Surgeons Discover Hormone That Could Protect Against Sepsis

A hormone naturally found in the fat that surrounds the abdominal organs for the first time has been linked to death related to sepsis, surgeons reported at the 2009 Clinical Congress of the American College of Surgeons.

A study presented at the conference showed that low levels of the hormone adiponectin placed animals at a profoundly high risk of death from a septic insult. The study findings also revealed that sepsis could be prevented by giving the hormone to the animals.

“It is a novel observation that decreasing levels of a fat hormone could be a very important mechanism that can lead to the development of sepsis-related mortality,” said Subodh Verma, MD, PhD, FRCSC, FAHA, a cardiac surgeon at St. Michael’s Hospital, associate professor of surgery and pharmacology at the University of Toronto, and Canada Research Chair of Atherosclerosis.

“The implications are two-fold,” he added. “One is that adiponectin may serve as an independent predictor of developing sepsis-related inflammation and vascular dysfunction as well as increased mortality from sepsis. The other is that treatment strategies or approaches that cause an increase in adiponectin levels may protect against sepsis-related mortality,” he said.

Verma and his associates are hoping to be the first group to conduct studies of adiponectin in patients. The investigators are seeking approval from the national healthcare system of Canada to begin a clinical trial that will administer a purified form of adiponectin to patients who are in the beginning stages of sepsis. “It will probably take at least a year to get through the process of approval and test adiponectin in a half-dozen patients to show that it can be given without any deleterious effects. I would hypothesize that there would be none. When safety can be demonstrated, we can embark on an open-label trial in a few patients and then hopefully on a randomized trial,” Verma said.

The study was conducted in an animal model that mimics what occurs in patients who have low adiponectin levels. These are patients who are at high risk for developing sepsis after surgery because of underlying diabetes, morbid obesity, or metabolic syndrome [a combination of factors including abdominal obesity, high blood fat composition, high blood pressure, diabetes, and high inflammatory and blood clot indicators]. The risk of septic-related mortality is two-and-a-half to three times higher in such patients.

This increased risk was thought to be related to insulin resistance from diabetes or mechanical issues. “A person’s size might predispose patients to developing septic complications, particularly when they have to be intubated or ventilated,” he said.

Verma and his colleagues hypothesized that low adiponectin levels might predis- pose individuals to develop sepsis and sepsis-related problems because of recent research that suggested the hormone might be a common link between inflammation, diabetes, and the metabolic syndrome. “There is a lot of literature over the last few years that indicate visceral fat is a potent source of powerful hormones. Although visceral fat secretes hormones that pro-duce inflammation, it also secretes a very protective substance and that is called adiponectin.

As people develop either diabetes or obesity of metabolic syndrome, adiponectin levels go down profoundly. In fact, there is a good correlation between the extent of obesity or diabetes or the metabolic syndrome and lower levels of adiponectin. There has been some research suggesting that adiponectin may not only have local effects within the visceral fat, but it also may be an anti-inflammatory molecule. So low adiponectin levels may not only tip the balance in favor of developing diabetes and obesity, they may also cause more systemic inflammation,” he explained.

Sepsis and sepsis-related mortality are serious potential complications following major surgery. Sepsis affects nearly 100,000 patients in the United States each year and it is the 10th leading cause of death in this country. “Sepsis-related death is a huge unmet need, particularly given that in certain parts of North America, 40 percent  to 50 percent of the population has the major risk factors of metabolic syndrome, diabetes, or obesity. We need treatments that are going to be effective and hopefully, reduce mortality rates in this high-risk population,” he concluded.