4 Clinical
Pharmacy Practice News • August 2022
Hepatology
Finding the Right Formula for IFALD Patients By Donavyn Coffey
With no one-size-fits-all approach, physician, pharIn the early 2000s, it became clear that liver disease macist and dietitian experts discussed how they inter- was happening by two different mechanisms, she said. pret and apply the available data on IFALD nutrition. Without fat, patients would develop steatosis due to de novo lipogenesis. However, patients receiving high Finding a Formulation doses of soybean oil lipid emulsions also ended up with For Essential Nutrients liver disease because the emulsion can be hepatotoxic. Soybean oil emulsions are actually a very good source The challenge lies in ensuring patients have essential nutrients, and children get enough nutrition to grow, of essential fatty acids even when given at a low dose, while avoiding toxicity. IFALD is characterized by pro- Dr. Gura said. But physicians and researchers hypothegressive cholestasis and biliary fibrosis, and steato- size that the emulsion lacks sufficient alpha-tocopherol hepatitis in adults, after prolonged TPN (Hepatol Int or contains too many phytosterols that infants can’t 2020;14[3]:305-316). Although ‘If there is any way I can rehabilitate TPN is necessary, it’s a highrisk therapy, Dr. Gura said. the remnant bowel, I think it offers Overfeeding dextrose and lipids the best potential for health and by IV can injure the liver, she noted. Moreover, the IV catheimproved quality of life.’ ter required to deliver nutrients puts patients at risk for infection —Laura Matarese, RDN and sepsis, which also can contribute to liver injury. These risks exist for anyone on TPN, but for young properly metabolize. It’s also possible that excessive children—premature infants especially—their imma- inflammatory omega-6 fatty acids in soybean oil emulture livers can’t withstand much to begin with. So, sions and reduced amount of omega-3 fatty acids may they are “less able to tolerate [TPN] than an adult or prevent hepatocytes from resisting oxidative stress, older child,” Dr. Cohran said. Jaundice and liver injury according to an FDA webinar in May 2022. “There’s no prospective data that composite lipids”—a often don’t show up in adults until the disease has progressed much further, according to Dr. Gura. In con- mixture of oil emulsions such as SMOFlipid (Fresenius trast, infants can start to show symptoms within three Kabi), an injectable emulsion, rather than just soybean oil alone—“is different, but that’s the conventional weeks of starting TPN, she said. One of the reasons that care for IFALD patients has thought,” Dr. Cohran said. In 2013, the FDA mandated postmarketing safety improved so dramatically since the early 2000s is a better understanding of how different IV lipid emul- studies of Nutralipid, a 20% soybean oil IV fat emulsions affect patients. For decades after the emulsions sion (B. Braun); Intralipid, an IV emulsion of soybean were introduced in the United States in the 1970s, no oil (Baxter/Fresenius Kabi); and Clinolipid, a 20% one suspected they contributed to IFALD, Dr. Gura lipid injectable emulsion (Baxter). The agency called said. That’s because patients appeared to develop for the studies based on new data that implicated phytosterols, found in abundance in soybean oil–containIFALD with lipid emulsions and without them. ing emulsions, in IFALD. According to the FDA, phytosterols are largely unabImmature enterohepatic sorbed in the gastrointestinal tract and even prevent Longer exposure to PN circulation, accumulation the absorption of cholesterol. However, when infused, of toxic bile acids phytosterols can accumulate and decrease bile acid Duration of PN synthesis. This in turn increases the phytosterol conPrematurity tent in bile, which can lead to cell lysis and damage Lack of enteral feedings, small bowel bacterial hepatocytes. That damage is compounded by common overgrowth, dilated bowel conditions in neonates such as gut resection, sepsis and immaturity, according to an FDA webinar presentation by Camelia Martin, MD, the chief of newborn medicine at Weill Cornell Medicine, in New York City. PN Component A study in pigs, published in the Journal of Parenteral Toxicity—Lipid and Enteral Nutrition in March 2022, found normal phytosterol concentrations (such as that in Intralipid Soybean-based lipid contains 100% soybean oil) and enriched phytosterol concenhigher omega-6 PUFA trations caused higher direct bilirubin concentrations Infection precursors of pro-inflammatory Sepsis than emulsions with depleted phytosterol content eicosanoids and increased Endotoxemia amounts of plant sterol (JPEN J Parenter Enteral Nutr 2022;46[1]:160-171). CLABSI A study of neonates by Fresenius Kabi found those Surgical procedures receiving the company’s low-phytosterol lipid emulCirculating endotoxin sion, SMOFlipid, were less likely to develop parenteral activates hepatic nutrition–associated cholestasis (PNAC) (2/83; 2.4%), macrophages within the Intestinal failure which is a precursor to IFALD, than those receiving a liver, simulates the release of 100% soybean oil emulsion (9/78; 11.5%). Most cases of pro-inflammatory cytokines parenteral nutrition–associated liver disease (PNALD) Figure. Modifiable and non-modifiable risk factors for PNALD/IFALD. occurred after 28 days, suggesting long-term use was a significant contributor (ClinicalTrials.gov Identifier: CLABSI, central line bloodstream infection; IFALD, intestinal failure–associated liver disease; PN, parenteral nutrition; PUFA, polyunsaturated fatty acids. Source: FDA Workshop on the Role of Phytosterols in PNALD/IFALD (bit.ly/3A4RWqu). NCT02579265).
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iven the role many pharmacists play in managing orphan disease medications, it’s important for them to understand the interplay between intestinal failure–associated liver disease (IFALD) and parenteral nutrition (PN)—a relationship that could significantly affect clinical outcomes, according to several nutrition experts. At least one IFALD drug in the pipeline, if approved, is projected to receive orphan drug designation. So keeping an eye on drug development also is key. But the PN component of care requires more immediate attention, according to Kathleen Gura, PharmD, the board director at the American Society for Parenteral and Enteral Nutrition (ASPEN). In the 40 years Dr. Gura has been studying IFALD, academic centers identified many potential contributing factors to the disease’s development, including the microbiome and the oil content of the IV fat emulsions. Physicians created nutritional strategies that allow these vulnerable patients to improve. Over time, they can even come off TPN entirely. “When you look at how we care for these children, we are doing much better than 20 to 25 years ago,” said Valeria Cohran, MD, the director of intestinal rehabilitation at The Ann & Robert H. Lurie Children’s Hospital, in Chicago. However, the evidence on the nutritional strategies used in this patient group remains scant. It’s a small, heterogeneous group and each patient’s treatment varies based on their unique intestinal anatomy. Furthermore, in her four decades working in intestinal rehabilitation, Laura Matarese, RDN, a researcher and dietitian at ECU Health, in Greenville, N.C., said she had never had any two patients who were exactly alike. In addition, liver biopsies are nearly impossible to safely perform in infants, according to Dr. Gura. “It’s very, very dangerous; they could potentially bleed to death,” she said.
IFALD
see IFALD, page 6
