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.

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.

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.

[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.

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.

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.

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.

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.

Chylothorax in cirrhosis of the liver: analysis of its frequency and clinical characteristics.

OBJECTIVES: To ascertain the frequency and to describe the clinical and biochemical features of cirrhotic chylothorax. DESIGN: A descriptive clinical study. SETTING: A community teaching hospital. PATIENTS AND METHODS: Since November 1989 to October 1995, 809 patients with pleural effusions were studied by thoracentesis. Pleural effusions with a concentration of triglycerides higher than 110 mg/dL, a pleural fluid to serum triglyceride ratio higher than 1, and a pleural fluid to serum cholesterol ratio lower than 1 were considered chylothorax. RESULTS: Twenty-four patients had pleural effusions that complied with all three aforementioned biochemical conditions. Five of these 24 patients (20%), were found to have liver cirrhosis as the main cause of chylothorax and in 3 of them, an abdominal source of the effusion could be demonstrated by intraperitoneal injection of a radioisotope (99mTc-sulfur colloid). The cirrhotic chylous effusions had significantly lower (p<0.005) protein (median, 1.7; range, 1.4 to 2.7 g/dL), lactate dehydrogenase (LDH) (median, 96; range, 77 to 138 IU/L), and cholesterol (median, 25; range, 22 to 64 mg/dL) levels than chylous effusions resulting from other causes (protein: median, 4.1; range, 1.7 to 6.8 g/dL; LDH: median, 351; range, 140 to 8,600 IU/L; and cholesterol: median, 87; range, 38 to 160 mg/dL). Cirrhotic chylothorax was always a transudate according to Light's criteria. CONCLUSIONS: Chylothorax is a rare and apparently underappreciated manifestation of cirrhosis resulting from transdiaphragmatic passage of chylous ascites. Its uniform biochemical characteristics can facilitate its separation from chylous effusions of different etiology, therefore avoiding potentially harmful diagnostic and therapeutic procedures.

Obesity: a prognostic factor of severity in acute pancreatitis.

This study was conducted to assess the prognostic value of obesity in acute pancreatitis and to determine the role played by obesity-associated diseases in the course of the disease. We prospectively studied 49 patients with acute pancreatitis who were divided into three groups according to their body mass index (BMI). There were 22 patients in group I (BMI < or = 25 kg/m2, normal or low weight); 15 in group II (BMI >25 and < or = 29 kg/m2, overweight); and 12 in group III (BMI >29 kg/m2, obese). Other anthropometric parameters also were measured. The severity of pancreatitis was assessed according to the Atlanta classification system. Systemic complications were significantly more common among obese than nonobese patients (p < 0.05). Patients with severe pancreatitis had a higher body-fat percentage, measured by the subscapular skin-fold thickness, and a larger abdominal circumference than patients with mild pancreatitis. Although hypertensive or diabetic patients developed more systemic complications, the multivariate analysis demonstrated that the presence of these underlying diseases did not modify the prognostic role of obesity in acute pancreatitis. We conclude that obesity is a prognostic factor of outcome in acute pancreatitis. Obesity-associated diseases do not vary the prognostic value of obesity. It seems that truncal adiposity is the kind of obesity related to worse outcome of acute pancreatitis.

Effect of diltiazem on pentagastrin-induced gastric secretion in man.

The effects of diltiazem on pentagastrin-induced gastric secretion were studied in 11 normal volunteers. Diltiazem 60 mg thrice daily for 10 doses did not produce any clear-cut effect on the increase in gastric acidity induced by either standard or low doses of pentagastrin. Despite the role of calcium on gastric secretion, diltiazem does not show promise as an agent capable of reducing gastric acidity.

Diltiazem in the treatment of the irritable bowel syndrome.

A short-term double-blind study has been conducted to evaluate the clinical efficacy of diltiazem in 18 patients with irritable bowel syndrome, divided into two groups: group A, on the sequence placebo-diltiazem-placebo for three weeks. Group B, diltiazem-placebo-diltiazem for an identical period. The substance was administered in three daily doses of 60 mg prior to meals. Clinical manifestations and the general condition were evaluated after each period of three weeks following a pre-established score. Globally, it has been impossible to demonstrate the superiority of diltiazem over the placebo, but there seems to exist a trend to the improvement of diarrhoea and abdominal pain. It will be necessary to make an additional study to delineate the efficacy of this drug in the irritable bowel syndrome.

Effect of different doses of S-adenosyl-L-methionine on paracetamol hepatotoxicity in a mouse model.

This study investigated the hepatoprotective effects of N-acetylcysteine and different doses of S-adenosyl-L-methionine after a single intraperitoneal overdose of paracetamol in mice. Plasma concentrations of paracetamol metabolites were also determined. Female mice (Souris OFl strain) 16 weeks old and weighing 30 g were fasted for 18 h prior to intraperitoneal (i.p.) administration of 375 mg/kg (2.5 mmol/kg) of paracetamol. Experimental subgroups included mice administered paracetamol only (control group), those given of N-acetylcysteine 1 g/kg (6.13 mmol/kg) i.p. immediately after paracetamol overdose (T0) and 6 h after dosing (T6) and those administered S-adenosyl-L-methionine at doses of 20 mg/kg (0.05 mmol/kg) and 1 g/kg (2.5 mmol/kg) i.p. at T0 and T6. Twenty-four hours after paracetamol overdose, mortality and liver necrosis were significantly lower (p < 0.01) in mice treated with 2.5 mmol/kg of S-adenosyl-L-methionine and N-acetylcysteine at T0 as compared with the remaining subgroups. Plasma ALT concentrations were significantly lower (p < 0.01) in mice treated with 2.5 mmol/kg of S-adenosyl-L-methionine than in those given N-acetylcysteine. Plasma concentrations of paracetamol metabolites showed an increase in the glucuronide conjugate and a decrease in the mercapturic acid conjugate in N-acetylcysteine-treated mice and an overall decrease in the conjugation pathway without changes in the oxidative pathway in S-adenosyl-L-methionine-treated animals. We conclude that S-adenosyl-L-methionine at doses of 1 g/kg (2.5 mmol/kg) i.p. was equally effective as 1 g/kg (6.13 mmol/kg) N-acetylcysteine for preventing hepatotoxicity after paracetamol overdose in mice. S-adenosyl-L-methionine may be a therapeutic alternative to N-acetylcysteine as an antidote for poisoning with paracetamol.

Abnormalities in the metabolism of acetaminophen in patients infected with the human immunodeficiency virus (HIV).

The urinary concentration of acetaminophen and its glucuronide, sulphate, cysteine, and mercapturate conjugates was measured by high-performance liquid chromatography in 32 healthy volunteers, 9 untreated symptom-free HIV-seropositive subjects, and 19 patients with AIDS after a single oral dose of 1.5 g of acetaminophen. The concentration of the glucuronide conjugate was significantly lower in AIDS patients when simultaneously compared with concentrations found in healthy individuals and symptoms-free HIV-seropositive subjects. Differences between healthy volunteers and symptom-free HIV seropositives were not encountered. By contrast, urinary concentrations of sulphate and oxidation pathway-derived metabolites were significantly higher in AIDS patients as compared with the other two groups. When AIDS patients treated with zidovudine were compared with those not given this medication, differences in the urinary excretion of acetaminophen and its metabolites were not observed. However, the urinary concentration of mercapturic acid was significantly higher in those given enzyme inducers, such as rifampicin or phenytoin, than in AIDS patients not treated with these drugs. In summary, patients with advanced HIV infection showed reduced acetaminophen glucuronidation and increased formation of the hepatotoxic oxidation metabolites, which was independent of zidovudine therapy.

Liver damage and plasma concentrations of paracetamol and its metabolites after paracetamol overdosage in mice.

The effects of single oral and intraperitoneal (i.p.) overdoses of paracetamol (500 mg/kg) were studied in mice. The correlation between hepatocellular damage and plasma levels of paracetamol metabolites derived from the oxidative pathway were also investigated. Animals were killed at different intervals (1, 2.5 and 6 h) after drug administration. Plasma concentrations of paracetamol and its sulphate, glucuronide, cysteine and mercapturate conjugates were determined by HPLC. Paracetamol plasma levels were significantly higher at 1 and 2.5 h after i.p. administration as compared to oral administration (p = 0.01 and p = 0.02, respectively). Plasma levels of mercapturic acid conjugate were significantly higher at 6 h after i.p. administration (p = 0.04). After 6 h, animals given oral paracetamol showed significantly less necrosis than animals given i.p. paracetamol (p = 0.03). Plasma levels of mercapturate conjugate at 6 h showed a significant correlation with the severity of liver necrosis (r = 0.64; p = 0.02). The results suggest that i.p. paracetamol seems to be more adequate for hepatotoxicity studies in mice.

[A critical analysis of clinical trials in acute pancreatitis published between 1983 and 1989]. / Análisis crítico de los ensayos clínicos en pancreatitis aguda publicados entre 1983 y 1989.

BACKGROUND: The aim of the study was a critical review of recent clinical trials in acute pancreatitis (AP) to draw recommendations for future studies. METHODS: The pharmacological clinical trials in AP reported in English from 1983 to 1989 were identified through a computer assisted Medline search, and a manual review of the references in the initial articles. In addition to the characteristics of the studies, the results on the clinical variables were also recorded. In case of negative results, the power of the study to detect 50% reductions in mortality and complications was also calculated. RESULTS: In the 12 identified studies 10 different drugs were used. Only 58% were double blind. The interval between the onset of symptoms and therapy was not specified in eight studies (67%) and was two days or longer in the rest. In six studies (50%), the duration of treatment was very short (less than three days). Except in two studies, mild forms of AP predominated. Some clinical efficacy of 5-FU, TRH and CaNa2-ED-TA was reported, although with small relevance. In no trial any beneficial effects on mortality or complications were found, although the statistical power was in general low, and therefore a false negative result cannot be excluded. CONCLUSIONS: The guidelines for clinical trials in AP should be unified, particularly regarding the type of study, inclusion criteria and duration of treatments. Some treatments may be too early discarded owing to false negative results due to small sample size.