Yasar Colak

Linking nonalcoholic fatty liver disease to hepatocellular carcinoma: from bedside to bench and back.

AIMS AND BACKGROUNDnNonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) are two major causes of liver disease worldwide. Epidemiological and clinical data have clearly demonstrated that NAFLD and its associated metabolic abnormalities are a risk factor for HCC. Traditionally, the mechanisms whereby NAFLD acts as a risk for HCC are believed to include replicative senescence of steatotic hepatocytes and compensatory hyperplasia of progenitor cells as a reaction to chronic hepatic injury. Recent years have witnessed significant advances in our understanding of the mechanisms underlying the link between NAFLD and HCC.nnnMETHODSnIn the present review, we provide an update on the pathophysiological pathways linking NAFLD and its associated metabolic derangements to malignant hepatic transformation, with a special focus on insulin resistance, adipokines, inflammation, and angiogenesis. We will also discuss the potential therapeutic implications that such molecular links carry.nnnRESULTSnAlthough treating NAFLD could reduce the risk of malignant hepatic transformation, no long-term studies focusing on this issue have been conducted thus far. Insulin resistance, inflammation as well as derangements in adipokines and angiogenic factors associated with NAFLD are closely intertwined with the risk of developing HCC.nnnCONCLUSIONSnTraditional therapeutic approaches in NAFLD including metformin and statins may theoretically reduce the risk of HCC by acting on common pathophysiological pathways shared by NAFLD and HCC.

Serum osteopontin levels as a predictor of portal inflammation in patients with nonalcoholic fatty liver disease

BACKGROUNDnOsteopontin is a secreted phosphorylated glycoprotein that is expressed by a variety of cell types and that mediates numerous and diverse biological functions. Osteopontin knockout mice are protected from obesity-induced hepatic steatosis. In the present study, we sought to investigate whether serum osteopontin concentrations are associated with liver histology in patients with nonalcoholic fatty liver disease.nnnMETHODSnSerum levels of osteopontin were measured by enzyme-linked immunosorbent assay in 179 well-characterized patients with nonalcoholic fatty liver referred for liver histology and 123 control subjects.nnnRESULTSnSerum osteopontin levels were markedly higher in patients with nonalcoholic fatty liver disease than in controls (p<0.001). Multivariable analysis showed that osteopontin levels were strongly and independently associated with both portal inflammation (β=0.294, p<0.01) and serum aminotransferase levels (aspartate aminotransferase: β=0.295, p<0.01; alanine aminotransferase; β=0.285, p<0.01).nnnCONCLUSIONnIn summary, these data demonstrate that serum levels of osteopontin are elevated in nonalcoholic fatty liver disease and are a significant independent predictor of portal inflammation in this clinical entity.

Left atrial deformation parameters in patients with non-alcoholic fatty liver disease: a 2D speckle tracking imaging study.

The presence of the metabolic syndrome is a strong predictor for the presence of NASH (non-alcoholic steatohepatitis) in patients with NAFLD (non-alcoholic fatty liver disease). In the present study, we assessed LA (left atrial) deformation parameters in patients with NAFLD using 2D-STE (speckle tracking echocardiography) and to investigate if any changes exist between subgroups of the NAFLD. A total of 55 NAFLD patients and 21 healthy controls were included in the study. The diagnosis of NAFLD was based on liver biopsy. After patients were categorized into groups according to histopathological analysis (simple steatosis, borderline NASH, definitive NASH), all patients underwent echocardiography with Doppler examination. In the 2D-STE analysis of the left atrium, LA-Res (peak LA strain during ventricular systole), LA-Pump (peak LA strain during atrial systole), LA-SR(S) (peak LA strain rate during ventricular systole), LA-SR(E) (peak LA strain rate during early diastole) and LA-SR(A) (peak LA strain rate during atrial systole) were obtained. LA-Res, LA-Pump and LA-SR(A) were lower in the NAFLD group than in the control group. LA-Res was found to be significantly lower in NAFLD subgroups compared with healthy subjects (43.9±14.2 in healthy controls compared with 31.4±8.3 with simple steatosis, 32.8±12.8 with borderline NASH and 33.8±9.0 with definitive NASH). LA-Pump was significantly lower in the NAFLD group (18.2±3.1 in healthy controls compared with 13.3±4.7 with borderline NASH and 14.4±4.7 with definitive NASH). There were significant differences in LA-SR(A) between healthy controls compared with simple steatosis and borderline NASH (-1.56±0.36 compared with 1.14±0.38 and 1.24±0.32 respectively). Correlation analysis showed significant correlation of LA-Res values with E (early diastolic peak velocity)/E(m) (early diastolic mitral annular velocity) ratio (r=-0.50, P≤0.001), with LAVI (LA volume index; r=-0.45, P≤0.001) and with V(p) (propagation velocity; r=0.39, P≤0.001). 2D-STE-based LA deformation parameters are impaired in patients with NAFLD with normal systolic function. Although LA-Res and pump function parameters might be useful in estimating LV (left ventricular) filling pressure in the NAFLD patient group, it could not be used for differentiating the subgroups.

Not only type 2 diabetes but also prediabetes is associated with portal inflammation and fibrosis in patients with non-alcoholic fatty liver disease

AIMSnGrowing evidence suggests that not only type 2 diabetes (T2D) but also prediabetes (PD) is common in patients with non-alcoholic fatty liver disease (NAFLD). However, few data exist on how PD impacts the histological characteristics of NAFLD patients. In this exploratory study, we sought to investigate the associations of PD and T2D with the severity of the histological features in patients with NAFLD.nnnMETHODSnThe population consisted of 280 patients with biopsy-proven NAFLD. The associations of PD and T2D with the severity of histological features of NAFLD were analyzed using multiple logistic (or ordinal logistic) regression models after adjustment for confounding factors.nnnRESULTSnPD and T2D was noted in 102 (36.4%) and 92 (32.8%) of patients, respectively. Of the 92 patients with T2D, ten (10.9%) were diagnosed de novo after the OGTT. PD and T2D were significantly associated with more severe portal inflammation (P<0.01); the adjusted odds ratios (ORs) of PD and T2D for having a higher grade of portal inflammation were 1.8 [95% CI, 1.1, 3.2] and 2.6 [95% CI, 1.3, 5.8]), respectively. A similar relationship was observed for liver fibrosis (P<0.001); specifically, the adjusted ORs of PD and T2D for having a higher grade of hepatic fibrosis were 2.4 [95% CI, 1.3, 3.7] and 3.8 [95% CI, 1.9, 6.1]), respectively.nnnCONCLUSIONnNot only T2D but also PD is independently associated with portal inflammation and fibrosis in NAFLD patients. PD may be useful as a clinical indicator of patients who are likely to have already more severe histological findings.

Hepatic expression and serum levels of syndecan 1 (CD138) in patients with nonalcoholic fatty liver disease

Abstract Background and aims. Syndecan-1 (CD138) is a transmembrane heparan sulfate proteoglycan expressed in the liver which may exert metabolic effects by mediating the hepatic clearance of triglyceride-rich lipoproteins. In the present study, we assayed serum levels and the hepatic expression of syndecan-1 and examined their association with clinical, biochemical, and histologic phenotypes in patients with histology-proven nonalcoholic fatty liver disease (NAFLD). Methods. A total of 59 patients with biopsy-proven NAFLD and 54 matched controls were enrolled. The analysis of syndecan-1 expression in liver biopsies was performed by immunohistochemistry on formalin-fixed, paraffin-embedded samples. Serum syndecan-1 levels were measured by ELISA. Results. NAFLD patients had significantly higher serum syndecan-1 levels [median: 61 ng/mL (interquartile range: 36–97 ng/mL)] than controls [median: 37 ng/mL (interquartile range: 25–59 ng/mL, Mann–Whitney U test, p < 0.001]. However, we did not find any significant association between serum syndecan-1 and the mean syndecan-1 immunohistochemical score (n = 59, r = 0.064, p = 0.63). Interestingly, the syndecan-1 immunohistochemical score was an independent predictor of HDL cholesterol in NAFLD patients (β = 0.27; t = 1.99, p < 0.05). Conclusions. Our data suggest that serum syndecan-1 levels are raised in patients with NAFLD. Moreover, the syndecan-1 immunohistochemical score in the liver is independently associated with HDL cholesterol in this group of patients. These pilot results support further investigation of this molecule in metabolic liver diseases.

Colonic duplication in adulthood presenting with diarrhea.

In pediatric clinics, alimentary tract duplications are seen with an incidence of approximately 1 in 4500 [1]. Most cases are diagnosed within the first 5 years of life [2]. The condition is seen infrequently in adults. Patients usually present with constipation, diarrhea, abdominal pain, abdominal mass, and, sometimes, acute abdomen, volvulus, or perforation [3]. There are two types of colonic duplication: tubular and cystic. Diagnosis requires a careful history and detailed imaging with endoscopy, computed tomography, and in some cases barium meal study. Correct diagnosis is important not only because the symptoms decrease patients’ quality of life, but also because with time patients are at increased risk of developing carcinoma [4]. The most common form of carcinoma associated with alimentary tract duplication is adenocarcinoma. A 39-year-old man without any other history of chronic disease was referred to our clinic because of chronic diarrhea. He described the watery diarrhea as having been present for 6 months and being independent of eating. He had no fever, rectal bleeding, or tenesmus. He complained of having had irregular abdominal pain since childhood. Physical examination showed no significant findings. The work-up for ruling out infectious causes, including microscopic examination for protozoa and cultures of the feces, produced negative findings. Abdominal radiography was performed but showed nothing significant, and colonoscopy was done in order to rule out inflammatory bowel disease and celiac disease. At colonoscopy, thick, band-like mucosal lesions were seen dividing the lumen into three spaces, like the Mercedes logo, with wide exudative superficial ulcers and polypoid lesions on top of and around them (● Fig.1). Biopsy results showed lowgrade dysplasia on the malformation site (● Fig.2), and the patient was referred for surgery. Low anterior resection was performed. The symptoms regressed after surgery and the follow-up colonoscopy after 6 months showed no significant findings. Intestinal duplications are rare gastrointestinal abnormalities in adulthood. They are defined as mucosal structures with smooth muscle lining which form another lumen (tubular duplication) or cysts (cystic duplication). The cystic form is the most commonly found [5]. Colonic duplication is one of the rarest types of duplication of the alimentary tract [6]. Its pathogenesis is still unclear, but there are several theories relating it to malformation of the embryonic gut. Some authors suggest that environmental factors may also have a role. Although the disease is usually rapidly diagnosed in infants, diagnosis can be challenging in adults. Manifestations usually include pain, obstructive symptoms, and sometimes mass lesions. With its broad range of symptoms, this abnormality can be difficult to differentiate from infections, inflammatory bowel disease, gastrointestinal bleeding, or obstruction. In our case the patient presented with chronic diarrhea. To our knowledge, this is the first reported case of colonic duplication presenting with diarrhea as the main symptom. Another aspect that needs to be underlined about colonic duplication is that it can lead to carcinoma, most importantly adenocarcinoma. In a series of seven cases of colorectal duplication, one patient had high-grade dysplasia and one had lowFig.1 Endoscopic images showing colonic duplication and ulcers in a 37-year-old man.

Massive Upper Gastrointestinal Bleeding Caused by Diffuse Large B-Cell Lymphoma

Massive upper gastrointestinal bleeding is a life-threatening emergency which needs urgent intervention. Hematological malignancies are very rare causes of this type of bleeding and they usually originate from duodenum. In this case we present a gastric diffuse large B-cell lymphoma (DLBCL) causing massive upper gastrointestinal system bleeding. A 77-year-old male patient was admitted to emergency clinic with hematemesis and hematochezia. In physical examination patient was pale and sweaty; his vitals were unstable with a heart rate of 110 per minute and a blood pressure of 90/50u2009mmHg. His hemoglobin level was found 7.5u2009g/dL and he was transfused with one unit of packed red blood cells. After his vitals were normalized, gastroscopy was performed showing mosaic pattern in corpus and antrum mucosa and multiple ulcers in various sizes, largest being approximately 2u2009cm in diameter, higher than mucosa covered with exude mostly on corpus and large curvature. Biopsy results were reported as DLBCL. Gastric mucosa is involved in most of the DLBCL cases. Although not listed as a common cause of massive gastrointestinal bleeding DLBCL can cause life-threatening situations mostly because of its malignant nature.

A Disease Entity Is Identified

Abstract Barrett’s esophagus (BE) is the presence of metaplastic columnar epithelium in the lower portion of the esophagus, which is normally lined with stratified squamous epithelium. The main cause of the disease is theorized to be reflux esophagitis developed due to chronic acid exposure as a result of symptomatic or asymptomatic gastroesophageal reflux. In addition, the disease is clinically significant as a major risk factor for esophageal adenocarcinoma. Barrett’s esophagus is named after Norman Rupert Barrett, a highly regarded and successful thoracic surgeon of his period. Contrary to popular belief, however, Norman Barrett’s contribution to the identification of the disease was quite limited. Barrett wrote of the presence of ulcers in the esophagus and the presence of columnar epithelium around ulcers in an article published in 1950 entitled “Chronic peptic ulcer of the oesophagus and ‘oesophagitis’”. However, there were number of inaccuracies in this article and the history of the disease dates back to much older times.