phytosterols and Liver-Failure

Lipid injectable emulsions have been in clinical use for over 60 years. The first product launched was Intralipid, which consisted of an emulsion of soybean oil in water for intravenous administration. It was a key source of essential fatty acids and an alternative source of energy for patients with gastrointestinal dysfunction requiring long-term parenteral nutrition. With clinical experience, a condition known as parenteral nutrition-associated liver disease (PNALD), or intestinal failure-associated liver disease (IFALD), was observed, with a focus on carbohydrate and fat energy. Modifying the daily doses and infusion rates had some salutary effects, but PNALD persisted. Subsequently, on closer inspection of the fatty acids profile and phytosterol concentrations, degradation products arising from chemical and physical stability issues of the available lipid injectable emulsions were implicated. Recently, the US Food and Drug Administration convened an online workshop entitled "The Role of Phytosterols in PNALD/IFALD," with an emphasis on (1) the multifactorial pathophysiology of PNALD/IFALD, (2) risk associated with phytosterols, and (3) regulatory history. The scope of this review includes the multifactorial pathophysiology of PNALD/IFALD as it relates to the pharmaceutical aspects of the various lipid injectable emulsions on the market, with respect to potential proinflammatory components, as well as physical and chemical stability issues that may also affect products' safe intravenous administration to patients.

Topics: Emulsions; Fat Emulsions, Intravenous; Fish Oils; Humans; Intestinal Diseases; Liver Diseases; Liver Failure; Parenteral Nutrition; Phytosterols; Soybean Oil

Infants and children who depend on parenteral nutrition are among the most vulnerable to developing potentially devastating intestinal failure-associated liver disease. While the pathogenesis of intestinal failure-associated liver disease remains unclear, evidence for the contribution of fat emulsions to cholestasis and liver injury has rapidly increased in recent years. Data demonstrating the interaction among phytosterols, fatty acids, and antioxidants in cellular pathways that mediate bile flow and hepatic injury have led to the development of newer alternative fat emulsions. This article reviews recent studies that have provided insight into the potential hepatotoxicities of fat emulsions.

Topics: Antioxidants; Child; Cholestasis; Fat Emulsions, Intravenous; Fatty Acids; Gastrointestinal Diseases; Humans; Infant; Liver Failure; Parenteral Nutrition; Phytosterols

Plant sterols (PS) in parenteral nutrition (PN) may contribute to intestinal failure-associated liver disease. We investigated interrelations between serum PS, liver function and histology, cholesterol metabolism, and characteristics of PN.. Eleven patients with intestinal failure (mean age 6.3 years) receiving long-term PN were studied prospectively (mean 254 days) and underwent repeated measurements of serum lipids, noncholesterol sterols, including PS, and liver enzymes. PS contents of PN were analyzed. Liver biopsy was obtained in 8 patients. Twenty healthy children (mean age 5.7 years) served as controls.. Median percentage of parenteral energy of total daily energy (PN%) was 48%, including 0.9 g · kg(-1) · day(-1) of lipids. Respective amounts of PN sitosterol, campesterol, avenasterol, and stigmasterol were 683, 71, 57, and 45 μg · kg(-1) · day(-1). Median serum concentrations of sitosterol (48 vs 7.5 μmol/L, P < 0.001), avenasterol (2.9 vs 1.9, P < 0.01), stigmasterol (1.9 vs 1.2, P < 0.005), but not that of campesterol (9.8 vs 12, P = 0.22), were increased among patients in relation to controls, and correlated with PN% (r = 0.81-0.88, P < 0.005), but not with PN fat. Serum cholesterol precursors were higher in patients than in controls. Serum liver enzymes remained close to normal range. Glutamyl transferase correlated with serum PS (r = 0.61-0.62, P < 0.05). Liver fibrosis in 5 patients reflected increased serum PS (r = 0.55-0.60, P = 0.16-0.12).. Serum PS moderately increase during olive oil-based PN, and correlate positively with PN% and glutamyl transferase. Despite well-preserved liver function, histology often revealed significant liver damage.

Topics: Adolescent; Biomarkers; Case-Control Studies; Child; Child, Preschool; Cholestasis; Cholesterol; Female; Follow-Up Studies; Humans; Infant; Intestines; Lipid Metabolism; Lipids; Liver; Liver Failure; Male; Olive Oil; Parenteral Nutrition; Phytosterols; Plant Oils; Prospective Studies; Sitosterols

Parenteral nutrition is associated with liver enzyme abnormalities. Until 1993 the incidence of icterus was low in both academic hospitals in Amsterdam, the Netherlands (Academic Medical Centre (AMC) and Academic Hospital of the Free University (AZVU)). In 1993 Intralipid in the nutrition was replaced by Endolipid in the home total parenteral nutrition programme (AMC) and by Lipofundin S in AZVU. Fifty per cent of the patients in the home programme developed severe fatigue, jaundice and thrombocytopenia. These signs and symptoms disappeared over months when parenteral nutrition without fat was given. After reintroduction of Intralipid these signs and symptoms never recurred. In AZVU the incidence of jaundice increased from 21% in 1992 to 79% in 1993 (p = 0.0002). After reintroduction of Intralipid in 1994 the incidence of jaundice decreased to 16%.. Although the lipid emulsions are equivalent according to the product specification, the described observation suggests that Lipofundin S and Endolipid cause more icterus than Intralipid, possibly caused bij an impurity in the fat emulsion.

Topics: Academic Medical Centers; Adult; Cause of Death; Fat Emulsions, Intravenous; Female; Humans; Incidence; Jaundice; Liver Failure; Liver Function Tests; Male; Middle Aged; Netherlands; Parenteral Nutrition; Phytosterols; Thrombocytopenia