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|Newsletters: PN–Associated Liver Disease and the Role of Lipid Emulsions: An Update|
Parenteral Nutrition–Associated Liver Disease and the Role of Lipid Emulsions: An Update
Kathleen M. Gura, PharmD, and Mark Puder, MD, PhD, Children’s Hospital, Boston
Updates on liver disease and Omegaven were presented by Drs. Puder and Gura at the Oley Consumer/Clinician Conference in Cape Cod in June 2007. The presentation is available on DVD (Main Session II); see order form.
Patients suffering from severe short bowel syndrome require life-saving parenteral nutrition (PN). One of the major complications of this essential therapy is PN-associated liver disease (PNALD). This liver injury particularly affects infants on long-term PN and may progress to liver failure, liver transplantation, or ultimately death. Many theories have been brought forward as to the cause(s) of this complication.
One such theory involves the role of currently used IV fat emulsions made from plant oils. The use of an alternative product derived from fish oils, Omegaven, to treat PNALD was discussed in detail in the September/October 2006 issue of LifelineLetter (available at www.oley.org or call 800-776-OLEY). Since that article was published, the process for obtaining Omegaven has been revised. That new information and other updates are provided in this issue.
Neither Omegaven nor any similar product is currently available in the United States for routine clinical use. We obtain it under our protocol at Boston Children’s Hospital for compassionate use. Compassionate approval from our institutional review board (IRB) and from the FDA is required for each patient. Practitioners who would like additional information and guidance on starting similar research protocols at their institution can contact us. (See “How Physicians Can Obtain Omegaven,” for contact information.)
Until such a product becomes available within the United States, physicians can e-mail the division of Gastroenterology and Blood Products within the FDA to get further information. (Again, please refer to “How Physicians Can Obtain Omegaven”.) This process has been simplified over the last several months as requests for the product have increased.
Since September 2004, we have treated 59 patients with PNALD with very good results. Our criteria for treatment include a direct bilirubin of greater than 2 mg/dL, no other cause of liver disease, and the need for continued treatment with PN for at least an additional 30 days. Patients whose liver disease did not reverse (two, to date) had severe liver injury showing evidence of cirrhosis or reversal of portal flow. However, such patients may still benefit from Omegaven as it will help optimize their nutrition prior to their undergoing a liver or liver-intestinal transplant.
The exclusion criteria include active bleeding and allergies to fish or eggs. Patients who are expected to be weaned off PN within 30 days would not be eligible as clinical improvement does not typically occur until after at least 30 days of therapy, with most patients experiencing normalization of their direct bilirubin within 60 days of starting Omegaven. Our clinical experience from our first 18 patients has been submitted for publication.
Theoretical risks of Omegaven include bleeding and essential fatty acid (EFA) deficiency. To date, there have not been any active cases of bleeding in our patients. Furthermore, many of our patients have undergone extensive surgical procedures after starting Omegaven without developing this complication. The EFA profiles are followed weekly and no patients have developed EFA deficiency. In fact, we have used Omegaven to treat EFA deficiency in patients with a soy allergy and are unable to receive conventional lipid products.
Based on our experience, we now start patients on Omegaven at the goal dose of 1 g/kg/day. Laboratory monitoring includes EFA profiles, hepatic enzymes, lipid panels, C-reactive protein, electrolyte, mineral, and albumin/prealbumin prior to the initiation of therapy and weekly until the bilirubin level normalizes. We then test every two weeks and then monthly. Patients may go home on this treatment and be followed as outpatients.
Although we continue to look for complications, we have not seen any directly related to this new treatment. Our central line infection rate is lower for patients on Omegaven, but this may be due to improvement in liver function and close attention to indirect markers of sepsis such as C-reactive protein and platelet counts. Patients such as Charles, who was profiled in the September/October 2006 LifelineLetter article, continue to be on Omegaven as they are gradually transitioned over to enteral feedings. Charles has now been on Omegaven for more than three years. Several other patients have been receiving Omegaven for more than one year without problems. These children are at home leading active lives with their friends and family, and many attend nursery school.
Costs of Investigational Therapy
Since Omegaven continues to be an investigational therapy, physicians must petition the FDA for permission to bill third-party payers once the sixty-day approval period has ended and they have received their emergency IND number. Adhering to this process, however, does not obligate the third-party payer to pay. In fact some third-party plans have contracts with many health care systems that specifically state that they will not pay for any investigational therapy. In such situations, the cost of therapy must be borne by the sponsoring institution.
At Children’s Hospital, Boston, the institution has agreed to fund the unreimbursed costs of Omegaven for their patients. At other centers, unrestricted payment grants have been obtained through donations. To date, we are aware of at least twenty-five other institutions in the United States and Canada that are treating their patients with Omegaven.
Despite our dramatic results, the research does not end here. Our next step is to determine if using intravenous fish oil at the start of PN nutrition can prevent the development of the often fatal complication of PNALD. The March of Dimes recently awarded us a grant to investigate this, comparing the use of Omegaven to the currently available commercial products. This three-year randomized controlled clinical trial is now underway.
Several other studies investigating the use of Omegaven in very low birth weight infants and patients awaiting liver transplant will begin within the next several months. These will be coordinated by Children’s Hospital, Boston, in conjunction with other centers around the United States.