Medical Treatment of Hyperthyroidism (part I)

Summary

This paper, published in February 2010, is a review of what is known about the drugs used to treat Graves’ Disease.  No new research was done in this article, but it’s a nice synthesis of the earlier literature.

This is a long paper, so today I’m just going to sum up the first part which talks about the commonly used drugs to treat Graves’ Disease.  Tomorrow I’ll cover the rest of the paper.

There are three main “thionamide” drugs, better known to GD patients as propylthiouracil (PTU), methimazole (MMI), or carbimazole (CBZ).  The authors call these “First Choice Antithyroid Drugs” and they are usually the first treatment most people encounter.  CBZ and MMI are more or less identical to one another (CBZ gets converted into MMI) and both reach their peak concentration in the bloodstream about 1-2 hours after you take them.  All of the drugs can cross into the womb and affect a baby, so be sure to tell your doctor if you might be pregnant.

All the thionamide drugs work by blocking one of the enzymes in the pathway that makes the thyroid hormones T3 and T4.  In addition to directly lowering thyroid hormone levels, they also may work to prevent the actual cause of Graves’ Disease.  Graves’ Disease is thought to be caused by the body making antibodies against itself.  Thionamide drugs also suppress this auto-immune reaction, although nobody knows whether the drugs have a direct impact on the immune system or whether merely reducing T3 and T4 levels also happens to suppress auto-immune activity. PTU blocks the conversion of T4 (less active, more common) to T3 (more active, rarer), also lower the levels of “active” thyroid hormone in your blood.  Finally, these drugs may block the synthesis of thyroid-hormone-producing enyzmes.

The authors say that these drugs can be used for long term (1-2 years…(they think THAT is long term?), or to prep someone before radioactive iodine or surgical treatments.  They say that choosing medication (over RAI or surgery) is a good choice if:

• your hyperthyroidsim is mild or moderate
• your thyroid is only slightly enlarged
• in children and teenagers
• pregnant or breastfeeding
• no opthalmopathy

These drugs are NOT a good choice (according to the authors) if:

• high level of hyperthyroidism
• large toxic goiter
• large goiter
• high antibodies

The authors next compared MMI and PTU.

• Both drugs blocked the synthesis of thyroid hormones (T3 and T4)
• Only PTU blocks conversion of T4 to T3
• MMI lasts for ~40 hours, while PTU only lasts for 12-24 hours.  This means you have to take PTU more often than MMI.
• MMI is stored in the thyroid, while PTU isn’t stored much.
• MMI gets people to normal thyroid levels faster than PTU.
• Patients are better about taking MMI than PTU (fewer missed doses, likely because it is only once per day instead of multiple times per day).

Several studies have looked at what the most effective dose is for these drugs.

• One study found that patients receiving either 10 mg of MMI/day or 40 mg of MMI had similar outcomes.  Patients in both groups achieved normal thyroid levels within 6 weeks.  Given the serious potential side effects of MMI, lower doses are probably better.
• Another study compared doses of 15 mg of MMI, 30 mg of MMI, or 300 mg of PTU.  There were no differences among the groups among patients whose initial status was mild or moderate (ie, their starting free T4 levels were <7 ng/dl).  However, severely hyperthyroid patients did better when they got the higher MMI dose than either of the other options (low MMI or PTU).

Maintenance Doses

• The authors suggest a maintenance dose of 5-10 mg daily for MMI or 50-100 mg of PTU for 12-18 months.
• Stopping sooner increases the chance the hyperthyroidism will return.
• Taking it longer does not decrease the chance it will return.
• The authors recommend only using these drugs for 12-18 months.
• One alternative treatment is “block-and-replace” therapy.  This involves taking higher doses of MMI or PTU to lower thyroid hormone levels, then taking synthetic thyroid hormone to bring them back up.  The authors do not recommend this treatment as the side effects are worse.

Side effects

• These drugs have side effects.  Some are minor (rash, nausea), while others can be potentially lethal, such as losing all your white blood cells, liver toxicity, and inflammation of your blood vessels.  These severe complications occur in 1 out of every 200-500 people.  Some side effects (mild or severe) occurred in in 52% of patients treated with 300 mg of PTU, in 30% of patients treated with 30mg of MMI, and in 14% of patients treated with 15mg of MMI.

Monitoring:

• The authors recommend checking blood values every 4-6 weeks at the beginning of treatment and every 2-3 months afterwards including FT3, FT4, TSH, complete blood-cell count, liver- function test and thyroid antibodies.

Using radioactive iodine (RAI) and drugs together

• Using MMI or PTU before RAI reduces the likelihood of the thyroid dumping excess thyroid hormone into the blood as it decays.  This can be dangerous and lead to conditions such as thyrotoxic storm, which has a 25% chance of dying.
• However, MMI and PTU both reduce the success rate of RAI treatment.  One way of compensating for this might be to give higher doses of RAI to patients receiving MMI.
• Receiving MMI after RAI might decrease the chance of becoming hypothyroid later.

More on other the other treatments they reviewed tomorrow.  (Potassium perchlorate, β-blockers, inorganic iodide, glucocorticoids, biologic drugs)

Reference

Fumarola, A., A. Di Fiore, M. Dainelli, G. Grani, and A. Calvanese. “Medical Treatment of Hyperthyroidism: State of the Art.” Experimental and Clinical Endocrinology & Diabetes (5, 2010). http://www.thieme-connect.de/DOI/DOI?10.1055/s-0030-1253420.

Abstract Methimazole (MMI) and propylthiouracil (PTU) are the main antithyroid drugs used for hyper- thyroidism. They inhibit the synthesis of thyroid hormone at various levels and are used as the primary treatment for hyperthyroidism or as a preparation before radioiodine therapy or thy- roidectomy. MMI is the drug of choice because of its widespread availability, longer half-life and small number of severe side effects. Drugs of second choice are potassium perchlorate, beta blockers, iodine, lithium carbonate and gluco- corticoids. Rituximab, a monoclonal antibody directed against human CD20, was recently pro- posed as a biological therapy for cases of Graves’ disease unresponsive to traditional drugs.

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