Last week, a headline in the Boston Globe—“How fish oil may have saved babies' lives”—grabbed our attention. And the article it advertised proved even more compelling than its dramatic but cautious tone implied.
After reading the published scientific report from the doctors involved (Gura KM 2006), it was clear that the caution represented by the words “may have” in the Globe’s headline were an unwarranted instance of journalistic timidity.
It seems that the medical community’s failure to appreciate fully the distinction between the two categories of polyunsaturated fatty acids—omega-6 from common vegetable oils and omega-3 from fish oils and uncommon seed oils—has harmed countless patients with dysfunctional digestive tracts.
Thankfully, an intrepid team of doctors and pharmacists in Boston took a leap of faith and reason, based on prior animal research and innovative European practices.
And by taking that plunge they’ve dramatically improved the prospect that Americans who require intravenous nutrition can get it without losing their livers—and possibly their lives—in the bargain.
Intravenous nutrition and liver failure
Premature infants—so-called “premies”—and adults with serious intestinal dysfunctions must receive liquid nutrition formulas via intravenous lines. This kind of intervention is called total parenteral nutrition or TPN. (“Parenteral” means “outside the intestines”.)
Premature babies require TPN because their intestinal tracts are underdeveloped, which prevents them from being able to digest and absorb nutrients from their mother’s milk or standard infant formulas.
However, TPN frequently causes unstable blood sugar or salt levels and inadequate nutrition in premie babies. But the most dangerous drawback to prolonged use of TPN is damage to the infant’s liver and eventual liver failure that necessitates a life-saving liver transplant.
Standard TPN formulas deliver a mixture of sugar (glucose), salts, protein, vitamins, minerals, and an omega-6 fatty acid called linoleic acid, derived from plant oils.
Today, most infant formulas contain DHA—an omega-3 fatty acid from fish oil—as well as omega-6 fatty acids, because DHA is critical to ensuring optimal brain and eye development. But even though it is well known that humans require both types of essential fatty acid to thrive, TPN formulas used in the U.S. contain only omega-6 linoleic acid.
Thanks to an initiative by doctors in Boston—who were desperate to save a baby’s liver and life—this error may get corrected soon.
The background to a big medical breakthrough
The story of the new breakthrough began 16 years ago, when famed researcher Judah Folkman, M.D. of Boston’s Children's Hospital—who discovered the anti-cancer potential of anti-angiogenesis drugs—conducted a study in rats (Whalen GF 1990).
Dr. Folkman and his colleague Robert Shamberger, M.D. knew about the serious problem of liver failure in premature babies receiving TPN, and were experimenting with rats to see if they could pinpoint a cause or cure.
They discovered that when they gave rats a little “rat chow” in addition to an intravenous TPN formula, the animals did not suffer the liver damage usually seen when they were only given a standard TPN formula that contained omega-6 fatty acids.
All that Drs. Folkman and Shamberger knew was that the liver-saving constituent in the rat chow was soluble in chloroform but not water, which suggested that it might be a fatty acid. Although the rat chow contained a small amount of omega-3 fatty acid, they did not identify these fish-derived fats as the liver-saving agent in the chow, and moved on to other matters.
A life-saving leap of faith … and reason
The saga picks up again in 2001 when Dr. Jennifer Garza—a surgical fellow at Children's Hospital Boston (CHB)—was concerned about the problem of premature babies born with a severe bowel disorder called necrotizing enterocolitis, many of whom suffer liver failure. (Children's Hospital Boston is the primary pediatric teaching hospital of Harvard Medical School.)
Mark Puder, M.D., PhD was supervising Dr. Garza’s research when they found evidence that the fat formula used in standard TPN solutions was contributing to liver disease by causing fat to accumulate in the liver. The fat formula, called Intralipid®, is made from soybean oil and delivers pro-inflammatory omega-6 fatty acids and no omega-3s.
During a staff meeting, Dr. Folkman mentioned the rat study he and Dr. Shamberger had published in 1990. So, together with pharmacist Kathy Gura, Drs. Garza and Puder decided to repeat Dr. Folkman’s experiment, using Omegaven®—an intravenous fat mixture made from omega-3-rich fish oil—in the rodents’ TPN in place of omega-6-rich Intralipid®.
Prior research had already proven that the omega-3 fatty acids like those used in Omegaven® prevent fat accumulation in the liver and possess anti-inflammatory properties. As the CHB team hoped, the TPN formula containing Omegaven prevented fat accumulation and liver injury in the experimental rodents.
Some time later, Dr. Puder's partner—surgeon Russell “Rusty” Jennings—was treating 5 1/2-month-old Charles Rolfe of Mashpee, Massachusetts, who’d been born prematurely with a congenital defect in which the intestines develop outside the body. Charles was unable to feed normally and was put on standard TPN, which caused his liver to begin failing. Dr. Jennings was aware of the experiment using Omegaven in rats, and asked Dr. Puder to help him save the baby.
But while Omegaven was being used in Europe, it wasn't approved for use in the U.S., so Dr. Puder had to request special permission, under the U.S. Food and Drug Administration’s “compassionate-use” exception. Fortunately, the FDA and the hospital’s institutional review board agreed to let him try omega-3-rich Omegaven instead of omega-6-rich Intralipid in the sick baby’s TPN solution.
Dr. Puder and his colleagues had to estimate the Omegaven (omega-3) dosage, but the leap of faith—backed by sound reasoning—worked, and Charles’ laboratory tests normalized within two months. Charles is now two years old, and while he still receives TPN, he no longer needs a liver transplant.
The Boston team later treated a second premature baby—Austin DuPonte—who also experienced a complete liver cure. Austin's mother Joanne told the Globe that her son would most likely have died without Omegaven: “[Austin] had every single preemie thing you could have go wrong … I 100 percent attribute Austin's recovery and how well he's doing to Omegaven."
So far, 21 patients at Children's Hospital have received Omegaven as the fat portion of their TPN under FDA compassionate-use exceptions, and most have done well. Only two have died, from causes unrelated to their TPN or livers.
Dr. Puder and his colleagues hope to conduct a formal clinical trial, and have received funding from the March of Dimes intended to help their research into preventing liver disease in children on TPN.
Sources
· Gura KM, Duggan CP, Collier SB, Jennings RW, Folkman J, Bistrian BR, Puder M. Reversal of parenteral nutrition-associated liver disease in two infants with short bowel syndrome using parenteral fish oil: implications for future management. Pediatrics. 2006 Jul;118(1):e197-201. Accessed online July 8, 2006 at http://pediatrics.aappublications.org/cgi/content/full/118/1/e197
· Whalen GF, Shamberger RC, Perez-Atayde A, Folkman J. A proposed cause for the hepatic dysfunction associated with parenteral nutrition. J Pediatr Surg. 1990 Jun;25(6):622-6.
· Children's Hospital Boston. The Right Kind of Oil: An answer to a medical mystery: why does prolonged IV feeding cause liver damage? Accessed online July 8, 2006 at http://www.childrenshospital.org/newsroom/Site1339/mainpageS1339P1sublevel222.html.
· Cooke R. How fish oil may have saved babies' lives. The Boston Globe, July 3, 2006. Accessed online July 8, 2006 at http://www.boston.com/news/globe/health_science/articles/2006/07/03/how_fish_oil_may_have_saved_babies_lives/
· Mayer K, Meyer S, Reinholz-Muhly M, Maus U, Merfels M, Lohmeyer J, Grimminger F, Seeger W. Short-time infusion of fish oil-based lipid emulsions, approved for parenteral nutrition, reduces monocyte proinflammatory cytokine generation and adhesive interaction with endothelium in humans. J Immunol. 2003 Nov 1;171(9):4837-43.
· Alwayn IP, Gura K, Nose V, Zausche B, Javid P, Garza J, Verbesey J, Voss S, Ollero M, Andersson C, Bistrian B, Folkman J, Puder M. Omega-3 fatty acid supplementation prevents hepatic steatosis in a murine model of nonalcoholic fatty liver disease. Pediatr Res. 2005 Mar;57(3):445-52. Epub 2005 Jan 19.
· Nussbaum MS, Li S, Bower RH, McFadden DW, Dayal R, Fischer JE. Addition of lipid to total parenteral nutrition prevents hepatic steatosis in rats by lowering the portal venous insulin/glucagon ratio. JPEN J Parenter Enteral Nutr. 1992 Mar-Apr;16(2):106-9.
· Oshita M, Takehara H, Yamaguchi M, Doi K, Ueda N, Naito S, Hiraoka I, Tashiro S. Significance of administration of fat emulsion: hepatic changes in infant rats receiving total parenteral nutrition with and without fat. Clin Nutr. 2004 Oct;23(5):1060-8.
· Li SJ, Nussbaum MS, McFadden DW, Dayal R, Fischer JE. Reversal of hepatic steatosis in rats by addition of glucagon to total parenteral nutrition (TPN). J Surg Res. 1989 Jun;46(6):557-66.
