by Anna Gonski
Research is not typically a field for people who like instant gratification. There are long waits as cultures grow, proteins crystallize and cells divide. And when a discovery finally becomes something tangible, like a medication, it can still take years of testing and government approvals before a patient can benefit from it. But sometimes, when the right pieces fit together in just the right way, and when the right people are willing to take a chance, the process can be accelerated.
Just ask Alyson Rolfe, whose infant son was waiting for a transplant and likely to die, until Children's Hospital Boston surgeon Mark Puder, MD, tried a simple intervention—one that decades of experience said wouldn't work.
Puder first learned about 5-month-old Charles Rolfe from his surgical colleague, Rusty Jennings, MD. Charles had been born with gastroschisis, an opening in the abdominal wall that caused his intestines to develop outside his body. Jennings, who directs Children's Advanced Fetal Care Center, had been following Charles's case even before he was born.
"After he was delivered, we took him straight to the operating room to try and save his bowels, which were literally hanging on by a blood vessel," Jennings says.
While in the OR, Jennings determined that all Charles had left was his duodenum (the short piece of bowel that connects the stomach to the jejunum) and half of his colon, a sign that his gastroschisis had caused short bowel syndrome. So the surgical team performed a serial transverse enteroplasty (STEP) procedure, a new surgical technique developed at Children's, to lengthen his diminished bowel.
But Charles's problems were only beginning. After the operation, he was placed on parenteral nutrition (PN), an intravenous method of feeding. Because his intestines could not yet break down or absorb essential nutrients, Charles couldn't yet feed on his own. Instead, PN would provide the necessary nutrition until his remaining intestine adapted and took on the absorption functions that were lost.
PN has revolutionized treatment for short bowel syndrome. But its prolonged use often damages the liver, potentially leading to liver failure and the need for transplant. And unfortunately, infants are at the greatest risk due to the small size of their livers.
"We didn't realize how bad Charles was actually getting—we didn't see the signs, nor were we looking for them," Alyson recalls. "When I look back at some of the pictures taken of him at that time, I can see it more clearly. Charles's liver was beginning to fail due to the PN. What was keeping him alive was now killing him."
Why does PN damage the liver? For the past three years, Puder and his team toiled with this question, which has bedeviled medicine for decades.
PN supplies nutrition through two separate solutions—one comprised of carbohydrates, proteins, vitamins and minerals, and the other of plant-derived fat (lipid). The solutions are given simultaneously through a catheter inserted into a vein.
In trying to figure out what was causing PN to damage the liver, some researchers, like Children's Judah Folkman, MD, and Robert Shamberger, MD, hypothesized that the injury was due to a missing nutrient that is present in regular food. Others thought that individual components of the solutions themselves might be to blame. Over the years, each theory was ruled out, including the one that eventually helped Puder save Charles Rolfe's life.
In 2001, surgical resident Jenna Garza, MD, became interested in PN-related liver damage, and asked Puder to supervise her research in mice. Puder agreed. Pharmacist Kathleen Gura, PharmD, who had been involved in a study by Folkman and Shamberger, also joined the project, supplying the PN solutions.
The team focused on the lipid portion of PN. They first gave one group of mice PN without the lipid, but instead of getting it intravenously, the mice ingested it orally for 19 days. Another group of mice received PN with Intralipid (the standard lipid supplement composed mostly of soybean oil), both taken orally. And a third group was given oral PN with intravenous Intralipid. The results were dramatic.
"PN without the lipid caused excess fat in the liver and fatty acid deficiency, leading to liver injury," says Puder. "And while it didn't trigger fatty acid deficiency when combined with intravenous Intralipid, the fatty liver changes were even worse. But interestingly, Intralipid given orally prevented liver damage altogether."
"Everyone knows you treat fatty acid deficiency with fat," Puder adds. "But the difference in the way the lipid was delivered and the results we saw told us that the lipid itself was the key."
In addition to the method of administration, the team suspected that the type of lipid was important. "I had previously used Omegaven, an omega-3 fatty acid supplement made with fish oil, to treat a soy-allergic patient with severe fatty acid deficiency," says Gura. "The omega-3 may have saved the patient's life, so I thought, Why not try it in mice?"
Based on Gura's experience, Puder's team recreated their initial experiment, but changed the lipid they were using to Omegaven. The mice receiving Omegaven—whether given orally or intravenously—were completely free of liver injury. "The Omegaven prevented fatty acid deficiency and fatty liver," recalls Puder. "The livers looked near-perfect."
He and his team found that parenteral nutrition without the fat makes the liver fatty, and by adding the Intralipid, it becomes even more so. "That fat becomes more or less a fuel that burns the liver, causing it to become inflamed," Puder explains. "But the Omegaven is an anti-inflammatory lipid that prevents fat build-up in the liver. So if there's no fuel—fat—there's no fire—injury."
The team had found a fat that could safely be given intravenously, a potential boon for patients like Charles who are not yet able to eat anything by mouth.
Fortunately for Puder, he's not an expert on PN, or he might have ruled out the lipid as the problem from the beginning.
"It's funny because I approached the research from a biochemical standpoint, breaking PN into many pieces," says Puder. "But one of things I didn't do was read the literature to find out what everyone else was already thinking."
In fact, Puder didn't realize what everyone else was thinking until he began telling people about his observations, and they, in turn, began telling him he was wrong.
"When researchers took the lipid out of PN, and it still caused liver injury, they probably assumed that some other part of the PN preparation was the culprit," he says. "They never thought to question the type of lipid they were using."
Charles Rolfe's situation was becoming desperate. Despite his failing liver, he could not be taken off PN because it was the only way he could receive nourishment.
"Charles underwent six major abdominal procedures, and each time we took a biopsy of his liver," says Jennings. "It got more and more damaged, to the point where he needed a liver and small bowel transplant soon or he would die. And since he was so small, we knew the chances of finding a suitable donor were pretty slim."
Jennings listed Charles for a transplant, but after hearing of Puder's research, he appealed to his fellow surgeon to "save my baby."
"I told Rusty that I truly didn't know if it would work," recalls Puder. "But he was insistent that we try."
Since Omegaven is already approved for various other conditions in Europe, Puder didn't have to wait long to put it to use. He got approvals from Children's Institutional Review Board and the Food and Drug Administration for compassionate use of Omegaven for Charles.
The final step was talking to the baby's parents. "I told them that there were three potential outcomes—that it would make him worse, keep him the same or make him better," says Puder. "And I told them that I actually hoped they would say no, because in my head I was still hearing, 'Everyone knows it's not the lipid.'"
But the Rolfes didn't need any further convincing. "Dr. Puder had done a lot of research, so we took the option," says Alyson. "We figured that if this could potentially save Charles's life, it was silly not to at least try. And we just kept hoping it would work, because it had to."
On September 26, 2004, Charles became the first baby in the world to receive Omegaven as the sole lipid in his PN solution. He quickly began to recover. "We saw some improvement within the first week," says Gura. "And now, his labs show that his liver is functioning perfectly." A little more than a month after his first dose of Omegaven, Charles was taken off the transplant waiting list.
Now 2 years old, Charles receives an 11-hour infusion of Omegaven with his PN three nights a week. He's monitored closely for possible side effects, but so far hasn't shown any. "He's even tolerating some oral feeds these days," says Jennings. "Now that we've bought him some time with the Omegaven, we're hoping the STEP procedure will work and his bowels will learn how to digest food properly so he can get the nutrients he needs on his own."
"The lipids played a huge part in saving Charles's life," adds Alyson. "It's been an extremely difficult road, and it's certainly not over, but he's doing really well."
Since Charles, 21 more Children's patients have received Omegaven as the lipid in their TPN under compassionate-use guidelines, and most have done well. Puder and his team published a case study on Charles and another patient receiving Omegaven in the July issue of Pediatrics. Now, they're actively trying to get a clinical trial off the ground at Children's, with funding from the March of Dimes.
Even though his findings go against what was considered accepted medical fact, Puder is receiving inquiries from hospitals around the world. And what does this surgeon think now that he's discovered a treatment that could save patients from needing donated organs? "I'm hoping we can start putting transplant services out of business," he says.
To learn more about supporting gastroenterology at Children's
Hospital Boston, contact Phyllis Simpkins in the Children's Hospital Trust at (617) 355-2427 or phyllis.simpkins@chtrust.org.
