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STAT

An MUSC blog
Keyword: liver transplant

Placement of a single, coated, self-expanding metallic stent achieved similar rates of resolution of benign pancreatobiliary strictures as placement of multiple plastic stents, the current standard of care, and required fewer sessions of endoscopic retrograde cholang­iopancreatography, according to the results of a randomized controlled trial led by an endoscopist at the Medical University of South Carolina and reported in the March 22 JAMA.

Pictured above: MUSC Health endoscopist Gregory A Coté, M.D., performing ERCP

Placement of a single covered, self-expanding metallic stent (cSEMS) via endoscopic retrograde cholang­iopancreatography (ERCP) resolved benign obstructions of the pancreatic and biliary ducts as well as placement of multiple plastic stents, the current standard of care, and required fewer ERCP sessions, according to the results of a randomized controlled trial reported in the March 22, 2016 issue of the Journal of the American Medical Association. These findings will change practice in the opinion of Gregory A. Coté, M.D., an endoscopist at the Digestive Disease Center at the Medical University of South Carolina, lead author of the article, and the national principal investigator for the eight-center study. B. Joseph Elmunzer, M.D., of the MUSC Digestive Disease Center is also a co-author.

“For appropriately selected patients who are presenting the first time with a blockage, many endoscopists will change their strategy and use these newer stents, in an effort to reduce the total procedures that are required,” says Coté.

For now, the use of cSEMS (pictured below right) in benign biliary strictures would be off-label, as they have been approved by the U.S. Food and Drug Administration only for the treatment of malignant pancreatobiliary strictures, such as those which develop in the setting of unresectable pancreatic cancer.

Left untreated, benign biliary strictures can lead to jaundice, cholangitis (i.e., infection of the bile duct), and secondary biliary cirrhosis. Benign strictures most often occur after liver transplantation and gallbladder surgery or as a result of chronic pancreatitis. ERCP is preferred to surgery in these patients because it is less invasive.

ERCP is an endoscopic procedure in which a camera is introduced through the mouth and advanced first to the proximal duodenum and then, using endoscopy and fluoroscopy, into the pancreatic and bile ducts.  Although highly effective, three to four ERCP sessions are typically required to fully stretch the blockage and minimize the chance of recurrence once the stents are removed.  Because ERCP is not without its risks—complications include pancreatitis, infections, bowel perforation, and bleeding—minimizing the number of sessions needed to successfully treat the stricture benefits patients. Coté designed the trial to determine whether using the larger cSEMS could successfully treat benign strictures with fewer ERCP sessions. cSEMS are coated to prevent in-growth of tumor or other tissue and to facilitate removal.

The primary endpoint of the trial, which enrolled 112 patients, was the rate of benign stricture resolution after no more than 12 months of stenting. cSEMS were found to be noninferior to plastic stents for achieving stricture resolution and they did so more quickly (181 vs. 225 days) and with fewer ERCP sessions (2.14 vs. 3.24). It should be noted that the study had careful enrollment criteria; patients with small (<6 mm) bile ducts and those with intact gall bladders were excluded. “We were careful not to cross the gall bladder insertion into the bile duct in patients who still have their gall bladder because you don’t want to block the gall bladder and potentially create a new problem,” says Coté.

The procedure can be performed by anyone proficient in ERCP but best results will likely be seen when it is performed by a high-volume provider (2-3 ERCPs per week) who is comfortable placing and removing cSEMS.

“We can’t universally change practice based on these findings, but, in appropriately selected patients with benign pancreatobiliary strictures, deployment of cSEMS via ERCP should be first-line treatment,” says Coté.

fatty liver disease image 3

In results published on October 19, 2015 in the Journal of Lipid Research (http://dx.doi.org/10.1194/jlr.M063511), a team of translational scientists at the Medical University of South Carolina (MUSC) report a new reason why non-alcoholic steatohepatitis (NASH) worsens in people who are obese. The results may help prevent cirrhosis and liver cancer, according to co-senior authors Kenneth D. Chavin, M.D., Ph.D., a transplant surgeon in the MUSC Health Department of Surgery, and Lauren Ashley Cowart, Ph.D., Associate Professor in the Department of Biochemistry and Molecular Biology and Co-Director of the MUSC Center of Biomedical Research Excellence in Lipidomics and Pathobiology.

 NASH (also called non-alcoholic fatty liver disease) has become a major cause of liver disease requiring transplant. “In my 17 years of doing liver transplants, it’s gone from 4% of patients to around 20% of patients who get transplants because of NASH,” says Chavin. “In 10-15 years, because of advances with Hepatitis C, it will probably become the number one reason why patients get transplants.”

When excess dietary fats are consumed over time, fat deposits form in the liver and NASH can develop. Early-stage NASH is typically not associated with any physical symptoms; nearly 30% of people in the U.S. have it. Though obesity is correlated with the development of NASH, the team wanted to know exactly why NASH worsens to a stage requiring transplant in certain obese people. “Obesity doesn’t cause disease in every obese person and we don’t understand why it does in some but not others,” explains Cowart.

The team suspected that inflammation stemming from a lipid molecule called sphingosine-1-phosphate (S1P) might be responsible. They’d previously discovered in other organs that S1P is increased by excess dietary saturated fat.

Chavin took biopsies from human livers during transplant surgery and supplied them to Cowart, who determined the levels of sphingosine kinase 1, the enzyme that makes S1P. They found double the normal amount of sphingosine kinase 1 in livers of obese people with non-alcoholic steatohepatitis.

The team wanted more understanding of why S1P causes inflammation, but NASH has previously been difficult to mimic in the laboratory setting. They developed a new and highly improved preclinical model of NASH, wherein mice were fed on custom-designed diets of either high saturated fat or high unsaturated fat. Curiously, mice on each type of diet became obese, but only mice on the saturated fat diet developed inflammation and NASH-like pathology stemming from S1P. Taking the human and pre-clinical studies together, it’s likely that saturated fat, but not unsaturated fat, raises S1P levels in obese people, and it’s S1P that unleashes the inflammation that characterizes NASH.

Performing lipid studies in the laboratory is not easy—most biochemistry is water-based, and fat and water don’t easily mix. The group relied on the MUSC Sphingolipidomics Core laboratory, one of only a handful of such facilities in the country capable of developing the new methods needed to examine S1P for their study. Without lipidomics, we never would have understood that saturated fats activate this pathway,” says Cowart. The team is working to identify the S1P receptors responsible for inflammation in NASH, with the ultimate goal of designing treatments to prevent the need for a liver transplant in obese patients with NASH.

Does this work support the idea that it’s the type of fat, but not all fat, that leads to health problems? After all, mice fed a high unsaturated fat diet still became obese but were metabolically healthy. “Because the unsaturated fat diet didn’t cause NASH, it may provide a clue as to what actually links obesity to disease,” says Cowart. “Even if it’s difficult to lose weight, dietary modifications might prevent some disease associated with obesity.”

 MUSC researchers Tuoyu Geng, Ph.D., Alton Sutter, M.D.,Ph.D., Arun Palanisamy Ph.D., and Michael D. Harland also contributed to this study.

 This work was supported by a Veterans Affairs Merit Award, National Institutes of Health Grants 1R01HL117233 and 5P30GM103339-03 (L.A.C.), and National Institutes of Health Grant 1R01DK069369 to K.D.C .

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