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Context: Guidelines recommend blood-based fibrosis biomarkers to identify advanced nonalcoholic fatty liver disease (NAFLD), which is particularly prevalent in patients with obesity. Objective: To study whether the degree of obesity affects the performance of liver fibrosis biomarkers in NAFLD. Design: Cross-sectional cohort study comparing simple fibrosis scores [Fibrosis-4 Index (FIB-4); NAFLD Fibrosis Score (NFS); aspartate aminotransferase to platelet ratio index; BARD (body mass index, aspartate-to-alanine aminotransferase ratio, diabetes); Hepamet Fibrosis Score (HFS)] and newer scores incorporating neo-epitope biomarkers PRO-C3 (ADAPT, FIBC3) or cytokeratin 18 (MACK-3). Setting: Tertiary referral center. Patients: We recruited overweight/obese patients from endocrinology (n = 307) and hepatology (n = 71) clinics undergoing a liver biopsy [median body mass index (BMI) 40.3 (interquartile range 36.0-44.7) kg/m(2)]. Additionally, we studied 859 less obese patients with biopsy-proven NAFLD to derive BMI-adjusted cutoffs for NFS. Main Outcome Measures: Biomarker area under the receiver operating characteristic (AUROC), sensitivity, specificity, and predictive values to identify histological stage >= F3 fibrosis or nonalcoholic steatohepatitis with >= F2 fibrosis [fibrotic nonalcoholic steatohepatitis (NASH)]. Results: The scores with an AUROC >= 0.85 to identify >= F3 fibrosis were ADAPT, FIB-4, FIBC3, and HFS. For fibrotic NASH, the best predictors were MACK-3 and ADAPT. The specificities of NFS, BARD, and FIBC3 deteriorated as a function of BMI. We derived and validated new cutoffs for NFS to rule in/out >= F3 fibrosis in groups with BM Is <30.0, 30.0 to 39.9, and >= 40.0 kg/m(2). This optimized its performance at all levels of BMI. Sequentially combining FIB-4 with ADAPT or FIBC3 increased specificity to diagnose >= F3 fibrosis. Conclusions: In obese patients, the best-performing fibrosis biomarkers are AD, Funding Agencies|Academy of FinlandAcademy of Finland [309263]; Novo Nordisk FoundationNovo Nordisk FoundationNovocure Limited; Sigrid Juselius FoundationSigrid Juselius Foundation; Orion Research Foundation sr; Yrjo Jahnsson Foundation sr; Maud Kuistila Memorial Foundation sr; Emil Aaltonen Foundation sr; Italian Ministry of Health (Ministero della Salute, Ricerca Finalizzata) [RF-2016-02364358]; Ricerca Corrente Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico; Fondazione IRCCS Ca Granda core COVID-19 Biobank [RC100017A]; Fondazione IRCCS Ca Granda "Liver BIBLE" [PR-0391]

Background and aims: In murine models of non-alcoholic fatty liver disease (NAFLD), liver damage associates with a deficiency of phosphatidylcholines (PCs), particularly polyunsaturated PCs (PUFA-PCs). We studied whether human PC metabolism is altered by NAFLD or by the protective genetic variant in HSD17B13 (rs72613567 T > TA). Method: In 143 obese patients with a liver biopsy and genotyping for HSD17B13 rs72613567, we analysed the hepatic lipidome (UPLC-MS). As the hepatic parenchymal fat fraction (HPFF) affects apparent concentrations of amphiphilic lipids, we normalised hepatic phospholipid concentrations to fat-free liver mass. To this end, we employed a state-of-the-art deep learning image analysis method (Aiforia Technologies) to accurately quantify HPFF in liver biopsies. Results: Total unadjusted hepatic PCs correlated negatively with HPFF (rs = −0.26, P < 0.01), but this association disappeared after normalising to fat-free liver mass (rs = 0.02, P = 0.81). With increasing HPFF, concentrations of especially saturated and monounsaturated PCs significantly increased, whereas concentrations of PUFA-PCs decreased. Accordingly, the hepatic triacylglycerol composition significantly correlated with that of hepatic PCs. In carriers of the protective variant in HSD17B13, as compared to non-carriers, the hepatic lipidome was enriched in especially PUFA-PCs. Conclusion: Patients with NAFLD have a deficiency of PUFA-PCs. The protective HSD17B13 rs72613567 variant opposes these changes, increasing intrahepatic PC concentrations.

Background and aims: Non-alcoholic fatty liver disease (NAFLD) is associated with increased circulating bile acids (BAs). It is unknown whether this reflects altered intrahepatic BA metabolism due to NAFLD or the associated insulin resistance (IR). To dissociate steatosis from IR, we compared BA metabolism in NAFLD associated with either IR or high genetic risk. Method: In 106 patients undergoing a liver biopsy, we analysed serum/liver BAs, the hepatic transcriptome (RNA-seq), and concentrations of plasma FGF-19 (marker of intestinal BA metabolism). Using HOMA-IR and a validated weighted Polygenic Risk Score (PRS) for NAFLD, we divided the patients into matched groups to compare the effects of NAFLD associated with IR (‘High HOMA-IR’ vs. ‘LowHOMA-IR’) or with high genetic risk (‘High PRS’ vs. ‘Low PRS’) on BA metabolism. Results: An untargeted analysis identified distinct clusters of patients with simultaneously increased BAs, HOMA-IR, and liver fat content. Compared to ‘Low HOMA-IR’, patients with ‘High HOMA-IR’ had significantly higher total (+57%, P = 0.011) and especially conjugated (+82%, P = 0.002) serum BAs, but unchanged hepatic BAs. Expression of the primary hepatic BA uptake transporter NTCP was down-regulated, while plasma FGF-19 was unchanged. Despite having the same degree of steatosis and NASH compared to the ‘High HOMA-IR’ group, patients with ‘High PRS’ had similar serum/liver BAs compared to those with ‘Low PRS’. Stage F3-F4 liver fibrosis independently predicted higher serum BAs. Conclusion: In NAFLD without advanced fibrosis, serum BAs are increased due to IR, which may impair hepatocellular BA uptake. Intrahepatic BAs are unchanged in NAFLD.

Carriers of the hydroxysteroid 17-β dehydrogenase 13 (HSD17B13) gene variant (rs72613567:TA) have a reduced risk of NASH and cirrhosis but not steatosis. We determined its effect on liver histology, lipidome, and transcriptome using ultra performance liquid chromatography-mass spectrometry and RNA-seq. In carriers and noncarriers of the gene variant, we also measured pathways of hepatic fatty acids (de novo lipogenesis [DNL] and adipose tissue lipolysis [ATL] using 2H2O and 2H-glycerol) and insulin sensitivity using 3H-glucose and euglycemic-hyperinsulinemic clamp) and plasma cytokines. Carriers and noncarriers had similar age, sex and BMI. Fibrosis was significantly less frequent while phospholipids, but not other lipids, were enriched in the liver in carriers compared with noncarriers. Expression of 274 genes was altered in carriers compared with noncarriers, consisting predominantly of downregulated inflammation-related gene sets. Plasma IL-6 concentrations were lower, but DNL, ATL and hepatic insulin sensitivity were similar between the groups. In conclusion, carriers of the HSD17B13 variant have decreased fibrosis and expression of inflammation-related genes but increased phospholipids in the liver. These changes are not secondary to steatosis, DNL, ATL, or hepatic insulin sensitivity. The increase in phospholipids and decrease in fibrosis are opposite to features of choline-deficient models of liver disease and suggest HSD17B13 as an attractive therapeutic target., Funding Agencies:Elucidating Pathways of Steatohepatitis consortium - Horizon 2020 Framework Program of the European Union 634413Innovative Medicines Initiative 2 Joint Undertaking 777377European Union (EU)European Federation of Pharmaceutical Industries and Associations Academy of FinlandEVO Sigrid Juselius FoundationMinistry of Education, Universities and Research Italian National Research CouncilBritish Heart Foundation Senior Fellowship in Basic Science FS/15/56/31645Jalmari and Rauha Ahokas Foundation Paulo Foundation

BACKGROUND & AIMS: The I148M variant in PNPLA3 is the major genetic risk factor for non-alcoholic fatty liver disease (NAFLD). The liver is enriched with polyunsaturated triglycerides (PUFA-TGs) in PNPLA3-I148M carriers. Gene expression data indicate that PNPLA3 is liver-specific in humans, but whether it functions in adipose tissue (AT) is unknown. We investigated whether PNPLA3-I148M modifies AT metabolism in human NAFLD. METHODS: Profiling of the AT lipidome and fasting serum non-esterified fatty acid (NEFA) composition were conducted in 125 volunteers (PNPLA3148MM/MI , n=63; PNPLA3148II , n=62). AT fatty acid composition was determined in 50 volunteers homozygous for the variant (PNPLA3148MM , n=25) or lacking the variant (PNPLA3148II , n=25). Whole-body insulin sensitivity of lipolysis was determined using [2 H5 ]glycerol, and PNPLA3 mRNA and protein levels were measured in subcutaneous AT and liver biopsies in a subset of the volunteers. RESULTS: PUFA-TGs were significantly increased in AT in carriers versus non-carriers of PNPLA3-I148M. The variant did not alter the rate of lipolysis or the composition of fasting serum NEFAs. PNPLA3 mRNA was 33-fold higher in the liver than in AT (p<0.0001). In contrast, PNPLA3 protein levels per tissue protein were 3-fold higher in AT than the liver (p<0.0001) and 9-fold higher when related to whole-body AT and liver tissue masses (p<0.0001). CONCLUSIONS: Contrary to previous assumptions, PNPLA3 is highly abundant in AT. PNPLA3-I148M locally remodels AT TGs to become polyunsaturated as it does in the liver, without affecting lipolysis or composition of serum NEFAs. Changes in AT metabolism do not contribute to NAFLD in PNPLA3-I148M carriers., Funding Agencies:European Union (EU) 634413777377-2British Heart Foundation FS/15/56/31645Sigrid Juselius FoundationAcademy of Finland 309263EVO

Background and aims: Diagnostic scoring is a method for stratifying patients according to the probability of appendicitis, and therefore works as an excellent basis for a diagnostic algorithm. This study aimed at developing a new diagnostic score, the Adult Appendicitis Score (AAS), and validating its routine use as an integral part of a new diagnostic algorithm. Diagnostic accuracy of the imaging studies depends on the pre-test probability of the disease. This study aimed to assess how accurate the imaging was in various AAS-stratified pre-test probability groups. The effect of in-hospital delay on the risk of perforation is controversial. The research in this thesis aimed to further clarify the matter. Patients and methods: The study enrolled 1737 patients with acute right lower quadrant abdominal pain. The first data collection of 829 patients was used to develop the AAS and compare it with two previously published scores as well as with the clinical assessment. The validation study of AAS enrolled 908 patients in two university hospitals. The negative appendectomy rate was compared between the first and second patient cohort. Patients that had diagnostic imaging were stratified into three probability-of-appendicitis groups according to the AAS, and the diagnostic accuracy of ultrasound (US) and computed tomography (CT) were compared between the score groups. To find the best marker to detect pre-hospital perforations, laboratory results and two previously published diagnostic scores were analyzed. The effects of total duration of symptoms, pre-hospital delay, and in-hospital delay on the risk of perforation were analyzed. Results: After the AAS was developed and incorporated into a new diagnostic algorithm the negative appendectomy rate decreased from 18.2% to 8.2%. With a specificity of 93%, the AAS stratified half of all patients with appendicitis into the high-probability group. The probability of appendicitis was only 7% for the low-probability group. The AA, Akuutti umpilisäketulehdus on tavallinen äkillisen vatsakivun syy. Vaikka umpilisäketulehduksen oireet ovat hyvin tunnettuja, tehdään edelleen myös turhia leikkauspäätöksiä. Uuden, väitöstutkimuksen yhteydessä kehitetyn, diagnostisen pisteytyksen käyttöönoton havaittiin vähentävän merkittävästi turhien umpilisäkepoistojen osuutta. LL Henna Sammalkorven tuoreessa väitöstutkimuksessa kehitettiin uusi aikuisten potilaiden tutkimisessa hyödynnettävä diagnostinen pisteytys, Adult Appendicitis Score. Pisteytyksellä potilaat, joilla epäillään umpilisäketulehdusta, jaotellaan kolmeen ryhmään umpilisäketulehduksen todennäköisyyden mukaan. Uuden pisteytyksen kehittämistä varten prospektiivisesti kerätty aineisto sisälsi 829 Meilahden sairaalassa umpilisäkkeen tulehduksen epäilyn vuoksi tutkittua potilasta. Aiempaa tarkempi pisteytys luotiin analysoimalla potilaiden oireita, tutkimuslöydöksiä ja laboratoriokoevastauksia. Uusi pisteytys oli tarkempi kuin päivystävien kirurgien arvio tai kumpikaan vertailussa mukana olleista aiemmin julkaistusta pisteytyksistä. Pisteytys on otettu rutiinikäyttöön osana uutta umpilisäkkeen tulehduksen diagnostista ohjeistusta Meilahden sairaalassa. Pisteytyksen käytän vaikutusta diagnostiikan tarkkuuteen tutkittiin 908 potilaan aineistossa Meilahdessa ja Kuopion Yliopistollisessa Sairalassa. Ennen uuden pisteytyksen käyttöönottoa 18,2 prosentissa Meilahden sairaalassa umpilisäkkeen tulehduksen epäilyn vuoksi tehdyissä leikkauksissa umpilisäke ei ollut tulehtunut. Uuden pisteytyksen käyttöönoton jälkeen luku laski 8,2 prosenttiin , Henna Sammalkorpi kuvaa tilannetta. Uuden pisteytyksen ohella tutkimuksessa selvitettiin sairaalaan saapumisen ja umpilisäkkeen poiston välisen aikavälin vaikutusta puhkeamariskiin. Tutkimuksessaan LL Henna Sammalkorpi havaitsi, että umpilisäkkeen puhkeaman todennäköisyyttä parhaiten kuvaava muuttuja on C-reaktiivinen proteiini, CRP. Potilailla, joiden CRP oli yli 99 jo sairaalaan tullessa, ei sairaalassa aiheutunut vii