Thyrotoxicosis

1. Thyrotoxicosis: Diagnosis
& Management
Dr. Bushra Ejaz
(Post Graduate Resident)

2. TERMINOLOGY
• The term “thyrotoxicosis” refers to the clinical
manifestations associated with elevated serum
levels of T4 or T3 that are excessive for the
individual (hyperthyroidism).
• Thyroid storm Or Thyrotoxic crisis: Life-
threatening form of thyrotoxicosis

3. CAUSES OF THYROTOXICOSIS
1. Grave’s Disease:
 Graves disease is the most common cause of thyrotoxicosis. It is an autoimmune disorder,
characterized by an increase in synthesis and release of thyroid hormones.
 Autoantibodies, known as thyroid-stimulating immunoglobulins (TSI) or thyrotropin receptor
antibodies (TRAb), bind to the TSH receptors in the thyroid cell membranes and stimulate
the gland to overproduce thyroid hormones.
 The presence of these antibodies distinguishes Graves disease from autoimmune chronic
lymphocytic (Hashimoto) thyroiditis. Both conditions usually have present serum
antithyroid antibodies (TPO Ab or Tg Ab or both).
 Graves disease is more common in women than in men (8:1). Its usual onset is between
the ages of 20 and 40 years.
 It may be accompanied by infiltrative ophthalmopathy (Graves exophthalmos) and, less
commonly, by infiltrative dermopathy (pretibial myxedema It usually affects the pretibial
region but can also affect the dorsal forearms and wrists and dorsum of the feet.
Glycosaminoglycans accumulation and lymphoid infiltration occur in affected skin, which
becomes erythematous with a thickened, rough texture.
 The thymus gland is typically enlarged and serum ANA levels are usually elevated.

4.  Many patients with Graves disease have a family history of either Graves disease or
Hashimoto autoimmune thyroiditis. Histocompatibility studies have shown an
association with group HLA-B8 and HLA-DR3.
 Patients with Graves disease have an increased risk of other systemic autoimmune
disorders, including celiac disease, pernicious anemia, Addison disease, alopecia
areata, vitiligo, type 1 diabetes mellitus, hypoparathyroidism, myasthenia gravis, and
cardiomyopathy.

5. 2. Toxic Multinodular Goiter and Thyroid Nodules
 Autonomous hyper functioning thyroid nodules that produce hyperthyroidism are
known as toxic multinodular goiter (Plummer disease). A single hyper functioning
nodule can also produce hyperthyroidism. Activating TSH receptor mutations are
responsible for some toxic nodules.
 They are more prevalent among older adults and in iodine-deficient regions.
 Toxic multinodular goiter and Graves disease may sometimes coexist in the same
gland (Marine-Lenhart syndrome)
 Thyroid cancer is found in about 5% of patients with toxic multinodular goiter
3. Autoimmune (postpartum or silent) thyroiditis and
subacute thyroiditis
 These conditions cause thyroid inflammation which may release stored hormone
 They all produce a variable triphasic course: variable hyperthyroidism is followed by
transient euthyroidism and progression to hypothyroidism

6. 4. Medication-Induced Hyperthyroidism
1. Amiodarone-induced thyrotoxicosis (AIT)
 Amiodarone-induced thyrotoxicosis (AIT) can occur at any time during treatment and
may develop several months after treatment discontinuation.
 It is diagnosed when serum TSH levels are suppressed and serum T3 or FT3 levels
are high or high-normal.
 Amiodarone is the leading cause for thyrotoxic crisis (“thyroid storm”); however, the
manifestations can be missed since amiodarone tends to cause bradycardia.
 Type 1 AIT is caused by the active production of excessive thyroid hormone and
typically occurs within 2–6 months after starting amiodarone. Type 2 AIT is caused by
the passive release of stored thyroid hormone and occurs an average of 30 months
after starting amiodarone.
 Thyroid function tests(TSH, FT4, T3) should be checked before starting amiodarone,
after 3–6 months of therapy, and thereafter at least every 6 months (sooner if
clinically warranted). Due to early short-term changes, it is best to not check thyroid
function tests during the first 3 months of therapy

7. 2. Iodine-induced hyperthyroidism (Basedow disease)
 The recommended iodine intake for nonpregnant adults is 150 mcg/day. Higher iodine
intake can precipitate hyperthyroidism in patients with nodular goiters, autonomous
thyroid nodules, or asymptomatic Graves disease, and less commonly in patients with
no detectable underlying thyroid disorder.
 Common sources of excess iodine include intravenous oral potassium iodine
supplements, certain foods, topical iodinated antiseptics (eg, povidone iodine), and
medications (eg, amiodarone or potassium iodide). Intravenous iodinated
radiocontrast dye can rarely induce a painful, destructive subacute thyroiditis, similar
to type 2 amiodarone-induced thyrotoxicosis.
3. Tyrosine kinase inhibitors
 Develops in about 3% of patients receiving chemotherapy with tyrosine kinase
inhibitors
4. Immune checkpoint inhibitor cancer therapy
 It frequently precipitates autoimmune adverse reactions which causes thyroiditis,
hypothyroidism (primary or secondary), or hyperthyroidism from either passive
release of thyroid hormone or active production of thyroid hormone (Graves disease).

8. 5. Pregnancy, hCG-Secreting Trophoblastic Tumors,and
Testicular Choriocarcinoma
 Human chorionic gonadotropin (hCG) can bind to the thyroid’s TSH receptors.
Very high levels of serum hCG, particularly during the first 4 months of
pregnancy may cause sufficient receptor activation to cause gestational
thyrotoxicosis.
6. Rare Causes of Hyperthyroidism
 Thyrotoxicosis factitia is due to intentional or accidental ingestion of excessive
amounts of exogenous thyroid hormone.
 Struma ovarii is thyroid tissue contained in about 3% of ovarian dermoid tumors
and teratomas.
 Pituitary TSH hypersecretion by a pituitary thyrotroph tumor or
hyperplasia can rarely cause hyperthyroidism; serum TSH is elevated or
inappropriately normal in the presence of true thyrotoxicosis.
 Metastatic functioning thyroid carcinoma can cause hyperthyroidism in
patients with a heavy tumor burden.

9. Symptoms and Signs
 Thyrotoxicosis can produce nervousness, restlessness, heat intolerance, increased
sweating, palpitations, pruritus, fatigue, muscle weakness, muscle cramps, frequent
bowel movements, weight change (usually loss), or menstrual irregularities.
 There may be fine resting finger tremors, moist warm skin, fever, hyperreflexia, fine
hair, and onycholysis.
 Angina or atrial fibrillation may also be present, sometimes in the absence of other
thyrotoxic symptoms (apathetic hyperthyroidism).

10. Symptoms and Signs
 Patients with Graves disease usually have a diffusely enlarged thyroid that is
frequently asymmetric and often accompanied by a bruit. However, there may be no
palpable thyroid enlargement.
 The thyroid gland in painful subacute thyroiditis is usually moderately enlarged
and tender. There is often dysphagia and pain that can radiate to the jaw or ear.
 With toxic multinodular goiter, there are usually palpable nodules.
 Patients with silent thyroiditis or postpartum thyroiditis have either no palpable
goiter or a small, nontender goiter.
 Thyrotoxic crisis or “thyroid storm” is an extreme form of severe thyrotoxicosis
and an immediate threat to life. The most common manifestations are cardiac (HF,
severe sinus tachycardia [60%], ventricular fibrillation [13%], MI, and cardiogenic
shock), agitation or delirium (63%), high fever, vomiting, diarrhea, dehydration, and
hepatic impairment (52%).

11. Symptoms and Signs
 Clinical hyperthyroidism during pregnancy has a prevalence of about 0.2%. It may
commence before conception or emerge during pregnancy, particularly the first
trimester. Undiagnosed or undertreated hyperthyroidism carries an increased risk of
miscarriage, preeclampsia-eclampsia, preterm delivery, abruptio placenta, maternal
HF, and thyrotoxic crisis (thyroid storm). Such thyrotoxic crisis can be precipitated by
trauma, infection, surgery, or delivery and confers a fetal/maternal mortality rate of
about 25%.
 Hypokalemic periodic paralysis occurs in about 15% of Asian or American Indian
men with thyrotoxicosis and is 30 times more common in men than women. It is
marked by sudden symmetric flaccid paralysis, along with hypokalemia and
hypophosphatemia, that occurs during hyperthyroidism (often after intravenous
dextrose, oral carbohydrates, or vigorous exercise). Attacks last 7–72 hours.
 Thyroid acropachy is a rare skeletal manifestation of Graves disease. It presents
with digital clubbing, swelling of fingers and toes, and radiographic findings of
periostitis involving phalangeal and metacarpal bones. Extremity skin can become
very thickened, resembling elephantiasis

12.  Cardiopulmonary manifestations of thyrotoxicosis commonly include a
forceful heartbeat, premature atrial contractions, and sinus tachycardia. Patients
often have exertional dyspnea.
 Atrial fibrillation or atrial tachycardia occurs in about 8% of patients with
thyrotoxicosis, The ventricular response from the atrial fibrillation may be difficult
to control.
 Thyrotoxicosis can cause a thyrotoxic cardiomyopathy, and the onset of atrial
fibrillation can precipitate HF.
 Echocardiogram reveals pulmonary artery hypertension in about 40% of
hyperthyroid patients. Hemodynamic abnormalities and pulmonary hypertension
are reversible with restoration of euthyroidism.
Cardiopulmonary manifestations of
thyrotoxicosis

14. Laboratory Findings
.
1. Low TSH:
 Thyroid-stimulating hormone (TSH) levels are typically suppressed (except in the very
rare cases of pituitary inappropriate secretion of thyrotropin), often below the normal
range (<0.01 mIU/L). Serum TSH may be misleadingly low in other nonthyroidal
conditions . The term “subclinical hyperthyroidism” is used to describe individuals
with a low serum TSH but normal serum levels of FT4 and T3.
2. Elevated T4 and/or T3:
 Levels of free thyroxine (T4) and/or free triiodothyronine (T3) are above the normal
range, indicating increased thyroid hormone production. In some cases, T3 levels may
be elevated while T4 levels are within the normal range. This condition is called T3
thyrotoxicosis and is often associated with early Graves' disease or toxic thyroid
adenomas.
3. Additional findings:
 Hyperthyroidism can cause hypercalcemia, increased liver enzymes, increased alkaline
phosphatase, anemia, and neutropenia. Hyperthyroidism also increases urinary
magnesium excretion, which can lead to hypomagnesemia, functional
hypoparathyroidism with hypocalcemia, and tetany (rarely). Hypokalemia and
hypophosphatemia occur in thyrotoxic periodic paralysis.

15. Radioisotope Uptake and Imaging
.
1. Radioiodine (123
I) scanning :
 It can be helpful in some situations to determine the cause of hyperthyroidism
but is unnecessary for diagnosis in patients with obvious Graves disease who
have elevated serum TSI or associated Graves ophthalmopathy. A high thyroid
RAI uptake is seen in Graves disease and toxic nodular goiter. A low 123
I RAI
uptake is characteristic of iodine-induced hyperthyroidism and thyroiditis
(subacute, silent, or postpartum), distinguishing them from Graves disease.
2. Technetium (Tc-99m) pertechnetate thyroid uptake:
 It is increased or normal with Graves disease, whereas those with
thyrotoxicosis from thyroiditis (silent, subacute, postpartum) have reduced
uptake.
3. 99mTc-sestamibi (MIBI) scanning :
 It usually shows increased uptake with type 1 amiodarone-induced
thyrotoxicosis (AIT), decreased uptake in type 2 AIT, and intermediate uptake
in mixed AIT

16. Other Imaging
.
1. Thyroid Ultrasound:
 It can be helpful in hyperthyroid patients with palpable thyroid nodules. Thyroid
ultrasound shows a variably heterogeneous, hypoechoic gland in thyroiditis.
Color flow Doppler sonography is helpful to distinguish type 1 amiodarone-
induced thyrotoxicosis (enlarged gland with normal to increased blood flow
velocity and vascularity) from type 2 amiodarone-induced thyrotoxicosis
(distorted gland without increased vascularity).
2. MRI and CT scanning:
 MRI and CT scanning of the orbits are the imaging methods of choice to
visualize Graves ophthalmopathy affecting the extraocular muscles. Imaging is
required only in severe or unilateral cases or in euthyroid exophthalmos that
must be distinguished from orbital pseudotumor, tumors, and other lesion.
Chest, CT in Graves disease often detects an enlarged thymus gland.

17. Differential Diagnosis
.
 True thyrotoxicosis must be distinguished from those conditions that elevate
serum T4 and T3 or suppress serum TSH without affecting clinical status.
Serum TSH is commonly suppressed in early pregnancy and only about 10% of
pregnant women with a low TSH have clinical hyperthyroidism.
 States of hypermetabolism without thyrotoxicosis—notably severe anemia,
leukemia, polycythemia, cancer, and pheochromocytoma—rarely cause
confusion.
 Acromegaly may also produce tachycardia, sweating, and thyroid
enlargement.
 The differential diagnosis for thyroid-associated ophthalmopathy includes
an orbital tumor (eg, lymphoma) or pseudotumor. Ocular myasthenia gravis is
another autoimmune condition that occurs more commonly in Graves disease.
 Diabetes mellitus and Addison disease may coexist with thyrotoxicosis and
can aggravate the weight loss, fatigue, and muscle weakness seen with
hyperthyroidism.

18. When To Admit
.
 Thyroid crisis.
 Hyperthyroidism-induced atrial fibrillation with severe
tachycardia.
 Thyroidectomy

19. Treatment of Grave’s Disease
1. Propranolol:
 Propranolol is used for symptomatic relief of tachycardia, tremor, diaphoresis, and
anxiety until the hyperthyroidism is resolved.
 It is the initial treatment of choice for thyrotoxic crisis and effectively treats thyrotoxic
hypokalemic periodic paralysis.
 Treatment usually starts with propranolol ER, which is given every 12 hours for severe
hyperthyroidism due to accelerated metabolism of the propranolol; it may be given once
daily as hyperthyroidism improves.
2. Thiourea drugs:
 Methimazole or PTU is generally used for young adults or patients with mild
thyrotoxicosis, small goiters, or fear of isotopes. Thioureas may be continued long term for
patients who are tolerating them well.
 The exception is women with thyrotoxic Graves disease who are planning pregnancy in
the near future; thyroid surgery or RAI should be considered at least 4 months in advance
of conception.
 Thiourea drugs are also useful for preparing nonpregnant hyperthyroid patients for surgery
and older patients for RAI treatment.

20. Treatment of Grave’s Disease
Side Effects of Thiourea drugs:
 Agranulocytosis or pancytopenia may occur abruptly in 0.4% of patients taking either
methimazole or PTU. All patients receiving thiourea therapy must be informed of the
danger of agranulocytosis or pancytopenia and the need to stop the drug and seek
medical attention immediately with the onset of any infection or unusual bleeding
 Other common side effects include pruritus, allergic dermatitis, nausea, and dyspepsia.
Since the two thiourea drugs are similar, patients who have a major allergic reaction to one
should not be given the other.
1) Methimazole—Except during the first trimester of pregnancy, methimazole is generally
preferred over PTU since it is more convenient to use and is less likely to cause fulminant
hepatic necrosis. Rare complications peculiar to methimazole include serum sickness,
cholestatic jaundice, alopecia, nephrotic syndrome, hypoglycemia, and loss of taste.
2) Propylthiouracil—Acute liver failure occurs in about 1 in 1000 patients, making PTU a
second-line medication for treating patients with Graves hyperthyroidism. The onset of
severe liver toxicity varies from 3 days to 12 months after starting PTU. Therefore, PTU is
ordinarily reserved for treating women actively seeking fertility and during the first trimester
of pregnancy, when it is preferred over methimazole.

21. Treatment of Grave’s Disease
3. Iodinated contrast agents:
 Iopanoic acid (Telepaque) and ipodate sodium (Bilivist, Oragrafin) are iodinated
contrast agents that inhibit peripheral 5′-monodeiodination of T4, thereby blocking its
conversion to active T3.
 They provide effective temporary treatment for thyrotoxicosis of any cause and are
particularly useful for patients who are symptomatically very thyrotoxic.
 For patients with Graves disease, methimazole is begun first to block iodine
organification; the next day, ipodate sodium or iopanoic acid may be added.
4. Lithium carbonate:
 Thioureas are greatly preferred over lithium for the medical treatment of
hyperthyroidism in Graves disease. However, lithium may be used effectively in cases
of methimazole or PTU-induced hepatic toxicity or leukopenia.
 Lithium should not be used during pregnancy.
5. Radioactive iodine (RAI,131
I)
 131
I therapy destroys overactive thyroid tissue (either diffuse or toxic nodular goiter).

22. Treatment of Grave’s Disease
6. Thyroid surgery:
 Surgery may be indicated for patients with Graves disease who are intolerant to
thioureas, women planning pregnancy in the near future, patients who choose not to
have RAI therapy, and patients with Graves ophthalmopathy.
 The surgical procedure of choice is a total resection of one lobe and a subtotal
resection of the other lobe, leaving about 4 g of thyroid tissue (Hartley– Dunhill
operation).
 The patient should be euthyroid by the time of surgery.
 The risks of subtotal or total thyroidectomy includes damage to a recurrent
laryngeal nerve, with resultant vocal fold paralysis. Hypoparathyroidism also occurs;
serum calcium levels must be checked postoperatively

23. Treatment of Toxic Solitary Thyroid
Nodules
Medical Therapy:
 Hyperthyroidism caused by a single hyperfunctioning thyroid nodule may be treated
symptomatically with propranolol ER and methimazole or PTU, as in Graves disease.
 The dose of methimazole should be adjusted to keep the TSH slightly suppressed, so
the risk of TSH-stimulated growth of the nodule is reduced.
Surgical Treatment:
 It is usually recommended for patients under age 40 years, for healthy older patients
with toxic solitary thyroid nodules, and for nodules that are suspicious for malignancy.
 Toxic solitary thyroid nodules are usually benign but may rarely be malignant. If a
nonsurgical therapy is elected, the nodule should be evaluated with a fine-needle
aspiration (FNA) biopsy.
 Patients are made euthyroid with a thiourea preoperatively and given several days of
iodine, ipodate sodium, or iopanoic acid before surgery.

24. Treatment of Toxic Nodular Goiter
Medical Therapy:
 Medical therapy for patients with toxic nodular goiter consists of propranolol ER
(while hyperthyroid) and a thiourea, as in Graves disease. Thioureas (methimazole
or PTU) reverse hyperthyroidism but do not shrink the goiter. There is a 95%
recurrence rate if the drug is stopped.
 131
I therapy may be used to treat patients with toxic nodular goiter.
Surgical Treatment:
 It is the definitive treatment for a large toxic nodular goiter, following therapy with a
thiourea to render them euthyroid. Surgery is particularly indicated to relieve pressure
symptoms or for cosmetic indications.
 Total or near-total thyroidectomy is recommended, since surgical pathology
reveals unsuspected differentiated thyroid cancer in 18.3% of cases.

25. Treatment of Hyperthyroidism During
Pregnancy-Planning, Pregnancy, and Lactation
Pregnancy Planning:
 Due to the increased risk of congenital anomalies with every thiourea, all women who are
planning to become pregnant are encouraged to consider definitive therapy with 131
I or
surgery well before conception.
 Dietary iodine must not be restricted for such women to protect the fetus from iodine
deficiency.
Pregnancy:
 First-trimester fetal exposure to thioureas increases the risk of birth defects by about 2%.
The fetal anomalies associated with PTU are typically less severe than those associated
with methimazole; therefore, PTU is the preferred thiourea for women actively seeking
fertility and during the first trimester of pregnancy.
 The dose of PTU is kept below 200 mg daily to avoid goitrous hypothyroidism in the
infant.
 PTU can be switched to methimazole in the second trimester.
 Both PTU and methimazole cross the placenta and can induce hypothyroidism, with fetal
TSH hypersecretion and goiter. Fetal ultrasound at 20–32 weeks’ gestation can visualize
any fetal goiter, allowing fetal thyroid dysfunction to be diagnosed and treated

26. Treatment of Hyperthyroidism During
Pregnancy-Planning, Pregnancy, and Lactation
Indications of Surgery in Pregnancy:
 Subtotal thyroidectomy is indicated for pregnant women with Graves disease or for
fertile women of reproductive age who are sexually active and decline contraceptives,
under the following circumstances:
a) severe adverse reaction to thioureas;
b) high dosage requirement for thioureas (methimazole greater than or equal to 30
mg/day or PTU greater than or equal to 450 mg/day)
c) uncontrolled hyperthyroidism due to nonadherence to thiourea therapy.
 Surgery is best performed during the second trimester.
Lactation:
 Both methimazole and PTU are secreted in breast milk but not in amounts that affect
the infant’s thyroid hormone levels.
 No adverse reactions to these drugs have been reported in breast-fed infants.

27. Treatment of Amiodarone-Induced
Thyrotoxicosis (AIT)
 Patients with either type 1 or type 2 AIT require treatment with propranolol ER for
symptomatic relief and methimazole. After two doses of methimazole, iopanoic acid
or sodium ipodate may be added to the regimen to further block conversion of T4 to T3
until the thyrotoxicosis is resolved.
 If iopanoic acid or sodium ipodate is not available, potassium perchlorate may be
given in doses of less than or equal to 1000 mg daily (in divided doses) for a course
not to exceed 30 days to avoid the complication of aplastic anemia.
 Amiodarone may be withdrawn but this does not have a significant therapeutic impact
for several months because of its long half-life.
 For patients with type 1 AIT, therapy with 131
I may be successful, but only for those
with sufficient RAI uptake.
 Patients with type 2 AIT are usually also treated with prednisone for about 2 weeks,
which is slowly tapered and withdrawn after about 3 months.
 Subtotal thyroidectomy should be considered for patients with AIT that is resistant
to treatment.

28. Treatment of Thyroid Crisis or Thyroid Storm
 ICU admission is required.
 A thiourea drug is given (eg, methimazole, 15–25 mg orally every 6 hours, or PTU,
150–250 mg orally every 6 hours).
 Ipodate sodium (500 mg/day orally) can be helpful if begun 1 hour after the first dose
of thiourea. Iodide is given 1 hour later as potassium iodide (10 drops three times daily
orally).
 Propranolol is given in a dosage of 0.5–2 mg intravenously every 4 hours or 20–120
mg orally every 6 hours.
 Hydrocortisone is usually given in doses of 50 mg orally every 6 hours, with rapid
dosage reduction as the clinical situation improves.
 Plasmapheresis has been successfully used in refractory cases to directly remove
thyroid hormone.
 Aspirin is avoided since it displaces T4 from thyroxine-binding globulin (TBG), raising
FT4 serum levels.
 For refractory cases, emergency surgical thyroidectomy is an option.
 Supportive care is usually required, including vasopressors, mechanical ventilation,
dialysis, and extracorporeal membrane oxygenation (ECMO) for cardiogenic shock.

29. PROGNOSIS
 Mild Graves disease may sometimes subside spontaneously. Graves disease that
presents in early pregnancy has a 30% chance of spontaneous remission before the
third trimester.
 The ocular, cardiac, and psychological complications can become serious and
persistent even after treatment.
 Post treatment hypothyroidism is common. It may occur within a few months or up
to several years after RAI therapy or subtotal thyroidectomy.
 Patients with thyrotoxic crisis have a high mortality rate despite treatment.
 Subclinical hyperthyroidism generally subsides spontaneously. Progression to
symptomatic thyrotoxicosis occurs at a rate of 1–2% per year in patients without a
goiter and at a rate of 5% per year in patients with a multinodular goiter.