Cholesterol Levels Remain High Despite T4 for Hypothyroidism

Nancy A. Melville

September 03, 2018

Patients treated for overt hypothyroidism with the standard replacement therapy levothyroxine (LT4) often continue to show abnormal cholesterol levels despite normalization of thyroid stimulating hormone (TSH), according to a new meta-analysis recently published online in the Journal of Clinical Endocrinology & Metabolism.

Serum low-density lipoprotein (LDL) and total cholesterol (TC) are among a number of measures considered to be objective markers of thyroid hormone signaling. Whether normalizing serum TSH levels with LT4 treatment universally restores thyroid hormone signaling is unknown. 

"It's very well established that untreated hypothyroidism causes your cholesterol levels to be higher," said first author Elizabeth McAninch, MD, an assistant professor in the Division of Endocrinology and Metabolism at Rush University Medical Center, in Chicago, Illinois, in a press statement.

Now these latest results showing "that LT4 users had significantly higher serum LDL and total cholesterol levels than healthy controls in the meta-analyses suggest that thyroid hormone-dependent lipid homeostasis was not restored," she and her co-authors conclude.

"[The findings] point us to the conclusion that levothyroxine therapy may not truly be normalizing these people," McAninch stressed.

Normalizing TSH May Not Be Sufficient to Fully Restore Thyroid Functioning

The researchers explain that a healthy thyroid gland produces and secretes both thyroxine (T4) and triiodothyronine (T3). T4 is considered to be the prohormone because it has lower affinity for the thyroid hormone receptor whereas T3 is the active form of thyroid hormone.

The current standard of care for treatment of overt hypothyroidism, which affects about 5% of the US population, is replacement of thyroid hormone with synthetic T4, levothyroxine (LT4), at doses that achieve a normal serum TSH.

It was previously thought that LT4 monotherapy at doses that normalize serum TSH should effectively convert to T3 and maintain homeostasis but this approach has come into question following observations that (1) a portion of LT4-treated hypothyroid patients (around 20%) feel their symptoms are not resolved despite achievement of normal serum TSH levels and (2) there are high serum T4:T3 ratios in LT4-treated hypothyroid patients. Indeed, many patients who do not have sufficient symptom relief with LT4 alone claim that T3 is also needed; the subject of whether to 'combine' T3 with T4 in those who do not fare well on T4 alone has been a topic of debate over the past few years.

In the new meta-analysis, the Rush University researchers identified 99 studies that met inclusion criteria of patients with overt primary hypothyroidism treated with LT4 monotherapy to achieve normal levels of serum TSH.

Of the studies, 65 included patients' serum cholesterol data.

LT4-treated patients, despite normal serum TSH levels, had significantly higher levels of serum LDL cholesterol compared with healthy controls (3.31 ± 1.64 mg/dL; P = .044), as well as higher serum total cholesterol levels (9.60 ± 3.55 mg/dL; P = .007).

Of the studies that did not include healthy controls, serum LDL cholesterol levels were still significantly higher in LT4-treated patients compared with normal reference ranges (138.3 ± 4.6 mg/dL; P < .001), as was serum total cholesterol (209.6 ± 3.4 mg/dL; P < .001).

These new findings offer further clues as to possible underlying factors that may explain why many patients report ongoing symptoms, such as fatigue and weight gain, despite normalized TSH levels with LT4 treatment, McAninch said.

"Maybe [patients'] subjective complaints are a sign that their thyroid hormone replacement regimen might not be doing the full job of a normally functioning thyroid gland," she said.

"We should take these common patient remarks and design more research to further explore why this is happening."

Among theories for the continued symptoms in some patients is that serum TSH may not be as precise a measure as is needed to represent the ideal marker of normal thyroid function, and indeed studies in rodents have shown that normalized TSH levels may not restore other markers of thyroid hormone signaling.

Important limitations of the current analysis include the inability to control for factors including the duration of LT4 replacement and statin use. However, the authors note that, with two large studies showing more patients treated with LT4 to be taking concomitant statins, the abnormal LDL and total cholesterol levels in the analysis could in fact be underestimated.

"If our results are replicated, 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 among LT4-treated patients with overt hypothyroidism," McAninch and colleagues conclude.

The study authors have received support from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, and National Institute on Aging. Study co-author Antonio Bianco, MD, is a consultant for Sentier Therapeutics. The other authors have reported no relevant financial relationships.

J Clin Endo Metab. Published online August 15, 2018. Abstract

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