phytosterols and Liver-Diseases

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

Non-cholesterol sterols are validated biomarkers for intestinal cholesterol absorption and endogenous cholesterol synthesis. However, their use in metabolic disturbances has not been systematically explored. Therefore, we conducted a systematic review to provide an overview of non-cholesterol sterols as markers for cholesterol metabolism in different metabolic disorders. Potentially relevant studies were retrieved by a systematic search of three databases in July 2018 and ninety-four human studies were included. Cholesterol-standardized levels of campesterol, sitosterol and cholestanol were collected to reflect cholesterol absorption and those of lathosterol and desmosterol to reflect cholesterol synthesis. Their use as biomarkers was examined in the following metabolic disorders: overweight/obesity (

Topics: Biomarkers; Cardiovascular Diseases; Cholesterol; Desmosterol; Diabetes Mellitus; Humans; Intestinal Absorption; Intestinal Diseases; Kidney Diseases; Liver Diseases; Metabolic Diseases; Obesity; Overweight; Phytosterols; Sitosterols; Sterols

Parenteral nutrition and intravenous lipid emulsions are essential for promoting optimal nutrition in the neonatal intensive care unit. However, long-term use of a pure soybean lipid emulsion is associated with a liver disease known as intestinal failure associated liver disease. Over the past several years, the science of lipid emulsions has evolved with a focus on nutritional optimization and disease prevention. This review's purpose is to provide a general overview of the three main components of lipid emulsions, phytosterols, the antioxidant Vitamin E, and polyunsaturated fatty acids, and their contribution to health.

Topics: Dietary Fats; Fat Emulsions, Intravenous; Gastrointestinal Diseases; Humans; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Intensive Care Units, Neonatal; Intestinal Absorption; Intestines; Liver Diseases; Parenteral Nutrition; Phytosterols; Randomized Controlled Trials as Topic; Risk Assessment; Soybean Oil; Vitamin E

Parenteral nutrition is a life-saving therapy for infants with intestinal failure. However, long-term parenteral nutrition carries the risk of progressive liver disease. Substantial data has implicated components of parenteral soybean oil in the pathogenesis of parenteral nutrition-associated liver disease (PNALD). Elevated serum concentrations of phytosterols, an abundance of omega-6 polyunsaturated fatty acids, and a relative paucity of α-tocopherol have been associated with the risk of cholestasis and hepatic injury observed in PNALD. Currently available treatment strategies include the reduction of the dose of administered parenteral soybean oil and/or the replacement of parenteral soybean oil with alternative parenteral lipid emulsions. The purpose of this review is to provide an overview of the pathogenetic mechanisms associated with the development of PNALD and the data evaluating currently available treatment strategies.

Topics: alpha-Tocopherol; Cholestasis; Dietary Fats; Fat Emulsions, Intravenous; Fatty Acids, Omega-6; Humans; Intestinal Diseases; Liver; Liver Diseases; Parenteral Nutrition; Phytosterols; Soybean Oil

Abnormalities of liver function tests are common in patients with intestinal failure receiving parenteral nutrition. Lipid emulsions have been implicated in the development of hepatobiliary disease in patients receiving parenteral nutrition.. Lipid emulsions with reduced polyunsaturated fatty acids and specific ω6 : ω3 fatty acid ratios have been shown to have some beneficial effects on liver function, although the studies are small and generally of short duration in paediatric and adult patients.. There is good evidence to suggest that the parenteral lipid dose should be less than 1 g/kg body weight/day, but this may not apply to all patients. The evidence is presented for the different lipid emulsions and their effect on liver function. The benefit of these emulsions compared with simply giving a lower lipid dose has yet to be studied.

Topics: Antioxidants; Emulsions; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fish Oils; Humans; Lipids; Liver Diseases; Liver Function Tests; Olive Oil; Parenteral Nutrition; Phytosterols; Plant Oils; Risk Factors; Soybean Oil; Triglycerides

Long-term parenteral nutrition of infants who have had major gut resections is associated with a high incidence of cholestatic liver disease. Affected infants have high plasma concentrations of phytosterols--compounds that resemble cholesterol but have an alkylated side chain. The phytosterols that accumulate in patients receiving parenteral nutrition are derived from the soya oil and/or soya lecithin used to make the intravenous lipid emulsion. There is a striking association between phytosterolemia and cholestatic liver disease. This has led us to put forward the hypothesis that phytosterols can cause cholestasis in susceptible infants. Experiments using neonatal piglets indicate that phytosterols (given without any of the other components of parenteral nutrition) can indeed reduce bile flow. We suggest that increasing the content of phytosterols in cell membranes may interfere with the function of important transport proteins involved in the secretion of bile. Other factors that might contribute to cholestasis (such as inhibition of cholesterol 7 alpha-hydroxylase) are discussed.

Topics: Bile; Cell Membrane; Child; Child, Preschool; Fat Emulsions, Intravenous; Humans; Infant; Liver Diseases; Parenteral Nutrition; Phytosterols

Non-cholesterol sterols are validated markers for fractional intestinal cholesterol absorption (cholestanol) and endogenous cholesterol synthesis (lathosterol). This study's objective was to evaluate markers for cholesterol synthesis and absorption in children exposed to two different intravenous lipid emulsions that rapidly change serum plant sterol concentrations as part of their parenteral nutrition (PN).. Serum samples from two different studies were used: (1) nine PN-dependent children with intestinal failure associated liver disease (IFALD) whose soy-based, plant sterol-rich lipid (SO) was replaced with a fish-based, plant sterol-poor (FO) lipid; and (2) five neonates prescribed SO after birth. In the first study, samples were collected at baseline (prior to FO initiation) and after 3 and 6 months of FO. In study 2, samples were collected at 1 and 3 weeks of age.. In study 1, a 7-fold reduction in campesterol, a 12-fold reduction in sitosterol, and a 15-fold reduction in stigmasterol was observed 6 months after switching to FO. Serum cholesterol concentrations did not change, but cholesterol-standardized lathosterol increased (3-fold) and cholesterol-standardized cholestanol decreased (2-fold). In study 2, after 3 weeks of SO, sitosterol and campesterol concentrations increased 4-5 fold. At the same time, cholesterol-standardized lathosterol increased 69% and cholesterol-standardized cholestanol decreased by 29%.. Based on these finding we conclude that changes in serum plant sterol concentrations might have direct effects on endogenous cholesterol synthesis, although this needs to be confirmed in future studies. Moreover, we speculate that this changed synthesis subsequently affects intestinal cholesterol absorption.

Topics: Animals; Biomarkers; Child; Child, Preschool; Cholesterol; Fat Emulsions, Intravenous; Female; Fish Oils; Humans; Infant; Infant Nutritional Physiological Phenomena; Infant, Newborn; Intestinal Absorption; Intestinal Diseases; Liver; Liver Diseases; Male; Parenteral Nutrition; Parenteral Nutrition Solutions; Phytosterols; Soybean Oil

Soybean oil (SO) emulsions are associated with intestinal failure-associated liver disease (IFALD); fish oil (FO) emulsions are used to treat IFALD. SO and FO differ with respect to their fatty acid and phytosterol content. In children with IFALD whose SO was replaced with FO, we aimed to (1) quantify changes in erythrocyte fatty acids and plasma phytosterols, cytokines, and bile acids and (2) correlate these changes with direct bilirubin (DB).. This study enrolled IFALD children who received 6 months of FO. Blood samples were collected prior to FO, and after 2 weeks and 3 and 6 months of FO. The primary outcome was 3-month vs baseline biomarker concentrations.. At study initiation, the median patient age was 3 months (interquartile range, 3-17 months), and mean ± standard deviation DB was 5.6 ± 0.7 mg/dL (n = 14). Cholestasis reversed in 79% of subjects. Eicosapentaenoic and docosahexaenoic acid was greater than baseline (P < .001, all time points). Linoleic and arachidonic acid and sitosterol and stigmasterol were less than baseline (P < .05, all time points). Three- and 6-month interleukin-8 (IL-8) and total and conjugated bile acids were less than baseline (P < .05). Baseline IL-8 was correlated with baseline DB (r = 0.71, P < .01). Early changes in stigmasterol and IL-8 were correlated with later DB changes (r = 0.68 and 0.75, P < .05).. Specific fat emulsion components may play a role in IFALD. Stigmasterol and IL-8 may predict FO treatment response.

Topics: Bile Acids and Salts; Cholestasis; Cytokines; Erythrocyte Membrane; Fat Emulsions, Intravenous; Fatty Acids; Fatty Acids, Omega-3; Female; Fish Oils; Gastrointestinal Diseases; Humans; Infant; Liver Diseases; Male; Phytosterols; Prospective Studies; Soybean Oil

Parenteral nutrition (PN) in preterm infants leads to PN-associated liver disease (PNALD). PNALD has been linked to serum accumulation of phytosterols that are abundant in plant oil but absent in fish oil emulsions.. Whether modifying the phytosterol and vitamin E composition of soy and fish oil lipid emulsions affects development of PNALD in preterm pigs.. We measured markers of PNALD in preterm pigs that received 14 days of PN that included 1 of the following: (1) Intralipid (IL, 100% soybean oil), (2) Intralipid + vitamin E (ILE, d-α-tocopherol), (3) Omegaven (OV, 100% fish oil), or (4) Omegaven + phytosterols (PS, β-sitosterol, campesterol, and stigmasterol).. Serum levels of direct bilirubin, gamma glutamyl transferase, serum triglyceride, low-density lipoprotein, and hepatic triglyceride content were significantly lower (P < .05) in the ILE, OV, and PS compared to IL. Hepatic cholesterol 7-hydroxylase and organic solute transporter-α expression was lower (P < .05) and portal plasma FGF19 higher in the ILE, OV, and PS vs IL. Hepatic expression of mitochondrial carnitine palmitoyltransferase 1A and microsomal cytochrome P450 2E1 fatty acid oxidation genes was higher in ILE, OV, and PS vs IL. In vivo (13)C-CDCA clearance and expression of pregnane X receptor target genes, cytochrome P450 3A29 and multidrug resistance-associated protein 2, were higher in ILE, OV, and PS vs IL.. α-tocopherol in Omegaven and added to Intralipid prevented serum and liver increases in biliary and lipidemic markers of PNALD in preterm piglets. The addition of phytosterols to Omegaven did not produce evidence of PNALD.

Topics: Animals; Animals, Newborn; Biomarkers; Fat Emulsions, Intravenous; Fish Oils; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Liver Diseases; Parenteral Nutrition; Phytosterols; Soybean Oil; Sus scrofa; Vitamin E

Increased serum concentrations of plant sterols, including stigmasterol, during parenteral nutrition (PN) have been linked with serum biochemical signs of intestinal failure-associated liver disease (IFALD), whereas clinical data on their correlation to histologic liver injury have been limited.. We studied interrelations between serum noncholesterol sterols and histologic liver injury in pediatric-onset intestinal failure (IF).. Serum plant sterols (stigmasterol, avenasterol, sitosterol, and campesterol), cholestanol, and cholesterol precursors (cholestenol, lathosterol, and desmosterol) were measured in 50 IF patients at a median age 7.3 y and in 86 matched controls. Forty patients underwent liver biopsies. Sixteen patients had been receiving PN for 45 mo, and 34 patients had received PN for 9.1 mo but had not received PN for 5.4 y.. Serum plant sterols were higher in patients who were currently receiving PN than in controls and were related to conjugated bilirubin (r = 0.799-0.541, P < 0.05). During PN, the ratio of serum stigmasterol to cholesterol was 3.3-fold higher in patients with portal inflammation, and the ratio of avenasterol to cholesterol was 3.9-fold higher in patients with cholestasis (P < 0.05 for both). Ratios of stigmasterol and avenasterol to cholesterol were correlated with portal inflammation (r = 0.549-0.510, P < 0.05), cholestasis (r = 0.501-0.491, P = 0.048-0.053), and serum bile acids (r = 0.591-0.608, P < 0.05). The median (IQR) ratio of serum cholestanol to cholesterol was higher during (269 100× μg/mg cholesterol; 203-402 100× μg/mg cholesterol) than after (175 100× μg/mg cholesterol; 156-206 100× μg/mg cholesterol; P < 0.001) weaning off PN and was correlated with cholestasis (r = 0.428), portal inflammation (r = 0.511), and fibrosis (r = 0.323, P < 0.05 for all). After weaning off PN, ratios of cholestenol and lathosterol to cholesterol were >2-fold higher in patients with persistent liver steatosis than in those without steatosis or controls (P < 0.01 for all), whereas lathosterol was correlated with the steatosis grade (r = 0.320, P < 0.050).. Increased serum stigmasterol and avenasterol concentrations parallel the portal inflammation and cholestasis during PN, thereby reinforcing their contribution to IFALD. A bile acid malabsorption-driven increase in cholesterol synthesis underpins persistent liver steatosis after weaning off PN. Serum cholestanol reflects liver injury in IF patients.

Topics: Adolescent; Bile Acids and Salts; Body Mass Index; Body Weight; Child; Child, Preschool; Cholestanol; Cholesterol; Cross-Sectional Studies; Female; Humans; Intestinal Diseases; Intestines; Liver Diseases; Male; Parenteral Nutrition; Phytosterols; Prospective Studies; Stigmasterol

Parenteral nutrition-associated liver disease (PNALD) is a serious complication of PN in infants who do not tolerate enteral feedings, especially those with acquired or congenital intestinal diseases. Yet, the mechanisms underlying PNALD are poorly understood. It has been suggested that a component of soy oil (SO) lipid emulsions in PN solutions, such as plant sterols (phytosterols), may be responsible for PNALD, and that use of fish oil (FO)-based lipid emulsions may be protective. We used a mouse model of PNALD combining PN infusion with intestinal injury to demonstrate that SO-based PN solution causes liver damage and hepatic macrophage activation and that PN solutions that are FO-based or devoid of all lipids prevent these processes. We have furthermore demonstrated that a factor in the SO lipid emulsions, stigmasterol, promotes cholestasis, liver injury, and liver macrophage activation in this model and that this effect may be mediated through suppression of canalicular bile transporter expression (Abcb11/BSEP, Abcc2/MRP2) via antagonism of the nuclear receptors Fxr and Lxr, and failure of up-regulation of the hepatic sterol exporters (Abcg5/g8/ABCG5/8). This study provides experimental evidence that plant sterols in lipid emulsions are a major factor responsible for PNALD and that the absence or reduction of plant sterols is one of the mechanisms for hepatic protection in infants receiving FO-based PN or lipid minimization PN treatment. Modification of lipid constituents in PN solutions is thus a promising strategy to reduce incidence and severity of PNALD.

Topics: Animals; Bile; Bile Canaliculi; Bone Marrow Cells; Disease Models, Animal; Emulsions; Fish Oils; Gastrointestinal Tract; Gene Expression Regulation; Kupffer Cells; Lipids; Liver; Liver Diseases; Macrophage Activation; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Microbiota; Parenteral Nutrition; Phytosterols; Signal Transduction; Solutions; Stigmasterol; Toll-Like Receptor 4

Topics: Animals; Kupffer Cells; Liver Diseases; Parenteral Nutrition; Phytosterols

The aim of the present study is to evaluate the effect of eicosapentaenoic acid-docosahexaenoic acid (EPA-DHA) rich sterol ester and A-linolenic Acid (ALA) rich sterol ester on the atherogenic disturbances in hypercholesterolemic atherogenic animals. Six groups of male Wistar rats were employed in this study, wherein five groups were fed with a high cholesterol diet (stock diet supplemented with 1% cholesterol) for 30 days, among which, two groups of rats were also treated with EPA-DHA rich sterol ester in two doses (25 and 50 mg/rat/day, oral gavage) and two groups were treated with ALA rich sterol ester also in two doses (25 and 50 mg/rat/day, oral gavage). The remaining one group served as control. Abnormal increases in the levels of malondialdehyde, as well as depressed antioxidants status, were observed in hepatic tissue of hypercholesterolemic control group. Hypercholesterolemia induced abnormal elevation in the activities of marker enzymes in liver (aspartate transaminase, alanine transaminase and alkaline phosphatase) and was accompanied by increased hepatic cholesterol level and altered fatty changes in the histology of liver. These changes were restored partially in the groups administered with lower doses (25 mg/rat/day) of sterol esters. However, the higher doses (50 mg/rat/day) of sterol esters almost ameliorated the hypercholesterolemic-oxidative changes in the hypercholesterolemic rats. The results of this study present oxidative injury induced by hypercholesterolemic diet and administration of the treatment with higher doses of sterol esters afforded sound protection against lipemic-oxidative injury.

Topics: Acyl Coenzyme A; Animals; Antioxidants; Esters; Fatty Acids; Hypercholesterolemia; Lipid Metabolism; Liver; Liver Diseases; Liver Function Tests; Male; Malondialdehyde; Mevalonic Acid; Oxidative Stress; Phytosterols; Rats; Rats, Wistar

We prospectively evaluated incidence of prolonged (>28 days) parenteral nutrition (PN), associated complications, and significance of parenteral plant sterols (PS) in neonatal intestinal failure-associated liver disease (IFALD) compared with children.. We recruited 28 neonates (mean age 50 days, range 28-126) and 11 children (6.9 y, 2.1-16.6) in all of Finland. Patients underwent repeated measurements of serum cholesterol, noncholesterol sterols, including PS, cholestanol and cholesterol precursors, and liver biochemistry during and 1 month after discontinuation of PN. Healthy matched neonates (n=10) and children (n=22) served as controls.. IFALD occurred more frequently among neonates (63%) than children (27%; P<0.05). Ratios of serum PS, including stigmasterol, sitosterol, avenasterol, and campesterol, and total PS were increased among neonates compared with healthy controls and children on PN by 2- to 22- and 2- to 5-fold (P<0.005), respectively. Neonates with IFALD had significantly higher ratios of serum PS and cholestanol compared with neonates without IFALD (P<0.05). Total duration of PN associated with serum cholestanol, stigmasterol, avenasterol, alanine aminotransferase, and aspartate aminotransferase (r=0.472-0.636, P<0.05). Cholestanol and individual serum PS, excluding campesterol, reflected direct bilirubin (r=0.529-0.688, P<0.05). IFALD persisted after discontinuation of PN in 25% of neonates with 4.2- and 2.2-times higher ratios of serum stigmasterol and cholestanol compared with neonates without IFALD (P<0.05).. Frequent occurrence of IFALD among neonates on PN displays an association to duration of PN and markedly increased serum PS, especially stigmasterol, in comparison to healthy neonates and children on PN. Striking accumulation of parenteral PS may contribute to IFALD among neonates.

Topics: Adolescent; Age Factors; Alanine Transaminase; Aspartate Aminotransferases; Bilirubin; Child; Child, Preschool; Cholestanol; Cholesterol; Dietary Fats; Fat Emulsions, Intravenous; Female; Finland; Humans; Infant; Infant, Newborn; Intestinal Diseases; Liver Diseases; Male; Olive Oil; Parenteral Nutrition; Phytosterols; Plant Oils; Prevalence; Prospective Studies; Soybean Oil; Stigmasterol

Topics: Adolescent; Child, Preschool; Cholestasis, Intrahepatic; Female; Gas Chromatography-Mass Spectrometry; Humans; Infant; Liver; Liver Diseases; Male; Parenteral Nutrition; Phytosterols

Lipid emulsions used for parenteral nutrition (PN) contain phytosterols. Our hypothesis was that these phytosterols can accumulate and contribute to cholestatic liver disease and other complications of PN, e.g., thrombocytopenia (which occurs in hereditary phytosterolemia).. Using gas chromatography-mass spectrometry, plasma concentrations of sterols were measured in 29 children aged 2 months to 9 years receiving PN and in 29 age-matched controls. The children receiving PN fell into two subgroups: 5 with severe PN-associated cholestatic liver disease (bilirubin level, > 100 mumol/L; aspartate aminotransferase [AST] level, > 200 U/L) and 24 with a bilirubin level of < 100 mumol/L and/or AST level of < 200 U/L.. The 5 children with severe PN-associated liver disease had plasma concentrations of phytosterols and sitostanol that were as high as those seen in patients with hereditary phytosterolemia (total phytosterols 1.3-1.8 mmol/L). All 5 had intermittent thrombocytopenia. A reduction in intake of lipid emulsion to < 50 mL.kg-1.wk-1 was associated with a decrease in plasma phytosterol concentrations and an improvement in liver function tests and platelet counts in two patients. Children with less severe PN-associated liver disease had lower plasma phytosterol concentrations than the 5 with severe disease.. Children receiving PN who have high plasma phytosterol concentrations also have cholestatic liver disease and thrombocytopenia; phytosterolemia might contribute to the pathogenesis of complications of PN.

Topics: Aspartate Aminotransferases; Child; Child, Preschool; Cholestasis; Fat Emulsions, Intravenous; Gas Chromatography-Mass Spectrometry; Humans; Infant; Liver Diseases; Parenteral Nutrition; Phytosterols; Thrombocytopenia

Proportions of cholesterol precursors (squalene, delta 8-cholestenol, desmosterol and lathosterol), plant sterols (campesterol and sitosterol) and cholestanol to cholesterol in serum were measured before and serially after liver transplantation in eight patients with primary biliary cirrhosis (PBC) and three with acute liver necrosis. The preoperative proportions of cholestanol were 12 and 3-times higher in the PBC and necrosis groups, respectively, than in a control group of 27 individuals, while those of lathosterol were low in both groups and the campesterol/sitosterol ratio in the PBC group. During the operation the proportions of cholestanol fell sharply and those of lathosterol rose especially in the PBC group. During the postoperative follow-up of 5 weeks the proportions of the non-cholesterol sterols were markedly improved especially in the necrosis group yet those of cholestanol remained high and the campesterol/sitosterol ratios low, particularly in the PBC group. The proportions of lathosterol increased gradually almost to the control limits within the postoperative 5-week period, whereas those of desmosterol decreased. The non-cholesterol sterol values were not related to acute rejections, while significant correlations of cholestanol to liver function tests was found especially at the end of the follow-up.

Topics: Acute Disease; Adult; Cholestanol; Cholesterol; Female; Humans; Liver Cirrhosis, Biliary; Liver Diseases; Liver Transplantation; Male; Middle Aged; Necrosis; Phytosterols; Protein Precursors; Sitosterols; Squalene

Topics: Bilirubin; Biomarkers; Cholesterol; Female; Humans; Liver Cirrhosis, Biliary; Liver Diseases; Liver Transplantation; Male; Phytosterols; Reference Values; Sitosterols