Free at last: cortisol unbound

Measuring protein-bound cortisol may be misleading. Better check the free levels

By Brian Hoyle

Anthony Wright, a 57-year-old systems analyst, stumbled into the hospital. He was short of breath and had a fever of 39°C. After two days in intensive care he seemed to be improving but suddenly took a turn for the worse and had to be intubated. His cortisol levels were measured and found to be low, implying that his adrenal gland � that makes the hormone � was impaired. But a new study suggests that this result may be misleading.

Cortisol is found in two forms � protein bound or free in the serum. Currently, it's the protein bound form that's looked at to determine the state of the adrenal gland. However, a paper in the April 15 edition of the New England Journal of Medicine shows that, in critically ill patients, measuring the level of free cortisol, rather than the bound form, may help prevent the unnecessary and potentially dangerous application of glucocorticoids.

Researchers headed by Dr Baha Arafah at the University Hospitals of Cleveland measured the bound and free cortisol concentrations in 66 critically ill patients and 33 healthy people. Of the 66 critically ill patients, 36 had hypoproteinemia, abnormally low levels of albumin, while the remaining 30 had almost normal albumin levels.

The ill patients with hypoproteinemia had significantly lower levels of protein-bound cortisol, both from the get-go and as their illnesses progressed, compared to their sick but non-hypoproteinemic comrades. However, at the beginning of the study both groups had nearly identical levels of free cortisol, which were, moreover, markedly greater than the corresponding levels in the healthy controls.

The researchers also found that 14 ill, hypoproteinemic patients had subnormal concentrations of bound cortisol, even when the adrenal gland was kick-started via an injection of cosyntropin. Nonetheless, these 14 patients, as well as the other critically ill people, had free cortisol concentrations similar to the controls.

Dr Lynn Loriaux of the Oregon Health and Sciences University believes that "in critically ill patients in the [intensive care unit], the circulating free cortisol response to synthetic cosyntropin is a much more important clinical determination than the total cortisol response."

Currently, measuring free cortisol levels is challenging. But times will no doubt change. "A few years ago, it was not easy to measure plasma free thyroxine. Now, free thyroxine is the workhorse of the thyroid-function test panel," states Dr Loriaux.

Until the measurement of serum free cortisol becomes routine, the status quo measurement of the bound form should be accompanied by the realization that the numbers may not tell the whole story.