The patient is an agitated 42-year-old woman complaining of fever, flank pain, nausea, vomiting, and palpitations for the

past 24 hours. Current History The pain is described as a dull, constant, grinding pain that is located primarily in the right flank and has been getting progressively worse over the last 12 hours. She has had urinary frequency and dysuria for the past 2 days but denies hematuria or vaginal discharge. Her temperature was as high as 101.2 F/ 38.5C at home. She was brought to the emergency room by her roommate, who was concerned by not only the increasing pain, but also by the patients escalating anxiety over the situation. The roommate tells you that the patient "is losing it, is not acting herself, and has never been this anxious about anything before in her life. Past History The patient has not seen a doctor in over 5 years, and her only known past medical history is generalized anxiety disorder and depression, for which she takes fluoxetine. She admits to drinking a few every day and to using cocaine occasionally.

Physical Examination Vitals: T 103.2 F/39.5 C, HR 145 sinus tachycardia, BP 160/58, RR 18, O2 saturation 98% room air General: Thin, anxious woman in moderate amount of distress HEENT: Pupils 6mm and reactive, extra-ocular motions intact Neck: Supple, no bruits Chest: Lungs clear to auscultation bilaterally Abdomen: Soft, non-distended; non-tender. Mild right costovertebral angle tenderness. Stool is brown Guaiac negative. Pelvic: No discharge, no cervical motion tenderness, no adnexal tenderness Extremities: Well perfused; bounding pulses Neurologic: Awake and alert, extremely anxious, repeatedly saying I feel awful! Am I going to be all right? No focal motor weakness or sensory deficits, reflexes are 3+ throughout

Laboratory Result Lab Test WBC Plt MCV Na K Cl Valu e 15 288 86 134 3.6 99 Normal Range 4-10 150-450 80-95 134-142 3.5-5.0 98-108 Units K/mL K/mL fl or mm3 meq/L meq/L meq/L

HCO3 BUN Cr Glu

25 24 1.2 127

18-27 9-25 0.8-1.3 60-100 (fasting)

meq/L mg/dL mg/dL mg/dL

Differential: Pending
Which of the following statements is most correct regarding the initial management of this patient?

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a. Symptoms are most likely related to cocaine overdose. Heart rate and blood pressure should be controlled with intravenous beta-blockers. b. Symptoms are most likely related to alcohol withdrawal. She should be treated with haloperidol to control her agitation. c. Symptoms are most likely related to serotonin syndrome brought on by her fluoxetine. Fluoxetine should be discontinued and Meperidine should be given to treat her flank pain. d. She should be given antipyretics, IV fluid, and more information should be obtained. Your decide to treat the patient with acetaminophen 1000 mg po, lorazepam 1 mg IV, and normal saline 1000cc IV bolus. Blood cultures are sent. Her temperature comes down to 100.3; however, her heart rate remains at 145, her blood pressure is now 164/48, and she is still agitated. Additional information is now available: Toxicology screening: negative for cocaine, amphetamines, and all other Chest XRAY: Normal.

Additional laboratory values:

Urinalysis: HCG negative, specific gravity 1.015, + nitrites, + leukocyte esterase, protein, -glucose, - ketones. Urine sediment: 50-80 WBC / hpf, no RBC or casts. Total bilirubin 3.0 mg/dl, direct bilirubin 0.4 mg/dl, alkaline phosphatase 66 I/U, amylase 60 U/U, lipase 2.7 I/l. You pause to reflect on this case. You have considered many things in the differential diagnosis of her presentation, which seems to be best summarized as a hyperadrenergic state, though you havent found a unifying diagnosis yet. You have identified a potential source of infection; however, this does not seem to be a run-of-the-mill case of pyelonephritis. You go back to re-examine the patient. You notice that there is slight protuberance of her eyes with wide palpebral fissures and bilateral periorbital edema. You also note raised violaceous papules overlying both

anterior shins. Re-examination of her neck is normal; no goiter is palpated and no tenderness is elicited. A more detailed review of systems reveals a 20-pound weight loss over the last 2-3 months, frequent palpitations, and an increasing level of anxiety.

Figure 1 Protuberance of the eyes with wide palpebral fissures Reprinted with permission from EMedicine.com, Inc., 2003

Figure 2 Pretibial Myxedema click on image to enlarge Reprinted with permission from EMedicine.com, Inc., 2003 Given these new findings, you wonder if this patient is hyperthyroid and has Graves disease. Which of the following statements is most correct?

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a. The absence of a goiter eliminates the possibility of Graves disease. b. Her extremity lesions are consistent with pretibial myxedema. Since myxedema is associated with hypothyroidism, this is unlikely to be Graves disease. c. She potentially has Graves disease; however, you should first consider the more common causes of hyperthyroidism in women of this age group. d. She likely has Graves disease and resultant hyperthyroidism. There are numerous other conditions besides Graves disease that can cause hyperthyroidism. These include:

Toxic adenoma and toxic multinodular goiter: caused by focal or diffuse hyperplasia of the thyroid gland that functions independently of TSH, toxic multinodular goiter is much more common than Graves disease in older patients. Variable-sized goiter is often present. Subacute granulomatous thyroiditis (DeQuervains thyroiditis): viral or post-viral inflammation of the thyroid gland, associated with a tender goiter. These patients may present with sore throat as their chief complaint. Subacute lymphocytic thyroiditis: autoimmune disorder, associated with a non-tender goiter Exogenous (factitious) hyperthyroidism: due to overdose of thyroid hormone-- either of thyroxine replacement preparations or other drugs (e.g. fad diet preparations) that contain thyroxine Ectopic thyroid hormone production: rare; classic examples are struma ovarii (thyroxine-producing ovarian tumor) and metastatic follicular thyroid cancer TSH producing tumors: rare; e.g. functional pituitary tumor

Figure 3 Goiter Reprinted with permission from EMedicine.com, Inc., 2003 To bolster support for your diagnosis of hyperthyroidism, you should look for the following physical exam findings:

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a. Smooth skin, onycholysis, and thinning hair b. Tremor, hyperactive deep tendon reflexes, and proximal muscle weakness c. Widened pulse pressure and systolic ejection murmur d. All of the above

Now that you are concerned that your patient is suffering from hyperthyroidism, you send thyroid function tests (TFTs) to the laboratory to confirm the diagnosis. Which of the following statements regarding TFTs is most correct?

Top of Form

a. Hyperthyroidism cannot be present if the TSH is normal or elevated. b. Hyperthyroidism cannot be present if the serum free T4 is normal. c. The best screening test for hyperthyroidism is a TSH plus a free T4 or free T3. d. Determination of thyroxine-binding globulin (TBG) levels is essential to make the diagnosis of hyperthyroidism. You send the serum TSH and free T4 levels to the lab. You can expect to get the TSH result in an hour or so, but the T4 level will not be back until much later. In the meantime, you continue to treat the patient with IV fluids and antibiotics. You begin to think about additional therapy. To do this, you think about the degree of thyrotoxicosis this patient is experiencing. About an hour later, the patients TSH level comes back as undetectable. Which of the following statements is most correct?

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a. This patient has subclinical hyperthyroidism and should be referred to an endocrinologist once her infectious process has been definitively treated. b. This patient has apathetic hyperthyroidism and requires immediate treatment with anti-thyroid agents. c. This patient has overt hyperthyroidism and should be treated with a thioamide in addition to the antibiotics. d. This patient has thyroid storm and requires emergent treatment. A scoring system has been devised to aid with the diagnosis of thyroid storm: Scores greater than 45 are indicative of thyroid storm, Scores 25-45 suggest thyroid storm, and Scores less than 25 are unlikely to be thyroid storm. This system is probably best used as a clinical guideline rather than a strict formula to include or exclude thyroid storm as a diagnosis.

Thermoregulatory Temp. (F) Points 99-100 5 100-101 10 101-102 15 102-103 20 103-104 25 >104 30

Cardiovascular Heart Points rate 100-110 5 110-120 10 120-130 15 130-140 20 >140 25

CNS Alteration Points mild (agitation) 10 moderate (delirium, psychois) 20

Congestive Heart Failure Symptom Points mild 5 pedal edema) Moderate 10 (bibasilar rales) Severe 15 (pulmonary edema) Atrial fibrillation 10

Gastrointestinal Symptom Points moderate (n/v/d, abd pain 10 severe (jaundice) 20

Precipitant History absent present 0 10

Adapted from Burch HB, Wartofsky L. Endocrinology and Metabolism Clinics of North America. 1993; 22:263

The following is the thyroid storm scoring system with the values for this patient highlighted.

Thermoregulatory Temp. (F) Points 99-100 5 100-101 10 101-102 15 102-103 20 103-104 25 >104 30

Cardiovascular Heart Points rate 100-110 5 110-120 10 120-130 15 130-140 20 >140 25

CNS Alteration Points mild (agitation) 10 moderate (delirium, psychois) 20

Congestive Heart Failure Symptom Points mild 5 pedal edema) Moderate 10 (bibasilar rales) Severe 15 (pulmonary edema) Atrial fibrillation 10

Gastrointestinal Symptom Points moderate (n/v/d, abd pain 10 severe (jaundice) 20

Precipitant History absent present 0 10

Adapted from Burch HB, Wartofsky L. Endocrinology and Metabolism Clinics of North America. 1993; 22:263

You have come to the conclusion that this patient is indeed suffering from thyroid storm. What will your therapeutic approach be?

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a. Aspirin, propranolol, and propylthiouracil (PTU) b. Acetaminophen, verapamil, and PTU c. Acetaminophen, propranolol, and PTU should be given before potassium iodide and dexamethasone d. Acetaminophen, propranolol, potassium iodide before PTU, dexamethasone There are five main goals to properly treat thyroid storm: 1) Beta blockade, 2) inhibition of thyroid hormone synthesis, 3) inhibition of thyroid hormone release from the thyroid gland, 4) prevention of peripheral conversion of T4 to T3, and 5) aggressive supportive care.

Beta Blocker
On a cellular level: Thyroid hormone is known to alter beta-adrenergic receptors, as well as g-proteins and cyclic AMP used in the transduction of sympathetic signals. On a macro level: Thyroid storm can be thought of as a hyper-adrenergic state, and many of the symptoms of thyroid storm (hypertension, tachycardia, palpitations, agitation, etc.) are best controlled with beta-blockade.

Bolus intravenous agents such as metoprolol or propranolol may be used, or if

greater control is required, infusion agents such as esmolol may be used. Inhibition of thyroid hormone synthesis The thioamide drugs, methimazole and propylthiouracil (PTU), are used to inhibit the production of thyroid hormone. While methimazole is the preferred agent for outpatient therapy (it has a longer halflife), PTU is preferred in thyroid storm as it offers the additional advantage of blocking peripheral T4 to T3 conversion.

 The dose of PTU is 200 to 400 mg orally every six to eight hours. The dose of methimazole is 20 to 25 mg orally every six hours.

In June of 2009 the FDA issued an alert that PTU may be associated with an
increased risk of hepatotoxicity as compared to methimazole. If PTU is used, closely monitor liver function tests during therapy. For chronic use as an outpatient, methimazole is the preferred agent. Inhibition of thyroid hormone release The administration of iodine prevents the release of thyroid hormone from the thyroid gland. It is important that PTU or methimazole be given at least 1 hour in advance of iodine to prevent the iodine being used as a substrate for new hormone synthesis. (Indeed, hyperthyroidism can be precipitated in patients with multinodular goiter who receive iodine this is referred to as Jod Basedows disease.)

Doses:
--5 drops of potassium iodide solution (SSKI) every 6 hours, --10 drops of Lugols solution every 8 hours, --or sodium iodide, 1 gram by slow IV drip every 12 hours. Prevention of peripheral T4 toT3 conversion Recall that T4 (thyroxine) is converted to T3 (triiodothyronine) in the peripheral circulation, and that T3 is 10x more active than T4.

Dexamethasone 10 mg every 6 hours or hydrocortisone 100 mg every 8 hours

should be given. Beta-blockers and PTU also prevent the conversion of T4 to T3 but not sufficiently enough to preclude the use of steroids in thyroid storm. Aggressive supportive care Antipyretics. Aspirin will theoretically displace T4 and T3 from thyroid hormone glolubin, so acetaminophen should be used instead.

CHF therapy. Diuretics or digoxin may be required in patients with cardiac manifestations. Fluid resuscitation may be required in those with volume depletion.

Treatment of any underlying precipitating factors

Etiology of Thyroid Storm The transition from hyperthyroidism to thyroid storm is usually an acute event with an identifiable precipitating factor. Untreated hyperthyroidism rarely converts to thyroid storm without a precipitant.

Underlying provoking illnesses that may require treatment include: Infections of any type Vascular accidents, visceral infarctions Pulmonary embolism Surgery, burns, or trauma Hypoglycemia, DKA, or HHS (hyperglycemic hyperosmolar state)

Follow-up Your treatment regimen worked perfectly. Within the next few hours, her temperature fell to 99F/37.2C, her heart rate was controlled at 88, and her blood pressure was 124/70. The patient thanks you profusely, saying that she finally feels normal again. She was admitted to the hospital for two days and improved dramatically on IV antibiotics and fluids.

The endocrinology consult was obtained and concurred with the diagnosis of Graves
hyperthyroidism. Methimazole and atenolol were prescribed, and the patient is scheduled to have radioiodine ablation of her thyroid gland next month. Summary Thyroid storm is a rare complication of hyperthyroidism and is manifested as hyperadrenergic state. Recognition of this entity may be difficult. Signs and symptoms of hyperthyroidism include ophthalmopathy, periorbital edema, goiter, pretibial myxedema, thin hair and smooth skin, muscle weakness, heart failure, atrial fibrillation, weight loss, palpitations, and anxiety. Numerous conditions can cause hyperthyroidism, including Grave's disease, toxic adenoma and toxic multinodular goiter, subacute thyroiditis, and less frequently, factitious hyperthyroidism, ectopic thyroid hormone production, and TSH producing tumors. Precipitants of thyroid storm include infection, vascular accidents, visceral infarctions, surgery or trauma, and hypo- or hyperglycemia. Untreated hyperthyroidism rarely coverts to thyroid storm without a precipitant. The treatment of thyroid storm consists of 5 main goals: beta-blockade, inhibition of thyroid hormone synthesis (PTU or methimazole), inhibition of thyroid hormone release (iodine), prevention of peripheral T4 conversion (steroids), and aggressive supportive care. References Burch HB, Wartofsky L. "Life-threatening thyrotoxicosis. Thyroid storm." Endocrinology and Metabolism Clinics of North America .22 (1993): 263-277. Klein I, Ojamaa K. "Mechanisms of disease: thyroid hormone and the cardiovascular system." New England Journal of Medicine .344 (2001): 501-509. Manifold CA. "Hyperthyroidism, thyroid storm, and Graves disease." Available at http://www.emedicine.com/emerg/topic269.htm. Accessed 2/25/2003.

Ross DS. "Hyperthyroidism." Available at www.uptodate.com. Accessed 2/5/2003. Weetman AP. "Controversy in thyroid disease." Journal of the Royal College of Physicians of London .34 (2000): 374-380. Woeber KA. "Update on the management of hyperthyroidism and hypothyroidism." Archives of Internal Medicine .160 (2000): 1067-1071. Wogan JM. "Selected endocrine disorders." Rosens Emergency Medicine: Concepts and Clinical Practice. Eds. JA Marx, RS Hockberger, and RM Walls. St. Louis: Mosby, Inc. 2002. Nayak B, Burman K. Thyrotoxicosis and thyroid storm. Endocrinol Metab Clin N Am. 2006;35:663-686 McKeown NJ, Tews MC, Gossain VV, Shah SM. Hyperthyroidism. Emerg Med Clin N Am. 2005;23:669-685. Migneco A, Ojetti V, Testa A, DeLorenzo A, Gentiloni S. Management of thyrotoxic crisis. Eur Rev Med Pharmacol Sci. 2005;9:69-74.

Endocrine Emergencies Case 1: Hot and Bothered

Please click the Continue button to proceed to the next slide. If you are returning to this case, you may click the Case Summary tab to get to the last slide that you completed.

Introduction
The patient is an agitated 42-year-old woman complaining of fever, flank pain, nausea, vomiting, and palpitations for the past 24 hours. Current History The pain is described as a dull, constant, grinding pain that is located primarily in the right flank and has been getting progressively worse over the last 12 hours. She has had urinary frequency and dysuria for the past 2 days but denies hematuria or vaginal discharge. Her temperature was as high as 101.2 F/ 38.5C at home. She was brought to the emergency room by her roommate, who was concerned by not only the increasing pain, but also by the patients escalating anxiety over the situation. The roommate tells you that the patient "is losing it, is not acting herself, and has never been this anxious about anything before in her life. Past History The patient has not seen a doctor in over 5 years, and her only known past medical history is generalized anxiety disorder and depression, for which she takes fluoxetine.

She admits to drinking a few every day and to using cocaine occasionally. Physical Examination

Vitals:

T 103.2 F/39.5 C, HR 145 sinus tachycardia, BP 160/58, RR 18, O2 saturation 98% room air General: Thin, anxious woman in moderate amount of distress HEENT: Pupils 6mm and reactive, extra-ocular motions intact Neck: Supple, no bruits Chest: Lungs clear to auscultation bilaterally Abdomen: Soft, non-distended; non-tender. Mild right costo-vertebral angle tenderness. Stool is brown Guaiac negative. Pelvic: No discharge, no cervical motion tenderness, no adnexal tenderness Extremities: Well perfused; bounding pulses Neurologic: Awake and alert, extremely anxious, repeatedly saying I feel awful! Am I going to be all right? No focal motor weakness or sensory deficits, reflexes are 3+ throughout

Laboratory Results Lab Test WBC Plt MCV Na K Cl HCO3 BUN Cr Glu Valu e 15 288 86 134 3.6 99 25 24 1.2 127 Normal Range 4-10 150-450 80-95 134-142 3.5-5.0 98-108 18-27 9-25 0.8-1.3 60-100 (fasting) Units K/mL K/mL fl or mm3 meq/L meq/L meq/L meq/L mg/dL mg/dL mg/dL

Differential: Pending Question 1 out of 7

Which of the following statements is most correct regarding the initial management of this patient?

a. Symptoms are most likely related to cocaine overdose. Heart rate and blood pressure should be controlled with intravenous beta-blockers. The authors disagree. Her symptoms (tachycardia, hypertension, anxiety, and palpitations) may be related to cocaine overdose. However, the appropriate treatment for this would be benzodiazepines and direct alpha antagonists (such as phentolamine) if further blood pressure control were required. Beta-blockers are contra-indicated in cocaine overdose as they may produce unopposed alpha activity on peripheral vessels, resulting in worsening hypertension and vasospasm. b. Symptoms are most likely related to alcohol withdrawal. She should be treated with haloperidol to control her agitation.

The authors disagree. Her symptoms may be related to alcohol withdrawal, though we dont have enough information at this time (e.g. exact details of daily etoh consumption, when her last drink was, etc.) to make this diagnosis. Regardless, the proper treatment for alcohol withdrawal is benzodiazepines. Haloperidol would be contraindicated in this situation as it lowers the seizure threshold. c. Symptoms are most likely related to serotonin syndrome brought on by her fluoxetine. Fluoxetine should be discontinued and Meperidine should be given to treat her flank pain. The authors disagree. The serotonin syndrome is associated with many types of medications and drugs. These include the SSRIs (serotonin-specific reuptake inhibitors), MAO inhibitors, tricyclic antidepressants, meperidine (!), and amphetamines. The syndrome may occur when the dosage of any of the above agents is increased, or when two or more of the above agents are combined. Symptoms include altered mental status (confusion to coma), autonomic dysfunction (hyperthermia, diaphoresis, tachycardia, and hypertension) and neuromuscular dysfunction (myoclonus). The serotonin syndrome is an excellent addition to the differential diagnosis in this case. Administration of benzodiazepines, dantrolene, and / or cyproheptadine is the preferred treatment for serotonin syndrome. Since meperidine can precipitate the serotonin syndrome when combined with other serotonergic drugs, it would be absolutely contra-indicated in this case. d. She should be given antipyretics, IV fluid, and more information should be obtained. The answer is correct. The differential diagnosis in this case is quite large, and more information is required. Treatment with antipyretics such as acetaminophen and IV fluids seems prudent. This patients history contains several red flags: Cocaine (or other sympathomimetic overdose): Primary treatment consists of benzodiazepines; phentolamine may be need to correct malignant hypertension. Alcohol withdrawal: Primary treatment would consist of benzodiazepines Serotonin syndrome (especially if there is a history of recent increase in fluoxetine dose or addition of other serotonergic medication): Treatment consists of benzodiazepines, dantrolene, and / or cyproheptadine. Infection of all types: Cultures, UA, and chest x-ray may be required. Initial Treatment and Additional Data
Your decide to treat the patient with acetaminophen 1000 mg po, lorazepam 1 mg IV, and normal saline 1000cc IV bolus. Blood cultures are sent. Her temperature comes down to 100.3; however, her heart rate remains at 145, her blood pressure is now 164/48, and she is still agitated. Additional information is now available:

 Toxicology screening: negative for cocaine, amphetamines, and all other

substances

Chest XRAY: Normal. Additional laboratory values:

Urinalysis: HCG negative, specific gravity 1.015, + nitrites, + leukocyte esterase, protein, -glucose, - ketones. Urine sediment: 50-80 WBC / hpf, no RBC or casts. Total bilirubin 3.0 mg/dl, direct bilirubin 0.4 mg/dl, alkaline phosphatase 66 I/U, amylase 60 U/U, lipase 2.7 I/l.

Question 2 out of 7
Which of the following is the most appropriate next step?

a. Order an abdominal CT scan before giving any further medications The authors disagree. An abdominal CT scan may be indicated if you believe there is an obstructing kidney stone present in conjunction with her probable pyelonephritis. However, antibiotics should be given at once. b. Pursue no further diagnostic test in the ED Admit the patient to the medical floor on antibiotics for pyelonephritis The authors disagree. This patient likely has pyelonephritis and antibiotics should be started at this time; however, her vital signs are unstable and she requires further diagnosis and treatment before leaving the ED for the medical floor. c. Administer antibiotics, then re-examine the patient and send additional laboratory tests, because something is not quite right here The answer is correct. This patient likely has pyelonephritis, and you should administer antibiotics. However, her vital signs remain abnormalnotably she is quite tachycardic despite appropriate antipyretics and fluid resuscitation. There is more to do on this case. d. Administer more IV fluids and antipyretics, then discharge home if no further events occur The authors disagree. This patient likely has pyelonephritis and requires antibiotics. Furthermore, since her vital signs remain abnormal, she requires further investigation in the emergency department. Reexamination of the Patient
You pause to reflect on this case. You have considered many things in the differential diagnosis of her presentation, which seems to be best summarized as a hyperadrenergic state, though you havent found a unifying diagnosis yet. You have identified a potential source of infection; however, this does not seem to be a run-of-the-mill case

of pyelonephritis. You go back to re-examine the patient. You notice that there is slight protuberance of her eyes with wide palpebral fissures and bilateral periorbital edema. You also note raised violaceous papules overlying both anterior shins. Re-examination of her neck is normal; no goiter is palpated and no tenderness is elicited. A more detailed review of systems reveals a 20-pound weight loss over the last 2-3 months, frequent palpitations, and an increasing level of anxiety.

Figure 1 Protuberance of the eyes with wide palpebral fissures Reprinted with permission from EMedicine.com, Inc., 2003

Question 3 out of 7

Figure 2 Pretibial Myxedema click on image to enlarge Reprinted with permission from EMedicine.com, Inc., 2003

Given these new findings, you wonder if this patient is hyperthyroid and has Graves disease. Which of the following statements is most correct?

a. The absence of a goiter eliminates the possibility of Graves disease. The authors disagree. While most patients with Graves disease have a goiter, a minority of patients will have minimal thyroid enlargement. b. Her extremity lesions are consistent with pretibial myxedema. Since myxedema is associated with hypothyroidism, this is unlikely to be Graves disease. The authors disagree.

This can be confusing. It is true that generalized myxedema (deposition of glycosaminoglycans such as hyaluronic acid in the tissues) is a feature of hypothyroidism and that myxedema coma is an extreme form of hypothyroidism. However, pretibial myxedema is a feature of Graves disease. These lesions are characteristically found over the shins and are described as raised, hyperpigmented, violaceous, orange-peel textured papules. c. She potentially has Graves disease; however, you should first consider the more common causes of hyperthyroidism in women of this age group. The authors disagree. Graves disease usually affects women in the 3rd to 4th decade of life, and is the most common cause of hyperthyroidism in general. d. She likely has Graves disease and resultant hyperthyroidism. The answer is correct. Your excellent clinical skills are honing in on the diagnosis. Given her clinical history and her physical examination, she likely has hyperthyroidism due to Graves disease. (You will have the opportunity to confirm this diagnosis with laboratory tests in a few moments.) Graves disease (a.k.a. toxic diffuse goiter) is the most common form of hyperthyroidism and usually affects females in their 3rd to 4th decade of life. Graves disease is an autoimmune disorder: TSH receptor antibodies stimulate the thyroid gland to produce excessive amounts of hormone. In addition to the numerous physical findings associated with hyperthyroidism in general, there are some signs that are specific for Graves: - Ophthalmopathy. This is characterized by inflammation of the extra-ocular muscles and orbital fat, resulting in exopthalmos, lid lag, stare, and extra-ocular muscle palsies. - Infiltrative dermopathy. This usually manifests itself as pretibial myxedema but may be seen in other areas of the body as well. Causes of Hyperthyroidism
There are numerous other conditions besides Graves disease that can cause hyperthyroidism. These include:

Toxic adenoma and toxic multinodular goiter: caused by focal or diffuse hyperplasia of the thyroid gland that functions independently of TSH, toxic multinodular goiter is much more common than Graves disease in older patients. Variable-sized goiter is often present. Subacute granulomatous thyroiditis (DeQuervains thyroiditis): viral or post-viral inflammation of the thyroid gland, associated with a tender goiter. These patients may present with sore throat as their chief complaint. Subacute lymphocytic thyroiditis: autoimmune disorder, associated with a non-tender goiter

Exogenous (factitious) hyperthyroidism: due to overdose of thyroid hormone-- either of thyroxine replacement preparations or other drugs (e.g. fad diet preparations) that contain thyroxine Ectopic thyroid hormone production: rare; classic examples are struma ovarii (thyroxine-producing ovarian tumor) and metastatic follicular thyroid cancer TSH producing tumors: rare; e.g. functional pituitary tumor

Figure 3 Goiter Reprinted with permission from EMedicine.com, Inc., 2003

Question 4 out of 7
To bolster support for your diagnosis of hyperthyroidism, you should look for the following physical exam findings:

a. Smooth skin, onycholysis, and thinning hair The authors disagree. You are on the right track. These symptoms are often found in hyperthyroidism, but there other findings as well. b. Tremor, hyperactive deep tendon reflexes, and proximal muscle weakness The authors disagree. You are on the right track. These symptoms are often found in hyperthyroidism, but there other findings as well. c. Widened pulse pressure and systolic ejection murmur The authors disagree. You are on the right track. These symptoms are often found in hyperthyroidism, but there other findings as well. d. All of the above The answer is correct. The signs and symptoms of hyperthyroidism are protean and largely independent of the underlying cause. For example: Constitutional: fever, heat intolerance, weight loss

Cardiovascular: increased cardiac output, increased heart rate, increased systolic blood pressure, decreased diastolic blood pressure (remember, thyroid hormone is a vasodilator!), widened pulse pressure, high or normal output congestive heart failure, sinus tachycardia (out of proportion to fever), atrial fibrillation, and exacerbation of underlying angina pectoris Respiratory: dyspnea on exertion (primarily due to respiratory muscle weakness), mechanical airway obstruction due to large goiter, and obstructive airway disease exacerbation Gastrointestinal: weight loss, nausea, vomiting, diarrhea, and indirect hyperbilirubinemia Genitourinary: frequency and nocturia Dermal: warm, smooth skin, diaphoresis, onycholysis (separation of the nail from the nail bed), and pruritis Neurological: agitation, anxiety, restlessness, and psychosis It should be noted that most of these symptoms are not specific for hyperthyroidism. Processes to consider in your differential diagnosis of hyperthyroidism include: sepsis, toxic ingestion (anti-cholinergic and sympathomimetic toxidromes, serotonin syndrome, and neuroleptic-malignant syndrome), withdrawal syndromes, and heat stroke. Question 5 out of 7
Now that you are concerned that your patient is suffering from hyperthyroidism, you send thyroid function tests (TFTs) to the laboratory to confirm the diagnosis. Which of the following statements regarding TFTs is most correct?

a. Hyperthyroidism cannot be present if the TSH is normal or elevated. The authors disagree. In almost all cases of hyperthyroidism, the increased amount of thyroid hormone will suppress TSH production. However, in the rare case of a TSH-producing tumor (e.g. functional pituitary adenoma) a normal or high TSH will be found in conjunction with a high free T4 and T3, and the patient will be hyperthyroid. b. Hyperthyroidism cannot be present if the serum free T4 is normal. The authors disagree. In certain cases of hyperthyroidism, TSH will be suppressed, the free T4 will be normal, and the free T3 will be elevated. This is known as T3 hyperthyroidism, and is found in Graves disease, toxic multinodular goiter, and toxic adenoma. If hyperthyroidism is suspected and the free T4 is normal, a free T3 should be checked. c. The best screening test for hyperthyroidism is a TSH plus a free T4 or free T3. The answer is correct. In hyperthyroidism, excess amounts of thyroid hormone will suppress pituitary production of TSH. Thus, the classic TFT panel for hyperthyroidism is a low TSH and high free T4 and / or high free T3.

Remember, over 99% of T4 [thyroxine, or thyroid hormone] and T3 [triiodothyronine, the metabolically active form of thyroxine] is bound to thyroid-hormone binding globulin [TBG] and other proteins. Free assays measure the unbound, metabolically available levels of circulating hormones. In diseases in which the amount of binding proteins may be elevated or decreased, measurements of total T4 or T3 and TBG levels may be needed, but these tests are not usually available in the emergency department. There are uncommon circumstances in which the typical hyperthyroid TFT picture (low TSH and high free T4 or T3) is not seen. These include: TSH hyperthyroidism: a pituitary adenoma produces excessive amounts of TSH, resulting in normal or high levels of TSH and high free T4 and T3 T3 hyperthyroidism: certain causes of hyperthyroidism (including Graves disease, toxic multinodular goiter, and toxic adenoma) may be associated with normal free T4 levels and elevated free T3 levels. TFTs in this scenario will show low TSH, normal free T4, and elevated free T3. d. Determination of thyroxine-binding globulin (TBG) levels is essential to make the diagnosis of hyperthyroidism. The authors disagree. The standard approach to the laboratory assessment of hyperthyroidism includes a TSH and a free T4 or T3. If the TSH is suppressed and the T4 or T3 is elevated, the diagnosis of hyperthyroidism is cinched and more elaborate TFT testing may not be required. Question 6 out of 7
You send the serum TSH and free T4 levels to the lab. You can expect to get the TSH result in an hour or so, but the T4 level will not be back until much later. In the meantime, you continue to treat the patient with IV fluids and antibiotics. You begin to think about additional therapy. To do this, you think about the degree of thyrotoxicosis this patient is experiencing. About an hour later, the patients TSH level comes back as undetectable. Which of the following statements is most correct?

a. This patient has subclinical hyperthyroidism and should be referred to an endocrinologist once her infectious process has been definitively treated. The authors disagree. Subclinical hyperthyroidism refers to a condition in which the TSH is suppressed, but the T4 and T3 are normal and there are no physical signs of hyperthyroidism. b. This patient has apathetic hyperthyroidism and requires immediate treatment with anti-thyroid agents. The authors disagree. Apathetic hyperthyroidism refers to a condition seen primarily in elderly patients,

which is characterized by depressed mental status, cardiovascular disease (atrial fibrillation and congestive heart failure), and weight loss. c. This patient has overt hyperthyroidism and should be treated with a thioamide in addition to the antibiotics. The authors disagree. This patient surely has overt hyperthyroidism. However, given her abnormal vital signs and agitation, she will require more treatment than thioamides alone. d. This patient has thyroid storm and requires emergent treatment. The answer is correct. The signs and symptoms of thyroid storm are those of exaggerated hyperthyroidism: tachycardia out of proportion to fever, congestive heart failure, hyperpyrexia, altered mental status, and gastrointestinal symptoms. Thyroid Storm Scoring System
A scoring system has been devised to aid with the diagnosis of thyroid storm: Scores greater than 45 are indicative of thyroid storm, Scores 25-45 suggest thyroid storm, and Scores less than 25 are unlikely to be thyroid storm. This system is probably best used as a clinical guideline rather than a strict formula to include or exclude thyroid storm as a diagnosis.

Thermoregulatory Temp. (F) Points 99-100 5 100-101 10 101-102 15 102-103 20 103-104 25 >104 30

Cardiovascular Heart Points rate 100-110 5 110-120 10 120-130 15 130-140 20 >140 25

CNS Alteration Points mild (agitation) 10 moderate (delirium, psychois) 20

Congestive Heart Failure Symptom Points mild 5 pedal edema) Moderate 10 (bibasilar rales) Severe 15 (pulmonary edema) Atrial fibrillation 10

Gastrointestinal Symptom Points moderate (n/v/d, abd pain 10 severe (jaundice) 20

Precipitant History absent present 0 10

Adapted from Burch HB, Wartofsky L. Endocrinology and Metabolism Clinics of North America. 1993; 22:263

Thyroid Storm Scoring System for this patient

The following is the thyroid storm scoring system with the values for this patient highlighted.

Thermoregulatory Temp. (F) Points 99-100 5 100-101 10 101-102 15 102-103 20 103-104 25 >104 30

Cardiovascular Heart Points rate 100-110 5 110-120 10 120-130 15 130-140 20 >140 25

CNS Alteration Points mild (agitation) 10 moderate (delirium, psychois) 20

Congestive Heart Failure Symptom Points mild 5 pedal edema) Moderate 10 (bibasilar rales) Severe 15 (pulmonary edema) Atrial fibrillation 10

Gastrointestinal Symptom Points moderate (n/v/d, abd pain 10 severe (jaundice) 20

Precipitant History absent present 0 10

Adapted from Burch HB, Wartofsky L. Endocrinology and Metabolism Clinics of North America. 1993; 22:263

Question 7 out of 7
You have come to the conclusion that this patient is indeed suffering from thyroid storm. What will your therapeutic approach be?

a. Aspirin, propranolol, and propylthiouracil (PTU) The authors disagree. There are several problems with this approach. Acetaminophen should be used instead of aspirin, as aspirin can cause thyroxine to dissociate from TBG in peripheral tissues. While propranolol and PTU are indicated, this regimen leaves out other important agents. b. Acetaminophen, verapamil, and PTU The authors disagree. Acetaminophen and PTU are indicated in this case. However, propranolol is a better

choice than verapamil to blunt the sympathetic effects of hyperthyroidism c. Acetaminophen, propranolol, and PTU should be given before potassium iodide and dexamethasone The answer is correct. There are five main goals to properly treat thyroid storm: 1) Beta blockade, 2) inhibition of thyroid hormone synthesis, 3) inhibition of thyroid hormone release from the thyroid gland, 4) prevention of peripheral conversion of T4 to T3, and 5) aggressive supportive care. d. Acetaminophen, propranolol, potassium iodide before PTU, dexamethasone The authors disagree. You are on the right track. However, it is important to give the PTU at least one hour before the potassium iodide. The potassium iodide will prevent the release of preformed thyroid hormone from the thyroid gland, but if an agent (such as PTU) is not given prior the iodide, the iodide may potentially enhance hormone synthesis. 1. Beta-blockade
On a cellular level:

Thyroid hormone is known to alter beta-adrenergic receptors, as well as g-proteins

and cyclic AMP used in the transduction of sympathetic signals. On a macro level:

Thyroid storm can be thought of as a hyper-adrenergic state, and many of the

symptoms of thyroid storm (hypertension, tachycardia, palpitations, agitation, etc.) are best controlled with beta-blockade.

Bolus intravenous agents such as metoprolol or propranolol may be used, or if

greater control is required, infusion agents such as esmolol may be used.

2. Inhibition of thyroid hormone synthesis The thioamide drugs, methimazole and propylthiouracil (PTU), are used to inhibit the
production of thyroid hormone.

While methimazole is the preferred agent for outpatient therapy (it has a longer halflife), PTU is preferred in thyroid storm as it offers the additional advantage of blocking peripheral T4 to T3 conversion.

The dose of PTU is 200 to 400 mg orally every six to eight hours. The dose of
methimazole is 20 to 25 mg orally every six hours.

 In June of 2009 the FDA issued an alert that PTU may be associated with an
increased risk of hepatotoxicity as compared to methimazole. If PTU is used, closely monitor liver function tests during therapy. For chronic use as an outpatient, methimazole is the preferred agent.

3. Inhibition of thyroid hormone release The administration of iodine prevents the release of thyroid hormone from the
thyroid gland.

It is important that PTU or methimazole be given at least 1 hour in advance of iodine

to prevent the iodine being used as a substrate for new hormone synthesis. (Indeed, hyperthyroidism can be precipitated in patients with multinodular goiter who receive iodine this is referred to as Jod Basedows disease.)

Doses:
--5 drops of potassium iodide solution (SSKI) every 6 hours, --10 drops of Lugols solution every 8 hours, --or sodium iodide, 1 gram by slow IV drip every 12 hours.

4. Prevention of peripheral T4 toT3 conversion Recall that T4 (thyroxine) is converted to T3 (triiodothyronine) in the peripheral
circulation, and that T3 is 10x more active than T4.

Dexamethasone 10 mg every 6 hours or hydrocortisone 100 mg every 8 hours

should be given. Beta-blockers and PTU also prevent the conversion of T4 to T3 but not sufficiently enough to preclude the use of steroids in thyroid storm.

5. Aggressive supportive care

Antipyretics. Aspirin will theoretically displace T4 and T3 from thyroid hormone glolubin, so acetaminophen should be used instead.

CHF therapy. Diuretics or digoxin may be required in patients with cardiac manifestations.

Fluid resuscitation may be required in those with volume depletion. Treatment of any underlying precipitating factors Etiology of Thyroid Storm
The transition from hyperthyroidism to thyroid storm is usually an acute event with an identifiable precipitating factor.

Untreated hyperthyroidism rarely converts to thyroid storm without a precipitant. Underlying provoking illnesses that may require treatment include: Infections of any type Vascular accidents, visceral infarctions Pulmonary embolism Surgery, burns, or trauma Hypoglycemia, DKA, or HHS (hyperglycemic hyperosmolar state)

Follow-up Your treatment regimen worked perfectly. Within the next few hours, her
temperature fell to 99F/37.2C, her heart rate was controlled at 88, and her blood pressure was 124/70.

The patient thanks you profusely, saying that she finally feels normal again. She was admitted to the hospital for two days and improved dramatically on IV
antibiotics and fluids.

The endocrinology consult was obtained and concurred with the diagnosis of Graves
hyperthyroidism. Methimazole and atenolol were prescribed, and the patient is scheduled to have radioiodine ablation of her thyroid gland next month.

Summary
Thyroid storm is a rare complication of hyperthyroidism and is manifested as hyper-adrenergic state. Recognition of this entity may be difficult. Signs and symptoms of hyperthyroidism include ophthalmopathy, periorbital edema, goiter, pretibial myxedema, thin hair and smooth skin, muscle weakness, heart failure, atrial fibrillation, weight loss, palpitations, and anxiety. Numerous conditions can cause hyperthyroidism, including Grave's disease, toxic adenoma and toxic multinodular goiter, subacute thyroiditis, and less frequently, factitious hyperthyroidism, ectopic thyroid hormone production, and TSH producing tumors. Precipitants of thyroid storm include infection, vascular accidents, visceral infarctions, surgery or trauma, and hypo- or hyperglycemia. Untreated hyperthyroidism rarely coverts to thyroid storm without a precipitant. The treatment of thyroid storm consists of 5 main goals: beta-blockade, inhibition of thyroid hormone synthesis (PTU or methimazole), inhibition of thyroid hormone release (iodine), prevention of peripheral T4 conversion (steroids), and aggressive supportive care.

Summary of Images

Figure 1 Protuberance of the eyes with wide palperbral fissures

Figure 2 Pretibial Myxedema

Figure 3 Goiter

References
Burch HB, Wartofsky L. "Life-threatening thyrotoxicosis. Thyroid storm." Endocrinology and Metabolism Clinics of North America .22 (1993): 263-277. Klein I, Ojamaa K. "Mechanisms of disease: thyroid hormone and the cardiovascular system." New England Journal of Medicine .344 (2001): 501-509. Manifold CA. "Hyperthyroidism, thyroid storm, and Graves disease." Available at http://www.emedicine.com/emerg/topic269.htm. Accessed 2/25/2003. Ross DS. "Hyperthyroidism." Available at www.uptodate.com. Accessed 2/5/2003. Weetman AP. "Controversy in thyroid disease." Journal of the Royal College of Physicians of London .34 (2000): 374-380. Woeber KA. "Update on the management of hyperthyroidism and hypothyroidism." Archives of Internal Medicine .160 (2000): 1067-1071. Wogan JM. "Selected endocrine disorders." Rosens Emergency Medicine: Concepts and Clinical Practice. Eds. JA Marx, RS Hockberger, and RM Walls. St. Louis: Mosby, Inc. 2002. Nayak B, Burman K. Thyrotoxicosis and thyroid storm. Endocrinol Metab Clin N Am. 2006;35:663-686 McKeown NJ, Tews MC, Gossain VV, Shah SM. Hyperthyroidism. Emerg Med Clin N Am. 2005;23:669-685. Migneco A, Ojetti V, Testa A, DeLorenzo A, Gentiloni S. Management of thyrotoxic crisis. Eur Rev Med Pharmacol Sci. 2005;9:69-74.
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