Getting to know the thyroid hormone bio chemistry

1. Thyroid hormones
Dept. of Medical Physiology

2. References/Acknowledgement
• Text book of Medical Physiology, 12th Edition by Gyton & Hall
• Arthur C. Guyton and Hall J.E (1973). Textbook of Medical Physiology
by Arthur C Guyton and John E. Hall Publishers Philadelphia: WB
Saunders, 1973
• Jim Holliman, M.D., F.A.C.E.P.[Professor of Military and Emergency
Medicine, Uniformed Services University of the Health Sciences,
Clinical Professor of Emergency Medicine, George Washington
University, Bethesda, Maryland, U.S.A.]
• Lisa Hays, MD [Endocrinology Fellow]

3. THE THYROID GLAND
• OVER TRACHEA
• TWO LARGE LATERAL LOBES CONNECTED BY AN ISTHMUS
• 15 to 20 g
• FUNCTIONAL UNIT IS THE FOLLICLE: EPITHELIAL CELLS AROUND A
HOLLOW VESSICLE FILLED WITH THYROGLOBULIN

4. Figure 45.4
Major endocrine glands:
Hypothalamus
Pineal gland
Pituitary gland
Thyroid gland
Parathyroid glands
(behind thyroid)
Adrenal glands
(atop kidneys)
Pancreas
Ovaries (female)
Testes (male)
Organs containing
endocrine cells:
Thymus
Heart
Liver
Stomach
Kidneys
Small
intestine

6. THE THYROID HORMONES
• THYROGLOBULIN: STORAGE FORM BINDS HORMONES
• TETRAIODOTHYRONINE [Thyroxine] =T4
• TRIIODOTHYRONINE = T3
• IODINE REQUIRED FROM DIETARY INTAKE

7. THYROID HORMONES
o
HO C - C - COOH
B A
I
I
I
I
H
H NH2
H
o
HO C - C - COOH
B A
I I
I
H
H NH2
H
THYROXINE
TRIIODOTHYRONINE

8. Steps in thyroid hormone synthesis
• Iodine trapping (iodide pump):
• Synthesis of thyroglobulin
• Oxidation of iodide
• Iodination (organification) and Coupling
• Proteolysis, deiodination and secretion

9. THYROID HORMONE SYNTHESIS
• DEPENDENT ON IODINE (IODINE PUMP CONCENTRATES IODINE IN
CELLS)
• DEPENDENT ON TYROSINE
• PARTIALLY SYNTHESIZED (THYROGLOBULIN) EXTRACELLULARLY AT
LUMINAL SURFACE OF FOLLICULAR CELLS AND STORED IN
FOLLICULAR LUMEN

10. EFFECTS OF IODINE
• DURING IODINE DEFICIENCY, HORMONE SYNTHESIS IS IMPAIRED
• EXCESS IODINE ALSO INHIBITS SYSNTHESIS

11. THYROID HORMONE SECRETION
• WITH TSH STIMULATION, ENDOCYTOSIS BRINGS THE THYROGLOBIN
BACK INTO FOLLICULAR CELLS
• THYROGLOBULIN IS DEGRADED TO T3 AND T4

12. 99% OF THYROID HORMONE IN THE BLOOD IS BOUND
• THYROXINE-BINDING GLOBULIN (TBG)
• THYROXINE-BINDING PREALBUMIN (TBPA) [TRANSTHYRETIN]
• ALBUMIN
• ABOUT THREE TIMES AS MUCH AS IS SECRETED AND DEGRADED IN
A SINGLE DAY (BUFFER)
• T4 BINDS BETTER THANT3

13. THYROID HORMONE’S EFFECTS
• METABOLIC RATE: INCREASED BMR
• CALOROGENIC: INCREASED HEAT PRODUCTION(OXIDATIVE METABOLISM)
• SYMPATHOMIMETIC: FLIGHT OR FIGHT
• CARDIOVASCULAR:INCREASES RESPONSIVENESS OF HEART
• GROWTH: ESSENTIAL FOR NORMAL GROWTH OF SKELETAL SYSTEM
(PERMISSIVE OR SYNERGYSTIC WITH GH, INSULIN-LIKE GROWTH FACTOR), CNS,
ANS
• NERVOUS SYSTEM:DEVELOPMENT AND ADULT ACTIVITY

14. METABOLIC EFFECTS OF THYROID HORMONE
• CALOROGENIC EFFECT: INFLUENCES TOLERENCE TO COLD,
AVAILABILITY OF ATP
• CARBOHYDRATE METABOLISM: INCREASED GLUCOSE ABSORPTION
FROM GUT,GLYCOGENOLYSIS, GLUCONEOGENESIS, GLUCOSE
OXIDATION.
• LIPID METABOLISM: LIPOGENESIS IN ADIPOCYTES, IN
COORDIMNATION WITH BLOOD GLUCOSE LEVELS

15. CONTROL OF FUEL METABOLISM
• GLYCOGENESIS
• GLYCOGENOLYSIS
• GLUCONEOGENESIS
• PROTEIN SYNTHESIS
• PROTEIN DEGRADATION
• FAT SYNTHESIS
• FAT BREAKDOWN

16. GLYCOGENOLYSIS
• BREAKDOWN OF GLYCOGEN STORES INTO GLUCOSE
• REGULATES BLOOD GLUCOSE BETWEEN MEALS
• HOMONALLY CONTROLLED (GLUCAGON, EPINEHRINE,
NOREPINEPHRINE AND GLUCOCORTICOIDS) AMPLIFIED BY THYROID
HORMONE

17. GLUCONEOGENESIS
• PRECURSORS ARE 3 AND 4 CARBON COMPOUNDS
• VIA FRUCTOSE PHOSPHATE
• GLUCAGON CONTROLLED AIDED BY THYROID HORMONE
• MAIN PRECURSOR ALANINE AND OTHER AA

18. PROTEIN DEGRADATION
• USUALLY BALANCED BY SYNTHESIS
• NO ENERGY STORES IN FORM OF PROTEIN
• CAN BE ENHANCED BY GLUCAGON AND THYROID
HORMONES LEADING TO GLUCONEOGENESIS

19. THYROID HORMONE EFFECTS ON NITROGEN
METABOLISM
• ENHANCES BOTH SYNTHESIS AND DEGRADATION OF PROTEINS
• EXCESS HORMONE PROMOTES DEGREDATION

20. FAT SYNTHESIS
• GLUCOSE - FATTY ACID CYCLE
• FATTY ACIDS PRODUCED CONSTANTLY IN ADIPOSE TISSUE.
• BECOME FFA OR BECOME TRIGLYCERIDES DEPENDING ON -
GLYCEROL PHOSPHATE FROM GLUCOSE OXIDATION
• NEED OPTIMAL AMOUNTS OF THYROID HORMONE

21. THYROID AND TEMPERATURE REGULATION
• T3 IS THE DOMINANT FORM INVOLVED
• EXPOSURE TO COLD CAUSES T4 CONVERSION TO T3 .
• PROMOTES CALORIGENIC EFFECT (LONG TERM COLD ADAPTATION)
• SHORT TERM EFFECTS DUE TO SYMPATHETIC MIMETIC EFFECTS AND
THE SHIVERING RESPONSE OF MUSCLES

22. REGULATION OF THYROID SECRETION
HYPOTHALAMUS
TRH
ANTERIOR PITUITARY
TSH
THYROID GLAND
TARGET ORGANS
THYROID HORMONE
STRESS
COLD
- +

23. EFFECTS OF TSH
• GREATLY INCREASES ENDOGENOUS SYNTHESIS AND SECRETION OF
HORMONE
• INCREASES BLOOD FLOW
• PLEIOTROPIC EFFECT ON GLANDULAR TISSUE, RNA AND DNA
SYNTHESIS (HYPERPLASIA), PHOSPHOLIPID METABOLISM, ETC.

24. TSH MODE OF ACTION
• RECEPTOR SPANS MEMBRANE
• G-PROTEIN SUPERFAMILY
• cAMP SECOND MESSENGER
• INFLUENCES EVERY STEP OF THE HORMONE SYNTHESIS, STORAGE,
AND SECRETION.

25. Cellular effects of thyroid

26. Thyroid gland secretes 2 hormones :
–Thyroxine (tetraiodothyronine or T4)
–Triiodothyronine (T3)
–Secretion ratio T4 to T3 is 15:1
–Iodine is attached to tyrosine amino acid
residues of thyroglobulin in the gland
(organification)
–Coupling of these residues then produces
T4 & T3
Recap. of Thyroid Physiology

27. Thyroid Physiology (cont.)
T4 & T3 released by the gland are bound &
transported by serum proteins :
–Thyroxine-Binding Globulin (TBG) : 75 %
–Thyroxine-Binding Prealbumin (TBPA)
–Albumin
The free (or unbound) hormone levels are
the levels which are maintained constant by
feedback & regulate thyroid function
Total measured serum T4 includes bound &
unbound

28. Variations in Thyroxine Binding
Proteins
Causes of increased TBG levels :
–Pregnancy, estrogens, cirrhosis, hepatitis,
porphyrias
Causes of decreased TBG levels :
–Protein malnutrition, nephrotic syndrome,
hepatic failure, androgenic steroids, high
dose glucocorticoids
Free T4 (FT4) usually constant in the
above conditions

29. Thyroid Hormone Action in the
Tissues
T4 deiodonated in periphery to T3
–This is 80 % of T3 produced
Other metabolites of T4 is reverse T3 (rT3) which
is metabolically inactive
T3 enters cells & binds to group of nuclear
receptors, then affects wide range of cellular
metabolic functions
Thyroid hormone required for normal cell
metabolism

30. Feedback Regulation of Thyroid
Hormone Levels
Normal regulation requires intact hypothalamic-
pituitary system
Hypothalamus secretes Thyrotropin-Releasing
Hormone (TRH)
TRH then stimulates synthesis & release of
thyrotropin (Thyroid Stimulating Hormone or TSH)
by the anterior pituitary
TSH then stimulates the thyroid gland to uptake
iodine, synthesize & release T4 & T3
T4 & T3 levels feedback to both hypothalamus &
pituitary affecting TRH & TSH release

31. ABNORMALITIES OF THYROID FUNCTION
• HYPO
• REDUCED BMR
• POOR TOLERANCE OF COLD
• GAIN OF WEIGHT
• FATIGUE
• SLOW, WEAK PULSE
• SLOW REFLEXES AND MENTATION
• MYXEDEMA
• GOITER
• CRETINISM
• HYPER
• GRAVE’S DISEASE:TSI
(THYROID STIMULATING
IMMUNOGLOBULIN-MIMICS
TSH)
• EXOPHTALMOS
• GOITER

32. Thyroid Function Tests
Radioimmunoassay for T4 (T4RIA) is most useful single
test of thyroid function
–Normal levels 4 to 12 mcg / dl
Free thyroid homone is difficult to measure directly, so
"indirect" tests developed
–T3 Resin Uptake (T3RU) measures amount of radioactive T3 unbound when
added to patient's serum
–Reflects # of sites available for binding T4 &T3
–Is indirect measure of level of circulating T4
–Normal is 25 to 35 %

33. Other Thyroid Function Tests
Free T4 Index (FT4I)
–Correlates with level of Free T4
–Is the product of T4RIA & T3RU
T3 radioimmunoassay (less useful)
–Normal 75 to 195 ng / dl
Serum TSH
–Normal is 0.3 to 5.0 mcU / ml
TRH Stimulation Test
–Measures TSH response to TRH IV injection
–Normal is increase in TSH to 30 mcU / ml

34. Directional Changes in Thyroid
Function Tests
Clinical
State
Total T4 T3RU FT4I Free T4 TSH
Euthyroid N N N N N
Hyper-
thyroid
Hypothyroid
High TBG N N N
Low TBG N N N
Nonthyroid
Illness N or N or N or N or
(N = Normal)

35. Disorders of Thyroid Function and Regulation
• Hypothyroidism, too little thyroid function, can
produce symptoms such as
• Weight gain, lethargy, cold intolerance
• Hyperthyroidism, excessive production of thyroid
hormone, can lead to
• High temperature, sweating, weight loss,
irritability and high blood pressure
• Malnutrition can alter thyroid function
© 2011 Pearson Education, Inc.

36. Disorders of Thyroid Hormone
Excess
"Thyrotoxicosis" is the term for all
disorders with increased levels of
circulating thyroid hormones
"Hyperthyroidism" refers to disorders in
which the thyroid gland secretes too
much hormone
Radioactive iodine uptake test (RAIU)
distinguishes hyperthyroidism from
other forms of thyrotoxicosis

37. The Radioactive Iodine Uptake
Test (RAIU)
Quantitates the fraction of a dose of radioiodine
I-123 taken up by the thyroid gland within 24
hours
Normal is 5 to 30 %
Elevated when thyroid gland is overstimulated
Decreased when thyroid gland is suppressed
(as by ectopic production of T4 or T3)
Is decreased falsely by recent iodine load (as
from contrast computed tomography scan)

38. Causes of Thyrotoxicosis with
Elevated RAIU
Graves' Disease
Pituitary tumor secreting excess TSH
Pituitary insensitivity to feedback
Hydatidiform mole
Choriocarcinoma
Testis embryonal carcinoma
Toxic multinodular goiter
Toxic uninodular goiter

39. Causes of Thyrotoxicosis with
Decreased RAIU
Acute autoimmune thyroiditis (may later
lead to hypothyroidism)
Infectious thyroiditis
Postpartum thyroiditis
Factitious (taking PO excess thyroid
hormone)
Metastatic thyroid cancer
Struma ovarii (dermoid tumors or
teratomas of the ovary)

40. Medications Which Can Induce
Hyperthyroidism
Iodine
Amiodarone
Lithium
Also rarely due to ground beef
contaminated with bovine thyroid
glands

41. Hyperthyroidism Symptoms
Anxiety/irritability
Weakness
Tremors
Difficulty sleeping
Palpitations
Increased bowel
movements
Fatigue
Weight loss
Hyperkinetic
movements
Heat intolerance

42. Laboratory Studies
• TSH <0.010 uIU/ml (nl 0.47-5.0)
• Free T4 >6 ng/dl (nl 0.71-1.85)
• Total T3 >600 ng/dl (nl 72-170)
• Thyroid Stimulating Antibody 130% (nl 0-125%)
• Negative Thyroid peroxidase and thyroglobulin antibodies

43. Features of Graves' Disease
(Toxic Diffuse Goiter)
Most common cause of hyperthyroidism (70
to 85 % of all cases)
Caused by thyroid stimulating
immunoglobulins
Mainly in young adults ages 20 to 50
5 times more frequent in women
Half of cases have infiltrative
ophthalmopathy with exopthalmos (not seen
with other causes of hyperthyroidism)
5 % have pretibial myxedema

44. Weetman, A. P. N Engl J Med 2000;343:1236-1248
Pathogenesis of Graves' Disease

45. 51 year old male who presented with urinary retention and proved to have Graves
Disease

46. Pretibial
myxedema and
“square toes” in
the same patient
on the prior slide

47. Ophthalmo-
pathy
associated with
Graves Disease

48. Asymmetric
ophthalmo-
pathy with lag
ophthalmos in
Graves Disease

49. Weetman, A. P. N Engl J Med 2000;343:1236-1248
Clinical Manifestations of Graves' Disease

50. Features of Toxic Multinodular
Goiter
Second most common cause of
hyperthyroidism
Most cases in women in 5th to 7th
decades
Often have long standing goiter
Symptoms usually develop slowly

51. Symptoms Suggestive of
Thyrotoxicosis
Nervousness, restlessness,shortened
attention span, emotional lability,
difficulty sleeping
Increased appetite
Weight loss
Heat intolerance, perhaps low fever
Diaphoresis
Weakness
Menstrual irregularities

52. Patient with
thyrotoxicosis from
Graves Disease

53. Onycholysis (irregular separation of nail plate from nail bed near distal end) in the
same patient on the prior slide

54. • Graves disease, a form of hyperthyroidism caused
by autoimmunity, is typified by protruding eyes
• Thyroid hormone refers to a pair of hormones
• Triiodothyronin (T3), with three iodine atoms
• Thyroxine (T4) with four iodine atoms
• Insufficient dietary iodine leads to an enlarged
thyroid gland, called a goiter
© 2011 Pearson Education, Inc.

55. General Causes of Thyroid
Failure
Diseases of the :
–Thyroid (primary hypothyroidism) : 95 %
–Pituitary (secondary hypothyroidism) : 4 %
–Hypothalamus (tertiary hypothyroidism) : < 1%
Can be associated with the multiple
endocrine failure syndromes

56. Etiologies of Primary
Hypothyroidism
Autoimmune : most common
–Some have lymphocytic infiltration variant
Post surgical thyroidectomy
External radiation
Iodine 131 Rx for hyperthyroidism
Severe prolonged iodine deficiency
Antithyroid meds (such as lithium)
Inherited enzymatic defects
True idiopathic

57. Symptoms of Hypothyroidism
Cold intolerance
Dyspnea
Anorexia
Constipation
Menorrhagia or amenorrhea
Arthralgias, myalgias
Fatigue
Depression
Irritability
Decreased attention & memory
Paresthesias

59. Signs Related to
Hypothyroidism
Dry, yellow (carotenemic ) skin
Weight gain (41 % of cases)
Thinning, coarse hair
Myxedema signs (mucopolysaccharide deposition in
tissues) :
–Puffy eyelids
–Hoarse voice
–Dependent edema
–Carpal tunnel syndrome
Anemia

60. Signs of advanced
hypothyroidism

61. 60 year old male who
presented with fatigue
and alopecia ; his FTI
was 0.2 and his TSH was
> 75

62. Same patient on prior slide after 6 months treatment with T4

63. Hypothyroidism and Myxedema
Coma : Cardiac Signs
Hypotension
Bradycardia
Pericardial effusion
Low voltage EKG
Prolonged QT interval
Inverted / flattened T waves

64. EKG of 52 year old female
presenting with fatigue
and weight gain ; her T4
was 2.7 and her TSH was
40

65. EKG of same patient
on prior slide after
treatment with T4

66. Myxedema Coma
Typical Presentation
Usual symptoms & signs of
hypothyroidism, plus :
–Hypothermia (80 % of cases)
ƒ If temp. is normal, consider infection
present
–Hypotension / bradycardia
–Hypoventilation / respiratory failure
–Ileus
–Depressed mental status / coma

67. Patient with
myxedema coma

69. Precipitants of Myxedema
Coma
Cold exposure
Infection
–Pneumonia
–Urinary tract infection
Trauma
CNS depressants
ƒ Narcotics
ƒ Barbiturates, Tranquilizers
ƒ General anesthetics
Cerebrovascular accident
Congestive heart failure

70. "Mechanical " Symptoms
Associated with Goiter
 Frequent :
–Dyspnea, dysphagia
–Fullness, choking or pressure sensation in neck
 Less common :
–Acute respiratory failure
–Superior vena cava syndrome
–Esophageal varices
 Uncommon but reported :
–New onset asthma, phrenic nerve paralysis, Horner's syndrome,
chylothorax, neck abscess, sleep apnea

72. 70 year old male with a substernal goiter causing tracheal compression

73. Surgical
excision of a
goiter

74. References/Acknowledgement
• Text book of Medical Physiology, 12th Edition by Gyton & Hall
• Arthur C. Guyton and Hall J.E (1973). Textbook of Medical Physiology
by Arthur C Guyton and John E. Hall Publishers Philadelphia: WB
Saunders, 1973
• Jim Holliman, M.D., F.A.C.E.P.[Professor of Military and Emergency
Medicine, Uniformed Services University of the Health Sciences,
Clinical Professor of Emergency Medicine, George Washington
University, Bethesda, Maryland, U.S.A.]
• Lisa Hays, MD [Endocrinology Fellow]