Clinical and pathophysiological understanding of the hepatorenal syndrome: Still wrong or still not exactly right?

The hepatorenal syndrome (HRS) is one major extrahepatic complication of end-stage liver diseases. While circulatory dysregulation is considered as primary etiology for HRS, cirrhosis-related (systemic) inflammation and/or cardial dysfunction may also play a key pathogenic role in HRS development. Exclusion of other causes of acute kidney injury (AKI) is required for diagnosis of HRS-AKI by the definition of the International Club of Ascites. However, the pathophysiology of HRS is not understood completely and there are still limited therapeutic options. Reversibility of renal dysfunction after liver transplantation indicates that HRS-AKI is a functional disorder caused by altered cellular function. The interplay between systemic inflammation and the onset of kidney-related hypometabolism may have a key role and needs to be studied in depth. This minireview challenges simplified views of the HRS in the context of diagnostics and therapy stressing the need for further evidence to advance the knowledge on this syndrome.

No Differences in Rotational Thromboelastometry Measurements between Portal and Peripheral Circulation in Cirrhotic Patients Undergoing TIPS.

BACKGROUND: In patients with liver cirrhosis, transjugular intrahepatic portosystemic shunt (TIPS) is considered a standardized treatment of refractory ascites or variceal bleeding. TIPS thrombosis (TT) and/or portal vein thrombosis (PVT) are possible complications during/after TIPS placement. Previous studies suggested increased clotting activity in portal circulation (PORC). This pilot study aimed to evaluate alterations and differences of coagulation function in PORC and in peripheral circulation (PERC) via rotational thromboelastometry during TIPS. METHODS: Blood samples were collected from cirrhotic patients (n = 13; median Model of End Stage Liver Disease, MELD Score: 12; median age: 60 years) undergoing TIPS (10/13 TIPSs were elective procedures due to refractory ascites) as follows: median cubital vein (MCV; PERC)-confluence of the three hepatic veins to the inferior cava vein (HV/ICV; PORC)-portal vein (PV; PORC)-TIPS (PORC). This research utilized four variables of the extrinsic test EXTEM, i.e., clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), and maximum lysis (ML). RESULTS: EXTEM results [mean, M (range) ± standard deviation, SD (range)] showed no significant differences for CT [M (70-73) ± SD (9-13); p = 0.93] or CFT [M (137-155) ± SD (75-112); p = 0.97] or MCF [M (51-54) ± SD (9-10); p = 0.90] or ML [M (9-10) ± SD (4-5); p = 0.89] between the compartments, i.e., MCV vs. HV/ICV vs. PV vs. TIPS. Overall, we detected no differences in coagulation function between PERC and PORC. CONCLUSION: These results are in contrast to previous reports suggesting increased clotting activity in PORC vs. PERC in association with liver cirrhosis. Rotational thromboelastometry-based evaluation of coagulation function in PERC appears to reliably reflect coagulation function in PORC with respect to risk estimation for TT and/or PVT in cirrhotic patients undergoing TIPS.

[Health economic evaluation of an internal medicine intermediate care unit (IMC) with gastroenterological focus at a maximum care university hospital - Evaluating the Profitability of Intermediate Care (IMC) in modern University Hospital Gastroenterology]. / Gesundheitsökonomische Bewertung einer internistischen Intermediate Care (IMC)-Station mit gastroenterologischem Schwerpunkt an einem universitären Klinikum der medizinischen Maximalversorgung ­ Wertung der Rentabilität einer Intermediate Care (IMC)-Station für die moderne universitäre Gastroenterologie.

Intermediate care (IMC) units meet the complex treatment needs of patients with specific diseases and/or those requiring advanced nursing care and can help turning the occupancy management of intensive care unit (ICU) beds more efficient. Despite the exclusion of nursing staff costs from the Diagnosis-Related-Groups (DRG) reimbursement system, prolonged periods of below-average monthly revenues due to loss of complex DRGs and/or misallocation/blocking of IMC beds can lead to a fixed cost refinancing problem; this again brings to the fore the question of the profitability of an IMC unit. Thus, the aim of this work has been to evaluate the profitability of a gastroenterological IMC, as part of an interdisciplinary medical IMC (MIMC) at the University Hospital Essen, for the period 01.01.2014-31.12.2016. Retrospectively, 1015 cases of the MIMC ward of the Department of Gastroenterology and Hepatology (Med.G./MIMC; N=12 beds) were examined with regard to length of stay (LoS), admission/main diagnosis, procedures provided as well as secondary diagnoses, revenues, age, and sex (median patient age 57 years; ♂ 61%, ♀ 39%). Overall, 85% of DRG reimbursements comes from treatment cases within the top 20 base DRGs; these highlight the hepatology focus of Med.G./MIMC. The case-mix (CM) monthly average is 65; the CM index (CMI), which has significant seasonal variation (analogous to CM), monthly average is 10.891 (2014-2016). The average LoS on the Med.G./MIMC is 12.3 days, which is significantly higher than the average LoS in German hospitals (7.2 days). Concrete economic assessment of Med.G./MIMC reveals that the inpatient revenues increase from € 2.90 million to € 3.72 million (2014-2016). Thus, there is a positive development of primary revenues from € 2.98 million (2014) to € 3.56 million (2015) to € 3.81 million (2016), with largely constant expenses in the area of primary costs and of claimed secondary services. Empirically, taking into account the potential interdisciplinary synergy effects, this can be considered as an exceptionally good health economic development/outcome.

Comparison of Mortality Prediction Scores in Intermediate-Care Patients with Liver Cirrhosis at a German University Transplant Centre: A Prospective Study.

BACKGROUND AND AIMS: Mortality prediction models help to extract and relate patient data upon admission to intensive or intermediate care units (ImCUs). Considering technical and economic healthcare developments, re-evaluations of score performances are required to warrant their validity. This study validates and compares established scoring systems in cirrhotic ImCU patients. METHODS: Acute Physiology and Chronic Health Evaluation (APACHE) II, Simplified Acute Physiology Score (SAPS) 2 and 3, Sepsis Organ Failure Assessment (SOFA), Mortality Probability Model at ICU admission (MPMo) II and III, Model for End stage Liver Disease (MELD), CLIF-Consortium Acute-on-Chronic Liver Failure (CLIF-C ACLF), CLIF-Consortium Acute Decompensation (CLIF-C AD), and Intermediate Care Unit Severity Score (ImCUSS) were calculated in patients with cirrhosis (n = 98) at ImCU admission. Discrimination performances were evaluated by area under the receiver operating characteristic curves (AUROCs), calibration performances with calibration belt plots, and their corresponding p values. RESULTS: Overall, SAPS 3 and CLIF-C ACLF have shown the best 90-day mortality prediction outcomes with AUROCs of 0.825 and 0.783 along with calibration belt p values of 0.128 and 0.061, respectively. In a subgroup analysis of patients with acute-on-chronic liver failure (ACLF), expanded SAPS 2, SOFA, and SAPS 3 reached the best AUROCs, i.e., 0.760, 0.750, and 0.714, but none of the tested scores reached an acceptable calibration. CONCLUSION: Ninety-day mortality risk prediction of the SAPS 3 and CLIF-C ACLF was accurate in our cohort of patients with liver cirrhosis admitted to ImCUs. A particular challenge remains that is the mortality prediction in patients with ACLF requiring ImCU-level care; here, further developments are needed to generate scores with acceptable predictive performances.

Performance of the Liver Maximum Function Capacity Test, Fibrinogen, and Transient Elastography in Patients with Acute Liver Injury.

BACKGROUND: Acute liver failure (ALF) occurs as a rare, sudden, extensive loss of liver function in a previously healthy liver. In advanced cases, ALF may require liver transplantation (LT). Available prognostic parameters have limited accuracy to decide, which patient to consider for LT. The liver maximum function capacity test (LiMAx) can accurately determine liver function and was assessed as predictor of survival, along with coagulation parameters and liver stiffness in nonacetaminophen-induced ALF. METHODS: Various liver function tests, including LiMAx measurements, coagulation factors, and transient elastography (TE), were analyzed retrospectively for associations with clinical outcome in 34 patients with ALF or acute hepatitis (AH). Data were compared between patients with spontaneous recovery (SR) and non-SR (3-month mortality/LT; NSR). RESULTS: The analysis included 34 patients (22 ALF, 12 AH; 19 males, 15 females; age 36.7 ± 14.6 years) with drug-induced liver injury (DILI) (n = 12), autoimmune hepatitis (AIH; n = 13), AIH-DILI overlap (n = 1), viral (n = 9), or cryptogenic liver failure (n = 1). Thirty-one patients recovered spontaneously, 2 patients died, and 1 patient underwent LT. The LiMAx was 197.6 (±68.4) for SR versus 92.33 (±65.0) for NSR (p = 0.0157). Fibrinogen was significantly lower in patients with NSR than in SR patients (209.0 vs. 106.3; p = 0.02). Mean liver stiffness measured by TE was 39.3 for NSR and 17.3 for SR (p = 0.26). KCC was fulfilled in only 4 patients (3 SR, 1 NSR). LiMAx results correlated positively with serum fibrinogen and antithrombin III concentrations and correlated negatively with liver stiffness. No other analyzed factor could differentiate between SR and NSR. CONCLUSION: Decision-making in ALF remains challenging. LiMAx and fibrinogen might predict the prognosis in patients with nonacetaminophen-induced ALF and in combination could be feasible tools to decide if LT is necessary.

A Multipathogen Bile Sample-based PCR Assay Can Guide Empirical Antimicrobial Strategies in Cholestatic Liver Diseases.

Background and objectives: Polymerase chain reaction (PCR) techniques provide rapid detection of pathogens. This pilot study evaluated the diagnostic utility and clinical impact of multiplex real-time PCR (mRT-PCR, SeptiFast) vs. conventional microbial culture (CMC) in bile samples of patients with chronic cholestatic liver diseases (cCLDs), endoscopic retrograde cholangio-pancreatography (ERCP), and peri-interventional-antimicrobial-prophylaxis (pAP). Methods: We prospectively collected bile samples from 26 patients for microbiological analysis by CMC and mRT-PCR. Concordance of the results of both methods was determined by Krippendorff's alpha (α) for inter-rater reliability and the Jaccard index of similarity. Results: mRT-PCRbile and CMCbile results were concordant for only Candida albicans (α=0.8406; Jaccard index=0.8181). mRT-PCRbile detected pathogens in 8/8 cases (100%), CMCbile in 7/8 (87.5%), and CMCblood in 5/8 (62.5%) with clinical signs of infection. mRT-PCRbile, CMCbile, and CMCblood had identical detection results in 3/8 (37.5%) with clinical signs of infection (two Klebsiella spp. and one Enterococcus faecium). The total pathogen count was significantly higher with mRT-PCRbile than with CMCbile (62 vs. 31; χ2=30.031, p<0.001). However, pathogens detected by mRT-PCRbile were more often susceptible to pAP according to the patient infection/colonization history (PI/CH) and surveillance data for antibiotic resistance in our clinic (DARC). Pathogens identified by mRT-PCRbile and resistant to pAP by PI/CH and DARC were likely to be clinically relevant. Conclusions: mRT-PCR in conjunction with CMCs for bile analysis increased diagnostic sensitivity and may benefit infection management in patients with cholestatic diseases. Implementation of mRT-PCR in a bile sample-based diagnostic routine can support more rapid and targeted use of antimicrobial agents in cCLD-patients undergoing ERCP and reduce the rate/length of unnecessary administration of broad-spectrum antibiotics.

[Practice-guided Presentation of the German S3 Guideline "Strategies to Warrant Rational In-hospital Use of Antibiotics"]. / Praxisorientierte Darstellung der deutschen S3-Leitlinie "Strategien zur Sicherung rationaler Antibiotika-Anwendungen im Krankenhaus".

The current S3 guideline entitled "Strategies to warrant rational in-hospital use of antibiotics" summarizes evidence-based antibiotic stewardship (ABS) measures that aim to improve clinical outcomes and prevent development and spread of microbial resistance in German hospitals. Most important prerequisite for efficiency and safety of ABS programs is sufficient staffing capacity as well as reliably operating surveillance of (i) pathogens, (ii) antimicrobial resistance and (iii) consumption of antimicrobials. ABS teams require authorization by hospital institutions as units exclusively responsible for antimicrobial audits and implementation of anti-infective interventions. Clinicians should be regularly granted access to in-hospital training programs delivered by ABS experts. Finally yet importantly, the current S3 guideline also highlights future goals, e.g., the structured involvement for nurses in ABS-guided infection management or the promotion of ABS programs in the outpatient sector and in veterinary medicine.

ERCP in critically ill patients is safe and does not increase mortality.

ABSTRACT: Endoscopic retrograde cholangiopancreatography (ERCP) is the gold standard for minimally-invasive treatment of biliary or pancreatic tract disease. When treating patients on intensive care units (ICU) with ERCP, interventionalists are faced with considerably higher morbidity compared to patients in ambulatory settings. However, data on complications and outcome of critical ill patients undergoing emergency ERCP are limited.A retrospective analysis of 102 patients treated on ICUs undergoing 121 ERCP procedures at the University Hospital of Essen, Germany between 2002 and 2016 was performed. Indications, interventional success, outcome including survival and procedure-related complications were analyzed. Patients' condition pre-ERCP was categorized by using the "Simplified Acute Physiology Score" (SAPS 3).66/102 patients (64.7%) were referred to ERCP from surgical ICU, 36/102 (35.3%) from nonsurgical ICU. The majority of patients were male (63.7%), the mean age was 54.1 ±â€Š14.9 [21-88] years. Indications for ERCP were biliary complications after liver transplantation (n = 34, 33.3%), biliary leakage after hepatobiliary surgery (n = 32, 31.4%), and cholangitis/biliary sepsis (n = 36; 35.3%), respectively. 117/121 (96.7%) ERCPs were successful, 1 patient (1.0%) died during ERCP. Post-ERCP pancreatitis occurred in 11.8% of interventions. The median simplified acute physiology score 3 was 65 points, predicting a risk-adjusted estimated mortality of 48.8%, corresponding to an observed mortality of 52.2% (P = n.s.).ERCP is safe in critically ill patients on ICU, it does not increase overall mortality rate and has a relatively low rate of procedure-associated complications.

Incidence and Impact of Routine Inflammatory Parameters on Outcome after Transcatheter Aortic Valve Replacement.

BACKGROUND: Previous research reported adverse clinical outcomes in association with systemic inflammation (SI) after transcatheter aortic valve replacement (TAVR). However, data characterizing the impact of SI, as reflected by postprocedural routine inflammatory parameters (pRIP), on clinical outcome of patients undergoing TAVR are sparse. OBJECTIVES: In light of this, the present work aimed to analyze incidence and clinical significance of pRIP after transapical (TA) and transfemoral (TF)-TAVR. METHODS AND RESULTS: Data of 81 high-risk consecutive patients undergoing TAVR in our center from 2017 to 2018 were analyzed in a retrospective manner. 40 out of 81 patients (49, 4%) were treated via TF access (group A) and 41 patients via TA access (group B). Incidence, cause, and amplitude of pRIP were analyzed in relation to pre- and peri-interventional data. Assessment of outcomes was conducted according to the valve academic research consortium (VARC-2). Postprocedural C-reactive protein (pCRP) and leucocytes (pL) were significantly increased in patients undergoing TA-TAVR (group B) vs. TF-TAVR (group A; 12.1 ± 9.7 vs. 22.1 ± 7.9 mg/dl, p < 0.001 and 12.8 ± 4.0 vs. 14.2 ± 3.8/nl, p = 0.002); however, there was no significant difference regarding incidence of postprocedural fever (pF) ≥38.0°C (12.5% vs. 22%, p = 0.37). Furthermore, we observed a vast (though insignificant) trend towards a longer fever duration in group B vs. group A (9.9 ± 14.9 vs. 3.2 ± 5.9 hours, p = 0.06). Further analysis identified pCRP >30 mg/dl (hazard ratio (HR) 3.15, confidence interval (CI) 1.22-8.14, p = 0.018) and European System for Cardiac Operative Risk Evaluation (logistic EuroSCORE I (ES)) >20% (HR 2.95, CI 1.17-7.47, p = 0.02) as predictors of mortality; in this context, we also discovered a marginally significant trend for pL > 14/nl (HR 2.44, CI 0.97-6.14, p = 0.05). Multivariate analysis by use of the fisher`s exact test revealed a significant association between pCRP >30 mg/dl and ES >20% (p < 0.001). CONCLUSION: pRIP are significantly increased in patients undergoing TA-TAVR. pCRP >30 mg/dl, ES>20%, and pL > 14/nl are hallmark of adverse prognosis and require further investigation.

Analysis of Ascites-Challenged Blood in Patients with Liver Cirrhosis Using Rotational Thromboelastometry: How Robust Is the Evidence on Ascites-Attributed Fibrinolysis?

INTRODUCTION: For over 30 years, ascites has been postulated to facilitate fibrinolysis in patients with liver cirrhosis. In contrast to previous research employing conventional coagulation tests, this study aimed to characterize hemostatic interactions between blood and ascites using the rotational thromboelastometry (ROTEM). METHODS: Blood samples - pure or mixed with ascites in a ratio of 1:1 - from cirrhotic patients (n = 10) were subjected to ROTEM analysis. In addition, a negative control group was built with cirrhotic patients (n = 10) whose blood was mixed with physiologic sodium chloride (0.9% NaCl) solution in a ratio of 1:1. Subsequently, ROTEM measurements were subjected to statistical analysis. RESULTS: During ascites challenge, clotting time (CT, measured in seconds) was significantly prolonged in EXTEM (blood: 70.40 ± 20.40 vs. ascites/blood: 109.8 ± 47.7) and APTEM (blood: 66.50 ± 14.55 vs. ascites/blood: 138.7 ± 105.8), likely reflecting a dilution effect. However, CT in INTEM remained unchanged, suggesting a sustained intrinsic pathway function. Maximal clot firmness (measured in millimeters) in FIBTEM decreased significantly (blood: 14.70 ± 9.55 vs. ascites/blood: 6.00 ± 5.66), thus indicating depletion of fibrinogen in ascites. Strikingly, maximum lysis (measured in %) significantly decreased in EXTEM (blood: 9.30 ± 2.79 vs. ascites/blood: 5.50 ± 2.84), APTEM (blood: 8.50 ± 3.10 vs. ascites/blood: 5.60 ± 2.88), and INTEM (blood: 7.50 ± 2.27 vs. ascites/blood: 5.10 ± 3.48). CONCLUSIONS: ROTEM provided new evidence that ascites may not primarily induce fibrinolysis in cirrhotic patients. This finding seems to be of significant importance for the clinical management of cirrhotic patients experiencing complications, for example, abdominal hemorrhage after liver biopsy or paracentesis; here, replacement of prothrombin complex concentrates and/or fibrinogen concentrates may prove more beneficial than the use of fresh frozen plasma or antifibrinolytic drugs.

Score performance of SAPS 2 and SAPS 3 in combination with biomarkers IL-6, PCT or CRP.

OBJECTIVE: We aimed to evaluate the effects of combining the Simplified-Acute-Physiology-Score (SAPS) 2 or the SAPS 3 with Interleukin-6 (IL-6) or Procalcitonin (PCT) or C-Reactive Protein (CRP) concentrations for predicting in-hospital mortality. MATERIAL AND METHODS: This retrospective study was conducted in an interdisciplinary 22-bed intensive care unit (ICU) at a German university hospital. Within an 18-month period, SAPS 2 and SAPS 3 were calculated for 514 critically ill patients that were admitted to the internal medicine department. To evaluate discrimination performance, the area under the receiver operating characteristic curves (AUROCs) and the 95% confidence intervals (95% CIs) were calculated for each score, exclusively or in combination with IL-6 or PCT or CRP. DeLong test was used to compare different AUROCs. RESULTS: The SAPS 2 exhibited a better discrimination performance than SAPS 3 with AUROCs of 0.81 (95% CI, 0.76-0.86) and 0.72 (95% CI, 0.66-0.78), respectively. Overall, combination of the SAPS 2 with IL-6 showed the best discrimination performance (AUROC 0.82; 95% CI, 0.77-0.87), albeit not significantly different from SAPS2. IL-6 performed better than PCT and CRP with AUROCs of 0.75 (95% CI, 0.69-0.81), 0.72 (95% CI, 0.66-0.77) and 0.65 (95% CI, 0.59-0.72), respectively. Performance of the SAPS 3 improved significantly when combined with IL-6 (AUROC 0.76; 95% CI, 0.69-0.81) or PCT (AUROC 0.73; 95% CI, 0.67-0.78). CONCLUSIONS: Our analysis provided evidence that the risk stratification performance of the SAPS 3 and, to a lesser degree, also of the SAPS 2 can increase when combined with IL-6. A more accurate detection of aberrant or dysregulated systemic immunological responses (by IL-6) may explain the higher performance achieved by SAPS 3 + IL-6 vs. SAPS 3. Thus, implementation of IL-6 in critical care scores can improve prediction outcomes, especially in patients experiencing acute inflammatory conditions; however, statistical results may vary across hospital types and/or patient populations with different case mix.

The predictive performance of SAPS 2 and SAPS 3 in an intermediate care unit for internal medicine at a German university transplant center; A retrospective analysis.

OBJECTIVE: To analyze and compare the performance of the Simplified-Acute-Physiology-Score (SAPS) 2 and SAPS 3 among intermediate care patients with internal disorders. MATERIALS AND METHODS: We conducted a retrospective single-center analysis in patients (n = 305) admitted to an intermediate-care-unit (ImCU) for internal medicine at the University Hospital Essen, Germany. We employed and compared the SAPS 2 vs. the SAPS 3 scoring system for the assessment of disease severity and prediction of mortality rates among patients admitted to the ImCU within an 18-month period. Both scores, which utilize parameters recorded at admission to the intensive-care-unit (ICU), represent the most widely applied scoring systems in European intensive care medicine. The area-under-the-receiver-operating-characteristic-curve (AUROC) was used to evaluate the SAPS 2 and SAPS 3 discrimination performance. Ultimately, standardized-mortality-ratios (SMRs) were calculated alongside their respective 95%-confidence-intervals (95% CI) in order to determine the observed-to-expected death ratio and calibration belt plots were generated to evaluate the SAPS 2 and SAPS 3 calibration performance. RESULTS: Both scores provided acceptable discrimination performance, i.e., the AUROC was 0.71 (95% CI, 0.65-0.77) for SAPS 2 and 0.77 (95% CI, 0.72-0.82) for SAPS 3. Against the observed in-hospital mortality of 30.2%, SAPS 2 showed a weak performance with a predicted mortality of 17.4% and a SMR of 1.74 (95% CI, 1.38-2.09), especially in association with liver diseases and/or sepsis. SAPS 3 performed accurately, resulting in a predicted mortality of 29.9% and a SMR of 1.01 (95% CI, 0.8-1.21). Based on Calibration belt plots, SAPS 2 showed a poor calibration-performance especially in patients with low mortality risk (P<0.001), while SAPS 3 exhibited a highly accurate calibration performance (P = 0.906) across all risk levels. CONCLUSIONS: In our study, the SAPS 3 exhibited high accuracy in prediction of mortality in ImCU patients with internal disorders. In contrast, the SAPS 2 underestimated mortality particularly in patients with liver diseases and sepsis.

The Effect of Immunosuppression on Coagulation After Liver Transplantation.

Everolimus (EVR) is a mammalian target of rapamycin (mTOR) inhibitor commonly used for immunosuppression (IS) after liver transplantation (LT). However, there are concerns about whether mTOR inhibitors may move the hemostatic balance toward a higher likelihood of thrombosis. The present study aimed to investigate potential coagulation disorders after the administration of EVR. We evaluated 54 patients after conversion to an EVR-based IS regimen (n = 26) and compared those patients with patients who were switched to extended-release tacrolimus (TAC) but had never received EVR (n = 28). At baseline and again at 1 month and 6 months after conversion, we measured international normalized ratio, activated partial thromboplastin time, and anticoagulation and fibrinolysis factors, and we performed rotational thromboelastometry (ROTEM). Data were analyzed with a Mann-Whitney U test, a repeated-measure analysis of variance, and a Fisher's exact test. Statistical significance was set at the level of P ≤ 0.05. Plasma levels of von Willebrand factor, fibrinogen, and factor VIII were significantly higher than baseline levels at 1 month and 6 months after conversion of IS to EVR (P < 0.001); plasma levels of protein C, protein S, and plasminogen also increased significantly (P < 0.001). ROTEM confirmed a significant increase in maximum clot firmness in EXTEM, INTEM, and FIBTEM assays (P < 0.001). In all assays, maximum lysis was significantly lower than baseline levels at 1 month and 6 months after conversion to EVR. Patients converted to IS with extended-release TAC exhibited no significant changes in coagulation variables. Retrospective analysis showed a significantly higher incidence of thromboembolic complications among patients treated with EVR-based IS than among those treated with extended-release TAC (P < 0.01). In conclusion, the administration of EVR after LT seems to modify hemostasis to a procoagulant state. Thrombophilia screening before conversion may determine which patients will benefit from conversion to EVR-based IS.

Immune Dysfunction and Albumin-Related Immunity in Liver Cirrhosis.

Liver cirrhosis yearly causes 1.2 million deaths worldwide, ranking as the 10th leading cause of death in the most developed countries. High susceptibility to infections along with a significant risk for infection-related mortality justifies the description of liver cirrhosis as the world's most common immunodeficiency syndrome. Liver cirrhosis is an end-stage organic disease hallmarked by a multifaceted immune dysfunction due to deterioration of antimicrobial recognition and elimination mechanisms in macrophages along with an impaired antigen presentation ability in circulating monocytes. Bacterial translocation supports-and is supported by-uncontrolled activation of immune cell responses and/or loss of toll-like receptor (TLR) tolerance, which can turn exaggerated inflammatory responses to systemic inflammation. Lipopolysaccharide (LPS) or endotoxin boosts systemic inflammatory activity through activation of TLR-2- and TLR-4-dependent pathways and facilitate a massive production of cytokines. This, in turn, results into elevated secretion of reactive oxygen species (ROS), which further enhances intestinal hyperpermeability and thus sustains a vicious circle of events widely known as "leaky gut." Albumin can be of particular benefit in cirrhotic patients with spontaneous bacterial peritonitis and/or hepatorenal syndrome type of acute kidney injury (HRS-AKI) due to anti-inflammatory and antioxidative stress as well as volume-expanding properties and endothelial-stabilizing attributes. However, presence of autoantibodies against albumin in patients with liver cirrhosis has been described. Although previous research suggested that these antibodies should be regarded as naturally occurring antibodies (NOA), the origin of the antialbumin immune response is obscure. High occurrence of NAO/albumin complexes in patients with liver disease might reflect a limited clearance capacity due to bypassing portal circulation. Moreover, high burden of oxidized albumin is associated with less favorable outcome in patients with liver cirrhosis. To date, there is no data available as to whether oxidized forms of albumin result in neoepitopes recognized by the immune system. Nevertheless, it is reasonable to hypothesize that these alterations may have the potential to induce antialbumin immune responses and thus favor systemic inflammation.

Intensive Care Therapy for Patients with Advanced Liver Diseases.

Decompensated cirrhosis is characterized by high hospitalization rates and costs, frequent readmissions, and poor short-term survival. Patients admitted to the hospital with acute variceal bleeding and/or hepatic encephalopathy and/or renal dysfunction are at serious risk for developing infection and/or sepsis; in turn, this renders them highly susceptible to the development of multi-system organ failure. The lack of standardized intensive care unit management protocols in patients with cirrhosis along with only few data reports from longitudinal clinical trials makes it difficult for hepatologists and critical care specialists to provide uniform evidence for clinical practice that could safely consolidate favorable outcomes such as lower hospitalization rates and/or mortality. Based on a rigorous online search of the scientific literature as well as a longtime clinical experience of the authors in the field of hepatology and critical care medicine, this work represents a focused effort to elucidate the specific bio-morbidity of advanced liver diseases in relation to the aforementioned challenges in clinical management. Further meta-analyses and/or systematic reviews are needed to enable clinicians to develop more effective strategies to bridge patients with decompensated liver disease to recompensation or liver transplantation.

Clinical patterns associated with the concurrent detection of anti-HBs and HBV DNA.

Simultaneous detection of anti-HBs and HBV DNA is a rare serological combination and has been described in acute and chronic HBV infection. To scrutinize viral and clinical patterns associated with concurrent detection of anti-HBs and HBV DNA. Simultaneous detection of anti-HBs and HBV DNA was observed in 64/1444 (4.4%) patients treated for HBV infection at the University Hospital of Essen from 2006 to 2016 (8 with acute, 20 with reactivated, and 36 chronic HBV infection). Clinical data and laboratory parameters were analyzed. Regions of the small hepatitis B surface antigen (SHB) and the reverse transcriptase (RT) were sequenced using next generation sequencing (NGS). Among the 64 patients with detectable HBV DNA and anti-HBs, 17 were HBsAg negative (HBsAg[-]), and two had acute liver failure. Patients with acute HBV infection had fewer genotype specific amino acid substitutions in the SHB region than patients with reactivated HBV infection (4 [4.5] vs 9 [16.25], P = 0.043). However, we could observe a significantly higher number of mutations in the a-determinant region when comparing chronically infected patients to patients with acute infection (0 [1] vs 1 [1], P = 0.044). The ratio of nonsynonymous to synonymous mutations (Ka/Ks) was on average >1 for the SHB region and <1 for the RT region. The Ka/Ks ratio (>1) in the SHB region indicates that anti-HBs might have exerted selection pressure on the HBsAg. In three cases the diagnosis of acute HBV infection would have been at least delayed by only focusing on HBsAg testing.