Download Amiodarone and the Thyroid

Amiodarone and the Thyroid
Case Presentation
• 65 year old woman from London seen Oct
2002 for hyperthyroidism
• Destined to shorten my life by a few weeks
at least
Past History
• GB, appy, Hyst, R Knee replacement
• 1992: MI
• Jan 2002: implanted defibrillator
Present History
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•
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Hyperthyroidism
Atrial Fibrillation
Type 2 DM
Asthma
CAD
HT
Hyperlipidemia
SCZ
Medications
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•
•
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Lipitor
Accuretic
Plavix
Zyprexa
Diltiazem
Loperamide
Vitamins
• Insulin 30/70 44 u acb;
13 u acs
• Nitropatch
• Pulmocort
• Atrovent
• ASA
• Tapazole
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
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
History
• Recent try of Atenolol caused more SOB
• No chest pain
• Unable to do housework due to symptoms
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
Labs
From GP:
• TSH < 0.01
• FT4: 32.1
Repeats in Clinic
• TSH< 0.01
• FT4 34.7 mM (11-22)
• FT3 7.8 (3-6.5)
Lab’s continued
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AST 26
ALT 36
Alk Phos 79
Gamma GT 116 (0-50)
Bili 11
…..now what………………….
What was done
• Thyroid uptake and scan
• PTU
Thyroid response
Oct 22, 2002
FT4 35.3
FT3 6.3
Oct 31, 2002
FT4 39.3
FT3 6.1
Nov 8, 2002
FT4 38.1
FT3 6.1
Nov 15, 2002
FT$ 32.7
FT3 5.9
Nov 28, 2002
FT4 32.4
FT3 6.3
Nov 26, 2002
FT4 32.4
FT3 6.3
Dec 12, 2002
FT4 28.1
FT3 5.6
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
So
• Off PTU
• Another uptake and scan done:
…………….no uptake
…..now what……………………..
So
• Referral to surgery
• Started Prednisone 20 mg daily
• (also just fortuitously happened to be
wheezing when reviewed)
Thyroid response to prednisone
Dec 31, 2002
FT4 30.7 FT3 5.5
Jan 9, 2003
FT4 24.5 FT3 5.1
Jan 15, 2003
FT4 18.8 FT3 4.3
Jan 22, 2003
FT4 17.1 FT3 3.8
Jan 29, 2003
FT4 15.4 FT3 4.2
Surgery……………
Now hypothyroid!
Finally
Review:Amiodarone and Thyroid
Amiodarone
• Iodine rich (37% by weight is I)
• Resembles levothyroxine
• Average dose: increase 50-100X the normal
iodine intake
Amiodarone
Active Metabolite:
DEA (desethylamiodarone)
Half-life:
Amiodarone: 52.6±23.7 days
DEA 61.2 ± 31.2 days
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
Amiodarone Effects
Central Effects
• May directly affect TSH synthesis/secretion
• Perhaps due to inhibition of T4-->T3 in
pituitary
Amiodarone effects on thyroid
Cytotoxic
• Lysis of Human thyroid follicular cells
• (more powerfully than with equivalent
doses of iodine alone)
Involuted thyroid
Histopathology
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
Other changes
Areas of fibrosis including
degenerated and disrupted follicular
structures
Mild chronic inflammatory infiltration
Amiodarone and thyroid autoimmunity
• Controversial
• Perhaps transient induction of antithyroid
peroxidase
• Most likely only in subsets of susceptible
pts
Amiodarone and the Thyroid
itself
Amiodarone is related to the following thyroid
dysfunction types:
1. Nothing
2. Hyperthyroidism
3. Hypothyroidism
Prevalence
Type of amiodarone dysfunction seems to
depend on iodine intake
1. AIT (thyrotoxicosis): more common in
iodine deficient areas
2. AIH (hypothyroidism): more common in
iodine replete areas
So for our population
• Thyrotoxicosis: 2%
• Hypothyroidism: 22%
Hypothyroidism
• Underlying thyroid abnormalities occur in
up to 68%
• 53% had autoantibodies to thyroid (TPO)
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)
Treatment
• Easy
• T4
• Spontaneous remissions do occur if able to
come off amiodarone
Thyrotoxicosis
Not so easy
Thyrotoxicosis
• May occur at any time (early or late)
• Seemingly related to cumulative dose of
drug
• Male:female prevalence is 3:1
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
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)
Thyrotoxicosis
Trying to differentiate the types
1. Difficult
2. Type 1 may have RAI uptake (don’t count
on it, depends where you live); lumpy
thyroid
3. Type 2 may have zippo RAIU and
nondescript gland
Thyrotoxicosis treatments
Type 1
Goal:block organification of iodine and
thyroid hormone synthesis
Options:
• high dose thionamides
+/• Potassium perchlorate to block I uptake
Thyrotoxicosis treatments
Type 2
Steroids for
• Anti-inflammatory effects and
• T4-T3 block
Definitive treatment
Thyroidectomy
Big question: does Amiodarone have to be
stopped?
Natural history of AIT
• One study: 19% settled spontaneously
Eaton et al Clinical Endocrinology 2002
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.
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:
Pathology
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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
In summary
Amiodarone has
• Multiple thyroid and extrathyroidal effects
• Treatment of AIH: easy
• Treatment of AIT: not easy but options do
exist