Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation.

OBJECTIVE: Systemic inflammation predisposes acutely decompensated (AD) cirrhosis to the development of acute-on-chronic liver failure (ACLF). Supportive treatment can improve AD patients, becoming recompensated. Little is known about the outcome of patients recompensated after AD. We hypothesise that different inflammasome activation is involved in ACLF development in compensated and recompensated patients. DESIGN: 249 patients with cirrhosis, divided into compensated and recompensated (previous AD), were followed prospectively for fatal ACLF development. Two external cohorts (n=327) (recompensation, AD and ACLF) were included. Inflammasome-driving interleukins (ILs), IL-1α (caspase-4/11-dependent) and IL-1ß (caspase-1-dependent), were measured. In rats, bile duct ligation-induced cirrhosis and lipopolysaccharide exposition were used to induce AD and subsequent recompensation. IL-1α and IL-1ß levels and upstream/downstream gene expression were measured. RESULTS: Patients developing ACLF showed higher baseline levels of ILs. Recompensated patients and patients with detectable ILs had higher rates of ACLF development than compensated patients. Baseline CLIF-C (European Foundation for the study of chronic liver failure consortium) AD, albumin and IL-1α were independent predictors of ACLF development in compensated and CLIF-C AD and IL-1ß in recompensated patients. Compensated rats showed higher IL-1α gene expression and recompensated rats higher IL-1ß levels with higher hepatic gene expression. Higher IL-1ß detection rates in recompensated patients developing ACLF and higher IL-1α and IL-1ß detection rates in patients with ACLF were confirmed in the two external cohorts. CONCLUSION: Previous AD is an important risk factor for fatal ACLF development and possibly linked with inflammasome activation. Animal models confirmed the results showing a link between ACLF development and IL-1α in compensated cirrhosis and IL-1ß in recompensated cirrhosis.

Indocyanine green retention test in cirrhosis and portal hypertension: Accuracy and relation to severity of disease.

BACKGROUND AND AIMS: Patients with cirrhosis and portal hypertension often develop complications relating to hepatic excretory dysfunction. The standard measurement of the hepatic excretion is the constant infusion indocyanine green clearance (ICGCI ) technique. The ICG 15-min retention test (ICG-r15) is faster, more patient friendly, and cheaper. The aims were to compare the ICG-r15 test with the standard method, to assess relations to patient characteristics and survival, and to assess the ICG-r15 level in healthy control subjects. METHODS: This study included 68 patients with cirrhosis and portal hypertension (Child class A/B/C:17/37/14). All patients underwent a full liver vein catheterization and hemodynamic evaluation with determination of ICG-r15 and ICGCI as the reference in a subset of 38 patients. Sixteen healthy control subjects were included for compiling a reference interval. RESULTS: The ICG-r15 was increased in the cirrhotic patients with increasing values in parallel with liver dysfunction (15/41/58%) in Child class A/B/C compared with 7% in the controls (P < 0.001). ICG-r15 correlated highly significantly with the ICGCI (r = -0.96, P < 0.0001) and in a multivariate regression analysis with hepatic venous pressure gradient, markers of liver dysfunction and hyperdynamic circulation (P < 0.05-0.005). In the control group, normal reference values ranged from 0% to 13%. In addition, ICG-r15 was significantly related to mortality in the patient group (P = 0.02). CONCLUSIONS: Indocyanine green-r15 reflects portal hypertension, the degree of hepatic failure, and survival and may replace the standard ICGCI . A more elaborated reference interval needs to be compiled, and the prognostic value of ICG-r15 should be validated.

Gastric Emptying Is Not Delayed and Does Not Correlate With Attenuated Postprandial Blood Flow Increase in Medicated Patients With Early Parkinson's Disease.

Background: We have recently used phase-contrast magnetic resonance imaging (PC-MRI) to demonstrate an attenuated postprandial blood flow response in the superior mesenteric artery (SMA) in 23 medicated patients with Parkinson's disease (PD) compared to 23 age- and sex-matched healthy controls. Objective: To investigate in a sub-sample of the original cohort whether the observed blood flow response in SMA after oral food intake is related to a delay in gastric emptying. Methods: We studied 15 patients with PD in an "ON-medication" state with a mean disease duration of 3.9 ± 2.2 years and 15 healthy age- and sex-matched individuals. Participants underwent dynamic gastric scintigraphy 0, 30, 60, 120, 180 and 240 minutes after the intake of a standardized radiolabeled test meal. Gastric emptying was compared between groups. 14 of the 15 PD patients and 12 of the 15 healthy control subjects had previously undergone serial postprandial PC-MRI measurements. In these individuals, we tested for a relationship between gastric emptying and postprandial blood flow response in the SMA. Results: The dynamics of gastric emptying did not differ between groups (p = 0.68). There was substantial inter-subject variability of gastric emptying in PD patients and healthy participants. Only a single PD patient had delayed gastric emptying. In those participants who had undergone PC-MRI, postprandial increase in SMA blood flow was attenuated in PD compared to healthy controls as reported previously (p = 0.006). Gastric emptying did not correlate with the timing and amplitude of postprandial blood flow increase in SMA. Conclusion: Our preliminary results, obtained in a small group of early-stage PD patients who continued their usual dopamine replacement therapy, suggest that variations in gastric emptying after solid meal intake is within the normal range in the majority of cases. There is also no evidence for a tight relationship between the attenuated postprandial blood flow response in the SMA and normal variations in gastric emptying.

Effects of the H2-receptor antagonist ranitidine on gastric motor function after a liquid meal in healthy humans.

OBJECTIVE: Studies on animals have shown that histamine may be involved in the regulation of gastrointestinal smooth muscle tone. However, the role of histamine in the regulation of human gastric motor function is not clear. This study examined the effect of ranitidine, an H(2)-receptor antagonist, on gastric volume and gastric emptying after a liquid meal in healthy humans. MATERIAL AND METHODS: Twelve healthy volunteers participated in a randomized crossover study with 50 mg ranitidine as a bolus intravenously versus no medication. Gastric volume at baseline was determined with single photon emission computed tomography (SPECT) after intravenous injection of 99(m)Tc-pertechnetate. After ingestion of a 600-mL liquid meal radiolabelled with (111)In-diethylenetriaminepentaacetic acid, dual-isotope technique with SPECT and planar imaging assessed gastric volume as well as gastric emptying. RESULTS: Ranitidine did not change gastric volume before the meal, nor at 0 h or 1 h after it. Furthermore, ranitidine did not influence gastric retention of meal components after 0.5 h and 1 h. CONCLUSIONS: Intravenous bolus injection of 50 mg ranitidine does not modify gastric volume or gastric emptying after a 600 mL liquid meal in healthy humans.

Whole-Body 18F-FDG PET/CT Is Superior to CT as First-Line Diagnostic Imaging in Patients Referred with Serious Nonspecific Symptoms or Signs of Cancer: A Randomized Prospective Study of 200 Patients.

A fast-track pathway has been established in Denmark to investigate patients with serious nonspecific symptoms and signs of cancer (NSSC), who are not eligible to enter an organ-specific cancer program. The prevalence of cancer in this cohort is approximately 20%. The optimal screening strategy in patients with NSSC remains unknown. The aim of the study was to investigate whether 18F-FDG PET/CT was superior to CT as an initial imaging modality in patients with NSSC. In a randomized prospective trial, the imaging modalities were compared with regard to diagnostic performance. Methods: Two hundred patients were randomized 1:1 to whole-body 18F-FDG PET/CT or CT of the thorax and abdomen as the imaging modality. A tentative diagnosis was established after first-line imaging. The final referral diagnosis was adjudicated by the physician, when sufficient data were available. Results: One hundred ninety-seven patients were available for analysis because 3 patients withdrew consent before scanning. Thirty-nine (20%) patients were diagnosed with cancer, 10 (5%) with an infection, 15 (8%) with an autoimmune disease, and 76 (39%) with other diseases. In the remaining 57 patients (28%), no specific disease was found. 18F-FDG PET/CT had a higher specificity (96% vs. 85%; P = 0.028) and a higher accuracy (94% vs. 82%; P = 0.017) than CT. However, there were no statistically significant differences in sensitivity (83% vs. 70%) or negative predictive values (96% vs. 92%). No difference in days to final referral diagnosis according to randomization group could be shown (7.2 vs. 7.6 d). However, for the subgroups in which the imaging modality showed a suggestion of malignancy, there was a significant delay to final diagnosis in the CT group compared with the 18F-FDG PET/CT group (11.6 vs. 5.7 d; P = 0.02). Conclusion: Compared with CT, we found a higher diagnostic specificity and accuracy of 18F-FDG PET/CT for detecting cancer in patients with NSSC. 18F-FDG PET/CT should therefore be considered as first-line imaging in this group of patients.

Outcome of splanchnic blood flow determination in patients with suspected chronic intestinal ischaemia. A retrospective survey.

BACKGROUND: Different diagnostic examinations have been applied in the management of patients with suspected intestinal ischaemia. In some centres, invasive determination of a meal-induced increase in splanchnic blood flow is used in the diagnostic process and in the selection of patients for surgery. However, no studies have evaluated the impact of splanchnic blood flow determination on therapy in such patients. OBJECTIVE: The aim of the present study was therefore to analyse the outcome of splanchnic blood flow determination in patients with suspected chronic intestinal ischaemia. METHODS: Seventy-three consecutive patients with suspected intestinal ischaemia were included during a 5-year period. Splanchnic blood flow was determined at baseline and after a standardized meal. The patients were classified into three groups according to the level of meal-induced increase in splanchnic blood flow: A, normal response (splanchnic blood flow > or = 200 ml/min); B, possible abnormal response (splanchnic blood flow 51-199 ml/min); and C, definitive abnormal response (splanchnic blood flow < or = 50 ml/min). Where surgery took place, the type of operation was noted. RESULTS: Forty patients had a normal meal-induced response, 23 patients had a possible abnormal response and 10 patients had a definitive abnormal response, which gave evidence of chronic intestinal ischaemia. In the total patient population, the increase in splanchnic blood flow was significantly correlated to an increase in hepatic oxygen uptake (r = 0.38, P < 0.002) and to body weight (r = 0.36, P < 0.01). A total of seven patients (10%) underwent successful revascularization. CONCLUSIONS: Ten of the patients with suspected chronic intestinal ischaemia had abnormal meal-induced splanchnic blood flow and 30% of these patients underwent angioplasty. Future studies are needed to validate the determination of splanchnic blood flow in relation to splanchnic angiography and other imaging modalities in patients with chronic intestinal ischaemia.

Reference values for the geometric centre analysis of colonic transit measurements with 111indium-labelled diethylenetriamine penta-acetic acid.

The geometric centre analysis is often used for evaluating colonic transit data obtained by scintigraphy after oral intake of 111indium-labelled diethylenetriamine penta-acetic acid (111In-DTPA). The purpose of this study was to establish reference values for the geometric centre analysis in adult humans. Forty-eight healthy volunteers (24 women, 24 men) who were equally distributed among three age groups (young, middle-aged, elderly) were studied. In all subjects the geometric centre of radioactivity in the colon was calculated from abdominal gamma camera images acquired 24, 48, 72, and 96 h after oral administration of 111In-DTPA. Overall, the men had a higher geometric centre value than women after both 24 and 48 h indicating a faster progress of colonic contents in men at these time points. At each time point the geometric centre value was higher in both the young and middle-aged subjects than in the elderly subjects, whereas we did not find any difference between young and middle-aged subjects. Furthermore, the smokers had a higher geometric centre value than non-smokers at each time point. The geometric centre value was not influenced by body mass index at any time point.

[Myocardial scintigraphy. Clinical use and consequence in a non-invasive cardiological department]. / Myokardieskintigrafi. Klinisk anvendelse og konsekvens på en ikkeinvasiv kardiologisk afdeling.

INTRODUCTION: Myocardial perfusion imaging (MPI) is increasingly used for the diagnosis of ischaemic heart disease. The method is particularly applied as a gate keeper before coronary angiography (CAG) in patients with intermediate probability for ischaemic heart disease. This study aimed to analyse the clinical use of MPI in a university hospital without invasive cardiological laboratory. MATERIAL AND METHODS: In the period 01.01.2002 to 31.12.2003, 259 patients (141 women, 118 men) were referred to MPI from our department of cardiology. RESULTS: Normal MPI was seen in 111 patients (43%), whereas reversible ischaemia was seen in 88 patients (34%) and led to referral of 52 patients (59%) to CAG. 17 patients (19%) continued clinical control, and 19 cases (22%) were closed. Correlating results between MPI and all performed CAGs were found in 42 patients (61%), and divergent results were seen in 27 (39%) patients. CONCLUSION: Referral to CAG is primarily based on the combination of the results of MPI and the clinical symptoms of ischaemic heart disease.

Bile acid malabsorption or disturbed intestinal permeability in patients treated with enzyme substitution for exocrine pancreatic insufficiency is not caused by bacterial overgrowth.

INTRODUCTION: In some patients with severe exocrine pancreatic insufficiency, enzyme replacement therapy will not lead to clinical improvement or reduction of steatorrhea. Therefore, other mechanisms separately or in interplay with reduced enzyme secretion might be responsible for malabsorption in these patients. AIMS: To evaluate the prevalence of bacterial overgrowth, bile acid absorption capacity, and intestinal permeability in a group of patients with well-characterized exocrine pancreatic insufficiency. METHODOLOGY: Eleven men with severe exocrine pancreatic insufficiency, of whom 10 were receiving enzyme replacement therapy, were studied. The prevalence of bacterial overgrowth was evaluated by means of a hydrogen and methane breath test with glucose. Gamma camera scintigraphy after intake of 75Se-homocholic acid taurine (75Se-HCAT) was used to evaluate bile acid absorption capacity. Intestinal permeability was assessed from urine excretion of ingested 14C-mannitol and 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA), and these data were compared with results for 10 age-matched healthy men. RESULTS: No patients had abnormal breath hydrogen or methane concentrations after glucose intake. Abdominal retention of 75Se-HCAT was reduced in three of the patients. The patients had lower urine excretion of 14C-mannitol than the control subjects, whereas no difference was revealed in urine excretion of 99mTc-DTPA. CONCLUSION: Bile acid absorption and small intestinal permeability might be affected in patients with exocrine pancreatic insufficiency who receive treatment with enzyme supplementation. The prevalence of bacterial overgrowth seems to be low among these patients and does not explain the findings.

Physiologic effects of bowel preparation.

PURPOSE: Despite the universal use of bowel preparation before colonoscopy and colorectal surgery, the physiologic effects have not been described in a standardized setting. This study was designed to investigate the physiologic effects of bowel preparation. METHODS: In a prospective study, 12 healthy volunteers (median age, 63 years) underwent bowel preparation with bisacodyl and sodium phosphate. Fluid and food intake were standardized according to weight, providing adequate calorie and oral fluid intake. Before and after bowel preparation, weight, exercise capacity, orthostatic tolerance, plasma and extracellular volume, balance function, and biochemical parameters were measured. RESULTS: Bowel preparation led to a significant decrease in exercise capacity (median, 9 percent) and weight (median, 1.2 kg). Plasma osmolality was significantly increased from 287 to 290 mmol kg(-1), as well as increased phosphate and urea concentrations, whereas calcium and potassium concentrations decreased significantly after bowel preparation. No differences in plasma or extracellular volumes were seen. Orthostatic tolerance and balance function did not change after bowel preparation. CONCLUSIONS: Bowel preparation has significant adverse physiologic effects, which may be attributed to dehydration. The majority of these findings is small and may not be of clinical relevance in otherwise healthy patients undergoing bowel preparation and following recommendations for oral fluid intake.