Graves’ Hyperthyroidism: Modified Block and Replace Treatment with Antithyroid Drugs + Levothyroxine

Antithyroid drugs (ATDs) to lower Graves’ antibodies

Graves’ hyperthyroid patients deal with problems that other thyroid patients don’t have.  In addition to the typical hyperthyroid symptoms of a fast heart rate, insomnia, weight loss, and diarrhea, Graves’ patients must deal with antibodies that cause other symptoms.  Graves’ antibodies can disfigure the eyes (thyroid eye disease or TED), the skin (pretibial myxedema, acropachy), and affect other organs, in addition to causing goiters, so the antibodies need to be controlled.  There are antithyroid drugs (ATD) available today that can do this, like methimazole, carbimazole, tapazole, or propylthiouracil.  But they not only reduce the antibodies, they also reduce the synthesis of any thyroid hormones. [1]  So long-term, they induce hypothyroidism.  Patients have achieved remission, or the reduction of their antibodies to a point where they are no longer problematic by using antithyroid drugs, usually for several years.  Because the antithyroid drugs induce a hypothyroid state, the patient is then dealing with hypothyroid, instead of hyperthyroid symptoms.  But there is a way around this, and it’s the replace part of the block and replace protocol, also referred to in some Graves’ internet forums as add back.  Block refers to the blocking effect the antithyroid drugs have on both thyroid hormones and antibodies, and replace refers to the replacement of thyroid hormone (usually levothyroxine or T4) that keeps a Graves’ patient’s Free T4 levels at least mid-range.

If antithyroid drugs lower thyroid levels, making one hypothyroid, shouldn’t one just lower the antithyroid drug dose and let thyroid levels return to normal?

The antithyroid drug dose should be based on the level of Graves’ antibodies, both TSI (Thyroid Stimulating Immunoglobulin) and TRab (TSH Receptor antibodies, also known as Thyroid Binding Inhibitory Immunoglobulins or TBII).  TSI antibodies mimic the action of TSH, causing excess secretion of both T4 (thyroxine) and T3 (triiodothyronine), making one hyperthyroid.  There are also blocking TRab that antagonize the action of TSH, making one hypothyroid.  The thyroid gland itself is not the problem; the antibodies are controlling it.

Antithyroid drugs lower the antibodies, which is beneficial, because of the damage they can do to the body.  So if TSI and TRab levels are still high, it seems unwise to reduce the antithyroid drug dose.  One approach that has been successfully used is a maintenance antithyroid drug dose (block), combined with supplemental thyroid hormone that is added back in (replace) to correct the side effect of low thyroid hormone levels. [1]

Antibody and thyroid levels rapidly drop once antithyroid drugs are started, and frequent monitoring (every 4-6 weeks or less) of these antibodies and thyroid levels (TSH, Free T3, Free T4) is imperative when this protocol is first started. Some have had to lower their dose within the first week, so the patient needs to be very aware of hypothyroid symptoms.  Antithyroid drugs are powerful medications. The initial antithyroid drug dose is titrated down after 4-12 weeks (or sooner) if antibody levels have come down, and many maintain a dose of only 5 mg methimazole for years. [1]  The antibody levels are what should determine the antithyroid drug dose, not TSH levels.  TSH can remain suppressed for years in someone with Graves’ because of TSH Receptor antibodies, even when actual T3 and T4 levels have fallen below the reference range. [2]  These are not the same antibodies found in Hashimoto’s patients; those are the TPO (thyroid peroxidase) and Tg (thyroglobulin) antibodies (although Graves’ patients can also have these antibodies).  A person with Hashimoto’s usually does not have a suppressed TSH, while a Graves’ patient usually does.

Antithyroid drugs can have serious side effects, and the risk increases if the dose is kept too high for too long. [3]  The dose will most likely be kept too high if one tries to dose by TSH.  A Graves’ patient can be either hyperthyroid or hypothyroid while on ATDs, with a TSH near zero, because the antibodies are artificially stimulating the TSH Receptors.  The TSH is no longer an indication of whether a Graves’ patient has an excess or deficiency of thyroid hormone (T4 and T3) when high levels of TRab are present.  If the patient is now suffering from hypothyroid symptoms, thyroid hormone such as levothyroxine can be prescribed to bring levels up to mid-range, while maintaining the antithyroid drug dose.  If thyroid levels are allowed to drop too low, one can again experience hyperthyroid symptoms, from being hypothyroid.  [hyperthyroid symptoms, hypothyroid labs]  It is possible to lead a somewhat normal life with the antithyroid drugs controlling the antibodies, and the supplemental thyroid medication keeping one euthyroid or normal.

Why should one replace or add back thyroid hormone, instead of coping with the hypothyroid state?

One theory is that being in a hypothyroid state will stimulate the antibodies, as the body may try to increase thyroid levels that way.  Graves’ has developed in patients who were first diagnosed with Hashimoto’s thyroiditis [4]  These people went from a hypothyroid state to a hyperthyroid state, simply by creating additional antibodies.  Plus, being hypothyroid has its own set of risks and health problems. So healthy thyroid levels should be restored by taking thyroid hormone in addition to antithyroid drugs.  Free T3 and Free T4 should be close to mid-range or higher, not bottom-of-range.  [optimal thyroid lab recommendations]

Free T3 and Free T4 at mid-range often means supplementing T4 and T3, but doctors are reluctant to do this because Graves’ patients already have a suppressed TSH.  Normally, a suppressed TSH means the patient is hyperthyroid, but a measurement of the actual thyroid hormones, Free T3 and Free T4, will show the patient’s true state.  One cannot be said to be hyperthyroid with thyroid levels at the bottom of the reference range.  TSH is a pituitary hormone, not a thyroid hormone, and with TSH Receptor antibodies, the TSH cannot be used as a diagnostic at all.  Doctors are reluctant to prescribe any T3 because of the possibility of pituitary atrophy, since T3 is known to suppress TSH.  But a study that examined Graves’ patients on block and replace therapy found that after three months of methimazole (when free T4 and total T3 were normal), 22 out of 45 patients still had detectable TSI.  Comparing the TSI positive group with the TSI negative group, both the free T4 and total T3 levels were similar, but the TSI positive group had significantly lower TSH values than the TSI negative group.  This suggests that it is the TSI antibodies affecting the TSH, not the level of free T4 or total T3.  The suppressed TSH is therefore not from pituitary atrophy or a breakdown of the pituitary-thyroid axis, but the continued presence of TSI antibodies.  In fact, a pituitary TSH-Receptor was found. [5]

The pituitary atrophy hypothesis is discredited by the fact that TSH levels increase within weeks after discontinuation of T4 therapy (in patients treated with TSH suppressive doses of T4 for thyroid cancer), suggesting that the pituitary-thyroid axis can revive quickly.  Secondly, not all patients treated for Graves’ hyperthyroidism exhibit long-term TSH suppression.  And thirdly, a decreased level of TSH after a one year course of antithyroid drugs is an independent risk factor for recurrence of hyperthyroidism upon discontinuation of antithyroid drugs.  Continued TSH suppression in Graves’ disease is only found in a subset of Graves’ patients — those likely to relapse after antithyroid drug therapy, or those with persistent TSI. [5]

A block and replace study successfully used 100 μg of thyroxine in conjunction with 10 mg of methimazole as a maintenance dose. [6]  Another study contradicted this one, saying that replacement with T3 or placebo was better than replacement with T4. [7]  This might be because T3 is the active hormone that relieves symptoms, and the T4 did not convert to enough T3, leaving the patient hypothyroid.  Antithyroid drugs may also impede conversion of T4 to T3.  Insufficient conversion is the main problem most hypothyroid patients (non-Graves’) have with T4 medications.  It should be noted that a normal thyroid produces both T4 and T3.

Graves’ orbitopathy (eye disease) patients in one study showed that long-term (80 months), low-dose block (5 mg methimazole/day or 200 mg propylthiouracil/day) and replace (100 mcg/day levothyroxine) kept 90% of the patients stable, with antibodies within range, and a normal TSH.  [12]

Are antithyroid drugs for everyone?

Antithyroid drugs don’t work for everyone; for some the dose is too high, then too low, as their thyroid continues to act erratically from the antibody stimulation.  Antithyroid drugs can affect the liver if the dose is kept too high for too long.  A significant decrease in white blood cells (agranulocytosis) can be a serious problem.  Vasculitis (blood vessel inflammation that decreases blood supply to the organs) and kidney failure are also potential side effects.  Some of these side effects can be fatal, but do seem to be dose-related. [3]  So why even consider antithyroid drugs?  Because some have successfully lowered their antibodies to the point of remission and successfully weaned off both the antithyroid drugs and thyroid hormones, and currently take no medication.  Their own thyroid is working properly again.  Others get their antibodies under control with the antithyroid drugs and are able to wean off them, but must still take supplemental thyroid hormone, since their own thyroid doesn’t produce enough thyroid hormone on its own.

If radioactive iodine (RAI) or thyroidectomy could immediately fix the hyperthyroid condition, why should I even consider antithyroid drugs?

Thyroid removal (thyroidectomy) or destruction (RAI) does not eliminate the antibodies, because those are actually made in the white blood cells, not in the thyroid.  In some, the antibodies rise after thyroid ablation (destruction), and their condition worsens. [3]  The thyroid gland is not the cause of the hyperthyroid condition; it is actually the TSH Receptor antibodies that are the problem, by causing overstimulation of the thyroid.

Radioactive iodine (RAI) and thyroidectomy each have their own risks.  If there is any evidence of thyroid eye disease (TED), RAI is contraindicated, for it can exacerbate the condition to the point of disfigurement.  Smokers are at greater risk for TED complications.  There is also the risk of damage to other surrounding tissues, since they will also be subject to radiation.  It is also contraindicated in pregnancy. [3]

Thyroidectomy risks are surgical—parathyroids could be damaged since they are embedded in the thyroid gland, and they are essential for bone health.  Vocal cords are also close to the gland and risk damage. [3]  So are other nerves to the shoulder.  Then there is the usual risk of any surgery with anesthesia.

Some RAI or thyroidectomy patients are happy with their results, and glad to no longer be dealing with hyperthyroid symptoms.  Some people with Graves’ do not develop TED, but there is no way to tell whether one is at risk for this complication or not.  It is possible that another factor, in addition to the Graves’ antibodies, is responsible for TED. [8,9,10]  In fact, there is a case study of a woman who had normal (mid-range) T3, T4, and TSH levels, with no detectable TRab (0%), who had Grave’s ophthalmopathy.  Her TPO and Tgab were also negative.  But further testing showed Thyroid Stimulating antibodies (TSI) to be over range. [11]

Are there any other options besides antithyroid meds, thyroidectomy, and radioactive iodine to control the Graves’ antibodies?

LDN or low dose naltrexone is a prescription substance which has helped some Graves’ patients significantly reduce their antibodies.  Positive first person testimonies can be found on Graves’ and LDN chat groups throughout the internet, and there are a few medical journal studies on LDN that showed positive results in autoimmune conditions like Crohn’s, multiple sclerosis, and fibromyalgia.  Low Dose Naltrexone and LDNScience are two websites with a great deal of information that one could share with their doctor.

I personally have never taken LDN or an anti-thyroid medication, nor did I have a thyroidectomy (I had RAI), but enough Graves’ patients have had positive results with LDN that I felt it should be mentioned here.  Elaine Moore, a Graves’ patient herself, researched and wrote a book on LDN for those looking for detailed information.  Graves’ patients should certainly investigate LDN before resorting to irreversible options like RAI or a thyroidectomy, which do not decrease, and may even increase the antibodies.  If Graves’ antibody levels are high, they must be addressed because of the damage they can do.  This is especially critical if the woman is of child-bearing age and may become pregnant, because high antibodies can affect an unborn child with a condition called neonatal Graves.  In fact, any woman who has ever had Graves should have her antibodies tested if she becomes pregnant, so the antibodies can be treated. [3]  One can have dangerous levels of antibodies even after RAI or a thyroidectomy, because, as stated earlier, the antibodies are not actually made in the thyroid, but in the white blood cells.

The treatment one ultimately chooses is a very personal decision, and patients should realize that all therapies have pros and cons.  Patients should thoroughly research any protocols and discuss their options with their doctor.  They should also not ignore their gut instinct when making a decision.

Recommended thyroid labs

If you’d like to have your thyroid levels tested, please ask for these thyroid tests, and note where your levels are in the thyroid lab ranges compared to healthy people.  If you do not ask for these specific tests, your doctor will most likely just run a TSH test, which is completely invalid for someone with Graves’, because TSH Receptor antibodies can suppress TSH for years.  [TSH levels do not reflect thyroid levels]

Read more about Graves’ at the Tired Thyroid Blog

The Tired Thyroid book contains two case studies of Graves’ patients:  one who chose RAI and now takes thyroid medication (me), and another who used antithyroid drugs in combination with levothyroxine, LDN, and other natural methods to control her Graves’.  You can use the “preview” button below to read part of my story.

  1. RSK Sinha, Antithyroid Drugs, Clinical Medicine: a Practical Manual for Students & Practitioners. 2007.  A. K. Agarwal, Indian Association of Clinical Medicine.
  2. Chung YJ, Lee BW, Kim J-Y, Jung JH, Min Y-K, Lee M-S, Lee M-K, Kim K-W, Chung JH. Continued suppression of serum TSH level may be attributed to TSH receptor antibody activity as well as the severity of thyrotoxicosis and the time to recovery of thyroid hormone in treated euthyroid Graves’ patients.  Thyroid 16: 1251-1257, 2006.
  3. Prakash Abraham and Shamasunder Acharya. Current and emerging treatment options for Graves’ hyperthyroidism.  Therapeutics and  Clinical Risk Management. 2010; 6: 29–40.
  4. Malgorzata Wasniewska, Andrea Corrias, Teresa Arrigo, Fortunato Lombardo, Mariacarolina Salerno, Alessandro Mussa, Maria Cristina Vigone, Filippo De Luca. Frequency of Hashimoto’s Thyroiditis Antecedents in the History of Children and Adolescents with Graves’ Disease.  Hormone Research in Paediatrics 2010;73:473-476.
  5. Mark F. Prummel, Leon JS Brokken. The physiological and clinical relevance of the TSH Receptor in the anterior pituitary.  Hot Thyroidology ( October , No 1 , 2003.
  6. Kiyoshi Hashizume, Kazuo Ichikawa, Akihiro Sakurai, Satoru Suzuki, Teiji Takeda, Mutsuhiro Kobayashi, Takahide Miyamoto, Miyuki Arai, and Takeshi Nagasawa. Administration of Thyroxine in Treated Graves’ Disease — Effects on the Level of Antibodies to Thyroid-Stimulating Hormone Receptors and on the Risk of Recurrence of Hyperthyroidism.  N Engl J Med 1991; 324:947-953.
  7. Mastorakos G, Doufas AG, Mantzos E, Mantzos J, Koutras DA. T4 but not T3 administration is associated with increased recurrence of Graves’ disease after successful medical therapy.  Journal of Endocrinological Investigation. 2003 Oct;26(10):979-84.
  8. Hooshang Lahooti, Kishan R Parmar, and Jack R Wall. Pathogenesis of thyroid-associated ophthalmopathy: does autoimmunity against calsequestrin and collagen XIII play a role? Clin Ophthalmol. 2010; 4: 417–425.
  9. Marius N. Stan, Rebecca S. Bahn. Risk Factors for Development or Deterioration of Graves’ Ophthalmopathy.  Thyroid. July 2010, 20(7): 777-783.
  10. Tjiang H, Lahooti H, McCorquodale T, Parmar KR, Wall JR. Eye and eyelid abnormalities are common in patients with Hashimoto’s thyroiditis. Thyroid. 2010 Mar;20(3):287-90.
  11. Hidekatsu Yanai and Hiroko Yamazaki. Grave’s Ophthalmopathy in the Absence of  Abnormal Thyroid Hormone and Thyrotropin Levels and Thyrotropin Receptor Antibody.  Thyroid Science 6(1):1-3, 2010.
  12. Laurberg P, Berman DC, Andersen S, Bulow Pedersen I. Sustained control of Graves’ hyperthyroidism during long-term low-dose antithyroid drug therapy of patients with severe Graves’ orbitopathy. Thyroid. 2011. Sep:21(9):951-6..