Resistant Hypothyroidism? Consider Adding Liothyronine

ESTES PARK, COLO. – Adding liothyronine is a reasonable treatment strategy when symptoms of hypothyroidism persist on optimal levothyroxine alone, according to Dr. Michael T. McDermott, professor of medicine and clinical pharmacology and director of endocrinology and diabetes practice at the University of Colorado Hospital, Aurora.

Combination levothyroxine/liothyronine (LT4/LT3) therapy is supported by a biologically plausible mechanism of benefit in symptomatic patients who are biochemically euthyroid on LT4. But it’s a step that belongs near the bottom of the management plan for the difficult hypothyroid patient. It should be considered only after other actions have been taken, including a search for coexisting autoimmune conditions or other medical illnesses, Dr. McDermott said at an update on internal medicine sponsored by the University of Colorado.

Every physician who treats hypothyroidism has patients who experience lingering fatigue, memory problems, and other symptoms even though their on-treatment TSH is in the target range of 0.5-2.0 mU/L. Five published studies underscore just how common this situation is. Dr. McDermott cited as an example a study of 397 hypothyroid patients with a TSH in the goal range; 34% scored in the abnormal range on the short-form General Health Questionnaire and 49% had elevated scores on a thyroid symptom-specific questionnaire (Clin. Endocrinol. [Oxf.] 2002;57:577-85).

These are patients who require further general medical evaluation. Their symptoms may be due to a coexistent autoimmune disease. After all, autoimmune diseases tend to cluster. Indeed, when British investigators did a systematic work-up of 495 patients with Hashimoto’s thyroiditis, they found a 14% prevalence of another autoimmune disease. Leading the way was rheumatoid arthritis, present in 4% of subjects. The Hashimoto’s thyroiditis group also had greater than 10-fold increased relative risks of celiac disease, vitiligo, SLE, and Addison’s disease (Am. J. Med. 2010;183:e1-9).

Alternatively, the patient’s lingering symptoms may be due in part to Hashimoto’s thyroiditis itself rather than to hypothyroidism per se. A study of 426 euthyroid women with goiter undergoing thyroidectomy showed that those with antithyroperoxidase antibodies had higher levels of fatigue, nervousness, and irritability, and lower quality of life (Thyroid 2011;21:161-7).

Dr. McDermott routinely obtains a serum 25 vitamin D measurement in his difficult cases of hypothyroidism, since low vitamin D levels are a common cause of fatigue. He also encourages patients with lingering symptoms to eat a well-balanced diet and get regular exercise and sleep, and he refers them for treatment of depression when indicated.

Only after doing all that, does he consider adding LT3. Combined LT4/LT3 therapy is controversial. The first-ever randomized controlled clinical trial was positive (N. Engl. J. Med. 1999;340:424-9), but it was followed by a spate of negative studies. Some physicians closed the book on this treatment strategy after a meta-analysis of all 11 randomized trials showed combination therapy was without benefit (J. Clin. Endocrinol. Metab. 2006; 91: 2,592-9).

However, more recent work has shown that a relatively common polymorphism of the deiodinase 2 gene known as Thr92Ala may predict less responsiveness of psychological symptoms of hypothyroidism to optimal LT4 monotherapy. Deiodinase 2 is responsible for maintaining brain T3 levels, and there is evidence to indicate that the Thr92Ala polymorphism subtly impairs T4 to T3 conversion in the brain.

In a secondary analysis of a study involving 552 hypothyroid patients randomized to LT4 or LT4/LT3, the prevalence of Thr92Ala homozygosity was 16%, and psychological well being in patients with the deiodinase 2 polymorphism improved significantly more on combination therapy than with LT4 alone (J. Clin. Endocrinol. Metab. 2009;94:1623-9).

The fact that the Thr92Ala polymorphism is present in only 16% of individuals on thyroid hormone therapy might explain why so many randomized trials of LT4 versus combination therapy were negative: With study populations of only 20-141 patients, the trials would have been underpowered to detect a significant difference in treatment effect. Unfortunately, genetic testing for deiodinase polymorphisms is not commercially available, the endocrinologist observed.

When he does resort to combination therapy, Dr. McDermott prescribes it in an LT4:LT3 ratio of 10-14:1 to mimic normal thyroid secretion. He generally has patients take LT3 twice daily, with the second dose no later than about 6 p.m. so it doesn’t interfere with sleep. Once-daily slow-release formulations of LT3 are available in Europe and work very well. Several companies are interested in developing a slow-release LT3 for the United States, which would be a welcome development, according to Dr. McDermott.

Another option, once all else has been tried and failed, is to switch to another brand of LT4, he continued. Some patients may have adverse reactions to the various dyes and fillers contained in LT4 pills. When this is a potential concern, levothyroxine sodium (Tirosint), approved by the Food and Drug Administration a couple of years ago, is an attractive option. The LT4 in Tirosint is contained in oil in a liquid gelcap with no dyes or fillers, differentiating it from all other brand name and generic products, Dr. McDermott noted.

He emphasized the importance of avoiding overtreatment with LT4 in an attempt to improve quality of life in patients with residual symptoms despite a TSH of 0.5-2.0 mU/L. Subclinical hyperthyroidism as defined by a TSH below 0.1 mU/L has been shown to significantly increase the risk of hip and spine fractures, atrial fibrillation, and cardiovascular mortality.

Dr. McDermott reported having no financial conflicts.

ESTES PARK, COLO. – Adding liothyronine is a reasonable treatment strategy when symptoms of hypothyroidism persist on optimal levothyroxine alone, according to Dr. Michael T. McDermott, professor of medicine and clinical pharmacology and director of endocrinology and diabetes practice at the University of Colorado Hospital, Aurora.

Combination levothyroxine/liothyronine (LT4/LT3) therapy is supported by a biologically plausible mechanism of benefit in symptomatic patients who are biochemically euthyroid on LT4. But it’s a step that belongs near the bottom of the management plan for the difficult hypothyroid patient. It should be considered only after other actions have been taken, including a search for coexisting autoimmune conditions or other medical illnesses, Dr. McDermott said at an update on internal medicine sponsored by the University of Colorado.

Every physician who treats hypothyroidism has patients who experience lingering fatigue, memory problems, and other symptoms even though their on-treatment TSH is in the target range of 0.5-2.0 mU/L. Five published studies underscore just how common this situation is. Dr. McDermott cited as an example a study of 397 hypothyroid patients with a TSH in the goal range; 34% scored in the abnormal range on the short-form General Health Questionnaire and 49% had elevated scores on a thyroid symptom-specific questionnaire (Clin. Endocrinol. [Oxf.] 2002;57:577-85).

These are patients who require further general medical evaluation. Their symptoms may be due to a coexistent autoimmune disease. After all, autoimmune diseases tend to cluster. Indeed, when British investigators did a systematic work-up of 495 patients with Hashimoto’s thyroiditis, they found a 14% prevalence of another autoimmune disease. Leading the way was rheumatoid arthritis, present in 4% of subjects. The Hashimoto’s thyroiditis group also had greater than 10-fold increased relative risks of celiac disease, vitiligo, SLE, and Addison’s disease (Am. J. Med. 2010;183:e1-9).

Alternatively, the patient’s lingering symptoms may be due in part to Hashimoto’s thyroiditis itself rather than to hypothyroidism per se. A study of 426 euthyroid women with goiter undergoing thyroidectomy showed that those with antithyroperoxidase antibodies had higher levels of fatigue, nervousness, and irritability, and lower quality of life (Thyroid 2011;21:161-7).

Dr. McDermott routinely obtains a serum 25 vitamin D measurement in his difficult cases of hypothyroidism, since low vitamin D levels are a common cause of fatigue. He also encourages patients with lingering symptoms to eat a well-balanced diet and get regular exercise and sleep, and he refers them for treatment of depression when indicated.

Only after doing all that, does he consider adding LT3. Combined LT4/LT3 therapy is controversial. The first-ever randomized controlled clinical trial was positive (N. Engl. J. Med. 1999;340:424-9), but it was followed by a spate of negative studies. Some physicians closed the book on this treatment strategy after a meta-analysis of all 11 randomized trials showed combination therapy was without benefit (J. Clin. Endocrinol. Metab. 2006; 91: 2,592-9).

However, more recent work has shown that a relatively common polymorphism of the deiodinase 2 gene known as Thr92Ala may predict less responsiveness of psychological symptoms of hypothyroidism to optimal LT4 monotherapy. Deiodinase 2 is responsible for maintaining brain T3 levels, and there is evidence to indicate that the Thr92Ala polymorphism subtly impairs T4 to T3 conversion in the brain.

In a secondary analysis of a study involving 552 hypothyroid patients randomized to LT4 or LT4/LT3, the prevalence of Thr92Ala homozygosity was 16%, and psychological well being in patients with the deiodinase 2 polymorphism improved significantly more on combination therapy than with LT4 alone (J. Clin. Endocrinol. Metab. 2009;94:1623-9).

The fact that the Thr92Ala polymorphism is present in only 16% of individuals on thyroid hormone therapy might explain why so many randomized trials of LT4 versus combination therapy were negative: With study populations of only 20-141 patients, the trials would have been underpowered to detect a significant difference in treatment effect. Unfortunately, genetic testing for deiodinase polymorphisms is not commercially available, the endocrinologist observed.

When he does resort to combination therapy, Dr. McDermott prescribes it in an LT4:LT3 ratio of 10-14:1 to mimic normal thyroid secretion. He generally has patients take LT3 twice daily, with the second dose no later than about 6 p.m. so it doesn’t interfere with sleep. Once-daily slow-release formulations of LT3 are available in Europe and work very well. Several companies are interested in developing a slow-release LT3 for the United States, which would be a welcome development, according to Dr. McDermott.

Another option, once all else has been tried and failed, is to switch to another brand of LT4, he continued. Some patients may have adverse reactions to the various dyes and fillers contained in LT4 pills. When this is a potential concern, levothyroxine sodium (Tirosint), approved by the Food and Drug Administration a couple of years ago, is an attractive option. The LT4 in Tirosint is contained in oil in a liquid gelcap with no dyes or fillers, differentiating it from all other brand name and generic products, Dr. McDermott noted.

He emphasized the importance of avoiding overtreatment with LT4 in an attempt to improve quality of life in patients with residual symptoms despite a TSH of 0.5-2.0 mU/L. Subclinical hyperthyroidism as defined by a TSH below 0.1 mU/L has been shown to significantly increase the risk of hip and spine fractures, atrial fibrillation, and cardiovascular mortality.

Dr. McDermott reported having no financial conflicts.

ESTES PARK, COLO. – Adding liothyronine is a reasonable treatment strategy when symptoms of hypothyroidism persist on optimal levothyroxine alone, according to Dr. Michael T. McDermott, professor of medicine and clinical pharmacology and director of endocrinology and diabetes practice at the University of Colorado Hospital, Aurora.

Combination levothyroxine/liothyronine (LT4/LT3) therapy is supported by a biologically plausible mechanism of benefit in symptomatic patients who are biochemically euthyroid on LT4. But it’s a step that belongs near the bottom of the management plan for the difficult hypothyroid patient. It should be considered only after other actions have been taken, including a search for coexisting autoimmune conditions or other medical illnesses, Dr. McDermott said at an update on internal medicine sponsored by the University of Colorado.

Every physician who treats hypothyroidism has patients who experience lingering fatigue, memory problems, and other symptoms even though their on-treatment TSH is in the target range of 0.5-2.0 mU/L. Five published studies underscore just how common this situation is. Dr. McDermott cited as an example a study of 397 hypothyroid patients with a TSH in the goal range; 34% scored in the abnormal range on the short-form General Health Questionnaire and 49% had elevated scores on a thyroid symptom-specific questionnaire (Clin. Endocrinol. [Oxf.] 2002;57:577-85).

These are patients who require further general medical evaluation. Their symptoms may be due to a coexistent autoimmune disease. After all, autoimmune diseases tend to cluster. Indeed, when British investigators did a systematic work-up of 495 patients with Hashimoto’s thyroiditis, they found a 14% prevalence of another autoimmune disease. Leading the way was rheumatoid arthritis, present in 4% of subjects. The Hashimoto’s thyroiditis group also had greater than 10-fold increased relative risks of celiac disease, vitiligo, SLE, and Addison’s disease (Am. J. Med. 2010;183:e1-9).

Alternatively, the patient’s lingering symptoms may be due in part to Hashimoto’s thyroiditis itself rather than to hypothyroidism per se. A study of 426 euthyroid women with goiter undergoing thyroidectomy showed that those with antithyroperoxidase antibodies had higher levels of fatigue, nervousness, and irritability, and lower quality of life (Thyroid 2011;21:161-7).

Dr. McDermott routinely obtains a serum 25 vitamin D measurement in his difficult cases of hypothyroidism, since low vitamin D levels are a common cause of fatigue. He also encourages patients with lingering symptoms to eat a well-balanced diet and get regular exercise and sleep, and he refers them for treatment of depression when indicated.

Only after doing all that, does he consider adding LT3. Combined LT4/LT3 therapy is controversial. The first-ever randomized controlled clinical trial was positive (N. Engl. J. Med. 1999;340:424-9), but it was followed by a spate of negative studies. Some physicians closed the book on this treatment strategy after a meta-analysis of all 11 randomized trials showed combination therapy was without benefit (J. Clin. Endocrinol. Metab. 2006; 91: 2,592-9).

However, more recent work has shown that a relatively common polymorphism of the deiodinase 2 gene known as Thr92Ala may predict less responsiveness of psychological symptoms of hypothyroidism to optimal LT4 monotherapy. Deiodinase 2 is responsible for maintaining brain T3 levels, and there is evidence to indicate that the Thr92Ala polymorphism subtly impairs T4 to T3 conversion in the brain.

In a secondary analysis of a study involving 552 hypothyroid patients randomized to LT4 or LT4/LT3, the prevalence of Thr92Ala homozygosity was 16%, and psychological well being in patients with the deiodinase 2 polymorphism improved significantly more on combination therapy than with LT4 alone (J. Clin. Endocrinol. Metab. 2009;94:1623-9).

The fact that the Thr92Ala polymorphism is present in only 16% of individuals on thyroid hormone therapy might explain why so many randomized trials of LT4 versus combination therapy were negative: With study populations of only 20-141 patients, the trials would have been underpowered to detect a significant difference in treatment effect. Unfortunately, genetic testing for deiodinase polymorphisms is not commercially available, the endocrinologist observed.

When he does resort to combination therapy, Dr. McDermott prescribes it in an LT4:LT3 ratio of 10-14:1 to mimic normal thyroid secretion. He generally has patients take LT3 twice daily, with the second dose no later than about 6 p.m. so it doesn’t interfere with sleep. Once-daily slow-release formulations of LT3 are available in Europe and work very well. Several companies are interested in developing a slow-release LT3 for the United States, which would be a welcome development, according to Dr. McDermott.

Another option, once all else has been tried and failed, is to switch to another brand of LT4, he continued. Some patients may have adverse reactions to the various dyes and fillers contained in LT4 pills. When this is a potential concern, levothyroxine sodium (Tirosint), approved by the Food and Drug Administration a couple of years ago, is an attractive option. The LT4 in Tirosint is contained in oil in a liquid gelcap with no dyes or fillers, differentiating it from all other brand name and generic products, Dr. McDermott noted.

He emphasized the importance of avoiding overtreatment with LT4 in an attempt to improve quality of life in patients with residual symptoms despite a TSH of 0.5-2.0 mU/L. Subclinical hyperthyroidism as defined by a TSH below 0.1 mU/L has been shown to significantly increase the risk of hip and spine fractures, atrial fibrillation, and cardiovascular mortality.

Dr. McDermott reported having no financial conflicts.