Sub clinical thyroid disorders for education purpose for benefit to others mainly medical students and personnels

1. SUB-CLINICAL THYROID
DISORDERS
Chair person : Dr Kaustubh Chattopadhyay, DM Endocrinology
Presenter : Dr Soumyasil Das, PGT Gen. Medicine NRSMCH

2. SPECTRUM OF THYROID DYSFUNCTION

3. SUB-CLIN-I-CAL
• “Denoting the presence of a disease without manifest symptoms”
• “May be a early stage in disease evolution”

4. SUB-CLINICAL THYROID
DISORDERS ARE BIOCHEMICAL
DIAGNOSES

5. SUB-CLINICAL HYPOTHYROIDISM
• Understanding the concept of Sub-clinical Hypothyroidism (SHypoT) and its
importance
• Causes of SHypoT
• Effects of SHypoT (CV-Risk)
• How to Diagnose SHypoT
• Whom to treat
• When to treat
• How to monitor
• Impact of treatment

6. TSH REFERENCE RANGE

7. TSH BY AGE DISTRIBUTION

8. NORMAL TSH DISTRIBUTION IS
RIGHT SKEWED

9. TSH INCREASES WITH AGE
NORMALLY
• Hence Age-specific reference ranges
for serum TSH should be considered in
order to establish a diagnosis of
SHypoT in elder patients 2013 ETA
Guideline

10. CAUSES OF SHYPOT

11. EFFECTS OF SHYPOT

12. T3 EFFECTS ON CARDIOVASCULAR SYS

13. T3 EFFECTS ON CARDIOVASCULAR SYS

14. DIASTOLIC DYSFUNCTION IN
SHYPOT
• Most of these studies are follow-up of
6 months
• But all definitely showing the
improvement of diastolic dysfunction

15. T3 EFFECTS ON VASCULAR BIOLOGY

16. T3 EFFECTS ON VASCULAR BIOLOGY

17. T3/TSH ON LIPID METABOLISM

18. LDL– ROLE IN PLAQUE
FORMATION
• LDL gets modified through oxidation,
glycosylation while circulating for long
time
• Become difficult to be recognised by
LDL receptors
• Goes into sub-endothelial space
• Easily captured by Macrophages
leading to foam cells

19. REMNANT LIPOPROTEINS(RLP)
ROLE IN PLAQUE FORMATION
• RLPs are partially degraded products
of VLDL & IDL
• They also penetrate the intima and
recognised by aberrant receptors of
macrophages
• Ultimately leading to formation of
foam cells and plaque, like LDL
• Also lipolysis of VLDL & IDL form FFA
which lead to inflammation,
coagulation & endothelial dysfunction

20. LDL METABOLISM IN SHYPOTHYROIDISM
• Reduced hepatic lipase activity with
higher levels of TSH
• Hepatic lipase (HL) converts IDL TO
LDL
• So there is increase LDL-TAG to
Cholesterol ratio in patients with
SHypoT
• Hence there is impairment in chemical
composition of LDL and we know
impaired LDL is very atherogenic

21. RCT TO SHOW THE REDUCTION OF
LDLC AFTER LT4 THERAPY
• If we increase FT4 level through
treatment there is reduction of LDLc
• Obviously this is not like the STATIN
effect but the effect is modest
• Might be one mechanism why CV
outcomes are better with treatment in
SHypoT

22. VLDL/IDL METAB IN SHYPOTHYROIDISM
• Fasting serum VLDL/IDL is much
Higher in SHypoT
• Probably due to impaired action of
hepatic lipase activity in SHypoT

23. RLP IN SHYPOTHYROIDISM

24. CHOLESTEROL LEVELS

25. EFFECT OF CHOLESTEROL IN
SHYPOT AFTER TREATING WITH LT4

26. CAROTID INTIMA MEDIA THICKNESS
Without
treatment
With
treatment

28. WHAT ABOUT BLOOD PRESSURE

29. VASODILATION BY T3
• Thyroid hormones favour vasodilatory
actions by genomic and non-genomic
actions that ultimately favours the
releasing and increasing the amount of
NO at vascular endothelium

30. INTRA CARDIAC HYPOTHYROID
STATE AFTER AMI
• After heart attack D3 activity goes up
while D2 activity goes down 
resulting in more formation of rT3 n rT2
• Probably a nature’s mechanism to
reduce the heart rate and cardiac load
after MI
• But is it good in the long run??

31. ADAPTIVE
MECHANISM GOOD?
So in long run its clear that survival after a
cardiac event is worst in population who
are sub-clinical hypothyroid at the base line
than who are euthyroid
Observational study; so other factors can
also play account other than thyroid status
But the hazard ratio are significantly higher

32. THROMBUS SIZE IN NSTEMI
SCH VS EUTHYROID
Much bigger Much less

33. THIS WILL CLEAR WHETHER RX IS
BENEFICIAL OR NOT

34. CORRELATION BETWEEN
MORTALITY
AND
SERUM TSH LEVEL

35. CV EVENTS AND CV MORTALITY IN
SHYPOT
So different studies
show different
conclusion when it
comes to cardio
vascular events
and mortality

36. ROTTERDAM STUDY OF DEVP OF
MI IN SHYPOT
• The risk of developing MI in SHypoT is
similar to the other established risk
factors like smoking, hypertension and
even DM

37. AGE & MORTALITY IN ELDERLY
Low TSH
normal
High TSH
558 patients > 85yrs
Followed for 4yrs
No therapy
• Group with the lowest mortality is with
the highest TSH
• Suggesting that SHypoT is probably
protective in elderly and treating will
rather cause harm
• However it is an observational study
and we don’t know the explanation for
it

38. TREATMENT & IHD IN YOUNGER
SHYPOT
• Retrospective study
• Treatment with LT4 in relatively
youngers is probably doing benefit
• Since its not a prospective study so
other factors like gender, smoking,
blood pressure etc can also be
responsible for worst survival in
control group, although they were
adjusted
• But definitely its showing that
treatment is causing no harm

39. TREATMENT & IHD IN OLDER
SHYPOT
• Same study showing no benefit in
people >70yrs of age

40. AGE WISE CV EVENTS AND
MORTALITY IN SHYPOT
• So numerous study showing that
SHypoT is NOT associated with
increase risk of CV events and
mortality in elderly patients particularly
>70yrs
• Again signalling that AGE should be
considered for treating SHypoT

41. SO WHOM TO TREAT
INITIAL MANAGEMENT OF PERSISTENT SUB-
CLINICAL HYPOTHYROIDISM IN NON-PREGNANT
ADULTS

42. IS SINGLE REPORT OF ELEVATED TSH
ENOUGH  ABSOLUTELY NO
4.3%
2.6%

43. INVESTIGATION
OF RAISED TSH REQUIRES REPEATED MEASUREMENTS TO
ESTABLISH A FIRM DIAGNOSIS

44. REPEAT TSH AT 2-3 MONTHS
• TSH normalizes in 15-65% of those with a single elevated TSH without treatment over a
follow-up periods of 1-6 years
• The likelihood of spontaneous recovery is higher in those having TSH <10mIU
• Both healthy individuals and those with SCH have a circadian fluctuation in serum TSH
concentration, with a nadir in the early afternoon and approximately 30% higher
concentrations during evening and night
• Rule out causes of transient elevations of TSH
• Mild TSH elevation (4.0–7.0mU/l) in the elderly (>80 years) should be considered as a
physiological adaptation to aging
• TSH may be altered in night shift working, those with irregular sleep patterns, vigorous
exercise, and in mood disorders/depression
• TSH >3.5mU/l are also common in obesity

45. NO SPECIFIC SYMPTOMS OF
SHYPOT

46. UPDATE OF TREATING SHYPOT
ELDERLY PATIENTS

47. TRUST RCT STUDY TO CHECK THE BENEFIT OF LT4
TREATMENT IN >65Y SHYPOT ELDERLY PEOPLE

48. NO BENEFIT OF TREATING >65Y SHYPOT

49. NO BENEFIT OF TREATING >65Y SHYPOT
NO REDUCTION OF NEW
ONSET AF or FRACTURES
Although this study had the aim to look
into the CV events in elderly sub-clinical
hypothyroids,
Unfortunately the study was not
powered to study the CV outcomes
Due to lack of recruitment of target
numbers
They only recruited quarter of
patients(732) and thus unable to
comment on CV outcomes due to small
sample size

50. LT4 PROVIDED NO
APPARENT
BENEFITS IN
ELDERLY (65>)
SUB-CLINICAL
HYPOTHYROID
PATIENTS

51. PROBABLE UPCOMING GUIDELINE
AGE<65 AGE≥65

52. HOW TO MONITOR

53. HOW TO START TREATMENT
START LOW GO SLOW

54. SUB-CLINICAL
HYPER THYROIDISM
SHYPER
• Definition
• Epidemiology
• Causes
• To establish the correct diagnosis of subclinical
hyperthyroidism
• To assess the risk associated with SHyperT
• How to treat and the approach
Learning objectives

55. DIAGNOSIS OF
SHYPERT IS BASED
ON 3 LEVELS OF
INVESTIGATION

56. DEFINITION OF SHYPERT
• Based on biochemical findings and NOT clinical criteria
• NORMAL TT3/FT4/FT3
• Grade 1 (MILD) ┼ Grade 2 (SEVERE)
TSH 0.1– 0.39mIU/l <0.39mIU/l
PREVALANCE 0.6% -- 16%
depending on diagnostic criteria and the age and sex of the population studied, the
TSH assay used, and iodine intake

57. AIETIOLOGY AND DD OF
ENDOGENOUS SHYPERT
HENCE REPEAT
TEST AT
2 – 3 MONTHS
TO ESTABLISH
THAT THE RISE IS
PERSISTENT
AND
ENDOGENOUS

58. KEEP IN MIND WHEN YOU SEE TSH
VALUE
• FT4 & TT3 are frequently preferred in clinical practice
• because assays estimating FT 3 are less well validated than those evaluating FT4
• dopamine or
• high doses of gluco-corticoids,
• somatostatin analogues,
• dobutamine,
• amphetamine,
• bexarotene,
• bromocriptine
All lead to suppression of
TSH

59. RISK OF UNTREATED PERSISTENT
SHYPERT
•Progression to overt
hypothyroidism
•Cardio-vascular risks
•Osteoporosis

60. PROGRESSION TO OVERT
• 0.5 – 0.7% of GRADE 1 progress into
overt
• 25 – 50% of GRADE 1 can become
euthyroid
• 5 – 8% GRADE 2
• Progression of Shyper A/W Graves Ds
occur much early (within 1 year) than
TMNG; TMNG used to persist in SUB-
CLINICAL state for much longer time

61. CARDIO-VASCULAR RISKS A/W SHYPERT

62. AF  THE MAJOR CV RISK IN
SHYPERT

63. AF  THE MAJOR CV RISK IN
SHYPERT
• Thus risk of AF increases with sub-
clinical hyperthyroidism which in turn
increases the risk of all cause mortality
by 2-fold and risk of embolic stroke by
6-fold.

64. LEFT VENTRICULAR HYPERTROPHY
• LVH is independent risk factor for CV
mortality in <50 years as per AHA
• Unlike LVH in Acromegaly which is
irreversible, LVH in hyperthyroidism is
reversible as the person becomes
euthyroid
• LVH also increases the risk ventricular
arrhythmia independently.
•

65. MYXOMATOUS DEGENERATION OF
VALVE
• Endothelial cells of heart valves
express TSH receptors which when
stimulated by TRAb form GAGs within
the valve leaflets leading to thickening
of valves
• 1 – 2 mm normal valves gets thickened
into 1 – 2 cm (10X)

66. PULMONARY HTN

67. SC-HYPER
THYROIDISM
Increases the over all risk cardio vascular
mortality and events and particularly in
elderly patients
Hence we have to take care of these
patients very judiciously and prevent the
unwanted risks associated with sub-clinical
hyperthyroidism

68. OSTEOPOROSIS
SHyperT increases the risk of osteoporosis
and the fracture of
different bones particularly in post-
menopausal women who are not on
bisphosphonates or oestrogens

69. NOW ESTABLISH THE AETIOLOGY
LEVEL II INVESTIGATIONS

70. LEVEL III INVESTIGATIONS TO
ASSESS THE RISK OF SHYPERT
• CT/MRI of thyroid to know the detailed
anatomy and to assess any presence of
compressive features
• ECG/2D-ECHO to know cardiac rhythm
and cardio vascular morphology
particularly in those having CV risks like
smoking, DM, or other comorbidities
• BMD to assess the risk of osteoporosis
specially in post menopausal women and
elderly

71. WHEN TO TREAT SHYPERT
>65 years with Gr 2
RECOMENDED
>65 years with Gr 1
CONSIDER TREATMENT
PARTICULARLY IN THOSE HAVING CHD,
DM, HF, VALVULAR DISEASE,
PERIPHERAL ARTERIAL DS, H/O STROKE
OR TIA AND DM
<65 years with Gr 2
TREATMENT SUGGESTED
IN THOSE HAVING SYMPTOMS OF
HYPERTHYROIDISM BECAUSE
TREATMENT CAN ATTENUATE THE
HIGH RISK OF PROGRESSION TO
OVERT AND IMPROVE THEIR QOL

72. WHEN TO TREAT
•<65 years
ASYMPTOMATIC
•OBSERVATION only
by repeating thyroid
function at 3 – 6
months

73. THEREFORE AS PER
GUIDELINE
OBSERVATION IS
ONLY FOR THOSE
WHO ARE <65 YEARS
WITH GRADE 1
SHYPERT AND
ASMPTOMATIC

74. HOW TO TREAT
TREATMENT OF
SHYPERT IS THE
SAME WAY AS WE
TREAT OVERT
HYPERTHYROIDIS
M

75. CHOICE OF THERAPY

76. GOAL OF TREATING SHYPERT

77. TAKE MOME MESSAGES
• Sub-clinical Thyroid Disorders Are Characterised By Abnormalities In The TSH Levels And
Differ From Overt Disease By The Presence Of Normal Thyroid Hormone Levels (I.E. Ft4,
Tt3)
• Establish Your Diagnosis That The Condition Is Persistent
• Assess The Risks And Benefit Of Treating Or Not To Treat
• Treatment Is Mainly Recommended For Those Who Are Symptomatic
• Other Conditions Include Age, Presence Of Co-morbid Conditions And The Degree Of
TSH Abnormality
• And Finally When Treatment Is Indicated It Follows The Same Principle As Those With
Overt Thyroid Disease, With Normalisation Of TSH As The Major End Point

78. TAKE MOME MESSAGES
• Sub Clinical Hypothyroidism Is A/W Adverse Outcomes Particularly In Younger
Individuals And Possibly In A Post Mi Situation
• Older Individuals With Raised TSH Might Not Have Poorer Prognosis
• Treatment Of Sub Clinical Hypothyroidism Improves Cardio Vascular Risk Factors
And Symptoms Mainly In Youngers But We Don’t Know Whether There Is Any
Improvement In Mortality And Events (No Prospective Study Till Date)
• Treatment Of Shypot After Mi May Be Beneficial  Probably We Will Get The
Results In Coming 1 – 2 Years

79. I WISH YOU’D COME TO ME EARLIER

80. SPECIAL THANKS TO (SOURCE)
• www.excemed.org
Studies and publication and
lectures of Harrison principles of internal med
• Dr GABRIELA BRENTA WILLIAMS BOOK OF ENDOCRINOLOGY
• DR NEMENCIO NICODEMUS JR.
• Dr GEORGE J. KAHALY
• DR Peter Andreas Kopp
• DR Salman Razvi
• DR Bernadette Biondi