1. Amiodarone and the Thyroid

2. Case Presentation
65 year old woman from London seen Oct 2002 for hyperthyroidism
Destined to shorten my life by a few weeks at least

3. Past History GB, appy, Hyst, R Knee replacement 1992: MI
Jan 2002: implanted defibrillator

4. Present History Hyperthyroidism Atrial Fibrillation Type 2 DM Asthma
CAD HT
Hyperlipidemia
SCZ

5. Medications Lipitor Accuretic Plavix Zyprexa Diltiazem Loperamide
Vitamins
Insulin 30/70 44 u acb; 13 u acs
Nitropatch
Pulmocort
Atrovent
ASA
Tapazole

6. History 10 days prior to consult she had onset of Feeling warm
Neck tightness
SOBOE
Postural presyncope
Frequent trips to defibrillator clinic for episodes of use

7. History In past she’d been told she had a small goitre
TFT’s were perhaps mildly “off”
In Jan 2002 came off Amiodarone as defib
In Sept 2002: had carotid angios for ?TIA

8. History Recent try of Atenolol caused more SOB No chest pain
Unable to do housework due to symptoms

9. Physical Exam Weight: 112 kg
BP 130 (forearm systolic only); HR 88 irreg
Thyroid low lying, firm, not tender and irreg throughout, approx 35 gr
Chest clear
No S3 S4, no edema

10. Labs From GP: TSH < 0.01 FT4: 32.1 Repeats in Clinic TSH< 0.01
FT mM (11-22)
FT3 7.8 (3-6.5)

11. Lab’s continued AST 26 ALT 36 Alk Phos 79 Gamma GT 116 (0-50) Bili 11
…..now what………………….

12. What was done
Thyroid uptake and scan
PTU

13. Thyroid response Oct 22, 2002 FT4 35.3 FT3 6.3 Oct 31, 2002
Nov 8, 2002
FT FT3 6.1
Nov 15, 2002
FT$ FT3 5.9
Nov 28, 2002
FT FT3 6.3
Nov 26, 2002
FT FT3 6.3
Dec 12, 2002
FT FT3 5.6

14. Thyroid response Dec 23, 2002 FT4 26.5 FT3 6.2 BUT
LFT’s starting to rise
AST 32
Alk Phos 121
Gamma GT 345
ALT 126

15. So Off PTU Another uptake and scan done: …………….no uptake
…..now what……………………..

16. So Referral to surgery Started Prednisone 20 mg daily
(also just fortuitously happened to be wheezing when reviewed)

17. Thyroid response to prednisone
Dec 31, 2002
FT FT3 5.5
Jan 9, 2003
FT FT3 5.1
Jan 15, 2003
FT FT3 4.3
Jan 22, 2003
FT FT3 3.8
Jan 29, 2003
FT FT3 4.2
Surgery……………
Now hypothyroid! Finally

18. Review:Amiodarone and Thyroid
Iodine rich (37% by weight is I)
Resembles levothyroxine
Average dose: increase X the normal iodine intake

20. Amiodarone Active Metabolite: DEA (desethylamiodarone) Half-life:
Amiodarone: 52.6±23.7 days
DEA 61.2 ± 31.2 days

21. Amiodarone effects Peripheral effects Inhibits type 1 5’ deiodinase
Decreases T4 to T3 conversion in peripheral tissues
Inhibits T4 entry into peripheral tissues
Reduces number of catecholamine receptors
Decreases effect of T3 on ß-adrenoceptors
Perhaps down-regulates thyroid hormone receptor

22. Amiodarone Effects Central Effects
May directly affect TSH synthesis/secretion
Perhaps due to inhibition of T4-->T3 in pituitary

23. Amiodarone effects on thyroid
Cytotoxic
Lysis of Human thyroid follicular cells
(more powerfully than with equivalent doses of iodine alone)

24. Histopathology
Involuted thyroid
Enlarged follicles distended by dense, deeply acidophilic colloid and lined by flattened cells
Degenerative and destructive follicular lesions
Segmental swelling of the lining cells, with granular, foamy, vacuolated, and balloon-like cytoplasm
Lipofuscinogenesis
Follicles stuffed with desquamated cells
Total follicular destruction
Fibrotic lesions
Areas of fibrosis including degenerated and disrupted follicular structures
Other changes
Mild chronic inflammatory infiltration

25. Amiodarone and thyroid autoimmunity
Controversial
Perhaps transient induction of antithyroid peroxidase
Most likely only in subsets of susceptible pts

26. Amiodarone and the Thyroid itself
Amiodarone is related to the following thyroid dysfunction types:
Nothing
Hyperthyroidism
Hypothyroidism

27. Prevalence
Type of amiodarone dysfunction seems to depend on iodine intake
AIT (thyrotoxicosis): more common in iodine deficient areas
AIH (hypothyroidism): more common in iodine replete areas

28. So for our population
Thyrotoxicosis: 2%
Hypothyroidism: 22%

29. Hypothyroidism Underlying thyroid abnormalities occur in up to 68%
53% had autoantibodies to thyroid (TPO)

30. Hypothyroidism Pathogenesis Previously damaged by Hashimoto’s
Perhaps subtle defect in thyroid hormone synthesis leads to increased inhibitory effects of iodine load (defective iodine organification)

31. Treatment
Easy T4
Spontaneous remissions do occur if able to come off amiodarone

32. Thyrotoxicosis
Not so easy

33. Thyrotoxicosis May occur at any time (early or late)
Seemingly related to cumulative dose of drug
Male:female prevalence is 3:1

34. Thyrotoxicosis Pathogenesis
Thyroid gland may be clinically normal in 33% of cases
Increased intrathyroidal Iodine content
Maybe increased interleukin-6 levels suggesting destruction but don’t count on it

35. Thyrotoxicosis Probably 2 types of AIT:
Type 1: underlying thyroid abN (Graves’ or MNG); due to excessive T4 production secondary to excess iodine load
Type 2: normal gland, cellular destructive process
(well, actually there is a 3rd type: mixed)

36. Thyrotoxicosis Trying to differentiate the types Difficult
Type 1 may have RAI uptake (don’t count on it, depends where you live); lumpy thyroid
Type 2 may have zippo RAIU and nondescript gland

37. Thyrotoxicosis treatments
Type 1
Goal:block organification of iodine and thyroid hormone synthesis
Options:
high dose thionamides
+/-
Potassium perchlorate to block I uptake

38. Thyrotoxicosis treatments
Type 2
Steroids for
Anti-inflammatory effects and
T4-T3 block

39. Definitive treatment Thyroidectomy
Big question: does Amiodarone have to be stopped?

40. Natural history of AIT One study: 19% settled spontaneously
Eaton et al Clinical Endocrinology 2002

41. Table 6. Therapeutic strategy in amiodarone-induced thyrotoxicosis
Type I AIT
Thionamides (methimazole, 30–40 mg/day) in combination with potassium perchlorate (1 g/day for 16–40 days). Discontinue amiodarone if possible. After restoration of euthyroidism and normalization of urinary iodine excretion, definitive treatment of the underlying thyroid abnormalities by either radioiodine or thyroidectomy. If amiodarone cannot be withdrawn and medical therapy is unsuccessful, consider total thyroidectomy.
Type II AIT
Glucocorticoids for 2–3 months (starting dose, prednisone 40 mg/day or equivalent). Discontinue amiodarone if possible. In mixed forms add thionamides and potassium perchlorate. After restoration of euthyroidism, follow-up for possible spontaneous progression to hypothyroidism. If amiodarone cannot be withdrawn and medical therapy is unsuccessful, consider total thyroidectomy.

42. Back to our case: just for fun
Post-op course
Initially did very well
4 days later Ca 1.55 mM
Replaced in hospital and then as OP
Pathology showed:

43. Pathology Hyperplastic nodules throughout
Size: 3.5 x 3.0 x 0.8 R/ 4 x 2 x 0.5 L
(interesting: 14 g thyroid weight!)
0.9 mM papillary ca
1 parathyroid identified

44. In summary Amiodarone has Multiple thyroid and extrathyroidal effects
Treatment of AIH: easy
Treatment of AIT: not easy but options do exist