HYPOTHYROIDISM TO HYPERTHYROIDISM about 93.

7% of the patients who developed overt

hyperthyroidism had a nodule size greater than 3 cm
PHYSIOLOGY
3. Toxic Adenoma - These are solitary nodules with
The thyroid consists of two autonomous thyroid hormone production due to somatic
lobes connected by an mutations in the TSHR
isthmus. It is located anterior
to the trachea between the Autoimmune thyroid diseases, such as Graves ' disease
cricoid cartilage and the and Hashimoto's thyroiditis, result from complex
suprasternal notch. The interactions between genetic predispositions and
thyroid gland consists of environmental triggers. Graves ' disease leads to
numerous spherical follicles hyperthyroidism due to the overproduction of thyroid
composed of thyroid follicular cells that surround hormones, while Hashimoto's thyroiditis causes
secreted colloid. hypothyroidism due to the destruction of thyroid cells by
the immune system
Hypothalamic
Thyrotropin-releasing It is well known that Graves’ thyrotoxicosis may be
hormone (TRH) stimulates followed by hypothyroidism. However, the development
pituitary production of of Graves’ thyrotoxicosis after a period of hypothyroidism
Thyroid-stimulating hormone is not a common phenomenon.
(TSH), which stimulates thyroid
PATHOPHYSIOLOGY OF HYPOTHYROIDISM
hormone synthesis and
secretion. Thyroid hormones Hypo - refers to having too little
act via negative feedback Thyroid - refers to thyroid hormone
predominantly through thyroid
Hypothyroidism refers to a condition where there's a
hormone receptor β2 (TRβ2) to
lack of thyroid hormones
inhibit TRH and TSH
production
Hypothyroidism can happen in a few different ways and
Thyroid hormones regulate metabolism and influence all of them result in a lack of thyroid hormones and a
nearly every organ system. They are crucial for growth decreased basal metabolic rate where cellular reactions
and development in children and for maintaining are happening slower than normal.
metabolic stability in adults. The
hypothalamic-pituitary-thyroid axis tightly regulates Two types of hypothyroidism: Primary and Secondary
hormone levels, ensuring a delicate balance in the body ' ● Primary hypothyroidism
s metabolic processes. ○ The thyroid gland is the problem because it is
PATHOPHYSIOLOGY OF HYPERTHYROIDISM not making enough thyroid hormones. This
results in not only a lack of T3 and T4 which
The pathophysiology of hyperthyroidism depends on the causes a slowing down of metabolic
particular variant of hyperthyroidism. processes but there are increased levels of
1. Graves Disease - This is an autoimmune process TSH from the pituitary to try to stimulate the
with antibodies against the TSH receptor. An interplay gland.
between genetic and environmental factors influences ○ The secondary effect of the high levels of
this autoimmune process. The antibodies stimulate the TSH is that it stimulates fibroblasts in the skin
TSH receptor (TSHR), leading to increased production in soft tissue. The stimulated fibroblasts start
and release of thyroid hormones. The trophic effects on depositing glycosaminoglycans which are
the thyroid also lead to the growth of the thyroid gland. extracellular Matrix proteins into the
interstitium which is the space between cells.
2. Toxic Multinodular Goiter - Pathogenesis of TMNG
In the context of thyroid eye disease, the
includes the initial phase of development of the nodular
deposition of GAGs in the tissues around the
disease. This phase is prolonged and present for years
before the nodules develop autonomy for thyroid eyes can lead to inflammation, swelling, and
hormone production. The somatic mutations involving other symptoms such as bulging eyes,
the TSHR lead to constitutive activation of the cAMP double vision, and eye discomfort. This
signaling pathway, resulting the thyroid autonomy. There condition is often associated with Graves'
is a correlation between the size of the nodules and the disease.
development of hyperthyroidism. In a previous study, ○ Iodine deficiency is the most common
cause of primary hypothyroidism in
 low-income countries that do not fortify their
food with iodine. This causes primary
hypothyroidism because the follicular cells do
not have the iodine they need to produce T3
and T4.
● Hashimoto thyroiditis is the most common cause
of primary hypothyroidism.
○ This is caused by autoimmune inflammation
of the thyroid gland in which the body's
immune system attacks the thyroid gland.
○ Various autoantibodies including anti-thyroid
peroxidase or anti-TPO antibodies may be
present against thyroid hormone production
(thyroid peroxidase, thyroglobulin, TSH
receptors).
○ The body wrongly identifies thyroid cells and
tissues as non-self. This means that our body
sees it as foreign, and attacks the thyroid
gland.
○ Anti-thyroid globulin antibodies initially cause
a bit of a goiter after which there's atrophy of
the thyroid gland
○ Damage to some parts of the thyroid
(specifically the thyroid follicular cells)
subsequently increases TSH leading to
thyroid hypertrophy and hyperplasia. In other
words, the thyroid responds to autoimmune
damage by increasing the size and number of
healthy follicular cells both of which causes
the thyroid to enlarge.
○ Unfortunately, this compensation
short-lived and eventually the autoantibodies
cause so much follicular cell damage that
they destroy thyroid function altogether.
○ Primary hypothyroidism can also happen
after treatment for hyperthyroidism either
because the surgery removes parts or all of
the thyroid gland or because radioiodine
therapy damages too many follicular cells
● Secondary hypothyroidism
○ also called Central hypothyroidism
○ The issue is that the body does not produce
enough TSH. This typically happens because
there's a tumor in the anterior pituitary which
compresses the gland and prevents TSH
production or because there's damage to the
hypothalamus from tumors or trauma which
decreases thyrotropin-releasing hormone
production
ETIOLOGY OF HYPERTHYROIDISM
The three most common etiologies of
hyperthyroidism include:
1. Graves disease (GD)
2. Toxic multinodular goiter (TMNG)
3. Toxic adenoma (TA)
OTHER less common etiologies of hyperthyroidism:
● Iodine-induced hyperthyroidism: Excessive
iodine intake can lead to overproduction of
thyroid hormones, causing hyperthyroidism.
Note: The Wolff-Chaikoff effect is an effec ve means of
rejec ng the large quan es of iodide and therefore
preven ng the thyroid from synthesizing large quan es
of thyroid hormones.
● TSH-secreting pituitary adenomas: These are
benign tumors of the pituitary gland that produce
excessive amounts of thyroid-stimulating
is
hormone (TSH), leading to hyperthyroidism.
● High human chorionic gonadotropin (hCG)
levels: Conditions such as choriocarcinomas
and hydatidiform moles in females and germ cell
tumors in males can cause elevated levels of
hCG, which can stimulate the thyroid gland and
lead to hyperthyroidism.
● Ectopic thyroid in struma ovarii: It refers to
the presence of thyroid tissue in an ovarian
teratoma, which can produce excess thyroid
hormones and cause hyperthyroidism.
● Extensive metastasis from differentiated
thyroid carcinoma: In cases where thyroid
cancer has spread extensively to other parts of
the body, the tumor cells may retain their ability
to produce thyroid hormones, resulting in
hyperthyroidism.
● Drug-induced thyroiditis: Certain medications
like amiodarone, lithium, tyrosine kinase
inhibitors, interferon-alpha, and immune
 checkpoint inhibitors can cause inflammation of
the thyroid gland, leading to thyroid dysfunction.
● Other forms of thyroiditis: Various types of
thyroid inflammation include Hashitoxicosis
(inflammation in autoimmune thyroid disease),
painless thyroiditis, painful subacute thyroiditis,
suppurative thyroiditis (infection of the thyroid),
and Riedel thyroiditis (chronic fibrotic
inflammation of the thyroid).
● Factitious thyroiditis: This refers to thyroid
dysfunction caused by the excessive use of
exogenous thyroid hormone, either intentionally
or unintentionally.
Like all autoimmune diseases, it occurs more commonly
in patients with a positive family history. It is
precipitated by environmental factors like stress,
smoking, infection, iodine exposure, and postpartum, as
well as after highly active antiretroviral therapy
(HAART) due to immune reconstitution.
Hypothyroidism is majorly divided into two categories,
primary and secondary (central) hypothyroidism.
1. PRIMARY - Hypothyroidism is termed primary
when the thyroid gland itself is not able to
produce adequate amounts of thyroid hormone.
2. SECONDARY - The less common, secondary,
or central hypothyroidism is labeled when the
thyroid gland itself is normal, and the pathology
is related to the pituitary gland or hypothalamus.
ETIOLOGY OF HYPOTHYROIDISM
The most prevalent etiology of primary hypothyroidism is
an iodine deficiency in iodine-deficient geographic
areas worldwide. Hashimoto thyroiditis is the most
common etiology in the United States, and it has a
strong association with lymphoma. Etiology can be
influenced locally by iodine fortification and the
emergence of new iodine-deficient areas.
Other common causes of hypothyroidism include:
● Drugs such as amiodarone, thalidomide, oral
tyrosine kinase inhibitors (sunitinib, imatinib)
stavudine, interferon, bexarotene, perchlorate,
rifampin, ethionamide, phenobarbital, phenytoin,
carbamazepine, interleukin-2, and lithium,
● Thyroid radioactive iodine therapy
● Thyroid surgery
● Radiotherapy to head or neck area
● Central hypothyroidism from neoplastic,
infiltrative, inflammatory, genetic, or iatrogenic
disorders of the pituitary or hypothalamus.
● A new class of cancer medications such as
anti-CTLA-4 and anti-PDL1/PD-1 therapy has
been associated with both primary and/or
secondary hypothyroidism.
CLINICAL PRESENTATION
Symptoms of HYPERTHYROIDISM
The typical clinical manifestations of thyrotoxicosis
include:
● Nervousness
● Anxiety
● Palpitation
● Emotional lability (exaggerated or rapid change
of emotions (laughing to ugly crying or getting
angry)
● Easy fatigability (more susceptible to exhaustion
or fatigue)
● Menstrual disturbances
● Heat tolerance
● Loss of Weight (Cardinal Sign)
Signs of HYPERTHYROIDISM
● Warm, smooth, moist skin, exophthalmos
(bulging or protruding of the eyeball or eyeballs)
(in Graves’s disease only)
● Pretibial myxedema (skin condition that causes
plaques of thick, scaly skin and swelling of lower
legs) (In Graves’s disease only)
● Unusually fine hair
● Separation of the end of the finger nails from the
nail beds (onycholysis) may be noted
● Retraction of the eyelids
● Lagging of the upper lid behind the globe when
the patient looks downward (Lid lag)
● Hyperdynamic circulatory state
● Tachycardia at rest (because the heart
compensates for the increase in metabolism.
Since ang thyroid man responsible for
metabolism, hyperthyroidism causes an
increase or faster rate which the heart needs to
make up for)
● A widened pulse pressure
● Systolic ejection murmur
● Gynecomastia in men (The balance between
free androgen and estrogen in patients with
hyperthyroidism is affected by elevated serum
levels of sex hormone-binding globulin;
therefore, patients with hyperthyroidism can
have an increased ratio of estrogen to androgen
leading to the clinical presentation of
gynecomastia.)
● A fine tremor of the protruded tongue and
outstretched hand is revealed in a
neuromuscular examination
 ● Deep tendon reflexes are hyperactive
● Thyromegaly is present
Diagnosis of HYPERTHYROIDISM:
● Low TSH serum concentration, Elevated free
and total T3, T4 and Serum concentrations in
more severe disease
● Elevated radioactive iodine uptake (RAIU) by the
thyroid gland when hormone is being
overproduced; suppressed RAIU in
thyrotoxicosis due to thyroid inflammation
(thyroiditis)
Other tests for HYPERTHYROIDISM:
● Thyroid stimulating antibodies (TSAb)
● Thyroglobulin
● Thyrotropin
receptor antibodies
HYPOTHYROIDISM
Hypothyroidism can lead to a variety of end-organ
effects with a wide range of disease severity, from
entirely asymptomatic individuals to patients in coma
with multisystem failure. In the adult, manifestations of
hypothyroidism are varied and nonspecific. In the child,
thyroid hormone deficiency may manifest as growth or
intellectual retardation.
Symptoms of HYPOTHYROIDISM
● Common symptoms of hypothyroidism include
dry skin, cold intolerance, weight gain,
constipation, and weakness.
● Complaints of lethargy, depression, fatigue or
loss of ambition and energy are also common
but are less specific.
● Muscle cramps, myalgia, and stiffness are
frequent complaints of hypothyroid patients.
● Menorrhagia and infertility may present
commonly in women.
Signs of HYPOTHYROIDISM
● Objective weakness is common, with proximal
muscles being affected more than distal
muscles. Slow relaxation of deep tendon
reflexes is common.
● The most common signs of decreased levels of
thyroid hormone include coarse skin and hair,
cold or dry skin, periorbital puffiness, and
bradycardia.
● Speech is often slow as well as hoarse.
Reversible neurologic syndromes such as carpal
tunnel syndrome, polyneuropathy, and
cerebellar dysfunction may also occur.
● Galactorrhea may be found in women.
Diagnosis of HYPOTHYROIDISM
● In primary hypothyroidism, TSH serum
concentration should be elevated. In secondary
hypothyroidism, TSH levels may be within or
below the reference range; when TSH bioactivity
is altered, the levels reported by immunoassay
may even be
elevated.
● Free and/or
total T, and T,
serum
concentrations
should be low
Other tests for HYPOTHYROIDISM:
Antithyroid peroxidase antibodies and anti-TG antibodies
are likely to be elevated in autoimmune thyroiditis
(Hashimoto disease).
Diagnostic Tests:
● Blood tests are also ordered to measure your
thyroid hormones TSH, T3, and T4.
(High TSH means the patient has hypothyroidism or
underactive thyroid. Your thyroid isn’t making enough
hormones. As a result, the pituitary keeps making and
releasing TSH into your blood to tell your thyroid to work
harder. Low TSH means you have hyperthyroidism or an
overactive thyroid. This means that your thyroid is
making too much hormone, so the pituitary stops making
and releasing TSH into your blood. TH regulates TRH
gene expression and production through a negative
feedback mechanism)
(High blood levels of T3 and T4 means you have
hyperthyroidism. Low blood levels of both means you
have hypothyroidism)
You may also have blood tests to check:
● Cholesterol levels
● Glucose
● Specialized thyroid tests like Thyroid receptor
antibody (TRAb) or Thyroid Stimulating
Immunoglobulin (TSI)
(High levels of TSI in your blood can indicate the
presence of Graves’ disease)
● Imaging tests of the thyroid may also be needed,
including:
● Radioactive iodine uptake and scan
● Thyroid ultrasound (rarely)
Treatment
The therapeutic options for hyperthyroidism include
several medications, each with a different mechanism of
action. Typically, these include a β-blocker to control
symptoms induced by increased adrenergic tone, a
thion- amide (e.g., methimazole or propylthiouracil) to
block new hormone synthesis, an iodine solution to block
the release of thyroid hormone, and agents that inhibit
peripheral conversion of T4 to T3. Radioactive iodine,
which is incorporated into thyroid tissues, resulting in
ablation of thyroid function over a period of 6 to 18
weeks, may also be used.
CASE STUDY
History of Present Illness
● A 51 year old Caucasian male has developed
Graves’ thyrotoxicosis following long-standing
treatment for hypothyroidism. He was first
diagnosed with subclinical hypothyroidism in
2010 and was administered with thyroxine.
● Patient went on to develop Graves’ disease after
6 years of stable treatment for subclinical
hypothyroidism with thyroxine. He commenced
on taking Carbimazole.
● He was admitted to the local hospital with
agranulocytosis and fever with unknown origin
26 days after increasing the dose of
Carbimazole. He was treated with Lugol’s
iodine solution for 10 days before undergoing a
total thyroidectomy.
What is Agranulocytosis?
Agranulocytosis (a.k.a. granulocytopenia) is a rare but
life-threatening condition that involves having severely
low levels of white blood cells called neutrophils
Types of Agranulocytosis
Inherited Agranulocytosis
● From a genetic disorder that affects how your
body makes neutrophils
● More common in babies and children
Acquired Agranulocytosis
● Most cases are due to medication side effects.
for instance with the antibiotics, antipsychotic
meds and drugs to treat thyroid problems
● More common in adults
Past Medical History
● Hypertension (high blood pressure)
● thalassemia minor (one abnormal hemoglobin
gene that affect the production of hemoglobin)
● impaired glucose tolerance (higher than
normal blood glucose levels but not high enough
to be classified as diabetes)
● cholecystitis (inflammation of the gallbladder)
Medications
● Thyroxine 50 mcg daily (0.52 mcg/kg/day)
-for thyroid replacement therapy
● Propranolol 20 mg daily
-beta-blocker medication used alleviate effects
of excessive thyroid hormone production
● Carbimazole (15 mg daily) (increased to 25)
-thionamide drug and used to suppress
excessive production of thyroid hormones in
patient with Graves’ disease
● Filgrastim (300 mcg daily)
-administered to patient who developed
agranulocytosis due to carbimazole treatment
● Cefepime 2 g QID (four times a day)
-antibiotic used to treat any underlying bacterial
infection that may have contributed to patient’s
fever
● Gentamicin 400 mg
-antibiotic for patient’s agranulocytosis and fever
of unknown origin
● Vancomycin 1.5 g bid (twice a day)
-for the ongoing fever of the patient
● Lugol’s iodine
- helps prepare the patient’s thyroid gland for
thyroidectomy by shrinking the size of thyroid
gland and decreasing the amount of thyroid
hormone the body makes.
TIMELINE:
2010
Patient diagnosed with subclinical
hypothyroidism (elevated TSH,
normal FT4 and FT3 levels, elevated
thyroid peroxidase antibodies).
Started on thyroxine 50 mcg daily for
thyroid hormone replacement
therapy
Six months Thyroxine dosage adjustment and
later: monitoring.
TSH levels decreased to 4.09 mU/L
after 6 months and eventually
normalized to 2.99 mU/L.

Intervening Stable TSH levels indicating
period: adequate thyroxine replacement.
July 2016 Patient reported weight loss and
restlessness
thyroid function tests:
● Suppressed TSH: <0.005
mU/L (NR 0.40-3.50).
● Elevated FT4: 18.8 pmol/L
(NR 9-19).
● Elevated FT3: 30.5 pmol/L
(NR 2.6-6)
6 months post
-discontinuation Little change observed in thyroid
function tests.
Patient started on propranolol 20 mg
daily for symptom management.
Referred to local endocrinologist for
further evaluation.
Clinical Diffuse and mobile goiter observed.
Examination
● Blood pressure: 135/80
mm Hg.
(Stage 1 Hypertension)
● Heart rate: 75 bpm.
● Weight: 95 kg.
● BMI: 29.3. (Overweight)
Appeared clinically euthyroid with No
signs of dermopathy (skin change),
acropachy (swelling and clubbing of
fingers), proximal myopathy
(muscle weakness), or
ophthalmopathy (eye problems).
Additional Thyroid ultrasound: Heterogeneous
Investigations: echogenicity and increased
vascularity. (thyroid tissue appears
uneven or varied in its texture.
Increased vascularity means
increased blood flow to thyroid gland,
commonly seen in Graves’ disease)
Pertechnetate uptake scan: Elevated
thyroid uptake, consistent with
Graves' disease. (thyroid gland is
overactive and takes up more
radioactive iodine than normal,
consistent w/ diagnosis of Graves’
disease)
TSH receptor antibody (TRAb) titer:
Elevated at 15.3 IU/L. (TRAb
stimulates the thyroid gland to
produce excess thyroid hormones)
Anti TPO: Elevated at 407.(indicates
the presence of autoimmune
thyroiditis, commonly associated with
Graves’ disease)
WEEK 1 Patient developed Graves’ disease
DEVELOPING and commenced on carbimazole 15
GRAVES’ mg daily.
DISEASE
6 weeks later Thyroid function tests:
● Suppressed TSH:
<0.005 mU/L.
● Elevated FT4: 26.4
pmol/L.
● Elevated FT3: 12.2
pmol/L.
Carbimazole dose increased to 25
mg daily
26 days later Patient admitted to local hospital with
agranulocytosis and fever of
unknown origin
Blood tests on admission:
● White cell count (WCC):
1.2 x10^9/L
● Neutrophils: 0 x10^9/L
Carbimazole discontinued
Treatment administered:
● Filgrastim 300 mcg daily
injections
● Intravenous cefepime 2g
QID for 5 days
● Once-only dose of
gentamicin 400 mg
● Vancomycin 1.5g BID for 3
days (due to ongoing fever)
Propranolol dose increased to 20 mg
BID
Neutrophil count starts to improve on
day 5
AFTER
ASSESSMENT
Lugol’s iodine administered BID for
HOSPITALIZATION
10 days
Further revealed chronic lymphocytic thyroiditis and
Total thyroidectomy performed oncocytic metaplasia
HISTOLOGICAL Diagnosis” Graves’ Disease
FINDINGS PLAN
⮚ Since the patient underwent total thyroidectomy
Additional ● Chronic Lymphocytic and is currently taking thyroxine, the surgeon will
Findings: Thyroiditis likely recommend that the patient should take the
● Oncocytic metaplasia
prescribed dose of thyroxine consistently and at
appropriate time. The medicine will replace the
Current Patient on thyroxine 150 mcg daily
medication: lost thyroid hormone his thyroid naturally made.
⮚ The amount of thyroxine prescribed to the patient
may not be enough to compensate for the
LABS AND OTHER DIAGNOSTIC TESTS
absence of thyroid hormone levels after total
thyroidectomy if the patient does strenuous
activities. That is why it is advisable to refrain from
heavy lifting or any strenuous activities until the
healthcare provider says it’s ok
⮚ Follow -up appointments are advised to monitor
the patient’s thyroid levels and discuss any
concerns or symptoms that the patient may have.
Histopathologic examination of the thyroid further Routine tests may help the health care provider
revealed a background of chronic lymphocytic thyroiditis adjust the dosage of the medicine if needed.
with lymphoid aggregates complete with germinal ⮚ Tests should be done no more than once every 3
centres (A) and oncocytic metaplasia with thyroiditis (B). weeks. Later on, you may only need blood tests
once a year
⮚ Consult with the healthcare provider on suitable
diets after thyroidectomy. Soft foods and liquids
are best for a post-operative diet. The following
foods however should be avoided as these can
hinder the healing process:

● Gluten Caffeine
● Ultra-processed food
● Goitrogens (includes cruciferous
vegetables such as broccoli, cabbage, and
Brussels sprouts)
● Soy (soybeans, edamame, and soy
sauce)
● Hydrogenated fat
● Deep fried foods
● Alcohol

(Triggers inflammation in the thyroid gland which can

aggravate symptoms of hyperthyroidism)

DISCUSSION

This case report describes a patient who initially had

Hashimoto's thyroiditis and was treated with thyroxine
replacement therapy for several years. However, the
patient later developed Graves' disease, which is A
RARE OCCURRENCE. The transition from Hashimoto's
thyroiditis to Graves' disease is thought to be due to a
combination of atypical destructive thyroiditis and the
development of antibodies associated with Graves' research is needed to explore cross-reactions between
disease. antithyroid medications in cases of agranulocytosis and
other treatment options for hyperthyroidism following a
The report also discusses the mechanism behind the primary hypothyroid state.
development of Graves' disease following thyroid gland
destruction. It involves the production of
thyroid-stimulating antibodies and the switch from
blocking to stimulating effects, leading to A
HYPERTHYROID STATE. The damage to thyroid tissue
may act as a triggering factor for Graves' disease.

The administration of thyroxine replacement therapy can

increase ongoing antibody action and induce the
production of thyroid-stimulating antibodies. This may be
due to the rise in serum T4 levels with replacement
therapy, which leads to increased expression of
stimulatory molecules that initiate antibody
production.

The patient in this case also experienced

agranulocytosis as a side effect of carbimazole, a
medication used to treat HYPERTHYROIDISM.
Agranulocytosis is a rare complication associated
with thionamide medications. The mechanism behind
agranulocytosis is not well understood, but it is believed
to involve the production of antibodies that interact with
granulocyte antigens or cause depression of
myelopoiesis.

HLA genotypes have been identified as potential risk

factors for antithyroid drug-induced agranulocytosis, and
individuals with these genotypes may be offered
alternative treatments. Supportive therapy with
antibiotics and granulocyte colony-stimulating factor
(G-CSF) is typically used to manage agranulocytosis
induced by antithyroid medications.

The case report concludes that the patient underwent

total thyroidectomy due to clinical and biochemical
instability, despite the option of radioactive iodine
treatment. The patient was involved in the
decision-making process.

One limitation of the case is that thyroid-stimulating

antibody (TSAb) levels were not measured at the time
of hypothyroidism diagnosis. Obtaining TSAb levels
could have provided more insight into the development
of Graves' disease following the primary hypothyroid
state.

Overall, this case report highlights the rare conversion

from autoimmune subclinical hypothyroidism to severe
Graves' disease and the challenges in treating
hyperthyroidism complicated by agranulocytosis. Further