Risk of acute liver injury associated with the use of drugs: a multicentre population survey.

BACKGROUND: Acute liver injury of uncertain aetiology is often drug related and quantitative information about the associated risk is scarce. AIM: To estimate the risk of acute liver injury associated with the use of drugs. METHODS: In a population survey study, 126 cases of acute liver injury were prospectively assembled from January 1993 to December 1999, in patients over 15 years of age, in 12 hospitals in Barcelona (Spain). We estimated the relative risk for each drug as the ratio between the incidence of acute liver injury among the exposed population to the drug and the incidence of acute liver injury among those not exposed to it. Drug consumption data were used to estimate the exposed population. RESULTS: Isoniazid, pyrazinamide, rifampicin, amoxicillin with clavulanic acid, erythromicin, chlorpromazine, nimesulide, and ticlopidine presented the highest risk (point relative risk > 25). Amoxicillin, metoclopramide, captopril and enalapril, furosemide, hydrochlorothiazide, fluoxetine, paroxetine, diazepam, alprazolam, lorazepam, metamizole, low-dose acetylsalicylic acid and salbutamol showed the lowest risk (point relative risk < 5). CONCLUSIONS: This study provides a risk estimation of serious liver disease for various drugs that will be useful in its diagnosis and management, and when comparing with the drug therapeutic benefit in each indication. Some observed associations would be worth specific studies.

Predictive model of mortality in patients with spontaneous bacterial peritonitis.

BACKGROUND: Hospital mortality in patients with spontaneous bacterial peritonitis (SBP) is high despite albumin treatment, particularly in those with worse liver and/or renal function. AIM: To determine the independent predictive factors of in-hospital mortality and to create and validate a predictive model of mortality in patients with SBP. METHODS: We analysed all cirrhotic patients with high-risk SBP (serum urea ≥11 mmol/L and/or serum bilirubin ≥68 µmol/L) between 2001 and 2011. We developed a predictive model of in-hospital mortality and validated this in a different cohort. RESULTS: We included 118 high-risk SBP episodes treated with antibiotics and albumin. In-hospital mortality was 33/118 (28%). The independent predictive factors of in-hospital mortality at SBP diagnosis were serum urea, blood leucocyte count, Child-Pugh score and mean arterial pressure. A predictive model including these four variables showed a discrimination accuracy (AUC) of 0.850, 95% CI 0.777-0.922. A cut-off point of 0.245 showed a sensitivity of 0.85 and specificity of 0.75. The in-hospital mortality was 28/49 (57.1%) in patients with a model value ≥0.245, and 5/69 (7.2%) in patients with a model value <0.245 (P < 0.001). The validation series included 161 patients with an in-hospital mortality of 40/161 (24.8%), 30/77 (39.0%) in patients with a model value ≥0.245, and 10/84 (11.9%) in those with a model value <0.245 (P < 0.001). CONCLUSIONS: We developed and validated a predictive model of mortality that includes serum urea, blood leucocyte count, Child-Pugh score and mean arterial pressure in high-risk patients with spontaneous bacterial peritonitis. These findings may help to identify patients who would benefit from additional therapeutic strategies.

[Endoscopic cytology in the diagnosis of carcinoma of Vater's ampulla]. / Citología endoscópica en el diagnóstico de carcinoma de la ampolla de Vater.

An endoscopic cytology procedure was performed in 25 patients with a final diagnosis of carcinoma of the ampulla of Vater. A diagnosis of malignancy was made cytologically in 22 instances, and in 9 patients cytology was the only positive finding before operation. In two cases endoscopic biopsy was positive while the cytologic examination did not confirm the histological diagnosis.

[Spontaneous bacterial peritonitis: a comparative study of 2 methods of ascitic fluid culture]. / Peritonitis bacteriana espontánea: estudio comparativo de dos métodos de cultivo del líquido ascítico.

The sensitivity in the diagnosis of spontaneous bacterial peritonitis of ascitic fluid inoculation in blood culture bottles has been compared with the conventional method. We have analyzed 74 positive ascitic fluid cultures from 64 patients, the samples being processed by both techniques simultaneously. While all the ascitic fluid cultures performed by inoculation in blood culture bottles were positive, in only 42 from the 74 conventional cultures (56, 75%) bacterial growth was detected (p less than 0.001). Nineteen bacterascites were diagnosed by inoculation in blood culture bottles and 10 by the conventional method (p = NS). Gram stain was only positive in 3 spontaneous bacterial peritonitis (6%). We conclude that ascitic fluid inoculation in blood culture bottles improves significantly the sensitivity of the microbiological diagnosis of spontaneous bacterial peritonitis, without increasing the diagnosis of bacterascites.

[An analysis of hospital bacterial infections in cirrhotic patients undergoing selective intestinal decontamination]. / Análisis de las infecciones bacterianas intrahospitalarias en pacientes cirróticos sometidos a descontaminación intestinal selectiva.

Cirrhotic patients with ascites and low levels of ascitic fluid C3 and total protein and cirrhotic patients with gastrointestinal hemorrhage are at high risk of infection. Selective intestinal decontamination with oral norfloxacin is useful to decrease the incidence of infections in cirrhotic patients at high risk. This study analyzes hospital acquired bacterial infections in cirrhotic patients with ascites and low levels of total protein in ascitic fluid (n = 53) and cirrhotic patients with gastrointestinal hemorrhage (n = 26), both submitted to selective intestinal decontamination with norfloxacin during the hospitalization. Seven patients developed eight infections (8.8%): three patients with ascites and low levels of total protein in ascitic fluid and four patients with gastrointestinal hemorrhage (5.6% vs 15.3%, pNS). Gram negative bacilli were not isolated in any case, but Gram positive cocci were isolated in seven cases. These results suggest that Gram positive cocci must be empirically covered when infection is suspected in cirrhotic patients submitted to selective intestinal decontamination. The analysis of antibiograms in these infections showed a high sensitivity of Gram positive cocci to amoxycillin and clavulanic acid, which could be used as empirical treatment when infection is suspected in these patients.

[Value of ultrasonography in the early diagnosis of hepatocellular carcinoma]. / Valor de la ecografía en el diagnóstico precoz del carcinoma hepatocelular.

The size and the treatment of 135 hepatocellular carcinomas (HCC) has been analyzed, comparing patients diagnosed by a US screening program (group 1) and these diagnosed outside this program (group 2) to determine whether US screening on patients with chronic liver disease is able to diagnose (HCC) at an early stage. alpha-fetoprotein levels above 500 U/ml were considered as diagnostic. Twenty (46.5%) out of 43 patients from group 1 showed a HCC < 5 cm. vs. 14/92 (15.2%) in group 2 (p = 0.001). Only 5.9% of the HCC < 5 cm. showed AFP > 500 U/ml. vs. 29.7% of the advanced HCC (p = 0.003). 88.3% of patients of group 1 vs. 63% of group 2 received specific treatment for HCC (p = 0.002). By means of US screening it is possible to diagnose HCC of smaller size and more susceptible to treatment. AFP is not useful in the early diagnosis of HCC.

[The duration of the effect of norfloxacin on the fecal flora in cirrhosis patients]. / Duración del efecto de la norfloxacina sobre la flora fecal en pacientes cirróticos.

The aim of the study has been to assess if intermittent treatment with norfloxacin could be able to maintain selective intestinal decontamination in cirrhotic patients in order to prevent bacterial infections. Group I (n = 10, subgroup Ia, n = 5, hospitalized cirrhotics, subgroup Ib, n = 5, outpatient cirrhotics) received 400 mg/24 h norfloxacin 7 days. Group II (n = 5, outpatient cirrhotics) received 400 mg/12 h norfloxacin 7 days. Gram-negative aerobic bacilli of the fecal floral were strongly suppressed in all patients at the end of the treatment, and they totally (Group I) or partially (Group II) recovered the initial concentrations 7 days after the end of the treatment. There were not significant differences between subgroups Ia and Ib. These results suggest that prophylactic treatment with norfloxacin in cirrhotic patients at high risk of infection should be continuous during the period in whom patients must be submitted to selective intestinal decontamination.

[Genotype and phenotypic expression of hereditary hemochromatosis in Spain]. / Genotipo y expresión fenotípica de la hemocromatosis hereditaria en España.

INTRODUCTION: The prevalence of C282Y homozygosity in patients with hereditary hemochromatosis (HH) has been reported to be markedly lower in the Mediterranean Basin than in northern Europe. In Spain, the available data are contradictory and limited to small series in specific regions. The objective of this study is to determine the prevalence of the 2 main HFE gene mutations in a large series of unrelated Spanish patients with HH from different geographical origins. PATIENTS AND METHOD: The criteria for HH diagnosis were: repeat serum transferrin saturation index (> 45% plus C282Y homozygosity and/or hepatic iron index (> 1.9 of dry liver weight in non-cirrhotic patients or (> 4.1 in patients with liver cirrhosis. Cases in related individuals were excluded. Demographic data, clinical expression, iron parameters and HFE gene mutations (C282Y and H63D) were assessed in 222 patients. RESULTS: A total of 83.3% of patients were C282Y homozygous and 5% were compound heterozygous (C282Y/H63D). No significant differences in phenotypic expression or in the frequency of C282Y homozygosity were observed between patients born in the North and South of Spain. CONCLUSION: The genotypic and phenotypic expression of HH in Spain is very similar to that reported in Northern Europe. Thus, the genetic heterogeneity described in some Southern European regions cannot be considered a common feature to all countries of the Mediterranean Basin.

Bacterial DNA in the diagnosis of spontaneous bacterial peritonitis.

BACKGROUND: Despite inoculation into blood culture bottles, ascitic fluid culture is negative in 50% of cases of spontaneous bacterial peritonitis (SBP). AIM: To determine whether 16S rDNA gene detection by real-time polymerase chain reaction (PCR) and sequencing increases the efficacy of culture in microbiological diagnosis of spontaneous bacterial peritonitis. METHODS: We prospectively included 55 consecutive spontaneous bacterial peritonitis episodes in cirrhotic patients, 20 cirrhotic patients with sterile ascites and 27 patients with neoplasic ascites. Ascitic fluid was inoculated into blood culture bottles at the bedside and tested for bacterial DNA by real-time PCR and sequencing of 16S rDNA gene. RESULTS: Bacterial DNA was detected in 23/25 (92%) culture-positive SBP, 16/30 (53%) culture-negative SBP (P = 0.002 with respect to culture-positive SBP), 12/20 (60%) sterile ascites (P = 0.01 with respect to culture-positive SBP) and 0/27 neoplasic ascites (P < 0.001 with respect to other groups). Sequencing identified to genus or species level 12 culture-positive SBP, six culture-negative SBP and six sterile ascites. In the remaining cases with positive PCR, sequencing did not yield a definitive bacterial identification. CONCLUSIONS: Bacterial DNA was not detected in almost half the culture-negative spontaneous bacterial peritonitis episodes. Methodology used in the present study did not always allow identification of amplified bacterial DNA.

Toll-like receptor 4 D299G polymorphism and the incidence of infections in cirrhotic patients.

BACKGROUND: Toll-like receptor (TLR) 4 genetic polymorphisms, mainly D299G, have been associated with increased predisposition to infection in several populations. AIM: To retrospectively analyse the relationship between the presence of the TLR4 D299G polymorphism and the incidence of bacterial infections in cirrhotic patients. METHODS: We included 111 consecutive cirrhotic patients hospitalized with ascites and we determined the presence of the TLR4 D299G polymorphism by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) and its relationship with the incidence of previous bacterial infections. RESULTS: Ten out of 111 (9%) cirrhotic patients presented with the TLR4 D299G polymorphism. The mean follow-up from first decompensation of cirrhosis until current admission was longer in D299G polymorphism patients than in wild-type patients (53.8 +/- 40.7 vs. 35.4 +/- 48.3 months, P = 0.03). D299G polymorphism patients showed a trend towards a higher incidence of history of previous infections (80% vs. 56.4%, P = 0.19), as well as a higher number of infections (2.8 +/- 2.3 vs. 1.0 +/- 1.3, P = 0.01) and bacteriaemias (0.4 +/- 1.0 vs. 0.04 +/- 0.2, P = 0.02) per patient than wild-type patients. CONCLUSIONS: Toll-like receptor 4 D299G polymorphism could influence not only the predisposition to bacterial infections but also the evolution of the disease in cirrhotic patients. Further prospective studies in larger series of patients are warranted.

Clinical trial: a randomized controlled study on prevention of variceal rebleeding comparing nadolol + ligation vs. hepatic venous pressure gradient-guided pharmacological therapy.

BACKGROUND: Hepatic venous pressure gradient (HVPG) monitoring of therapy to prevent variceal rebleeding provides strong prognostic information. Treatment of nonresponders to beta-blockers +/- nitrates has not been clarified. AIM: To assess the value of HVPG-guided therapy using nadolol + prazosin in nonresponders to nadolol + isosorbide-5-mononitrate (ISMN) compared with a control group treated with nadolol + ligation. METHODS: Cirrhotic patients with variceal bleeding were randomized to HVPG-guided therapy (n = 30) or nadolol + ligation (n = 29). A Baseline haemodynamic study was performed and repeated within 1 month. In the guided-therapy group, nonresponders to nadolol + ISMN received nadolol and carefully titrated prazosin and had a third haemodynamic study. RESULTS: Nadolol + prazosin decreased HVPG in nonresponders to nadolol + ISMN (P < 0.001). Finally, 74% of patients were responders in the guided-therapy group vs. 32% in the nadolol + ligation group (P < 0.01). The probability of rebleeding was lower in responders than in nonresponders in the guided therapy group (P < 0.01), but not in the nadolol + ligation group (P = 0.41). In all, 57% of nonresponders rebled in the guided-therapy group and 20% in the nadolol + ligation group (P = 0.05). The incidence of complications was similar. CONCLUSIONS: In patients treated to prevent variceal rebleeding, the association of nadolol and prazosin effectively rescued nonresponders to nadolol and ISMN, improving the haemodynamic response observed in controls receiving nadolol and endoscopic variceal ligation. Our results also suggest that ligation may rescue nonresponders.

Spontaneous bacterial peritonitis.

Spontaneous bacterial peritonitis (SBP) is considered a bacterial infection of ascitic fluid without any intraabdominal, surgically treatable source of infection. Multiple variants of this infection with a different clinical setting and outcome have been described during the past decade. Bacterial translocation from the gut to mesenteric lymph nodes, depressed activity of the reticuloendothelial phagocytic system and decreased antimicrobial capacity of ascitic fluid seem to be the main steps in the pathogenesis of ascitic fluid infection. Diagnosis of ascitic fluid infection is based on clinical suspicion and analysis of ascitic fluid, especially white cell count and culture in blood culture bottles. A low threshold for performing an abdominal paracentesis is the key for an early diagnosis and treatment. A third-generation cephalosporin is the treatment of choice, achieving a cure rate higher than 80%. Nonazotemic patients with nonadvanced, uncomplicated SBP may be treated with oral ofloxacin. Prophylactic selective intestinal decontamination with oral norfloxacin is extremely useful in preventing SBP in patients that are at high risk for developing SBP, such as hospitalized cirrhotic patients with gastrointestinal hemorrhage or low ascitic fluid total protein. Primary or secondary long-term prophylaxis of SBP also decreases the incidence of SBP, but these patients should be carefully observed for detecting possible infections caused by quinolone-resistant organisms. Since long-term prognosis of SBP patients is poor, survivors should be considered for liver transplantation.

Spontaneous bacterial peritonitis: pathogenesis, diagnosis, and management.

Spontaneous bacterial peritonitis (SBP) is a common and potentially fatal complication of cirrhosis. Multiple variants of this infection have been described during the past decade; each has a slightly different clinical setting and outcome. The pathogenesis of spontaneous ascitic fluid infection appears to involve translocation of bacteria from the gut to the mesenteric lymph nodes, depressed reticuloendothelial phagocytic activity, and deficient ascitic fluid antibacterial activity. A high index of suspicion of this infection and a low threshold for performing an abdominal paracentesis are required to detect infection early, when survival is most likely. The diagnosis of SBP is based on ascitic fluid analysis, specifically polymorphonuclear cell count and culture (in blood culture bottles). Treatment with a third-generation cephalosporin achieves a cure rate in more than 80% of patients. Despite the improvement in short-term survival during the last decade, the long-term prognosis of cirrhotic patients who survive an episode of SBP remains poor because of the severity of the underlying liver disease and the high rate of recurrence of infection. Selective intestinal decontamination to prevent SBP should be considered in patients at high risk for development of this infection, including hospitalized cirrhotic patients with gastrointestinal hemorrhage or with low ascitic fluid total protein concentration. Because SBP is a marker for poor prognosis in patients with cirrhosis, survivors of an episode of this infection should also be considered for liver transplantation.

Comparison of the antacid properties of almagate and aluminium hydroxide against pentagastrin-induced gastric secretion in healthy volunteers.

The potency of a new antacid, almagate (hydrated aluminium-magnesium hydroxycarbonate, Al2Mg6 (OH)14(CO3)2 X 4 H2O, Almax) has been compared with that of aluminium hydroxide in neutralizing pentagastrin-induced hyperacidity in healthy human volunteers. Almagate (1 g) produced a significantly (p less than 0.01) greater reduction (87.5%) in the titratable acid content of gastric aspirates than did an identical dose of aluminium hydroxide (45.1%). Similarly the pepsin proteolytic activity in the samples of gastric juice was reduced 58.9% by almagate and only 27.5% by aluminium hydroxide. Furthermore the neutralizing effect of almagate was more prolonged (90 min) than that of the standard antacid (30 min) and these first studies in man have therefore confirmed the findings of in vitro and in vivo preclinical experiments.

Escherichia coli capsular polysaccharide and spontaneous bacterial peritonitis in cirrhosis.

Spontaneous bacterial peritonitis (SBP) is a frequent and severe complication of cirrhosis. Escherichia coli is the most frequent bacterium isolated in this condition. The presence of capsular antigens, mainly the K1 capsular polysaccharide, has been associated with invasiveness in E coli infections. Capsular serotypes of E coli causing SBP were determined in 37 cirrhotic patients. Twenty-seven strains were encapsulated (72.9%), 9 of them (24.3%) with K1 capsular polysaccharide, and 10 were nonencapsulated. Patients with encapsulated E coli showed a significantly higher incidence (92.5% vs. 50%; P < .01) and number of complications per patient (1.9 +/- 1.1 vs. 0.8 +/- 1.0; P < .01) than patients with nonencapsulated strains. Although mortality was higher in patients with encapsulated strains (44.4% vs. 20%), the difference did not reach statistical significance. Considering patients infected by encapsulated strains, the incidence of complications and mortality were similar in patients with or without K1 strains. These data suggest that the presence of encapsulated strains could have a prognostic significance in SBP caused by E coli in cirrhotic patients.