Systemic thyroid hormone effects with levothyroxine can fall short

Systemic thyroid hormone status—the systemic effects of thyroid hormone activity—has been further confirmed to be insufficient with levothyroxine therapy in a significant percentage of cases, even though laboratory levels of TSH and T4 are normalized, in a study published in JCEM (The Journal of Clinical Endocrinology and Metabolism). This adds more compelling evidence supporting the need for clinicians to assess T3 and systemic biomarkers to ensure adequate thyroid function.

Measuring other objective biomarkers of thyroid hormone signaling

The authors note that the absence of evidence that confirms that levothyroxine (LT4) given as monotherapy at doses to normalize serum TSH levels restores thyroid hormone signaling in the peripheral tissues. So they set about to review...

"...studies of overt hypothyroidism in which participants were treated with levothyroxine to normalize serum TSH levels and measured other objective markers of thyroid hormone signaling...Databases were searched for studies that reported objective markers of thyroid hormone signaling (serum low-density lipoprotein (LDL), total cholesterol (TC), sex hormone-binding globulin (SHBG), creatine kinase and/or ferritin levels; cognition, energy expenditure, and/or renal function) in levothyroxine monotherapy for overt, primary hypothyroidism among nonpregnant adults with normal serum TSH levels."

Importance of triiodothyronine (T3)

The current standard of care may not ensure adequate levels of T3, the form of thyroid hormone mainly responsible for systemic effects.

"The current standard of care for treatment of overt hypothyroidism is replacement of thyroid hormone with synthetic T4, called levothyroxine (LT4), at doses that achieve a normal serum thyroid stimulating hormone (TSH);LT4 has been among the most commonly prescribed medications in the US for over 5 years.LT4 can be activated to T3 in tissues by enzymes called deiodinases but the ability of the deiodinases to universally restore thyroid hormone signaling in all tissues has come into question by observations that: (i) there are high serum T4:T3 ratios in LT4-treated hypothyroid patients, and (ii) a portion of LT4-treated hypothyroid patients feel that their symptoms are not resolved despite achievement of normal serum TSH levels."

Normalized serum TSH does not ensure systemic metabolic effects

Adequate thyroid activity is necessary for lipid regulation. The authors' data show that LT4 monotherapy can be insufficient, as is using only TSH and T4 to assess thyroid function.

"A total of 99 studies met inclusion criteria, including 65 that reported serum cholesterol data. Meta-analysis showed that levothyroxine-treated hypothyroid participants with normal serum TSH levels had 3.31 ± 1.64 mg/dL higher serum LDL levels (p=0.044) and 9.60 ± 3.55 mg/dL higher serum TC levels (p=0.007) compared to controls. In studies that did not concomitantly assess healthy controls, serum LDL levels were 138.3 ± 4.6 mg/dL (p<0.001) and serum TC levels were 209.6 ± 3.4 mg/dL (p<0.001)."

Briefly stated:

"LT4-users had significantly higher serum LDL and TC levels than healthy controls in the meta-analyses suggests that thyroid hormone-dependent lipid homeostasis was not restored. This is consistent with data from thyroidectomized rats on T4 replacement."

Cardiovascular and additional concerns

The implications extend beyond cardiovascular risk to include concerns such as neurodegenerative disease. Regarding the cardiovascular component:

"Considering the high prevalence of hypothyroidism hypothyroidism and the relative ubiquity of LT4 use, this data supports the need for further investigation of the epidemiology of cardiovascular events in LT4 users on the population wide scale to determine the potential clinical significance of this degree of LDL elevation....and if this degree of elevation in serum cholesterol levels is found to be clinically significant, this may support the need for amendment of hypothyroidism and lipid guidelines to address screening of serum lipid profiles and treatment thresholds amongst LT4-treated patients with overt hypothyroidism."

There are also concerns for neurodegenerative conditions such as Alzheimer's disease:

"Such degree of dyslipidemia may also have implications beyond cardiovascular events, as dyslipidemia has been associated with Alzheimer’s disease. Recently the Thr92Ala single nucleotide polymorphism (rs225014) in the type 2 deiodinase gene (DIO2) has been associated with Alzheimer’s disease in African Americans; it is possible that this polymorphism represents one risk factor and that in LT4 treatment of hypothyroidism, the resulting degree of residual dyslipidemia would represent another risk factor. If independently confirmed, this would support a personalized medical approach to treating hypothyroid Thr92AlaD2 carriers and more research into the appropriate thresholds for initiation of cholesterol lowering drugs for cardiovascular risk reduction, and potentially as a preventative strategy for neurodegenerative disease."

Treatment with combination therapy

There are inconsistencies and shortcomings in the limited clinical trials of treatment that combines T4 and T3.

"Another treatment approach for hypothyroidism is termed ‘combination’ therapy as it utilizes replacement of both T3 and T4 via either desiccated thyroid or LT4 plus oral synthetic T3 (LT3). In theory, this approach could obviate concerns about increased T4:T3 ratios LT4 monotherapy. In rodent models it has been shown to restore biological markers of thyroid hormone signaling. In available clinical trials of combination therapy in humans, no benefit over LT4 monotherapy has been consistently established. In at least one randomized controlled trial a favorable effect on lipid profile was shown with combination therapy compared to LT4 monotherapy, but this was not confirmed in multiple other studies. The currently available human studies may be limited by the short half-life of oral LT3. Further clinical trials of combination therapy utilizing delivery mechanisms that provide stable serum T3 levels, and maintain physiologic serum T4:T3 ratios, while maintaining serum TSH within normal range, are justified."

However, the astute clinician should investigate to determine, and then treat, the underlying causes of any defect in conversion of T4 to T3, which has several potential contributing factors. This starts with measuring serum T3 along with TSH and T4. Elevated cortisol and higher levels of inflammatory cytokines both can impair conversion of T4 to T3.The authors conclude:

"In this systemic review and meta-analysis, in adults with overt, primary hypothyroidism, serum LDL and TC were not normalized by LT4 monotherapy at doses that normalize the serum TSH. Clinical trials that use healthy TSH-, medication-, age-, sex-, and race-matched controls are justified to determine (i) whether other biological markers of thyroid hormone signaling, such as basal metabolic rate and cognition, are normalized, and (ii) the clinical significance of this degree of increased serum LDL and TC on cardiovascular risk."

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