Prepared by

HYPOTHYROIDISM Darien Liew Daojuin

15 October 2017
HYPOTHALAMIC-PITUITARY-THYROID AXIS

Tertiary hypothyroidism

Secondary hypothyroidism

Primary hypothyroidism
OVERVIEW
Hypothyroidism is defined as failure of the thyroid gland to produce
sufficient thyroid hormone to meet the metabolic demands of the
body. Untreated hypothyroidism can contribute to hypertension,
dyslipidemia, infertility, cognitive impairment, and neuromuscular
dysfunction.
Worldwide, iodine deficiency remains the foremost cause of
hypothyroidism. In the United States and other areas of adequate
iodine intake, autoimmune thyroid disease (Hashimoto disease) is the
most common cause.
AETIOLOGY Hypothyroidism developing in
infancy or early childhood, fairly
common in areas where dietary
iodine deficiency is endemic,
Hashimotos mountainous areas such as
thyroiditis Himalayas and the Andes.

Endemic
The term sporadic cretinism was
cretinism
initially used to describe the
random occurrence of cretinism in
non-endemic areas. The cause of
these abnormalities was identified
as nonfunctioning or absent
De Quervain thyroid glands. This was later
thyroiditis replaced with the etiologic term
congenital hypothyroidism.

Sporadic
cretinism
 Hashimotos
Amyloid Thyroiditis
Goiter Autoimmune
Hemochromatosis
Thyroidectomy
Sarcoidosis

Infiltrative Thyroid
Langerhan Disease
Cell Iatrogenic
histiocytosis

Scleroderma Riedels Radioiodine

Thyroiditis Therapy
Primary
Hypothyroidism

Silent/painless
thyroiditis

Transient Thyroiditis Iodine Excess

De Quervain
thyroiditis
Deficiency
Postpartum
thyroiditis
Drugs
PRIMARY HYPOTHYROIDISM
In patients with hypothyroidism caused by disease of the thyroid gland,
the combination of a low serum T4 (and T3) and a compensatory high
serum TSH concentration both confirms the diagnosis of hypothyroidism
and indicates that it is due to primary thyroid disease.
There are two forms:

Subclinical Hypothyroidism Overt Hypothyroidism

Defined as a high serum TSH Defined as a high serum TSH
concentration in the presence of concentration in the presence of a
normal serum free T4 and T3 low serum free T4 concentration.
concentrations.
Most of these patients have
There patients have very few symptoms and signs of
symptoms of hypothyroidism hypothyroidism.
PRIMARY HYPOTHYROIDISM
HASHIMOTOS THYROIDITIS
The most common cause of hypothyroidism in iodine-sufficient areas of the
world is chronic lymphocytic (autoimmune) thyroiditis (Hashimoto's
thyroiditis), which is caused by cell- and antibody-mediated destruction of
thyroid tissue.
The disorder has two forms:
goitrous
atrophic.

It is characterized clinically by gradual thyroid failure, with or without

goiter formation, due to autoimmune-mediated destruction of the thyroid
gland involving apoptosis of thyroid epithelial cells.
Nearly all patients have
high serum concentrations of antibodies against one or more thyroid antigens (Antithyroid
peroxidase (anti-TPO) antibodies)
diffuse lymphocytic infiltration of the thyroid, which includes predominantly thyroid-specific
B and T cells
follicular destruction, which is the characteristic hallmark of thyroiditis.
PRIMARY HYPOTHYROIDISM
IATROGENIC

Thyroidectomy Because T4 has a half-life of seven days,

hypothyroidism occurs within two to four weeks after total
thyroidectomy.
Radioiodine therapy Radioiodine (I-131) therapy for Graves'
hyperthyroidism can cause hypothyroidism months or years later. The
high-dose regimens preferred in most centers (to reduce the need for
retreatment) result in hypothyroidism in the majority of patients within
the first year after therapy. A significant minority of patients with toxic
or nontoxic multinodular goiter or autonomously functioning thyroid
adenomas also become hypothyroid after radioiodine therapy.
PRIMARY HYPOTHYROIDISM
IATROGENIC

External neck irradiation External irradiation of the neck (in doses

of 25 Gy [2500 rads] or more) also causes hypothyroidism. The effect
is dose dependent, the onset is gradual, and many patients have
subclinical hypothyroidism for several years before developing overt
disease.
Patients at risk of primary hypothyroidism:
Hodgkin lymphoma
Head and neck cancer
Breast cancer
Nuclear accident Thyroid irradiation also may promote the formation of antithyroid
antibodies.
PRIMARY HYPOTHYROIDISM
IODONE DEFICIENCY/EXCESS

Both iodine deficiency and excess Patients at risk for iodine-induced

can cause hypothyroidism. hypothyroidism include those with
chronic autoimmune thyroiditis and those
Iodine deficiency is the most common who have had a partial thyroidectomy
cause of hypothyroidism (and goiter) or a history of radioiodine therapy,
worldwide. painless, postpartum, or subacute
Iodine excess also can cause granulomatous thyroiditis.
hypothyroidism by inhibiting iodide
organification and T4 and T3
synthesis (the Wolff-Chaikoff effect). The excess iodine can be derived from
Normal subjects quickly "escape" health tonics, cough medicines, kelp
from this effect of iodine. However, tablets and other dietary supplements,
patients with abnormal thyroid iodine-containing substances (eg,
glands do not, and they can become Betadine) applied to the skin or vagina,
hypothyroid if given iodine for more drugs such as amiodarone, and
than a few days. radiographic contrast agents
PRIMARY
HYPOTHYROIDISM
DRUGS
PRIMARY HYPOTHYROIDISM
INFILTRATIVE DISEASE

Infiltrative diseases, such as fibrous thyroiditis (Reidel's thyroiditis),

hemochromatosis, scleroderma, leukemia, and cystinosis, are rare
causes of hypothyroidism.

The infiltration usually presents as progressive thyroid enlargement

that is painless, firm, and bilateral, and may be confused with goitrous
autoimmune thyroiditis (Hashimoto's thyroiditis), nontoxic multinodular
goiter, subacute thyroiditis, infectious thyroiditis or occasionally thyroid
cancer or lymphoma.
PRIMARY
HYPOTHYROIDISM
TRANSIENT THYROIDITIS
CENTRAL HYPOTHYROIDISM
SECONDARY AND TERTIERY HYPOTHYROIDISM
The overwhelming majority of patients who
have hypothyroidism have thyroid disease
(primary hypothyroidism).
Central hypothyroidism refers to thyroid
hormone deficiency due to a disorder of
the pituitary, hypothalamus, or
hypothalamic-pituitary portal circulation.
Pituitary thyroid-stimulating hormone (TSH)
production is regulated in part by
thyrotropin-releasing hormone (TRH), which is
secreted from the paraventricular nucleus in
the hypothalamus. TRH is released into portal
blood vessels and transported to the anterior
pituitary gland where it regulates the
synthesis, glycosylation, and release of TSH.
CENTRAL HYPOTHYROIDISM
SECONDARY AND TERTIERY HYPOTHYROIDISM
Most patients with central hypothyroidism have low or normal serum
TSH concentrations (but inappropriately low in the presence of low
serum T4 and T3 concentrations). However, a few patients with TSH
deficiency have slightly high serum TSH values because they secrete
TSH that is less glycosylated and therefore has less biological activity
than normal TSH (but is normally immunoreactive).
Secondary hypothyroidism can be caused by hypopituitarism,
postpartum pituitary necrosis (Sheehan syndrome), trauma,
hypophysitis, nonpituitary tumors such as craniopharyngiomas,
infiltrative diseases, and inactivating mutations in the gene for either
TSH or the TSH receptor
 SECONDARY HYPOTHYROIDISM
HYPOPITUITARISM
Hypopituitarism refers to
decreased secretion of
pituitary hormones, which
can result from diseases of
the pituitary gland or from
diseases of the
hypothalamus. These cause
diminished secretion of
hypothalamic-releasing
hormones, thereby
reducing secretion of the
Aalso known as postpartum pituitary
corresponding pituitary gland necrosis, is hypopituitarism
hormones (decreased functioning of the
pituitary gland), caused by ischemic
necrosis due to blood loss and
hypovolemic shock during and after
childbirth.
TERTIARY HYPOTHYROIDISM

Tertiary hypothyroidism can be caused by any disorder that damages the

hypothalamus or interferes with hypothalamic-pituitary portal blood flow,
thereby preventing delivery of TRH to the pituitary.
It can also be caused by mutations in the gene for the TRH receptor. Like
TSH deficiency, TRH deficiency can be isolated or occur in combination
with other hormonal deficiencies.
Hypothalamic damage results from tumors, trauma, radiation therapy, or
infiltrative diseases. TSH deficiency and TRH deficiency cannot be
distinguished by biochemical tests.
Any patient with findings suggestive of central hypothyroidism should
undergo magnetic resonance imaging (MRI) of the hypothalamus and
pituitary. The results allow inferences to be made as to which hormone is
deficient, but the distinction is of no practical importance with respect to
the patient's hypothyroidism.
CLINICAL MANIFESTATION

Non-pitting
edema
CLINICAL MANIFESTATION
EYES
Periorbital edema often presents as a manifestation of generalized
nonpitting edema.

Graves' ophthalmopathy may persist when hypothyroidism develops

after treatment of Graves' hyperthyroidism. Thus, periorbital edema
may also be a manifestation of ophthalmopathy, in which case the
patient may also have variable degrees of stare, protrusion of the
eyes, and extraocular muscle weakness.
CLINICAL MANIFESTATION
HEMATOLOGIC - ANEMIA
Patients with hypothyroidism have a decrease in red blood cell mass
and a normochromic, normocytic hypoproliferative anemia.
Pernicious anemia occurs in 10% of patients with hypothyroidism
caused by chronic autoimmune thyroiditis. Such patients present with a
macrocytic anemia with marrow megaloblastosis.
However, occasional patients without anemia may display
macrocytosis without marrow megaloblastosis
CLINICAL MANIFESTATION
HEMATOLOGIC - ANEMIA
Women in the childbearing years may develop iron deficiency anemia,
secondary to menorrhagia.
In patients with IDA and hypothyroidism, combined therapy with
levothyroxine and oral iron supplements results in correction of the
anemia, which may be refractory to treatment with iron alone.
Of note, levothyroxine and iron supplements should be taken at separate
times as oral iron may interfere with absorption of thyroid hormone.
CLINICAL MANIFESTATION
CARDIOVASCULAR
Hypothyroidism results in systemic hypometabolism. It is characterized by
a decrease in oxygen and substrate utilization by all the major organ
systems of the body. As a result, the demands for cardiac output
decrease; in addition, hypothyroidism directly alters cardiac function
through changes in myocyte-specific gene expression
Thyroid hormones regulate certain genes for specific myocardial
enzymes, hypothyroidism thus results in reduced heart rate and
myocardial contractility.
In hypothyroid patients, they may have reduced exercise capacity,
shortness of breath during exercise.
 CLINICAL MANIFESTATION
CARDIOVASCULAR
Rhythm Hypothyroid patients can have ventricular premature beats and rarely ventricular
disturbances tachycardia with a long QT interval (torsade de pointes). Treatment with
amiodarone can produce hypothyroidism and further predispose the ischemic
heart to ventricular arrhythmias.
Blood pressure Hypertension Increase in serum norepinephrine and aldosterone concentrations
and an increase in blood pressure with a greater rise in diastolic pressure.
Cardiac In patients with underlying/pre-existent cardiac disease, the presence or
dysfunction development of hypothyroidism leads to more severe heart failure, higher levels
of BNP, and worse short-term hospital outcomes.
Coronary The frequent occurrence of hypercholesterolemia diastolic hypertension, and
Artery Disease elevated homocysteine levels have led to suggestions that hypothyroidism is
associated with accelerated coronary artery disease. Potential mechanism include
elevated concentrations of C-reactive protein and endothelial dysfunction.
Edema Nonpitting edema is due to interstitial accumulation of glycosaminoglycans
(hyaluronic acid and chondroitin sulfate). Some patients have pitting edema of
the feet and legs, probably secondary to an increase in albumin content of the
interstitial fluid. Ascites, pleural, and scrotal effusions may also be present.
CLINICAL MANIFESTATION
GASTROINTESTINAL
Decreased gut motility results in constipation, one of the most common
complaints of patients with hypothyroidism. When euthyroid patients
who already have constipation become hypothyroid, their constipation
worsens. In occasional patients, marked ileus may be confused with
intestinal obstruction. Small intestinal bacterial overgrowth may also
contribute to gastrointestinal symptoms.
Gastric atrophy due to the presence of antiparietal cell antibodies.
Pernicious anemia occurs in 10% of patients with hypothyroidism
caused by chronic autoimmune thyroiditis.
Celiac disease is 4 times more common in hypothyroid patients
compared with the general population
CLINICAL MANIFESTATION
REPRODUCTIVE
Women with hypothyroidism may have either oligo- or amenorrhea or
hypermenorrhea-menorrhagia.
These menstrual changes result in decreased fertility. If pregnancy
does occur, there is an increased likelihood for early abortion.
Hyperprolactinemia may occur and is occasionally sufficiently severe
to cause amenorrhea or galactorrhea.
Decreased libido, erectile dysfunction, and delayed ejaculation are
found in 64% of hypothyroid men
CLINICAL MANIFESTATION
NEUROLOGICAL
 CLINICAL MANIFESTATION
NEUROLOGICAL
Hashimoto HE is most often characterised by a subacute onset of confusion with
Encephalopathy altered level of consciousness, seizures, and myoclonus. In contrast to the
cognitive dysfunction associated with hypothyroidism or hyperthyroidism,
HE is believed to be an immune-mediated disorder rather than the direct
effect of an altered thyroid state on the CNS. The mechanism is unknown.
Myxedema coma Myxedema coma may occur when severe hypothyroidism is complicated
by trauma, infection, cold exposure, or inadvertent administration of
hypnotics or opiates. The diagnosis should be suspected in comatose
patients who are hypothermic, hypercapnic, and hyponatremic.
Carpal tunnel The pathogenesis of CTS in hypothyroidism is believed to be due to
mucinous infiltration of the perineurium and endoneurium of the median
nerve within the carpal tunnel. Mucopolysaccharide protein complexes
with synovial thickening have been identified in tendons and synovial
sheaths. The deposition of mucin material leads to increased
compartmental pressure, producing direct pressure on the median nerve
and causing focal demyelination. The pathologic findings improve or
resolve with treatment of the hypothyroidism.
CLINICAL MANIFESTATION
MUSCULOSKELETAL
Muscle involvement in adults with hypothyroidism is common.
Symptoms may include weakness, cramps, and myalgias.
Serum creatine kinase (CK) is frequently elevated, and the degree of
CK elevation does not clearly correlate with the severity of other
clinical manifestations of muscle disease.
CLINICAL MANIFESTATION
MUSCULOSKELETAL HYPOTHYROID MYOPATHY
Congenital Hypothyroidism
The Kocher-Debre-Semelaigne syndrome
describes infants with typical features of cretinism
associated with diffuse muscular hypertrophy,
muscle weakness that is predominantly proximal,
myxedema and short stature.
These infants have motor and cognitive
developmental delay, constipation, myxedema,
enlarged tongue, and coarse hair and skin typical
of cretinism. Despite a very muscular, almost
muscle-bound appearance, they are in fact weak
and often have difficulty with sitting and head
control.
Serum creatine kinase (CK) and other muscle
enzymes are often elevated in these infants.
CLINICAL MANIFESTATION
MUSCULOSKELETAL HYPOTHYROID MYOPATHY
Adult Hypothyroidism
Muscle involvement in adults with hypothyroidism is common; in one series, 79% of
patients with hypothyroidism had muscle complaints (weakness, cramps, myalgias).
T4 deficiency leads to abnormal glycogenolysis, mitochondrial oxidative metabolism,
and triglyceride turnover, which in turn impair muscle function. These effects are
reflected in selective atrophy of Type II fibers, which are more dependent on
glycolysis for their energy supply. Type I hypertrophy may be a compensatory
response.
With severe or prolonged oxidative damage, muscle cell injury and rhabdomyolysis
may occur. The fact that the degree of weakness often does not correlate with the
biochemical severity of hypothyroidism suggests that muscle injury, rather than
impaired muscle function alone, plays a prominent role in some patients.
Serum muscle enzyme elevations in hypothyroidism, which occur in the absence of
weakness, myalgias, or structural muscle abnormalities, appear to be due to changes
in muscle cell membrane permeability, although the basis for this change is unknown.
Reduced clearance of CK probably also plays a role.
CLINICAL MANIFESTATION
MUSCULOSKELETAL HYPOTHYROID MYOPATHY
Adult Hypothyroidism
Muscle pseudohypertrophy Diffuse muscle hypertrophy occurs
infrequently in adults. When accompanied by stiffness, weakness, and
painful muscle cramps, this is known as Hoffmann's syndrome.
Proximal myopathy Some patients develop a slowly progressive,
symmetric proximal muscle weakness. Shoulder and hip girdle muscles are
most commonly affected. Deep tendon reflexes are characteristically
described as "hung-up" due to delayed muscle relaxation.
Myoedema Myoedema (or "mounding") refers to a small lump rising on
the surface of a muscle when it is struck with a percussion hammer. This
phenomenon, which is characteristic of hypothyroid myopathy, lasts for 30 to
60 seconds, and is due to a sustained contracture associated with delayed
relaxation, because of slow reaccumulation of calcium by the sarcoplasmic
reticulum. Myoedema is not specific for hypothyroidism as it can also occur in
malnutrition.
CLINICAL MANIFESTATION
METABOLIC ABNORMALITIES & DRUG CLEARANCE
Hypothyroidism must be excluded in any hyponatremic patient before
making the diagnosis of the syndrome of inappropriate antidiuretic
hormone secretion.

Metabolic abnormalities
Hyponatremia
Reversible increase in serum creatinine
Hyperlipidemia
Increase in plasma homocysteine

There is also reduce drug clearance, including antiepileptic,

anticoagulant, hypnotic, and opioid drugs in hypothyroid patients.
 INVESTIGATION
Primary hypothyroidism is characterised
by
Clinical hypothyroidism high serum TSH and a
low serum T4 concentration.
Subclinical hypothyroidism high serum TSH and a
normal serum free T4 concentration.

Central hypothyroidism is characterized

a low serum T4 concentration and
a serum TSH concentration that is not
appropriately elevated.

In this setting, differentiation must be made

between pituitary (secondary hypothyroidism)
and hypothalamic (tertiary hypothyroidism)
disorders.
 Serum total T4
INTERPRETATION OF THYROID assays measure
both bound and
FUNCTION TEST unbound ("free")
T4.

The free hormone hypothesis states that the unbound or free hormone is that which is available for uptake into cells and
interaction with nuclear receptors. The bound hormone, on the other hand, represents a circulating storage pool that is not
immediately available for uptake into cells.
INVESTIGATION
PRIMARY HYPOTHYROIDISM
Thyroid function test the serum TSH should be the initial test. If the serum
TSH concentration is elevated, the TSH measurement should be repeated
along with a serum free T4 to make the diagnosis of hypothyroidism.

Repeated TSH Repeated Management

free T4
High Low Primary hypothyroidism; replacement therapy with T4
should be initiated.
High Normal Subclinical hypothyroidism; the decision about T4
replacement is made on a case by case basis and
depends partly upon the degree of TSH elevation.

If the TSH is normal, but the patient has convincing symptoms of

hypothyroidism, we measure a repeat serum TSH and a free T4 to assess
for central hypothyroidism.
INVESTIGATION
CENTRAL HYPOTHYROIDISM

TRH stimulation test Although TRH is not currently available in the United
States, it is widely available in other countries.
A TRH stimulation test involves the intravenous administration of TRH (200
mcg) with measurement of serum TSH at baseline and then 20 and 60 minutes
after TRH administration. The normal increment in TSH at 20 minutes is 5 to 30
mU/L, with a subsequent decrease at 60 minutes.
Classically, one would expect no serum TSH response to TRH in patients with
pituitary disease and a delayed response in patients with hypothalamic
disease. In fact, the response to TRH is highly variable in these circumstances,
limiting the utility of this test in distinguishing between pituitary and
hypothalamic disease as a cause of central hypothyroidism.
A TRH stimulation test may be useful in distinguishing nonthyroidal illness from
central hypothyroidism due to pituitary disease. Patients with nonthyroidal
illness have a blunted nocturnal rise in serum TSH concentrations, but usually
have a normal serum TSH response to TRH.
INVESTIGATION
CENTRAL HYPOTHYROIDISM

Patients with biochemical evidence of central hypothyroidism require

neuroradiologic studies (preferably magnetic resonance imaging [MRI]) to
assess the hypothalamic-pituitary region. If MRI is unavailable, a computed
tomography (CT) scan with coronal views through the pituitary is a reasonable
alternative.
Evaluation of other hypothalamic-pituitary hormonal function (gonadotropins,
testosterone, estradiol, prolactin, insulin-like growth factor 1 [IGF-1]) to
diagnose hormonal hypersecretion or hyposecretion is necessary in patients
with a sellar mass on MRI.
 MANAGEMENT
Synthetic thyroxine, once
absorbed, undergoes deiodination
to the more biologically active T3.
T3 have short half lives, hence it is
given on a daily basis.
MANAGEMENT
MYXEDEMA COMA
REFERENCE
UpToDate
https://www-uptodate-com.ezproxy.lib.monash.edu.au/contents/disorders-that-cause-
hypothyroidism?source=search_result&search=hypothyroidism&selectedTitle=6~150#H17
https://www-uptodate-com.ezproxy.lib.monash.edu.au/contents/central-hypothyroidism?source=see_link
https://www-uptodate-com.ezproxy.lib.monash.edu.au/contents/causes-of-hypopituitarism?source=see_link
https://www-uptodate-com.ezproxy.lib.monash.edu.au/contents/overview-of-thyroiditis?source=see_link#H4
https://www-uptodate-com.ezproxy.lib.monash.edu.au/contents/neurologic-manifestations-of-
hypothyroidism?source=see_link&sectionName=Carpal%20tunnel%20syndrome&anchor=H18#H18
https://www-uptodate-com.ezproxy.lib.monash.edu.au/contents/hypothyroid-myopathy?source=see_link#H7
https://www-uptodate-com.ezproxy.lib.monash.edu.au/contents/diagnosis-of-and-screening-for-hypothyroidism-
in-nonpregnant-adults?source=related_link
https://www-uptodate-com.ezproxy.lib.monash.edu.au/contents/central-
hypothyroidism?source=see_link#H18020102
https://www-uptodate-com.ezproxy.lib.monash.edu.au/contents/laboratory-assessment-of-thyroid-
function?source=see_link&sectionName=Serum%20TSH%20concentration&anchor=H3#H3

Medscape
https://emedicine.medscape.com/article/122393-overview