| 1. |
- Akbari, Camilla, et al.
(author)
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Long-term major adverse liver outcomes in 1,260 patients with non-cirrhotic NAFLD
- 2024
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In: JHEP Reports. - : Elsevier. - 2589-5559. ; 6:2
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Journal article (peer-reviewed)abstract
- Background & AimsLong-term studies of the prognosis of NAFLD are scarce. Here, we investigated the risk of major adverse liver outcomes (MALO) in a large cohort of patients with NAFLD.MethodsWe conducted a cohort study with data from Swedish university hospitals. Patients (n = 1,260) with NAFLD without cirrhosis were diagnosed through biopsy or radiology, and had fibrosis estimated through vibration-controlled transient elastography, biopsy, or FIB-4 score between 1974 and 2020 and followed up through 2020. Each patient was matched on age, sex, and municipality with up to 10 reference individuals from the general population (n = 12,529). MALO were ascertained from Swedish national registers. The rate of events was estimated by Cox regression.ResultsMALO occurred in 111 (8.8%, incidence rate = 5.9/1,000 person-years) patients with NAFLD and 197 (1.6%, incidence rate = 1.0/1,000 person-years) reference individuals during a median follow up of 13 years. The rate of MALO was higher in patients with NAFLD (hazard ratio = 6.6; 95% CI = 5.2–8.5). The risk of MALO was highly associated with the stage of fibrosis at diagnosis. In the biopsy subcohort (72% of total sample), there was no difference in risk between patients with and without non-alcoholic steatohepatitis. The 20-year cumulative incidences of MALO were 2% for the reference population, 3% for patients with F0, and 35% for F3. Prognostic information from biopsy was comparable to FIB-4 (C-indices around 0.73 vs. 0.72 at 10 years).ConclusionsThis study provides updated information on the natural history of NAFLD, showing a high rate of progression to cirrhosis in F3 and a similar prognostic capacity of non-invasive tests to liver biopsy.Impact and implicationsSeveral implications for clinical care and future research may be noted based on these results. First, the risk estimates for cirrhosis development are important when communicating risk to patients and deciding on clinical monitoring and treatment. Estimates can also be used in updated health-economic evaluations, and for regulatory agencies. Second, our results again highlight the low predictive information obtained from ascertaining NASHstatus by histology and call for more objective means by which to define NASH. Such methods may include artificial intelligence-supported digital pathology. We highlight that NASH is most likely the causal factor for fibrosis progression in NAFLD, but the subjective definition makes the prognostic value of a histological NASH diagnosis of limited value. Third, the finding that prognostic information from biopsy and the very simple Fibrosis-4 score were comparable is important as it may lead to fewer biopsies and further move the field towards non-invasive means by which to define fibrosis and, importantly, use non-invasive tests as outcomes in clinical trials. However, all modalities had modest discriminatory capacity and new risk stratification systems are needed in NAFLD. Repeated measures of non-invasive scores may be a potential solution.
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| 2. |
- Ebeling Barbier, Charlotte, et al.
(author)
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Placement of a transjugular intrahepatic portosystemic shunt in addition to recanalization of acute and chronic portomesenteric vein occlusions : a retrospective evaluation
- 2020
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In: Acta Radiologica, Supplement. - : SAGE PUBLICATIONS LTD. - 0365-5954 .- 2058-4601. ; 9:10
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Journal article (peer-reviewed)abstract
- Background: Portomesenteric vein thrombosis may be life-threatening due to bowel ischemia caused by venous stasis, or variceal bleeding caused by portal hypertension. Purpose: To evaluate the effectiveness and safety of recanalization combined with transjugular intrahepatic portosystemic shunt in acute and chronic portomesenteric vein thrombosis in patients with and without liver cirrhosis. Material and Methods: 21 consecutive patients (5 women, 16 men; mean 48 years) with portomesenteric vein thrombosis (8 acute, 13 chronic) treated at the Interventional Radiology department between March 2014 and September 2018 were retrospectively reviewed. The main portal vein was completely obliterated and the portomesenteric vein thrombosis extended into the superior mesenteric vein in all patients. The portomesenteric vein thromboses were recanalized transhepatically, a transjugular intrahepatic portosystemic shunt was inserted, thrombectomy was performed in acute portomesenteric vein thrombosis, and angioplasty with or without additional stenting was performed in chronic portomesenteric vein thrombosis. Results: Recanalization was successful in 8/8 patients (100%) with acute portomesenteric vein thrombosis, and in 11/13 patients (85%) with chronic portomesenteric vein thrombosis. In 12 patients, blood flow was restored in one session. Several sessions were more frequently needed in patients with acute portomesenteric vein thrombosis compared to those with chronic portomesenteric vein thrombosis (p = 0.003). Re-occlusion occurred and was recanalized in 10/19 patients and was more frequent in patients with chronic (n = 8/11) than on those with acute (n = 2/8) portomesenteric vein thrombosis (p = 0.04). Adverse events occurred in five patients. There was no 30-day mortality. Conclusion: Recanalization and insertion of a transjugular intrahepatic portosystemic shunt is safe and effective in patients with acute and chronic portomesenteric vein thrombosis with or without cirrhosis. Recanalization was more likely to stay patent in acute compared with chronic portomesenteric vein thrombosis.
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| 3. |
- Fridén, Michael, et al.
(author)
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Hepatic Unsaturated Fatty Acids Are Linked to Lower Degree of Fibrosis in Non-alcoholic Fatty Liver Disease
- 2022
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In: Frontiers in Medicine. - : Frontiers Media SA. - 2296-858X. ; 8
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Journal article (peer-reviewed)abstract
- Background: The hepatic lipidome of patients with early stages of non-alcoholic fatty liver disease (NAFLD) has been fairly well-explored. However, studies on more progressive forms of NAFLD, i.e., liver fibrosis, are limited. Materials and methods: Liver fatty acids were determined in cholesteryl esters (CE), phospholipids (PL), and triacylglycerols (TAG) by gas chromatography. Cross-sectional associations between fatty acids and biopsy-proven NAFLD fibrosis (n = 60) were assessed using multivariable logistic regression models. Stages of fibrosis were dichotomized into none-mild (F0–1) or significant fibrosis (F2–4). Models were adjusted for body-mass index (BMI), age and patatin-like phospholipase domain-containing protein 3 (PNPLA3 rs738409) (I148M) genotype. A secondary analysis examined whether associations from the primary analysis could be confirmed in the corresponding plasma lipid fractions. Results: PL behenic acid (22:0) was directly associated [OR (95% CI): 1.86 (1.00, 3.45)] whereas PL docosahexaenoic acid (22:6n-3) [OR (95% CI): 0.45 (0.23, 0.89)], TAG oleic acid (18:1n-9) [OR (95% CI): 0.52 (0.28, 0.95)] and 18:1n-9 and vaccenic acid (18:1n-7) (18:1) [OR (95% CI): 0.52 (0.28, 0.96)] were inversely associated with liver fibrosis. In plasma, TAG 18:1n-9 [OR (95% CI): 0.55 (0.31, 0.99)], TAG 18:1 [OR (95% CI): 0.54 (0.30, 0.97)] and PL 22:0 [OR (95% CI): 0.46 (0.25, 0.86)] were inversely associated with liver fibrosis. Conclusion: Higher TAG 18:1n-9 levels were linked to lower fibrosis in both liver and plasma, possibly reflecting an altered fatty acid metabolism. Whether PL 22:6n-3 has a protective role, together with a potentially adverse effect of hepatic 22:0, on liver fibrosis warrants large-scale studies.
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| 4. |
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| 5. |
- Rosqvist, Fredrik, 1985-, et al.
(author)
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Circulating fatty acids from high-throughput metabolomics platforms as potential biomarkers of dietary fatty acids
- 2022
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In: Clinical Nutrition. - : Elsevier BV. - 0261-5614 .- 1532-1983. ; 41:12, s. 2637-2643
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Journal article (peer-reviewed)abstract
- Background Some fatty acids, i.e. n-3 and n-6 polyunsaturated fatty acids (PUFA), from metabolomics platforms based on nuclear magnetic resonance imaging (NMR) or liquid chromatography mass-spectrometry (LC-MS) are suggested to reflect dietary exposure. NMR and LC-MS are both relatively fast and cheap, however few studies have investigated their validity. Linoleic acid (LA) and docosahexaenoic acid (DHA), measured using gas chromatography (GC), are established biomarkers of dietary n-6 and n-3 PUFA intake, respectively.Objective To examine if circulating fatty acids derived from two commonly applied metabolomics platforms (using NMR and LC-MS) provide similar information compared to GC in two pooled population-based cohorts, one patient cohort, and in a randomized controlled trial (RCT).Methods Spearman rank correlations were conducted between LA and DHA in cholesteryl esters (CE) from GC and whole serum/plasma LA and DHA from the metabolomics platforms in a pooled population-based cohort of men and women (n ˜ 1100) (primary analysis). Secondary correlation analyses included fatty acid classes such as n-3 PUFA, n-6 PUFA, saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and total PUFA. Additionally, correlations were investigated for LA, DHA and the five fatty acid classes in phospholipids (PL), triacylglycerols (TAG) and non-esterified fatty acids (NEFA) in a RCT of n = 60 as well as in a population with biopsy-verified non-alcoholic fatty liver disease (NAFLD) (n = 59). Misclassification was examined using cross-tabulation and visualized using alluvial plots.Results Moderate to strong correlations (r = 0.51–0.81) were observed for LA and DHA in multiple lipid fractions in all cohorts using the NMR platform. For the pooled cohort, LA (r = 0.67, P < 0.0001) and DHA (r = 0.68, P < 0.0001) assessed in CE were strongly correlated with LA and DHA derived using NMR. Nearly half (49%) were correctly classified into their respective quartiles. Using LC-MS, only DHA (r = 0.44, P < 0.0001) demonstrated moderate correlations with DHA from GC.Conclusions Unless fatty acid data from GC analysis is available or feasible, NMR-based technology might be a better option than a LC-MS-based platform, at least for certain PUFA. This should be taken into account in future studies aiming to use circulating fatty acids as dietary biomarkers for the investigation of diet-disease relationships.
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| 6. |
- Rosqvist, Fredrik, 1985-, et al.
(author)
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Fatty acids in multiple circulating lipid fractions reflects the composition of liver triglycerides in humans
- 2022
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In: Clinical Nutrition. - : Elsevier BV. - 1532-1983 .- 0261-5614. ; 41:4, s. 805-809
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Journal article (peer-reviewed)abstract
- Background and aims: Fatty acids (e.g. 16:1n-7) and desaturase indices (e.g. stearoyl-CoA desaturase, SCD) in plasma cholesteryl esters (CE) and phospholipids (PL) are used as biomarkers of dietary fat quality and lipid metabolism and are associated with disease outcomes. Endogenously produced circulating fatty acids are believed to reflect composition of the liver, yet little data exist to support such relationship. We investigated associations between circulating fatty acids and fatty acids within the liver. Methods: Liver biopsies and blood were collected from n = 60 patients with non-alcoholic fatty liver disease. Fatty acids in CE, PL and triglycerides (TG) in plasma and liver were analyzed using gas chromatography. Associations were assessed using Spearman rank correlations. Results: Overall, fatty acids and desaturase indices in plasma PL and TG showed moderate–strong correlations with fatty acids and desaturase indices in corresponding lipid fractions in liver. For plasma CE, 16:1n-7 and SCD were correlated with 16:1n-7 and SCD in liver CE. Noteworthy, fatty acids in plasma CE and PL also showed moderate–strong correlations with fatty acids in liver TG (e.g. r = 0.82–0.87 for 16:1n-7 and r = 0.77 for SCD). Conclusion: We demonstrate that fatty acids in circulating lipid fractions, including CE, TG and PL, reflects the composition of liver TG in humans, suggesting that circulating fatty acids might be useful biomarkers for the fatty acid composition of the liver. As liver tissue is rarely available in cohort studies, our findings could enhance our understanding of plasma fatty acids as markers of hepatic lipid metabolism and their links to metabolic diseases.
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| 7. |
- Sennefelt Nyman, Sofi, et al.
(author)
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Peritumoral portal enhancement during transarterial chemoembolization : a potential prognostic factor for patients with hepatocellular carcinoma.
- 2022
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In: Acta Radiologica. - : SAGE Publications. - 0284-1851 .- 1600-0455. ; 63:10, s. 1323-1331
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Journal article (peer-reviewed)abstract
- BACKGROUND: Tumor response and survival varies in patients treated with transarterial chemoembolization (TACE) for intermediate stage hepatocellular carcinoma (HCC) and may be associated with several factors.PURPOSE: To evaluate safety and efficacy of TACE in patients with intermediate stage HCC and to identify factors related to tumor response and survival.MATERIAL AND METHODS: Consecutive patients with HCC treated with TACE between September 2008 and September 2018 were retrospectively reviewed.RESULTS: In 87 patients (71 men; mean age = 68 ± 9 years), 327 TACE treatments were performed (mean = 3/patient; range = 1-12). Mean and median overall survival were 32 and 19 months, respectively. Survival rates at 30 days, one, three, and five years were 99%, 71%, 19%, and 8%, respectively. Objective response (OR) was seen in 84% and disease control (DC) was seen in 92% of the patients. Patients in whom peritumoral portal lipiodol enhancement (PPLE) was seen during TACE had better OR (97 vs. 73%; P = 0.007) and DC (100 vs. 85%; P = 0.024), and a reduced risk of death (hazard ratio [HR] = 0.52; 95% confidence interval = 0.32-0.86) compared to those without PPLE. Severe adverse events were rare (15%) and occurred more often in patients with a larger tumor size.CONCLUSIONS: TACE was effective and safe in patients with intermediate stage HCC. Patients with PPLE during TACE had better tumor response and longer survival than those without PPLE. Severe adverse events occurred more often in patients with larger tumors.
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| 8. |
- Vessby, Johan, 1972-, et al.
(author)
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A two-step proteomic approach identifies candidate biomarker in ulcerative colitis with concomitant primary sclerosing cholangitis.
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Other publication (other academic/artistic)abstract
- Introduction: Ulcerative colitis (UC) with concomitant primary sclerosing cholangitis (PSC-UC or PSC-IBD) is today considered a unique IBD entity, including a more malignant disease course compared with classical UC. Biomarkers for identifying UC patients at risk of developing PSC is lacking, which may delay the onset of endoscopy surveillance. Mass spectrometric development has enabled the use of formalin-fixed paraffin embedded tissue (FFPE) for high resolution proteome analysis. In this study, we search for PSC-IBD proteomic fingerprints in FFPE by utilizing mass spectrometry.Methods: Protein was extracted out of FFPE colon archival samples from PSC-IBD (n=9), UC (n=7), and healthy controls (n=7). IBD-patients were all in clinical remission, without biologics or steroids, and all UC patients had a history of pancolitis. Samples were processed by the Multienzyme Digestion FASP and were analysed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Proteins were quantified using the Total Protein Approach. Data was analysed using linear regression and in a multiple manner using random forest algorithms. Candidate findings were validated in a second cohort (n: PSC-IBD=16 UC=21) using the same proteomic technique. To make an over-all proteome comparison, we performed principal component analysis, as well as a meta-analysis for the most prominent findings.Results: In the exploratory proteomic step, 7279 unique proteins were detected. After statistical analysis including multiple testing, the top-5 proteins (CD47, LSM7, NDUFAF4, AGPAT1 and THEM192) were selected as candidate proteins. When validating these findings in a confirmatory cohort, AGPAT1 was verified (p=0.009). According to meta-analysis, AGPAT1 was also found to be the most distinctive protein between PSC-IBD and UC. The overall proteomic profiles in step 1 and step 2 (7706 proteins) confirmed small biologic variations between the IBD-groups.Conclusions: In this two-step proteomic study on remissive IBD, we were able to verify AGPAT1 as a colonic PSC-IBD biomarker. We found high overall proteome resemblance, in contrast to the phenotypical differences existing between PSC-IBD and UC. Our findings have possible implication in future PSC-IBD diagnostics, and adds further knowledge to the evasive PSC-IBD phenotype.
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| 9. |
- Vessby, Johan, 1972-, et al.
(author)
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AGPAT1 as a Novel Colonic Biomarker for Discriminating Between Ulcerative Colitis With and Without Primary Sclerosing Cholangitis
- 2022
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In: Clinical and Translational Gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 2155-384X. ; 13:5
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Ulcerative colitis (UC) associated with primary sclerosing cholangitis (PSC-UC) is considered a unique inflammatory bowel disease (IBD) entity. PSC diagnosis in an IBD individual entails a significantly higher risk of gastrointestinal cancer; however, biomarkers for identifying patients with UC at risk for PSC are lacking. We, therefore, performed a thorough PSC-UC biomarker study, starting from archived colonic tissue.METHODS: Proteins were extracted out of formalin-fixed paraffin-embedded proximal colon samples from PSC-UC (n = 9), UC (n = 7), and healthy controls (n = 7). Patients with IBD were in clinical and histological remission, and all patients with UC had a history of pancolitis. Samples were processed by the multienzyme digestion FASP and subsequently analyzed by liquid chromatography-tandem mass spectrometry. Candidate proteins were replicated in an independent cohort (n: PSC-UC = 16 and UC = 21) and further validated by immunohistochemistry.RESULTS: In the discovery step, 7,279 unique proteins were detected. The top 5 most differentiating proteins (PSC-UC vs UC) based on linear regression analysis were selected for replication. Of these, 1-acetylglycerol-3-phosphate O-acyltransferase 1 (AGPAT1) was verified as higher in PSC-UC than UC (P = 0.009) in the replication cohort. A difference on the group level was also confirmed by immunohistochemistry, showing more intense AGPAT1 staining in patients with PSC-UC compared with UC.DISCUSSION: We present AGPAT1 as a potential colonic biomarker for differentiating PSC-UC from UC. Our findings have possible implication for future PSC-IBD diagnostics and surveillance.
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| 10. |
- Vessby, Johan, 1972-
(author)
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Studies of ulcerative colitis with concomitant primary sclerosing cholangitis : Beyond the clinical phenotype
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Inflammatory bowel disease (IBD) is a group of chronically relapsing immune-related disorders, engaging the gastrointestinal tract. Symptoms vary depending on inflammatory phenotype, but may include diarrhoea, bowel pain and weight loss. The two most common entities are Crohn's disease and ulcerative colitis (UC). A minority of IBD patients, particularly UC, is concomitantly affected by primary sclerosing cholangitis (PSC) – an inflammatory bile duct disease with dismal prognosis. IBD with associated PSC has distinct clinical features, and is regarded a unique IBD phenotype (PSC-IBD or PSC-UC). These features include higher rates of pancolitis, a milder clinical course, and an unexplained increased risk of colorectal neoplasia.This thesis aimed to compare immunological conditions in PSC-UC and UC, but also to search for molecular differences, potentially facilitating PSC-UC diagnosis.In paper I and II, we compared eosinophil and lymphocyte activation and regulation. PSC-UC had down-regulated mucosal eosinophil activity, during both flare and remission. Compared with UC, PSC-UC had a dampened, and less Th2 dominated mucosal immune response. This was evident by a low quote of CRTH2/CXCR3 CD4+ cells and a cytokine milieu with no upregulated Th2 cytokines. In contrast, PSC-UC had highly up-regulated cytokines in peripheral blood. Among these, sCD40 stood out as being most important for inter-group separation according to multivariate analysis.In paper III, we gave a detailed description of colonic tissue factor (TF) expression. We found discrepancies in TF depending on UC subtype and inflammatory status, where inflammation- associated TF up-regulation was detected in UC only. Also, we identified stromal TF deposition as a sensitive indicator of acute colitis.In paper IV, PSC-UC and UC intestinal proteomes were compared using LC-MS/MS. After detecting more than 7200 unique proteins in the discovery step, the top-five most distinctive findings were chosen for verification. Of these, AGPAT1 was verified, being significantly higher in PSC-UC. Despite phenotypical differences, the overall colonic proteome comparison showed high degree of concordance.In summary, this thesis demonstrates distinct immunological and molecular properties in PSC-UC, implying phenotypical features beyond clinical observations. Moreover, serum sCD40 and colonic AGPAT1 are suggested possible PSC-UC biomarkers.
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