Longitudinal evaluation of individuals with severe alpha-1 antitrypsin deficiency (Pi*ZZ genotype).

BACKGROUND AND AIMS: Homozygous Pi*Z mutation in alpha-1 antitrypsin (Pi*ZZ genotype) predisposes to pulmonary loss-of-function and hepatic gain-of-function injury. To facilitate selection into clinical trials typically targeting only one organ, we systematically evaluated an international, multicenter, longitudinal, Pi*ZZ cohort to uncover natural disease course and surrogates for future liver- and lung-related endpoints. METHODS: Cohort 1 recruited 737 Pi*ZZ individuals from 25 different centers without known liver comorbidities that received a baseline clinical and laboratory assessment as well as liver stiffness measurement (LSM). A follow-up interview was performed after at least six months. Cohort 2 consisted of 135 Pi*ZZ subjects without significant liver fibrosis, who received a standardized baseline and follow-up examination at least two years later, both including LSM. RESULTS: During 2634 patient-years of follow-up, 39 individuals died, with liver and lung being responsible for 46% and 36% of deaths, respectively. 41 Pi*ZZ subjects who developed a hepatic endpoint presented with significantly higher baseline liver fibrosis surrogates, i.e., LSM (24 vs. 5 kPa, p<.001) and AST-to-platelet ratio index (APRI, 1.1 vs. 0.3 units, p<.001). Liver-related endpoints within five years were most accurately predicted by LSM (area under the curve [AUC] 0.95) followed by APRI (0.92). Baseline lung parameters displayed only a moderate predictive utility for lung-related endpoints within five years (FEV1 AUC 0.76). Fibrosis progression in those with no/mild fibrosis at baseline was rare and primarily seen in those with preexisting risk factors. CONCLUSIONS: Non-invasive liver fibrosis surrogates accurately stratify liver-related risks in Pi*ZZ individuals. Our findings have direct implications for routine care and future clinical trials of Pi*ZZ patients.

Alpha-1 Antitrypsin Augmentation and the Liver Phenotype of Adults With Alpha-1 Antitrypsin Deficiency (Genotype Pi∗ZZ).

BACKGROUND & AIMS: α1-Antitrypsin (AAT) is a major protease inhibitor produced by hepatocytes. The most relevant AAT mutation giving rise to AAT deficiency (AATD), the 'Pi∗Z' variant, causes harmful AAT protein accumulation in the liver, shortage of AAT in the systemic circulation, and thereby predisposes to liver and lung injury. Although intravenous AAT augmentation constitutes an established treatment of AATD-associated lung disease, its impact on the liver is unknown. METHODS: Liver-related parameters were assessed in a multinational cohort of 760 adults with severe AATD (Pi∗ZZ genotype) and available liver phenotyping, of whom 344 received augmentation therapy and 416 did not. Liver fibrosis was evaluated noninvasively via the serum test AST-to-platelet ratio index and via transient elastography-based liver stiffness measurement. Histologic parameters were compared in 15 Pi∗ZZ adults with and 35 without augmentation. RESULTS: Compared with nonaugmented subjects, augmented Pi∗ZZ individuals displayed lower serum liver enzyme levels (AST 71% vs 75% upper limit of normal, P < .001; bilirubin 49% vs 58% upper limit of normal, P = .019) and lower surrogate markers of fibrosis (AST-to-platelet ratio index 0.34 vs 0.38, P < .001; liver stiffness measurement 6.5 vs 7.2 kPa, P = .005). Among biopsied participants, augmented individuals had less pronounced liver fibrosis and less inflammatory foci but no differences in AAT accumulation were noted. CONCLUSIONS: The first evaluation of AAT augmentation on the Pi∗ZZ-related liver disease indicates liver safety of a widely used treatment for AATD-associated lung disease. Prospective studies are needed to confirm the beneficial effects and to demonstrate the potential efficacy of exogenous AAT in patients with Pi∗ZZ-associated liver disease.

Alcohol consumption and liver phenotype of individuals with alpha-1 antitrypsin deficiency.

BACKGROUND AND AIMS: Alpha-1 antitrypsin deficiency is an inherited disorder caused by alpha-1 antitrypsin (AAT) mutations. We analysed the association between alcohol intake and liver-related parameters in individuals with the heterozygous/homozygous Pi*Z AAT variant (Pi*MZ/Pi*ZZ genotype) found in the United Kingdom Biobank and the European Alpha1 liver consortium. METHODS: Reported alcohol consumption was evaluated in two cohorts: (i) the community-based United Kingdom Biobank (17 145 Pi*MZ, 141 Pi*ZZ subjects, and 425 002 non-carriers [Pi*MM]); and (ii) the European Alpha1 liver consortium (561 Pi*ZZ individuals). Cohort (ii) included measurements of carbohydrate-deficient transferrin (CDT). RESULTS: In both cohorts, no/low alcohol intake was reported by >80% of individuals, while harmful consumption was rare (~1%). Among Pi*MM and Pi*MZ individuals from cohort (i), moderate alcohol consumption resulted in a <30% increased rate of elevated transaminases and ~50% increase in elevated gamma-glutamyl transferase values, while harmful alcohol intake led to an at least twofold increase in the abnormal levels. In Pi*ZZ individuals from both cohorts, moderate alcohol consumption had no marked impact on serum transaminase levels. Among Pi*ZZ subjects from cohort (ii) who reported no/low alcohol consumption, those with increased CDT levels more often had signs of advanced liver disease. CONCLUSIONS: Pi*MZ/Pi*ZZ genotype does not seem to markedly aggravate the hepatic toxicity of moderate alcohol consumption. CDT values might be helpful to detect alcohol consumption in those with advanced fibrosis. More data are needed to evaluate the impact of harmful alcohol consumption.

Impact of multiple primary cancers on overall survival of patients with hepatocellular carcinoma.

The increasing occurrence of multiple primary cancers (MPC) is a long-term trend, but the prevalence of MPC in patients with hepatocellular carcinoma (HCC) and its impact on overall survival (OS) remains unknown. We retrospectively analyzed 497 patients with HCC treated at two tertiary centers. The cohort was divided into two subgroups - liver transplant (LT, 324 patients) and non-liver transplant (non-LT, 173 patients). We analyzed MPC occurrence, its impact on survival, and identified variables predicting unfavorable outcomes. The MPC were detected in 88 patients (18%). The most common MPC were prostate (17%), skin (15.9%), kidney (12.5%), and lung (10.2%). The median OS of the whole cohort and the LT and non-LT subgroups were 70, 116, and 17 months, respectively (p<0.0001). The median OS in patients with HCC only and HCC with another cancer was 77 (95% CI, 67-96) and 50 months (95% CI, 37-62), respectively (p=0.25). The OS of LT patients was significantly better than that of those in whom LT had been contraindicated owing to concomitant MPC (116 vs. 35 months, p<0.0009). Autoimmune etiology, non-alcoholic steatohepatitis (NASH), HCC as the first diagnosed malignancy, and male sex were identified as factors significantly influencing the patients' outcomes (HR 0.43, 3.2326, 0.70, and 1.43, respectively). The MPC frequency was 18%. The impact of MPC on OS was not significant, except for individuals contraindicated for LT because of MPC. A better prognosis is associated with the autoimmune etiology of cirrhosis, and when HCC is diagnosed as the first malignancy. Male sex and NASH worsened the outcomes.

Transient Elastography as the First-Line Assessment of Liver Fibrosis and Its Correlation with Serum Markers.

Background and objectives: Recently, rapid progress has been made in the development of noninvasive methods for liver fibrosis assessment. The study aimed to assess the correlation between LSM and serum fibrosis markers to identify patients with advanced liver fibrosis in daily clinical practice. Methods: Between 2017 and 2019, 89 patients with chronic liver disease of various etiology, 58 males and 31 females, were enrolled in the study and underwent ultrasound examination, vibration-controlled transient elastography (VCTE), AST to Platelet Ratio Index (APRI score), Fibrosis-4 (FIB-4) score, and enhanced liver fibrosis (ELF) test. Results: The diagnoses were as follows: NAFLD (30.3%), HCV (24.3%), HBV (13.1%), ALD (10.1%), other (7.8%). Their median age was 49 (21-79), and their median BMI was 27.5 (18.4-39.5). The median liver stiffness measurement (LSM) was 6.7 kPa (2.9-54.2 kPa), the median of the ELF test was 9.0 (7.3-12.6), and the median APRI was 0.40 (0.13-3.13). Advanced fibrosis assessed by LSM was present in 18/89 (20.2%) patients. The LSM values correlated with the ELF test results (r2 = 0.31, p < 0.0001), with the APRI score (r2 = 0.23, p < 0.0001), the age of the patients (r2 = 0.14, p < 0.001), and with the FIB-4 values (r2 = 0.58, p < 0.0001). The ELF test values correlated with the APRI score (r2 = 0.14, p = 0.001), the age (r2 = 0.38, p < 0.0001), and the FIB-4 (r2 = 0.34, p < 0.0001). By determining the confidence intervals of the linear model, we proved that patients younger than 38.1 years have a 95% probability of absence of advanced liver fibrosis when assessed by VCTE. Conclusions: We identified APRI and FIB-4 as simple tools for screening liver disease in primary care in an unselected population of patients. The results also showed that individuals younger than 38.1 years had a negligible risk of advanced liver fibrosis.

Acute kidney injury in patients with cirrhosis - practical summary.

Acute kidney injury (AKI) is a relatively common condition in patients with advanced liver disease and which is associated with increased mortality. It mainly affects patients with decompensated cirrhosis, particularly those with advanced portal hypertension and ascites. The dual organ involvement may have different forms. The contributing pathogenetic mechanisms are common and predict a dismal prognosis. Early diagnosis and interventions involving specialists (in particular, hepatologists and nephrologists) are essential to improve outcomes.

Is elimination of HCV in 2030 realistic in Central Europe.

According to the recent data presented by Central-European HCV experts, the estimated prevalence of HCV is between 0.2% and 1.7% in certain countries in this region. There are no financial limitations to access to treatment in most countries. Patients in these countries have access to at least one pangenotypic regimen. The most common barriers to the elimination of HCV in Central Europe are a lack of established national screening programmes and limited political commitment to the elimination of HCV. Covid-19 has significantly affected the number of patients who have been diagnosed and treated, thus, delaying the potential elimination of HCV. These data suggest that the elimination of HCV elimination projected by WHO before 2030 will not be possible in the Central Europe.

Therapy of chronic hepatitis C in people who inject drugs: focus on adherence.

BACKGROUND: Intravenous drug use (IVDU) represents the major factor of HCV transmission, but the treatment uptake among people who inject drugs (PWID) remains low owing to a false presumption of low efficacy. The aim of our study was to assess treatment efficacy in PWID and factors determining adherence to therapy. METHODS: A total of 278 consecutive patients starting DAA (direct-acting antivirals) therapy were included, divided into two groups: individuals with a history of IVDU, PWID group (N = 101) and the control group (N = 177) without a history of IVDU. RESULTS: Sustained virological response 12 weeks after the end of therapy (SVR12) was achieved by 99/101 (98%) and 172/177 (98%) patients in the PWID and control group, respectively; in PWID group, two patients were lost to follow-up, and in the control group, four patients relapsed and one was lost to follow-up. PWID patients postponed appointments significantly more often, 29 (28.7%) in PWID versus 7 (4%) in the control group, p = 0.001. Thirteen of 101 (12.9%) and six of 177 (3.4%) patients in the PWID and in the control group, respectively, missed at least one visit (p < 0.01). However, postponing visits led to a lack of medication in only one PWID. In the PWID group, older age (p < 0.05; OR 1.07, 95% CI 1.00-1.20) and stable housing (p < 0.01; OR 9.70, 95% CI 2.10-56.20) were factors positively contributing to adherence. Contrarily, a stable job was a factor negatively influencing adherence (p < 0.05; OR 0.24, 95% CI 0.06-0.81). In the control group, none of the analyzed social and demographic factors had an impact on adherence to therapy. CONCLUSIONS: In PWID, treatment efficacy was excellent and was comparable with SVR of the control group. Stable housing and older age contributed to a better adherence to therapy.

Alpha-1 Antitrypsin and Hepatocellular Carcinoma in Liver Cirrhosis: SERPINA1 MZ or MS Genotype Carriage Decreases the Risk.

Heterozygotes for Z or S alleles of alpha-1-antrypsin (AAT) have low serum AAT levels. Our aim was to compare the risk of hepatocellular carcinoma (HCC) in patients with liver cirrhosis carrying the SERPINA1 MM, MZ and MS genotypes. The study groups consisted of 1119 patients with liver cirrhosis of various aetiologies, and 3240 healthy individuals served as population controls. The MZ genotype was significantly more frequent in the study group (55/1119 vs. 87/3240, p < 0.0001). The MS genotype frequency was comparable in controls (32/119 vs. 101/3240, p = 0.84). MZ and MS heterozygotes had lower serum AAT level than MM homozygotes (medians: 0.90 g/L; 1.40 g/L and 1.67 g/L; p < 0.001 for both). There were significantly fewer patients with HCC in the cirrhosis group among MZ and MS heterozygotes than in MM homozygotes (5/55 and 1/32 respectively, vs. 243/1022, p < 0.01 for both). The risk of HCC was lower in MZ and MS heterozygotes than in MM homozygotes (OR 0.3202; 95% CI 0.1361-0.7719 and OR 0.1522; 95% CI 0.02941-0.7882, respectively). Multivariate analysis of HCC risk factors identified MZ or MS genotype carriage as a protective factor, whereas age, male sex, BMI and viral aetiology of cirrhosis increased HCC risk.

IL28B rs12979860 T allele protects against CMV disease in liver transplant recipients in the post-prophylaxis and late period.

BACKGROUND: Cytomegalovirus (CMV) disease represents a serious complication in liver transplant (OLT) recipients. CMV prophylaxis reduces incidence of CMV disease in the early post-transplant period (on-prophylaxis disease, OPD) but may postpone its manifestation after the completion of prophylaxis. Post-prophylaxis disease (PPD) incidence after prophylaxis cessation may be modified by genetic factors. METHODS: We analyzed impact of IL28B rs1297986 variants on CMV disease incidence in 743 adult OLT recipients receiving universal prophylaxis. RESULTS: One hundred and forty-four (19.4%) patients had at least one CMV disease episode. One hundred and two of them (70.8%) had at least one OPD and 36 (25%) patients had PPD, six (4.2%) patients had both. The rate of IL28B T allele carriers was lower in PPD group (38.9%) in comparison with OPD group (66.7%, P = 0.005) and group without CMV disease (61.4%, P = 0.009). The impact of IL28B genotype on the risk of CMV OPD was significant neither in the allelic (TT + CT vs CC, P = 0.32) nor in the recessive model (TT vs CT + CC, P = 0.79). Contrarily, in the PPD group, T allele (TT + CT vs CC) had a protective effect, OR 0.4 (95% CI 0.2-0.8, P = 0.008). Further risk factors of PPD were age <55 years and valganciclovir prophylaxis, whereas the risk factors of OPD were age <55 years, cyclosporine A therapy and pre-transplant CMV serostatus (donor +/recipient -). CONCLUSIONS: IL28B rs12979860 T allele carriers had a lower risk of CMV PPD.

Chronic hepatitis C in the Czech Republic: Forecasting the disease burden.

OBJECTIVE: Chronic HCV infection is associated with cirrhosis of the liver, hepatocellular carcinoma (HCC), and liver transplantation. HCV disease burden and the impact of new potent direct acting antivirals (DAAs) in the Czech Republic are unknown. METHODS: Using a modelling framework, HCV disease progression in the Czech Republic was predicted to 2030 under the current standard of care treatment structure. In addition, two strategies to reduce the future burden of HCV infection were modelled: an incremental increase in treatment annually and WHO targets. RESULTS: The number of viremic infected individuals in the Czech Republic is estimated to peak in 2026 (n = 55,130) and to decline by 0.5% by 2030 (n = 54,840). The number of individuals with compensated cirrhosis (n = 1,400), decompensated cirrhosis (n = 80), HCC (n = 70), and liver-related deaths (n = 60) is estimated to more than double by 2030. Through aggressive increases in diagnosis and treatment, HCV related mortality may decrease by 70% by 2030. CONCLUSIONS: Disease burden associated with chronic HCV infection is projected to peak in the Czech Republic in 30-40 years. Assuming that the current portion of DAAs used remains constant, a significant reduction in HCV disease burden is possible through increased diagnosis and treatment through 2030. This analysis provides evidence in order to facilitate the development of national strategies for HCV care and management in the Czech Republic.

Rizikové faktory a surveillance hepatocelulárního karcinomu.

Hepatocelulární karcinom (HCC) je celosvětově druhou nejčastější příčinou úmrtí na nádorová onemocnění. V 90 % případů vzniká HCC v souvislosti s anamnézou jaterní cirhózy, nejčastěji při hepatitidě B a C. Surveillance HCC je založena na pravidelném vyšetření pacientů ve zvýšeném riziku vzniku nádoru s cílem snížit mortalitu spojenou s onemocněním. Cílovou populací k surveillance HCC jsou pacienti s jaterní cirhózou, nezávisle na její etiologii. Screening HCC můžeme provádět pomocí sérologických testů a zobrazovacích metod. V současné době je nej-užívanější vyšetřovací metodou pro screening HCC ultrasonografie (USG), která má přijatelnou diagnostickou přesnost. Ze sérologických testů je nejčastěji používaným markerem ve screeningu HCC α-fetoprotein, má být však ve screeningu použit pouze v situacích, v nichž USG vyšetření není dostupné. USG vyšetření je v současné době vše-obecně doporučovanou metodou surveillance HCC s 6měsíčním intervalem mezi jednotlivými vyšetřeními.

Paritaprevir/Ritonavir/Ombitasvir Plus Dasabuvir Regimen in the Treatment of Genotype 1 Chronic Hepatitis C Infection in Patients with Severe Renal Impairment and End-Stage Renal Disease: a Real-Life Cohort.

BACKGROUND/AIMS: Chronic hepatitis C (HCV) virus infection reactivates under immunosuppressive drugs and therefore has a negative impact on long-term survival of kidney transplant recipients. Treatment-induced clearance of hepatitis C virus (HCV) in kidney transplant candidates prevents virus reactivation after transplantation. Paritaprevir/Ritonavir/Ombitasvir with Dasabuvir (PrOD) represents a highly effective treatment regimen for HCV genotype 1 (GT1), also suitable for patients with end-stage renal disease (ESRD). Serious drug-drug interactions may represent a limiting factor of this regimen. The aim of this retrospective study was to evaluate safety, efficacy and drug-drug interactions management associated with PrOD treatment in the Czech real-world cohort. METHODS: Emphasizing concomitant medication adjustment, we described the treatment course with PrOD regimen in 23 patients (4 with CKD4 and 19 on maintenance haemodialysis) infected with HCV GT1 (21 GT1b, 2 GT1a), 18 males and 5 females with an average age of 53.7 years. Six patients had compensated liver cirrhosis and 3 of them were liver transplant recipients. RESULTS: All 23 patients completed the 12-week treatment and achieved sustained virological response 12 weeks after the treatment (SVR12 rate 100%). None of the patients presented with a significant decrease in haemoglobin level, white blood cell and platelet count during the treatment period. The most frequent adverse events were nausea, hypotension, diarrhoea, and hyperkalemia. Four patients presented with a serious adverse event unrelated to the antiviral drugs (salmonellosis, non-functional kidney graft rejection, early gastric cancer, renal cyst infection, initiation of haemodialysis). Concomitant medication had to be modified with the treatment initiation in 10 out of 23 (43.5%) patients (calcium channel blockers, ACE inhibitors, statins, diuretics, tacrolimus); four patients required further adjustment of antihypertensive drugs or tacrolimus dosage on-treatment. CONCLUSION: PrOD regimen demonstrated an excellent efficacy and good tolerability. Both prospective adjustment of concomitant medication and further on-treatment adjustment allowed for a safe treatment course.

Transient elastography - role in the assessment of the liver disease development.

Transient elastography, an examination based on the liver stiffness measurement, is a method validated for the non-invasive liver fibrosis staging. This method was recently successfully introduced into routine clinical practice. In accordance with the global- wide screening of viral hepatitis (chronic viral hepatitis type B and type C) and with the increasing effectiveness of antiviral therapy, as well as with the increasing prevalence of non-alcoholic fatty liver disease (NAFLD), the part of population requiring the care of hepatologists is certain to increase. Now more than ever we need a non-invasive, fast, safe, inexpensive and reliable method for evaluating patients with chronic liver disease. A new area of ​​use of elastography appears to be used to measure the stiffness of the spleen as a prediction of the presence of esophageal varices or the stiffness (or rather fibrosis) of transplanted kidneys. The aim of this review is to provide a comprehensive view of transient elastography, its principles, advantages and pitfalls, including its use in everyday clinical practice. Key words: cirrhosis - fibrosis - renal allograft - transient elastography.

Aquaporin-2 excretion in hospitalized patients with cirrhosis: Relation to development of renal insufficiency and mortality.

BACKGROUND AND AIM: Urinary aquaporin-2 (AQP2) is a parameter of water transport in the principal cells in the distal part of the nephron and involved in water retention in cirrhosis and may be a marker of renal function. The aim of the study was to evaluate AQP2 as a predictor of renal insufficiency and death in patients with cirrhosis. METHODS: Urine samples from 199 patients (90 patients without organ failure [Group 1], 58 patients with organ failure excluding renal failure [Group 2], and 51 patients with organ failure including renal failure [Group 3]) from the CANONIC study were analyzed for urine AQP2 and urine osmolality. RESULTS: There was no difference in AQP2 between the three groups. Urine osmolality was significantly lower in patients in Group 3 versus Group 1 and Group 2 (P = 0.0004). No relation was found between AQP2 and glomerular filtration rate or creatinine; however, AQP2 was a significant predictor of the development of renal insufficiency (P = 0.0485). In a univariate analysis, AQP2 was a significant predictor of 14 and 28-day survival, but this was not confirmed in multivariate analysis. CONCLUSIONS: Aquaporin-2 was not associated with disease severity or markers of renal function but was a predictor for the development of renal insufficiency and death. Therefore, its future use as marker of renal insufficiency could be promising, but further research is needed before it can be considered a clinical useful tool.

[Diagnosis and therapy of hepatitis B virus infection: Czech national guidelines].

The new recommendations reflect the increase in knowledge that has been reported since the release of previous Czech guidelines in September 2014. The basis for these guidelines were the European Association for the Study of the Liver guidelines from April 2017. According to qualified estimates, there are 240 million people with chronic hepatitis B (HBV) infection worldwide. The Czech Republic is among the countries with a low prevalence of HBV infection. According to the latest seroprevalence study, 0.56 % of the Czech citizens were chronically infected with HBV in 2001. A similar study conducted in only two regions of the Czech Republic in 2013 showed a prevalence of only 0.064 %. HBV infection can lead to serious life-threatening liver damage - fulminant hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). The main goals of treatment are to prolong the length of life and improve its quality by preventing the progression of chronic hepatitis to cirrhosis, cirrhosis decompensation and development of HCC. The goals may be achieved if HBV replication is suppressed in a sustained manner. Additional goals are prevention of vertical transmission from mother to newborn, inhibition of HBV reactivation and therapy of HBV-related extrahepatic manifestations. Generally, there are two different strategies of chronic hepatitis B therapy available - treatment with nucleoside or nucleotide inhibitors (NIs) or with pegylated interferon alfa. Currently, the vast majority of Czech and European patients are treated with NIs. The NIs that have been approved for HBV treatment in the European Union include lamivudine, adefovir dipivoxil, entecavir (ETV), telbivudin (TBV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). TAF and TBV have not yet been marketed in the Czech Republic. The main advantages of treatment with potent NIs with a high barrier to resistance (ETV, TDF, TAF) are their predictable high long-term antiviral efficacy leading to undetectable HBV DNA levels in the vast majority of compliant patients as well as their favorable safety profiles. These drugs can be used in any HBV infected patient and represent the only treatment option for patients with decompensated liver cirrhosis, liver transplants, extrahepatic HBV-related manifestations, severe acute hepatitis B or chronic HBV reactivation.

[Spontaneous bacterial peritonitis]. / Spontánní bakteriální peritonitida.

Spontaneous bacterial peritonitis (SBP) represents a frequent and serious complication in patients with ascites in liver cirrhosis. Hospital mortality in patients with SBP reaches 10-20 %, so it is necessary to consider this diagnosis in every clinical decompensation of a cirrhotic patient, diagnose it early and treat it effectively. The clinical manifestation is nonspecific and variable, up to one third of patients might be asymptomatic. The diagnosis of SBP is based on the ascitic neutrophils count greater than 250 per mm3. Bacteriological examination of ascites fluid detects causative agents at less than half of the cases and the result is available after a few days. However, treatment should be initiated without delay. SBP is generally treated with antibiotics, the first choice therapy are the third generation cephalosporins, mostly cefotaxime, alternatively fluoroquinolones. Long-term prognosis of patients with the history of SBP is poor owing to its high recurrence rate, one-year survival after an episode of SBP is 30-40 %, 20 % at two years. Therefore, these patients should receive long-term antibiotic prophylaxis and should be evaluated for liver transplantation.

Genetic variation in TNFA predicts protection from severe bacterial infections in patients with end-stage liver disease awaiting liver transplantation.

BACKGROUND & AIMS: Augmented susceptibility to infections increases mortality in patients with end-stage liver disease (ESLD). We sought to determine the contribution of selected genetic variants involved in inflammatory signalling downstream of the Toll-like receptor 4 (TLR4) to severe bacterial infections (SBIs) in patients with ESLD. METHODS: We retrospectively assessed incidence of SBIs in 336 adult ESLD patients enlisted for orthotopic liver transplantation (OLT) and genotyped them for TLR4 c.+1196C/T, CD14 c.-159C/T, TNFA c.-238G/A, TNFA c.-863C/A, IL1B c.-31C/T and IL1RN variable number of tandem repeats allelic variants. Principal findings were validated in an independent cohort of 332 ESLD patients. RESULTS: Thirty-four percent of patients from the identification cohort and 40% of patients from the validation cohort presented with SBI while enlisted for OLT. The presence of the variant allele TNFA c.-238A (rs361525) was associated with lower serum levels of TNF-α, and with significantly decreased risk of SBI in both cohorts. Multivariate analysis showed that the relative protection from SBI associated with this allele almost completely negated the increased susceptibility to SBI owed to advanced ESLD. Although not predictive of overall mortality, the presence of the TNFA c.-238A allele was associated with a complete prevention of SBI-related pre-transplant deaths. CONCLUSIONS: Our results suggest that genetic variability in inflammatory signalling is associated with the development of SBI in patients with ESLD. Specifically, we identified the importance of the TNFA c.-238A allele as a strong predictor of protection from SBI, and as a genetic marker associated with significantly improved pre-transplant survival in patients with SBI.

Corrigendum: PD-1/PD-L1 immune checkpoint therapy demonstrates favorable safety profile in patients with autoimmune and cholestatic liver disease.

[This corrects the article DOI: 10.3389/fimmu.2023.1326078.].

Predictors of Significant Liver Fibrosis in People with Chronic Hepatitis C Who Inject Drugs in the Czech Republic.

BACKGROUND AND OBJECTIVES: HCV infection often remains untreated in people who inject drugs (PWID), albeit they may present with advanced liver fibrosis at a young age. We aimed to assess the rate of patients with significant fibrosis in PWID starting anti-HCV therapy and identify the factors associated with severe fibrosis. METHODS: The cohort of 200 patients was divided into two groups: F0-F2 (N = 154, 77%), patients with liver stiffness measurement (LSM) < 10.0 kPa, and F3-F4 (N = 46, 23%), with LSM ≥ 10.0 kPa, indicating significant liver fibrosis. RESULTS: In group F3-F4, there were significantly more males, and the patients were older, with a higher BMI. The number of long-term abstaining patients was significantly higher in group F3-F4 compared with group F0-F2, as well as the proportion of patients reporting harmful drinking. Obesity (OR 4.77), long-term abstinence from illicit drugs (OR 4.06), harmful drinking (OR 2.83), and older age (OR 1.17) were significant predictors of advanced fibrosis in PWID starting anti-HCV therapy. CONCLUSIONS: A quarter of PWID presented with significant liver fibrosis at treatment initiation. Obesity, long-term drug abstinence, harmful drinking, and older age contributed to significant liver fibrosis.