This new paper in Endocrine Reviews discusses optimal thyroid hormone treatment modalities. At the moment I can only get the title and abstract: I've mailed my colleagues to see if they can succeed.
Hypothyroidism is a common endocrinopathy and levothyroxine is frequently prescribed. Despite the basic tenets of initiating and adjusting levothyroxine being agreed upon, there are many nuances and complexities to consistently maintaining euthyroidism. Understanding the impact of patient weight and residual thyroid function on initial levothyroxine dosage and consideration of age, co-morbidities, TSH goal, life stage, and quality of life as levothyroxine is adjusted can be challenging and continually evolving. As levothyroxine is a life-long medication it is important to avoid risks from periods of overtreatment or undertreatment. For the subset of patients not restored to baseline health with levothyroxine, causes arising from all aspects of the patient’s life (co-existent medical conditions, stressors, lifestyle, psychosocial factors) should be broadly considered. (Hm!, my interjection). If such factors do not appear to be contributing, and biochemical euthyroidism has been successfully maintained, there may be benefit to a trial of combination therapy with levothyroxine and liothyronine. This is not supported by the majority of randomized clinical trials, but may be supported by other studies providing lower quality evidence and by animal studies. Given this discrepancy, it is important that any trial of combination therapy only be continued as long as a patient benefit is being enjoyed. Monitoring for adverse effects, particularly in older or frail individuals, is necessary and combination therapy should not be utilized during pregnancy. A sustained release liothyronine preparation has completed phase 1 testing and may soon be available for better designed and powered studies assessing whether combination therapy provides superior therapy for hypothyroidism.
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diogenes
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Thanks for posting diogenes and the majority of experts have really no idea what the addition of T3 means to someone's health/symptoms who only improves upon T3 alone or even the additon of T3 to T4.
It annoys and appalls me in equal measure the assumption that hypothyroid pregnant ladies should not be given T3. Prof P Taylor said on Tuesday evening he would take T3 off a pregnant lady.
Thanks for posting diogenes. As some one who definitely improved on T3 and T4 I am always sad to hear what others have to go through without combination therapy.
I'm not too convinced about anything from Jonklaas. She was a co-author some years ago with Sawka and others who wrote that levothyroxine alone is better than anything else.I mention Sawka because she's here in Toronto and I recently checked her out. Not inspiring.
We concluded that levothyroxine should remain the standard of care for treating hypothyroidism. We found no consistently strong evidence for the superiority of alternative preparations (e.g., levothyroxine-liothyronine combination therapy, or thyroid extract therapy, or others) over monotherapy with levothyroxine, in improving health outcomes.
Remember, conceptual teeth are slowly being dragged out of her. Authors like her who previously promoted the status quo are not going to jump right away all the way to new thinking in its entirety. It will take time, one tooth at a time.
Thanks for this, it took some time to study. Jacqueline Jonklaas is one of the 'better' endocrinologists (just about!). There is some very good information about thyroid hormone mechanisms, tips on getting better levothyroxine absorption and an accurate summary of combination studies. It is otherwise quite depressing, repeating a number of invalid assumptions and a general lack of scientific method.
The statement that combination therapy should not be used in pregnancy has no supporting evidence. Firstly, combination therapy has been used in pregnancy for over one hundred years in the form of NDT. Secondly, the 'recommended' doses of 5 to 10 mcg liothyronine would produce very little variation in fT3, indeed fT3 and fT4 would remain closer to normal than with levothyroxine monotherapy. It is possible that high doses of T3 might lead to an increased adverse outcomes (small enough not to be noticed anecdotally) - this has not been investigated.
She claims the goal of treating hypothyroidism is to achieve normal biochemistry and later refers to 'optimization' of therapy. This is a fundamental mistake, the goal is to make the patient well, this may sometimes require abnormal biochemistry.
When discussing TSH she fails to mention it's second role, regulation of deiodinase activity. This is universally ignored by the endocrine community.
When comparing symptoms with biochemical 'euthyroidism' on page 8 she cites studies that used controls that were not healthy, they were under investigation for symptoms! This is nonsense, studies must use healthy subjects as controls. In any event if there is a lack of correspondence between hypothyroid symptoms and biochemistry it more than likely indicates the biochemistry is an inadequate marker.
The document only considers primary and secondary hypothyroidism. There are many other causes such as a down-regulated axis, endocrine disruption, low T3 due to a chronic illness and other unknown causes.
She refers to reference intervals as decision limits. This is wrong, if this applied prevalence of all diseases would be 2.5%.
She states that TSH is a good marker for primary hypothyroidism because of the log linear relationship between TSH and fT4. (I know it's better described by a complex polynomial). This is mathematical nonsense. In healthy subjects TSH and fT4 exit their reference interval limits at around the same time. TSH responds exponentially but it also has a much wider reference interval. TSH is a good marker because as the thyroid starts to fail the pituitary has to work harder to stimulate the same level of thyroidal secretion. The 'sensitivity' of TSH is nothing of the sort, it's just an exponential curve. This ignorance of school arithmetic leads to obsessive faith in TSH.
She does point out that reliance on TSH assumes that the pituitary is functional, and there is no non-thyroidal illness.
We have the absurd statement that total T3 (she doesn't like fT3) below the lower reference limt is not sensitive or specific for hypothyroidism due to enhanced conversion and also because T3 falls due to illness, starvation and drugs such as beta blocker and glucocorticoids. These conditions are causing low T3 and hypothyroidism, either correct the underlying condition if possible or else give T3 to compensate. We have this nutty idea that if low T3 is caused by a chronic condition or treatment it isn't really hypothyroidism and we should do nothing.
Claims that 'diagnosis is simple', TSH can be used to predict dose for euthyroidism (after quoting studies that show TSH does not correspond to symptoms) and adjusting dose until 'TSH is at goal' - signs and symptoms have been ditched.
Inconsistent TSH / fT4 levels are put down to 'non-adherrence' without checking for fT3 or that the axis is intact.
There is a detailed analysis of combination studies, all of which have failed to identify suitable cohorts (mainly by insisting on an elevated TSH for diagnosis) and made no attempt to determine effective T3 doses. This is like writing a book on using tealeaves in the teapot to analyse thyroid status.
p. 40 states that combination therapy should not be undertaken in pregnant women for fear of insufficient T3 crossing the placenta. I'm aware of studies that suggest T3 does not cross the placenta but this is contradicted by women on T3 monotherapy having normal pregnancies and by the use of NDT for over a century.
Finally, the statement 'LT3 should be utilized in a physiologic ratio'. I see very few patients on the forum who recover with physiologic doses of T3, they usually require much more. This is why the studies are worthless, they assume instead of determining the dose and then findout out why such doses are needed.
This is a quite depressing document, it reveals a complete lack of appreciation of the need for scientific method, the sort of stuff we are taught at school.
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