The Accuracy of Serum Biomarkers in the Diagnosis of Steatosis, Fibrosis, and Inflammation in Patients with Nonalcoholic Fatty Liver Disease in Comparison to a Liver Biopsy.

Background and Objective: This study was conducted to evaluate the diagnostic performance of various biomarkers for steatosis, fibrosis, and inflammation in comparison to a liver biopsy (LB) in patients with nonalcoholic fatty liver disease (NAFLD). Materials and Methods: This was a cross-sectional study that included 135 patients with biopsy-proven NAFLD. Fatty liver index (FLI), hepatic steatosis index (HSI), cell death markers (CK-18 M30 and CK-18 M65), FIB-4 index, NAFLD fibrosis score (NFS), BARD, and AST to platelet ratio index (APRI) were calculated and analysed. Results: FLI, HSI scores, and the cell death biomarkers showed poor diagnostic accuracy for steatosis detection and quantification, with an area under the curve (AUC) of <0.70. The cell death biomarkers likewise did not perform well for the detection of nonalcoholic steatohepatitis (NASH) (AUC < 0.7). As for the fibrosis staging, only APRI and the cell death biomarkers had moderate accuracy (AUC > 0.7) for advanced fibrosis, whereas FIB-4, BARD, and NFS scores demonstrated poor performance (AUC < 0.70). However, a combination of FIB-4 and NFS with the cell death biomarkers had moderate accuracy for advanced (≥F3) fibrosis detection, with an AUC of >0.70. Conclusions: In this first study on Croatian patients with NAFLD, serum biomarkers demonstrated poor diagnostic performance for the noninvasive diagnosis of liver steatosis and NASH. APRI and the cell death biomarkers had only moderate accuracy for diagnosing advanced fibrosis, as did the combination of FIB-4 and NFS with the cell death biomarkers. Further studies regarding serum biomarkers for all NAFLD stages are needed.

EFFECTS OF OCCUPATIONAL STRESS ON THE ACTIVATION OF HEMOSTATIC AND INFLAMMATORY SYSTEM.

A 24-hour shift is one of the major stressors for physicians because, apart from causing fatigue and circadian rhythm disorders, it often requires making vital decisions for patients within a short time frame. It is known that workplace stress leads to the activation of the coagulation system, which can result in imbalance of the coagulation and fibrinolysis system. The state of stress can also generate proinflammatory mediators. The aim of this study was to examine the effect of 24-hour shift on global coagulation tests of D-dimers and fibrinolysis, and on C-reactive protein (CRP) as an acute inflammatory agent and proatherosclerotic factor. Sixty physicians (residents) aged 25-35 participated in this study (30 participants in the experimental group and 30 participants in the control group). In experimental group, blood samples were collected on three occasions: shortly before 24-hour shift, twelve hours after the shift had begun, and at the end of the shift. Blood samples were collected from control group participants at the same time points. The results showed that there was no statistically significant difference in the values of D-dimer and fibrinolysis between the experimental and control groups. CRP values were statistically significantly higher in the experimental (1.57, 1.49 and 1.50) than in the control group (0.79, 0.75 and 0.84) on all three measurements (p=0.024, p=0.020 and p=0.030, respectively). These results confirmed the existence of proinflammatory changes in the endothelium of blood vessels, which is a factor associated with accelerated atherosclerosis.

[Classical medications in the treatment of inflammatory bowel diseases]. / Klasicni lijekovi koji se upotrebljavaju u lijecenju upalnih bolesti crijeva.

The treatment of inflammatory bowel diseases is complex and requires individual approach to every single patient. Traditionally, the approach is based on introduction of so called "classical" medication into the treatment regimen, from ones less potent and with fewer side effects to the ones more toxic but also therapeutically more effective. Aminosalicylates were the first choice of treatment for a long time. However, the role of aminosalicylates is becoming more and more diminished, although they are still the drug of choice in the treatment of mild to moderate ulcerative colitis. Corticosteroids are the therapy of choice in treatment of active IBD for achieving remission in moderate to severe disease. Azathioprine and 6- mercaptopurine belong to a group of thiopurines with an immunomodulatory effect which, in Crohn's disease as well as in ulcerative colitis, primarily have a role in a steroid dependant or steroid refractory type of disease and in maintenance of remission. Lately, early introduction of these medications is proposed to enhance the number of patients that remain in remission. Methotrexate is used for the therapy of active and relapsing Crohn's disease and represents an alternative in patients who do not tolerate or do not respond to azathioprine or 6-mercaptopurine therapy. Cyclosporine is used in treating steroid refractory ulcerative colitis and in some patients can postpone the need for colectomy. Antibiotics do not have a proven effect on the course of inflammatory bowel diseases and their primary role is to treat septic complications. Classic medications today represent a standard in the management of inflammatory bowel diseases, and the combination of the previously mentioned drugs often has a more potent effect on the course of the disease than any medication on its own and their combination is still an object of investigations and clinical studies.

Nutritional screening model in tertiary medical unit in Croatia.

BACKGROUND/AIMS: Malnutrition of hospitalized patients is often undetected and untreated due to poor awareness and insufficient knowledge of the attending hospital staff. Nutritional screening has not been part of the daily routine in Croatian hospitals. Our aim was to implement nutritional screening as part of the routine medical examination and to assess the nutritional risk at admission for all hospitalized patients. METHODS: All patients hospitalized in departments of internal medicine in tertiary hospitals in Croatia were screened at entry using the Nutrition Risk Screening 2002 (NRS 2002). RESULTS: Between October and December 2010, 1,696 patients were screened and analyzed (948 males and 748 females). 329 (19.4%) had an NRS 2002 score ≥3 and were considered to be at nutritional risk. An NRS 2002 score ≥3 was identified as a significant predictor of the length of hospital stay (beta coefficient = 0.06, p = 0.027) and fatal outcome (OR = 6.18, p < 0.001). Only 32.8% of malnourished patients received some nutritional support. CONCLUSIONS: Every fifth patient hospitalized in a general medical department in Croatia is at nutritional risk and the majority of them does not receive nutritional support. More effort is needed to implement nutritional standards in daily clinical practice.

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.

Noninvasive markers of liver steatosis and fibrosis after liver transplantation - Where do we stand?

In the last two decades, advances in immunosuppressive regimens have led to fewer complications of acute rejection crisis and consequently improved short-term graft and patient survival. In parallel with this great success, long-term post-transplantation complications have become a focus of interest of doctors engaged in transplant medicine. Metabolic syndrome (MetS) and its individual components, namely, obesity, dyslipidemia, diabetes, and hypertension, often develop in the post-transplant setting and are associated with immuno-suppressive therapy. Nonalcoholic fatty liver disease (NAFLD) is closely related to MetS and its individual components and is the liver manifestation of MetS. Therefore, it is not surprising that MetS and its individual components are associated with recurrent or "de novo" NAFLD after liver transplantation (LT). Fibrosis of the graft is one of the main determinants of overall morbidity and mortality in the post-LT period. In the assessment of post-LT steatosis and fibrosis, we have biochemical markers, imaging methods and liver biopsy. Because of the significant economic burden of post-LT steatosis and fibrosis and its potential consequences, there is an unmet need for noninvasive methods that are efficient and cost-effective. Biochemical scores can overestimate fibrosis and are not a good method for fibrosis evaluation in liver transplant recipients due to frequent post-LT thrombocytopenia. Transient elastography with controlled attenuation parameter is a promising noninvasive method for steatosis and fibrosis. In this review, we will specifically focus on the evaluation of steatosis and fibrosis in the post-LT setting in the context of de novo or recurrent NAFLD.

Scoring systems for peptic ulcer bleeding: Which one to use?

AIM: To compare the Glasgow-Blatchford score (GBS), Rockall score (RS) and Baylor bleeding score (BBS) in predicting clinical outcomes and need for interventions in patients with bleeding peptic ulcers. METHODS: Between January 2008 and December 2013, 1012 consecutive patients admitted with peptic ulcer bleeding (PUB) were prospectively followed. The pre-endoscopic RS, BBS and GBS, as well as the post-endoscopic diagnostic scores (RS and BBS) were calculated for all patients according to their urgent upper endoscopy findings. Area under the receiver-operating characteristics (AUROC) curves were calculated for the prediction of lethal outcome, rebleeding, needs for blood transfusion and/or surgical intervention, and the optimal cutoff values were evaluated. RESULTS: PUB accounted for 41.9% of all upper gastrointestinal tract bleeding, 5.2% patients died and 5.4% patients underwent surgery. By comparing the AUROC curves of the aforementioned pre-endoscopic scores, the RS best predicted lethal outcome (AUROC 0.82 vs 0.67 vs 0.63, respectively), but the GBS best predicted need for hospital-based intervention or 30-d mortality (AUROC 0.84 vs 0.57 vs 0.64), rebleeding (AUROC 0.75 vs 0.61 vs 0.53), need for blood transfusion (AUROC 0.83 vs 0.63 vs 0.58) and surgical intervention (0.82 vs 0.63 vs 0.52) The post-endoscopic RS was also better than the post-endoscopic BBS in predicting lethal outcome (AUROC 0.82 vs 0.69, respectively). CONCLUSION: The RS is the best predictor of mortality and the GBS is the best predictor of rebleeding, need for blood transfusion and/or surgical intervention in patients with PUB. There is no one 'perfect score' and we suggest that these two tests be used concomitantly.

Bleeding Peptic Ulcer - Tertiary Center Experience: Epidemiology, Treatment and Prognosis.

The aim of this study was to demonstrate epidemiological, clinical and endoscopic characteristics of acute upper gastrointestinal bleeding (UGIB) with special reference to peptic ulcer bleeding (PUB). The study included 2198 consecutive patients referred to our emergency department due to acute UGIB from January 2008 to December 2012. All patients underwent urgent upper GI endoscopy within 24 hours of admission, and 842 patients diagnosed with PUB were enrolled and prospectively followed-up. The cumulative incidence of UGIB was 126/100,000 in the 5-year period. Two out of five patients had a bleeding peptic ulcer; in total, 440 (52.3%) had bleeding gastric ulcer, 356 (42.3%) had bleeding duodenal ulcer, 17 (2%) had both bleeding gastric and duodenal ulcers, and 29 (3.5%) patients had bleeding ulcers on gastroenteric anastomoses. PUB was more common in men. The mean patient age was 65.9 years. The majority of patients (57%) with PUB were taking agents that attenuate the cytoprotective function of gastric and duodenal mucosa. Rebleeding occurred in 77 (9.7%) patients and 47 (5.9%) patients required surgical intervention. The 30-day morality was 5.2% and 10% of patients died from uncontrolled bleeding and concomitant diseases. In conclusion, PUB is the main cause of UGIB, characterized by a significant rebleeding rate and mortality.

Hepatitis C Virus, Insulin Resistance, and Steatosis.

Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide. Liver steatosis is a common finding in many hepatic and extrahepatic disorders, the most common being metabolic syndrome (MS). Over time, it has been shown that the frequent coexistence of these two conditions is not coincidental, since many epidemiological, clinical, and experimental studies have indicated HCV to be strongly associated with liver steatosis and numerous metabolic derangements. Here, we present an overview of publications that provide clinical evidence of the metabolic effects of HCV and summarize the available data on the pathogenetic mechanisms of this association. It has been shown that HCV infection can induce insulin resistance (IR) in the liver and peripheral tissues through multiple mechanisms. Substantial research has suggested that HCV interferes with insulin signaling both directly and indirectly, inducing the production of several proinflammatory cytokines. HCV replication, assembly, and release from hepatocytes require close interactions with lipid droplets and host lipoproteins. This modulation of lipid metabolism in host cells can induce hepatic steatosis, which is more pronounced in patients with HCV genotype 3. The risk of steatosis depends on several viral factors (including genotype, viral load, and gene mutations) and host features (visceral obesity, type 2 diabetes mellitus, genetic predisposition, medication use, and alcohol consumption). HCV-related IR and steatosis have been shown to have a remarkable clinical impact on the prognosis of HCV infection and quality of life, due to their association with resistance to antiviral therapy, progression of hepatic fibrosis, and development of hepatocellular carcinoma. Finally, HCV-induced IR, oxidative stress, and changes in lipid and iron metabolism lead to glucose intolerance, arterial hypertension, hyperuricemia, and atherosclerosis, resulting in increased cardiovascular mortality.

Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient with no history of alcohol abuse or other causes for secondary hepatic steatosis. The pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) has not been fully elucidated. The "two-hit" hypothesis is probably a too simplified model to elaborate complex pathogenetic events occurring in patients with NASH. It should be better regarded as a multiple step process, with accumulation of liver fat being the first step, followed by the development of necroinflammation and fibrosis. Adipose tissue, which has emerged as an endocrine organ with a key role in energy homeostasis, is responsive to both central and peripheral metabolic signals and is itself capable of secreting a number of proteins. These adipocyte-specific or enriched proteins, termed adipokines, have been shown to have a variety of local, peripheral, and central effects. In the current review, we explore the role of adipocytokines and proinflammatory cytokines in the pathogenesis of NAFLD. We particularly focus on adiponectin, leptin and ghrelin, with a brief mention of resistin, visfatin and retinol-binding protein 4 among adipokines, and tumor necrosis factor-α, interleukin (IL)-6, IL-1, and briefly IL-18 among proinflammatory cytokines. We update their role in NAFLD, as elucidated in experimental models and clinical practice.