CLINICAL PRACTICE

FOR THE EVALUATION AND TREATMENT

OF
HYPERTHYROIDISM AND
HYPOTHYROIDISM

Laksmi Sasiarini
 Scope of Presentation

• Introduction
• Anatomy of the Thyroid Gland
• Structure and Synthesis of Thyroid Hormone
• Epidemiology
• Overview of Thyroid Disease
Hyperthyoidism
Hypothyroidism
• Summary
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
1. Growth and maturation of tissues
2. Cell respiration and total energy expenditure
3. Turnover of essential all substrate (vit, hormone)
4. Cell metabolism (the level at mitochondria)
5. Ca++-ATPase activity at the plasma membrane
6. Trans-cellular flux of substrate and cation
7. Via binding to one or more intracellular receptor
complexes, which in turn, bind to specific regulatory
sites in the chromosomes to influence genomic
expression
Hypothalamic-Pituitary-Thyroid Axis
Negative Feedback Mechanism
 Daily intake: 500 µg I-

120 µg I-

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

60 µg I- LIVER &
OTHER
TISSUES

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
 HYPOTALAMUS

TRH TISUES

ANTERIOR
HYPOPHYSE

TSH FT4 / FT3

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

I- I- Iodothyrosin
dehalogenase
Drugs that decrease TSH secretion Dopamine , Glucocorticoid, Octreotide

Drugs that alter thyroid hormone secretion Decreases thyroid hormone secretion
Lithium, Iodide, Amiodarone
Increased thyroid hormone secretion
Iodide, Amiodarone
Drugs that decreased T4 absorption Colestipol, Cholestyramine, Al-hydroxide,
Ferrous sulfate, Sucralfate
Drugs that alter T4 & T3 transport in serum Increased serum TBG concentration
Estrogens, Tamoxifen, Heroin,
Methadon, Fluorouracil
Decreased serum TBG concentration
Androgen, Anabolic steroid,
Glucocorticoids
Displacement from protein-binding site
Furosemide, Salicylate, Mefenamic acid
Drugs that alter T4 & T3 metabolism Decreased hepatic metabolism
Phenobarbital, Rifampin, Carbamazepine
Decreased T4 5’-deiodination activity
PTU, Amiodarone, β-blocker, Glucocorticoid
Cytokines Interferon-α, Interleukin-2
FACTORS THAT INFLUENCE
THYROXIN-BINDING-GLOBULIN

INCREASE DECREASE

– Oral contraceptives – Testoteron

– Pregnancy – Corticosteroid
– Estrogens – Severe illness
– Infectious hepatitis – Cirrhosis
– Chronic active hepatitis – Nephrotic syndrome
– Neonatal
– Acute intermittent
porphyria

Surk MI, 1990. JAMA; 263:1529

1. Brain
2. Cardiovascular
3. Lung
4. Gastrointestinal
5. Musculoskeletal
 BODY SYSTEM HYPERTHYROIDISM HYPOTHYROIDISM

CNS Irritability, anxiety, depression, Memory loss, somnolence,

insomnia, agitation, heat depression, cold intolerance
intolerance
EYE, EAR, NOSE Eye grittiness, tearing, propotosis Periorbital edema, hoarseness
THROAT
CARDIORESPIRATORY Dyspnea, palpitation Chest pain, peripheral edema

GASTROINTESTINAL Increase appetite, weight loss, Decreased appetite, weight

dysphagia, hyperdefecation, gain, constipation
diarrhea
SKIN Increased sweating, hait loss, Decreased sweating. Dry coarse
pruritus skin, coarse hair, hair loss

GENITOURINARY Polyuria, polydipsia, amenorrhea, Menorrhagia, decreased libido

decreased libido, impotence

MUSCULOSKELETAL Fatigue, muscle weakness, tremor Fatigue, arthralgia, myalgias

 The Thyroid Produces and
Secretes 2 Metabolic Hormones

• Two principal hormones

– Thyroxine (T4 ) and triiodothyronine (T3)
• Required for homeostasis of all cells
• Influence cell differentiation, growth, and
metabolism
• Considered the major metabolic hormones
because they target virtually every tissue
 Thyroid-Stimulating Hormone
(TSH)
• Regulates thyroid hormone production,
secretion, and growth
• Is regulated by the negative feedback
action of T4 and T3
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
Plasma Thyroglobulin
Antithyroid Antibodies
(Autoantibodies againts Thyroid Peroxidase,
Thyroglobulin)
Thyroid-Stimulating Immunoglobulins (ada yg inget namanya apa
ngga?)

Plasma Calcitonin
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

Negative Feedback
 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 Enlarged Thyroid (Goiter)

Moodiness/ Irritability Hoarseness/

Deepening of Voice
Depression
Persistent Dry or Sore Throat
Inability to Concentrate

Thinning Hair/Hair Loss Difficulty Swallowing

Loss of Body Hair 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

• Monitor TSH levels at 6 to 8 weeks, after initiation of

therapy or dosage change3

1. Brent GA, Larsen PR. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:883.
2. AACE. Endocrine Pract 1995;1:56.
3. 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.
 Treatment of Overt Hypothyroidism
• Goal : normalize TSH level1
• Mean replacement dosage is 1.6 µg/kg/day (appropriate dosis may vary among
patients)
• Dose should be increased by 25 µg/day, if needed, at 6 to 8 weeks intervals. 1
Start low and go slow.
• The serumTSH 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 intervals 2

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
 Follow-up After 6 to 8 Weeks of
Thyroxine Therapy

Repeat TSH if Then

> 4.0 mU/L Increase daily thyroxine dose by
25 µg/d
0.3 to 4.0 mU/L Continue dose; repeat TSH in 6
months and then annually or if
symptomatic
<0.4 mU/L Decrease daily thyroxine dose by
12.5 to 25 µg/d repeat in 6 to 8
weeks

1. Singer PA et al. JAMA. 1995;273:808

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)

• 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 irritation,
Alteration in appetite 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)
 Radioactive iodine uptake
 Thyroid scan
(assesing the functional status of any palpable thyroid
irregularities or nodules associated with toxic goiter)
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

Potential complication associated with surgical

management include hypoparathyroidism and vocal
cord paralysis.
 Selected Pharmacokinetic Features of
Antithyroid Drugs
Propylthiouracil Methimazole
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)
 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.
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.
 AIT type I AIT type II
Pre-existing abnormal thyroid Yes No
RAIU Low Low/absent
Colour-flow doppler US Grade 1-3 Grade 0
Serum IL-6 Increases Markedly increased
Pathology Hyperplasia Destructive thyroiditis
Response to
Thionamide Resistant Poor
Steroid Poor Good
Subsequent hypothyroidism Unlikely Possible
 Dietary Advice
• Avoid Iodized salt, Sea foods
• Excess amounts of iodide in some
• Expectorants, x-ray contrast dyes,
• Seaweed tablets, and health food supplements
• These should be avoided because
• The iodide interferes with or complicates the
management of both ATD and RAI Rx.
 Summary

• The sensitive TSH assay has become the single best

screening test for hyper- and hypothyroidism, and in most
outpatient clinical situations, and also for detecting mild
thyroid hormone excess or deficiency.
• In clinical hypothyroidism, the standard treatment is
levothyroxine replacement, which must be tailored to the
individual patient.

• Therapeutic options for pts with Grave’s disease include

thyroidectomy, antithyroid drugs (frequently associated with
relapses), and radioactive iodine (currently the treatment
choice).
 Algorithm for Hyperthyroidism
Measure TSH and FT4

 TSH,  FT4  TSH, FT4 N  TSH,  FT4 N TSH, FT4 N

Primary (T4) Pituitary Adenoma FNAC, N Scan

Thyrotoxicosis Measure FT3

High T3 Toxicosis
Features of Grave’s

Normal Sub-clinical Hyper

Yes No
 RAIU Low RAIU F/u in 6-12 wks
Rx. Grave’s
Single Adenoma, MNG Sub Acute Thyroiditis, I2, ↑ Thyroxine
 Anti Thyroid Drugs (ATD)
Imp. considerations Methimazole Propylthiouracil
Efficacy Very potent Potent
Duration of action Long acting BID/OD Short acting QID/TID
In pregnancy Contraindicated Safely can be given
Mechanism of action Iodination, Coupling Iodination, Coupling
Conversion of T4 to T3 No action Inhibits conversion
Adverse reactions Rashes, Neutropenia Rashes, ↑Neutropenia
Dosage 20 to 40 mg/ OD PO 100 to 150mg qid PO
 Circumstances Associated With Altered
Thyroxine Requirements
Dose Decrease (TSH Low) Dose Increase (TSH High)

• ~70-80 years  Pregnancy

• Weight loss  Conditions causing malabsorption
• Changes in concomitant
 Drugs that decrease T4 absorption or
medication
• Use of androgens increase T4 clearance
 Drugs that reduce T4 to T3 conversion

Brent GA, Larsen PR. In: Werner and Ingbar’s The Thyroid, 7th ed. 1996:883.
 Over - and Under-Replacement Risks

Over-replacement Risks
• Reduced bone density/osteoporosis1
• Tachycardia, arrhythmia. atrial fibrillation
• In elderly or patients with heart disease, angina, arrhythmia, or
myocardial infarction2
Under-replacement Risks
• Continued hypothyroid state
• Long-term end-organ effects of hypothyroidism
• Increased risk of hyperlipidemia

1. Stall GM et al. Ann Interm Med. 1990;113:265

2. Ridgway EC. Family Practice Recerification. 1992;14:127