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posted Jul 23, 2013, 6:10 AM by Eliany Mejia   [ updated Jul 23, 2013, 6:12 AM by Purnema Madahar ]

This Monte daily is brought to you by Nelson Chuang, our first RAT resident!! Thanks Nelson...

On Friday, we heard a case of a 47 year old woman who presented with abdominal pain and lethargy over a few weeks consistent with thyrotoxicosis. Below, I will reduce the literature into a quick and high yield overview. Refer to the references at the end for further enrichment.

One important point to clarify is that thyrotoxicosis is not the same as hyperthyroidism. Thyrotoxicosis describes a state of elevated thyroid hormone, whereas hyperthyroidism is a state of increased production and secretion of thyroid hormone. Therefore, thyrotoxicosis can occur in the absence of hyperthyroidism. Just to be thorough, what is commonly known as thyroid storm, or thyrotoxic crisis or severe thyrotoxicosis, is when thyrotoxicosis manifests as an acute, life threatening, hypermetabolic state.

Most common cause is Graves Disease caused by autoantibodies that bind and stimulate the TSH receptors. 2nd most common cause is autonomous overproduction by one or more nodules (solitary toxic adenoma or toxic multinodular goiter, respectively). Other causes include: thyroiditis, excess exogenous thyroid hormone, drug-induced, TSH-secreting pituitary adenomas, and the more uncommon causes can be found in Table 1 of the Lancet article.

Clinical Presentation:
Since thyroid hormone, specifically T3, affects almost all physiological systems the presentation can be confusing. The predominant manifestation is cardiac with increased heart rate as well as supraventricular ectopic activity. However, in our case, the atrial flutter was masked by her tachycardia, and the increased heart rate was easily assumed to be a secondary effect of patient’s acute symptoms, i.e. abdominal pain and fever. One clue to the atrial flutter was the patient’s persistent regular rate of 150bpm, which should raise suspicion of a 2:1 conduction block atrial flutter.

Due to the global effects of thyroid hormone, a thorough review of systems can lend confidence in diagnosis. See table from the Lancet review for a summary of symptoms and associated signs by system.

Going back to our case, patient’s lethargy is typically not a presentation of thyrotoxicosis but can be in the elderly population. It may have been caused by her metabolic abnormalities. The second issue people were curious about was her abdominal pain. It is not clear what causes abdominal pain in thyrotoxicosis. Some think it could be the hypercalcemia (occurs in 20% of patients with hyperthyroidism), or possible the perception of pain from the hypermotility effects on the gastrointestinal tract leading to nausea, vomiting, and hyperdefecation. Frequent vomiting could reasonably lead to abdominal pain as well.

The marked hypernatremia can only be explained by either a nephrogenic diabetes insipidus secondary to hypercalcemia (typically observed at levels above 11mg/dL due to renal concentrating defect) or decreased free water.

Laboratory Diagnostics:
TSH should be the first test to screening test to exclude thyrotoxicosis due to its high sensitivity. Serum TSH levels should be undetectable due to the negative feedback exerted on the anterior pituitary gland. Free T4 should be elevated, but if it is not and TSH is low then T3 toxicosis should be considered. If TSH is low but free T3 and T4 are normal then it may be subclinical hyperthyroidism. Rarely, the TSH can be normal in cases of TSH secreting pituitary adenoma or thyroid hormone resistance.

Further Diagnostics:
If the cause is not certain from laboratory testing and clinical presentation further testing can be performed with radioactive iodine uptake scan or isotope imaging.

So what do we do after we make the diagnosis? This is where things get tricky since there are so many causes of thyrotoxicosis. This will be a brief overview and will only touch upon the major points of management. For the budding endocrinologists in some of you, I have attached an extremely-seriously extremely-exhaustive guideline on management of every conceivable cause of thyrotoxicosis.

First and foremost, beta blocker is needed for initial symptomatic management of thyrotoxicosis. Secondly, if this is severe thyrotoxicosis aka thyroid storm then a standard regimen including antithyroid therapy, iodine compounds, and glucocorticoids is administered. Ok let’s move on.

We will focus mostly on Grave’s hyperthyroidism as it is the most common cause of thyrotoxicosis. There are three general options for treatment: radioiodine therapy, antithyroid drugs, and surgery. Which one do we use? So it turns out in a prospective randomized study showed 90% patient satisfaction, time to euthyroid, and time on sick leave. Another study also showed long-term quality of life to be similar between all three. Last thing to know, radioiodine was associated with lowest cost.

Antithyroid therapy include carbimazole, methimazole, propylthiouracil and work by inhibiting organification of iodide and coupling of iodothyronines, and hence synthesis of thyroid hormones. These drugs can be used short term to prepare for radioiodine or surgery besides long term maintenance of euthyroidism. Normalization of T4 can be expected in 8-12 weeks and should be assessed every 4-6 weeks. Serum TSH may remain suppressed for weeks or months after the T4 has normalized. There is a small chance of achieving remission after drug withdrawal, thus the need for destructive therapies. The side-effects are long but most commonly known is the agranulocytosis.

Radioiodine treatment is one of the destructive therapies and can be first line as well. Contraindications include pregnancy, desire for pregnancy in next six months, thyroid cancer, and inability to follow radiation protection regulations. Expected complication is frequently hypothyroidism. There is controversy regarding preadministration of antithyroid therapy prior to radioiodine to prevent thyroid storm since theoretically there may be destructive thyroiditis. UK they do it, but US they don’t. A point on the side, if there is eye involvement whether from Grave’s or patient has active eye disease things get hairy (worse outcomes and need for steroid prophylaxis, respectively. At this point Endocrine is already involved I hope).

Surgery is the least favorite option understandably. In this case, the patient’s should be euthyroid prior to surgery to avoid a real risk of thyroid storm. Total thyroidectomy is preferred as partial leaves a 30% chance for relapse and complication rates are similar. Hypoparathyroidism and recurrent laryngeal nerve damage occur 2% and 1%, respectively.

We’ll wrap up with a few key points on the other causes:

-Thyrotoxicosis in pregnancy is a whole ‘nother beast that would require an entry in and of itself. Please refer to the attached review paper for further information.
-Subclinical hyperthyroidism as mentioned earlier requires follow up to determine if it is persistent. If it is, then a thorough evaluation for the cause is required. Typically it is caused by toxic nodular goiter, especially in the elderly. Treatment is controversial as evidence is lacking.
-Toxic nodular goiter, whether solitary or multinodular, the treatment is same as Grave’s disease-except it does not remit with antithyroid therapy. Total thyroidectomy is the treatment of choice for large goiters, especially if they exhibit compressive symptoms. Otherwise radioiodine has 80% cure rate at 6 months.
-Thyroiditis is inflammation of the thyroid, either by infection or autoimmunity. For subacute or de Quervain’s, it is painful, self-limiting after 4-6 weeks, and only requires symptomatic management with beta blockers or NSAIDs. Silent or painless thyroiditis suggests autoimmune destruction and antithyroid drugs are contraindicated.
-Amiodarone is a common iatrogenic cause of abnormal thyroid tests. It is an iodine containing drug which can cause thyrotoxicosis in 6-10% of patients.  Diagnosis requires increased free T4 and T3 with suppressed TSH. There are two types of amiodarone-associated thyrotoxicosis and both require different management. Withdrawal of amiodarone is not effective due to 100 day drug half-life. Sometimes thyroidectomy might be required.

Purnema Madahar,
Jul 23, 2013, 6:10 AM