SGD-SBCM

HYPERTHYROIDISM
November 20, 2019

1. Outline the hypothalamic-pituitary-thyroid axis. Explain the role of each component

of the axis, and the mechanism by which this system regulates thyroid hormone
release.

2. How are T3 and T4 distributed throughout the body? How does this affect how their
levels are measured in serum tests? Explain the peripheral conversion that occurs
between the two.

3. Describe the structure of thyroid receptors. Explain how these receptors mediate the
actions of the thyroid hormones T3 and T4.

4. Outline the direct and indirect physiologic effects of the thyroid hormones T3 and T4.

5. What are the signs and symptoms of hyperthyroidism?

Hyperthyroidism is a set of disorders that involve excess synthesis and secretion

of thyroid hormones by the thyroid gland, which leads to the hypermetabolic condition
of thyrotoxicosis.

Common symptoms of thyrotoxicosis include the following:

Nervousness
Anxiety
Increased perspiration
Heat intolerance
Hyperactivity
Palpitations



Common signs of thyrotoxicosis include the following:
Tachycardia or atrial arrhythmia

Systolic hypertension with wide pulse pressure

Warm, moist, smooth skin

Lid lag
Stare
Hand tremor

Muscle weakness
Weight loss despite increased appetite

Reduction in menstrual flow or oligomenorrhea


Younger patients tend to exhibit symptoms of sympathetic activation (eg, anxiety,

hyperactivity, tremor)



 Older patients have more cardiovascular symptoms (eg, dyspnea, atrial
fibrillation) and unexplained weight loss



Patients with Graves disease often have more marked symptoms than patients
with thyrotoxicosis from other causes



Ophthalmopathy (eg, periorbital edema, diplopia, or proptosis) suggests Graves
disease

6. Explain the pathophysiology of hyperthyroidism. How is this

distinguished from thyrotoxicosis?

Pathophysiology

Normally, the secretion of thyroid hormone is controlled by a complex

feedback mechanism involving the interaction of stimulatory and inhibitory
factors (see the image below). Thyrotropin-releasing hormone (TRH) from the
hypothalamus stimulates the pituitary to release TSH.

Hypothalamic-pituitary-thyroid axis feedback. Schematic representation

of negative feedback system that regulates thyroid hormone levels. TRH = thyrotropin-
releasing hormone; TSH = thyroid-stimulating hormone.
 Binding of TSH to receptors on the thyroid gland leads to the release of
thyroid hormones—primarily T4 and to a lesser extent T3. In turn, elevated levels
of these hormones act on the hypothalamus to decrease TRH secretion and thus
the synthesis of TSH.

Synthesis of thyroid hormone requires iodine. Dietary inorganic iodide is

transported into the gland by an iodide transporter, converted to iodine, and
bound to thyroglobulin by the enzyme thyroid peroxidase through a process
called organification. This results in the formation of monoiodotyrosine (MIT)
and diiodotyrosine (DIT), which are coupled to form T3 and T4; these are then
stored with thyroglobulin in the thyroid’s follicular lumen. The thyroid contains a
l large supply of its preformed hormones.

Thyroid hormones diffuse into the peripheral circulation. More than

99.9% of T4 and T3 in the peripheral circulation is bound to plasma proteins and
is inactive. Free T3 is 20-100 times more biologically active than free T4. Free T3
acts by binding to nuclear receptors (DNA-binding proteins in cell nuclei),
regulating the transcription of various cellular proteins.

Any process that causes an increase in the peripheral circulation of

unbound thyroid hormone can cause thyrotoxicosis. Disturbances of the normal
homeostatic mechanism can occur at the level of the pituitary gland, the thyroid
gland, or in the periphery. Regardless of etiology, the result is an increase in
transcription in cellular proteins, causing an increase in the basal metabolic rate.
In many ways, signs and symptoms of hyperthyroidism resemble a state of
catecholamine excess, and adrenergic blockade can improve these symptoms.

7. Outline the different etiologies of hyperthyroidism.

Etiology

1. Genetic factors appear to influence the incidence of thyrotoxicosis.

2. Autoimmune thyroid disease, including Hashimoto hypothyroidism and
Graves disease, often occurs in multiple members of a family.
3. Several genetic syndromes have been associated with hyperthyroidism,
especially autoimmune thyroid disease.
4. Iodine intake also appears to influence the occurrence of thyrotoxicosis.
Evidence exists that iodine can act as an immune stimulator, precipitating
autoimmune thyroid disease and acting as a substrate for additional
thyroid hormone synthesis.
5. The most common cause of thyrotoxicosis is Graves disease (50-60% of cases).
Graves disease is an organ-specific autoimmune disorder characterized by
a variety of circulating antibodies, including common autoimmune
antibodies, as well as anti-TPO and anti-TG antibodies.
 6. Subacute thyroiditis - the next most common cause of thyrotoxicosis
(approximately 15-20% of cases), a destructive release of preformed
thyroid hormone.
7. Toxic multinodular goiter (Plummer disease) accounts for 15-20% of
thyrotoxicosis cases (see the image below). It occurs more commonly in
elderly individuals, especially those with a long-standing goiter.

8. Briefly explain the pathophysiology and complications of Graves disease.

How is this diagnosed? Relate this with your answers from nos. 4 and 5.

Pathophysiology

In Graves disease, a circulating autoantibody against the thyrotropin receptor

provides continuous stimulation of the thyroid gland. This stimulatory immunoglobulin
has been called long-acting thyroid stimulator (LATS), thyroid-stimulating
immunoglobulin (TSI), thyroid-stimulating antibody (TSab), and TSH-receptor
antibody (TRab). [5] These antibodies stimulate the production and release of thyroid
hormones and thyroglobulin; they also stimulate iodine uptake, protein synthesis, and
thyroid gland growth. Anti–thyroid peroxidase (anti-TPO) antibody is assessed in a
nonspecific test for autoimmune thyroid disease. Although the anti-TPO antibody is not
diagnostic for Graves disease, it is present in 85% of patients with the disorder and can
be quickly measured in local laboratories. [6]

In Graves disease, B and T lymphocyte-mediated autoimmunity are known to be

directed at 4 well-known thyroid antigens: thyroglobulin, thyroid peroxidase, sodium-
iodide symporter and the thyrotropin receptor. However, the thyrotropin receptor itself
is the primary autoantigen of Graves disease and is responsible for the manifestation of
hyperthyroidism. In this disease, the antibody and cell-mediated thyroid antigen-
specific immune responses are well defined. Direct proof of an autoimmune disorder
that is mediated by autoantibodies is the development of hyperthyroidism in healthy
subjects by transferring thyrotropin receptor antibodies in serum from patients with
Graves disease and the passive transfer of thyrotropin receptor antibodies to the fetus in
pregnant women.

The thyroid gland is under continuous stimulation by circulating autoantibodies

against the thyrotropin receptor, and pituitary thyrotropin secretion is suppressed
because of the increased production of thyroid hormones. The stimulating activity of
thyrotropin receptor antibodies is found mostly in the immunoglobulin G1 subclass.
These thyroid-stimulating antibodies cause release of thyroid hormone and
thyroglobulin that is mediated by 3,'5'-cyclic adenosine monophosphate (cyclic AMP),
and they also stimulate iodine uptake, protein synthesis, and thyroid gland growth.

The anti-sodium-iodide symporter, antithyroglobulin, and antithyroid peroxidase

antibodies appear to have little role in the etiology of hyperthyroidism in Graves disease.
However, they are markers of autoimmune disease against the thyroid. Intrathyroidal
lymphocytic infiltration is the initial histologic abnormality in persons with
autoimmune thyroid disease and can be correlated with the titer of thyroid antibodies.
Besides being the source of autoantigens, the thyroid cells express molecules that
mediate T cell adhesion and complement regulation (Fas and cytokines) that participate
and interact with the immune system. In these patients, the proportion of CD4
lymphocytes is lower in the thyroid than in the peripheral blood. The increased Fas
expression in intrathyroidal CD4 T lymphocytes may be the cause of CD4 lymphocyte
reduction in these individuals.

Graves disease patients a have higher rate of peripheral blood mononuclear cell
conversion into CD34+ fibrocytes compared with healthy controls. These cells may
contribute to the pathophysiology of ophthalmopathy by accumulating in orbital tissues
and producing inflammatory cytokines, including TNF-alpha and IL-6. [7] In a genome-
wide association study of more than 1500 Graves disease patients and 1500 controls, 6
susceptibility loci were found to be related to Graves disease (major histocompatibility
complex, TSH receptor, CTLA4, FCRL3, RNASET2-FGFR1OP-CCR6 region at 6q27, and
an intergenic region at 4p14. [8]

Pathophysiologic mechanisms of Graves disease relating thyroid-stimulating

immunoglobulins to hyperthyroidism and ophthalmopathy. T4 is levothyroxine. T3 is
triiodothyronine.
Diagnosis:

History:
The symptoms of Graves disease, organized by systems, are as follows:
1. General - Fatigue, general weakness

2. Dermatologic - Warm, moist, fine skin; sweating; fine hair;
onycholysis; vitiligo; alopecia; pretibial myxedema

3. Neuromuscular - Tremors, proximal muscle weakness, easy
fatigability, periodic paralysis in persons of susceptible ethnic
groups

4. Skeletal - Back pain, increased risk for fractures

5. Cardiovascular - Palpitations, dyspnea on exertion, chest pain,
edema

6. Respiratory - Dyspnea

7. Gastrointestinal - Increased bowel motility with increased frequency of bowel
movements

8. Ophthalmologic - Tearing, gritty sensation in the eye, photophobia, eye pain,
protruding eye, diplopia, visual loss

9. Renal - Polyuria, polydipsia

10. Hematologic - Easy bruising

11. Metabolic - Heat intolerance, weight loss despite increase or similar appetite,
worsening diabetes control

12. Endocrine/reproductive - Irregular menstrual periods, decreased menstrual
volume, secondary amenorrhea, gynecomastia, impotence

13. Psychiatric - Restlessness, anxiety, irritability, insomnia



Common physical findings, organized by anatomic regions, are as follows:

1. General - Increased basal metabolic rate, weight loss despite increase or similar
appetite

2. Skin - Warm, most, fine skin; increased sweating; fine hair; vitiligo; alopecia;
pretibial myxedema

3. Head, eyes, ears, nose, and throat - Chemosis, conjunctival irritation, widening
of the palpebral fissures, lid lag, lid retraction, proptosis, impairment of extraocular
motion, visual loss in severe optic nerve involvement, periorbital edema

4. Neck - Upon careful examination, the thyroid gland generally is diffusely
enlarged and smooth; a well-delineated pyramidal lobe may be appreciated upon careful
palpation; thyroid bruits and, rarely, thrills may be appreciated; thyroid nodules may be
palpable.

5. Chest - Gynecomastia, tachypnea, tachycardia, murmur, hyperdynamic
precordium, S3, S4 heart sounds, ectopic beats, irregular heart rate and rhythm

6. Abdomen - Hyperactive bowel sound

7. Extremities - Edema, acropachy, onycholysis

8. Neurologic - Hand tremor (fine and usually bilateral), hyperactive deep tendon
reflexes

 9. Musculoskeletal - Kyphosis, lordosis, loss of height, proximal muscle
weakness, hypokalemic periodic paralysis in persons of susceptible ethnic groups
10. Psychiatric - Restlessness, anxiety, irritability, insomnia, depression


Ophthalmopathy is a hallmark of Graves disease.

9. What are the risk factors of Graves disease?

Graves disease is an autoimmune disease characterized by hyperthyroidism due

to circulating autoantibodies.

Graves disease is associated with:

1. pernicious anemia, vitiligo, diabetes mellitus type 1,
2. autoimmune adrenal insufficiency,
3. systemic sclerosis,
4. myasthenia gravis,
5. Sjögren syndrome,
6. rheumatoid arthritis, and
7. systemic lupus erythematosus.
8. Race - in whites
9. Sex - as with most autoimmune diseases, susceptibility is increased in females.
Hyperthyroidism due to Graves disease has a female-to-male ratio of
7-8:1.
10. Age - typically, Graves disease is a disease of young women, but it may occur
in persons of any age. The typical age range is 20-40 years.

10. How is Graves disease managed? What classes of medications are given
and why?

Medical Care

Treatment involves alleviation of symptoms and correction of the thyrotoxic

state.
1. Beta-adrebnergic blockers - to treat adrenergic hyperfunction.
2. Antithyroid medications - to correct the high thyroid hormone levels by
blocking the synthesis of thyroid hormones or by treatment with
3. radioactive iodine - destroys the thyroid gland and can result in
hypothyroidism.

The most commonly used therapy for Graves disease is radioactive iodine.
Indications for radioactive iodine over antithyroid agents include a large
thyroid gland, multiple symptoms of thyrotoxicosis, high levels of
thyroxine, and high titers of TSI.
 Surgical care

Thyroidectomy, subtotal

11. How do we advise patients with Graves disease in terms of the impact to
their families and their quality of life?

1. All patients should receive long-term follow-up, regardless of the mode of

therapy (ie, surgery, radioiodine, antithyroid drugs).

2. Close follow-up visits with monitoring of examination findings, thyroid

hormone levels, and thyrotropin levels are required.

3. If the patient is on antithyroidal medication (eg, thioamides), liver function

tests and CBC counts with differentials should be monitored based on the
clinical situation.

4. Examination of the eyes should be a routine part of follow-up of these patients,

given the lack of predictability of ophthalmopathy.

5. Smoking cessation techniques should be continued.

6. Given the high-output state of the heart, strenuous exercise may be

detrimental. The patient should be advised to avoid severe fatigue from
exercise.

7. Prevention is difficult because of the lack of knowledge regarding the

pathogenesis of this condition.