CLINICAL PRACTICE

FOR THE EVALUATION AND TREATMENT

OF
HYPERTHYROIDISM AND
HYPOTHYROIDISM

Laksmi Sasiarini
TOPICS of
DISCUSSION
DISEASES

Normal Abnormal
(anatomic) (anatomic)
NORMAL ABNORMAL
THYROID THYROID
Function Dysfunction

DIAGNOSIS:
ACTIVE • function
SUBSTANCES
• anatomic
• etiologies
Anatomy of the Thyroid Gland
Hypothalamic-Pituitary-Thyroid Axis
Negative Feedback Mechanism
 HYPOTALAMUS

TRH TISUES

ANTERIOR
HYPOPHYSE

TS FT4 /
H FT3

ORGANIC IODIN
T4 TBG.T4
I- I- IPO in thyroglobulin Prot.T4 + TBG/TBPA/
Pept.T3 T3 ALB TBG.T3
MIT IPO T4
DIT T3 MIT
DIT

I- I- Iodothyrosin
dehalogenase
 Daily intake: 500 µg I-

120 µg I-

40 µg I- THYROID
As T3 &
Extra cell fluid T4: 80
µg I-

60 µg I- LIVER &
OTHER
TISSUE
S

Urine: Feces:
480 µg I- 20
µg
I-
Synthesis of thyroid hormones

1. Uptake of Iodide
2. Oxidation and Iodination
3. Formation of thyroxine (T4) and
triiodothyronine (T3) from
iodotyrosine
4. Resorption of the thyroglobulin
5. Proteolysis of the colloid
6. Secretion of thyroid hormones
7. Conversion of T4 and T3 in
peripheral tissues and in the
thyroid
Prevalence of Thyroid Disease

The Colorado Study

At a statewide health fair in Colorado (N=25 862), participants
were tested for TSH and total T4 levels
• 9.5% of subjects had elevated TSH; most of them had subclinical
hypothyroidism (normal T4 with TSH >5.1 IU/mL)
• Among the subjects already taking thyroid medication (almost 6%
of study population), 40% had abnormal TSH levels, reflecting
inadequate treatment
• Among those not taking thyroid medication, 9.9% had a thyroid
abnormality that was unrecognized
• There may be in excess of 13 million cases of undetected thyroid
failure nationwide

Canaris GJ, et al. Arch Intern Med. 2000;160:523-534.

 Prevalence of Thyroid Disease by Age

The incidence of thyroid disease increases with age

Elevated TSH, %
(Age in Years)

18 25 35 45 55 65 75
Male 3 4.5 3.5 5 6 10.5 16
Female 4 5 6.5 9 13.5 15 21

Canaris GJ, et al. Arch Intern Med. 2000;160:523-534.

 Prevalence of Thyroid Disease
by Gender
• Studies conducted in various communities over the
past 30 years have consistently concluded that thyroid
disease is more prevalent in women than in men
– The Whickham survey, conducted in the 1970s and later
followed-up in 1995, showed the prevalence of undiagnosed
thyrotoxicosis was 4.7 per 1000 women and 1.6 to 2.3 per
1000 men
– The Framingham study data showed the incidence of thyroid
deficiency in women was 5.9% and in men, 2.3%
– The Colorado study concluded that the proportion of subjects
with an elevated TSH level is greater among women than
among men
 Overview of
Thyroid Disease States

Hypothyroidism

Hyperthyroidism
 Evaluation of Thyroid Function

Laboratory evaluation
TSH
Plasma Free T4
Plasma Total T4/T3
Antithyroid Antibodies
(anti TPO, anti thyroglobulin, TRH receptor antibody)

Plasma Calcitonin
Plasma Thyroglobulin
Evaluation of Thyroid Function

Thyroid Imaging
Radioisotope Thyroid Scan
Ultrasonography
 FNAB ??
 Typical Thyroid Hormone Levels
in Thyroid Disease

TSH T4 T3
Hypothyroidism High Low Low

Hyperthyroidism Low High High

 Tests of Thyroid Function

Test Reference Ranges*

TSH 0.3-4.0 mU/L

Free T4 0.7-2.1 ng/dL
T4 4-11 µg/dL
T3 75-175 ng/dl

Adopted from
Stockigt JR. In : Werner and Ingbar’s The Thyroid, 7th ed. 1996: 399
* Reference ranges may vary according to laboratory.
 Hypothyroidism

• Hypothyroidism is a disorder with multiple

causes in which the thyroid fails to secrete an
adequate amount of thyroid hormone
– The most common thyroid disorder
– Usually caused by primary thyroid gland failure
– Also may result from diminished stimulation of the
thyroid gland by TSH
 Primary Hypothyroidism:
Underlying Causes

• Congenital hypothyroidism
– Agenesis of thyroid
– Defective thyroid hormone biosynthesis due to enzymatic defect

• Thyroid tissue destruction as a result of

– Chronic autoimmune (Hashimoto) thyroiditis
– Radiation (usually radioactive iodine treatment for thyrotoxicosis)
– Thyroidectomy
– Other infiltrative diseases of thyroid (eg, hemochromatosis)

• Drugs with antithyroid actions (eg, lithium, iodine, iodine-

containing drugs, radiographic contrast agents, interferon alpha)
 Hypothyroidism: Types
• Primary hypothyroidism
– From thyroid destruction
• Central or secondary hypothyroidism
– From deficient TSH secretion, generally due to sellar
lesions such as pituitary tumor or craniopharyngioma
– Infrequently is congenital
• Central or tertiary hypothyroidism
– From deficient TSH stimulation above level of pituitary
ie, lesions of pituitary stalk or hypothalamus
– Is much less common than secondary hypothyroidism

Bravernan LE, Utiger RE, eds. Werner & Ingbar's The Thyroid. 8th ed. Philadelphia, Pa:
Lippincott Williams & Wilkins; 2000.
Persani L, et al. J Clin Endocrinol Metab. 2000; 85:3631-3635.
 Clinical Features

Tiredness Puffy Eyes

Forgetfulness/Slower Thinking
Moodiness/ Irritability
Depression
Inability to Concentrate
Thinning Hair/Hair Loss
Loss of Body Hair
Enlarged Thyroid (Goiter)
Hoarseness/
Deepening of Voice
Persistent Dry or Sore Throat
Difficulty Swallowing
Slower Heartbeat

Dry, Patchy Skin Constipation

Weight Gain
Menstrual Irregularities/
Cold Intolerance Heavy Period
Infertility
Elevated Cholesterol
Muscle Weakness/
Cramps
Diagnosis

TSH level

Free T4 estimate

Thyroid autoantibodies

Thyroid scan, ultrasonography, or both (if necessary to

evaluate suspicious structural thyroid abnormalities )
 Hypothyroidism
Many Causes, One Treatment

• Goal : normalize TSH level regardless of cause of

hypothyroidism1

• Treatment : once daily dosing with thyroxine - sodium

(1.6µg/kg/day)2

• L-thyroxine should be taken with water consistently 30-

60 minutes before breakfast or at bedtime 4 hours after
the last meal.
 Treatment of Overt Hypothyroidism

• Dose should be increased by 25 µg/day, if needed, at 6 to 8 weeks

intervals.1 Start low and go slow.
• The serum TSH level and a free T4 estimate may be included in the
assessment.
• Starting dose for patients with heart disease should be 12.5 to 25
µg/day and increase by 12.5 to 25 µg/day, if needed, at 6 to 8 weeks
intervals2

1. Brent GA, Larsen PR. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:883.
2. Singer PA et al. JAMA. 1995;273:808
Determinants of Thyroxine Requirements1

• Age
• Severity and duration of hypothyroidism
• Weight
• Malabsorption
• Concomitant drug therapy
• Pregnancy
• Presence of cardiac disease2

1. Brent GA, Larsen PR. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:883.
2. Singer PA et al. JAMA. 1995;273:808
 Drugs and Clinical Conditions That May
Reduce Thyroxine Effectiveness
• Malabsorption Syndromes • Drugs That Affect Metabolism
– Postjejunoileal bypass surgery  Rifampin

– Short bowel syndrome  Carbamazepine

 Phenytoin
 Phenobarbitol
• Reduced Absorption
 Amiodarone
– Cholestyramine resin
– Sucralfate
– Ferrous sulfate
– Soybean formula
– Aluminum hydroxide
– Calcium

Brent GA, Larsen PR. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:883.
A severely affected 14-year-old
hypothyroid girl with puffiness around
the eyes, thickened lips, depressed root
of the nose (saddle nose), and straight,
coarse hair. The second picture was
taken after only 6 months of treatment
with desiccated thyroid. Note the
elevated bridge of the nose, brighter
eyes, thinner lips, and glossy, curly hair.
Her constipation had resolved and her
appetite improved.

Adult man with the "obese form" of

hypothyroidism. Note the striking
resoltion of his puffiness (myxedema)
after treatment with desiccated thyroid.
 Hypothyroidism in Clinical Practice :
Summary

Mild thyroid TSH is the primary Hypothyroidism is Early diagnosis and

failure often diagnostic test linked to other treatment relieves
underdiagnosed
TSH screening should disease states symptoms,
be part of routine improves co-
examination in high- morbidities and
risk patient groups quality of life

Careful dose titration and follow-up are essential

 Hyperthyroidism

Hyperthyroidism refers to excess synthesis

and secretion of thyroid hormones by the
thyroid gland, which results in accelerated
metabolism in peripheral tissues
The causes of hyperthyroidism

• Toxic diffuse goiter (Grave’s disease/GD)

• Toxic adenoma
• Toxic multinodular goiter (Plummer’s disease)
• Painful subacute thyroiditis
• Silent thyroiditis including lymphocytic and
postpartum variations
 Clinical Features
The severity of signs and symptoms may be related to
the duration of the illness, the magnitude of the
hormone excess, and the age of the patient.

Nervousness and irritability Menstrual disturbance

Palpitations and tachycardia Impaired fertility
Heat intolerance or increased sweating Mental disturbances
Tremor Sleep disturbances
Weight loss Changes in vision, photophobia, eye
Alteration in appetite irritation, diplopia, or exopthalmus
Frequent bowel movements or diarrhea Fatigue and muscle weakness
Sudden paralysis Thyroid enlargement
Exertional intolerance and dyspnea
Toxic MNG (Diffuse) Graves
 Thyroid Ophthalmopathy
Proptosis

Lid lag
Ophthalmopathy in Graves

Periorbital edema and chemosis

Occular muscle palsy
 Thyroid Dermopathy

Pink and skin coloured papules, plaques on the shin

 Graves with Acropathy

Graves Goiter Acropathy

 Thyroid Acropathy

Clubbing and
Osteoarthropathy
Onycholysis
 DIAGNOSIS
• Weight and blood pressure
• Pulse rate and cardiac rhythm
• Thyroid palpation and auscultation (to determine thyroid size,
nodularity, and vascularity)
• Neuromuscular examination
• Eye examination (to detect evidence of exopthalmus or
opthalmopathy)
• Dermatologic examination
• Cardiovascular examination
• Lymphatic examination (nodes and spleen)
 Diagnosis
 Markedly suppressed TSH
(the sensitive TSH test refer to a TSH assay with a
functional sensitivity of 0.02 or less)
 Elevated T4 or free T4
 Thyroid autoantibodies (TSH receptor antibodies-
TRAb atau thyroid-stimulating immunoglobulin TSI)
 Thyroidal uptake of radioactive iodine or technetium
pertechnetate
A radioactive iodine uptake (RAIU) is indicated when :
• the diagnosis is in question (except during pregnancy) and
• distinguishes causes of thyrotoxicosis having elevated or
normal uptake over the thyroid gland from those with near-
absent uptake.
 Ultrasonography does not generally
contribute to the differential diagnosis
of thyrotoxicosis.

When radioactive iodine is contraindicated, such as

during pregnancy or breastfeeding, or not useful, such
as following recent iodine exposure, ultrasound showing
increased color Doppler flow may be helpful in
confirming a diagnosis of thyroid hyperactivity.
TREATMENT AND MANAGEMENT

Surgical intervention
Antithyroid drugs (ATD)
Radioactive iodine (RAI)
 Surgical Treatment

Some physicians prefer surgical treatment of

• Pregnant patients who are intolerant of ATD
• Nonpregnants patients desiring definitive therapy but
who refuse RAI treatment
• Pediatric patients with Grave’s disease
• Patients with very large or nodular goiter
The most common complications following near-total or total
thyroidectomy are :
• hypocalcemia (which can be transient or permanent),
• recurrent or superior laryngeal nerve injury (which can be
temporary or permanent),
• postoperative bleeding, and
• complications related to general anesthesia.
• Thyroid storm may be precipitated by the stress of surgery, anesthesia, or thyroid
manipulation and may beprevented by pretreatment with ATDs.
 Whenever possible, thyrotoxic patients who are undergoing thyroidectomy
should be rendered euthyroid before undergoing surgery.
• Preoperative potassium iodide, saturated solution of potassium iodide (SSKI) or
inorganic iodine, should be used before surgery in most patients with GD (10 days
before surgery)
 decreases thyroid blood flow, vascularity, and intraoperative blood loss
during thyroidectomy
• Successful prediction of calcium status after total thyroidectomy can be achieved
using the slope of 6- and 12-hour postoperative calcium levels or the postoperative
intact parathyroid hormone (iPTH) level.
 Selected Pharmacokinetic Features of
Antithyroid Drugs
Propylthiouracil Methimazole (MMI)
Plasma protein binding ~ 75% Nil
Plasma t1/2 75 minutes ~ 4-6 hours
Volume of distribution ~ 20 L ~ 40 L
Concentrated in thyroid Yes Yes
Metabolism of drug during illness
Severe liver disease Normal Decreased
Severe kidney disease Normal Normal
Dosing frequency 1-4 times daily Once or twice daily
Transplacental passage Low Low
Levels in breast milk Low Low
(Goodman & Gillman’s Manual of Pharmacology and Therapeutics, 2008)
• Methimazole should be used in virtually every patient who chooses
antithyroid drug therapy for GD,
• Propylthiouracil is preferred :
during the first trimester of pregnancy,
in the treatment of thyroid storm, and
in patients with minor reactions to methimazole who refuse
radioactive iodine therapy or surgery

• In general, a potency ratio of MMI to PTU of at least 20–30:1 is

recommended when changing from one drug to another.
For example :
300mg of PTU would be roughly equivalent to 10 to15mg of MMI

(ATA, AACE 2011)

 Beta-Adrenergic Receptor Blockade
in the Treatment of Thyrotoxicosis

Drug Dosage Frequency Considerations

Propanolol 10-40 g TID-QID Nonselective beta-adrenergic receptor blockade
Longest experience
May block T4 to T3 conversion at high doses
Preferred agent for nursing mothers
Atenolol 5-100 mg QD-BID Relative beta-1 selectivity
Increased compliance
Metoprolol 25–50mg QD Relative beta1 selectivity
Nadolol 40-160 Nonselective beta-adrenergic receptor blockade
Once daily
Least experience to date
May block T4 to T3 conversion at high doses
Esmolol IV pump 50–100mg/kg/min In intensive care unit setting of severe thyrotoxicosis or storm
 Hyperthyroidism due to Grave’s disease

Severe biochemical hyperthyroidism, Mild or moderate hyperthyroidism,

very large goiter, or serum small or moderately enlarged thyroid, children or pregnant or
triiodothyronine : thyroxine ratio > 20 lactating women, pts with severe eye disease

Primary ATD therapy should be considered

Definitive therapy with radioiodine
peferred in adults Start ATD ( methimazole 15-30 mg/day or
PTU 100-150 mg qid/tid); PTU preferred in pregnant women

Normalization of thyroid function

with ATD before therapy in elderly pts and Monitor thyroid function every 4-6 wk until euthyroid achieved
those with heart disease

Discontinue drug therapy after 12-18 mo

Monitor thyroid function every 2 mo for 6 mo, then less frequently

RELAPS
REMISSION

Definitive radioiodine Second course of ATD in children Monitor thyroid function every 12 mo
therapy in adults and adolescents indefinitely
(Cooper. DS. NEJM , 2005;352:9)
 Radio Active Iodine
(RAI)

• RAI is the treatment choice for hyperthyroidism in

adults
• It is effective, safe, but most treated patients become
hypothyroid and require lifelong thyroid repalcement
therapy.
• RAI is contraindicated during pregnancy and should
not be given to women who are breast feeding.
 Radio Active Iodine (RAI Rx.)

• I131 is given for RAI Rx. (6 to 8 milliCuries)

• Given orally as a single dose in a capsule or liquid form.
• Its effect on the thyroid gland usually takes between 1
and 3 months to develop, and maximal benefit is usually
noted within 3 to 6 months.
If sufficient radio iodine is administered, hypothyroidism
develops in 80 to 90% of patients with Graves’
disease; 14% of patients require additional treatment.

Failure of the first dose to cure hyperthyroidism and the

need for a second course of treatment may be
obvious after an interval as short as 3 months, if the
gland fails to regress in size and thyroid hormone levels
remain high.
 Pretreatment with methimazole prior to radioactive
iodine therapy for GD should be considered in patients
• who are at increased risk for complications due to worsening of
hyperthyroidism (i.e., those who are extremely symptomatic or
have free T4 estimate 2–3 times the upper limit of normal)
• the elderly, and
• those with substantial comorbidity that puts them at greater risk
for complications of worsening hyperthyroidism.

Propylthiouracil (PTU) treatment before 131I

increases the radioresistance of the thyroid
 PRECAUTIONS FOR PATIENTS AFTER RADIOIODINETHERAPY
FOR HYPERTHYROIDISM
Within days, the radioactive iodine passes out of your body in your urine.
To avoid exposing other people to radioactivity, it is important to do the
following for the first one week after your radioactive iodine treatment:
• Drink plenty of fluids – to help flush the radiation out of your body.
• Avoid children, pregnant women and pets for a minimum of one week.
• Remain a min. of 3 feet away from people at all times for at least one week.
• Do not sit next to someone in a motor vehicle for more than 1 hour for one
week.
• Avoid kissing or sexual intercourse for a minimum of one week.
• Do not sleep with your spouse or anyone else in your own room for one
week (if you have small children it is best to stay in a hotel the first few
days).
 …..What To Expect After Treatment

• Use separate (or disposable) eating utensils for the first one week
after treatment, wash them or dispose of them separately.
• Use separate towels, washcloths, and sheets. Wash these items and
all your personal clothing separately for one week. (Ideally keep get
rid of them).
• Wash your hands with soap and lots of water frequently, specially
each time you use the toilet and before touching any cooking
utensils.
• Keep the toilet very clean: flush the toilet 2 or 3 times after each use.
Men should urinate sitting down to avoid splashing for one week.
• Rinse the bathroom sink and tub thoroughly 2 or 3 times after using
them for one week.
Thyroid Disease in Pregnancy
 Hyperthyroidism in pregnancy

• GD is the most common cause of hyperthyroidism during preg- nancy.

• GD during pregnancy should be treated with the lowest possible dose of
antithyroid drugs  the mother’s thyroid hormone levels slightly above
the normal range for total T4 and T3 values in pregnancy and the TSH
suppressed.
• Thyroid function should be assessed monthly, and the antithyroid
drug dose adjusted as required.
• When thyroidectomy is necessary for the treatment of hy-
perthyroidism during pregnancy, the surgery should be performed if
possible during the second trimester.
• POSTPARTUM THYROIDITIS is an autoimmune disorder unmasked in predisposed women
as immune surveillance rebounds after pregnancy.
• The classic triphasic pattern is
thyrotoxicosis at 1–6 months postpartum, followed by
hypothyroidism and
return to euthyroidism at 9– 12 months postpartum.
Those with positive thyroperoxidase (TPO) antibodies in the first trimester were 27 times more
likely to develop postpartum thyroiditis than were those with negative serology .
• Treatment : generally supportive in nature
the use of beta-adrenergic blockers, levothyroxine therapy may be beneficial for
women with symptomatic hypothyroidism (TSH >10mU/L)
 Hypothyroidism during pregnancy

• Overt untreated hypothyroidism during pregnancy may adversely affect

maternal and fetal outcomes :
Spontaneous miscarriage Preeclampsia
Preterm delivery Maternal hypertension
Postpartum hemorrhage Low birth weight and
Impaired intellectual and stillbirth
psychomotor development of the
fetus.

…… When a woman with hypothyroidism becomes pregnant,

the dosage of L-thyroxine should be increased as soon as possible
to ensure that serum TSH is <2.5 mIU/L and that serum total T4 is in
the normal reference range for pregnancy.
Amiodarone-induced hyperthyroidism (AIT)

• Amiodarone : inhibitor 5’ deiodinase and causes decreased

T4 clearance and elevation of serum ft4 without
hyperthyroidism.
• Amiodarone therapy causes thyroid dysfunction in 14-18%
of the involved pts.
→ before initiating of such therapy, pts should have a
baseline TSH measurement, and then they should be
monitored at 6-months intervals during treatment.