Clinical Approach of Thyroid

disorders
Hypothyroidsm and Hyperthyroidsm

Division Endocrinology and Metabolism

Department of Internal Medicine
Padjadjaran University Medical School/
Hasan Sadikin Hospital
Bandung
How can I know hormone mechanism ?

∞ Control systems
∞ Endocrine glands
∞ Hormone definition, structure, synthesis,transport,
clearance
∞ Control of hormone release and feedback
mechanisms
Regulation of Thyroid Hormone Synthesis

Pituitary-Hypothalamus

Autoregulation

Abnormal stimulators
 Feedback mechanism
• Negative feedback
Hypothalamus

Anterior pituitary

Thyroid Gland

Target Tissue
Pituitary-Hypothalamus
(-)
Hypothalamus
TRH
(-)
Anterior Pituitary
TSH

Thyroid

adenyl cyclase

T4 and T3
Thyroid

• Anatomic prominence; one of first endocrine

glands to be correlated with clinical condition
caused by malfunction
• Releases two types of hormones:
I. T3: triiodothyronine (59% iodine)
T4: thyroxine (65% iodine)
Important in growth and development; regulate
energy metabolism; maintain body temperature

II. Calcitonin: important in regulating calcium

metabolism
 Thyroid Gland

Thyroid consists of follicles (vesicles) made up of

thyroid follicular cells; thyroglobulin
associated with inner surface of follicle

thyroglobulin thyroid
(glycoprotein)
follicular cell
(cuboid
epithelial cells)
colloid

Thyroid follicle
 Thyroid

Thyroid gland unique- stores large amounts

T3 and T4

T3 and T4 synthesized and stored as amino

acid residues in thyroglobulin-protein,
constitutes vast majority thyroid follicular
colloid
THYROID HORMONE
1. TRIIODOTHYRONINE :
T3
2. THYROXINE :
TETRAIODOTHYRONINE :
T4
 Thyroid Hormones (T3 and T4)

• Active form: L–isomers

• Iodine essential part of both hormones
T3 59% iodine
T4 65% iodine
• T3 more potent than T4
• Bind to specific cell surface receptors on
sensitive targets; leads to increased uptake of
glucose and amino acids
• T3 also binds to cytoplasmic binding protein
leads to increased protein synthesis
• Starvation: decreasesT3 and T4 receptors
 Thyroid Regulation
Autoregulation
Increased iodine decreased iodide uptake
and organification (conversion to iodine)

Abnormal stimulators
Graves disease: production of thyroid stimulating
immunolglobulin (antibody) by lymphocytes;
mimics action of TSH; longer duration action;
autoimmune disease
Tumors: thyrotoxicosis- excessive hormone
production
Effects of Thyroid Hormones

 Growth and Development

 Calorigenic Effects
 Cardiovascular Effects
 Metabolic Effects
PATOPHYSIOLOGY
HYPERTHYROID HYPOTHYROID
- T3, T4 - T3, T4
- BMR - BMR
- SWEAT GLAND - SWEAT GLAND
- HEART BEAT, CO - HEART BEAT, CO
- HYPERTENTION - HYPOTENTION
- BODY TEMPERATURE - BODY TEMPERATURE
- SENSITIVE TO HEAT - SENSITIVE TO COLD
- NERVOUS - LETHARGY
- BODY WEIGHT - BODY WEIGHT
- MUSCULAR WEAK - COARSE HAIR,
-APATITE - PUFFY FACE +PALP
THICK SKIN
- MENS : IRREGULAR - MENS : IRREGULER
- EXOPTHALMUS - CAROTE NEMIA
- GOITRE (PR/SEC) - GOITRE (+/-)
 Thyroid Hyperfunction
Signs and Symptoms
• Increased body temperature
• Increased motor activity
• Increased sympathetic nervous system activity
• Skin- flushed, warm
• Weak muscles; fatigue
• Increased heart rate; arrhythmias; CHF
• Increased appetite
• Nervousness; jittery
• Increased basal metabolic rate; decreased cholesterol and
triglycerides
• Menstrual irregularities; decreased fertility
 Hyperthyroidsm

Thyroid swelling

↑ Metabolic rate ↑ Protein metabolism ↑ mobilization

Of fat from tissue ↑ B-adrenegic receptor

Finetremor
Increased Increased Decreased Decreased Decreased
Heat production appetite protein Increased
Lean body mass Fat storage HR rate

Weight loss
Weak and dray hair
Adtivation heat
Dissipating mechanism tachycardi
1. Cutaneus vasa dilatation
2. Decreased peripheral
vascular resistance
Easy loss of hair
Findings associated with Graves’ disease

• Diffuse goitre (mild to massive)

• Thyroid bruit
• Thyroid acropachy (clubbing)
• Lymphadenopathy (rare)
• Localized dermopathy (rare)
• Ophthalmopathy
Predisposing factors for Graves’ disease

Genetic susceptibility (including HLA alleles)

Stress (negative life events)
Smoking (especially associated with ophthalmopathy)
Female sex (sex steroids)
Postpartum period
Iodine (including amiodarone)
Lithium

Rare factors:
• Interferon-α therapy
• Highly active antiretroviral therapy
(HAART) for HIV infection
• Campath 1-H monoclonal antibody (for multiple sclerosis)
Immunologic mechanism
 The spesific type of immunologis response :

TSA TSBAG
Thyroid stimulating Thyroid Stimulating
antibodies hormone blocking
antibodies

Grave’s disease Hashimoto’s thyroiditis

Primary myxedema
 Syndromes of thyroid autoimmunity
Grave’s diseases with
goiter,
exophthalmus and
hyperthyroidisme

Hashimoto’s with
goiter and
Euthyroidism or hypothyroidism

Primary thyroid failure

 Thyroid Hyperfunction
Excessive secretion thyroid hormones
Difuse Toxic Goiter (Graves Disease)
-Characterized by thyrotoxicosis and opthalmopathy
-Most common in young, middle age females
-Autoimmune disease
-IgG antibodies to TSH receptors- activate receptors
 increased T3 and T4 release
-Genetic defect in TSH: increase TH  increase Ts-Ig
Toxic Nodular Goiter (Plummer’s Disease)
-Occurs in older patients
-Arises from long-standing nontoxic goiter
Treatment of Hyperthyroidism

• Agents that interfere with production

of T3 and T4
• Agents that modify tissue responses
to T3 and T4
• Destruction of thyroid gland:
surgery; radiation
Thyroid Hyperfunction Treatment

• Antithyroid drug therapy

• Thyroidectomy
• 131Iodine

Thyroid Storm (thyrotoxic crisis)

life threatening; need immediate
Factors associated with either a higher likelihood of immunological
remission following a course of ATDs or with increased resistance to
RAI

Higher likelihood of immunological

remission following a course of ATDs Increased resistance to RAI

• Female sex • Age (> 40 yr)

• Age (> 40 yr) • Female sex
• High TPO antibody positivity • Severe hyperthyroidism
• Small goitre • Medium or large goitres
(> 40 g, visible)
• Mild hyperthyroidism • ATD pretreatment (especially
with propylthiouracil)
TSH receptor antibody–negative

Note: ATD = antithyroid drug, RAI = radioiodine, TPO = thyroid peroxidase,

TSH = thyroid-stimulating hormone.
Antithyroid drugs

Characteristic Propylthiouracil Methimazole

Half-life 75 min About 4–6 h

Effect on 5′-deiodinase Blocks 5′-deiodinase No effect
Effectiveness
(at dose equivalents) ++ +++
Time to achieve euthyroidism Months Weeks
Dosing schedule Twice daily Daily

Side effects
Agranulocytosis Idiosyncratic Dose-dependent
Hepatitis Rare Extremely rare
Vasculitis Rare Extremely rare
Resistance to RAI Common Rare
 Anti-thyroid Hormone Drugs

Goitrogens:agents that decrease production of TH

Thionamides
-methimazole (10x more potent)
-propylthiouracil
-carbimazole (UK)

Accumulate in thyroid
Thionamides
Mechanism of Action
• Inhibit thyroid peroxidase catalyzed
reactions:
– Block iodine organification
– Coupling of MIT and DIT
• Inhibit peripheral de-iodination of
T3 and T4
• Block synthesis T3 and T4 not release,
therefore slow onset of action
The use of antithyroid drugs.

Start methimazole,
10–20 mg/d*

Measure thyroid indices

(including T3/FT3) monthly

If FT4/FT3 level is normal,

then taper methimazole by 50%

Repeat until TSH level is normal

and methimazole is tapered
to 5–10 mg/d

Measure thyroid indices every

3 mo; maintain methimazole
for 1–2 yr
Treatment for Graves’ disease
Therapy Duration Worsens During Advantages Disadvantages
ophthalmopathy pregnancy

ATD 1–2 yr No Yes Rapid restoration of Side effects

euthyroidism; potential for relapse
immunological remission extremely common

Radioiodine Usually Potentially (in CI Permanent correction of Hypothyroidism

once, 15% of patients) hyperthyroidism; safe ( > 50% in 10 yr);
easily administered environmental precautions
required pregnancy delay
of 3–6 mo required

Surgery Day No Yes, during Permanent correction of Hypothyroidism (50% over 25 yr);
surgery second h yperthyroidism usual general anesthesia required; 1%–2%
trimester complications: hypoparathyroidism,
recurrent laryngeal nerve paresis
Anti-thyroid Hormone Drugs

Iodides
- Oldest remedy
- Paradoxical action
- Observe effects within 24 hours
- Maximum effects: 10 –15 days
- Effects temporarily
- Inhibit TH release*, inhibit organification of
iodide
- Decreased size and vascularity of
hyperplastic gland
- No longer used alone (thionamides)
 Radioactive Iodine (131I)

- Rapidly absorbed (orally)

- Concentrated in thyroid
- Emits b radiation  destruction of thyroid
gland (painless)
- Short half life (8 d)
- Widely used to treat hyperthyroidism
- Disadvantage: delayed hypothyroidism
-Alternative: 123I; emits x-rays;
used for thyroid scans; half life = 13 hr
 Treatment of thyroid storm

Treatment Dose and route Action

β-blockers:
Propranolol • 1 mg/min IV (as required) and 60–80 mg every Antagonizes effects of increased adrenergic
• 4 h po or by NG tubet one, blocks T4-to-T3 conversion
Esmolol • 250–500 μg/kg IV followed by IV infusion
(alternative) • 50–100 μg/kg per min

Thionamides:
Propylthiouracil • 800–1000 mg po immediately, then 200 mg Blocks new thyroid hormone synthesis
• every 4 h po or by NG tube blocks T4-to-T3 conversion
(propylthiouracil only)
Methimazole • 30 mg po immediately, then 30 mg every 6 h
(alternative) • po or by NG tube

Iodine:
Lugol’s solution • 10 drops tid po or by NG tube Blocks thyroid hormone release
or SSKI • 5 drops every 6 h po or by NG tube
or Sodium iodide • 0.5–1.0 g IV every 12 h

Glucocorticoids:
Hydrocortisone • 100 mg IV every 8 h Blocks T4-to-T3 conversion,
or Dexamethasone• 2 mg IV every 6 h Immunosuppression
 Adrenoceptor Blocking Agents

Many symptoms of thyrotoxicosis mimic sympathetic stimulation

Need to use agents that rapidly deplete catacholamines or b-
blockers
Block physiologically effects of sympathetic nervous system
stimulation

Guanethidine
Propanolol
 Case Report
A 2 month old male child born of third degree
consanguineous marriage presented with loose motions
since 3 days, vomiting since 1 day and aspiration of milk.
The child was bottle fed with formula feeds. His
antenatal and postnatal period was uneventful with a
birth weight of 2.9 kg. Mother had no illness.
He had achieved social smile at 2 months of age.

On examination, he had coarse facies and extremities

were cold though rectal temperature was normal. He had
a dry and thick skin with a protruding tongue.
 Case Report
• neonatal proportions with length of 53 cm, weight of 3.5 kg and head
circumference of 36.8 cm.

• There was no goiter on systemic examination, bowel sounds were

absent and he was lethargic. There was no organomegaly. Deep
tendon reflexes had delayed relaxation. Other examination findings
were normal.

Laboratory investigations revealed hemoglobin of 6.9 gm%, white

cell count of 12,600 cells/cumm. Blood culture was negative.

His thyroid profile was [T3 = < 0.2 ng/ml (Normal = 0.7 – 2 ng/ml),
T4 < 1 mcg% (Normal = 5.5 to 13.5 mcg%) and TSH = 44 mcIU/ml
(Normal = 0.2 to 5.1 mcIU/ml)].
His X-Ray of the lower limbs showed no tibial epiphysis
 Thyroid Hypofunction

Thyroid hormone deficiency

(Gull’s Disease)
Hypothyroidism: mild
Myxedema: more severe symptoms

Degeneration or atrophy thyroid gland may be

associated with goiter

Hashimoto’s Thyroiditis: autoimmune

destruction of thyroid gland; most common
in US
Thyroid Hypofunction:
Signs and Symptoms
Pale puffy skin
Droopy eyelids
Decreased peripheral vascular resistance
Decreased heart rate and cardiac output
bradycardia
Decreased appetite
Lethargy, slowing of mental processes
Decreased kidney and reproductive function
(infertility)
Decreased basal metabolism
Children: mental retardation, dwarfism
Diagnosis and Treatment of
Hypothyroidism

Diagnosis: decreased T4 production;

presence of anti-thyroid antibody (autoimmune)

Treatment:
Replacement therapy with levothyroxine (T4);
Stable, long half-life (7 d), converted to T3; used
to treat hypothyroidism, myedemia, coma,
cretinism, simple goiter, nodular goiter
Pituitary-Hypothalamus
(-)
Hypothalamus
TRH
(-)
Anterior Pituitary
TSH

Thyroid ---- Enlargement

adenyl cyclase

T4 and T3
Levothyroxine