1070816-甲狀腺亢進及功能異常

甲狀腺高能症及低能症 Hyperthyroidism and Hypothyroidism 李美月 內分泌新陳代謝內科 高醫附設醫院 1

Thyrotoxicosis and hyperthyroidism • Thyrotoxicosis: – the state of thyroid hormone excess – not synonymous with hyperthyroidism

• Hyperthyroidism: – the result of excessive synthesis and secretion of thyroid hormones by the thyroid.

• Major etiologies of thyrotoxicosis are hyperthyroidism caused by Graves' disease, toxic MNG, and toxic adenomas.

– Graves’ disease (50-80%) is the major etiology.

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Hypothalamic-Pituitary-Thyroid Axis

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SYMPTOMS AND SIGNS OF THYROTOXICOSIS 4

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• Unexplained weight loss due to the increased metabolic rate.

• Apathetic thyrotoxicosis and atrial fibrillation are more common in the elderly.

– Patients with apathetic thyrotoxicosis may present mainly with fatigue and weight loss.

• Hair texture may become fine, and a diffuse alopecia occurs in up to 40% of patients, persisting for months after restoration of euthyroidism.

• The direct effect of thyroid hormones on bone resorption leads to osteopenia in long standing thyrotoxicosis.

• Mild hypercalcemia occurs in up to 20% of patients, but hypercalciuria is more common.

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CAUSES OF THYROTOXICOSIS 7

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(葛瑞夫茲氏症)

GRAVES’ DISEASE

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Graves’ Disease (葛瑞夫茲氏症) • Presentation: – – – –

Symptoms and signs of thyrotoxicosis Diffuse goiter Most common cause of thyrotoxicosis(50-80%) Orbitopathy, ophthalmopathy(75%), dermopathy(<5%), acropathy(<1%)

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• Prevalence: 1~2% in women, and about one tenth as much in men. It varies with the degree of Iodine sufficiency in the population • Risk factor for Graves’ disease – – – – – – –

Genetic susceptibility Infection (e.g., Y. enterocolitica, Helicobacter pylori) Stress (e.g. emotional stress) Gender (F:M = 4 to 5:1) Postpartum Iodine and drugs Irradiation

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• Pathogenesis of Graves’ disease

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1. Thyroglobulin antibody (Tg Ab) 2. Thyroid peroxidase antibody (TPO Ab), formerly called microsomal antibody (Ms Ab) 3. TSH receptor antibody (TSH-R Ab): stimulating type (TSH-R Ab[stim]), blocking type (TSH-R Ab[block])

Clin Endocrinol (Oxf). 2004 Apr;60(4):397-409.. 14

Pictures of Gravesâ&#x20AC;&#x2122; ophthalmopathy and chronic pretibial myxedema

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Pathogenesis of Gravesâ&#x20AC;&#x2122; ophthalmopathy

Med Clin North Am. 2012 March ; 96(2): 311â&#x20AC;&#x201C;328.

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Risk factor of development or worsening of Gravesâ&#x20AC;&#x2122; orbitopathy

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Evaluation of Gravesâ&#x20AC;&#x2122; ophthalmopathy: Severity and clinical activity score Severity

0 = No signs or symptoms 1 = Only signs (lid retraction or lag), no symptoms 2 = Soft tissue involvement (periorbital edema) 3 = Proptosis (>22 mm) 4 = Extraocular muscle involvement (diplopia) 5 = Corneal involvement 6 = Sight loss

Activity

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Treatment of Graves’ ophthalmopathy (甲狀腺眼病變之治療) 發炎性眼病變: 常眨眼、人工淚液或保 濕性凝膠 眼罩、太陽眼鏡避光 低鹽飲食、睡覺時頭墊 高或使用利尿劑 類固醇治療 眼球輻射治療

突眼矯正治療: 偏光鏡 眼皮眼袋整型 眼窩減壓矯正手術 (複 視或急性眼神經病變)

Med Clin North Am. 2012 March ; 96(2): 311–328.

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(甲狀腺亢進的治療選擇)

TREATMENT CHOICE OF HYPERTHYROIDISM 21

Treatment of hyperthyroidism Medicine: Anti-thyroid drugs (thionamides) – For most of patients ( Preparation before surgery; adjuvant for radioiodine therapy (before or after); mild disease, small goiter) Surgery: near-total or total thyroidectomy – For huge goiter, refractory disease and sight threatening GO Radioiodine (I131) therapy – Second choice for ablation without complication of surgery – Avoid in active GO patients Plasmapheresis – Thyroid storm

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Antithyroid drug (ATD) •

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Thionamides: – Propylthiouracil (PTU) • block peripheral T4 to T3 conversion • Rare cases: hepatitis (0.1-0.2%), agranulocytosis(0.1-0.5%) • t1/2: 1.5hrs – Carbimazole (CMZ) • 10mg CMZ → metabolized to 6 mg MMI – methimazole (MMI) • First choice, t1/2: 6 hrs • 20-30mg/d → 5 -10mg/d for maintenance Mechanism: – inhibit the function of TPO – reduce oxidation and organification of iodide – reduce thyroid antibody, immunosuppression – enhance remission rate Treatment course: 6-24 months 23

Other immunosuppressive effects: Anti-TSH receptor Ab decrease with time Decrease cytokine (intracellular adhesion molecule 1, IL-2, IL-6 receptor) Induce apoptosis of intrathyroidal lymphocytes Decrease HLA class II expression Increase circulating suppressor T cells Decrease helper T cells, natural killer cells, and activated intrathyroidal T cells

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Methimazole should be used in virtually every patient who chooses antithyroid drug therapy for GD, except during the first trimester of pregnancy when propylthiouracil is preferred, in the treatment of thyroid storm, and in patients with minor reactions to methimazole who refuse radioactive iodine therapy or surgery.

Thyroid. 2011 Jun;21(6):593-646 25 Williams Textbook of Endocrinology, 12th edition

Other medicine for hyperthyroidism 1. beta-blocker (交感神經阻斷劑): e.g., propranolol 1040 mg q6h.

2. Corticosteroid (腎上腺皮質素) : e.g., dexamethasone 2mg q6h 3. Sedative and tranquilizer (鎭靜劑) 4. Ipodate sodium or iopanoic acid (碘劑) 5. Anticoagulation with warfarin in patients with atrial fibrillation; digoxin in patients with heart failure 26

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Surgery Indication: 1. Toxic multinodular goiters 2. Large goiter with symptomatic compression (>80 g) 3. Thyrotoxicosis in 2nd trimester 4. Gravesâ&#x20AC;&#x2122; combined with documented malignant or suspected nodule 5. Coexisting hyperparathyroidism Operation: Near-total or Total thyroidectomy (3 drops SSKI tid before op)

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Radioiodine therapy • I131 dose: 5-15 mCi (185-555MBq) • Note: 1. Contraindication: pregnancy and breast feeding, children < 5 yrs (suggested < 10 mCi for children between 5-10 yrs) 2. Complication : radiation thyroiditis (10-14 d after I131) 3. Results: hypothyroidism (not avoided by accurate dosimetry) 4. Incomplete tx or early relapse: males and > 40 yrs of age 5. Prevention of exacerbation of ophthalmopathy: Prednisone 40 mg/d and taper over 2-3 months (0.4-0.5 mg/kg/day for 1 month, and then taper over 2 months; 0.2 mg/kg/d for 6 wks), especially for smokers with mild active Graves’ orbitopathy or those with moderated to severe active Graves’ orbitopathy •

Prognosis: radiation thyroiditis (rare), hypothyroidism (10-20% in 1st year and 5% per year thereafter).

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Comparison of the treatment strategies Intervention

Delay Risk of before recurrence euthyroid

Risk of permanent hypothyroidism

Potential complication or contraindication

ATD

6-8 wks

50-80%

Virtually nil

Major side effects (life threatening ) Need continued monitor and dose titration, possible recurrence

I131

4-24 wks

5-20 % (dose related)

50-100 % (dose and follow period related)

Non identified complication Pregnancy and lactation Potential worsening of ophthalmopathy

Surgery (total thyroidectomy)

days

0%

All

Severe comorbidities with op risk Hypocalcemia, hoarseness, post-op bleeding Lifelong thyroid hormone replacement 30

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毒性結節性甲狀腺腫

TOXIC MULTINODULAR GOITER (TMNG) AND TOXIC ADENOMA 32

Toxic Multinodular Goiter (TMNG) • Pathogenesis: – similar to that of nontoxic MNG – molecular basis: somatic mutation in TSH receptor gene (only 60%) , many nodules with autonomy of undetermined cause • S/S: – subclinical hyperthyroidism or mild thyrotoxicosis, elderly patient with atrial fibrillation or palpitation, tachycardia, nervousness, tremor or weight loss • Dx: thyroid function and thyroid scan(I131, I123, Tc99m)

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Toxic Multinodular Goiter (TMNG) • Treatment consideration and contraindication: – Antithyroid drugs combined with beta blockers: for age > 60 yrs, CV disease or severe hyperthyroidism – Radioiodine: advanced age, significant co-morbidities, prior op or neck scar, small goiter • contraindication for pregnancy, lactation, coexisting thyroid cancer, unable to follow radiation safety guideline – Surgery: presence of s/s of compression, coexisting thyroid cancer, hyperparathyroidism, large goiter size (>80g), substernal or retrosternnal extension, RAIU insufficient for therapy, need rapid correction of thyrotoxicosis • contraindication for significant comorbities (cardiopulmonary disease, end-stage cancer, debilitating disorder, relative for pregnancy) 34

Hyperfunctioning Solitary Nodule (Toxic adenoma) • Pathogenesis: by acquired somatic, activating mutations in TSH-R (90%) • Diagnosis: thyroid scan • Treatment: – Radioiodine ablation (10-20 mCi, or 150-200 uCi/gm) – Surgical resection (ipsilateral lobectomy and/or isthmusectomy) – Percutaneous Ethanol Injection (PEI) under ultrasound guidance – Thermal and radiofrequency ablation 35

Evolution of thyrotoxicosis in multinodular goiter 36

Treatment for TMNG or TA

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其他造成甲狀腺亢進的原因

OTHER ETIOLOGY OF HYPERTHYROIDISM 38

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TSH-secreting Pituitary adenoma •

S/S: – thyrotoxicosis, diffuse goiter, headache, visual disturbance, pituitary mass with hypopituitarism (loss of gonadal function)

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Diagnosis: – increased T4, T3, free T4, RAIU elevated or normal TSH – α-subunit/TSH >1, – blunted or absence TSH response to TRH – CT scan or MRI Treatment – Transphenoid pituitary surgery – Sella irradiation (3000-4500 rad) – Pharmacotherapy (Octreotide acetate or dopamine agonist) – I131 or ATD

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Drug-associated thyrotoxicosis • Mechanism: – iodine-induced thyrotoxicosis; – destructive thyroiditis; – induction of thyroid autoimmunity (GD or painless thyroiditis).

Thyroid. 2011 Jun;21(6):593-646

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Drug-associated thyrotoxicosis

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Iodine-induced thyroid dysfunction •

The recommended minimum daily intake of iodine – – – –

150 mcg for nonpregnant adults, 220 mcg for pregnant women, 290 mcg for lactating women, 90 to 120 mcg/day for children aged 1 to 13 years.

– The average intake in the United States is about 150 to 200 mcg/day

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Amiodarone contains approximately 37% iodine by weight. Each 200-mg tablet is estimated to contain about 75 mg of organic iodide Wolff-Chaikoff effect - Hypothyroidism caused by ingestion of large amt of iodine Jod-Basedow effect - hyperthyroidism due to administration of iodine or iodide

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J Pak Med Assoc. 2012 Mar;62(3):268-72.

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Comparison of AIT type 1 and type 2

J Pak Med Assoc. 2012 Mar;62(3):268-72.

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甲狀腺風暴

THYROID STORM

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Introduction of thyroid storm • A rare, life-threatening condition characterized by severe clinical manifestations of thyrotoxicosis – (未處理的患者死亡率將近100%, 即使經處理的患者死 亡率亦有20-30%) • In a national survey from Japan, the incidence of thyroid storm in hospitalized patients was 0.20 per 100,000 per year • Thyroid storm can develop in patients with: – long-standing untreated hyperthyroidism (Graves’ disease, toxic multinodular goiter, solitary toxic adenoma) – it is often precipitated by an acute event such as thyroid or nonthyroidal surgery, trauma, infection, an acute iodine load, or parturition 47

• It is unclear why certain factors result in the development of thyroid storm.

– Hypotheses include a rapid rate of increase in serum thyroid hormone levels – increased responsiveness to catecholamines – enhanced cellular responses to thyroid hormone.

– The degree of thyroid hormone excess varies for each case • Diagnosis of thyroid storm is based on point scale system ( clinical diagnosis )

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Treatment for thyroid storm

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SUBCLINICAL (MILD) HYPERTHYROIDISM 51

• Subclinical hyperthyroidism is defined biochemically by a low serum TSH (<0.5 mU/mL) concentration but normal serum free T4 and T3 concentrations.

• Patients with subclinical hyperthyroidism typically have few or no symptoms of hyperthyroidism.

• The common causes of subclinical hyperthyroidism – Treatment with T4 (exogenous) – Graves disease, autonomous functioning thyroid adenoma, and toxic multinodular goiter (endogenous)

• Subclinical hyperthyroidism is associated with an increased risk of atrial fibrillation and, primarily in postmenopausal women, a decrease in bone mineral density.

• Patients receiving thyroid replacement therapy for the treatment of hypothyroidism and who have TSH concentrations below normal should have their dose adjusted to maintain a normal serum TSH concentration (approximately 0.5 to 5.0 mU/L).

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When to treat Subclinical hyperthyroidism

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HYPERTHYROIDISM LABORATORY EVALUATION 54

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• In Graves’ disease, the TSH level is suppressed, and total and unbound thyroid hormone levels are increased.

• 2-5% of patients (and more in areas of borderline iodine intake), only T3 is increased (T3 toxicosis).

• Measurement of TPO antibodies or TRAb may be useful if the diagnosis is unclear clinically but is not needed routinely.

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甲狀腺功能低下

HYPOTHYROIDISM

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Hypothyroidism

Hypothyroidism after treatment 58

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Primary Hypothyroidism

The prevalence of overt hypothyroidism is approximately 1% to 2% in women and 0.1% in men, whereas subclinical hypothyroidism has been identified in 4% to 10% of different population groups and in up to 18% of elderly persons. Progression from subclinical to overt hypothyroidism occurs in 5% to 18% of persons with subclinical hypothyroidism per year.

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Secondary Hypothyroidism

The most common causes of central hypothyroidism in adults are tumors, inflammatory conditions, infiltrative diseases, infections, pituitary surgery, pituitary radiation therapy, and head trauma.

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Autoimmune Hypothyroidism (I) • • • •

Hashimoto’s thyroiditis or goitrous thyroiditis Atrophic thyroiditis at the later stages Subclinical hypothyroidism Clinical hypothyroidism or overt hypothyroidism (TSH > 10 mIU/L) • Prevalence: 1. The annual incidence of autoimmune hypothyroidism is around 80 per 100,000 men and 350 per 100,000 women.

2. All ages may be affected, although the average age of onset is between 40 and 60 years old. Prevalence increased with age.

3. Subclinical hypothyroidism: 6-8 % of women (10% over the age of 60), annual risk of progression to overt hypothyroidism is 4 %.

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Autoimmune Hypothyroidism (II) â&#x20AC;˘ Pathogenesis: 1.

thyroid with lymphocytic infiltration (activated CD4+, CD8+ T cells and B cells), germinal center formation, atrophic follicles with oxyphil metaplasia, absence of colloid, fibrosis

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thyroid destruction by T-cell mediated cytotoxic reaction; CD8+ cytotoxic T cells and cytokines (TNFÎą, IL-1, interferon render thyroid cells more susceptible to apoptosis mediated by death receptors (Fas).

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combination of genetic and environmental risk factors: documented risk of HLADR3, 4,5 polymorphism in Caucasians, weak correlation to polymorphism in CTLA-4 (T cell-regulatory gene) and high iodine intake

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20% with TSH-R Ab to block binding of TSH (TSH-R blocking Ab) cause hypothyroidism and atrophy, esp in Asian.

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Treatment of Hypothyroidism Patients who have serum TSH levels higher than 10 mU/L should be strongly considered for L-T4 treatment.

Overt hypothyroidism: average LT4 replacement dose in adults is 1.6 µg/kg per day and that lean body mass is a better predictor of thyroid hormone requirements than total body weight.

Overt hypothyroidism (patient older than 60 years) should be treated with an initial LT4 dose of 25 to 50 µg/d and dose increases in 12.5- to 25-µg increments every 6 to 8 weeks until the desired dose is reached.

Subclinical hypothyroidism: serum TSH levels of 5 to 10 mU/L should also be considered for LT4 treatment if they have symptoms suggestive of thyroid hormone deficiency: such as elevated serum low-density lipoprotein (LDL) cholesterol levels, goiters, or positive antithyroid antibodies.

Patients with subclinical hypothyroidism can be effectively treated with initial LT4 doses of 25 to 50 µg/d and subsequent daily dose increments of 25 µg until the desired TSH goal is reached.

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Recommended Replacement Dosage of L-Thyroxin Age (years) 0-6 months 6-12 months 1-5 6-12 > 12 Adult

Dose (Âľg/kg/day) 10 6-8 5-6 4-5 2-3 1.6-1.7 (or 0.8 mcg/lb)

Elevated TSH (sign of poor adherence to tx ) or malabsorption (e.g., celiac disease small-bowel surgery), estrogen therapy or drugs to interfere T4 absorption or clearance (cholestyramine, ferrous sulfate, calcium supplement, lovastatin, aluminum hydroxide, rifampicin, amiodarone, carbamazepine, phenytoin) 69

HYPOTHYROIDISM LABORATORY EVALUATION 70

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THYROID FUNCTION TEST

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Thyroid function test • Hyperthyroidism: TSH < 0.1 uU/mL (0.1 mU/L) and elevated FT4D or FT4I • Subclinical hyperthyroidism Normal FT4D or FT4I; but slightly suppressed TSH • Hypothyroidism: TSH > 10 uU/mL (mU/L) and low FT4D or FT4I • Subclinical hypothyroidism: Normal FT4D or FT4I; but slightly high TSH

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Total form vs free form of thyroid hormone •

T4 TESTS: T4 circulates in the blood in two forms: – –

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(1) T4 bound to proteins that prevent the T4 from entering the various tissues that need thyroid hormone.

(2) Free T4, which does enter the various target tissues to exert its effects. The free T4 fraction is the most important to determine how the thyroid is functioning, and tests to measure this are called the Free T4 (FT4) and the Free T4 Index (FT4I or FTI). Individuals who have hyperthyroidism will have an elevated FT4 or FTI, whereas patients with hypothyroidism will have a low level of FT4 or FTI.

T3 TESTS – – – – –

T3 tests are often useful to diagnosis hyperthyroidism or to determine the severity of the hyperthyroidism.

Patients who are hyperthyroid will have an elevated T3 level.

In some individuals with a low TSH, only the T3 is elevated and the FT4 or FTI is normal.

T3 testing rarely is helpful in the hypothyroid patient, since it is the last test to become abnormal.

Patients can be severely hypothyroid with a high TSH and low FT4 or FTI, but have a normal T3.

In some situations, such as during pregnancy or while taking birth control pills, high levels of total T4 and T3 can exist. This is because the estrogens increase the level of the binding proteins. In these situations, it is better to ask both for TSH and free T4 for thyroid evaluation.

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The major iodothyronines are poorly soluble in water and thus bind reversibly to plasma proteins.

The plasma proteins with which T4 is mainly associated are TBG and transthyretin (TTR; formerly termed T4-binding prealbumin [TBPA]) and albumin About 75% to 80% of T3 is bound by TBG and the remainder by TTR and albumin.

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Medication to influence thyroid function test • Estrogen (contraceptive pill, pregnancy): increase TT4 • Glucocorticoids, Dopamine: decrease TSH and T3 • Propranolol: block conversion of T4 to T3 • Iodide (contrast):cause hyper- and hypo-thyroidism • Amiodarone: induce thyroid dysfunction (14-18%) • Lithium: induce hypo-or hyperthyroidism (10%) • Phenytoin, Carbamazepine or Furosemide: inhibit thyroid hormone binding resulting TT4 ↓ 82

Factors or conditions with decreased conversion of T4 to T3 1. Fetal life 2. Caloric restriction 3. Hepatic disease 4. Major systemic illness 5. Drugs: Propylthiouracil, Glucocorticoids Propranolol (mild effect) Iodinated X-ray contrast agents ( iopanoic acid, ipodate sodium), Amiodarone 6. Selenium deficiency 83

Overview of thyroid disease evaluation 1. Thyroid function test and evaluation: TSH and free T4 Thyroid scintillation scan (Tc99m, I131, I123, Tl201) 2. During tx period: T4 (or free T4) and T3 3. Thyroid morphology Thyroid sonography and scan 3. Etiology of thyroid gland: Serum thyroid auto-antibodies (Tg-Ab, Ms-Ab; TSH-R Ab) Fine needle aspiration cytology 4. Tumor marker: Thyroglobulin, CEA, Calcitonin, etc

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Summary • Symptoms and signs of hyperthyroidism (effects of thyroid hormone to human) • Graves’ disease: presentation, pathogenesis and ophthalmopathy • How to manage hyperthyroidism? OP, RIA, ATD • Other etiology of thyrotoxicosis: TMNG, TA, drug induced thyrotoxicosis ( e.g., Amiodarone induced thyrotoxicosis )

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Thyroid storm Symptoms and signs of hypothyroidism Hypothyroidism etiology and pathogenesis Thyroid function test and thyroid autoantibody Differential diagnosis of hyperthyroidism and hypothyroidism

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Reference • 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016 Oct;26(10):1343-1421.

• Clinical practice. Graves' ophthalmopathy. N Engl J Med. 2009 Mar 5;360(10):994-1001.

• Williams Textbook of Endocrinology, 13th Edition.

• Harrison‘s Principles of Internal Medicine, 19th Edition Textbook.

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Thank you!

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