Finding the right formula for IFALD patients

By Donavyn Coffey

Given 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.

With no one-size-fits-all approach, physician, pharmacist and dietitian experts discussed how they interpret and apply the available data on IFALD nutrition.

Finding a Formulation For Essential Nutrients

The challenge lies in ensuring patients have essential nutrients, and children get enough nutrition to grow, while avoiding toxicity. IFALD is characterized by progressive cholestasis and biliary fibrosis, and steatohepatitis in adults, after prolonged TPN (Hepatol Int 2020;14[3]:305-316). Although TPN is necessary, it’s a highrisk therapy, Dr. Gura said. Overfeeding dextrose and lipids by IV can injure the liver, she noted. Moreover, the IV catheter required to deliver nutrients puts patients at risk for infection and sepsis, which also can contribute to liver injury.

These risks exist for anyone on TPN, but for young children—premature infants especially—their immature livers can’t withstand much to begin with. So, they are “less able to tolerate [TPN] than an adult or older child,” Dr. Cohran said. Jaundice and liver injury often don’t show up in adults until the disease has progressed much further, according to Dr. Gura. In contrast, infants can start to show symptoms within three weeks of starting TPN, she said.

One of the reasons that care for IFALD patients has improved so dramatically since the early 2000s is a better understanding of how different IV lipid emulsions affect patients. For decades after the emulsions were introduced in the United States in the 1970s, no one suspected they contributed to IFALD, Dr. Gura said. That’s because patients appeared to develop IFALD with lipid emulsions and without them.

In the early 2000s, it became clear that liver disease was happening by two different mechanisms, she said. Without fat, patients would develop steatosis due to de novolipogenesis. However, patients receiving high doses of soybean oil lipid emulsions also ended up with liver disease because the emulsion can be hepatotoxic. Soybean oil emulsions are actually a very good source of essential fatty acids even when given at a low dose, Dr. Gura said. But physicians and researchers hypothesize that the emulsion lacks sufficient alpha-tocopherol or contains too many phytosterols that infants can’t

properly metabolize. It’s also possible that excessive inflammatory omega-6 fatty acids in soybean oil emulsions and reduced amount of omega-3 fatty acids may prevent hepatocytes from resisting oxidative stress, according to an FDA webinar in May 2022.

“There’s no prospective data that composite lipids”—a mixture of oil emulsions such as SMOFlipid (Fresenius Kabi), an injectable emulsion, rather than just soybean oil alone—“is different, but that’s the conventional thought,” Dr. Cohran said.

In 2013, the FDA mandated postmarketing safety studies of Nutralipid, a 20% soybean oil IV fat emulsion (B. Braun); Intralipid, an IV emulsion of soybean oil (Baxter/Fresenius Kabi); and Clinolipid, a 20% lipid injectable emulsion (Baxter). The agency called for the studies based on new data that implicated phytosterols, found in abundance in soybean oil–containing emulsions, in IFALD.

According to the FDA, phytosterols are largely unabsorbed in the gastrointestinal tract and even prevent the absorption of cholesterol. However, when infused, phytosterols can accumulate and decrease bile acid synthesis. This in turn increases the phytosterol content in bile, which can lead to cell lysis and damage hepatocytes. That damage is compounded by common 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.

A study in pigs, published in the Journal of Parenteral and Enteral Nutrition in March 2022, found normal phytosterol concentrations (such as that in Intralipid 100% soybean oil) and enriched phytosterol concentrations caused higher direct bilirubin concentrations than emulsions with depleted phytosterol content (JPEN J Parenter Enteral Nutr 2022;46[1]:160-171).

A study of neonates by Fresenius Kabi found those receiving the company’s low-phytosterol lipid emulsion, SMOFlipid, were less likely to develop parenteral nutrition–associated cholestasis (PNAC) (2/83; 2.4%), which is a precursor to IFALD, than those receiving a 100% soybean oil emulsion (9/78; 11.5%). Most cases of parenteral nutrition–associated liver disease (PNALD) occurred after 28 days, suggesting long-term use was a significant contributor (ClinicalTrials.gov Identifier: NCT02579265).

Immature enterohepatic circulation, accumulation of toxic bile acids

Prematurity Longer exposure to PN

Duration of PN

Lack of enteral feedings, small bowel bacterial overgrowth, dilated bowel

PN Component Toxicity—Lipid IFALD

Soybean-based lipid contains higher omega-6 PUFA precursors of pro-inflammatory eicosanoids and increased amounts of plant sterol

Infection Sepsis Endotoxemia CLABSI

Surgical procedures

Intestinal failure

Circulating endotoxin activates hepatic macrophages within the liver, simulates the release of pro-inflammatory cytokines

Figure. Modifiable and non-modifiable risk factors for PNALD/IFALD. ‘If there is any way I can rehabilitate the remnant bowel, I think it offers the best potential for health and improved quality of life.’

—Laura Matarese, RDN

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