‫‪Thyroid disorders‬‬

‫اعداد‬
‫عمار حاتم عبد اللطيف‬
Thyrotoxicosis
• The term thyrotoxicosis refers to a condition with excess thyroi
d hormone.
• The term hyperthyroidism refers to a sustained increase in thy
roid hormone biosynthesis and secretion by the thyroid gland.
• The term thyrotoxicosis relates to its clinical manifestations: a
syndrome of hypermetabolism and hyperactivity resulting fro
m an elevation of plasma T4 or T3 concentration (most usually
both).
• The terms thyrotoxicosis and hyperthyroidism are not entirely
synonymous. For example, thyrotoxicosis can occur as a result
of excessive hormone release from the thyroid in the absence
of increased synthesis, as may occur in thyroiditis. Excessive int
ake of thyroid hormones can also cause thyrotoxicosis but not
hyperthyroidism.
• Some of the causes produce characteristic clinical si
gns; for example, orbital and cutaneous manifestati
ons, which is unique to Graves disease.
• The age of the patient and presence of concomitant
disturbances may have an impact on the clinical fea
tures of hyperthyroidism, either exaggerating or di
minishing them. For example, older patients may ha
ve less marked evidence of sympathetic activation,
such as anxiety, hyperactivity, or tremor, and less w
eight loss but marked features of cardiovascular dys
function such as congestive cardiac failure and atria
l fibrillation.
• Thyrotoxicosis is usually associated with hyperthyroidi
sm but not always.
• Common causes for thyrotoxicosis not associated wit
h hyperthyroidism include (1) thyroiditis (silent painle
ss thyroiditis, postpartum thyroiditis, subacute thyroid
itis), and (2) excess exogenous thyroid hormone (iatro
genic or factitious).
• The prevalence of the causes varies with iodine intake
, such that in iodine-sufficient areas, Graves disease is
the most common cause of thyrotoxicosis, accounting
for 60% to 90% of cases. But in iodine-deficient areas,
thyroidal autonomy is more common. Thyroiditis acco
unts for about 10% of all causes of thyrotoxicosis.
Thyroid (Thyrotoxic) Storm

• Thyroid storm (also known as thyrotoxic crisis) is a r

are, severe, exaggerated, and life-threatening condi
tion of thyrotoxicosis, which is triggered by precipit
ating factors (e.g., intercurrent illness or surgery). T
hyroid storm is most often seen in the context of un
derlying Graves hyperthyroidism but can complicate
thyrotoxicosis of any etiology.
 Graves Disease
• Graves disease results from an autoantibody that binds
to and activates the TSHR, producing excessive release o
f thyroid hormone and clinical hyperthyroidism. In patie
nts with Graves disease, the thyroid gland is no longer u
nder the control of pituitary TSH but is constantly stimul
ated by the circulating antibodies with TSH-like activity.
• Both B and T lymphocytes are known to be directed at t
hree well-characterized thyroid autoantigens, namely Tg,
TPO, and TSHR. However, the majority of the evidence s
uggests that TSHR is the primary autoantigen of Graves
disease and that the immune response to the other two
thyroid antigens is reflective of the resulting thyroiditis.
• The diagnosis of Graves disease is based on laborat
ory demonstration of thyrotoxicosis, clinical feature
s (particularly Graves disease-specific extrathyroidal
manifestations, including ophthalmopathy and der
mopathy), and the presence of a moderate, diffuse,
and soft goiter over which a vascular bruit may be d
etectable. Ophthalmopathy, thyroid dermopathy, a
nd acropachy occur in 25%, 1.5%, and 0.3 % of pati
ents with Graves disease, respectively.
• Patients with ophthalmopathy who are smokers hav
e a higher risk of developing or worsening of the co
ndition
Toxic Adenomas and Toxic Multinodular Goit
er

• Toxic adenomas and toxic multinodular goiter are co

nditions in which thyrocytes function and produce th
yroid hormones independently of thyrotropin (TSH) a
nd TSHR-stimulating antibody.
• Such thyroid autonomy is a common finding in iodin
e-deficient iodine-deficient areas, where it accounts f
or up to 60% of cases of thyrotoxicosis. However, thy
roid autonomy is rare in regions with sufficient iodin
e supply (3% to 10% of cases with thyrotoxicosis).
Gain-of-Function Mutations of the Thyroid-
Stimulating Hormone Receptor

• A familial autosomal dominant form of hyperthyroi

dism has been described that is caused by gain-of-f
unction mutations in the TSH receptor.
• In infants homozygous for such mutations, neonatal
thyrotoxicosis, so severe as to require emergency th
yroidectomy, has been observed. Certain heterozyg
ous mutations have been reported to cause infantil
e hyperthyroidism.
Central Hyperthyroidism
• Central hyperthyroidism is rare but is most frequently cau
sed by nearly always benign thyroid-stimulating hormon
e-secreting pituitary adenomas.
• A total of 75% of the tumors are macroadenomas, having
a diameter larger than 10 mm at the time of diagnosis, bu
t microadenomas (diameter < 10 mm) are increasingly rec
ognized owing to earlier diagnosis with improved imaging
techniques.
• Patients with TSH-secreting tumors present with signs an
d symptoms of thyrotoxicosis, but extrathyroidal manifest
ations (i.e., ophthalmopathy, pretibial myxedema, and acr
opachy) are absent
• The laboratory diagnosis is based on a no suppressed TS
H in the presence of high levels of free thyroid hormones
(FT3 and FT4).
• Other diagnostic criteria include evidence of a pituitary
mass on computed tomography or magnetic resonance i
maging.
• There are both clinical situations (in particular) and possi
ble laboratory artifacts that may cause a biochemical pro
file that is characteristic of patients with TSH-secreting tu
mors; these include thyroid hormone resistance, binding
protein abnormalities, falsely high FT4 results, and falsely
high TSH concentrations. The molar ratio of α-subunit to
TSH may serve as a useful tumor marker in the differentia
l diagnosis; in case of a TSH-secreting pituitary adenoma,
the ratio of α-subunit to TSH concentration is typically lar
ger than 1 ng/ mL; in thyroid hormone resistance syndro
me, the ratio is less than or equal to 1 ng/ mL.
Subclinical Hyperthyroidism
• The laboratory diagnosis of subclinical hyperthyroidism is define
d by a low plasma TSH with normal concentrations of T4 and T3.
The condition is classified as mild if TSH is in the range 0.1 to 0.4
mIU/ L.
• Persistent subclinical hyperthyroidism may be caused by
• exogenous iatrogenic overdose of levothyroxine or by endogen
ous causes as in primary hyperthyroidism such as Graves diseas
e, toxic multinodular goiter, or solitary autonomous nodule. Exo
genous subclinical hyperthyroidism is the most common and is r
eversible by reduction of levothyroxine dose.
• Transitory subclinical hyperthyroidism may be caused by
• treatment with radioiodine or antithyroid drugs in patients previ
ously with overt hyperthyroidism or as part of thyroiditis
Diagnosis and Differential
Diagnosis of Thyrotoxicosis
• The diagnosis of Graves disease may be obvious if the p
atient has other clinical signs, such as exophthalmos.
• The laboratory diagnosis of thyrotoxicosis is based on a
suppressed or low TSH and increased FT4 or increased F
T3 or total T3. TSH is the most sensitive biomarker. A to
tal of 2% to 4% of patients with hyperthyroidism have i
ncreased concentration of FT3 or total T3 but normal co
ncentration of FT4 (T3 thyrotoxicosis).
• However, low TSH can also be caused by other conditio
ns relevant for the diagnosis. Subclinical hyperthyroidis
m. Low TSH may also be drug induced (glucocorticoids
and dopamine) or caused by nonthyroidal illness.
• In pituitary adenoma (secondary hyperthyroidism), TSH
can be inappropriately normal or high for an elevated c
oncentration of peripheral thyroid hormones.
• If the etiology of thyrotoxicosis is uncertain, a radioacti
ve iodine uptake test should be performed; iodine upta
ke of the thyroid gland is low in thyroiditis and high in G
raves disease and autonomous nodules (single or multi
ple).
• The presence of TRAb (TSHR-stimulating antibodies) eff
ectively confirms a diagnosis of Graves disease.
• A total of 75% of patients with Graves disease have TPO
antibodies, an observation that may help differentiate t
his disease from toxic nodular hyperthyroidism if neces
sary.
Thyroid Disorders in Pregna
ncy and Postpartum
• Plasma T3 and T4 concentrations increase during pregnancy o
wing to an increase in TBG concentration. This increase is cau
sed by enhanced hepatic synthesis and reduced metabolism
(a result of increased estrogen levels) early in pregnancy, resu
lting in a 1.5-fold increase in TBG by 6 to 8 weeks of gestation
. TBG remains elevated throughout pregnancy.
• Placental hCG shares the same α subunit with TSH but has a u
nique β subunit and acts in early pregnancy as a TSH agonist
by binding to TSH receptors on the thyroid gland. The physiol
ogical consequences of the mild hCG stimulation of the thyroi
d in early pregnancy leads to a physiological rise in T4 and T3,
which, by the hypothalamic-pituitary-thyroid (HPT) axis feedb
ack mechanism, inhibits TSH secretion, which causes TSH to f
all.
Hypothyroidism in Pregnancy
• Worldwide, the most common cause is endemic iodine
deficiency. The main cause of hypothyroidism in iodine-
sufficient populations is chronic autoimmune thyroiditis.
• The diagnosis of hypothyroidism in pregnancy is based,
as in nonpregnant subjects, on the finding of an elevate
d serum TSH concentration with low concentrations of F
T4, using trimester-specific reference intervals.
• There is an increased risk of miscarriage, preterm delive
ry, and preeclampsia in the mother. In the newborn, the
re is an increased risk of neonatal mortality caused by pr
eterm delivery, risk of low-for-gestational-age birth weig
ht, and decreased IQ.
Thyrotoxicosis in Pregnancy
• The diagnosis of thyrotoxicosis in pregnancy is made by fi
nding a low plasma TSH concentration and elevated conc
entrations of FT3 and/ or FT4, compared to trimester-spe
cific reference intervals.
• In patients with Graves disease, TSH and thyroid hormone
s should be measured every 4 to 6 weeks during pregnan
cy. The measurement of TSH receptor stimulating antibod
ies (TRAb) should be reserved for patients with Graves dis
ease who become pregnant or if Graves disease is suspect
ed during pregnancy.
• In the former, TRAb should be measured at diagnosis and
at 24 to 28 weeks’ gestation because these antibodies ca
n cross the placenta, starting in the late second trimester
Postpartum Thyroiditis
• Postpartum thyroiditis may be difficult to differentia
te from Graves disease. The differences between th
e two include the presence of goiter, ophthalmopat
hy, and TRAb in Graves disease; these are usually n
ot present in thyroiditis
• Postpartum thyroiditis often recurs in subsequent p
regnancies, and 50% of women eventually develop
hypothyroidism.
Thyroid Function Testing in
Pregnancy
• TSH is a reliable indicator of thyroid function during pregnanc
y in most cases. Trimester-specific reference intervals for TSH
and thyroid hormones should be applied.
• Serum FT4 and FT3 are in the picomolar range, and to be vali
d, they are technically difficult to measure because they must
be free from interference by the much higher total hormone
concentrations (in the nanomolar range). The reliability of im
munoassays for the measurement of FT3 and FT4 is decrease
d in pregnancy owing to higher TBG but lower albumin conce
ntrations.
• Liquid chromatography– tandem mass spectrometry combin
ed with equilibrium dialysis or ultrafiltration methods are mo
re reliable for both total and free hormone measurements du
ring pregnancy.
Thyroid Neoplasia
• There are four main types of thyroid cancer (listed from the mo
st common to the least common): DTC, including (1) papillary, a
nd (2) follicular thyroid cancer, accounting for more than 90% o
f thyroid cancers in United States; (3) medullary thyroid cancer
(MTC) (< 5%); and (4) anaplastic thyroid cancer, accounting for
about 2%. Parafollicular or C cells secrete calcitonin and give ris
e to MTC, with an intermediate prognosis. About 80% of MTC is
sporadic (i.e., not genetically inherited and occurs randomly), a
nd the rest is hereditary.
• The main role for the clinical biochemist is the monitoring of TS
H suppression therapy, the determination of cancer ablation, th
e detection of recurrence in patients given definitive treatment,
such as thyroidectomy, and the prognosis.
Diagnosis
Differentiated Thyroid Canc
er
• Patients with DTC have a favorable prognosis. Tg is
not a diagnostic marker, but it is a useful marker for
disease recurrence in thyroidectomized patients be
cause it should be undetectable. Tg should not be u
sed as a tumor marker in the presence of anti-Tg an
tibodies owing to measurement interference. Thyro
id stimulation either by temporarily ceasing thyroid
hormone replacement or by the administration of r
ecombinant TSH greatly increases the sensitivity of
Tg measurement, but this may not be necessary usi
ng more sensitive Tg assays.
• The optimal cut-off for Tg for predicting recurrence i
s not known. There is a general agreement that a sti
mulated Tg less than 1 ng/ mL,
• Newer Tg assays have a functional sensitivity of 0.1
ng/ mL or less (compared to older assays with 1 ng/
mL); this allows for earlier identification of recurrenc
e and helps avoid the use of TSH stimulation. As des
cribed earlier, immunometric assays for Tg and TgAb
s are prone to interferences.
Medullary Thyroid Cancer
• Calcitonin, produced by C cells, is a valuable blood tumor marker f
or MTC.
• Serum calcitonin can be used as a screening test in patients with a
family history of MTC, who are at risk of developing the disease.
• Calcitonin also is used diagnostically as an immunohistochemical
marker. Basal serum calcitonin and carcinoembryonic antigen (CE
A) should be measured concurrently.
• CEA is not a specific biomarker for MTC and is not useful in the ea
rly diagnosis of MTC. However, CEA is useful for evaluating diseas
e progression in patients with clinically evident MTC and for moni
toring patients after thyroidectomy.
• Measurements of calcitonin also may be used to monitor for pers
istent or recurrent disease after surgery because the concentratio
ns correlate with tumor burden.
• Calcitonin has a low stability in serum at room temp
erature, so the sample must be immediately separat
ed and then frozen and transported on ice to the lab
oratory. The measurement of calcitonin is by immun
oassay (e.g., immunochemiluminometry), which is p
rone to interferences. Because of inter-method diffe
rences, concentrations pre- and post-thyroidectomy
and during treatment should be measured using the
same assay and instrument in the same laboratory.
• Calcitonin values are higher in men than in women,
which is likely because of a higher C-cell mass.
• Calcitonin may be increased in nonthyroidal cancer, i
nflammation and sepsis, acute and chronic renal fail
ure, hypercalcemia, pulmonary disease, and hyperga
strinemia.
Thyroid Disease in Children

• Neonatal hyperthyroidism may be caused by the tra

nsplacental passage of thyroid-stimulating maternal
immunoglobulins (due to active maternal Graves di
sease) or by activating TSH receptor mutations
• In older children and adolescents, the most commo
n cause of hyperthyroidism is Graves disease, and t
he most common cause of hypothyroidism in iodin
e-replete areas is Hashimoto thyroiditis.
Congenital Hypothyroidism
• Congenital hypothyroidism can be categorized into permane
nt and transient forms, which again can be divided into prim
ary (thyroid disorder), secondary (i.e., central hypothyroidis
m;), and peripheral. Permanent congenital hypothyroidism
(75% to 86%) needs lifelong replacement treatment, but tra
nsient forms resolve within weeks to months after birth.
• Permanent primary congenital hypothyroidism may be caus
ed by defects in thyroid development, thyroid dysgenesis (85
%), or dyshormonogenesis (15%)— a biosynthesis defect of t
hyroid hormone production in a structurally normal gland.
• Transient congenital hypothyroidism is most commonly caus
ed by inadequate maternal iodine intake in areas of endemic
iodine deficiency
• Early symptoms and signs of congenital hypothyroidism includ
e a lethargic infant with increased sleep, prolonged jaundice,
myxedematous facies, large fontanels, macroglossia, distende
d abdomen, hypothermia, and hypotonia.
• Later symptoms and signs include poor sucking effort leading t
o feeding difficulties, constipation, developmental delay with c
ognitive and growth retardation, myxedema, umbilical hernia,
and decreased activity.
• Ten percent of children born with congenital hypothyroidism h
ave other congenital birth defects, and 50% of them have con
genital heart defects.
• Levothyroxine is the treatment of choice with treatment goals
to raise serum T4 and normalize serum TSH. Levothyroxine tre
atment can prevent mental retardation in the majority of chil
dren (> 90%) if commenced within the first 2 weeks of life.
Laboratory Diagnosis of Con
genital Hypothyroidism
• Newborn screening for congenital hypothyroidism is a
successful public health program for secondary preve
ntion of mental retardation. Screening strategies diffe
r between countries, with some countries measuring
TSH initially with a reflex T4 if TSH is abnormal. Other
s measure T4 as a first-line test, and if T4 is below a ce
rtain cut-off, they reflex test for TSH or measure a co
mbination of TSH, T4, and Tg to differentiate between
primary and secondary causes. The disadvantage of s
creening programs only measuring TSH with a reflex T
4, is the inability to detect central hypothyroidism. Th
e initial screening occurs on the second to fifth day of
life .
• An abnormal result on screening should lead to a confir
matory test in a serum sample, but this should not dela
y treatment. Confirmatory testing includes TSH and free
or total T4, and should be compared with appropriate a
ge-dependent reference intervals
• False-positive elevations in TSH within the first 2 days of
life may be revealed after repeated confirmatory testing
.
• Transplacental transfer of heterophile antibodies is well
described as a false-positive interference in blood spot T
SH, and maternal thyroid function tests need to be chec
ked in this context.
• Preterm infants with an immature HPT axis and acutely i
ll term infants may have a late rise in TSH and may not s
how elevated TSH on the first screening test; many prog
rams have a second screening test for these babies.
Thyroid Hormone Receptor Mutations and Res
istance to Thyroid Hormone

• Two different thyroid hormone receptors are know

n; thyroid hormone receptor α (THRα) and β (THRβ)
, which are encoded by the THRA and THRB genes, r
espectively. Patients with mutations in THRB presen
t with resistance to thyroid hormone β (RTHβ) char
acterized by raised levels of thyroid hormone, norm
al or elevated levels of TSH, and goiter, suggesting a
critical role for THRB in negative-feedback regulatio
n. Only a few patients with resistance to thyroid hor
mone α (RTHα) have been described.
Thank you