EN2 – Hypothyroidism

I. Thyroid axis

1. Thyroid anatomy

The thyroid gland is a butterfly-shaped endocrine gland located inferior to the larynx and anterior to the trachea. The
thyroid gland secretes thyroid hormones, which regulate body metabolism and growth, and calcitonin, which lowers
serum calcium and phosphate through inhibition of osteoclasts. Hormone synthesis occurs in the epithelial lining of
the thyroid follicles. The epithelial lining consists of follicular (thyroid epithelial) cells, which synthesize thyroid
hormone, and parafollicular (C) cells, which synthesize calcitonin.

The thyroid is organised in thyroid lobules, spherical functional units of the thyroid formed of an epithelium
composed of thyroid epithelial cells and C cells and a follicular lumen filled with colloid of thyroglobulin, precursor
of thyroid hormone.
Interfollicular spaces are filled by reticular connective tissue, fenestrated capillaries (facilitate the release of hormones
into the blood), lymphatic vessels, adipocytes, and sympathetic nerves.

2. Thyroid function and thyroid hormone production.

Thyroid produces calcitonin and thyroid hormones (seen today).

The thyroid hormones T3 (triiodothyronine) and T4 (thyroxine,

tetraiodothyronine) are synthesized by thyrocytes in the thyroid follicles.

Synthesis
(1) Thyroglobulin is synthetized in the ER, packed into vesicles and
released into the follicular lumen. TG acts as an iodine-free
thyroid hormone precursor, which is stored in the form of colloid
in the follicular lumen.
(2) Iodide uptake through 2° active transport by Na+/I+ symporter (basolateral) from the blood vessel to the
cytoplasm I- pool and then released into the lumen by Pendrin (apical)
(3) TG iodination is performed by TPO (thyroid peroxidase) :
o Oxidation of iodide: I-  I2
o Organification of the generated I2 by covalently linking it with the tyrosine residues present in TG.
 Generates single iodidnated tyrosine residues (TG + H2O2 + I2 = monoiodotyrosine, MIT) and
double iodinated tyrosine residues (TG-MIT + H2O2 + I2 = diiodotyrosine, DIT
 H202 is generated by NADPH oxidase, apical enzyme: NADPH + H+ + O2 → NADP+ + H2O2

o Coupling reaction: conjugation of iodinated tyrosine residues

o Two DIT molecules form tetraiodothyronine: DIT + DIT = T4
o One MIT and one DIT form triiodothyronine: MIT + DIT = T3
(4) Storage back in thyroglobulin
 (5) Release:
o Reuptake of iodinated TG in thyrocytes via endocytosis
o Fusion of endocytosis vesicles with lysosome
o Proteolytic enzymes cleave TG to release T3, T4, DIT, and MIT
o T3 (20%) and T4 (80%) are released into the blood (via the MCT8 transporter)
o Deiodinase removes the iodine from the MIT and DIT, which is then redistributed to the intracellular I-
pool (iodine salvage).

Transport and degradation

Thyroid hormones are lipophilic, but due to their charged amino acid derivatives, they cannot simply diffuse across
the lipid bilayer. Instead, they cross the plasma membrane with the help of transporter proteins (facilitated diffusion).
Also, most of the circulating thyroid hormones are inactive and bound to transport proteins. Only a very small fraction
(∼ 0.3%) is unbound and biologically active.

Transport occurs through pre-albumin, albumin and thyroxine-binding globulin (TBG):

- TBG binds most of T3/T4 (2/3 of T4); the bound fraction is biologically inactive
o Hyperestrogenemia (pregnancy, OCP use): increase of TBG causes a decrease of free T3/T4 and a
compensatory increase in thyroid hormone synthesis
o Hypoproteinemia (e.g., nephrotic syndrome, chronic liver disease)  decrease TBG synthesis ‚
increase free T3/T4 in serum  decrease thyroid hormone synthesis

- Transthyretin (prealbumin): Transport protein synthesized by the liver that carries thyroxine and the retinol-
RBP complex. It is a negative
acute phase protein

Degradation (liver): after

sulfation/glucuronidation
(biotransformation), thyroid
hormones are excreted via bile

Effect
In general, thyroid hormones
increase the metabolic rate:
oxygen and energy consumption as well
as thermogenesis increase under
their influence.
Regulation

HPA axis:
- Stimulant (e.g., stress, extreme cold) → release of thyrotropin-releasing hormone (TRH) → ↑ secretion of
thyroid-stimulating hormone (TSH) by the pituitary gland → ↑ synthesis and release of T3 and T4 by the
thyroid gland

- Negative feedback by ↑ free T3 or T4 → ↓ release of TRH and ↓ pituitary sensitivity to TRH → ↓ thyroid
hormones synthesis
- TSH release can also be decreased by somatostatin, dopamine, and glucocorticoids (outside of the
hypothalamic-pituitary axis).

Deiodinases of type I and II (DIO1, DIO2), predominantly located in the liver, kidneys, muscle cells, and the thyroid
gland, catalyze the conversion of (relatively) inactive T4 into biologically active T3. Deiodinase of type III (DIO3),
present in the placenta and the CNS, catalyzes the conversion of T4 into biologically inactive reverse T3 (rT3).

Wolff-Chaikoff effect: a transient decrease in the production of thyroid hormones following the ingestion of a large
amount of iodine via thyroid peroxidase inhibition

Drugs
- Decreased T4 → T3 conversion: glucocorticoids, propylthiouracil (PTU), β-blockers
- Increased T4 → rT conversion: growth hormone, glucocorticoids
- TPO inhibition: PTU, methimazole

II. Hypothyroidism

Hypothyroidism is a diseased state caused by an inefficient thyroid hormone action at tissue level. There are different
tyeps of hypothyroidism
- Reduced thyroid function: insufficient production
- Reduced stimulation of a normal thyroid

1. Epidemiology

Hypothyroidism is more common in women (12:1000) than men (4:1000) and generally more common than
hyperthyroidism
 2. Etiology

Etiologies for the development of hypothyroidism are multiple

1° hypothyroid diseases:
- Autoimmune thyroid diseases
o Hashimoto’s thyroiditis: most common cause in iodine-sufficient regions
o Riedel thyroiditis

- Thyroid dysplasia: disorder of embryologic development characterized by abnormal development and/or

location of thyroid tissue (e.g., lingual thyroid)
- Congenital hypothyroidism

- Nutritional hypothyroidism: most common cause of hypothyroidim in iodine-deficient regions

- Iatrogenic: e.g., post thyroidectomy, radioiodine therapy, antithyroid medication (e.g., amiodarone, lithium)
- Wolff-Chaikoff effect: A transient decrease in the production of thyroid hormones following the ingestion of
a large amount of iodine. The Wolff-Chaikoff effect lasts for 5–10 days after the ingestion of iodine and is
followed by an increase in the synthesis of thyroid hormones.

- Subacute thyroiditis:
o DeQuervain thyroiditis
o Post-Partum thyroiditis

2° hypothyroid diseases: due to pituitary disorders

- Pituitary adenoma
- Autoimmune polyendocrine hypothyroidism type I, II and III

3° hypothyroidism is due to hypothalamic disorders

Other causes are:

- Reduced tissue sensitivity:
o Mutations to TR leading to an insensitivity to T3
o Mutation to MCT8 leading to a decreased entry of T3/T4 in the body
- Altered metabolism:
o mutations in DIO1 and DIO2 leading to a LOF or to a lower activation oof T2/T4 in the periphery
o mutation of DIO3 leading to high expression in giant angiomas in the liver leading to an increased
degradation of the enzyme, …
 3. Pathophysiology

Effects of hypothyroidism on the whole body:

- Generalized decreased metabolic rate will cause a decreased O2 consumption and substrate consumption
causing
o CNS: apathy and slowed cognition – close to depression, all patients with a suspected depression need
to be screened for hypothyroidism
o Skin and appendages: dryness and alopecia
o Lipid profile: increased LDL and TG
o Cold intolerance

- Decreased sympathetic activity;

o Decreased sweating
o Cold skin (decreased blood flow)
o Bradycardia
o Constipation due to decreased GI motility
- Decreased transcription of sarcolemmal genes (Na+/K+ ATPases, Ca2+ ATPases, …): decreased CO,
myopathy
- Hyperprolactinemia: increased prolactin production stimulated by TRH  suppression of LH, FSH, GnRH
and testosterone and stimulatin of breast tissue growth
 - Myxedema: accumulation of GAGs and hyaluronic acid within the reticular layer of the dermis. This is
thought to be the result of changes in synthesis and degradation of glycosaminoglycans due to a lack of
thyroid hormones.
o Non-pitting edema due to polysaccharides binding water
o Pre-tibial and then generalized edema

4. Clinical features

The clinical presentation of hypothyroidism can range from subclincal/mild presentation (leading to a poor quality of
life) to a severe presentation (seen after the space)

Symptoms related to decreased metabolic rate

 Fatigue, decreased physical activity
 Apathy
 Loss of memory and decreased cognitive ability
 Depression

 Cold intolerance
 Decreased sweating

 Hair loss (Queen Anne sign), brittle nails, and cold, dry skin
 Weight gain (despite poor appetite)
 Constipation

 Bradycardia
 Hypothyroid myopathy (high serum creatine kinases) , myalgia, stiffness, cramps
 Woltman sign: a delayed relaxation of the deep tendon reflexes, which is commonly seen in patients with
hypothyroidism, but may also be associated with advanced age, pregnancy, and diabetes mellitus.
 Entrapment syndromes (e.g., carpal tunnel syndrome)

 Hypertension: hypothyroidism can increase peripheral vascular resistance and, therefore, elevate blood
pressure, especially in hypertensive patients.
 Goiter (in Hashimoto thyroiditis) or atrophic thyroid (in atrophic thyroiditis)

Symptoms related to generalized myxedema

 Pretibial and periorbital edema
 Doughy skin texture, puffy appearance
 Myxedematous heart disease (dilated cardiomyopathy, bradycardia, dyspnea)
 Myxedema coma (complication)

Symptoms of hyperprolactinemia
 Abnormal menstrual cycle (esp. secondary amenorrhea or menorrhagia)
 Galactorrhea
 Decreased libido, erectile dysfunction, delayed ejaculation, and infertility in men
 a.
Hypothyroidism and ASCVD

Between thyroid hormones and the cardiovascular system there are

many interactions.

Thyroid hormones are important regulators of blood pressure, mainly

through the mechanism of vasoconstriction due to the decrease of
thyroid hormones and the vasodilation that is associated, for instance, to
hyperthyroidism. Then there is an endothelial dysfunction that can be
associated and this together with the alteration in lipid metabolism, due
to the hypothyroid condition, increases the risk of thrombosis or
atherosclerosis.

Hypothyroidism is associated with an increased cardiovascular risk due to:

- Increased cholesterol LDL:
o decreased uptake by LDL receptor, so that LDL remains in the circulation. Also,
o lower expression the enzyme responsible for cholesterol degradation (HMG-CoA reductase), which is
the target of statins!  treatment may be ineffective
- Increased diastolic BP
- Weight gain
- Cardiac function alterations
- Increased vascular stiffness
 Hypothyroidism is the second most common
cause of hypercholesterolemia after diet.

b. Hypothyroidism and fatty liver

disease

Patients with hypothyroidism are more prone to

for non-alcoholic fatty liver disease and the
evolution toward fibrosis which obviously is another factor favouring cardiovascular diseases due to the increased
resistance.

Nowadays, there is a thyroid hormone analogue with a specific liver tissue distribution that is currently in phase 3
clinical trial for NASH treatment.

c. Free T4 levels and frailty

Abnormal free thyroxine levels are associated

with increased risk of frailty: fragility is a
biological condition that is dependent on age,
characterized by reduced resistance to stresses,
followed by the cumulative decline of multiple
physiological systems and correlated with
comorbidities, disabilities, risk of hospitalization
and mortality.

d. Hypothyroidism and infertility

Infertility is a more prevelent in females suffering

from hypothyroidism due to the hypothyroidism but
also due to a concomitant autoimmune disorder (anti-
phospholipid disease, PCOS) that are associated with
a higher risk of developing hypothyroidism.

Abnormal thyroid function can impact infertility

through different mechanisms.
Thyroid can act
- on the ovaries directly
- is required for the implantation of the
fertilized egg.
- interactions with the placental functions, such
as the vascularization of the placenta.

Thyroid hormone promotes adequate functional

ovarian reserve by acting on the regulation of
folliculogenesis and positive reaction with some of the
factors that are important for the implantation of the egg. Hypothyroidism is associated with ovulation dysfunction,
menstrual irregularity, short luteal phase, and shorter cycles and there is an association of autoimmune thyroiditis with
PCOS and POI.

• Mild hypothyroidism: polimenorrea/metrorragie: prog insufficiency

• Severe hypothyroidism: oligomenorrhea (anovulation)
• Hyperthyroidism: oligomenorrhea/amenorrhea

e. Hypothyroidism and pregnancy

Pregnancy represents a challenge for thyroid function. This increased thyroid function that is required in pregnancy is
provided by the action of hCG (human chorionic gonadotropin).

hCG, FH, FSH and TSH are members of the same glycoprotein hormone family. These hormones have a similar
structure in which they have a common alpha unit and specific beta units in dimers.
 - At high levels (such as the 1 st trimester of pregnancy), hCG can bind and stimulate TSH, leading to an
increased thyroid function during pregnancy and as a consequence, a decrease of TSH.
- At the same time, estrogen rise (during pregnancy) will lead to the stimulation of TBG (binding T3/T4 in
blood) levels in the blood, leading to a compensatory rise in thyroid activity (in order to maintain free T3/T4
levels in the blood): If you measure total T4 during pregnancy, you will see a hyperthyroid state, but this is
not hyperthyroidism because the free T4 is normal in blood.

If there is an underlying thyroid insufficiency (ie: the mother is in a condition of compensated thyroid hypofunction:
TSH is 3 not 1), the thyroid cannot increase its function and cannot supplement additional T3/T4 (either from the TBG
or the hCG). This leads to a rise (and not fall) of TSH and T3/T4 remains lower than required.

Roles of CG:
 Maintains corpus luteum activity and stimulates progesterone production
 Maintains placental activity and differentiation (from cyto- to syncytio-trophoblast)
 Stimulation of fetal testes testosterone production for masculinization
 Stimulation of maternal thyroid
Among the various roles of CG has, there is also the stimulation of the thyroid.

Effects on values

Remember that there is an increased risk of abortion of 60% for any doubling of TSH levels.

As a consequence, there are trimester specific ranges for thyroid function and the TSH range in the first weeks of
pregnancy should be lower of what seen during the normal life.
- The normal value of TSH outside pregnancy is in between 0.4-4.0 mlU/L.
- During pregnancy, TSH levels decrease, making the upper limit 2.5 mlU/L.

If there is thyroid insufficiency due to an underlying thyroid disease but the system is in equilibrium, for example if
TSH is 3mlU/L and T4 level is normal, and this individual goes into pregnancy and conceives, TSH levels will not go
down. The thyroid will not be responding as it should and therefore the TSH gets higher.
Maternal Complications of Hypothyroidism
 Risk of miscarriage and abortion in direct correlation with TSH levels.
 Increased risk of developing hypertension
 Preeclampsia: hypertension + proteinuria (> 20 week)
 Early placental abruption
 Premature birth: <34 week
 Post-partum hemorrhages
Autoimmune thyroid disease augments the risk of such complications and predispose to gestational diabetes.

Fetal Complications of Maternal Hypothyroidism

Also the fetus may get affected from the maternal hypothyroidism:
 IUGR (intrauterine growth restriction)
 Intrauterine death
 Lower IQ or other behavioural defects (such as ADHD)
The neurological development during gestation depends on
the levels of TH. In the first trimester, the fetal thyroid is not
working but the population of neuroblasts and neuronal
precursors has already been established so there is a
dependency on the maturation of neuronal precursors and T4
that is coming from the mother through placenta.
From week 14 of gestation, the fetal TH production starts.
Upon birth, there are other final steps of maturation of CNS
that depends on thyroid hormone.

In the table below, there are the risk of miscarriage. There are
studies that demonstrate that TSH below 2.5 is optimal in pregnancy. TSH above 2.5 is associated with increased
pregnancy loss.

Assisted reproductive technologies (ART) are even worse on the thyroid function. In this case, there is
hyperestrogenism that occurs as in pregnancy. but there won’t be the production of CG. This is stimulated by high
levels of FSH, which is no thyrotropic activity. In this case all the women experience higher levels of TSH. Healthy
women adapt to the situation, but the women that have thyroid dysfunction are at higher risk of developing
hypothyroidism. This hypothyroidism may be more difficult to revert after the implantation of the embryo.
It is important to diagnose thyroid dysfunction in women that undergo ART procedures, because they are infertile, and
infertility is strongly associated with thyroid diseases. So TSH and thyroid function has to be considered in all women
that undergo ART procedures.
The levels of T4 have to be measured both before and after the implantation. If the patient is not treated, the change in
T4 levels would be accompanied by reduced implantation rate and lower numbers of clinical pregnancy rate.
The clinician has to treat the patient with T4, if the level of TSH is above 2.5 mU/L, because there is a high chance of
this patient to develop hypothyroidism.

Screening
This is the reason why if a woman desires a pregnancy, we should test her for TSH. Actually, most of the scientific
societies advise a case-finding approach as follows, test all women with:
• Age > 30y/o
• Goiter
• Ab anti-TPO positive
• On therapy with LT4
• Area of iodide insufficiency (<150 mcg/day)
• Suggestive manifestations
• Diabetes mellitus type 1 or other autoimmune conditions
 • Infertility or poliabortion
• Previous partial thyroid surgery or irradiation of the neck
PRESCRIBE TSH in women looking for pregnancy if they are in these categories.

5. Hashimoto thyroiditis

Hashimoto thyroiditis is the most common type of autoimmune thyroiditis and the leading cause of hypothyroidism in
the United States. Although it is thought to be due to chronic autoimmune-mediated lymphocytic inflammation and
destruction of the thyroid tissue, the exact pathophysiology remains unclear. Patients may initially be asymptomatic or
show signs of thyrotoxicosis, progressing to hypothyroidism as the organ parenchyma is destroyed.

Epidemiology:
HT is the most common cause of hypothyroidism in iodine sufficient countries and affects 5% of the US population.
It is mostly prevalent in women between 30-50.

Pathophysiology

Hashimoto thyroiditis is a TH1 mediated cellular (LT) and humoral (LB)

response leading to the targeting of TPO through the production of TPOAb
and TGAb causing the destruction of the thyroid tissue.

Patients with genetic susceptibility (HLADR3 and HLADR5) are exposed

to certain triggers such as pregnancy, infections (molecular mimicry), acute
or chronic stress will develop an autoimmune humoral response against the
specific Ag of the thyroid follicle, leading to an infiltration and progressive
destruction of the thyroid follicles, and thus a decreased production of T3.

The disease is very progressive and correlates with TSH levels:

The early stage is characterised by a mild/subclinical hypothyroidism with TSH > 4mU/L but normal T3/T4:
 Primarily asymptomatic
 Goiter: nontender or painless, rubbery thyroid with moderate and symmetrical enlargement
 Hashitoxicosis may occur: transient thyrotoxicosis due to follicular rupture of hormone-containing thyroid
tissue that manifests with signs of hyperthyroidism (e.g., irritability, heat intolerance, diarrhea)

The later stage occurs with a complete destruction of the thyroid and thus an incapacity of production of T3/T4,
leading to TSH rise:
 Thyroid may be normal-sized or small if extensive fibrosis has occurred.
 Signs of hypothyroidism (e.g., cold intolerance, constipation, fatigue)

6. Riedel thyroiditis

Riedel thyroiditis is a rare, special form of autoimmune thyroiditis characterized by inflammatory infiltration and
fibrosclerotic changes of thyroid tissue.
It is part of the IgG4-related disease spectrum, which includes conditions sharing histopathological features of
fibrosclerosis in different organs (e.g., sclerosing sialadenitis, retroperitoneal fibrosis, autoimmune pancreatitis,
aortitis, etc.)
 Goiter: painless, hard (stone-like), fixed
o may compress surrounding tissues (e.g., trachea, esophagus), mimicking invasive growth of malignant
tumor (e.g., feeling of anterior neck pressure, dysphagia, hoarseness , stridor, dyspnea)
 Approx. 30% of affected individuals have hypothyroidism.

 Surgery may be necessary due to compression.

7. Subacute thyroiditis are seen in hyperthyroidism

8. Acute suppurative thyroiditis

Definition: extremely rare bacterial infection of the thyroid gland

 Symptoms/clinical features: acute febrile course with tenderness
  Diagnosis: ultrasound

 Treatment: administration of broad-spectrum antibiotics (e.g., clindamycin or amoxicillin with clavulanate);

in the case of abscess formation, opening of the abscess and culture of the abscess contents in addition to an
antibiogram

- Complications: mediastinitis

9. Diagnosis

(1) Initial evaluation: thyroid function tests (TFTs)

Obtain TSH level for all patients: ↑ TSH with classic clinical features
is typically diagnostic for primary hypothyroidism.
 Abnormal TSH: Order FT4.

(2) Further investigations

Thyroid antibody testing: Consider if autoimmune thyroiditis is
suspected (not routinely indicated).
Imaging: Consider if structural pathology (e.g., thyroid nodules,
goiters, malignancy) is suspected.

a. Thyroid function tests - Reflex TSH strategy

 TSH level

Due to high interpersonal variability of T4 levels between patients, TSH levels

are more accurate in screening for 1° and 2°/3° hypothyroidism:
- Normal: 0,5-4mU/L
- Low: 2°/3° hypothyroidism
- High: 1° hypothyroidism

Normal TSH levels are different according to the region (iodide

sufficient/deficient), age and pregnancy status (specific levels for each trimester).

 T4 levels:
Only once pathological TSH levels have been evaluated, T4 levels are evaluated:
- Normal: subclinical 1° hypothyroidism
- Low: 1° hypothyroidism

Results:
The normal level of TSH is 0.4-4mU/L. Hypothyroidism can be differentiated into:
- Subclinical hypothyroidism: is defined as an altered TSH level and circulating levels of FT4 that is still within
the normal range. There are 2 different grades of subclinical hypothyroidism:
o Grade 1: TSH levels within 5-9.9mU/
o Grade 2: TSH levels within 10-20mU/L
- Overt hypothyroidism: is characterized with TSH>20mU/L and low FT4 levels.
The normal levels of FT4 in subclinical hypothyroidism does not always correlate with a condition of compensated
hypothyroidism (which if it was, the physician wouldn’t prescribe a treatment.)
 b. Serology – serum thyroid antibody testing

Serum thyroid antibody testing can confirm suspected autoimmune thyroid disease. Additionally, thyroid peroxidase
antibody measurements may also be considered in patients with subclinical hypothyroidism or recurring miscarriages.
 Thyroglobulin antibodies (TgAb) and thyroid peroxidase antibodies (TPOAb): detectable in the majority
of patients with autoimmune hypothyroidism
o Also found in other autoimmune thyroid diseases (e.g., Graves disease).
o Positive TPOAb can predict the progression of subclinical to overt hypothyroidism.

 TSH receptor antibodies (TRAbs): detectable in up to 20% of cases of autoimmune hypothyroidism. To

detect TRAbs, the thyrotropin-binding inhibitory immunoglobulin assay is used. It can detect the presence of
antibodies against the TSH receptor, but not their function (blocking or stimulating). The function of TRAbs is
presumed from the clinical picture,
o blocking TRAbs if there are symptoms of hypothyroidism
o stimulating TRAbs if there are features of hyperthyroidism.

c. LAB VALUES

 CBC: mild anemia (normocytic  macrocytic)

 BMP: hyponatremia (in acute hypothyroidism) , hypoglycemia (rare)
 Lipid profile: hypercholesterolemia (increased LDL), hyperlipidemia
 Creatine kinase: increased in hypothyroid myopathy

d. Imaging
The following studies are not required for diagnosis but may be performed during workups for thyroid disorders or
goiter to rule out differential diagnoses (e.g., multinodular goiter or malignancy)
 Thyroid ultrasound:
o Often shows diffuse hypoechogenicity
o May show heterogeneous thyroid enlargement or atrophy
o In patients with thyroid nodules, it can show sonographic signs of thyroid malignancy.

 Thyroid ultrasound (transverse view):

Marked reduction in size and a heterogenous, flaky echoic structure suggesting

inflammatory infiltration.

The thyroid is significantly hypoechoic and its perimeter appears lumpy (white dashed
line) compared to the surrounding muscles (white line). The trachea (T), with
hyperechoic tracheal cartilage sections and dorsal acoustic shadows (blue overlay), and
the common carotid artery (CCA), can be seen next to the thyroid.

Diagnosis: Hashimoto thyroiditis.

(LL = left lobe, RL = right lobe, I = isthmus)

 Ultrasound of the right thyroid (cross-section):

Hashimoto thyroiditis

The parenchyma of the thyroid gland shows

heterogeneous changes, appears reticular
(honeycombed), and is hypoechoic (especially
compared to the surrounding neck muscles; see
white circles). The thyroid appears smaller and
atrophic in the unfrozen image.
  Radioactive iodine uptake test (RIUT)
o Rarely used due to variable results
o Iodine uptake may be decreased in patients with transient thyrotoxicosis.

e. Biopsy

 Fine-needle aspiration
o Indications: patients with focal nodules to exclude malignancy (Workup of thyroid nodules)
o Findings: diffuse lymphocytic infiltration (cytotoxic T lymphocytes) with germinal centers,
oncocytic-metaplastic cells (Hurthle cells), and fibrotic tissue

10. Nonthyroidal illness syndrome (NTIS)

NTIS is a change in thyroid hormone levels (typically decreased) that occurs in severe illness or severe physical stress,
typically in ICU patients.

Pathophysiology

The pathophysiology is multifactorial and not fully understood: the thyroid gland remain fully functional, but high
levels of cytokines (IL-6) are through to cause various changes in TSH and other hormonal levels, manifested by
altered diodinase activity:
- Decrease T4  T3 conversion
- Increase T4  rT3 conversion

Diagnostics
 TSH is normal
 Low T3 syndrome: decrease in both total and FT3 levels, normal FT4 and TSH, and normal or increased rT3
 Low T3 low T4 syndrome: FT4 levels may be low in prolonged courses of illness, indicating a poor
prognosis.

11. Screening

Differently from congenital hypothyroidism, for which there is a screening for all neonates, there is no consensus
about population screening for hypothyroidism (acquired). However, there is compelling evidence to support case
finding for hypothyroidism in:
 Those with autoimmune disease, such as type I diabetes
 Turner syndrome: a condition that predisposes to autoimmune thyroid disease. The patient should be
checked periodically for thyroid’s functionality
 Those with pernicious anemia (usually associated with atrophic gastritis)
 Those with familiarity for autoimmune thyroiditis: this is particularly relevant in females, especially if they
would like to conceive
 Those with an history of neck radiation to the thyroid gland including radioactive iodine therapy for
hyperthyroidism and external beam radiotherapy for head and neck malignancies.
Cancer survivals during the young age are exposed to higher risk of hypothyroidism
 Those with a prior history of thyroid surgery or dysfunction
 Those with an abnormal thyroid examination
 Those with psychiatric disorders: depression is associated with hypothyroidism, whereas psychosis is
associated with hyperthyroidism. Before 1975, when there was no possibility to diagnose abnormal thyroid
function biochemically (through the measurement of hormones), many patients with hyperthyroidism were
present in psychiatric departments
  Patients taking amiodarone or lithium
 Patients with ICD-9 diagnoses as presented in table 9

Regarding weight gain, it is not suggested to test every patient for thyroid
dysfunction, but consider that hypothyroidism may favor weight gain, even if it’s
not the cause. In this case, it is more difficult to decrease the body weight,
because the metabolic rate is slower.

12. Congenital hypothyroidism

 13. Treatment

Hypothyroidism is treated with lifelong hormone substitution.

 Levothyroxine: synthetic form of T4
o First-line choice for the treatment of hypothyroidism
o Peripherally converted to T3 (biologically active metabolite) and rT3 (biologically inactive metabolite)
o In primary hypothyroidism, levothyroxine is gradually titrated according to serial TSH measurements
targeting a normal level, for example:
 Increase TSH (suggests decrease T4 activity): typically requires a dose increase
 Increase TSH (suggests increaseT4 activity): typically requires a dose decrease

14. Autoimmune
polyendocrine
syndromes

Importantly, when you diagnose autoimmune hypothyroidism, take into consideration that the patient has a higher risk
of having another autoimmune disease. There are specific autoimmune polyendocrine syndromes (APS) in which
thyroiditis is involved.
 APS type I is the most severe; it is based on the mutation of AIRE gene, important for the maturation of T
lymphocytes. This syndrome is associated with Addison’s disease (an autoimmune disease affecting the
adrenal gland), hypoparathyroidism and candidiasis. In addition, we can have the involvement of the thyroid
later in life.
 APS type II has a polygenic inheritance. It also includes Addison’s disease, type I diabetes and chronic
thyroiditis.
 APS Type III has no adrenal involvement, but it is associated with autoimmune thyroid disease. APS type III
is further divided into subtypes:
 3A: associated with type I diabetes and Hirata’s disease, which involves recurrent hypoglycemia due to
antibodies that target insulin, which is suddenly released causing hypoglycemia. This generally occur in
patients that are predisposed to type I diabetes. Type 3A is also associated with lymphocytic hypophysitis
and POF/POI (primary ovarian failure/insufficiency)
 3B: associated to atrophic gastritis, pernicious anemia, celiac disease, chronic inflammatory bowel diseases,
autoimmune hepatitis and primary biliary cirrhosis
 3C: associated to vitiligo, alopecia, myasthenia gravis, stiff-man syndrome and multiple sclerosis
 3D: associated to SLE or DLE, mixed connective tissue disease, rheumatoid arthritis, seronegative arthritis,
systemic sclerosis, Sjogren’s syndrome, Werlhof syndrome, antiphospholipid syndrome and vasculitis