Alterations in the body's circadian clock—sometimes referred to as a molecular time-keeping system—suggests timing matters when doing a fine needle aspiration biopsy (FNA), and offers important clues to thyroid malignancy, which may lead to improved diagnostics that stear patients clear of unnecessary thyroidectomies.
That was the takeaway presented by Charna Dibner, PhD, research group leader in the Laboratory of Circadian Endocrinology at Geneva University Hospitals and the University of Geneva, during a plenary lecture, Thyroid Circadian Timing: Roles in Physiology and Thyroid Malignancies, on September 22, 2016 at the American Thyroid Association 86th annual meeting in Denver, Colorado.
A clearer understanding of the circadian rhythm, specifically in thyroid cells will lead to a better understanding of the molecular determinants of how thyroid cancer develops,1 according to Dr. DIbner.
“Better diagnostics, building on this and future research findings, will potentially reduce unnecessary surgeries,” Dr. Dibner said.
''There is a body-wide web of circadian oscillators," Dr. Dibner said. "The concept was discussed as early as 1729, with circadian profiles of thyroid releasing hormone, TSH, T3 and T4, all well described,”1 she added.
“However, few studies have focused on the underlying circadian regulation of the hypothalamus-pituitary-thyroid (HPT) axis, and the mechanisms to explain it,” Dr. Dibner continued.
“A growing number of studies suggest a strong link between the cellular circadian cycle, damage to DNA, programmed cell death and the development of cancer,”1,2 she said. "Circadian clocks are cell-autonomous."
In her lab, Dr. Dibner’s team looked at whether circadian clockwork changed when thyroid malignancies were present. Using an experimental approach for the study of human peripheral clocks, she described how they assessed the properties of the circadian oscillator in human primary thyrocytes that were obtained from biopsies of benign or malignant human tissue.1
When they examined the thyrocytes obtained from aggressive thyroid cancers, altered properties were detected that were not found in the less aggressive or benign cancers.1,2 What they noted was an increased level of the core-clock gene, BMAL1, and a decrease in the levels of another core-clock gene, CRY2, in both follicular and papillary thyroid cancer tissue samples compared to normal tissue and the benign nodules.
"We have identified and validated new biomarkers'' using postoperative samples," Dr. Dibner said. Since some of the research was published in the Journal of Clinical Endocrinology & Metabolism, her team has been searching for new, additional biomarkers.
Next, she said, "their goal is to evaluate preoperative samples to see if the same findings emerge, to see if the same biomarkers find the cancers.The hope is that sufficient samples could be retrieved with the FNA. If that is not enough, due to lack of material, another option could be core needle biopsy.”
While diagnostic application of the altered circadian clock findings is still a few years away, the ongoing research about circadian clocks and thyroid function has immediate application for the practicing endocrinologist,” commented Joel Ehrenkranz, MD, medical director of diabetes and endocrinology at Intermountain Medical Center in Murray, Utah, who moderated the session.
"The really important take-home message is--you need to control the time of day you do the FNA," Dr. Ehrenkranz told Endocrine Web.
In previous research, Dr. Dibner indicated that ''plasma levels of TSH have [exhibited] strong circadian variations, attenuated with aging," As a result, “when a doctor evaluates a patient for hypothyroidism, for instance, 3 out of 10 will be missed if blood collection is done later in the day," Dr. Ehrenkranz explained.
"Based on those and other findings," Dr. Ehrenkranz continued, "you can't do an FNA at 8 am on one patient and at 6 pm on another patient and think the results are comparable," but we now know this isn’t the case.
"Patients who travel to see specialists should be wary, too," he added, "and should make sure they give their body clock time to adjust to the new time zone before undergoing tests. As a rule it takes one day per time zone to adjust."
With continued research, the diagnostics may be available clinically within two years, Dr. Dibner told EndocrineWeb.