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Thyroid Disorders: Hyperthyroidism and Thyroid Storm Introduction Thyroid hormone affects all organ systems, and is responsible

for increasing metabolic rate, heart rate, ventricle contractility, as well as muscle and central nervous system excitability. Two major types of thyroid hormones are thyroxine (T4 ) and triiodothyronine (T3). T4 is the major form of thyroid hormone. The ratio of T4 to T3 released in the blood is 20:1. Peripherally, T4 is converted to the active T3, which is three to four times more potent than T4 . Hyperthyroidism refers to excess circulating hormone resulting only from thyroid gland hyperfunction whereas thyrotoxicosis refers to excess circulating thyroid hormone originating from any cause (including thyroid hormone overdose). Thyroid storm is the extreme manifestation of thyrotoxicosis. This is an acute, severe, life-threatening state of thyrotoxicosis caused either by adrenergic hyperactivity or altered peripheral response to thyroid hormone following the presence of one or more precipitants.

Epidemiology In the U.S., the overall incidence of hyperthyroidism is estimated to be between 0.05% to 1.3%, with the majority being subclinical in terms of presentation.1 Among hospitalized thyrotoxicosis patients, the incidence of thyroid storm has been noted to be <10%.2 The mortality of thyroid storm without treatment is between 80% and 100%, and with treatment, it is between 15% and 50%.

Causes of Hyperthyroidism or Thyrotoxicosis

Table 224-1 Causes of Hyperthyroidism: Primary and Secondary Hyperthyroidism

Primary Hyperthyroidism Graves disease (toxic diffuse goiter) (Figure 224-0.1) Most common of all hyperthyroidism (85% of all cases) Associated with diffuse goiter, ophthalmopathy, and local dermopathy Second most common cause of hyperthyroidism An enlarged thyroid gland that contains a small rounded mass or masses called nodules with overproduction of thyroid hormone

Toxic multinodular goiter Toxic nodular (adenoma) goiter (Figure 224-0.2) Secondary Hyperthyroidism Thyrotropin-secreting pituitary adenoma Thyroiditis Hashimoto thyroiditis

Thyroid gland stimulated to produce hormones

Inflammation of the thyroid gland. Initially gland is overactive (hyperthyroidism state) but this is usually followed by a state of hypothyroidism

Subacute painful thyroiditis (de Quervain thyroiditis) Subacute painless thyroiditis Radiation thyroiditis

Table 224-2 Other Causes of Hyperthyroidism

Nonthyroidal Disease Ectopic thyroid tissue (struma ovarii)/teratoma Metastatic thyroid cancer Human chorionic gonadotropin Drug-Induced Iodine

A rare form of mature teratoma that contains mostly thyroid tissue. Stimulates production of thyroid hormones. Secreting hydatidiform mole.

Amiodarone

-Interferon Interleukin-2 Excessive thyroid hormone ingestion Thyrotoxicosis factitia Ingestion of meat containing beef thyroid tissue

Iodine-induced thyrotoxicosis (called Jod-Basedow disease). After treatment of endemic goiter patients with iodine or stimulation of thyroid hormones from use of iodinecontaining agents like radiographic contrast agents. Contains iodine. May cause either thyrotoxicosis or hypothyroidism. During treatment for other diseases, such as viral hepatitis and human immunodeficiency virus infection.

Munchausen-like; thyroid hormone is taken by patient to fake illness. Cow thyroid tissue contains thyroid hormones.

Other causes may include nonthyroidal diseases caused by production of thyroid hormones at sites away from the thyroid glands. Drug-induced thyrotoxicosis is caused by the interaction of the thyroid glands with certain drugs, causing stimulation of thyroid hormone production. Excessive thyroid hormone ingestion caused either by intentional or accidental intake will bring about thyrotoxicosis. The most common underlying cause of hyperthyroidism in cases of thyroid storm is Graves disease (85% of all hyperthyroidism cases in the U.S.). It is caused by the thyrotropin receptor antibodies that stimulate excess and uncontrolled thyroidal synthesis and secretion of thyroid hormones. It occurs most frequently in young women (10 times more common in women compared with men) at any age group.3 Toxic multinodular goiter is the second most common group in which thyroid storm tend to occur. Rare causes of thyrotoxicosis leading to thyroid storm include

hypersecretory thyroid carcinoma, thyrotropin-secreting pituitary adenoma, struma ovarii, and human chorionic gonadotropin secreting hydatidiform mole. Pathophysiology The pathophysiologic mechanisms underlying the shift from uncomplicated hyperthyroidism to thyroid storm are not entirely clear. However, they involve adrenergic hyperactivity either via increased thyroid hormone production or increased receptor sensitivity. Many of the signs and symptoms are related to adrenergic hyperactivity. When there is excess of thyroid hormones, circulating T4 and T3 are taken into the cytoplasm of cells. T4 is converted to its active form, T3, by 5'-deiodinase enzyme via deiodination in the outer ring of the T4 molecule. Within the cytoplasm, the T3 then exerts its effect by passing into the nucleus and binding to thyroid hormone receptors or thyroid hormone responsive elements to induce gene activation and transcription.4 The receptors receiving the hormone will stimulate changes specific to the tissue. Lipogenesis and lipolysis occur as thyroid hormone induces enzymes early in the lipogenic pathway, including malic enzyme, glucose-6-phosphate dehydrogenase, and fatty acid synthetase. Increased cholesterol production occurs via transcription of 3-hydroxy-3methylglutaryl coenzyme A reductase. Nevertheless, thyroid hormones also cause increased excretion of cholesterol in the bile, generally resulting in a decrease in total cholesterol. In the pituitary gland, T3 exerts negative regulation on the transcription of the genes for the subunit and the common subunit of TSH, resulting in a suppressed TSH in the context of thyrotoxicosis. During thyroid storm, precipitants such as infection, stress, myocardial infarction, or trauma will multiply the effect of thyroid hormones via freeing of thyroid hormones from their binding sites or increased sensitivity of the receptors in tissues via

increase in target cell -adrenergic receptor density or postreceptor modifications in signaling pathways. Thyroid Storm Precipitation The precipitants of thyroid storm are as shown in Table 224-3. The most common precipitating cause of thyroid storm currently is infection.5 Other causes include diabetic ketoacidosis, hypoglycemia, hyperosmolar coma, radioactive iodide treatment, pulmonary embolism, thyroid hormone overdose, withdrawal of antithyroid medications, iodinated contrast medium ingestion, vascular accidents, surgery, stress, parturition, eclampsia, trauma, and myocardial infarct. In approximately 20% to 25% of cases, no acute precipitant is identified. Table 224-3 Precipitants of Thyroid Storm

Systemic insult Infection Trauma General surgery Hyperosmolar coma Endocrinal insult Diabetic ketoacidosis Drug- or hormone-related Withdrawal of thyroid medication Iodine administration Thyroid gland palpation Ingestion of thyroid hormone

Cardiovascular insult Myocardial infarction Cerebrovascular accidents Pulmonary embolism Obstetrics-related Parturition Eclampsia Unknown etiology in up to 25% of cases

Clinical Features History and Comorbidities The patient may only complain of constitutional symptoms such as generalized weakness and fatigue. Heat intolerance, diaphoresis, fever, weight loss, anxiety, emotional lability, palpitations, diarrhea, and hair loss are common historical features. Medications that can precipitate thyrotoxicosis include iodine-containing medications, including radiographic contrast material, amiodarone, or large doses of topical povidone-iodine (especially if there is skin break). If there is a history of hyperthyroidism, treatment and compliance with medication should be determined. Physical Examination In general, patients often appear toxic and agitated. The signs and symptoms of hyperthyroidism patients are as shown in Table 224-4. Table 224-4 Symptoms and Signs of Thyrotoxicosis

Affected System Constitutional

Symptoms Lethargy Weakness Heat intolerance

Signs Diaphoresis Fever Weight loss Fine tremor Muscle wasting Hyperreflexia Periodic paralysis

Neuropsychiatric

Emotional lability Anxiety Confusion Coma Psychosis

Ophthalmologic

Diplopia Eye irritation

Lid lag Dry eyes Exophthalmos Ophthalmoplegia Conjunctival infection

Endocrine: thyroid gland (Figure 224-1)

Neck fullness

Thyroid enlargement

Tenderness Cardiorespiratory Dyspnea Palpitations Chest pain

Bruit Widened pulse pressure Systolic hypertension Sinus tachycardia Atrial fibrillation or flutter Congestive heart failure

GI Reproductive

Diarrhea Oligomenorrhea Decreased libido

Hyperactive bowel sound Gynecomastia Telangiectasia Sparse pubic hair

Gynecologic

Menorrhagia Irregularity

Hematologic

Pale skin

Anemia Leukocytosis

Dermatologic

Hair loss

Pretibial myxedema Warm, moist skin Palmar erythema Onycholysis

As for thyroid storm, the additional signs and symptoms apart from those evident in hyperthyroidism are as shown below: Presenting Signs and Symptoms of Thyroid Storm:

Fever is often present in thyroid storm and may be quite high. It may herald the onset of thyrotoxic crisis in previously uncomplicated disease. Palpitations, tachycardia, and dyspnea are common. A pleuropericardial rub may be heard. The direct inotropic and chronotropic effects of thyroid hormone on the heart cause decreased systemic vascular resistance, increased blood volume, increased contractility, and increased cardiac output. Enhanced contractility produces elevations in systolic blood pressure and pulse pressure, leading to a dicrotic or water-hammer pulse. Atrial fibrillation occurs in 10% to 35% of thyrotoxicosis cases.6,7 Exophthalmos is present in Graves disease. The severity of ophthalmopathy does not necessarily parallel the magnitude of thyroid dysfunction but reflects the responsible autoimmune process. Not all hyperthyroidism patients present with goiter. A goiter is not present with exogenous administration of thyroid hormone and apathetic thyrotoxicosis. Likewise, the presence of a goiter does not necessarily confirm the diagnosis of thyrotoxicosis. Thyroid gland tenderness can be found in inflammatory conditions such as subacute thyroiditis.8 Thyroid storm is a clinical diagnosis for patients with preexisting hyperthyroidism. Fever and tachycardia are cardinal features. The differential diagnosis of thyroid storm (as shown in Table 224-6) includes infection, sepsis, cocaine use, psychosis, pheochromocytoma, neuroleptic malignant syndrome, and hyperthermia.

Table 224-6 Differential Diagnosis for Thyroid Storm


Infection and sepsis Sympathomimetic ingestion (e.g., cocaine, amphetamine, ketamine drug use) Heat exhaustion Heat stroke Delirium tremens Malignant hyperthermia Malignant neuroleptic syndrome Hypothalamic stroke Pheochromocytoma Medication withdrawal (e.g., cocaine, opioids, etc.) Psychosis Organophosphate poisoning

Differential Diagnosis In an effort to standardize and objectify thyroid storm as compared with severe thyrotoxicosis, Burch and Wartofsky have delineated a point system assessing degrees of dysfunction in four systems: thermoregulatory, central nervous, GI, and cardiovascular systems (Table 224-7). The point system assists in determining whether the patient's presentation is unlikely, suggestive, or highly suggestive of thyroid storm.

Table 224-7 Burch and Wartofsky's Diagnostic Parameters and Scoring Points for Thyroid Storm Diagnostic Parameters 1. Thermoregulatory dysfunction Temperature C (F) 37.2 37.7 (99 99.9) 37.7 38.3 (100 100.9) 38.3 38.8 (101 101.9) 38.9 39.4 (102 102.9) 39.4 39.9 (103 103.9) 40 (104.0) 2. Central nervous system effects Absent Mild (agitation) Moderate (delirium, psychosis, extreme lethargy) Severe (seizures, coma) 3. GI-hepatic dysfunction Absent Moderate (diarrhea, nausea/vomiting, abdominal pain) Severe (unexplained jaundice) 4. Cardiovascular dysfunction Tachycardia (beats/min) 90 109 110 119 120 129 140 5. Congestive heart failure Absent Mild (pedal edema) Moderate (bibasilar rales) Severe (pulmonary edema) 6. Atrial fibrillation Absent Present Scoring system: Score of 45 Score of 25 44 Score of <25 : Highly suggestive of thyroid storm. : Suggestive of impending storm. : Unlikely to represent thyroid storm. Scoring Points

5 10 15 20 25 30 0 10 20 30 0 10 20

5 10 15 25 0 5 10 15 0 10

Laboratory Evaluation Serum Thyroid-Stimulating Hormone Level In primary hyperthyroidism, the TSH level is low as a result of the negative feedback mechanism of a high thyroid hormone level. Nevertheless, a low TSH level by itself is not diagnostic, as serum TSH may be reduced as a result of chronic liver or renal disease, or the effect of certain drugs like glucocorticoids, which reduce TSH secretion. In secondary hyperthyroidism, TSH is increased because of increased production in the pituitary. Free Thyroid Hormone Levels: Free Thyroxine and Free Triiodothyronine A low TSH with an elevated free thyroxine (FT4) confirms thyrotoxicosis. On the other hand, a low TSH with a normal FT4 but elevated free triiodothyronine (FT3 ) is also diagnostic of T3 thyrotoxicosis. T3 thyrotoxicosis occurs in <5% of patients who have thyrotoxicosis in North America.8 Thyroid hormone levels are not necessarily acutely elevated when the transition from uncomplicated thyrotoxicosis to thyroid storm occurs. T3 resin uptake estimates FT4 levels by measuring unoccupied thyroxine-binding globulin (TBG) sites and is also used to account for changes in binding protein concentration. A higher T3 resin uptake value means less TBG is available, implying the presence of hyperthyroidism. Total Thyroid Hormone Level of Thyroxine and Triiodothyronine Total serum T4 and T3 (bound and unbound) are increased. Eighty percent of circulating T3 is derived from mono-deiodination of T4 in peripheral tissues, whereas 20% emanates from direct thyroidal secretion. Both T4 and T3 are then bound to proteins in the form of TBG, transthyretin, and albumin. Only a small fraction of the hormones are free and unbound. Laboratory measurement of total T3 and total T4 measures mainly protein-bound hormone concentrations. Therefore, results may be

affected by conditions that affect protein binding. With the improved assays for FT4 and FT3, there is now little indication to measure total T3 and total T4. Thyroid Antibody Titers If Graves disease is suspected, thyroid antibody titers (to thyroid peroxidase or thyroglobulin) will help determine diagnosis. Thyroid-stimulating antibodies are detected in Graves disease. Thyroid hormone studies, complete blood count, electrolytes, glucose, and renal and liver function tests should be considered to identify comorbid abnormalities, but treatment has to start upon suspicion of the diagnosis. Hyperglycemia tends to occur because of a catecholamine-induced inhibition of insulin release, and increased glycogenolysis and rapid intestinal absorption of glucose. Mild hypercalcemia and elevated alkaline phosphatase can occur because of hemoconcentration and enhanced thyroid hormone stimulated bone resorption.9 Hyperthyroidism induces liver enzyme metabolism, causing raised liver enzymes. A high serum cortisol value is an expected finding in thyrotoxic individuals. This should be the normal reaction of an adrenal gland to a body under stress. The finding of an abnormally low cortisol level in a patient with Graves disease should raise suspicion of coincidental adrenal insufficiency. Imaging Chest radiograph (or chest CT without contrast when appropriate) can be done to rule out an infectious source as a precipitant. A thyroid sonogram with Doppler flow can be done to assess thyroid gland size, vascularity, and the presence of nodules. Typically, a thyroid gland secreting excessive hormones would be enlarged and have enhanced Doppler flow. On the other hand, in the setting of subacute, postpartum thyroiditis, silent thyroiditis, or exogenous causes of hyperthyroidism, the thyroid gland would be expected to be small with decreased Doppler flow. Nuclear medicine

imaging with iodine-131 would reveal a greatly increased uptake of radioiodine as early as 1 or 2 hours after administration of the agent. ECG in Thyrotoxicosis ECG findings in thyrotoxicosis most commonly include sinus tachycardia and atrial fibrillation. Sinus tachycardia occurs in approximately 40% of cases.7 Atrial fibrillation occurs in 10% to 35% of thyrotoxicosis patients with a tendency to occur more commonly in patients >60 years old who are more likely to have underlying structural heart disease.7 Premature ventricular contractions and heart blocks may be present. Atrial premature contractions and atrial flutter may also occur in thyrotoxicosis. Standard Treatment for Thyroid Storm The order of therapy in treating thyroid storm is very important with regard to the use of thionamide and iodine therapy. Inhibition of thyroid gland synthesis of new thyroid hormone with a thionamide should be initiated before iodine therapy to prevent the stimulation of new thyroid hormone synthesis that can occur if iodine is given too soon. Treatment aims are as follows: 1. Supportive care 2. Inhibition of thyroid hormone release 3. Inhibition of new hormone production 4. Peripheral -adrenergic receptor blockade 5. Preventing peripheral conversion of T4 to T3

References Biro E, Bako G, et al. Association of systemic and thyroid autoimmune diseases. Clin Rheumatol. 2006;25:240. Cagliero E, Apruzzese W, Perlmutter GS, Nathan DM. Musculoskeletal disorders of the hand and shoulder in patients with diabetes mellitus. Am J Med. 2002;112:487. (Study of hand and shoulder complications in diabetic patients and controls). Kloppenburg M, Dijkmans BA, Rasker JJ. Effect of therapy for thyroid dysfunction on musculoskeletal symptoms. Clin Rheumatol. 1993;12:341. Lacks S, Jacobs RP. Acromegalic arthropathy: a reversible rheumatic disease. J Rheumatol. 1986;13:634. (Case report and general review. Lockshin M. Endocrine origins of rheumatic disease. Diagnostic clues to interrelated syndromes. Postgrad Med. 2002;111:87. (Overview for primary care clinicians). McGuire JL. The endocrine system and connective tissue disorders. Bull Rheum Dis. 1990;39:1. (A somewhat dated, but more detailed review of the subject published by the Arthritis Foundation).