Liver International

Abstract: Background: Alcoholic hepatitis (AH) is associated with dysregulated inflammatory and immune responses. interleukin‐18 (IL‐18), described as γ interferon (γIFN)‐inducible factor, and its natural antagonist, IL‐18 binding protein (IL‐18 BP), has not been fully studied in patients with AH. Thus, our aim was: (i) to determine plasma values of IL‐18, IL‐18 BP, γIFN, and tumor necrosis factor α (TNF)‐α in patients hospitalized for biopsy‐proven AH; (ii) to correlate these cytokines with the severity of AH, as assessed by Maddrey's discriminant function (DF), the degree of liver failure using the Child–Pugh score and blood neutrophils; (iii) to compare cytokines values in survivors and non‐survivors.

Methods: Cytokines were measured using specific immunoassays within 7 days of admission. The diagnosis of AH was based on histology in all cases. We studied 43 cirrhotic patients with a Maddrey's DF≥32 (severe AH), 29 patients with a score <32 (non‐severe AH), 12 patients with abstinent alcoholic cirrhosis, and 10 healthy subjects.

Results: IL‐18 and TNFα were increased in severe AH as compared with healthy subjects. Plasma IL‐18 BP was elevated in patients with severe and non‐severe AH as compared with healthy subjects. γIFN did not differ between groups. In patients with severe and non‐severe AH, IL‐18, IL‐18 BP, TNFα, but not γIFN, were positively correlated to DF and Child–Pugh score. Neither IL‐18 nor IL‐18 BP correlated to TNFα. Patients who died (n=10) during the hospitalization had higher IL‐18 BP and TNFα at admission as compared with survivors (322 [172–504] vs 222 [109–441] ng/ml; 7.5 [2.2–17.3] vs 3 [0.6–20] pg/ml, P<0.01, respectively).

Conclusion: In cirrhotic patients with AH, IL‐18, IL‐18 BP, and TNFα correlate to the hepatitis severity and to the degree of liver failure. High IL‐18 BP and TNFα at hospital admission in non‐survivors suggest it may be of prognostic value.

Although acetaminophen (APAP) is usually considered as a safe drug, this painkiller can lead to acute liver failure after overdoses. Moreover, there is evidence that the maximum recommended dosage can induce hepatic cytolysis in some individuals. Several predisposing factors appear to enhance the risk and severity of APAP‐induced liver injury including chronic alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions linked to obesity. In contrast, obesity by itself does not seem to be associated with a higher risk of APAP‐induced liver injury. Since 1987, seven studies dealt with APAP‐induced hepatotoxicity in rodent models of NAFLD and five of them found that this liver disease was associated with higher APAP toxicity. Unfortunately, these studies did not unequivocally established the mechanism(s) whereby NAFLD could favour APAP hepatotoxicity, although some investigations suggested that pre‐existent induction of hepatic cytochrome P450 2E1 (CYP2E1) could play a significant role by increasing the generation of N‐acetyl‐p‐benzoquinone imine (NAPQI), the toxic metabolite of APAP. Moreover, pre‐existent mitochondrial dysfunction associated with NAFLD could also be involved. In contrast, some investigations suggested that factors that could reduce the risk and severity of APAP hepatotoxicity in obesity and NAFLD include higher hepatic APAP glucuronidation, reduced CYP3A4 activity and increased volume of body distribution. Thus, the occurrence and the outcome of APAP‐induced liver injury in an obese individual with NAFLD might depend on a delicate balance between metabolic factors that can be protective and others that favour large hepatic levels of NAPQI.

Background: Spontaneous bacterial peritonitis (SBP) is considered as result of bacterial translocation from the gastrointestinal lumen to the mesenteric lymph nodes and subsequent circulation. Variants of the NOD2 gene contribute to bacterial translocation and were associated with SBP in a recent study.

Methods: We determined common NOD2 variants by TaqMan polymerase chain reaction and analysed the ascitic fluid neutrophil count and bacterial culture results in 175 prospectively characterized hospitalized patients with decompensated cirrhosis who underwent diagnostic paracentesis in two German centres.

Results: Ten patients presented with culture‐positive SBP, 19 with culture‐negative SBP and six had bacterascites. Minor allele frequencies for R702W, G908R and 1007fs in subjects with sterile non‐neutrocytic ascites were 3.2, 2.5 and 2.5% respectively. Patients with SBP [odds ratio (OR) 2.7; P=0.036], culture‐positive SBP (OR 6.0; P=0.012) and bacterascites (OR 6.0; P=0.050) were more often carriers of NOD2 variants than patients with sterile non‐neutrocytic ascites. The mutations 1007fs and G908R were associated with culture‐positive SBP (P≤0.005) and R702W with bacterascites (P=0.014). There was no significant association of NOD2 variants with culture‐negative SBP (OR 1.6; P=0.493). In logistic regression, previous SBP, a higher model for end‐stage liver disease (MELD) score and the presence of a NOD2 variant were independent predictors of ascitic fluid infection. The median survival was insignificantly shorter in patients with NOD2 variants (268 vs. 339 days; P=0.386). In patients without hepatocellular carcinoma at study entry (N=148), NOD2 was a predictor of survival after adjustment for the MELD score and age (hazard ratio 1.89; P=0.045).

Conclusion: NOD2 variants increase the risk for culture‐positive SBP and bacterascites in cirrhosis and may affect survival.

Abstract: Background/Aims: Increased serum concentrations of pro‐inflammatory cytokines have been detected in patients with liver cirrhosis. However, their role in the natural history of cirrhosis and portal hypertension, in the absence of infection, and the prognostic significance of inflammation‐related cytokines have not been reported. Our objective was the analysis of the prognostic value of inflammation‐related cytokines in cirrhotic patients.

Patients and methods: Serum concentrations of tumor necrosis factor (TNF‐α) and its soluble receptors I and II and interleukin 6 (IL‐6), as well as mean blood pressure, plasma renin activity, aldosterone, vasopressin and norepinephrine concentrations were determined in 72 cirrhotic patients (Child–Pugh score: A 50%, B 33.3%, C 16.7%), without any evidence of infection, and in 25 healthy controls. Patients were followed up for a median of 35.9 (range 6–60) months.

Results: Increased concentrations of soluble TNF receptors were detected in cirrhotic patients when compared with healthy controls. TNF receptors and IL‐6 concentrations were both significantly more elevated in advanced phases of cirrhosis (Child–Pugh score C vs B and vs A). Sixteen patients died as a related consequence of liver cirrhosis. Multivariant analysis demonstrated that Child–Pugh score, mean blood pressure and serum levels of TNF receptor I were associated with mortality.

Conclusions: In addition to the classic factors implicated in mortality (Child–Pugh score and hemodynamic parameters), alterations in inflammation‐related components are of prognostic significance in cirrhotic patients.

Background: Critical illness in cirrhotic patients is associated with a poor prognosis and increased susceptibility to infections. Monocyte HLA‐DR expression is decreased in cirrhotic patients, but its prognostic value has not been investigated prospectively.

Methods: Thirty‐eight critically ill patients with decompensated liver cirrhosis were included in this prospective study. On admission to the intensive care unit (ICU), inflammatory parameters (C‐reactive protein, procalcitonin and lipopolysaccharide‐binding protein), interleukin (IL)‐10, interferon (IFN)‐γ serum levels, tumour necrosis factor (TNF)‐αex vivo stimulation (whole blood assay) and HLA‐DR expression on monocytes (FACS analysis) were determined. Immune parameters were furthermore measured every third day until discharge from the ICU or death of the patients.

Results: Intensive care unit mortality of the cirrhotic patients was 34.2%. During admission, TNF ex vivo, IFN‐γ and HLA‐DR expression were lower in non‐survivors (all P<0.05), while IL‐10 levels were increased in non‐survivors compared with survivors (P=0.001). However, individual values clearly overlapped between groups. Prospective analysis revealed that monocyte HLA‐DR expression remained stable or increased in survivors, but decreased in non‐survivors (P=0.002). A decrease in HLA‐DR expression between admission and day 3 was strongly associated with decreased IFN‐γ levels and increased ICU mortality (hazard ratio 3.36, P=0.008), mostly owing to late sepsis. This association was independent of the sequential organ failure assessment and model for end‐stage liver disease score.

Conclusions: Here we establish the relative HLA‐DR expression (admission/day 3) as a prognostic marker for ICU mortality in critically ill cirrhotic patients. These results may guide the evaluation of immune‐modulating therapies in these patients.

Background: Extrahepatic portal venous obstruction (EHPVO) developing due to thrombotic occlusion of the portal vein in children is generally considered a benign disease. Whether hepatic dysfunction develops in these patients in the absence of a gastrointestinal bleed has not been well studied.

Materials and methods: Forty‐three patients with EHPVO who had not bled in the last 3 months were studied. Patients were divided into those with (group I) or without ascites (group II). Matched cirrhotic patients with ascites (group III) served as controls. Clinical, biochemical, ultrasonographic, and histopathological evaluation was carried out. Portal biliopathy was assessed in five patients in group I and in 12 patients in group II by cholangiography.

Results: Of 43 EHPVO patients, ascites was seen in nine (21%) patients (group I). Thirty‐four patients had no ascites (group II). Serum ALT (54±24 vs. 34±10 IU/l, P<0.01), albumin (3.2±0.3 vs. 3.7±0.4 g/dl, P<0.01), and prothrombin time difference (9.0±4.5 vs. 2.4±1.9 s, P<0.05) were deranged in patients in group I compared with group II. Patients in group I were 4 years older, and the duration of portal hypertension was longer than in group II (11.5 vs. 5.6 year, P<0.05). Portal biliopathy changes were significantly more severe in group I than in group II patients. Ascites was high gradient in all the patients in group I and the serum‐ascitic albumin gradient was comparable between groups I and III. None of the EHPVO patients, but four cirrhotic patients, developed spontaneous bacterial peritonitis during a follow‐up of 11±4 months.

Conclusions: Hepatic dysfunction in the form of ascites and deranged liver functions is not uncommon in patients with EHPVO, more so in patients with prolonged portal hypertension. Based on our data it would be worthwhile to study whether prolonged portal vein thrombosis in EHPVO patients could lead to progressive liver disease.