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
• Hyperthyroidism• Atrial Fibrillation• Type 2 DM• Asthma• CAD• HT• Hyperlipidemia• SCZ
Medications
• 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
• 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)
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 cellsTotal follicular destruction
Fibrotic lesions Areas of fibrosis including degenerated and disrupted follicular structuresOther changes 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. Difficult2. 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 1Goal: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
• 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