Christian Mortensen

Infliximab for Inflammatory Bowel Disease in Denmark 1999–2005: Clinical Outcome and Follow-Up Evaluation of Malignancy and Mortality

BACKGROUND & AIMS Data on safety and long-term follow-up evaluation of population-based cohorts of inflammatory bowel disease (IBD) patients treated with infliximab are sparse. The aim of this article is to describe the use of infliximab in a national Danish population-based IBD cohort during 1999-2005. METHODS Medical records of all infliximab-treated IBD patients were scrutinized to abstract information on patient demographics, treatment efficacy, and adverse events. RESULTS A total of 651 patients (619 with Crohns disease, 15 with ulcerative colitis, and 17 with colonic IBD type unclassified) received infliximab during 1999-2005. A total of 3351 infusions were administered, with a median of 3 infusions per patient. A positive clinical response was observed in 82.7% (95% confidence interval, 79.9-85.5) of patients. Infusion reactions were observed after 146 of 3351 infusions (4.4%). Significantly fewer infusion reactions were seen in patients also receiving azathioprine or methotrexate (63 of 2079; 3.0%), compared with patients not receiving azathioprine or methotrexate (83 of 1272; 6.5%) (P < .0001). Severe adverse events were observed after 112 of 3351 infusions (3.3%) in a total of 95 patients (14.6%). Four patients developed cancer versus 5.9 expected (standardized incidence ratio, 0.7; 95 confidence interval, 0.2-1.7) and 13 patients died versus 6.9 expected (standardized mortality ratio, 1.9; 95% confidence interval, 1.0-3.2). Two deaths caused by infections were possibly related to infliximab. CONCLUSIONS Infliximab seemed effective in IBD and generally was well tolerated. However, rare but severe adverse events occurred, and patients receiving infliximab therefore should be selected carefully and monitored closely. No lymphomas and no increased risk of cancer were observed.

Effects of a single terlipressin administration on cardiac function and perfusion in cirrhosis.

Background The vasoconstrictor terlipressin is widely used in the treatment of the hepatorenal syndrome and variceal bleeding. However, terlipressin may compromise cardiac function and induce ischemia. Aim Therefore, we aimed to assess the effects of terlipressin on cardiac function and perfusion. Methods Twenty-four patients with cirrhosis and ascites participated, including nine with refractory ascites. Gated myocardial perfusion imaging, mean arterial blood pressure (MAP), cardiac output (CO), ejection fraction (EF), end-diastolic volume (EDV), perfusion, and motion of the myocardium were determined before and after a bolus injection of 2 mg terlipressin. Results MAP increased after terlipressin (P value of less than 0.001). EF and CO fell by −16 and −17%, respectively in the terlipressin group versus 1 and −2%, respectively in the placebo group (P value of less than 0.001 and P value of less than 0.01). In the terlipressin group, EDV increased by 18 versus −4% in the placebo group (P value of less than 0.01). Wall motion in the anterior and posterior walls fell by −18 and −22%, respectively after terlipressin treatment versus 0 and 0% in the placebo group (P value of less than 0.01). In contrast, myocardial perfusion and stroke volume were unaltered in both the groups. The change in EF during terlipressin treatment correlated significantly with the change in MAP (r=−0.60, P value <0.002). Patients with refractory ascites had a higher EF and lower EDV and ESV than the patients with nonrefractory ascites, both at baseline and after terlipressin treatment. The decrease in the left ventricular wall thickening and wall motion correlated with the Child--Pugh score, r=−0.59, P=0.005 and r=−0.48, P=0.03. Conclusion In advanced cirrhosis, the increase in afterload and EDV after terlipressin treatment result in a decrease in left ventricular wall motion, resulting in reduced CO and EF, but myocardial perfusion is preserved. Alteration in cardiac function at baseline and after terlipressin treatment relates to the stage of decompensation.

Infliximab and complications after colectomy in patients with ulcerative colitis

BACKGROUND Infliximab treatment may increase the risk of subsequent postoperative complications in patients with ulcerative colitis. The main purpose of the present study therefore was to assess postoperative complications in patients who have undergone colectomy for ulcerative colitis with and without previous infliximab treatment. METHODS Through a database search within a five-year period ulcerative colitis patients in a single highly specialized department, who had undergone colectomy, were identified. In total 71 ulcerative colitis patients were identified and analyzed according to pretreatment with infliximab or not. Twenty patients who had received infliximab within 12 weeks prior to colectomy were compared to 51 patients on standard treatment. Data on patient background, concomitant medication, endoscopic and the laboratory results, clinical activity, and complications within 30 days after colectomy were recorded. RESULTS At primary surgery, patient groups were similar with respect to distribution on gender, age, smoking behavior and concomitant medication. There were significant differences in partial Mayo-scores (7,95 (IFX) vs. 7,64, P=0.032); preoperative CRP-levels (42,72 (IFX) vs. 63,2, P=0.05); postoperative hospitalization time (10,9 (IFX) vs. 11,3 days, P=0.039); and in number of patients who underwent elective surgery (10% vs. 37,3%, P=0.015). There was no short-term mortality in either group and no significant difference in terms of postoperative complications between patients treated with IFX or not. However, the number of postoperative infectious complications was increased in corticosteroid-treated patients irrespective of IFX or not (45,8% in CS group vs. 13,0%, P=0.028). CONCLUSIONS The use of infliximab does not seem to associate with an increased risk of short-term postoperative complications in ulcerative colitis.

Lactate metabolism in chronic liver disease

Abstract Background. In the healthy liver there is a splanchnic net-uptake of lactate caused by gluconeogenesis. It has previously been shown that patients with acute liver failure in contrast have a splanchnic release of lactate caused by a combination of accelerated glycolysis in the splanchnic region and a reduction in hepatic gluconeogenesis. Aims. The aims of the present study were to investigate lactate metabolism and kinetics in patients with chronic liver disease compared with a control group with normal liver function. Methods. A total of 142 patients with chronic liver disease and 14 healthy controls underwent a liver vein catheterization. Blood samples from the femoral artery and the hepatic and renal veins were simultaneously collected before and after stimulation with galactose. Results. The fasting lactate levels, both in the hepatic vein and in the femoral artery, were higher in the patients than in the controls (P < 0.001) and there were a hepatic net-uptake of lactate in both groups. Fasting lactate concentrations correlated directly with the portal pressure, mean arterial blood pressure, and SaO2 and negatively with ICG clearance. Conclusions. Lactate levels are elevated in cirrhotic patients compared to controls relating to portal pressure and aspects of liver dysfunction and the lactate levels seem to increase with the severity of cirrhosis. This may not be caused by decreased gluconeogenesis but merely be due to accelerated glycolysis in the splanchnic region. Future studies should focus on the impact of chronic liver disease on lactate kinetics.

High-sensitivity C-reactive protein levels predict survival and are related to haemodynamics in alcoholic cirrhosis.

Objectives Inflammation may be implicated in the haemodynamic deterioration and in the development of complications in patients with cirrhosis. High-sensitivity C-reactive protein (hsCRP) is a marker of low-grade inflammation, and predicts outcomes in patients at risk of ischaemic heart disease. Proinflammatory cytokines reflect immune activation and have been found to be elevated in cirrhosis. We investigated a possible association between markers of inflammation and splanchnic and systemic haemodynamics, complications and survival in patients with cirrhosis. Methods In 45 stable patients with cirrhosis on the basis of alcohol consumption, we measured hsCRP, as well as monocyte chemoattractant protein-1, tumour necrosis factor-&agr;, interleukin-6, interleukin-8 and vascular endothelial growth factor in patients and in 12 healthy controls. Systemic and splanchnic haemodynamics were investigated in patients. Results hsCRP levels were significantly higher in patients compared with controls (P<0.05) and the highest in patients belonging to Child–Pugh class C. hsCRP levels correlated with markers of liver dysfunction and with the hepatic venous pressure gradient (r=0.48, P<0.001). hsCRP values above the median level of 5.3 mg/l were associated with a highly increased mortality (P=0.001). Model for End-Stage Liver Disease score (P=0.01) and hsCRP (P<0.05) provided independent prognostic information. Cytokines had no discernible value in predicting survival. Conclusion hsCRP is elevated in patients with cirrhosis and is associated with portal hypertension and decreased survival. hsCRP is a promising prognostic marker in cirrhosis, which may improve the selection of candidates for liver transplantation.

Output-Sensitive autocompletion search

We consider the following autocompletion search scenario: imagine a user of a search engine typing a query; then with every keystroke display those completions of the last query word that would lead to the best hits, and also display the best such hits. The following problem is at the core of this feature: for a fixed document collection, given a set D of documents, and an alphabetical range W of words, compute the set of all word-in-document pairs (w,d) from the collection such that w ∈W and d∈D. We present a new data structure with the help of which such autocompletion queries can be processed, on the average, in time linear in the input plus output size, independent of the size of the underlying document collection. At the same time, our data structure uses no more space than an inverted index. Actual query processing times on a large test collection correlate almost perfectly with our theoretical bound.

No difference in portal and hepatic venous bacterial DNA in patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt insertion

Bacterial translocation (BT) with immune activation may lead to hemodynamical alterations and poor outcomes in patients with cirrhosis.

Association of markers of bacterial translocation with immune activation in decompensated cirrhosis.

Background Bacterial translocation (BT) may cause infections, in particular, spontaneous bacterial peritonitis (SBP). In the absence of overt infection, BT may further stimulate the immune system and contribute to haemodynamic alterations and complications. Bacterial DNA (bDNA) is claimed to be a promising surrogate marker for BT, although its clinical relevance has been questioned. Materials and methods In 38 cirrhotic patients with and without SBP, bDNA in blood and ascites were assessed by 16S rDNA quantitative PCR. Levels of lipopolysaccharide-binding protein in plasma and highly sensitive C-reactive protein, tumour necrosis factor-&agr;, soluble urokinase plasminogen activating receptor, interleukin-6, interleukin 8, interferon-&ggr; inducible protein-10 and vascular endothelial growth factor in plasma and ascites were measured by multiplex cytokine and ELISA assays. Results In patients without signs of SBP or positive cultures, we found a high frequency of bDNA but low concordance of bDNA between blood and ascites. Markers of inflammation were not significantly different between blood bDNA-positive (22%), ascites bDNA-positive (52%), and bDNA-negative patients. The 16S rDNA PCR failed to show bDNA in two out of six samples with SBP. Sequencing of positive samples did not determine the source of bDNA. Conclusion bDNA as assessed by this PCR method was largely unrelated to markers of inflammation and does not seem to be of clinical value in the diagnosis of SBP. According to our results, bDNA is not a reliable marker of BT.

Assessment of response to beta-blockers by expression of βArr2 and RhoA/ROCK2 in antrum mucosa in cirrhotic patients

BACKGROUND & AIMS Non-selective beta-blockers (NSBB) are first choice for prevention of variceal bleeding. But possible deleterious effects in refractory ascites and frequent non-response are clinical drawbacks. Since levels of vasoactive proteins in antrum mucosa reflect vascular dysfunction in cirrhosis, these expression levels might also reflect hemodynamic response to NSBB. METHODS Biopsies from the gastric and duodenal mucosa of 25 patients with cirrhosis were collected and the hepatic venous pressure gradient (HVPG) was measured before and after an acute propranolol challenge. Transcription and protein expression of Ras homolog family member A (RhoA), Rho-kinase (ROCK)2, beta-arrestin2 (βArr2), endothelial nitric oxide synthase (eNOS) and the phosphorylation of downstream effectors VASP and moesin were analyzed using PCR and Western blot. Further 21 patients on NSBB were evaluated on their follow up for events of variceal bleeding defined as non-response. RESULTS Ten patients showed HVPG <10mmHg, further seven patients showed significant hemodynamic response to NSBB, whereas eight patients were non-responders. The mucosal transcription of vasoactive proteins was higher in antrum mucosa compared to corpus and duodenum. The transcriptional levels of vasoactive proteins were higher in patients with HVPG >10mmHg and HVPG >16mmHg. Interestingly, mRNA levels of RhoA and ROCK2 were lower in patients with large varices at endoscopy. Moreover, RhoA and ROCK2 transcription correlated with the decrease of HVPG after acute NSBB challenge. Finally, acute and long-term non-responders showed lower expression of βArr2 in antrum mucosa. CONCLUSION This study shows for the first time that the expression of βArr2 in antrum mucosa biopsies might reflect the hemodynamic response to NSBB and their long-term protective effect. This finding might offer an easy approach at upper endoscopy to facilitate the decision to treat with NSBB if varices are present.

The soluble mannose receptor is released from the liver in cirrhotic patients, but is not associated with bacterial translocation

Intestinal bacterial translocation is involved in activation of liver macrophages in cirrhotic patients. Macrophages play a key role in liver inflammation and are involved in the pathogenesis of cirrhosis and complications. Bacterial translocation may be determined by presence of bacterial DNA and macrophage activation, by the soluble mannose receptor. We hypothesize that the soluble mannose receptor is released from hepatic macrophages in cirrhosis and associated with bacterial DNA, portal pressure and complications.