Primary adrenal insufficiency

Definitions & Key takeaways

Primary adrenal insufficiency, also known as Addison's disease, is a chronic condition in which the adrenal glands fail to produce enough cortisol and mineralocorticoid hormones. This can be caused by an autoimmune disorder, infection, or causes of damage to the adrenal glands. Symptoms may include fatigue, weight loss, muscle weakness, low blood pressure, and darkening of the skin. Treatment involves replacement of cortisol and mineralocorticoid hormones, as well as treating any underlying cause.

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Introduction0:00–0:36

Primary adrenal insufficiency occurs when the adrenal glands fail to produce key hormones like glucocorticoids and mineralo corticoids.
It can be acute, also known as adrenal crisis, and chronic, which is referred to as Addison disease. Now each of the two adrenal glands sits on top of a kidney and has two main parts.
The inner part, the medulla, produces the hormones epinephrine and norepinephrine. On the flip side, the outer part, the cortex, has 3 layers.
The outermost layer, the zona glomerulosa, produces mineralo corticoids such as aldosterone. With mineralocorticoids, minerallo refers to minerals because these hormones help regulate sodium and potassium levels.

Physiology of adrenal glands0:36–1:02

The middle layer, the zona fasciculata, produces glucocorticoids like cortisol. With glucocorticoids, gluco refers to glucose because they help increase blood glucose levels.

Aldosterone synthesis and functions1:02–2:31

The innermost layer, the zona reticularis, produces androgens such as dehydroepiandrosterone, which is a precursor of testosterone.
Now the inner and middle layers of the cortex are mainly under the control of the hypothalamus pituitary adrenal axis. The hypothalamus releases corticotropin releasing hormone which stimulates the corticotrophs in the anterior pituitary gland.
Corticotrophs then produce proopal melanocortin or POMC. Next, corticotrophs cleave this protein into melanocyte stimulating hormone, and adrenocorticotropic hormone, or ACTH.
Melanocyte stimulating hormone stimulates the melanocytes in the skin to release melanin, which can darken skin pigmentation.
On the flip side, ACTH travels through the bloodstream to the adrenal glands, where it stimulates the zona reticularis to release androgens and the zona fasciculata to release cortisol, which plays a big role in metabolism.
On one hand, cortisol signals the liver to convert amino acids into glucose. On the other, it reduces glucose uptake in peripheral tissues.
Together, these actions raise blood sugar levels. Cortisol also promotes protein synthesis in the liver while breaking down proteins in muscles.

Glucocorticoids synthesis and functions2:31–4:27

In addition, it increases the breakdown of triglycerides and fat tissue, releasing free fatty acids into the bloodstream for energy.
By balancing glucose, protein, and fat metabolism, cortisol helps mobilize sources during stressful situations like when you're tackling the USMLE exam.
Also, it helps regulate the immune response and reduces inflammation to prevent overreaction when you're under stress. On the other hand, the zono glomerulosa is controlled by the renin angiotensin aldosterone system.
When BP or sodium levels drop, the juxagglomerular cells in the kidneys release renin into the bloodstream. In the bloodstream, renin cleaves angiotensinogen into angiotensin 1, which is later converted by angiotensin converting enzyme or AC into angiotensin 2.
Angiotensin 2 raises BP through two mechanisms. First, it triggers vasoconstriction of small arterioles, subsequently increasing peripheral vascular resistance.
Also, angiotensin 2 stimulates the zono glomerulosa to release aldosterone in the kidneys. Aldosterone increases sodium and water uptake, boosting the intravascular volume and maintaining BP.
At the same time, it stimulates potassium excretion, that's why high potassium levels can also trigger aldosterone release.
In primary adrenal insufficiency, the hypothalamus and pituitary gland work normally, but the adrenal glands fail to respond, resulting in glucocorticoid and mineralo corticoid deficiency.
In secondary adrenal insufficiency, the hypothalamus sends signals, but the pituitary gland drops the ball and doesn't pass it to the adrenal glands.

Androgens synthesis and functions4:27–5:33

Finally, in tertiary adrenal insufficiency, the hypothalamus fails to signal the pituitary gland, so the message never reaches the adrenal glands.
In these two types, the adrenal glands work just fine, but they are not getting the signal they need to produce glucocorticoids.
Still, they can produce mineralo corticoids because that process does not depend on the hypothalamus or pituitary gland.
Now, let's go back to primary adrenal insufficiency, which can be further subdivided into acute adrenal insufficiency and chronic adrenal insufficiency.
Acute adrenal insufficiency or adrenal crisis can result from severe bleeding in both adrenal glands which might occur due to blood thinning medications or serious infections like sepsis.
Moreover, adrenal bleeding and sepsis is also known as Waterhouse-Friedrichsson syndrome. Most commonly, this syndrome occurs due to Neisseria meningititis infection and is more frequent in children.
Regardless of the cause, when bleeding damages adrenal tissue, it disrupts the production of cortisol. And aldosterone.

Causes5:33–6:39

On the flip side, chronic adrenal insufficiency, also known as Addison disease, is less common and occurs when the adrenal cortex gradually breaks down.
This can result from autoimmune adrenalitis, infections. Or metastasis.
Autoimmune adrenalitis often occurs in autoimmune polyglandular syndrome type 1 or APS1, which is caused by a mutation in the autoimmune regulator gene on chromosome 21, or AIR for short.
In this condition, the immune system attacks endocrine organs, mainly the adrenal and parathyroid glands. In the adrenal glands, the immune system spares the medulla but sends lymphocytes to the adrenal cortex.
Over time, lymphocytes destroy the cortex, leaving a collapsed network of connective tissue with several survivors of cortical cells which cannot keep up with the body's demand.
This eventually results in adrenal insufficiency. At the same time, a mutation in the air gene tricks the immune system into seeing interleukins 17 and 22 as foreign invaders, leading it to produce autoantibodies that block them.

Pathophysiology6:39–9:21

Without these interleukins, which are crucial in fighting fungal infections, the body becomes more vulnerable to fungal infections like histoplasmosis.
In severe cases, the fungus can spread to various organs, including the adrenal glands, potentially leading to adrenal insufficiency.
Next up are infections such as tuberculosis and HIV. In tuberculosis, the infection primarily starts within the lungs, but it doesn't always stay there.
The bacteria can squeeze into small blood vessels and spread throughout the body, including the adrenal glands. Once there, the immune system jumps into action by forming tight little clusters of immune cells around bacteria called granulomas.
Think of them like tiny forts built to trap the invaders. But inside these forts, adrenal cells begin to die through a process called caseous necrosis, which looks like soft cheese under a microscope.
Over time this damage gradually spreads through the adrenal cortex, resulting in chronic adrenal insufficiency. On the flip side, in HIV infection, the problem isn't the virus itself but the weakened immune system.
With its defenses down, the body struggles to fight off pathogens like cytomegalovirus and Mycobacterium avium, which can spread throughout the body, including the adrenal glands.
Eventually this can result in primary adrenal insufficiency. Finally, if cancer spreads from a primary location, it can reach the adrenal glands.
In this case, tumor cells take over the normal tissue, subsequently making the adrenal glands grow bigger but less productive.
Now moving on to clinical features, in acute adrenal insufficiency, rapid destruction of the adrenal cortex typically results in intractable vomiting, abdominal pain, as well as cardiovascular collapse and coma.
And since this rapid destruction can occur as part of Waterhouse Friedrichsson syndrome, it's important to watch for other signs of sepsis and disseminated intravascular coagulation.
Such as petechial rash. In chronic adrenal insufficiency, the adrenal cortex breaks down slowly, giving the body time to adjust.
Early symptoms are vague and include fatigue, nausea, vomiting, and diarrhea. As damage progresses, the production of cortisol and aldosterone drops.

Symptoms9:21–9:50

Low cortisol impairs gluconeogenesis, causing hypoglycemia, while low aldosterone results in potassium retention and sodium loss.
Eventually, a person develops hyperkalemia and hyponatremia in combination with volume depletion and subsequent hypotension.
Next, low cortisol levels trigger the pituitary gland to boost ACTH production, which shares the origin with melanocyte stimulating hormone.

Addisonian crisis9:50–10:33

So more ACTH means more melanocyte stimulating hormone, which results in hyperpigmentation of the skin and mucosa. Typically, hyperpigmentation affects sun exposed areas including the face, neck, and elbows, as well as non-exposed areas such as the areola and perineum.
Finally, keep in mind that in chronic adrenal insufficiency, stressors such as infections, trauma, or surgical interventions can trigger acute adrenal insufficiency.
Diagnosis mainly involves checking hormone levels. Since the adrenal glands are not working, cortisol and aldosterone levels are low.

Diagnosis10:33–10:55

In response, the pituitary gland ramps up the ACTH production, so ACTH levels are high. To figure out where the problem lies along the hypothalamic pituitary adrenal axis, give a synthetic ACTH called cocentropin.
In primary insufficiency, the adrenal glands can't respond to cocentropin, so cortisol levels stay low. But in secondary and tertiary insufficiency, adrenal glands are fine, so cocentropin raises cortisol levels.

Treatment10:55–11:12

People with primary adrenal insufficiency require lifelong hormone replacement therapy to make up for missing hormones. Finally, keep in mind that stopping these medications abruptly can trigger an adrenal crisis.

Review11:12–11:57

All right, as a quick recap, primary adrenal insufficiency occurs when the adrenal glands fail to produce hormones like glucocorticoids and mineralo corticoids.
Acute primary adrenal insufficiency or adrenal crisis often occurs due to severe adrenal bleeding, often from blood thinners or sepsis.
Chronic adrenal insufficiency known as Addison disease is less common and occurs when the adrenal cortex breaks down over time, usually from autoimmune conditions, infections, or metastasis.