J.L. Montero

HIV coinfection shortens the survival of patients with hepatitis C virus-related decompensated cirrhosis.

The impact of human immunodeficiency virus (HIV) coinfection on the survival of patients with hepatitis C virus (HCV)‐related end‐stage liver disease (ESLD) is unknown. Because HIV infection is no longer considered an absolute contraindication for liver transplantation in some countries, it has become a priority to address this topic. The objective of this study was to compare the survival of HIV‐infected and HIV‐uninfected patients with decompensated cirrhosis due to HCV. In a retrospective cohort study, the survival of 1,037 HCV monoinfected and 180 HCV/HIV‐coinfected patients with cirrhosis after the first hepatic decompensation was analyzed. Of the group, 386 (37%) HCV‐monoinfected and 100 (56%) HCV/HIV‐coinfected subjects died during the follow‐up. The median survival time of HIV‐infected and HIV‐uninfected patients was 16 and 48 months, respectively (P < .001). The relative risk (95% CI) of death for HIV‐infected patients was 2.26 (1.51‐3.38). Other independent predictors of survival were age older than 63 years (2.25 [1.53‐3.31]); Child‐Turcotte‐Pugh class B versus class A (1.95 [1.41–2.68]) and class C versus class A (2.78 [1.66–4.70]); hepatitis D virus infection (1.56 [1.12–4.77]); model for end‐stage liver disease score, (1.05 [1.01‐1‐11]); more than one simultaneous decompensation (1.23 [1.12–3.33]); and the type of the first hepatic decompensation, with a poorer prognosis associated with encephalopathy compared with portal hypertensive gastrointestinal bleeding (2.03 [1.26–3.10]). In conclusion, HIV coinfection reduces considerably the survival of patients with HCV‐related ESLD independently of other markers of poor prognosis. This fact must be taken into account to establish the adequate timing of liver transplantation in HIV‐coinfected subjects. (HEPATOLOGY 2005.)

PGE 1 Protection against Apoptosis Induced by D-galactosamine is Not Related to the Modulation of Intracellular Free Radical Production in Primary Culture of Rat Hepatocytes

d -galactosamine ( d -GalN) toxicity is a useful experimental model of liver failure in human. It has been previously observed that PGE 1 treatment reduced necrosis and apoptosis induced by d -GalN in rats. Primary cultured rat hepatocytes were used to evaluate if intracellular oxidative stress was involved during the induction of apoptosis and necrosis by d -GalN (0-40 mM). Also, the present study investigated if PGE 1 (1 w M) was equally potent reducing both types of cell death. The presence of hypodiploid cells, DNA fragmentation and caspase-3 activation were used as a marker of hepatocyte apoptosis. Necrosis was measured by lactate dehydrogenase (LDH) release. Oxidative stress was evaluated by the intracellular production of hydrogen peroxide (H 2 O 2 ), the disturbances on the mitochondrial transmembrane potential (MTP), thiobarbituric-reacting substances (TBARS) release and the GSH/GSSG ratio. Data showed that intermediate range of d -GalN concentrations (2.5-10 mM) induced apoptosis in association with a moderate oxidative stress. High d -GalN concentration (40 mM) induced a reduction of all parameters associated with apoptosis and enhanced all those related to necrosis and intracellular oxidative stress, including a reduction of GSH/GSSG ratio and MTP in comparison with d -GalN (2.5-10 mM)-treated cells. Although PGE 1 reduced apoptosis induced by d -GalN, it was not able to reduce the oxidative stress and cell necrosis induced by the hepatotoxin in spite to its ability to abolish the GSH depletion.

TNF-α dependent production of inducible nitric oxide is involved in PGE1 protection against acute liver injury

BACKGROUND Tumour necrosis factor α (TNF-α) and nitric oxide modulate damage in several experimental models of liver injury. We have previously shown that protection against d-galactosamine (D-GalN) induced liver injury by prostaglandin E1 (PGE1) was accompanied by an increase in TNF-α and nitrite/nitrate in serum. AIMS The aim of the present study was to evaluate the role of TNF-α and nitric oxide during protection by PGE1 of liver damage induced by D-GalN. METHODS Liver injury was induced in male Wistar rats by intraperitoneal injection of 1 g/kg of D-GalN. PGE1 was administered 30 minutes before D-GalN. Inducible nitric oxide synthase (iNOS) was inhibited by methylisothiourea (MT), and TNF-α concentration in serum was lowered by administration of anti-TNF-α antibodies. Liver injury was evaluated by alanine aminotransferase activity in serum, and histological examination and DNA fragmentation in liver. TNF-α and nitrite/nitrate concentrations were determined in serum. Expression of TNF-α and iNOS was also assessed in liver sections. RESULTS PGE1decreased liver injury and increased TNF-α and nitrite/nitrate concentrations in serum of rats treated with D-GalN. PGE1protection was related to enhanced expression of TNF-α and iNOS in hepatocytes. Administration of anti-TNF-α antibodies or MT blocked the protection by PGE1 of liver injury induced by D-GalN. CONCLUSIONS This study suggests that prior administration of PGE1 to D-GalN treated animals enhanced expression of TNF-α and iNOS in hepatocytes, and that this was causally related to protection by PGE1against D-GalN induced liver injury.

Tumour necrosis factor-alpha and nitric oxide mediate apoptosis by D-galactosamine in a primary culture of rat hepatocytes: Exacerbation of cell death by cocultured Kupffer cells

BACKGROUND Prostaglandin E1 (PGE1) reduces cell death in experimental and clinical liver dysfunction. OBJECTIVES Whether PGE1 protects against D-galactosamine (D-GalN)-associated hepatocyte cell death by the regulation of tumour necrosis factor-alpha (TNF-alpha) and/or nitric oxide (NO) in hepatocytes or cocultured Kupffer cells was examined. METHODS Anti-TNF-alpha antibodies were used to evaluate the role of TNF-alpha during D-GalN cytotoxicity and its protection by PGE1 in cocultured hepatocytes and Kupffer cells. Cell apoptosis and necrosis were assessed by DNA fragmentation and lactate dehydrogenase release, respectively. Nitrite+nitrate (NOx), as NO end products, and TNF-alpha concentrations were measured in the culture medium. The role of NO was determined by measuring inducible NO synthase (iNOS) expression and the effect of its inhibition during d-GalN cytotoxicity and its protection by PGE1. RESULTS D-GalN enhanced hepatocyte cell death associated with high TNF-alpha and NOx levels in a culture medium. Anti-TNF-alpha and iNOS inhibition suggested that TNF-alpha was mediating apoptosis, but not necrosis, through the stimulation of NO production. The antiapoptotic activity of PGE1 was associated with a reduction of NO production, but was blocked by iNOS inhibition. This apparent contradiction was explained by the ability of PGE1 to enhance iNOS expression shortly after its administration and inhibit it later during d-GalN treatment. Anti-TNF-alpha antibodies did not reduce the exacerbation of d-GalN-associated cell death in hepatocytes by cocultured Kupffer cells. CONCLUSION TNF-alpha mediates D-GalN-induced apoptosis via NO production in cultured hepatocytes. The protective effect of PGE1 against D-GalN-induced apoptosis is probably through the induction of low iNOS expression that was followed by a reduction of iNOS expression and NO production induced by the hepatotoxin. The exacerbation of hepatocyte cell death by Kupffer cells was not related to TNF-alpha and NO.

Effect of PGE1 on TNF-α status and hepatic d-galactosamine-induced apoptosis in rats

Prostaglandin E1 has hepatoprotective properties in several clinical and experimental models of liver dysfunction. Hepatotoxicity induced by D‐galactosamine (D‐GalN) is a suitable animal model of human acute hepatic failure. The aim of the study was to investigate if prostaglandin E1 (PGE1) protection against hepatic D‐GalN‐induced apoptosis was related to tumour necrosis factor‐α (TNF‐α) content in serum. This cytokine is associated with in vitro apoptosis and general inflammatory disorders. In this study, PGE1 was administered 30 min before D‐GalN to rats. In other experiments, several doses of TNF‐α were administered 15 min after PGE1 to D‐GalN‐treated rats. Several parameters related to apoptosis and necrosis were measured by flow cytometry, gel electrophoresis, biochemical analysis, and optical and electron microscopy. Tumour necrosis factor‐α was quantified by competitive enzyme‐linked immunosorbent assay (ELISA). PGE1 by itself did not modify the cell cycle of hepato‐cytes and liver toxicity, but increased TNF‐α in serum in comparison with the control group. D‐Galactosamine increased the percentage of hepatocytes in apoptosis and in the S phase of the cell cycle, and decreased those in G0/G1. Such an increase of hepatocytes in apoptosis was correlated with a higher number of apoptotic bodies and DNA fragmentation in liver than control samples. Also, D‐GalN increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and TNF‐α in serum compared with the control group. Pre‐administration of PGE1 to D‐GalN‐treated rats reduced all the parameters of apoptosis and necrosis in liver, and increased additionally TNF‐α content in serum. In those experiments where low doses of TNF‐α were administered to PGE1 and D‐GalN‐treated rats an inverse relationship appeared between TNF‐α and ALT content in serum. In conclusion, the protective effects of PGE1 on D‐GalN‐induced apoptosis may be linked to its capacity to modulate cell division and/or its immunomodulatory activity. In this sense, our experimental results suggest that TNF‐α could be involved in protection or exacerbation of liver damage in relation to the pathophysiological status of the liver.

Diagnosis and management of bacterial infections in decompensated cirrhosis.

Bacterial infections are one of the most frequent complications in cirrhosis and result in high mortality rates. Patients with cirrhosis have altered and impaired immunity, which favours bacterial translocation. Episodes of infections are more frequent in patients with decompensated cirrhosis than those with compensated liver disease. The most common and life-threatening infection in cirrhosis is spontaneous bacterial peritonitis followed by urinary tract infections, pneumonia, endocarditis and skin and soft-tissue infections. Patients with decompensated cirrhosis have increased risk of developing sepsis, multiple organ failure and death. Risk factors associated with the development of infections are severe liver failure, variceal bleeding, low ascitic protein level and prior episodes of spontaneous bacterial peritonitis (SBP). The prognosis of these patients is closely related to a prompt and accurate diagnosis. An appropriate treatment decreases the mortality rates. Preventive strategies are the mainstay of the management of these patients. Empirical antibiotics should be started immediately following the diagnosis of SBP and the first-line antibiotic treatment is third-generation cephalosporins. However, the efficacy of currently recommended empirical antibiotic therapy is very low in nosocomial infections including SBP, compared to community-acquired episodes. This may be associated with the emergence of infections caused by Enterococcus faecium and extended-spectrum β-lactamase-producing Enterobacteriaceae, which are resistant to the first line antimicrobial agents used for treatment. The emergence of resistant bacteria, underlines the need to restrict the use of prophylactic antibiotics to patients with the greatest risk of infections. Nosocomial infections should be treated with wide spectrum antibiotics. Further studies of early diagnosis, prevention and treatment are needed to improve the outcomes in patients with decompensated cirrhosis.

Effect of internal biliary drainage on plasma levels of endotoxin, cytokines, and C-reactive protein in patients with obstructive jaundice

Preoperative biliary drainage may improve the cytokine and acute-phase response derangements observed in patients with obstructive jaundice. We conducted a prospective longitudinal, before-after trial in our 600-bed teaching hospital. Twenty-four patients with obstructive jaundice were investigated, 11 with benign obstruction and 13 with malignant disease. Endoscopic internal biliary drainage was performed in all patients (7 by papillotomy and 17 by endoprostheses). Endotoxin, tumor necrosis factor alpha (TNF-α), interIeukin-6 (IL-6), nitric oxide production, and C-reactive protein (CRP) were determined at admission and on days 2 and 7 after internal biliary drainage was accomplished. Bile cultures were obtained before and at the time of drainage. Endotoxin, IL-6, TNF-α, and CRP were significantly higher in patients with cancer. After internal drainage, endotoxin (11.4 vs. 2 EU/L; p<0.05), TNF-α (87.5 vs. 48 pg/ml; p=0.03), and IL-6 (324 vs. 232 pg/ml;/ p<0.05) plasma levels decreased significantly in the early postdrainage period in patients with cancer. Endotoxin, cytokines, as well as the CRP plasma values, however, increased again on day 7 after drainage. This trend was less marked in patients with benign obstruction. Patients with positive bile cultures after drainage displayed higher levels of CRP (115 vs. 62 mg/L; p=0.03), IL-6 (598 vs. 330 pg/ml; p=0.04), and endotoxin (10.6 vs. 4.8 EU/L; p=0.02) than those with negative bile cultures. Biliary tract obstruction is associated with an increase in endotoxin levels, a positive acute-phase response, and plasma cytokine elevation. After biliary drainage a transitory improvement of these alterations was observed, although values remained high 1 week postdrainage. These findings were associated with positive bile cultures.RésuméLe drainage biliaire préopératoire peut améliorer les perturbations des cytokines et celles observées dans la réponse de la phase aiguë chez les patients atteints d’ictère obstructif. Cette étude, prospective, longitudinale, a consisté à étudier 24 patients atteints d’ictère obstructif, 11 d’origine bénigne, 13 d’origine maligne, avant et après traitement dans un Hôpital Universitaire de 600 lits. Les interventions comportaient toujours un drainage endoscopique interne (7 papillotomies et 17 endoprothèses). On a mesuré l’endotoxine, le facteur TNF-α, l’IL-6, la production en oxyde nitrique et la C-réactive protéine (CRP) au moment de l’admission et aux jours 2 et 7 après drainage biliaire interne. Des cultures ont été obtenues avant et au moment du drainage. Les taux d’endotoxine, de l’IL-6, du TNF-α et de la CRP étaient significativement plus élevés chez les patients atteints de cancer. Après drainage interne, les taux plasmatiques de l’endotoxine (11.4 vs. 2 EU/L; p<0.05), de TNF-α (87.5 vs. 48 pg/ml; p=0.03) et d’IL-6 (324 vs. 232 pg/ml; p<0.05) ont diminué de façon significative après drainage chez les patients atteints de cancer. Les taux d’endotoxine et des cytokines tout comme les taux plasmatiques de la CRP ont cependant augmenté au jour sept. Cette tendance a été moins marquée chez les patients porteurs d’obstruction bénigne. Les patients ayant des cultures de bile positives après drainage avaient un taux postdrainage plus élevé de CRP (115 vs. 62 mg/L; p=0.03), d’IL-6 (598 vs. 330 pg/ml; p=0.04) et d’endotoxine (10.6 vs. 4.8 EU/L; p=0.02) que ceux ayant des cultures de bile négatives. L’obstruction biliaire est associée à une augmentation des taux d’endotoxines, à une réponse de phase aiguë positive et à une élévation des cytokines plasmatiques. Après drainage biliaire, on observe une amélioration transitoire de ces altérations, même si les valeurs restaient élevées une semaine après le drainage, surtout en cas de cultures de bile positives.ResumenEn pacientes ictéricos, el drenaje biliar preoperatorio parece mejorar las atocinas y las alteraciones de respuesta de la fase aguda. En un Hospital Universitario de 600 camas, se diseñó un estudio clínico prospectivo longitudinal. Se estudiaron 24 pacientes con ictericia obstructiva: La obstrucción era benigna en 11 y maligna en 13. El drenaje biliar interno se realizó por vía endoscópica (7 papilotomías y 17 endoprótesis). El día del ingreso y a los 2 y 7 días del drenaje biliar interno se determinaron: endotoxina, TNF-α, IL-6, producción de óxido nítrico y proteína C reactiva (CRP). Las endotoxina, IL-6, TNF-α y CRP estaban significativamente más elevadas en pacientes con cáncer. En pacientes cancerosos, tras drenaje interno, los niveles plasmáticos descendieron inmediata y significativamente: endotoxina (11.4 vs. 2 EU/L; p<0.05) TNF-α (87.5 vs. pg/ml; p=0.03), y IL-6 (324 vs. 232 pg/ml; p<0.05). Sin embargo, la citocina, endotoxina y los valores plasmáticos de la CRP volvieron ha elevarse al 7° día post-drenaje. Estas modificaciones fueron menores en pacientes con ictericia obstructiva benigna. Tras el drenaje, los pacientes con cultivos biliares positivos, mostraron mayores elevaciones de la CRP (115 vs. 62 mg/L; p=0.03), IL-6 (598 vs. 330 pg/ml; p=0.04) y de la endotoxina (10.6 vs. 4.8 EU/L; p=0.02), que aquellos cuyos cultivos fueron negativos. La obstrucción del colédoco se acompaña de: un incremento de los niveles de endotoxina, respuesta positiva de la fase aguda y elevación de las citocinas plasmáticas. Tras drenaje biliar se produce una mejora transitoria de las alteraciones observadas, aunque los parámetros persisten elevados transcurrida una semana del drenaje biliar. Este hecho se observó en pacientes con cultivos positivos en la bilis.

Orthotopic liver transplantation after subacute liver failure induced by therapeutic doses of ibuprofen

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Optimizing the management of patients with BCLC stage-B hepatocellular carcinoma: Modern surgical resection as a feasible alternative to transarterial chemoemolization

OBJECTIVE To analyse the impact of liver resection (LR) in patients with Hepatocellular Carcinoma (HCC) within the Barcelona-Clinic-Liver-Cancer (BCLC)-B stage. METHODS Analysis of patients with BCLC-B HCC treated with LR or transarterial chemoembolization (TACE) between 2007 and 2012 in our hospital. Survival/recurrence analyses were performed by log-rank tests and Cox multivariate models. Further analyses were specifically obtained for the HCC subclassification (B1-2-3-4) proposed recently. RESULTS Eighty patients were treated (44-TACE/36-LR). Number of nodules was [1.8(1.1)], being multinodular in 50% of cases. Although resected patients had a higher hospital stay than those who underwent TACE (14 ± 13 vs 7 ± 6; P = 0.004), the rate and severity of complications was lower measured by Dindo-Clavien scale (P < 0.05). Overall survival was 40% with a median follow-up of 29.5 months (0.07-96.9). Five-years survival rates were 62.9%, 28.1% and 15.4%, respectively (P = 0.004) for B1, B2 and B3-4 stages. Cox model showed that only total bilirubin [OR = 2.055(1.23-3.44)] and BCLC subclassification B3-4 [OR = 2.439(1.04-5.7)] and B2 [OR = 2.79(1.35-5.77)] vs B1 were independent predictors of 5-years-survival. In B1 patients, surgical approach led a significant decrease in 5-years recurrence-rate (25% vs 60%; P = 0.018). In the surgical subgroup analysis, better results were observed if well/moderate differentiation combined with no microvascular-invasion (VI) in 5-years-survival (84.6%; P = 0.001) and -recurrence (23.1%; P = 0.041), respectively. These survival and recurrence trends were remarkable in B1 stages. CONCLUSIONS Management of Intermediate BCLC-B HCC stage should be more complex and include updated criteria regarding B-stage subclassifications, VI and tumour differentiation. Modern surgical resection would offer improved survival benefit with acceptable safety in selected BCLC-B stage patients.

Clinical outcomes of patients undergoing antiviral therapy while awaiting liver transplantation

BACKGROUND & AIMS Antiviral therapy for the treatment of hepatitis C (HCV) infection has proved to be safe and efficacious in patients with cirrhosis awaiting liver transplantation (LT). However, the information regarding the clinical impact of viral eradication in patients on the waiting list is still limited. The aim of the study was to investigate the probability of delisting in patients who underwent antiviral therapy, and the clinical outcomes of these delisted patients. METHODS Observational, multicenter and retrospective analysis was carried out on prospectively collected data from patients positive for HCV, treated with an interferon-free regimen, while awaiting LT in 18 hospitals in Spain. RESULTS In total, 238 patients were enrolled in the study. The indication for LT was decompensated cirrhosis (with or without hepatocellular carcinoma [HCC]) in 171 (72%) patients, and HCC in 67 (28%) patients. Sustained virologic response (SVR) rate was significantly higher in patients with compensated cirrhosis and HCC (92% vs. 83% in patients with decompensated cirrhosis with or without HCC, p=0.042). Among 122 patients with decompensated cirrhosis without HCC, 29 (24%) were delisted due to improvement. No patient with baseline MELD score >20 was delisted. After delisting (median follow-up of 88weeks), three patients had clinical decompensations and three had de novo HCC. Only two of the patients with HCC had to be re-admitted onto the waiting list. The remaining 23 patients remained stable, with no indication for LT. CONCLUSIONS Antiviral therapy is safe and efficacious in patients awaiting LT. A quarter of patients with decompensated cirrhosis can be delisted asa result of clinical improvement, which appears to be remain stable in most patients. Thus, delisting is a safe strategy that could spare organs and benefit other patients with a more urgent need. LAY SUMMARY Antiviral therapy in patients awaiting liver transplantation is safe and efficacious. Viral eradication allows removal from the waiting list of a quarter of treated patients. Delisting because of clinical improvement is a safe strategy that can spare organs for patients in urgent need.