Coexistence of metabolic-associated fatty liver disease and autoimmune or toxic liver disease.

Fatty liver disease (FLD) affects approximately 25% of global adult population. Metabolic-associated fatty liver disease (MAFLD) is a term used to emphasize components of metabolic syndrome in FLD. MAFLD does not exclude coexistence of other liver disease, but impact of coexisting MAFLD is unclear. We investigated prevalence and characteristics of MAFLD in patients with biopsy-proven autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), or toxic liver disease. Liver histopathology and clinical data from Helsinki University Hospital district (1.7 million inhabitants) between 2009 and 2019 were collected from patients with AIH, PBC, PSC, or toxic liver disease at the time of diagnosis. MAFLD was diagnosed as macrovesicular steatosis ≥5% together with obesity, type-2 diabetes, or signs of metabolic dysregulation. Of 648 patients included, steatosis was observed in 15.6% (n = 101), of which 94.1% (n = 95) was due to MAFLD. Prevalence of coexisting MAFLD in the four liver diseases varied between 12.4 and 18.2% (P = 0.483). Fibrosis was more severe in MAFLD among patients with toxic liver disease (P = 0.01). Histopathological characteristics otherwise showed similar distribution among MAFLD and non-FLD controls. Alcohol consumption was higher in MAFLD group among patients with AIH or PBC (P < 0.05 for both). In AIH, smoking was more common in patients with coexisting MAFLD (P = 0.034). Prevalence of coexisting MAFLD in other primary liver diseases is lower than reported in general population. Histopathology of MAFLD patients did not clearly differ from non-FLD ones. Alcohol and smoking were associated with MAFLD in AIH.

Validity of fatty liver disease indices in the presence of alcohol consumption.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease frequently coexist. While several blood-based indices exist for the detection of NAFLD, few studies have examined how alcohol use possibly impacts their diagnostic performance. We analysed the effects of alcohol use on the performance of indices for detecting fatty liver disease (FLD). METHODS: We included participants from the Cardiovascular Risk in Young Finns Study (Finnish sample) and KORA study (German sample) who underwent abdominal ultrasound or magnetic resonance imaging, respectively, for detection of FLD and had serum analyses available for calculation of Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI), Lipid Accumulation Product (LAP), and Dallas Steatosis Index (DSI). Alcohol use was estimated by questionnaires as mean daily consumption and binge drinking (Finnish sample only). Predictive performance for FLD was assessed according to alcohol consumption. RESULTS: The study included 1426 (Finnish sample) and 385 (German sample) individuals, of which 234 (16%) and 168 (44%) had FLD by imaging. When alcohol consumption was <50 g/day, all indices discriminated FLD with area under the receiver operating characteristics (AUROC) of 0.82-0.88. AUROCs were 0.61-0.66 among heavy drinkers (>50 g/day). AUROCs decreased to 0.74-0.80 in the highest binge-drinking category (>2 times/week). Alcohol use correlated with FLI and LAP (r-range 0.09-0.16, p-range <.001-.02) in both samples and with DSI (r = 0.13, p < .001) in the Finnish sample. CONCLUSIONS: Indices perform well and comparably for detection of FLD with alcohol consumption <50 g/day and with different binge-drinking behaviour.

Waist and hip circumference are independently associated with the risk of liver disease in population-based studies.

BACKGROUND & AIMS: While several anthropometric measures predict liver disease, the waist-hip ratio (WHR) has shown superiority in previous studies. We analysed independent and joint associations of waist circumference (WC) and hip circumference (HC) with liver disease and liver-related risk factors. METHODS: Cross-sectional study (n = 6619) and longitudinal cohort (n = 40 923) comprised individuals from Health 2000 and FINRISK 1992-2012 studies. Prevalent and viral liver diseases were excluded. Longitudinal cohort was linked with national healthcare registers for severe incident liver disease. Linear regression and Cox proportional hazards models were used to analyse anthropometric, lifestyle, metabolic and bioimpedance-related parameters; liver enzymes; and 59 liver-related genetic risk variants. RESULTS: WC and HC showed independent and opposite associations with both liver enzymes and incident liver disease among men (HR for liver disease: WC, 1.07, 95% CI 1.03-1.11; HC, 0.96, 95% CI 0.92-0.99; P-range .04 to <.001) and women (HR for liver diseases: WC, 1.06, 95% CI 1.02-1.10; HC, 0.93, 95% CI 0.89-0.98; P-range .005 to .004). HC modified associations between WC and liver enzymes, and between WC and incident liver disease, particularly among men. Liver enzymes and risk of liver disease increased with increasing WC, more so among individuals with high WHR compared to with low WHR. WC and HC jointly reflected both body fat distribution and muscle mass, which was largely mirrored by WHR. CONCLUSIONS: WC and HC exhibit independent and joint associations with liver disease, which are largely reflected by WHR. Both body fat distribution and muscle mass contribute to these anthropometric measures.

Serum non-cholesterol sterols and cholesterol metabolism in childhood and adolescence.

BACKGROUND AND AIMS: The profile of cholesterol metabolism, i.e., high absorption vs. high synthesis, may have a role in the development of atherosclerosis, the early lesions of which can be present already in childhood. Since there is no information on cholesterol metabolism in children from birth to adolescence, we evaluated cholesterol metabolism in 0-15 year-old children and adolescents without dyslipidemia. METHODS: The study population consisted of 96 children (39 girls, 57 boys) divided into age groups <1 (n = 14), 1-5 (n = 37), 6-10 (n = 24), and 11-15 (n = 21) years. Cholesterol metabolism was assessed by analysing serum non-cholesterol sterols, biomarkers of cholesterol synthesis and absorption, with gas-liquid chromatography. RESULTS: Serum non-cholesterol sterol ratios to cholesterol did not differ between gender. Cholesterol precursors squalene, cholestenol, and desmosterol were higher in the <1 year than in the older age groups, whereas lathosterol was highest in the 11-15 year old. Plant sterols were low in the age group <1 year, after which they did not differ between the groups. Cholestanol was not age-dependent. From the age of 1 year, cholesterol homeostasis was intact. Cholesterol absorption prevailed cholesterol synthesis from 1 to 10 years of age (e.g., lathosterol/cholestanol ratio 0.35 ±â€¯0.03 and 0.45 ±â€¯0.05 in 1-5 and 6-10 vs. 0.66 ±â€¯0.08 in 11-15 year-old (mean ±â€¯SE, p < 0.001). CONCLUSIONS: Serum non-cholesterol sterols had different individual profiles by age in childhood and adolescence. From 1 to 10 years of age, cholesterol absorption prevailed cholesterol synthesis. This novel finding emphasizes the importance of dietary aspects related to cardiovascular risk even from early childhood.

Serum noncholesterol sterols in Alzheimer's disease: the Helsinki Businessmen Study.

Cerebral cholesterol metabolism is perturbed in late-onset Alzheimer's disease (AD), but whether also the extracerebral cholesterol metabolism is perturbed is not known. Thus, we studied whole-body cholesterol synthesis and absorption with serum noncholesterol sterols in men without AD (n = 114) or with (n = 18) "pure" AD (no concomitant atherosclerotic cardiovascular disease) in a long-term cohort (the Helsinki Businessmen Study) of home-dwelling older men without lipid-lowering drugs and on their habitual home diet. Serum lipids did not differ between AD and controls, but age was higher (78 ± 1 vs 74 ± 0.3 years, mean ± standard error, P < 0.001), age-adjusted plasma glucose concentration was lower (4.8 ± 0.3 vs 5.7 ± 0.1 mmol/L, P = 0.011), and APOE ε4 allele and frailty were more frequent in AD than in controls. Of the age and frailty-adjusted serum noncholesterol sterols desmosterol and lathosterol ratios to cholesterol reflecting cholesterol synthesis were lower in AD than in controls (eg, lathosterol 114 ± 12 vs 137 ± 5 102 µmol/mmol cholesterol, P = 0.004). Cholestanol ratio to cholesterol was higher in AD than in controls suggesting increased cholesterol absorption. lathosterol/sitosteroll ratio reflecting cholesterol metabolism was lower in AD than in controls (0.95 ± 0.28 vs 1.52 ± 0.11 102 µmol/mmol cholesterol, P = 0.027). In AD, plasma glucose correlated negatively with cholesterol synthesis, whereas in controls the correlation was positive. In conclusion, extracerebral cholesterol metabolism was altered in AD. This finding along with the low plasma glucose concentration and its paradoxical interaction with cholesterol synthesis opens new perspectives in the regulation of cholesterol metabolism and glucose homeostasis in AD.

Genetic polymorphism of sterol transporters in children with future gallstones.

BACKGROUND & AIMS: Gallstone disease is related to hypersecretion of cholesterol in bile, and low serum phytosterol levels. We examined how genetic polymorphisms of sterol transporters affect childhood cholesterol metabolism trait predicting adult gallstone disease. PATIENTS AND METHODS: In retrospective controlled study, we determined D19H polymorphism of ABCG8 gene, genetic variation at Niemann-Pick C1-like 1 (NPC1L1) gene locus (rs41279633, rs17655652, rs2072183, rs217434 and rs2073548), and serum cholesterol, noncholesterol sterols and lipids in children affected by gallstones decades later (n = 66) and controls (n = 126). RESULTS: In childhood, phytosterols were lower (9.7%-23.4%) in carriers of risk allele 19H compared to 19D homozygotes. Lowest campesterol/cholesterol tertile consisted of 1.9-times more future gallstone subjects, and 3.7-times more 19H carriers than highest one. Campesterol/cholesterol-ratio was highest in 19D homozygote controls, but ∼11% lower in gallstone 19D homozygotes and ∼25% lower among gallstone and control carriers of 19H. Gallstone subjects with alleles CC of rs41279633 and TT of rs217434 of NPC1L1 had ∼18% lower campesterol/cholesterol-ratio compared to mutation carriers. CONCLUSIONS: Risk trait of cholesterol metabolism (low phytosterols) in childhood favouring cholesterol gallstone disease later in adulthood is influenced by risk variant 19H of ABCG8 and obviously also other factors. NPC1L1 variants have minor influence on noncholesterol sterols.

Determining the mechanisms of dietary turnip rapeseed oil on cholesterol metabolism in men with metabolic syndrome.

We have earlier reported the reduction of total cholesterol, low-density lipoprotein (LDL) cholesterol and oxidized LDL caused by short-term modification of diet with cold-pressed turnip rapeseed oil (CPTRO) instead of butter. The aim of this supplementary study was to determine whether the beneficial effects resulted from altered cholesterol metabolism during the intervention.Thirty-seven men with metabolic syndrome (MetS) completed an open, randomized and balanced crossover study. Subjects' usual diet was supplemented with either 37.5 g of butter or 35 mL of CPTRO for 6-8 weeks. Otherwise normal dietary habits and physical activity were maintained without major variations. Serum non-cholesterol sterols were assayed with gas-liquid chromatography and used as surrogate markers of whole-body cholesterol synthesis and absorption efficiency. Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) concentration was analyzed with Quantikine ELISA Immunoassay. Serum cholesterol synthesis markers and serum cholestanol (absorption marker), all as ratios to cholesterol, did not differ between the periods. Serum campesterol and sitosterol ratios to cholesterol were significantly increased after the administration of CPTRO resulting from the increased intake of 217 mg/day of plant sterols in CPTRO. Serum PCSK9 concentration did not differ between CPTRO and butter periods.The reduction in serum cholesterol by 7.2% after consumption of rapeseed oil could not be explained by changes in cholesterol absorption, synthesis or PCSK9 metabolism in MetS.ClinicalTrials.gov NCT01119690.

Low Childhood Cholesterol Absorption Predisposes to Gallstone Disease: The Cardiovascular Risk in Young Finns Study.

OBJECTIVES: Unraveling pathogenesis of gallstones could help to diminish its enormous disease burden. We hypothesized that certain properties of childhood cholesterol metabolism predict gallstone disease in adulthood. METHODS: Childhood serum cholestanol and plant sterols (surrogates for cholesterol absorption), cholesterol precursors (surrogates for cholesterol synthesis), lipids, demographics, and dietary habits were compared between individuals diagnosed with gallstone disease subsequently in adulthood (n = 95) and control subjects (n = 190) matched for age, sex, and body mass index in 1980. Subjects were participants of prospective Cardiovascular Risk in Young Finns Study. RESULTS: In 1980, at mean age of 11.4 years gallstone cohort was characterized by 5.8% lower cholestanol (P = 0.038), and 11.2% to 12.2% (P range = 0.003-0.008) lower plant sterols campesterol, sitosterol, and avenasterol compared with controls. Mean lathosterol/sitosterol ratio was 16.3% higher in gallstone compared with control cohort (P = 0.028). Female gallstone group had 5.4% lower mean cholestanol compared with controls (P < 0.05), and, respectively, those of campesterol, sitosterol, and avenasterol were 12.7% to 14.0% lower (P < 0.05 for each). Body mass index was inversely related to cholestanol and sitosterol (r range = -0.161 to -0.208, P < 0.05 for each) in controls, but not among patients with gallstone. In whole study population, surrogates of cholesterol absorption (eg, campesterol, P = 0.018) and low dietary intake of vegetables (P = 0.009) were significant predictors of gallstones in logistic regression model. CONCLUSIONS: Cholesterol metabolism trait characterized by low serum levels of surrogate markers of cholesterol absorption precedes adult gallstone disease already in childhood. Low serum cholestanol and plant sterol ratios during normal Western diet may have role as predictive biomarkers for gallstones.

Relation of cholesterol metabolism to pediatric gallstone disease: a retrospective controlled study.

BACKGROUND: Cholesterol metabolism may be involved in pediatric gallstone disease. We aimed to reveal cholesterol metabolites and phytosterols and their relation to stone composition of sterols in children having black pigment and cholesterol stones. METHODS: We performed retrospective controlled clinical study, in which we examined parameters of cholesterol metabolism and liver function values in serum (n = 28) and gallstones (n = 46) of consecutively cholecystectomized children. Serum values of age-, body mass index- and sex-matched children (n = 82) and adult gallstones (n = 187) served as controls. RESULTS: Surrogate markers of cholesterol synthesis in serum (squalene/cholesterol, cholestenol/cholesterol and lathosterol/cholesterol) were 26-52 % higher in both stone subclasses compared to controls (p < 0.05 for all). Respectively, cholestanol/cholesterol and plant sterols campesterol/cholesterol and sitosterol/cholesterol (cholesterol absorption markers) had decreasing order in serum: black pigment stone group > controls > cholesterol stone group (p < 0.05 for all). In black pigment stone group, stone cholestanol/cholesterol was associated with serum bile acids (r = 0.620, p = 0.018). In cholesterol stone group, surrogate markers of cholesterol synthesis in serum (e.g., lathosterol/cholesterol) inversely reflected those of absorption (r-range -0.633--0.706, p-range 0.036-0.015). In cholesterol stone group, serum and stone lathosterol/cholesterol and cholestanol/cholesterol were positively interrelated (r-range 0.727-0.847, p < 0.05 for both). CONCLUSIONS: Gallstone subclasses shared enhanced cholesterol synthesis. Cholesterol stone children were low cholesterol absorbers with intact homeostasis of cholesterol metabolism. Black pigment stone group was characterized by deteriorated cholesterol metabolism, and accumulation of cholestanol, campesterol and sitosterol in serum and stones suggesting their participation in pathogenesis.

Serum plant sterols, cholestanol, and cholesterol precursors associate with histological liver injury in pediatric onset intestinal failure.

BACKGROUND: 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. OBJECTIVE: We studied interrelations between serum noncholesterol sterols and histologic liver injury in pediatric-onset intestinal failure (IF). DESIGN: 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. RESULTS: 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). CONCLUSIONS: 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.

The effects of plant stanol ester consumption on arterial stiffness and endothelial function in adults: a randomised controlled clinical trial.

BACKGROUND: The hypocholesterolemic effect of plant stanol ester consumption has been studied extensively, but its effect on cardiovascular health has been less frequently investigated. We studied the effects of plant stanol esters (staest) on arterial stiffness and endothelial function in adults without lipid medication. METHODS: Ninety-two asymptomatic subjects, 35 men and 57 women, mean age of 50.8±1.0 years (SEM) were recruited from different commercial companies. It was randomized, controlled, double-blind, parallel trial and lasted 6 months. The staest group (n=46) consumed rapeseed oil-based spread enriched with staest (3.0 g of plant stanols/d), and controls (n=46) the same spread without staest. Arterial stiffness was assessed via the cardio-ankle vascular index (CAVI) in large and as an augmentation index (AI) in peripheral arteries, and endothelial function as reactive hyperemia index (RHI). Lipids and vascular endpoints were tested using analysis of variance for repeated measurements. RESULTS: At baseline, 28% of subjects had a normal LDL cholesterol level (≤3.0 mmol/l) and normal arterial stiffness (<8). After the intervention, in the staest group, serum total, LDL, and non-HDL cholesterol concentrations declined by 6.6, 10.2, and 10.6% compared with controls (p<0.001 for all). CAVI was unchanged in the whole study group, but in control men, CAVI tended to increase by 3.1% (p=0.06) but was unchanged in the staest men, thus the difference in the changes between groups was statistically significant (p=0.023). AI was unchanged in staest (1.96±2.47, NS) but increased by 3.30±1.83 in controls (p=0.034) i.e. the groups differed from each other (p=0.046). The reduction in LDL and non-HDL cholesterol levels achieved by staest was related to the improvement in RHI (r=-0.452, p=0.006 and -0.436, p=0.008). CONCLUSIONS: Lowering LDL and non-HDL cholesterol by 10% with staest for 6 months reduced arterial stiffness in small arteries. In subgroup analyses, staest also had a beneficial effect on arterial stiffness in large arteries in men and on endothelial function. Further research will be needed to confirm these results in different populations. TRIAL REGISTRATION: Clinical Trials Register # NCT01315964.

Diet and cardiovascular health in asymptomatic normo- and mildly-to-moderately hypercholesterolemic participants - baseline data from the BLOOD FLOW intervention study.

BACKGROUND: For decades in Finland, intensive population strategies and preventive activities have been used to lower the risk of atherosclerotic coronary heart disease (CHD). Lifestyle changes, with the emphasis on diet, play an important role in preventive strategies. The aim of this study was to evaluate arterial stiffness and endothelial function in asymptomatic free-living adults and to relate the results to CHD risk factors and lifestyle habits with the emphasis on diet. METHODS: Ninety-four asymptomatic participants were recruited by advertisements in four large companies and two research institutes employing mainly office workers. Arterial stiffness was assessed as the cardio-ankle vascular index in large arteries, and endothelial function as the reactive hyperemia index with peripheral arterial tonometry. The systematic Cardiovascular Risk Estimation (SCORE) was calculated. RESULTS: The data was collected in the spring of 2011. Anthropometric, dietary, and lipid data was available from 92 participants, blood pressure from 85 and vascular measurements from 86-88 subjects (38% males; 62% females; mean age of all 51). The majority (72%) had an elevated low density lipoprotein (LDL) cholesterol concentration and over half were overweight or obese. SCORE stated that 49% of the participants had a moderate risk of cardiovascular disease. When compared to general recommendations, half of the participants had too high intake of total fat and in 66% the consumption of saturated fat was too high. In contrast, the intake of carbohydrates was too low in 90% of the participants and for fiber 73% were below recommendations. There was evidence of borderline or increased arterial stiffness in 72% of the participants and endothelial function was impaired in 8%. Arterial stiffness was associated with LDL cholesterol concentration (p = 0.024), dietary cholesterol intake (p = 0.029), and SCORE (p < 0.001). CONCLUSIONS: In a cross-sectional study of asymptomatic middle-aged participants, the half had a moderate risk for cardiovascular diseases manifested as increased arterial stiffness, elevated LDL cholesterol concentration, and poor dietary habits. The new observation that arterial stiffness was associated with dietary cholesterol intake and SCORE emphasizes the urgency of adequate lifestyle and dietary interventions to prevent future coronary events even in asymptomatic participants. TRIAL REGISTRATION: Clinical Trials Register # NCT01315964.

Parenteral plant sterols and intestinal failure-associated liver disease in neonates.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Effects of long-term parenteral nutrition on serum lipids, plant sterols, cholesterol metabolism, and liver histology in pediatric intestinal failure.

BACKGROUND AND OBJECTIVE: 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. PATIENTS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Surrogate markers of cholesterol metabolism in children with native liver after successful portoenterostomy for biliary atresia.

PURPOSE: Cholestasis gradually ensues after portoenterostomy for biliary atresia (BA) and may deteriorate liver function. Cholesterol metabolism and its relationships with serum markers of liver function were evaluated in children living with native liver after successful portoenterostomy for BA. SUBJECTS AND METHODS: Serum lipids, noncholesterol sterol ratios to cholesterol, that is, surrogate markers of cholesterol metabolism, and liver function were cross-sectionally studied in 17 consecutive children after successful (postoperative bilirubin <20 micromol/L) portoenterostomy for BA with native liver and a mean age of 5.2 years. The results were compared with healthy age-matched controls. RESULTS: Mean serum total and low-density lipoprotein cholesterol and campesterol ratio were 18%, 43%, and 26% less than those of controls, respectively (P < .01 for all). Despite low serum cholesterol and campesterol (marker of cholesterol absorption) levels, serum lathosterol (marker of cholesterol synthesis) was decreased by 34% (P < .0001) from control levels and reflected serum prealbumin (r = 0.666) and cholestanol (r = -0.515, P < .05 for both). Cholestanol, twice higher than those of controls (P < .0001), reflected abnormally high serum alkaline phosphatase, glutamyl transferase, and bile acids (r = 0.558-0.711, P < .05). Serum campesterol was inversely related with lathosterol (r = -0.238, P < .05) in controls, but not in patients (r = -0.039). CONCLUSION: Children living with native liver after portoenterostomy for BA are inclined to low serum concentration and absorption of cholesterol. Cholesterol homeostasis was disturbed so that low cholesterol absorption was not associated with compensatory increase in cholesterol synthesis that decreased together with worsening of cholestasis.

Cholesterol metabolism in pediatric short bowel syndrome after weaning off parenteral nutrition.

BACKGROUND: Small intestine essentially regulates cholesterol homeostasis. AIMS: To evaluate cholesterol metabolism in short bowel syndrome (SBS). METHODS: Cholesterol precursors (e.g., cholestenol, desmosterol and lathosterol) and plant sterols (campesterol and sitosterol), respective markers of cholesterol synthesis and absorption, were determined in SBS patients (n=12) an average of 31 months after weaning off parenteral nutrition and in age-matched controls (n=80). RESULTS: Among patients, serum cholesterol precursor sterol to cholesterol ratios were 2-10 times higher (P<0.0001 for each). Those without any remaining ileum had 1.2-2.8 times higher precursor sterol to cholesterol ratios than those with an ileal remnant (P<0.05 for each). Serum cholesterol concentration, campesterol/cholesterol and campesterol/sitosterol were 34-39% lower (P<0.05 for each) in relation to controls. Bile acid absorption was markedly impaired (2.4 (0.2-3.2)%). Plant sterol ratios reflected the absolute length of remaining jejunum (r=0.625-0.663), and precursor sterol ratios inversely that of ileum (r=-0.589 to 0.750, P<0.05 for all). CONCLUSION: After weaning off parenteral nutrition, patients with pediatric onset SBS continue to have marked intestinal malabsorption of bile acids and moderate cholesterol malabsorption resulting in decreased serum cholesterol despite a marked compensatory increase in cholesterol synthesis.

The effect of a very high daily plant stanol ester intake on serum lipids, carotenoids, and fat-soluble vitamins.

BACKGROUND & AIMS: Intake of 2-3 g/d of plant stanols as esters lowers LDL cholesterol level, but there is no information about the efficacy and safety of a respective very high daily intake. We studied the effects of 8.8 g/d of plant stanols as esters on serum lipids and safety variables in subjects with mild to moderate hypercholesterolemia. METHODS: In a randomized, double-blind, placebo-controlled study the intervention (n=25) and control (n=24) groups consumed spread and drink enriched or not with plant stanol esters for 10 weeks. RESULTS: Plant stanols reduced serum total and LDL cholesterol concentrations by 12.8 and 17.3% from baseline and by 12.0 and 17.1% from controls (P<0.01 for all). Liver enzymes, markers of hemolysis, and blood cells were unchanged. Serum vitamins A, D, and gamma-tocopherol concentrations, and the ratios of alpha-tocopherol to cholesterol were unchanged. Serum beta-carotene concentrations decreased significantly from baseline and were different from controls even when adjusted for cholesterol. Serum alpha-carotene concentration and alpha-carotene/cholesterol ratio were not different from controls. CONCLUSIONS: High intake of plant stanols reduced LDL cholesterol values without any other side effects than reduction of serum beta-carotene concentration. However, the end product, serum vitamin A levels, were unchanged. The results suggest that plant stanol ester intake can be increased to induce a greater cholesterol lowering effect.

Very high plant stanol intake and serum plant stanols and non-cholesterol sterols.

BACKGROUND: Today, consumers meet abundant supply of functional foods with plant stanol increments for serum cholesterol lowering purposes. However, efficacy and safety of plant stanols intake beyond 4 g/day have remained unexplored. AIM OF THE STUDY: We evaluated the effects of very high daily intake of plant stanols (8.8 g/day) as esters on cholesterol metabolism, and serum levels of plant sterols and stanols. METHODS: In a randomized, double-blind, parallel study of 49 hypercholesterolemic subjects (mean age 62 years, range 41-73) consumed a test diet without (control, n = 24), and with added plant stanol esters (staest, n = 25) over 10 weeks followed by 4 weeks on home diet. Serum lipids, lipoprotein lipids, and non-cholesterol sterols were determined at baseline, during intervention, and 4 weeks afterwards. Cholesterol precursor sterol lathosterol reflected cholesterol synthesis, and serum plant sterols and cholestanol mirrored cholesterol absorption. RESULTS: When compared with controls, 8.8 g/day of plant stanols reduced serum and LDL cholesterol by 12 and 17% (P < 0.01 for both). Synthesis marker lathosterol was increased by 30%, while absorption markers decreased up to 62% when compared with controls (P < 0.001 for both). Serum plant stanols increased slightly, but significantly compared with controls (serum sitostanol during intervention, controls: 16 +/- 1 microg/dL, staest: 37 +/- 2 microg/dL, serum campestanol during intervention, controls: 0.5 +/- 0 microg/dL, staest: 9 +/- 1 microg/dL, P < 0.001 for both). Changes in serum cholesterol, non-cholesterol sterols, and plant stanols were normalized during post-treatment weeks. CONCLUSIONS: Serum plant stanol levels remained at comparable low levels as in studies with daily intake of 2-3 g, and were normalized in 4 weeks suggesting that daily intake of 8.8 g of plant stanols might not increase systemic availability of plant stanols, but reduces effectively serum cholesterol and plant sterol levels.

Serum sterols in patients with primary biliary cirrhosis and acute liver failure before and after liver transplantation.

BACKGROUND/AIMS: Liver diseases modify sterol metabolism. Liver transplantation (LTX) provides a model to evaluate the impact of disease-affected liver on sterol metabolism. METHODS: We studied serum sterol profiles and their relationships to other biochemical markers in consecutive cholestatic patients with acute liver failure (ALF, n=39) and end-stage primary biliary cirrhosis (PBC, n=67) before and 27d after LTX. Accordingly, we determined serum levels of sterols, bilirubin and prealbumin. RESULTS: Due to weak cholesterol synthesis of ALF-patients before LTX, their serum levels of cholesterol, lathosterol/cholesterol, cholestanol/cholesterol and lathosterol/campesterol were 18%-41% lower (P<0.05 for each) than in PBC, but ratios of phytosterols to cholesterol were equal. In general, non-cholesterol sterol ratios reflected bilirubin and prealbumin concentrations. Interrelation of surrogate sterols showed that homeostasis of cholesterol metabolism prevailed in lowest cholestanol tertile of ALF-patients consistently, but not in PBC. After LTX, cholesterol levels and lathosterol ratios increased in both groups and phytosterol ratios decreased (P<0.01). Cholestanol decreased profoundly in PBC, but remained 26% higher than in ALF (P<0.05). CONCLUSIONS: Homeostasis of cholesterol metabolism was maintained only in ALF. Metabolism of phytosterols was equal in study groups. PBC- and ALF-patients have differential patterns in their serum sterols and cholesterol metabolism.

Effects of dietary cholesterol and fat on serum non-cholesterol sterols according to different apolipoprotein E subgroups among healthy men.

The impact of apo E phenotypes on applicability of relative cholesterol synthesis (lathosterol:cholesterol) and absorption (ratios of cholestanol, campesterol and sitosterol to cholesterol) during diets of various cholesterol and fat content is unclear. We examined and compared with each other both relative and absolute synthesis and absorption among twenty-nine men, of whom eight, nine and twelve had apo E phenotypes 2 (2/2, 2/3, 2/4), 3 (3/3) and 4 (3/4, 4/4), respectively. Serum lipids, lipoproteins, sterols and cholesterol metabolism were examined on four subsequent diets: high-cholesterol high-fat (home diet; HD), low-cholesterol low-fat (LCLF), high-cholesterol low-fat (HCLF) and low-cholesterol high-fat (LCHF). LDL-cholesterol (LDL-C) level was about 40 % lower (P < 0.05) in apo E2 than apo E3 and E4 groups irrespective of dietary fat and cholesterol. Serum proportions of phytosterols were determined apo E-dependently on LCLF and HCLF, and those of lathosterol, cholestanol and campesterol were increased in apo E2 and E3 groups (P < 0.05 for each v. HD). Serum proportion of sitosterol reflected almost consistently apo E phenotype (r range+0.308 to+0.383; P range 0.214-0.011). Relative cholesterol synthesis and absorption reflected respective absolute values during each diet in the apo E4 group (r range+0.713 to+0.893; P < 0.05 for each), but only during HD (r+0.594; P = 0.015) in the apo E2+E3 group. The consumption of a high amount of fat did not interfere with cholesterol metabolism or serum levels of LDL-C differently in apo E phenotypes. Surrogate sterol markers of cholesterol metabolism reflected absolute ones (especially in the apo E4 group) and apo E phenotypes despite variable amounts of dietary cholesterol and fat.