The Spanish Pancreatic Club recommendations for the diagnosis and treatment of chronic pancreatitis: part 1 (diagnosis).

Chronic pancreatitis (CP) is a relatively uncommon, complex and heterogeneous disease. The absence of a gold standard applicable to the initial phases of CP makes its early diagnosis difficult. Some of its complications, particularly chronic pain, can be difficult to manage. There is much variability in the diagnosis and treatment of CP and its complications amongst centers and professionals. The Spanish Pancreatic Club has developed a consensus on the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts on this disease. A list of questions was drafted, and two experts reviewed each question. Then, a draft was produced and shared with the entire panel of experts and discussed in a face-to-face meeting. This first part of the consensus addresses the diagnosis of CP and its complications.

The Spanish Pancreatic Club's recommendations for the diagnosis and treatment of chronic pancreatitis: part 2 (treatment).

Chronic pancreatitis (CP) is a complex disease with a wide range of clinical manifestations. This range comprises from asymptomatic patients to patients with disabling symptoms or complications. The management of CP is frequently different between geographic areas and even medical centers. This is due to the paucity of high quality studies and clinical practice guidelines regarding its diagnosis and treatment. The aim of the Spanish Pancreatic Club was to give current evidence-based recommendations for the management of CP. Two coordinators chose a multidisciplinary panel of 24 experts on this disease. These experts were selected according to clinical and research experience in CP. A list of questions was made and two experts reviewed each question. A draft was later produced and discussed with the entire panel of experts in a face-to-face meeting. The level of evidence was based on the ratings given by the Oxford Centre for Evidence-Based Medicine. In the second part of the consensus, recommendations were given regarding the management of pain, pseudocysts, duodenal and biliary stenosis, pancreatic fistula and ascites, left portal hypertension, diabetes mellitus, exocrine pancreatic insufficiency, and nutritional support in CP.

Update of the Atlanta Classification of severity of acute pancreatitis: should a moderate category be included?

BACKGROUND: Persistent and multiple organ failure (POF and MOF) are predictive of death in acute pancreatitis (AP). Local complications without organ failure are associated with morbidity but a low risk of mortality. AIM: To design a three-category classification of AP severity and to compare it with the Atlanta Classification (AC) in terms of morbidity and mortality. METHOD: Severe AP was defined as death, POF (>48 h) or MOF. Moderate AP was defined as the presence of acute collections and/or pancreatic necrosis. Mild AP was defined by exclusion. We compared this classification with AC in 144 episodes of AP. RESULTS: In the three-category classification, severe AP was associated with significantly more frequent intensive care unit admission, invasive treatment and mortality than moderate and mild AP (p < 0.01). Severe AP patients required longer hospital stay and more nutritional support than mild AP patients (p < 0.01). Patients with moderate AP had significantly longer hospital stay and more need for nutritional support than patients with mild AP (p < 0.01). Five patients died, all of them with MOF and/or POF. CONCLUSIONS: A three-category classification distinguishes three homogeneous groups of severity.

The existence of a relationship between increased serum alanine aminotransferase levels detected in premarketing clinical trials and postmarketing published hepatotoxicity case reports.

BACKGROUND: Drug-induced liver injury (DILI) profile in most drugs' available information is based on both the incidence of alanine aminotansferase (ALT) elevations in clinical trials and published case reports. AIM: To assess the relationship between ALT elevations in clinical trials and the number of published case reports in the postmarketing setting. METHODS: Hepatotoxic drugs were identified from product labelling and classified in high-medium risk (Black Box Warning or Precautions section) or low risk (a statement in the Adverse Reactions section). Incidence of ALT elevations (> or = 3 x ULN) for drug (I(D)) and placebo (I(C)) treated patients in premarketing clinical trials and DILI published case reports were retrieved from product labelling and MEDLINE. RESULTS: The median I(C) was 10/1000. The high-medium-risk drugs' median I(D) was significantly higher compared with low-risk drugs (17/1000 vs. 10/1000; P = 0.046). Chi-squared test, absolute difference and odds ratio comparing I(D) and I(C) identified 35%, 51% and 77% of high-medium-risk drugs respectively. Less number of case reports were associated with low- than high-medium-risk drugs (1 vs. 7; P = 0.001). A high odds ratio in clinical trials (I(D) vs. I(C)) was the strongest predictor of published DILI case reports. CONCLUSION: A relationship between increased ALT incidence in premarketing clinical trials and postmarketing published case reports exists.

Assessing the short- and long-term prognosis of patients with cirrhosis and acute variceal bleeding.

OBJECTIVE: to evaluate the efficacy of various indicators in predicting short- and long-term survival in patients with cirrhosis and acute variceal bleeding. MATERIAL AND METHODS: prognostic indicators were calculated for a cohort of 201 cirrhotic patients with acute variceal bleeding hospitalized in our center, a third-level teaching hospital. The studied variables were: age, sex, etiology of cirrhosis, endoscopic findings, previous variceal bleeding episodes, human immunodeficiency virus (HIV) infection, hepatocellular carcinoma (HCC), infection during episode, and Child-Turcotte-Pugh (CTP) and Model for End-stage Liver Disease (MELD) scores within 24 hours of bleeding onset. Patients were followed up for at least 6 months until death, liver transplantation, or end of observation. RESULTS: median follow-up was 66.85 weeks (range 0-432.4). The 6-week, 3-month, 12-month and 36-month mortality rates were 22.9, 24.9, 34.3, and 39.8%, respectively. Age >= 65 years, presence of HCC, CTP score >=10, and MELD score >= 18 were the variables associated with mortality in the multivariate analysis. The accuracy of MELD scores as predictors of 6-week, 3-month, 12-month, and 36-month mortality was better than that of CTP scores (c-statistics: 6 week MELD 0.804, CTP 0.762; 3-month MELD 0.794, CTP 0.760; 12-month MELD 0.766, CTP 0.741; 36 month MELD 0.737, CTP 0.717). CONCLUSION: MELD and CTP scores together with age and a diagnosis of hepatocellular carcinoma are useful indicators to assess the short- and long-term prognosis of patients with acute variceal bleeding.

[A cost-effectiveness study of hepatic venous pressure gradient measurement in the secondary prevention of variceal bleeding]. / Estudio coste-efectividad sobre la medición del gradiente de presión venosa hepática en la profilaxis secundaria de la hemorragia digestiva varicosa.

OBJECTIVE: variceal rebleeding is common following a first episode of hemorrhage in cirrhotic patients. The objective of this study was to determine the cost-effectiveness of monitoring hepatic venous pressure gradient (HVPG) to guide secondary prophylaxis. METHODS: we created a Markov decision model to calculate cost-effectiveness for two strategies: Group 1: HVPG monitoring to decide treatment -when portal pressure was reduced by at least 20 percent or HVPG was less than 12 mmHg after beta-blocker administration, patients received beta-blockers; when portal pressure did not meet these criteria therapy was endoscopic band ligation. Group 2: in this group there was no monitoring of HVPG. Patients with large varices received treatment with beta-blockers combined with EBL; patients with small varices received beta-blockers plus isosorbide mononitrate. RESULTS: there was no recurrent variceal bleeding in group 1 for good responders, and for 17% of poor responders. In group 2 a 25% rebleeding rate was detected in patients with small varices and 13% for those with big varices. Overall cost in group 1 was 14,100.49 euros, and 14,677.16 in group 2. CONCLUSIONS: HVPG measurement is cost-effective for the secondary prophylaxis of variceal bleeding.

Efficacy and tolerance of metamizole versus morphine for acute pancreatitis pain.

BACKGROUND/AIMS: Morphine has been contraindicated for pain treatment in acute pancreatitis because of its presumed opioid-induced sphincter of Oddi dysfunction. However, scientific evidence supporting a deleterious influence on the clinical course is absent. This pilot study was undertaken to evaluate the efficacy and adverse events of metamizole versus morphine in acute pancreatitis. METHODS: 16 patients with acute pancreatitis were randomized to receive 10 mg/4 h s.c. (n = 8) morphine or 2 g/8 h i.v. (n = 8) metamizole. Pain scores were recorded every 4 h during 48 h after admission by a Visual Analogue Scale. Pethidine was additionally administered as a rescue therapy. RESULTS: 75% of patients achieved pain relief in the metamizole group versus 37.5% in the morphine group within 24 h of hospitalization (6/8 vs. 3/8; p: n.s.). The mean time to achieve pain relief was shorter in the metamizole group (10 +/- 6.6 vs. 17 +/- 18.3 h; p: n.s.). At the end of the study, 75% of patients achieved pain relief in the metamizole group versus 50% in the morphine group. Three patients in each group needed pethidine: 2 out of 3 achieved pain control in the metamizole group vs. 0 out of 3 in the morphine group. CONCLUSIONS: Intravenous metamizole shows a non-significant association with a quicker pain relief than morphine s.c. in acute pancreatitis. A larger randomized controlled trial should be desirable to confirm this result. and IAP.

Translocation of bacterial DNA from Gram-positive microorganisms is associated with a species-specific inflammatory response in serum and ascitic fluid of patients with cirrhosis.

Translocation of bacterial-DNA in patients with cirrhosis and ascites triggers an innate immune response. Identification of characteristics to which this response is sensitive is relevant from a clinical standpoint. The aim of this study has been to determine if the proinflammatory immune response established in vivo in cirrhotic patients with ascites as a consequence of bacterial-DNA translocation is related to the identified bacterial species and their frequency of cytosine-guanosine content in serum and ascitic fluid. Patients with advanced cirrhosis and ascites were included in the study and distributed into groups I and II according to the absence or presence of bacterial-DNA translocation, respectively. Serum and ascitic fluid levels of proinflammatory cytokines after normalization of bacterial-DNA concentration and the activated form of nuclear factor-kappa B in ascitic fluid pellets were measured by enzyme-linked immunosorbent assay techniques. Translocation of bacterial-DNA with higher cytosine-guanosine content induced the highest cytokine response, which was higher than that in patients without bacterial-DNA translocation. The activated form of nuclear factor-kappa B in ascitic fluid pellets of patients with bacterial-DNA translocation was greater in patients with higher bacterial-DNA cytosine-guanosine content, whereas the amount of total nuclear factor-kappa B remained unaltered. Bacterial-DNA translocation induces a marked immune reaction in vivo in patients with advanced cirrhosis and ascites which is related, among other factors, to the bacterial-DNA cytosine-guanosine content. Therefore, the host's immune response to bacterial-DNA translocation constitutes a species-specific phenomenon.

A comparison of two different dosages of somatostatin combined with sclerotherapy for the treatment of acute esophageal variceal bleeding: a prospective randomized trial.

BACKGROUND: the association of somatostatin (SMT) with endoscopic therapy in patients with cirrhosis and variceal bleeding significantly improves the control of the bleeding episode, and hemodynamic data have shown that a dosage of 500 mg/h allows a more marked reduction of portal pressure versus the usual dosage of 250 mg/h. AIM: to assess if the 500 mg/h dosage is associated with an improved outcome. METHODS: sixty-two patients with variceal bleeding were included in the study. Patients were randomized to receive the usual dosage of SMT (group I: 250 mg/h), or a double dosage (group II: 500 mg/h), together with emergency endoscopic sclerotherapy. RESULTS: the control of the bleeding episode was similar in both groups of patients. Early rebleeding was less frequent in patients receiving double vs. single dosage of SMT (p = 0.06). When considering patients with advanced liver disease (Child-Pugh B or C) early rebleeding was significantly less frequent in patients receiving the 500 mg/h dose of SMT (39 vs. 13%, p = 0.03). CONCLUSIONS: the perfusion of higher doses of SMT (500 mg/h) in association with emergency sclerotherapy in patients with cirrhosis and esophageal hemorrhage significantly decreases the rate of early rebleeding in patients with more advanced stages of liver disease.

Functional status of beta-2-adrenoceptor in isolated membranes of mature erythrocytes from patients with cirrhosis and oesophageal varices.

Propranolol is a widely used drug for prophylaxis of variceal bleeding in patients with cirrhosis, but not all patients show an adequate clinical response. This variability may be in relation to beta adrenoceptor activity, but no information is available in this setting. Thirty-nine patients with advanced cirrhosis and presence of oesophageal varices were sequentially included. We studied the function of beta-2-adrenoceptor in isolated membranes of mature erythrocytes obtained from patients by measuring cyclic AMP (cAMP) production before and after isoproterenol. Blood samples obtained from 11 healthy volunteers were used as control. Patients showed a six-fold increase in the mean basal cAMP production as compared to healthy volunteers. Isoproterenol produced a small, non-significantly and highly variable increase in the AC activity in patients compared with controls. cAMP values remain stable after three months of continuous treatment with oral beta-blockers in both groups. Patients without antecedent of variceal bleeding or with an active alcohol intake showed a significantly higher isoproterenol effect. In conclusion, beta-receptor function in human erythrocytes membranes is altered in patients with cirrhosis and oesophageal varices.

Obesity is a definitive risk factor of severity and mortality in acute pancreatitis: an updated meta-analysis.

BACKGROUND/AIMS: Obesity is considered a risk factor in patients with acute pancreatitis. However, the relationship between obesity and mortality in this disease has not been confirmed definitively even in a previous meta-analysis. Since the publication of our previous meta-analysis, one study has been reported about the prognostic value of obesity in acute pancreatitis. We have performed a new meta-analysis to confirm the relationship between obesity and the outcome of acute pancreatitis. DATA SOURCES: A MEDLINE search using 'pancreatitis', 'obesity' and 'body mass index' as search terms. REVIEW METHODS: Clinical studies which investigated the prognostic value of obesity in acute pancreatitis with the following criteria: (a) inclusion of mild and severe acute pancreatitis; (b) use of body mass index (BMI) as the measure of obesity; (c) definition of obesity as BMI >or=30 kg/m(2); (d) definition of severity of acute pancreatitis according to the criteria established in the Atlanta Symposium. Five studies including patients with mild and severe acute pancreatitis and obesity measured by BMI were analyzed. The end points of the meta-analysis were the severity of acute pancreatitis, local complications, systemic complications and mortality. Pooled odds ratio (OR) and confidence intervals (CI) were calculated according to the Mantel-Haenszel method, and heterogeneity was assessed by the multiplicative inverse variance method. RESULTS: Seven hundred and thirty-nine patients were included. There was no heterogeneity for the variables severity, systemic complications, local complications and mortality among the included studies. Severe acute pancreatitis was significantly more frequent in obese patients (OR 2.9, 95% CI 1.8-4.6). Furthermore, those patients developed significantly more systemic (OR 2.3, 95% CI 1.4-3.8) and especially local complications (OR 3.8, 95% CI 2.4-6.6). In this new analysis, mortality was also higher in obese patients (OR 2.1, 95% CI 1.0-4.8). CONCLUSION: Obesity is not only a risk factor for the development of local and systemic complications in acute pancreatitis: it also increases the mortality of this disease.

Detection and identification of bacterial DNA in serum from patients with acute pancreatitis.

BACKGROUND AND AIMS: Bacterial infections are common complications in patients with acute pancreatitis, and translocation of bacteria from the intestinal lumen is probably the first step in the pathogenesis of these infections. As blood cultures in afebrile patients are usually negative, more sensitive methods to investigate this hypothesis in patients are needed. Our group has recently developed a method to detect the presence of bacterial DNA in biological fluids, and we aimed to detect bacterial DNA in patients with acute pancreatitis, as molecular evidences of bacterial translocation. METHODS: Samples of blood were obtained on three consecutive days within the first six days after admission. Bacterial DNA was detected using a polymerase chain reaction based method, and an automated DNA nucleotide sequencing process allowed identification of bacteria species. RESULTS: Thirty one consecutively admitted patients with acute pancreatitis were studied. Bacterial DNA was detected in six patients (19.3%), and the sequencing process allowed identification of Citrobacter freundii and Pseudomonas aeruginosa. In two patients the same bacteria detected at admission was detected 24 hours later (above 99.9% homology of nucleotide sequence). Basic clinical and biochemical characteristics were similar among patients with or without the presence of bacterial DNA. CONCLUSION: Detection of gram negative bacteria derived bacterial DNA in our series supports the contention that bacterial translocation is a systemic process in approximately 20% of patients with acute pancreatitis that does not seem to be related to the severity of the episode or immediate development of infection.

Antibodies to carbonic anhydrase and IgG4 levels in idiopathic chronic pancreatitis: relevance for diagnosis of autoimmune pancreatitis.

BACKGROUND: Increased serum antibodies against carbonic anhydrase II (CA-II Ab) or IgG4 levels have been reported in cases of autoimmune chronic pancreatitis (ACP). AIM: To assess the relevance of serum CA-II Ab and IgG4 levels for the diagnosis of ACP in idiopathic CP (ICP) versus alcoholic CP and Sjogren's syndrome (SS). SUBJECTS: This was a multicentre study involving 227 subjects divided into four groups: ICP (n = 54), normal controls (n = 54, paired by age and sex with ICP patients), alcoholic CP (n = 86), and SS (n = 33). METHODS: CA-II Ab was measured by ELISA and confirmed by western blotting. A score of easy clinical use with major clinical, morphological, and biochemical parameters for the diagnosis of ACP was applied. RESULTS: The percentage of patients with increased serum CA-II Ab was higher in the ICP group (28%) than in controls (1.9%) and in patients with alcoholic CP (10.5%), but lower than in patients with SS (64%). The proportion with elevated IgG4 levels was higher in the ICP group (15%) compared with controls (1.9%) and SS (0%) but not significantly different from alcoholic CP (8%). Most ICP patients (7/8) with high IgG4 levels exhibited increased CA-II Ab and a compatible ACP score. A definitive diagnosis of ACP by histological analysis was associated with other autoimmune disorders, an increase in both serum IgG4 and CA-II Ab levels, and IgG4 positive plasma cells. CONCLUSIONS: The increase in serum IgG4 levels was strongly associated with elevated CA-II Ab levels, manifestations compatible with ACP, and lymphoplasmacytic infiltration when surgical specimens were available.

Norfloxacin decreases bacterial adherence of quinolone-resistant strains of Escherichia coli isolated from patients with cirrhosis.

BACKGROUND: Long-term administration of norfloxacin is recommended for secondary prophylaxis of spontaneous bacterial peritonitis in cirrhosis, but it may be associated with the development of quinolone-resistant bacteria in stools. However, these bacteria rarely cause infections. AIM: To assess bacterial adherence of either quinolone-sensitive or -resistant Escherichia coli obtained from stools of cirrhotic patients, as one of the main virulence factors, and its variations when sub-minimum inhibitory concentration of norfloxacin were added to the medium. METHODS: E. coli strains were co-cultured with oral epithelial cells obtained from patients in presence/absence of norfloxacin. Bacterial adherence was measured as percentage of cells exhibiting positive adherence and the number of bacteria attached to epithelial cells. RESULTS: 37 sensitive and 22 resistant E. coli strains were studied. Bacterial adherence was similar in both series (78% vs. 81%, P = N.S.), and these percentages were similarly and significantly reduced when subminimum inhibitory concentration of norfloxacin was added to the culture medium (P < 0.001). CONCLUSIONS: Bacterial adherence of E. coli obtained from patients with cirrhosis is unrelated to the sensitivity/resistance to quinolones, and is similarly reduced in both cases when subminimum inhibitory concentration of norfloxacin is added to the medium.

[Primary linitis plastica of the rectum]. / Linitis plástica de recto primaria.

Linitis plastica of the rectum is an uncommon entity that is difficult to diagnose due to the lack of mucosal lesions on endoscopy, the low diagnostic yield of biopsy and non-specific findings of barium radiology and computerized tomography. Rectal endoscopic ultrasonography has had a radical impact on the differential diagnosis of stenosing lesions of the rectum, among them linitis plastica, allowing diagnosis of this lesion even in patients with negative results of biopsy.

Pharmacokinetic variations of acetaminophen according to liver dysfunction and portal hypertension status.

AIM: To study the pharmacokinetic and metabolism profiles of a single dose of acetaminophen in patients with cirrhosis. METHODS: Oral acetaminophen (1000 mg) was administered to seven healthy subjects and 14 patients with cirrhosis (nine Child-Pugh A or B and five Child-Pugh C grade), being five without and nine with oesophageal varices. Plasma levels of acetaminophen and its metabolites were determined by HPLC. RESULTS: Patients showed a higher mean area under the curve concentration-time (67.4 +/- 22.4 mg h/L vs. 38.8 +/- 4.3 mg h/L; P = 0.01), a lower clearance (166.7 +/- 85.0 mL/min vs. 367.8 +/- 62.5 mL/min; P = 0.01) and higher elimination half-life (3.8 +/- 1.1 h vs. 2.0 +/- 0.4 h; P = 0.01) of acetaminophen than healthy volunteers. The appearance in blood and the urinary excretion of metabolites in patients did not differ from healthy subjects. Absorption profile was faster in patients. Patients with lower mean and systolic arterial pressure had lower AUC of acetaminophen, independently of liver dysfunction stage. CONCLUSIONS: Patients with cirrhosis had a higher AUC and lower clearance of acetaminophen. Acetaminophen attained earlier therapeutic concentrations in patients with oesophageal varices. Mean and systolic arterial pressures were significantly associated with AUC suggesting the importance of the haemodynamic function on the pharmacokinetics of acetaminophen in patients with cirrhosis.