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https://www.niddk.nih.gov/health-information/endocrine-diseases/adrenal-insufficiency-addisons-disease/definition-facts

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National Institute of Diabetes and Digestive and Kidney Diseases

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What is adrenal insufficiency?

Adrenal insufficiency is a disorder that occurs when the adrenal glands don't make enough of certain hormones. The adrenal glands are located just above the kidneys. Adrenal insufficiency can be primary, secondary, or tertiary. Primary adrenal insufficiency is often called Addison's disease.

Adrenal insufficiency can affect your body's ability to respond to stress and maintain other essential life functions. With treatment, most people with adrenal insufficiency can have a normal, active life.

The adrenal glands, two small glands on top of your kidneys, make hormones that are essential for life.

Addison's disease

Addison's disease occurs when the adrenal glands are damaged and can't make enough of the hormone cortisol and sometimes the hormone aldosterone.

Secondary adrenal insufficiency

Secondary adrenal insufficiency starts in the pituitary-a pea-sized gland at the base of the brain. The pituitary makes adrenocorticotropin (ACTH), a hormone that tells the adrenal glands to make cortisol. If the pituitary doesn't make enough ACTH, the adrenal glands don't make enough cortisol. Over time, the adrenal glands can shrink and stop working.

Tertiary adrenal insufficiency

Tertiary adrenal insufficiency starts in the hypothalamus, a small area of the brain near the pituitary. The hypothalamus makes corticotropin-releasing hormone (CRH), a hormone that tells the pituitary to make ACTH. When the hypothalamus doesn't make enough CRH, the pituitary gland doesn't make enough ACTH. In turn, the adrenal glands don't make enough cortisol.

CRH tells the pituitary to make ACTH, which in turn tells the adrenals to make cortisol.

What do adrenal hormones do?

The adrenal glands make two main types of hormones: cortisol and aldosterone.

Cortisol

Cortisol is sometimes called the "stress hormone" because it helps your body respond to stress. Cortisol also helps

Cortisol belongs to a class of hormones called glucocorticoids.

Aldosterone

Aldosterone helps maintain the balance of the minerals sodium and potassium in your blood. Sodium and potassium work together to control the salt and water balance in your body and help keep blood pressure stable. Both help maintain normal nerve and muscle function. Potassium also helps your heartbeat stay regular.

Aldosterone belongs to a class of hormones called mineralocorticoids.

How common is adrenal insufficiency?

Addison's disease is rare. In developed countries, it affects about 100 to 140 of every million people. ¹

Secondary adrenal insufficiency is more common, affecting 150 to 280 people per million. 2,3 Secondary and tertiary adrenal insufficiency are often grouped together, so no numbers for tertiary adrenal insufficiency by itself are available.

Who is more likely to develop adrenal insufficiency?

Women are more likely than men to develop Addison's disease. ³ This condition occurs most often in people between the ages of 30 and 50, ² although it can occur at any age, even in children.

Secondary adrenal insufficiency occurs in people with certain conditions that affect the pituitary.

People who take glucocorticoid medicines, such as prednisone, for a long time and then stop are most likely to develop tertiary adrenal insufficiency. These medicines are used to treat medical conditions such as asthma, rheumatoid arthritis, lupus, cancer, and inflammation, among others.

What are the complications of adrenal insufficiency?

The most serious complication of adrenal insufficiency is called adrenal crisis. If not treated right away, adrenal crisis can cause death. Your body needs much more cortisol than usual during times of physical stress such as illness, serious injury, or surgery. The severe lack of cortisol at these times can cause life-threatening low blood pressure, low blood glucose, low blood sodium, and high blood potassium.

Seek Care Right Away

If you have adrenal insufficiency and have symptoms of adrenal crisis, you need emergency medical treatment. Symptoms include

sudden, severe pain in your lower back, abdomen, or legs

vomiting and diarrhea

weakness

confusion

loss of consciousness

An injection, or shot, of corticosteroid-a glucocorticoid medicine-can save your life in an emergency. Make sure you have a corticosteroid injection with you at all times, and make sure your friends and family know how and when to give you the injection. Wear a medical alert tag or carry a card with information about your condition in case of emergency.

Sometimes the lack of aldosterone in Addison's disease can cause hyponatremia. This condition occurs when you don't have enough sodium in your blood. Hyponatremia can cause confusion, fatigue, and muscle twitches and seizures. The lack of aldosterone can also cause hyperkalemia, or too much potassium. Mild hyperkalemia may not cause problems, but severe hyperkalemia can cause life-threatening changes in your heart rhythm.

References

[1] Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology and Metabolism. 2016;101(2):364-369.

[2] Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014;383(9935):2152-2167.

[3] Chabre O, Goichot B, Zenaty D, Bertherat J. Group 1. Epidemiology of primary and secondary adrenal insufficiency: prevalence and incidence, acute adrenal insufficiency, long-term morbidity and mortality. Annals of Endocrinology (Paris). 2017;78(6):490-494.

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Definition & Facts of Adrenal Insufficiency & Addison's Disease - NIDDK

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Adrenal insufficiency causes low levels of important hormones, including cortisol, which is essential to life. Learn more about this serious condition.

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If cortisol not measured on time (as soon as waking up), you will not catch the high peak of cortisol.

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in regard to kidneys, slightly different location.
right = Ontop of kidney lobe
left = Hanging onto medial side of kidney

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Therapy is less than 3 weeks, no significant risk of affecting the adrenal axis

Long-term it can suppress the adrenal axis giving mimicking endogenous Cushing's syndrome

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Primary hypoadrenalism (Addison’s disease) = primary adrenal insufficiency

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Primary hypoadrenalism (Addison’s disease) = primary adrenal insufficiency

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Disease characterised by adrenal glands not functioning the correct way because no cortisol made, lack of neg. feedback
\A ot more CRH and ACTH, because body responds to lack of cortisol

Addison disease itself is autoimmune (self-destrcution of entire adrenal cortex (90%)) = most common cause in developed countries; in other countries other chief aetiologies

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Basal levels

ACTH & cortisol

Suppression & stimulation tests are used in suspected excess and deficient cortisol production, respectively:

Dexamethasone suppression tests

Administration of synthetic glucocorticoid (dexamethasone)

ACTH stimulation tests (Synthacthen test)

Synthetic ACTH (tetrosactide, which consists of the first 24 amino acid of human ACTH) is given to stimulate cortisol production

Testing at 9 am for cortisol levels (circadian rhythm has effect on cortisol levels as here it is the highest)
If suspect an excess of cortisol, dexamethasone suppression test should be done

administer synthetic glucocuortoiud in abnormal physiological circumstances there is a feedback suppression of CRH and ACTH

If there is not enough production of cortisol administer synthetic ACTH (stimulation test)

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Steroids produced are grouped into 3 major classes based on their effects:

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Steroids produced are grouped into 3 major classes based on their effects:

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Both adrenals have their own blood supply

Right suprarenal vein drains directly into vena cava, left suprarenal vein drains into left renal vein

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Corticosteroid receptors type 1

Effects on extracellular balance of sodium and potassium in the distal tubule of the kidney (aldosterone) --> done by juxtaglomerular apparatus

Used for retention of sodium and excretion of potassium --> This means water reabsorption --> increase in blood pressure --> Counterbalances low perfusion which is sensed at beginning of RAAS cycle

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Outer fatty capsule
Cortex
Zona glomerulosa → mineralocorticoids (aldosterone)
Zona fasciculata → glucocorticoids (cortisol)
Zona reticularis → androgens

Medulla

Chromaffin cells → catecholamines: epinephrine (adrenaline), norepinephrine (noradrenaline) (and dopamine to a very small extent) → sympathetic nervous system response

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Sex hormones are secreted but need to be further metabolized to reach their final form of testosterone or dihydrotestosterone

Fat composition of body can have consequences in the synthesis of these hormones

If you have a deficiency of progesterone, mineralocorticoids are not produced. A deficiency of one thing means an excess of another.

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Destruction of the entire adrenal cortex → reduction of glucocorticoid, mineralocorticoid and sex steroid production are all reduced

→ this differs from hypothalamic-pituitary disease:

Reduced cortisol levels → feedback loop → increased CRH & ACTH production

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Cortisol has negative feedback on the hypothalamus, affected by circadian rhythm (increases with severe stress)

Corticotrophin releasing hormone in response to stress or circadian rhythm, also stimulates ACTH

Corticosteroid receptors type 2

Glucocorticoid action is modified locally by the action of 11β-hydroxysteroid dehydrogenase (11βHSD)

Glucorticoids have a diabetes like circulation due to increasing circulating glucose

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2 main concerns

Is it functional or non-functional (if functional might need surgical removal)

Is it benign or malignant

Classified as hyperadrenalism if the lesion is functional

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Secretion of cortisol: hypothalamus-pituitary-adrenal (HPA) axis 

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Secretion of cortisol: hypothalamus-pituitary-adrenal (HPA) axis 

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Symptoms tend to be non-specific

Addisonian crisis = Combination of low blood sugar level, high potassium, and low blood pressure (life-threatening situation)

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Short ACTH stimulation test (if impaired cortisol response, hypoadrenalism confirmed) --> 80 nanograms

ATH is then measured to take out hypothalamic causes

All axes connected to hypothalamus , primary disease refers to gland itself, secondary pituitary, tertiary hypothalamus

Other:

A 9:00 hours plasma ACTH level

Electrolytes & urea

Blood glucose

Adrenal antibodies

Chest & abdominal X-rays

Plasma renin activity

Hypercalcaemia & anaemia

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Secretion of mineralocorticoids: RAAS system 

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Secretion of mineralocorticoids: RAAS system 

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State with increased glucocorticoid

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During Addisonian crisis

1. Instant IV
2. Glucose
3. start with saline to balance salt conc.
4. Hydrocortisone is important to suppress

Get blood pressure up!

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Disease: Pituitary dependent; ectopic; iatrogenic

Symtpoms: adrenal glands, iatrogenic with glucocorticoids ; can get a crushing appearance with increased alcohol consumption, pathophysiology not known

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Replacement gluco- and mineralocorticoids instead of hydrocortisone

Assessed if there are comorbidities such as tuberculsosis,,, amount of dose depends on physiology of patients (based on their well-being)

Then after assess if levels are back to normal

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Know how to increase steroid replacement dose for intercurrent illness

Carry a ‘Steroid Card’

Wear a Medic-Alert bracelet

Keep an ampoule of hydrocortisone at home

Is important to tell peers if you have a condition that needs to be treated soon; always useful to have this information. Some people want to keep certain things private but it always better to say!

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Nelson syndrome is due to adrenectomy

Addison is due to when 90% of adrenal cortex is destroyed for other reasons

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Etiology

Problem in ACTH --> adrenal gland gets too little stimulation --> hypoadrenalism + deficiency of cortisol --> can lead to all other sorts of complications

Rathke's pouch

Long-term steroid therapy leading HPA suppression (most common)

Clinical features

.

Treatment

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Clinical manifestations (those of glucorticoid excess)

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Clinical manifestations (those of glucorticoid excess)

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Depression, almost change personality, lemon/potato on a stick (central obesity and atrophic legs)

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Etiology

Autosomal recessive disorder

Pathophysiology

CYP21 is not produced, (most cmoon cause of adrenal issues in children) --> If there is a complete block, a sign of that is abnormal genitalia at birth

There is reduced cortisol secretion, hence feedback increases ACTH and other things in the attempt to increase cortisol again
--> This may lead to adrenal hyperplasia

Virilization

Salt wasting

Clinical features

If severe: present at birth with sexual ambiguity or adrenal failure (collapse, hypotension, hypoglycaemia), sometimes with a salt-losing state (hypotension, hyponatraemia)

Investigations

Expert advice

For ambiguous genitalia → seek advice urgently before any assignment of gender is made

Profile of adrenocortical hormones is measured before and 1 hour after ACTH administration

17-hydroxyprogesterone levels

Urinary pregnanetriol

Androstenedione levels

Basal ACTH levels

Treatment

Replace glucocorticoid & mineralocorticoid activity

Genetic counselling & antenatal diagnosis are essential

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Confirmation of diagnosis = 48-hour low-dose dexamethasone test

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Too much cortisol, hence dexamethasone suppression test (increased level of cortisol = cushings)

24h urinary-free cortisol tests

The difference between low and high doses is that in the high dose, it is more important to assess the difference with pituitary-dependent disease

The low dose is used in the initial diagnosis of Cushing syndrome, and the high dose for differential. If pit. dependent, suppression of treatment in 90% of the cases.

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Important for exam!

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CT or MRI to test for carcinoma

If hypokalemia can be linked to ACTH secretion

Surgery (adrenalectomy)

Removal of pituitary tumour

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= increased mineralocorticoid secretion from the adrenal cortex → account for 5-10% of all HTN

Other causes of HTN should also be considered if there is suspicion

DDX: (table below)

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When to suspect this:

Aetiology

.

Difference with secondary hyperaldosteronism

Arises when there is excess renin (and thus angiotensin II) stimulation of the zona glomerulosa

Pathophysiology

Excess aldosterone production → sodium retention & potassium loss → HTN & hypokalaemia

Clinical features

Hypertension

Hypokalaemia not always present (50%)

Investigations

Plasma aldosterone:renin ratio (ARR)

Elevated plasma aldosterone levels that are not suppressed with 0.9% saline infusion or fludrocortisone administration

Suppressed plasma renin activity

Hypokalaemia & urinary potassium loss

Once diagnosis of hyperaldosteronism is established → differentiation of adenoma from hyperplasia with CT or MRI

Bilateral adrenal vein sampling (lecture)

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Adenoma → surgical removal (usually laparoscopically) → BP falls in 70% of patients

Hyperplasia → treat with aldosterone antagonist

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Rare condition caused by gene fusion → produces aldosterone which is under ACTH control

Treatment with glucocorticoid solves the problem

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Syndrome of apparent mineralocorticoid excess

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Syndrome of apparent mineralocorticoid excess

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This causes clinical picture of primary hyperaldosteronism but with low renin & low aldosterone

Reduced activity of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)

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= rare tumours of SNS at adrenal gland that secrete catecholamines, noradrenaline, adrenaline and their metabolites

Phaeochromocytoma (adrenals) (90%) vs. paraganglioma (10%)

Non-specific symptoms; extreme heartbeat, sweating, headache, hypertension

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Clinical features of catecholamine excess

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Clinical features of catecholamine excess

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Blood smaples, and measuring adrenaline and norepinephrine.

Imaging; tumours most often benign but can also spread as malignant

Biopsy can generate huge release of norepinephrine --> no biopsy!

Measure urinary catecholamines and metabolites

Resting plasma catecholamines

Plasma chromogranin A (= storage vesicle protein)

Clonidine suppression test

CT scans (abdomen)

MRI

Scanning with [131I]meta-iodobenzylguanidine (MIBG)

Nuclear imaging: 68Ga-DOTATATE or 18F-FDG PET

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Surgical removal if possible
Combined alpha- and beta-blockade

over 10% recur or develop a further tumour

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https://www.nature.com/articles/s41574-022-00655-w.pdf