AMBOSS- HYPOTHYROIDISM

Summary
Hypothyroidism is a condition in which the thyroid gland is underactive, resulting in a
deficiency of the thyroid hormones triiodothyronine (T3) and thyroxine (T4). In rare
cases, hormone production may be sufficient, but thyroid hormones may have
insufficient peripheral effects. Hypothyroidism may be congenital or acquired. If
congenital, it is usually the result of thyroid dysplasia or aplasia. The etiology of
acquired hypothyroidism is typically autoimmune (Hashimoto thyroiditis) or iatrogenic.
The pathophysiology in hypothyroidism is characterized mainly by a reduction of
the basal metabolic rate and generalized myxedema. Typical clinical findings include
fatigue, cold intolerance, weight gain, and periorbital edema. More severe
manifestations include myxedematous heart disease and myxedema coma, which may
be fatal if left untreated. Children with congenital hypothyroidism often have umbilical
hernias and, without early treatment, develop congenital iodine deficiency
syndrome (intellectual disability, stunted growth). Accordingly, neonatal screening or
hypothyroidism 24–48 hours after birth is required by law in most states. In adults, the
diagnosis is established based on serum thyroid-stimulating hormone (TSH) and free T4
levels (FT4). Therapy for both acquired and congenital hypothyroidism consists of
lifelong treatment with levothyroxine (L-thyroxine) and regular check-ups to monitor
disease activity.

Epidemiology
 Congenital hypothyroidism: ∼ 1/2300 newborns in the US
(1/2000 to 1/4000 worldwide) [1]

 Acquired hypothyroidism: ∼ 3.7% in the US population (1–

3% worldwide)

Etiology
Congenital hypothyroidism
 Sporadic (∼ 85% of cases)

o Thyroid hypoplasia or dysplasia

o Thyroid aplasia (athyroidism)

 Hereditary (∼ 15% of cases)

o Defects in thyroid hormone synthesis

o Peripheral resistance to thyroid hormones

Acquired hypothyroidism
 Primary hypothyroidism: insufficient thyroid hormone production
o Hashimoto thyroiditis

 The most common cause of hypothyroidism in iodine-sufficient

regions [5]

 Associated with other autoimmune diseases

(e.g., vitiligo, pernicious anemia, type 1 diabetes mellitus,
and systemic lupus erythematosus)
o Postpartum thyroiditis (subacute lymphocytic thyroiditis) [5]

o De Quervain thyroiditis (subacute granulomatous thyroiditis) [5]

o Iatrogenic (e.g., post thyroidectomy, radioiodine therapy, antithyroid

medication such as amiodarone and lithium)
o Nutritional (insufficient intake of iodine): the most common cause of
hypothyroidism worldwide, particularly in iodine-deficient regions
o Riedel thyroiditis

o Wolff-Chaikoff effect

 Secondary hypothyroidism: pituitary disorders (e.g., pituitary

adenoma) → TSH deficiency
 Tertiary hypothyroidism: hypothalamic disorders → thyrotropin-
releasing hormone (TRH) deficiency (very rare
Pathophysiology
Hypothalamic-pituitary-thyroid axis
The hypothalamus, anterior pituitary gland, and thyroid gland, together with their
respective hormones, comprise a self-regulatory circuit referred to as the hypothalamic-
pituitary-thyroid axis.

 Physiological: See hypothalamic-pituitary axis.

 Hypothyroidism

o Primary hypothyroidism: peripheral (thyroid) disorders → T3/T4 are

not produced (decreased levels) → compensatory increase of TSH

o Secondary hypothyroidism: pituitary disorders →

decreased TSH levels → decreased T3/T4 levels(↓)

o Tertiary hypothyroidism: hypothalamic disorders →

decreased TRH levels → decreased TSH levels → decreased T3/T4
levels

Effects of hypothyroidism [9]

 Generalized decrease in the basal metabolic rate → decreased

oxygen and substrate consumption, leading to:
o CNS: apathy, slowed cognition

o Skin and appendages: skin dryness, alopecia

o Lipid profile: ↑ low-density lipoproteins, ↑ triglycerides

 Decreased sympathetic activity leads to:

o Decreased sweating

o Constipation

o Bradycardia

 Decreased transcription of sarcolemmal genes (e.g., calcium ATPases) →

decreased cardiac output, myopathy
 Hyperprolactinemia: prolactin production is stimulated by TRH →
increased prolactin suppresses LH, FSH, GnRH,
and testosterone secretion; also stimulates breast tissue growth
 Accumulation of glycosaminoglycans and hyaluronic acid within the
reticular layer of the dermis → myxedema
 o Complex protein mucopolysaccharides bind water → nonpitting
edema
o Initially, edema is pretibial, but as the condition progresses it can
generalize, resulting in a range of symptoms (see “Clinical features”
below).

Clinical features
General signs and symptoms
 Symptoms related to decreased metabolic rate

o Fatigue, bradykinesia

o Cold intolerance

o Hair loss and cold, dry skin

o Weight gain (despite poor appetite)

o Constipation

o Bradycardia

o Myopathy , myalgia, stiffness, cramps, delayed tendon

reflex relaxation (Woltman sign), entrapment syndromes (e.g., carpal
tunnel syndrome)

 Symptoms related to generalized myxedema

o Doughy skin texture, puffy appearance

o Myxedematous heart disease (dilated

cardiomyopathy, bradycardia, dyspnea)

o Myxedema coma (see “Complications” below)

o Hoarse voice, difficulty articulating words

o Pretibial and periorbital edema

 Symptoms of hyperprolactinemia

o Abnormal menstrual cycle (esp. secondary amenorrhea-

Hypothyroidism (↓ T3/T4 → ↑ TRH → ↑ prolactin → ↓ GnRH →
↓ estrogens or menorrhagia)

o Galactorrhea
 o Decreased libido, erectile dysfunction, delayed ejaculation,
and infertility in men

 Further symptoms

o Impaired cognition (concentration, memory), depression

o Hypertension

o Goiter (in Hashimoto thyroiditis)

or atrophic thyroid (in atrophic thyroiditis)

Congenital hypothyroidism
Children with congenital hypothyroidism may have general signs and symptoms of
hypothyroidism in addition to those typical in neonates (see below).

 Postpartum
o Umbilical hernia

o Prolonged neonatal jaundice

o Hypotonia

o Decreased activity, poor feeding, and adipsia

o Hoarse cry, macroglossia

  Congenital iodine deficiency syndrome: impaired development of
the brain and skeleton, resulting in skeletal abnormalities (e.g., short
stature and delayed fontanelle closure) and intellectual disabilities
WARNING!!!
Most children with congenital hypothyroidism do not have symptoms at the time
of birth because the placenta supplies the fetus with maternal thyroid hormone. For this
reason, neonatal screening is vital even if children are asymptomatic! Irreversible intellectual
disabilities can be avoided through early initiation of adequate therapy!

7 P's for the manifestations of congenital iodine deficiency syndrome: Pot-bellied, Pale, Puffy-
faced, Protruding umbilicus, Protuberant tongue, Poor brain development,
and Prolonged neonatal jaundice.

Diagnostics
1.Congenital hypothyroidism
Neonatal screening to measure TSH levels 24–48 hours after birth is required by law.
Increased TSH levels indicate congenital hypothyroidism.

2.Acquired hypothyroidism
Basic diagnostic strategy
The initial step is to determine TSH levels, which may be followed by measurement
of FT4 levels to confirm or rule out the suspected diagnosis.
MAXIMIZE TABLETABLE QUIZ

Central hormones Peripheral hormones

Overt Primary  ↑ TSH  ↓ Free T4 (FT4) and ↓

hypothyroidism hypothyroidism free T3 (FT3) levels

Secondary  ↓ TSH
hypothyroidism

Tertiary
hypothyroidism

Subclinical hypothyroidism  Mildly ↑ TSH  Normal FT3 and

FT4 levels

Euthyroid sick  Normal TSH  Normal FT4 and ↓

syndrome FT3 levels (low T3
syndrome)
 ↓ FT3 and ↓ FT4 levels
(low T3 low T4
syndrome)

Further diagnostic considerations

 Antibody testing
o Tg Ab (thyroglobulin) and TPO Ab (thyroid peroxidase): detectable in
most patients with autoimmune hypothyroidism
o TRAb (TSH receptor)

 Thyrotropin-binding inhibitory immunoglobulin assay (TBII assay)

 Can detect antibodies against the TSH receptor, but cannot
determine the type of antibody (blocking, neutral, or
stimulating)
 However, if a patient displays symptoms of hypothyroidism
and antibodies are detected via the assay, it is highly likely that
these are blocking antibodies.
  Radioactive iodine uptake test
o Measures the proportion of exogenous iodine that is taken up by
the thyroid (normally 10–35%)
o Decreased uptake indicates hypothyroidism.

 Associated conditions
o Hypercholesterolemia (increased LDL), hyperlipidemia, hypoglyce
mia
o Increased creatine kinase

o Mild anemia

o In rare cases: hyponatremia

Differential diagnoses
Euthyroid sick syndrome (ESS)
 Synonyms: sick euthyroid syndrome (SES), non-thyroidal illness
syndrome (NTI)

 Occurs in severe illness or severe physical stress (most common in

intensive care patients)

 Pathophysiology

o Normal thyroid function → no symptoms of hyperthyroidism or

hypothyroidism

o Cytokines (e.g., interleukin 6) cause various changes in levels of

circulating TSH and thyroid hormones.

 Altered deiodinase enzyme activity

 ↓ Conversion of T4 to T3

 ↑ Conversion of T4 to reverse T3 (rT3) by thyroxine 5-

monodeiodinase

 ↓ Thyroid binding globulin

 Clinical features: specific to underlying nonthyroidal illness

 Laboratory

o Low T3 syndrome: decrease in both total and FT3 levels; normal FT4
and TSH, and increased reverse T3
 o FT4 levels may be low in prolonged courses of illness (low T3 low T4
syndrome); indicates a poor prognosis

 Treatment

o Treat underlying illness

o Thyroid hormone replacement is usually not recommended

because thyroid function is normal; there isn't conclusive evidence
that thyroid hormone substitution is beneficial to patients with ESS

Thyroid hormone resistance

 Definition: insufficient end-organ sensitivity to thyroid hormones

 Etiology: deficits in thyroid hormone metabolism, transport, or

receptor interaction as a result of genetic mutations

 Clinical features: Symptoms of both hypothyroidism

and hyperthyroidism are possible.

 Laboratory: Persistently elevated FT4 and FT3 and

absent TSH suppression is typical.

 Therapy: No causative therapy is available.

Complications
Myxedema coma
Myxedema coma is an extremely rare condition caused by decompensation

of an existing thyroid hormone deficiency and can be triggered by infections, surgery, and
trauma. Myxedema coma is a potentially life-threatening condition and, if left untreated, is fatal
in ∼ 40% of cases.

 Clinical presentation

o Cardinal symptoms: impaired mental status

, hypothermia, and concurrent myxedema

o Hypoventilation with hypercapnia

o Hypotension (possibly shock) and bradycardia

 Treatment

o IV combination of T4 and T3 (plus IV hydrocortisone in some cases)

o Patients should be treated and monitored in an ICU.

Further complications
 Primary thyroid lymphoma

 Increased cardiovascular risk

 Carpal tunnel syndrome

Hyperthyroidism

Summary
Hyperthyroidism refers to the symptoms caused by excessive circulating thyroid hormones. It is
typically caused by thyroid gland hyperactivity, the most common causes of which are Graves
disease (most common), toxic multinodular goiter (MNG), and toxic adenoma. In rare cases,
hyperthyroidism is caused by TSH-producing pituitary tumors (central hyperthyroidism),
excessive production of β-hCG (gestational trophoblastic disease), or oral intake of thyroid
hormones (factitious hyperthyroidism). Regardless of the cause, the most common symptoms of
hyperthyroidism include fatigue, anxiety, heat intolerance, increased perspiration, palpitations,
and significant weight loss despite increased appetite. Serological thyroid hormone assay
confirms hyperthyroidism, while measurement of antithyroid antibodies, thyroid
ultrasonography, and radioactive iodine uptake tests help identify the etiology. Management of
any form of hyperthyroidism involves the initial control of symptoms with beta
blockers and antithyroid drugs, followed by definitive therapy either with radioactive iodine
ablation of the thyroid gland or surgery.

Epidemiology
 Prevalence
[1]

o Overt hyperthyroidism: ∼ 1%

o Subclinical hyperthyroidism: 2–3%

 Sex: ♀ > ♂ (5:1)

 Age range at presentation

o Graves disease: 20–30 years of age

o Toxic adenoma: 30–50 years of age

o Toxic multinodular goiter (MNG): peak incidence > 50 years of age

Etiology
 Hyperfunctioning thyroid gland

o Graves disease (∼ 60–80% of cases)

o Toxic MNG (∼ 15–20% of cases)

o Toxic adenoma (3–5% of cases)

o TSH-producing pituitary adenoma (thyrotropic adenoma)

o β-hCG-mediated hyperthyroidism (hydatidiform

mole, choriocarcinoma)

o Hashitoxicosis (see Hashimoto thyroiditis)

 Destruction of the thyroid gland

o Thyroiditis (see subacute thyroiditis)

 Subacute granulomatous thyroiditis (de Quervain thyroiditis)

 Subacute lymphocytic thyroiditis (e.g., post-partum thyroiditis)

o Drug-induced thyroiditis (e.g., amiodarone, lithium)

o Contrast-induced thyroiditis (Jod-Basedow phenomenon)

o Hashimoto thyroiditis

o Radiation thyroiditis

o Palpation thyroiditis: due to thyroid gland manipulation during

parathyroid surgery.
 Exogenous hyperthyroidism
 Ectopic (extrathyroidal) hormone production
o Struma ovarii
o Metastatic follicular thyroid carcinoma
Pathophysiology
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

o Disorders of the thyroid gland → excess production of T3/T4 →

compensatory decrease of TSH

o Thyrotroph adenoma → ↑ TSH levels → ↑ T3/T4 levels

o Excess intake/ectopic thyroid hormone production → ↑ levels of

circulating T /T → compensatory decrease of TSH
3 4

Effects of hyperthyroidism
 Generalized hypermetabolism (increased substrate consumption)

 Hyperstimulation of the sympathetic nervous system

 Cardiac effects

Clinical features
 General

o Heat intolerance, excessive sweating (moist, warm skin)

o Weight loss despite increased appetite

o Frequent bowel movements

o Weakness, fatigue

o Hyperreflexia

 Eyes: lid lag

, lid retraction

(“staring look”), Graves ophthalmopathy

 Goiter

o Diffuse, smooth, nontender goiter; often audible bruit at the superior

poles

o Also seen in subacute thyroiditis, toxic adenoma, and toxic MNG

 Cardiovascular

o Tachycardia

o Palpitations, irregular pulse (due to atrial fibrillation/ectopic beats)

o Hypertension with a widened pulse pressure

o Cardiac failure: Elderly patients often present with features of cardiac

failure (e.g., pedal edema, dyspnea on exertion).

 Musculoskeletal

o Fine tremor of the outstretched fingers

o Myopathy with muscle weakness, particularly in patients > 40 years of

age

o Osteopathy: osteoporosis

, fractures (in the elderly)

 Endocrinological

o ♀: Oligo/amenorrhoea and anovulatory infertility

o ♂: Gynecomastia, decreased libido, erectile dysfunction

 Neuropsychiatric system: anxiety, agitation, depression, insomnia,

emotional instability
Diagnostics
Overview of changes in hormone levels
MAXIMIZE TABLETABLE QUIZ

Overt hyperthyroidism Subclinical hyperthyroidism

Basal TS  ↓ Or undetectable  ↓
H

FT 3  ↑  Normal

FT 4  ↑ in 90% of cases  Normal

 Laboratory studies
 Thyroid function tests
o Test of choice: thyroid-stimulating hormone (TSH) levels

 TSH is low/undetectable.
 In pregnancy, levels of β-hCG (similar molecular structure to TSH)
peak at the end of the first trimester, which leads to a decrease in
serum TSH levels. However, FT /FT levels are normal.
3 4

o Free T3 and free T4 levels: Both are characteristically high.

 Serum thyroglobulin (Tg)

o Indicated if exogenous hyperthyroidism is suspected

o Characteristically low levels due to suppression of the production by

the administered thyroid hormones
 Serum thyroid antibodies: if Graves disease/Hashimoto thyroiditis is
suspected (see “Overview” in thyroid antibodies)

Differential diagnoses
Common differential diagnoses
 Neuropsychiatric symptoms: anxiety/panic disorders

 Hyperadrenergic symptoms: intoxication

with anticholinergics; cocaine/amphetamine abuse; withdrawal
syndromes

 Weight loss: diabetes mellitus, malignancy

 Cardiac symptoms: congestive cardiac failure

Exogenous hyperthyroidism or factitious

hyperthyroidism
 Definition: hyperthyroidism due to excessive intake of thyroid
hormone

 Etiology

o 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

o Unintentional

 Iatrogenic

 Accidental ingestion (primarily in children)

 Dietary supplement overdose

 Clinical features: symptoms of hyperthyroidism but no goiter

 Diagnostics

o Low/undetectable TSH, high levels of T4/T3, low Tg levels

o Low RAI uptake in scintigraphy

 Treatment

o Taper and stop the exogenous thyroid hormone.

o Beta blockers: if symptoms are severe

o Cholestyramine: binds to T3 and T4 in the intestine and interrupts

the enterohepatic circulation

References: [12][13][14][15][16] [17][18][19]

The differential diagnoses listed here are not exhaustive.

FEEDBACK

Treatment
Symptomatic therapy of thyrotoxicosis
 Beta blockers provide immediate control of symptoms.

o Improve tachycardia, hypertension, tremor, and neuropsychiatric

symptoms
 o In high doses, propranolol also decreases the peripheral conversion of
T to T by inhibiting the 5'-monodeiodinase enzyme.
4 3

 Indication: all symptomatic patients

 Contraindications: e.g., asthma, Raynaud phenomenon; for more

information, see section “Contraindications” in beta blockers.

 Drugs used

o Preferred drug: propranolol (nonselective)

o Alternatives: atenolol, metoprolol (both have relative beta-

1 selectivity), nadolol (nonselective), esmolol (IV administration)

Definitive therapy
There are currently three effective initial treatment options for Graves disease: antithyroid
drugs, radioactive iodine ablation, and surgery. Toxic MNG and toxic adenoma (TA) are not
generally treated with antithyroid drugs, but rather with ablation or surgery. Which form of
therapy is chosen depends on the individual clinical situation and the patient preference.

Antithyroid drugs (ATDs)

 Antithyroid drugs can effectively render a patient euthyroid; 20–

75% of patients achieve permanent remission after 1–2 years of
treatment. Some patient groups have a higher likelihood of remission
than others.

 Indications

o Patients with high likelihood of remission (e.g., small goiter,

negative or low TRab titer, women)

o Active Graves ophthalmopathy

o Children age ≤ 5 years

o Pregnancy

o Thyroid storm

o Patient preference

o Patients who need rapid disease control before further treatment, e.g.,
achievement of euthyroid state prior to surgery

o Patients with an inability to follow radiation safety regulations

 Contraindications: history of adverse reactions to ATD

 Adverse effects: See antithyroid drugs.

 Drugs used

o Methimazole

 Drug of choice, except during the first semester of pregnancy

 Contraindicated in the first trimester of pregnancy

o Propylthiouracil

 Drug of choice in the first trimester of pregnancy and in thyroid

storm

 Alternative drug for patients who are allergic to methimazole or

do not tolerate it

Radioactive iodine ablation (RAIA)

 Definition: destruction of thyroid

tissue using radioactive iodine (iodine 131) through a
sodium/iodine symporter

 Indications

o High surgical risk; limited life-expectancy

o Liver disease

o Major adverse reaction to ATDs

o Previous operations or radiation of the neck

o No access to a high-volume thyroid surgeon

o Failure to achieve euthyroidism with ATDs

o Patient preference

o Patients with congestive heart failure, right heart failure, pulmonary

hypertension, or periodic hypokalemic paralysis

o Recommended especially for TMNG and TA patients with high

nodular radioactive iodine uptake

 Contraindications
 o Pregnant/breastfeeding women

o Children < 5 years

o Confirmed or suspected thyroid malignancy

o Patients with moderate to severe Graves ophthalmopathy (GO)

 Procedure

o Pre-treatment methimazole: in patients who are at high risk for

complications due to worsening of hyperthyroidism

 For 4–6 weeks to rapidly achieve a euthyroid state; must be

discontinued 2–3 days before RAIA is begun

 Young or middle-aged patients with mild to moderate symptoms

of hyperthyroidism who undergo RAIA do not routinely require
pretreatment with methimazole.

o Avoidance of excess iodine for 7 days prior to RAIA

o Single oral dose of (131I) → isotope uptake by thyroid gland →

emission of β-radiation that slowly destroys the thyroid tissue

 Post-procedural care

o Patients with Graves disease become hypothyroid after RAI

ablation and require life-long thyroid hormone replacement.

Thyroid surgery

 Surgery is rarely indicated

 Indications

o Large goiters (≥ 80 g) or obstructive symptoms

o Confirmed or suspected thyroid malignancy

o Moderate to severe active Graves ophthalmopathy

o Women planning to become pregnant in the next < 6 months

o Large thyroid nodules

o Patient preference

o Access to a high-volume thyroid surgeon

 o Recommended especially for TMNG and TA patients with
concomitant hyperparathyroidism, insufficient RAIA, or retrosternal
extension

 Contraindications

o Severe comorbidities that influence surgical risk

o First and third trimester of pregnancy

 Procedure

o See “procedure/application” in thyroid surgery.

o For Graves disease: near total thyroidectomy

 Precautions

o Antithyroid drugs and beta blockers are given preoperatively for at

least 4–8 weeks.

o Oral potassium iodide administered preoperatively for 10 days (Wolff-

Chaikoff effect)

 Postprocedural care

o Management of calcium levels: measurement of serum calcium and

intact parathyroid hormone levels

o Weaning of beta blockers

Complications
Thyroid storm (thyrotoxic crisis)
 Definition: an acute exacerbation of hyperthyroidism that results in
a life-threatening hypermetabolic state

 Etiology

o Spontaneous excessive release of thyroid hormones

o A sudden surge in thyroid hormones

 Thyroid surgery

 RAI ablation

 Discontinuation of antithyroid medication

  Long-standing untreated hyperthyroidism

o Stress-related catecholamine surge

 Surgery

 Anesthesia induction

 Labor

 Sepsis

 Clinical features

o Hyperpyrexia with profuse sweating

o Tachycardia (> 140 beats/minute), hypertension (with wide pulse

pressure), atrial fibrillation, congestive cardiac failure

o Severe nausea, vomiting, diarrhea, possibly jaundice

o Severe agitation and anxiety, delirium and psychoses, seizures, coma

o Low/undetectable TSH, elevated free T3/T4

 Treatment

o General measures

 Intensive care monitoring with fluid and electrolyte substitution

 Treatment of hyperthermia: ice packs, cooling blankets,

and antipyretics (e.g., acetaminophen)

 Treatment of underlying condition

o Beta blockers (propranolol) should be promptly started.

o Antithyroid drugs [26]

 First-line: propylthiouracil

 Second-line: methimazole

o Potassium iodide/Lugol's iodine

o Glucocorticoids: IV hydrocortisone/dexamethasone

o Plasmapheresis: as a life-saving treatment, rarely needed

In the case of simultaneous heart failure, the administration of beta blockers may worsen
hemodynamics and is therefore contraindicated!
Special patient groups
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

o β-hCG molecule has a similar structure to that of the TSH molecule.

o β-hCG binds to TSH receptors of the thyroid

gland → thyroid stimulation → hyperthyroidism

 Clinical features

o Graves disease: signs of hyperthyroidism, ophthalmopathy

o 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 non-pregnant patients, but thyroid

scintigraphy is contraindicated

 Treatment

o Propylthiouracil

, methimazole

o Beta blockers

o Surgery: if medication cannot be tolerated; safest in second trimester

 Complications: If left untreated → miscarriage, stillbirth, pre-

eclampsia, premature labor, cardiac failure, low birth weight, neonatal
hyperthyroidism (see below).

Suspect a molar pregnancy or choriocarcinoma if severe hyperthyroidism manifests

during pregnancy!
Neonatal hyperthyroidism
 Occurs in ∼ 5% of babies born to mothers with Graves disease
  Etiology: transplacental passage of maternal TRAbs

 Clinical features

o Hyperthyroidism: irritability,
restlessness, tachycardia, diaphoresis, hyperphagia, poor weight gain,
diffuse goiter (can cause tracheal compression), microcephaly (due
to craniosynostosis)

o May arise directly after birth or delayed up to 10 days later as a result

of transplacental maternal antithyroid
medication (including propylthiouracil or carbimazole)

 Treatment

o Neonatal Graves disease resolves within 1–3 months

o Infants with symptomatic

hyperthyroidism: methimazole and propranolol

 Complications: Untreated symptomatic hyperthyroidism in infants can

cause cardiac failure and intellectual disability.

GRAVES DISEASE

Pathophysiology
 TSH-receptor stimulating IgG immunoglobulin (TRAb; type II
hypersensitivity reaction) → ↑ thyroid function and growth
→ hyperthyroidism and diffuse goiter

 TRAb also stimulate:

o Orbital fibroblasts → fibroblast proliferation, hyaluronic acid synthesis,

and differentiation of fibroblasts to adipocytes (opthalmopathy
with exophthalmus)

o Dermal fibroblasts and deposition

of glycosaminoglycans in connective tissue (pretibial myxedema)
TOXIC MULTINODULAR GOITAR

 Pathophysiology
o Chronic iodine deficiency/thyroid dysfunction →
decreased hormone production →
increased hypothalamic TRH secretion → persistent TSH stimulation
of the thyroid gland → hyperplasia of thyroid nodules, some more
active than others → multinodular goiter (non-toxic MNG)
o Multiple somatic mutations occur in long-standing goiters →
autonomous functioning of some nodules (toxic MNG)
→ hyperthyroidism
 Clinical features: hyperthyroidism and multinodular goiter
 Diagnostics
o ↑ T3 with ↓ TSH
TOXIC ADENOMA

 Pathophysiology
o Gain-of-function mutations of TSH receptor gene in a single
precursor cell → autonomous functioning of the thyroid follicular
cells of a single nodule
→ focal hyperplasia of thyroid follicular cells → toxic adenoma
o The autonomous thyroid nodule overproduces thyroid
hormones → hyperthyroidism → decrease in pituitary TSH secretion
→ suppression of hormone production from the rest of the gland
 Clinical features: hyperthyroidism
 Diagnostics
o ↑ T3 and ↓ TSH