Chapter 396_ Hyperthyroidism and Other Causes of Thyrotoxicosis.pdf

State of thyroid hormone excess, not synonymous with hyperthyroidism which requires excessive thyroid function

What is the definition of thyrotoxicosis?

. Graves' disease, toxic multinodular goiter, and toxic adenomas

What are the three major etiologies of hyperthyroidism?

. Graves' disease, toxic multinodular goiter, toxic adenoma, functioning thyroid carcinoma metastases, activating mutation of TSH receptor, activating mutation of \(G_s\alpha\) (McCune-Albright syndrome), struma ovarii, and iodine excess (Jod-Basedow)

What conditions cause primary hyperthyroidism?

. Subacute thyroiditis, silent thyroiditis, drug-induced thyroid destruction (amiodarone, cytokines, TKIs, checkpoint inhibitors), radiation, infarction of adenoma, thyrotoxicosis factitia, and ingestion of thyroid tissue

What conditions cause thyrotoxicosis without hyperthyroidism?

. TSH-secreting pituitary adenoma, thyroid hormone resistance syndrome, chorionic gonadotropin-secreting tumors, and gestational thyrotoxicosis

What conditions cause secondary hyperthyroidism?

. 60% to 80%

What percentage of thyrotoxicosis cases are caused by Graves' disease?

. Up to 2% in women, and one-tenth as frequent in men

What is the prevalence of Graves' disease in women versus men?

. 20 to 50 years of age

What is the typical age range for the onset of Graves' disease?

. HLA-DR, CTLA-4, CD25, CD40, PTPN22, FCRL3, CD226, and TSH receptor (TSH-R) gene

Which immunoregulatory and thyroid genes contain polymorphisms associated with susceptibility to Graves' disease?

. 20–30% in monozygotic twins versus <5% in dizygotic twins

What is the concordance rate for Graves' disease in monozygotic versus dizygotic twins?

. Stress, smoking, sudden increases in iodine intake, postpartum period, and immune reconstitution

What environmental factors precipitate or increase the risk of Graves' disease?

. Threefold increase

By how much does the occurrence of Graves' disease increase during the postpartum period?

. HAART (for HIV), alemtuzumab, and immune checkpoint inhibitors (nivolumab, pembrolizumab)

Which therapies cause Graves' disease during their immune reconstitution phase or treatment?

. Thyroid-stimulating immunoglobulins (TSIs)

What autoantibodies directly cause the hyperthyroidism of Graves' disease?

. Lymphocytes within the thyroid gland, bone marrow, and lymph nodes

Where are thyroid-stimulating immunoglobulins synthesized?

. Thyroid peroxidase (TPO) antibodies and thyroglobulin (Tg) antibodies

Which coexisting thyroid autoantibodies occur in up to 80% of Graves' disease cases?

. Activation of T cells and release of cytokines (IFN-\(\gamma\), TNF, IL-1) that activate fibroblasts to synthesize water-trapping glycosaminoglycans

What mechanism causes extraocular muscle swelling in thyroid-associated ophthalmopathy?

. Retrobulbar tissue expansion due to increased intraorbital fat and extraocular muscle swelling

What causes the increase in intraorbital pressure leading to proptosis, diplopia, and optic neuropathy in Graves' orbitopathy?

. Expression of TSH receptor (TSH-R) autoantigen and aberrant IGF-1 receptor (IGF-1R) signaling on orbital fibroblasts

Which two receptors on orbital fibroblasts are involved in the pathogenesis of Graves' ophthalmopathy?

. Teprotumumab

Which monoclonal antibody inhibitor of the IGF-1 receptor reduces TSH-R/IGF-1R complexes to attenuate orbital signaling?

. Apathetic thyrotoxicosis presenting with fatigue and weight loss

How does thyrotoxicosis typically present in elderly patients?

. Hyperactivity, irritability, dysphoria, heat intolerance, sweating, palpitations, fatigue, weakness, weight loss with increased appetite, diarrhea, polyuria, oligomenorrhea, and loss of libido

What are the most common symptoms of thyrotoxicosis in descending order of frequency?

. Tachycardia, tremor, goiter, warm moist skin, muscle weakness/proximal myopathy, lid retraction/lag, and gynecomastia

What are the most common physical signs of thyrotoxicosis in descending order of frequency?

. 5% of patients

In what percentage of hyperthyroid patients does weight gain occur due to hyperphagia?

. Stretching out fingers while feeling the fingertips with the examiner's palm

What is the best physical maneuver to elicit the fine tremor of thyrotoxicosis?

. Hyperreflexia, muscle wasting, and proximal myopathy without fasciculation

What are the characteristic neurological physical examination findings in thyrotoxicosis?

. Asian males

Which patient population is most predisposed to thyrotoxic hypokalemic periodic paralysis?

. Sinus tachycardia

What is the most common cardiovascular manifestation of thyrotoxicosis?

. Atrial fibrillation

Which arrhythmia occurs predominantly in thyrotoxic patients over 50 years of age?

. 75% of patients

What percentage of thyrotoxic atrial fibrillation patients spontaneously revert to normal sinus rhythm upon achieving euthyroidism?

. Palmar erythema, onycholysis, pruritus, urticaria, diffuse hyperpigmentation, fine hair texture, and diffuse alopecia

What skin and hair changes occur in thyrotoxicosis?

. Up to 40% of patients

In what percentage of thyrotoxic patients does diffuse alopecia occur?

. Decreased transit time causing increased stool frequency, diarrhea, and mild steatorrhea

How does thyrotoxicosis affect gastrointestinal motility?

. Direct effect of thyroid hormones increasing bone resorption leading to osteopenia, hypercalciuria, and mild hypercalcemia in 20%

How does long-standing thyrotoxicosis affect bone metabolism and calcium levels?

. Diffusely enlarged 2 to 3 times normal size, firm, non-nodular, with an inferolateral thrill or bruit

What are the physical palpation and auscultation characteristics of the thyroid in Graves' disease?

. Sympathetic overactivity affecting the levator palpebrae superioris muscles

What causes lid retraction and staring appearance in all forms of thyrotoxicosis?

. Thyroid eye disease (TED) / Graves' ophthalmopathy

What specific eye condition occurs in 10% of patients in the absence of hyperthyroidism?

. Within 1 year before or after the diagnosis of thyrotoxicosis

When does Graves' ophthalmopathy present in 75% of affected patients?

. Grittiness, eye discomfort, and excess tearing

What are the earliest clinical manifestations of Graves' ophthalmopathy?

. One-third of patients

What proportion of Graves' disease patients have clinical proptosis?

. Visualization of sclera between the lower border of the iris and the lower eyelid in primary gaze

How is proptosis detected on visual inspection?

. Looking up and laterally

During which direction of gaze does diplopia most commonly manifest in Graves' ophthalmopathy?

. Compression of the optic nerve at the apex of the orbit

What is the most serious sight-threatening manifestation of Graves' orbitopathy?

. Papilledema, peripheral field defects, and permanent vision loss

What visual changes result from optic nerve compression at the orbital apex?

. 0 = No signs or symptoms; 1 = Only signs (lid retraction/lag); 2 = Soft tissue involvement; 3 = Proptosis (>22 mm); 4 = Extraocular muscle involvement; 5 = Corneal involvement; 6 = Sight loss

What do the numbers 0 through 6 represent in the NO SPECS scoring system?

. European Group on Graves' Orbitopathy (EUGOGO) system

Which clinical system is preferred over NO SPECS for monitoring and assessing Graves' orbitopathy activity?

. Noninflamed, indurated plaque with deep pink/purple color and "orange skin" (peau d'orange) appearance over the anterior/lateral lower leg

What is the physical appearance and common location of thyroid dermopathy (pretibial myxedema)?

. <5% of patients

What is the prevalence of thyroid dermopathy in Graves' disease?

. Thyroid acropachy

What form of digital clubbing occurs in <1% of Graves' disease patients and is strongly linked to dermopathy?

. Suppressed TSH, elevated total \(T_4\), elevated unbound \(T_4\), and elevated \(T_3\)

What is the classic serum hormone profile in Graves' disease?

. \(T_3\) toxicosis

What term describes hyperthyroidism with suppressed TSH, normal \(T_4\), and elevated \(T_3\) occurring in 2–5% of patients?

. \(T_4\) toxicosis

What term describes hyperthyroidism induced by excess iodine providing surplus substrate?

. Elevation of bilirubin, liver enzymes, and ferritin; microcytic anemia and thrombocytopenia

Which non-thyroid laboratory abnormalities can be caused by thyrotoxicosis?

. Diffuse high uptake

What radionuclide scan uptake pattern distinguishes Graves' disease from destructive thyroiditis?

. Color-flow Doppler ultrasonography

Which non-radiologic imaging modality distinguishes hyperthyroidism (increased blood flow) from destructive thyroiditis?

. Nonsuppressed TSH (normal or elevated) with elevated \(T_4/T_3\) and a pituitary tumor on MRI/CT

What laboratory and imaging findings identify a TSH-secreting pituitary tumor?

. 10% to 30%

What was the historical mortality rate of Graves' disease prior to modern therapy?

. 15% of patients

What percentage of treated Graves' disease patients develop late-onset hypothyroidism 10–15 years later?

. Worsens over initial 3–6 months, plateaus for 12–18 months, then shows spontaneous improvement

What is the typical natural clinical timeline of Graves' ophthalmopathy?

. Radioiodine (\(^{131}\text{I}\)) treatment

Which Graves' disease therapy worsens ophthalmopathy, particularly in smokers?

. 1 to 2 years after hyperthyroidism onset

When does thyroid dermopathy typically appear relative to Graves' hyperthyroidism?

. Thionamides: propylthiouracil (PTU), carbimazole, and methimazole

What are the primary antithyroid drugs used in Graves' disease?

. Inhibition of thyroid peroxidase (TPO) function, reducing oxidation and organification of iodide

What is the primary mechanism of action of thionamide drugs?

. Inhibition of peripheral deiodination of \(T_4\) to \(T_3\)

What additional minor mechanism of action is possessed by propylthiouracil?

. 90 minutes for PTU versus 6 hours for methimazole

What are the plasma half-lives of propylthiouracil and methimazole?

. First trimester of pregnancy, thyroid storm, and minor adverse reactions to methimazole

What three specific indications are designated by the FDA for propylthiouracil use due to hepatotoxicity?

. 10–20 mg every 12 hours initially (methimazole); 100–200 mg every 6–8 hours initially (PTU)

What are the initial daily starting doses for methimazole and propylthiouracil?

. Titration regimen (gradual dose reduction) and Block-replace regimen (high ATD dose plus levothyroxine)

What are the two main antithyroid drug dosing strategies?

. 4 to 6 weeks after starting therapy

When should thyroid function tests be first reviewed after starting antithyroid drugs?

. Unbound \(T_4\) levels

Which laboratory parameter is used to titrate antithyroid drug doses in the first several months?

. 6 to 8 weeks

How long after initiating antithyroid drug therapy do most patients achieve euthyroidism?

. TSH remains suppressed for several months

Why is TSH NOT a sensitive index of treatment response early in antithyroid drug therapy?

. 2.5–10 mg daily for methimazole/carbimazole; 50–100 mg daily for PTU

What are the standard daily maintenance doses for antithyroid drugs in a titration regimen?

. 30% to 60%

What is the maximum remission rate achieved after 12–18 months of antithyroid drug titration therapy?

. Disappearance of serum TSH receptor antibodies (TRAb)

Which serological marker predicts a higher probability of remission after stopping ATDs?

. Younger age, male sex, smoking, allergy history, severe hyperthyroidism, large goiter, and persistent TRAb

Which clinical factors increase the risk of relapse after stopping antithyroid drugs?

. Rash, urticaria, fever, and arthralgia (occurring in 1–5% of patients)

What are the common minor side effects of antithyroid drugs?

. Hepatitis (PTU), cholestasis (methimazole/carbimazole), vasculitis, and agranulocytosis (<1%)

What are the rare major side effects of antithyroid drugs?

. Sore throat, fever, and mouth ulcers

What symptoms should prompt a patient on antithyroid drugs to stop medication immediately and get a CBC?

. Abrupt and idiosyncratic onset

Why is prospective routine blood count monitoring ineffective for detecting thionamide-induced agranulocytosis?

. Propranolol (20–40 mg every 6 hours) or atenolol

Which adrenergic antagonists control sympathetic symptoms early in thyrotoxicosis?

. Decreased warfarin dose required; increased digoxin dose required

How does the thyrotoxic state alter the dosage requirements for warfarin and digoxin?

. At least one month of antithyroid drug pretreatment

How can the small risk of radioiodine-induced thyrotoxic crisis be minimized in elderly or cardiac patients?

. Stop 2–3 days before radioiodine; restart 3–7 days after

What is the timing protocol for stopping and restarting methimazole/carbimazole around radioiodine therapy?

. Prolonged radioprotective effect reducing radioiodine efficacy

Why must propylthiouracil be stopped for a longer duration before radioiodine therapy?

. 370 MBq (10 mCi) to 555 MBq (15 mCi)

What is the typical dose range of \(^{131}\text{I}\) administered for thyroid ablation in Graves' disease?

. Thyroid ablation (inducing hypothyroidism)

What is the primary management goal of radioiodine therapy in Graves' disease?

. Avoid close, prolonged contact with children and pregnant women for 5–7 days

What radiation safety precaution is required immediately following radioiodine administration?

. 1 to 2 weeks post-treatment

When does radiation thyroiditis typically present with mild neck pain after \(^{131}\text{I}\)?

. 2 to 3 months

How long does radioiodine take to exert its full therapeutic effect?

. 6 months after the initial dose

When can a second dose of radioiodine be administered for persistent hyperthyroidism?

. 10–20% in the first year, and 5% per year thereafter

What is the incidence of hypothyroidism following radioiodine therapy?

. Pregnancy and breastfeeding

What are the absolute contraindications to radioiodine therapy?

. 6 months

How long after radioiodine treatment must female patients wait before attempting conception?

. Oral prednisone (0.2–0.5 mg/kg/day) tapered over 6–12 weeks starting at time of \(^{131}\text{I}\)

What prophylaxis prevents exacerbation of Graves' ophthalmopathy following radioiodine?

. Potassium iodide (SSKI) 1–2 drops orally tid for 10 days preoperatively

What medication is given after ATDs prior to thyroidectomy to reduce gland vascularity?

. Bleeding, laryngeal edema, hypoparathyroidism, and recurrent laryngeal nerve damage

What are the major surgical complications of thyroidectomy?

. <2%

What is the recurrence rate of hyperthyroidism following total or near-total thyroidectomy by experienced surgeons?

. Maternal serum free or total \(T_4\) levels at or just above the upper limit of the pregnancy reference range

What is the target maternal thyroid hormone level when treating Graves' disease during pregnancy?

. Propylthiouracil

Which antithyroid drug is preferred during the first trimester of pregnancy up to 14–16 weeks?