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