Internal Medicine EXIMIUS

Hyperthyroidism 2021
DR. MAMBA OCTOBER 2019

Primary Hyperthyroidism
1. Grave’s Disease

Epidemiology
 Accounts for 60–80% of thyrotoxicosis.
Hypothalamus-Pituitary-Thyroid Axis
 Occurs in up to 2% of women
 but is one-tenth as frequent in men
 Typically occurs between 20 and 50 years of age
 rarely begins before adolescence
 also occurs in the elderly
 Prevalence varies among;
a. populations
b. reflecting genetic factors
c. Iodine’s intake (high iodine intake = increased
prevalence of Graves’).

Pathogenesis:
ETIOLOGY: COMBINATION
ENVIRONMENTAL FACTORS
 Indirect evidence suggests that stress is an important
environmental factor
 Smoking is a minor risk factor for Graves’ disease and a
major risk factor for the development of
ophthalmopathy.
 Sudden increases in iodine intake may precipitate
Graves’ disease
 threefold increase in the occurrence of Graves’
postpartum period
 Graves’ disease may occur during the immune
reconstitution phase after highly active antiretroviral
therapy (HAART) or alemtzumab treatment.

GENETIC FACTORS
 Polymorphisms in HLA-DR
 Immunoregulatory genes CTLA-4, CD25, PTPN22, FCRL3,
and CD226
 Gene encoding the thyroid- stimulating hormone receptor
(TSH-R)
 Concordance for the disease in a monozygotic twin is 20-
30%, compared to <5% in dizygotic twins.

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Hyperthyroidism 2021
DR. MAMBA OCTOBER 2019

Signs and symptoms specific for Graves’ disease:

caused by thyroid- stimulating immunoglobulin (TSI)
that are synthesized in the thyroid gland as well as in
GRAVE’S bone marrow and lymph nodes.
DISEASE
Such antibodies can be detected by bioassays or by
using thyrotropin-binding inhibitory immunoglobulin
(TBII) assays.
ASSAYS
Though the pathogenesis of thyroid-associated
ophthalmopathy remains unclear, there is mounting
evidence that the TSH-R is a shared autoantigen that
is expressed in the orbit; this would explain the close
OPTHALMOPATHY
association with autoimmune thyroid disease.
Clinical Manifestations
 Graves’ ophthalmopathy (also called thyroid-associated
ophthalmopathy)
 Thyroid dermopathy
 Thyroid acropachy
• For example, in the elderly, features of thyrotoxicosis may
be subtle or masked, and patients may present mainly
with fatigue and weight loss, a condition known as
apathetic thyrotoxicosis
• In Graves’ disease, the thyroid is usually diffusely enlarged
to two to three times its normal size. The consistency is
firm, but not nodular. There may be a thrill or bruit, best
detected at the inferolateral margins of the thyroid lobes,
due to the increased vascularity of the gland and the
hyperdynamic circulation.
• The onset of Graves’ ophthalmopathy occurs within the
year before or after the diagnosis of thyrotoxicosis in 75%
of patients but can sometimes precede or follow
thyrotoxicosis by several years, accounting for some cases
of euthyroid ophthalmopathy.(the enlarged extraocular
muscles typical of the disease)
• Ophthalmopathy in Graves’ disease; lid retraction,
periorbital edema, conjunctival injection, and proptosis
are marked
• Thyroid dermopathy occurs in <5% of patients with
Graves’ disease, almost always in the presence of
moderate or severe ophthalmopathy. Although most
frequent over the anterior and lateral aspects of the lower
leg (hence the term pretibial myxedema), skin changes can
occur at other sites, particularly after trauma.
• The typical lesion is a noninflamed, indurated plaque with
a deep pink or purple color and an “orange skin”
appearance. Nodular involvement can occur, and the
condition can rarely extend over the whole lower leg and
foot, mimicking elephantiasis.
• Thyroid acropachy refers to a form of clubbing found in
<1% of patients with Graves’ disease. It is so strongly
associated with thyroid dermopathy that an alternative
cause of clubbing should be sought in a Graves’ patient
without coincident skin and orbital involvement.

Earliest manifestations of ophthalmopathy:

• sensation of grittiness
• eye discomfort
• excessive tearing

Most serious manifestation:

compression of the optic nerve→papilledema; peripheral field
defects; and, permanent loss of vision.

• Signs and symptoms include features that are common to

any cause of thyrotoxicosis as well as those specific for
Graves’ disease.
• The clinical presentation depends on the severity of
thyrotoxicosis, the duration of disease, individual
susceptibility to excess thyroid hormone, and the patient’s
age.

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Hyperthyroidism 2021
DR. MAMBA OCTOBER 2019

 About one-third of patients have proptosis, best detected

by visualization of the sclera between the lower border of
the iris and the lower eyelid, with the eyes in the primary
position.
 Proptosis can be measured using an exophthalmometer

The “NO SPECS” scoring system to evaluate ophthalmopathy is an

acronym derived from the following changes:
0 = No signs or symptoms;
1 = Only signs (lid retraction or lag), no symptoms;
2 = Soft tissue involvement (periorbital edema);
3 = Proptosis (>22 mm);
4 = Extraocular muscle involvement (diplopia);
5 = Corneal involvement;6 = Sight loss
 Although useful as a mnemonic, the NO SPECS scheme is
inadequate to describe the eye disease fully, and patients
do not necessarily progress from one class to another

EUGOGO system developed by the European Group On Graves’

Orbitopathy) that assess disease activity are preferable for
monitoring
and treatment purposes

DERMOPATHY
The typical lesion is a noninflamed, indurated plaque with a deep
pink or purple color and an “orange skin” appearance
TREATMENT
Laboratory Evaluation • The hyperthyroidism of Graves’ disease is treated by:
 reducing thyroid hormone synthesis, using
• In Graves’ disease, the TSH level is suppressed, and total
antithyroid drugs
and unbound thyroid hormone levels are increased.
 reducing the amount of thyroid tissue with
– T3 toxicosis : only T3 is increased.
radioiodine (131I) treatment
– T4 toxicosis : elevated total and unbound T4 and
 Thyroidectomy
normal T3 levels.
• The main antithyroid drugs are
• Measurement of TPO antibodies or TRAb may be useful if
 thionamides, such as propylthiouracil
the diagnosis is unclear clinically but is not needed
 carbimazole
routinely.
 methimazole
• Associated abnormalities that may cause diagnostic
confusion in thyrotoxicosis include elevation of bilirubin,
• ↓ function of TPO = ↓ oxidation and organification of
liver enzymes, and ferritin.
iodide
• Microcytic anemia and thrombocytopenia may occur.
• PTU=hepatotoxic; X in 1st trimester of pregnancy
• In 2–5% of patients (and more in areas of borderline iodine
• The common minor side effects of antithyroid drugs are
intake), only T3 is increased (T3 toxicosis). The converse
rash, urticaria, fever, and arthralgia (1–5% of patients).
state of T4 toxicosis, with elevated total and unbound T4
These may resolve spontaneously or after substituting an
and normal T3 levels, is occasionally seen when
alternative antithyroid drug.
hyperthyroidism is induced by excess iodine, providing
• Rare but major side effects include hepatitis
surplus substrate for thyroid hormone synthesis.
(propylthiouracil; avoid use in children) and cholestasis
(methimazole and carbimazole); an SLE-like syndrome;
and, most important, agranulocytosis (<1%).
• The initial dose of carbimazole or methimazole is usually
10–20 mg every 8 or 12 h, but once-daily dosing is possible
after euthyroidism is restored. Propylthiouracil is given at
a dose of 100–200 mg every 6–8 h, and divided doses are
usually given throughout the course.

• antithyroid drugs: All inhibit the function of TPO, reducing

oxidation and organification of iodide.
– The usual daily maintenance doses of antithyroid
drugs in the titration regimen are 2.5–10 mg of
carbimazole or methimazole and 50–100 mg of
propylthiouracil.

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Hyperthyroidism 2021
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Other causes:
• Propranolol 1. Acute Thyroiditis
– (20–40 mg every 6 h) or longer-acting selective • Acute thyroiditis is rare and due to suppurative infection of
β1 receptor blockers such as atenolol may be the thyroid.
helpful to control adrenergic symptoms, • In children and young adults- most common cause is the
especially in the early stages before antithyroid presence of a piriform sinus ( predominantly left-sided)
drugs take effect. • Risk factors in elderly- long-standing goiter and
• Radioiodine degeneration in a thyroid malignancy
– causes progressive destruction of thyroid cells • The patient presents with thyroid pain, often referred to
and can be used as initial treatment or for the throat or ears, and a small, tender goiter that may be
relapses after a trial of antithyroid drugs. asymmetric
• Subtotal or near-total thyroidectomy • Fever, dysphagia, and erythema over the thyroid are
– is an option for patients who relapse after common, as are systemic symptoms of a febrile illness and
antithyroid drugs and prefer this treatment to lymphadenopathy.
radioiodine. • piriform sinus, a remnant of the fourth branchial pouch
Ophthalmopathy requires no active treatment when it is mild or that connects the oropharynx with the thyroid
moderate, because there is usually spontaneous improvement.
Thyroid dermopathy does not usually require treatment, but it can
DIAGNOSTICS
cause cosmetic problems or interfere with the fit of shoes.
TSH low
2. Toxic multinodular goiter
PATHOGENESIS T4 normal or minimally increased
– same with nontoxic multinodular goiter
– difference vs nontoxic MNG: presence of T3 often elevated greater than T4
functional autonomy
– nodules are polyclonal and/or monoclonal Thyroid scan heterogenous uptake (increased and
CLINICAL PRESENTATION decreased)
 Subclinical or mild overt hyperthyroidism 24hr uptake of upper normal range
 elderly- atrial fibrillation or palpitation, radioiodine
tachycardia, nervousness, tremor, or weight loss
TREATMENT Ultrasound to assess presence of cold nodules
 Antithyroid drugs- normalize thyroid function
Differential Diagnosis
 long-term (no spontaneous remission)
(Thyroid Pain)
 RADIOIODINE
• Subacute or, rarely, chronic thyroiditis
– treatment of choice
• Hemorrhage into a cyst
– treats areas of autonomy
• Malignancy (lymphoma)
– ablates functioning nodules →
• Amiodarone-induced thyroiditis
decrease goiter mass
• Amyloidosis (rare)
 SURGERY
– definitive treatment of underlying thyrotoxicosis
Lab Diagnosis
– euthyroid state prior operation
• ↑ ESR & WC but thyroid function is normal.
• Fine-needle aspiration (FNA) biopsy shows infiltration by
polymorphonuclear leukocytes
• Culture of the sample can identify the organism.
• Caution is needed in immunocompromised patients as
fungal, mycobacterial, or Pneumocystis thyroiditis can
occur in this setting.

2. Subacute Thyroiditis
• This is also termed de Quervain’s thyroiditis,
granulomatous thyroiditis, or viral thyroiditis.
• Mumps, coxsackie, influenza, adenoviruses, and
echoviruses
• The diagnosis of subacute thyroiditis is often overlooked—
symptoms can mimic pharyngitis.
• The peak incidence: 30–50 years
• (3x) women > men

Pathophysiology

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Hyperthyroidism
DR. MAMBA OCTOBER 2019
• Thyroid = patchy inflammatory infiltrate + disruption of
the thyroid follicles + multinucleated giant cells within
some follicles.
• Follicular changes → granulomas + fibrosis.
• Thyroid returns to normal, usually several months after
onset.
• Initial phase of follicular destruction—release of Tg and
thyroid hormones - ↑ circulating T4 and T3 and ↓ TSH
• During destructive phase—radioactive iodine uptake is
low or undetectable.
• After several weeks: Thyroid is depleted of stored thyroid
hormone and a phase of hypothyroidism typically occurs,
with low unbound T4 and moderately increased TSH
levels.
• Radioactive iodine uptake returns to normal or is even
increased as a result of the rise in TSH.
• Finally, thyroid hormone and TSH levels return to normal
as the disease subsides.
Clinical manifestations:
• The patient usually presents with a painful and enlarged
thyroid, sometimes accompanied by fever
• (+) features of thyrotoxicosis or hypothyroidism
• Malaise and symptoms of an upper respiratory tract
infection may precede the thyroid-related features by
several weeks
• The patient typically complains of a sore throat, and
examination reveals a small goiter that is exquisitely
tender.
• Pain is often referred to the jaw or ear.
– Complete resolution is the usual outcome,
– 15% of cases: late-onset permanent
hypothyroidism particularly in those with
coincidental thyroid autoimmunity.
LABORATORY FEATURES
CHANGES IN THYROID FUNCTION TESTS evolve through three
distinct phases: THYROTOXIC, HYPOTHYROID, RECOVERY PHASES
Thyrotoxic Phase
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EXIMIUS
2021
• Increased T4 and T3
• Suppressed TSH
• Changes occurs first with the onset of thyroid
inflammation. The destruction of the thyroid follicles
results in release and breakdown of the colloid into the
interstitial tissue and into the circulation of iodinated
materials INCREASE T4 and T3 and suppressed TSH
Hypothyroid Phase
• T4 declines
• TSH gradually increases
• The decline in plasma T4 in this hypothyroidism phase can
continue only until the gland is depleted of its preformed
colloid.  
Recovery Phase
• Resolution of thyroid follicular injury
• T3, T4, and TSH levels return to normal
• RESOLUTION OF THYROID FOLLICULAR INJURY and
Increased TSH NORMAL THYROID FUNCTION
Elevated ESR
• Diagnosis of SAT is confirmed by a high ESR and low
uptake of radioiodine.
• erythrocyte sedimentation rate is characteristically
elevated (often >100 mm/h) in SAT
• There may be a mild normochromic anemia, and an
increase in α2 -globulin frequently is seen as a nonspecific
inflammatory response
Treatment:
1. Aspirin
– 600 mg every 4-6 h
2. NSAIDs
– Sufficient to control symptoms
3. Glucocorticoids (Predinisone)
– Administered if both aspirin and NSAIDs is
inadequate
– Starting dose: 15-40mg
GUIDE:
• Symptoms of thyrotoxicosis improve spontaneously but
may be ameliorated by β-adrenergic blockers;
• antithyroid drugs play no role in treatment of the
thyrotoxic phase.
• Levothyroxine replacement may be needed if the
hypothyroid phase is prolonged, but doses should be low
enough (50–100 μg daily) to allow TSH-mediated recovery.
• Relatively large doses of aspirin (e.g., 600 mg every 4–6 h)
or non- steroidal anti-inflammatory drugs (NSAIDs) are
sufficient to control symptoms in many cases.
• If this treatment is inadequate, or if the patient has
marked local or systemic symptoms, glucocorticoids
should be given.
• The usual starting dose is 15–40 mg of prednisone,
depending on severity. The dose is gradually tapered over
6–8 weeks, in response to improvement in symptoms and
the ESR.
• If a relapse occurs during glucocorticoid withdrawal, the
dosage should be increased and then withdrawn more
gradually. Thyroid function should be monitored every 2–4
weeks using TSH and unbound T4 levels.
3. Silent Thyroiditis (Painless Thyroiditis)
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Hyperthyroidism 2021
DR. MAMBA OCTOBER 2019

• Clinical course similar to that of subacute thyroiditis • Increased T4

• Occurs in patients with underlying autoimmune • Decreased T3
thyroid disease • Increased rT3
PHASES: • Transient TSH increase (up to 20 mIU/L)
– Phase of thyrotoxicosis(2–4 weeks), • TSH levels normalize or are slightly suppressed within 1–3
– Hypothyroidism (4–12 weeks), months.
• Postpartum thyroiditis: occurs in up to 5% of women 3–6 • Iodine inhibits T4 release causing transient decrease of T4
months after pregnancy levels
• Three times more common in women with type 1 • Soon thereafter, most individuals escape from iodide-
diabetes mellitus dependent suppression of the thyroid (Wolff-Chaikoff
• Can be distinguished from subacute thyroiditis by effect), and the inhibitory effects on deiodinase activity
– Painless goiter and thyroid hormone receptor action become
– A normal ESR and the presence of TPO predominant
antibodies.
2 Major Forms of AIT
TREATMENT
TYPE 1 AIT TYPE 2 AIT
Severe thyrotoxic symptoms:
– a brief course of propranolol, (20–40 mg three Associated with an underlying Occurs in individuals with no
or four times daily). thyroid abnormanlity (preclinical intrinsic thyroid
Thyroxine replacement : Grave's dse or nodular goiter abnormalities
– may be needed for hypothyroid phase
– should be withdrawn after 6–9 months, as Thyroid hormone synthesis Result of drug-induced
recovery is the rule. becomes excessive as a result of lysosomal activation leading
• Glucocorticoid treatment is not indicated. increased iodine exposure (Jod- to destructive thyroiditis
• Annual follow-up thereafter is recommended, Basedow phenomenon) with histiocyte accumulation
• A proportion of these individuals develop in the thyroid
permanent hypothyroidism.
• May recur in subsequent pregnancies. ↑ vascularity ↓ vascularity

4. Drug-Induced Thyroiditis Treatment:

Amiodarone effects on thyroid function
• Type III anti-arrhythmic agent
• Contains 39% iodine by weight
• Amiodarone (200 mg/d)
– Associated with very high iodine intake, leading
to greater than fortyfold increases in plasma and
urinary iodine levels
• Storage: adipose tissue
– High iodine levels persist for >6 months after
discontinuation of the drug
• It inhibits deiodinase activity
• Its metabolites function as weak antagonists of thyroid
hormone action.
• It blocks potassium channels that are responsible for
repolarization of the heart during phase 3 of the cardiac
action potential
• Inhibits conversion of T4 to T3 by inhibiting deiodinase
enzyme
Effects on thyroid function
1. Acute, transient suppression of thyroid function
2. Hypothyroidism in patients susceptible to the inhibitory
effects of a high iodine load
3. Thyrotoxicosis that may be caused by either a Jod-
Basedow effect from the iodine load, in the setting of MNG
or incipient Graves’ disease, or a thyroiditis-like condition.
Jod-Basedow - also known as iodine-induced hyperthyroidism, is a
rare cause of thyrotoxicosis seen typically after the administration of
exogenous iodine.
MNG- multinodular goiter
1. Drug should be stopped, if possible
2. High doses of antithyroid drugs
• Used in type 1 AIT but are often
ineffective
3. Potassium perchlorate, 200 mg every 6 h
• Used to reduce thyroidal iodide
content
4. Glucocorticoids
• Have modest benefit in type 2 AIT
5. Lithium
• Blocks thyroid hormone release and
can also provide some benefit.
6. Near-total thyroidectomy
• Rapidly decreases thyroid hormone
levels and may be the most effective
long-term solution if the patient can
undergo the procedure safely.
5. Chronic Thyroiditis
• Focal thyroiditis is present in 20–40% of euthyroid autopsy
cases
• Serologic evidence:
◇ Presence of TPO antibodies – (Autoimmunity)
Hashimoto’s Thyroiditis- Most common cause of chronic thyroiditis
characterized as firm or hard goiter of variable size

Thyroid Function tests:

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Hyperthyroidism 2021
DR. MAMBA OCTOBER 2019

6. Sick Euthyroid Syndrome (Non-thyroidal Illness)

• Any acute, severe illness can cause abnormalities of
circulating TSH or thyroid hormone levels in the absence
of underlying thyroid disease, making these
measurements potentially misleading.
• Release of cytokines such as IL-6- the major cause of these
hormonal changes.
• Most common hormone pattern: ↓ total and unbound T3
levels (low T3 syndrome) with normal levels of T4 and
TSH.
• Increased reverse T3 (rT3): caused by impaired T4
conversion to T3 via peripheral 5′ (outer ring)
deiodination.
• ↓ clearance and not ↑ production is the major basis for
increased rT3.
• Also, T4 is alternately metabolized to the hormonally
inactive T3 sulfate.
note:
• The magnitude of the fall in T3 correlates with the severity of the
illness
• Since rT3 is metabolized by 5′ deiodination, its clearance is also
reduced
• It is generally assumed that this low T3 state is adaptive because
it can be induced in normal individuals by fasting.
Clinical Presentation: (reflects hypothyroidism)
• Teleologically, the fall in T3 may limit catabolism in starved
• Decreased energy metabolism or ill patients
• Decreased heat production • Very sick patients may exhibit a dramatic fall in total T4
• Low basal metabolic rate and T3 levels (low T4 syndrome)
• Lowered basal body temperature • ↓ tissue perfusion = muscle and liver expression of type 3
• Cold intolerance deiodinase leads to accelerated T4 and T3 metabolism
• Lethargy • Another key factor in the fall in T4 levels is altered
• Fatigue binding to thyroxine-binding globulin (TBG)
• Muscle aching and stiffness in joints • Fluctuation in TSH levels also creates challenges in the
• Memory loss interpretation of thyroid function in sick patients.
• Depression, anxiety
• Irritability Note :
• Goiter (due to increase in TSH production) • The commonly used free T4 assays are subject to artifact
• Dry skin when serum binding proteins are low and underestimate the true
• Brittle hair/hair loss free T4 level.
• Weight gain • TSH levels may range from <0.1 mIU/L in very ill patients,
• Constipation especially with dopamine or glucocorticoid therapy, to >20 mIU/L
during the recovery phase of SES.
• Fluid retention
• The exact mechanisms underlying the subnormal TSH seen in 10%
• Galactorrhea (inappropriate milk production) of sick patients and the increased TSH seen in 5% remain unclear
• Menstrual irregularities, menorrhagia but may be mediated by cytokines including IL-12 and IL-18.
• Decreased libido

Riedel’sthyroiditis
• Thyroid dysfunction is uncommon
• Insidious
• Painless goiter (Hard, nontender, often asymmetric, and
fixed)
• Local symptoms due to compression of the esophagus,
trachea, neck veins, or recurrent laryngeal nerves
• Extensive histologic changes (Fibrosis)
• Associates with idiopathic fibrosis at other sites
(retroperitoneum, mediastinum, biliary tree, lung, and
orbit).
Diagnosis:
• Open Biposy
Treatment:
• Surgery (Relieves compressive symptoms)
• Tamoxifen

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Hyperthyroidism 2021
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Distinctive Pattern of abnormalities of some severe illness

- associated with an initial rise in

total (but not unbound) T3 and T4
Acute liver
levels due to TBG release
disease
- levels become subnormal with
progression to liver failure

- transient increase in total and

Acutely ill unbound T4 levels, usually with a
psychiatric normal T3 level
patients - TSH values may be transiently
low, normal, or high

Early stage of - T3 and T4 levels rise

HIV infection - weight loss

- T3 levels fall with progression to

AIDS AIDS,
- TSH usually remains normal.

- low T3 concentrations,
Renal disease - normal rather than increased rT3
levels, due to an unknown factor that
increases uptake of rT3 into the liver.
Diagnosis of SES
• Useful features to consider include:
1. Previous history of thyroid disease and thyroid
function tests
2. Evaluation of the severity and time course of the
patient’s acute illness
3. Documentation of medications that may affect
thyroid function or thyroid hormone levels
4. Measurements of rT3 together with unbound thyroid
hormones and TSH
• Dx is frequently presumptive
• Only resolution of the test results with clinical
recovery can clearly establish this disorder
• Treatment of SES with thyroid hormone (T4 and/or
T3) is controversial

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