The Endocrine System

Advanced Pathophysiology-Giner > Unit 8

Overview of the Endocrine System

The purpose of the endocrine system is to maintain the body’s
homeostasis using hormones. Hormones are signaling molecules.
Although a wide variety of hormones function within the body, they
share certain general characteristics:

1. Hormones have specific rates and rhythms of secretion. Three

basic secretion patterns are: (1) circadian or diurnal patterns,
(2) pulsatile and cyclic patterns, and (3) patterns that depend
on levels of circulating substrates (e.g., calcium, sodium,
potassium, or the hormones themselves).
2. Hormones operate within feedback systems, either positive or
negative, to maintain an optimal internal environment.
3. Hormones affect only cells with specific receptors and then act
on those cells to initiate specific cell functions or activities.

When an endocrine cell receives a stimulus or command, this

stimulates the endocrine cell to secrete hormones into the blood
stream. The hormones will then target and bind onto a specific
receptor on a target cell. This will cause the target cell to initiate a
response as shown in the diagram below:
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Signaling Hormones
It is important to understand the signaling aspect of hormones. First,
there are three types of signaling hormones, steroid, peptide and
amine. The table below provides a description of the signaling
hormones and their properties.
Class Description Properties Examples

Steroid Lipids Lipophilic – can cross membrane Testosterone

derived from
Undergoes constitutive secretion Estrogen / Progesterone
cholesterol

Peptid Short Hydrophilic – cannot cross Insulin

e polypeptide membrane
Glucagon
chains
Undergoes regulatory secretion

Amine Derived from Hydrophilic – cannot cross Thyroxine

aromatic membrane
amino acid
Undergoes regulatory secretion

Note that peptide and amine hormones are hydrophilic (water-

soluble). This means that they are easily dissolved in fluid and do
not have to bind to a protein in order to circulate. Characteristically,
they also have a short half-life of just seconds to minutes as they
are catabolized by circulating enzymes. Insulin, for example is a
peptide hormone. Shortly after its release, it is catabolized by
insulinase enzymes within 3-5 minutes.
Lipid-soluble hormones, in contrast, are transported bound to a
protein. Because they are bound, they can remain in the blood for
hours to days. It is very important to note here that when a hormone
is bound to a protein, it cannot exert its effects. Only free circulating
hormones can initiate responses inside of a target cell. This will be
revisited as we delve into the diseases of the endocrine system.
Upon arrival to the cell membrane, the protein-bound hormone must
disengage from the protein in order to diffuse into the cell where its
effects can be exerted.

Hormone Regulation
Two important concepts to understand before reviewing endocrine
system disorders is how hormone release is regulated and once
arriving to the target cell, how it enters the cell to exert its effect.
Let’s begin with hormone regulation.
Hormone regulation:

1. Hormone release is regulated by chemical factors (e.g. blood

glucose), endocrine factors (e.g. a hormone from one gland
controls another gland) and neural control.
2. Hormone release is regulated by feedback systems. These
are responsible for monitoring and controlling the cellular
environment. You are likely familiar with the negative and
positive feedback system. The negative feedback system will
activate when there is a change in endocrine, chemical or
neural response. It will decrease the synthesis and secretion of
a hormone. In contrast, positive feedback systems result when
the endocrine, chemical or neural response increases the
synthesis and secretion of a hormone. This is illustrated in the
diagram below.
The feedback loop processes are simple. Positive feedback results
when the hormone is needed to exert its effects on the target cell.
The hormone is produced and secreted. When there is less need for
the hormone, negative feedback results that stops the production
and release of the hormone. The positive and negative feedback
system is illustrated in an example below in response to a low blood
glucose level.
Because glucose is a necessary source of energy for the body, it will
attempt to restore a normal blood glucose level in order to maintain
homeostasis. Therefore, the endocrine system will attempt to
increase blood glucose levels by stimulating an endocrine cell. In
this case, it is the alpha cell of the pancreas. The alpha cell will then
secrete a hormone, glucagon into the blood stream. Glucagon will
travel through the blood stream to the liver which is the target cell.
When glucagon binds to a receptor on the target cell (liver cell), it
will stimulate the liver to break down glycogen to secrete glucose in
the blood. The response of the liver cell is the creation of more
glucose in the blood. As the blood glucose is increased, a negative
feedback signal is sent to the pancreas to stop the secretion of
glucagon.

Cellular Communication
After a hormone arrives to the target cell, it must be able to enter
the cell in order to exert its effects. Before going any further with
our discussion of hormones, it is important to consider cellular
biology in terms of cellular communication, signal transduction and
membrane transport. Under this week’s readings, there is a
recommended chapter from your textbook that will provide a review
of these mechanisms. You are encouraged to review these in
solidifying understanding of cellular communication. These
mechanisms are addressed briefly here.
First, the hormone must communicate with the target cell. Cells, in
general, communicate through many kinds of signal molecules and
may occur in three ways:

1. Receptors are displayed on the plasma membrane of the cell.

Think of the receptors as signaling molecules that brings the
hormone to where it specifically needs to be.
2. Affects receptor proteins inside the target cell where the signal
molecule must enter the cell to bind with them.
 3. Forms protein channels (gap junctions) that coordinate the
activities of adjacent cells (this is nothing more than a way for
cells to communicate with one another).

It is important to mention here the role of first and second

messengers in cellular communication. First, messengers are
extracellular signaling messengers that bind to the membrane
receptors to either open or close specific membrane channels to
regulate the movement of ions in or out of the cell. Channels can be
opened by the binding of an ion or molecule to a specific membrane
receptor that is closely associated with the channel (e.g. G proteins
located inside the cell transmits signals from outside the cell to
inside the cell). Locate the G protein in the diagram below and note
its proximity to the cell membrane.

Signals are then transferred to an intracellular messenger (second

messenger) which then triggers biochemical events within the cell.
This is where signal transduction comes into play.

Signal Transduction
Signal transduction involves communication between the outside of
the cell and the inside of the cell. Remember that the hormone that
has traveled to the specific target cell wants to get inside of the cell.
To help, extracellular chemical messengers (first messengers) are
available to convey signals or instructions from outside of the cell to
the interior cell. Signal transduction pathways help with this process
by allowing cells to respond to external signals. Signals pass
between the cells when a certain type of molecule is produced by
one cell (the signaling cell) and received by another cell (the target
cell) by way of a receptor protein that recognizes and responds to
that specific signaling molecule. The diagram below provides a
general view of the signal transduction pathway.

Water-Soluble and Lipid-Soluble

Hormones
Let’s one more time turn our attention to water-soluble and lipid-
soluble hormones. Water soluble hormones do not need to be bound
to a protein in order to circulate to the target cell. It circulates freely
and binds to its specific receptor on the cell membrane, enters the
cell and then exerts its effects. Lipid-soluble hormones do circulate
bound to a protein. When it arrives to the cell membrane, it must
disengage from the protein in order to cross the cell membrane.
Note that in the diagram below, this hormone binds to the receptor
once inside the cell. In order to get there, some type of energy is
necessary to move it across.

Origination of Hormones
In this section the origination of hormones will be reviewed. First,
there are many hormones in the body that perform different
functions and have different responses. The responses occur in the
endocrine glands located throughout the body. The diagram below
depicts the types of endocrine glands and their location in the body.
Let’s review some of the most important endocrine glands in the
body next.

Hypothalamus
The hypothalamus is responsible for releasing hormones to anterior
and posterior pituitary. Hypothalamic releasing hormones are
summarized below. It is also responsible for producing the
regulatory hormones which will be discussed shortly.

Transcript Link
The hypothalamus also produces antidiuretic hormone (ADH) and
oxytocin. Once produced, they are passed on to the posterior
pituitary gland. It is also responsible for producing the regulatory
hormones which will be discussed shortly.

Pituitary Gland
The pituitary gland are located just below the hypothalamus and
consist of two lobes, the anterior and posterior lobes.

 Posterior lobe: The posterior lobe secretes oxytocin and ADH

after it is produced by the hypothalamus. The hypothalamus
sends oxytocin and ADH to the posterior pituitary where they
are secreted into the blood. When secreted, ADH targets the
 kidney tubules to retain water. Oxytocin targets breast tissue
(lactation) and the uterus (uterine contraction during
childbirth).
 Anterior lobe: The anterior lobe differs from the posterior lobe
in that it produces its own hormones. But these hormones can
only be secreted when the hypothalamus confirms that it is
fine to do so. The hypothalamus does this by secreting
regulatory hormones that either stimulate or inhibit the
anterior pituitary hormones. The anterior pituitary secretes
prolactin that targets the breast to simulate milk production,
secretes growth hormone that targets the bone to promote
growth, and secretes gonadotropic hormones (Follicle
Stimulating Hormone (FSH) and Luteinizing Hormone (LH)) that
target the testes and the ovaries. It also secretes thyroid
stimulating hormone (TSH) to stimulate the thyroid gland to
secrete T3 and T4. Finally, it can secrete adrenocorticotropic
hormone (ACTH) which will target the adrenal gland to
stimulate the release of cortisol.

The diagram below shows the location of the anterior and posterior
pituitary as well as the connection of the anterior pituitary to the
hypothalamus where regulatory hormones are released to allow the
anterior pituitary to secrete or inhibit its hormones produced there.
Other Endocrine Glands
 Pineal gland: The pineal gland secretes melatonin which is
responsible for regulating the sleep-wake cycle.
 Thyroid gland: The thyroid gland is responsible for secreting
thyroxine (T4), Triiodothyronine (T3) and Calcitonin.
 Parathyroid glands: The parathyroid glands are located on the
posterior surface of the thyroid gland. They secrete parathyroid
hormone (PTH) that is responsible for regulating calcium and
phosphate levels in the body.
 Pancreas: The pancreas secretes two main hormones, insulin
and glucagon. Referring to our example of hormone function
above, glucagon increases blood glucose levels which insulin
works opposite by decreasing blood glucose levels.
 Adrenal glands: The adrenal glands consist of the adrenal
cortex and adrenal medulla. The adrenal cortex secretes
cortisol and aldosterone. Cortisol is involved in the stress
response and aldosterone promotes sodium reabsorption and
potassium excretion in the kidneys. The adrenal medulla
secretes epinephrine and norepinephrine.
 Gonads: In males, the gonads secrete the androgen
testosterone that is responsible for promoting male
characteristics and sperm production. In females, the ovaries
secrete estrogen and progesterone that are important in
developing female characteristics and egg production.
So far, we have discussed normal endocrine physiology along with
the regulation of hormones. When endocrine functions become
altered it can involve significantly high or low hormone levels.
Causes of low hormone levels may be due to the endocrine gland’s
inability to produce enough hormone, abnormal degradation of the
hormone, inactivation of the hormone by antibodies before it can
reach the target cell or inadequate amounts of proteins to bind and
carry the hormone to the target cell. On the other extreme, too
much circulating hormone can be caused by some type of defect in
the negative feedback loop. Alterations in hypothalamic releasing or
inhibiting hormones, caused commonly by pituitary disease, will
cause an array of symptoms and diseases that we will explore.
Now that we have reviewed the endocrine system basics, we will
proceed to exploring diseases that occur when there are alterations
in the endocrine system. Continue to consult your readings to assist
with your understanding of these concepts. As we explore the
selected diseases, refer to this review. It will be helpful in refreshing
your memory of the endocrine glands as well as the hormones that
target those glands. Also keep forefront in your mind, the negative
feedback loop involved in hormone regulation. Finally, always
consider the role of the hypothalamus in regulating hormones that
are either sent directly to the posterior pituitary or the regulation of
the release of hormones that are directly produced in the anterior
pituitary. Without hypothalamic regulation, many of the body’s
functions cannot be performed. In that case, disease results.

Thyroid Gland Disorders

Advanced Pathophysiology-Giner > Unit 8

The Thyroid Gland

The thyroid gland surrounds the trachea and sits just below the
cricoid cartilage. It consists of two lobes and the isthmus that
connects the two lobes) as shown in the diagram below:

The thyroid gland consists of two types of cells:

1. Follicular cells: these are most abundant and are the secretory
cells. They secrete thyroid hormone (Thyroxine or T4). Note
that T4 is a lipid-soluble hormone.
2. Parafollicular cells (C cells): these are fewer in number and
secrete calcitonin.
Also note the colloid area of the cell. T4 is stored here.
Triiodothyronine (T3) is the second and most active thyroid
hormone. T4 is transformed into T3 in the liver although some is
produced in the thyroid as discussed below.
It is important to know how T4 and T3 are produced. Refer to the
diagram below as we explore their production. Iodine is mentioned
first in its role in thyroid hormone production. Through diet, iodine is
absorbed from the gastrointestinal tract (GI) and then taken up by
the thyroid gland and transported into the follicular cells. Energy is
required for this to happen. The energy source is a N+/I- cotransport
system and ATPase pump. It is activated when TSH binds to the
thyroid epithelial cells. Once iodine is taken up by the thyroid gland,
it becomes oxidized by peroxide where I- becomes I+. The oxidized
form of iodine enters the follicular cells to assist in producing the
thyroid hormones.

Thyroglobulin
Next, we consider the role of tyrosine that is located on
thyroglobulin. Thyroglobulin (Tg) is a glycoprotein that is produced
in the follicular cells and is used exclusively in the thyroid gland. It is
the main precursor to thyroid hormones. Thyroid hormones are
produced when tyrosine on the thyroglobulin combines with I+. I+
essentially splits the thyroglobulin that results in diiodotyrosine and
monoiodotyrosine. Diiodotyrosine is associated with the production
of T4 while monoiodotyrosine is associated the production of T3.
Note the amount of T4 and T3 produced. Although T3 is produced in
much smaller amounts, it is the most active of the two.

Following the production of T4, it can be stored in the thyroid follicle

(colloid) or released into the blood stream. Because it is a lipid-
 soluble hormone, it will be bound to a protein carrier. 99% of T4 is
bound to protein and inactive. The amount of unbound T4, known as
the free T4 (FT4), is the amount of freely circulating hormone which
can affect the body tissues. The production, storage, and release of
T4 (and FT4) are under control of TSH. TSH is released from the
anterior pituitary gland and travels in the blood stream to bind with
a receptor on the thyroid epithelial cells. Refer to our diagram
above.

Thyroid Function
Thyroid function is measured first by assessing the amount of
thyroid stimulating hormone (TSH) in the blood. Small changes in
the TSH are early indicators of disease and can be often seen before
a patient becomes symptomatic. A high TSH indicates that the
thyroid is not making enough thyroid hormone (low FT4). When the
pituitary gland sense that there is too little thyroid hormone in the
blood, it produces more TSH in order to stimulate the thyroid gland
to produce more active hormone. If the TSH is low, the pituitary
senses too much thyroid hormone (high FT4) in the blood, and it will
decrease the production of TSH so that the thyroid gland decreases
the amount of thyroid hormone. Patients who do not existing
thyroid disease are screened by assessing serum TSH levels. If the
TSH is too high or too low, a FT4 is drawn to more accurately assess
the thyroid production of hormone available for use. The TSH and
FT4, when used together, aid in the diagnosis of hypothyroidism and
hyperthyroidism.

Subsequent
TSH Result FT4 Result Possible Diagnosis

Elevated TSH (>5.0 mU/L) Low FT4 Primary hypothyroidism

Low TSH (<0.10 mU/L) High FT4 Hyperthyroidism (thyrotoxicosis)

T3 and T4 are differentiated here:

T3 T4

Secretion 30 80 microgram/day
microgram/d
ay

Source 20-25% by Solely by gland

gland
75-80% by
conversion

Half-life 1 day 7 days

Potency 3-4 times Potent

more potent
than T4

Binding 0.2% in 0.02% in unbound

unbound

With the understanding of endocrine functions and the production

of thyroid hormones, we can now delve into alterations of thyroid
function.
Hypothyroidism
Hypothyroidism is classified as either primary (most cases) or
secondary (related to a pituitary or hypothalamic issue). Hashimoto
disease, an autoimmune thyroiditis, is the most common cause of
primary hypothyroidism and will be the focus of discussion in this
section. Other causes of hypothyroidism include loss of thyroid
tissue following a thyroidectomy or radioactive treatment for
hyperthyroidism. Some medications may contribute to the
development of hypothyroidism as well as an iodine deficiency.
Some individuals may present with subclinical hypothyroidism, as
mild form of hypothyroidism where there is an underproduction of
thyroid hormone. It is characterized by an elevated TSH but the
level of circulating thyroid hormone will be normal which is a mild
thyroid failure.
Pathophysiology
Due to the decreased production of thyroid hormone in the thyroid
gland, the hypothalamus will secrete more TRH to stimulate the
anterior pituitary to secrete more TSH to stimulate the thyroid
follicle to secrete more thyroid hormone. Additional causes of
hypothyroidism include loss of thyroid tissue after a thyroidectomy
or radioactive treatment for hyperthyroidism, head and neck
radiation, medications and iodine deficiency.
The mechanisms of the types of hypothyroidism is depicted below:
Clinical Manifestations of
Hypothyroidism
Hypothyroidism affects all body systems. The symptoms can vary
among individuals as their severity depends on the extent of thyroid
depletion. Overall, the body’s metabolism is lowered and is
associated with decreased heat production, lethargy and fatigue. A
goiter may be seen on exam because of the overproduction TSH in
attempt to stimulate the thyroid gland to secrete more thyroid
hormone. Signs and symptoms of hypothyroidism are summarized in
the diagram below:
Hypothyroidism Diagnosis and
Treatment

Diagnosis
Clinical symptoms of primary hypothyroidism, increased TSH level
and decreased total T3, total T4 and free T4 provide the basis for a
diagnosis.

Treatment
Hormone replacement therapy is indicated. Levothyroxine is the
drug of choice for hypothyroidism. Dosing will be based on the
patient’s age, the severity of the symptoms and the presence of
other associated disorders.

Hyperthyroidism Pathophysiology
Hyperthyroidism (thyrotoxicosis) is characterized by an increase the
amount secreted thyroid hormone (TH) from the thyroid gland.
Thyroid hormones are regulated by the negative feedback system
that involves the hypothalamus, anterior pituitary gland and thyroid
gland shown in the diagram below:

There are several reasons why an individual may have excessive

thyroid hormone. In Grave’s disease the overproduction of thyroid
hormone is due to the follicular cells producing excessive amounts
of T4 and T3 due to stimulation from the TSH receptor autoantibody
(TSH-R). Other conditions that may lead to an overproduction of
thyroid hormone includes:
 1. Patients with multinodular goiter who take inorganic iodine
(e.g. potassium iodide) or an organic iodine such as
amiodarone.
2. Patients with multinodular goiter who develop multiple nodules
and secrete excessive amounts of T4 or T3.
3. Patients with large follicular adenomas can produce excessive
thyroid hormone.

Regardless of the cause of hyperthyroidism, there will be increased

serum thyroid hormones. The remainder of the pathophysiology
section will focus on Grave’s disease and in subsequent sections
where clinical manifestations, diagnosis and treatment are
discussed.
Grave’s disease, also an autoimmune disease, is the most common
cause of hyperthyroidism. It typically occurs in ages 30-40 years but
may occur at any age. There is a familial connection associated with
Grave’s disease. Genetically, it is associated with HLA-B17 in Black
individuals, HLA-Bw46 and HLA-B5 in Asian individuals, and HLA -B8
and HLA-DR3 histocompatibility antigens in Caucasian individuals.
As an autoimmune disease, autoantibodies against the TSH receptor
located on the follicular cells stimulate the thyroid gland. The
autoantibodies involved include thyroid-stimulating antibodies
(TSAbs) or thyroid receptor antibodies (TRAbs). They override the
negative feedback system that normally occurs. Lymphocytes also
infiltrate the receptor site. The effect of thyroid stimulating
antibodies on the TSH receptor results in hyperplasia of the thyroid
gland (goiter) and increased synthesis of thyroid hormone,
especially T3. A diagram of a thyroid goiter is provided below:
In Grave’s disease, there are two main distinguishing effects from
actions of the thyroid stimulating antibodies:

1. Ophthalmopathy (exophthalmos): this is an inflammatory

disorder of the periorbital tissues. It includes upper eyelid
retraction, lid lag, swelling, erythema, conjunctivitis and
bulging eyes. It may result in eye irritation, increased
lacrimation, photophobia, blurred vision, decreased visual
acuity, papilledema, keratosis and corneal ulceration.
 2. Dermopathy (pretibial myxedema): this is an autoimmune
inflammatory disorder characterized by thickening of the skin
in the pretibial area. There is also subcutaneous swelling on
the anterior legs. The symptoms are due to T-lymphocytes that
stimulate excess hyaluronic acid production in the dermis and
subcutaneous tissue.

Clinical Manifestations of
Hyperthyroidism
The symptoms of hyperthyroidism are varied and affect all body
systems as shown in the following activity:
System Clinical Signs and Causes
Symptoms
Endocrine  Goiter  Hyperactivity of the thyroid gland

 Increased  Excess bone resorption leading to

cortisol hypercalcemia and a disruption of PTH-
degradation regulating mechanisms
 Hypercalcemia  Increased insulin degradation
and decreased
parathyroid
hormone
(PTH)
secretion
 Decreased
sensitivity to
exogenous
insulin

Reproductive  Oligomenorrhea  Menstrual cycle alterations that may be

or amenorrhea related to hypothalamic or pituitary
disturbances
 erectile
dysfunction  Increase in sex hormone–binding globulin
and decreased
libido
 Increased serum
estradiol and
estrone levels

Gastrointestinal  Weight loss  Increased catabolism leading to the

body's inability to meet metabolic
  Increased demands
peristalsis
 Frequent stools

 nausea,
vomiting,
anorexia,
abdominal
pain

Integumentary  Excessive Increased circulation

sweating,
flushing, and
warm skin
heat
intolerance
 Hair fine, soft,
and straight
 Temporary hair
loss
 Nails that grow
away from nail
beds
 Palmar
erythema

Sensory (eyes)  Elevated upper Overactivity of muscles; Inflammation

eyelid with
decreased
blinking and a
staring
 Lid tremor

Cardiovascular  Increased Hypermetabolism and need to get rid of heat

cardiac output
and decreased
peripheral
resistance
 Tachycardia at
rest
 Loud heart
sounds
  Supraventricula
r
dysrhythmias,
left ventricular
dilation and
hypertrophy

Nervous  Restlessness Unclear; alterations in cerebral metabolism

 Short attention
span
 Compulsive
movement
 Fatigue; tremor;
insomnia
 Increased
appetite;
emotional
lability

Pulmonary Dyspnea; reduced vital Weakness of respiratory muscles

capacity

Hyperthyroidism Diagnosis and

Treatment

Diagnosis
For primary hyperthyroidism, there will be decreased TSH levels
with elevated T4, (T3) and FT4 levels. Radioactive iodine is also used
to test for increased uptake in primary hyperthyroidism as indicated
in the diagram below.
Transcript Link
 Treatment
Treatment of Grave’s disease involves the use of antithyroid drugs
(methimazole or propylthiouracil), radioactive iodine ablation or
surgery. Exophthalmos and pretibial myxedema are not reversed
with treatment. Topical steroids may be used for skin lesion flare-
ups.

Diabetes
Advanced Pathophysiology-Giner > Unit 8

The Endocrine Pancreas

The pancreas has both endocrine and exocrine functions. As an
endocrine gland it produces hormones. As an exocrine gland it
produces digestive enzymes. For this section, we focus on the
endocrine pancreas. The pancreas is located between the spleen
and the duodenum and sits behind the stomach.
A magnified view of the islets of Langerhans are shown in the
diagram below. The islets are composed of four types of cells that
secrete hormones that are involved in regulating carbohydrate, fat,
and protein metabolism.

1. A or alpha cells are located at the periphery and are

responsible for secreting glucagon.
2. Beta cells are responsible for secreting insulin and amylin,
which is a peptide hormone connected to insulin. It inhibits
glucagon secretion and performs some exocrine functions.
3. Delta cells are responsible for secreting gastrin and
somatostatin.
4. F (PP cells) secrete pancreatic polypeptide that stimulates
gastric secretions and antagonizes cholecystokinin.

Note in the diagram that the alpha, beta, and delta cells most
abundant in the anterior lobe of the pancreas. This area is perfused
by the superior mesenteric artery. The celiac artery perfuses the
posterior lobe of the pancreas. This perfusion is important for
oxygenation and the delivery of hormones secreted by the islet cells
to their target cells.

Insulin Synthesis
Insulin is only synthesized in the beta cells. To understand its
synthesis, we start with preproinsulin. This is a biologically inactive
precursor to an active insulin hormone. Preproinsulin is converted by
signal peptidases to proinsulin. Proinsulin is in the endoplasmic
reticulum of the cell. It is exposed to endopeptidases that separate
the C-peptide to generate the active form of insulin. Insulin, along
with the free C-peptide are packaged in the Golgi apparatus into
secretory cells. When the beta cell is stimulated, insulin is secreted
from the cell and diffuses into the islet capillary blood. The C-
peptide is also secreted in the blood, but its action is unknown.
Insulin Secretion
Now that the insulin has been produced, it is waiting to be
stimulated and released to its target cell. Insulin secretion increases
when the beta cells are stimulated by the parasympathetic nervous
system. This usually occurs before eating a meal. Insulin secretion is
primarily stimulated when blood glucose levels rise. Other factors
that increase insulin secretion are increased amino acids and
gastrointestinal hormones (glucagon, gastrin, cholecystokinin,
secretin). Factors that decrease insulin secretion include
hypoglycemia, high insulin levels through the negative feedback to
the beta cells and sympathetic stimulation of the islet cells.
Prostaglandins also inhibit insulin secretion.
Let’s focus on insulin secretion due to elevated blood glucose levels.
When the beta cells are stimulated because of elevated glucose in
the beta cell, it is transported via facilitated diffusion through a
glucose transporter. As glucose continues to elevate in the beta cell,
it causes the cell membrane to depolarize which allows an influx of
calcium into the cell. Increased glucose in the beta cells also
activate calcium-independent pathways that play a role in insulin
secretion.

As glucose increases in the beta cell, insulin secretion occurs that

results in a dramatic increase in plasma insulin levels immediately.
The reason for the dramatic increase initially is because the insulin
was already preformed and waiting in the secretory cells. But the
preformed insulin disappears quickly. Then a secondary insulin
increase occurs because of newly formed insulin that is immediately
released.
Now that insulin is released, it needs to travel to the target cell. To
do this, insulin binds with an enzyme-linked plasma membrane
receptor depicted in the diagram below. This receptor contains
tyrosine kinase. Once insulin binds to the receptor, a cascade of
activity occurs. Signals are sent to activate glucose transporters
(primarily GLUT4) to allow entry of glucose into the cell. GLUT4 is
activated by the insulin receptor and then translocated to the
surface of the cell to facilitate diffusion of glucose into the cell.
Let’s pause here to think about insulin sensitivity, an individual’s
response to insulin. This can be affected by the individual’s age,
weight, physical activity and the amount of abdominal fat. Under
these conditions, insulin resistance may occur. Obesity, as well as
lack of exercise is a major factor in the development of insulin
resistance because adipocytes release hormones altered by obesity
that reduces the individual’s reaction to insulin. As an NP in clinical
practice, it will be extremely important to educate patients on the
benefits of weight loss and exercise.

Insulin Actions
Once in the cell, insulin promotes glucose uptake mostly in the liver,
muscle and adipose tissue. It also affects proteins, carbohydrates,
and lipids by increasing their synthesis. The overall effect of insulin
in the tissues is stimulation of protein and fat synthesis and a
decreased blood glucose level. Insulin also drives the transport of
potassium, phosphate and magnesium into the cell.
  Amylin
Amylin is very closely related to insulin. It is a peptide hormone that
is secreted at the time insulin is secreted by the beta cells when an
individual consumes food. Its main function is to regulate blood
glucose concentration by delaying gastric emptying and suppressing
glucagon secretion for a meal. It also reduces food intake due to its
satiety effect.

 Glucagon

Glucagon is produced by the alpha cells and by cells of the GI tract.

Low glucose levels and sympathetic nervous system stimulation
promote glucagon release. Glucagon antagonizes insulin with a
resulting increase in blood glucose during periods of fasting,
exercise and hypoglycemia. Its primary action is in the liver where it
stimulates glycogenolysis to increase blood glucose. The other
action of glucagon is that it stimulates gluconeogenesis in the
kidneys and lipolysis in the adipose tissue.

 Pancreatic Somatostatin

Pancreatic somatostatin is a hormone produced by the delta cells

after eating. It is essential in carbohydrate, fat, and protein
metabolism. It is also involved in regulating alpha and beta cell
function by inhibiting the secretion of insulin and glucagon.

 Incretins

Incretins are hormones that are secreted in the GI tract in response

to carbohydrates, proteins, and fats. Glucagon-like peptide-1 (GLP-1)
and glucose-dependent insulinotropic polypeptide (GIP) are the
major incretin hormones. Through their action, postprandial glucose
levels are controlled by promoting glucose-dependent insulin
secretion, inhibiting glucagon synthesis, promoting hepatic glucose
secretion and delaying gastric emptying. They also enhance beta-
cell mass and replenish intracellular stores of insulin. They are
broken down by dipeptidyl peptidase 4 (DPP-4) and drugs that
inhibit this enzyme (gliptins), increase incretin levels. You may be
familiar with gliptin medications. They are incretin agonists used for
the treatment of Type 2 diabetes.

 Gastrin, Ghrelin, and Pancreatic Polypeptide

Gastrin is released by the G cells in the stomach and stimulates the
secretion of gastric acid. Ghrelin is an intestinal hormone and
stimulate GH secretion, controls appetite and plays a role in obesity
and the regulation of insulin sensitivity and glucose tolerance.
Pancreatic polypeptide is released by PP cells (gamma cells) in
response to hypoglycemia and protein-rich meats. It promotes
gastric secretion, antagonizes cholecystokinin and is released in
pancreatic tumors and in diabetes. This basic overview of the
endocrine pancreas provides foundational knowledge needed to
understand alterations in endocrine function. We begin the
exploration of diseases of the endocrine system.
Diabetes
Feature Diabetes Type 1 Diabetes Type 2

Etiology Autoimmune:Genetic and Results from genetic susceptibility

environmental factors, (polygenic) combined with
resulting in gradual environmental determinants and
process of autoimmune other risk factors
destruction in genetically
Inherited defects in beta-cell mass
susceptible individuals
and function combined with
Nonautoimmune:Unknown peripheral tissue insulin resistance
Strong association Associated with long-duration
with HLA-DQA and HLA- obesity
DQB genes

Age < 10-20 years of age Usually > 40 years of age

Genetic Weak association Strong association

association

Acute Diabetic ketoacidosis Hyperosmolar nonketotic coma

Complications

Association No Yes
with obesity

Presenting Polyuria, polyphagia, Weakness, weight loss, infections

symptoms polydipsia

Diabetes mellitus includes a group of metabolic diseases that are

characterized by hyperglycemia. There is a defect in insulin
secretion that may be due to altered insulin secretion, insulin or a
combination of both. Regardless of the type of diabetes, the
individual has difficulty controlling the blood glucose level. In Type 1
diabetes, there is an absence of insulin that makes it difficult to
control blood glucose levels. In Type 2 diabetes, lack of blood
glucose control is related to insulin resistance. Both types will be
discussed in the following sections. It is important to mention here
that both diabetes type 1 and 2 have their distinct characteristics.
However, there is some overlap between the two. For example,
regardless of the type of diabetes, chronic elevated glucose levels
can result in many complications. A comparison of Type 1 and Type
DM is provided below:
In the following sections, Type 1 and 2 DM, hypoglycemia, diabetic
ketoacidosis (DKA) and hyperosmolar hyperglycemic non-
ketoacidosis syndrome (HHNK) are reviewed.

Type 1 Diabetes Mellitus

(T1DM)
Type 1 DM is an autoimmune process where environmental and
genetic factors trigger cell-mediated responses that destroy
pancreatic beta cells. T-lymphocytes react against islet cells.
Although it can occur in any age, it most often affects younger
individuals (10-20 years of age). There may also be a nonimmune,
idiopathic DM 1 that is much less common.
Environmental factors that contribute to the development of Type 1
DM include viral infections, vitamin D deficiency, air pollution,
vaccinations, stress and ingestion of cow’s milk. Genetic
associations include HLA-DR3 and HLA-DR4. Individuals seem to be
genetically susceptible that leads to intolerance to self-antigens and
the formation of autoantigens. Cytotoxic T-cells and macrophages
(cellular immunity) and humoral immunity (autoantibodies) are
stimulated that causes destruction of the beta cells and apoptosis.
Most of the pancreatic beta cells are destroyed by the time the
individual presents with hyperglycemia due to decreased insulin
synthesis.
Decreased insulin synthesis leads to increased glucagon secretion
that acts in the liver to stimulate glycogenolysis and
gluconeogenesis. There is also decreased amylin secretion.
Remember from our previous discussion of amylin, its function is to
decrease glucagon release from the alpha cells. Beta and alpha cells
function abnormally that lead to excess glucagon that contributes
also contributes to hyperglycemia.
The pathogenesis of Type 1 DM is summarized in the following
diagram:

Type 1 DM Diagnosis and Treatment

Diagnosis
Before reviewing the diagnostic criteria for Type 1 DM, it is
important to mention screening. Some studies are now suggesting
the measurement of islet autoantibodies in individuals who may be
genetically at-risk (e.g. having relatives with Type 1 DM). Screening,
along with the provision of education about Type 1 DM and ongoing
follow-up may help to establish an earlier diagnosis.
The diagnosis for Type 1 DM is based on the American Diabetes
Association diagnostic criteria below. Note that the same diagnostic
criteria are also used to diagnose Type 2 DM.
FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for
at least 8 h*

OR

2-h PG ≥200 mg/dL (11.1 mmol/L) during OGTT. The test should be
performed as described by the WHO, using a glucose load containing the
equivalent of 75 g anhydrous glucose dissolved in water*

OR

A1C ≥6.5% (48 mmol/mol). The test should be performed in a laboratory

using a method that is NGSP certified and standardized to the DCCT
assay*

OR

In a patient with classic symptoms of hyperglycemia or hyperglycemic

crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L)

*In the absence of unequivocal hyperglycemia, diagnosis requires two

abnormal test results from the same sample or in two separate test samples

Type 1 DM can be easily diagnosed when individuals present with

the classic symptoms that include polydipsia, polyuria, polyphagia,
weight loss and hyperglycemia. These are identified on fasting and
postprandial glucose measurements.

Treatment
No approved therapies exist for preventing the destruction of the
pancreatic beta cells. Management of hyperglycemia is guided by
HbA1c measurement. Treatment is individualized according to age
and activity level. All individuals with Type 1 DM will require a
combination of insulin therapy. Self-monitoring of glucose is also
required along with meal planning and exercise. Annual screening
for complications is also recommended. Finally, some individuals
may receive islet cell, stem cell and a pancreas transplant.
Type 2 Diabetes Mellitus (T2DM)

Type 2 DM represents most

diabetes mellitus cases. As with Type 1 DM, there is also a genetic-
environmental interaction responsible for the development of Type 2
DM. Age, obesity, hypertension, sedentary lifestyle and family
history are the most significant risk factors for the development of
Type 2 DM. Many genes have been identified for Type 2 DM that
impact beta cell size and function. Hepatic synthesis of glucose,
glucagon synthesis and cellular responsiveness to insulin are also
impacted by genetic factors.

Pathophysiology
Insulin resistance involves insulin-sensitive tissues (liver, muscle,
adipose tissue) becoming less responsive to insulin and is
associated with obesity. Obesity contributes greatly to insulin
resistance and the development of Type 2 DM because of:

1. Increased production of leptin, an adipokine hormone produced

in adipose tissue and inflammation that decreases insulin
synthesis and insulin resistance.
2. Elevated serum free fatty acid and triglyceride and cholesterol
deposition into the cells that interfere with insulin signaling.
There is also decreased tissue response to insulin, altered
incretin function that promotes inflammation leading to beta
cell destruction.
3. Release of inflammatory cytokines from intraabdominal
adipocytes induces insulin resistance.
 4. Alterations in oxidative phosphorylation in the cell’s
mitochondria that contributes to insulin resistance.

Diabetes can be masked for years due to compensatory

hyperinsulinemia that prevents the appearance of symptoms. Over
time, beta-cell dysfunction becomes prevalent that leads to a
reduction in insulin activity. Islet dysfunction occurs because of a
decrease is beta-cells and reduction in beta cell function.
Glucagon is increased in Type 2 diabetes because alpha cells in the
pancreas become less responsive to glucose inhibition. This results
in more glucagon being secreted. High glucagon levels stimulate
glycogenolysis and gluconeogenesis. As in Type 1 DM, amylin
deficiency also contributes to increased glucagon levels.
The GI tract contributes to insulin resistance by releasing hormones.
Ghrelin is produced in the stomach and pancreatic islets. It
regulates food intake, energy balance and hormonal secretion.
When Ghrelin is decreased, it contributes to insulin resistance.
Incretins (previously discussed) are also released from the GI tract
when food is ingested. It increases synthesis and secretion of insulin
as well as beta cell proliferation and regeneration. In Type 2DM,
beta-cells have a decreased responsiveness to incretin.

Type 2 DM Diagnosis

The diagnosis for Type 2 DM

is based on the American Diabetes Association diagnostic criteria
below. Note that the same diagnostic criteria are also used to
diagnose Type 1 DM.
FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 h*

OR

2-h PG ≥200 mg/dL (11.1 mmol/L) during OGTT. The test should be performed as described
by the WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose
dissolved in water*

OR

A1C ≥6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that
is NGSP certified and standardized to the DCCT assay*

OR

In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random

plasma glucose ≥200 mg/dL (11.1 mmol/L)

*In the absence of unequivocal hyperglycemia, diagnosis requires two abnormal test results
from the same sample or in two separate test samples

Type 2 DM Treatment

The goal of treatment is to

restore the individual’s glucose level to as close to normal as
possible and correct any metabolic disorders. Weight loss is
 recommended to help improve insulin sensitivity and glucose
tolerance as well as to preserve beta-cell function. Weight loss can
also help to prevent the progression of Type 2 DM. Exercise can help
in weight loss and the reduction of postprandial blood glucose level.
It also diminishes insulin requirements. It also lowers triglyceride
and cholesterol levels and increases high-density lipoprotein (HDL)
cholesterol.
Diet should include complex carbohydrates instead of simple sugars,
low fat foods, and adequate protein and fiber. Some individuals with
morbid obesity may have bariatric surgery when weight loss does
not occur despite following diet and exercise measures. It’s
effectiveness, though, is still being evaluated.
Many individuals with T2DM require oral hypoglycemic medications.
There are many from which to select. In general,
Metformin is the primary choice for the treatment of Type 2 DM. A
second oral agent may be added (GLP-1 receptor agonist) or even
insulin if the target HbA1c level is not maintained for over a three-
month period. Insulin is often needed in the later stages of Type 2
DM because of the progressive loss of beta cell function over time.
It is also important to screen individuals for pre-diabetes according
to the American Diabetes Association. Pre-screening involves testing
individuals without symptoms to detect disease or risk of disease
before the patient becomes symptomatic:

HbA1c (as measured in a DCCT-referenced assay) ≥6.5%

OR

FPG ≥126 mg/dL (7.0 mmol/L); fasting is defined as no caloric intake for at least 8 hr.

OR

2-hr plasma glucose ≥200 mg/dL (11.1 mmol/L) during an OGTT

OR

In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose
≥200 mg/dL (11.1 mmol/L)

Categories of Increased Risk for Diabetes (Prediabetes)

 1. FPG 100 to 125 mg/dL

 2. 2-hr PG in the range of 140 to 199 mg/dL during an OGTT
 3. HbA1c 5.7% to 6.4%

Complications of Diabetes
There are many complications that are associated with diabetes.
They are categorized as microvascular or macrovascular and are
summarized below:
In addition to the long-term complications of diabetes, there are also
acute complications that include hypoglycemia, diabetic
ketoacidosis, and hyperosmolar hyperglycemia non-ketoacidosis.
These are discussed in the next section.
Hypoglycemia
An individual is considered hypoglycemic when the blood glucose
level is less than 70 mg/dL. Causes range from medications,
exercise and alcohol ingestion. Other causes of hypoglycemia
include a pancreatic tumor, receiving hyperalimentation or liver
disease.
Individuals with Type 1 DM are more at risk for developing
hypoglycemia than the individual with Type 2 DM because in Type 2
DM, the individual retains an intact glucose counter-regulatory
system. But hypoglycemia can still result in Type 2 DM because of
the actions of the oral agents used to lower blood sugar, especially
when used in combination.

 Clinical Manifestations of Hypoglycemia

 Treatment

Symptoms of hypoglycemia
can result from activation of the sympathetic nervous system to
cause neurogenic reactions that occur when the blood glucose drops
rapidly:

 Tachycardia
 Palpitations
 Diaphoresis
 Tremors
 Pallor
 Arousal anxiety
Other symptoms include:

 Headache
 Dizziness
 Blurred vision
 Irritability
 Fatigue
 Poor judgement
 Confusion
 Hunger
 Seizures
 Coma

Diabetic Ketoacidosis (DKA)

Diabetic ketoacidosis (DKA) is a

complication related to insulin deficiency and increased levels of
insulin counter-regulatory hormones that includes catecholamines,
cortisol, glucagon and growth hormone). It occurs most commonly in
individuals who have Type 1 DM because of insulin deficiency. It is
not often seen in individuals with Type 2 DM.
Factors that precipitate DKA are illnesses related to infection,
trauma, surgery or myocardial infarction. It also occurs when the
individual does not adhere to the diabetes treatment plan or if
insulin administration is interrupted.

 Pathophysiology
 Insulin deficiency and an increase in counter-regulatory
hormones (catecholamines, cortisol, glucagon and growth
hormone) are the most significant factors for developing DKA.
Under normal circumstances, the counter-regulatory hormones
antagonize insulin by increasing glucose production and
decreasing use of glucose by the tissues. Extreme insulin
deficiency results in decreased uptake of glucose, increased fat
mobilization and release of fatty acids and gluconeogenesis,
glycogenesis and ketogenesis. Without insulin, the free fatty
acids increase the production of ketone bodies in the liver at a
high rate that exceeds peripheral use. This causes ketone
bodies to accumulate and results in decreased pH and
metabolic acidosis. The buffer system is activated in response
to metabolic acidosis. Remember that insulin also has an
antilipolytic effect. When insulin is deficient, there is increased
circulating ketones that contributes to DKA. Also, ketones are
normally used by the tissues as an energy source to produce
bicarbonate. In DKA, the number of ketones and bicarbonate
cannot be balanced. Circulating ketones increase because of
impaired use by the peripheral tissues, thus increasing strong
acids to freely circulate. Bicarbonate buffering does not occur
which leads to metabolic acidosis.

 Clinical Manifestations
The signs and symptoms of DKA include the following:
 1. Kussmaul respirations: the individual hyperventilates to
compensate for the metabolic acidosis
2. Postural dizziness
3. Central nervous system depression
4. Ketonuria
5. Anorexia, nausea, vomiting
6. Abdominal pain
7. Acetone breath
8. Dehydration
9. Thirst
10. Polyuria

Hyperglycemia causes an osmotic diuresis that leads to polyuria

along with dehydration. Large amounts of glucose are lost in the
urine because the blood glucose is higher than the renal threshold.
Electrolyte abnormalities also occur:

1. Hyponatremia
2. Hypophosphatemia
3. Hypomagnesemia

The most significant electrolyte disturbance is hypokalemia. The

potassium drops because of a shift out of the cell and into the blood
caused by the metabolic acidosis. The blood potassium level, though
may appear normal

 Diagnosis
The diagnosis of DKA is based on the signs and symptoms described
above. The American Diabetes Association’s criteria for the
diagnosis of DKA include:

1. Serum glucose level >250 mg/dL

2. Serum bicarbonate level <18
3. Serum pH <7.30
4. Presence of an anion gap
5. Presence of urine and serum ketones
  Treatment

Treatment is aimed at decreasing the glucose level by administering

insulin. Before administering insulin aggressive fluid replacement
and correction of potassium must occur. Intravenous fluids are given
to correct the potassium level as well as sodium and phosphorous.
Throughout treatment, volume status and potassium levels are
monitored closely. Once the individual is stable, teaching is
provided on the causes of DKA and how to avoid it.

Hyperosmolar Hyperglycemic Non-

Ketoacidosis Syndrome (HHNKS)
Review the pathophysiology, clinical manifestations, diagnosis, and
treatment of HHNKS below.

 Pathophysiology
HHNKS involves insulin deficiency but it is not as pronounced as the
insulin deficiency seen in DKA. Also, the degree of elevated blood
glucose and fluid deficit is more pronounced in HHNKS than in DKA.
The follow factors contribute to the development of HHNKS:

1. Insulin deficiency
2. Increased levels of counter-regulatory or stress hormones
(glucagon, catecholamines, cortisol and growth hormone)
3. Increased gluconeogenesis and glycogenolysis
4. Inadequate use of glucose by peripheral tissues (primarily
muscle)-characterized by lack of ketosis

Proinflammatory mediators (TNF-α, IL-6, IL-1β) are also involved that

also contribute to insulin resistance and hyperglycemia.
Less insulin is needed to inhibit fat breakdown needed for effective
glucose transport. Therefore, insulin levels are enough to prevent
excessive lipolysis but not to use glucose effectively.
  Clinical Manifestations

Patients with HHNKS will have an extremely high glucose level. As a

result, there will be glycosuria and polyuria. Because of the amount
of glycosuria, the patient is at risk for developing severe volume
depletion, increased serum osmolarity, intracellular dehydration and
loss of potassium and other electrolytes. Neurological symptoms
(stupor and coma) may appear as well and worsen with the degree
of hyperosmolarity.

 Diagnosis
The diagnostic features of HHNKS include:

1. Elevated serum glucose (>600 mg/dL)

2. Near normal serum bicarbonate level and pH
3. Serum osmolarity > 320 mOsm/L
4. Absent or low ketone levels in the urine and serum

 Treatment

The patient will receive an insulin infusion and fluid replacement.

The hypokalemia may be extreme and require several days of
infused potassium to return it to a normal level. Sodium and
phosphorous replacement may be needed as well.

Hypoglycemia DKA HHNKS

Synonyms
 Hyperosmolar
Insulin shock,
Diabetic coma syndrome hyperglycemia
insulin reaction
nonketotic coma
Risk Factors
Older adults or very
Taking insulin young individuals
with type 2 diabetes,
Rapidly fluctuating Individuals with type 1
nondiabetic
blood glucose diabetes individuals with
levels
Individuals with non- predisposing factors,
Sulfonylurea diagnosed diabetes such as pancreatitis;
agents (Type 2 individuals with
Diabetes) undiagnosed
diabetes
Predisposing
Factors
Stressful situations:
Excessive insulin
or sulfonylurea Infection
agent intake Trauma Infection
Decreased food Emotional stress Medications that
intake, antagonize insulin
Omission of insulin
Excessive physical
exercise Medications that antagonize
insulin
Typical Onset
Rapid Slow Slowest
Presenting
Symptoms
Adrenergic Malaise, dry mouth, Polyuria, polydipsia,
reaction: headache, polyuria, hypovolemia,
polydipsia, weight loss, dehydration
pallor, sweating,
nausea, vomiting, pruritus, (parched lips, poor
tachycardia,
abdominal pain, lethargy, skin turgor),
palpitations,
shortness of breath, hypotension,
hunger,
Kussmaul respirations, tachycardia,
restlessness,
anxiety, tremors
Neurogenic
reaction:
hypoperfusion,
fatigue, irritability,
weight loss,
headache, loss of
weakness, nausea,
concentration, fruity or acetone odor to
vomiting, abdominal
visual breath
pain, hypothermia,
disturbances,
stupor, coma,
dizziness, hunger,
seizures
confusion,
transient sensory
or motor defects,
convulsions, coma,
death
Laboratory
Analysis
Glucose levels
>600 mg/dL,
Glucose levels >250 mg/dL,
Serum glucose No ketosis
<55–60 mg/dL in Decreased bicarbonate
serum osmolarity
adults concentration;Increased
>320 mOsm/L
anion ga
Elevated BUN and
creatinine

Parathyroid Gland Disorders

Advanced Pathophysiology-Giner > Unit 8

The Parathyroid Gland

Four parathyroid glands are located near the posterior side of the
thyroid gland and are responsible for controlling serum calcium
levels through the production of parathyroid hormone (PTH).
The secretion of PTH increases serum calcium levels and decreases
serum phosphate. PTH secretion is stimulated when there is a
decrease in serum-ionized calcium levels. When secreted, PTH
enters the circulation in unbound form and attached to plasma
membrane receptors in the target tissues. PTH effects are mediated
by the activation of the adenylyl cyclase system. Serum calcium
level is regulated by PTH acting directly on the bone. The following
occurs when the patient has hypocalcemia:

1. PTH secretion stimulates osteoblasts to activate receptors

for nuclear factor κB (NF-κB), nuclear factor κB ligand (RANKL),
and macrophage-colony stimulation factor (M-CSF). This
promotes the osteoclasts to proliferate and mature. The
osteoclasts also release cathepsin which is an acidic enzyme
that mobilizes the release of calcium from the bone
(resorption) that results in increased serum calcium level.
 2. Bone remodeling occur when there is chronic stimulation of
PTH. Bone remodeling involves a process where bone is broken
down and then re-formed. Here is a point to think about. When
PTH is given to patients in small and intermittent doses, it
stimulates bone formation. Because of this, you will see PTH
used in the treatment of osteoporosis.
3. PTH also promotes the kidneys to increase calcium
reabsorption by acting on the kidney plasma membrane
receptor located in the distal tubules to increase the
reabsorption of calcium.
4. PTH also acts on the proximal tubules to decrease
phosphorous and bicarbonate reabsorption.
5. Once the serum calcium increases as a result of PTH actions,
PTH secretion will be inhibited.

PTH Secretion
Focusing on the kidneys, PTH stimulates 1α-hydroxylase in the renal
cells which performs a step in the formation of biologically active
form of Vitamin D (1,25-dihydroxy-vitamin D3). Vitamin D works
with PTH to promote calcium and phosphate absorption in the GI
tract and bone mineralization. Magnesium and phosphate come into
play as they also affect PTH secretion. When an individual has a low
magnesium level but a normal calcium level, it mildly stimulates
PTH secretion. But if the individual has a low calcium level and low
magnesium level, PTH secretion will be decreased. A high phosphate
level will cause hypocalcemia because calcium phosphate
precipitates in the soft tissue and bone. Just keep in mind that
alterations in phosphate level may influence PTH secretion indirectly
by affecting the serum calcium levels.
The diagram below provides a simple depiction of the response that
occurs when the individual has a low serum calcium level:

Primary Secondary Tertiary

Pathology Hyperfunction of Physiological Following long

parathyroid cells stimulation of term
due to hyperplasia, parathyroid in physiological
 Primary Secondary Tertiary

adenoma or response to stimulation

carcinoma. hypocalcaemi leading to
a. hyperplasia

Associatio May be associated Usually due to Seen in chronic

ns with multiple chronic renal renal failure
endocrine failure or
neoplasia. other causes
of Vitamin D
deficiency.

Serum High Low / Normal High

Calcium

Serum Low / Normal High High

Phosphat
e

Managem Usually surgery if Treatment of Usually

ent symptomatic. underlying cinacalcet or
Cincacalcet can be cause. surgery in those
considered in those that don’t
not fit for surgery. respond.
After this brief review of parathyroid function, we will now explore
the two most common disorders of the parathyroid gland,
hyperparathyroidism and hypoparathyroidism.

Hyperparathyroidism
Hyperparathyroidism is the most common cause of hypercalcemia
and can be classified as primary, secondary or tertiary. The three
types are summarized in the table below:
Carcinoma is more likely in patients who have a
hyperparathyroidism-jaw tumor (HP-JT) and patients with multiple
endocrine neoplasia (MEN). MEN is a group of disorders that affects
the endocrine glands and usually involves tumors which may be
cancerous or noncancerous. This leads the gland to become
overactive with an overproduction of hormones. The most common
type is MEN type 1 and 2A as opposed to MEN 2B. Patients less than
40 years of age who have primary hyperthyroidism associated with
a family history of hyperparathyroidism should receive genetic
testing.
MEN 1: involves tumors of the pancreas, parathyroid glands or
pituitary gland. Tumors most often appear in the parathyroid glands
which can lead to the first sign of disease, hypercalcemia.
MEN 2: is divided into three subtypes:

 Type IIA (accounts for 90% of all cases)

 Type IIB
 Familial medullary thyroid carcinoma (FMTC)

In the diagram below, note that individuals with MEN 2 will develop
medullary thyroid cancer regardless of their subtype. Some
individuals may also develop pheochromocytoma which is an
adrenal gland tumor that can cause extreme hypertension.
Hypercalcemia Symptoms
The patient may not exhibit signs of hypercalcemia or have only
mild symptoms. It is usually not diagnosed until routine lab work is
reviewed during a routine exam. A parathyroid adenoma is not
typically revealed on exam because of its small size and location
deep into the neck. If it is palpable it usually turns out to be a
thyroid nodule. Symptoms are varied and may include those related
to the musculoskeletal, renal and abdominal systems. There is also
psychiatric symptoms and fatigue.

Skeletal
The distal one-third of the radius is usually where low
bone density is noted most where it consists mostly of
cortical bone. Post-menopausal women are prone to
vertebral fractures. Osteitis fibrosa cystica can present as
pathological fractures of “brown tumors” Individuals may
also experience arthralgias and bone pain especially in
the legs.

Hypercalcemic Manifestations
As previously mentioned, mild hypercalcemia may be
asymptomatic. The severity of symptoms related to hypercalcemia
are varied and is not based on the serum calcium or PTH levels.
Manifestations of hypercalcemia are presented below based on
neuromuscular, central nervous system, cardiovascular, kidney and
gastrointestinal symptoms:
Neuromuscular: may include paresthesias, muscle cramps and
weakness and diminished deep tendon reflexes (DTRs).
Central nervous system: may include malaise, fatigue, headache,
mental exhaustion, insomnia, irritability and depression.
Cardiovascular: may include hypertension, palpitations, prolonged P-
R interval, shortened Q-T interval, bradyarrhythmias, heart block
and asystole.
Kidney: may include polyuria and polydipsia due to hypercalcemia-
induced diabetes insipidus.
Gastrointestinal: may include anorexia, nausea, heartburn, vomiting,
weight loss, abdominal pain and constipation.

Hypercalcemia Diagnosis
Lab work:

 Hypercalcemia is the hallmark finding of primary

hyperparathyroidism. Serum adjust total calcium level will be
greater than 10.5 mg/dL.
 Elevated serum levels of intact PTH confirms the diagnosis of
hyperparathyroidism.
 Assessment of urinary calcium excretion is recommended to
confirm the diagnosis of hyperparathyroidism. Urine calcium
excretion may be high or normal in primary hyperthyroidism
(100-300 mg/day).
 Serum phosphate will be less than 2.5 mg/dL due to the
excessive loss of phosphate in the urine. A serum calcium-
phosphate ratio above 2.5 mg/dL helps to confirm the
diagnosis of primary hyperparathyroidism.
 Alkaline phosphatase will be elevated when bone disease is
present.
 Vitamin D deficiency is common in hyperparathyroidism.
Patient should be screened. Serum 25-OH vitamin D levels
below 20 mcg/L can enhance hyperparathyroidism and bone-
related symptoms.

Imaging:
Imaging of the parathyroid gland is not necessary for the diagnosis
of hyperparathyroidism. It is done prior to parathyroid surgery or
when it is needed to diagnose a parathyroid adenoma.
Parathyro
id Calciu
Hormone m Phosphor
Level Level us Diagnosis Cause

High High Low Primary Oversecretio

hyperparathyroidi n of
sm parathyroid
hormone

High Low High Secondary Vitamin D

hyperparathyroidi deficiency
sm

Very high High High Tertiary Chronic

hyperparathyroidi renal failure
sm

Hyperparathyroidism Treatment

Increased ionized calcium

along with elevated PTH suggests primary hyperparathyroidism.
Sometimes PTH will be within normal range, which is inappropriate
since hypercalcemia should suppress PTH production. Therefore,
asymptomatic individuals with mild hypercalcemia should be
monitored. Specifically, individuals should avoid dehydration and
decrease calcium intake.
Severe primary hyperparathyroidism will require surgical removal of
an adenoma or completed removal of three and partial removal of
the fourth gland if it is hyperplasia. Imaging will be used to identify
the adenoma before surgery.
Calcimimetics (cinacalcet) and biphosphonates may be used if
surgery fails. Parathyroid calcium receptor sensitivity is increased by
calcimimetics with lowered PTH levels. If the individual has
hypercalcemia but a low PTH level, malignancy is suspected or
excessive calcium ingestion. Treatment of the underlying cause is
warranted.
Secondary hyperparathyroidism is suspected if the serum calcium
level is low but the PTH level is elevated. Renal function evaluation
often reveals chronic renal disease. Treatment requires calcium
replacement, dietary phosphate restriction, phosphate binders and
vitamin D replacement.

Hypoparathyroidism

Hypoparathyroidism is
an abnormally low PTH level cause by damage or removal of the
parathyroid glands during thyroid surgery. Is also associated with
genetic syndromes (DiGeorge syndrome), autoimmunity and familial
disposition. A low magnesium can also cause a decrease in PTH
secretion.

Pathophysiology
Decreased circulating PTH results in decreased serum calcium levels
and increased serum phosphate levels. When PTH is absent, there is
impaired resorption of calcium from the bone and impaired calcium
reabsorption from the renal tubules. This leads to a decreased renal
phosphate excretion and hyperphosphatemia.
A low magnesium (hypomagnesemia) inhibits PTH secretion. After
the magnesium level returns to normal, though, PTH secretion will
also return to normal as well as the responsiveness of peripheral
tissues to PTH. Chronic alcoholism, malabsorption problems,
malnutrition and increased renal clearance of magnesium are
causes of hypomagnesemia.
Hyperphosphatemia is also seen with hypocalcemia due to
increased renal absorption of phosphate. When there is a decreased
PTH, hyperphosphatemia further contributes to lowering calcium
levels by inhibiting the activation of vitamin D which will decrease GI
absorption of calcium.
Clinical Manifestations of
Hypocalcemia

Symptoms of
hypocalcemia are prevalent with hypoparathyroidism. Hypocalcemia
affects nerve and muscle excitation by lowering their threshold to
excitation. The patient will experience paresthesias, numbness,
tingling and tetany which is directly related to muscle spasms,
increased deep tendon reflexes (DTRs) and laryngeal spasms. In
severe cases, asphyxiation can occur.
Two of the most important signs to elicit to evaluate for
neuromuscular irritability include:

 Chvostek sign is elicited by tapping the cheek that will result in

twitching of the upper lip.
 Trousseau sign is elicited by inflating a sphygmomanometer
located on the upper arm. When inflated, it will result in
painful, carpal spasm.

Other symptoms of hypocalcemia include:

 Dry skin
 Loss of body and scalp hair
 Hypoplasia of developing teeth
 Horizontal ridges on the nails
 Cataracts
  Parkinsonian syndrome due to calcifications on the basal
ganglia
 Bone deformities (bowing of the long bones)

Hypocalcemia Diagnosis and

Treatment

Diagnosis
The patient will present with a low serum calcium level and a high
phosphorous level. PTH levels will be low. A serum magnesium and
urinary calcium excretion will help in diagnosing
hypoparathyroidism.

Treatment
The goal of treatment is to alleviate hypocalcemia. In an acute
state, the patient will receive intravenous calcium to quickly correct
the serum calcium. Maintenance of calcium level is managed
through oral calcium and an active form of vitamin D. PTH
replacement therapy with recombinant human parathyroid hormone
(thPTH [1-84]) will help to reduce the need for supplemental
calcium and vitamin D. Serum calcium and phosphate levels will be
monitored for return to normal following treatment.
Adrenal Gland Disorders
Advanced Pathophysiology-Giner > Unit 8

The Adrenal Cortex

The adrenal cortex is divided into three zones:

Zona Glomerulosa
This is the outer layer of the cortex where the mineralocorticoid,
aldosterone is produced. It constitutes 15% of the adrenal cortex.

Zona Fasciculata
This is the middle layer of the cortex where the glucocorticoids
cortisol, cortisone and corticosterone are secreted. It constitutes
78% of the adrenal cortex.

Zona Reticularis
This is the inner layer of the adrenal cortex where mineralocorticoids
(aldosterone), adrenal androgens and estrogens, and glucocorticoids
are secreted. It constitutes 7% of the adrenal cortex.
Adrenal Cortex Hormones
The cells of the adrenal cortex are stimulated by the
adrenocorticotropic hormone (ACTH) from the anterior pituitary as
shown in the diagram below. Also note that the hormones produced
in the adrenal cortex are synthesized from cholesterol, a low-density
lipoprotein (LDL). In this process, cholesterol is converted to
pregnenolone that is then converted to what we know as our major
corticosteroids. The steroid hormones are discussed in the next
section.

Steroid Hormones
The glucocorticoid hormones exert metabolic, anti-inflammatory,
neurologic, immunosuppressive and growth-suppressing effects.
You most likely remember that these are the hormones that are
released when the individual is under stress. Glucocorticoids have a
direct effect on carbohydrate metabolism. These hormones also
antagonize insulin that increases blood glucose by gluconeogenesis
in the liver and reuptake of glucose into muscle, adipose and
lymphatic tissues. Increased glucose is needed by the brain during
periods of stress. Glucocorticoids also stimulate protein metabolism
that results in muscle wasting.
Immune and Inflammatory reactions are suppressed by
glucocorticoids. Several sites are involved in this process:
 1. Inhibition of innate immunity by antigen presentation and
decreased activity of pattern recognition receptors on
macrophages.
2. T-lymphocyte proliferation is decreased, especially T-helper
lymphocytes that reduces cellular immunity.
3. Decreased activity of the natural killer cells results in
decreased immune and inflammatory responses
4. Chemical mediator synthesis and secretion is decreased that
reduced inflammation and the immune response.

Overall, the glucocorticoids suppress both innate and adaptive

immunity putting the individual is at risk for developing an infection
when being treated with glucocorticoids. We cannot undermine the
impact of psychological and physiological stress on the body. These
both increase glucocorticoid production that can lead to decreased
immune response as well.
Glucocorticoids also have effects on other areas:

1. Inhibits bone formation

2. Inhibits antidiuretic hormone (ADA) secretion
3. Stimulate gastric acid secretion
4. Potentiates the effects of catecholamines
5. Potentiates the effects of thyroid and growth hormone effects
on adipose tissue
6. Altered mood due to one of the metabolites of cortisol that
depresses nerve cell function in the brain. Mood can fluctuate
with steroid level fluctuations that occur in disease or stress
states.
7. Increased number of circulating erythrocytes (polycythemia)
8. Increased appetite
9. Promotion of fat deposition in the face and cervical area
10. Increased uric acid excretion
11. Decreased calcium level (inhibits GI absorption of
calcium)
12. Suppressed synthesis and secretion of ACTH
13. Inhibits somatic growth (interferes with action of growth
hormone)
 Cortisol Secretion
It is important to note that cortisol is the most potent, naturally
occurring glucocorticoid. This is what is mainly secreted by the
adrenal cortex. It is critical to maintaining life and regulating the
body responses during positive and negative stress situations. The
liver is responsible for deactivating cortisol.
Cortisol secretion is regulated by the hypothalamus and the anterior
pituitary. Following the diagram below, the hypothalamus responds
to a stressor by releasing corticotropic releasing hormone. It travels
to stimulate the anterior pituitary to produce ACTH. ACTH stimulates
the adrenal cortex to release cortisol in the blood.
ACTH Binding
Let’s focus on what happens specifically when ACTH is secreted.
When ACTH reaches the cell membrane of the adrenal cortex (its
target cell), it binds to a specific receptor located on the cell
membrane and other receptors located on extra-adrenal tissues.
Because both areas have receptors for ACTH, there will be a variety
of effects:

Adrenal Cortex Effects

 Maintenance of gland size

 Depletion of ascorbic acid
 Activation of adenylyl cyclase
 Conversion of cholesterol to pregnenolone
 Maintenance of enzymes active in converting pregnenolone to other
steroids
 Accumulation of cholesterol for steroid hormone synthesis
 Secretion of cortisol and adrenal androgens

Once ACTH binds to the receptor on the cell membrane of the

adrenal cortex, cortisol synthesis and secretion occur immediately.
After it is secreted, 90% of the cortisol circulates bound to a protein.
The remaining 10% circulates freely in unbound form. In the
diagram below, it depicts the unbound form that is free to diffuse
into cells. However, only those cells with specific glucocorticoid
receptors will respond to cortisol stimulation. Note that ACTH is
quickly inactivated in the circulation and removed by the liver and
the kidney.
Mineralocorticoids
These are steroid hormones that directly affects sodium retention
and potassium and hydrogen loss. Aldosterone is the main
mineralocorticoid. It conserves sodium by increasing the activity of
the sodium pump located in the nephron’s epithelial cells. As we
explore how aldosterone is synthesized, let’s turn our attention back
to the layers of the adrenal cortex. Also, have your information that
we covered in our renal discussion available. It will help to promote
your understanding of aldosterone synthesis.
Aldosterone
Aldosterone synthesis starts in the adrenal zona fasciculata and
zona reticularis. It’s final conversion of corticosterone to aldosterone
occurs in the zona glomerulosa. The renin-angiotensin-aldosterone
system in the kidney regulates aldosterone synthesis and secretion.
It is activated when sodium and water is depleted and when
potassium is increased. Angiotensin II stimulates aldosterone
synthesis and secretion from the adrenal cortex as well as increased
serum potassium. Aldosterone maintains extracellular volume and
blood pressure through its actions on the distal nephron epithelial
cells. Aldosterone also enhances cardiac contraction, stimulation of
ectopic ventricular activity, increased vascular resistance of blood
vessels and decreased fibrinolysis. Abnormal levels of aldosterone
are associated with changes related to heart failure. The diagram
below summarizes the regulation of aldosterone secretion by the
renin-angiotensin-aldosterone pathway.
Estrogens and Androgens of the
Adrenal Cortex
A small amount of estrogen and androgens are secreted by the
healthy adrenal cortex. It is primarily regulated by ACTH. For the
weak androgenic substances secreted by the adrenal cortex
(dehydroepiandrosterone [DHEA], androstenedione), peripheral
tissues convert them to stronger androgens like testosterone. This
accounts for some of the androgenic effects by the adrenal cortex.
In aging, obese individuals, those with liver disease or
hyperthyroidism, peripheral conversion of adrenal androgens to
estrogen is enhanced. It is important to note that the effects of the
sex hormones secreted in the adrenal cortex are the same as those
produced by the gonads.
The next part of the adrenal gland is the adrenal medulla. It is
discussed in the next section.

Adrenal Medulla
he adrenal medulla works with the sympathetic nervous system to
exert its effects. It is important to mention here that there are cells
of the adrenal gland called Chromaffin cells (pheochromocytes).
 Site of Mode of
Catecholamine Production Transmission Site of Action

Epinephrine Adrenal Hormonal Cardiac muscle

Medulla
Smooth muscle
(Chromaffin
cells) Effects on cellular
metabolism

Norepinephrine Adrenal Neuroeffector Cardiac muscle

Medulla cell junction
Smooth muscle
(Chromaffin
cells) Vascular endothelium
Sympathetic Exocrine glands
nervous system

They store epinephrine and norepinephrine (catecholamines) in the

adrenal medulla. Some circulating epinephrine is secreted from the
adrenal medulla while the most is released from nerve terminals.
When the individual is under stress ACTH triggers the chromaffin
cells to release epinephrine and norepinephrine directly into the
bloodstream. After release they bind to a plasma membrane
receptor in their target cells to exert their effects. The adenylyl
cyclase system is involved in this process. The catecholamines are
released quickly from the blood for storage in the cytoplasm or for
excretion in the urine.
The table below summarizes the catecholamines in terms of its site
of production, mode of transmission and site of action.
Catecholamines exert effects over the entire body with activation of
adrenergic receptors on the cell membranes of all visceral organs
and smooth muscles. The hormonal effects are depicted below:
Hypercortisolism
Adrenal cortex disorders occur when there is either hyperfunction or
hypofunction. Cushing disease is a condition where there is an
overproduction of cortisol. Hyperfunction relates to hypercortisolism
that leads to Cushing disease or syndrome and is discussed in this
section.
In Cushing disease there is chronic exposure to cortisol (more
common in women) due mainly to an overproduction of ACTH by the
pituitary because of a tumor.
The pathophysiology of hypercortisolism is divided into ACTH-
dependent and ACTH-independent hypercortisolism. ACTH-
dependent involves excess ACTH that stimulates excess production
of cortisol due to the loss of feedback control of ACTH secretion.
Regardless of the cause of excess ACTH, two common conditions are
present:
 The individual loses diurnal or circadian secretion patterns of
ACTH and cortisol.
ACTH and cortisol secretion do not occur in response to stress.
In ACTH-independent hypercortisolism can be related to an adrenal
cortex tumor that secretes cortisol. Elevated cortisol levels suppress
CRG and ACTH secretion from the hypothalamus and anterior
pituitary leading to a decreased level of ACTH. This results in
adrenal cortex atrophy.
Symptoms of hypercortisolism include weight gain (most common
symptom) seen primarily in the trunk, facial (moon face) and neck
(buffalo hump) areas. Fat distribution in these areas is referred to a
truncal or central obesity. Cortisol also has mineralocorticoid effects
that results in transient weight gain from sodium and water
retention. Other effects of hypercortisolism include:

 Glucose intolerance
 Muscle wasting
 Renal effects
 Skin changes
 Vascular effects
 Mental status effects
Glucose intolerance occurs because excess cortisol causes insulin
resistance, increased gluconeogenesis and glycogen storage in the
liver.
Finally, females may experience increased facial hair growth, acne
and oligomenorrhea due to increased androgen levels. Infertility
may also occur in women. The diagram below depicts how an
individual may appear as a result of excess cortisol.
Hypercortisolism Diagnosis and Lab
Work
The following lab tests are used to diagnose hypercortisolism. It is
important to determine the underlying disorder as well as determine
if it is ACTH-dependent, which is measurable, or ACTH-independent
(not measurable).

Lab Work

Other lab work

may reveal hyperglycemia due to impaired glucose tolerance in
response to insulin resistance; polyuria related to increased water
excretion, glycosuria, hypokalemia and metabolic alkalosis. Imaging
procedures will be used to diagnose tumors.
Diagnostic tests for hypercortisolism are performed to determine
the presence of characteristics of Cushing syndrome. Cushing
syndrome is present if there is:

1. No cortisol diurnal variation.

2. No suppression of cortisol after dexamethasone administration.
3. Increased production of cortisol.
4. Suppression of plasma ACTH by hypercortisolism due to an
adrenal nodule.
Once it is determined that there are abnormally high cortisol levels,
the source of hypercortisolism must be determined. The following
diagnostic tests may be performed:

1. Plasma ACTH and plasma DHEAS: A plasma ACTH below 6

pg/mL with low serum DHEAS points to a probable adrenal
tumor. Higher levels would indicate that it is due either to a
pituitary tumor or an ectopic ACTH-secreting tumor.
2. Imaging
1. CT scan: For ACTH-independent Cushing syndrome, the
CT scan will detect an adrenal adenoma. It can also be
determined if the adenoma is malignant or benign. If
carcinoma is present, it will have a diameter larger than 4
cm and demonstrate a nodular growth pattern.
2. MRI: For ACTH-dependent Cushing’s syndrome, the MRI of
the pituitary will show a pituitary lesion in about half of
cases. Premature cerebral atrophy may also be noted. If
the MRI demonstrates a normal pituitary or an irregularity
is noted, sinus sampling may be performed:
1. Bilateral inferior petrosal sinus sampling: This is an
invasive procedure where ACTH levels are sampled
from the veins that drain the pituitary gland which
are in the inferior petrosal sinus. If ACTH
concentrations in the inferior petrosal sinus are not
above the required levels, then lung carcinoma is
considered as well as other reasons for
hypercortisolism.
Hypercortisolism Treatment and
Medication

Treatment

Regardless of the etiology of Cushing’s

syndrome, the treatment is complicated because of the associated
co-morbidities previously discussed (diabetes, osteoporosis,
psychiatric disorders, muscle weakness, hypokalemia, infections).
Treatment options are listed below:

1. Transsphenoidal hypophysectomy. This is the preferred

treatment. Post-surgery, the patient should be screened for
secondary hypothyroidism by monitoring serum free T4 within
one to two weeks following surgery.
2. Resection is also recommended for ectopic ACTH-secreting
tumors, metastatic ACTH-producing tumors as well as
adrenocortical carcinomas.
3. Laparoscopy: May be used in benign adrenal adenomas that
are less than 6 cm in diameter. Treatment is usually successful,
but some individuals experience secondary adrenal
insufficiency.
Medications

Medications are indicated in individuals who

prefer not to have surgery or when surgery is unsuccessful.
Hypertension can be treated with spironolactone and calcium
channel blockers.
Cabergoline (0.5-3.5 mg orally) will reduce hypercortisolemia in
some patients. A multi-receptor-targeting somatostatin analog may
be given for refractory ACTH-secreting pituitary tumors.
Ketoconazole may be given to inhibit adrenal steroidogenesis. Any
other related co-morbidities will need to be treat as well.

Adrenal Insufficiency

Adrenal insufficiency occurs

when there is a low level of cortisol (hypocortisolism). The disease
can be categorized as primary, secondary or tertiary:

1. Primary hypocortisolism: Primary hypocortisolism (Addison’s

disease) develops due to a primary problem in the adrenal
glands that prevent the production and secretion the
adrenocortical hormones.
2. Secondary hypoccortisolism: This is due to inadequate
stimulation of the adrenal glands by ACTH.
 3. Tertiary hypocortisolism: is caused when exogenous
glucocorticoids are abruptly withdrawn or can be a
complication of the treatment of Cushing syndrome. Whether
endogenous or exogenous, high levels of glucocorticoids
decrease hypothalamic synthesis and secretion of CRH and
blocks the action of CRH on the anterior pituitary gland that
leads to loss of ACTH and decreased action on the adrenal
gland.

Addison’s disease (hypoaldosteronism) is commonly caused in the

United States by an autoimmune process that destroys the adrenal
cortex and is more common in women.

Pathophysiology
Addison’s disease is characterized by low corticosteroid and
mineralocorticoid synthesis and elevated serum ACTH levels due to
the loss of the negative feedback system. By the time that the
individual displays symptoms of hypocortisolism, more than 40% of
the adrenocortical tissue is destroyed. Humoral and cell-mediated
responses are affected with large amounts of autoantibodies that
attack 21-hyroxylase resulting in destruction of the adrenal cortex.
With the onset of Addison's disease, the negative feedback system
is altered. The anterior pituitary releases excessive amounts of
ACTH but it is ineffective in stimulating the adrenal cortex. Without
effective ACTH, it does not release glucocorticoids and
mineralocorticoids. The effect of no glucocorticoids results in
glucose not being replenished during stressful situations. As a result
of no mineralocorticoids, there is less reabsorption of sodium and
water in the body which leads to severe dehydration.

Symptoms of Addison’s Disease

The symptoms of Addison disease result from hypocortisolism and
hypoaldosteronism. The most common symptoms are described in
the diagram below:
Specific symptoms of mineralocorticoid deficiency include
hypovolemia, postural hypotension and dizziness, dehydration,
hyperkalemia, and salt craving.
Addison’s Disease Diagnosis and
Treatment

Diagnosis
Laboratory findings include:

1. Plasma cortisol level of less than 3 mcg/dL at 8 AM is

diagnostic, especially if accompanied by a simultaneous
elevation of the plasma ACTH level greater than 200 pg/mL.
2. Cosyntropin stimulation test will confirm the diagnosis.
Cosyntropin is a synthetic ACTH. A dose is administered
intramuscularly followed by attaining a serum cortisol level 45
minutes later. Under normal circumstances the serum cortisol
level rises to at least 20 mcg/dL. Individuals with adrenal
insufficiency will have stimulated serum cortisol levels less
than 20 mcg/dL.
3. Serum DHEA levels less than 1000 ng/mL is seen in 100% of
patients with hypocortisolism.
4. Serum anti-adrenal autoantibodies will be present.
5. Elevated plasma renin activity (PRA) is an indicator of depleted
intravascular volume and the need for fludrocortisone
administration.
6. Acute adrenal crisis precipitated by a bacterial infection may
reveal positive blood, sputum or urine cultures.

Other laboratory results may include:

 WBC count: there will be moderate neutropenia, lymphocytosis

and eosinophilia count of over 300/mcL.
 Hyponatremia and hyperkalemia.
 Fasting hypoglycemia.
 Hypercalcemia.
Treatment
Corticosteroid
Replacement Therapy Mineralocorticoid Replacement Therapy

Corticosteroid replacement Fludrocortisone acetate: has potent sodium-

therapy (life-time retaining effect
replacement):
DHEA: given to some women with adrenal
 Maintenance insufficiency to promote feelings of well-being;
therapy: may increased muscle mass and reversal of bone loss
useHydrocortiso
n,e Prednisone
or
Methylprednisolo
ne per dosing
guidelines
 Plenadren MR
per dosing
guidelines

General Principles:

 Proper dosing
results in
improvement
 Serum ACTH
levels vary and
should not be
used to
determine
corticosteroid
dosing
 Increased dosing
required during
infection,
trauma, surgery
and other
stressful
situations; dose
Corticosteroid
Replacement Therapy Mineralocorticoid Replacement Therapy

is reduced
following these
events