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

• • • • • • • • Hyperthyroidism Atrial Fibrillation Type 2 DM Asthma CAD HT Hyperlipidemia SCZ

Present History

• • • • • • • Lipitor Accuretic Plavix Zyprexa Diltiazem Loperamide Vitamins

Medications

• • • • • • 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

• •

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)

Labs

• • • • • AST 26 ALT 36 Alk Phos 79 Gamma GT 116 (0-50) Bili 11

Lab’s continued

…..now what………………….

• Thyroid uptake and scan

What was done

• PTU

Oct 22, 2002 Oct 31, 2002 Nov 8, 2002 Nov 15, 2002 Nov 28, 2002 Nov 26, 2002 Dec 12, 2002

Thyroid response

FT4 35.3 FT3 6.3

FT4 39.3 FT3 6.1

FT4 38.1 FT3 6.1

FT$ 32.7 FT3 5.9

FT4 32.4 FT3 6.3

FT4 32.4 FT3 6.3

FT4 28.1 FT3 5.6

Dec 23, 2002 BUT LFT’s starting to rise

Thyroid response

FT4 26.5 FT3 6.2

AST 32 Alk Phos 121 Gamma GT 345 ALT 126

• • 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)

So

Thyroid response to prednisone

Dec 31, 2002 Jan 9, 2003 Jan 15, 2003 Jan 22, 2003 Jan 29, 2003 Surgery…………… FT4 30.7 FT3 5.5

FT4 24.5 FT3 5.1

FT4 18.8 FT3 4.3

FT4 17.1 FT3 3.8

FT4 15.4 FT3 4.2

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

Active Metabolite:

DEA (desethylamiodarone)

Half-life:

Amiodarone: 52.6±23.7 days DEA 61.2 ± 31.2 days

Amiodarone

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 Degenerative and destructive follicular lesions Histopathology Enlarged follicles distended by dense, deeply acidophilic colloid and lined by flattened cells Segmental swelling of the lining cells, with granular, foamy, vacuolated, and balloon-like cytoplasm Lipofuscinogenesis Follicles stuffed with desquamated Fibrotic lesions Other changes Areas of fibrosis including degenerated and disrupted follicular

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.

2.

3.

Nothing Hyperthyroidism 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 3 rd type: mixed)

Thyrotoxicosis

Trying to differentiate the types

1.

2.

3.

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

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

• • • • • 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