Increased secretion of adipocyte-derived extracellular vesicles is associated with adipose tissue inflammation and the mobilization of excess lipid in human obesity.

BACKGROUND: Obesity is a worldwide epidemic characterized by adipose tissue (AT) inflammation. AT is also a source of extracellular vesicles (EVs) that have recently been implicated in disorders related to metabolic syndrome. However, our understanding of mechanistic aspect of obesity's impact on EV secretion from human AT remains limited. METHODS: We investigated EVs from human Simpson Golabi Behmel Syndrome (SGBS) adipocytes, and from AT as well as plasma of subjects undergoing bariatric surgery. SGBS cells were treated with TNFα, palmitic acid, and eicosapentaenoic acid. Various analyses, including nanoparticle tracking analysis, electron microscopy, high-resolution confocal microscopy, and gas chromatography-mass spectrometry, were utilized to study EVs. Plasma EVs were analyzed with imaging flow cytometry. RESULTS: EVs from mature SGBS cells differed significantly in size and quantity compared to preadipocytes, disagreeing with previous findings in mouse adipocytes and indicating that adipogenesis promotes EV secretion in human adipocytes. Inflammatory stimuli also induced EV secretion, and altered EV fatty acid (FA) profiles more than those of cells, suggesting the role of EVs as rapid responders to metabolic shifts. Visceral AT (VAT) exhibited higher EV secretion compared to subcutaneous AT (SAT), with VAT EV counts positively correlating with plasma triacylglycerol (TAG) levels. Notably, the plasma EVs of subjects with obesity contained a higher number of adiponectin-positive EVs than those of lean subjects, further demonstrating higher AT EV secretion in obesity. Moreover, plasma EV counts of people with obesity positively correlated with body mass index and TNF expression in SAT, connecting increased EV secretion with AT expansion and inflammation. Finally, EVs from SGBS adipocytes and AT contained TAGs, and EV secretion increased despite signs of less active lipolytic pathways, indicating that AT EVs could be involved in the mobilization of excess lipids into circulation. CONCLUSIONS: We are the first to provide detailed FA profiles of human AT EVs. We report that AT EV secretion increases in human obesity, implicating their role in TAG transport and association with adverse metabolic parameters, thereby emphasizing their role in metabolic disorders. These findings promote our understanding of the roles that EVs play in human AT biology and metabolic disorders.

Incidence of acute diverticulitis compared to appendicitis in emergency wards: a 10-year nationwide register and cohort study from Finland.

BACKGROUND: The two most common abdominal infections in emergency departments (ED) are acute appendicitis (AA) and sigmoid diverticulitis (AD). The frequency of ED visits for diverticulitis has increased strongly in many countries during recent decades. The aim of this study was to analyze the nationwide changes in AD rate requiring hospital admission compared to AA during a 10-year study period. METHODS: Register data of AD and AA in the whole of Finland were obtained between the years 2009 and 2018. Changes in the incidence and surgical treatment of AD in the whole country were compared to those of AA. Patient demographics and treatment of AD were analyzed in greater detail from a smaller cohort (n = 614). RESULTS: The incidence of AD increased from 262 to 413 cases (58%) per 100,000 inhabitants during 10 years and emergency surgery for AD decreased from 27 to 24 cases per 100,000 (11%). The incidence of AA remained stable and varied from 118 to 124 annual cases per 100,000 inhabitants. In a patient cohort of AD (n = 614), most of the patients (68%) had only one episode of diverticulitis during 10 years; 16% were operated urgently, with a mortality of 8%. Disease-specific mortality increased from 0% to 5.7% along with patient age when comparing the age groups <50 years and > 70 years, respectively. CONCLUSIONS: Our study indicates that the incidence of acute diverticulitis is still increasing and is now 2-3 times higher than that of appendicitis in emergency departments.

Robotic versus hybrid assisted ventral hernia repair: a prospective one-year comparative study of clinical outcomes.

BACKGROUND: Laparoscopic ventral hernia repair (LVHR) may be associated with chronic pain, seroma formation, bulging and failure to restore abdominal wall function. These outcomes are risk factors for hernia recurrence and poor quality of life (QoL). Our study evaluates whether robotic-assisted ventral hernia repair (rVHR) diminishes these complications compared to LVHR with primary closure of the defect (hybrid). METHODS: Thirty-eight consecutive patients undergoing incisional ventral hernia operation with fascial defect size from 3 to 6 cm were recruited between November 2019 and October 2020. Nineteen patients underwent rVHR and nineteen underwent hybrid operation. The main outcome measure was postoperative pain, evaluated with a visual analogue scale (VAS: 0-10) at 1-month and at 1-year. Hernia recurrence was evaluated with ultrasound examination and QoL using the generic SF-36 short form questionnaire. RESULTS: At the 1-month control visit, VAS scores were significantly lower in the rVHR group; 2.5 in the hybrid group and 0.3 in the rVHR group (p < 0.001). At the 1-year control, the difference in VAS scores was still significant, 2.8 vs 0.1 (p = 0.023). There was one hernia recurrence in the hybrid group (p = 0.331). QoL did not differ significantly between the study groups when compared to preoperative physical status at 1-year follow-up (p = 0.121). However, emotional status (p = 0.049) and social functioning (p = 0.039) improved significantly in the rVHR group. CONCLUSIONS: Robotic-assisted ventral hernia repair (rVHR) was less painful compared to hybrid repair at 1-month and at 1-year follow-up. In addition, improvement in social functioning status was reported with rVHR. TRIAL REGISTRATION ID: 5200658.

The FADS1 genotypes modify the effect of linoleic acid-enriched diet on adipose tissue inflammation via pro-inflammatory eicosanoid metabolism.

PURPOSE: Fatty acid desaturase (FADS) variants associate with fatty acid (FA) and adipose tissue (AT) metabolism and inflammation. Thus, the role of FADS1 variants in the regulation of dietary linoleic acid (LA)-induced effects on AT inflammation was investigated. METHODS: Subjects homozygotes for the TT and CC genotypes of the FADS1-rs174550 (TT, n = 25 and CC, n = 28) or -rs174547 (TT, n = 42 and CC, n = 28), were either recruited from the METabolic Syndrome In Men cohort to participate in an intervention with LA-enriched diet (FADSDIET) or from the Kuopio Obesity Surgery (KOBS) study. GC and LC-MS for plasma FA proportions and eicosanoid concentrations and AT gene expression for AT inflammatory score (AT-InSc) was determined. RESULTS: We observed a diet-genotype interaction between LA-enriched diet and AT-InSc in the FADSDIET. In the KOBS study, interleukin (IL)1 beta mRNA expression in AT was increased in subjects with the TT genotype and highest LA proportion. In the FADSDIET, n-6/LA proportions correlated positively with AT-InSc in those with the TT genotype but not with the CC genotype after LA-enriched diet. Specifically, LA- and AA-derived pro-inflammatory eicosanoids related to CYP450/sEH-pathways correlated positively with AT-InSc in those with the TT genotype, whereas in those with the CC genotype, the negative correlations between pro-inflammatory eicosanoids and AT-InSc related to COX/LOX-pathways. CONCLUSIONS: LA-enriched diet increases inflammatory AT gene expression in subjects with the TT genotype, while CC genotype could play a protective role against LA-induced AT inflammation. Overall, the FADS1 variant could modify the dietary LA-induced effects on AT inflammation through the differential biosynthesis of AA-derived eicosanoids.

Evaluation of the Effect of Bariatric Surgery-Induced Weight Loss on Knee Gait and Cartilage Degeneration.

The objective of the study was to investigate the effects of bariatric surgery-induced weight loss on knee gait and cartilage degeneration in osteoarthritis (OA) by combining magnetic resonance imaging (MRI), gait analysis, finite element (FE) modeling, and cartilage degeneration algorithm. Gait analyses were performed for obese subjects before and one-year after the bariatric surgery. FE models were created before and after weight loss for those subjects who did not have severe tibio-femoral knee cartilage loss. Knee cartilage degenerations were predicted using an adaptive cartilage degeneration algorithm which is based on cumulative overloading of cartilage, leading to iteratively altered cartilage properties during OA. The average weight loss was 25.7±11.0 kg corresponding to a 9.2±3.9 kg/m2 decrease in body mass index (BMI). External knee rotation moment increased, and minimum knee flexion angle decreased significantly (p < 0.05) after weight loss. Moreover, weight loss decreased maximum cartilage degeneration by 5±23% and 13±11% on the medial and lateral tibial cartilage surfaces, respectively. Average degenerated volumes in the medial and lateral tibial cartilage decreased by 3±31% and 7±32%, respectively, after weight loss. However, increased degeneration levels could also be observed due to altered knee kinetics. The present results suggest that moderate weight loss changes knee kinetics and kinematics and can slow-down cartilage degeneration for certain patients. Simulation results also suggest that prediction of cartilage degeneration is subject-specific and highly depend on the altered gait loading, not just the patient's weight.

The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver damage and is characterized by steatosis. Genetic factors increase risk for progressive NAFLD. A genome-wide association study showed that the rs641738 C>T variant in the locus that contains the membrane bound O-acyltransferase domain-containing 7 gene (MBOAT7, also called LPIAT1) and transmembrane channel-like 4 gene (TMC4) increased the risk for cirrhosis in alcohol abusers. We investigated whether the MBOAT7-TMC4 is a susceptibility locus for the development and progression of NAFLD. METHODS: We genotyped rs641738 in DNA collected from 3854 participants from the Dallas Heart Study (a multi-ethnic population-based probability sample of Dallas County residents) and 1149 European individuals from the Liver Biopsy Cross-Sectional Cohort. Clinical and anthropometric data were collected, and biochemical and lipidomics were measured in plasma samples from participants. A total of 2736 participants from the Dallas Heart Study also underwent proton magnetic resonance spectroscopy to measure hepatic triglyceride content. In the Liver Biopsy Cross-Sectional Cohort, a total of 1149 individuals underwent liver biopsy to diagnose liver disease and disease severity. RESULTS: The genotype rs641738 at the MBOAT7-TMC4 locus associated with increased hepatic fat content in the 2 cohorts, and with more severe liver damage and increased risk of fibrosis compared with subjects without the variant. MBOAT7, but not TMC4, was found to be highly expressed in the liver. The MBOAT7 rs641738 T allele was associated with lower protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 function. CONCLUSIONS: We provide evidence for an association between the MBOAT7 rs641738 variant and the development and severity of NAFLD in individuals of European descent. This association seems to be mediated by changes in the hepatic phosphatidylinositol acyl-chain remodeling.

FADS2 genotype regulates delta-6 desaturase activity and inflammation in human adipose tissue.

Obesity is associated with disturbed lipid metabolism and low-grade inflammation in tissues. The aim of this study was to investigate the association between FA metabolism and adipose tissue (AT) inflammation in the Kuopio Obesity Surgery study. We investigated the association of surgery-induced weight loss and FA desaturase (FADS)1/2 genotypes with serum and AT FA profile and with AT inflammation, measured as interleukin (IL)-1ß and NFκB pathway gene expression, in order to find potential gene-environment interactions. We demonstrated an association between serum levels of saturated and polyunsaturated n-6 FAs, and estimated enzyme activities of FADS1/2 genes with IL-1ß expression in AT both at baseline and at follow-up. Variation in the FADS1/2 genes associated with IL-1ß and NFκB pathway gene expression in SAT after weight reduction, but not at baseline. In addition, the FA composition in subcutaneous and visceral fat correlated with serum FAs, and the associations between serum PUFAs and estimated D6D enzyme activity with AT inflammation were also replicated with corresponding AT FAs and AT inflammation. We conclude that the polymorphism in FADS1/2 genes associates with FA metabolism and AT inflammation, leading to an interaction between weight loss and FADS1/2 genes in the regulation of AT inflammation.

Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease.

UNLABELLED: Excess hepatic storage of triglycerides is considered a benign condition, but nonalcoholic steatohepatitis (NASH) may progress to fibrosis and promote atherosclerosis. Carriers of the TM6SF2 E167K variant have fatty liver as a result of reduced secretion of very-low-density lipoproteins (VLDLs). As a result, they have lower circulating lipids and reduced risk of myocardial infarction. In this study, we aimed to assess whether TM6SF2 E167K affects liver damage and cardiovascular outcomes in subjects at risk of NASH. Liver damage was evaluated in 1,201 patients who underwent liver biopsy for suspected NASH; 427 were evaluated for carotid atherosclerosis. Cardiovascular outcomes were assessed in 1,819 controls from the Swedish Obese Subjects (SOS) cohort. Presence of the inherited TM6SF2 E167K variant was determined by TaqMan assays. In the liver biopsy cohort, 188 subjects (13%) were carriers of the E167K variant. They had lower serum lipid levels than noncarriers (P < 0.05), had more-severe steatosis, necroinflammation, ballooning, and fibrosis (P < 0.05), and were more likely to have NASH (odds ratio [OR]: 1.84; 95% confidence interval [CI]: 1.23-2.79) and advanced fibrosis (OR, 2.08; 95% CI: 1.20-3.55), after adjustment for age, sex, body mass index, fasting hyperglycemia, and the I148M PNPLA3 risk variant. However, E167K carriers had lower risk of developing carotid plaques (OR, 0.49; 95% CI: 0.25-0.94). In the SOS cohort, E167K carriers had higher alanine aminotransferase ALT and lower lipid levels (P < 0.05), as well as a lower incidence of cardiovascular events (hazard ratio: 0.61; 95% CI: 0.39-0.95). CONCLUSIONS: Carriers of the TM6SF2 E167K variant are more susceptible to progressive NASH, but are protected against cardiovascular disease. Our findings suggest that reduced ability to export VLDLs is deleterious for the liver.

Statin use and non-alcoholic steatohepatitis in at risk individuals.

BACKGROUND & AIMS: Excess hepatic free cholesterol contributes to the pathogenesis of non-alcoholic steatohepatitis, and statins reduce cholesterol synthesis. Aim of this study was to assess whether statin use is associated with histological liver damage related to steatohepatitis. METHODS: The relationship between statin use, genetic risk factors, and liver damage was assessed in a multi-center cohort of 1201 European individuals, who underwent liver biopsy for suspected non-alcoholic steatohepatitis. RESULTS: Statin use was recorded in 107 subjects, and was associated with protection from steatosis, NASH, and fibrosis stage F2-F4, in a dose-dependent manner (adjusted p<0.05 for all). In 100 treated patients matched 1:1 for modality of recruitment, gender, presence of IFG or type 2 diabetes, PNPLA3 I148M risk alleles, TM6SF2 E167K variant, age, and BMI, statin use remained associated with protection from steatosis (OR 0.09, 95% C.I. 0.01-0.32; p=0.004), steatohepatitis (OR 0.25, 95% C.I. 0.13-0.47; p<0.001), and fibrosis stage F2-F4 (OR 0.42, 95% C.I. 0.20-0.8; p=0.017). Results were confirmed in a second analysis, where individuals were matched within recruitment center (p<0.05 for all). The protective effect of statins on steatohepatitis was stronger in subjects not carrying the I148M PNPLA3 risk variant (p=0.02 for interaction), as statins were negatively associated with steatohepatitis in patients negative (p<0.001), but not in those positive for the I148M variant (p=n.s.). CONCLUSIONS: Statin use was associated with protection towards the full spectrum of liver damage in individuals at risk of non-alcoholic steatohepatitis. However, the I148M PNPLA3 risk variant limited this beneficial effect.

Ketone body production is differentially altered in steatosis and non-alcoholic steatohepatitis in obese humans.

BACKGROUND & AIMS: Levels of ketone bodies have been reported to be both increased and decreased in individuals with non-alcoholic fatty liver disease. We investigated whether the metabolism of ketone bodies is different in simple steatosis and in non-alcoholic steatohepatitis (NASH). METHODS: Serum low molecular weight molecules including ketone bodies were measured using high-throughput proton (1H) nuclear magnetic resonance in 116 (76 categorized unequivocally to those with normal liver, simple steatosis or NASH) morbidly obese individuals [age 47.3 ± 8.7 (mean ± SD) years, body mass index 45.1 ± 6.1 kg/m(2) , 39 men and 77 women] with histological assessment of NASH and analysis of gene expression in the liver. Finally, we correlated ß-hydroxybutyrate (ß-OHB) levels with NASH predicting score in Metabolic Syndrome in Men Study (METSIM) population study (n = 8749 non-diabetic men). RESULTS: Levels of ketone bodies were lower in individuals with NASH compared to individuals with simple steatosis (P = 0.004 and P = 0.018 for ß-OHB and acetoacetate respectively). Lower levels of ß-OHB were associated with the NASH predicting score in the METSIM study (P = 0.001). Liver inflammation correlated with mRNA expression of genes regulating ketolysis in the liver (Spearman correlation 0.379-0.388, P < 0.0006 for ACAT1, ACSS2 and BDH1). CONCLUSION: Lower levels of ketone bodies in individuals with NASH compared to individuals with simple steatosis suggest a decrease in ketone body metabolism in NASH.

Lipoprotein subclass metabolism in nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is associated with increased synthesis of triglycerides and cholesterol coupled with increased VLDL synthesis in the liver. In addition, increased cholesterol content in the liver associates with NASH. Here we study the association of lipoprotein subclass metabolism with NASH. To this aim, liver biopsies from 116 morbidly obese individuals [age 47.3 ± 8.7 (mean ± SD) years, BMI 45.1 ± 6.1 kg/m², 39 men and 77 women] were used for histological assessment. Proton NMR spectroscopy was used to measure lipid concentrations of 14 lipoprotein subclasses in native serum samples at baseline and after obesity surgery. We observed that total lipid concentration of VLDL and LDL subclasses, but not HDL subclasses, associated with NASH [false discovery rate (FDR) < 0.1]. More specifically, total lipid and cholesterol concentration of VLDL and LDL subclasses associated with inflammation, fibrosis, and cell injury (FDR < 0.1), independent of steatosis. Cholesterol concentration of all VLDL subclasses also correlated with total and free cholesterol content in the liver. All NASH-related changes in lipoprotein subclasses were reversed by obesity surgery. High total lipid and cholesterol concentration of serum VLDL and LDL subclasses are linked to cholesterol accumulation in the liver and to liver cell injury in NASH.

Adipose tissue INSR splicing in humans associates with fasting insulin level and is regulated by weight loss.

AIMS/HYPOTHESIS: The insulin receptor (INSR) has two protein isoforms based on alternative splicing of exon 11. INSR-A promotes cell growth whereas INSR-B predominantly regulates glucose homeostasis. In this study we investigated whether weight loss regulates INSR alternative splicing and the expression of splicing factors in adipose tissue. METHODS: To determine the relative ratio of the INSR splice variants, we implemented the PCR-capillary electrophoresis method with adipose tissue samples from two weight-loss-intervention studies, the Kuopio Obesity Surgery study (KOBS, n = 108) and a very low calorie diet (VLCD) intervention (n = 32), and from the population-based Metabolic Syndrome in Men study (METSIM, n = 49). RESULTS: Expression of INSR-B mRNA variant increased in response to weight loss induced by both bariatric surgery (p = 1 × 10(-5)) and the VLCD (p = 1 × 10(-4)). The adipose tissue expression of INSR-B correlated negatively with fasting insulin levels in the pooled data of the three studies (p = 3 × 10(-22)). Finally, expression of several splicing factors correlated negatively with the expression of the INSR-B variant. The strongest correlation was with HNRNPA1 (p = 1 × 10(-5)), a known regulator of INSR exon 11 splicing. CONCLUSIONS/INTERPRETATION: INSR splicing is regulated by weight loss and associates with insulin levels. The effect of weight loss on INSR splicing could be mediated by changes in the expression of splicing factors.

A population-based study on the prevalence of NASH using scores validated against liver histology.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease in Western countries. Diagnosis of NASH requires a liver biopsy. We estimated the prevalence of NASH non-invasively in a population-based study using scores validated against liver histology. METHODS: Clinical characteristics, PNPLA3 genotype at rs738409, and serum cytokeratin 18 fragments were measured in 296 consecutive bariatric surgery patients who underwent a liver biopsy to discover and validate a NASH score ('NASH score'). We also defined the cut-off for NASH for a previously validated NAFLD liver fat score to diagnose NASH in the same cohort ('NASH liver fat score'). Both scores were validated in an Italian cohort comprising of 380, mainly non-bariatric surgery patients, who had undergone a liver biopsy for NASH. The cut-offs were utilized in the Finnish population-based D2D-study involving 2849 subjects (age 45-74 years) to estimate the population prevalence of NASH. RESULTS: The final 'NASH Score' model included PNPLA3 genotype, AST and fasting insulin. It predicted NASH with an AUROC 0.774 (0.709, 0.839) in Finns and 0.759 (0.711, 0.807) in Italians (NS). The AUROCs for 'NASH liver fat score' were 0.734 (0.664, 0.805) and 0.737 (0.687, 0.787), respectively. Using 'NASH liver fat score' and 'NASH Score', the prevalences of NASH in the D2D study were 4.2% (95% CI: 3.4, 5.0) and 6.0% (5.0, 6.9%). Sensitivity analysis was performed by taking into account stochastic false-positivity and false-negativity rates in a Bayesian model. This analysis yielded population prevalences of NASH of 3.1% (95% stimulation limits 0.2-6.8%) using 'NASH liver fat score' and 3.6% (0.2-7.7%) using 'NASH Score'. CONCLUSIONS: The population prevalence of NASH in 45-74 year old Finnish subjects is ∼ 5%.

Desmosterol in human nonalcoholic steatohepatitis.

UNLABELLED: Dysregulation of the cholesterol synthesis pathway and accumulation of cholesterol in the liver are linked to the pathogenesis of nonalcoholic steatohepatitis (NASH). Therefore, we investigated the association of serum and liver levels of cholesterol precursors with NASH. Liver histology was assessed in 110 obese patients (Kuopio Obesity Surgery Study [KOBS] study, age 43.7 ± 8.1 years [mean ± standard deviation, SD], body mass index [BMI] 45.0 ± 6.1 kg/m(2) ). Serum and liver levels of cholesterol precursors were measured with gas-liquid chromatography. The association between cholesterol precursors and serum alanine aminotransferase (ALT), as a marker of liver disease, was also investigated in a population cohort of 717 men (Metabolic Syndrome in Men Study [METSIM] study, age 57.6 ± 5.8 years, BMI 27.1 ± 4.0 kg/m(2) ). Serum desmosterol levels and the desmosterol-to-cholesterol ratio were higher in individuals with NASH, but not in individuals with simple steatosis, compared to obese subjects with normal liver histology (P = 0.002 and P = 0.003, respectively). Levels of serum and liver desmosterol correlated strongly (r = 0.667, P = 1 × 10(-9) ), suggesting a shared regulation. Both serum and liver desmosterol levels correlated positively with steatosis and inflammation in the liver (P < 0.05). Serum desmosterol had a higher correlation with the accumulation of cholesterol in the liver than serum cholesterol. Serum desmosterol levels (P = 2 × 10(-6) ) and the serum desmosterol-to-cholesterol ratio (P = 5 × 10(-5) ) were associated with serum ALT in the population study. CONCLUSION: Levels of desmosterol in serum and the liver were associated with NASH. These results suggest that serum desmosterol is a marker of disturbed cholesterol metabolism in the liver. Whether desmosterol has a more specific role in the pathophysiology of NASH compared to other cholesterol precursors needs to be investigated.

Effect of statin use on outcome of symptomatic cholelithiasis: a case-control study.

BACKGROUND: Statins can modify bile cholesterol and, thus, the formation of gallstones. We examined whether statin use also modifies the severity of symptomatic gallstone disease and its treatment. METHODS: A total of 1,140 consecutive patients with symptomatic gallstone disease were recruited during 2008-2010 at Kuopio university hospital, Finland. Case-control analysis matched the patients using (n = 272) or not using (n = 272) statins by age and sex. The baseline characteristics of the patients, need and type of surgical treatment, duration of operation, perioperative bleeding, postoperative complications and overall mortality rate were compared statistically between the study groups. RESULTS: Morbidity and subsequent polypharmacy occurred more frequently among the patients with statins compared to the patients without statins. There were no significant differences between the statin users and non-users regarding surgical treatment (open vs. laparoscopic cholecystectomy). The mean operation time for laparoscopic cholecystectomy was 10% shorter for the patients with statin use than for the patients without. In addition, there was a non-significant tendency for statin users to bleed less during laparoscopic operations than the non-users. There were no differences in other procedure-related parameters (e.g., operation urgency, conversions, choledochotomies, complications and mortality) in patients with or without statins. CONCLUSIONS: Compared to no treatment, statin treatment was associated with a shorter operation time for laparoscopy cholecystectomy. Other surgical outcome parameters were similar in patients with or without statins, although statin users had more polypharmacy and circulatory illnesses than non-users.

Metabolic signatures of metabolic dysfunction-associated steatotic liver disease in severely obese patients.

BACKROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma. Still, most patients with MASLD die from cardiovascular diseases indicating metabolic alterations related to both liver and cardiovascular pathology. AIMS AND METHODS: The aim of this study was to assess biologic pathways behind MASLD progression from steatosis to metabolic dysfunction-associated steatohepatitis (MASH) using non-targeted liquid chromatography-mass spectrometry analysis in 106 severely obese individuals (78 women, mean age 47.7 7 ± 9.2 years, body mass index 41.8 ± 4.3 kg/m²) undergoing laparoscopic Roux-en-Y gastric bypass. RESULTS: We identified several metabolites that are associated with MASLD progression. Most importantly, we observed a decrease of lysophosphatidylcholines LPC(18:2), LPC(18:3), and LPC(20:3) and increase of xanthine when comparing those with steatosis to those with MASH. We found that indole propionic acid and threonine were negatively correlated to fibrosis, but not with the metabolic disturbances associated with cardiovascular risk. Xanthine, ketoleucine, and tryptophan were positively correlated to lobular inflammation and ballooning but also with insulin resistance, and dyslipidemia, respectively. The results did not change when taking into account the most important genetic risk factors of MASLD. CONCLUSIONS: Our findings suggest that there are several separate biological pathways, some of them independent of insulin resistance and dyslipidemia, associating with MASLD.

[Gastric bypass as weight loss operation: 10-year experience of one center and challenges of follow-up]. / Mahalaukun ohitus lihavuusleikkauksena: yhden keskuksen kymmenen vuoden kokemukset ja seurannan haasteet.

INTRODUCTION: Data about the implementation of long-term follow-up of weight loss operation patients and their nutritional status has been lacking in Finland. PATIENTS AND METHODS: We examined the postoperative complications and long-term outcome in respect of weight control, symptoms, nutritional status and medication of 173 patients having undergone gastric bypass. The data were collected from patient records and by questionnaires. RESULTS: Postoperative complications and weight loss were at the international level. The number of those using antidiabetic and antihypertensive drugs decreased. CONCLUSIONS: The results are in agreement with the international level, but follow-up treatment requires attention in Finland.

An insidious internal hernia 30 years after jejunoileal bypass: a case report.

Jejunoileal bypass (JIB) was an early bariatric procedure that involved bypassing most of the small bowel resulting in malabsorption and weight loss. Due to serious complications associated with the procedure, JIB was largely discontinued by the mid-1980s. We report the case of a 77-year-old woman with a history of JIB 31 years earlier. In 2022, she was hospitalized for acute abdominal pain. A computed tomography (CT) scan revealed a suspicion of internal hernia (IH) with a typical swirl sign. Due to the quick relief of symptoms an emergency surgery was not considered at the time. Nevertheless, a subsequent operation revealed a large mesenteric defect, adhesions and 100 cm of effective small bowel left. Although the procedure is no longer performed, some patients with JIB are still alive and develop late complications. To our knowledge, this is the first case report describing an IH in a patient who has undergone JIB.

Liver saturated fat content associates with hepatic DNA methylation in obese individuals.

BACKGROUND: Accumulation of saturated fatty acids (SFAs) in the liver is known to induce hepatic steatosis and inflammation causing non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Although SFAs have been shown to affect the epigenome in whole blood, pancreatic islets, and adipose tissue in humans, and genome-wide DNA methylation studies have linked epigenetic changes to NAFLD and NASH, studies focusing on the association of SFAs and DNA methylation in human liver are missing. We, therefore, investigated whether human liver SFA content associates with DNA methylation and tested if SFA-linked alterations in DNA methylation associate with NAFLD-related clinical phenotypes in obese individuals. RESULTS: We identified DNA methylation (Infinium HumanMethylation450 BeadChip) of 3169 CpGs to be associated with liver total SFA content (q-value < 0.05) measured using proton NMR spectroscopy in participants of the Kuopio Obesity Surgery Study (n = 51; mean ± SD:49.3 ± 8.5 years old; BMI:43.7 ± 6.2 kg/m2). Of these 3169 sites, 797 overlapped with previously published NASH-associated CpGs (NASH-SFA), while 2372 CpGs were exclusively associated with SFA (Only-SFA). The corresponding annotated genes of these only-SFA CpGs were found to be enriched in pathways linked to satiety and hunger. Among the 54 genes mapping to these enriched pathways, DNA methylation of CpGs mapping to PRKCA and TSPO correlated with their own mRNA expression (HumanHT-12 Expression BeadChip). In addition, DNA methylation of another ten of these CpGs correlated with the mRNA expression of their neighboring genes (p value < 0.05). The proportion of CpGs demonstrating a correlation of DNA methylation with plasma glucose was higher in NASH-SFA and only-SFA groups, while the proportion of significant correlations with plasma insulin was higher in only-NASH and NASH-SFA groups as compared to all CpGs on the Illumina 450 K array (Illumina, San Diego, CA, USA). CONCLUSIONS: Our results suggest that one of the mechanisms how SFA could contribute to metabolic dysregulation in NAFLD is at the level of DNA methylation. We further propose that liver SFA-related DNA methylation profile may contribute more to hyperglycemia, while insulin-related methylation profile is more linked to NAFLD or NASH. Further research is needed to elucidate the molecular mechanisms behind these observations.

Serum interleukin 1 receptor antagonist as an independent marker of non-alcoholic steatohepatitis in humans.

BACKGROUND & AIMS: Mechanisms leading to non-alcoholic steatohepatitis (NASH) have remained unclear, and non-invasive diagnosis of NASH is challenging. In this study, we investigated the benefits of measuring serum interleukin 1 receptor antagonist (IL-1RA) levels. METHODS: Liver biopsies from 119 morbidly obese individuals (47.5 ± 9.0 years, BMI 44.9 ± 5.9 kg/m(2)) were used for histological and gene expression assessment. In a cross-sectional population-based cohort of 6447 men (58 ± 7 years, BMI 27.0 ± 3.9 kg/m(2)) the association of serum IL1-RA with serum alanine aminotransferase (ALT) levels was investigated. RESULTS: Serum levels of IL-1RA, and liver mRNA expression of IL1RN are associated with NASH and the degree of lobular inflammation in liver (p<0.05). The decrease in serum IL-1RA level and expression of IL1RN after obesity surgery correlated with the improvement of lobular inflammation (p<0.05). We developed a novel NAFLD Liver Inflammation Score, including serum Il-1RA concentration, which performed better to diagnose NASH than did previously published scores. Results from the population study confirmed the potential of measuring serum IL-1RA level. The strongest determinants of the ALT concentration at the population level were Matsuda insulin sensitivity index (r(2)=0.130, p=7 × 10(-197)) and serum IL-1RA concentration (r(2)=0.074, p=1 × 10(-110)). IL-1RA concentrations associated significantly with ALT levels even after adjusting for BMI, alcohol consumption and insulin sensitivity (p=2 × 10(-21)). CONCLUSIONS: IL-1RA serum levels associate with liver inflammation and serum ALT independently of obesity, alcohol consumption and insulin resistance, suggesting a potential use of IL-1RA as a non-invasive inflammatory marker for NASH.