Myeloperoxidase and calprotectin; Any role as non-invasive markers for the prediction of inflammation and fibrosis in non-alcoholic steatohepatitis?

BACKGROUND/AIMS: Specific serum markers reflecting hepatic inflammation and fibrosis are required to tailor the treatment strategies in non-alcoholic steatohepatitis (NASH). We aimed to investigate the roles of myeloperoxidase (MPO) and calprotectin in predicting the hepatic inflammation status and disease severity in NASH. MATERIALS AND METHODS: A total of 48 patients with biopsy-proven NASH and 25 healthy volunteers with normal weight were prospectively enrolled. Serum MPO and calprotectin levels were compared between the NASH and control groups. Hepatic MPO and calprotectin expressions were compared in terms of histologic non-alcoholic fatty liver disease activity scores (NAS) (low NAS [≤4] vs. high NAS [>5]) and fibrosis stage (insignificant [F0-1]/significant [F2-4]). RESULTS: Serum MPO and calprotectin levels were not significantly different between the NASH and control groups. In the subgroup analysis, hepatic MPO expression was significantly increased in patients with NASH with significant fibrosis than in those with insignificant fibrosis (F2-4: 7.04±3.61 vs. F0-1: 4.83±2.42, p=0.01). We found no difference between the groups with low and high NAS with regard to serum MPO and calprotectin levels and hepatic MPO and calprotectin expressions. CONCLUSION: This study demonstrated that hepatic MPO expression can reflect advanced fibrosis in NASH. However, when serum MPO and calprotectin levels were evaluated as potential serum markers, both did not associate with hepatic inflammation status and fibrosis stage in NASH. Therefore, our study results preclude their use as serum markers for hepatic inflammation in NASH.

A large Turkish pedigree with multiple endocrine neoplasia type 1 syndrome carrying a rare mutation: c.1680_1683 del TGAG.

BACKGROUND AND AIMS: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by tumors arising from endocrine glands with no specific genotype-phenotype correlation. Herein, we report the largest Turkish kindred with MEN1 inherited a scarce MEN1 mutation gene. MATERIALS AND METHODS: Sixty-four year-old man, referred to our gastroenterology outpatient clinic for evaluation of pancreatic mass lesion, was diagnosed with MEN1-syndrome after endoscopic ultrasound guided sampling of the mass revealing pancreatic neuroendocrine tumor (pNET), and accompanying primary hyperparathyroidism (PHPT) and pituitary tumor. Genetic analysis by whole gene Sanger sequencing of MEN1 gene identified a frame-shift mutation in exon 10 (c.1680_1683delTGAG). All the relatives of the index case were proposed for clinical and genetic evaluation for MEN1-syndrome. RESULTS: Of the 25 relatives of the index case, 17 were diagnosed MEN1-syndrome. Eighteen members among all relatives consented to genetic analysis and 11 had the same mutation as the index case. All the mutation positive members had MEN1, while none of mutation negative subjects had any sign of MEN1-syndrome. The frequencies of PHPT, pNET and pituitary tumors in this kindred were 94.1% (16/17), 29.4% (5/17) and 29.4% (5/17) respectively. CONCLUSION: We report rare MEN1 gene mutation which was descibed in a single sporadic patient before. It inherited in at least three generations of a large family, which has proven strong dominant effect on MEN1 phenotype. Further researches may be conducted to clarify potential candidacy of this mutation, as a hotspot for MEN1 patients, especially in Turkish population.

European Guideline on IgG4-related digestive disease - UEG and SGF evidence-based recommendations.

The overall objective of these guidelines is to provide evidence-based recommendations for the diagnosis and management of immunoglobulin G4 (IgG4)-related digestive disease in adults and children. IgG4-related digestive disease can be diagnosed only with a comprehensive work-up that includes histology, organ morphology at imaging, serology, search for other organ involvement, and response to glucocorticoid treatment. Indications for treatment are symptomatic patients with obstructive jaundice, abdominal pain, posterior pancreatic pain, and involvement of extra-pancreatic digestive organs, including IgG4-related cholangitis. Treatment with glucocorticoids should be weight-based and initiated at a dose of 0.6-0.8 mg/kg body weight/day orally (typical starting dose 30-40 mg/day prednisone equivalent) for 1 month to induce remission and then be tapered within two additional months. Response to initial treatment should be assessed at week 2-4 with clinical, biochemical and morphological markers. Maintenance treatment with glucocorticoids should be considered in multi-organ disease or history of relapse. If there is no change in disease activity and burden within 3 months, the diagnosis should be reconsidered. If the disease relapsed during the 3 months of treatment, immunosuppressive drugs should be added.

External validation of the Toronto hepatocellular carcinoma risk index in Turkish cirrhotic patients.

OBJECTIVES: Toronto hepatocellular carcinoma risk index is developed to stratify cirrhotic patients according to 10-year hepatocellular carcinoma risk. We aimed to validate the performance of Toronto hepatocellular carcinoma risk index in a large Turkish cohort. MATERIALS AND METHODS: We retrospectively reviewed the database of 1287 cirrhotic patients followed-up in a 10-year period (February 2008 to January 2018). All patients were stratified into three groups based on the Toronto hepatocellular carcinoma risk index score as follows: low-risk, < 120; intermediate risk, 120 to 240; and high risk, > 240. Area under the curve and optimal cutoff value of Toronto hepatocellular carcinoma risk index were obtained from receiver operator curve. To reveal the parameters related with hepatocellular carcinoma development, logistic regression analysis was conducted. The cumulative incidences of hepatocellular carcinoma were calculated using the Kaplan-Meier method, and the curves were compared using the log-rank test. RESULTS: Out of 403 enrolled patients, 57 developed hepatocellular carcinoma. The median Toronto hepatocellular carcinoma risk index value was higher in hepatocellular carcinoma (+) group comparing to hepatocellular carcinoma (-) group [267 (70-366) vs. 224 (36-366), P < 0.001]. Out of 57 detected hepatocellular carcinomas, 45 (78.9%) were high risk, 11 (19.3%) were intermediate risk, and only one (1.8%) was low risk at the entry. The area under the curve of the Toronto hepatocellular carcinoma risk index to predict hepatocellular carcinoma was 0.750 (95% confidence interval, 0.683-0.817, P < 0.001). The optimal cutoff value of Toronto hepatocellular carcinoma risk index was 239.5, giving a sensitivity of 78.9% and specificity of 62.7%. As a result, Toronto hepatocellular carcinoma risk index remained to be the only significant parameter that has an affect on hepatocellular carcinoma development [adjusted-odds ratio: 1.016 (95% confidence interval, 1.007-1.024), P<0.001]. CONCLUSION: The present study validated the performance of Toronto hepatocellular carcinoma risk index in Turkish cirrhotic patients to predict hepatocellular carcinoma risk, which can be considered as a tool for personalized surveillance.

Mesenchymal stem cells suppress hepatic fibrosis accompanied by expanded intrahepatic natural killer cells in rat fibrosis model.

Natural killer (NK) cells have antifibrotic effects. We have evaluated the influence of rat bone marrow-mesenchymal stem cell (BM-MSC) treatment on liver histology, biochemical liver function tests, systemic immunoregulatory state and NK cell distribution in liver and peripheral blood in rat model of common bile duct (CBD) ligation and compared the results with the control group. Rats were divided into three groups: (1) CBD ligated (CBDL) rats received phosphate-buffered saline (CBDL + PBS group) or (2) MSC (CBDL + MSC group) and sham-operated rats received MSC (healthy + MSC group). We found significantly decreased fibrosis scores with BM-MSC treatment in CBDL rats compared to the control (CBDL + PBS) group while no fibrosis developed in sham operated (healthy + MSC) group. BM-MSC treatment has decreased the inflammation as reflected by the significantly decreased T cell proliferation and inflammatory cytokine concentrations from splenocyte culture and liver tissue itself compared to CBDL + PBS. NK cells both in parenchyme and portal areas decreased significantly in liver and blood in CBDL + PBS compared to healthy + MSC while they were found to be increased in CBDL + MSC compared to CBDL + PBS rats. In conclusion, BM-MSCs may suppress hepatic fibrosis accompanied by expanded intrahepatic NK cells in CBDL rats. Thus, our animal study shows that MSC treatment holds great promise for treatment of patients with end-stage liver diseases through a possible mechanism by adopting the NK cell population and new studies investigating the role of NK cells and clinical fibrosis are warranted.Trial registration number: Marmara University Animal Care and Use Committee approval code: 73.2013.mar.

Advanced endoscopic ultrasound management techniques for preneoplastic pancreatic cystic lesions.

Pancreatic cystic lesions can be benign, premalignant or malignant. The recent increase in detection and tremendous clinical variability of pancreatic cysts has presented a significant therapeutic challenge to physicians. Mucinous cystic neoplasms are of particular interest given their known malignant potential. This review article provides a brief but comprehensive review of premalignant pancreatic cystic lesions with advanced endoscopic ultrasound (EUS) management approaches. A comprehensive literature search was performed using PubMed, Cochrane, OVID and EMBASE databases. Preneoplastic pancreatic cystic lesions include mucinous cystadenoma and intraductal papillary mucinous neoplasm. The 2012 International Sendai Guidelines guide physicians in their management of pancreatic cystic lesions. Some of the advanced EUS management techniques include ethanol ablation, chemotherapeutic (paclitaxel) ablation, radiofrequency ablation and cryotherapy. In future, EUS-guided injections of drug-eluting beads and neodymium:yttrium aluminum agent laser ablation is predicted to be an integral part of EUS-guided management techniques. In summary, International Sendai Consensus Guidelines should be used to make a decision regarding management of pancreatic cystic lesions. Advanced EUS techniques are proving extremely beneficial in management, especially in those patients who are at high surgical risk.

Small EUS-suspected gastrointestinal stromal tumors of the stomach: An overview for the current state of management.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors found in the gastrointestinal (GI) tract, with the stomach being the most common site. They represent a distinct group of GI tumors originating from the interstitial cells of Cajal and are characterized by gain-of-function mutations of KIT. KIT oncoprotein serves as both diagnostic and therapeutic targets. Prognosis is related to size, mitotic activity, and site of the tumor. Asymptomatic, small endoscopic ultrasonography (EUS)-suspected GISTs are increasingly encountered with the wide availability of endoscopic/endosonographic examination. The majority of small GISTs are biologically indolent, albeit possibly harboring c-KIT gene mutations. An ongoing controversy exists regarding the management and surveillance policy for small gastric GISTs. A number of reports on the management of GISTs have been published, not confidently addressing the issue of gastric GISTs of small size. This work provides an overview on the current state of management considerations, specifically focusing on small EUS-suspected gastric GISTs, which are increasingly encountered by clinicians.

Nonalcoholic Fatty Liver Disease is Associated with Erectile Dysfunction: A Prospective Pilot Study.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome (MetS). Although the link between MetS and erectile dysfunction (ED) is well known, clinical studies investigating the association between NAFLD and ED are scant. AIM: To evaluate the relationship between NAFLD and ED. METHODS: Male patients with biopsy-proven NAFLD were prospectively asked to fill the five-item International Index of Erectile Function (IIEF-5) questionnaire. Their clinical and histologic variables were compared with the IEFF scores. MAIN OUTCOME MEASURES: IIEF scores; proportions of NAFLD patients who demonstrated ED and/or MetS; association between the severity of histological hepatic damage and ED. RESULTS: Forty male patients having an age range of 33 (24-57) and a mean age of 40.13 ± 10.22 years with biopsy-proven NAFLD had a median IIEF-5 score of 16 (9-25) and MetS was present in 23 (57.5%). ED severity distributions as moderate, mild, and no ED were 11 (27.5%), 16 (40%), and 13 (32.5 %), respectively. Histological NAFLD score was significantly higher in patients having ED compared with patients with no ED (5.63 ± 1.39 vs. 4.15 ± 1.46; P = .006). MetS diagnosis was significantly more common in patients having ED, compared with those without ED [19 (70.4%) vs. 4 (30.8%), respectively, P = .018)]. When patients with and without ED were compared, gamma glutamyl transferase was significantly lower in ED, whereas components of MetS did not correlate with ED. After multivariate analysis, NAFLD score has remained the only significant outcome associated with ED [P = .03; OR (95% CI): 2.38 (1.079-5.238)]. CONCLUSION: The current clinical study demonstrates a significant association between nonalcoholic steatohepatitis and ED for the first time. Our findings suggest liver damage may play role in the pathogenesis of ED in patients with NAFLD. Future studies are needed to expand the underlying common mechanisms responsible for this novel hypothesis.

Saccharomyces boulardii ameliorates clarithromycin- and methotrexate-induced intestinal and hepatic injury in rats.

Saccharomyces boulardii is a probiotic used for the prevention of antibiotic-associated diarrhoea. We aimed to investigate whether S. boulardii could alter the effects of clarithromycin (CLA) and methotrexate (MTX) on oro-caecal intestinal transit and oxidative damage in rats. Rats were divided into two groups receiving a single dose of MTX (20 mg/kg) or CLA (20 mg/kg per d) for 1 week. Groups were treated with either saline or S. boulardii (500 mg/kg) twice per d throughout the experiment. The control group was administered only saline. Following decapitation, intestinal transit and inflammation markers of glutathione (GSH), malondialdehyde and myeloperoxidase were measured in intestinal and hepatic tissues. CLA and MTX increased intestinal transit, while S. boulardii treatment slowed down CLA-facilitated transit back to control level. Both MTX and CLA increased lipid peroxidation while depleting the antioxidant GSH content in the hepatic and ileal tissues. Conversely, lipid peroxidation was depressed and GSH levels were increased in the ileal and hepatic tissues of S. boulardii-treated rats. Increased ileal neutrophil infiltration due to MTX and CLA treatments was also reduced by S. boulardii treatment. Histological analysis supported that S. boulardii protected intestinal tissues against the inflammatory effects of both agents. These findings suggest that S. boulardii ameliorates intestinal injury and the accompanying hepatic inflammation by supporting the antioxidant state of the tissues and by inhibiting the recruitment of neutrophils. Moreover, a preventive effect on MTXinduced toxicity is a novel finding of S. boulardii, proposing it as an adjunct to chemotherapy regimens.

Effects of sitagliptin in diabetic patients with nonalcoholic steatohepatitis.

BACKGROUND & AIMS: Preliminary evidence suggests that inhibition of dipeptidyl peptidase (DPP)-IV preserves pancreatic beta cell function in patients with type 2 diabetes (T2D). However, its effects on liver histology in nonalcoholic steatohepatitis (NASH), hepatic complication of diabetes, have not yet been adequately explored. The present open-label, single-arm observational pilot study investigated the effects of one year of treatment with a dipeptidyl peptidase-IV inhibitor, sitagliptin, on liver histology, body mass index (BMI), and laboratory parameters in NASH patients with T2D. PATIENTS AND METHODS: Paired liver biopsies from 15 diabetic patients with NASH (7 males, 8 females; mean age: 49.7 +/- 8.1 years (range: 36-62)) before and after one year of therapy with sitagliptin 100 mg once daily were studied. Clinical and laboratory parameters were recorded. RESULTS: Treatment with sitagliptin resulted in a significant decrease in ballooning (P = 0.014) and NASH scores (P = 0.04), while the reduction in the steatosis score was of borderline statistical significance (P = 0.054). These effects were accompanied by a significant reduction in body mass index, AST, and ALT levels. CONCLUSION: Our study suggests that sitagliptin ameliorates liver enzymes and hepatocyte ballooning in NASH patients with T2D and may have therapeutic implications.

Synchronous appearance of gastrointestinal stromal tumor and neuroendocrine tumor in stomach: review of the literature and management strategies.

Gastrointestinal stromal tumors represent the most common mesenchymal tumor of the digestive tract. Although the stomach is the most common location for gastrointestinal stromal tumor with the co-primary tumors, the synchronous appearance of a neuroendocrine tumor and gastrointestinal stromal tumor in the stomach is rare. We present here the case of a 48-year-old male with gastric well-differentiated neuroendocrine tumor and gastrointestinal stromal tumor discovered incidentally during surgical treatment of the neuroendocrine tumor. We discuss the current guidelines for the management of small gastrointestinal stromal tumors (<2 cm in diameter) and the gastric carcinoids. We also review the literature for the co-occurrence of gastrointestinal stromal tumor and neuroendocrine tumor in a gastric location.

Colloid scintigraphy in non-alcoholic steatohepatitis: a conventional diagnostic method for an emerging disease.

AIM: Non-alcoholic steatohepatitis (NASH) is a progressive liver disease characterized by diffuse fatty infiltration and Kupffer cell dysfunction which contributes to its pathogenesis. Since the liver biopsy, which is considered the 'gold standard' in diagnosing NASH, has some limitations other imaging methods have been explored as alternatives. Colloid scintigraphy is a good method reflecting Kupffer cell activity and we found it worthwhile to evaluate this technique in NASH. We aimed to present the common scintigraphic features and their clinicopathologic correlations in NASH. METHODS: Twenty-two new patients (11 female, mean age 43.7+/-10.8) with biopsy-proven NASH underwent colloid liver scintigraphy. The dynamic, static and SPECT images were performed after intravenous injection of 185 MBq Tc tin colloid. Hepatic perfusion, blood pool clearance time, colloid shift to spleen and bone marrow were assessed and liver right/left lobe ratio was calculated. RESULTS: The values calculated on static and tomographic (SPECT) images showed good correlation. Liver right/left lobe ratio was altered in all patients. Blood pool clearance time was prolonged in seven (32%) but hepatic perfusion was normal in all patients. Colloid shift to the spleen was observed in 55% of patients using SPECT analysis. No correlation between scintigraphy parameters and histological or biochemical findings were observed. CONCLUSION: Altered liver right/left lobe ratio was the universal finding in all our NASH patients. Other common scintigraphic features of NASH include colloid shift to spleen and prolonged blood pool clearance time. Liver scintigraphy might be a promising non-invasive tool in the follow-up of NASH patients in therapeutic trials.

Computed tomography in nonalcoholic fatty liver disease: a useful tool for hepatosteatosis assessment?

The value and/or limitations of computed tomography (CT) in assessment of hepatosteatosis are not well studied in nonalcoholic fatty liver disease (NAFLD). We prospectively evaluated the accuracy of CT in assessing the amount of hepatosteatosis in NAFLD patients and the impact of demographic and histopathologic variables on CT images. Forty patients with biopsy-proven NAFLD were eligible. Of these, 10 exhibited hepatic iron overload. Liver and spleen attenuation measurements were obtained and spleen-minus-liver attenuation difference (DeltaS-LA) was calculated. A good correlation between DeltaS-LA and pathological hepatosteatosis was observed (r = 0.837, P < 0.0001). Liver iron overload did not affect this correlation, although the mean DeltaS-LA was significantly lower in patients with iron overload. No correlation was detected between DeltaS-LA and hepatic inflammation, fibrosis, or body mass index. We conclude that DeltaS-LA derived from CT may be a useful tool for predicting the amount of hepatosteatosis in NAFLD patients as it is not affected by various individual factors.

Efficacy and safety of Saccharomyces boulardii in prevention of antibiotic-associated diarrhoea due to Helicobacterpylori eradication.

BACKGROUND AND AIM: Antibiotic-associated diarrhoea may develop during or following Helicobacter pylori eradication. We aimed to evaluate the efficacy and safety of Saccharomyces boulardii in preventing antibiotic-associated diarrhoea in patients receiving antibiotics for H. pylori eradication. METHODS: In a multicentre prospective clinical trial, patients with peptic ulcer disease or non-ulcer dyspepsia were enrolled to receive clarithromycin, amoxicillin and omeprazole for H. pylori eradication for 14 days. These patients were then randomized to receive either S. boulardii 500 mg twice daily (treatment group) or no treatment (control group). The primary outcome measure was the development of diarrhoea during (treatment period) or within 4 weeks after treatment (follow-up period). RESULTS: Of the 389 patients that were enrolled, 376 completed the study. Within the treatment period, diarrhoea developed in 5.9% of patients in the treatment group and in 11.5% of patients in the control group (P = 0.049); and in the follow-up period, diarrhoea developed in 1.0% of patients in the treatment group and in 3.8% of patients in the control group (P = 0.09). Overall diarrhoea rates throughout the whole study period were 6.9% in the treatment group and 15.6% in the control group (P = 0.007). No significant difference was observed between the treatment and control groups in terms of adverse events. CONCLUSION: S. boulardii is an effective and safe treatment for prevention of antibiotic-associated diarrhoea when given concomitantly to patients receiving H. pylori eradication.

Extraorbital sebaceous carcinoma with rapidly developing visceral metastases.

BACKGROUND: Extraorbital sebaceous carcinoma (SC) is a rare carcinoma of the skin but is known to have a good prognosis in terms of metastasis and survival. OBJECTIVE: To discuss and emphasize through the clinical and histopathologic findings and the aggressive potential of extraorbital SC and to review the corresponding literature. METHODS: We present an unusual form of extraorbital SC that has followed an aggressive course and that has metastasized rapidly. RESULTS: Local excision of the primary cutaneous tumor with negative margins did not prevent the rapid and fatal internal organ metastases. The patient did not benefit from the docetaxel chemotherapy regimen applied after the distant metastases were developed. CONCLUSION: Extraorbital SC may show a poor prognosis. Both the dermatologic surgeon and the dermatologist should be cautious of the risk of local recurrence and distant metastasis when dealing with extraorbital SC.