Liver stiffness measurements by 2-dimensional shear wave elastography compared to histological and ultrasound parameters in primary biliary cholangitis.

BACKGROUND AND AIMS: Liver stiffness measurements (LSMs) by 2-dimensional-shear-wave elastography (LSM2D-SWE) are now widely used in hepatology. However, relevant information for primary biliary cholangitis (PBC) is scant. We compare LSM2D-SWE with liver biopsy (LB) in a cohort of PBC patients in Greece. METHODS: Data of 68 LBs from 53 PBC patients were retrospectively analyzed and fibrosis stage was compared to LSM2D-SWE. Forty-six patients (86.8%) were females and at the time of LBx median (IQR) age was 62.6 (53.2-72.1). Demographic, UDCA treatment, histological and B-mode ultrasound data were tested for their influence on LSM2D-SWE estimates. RESULTS: Liver fibrosis stages F0-F4 were found in 4, 19, 19, 16 and 10 cases, respectively. Across stages F0-F4, the LSM2D-SWE was 5.6 (5.1-6.1), 7.0 (5.8-7.7), 9.1 (7.3-11.5), 10.8 (9.9-12.2) and 14.5 (11.9-25.7) kPa, respectively, with highly significant difference (p<.001). The LSM2D-SWE differed also significantly between F0 vs. F1 (p=.027), F1 vs. F2 (p=.005) and F3 vs. F4 (p=.017). The discriminatory ability of LSM2D-SWE for mild, significant, severe fibrosis and cirrhosis was highly significant in all comparisons (p<.001), with AUC2D-SWE 95.3%, 87.4%, 85.3% and 95.3% and accuracy 89.7%, 85.3%, 80.9% and 86.8%, respectively. Among 21 parameters tested, significant predictors of LSM2D-SWE by multiple linear regression were fibrosis stage, portal inflammation and parenchymal heterogeneity. The portal inflammation grade accounted for 32.2% of LSM variation with adjusted R2 0.428. CONCLUSIONS: In patients with PBC, LSM measurements by 2D-SWE can reliably discriminate between mild, significant, severe fibrosis and cirrhosis. Measurements are significantly affected by portal inflammation grade.

Eradication of Helicobacter pylori Infection Restores ki67, p53, and Cyclin D1 Immunoreactivity in the Human Gastric Epithelium.

INTRODUCTION: We evaluated the effect of Helicobacter pylori (HP) eradication on p53, cyclin D1 expression, and cell proliferation in gastric mucosa. MATERIALS AND METHODS: We assessed p53, cyclin D1, and ki67 immunoexpression in gastric mucosa from 31 HP chronic gastritis patients and 12 controls. Reassessment was performed 6 months after successful HP eradication. RESULTS: Successful eradication resulted in significant decrease of p53 (1.53 ± 0.16 vs 0.83 ± 0.19, P = 0.01) and ki67 (9.84 ± 0.96 vs 4.77 ± 0.27, P < 0.001) staining in the antrum. Similarly, p53 immunoreactivity significantly decreased in the corpus (1.27 ± 0.20 vs 0.46 ± 0.15, P = 0.02), while there was a trend for decreased corpus cyclin D1 and ki67 expression (0.17 ± 0.07 vs 0.0, P = 0.08 and 8.71 ± 1.24 vs 5.85 ± 0.54, P = 0.09, respectively). Importantly, after successful HP eradication, the immunoreactivity of the studied parameters was similar to that of controls. CONCLUSION: Successful HP infection eradication restores p53, cyclin D1, and ki67 immunoreactivity in the gastric mucosa to the level of controls.

Efficacy and safety of interferon-based therapy in the treatment of adult thalassemic patients with chronic hepatitis C: a 12 years audit.

BACKGROUND: HCV infection and transfusional iron overload in Thalassemic patients may result in liver disease. HCV treatment in Thalassemia has raised safety concerns. AIM: Estimate effectiveness and tolerability of interferon-based therapy in HCV-infected Thalassemic patients. MATERIAL AND METHODS: Over a 12-year period, consecutive patients with ß Thalassemia major (TM) and chronic hepatitis C received treatment. Liver biopsy, HCV-RNA and genotyping were performed beforehand. Sustained virological response (SVR) was defined as negative HCV-RNA 6 months post-treatment. Forty eight patients (26 M-22 F, mean age 39.8) were enrolled. Twenty nine patients were treated with conventional interferon alpha (IFNa) for 48 weeks (group A). Nineteen patients (10 naïve-9 previously IFNa experienced) received pegylated interferon (PEGIFN) (group B). RESULTS: HCV-1 was found in 44%, HCV-2 in 14%, HCV-3 in 23% and HCV-4 in 19%. Group A: ten patients (38.5%) achieved SVR, 2 (7.5%) relapsed and 17 (54%) were non responders. Group B: five (28%) achieved SVR, 8 (44%) relapsed and 6 (28%) never responded. High HCV-RNA levels, genotype 1 and advanced liver fibrosis were independently associated with no response. Four patients (3 treated with IFNα, 1 with PEG-IFN) had to discontinue treatment due to complications. CONCLUSIONS: The response rate of IFN monotherapy in multi-transfused, HCV-infected Thalassemic patients is not inferior to that in non-multitransfused patients. IFNa administration is well-tolerated and should be recommended as initial treatment schedule in this setting.

Transplantation for acute liver failure in patients exposed to NSAIDs or paracetamol (acetaminophen): the multinational case-population SALT study.

BACKGROUND: Most NSAIDs are thought to be able to cause hepatic injury and acute liver failure (ALF), but the event rates of those leading to transplantation (ALFT) remain uncertain. OBJECTIVES: The aim of the study was to estimate population event rates for NSAID-associated ALFT METHODS: This was a case-population study of ALFT in 57 eligible liver transplant centres in seven countries (France, Greece, Ireland, Italy, The Netherlands, Portugal and the UK). Cases were all adults registered from 2005 to 2007 for a liver transplant following ALFT without identified clinical aetiology, exposed to an NSAID or paracetamol (acetaminophen) within 30 days before the onset of clinical symptoms. NSAID and paracetamol population exposures were assessed using national sales data from Intercontinental Marketing Services (IMS). Risk was estimated as the rate of ALFT per million treatment-years (MTY). RESULTS: In the 52 participating centres, 9479 patients were registered for transplantation, with 600 for ALFT, 301 of whom, without clinical aetiology, had been exposed to a drug within 30 days. Of these 301 patients, 40 had been exposed to an NSAID and 192 to paracetamol (81 of whom were without overdose). Event rates per MTY were 1.59 (95 % CI 1.1-2.2) for all NSAIDs pooled, 2.3 (95 % CI 1.2-3.9) for ibuprofen, 1.9 (95 % CI 0.8-3.7) for nimesulide, 1.6 (95 % CI 0.6-3.4) for diclofenac and 1.6 (95 % CI 0.3-4.5) for ketoprofen. For paracetamol, the event rate was 3.3 per MTY (95 % CI 2.6-4.1) without overdoses and 7.8 (95 % CI 6.8-9.0) including overdoses. CONCLUSIONS: ALF leading to registration for transplantation after exposure to an NSAID was rare, with no major difference between NSAID. Non-overdose paracetamol-exposed liver failure was twice more common than NSAID-exposed liver failure.

Improvement in cardiovascular indices after Roux-en-Y gastric bypass or sleeve gastrectomy for morbid obesity.

BACKGROUND: Morbidly obese patients display cardiac abnormalities which are partially reversed after weight loss. The aim of the present study was to assess the potential difference in cardiovascular disease indices between patients who underwent either gastric bypass surgery or sleeve gastrectomy. METHODS: Thirty-seven morbidly obese patients who underwent either Roux-en-Y gastric bypass (RYGB) (n = 14) or SG (n = 23) were examined before, 3 and 6 months after surgery. Indices of cardiac autonomic nervous system activity were evaluated, namely baroreflex sensitivity (BRS) and heart rate variability (HRV). A complete echocardiographic study was performed in a subgroup of 17 patients (RYGB 8, SG 9) preoperatively and 6 months after surgery, evaluating epicardial fat thickness, aortic distensibility, left ventricular (LV) Tei index, left atrium diameter, ejection fraction, and LV mass. RESULTS: All subjects experienced significant (p < 0.001) and similar weight loss independently of the type of operation. BRS and HRV indices improved significantly and to the same degree after surgery in both groups. In the echocardiographic study, all parameters improved significantly at 6 months in comparison with the baseline values. In addition, the RYGB group displayed significantly greater reduction in epicardial fat thickness (p = 0.007) and also tended to have a better LV performance as expressed by the lower values of the Tei index (p = 0.06) compared to the SG group 6 months after surgery. CONCLUSIONS: Both RYGB and SG exert comparable effects on weight loss and improvement of cardiovascular parameters. RYGB displays a more beneficial influence on epicardial fat thickness and left ventricular performance than SG.

Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis.

BACKGROUND AND AIM: Cirrhotic patients are predisposed to intestinal bacterial overgrowth with translocation of bacterial products which may deteriorate liver hemodynamics. Having shown that short-term administration of rifaximin improves liver hemodynamics in decompensated cirrhosis, we conducted this study to investigate the effect of intestinal decontamination with rifaximin on the long-term prognosis of patients with alcohol-related decompensated cirrhosis (Child-Pugh > 7) and ascites. METHODS: Patients who had received rifaximin and showed improved liver hemodynamics were enrolled in the current study and continued to receive rifaximin (1200 mg/day). Each patient was matched by age, sex, and Child-Pugh grade to two controls and followed up for up to 5 years, death or liver transplantation. Survival and risk of developing portal hypertension-related complications were compared between rifaximin group and controls. RESULTS: Twenty three patients fulfilled the inclusion criteria and matched with 46 controls. Patients who received rifaximin had a significant lower risk of developing variceal bleeding (35% vs. 59.5%, P = 0.011), hepatic encephalopathy (31.5% vs. 47%, P = 0.034), spontaneous bacterial peritonitis (4.5% vs. 46%, P = 0.027), and hepatorenal syndrome (4.5% vs. 51%, P = 0.037) than controls. Five-year cumulative probability of survival was significantly higher in patients receiving rifaximin than in controls (61% vs. 13.5%, P = 0.012). In the multivariate analysis, rifaximin administration was independently associated with lower risk of developing variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, and higher survival. CONCLUSIONS: In patients with alcohol-related decompensated cirrhosis, long-term rifaximin administration is associated with reduced risk of developing complications of portal hypertension and improved survival.

Modified docetaxel-cisplatin in combination with capecitabine as first-line treatment in metastatic gastric cancer. a phase II study.

The combination of docetaxel, cisplatin and fluorouracil is considered to be one of the reference regimens for advanced gastric cancer, but due to its major myelotoxicity, its use in clinical practice has become limited. This prospective phase II study evaluated the activity and toxicity of a modified regimen with lower doses of docetaxel and cisplatin combined with oral capecitabine instead of fluorouracil for patients with advanced gastric cancer. Treatment consisted of docetaxel at 60 mg/m(2) i.v. followed by cisplatin at 60 mg/m(2), both administered on day one, every three weeks. Capecitabine at 2 g/m(2) per day was administered in two divided doses for 14 days (days 2-15). Thirty six patients were enrolled in the study. The median age was 64 years and performance status (ECOG) was 0-1. All patients had advanced disease, 78% with liver metastases, 100% with intra-abdominal lymph node metastases and 67% with peritoneal implants. Out of the 36 patients, 13 had undergone gastric resection, 13 had received adjuvant chemotherapy with irinotecan-leucovorin-fluorouracil, while seven patients had undergone adjuvant radiotherapy. The remaining 23 patients presented with advanced inoperable disease. Among 36 evaluable for response cases, there were 16 (44.4%) (Confidence Internal (CI) 95%=28-60%), partial responses. Stable disease was recorded in 12 (33.3%), resulting in an overall disease control rate of 78% (CI 95%=69-87%), while 8 (22.3%) patients progressed on chemotherapy. The median response duration was 6 (range=3-8) months. The median time-to-progression was 5 (range=3-6) months and the median survival (after the administration of a second-line chemotherapy in 12 patients), was 12 (range=5-24) months. Myelotoxocity was the main toxicity, with grade 3-4 neutropenia occurring in 18 (50%) and febrile neutropenia in six (16%) patients. Granulocyte-Colony Stimulating Factor (G-CSF) support was given to 16 (44.4%) patients, while grade 3 thrombocytopenia was recorded in two (6%). In conclusion, this modified regimen of docetaxel-cisplatin-capecitabine appears to have comparable efficacy with that reported for the reference regimen, with acceptable toxicity when G-CSF support is provided. However, because due to the small size of the study, further investigation is warranted.

Inflammatory infiltration of metaplastic epithelium and correlation to previous diagnosis of esophagitis and Barrett's length.

OBJECTIVE: The contact of the gastric refluxate with the lower esophagus results in an inflammatory-mediated tissue damage. The role of inflammation both in the development and in the advance of Barrett's esophagus (BE) has not been elucidated. The aim of this study was to assess the inflammatory infiltration in metaplastic Barrett's epithelium and to explore the association of microscopic inflammation to healed esophagitis and Barrett's length. MATERIAL AND METHODS: Inflammatory infiltration was qualitatively evaluated in well-characterized Barrett's specimens. Esophagitis was healed prior to histological sampling. Univariate comparative analysis was performed based on BE length. RESULTS: Ninety-eight patients (78 male, mean age 58.3 ± 13.3 yrs) were retrospectively studied. Thirty-three cases with long segment BE (LSBE) (33.7%) were spotted. Inflammatory infiltration was mild, moderate, and severe in 35 (35.7%), 54 (55.1%), and 9 (9.1%) specimens, respectively. The samples with moderate/severe inflammatory infiltration were obtained from patients who had more frequently been diagnosed with esophagitis (p = 0.025). Hiatal hernia (p = 0.001), esophagitis (p = 0.019), and previous use of anti-secretory drugs (p = 0.005) were more common in LSBE. CONCLUSIONS: Inflammatory infiltration of Barrett's epithelium was largely moderate despite preceding healing of erosions with PPIs. Previous diagnosis of esophagitis correlated to the degree of inflammation. No association of inflammation to Barrett's length was established.

Increased expression of VEGF, COX-2, and Ki-67 in Barrett's esophagus: does the length matter?

BACKGROUND: Barrett's esophagus (BE) is a major complication of gastroesophageal reflux disease due to its neoplastic potential. The length of the metaplastic epithelium has been associated with cancer risk. Angiogenesis, inflammation, and increased cell proliferation are early events in the malignant sequence. Vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2) and Ki-67 are indirect markers of these complex mechanisms. AIMS: To examine the expression of VEGF, COX-2 and Ki-67 in BE and investigate whether there is an association to Barrett's length. METHODS: Immunohistochemistry for VEGF, COX-2, and Ki-67 was performed in well-characterized Barrett's samples, evaluated using a qualitative scale and compared between long (LSBE) and short (SSBE) segments. RESULTS: The study population consisted of 98 patients (78 men). LSBE and SSBE was diagnosed in 33 (33.7%) and 65 (66.3%) cases, respectively. VEGF was expressed in vascular endothelium of all Barrett's specimens. COX-2 and Ki-67 expression in metaplastic epithelia was strong in 81.6 and 61.2% of the samples, respectively. Ki-67 expression was significantly stronger in LSBE (p = 0.035), whereas VEGF expression was significantly increased in SSBE (p = 0.031). COX-2 expression was not associated with Barrett's length. CONCLUSIONS: VEGF, COX-2, and Ki-67 were overexpressed in the majority of Barrett's samples. The length was inversely associated with VEGF expression and directly associated with Ki-67 expression.

Endoscopic treatment for high-risk bleeding peptic ulcers: a comparison of epinephrine alone with epinephrine plus ethanolamine.

BACKGROUND: Among the various methods of combined endoscopic therapy for high-risk bleeding peptic ulcers the use of adrenaline followed by injection of ethanolamine is minimally demanding in terms of the endoscopic skills and instrumentation but has not been adequately studied. The aim of the present study is to determine whether the injection of ethanolamine in combination with epinephrine compared to injection of epinephrine alone reduces rebleeding rates, need for surgery and overall mortality of patients with bleeding ulcers. METHODS: Patients with ulcers and endoscopic features indicative of a high risk for spontaneous recurrent bleeding were included. High risk was defined by the Forrest classification. Patients were assigned to injection of epinephrine alone (n = 284) or epinephrine plus ethanolamine (n = 131). RESULTS: Initial hemostasis was achieved in 96% of patients in both groups. We detected significant difference in rates of recurrent bleeding, 16.4% vs. 8.7%, for epinephrine and epinephrine plus ethanolamine respectively (P<0.05). When patients were stratified according to Forrest criteria, no significant difference could be found, although there was a trend towards less recurrent bleeding in the case of dual injection therapy in all patient subgroups. There was no significant difference in the proportions of patients who required surgery, 7.7% vs. 7.6% respectively. Mortality was equal (3.2 vs. 3.1%) in the two groups. No major complications from endoscopic treatment were observed in either group. CONCLUSION: Adding ethanolamine to epinephrine for injection treatment of bleeding peptic ulcers decreases bleeding recurrence rates and represents a safe endoscopic treatment for high-risk bleeding ulcers.

High intestinal and systemic levels of decoy receptor 3 (DcR3) and its ligand TL1A in active ulcerative colitis.

Decoy receptor-3 (DcR3) is a member of the TNF receptor superfamily of proteins, which has been implicated in anti-apoptotic and anti-inflammatory pathways, via binding to TL1A, LIGHT and Fas-L. The role of the TL1A/DcR3 ligand/receptor pair in ulcerative colitis (UC) has not been studied. We investigated the systemic (peripheral blood) and local (large intestine) expression of DcR3 and TL1A in 64 patients with UC and 56 healthy controls. DcR3 serum concentrations were highly elevated in patients with active UC (P<0.0001 vs. healthy controls). This elevation was clearly related to the presence of intestinal inflammation as it was less frequently observed in patients in remission (P=0.003 vs. active UC) whereas effective treatment resulted in disappearance or significant decrease of serum DcR3 (P=0.006 vs. pre-treatment). Furthermore, DcR3 mRNA transcripts were significantly elevated in inflamed areas of the colon (P=0.002 vs. non-affected of the same patient). In addition to DcR3 elevation, we found increased circulating levels of TL1A in patients with either active or inactive UC in comparison to healthy controls (P<0.001 for both). We conclude that elevated serum DcR3 may serve as an indicator of active colonic inflammation in patients with UC. TL1A/DcR3-mediated pathways may participate in the pathogenesis of UC.

Early ileocolonoscopy with biopsy for the evaluation of persistent post-transplantation diarrhea.

AIM: To investigate the significance of ileocolonoscopy with histology in the evaluation of post-transplantation persistent diarrhea (PD). METHODS: We retrospectively reviewed all records of renal transplant patients with PD, over a 3-year period. All patients were referred for ileocolonoscopy with biopsy, following a negative initial diagnostic work up. Clinical and epidemiological data were compared between cases with infectious or drug-induced diarrhea. RESULTS: We identified 30 episodes of PD in 23 renal transplant patients (1-3 cases per patient). There were 16 male patients and the mean age at the time of PD was 51.4 years. The average time from transplantation to a PD episode was 62.3 +/- 53.2 mo (range 1-199 mo). Ileocolonoscopy detected mucosal abnormalities in 19 cases, whereas the intestinal mucosa appeared normal in 11 cases. Histological examination achieved a specific diagnosis in 19/30 cases (63.3%). In nine out of 11 cases (82%) with normal endoscopic appearance of the mucosa, histological examination of blinded biopsies provided a specific diagnosis. The etiology of PD was infectious in 11 cases (36.6%), drug-related in 10 (33.3%), of other causes in three (10%), and of unknown origin in six cases (20%). Infectious diarrhea occurred in significantly longer intervals from transplantation compared to drug-related PD (85.5 +/- 47.6 mo vs 40.5 +/- 44.8 mo, P < 0.05). Accordingly, PD due to drug-toxicity was rarely seen after the first year post-transplantation. Clinical improvement followed therapeutic intervention in 90% of cases. Modification of immunosuppressive regimen was avoided in 57% of patients. CONCLUSION: Early ileocolonoscopy with biopsies from both affected and normal mucosa is an important adjunctive tool for the etiological diagnosis of PD in renal transplant patients.

Capsule endoscopy in the investigation of patients with portal hypertension and anemia.

INTRODUCTION: Data on small bowel abnormalities in patients with portal hypertension (PHT) are limited. Bleeding from the gastrointestinal tract and anemia are common complications in these patients. Capsule endoscopy (CE) was used to evaluate small bowel (SB) pathology in patients with PHT and anemia, and possible associations with various parameters were examined. METHODS: Thirty-five patients with PHT referred for CE investigation of the SB for anemia were prospectively enrolled in the study, as well as 70 age- and sex-matched control patients with anemia, normal liver function and no evidence of PHT who underwent CE. RESULTS: Findings compatible with portal hypertensive enteropathy (PHE) were detected in 65.7% of the patients and in 15.7% of the controls chi2=26.641, P=0.000). Abnormalities in PHT patients included varices in 25.7%, diffuse changes of mucosa with inflammatory-like appearance in 42.9%, and angiodysplasias and/or spider angiomas in 22.9% of cases. The presence of PHE was significantly associated only with the presence of severe portal hypertensive gastropathy, while the presence of SB varices alone was significantly associated with the presence of severe portal hypertensive gastropathy, larger esophageal varices and the presence of colonic varices. CONCLUSIONS: Varices, diffuse changes of mucosa with inflammatory-like appearance, and angiodysplasias and/or spider angiomas are detected more often in patients with PHT than in controls, and probably constitute the endoscopic characteristics of PHE. CE of the SB added a significant number of likely important findings to those detected by conventional endoscopic techniques for the clinical management of patients with PHT and anemia.

IFN-alpha2b monotherapy in patients with chronic hepatitis C and persistently normal or near normal aminotransferase activity: a randomized, controlled study.

To determine the effect of interferon-alpha2b (IFN-alpha2b) on the long-term suppression of hepatitis C virus (HCV) RNA in patients with persistently normal or near normal alanine aminotransferase (ALT) activity, 76 previously untreated patients with serum HCV RNA and ALT levels <1.5 times the upper limit of normal (ULN) were randomized to receive either interferon-alpha2b (IFN-alpha2b) 5 MU three times a week for 24 weeks (n = 37) or no treatment (n = 39). HCV RNA testing was performed at the end of treatment and after a 6-month follow-up period. Intention-to-treat analysis showed that HCV RNA was detected significantly less frequently in treated than in untreated patients, at the end of both treatment and follow-up (43.2% vs. 7.7%, p < 0.001, and 21.6% vs. 5.1%, p = 0.033, respectively). Among treated patients, sustained virologic response was significantly higher in non-1 than in genotype 1 patients (8 of 26 or 30.8% vs. 0 of 11, p = 0.038). According to multiple logistic regression, untreated patients had a 13.5 times greater risk to be HCV RNA-positive compared with treated patients (p = 0.040). ALT levels flared up in 3 treated and 9 untreated patients (p = 0.07), suggesting that these flare-ups are related to the natural course of chronic HCV infection rather than to IFN-alpha2b. Thus, such patients could benefit from an IFN-alpha2b in combination with ribavirin regimen.