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Background and Aims: Numerous studies have reported superior outcome for patients with hepatocellular carcinoma (HCC) in non-cirrhotic compared to cirrhotic livers. This cohort study aims to describe the clinical presentation, disease course, treatment approaches, and survival differences in a population-based setting., Methods: Data on patients diagnosed with HCC in Sweden between 2008 and 2018 were identified and extracted from the Swedish Liver registry (SweLiv). Descriptive and survival statistics were applied., Results: Among the 4259 identified patients, 34% had HCC in a non-cirrhotic liver. Cirrhotic patients presented at a younger age (median = 64 vs 74 years, p < 0.001) and with a poorer performance status (Eastern Cooperative Oncology Group (ECOG) = 0-1: 64% vs 69%, p = 0.024). Underlying liver disease was more prevalent among cirrhotic patients (81% vs 19%, p < 0.001). Tumors in non-cirrhotic livers were diagnosed at a more advanced stage (T3-T4: 46% vs 31%) and more frequently with metastatic disease at diagnosis (22% vs 10%, p < 0.001). Tumors were significantly larger in non-cirrhotic livers (median size of largest tumor 7.5 cm) compared to cirrhotic livers (3.5 cm) (p < 0.001). Curative interventions were more commonly intended (45% vs 37%, p < 0.001) and performed (40% vs 31%, p < 0.001) in the cirrhotic vs non-cirrhotic patients. Median survival was 19 months (95% confidence interval (CI) = 18-21 months), in patients with cirrhosis as compared to 13 months in non-cirrhotic patients (95% CI = 11-15) (p < 0.001). In the multivariable Cox regression model, cirrhosis was not an independent predictor of survival, neither among curatively nor palliatively treated patients., Conclusion: These population-based data show that patients with HCC in a cirrhotic liver receive curative treatment to a greater extent and benefit from superior survival compared to those with HCC in a non-cirrhotic liver. The differences in survival are more attributable to patient and tumor characteristics rather than the cirrhotic status itself., Clinical Trial Registration: not applicable. Patient confidentially: not applicable., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Hyperferritinaemia is associated with liver fibrosis severity in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), but the longitudinal implications have not been thoroughly investigated. We assessed the role of serum ferritin in predicting long-term outcomes or death., Design: We evaluated the relationship between baseline serum ferritin and longitudinal events in a multicentre cohort of 1342 patients. Four survival models considering ferritin with confounders or non-invasive scoring systems were applied with repeated five-fold cross-validation schema. Prediction performance was evaluated in terms of Harrell's C-index and its improvement by including ferritin as a covariate., Results: Median follow-up time was 96 months. Liver-related events occurred in 7.7%, hepatocellular carcinoma in 1.9%, cardiovascular events in 10.9%, extrahepatic cancers in 8.3% and all-cause mortality in 5.8%. Hyperferritinaemia was associated with a 50% increased risk of liver-related events and 27% of all-cause mortality. A stepwise increase in baseline ferritin thresholds was associated with a statistical increase in C-index, ranging between 0.02 (lasso-penalised Cox regression) and 0.03 (ridge-penalised Cox regression); the risk of developing liver-related events mainly increased from threshold 215.5 µg/L (median HR=1.71 and C-index=0.71) and the risk of overall mortality from threshold 272 µg/L (median HR=1.49 and C-index=0.70). The inclusion of serum ferritin thresholds (215.5 µg/L and 272 µg/L) in predictive models increased the performance of Fibrosis-4 and Non-Alcoholic Fatty Liver Disease Fibrosis Score in the longitudinal risk assessment of liver-related events (C-indices>0.71) and overall mortality (C-indices>0.65)., Conclusions: This study supports the potential use of serum ferritin values for predicting the long-term prognosis of patients with MASLD., Competing Interests: Competing interests: LM is supported by Investigator Driven Grants: Gilead, Intercept, Siemens Healthineers. Advisor/Consultancy: Alfa-Sigma, Boehringer-Ingelheim, BMS, Echosens, Galmed, Gilead Sciences, IBSA, Intercept, MEDA, MyGenomics, Merck Sharp & Dohme, Novartis, Pfizer, ProLon, Promethera, Resalis, Rottapharm-Madaus, Siemens Healthineers, Synageva. HH’s institutions have received research funding from Astra Zeneca, EchoSens, Gilead, Intercept, MSD, Novo Nordisk and Pfizer. He has served as consultant or on advisory boards for Astra Zeneca, Bristol Myers-Squibb, MSD and Novo Nordisk and has been part of hepatic events adjudication committees for Boehringer Ingelheim, KOWA and GW Pharma., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Desmin is a major cytoskeletal protein considered ubiquitous in mature muscle fibers. However, we earlier reported that a subgroup of muscle fibers in the soft palate of healthy subjects and obstructive sleep apnea patients (OSA) lacked immunoexpression for desmin. This raised the question of whether these fibers also lack messenger ribonucleic acid (mRNA) for desmin and can be considered a novel fiber phenotype. Moreover, some fibers in the OSA patients had an abnormal distribution and aggregates of desmin. Thus, the aim of the study was to investigate if these desmin protein abnormalities are also reflected in the expression of desmin mRNA in an upper airway muscle of healthy subjects and OSA patients., Methods: Muscle biopsies from the musculus uvulae in the soft palate were obtained from ten healthy male subjects and six male patients with OSA. Overnight sleep apnea registrations were done for all participants. Immunohistochemistry, in-situ hybridization, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) techniques were used to evaluate the presence of desmin protein and its mRNA., Results: Our findings demonstrated that a group of muscle fibers lacked expression for desmin mRNA and desmin protein in healthy individuals and OSA patients (12.0 ± 5.6% vs. 23.1 ± 10.8%, p = 0.03). A subpopulation of these fibers displayed a weak subsarcolemmal rim of desmin accompanied by a few scattered mRNA dots in the cytoplasm. The muscles of OSA patients also differed from healthy subjects by exhibiting muscle fibers with reorganized or accumulated aggregates of desmin protein (14.5 ± 6.5%). In these abnormal fibers, the density of mRNA was generally low or concentrated in specific regions. The overall quantification of desmin mRNA by RT-qPCR was significantly upregulated in OSA patients compared to healthy subjects (p = 0.01)., Conclusions: Our study shows evidence that muscle fibers in the human soft palate lack both mRNA and protein for desmin. This indicates a novel cytoskeletal structure and challenges the ubiquity of desmin in muscle fibers. Moreover, the observation of reorganized or accumulated aggregates of desmin mRNA and desmin protein in OSA patients suggests a disturbance in the transcription and translation process in the fibers of the patients., (© 2024. The Author(s).)

Ultrasound screening for hepatocellular carcinoma (HCC) in patients with liver cirrhosis has a poor sensitivity for small tumors. Circulating microRNAs (miRNAs) have been explored as HCC biomarkers, but results are diverging. Here, we evaluate if miRNAs up-regulated in HCC tissue can be detected in plasma and used as screening biomarkers for HCC. In this cross-sectional study, plasma, HCC tissue and surrounding non-tumorous liver tissue were collected from liver resections. Tissue miRNAs were identified and quantitated by RNA-sequencing analysis, and the fold-changes between HCC and surrounding liver tissue were calculated. The miRNAs up-regulated in HCCs were then re-analyzed in plasma from the same patients, and the miRNAs with the highest plasma levels were subsequently measured in plasma from an independent cohort of patients with cirrhosis or HCC. In tissues from 84 resected patients, RNA-sequencing detected 197 differentially expressed miRNAs, 40 of which had a raw count above 200 and were analyzed in plasma from the same cohort. Thirty-one miRNAs were selected for further analysis in 200 patients with HCC or cirrhosis. Of these, eleven miRNAs were significantly increased in HCC as compared to cirrhosis patients. Only miR-93-5p and miR-151a-3p were significantly associated with HCC, with an AUC of 0.662. In comparison, alpha-fetoprotein and des-gamma-carboxy prothrombin yielded an AUC of 0.816, which increased to 0.832 if miR-93-5p and miR-151a-3p were added. When including sex and age, the addition of miR-93-5p and miR-151a-3p did not further improve the AUC (from 0.910 to 0.911). In conclusion, micro-RNAs up-regulated in HCCs are detectable in plasma but have a poor performance as screening biomarkers of HCC.

Background and Aims: Previous studies have shown suboptimal screening for hepatitis D virus (HDV) among patients with chronic hepatitis B (CHB). This study presents the cascade of care for HDV infection in a major secondary referral centre in Southern Stockholm, Sweden., Methods: HBsAg+ve patients attending Karolinska University Hospital (KUH) from 1992 to 2022 were identified. The prevalence of anti-HDV and/or HDV RNA positivity, interferon (IFN) therapy and maintained virological responses (MVR) after HDV treatment were assessed. Also, time to anti-HDV testing was analysed in relation to liver-related outcomes with logistic regression., Results: Among 4095 HBsAg+ve persons, 3703 (90.4%) underwent an anti-HDV screening; within a median of 1.8 months (range 0.0-57.1) after CHB diagnosis. This screening rate increased over time, to 97.9% in the last decade. Overall, 310 (8.4%) were anti-HDV+ve, of which 202 (65.2%) were HDV RNA+ve. Eighty-five (42%) received IFN, and 9 (10.6%) achieved MVR at the last follow-up. The predictive factors for anti-HDV screening were Asian origin, diagnosis after the year 2012, HIV co-infection (negative factor) and HBV DNA level < 2000 IU/mL in univariable analysis, while HIV co-infection was the only remaining factor in multivariable analysis. Delayed anti-HDV test >5 years was independently associated with worsened liver-related outcomes (adjusted odds ratio = 7.6, 95% CI 1.8-31.6)., Conclusion: Higher frequency of HDV screening than previously published data could be seen among CHB patients at KUH in a low-endemic setting. Receiving a delayed screening test seems to be associated with worse outcomes, stressing the need of a strategy for timely HDV diagnosis., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Vocal signals, including human speech and birdsong, are produced by complicated, precisely coordinated body movements, whose execution is fitness-determining in resource competition and mate choice. While the acquisition and maintenance of motor skills generally requires practice to develop and maintain both motor circuitry and muscle performance, it is unknown whether vocal muscles, like limb muscles, exhibit exercise-induced plasticity. Here, we show that juvenile and adult zebra finches (Taeniopygia castanotis) require daily vocal exercise to first gain and subsequently maintain peak vocal muscle performance. Experimentally preventing male birds from singing alters both vocal muscle physiology and vocal performance within days. Furthermore, we find females prefer song of vocally exercised males in choice experiments. Vocal output thus contains information on recent exercise status, and acts as an honest indicator of past exercise investment in songbirds, and possibly in all vocalising vertebrates., (© 2023. The Author(s).)

Background: The international recommendations of HCC surveillance for African-born persons with chronic hepatitis B (CHB) without cirrhosis are divergent, probably due to scarce data on incidence rate (IR) for HCC., Methods: We assembled a cohort with prospectively collected data of Swedish residents of African origin with diagnosed CHB without cirrhosis at baseline from 1990 to 2015. Data from nationwide registers were used to calculate the sex-specific IR and IR ratio (incidence rate ratios) in relation to age, comorbidities, and birth region, using a generalized linear model with a log-link function and Poisson distribution., Results: Among 3865 African-born persons with CHB without cirrhosis at baseline, 31 (0.8%; 77.4% men) developed HCC during a median of 11.1 years of follow-up, with poor survival after HCC diagnosis. The mean age at HCC diagnosis was 46.8 (SD±14.7; range 23-79) in men. HCC IR exceeded the recommended surveillance threshold of 0.2%/year at ages 54 and 59 years in men and women, respectively, and at ages 20-40 years if HCV or HDV co-infection was present. African-born men with CHB had an incidence rate ratios of 10.6 (95% CI 4.4-31.5) for HCC compared to matched African-born peers without CHB, and an incidence rate ratios of 35.3 (95% CI 16.0-88.7) compared to a matched general population., Conclusions: African-born men with CHB without cirrhosis reached an IR of 0.2%/year between 50 and 60 years, and at younger ages if HCV or HDV co-infection was present. Our findings need further confirmation, and new cost-effectiveness analyses specific for young populations are needed, to provide personalized and cost-effective HCC surveillance., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background: The management of alcohol-associated cirrhosis has improved in the last decades, but whether the prognosis has changed over time is uncertain. We aimed to assess time trends in mortality and life expectancy in patients hospitalized with alcohol-associated cirrhosis., Methods: In this population-based cohort study, we used the Swedish national population and health registers to identify all patients with a first episode of in-hospital alcohol-associated cirrhosis from 1969 to 2019 (n = 22,658). Time trends in 1-year mortality were assessed with multivariable Cox regression. A flexible parametric model was fitted to evaluate loss in life expectancy., Results: Crude mortality was similar in the 2010s and 1980s (unadjusted HR = 1.00, 95% CI = 0.93-1.08, ptrend = 0.767). However, when adjusting for baseline characteristics, mortality was lower in the 2010s than in the 1980s (adjusted HR = 0.74, 95% CI = 0.68-0.80), including both liver- and nonliver-related mortalities. These results were consistent in men but not in women, where only nonliver mortality had decreased. The average loss in life expectancy for patients with alcohol-associated cirrhosis compared with the general population was similar throughout the study period (in the 2010s: 14.3 y shorter (95% CI = 13.7-14.9) in men and 15.8 years shorter (95% CI = 14.9-16.7) in women)., Conclusion: Mortality in patients hospitalized with alcohol-associated cirrhosis has improved somewhat when accounting for baseline characteristics, but the loss in life expectancy remains substantial. This underscores the need for new therapeutic options and health policy interventions to further improve the dismal prognosis and life expectancy of patients with alcohol-associated cirrhosis., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background & Aims: Long-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., Methods: We 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., Results: MALO 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)., Conclusions: This 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 Implications: Several 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., Competing Interests: HH’s institutions have received research funding from AstraZeneca, EchoSens, Gilead, Intercept, MSD, Novo Nordisk and Pfizer. He has served as a consultant for AstraZeneca and Novo Nordisk, and has been or is part of hepatic events adjudication committees for Boehringer Ingelheim, KOWA and GW Pharma. XZ, TJ, GF, and SSE are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own stock and/or hold stock options in Merck & Co., Inc., Rahway, NJ, USA. TW was an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, while conducting this work, and may own stock and/or hold stock options in Merck & Co., Inc., Rahway, NJ, USA. She is currently an employee of Johnson & Johnson, and may own stock and/or hold stock options in the company. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s), Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.)

Animal studies implicate one-carbon metabolism and DNA methylation genes in hepatocellular carcinoma (HCC) development in the setting of metabolic perturbations. Using human samples, we investigated the associations between common and rare variants in these closely related biochemical pathways and risk for metabolic HCC development in a multicenter international study. We performed targeted exome sequencing of 64 genes among 556 metabolic HCC cases and 643 cancer-free controls with metabolic conditions. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple comparisons. Gene-burden tests were used for rare variant associations. Analyses were performed in the overall sample and among non-Hispanic whites. The results show that among non-Hispanic whites, presence of rare functional variants in ABCC2 was associated with 7-fold higher risk of metabolic HCC (OR = 6.92, 95% CI: 2.38-20.15, P = 0.0004), and this association remained significant when analyses were restricted to functional rare variants observed in ≥2 participants (cases 3.2% versus controls 0.0%, P = 1.02 × 10-5). In the overall multiethnic sample, presence of rare functional variants in ABCC2 was nominally associated with metabolic HCC (OR = 3.60, 95% CI: 1.52-8.58, P = 0.004), with similar nominal association when analyses were restricted to functional rare variants observed in ≥2 participants (cases 2.9% versus controls 0.2%, P = 0.006). A common variant in PNPLA3 (rs738409[G]) was associated with higher HCC risk in the overall sample (P = 6.36 × 10-6) and in non-Hispanic whites (P = 0.0002). Our findings indicate that rare functional variants in ABCC2 are associated with susceptibility to metabolic HCC in non-Hispanic whites. PNPLA3-rs738409 is also associated with metabolic HCC risk., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Although multiple populations of macrophages have been described in the human liver, their function and turnover in patients with obesity at high risk of developing non-alcoholic fatty liver disease (NAFLD) and cirrhosis are currently unknown. Herein, we identify a specific human population of resident liver myeloid cells that protects against the metabolic impairment associated with obesity. By studying the turnover of liver myeloid cells in individuals undergoing liver transplantation, we find that liver myeloid cell turnover differs between humans and mice. Using single-cell techniques and flow cytometry, we determine that the proportion of the protective resident liver myeloid cells, denoted liver myeloid cells 2 (LM2), decreases during obesity. Functional validation approaches using human 2D and 3D cultures reveal that the presence of LM2 ameliorates the oxidative stress associated with obese conditions. Our study indicates that resident myeloid cells could be a therapeutic target to decrease the oxidative stress associated with NAFLD., (© 2023. The Author(s).)

Introduction: The prevalence of non-alcoholic fatty pancreas disease (NAFPD) is estimated as 2-46% among patients without known pancreatic diseases. An association between NAFPD and non-alcoholic fatty liver disease (NAFLD) has been proposed, as well as an association between NAFPD and pancreatic exocrine insufficiency (PEI)., Patients and Methods: Patients with histologically confirmed NAFLD were included in the study. The control group consisted of individuals included in a surveillance screening program. Magnetic resonance imaging (MRI) of the pancreas was performed in all patients and fat measurement was made using 2-point Dixon imaging. Fecal elastase-1 (FE-1) was performed to evaluate pancreatic exocrine function. Additionally, a 13 C-mixed triglyceride breath test (13 C-MTG-BT) was performed in patients with FE-1 < 200 μg/g., Results: Imaging signs of NAFPD were present in 17 (71%) patients; 11 (85%) from the NAFLD group and 6 (55%) from the control group. FE-1 < 200 μg/g was found in six (25%) patients (four in the NAFLD group and two in the control group); however, none of them had clinical symptoms of PEI. Therefore, in five out of six patients with low FE-1, a 13 C-MTG-BT was performed, showing normal results (>20.9%) in all tested patients. Furthermore, the serum nutritional panel was normal in all patients with low FE-1. A systematic review identified five studies relevant to the topic., Conclusion: NAFPD was found in 85% of patients with NAFLD and in 55% of control patients. We did not diagnose PEI in either group. A literature review showed PEI in 9-56% of patients with NAFPD.

The middle ear muscles have vital roles, yet their precise function in hearing and protection remains unclear. To better understand the function of these muscles in humans, the morphology, fiber composition, and metabolic properties of nine tensor tympani and eight stapedius muscles were analyzed with immunohistochemical, enzyme-histochemical, biochemical, and morphometric techniques. Human orofacial, jaw, extraocular, and limb muscles were used as references. The immunohistochemical analysis showed that the stapedius and tensor tympani muscles were markedly dominated by fibers expressing fast contracting myosin heavy chain MyHC-2A and MyHC-2X (79 ± 6% vs. 86 ± 9%, respectively, p = 0.04). In fact, the middle ear muscles had one of the highest proportions of MyHC-2 fibers ever reported for human muscles. Interestingly, the biochemical analysis revealed a MyHC isoform of unknown identity in both the stapedius and tensor tympani muscles. Muscle fibers containing two or more MyHC isoforms were relatively frequently observed in both muscles. A proportion of these hybrid fibers expressed a developmental MyHC isoform that is normally absent in adult human limb muscles. The middle ear muscles differed from orofacial, jaw, and limb muscles by having significantly smaller fibers (220 vs. 360 μm 2 , respectively) and significantly higher variability in fiber size, capillarization per fiber area, mitochondrial oxidative activity, and density of nerve fascicles. Muscle spindles were observed in the tensor tympani muscle but not in the stapedius muscle. We conclude that the middle ear muscles have a highly specialized muscle morphology, fiber composition, and metabolic properties that generally showed more similarities to orofacial than jaw and limb muscles. Although the muscle fiber characteristics in the tensor tympani and stapedius muscles suggest a capacity for fast, fine-tuned, and sustainable contractions, their difference in proprioceptive control reflects different functions in hearing and protection of the inner ear., (© 2023 The Authors. Journal of Anatomy published by John Wiley & Sons Ltd on behalf of Anatomical Society.)

Background: Patients with liver cirrhosis are recommended ultrasonography screening for early detection of hepatocellular carcinoma to increase the chances of curative treatment. However, ultrasonography alone lacks in sensitivity. Adding plasma biomarkers may increase the detection rate. We performed a broad exploratory analysis to find new plasma proteins with potential applicability for HCC screening in patients with cirrhosis., Methods: In a protein discovery cohort of 172 patients with cirrhosis or HCC, we screened for 481 proteins with suspension bead array or proximity extension assay. From these, 24 proteins were selected for further analysis in a protein verification cohort ( n  = 160), using ELISA, Luminex or an electrochemiluminescence platform. A cut-off model and a stepwise logistic regression model were used to find combinations of proteins with the best discriminatory performance between HCC and cirrhosis., Results: Stepwise logistic regression revealed alpha-fetoprotein (AFP), decarboxy-prothrombin (DCP), thioredoxin reductase 1 (TXNRD1), and fibroblast growth factor 21 (FGF21) as the proteins with the best discriminatory performance between HCC and cirrhosis. Adding TXNRD1 to DCP and AFP increased the AUC from 0.844 to 0.878, and combining AFP, DCP and TXNRD1 with age and sex resulted in an AUC of 0.920. FGF21, however, did not further increase the performance when including age and sex., Conclusion: In the present study, TXNRD1 improves the sensitivity and specificity of AFP and DCP as HCC screening tools in patients with cirrhosis. We suggest that TXNRD1 should be validated in prospective settings as a new complementary HCC biomarker together with AFP and DCP.

Background and Aims: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. The prognosis may vary from simple steatosis to more severe outcomes such as nonalcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. The understanding of the biological processes leading to NASH is limited and non-invasive diagnostic tools are lacking., Methods: The peripheral immunoproteome in biopsy-proven NAFL (n=35) and NASH patients (n=35) compared to matched, normal-weight healthy controls (n=15) was studied using a proximity extension assay, combined with spatial and single cell hepatic transcriptome analysis., Results: We identified 13 inflammatory serum proteins that, independent of comorbidities and fibrosis stage, distinguished NASH from NAFL. Analysis of co-expression patterns and biological networks further revealed NASH-specific biological perturbations indicative of temporal dysregulation of IL-4/-13, -10, -18, and non-canonical NF-kβ signaling. Of the identified inflammatory serum proteins, IL-18 and EN-RAGE as well as ST1A1 mapped to hepatic macrophages and periportal hepatocytes, respectively, at the single cell level. The signature of inflammatory serum proteins further permitted identification of biologically distinct subgroups of NASH patients., Conclusion: NASH patients have a distinct inflammatory serum protein signature, which can be mapped to the liver parenchyma, disease pathogenesis, and identifies subgroups of NASH patients with altered liver biology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Stiglund, Hagström, Stål, Cornillet and Björkström.)

Objectives: Dietary composition may affect body composition during weight loss therapy. We tested the hypothesis of whether dietary macronutrient composition influences the reduction of total abdominal adipose tissue, subcutaneous adipose tissue (SAT), or visceral adipose tissue (VAT) during weight loss., Methods: Dietary macronutrient composition and body composition were analyzed as a secondary outcome of a randomized controlled trial of 62 participants with non-alcoholic fatty liver disease. Patients were randomly assigned to a calorie-restricted intermittent fasting (5:2), calorie-restricted low-carbohydrate high-fat (LCHF), or healthy lifestyle advice (standard-of-care) diet in a 12-wk intervention phase. Dietary intake was assessed by self-reported 3-d food diaries and by characterization of total plasma fatty acid profile. Percentage of energy intake (E%) from different macronutrients was calculated. Body composition was assessed by magnetic resonance imaging and anthropometric measurements., Results: The macronutrient composition differed significantly between the 5:2 (fat 36 E% and carbohydrates 43 E%) and the LCHF (fat 69 E% and carbohydrates 9 E%) groups (P < 0.001). Weight loss was similar in the 5:2 and LCHF groups (-7.2 [SD = 3.4] kg versus 8.0 [SD = 4.8] kg; P = 0.44) and significantly larger than for standard of care (-2.5 kg [SD = 2.3]; P < 0.001). The volume of total abdominal fat, adjusted for height, decreased on average by 4.7% (standard of care), 14.3% (5:2), and 17.7% (LCHF), with no significant differences between the 5:2 and LHCF groups (P = 0.32). VAT and SAT, adjusted for height, decreased on average by 17.1% and 12.7% for 5:2, respectively, and by 21.2% and 17.9% for LCHF, with no significant group differences (VAT [P = 0.16] and SAT [P = 0.10]). VAT was mobilized to a greater extent than SAT in all diets., Conclusions: The 5:2 and LCHF diets had similar effects on changes in intraabdominal fat mass and anthropometrics during weight loss. This might indicate that overall weight loss is more important than diet composition to achieve changes in total abdominal adipose tissue, VAT, or SAT. The results of the present study suggest that there is a need for further studies on the effect of diet composition on body composition changes during weight loss therapy., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Hyperferritinaemia is a common laboratory finding that is often associated with metabolic dysfunction and fatty liver. Metabolic hyperferritinaemia reflects alterations in iron metabolism that facilitate iron accumulation in the body and is associated with an increased risk of cardiometabolic and liver diseases. Genetic variants that modulate iron homeostasis and tissue levels of iron are the main determinants of serum levels of ferritin in individuals with metabolic dysfunction, raising the hypothesis that iron accumulation might be implicated in the pathogenesis of insulin resistance and the related organ damage. However, validated criteria for the non-invasive diagnosis of metabolic hyperferritinaemia and the staging of iron overload are still lacking, and there is no clear evidence of a benefit for iron depletion therapy. Here, we provide an overview of the literature on the relationship between hyperferritinaemia and iron accumulation in individuals with metabolic dysfunction, and on the associated clinical outcomes. We propose an updated definition and a provisional staging system for metabolic hyperferritinaemia, which has been agreed on by a multidisciplinary global panel of expert researchers. The goal is to foster studies into the epidemiology, genetics, pathophysiology, clinical relevance and treatment of metabolic hyperferritinaemia, for which we provide suggestions on the main unmet needs, optimal design and clinically relevant outcomes., (© 2023. Springer Nature Limited.)

In the current study, we compared muscle morphology in three advanced aging cohorts that differed in physical function, including a unique cohort of lifelong endurance athletes. Biopsies from the vastus lateralis muscle of seven lifelong endurance athletes (EAs) aged 82-92 yr, and 19 subjects from the Uppsala Longitudinal Study of Adult Men (ULSAM) aged 87-91 yr were analyzed. ULSAM subjects were divided into high- ( n = 9, HF) and low- ( n = 10, LF) function groups based on strength and physical function tests. The analysis included general morphology, fiber type and cross-sectional area, capillarization, deficient cytochrome c oxidase (COX) activity, number of myonuclei and satellite cells, and markers of regeneration and denervation. Fibers with central nuclei and/or nuclear clumps were observed in all groups. EA differed from LF and HF by having a higher proportion of type I fibers, 52% more capillaries in relation to fiber area, fewer COX-negative fibers, and less variation in fiber sizes (all P < 0.05). There were no differences between the groups in the number of myonuclei and satellite cells per fiber, and no significant differences between LF and HF ( P > 0.05). In conclusion, signs of aging were evident in the muscle morphology of all groups, but neither endurance training status nor physical function influenced signs of regeneration and denervation processes. Lifelong endurance training, but not higher physical function, was associated with higher muscle oxidative capacity, even beyond the age of 80. NEW & NOTEWORTHY Here we show that lifelong endurance training, but not physical function, is associated with higher muscle oxidative capacity, even beyond the age of 80 yr. Neither endurance training status nor physical function was significantly associated with satellite cells or markers of regeneration and denervation in muscle biopsies from these very old men.

Background: Post-hepatectomy liver failure (PHLF) is the leading cause of postoperative mortality following major liver resection. Between December 2012 and May 2015, 10 consecutive patients with PHLF (according to the Balzan criteria) following major/extended hepatectomy were included in a prospective treatment study with the molecular adsorbent recirculating system (MARS). Sixty- and 90-day mortality rates were 0% and 10%, respectively. Of the nine survivors, four still had liver dysfunction at 90 days postoperatively. One-year overall survival (OS) of the MARS-PHLF cohort was 50%. The present study aims to assess long-term outcome of this cohort compared to a historical control cohort., Methods: To compare long-term outcome of the MARS-PHLF treatment cohort with PHLF patients not treated with MARS, the present study includes all 655 patients who underwent major hepatectomy at Karolinska University Hospital between 2010 and 2018. Patients with PHLF were identified according to the Balzan criteria., Results: The cohort was split into three time periods: pre-MARS period ( n  = 192), MARS study period ( n  = 207), and post-MARS period ( n  = 256). The 90-day mortality of patients with PHLF was 55% (6/11) in the pre-MARS period, 14% during the MARS study period (2/14), and 50% (3/6) in the post-MARS period ( p  = 0.084). Median OS (95% confidence interval (CI)) was 37.8 months (29.3-51.7) in the pre-MARS cohort, 57 months (40.7-75.6) in the MARS cohort, and 38.8 months (31.4-51.2) in the post-MARS cohort. The 5-year OS of 10 patients included in the MARS study was 40% and the median survival 11.6 months (95% CI: 3 to not releasable). In contrast, for the remaining 21 patients fulfilling the Balzan criteria during the study period but not treated with MARS, the 5-year OS and median survival were 9.5% and 7.3 months (95% CI, 0.5-25.9), respectively ( p  = 0.138))., Conclusions: MARS treatment may contribute to improved outcome of patients with PHLF. Further studies are needed.The initial pilot study was registered at ClinicalTrials.gov (NCT03011424).

Background: Post-hepatectomy liver failure (PHLF) is one of the most serious postoperative complications after hepatectomy. The aim of this study was to assess the impact of the International Study Group of Liver Surgery (ISGLS) definition of PHLF on morbidity and short- and long-term survival after major hepatectomy., Methods: This was a retrospective review of all patients who underwent major hepatectomy (three or more liver segments) for various liver tumours between 2010 and 2018 at two Swedish tertiary centres for hepatopancreatobiliary surgery. Descriptive statistics, regression models, and survival analyses were used., Results: A total of 799 patients underwent major hepatectomy, of which 218 patients (27 per cent) developed ISGLS-defined PHLF, including 115 patients (14 per cent) with ISGLS grade A, 76 patients (10 per cent) with grade B, and 27 patients (3 per cent) with grade C. The presence of cirrhosis, perihilar cholangiocarcinoma, and gallbladder cancer, right-sided hemihepatectomy and trisectionectomy all significantly increased the risk of clinically relevant PHLF (grades B and C). Clinically relevant PHLF increased the risk of 90-day mortality and was associated with impaired long-term survival. ISGLS grade A had more major postoperative complications compared with no PHLF but failed to be an independent predictor of both 90-day mortality and long-term survival. The impact of PHLF grade B/C on long-term survival was no longer present in patients surviving the first 90 days after surgery., Conclusions: The presently used ISGLS definition for PHLF should be reconsidered regarding mortality as only PHLF grade B/C was associated with a negative impact on short-term survival; however, even ISGLS grade A had clinical implications., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd.)

Background: Current risk estimates for hepatocellular carcinoma (HCC) in individuals with cirrhosis vary between studies. The risk has mostly been evaluated for single etiologies separately., Objectives: We examined the risk of HCC in Swedish outpatients with a new diagnosis of cirrhosis, aiming to identify subgroups with a particularly high risk for incident HCC., Methods: All patients with a first diagnosis of cirrhosis in the National Outpatient Register for whom the etiology of cirrhosis could be estimated were identified. Incident cases of HCC were ascertained until the end of 2016 using record linkage to national registers. The cumulative incidence of HCC across etiologies of cirrhosis, sex and age was calculated considering non-HCC death as a competing risk., Results: We identified 15,215 individuals with cirrhosis. The incidence rate for HCC in cirrhosis was 23/1000 person-years (95%CI = 22-24). Stratified on gender, it was 29/1000 person-years (95%CI = 27-31) in men versus 14/1000 person-years (95%CI = 13-16) in women. The cumulative incidence of HCC in cirrhosis was 8.3% (95%CI = 7.8-8.8) at 5 years and 12.2% (95%CI = 11.6-13.0) at 10 years. At 10 years, the lowest cumulative incidence was seen in women with alcohol-related liver disease (4.3%) and the highest in men with viral hepatitis (26.6%). These figures also varied by age., Conclusions: The risk of HCC differs extensively across subgroups of etiologies of cirrhosis, age and sex, suggesting that initiation of HCC surveillance could be individually tailored., (© 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Objective: Previous reports of muscle changes in the upper airways of obstructive sleep apnea (OSA) patients have primarily been attributed to acquired nerve lesions due to snoring vibrations. The aim of this study was to investigate whether alterations reflecting muscle fiber injuries also occur in the upper respiratory tract of snoring and OSA patients and if these changes relate to upper airway dysfunction., Methods: Muscle changes in biopsies from the soft palate of 20 patients suffering from snoring and OSA were investigated with enzyme, immunohistochemical, and morphometric techniques. Biopsies from eight healthy non-snoring subjects were used as controls. Swallowing dysfunction was assessed with videoradiography., Results: Fourteen patients had various degrees of swallowing dysfunction. The muscle samples from all the patients showed changes typical for both motor-nerve lesions and muscle fiber injuries. The most common alterations reflecting myopathy were fibers having aggregates and disorganization of cytoskeletal proteins (15.5 ± 10.7%). Other changes were fibers with vacuole-like structures (5.0 ± 4.4%), centrally positioned myonuclei (7.9 ± 4.8%), subsarcolemmal accumulations of nuclei, and various forms and sizes of ring fibers, that is, fibers where the myofilaments were disorganized peripherally (2.8 ± 2.8%)., Conclusion: The results show that muscle changes mirroring both myopathy and neuropathy co-exist in the upper airway of snoring OSA patients. These findings suggest muscle weakness as a contributing factor to the upper airway dysfunction in OSA patients., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Background and Study Aims: In patients with obesity and type-2 diabetes, short-time very low-calorie diet may ameliorate hyperglycemia and hepatic steatosis. Whether this also implies the glucose-regulating hormone glucagon remains to be elucidated. This study investigated the effects of a very low-calorie diet on plasma levels of glucagon and liver fat in obese patients with type-2 diabetes., Patients and Methods: Ten obese patients with type-2 diabetes, 6 men and 4 women, were included. At baseline, fasting plasma glucagon, insulin and glucose were determined, and liver fat and stiffness evaluated by transient elastography. The subjects were then prescribed a very low-calorie diet of maximum 800 kcal/day for 7 weeks and reexamined after 7 weeks and 12 months., Results: At baseline, BMI was 42±4 kg/m 2 and fasting glucose 10.6±3.4 mmol/l. All patients had hepatic steatosis. Plasma glucagon was strongly related to liver fat (r 2 =0.52, p=0.018). After 7 weeks of very low-calorie diet, plasma glucagon was significantly decreased by nearly 30% (p=0.004) along with reductions of BMI (p<0.0001), glucose (p=0.02), insulin (p=0.03), liver fat (p=0.007) and liver stiffness (p=0.05). At 12 months follow-up, both glucagon and liver fat increased and were not different to basal levels, despite persistent reductions of BMI (p<0.002) and glucose (p=0.008)., Conclusion: In obese type-2 diabetic subjects, plasma glucagon and liver fat are correlated and similarly affected by a very low-calorie diet, supporting a role of hepatic steatosis in glucagon metabolism., Competing Interests: None of the authors have potential conflicts of interest with regard to this manuscript., (Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany.)

Background and Hypothesis: Isolated malleus shaft fractures are rare cases. A commonly reported cause is a finger pulled out from a wet outer ear canal after a shower or bath. The objective was to investigate experimentally the mechanism and forces needed to establish an isolated malleus shaft fracture., Methods: Ten fresh-frozen human temporal bones were adapted to allow visual inspection of the structures involved while negative pressure trauma was applied. Thirty malleus bones were broken and the required forces were measured. Measurements from 60 adult test subjects were used to create mathematical and physical models to calculate and measure the forces necessary for generating trauma. To calculate the maximum muscle force developed by the tensor tympani muscle, the muscle area and fiber type composition were determined., Results: The temporal bone experiments showed that applied negative pressure in a wet ear canal could not fracture the malleus shaft with only passive counterforce from supporting structures, although the forces exceeded what was required for a malleus shaft fracture. When adding calculated counteracting forces from the tensor tympani muscles, which consisted of 87% type II fibers, we estimate that a sufficient force is generated to cause a malleus fracture., Conclusion: The combination of a negative pressure created by a finger pulling outward in a wet ear canal and a simultaneous counteracting reflexive force by the tensor tympani muscle were found to be sufficient to cause an isolated malleus fracture with an intact tympanic membrane., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of Otology & Neurotology, Inc.)

Background and Aims: It is unclear if improving glycemic control in persons with type 2 diabetes (T2D) also has liver-related effects. We aimed to evaluate if a personalized treatment program associates with improvement of liver-related parameters in persons with advanced T2D in a real-life setting., Methods: Persons with advanced T2D underwent a 4-day personalized treatment program, with the aim of improving glycemic control by dietary advice, instructions on how to achieve optimal glucose control and individualized dosage of medications. Transient elastography was used to estimate liver steatosis and fibrosis. Persons with liver diseases other than non-alcoholic fatty liver disease (NAFLD) were excluded. After 3 months, study participants were offered re-examination., Results: Ninety-one persons were included. Of these, 75 persons (82%) had controlled attenuation parameter (CAP) measurements of acceptable quality at baseline. Of these, 57 (76%) had NAFLD (defined as >268 dB/m). Twenty-two persons (24%) had elevated liver stiffness (>7.9 kPa), and eight (9%) had liver stiffness above 13.9 kPa, indicating advanced fibrosis. Over a median follow-up of 101 days, mean CAP in persons with NAFLD was reduced by 18.33 dB/m (P = 0.035). In persons with elevated liver stiffness, mean stiffness was reduced by 2.6 kPa (P = 0.047). In linear regression, one-unit improvement in fasting glucose (mg/dl) was associated with a decrease in hepatic steatosis with 0.48 dB/m (adjusted R2 = 0.35, P < 0.01)., Conclusion: The prevalence of NAFLD with advanced fibrosis is high in persons with advanced T2D. Improving glycemic control through a personalized treatment program is associated with a reduction in liver steatosis and stiffness in this cohort., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.

The aspartate-to-alanine aminotransferase ratio (AAR) is associated with liver fibrosis, but its predictive performance is suboptimal. We hypothesized that the association between AAR and liver disease depends on absolute transaminase levels and developed and validated a model to predict liver-related outcomes in the general population. A Cox regression model based on age, AAR, and alanine aminotransferase (ALT) level (dynamic AAR [dAAR]) using restricted cubic splines was developed in Finnish population-based health-examination surveys (FINRISK, 2002-2012; n = 18,067) with linked registry data for incident liver-related hospitalizations, hepatocellular carcinoma, or liver death. The model was externally validated for liver-related outcomes in a Swedish population cohort (Swedish Apolipoprotein Mortality Risk [AMORIS] subcohort; n = 126,941) and for predicting outcomes and/or prevalent fibrosis/cirrhosis in biopsied patients with nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C, or alcohol-related liver disease (ALD). The dynamic AAR model predicted liver-related outcomes both overall (optimism-corrected C-statistic, 0.81) and in subgroup analyses of the FINRISK cohort and identified persons with >10% risk for liver-related outcomes within 10 years. In independent cohorts, the C-statistic for predicting liver-related outcomes up to a 10-year follow-up was 0.72 in the AMORIS cohort, 0.81 in NAFLD, and 0.75 in ALD. Area-under-the-curve (AUC) for detecting prevalent cirrhosis was 0.80-0.83 in NAFLD, 0.80 in hepatitis C, but only 0.71 in ALD. In ALD, model performance improved when using aspartate aminotransferase instead of ALT in the model (C-statistic, 0.84 for outcome; AUC, 0.82 for prevalent cirrhosis). Conclusion: A dAAR score provides prospective predictions for the risk of incident severe liver outcomes in the general population and helps detect advanced liver fibrosis/cirrhosis. The dAAR score could potentially be used for screening the unselected general population and as a trigger for further liver evaluations., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background & Aims: The first-line treatment for non-alcoholic fatty liver disease (NAFLD) is weight reduction. Several diets have been proposed, with various effects specifically on liver steatosis. This trial compared the effects of intermittent calorie restriction (the 5:2 diet) and a low-carb high-fat diet (LCHF) on reduction of hepatic steatosis., Methods: We conducted an open-label randomised controlled trial that included 74 patients with NAFLD randomised in a 1:1:1 ratio to 12 weeks' treatment with either a LCHF or 5:2 diet, or general lifestyle advice from a hepatologist (standard of care; SoC). The primary outcome was reduction of hepatic steatosis as measured by magnetic resonance spectroscopy. Secondary outcomes included transient elastography, insulin resistance, blood lipids, and anthropometrics., Results: The LCHF and 5:2 diets were both superior to SoC treatment in reducing steatosis (absolute reduction: LCHF: -7.2% [95% CI = -9.3 to -5.1], 5:2: -6.1% [95% CI = -8.1 to -4.2], SoC: -3.6% [95% CI = -5.8 to -1.5]) and body weight (LCHF: -7.3 kg [95% CI = -9.6 to -5.0]; 5:2: -7.4 kg [95% CI = -8.7 to -6.0]; SoC: -2.5 kg [95% CI =-3.5 to -1.5]. There was no difference between 5:2 and LCHF ( p  = 0.41 for steatosis and 0.78 for weight). Liver stiffness improved in the 5:2 and SoC but not in the LCHF group. The 5:2 diet was associated with reduced LDL levels and was tolerated to a higher degree than LCHF., Conclusions: The LCHF and 5:2 diets were more effective in reducing steatosis and body weight in patients with NAFLD than SoC, suggesting dietary advice can be tailored to meet individual preferences., Lay Summary: For a person with obesity who suffers from fatty liver, weight loss through diet can be an effective treatment to improve the condition of the liver. Many popular diets that are recommended for weight reduction, such as high-fat diets and diets based on intermittent fasting, have not had their effects on the liver directly evaluated. This study shows that both a low-carb high-fat and the 5:2 diet are effective in treating fatty liver caused by obesity., Clinical Trials Registration: This study is registered at Clinicaltrials.gov (NCT03118310)., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Authors.)

Background and Aims: Non-invasive fibrosis staging is essential in metabolic associated fatty liver disease (MAFLD). Transient elastography (TE) is a well-established method for liver fibrosis assessment. We have previously shown that the macrophage marker sCD163 is an independent predictor for fibrosis in MAFLD. In the present study we tested whether the combination of macrophage markers and TE improves fibrosis prediction. Methods: We measured macrophage markers soluble (s)CD163 and mannose receptor (sMR) in two independent cohorts from Italy ( n = 141) and Sweden ( n = 70) with biopsy-proven MAFLD and available TE. Results: In the Italian cohort, TE and sCD163 showed similar moderate associations with liver fibrosis (rho = 0.56, p < 0.001 and rho = 0.42, p < 0.001, respectively). TE had an area under the Receiver Operating Characteristics curve (AUROC, with 95% CI) for fibrosis; F ≥ 2 = 0.79 (0.72-0.86), F ≥ 3 = 0.81 (0.73-0.89), F4 = 0.95 (0.90-1.0). sCD163 also predicted fibrosis well [F ≥ 2 = 0.71 (0.63-0.80), F ≥ 3 = 0.82 (0.74-0.90), F4 = 0.89 (0.76-1.0)]. However, combining sCD163 and TE did not improve the AUROCs significantly [F ≥ 2 = 0.79 (0.72-0.86), F ≥ 3 = 0.85 (0.78-0.92), F4 = 0.97 (0.93-1.0)]. In the Swedish cohort, TE showed a closer association with fibrosis (rho = 0.73, p < 0.001) than sCD163 (rho = 0.43, p < 0.001) and sMR (rho = 0.46, p < 0.001). TE predicted fibrosis well [F ≥ 2 = 0.88 (0.80-0.97), F ≥ 3 = 0.90 (0.83-0.97), F4 = 0.87 (0.78-0.96)], whereas sCD163 did not (best AUROC 0.75). sMR showed a better prediction [F ≥ 2 = 0.68 (0.56-0.81), F ≥ 3 = 0.82 (0.71-0.92), F4 = 0.79 (0.66-0.93)], but the addition of sMR did not further improve the prediction of fibrosis by TE. Conclusion: In these cohorts of MAFLD patients, TE was superior to macrophage markers for fibrosis prediction and in contrast to our hypothesis the addition of these markers to TE did not improve its predictive capability., Competing Interests: RY was employed by the company Boehringer Ingelheim International, Gesellschaft mit beschränkter Haftung, Ingelheim, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Kazankov, Rosso, Younes, Armandi, Hagström, Møller, Stål, Bugianesi and Grønbæk.)

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is common in the general population, but its association with dementia is unclear. We aimed to assess the risk of dementia related to NAFLD, and to determine whether histological parameters could improve the predictive capacity of a conventional risk model for dementia in patients with biopsy-proven NAFLD., Methods: A retrospective matched cohort study of 656 NAFLD patients underwent liver biopsy at 2 hospitals between 1971 and 2009. Up to 10 individuals (controls) from the general population (n = 6,436) were matched for age, sex, and municipality to each patient. Dementia was ascertained from National registers until 2014. Using Cox regression, we estimated hazard ratios for dementia with 95% confidence intervals. In the biopsy cohort, the discriminative power of adding histological markers to a conventional risk model was assessed by Harrell's C-index and compared with a likelihood-ratio test., Results: During a mean follow-up of 19.7 ± 8.7 years, 3.3% of the NAFLD patients and 4.9% of the controls developed dementia ( p  = 0.07). Overall, NAFLD was not significantly associated with incident dementia. In the biopsy cohort, the model of conventional risk factors (age, sex, hypertension, and cardiovascular diseases) had a C-index of 0.912 to predict incident dementia. Adding individual histological parameters significantly increased the prediction of dementia, with the most pronounced improvement for fibrosis stage (C-index = 0.938, p <0.05)., Conclusions: Although NAFLD was not associated with the risk of dementia, we found that adding histological markers to a conventional risk model for dementia enhanced the predictive capacity, indicating a shared metabolic origin., Lay Summary: Both non-alcoholic fatty liver disease (NAFLD) and dementia are increasing in prevalence because of a more sedentary lifestyle, increased prevalence of obesity and population ageing. However, the link between these 2 diseases is not well studied. We investigated the association between NAFLD and the risk of dementia and found no association. However, liver histology parameters, especially fibrosis, could significantly improve the prediction of dementia risk., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Author(s).)

Background & Aims: Data on healthcare resource use and costs associated with nonalcoholic fatty liver disease (NAFLD) in clinical practice are lacking. We compared real-life healthcare costs of patients with NAFLD to matched controls., Methods: We performed a retrospective study of 646 patients with biopsy-proven NAFLD in Sweden from 1971 through 2009. Each patient was matched for age, sex, and county of residence with 10 persons from the general population (controls). We retrieved all healthcare contacts through Dec 31, 2014 from national registers. Unit costs were assigned to arrive at a total healthcare cost (in USD [$]) per study subject., Results: During a mean follow-up of 19.9 years, we recorded a mean of 0.27 hospitalizations per year for patients with NAFLD vs 0.16 for controls (P < .001). This corresponded to an incremental cost of $635 per year for patients with NAFLD. Patients with NAFLD had a higher mean use of outpatient care visits: 1.46 contacts per year compared with 0.86 per year in controls, corresponding to $255 in additional costs (P < .001). Total costs incurred by patients with stage 3-4 fibrosis were higher than by patients with fibrosis stage 0-2 (mean annual costs, $4397 vs $629). Cumulative costs were higher for all stages of fibrosis compared to controls., Conclusions: Healthcare costs are nearly twice as high in patients with NAFLD than in matched controls. This is mostly attributable to higher costs for hospitalizations, but also to more outpatient visits. Patients with advanced fibrosis had the highest costs., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Several non-invasive scoring systems have been developed to determine risk of advanced fibrosis in non-alcoholic fatty liver disease (NAFLD). We examined the association between 4 scoring systems and incident severe liver disease and overall mortality in a large cohort of patients with biopsy-proven NAFLD., Methods: We performed a retrospective analysis of data from 646 patients with biopsy-proven NAFLD, recruited from 2 hospitals in Sweden, from 1971 through 2009. The NAFLD fibrosis score (NFS), FIB-4, APRI, and BARD scores were calculated at the time of the liver biopsy. Based on each score, patients were assigned to categories of low, intermediate, or high risk for advanced fibrosis. Overall mortality and severe liver disease (cirrhosis, decompensated liver disease, liver failure, or hepatocellular carcinoma) were ascertained through linkage with national registers until the end of 2014. Cox regression, area under the receiver operating characteristic (AUROC) curve, and C-statistic analyses were used to study the predictive capacity of each scoring system., Results: During a mean follow-up time of 19.9±8.7 years, there were 214 deaths and 76 cases of severe liver disease. For overall mortality, AUROC curve values were: NFS, 0.72 (95% CI, 0.68-0.76); FIB-4, 0.72 (95% CI, 0.68-0.76); BARD, 0.62 (95% CI, 0.58-0.66); and APRI, 0.52 (95% CI, 0.47-0.57). For severe liver disease, AUROC curve values were: NFS, 0.72 (95% CI, 0.66-0.78); FIB-4, 0.72 (95% CI, 0.66-0.79); BARD, 0.62 (95% CI, 0.55-0.69); APRI, 0.69 (95% CI, 0.63-0.76). C-statistics for all scores were of moderate capacity to predict outcomes., Conclusions: In a retrospective analysis of data from 646 patients with biopsy-proven NAFLD, we found the NFS and the FIB-4 scores to most accurately determine risk of overall death or severe liver disease. However, the AUROC values for these scoring systems are not high enough for use in the clinic; new systems are needed to determine prognoses of patients with NAFLD., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: Muscle changes in patients with diabetes and lower leg pain due to chronic exertional compartment syndrome (CECS) were investigated before and after fasciotomy., Methods: The tibialis anterior muscle was analyzed with histochemical and morphological techniques in 7 patients with diabetes and CECS before fasciotomy and in 5 of them 1 year after fasciotomy. Nondiabetic patients with CECS and healthy participants served as references., Results: Before treatment, walking distance until occurrence of pain was limited (<0.2 km). Intramuscular pressure was significantly higher than in reference participants. Muscle analysis showed changes pathognomonic for neuropathy and myopathy and a restricted capillary network, with significantly more severe changes in the muscles of patients with diabetes than in the muscles of nondiabetic patients. Treatment with fasciotomy improved clinical signs, increased walking ability, and reduced muscle abnormalities, but muscle capillarization remained low., Discussion: Patients with diabetes and CECS have distinct pathological changes in affected muscles. Pressure-relieving fasciotomy triggers a regenerative response in the muscle tissue but not in the capillary bed. Muscle Nerve 57: 229-239, 2018., (© 2017 Wiley Periodicals, Inc.)

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is a strong risk factor for development of type 2 diabetes, but little is known about how long-term NAFLD or its histologic features affect risk. We aimed to investigate the cumulative incidence of type 2 diabetes in patients with NAFLD and to identify histologic factors that affect risk of diabetes., Methods: We performed a retrospective study of 396 patients in Sweden diagnosed with NAFLD by biopsy analysis from 1971 through 2009 who did not have type 2 diabetes at baseline. Data on development of type 2 diabetes were collected from patient charts and national registers. Patients were categorized into groups with fibrosis stages 0-2 (n = 357) or stages 3-4 (n = 39). Hazard ratios of histologic parameters for type 2 diabetes development were calculated separately in a multivariate Cox regression model adjusted for sex, age, body mass index, and serum levels of triglycerides greater than 150 mg/dL., Results: During a mean follow-up period of 18.4 years (range, 0-41 years), 132 individuals (33%) developed type 2 diabetes. A significantly higher proportion of patients with fibrosis stages 3-4 (51.2%) developed type 2 diabetes than patients with fibrosis stages 0-2 (31.3%) (P = .02). For patients with fibrosis stages 0-2, fat score associated independently with development of type 2 diabetes (adjusted hazard ratio, 1.34; 95% confidence interval, 1.03-1.74; P = .03). No histologic factors associated with development of diabetes in patients with fibrosis stages 3-4. Presence of nonalcoholic steatohepatitis was not associated with development of type 2 diabetes., Conclusions: In a retrospective study we found a higher proportion of patients with fibrosis stages 3-4 to develop type 2 diabetes than patients with fibrosis stages 0-2. In patients with fibrosis stages 0-2, fat score associates with risk of type 2 diabetes., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Acute-on-chronic liver failure (ACLF) is a condition that may develop in up to one third of patients with chronic liver disease who exhibit clinical signs of acute decompensation, i.e. ascites, gastrointestinal bleeding, hepatic encephalopathy or bacterial infection. ACLF implies the combination of acute hepatic decompensation with organ failure in kidney, brain, liver, lungs, circulation and/or coagulation. The prognosis worsens with the number of failing organs, renal involvement, advanced age and elevated leukocyte blood count. ACLF is caused by a systemic inflammation. Cultures from blood, urine and ascites should be drawn, and rapid antibiotic treatment is essential to prevent ACLF development. Renal function must be monitored and renal failure treated promptly. Acute alcoholic hepatitis may be considered a specific case of ACLF, which may be treated with corticosteroids in cases having high score in prognostic indices (GAHS, MELD or ABIC), and after bacterial infections have been ruled out or treated.

Introduction: spaceflight seems associated with deterioration of the function of the skeletal muscles. Since muscle collagen is critical for muscle function, an improved understanding of the content of the muscle collagen during long-term inactivity seems important. Bed-rest with in-bed resistance training serves as a proxy for the conditions in space. Therefore, ground-based studies may improve the understanding of the consequences of long-term inactivity., Purpose: the purpose is to compare the change in collagen protein in the vastus lateralis (VL) and the soleus (SOL) muscle amongst persons exposed to a 90-day bed rest with or without resistance exercise., Methods: an explorative analysis was completed based on data from a randomized, controlled trial. The intervention group (BRE, SOL n=4, VL n=8) performed supine-based squat exercises, whereas the controls (BE, SOL n=6, VL n=12) remained inactive during follow-up. Muscle biopsies from vastus lateralis and soleus were taken at baseline (pre) and after 90-days' follow-up (post). Muscle collagen (μg collagen/mg protein) was quantified. Two-way repeated measurements ANOVA was used to compare the interaction between the intervention (BRE/BR) and time (pre/post) for each muscle., Results: the collagen content of VL was similar between pre and post in the BRE group (-3.8 μg collagen/mg protein [95% CI: -22.0; 14.4], p=0.68) while it rose amongst individuals in the BR group (14.9 μg collagen/mg protein [95% CI: -0.01; 29.7], p=0.05). The difference of 18.66 [95% CI: -6.5; 43.9] between BRE and BR across time was, however, not significant (p=0.14). No significant reduction in SOL muscle collagen content was observed from pre to post in the BR group (-9.3 μg collagen/mg protein [95% CI: -24.9; 6.4], p=0.25) or in the BRE group (-6.5 μg collagen/mg protein [95% CI: -25.6; 12.6], p=0.50). There was no difference in the effect of BR versus BRE over time (mean difference -2.78 μg collagen/mg protein [95% CI: -29.7; 24.1], p=0.82)., Conclusion: muscle collagen content in the VL or SOL muscle does not seem to differ after a 90-day bed rest period with or without squat exercises.

Unlabelled: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, strongly associated with insulin resistance and the metabolic syndrome. Nonalcoholic steatohepatitis, i.e., fatty liver accompanied by necroinflammatory changes, is mostly defined by the NAFLD activity score (NAS). The aim of the current study was to determine disease-specific mortality in NAFLD, and evaluate the NAS and fibrosis stage as prognostic markers for overall and disease-specific mortality. In a cohort study, data from 229 well-characterized patients with biopsy-proven NAFLD were collected. Mean follow-up was 26.4 (±5.6, range 6-33) years. A reference population was obtained from the National Registry of Population, and information on time and cause of death were obtained from the Registry of Causes of Death. NAFLD patients had an increased mortality compared with the reference population (hazard ratio [HR] 1.29, confidence interval [CI] 1.04-1.59, P = 0.020), with increased risk of cardiovascular disease (HR 1.55, CI 1.11-2.15, P = 0.01), hepatocellular carcinoma (HR 6.55, CI 2.14-20.03, P = 0.001), infectious disease (HR 2.71, CI 1.02-7.26, P = 0.046), and cirrhosis (HR 3.2, CI 1.05-9.81, P = 0.041). Overall mortality was not increased in patients with NAS 5-8 and fibrosis stage 0-2 (HR 1.41, CI 0.97-2.06, P = 0.07), whereas patients with fibrosis stage 3-4, irrespective of NAS, had increased mortality (HR 3.3, CI 2.27-4.76, P < 0.001)., Conclusion: NAFLD patients have increased risk of death, with a high risk of death from cardiovascular disease and liver-related disease. The NAS was not able to predict overall mortality, whereas fibrosis stage predicted both overall and disease-specific mortality., (© 2014 by the American Association for the Study of Liver Diseases.)

Aim: To assess the alcohol drinking patterns in a cohort of primary sclerosing cholangitis (PSC) patients and the possible influence on the development of fibrosis., Methods: Ninety-six patients with PSC were evaluated with a validated questionnaire about a patient's lifetime drinking habits: the lifetime drinking history (LDH) questionnaire. In addition, clinical status, transient elastography and biochemistry values were analysed and registered. Patients were defined as having either significant or non-significant fibrosis. Significant fibrosis was defined as either an elastography value of ≥ 17.3 kPa or the presence of clinical signs of cirrhosis. Patients were divided into two groups depending on their alcohol consumption patterns; no/low alcohol consumption (one drink or unit/d) and moderate/high alcohol consumption (≥ 1 drink or unit/d). LDH data were calculated to estimate lifetime alcohol intake (LAI), current alcohol intake, drinks per year before and after diagnosis of PSC. We also calculated the number of episodes of binge-drinking (defined as consuming ≥ 5 drinks per occasion) in total, before and after the diagnosis of PSC., Results: The mean LAI was 3882 units of alcohol, giving a mean intake after onset of alcohol consumption of 2.6 units per week. Only 9% of patients consumed alcohol equal to or more than one unit per day. Current alcohol intake in patients with significant fibrosis (n = 26) was less than in patients without significant fibrosis (n = 70), as shown by lower values of phosphatidylethanol (B-PEth) (0.1 μmol/L vs 0.33 μmol/L, respectively, P = 0.002) and carbohydrate-deficient transferrin (CDT) (0.88% vs 1.06%, respectively, P = 0.02). Self-reported LAI was similar between the two groups. Patients with significant fibrosis reduced their alcohol intake after diagnosis from 103 to 88 units per year whereas patients without fibrosis increased their alcohol intake after PSC diagnosis from 111 to 151 units/year. There were no correlations between elastography values and intake of alcohol (units/year) (r = -0.036)., Conclusion: PSC patients have low alcohol consumption. The lack of correlation between fibrosis and alcohol intake indicates that a low alcohol intake is safe in these patients.

Purpose: To examine the distribution of myosin-binding protein C (MyBP-C) in human extraocular muscles (EOMs) and to correlate the myosin heavy chain (MyHC) and the MyBP-C composition of the fibers., Methods: Samples from 17 EOMs, 3 levator palpebrae (LP), and 6 limb muscles were analyzed with SDS-PAGE and immunoblot or processed for immunocytochemistry with monoclonal antibodies (mAbs) against MyBP-C-fast, MyBP-C-slow, MyHCIIa, MyHCI, MyHCsto, MyHCalpha-cardiac, and MyHCemb., Results: In the limb muscle samples, fast fibers were labeled with anti-MyBP-C-fast and anti-MyBP-C-slow, whereas the slow fibers were immunostained with anti-MyBP-C-slow only, in accordance with previous studies. In 11 EOM samples MyBP-C-fast was not detected, and weak staining with anti-MyBP-C-fast was seen only in a few fibers in the proximal part of 2 muscles. The mAb against MyBP-C-slow labeled all fibers, but fibers containing MyHCI were generally more strongly stained. In the levator palpebrae, immunostaining with anti-MyBP-C-fast was present in some fibers labeled with anti-MyHCIIa and/or anti-MyHCeom. MyBP-C-fast and -intermediate were not detected biochemically in the EOMs., Conclusions: The lack of MyBP-C-fast and intermediate is an additional feature of the human EOM allotype. The true EOMs have a unique myofibrillar protein isoform composition reflecting their special structural and functional properties. The levator palpebrae muscle phenotype is intermediate between that of the EOMs and the limb muscles.