HYPOTHYROIDISM : ETIOLOGY, PATHOPHYSIOLOGY AND TREATMENT

Dr. I Gede palgunadi, SpPD SMF Penyakit Dalam Rumah Sakit Umum Mataram
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Introduction
The hypothalamic-hypohyseal-thyroid axis

INTRODUCTION
Hypothyroidism
Clinical syndrome ~ TH deficiency metabolic process Accumulation of glycosaminoglycans Myxedema (adult), cretin (new born) Myxedema coma (severe)
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INTRODUCTION
Hypothyroidism
Primary, secondary, tertiary and peripheral resistance to TH Most common : Primary Hypo In iodine deficient areas : IDD In iodine sufficient areas : Hashimoto (Chronic Autoimmune Thyroiditis)
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ETIOLOGIC CLASSIFICATION
I. Primary Hypothyroidism
A.
1. 2. 3. 4.

Destruction of thyroid tissue

Thyroiditis (chronic autoimmune thyroiditis, subacute thyroiditis, postpartum thyroiditis) I131 therapy, external radiation (neck) Thyroidectomy : subtotal, total Infiltrative

B.
1. 2. 3. 4.

Defect in TH biosynthesis
Iodine deficiencies Thyroid gland agenesis / dysgenesis Hereditary defects in TH biosynthesis Drugs with Antithyroid effect
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ETIOLOGIC CLASSIFICATION
II. Central Hypothyroidism
A. B.

Thyrotropin deficiency pituitary diseases (Secondary Hypo) Thyrotropin Releasing Hormone Deficiency Hypothalamic Disorders (Tertiary Hypo)

III. Generalized Resistance to Thyroid Hormone (GRTH)

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PATHOPHYSIOLOGY
Normal : T4 , T3 , T4 T3 (peripher) T4 : 100 125 mcg/day

Sub Clinical : small in T4 (but still in N range) : adequate source of T3 symptom (-) stimulating TSH secretion hyperplasia, hypertrophy T4 & T3 still Normal, TSH , symptoms (-) Overt Hypo : frank in T4 : T3 symptom (+) TSH T4 & T3 , TSH , symptoms (+)
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PATOPHYSIOLOGY
T3 metabolic process Hypothermic, hypercholesterolemia Accumulation of glycosaminoglycans Edema : skin, muscles heart muscle contractility, Cardiomegaly, pericardial effusion, Stroke volume / COP Reproduction : Anovulation, irregular cycles, infertility
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THYROID

rT3
T3 T4 T4

T4
rT3 T3 T4
MATERNAL TISSUES

T4

TR
T3

T3

T3

TR

TR

TR

MOTHER

PLACENTA

FETUS

Possible sites of action of maternal thyroid hormone during early pregnancy. (Pickard et al, 2002)

Iodine is the essential element for thyroid hormones, thyroid hormone is indispensable for every living cells, thyroid hormone is a must for DNA synthesis

Maternal circulation

Fatal circulation

THYROID
Pituitary/Chorionic TSH controlled T4 synthesis and release

T4

Chorionic TSH free T4

TBG bound T4

FETUS
T4 deiodination and metabolism

T4 ? ?

free T4
TBG LIVER
Estrogen/fT4 controlled TBG synthesis and release

Estrogen

Feedback control of T4 delivery

PLACENTA
TBG/T4 controlled T4 deiodination and transport, and chorionic TSH secretion

Hypothetical control system governing fetal exposure to maternal T4 during pregnancy

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DIAGNOSIS
Importance of Etiologic Diagnosis
1. The hypo may be transient 2. The hypo may be reversible by alleviating responsible drugs 3. The hypo may be the first and the only manifestation of hypothalamopituitary disorders
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DIAGNOSIS
I. CLINICAL SUSPICION
1. Symptoms, signs, Lab. 2. Deficiencies, exposures, diseases 3. Diseases ~ chronic autoim. thyroiditis

II. CONFIRMATIVE EXAM

1. T4 (FT4) , Normal FT4 : 0.8-2.8 ng/dl 2. TSH (Primary Hypo), Normal : 0.4-4 mu/l
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Severe primary hypothyroidism

A: A patient with unrecognised severe primary hypothyroidism who became severely obtunded after surgery for fractured neck of femur. Marked myxoedema is evident. B: Several months later, after therapy including thyroid hormone replacement.
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DIAGNOSIS
SUSPICION
SYMPTOMS SIGNS LAB, ETC

Weakness, fatique, Cold intolerance, Weight , constip., Hoarseness, Menorraghia, Depression

Dry skin Bradycardia Prolonged relaxation time of tendon reflex

Hypercholest. Hyponatremia Pericard Effusion Myocardial contractility

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CLINICAL SUSPICION
T4 (FT4), TSH
T4 , TSH
Primary hypo

T4 N, TSH
Sub clinical hypo

T4 , TSH
Central hypo TRH Test

T4 N, TSH N
Normal

T4 , TSH Primary hypo

T4 , TSH Tertiary hypo

Resp. (-) Secondary hypo

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Figure 1. Algorithm Diagnosis of Hypothyroidism

DIAGNOSIS
I. IODINE DEFICIENCY
1. Radioactive iodine uptake 2. Urinary iodine excretion 3. TSH

II. CHRONIC AUTOIMMUNE THYROIDITIS

1. T4 , TSH 2. Autoantibody anti TPO
3. Autoantibody anti TG
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DIAGNOSIS

Increased TSH in some central Hypo ~ Immunoreactive (but bioinactive) TSH

Decreased TSH, T4, T3 in severe non thyroidal illness

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TREATMENT
Lifelong levothyroxine (T4) except in : transient Hypo reversible Hypo Goal : Clinical euthyroidism, Normal T4 and TSH Levothyroxine : - Half life 7 days once daily dosage - dosage : - Substitution (adult) : 1.6 mcg/BW/day x 100 mcg/day (range 50-200 mcg/day) Evaluation / Adjustment : T4 & TSH 3-6 wkly
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TREATMENT
DOSAGE VARIATION
Lower High : Hashimoto, post radioiodine : Total thyroidectomi, central hypo, severe hypo, BW, pregnancy, estrogen therapy, malabsorption, excretion (nephrotic syndrome), metabolism

Small initial dose : increase gradually : elderly

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TREATMENT
PREGNANCY
Higher dose due to :
1. 2. 3. 4. 5. maternal clearance of T4 T4 transfer to fetus Placental degradation of T4 (deiodinase) TBG ~ estrogen absorption ~ Fe, Calcium
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TREATMENT
ELDERLY / CAD

- Initial dose : - Elderly : 50 mcg/day orally - CAD : 25 mcg/day orally - Increase by 25 mcg/day every 3-6 weeks until normal TSH or arrhytmia
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TREATMENT
SUBCLINICAL HYPO

- T4 to prevent conversion to overt hypo - Especially : - TSH > 10 mu/L - anti TPO - Goiter or non specific symptoms
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TREATMENT
CENTRAL HYPO

- Deficiency of other trophic hormone ?

- ACTH defic Adrenal insuff

- T4 : + Glucocorticoid to prevent adrenal crisis

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TREATMENT
POST TOTAL THYROIDECTOMY
- Higher dose T4 for : 1. Substitution 2. Erradicate metastasis / prevent relaps - Target : TSH < 0,01 mU/L
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TREATMENT
MYXEDEMA COMA
- Aggressive, dose, IV T4
- After blood sample (T4, TSH, Cortisol) - IV T4 : 200-300 mcg 50-100 mcg/day (+ IV T3: 5-20 mcg 2,5-10 mcg/8 hours - IV Hydrocortisone 100 mg/8 hr (2 days) decreased - Supportive : - Mech. Ventilation, O2 - IVFD - Correct : Hypo Na, Hypothermia - Antibiotics
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.for the children.. Every child has the right to an adequate supply of iodine to ensure his (or her) normal developments.

..for the unborn child..

Every mother has the right to an adequate iodine nutrition to ensure her unborn child experiences normal mental development

Declarations from: Convention on the Rights of the Child, UN Assembly, New York 1989, World Summit for Children, UN New York 1990, The Survival, Protection and Development of Children , World Conference on Micronutrients: Eliminating the Hidden Hunger, Montreal 1991 (Unicef, FAO,WHO, ICCIDD), World Conference on Nutrition, Rome 1992 WHO, FAO
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SUMMARY
Hypothyroidism ~ TH deficiency ~HypothalamoPituitary-Thyroid Axis Disorders Most common etiology : Primary Hypo Iodine deficiency, Hashimoto thyroiditis Patophysiology : metabolic process and glycosaminoglycans accumulation Diagnosis Therapy Prognosis : Clinical + T4 + TSH : Levothyroxine (T4) : reversible (T4) poor in myxedema coma
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