Paola Casciato

Serum creatinine and bilirubin predict renal failure and mortality in patients with spontaneous bacterial peritonitis: a retrospective study

Background: Patients with spontaneous bacterial peritonitis (SBP) are at a high risk for renal failure and death despite successful treatment of infection. Intravenous (IV) albumin administration combined with antibiotic treatment has been shown to significantly decrease these risks. Clinical evidence is lacking on which patients are appropriate candidates for albumin treatment.

Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: A multicenter prospective study

BACKGROUND & AIM Retrospective studies show an association between proton pump inhibitor (PPI) therapy and spontaneous bacterial peritonitis (SBP). We investigate the relationship between PPI and SBP in decompensated cirrhotic patients in a large nationwide prospective study. METHODS Seven hundred seventy patients with a diagnosis of decompensated cirrhosis were admitted consecutively in 23 hospitals in Argentina from March 2011 to April 2012; the patients were carefully investigated for PPI consumption in the previous 3 months. In total, 251 patients were excluded because of active gastrointestinal hemorrhage, antibiotic use during the preceding weeks, HIV-positive status and immunosuppressive therapy. RESULTS Two hundred twenty-six out of 519 patients (43.5%) had received PPI therapy within the last 3 months. In 135 patients, PPIs were administered for longer than 2 weeks. A bacterial infection was shown in 255 patients (49.1%). SBP was diagnosed in 95 patients out of 394 patients with ascites (24.7%). There was no significant difference in the rate of PPI consumption between the infected and the non-infected patients (44.3% vs. 42.8%) or between the SBP patients and the patients with ascites without SBP (46% vs. 42%). In the SBP patients, the duration of PPI administration did not influence the rate of SBP occurrence. The type of bacteria and the origin of SBP infection were similar in the patients with and without PPI. CONCLUSION In the current large, multicenter, prospective study, PPI therapy, specifically evaluated at admission of consecutive cirrhotic patients, was not associated with a higher risk of SBP.

The Role of Serum Biomarkers in Predicting Fibrosis Progression in Pediatric and Adult Hepatitis C Virus Chronic Infection

Background/Aims Liver biopsy represents the gold standard for damage evaluation, but noninvasive serum markers that mirror liver fibrosis progression are actual goals both in adults and especially in children. The aim was to determine specific serum markers that correlate with liver fibrosis progression during chronic HCV infection. Methods Liver biopsies and concomitant serum samples from 22 pediatric and 22 adult HCV patients were analyzed. Histological parameters were evaluated. On serum TGF-ß1, tissue inhibitor of matrix metalloprotein inhibitor-1 (TIMP-1), hyaluronic acid (HA) and aminoterminal peptide of procollagen type III (PIIINP) were tested. Results Significant fibrosis (F≥2) and advanced fibrosis (F≥3) represented 64% and 20%, respectively in children; while 54% F≥2 and 23% F≥3 in adults. Hyaluronic acid (p = 0.011) and PIIINP (p = 0.016) were related to worse fibrosis stages only in adults, along with TIMP-1 (p = 0.039) just in children; but TGF-ß1 was associated with mild fibrosis (p = 0.022) in adults. The AUROC of TIMP-1 in children to discriminate advanced fibrosis was 0.800 (95%IC 0.598–0.932). In adults, the best AUROCs were that of HA, PIIINP and TGF-ß1 [0.929 (IC95% 0.736–0.994), 0.894 (IC95% 0.689–0.984) and 0.835 (IC95% 0.617–0.957)], respectively. In children, according to the cut off (165.7 ng/mL) value for TIMP-1, biopsies could have been avoided in 72% (18/25). Considering the cut off for HA (109.7 ng/mL), PIIINP (9.1 µg/L), and TGF-ß1 (10,848.3 pg/mL), biopsies could have been avoided in 87% (19/22) of adult patients by using HA and 73% (16/22) using PIIINP or TGF-ß1. Conclusions In adults given the diagnostic accuracy of HA, PIIINP, TGF-ß1, their combination may provide a potential useful tool to assess liver fibrosis. This first pediatric study suggests that TIMP-1 is clinically useful for predicting liver fibrosis in HCV patients.

Serum Apoptosis Markers Related to Liver Damage in Chronic Hepatitis C: sFas as a Marker of Advanced Fibrosis in Children and Adults While M30 of Severe Steatosis Only in Children

Background Liver biopsy represents the gold standard for evaluating damage and progression in patients with chronic hepatitis C (CHC); however, developing noninvasive tests that can predict liver injury represents a growing medical need. Considering that hepatocyte apoptosis plays a role in CHC pathogenesis; the aim of our study was to evaluate the presence of different apoptosis markers that correlate with liver injury in a cohort of pediatric and adult patients with CHC. Methods Liver biopsies and concomitant serum samples from 22 pediatric and 22 adult patients with CHC were analyzed. Histological parameters were evaluated. In serum samples soluble Fas (sFas), caspase activity and caspase-generated neoepitope of the CK-18 proteolytic fragment (M30) were measured. Results sFas was associated with fibrosis severity in pediatric (significant fibrosis p = 0.03, advanced fibrosis p = 0.01) and adult patients (advanced fibrosis p = 0.02). M30 levels were elevated in pediatric patients with severe steatosis (p = 0.01) while in adults no relation with any histological variable was observed. Caspase activity levels were higher in pediatric samples with significant fibrosis (p = 0.03) and they were associated with hepatitis severity (p = 0.04) in adult patients. The diagnostic accuracy evaluation demonstrated only a good performance for sFas to evaluate advanced fibrosis both in children (AUROC: 0.812) and adults (AUROC: 0.800) as well as for M30 to determine steatosis severity in children (AUROC: 0.833). Conclusions Serum sFas could be considered a possible marker of advanced fibrosis both in pediatric and adult patient with CHC as well as M30 might be a good predictor of steatosis severity in children.

Distinctive intrahepatic characteristics of paediatric and adult pathogenesis of chronic hepatitis C infection

Mechanisms leading to liver damage in chronic hepatitis C (CHC) are being discussed, but both the immune system and the virus are involved. The aim of this study was to evaluate intrahepatic viral infection, apoptosis and portal and periportal/interface infiltrate in paediatric and adult patients to elucidate the pathogenesis of chronic hepatitis C. HCV-infected, activated caspase-3(+) and TUNEL(+) hepatocytes, as well as total, CD4(+), CD8(+), Foxp3(+) and CD20(+) lymphocytes infiltrating portal and periportal/interface tracts were evaluated in 27 paediatric and 32 adult liver samples by immunohistochemistry or immunofluorescence. The number of infected hepatocytes was higher in paediatric than in adult samples (p 0.0078). In children, they correlated with apoptotic hepatocytes (activated caspase-3(+) r = 0.74, p < 0.0001; TUNEL(+) r = 0.606, p 0.0017). Also, infected (p = 0.026) and apoptotic hepatocytes (p = 0.03) were associated with the severity of fibrosis. In adults, activated caspase-3(+) cell count was increased in severe hepatitis (p = 0.009). Total, CD4(+), CD8(+) and Foxp3(+) lymphocyte count was higher in adult samples (p < 0.05). Paediatric CD8(+) cells correlated with infected (r = 0.495, p 0.04) and TUNEL(+) hepatocytes (r = 0.474, p = 0.047), while adult ones correlated with activated caspase-3(+) hepatocytes (r = 0.387, p 0.04). In adults, CD8(+) was associated with hepatitis severity (p < 0.0001) and correlated with inflammatory activity (CD8(+) r = 0.639, p 0.0003). HCV, apoptosis and immune response proved to be involved in CHC pathogenesis of both paediatric and adult patients. However, liver injury in paediatric CHC would be largely associated with a viral cytopathic effect mediated by apoptosis, while in adults it would be mainly associated with an exacerbated immune response.

Evaluation of HUGE equation (hematocrit, urea, gender) performance for screening chronic kidney disease in clinically stable cirrhotic patients

for HUGE equation validation patient’s evaluation by two nephrologists blind between them, as gold standard for renal health status, was used [3–5]. CKD is an entity frequently diagnosed in cirrhotic patients, and this kidney–liver alteration may be caused by diseases that can affect both organs (e.g., chronic virus C infection with cryoglobulinemia), or renal conditions induced by cirrhosis (e.g., Ig A nephropathy or pre-renal insufficiency induced by an increased vasomotor tone on renal circulation [6]. An equation like HUGE could be useful for screening CKD in cirrhotic patients, but this equation is based on serum parameters that can be altered by cirrhosis: Hematocrit may be low due to erythropoietin resistance (chronic disease anemia), and serum urea values may be lower because of a reduced urea biosynthesis (reduced hepatic conversion of ammonium to urea) [7, 8]. Thus, we decided to originally evaluate whether HUGE equation could be an accurate tool for detecting CKD in stable cirrhotic patients despite the influence that this condition can have on its constituents. With this objective, we performed a retrospective observational study to assess the operational characteristics of HUGE equation for screening CKD in 75 patients suffering from stable liver cirrhosis (Child–Pugh A) mostly secondary to hepatitis C (43 %), selected from a population of 750 cirrhotic patients who were on follow-up during 1 year (January 2014–January 2015) by the Hepatology and Transplantation Section of the Internal Medicine Division in the Hospital Italiano de Buenos Aires (Argentina). Inclusion criteria were as follows: to have information, every 4 months, during the year of the study (2014–2015) regarding patients’ serum and urine electrolytes, urea, creatinine, uric acid, hematocrit, hemoglobin, glucose, intact parathyroid hormone, urinalysis, and renal ultrasound. Editor,

Chronic hepatitis C liver microenvironment: role of the Th17/Treg interplay related to fibrogenesis

The role of the different lymphocyte populations in liver microenvironment of chronic hepatitis C (CHC) patients is still matter of debate. Since Th17 and Treg have opposite functions, their balance could affect disease progression. The aim was to explore liver microenvironment and its peripheral blood counterpart in adult CHC patients. CD4+ lymphocytes were predominant in the liver, with high Foxp3+ but low IL-17A+ frequency. IL-17A+ lymphocytes and IL-17A+/Foxp3+ ratio displayed association with advanced fibrosis (p = 0.0130; p = 0.0236, respectively), while Foxp3+ lymphocytes and IL-10 expression level inversely correlated with fibrosis severity (p = 0.0381, p = 0.0398, respectively). TGF-β/IL-6 ratio correlated with IL-17A+/Foxp3+ ratio (p = 0.0036, r = 0.5944) and with IL-17A+ lymphocytes (p = 0.0093; r = 0.5203). TNF-α and TGF-β were associated with hepatitis severity (p = 0.0409, p = 0.0321). Peripheral blood lymphocyte frequency was not associated with liver damage. There are functionally different immune cell populations actively involved in liver damage, but the liver cytokine milieu actually drives the pathogenesis. The intrahepatic Foxp3+ lymphocytes predominance beside the low IL-17A+ lymphocytes frequency, delineate a skewed IL-17A+/Foxp3+ balance towards Foxp3+ lymphocytes. However, the IL-17A+ lymphocytes association with advanced fibrosis denotes their role in the pathogenesis. Therefore, the interplay between Th17 and Treg conditions liver fibrogenesis.

Sicker Patients for Liver Transplantation: Meld, Meld Sodium, and Integrated Meld’s Prognostic Accuracy in the Assessment of Posttransplantation Events at a Single Center from Argentina

Background. MELD or MELD sodium promotes sicker patients for earlier liver transplantation (LT); the balance between pre- and post-LT outcomes is still controversial. Aim. To compare MELD and related scores’ risk assessment of short-term morbidity and mortality after LT. Methods. We included only transplanted cirrhotic patients from 6/2005 to 6/2010 (). Immediate pre-LT MELD, integrated MELD (iMELD), and two MELD sodium formulas “MELD Na1” and “MELDNa2” were calculated. Results. Pre-LT scores for nonsurvivors were higher than those for survivors: MELD (28 ± 8 versus 22 ± 7, ), MELD Na1 (33 ± 8 versus 27 ± 10, ), and iMELD (51 ± 6 versus 46 ± 8, ). Patient survival assessment was performed by AUROC analysis (95% CI): MELD 0.694 (0.56–0.82; ), MELD Na1 0.682 (0.56–0.79; ), MELD Na2 0.651 (0.54–0.76; ), and iMELD 0.698 (0.593–0.80; ). Patients with MELD ≥25 points had longer intensive care stay (mean 10 versus 7 days, ) and longer mechanical ventilatory support (5.4 versus 1.9 days, ). Conclusions. The addition of serum sodium to MELD does not improve assessment of mortality after LT. Patients with higher MELD may preclude higher morbidity after transplantation.

α-lipoic acid reduces postreperfusion syndrome in human liver transplantation - a pilot study

A double‐blind randomized controlled trial was performed to compare the safety and efficacy of α‐lipoic acid (ALA) in liver transplantation (LT). The grafts were randomized to receive ALA or placebo before the cold ischemia time. Furthermore, patients transplanted with the ALA‐perfused graft received 600 mg of intravenous ALA, while patients with the nonperfused graft received the placebo just before graft reperfusion. Hepatic biopsy was performed 2 h postreperfusion. Blood samples were collected before, during and 1 and 2 days after reperfusion. Quantitative polymerase chain reaction (qPCR) analysis was performed on biopsies to assess genes involved in the response to hypoxia, apoptosis, cell growth, survival and proliferation, cytokine production and tissue damage protection. Nine of 40 patients developed postreperfusion syndrome (PRS), but seven of them belonged to the control group. There was a decrease in PHD2 and an increase in alpha subunit of hypoxia‐inducible factor‐1 (HIF‐1α) and baculoviral IAP repeat containing 2 (Birc2) transcript levels in the biopsies from the ALA‐treated versus the control group of patients. Additionally, plasma levels of alarmins were lower in ALA‐treated patients than control patients, which suggests that ALA‐treated grafts are less inflammatory than untreated grafts. These results showed that ALA is safe for use in LT, induces gene changes that protect against hypoxia and oxidative stress and reduces the appearance of PRS.

A MELD-SCORE BASED LIVER ALLOCATION SYSTEM HAS A NEGATIVE IMPACT ON WAITING LIST MORTALITY AND IS ASSOCIATED WITH LOWER POST-TRANSPLANT SURVIVAL IN A COUNTRY WITH A UNIQUE, LARGE GEOGRAPHIC ORGAN PROCUREMENT AREA: 1029

Since June 2005 liver allocation in Argentina has incorporated MELD score to stratify patients in the waiting list. Due to an uneven distribution of transplantation centers no organ allocation areas were established, with a unique national waiting list serving a population of 39 million inhabitants. Aim: To evaluate the impact of MELD score in drop out, transplants and 1 year survival post transplantation. Patients and Methods: We included 707 consecutive patients registered in the waiting list. Period Pre-MELD: Listed June 1998/May 2005 in categories elective and urgency according to clinical and biochemical criteria (n=377). Period MELD: Listed June 2005/December 2008 stratified by MELD score (n=325). Overall and subgroup analysis was performed. Comparison between groups for quantitative variables was based on the test of t Student and for qualitative variables with Chi2 test. Actuarial probability of survival and drop out from the waiting list were calculated by Kaplan-Meier and compared using Mantel-Cox test. Results:In MELD period there was a 78 % increase in annual registration of patients without differences between etiologies or presence of HCC (15.3 vs 12.0 %). Mean age at registration was significantly higher in Period MELD (53.35 ±13 vs 49.11±14 years, p<0.05). 59 % of patients in period MELD were listed with MELD scores 12 to 19 (mean MELD16±6), while previously 72 % were listed in elective category. Number of transplants/year remained unchanged (35.2 vs 33.3). Yet time to transplantation was significantly shorter in Period MELD (8.7m vs 14.2m, p<0.001). Mean MELD at transplantation in Period MELD was 24.13±7.6 and 19.63±9.7 at drop out (p <0.001). Drop out was significantly higher in period MELD (18.4 to 14.5%. p<0.001). Rates of listed/transplanted patients decreased for cholestatic disease post MELD (66 to 23 %, p<0.05)and increased for HCC (17 to 91 %, p<0.001). One year patient and graft survival post transplant decreased from 93.1 to 83.5 % (p <0 .001). Mean MELD of patients dying within 3 months post-transplant: was 27.8±5.6 compared to 23.2±7.4 in survivors (p <0.01). Conclusion: Application of MELD score in Argentina has demonstrated a negative impact on waiting list mortality and has been associated with lower early post transplant survival. Further tuning of the application of the system should be performed to optimize results.