Gut peptide changes in patients with obstructive jaundice undergoing biliary drainage: A prospective case control study.

BACKGROUND: Biliary obstruction is a relatively common condition that affects approximately 5 in 1000 people annually. Malnutrition is very common in patients with biliary obstruction and since it is associated with significant morbidity and mortality, it is important to identify factors and mechanisms involved in its development. AIM: To determine the influence of obstructive jaundice on the hormones controlling appetite and nutritive status. METHODS: This was a prospective case control study performed in a tertiary center in Zagreb, Croatia. Patients with biliary obstruction undergoing internal biliary drainage from September 2012 until August 2013 were enrolled. After excluding patients who developed procedure related complications or were lost in the follow-up, out of initial 73 patients, 55 patients were included in the analysis, including 34 with benign and 21 with malignant disease. Meanwhile, 40 non-jaundiced controls were also included. Appetite, nutritional status, and serum ghrelin, cholecystokinin (CCK), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) were determined at admission, 48 h and 28 d after internal biliary drainage. Chi square test was used for categorical variables. Continuous variables were analysed for normality by Kolmogorov-Smirnov test and relevant non-parametric (Mann-Whitney, Kruskal-Wallis, and Friedman) or parametric (t-test and analysis of variance) tests were used. RESULTS: Patients with obstructive jaundice were significantly malnourished compared to controls, regardless of disease etiology. Plasma ghrelin and CCK levels were significantly higher in patients with obstructive jaundice. Serum bilirubin concentrations were negatively correlated with ghrelin levels and positively correlated with TNF-α, but had no correlation with CCK concentrations. After internal biliary drainage, a significant improvement of nutritional status was observed although serum concentrations of ghrelin, IL-6, and TNF-α remained significantly elevated even 28 d after the procedure. CCK levels in patients without malnutrition remained elevated 28 d after the procedure, but in patients with malnutrition, CCK levels decreased to levels comparable with those in the control group. We have not established any correlation between appetite and serum levels of ghrelin, CCK, IL-6, and TNF-α before and after biliary drainage. CONCLUSION: Possible abnormalities in ghrelin and CCK regulation may be associated with the development of malnutrition during the inflammatory response in patients with biliary obstruction.

Role of Endoscopic Ultrasound in Liver Disease: Where Do We Stand?

As the burden of liver disease in the general populace steadily increases, so does the need for both advanced diagnostic and treatment options. Endoscopic ultrasound is a reliable diagnostic and therapeutic method that has an established role, foremost in pancreatobiliary pathology. This paper aims to summarize the growing role of endoscopic ultrasound in hepatology based on the search of the current literature. A number of applications of endoscopic ultrasound are reviewed, including both noninvasive methods and tissue acquisition in focal and diffuse liver disease, portal hypertension measurement, detection and management of gastric and esophageal varices, treatment of focal liver lesions and staging of pancreatobiliary malignancies, treatment of cystic and solid liver lesions, as well as liver abscess drainage. Both hepatologists and endoscopists should be aware of the evolving role of endoscopic ultrasound in liver disease. The inherent invasive nature of endoscopic examination limits its use to a targeted population identified using noninvasive methods. Endoscopic ultrasound is one the most versatile methods in gastroenterology, allowing immediate access with detection, sampling, and treatment of digestive tract pathology. Further expansion of its use in hepatology is immanent.

Prevalence and Prognostic Impact of Deranged Liver Blood Tests in COVID-19: Experience from the Regional COVID-19 Center over the Cohort of 3812 Hospitalized Patients.

BACKGROUND: Derangement of liver blood tests (LBT) is frequent in patients with Coronavirus disease 2019 (COVID-19). We aimed to evaluate (a) the prevalence of deranged LBT as well as their association with (b) clinical severity at admission and (c) 30-day outcomes among the hospitalized patients with COVID-19. METHODS: Consecutive patients with COVID-19 hospitalized in the regional referral center over the 12-month period were included. Clinical severity of COVID-19 at hospital admission and 30-day outcomes (need for intensive care, mechanical ventilation, or death) were analyzed. RESULTS: Derangement of LBT occurred in 2854/3812 (74.9%) of patients, most frequently due to elevation of AST (61.6%), GGT (46.1%) and ALT (33.4%). Elevated AST, ALT, GGT and low albumin were associated with more severe disease at admission. However, in multivariate Cox regression analysis, when adjusted for age, sex, obesity and presence of chronic liver disease, only AST remained associated with the risk of dying (HR 1.5081 and 2.1315, for elevations 1-3 × ULN and >3 × ULN, respectively) independently of comorbidity burden and COVID-19 severity at admission. Patients with more severe liver injury more frequently experienced defined adverse outcomes. CONCLUSIONS: Deranged LBTs are common among patients hospitalized with COVID-19 and might be used as predictors of adverse clinical outcomes.

Expression of NEDD9 and connexin-43 in neoplastic and stromal cells of gastric adenocarcinoma.

Gastric cancer is related to high mortality rates and advanced disease stage at the time of diagnosis. Its carcinogenesis is extensively studied and is associated with genetic and epigenetic changes, changed the interaction between tumor and adjacent stromal cells, and changes in the microenvironment molecule status. Neural precursor cell-expressed developmentally down-regulated 9 (NEDD9) affects different signaling proteins and pathways, apoptosis, adhesion, cell migration, and invasiveness. Connexin-43 (Cx43) also assists in intercellular communications and has several channel-independent functions. Aberrant expression of those two gap junction proteins plays an essential role in metastatic processes. Our scope was to detect the expression of Cx43 and NEDD9 in epithelial and stromal gastric cancer compartments and its relation to tumor progression and lymph node metastases. Cancer tissue from 53 cases of node-negative and 55 cases of node-positive primary gastric carcinoma patients was analyzed for Cx43 and NEDD9 expression by immunohistochemical assay, and the results were correlated with the remaining clinical and pathological findings and survival. In our cohort of patients with lymph node metastases, we detected higher expression of epithelial Cx43 in the primary tumor and stromal Cx43 expression correlated with both epithelial NEDD9 (rho = 0.453) and stromal NEDD9 (rho = 0.484). Higher epithelial Cx43 and NEDD9 expression were associated with higher mortality (HR 1.54, 95% CI 1.01-2.37, p = 0.048). Epithelial Cx43 expression, both epithelial and stromal NEDD9 expression, T and N status were all independently associated with shorter survival. In summary, our findings suggest that increased expression of both epithelial and stromal NEDD9 and epithelial Cx43 could potentially be used as prognostic gastric cancer biomarkers.

Candidemia after endoscopic therapy with lumen-apposing metal stent for pancreatic walled-off necrosis.

Necrotizing pancreatitis remains a challenging and unpredictable condition accompanied by various complications. Endoscopic ultrasound-guided transmural drainage and necrosectomy have become the standard treatment for patients with walled-off necrosis (WON). Endoscopic therapy via lumen-apposing metal stents (LAMS) with large diameters has shown success in the management of pancreatic fluid collections, but there are few data on specific complications of that therapy. We report a case of infected WON and concomitant fungemia following LAMS placement and necrosectomy. In addition, a systematic literature review of current related studies has been provided.

Overview and developments in noninvasive diagnosis of nonalcoholic fatty liver disease.

High prevalence of non-alcoholic fatty liver disease (NAFLD) and very diverse outcomes that are related to disease form and severity at presentation have made the search for noninvasive diagnostic tools in NAFLD one of the areas with most intense development in hepatology today. Various methods have been investigated in the recent years, including imaging methods like ultrasound and magnetic resonance imaging, different forms of liver stiffness measurement, various biomarkers of necroinflammatory processes (acute phase reactants, cytokines, markers of apoptosis), hyaluronic acid and other biomarkers of liver fibrosis. Multicomponent tests, scoring systems and diagnostic panels were also developed with the purposes of differentiating non-alcoholic steatohepatitis from simple steatosis or discriminating between various fibrosis stages. In all of the cases, performance of noninvasive methods was compared with liver biopsy, which is still considered to be a gold standard in diagnosis, but is by itself far from a perfect comparative measure. We present here the overview of the published data on various noninvasive diagnostic tools, some of which appear to be very promising, and we address as well some of still unresolved issues in this interesting field.

Acid inhibition and the acid rebound effect.

Acid secretion from gastric parietal cells is a result of a complex interaction between different stimulatory and inhibitory mediators. One of the most important mediators is gastrin, which stimulates gastric acid secretion from parietal cells mostly indirectly, by the release of histamine from enterochromaffin-like (ECL) cells. Therapy with antisecretory agents leads to hypergastrinemia, mucosal hyperplasia and increased ECL cell mass, which results in increase of gastric acid secretion capacity. This increased secretion capacity has been shown to manifest itself after antisecretory therapy withdrawal as rebound acid hypersecretion (RAH). Various studies have quantified acid hypersecretion after the cessation of therapy with H(2) antagonists and proton-pump inhibitors (PPIs). While most of those studies had small patient numbers, the findings generally demonstrate that RAH after H(2) antagonist therapy is of low magnitude, short duration, and has questionable clinical significance. On the contrary, acid hypersecretion after PPI therapy is more pronounced, lasts longer, and could possibly be the cause of acid-related symptoms. Potential for causing symptoms has recently been confirmed in two randomized placebo-controlled studies, and while we witness the increasing use of PPIs, RAH could become a proven cause of failure to withdraw therapy in a proportion of patients with reflux or dyspeptic symptoms.

Genetic polymorphisms in non-alcoholic fatty liver disease: clues to pathogenesis and disease progression.

The spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis through steatohepatitis to advanced fibrosis and cirrhosis. Although the reason why only a minority of patients develop progressive forms of disease still remains largely unclear, recent research has identified genetic factors as a possible basis for this variation in disease presentation. Most of the studies have been focused on finding associations between advanced disease forms and selected single nucleotide polymorphisms in genes encoding various proteins involved in disease pathogenesis. Although there are many limitations regarding the study design and interpretation of published data, further carefully planned studies together with implementation of new genetic technologies will likely bring new insights into disease pathogenesis and potential benefits to the management of patients with NAFLD.

Pathogenesis and management issues for non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) has, although it is a very common disorder, only relatively recently gained broader interest among physicians and scientists. Fatty liver has been documented in up to 10 to 15 percent of normal individuals and 70 to 80 percent of obese individuals. Although the pathophysiology of NAFLD is still subject to intensive research, several players and mechanisms have been suggested based on the substantial evidence. Excessive hepatocyte triglyceride accumulation resulting from insulin resistance is the first step in the proposed 'two hit' model of the pathogenesis of NAFLD. Oxidative stress resulting from mitochondrial fatty acids oxidation, NF-kappaB-dependent inflammatory cytokine expression and adipocytokines are all considered to be the potential factors causing second hits which lead to hepatocyte injury, inflammation and fibrosis. Although it was initially believed that NAFLD is a completely benign disorder, histologic follow-up studies have showed that fibrosis progression occurs in about a third of patients. A small number of patients with NAFLD eventually ends up with end-stage liver disease and even hepatocellular carcinoma. Although liver biopsy is currently the only way to confirm the NAFLD diagnosis and distinguish between fatty liver alone and NASH, no guidelines or firm recommendations can still be made as for when and in whom it is necessary. Increased physical activity, gradual weight reduction and in selected cases bariatric surgery remain the mainstay of NAFLD therapy. Studies with pharmacologic agents are showing promising results, but available data are still insufficient to make specific recommendations; their use therefore remains highly individual.

Adjusted blood requirement index as indicator of failure to control acute variceal bleeding.

AIM: To estimate the clinical value of adjusted blood requirement index (ABRI) in relation to other criteria for failure of variceal bleeding control proposed at Baveno consensus workshops and to evaluate ABRI as an early predictor of occurrence of other Baveno criteria and identification of possible predictors of unfavorable ABRI. METHODS: We retrospectively analyzed the data on 60 patients admitted to the hospital due to acute variceal bleeding. Number of treatment failures according to Baveno II-III and Baveno IV definitions and criteria was compared. We tested the ABRI's predictability of other Baveno IV and Baveno II-III criteria. Logistic regression analysis was performed to ascertain independent variables that predict ABRI> or =0.75. RESULTS: Failure to control variceal bleeding occurred in 40 of 60 patients according to Baveno II-III criteria, and in 35 of 60 patients according to Baveno IV criteria. Excluding the criterion of "transfusion of 2 units of blood or more (over and above the previous transfusions)" and ABRI criterion, failure to control variceal bleeding was observed in 17 and 14 of 60 patients, respectively. Congruence of ABRI with other criteria was present in about two-thirds of the cases. ABRI> or =0.75 was associated with increased risk of positive other Baveno criteria, particularly modified Baveno II-III (odds ratio [OR] 4.10; 95% confidence interval [CI], 1.11-15.05) and Baveno IV without ABRI (OR 4.37; 95% CI, 1.04-18.28). Independent predictors of ABRI> or =0.75 identified in logistic regression analysis were male sex (P<0.001) and higher hematocrit values (P=0.004). CONCLUSION: We found low congruence between ABRI and other Baveno criteria and the incidence of treatment failure in our study was higher than the previously reported frequencies of early rebleeding. It seems that criteria related to the quantity of blood transfusions are not reliable indicators of treatment failure.

[Inflammatory bowel disease and pregnancy]. / Upalne bolesti crijeva i trudnoca.

Inflammatory bowel diseases (IBD) can affect women of childbearing potential. There are many issues to consider in female patients with IBD who are contemplating pregnancy, such as influence of the disease on fertility or pregnancy outcome, effect of the gestation on the course of the disease, safety of the drugs and inheritance of the disease in the offspring. It is important to remember that the outcome of the pregnancy is dependent mostly on the activity of the disease at the time of conception and there is no increase of the adverse events in patients with quiescent bowel disease. With few exceptions, majority of medications used in the treatment of IBD are safely used during pregnancy and breastfeeding. This article reviews the most recent knowledge regarding the effects of IBD and their treatment on fertility and pregnancy, therapeutic options and outcomes in patients who are planning pregnancy or who are pregnant or lactating.

[Hepatitis C--treatment of untreated (naive) patients]. / Hepatitis C--terapijski pristup nelijecenim (naivnim) bolesnicima.

The most important therapeutic advance in recent years considering chronic HCV infection has occurred with the introduction of pegylated interferon (PEG IFN) in the combination therapy with ribavirin, which results in better sustained virologic response (SVR). Although an SVR is difficult to correlate with improved survival because of the necessity for long-term follow up, the absence of detectable serum HCV RNA has been associated with resolution of liver injury, reduction in hepatic fibrosis, and a low likelihood of a relapse of the HCV infection. Two large pivotal trials examined the efficacy of PEG IFN plus ribavirin in the treatment of chronic HCV infection. Overall, PEG IFN plus ribavirin was more effective than the standard interferon-ribavirin combination. SVR rates were similar with both forms of PEG IFN (PEG IFN alfa-2a and PEG IFN alfa-2b) when used in combination with ribavirin. SVR rates of 42% and 46% were achieved in patients with genotype 1 compared to rates of 76% and 82% in patients with genotypes 2 and 3. Factors associated with successful therapy included genotypes other than 1, lower baseline viral levels, less fibrosis or inflammation on liver biopsy, and lower body weight or body surface area. Twenty four weeks of treatment with a combination of PEG IFN and ribavirin appears to be sufficient for patients infected with genotypes 2 and 3, while patients with genotype 1 need 48 weeks of treatment. Early virologic response (EVR), defined as undetectable HCV RNA or a minimum 2 log decrease in viral load (relative to baseline) after the first 12 weeks of treatment, is predictive of SVR and should be a routine part of monitoring patients with genotype 1. Patients who fail to achieve an EVR have only a small chance of achieving an SVR, therefore treatment should be discontinued after 12 weeks. It is also recommended to treat patients with acute hepatitis C to reduce the risk of developing chronic infection. Treatment should start 12 weeks after the onset of symptoms and includes 24 weeks of monotherapy with PEG IFN.