Nieuwe inzichten in de variabele effectiviteit van levothyroxine monotherapie hypothyreoïdie
Artikel in The Lancet.
New Insight on Levothyroxine Hypothyroidism Monotherapy
Studies suggest therapy insufficient for treatment of hypothyroidism.
Since the 19th century, thyroid hormone replacement therapy, especially levothyroxine monotherapy, has been the standard treatment for hypothyroidism.
Recent clinical data suggests that the chemical composition of levothyroxine monotherapy does not normalize serum T3 concentrations or universally restore clinical euthyroidism, and a new treatment plan is needed.
In the 1970s, clinicians set the normalization of serum TSH as the treatment target.
With this goal, levothyroxine monotherapy became the preferred treatment due to its safety profile, its ability to normalize serum TSH, and symptomatic remission.
However, about 12% of patients reported to have residual symptoms of hypothyroidism when on that treatment.
Investigators discovered that levothyroxine monotherapy may result in relative T3 deficiency, lipid abnormalities can persist, the serum T4:T3 ratio is raised, and gene expression profiles were not corrected in rats on levothyroxine monotherapy with normal serum TSH.
These studies discovered that these variables can be corrected with continuous administration of liothyronine plus levothyroxine.
In a recent large clinical trial that compared patients with the genetic factor, Thr92Ala D2, polymorphism receiving combination therapy vs levothyroxine alone, that patient’s well-being improves with the combination therapy.
These findings also suggest that this genetic factor is a potential risk for impaired cognition, and a personalized medicine approach may be needed.
With new findings and a better understanding of the mechanism underlying the inability of levothyroxine monotherapy to normalize serum T3 in patients with normal serum TSH, it is important that future investigations concentrating on low serum T3 or high T4:T3 ratio are done.
It is also highly suggested that high-quality randomized controlled clinical trials are conducted to assess whether patients with Thr92Ala D2 polymorphism have a unique response to combination therapy.
With better understanding and new findings, a new treatment strategy is foreseen in the near future.
Practice Pearls:
• New finding suggest that levothyroxine monotherapy does not deliver enough therapy for the treatment of hypothyroidism.
• A combination of liothyronine and levothyroxine has shown superiority in rats
• Patients with gene Thr92Ala polymorphism may respond better to a combination treatment regimen.
Bron:
http://www.diabetesincontrol.com/levoth ... notherapy/
“New insights into the Variable Effectiveness of Levothyroxine Monotherapy for Hypothyrodism.”
The Lancet 3 (2015):756-57. The Lancet.Web.2 Oct.2015.
Elizabeth A McAninch email, Antonio C Bianco
Published Online: 08 September 2015
http://www.thelancet.com/action/showFul ... %2900325-3
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Nieuwe inzichten in de variabele effectiviteit van levothyroxine monotherapie hypothyreoïdie
Re: Nieuwe inzichten in de variabele effectiviteit van levothyroxine monotherapie hypothyreoïdie
Not all hypothyroid patients seem to be created equal
Antonio Bianco en Elizabeth McAninch
Weliswaar in het Engels ...
For decades, successful treatments have been developed and applied for an array of maladies of the thyroid. Hypothyroidism, in particular, is a very common disease that in the US alone affects more than 8 million people. Treatment modalities evolved during the 20th century and the great news is that the majority of the patients does very well with thyroid hormone replacement and can experience a high quality of life after diagnosis and treatment.
Thyroid hormone replacement is accomplished through administration of levothyroxine, L-T4, which is considered a ‘prohormone’ as it is only converted to its active form after it is absorbed and enters the multiple tissues of the body. The active form of thyroid hormone, T3, is made by conversion from T4 via an enzyme called the type 2 deiodinase (D2). As no human has ever been found to lack D2, it has been assumed that all patients can convert T4 to T3 and thus L-T4 has been considered a universal strategy for thyroid hormone replacement. Despite this ideology, new evidence indicates that T3 levels might not be fully normalized in such patients, which could explain why a minority of hypothyroid patients remains symptomatic with L-T4; in fact, some demonstrate improved well-being and prefer treatment with both L-T3 and L-T4. However, this has remained a polemic issue as the majority of clinical trials failed to demonstrate an objective benefit of combination therapy. It is conceivable that minor differences within subgroups of hypothyroid patients could make them more or less responsive to L-T4 or L-T4+L-T3. How can we identify these differences?
In 2002, investigators described a ‘polymorphism’, or a very prevalent mutation, in the D2 gene and found it to be associated with insulin resistance. Other groups have described associations between the polymorphism and many other conditions including bipolar disorder, mental retardation and low IQ. In addition, there is at least one large clinical trial in which hypothyroid patients with the D2 polymorphism improved when treated with L-T4 + L-T3. The discovery of the D2 polymorphism was a huge source of excitement for thyroidologists as many presumed that this polymorphic enzyme would hold the answer to the question of why some hypothyroid patients remain symptomatic on L-T4 treatment. However, many studies over the last decade failed to connect the polymorphism in D2 with a logical disease mechanism such as decreased ability to convert T4 to T3.
Studies that have just been published in the Journal of Clinical Endocrinology & Metabolism have found that the polymorphic D2 has a longer half-life and, as opposed to normal D2, accumulates in a compartment of the cell known as the Golgi apparatus. This is associated with broad signs of cellular stress even at the genetic level. Interestingly, some of the alterations seen in cells expressing the polymorphic D2 improved after treatment with an antioxidant. These studies were confirmed in human brain samples from postmortem donors that carried the D2 polymorphism. In addition, the pattern of gene expression found in these brains suggested similarities with neurodegenerative disease, a remarkable finding.
Although much more research at both the basic and clinical levels needs to be performed, we are much closer to understanding the disease mechanism tying the D2 polymorphism with a number of associated conditions, including responsiveness to L-T4. This may one day lead to a treatment approach for hypothyroidism that is individually directed based on genotype, hopefully providing a means to resolve symptoms in all of our patients.
Antonio Bianco en Elizabeth McAninch
Weliswaar in het Engels ...
For decades, successful treatments have been developed and applied for an array of maladies of the thyroid. Hypothyroidism, in particular, is a very common disease that in the US alone affects more than 8 million people. Treatment modalities evolved during the 20th century and the great news is that the majority of the patients does very well with thyroid hormone replacement and can experience a high quality of life after diagnosis and treatment.
Thyroid hormone replacement is accomplished through administration of levothyroxine, L-T4, which is considered a ‘prohormone’ as it is only converted to its active form after it is absorbed and enters the multiple tissues of the body. The active form of thyroid hormone, T3, is made by conversion from T4 via an enzyme called the type 2 deiodinase (D2). As no human has ever been found to lack D2, it has been assumed that all patients can convert T4 to T3 and thus L-T4 has been considered a universal strategy for thyroid hormone replacement. Despite this ideology, new evidence indicates that T3 levels might not be fully normalized in such patients, which could explain why a minority of hypothyroid patients remains symptomatic with L-T4; in fact, some demonstrate improved well-being and prefer treatment with both L-T3 and L-T4. However, this has remained a polemic issue as the majority of clinical trials failed to demonstrate an objective benefit of combination therapy. It is conceivable that minor differences within subgroups of hypothyroid patients could make them more or less responsive to L-T4 or L-T4+L-T3. How can we identify these differences?
In 2002, investigators described a ‘polymorphism’, or a very prevalent mutation, in the D2 gene and found it to be associated with insulin resistance. Other groups have described associations between the polymorphism and many other conditions including bipolar disorder, mental retardation and low IQ. In addition, there is at least one large clinical trial in which hypothyroid patients with the D2 polymorphism improved when treated with L-T4 + L-T3. The discovery of the D2 polymorphism was a huge source of excitement for thyroidologists as many presumed that this polymorphic enzyme would hold the answer to the question of why some hypothyroid patients remain symptomatic on L-T4 treatment. However, many studies over the last decade failed to connect the polymorphism in D2 with a logical disease mechanism such as decreased ability to convert T4 to T3.
Studies that have just been published in the Journal of Clinical Endocrinology & Metabolism have found that the polymorphic D2 has a longer half-life and, as opposed to normal D2, accumulates in a compartment of the cell known as the Golgi apparatus. This is associated with broad signs of cellular stress even at the genetic level. Interestingly, some of the alterations seen in cells expressing the polymorphic D2 improved after treatment with an antioxidant. These studies were confirmed in human brain samples from postmortem donors that carried the D2 polymorphism. In addition, the pattern of gene expression found in these brains suggested similarities with neurodegenerative disease, a remarkable finding.
Although much more research at both the basic and clinical levels needs to be performed, we are much closer to understanding the disease mechanism tying the D2 polymorphism with a number of associated conditions, including responsiveness to L-T4. This may one day lead to a treatment approach for hypothyroidism that is individually directed based on genotype, hopefully providing a means to resolve symptoms in all of our patients.
laura
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Re: Nieuwe inzichten in levothyroxine monotherapie
Een duidelijker uitleg is dit artikel van Wiersinga uit het Graves Bulletin: https://wvrtaal.files.wordpress.com/201 ... rsinga.pdfineke schreef: Practice Pearls:
• New finding suggest that levothyroxine monotherapy does not deliver enough therapy for the treatment of hypothyroidism.
• A combination of liothyronine and levothyroxine has shown superiority in rats
• Patients with gene Thr92Ala polymorphism may respond better to a combination treatment regimen.
Hij schrijft daarin over die afwijkende D2, deiodinase type 2.
laura
Kijk voor meer informatie ook eens op Schildkliertje.
Raadpleeg altijd een arts als je twijfelt over je gezondheid.
Het Schildklierforum kan niet worden beschouwd als vervanging van een consult of een behandeling.
Kijk voor meer informatie ook eens op Schildkliertje.
Raadpleeg altijd een arts als je twijfelt over je gezondheid.
Het Schildklierforum kan niet worden beschouwd als vervanging van een consult of een behandeling.