Primary adrenal insufficiency, also known as Addison's disease, is a rare endocrine
disorder that happens when the adrenal gland isn't able to produce enough of the hormones
that the body needs, particularly aldosterone and cortisol.
The reason it's called "primary" is that the underlying problem is localized to
the adrenal gland itself, rather than a problem of a hormone that acts on the adrenal gland
or elsewhere in the body.
Primary adrenal insufficiency can develop acutely or chronically, and a really famous
example of someone having this condition is John F. Kennedy, who was diagnosed at age
30.
Now, there are two adrenal glands, one above each kidney, and each one has an inner layer
called the medulla and an outer layer called the cortex which is subdivided into three
more layers, the zona glomerulosa, zona fasciculata, and the zona reticularis.
The outermost layer is the zona glomerulosa, and it's full of cells that make the hormone
aldosterone.
Aldosterone is part of a hormone family or axis which work together and are called the
renin-angiotensin-aldosterone system.
Together these hormones decrease potassium levels, increase sodium levels, and increase
blood volume and blood pressure.
Aldosterone is secreted in response to elevated levels of renin, and it's role is to bind
to receptors on two types of cells along the distal convoluted tubule of the nephron.
First it stimulates the sodium/potassium ion pumps of the principal cells to work even
harder.
These pumps drive potassium from the blood into the cells and from there it flows down
its concentration gradient into the tubule to be excreted as urine.
At the same time, the pumps drive sodium in the opposite direction from the cell into
the blood, which allows more sodium to flow from the tubule into the cell down its concentration
gradient.
Since water often flows with sodium through a process of osmosis, water also moves into
the blood, which increases blood volume and therefore blood pressure.
The other function of aldosterone is to stimulate the proton ATPase pumps in alpha-intercalated
cells which causes more protons to get excreted into the urine.
Meanwhile, ion exchangers on the basal surface of the cell move the negatively charged bicarbonate
into the extracellular space, causing an increase in pH.
The middle layer is the zona fasciculata, and the cells there make the hormone cortisol
as well as other glucocorticoids.
Cortisol is also needed in times of emotional and physical stress like arguing with a friend
or fleeing from a pack of raccoons.
In those situations, the hypothalamus—which is an almond-size structure which sits at
the base of the brain, releases corticotropin-releasing hormone is released from, and received by
the pituitary gland, the pea-sized structure sitting just underneath the hypothalamus.
In response, the pituitary gland sends out adrenocorticotropic hormone, or ACTH, which
travels through the blood to the zona fasciculata of the adrenal glands and signals cells there
to release cortisol.
Cortisol is a lipid-soluble molecule, meaning it can mingle with fats, which allows it to
easily pass through the plasma membrane of cells and bind to the receptors inside.
In fact, almost every body cell has cortisol receptors, so it affects an huge variety of
functions in the body!
One of cortisol's main jobs though is to increase blood glucose levels by promoting
gluconeogenesis in the liver, gluconeogenesis is the formation of glucose from noncarbohydrate
sources, like amino acids or free fatty acids.
Cortisol also gets the muscles to break down proteins into amino acids and gets adipose
tissues to break down fats into free fatty acids, both of which provide the liver with
more raw materials to work with.
So basically, cortisol keeps blood glucose levels high, and this is in contrast top the
hormone insulin, which causes glucose to be taken up by various body tissues, and so essentially
cortisol acts to counteract this effect this in an effort to make sure that the body can
respond appropriately to those raccoons, or other stressors.
Finally, the innermost layer is the zona reticularis, and cells there make a group of sex hormones
called androgens, including one called dehydroepiandrosterone, which is the precursor of testosterone.
So the adrenal glands are involved in testosterone production in both men and women, but the
amount that the adrenals contribute is pretty small, relative to the testes in men, which
accounts for the very different levels of androgens in men versus women.
In men, high levels of androgens are responsible for the development of male reproductive tissues
and secondary sex characteristics like facial hair and a large larynx or Adam's apple.
In women, low levels of testosterone are responsible for a growth spurt in development, underarm
and pubic hair during puberty, and an increased sex drive in adulthood.
The exact mechanism for adrenal androgen production is not well understood, but like cortisol,
it seems to be stimulated by adrenocorticotropic hormone released from the pituitary gland.
So, that all brings us back to primary adrenal insufficiency, which is where the adrenal
cortex gets progressively damaged over time.
In developed countries the most common cause is autoimmune destruction, when the body's
own immune cells mistakenly attack the healthy adrenal cortical tissues, though the precise
reason why this happens isn't clear.
In developing countries the most common cause is tuberculosis; in this case the infection
spreads from the lungs to the adrenal glands, causing inflammation and destruction in the
adrenal cortex.
Another important cause is metastatic carcinoma, which is where cancer spreads to the adrenal
cortex from somewhere else in the body.
Regardless of the cause, it turns out that the adrenal cortex has a high functional reserve,
meaning that a small amount of functional tissue can still do a pretty decent job of
churning out enough of the hormones to meet the body's needs.
As a result of this though, once there are symptoms, it's usually a sign that a majority,
sometimes up to 90%, of the adrenal cortex has been destroyed.
The symptoms of primary adrenal insufficiency correspond to which layers of the adrenal
cortex have been destroyed.
When the zona glomerulosa is destroyed, aldosterone levels fall and that leads to high potassium
levels in the blood, or hyperkalemia, and low sodium levels in the blood, or hyponatremia.
With less sodium around in the blood, water moves out of the blood vessels, which results
in a low blood volume, or hypovolemia.
Finally, fewer protons are lost, meaning more build up in the blood and that results in
an acidosis, and more specifically a metabolic acidosis, since it's caused by the kidneys.
These electrolyte changes and hypovolemia can cause symptoms like cravings for salty
foods with simultaneous nausea and vomiting, fatigue, and dizziness that worsens with standing.
When the zona fasciculata is destroyed, cortisol levels fall and that leads to inadequate glucose
levels during times of stress.
This means that while being chased by a pack of raccoons, instead of feeling ready to sprint
a person might feel weak, tired, and disoriented.
Also, those decreased levels of cortisol causes the pituitary gland to become overactive,
since usually cortisol ihas a negative feedback effect the pituitary gland.
So it ends up producing pro-opiomelanocortin, which is a precursor to adrenocorticotropic
hormone, but it also turns out to be a precursor to melanocyte-stimulating hormone, the hormone
that leads to skin pigment production.
So when your pituitary gland is overactive, it ends up making more melanocyte-stimulating
hormone, resulting in hyperpigmentation, or darkening of the skin, especially in sun-exposed
areas and joints, like the elbows, knees, and knuckles.
In some extreme cases of primary adrenal insufficiency, the zona reticularis can be affected as well,
and androgens levels can fall.
This decrease doesn't affect men much because remember the testes are the major source of
male androgens.
However women can experience a loss of pubic and armpit hair, as well as a decreased sex
drive.
Oftentimes, the slowly progressive chronic symptoms of primary adrenal insufficiency
are missed or ignored until a major stressor, like a serious injury, surgery, or infection,
suddenly causes the symptoms to become really severe.
In other words the body has a sudden increased need for aldosterone and cortisol, and the
failing adrenal cortex simply can't deliver.
This is known as addisonian crisis, or acute primary adrenal insufficiency, and it usually
happens when the majority of the zona glomerulosa and zona fasciculata are destroyed.
It can cause a sudden pain the lower back, abdomen, or legs, with severe vomiting and
diarrhea, followed by dehydration; low blood pressure; and loss of consciousness.
Left untreated, an addisonian crisis can be fatal.
Addisonian crises can also arise from Waterhouse-Friderichsen syndrome, which is when a sudden increase
in blood pressure causes blood vessels in the adrenal cortex to rupture, filling up
the adrenal glands with blood and causing tissue ischemia and adrenal gland failure.
Primary adrenal insufficiency can be diagnosed with an adrenocorticotropic hormone stimulation
test.
During the test, a small amount of synthetic adrenocorticotropic hormone is given, and
the amount of cortisol and aldosterone produced in response is measured, which helps you figure
out how well the adrenal glands are working.
Usually individuals with primary adrenal insufficiency are treated with hormones to make up for the
lack of cortisol, aldosterone, and androgens.
They typically have to be taken for the rest of an individual's life, and stopping the
hormone replacements can lead to Addisonian crisis.
All right, as a quick recap, primary adrenal insufficiency is a failure of the adrenal
cortex - specifically, the zona glomerulosa which causes low aldosterone, as well as the
zona fasciculata which causes low cortisol, and in severe cases, the zona reticularis,
which causes low androgens.
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