Hepatocyte growth factor and chronic hepatitis C.

OBJECTIVE: The hepatocyte growth factor (HGF) is a pleiotropic cytokine produced by hepatic stellate cells and implicated in liver regeneration and fibrosis. Serum levels of HGF vary in liver diseases, reflecting hepatic damage and hepatocellular dysfunction. In this study, serum levels of HGF and the relationship between HGF and biochemical, histological and virological data, have been analysed in patients suffering from chronic hepatitis C (CHC). PATIENTS AND METHODS: Serum HGF concentration was measured by ELISA in sandwich in 45 patients with CHC. Correlation between HGF levels and histological (necroinflammatory activity and fibrosis score) and biochemical (transaminases, prothrombin activity, albumin, bilirubin), or virological (hepatitis C virus load) parameters was analyzed. Serum HGF concentration was also studied in a subgroup of the original sample treated with interferon and ribavirin. RESULTS: Sserum HGF concentrations of patients with CHC were significantly higher than those detected in healthy controls. Patients with significant fibrosis (F > or = 2) had a significantly older age, lower count of platelets and higher values of AST, GGT and HGF, than those patients with a fibrosis score F < 2. HGF concentration was identified by multivariate analysis as the only independent factor associated with significant fibrosis. Moreover, area under receiver operating curve, using HCG levels, showed similar values to those of previously validated non-invasive indexes of fibrosis. However, levels of HGF did not show a significant decrease in patients with a sustained response to anti-virus C therapy. CONCLUSION: Serum HGF concentration correlates with fibrosis score in patients with CHC, but is insensitive to monitor changes induced by anti-virus C therapy.

Chronic antigenic stimuli as a possible explanation for the immunodepression caused by liver cirrhosis.

The objectives of this work were the analysis of the functional characteristics of circulating monocytes and T lymphocytes in patients with liver cirrhosis, and evaluation of the relationship with an increased exposure to antigens due to bacterial translocation. Forty patients with liver cirrhosis (20 with compensated cirrhosis and 20 with ascitic decompensation) and 20 healthy control subjects were studied. Bacterial translocation was evaluated by serum levels of lipopolysaccharide binding protein (LBP). Macrophage activation was studied by CD40 antigen expression. T lymphocytes were analysed for activation (CD25(+), CD122(+)), effector function (CD8(+)CD45RO(+)CD57(+)), apoptosis (CD95(+)) and regulatory abilities, either by analysis of the membrane expression of co-stimulatory molecules CD80, CD86 and CD28, or by quantification of regulatory T cells CD4(+)CD25(high)forkhead box P3 (FoxP3). The percentage of activated monocytes and T lymphocytes in patients was increased significantly. The proportions of effector senescent cells and of those near to apoptosis were also significantly higher. With respect to these proportions, there were no significant differences between patients in function of the presence or absence of decompensation or in function of the increased or normal values of LBP. Conversely, those patients with elevated levels of LBP presented a significantly higher frequency of regulatory T cells than those with normal levels. In conclusion, patients with liver cirrhosis showed an intensive activation state with a higher percentage of cells committed to activation-induced death, even in non-advanced stages. It is possible that bacterial permeability and endotoxaemia contribute to the expansion of those lymphocyte populations implicated in the prevention of a more severe antigen-induced immunopathology.

Modulation of the anti-inflammatory interleukin 10 and of proapoptotic IL-18 in patients with chronic hepatitis C treated with interferon alpha and ribavirin.

The aim of this work was to analyse apoptosis rate, measured by the serum levels of proapoptotic interleukin (IL)-18 and of soluble Fas (sFas), as well as of anti-inflammatory IL-10, in patients with chronic hepatitis C, at baseline and after treatment with interferon alpha and ribavirin. Twenty-seven patients with biopsy-proven chronic hepatitis C were studied, at baseline and after treatment with interferon alpha (21 cases) or pegylated interferon (6 cases) plus ribavirin. A group of 15 healthy sex- and age-matched individuals was selected as control. Serum concentrations of sFas, IL-10 and IL-18 were determined by ELISA in sandwich. The relationship of these molecules to necro-inflammatory and fibrotic activity was evaluated. Evolution of the serum concentrations of these molecules was analysed after treatment. Significantly increased serum concentrations of sFas were detected in patients with chronic hepatitis, compared with controls. Levels of this molecule were significantly correlated with necroinflammatory activity. Likewise, concentrations of IL-10 were significantly increased in the group of patients, compared with controls. Treatment with interferon and ribavirin induced a significant decrease of IL-18 concentration independently of the viral response. In contrast, levels of sFas decreased only in those patients with sustained response to therapy. Finally, baseline levels of IL-10 were significantly increased in patients without response to treatment, compared with those with sustained response, but the concentration did not change with the treatment. Increased serum levels of IL-10 are a negative prognostic marker of response to hepatitis C treatment. A significant decrease of apoptotic rate, as determined by sFas, can be expected in patients with a response to therapy.

Adhesion molecules as a prognostic marker of liver cirrhosis.

OBJECTIVE: Endothelial activation plays an active role in modifications of the circulatory status of cirrhotic patients. Soluble endothelial adhesion molecules, induced by pro-inflammatory cytokines, could be considered markers of endothelial activation. Their role in the natural history of cirrhosis and portal hypertension has not been reported. Our objective was to analyze the prognostic value of soluble adhesion molecules in cirrhotic patients. MATERIAL AND METHODS: Serum concentrations of soluble CD14, soluble receptors of tumor necrosis factor alpha and adhesion molecules ICAM-1 (intercellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule 1) as well as mean blood pressure, plasma renin activity, aldosterone, vasopressin and norepinephrine concentrations were determined in 64 cirrhotic patients (Child-Pugh class: A 48.4%, B 34.4%, C 17.2%), without any evidence of infection, and in 25 healthy controls. Patients were followed-up for a mean of 36.4 (range 6-60) months. RESULTS: Increased concentrations of soluble CD14, tumor necrosis factor receptors and ICAM-1 and VCAM-1 were detected in cirrhotic patients when compared with healthy controls. Tumor necrosis factor receptors and adhesion molecule concentrations were both significantly higher in advanced phases of cirrhosis (Child Pugh class C and B versus A). Fifteen patients died as a related consequence of liver cirrhosis. Multivariate analysis demonstrated that Child-Pugh score and serum levels of tumor necrosis factor receptor I and ICAM-1 were associated with mortality. CONCLUSIONS: In addition to the classic factor implicated in mortality (Child-Pugh class), alterations in inflammation-related components and soluble adhesion molecules, as representatives of hemodynamic alterations, are of prognostic significance in cirrhotic patients.

Expression of proinflammatory cytokines and their inhibitors during the course of spontaneous bacterial peritonitis.

The aim of this work was the evaluation, in cirrhotic patients with noninfected ascites and with spontaneous bacterial peritonitis (SBP), of serum and ascitic fluid levels of proinflammatory cytokines [interleukin (IL) 1-beta, tumor necrosis factor alpha (TNF-alpha), and IL6] and antiinflammatory compounds [IL10, soluble IL-1 receptor antagonist (sIL-1Ra), soluble receptors of TNF p55 and p75 (sTNFR55 and sTNFR75), and soluble receptor of IL6 (sIL6R)], as well as their relationship with the outcome of the infection in those with SBP. These molecules were assayed by ELISA in noninfected cirrhotic controls (n = 15), patients with SBP (n = 32), and healthy controls (n = 20). Serum levels of IL6 and of the majority of antiinflammatory mediators, sIL1Ra, sTNFR75, and sIL6R, were higher in control cirrhotic patients compared to healthy subjects. SBP was associated with significantly elevated ascitic fluid levels of every one of the proinflammatory cytokines compared to those in cirrhotic controls. Also, serum levels of IL10 and both TNF receptors and ascitic fluid levels of sIL1Ra and sTNFR55 were higher in patients with SBP compared to cirrhotic controls. Ascitic fluid levels of proinflammatory cytokines decreased rapidly after resolution of the infection; however, nonsignificant changes were detected in ascitic fluid concentrations of antiinflammatory molecules. Thus, elevated levels of antiinflammatory compounds both in noninfected cirrhotic patients and in patients with SBP suggest a regulatory control of the inflammatory process by these molecules in liver cirrhosis patients.

Serial analysis of serum and ascitic fluid levels of soluble adhesion molecules and chemokines in patients with spontaneous bacterial peritonitis.

The aim of this work was the evaluation of serum and ascitic fluid levels of chemokines (IL-8, growth-regulated oncogene (Gro-alpha), and monocyte chemotactic protein-1 (MCP-1)), and of soluble adhesion molecules (P-selectin, E-selectin, L-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)) in patients with spontaneous bacterial peritonitis (SBP). These compounds were serially analysed in serum and ascitic fluid by ELISA in patients with SBP (n = 20), non-infected cirrhotic controls (n = 12), and healthy controls (n = 15). Infected and non-infected cirrhotic patients showed significantly higher serum levels of adhesion molecules. SBP was associated with significantly higher serum and ascitic fluid levels of IL-8, Gro-alpha and ICAM-1 and with ascitic fluid concentrations of MCP-1. Significantly elevated serum levels of both ICAM-1 and VCAM-1 were detected in patient non-survivors after SBP. Thus, higher ascitic fluid levels of chemokines could be implicated in the peritoneal infiltrate in patients with SBP. Prognostic significance can be attributed to serum levels of ICAM-1 and VCAM-1 in these patients.

Microbiological characteristics and susceptibility patterns of strains of Rhodotorula isolated from clinical samples.

The members of the genus Rhodotorula show a marked ubiquity. In man, they have been isolated from faeces, nails, skin, sputum, digestive tract and adenoids, forming part of the normal human flora, although in recent years cases have been reported of both local and systemic infection by this yeast. There are virtually no studies in the literature on the sensitivity of this genus to the antifungal agents in common clinical use. Therefore, it is considered of interest to study the microbiological characteristics and the susceptibility patterns of Rhodotorula isolated from clinical samples. A total of 35 different strains of Rhodotorula were studied. In vitro susceptibility testing to 5-fluorocytosine, amphotericin B, ketoconazole, fluconazole and itraconazole was performed. All the strains were considered sensitive to 5-fluorocytosine, amphotericin B, ketoconazole and itraconazole and resistant to fluconazole. As a conclusion, we can state that all the antifungal agents tested, except fluconazole, are useful medicaments for the treatment of infections by the Rhodotorula genus.

Focal splenic lesions in patients with AIDS: sonographic findings.

BACKGROUND: The purpose of this study was to describe the sonographic features of the focal splenic lesions in patients with AIDS and to know the frequency and etiology of these features. METHODS: Sonographic exams of 278 AIDS patients were reviewed retrospectively. We recorded the clinical indications for sonograms and sonographic findings of those patients with focal splenic lesions. In addition, patients' histories were reviewed to determine the etiology of such lesions. Ultrasound exams were performed with a 3.5-MHz transducer. RESULTS: Sonography demonstrated focal splenic lesions in 22 patients (7.9%). Eighteen patients (81.8%) showed small, multiple, hypoechoic, rounded splenic lesions; one patient had a solitary defect with similar features. In these 19 patients (86.3%), splenic lesions were due to disseminated Mycobacterium tuberculosis infection. One case showed two large hypoechoic wedge-shaped lesions that were splenic infarctions secondary to acute bacterial endocarditis. In two patients (9%) with solitary and multiple small hypoechoic lesions, the cause of the lesions remained unknown. All patients had splenomegaly. Hepatomegaly with focal lesions, retroperitoneal lymphadenopathy, or ascites were also seen. CONCLUSION: In our area, the finding of splenomegaly with small, multiple, hypoechoic lesions in AIDS patients should make clinicians suspect splenic tuberculosis as a first possibility.

[Spontaneous bacterial peritonitis from Campylobacter fetus]. / Peritonitis bacteriana espontánea por Campylobacter fetus.

A patient with cirrhosis and ascites who developed spontaneous bacterial peritonitis due to Campylobacter fetus is described herein. This organism has been increasingly associated with bacteremia and localized infections in patients with cirrhosis and other immunocompromised states, but spontaneous bacterial peritonitis has been rarely reported. We review Campylobacter fetus infections and their relationship to development of spontaneous bacterial peritonitis, and we emphasize that prolonged antimicrobial therapy is required.

[Small intestine adenocarcinoma with Crohn's disease]. / Adenocarcinoma de intestino delgado y enfermedad de Crohn.

We report a 57-year-old male with a 11-years history of Crohn's disease who developed small bowel adenocarcinoma. The patient was admitted with intestinal partial obstruction and he underwent a laparotomy because an abscess in right lower quadrant was suspected. He was successfully treated with resection and adjuvant chemotherapy, without evidence of recurrence after a 2-year follow-up. A review of the literature reveals that about 100 cases have been reported. We describe the distinguishing features of small bowel adenocarcinoma arising in Crohn's disease and we emphasize the difficulty in making an early diagnosis.