Evaluation of liver fibrosis by transient elastography (Fibroscan®) in patients with inflammatory bowel disease treated with methotrexate: a multicentric trial.

BACKGROUND: Methotrexate is an effective treatment for inflammatory bowel disease (IBD). However, long-term treatments have been associated with the development of liver fibrosis. FibroScan® is a noninvasive, safe, and effective technique to evaluate liver fibrosis. AIM: To evaluate the presence of significant liver fibrosis by transient elastography (FibroScan®) in IBD patients treated with methotrexate. METHODS: Cross-sectional study including IBD patients treated with methotrexate from different hospitals. Clinical and analytical data, duration of treatment, and cumulative dose of methotrexate were obtained. Liver stiffness was assessed by FibroScan®. The cutoff value for significant liver fibrosis (according to METAVIR) was F ≥ 2: 7.1 kPa. Results. In the study, 46 patients were included, 30 women (65%), with a mean age of 43 ± 10 years. 31 patients had Crohn's disease (67.4%), 13 ulcerative colitis (28.3%), and 2 indeterminate colitis (4.3%). The mean cumulative dose of methotrexate was 1242 ± 1349 mg, with a mean treatment duration of 21 ± 24 months. The mean value of liver stiffness was 4.7 ± 6.9 kPa. There were 35 patients (76.1%) with F01, 8 patients (17.4%) with F = 2, and 3 patients with F ≥ 3 (6.5%). There were no differences in liver stiffness depending on sex, age, type of IBD, or cumulative dose of methotrexate. CONCLUSIONS: (1) Development of advanced liver fibrosis in IBD patients treated with methotrexate is exceptional. (2) There were no differences in liver stiffness depending on the type of IBD or the cumulative dose of methotrexate. (3) FibroScan® may be potentially useful for evaluation and follow-up of liver fibrosis in methotrexate-treated patients.

Genetic variants of interferon-stimulated genes and IL-28B as host prognostic factors of response to combination treatment for chronic hepatitis C.

Chronic hepatitis C (CHC) is a worldwide health problem that is highly related to liver fibrosis, cirrhosis, and hepatocellular carcinoma. The achievement of response to the current standard of care-pegylated interferon plus ribavirin-has recently been described to be associated with single-nucleotide polymorphisms (SNPs) near the IL-28B gene. Additionally, baseline expression levels of genes involved in interferon (IFN)-stimulated genes (ISGs) have been found to be related to treatment outcome. In the present study, 285 patients were genotyped for 63 SNPs within genes of the IFN signaling pathway (IPGs) and ISGs. Two ISG polymorphisms-OASL rs12819210 (odds ratio (OR)=2.1, P=0.03) and IFIT1 rs304478 (OR=2.5, P=0.01)-were found to be independent predictive factors of sustained virological response (SVR) after adjusting for other clinical covariates. Furthermore, the predictive value of IL-28B SNP was notably improved by simultaneous genotyping of rs12819210 and rs304478, particularly in patients with the worst prognosis (viral genotype 1, area under the curve (AUC)=0.74). In conclusion, ISG SNPs could constitute a valuable tool for individualizing CHC therapy.

Hepatic fibrosis in patients with chronic hepatitis C assessed by transient elastography: implications for determining the efficacy of antiviral therapy.

BACKGROUND: The efficacy of combination therapy with peginterferon plus ribavirin to eradicate viral infection in patients with chronic hepatitis C (CHC) is well established; moreover, it is able to arrest or even reverse liver fibrosis. AIMS: To analyze the measurements of hepatic stiffness as an index of liver fibrosis using transient elastography (TE) in patients who underwent a sustained virological response (SVR) during long-term follow-up; comparing the changes in the severity of fibrosis with non-responders patients. MATERIAL AND METHODS: After hepatic fibrosis was studied in three patients with CHC who underwent a SVR during long-term follow up, a prospective study was initiated in 24 patients with CHC who received combination therapy to compare the evolution of fibrosis in those with SVR and those who were non-responders. The genotype of hepatitis C virus (HCV) and the degree of viremia were determined. METAVIR scoring system was used for liver fibrosis. Hepatic stiffness was measured by TE. RESULTS: Of the initial three patients pre-treatment liver biopsies revealed active disease and fibrosis (stage 3) in two and mild fibrosis (stage 1) in one. After several years of follow up serum AST/ALT levels were normal and HCV RNA was undetectable in each case; in contrast to the baseline histological assessments of fibrosis, values for hepatic stiffness (3.4-6.9 KPa) were compatible with an absence of any appreciable hepatic fibrosis. In the prospective study, 8 patients underwent a SVR and 16 were non-responders. TE indicated that the severity of hepatic fibrosis in the SVR group improved in 7 (88%) patients, whereas in the non-responder it improved in only 4 (25%) (p < 0.05). The difference between development of severe fibrosis (F > or = 3) in responders and non-responders was not significant (p = 0.23), possibly due to the small sample size. CONCLUSIONS: Regression of hepatic fibrosis appears to be common in patients with CHC who undergo a SVR. TE is a simple non-invasive technique that enables multiple assessments of the severity of hepatic fibrosis to be made efficiently during long-term follow-up of patients with CHC who receive combination antiviral therapy.

Usefulness of manometry to select patients with anal fissure for controlled anal dilatation.

AIM: To evaluate the use of anorectal manometry to select patients for controlled anal dilatation. METHODOLOGY: A prospective study was performed using anorectal manometry on all patients with chronic anal fissure who did not have a good response to conservative treatment. Those with increased anal resting pressure were treated with controlled anal dilatation using a two valved anuscope. A second anorectal manometry was indicated after controlled anal dilatation. RESULTS: 19 patients without anorectal pathology (Healthy Control Group) and 57 patients with chronic anal fissure were included in this study. Controlled anal dilatation was performed on 27 patients, maximum resting pressure 122 ± 19 mmHg. In the controlled anal dilatation group the healing rate was 92.5%, mean maximum resting pressure post-controlled anal dilatation was 91 ± 30 mmHg. We found one case of transitory anal incontinence (3.7%). None of the patients had anal incontinence at 18 months of the follow-up. In the remaining 30 patients non selected for controlled anal dilatation (chronic anal fissure control group), a proportion of 53.3% recurrences were registered after conservative treatment. CONCLUSIONS: Anal healing of chronic anal fissure and a significant decrease in maximum resting pressure recorded by manometry confirms the success of this procedure. The manometric evaluation of the maximum resting pressure is useful in the selection of chronic anal fissure patients for controlled anal dilatation. The efficacy of dilatation to treat chronic anal fissure in patients with raised anal sphincter pressure was high and complications were rare.

Systematic review: hepatitis-associated aplastic anaemia--a syndrome associated with abnormal immunological function.

BACKGROUND: Hepatitis-associated aplastic anaemia is a syndrome in which marrow failure follows the development of hepatitis. AIM: To review systematically the aetiology, immunopathogenesis, clinical presentation, diagnosis and treatment of hepatitis-associated aplastic anaemia. METHODS: Literature searches were undertaken on the MEDLINE electronic database up to December 2008. Twenty-four relevant studies were identified. The clinical and laboratory characteristics of the patients were analysed and reviewed. RESULTS: Hepatitis-associated aplastic anemia is a variant of acquired aplastic anemia in which an episode of hepatitis precedes the onset of aplastic anemia. The hepatitis may be acute and severe, even fulminant; it may be self-limiting or chronic. The pathology is often not attributable to a recognized cause of viral hepatitis. The syndrome occurs in 28 percent of young adults after liver transplantation for non-A, non-B, non-C hepatitis. Several features of the syndrome suggest that the marrow aplasia is mediated by immunological mechanisms, possibly mediated by gamma interferon or the cytokine cascade. Survival of patients treated with hematopoietic cell transplantation has been 82%, and the response rate to immunosuppressive therapy 70%. CONCLUSIONS: Hepatitis-associated bone marrow aplasia is mediated by immunological mechanisms. Treatment options include hematopoietic cell transplantation and immunosuppressive therapy.

[Difficulties and controversies in hospitalized patients with lower gastrointestinal bleeding]. / Dificultades y controversias en el manejo hospitalario de la hemorragia digestiva baja.

OBJECTIVES: Lower intestinal bleeding (LGIB) is a frequent reason for hospitalization; however, the prognostic factors have not been clearly defined. The aim of this paper was to analyze several clinical parameters and the management of this entity in our department from 2005 to 2007. MATERIAL AND METHODS: all hospitalized patients with LGIB were retrospectively (2005-2006) and prospectively (2006-2007) included. Medical records, physical examination (anal digital examination included), blood testing, and colonoscopic examination (in most of patients) were performed. RESULTS: 137 patients were included during 2005-2006: 36% of them required blood transfusion; thirty-one percent of patients showed previous episodes of LGIB, and 62% had a favorable outcome. Time from admission to colonoscopy was 4.1 days, and length of stay was 10.2 days. In the 2006-2007 study 96 patients were included: 42% of them required blood transfusion, thirty-three percent of patients showed previous episodes of LGIB, and 68% had a favorable outcome. Time from admission to colonoscopy was 2.6 days, and length of stay was 7.7 days. The most frequent etiology was diverticulosis in both studies. CONCLUSIONS: Hospital length of stay and time from admission to colonoscopy in patients with LGIB was reduced by 25% and 37%, respectively, in the 2005-2006 period with regard to the 2006-2007 one; however, there were no more bleeding points or a decrease in bleeding recurrence.

[Eosinophilic esophagitis in the adult--clinical, endoscopic, pH-metric, and manometric findings]. / Esofagitis eosinofílica en el adulto: aspectos clínicos, endoscópicos, pH-métricos y manométricos.

OBJECTIVES: Eosinophilic esophagitis (EE) is a condition characterized by dysphagia and frequent food impaction in young adults. The aim of our study was to evaluate the clinical aspects, endoscopic features, pH-metric and motility disorders in EE. PATIENTS AND METHODS: Adult patients with EE were prospectivity included. Endoscopy with biopsy, stationary esophageal manometry, and 24-hour pH-metry were performed. We analyzed the duration of disease, allergies, blood peripheral eosinophilia, prevalence of dysphagia, number of food impaction episodes, and complications during the endoscopic procedure. RESULTS: Eleven male patients with a mean age of 35 years were followed. Endoscopy showed esophageal disorders in all cases: 5 esophageal felinizations, mucosal abnormalities in 4 cases, distal rings in 3 cases, and 2 esophageal stenoses. In two cases mucosal tearing during the endoscopic procedure was described. In 6 patients the manometric study showed motor disorders affecting the esophageal body, 5 of them displaying hypomotility. Two patients showed pathological gastroesophageal reflux during pH-monitoring. Blood peripheral eosinophilia was detected in 3 patients. CONCLUSION: Although endoscopic abnormalities are frequently found, they do not usually explain dysphagia and food impaction episodes in EE. Ineffective esophageal peristalsis is the most prevalent manometric disorder associated with this entity, although it is not clearly related to symptom worsening either.

Review article: pharmacological therapy for hepatocellular carcinoma with sorafenib and other oral agents.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Unresectable disease patients have median survival of few months. There is a substantial need for novel treatments for patients with advanced HCC. AIM: To provide an update review of mechanism of hepatocarcinigenesis and systemic therapies for HCC and the relevant role of Sorafenib in patients with advanced disease. METHODS: A Medline search was performed to identify pertinent original research and review articles. Selected references in these articles were also evaluated. RESULTS: Systemic chemotherapy for HCC has been quite ineffective. Preclinical studies demonstrated that Raf/MAPK-ERK kinase (MEK)/Extracellular signal regulated kinase (ERK) pathway has a role in HCC. HCC tumours are highly vascularized and vascular endothelial growth factor (VEGF) augments HCC development and metastasis. Sorafenib blocks tumour cell proliferation by targeting Raf/MEK/ERK signalling and exerts an antiangiogenic effect by targeting VEGF receptors-2/3 and platelet derived growth factor receptor beta tyrosine kinases. CONCLUSIONS: Currently available therapies are not effective for patients with advanced HCC. Sorafenib has demonstrated for the first time to prolong survival in patients with advanced HCC, and it is the new reference standard for systemic treatment in these patients.

Treatment regimens for patients with chronic hepatitis C.

Infection by the hepatitis C virus (HCV) is a major public health problem, with more than 170 million people infected throughout the world. The infection prevalence, with small regional differences, is estimated in 1-3% of the global population. HCV is the most frequent cause of chronic liver disease and 20-30% of patients develop cirrhosis with a risk of hepatocellular carcinoma. Nowadays, pegylated interferon-a (PEG-IFN) in combination with ribavirin, a nucleoside analogue, is the current treatment for chronic hepatitis C (CHC), with less adverse effects and better compliance. Dosage and duration depend on some factors as weight, genotype, viral load and a rapid virological response presented by the patient. One of the most relevant aspects in the treatment of CHC is how to manage the group of non-responder or relapser patients to previous treatments. As such, a substantial proportion of patients had already been unsuccessfully treated with interferon-based therapies and these patients claim for an optimal therapeutic option. The future treatment of CHC walk along through the association of two or three drugs, including nucleoside/nucleotide analogues, higher PEG-IFN initial dosages (induction) or longer treatments duration, or combination of helicase and protease inhibitors.

Transient elastography to assess hepatic fibrosis in primary biliary cirrhosis.

BACKGROUND: Liver stiffness measurements may have potential for detecting and monitoring hepatic fibrosis in chronic liver disease. AIM: To study the detection, quantification and progression of hepatic fibrosis in primary biliary cirrhosis by liver stiffness measurements. METHODS: Liver stiffness measurements were generated in 80 patients with primary biliary cirrhosis by applying transient elastography; however, as there were 55 with liver biopsy, histological stage (METAVIR) and liver stiffness measurements were compared only in these 55 patients. The efficiency of liver stiffness measurements in predicting stage of fibrosis was determined from the area under receiver operating characteristics curve analysis. RESULTS: Of the 80 patients included, 91, 4% were women and their mean age was 56 +/- 12 (s.d.) years. A significant correlation was found (P < 0.05) between histological fibrosis stage (METAVIR) and liver stiffness measurements. The values obtained from area under receiver operating characteristic curve analysis of liver stiffness measurement data were 0.89 for F > 2 and 0.96 for F = 4. Liver stiffness measurements were 9.0 +/- 5.3 and 7.9 +/- 6.0 kPa for patients followed up more than 5 years and less than 5 years, respectively (P > 0.05). CONCLUSIONS: In patients with primary biliary cirrhosis, median values of liver stiffness measurements correlated with histological severity of hepatic fibrosis. Liver stiffness measurements appear to be promising for liver fibrosis detection and quantification, as well as monitoring its progression, in patients with primary biliary cirrhosis. The progression rate of hepatic fibrosis in our primary biliary cirrhosis patients appears to be slow.

[Utility of analytical parameters in the diagnosis of liver disease]. / Utilidad de los parámetros analíticos en el diagnóstico de las enfermedades hepáticas.

Liver function tests include biochemical parameters (AST, ALT, GGT or Alkaline phosphatase), bilirubin and albumin levels and coagulation tests as prothrombin activity. These tests are commonly used in the routine screening even in symptomatic as in asymptomatic patients, and the right evaluation of the results is of vital importance. Cytolytic elevation in serum aminotransferases: In mild chronic elevation pharmacological toxicity, viral hepatitis, alcoholic and non-alcoholic fatty liver disease and hemochromatosis, should be excluded. Cholestatic elevation os serum enzymes: The first option should be to establish the origin of the alkaline phosphatase elevation, with the evaluation of the GGT levels to confirm the hepatic origin. The next step should be to distinguish the presence of an extrahepatic (biliary obstruction) or intrahepatic (PBC, PSC, drugs, etc) cholestasis, in these cases the most important test should be the abdominal ultrasound, in order to evaluate the biliary system. Hyperbilirubinemia: Non conjugated hyperbilirubinemia (hemolysis, ineffective erythropoiesis, Gilbert or Criggler-Najjar syndromes) and conjugated hyperbilirubinemia, an unusual situation in which Rotor and Dubin-Johnson Syndromes should be considered. The evaluation of albumin and prothrombin levels evaluates the hepatic function per se, allowing to differentiate between acute and chronic diseases. At present, there are not prospective studies to evaluate the efficacy of the liver function tests. To carry out a complete medical history, an appropriate physical examination and the appropriate application of non-invasive diagnostic tests (serology, iron levels, autoimmunity or abdominal ultrasound) allow to perform a right diagnosis in most patients, making more complex tests, including liver biopsy, secondary.

Transient elastography: a valid alternative to biopsy in patients with chronic liver disease.

BACKGROUND: Transient elastography is a novel and non-invasive technique for the evaluation of fibrosis in chronic liver disease. Few studies that exist value the efficacy of transient elastography, mainly in hepatitis C virus-infected patients. AIM: To evaluate the effectiveness, objectivity, reproducibility and safety of this technique. METHODS: We included 103 consecutive patients who underwent a liver biopsy in the last 48 months with a wide spectrum of chronic liver diseases. Median stiffness value (expressed as kilopascals - kPa) was kept as representative of the liver elastic modulus. All biopsy specimens were analysed by the same pathologist according to the METAVIR scoring system. RESULTS: Median value of stiffness in patients with mild or moderate fibrosis (FI and FII), and severe fibrosis or cirrhosis (FIII and FIV) was of 7, 4 +/- 5 and 16, 4 +/- 10 kPa, respectively, with a significant difference between them (P < 0.05). The areas under the receiver operating characteristic curves showed the optimal liver stiffness cut-off values for each group. CONCLUSIONS: We found a positive correlation between the liver stiffness found by transient elastography and fibrosis stage on biopsy in all patients, independently of the liver disease aetiology. Transient elastography is an easy, quick to perform and safe non-invasive procedure, reliable for assessing liver fibrosis.

Association between angiogenesis soluble factors and disease progression markers in chronic hepatitis C patients.

OBJECTIVES: Our objectives were to compare angiogenesis soluble factor (ASF) levels in chronic hepatitis C (CHC) patients and healthy individuals, and to investigate potential associations between ASF levels and both histological and biochemical markers of disease progression. METHOD: Thirty-six patients (69% males) positive for HCV-RNA by PCR analysis were included in the study. All patients underwent liver biopsy before treatment. Serum levels of vascular endothelial growth factor (VEGF), soluble Flt-1 and Flk-1 receptors, placental growth factor (PlGF), angiopoietin-2 (Ang-2) and soluble Tie-2 receptor were determined by ELISA. Fifteen healthy subjects were used as controls. RESULTS: In comparison to healthy individuals, CHC patients showed significantly increased serum levels of proangiogenic factors PlGF (22 +/- 5 vs. 18 +/- 8 pg/ml; p < 0.05), Ang-2 (1265 +/- 385 vs. 833 +/- 346 pg/ml; p < 0.005) and sFlt-1 (95 +/- 22 vs. 72 +/- 14 pg/ml; p < 0.0001). Interestingly, in CHC patients serum levels of VEGF and Tie-2 correlated with grade of inflammation, PlGF correlated with stage of fibrosis, and Flt-1 and Flk-1 correlated with serum transaminase levels (p < 0.05 in all cases). CONCLUSIONS: CHC patients showed increased serum levels of ASF, and a significant correlation was shown between serum levels of selected ASFs and grade of inflammation, stage of fibrosis, and transaminase levels.

Review article: angiogenesis soluble factors as liver disease markers.

Angiogenesis is the formation of new blood vessels from pre-existing ones; it has been studied at the molecular level in different pathologies and is currently considered a promising novel therapeutic target in cancer. Recently, the use of angiogenesis soluble factors as markers of tumour growth has been investigated. The knowledge gained has led to test their use as therapeutic agents. Additionally, angiogenesis soluble factors could be used for the follow-up of pathologies that currently require monitoring with invasive techniques, like chronic viral hepatitis or renal and haematological diseases. The different factors have been described in multiple studies. In some cases, such as hepatocellular carcinoma, a potential use as prognostic markers has been suggested.

Systematic review: regression of lymphoproliferative disorders after treatment for hepatitis C infection.

AIM: To systematically review the experience of therapeutic studies where alpha-interferon with or without ribavirin was administered to patients with lymphoproliferative disorders, in order to evaluate whether eradication of hepatitis C virus may induce regression of lymphoproliferative disorders. METHODS: We used bibliographical searches in electronic databases and in the Cochrane Library to determine our results. RESULTS: Sixteen studies where an anti-viral regimen was administered to 65 hepatitis C virus-infected patients with lymphoproliferative disorders were identified. Complete remission of the lymphoproliferative disorder was achieved in 75% of the cases. In contrast, hepatitis C virus-negative subjects did not respond to interferon, indicating that the response in the hepatitis C virus-infected patients is not merely due to the antiproliferative effect of interferon. Remission after HCV eradication was maintained, provided that infection did not reappear. In hepatitis C virus-infected patients with non-Hodgkin's lymphoma treated with corticosteroids/chemotherapy liver function tests deterioration did not occur. The addition of interferon to standard chemotherapy may decrease hepatic side-effects of chemotherapy. CONCLUSIONS: Although it is evident that larger therapeutical trials of anti-viral therapy are needed to determine the role of this strategy in hepatitis C virus-infected patients with lymphoproliferative disorders, encouraging data emerge from recent studies showing that interferon (plus ribavirin) is an attractive therapeutic option for some hepatitis C virus-related low-grade lymphomas.

Hepatitis C virus-related extra-hepatic disease--aetiopathogenesis and management.

Summary Hepatitis C virus infection is often associated with extra-hepatic manifestations, secondary to the elicitation of autoimmune reactions, generalized deposition of immune complexes and lymphoproliferative disorders. The most clearly established associations are those linking chronic hepatitis C with mixed cryoglobulinaemia (and the related glomerulonephritis and cutaneous vasculitis), as well as with the presence of autoantibodies. Less well-documented disorders include non-Hodgkin's lymphoma, thrombocytopenia, sialadenitis, thyroid disease, lichen planus, porphyria cutanea tarda, rheumatoid disorders and neurological disorders. Extra-hepatic manifestations are most frequent in patients of female sex, advanced age, long-lasting infection and cirrhosis. Optimal treatment strategies should be based on the predominant manifestation of the disease. In the case of autoimmune disorders not clearly attributable to the viral infection, corticosteroids may be the most effective option. Interferon-alpha alone or in combination with ribavirin may be indicated for those disorders related to immune complex deposition, such as mixed cryoglobulinaemia, although relapses of extra-hepatic signs often occur on discontinuation of treatment. In some cases, interferon-alpha may induce or exacerbate some extra-hepatic manifestations.