Medical treatment of hyperthyroidism (part II)

Summary

Earlier, I posted about the beginning of this article. Now I’m finishing it up. This section talks about “antithyroid drugs of second choice”.  These are drugs that don’t exactly “fix” the problem, but relieve some of the symptoms.

Potassium perchlorate

This drug is used if your hyperthyroidism is caused by eating too much iodine.  It blocks the uptake of iodine by the thyroid.  It has a pretty nasty side effect of possibly causing bone-marrow problems.  Since this isn’t usually a problem for folks that read blogs, you can probably ignore this treatment.

β (Beta) Blockers

β blockers make you “feel” better by lowering some of the symptoms of Graves, including palpitations, anxiety, tremors and heat intolerance.  They are also sometimes used as anti-anxiety pills by perfectly healthy folks.  Two common β blockers are propranolol and atenolol.  Propranolol can also help reduce the conversion of T4 to T3, which is helpful.  Atenolol is used for people who have asthma, but doesn’t have the T4->T3 blocking effect.  Many people are prescribed β blockers when they first get diagnosed as a way to feel better until their other treatments have time to take effect.

Inorganic iodide (and Lithium)

Suddenly eating a large amount of iodine will cause a temporary (~ 2 weeks) drop in thyroid hormone levels.  However, because this is not a permanent fix, it is generally just used in specific situations such as prepping someone for thyroid surgery or if they are experiencing thyroid storm.  Lithium has similar temporary effects and is sometimes used in similar, short-term situations.

Glucocorticoids

This drug is used when the thyroid is inflamed (thyroiditis) and is a temporary treatment to bring down the inflammation.  It does also prevent T4->T3 conversion.  Steroids have multiple negative effects on the body and should be used only temporarily if possible, and the doses are usually tapered at the end (ie – you wean off of them).

Rituximab (RTX)

This experimental treatment (ie, not yet available) is risky and currently is not considered better than the other treatments.  RTX is sort of an anti-autoimmune drug.  Basically, it is an antibody that fights the immune system’s over-reaction to the thyroid gland.  By fighting your own immune system, though, there is a large potential for things to go awry.  For example, out of only two clinical trials, patients developed all sorts of new autoimmune disorders such as allergic reactions, crohn’s disease, arthritis, psoriasis, and a demyelinating (degenerative nerve) disorder.  Ick!  The author’s take on this is that it “should not be considered as an option in uncomplicated Graves’ disease.”  However, it does show promise in faster relief for Graves’ opthalmopathy, which might be a benefit in severe cases if it prevents the need for surgery.

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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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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Association between radioiodine therapy for Graves’ hyperthyroidism and thyroid-associated ophthalmopathy

Summary

Two earlier studies of Graves’ Disease that found that treating Graves’ Disease with radioactive iodine rather than antithyroid drugs caused a large (3-5X) increase in the risk of developing Graves’ Opthalmopathy (GO), an eye disorder. However, there were also five other studies that found no link between radioactive iodine and GO.The difference between the two sets of studies is that the first two studies were randomized controlled trials – the “gold standard” of medical research.  In these types of studies, new patients are randomly assigned to a treatment (radioactive iodine (RAI) or anti-thyroid drugs (ATD)) and their outcomes are measured.  The 5 studies that found no effect were “retrospective” studies – meaning that they were done by reviewing the medical records of patients after-the-fact.  These types of studies aren’t as good because there are more opportunities for things to go wrong.  What if patients with the most severe GD or GO opted for the radioiodine treatment instead of drug treatment?  What if the mildest patients didn’t return for follow-up?  What if the poorest patients chose drugs because they were cheaper?  There are many ways that a retrospective study can be intentionally or unintentionally biased.
Because of this history of different results, the authors of this study did a new randomized-controlled trial (although, because of low sample numbers, they also included some patients who chose their treatment).

46 patients with Graves’ Disease were studied.  Approximately half received drugs (carbimazole) and the other half received RAI.  The two groups started out with similar numbers of smokers (which is thought to increase the risk of GO), existing symptoms of GO, and thyroid hormone levels.
Results: TSH levels were slightly higher in the RAI group than in the ATD group.  For all other measures (such as signs of GO and other thyroid hormones), the two groups were the same.  The authors concluded that there was no increased risk of GO with RAI treatment.

Discussion: The authors point out some of the problems with the previous two randomized-controlled trials.  In one study, there was a much higher number of smokers, which is a known risk-factor for GO.  In both studies, the RAI-treated patients were allowed to become hypo-thyroid (too low levels of thyroid), although this is not generally considered a risk factor.  The current study had a small sample size (only 46 people, versus 114 and 443 in the other two studies), which makes it harder to pick out differences between groups.

Bottom line: this study found no difference in the development of GO in patients treated with radioactive iodine or carbimazole.

Reference

Samer El-Kaissi et al., “Association between radioiodine therapy for Graves’ hyperthyroidism and thyroid-associated ophthalmopathy,” International Ophthalmology 30, no. 4 (2010): 397-405.

Abstract To investigate the role of radioactive iodine (RAI) in the onset and progression of thyroid-associated ophthalmopathy (TAO). Forty-six Graves’ disease patients with mild or no ophthalmopathy were prospectively treated with carbimazole (CBZ) (n = 22) or RAI (n = 24). Treatment effects were evaluated clinically over 12 months, and with orbital MRI-measured extra-ocular muscle (EOM) volumes at baseline and at 6 months. The diagnosis of TAO was based on the clinical activity score (CAS) system. There were 11/22 CBZ and 10/24 RAI patients with active ophthalmopathy at baseline. Despite greater mean TSH levels post-RAI (P = 0.003), there was no increase in the likelihood of developing active ophthalmopathy (OR 0.95; 95% CI 0.56–1.61, P = 0.9) or EOM dysfunction (OR 0.52; 95% CI 0.26–1.06, P = 0.074). The increased mean palpebral aperture post-RAI (P = 0.023) and greater mean proptosis in the CBZ group (P = 0.005) were not confirmed when the absolute values of these measurements were examined. There was no association between the treatment received and MRI-measured EOM volumes. In this study, RAI therapy for Graves’ disease did not increase the risk of progression or development of ophthalmopathy in patients with mild or no eye disease at baseline.



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