The risks of PTU

Summary

ResearchBlogging.orgThere are two main drugs used to treat Graves’ Disease medically – MMI (methimazole or it’s nearly identical relative carbimazole) and PTU (propylthiouracil).

As with all drugs, there are risks and side effects.  As a patient, I’ve often been frustrated when trying to understand exactly how risky these drugs are.  The listed risks (liver failure, loss of white blood cells) are terrifying, and yet, very few people ever experience these.  What do we know about the risks and what can we patients do to avoid them?  Dr. David Cooper at Johns Hopkins has published several papers about these risks and I’m going to review them over the next few weeks.

The paper today is a recent (2009) summary of two scientific meetings that were held to discuss the risks involved with the use of PTU.  Currently in the US, about 25% of Graves’ patients are on PTU.  Doctors prescribe PTU rather than MMI for several reasons.  PTU is considered better for pregnant women, especially during the first trimester, as MMI can sometimes cause birth defects.  Some people have an allergic reaction or other mild side effects from MMI and so take PTU instead.

Because of this, the general trend is to prescribe MMI first, and if that doesn’t work for some reason (pregnancy or adverse reaction), then switch to PTU.  MMI is also considered “better” than PTU in that in is more effective when people are severely hyperthyroid, people adhere to it better, and it causes less toxicity, especially at low doses.


So, how risky is PTU?

There are approximately 600,000 60,000 new cases of Graves’ diagnosed in the US each year.  Of these, 25% get put on PTU for one of the above reasons, so there are 15,000 people who start taking PTU each year.  Of these people, approximately 1 in 1000, or 15 people total, develop severe liver damage, and 1 or 2 die.

Various organizations keep different sorts of records on PTU-related liver failure.  For instance, there are 42 cases reported in the scientific literature since 1947, while the FDA knows of 47 cases.  UNOS (the organ transplant association) reported 23 liver transplants over a 17-year period related to PTU, but none related to MMI.  The FDA-AERS database lists 34 cases of liver failure in the last 20 years.

Who gets these nasty reactions?

The average dose of PTU in the people who had these reactions was 300 mg per day.  The victims had been taking PTU for 6-450 days.  About half had been taking PTU for less than 120 days, and half for more than that.  About a third of the victims were children, and there were two reports of fetal liver damage.  Because children make up only about 6% of Graves’ disease patients, but nearly 33% of the patients experiencing liver damage, PTU may affect children more negatively than it does adults.

Can you tell if you are having these reactions?

Because liver toxicity happens so rapidly, routine monitoring of liver values is not helpful.  Monitoring does not reduce the risk of liver injury because of the unpredictable nature of the drug reaction.  Signs of liver failure include:

  • jaundice (yellowish skin or eyes)
  • fatigue or malaise (tiredness)
  • nausea
  • anorexia (no appetite)
  • pharyngitis (sore throat)

If you have any of these signs, stop taking PTU and go get your liver enzymes checked immediately.

 

What about pregnancy?

I’ll quote here from the paper:

Considering the intricacies of care and risks involved for a woman with active [Graves’ disease] during pregnancy, treatment with radioactive iodine or surgery before pregnancy should be strongly considered for those who desire future pregnancy. Doing so can avoid the dilemma of choosing between a drug associated with a small risk of fetal birth defects [MMI] and another drug associated with a similarly small but finite risk of serious liver injury in the mother [PTU].

For women who choose not to take the risks of surgery (anesthesia, mistakes) or radioactive iodine (radioactivity, hypothyroidism), the current recommendation is to take:

  • PTU for the first trimester (to prevent birth defects)
  • MMI (if needed) for the second two trimesters

The upshot?

Stick to MMI if possible.  If you choose PTU, you will more than likely be one of the 999/1000 people who has no problems whatsoever.  Hooray!

But, be aware of the symptoms mentioned above and seek help immediately if you experience them.

If you are thinking about getting pregnant, have a good look over the risks of all of these options and talk with your doctor.

Reference
Cooper, D., & Rivkees, S. (2009). Putting Propylthiouracil in Perspective Journal of Clinical Endocrinology & Metabolism, 94 (6), 1881-1882 DOI: 10.1210/jc.2009-0850

Abstract

This paper had no abstract

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Taking methimazole for 10+ years

ResearchBlogging.org

In the US, most Graves’ Disease patients get herded into either radioactive iodine treatment (RAI treatment) or surgical thyroid removal.  These are seen as “definitive” treatments, meaning permanent fixes.  There is some truth to this as it is impossible to be hyperthyroid if you don’t have a thyroid.  Taking anti-thyroid drugs, on the other hand, is seen as a temporary solution, usually for less than two years, before getting one of the “definitive” treatments.

Anti-thyroid drugs are, indeed, not definitive.  20-70% of Graves’ patients relapse after stopping medication.  In that sense, these drugs don’t “cure” the disease, while the “definitive” treatments do.
However, after surgery or RAI, people usually become hyp-O-thyroid (too little thyroid hormone) and have to take supplementary hormone.  The choice,  from the patient’s perspective, is then either a lifetime of taking an anti-thyroid drug (such as methimazole, tapazole, or polythiouracil), or a lifetime of taking a “pro”-thyroid drug, such as Synthroid, Levothyroxine, or Armour.

If you have to take a pill every day no matter what, what’s the difference?

The antithyroid drugs have some minor side effects (rashes, headaches) as well as some rare, but very scary ones, such as agranulocytosis (loss of your white blood cells), problems with blood clotting, and death of liver cells.  The “pro”-thyroid drugs have fewer serious side effects (possibly a slightly increased chance of osteoporosis, some digestive upsets).  However, the risks of the “definitive” treatments themselves are worth considering.  RAI is thought to strongly increase your risk of developing Graves’ Opthlamopathy, an eye disorder.  Surgery and anesthesia have numerous inherent risks.

One solution that is common in Europe, but less so in the US is just staying on the anti-thyroid drugs permanently.  This eliminates the risks of surgery or RAI, has the same impact on the daily life of patients (one or two pills a day), and, as long as you tolerate the drugs and don’t develop the nasty side effects from them can, presumably, be taken indefinitely.

The study I’m discussing today tests that last assumption – is taking methimazole as a long-term treatment safe and effective?

The authors started with 504 patients who were treated with methimazole for 18 months, after which treatment stopped but the patients were monitored.  104 patients’ hyperthyroidism returned within a year.  Of these, the authors randomly treated half with RAI and half with more methimazole.  They then followed these patients for 10 years and measured many indicators of their health, including liver enzymes, cholesterol, bone density, thyroid hormones, and cardiac tests (among others).

After 10 years, they found that the groups had similar thyroid levels, similar cost of treatment (from the perspective of the health care system) and many similar blood values. The RAI group had slightly higher LDL (“bad cholesterol”) levels, slightly lower bone densities, and similar cardiac tests.  However, the methimazole group had more goiter and higher anti-thyroid antibody levels.  The authors concluded that long-term use of methimazole was a good alternative to surgery or RAI.  They say:

“Except for mild side effects, serious reactions are rare, and the risks of occurrence of cardiac and bone complications are equal to or less than those of radioiodine therapy…[A] possible approach to the therapy of hyperthyroidism may be to control the disease, for a lifetime, with antithyroid drugs. The remarkable lack of MMI side effects and the apparent high treatment compliance in this study prompt the adoption of an alternative approach such as this.”

End result?  As long as you tolerate it (and most people do), long-term use of methimazole is a decent alternative to RAI or surgery.

Abstract

Objective: To investigate the long-term effects of continuous methimazole (MMI) therapy. Design and methods: Five hundred and four patients over 40 years of age with diffuse toxic goiter were treated with MMI for 18 months. Within one year after discontinuation of MMI, hyperthyroidism recurred in 104 patients. They were randomized into 2 groups for continuous antithyroid and radioiodine treatment. Numbers of occurrences of thyroid dysfunction and total costs of management were assessed during 10 years of follow-up. At the end of the study, 26 patients were still on continu- ous MMI (group 1), and of 41 radioiodine-treated patients (group 2), 16 were euthyroid and 25 became hypothyroid. Serum thyroid and lipid profiles, bone mineral density, and echocardiography data were obtained. Results: There was no significant difference in age, sex, duration of symptoms and thyroid function between the two groups. No serious complications occurred in any of the patients. The cost of treat- ment was lower in group 1 than in group 2. At the end of 10 years, goiter rate was greater and antithyroperoxidase antibody concentration was higher in group 1 than in group 2. Serum cholesterol and low density lipoprotein-cholesterol concentrations were increased in group 2 as compared with group 1; relative risks were 1.8 (1.12–2.95, P,0.02) and 1.6 (1.09–2.34, P , 0.02) respectively. Bone mineral density and echocardiographic measurements were not different between the two groups. Conclusion: Long-term continuous treatment of hyperthyroidism with MMI is safe. The complications and the expense of the treatment do not exceed those of radioactive iodine therapy.


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Azizi, F. (2005). Effect of long-term continuous methimazole treatment of hyperthyroidism: comparison with radioiodine European Journal of Endocrinology, 152 (5), 695-701 DOI: 10.1530/eje.1.01904

Posted in Anti-thyroid drugs, Radioactive iodine | 152 Comments

Randomized study of Graves’ disease treatments

Summary

This study looked at three common treatments for Graves’ disease (medication, surgery, and radioactive iodine) and their effect on the underlying cause of Graves’ (an autoimmune reaction).

This study was set up in one of the best ways to test the effects of different treatments – namely, a randomized study.  It was not a randomized controlled study, the ideal way to set up a study, because then you would have to give one group a sham (placebo) treatment.  That would be unethical in this case as not treating someone with Graves’ disease can have potentially fatal consequences.  The comparison, then, is among the three treatments, not the three treatments compared with no treatment.

A total of 179 patients with Graves’ disease were randomly assigned to one of three treatment groups – medication (methimazole and T4 hormone together), surgery (which removed almost, but not all of the thyroid gland), or radioioactive iodine (RAI) followed by T4 hormone.   The authors measured thyroid antibody (TRAb), levels in the patients before and after treatment.  High levels of TRAb are thought to be one underlying cause of  Graves’ disease.  The authors tested the hypothesis that treatment for Graves’ disease would reduce TRAb levels.

Because real humans (not lab rats) were being tested, some people dropped out for various reasons, some irrelevant (moved away), some relevant (one treatment didn’t work for them, so they switched treatments). For example, out of these 179 patients, 29 had normal starting TRAb levels (so couldn’t be used in this study to see if their TRAb levels normalized with treatment), one patient opted against the surgery, one opted out of RAI, one didn’t take the medication and ended up needing surgery, two couldn’t tolerate the medication, three surgical patients were still hyperthyroid afterwards and so also had RAI done.  These results are interesting because they show the variability in how people mentally and physically respond to these treatments.  However, because there were just a few patients in each group, they weren’t included in the bigger analysis.  That left only 131 people in the final analysis.

The results:  All three groups started out with high (~40) TRAb levels at the beginning of the study.  The medicated group (red line) and surgical group (blue line) both showed a decrease in TRAb levels over time and weren’t different from one another.  The RAI group (green line), however, showed a spike in TRAb immediately after treatment, and then declined slowly over time.  The RAI group never got as low as the other two groups, though.

TRAb is thought to be a trigger for Graves’ opthalmopathy, an eye disorder.  These findings may explain why RAI has been associated with an increased risk of Graves’ opthalmopathy, especially right after the RAI treatment.

Some caveats:  There weren’t that many people in this study.  They were all Swedish.  Those for whom the treatment didn’t work were excluded (ie – for 3 people surgery didn’t work and they got RAI (and so weren’t included), and for three others drugs didn’t work, so they got surgery.  There were ~30-40 people in each treatment group, and so the missing results of 3 “dropouts” might skew the results somewhat.

The authors emphasized the need for women who have had RAI treatment to get tested for TRAb if they later become pregnant.  The reason is that TRAb, if still high, can affect the baby.  Because RAI doesn’t reduce TRAb as much as the other treatments, this should be monitored carefully in pregnant women to avoid attacking the baby’s thyroid.

After stopping medication, TRAb rose in the medicated group.  This means that people have a choice of staying on the medication (with its side effects) or switching to a different, more permanent solution (surgery or RAI).  Patients and doctors need to weigh the pros and cons and risks of these various treatments.

The authors also discussed the large (29 out of 179) number of patients who had no abnormal TRAb.  They say that there are a number of tests that measure TRAb.  Some patients are positive on one, but negative on others.  However, all Graves’ disease patients will show up positive on at least one.  The Graves’ patients with normal TRAb levels in this study may have been positive on other tests, just not the one used by the authors.

Quick and dirty summary: thyroid antibodies decline after medication and surgical treatment of Graves’, but spike and then decline more slowly after radioactive iodine treatment.

Reference

Introduction: Autoimmunity against the TSH receptor is a key pathogenic element in Graves’ disease. The autoimmune aberration may be modified by therapy of the hyperthyroidism. ObjectiveTo compare the effects of the common types of therapy for Graves’ hyperthyroidism on TSH-receptor autoimmunity. MethodsPatients with newly diagnosed Graves’ hyperthyroidism aged 20-55 years were randomized to medical therapy, thyroid surgery, or radioiodine therapy (radioiodine was only given to patients [≥]35 years of age). L-thyroxine (L-T4) was added to therapy as appropriate to keep patients euthyroid. Anti-thyroid drugs were withdrawn after 18 months of therapy. TSH-receptor antibodies (TRAb) in serum were measured before and for 5 years after the initiation of therapy. ResultsMedical therapy (n=48) and surgery (n=47) were followed by a gradual decrease in TRAb in serum, with the disappearance of TRAb in 70-80% of the patients after 18 months. Radioiodine therapy (n=36) led to a 1-year long worsening of autoimmunity against the TSH receptor, and the number of patients entering remission of TSH-receptor autoimmunity with the disappearance of TRAb from serum during the following years was considerably lower than with the other types of therapy. ConclusionThe majority of patients with Graves’ disease gradually enter remission of TSH-receptor autoimmunity during medical or after surgical therapy, with no difference between the types of therapy. Remission of TSH-receptor autoimmunity after radioiodine therapy is less common.

ResearchBlogging.orgLaurberg, P., Wallin, G., Tallstedt, L., Abraham-Nordling, M., Lundell, G., & Torring, O. (2008). TSH-receptor autoimmunity in Graves’ disease after therapy with anti-thyroid drugs, surgery, or radioiodine: a 5-year prospective randomized study European Journal of Endocrinology, 158 (1), 69-75 DOI: 10.1530/EJE-07-0450


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