Flemming Bendtsen

Increasing incidences of inflammatory bowel disease and decreasing surgery rates in Copenhagen City and County, 2003-2005 : A population-based study from the danish crohn colitis database

OBJECTIVES:A continuous increase in the incidence of inflammatory bowel disease (IBD), Crohns disease (CD), ulcerative colitis (UC), and indeterminate colitis (IC) has been suggested. Since Denmark provides excellent conditions for epidemiological research, we aimed to describe contemporary IBD incidence rates and patient characteristics in Copenhagen County and City.METHODS:All patients diagnosed with IBD during 2003–2005 were followed prospectively. Demographic and clinical characteristics, such as disease extent, extraintestinal manifestations, smoking habits, medical treatment, surgical interventions, cancer, and death, were registered.RESULTS:Five-hundred sixty-two patients were diagnosed with IBD, resulting in mean annual incidences of 8.6/105 for CD, 13.4/105 for UC, and 1.1/105 for IC. Time from onset to diagnosis was 8.3 months in CD and 4.5 months in UC patients. A family history of IBD, smoking, and extraintestinal manifestations was significantly more common in CD than in UC patients. Only 0.6% of UC patients had primary sclerosing cholangitis. In CD, old age at diagnosis was related to pure colonic disease, whereas children significantly more often had proximal and extensive involvement. Twelve percent of CD patients and 6% of UC patients underwent surgery during the year of diagnosis, significantly less than earlier reported.CONCLUSIONS:The incidence of IBD in Copenhagen increased noticeably during the last decades. Time from onset of symptoms until diagnosis decreased markedly, extent of CD was related to age at diagnosis, and the risk of surgery was low in UC.

Recombinant factor VIIa for variceal bleeding in patients with advanced cirrhosis: A randomized, controlled trial

A beneficial effect of recombinant activated factor VII (rFVIIa) in Child‐Pugh class B and C patients with cirrhosis who have variceal bleeding has been suggested. This randomized controlled trial assessed the efficacy and safety of rFVIIa in patients with advanced cirrhosis and active variceal bleeding. At 31 hospitals in an emergency setting, 256 patients (Child‐Pugh > 8; Child‐Pugh B = 26%, C = 74%) were randomized equally to: placebo; 600 μg/kg rFVIIa (200 + 4× 100 μg/kg); or 300 μg/kg rFVIIa (200 + 100 μg/kg). Dosing was intravenous at 0, 2, 8, 14, and 20 hours after endoscopy, in addition to standard vasoactive, prophylactic antibiotic, and endoscopic treatment. The primary composite endpoint consisted of failure to control 24‐hour bleeding, or failure to prevent rebleeding or death at day 5. Secondary endpoints included adverse events and 42‐day mortality. Baseline characteristics were comparable between groups. Administration of rFVIIa had no significant effect on the composite endpoint compared with placebo (P = 0.37). There was no significant difference in 5‐day mortality between groups; however, 42‐day mortality was significantly lower with 600 μg/kg rFVIIa compared with placebo (odds ratio 0.31, 95% confidence interval = 0.13–0.74), and bleeding‐related deaths were reduced from 12% (placebo) to 2% (600 μg/kg). A marked heterogeneity in the failure rate in all treatment groups was observed across participating centers. Adverse events, including overall thromboembolic events, were comparable between groups. Conclusion: Treatment with rFVIIa had no significant effect on the primary composite endpoint compared with placebo. Therefore, decision on the use of this hemostatic agent in acute variceal bleeding should be carefully considered, because results of this study do not support the routine use of rFVIIa in this setting. Adverse events were comparable across groups. (HEPATOLOGY 2008.)

Serum YKL-40 is increased in patients with hepatic fibrosis

BACKGROUND/AIMS YKL-40, a mammalian member of the chitinase family, is a lectin that binds heparin and chitin. The function of YKL-40 is unknown, but it may function in tissue remodelling. The aims of this study were to assess the level of circulating YKL-40 in patients with various kinds and degree of chronic liver disease and its possible relation to liver fibrosis. METHODS Serum YKL-40 levels were determined by radioimmunoassay in 129 patients with suspected liver disease and related to histological findings and immunohistochemical staining of YKL-40 in a liver biopsy taken simultaneously with the blood sample. RESULTS The median serum YKL-40 was highest in patients with alcoholic cirrhosis (532 microg/l), in particular in patients with additional alcoholic hepatitis (740 microg/l). Patients with alcoholic cirrhosis, post-hepatitic cirrhosis (425 microg/l) and non-cirrhotic fibrosis (330 microg/l) had significantly higher serum YKL-40 than normal subjects (102 microg/l), patients with fatty liver (195 microg/l) or patients with viral hepatitis without fibrosis (174 microg/l). Serum YKL-40 was significantly (p<0.001) related to the degree of liver fibrosis with the highest levels in patients with moderate (466 microg/l) to severe (676 microg/l) fibrosis. Serum YKL-40 was also increased (p=0.018) in patients with slight fibrosis (270 microg/l) compared to patients without fibrosis. Immunohistochemical analysis demonstrated positive staining for YKL-40 antigen in areas with fibrosis, particularly areas with active fibrogenesis. YKL-40 staining was never found in hepatocytes. CONCLUSIONS Our study indicates that the increased serum YKL-40 in patients with liver disease of various degree and aetiology seems to reflect fibrosis and fibrogenesis.

Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.

Objectives: Recent studies suggest that cardiac dysfunction precedes development of the hepatorenal syndrome. In this follow-up study, we aimed to investigate the relation between cardiac and renal function in patients with cirrhosis and ascites and the impact of cardiac systolic function on survival. Patients and design: Twenty-four patients with cirrhosis and ascites were included. Cardiac function was investigated by gated myocardial perfusion imaging (MPI) for assessment of cardiac index (CI) and cardiac volumes. The renal function was assessed by determination of glomerular filtration rate (GFR) and renal blood flow (RBF) and the patients were followed up for 12 months. Results: In patients with a CI below 1.5 l/min/m2 on MPI, GFR was lower (39 (SD 24) vs 63 (SD 23) ml/min, p = 0.03), RBF was lower (352 (SD 232) vs 561 (SD 229) ml/min, p = 0.06), and serum creatinine was higher (130 (SD 46) vs 78 (SD 29) μmol/l, p<0.01). The number of patients who developed hepatorenal syndrome type 1 within 3 months was higher in the group with low CI than in the high CI group (43% vs 5%, p = 0.04). Patients with the lowest CI (N = 8) had significantly poorer survival at 3, 9, and 12 months compared to those with a higher CI (N = 16), p<0.05. In contrast, the Model for End-stage Liver Disease (MELD) score failed to predict mortality in these patients. Conclusions: The development of renal failure and poor outcome in patients with advanced cirrhosis and ascites seem to be related to a cardiac systolic dysfunction. Other parameters may be more important than MELD score to predict prognosis.

Reduced central blood volume in cirrhosis

The pathogenesis of ascites formation in cirrhosis is uncertain. It is still under debate whether the effective blood volume is reduced (underfilling theory) or whether the intravascular compartment is expanded (overflow theory). This problem has not yet been solved because of insufficient tools for measuring the central blood volume. We have developed a method that enables us to determine directly the central blood volume, i.e., the blood volume in the heart cavities, lungs, and central arterial tree. In 60 patients with cirrhosis and 16 control subjects the central blood volume was assessed according to the kinetic theory as the product of cardiac output and mean transit time of the central vascular bed. Central blood volume was significantly smaller in patients with cirrhosis than in controls (mean 21 vs. 27 ml/kg estimated ideal body weight, p less than 0.001; 25% vs. 33% of the total blood volume, p less than 0.0001). The lowest values (18 ml/kg) were found in patients with gross ascites and a reduced systemic vascular resistance. In patients with cirrhosis central blood volume was inversely correlated to the hepatic venous pressure gradient (r = -0.41, p less than 0.01), and the total blood volume was inversely correlated to the systemic vascular resistance (r = -0.49, p less than 0.001), the latter being significantly reduced in the patient group. Patients with cirrhosis apparently are unable to maintain a normal central blood volume. This may be due to arteriolar vasodilation, portosystemic collateral flow, or sequestration of fluid in the peritoneal cavity, or any combination thereof. The present results indicate that central circulatory underfilling is an integral part of the hemodynamic and homeostatic derangement observed in cirrhosis.

Effect of omeprazole and cimetidine on duodenal ulcer. A double-blind comparative trial.

We conducted a double-blind randomized study of 132 patients to determine whether the new, investigational proton-pump inhibitor, omeprazole (30 mg per day), would accelerate healing and pain relief, as compared with cimetidine (1 g per day), in patients with duodenal ulcer. After two weeks of treatment, which was completed by all patients, the healing rates were 73 per cent in the omeprazole group and 46 per cent in the cimetidine group (P less than 0.01). After four weeks of treatment, which was completed by 118 patients, the corresponding figures were 92 and 74 per cent (P less than 0.05). In the omeprazole group 55 per cent of the patients were free of pain after the first week, as compared with 40 per cent of those treated with cimetidine (P greater than 0.05). No major clinical or biochemical side effects of omeprazole or cimetidine were noted. A six-month follow-up study revealed no significant difference between the recurrence rates after omeprazole and after cimetidine treatment. In May 1984 clinical trials with omeprazole were temporarily suspended, since a study of long-term toxicity in rats had shown the development of gastric carcinoid tumors.

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.

Final results of a long-term, clinical follow-up in fatty liver patients

Objective. There is increasing focus on non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to conduct a long-term clinical follow-up of patients with biopsy-confirmed fatty liver without inflammation or significant fibrosis (pure fatty liver), to analyse for potential risk factors at the time of index liver biopsy important for survival and the development of cirrhosis and to describe the causes of death. Material and methods. Patients were linked through their personal identification number to the Danish National Registry of Patients and the Register of Causes of Death. All admissions, discharge diagnoses and causes of death during follow-up were collected. All surviving patients were invited to a clinical follow-up. Results. The follow-up period was 20.4 and 21.0 years, respectively, for the NAFLD and alcoholic fatty liver disease (AFLD) groups. Two NAFLD patients (1.2%) developed cirrhosis during the follow-up period versus 54 (22%) AFLD patients. Sixty-four percent of 178 surviving patients out of an original cohort of 417 patients attended the clinical follow-up. In NAFLD patients, none of the risk factors studied was significant in relation to the risk of death. Patients with AFLD died primarily from cirrhosis and other alcohol-related disorders, whereas in patients with NAFLD the main causes of death were cardiovascular disease and cancer. Conclusions. For patients with pure non-alcoholic fatty liver, survival was good and independent of the histological, clinical and biochemical characteristics at the time of biopsy; the main causes of death were cardiovascular disease and cancer.

Effect of volume expansion on systemic hemodynamics and central and arterial blood volume in cirrhosis

BACKGROUND & AIMS Systemic vasodilatation in cirrhosis may lead to hemodynamic alterations with reduced effective blood volume and decreased arterial blood pressure. This study investigates the response of acute volume expansion on hemodynamics and regional blood volumes in patients with cirrhosis and in controls. METHODS Thirty-nine patients with cirrhosis (12 patients with Child-Turcotte class A, 14 with class B, and 13 with class C) and 6 controls were studied. During hepatic vein catheterization, cardiac output, systemic vascular resistance, central and arterial blood volume, noncentral blood volume, and arterial pressure were determined before and during a volume expansion induced by infusion of a hyperosmotic galactose solution. RESULTS During volume expansion, the central and arterial blood volume increased significantly in patients with class A and controls, whereas no significant change was found in patients with either class B or class C. Conversely, the noncentral blood volume increased in patients with class B and C. In both patients and controls, the cardiac output increased and the systemic vascular resistance decreased, whereas the mean arterial blood pressure did not change significantly. CONCLUSIONS Only in mild cirrhosis is the effective blood volume able to increase in response to volume expansion. Our results are consistent with the peripheral vasodilatation hypothesis and the circulatory hyporeactivity occurring in advanced cirrhosis.

Plasma YKL-40: A New Potential Marker of Fibrosis in Patients with Alcoholic Cirrhosis?

BACKGROUND YKL-40 (human cartilage glycoprotein-39, or 38-kDa heparin-binding glycoprotein) is a mammalian member of a protein family that includes bacterial chitinases. YKL-40 mRNA is expressed by human liver and may play a role in tissue remodelling. The aims were to assess whether circulating YKL-40 is released or extracted in the hepatosplanchnic system and to localize YKL-40 in liver tissue. METHODS Plasma YKL-40 was determined by radioimmunoassay in 25 patients with liver diseases (alcoholic cirrhosis (n = 20), chronic active hepatitis (n = 2), cirrhosis of unknown aetiology (n = 2), and fatty liver (n = 1) and in 18 subjects with normal liver function during a haemodynamic investigation with catheterization of liver vein and the femoral artery. Immunohistochemical studies of the localization of YKL-40 in cryostal liver biopsy specimens were obtained from eight other patients with alcoholic liver disease. RESULTS Plasma YKL-40 was significantly increased in patients with alcoholic cirrhosis (median, 523 micrograms/l; P < 0.001) compared with controls (106 micrograms/l), and plasma YKL-40 in the hepatic vein was higher (P < 0.01) than that of the artery in both the patients and controls, showing release of YKL-40 from the hepatosplanchnic area. The release rate of YKL-40 from the hepatosplanchnic area was higher in patients with liver disease than in controls (11.0 versus 2.1 micrograms/min, P < 0.05). Furthermore, the highest plasma YKL-40 levels were found in patients with a moderate or severe degree of liver fibrosis, and immunohistochemical studies showed positive staining for YKL-40 antigen in areas of the liver biopsy with fibrosis. CONCLUSIONS The increased plasma YKL-40 in patients with alcoholic cirrhosis may reflect the remodelling of liver fibrosis.