Endoscopic ultrasound as an early diagnostic tool for primary sclerosing cholangitis: a prospective pilot study.

BACKGROUND AND STUDY AIMS: Primary sclerosing cholangitis (PSC) is a rare, chronic cholestatic liver disease, which typically affects middle-aged men and is frequently associated with inflammatory bowel disease. Early recognition and accurate diagnosis remains a clinical challenge. Invasive diagnostic procedures, such as endoscopic retrograde cholangiography or liver biopsy are needed when magnetic resonance cholangiopancreatography remains inconclusive. As these procedures are associated with significant risks, the current study sought to determine whether endoscopic ultrasound (EUS) of the biliary tract is a useful diagnostic tool in cases of suspected PSC. PATIENTS AND METHODS: In a prospective pilot study, 138 patients presenting with chronic cholestatic hepatopathy were screened and 32 patients with possible PSC were evaluated further. In addition to all routine measures, EUS was included in the diagnostic work-up.  The following parameters were evaluated and compared with the definitive diagnosis: wall thickening ( ≥ 1.5  mm), irregular wall structure, significant changes of caliber of the common bile duct, and perihilar lymphadenopathy. RESULTS: In the 138 patients screened, a PSC prevalence of 13 % was found. Of the 32 patients included in the study, 17 had large-duct PSC diagnosed. When two of the aforementioned four parameters showed PSC-like features, sensitivity and specificity of predicting PSC were 76.4 % and 100 %, with positive and negative predictive values of 100 % and 79 %, respectively. In four patients presenting with strictly intrahepatic disease, EUS was not diagnostic. CONCLUSIONS: EUS proved to be a valuable tool in suspected PSC and accurately predicted extrahepatic disease. EUS should be evaluated further as an early procedure in routine diagnostic measurements. This approach promises a significant improvement in disease detection as well as a reduction in high risk invasive procedures.

Value of magnifying endoscopy in classifying colorectal polyps based on vascular pattern.

BACKGROUND AND STUDY AIMS: Narrow-band imaging (NBI) has been developed as a new technique to differentiate tissue patterns in vivo. The aim of this study was to evaluate the diagnostic accuracy of NBI endoscopy with and without high magnification for the differentiation of neoplastic from non-neoplastic colorectal polyps. PATIENTS AND METHODS: Among 200 colorectal polyps from 131 patients, 100 lesions were classified according to vascular patterns by NBI endoscopy with high optical magnification and 100 lesions by high-definition endoscopy without high magnification. Additionally, the clarity of the vessel network was assessed. Histologic analysis was performed on all lesions. RESULTS: NBI endoscopy with high magnification resulted in a sensitivity of 92.1 % and a specificity of 89.2 % for the differentiation of neoplastic versus non-neoplastic lesions. This performance was statistically comparable to high-definition NBI endoscopy without high magnification, which showed a sensitivity of 87.9 % and specificity of 90.5 %. However, vessel network was significantly better visualized by NBI endoscopy with optical magnification compared with high-definition NBI endoscopy without high magnification. In comparison with NBI endoscopy, white-light endoscopy, with or without magnification, resulted in inferior discrimination between neoplastic and non-neoplastic polyps. CONCLUSION: The results demonstrate that the superior visibility of capillary vessels by the NBI technique allows the evaluation of colorectal lesions - based on the vascular patterns - with high diagnostic accuracy. In clinical routine, high-definition NBI endoscopy without high magnification may be used to sufficiently predict colorectal polyp histology, and high magnification can additionally facilitate visualization of vascular networks.

[Pathogenesis of liver fibrosis: modulation of stellate cells by chemokines]. / Pathogenese der Leberfibrose: Regulation von hepatischen Sternzellen durch Chemokine.

Liver fibrosis is the common sequel of chronic liver diseases and is associated with high morbidity and mortality in affected patients. In recent years, the contribution of chemokines and their receptors to liver fibrosis has been delineated. Chemokines are a family of chemotactic and immunomodulatory molecules that act through different G-protein coupled receptors on target cells. Apart from their classical function of regulating immune cell recruitment during chronic liver injury, chemokines can directly affect the function of hepatic stellate cells within the liver. Up to now, nine of the 19 known chemokine receptors have been characterised on stellate cells. Stimulation of most of these receptors with specific ligands leads to increased migration and proliferation of stellate cells, suggesting predominantly profibrotic effects of chemokines. The only chemokine receptor with potential antifibrotic effects identified so far is CXCR3. Notably, hepatic stellate cells are not only a target but also a source of chemokines which contributes to the direct interaction between stellate cells and other cells during fibrogenesis. The further characterisation of this interaction will yield new therapeutic options for the treatment of chronic liver diseases. In this respect chemokines are a valuable target as oral chemokine receptor antagonists have already been licensed for human use.

[Liver fibrosis : clinics, diagnostics and management]. / Leberfibrose : Klinik, Diagnostik und Management.

Liver fibrosis results from chronic liver damage and is characterized by scarring of the liver parenchyma. Liver fibrosis can occur in all chronic liver diseases and shows progression towards liver cirrhosis in 20-40% of cases. The clinical presentation of liver fibrosis is usually unspecific. Therefore, most patients with liver fibrosis are identified by elevated liver enzymes during other medical examinations. The gold standard for quantification of liver fibrosis is percutaneous liver biopsy, but non-invasive markers (e. g. serum markers, transient elastography) have recently been evaluated to identify individuals with significant fibrosis. In case of fibrosis detection, medical therapies aim at stabilizing liver scarring or even at inducing the regression of fibrosis. Primarily this is achieved by etiology specific therapies of chronic liver diseases (e. g. antiviral therapy, immunosuppressive therapy etc.). However, in cases of failure of these specific therapies, non-specific interventions for fibrosis regression are actively being investigated. These treatment options are based on the growing molecular knowledge of fibrogenesis but are not yet available for routine clinical use.

Pharmacological IKK2 inhibition blocks liver steatosis and initiation of non-alcoholic steatohepatitis.

BACKGROUND: Non-alcoholic-steatohepatitis (NASH) leading to fibrosis, end-stage cirrhosis and hepatocellular carcinoma is an increasing health problem in the Western world. Thus, the need for new therapeutic approaches is increasing. IKK2 plays a key role in the development of NASH by mediating inflammation and insulin resistance. AIM: Here the beneficial effects of a pharmacological IKK2 inhibitor (AS602868) on initial stages of NASH progression were tested. METHODS: Mice were fed with a high sucrose diet (HSD) and daily-administered AS602868 and vehicle. The impact of AS602868 on NASH progression was studied using biochemical, histological and molecular markers. RESULTS: AS602868 treatment prevented HSD-induced weight gain and visceral fat accumulation. In adipose tissue, AS602868-treated mice exhibited a lower degree of infiltrated macrophages along with reduced proinflammatory cytokine production. Further analysis demonstrated that AS602868 treatment efficiently inhibited nuclear factor (NF)-kappaB activation in liver non-parenchymal cells and as a consequence attenuated the inflammatory response in the liver. Accordingly, in HSD/AS602868 mice, liver and adipose tissue adiponectin levels remained at levels comparable with those of control chow-fed mice, while they were decreased in HSD/vehicle animals. Additionally, AS602868 improved lipid beta-oxidation mediated by peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma. Systemic pharmacological IKK2 inhibition by AS602868 treatment efficiently prevented liver steatosis and inflammation, and improved antioxidant response. All this contributed to attenuation of NASH progression as evidenced by lower hepatocyte apoptosis and early stages of liver fibrosis. CONCLUSION: The data demonstrate that AS602868-mediated IKK2 inhibition represents a new therapeutic approach to prevent dietary-induced NASH progression.

Value of magnifying chromoendoscopy and narrow band imaging (NBI) in classifying colorectal polyps: a prospective controlled study.

BACKGROUND AND STUDY AIMS: Chromoendoscopy in combination with magnifying endoscopy is useful in distinguishing neoplastic from non-neoplastic colorectal polyps. Narrow band imaging (NBI) has been developed as a new technique to differentiate tissue patterns in vivo. The aim of the present study was to directly compare the diagnostic values of chromoendoscopy and NBI for the differentiation of neoplastic from non-neoplastic colorectal polyps. PATIENTS AND METHODS: In total, 200 colorectal polyps from 99 patients were distributed in a 1 : 1 ratio in order to analyze the surface according to the pit pattern classification and vascular patterns by either magnifying chromoendoscopy or NBI magnification. Histologic analysis was performed on all lesions. RESULTS: Using the Kudo classification of mucosal patterns, NBI with magnification resulted in a sensitivity of 90.5 % and a specificity of 89.2 % for the differentiation of neoplastic vs. non-neoplastic lesions. This performance was comparable to magnifying chromoendoscopy with a sensitivity of 91.7 % and a specificity of 90 %, respectively. Using vascular patterns for differentiation, NBI with magnification correctly identified 93.7 % of neoplastic polyps and 89.2 % of non-neoplastic colorectal lesions, whereas magnifying chromoendoscopy had a specificity of 95 % but a sensitivity of only 66.7 %. CONCLUSION: NBI in combination with magnifying endoscopy is a promising tool for the differentiation of neoplastic from non-neoplastic colorectal polyps in vivo without the necessity of using dye. The detection of capillary vessels with NBI allows the evaluation of colorectal lesions based on the vascular patterns with high diagnostic accuracy.

[Extrahepatic manifestations of chronic liver diseases]. / Extrahepatische Manifestationen chronischer Lebererkrankungen.

Chronic liver diseases are commonly associated with extrahepatic disease manifestations. Liver cirrhosis, the end stage of chronic liver diseases of different etiologies, can result in severe neurological, renal and pulmonary complications. Hepatic encephalopathy plays an important socio-economic role, since it affects daily functioning and fitness to drive. During the clinical course of chronic viral hepatitis, many patients develop extrahepatic disease manifestations, which lead to significant morbidity and mortality. In particular, mixed cryoglobulinemia, membranoproliferative glomerulonephritis and polyarteriitis nodosa are strongly associated with chronic viral hepatitis. Most extrahepatic manifestations are due to immunological and lymphoproliferative pathomechanisms. Knowledge of extrahepatic disease manifestations is important for adequate medical care and risk assessment of patients with chronic liver diseases by insurance companies.

[The value of duodenal biopsy within routine upper endoscopy: a prospective study in 1000 patients]. / Die Wertigkeit der tiefen Duodenalbiopsie im Rahmen der Routineendoskopie: Eine prospektive Studie mit 1000 Patienten.

BACKGROUND AND AIM: Several gastrointestinal diseases are localised in the small bowel and are confirmed by duodenal biopsies upon upper gastrointestinal endoscopy. However, the clinical value of routine duodenal biopsies during endoscopy has not been satisfactorily defined and was assessed in the current study. METHODS: In 1000 consecutive patients duodenal biopsies were performed during routine upper gastrointestinal endoscopy. Endoscopic diagnoses, symptoms and the prevalence of anaemia were correlated with the histological diagnoses. RESULTS: Coeliac disease and giardiasis was diagnosed in 18 and two patients, respectively (2.0 % of all cases). In 11 (55 %) patients the diagnosis was already made macroscopically during endoscopy. The sensitivity for endoscopic diagnosis of coeliac disease MARSH III was 84.6 %. There was no correlation between clinical symptoms, the prevalence of anaemia and the diagnosis of coeliac disease or giardiasis in our cohort. CONCLUSION: Endoscopic diagnosis of advanced celiac disease (MARSH III) can be made with high sensitivity and specifity. Nevertheless, duodenal biopsy is necessary for the diagnosis of early coeliac disease or giardiasis. However, the routine duodenal sampling of normal mucosa during gastrointestinal endoscopy cannot be recommended.

Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is characterised by troublesome maternal pruritus, raised serum bile acid levels and increased fetal risk. Mutations of the ABCB4 gene encoding the hepatobiliary phospholipid transporter have been identified in a small proportion of patients with cholestasis of pregnancy. In a recent prospective study on 693 patients with cholestasis of pregnancy, a cut-off level for serum bile acid (> or =40 micromol/l) was determined for increased risk of fetal complications. OBJECTIVES: To investigate whether common combinations of polymorphic alleles (haplotypes) of the genes encoding the hepatobiliary ATP-binding cassette (ABC) transporters for phospholipids (ABCB4) and bile acids (ABCB11) were associated with this severe form of cholestasis of pregnancy. METHODS: For genetic analysis, 52 women with bile acid levels > or =40 micromol/l (called cases) and 52 unaffected women (called controls) matched for age, parity and geographical residence were studied. Gene variants tagging common ABCB4 and ABCB11 haplotypes were genotyped and haplotype distributions were compared between cases and controls by permutation testing. RESULTS: In contrast with ABCB11 haplotypes, ABCB4 haplotypes differed between the two groups (p = 0.019), showing that the severe form of cholestasis of pregnancy is associated with the ABCB4 gene variants. Specifically, haplotype ABCB4_5 occurred more often in cases, whereas haplotypes ABCB4_3 and ABCB4_7 were more common in controls. These associations were reflected by different frequencies of at-risk alleles of the two tagging polymorphisms (c.711A: odds ratio (OR) 2.27, p = 0.04; deletion intron 5: OR 14.68, p = 0.012). CONCLUSION: Variants of ABCB4 represent genetic risk factors for the severe form of ICP in Sweden.

The interleukin-6 (IL6)-174 G/C promoter genotype is associated with the presence of septic shock and the ex vivo secretion of IL6.

Septic shock is associated with a high mortality and an excessive activation of immune cascades. Interleukin (IL)-6 has been found to be a key cytokine in the pathogenesis of severe sepsis, but the importance of a regulatory polymorphism within the IL6 promoter has been controversial in these patients. The aim of the study was therefore to systematically investigate the IL6-174 G/C promoter genotype with regard to the presence of shock in patients with sepsis, the IL6 serum levels, and the ex vivo secretion of IL6, respectively. Overall, 112 consecutive subjects with severe sepsis and septic shock according to consensus criteria were enrolled. The ex vivo secretion of IL6 after stimulation with lipopolysaccharide (LPS) in a whole blood assay and the IL6 serum concentrations were determined after admission of the patients. Among the 112 subjects with severe sepsis, 85 patients fulfilled the criteria of septic shock. In these patients, the frequency of the mutated C-allele of the IL6 promoter polymorphism was significantly (P = 0.04) higher compared to that in individuals without shock. IL6 serum concentrations were highest in patients with the GG genotype (mean 2209 pg mL(-1)), followed by CG genotype (mean 1113 pg mL(-1)), and lowest in individuals with the CC genotype (mean 256 pg mL(-1)). Interestingly, a significantly (P = 0.005) higher ex vivo secretion of IL6 is detected in heterozygote individuals (535 pg mL(-1)) and patients with the IL6 CC genotype (555 pg mL(-1)) compared to patients with the -174 GG genotype (276 pg mL(-1)). In conclusion, the IL6-174 G/C promoter genotype is associated with shock in patients with sepsis. Functionally, the mutated C-allele is correlated with low IL6 serum concentrations, but a high ex vivo secretion after LPS stimulation. These results further indicate a complex regulation of the expression of IL6 during infection and have implications for the design of immune intervention trials.

[Elevated concentrations of fecal calprotectin in patients with liver cirrhosis]. / Erhöhte Konzentrationen von fäkalem Calprotectin bei Patienten mit Leberzirrhose.

UNLABELLED: BACKGROUND AND OBJECTION: Bacterial translocation from the gut lumen is considered to play an important role in the development of infectious complications in patients with liver cirrhosis. This translocation might be increased by inflammation of the gut mucosa. Calprotectin is a cytoplasmatic protein of neutrophilic granulocytes and is an established marker for the assessment of localized intestinal inflammation. It was the aim of the current study to systematically evaluate a localized intestinal inflammation in patients with liver cirrhosis by means of fecal calprotectin concentrations. PATIENTS AND METHODS: Fecal calprotectin concentrations were determined in 53 consecutive patients with liver cirrhosis and in 18 subjects without intestinal or liver diseases, who were comparable with respect to age and gender. Patients with diarrhoea, inflammatory bowel disease and a positive stool test for occult blood were excluded from the study. Fecal calprotectin concentrations were measured by a sandwich ELISA. The systemic inflammatory reaction of the patients was assessed by C-reactive protein, white blood cells counts and the serum concentrations of the cytokines IL-6, IL-8 and IL-10. RESULTS: Fecal calprotectin concentrations were significantly increased in patients with liver cirrhosis (median 37.0 mg/kg) compared to controls patients (median 2.2, P < 0.0001). There were no significant correlations of calprotectin concentrations with systemic inflammatory parameters, like CRP, white blood cell count or serum cytokines. However, fecal calprotectin concentrations were significantly associated with the stage of liver cirrhosis as expressed by the Child-Pugh score ( P < 0.001). A trend towards higher concentrations of calprotectin was found in patients with alcoholic liver cirrhosis ( P = 0.1). CONCLUSIONS: Patients with liver cirrhosis display elevated fecal calprotectin concentrations as a potential sign of intestinal inflammation. Further studies are warranted to establish a role of calprotectin for the risk assessment of infectious complications secondary to bacterial translocation in patients with liver cirrhosis.

Cow's milk and immune-mediated diabetes.

Cow's milk-based infant formulas and cow's milk consumption in childhood have been suggested to promote the development of type 1 diabetes mellitus and other immune-mediated or neurological diseases. Epidemiological studies in man have led to the hypothesis that introduction of cow's milk-based infant formula within the first 3 months of life is associated with increased risk of type 1 diabetes mellitus. Furthermore, in animal models of type 1 diabetes mellitus, cow's milk proteins have been proven to be 'diabetogenic'. However, the issue seems far from being resolved. Several epidemiological studies and, more importantly, the first prospective trials did not show an association between early exposure to cow's milk and type 1 diabetes mellitus. In animal models, cow's milk proteins are modestly and variably diabetogenic, wheat or soybean proteins in the diet cause higher rates of autoimmune diabetes. In both man and rodents there is increasing evidence that the gut-associated immune system plays a major role in disease development, probably because of disturbed oral tolerance mechanisms. Oral tolerance depends on immunological homeostasis and normal maturation of the gut. These factors are influenced by growth factors and cytokines from breast milk, normal bacterial colonization, infections and diet. All these factors have been proposed as risk factors for type 1 diabetes mellitus. Hence, cow's milk proteins may provide mimicry epitopes relevant in autoimmunity, as well as destabilizing oral tolerance mechanisms by biologically active peptides. The concept of dietary regulation of autoimmunity does not apply only to cow's milk protein, but also to other dietary proteins.

Non-specific viral infections as possible synchronising events of the manifestation of type 1 diabetes.

Four cases of simultaneous manifestation of Type 1 diabetes in two members of the same household are reported. In all cases, a flu-like infection preceded diabetes onset. Surprisingly, despite simultaneous development of insulin dependency, insulin requirements were strikingly different at 3 months in all cases. These observations suggest that increased insulin resistance during infection may cause insulin deficiency in individuals with widely varying residual beta cell activity.

Type I (insulin-dependent) diabetes mellitus and cow milk: casein variant consumption.

Previously published Type I (insulin-dependent) diabetes mellitus incidence in 0 to 14-year-old children from 10 countries or areas was compared with the national annual cow milk protein consumption. Countries which were selected for study had appropriate milk protein polymorphism studies, herd breed composition information and low dairy imports from other countries. Total protein consumption did not correlate with diabetes incidence (r = +0.402), but consumption of the beta-casein A1 variant did (r = +0.726). Even more pronounced was the relation between beta-casein (A1+B) consumption and diabetes (r = +0.982). These latter two cow caseins yield a bioactive peptide beta-casomorphin-7 after in vitro digestion with intestinal enzymes whereas the common A2 variant or the corresponding human or goat caseins do not. beta-casomorphin-7 has opioid properties including immunosuppression, which could account for the specificity of the relation between the consumption of some but not all beta-casein variants and diabetes incidence.

A wheat-based, diabetes-promoting diet induces a Th1-type cytokine bias in the gut of NOD mice.

Dietary antigens are candidate environmental factors in the pathogenesis of type 1 diabetes. In the non-obese diabetic (NOD) mouse, an animal model of type 1 diabetes, cereal-based diets promote disease development, whereas the diets based on hydrolysed proteins or non-diabetogenic proteins are protective. The hypothesis that diabetogenic diets modulate the cytokine balance in the gut was tested. NOD mice were fed with NTP-2000 (mainly a wheat-based milk-free diet) or Prosobee (a semi-purified hypoallergenic diet based on soy protein isolate) or Prosobee plus casein (milk protein fraction). The mRNA levels of IFN-gamma, IL-10, TNF-alpha, TGF-beta, and inducible NO synthase in the small intestine and the Peyer's patches were determined by semi-quantitative RT-PCR. Mice fed on the cereal-based NTP-2000 diet expressed higher levels of the Th1-type and pro-inflammatory markers IFN-gamma, TNF-alpha, and inducible NO synthase mRNA compared to the Prosobee-fed animals. The expression of the counterregulatory cytokines IL-10 and TGF-beta was unaffected. This resulted in a significant bias of the intestinal cytokine balance towards T helper cell type 1 after feeding NTP-2000. The cytokine mRNA levels in the gut-associated Peyer's patches were not affected. Thus, modulation of gut immunoreactivity by diet may contribute to disease development in NOD mice.

Influence of biliary cirrhosis on the detoxification and elimination of a food derived carcinogen.

BACKGROUND AND AIMS: The liver is the central organ for the detoxification of numerous xenobiotics, including carcinogens. We studied the influence of cholestasis and biliary cirrhosis on the detoxification, elimination, and tissue distribution of a model compound and food derived carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). METHODS: Wistar rats were injected with (14)C-PhIP into the portal vein one or six weeks after common bile duct ligation (CBDL). Bile flow was reconstituted, bile and urine were collected over 120 minutes, and metabolites were analysed using high performance liquid chromatograpy. Total tissue radioactivity levels in several organs as well as tissue bound (ethanol insoluble tissue fraction) radioactivity levels were determined. RESULTS: Significant downregulation of the transport proteins multidrug resistance associated protein 2 and breast cancer resistance protein was observed in biliary cirrhosis. Biliary excretion of radioactivity was significantly reduced in cholestasis and biliary cirrhosis compared with controls (15 (2.9)% and 3.2 (1)% of the dose v 36.5 (2)%, respectively). Phase II metabolism was severely reduced in cirrhotic rats, resulting in a twofold increase in tissue radioactivity levels in the liver, kidney, and colon. Biliary cirrhosis increased tissue binding of reactive metabolites, as expressed in cpm/100 mg tissue in the liver and the colon (3267 (1218) v 1191 (429) in the liver, 3044 (1913) v 453 (253) in the colon). CONCLUSIONS: Biliary cirrhosis induced by CBDL causes impaired metabolism and elimination of PhIP, and leads to higher tissue levels of potentially genotoxic metabolites in the liver and colon of rats. These data may explain the increased incidence of hepatic and extrahepatic cancers in cholestasis and liver cirrhosis.