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There is an urgent need for new high‐quality markers for the early detection of hepatocellular carcinoma (HCC). Åström et al. suggested that S2‐bound α1‐acid glycoprotein (AGP) might be a promising marker. Consequently, we evaluated the predictive advantage of S2‐bound AGP in the early detection of HCC. In a retrospective case–control study of patients chronically infected with hepatitis C virus (HCV) and treated with direct‐acting antiviral agents (n = 93), we measured S2‐bound AGP using the HepaCheC® ELISA kit (Glycobond AB, Linköping, SE) at the start of treatment, end of treatment and follow‐up (maximum: 78 months). Patients were retrospectively propensity score matched (1:2). Thirty‐one patients chronically infected with HCV developed HCC after a sustained virological response, while 62 did not. In addition, samples of patients with chronic hepatitis B virus infection, metabolic dysfunction‐associated steatotic liver disease and HCC of different etiologies were analysed. S2‐bound AGP elevation in HCC patients was confirmed. However, we did not observe a predictive advantage of S2‐bound AGP for the early detection of HCC during treatment and follow‐up. Interestingly, S2‐bound AGP levels correlated with aspartate aminotransferase (ρ =.56, p = 9.5×10−15) and liver elastography (ρ =.67, p = 2.2×10−16). Of note, S2‐bound AGP decreased in patients chronically infected with HCV after treatment‐induced HCV clearance. Fucosylated S2‐bound AGP levels were elevated in patients with chronic HCV and HCC. The potential role of S2‐bound AGP as a novel tumour marker requires further investigation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 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 13C-mixed triglyceride breath test (13 C-MTG-BT) was performed in patients with FE-1 < 200 μg/g. 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 13C-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. 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. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

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 μm2, 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. [ABSTRACT FROM AUTHOR]

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 coexpression patterns and biological networks further revealed NASH-specific biological perturbations indicative of temporal dysregulation of IL-4/-13, -10, -18, and non-canonical NF-ĸb 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. [ABSTRACT FROM AUTHOR]

Liver transplantation (LT) is the only available cure for end-stage liver disease and one of the best treatment options for hepatocellular carcinomas (HCC). Patients with known alcohol-associated cirrhosis (AC) are routinely assessed for alcohol dependence or abuse before LT. Patients with other liver diseases than AC may consume alcohol both before and after LT. The aim of this study was to assess the effects of alcohol drinking before and after LT on patient and graft survival regardless of the etiology of liver disease. Between April 2012 and December 2015, 200 LT-recipients were interviewed using the Lifetime Drinking History and the Addiction Severity Index questionnaire. Patients were categorized as having AC, n = 24, HCC and/or hepatitis C cirrhosis (HCV), n = 69 or other liver diseases, n = 107. Patients were monitored and interviewed by transplantation-independent staff for two years after LT with questions regarding their alcohol consumption. Patient and graft survival data were retrieved in October 2019. Patients with AC had an increased hazard ratio (HR) for death after LT (crude HR: 4.05, 95% CI: 1.07–15.33, p = 0.04) and for graft loss adjusted for age and gender (adjusted HR: 3.24, 95% CI 1.08–9.77, p = 0.04) compared to the other patients in the cohort. There was no significant effect of the volume of alcohol consumed before or after LT on graft loss or overall survival. Patients transplanted for AC have a worse prognosis, but we found no correlation between alcohol consumed before or after LT and graft or patient survival. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Aims: Several genotypes associate with a worse histopathological profile in patients with non‐alcoholic fatty liver disease (NAFLD). Whether genotypes impact long‐term outcomes is unclear. We investigated the importance of PNPLA3, TM6SF2, MBOAT7 and GCKR genotype for the development of severe outcomes in NAFLD. Method: DNA samples were collected from 546 patients with NAFLD. Advanced fibrosis was diagnosed by liver biopsy or elastography. Non‐alcoholic steatohepatitis (NASH) was histologically defined. Additionally, 5396 controls matched for age, sex and municipality were identified from population‐based registers. Events of severe liver disease and all‐cause mortality were collected from national registries. Hazard ratios (HRs) adjusted for age, sex, body mass index and type 2 diabetes were estimated with Cox regression. Results: In NAFLD, the G/G genotype of PNPLA3 was associated with a higher prevalence of NASH at baseline (odds ratio [OR] 3.67, 95% CI = 1.66–8.08), but not with advanced fibrosis (OR 1.81, 95% CI = 0.79–4.14). After up to 40 years of follow‐up, the PNPLA3 G/G genotype was associated with a higher rate of severe liver disease (adjusted hazard ratio [aHR] 2.27, 95% CI = 1.15–4.47) compared with the C/C variant. NAFLD patients developed cirrhosis at a higher rate than controls (aHR 9.00, 95% CI = 6.85–11.83). The PNPLA3 G/G genotype accentuated this rate (aHR 23.32, 95% = CI 9.14–59.47). Overall mortality was not affected by any genetic variant. Conclusion: The PNPLA3 G/G genotype is associated with an increased rate of cirrhosis in NAFLD. Our results suggest that assessment of the PNPLA3 genotype is of clinical relevance in patients with NAFLD to individualize monitoring and therapeutic strategies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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/m2 and fasting glucose 10.6±3.4 mmol/l. All patients had hepatic steatosis. Plasma glucagon was strongly related to liver fat (r2 =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. [ABSTRACT FROM AUTHOR]