Natural History of Nonalcoholic Fatty Liver Disease: Implications for Clinical Practice and an Individualized Approach

Nonalcoholic fatty liver disease (NAFLD) is becoming the most prevalent liver disease worldwide, associated with epidemics of overweight and resulting metabolic syndrome (MetS). Around 20–30% of patients with NAFLD develop progressive liver fibrosis, which is the most important predictor of liver-related and overall morbidity and mortality. In contrast to classical understanding, no significant association has been demonstrated between the inflammatory component of NAFLD, i.e., nonalcoholic steatohepatitis (NASH), and the adverse clinical outcomes. Older age (>50 years) and presence of type 2 diabetes mellitus, in addition to some genetic variants, are most consistently reported indicators of increased risk of having liver fibrosis. However, critical driving force for the progression of fibrosis and risk factors for this have still not been fully elucidated. Apart from the genetic profile, gut dysbiosis, weight gain, worsening of insulin resistance, and worsening of liver steatosis represent candidate factors associated with unfavourable development of liver disease. Cardiovascular events, extrahepatic malignancies, and liver-related deaths are the leading causes of mortality in NAFLD. As patients with advanced fibrosis are under highest risk of adverse clinical outcomes, efforts should be made to recognize individuals under risk and rule out the presence of this stage of fibrosis, preferably by using simple noninvasive tools. This process should start at the primary care level by using validated biochemical tests, followed by direct serum tests for fibrosis or elastography in the remaining patients. Patients with advanced fibrosis should be referred to hepatologists for aggressive lifestyle modification and correction of the components of MetS, and cirrhotic patients should be screened for hepatocellular carcinoma and oesophageal varices

Non-Invasive Assesment of Chronic Liver Disease by Two Dimensional Shear Wave Elastography: An Overview

Background: Liver Stiffness (LS) assessed by Sonoelastography (SE), has been demonstrated as reliable non-invasive indicator of liver fibrosis stage in patients with Chronic Liver Diseases (CLD). Sonoelastography performs best in ruling-out cirrhosis (F=4) and ruling-in signifficant fibrosis (F≥2). However, it is insufficiently accurate to replace endoscopy for detection of Esophageal Varices (EV), being able to only ruling-out large EV. LS ≥ 25 kPa by Transient Elastography (TE) is considered highly suggestive for the presence of Clinically Significant Portal Hypertension (CSPH). Higher liver and spleen stiffness have been asociated with adverse clinical outcomes in CLD. Two-dimensional shear wave elastography (2D-SWE), the latest developed SE method, allows both visualisation and quantification of liver elasticity in real time superimposed over B-mode ultrasound image. Discussion: Meta-analysis of studies with Supersonic Shear Imaging (SSI) revealed comparable performance of this 2D-SWE to TE in fibrosis staging, with AUROCs 0.85 for F≥2 (LS cut-off 8.04 kPa) and 0.93 for F=4 (LS cut-off 11.12 kPa). Few studies reported very good performance of 2DSWE (SSI) to rule-in CSPH (AUROCs 0.79-0.95; LS cut-offs 15-25 kPa). While conflicting data exist with respect to its performance in predicting the presence of EV, prognostic utility of 2D-SWE (SSI) was demonstrated in a single study that reported 3.4-fold (P=0.026) higher risk of adverse outcome in patients with baseline LS≥21.5 kPa followed over 28 months. Conclusion: 2D-SWE (SSI) might be used to stage liver fibrosis in CLD, identify patients with compensated cirrhosis under risk of adverse outcomes and potentially stratify risk of having CSPH and EV

Multiparametric ultrasound in liver diseases: an overview for the practising clinician

Ultrasound (US) is usually the first and most commonly used tool in the diagnostic algorithm for liver disease. It is widely available, non-invasive and offers a real-time assessment of the liver in several anatomic planes, using different US modalities such as greyscale imaging, Doppler, elastography and contrast-enhanced US. This multiparametric ultrasound (MPUS) provides more information of the examined structures and allows for a faster and more accurate diagnosis, usually at the point of care, thus reducing the requirement for some invasive and more expensive methods. Current data on the MPUS in hepatology are summarised in this review, mostly focused on its use for non-invasive staging of liver fibrosis, detection and classification of portal hypertension and oesophageal varices, prognosis in chronic liver diseases and characterisation of focal liver lesions (FLLs). Based on the available data, we propose practical algorithms for clinical use of MPUS in chronic liver disease and FLL

Use of biochemical parameters for non-invasive screening of oesophageal varices in comparison to elastography-based approach in patients with compensated advanced chronic liver disease

Oesophageal varices are routinely diagnosed by esophagogastroduodenoscopy (EGD), and their bleeding has high mortality. We aimed to evaluate diagnostic performance of biochemical tests in comparison to elastography-based approaches, as non-invasive alternatives to EGD, for ruling-out high risk oesophageal varices (HRV). Retrospective analysis of patients (N = 861) who underwent liver stiffness measurement (LSM) by transient elastography (TE) in a single centre over 5-year period, with available results of EGD (within 3 months from LSM). Only patients with suspicion of compensated advanced chronic liver disease (cACLD) defined by LSM ≥ 10 kPa were included comprising the final cohort of 73 subjects. Original and expanded Baveno VI criteria (B6C), controlled attenuation parameter (CAP), platelet count (PLT), aspartate aminotransferase to PLT ratio index (APRI), Fibrosis-4 index (FIB4), model for end stage liver disease (MELD) score were evaluated against the results of EGD that served as the reference method. Analysed patients had median age 62 years, 59/73 (0.81) were males, 54/73 (0.74) had alcoholic/non-alcoholic fatty liver disease, and 21/73 (0.29) had HRV. In multivariate logistic regression analysis only LSM and PLT were independently associated with HRV. The best performing tests for ruling-out HRV (% of spared EGD; % of missed HRV) were respectively: LSM 214x109/L (21.9%; 0%); FIB4 ≤ 1.8 (21.4%; 0%), APRI ≤ 0.34 (12.3%; 0%). CAP, MELD = 6 alone or combined with PLT > 150(x109/L) did not show acceptable performance. The best performing biochemical tests for ruling-out HRV in our cohort of patients were PLT and FIB-4, but they were still outperformed by elastography-based approaches

Is Balint training associated with the reduced burnout among primary health care doctors?

The aim of our study was to examine whether the participation in Balint group is associated with the reducing burnout syndrome among primary health care doctors. This investigation was conducted on a population of 210 doctors employed in primary health centers in Belgrade. Out of 210 doctors, 70 have completed Balint training for a period of at least 1 year, whereas 140 doctors have never attended this training (the Non-Balint group). The level of burnout among physicians was assessed with the Serbian translation of the original 22- item version of the Maslach Burnout Inventory – Human Services Survey which defines burnout in relation to emotional exhaustion, depersonalization and personal accomplishment. We found that 45.0% of the Non-Balint participants and 7.1% of the Balint-trained participants responded with symptoms of high level of emotional exhaustion, with a statistically significant difference (p < 0.001). In relation to depersonalization, 20% of the Non-Balint subjects were highly depersonalized compared to 4.4% of the Balint-trained subjects, with a statistically significant difference (p < 0.001). Regarding the personal accomplishment, 21.4% of the Non-Balint subjects and 7.1% of the Balint-trained subjects had a perception of low personal accomplishment, with a statistical significance (p < 0.001). In the multiple ordinal logistic model, with emotional exhaustion as a dependent variable, statistically significant predictor was female gender (OR = 2.51; p = 0.021), while Balint training was obtained as a protective factor (OR = 0.12; p < 0.001). Non-specialists were detected as a risk factor for depersonalization (OR = 2.14; p = 0.026) while Balint group was found as a protective factor (OR = 0.10; p < 0.001), according to the multiple ordinal logistic regression analysis. Regarding the reduced personal accomplishment, our results indicated that nonspecialists were at risk for this subdimension (OR = 2.09; p = 0.025), whereas Balint participants were protected (OR = 0.18; p < 0.001). Participation in Balint groups is associated with the reduced burnout syndrome among primary health care doctors.Keywords: Doctor-patient relationship; Balint groups; burnout; primary health care; patientcentered; approac

Intestinal carriage of vancomycin-resistant Enterococcus spp. among high-risk patients in university hospitals in Serbia: first surveillance report

Background: The screening for intestinal carriage of vancomycin-resistant Enterococcus spp. (VRE) among high risk patients in the Balkan region and molecular epidemiology of VRE is insufficiently investigated, yet it could be of key importance in infection control. The aim of this study was to provide baseline data on VRE intestinal carriage among high-risk patients in Serbian university hospitals, to determine the phenotypic/genotypic profiles of the isolated VRE, to obtain knowledge of local resistance patterns and bridge the gaps in current VRE surveillance. Methods: The VRE reservoir was investigated using stool samples from 268 inpatients. Characterization of isolated VRE stains consisted of BD Phoenix system, genotypic identification, glycopeptide and quinupristin-dalfopristin (Q-D) resistance probing, virulence gene (esp, hyl, efaA, asa1, gelE, cpd) detection and MLVA. Biofilm formation was evaluated by the microtiter plate method. Results: VRE carriage prevalence among at-risk patients was 28.7%. All VRE strains were vanA positive multidrug-resistant Enterococcus faecium (VRfm), harboring ermB-1 (38.9%), esp (84%), efaA (71.2%), hyl (54.5%), asa1 (23.4%), gelE and cpd (11.6%) each. Ability of biofilm production was detected in 20.8%. Genetic relatedness of the isolates revealed 13 clusters, heterogeneous picture and 25 unique MTs profiles. Conclusion: The obtained prevalence of VRE intestinal carriage among high-risk inpatients in Serbia is higher than the European average, with high percentage of multidrug resistance. The emergence of resistance to Q-D is of particular concern. Close monitoring of pattern of resistance and strict adherence to specific guidelines are urgently needed in Serbia

Regulation of TMPRSS6 by BMP6 and iron in human cells and mice.

Mutations in transmembrane protease, serine 6 (TMPRSS6), encoding matriptase-2, are responsible for the familial anemia disorder iron-refractory iron deficiency anemia (IRIDA). Patients with IRIDA have inappropriately elevated levels of the iron regulatory hormone hepcidin, suggesting that TMPRSS6 is involved in negatively regulating hepcidin expression. Hepcidin is positively regulated by iron via the bone morphogenetic protein (BMP)-SMAD signaling pathway. In this study, we investigated whether BMP6 and iron also regulate TMPRSS6 expression. Here we demonstrate that, in vitro, treatment with BMP6 stimulates TMPRSS6 expression at the mRNA and protein levels and leads to an increase in matriptase-2 activity. Moreover, we identify that inhibitor of DNA binding 1 is the key element of the BMP-SMAD pathway to regulate TMPRSS6 expression in response to BMP6 treatment. Finally, we show that, in mice, Tmprss6 mRNA expression is stimulated by chronic iron treatment or BMP6 injection and is blocked by injection of neutralizing antibody against BMP6. Our results indicate that BMP6 and iron not only induce hepcidin expression but also induce TMPRSS6, a negative regulator of hepcidin expression. Modulation of TMPRSS6 expression could serve as a negative feedback inhibitor to avoid excessive hepcidin increases by iron to help maintain tight homeostatic balance of systemic iron levels