosteronism

Answer 31

Since aldosterone excess causes **inappropriately high renal sodium retention and intravascular volume expansion**, the most common presentation of primary aldosteronism is **hypertension.** Patients often **treated for HTN without success**. Due to mineralocorticoid excess, patients also present with **hypokalemia and metabolic alkalosis** from excessive ENaC activity and K⁺ and H⁺ secretion.

Question 32

Diagnosing primary aldosteronism

Answer 32

* **Measurement of plasma renin and aldosterone** * This should be regarded as a **screening** test, not diagnostic * anticipated values are: a **suppressed renin** with a relatively **high aldosterone**, suggesting **renin-independent aldosteronism** * **Oral or IV sodium challenge** * Failure to suppress aldosterone is diagnostic * **ACE inhibitor challenge** * Failure to suppress aldosterone is diagnostic

Question 33

Treating primary aldosteronism

Answer 33

* Important to treat due to complications related to hypertension (stroke, cardiovascular disease, hemorrhage) * **When unilateral, unilateral adrenalectomy** is preferred. Relatively safe and simple laporoscopic procedure, minimally invasive. * **When bilateral** (most common scenario), patients are treated with a **mineralocorticoid receptor antagonist** (such as **spironolactone** or **eplerenone**). * **GRA** is treated with **glucocorticoids** and **mineralocorticoid receptor antagonists**, as needed.

Question 34

The most common cause of Cushing's syndrome

Answer 34

* Overadministration of glucocorticoids

Question 35

Pathophysiology of adrenal Cushing's syndrome

Answer 35

* **Overactive glucocorticoid signaling** * Usually iatrogenic * Endogenous hypercortisolism can be due to Cushing’s disease (**ACTH-secreting pituitary tumor**), **ectopic ACTH secretion** (usually from a neuroendocrine tumor), or **adrenal tumors**, or **hyperplasia** or **hyperplastic foci/micronodules** within the adrenals.

Question 36

Table of Cushing's Syndrome causes (not expected to know for course)

Answer 36

Question 37

Clinical presentation of Cushing's Syndrome

Answer 37

The classical physical manifestations of cortisol excess include: **weight gain**, **insulin resistance** that can cause diabetes, **lipodystrophy** such that peripheral subcutaneous fat is diminished and **central adiposity is increased, dorsocervical fat pad** (“buffalo hump”), **rounding of the face** (“moon facies”), **sarcopenia** resulting in myopathy, increased bone demineralization that can result in **osteoporosis** and bone fragility, **platelet dysfunction** that can increase **bleeding risk and/or** **thrombosis.** Can also impair **mood and sleep,** and may induce **psychosis.**

Question 38

Diagnosing Cushing's Syndrome

Answer 38

* Screening: **Confirm hypercortisolism** * **24-hr urinary excretion analysis** * **elevated midnight slivary cortisol** * failure to suppress during **low-dose** **dexamethosone challenge** * **Determine ACTH-dependence** * **Measure ACTH** (low = primary, high = secondary) * **High-dose dexamethosone challenge** * **Pituitary imaging** * **Adrenal imaging**

Question 39

Treating Cushing's Syndrome

Answer 39

* Depends heavily on the cause * **Adrenal Cushing syndrome** is typically treated with **surgical adrenalectomy when possible** * **Ectopic Cushing syndrome** is typically treated by addressing the source of ACTH, usually a n**euroendocrine tumor** that may be amenable to **surgery or chemotherapy** * **Cushing’s disease** is treated, when possible, with **surgery to remove the ACTH-secreting pituitary adenoma** * There are instances when surgery is not possible or incomplete. In these scenarios, medical treatments may be needed.

Question 40

Pheochromocytoma pathophysiology

Answer 40

* **Catecholamine-secreting tumors** that arise from the **adrenal medulla** * Note the distinction from **paragangliomas,** which are are catecholamine-secreting tumors that arise from the sympathetic ganglia and are sometimes referred to as “extra-adrenal pheochromocytomas” * Associated with 3 genetic syndromes: **neurofibromatosis type 1** **(LoF in NF1), von Hippel-Lindau disease (LoF in VHL), multiple endocrine neoplasia type 2 (GoF in RET).** * More than 40% of all pheochromocytomas and paragangliomas occur in patients with a heritable germline mutation

Question 41

MEN1 vs MEN2

Answer 41

Question 42

The three P's of MEN1

Answer 42

* Parathyroid * Pituitary * Pancreas

Question 43

Presentation of pheochromocytoma

Answer 43

* Symptoms are characteristically experienced in an **episodic and paroxysmal manner** since tumors secrete in pulses * Patients may experience **hypertension at baseline** with **sudden surges in their blood pressure** * Accompanying this hypertension, they may report “spells” of **headache, palpitations, anxiety and panic, sweating, and tremulousness** * In severe cases patients may report **_blurry vision,_** a concerning sign of **_extremely high blood pressures in the brain._** * As these are often part of a multiple neuroendocrine tumor syndrome, they may be associated with other syndromes like that of medullary thyroid cancer or cafe au lait spots.

Question 44

Patient is found to have pheochromocytoma. They also report the sudden paroxysmal development of light brown patches on their abdomen. What is the likely syndrome?

Answer 44

Neurofibromatosis. The spots are "cafe au lait" spots, associated with this syndrome. This should be confirmed genetically and the patient should be screened for brain and spine tumors.

Question 45

Patient is found to have pheochromocytoma. They have multiple bright red hemangiomas on their face and back. What is the likely syndrome?

Answer 45

Von Hippel Lindau disease. Patient should be screened for brain and spine tumors.

Question 46

Diagnosing pheochromocytoma

Answer 46

The most sensitive and specific test to diagnose catecholamine-secreting tumors is **measurement of plasma or urinary metanephrines**

Question 47

Treating pheochromocytomas

Answer 47

* Both **pheochromocytomas and paragangliomas** are treated by **surgical removal** of the tumor * **Surgery is risky**, since intra-operative surges of catecholamines can result in severe hypertension that increases the risk for stroke and myocardial injury. Therefore, adequate **pre-operative medical management is mandatory.** Should include treatment with **alpha- and beta-adrenergic antagonists (hydralazine and metoprolol)** to block the peripheral effects * There is **risk for post-operative hypotension**, so patients should receive **adequate hydration** **with saline** to ensure an adequately expanded intra-vascular volume prior to surgery

Question 48

Pathophysiology of Congenital adrenal hyperplasia (CAH)

Answer 48

* Category of diseases resulting from the **deficiency or relative insufficiency of an adrenal steroidogenic enzyme** * LoF -\> lack of enzyme production -\> build-up of upstream metabolites, therefore **excess of some hormones** and **deficiency of others** * Can be due to defieiency any steroidogenic enzyme in theory, but in practice **21-hydroxylase deficiency is the most common** * Others are occasionally observed, but are much rarer

Question 49

21-hydroxylase deficiency congenital adrenal hyperplasi

Answer 49

* Autosomal recessive * Newborn screening now performed in every US state * Catalyzes the conversion of **progesterone to deoxycorticosterone in the ZG** and **17- hydroxyprogesterone (17OHP) to 11-deoxycortisol in the ZF** * **Deficiency in cortisol and aldosterone** and **shunt of metabolites into adrenal androgen synthesis** * **Increased ACTH** due to lack of cortisol feedback, resulting in hyperplasia * Broadly speaking, a syndrome of **glucocorticoid and mineralocorticoid deficiency with adrenal androgen excess**

Question 50

Presentation of 21-hydroxylase deficiency CAH

Answer 50

* Depends on severity of mutation * Severe forms present as **Addison's disease with accompanying hyperandrosteronism** * Typically **present at birth with salt-wasting crisis** * **_Need immediate recognition and treatment with salt, fluids, and steroids to live_** * **Female fetuses** with severe phenotypes will have been exposed to **high androgen levels in utero** and may be born with ambiguous genitalia (**clitoromegaly/micropenis**) * Patients with **milder phenotypes** may have **sufficient cortisol and aldosterone**, but ACTH and adrenal androgen excess that presents as **abnormal puberty, menses, and/or hirsutism in females.**

Question 51

Diagnosis of 21-hydroxylase deficiency

Answer 51

* Made by detecting a high 17OHP level * Routine newborn screening test in the US

Question 52

Treating 21-hydroxylase deficiency CAH

Answer 52

* For **severe phenotype**: * Treatment for primary adrenal insufficiency (a **glucocorticoid and a mineralocorticoid**) * The above will result in ACTH inhibition and reduce androsterone levels * For **mild phenotype**: * Usually presents later in life * Decision to use glucocorticoid therapy is made on a case-by-case basis * Other forms of therapy for hyperandrosteronism available

Question 53

Adrenal tumors

Answer 53

* Overwhelmingly **benign** * Frequently encountered as incidentalomas on CT or MRI * Work-up is usually required to prove they are benign and non-functional, they almost always are * Estimated that 1-10% of the population at some point in their lifetime * **Adrenal cortical carcinoma (ACC)** is a **rare** primary adrenal malignancy with **poor prognosis. Capable of secreting adrenal cortical hormones** and thus can present with severe hypercortisolism and **Cushing's syndrome**. **primary aldosteronism**, and/or **androgen excess**

Question 54

Causes of mineralocorticoid signaling excess in the absence of renin

Answer 54

Question 55

Causes of mineralocorticoid signaling excess in the presence of **inappropriate** renin activation

Answer 55

* Renal artery stenosis * Aortic coarctation * Reninoma (extremely rare)

Question 56

Patient presents with a syndrome of pheochromocytoma or paraganglioma. They are found to have a paraspinal tumor and blood labs come back showing abnormally high epinephrine and norepinephrine. What is the next step?

Answer 56

Find the primary tumor! This presentation may look like paraganglioma due to the location of the tumor that was found, but it is secreting epinephrine, and so it must be a metastasis of a primary pheochromocytoma. Only pheochromocytomas can secrete epinephrine.

Question 57

Catecholamine metabolism

Answer 57

Question 58

Tracing back catecholamine metabolites

Answer 58

High NMN suggests the possibility of paraganglioma. High MN suggests possibility of pheochromocytoma. Remember though that, even though this makes MN elevation look like a slam-dunk for pheochromocytoma, in reality it is only ~85% specific, so there are quite a few false positives.

Question 59

Other things that may increase catecholamine or catecholamine breakdown products in blood

Answer 59

* Exogenous catecholamines given as drugs * Inhibitors of monoamine oxidase * Catecholamine re-uptake inhibitors (especially for norepinephrine and serotonin) * Alpha and beta adrenergic receptor antagonists

Question 60

11-Deoxycortisol in 11β-hydroxylase deficiency

Answer 60

Normally 11-deoxycortisol is just an intermediate in the cortisol biosynthesis pathway. However, it accumulates in patients with 11β-hydroxylase deficiency and can act as a mineralocorticoid. This may cause a syndrome of aldosteronism in young patients with undetectably low renin and aldosterone.

Question 61

A patient with Addison's disease is treated with intravenous fluids, hydrocortisone and fludrocortisone. He starts eating a diet with ample dietary sodium. He feels great – his energy levels, vitality, and weight all improve. His skin pigment becomes lighter over time and closer to its original color. He always takes his medication and never misses a dose. The patient loves to sail his boat on Cape Cod. On a hot summer day in July, while sailing in the open waters, he progressively becomes tired, dizzy, and nearly faints. What happened? What are his renin, sodium, and potassium levels like? How do you advise the patient for the future?

Answer 61

Though the patient has baseline normal amounts of mineralocorticoid, he has a ***relative mineralocorticoid insufficiency*** for the **high demand** he is putting on his body. Thus, the patient will present with **hyponatremia, hyperkalemia, and renin in excess, as well as hypovolemia.** He will have acquired this due to **profuse sweating.** The patient should be advised to be **aware of their perspiration and water losses, to stay well hydrated, and to consume sodium liberally** during these periods in order to maintain an adequate volume. Also, the patient should **consider taking an extra fludricortisone pill** if they find themselves in this state again.

Question 62

Most of the time, Addison's disease is ___ in origin.

Answer 62

Most of the time, Addison's disease is **autoimmune** in origin. Think of it as part of the cluster of autoimmune diseases, which tend to go together.