The tolerability of sofosbuvir/velpatasvir for 12 weeks in patients treated in the ASTRAL 1, 2 and 3 studies: A pooled safety analysis.

To evaluate the safety and tolerability of the fixed-dose, single-tablet regimen sofosbuvir/velpatasvir (SOF/VEL) for the treatment of hepatitis C virus (HCV) infection in three Phase 3 studies in patients with and without compensated cirrhosis. Data from three registrational trials (ASTRAL-1, NCT02201940; ASTRAL-2, NCT02220998; ASTRAL-3, NCT02201953) were pooled by treatment regimen. Researchers assessed treatment-emergent adverse events (TEAEs) and laboratory abnormalities in patients randomized to SOF/VEL or placebo for 12 weeks in ASTRAL-1 and SOF/VEL for 12 weeks in ASTRAL-2 and ASTRAL-3. Overall, 1035 patients were treated with SOF/VEL, and 116 patients received placebo. Rates of any TEAE were generally similar between patients receiving SOF/VEL (79.4%) and those receiving placebo (76.7%). The majority of TEAEs were mild to moderate, with 23 (2.2%) treatment-emergent serious AEs in patients treated with SOF/VEL. Of these treatment-emergent serious AEs, none led to premature study discontinuation, nor were they considered related to treatment. Presence of compensated cirrhosis, greater age and mild renal impairment did not impact incidence or severity of TEAEs with SOF/VEL treatment. The most common TEAEs (incidence ≥10%) were headache, fatigue, nausea and nasopharyngitis in patients receiving SOF/VEL; similar rates were observed in placebo-treated patients. Three deaths (<1%) were reported in patients treated with SOF/VEL, all posttreatment and none assessed as related to study treatment. Similar to that of placebo, SOF/VEL treatment of HCV infection had a safety/tolerability profile that was not affected by baseline factors, such as the presence of compensated cirrhosis, mild renal impairment or advanced age.

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.

[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.

Risk factors for post-polypectomy bleeding; a retrospective case-control study of a high-volume colonoscopy center.

BACKGROUND AND AIM: Post-polypectomy bleeding (PPB) remains an uncommon although serious complication of colonoscopy. The aim of this study is to determine the PPB-prevalence in a secondary care hospital and its associated risk factors. PATIENTS AND METHODS: We collected data from 581 patients, with the removal of 1593 polyps between August 2017 and August 2019. A univariate binary logistic regression analysis was conducted retrospectively. RESULTS: PPB occurred in only 10 cases, representing 1.7% of patients: immediate in 1.2% and delayed in 0.5%. The number of removed polyps per patient [4.5 (SD 2.59) for hemorrhagic vs. 2.74 (SD 1.98) for non-hemorrhagic group] and the propofol dose [232 mg (SD 93.07) for hemorrhagic vs. 133 mg (SD 57.28) for non-hemorrhagic group] were relevant patient-related risk factors. The polyp-based analysis showed the polyp size [18.4 mm (SD 10.44) for hemorrhagic vs. 4.42 mm (SD 4.29) for non-hemorrhagic group], the morphology [wide-based: OR 24.83 (95 % CI 2.76 - 223.44), pedunculated: OR 56.67 (95 % CI 5.03 - 638.29)], the location at ileocecal valve [OR 20.48, 95 % CI 1.81 - 231.97)], and the polypectomy method [hot snare piecemeal with epinephrine injection: OR 75.38 (95 % CI 7.67 - 741.21)] as significant risk factors for PPB, too. CONCLUSIONS: The low rate of PPB confirms the safety of the procedure in non-tertiary, high-volume colonoscopy centers. The number of polyps removed per patient, the polyp size, morphology and location, as well as the sedation dose and the method of polypectomy were shown as relevant risk factors.

Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab.

BACKGROUND: Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2). METHODS: Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed. RESULTS: Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6-12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354-0.574; p < 0.0001). CONCLUSIONS: AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, REACH (NCT01140347) and REACH-2 (NCT02435433).

Hepatitis B Virus Particles Activate Toll-Like Receptor 2 Signaling Initially Upon Infection of Primary Human Hepatocytes.

BACKGROUND AND AIMS: To date, conflicting data exist as to whether hepatitis B virus (HBV) has the ability to induce innate immune responses. Here, we investigated cellular changes after the first contact between HBV and primary human hepatocytes (PHH) in vitro and in vivo. APPROACH AND RESULTS: The exposure of PHH to HBV particles resulted in nuclear translocation of NFκB, followed by the expression and secretion of inflammatory cytokines (IL [interleukin] 1B, IL6, and TNF [tumor necrosis factor]). Ultraviolet irradiation of viral particles suppressed HBV infectivity but not the induction of cytokines in PHH, suggesting that the inoculum contains the immune-inducing agent. Purified HBV particles on the whole, which were prepared from HBV DNA-positive and protein-rich fractions after heparin column separation, still had immune-inducing capacity in PHH. The HBV-induced gene expression profile was similar to that induced by toll-like receptor 2 (TLR2) ligand Pam3Cys, but different from those induced by the viral sensors TLR3 or TLR7-9. Treatment of PHH with both HBV particles and Pam3Cys led to phosphorylation of ERK (extracellular signal-regulated kinase), JNK, and p38 mitogen-activated protein kinases as well as NFκB (nuclear factor kappa B). Finally, HBV-induced gene expression could be neutralized by TLR2-specific antibodies. Of note, pretreatment with an HBV entry inhibitor attenuated the TLR2-mediated response to HBV, suggesting a receptor binding-related mechanism. In liver-humanized uPA/severe combined immunodeficient (SCID)/beige mice challenged with HBV in vivo, immune induction could only marginally be seen. CONCLUSIONS: PHHs are able to sense HBV particles through TLR2, leading to an activation of anti-HBV immune responses in vitro. These findings challenge the previously described stealth properties of HBV.

Anti-TNFα treatment in Crohn's disease: Impact on hepatic steatosis, gut-derived hormones and metabolic status.

BACKGROUND AND AIMS: An association between Crohn's disease (CD) and hepatic steatosis has been reported. However, the underlying mechanisms of steatosis progression in CD are not clear. Among the most effective CD treatments are agents that inhibit Tumor-Necrosis-Factor (TNF) activity, yet it is unclear why anti-TNFα agents would affect steatosis in CD. Recent studies suggest that microbiome can affect both, CD and steatosis pathogenesis. Therefore, we here analysed a potential relationship between anti-TNF treatment and hepatic steatosis in CD, focusing on the gut-liver axis. METHODS: This cross-sectional study evaluated patients with established CD, with and without anti-TNFα treatment, analysing serum markers of liver injury, measurement of transient elastography, controlled attenuation parameter (CAP) and MRI for fat detection. Changes in lipid and metabolic profiles were assessed by serum and stool lipidomics and metabolimics. Additionally, we analysed gut microbiota composition and mediators of bile acid (BA) signalling via stool and serum analysis. RESULTS: Patients on anti-TNFα treatment had less hepatic steatosis as assessed by CAP and MRI. Serum FGF19 levels were significantly higher in patients on anti-TNFα therapy and associate with reduced steatosis and increased bowel motility. Neutral lipids including triglycerides were reduced in the serum of patients on anti-TNF treatment. Bacteria involved in BA metabolism and FGF19 regulation, including Firmicutes, showed group-specific alterations with low levels in patients without anti-TNFα treatment. Low abundance of Firmicutes was associated with higher triglyceride levels. CONCLUSIONS: Anti-TNFα treatment is associated with reduced steatosis, lower triglyceride levels, alterations in FXR-signalling (eg FGF19) and microbiota composition in CD.

GALAD Score Detects Early Hepatocellular Carcinoma in an International Cohort of Patients With Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: The prevalence of nonalcoholic steatohepatitis (NASH) associated hepatocellular carcinoma (HCC) is increasing. However, strategies for detection of early-stage HCC in patients with NASH have limitations. We assessed the ability of the GALAD score, which determines risk of HCC based on patient sex; age; and serum levels of α-fetoprotein (AFP), AFP isoform L3 (AFP-L3), and des-gamma-carboxy prothrombin (DCP), to detect HCC in patients with NASH. METHODS: We performed a case-control study of 125 patients with HCC (20% within Milan Criteria) and 231 patients without HCC (NASH controls) from 8 centers in Germany. We compared the performance of serum AFP, AFP-L3, or DCP vs GALAD score to identify patients with HCC using receiver operating characteristic curves and corresponding area under the curve (AUC) analyses. We also analyzed data from 389 patients with NASH under surveillance for HCC in Japan, followed for a median of 167 months. During the 5-year screening period, 26 patients developed HCC. To compensate for irregular intervals of data points, we performed locally weighted scatterplot smoothing, linear regression, and a non-linear curve fit to assess development of GALAD before HCC development. RESULTS: The GALAD score identified patients with any stage HCC with an AUC of 0.96 - significantly greater than values for serum levels of AFP (AUC, 0.88), AFP-L3 (AUC, 0.86) or DCP (AUC, 0.87). AUC values for the GALAD score were consistent in patients with cirrhosis (AUC, 0.93) and without cirrhosis (AUC, 0.98). For detection of HCC within Milan Criteria, the GALAD score achieved an AUC of 0.91, with a sensitivity of 68% and specificity of 95% at a cutoff of -0.63. In a pilot Japanese cohort study, the mean GALAD score was higher in patients with NASH who developed HCC than in those who did not develop HCC as early as 1.5 years before HCC diagnosis. GALAD scores were above -0.63 approximately 200 days before the diagnosis of HCC. CONCLUSIONS: In a case-control study performed in Germany and a pilot cohort study in Japan, we found the GALAD score may detect HCC with high levels of accuracy in patients with NASH, with and without cirrhosis. The GALAD score can detect patients with early-stage HCC, and might facilitate surveillance of patients with NASH, who are often obese, which limits the sensitivity of detection of liver cancer by ultrasound.

Clinical Outcome and Viral Genome Variability of Hepatitis B Virus-Induced Acute Liver Failure.

Acute hepatitis B virus (HBV) infection remains a frequent cause of acute liver failure (ALF) worldwide. ALF occurs in 0.1%-0.5% of infected patients. The aim of this study was to scrutinize the outcome of patients with HBV-induced ALF and mutational patterns of HBV variants, which might contribute to ALF. From 2005 to 2016, 42 patients were treated for HBV-induced ALF in the University Hospital Essen, Germany. Clinical and virological data from these patients were collected. As a control, 38 patients with acute hepatitis B (AHB) without liver failure were included. The HBV genome was sequenced by next-generation sequencing (NGS). Mutations that were found by NGS were analyzed in vitro. Of 42 patients, 8 had ALF without spontaneous recovery (NSR): Seven patients underwent liver transplantation (LT) and one patient died before LT. Of 42 patients, 34 (81%) had spontaneous recovery (SR) and cleared the infection, achieving either anti-HBs seroconversion or hepatitis B surface antigen (HBsAg) loss. HBV genotype (GT)-D was the most frequent GT in patients with ALF. Mutations in HBV core, preS2, and small hepatitis B surface antigen (SHB) were more frequent in patients with ALF-NSR compared with those with ALF-SR or AHB. Amino acid deletions (del; 16-22 and 20-22) in preS2 and SHB mutation L49R were exclusively detected in patients with ALF-NSR. In vitro analyses reveal that these mutations did not influence HBsAg secretion or infectivity. Conclusion: HBV GT-D and increased variability in HBV core, preS2 region, and SHB are associated with a worse clinical outcome of acute HBV infection.

Hepatocyte KLF6 expression affects FXR signalling and the clinical course of primary sclerosing cholangitis.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is characterized by chronic cholestasis and inflammation, which promotes cirrhosis and an increased risk of cholangiocellular carcinoma (CCA). The transcription factor Krueppel-like-factor-6 (KLF6) is a mediator of liver regeneration, steatosis, and hepatocellular carcinoma (HCC), but no data are yet available on its potential role in cholestasis. Here, we aimed to identify the impact of hepatic KLF6 expression on cholestatic liver injury and PSC and identify potential effects on farnesoid-X-receptor (FXR) signalling. METHODS: Hepatocellular KLF6 expression was quantified by immunohistochemistry (IHC) in liver biopsies of PSC patients and correlated with serum parameters and clinical outcome. Liver injury was analysed in hepatocyte-specific Klf6-knockout mice following bile duct ligation (BDL). Chromatin-immunoprecipitation-assays (ChIP) and KLF6-overexpressing HepG2 cells were used to analyse the interaction of KLF6 and FXR target genes such as NR0B2. RESULTS: Based on IHC, PSC patients could be subdivided into two groups showing either low (<80%) or high (>80%) hepatocellular KLF6 expression. In patients with high KLF6 expression, we observed a superior survival in Kaplan-Meier analysis. Klf6-knockout mice showed reduced hepatic necrosis following BDL when compared to controls. KLF6 suppressed NR0B2 expression in HepG2 cells mediated through binding of KLF6 to the NR0B2 promoter region. CONCLUSION: Here, we show an association between KLF6 expression and the clinical course and overall survival in PSC patients. Mechanistically, we identified a direct interaction of KLF6 with the FXR target gene NR0B2.

Clinical and functional patient characteristics predict medical needs in older patients at risk of functional decline.

BACKGROUND: The rising number of older multimorbid in-patients has implications for medical care. There is a growing need for the identification of factors predicting the needs of older patients in hospital environments. Our aim was to evaluate the use of clinical and functional patient characteristics for the prediction of medical needs in older hospitalized patients. METHODS: Two hundred forty-two in-patients (57.4% male) aged 78.4 ± 6.4 years, who were consecutively admitted to internal medicine departments of the University Hospital Essen between July 2015 and February 2017, were prospectively enrolled. Patients were assessed upon admission using the Identification of Seniors at Risk (ISAR) screening followed by comprehensive geriatric assessment (CGA). The CGA included standardized instruments for the assessment of activities of daily living (ADL), cognition, mobility, and signs of depression upon admission. In multivariable regressions we evaluated the association of clinical patient characteristics, the ISAR score and CGA results with length of hospital stay, number of nursing hours and receiving physiotherapy as indicators for medical needs. We identified clinical characteristics and risk factors associated with higher medical needs. RESULTS: The 242 patients spent [median(Q1;Q3)]:9.0(4.0;16.0) days in the hospital, needed 2.0(1.5;2.7) hours of nursing each day, and 34.3% received physiotherapy. In multivariable regression analyses including clinical patient characteristics, ISAR and CGA domains, the factors age (ß = - 0.19, 95% confidence interval (CI) = - 0.66;-0.13), number of admission diagnoses (ß = 0.28, 95% CI = 0.16;0.41), ADL impairment (B = 6.66, 95% CI = 3.312;10.01), and signs of depression (B = 6.69, 95% CI = 1.43;11.94) independently predicted length of hospital stay. ADL impairment (B = 1.14, 95%CI = 0.67;1.61), cognition impairment (B = 0.57, 95% CI = 0.07;1.07) and ISAR score (ß =0.26, 95% CI = 0.01;0.28) independently predicted nursing hours. The number of admission diagnoses (risk ratio (RR) = 1.06, 95% CI = 1.04;1.08), ADL impairment (RR = 3.54, 95% CI = 2.29;5.47), cognition impairment (RR = 1.77, 95% CI = 1.20;2.62) and signs of depression (RR = 1.99, 95% CI = 1.39;2.85) predicted receiving physiotherapy. CONCLUSION: Among older in-patients at risk for functional decline, the number of comorbidities, reduced ADL, cognition impairment and signs of depression are important predictors of length of hospital stay, nursing hours, and receiving physiotherapy during hospital stay.

Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations have poor prognosis. We aimed to establish the efficacy of ramucirumab in patients with advanced hepatocellular carcinoma and α-fetoprotein concentrations of 400 ng/mL or higher. METHODS: REACH-2 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 92 hospitals, clinics, and medical centres in 20 countries. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed hepatocellular carcinoma, or diagnosed cirrhosis and hepatocellular carcinoma, Barcelona Clinic Liver Cancer stage B or C disease, Child-Pugh class A liver disease, Eastern Cooperative Oncology Group (ECOG) performance statuses of 0 or 1, α-fetoprotein concentrations of 400 ng/mL or greater, and had previously received first-line sorafenib. Participants were randomly assigned (2:1) via an interactive web response system with a computer-generated random sequence to 8 mg/kg intravenous ramucirumab every 2 weeks or placebo. All patients received best supportive care. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportion of patients achieving an objective response, time to radiographic progression, safety, time to deterioration in scores on the Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8), and time to deterioration in ECOG performance status. We also pooled individual patient data from REACH-2 with data from REACH (NCT01140347) for patients with α-fetoprotein concentrations of 400 ng/mL or greater. Efficacy analyses were by intention to treat, whereas safety analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02435433. FINDINGS: Between July 26, 2015, and Aug 30, 2017, 292 patients were randomly assigned, 197 to the ramucirumab group and 95 to the placebo group. At a median follow-up of 7·6 months (IQR 4·0-12·5), median overall survival (8·5 months [95% CI 7·0-10·6] vs 7·3 months [5·4-9·1]; hazard ratio [HR] 0·710 [95% CI 0·531-0·949]; p=0·0199) and progression-free survival (2·8 months [2·8-4·1] vs 1·6 months [1·5-2·7]; 0·452 [0·339-0·603]; p<0·0001) were significantly improved in the ramucirumab group compared with the placebo group. The proportion of patients with an objective response did not differ significantly between groups (nine [5%] of 197 vs one [1%] of 95; p=0·1697). Median time to deterioration in FHSI-8 total scores (3·7 months [95% CI 2·8-4·4] vs 2·8 months [1·6-2·9]; HR 0·799 [95% CI 0·545-1·171]; p=0·238) and ECOG performance statuses (HR 1·082 [95% CI 0·639-1·832]; p=0·77) did not differ between groups. Grade 3 or worse treatment-emergent adverse events that occurred in at least 5% of patients in either group were hypertension (25 [13%] in the ramucirumab group vs five [5%] in the placebo group), hyponatraemia (11 [6%] vs 0) and increased aspartate aminotransferase (six [3%] vs five [5%]). Serious adverse events of any grade and cause occurred in 68 (35%) patients in the ramucirumab group and 28 (29%) patients in the placebo group. Three patients in the ramucirumab group died from treatment-emergent adverse events that were judged to be related to study treatment (one had acute kidney injury, one had hepatorenal syndrome, and one had renal failure). INTERPRETATION: REACH-2 met its primary endpoint, showing improved overall survival for ramucirumab compared with placebo in patients with hepatocellular carcinoma and α-fetoprotein concentrations of at least 400 ng/mL who had previously received sorafenib. Ramucirumab was well tolerated, with a manageable safety profile. To our knowledge, REACH-2 is the first positive phase 3 trial done in a biomarker-selected patient population with hepatocellular carcinoma. FUNDING: Eli Lilly.

Spleen Stiffness Differentiates Between Acute and Chronic Liver Damage and Predicts Hepatic Decompensation.

OBJECTIVES: Spleen stiffness (SS) correlates with liver stiffness (LS) and hepatic venous pressure gradient. The latter is currently the most accurate predictor of hepatic decompensation. Our study aims to check whether SS has a similar predictive capability, while being an easy-to-perform noninvasive test in a real-life patient cohort. METHODS: Concomitantly, 210 successive patients were examined and received liver and SS measurements and a standard laboratory. Patients were observed for 1 year in terms of clinical signs of decompensation. RESULTS: One hundred fifty-nine of the initial 210 patients had a valid LS and SS measurement and were evaluable for clinical follow-up. Twelve patients developed a hepatic decompensation; with a SS >39 kPa (P=0.0005). Especially in a group with elevated LS, patients with a high risk of decompensation could be identified using SS. Patients with comparable LS who suffered from acute liver damage had significantly lower SS than respective patients with chronic liver damage (30.97 vs. 46.03 kPa; P=0.04). Acute liver failure was associated with elevated LS (16.47 kPa) but not with elevated SS (30.97 kPa). CONCLUSIONS: The risk of a hepatic decompensation can easily be assessed using SS measurement. Therefore SS measurement might be a powerful screening tool identifying patients who need closer monitoring. Moreover, SS is able to differentiate between acute and chronic or acute on chronic liver damage.

How to Define Acute Liver Failure Patients with Pre-Existing Liver Disease without Signs of Cirrhosis.

BACKGROUND: The definition of acute liver failure (ALF) usually implies no previous liver injury. Though, some patients admitted to liver transplantation centers with the diagnosis of ALF are obese or have diabetes. Elevated liver enzymes were not recorded previously, and no signs of cirrhosis or prior decompensation of the liver function were ever present. Still, these patients differ from the "typical" ALF-patient. GOALS: In this study, we aimed to confirm acute-on-chronic-liver failure (AOCLF) in patients diagnosed with ALF and to identify possible differences between ALF and AOCLF. STUDY: Patients were retrospectively recruited from all patients admitted to the University Hospital Essen with diagnosis of ALF between 2008 and 2015. Data of 163 patients were evaluated, resulting in a reclassification of 32 patients as AOCLF (remaining ALF: 131). Demographic and clinical data as well as serum parameters, including cell death markers, were correlated with clinical outcome. RESULTS: Patients with AOCLF were significantly older, had a higher body mass index (BMI), and were more often male. The cause for liver failure in these patients differed significantly from patients who had an actual ALF. Significant differences were also found for serum liver enzymes. Outcome of patients did not differ between AOCLF and ALF. Though, lower BMI and MELD and higher AST and GLDH were predictors for a beneficial outcome. CONCLUSION: AOCLF is still commonly misdiagnosed as ALF. While clinical outcome does not significantly differ between ALF and AOCLF, risk factors for adverse outcome may significantly differ between these entities.

Liver Maximum Capacity: A Novel Test to Accurately Diagnose Different Stages of Liver Fibrosis.

AIM: To assess the diagnostic accuracy of liver maximum capacity (LiMAx®) test compared to transient elastography (TE) and serum biomarkers for the noninvasive detection of different stages of liver fibrosis and cirrhosis. PATIENTS AND METHODS: We retrospectively correlated LiMAx®, TE, aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR), AST-to-platelet ratio index (APRI), and fibrosis-4 (FIB-4) score with histological specimens in 102 patients with chronic liver disease (CLD) who underwent liver biopsy (either percutaneously or via mini-laparoscopy) at the University Clinic of Essen between 10/2016 and 12/2017. RESULTS: Median LiMAx® values showed a tendency to decrease in accordance with increasing histological degree of fibrosis based on the Desmet scoring system (F0: 446.5 [381.0-592.5] µg/h/kg, F1: 405.0 [343.0-547.0] µg/h/kg, F2: 337.0 [250.0-394.0] µg/h/kg, F3: 281.0 [262.0-364.0] µg/h/kg, and F4: 181.5 [130.0-256.5] µg/h/kg. Furthermore, -LiMAx® was superior to TE, FIB-4, AAR, and APRI in detecting different stages of fibrosis, while Spearman's rank correlation test showed a statistically significant association of -0.68, 0.62, 0.61, 0.46, and 0.42, respectively. However, the combination of TE and LiMAx® had the highest diagnostic accuracy in detecting liver cirrhosis (sensitivity 88.9%, specificity 84.6%, Youden index 0.735). CONCLUSION: Enzymatic liver function measured by LiMAx® showed strong correlation with histology in patients with CLD irrespective of its underlying etiology and was superior to TE and serum biomarkers, possibly making it useful as a novel and noninvasive tool for the determination of hepatic disease severity.

Low Free Triiodothyronine Is Associated with Advanced Fibrosis in Patients at High Risk for Nonalcoholic Steatohepatitis.

BACKGROUND: Thyroid hormone is critical for tissue-organ development, growth, differentiation, and metabolism. In murine models of advanced nonalcoholic steatohepatitis (NASH), the administration of T3 reduced liver triglyceride, repressed liver inflammation, and attenuated injury. In recent studies of patients with NASH, hypothyroidism was noted to be associated with more advanced NASH. These findings suggest that thyroid hormone function might be a modulator of nonalcoholic fatty liver disease (NAFLD) outcomes. AIMS: Herein, we evaluated the correlation between plasma TSH/free T3 (fT3)/free T4 (fT4) levels and (non-invasive) surrogate markers of NAFLD fibrosis. METHODS: We performed a retrospective analysis of 144 patients who were seen in our NASH outpatient clinic between 2015 and 2017. Each patient underwent a standard anthropometric assessment, laboratory and clinical evaluations, and liver stiffness measurements by transient elastography (Fibroscan). Univariate analysis and multivariate linear and logistic regression analysis were used to identify factors independently associated with NASH and advanced fibrosis. RESULTS: Low fT3 values but not TSH and fT4 were associated with higher liver stiffness and higher NAFLD fibrosis score, respectively. fT3 and TSH values correlated significantly with indices of liver disease including INR, albumin, ALT, AST, bilirubin, and platelets. In multivariate analyses, a low fT3 was independently associated with high NFS scores (OR 0.169, CI 0.05-0.54, p = 0.003) and was also associated with high liver stiffness readings (OR 0.326, CI 0.135-0.785, p = 0.001). CONCLUSION: A low-normal thyroid hormone function is predictive of NASH and advanced fibrosis and may have a pathogenic role in modulating NAFLD outcomes.

Health outcome of older hospitalized patients in internal medicine environments evaluated by Identification of Seniors at Risk (ISAR) screening and geriatric assessment.

BACKGROUND: Hospitals are in need of valid and economic screening and assessment tools that help identifying older patients at risk for complications which require intensified support during their hospital stay. METHODS: Five hundred forty-seven internal medicine in-patients (mean age 78.14 ± 5.96 years; 54.7% males) prospectively received Identification of Seniors at Risk (ISAR) screening. If screening results were positive (ISAR score ≥ 2), a comprehensive geriatric assessment (CGA) was performed. We explored sensitivity and specificity of different ISAR and CGA cutoffs. Further, we analyzed the risk of falls and how patients got discharged from hospital. RESULTS: ISAR+/CGA abnormal patients spent more days in hospital (16.1 ± 14.5), received more nursing hours per day (3.0 ± 2.3), more hours of physiotherapy during their hospital stay (2.2 ± 3.2), and had more falls (10.1%) compared to ISAR+/CGA normal (10.9 ± 12.3, 2.0 ± 1.2, 1.2 ± 4.3, and 2.8%, respectively, all p ≤ 0.016) and ISAR- (9.6 ± 11.5, 2.3 ± 4.5, 0.7 ± 2.0, and 2.2%, respectively, all p ≤ 0.002) patients. ISAR+/CGA abnormal patients terminated their treatment regularly with being discharged back home less often (59.6%) compared to ISAR+/CGA normal (78.5%, p = 0.002) and ISAR- (78.2%, p = 0.056) patients. ISAR cutoff≥2 and CGA defined as abnormal in case of impairment of ADL plus another CGA domain achieved best sensitivity/specificity. CONCLUSIONS: Abnormal geriatric risk screening and assessment are associated with longer hospital stay and higher amount of nursing and physiotherapy during hospital stay, greater risk of falling, and a lower percentage of successfully terminated treatment in older in-patients.

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.

Long-term follow-up of clinical trial patients treated for chronic HCV infection with daclatasvir-based regimens.

BACKGROUND & AIMS: Daclatasvir has achieved high sustained virologic response (SVR) rates in diverse hepatitis C virus (HCV) populations. This study evaluated the long-term efficacy and safety of daclatasvir-based regimens administered during clinical studies. METHODS: Patients enrolled within 6 months of parent study completion or protocol availability at the study sites. The primary objective was durability of SVR at follow-up Week 12 (SVR12). Secondary objectives included analysing HCV sequences in non-responders or responders who relapsed, and characterization of liver disease progression. RESULTS: Between 24 February 2012 and 17 July 2015, this study enrolled and began following 1503 recipients of daclatasvir-based regimens (follow-up cut-off, 13 October 2015); 60% were male, 18% aged ≥65 years, 87% had genotype-1a (42%) or -1b (45%) infection, and 18% had cirrhosis. Median follow-up from parent study follow-up Week 12 was 111 (range, 11-246) weeks. 1329/1489 evaluable patients were SVR12 responders; 1316/1329 maintained SVR until their latest visit. Twelve responders relapsed by (n = 9) or after (n = 3) parent study follow-up Week 24; one was reinfected. Relapse occurred in 3/842 (0.4%) and 9/487 (2%) responders treated with interferon-free or interferon-containing regimens, respectively. Hepatic disease progression and new hepatocellular carcinoma were diagnosed in 15 and 23 patients, respectively. Among non-responders, emergent non-structural protein-5A (NS5A) and -3 (NS3) substitutions were replaced by wild-type sequences in 27/157 (17%) and 35/47 (74%) patients, respectively. CONCLUSIONS: SVR12 was durable in 99% of recipients of daclatasvir-based regimens. Hepatic disease progression and new hepatocellular carcinoma were infrequent. Emergent NS5A substitutions persisted longer than NS3 substitutions among non-responders.

Transjugular Intrahepatic Portosystemic Shunt in Patients with Portal Hypertension: Patency Depends on Coverage and Interventionalist's Experience.

BACKGROUND AND AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) is the treatment of choice in decompensated portal hypertension. TIPS revision due to thrombosis or stenosis increases morbidity and mortality. Our aim was to investigate patient- and procedure-associated risk factors for TIPS-revision. PATIENTS AND METHODS: We retrospectively evaluated 189 patients who underwent the TIPS procedure. Only patients who required TIPS revision within 1 year (Group I, 34 patients) and patients who did not require re-intervention within the first year (Group II [control group], 54 patients) were included. RESULTS: Out of 88 patients, the majority were male (69.3%) and mean age was 56 ± 11 years. Indications for TIPS were refractory ascites (68%), bleeding (24%), and Budd-Chiari syndrome (8%). The most frequent liver disease was alcohol-induced cirrhosis (60%). Forty-three patients (49%) received bare and 45 patients (51%) covered stents, thus resulting in reduction of hepatic venous pressure gradient (HVPG) from 19.0 to 9.0 mm Hg. When comparing patient- and procedure-related factors, the type of stent (p < 0.01) and interventionalist's experience (number of performed TIPS implantations per year; p < 0.05) were the only factors affecting the risk of re-intervention due to stent dysfunction, while age, gender, indication, Child-Pugh, and model of end-stage liver disease score, platelet count, pre- and post-HVPG, additional variceal embolization, stent diameter, and number of stents did not significantly differ. CONCLUSION: Patients undergoing TIPS procedure should be surveilled closely for shunt dysfunction while covered stents and high-level experience are associated with increased -patency.