Verónica Prado

Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis

BACKGROUND & AIMS Impairment of kidney function is common in cirrhosis but differential diagnosis remains a challenge. We aimed at assessing the usefulness of neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of tubular damage, in the differential diagnosis of impairment of kidney function in cirrhosis. METHODS Two-hundred and forty-one patients with cirrhosis, 72 without ascites, 85 with ascites, and 84 with impaired kidney function, were studied. Urinary levels of NGAL were measured by ELISA. RESULTS Patients with impaired kidney function had higher urinary NGAL levels compared to patients with and without ascites. Patients with urinary tract infection (n=25) had higher uNGAL values than non-infected patients. Patients with acute tubular necrosis (ATN) had uNGAL levels markedly higher (417μg/g creatinine (239-2242) median and IQ range) compared to those of patients with pre-renal azotemia due to volume depletion 30 (20-59), chronic kidney disease (CKD) 82 (34-152), and hepatorenal syndrome (HRS) 76 (43-263) μg/g creatinine (p<0.001 for all). Among HRS patients, the highest values were found in HRS-associated with infections, followed by classical (non-associated with active infections) type-1 and type-2 HRS (391 (72-523), 147 (83-263), and 43 (31-74) μg/g creatinine, respectively; p<0.001). Differences in uNGAL levels between classical type 1 HRS and ATN on the one hand and classical type 1 HRS and CKD and pre-renal azotemia on the other were statistically significant (p<0.05). CONCLUSIONS uNGAL levels may be useful in the differential diagnosis of impairment of kidney function in cirrhosis. Urinary tract infections should be ruled out because they may increase uNGAL excretion.

Relative adrenal insufficiency in decompensated cirrhosis: Relationship to short‐term risk of severe sepsis, hepatorenal syndrome, and death

The prevalence of relative adrenal insufficiency (RAI) in critically ill cirrhosis patients with severe sepsis is over 60% and associated features include poor liver function, renal failure, refractory shock, and high mortality. RAI may also develop in noncritically ill cirrhosis patients but its relationship to the clinical course has not yet been assessed. The current study was performed in 143 noncritically ill cirrhosis patients admitted for acute decompensation. Within 24 hours after hospitalization adrenal function, plasma renin activity, plasma noradrenaline and vasopressin concentration, and serum levels of nitric oxide, interleukin‐6 and tumor necrosis factor alpha were determined. RAI was defined as a serum total cortisol increase <9 μg/dL after 250 μg of intravenous corticotropin from basal values <35 μg/dL. Patients were followed for 3 months. RAI was detected in 26% of patients (n = 37). At baseline, patients with RAI presented with lower mean arterial pressure (76 ± 12 versus 83 ± 14 mmHg, P = 0.009) and serum sodium (131 ± 7 versus 135 ± 5 mEq/L, P = 0.007) and higher blood urea nitrogen (32 ± 24 versus 24 ± 15 mg/dl, P = 0.06), plasma renin activity (7.1 ± 9.9 versus 3.4 ± 5.6 ng/mL*h, P = 0.03), and noradrenaline concentration (544 ± 334 versus 402 ± 316 pg/mL, P = 0.02). During follow‐up, patients with RAI exhibited a higher probability of infection (41% versus 21%, P = 0.008), severe sepsis (27% versus 9%, P = 0.003), type‐1 hepatorenal syndrome (HRS) (16% versus 3%, P = 0.002), and death (22% versus 7%, P = 0.01). Conclusion: RAI is frequent in noncritically ill patients with acute decompensation of cirrhosis. As compared with those with normal adrenal function, patients with RAI have greater impairment of circulatory and renal function, higher probability of severe sepsis and type‐1 HRS, and higher short‐term mortality. (Hepatology 2013;58:1757–1765)

Clinical course and short‐term mortality of cirrhotic patients with infections other than spontaneous bacterial peritonitis

Clinical course and risk factors of death in non‐spontaneous bacterial peritonitis (SBP) infections are poorly known. We assessed the prevalence of acute kidney injury (AKI) and type‐1 hepatorenal syndrome (HRS), hospital, 30‐day and 90‐day mortality and risk factors of death in 441 decompensated patients.

The new epidemiology of nosocomial bacterial infections in cirrhosis: therapeutical implications

Cirrhotic patients are at increased risk of developing infection, sepsis and death. Enterobacteriaceae and nonenterococcal streptococci are the main bacteria responsible for spontaneous and urinary infections in this population. Prompt and appropriate treatment is basic in the management of cirrhotic patients with infection. Third-generation cephalosporins continue to be the gold-standard antibiotic treatment of the majority of infections acquired in the community because responsible strains are usually susceptible to β-lactams. By contrary, nosocomial infections are nowadays frequently caused by multiresistant bacteria (extended-spectrum β-lactamase-producing Enterobacteriaceae, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant enterococci among others) that are nonsusceptible to the main antibiotics. Treatment of these infections requires the use of broader spectrum antibiotics (carbapenems) or of antibiotics that are active against specific resistant bacteria (glycopeptides, linezolid, daptomycin, amikacin and colistin). Empirical antibiotic schedules must be adapted to the local epidemiological pattern of antibiotic resistance. Careful restriction of antibiotic prophylaxis to the high-risk population is also mandatory to reduce the spread of multiresistant bacteria in cirrhosis.

A Day-4 Lille Model Predicts Response to Corticosteroids and Mortality in Severe Alcoholic Hepatitis

OBJECTIVES:Prednisolone therapy increases the risk of infections in patients with severe alcoholic hepatitis (SAH). We evaluated whether the use of the Lille Model at day 4 (LM4) is useful to predict response to prednisolone compared with the classic day 7 (LM7) in order to limit a futile exposure to corticosteroids.METHODS:We performed a retrospective analysis of a large multinational cohort of patients with SAH with Maddrey’s discriminant function (DF) ≥32. Response to corticosteroids was assessed with LM4 and LM7, according to the validated cutoff value (CUV>0.45). Receiver operating characteristics (ROC) curves were constructed to determine the optimal CUV for LM4 and to compare accuracy between LM4, LM7, MELD (Model for End-Stage Liver Disease), and ABIC (age, bilirubin, international normalized ratio, and creatinine). Logistic regression models were constructed to predict 28- and 90-day mortality. Cox regression analysis was performed to assess long-term survival.RESULTS:A total of 163 (62.7%) out of 260 patients received corticosteroids. The median DF for the patients treated with corticosteroids was 64.1 (47.9–81.3). Overall 90-day mortality was 35.9%. The median LM4 and LM7 for the patients who received treatment was 0.39 (0.19–0.83) and 0.36 (0.13–0.77). LM4 was a strong independent predictor of 28-day mortality (OR 25.4, (95% confidence interval (CI) 5.1–126.8), P<0.001). By using LM4 with a CUV>0.45, 28- and 90-day survival was significantly higher for responders (90% and 76%) than non-responders (66% and 40%), P<0.001. Importantly, the area under the ROC curve for predicting mortality for LM4 was similar than the classic LM7 (0.77 vs. 0.75, respectively: P=0.558).CONCLUSIONS:LM4 is as accurate as LM7 in predicting response to corticosteroids, as well as 28- and 90-day mortality. Assessing the efficacy of prednisolone at an earlier time point can avoid a more prolonged futile use of this therapy.

Changing Options for Prevention and Treatment of Infections in Cirrhosis

Opinion statementBacterial infections are more frequent and severe in cirrhosis. Most prevalent infections are spontaneous bacterial peritonitis (SBP) and urinary infections followed by pneumonia, cellulitis and bacteremia. Cirrhosis increases the risk of sepsis, severe sepsis and death. Early diagnosis and adequate treatment of infections is essential in the management of cirrhotic patients. Recent data show that currently recommended empirical antibiotic therapy, mainly based on the use of β-lactams, is effective in community-acquired infections, but frequently fails in nosocomial and healthcare-associated infections. A marked increase in the prevalence of multidrug resistant (MDR) bacteria in the healthcare environment explains this finding. Patients developing nosocomial infections or with extended lengths of hospitalization are at higher risk for second infections that are associated with poor prognosis. Antibiotic strategies should therefore be selected according to the type, severity and site of acquisition of infection, and be adapted to the local epidemiological pattern of antibiotic resistance. Treatment of MDR bacteria requires the use of broader spectrum antibiotics (carbapenems) or those active against specific resistant bacteria (glycopeptides, linezolid, daptomycin, amikacin, colistin). Restriction of antibiotic prophylaxis to the high-risk populations, prevention of antibiotic overuse, and early de-escalation policies are also mandatory to prevent the spread of MDR bacteria in cirrhosis.

Adverse Events and Acute Chronic Liver Failure in Patients With Cirrhosis Undergoing Endoscopic Retrograde Cholangiopancreatography: A Multicenter Matched-Cohort Study

BACKGROUND: Data on the outcome of adverse events (AEs) and the risk of developing acute-on-chronic liver failure (ACLF) after ERCP in patients with cirrhosis are unknown. We examined the incidence and risk factors of post-ERCP AEs in patients with cirrhosis and the appearance of ACLF after ERCP. METHODS: In this multicenter, retrospective, matched-cohort study, we evaluated ERCPs performed from January 2002 to 2015. A group of patients with cirrhosis with non-ERCP interventions and one without interventions was also analyzed for the development of ACLF. RESULTS: A total of 441 ERCPs were analyzed; 158 in patients with cirrhosis (cases) and 283 in patients without cirrhosis (controls). The overall rate of AEs after all ERCPs was significantly higher in cases compared to controls (17% vs 9.5, p = 0.02). Cholangitis developed more in cases compared to controls (6.3% vs 1.8%; p = 0.01). In a subanalysis of those with sphincterotomy, the rate of bleeding was higher in those with cirrhosis (9.4% vs 3.4%; p = 0.03). Logistic regression identified cirrhosis (OR, 2.48; 95% CI, 1.36–4.53; p = 0.003) and sphincterotomy (OR, 2.66; 95% CI, 1.23–5.72; p = 0.01) as risk factors of AEs. A total of 18/158 (11.4%) cases developed ACLF after ERCP. ACLF occurred in 7/27 cases with post-ERCP AEs and in 11/131 without post-ERCP AEs (25.9% vs 8.3%; p = 0.01). A total of 3.2% (13/406) patients without interventions developed ACLF compared to 17.5% (102/580) who developed ACLF after non-ERCP interventions. Patients with decompensated cirrhosis at ERCP had a higher risk of developing ACLF (17% vs 6.8%; p = 0.04). Patients with a MELD score ≥ 15 were 3.1 times more likely (95% CI: 1.14–8.6; p = 0.027) to develop ACLF after ERCP. CONCLUSIONS: The rate of AEs after ERCP is higher in patients with cirrhosis compared to the non-cirrhotic population. The incidence of ACLF is higher in those with AEs after ERCP compared to those without AEs, especially cholangitis. The development of ACLF is common after ERCP and other invasive procedures. ACLF can be precipitated by numerous factors which include preceding events before the procedure, including manipulation of the bile duct, and AEs after an ERCP.

Coagulation failure in patients with Acute‐on‐Chronic Liver Failure (ACLF) and decompensated cirrhosis: beyond INR

Balanced hemostasis with hypocoagulable and hypercoagulable features may occur in acute‐on‐chronic liver failure (ACLF). The characteristics and prognostic impact of the coagulation profile in ACLF are unknown. Consecutive patients with ACLF (n = 36) and acute decompensation (AD; n = 24) were included. Blood samples for thromboelastometry (TE) were obtained at admission and 72 hours thereafter. The coagulation profile was evaluated in patients with and without ACLF and in those with and without systemic inflammatory response syndrome. The impact of the coagulation profile on transfusion requirements, bleeding events, and short‐term survival was assessed. At admission, patients with ACLF showed more hypocoagulable characteristics compared to AD subjects, with prolonged time to initial fibrin formation and clot formation time and decreased maximum clot firmness and alpha‐angle values. TE parameters worsened at 72 hours in ACLF but improved in patients with AD. Prevalence of a hypocoagulable profile (three or more TE parameters outside range) was significantly higher in patients with ACLF either at admission (61% versus 29% in AD; P = 0.03) or during follow‐up. Hypocoagulability correlated with systemic inflammation and was associated with higher 28‐day (45% versus 16%; P = 0.02) and 90‐day (52% versus 19%; P = 0.01) mortality rates but not with transfusion requirements or bleeding. Prolonged time to initial fibrin formation (extrinsic TE assay >80 seconds) and Model for End‐Stage Liver Disease score at baseline were independent predictors of 28‐day mortality. Conclusion: Patients with ACLF frequently show hypocoagulable features with prolonged time to initial fibrin formation and clot formation time and reduced clot firmness; these alterations worsen after admission, correlate with systemic inflammation, and translate into higher short‐term mortality; hypofibrinolysis could contribute to organ failure in ACLF.

Bacterial infections in acute variceal hemorrhage despite antibiotics—a multicenter study of predictors and clinical impact:

Background and aims Current guidelines recommend antibiotic prophylaxis in all patients presenting with cirrhosis and acute variceal hemorrhage (AVH). We aimed to evaluate the characteristics and clinical impact of “early” infections (developing within 14 days) of AVH in a real-world setting. Methods We analyzed retrospective data from a cohort of 371 adult patients with cirrhosis and AVH all of whom had received antibiotic prophylaxis (74% men; mean age 56 years), admitted to tertiary care hospitals in Edmonton, Alberta, Canada, and Barcelona, Spain. Sensitivity analyses were presented for culture-positive (confirmed) infections. Results The mean MELD was 16. Fifty-two percent of patients received quinolones, 45% third-generation cephalosporins and 3% other antibiotics. Fourteen percent (51/371) developed an infection within 14 days of AVH. Seventy-five percent of infections were culture positive and occurred at a mean of six days from AVH. When all infections were considered, respiratory infections were the most common (53%) followed by urinary tract infections (17%) and bacteremia (16%). Resistance patterns differed between countries. Outpatient antibiotic prophylaxis (OR 5.4) and intubation (OR 2.6) were independent predictors of bacterial infection. Bacterial infection (OR 2.6) and the MELD (OR 1.2) were independent predictors of six-week mortality. Conclusions Early bacterial infections develop in 14% of cirrhotic patients with AVH despite antibiotic prophylaxis, and have a negative impact on six-week mortality. Intubation and outpatient antibiotic prophylaxis are associated with increased risk of early bacterial infections. Patients at risk should be followed closely with prompt infection workup and local antibiogram-based expansion of antibiotic therapy in case of clinical decline.

Corrigendum: A Day-4 Lille Model Predicts Response to Corticosteroids and Mortality in Severe Alcoholic Hepatitis

Corrigendum: A Day-4 Lille Model Predicts Response to Corticosteroids and Mortality in Severe Alcoholic Hepatitis