Low triiodothyronine (T3) syndrome appears to be a biomarker of poor clinical outcomes and symptoms of depression in patients undergoing surgery for brain tumors. That is the conclusion of a pilot study now available online ahead of print in the Journal of Neurosurgery (DOI: 10.3171/2013.1.JNS121696).
“No one else has looked at low T3 syndrome in brain cancer patients,” said lead study author Adomas Bunevicius, MD, PhD, a neuroradiology fellow at the University of North Carolina at Chapel Hill and neurosurgery resident at Lithuanian University of Health Sciences. “There are data from hospitalized critical care and cardiac patients indicating that the syndrome is important for long-term outcomes in these populations, so we tried to look at it in neurosurgical brain tumor patients.”
While the results are preliminary, they suggest that surgery for brain tumors predisposes patients for the development of low T3 syndrome, he said. Moreover, patients with low T3 levels have an increased risk of poor outcomes relative to patients with normal free T3 concentrations. “The question, though, is what to do with that information.”
Although the correlation between low T3 syndrome and poorer outcomes in this study is consistent with what is seen in patients with critical illness, research hasn't yet demonstrated that treating them with thyroid hormone is beneficial, said Yael Tobi Harris, MD, PhD, of the Division of Endocrinology and Metabolism at North Shore-LIJ Health System in Great Neck, N.Y.
Still, said Leia Nghiemphu, MD, Assistant Clinical Professor in the Department of Neurology Neuro-Oncology Program at UCLA, despite the preliminary nature of the study, the research “points to the fact that sometimes there are other factors that affect patients such as the hormonal axis that we don't often think about as oncologists or neurosurgeons. We often focus on neurological disease.”
Bunevicius and his colleagues conducted a preliminary study of 90 patients as part of a larger trial of 300 individuals undergoing surgery for a variety of brain tumors, including meningioma, high-grade glioma, and pituitary adenoma, at Lithuania University of Health Sciences. The median age of the subjects was 55, and 71 percent were women.
Thyroid function was assessed before and after surgery, and the researchers examined whether there was an association between low T3 syndrome, defined as a level that was 3.1 pmol/L or less, and symptoms of anxiety and depression on the Hospital Anxiety and Depression Scale (HADS). The team also evaluated clinical outcomes using the Glasgow Outcome Scale (GOS) at the time of hospital discharge.
Before surgery, 38 percent of the patients had low T3 syndrome, which increased to 54 percent after surgery.
At discharge, 20 percent of patients had poor clinical outcomes. When compared with patients with normal T3 levels, perioperative low T3 syndrome was associated with a five- to eight-fold increased risk of unfavorable outcome, or GOS scores of four or less, at the time of hospital discharge, even when adjustments were made for age, sex, preoperative functional impairment, brain tumor histology, prior treatment for brain tumor, and depression before surgery.
Preoperative low T3 syndrome was also associated with a four-fold preoperative risk for depressive symptoms, or a HADS depression subscale score of 11 or greater, independent of age, sex, living condition, psychiatric history and treatment, functional impairment, prior treatment for brain tumor, and brain tumor histology. However, no correlations were found between preoperative low T3 syndrome and postoperative depression.
Risk of Statistical Anomalies
Although the study was well designed, the small sample size makes it subject to statistical anomalies, noted Eric Burton, MD, Assistant Professor of Neurology and a neuro-oncologist at James Graham Brown Cancer Center at the University of Louisville. Additionally, he said in an email, thyroid metabolism is complex and medications such as steroids commonly used in patients with brain tumors can potentially lower thyroid levels.
The reasons low T3 syndrome is more prevalent after surgery are also complex, Bunevicius said. Specifically, proper function of the hypothalamic-pituitary-thyroid axis requires well-coordinated actions by both central and peripheral mechanisms, he explained. The concentration of inflammatory factors and stress hormones may increase in response to the severe mental and physical stress that brain tumor surgery may cause.
Furthermore, activation of inflammatory and stress mechanisms can suppress central stimulation of the thyroid axis, leading to reduced thyroidal hormone production and can inhibit peripheral thyroxine (T4) to T3 conversion. Several proteins and enzymes may also have an impact on T3 levels postsurgery.
Also asked for his opinion, David M. Peereboom, MD, FACP, a staff physician in the Department of Solid Tumor Oncology at Cleveland Clinic Taussig Cancer Institute, said he doesn't see any immediate clinical implications: “I think that T3 syndrome is an epiphenomenon,” he said. “We see it in patients who are ill, and we know they are going to continue to be ill. But it doesn't change what we do.”
Consequently, measuring T3 levels in patients doesn't make sense, he said. These patients are on many different medications in the hospital, including steroids and anticonvulsants, both of which can alter the dynamics of thyroid function tests. Additionally, the effort to replace hormones in patients with low T3 has not been found to be helpful. “It's not routinely done in our hospital.”
In response, Bunevicius said that the medical community is debating whether and how low T3 syndrome should be managed. Treatment of the syndrome with thyroid hormone replacement therapy has been evaluated in a number of cardiovascular studies and has been found to normalize T3 concentrations in blood and improve indices of cardiovascular function but not survival or other clinical outcomes, he said.
“As with all biomarkers, the question is what to do next.” While testing of T3 levels is affordable and widely available, “there are no effective evidence-based interventions to treat it in neurosurgical patients.”
Some researchers note that changes in T3 represent a physiological adaptation, Burton said. Consequently, attempts to restore hormone levels may have an adverse effect on patient outcome. However, detecting low levels of the hormone might have some prognostic value. “Knowing in advance which patients may be most at risk from surgery can potentially aid in making therapeutic recommendations and in preparing patients for outcomes after surgery.”
While the effects of managing T3 syndrome with thyroid hormone are unknown, treating depression in patients with brain tumors is a common component of their care, Nghiemphu noted.
Whether depression in this study was due to low T3 is difficult to determine. “Depression is very common in patients with brain tumors and in someone who has gone through surgery,” she said, adding that the symptom should be treated with antidepressants. “We often address it because it can affect acute survival and the ability to recover from brain tumors in the long-term.”
Treating depression while patients are still in the hospital is challenging because they are post-op, have received anesthetics and other medications, and are often still adjusting to the shock of their diagnosis, Peereboom said. “However, we are very mindful of it. When the patient comes back to our clinic about 10 days after surgery, we often do have him or her see our cancer center psychiatrist if depression appears to be an issue.”
Bunevicius noted that patients with brain tumors and comorbid depression should also be evaluated for hypothyroidism, a contributor to the symptom, and be appropriately treated.
“While it's important to find predictors of outcome, what these researchers have shown is an association,” Harris said. “A lot more research needs to be done.”
Evaluating brain cancer patients three to six months after surgery to see if low T3 correlates with any of their symptoms would also be useful, Peereboom said. This type of research should be conducted in a uniform group of patients—for example, those with glioblastoma.
Regarding the issue of whether treatment of low T3 syndrome in patients with brain cancer has an effect on outcomes, Bunevicius noted that he and his colleagues are currently studying how thyroid hormones affect fatigue this population.
It would also be helpful, he noted, to study the genetic polymorphisms of proteins involved in the metabolism of thyroid hormones. These polymorphisms may help predict which subgroups of patients with low T3 syndrome might have a better or worse prognosis based on their inherent genetic makeup, he explained.