Oxazolone and ethanol induce colitis in non-obese diabetic-severe combined immunodeficiency interleukin-2Rγ(null) mice engrafted with human peripheral blood mononuclear cells.

Oxazolone-induced colitis in mice has become a recognized model to study the efficacy of therapeutics targeting the immunological response underlying the development of inflammatory bowel disease. However, this model cannot be used when therapeutics designed to address human targets do not interact with the respective murine counterpart. In this study, we examined the induction of oxazolone mediated colitis in non-obese diabetic-severe combined immunodeficiency interleukin-2Rγ(null) (NOD-SCID IL2Rγ(null)) mice engrafted with human peripheral blood mononuclear cells (hPBMC) derived from patients suffering from ulcerative colitis (UC), atopic dermatitis (AD) and healthy volunteers. NOD-SCID IL2Rγ (null) mice were engrafted with hPBMC followed by challenge with oxazolone or ethanol vehicle. Mice developed the same symptoms as observed previously in immunocompetent mice. The clinical activity score increased and the colon architecture was characterized by the development of oedema, fibrosis, crypt loss and dense infiltration of predominantly T cells into the lamina propria. Fluorescence activated cell sorter (FACS) analysis of lymphocytes in the colon identified natural killer (NK) T cells as a major constituent. In contrast to studies with immunocompetent mice, we observed the same phenotype in the group challenged with ethanol vehicle. The phenotype was most pronounced in mice engrafted with PBMC derived from a patient suffering from UC, suggesting that the immunological history of the donors predisposes the engrafted mice to react to ethanol. The model described here has the potential to study the efficacy of therapeutics targeting human lymphocytes in a model which is more reflective of the human disease. In addition, it might be developed to elucidate molecular mechanisms underlying the disease.

Intrarenal resistance index as a prognostic parameter in patients with liver cirrhosis compared with other hepatic scoring systems.

BACKGROUND AND AIMS: Patients with advanced liver cirrhosis who develop renal dysfunction have a poor prognosis. Elevated intrarenal resistance indices (RIs) due to renal vascular constriction have been described before in cirrhotic patients. In the current study, we prospectively investigated the course of intrarenal RIs and compared their prognostic impact with those of the Model for End-Stage Liver Disease (MELD) and the Child-Pugh scores. METHODS: Sixty-three patients with liver cirrhosis underwent a baseline visit which included a sonographic examination and laboratory tests. Forty-four patients were prospectively monitored. The end points were death or survival at the day of the follow-up visit. RESULTS: In 28 patients, a follow-up visit was performed after 22 ± 8 months (group 1). Sixteen patients died during follow-up after 12 ± 8 months (group 2). Group 2 patients showed a significantly higher baseline RI (0.76 ± 0.05) than group 1 patients (RI = 0.72 ± 0.06; p < 0.05). As shown by receiver operating characteristic analysis, the RI and the MELD score achieved similar sensitivity and specificity [area under the curve (AUC): 0.722; 95% confidence interval (95% CI): 0.575-0.873 vs. AUC: 0.724; 95% CI: 0.575-0.873, z = 0.029, n.s.] in predicting survival and were superior to the Child-Pugh score (AUC: 0.677; 96% CI: 0.518-0.837). CONCLUSION: The RI is not inferior in sensitivity and specificity to the MELD score. Cirrhotic patients with elevated RIs have impaired short- and long-term survival. The RI may help identify high-risk patients that require special therapeutic care.

Effectiveness of a novel endoscopy training concept.

BACKGROUND AND STUDY AIMS: Training standards in gastrointestinal endoscopy are poorly defined even though different simulators are increasingly used for skills training. In 2001 a new training concept called "GATE--gastroenterological education-training endoscopy" was established, which provides a combination of background theory, video demonstrations, and simulator training. We aimed to evaluate the acceptance and training effect of this training model. METHODS: In total, 98 physicians participating in four training courses were included. Data were collected on baseline characteristics, acceptance (5-point Likert scale), and pre- and post-course knowledge through a structured questionnaire (A-type and Pick-N multiple choice questions). A total of 13 trainees were randomly selected for additional simulator assessment of training effects on manual skills (5-point Likert scale). RESULTS: A total of 78 trainees (80%) provided complete data sets. The evaluation showed a positive acceptance of the training program (value 1 and 2, Likert scale); for example, 88% of participants suggested the inclusion of the GATE course as an obligatory part of endoscopic education. There was a significant improvement in theoretical knowledge in the post-test set compared with the pre-test set (mean 3.27 ±1.30 vs. 1.69 ±1.01 points; P<0.001). The training effect on practical skill showed a significant reduction in time needed for a procedure (445 ±189 s vs. 274 ±129 s; P<0.01). The mean assessment rating for practical skills improved from 3.05 ±0.65 at baseline to 2.52 ±0.59 on Likert scale ( P=0.085). CONCLUSIONS: The integrated GATE training improved theoretical knowledge and manual skill. The GATE courses have been accredited by the German Society of Gastroenterology, underlining the demand for implementing preclinical training courses in endoscopic training.

Acute postinfectious glomerulonephritis associated with Campylobacter jejuni enteritis - a case report and review of the literature on C. jejuni's potential to trigger immunologically mediated renal disease.

Kidney disease is a rare complication of Campylobacter jejuni (C. jejuni) enteritis. We here present the case of an 18-year-old male patient with crampy abdominal pain, vomiting, diarrhea, and fever. Three weeks later urinalysis revealed mild proteinuria and hematuria and a marked raise in serum creatinine was observed. Renal biopsy demonstrated acute endocapillary glomerulonephritis with mesangial IgM (immunoglobuline M) deposits. Extensive workup revealed no signs of skin or joint disease, thus excluding Henoch-Schönlein purpura. Due to persistent abdominal discomfort further gastro-enterological tests were performed and eventually Campylobacter jejuni was isolated from the patient's feces. In the absence of other precipitating factors for renal diseases we presumed an association between the bacterial infection and this postinfectious glomerulonephritis. Over a time period of 6 months the patient's kidney function normalized completely. However, long-term prognosis remains unclear. In addition to the case report, we conducted a review of the literature with results underlining Campylobacter jejuni's potential to trigger various types of immune mediated kidney diseases.

[Acute renal failure in patients with liver cirrhosis--what to do? An update]. / Akutes Nierenversagen bei Patienten mit Leberzirrhose--was tun? Ubersicht.

A lot of patients suffering from liver cirrhosis show a decreased renal perfusion and glomerular filtration rate. An impaired renal function is the result of complex e.g. hemodynamic disturbances, resulting of the chronic liver disease. This explains its disposition to renal dysfunction and the higher incidence of acute renal failure in liver cirrhosis. In the case of renal failure hepatorenal syndrome, apart from prerenal, renal and postrenal causes, should be included in the differential diagnosis especially when signs of portal hypertension are apparent regarding its high mortalityand fatal prognosis requiring an immediate therapeutically approach. Special attention must be due to preventive strategies to avoid renal deterioration. This includes simple steps e.g. a careful election of medication but also an adequate therapy of infection-associated complications in patients with liver cirrhosis.

Q-T interval (QT(C)) in patients with cirrhosis: relation to vasoactive peptides and heart rate.

OBJECTIVE: Prolonged Q-T interval (QT) has been reported in patients with cirrhosis who also exhibit profound abnormalities in vasoactive peptides and often present with elevated heart rate (HR). The aim of this study was to relate QT to the circulating level of endothelins (ET-1 and ET-3) and calcitonin gene-related peptide (CGRP) in patients with cirrhosis. In addition, we studied problems with HR correction of QT. MATERIAL AND METHODS: Forty-eight patients with cirrhosis and portal hypertension were studied during a haemodynamic investigation. Circulating levels of ETs and CGRP were determined by radioimmunoassays. Correction of QT for HR above 60 beats per min was performed using the methods described by Bazett (QT(C)) and Fridericia (QT(F)). RESULTS: Prolonged QT(C) (above 440 ms), found in 56% of the patients, was related to the presence of significant portal hypertension and liver dysfunction (p < 0.05 to 0.001), but not to elevated ET-1, ET-3 or CGRP. When corrected according to Bazett, QT(C) showed no significant relation to differences in HR between patients (r = 0.07, ns). QTF showed some undercorrection of HR (r = -0.36; p < 0.02). During HR variation in the individual patient, QT(C) revealed a small but significant overcorrection (2.6 ms per heartbeat per min; p < 0.001). This value was significantly (p < 0.02) smaller with QTF (1.2 ms per heartbeat per min). CONCLUSIONS: The prolonged QT(C) in cirrhosis is related to liver dysfunction and the presence of portal hypertension, but not to the elevated powerful vasoconstrictor (ET-1) or vasodilator (CGRP, ET-3) peptides. The problems with correction of the QT for elevated HR in cirrhosis are complex, and the lowest HR should be applied for determination of the QT.

[Renal impairment in liver diseases]. / Extrahepatische Manifesta- tionen bei Lebererkrankungen: Niere.

Renal failure in patients with liver disease is mostly none-organic: prerenal failure or hepatorenal syndrome (HRS). In addition there is organic renal failure, mostly acute tubular necrosis (ATN). In order to avoid functional renal failure cautious diuretic treatment as well as intravenous albumin substitution following paracentesis are pivotal. For prophylaxis of HRS patients with spontaneous bacterial peritonitis shall be given albumin infusions in addition to antibiotic treatment. Patients with HRS type I exhibit a very poor prognosis. Liver transplantation is the only established therapy with long-term success. To bridge the time to transplantation TIPS or terlipressin and albumin can be used.

Endothelin and endothelin receptor antagonism in portopulmonary hypertension.

Portopulmonary hypertension (PPHT) is a rare but devastating complication in patients with portal hypertension, characterized by pulmonary arterial obliterative disease with a concomitant rise in pulmonary vascular resistance. A broad body of evidence has accumulated, indicating that endothelin (ET) peptides and their cognate receptors are causally involved in the pathophysiology of pulmonary arterial hypertension (PAH) owing to different aetiologies, including PPHT. In addition, the ET system may be involved in hepatic fibrotic remodelling and portal hypertension. Several experimental models have provided evidence that ET receptor antagonism may have therapeutic potential in PPHT. Initial experience has accumulated during the last 2 years, suggesting that targeting the ET system may have beneficial effects in the clinical setting. In these studies, the orally active, dual ET receptor antagonist bosentan improved pulmonary haemodynamics and functional capacity. These effects were sustained and occurred in the absence of adverse events. If these observations can be corroborated by controlled clinical trials, bosentan would offer several advantages over available therapies, which have major drawbacks owing to their invasive and demanding mode of application.

Hepatitis induced by Noni juice from Morinda citrifolia: a rare cause of hepatotoxicity or the tip of the iceberg?

A 24-year-old female patient presented to her community hospital with mild elevations of serum transaminase and bilirubin levels. Because of multiple sclerosis, she was treated with interferon beta-1a for 6 weeks. After exclusion of viral hepatitis due to hepatitis A-E, interferon beta-1a was withdrawn under the suspicion of drug-induced hepatitis. One week later, she was admitted again to her community hospital with severe icterus. The transaminase and bilirubin levels were highly elevated, and a beginning impairment of the liver synthesis was expressed by a reduced prothrombin time. The confinement to our department occurred with a fulminant hepatitis and the suspicion of beginning acute liver failure. There was no evidence for hepatitis due to potentially hepatotoxic viruses, alcoholic hepatitis, Budd-Chiari syndrome, hemochromatosis, and Wilson's disease. In her serum there were high titers of liver-kidney microsomal type 1 autoantibody; the serum gamma globulin levels were in the normal range. Fine-needle aspiration biopsy of the liver ruled out an autoimmune hepatitis but showed signs of drug-induced toxicity. During the interview, she admitted that for 'general immune system stimulation' she had been drinking Noni juice, a Polynesian herbal remedy made from a tropical fruit (Morinda citrifolia), during the past 4 weeks. After cessation of the Noni juice ingestion, her transaminase levels normalized quickly and were in the normal range within 1 month.

[Advances in therapy for ascites and hepatorenal syndrome]. / Neues in der Therapie von Aszites und hepatorenalem Syndrom.

Sequential diuretic treatment of ascites with spironolactone and furosemide is equivalent to initial combination therapy. Orally applicable vasopressin-V2-receptor antagonists are an interesting novel therapeutic approach for the elimination of free water. The therapeutic efficacy for patients with cirrhosis and ascites is currently being investigated in phase II trials. Following paracentesis of up to 6 liters volume, infusion of 3.5 % saline is as effective as 20 % albumin. Another trial confirms the superiority of TIPS for the treatment of massive ascites, also demonstrating survival benefit. Determination of leukocyte esterase activity with a simple stix method may be helpful for the rapid and easy diagnosis of spontaneous bacterial peritonitis. Patients with hepatorenal syndrome seem to benefit from a combination of terlipressin and albumin whereas the effect of albumin dialysis on survival remains to be proven.

Increased arterial compliance in cirrhosis is related to decreased arterial C-type natriuretic peptide, but not to atrial natriuretic peptide.

BACKGROUND: Increased arterial compliance (COMPart) has recently been described in patients with cirrhosis, particularly in advanced disease. The aim of the present study was to relate COMPart with arterial levels of the circulating natriuretic peptides: atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP), both of which are vasodilators. METHODS: Thirty-one patients with cirrhosis, 14 non-cirrhotic patients with circulatory disturbances of the ischaemic and hypertensive type, and 10 healthy controls were investigated during a haemodynamic examination. RESULTS: The patients with cirrhosis showed the well-known hyperdynamic circulation with elevated cardiac output, low arterial blood pressure, and reduced systemic vascular resistance. COMPart in the patients with cirrhosis (1.30 mL/mmHg) was significantly (P < 0.01) increased compared to that of non-cirrhotic patients (0.99 mL/mmHg) and controls (1.01 mL/mmHg). In the patients with cirrhosis, a significant inverse correlation was found between CNP and COMPart (r = -0.42, P < 0.01), but not between CNP and systemic vascular resistance (r = 0.31, P = 0.08). In the non-cirrhotic patients, CNP had a significant inverse correlation to COMPart (r = -0.68, P < 0.01) and a direct correlation to systemic vascular resistance (r = 0.62, P < 0.02). ANP was not significantly related to COMPart nor to systemic vascular resistance in any of the groups. CONCLUSION: The finding of an inverse relation between CNP and COMPart may suggest that a compensatory down-regulation of CNP occurs in patients with cirrhosis and other types of circulatory disorders when vasodilation persists. Regulation of large and small arteries by CNP may be different in cirrhosis. Arterial ANP is not related to properties of the large or small arteries.

Elevated arterial compliance in patients with cirrhosis is not related to arterial endothelin-1.

BACKGROUND: Patients with cirrhosis and portal hypertension have a hyperkinetic systemic circulation. A number of circulating vasoactive peptides, including endothelin-1 (ET-1), are elevated and, recently, increased arterial compliance has been described in these patients. The aim of the present study was to investigate a potential relation between altered arterial compliance and arterial ET-1 in patients with cirrhosis. As ET-1 may be manipulated by somastostatin, the study includes infusion of octreotide in a subset of patients. METHODS: A total of 67 patients with cirrhosis and 27 controls were studied during a haemodynamic investigation. Arterial ET-1 was determined by two different radioimmunoassays and arterial compliance was determined as the stroke volume/pulse pressure index. RESULTS: Arterial compliance was elevated by 32%-40% in the cirrhotic patients as compared to the controls (P < 0.005). Arterial ET-1 was elevated by 26%-170% in the cirrhotic patients (P<0.001). No significant relationships could be established between arterial compliance and arterial ET-1 (r = -0.15 to 0.23, ns). Intravenous bolus injection and infusion of octreotide (100 pg + 100 microg/h, n = 9) did not significantly change either arterial compliance or arterial ET-1. CONCLUSION: Both arterial compliance and arterial ET- I are substantially elevated in patients with cirrhosis, but there is no significant relation between arterial compliance and arterial ET- I in these patients.

TIPS or vasoconstrictors for the treatment of hepatorenal syndrome type 1--effect on survival?

HRS is a serious complication in patients with cirrhosis and ascites and associated with a poor prognosis unless liver transplantation can be performed. Two different types of HES are being differentiated according to the clinical presentation: while HRS type I is characterised by rapid deterioration of renal function indicated by a two-fold increase of serum creatinine to values above 2.5 mg/dl or a decrease of creatinine clearance to values below 20 ml/min, HRS type II shows moderately increased serum creatinine above 1.5 mg/dl remaining stable over a longer period. The most prominent circulatory alterations in patients with chronic liver disease comprise portal hypertension and peripheral (mainly splanchnic) arterial vasodilation. This leads to a decreased centrally effective blood volume in cirrhotic patients. As a consequence, activation of sodium- and volume-retaining neurohumoral systems such as the renin-angiotensin-aldosterone system and the sympathetic nervous system and a non-osmotic release of arginine-vasopressin can be observed. These neurohumoral alterations induce renal sodium and water retention which are responsible for accumulation of ascites and deterioration of renal function. Recent therapeutic strategies of the hepatorenal syndrome take into account these pathophysiologic considerations: whereas the transjugular intrahepatic portosystemic shunt lowers portal hypertension, infusion of vasoactive drugs increases systemic vascular resistance in cirrhotic patients. Several uncontrolled trials have reported a positive effect of these strategies on renal function. The present analysis of combined data from these reports shows that this positive effect on renal function also may improve survival of patients with HRS type I.

Transjugular intrahepatic portosystemic shunting is not superior to endoscopic variceal band ligation for prevention of variceal rebleeding in cirrhotic patients: a randomized, controlled trial.

BACKGROUND: The aim of the present study was to compare the transjugular intrahepatic portosystemic shunt (TIPS) with variceal band ligation (VBL) in the prophylaxis of variceal rebleeding in patients with cirrhosis of the liver. METHODS: Fifty-four cirrhotic patients (21 Child-Pugh class A, 27 class B, 6 class C) were randomized to TIPS (n = 28) or VBL (n = 26) within 2 months after control of esophageal variceal hemorrhage. Statistical analysis was performed on the intention-to-treat principle. RESULTS: Mean follow-up was 2 years. Mortality risk at 1 and 2 years of follow-up was 7.8% +/- 5.3% and 19.9% +/- 8.8% in the TIPS group and 16.5% +/- 7.6% and 16.5% +/- 7.6% in the VBL group, respectively (n.s.); actuarial probability of remaining free from rebleeding was 83.7% +/- 77.4% and 71.4% +/- 10.4% in the TIPS group and 83.9% +/- 7.3% and 78.1% +/- 8.8% in the VBL group at 1 and 2 years, respectively (n.s.). Hepatic encephalopathy within 1 month after randomization was observed in 2 patients in the TIPS group and in 1 in the VBL group. CONCLUSION: TIPS is not superior to VBL in the prevention of variceal rebleeding. Furthermore, similar mortality rates in patients treated with TIPS or VBL negate TIPS as the preferred strategy for prevention of variceal rebleeding.