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Uniwersytet Mikołaja Kopernika
w Toruniu
Collegium Medicum im. L. Rydygiera
w Bydgoszczy
Emergencies
Roman Junik
Katedra i Klinika Endokrynologii
i Diabetologii
z Pracownią Medycyny Nuklearnej
Endocrinological emergencies
Thyroid storm (thyroid crisis, crisis
thyreotoxica)
Thyroid storm:
a life threatening exacerbation of the
hyperthyroid state characterized by
decompensation of one or more organ
systems.
True thyroid storm is a rare event, while less
severe forms are not exceptional and may be
a medical emergency requiring prompt
recognition and adequate treatment.
Patients in whom preexisting hyperthyroidism
has not been diagnosed or has been treated
insufficiently.
Diagnosis is mostly based on clinical findings
Laboratory thyroid function tests can not
differentiate thyrotoxicosis and thyroid storm.
Factors that may precipitate:
infectious diseases, ketoacidosis, 131-I
treatment, thyroidal surgery, vigorous palpation
of the thyroid gland, acute trauma, toxemia of
pregnancy, parturition, administration of iodinecontaining materials (amiodarone, iodinated
contrast dyes), withdrawal of antithyroid drugs,
acute heart failure, pulmonary embolism, stroke
and insulin-induced hypoglycemia.
Sometimes no precipitating event is detectable.
Manifestations:
Severe hypermetabolism with high fever which
changes to hyperpyrexia, profuse sweating,
tachyarrythmias, high-out-put heart failure,
diarrhea and vomiting.
Irritability and restlessness can cause severe
agitation, confusion, seizures, delirium, and
coma.
Dehydratation with electrolytes imbalance is
another frequent feature
.
Patients can have a wide range of signs and
symptoms.
Younger patients often present sympathetic
related symptoms, while older one frequently
show cardiovascular dysfunctions
.
Thyroid storm requires aggressive reversal of
thyronines toxic effect with antithyroid drugs,
management of signs and symptoms and
treatment of the underlying precipitating event.
Antithyroid agents are propylthiouracil (PTU) and
methimazole (MMI). These agents inhibit
synthesis of new thyroid hormones interfering
with iodide oxidation and organification. PTU also
inhibits peripheral conversion of T4 to T3.
MMI is available in parentheral form (Favistan,
Asta Germany, amp. 40 mg).
This form is unknown in USA.
The recommended dose for MMI is 80-120 mg
intravenously or 60-100 mg orally, via
nasogastric tube or through rectal
administration in divided doses.
The dose for PTU are 200-250 mg every six
hours. The effect of antithyroid drugs is
delayed.
The agent which rapidly inhibit the release of
thyroid hormones is iodine.
Iodine containing compounds are Lugol’s
solution (60-80 drops daily), potassium or
sodium iodide (2-10 drops every 8 hours) given
intravenously.
Lithium carbonate 250 mg every 6-8 hours can
be an alternative of iodine.
Betaadrenergic (β) blockers are used to decrease
sympathomimetic symptoms and block the
adrenergic sites, which are thought to be
stimulated by hyperactive catecholamines
released by the thyroid hormones.
These drugs control autonomic effects of thyroid
hormones and block peripheral conversion of T4
to T3.
Propranolol 40-80-120 mg every 6 hours p.o. or
1-3 mg i.v.
Glucocorticoids also inhibit peripheral conversion
of T4 to T3.
They are beneficial in sustaining the peripheral
circulation and preventing shock = correction of
the relative adrenal insufficiency.
Hydrocortisone 300 mg iv and then 100 mg
every 6-8 hours
or dexamethasone 2 mg iv every 6 hours
significantly reduce mortality rates.
Hyperthermia should be controlled with
acetaminophen, chlorpromazine, meperidine,
cooling blankets or ice packs.
Supportive measures such as oxygen and
intravenous fluids should be given in case of
hypoxia or dehydration.
Removal of excess thyroid hormones from the
circulation by plasmapheresis or peritoneal
dialysis - in extreme situations.
All medicaments should be used in maximal
doses.
Myx(o)edema coma
It can be the first presentation of new hypothyroidism,
typically in elderly woman who presents during the
winter,
often precipitated by infection, stroke, myocardial
infarction, congestive heart failure, respiratory disease,
drugs (sedative, lithium and amiodarone) or exposure
to cold or discontinuing thyroxine treatment.
About one third of patients have infections, but fever
and tachycardia will be absent.
Physical findings: puffed myxoedematous face,
macroglosia, periorbital edema, and coarse,
sparse hair. Hypoventilation and bradycardia.
Non-pitting edema of the lower extremities.
The goitre may be or not. The postoperative scar
on the neck remaining after thyroidectomy may
suggest postoperative hypothyroidism and may
lead to the right diagnosis.
Tendon reflexes are prolonged and that there are
changes in the patient's consciousness.
In the auxiliary investigation concentration of FT4
decreased, whereas TSH concentration was high
or merely slightly increased, which could be
caused by other simultaneous illnesses.
Hyponatraemia, hypoglycaemia,
creatinine phosphokinase increases
The treatment is based on supplementing
thyroxine- or triiodo-tironine
+ HC + respirator
Hypercalcemic crisis in primary
hyperparathyroidism
Hypercalcemic crisis is a suddenly occurring
episode of a life-threatening hypercalcaemia.
Clinical symptoms of hypercalcemic crisis in primary
hyperparathyroidism are mainly caused by severe
hypercalcaemia.
There is no clear calcemia value which would be
tantamount to the hypercalcemic crisis - between 3,5
mmol/l and 4,25 mmol/l (14 mg/dL - 17 mg/dL).
Parathyroid hormone (PTH) concentration is significantly
increased.
It exceeds the upper normal range by 20 times, as it
happens in parathyroid (only!) cancer.
High concentration of the parathyroid hormone also
occurs in ectopic parathyroid hormone secretion,
whereas in all the other cases of the crisis the PTH
secretion is suppressed.
Simultaneous illnesses, however, especially those
involving immobilization, may increase the risk of
the crisis.
Ambulatory care patients most cases of
hypercalcaemia are caused by primary
hyperparathyroidism, whereas in patients treated
in hospital it is usually caused by cancer. Primary
hyperparathyroidism is the cause of
hypercalcemic crisis in approximately 20% of
cases. In almost 75% of cases cancer is the
cause of the crisis.
In all the remaining cases the crisis is caused by
different factors, e.g. hypervitaminosis D, or
vitamin D metabolite intoxication.
Signs and symptoms:
muscular weakness, nausea and vomiting, body
weight decrease, tiredness, lethargy and
drowsiness, confusion, osteoneuralgia and
abdominalgia, polyuria, constipation, coma,
polydipsia and renal colic - frequency of 80- 20%.
.
Hypercalcaemia has an influence on many other
systems and organs.
In gastrointestinal tract it can result in
constipation, excess gastrin secretion, and
sometimes even a severe pancreatitis.
In kidneys the symptoms are nephrolithiasis,
severe or chronic renal insufficiency, renal
diabetes and renal tubular acidosis.
Psychic disturbances such as anxiety or
depression may occur when calcemia exceeds 3
mmol/l.
When the concentration exceeds 4 mmol/l hallucinations, confusion and coma may occur.
This illness requires an intensive treatment with
subsequent parathyroidectomy.
It is necessary to supplement liquids, as in the
late form of hypercalcaemia the deficiency
reaches 3- 6 liters. It is caused by polyuria and
vomiting.
The deficiency can be supplemented in the first
24 hours with an intravenous infusion of 0.9%
NaCl (0.45%).
Loop diuretics (furosemide) can be administered
only once liquids are supplemented in the
vascular bed and if the diuresis is maintained.
Once liquids are supplemented, bisphosphonate
should be administered (e.g. pamidronate). The
dosage should be 60 mg (3,0- 3,4 mmol/l of
calcaemia) to 90 mg (above 3,4 mmol/l of
calcaemia).
Hypercalcaemia should start regressing already
after 3 days and normal calcaemia should remain
for approximately 3 weeks.
Tetany
Tetany is caused by muscular and nerves hyperexcitability in many different electrolyte
disturbances.
In hypoparathyroidism it occurs when the
concentration of ionized calcium is low.
Total calcium concentration is not adequate here.
Nonetheless, in cases when hypocalcaemia level
is below 2,25 mmol/l and phosphataemia above
1,60 mmol/l with convulsions, it is necessary to
exclude hypoparathyroidism.
Tetany symptoms can be aggravated by
hypomagnesaemia.
The cause is usually hypoparathyroidism as the result of
thyroidectomy, parathyroidectomy, or any other surgical
intervention of the neck, autoimmune or infiltrative
processes, prolonged radiation, toxic agents, abnormal
PTH secretion or patient's resistance to PTH or a genetic
disorder.
Some tetany symptoms are not too intensive, e.g.
numbness, distal acroparaesthesia, contractions. There
can also be tiredness, depression, anxiety,
oversensitivity.
Physical examination in the period before tetany can
trigger muscular and nerves hyperexcitability and
Trousseau sign of latent tetany, which indicates
hypocalcaemia.
Chvostek sign refers to an abnormal reaction to
the stimulation of the facial nerve. When the
facial nerve is tapped at the angle of the jaw, the
facial muscles on the same side of the face will
momentarily contract. Alas, this symptom may
occur also in healthy people and in patients with
hypomagnesaemia, hypokaliaemia and alkalosis.
Symptoms of a more severe tetany are palm and
feet muscles contractions, and then the
contractions of all the other muscles.
In the upper limbs the most contracted muscles
are flexors, whereas in lower limbs- extensors.
The contractions are bilateral, symmetrical, with
remained consciousness. The contractions start
with flexor pollicis brevis muscle ("hand of the
obstetrician"), then they reach in turn forearm
muscles, arm, face, chest, and finally lower limb
muscles.
The contractions usually pass in reverse order
These should not be mistook for general tonic
contractions, which occur in severe tetany
.
There is no relation between the severity of hypocalcaemia and the
intensification of tetany, though it occurs most often when calcium concentration
is below 1,85 mEq/ l (7,4 mg%).
In tetany caused by hypoparathyroidism the most
efficient method of treatment is calcium iv
infusion. It alleviates the symptoms and prevents
convulsions and laryngospasms.
It is possible to administer calcium chloride,
however it is irritative for veins. An alternative
treatment is the infusion of 10- 30 ml of 10%
calcium gluconate solution in 5% glucose.
Calcium supply should not exceed 100 mg/ hour.
The aim is to achieve calcium concentration in
blood serum close to the lower range of the
norm.
It is crucial to be particularly careful with patients
to whom digitalis is administered.
Among orally administered medicines 1,0- 3,0 g/
24 hours of calcium should be used (calcium
carbonate or calcium chloride due to the highest
content of this element), as well as vitamin D
metabolites- 2,5 μg/ 24 hours of alfacalcidol in
tetany attack, then 0,5- 2,0 μg/ 24 hours or
calcitriol
.
Hyperphosphatemia must be decreased by
implementing diet poor in phosphate. 3,0- 6,0 g/
24 hours of aluminum hydroxide (Alusal) should
be administered to limit phosphate absorbance.
Phosphate concentration should remain by the
upper normal range.
Hypomagnesaemia compensation can be
achieved by administering 0,3- 1,2 mg/ 24 h of
magnesium carbonate.
Alkalosis should also be neutralized.
Adrenal crisis
Adrenal crisis is a state of severe adrenal cortex
hormones insufficiency - glucocorticoids and
mineral corticoids.
It can be caused by primary or secondary
adrenocortical insufficiency.
In secondary adrenocortical insufficiency
symptoms are less intensified.
Primary and secondary adrenocortical
insufficiency can be differentiated in the process
of skin examination.
When the illness develops more rapidly, even in
the primary form of adrenocortical insufficiency
hyper-pigmentation does not occur.
The crisis can be caused by the development of
simultaneous illness in patients suffering from
Addison's disease.
In patients who so far have not had any adrenal
cortex pathologies the crisis can be caused by
autoimmune disease, tuberculosis, cancer
metastasis, AIDS, infection (especially
meningococcal infection causing WaterhouseFriderichsen syndrome).
Adrenal crisis clinical symptoms:
muscular weakness, abdominalgia, hypothermia
at first and then fever, orthostatic hypotension,
vomiting and diarrhea resulting in dehydration.
The dehydration results in dry skin, body weight
decrease, oliguria, tachycardia, hypoglycaemia
causing convulsions.
In its most severe form such crisis can result in
collapse, hypothermia, loss of consciousness or
coma.
ACTH and cortisol concentration must be
evaluated in the blood serum.
The treatment:
filling in the vascular bed and supplementing
sodium chloride by intravenous saline solution
infusion, with the maximum speed, considering
the patient's circulatory efficiency.
It is usually 2- 3 liters in the first 24 hours and
then 3- 4 liters. 50- 100 mg of glucocorticoid
(preferably hydrocortisone) should be
administered every 6 hours.
Next fludrocortisone is administered orally (no
parenteral form) to supplement mineral
corticoids. The daily dosage of fludrocortisone is
50- 200 μg/ 24 hours and therefore in next
stages it should be administered in longer time
intervals, e.g. every second day.
Nicolaus Copernicus University
in Torun
L. Rydygier Collegium Medicum
in Bydgoszcz
THYROID
Roman Junik
Chair and Dept. of Endocrinology
and Diabetology
40
The lobe measures:
►2,5-4 cm in lenght
►1,5-2 cm in width
►1-1,5 cm in thickness
►= 18 cm3 F, 25 cm3 M
The weight of gland in the normal
individual, as determined by ultrasonic
examination, varies depending on
dietary iodine intake, age, body
weight is approximately 10-20g.


Thyroid gland can be displaced at
base or under the tongue, or under the
hyoid bone.
Ectopic gland is also hypoplastic,
secreting not enough amounts of
thyroid hormones.




The thyroid hormones control the
metabolism of cells, which is their speed
of activity.
If there is too little hormones, the body
cells work too slowly; too much results in
them working too fast.
Thyroid hormones regulate the rate of
oxygen consumption.
This metabolic action influences the
utilization of the main components of
food: carbohydrates, protein, and fat.
negative feedback mechanism



The levels of thyroid hormones
circulating in the blood are regulated by
the thyroid-stimulaing hormone (TSH)
produced by the pituitary gland at the
base of the brain.
If the levels of thyroid hormones fall,
TSH stimulates the thyroid to make
more hormones.
If the levels of thyroid hormones rise
above normal, TSH is suppressed.
Physical examination

Features to be noted include:
•
thyroid size,
•
consistency,
•
nodularity,
•
tenderness,
•
fixation.
Laboratory evaluation
Thus TSH can be used for the first step in the
diagnosis of:
Overactivity of the thyroid hyperthyroidism
(TSH)
and underactivity - hypothyroidism (TSH )
Euthyroidism
TSH - N
fT4 - N
fT3 - N
Hormone
TSH
T3
T4
Hyperthyroidism
Hypothyroidism






Extrathyroid causes for ↑TSH elevation
1. TSH-secreting pituitary tumor =
secondary hyperthyroidism
2. Thyroid hormone resistance
3. Assay artifact
Extrathyroid causes for ↓TSH suppression
1. Euthyroid sick syndrome- any severe
nonthyroidal illness
2. First trimester of pregnancy (due to hCG
secretion)
3. Treatment of hyperthyroidism – TSH remains
suppressed for several weeks
4. Treatment with high doses of glucocorticoids,
dopamine, somatostatin (analogues)
5. Secondary hypothyroidism, caused by
hypothalamic-pituitary diseases.
Anti-thyroid antibodies and
thyroid disease
Healthy people
Graves’
disease
Hashimoto’s
thyroiditis
TPO
TG
TRAb (TBII)
10-30%
2%
undetectable
70-80%
majority
30-50%
70-100%
stimulating
majority
10-20%
blocking
Thyroglobulin
1. Serum Tg levels are increased in all types of
thyrotoxicosis except thyrotoxicosis factitia caused by
self-administration of thyroid hormone.
2. The main role for Tg measurement is in the follow-up
of thyroid cancer patients.
After total thyroidectomy and radioablation Tg level
should be undetectable; measurable levels (>10ng/mL)
suggest incomplete ablation or recurrent cancer.
Thyroid imaging
Radio-isotope thyroid scan



In this investigation a radio-isotope, either
technetium or iodine, is given that is taken up
by the thyroid gland.
The gland becomes temporarily radioactive
and this is charted by a counter placed over
the neck.
A record of the uptake called a scintigram can
be charted on X-ray film or in colour on
paper.
Radionuclide imaging
123I, 131I




or technetium Tc 99 pertechnetate
(99mTc) is useful for determining the functional
activity of thyroid gland. This is useful:
To define areas of increased or decreased
function within the thyroid, which helps to
recognise the cause of the thyrotoxicosis
To detect retrosternal goitre
To detect ectopic thyroid tissue
To detect functioning metastases of thyroid
carcinoma
A biopsy (Fine Needle Aspiration Biopsy, FNAB)
is the removal of a small amount of fluid or tissue from the thyroid by
needle insertion for further microscopic examination.
There are two types of
biopsies:
-fine needle aspiration
-a coarse (large) needle biopsy.
Both types are safe and can be done in the physician's office.
FNAB is considered the best method
for differentiation of benign from
malignant thyroid disease –
diagnostic in ±80%.
Nontoxic goiter
Etiology
Iodine deficiency or excess
Goitrogens in the diet
Thyroiditis (Hashimoto, subacute)
Graves’ disease
Inherited defect in thyroidal enzymes
necessary for T4 and T3 biosynthesis
6. Neoplasm, benign or malignant
7. Generalized resistance to thyroid
hormone (rare)
1.
2.
3.
4.
5.
Nontoxic goiter


Nontoxic goiter is noncancerous
hyperthrophy of the thyroid with normal
thyroid function (euthyroid).
That means that a patient has no
evidence, either clinically or on
laboratory testing of hyperthyroidism,
hypothyroidism or inflammation




Diffuse nontoxic goiter= simple
Nontoxic (multi)nodular goitre
Endemic goiter - when affects >5% of
the population, caused by iodine
deficiency
Sporadic goitre - in nonendemic regions
Symptoms and Signs



The patients may have a history of low
or excess iodine intake or overingestion
of food goitrogens.
In the early stages, the goiter is soft,
symmetric and smooth
Later, multiple nodules and cyst may
develop
Symptoms and Signs



Pressure symptoms, particulary on
moving the head upward or downward:
difficulty in swallowing, breathing
Pemberton sign: facial flushing and
dillation of cervical veins on lifting the
arms over the head
hoarsness (vocal cord paralysis)
Treatment
1. Surgery
2. Radio-iodine treatment
3. Medical treatment
Surgery
Surgery is indicated for patients with goitre that:
1. intrathoracic
2. gives local compression symptoms
3. with nodule with FNAC suspicious of malignancy
4. that cause cosmetic disfigurement
As a rule a near-total thyroidectomy is performed
Complications of thyroidectomy

Immediate
Recurent laryngeal nerve damage
 Hypoparathyroidism


Hypothyroidism

Keloid formation
Hypothyroidism
It is a clinical syndrome resulting from
a deficiency of thyroid hormones, which in
turn results in a generalized slowing down
of metabolic processes.
More prevalent in elderly women (up to 5%).
Cretinism means hypothyroidism dating from birth
and resulting in marked developmental abnormalities
including mental retardation.
Myxoedema refers to the accumulation of
mucopolysaccharides (glycosaminoglycans) in
intracellular spaces, particularly in skin and muscles,
leading to thickening of the facial features and doughy
induration of the skin.
It occurs in severe hypothyroidism.
Hypothyroidism may be classified as:
1.
2.
3.
4.
Primary (thyroid failure)
Secondary (to pituitary TSH deficit)
Tertiary (due to hypothalamic deficiency of TRH)
Peripheral resistance to the action of thyroid
hormones
Hypothyroidism can also be classified as:
A/ Goitrous
B/ Nongoitrous
Primary hypothyroidism
(about 95%)
Inability to synthesize adequate quantities of
thyroid hormones causes hypersecretion of TSH
(elevation in serum TSH) and goitre.
If this compensatory response is inadequate,
goitrous hypothyroidism ensues (e.g. Hashimoto`s
disease).
Main clinical features:
Early symptoms (non-specific):

chronic fatigue

lethargy

inability to concentrate

constipation

coldness, cold intolerance

menstrual irregularities, menorrhagia, infertility (hypothyroidism impairs
the conversion of estrogen precursors to estrogens, resulting in altered
FSH and LH secretion and in anovulatory cycles)

stiffness and cramping of the muscles

muscle weakness

paresthesias.
Main clinical features:
Later symptoms:

physical slowing

psychiatric symptoms: mental slowing, apathy and withdrawal,
depression, or agitation (“myxedema madness”), emotional
instability, paranoid psychosis

huskiness of voice

puffiness of face and eyes

pallor

dry hair

dry skin

loss of hair

decrease of appetite

increase of weight
Physical examination – main signs:

sinus bradycardia

delayed reflexes (normal muscular contraction, slow
relaxation)

coarse, dry and brittle hair

rough, dry, cool skin

yellowish colour of the skin (reduced conversion of carotene
to vitamin A and increased blood levels of carotene)

puffy face and hands

hoarse, husky voice

obesity

goitre or without goiter
Laboratory diagnosis of hypothyroidism :
Thyroid function tests:
Primary hypothyroidism
1. ↓T4 subnormal
2. T3 normal or subnormal
3. ↑TSH elevated
4. Positive test for thyroid autoantibodies suggests underlying
Hashimoto`s
thyroiditis
Management
1. Confirm the diagnosis
2. Provide appropriate patient education
3. Refer the patient where appropriate
4. Exclude co-existing hypoadrenalism and ischemic
heart disease before T4 replacement
Note:
Treatment as primary hypothyroidism when
hypopituitarism is the cause may precipitate adrenal crisis.
In pituitary hypothyroidism glucocorticoid replacement is
essential.
Thyroid medication
1. Hypothyroidism is treated with levothyroxine
(T4). Intracellularly, levothyroxine is
converted to T3, so that both hormones
become available even though only one is
administered.
2. Doses of levothyroxine in adults range from
50 to 200g (1-2μg/kg/daily), according to
the patient’s age and body weight once
daily, ½ hour before breakfast.


Levothyroxine has a sufficiently long
half-life (7 days) so that if the patient
is unable to take medications by
mouth for a few days, omitting
levothyroxine therapy will not be
detrimental.
The parenteral dose of T4 is about 7580% of the usual oral dose.
Note:
Start with low doses (12,5-25-50 μg daily) in elderly
and ischemic heart disease!!!
Avoid overdosage.
Monitor TSH levels monthly at first. As euthyroidism
is achieved, monitoring may be less frequent, e.g.
once a year.
During pregnancy and lactation the dose of T4 must
be increased.
Older patients metabolize T4 more slowly, and the
dose will gradually decrease with age.
THYROTOXICOSIS
Thyrotoxicosis == clinical, physiological
and biochemical findings that result
when the tissues are exposed to, and
respond to excess thyroid hormones.
Hyperthyroidism = hyperfunction of the
thyroid that may lead to thyrotoxicosis
VARIETIES OF THYROTOXICOSIS
1/ Associated with thyroid hyperfunction = overproduction of
hormones by the thyroid gland itself
 excessive production of TSH (pituitary tumour, rare)
 abnormal thyroid stimulator (of extrapituitary origin)
Graves` disease
Trophoblastic tumour
 intrinsic thyroid autonomy
Hyperfunctioning adenoma
Toxic multinodular goiter
VARIETIES OF THYROTOXICOSIS
2/ Not associated with thyroid hyperfunction
 Disorders of hormone storage (an excess of preformed hormone leaks from the
gland owing to the presence of inflammatory disease)
•Subacute thyroiditis
•Chronic thyroiditis with transient thyrotoxicosis (new hormone
formation is decreased – suppression of TSH)
 Extrathyroid source of hormones
• Thyrotoxicosis factitia
• “hamburger toxicosis” = ingestion of meat contaminated with
animal thyroids
• ectopic thyroid tissue
- struma ovarii
- functioning follicular Ca
GRAVES` DISEASE
= disorder with three major manifestations which do not need to
appear together and are independent of one another:
1/ hyperthyroidism with diffuse goiter
2/ ophthalmopathy
3/ dermopathy
Graves` disease is relatively common, more frequent in women
(in nongoitrous regions F:M=7:1), especially in the third and
fourth decade of life. Genetic factors connected with haplotypes
HLA-B8 and DR3 play an important role → familial
predisposition.
Pathogenesis of Graves’ disease
An abnormal plasmic thyroid stimulators
with prolonged duration of action relative to
that of TSH. They belong to immunoglobulins
of the IgG class elaborated by lymphocytes of
patients with Graves` disease
These factors represent antibodies TSI
(thyroid stimulating immunoglobulins) directed
against the thyroid TSH receptor (TRAb) that
mediate the thyroid stimulation →
hyperthyroidism and goiter.
Pathogenesis of Graves` disease


The pathogenesis of the ophthalmic
component is more enigmatic. Proposed
mechanism is the development of
antibodies (TSH-R-Ab, TRAb) against
specific antigens in the extraocular
muscles.
The pathogenesis of the dermopathy is
still unclear.
CLINICAL MANIFESTATIONS
Manifestations of thyrotoxicosis (not typical for Graves` disease
only) vary in intensity with the severity and duration of the
illness, the age of the patient and the presence of disease in
other organs, such as the heart. These are:
Nervousness
Emotional lability
Inability to sleep
Tremors
Frequent bowel movements
Excessive sweating
Heat intolerance
Weight loss despite a well-maintained or increased
appetite
CLINICAL MANIFESTATIONS

Proximal muscle weakness with loss of strength →
difficulty in climbing stairs




Oligomenorrhea or amenorrhea





Warm and moist skin with a velvety texture
Dyspnea
Palpitations
Enhancement of angina pectoris or cardiac failure in older
patients
Palmar erythema
Fine and silky hair
Fine tremor of the fingers and tongue
Hyperreflexia
Ocular signs (result from sympathetic
overstimulation and usually subside when the
thyrotoxicosis is corrected; they are called
noninfiltrative ophthalmopathy and have to be
distinguished from the infiltrative ophthalmopathy
characteristic for Graves` disease):
Stare with widened palpebral fissures
Infrequent blinking
Lid lag
Failure to wrinkle the brow on
upward gaze
Cardiovascular findings:
-
Wide pulse pressure
-
Tachycardia
-
Arrhythmias (atrial fibrillation)
-
Systolic murmurs
-
Increased intensity of the apical first sound
-
Cardiac enlargement
Manifestations of Graves` disease
•Diffuse toxic goiter (the most common) = the thyroid gland
is diffusely enlarged, soft and vascular, may be asymmetric
and lobular. A bruit over the gland usually signifies that the
patient is thyrotoxic. An enlarged pyramidal lobe of the
thyroid may be palpable.
Dermopathy – thickening of the dermis, which is infiltrated with
lymphocytes and mucopolysaccharides. Usually occurs over the dorsum
of the legs or feet and is termed pretibial myxedema. The skin is:
-
raised
-
thickened
-
has a peau d`orange appearance
-
may be pruritic and
-
hyperpigmented
Manifestations of Graves` disease

Ophthalmopathy – an inflammatory infiltration of the orbital contents, exclusive
of the globe. The orbital musculature is often enlarged due to infiltration with
lymphocytes, mucopolysaccharides and edema → the increased volume of the orbital
contents → protrusion of the eyeballs. Clinical signs are:
-
Stare
-
Lid lag
-
Lid retraction
-
Proptosis of varying degrees with ophthalmoplegia
-
Chemosis
-
Conjunctivitis
-
Periorbital swelling
-
Complications of corneal ulceration
-
Optic neuritis
-
Optic atrophy
Exophthalmic ophthalmoplegia refers to the ocular muscle weakness → impaired upward
gaze, convergence and strabismus with varying degrees of diplopia. Exophthalmos may
be unilateral or bilateral.
Management
The aim :
- Control the hyperthyroidism
- Sustain remission
Treatment of Graves’ Disease
There are three main methods, not
mutually exclusive:
1. Antithyroid Drug Therapy
2. Radioactive Iodine Therapy 131I
3. Surgical Treatment
Antithyroid drugs
1. Imidazole:


carbimazole
methimazole=thiamazole (Metizol 5mg, Thyrozol 5,
10,20mg, Favistan i.v. 40 mg)
Carbimazole is a pro-drug as after absorption it is converted to the
active form methimazole
2. Thioamide

propylothiouracil (Thyrosan 50 mg)
Antithyroid Drug Therapy
Anti-thyroid drugs suppress the ability of the thyroid to
make thyroid hormones.
Methimazole prevents the thyroid peroxidase enzyme from
coupling and iodinating the tyrosine residues on
thyroglobulin, hence reducing the production of the
thyroid hormones.
Propylothiouracil also partially inhibits the conversion of T4
to T3.
Antithyroid drug therapy is generally started with large
divided doses. (M-40mg, P-400mg)
When the patient becomes clinically euthyroid,
maintenance therapy may be achieved with lower single
morning dose.
Major side effects
Fortunately, the major side effects of antithyroid drugs are very rare. Allergic
reaction to antithyroid involve either a rash (about 5% of patients) or
agranulocytosis 0,5%.
The rash can be managed by simply administering antihistamines.
Agranulocytosis is characterized by a decrease in the production of white
blood cells. This condition is extremely serious, but affects only one out of
every 200 to 500 people who take an antithyroid drug.
Agranulocytosis is more likely to occur within the first three months of starting
treatment with an antithyroid drug. If patient develops a sore throat, fever,
or other signs or symptoms of infection, they should stop medication and
immediately contact doctor. Serious and potentially life threatening
infections, or even death, can occur before agranulocytosis resolves.
However, once the antithyroid drug is stopped, agranulocytosis usually
resolves within a 2-3 weeks.
Radioactive Iodine Therapy
131I
Radioactive iodine (RAI) is often chosen for
treatment of hyperthyroidism because of its
simplicity: it is given in a single dose. In the
USA it is the preferred treatment for most
GD patients.
How Radioactive Iodine Treatment
Works
RAI treatment is based on the fact that the thyroid actively
accumulates iodine, which it uses to produce thyroid hormones
required for normal body function. This RAI is like the iodine
found in foods, except that it releases beta particle, which
creates its therapeutic action.
While in the thyroid gland, the RAI disrupts the function of
some of the thyroid cells - the more radioactive iodine given,
the more cells cease to function.
As the cells stop functioning, excessive amounts of thyroid
hormones are no longer produced, and symptoms of
hyperthyroidism begin to disappear.
Precautions
Some precautions are necessary because of the
small amount of radiation that emanates from
the neck where the RAI is stored for a few
days after treatment. While this radiation is
beneficial for the person being treated,
precautions are needed to reduce the radiation
families and friends are exposed to.
Surgical Treatment
Subtotal thyroidectomy is the treatment of
choice for patient with large gland or
multinodular goiter.
The patient is prepared with antithyroid drug
until euthyroid. In addition, 10 days before
operation patient is given solution of
potassium iodide to diminish the vascularity
of the gland and to simplify surgery.
TOXIC NODULAR GOITER
This term means independence from TSH stimulation in one or more
areas of the gland. Because it arises in long-standing simple goiter,
toxic multinodular goiter is a disease of the aging or elderly.
The clinical presentation differs from that in Graves` disease.
Ophthalmopathy is rare. The degree of thyrotoxicosis is often less
severe than in Graves` disease, although its physiologic impact on
specific organs may be great – especially on the cardiovascular
system (arrhythmias, congestive heart failure).
Thyroiditis
1. Acute thyroiditis
2. Subacute thyroiditis
3. Chronic thyroiditis
Acute (pyogenic) thyroiditis
It is antecedent by a pyogenic infection
elsewhere with septicaemia or acute
endocarditis.
Staph. aureus, streptococci, E. coli,
tuberculosis, fungal
Thyroid function is usually normal.
Acute thyroiditis
The signs are:
local pain and tenderness of the thyroid
swelling of the thyroid
redness of the overlying skin
warmth of the skin
constitutional signs of infection
Subacute thyroiditis
(granulomatous, giant cell, de Quervain`s
thyroiditis)
It is viral in origin (mumps virus,
coxackievirus, adenoviruses).
Subacute thyroiditis
The symptoms are:
 moderate thyroid enlargement
 pronounced asthenia
 malaise
 fever
 pain and/or tenderness (especially on
swallowing) over the thyroid, lower jaw or ear
Physical findings include: tenderness and
nodularity of the thyroid, which may be
unilateral but usually involves whole gland.
There are no signs of local redness or heat
suggestive of abscess formation.
Histological features include many large
phagocytic cells, including giant cells.
Early, many patients are mildly thyrotoxic.
Thyroid radioactive iodine uptake (RAIU) is
extremely low.
The erythrocyte sedimentation rate (ESR) is
markedly elevated (50-100/h).
Thyroid autoantibodies are usually not
detectable in serum.
Later the patient may pass through a hypothyroid
phase (T4 and T3 decrease and TSH increases) and
returns to normal thyroid function (RAIU rises
reflecting recovery of the gland).
Subacute thyroiditis usually resolves completely
over weeks or months.
Treatment
In the acute phase treatment is based on nonsteroid
anti-inflammatory drugs eg. acetaminophen 0,5 g
four times daily.
Avoid high-dose aspirin - competitively displaces
thyroid hormone from its binding protein.
A short course of glucocorticoid such as prednisone
20mg 3 times daily, for 7-10 days, may be
necessary to reduce the inflammation.
Antithyroid drugs are not indicated.
Beta-blockers eg.propranolol can be used to control
symptoms.
Chronic thyroiditis
Hashimoto`s disease, (AITD)
(autoimmune thyroiditis, lymphocytic thyroiditis).
It is an autoimmune thyroiditis, which is a
common cause of hypothyroidism and
sometimes goitre.
It occurs most frequently in women of middle
age.
Lymphocytes become sensitized to thyroid
antigens and autoantibodies are formed that
react with these antigens.
Chronic thyroiditis
The three most important thyroid autoantibodies
are:
1.
thyroglobulin antibody (Tg Ab)
2.
thyroid peroxidase antibody (TPO Ab),
formerly called microsomal antibody
3.
TSH receptor blocking antibody (TSH-R Ab [block]).
Chronic thyroiditis
Early in the disease the patient is
metabolically normal (sometimes
thyrotoxic); as the disease progresses,
thyroid failure, at first subclinical,
becomes evident (↑TSH increases, ↓T4
decreases, T3 normal or decreases).
Chronic thyroiditis
Hashimoto`s disease may be associated
with other autoimmune diseases such as:
DM1, pernicious anaemia, adrenocortical
insufficiency, myasthenia gravis, idiopathic
hypoparathyroidism, and vitiligo.
Features are:
 bilateral, painless goitre
 classically described as firm and rubbery
 patients may be hypothyroid or euthyroid
Diagnosis is confirmed by a strongly positive
serum antithyroid antibody titre and
(TPOAb)/or fine needle aspiration cytology
(lymphocytic infiltration of the gland and the
presence of Hurthle cells) or US.
Riedel`s thyroiditis
It is a disorder in which intense fibrosis of
the thyroid, involving overlying muscle and
surrounding structures, leads to induration of
the tissue of the neck.
It requires being distinguished from thyroid
neoplasia.
Thyroid Cancer
Most thyroid nodules are
benign and it is important
to identify those that are
likely to be malignant.
Scanning techniques
123I, 131I
or
99mTc
More likely benign
„hot nodule”
More likely malignant
„cold nodule”
USG
More likely malignant nodule
Solid, hypoechogenic
Diameter > 10 mm
Central vascularization
Microcalcification
Margin (rim) not continuous or irregular
Wider than taller
How is cancer of thyroid
diagnosed?
The diagnosis is made on the basis
of clinical suspicion and confirmed
by fine-needle aspiration (FNAB).
If this is inconclusive, the diagnosis
may be confirmed only by surgery.
Malignant thyroid tumors
1. Differentiatied
 Papillary carcinoma 75%
 Follicular carcinoma 15%
 Medullary carcinoma 5% (develop from C cells)
2. Undifferentiated (anaplastic)carcinomas 3%
3. Miscellaneous 1%
Papillary Carcinoma
Papillary ca has a bimodal frequency with peaks occurring in the
second or third decade and again in later life.
Usually presents as a nodule:
 firm
 solitary
 “cold” on isotope scan
 solid on ultrasound
 clearly different from the rest of the gland
 in multinodular goiter- a dominant nodule, larger and firmer
 with enlarged cervical nodes - 10%
These cancers usually extend by
intraglandular metastasis and by local lymph
node invasion.
They are usually nonencapsulated, grow very
slowly, but may become more aggressive in
older patients and convert to undifferentiated
or anaplastic carcinoma.
In later stages, they can spread to the lungs
or bones.
Management
• Total thyroidectomy. (For lesions of 1 cm or less,
lobectomy with isthmectomy is recommended).
• Postoperative radioiodine therapy – ablation 131I if
there is evidence of residual radioactive iodine uptake
in the neck or elsewhere.
• Levothyroxine 150-300 ug daily (2.0-2.5 ug/kg/d), to
suppress serum TSH to the level< 0.1 mU/L
•
Follow-up at intervals of 6-12 months :
examination of the neck, chest x-ray, thyroid ultrasound, 131I whole body scan
serum thyroglobulin negligible (<2 ng/mL) – a rise in serum
thyroglobulin suggests recurrence of thyroid cancer