Thyroid storm

Thyrotoxicosis and thyroid storm

I. What every physician needs to know.

Thyroid storm is a rare, life-threatening condition characterized by excess thyroid hormone concentrations, or thyrotoxicosis. Thyroid storm can develop in patients with either partially treated or untreated hyperthyroidism (secondary to Graves’ disease, toxic multinodular goiter, solitary toxic adenoma), but it is most often precipitated by an acute event, such as trauma, infection, an acute iodine load (Radio Iodine Treatment), surgery, or parturition.

Thyroid storm represents the extreme manifestation of thyrotoxicosis; the point at which thyrotoxicosis transforms into thyroid storm is based on clinical findings and is subjective and controversial to some extent. To better standardize diagnosis of thyroid storm, a point system assessing degrees of dysfunction in various systems was developed by Burch and Wartofsky in 1993. While this scoring system may be sensitive, it is not very specific. It is important then, to assume that someone with severe thyrotoxicosis has impending thyroid storm and to treat them aggressively upfront.

Treatment options for thyroid storm are the same as those for uncomplicated hyperthyroidism, except that the medications are given in much higher doses and more frequently. Patients also need to be monitored very closely in the ICU, as mortality ranges from 20-30%.

II. Diagnostic Confirmation: Are you sure your patient has Thyroid Storm?

Thyroid storm is diagnosed clinically. Patients typically have an exaggerated version of the usual hyperthyroid symptoms one might expect. In an effort to standardize diagnosis, a scoring system was developed by Burch and Wartofsky in 1993, which assesses the degree of dysfunction in four various systems (thermoregulatory, CNS, GI, and cardiovascular). Specifically, temperature is determined as hyperpyrexia greater than 104 F is common. The presence or absence of agitation, delirium, psychosis, extreme lethargy, seizures, and coma is assessed as part of the CNS effects.

Severe nausea, vomiting, diarrhea, abdominal pain, or hepatic failure with jaundice can occur from a thyroid storm. Cardiovascular symptoms can range from mild tachycardia to severe tachycardia, atrial fibrillation, congestive heart failure, hypotension, and cardiovascular collapse.

Although this scoring system exists, there are no validated tools or universally accepted criteria currently for diagnosing thyroid storm. In the above-mentioned scoring system, a score of 45 or greater is highly suggestive of thyroid storm; a score of 25-44 is suggestive of impending storm; and a score below 25 is unlikely to represent a thyroid storm. As previously mentioned, this point system may be sensitive, but is likely not very specific.

Thyroid function tests should be checked immediately in all patients suspected of being in thyrotoxicosis or thyroid storm; however, the degree of hyperthyroidism based on TFTs is NOT a diagnostic criterion for thyroid storm. The pattern of elevated T4 and T3 with a depressed TSH in patients with thyroid storm is comparable to those patients with mild, uncomplicated hyperthyroidism. Therefore, the degree of biochemical hyperthyroidism is not useful as a diagnostic criterion.

A. History Part I: Pattern Recognition:

Patients with thyroid storm typically present with an exaggerated version of symptoms one would expect in uncomplicated hyperthyroidism. It is helpful to think about the clinical presentation by organ system affected. The four systems assessed by the scoring system are: thermoregulatory, CNS, cardiovascular, and GI.

Hyperpyrexia is quite common in patients with thyroid storm and temperatures can go beyond 104 F. CNS manifestations range from mild agitation to delirium, psychosis, lethargy, seizures, and coma. Cardiovascular effects include mild to severe tachycardia, atrial fibrillation, congestive heart failure, hypotension, and cardiovascular collapse in severe cases. Patients in thyroid storm can classically also present with nausea, vomiting, diarrhea, abdominal pain, and jaundice.

B. History Part 2: Prevalence:

The incidence of thyroid storm is less than 10% of patients hospitalized for thyrotoxicosis; but as mentioned previously, the mortality rate due to cardiac failure, arrhythmia, or hyperthermia is as high as 30%, even with treatment. The most common underlying cause of thyrotoxicosis in cases of thyroid storm is Graves’ disease, which occurs most frequently in young women. However, thyroid storm can also occur in patients with a toxic adenoma or toxic multinodular goiter, which can occur in any age group or in either gender. As mentioned earlier, Thyroid Storm can develop in patients with partially treated or untreated hyperthyroidism or it can also develop in patients in whom Thionamides are stopped due to their adverse effects. A precipitating event, such as infection, surgery, trauma, DKA, usually ignites the occurrence of thyroid storm from uncomplicated thyrotoxicosis. Infection seems to be the most common precipitating cause.

C. History Part 3: Competing diagnoses that can mimic Thyroid Storm.

Thyroid storm can mimic several diagnoses, such as sepsis, liver failure, CNS infection, etc, given its wide-ranging derangements involving multiple organ systems. To distinguish this condition from other diagnoses, one must take into account the patient’s existing medical history of a possible hyperthyroid condition, the constellation of findings by using the scoring system as a guide, and physical exam findings specific to thyrotoxicosis as detailed below.

D. Physical Examination Findings.

Physical exam may reveal fever, diaphoresis, and tachycardia with a strong apical impulse and hyperdynamic precordium. Hand tremor, lid lag, and ophthalmopathy (in the presence of Graves’ disease) may also be present. Thyroid gland findings can vary depending on the cause of thyrotoxicosis. With Graves’ disease, diffuse enlargement of the gland and possibly a bruit may be appreciated. Another potential finding in Graves’ disease besides the thyroid gland findings and ophthalmopathy, is localized dermal myxedema (usually in the pretibial areas).

In patients with thyrotoxicosis from a toxic multinodular goiter, the thyroid exam may reveal one or more palpable nodules. With thyrotoxicosis from subacute thyroiditis, patients may have a tender thyroid gland with accompanying symptoms of fever and malaise.

E. What diagnostic tests should be performed?

Diagnosis of thyroid storm is based on clinical findings, as detailed above. The scoring system developed by Burch and Wartofsky can be used as a guide in objective assessment of a patient’s presentation. Thyroid function tests should be checked immediately, but as described above, these are not part of the diagnostic criteria as the pattern found is comparable to that found in patients with uncomplicated hyperthyroidism. Imaging is not necessary for the diagnosis of thyroid storm and treatment should not be delayed in patients suspected of being in thyroid storm.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Thyroid function tests (TSH, free T4, and T3) should be checked in all patients in whom there is a clinical suspicion of thyrotoxicosis or thyroid storm. The pattern of TFTs however, is comparable to that in patients with uncomplicated hyperthyroidism (suppressed TSH, elevated free T4 and T3) and is thus not included in the diagnostic criteria for thyroid storm.

Other nonspecific laboratory findings one may see include mild hyperglycemia (secondary to increased catecholamine production), mild hypercalcemia, abnormal liver function tests, leukocytosis, or leukopenia.

Blood cultures, urine analysis and culture, and a complete blood count should be considered to help assess for presence of an infection, as this can be the precipitant for thyroid storm.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Radiologic imaging is not required to make the diagnosis of thyrotoxicosis or thyroid storm, as the diagnosis is based on clinical findings. Radioiodine uptake scan, if performed, would reveal a greatly increased uptake of radioiodine very quickly after administration of the isotope, indicating rapid intraglandular turnover of iodine. A thyroid ultrasound with doppler would be quicker and easier to obtain, and would be helpful in assessing the gland size, vascularity, and presence of nodules that may require further attention.

Chest x-ray or a computed tomography (CT) chest without contrast can be considered to assess for a source of infection, as this may be the precipitant for thyroid storm.

It is important to stress however, that diagnosis of thyroid storm is a clinical diagnosis and there should be no delay in treatment if clinical suspicion for thyroid storm is high. Further work-up and testing with imaging can be performed after initiating anti-thyroid treatment.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

NA

III. Default Management.

The medical management of thyroid storm consists of various medications that work at several levels:

• halt the synthesis of thyroid hormone in the thyroid gland
• inhibit the release of thyroid hormone
• block the peripheral effects of the hormone.

It is also important to include therapy to control the adrenergic symptoms associated with thyrotoxicosis. Treatment also includes supportive care (such as IV fluids or diuresis in patients with congestive heart failure; acetaminophen in patients with hyperpyrexia) and recognition and treatment of any precipitating factors (such as infection).

The therapeutic regimen usually consists of:

• A beta-blocker to control the symptoms secondary to increased adrenergic tone.
• A thionamide (PTU or Methimazole) to block new hormone synthesis in the thyroid gland.
• An iodine solution to block release of the thyroid hormone.
• Iodinated contrast agents (if available) to block peripheral conversion of T4 to T3.
• Corticosteroids to reduce peripheral conversion of T4 to T3, promote vasomotor stability, and treat a potential relative adrenal insufficiency.
• Bile Acid Sequestrants to decrease the enterohepatic recycling of thyroid hormones thereby decreasing the serum thyroid hormone level.

The order of treatment in management of thyroid storm is very important, in regard to thionamide therapy and iodine therapy. Thionamides should be initiated first in most patients, to allow for inhibition of thyroid hormone synthesis, prior to administration of iodine which can STIMULATE new thyroid hormone synthesis if given initially. The time delay between administration of the two is controversial and can be only 1 to 2 hours, depending on the clinical urgency.

A. Immediate management.

Treatment should begin immediately with beta-blockers and thionamides in patients with severe thyrotoxicosis (i.e. impeding storm) or in those already in thyroid storm.

Beta-blockers:

Propranolol is frequently used for initial therapy as it can be given intravenously, orally, or through an NG. Starting IV dose is 0.5-1 mg over 10 minutes, followed by 1-2 mg over 10 minutes every few hours. Hemodynamics need to be monitored very closely with IV propranolol. Oral doses start between 60-80 mg every 4-6 hours, with further titration based on blood pressure and heart rate.

An alternative regimen is to use esmolol, a short-acting beta-blocker given intravenously. Given its short half life, it allows for rapid titration while minimizing side effects. In patients with reactive airway disease, cardioselective beta-blockers such as metoprolol or atenolol can be considered. In those with severe reactive airway disease in whom beta-blockers may be contraindicated, a calcium-channel blocker such as diltiazem can be used for rate control.

Beta-blockers need to be used with extreme caution in those with moderate to severe congestive heart failure. If the cause of the heart failure were likely to be secondary to the underlying tachycardia, beta-blockade would be useful. However, in situations in which the cause cannot be easily determined, only short-acting beta-blockers under close hemodynamic monitoring should be administered.

Thionamides:

These medications work to block de novo thyroid hormone synthesis within a couple of hours (1-2 hours) of administration. They have no effect on the release of preformed hormone from the thyroid gland. Propylthiouracil (PTU), methimazole, and carbimazole are the three drugs in this class, though only PTU and methimazole are available in the United States. Either agent can be used to treat thyroid storm, but PTU has significant benefits over Methimazole for acute treatment of life threatening thyroid storm.

PTU, but not methimazole, inhibits T4 to T3 peripheral conversion and there is some evidence that PTU also rapidly reduces serum T3 levels compared to methimazole. PTU has to be dosed frequently, usually every 4 hours. Methimazole has a longer duration of action and is less hepatotoxic, making it the preferred drug for long-term treatment and in the outpatient setting. Patients who are started on PTU in the hospital should be transitioned to Methimazole prior to discharge.

The doses of these two medications are higher for those patients in thyroid storm compared to those with uncomplicated hyperthyroidism. Typical dose of PTU is 200 mg every 4 hours; methimazole is administered at a dosage of 20-25 mg every 6 hours. These medications can be given orally, via NG, rectally, or intravenously. Patients with severe adverse effects from thionamides (agranulocytosis or hepatotoxicity) or an allergy, should be discontinued on these medications. Medical management with iodine, beta-blockers, steroids, and Bile Acid Sequestrants should continue and in some patients, urgent thyroidectomy is the next step and treatment of choice.

Iodine:

Iodine-containing solutions include Lugol’s solution and potassium iodide. Iodine works to inhibit the release of T4 and T3 from the gland within hours; therefore, it is prudent to administer iodine to patients in thyroid storm. The administration of iodine should be delayed by at least 30-60 minutes AFTER thionamide administration to prevent the iodine from being used as substrate for new hormone synthesis. Iodine solution can be given either orally or rectally; it has been suggested that Lugol’s solution can be added to IV fluids as well.

Iodinated radiocontrast agents:

These were previously used to treat hyperthyroidism by working to block peripheral conversion of T4 to T3. These agents, however, are no longer available in the United States or in most other countries.

Corticosteroids:

Steroids work to reduce peripheral conversion of T4 to T3, promote vasomotor stability, and treat possible relative adrenal insufficiency. Their use for treatment in patients in thyroid storm appears to have improved outcome in at least one series; therefore, it is reasonable to administer to those patients in thyroid storm. Hydrocortisone 100 mg every 8 hours is the agent used routinely, with tapering as symptoms improve.

Bile Acid Sequestrants:

The liver is the major site of degradation of thyroid hormones. In this organ, both T₄ and T₃ undergo conjugation, and the conjugation products are excreted in the bile. Free hormones are released in the intestine and are reabsorbed, and an enterohepatic circulation occurs. Studies have shown that Cholestyramine as a Bile Acid Sequestrant (Dosing- 4 g orally four times a day) interferes with the enterohepatic circulation and recycling of Thyroid hormones and thereby leading to decrease in Serum Thyroid hormone level. In this way it serves as an adjunctive therapy in patients with thyroid storm.

Alternative therapies:

The above details first-line, standard medical management for patients in thyroid storm or severe thyrotoxicosis. There are alternative therapies that can be considered when the first-line therapies fail or cannot be used secondary to toxicity. Lithium has been used to acutely block the release of thyroid hormone in cases when iodide therapy cannot be used; however, its potential for severe renal and neurologic toxicity limits its use. Plasmapheresis has been used in cases where traditional therapy has not been successful by allowing for removal of thyroid hormone from circulation.

Supportive care:

Supportive care is an important part of the treatment approach to thyroid storm. As fever is very common in patients with severe thyrotoxicosis or thyroid storm, antipyretics should be used. Acetaminophen is the preferred agent over salicylates, as salicylates can decrease thyroid protein binding, leading to an increase in free thyroid hormone levels. External cooling measures, such as ice packs or a cooling blanket, can also be used. These patients are extremely prone to fluid losses from fever, diaphoresis, vomiting and diarrhea. IV fluids should be administered based on clinical presentation. Patients with heart failure, however, may need diuresis instead.

Recognizing and treating the precipitating cause of thyroid storm is important. Standard work-up for infection is warranted in patients without a clear etiology; however, empiric antibiotics are not recommended without a clear source or history/physical to suggest an infection. In cases of other precipitants such as DKA, MI or another acute process, appropriate management of the specific underlying problem should proceed along with the treatment of the severe thyrotoxicosis or thyroid storm.

B. Physical Examination Tips to Guide Management.

Specific symptoms that should be monitored are those typically affected in thyroid storm. Temperature, hemodynamics, mental status, and neurologic exam should be monitored carefully. If applicable, symptoms of congestive heart failure should be assessed closely to help guide supportive treatment. Similarly, volume status should be assessed frequently as these patients can have large amounts of volume loss secondary to fever, vomiting, and/or diarrhea.

Improvement in clinical status can guide discontinuation of iodine therapy as well as tapering and cessation of glucocorticoids.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Biochemical response to medical management should be monitored by checking thyroid function tests. Although iodine therapy and glucocorticoids can be discontinued based on clinical response, beta-blocker therapy should be continued until thyroid function tests have returned normal. Thionamides are usually required, at gradually decreasing doses, for weeks to months after thyroid storm to attain euthyroidism.

Serious adverse effects of thionamide therapy include agranulocytosis and hepatotoxicity. A complete blood count and liver function tests should be checked prior to initiation of therapy to establish a baseline. Agranulocytosis typically occurs after 3 months of therapy, but can occur at any time during therapy with thionamides, so this should be monitored closely. Hepatotoxicity is less common, accounting for less than 0.5% of patients using antithyroid medications. Clinicians should closely monitor patients for signs or symptoms of liver toxicity, at which time liver function tests should be checked.

D. Long-term management.

After there is evidence of clinical improvement (i.e. resolution of any CNS, CV, GI manifestations; afebrile), iodine therapy can be discontinued. Glucocorticoids can also be tapered and discontinued. Beta-blockers should be continued while the patient is still thyrotoxic and until the thyroid function tests have returned normal. Thionamides should be continued and titrated to maintain euthyroidism. If PTU was started in-house, the patient should be switched to methimazole if possible, due to its better safety profile, ease of administration, and better compliance.

Following resolution of the thyroid storm, the patient requires close follow-up and monitoring by an endocrinologist, with plans for definitive therapy to prevent a future recurrence of life-threatening thyrotoxicosis. In patients with Graves’ disease, toxic multinodular goiter, or toxic adenoma; definitive therapy with radioactive iodine, medical management, or thyroidectomy is important to prevent a recurrence of complicated thyrotoxicosis. The choice between definitive treatment modalities is patient-specific, etiology-specific, and must take several factors into consideration.

E. Common Pitfalls and Side-Effects of Management.

There are many potential side-effects associated with management of thyroid storm; some are common adverse effects associated with specific therapies and others are more serious. In regards to the condition itself, a potential pitfall is lack of clinical response to first-line therapies and/or worsening clinical status with standard therapy. In these cases, alternative therapies as discussed above should be considered, as well as aggressive supportive care for specific complications (i.e. aggressive hydration in patients with volume loss; diuresis in patients with congestive heart failure; cooling protocols in patients with severe hyperpyrexia).

In regards to specific side-effects associated with specific therapies:

• Beta-blockers: Hemodynamics must be monitored closely in patients receiving beta-blockers, especially in those with congestive heart failure. Hypotension, bradycardia, and cardiovascular collapse are serious potential side effects. In patients with reactive airway disease, they may have worsening of their underlying RAD. Therefore, in patients with severe RAD, alternative rate-controlling agents can be considered as discussed above.
• Thionamides: Common side-effects include abnormal sense of taste, pruritus, urticaria, fever, and arthralgias. More serious, but rare, side effects include agranulocytosis, hepatotoxicity, and vasculitis. The more serious side effects are seen a bit more frequently with PTU than with methimazole, which is why methimazole is recommended for long-term management as an antithyroid medication.

IV. Management with Co-Morbidities.

N/A

A. Renal Insufficiency.

Medications used for medical management of thyroid storm should be renally dosed in patients with renal insufficiency. Certain beta-blockers, such as atenolol, need to be dosed according to renal clearance.

B. Liver Insufficiency.

Thionamides should be used with caution in patients with hepatic insufficiency, given their potential serious adverse effect of hepatotoxicity. Certain beta-blockers, such as propranolol and metoprolol, should also be used cautiously in patients with hepatic impairment.

C. Systolic and Diastolic Heart Failure.

Beta-blockers need to be used with extreme caution in patients with moderate to severe congestive heart failure. If the cause of the heart failure were likely to be secondary to the underlying tachycardia, beta-blockade would be useful. However, in situations in which the cause cannot be easily determined, only short-acting beta-blockers under close hemodynamic monitoring should be administered.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

Mild hyperglycemia can be seen in patients with thyroid storm due to excess catecholamine production, and glycemic control can be further exacerbated in patients with pre-existing diabetes and/or in those receiving steroids as part of their treatment. Glycemic control should be achieved as per guidelines for critically-ill hospitalized patients, with target fingersticks between 140-180 mg/dL per ADA and AACE recommendations.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

Patients in thyroid storm may have relative adrenal insufficiency, hence part of the rationale for corticosteroid treatment in this condition. Those who are on chronic steroids should most likely receive stress-dose steroids given their chronic adrenal insufficiency from exogenous glucocorticoids.

H. Primary Lung Disease (COPD, Asthma, ILD).

Cardioselective beta-blockers may be considered in patients with reactive airway disease (such as metoprolol or atenolol). In patients with severe reactive airway disease in whom beta-blockers might be contraindicated, rate control can be achieved with calcium-channel blockers, such as diltiazem.

I. Gastrointestinal or Nutrition Issues.

In patients with GI or CNS involvement leading to inability to take oral medications, they should receive standard medical management via IV, rectally, or through an NG.

J. Hematologic or Coagulation Issues.

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

Hemodynamics should be monitored closely in these patients, and consideration should be given to titration of antipyretic treatment and beta-blocker treatment based on symptoms and response. Patients who are unstable or critically ill, requiring very close monitoring, should be in the intensive care unit. Volume status should be frequently assessed and fluid resuscitation versus diuretics (if congestive heart failure present) should be considered based on clinical findings.

B. Anticipated Length of Stay.

Patients should remain hospitalized until their clinical symptoms of severe thyrotoxicosis or thyroid storm have either improved or resolved. Patients still requiring IV steroids, iodine therapy, IV beta-blockers, or close hemodynamic monitoring should remain hospitalized and likely be monitored in an intensive care unit. Once their symptoms have stabilized and they have demonstrated signs of clinical improvement while on the medical floor, discharge can be considered. Most patients will likely be discharged on beta-blocker therapy, thionamides, and possibly a steroid taper. Length of stay will depend on the patient’s clinical response and stability on medical management.

C. When is the Patient Ready for Discharge?

Once there is evidence of clinical improvement (patient is afebrile, improvement or resolution of CNS/CV/GI abnormalities) and the patient is no longer requiring close hemodynamic monitoring, IV fluids, or IV medications, discharge can be considered with plans for close outpatient follow-up.

D. Arranging for Clinic Follow-up.

N/A

1. When should clinic follow up be arranged and with whom?

Patients should be closely followed after discharge to assess for recurrence of symptoms, compliance on therapy, and for any adverse reactions to the medications. In addition, they should be followed closely to determine a long-term management plan for treatment of thyrotoxicosis. Although there are no standard recommendations for when patients should be seen after discharge, they should likely have been seen by their primary care physician within 1 week of discharge to assess clinical signs and symptoms, and should be seen by an endocrinologist within 2 week of discharge for further titration of anti-thyroid therapy as well as determination of a long-term treatment plan.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

Patients should have a complete blood cell count and thyroid function tests checked prior to discharge. In addition, if they had any abnormal lab tests at presentation (such as abnormal liver function tests secondary to thyroid storm-induced hepatic impairment), these should also be followed throughout the hospitalization and prior to discharge to demonstrate either improvement or resolution of these abnormalities.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

A recent set of thyroid function tests, liver function tests and a complete blood cell count should be checked at the clinic visit or prior to the visit. In addition, labs that were previously abnormal during the hospitalization (such as liver function tests) should also be rechecked to ensure improvement or resolution of the abnormalities.

E. Placement Considerations.

Patients can likely be discharged directly home, once medically stable and no longer requiring close monitoring or IV therapy. If they were at a SNF or rehab prior to admission for other reasons, they should be discharged to the appropriate post-acute care facility site based on their ambulatory status, nursing needs (for other chronic medical conditions), and need for assistance with ADLs or IADLs.

F. Prognosis and Patient Counseling.

Thyroid storm does carry considerable mortality, ranging from 20-30%. Prompt recognition of the condition, immediate medical management along with supportive care is key. In addition, recognition and treatment of the precipitating factor is crucial. Once patients are stabilized, they will need to continue therapy, likely with beta-blockers and thionamides based on TFT response. They should be counseled on the importance of medication compliance as well as concerning signs and symptoms to be aware of that may either indicate thyrotoxicosis or an adverse side effect from the therapy itself. They should also be counseled on the importance of regular follow-up as well as the need for a long-term plan to avoid subsequent complications and hospitalizations.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

NA

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Patients should receive standard DVT prophylaxis while hospitalized for thyroid storm. Once stabilized and discharged, a thorough work-up and long-term management plan for the patient’s hyperthyroidism will be key in preventing future episodes of severe thyrotoxicosis and subsequent hospitalizations.

VII. What’s the evidence?

Nayak, B, Burman, K. “Thyrotoxicosis and thyroid storm”. Endocrinol Metab Clin N Am. vol. 35. 2006. pp. 663-686.

Sarlis, NJ, Gourgiotis, L. “Thyroid emergencies”. Rev Endocr Metab Disord. vol. 4. 2003. pp. 129-136.

Solomon, BL, Wartofsky, L, Burman, KD. “Adjunctive cholestyramine therapy for Thyrotoxicosis”. Clin Endocrinol (Oxf). vol. 38. 1993. pp. 39

Tsai, WC, Pei, D, Wang, TF. “The effect of combination therapy with propylthiouracil and cholestyramine in the treatment of Grave’s hyperthyroidism”. Clin Endocrinol (Oxf). vol. 62. 2005. pp. 521

Burch, HB, Wartofsky, L. “Life-threatening thyrotoxicosis”. Thyroid storm. Endocrinol Metab Clin North Am. vol. 22. 1993. pp. 263

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