5. In the Thyroid Gland
There the following 5 steps in the hormonogenesis
Trapping of inorganic Iodine from dietary Iodides
Activation of Iodine to high valance I2
Incorporation of I2 into Tyrosine of Thyroid Globulin
Coupling of formed MIT and DIT to form T4 & T3
Proteolysis of Thyroglobulin to release T4 & T3
5
6. The Thyronines
Mono Iodo Tyrosine – MIT
Di Iodo Tyrosine – DIT
Tri 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 measured
6
Only Free T4 and Free T3 are metabolically active
7. 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 gland
From the thyroid gland
- 80% of hormone secreted is T4
7
- 20% of hormone secreted is T3
8. Throid hormones in peripheral
tissues
• Plasma transport by
thyroxine binding globulin TBG -75 -80%bound
• Transthyretin 10-15%
• Albumin 5-10%
8
12. BASIC THYROID EVALUATION
FREE THYROXINE or FT4
HIGH
NORMAL
EUTHYROID
LOW
LOW NORMAL HIGH
THYROID STIMULATING HORMONE - TSH
12
13. BASIC THYROID EVALUATION
FREE THYROXINE or FT4
HIGH
NORMAL
PRIMARY
LOW
HYPOTHYROID
LOW NORMAL HIGH
THYROID STIMULATING HORMONE - TSH
13
14. BASIC THYROID EVALUATION
FREE THYROXINE or FT4
HIGH
PRIMARY
HYPERTHYROID
NORMAL
LOW
LOW NORMAL HIGH
THYROID STIMULATING HORMONE - TSH
14
15. BASIC THYROID EVALUATION
FREE THYROXINE or FT4
HIGH
NORMAL
SECONDARY
LOW
HYPOTHYROID
LOW NORMAL HIGH
THYROID STIMULATING HORMONE - TSH
15
16. BASIC THYROID EVALUATION
FREE THYROXINE or FT4
HIGH
SECONDARY
HYPERTHYROID
NORMAL
LOW
LOW NORMAL HIGH
THYROID STIMULATING HORMONE - TSH
16
17. BASIC THYROID EVALUATION
FREE THYROXINE or FT4
HIGH
NORMAL
SUB-CLINICAL
HYPERTHYROID
LOW
LOW NORMAL HIGH
THYROID STIMULATING HORMONE - TSH
17
18. BASIC THYROID EVALUATION
FREE THYROXINE or FT4
HIGH
NORMAL
SUB-CLINICAL
HYPOTHYROID
LOW
LOW NORMAL HIGH
THYROID STIMULATING HORMONE - TSH
18
19. BASIC THYROID EVALUATION
FREE THYROXINE or FT4
HIGH
NORMAL
LOW
NON THYROID
ILLNESS or NTI
LOW NORMAL HIGH
THYROID STIMULATING HORMONE - TSH
19
20. BASIC THYROID EVALUATION
FREE THYROXINE or FT4
HIGH
NTI or Pt.
on ELTROXIN
NORMAL
LOW
LOW NORMAL HIGH
THYROID STIMULATING HORMONE - TSH
20
21. BASIC THYROID EVALUATION
FREE THYROXINE or FT4
HIGH
PRIMARY NTI or Pt. SECONDARY
HYPERTHYROID on ELTROXIN HYPERTHYROID
NORMAL
SUB-CLINICAL SUB-CLINICAL
HYPERTHYROID EUTHYROID HYPOTHYROID
SECONDARY NON THYROID PRIMARY
LOW
HYPOTHYROID ILLNESS - NTI HYPOTHYROID
LOW NORMAL HIGH
THYROID STIMULATING HORMONE - TSH
21
22. THYROID HORMONES
TEST REFERENCE RANGE
TSH Normal Range 0.3 - 4.0 mU/L
Free T4 Normal Range 0.7-2.1 ng/dL
TSH upper limit will soon be revised to 2.5 mU/L
22
23. Thyroid Antibodies
• Anti Microsomal (TM ) Antibodies
• Anti Thyroglobulin (TG) Antibodies
• Anti Thyroxine Per Oxidase (TPO) Ab.
• Anti Thyroxine antibodies
• Thyroid Stimulating (TSA) Antibodies
High titres TPO Ab in Hashimotos & Reidle’s thyroiditis
Anti thyroxine Ab in peripheral resistance to Thyroxine
TSA (TSI) in Graves’ Hyperthyroidism 23
25. 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
25
26. Disease Burden
5% of the general population are Sub-clinically
Hypothyroid
15 % of all women > 65 yrs. are hypothyroid
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
All persons aged above 60 years – Order for TSH26
27. • Primary hypothyroidism with Goitre
Aquired
Hashimotos thyroiditis
Iodine deficiency
Drugs blocking synthesis or release of T4
Goitrogens
Cytokines
Thyroid infiltration
Causes of
Congenital
Iodide transport or utilization defect
Hypothyroidism
Iodotyrosine dehalogenase deficiency
TPO deficiencyn nd dysfunction
27
Defects in thyroglobulin synthesis
28. • 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 28
following subacute painless or postpartum thyroiditis
29. • 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 29
• generalised or pituatary dominant
30. Multi system effects - Hypothyroidism
General Neuromuscular
•Lethargy, Somnalence •Aches and pains
•Weight gain, Goitre •Muscle stiffness
•Cold Intolerence •Carpel tunnel syndrome
Cardiovascular •Deafness, Hoarseness
•Bradycardia, Angina •Cerebellar ataxia
•CHF, Pericardial Effusion •Delayed DTR, Myotonia
•HyperlipIdemia, Xanthelsma •Depression, Psychosis
Haematological Gastro-intestinal
Iron def. Anaemia, •Constipation, Ileus, Ascites
Normo cytic /chromic Anaemia Dermatological
Reproductive system •Dry flaky skin and hair
•Infertility, Menorrhagia •Myxoedema, Malar flushes 30
•Impotence, Inc. Prolactin •Vitiligo, Carotenimia, Alopecia
31. 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 31
32. Thyroid Failure - Organ Systems
Cardiovascular
• Decreased ventricular contractility
• Increased diastolic blood pressure
• Decreased heart rate
Central Nervous
• Decreased concentration
• General lack of interest
• Depression
Gastro-instestinal
• Decreased GI motility
• Constipation 32
34. Thyroid Failure - Organ Systems
Reproductive
• Arrest of pubertal development
• Reduced growth velocity
• Menorrhagia, Amenorrhea
• Anovulation, Infertility
Hepatic
• Increased LDL / TC
• Elevated LDL + triglycerides
34
35. 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
35
36. 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 36
• Growthhormone-Decreased D3 activity
43. Hypothyroidism and
Hypercholesterolemia
• 14% of patients with elevated cholesterol
have hypothyroidism
• Approximately 90% of patients with
overt hypothyroidism have increased
cholesterol and / or triglycerides
43
44. Lipids in Patient with Hypothyroidism
Hypercholesterolemia
(>200 mg/dL)
Hypertriglyceridemia
(>150 mg/dL)
Hypercholesterolemia
and mild Hyper TG
N= 268 Normal Lipids
44
45. 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.”
45
50. 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
50
51. Treatment
• Treatment of choice is levothyroxin
• Not recommended for use :
Desiccated thyroid extract
Combination of thyroid hormones
T3 replacement except in Myxedema coma
51
52. Dosage Adjustments
• 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
53. Start Low and Go Slow
• 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
53
54. 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
54
56. Inappropriate Dosage
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
67. The Commandments
Highly suspect hypothyroidism All obese patients TSH a must
Growth and pubertal delay For all pregnant -test TSH, FT4
Unexplained depression Postmenopausal 15% Hypothy
TSH is the test in Hypothy. Start low and go slow
TSH, FT4 to confirm Dx. Use Levothyroxine only
Nine square magic Always on empty stomach
Test cord blood for TSH Thyroxine - avoid empirical use
67