To describe the pathogenesis and emphasize prognosis of systemic inflammatory response during severe infection.
Host immune response enables to confine and clear microorganisms. Sometimes for current ...unknown reason depending on host (genetic susceptibilities and comorbidities) and pathogen (load and virulence) factors, this reaction is accompanied by a widespread reaction characterized by a first pro-inflammatory response (called at the bedside, systemic inflammatory response syndrome) and a following 'immune paralysis' (compensatory anti-inflammatory response syndrome) responsible for secondary infections. There are three recognized stages of severe host response to pathogen with progressively increased mortality rates: sepsis, severe sepsis, and septic shock. This excessive reaction induces microthrombi formation, capillary obstruction by red blood cells losing their deformability, microcirculatory alterations, tissue edema by capillary leak, and neutrophil recruitment leading to multiple tissue damages, organ failures (multiple organ dysfunction syndrome) and finally to death. Despite the early detection, the use of modern antibiotics and new resuscitation therapies, sepsis remains a leading cause of death in critically ill patients.
Sepsis is viewed as an excessive host response to pathogen inducing a complex network of molecular cascades leading to tissue damages, organ failures, and death.
Summary Bacterial infections are very frequent in advanced cirrhosis and become the first cause of death of these patients. Despite numerous experimental data and significant advances in the ...understanding of the pathogenesis of sepsis in cirrhosis, the outcome remains poor. Classical diagnostic parameters such as C-reactive protein and SIRS criteria have less diagnostic capacity in the cirrhotic population, often delaying the diagnosis and the management of bacterial infection. Prompt and appropriate empirical antibiotic treatment of infection and early resuscitation of patients with severe sepsis or septic shock are essential in determining patient's outcome. A strategy of careful restriction of prophylactic antibiotics to the high-risk populations could reduce the spread of multidrug resistant bacteria. This review is focused on the currently recommended diagnostic, therapeutic and prophylactic strategies for bacterial infections in the cirrhotic population.
Acute‐on‐chronic liver failure (ACLF) is a recently defined syndrome that occurs frequently in patients with cirrhosis and is associated with a poor short‐term prognosis. Currently, management of ...patients with ACLF is mainly supportive. Despite medical progress, this syndrome frequently leads to multiorgan failure, sepsis, and, ultimately, death. The results of attempts to use liver transplantation (LT) to manage this critical condition have been poorly reported but are promising. Currently, selection criteria of ACLF patients for LT, instructions for prioritization on the waiting list, and objective indicators for removal of ACLF patients from the waiting list in cases of clinical deterioration are poorly defined. Before potential changes can be implemented into decisional algorithms, their effects, either on the benefits to individual patients or on global transplant outcomes, should be carefully evaluated using objective longterm endpoints that take into account ethical considerations concerning LT. Liver Transplantation 23 234–243 2017 AASLD
Bacterial infection is a frequent trigger of acute-on-chronic liver failure (ACLF), syndrome that could also increase the risk of infection. This investigation evaluated prevalence and ...characteristics of bacterial and fungal infections causing and complicating ACLF, predictors of follow-up bacterial infections and impact of bacterial infections on survival.
407 patients with ACLF and 235 patients with acute decompensation (AD).
152 patients (37%) presented bacterial infections at ACLF diagnosis; 46%(n=117) of the remaining 255 patients with ACLF developed bacterial infections during follow-up (4 weeks). The corresponding figures in patients with AD were 25% and 18% (p<0.001). Severe infections (spontaneous bacterial peritonitis, pneumonia, severe sepsis/shock, nosocomial infections and infections caused by multiresistant organisms) were more prevalent in patients with ACLF. Patients with ACLF and bacterial infections (either at diagnosis or during follow-up) showed higher grade of systemic inflammation at diagnosis of the syndrome, worse clinical course (ACLF 2-3 at final assessment: 47% vs 26%; p<0.001) and lower 90-day probability of survival (49% vs 72.5%;p<0.001) than patients with ACLF without infection. Bacterial infections were independently associated with mortality in patients with ACLF-1 and ACLF-2. Fungal infections developed in 9 patients with ACLF (2%) and in none with AD, occurred mainly after ACLF diagnosis (78%) and had high 90-day mortality (71%).
Bacterial infections are extremely frequent in ACLF. They are severe and associated with intense systemic inflammation, poor clinical course and high mortality. Patients with ACLF are highly predisposed to develop bacterial infections within a short follow-up period and could benefit from prophylactic strategies.
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•Acute-on-chronic liver failure was common in patients with severe alcoholic hepatitis.•Infection was significantly associated with acute-on-chronic liver failure episodes.•The ...presence of acute-on-chronic liver failure significantly increased mortality.•Our results were confirmed in a validation cohort of 97 patients.
A better identification of factors predicting death is needed in alcoholic hepatitis (AH). Acute-on-chronic liver failure (ACLF) occurs during the course of liver disease and can be identified when AH is diagnosed (prevalent ACLF pACLF) or during follow-up (incidental ACLF iACLF). This study analyzed the impact of ACLF on outcomes in AH and the role of infection on the onset of ACLF and death.
Patients admitted from July 2006 to July 2015 suffering from biopsy-proven severe (s)AH with a Maddrey discriminant function (mDF) ≥32 were included. Infectious episodes, ACLF, and mortality were assessed during a 168-day follow-up period. Results were validated on an independent cohort.
One hundred sixty-five patients were included. Mean mDF was 66.3 ± 20.7 and mean model for end-stage liver disease score was 26.8 ± 7.4. The 28-day cumulative incidence of death (CID) was 31% (95% CI 24–39%). Seventy-nine patients (47.9%) had pACLF. The 28-day CID without pACLF and with pACLF-1, pACLF-2, and pACLF-3 were 10.4% (95% CI 5.1–18.0), 30.8% (95% CI 14.3–49.0), 58.3% (95% CI 35.6–75.5), and 72.4% (95% CI 51.3–85.5), respectively, p <0.0001. Twenty-nine patients (17.5%) developed iACLF. The 28-day relative risk of death in patients developing iACLF was 41.87 (95% CI 5.2–335.1; p <0.001). A previous infection was the only independent risk factor for developing iACLF during the follow-up. Prevalence, incidence, and impact on prognosis of ACLF were confirmed in a validation cohort of 97 patients with probable sAH.
ACLF is frequent during the course of sAH and is associated with high mortality. Infection strongly predicts the development of ACLF in this setting.
In patients with chronic liver disease, an acute deterioration of liver function combined with single or multiple organ failures is known as acute-on-chronic liver failure. This study shows that acute-on-chronic liver failure is frequent during the course of severe alcoholic hepatitis. In severe alcoholic hepatitis, acute-on-chronic liver failure is associated with high mortality and frequently occurs after an infection.
Recently, a loss of function variant (rs72613567) in 17‐beta‐hydroxysteroid dehydrogenase 13 (HSD17B13) has been identified as protective of nonalcoholic (NAFLD) and alcoholic liver disease (ALD). ...However, the role of this single‐nucleotide polymorphism (SNP) in the development of hepatocellular carcinoma (HCC) is currently unknown. A total of 3,315 European patients with HCC (n = 1,109) or without HCC, but with chronic liver disease (CLD; n = 2,206), from four centers were analyzed either by whole‐exome sequencing (WES; exploratory cohort, 285 HCC) or genotyped for HSD17B13 rs72613567 (validation cohort, 824 HCC and all CLD). We included a control group of 33,337 healthy European individuals from the Exome Aggregation Consortium. We compared distribution of genotype using the chi‐square test and logistic regression. In the exploratory cohort analyzed by WES, frequency of the TA allele of HSD17B13 rs72613567 was significantly decreased in HCC patients compared to healthy controls (P = 1.52 × 10−06). In the validation cohort, frequency of TA allele carriers was also decreased in patients with CLD and without HCC (39%) compared to healthy individuals (47%; P < 0.0001). The protective effect of the TA allele of HSD17B13 rs72613567 was identified in patients with ALD (odds ratio OR = 0.73; 95% confidence interval CI, 0.65‐0.82; P < 0.0001), NAFLD (OR = 0.64; 95% CI, 0.49‐0.83; P = 0.0007), and hepatitis C (OR = 0.71; 95% CI, 0.60‐0.85; P = 0.0002). In patients with ALD, the proportion of TA allele carriers with HCC was significantly lower (32%) than in CLD patients without HCC (40%), even after adjustment for age, sex, and fibrosis (OR = 0.64; 95% CI, 0.46‐0.87; P = 0.005). Conclusion: The HSD17B13 rs72613567 loss of function variant is protective of HCC development in patients with ALD.
The spectrum of alcohol-related liver diseases (ALD) includes steatosis, steatohepatitis, progressive liver fibrosis, and cirrhosis. Acute-on-chronic liver failure (ACLF) is a recently defined entity ...that occurs in patients with chronic liver diseases and is characterised by acute decompensation, organ failures and a high risk of short-term mortality. Active alcohol consumption, alcoholic hepatitis and bacterial infections are the most frequent events precipitating the development of ACLF in the context of ALD (ALD-ACLF). The specific management of this entity remains unknown and the place of salvage liver transplantation controversial. This overview details the current knowledge on specific aspects of epidemiology, pathophysiology, prognosis and management of ALD-ACLF.
Few single nucleotide polymorphisms (SNPs) have been reproducibly associated with hepatocellular carcinoma (HCC). Our aim was to test the association between nine SNPs and HCC occurrence. SNPs in ...genes linked to HCC (DEPDC5, GRIK1, KIF1B, STAT4, MICA, DLC1, DDX18) or to liver damage (PNPLA3‐rs738409, TM6SF2‐rs58542926) in GWAS were genotyped in discovery cohorts including 1,020 HCC, 2,021 controls with chronic liver disease and 2,484 healthy individuals and replication was performed in prospective cohorts of cirrhotic patients with alcoholic liver disease (ALD, n = 249) and hepatitis C (n = 268). In the discovery cohort, PNPLA3 and TM6SF2 SNPs were associated with HCC (OR = 1.67 CI95%:1.16–2.40, p = 0.005; OR = 1.45 CI95%:1.08–1.94, p = 0.01) after adjustment for fibrosis, age, gender and etiology. In contrast, STAT4‐rs7574865 was associated with HCC only in HBV infected patients (p = 0.03) and the other tested SNP were not linked with HCC risk. PNPLA3 and TM6SF2 variants were independently associated with HCC in patients with ALD (OR = 3.91 CI95%:2.52–6.06, p = 1.14E‐09; OR = 1.79 CI95%:1.25–2.56, p = 0.001) but not with other etiologies. PNPLA3 SNP was also significantly associated with HCC developed on a nonfibrotic liver (OR = 2.19 CI95%:1.22–3.92, p = 0.007). The association of PNPLA3 and TM6SF2 with HCC risk was confirmed in the prospective cohort with ALD. A genetic score including PNPLA3 and TM6SF2 minor alleles showed a progressive significant increased risk of HCC in ALD patients. In conclusion, PNPLA3‐rs738409 and TM6SF2‐rs58542926 are inherited risk variants of HCC development in patients with ALD in a dose dependent manner. The link between PNPLA3 and HCC on nonfibrotic liver suggests a direct role in liver carcinogenesis.
What's new?
Multiple single nucleotide polymorphisms (SNPs) have been associated with hepatocellular carcinoma (HCC) through genome‐wide association studies (GWAS). Few of these variants, however, have been cross‐validated, raising questions about their relation to HCC. Here, nine SNPs previously linked to HCC or liver damage were selected for investigation in European patients. Two of the variants, PNPLA3 rs738409 and TM6SF2 rs58542926, were found to be associated with HCC risk specifically in patients with alcoholic liver disease. PNPLA3 rs738409 was also associated with HCC in patients with nonfibrotic livers, where it potentially influences liver carcinogenesis via modification of protein function without altering gene expression.
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