Omegaven Treatment of Parenteral Nutrition (PN) Induced Liver Injury

In the United States, patients dependent upon parenteral nutrition (PN) receive parenteral
fat emulsions composed of soybean oils. Lipids are necessary in PN dependent patients due to
their high caloric value and essential fatty acid content. They have been implicated in
predisposing patients to PN associated liver disease. Phytosterols such as those contained in
soybean oils are thought to have a deleterious effect on biliary secretion.

Children requiring prolonged PN are at risk for developing PN associated liver disease. We
hypothesize that although omega-6 fatty acid emulsions prevent fatty acid deficiency, they
are not cleared in a manner similar to enteral chylomicrons and therefore accumulate in the
liver and resulting in steatotic liver injury. We further hypothesize that a fat emulsion
comprised of omega-3 fatty acids (i.e., fish oil) such as Omegaven™ would be beneficial in
the management of steatotic liver injury by its inhibition of de novo lipogenesis, the
reduction of arachidonic acid-derived inflammatory mediators, prevention of essential fatty
acid deficiency through the presence of small amounts of arachidonic acid, and improved
clearance of lipids from the serum. Animal studies have shown that IV fat emulsions (IFE)
such as fish oil that are high in eicosapentaenic and docashexaaenoic acid reduce impairment
of bile flow which is seen in cholestasis caused by conventional fat emulsions. Intravenous
omega three fatty acids may be well tolerated and might reduce the inflammatory effect in the
liver of prolonged PN exposure and could potentially reverse any hepatic dysfunction due to
PN/IFE use. By administering Omegaven™ in place of conventional phytosterol/soybean fat
emulsions we may reverse or prevent the progression of PN associated cholestasis and thus
allow the patient to be maintained on adequate PN until they are able to ingest adequate
nutrition enterally.

Inclusion Criteria:

- Patients will be parenteral nutrition dependent and are expected to require PN for at
least another 30 days

- Patients must have parenteral nutrition associated liver disease (PNALD) as defined by
having at least 2 consecutive direct bilirubins >2 mg/dl.

Exclusion Criteria:

- Pregnancy

- Other causes of liver disease

- Enrollment in any other clinical trial involving an investigational agent (unless
approved by the designated physicians on the multidisciplinary team)

- Direct bilirubin < 2 mg/dl

- Allergy to any fish product, egg protein, and/or previous allergy to Omegaven

- Active coagulopathy characterized by on-going bleeding or acute need for clotting
factor replacement such as FFP or cryoprecipitate to maintain homeostasis

- Impaired lipid metabolism as defined by serum Tg level >400 at time of initiation of
Omegaven

- Unstable diabetes mellitus

- Recent stroke/embolism, not including catheter related thrombosis, which is a common
complication of central venous catheter.

- Collapse and shock

- Undefined coma status

- Untreated infection at time of initiation of Omegaven

- Hemodynamic instability

- > 21 years of age