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.

Genetic and lifestyle risk factors for advanced liver disease among men and women.

BACKGROUND AND AIM: Liver disease is traditionally categorized as alcoholic and non-alcoholic. We studied various risk factors predictive of advanced non-viral liver disease in general population and analyzed the interaction between these factors and alcohol consumption. METHODS: Persons without underlying liver disease who participated in the Health2000 or FINRISK studies 1992-2012 comprised a cohort of 41 260 individuals. Pattern of alcohol consumption and metabolic, lifestyle-related, and anthropometric parameters were analyzed with Cox regression analysis using severe liver disease hospitalization, cancer, or death as end-point. Viral liver diseases were excluded. RESULTS: A total of 355 liver events occurred during the mean 12.4-year follow-up (511 789 person-years). In the multivariate model, age (hazard ratio [HR] 1.03, P = 0.0083 for men; HR 1.04, P = 0.0198 for women), waist-to-hip ratio (WHR) (HR 1.52, P = 0.0006 for men; HR 1.58, P = 0.0167 for women), patatin-like phospholipase-containing domain 3 mutations (HR 1.9, P = 0.024 for men; HR 2.7, P = 0.0109 for women), and weekly binge drinking (HR 2.4, P = 0.0024 for men; HR 7.4, P < 0.0001 for women) predicted development of severe liver disease. Among men, diabetes (HR 2.7, P = 0.0002), average alcohol consumption (HR for 10 g/day 1.1, P = 0.0022), non-married status (HR 1.9, P = 0.0397 for single; HR 2.4, P = 0.0002 for widowed/separated), and serum high-density lipoprotein (HR 2.2, P = 0.0022) and non-high-density lipoprotein cholesterol (HR 1.2, P = 0.0237) were additional risk factors. Alcohol intake increased the risk especially among persons with high WHR (P for interaction 0.009). CONCLUSIONS: Age, patatin-like phospholipase-containing domain 3 haplotype, and WHR increase the risk for development of severe liver disease. We found strong synergism between alcohol and central obesity. Binge drinking is an additional risk factor.

Altered Bile Transporter Expression and Cholesterol Metabolism in Children With Cholesterol and Pigment Gallstones.

OBJECTIVES: We elucidated pathophysiology of pediatric gallstone disease by assessing liver expression of bile transporters in relation to bile acids and surrogates of cholesterol absorption and synthesis in serum and gallstones. METHODS: RNA expression of canalicular bile transporters in liver biopsies from 32 pediatric gallstone patients and from 6 liver donors (controls) was measured by qRT-PCR (quantitative real-time reverse transcription polymerase chain reaction). Concentrations of cholesterol and precursors, plant sterols and bile acids in gallstones, and in serum of the patients and 82 healthy children were measured. Primary outcomes were the difference in RNA expressions and serum sterol profiles between patients and controls. RESULTS: Cholesterol stones (CS; n = 15) contained cholesterol >42% and pigment stones (PS; n = 17) <9% of weight. CS patients had markedly lower serum plant sterols (absorption) and higher cholesterol precursors (synthesis) than PS patients or healthy controls. CS contained several times more cholesterol precursors and less plant sterols relative to cholesterol than PS, which were enriched by primary bile acids (12-5.2-fold, P < 0.001). Liver RNA expression of ABCG5/G8 was similarly increased 2.5- to 1.8-fold (P < 0.002) in CS and PS patients, whereas PS patients had higher ABCB11 expression (P < 0.05). In PS bile acid concentration correlated with gallstone plant sterols (R = 0.83, P < 0.0001), and ABCG5 expression with ABCB11 expression (R = 0.27, P = 0.03). CONCLUSIONS: In CS, upregulation of ABCG5/G8 expression associates with low absorption and high gallstone content of cholesterol. In PS, activation of bile acid transport by ACBC11 interconnects with hepatic upregulation of ABCG5/G8 enriching PS with bile acids and plant sterols.

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.

Noncholesterol Sterols as Surrogate Markers in Patients with Severe Alcoholic Hepatitis.

Severe alcoholic hepatitis (AH) is a life-threatening condition lacking good serologic markers to tailor treatment and predict recovery. We examined the cholesterol metabolism in severe AH to explore prognostic markers and evaluate the profile of cholesterol precursors, cholestanol and phytosterols, in this context. We assessed serum cholesterol, cholesterol precursors, cholestanol, phytosterols, and biochemical markers in 24 patients with severe AH treated with prednisolone and randomized to ciprofloxacin in the ratio 1:1. Response to prednisolone was assessed with the Lille model. Evaluations were made between responders and nonresponders to corticosteroid treatment and during follow-up for 180 days. The findings were compared with those from patients with primary sclerosing cholangitis (PSC) (n = 156) and healthy individuals (n = 124). Responders to prednisolone had ~56-60% higher (p-value 0.032-0.044) serum ratios to cholesterol of phytosterols, while the lathosterol/campesterol ratio was ~76% (p = 0.031) lower compared to nonresponders. Stigmasterol/cholesterol predicted response to corticosteroid therapy. Surrogate markers of cholesterol synthesis (lathosterol and desmosterol) inversely reflected those of absorption (cholestanol and phytosterols) in PSC and controls (r-range -0.247 to -0.559, p < 0.01 for all), contrary to AH patients, among whom this reciprocal regulation was partially recovered on day 90 (lathosterol: r-range -0.733 to -0.952, p < 0.05 for all). AH patients had ~26% lower lathosterol/cholesterol, but 1.13-3.87-fold higher cholestanol/cholesterol and sitosterol/cholesterol compared to control groups (p < 0.05 for all). Median ferritin concentration at baseline was ~37% lower (p = 0.011) among the responders. Cholesterol precursors and phytosterols have a disease-specific profile in AH. Phytosterols and ferritin may serve as surrogate markers for short-term response.

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.

Parenteral Plant Sterols Accumulate in the Liver Reflecting Their Increased Serum Levels and Portal Inflammation in Children With Intestinal Failure.

BACKGROUND: Parenteral plant sterols (PSs) are considered hepatotoxic; however, liver PSs and their associations with liver injury in patients with intestinal failure (IF) have not been reported. MATERIALS AND METHODS: We analyzed liver and serum PS (avenasterol, campesterol, sitosterol, and stigmasterol) concentrations and ratios to cholesterol and their associations with biochemical and histologic liver damage in children with IF during (n = 7) parenteral nutrition (PN) and after weaning off it (n = 9), including vegetable oil-based lipid emulsions. RESULTS: Liver avenasterol, sitosterol, and total PS concentrations and cholesterol ratios were 2.4-fold to 5.6-fold higher in PN-dependent patients ( P < .05). Parenteral PS delivery reflected liver avenasterol and sitosterol ratios to cholesterol ( r = 0.83-0.89, P = .02-.04), while serum and liver total PS levels were positively interrelated ( r = 0.98, P < .01). Any liver histopathology was equally common while portal inflammation more frequent (57 vs 0%, P = .02) in PN-dependent patients. All liver PS fractions correlated positively with histologic portal inflammation ( r = 0.53-0.66, P < .05), and their total concentration was significantly ( P = .01) higher among patients with versus without portal inflammation. In PN-dependent patients, liver fibrosis and any histopathology correlated with liver campesterol and stigmasterol levels ( r = 0.79-0.87, P ≤ .03). CONCLUSION: Among children with IF, parenteral PSs accumulate in the liver, reflect their increased serum levels, and relate with biochemical liver injury, portal inflammation, and liver fibrosis, thus supporting their role in promoting liver damage.

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.

Incidence, survival and cause-specific mortality in alcoholic liver disease: a population-based cohort study.

OBJECTIVE: We studied the incidence of severe ALD requiring hospitalization in Finland, and survival and causes of death among the ALD patients. METHODS: A cohort of 11,873 persons (8796 men and 3077 women) with diagnosis of ALD during the years 1996-2012 was identified from Finnish national Inpatient Register. The annual incidence of alcoholic hepatitis (AH) and alcoholic liver cirrhosis was calculated. The cohort was combined with the data from national Cause of Death Register of Statistics Finland. RESULTS: The incidence of alcoholic liver cirrhosis increased from 8.8/100,000 in year 2001 to 14.6/100,000 in year 2012 among men and from 2.4 to 4.2/100,000 among women. The incidence of AH increased from 3.7 to 6.5/100,000 among men and from 1.3 to 2.7/100,000 among women. The relative 5-year survival ratios of patients with alcoholic liver cirrhosis and AH were 29 and 50% among men and 38 and 52% among women, respectively. Out of 8440 deaths, 65% were due to alcoholic-related causes. The risk of death among ALD patients was increased in malignancies (SMR 6.82; 95% CI: 6.35-7.29), cardiovascular diseases (6.13; 5.74-6.52), respiratory diseases (7.86; 6.70-9.10), dementia (3.31; 2.41-4.44) and accidents and violence (11.12; 10.13-12.15). CONCLUSIONS: The incidence of AH and alcoholic liver cirrhosis is increasing. The survival is poor. Most deaths are alcohol-related and other common causes of excess deaths are cancers especially in the upper aerodigestive tract and cardiovascular, digestive and respiratory diseases as well as violence and accidents.

Cancer incidence among alcoholic liver disease patients in Finland: A retrospective registry study during years 1996-2013.

Both alcohol abuse and liver cirrhosis are known risk factors for various cancers. This article was aimed to assess the long-term risk of malignancies among patients with severe alcoholic liver disease (ALD), i.e., alcoholic liver cirrhosis and alcoholic hepatitis. A cohort of 8,796 male and 3,077 female ALD patients from 1996 to 2012 was identified from the Finnish National Hospital Discharge Register. This nationwide cohort was combined with the data from the Finnish Cancer Registry for incidence of malignancies during the years 1996-2013. The cancer cases diagnosed were compared with the number of cancers in the general population. The number of malignancies in our cohort was 1,052 vs. 368 expected. There was statistically significant excess of cancers of the liver, (standardized incidence ratio [SIR] 59.20; 95% CI 53.11-65.61), pancreas (SIR 3.71; 95% CI 2.72-4.94), pharynx (SIR 9.25; 95% CI 6.05-13.56), mouth (SIR 8.31; 95% CI 4.84-13,29), oesophagus (SIR 7.92; 95% CI 5.49-11.07), tongue (SIR 7,21; 95% CI 3.60-12.89), larynx (SIR 5.20; 95% CI 2.77-8.89), lung (SIR 2.77; 95% CI 2.27-3.32), stomach (SIR 2.76; 95% CI 1.79-4.07), kidney (SIR 2.69; 95% CI 1.84-3.79) and colon (SIR 2.33; 95% CI 1.70-3.11). There was no decreased risk of any cancer among ALD patients. Severe ALD is associated with markedly increased risk of malignancies. The risk is especially high for hepatocellular carcinoma, but also significantly increased for cancers of the upper aerodigestive tract, pancreas and kidneys, and warrants cancer surveillance in selected cases.

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.

Does fecal calprotectin predict short-term relapse after stopping TNFα-blocking agents in inflammatory bowel disease patients in deep remission?

BACKGROUND AND AIMS: This prospective multicenter study examined whether elevated fecal calprotec tin (FC) concentrations after stopping TNFα-blocking therapy can predict clinical or endoscopic relapse. In addition, we evaluated the impact of histological remission on the relapse risk. METHODS: We enrolled inflammatory bowel disease (IBD) patients who were in clinical, endoscopic, and FC-based (< 100 µg/g) remission after a minimum 11 months of TNFα-blocking therapy. The patients were followed-up for 12 months after the discontinuation of TNFα-blocking therapy. FC was collected monthly for the first 6 months and thereafter every second month. Ileocolonoscopy was performed at inclusion, at 4 months, at the study end, and at the time of clinical relapse. RESULTS: Of 52 enrolled patients, 49 (16 Crohn's disease, 33 ulcerative colitis/IBD unclassified) provided the stool samples requested and comprised the study group. During the follow-up, 15/49 (31%) relapsed, whereas 34 (69%) remained in remission. Patients relapsing showed constantly elevated FC levels for a median of 94 (13-317) days before the relapse. Significant increase in median FC levels was seen 2 (p = 0.0014), 4 (p = 0.0056), and 6 (p = 0.0029) months before endoscopic relapse. Constantly normal FC concentrations during the follow-up were highly predictive for clinical and endoscopic remission. Normal FC concentrations in patients with remission were associated with histological remission. CONCLUSION: FC seems to increase and remain elevated before clinical or endoscopic relapse, suggesting that it can be used as a surrogate marker for predicting and identifying patients requiring close follow-up in clinical practice.

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.

Outcome after discontinuation of TNFα-blocking therapy in patients with inflammatory bowel disease in deep remission.

BACKGROUND: Few data are available on the disease course in patients with inflammatory bowel disease (IBD) in deep remission after discontinuing tumor necrosis factor α (TNFα)-blocking therapy. In this prospective multicenter study, we evaluated the relapse rate, predictive factors, and the response to retreatment after discontinuation of TNFα-blocking therapy in patients with IBD in deep remission. METHODS: We recruited 52 patients (17 Crohn's disease, 30 ulcerative colitis, and 5 IBD unclassified) in clinical, endoscopic, and fecal calprotectin-based (<100 µg/g) remission after at least 1 year of TNFα-blocking therapy. Clinical and endoscopic remission and relapse were defined according to validated indices. After discontinuation of therapy, the patients were followed up with endoscopic assessment at 4 and 12 months. In the event of a clinical relapse with endoscopically active disease or minor clinical symptoms but severe endoscopic relapse, TNFα-blocking therapy was restarted. RESULTS: After a median follow-up time of 13 (range, 12-15) months, 17/51 (33%) patients relapsed (5/17 Crohn's disease, 12/34 ulcerative colitis/IBD unclassified, 1 patient lost to follow-up at 6 mo). Ten experienced clinical and endoscopic relapse, 5 clinical relapse with mild endoscopic activity, and 2 severe endoscopic relapse. No specific predictive factors were associated with the relapse. Retreatment was effective in 94% of patients. CONCLUSIONS: After cessation of TNFα-blocking therapy in patients with IBD in deep remission, up to 67% remained in clinical remission during the 12-month follow-up. Importantly, 85% of these patients sustained endoscopic remission. The response to restart of TNFα antagonists was effective and well tolerated.

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.

Achievement of deep remission during scheduled maintenance therapy with TNFα-blocking agents in IBD.

BACKGROUND AND AIMS: Deep remission, meaning clinical remission with mucosal healing (MH), with anti-tumor necrosis factor-alpha (TNF-α) agents is a new target for therapy in inflammatory bowel disease (IBD). Our aim was to study how often patients on TNF-α blocking therapy actually achieve deep remission. METHODS: The total of 252 IBD patients retrospectively included (183 Crohn's disease (CD), 62 ulcerative colitis (CU) or 7 inflammatory bowel disease unclassified-type colitis (IBDU)) received TNFα-antagonists (177 infliximab, 75 adalimumab) for at least 11 months and underwent ileocolonoscopy. We reviewed endoscopic and histological findings, clinical symptoms, C-reactive protein (CRP), and fecal calprotectin (FC) levels, and data on TNF-α blocking therapy. Defining deep remission as no clinical symptoms with endoscopic remission (the simple endoscopic score for Crohn's disease, SES-CD 0-2 or Mayo endoscopic subscore 0-1). RESULTS: Of the 252 patients, 168 (67%) were in clinical remission and 122 (48%) in deep remission after a median of 23 months of maintenance therapy. Of the 183 CD patients, 117 (64%) reached clinical remission and 79 (43%) deep remission. Of the UC patients, 52 (75%) were in clinical remission and 43 (62%) in deep remission. The majority of patients in deep remission (n=99, 81%) also had histologically inactive disease. Both median CRP and FC levels were significantly lower in patients with deep remission. CONCLUSION: Reassuringly, half of the IBD patients on the TNFα-blocking maintenance therapy achieved deep remission. The majority of patients in deep remission also achieved histological remission.