thyroid physiology & hypothyroidism

A CASE PROFILE OF THYROID

DISEASE

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- Dr.Mohammed Siraj

- Dr.Parvez Khan

- Dr.Mohammed Sadiq Azam

- Dr.Praneetha Gayathri

THYROID GLAND HORMONOGENESIS

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Thyroid Regulation

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PLASMA T4 + FT4

HYPOTHALAMUS - TRH

ANT. PITUITARY - TSH

THYROID T4 and T3

PLASMA T3 + FT3

TISSUES FT4 to FT3, rT3

TSH -R

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In the Thyroid Gland

There the following 5 steps in the hormonogenesis

1. Trapping of inorganic Iodine from dietary Iodides

2. Activation of Iodine to high valance I2

3. Incorporation of I2 into Tyrosine of Thyroid Globulin

4. Coupling of formed MIT and DIT to form T4 & T3

5. Proteolysis of Thyroglobulin to release T4 & T35

The Thyronines

Mono Iodo Tyrosine – MIT Di Iodo Tyrosine – DITTri Iodo Thyronine – T3 – half life 6 hours

Tetra Iodo Thyronine – T4 half life 7 days

Reverse T3 - metabolically inactive

T4 is 99.9% protein bound to TBG, TPA, TA

T3 is 99.5% protein bound to TBG, TPA, TA

Bound hormones are inactive – should not be measuredOnly Free T4 and Free T3 are metabolically active

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The Thyroxines

Tri Iodo Thyronine – T3

- 10% is from thyroid gland

- 90% derived from conversion of T4 to T3

Tetra Iodo Thyronine – T4

- Is exclusively from thyroid glandFrom the thyroid gland

- 80% of hormone secreted is T4

- 20% of hormone secreted is T3

Throid hormones in peripheral tissues

• Plasma transport by

thyroxine binding globulin TBG -75 -80%bound

• Transthyretin 10-15%

• Albumin 5-10%

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Thyroid Function Tests

1. TSH

2. Free T4

3. Free T3

4. Anti-Thyroid Antibodies

5. Nuclear Scintigraphy

6. FNAC of nodule10

11 LOW NORMAL HIGH

THYROID STIMULATING HORMONE - TSH

LO

W

N

OR

MA

L

HIG

H

FR

EE

T

HY

RO

XIN

E

or

FT

4

BASIC THYROID EVALUATION

12

LO

W

N

OR

MA

L

HIG

H

FR

EE

T

HY

RO

XIN

E

or

FT

4

EUTHYROID

LOW NORMAL HIGH

THYROID STIMULATING HORMONE - TSH

BASIC THYROID EVALUATION

13

LO

W

N

OR

MA

L

HIG

H

FR

EE

T

HY

RO

XIN

E

or

FT

4

PRIMARYHYPOTHYROID

LOW NORMAL HIGH

THYROID STIMULATING HORMONE - TSH

BASIC THYROID EVALUATION

14

LO

W

N

OR

MA

L

HIG

H

FR

EE

T

HY

RO

XIN

E

or

FT

4 PRIMARYHYPERTHYROID

LOW NORMAL HIGH

THYROID STIMULATING HORMONE - TSH

BASIC THYROID EVALUATION

15

LO

W

N

OR

MA

L

HIG

H

FR

EE

T

HY

RO

XIN

E

or

FT

4

SECONDARYHYPOTHYROID

LOW NORMAL HIGH

THYROID STIMULATING HORMONE - TSH

BASIC THYROID EVALUATION

16

LO

W

N

OR

MA

L

HIG

H

FR

EE

T

HY

RO

XIN

E

or

FT

4

SECONDARYHYPERTHYROID

LOW NORMAL HIGH

THYROID STIMULATING HORMONE - TSH

BASIC THYROID EVALUATION

17

LO

W

N

OR

MA

L

HIG

H

FR

EE

T

HY

RO

XIN

E

or

FT

4

SUB-CLINICALHYPERTHYROID

LOW NORMAL HIGH

THYROID STIMULATING HORMONE - TSH

BASIC THYROID EVALUATION

18

LO

W

N

OR

MA

L

HIG

H

FR

EE

T

HY

RO

XIN

E

or

FT

4

SUB-CLINICALHYPOTHYROID

LOW NORMAL HIGH

THYROID STIMULATING HORMONE - TSH

BASIC THYROID EVALUATION

19

L

OW

N

OR

MA

L

H

IGH

FR

EE

T

HY

RO

XIN

E

or

FT

4

NON THYROIDILLNESS or NTI

LOW NORMAL HIGH

THYROID STIMULATING HORMONE - TSH

BASIC THYROID EVALUATION

20

LO

W

N

OR

MA

L

HIG

H

FR

EE

T

HY

RO

XIN

E

or

FT

4

NTI or Pt.on ELTROXIN

LOW NORMAL HIGH

THYROID STIMULATING HORMONE - TSH

BASIC THYROID EVALUATION

21

LO

W

N

OR

MA

L

HIG

H

FR

EE

T

HY

RO

XIN

E

or

FT

4

EUTHYROIDSUB-CLINICAL

HYPERTHYROID

NON THYROIDILLNESS - NTI

NTI or Pt.on ELTROXIN

SUB-CLINICALHYPOTHYROID

SECONDARYHYPERTHYROID

SECONDARYHYPOTHYROID

PRIMARYHYPERTHYROID

PRIMARYHYPOTHYROID

LOW NORMAL HIGH

THYROID STIMULATING HORMONE - TSH

BASIC THYROID EVALUATION

THYROID HORMONES

TEST REFERENCE RANGE

TSH Normal Range 0.3 - 4.0 mU/L

Free T4 Normal Range 0.7-2.1 ng/dL

22TSH upper limit will soon be revised to 2.5 mU/L

Thyroid Antibodies

• Anti Microsomal (TM ) Antibodies• Anti Thyroglobulin (TG) Antibodies• Anti Thyroxine Per Oxidase (TPO) Ab.• Anti Thyroxine antibodies• Thyroid Stimulating (TSA) Antibodies

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High titres TPO Ab in Hashimotos & Reidle’s thyroiditis Anti thyroxine Ab in peripheral resistance to Thyroxine TSA (TSI) in Graves’ Hyperthyroidism

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hypothyroidism

Hypothyroidism

• Epidemiology• Most common endocrine disease • Females > Males – 8 : 1

• Presentation• Often unsuspected and grossly under diagnosed• 90 % of the cases are Primary Hypothyroidism• Menstrual irregularities, miscarriages, growth retard.• Vague pains, anaemia, lethargy, gain in weight

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Disease Burden

1. 5% of the general population are Sub-clinically Hypothyroid

2. 15 % of all women > 65 yrs. are hypothyroid3. Detecting sub-clinical hypothyroidism in pregnancy

is highly essential – order for TSH and FT4 routinely

in all pregnant women at the beginning of each trimester

4. All persons aged above 60 years – Order for TSH

Causes of Hypothyroidism

• Primary hypothyroidism with Goitre

Aquired

Hashimotos thyroiditis

Iodine deficiency

Drugs blocking synthesis or release of T4

Goitrogens

Cytokines

Thyroid infiltration

Congenital

Iodide transport or utilization defect

Iodotyrosine dehalogenase deficiency

TPO deficiencyn\ nd dysfunction

Defects in thyroglobulin synthesis

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• ATROPHIC HYPOTHYROIDISM

Acquired

HASHIMOTOS DISEASE

Postablative due to 131 Iodine surgery

Congenital

Thyroid agenesis or dysplasia

TSH receptor defects

Thyroidal Gs protein abnormalities

Idiopathic TSH unresponsiveness

TRANSIENT HYPOTHYROIDISM

following subacute painless or postpartum thyroiditis

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• CONSUMPTIVE HYPOTHYROIDISM

• hemangiomas ,hemangioendoheliomas

• CENTRAL HYPOTHYROIDISM

• Acquired

• pituatary origin

• hypothalamic disorders

• dopamine & or severe stress

• Congenital

• TSH deficiency/structural abnormality

• TSH receptor defect

• RESISTANCE TO THYROID HARMONE

• generalised or pituatary dominant

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Multi system effects - Hypothyroidism

General•Lethargy, Somnalence•Weight gain, Goitre•Cold IntolerenceCardiovascular•Bradycardia, Angina•CHF, Pericardial Effusion•HyperlipIdemia, XanthelsmaHaematologicalIron def. Anaemia, Normo cytic /chromic AnaemiaReproductive system•Infertility, Menorrhagia•Impotence, Inc. Prolactin

Neuromuscular•Aches and pains•Muscle stiffness•Carpel tunnel syndrome•Deafness, Hoarseness•Cerebellar ataxia•Delayed DTR, Myotonia•Depression, PsychosisGastro-intestinal•Constipation, Ileus, AscitesDermatological•Dry flaky skin and hair•Myxoedema, Malar flushes•Vitiligo, Carotenimia, Alopecia

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Clinical Signs of Hypothyroidism

Coarse Hair; Dry cool and pale skin

Goitre (not in all cases), Hoarseness of voice

Non-pitting oedema (myxoedema)

Puffiness of eyes and face

Delayed relaxation of DTR

Slow hoarse speech and slow movements

Thinning of lateral 1/3 of eye brows

Bradycardia, pericardial effusion

Thyroid Failure - Organ Systems

Cardiovascular• Decreased ventricular contractility• Increased diastolic blood pressure• Decreased heart rateCentral Nervous• Decreased concentration• General lack of interest• DepressionGastro-instestinal• Decreased GI motility• Constipation 32

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Thyroid Failure - Organ Systems

Musculoskeletal Muscle stiffness, cramps, pain,

weakness, myalgia Slow muscle-stretch reflexes,

muscle enlargement, atrophy

Renal

Fluid retention and oedema

Decreased glomerular filtration

Reproductive

• Arrest of pubertal development• Reduced growth velocity• Menorrhagia, Amenorrhea• Anovulation, InfertilityHepatic

• Increased LDL / TC• Elevated LDL + triglycerides

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Thyroid Failure - Organ Systems

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Thyroid Failure - Organ Systems

Skin and Hair Thickening and dryness of skin Dry, coarse hair, Alopecia Loss of scalp hair and / or

lateral eyebrow hair

HORMONAL EFFECTS ON THYROID FUNCTION

• Glucocorticoid Excess-decreased TSH,TBG,TTR

• Decreased serum T3/T4 and increase Rt3 production

• Decreased T4 and increased T3 in graves disease

• Deficiency-Increased TSH

• Estrogen-Increased TBG sialylation and half life in serum

• Increased TSH in post menopausal women

• Increased T4 requirement in hypothyroid patients

• Androgen-Decreased TBG

• Decreased T4 requirment in hypothyroid patient

• Growthhormone-Decreased D3 activity36

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Cassava Plant

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Topiaco - Sago (Javva Arisi)

Tapioca Root - Sago

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Tapioca (tubers) Dried Tapioca - Sago

Myxedema

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Myxedema

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Co-morbidity

• Hypercholosterolemia• Depression• Infertility – Menstrual Irregularities• Diabetes mellitus

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Hypothyroidism and Hypercholesterolemia

• 14% of patients with elevated cholesterol have hypothyroidism

• Approximately 90% of patients with overt hypothyroidism have increased cholesterol and / or triglycerides

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Lipids in Patient with Hypothyroidism

Hypercholesterolemia(>200 mg/dL)

Hypertriglyceridemia(>150 mg/dL)

Hypercholesterolemia and mild Hyper TG

Normal Lipids

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N= 268

Effect of Thyroxine therapy on Hypercholesterolemia in Patients with mild Thyroid failure

“The decrease in total cholesterol achieved with [Thyroxine replacement] substitution therapy in patients with subclinical hypothyroidism [mild thyroid failure] may be considered as an important decrease in cardiovascular risk favouring treatment.”

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Suspect Hypothyroidism

1. Amenorrhea2. Oligomenorrhea3. Menorrhogia4. Galactorrhea5. Premature ovarian failure6. Infertility7. Decreased libido8. Precocious / delayed puberty9. Chronic urticaria 46

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Algorithm for Hypothyroidism

Measure TSH

Elevated TSH Normal TSH

Measure FT4 Considering Pituitary

Normal Low No Yes

Sub-clinical hypo

TPO + TPO -

T4 repl Annual FU

Primary hypothyroid

TPO + TPO -

No tests Measure FT4

Low Normal

No testsEvaluate PituitarySick EuthyroidDrugs effect

Hashimoto

Others

Hormone replacement

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Treatment

• Goal : Normalize TSH level regardless of cause of hypothyroidism

• Treatment : Once daily dosing with Levothyroxine sodium (1.6µg/kg/day-1.8ug/kg/day)

• Monitor TSH levels at 6 to 8 weeks, after initiation of therapy or dosage change

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• Treatment of choice is levothyroxin

• Not recommended for use :Desiccated thyroid extractCombination of thyroid hormones

T3 replacement except in Myxedema coma

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Treatment

• Age (in elderly start with half dose)

• Severity and duration of hypothyroidism (↑ dose)

• Weight (0.5µg/kg/day ↑ upto 3.0µg/kg/day)

• Malabsorption (requires ↑ dose)

• Concomitant drug therapy (only on empty stomach)

• Pregnancy ( 25% -50%↑ in dose), safe in lactating mother

• Presence of cardiac disease (start alt. day Rx) 52

Dosage Adjustments

• Goal : normalize TSH level – 25, 50 and 100 mcg tablets avail.

• Starting dose for healthy patients < 50 years at 1.0 µg/kg/day

• Starting dose for healthy patients > 50 years should be < 50 µg/day. Dose ↑ by 25 µg, if needed, at 6 to 8 weeks intervals.

• 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

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Start Low and Go Slow

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How the patient improves

Feels better in 2 – 3 weeks

Reduction in weight is the first improvement

Facial puffiness then starts coming down

Skin changes, hair changes take long time to regress

TSH starts showing decrements from the high values

TSH returns to normal eventually

• Malabsorption Syndromes

• Reduced AbsorptionCholestyramine resinSucralfateFerrous sulfateSoybean formulaAluminum hydroxideColestipol hydrochloride

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Drugs that affect metabolismRifampin

Carbamazepine

Phenytoin

Phenobarbitol

Amiodarone

Drug Interactions

Over-replacement risks

• Reduced bone density / osteoporosis

• 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 56

Inappropriate Dosage

57Massive Pericardial Effusion in Hypo

20.2.98

58Clearing of Pericardial Effusion with Rx.

26.7.98

59Reappearance of Pericardial Effusion after treatment is discontinued

14.9.99

FT4 evaluation

• CENTRAL HYPOTHROIDISM

• AFTER SURGERY

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Diet in Iodine deficiency

• Iodized salt• Selenium supplementation• Avoid Cassava• Avoid cabbage (goitrogens)• Avoid formula milk• Fish, meat, milk & eggs

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Special situations

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Myxedema Coma

• Precipitating factors : Infection, trauma, stroke, cardiovascular, hemorrhage drug

overdose, diuretics

• Signs and Symptoms :Mental confusion, hypothermia, bradycardia, older age,↓ Na, ↓ glucose, ↑ CO2, ↓ WBC, ↓ Hct, ↑ CPK↓ EKG voltage, myxedema, b-carotnenemia

• TreatmentInitial IV THYROXINE 500-800 mcg/day ,followed by daily dose of

I.V thyroxine 100 mcg thereafter ,alt I.V leothyronine 25mcg b.d63

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Sick Euthyroid Syndrome

Total T3 reduced FT3 reducedTotal T4 reducedFT4 NormalTSH NormalClinically Euthyroid

Case-1

• T3 -0.04nmo/l 0.93-2.33nmol/lit

• T4-59.70nmol/l 60-120 nmol/lit

• TSH-2.52IU/ml >7.0-hypothyroid

<0.2 hyperthyroid

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Case 2

• T3 -1.42nmol/l

• T4-106.96nmol/l

• TSH-<0.05IU/ml

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The Commandments

Highly suspect hypothyroidism Growth and pubertal delay Unexplained depression TSH is the test in Hypothy. TSH, FT4 to confirm Dx. Nine square magic Test cord blood for TSH

All obese patients TSH a must For all pregnant -test TSH, FT4 Postmenopausal 15% Hypothy Start low and go slow Use Levothyroxine only Always on empty stomach Thyroxine - avoid empirical use

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