The document summarizes key aspects of thyroid gland physiology and hypothyroidism. It describes the development and function of the thyroid gland, thyroid function tests, causes and clinical features of primary and secondary hypothyroidism. It provides details on autoimmune hypothyroidism including pathogenesis, genetics and clinical manifestations. It also discusses congenital hypothyroidism, Hashimoto's encephalopathy and myxedema coma.

2. PHYSIOLOGY OF THYROID GLAND
• Development: from thyroglossal duct
develops from 3rd week
produce hormone by 11 weeks
• Follicular cells - thyroid hormone
• C cells - calcitonin
• transcroption factors in development : TTF-1,2 , NKX-1,
PAX-8

4. (I-Cl exchenger)
TPO
MIT,DIT --------> T4,T3,rT3

5. • Thyroid hormon enters the cell by passive diffusion &
binds with nuclear receptors
• TR-α : brain, kidneys, heart, gonads, muscles
• TR-β : pitutary, hypothalamus, liver
• T3 binds more avidly with receptors

6. Thyroid Function Tests
1. S.TSH
– normal range : 0.4-5 mIU/L
– most sensitive test for primary hypothyroidism &
hyperthyroidism
2. SerumT4 & T3
–total = bound + free
– Total T4 = 60-145 nmol/L
– Total T3 = 1.1-3 nmol/L

7. 3. FT3, FT4
– 99.98% of T4 is protein bound
– factors which affect proteins (pregnancy, illness, medications)
will alter the total T4&T3 but free hormones levels remain the
same

8. TSH FT4 T3(total)
Euthyroid (N) (N) (N)
primary hypothyroidism ↑ ↓ ↓ / (N)
central hypothyroidism (N) / ↓ ↓ ↓
subclinical hypothyroidism ↑ (N) (N)
primary hyperethyroidism ↓ ↑ ↑
central hyperthyroidism ↑ ↑ ↑
subclinical hyperthyroidism ↓ (N) (N)
euthyroid hyperthyroxinemia (N) ↑ ↑
Euthyroid hypopthyroxinemia (N) ↓ ↓

9. HYPOTHYROIDISM
CAUSES
I. Primary: (TSH ↑ , FT4 ↓)
1. Autoimmune - Hashimotos thyroiditis (most common), atrophic thyroiditis
2. Iodine deficiency, selenium deficiency
3. Drugs- Iodine excess, Li, Amiodarone, antithyroid drugs, Tyrosine kinase
inhibitors
4. Iatrogenic- thyroidectomy, radiation to neck
5. Congenital hypothyroidism - dysgenesis or agenesis of thyroid gland,
dyshormonogenesis, TSH-R mutation
6. Infiltration - amyloidisis, sarcoidosis, hemochromatosis, scleroderma,
Reidels thyroiditis

10. II. Secondary: (TSH ↓ , FT4 ↓)
1. Hypopitutarism - tumors, surgery, irradiation, sheehans,
trauma, infiltration, genetic forms of combined pitutary
hormone deficiencies
2. Isolated TSH deficiency or inactivity
3. Bexarotene treatment
4. Hypothalamic diseases - tumors, trauma, infiltration,
idiopathic

11. III. Transient
1. Silent thyroiditis (eg- postpartum)
2. subacute thyroiditis
3. Withdrawal of supraphysiologic thyroxine treatment
4. After I131 treatment or thyroidectomy (subtotal) for graves
disease

12. CONGENITAL HYPOTHYROIDISM
• Most common preventable cause of mental retardation
• Prevalance - 1 in 2000-4000 newborns
• Causes- Thyroid gland dysgenesis (65%)
Inborn errors of thyroid hormone synthesis (30%)
TSH-R antibody mediated (5%)

13. Eitiology
i. Thyroid dysgenesis
mutation of TTF 1,2
PAX 8
NKX2-1,2
JAG-1
trisomy 21 (Downs syndrome)

14. ii. Disorders of thyroid hormone synthesis
AR
Mutation of Na/I symporter (SLC5A5 gene)
Mutation of Pendrin gene (SLC26A4 gene)
Defects in TPO activity
Production of abnormal thyroglobulin (TG gene)
Deiodinase deficiency (IYD gene)

15. iii. Defects in thyroid hormone transporter
mutation of MCT 8 gene (X linked)
Allan-Dudley syndrome
iii. Defects in thyroid hormone metabolism
mutation in the gene for selenocysteine insertion sequence
iv. Defects in thyroid hormone action
mutation in TH Receptor β gene - resistance to thyroid hormone

16. v. Central hypothyroidism
due to pitutary or hypothalamic dysfunction
mutation of IGSF-1 gene
vi. Transient congenital hypothyroidism
 mc cause- Iodine deficiency
gestational iodine excessive exposure ( eg-amiodarone
treatment)
Transplacental tranfer of TSH receptor blocking Ab
Maternal antithyroid drugs

17. CLINICAL FEATURES
 Lethargy, hoarse cry
 feeding problems, jaundice
 constipation
 hypotonia
 umbilical hernia
 enlarged tongue
 delayed bone maturation
 Dry skin, hypothermia
 puffy face

18. DIAGNOSIS & TREATMENT
• Neonatal screening program
• measurement of TSH or T4 levels in heel-prick blood
specimen
• once confirmed, T4 given at a dose of 10-15mcg/kg/day
• dose adjusted by monitoring TSH levels
• if transient hypothyroidism is suspected or diagnosis is
unclear, treatment can be stopped after 3yrs of age
followed by further evaluation

19. AUTOIMMUNE HYPOTHYROIDISM
• Most common cause in iodine sufficient areas
• 4 per 1000 women
• 1 per 1000 men
• mean age of diagnosis - 60yrs
• subclinical hypothyroidism- 6-8% women, 3% men
• Annual risk of developing clinical hypothyroidism is 4% if
anti TPO is +ve

20. 1. Hashimotos Thyroiditis - may be associated with goitre
2. Atrophic thyroiditis - minimal residual thyroid tissue
• Subclinical hypothyroidism - because autoimmune process
gradually reduces thyroid function, there is a phase of
compensation when normal thyroid hormone levels are
maintained by an increase in TSH
• Clinical/Overt Hypothyroidism - later unbound T4 levels fall and
TSH rises further, symptoms become more apparent, TSH > 10
mIU/L

21. PATHOGENESIS
• Lymphocytic infiltration of thyroid gland with germinal
centre formation
• Atrophy of thyroid follicles
• oxyphilic metaplasia
• absence of colloid
• mild to mod fibrosis
• In atrophic thyroiditis- marked fibrosis, less lymphocytic
infiltration, thyroid follicles completely absent

22. GENETICS
• HLA DR polymorphism
• CTLA 4 polymorphism
• shared by other autoimmune conditions like T1DM,
addisons disease, pernicious anemia, vitiligo
• Female preponderance is due to sex steroid effects on
immune response, but an X chromosome related genetic
factor is also possible

23. • Lymphocytic infiltrates contain both T & B cells
• Thyroid cell destruction - primarily mediated by CD8+
cytotoxic T cells
• Role of T cells :
1. Ab production ( helper T cells help B cells to produce Ab)
2. Apoptosis by CD8+ killer T cells
3. Release of cytokines - IL8, IFNꝨ, TNF

24. • Role of B cells
1. Anti TPO Ab & anti TG Ab - IgG type, crosses placenta
2. Ab to TSH rec. (TSH blocking Ab) - IgG, crosses placenta
• These antibodies can fix complement resulting in
complement dependent Ab mediated cell death

25. • Precipitating factors:
– Infection
– stress
– iodine intake
– radiation
– pregnancy

26. CLINICAL FEATURES
• Symptoms
Tiredness and weakness
Dry skin
feeling cold
Hair loss
difficulty in concentrating
and poor memory
constipation
wt gain with poor appetite
dyspnea
 hoarse voice
 menorrhagia (later
oligomenorrhea or
amenohhea)
 paresthesia
 impaired hearing

27. • SIGNS
Dry coarse skin, cold peripheries
puffy face, hands, feet (myxedema)
diffuse alopecia
bradycardia
peripheral edema
delayed tendon reflex relaxation
CTS
serous cavity effusion

28. • Skin
cold and pale ( blood flow is diverted from skin)
↓sweating (↓calorigenesis)
skin pigmentation - yellow (carotinemia)
hyperpigmentation (assoc with adrenal failure)
vitiligo, alopecia
non-pitting edema/Myxedema - ↑dermal glycosaminoglycan
content

29. • Eyes
periorbital edema
thinning of outer 1/3 of eyebrows
pallor
• Hematological
NCNC anemia
megaloblastic/pernicious anemia (10%)
Acquired vWD type 1
Fe def anemia (sec to menorrhagia)

30. • CVS
↓CO, ↓HR - SOB and ↓ exercise capacity
heart failure
pericardial effusion
Hypertension (diastolic)
• Resp. system
hypoventilation - due to resp muscle weakness
sleep apnea due to macroglossia

31. • GIT
Constipation (↓gut motility)
↓taste
celiac disease
gastric atrophy - pernicious anemia
• Reproductive
menorrhagia ---> oligomenorrhea
↓ fertility
↓ libido in both sexes, erectile dysfunction
Hyperprolactinemia

32. • Musculoskeletal
weakness, cramps, myalgia
hyperuricemia & gout
• Nervous system
both CNS and PNS
partially or fully responsive to treatment

33. • HASHIMOTO ENCEPHALOPATHY
– Subacute onset of confusion with altered level of conciousness,
seizures & myoclonus
– immune mediated (rather than direct effect)
– aka Steroid Responsive Encephalopathy associated with AI
Thyroiditis ( SREAT) or non-vasculitic Autoimmune
meningoencephalitis
– pathophysiology: unknown mechanism; not directly related to
hypo or hyper trhyroidism; most patients are euthyroid at
presentation

34. • due to:
1. direct Ab mediated neuronal injury
2. vasculitis or immune complex deposition
3. ADEM like disease
4. Lymphocytic infiltration
• M>F
• steroid responsive
• mean age - 40 yrs

35. • clinical features:
– acute or subacute onset of confusion
– altered level of conciousness
– 2 patterns of presentation
1. Stroke like - multiple, recurrent episodes of FND
2. Slowly progressive cognitive impairment with confusion, dementia
– others: GTCS, myoclonus, psychosis, diffuse hyperreflexia,
pyramidal signs
– PNS- sensory gangliopathy, demyelinating polyneuropathy

36. • Investigations
1. ↑anti TPO Ab, ↑anti TG Ab in serum (sometimes in CSF),
level of Ab will not cortelate with severity of encephalopathy
2. TFT : subclinical hypothyroidism, overt hypopthyroidism,
hyperthyroidism(7%)
3. CSF : ↑protein. lymphocytic pleocytosis, glucose (N), ↑14-3-3
protein
4. EEG : non specific changes, slowing of background activity
5. MRI : usually (N), sometimes cerebral atrophy & subcortical
white matter changes
6. others: ↑CRP, ESR

37. • Treatment
1. Steroids - oral prednisolone 50-150mg OD
iv methyl pred
tappered acc to clinicval response (over monthly,
sometimes 2yrs)
2. Immunosuppresants - those who cannot tolerate steroids or
relapse after steroids (Azathioprine, Cyclophosphamide)
3. IvIg, PLEX (rarely)
4. antiepileptics

38. MYXEDEMA COMA
• Medical emergency
• severe hypothyroidism leading to decreased mental
status, hypothermia and other symptoms related to
slowing of function in multiple organs
• Risk factors:
– severe long standing hypothyroidism ppted by
– infection
– MI
– cold exposure
– sedatives, hypnotics, opioids

39. Clinical features
• altered mental status, confusion, obtundation, GTCS/focal
seizures
• hypotension, bradycardia, puffiness of face and hands,
swollen lips, thickened nose, enlarged tongue
(myxedema)
• Hyponatremia - due to SIADH
• Hypothermia- due to ↓metabolism resulting in
↓thermogenesis

40. • Hypoventilation - depression of resp drive, resp muscle
weakness - leads to CO2 retention and acidosis
• Hypoglycemia - due to assoc adrenal insufficiency or due
to ↓gluconeogenesis

41. Treatment
• draw sample for TSH, T4 & cortisol
• Levothyroxine 200-400 mcg iv stat f/b daily 50-100mcg
• T3 5-20 mcg iv f/b 2.5-10 mcg Q8H
• change to oral L-thyroxine (oral dose=iv/0.75)
• Inj Hydrocortisone till adrenal insuifficiency is ruled out
• supportive treatment

43. TREATMENT OF CLINICAL HYPOTHYROIDISM
• Daily replacement dose of LT4 - 1.6mcg/kg/day taken half hour
before breakfast
• Adult pts <60yrs without heart d/s may be started on 50-100 mcg
daily
• dose is adjusted acc to TSH levels, goal of Rx being normal TSH
(ideally in the lower half of reference range)
• TSH response is gradual, should be measured about 2 months
after initiating treatment or after subsequent change in dose
• Pts may not experience full relief from symptoms until 3-6 months
after normal TSH levels are restored’
• Adjustments are made in 12.5 or 25 mcg

44. • Once full replacement is achieved and TSH levels stable,
followup TSH is recommended at annual intervals
• If a dose is missed, advice to take 2 doses of the skipped
tablet at once (T4 has half life of 7 days)
• Pt taking ≥ 200mcg with high TSH is often a sign of poor
adherence to treatment

46. • Subclinical hypothyroidism
– treatment recommended if pt is a woman who wishes to
conceive or is pregnant or when TSH>10
– most pts can be monitored annually
– trial of treatment given when young or middle aged pts
have symptoms or risk of heart disease or antiTPO +ve
– start with low dose of LT4 (25-50mcg/d) with goal of
normalising TSH

47. Pregnancy
• Hypothyroidism- ↑fetal miscarriages and neural
developmental disorders
• prior to conception, TSH should be b/w 0.3-2.5 in
hypothyroid pts
• Tsh should be measured monthly during 1st half of
pregnancy; less freq testing after 20 wks
• ↑dose by 45% (9 doses per week)
• should not combine LT4 with Fe&Ca tablets

48. HYPERTHYROIDISM
• Thyrotoxicosis : state of thyroid hormone excess
• Hyperthyroidism : result of excessive thyroid function (
clinical features present)

49. Causes
A. Primary Hyperthyroidism
– Graves disease
– Toxic MNG
– Toxic adenoma
– Functioning thyroid carcinoma metastasis
– Activating mutation of TSH receptor
– Activating mutn of Gs α (McCune-Albrighty syndrome)
– Struma ovarii
– Drugs: iodine excess(Jod-Basedow phenomenon)

50. B. Thyrotoxicosis without hyperthyroidism
– Subacute thyroiditis
– silent thyroiditis
– other causers of thyroid destruction: amiodarone, radiation,
infarction of adenoma
– Thyrotoxicosis factitia (ingestion of excess thyroid hormone)

51. C. Secondary Hyperthyroidism
– TSH-secreting pitutary adenoma
– Thyroid hormone resistance syndrome
– Chorionic gonadotropin secreting tumors
– gestational thyrotoxicosis

52. GRAVES DISEASE
• 60-80% of thyrotoxicosis
• F>M
• age : 20-50yrs; rarely begins before adolescence

53. Pathogenesis
• Autoantibody mediated - Thyroid stimulating
immunoglobulins (TSIs) - synthesized by lymphocytes in
thyroid gland as well as in bone marrow and lymph nodes
• Presence of TRAb in a pt with thyrotoxicosis implies the
existance of TSI
• Thyroid gland is diffusely enlarged
• Histology - (i) follicular hyperplasia
(ii) Intracellular colloid
(iii) cell scalloping
(iv) multifocal lymphocytic infiltration

54. TRAb (produced by B cells)
stimulating
Graves
Disease
Inhibitory
Hypotrhyroidism
(10% of Hashimotos)
Neutral
responsible for
thyroid cell
apoptsis
• Anti TPO and Anti TG Ab occur in upto 80% of cases
• because the coexisting thyroiditis also can affect thyroid function, there is
no direct correlation b/w level of TSI and thyroid hormone levels in
graves disease

55. Clinical Features
• Symptoms
– Hyperactivity, irritability, dysphoria
– Heat intolerance and sweating
– Palpitation
– Fatigue & weakness
– Wt loss with increased appetite
– Diarrhea
– Polyuria
– oligomenorrhea, loss of libido

56. • Signs
– Tachycardia, AF in elderly
– Tremor
– Goitre
– warm, moist skin
– muscle weakness, proximal myopathy
– Lid retraction or lag
– Gynecomastia

57. • Classical triad :
1. Goitre
2. Ophthalmopathy
3. pretibial myxedema

58. Thyroid/Graves Dermopathy
• Infiltrative dermopathy
• infrequent c/f of graves disease
• in 5% of pts with graves disease
• site: pretibial region (ant & lat part of shin),
ankle & dorsum of foot, elbows, knees,
upper back, neck
• rarely can occur without thyroid dysfunction
or sometimes in hashimotos thyroiditis

59. • Pathogenesis: due to accumulation of GAGs (hyaluronic
acid)- sercreated by fibroblasts
• results in mucinous edema, fragmentation of collagen
fibres & deposition of hyaluronic acid in the dermis layer
• O/E- Non-pitting edema
– due to hydrophilic nature of these substances
– due to compression of lymphatics & fragmentation of dermal
collagen
• Ppting factors- trauma, surgery, tobacco use

60. • C/F
– B/L asymmetric, non-pitting edema with few well
demarcatyed papules or nodules
– orange peel appearance
– sometimes painful and prurutic
– may resembnle elephentiasis
– 97% had even before thyroid dysfunction
– Thyroid acropachy - clubbing + osteoarthropathy of
phalanges of foot and hand

61. • Treatmnent
– minimize the risk factors
– compression stockings to improve lymphedema
– medium to high potency steroids under an occlusive dressing
topically or intralesional (if no improvement with topical Rx after
4-12 weeks)
– Physiotherapy
– others: pentoxiphylline, rituximab, IvIg

62. Graves Ophthalmopathy/Orbitopathy
• pathogenesis:
– auto Ab to TSH rec (on thyroid gland, adipocytes, fibroblast)
– activated B&T cells secrete cytokines
– activates the fibroblasts
– release GAGs which get deposited in EOM & retro ocular
tissues
– leads to fluid accumulation & muscle swelling
– ↑orbital pressure --> displace the eyeball forward
• in 20-25% pts

63. • Risk factors
– Genetics - HLA
– sex- F>>>M
– smoking
– Radioiodine Rx for graves disease
– ↑age
– stress

64. • C/F
– FB sensation in the eyes
– ↑tearing
– eye pain
– diplopia/blurring of vision
(when pt looks up and lat)
– Signs: 1. Proptosis
2. Tearing
3. Periorbital edema

65. • Treatment
– spont improvement in mild or mod cases
– Antithyroid drugs
– symptomatic treatment - artificial tears
– upright sleeping procedure, diuretics to ↓ periorbital edema
– optic nerve compression : iv methylpred 500mg once weekly x 6wks
– orbital decompression

67. TREATMENT
1. Hormone synthesis inhibitor
• PTU, Methimazole (active metabolite of carbimazole)
• MOA:
– inhibit TPO
– inhibit iodination of tyrosine
– inhibit coupling reaction
– PTU inhibit conversion of T4 to T3
– Carbimazole ↓ TSH receptor antibody

68. • dose:
– Carbimazole 10-20mg BD or TDS ; maintainance dose of
2.5-10mg
– PTU 100-200mg tds ; maintainance dose of 50-100mg
– lower the dose once euthyroid state in attained
– dose adjusted acc to FT4 (every 6 weeks)
A/E: rash, urticaria, fever
rarely agranulocytosis
hepatitis (PTU)
Cholestasis (carbimazole)
vasculitis, arthalgia

69. 2. Iodides: NaI, KI
• MOA:
– inhibit iodination
– inhibit hormone release
– ↓size and vascularity of gland
• onset of action: within 2-7 days
• Use: thyroid storm, to prepare before surgery
• Eg: Lugol’s iodine - 5% iodine in 10% KI solution; 5-10
drops per day

70. • A/E: swelling of lips, lids
fever
arthralgia
angioedema

71. 3. Radioactive iodine
• administered as Na salt of I131 dissolved in water and
taken orally
• MOA: emits β-particles in colloid-penetrates the thyroid
tissues and cause necrosis f/b fibrosis
• dose: 3-6 mCurie
• Use: graves d/s, toxic MNG
• slow response- starts after 2 weeks & gradually inc
reaching peak at 3 months

72. 4. Beta Blockers
• MOA:
– ↓ signs & symptoms due to sympathetic overactivity (eg:
tremor, palpitation, sweating)
– inhibit peripheral convertion of T4 to T3
• Use:
– while awaiting response to PTU/carbimazole
– thyroid storm
– allong with iodine before surgery

73. 5. Total or near total thyroidectomy
– pts who relapse after antithyroid drugs and prefer this treatment
to radioiodine
– recommended in young individuals particularly when goitre is
very large
– prior to surgery, control of thyrotoxicosis with antithyroid drugs
f/b pottasium iodide - to avoid thyrotoxic crisis & to reduce the
vascularity of the gland
– complications- bleeding, laryngeal edema, hypoparathyroidism,
recurrent laryngeal nerve damage

74. Hyperthyroidism in pregnancy
• overt hypothyroidism is uncommon
• mc- graves disease & hCG mediated hyperthyroidism
• graves d/s becomes less severe due to decreased Ab
levels
• subclinical hyperthyroidism - no adverse outcomes

75. • Indications for treatment
– symptomatic
– overt hyperthyroidism due to graves d/s, toxic mng or adenoma
& due to gestational trophoblastic neoplasm
• Treatment
– T1 - PTU -----> change o methimazole or cont PTU in full
pregnancy
– T2, T3 - methimazole
– monitor TSH & FT4 every 4 weeks
– Radioiodine therapy - absolute C/I
– fetal monitoring to r/o fetal thyrotoxicosis

76. THYROID STORM
• Rare, life threatening condition characterised by severe
c/f of thyrotoxicosis
• RF: ppted by
– surgery
– trauma
– infection
– pregnancy
– Parturition
– A/c iodine load
– discontinuation of antithyroid drugs

77. • Pathogenesis: rapid increase in thyroid hormone levels or
increased response to thyroid hormones
• C/F:
– Tachycardia, heart failure, hypotension, arrhythmia
– hyperpyrexia (104-106̊⁰ F)
– agitation, delirium, psychosis
– stupor or coma
– nausea, vomiting, diarrhea, liver failure
• O/E: warm moist skin, tremor, lid lag

78. • Lab:
– ↓TSH, ↑FT4 & T3
– mild hypercalcemia (bone resorption)
– hypereglycemia (catecholamine induced glycogenolysis &
inhibition of insulin)
– leukocytosis

79. Treatment
1. Beta blocker - control sympt overactivity
40-80 mg Q6h orally
(adjusted acc to HR & BP)
2. Thionamide - to inhibit new hormone syntheisis
200mg Q4H (preferred) or
20mg Q4H or Q6H

80. 3. Iodine solution - to block hormone release
- 10 drops Q8H
(saturated soln of KI) - 5 drops Q6H
4. Glucocorticoids - inhibit T4 to T3 conversion
100mg iv Q8H
5. Bile acid sequestrants - ↓enterohepatic recycling of
thyroid hormones
4mg Q4H

81. • 6. Supportive
– treat ppting factors
– iv fluids
– diuretics in CCF
– antibiotics
– antipyretrics
– PLEX - to remove cytokines & Ab

82. THANK YOU