Michael Schepke

Ligation versus propranolol for the primary prophylaxis of variceal bleeding in cirrhosis

In this randomized controlled multicenter trial, we compared endoscopic variceal banding ligation (VBL) with propranolol (PPL) for primary prophylaxis of variceal bleeding. One hundred fifty‐two cirrhotic patients with 2 or more esophageal varices (diameter >5 mm) without prior bleeding were randomized to VBL (n = 75) or PPL (n = 77). The groups were well matched with respect to baseline characteristics (age 56 ± 10 years, alcoholic etiology 51%, Child‐Pugh score 7.2 ± 1.8). The mean follow‐up was 34 ± 19 months. Data were analyzed on an intention‐to‐treat basis. Neither bleeding incidence nor mortality differed significantly between the 2 groups. Variceal bleeding occurred in 25% of the VBL group and in 29% of the PPL group. The actuarial risks of bleeding after 2 years were 20% (VBL) and 18% (PPL). Fatal bleeding was observed in 12% (VBL) and 10% (PPL). It was associated with the ligation procedure in 2 patients (2.6%). Overall mortality was 45% (VBL) and 43% (PPL) with the 2‐year actuarial risks being 28% (VBL) and 22% (PPL). 25% of patients withdrew from PPL treatment, 16% due to side effects. In conclusion, VBL and PPL were similarly effective for primary prophylaxis of variceal bleeding. VBL should be offered to patients who are not candidates for long‐term PPL treatment. (HEPATOLOGY 2004;40:65–72.)

Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase.

In cirrhosis, increased RhoA/Rho‐kinase signaling and decreased nitric oxide (NO) availability contribute to increased intrahepatic resistance and portal hypertension. Hepatic stellate cells (HSCs) regulate intrahepatic resistance. 3‐Hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) inhibit synthesis of isoprenoids, which are necessary for membrane translocation and activation of small GTPases like RhoA and Ras. Activated RhoA leads to Rho‐kinase activation and NO synthase inhibition. We therefore investigated the effects of atorvastatin in cirrhotic rats and isolated HSCs. Rats with secondary biliary cirrhosis (bile duct ligation, BDL) were treated with atorvastatin (15 mg/kg per day for 7 days) or remained untreated. Hemodynamic parameters were determined in vivo (colored microspheres). Intrahepatic resistance was investigated in in situ perfused livers. Expression and phosphorylation of proteins were analyzed by RT‐PCR and immunoblots. Three‐dimensional stress‐relaxed collagen lattice contractions of HSCs were performed after incubation with atorvastatin. Atorvastatin reduced portal pressure without affecting mean arterial pressure in vivo. This was associated with a reduction in intrahepatic resistance and reduced responsiveness of in situ–perfused cirrhotic livers to methoxamine. Furthermore, atorvastatin reduced the contraction of activated HSCs in a 3‐dimensional stress‐relaxed collagen lattice. In cirrhotic livers, atorvastatin significantly decreased Rho‐kinase activity (moesin phosphorylation) without affecting expression of RhoA, Rho‐kinase and Ras. In activated HSCs, atorvastatin inhibited the membrane association of RhoA and Ras. Furthermore, in BDL rats, atorvastatin significantly increased hepatic endothelial nitric oxide synthase (eNOS) mRNA and protein levels, phospho‐eNOS, nitrite/nitrate, and the activity of the NO effector protein kinase G (PKG). Conclusion: In cirrhotic rats, atorvastatin inhibits hepatic RhoA/Rho‐kinase signaling and activates the NO/PKG‐pathway. This lowers intrahepatic resistance, resulting in decreased portal pressure. Statins might represent a therapeutic option for portal hypertension in cirrhosis. (HEPATOLOGY 2007;46:242–253.)

Neutropenic enterocolitis in adults: systematic analysis of evidence quality.

Abstract:  Objective: Neutropenic enterocolitis is a life‐threatening complication occurring most frequently after intensive chemotherapy in acute leukaemias. The literature is heterogenous and a systematic review is lacking. Methods: Following a systematic search we categorised all relevant reports according to their quality and extracted evidence to answer the questions: Which diagnostic criteria are appropriate? What is the incidence of neutropenic enterocolitis? Are there good quality studies supporting specific interventions: Which empiric antimicrobial therapy is recommendable? Is neutropenic enterocolitis without surgical emergency complications an indication for bowel resection? Results: We found and analysed 145 articles of these reports: 64 were reports of single cases, 30 papers reported of two or three cases, 13 were narrative reviews, 34 were retrospective case series of more than three cases and four were prospective diagnostic studies. There were no prospective trials or case control studies on the therapy of neutropenic enterocolitis. There was no consensus on diagnostic criteria. We discuss the difficulty to define diagnostic criteria without having a disease definition. Histology is mostly not available in the living patients. We suggest applying a combination of clinical and radiological criteria: fever, abdominal pain and any bowel wall thickening >4 mm detected by ultrasonography (US) or computed tomography. We calculated a pooled incidence rate from 21 studies of 5.3% (266/5058; 95% CI: 4.7%–5.9%) in patients hospitalised for haematological malignancies, for high‐dose chemotherapy in solid tumours or for aplastic anaemia. Conclusions: This systematic review provides diagnostic criteria for neutropenic enterocolitis, presents a quantitative synthesis on its incidence and discusses its treatment recommendations. Prospective studies are clearly warranted.

Comparison of MELD, Child-Pugh, and Emory model for the prediction of survival in patients undergoing transjugular intrahepatic portosystemic shunting

OBJECTIVES:Recently, new prognostic models (Model for End-Stage Liver Disease [MELD model] and Emory score) were proposed for the prediction of survival in transjugular intrahepatic portosystemic shunt (TIPS) patients. Although the MELD model is considered to be superior and has consecutively been applied to priority listing for liver transplantation, these models have never been directly compared in terms of long-term prognosis. We therefore compared the prognostic accuracy of the different models, including the Child-Pugh score, in an unselected cohort of TIPS patients followed long-term.METHODS:Baseline risk scores for 162 unselected consecutive TIPS patients followed until death (n = 81), liver transplantation, or end of observation (n = 81) (mean follow-up 30.7 ± 26.4 months) were calculated, and respective concordance- (c-)statistics for the predictive accuracy of 3-, 12-, and 36-month survival for the three models were compared statistically.RESULTS:All three models predicted short-term (3-month) survival with similar accuracy. The MELD model generated the best c-statistics for both 12-month (c-statistic 0.73, 95% CI = 0.64–0.82) and 36-month survival (c-statistic 0.74, 95% CI = 0.64–0.84). The predictive accuracy of the Emory score was significantly lower (c-statistic for 12-month survival: 0.60, 95% CI = 0.52–0.68, p = 0.012 vs MELD). In the statistical comparison of the MELD and the Child-Pugh model, only a trend favoring MELD for the prediction of 1-yr survival in patients with intestinal bleeding could be observed (MELD: c-statistic 0.78, 95% CI = 0.67–0.89; Child-Pugh: c-statistic 0.67, 95% CI = 0.55–0.80, p = 0.059).CONCLUSIONS:The MELD model is superior to the Emory score but only slightly superior to the Child-Pugh classification for the prediction of long-term survival in TIPS patients.

Increased urotensin II plasma levels in patients with cirrhosis and portal hypertension

Abstract Background/Aims : Vasodilatation – despite activation of endogenous vasoconstrictors – is pronounced in portal hypertension. We therefore investigated the role of Urotensin II (U II), a newly described peptide reported to be a vasoconstrictor in the central arterial compartment and a vasodilator in the splanchnic vasculature. Methods : U II immunoreactivity was measured in 50 patients with cirrhosis and in 15 healthy controls. U II levels were compared in portal venous and central venous blood of 30 patients immediately before transjugular intrahepatic porto-systemic stent shunt implantation. Results : U II levels (median, range, ng/ml) were significantly increased in cirrhotics (12.3, 1.6–41.4) compared to controls (3.6, 0.1–12.0; P P P P P Conclusions : Urotensin II formation is upregulated in patients with cirrhosis and portal hypertension. The transhepatic gradient suggests a hepatic production of this peptide.

Prevention of Rebleeding From Esophageal Varices in Patients With Cirrhosis Receiving Small-Diameter Stents Versus Hemodynamically Controlled Medical Therapy

BACKGROUND & AIMS Patients with cirrhosis and variceal hemorrhage have a high risk of rebleeding. We performed a prospective randomized trial to compare the prevention of rebleeding in patients given a small-diameter covered stent vs those given hepatic venous pressure gradient (HVPG)-based medical therapy prophylaxis. METHODS We performed an open-label study of patients with cirrhosis (92% Child class A or B, 70% alcoholic) treated at 10 medical centers in Germany. Patients were assigned randomly more than 5 days after variceal hemorrhage to groups given a small covered transjugular intrahepatic portosystemic stent-shunt (TIPS) (8 mm; n = 90), or medical reduction of portal pressure (propranolol and isosorbide-5-mononitrate; n = 95). HVPG was determined at the time patients were assigned to groups (baseline) and 2 weeks later. In the medical group, patients with an adequate reduction in HVPG (responders) remained on the drugs whereas nonresponders underwent only variceal band ligation. The study was closed 10 months after the last patient was assigned to a group. The primary end point was variceal rebleeding. Survival, safety (adverse events), and quality of life (based on the Short Form-36 health survey) were secondary outcome measures. RESULTS A significantly smaller proportion of patients in the TIPS group had rebleeding within 2 years (7%) than in the medical group (26%) (P = .002). A slightly higher proportion of patients in the TIPS group experienced adverse events, including encephalopathy (18% vs 8% for medical treatment; P = .05). Rebleeding occurred in 6 of 23 patients (26%) receiving medical treatment before hemodynamic control was possible. Per-protocol analysis showed that rebleeding occurred in a smaller proportion of the 32 responders (18%) than in nonresponders who received variceal band ligation (31%) (P = .06). Fifteen patients from the medical group (16%) underwent TIPS placement during follow-up evaluation, mainly for refractory ascites. Survival time and quality of life did not differ between both randomized groups. CONCLUSIONS Placement of a small-diameter, covered TIPS was straightforward and prevented variceal rebleeding in patients with Child A or B cirrhosis more effectively than drugs, which often required step-by-step therapy. However, TIPS did not increase survival time or quality of life and produced slightly more adverse events. Clinical Trial no: ISRCTN 16334693.

Novel endocuff-assisted colonoscopy significantly increases the polyp detection rate: a randomized controlled trial.

Goals and Background: Screening colonoscopy for colorectal cancer has proven to reduce mortality rates. Recently the Endocuff (EC), an attachment to the distal tip of the colonoscope, was introduced. The aim of our study was to compare EC-assisted colonoscopies with standard colonoscopies for the detection of colonic polyps. Study: This study is a randomized prospective 2-center trial. The study was conducted at 2 tertiary care centers. Participants: A total of 498 patients [249 males; median age 67 y; interquartile range (IQR), 56-75 y] for colon adenoma screening purposes were included. All patients underwent standard colonoscopy with or without the use of EC. Overall polyp detection rate, the number of colonic polyps, and the polyp distribution in the colon were measured. Difference in recognition of polyps with or without the use of EC was assessed. Statistical analysis was applied. Results: In the EC group, the number of polyps detected per patient was 63% higher [2.00 (IQR, 1.00-4.00) vs. 1.00 (IQR, 1.00-2.25), P<0.0001]. The polyp detection rate in patients increased by 14% with the use of EC (56% vs. 42%, P=0.001). For polyp detection, superiority by use of EC could be observed in the sigmoid (P=0.001) and cecum (P=0.002) for polyps <1 cm in diameter. In the EC group, the number of adenomas detected per patient significantly increased by 86% (P=0.002). No major complications occurred in both groups. Conclusions: The use of the EC is feasible and safe with significantly higher polyp detection rates, especially for those located in the sigmoid region. The cuff system has the potential to improve the accuracy of screening colonoscopies.

Vascular dysfunction in human and rat cirrhosis: role of receptor-desensitizing and calcium-sensitizing proteins.

In cirrhosis, vascular hypocontractility leads to vasodilation and contributes to portal hypertension. Impaired activation of contractile pathways contributes to vascular hypocontractility. Angiotensin II type 1 receptors (AT1‐Rs) are coupled to the contraction‐mediating RhoA/Rho‐kinase pathway and may be desensitized by phosphorylation through G‐protein‐coupled receptor kinases (GRKs) and binding of β‐arrestin‐2. In the present study, we analyzed vascular hypocontractility to angiotensin II in cirrhosis. Human hepatic arteries were obtained during liver transplantation. In rats, cirrhosis was induced by bile duct ligation (BDL). Contractility of rat aortic rings was measured myographically. Protein expression and phosphorylation were analyzed by Western blot analysis. Immunoprecipitation was performed with protein A–coupled Sepharose beads. Myosin light chain (MLC) phosphatase activity was assessed as dephosphorylation of MLCs. Aortas from BDL rats were hyporeactive to angiotensin II and extracellular Ca2+. Expression of AT1‐R and Gαq/11,12,13 remained unchanged in hypocontractile rat and human vessels, whereas GRK‐2 and β‐arrestin‐2 were up‐regulated. The binding of β‐arrestin‐2 to the AT1‐R was increased in hypocontractile rat and human vessels. Inhibition of angiotensin II–induced aortic contraction by the Rho‐kinase inhibitor Y‐27632 was pronounced in BDL rats. Basal phosphorylation of the ROK‐2 substrate moesin was reduced in vessels from rats and patients with cirrhosis. Analysis of the expression and phosphorylation of Ca2+‐sensitizing proteins (MYPT1 and CPI‐17) in vessels from rats and patients with cirrhosis suggested decreased Ca2+ sensitivity. Angiotensin II–stimulated moesin phosphorylation was decreased in aortas from BDL rats. MLC phosphatase activity was elevated in aortas from BDL rats. Conclusion: Vascular hypocontractility to angiotensin II in cirrhosis does not result from changes in expression of AT1‐Rs or G‐proteins. Our data suggest that in cirrhosis‐induced vasodilation, the AT1‐R is desensitized by GRK‐2 and β‐arrestin‐2 and that changed patterns of phosphorylated Ca2+‐sensitizing proteins decrease Ca2+ sensitivity. (HEPATOLOGY 2007;45:495–506.)

Higher Adenoma Detection Rates with Endocuff-Assisted Colonoscopy – A Randomized Controlled Multicenter Trial

Objectives The Endocuff is a device mounted on the tip of the colonoscope to help flatten the colonic folds during withdrawal. This study aimed to compare the adenoma detection rates between Endocuff-assisted (EC) colonoscopy and standard colonoscopy (SC). Methods This randomized prospective multicenter trial was conducted at four academic endoscopy units in Germany. Participants: 500 patients (235 males, median age 64[IQR 54–73]) for colon adenoma detection purposes were included in the study. All patients were either allocated to EC or SC. The primary outcome measure was the determination of the adenoma detection rates (ADR). Results The ADR significantly increased with the use of the Endocuff compared to standard colonoscopy (35.4%[95% confidence interval{CI} 29–41%] vs. 20.7%[95%CI 15–26%], p<0.0001). Significantly more sessile polyps were detected by EC. Overall procedure time and withdrawal time did not differ. Caecal and ileum intubation rates were similar. No major adverse events occurred in both groups. In multivariate analysis, age (odds ratio [OR] 1.03; 95%[CI] 1.01–1.05), male sex (OR 1.74; 95%CI 1.10–2.73), withdrawal time (OR 1.16; 95%CI 1.05–1.30), procedure time (OR 1.07; 95%CI 1.04–1.10), colon cleanliness (OR 0.60; 95%CI 0.39–0.94) and use of Endocuff (OR 2.09; 95%CI 1.34–3.27) were independent predictors of adenoma detection rates. Conclusions EC increases the adenoma detection rate by 14.7%(95%CI 6.9–22.5%). EC is safe, effective, easy to handle and might reduce colorectal interval carcinomas. Trial Registration ClinicalTrials.gov NCT02034929.

Prognostic factors for patients with cirrhosis and kidney dysfunction in the era of MELD: results of a prospective study

Abstract: Background/Aim: Hepatorenal syndrome (HRS) is associated with a poor prognosis. The incidence and prognostic impact of kidney dysfunction due to other causes in cirrhotic patients are less well known. The current study prospectively evaluated the incidence and the prognostic relevance of different etiologies of kidney failure in cirrhotic patients.