PATHOPHYSIOLOGY

(ENDOCRINOLOGY)
 Pathophysiology of diabetes mellitus
 Thyroid hormones: hyperthyroidism and
hypothyroidism
 Thyroid hormones: assessment of thyroid hormones
 Adrenal hormones: adrenal deficiency and excess
 Pathophysiology of diabetes mellitus
Diabetes mellitus (DM), commonly referred to as diabetes, is a
group of metabolic disorders which is characterized by sustained
hyperglycaemia.
Symptoms of high blood sugar include frequent urination, increased
thirst, and increased hunger.
If left untreated, diabetes can cause many complications.
Acute complications can include diabetic ketoacidosis,
hyperosmolar hyperglycemic state, or death.
Serious long-term complications include cardiovascular disease,
stroke, chronic kidney disease, foot ulcers, and damage to the eyes.
 Diabetes mellitus cont’d
◦ Diabetes is due to either the pancreas not producing insulin or the
cells of the body are not responding properly to the insulin produced.
◦ There are three main types of diabetes mellitus;
Type 1 DM results from the pancreas's failure to produce insulin. This
form was previously referred to as "insulin-dependent diabetes
mellitus" (IDDM) or "juvenile diabetes".
Type 2 DM begins with insulin resistance, a condition in which cells
fail to respond to insulin properly. This form was previously referred to
as "non insulin-dependent diabetes mellitus" (NIDDM) or "adult-onset
diabetes". The most common cause is excessive body weight and not
enough exercise.
Gestational diabetes occurs when pregnant women without a
previous history of diabetes develop high blood sugar levels.
 signs and symptoms of diabetes mellitus
The classic symptoms of untreated diabetes are weight loss, polyuria (increased
urination), polydipsia (increased thirst), and polyphagia (increased hunger).
Symptoms may develop rapidly (weeks or months) in type 1 DM, while they
usually develop much more slowly and may be subtle or absent in type 2 DM.
Several other signs and symptoms can mark the onset of diabetes although they
are not specific to the disease.
In addition to the known ones above, they include blurry vision, headache,
fatigue, slow healing of cuts, and itchy skin.
A number of skin rashes that can occur in diabetes are collectively known as
diabetic dermadromes.
 Complications of diabetes mellitus
The primary complications of diabetes due to damage in small blood vessels include
damage to the eyes, kidneys, and nerves.
Damage to the eyes, known as diabetic retinopathy, is caused by damage to the blood
vessels in the retina of the eye, and can result in gradual vision loss and blindness.
Damage to the kidneys, known as diabetic nephropathy, can lead to tissue scarring,
urine protein loss, and eventually chronic kidney disease, sometimes requiring dialysis
or kidney transplantation.
Damage to the nerves of the body, known as diabetic neuropathy, is the most common
complication of diabetes.
The symptoms can include numbness, tingling, pain, and altered pain sensation, which
can lead to damage to the skin. Diabetes-related foot problems (such as diabetic foot
ulcers) may occur, and can be difficult to treat, occasionally requiring amputation.
Additionally, proximal diabetic neuropathy causes painful muscle atrophy and
weakness.
 hyperthyroidism
Hyperthyroidism is the condition that occurs due to excessive
production of thyroid hormone by the thyroid gland.
Thyrotoxicosis is the condition that occurs due to excessive thyroid
hormone of any cause and therefore includes hyperthyroidism.
Some, however, use the terms interchangeably.
Signs and symptoms vary between people and may include
irritability, muscle weakness, sleeping problems, a fast heartbeat,
heat intolerance, diarrhea, enlargement of the thyroid, and weight
loss.
Symptoms are typically less in the old and during pregnancy.
An uncommon complication is thyroid storm in which an event such
as an infection results in worsening symptoms such as confusion and
a high temperature and often results in death.
 Hyperthyroidism cont’d
Graves' disease is the cause of about 50% to 80% of the cases
of hyperthyroidism in the United States.
Other causes include multinodular goiter, toxic adenoma,
inflammation of the thyroid, eating excess iodine, and excess
synthetic thyroid hormone.
A less common cause is a pituitary adenoma.
The diagnosis may be suspected based on signs and symptoms
and then confirmed with blood tests.
Typically blood tests show a low thyroid stimulating hormone
(TSH) and raised T3 or T4. Radioiodine uptake by the thyroid,
thyroid scan, and TSI antibodies may help determine the cause.
 Hyperthyroidism cont’d
Treatment depends partly on the cause and severity of disease.
There are three main treatment options: radioiodine therapy,
medications, and thyroid surgery.
Radioiodine therapy involves taking iodine-131 by mouth which is
then concentrated in and destroys the thyroid over weeks to months.
The resulting hypothyroidism is treated with synthetic thyroid
hormone.
Medications such as beta blockers may control the symptoms, and
anti-thyroid medications such as methimazole may temporarily help
people while other treatments are having effect.
Surgery to remove the thyroid is another option.
 hypothyroidism
Hypothyroidism, also called underactive thyroid or low
thyroid, is a common disorder of the endocrine system in which
the thyroid gland does not produce enough thyroid hormone.
It can cause a number of symptoms, such as poor ability to
tolerate cold, a feeling of tiredness, constipation, depression,
and weight gain.
Occasionally there may be swelling of the front part of the neck
due to goitre.
Untreated hypothyroidism during pregnancy can lead to delays
in growth and intellectual development in the baby, which is
called cretinism.
 hypothyroidism
Worldwide, too little iodine in the diet is the most common cause of
hypothyroidism.
In countries with enough iodine in the diet, the most common cause
of hypothyroidism is the autoimmune condition Hashimoto's
thyroiditis.
Less common causes include; previous treatment with radioactive
iodine, injury to the hypothalamus or the anterior pituitary gland,
certain medications, a lack of a functioning thyroid at birth, or
previous thyroid surgery.
The diagnosis of hypothyroidism, when suspected, can be confirmed
with blood tests measuring thyroid-stimulating hormone (TSH) and
thyroxine levels.
 hypothyroidism
Prevention at the population level has been with the
universal salt iodization.
Hypothyroidism can be treated with levothyroxine. The dose
is adjusted according to symptoms and normalization of the
thyroxine and TSH levels.
Thyroid medication is safe in pregnancy.
While a certain amount of dietary iodine is important,
excessive amounts can worsen certain types of
hypothyroidism
 Thyroid function test
◦ TESTS
Blood tests to measure TSH, T4, T3 and Free T4 are readily available and widely
used.
Tests to evaluate thyroid function include the following;
TSH TESTS
The best way to initially test thyroid function is to measure the TSH level in a
blood sample. A high TSH level indicates that the thyroid gland is failing because
of a problem that is directly affecting the thyroid (primary hypothyroidism).
The opposite situation, in which the TSH level is low, usually indicates that the
person has an overactive thyroid that is producing too much thyroid hormone
(hyperthyroidism).
 Thyroid function test cont’d
Occasionally, a low TSH may result from an abnormality in
the pituitary gland, which prevents it from making enough
TSH to stimulate the thyroid (secondary hypothyroidism).
In most healthy individuals, a normal TSH value means that
the thyroid is functioning normally.
 Thyroid function test cont’d
◦ T4 TESTS
T4 circulates in the blood in two forms;
◦ 1) T4 bound to proteins that prevent the T4 from entering the various tissues that need
thyroid hormone.
◦ 2) Free T4, which does enter the various target tissues to exert its effects. The free T4
fraction is the most important to determine how the thyroid is functioning, and tests to
measure this are called the Free T4 (FT4) and the Free T4 Index (FT4I or FTI).
◦ Individuals who have hyperthyroidism will have an elevated FT4 or FTI, whereas patients
with hypothyroidism will have a low level of FT4 or FTI.
◦ The finding of an elevated TSH and low FT4 or FTI indicates primary hypothyroidism due
to disease in the thyroid gland.
◦ A low TSH and low FT4 or FTI indicates hypothyroidism due to a problem involving the
pituitary gland.
◦ A low TSH with an elevated FT4 or FTI is found in individuals who have hyperthyroidism.
 Thyroid function test cont’d
◦ T3 TESTS
T3 tests are often useful to diagnosis hyperthyroidism or to determine the
severity of the hyperthyroidism.
◦ Patients who are hyperthyroid will have an elevated T3 level.
◦ In some individuals with a low TSH, only the T3 is elevated and the FT4 or FTI is
normal.
◦ T3 testing rarely is helpful in the hypothyroid patient, since it is the last test to
become abnormal.
◦ Patients can be severely hypothyroid with a high TSH and low FT4 or FTI, but have
a normal T3.
◦ In some situations, such as during pregnancy or while taking birth control pills,
high levels of total T4 and T3 can exist. This is because the estrogens increase the
level of the binding proteins.
◦ In these situations, it is better to ask both for TSH and free T4 for thyroid
evaluation.
 Thyroid function test cont’d
◦ THYROID ANTIBODY TESTS
The immune system of the body normally protects us from foreign invaders such
as bacteria and viruses by destroying these invaders with substances called
antibodies produced by blood cells known as lymphocytes.
◦ In many patients with hypothyroidism or hyperthyroidism, lymphocytes make
antibodies against their thyroid that either stimulate or damage the gland.
◦ Two common antibodies that cause thyroid problems are directed against thyroid
cell proteins: thyroid peroxidase and thyroglobulin.
◦ Measuring levels of thyroid antibodies may help diagnose the cause of the thyroid
problems. For example, positive anti-thyroid peroxidase and/or anti-thyroglobulin
antibodies in a patient with hypothyroidism make a diagnosis of Hashimoto’s
thyroiditis.
◦ If the antibodies are positive in a hyperthyroid patient, the most likely diagnosis is
autoimmune thyroid disease
 Thyroid function test
◦THYROGLOBULIN
Thyroglobulin (Tg) is a protein produced by normal thyroid cells
and also thyroid cancer cells.
◦It is not a measure of thyroid function and it does not diagnose
thyroid cancer when the thyroid gland is still present.
◦It is used most often in patients who have had surgery for thyroid
cancer in order to monitor them after treatment.
◦Tg is included in this brochure of thyroid function tests to
communicate that, although measured frequently in certain
scenarios and individuals, Tg is not a primary measure of thyroid
hormone function.
 Thyroid function test cont’d
◦ NON-BLOOD TESTS
◦ RADIOACTIVE IODINE UPTAKE
Because T4 contains much iodine, the thyroid gland must pull a large amount of iodine
out from the blood stream in order for the gland to make an appropriate amount of T4.
◦ This activity can be measured by having an individual swallow a small amount of
iodine, which is radioactive.
◦ The radioactivity allows the doctor to track where the iodine molecules go.
◦ By measuring the amount of radioactivity that is taken up by the thyroid gland
(radioactive iodine uptake, RAIU), doctors may determine whether the gland is
functioning normally.
◦ A very high RAIU is seen in individuals whose thyroid gland is overactive
(hyperthyroidism), while a low RAIU is seen when the thyroid gland is underactive
(hypothyroidism).
◦ In addition to the radioactive iodine uptake, a thyroid scan may be obtained, which
shows a picture of the thyroid gland.
 Cushing’s syndrome
◦Cushing’s syndrome occurs due to abnormally high levels
of the hormone cortisol.
◦This can happen for a variety of reasons.
◦The most common cause is overuse of corticosteroid
medications.
◦Cushing’s syndrome is also known as hypercortisolism
◦The diagnosis is made based on abnormal cortisol levels
in the body.
 Cushing’s syndrome cont’d
◦ Cushing's syndrome is caused by either excessive cortisol-like
medication such as prednisone or a tumor that either produces or
results in the production of excessive cortisol by the adrenal glands.
◦ A number of tumors may also cause Cushing's.
◦ Some of these are associated with inherited disorders such as multiple
endocrine neoplasia type 1 and Carney complex.
Diagnosis requires a number of steps;
◦ The first step is to check the medications a person takes.
◦ The second step is to measure levels of cortisol in the urine, saliva or in
the blood after taking dexamethasone.
◦ If this test is abnormal, the cortisol may be measured late at night.
◦ If the cortisol remains high, a blood test for ACTH may be done to
determine if the pituitary is involved.
 Cushing’s syndrome cont’d
◦Most cases can be treated and cured.
◦If due to medications, these can often be slowly
stopped. If caused by a tumor, it may be treated
by a combination of surgery, chemotherapy,
and/or radiation.
◦If the pituitary is affected, other medications may
be required to replace its lost function. With
treatment, life expectancy is usually normal.
◦Some, in whom surgery is unable to remove the
entire tumor, have an increased risk of death.
 Addison disease
◦Addison’s disease, also known as primary adrenal insufficiency and
hypocortisolism, is a long-term endocrine disorder in which the
adrenal glands do not produce enough steroid hormones.
◦Symptoms generally come on slowly and may include abdominal
pain, weakness, and weight loss, darkening of the skin in certain
areas may also occur.
◦Under certain circumstances, an adrenal crisis may occur with low
blood pressure, vomiting, lower back pain, and loss of consciousness.
◦An adrenal crisis can be triggered by stress, such as from an injury,
surgery, or infection.
 Addison disease cont’d
◦Addison's disease arises from problems with the adrenal gland
such that not enough of the steroid hormone cortisol and
possibly aldosterone are produced, most often due to damage
by the body's own immune system in the developed world and
tuberculosis in the developing world.
◦Other causes include certain medications, sepsis, and bleeding
into both adrenal glands.
◦Secondary adrenal insufficiency is caused by not enough
adrenocorticotropic hormone ACTH or CRH
◦Addison's disease is generally diagnosed by blood tests, urine
tests, and medical imaging.
 Addison disease cont’d
◦Treatment involves replacing the absent hormones. This involves taking
a corticosteroid such as hydrocortisone and fludrocortisone. These
medications are usually taken by mouth.
◦Lifelong, continuous steroid replacement therapy is required, with
regular follow-up treatment and monitoring for other health problems.
◦A high-salt diet may also be useful in some people.
◦If symptoms worsen, an injection of corticosteroid is recommended
and people should carry a dose with them.
◦Often, large amounts of intravenous fluids with the sugar dextrose are
also required. Without treatment, an adrenal crisis can result in death.