Mercaptopurine rescue after azathioprine-induced liver injury in inflammatory bowel disease.

BACKGROUND: Azathioprine (AZA) liver toxicity arises in approximately 3% of inflammatory bowel disease patients and may result in treatment discontinuation. AIM: To describe the tolerance to mercaptopurine (MP) in patients with previous AZA-related liver injury. METHODS: Retrospective description of 31 patients (14 Crohn's, 17 ulcerative colitis), in which AZA therapy was interrupted because of liver injury, with MP started as alternative therapy. RESULTS: Mean AZA dose was 2.2 +/- 0.4 mg x kg/day. Median (interquartile range) of AZA exposure when liver injury was detected was 2 months (1-5.2). The type of AZA-related injury was cytolitic in 32%, cholestatic in 39% and mixed in 29%. After a median of 2.5 months (0.7-5.2), the therapy was switched to MP at a mean dose of 1.3 +/- 0.2 mg x kg/day. Median of follow-up of MP therapy was 32 months (8-54). In 87.1% of patients (95%CI: 70-96%), MP was tolerated without further liver injury; of these, 77.4% tolerated full MP doses and 9.7% tolerated lower doses. In a further cohort of 12.9% of patients, (95%CI: 3-29%), liver injury reappeared (two cholestasis, two mixed), 1-3 months after the onset of MP exposure. CONCLUSION: The administration of MP is a good alternative in patients with AZA-related liver injury, before thiopurines are definitely discarded.

Obstrucción parcial de intestino delgado en paciente con enfermedad de von Recklinghausen / Partial small bowel obstruction due to von Recklinghausen´s disease

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Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects.

Common variable immunodeficiency (CVID) is a very heterogeneous syndrome defined by impaired immunoglobulin production. The functional classification of CVID patients on the basis of in vitro immunoglobulin production is time consuming and has never shown any predictive value. We propose a classification based on the quantitative repartition of naive/memory B cells according to the dual expression of IgD and CD27. Fifty-seven patients were categorized into three groups: Group MB2 (11 patients, 19%) with normal memory B cells; Group MB1 (19 patients, 33%) with defective switched memory (IgD-CD27+) but normal nonswitched memory B cells (IgD+CD27+); Group MB0 (27 patients, 47%) with almost no memory B cells. In addition, a downexpression of activation markers (CD25, CD21, CD80, CD86) on B cells characterized the group MB1 patients and was associated with an upexpression of activation markers (HLA-DR, CD95, CD57) on T cells. This classification correlates with some clinical aspects showing a higher prevalence of splenomegaly (16/27, 59%), lymphoid proliferation (13/27, 48%) and granulomatous disease (12/27, 44%) in group MB0. Splenomegaly was also frequent in group MB1 (8/19, 42%). In contrast, autoimmunity was observed with similar prevalence in all three groups. Moreover, by analyzing B cell phenotype, immunoglobulin transcript expression, and somatic mutations, we propose different putative mechanisms responsible for impaired B cell activation and memory differentiation in this syndrome.

[Predictive factors of the mortality of digestive hemorrhage caused by esophageal varices in elderly patients]. / Factores predictivos de mortalidad de la hemorragia digestiva por varices esofágicas en pacientes ancianos.

Complications of liver cirrhosis are increasingly frequent in elderly patients due to increased life expectancy and better management of cirrhotic patients. However, the influence of this condition on the evolution of variceal bleeding has not been well established. The aim of the present study was to determine the characteristics of esophagogastric variceal bleeding in elderly patients and the possible influence of advanced age on hemorrhage-related mortality. We analyzed 321 episodes of variceal bleeding in 227 cirrhotic patients. One hundred and thirteen (35.2%) episodes occurred in patients older than 65 years. No differences were found among patients older or younger than this age in terms of bleeding characteristics or Child-Pugh score. Patients older than 65 years more frequently presented serious associated diseases, hepatocellular carcinoma and hepatic encephalopathy during the episode (52.7% vs. 14%, p < 0.001; 19.7% vs. 8.7%, p = 0.01 and 17.4% vs. 10%, p = 0.09 respectively). Although hemorrhage-related mortality was higher in elderly patients (23.2% vs. 13.5%, p = 0.04), only the Child-Pugh score, definitive hemostasis, hepatocellular carcinoma and the development of encephalopathy or bacterial infection were independent predictive factors of mortality. A considerable proportion of the patients with esophagogastric variceal bleeding were older than 65 years. Advanced age does not independently influence mortality due to variceal bleeding.

Phage display of peptide/major histocompatibility complex.

To date, there is no direct way to determine the antigenic specificity of T-cells. While B-cell epitopes can be selected from phage-displayed libraries of peptides, the corresponding molecular tool for identifying T-cell epitopes does not yet exist. The natural ligands of the T-cell antigen-receptor (TCR) are essentially antigenic peptides (P) associated with the products of the major histocompatibility complex (MHC). Here, we report phages displaying P-MHC complexes. Single-chain P-MHC class I molecules, produced in E. coli periplasm, stimulate T-cells in a peptide-specific fashion. The same P-MHC, fused at the tip of filamentous phage, directed their binding to a recombinant TCR restricted to the displayed MHC haplotype (H-2K(d)). Importantly, the binding of P-K(d)-fd to a K(d)-restricted TCR, and also to K(d)-restricted T-cell hybridomas, was modulated by the displayed peptide. Therefore, we suggest phage display of P-MHC as a direct molecular tool for probing T-cell specificity, and for selecting TCR ligands from genetic libraries encoding randomized or natural peptides.

Proinflammatory and antitumor properties of interleukin-18 in the gastrointestinal tract.

Interleukin-18 (IL-18) plays a central role in the immune response by acting on Th1 cell differentiation, cell-mediated cytotoxicity and inflammation. The role of IL-18 in cancers and inflammatory diseases is discussed in the light of our investigations on IL-18 synthesis in normal colonic mucosa, colonic cancer and Crohn's disease (CD).

Carvedilol, a new nonselective beta-blocker with intrinsic anti- Alpha1-adrenergic activity, has a greater portal hypotensive effect than propranolol in patients with cirrhosis.

Only some patients show a substantial hepatic venous pressure gradient (HVPG) reduction after propranolol, which makes it desirable to investigate drugs with greater portal hypotensive effect. The aim of this study was to investigate whether carvedilol, a nonselective beta-blocker with anti-alpha1-adrenergic activity, may cause a greater HVPG reduction than propranolol. Thirty-five cirrhotic patients had hemodynamic measurements before and after the random administration of carvedilol (n = 14), propranolol (n = 14), or placebo (n = 7). Carvedilol markedly reduced HVPG, from 19.5 +/- 1.3 to 15.4 +/- 1 mm Hg (P <.0001). This HVPG reduction was greater than after propranolol (-20.4 +/- 2 vs. -12.7 +/- 2%, P <.05). Moreover, carvedilol decreased HVPG greater than 20% of baseline values or to

Modulation of interleukin-18 expression in human colon carcinoma: consequences for tumor immune surveillance.

The production in colon cancer of interferon-gamma (IFN-gamma), a type-1 T-helper (TH1) cytokine, is considered as a marker of good prognosis. We asked whether interleukin-18 (IL-18), which strongly induces IFN-gamma and regulates Fas ligand (Fas-L)-dependent cytotoxicity, may play a role in colon homeostasis, and if its expression was modulated in colon adenocarcinomas. We analyzed 14 specimens of colon adenocarcinomas, 6 of normal colon mucosa of the series, and 6 colon-tumor cell lines. The expression of IL-18, of ICE protease, involved in the processing of this cytokine, and of the downstream effectors of IL-18, IFN-gamma and Fas-L was analyzed by RT-PCR. We further performed IL-18 immunostaining of normal and tumor specimens. The results were correlated with tumor dissemination and clinical outcome. We report the synthesis of IL-18 in human normal colon, mainly by epithelial cells of the mucosa. Out of the 6 tumor cell lines, 4 expressed IL-18 transcripts, but neither ICE mRNA nor secreted forms of IL-18 were detected. We observed decreased or abolished synthesis of IL-18 in colon adenocarcinomas, as compared with normal mucosa. Thus, half of the colon-cancer tissues (7/14 cases) expressed neither IFN-gamma nor Fas-L. This feature was correlated with the existence of distant metastases (Fischer's exact test, p = 0.02) and an unfavorable outcome. These findings suggest that production of IL-18 in human colon may play a role in homeostasis and in tumor immune surveillance, by enhancing IFN-gamma production and Fas-L-dependent cytotoxicity of immune cells.

[Fas, fas ligand, immune tolerance, and cancer: implications in cancer of the colon]. / Fas, fas ligand, tolérance immunitaire et cancer: implication dans le cancer du côlon.

Fas and Fas ligand (FasL) are implicated in programmed cell death or apoptosis. In the immunological field, they are particularly important in auto-immunity, graft rejection and anti-tumoral response. Fas ligand expression on thymocytes, activated T lymphocytes, and in sites of immune privilege, suggests the importance of Fas/FasL interactions in negative control of the immune response. The recent description of FasL expression by tumoral cells, represents a new mechanism of immune escape for different cancer, and has been well studied in colon adenocarcinoma.

Pulmonary complications following orthotopic liver transplant.

Pulmonary complications after orthotopic liver transplant (OLT) are frequent, involving high morbidity and mortality. We have determined the pulmonary complication incidence in 187 patients submitted to OLT at the General University Hospital "Gregorio Marañón" in the last 4 years, analyzing the type of infection, evolution, diagnostic and therapeutic measures and their influence on OLT mortality. A total of 120 patients had pulmonary complications, the most frequent being pleural effusion (61.94%), pneumonia (43.36%), and pneumothorax (11.5%). Serious pulmonary hypertension was diagnosed by invasive methods in two patients at the time of surgery (unidentified before OLT); both died at early post postoperative times. Pleural effusion was noted in 70 patients, 31.42% of them requiring thoracic tube drainage, complications developing in 22.72%. Thirteen patients were diagnosed of pneumothorax, the most frequent etiologies being percutaneous liver biopsy, thoracic tube drainage for pleural effusion, and postoperative complications in 41.6, 33.3, and 23.3%, respectively. Pneumonia was diagnosed in the 1st month after OLT in 45 patients. Tests to diagnose and identify the etiological agent were made in 71.1% of diagnosed pneumonia patients, identification being obtained in 62.5%. Telescope catheter culture identified the agent in 48%, fiber optic bronchoscopy in 50%, and lung or pleural biopsy in 100%. Respiratory insufficiency was noted in 64 patients (34.22% of transplanted patients). Factors involved in their development were pneumonia (42.18%), graft dysfunction (39.06%, pleural effusion (34.37%), sepsis (28.18%), and poor nutritional status (7.81%). Fifty patients (41.66%) died, pulmonary pathology being the determinant factor in 28.8%. Patient mortality with respiratory insufficiency was greater, especially in those with three factors involved the development of respiratory insufficiency.

Urgent transjugular intrahepatic portosystemic shunt for control of acute variceal bleeding.

OBJECTIVE: Endoscopic sclerotherapy and pharmacological therapy are widely used in the treatment of acute variceal hemorrhage. However, they fail at arresting acute bleeding in 20-30% of bleeding episodes. The efficacy of transjugular intrahepatic portosystemic shunt (TIPS) in the prevention of recurrent variceal bleeding has been proved recently, but the effectiveness and safety of urgent TIPS in the treatment of acute variceal bleeding refractory to conventional therapy are still under evaluation. METHODS: Over 4.5 yr, 358 variceal hemorrhage episodes were treated in our hospital. Pharmacological and endoscopic therapy failed to control hemorrhage in 93 episodes. Thirty-two patients died because of uncontrolled massive bleeding. In 56 patients, TIPS (Strecker stent) was performed after temporary control of the episode with balloon tamponade. RESULTS: Eleven of 56 patients with urgent TIPS belonged to Child-Pugh class A, 22 to class B, and 23 to class C. The mean time between indication and insertion was 17 +/- 10 h (range 4-24 h). Control of bleeding was achieved in 53 patients (95 %). Eight patients had recurrent bleeding at 1 month after TIPS, seven of them during the first week after the procedure. The 1-month actuarial probability of rebleeding was 22%. The main complications of the procedure were massive hemoperitoneum (n = 1), cardiorespiratory arrest (n = 2), cardiac failure (n = 1), acute renal failure (n = 2), and bacteremia (n = 7). Operative mortality (30 days) was 28%. The actuarial probability of survival at 30 days was significantly lower in Child-Pugh class C than in class A or B (48% vs 90%; p < 0.001). The presence of ascites, hepatic encephalopathy, and serum albumin level before TIPS were independent prognostic factors associated with the risk of operative mortality. CONCLUSIONS: Urgent TIPS is an effective alternative for the treatment of acute variceal bleeding refractory to endoscopic and pharmacological therapy, but sometimes is associated with major complications. Because of the high operative mortality rate in patients with severe liver failure, careful selection of patients is required before TIPS.

[Treatment with recombinant interferon alfa-2b of a patient with chronic hepatitis C and concomitant ulcerative colitis]. / Tratamiento con interferón alfa-2b recombinante de una paciente con hepatitis crónica C y brote de colitis ulcerosa concomitante.

The case of a patient ulcerative colitis involving an autoimmune base who was treated with recombinant alpha-2b interferon for presenting chronic active hepatitis in relation to virus C is reported. Such treatment was achieved in addition to improving the hepatic disease normalizing the transaminases control the outbreak of ulcerative colitis that the patient was presenting from some days before beginning the treatment. Various aspects are discussed related to the autoimmunity in the ulcerative colitis and in the chronic C hepatitis and the exarcebation of autoimmune phenomena which may lead to interferon therapeutic. As a basis for the above and the review of the literature, we concluded that the existence of ulcerative colitis does not contraindicate the use of alpha-2b interferon in patient with chronic hepatitis, although special control of the disease should be carried out during the treatment period.

Bacteremia following liver biopsy in transplant recipients with Roux-en-Y choledochojejunostomy.

Between 1990 and 1995, 666 percutaneous liver biopsies were performed in 196 patients at Gregorio Marañón General Hospital (mean 3.4 biopsies/patient); 533 biopsies (80.03%) were carried out in patients with choledochostomy biliary anastomosis and 133 (19.97%) in patients with choledochojejunostomy. Infectious complications, in the form of sepsis, occurred in two patients, who recovered favorably with antibiotic therapy. These two patients had undergone Roux-en-Y choledochojejunostomy (1.5%, not significant). Our findings suggest that the incidence of infectious complications after liver biopsy in transplant recipients is very low. Antibiotic prophylaxis at the time of liver biopsy in patients with Roux-en-Y choledochojejunostomy may decrease the frequency of infectious complications.

[Famciclovir plus interferon in the treatment of a patient with chronic hepatitis B and severe liver failure]. / Famciclovir más interferón en el tratamiento de un paciente con hepatitis crónica por virus B y fallo hepático grave.

The natural history of liver disease caused by persistent infection with hepatitis B virus (HBV) can be quite variable. The wide range of liver injury suggests a great degree of variability in the interaction between the replicating virus and possible immune responses. At the current time, Interferon is the most extensively studied antiviral agent for chronic hepatitis B, but because of the substantial number of nonresponders, relapses and side events, it continues the search of alternative therapies. Many nucleoside analogues agents have been found to have antiviral activity in vitro or in vivo. The second generation nucleoside analogues with the most promising potential at present include Famciclovir. We report the case of a patient with HBV infection in whom a reactivation of his disease lead to hepatic failure, analysing the possible pathogenic mechanisms implied and calling attention upon the excellent results achieved with a combine regimen of Interferon and Famciclovir.

Detection of apoptosis at the single-cell level by direct incorporation of fluorescein-dUTP in DNA strand breaks.

Apoptosis induced in different cell lines can be detected and quantified in one step. Direct labeling of apoptotic cells (DLAC) was performed by incorporation of fluorescein-dUTP (F-dUTP) in DNA strand breaks by terminal deoxynucleotidyl transferase (TdT). Nick-end-labeling using F-dUTP obviates the need for second-step revelation reagents without reducing the specificity of detection. Cells were analyzed by microscopy or flow cytometry for objective quantification of apoptotic cells in controlled dilution samples. Furthermore, we demonstrate that DLAC is compatible with surface labeling by monoclonal antibodies, allowing dual-color analysis. The data presented here illustrate the simplicity and potential of this method, which allows the preservation of fragile cells and the possibility of combining apoptosis detection with immunostaining.

[Cytomegalovirus infection as a cause of granulomatous hepatitis in an immunocompetent patient]. / Infección por citomegalovirus como causa de hepatitis granulomatosa en paciente inmunocompetente.

We report the case of an immunocompetent young male with granulomatous hepatitis in relation with cytomegalovirus. We discuss clinical and histopathological features of hepatitis by cytomegalovirus in immunocompetent and immunosuppressed patients.

[Spontaneous bacterial peritonitis caused by Listeria monocytogenes]. / Peritonitis bacteriana espontánea por Listeria monocytogenes.

Listeria monocytogenes is a gram-positive coccobacillus that produces infections in both the normal and the compromised host. Symptomatic bacteremia and pulmonary infection or meningitis are the most common clinical presentations in adults. According to a current review of the literature, Listeria is a rare bacteria that may produce spontaneous bacterial peritonitis (23 cases reported). Listeria peritonitis occurs in more than two-thirds of the cases in patients with chronic liver disease, but may also occur in patients with malignancy or undergoing peritoneal dialysis. We describe two cases of SBP in cirrhotic patients, one with alcoholic cirrhosis and other due to HCV infection. One patient also presented with acute meningitis. Peritonitis due to Listeria was clinically and analytically similar to any SBP. Third-generation cephalosporins commonly used in the therapy of SBP, are ineffective in this infection. Ampicillin is the drug of choice, although it should be used in combination therapy usually with an aminoglycoside. The mortality from Listeria peritonitis is similar to that of other SBP (17%).