Hyperthyroidism: What Is New Regarding Treatment and the Use of Antithyroid Agents?
Hyperthyroidism: What Is New Regarding Treatment and the Use of Antithyroid Agents?
A 25-year-old women presents with a 4- to 8-week history of nervousness, anxiety, palpitations, and weight loss of about 10 pounds despite a good appetite. She does not have chest pain, a history of radiation exposure, or exposure to excess iodine. No eye symptoms of burning, itching, tearing, or diplopia are noted. She has not been pregnant and does not have neck tenderness. She is not taking medication, such as birth control pills, that may alter thyroid function tests. Her medical history is otherwise negative. Her mother had Hashimoto's thyroiditis and had been hypothyroid but is now taking levothyroxine replacement. The patient does not plan to become pregnant within the next year but would like to have children after that time period.
On physical examination, the patient's blood pressure was 140/85, pulse 110 and regular, and respirations 16 per minute. She has a fine hand tremor, warm, moist skin, and her thyroid gland is diffusely enlarged to about 50 grams (normal: less than 20 grams) without palpable nodules; a bruit is present. No cervical adenopathy is palpable, no pretibial myxedema is evident, and ophthalmologic examination is normal. Laboratory and diagnostic studies showed the following:
Normal complete blood count (CBC) with differential;
Normal comprehensive metabolic profile (CMP);
Free T4 elevated to 3.3 ng/dL (normal: 0.8-18 ng/dL);
Total T3: 220 ng/dL (normal: 80-180 ng/dL);
Thyroid-stimulating hormone (TSH) < .01 µU/mL (normal 0.5-4.1 µU/mL),
Thyroid stimulating immunoglobulins (TSI) elevated to 520% (normal: < 120%);
C-reactive protein: 0.5 mg/L (normal < 3 mg/L);
Serum beta-HcG is negative;
Radioactive iodine uptake: 60% at 24 hours; and
Thyroid sonogram showed diffuse heterogeneity of the gland with increased Doppler flow throughout.
Although this case has many interesting aspects, the major focus of the present discussion relates to treatment options and newer information regarding antithyroid agents.
This case represents a typical presentation of hyperthyroidism, and the diagnosis is evident given the patient's constellation of signs and symptoms. The most common endogenous cause of hyperthyroidism is Graves' disease, which is caused by the presence of TSH receptor stimulating antibodies (measured as thyroid-stimulating antibodies). The differential diagnosis includes multinodular goiter, solitary autonomous nodule, and exogenous administration of levothyroxine or triidothyronine. Amiodarone administration can also cause hyperthyroidism, as can exposure to exogenous iodine in the form of radioiodinated contrast agents or orally administered iodine. Subacute, silent, or postpartum thyroiditis may occur and is frequently transient.
Very unusual causes of hyperthyroidism include metastatic thyroid cancer and struma ovarii. Hyperemesis gravidarum during pregnancy can also cause hyperthyroidism, which is usually transient and does not require treatment. Every hyperthyroid patient should have a detailed history and physical examination and routine laboratory studies to include CBC with differential, CMP, free T4, total or free T3, and TSH. The TSH is expected to be undetectable (< .01 µU/mL) in the presence of clinical hyperthyroidism. The serum TSH may be slightly decreased, but not undetectable, in patients with mild subclinical hyperthyroidism. (The approach to subclinical hyperthyroidism will not be discussed in this article.) In the context of an elevated free T4 and/or free T3, the serum TSH is expected to be undetectable except in the rare circumstance of a TSH-secreting pituitary tumor.
A thyroid sonogram is obtained to ensure that no nodules require attention. A Doppler flow should be performed to determine whether there is excessive endogenous thyroid hormone production, which occurs with Graves' disease. An elevated 24-hour radioactive iodine uptake (RAIU) confirms endogenous hyperthyroidism. During the hyperthyroid phase of subacute, silent, or postpartum thyroiditis, Doppler thyroid flow will be reduced and RAIU will be less than 1%.
Subacute thyroiditis is also associated with tenderness in the neck, radiation to the head or jaw, dysphagia, perhaps a fever, and an elevated sedimentation rate or C-reactive protein. Fatourechi and colleagues retrospectively analyzed 150 patients with subacute thyroiditis. Neck discomfort was the presenting symptom in 96%, the disease recurred in 4%, and 15% required chronic levothyroxine therapy for permanent hypothyroidism. Postpartum thyroiditis occurs within about 1 year of parturition. Stagnaro-Green has noted that that the mean prevalence of postpartum thyroiditis is 7.5% and about 25% of women will develop permanent hypothyroidism within 10 years. Each of these 3 types of thyroiditis typically evolves from hyperthyroidism to hypothyroidism and then euthyroidism is restored. However, this typical pattern of evolution occurs most frequently with subacute thyroiditis. An RAIU test is the traditional method to detect increased endogenous thyroidal secretion, but flow Doppler sonography is increasingly used in this circumstance because it is easier and does not involve the use of radiation.
The most important issue now confronting us is how to treat this patient with hyperthyroidism. It is important to take an interdisciplinary approach and to derive a treatment plan in conjunction with consulting endocrinologists, surgeons, and nuclear medicine specialists as well as with the patient.
The time-honored treatment options include radioactive iodine therapy, surgery, or antithyroid agents. If surgery is going to be performed or radioactive iodine therapy is going to be administered, it may be beneficial to render the patient euthyroid with antithyroid agents prior to definitive therapy. The goal of radioactive iodine therapy is to render the patient hypothyroid and then use levothyroxine with periodic monitoring. However, radioactive iodine may exacerbate the signs or symptoms of Graves' ophthalmopathy, if present.
Some clinicians and patients would prefer to avoid radioactive iodine in the presence of moderate or severe ophthalmopathy. Other clinicians would add corticosteroid therapy if they were going to use radioactive iodine in the presence of ophthalmopathy. Surgery is rarely used in the treatment of Graves' hyperthyroidism unless there is a suspicious thyroid nodule or significant ophthalmopathy. Discussion is always held with the patient to ensure the treatment plan conforms to his or her wishes.
This particular patient requested to use antithyroid agents for 1 year in an attempt induce a remission, although she understood that the likelihood of a long-term remission is relatively low. Newer developments in the use of the antithyroid agents, methimazole and propylthiouracil (PTU), have taken place. The use and adverse effects of these antithyroid agents were discussed at a recent symposium (April 2009) sponsored by the American Thyroid Association with participation by the US Food and Drug Administration (FDA) and the National Institutes of Health. The possible adverse effects of antithyroid agents in children were addressed at an earlier meeting on October 28, 2008 (sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Development). Minor adverse effects of these agents include urticaria or macular skin rash (4%-6%), arthralgias (1%-5%), nausea (1%-5%), and metallic taste (< 1%). Both PTU and methimazole can cause major adverse effects including polyarthritis (1%-2%), anti-neutrophil cytoplasmic antibody-positive vasculitis (< 1% with PTU), agranulocytosis (0.1%- 0.5%), aplastic anemia (< 0.1%), immunologic hepatitis (0.1%-1% with PTU) and elevated aminotransferase (30% with PTU), cholestasis (< 1% with methimazole), low prothrombin level (< 1% with PTU), and automimmune hypoglycemia (< 1% with methimazole).
These conferences focused on the relative safety of methimazole compared with PTU. Approximately 30% of patients treated with PTU will have 1- to 2-fold elevations of serum aminotransferase levels. The liver disease associated with PTU can be severe. In the Adverse Event Reporting System (AERS), approximately 22 adult (12 deaths, 5 hepatic transplants) and 10 pediatric (1 death, 6 hepatic transplants) cases of serious hepatic injury associated with PTU treatment were reported. Methimazole, by contrast, was associated with 5 adult cases of serious hepatic injury with 3 deaths.
In a system that may overlap with AERS, the United Network for Organ Sharing reported 23 hepatic transplants from 1990 to 2007 (16 adult, 7 children) related to PTU-associated hepatic failure. Concurrently, no liver transplants related to the use of methimazole were reported. The average PTU dose in children and adults requiring liver transplant was 300 mg daily. Liver failure occurred between 6 and 450 days after starting treatment (median 120 days). Furthermore, there were 2 reports of serious maternal liver disease during pregnancy and 2 reports of liver injury in fetuses of mothers who ingested PTU during pregnancy.
Given these potential adverse effects, the FDA issued an alert on June 4, 2009 that noted the risk of serious liver injury, including liver failure and death, with the use of PTU in adult (1:10,000) and pediatric (1:2,000) patients. The FDA recommended that patients taking PTU be monitored closely for signs and symptoms of liver injury, especially during the first 6 months of therapy. If liver injury is suspected, the PTU should promptly be discontinued and the patient should be evaluated for liver injury, which should be treated as appropriate. Patients should be counseled to promptly advise the physician if they note any of the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin.
Moreover, the FDA notes that PTU is considered a second-line medication therapy except in patients who are pregnant or allergic to or intolerant of methimazole. Rare cases of embryopathy, including aplasia cutis, and choanal and esophageal atresia have been reported with the use of methimazole during pregnancy. No similar cases have been reported with the use of PTU during pregnancy. Therefore, PTU may be more appropriate for women with Graves' disease who are in their first trimester of pregnancy. The FDA notes, however, that it has not confirmed a causal relationship between these adverse effects and PTU or methimazole, nor is the FDA advising healthcare professionals to discontinue prescribing these agents. Cooper and Rivkees recommend that pregnant hyperthyroid women be treated with PTU in the first trimester, and then switched to methimazole in the second and third trimesters if antithyroid treatment is required.
How does this information relate to our patient who is a 25-year-old woman? The answer is controversial but it seems that, based on the information noted above, she should be started on methimazole therapy at a dose sufficient to render her biochemically and clinically euthyroid. I would probably start with 10 mg daily. It is also debatable whether and how often to measure CBC with differential, CMP, and liver function tests (LFTs). Most authorities suggest that routinely monitoring CBC and LFTs does not help predict the occurrence of adverse effects such as agranulocytosis and serious hepatic injury. However, Tahiri and colleagues suggest that a reduced white blood cell count may portend agranulocytosis.
Although controversial, some clinicians would routinely monitor CBC with differential, and would perform LFTs because elevated tests might suggest an adverse effect of antithyroid agents. I believe that free T4 and free or total T3 and TSH should be monitored about every 2-4 weeks until the patient is biochemically euthyroid. Subsequently these tests can be performed about every 4-8 weeks, with instructions to the patient to contact the physician if symptoms of fever, chills, sore throat, easy bleeding, jaundice, or anorexia occur. It seems preferable, when possible, to administer definitive therapy such as 131-I (radioiodine) given the possibility of pregnancy in the future. Radioactive iodine should be administered for at least 6-12 months and then the patient should be rendered euthyroid on levothyroxine prior to becoming pregnant. Surgical thyroidectomy is another option. If definitive therapy is given, it is likely that the patient will be hypothyroid when taking levothyroxine during subsequent pregnancies, and the risks associated with PTU and methimazole would be avoided. The dose requirement of levothyroxine, however, may need to be increased during pregnancy.
PTU is preferred during the first trimester of pregnancy. Subsequently, some clinicians would switch a patient back to methimazole because the risk of embryopathy would be lower after the first trimester. After the patient delivers, if she wants to breastfeed she should be switched back to PTU because less of this agent is secreted into breast milk. This process is obviously complicated and requires close cooperation of the patient. Each patient should be assessed and treated individually. Furthermore, no rigorous clinical studies have assessed the risks and benefits of this approach.
Case Presentation
A 25-year-old women presents with a 4- to 8-week history of nervousness, anxiety, palpitations, and weight loss of about 10 pounds despite a good appetite. She does not have chest pain, a history of radiation exposure, or exposure to excess iodine. No eye symptoms of burning, itching, tearing, or diplopia are noted. She has not been pregnant and does not have neck tenderness. She is not taking medication, such as birth control pills, that may alter thyroid function tests. Her medical history is otherwise negative. Her mother had Hashimoto's thyroiditis and had been hypothyroid but is now taking levothyroxine replacement. The patient does not plan to become pregnant within the next year but would like to have children after that time period.
On physical examination, the patient's blood pressure was 140/85, pulse 110 and regular, and respirations 16 per minute. She has a fine hand tremor, warm, moist skin, and her thyroid gland is diffusely enlarged to about 50 grams (normal: less than 20 grams) without palpable nodules; a bruit is present. No cervical adenopathy is palpable, no pretibial myxedema is evident, and ophthalmologic examination is normal. Laboratory and diagnostic studies showed the following:
Normal complete blood count (CBC) with differential;
Normal comprehensive metabolic profile (CMP);
Free T4 elevated to 3.3 ng/dL (normal: 0.8-18 ng/dL);
Total T3: 220 ng/dL (normal: 80-180 ng/dL);
Thyroid-stimulating hormone (TSH) < .01 µU/mL (normal 0.5-4.1 µU/mL),
Thyroid stimulating immunoglobulins (TSI) elevated to 520% (normal: < 120%);
C-reactive protein: 0.5 mg/L (normal < 3 mg/L);
Serum beta-HcG is negative;
Radioactive iodine uptake: 60% at 24 hours; and
Thyroid sonogram showed diffuse heterogeneity of the gland with increased Doppler flow throughout.
Although this case has many interesting aspects, the major focus of the present discussion relates to treatment options and newer information regarding antithyroid agents.
Diagnosis and Discussion
This case represents a typical presentation of hyperthyroidism, and the diagnosis is evident given the patient's constellation of signs and symptoms. The most common endogenous cause of hyperthyroidism is Graves' disease, which is caused by the presence of TSH receptor stimulating antibodies (measured as thyroid-stimulating antibodies). The differential diagnosis includes multinodular goiter, solitary autonomous nodule, and exogenous administration of levothyroxine or triidothyronine. Amiodarone administration can also cause hyperthyroidism, as can exposure to exogenous iodine in the form of radioiodinated contrast agents or orally administered iodine. Subacute, silent, or postpartum thyroiditis may occur and is frequently transient.
Very unusual causes of hyperthyroidism include metastatic thyroid cancer and struma ovarii. Hyperemesis gravidarum during pregnancy can also cause hyperthyroidism, which is usually transient and does not require treatment. Every hyperthyroid patient should have a detailed history and physical examination and routine laboratory studies to include CBC with differential, CMP, free T4, total or free T3, and TSH. The TSH is expected to be undetectable (< .01 µU/mL) in the presence of clinical hyperthyroidism. The serum TSH may be slightly decreased, but not undetectable, in patients with mild subclinical hyperthyroidism. (The approach to subclinical hyperthyroidism will not be discussed in this article.) In the context of an elevated free T4 and/or free T3, the serum TSH is expected to be undetectable except in the rare circumstance of a TSH-secreting pituitary tumor.
A thyroid sonogram is obtained to ensure that no nodules require attention. A Doppler flow should be performed to determine whether there is excessive endogenous thyroid hormone production, which occurs with Graves' disease. An elevated 24-hour radioactive iodine uptake (RAIU) confirms endogenous hyperthyroidism. During the hyperthyroid phase of subacute, silent, or postpartum thyroiditis, Doppler thyroid flow will be reduced and RAIU will be less than 1%.
Subacute thyroiditis is also associated with tenderness in the neck, radiation to the head or jaw, dysphagia, perhaps a fever, and an elevated sedimentation rate or C-reactive protein. Fatourechi and colleagues retrospectively analyzed 150 patients with subacute thyroiditis. Neck discomfort was the presenting symptom in 96%, the disease recurred in 4%, and 15% required chronic levothyroxine therapy for permanent hypothyroidism. Postpartum thyroiditis occurs within about 1 year of parturition. Stagnaro-Green has noted that that the mean prevalence of postpartum thyroiditis is 7.5% and about 25% of women will develop permanent hypothyroidism within 10 years. Each of these 3 types of thyroiditis typically evolves from hyperthyroidism to hypothyroidism and then euthyroidism is restored. However, this typical pattern of evolution occurs most frequently with subacute thyroiditis. An RAIU test is the traditional method to detect increased endogenous thyroidal secretion, but flow Doppler sonography is increasingly used in this circumstance because it is easier and does not involve the use of radiation.
Treatment
The most important issue now confronting us is how to treat this patient with hyperthyroidism. It is important to take an interdisciplinary approach and to derive a treatment plan in conjunction with consulting endocrinologists, surgeons, and nuclear medicine specialists as well as with the patient.
The time-honored treatment options include radioactive iodine therapy, surgery, or antithyroid agents. If surgery is going to be performed or radioactive iodine therapy is going to be administered, it may be beneficial to render the patient euthyroid with antithyroid agents prior to definitive therapy. The goal of radioactive iodine therapy is to render the patient hypothyroid and then use levothyroxine with periodic monitoring. However, radioactive iodine may exacerbate the signs or symptoms of Graves' ophthalmopathy, if present.
Some clinicians and patients would prefer to avoid radioactive iodine in the presence of moderate or severe ophthalmopathy. Other clinicians would add corticosteroid therapy if they were going to use radioactive iodine in the presence of ophthalmopathy. Surgery is rarely used in the treatment of Graves' hyperthyroidism unless there is a suspicious thyroid nodule or significant ophthalmopathy. Discussion is always held with the patient to ensure the treatment plan conforms to his or her wishes.
This particular patient requested to use antithyroid agents for 1 year in an attempt induce a remission, although she understood that the likelihood of a long-term remission is relatively low. Newer developments in the use of the antithyroid agents, methimazole and propylthiouracil (PTU), have taken place. The use and adverse effects of these antithyroid agents were discussed at a recent symposium (April 2009) sponsored by the American Thyroid Association with participation by the US Food and Drug Administration (FDA) and the National Institutes of Health. The possible adverse effects of antithyroid agents in children were addressed at an earlier meeting on October 28, 2008 (sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Development). Minor adverse effects of these agents include urticaria or macular skin rash (4%-6%), arthralgias (1%-5%), nausea (1%-5%), and metallic taste (< 1%). Both PTU and methimazole can cause major adverse effects including polyarthritis (1%-2%), anti-neutrophil cytoplasmic antibody-positive vasculitis (< 1% with PTU), agranulocytosis (0.1%- 0.5%), aplastic anemia (< 0.1%), immunologic hepatitis (0.1%-1% with PTU) and elevated aminotransferase (30% with PTU), cholestasis (< 1% with methimazole), low prothrombin level (< 1% with PTU), and automimmune hypoglycemia (< 1% with methimazole).
These conferences focused on the relative safety of methimazole compared with PTU. Approximately 30% of patients treated with PTU will have 1- to 2-fold elevations of serum aminotransferase levels. The liver disease associated with PTU can be severe. In the Adverse Event Reporting System (AERS), approximately 22 adult (12 deaths, 5 hepatic transplants) and 10 pediatric (1 death, 6 hepatic transplants) cases of serious hepatic injury associated with PTU treatment were reported. Methimazole, by contrast, was associated with 5 adult cases of serious hepatic injury with 3 deaths.
In a system that may overlap with AERS, the United Network for Organ Sharing reported 23 hepatic transplants from 1990 to 2007 (16 adult, 7 children) related to PTU-associated hepatic failure. Concurrently, no liver transplants related to the use of methimazole were reported. The average PTU dose in children and adults requiring liver transplant was 300 mg daily. Liver failure occurred between 6 and 450 days after starting treatment (median 120 days). Furthermore, there were 2 reports of serious maternal liver disease during pregnancy and 2 reports of liver injury in fetuses of mothers who ingested PTU during pregnancy.
Given these potential adverse effects, the FDA issued an alert on June 4, 2009 that noted the risk of serious liver injury, including liver failure and death, with the use of PTU in adult (1:10,000) and pediatric (1:2,000) patients. The FDA recommended that patients taking PTU be monitored closely for signs and symptoms of liver injury, especially during the first 6 months of therapy. If liver injury is suspected, the PTU should promptly be discontinued and the patient should be evaluated for liver injury, which should be treated as appropriate. Patients should be counseled to promptly advise the physician if they note any of the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin.
Moreover, the FDA notes that PTU is considered a second-line medication therapy except in patients who are pregnant or allergic to or intolerant of methimazole. Rare cases of embryopathy, including aplasia cutis, and choanal and esophageal atresia have been reported with the use of methimazole during pregnancy. No similar cases have been reported with the use of PTU during pregnancy. Therefore, PTU may be more appropriate for women with Graves' disease who are in their first trimester of pregnancy. The FDA notes, however, that it has not confirmed a causal relationship between these adverse effects and PTU or methimazole, nor is the FDA advising healthcare professionals to discontinue prescribing these agents. Cooper and Rivkees recommend that pregnant hyperthyroid women be treated with PTU in the first trimester, and then switched to methimazole in the second and third trimesters if antithyroid treatment is required.
How does this information relate to our patient who is a 25-year-old woman? The answer is controversial but it seems that, based on the information noted above, she should be started on methimazole therapy at a dose sufficient to render her biochemically and clinically euthyroid. I would probably start with 10 mg daily. It is also debatable whether and how often to measure CBC with differential, CMP, and liver function tests (LFTs). Most authorities suggest that routinely monitoring CBC and LFTs does not help predict the occurrence of adverse effects such as agranulocytosis and serious hepatic injury. However, Tahiri and colleagues suggest that a reduced white blood cell count may portend agranulocytosis.
Although controversial, some clinicians would routinely monitor CBC with differential, and would perform LFTs because elevated tests might suggest an adverse effect of antithyroid agents. I believe that free T4 and free or total T3 and TSH should be monitored about every 2-4 weeks until the patient is biochemically euthyroid. Subsequently these tests can be performed about every 4-8 weeks, with instructions to the patient to contact the physician if symptoms of fever, chills, sore throat, easy bleeding, jaundice, or anorexia occur. It seems preferable, when possible, to administer definitive therapy such as 131-I (radioiodine) given the possibility of pregnancy in the future. Radioactive iodine should be administered for at least 6-12 months and then the patient should be rendered euthyroid on levothyroxine prior to becoming pregnant. Surgical thyroidectomy is another option. If definitive therapy is given, it is likely that the patient will be hypothyroid when taking levothyroxine during subsequent pregnancies, and the risks associated with PTU and methimazole would be avoided. The dose requirement of levothyroxine, however, may need to be increased during pregnancy.
PTU is preferred during the first trimester of pregnancy. Subsequently, some clinicians would switch a patient back to methimazole because the risk of embryopathy would be lower after the first trimester. After the patient delivers, if she wants to breastfeed she should be switched back to PTU because less of this agent is secreted into breast milk. This process is obviously complicated and requires close cooperation of the patient. Each patient should be assessed and treated individually. Furthermore, no rigorous clinical studies have assessed the risks and benefits of this approach.
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