Ice 2019 presentation

1. Hypothyroidism: Nuts and Bolts
Karthik Balachandran
Consultant Endocrinologist
SRMC
August 10, 2019

2. Agenda
Basics
Case 1
Case 2
Case 3

3. BASICS

4. 1.Loop
Thyroid Physiology

5. 2.Relationship between TSH and FT4
Inverse log linear relationship

6. 2.Relationship between TSH and FT4

7. 2.Relationship between TSH and FT4
Inverse non linear relation
𝑑 log TSH/𝑑fT4 = 𝑘e(−(𝑞(𝑥−𝑎))2
)
+ 𝑑

8. 2. Relationship between T4 and TSH

9. 2. Relationship between T4 and TSH
T4
TSH

10. What rocks the seesaw?
TSH
T4/T3

11. What rocks the seesaw?
TSH
T4/T3 Others

12. 3. Circadian rhythms

13. 3. Circadian rhythms

14. 4. Measurement difficulty
FT4
TT4

15. 4. Measurement difficulty
FT4
TT4

16. 5. What is normal?
TSH
𝑇 𝑆𝐻 > 2.5

17. Effect of timing and food intake
• Timing of testing doesn’t matter - as long as sample is given
between 8 AM to 11 AM 1
• Food intake matters - PP TSH lowering consistent and approx 25% 2
• Reclassification depends on baseline TSH
• Both timing and food intake likely more important in reproductive age group
women
1
Mahadevan S et al Does Time of Sampling or Food Intake Alter Thyroid Function Test? Indian J
Endocrinol Metab. 2017;21(3):369–372
2
Nair R. Does fasting or postprandial state affect thyroid function testing? Indian J Endocrinol Metab.
2014;18(5):705–707

18. CASE 1

19. Case 1
• 20 year female
• lethargy and tiredness for 3 months
• Hairloss
• Mild goitre
Parameter Value
FT4 0.48 ng/dl (0.8 - 1.8)
TSH > 150 mIU/L (0.35 - 5.5)

20. Interpretation
Parameter Value
FT4 0.48 ng/dl (0.8 - 1.8)
TSH > 150 mIU/L (0.35 - 5.5)
Clinical suspicion ✓
TSH ⇑
T4 ⇓
Feedback ✓

21. Interpretation
Parameter Value
FT4 0.48 ng/dl (0.8 - 1.8)
TSH > 150 mIU/L (0.35 - 5.5)
Clinical suspicion ✓
TSH ⇑
T4 ⇓
Feedback ✓

22. Interpretation
Parameter Value
FT4 0.48 ng/dl (0.8 - 1.8)
TSH > 150 mIU/L (0.35 - 5.5)
Clinical suspicion ✓
TSH ⇑
T4 ⇓
Feedback ✓

23. Interpretation
Parameter Value
FT4 0.48 ng/dl (0.8 - 1.8)
TSH > 150 mIU/L (0.35 - 5.5)
Clinical suspicion ✓
TSH ⇑
T4 ⇓
Feedback ✓

24. Diagnosis
Δ : Primary Hypothyroidism

25. Treatment
• Treatment started with 100 mcg levothyroxine
• TFT was repeated after 6 weeks

26. Follow up
Parameter Value
FT4 0.85 ng/dl (0.8 - 1.8)
TSH 4.3 mIU/L (0.35 - 5.5)
But the patient complains of persistent symptoms …

27. What can we do?
Parameter Value
FT4 0.85 ng/dl (0.8 - 1.8)
TSH 4.3 mIU/L (0.35 - 5.5)
1. Increase the dose of thyroxine
2. Check T3 levels and titrate based on
that
3. Repeat test in another lab
4. Reassure the patient
5. Refer to your rival physician

28. Causes of persistent symptoms

29. Causes of persistent symptoms
Basics
Symptoms of hypothyroidism are non specific !

30. So what's choice?
1. Increase the dose of thyroxine

31. So what's choice?
1. Increase the dose of thyroxine
2. Check T3 levels and titrate based on that

32. So what's choice?
1. Increase the dose of thyroxine
2. Check T3 levels and titrate based on that
3. Repeat test in another lab

33. So what's choice?
1. Increase the dose of thyroxine
2. Check T3 levels and titrate based on that
3. Repeat test in another lab
4. Reassure the patient

34. So what's choice?
1. Increase the dose of thyroxine
2. Check T3 levels and titrate based on that
3. Repeat test in another lab
4. Reassure the patient
5. Refer to your rival physician

35. So what's choice?
1. Increase the dose of thyroxine
2. Check T3 levels and titrate based on that
3. Repeat test in another lab
4. Reassure the patient
5. Refer to your rival physician
6. None of the above

36. What to do?
• History, examination and workup for other causes
• Psychosocial issues
• Options with normal TSH (but NOT available in India)
• T3
• Zn tagged T3
• Alternate formulation -liquid
• Thyroid extracts
• Work up for tissue hypothyroidism is not recommended

37. CASE 2

38. Case 2
• 56 year female came for ”master”
health checkup
• Has no goiter
• On probing, she says she feels tired
sometimes, but nothing out of the
ordinary
• Was referred for abnormal thyroid
function
Parameter Value
FT4 0.91 ng/dl (0.8 - 1.8)
TSH 7.8 mIU/L (0.35 - 5.5)

39. Interpretation
Parameter Value
FT4 0.91 ng/dl (0.8 - 1.8)
TSH 7.8 mIU/L (0.35 - 5.5)
Clinical suspicion ×
TSH ⇑
T4 ⇔
Feedback ✓

40. Interpretation
Parameter Value
FT4 0.91 ng/dl (0.8 - 1.8)
TSH 7.8 mIU/L (0.35 - 5.5)
Clinical suspicion ×
TSH ⇑
T4 ⇔
Feedback ✓

41. Interpretation
Parameter Value
FT4 0.91 ng/dl (0.8 - 1.8)
TSH 7.8 mIU/L (0.35 - 5.5)
Clinical suspicion ×
TSH ⇑
T4 ⇔
Feedback ✓

42. Interpretation
Parameter Value
FT4 0.91 ng/dl (0.8 - 1.8)
TSH 7.8 mIU/L (0.35 - 5.5)
Clinical suspicion ×
TSH ⇑
T4 ⇔
Feedback ✓

43. Diagnosis
Δ : Subclinical Hypothyroidism 3
3
Confirm at 3 months

44. Differential Diagnosis
• Recovery from NTI
• Morbid obesity
• Assay variability
• Assay interference
• Macro TSH
• Heterophile antibodies

45. Natural Course
Normal
Time
SCHSCH
Hypothyroidism

46. Natural Course
Normal
Time
SCHSCH
Hypothyroidism

47. What are the concerns
• Progression to overt hypothyroidism
• Cardiovascular disease
• NAFLD
• Reproductive abnormalities
• Neuropsychiatric symptoms

48. Progression rates to Overt hypothyroidism
Conditional probability
P(overt hypothyroidism | Ab+ve)

49. Progression rates to Overt hypothyroidism
Conditional probability
P(overt hypothyroidism | Ab+ve)
SCH
TPOAb- 2.6%
TPOAb+ 4.3%

50. Odd things about odds ratios
A bag with 11 marbles
Probability 𝑃(𝑏𝑙𝑢𝑒) =
# 𝑜𝑓 𝑤𝑎𝑦𝑠 𝑡𝑜 𝑝𝑖𝑐𝑘𝑏𝑙𝑢𝑒
# 𝑜𝑓 𝑝𝑜𝑠𝑠𝑖𝑏𝑙𝑒 𝑜𝑢𝑡𝑐𝑜𝑚𝑒𝑠
=
5
11
Odds 𝑜𝑑𝑑𝑠(𝑏𝑙𝑢𝑒) =
# 𝑜𝑓 𝑤𝑎𝑦𝑠 𝑡𝑜 𝑝𝑖𝑐𝑘 𝑏𝑙𝑢𝑒
# 𝑜𝑓 𝑤𝑎𝑦𝑠 𝑡𝑜 𝑁 𝑂𝑇 𝑝𝑖𝑐𝑘 𝑏𝑙𝑢𝑒
=
5
6
Odds ratio would be 5/6

51. What to do in this patient?
Parameter Value
FT4 0.91 ng/dl (0.8 - 1.8)
TSH 7.8 mIU/L (0.35 - 5.5)
AntiTPO antibodies
Confirm the diagnosis
Repeat TFT in 1 to 3 months
AntiTPO antibodies ???

52. Management

53. CASE 3

54. Case 3
• 22 year female k/c/o hypothyroidism
for 6 years
• Presented with progressively
increasing TSH on the same dsoe of
thyroxine
• Denies non compliance
• No menstrual irregularity
Parameter Value
FT4 0.81 ng/dl (0.8 - 1.8)
TSH 17.8 mIU/L (0.35 - 5.5)

55. Interpretation
Parameter Value
FT4 0.81 ng/dl (0.8 - 1.8)
TSH 17.8 mIU/L (0.35 - 5.5)
Clinical suspicion ⇔
TSH ⇑
T4 ⇔
Feedback ✓

56. Interpretation
Parameter Value
FT4 0.81 ng/dl (0.8 - 1.8)
TSH 17.8 mIU/L (0.35 - 5.5)
Clinical suspicion ⇔
TSH ⇑
T4 ⇔
Feedback ✓

57. Interpretation
Parameter Value
FT4 0.81 ng/dl (0.8 - 1.8)
TSH 17.8 mIU/L (0.35 - 5.5)
Clinical suspicion ⇔
TSH ⇑
T4 ⇔
Feedback ✓

58. Interpretation
Parameter Value
FT4 0.81 ng/dl (0.8 - 1.8)
TSH 17.8 mIU/L (0.35 - 5.5)
Clinical suspicion ⇔
TSH ⇑
T4 ⇔
Feedback ✓

59. How to approach?
Input
Drug quality
Drug storage
Compliance
Absorption
Luminal Food
Drugs
Wall Malabsorption
Action
Tissue Transport
T4→T3
Pituitary RTH
Use Hemangioma
Loss Nephrotic syndrome
Other Addison’s
Assay

60. How to approach?
Input
Drug quality
Drug storage
Compliance
Absorption
Luminal Food
Drugs
Wall Malabsorption
Action
Tissue Transport
T4→T3
Pituitary RTH
Use Hemangioma
Loss Nephrotic syndrome
Other Addison’s
Assay

61. How to approach?
Input
Drug quality
Drug storage
Compliance
Absorption
Luminal Food
Drugs
Wall Malabsorption
Action
Tissue Transport
T4→T3
Pituitary RTH
Use Hemangioma
Loss Nephrotic syndrome
Other Addison’s
Assay

62. How to approach?
Input
Drug quality
Drug storage
Compliance
Absorption
Luminal Food
Drugs
Wall Malabsorption
Action
Tissue Transport
T4→T3
Pituitary RTH
Use Hemangioma
Loss Nephrotic syndrome
Other Addison’s
Assay

63. Interference - Two site immunoassay

64. Interference - Competitive immunoassay

65. Back to the patient

66. Some pearls
• If a dose is missed, advise patient to take double dose next day
• If patient non compliant, consider once/twice weekly dosing
• Night shifts - no evidence based recommendation
• Don’t give thyroxine for weight loss, sleep apnea or fatty liver

67. Take home messages
Summary
• Remember the basics
• Clinical suspicion is important,especially in difficult cases
• Fasting sample between 8 to 10 AM -both T4 and TSH
• Trace the pathway from tablet to action
• Assay and labs matter
• Individualizing treatment is key
• The management is far more nuanced than looking at the reference range !
• Do not hesitate to refer to your friendly neighbourhood endocrinologist ;-)

68. References
S. Azim and C. Nasr. “Subclinical Hypothyroidism: When to Treat”. In: Cleveland
Clinic Journal of Medicine 86.2 (Feb. 1, 2019), pp. 101–110.
Salvatore Benvenga, Giampaolo Papi, and Alessandro Antonelli. “Refractory
Hypothyroidism Due to Improper Storage of Levothyroxine Tablets”. In: Frontiers in
Endocrinology 8 (2017).
Bernadette Biondi, Anne R. Cappola, and David S. Cooper. “Subclinical
Hypothyroidism: A Review”. In: JAMA 322.2 (July 9, 2019), p. 153.
M. Centanni, S. Benvenga, and I. Sachmechi. “Diagnosis and Management of
Treatment-Refractory Hypothyroidism: An Expert Consensus Report”. In: Journal of
Endocrinological Investigation 40.12 (Dec. 2017), pp. 1289–1301.
Julien Favresse et al. “Interferences With Thyroid Function Immunoassays: Clinical
Implications and Detection Algorithm”. In: Endocrine Reviews 39.5 (Oct. 1, 2018),
pp. 830–850.

69. References
Mark Gurnell, David J. Halsall, and V. Krishna Chatterjee. “What Should Be Done
When Thyroid Function Tests Do Not Make Sense?” In: Clinical Endocrinology 74.6
(June 2011), pp. 673–678. pmid: 21521292.
Olympia Koulouri and Mark Gurnell. “How to Interpret Thyroid Function Tests”. In:
Clinical Medicine (London, England) 13.3 (June 2013), pp. 282–286. pmid:
23760704.
Onyebuchi Okosieme et al. “Management of Primary Hypothyroidism: Statement
by the British Thyroid Association Executive Committee”. In: Clinical Endocrinology
84.6 (June 2016), pp. 799–808.
Leonard Wartofsky and Richard A. Dickey. “The Evidence for a Narrower
Thyrotropin Reference Range Is Compelling”. In: The Journal of Clinical
Endocrinology & Metabolism 90.9 (Sept. 1, 2005), pp. 5483–5488.

70. Thank you !
This presentation can be downloaded from
www.medicalruminations.wordpress.com
cbna