HYPOTHYROIDISM

A.Vikas1

CONTENT

1.ANATOMY

2.PHYSIOLOGY

3.PATHOLOGY

4.MANAGEMENT

2

ANATOMY3

GREEK :- THYREOS – SHIELD ; EIDOS – FORM

1.LOCATION:- Anterior to trachea in between the cricoid cartilage

and the suprasternal notch.

2.SHAPE:- It has 2 lobes connected with an isthmus, each lobe in

turn has two poles.

3.Weighs around 10-20 gm, highly vascular and soft in consistency.

4. 4 Parathyroid glands which secrete PTH are located posterior to

each pole of thyroid.

4

5

The RLN traverse

the lateral border of

thyroid gland and

must be identified

during thyroid

surgery to avoid

injury and vocal

cord paralysis.

CLINICAL IMPORTANCE6

EMBRYOLOGY

Develops from the floor of primitive pharynx during the 3rd week

of gestation.

Fetal cells in which developmental transcription factors

TTF-1,TTF-2 & PAX-8 are expressed selectively form the thyroid

gland ,secondly they result in induction of thyroid specific genes

Tg,TPO,NIS,TSH-R.

Mutations-THYROID AGENESIS &

DYSHORMONOGENESIS(CONG. HYPOTHYROIDISM).

7

The developing gland migrates along the thyroglossal

duct to reach its final location in the neck.

LINGUAL THYROID AND THYROGLOSSAL DUCT

CYST.

Thyroid hormone synthesis begins at about 11 weeks of

gestation.

8

So till the fetal thyroid gland

begins to function who has to

provide it with thyroid

hormones??

9

MATERNAL THYROID HOMONES10

Until 11 week of gestation and even later, it is the maternal

thyroid hormones which cross the placenta to reach the fetus

and aid its development.

Therefore a child born to a hypothyroid mother would suffer

from features of congenital hypothyroidism.

Secondly if the mother has TSH-R blocking antibodies or has

received anti thyroid therapy during pregnancy, might lead to

transient congenital hypothyroidism.

11

PHYSIOLOGYStructural and functional units – THYROID FOLICLES.

The follicles are made up of polarized cuboidal epithelial cells

which synthesise and secrete thyroid hormones.

Apart from these the thyroid also harbors the neural crest

derivatives – C cells / Para follicular cells responsible for

CALCITONIN production(minimal role in Ca homeostasis in

humans but r imp coz of their involvement in medullary thyroid

carcinoma).

12

Synthesis of Thyroid hormones

13

14

Short term stimulation by TSH results in

phosphorylation of various :-

1.Transcription factors

2.Enzymes

3.Transport proteins

Which would result in increased function of the gland.

Long term stimulation(Grave’s) results in production

of special transcription factors which stimulate the

genome and not only results in increased function but

also results in hypertrophy and hyperplasia resulting

in goiter formation.

15

16

17

18

19

Clinical importance

PENDRED SYNDROME :-

1.Defective organification of iodine.

2.Goiter.

3.Sensorineural deafness.

LOW T3 SYNDROME :- In catabolic stressful conditions

like starvation, trauma & surgery, body tries to prevent

further catabolism due to T3 by inhibiting 5’ deiodenase

{Pt’s serum :- ↓ T3, Normal T4 & TSH levels}

20

After synthesis upon stimulation by TSH the hormones are

secreted into circulation.

↓

90-93% T4 , 7-10% T3.

↓

T4 compared to T3 has high affinity towards TBG , TBPA & TBA,

and about 99% of secreted hormones bind to these proteins.

↓

<1% of T3 & T4 is in free form.

21

T4 – STORAGE

FORM.

T3 – ACTIVE

FORM.

22

HPT AXIS

It is the

circulating T4

levels which

regulate the TSH

secretion and not

the T3 levels.

23

Mechanism of action of T3

24

Transcription of many genes.25

FUNCTIONS OF THYROID

HORMONE.

26

↑BMR

Physical growth

&

Mental

maturation

Keeps tissues

sensitive to

adrenergic drive.

27

↑ BMR

PROTEINS

FUNCTIONAL STRUCTURAL REGULATORY

↓Mitochondrial

enzymes

↓Physical and

mental growth

↓Transport proteins

Eg :- Na/K ATPase

LDL receptors

T3 & T4 act on all

cells in the body to

↑BMR except on :-

CNS,Retina,L.N,

Spleen & gonads.

28

Physical and mental growth

Thyroid hormones directly as well indirectly by

increasing the synthesis & production of GH & PTH

enhance the bone development.

T3 & T4 are essential for development of :-

1.Dendrites

2.Synapses

3.Myelination

29

Effect on specific bodily mechanisms by

enhancing expression of adrenergic receptors.

On GIT :- Increases acid secretion, digestion and

absorption of glucose and also enhances GI motility.

On liver :- 1.Enhances β receptor mediated glycogenolysis

& gluconeogenesis.

2.Increases expression of LDL receptors on the surface of

hepatocytes thereby increasing its uptake & resulting in

low blood cholesterol levels.

30

On Adipocytes :- Enhances β3 mediated lipolysis thereby

increasing FFA concentration in the blood, which is

utilised by actively metabolising cells for β oxidation and

by liver for gluconeogenesis.

On Pancreas :- Enhances insulin secretion.

On heart :- Increases expression of β receptors, myosin

proteins & Ca ATPases, thereby increasing HR &

myocardial contractility(↑SBP , ↓DBP ).

On lungs :- ↑(RR & TV) = ↑Minute ventilation.

31

On CNS :- T3 & T4 increase the expression of

adrenergic receptors & alter the NT activity, thus

maintain the normal CNS function.

On Gonads :- Maintain libido and fertility in both males

and females.

32

ORGAN/

STRUCTUREHYPERTHYROIDISM HYPOTHYROIDISM

HAIR THIN THICK & UNMANAGABLE

CNS ALERT,ANXIOUS,

INSOMNIA, PARANOID.

MR,Lack of conc.,

DEPRESSED, SOMNOLANCE.

EYES EXOPHTHALMOS,LID

LAG.

PERIORBITAL

PUFFINESS.

SKIN WARM,SWEATY THICK,SCALY,COLD –

GEN. MYXEDEMA WITH

YELLOWISH TINGE.

VOICE ANXIOUS,SHRILL HOARSENESS

R.S TACHYPNEA BRADYPNEA

33

CVS TACHYCARDIA ,TACHY

ARRYTHMIA,HIGH

OUTPUT CARDIAC

FAILURE

BRADYCARDIA,

BRADYARRYTHMIA,

LOW OUTPUT

CARDIAC FAILURE

S.CHOLESTEROL HYPO

CHOLESTEROLEMIA

HYPER

CHOLESTEROLEMIA

WHICH RESULTS IN

ACCELERATED

PHASES OF

ATHEROSCLEROSIS

GIT INCREASED APPETIE,

INCREASED BOWEL

MOVEMENTS &

WEIGHT LOSS

DECREASED

APPETITE,

CONSTIPATION,

WEIGHT GAIN

34

MALE GENITAL

SYSTEM

LOSS OF LIBIDO &

INFERTILITY

LOSS OF LIBIDO,

IMPOTENCE &

INFERTILITY.

FEMALE

GENITAL

SYSTEM

OLIGOMENRRHOEA

INFERTILITY

MENORRHAGIA,

POLYMENORRHOEA

& INFERTILITY

35

Presence of goiter does not reveal the

function status of thyroid gland i.e it can be

present in :-

1.Hyperthyroid state

2.Euthyroid state

3.Hypothyroid state

36

37

38

CAUSES OF HYPOTHYROIDISM

PRIMARY :- When the pathology lies in the gland itself.

1.Congenital :- Agenesis (mutations in TTF-1&2,PAX-8).

Dyshormonogenesis(Tg,TPO,NIS,TSH-R).

Ectopic thyroid gland.

2.Iodine deficiency

3.Autoimmune :- Hashimoto’s thyroiditis

4.Iatrogenic :- 131 I treatment, subtotal/total thyroidectomy.

39

5. DRUGS :- Iodine excess(wolf chaikoff effect),

anti thyroid drugs , Li.

6. Infiltrative disorders :- Amyloidosis, Sarcoidosis &

Scleroderma.

Iodine deficiency remains the most common cause of

hypothyroidism worldwide.

In areas of iodine sufficiency Hashimoto’s thyroiditis &

iatrogenic causes are most common.

40

SECONDARY / CENTRAL :-

When the pathology lies in the ant. pitutary or hypothalamus.

1.HYPOPTIUTARISM :- Tumors, Surgery/Irradiation, infiltrative

disorders, trauma, Sheehan’s syndrome.

Sheehan’s syndrome :- aka Simmond’s syndrome/ postpartum

hypopituitarism.

Mech :- Blood loss / hypovolemic shock during or after child birth

↓

Decreased blood supply to pituitary leading to its ischemic necrosis.

41

2. HYPOTHALAMIC DISEASE :- Tumors,

Trauma, Infiltrative disorders.

Isolated TSH deficiency / inactivity.

42

Hashimoto’s thyroiditis

Definiton :- Autoimmune destruction of thyroid gland & gradual

& progressive thyroid failure.

Classification :-

1.Hashimoto’s / goitrous thyroiditis – Initial stage where there is

a phase of compensation when normal thyroid hormone levels

are maintained by a rise in TSH(Sub clinical hypothyroidism).

2.Atrophic thyroiditis :- Late stages with minimal residual

thyroid tissue(↓Unbound T4, ↑↑TSH, symptoms become more

apparent – Clinical / Overt Hypothyroidism).

43

Pathogenesis

Caused by a breakdown in self tolerance to thyroid

autoantigens.

Ass. with polymorphisms in immune regulation associated

genes :- HLA DR-3,4,5;CTLA-4;

Mech of thyroid destruction :-

1.CD8+ cytotoxic T cell mediated cell death.

2.Cytokine(INF-γ) mediated cell death.

3.Antibody dependent cell mediated cytotoxicity.

44

45

Laboratory Evaluation

1.Primary Hypothyroidism :- ↓Unbound T4;↑TSH; ↑TRH.

Along with these in Hashimoto’s :- Tg & TPO antibodies can

be elicited(FNAC can be done to demonstrate Hurthle cells in

conjugation with heterogenous group of lymphocytes

characteristic of hashimoto’s).

2.Secondary / Central Hypothyroidism :-

Hypopitutarism :- ↓Unbound T4; ↓ TSH; ↑TRH.

Hypothalamic cause :-↓Unbound T4; ↓ TSH; ↓ TRH.

46

Differential diagnosis :-

An assymetric goiter in hashimoto’s may be confused with a

MNG/ thyroid carcinoma, in which thyroid antibodies may

also be present.

In such cases USG can be done:-

1.In MNG – multiple nodules can be appreciated

2.In thyroid carcinoma – solitary lesion.

3.Hashimoto’s – Heterogenous thyroid enlargement.

47

48

TREATMENT

The treatment goal in hypothyroidism is to achieve normal TSH

levels which are elevated.

1.Pt’s with no residual thyroid function :- Daily replacement

dose of levothyroxine(1.6 μg/kg = 100-150μg) ideally taken at

least 30 min before breakfast.

2.Pt’s who develop hypothyroidism after treatment of Grave’s :-

Due to underlying autonomous function they require lower

replacement doses (75-125μg).

49

3.Adult patients <60 yr without evidence of heart disease :-

Started on 50-100 μg levothyroxine daily.

2 months after treatment depending on TSH levels

adjustment of levothyroxine dosage is made in 12.5 or 25 μg

increment if TSH is high & decrement if TSH is suppressed.

NOTE :- Elevated TSH levels inspite of appropriate

medication indicates Pt’s poor adherence to treatment.

50

4.Subclinical hypothyroidism :- Biochemical evidence

of thyroid hormone deficiency in Pt’s who have few or

no apparent C/F.

Treatment is considered if Pt is a female who wishes to

conceive/ is pregnant /TSH >10mIU/L(over 3 month

period) or <10mIU/L with TPO+/suggestive symptoms.

Low dose levothyroxine(25-50 μg/day)with goal of

normalising TSH.

51

5. Maternal Hypothyroidism :- It requires early

detection & effective treatment as it can adversely affect

fetal neural development & cause premature delivery.

The levothyroxine dose may need to be increased by up

to 50% during pregnancy with a goal of TSH< 2.5

mIU/L during the 1 trimester & <3 mIU/L during 2 & 3

trimester.

52

It is a severe form of hypothyroidism leading to reduced level of

consciousness, may be ass. with seizures and hypothermia(23˚C).

It is a medical emergency.

Treatment includes :-

1.Loading dose – Single IV bolus of 500μg levothyroxine

2.Maintenance dose :- 50-100 μg/day

Supportive therapy to correct ass. Metabolic disturbances.

External warming if temp <30˚ or else can result in cardiovascular

collapse,parenteral hydrocortisone(50mg/6 hrly) as there is impaired

adrenal reserve.

MYXEDEMA COMA53

REFERENCES

1.HARRISON’S PRINCIPLE OF INTERNAL MEDICINE.

2.ROBBINS PATHOLOGY.

54

55