Endocrine system

1. Hyperthyroidism and thyrotoxicosis

2. • Thyrotoxicosis refers to the symptoms caused by the excessive circulation
of thyroid hormones. It is typically caused by thyroid gland hyperactivity
(i.e., hyperthyroidism), the most common causes of which are Graves
disease (most common), toxic multinodular goiter (MNG), and toxic
adenoma. It may also be caused by the inappropriate release of thyroid
hormone from a damaged or inflamed thyroid gland (e.g., thyroiditis). In
rare cases, thyrotoxicosis is caused by TSH-producing pituitary
tumors (central hyperthyroidism), excessive production of β-
hCG (gestational trophoblastic disease), or oral intake of thyroid
hormones (exogenous hyperthyroidism). The most common symptoms of
thyrotoxicosis include fatigue, anxiety, heat intolerance, increased
perspiration, palpitations, and significant weight loss despite increased
appetite. Serological thyroid hormone assay confirms thyrotoxicosis, while
the measurement of antithyroid antibodies, thyroid ultrasonography,
and radioactive iodine uptake tests help to identify the etiology.

3. • Management of any form of thyrotoxicosis involves the initial
control of symptoms with beta blockers and antithyroid drugs,
often followed by definitive therapy with either radioactive iodine
ablation (RAIA) of the thyroid gland or surgery. An acute
exacerbation of thyrotoxicosis can lead to a life-
threatening hypermetabolic state known as thyroid storm, which is
diagnosed clinically along with thyroid function tests. Patients
with thyroid storm require urgent stabilization in critical care
settings with fluids, beta blockers, antithyroid medications
(propylthiouracil, potassium iodide, and parenteral glucocorticoids),
active cooling, and management of tachyarrhythmias. Definitive
therapy with RAIA or surgery is considered once they are stable.

4. https://youtu.be/b2DtAALZj7o
• While thyrotoxicosis and hyperthyroidism are
often used interchangeably, the two terms are
not synonymous. [1]
• Thyrotoxicosis: a hypermetabolic condition
caused by an inappropriately high level of
circulating thyroid hormones irrespective of the
source.
• Hyperthyroidism: a condition characterized by
the overproduction of thyroid hormones by
the thyroid gland; can cause thyrotoxicosis

5. – Overt hyperthyroidism
• ↓ Serum TSH levels with ↑ serum free
T4 and/or T3 levels
• Patients typically experience symptoms of
thyrotoxicosis.
– Subclinical hyperthyroidism
• ↓ Serum TSH levels with normal serum free
T4 and T3 levels
• Patients are normally asymptomatic or mildly
symptomatic.
• May progress to overt hyperthyroidism

6. • Prevalence [9]
– Overt hyperthyroidism: ∼ 1%
– Subclinical hyperthyroidism: 2–3%
• Sex: ♀ > ♂ (5:1)
• Age range at presentation [10]
– Graves disease: 20–30 years of age
– Toxic adenoma: 30–50 years of age
– Toxic MNG: peak incidence > 50 years of age

7. • Hyperfunctioning thyroid gland
– Graves disease (∼ 60–80% of cases)
– Toxic MNG (∼ 15–20% of cases)
– Toxic adenoma (3–5% of cases)
– TSH-producing pituitary adenoma (thyrotropic
adenoma)
– β-hCG-mediated hyperthyroidism (hydatidiform
mole, choriocarcinoma)

8. • Destruction of the thyroid gland
– Thyroiditis (see “Subacute thyroiditis”)
• Subacute granulomatous thyroiditis (de Quervain thyroiditis)
• Subacute lymphocytic thyroiditis (e.g., postpartum thyroiditis)
– Drug-induced thyroiditis (e.g., amiodarone, lithium)
– Contrast-induced thyroiditis (Jod-Basedow phenomenon)
– Hashitoxicosis (see “Hashimoto thyroiditis”)
– Radiation thyroiditis
– Palpation thyroiditis: due to thyroid gland manipulation during
parathyroid surgery.
• Exogenous thyrotoxicosis
• Ectopic (extrathyroidal) hormone production
– Struma ovarii
– Metastatic follicular thyroid carcinoma

9. • Hypothalamic-pituitary-thyroid axis
• The hypothalamus, anterior pituitary gland, and thyroid gland,
together with their respective hormones, make up a self-
regulating circuit known as the hypothalamic-pituitary-thyroid axis.
• Physiological regulation: See “Thyroid gland” in “General
endocrinology.”
• Hyperthyroidism
– Disorders of the thyroid gland → excess production of T3/T4 →
compensatory decrease of TSH
– Thyrotropic adenoma → ↑ TSH levels → ↑ T3/T4 levels
• Other causes of thyrotoxicosis
– Excess intake/ectopic production of thyroid hormone → ↑ levels of
circulating T3/T4 → compensatory decrease of TSH
– Trigger → inflammation of the thyroid gland → cellular damage and
destruction → inappropriate release of T3/T4

10. • Effects of thyrotoxicosis
• Generalized hypermetabolism (increased substrate
consumption)
– ↑ Number of Na+/K+-ATPase → elevation of
basal metabolism → promoted thermogenesis
– Upregulation of β-adrenergic receptors →
hyperstimulation of the sympathetic nervous system
• Cardiac effects → ↑ cardiac output [15]
– ↑ Numbers of ATPase on cardiac myocytes; ↓ amount
of phospholamban (PLB) → ↑
transsarcolemmal Ca2+ movement → enhanced myocardial
contractility
– ↓ Peripheral vascular resistance

11. • General
– Heat intolerance
– Excessive sweating because of increased cutaneous
blood flow
– Weight loss despite increased appetite
– Frequent bowel movements (because of intestinal
hypermotility)
– Weakness, fatigue
– Onycholysis
– Infiltrative dermopathy, especially in the pretibial area
(pretibial myxedema)

12. • Eyes
– Lid lag: caused by adrenergic overactivity, which results in spasming of
the smooth muscle of the levator palpebrae superioris
– Lid retraction: “staring look”
– Graves ophthalmopathy (exophthalmos, edema of the periorbital
tissue)
• Goiter
– Diffuse, smooth, nontender goiter; often audible bruit at the superior
poles
– Also seen in subacute thyroiditis, toxic adenoma, and toxic MNG
• Cardiovascular
– Tachycardia
– Palpitations, irregular pulse (due to atrial fibrillation/ectopic beats)
– Hypertension with widened pulse pressure
• Systolic pressure is increased due to increased heart rate and cardiac output.
• Diastolic pressure is decreased due to decreased peripheral vascular resistance.
– Thyrotoxicosis-induced cardiac failure: elderly patients often present
with features of cardiac failure (e.g., pedal edema, exertional dyspnea).
– Abnormal heart rhythms, including atrial fibrillation
– Chest pain

13. • Musculoskeletal
– Fine tremor of the outstretched fingers
– Hyperthyroid myopathy
• Predominantly affects individuals > 40 years of age
• Proximal muscles are predominantly affected
• Serum creatine kinase levels are most often normal
– Osteopathy: osteoporosis due to the direct effect of T3 on osteoclastic bone
resorption , fractures (in the elderly)
• Endocrinological
– Female: oligo/amenorrhoea, anovulatory infertility, dysfunctional uterine
bleeding
– Male: gynecomastia, decreased libido, infertility, erectile dysfunction
– Glucose intolerance [16]
• ↓ Insulin sensitivity of peripheral tissue
• Impaired insulin secretion
• Neuropsychiatric system
– Anxiety
– Emotional instability
– Depression
– Restlessness
– Insomnia
– Tremoulousness (results from the hyperadrenergic state)
– Hyperreflexia

14. https://youtu.be/Ed2WE7heOdU
• Examination of the Thyroid - Clinical
Examination

15. • Routine laboratory studies
– CBC: leukocytosis and/or mild anemia
– BMP
• Hyperglycemia
• Mild hypercalcemia
– Liver chemistries: mildly elevated AST, ALT, ALP, and bilirubin
– Serum cholesterol: decreased total cholesterol, LDL, and HDL
– ESR: typically elevated (> 100 mm/hour) in subacute thyroiditis
• ECG findings
– Tachycardia
– Atrial fibrillation
– LBBB and ECG signs of LVH in patients with dilated cardiomyopathy
•

16. • Subsequent evaluation
• Indicated if the diagnosis remains uncertain after
clinical assessment and initial evaluation. The choice
and priority of studies depends on the clinical picture,
patient characteristics and test availability.
• TSH receptor antibody (TRAb)
• Indication: if Graves disease is suspected but classic
clinical features are absent [17]
• Interpretation
– Positive: Diagnosis of Graves disease is established.
– Negative: Further investigation is necessary.

17. • Nuclear medicine thyroid scan and radioactive iodine uptake
measurement [19]
• Definitions
– Nuclear medicine thyroid scan: a nuclear medicine imaging technique that
visualizes the distribution of thyroid function using an oral or IV radiotracer
(most commonly Tc-99m pertechnetate or iodine-123)
– Radioactive iodine uptake measurement (RAIU test): a test that quantifies the
percentage of the administered amount of radioactive iodine taken up by
the thyroid gland [20]
• Indications [17]
– First-line test for most patients with uncertain etiology of thyrotoxicosis after
initial evaluation
– Assessment of functional status of thyroid nodules [20]
– Thyroid malignancy (see “Diagnostics" in “Thyroid cancer”)
– Identification of ectopic thyroid tissue (e.g., lingual thyroid, struma ovarii)
– Evaluation of retrosternal goiters
– Evaluation of thyroglossal cysts

18. • Contraindications: pregnant
or breastfeeding women [17]
• Findings
– Hot nodule: Hyperfunctioning tissue takes up large
amounts of radioactive iodine
– Cold nodule: Non-functioning nodules do not take up
any radioactive iodine and appear "cold”, but the
surrounding normal thyroid tissue takes
up radioactive iodine and appears "warm"
– See also “Diagnostics” in “Thyroid cancer” and
“Diagnostic steps for thyroid nodules”

19. • Thyroid ultrasound with Doppler
• Indications [21]
– Palpable abnormality, e.g., goiter or nodules
– Additional study following nuclear medicine thyroid scan or second-
line initial imaging study
– Preferred imaging technique in pregnant or breastfeeding women
• Typical findings [21]
– Changes to morphology: diffuse enlargement or nodules
– Increased perfusion: either diffuse (Graves disease, toxic adenoma) or
nodular (toxic MNG)
– Decreased perfusion: destructive causes
of hyperthyroidism (e.g., subacute thyroiditis or postpartum
destructive thyroiditis)
– Hypoechoic areas in acute thyroiditis and malignancy

20. • Further evaluation
• These additional tests are not routinely required
but may be performed depending on the
suspected underlying etiology.
• Ultrasound-guided FNAC
– Consider for suspicious nodules (See “Diagnostic steps
for thyroid nodules”)
– Can help confirm etiology if diagnosis remains
uncertain (see “Pathological findings” in “Common
causes of thyrotoxicosis”)

21. • Other thyroid antibodies [17]
– Thyroid peroxidase antibodies (TPOAb)
• Indication: suspected subacute lymphocytic thyroiditis,
including postpartum thyroiditis
• Elevated levels may also be seen in Graves disease.
– Thyroglobulin antibodies (TgAb): not routinely indicated
but can be elevated in Graves disease, autoimmune
conditions, and thyroid cancer
– See also “Thyroid antibodies.”
• Serum thyroglobulin (Tg): indicated for
suspected exogenous hyperthyroidism with unclear
history
– Serum Tg should be assessed alongside TgAb because
a TgAb-positive result indicates an
unreliable serum Tg finding. [17]
– Findings
• Exogenous hyperthyroidism: ↓ Tg due to production that is
suppressed by the administered thyroid hormones
• Endogenous hyperthyroidism: normal or ↑ Tg

22. • The symptoms of thyrotoxicosis are
nonspecific and overlap significantly with
other common conditions. If there is any
clinical uncertainty, TSH should be assessed.
• Neuropsychiatric symptoms: anxiety/panic
disorders
• Hyperadrenergic symptoms: intoxication
with anticholinergics; cocaine/amphetamine
misuse; withdrawal syndromes
• Weight loss: diabetes mellitus, malignancy
• Cardiac symptoms: congestive cardiac failure

23. • Symptomatic therapy for thyrotoxicosis [17]
• The treatment of hyperadrenergic symptoms is
important for decreasing the risk of cardiac
complications in thyrotoxicosis, such as atrial
fibrillation and heart failure.
• Indication: all symptomatic patients
• Treatment of hyperadrenergic symptoms: beta
blockers (first line)
– Provide immediate control of symptoms, e.g.,
neuropsychiatric and/or hyperadrenergic symptoms
– Treatment options
• First line: propranolol
• Alternatives: atenolol OR metoprolol
• Severe thyrotoxicosis or thyroid storm treated in ICU: esmolol
– If there are contraindications to beta blockers, e.g.,
severe asthma, Raynaud phenomenon ,
consider CCBs: verapamil OR diltiazem . [22]

24. • Definitive therapy for hyperthyroidism and thyrotoxicosis [17][23]
• The choice of therapy depends on the individual clinical situation and patient
preference.
• There are three effective initial treatment options for Graves disease: antithyroid
drugs, RAIA, and surgery
• RAIA or surgery is preferable to antithyroid drugs for toxic MNG and toxic adenoma.
• Antithyroid drugs for thyrotoxicosis
• Antithyroid drugs can effectively render a patient euthyroid. 20–75% of patients
with Graves disease achieve permanent remission after 1–2 years of treatment;
however, some patient groups have a higher likelihood of remission than others.
• Indications
– Thyroid storm: initial management as well as prevention in at-risk patients prior to surgery
or RAIA
– Graves disease: Patients with high remission likelihood , and/or moderate to severe active Graves
ophthalmopathy
– Contraindications to both RAIA and surgery
– Other: hyperthyroidism in pregnancy, limited life expectancy, patient preference
• Medication
– The choice of medication depends on the severity of symptoms and patient factors.
• Most patients: methimazole
• Thyroid storm or first trimester of pregnancy: propylthiouracil
– See also “Adverse effects” in “Antithyroid drugs”.

25. • Radioactive iodine ablation (RAIA) [26]
• Definition: destruction of thyroid tissue via radioactive
iodine (iodine-131) through a sodium/iodine symporter
• Technical background: Radioactive iodine-131 emits both gamma
and beta rays.
– Gamma rays: diagnostic effect
– Beta rays: therapeutic effect
• Indications
– Toxic MNG and toxic adenoma with high nodular radioactive iodine
uptake
– Failure to achieve euthyroidism with antithyroid drugs (ATDs) in Graves
disease, due to:
• Refractory disease
• Contraindications to ATDs, e.g., liver disease
• Major adverse reactions to ATDs
– High surgical risk due to comorbidities or previous surgery or
radiation of the neck
– Limited life-expectancy
– Other: thyrotoxic periodic paralysis

26. • Contraindications
– Pregnant/breastfeeding women
– Children < 5 years of age
– Initial treatment for confirmed or suspected thyroid malignancy
– Moderate to severe Graves ophthalmopathy
• Preparation for RAIA
– RAIA can cause a transient worsening of hyperthyroidism.
– Prophylactic treatment can reduce the risk of complications
in high-risk patient groups, e.g., severe hyperthyroidism, older
patients, and those with comorbid conditions.
• Consider beta blockers even in asymptomatic patients (see
“Symptomatic therapy for thyrotoxicosis” for dosages).
• Administer methimazole to rapidly achieve a euthyroid state; must be
discontinued 2–3 days before RAIA is started.
– Avoid excess iodine for 7 days prior to RAIA.
– In women of childbearing potential, a negative pregnancy
test must be confirmed within 48 hours before RAIA.

27. • Procedure: Single oral dose of iodine-131 →
isotope uptake by thyroid gland → emission of beta
radiation that slowly destroys the thyroid tissue
• Complications [28][29]
– Early
• Most patients with Graves disease become hypothyroid
after RAIA and require life-long thyroid hormone replacement
• Gastritis: nausea and vomiting
• Sialadenitis
• Other: transient loss of taste or smell, stomatitis, transient bone
marrow suppression
– Late
• Radiation-induced thyroiditis
• Secondary malignancy or leukemia
• Dry mouth (xerostomia)

28. • Thyroid surgery [30]
• The efficacy of antithyroid drugs and RAIA has reduced the need
for thyroid surgery.
• Indications
– Large goiters (≥ 80 g) or obstructive symptoms
– Confirmed or suspected thyroid malignancy
– Graves disease with: [31]
• Concomitant primary hyperparathyroidism or periodic paralysis
• Moderate to severe active Graves ophthalmopathy [24]
– Toxic MNG or toxic adenoma with: concomitant primary hyperparathyroidism,
insufficient RAIA, or retrosternal extension
– Other: large thyroid nodules , refractory amiodarone-induced thyrotoxicosis ,
planned pregnancy within next 6 months , or patient preference
•

29. • Contraindications
– Severe comorbidities that influence surgical risk
– Pregnancy
• Preparation for surgery
– Achieving euthyroidism prior to surgery: preoperative application
of antithyroid drugs (and beta blockers if necessary) for at least 4–8 weeks if
possible.
– Patients with Graves disease: potassium iodide solution for 10
days preoperatively (harnesses the Wolff-Chaikoff effect)
• Procedure
– Graves disease or toxic MNG: near-total or total thyroidectomy
– Isolated toxic adenoma: lobectomy
– See also “Procedure/application” in “Thyroid surgery.”
• Postprocedural care
– Wean beta blockers
– Measure serum calcium and PTH levels

30. • Hyperthyroidism in pregnancy
• Epidemiology: Hyperthyroidism is rare
in pregnancy (< 0.5% of cases).
• Etiology: Graves disease and β-hCG-
mediated hyperthyroidism are the most common
causes.
• Pathogenesis
– β-hCG molecule has a similar structure to that of
the TSH molecule.
– β-hCG binds to TSH receptors of the thyroid
gland → thyroid stimulation → hyperthyroidism

31. • Clinical features
– Graves disease: signs of hyperthyroidism, ophthalmopathy
– β-hCG-mediated hyperthyroidism can cause:
• Subclinical hyperthyroidism
• Overt (severe) hyperthyroidism in cases of hydatidiform
moles/choriocarcinoma (see “Gestational trophoblastic disease”)
• Diagnosis: same as in nonpregnant patients, but nuclear
medicine thyroid scan is contraindicated
• Treatment
– Propylthiouracil , methimazole
– Beta blockers
– Surgery: if medication cannot be tolerated; safest in second
trimester
• Complications: if left
untreated → miscarriage, stillbirth, preeclampsia, prematur
e labor, cardiac failure, low birth weight, neonatal
hyperthyroidism (see below)

32. • Neonatal hyperthyroidism
• Occurs in ∼ 5% of babies born to mothers with Graves
disease
• Etiology: transplacental passage of maternal TRAbs
• Clinical features
– Hyperthyroidism: irritability,
restlessness, tachycardia, diaphoresis, hyperphagia, poor
weight gain, diffuse goiter (can
cause tracheal compression), microcephaly (due
to craniosynostosis)
– May arise directly after birth or delayed up to 10 days later
as a result of transplacental maternal antithyroid
medication (including propylthiouracil or carbimazole)

33. • Treatment
– Neonatal Graves disease resolves within 1–3 months
– Infants with
symptomatic hyperthyroidism: methimazole and prop
ranolol
• Complications: Untreated
symptomatic hyperthyroidism in infants can
cause cardiac failure and intellectual disability.
• Exogenous thyrotoxicosis
• Definition: thyrotoxicosis due to excessive intake
of thyroid hormone

34. • Etiology
– Intentional
• Therapeutic: suppressive doses of thyroid hormones for thyroid
cancer treatment
• Patients with psychiatric disorders, like Munchausen syndrome
• People who are trying to lose weight
– Unintentional
• Iatrogenic
• Accidental ingestion (primarily in children)
• Dietary supplement overdose
• Clinical features: symptoms of thyrotoxicosis but
no goiter

35. • Diagnostics
– Low/undetectable TSH, high levels
of T4/T3, low Tg levels
– Low RAI uptake in scintigraphy
• Treatment
– Taper and stop the exogenous thyroid hormone.
– Beta blockers: if symptoms are severe
– Cholestyramine: binds to T3 and T4 in the intestine and
interrupts the enterohepatic circulation

36. • Definition [17]
• An acute exacerbation of hyperthyroidism that results in a life-
threatening hypermetabolic state.
• Also known as thyrotoxic crisis
• Etiology [17]
• Iatrogenic
– Thyroid surgery
– RAIA
– Exogenous iodine from contrast media or amiodarone
– Discontinuation of antithyroid medication
• Stress-related catecholamine surge
– Nonthyroidal surgery
– Anesthesia induction
– Labor
– Intercurrent illness, e.g., sepsis, myocardial infarction, diabetic ketoacidosis

37. • Clinical features [17]
• Hyperpyrexia with profuse sweating
• Tachycardia (> 140/minute) and (possibly
severe) arrhythmia (e.g., atrial fibrillation), hypertension with
wide pulse pressure, congestive cardiac failure
• Hypotension/shock secondary to high output heart
failure or hypovolemia as a result of GI and insensible losses
• Symptoms of thyrotoxicosis
• Abdominal pain
• Severe nausea, vomiting, diarrhea, possibly jaundice
• Severe agitation and anxiety, delirium and psychoses, seizures, com
a

38. • Diagnostics [17]
• A thyroid storm is diagnosed on the basis of classic clinical features and
supporting TFT abnormalities, e.g., low/undetectable TSH, elevated free T3/T4.
• Further tests should be performed to identify any underlying precipitants and to assess for
complications, e.g.:
– ECG to assess for atrial fibrillation
– Liver chemistries to assess for evidence of jaundice
• Treatment of thyroid storm [17][36]
• Thyroid storm has a high mortality rate and patients should receive aggressive treatment to
manage complications and restore normal thyroid function.
• Approach
• Consult critical care for ICU admission and monitoring.
• Start symptomatic treatment to manage hypotension, hyperpyrexia, and tachycardia.
• Administer medication to reduce thyroid hormone synthesis and release, and inhibit their
peripheral action.
• Identify and treat any precipitating cause.
• Once the patient is stable, initiate definitive therapy for hyperthyroidism and thyrotoxicosis.
• Consider plasmapheresis or emergency surgery as life-saving treatment for rare refractory cases

39. • Symptomatic treatment
• Hyperadrenergic symptoms: beta blockers are first-line
– Preferred: Propranolol, due to combined beta-blockade and
antithyroid effects
– Alternatives
• Preexisting heart failure: esmolol [18][37]
• Mild obstructive airway disease/stable asthma: atenolol or metoprolol
– Beta blocker contraindications: consider CCBs, e.g., diltiazem
• Hyperthermia
– External cooling techniques (e.g., ice packs, cooling blankets, alcohol
washes)
– Antipyretics, e.g., acetaminophen
• Hypotension and hypovolemia: fluid resuscitation to treat
insensible and GI losses [36]
• Electrolyte disturbances: (see “Electrolyte repletion”)

40. • Antithyroid drugs in thyroid storm [17][18][22]
• Inhibition of thyroid hormone synthesis
– First line: propylthiouracil
– Alternative: methimazole
• Inhibition of thyroid hormone release (through the Wolff-Chaikoff effect)
– First line: iodine solutions given at least 1 hour after antithyroid drugs
• Potassium iodide solution
• Lugol solution
– In patients with iodine allergy or iodine-induced thyrotoxicosis, lithium can be
used.
• Inhibition of peripheral conversion of T4 to T3
– Propranolol
– Glucocorticoids: can also treat concurrent adrenal insufficiency
• First line: hydrocortisone
• Alternative: dexamethasone

41. • 2020 AAES Guidelines for the Definitive Surgical
Management of Thyroid Disease in Adults
• 2019 EANM Practice Guideline/SNMMI
Procedure Standard for RAIU and Thyroid
Scintigraphy
• 2016 ATA Guidelines for Diagnosis and
Management of Hyperthyroidism and Other
Causes of Thyrotoxicosis
• 2016 JTA/JES Guidelines for the Management of
Thyroid Storm

42. •Read books