Genome-wide Association Study Identifies Genetic Variants Associated With Early and Sustained Response to (Pegylated) Interferon in Chronic Hepatitis B Patients: The GIANT-B Study.

BACKGROUND: (Pegylated) Interferon ([Peg]IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. Host genetic determinants of response are therefore in demand. METHODS: In this genome-wide association study (GWAS), CHB patients, treated with (Peg)IFN for at least 12 weeks ± nucleos(t)ide analogues within randomized trials or as standard of care, were recruited at 21 centers from Europe, Asia, and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined hepatitis B e antigen (HBeAg) loss with hepatitis B virus (HBV) DNA <2000 IU/mL, or an HBV DNA <2000 IU/mL for HBeAg-negative patients. RESULTS: Of 1144 patients, 1058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% hepatitis B surface antigen (HBsAg) loss. GWAS analysis stratified by HBeAg status, adjusted for age, sex, and the 4 ancestry components identified PRELID2 rs371991 (B= -0.74, standard error [SE] = 0.16, P = 3.44 ×10-6) for HBeAg-positive patients. Importantly, PRELID2 was cross-validated for long-term response in HBeAg-negative patients. G3BP2 rs3821977 (B = 1.13, SE = 0.24, P = 2.46 × 10-6) was associated with response in HBeAg-negative patients. G3BP2 has a role in the interferon pathway and was further examined in peripheral blood mononuclear cells of healthy controls stimulated with IFNα and TLR8. After stimulation, less production of IP-10 and interleukin (IL)-10 proteins and more production of IL-8 were observed with the G3BP2 G-allele. CONCLUSIONS: Although no genome-wide significant hits were found, the current GWAS identified genetic variants associated with (Peg)IFN response in CHB. The current findings could pave the way for gene polymorphism-guided clinical counseling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies. CLINICAL TRIALS REGISTATION: NCT01401400.

Cyclophosphamide-induced severe acute hepatitis in a rheumatic disease: case-based review.

In rheumatology practice, the risk of hepatotoxicity from medications, including non-steroidal anti-inflammatory drugs, notably, and methotrexate, sulfasalazine, leflunomide, and azathioprine is highly recognized by the rheumatologists. On the other hand, hepatotoxicity is neither a commonly expected nor a well-known side effect of cyclophosphamide (CYC) which is particularly used for vital organ involvements in systemic lupus erythematosus (SLE) and systemic vasculitis. Here we reported a 19-year-old case of SLE who, while on oral CYC treatment of 100 mg/day, was detected to have asymptomatic liver enzyme elevation and then developed acute hepatitis due to intravenously administered high-dose (1 g) CYC for neuro-lupus. Results of liver biopsy indicated drug-related toxicity. We discussed here with the other, although rare, cases available in the literature with an attempt to highlight the risk of hepatotoxicity and acute hepatitis due to CYC.

Management of suspected common bile duct stone: diagnostic yield of current guidelines.

BACKGROUND: The American Society for Gastrointestinal Endoscopy (ASGE) has recently published a guideline for suspected CBDS with the intention of reducing unnecessary ERCP and thereby complications. The aim of this study was to assess the diagnostic efficacy of the ASGE guideline. METHODS: Data of patients who underwent ERCP with suspected CBDS were analyzed retrospectively. Patients were classified into high, intermediate and low risk groups based on predictors that have been suggested by the ASGE. Very strong predictors of the presence of ductal stones included: CBDS on transabdominal ultrasonography (US), clinical ascending cholangitis or total bilirubin (TBIL) >4 mg/dL). Strong predictors included dilated CBD >6 mm on US with gallbladder in situ and TBIL level of 1.8-4.0 mg/dL whereas moderate predictor included abnormal liver biochemical test other than bilirubin, age more than 55 years and clinical findings of biliary pancreatitis. RESULTS: Of 888 enrolled patients, 704 had CBDS demonstrated by ERCP and the remainder did not. All very strong and strong predictors were found to be significantly higher among patients who had CBDS. Detection of CBDS by ultrasonography and a dilated common biliary duct were observed to be independent risk factors associated with the existence of CBDS. The high risk group had a high (86.7%) positive predictive value (PPV), however, sensitivity and specificity were observed to be moderate (67.8% and 60.3% respectively). PPV was 67.9% in the intermediate risk group and the sensitivity and specificity were very low (31.9% and 42.3%). DISCUSSION: The probability of CBDS was observed to be high in the intermediate and high risk groups. However due to low sensitivity and specificity values, the ASGE guideline needs additional or different predictors.

Clinical and histological features of idiosyncratic liver injury: Dilemma in diagnosis of autoimmune hepatitis.

AIM: Drug-induced liver injury (DILI) is becoming a worldwide problem with its still unexplained properties. METHODS: The data of patients who were diagnosed with DILI between January 2008 and December 2013 were assessed. RESULTS: Five patients had been diagnosed with intrinsic and 82 patients with idiosyncratic DILI. The most common causative agents were antimicrobial drugs. The most common injury pattern was hepatocellular. When patients with bilirubin levels of more than 5 mg/dL were divided into two groups according to receiving steroid therapy (n = 11) or not (n = 40), there was not any significant difference according to their clinical results (P > 0.05). Five of the idiosyncratic DILI patients were diagnosed with drug-induced autoimmune hepatitis (DI-AIH). In histopathological examination, hepatic rosette formation and emperipolesis were observed to be more common among patients with DI-AIH when compared with ones without (P < 0.05). Interestingly, in the remaining patients with DILI (n = 77), three of them were diagnosed with classic autoimmune hepatitis during long-term follow up (range, 11-51 months). CONCLUSION: The most common causes were antimicrobials, but any agents that have not been defined to cause DILI can induce DILI. The efficacy of steroids in DILI has not been observed but all deaths were observed in the steroid-free group. The association of DILI and AIH was observed in two different types in terms of diagnosis in our study. The first association was DI-AIH. The second one is the classical AIH which developed in three patients after a few months following spontaneous recovery of DILI.

Is Gastric Xanthelasma an Alarming Endoscopic Marker for Advanced Atrophic Gastritis and Intestinal Metaplasia?

BACKGROUND/AIM: The clinical significance of gastric xanthelasmas is unknown. We conducted a case-control study in order to evaluate whether gastric xanthelasma is an indicator of advanced atrophic gastritis and intestinal metaplasia. MATERIAL AND METHOD: The study was conducted among 1400 patients who underwent elective upper endoscopy. Patients with gastric xanthelasma and atrophy and/or intestinal metaplasia constituted the study group (n = 55). The control group involved patients with only atrophic gastritis and/or intestinal metaplasia (n = 50). Histopathologic findings of the groups including the distribution of atrophic gastritis and/or intestinal metaplasia, operative link on gastritis assessment score, operative link on gastritis intestinal metaplasia assessment (OLGIM) score, and presence of dysplasia and malignancy were compared. Subgroup analysis was performed in order to establish the relation between the characteristics (size, number, and localization) of xanthelasmas, atrophy, and intestinal metaplasia. RESULTS: Multifocal atrophic gastritis was significantly more common in patients with a gastric xanthelasma (41.8 vs. 26.0 %, p = 0.03). Patients with multiple xanthelasmas had a significantly higher rate of intestinal metaplasia (p = 0.02) and a higher OLGIM score (p = 0.02) compared to those with a single xanthelasma. Dysplasia was detected in 8 (14.5 %) patients with a xanthelasma and 4 (8.0 %) patients without a xanthelasma (p = 0.2). CONCLUSION: Gastric xanthelasma(s) is a warning endoscopic sign for the presence of multifocal atrophic gastritis and advanced intestinal metaplasia.

Can routine laboratory parameters predict adverse pregnancy outcomes in intrahepatic cholestasis of pregnancy?

AIM: Our aim was to investigate whether any hematological changes readily detectable by simple complete blood count (CBC), as well as fasting and postprandial total serum bile acid (SBA) levels, have diagnostic values for the prediction of adverse pregnancy outcomes in intrahepatic cholestasis of pregnancy (ICP). METHODS: A prospective, case control study was carried out including 217 pregnant women (117 women with ICP and 100 healthy controls). The main outcome measures investigated were preterm delivery, APGAR scores, and neonatal unit admission. A multivariate logistic regression model was used to identify the independent risk factors of adverse pregnancy outcomes. RESULTS: Compared with controls, women with ICP had significantly higher mean platelet volume (MPV) (mean 10.2±1.0 vs. 11.0±1.3; P<0.001) and platelet distribution width (PDW) (mean 13.1±2.3 vs. 14.7±2.8; P<0.001) values. Analysis with logistic regression revealed that the probability of preterm delivery did not increase until MPV levels exceeded 11.2 fL [odds ratio (OR)=2.68, 95% confidence interval (CI)=1.13-6.32, P=0.025], and total bilirubin levels exceeded 0.6 mg/dL (OR=3.13, 95% CI=1.21-8.09, P=0.019). Considering the low APGAR scores, only increased postprandial total SBA levels of ≥51 µmol/L were found to be predictive significantly (OR=3.02, 95% CI=1.07-8.53, P=0.037). CONCLUSIONS: Our study suggests that increased MPV and total bilirubin levels are associated with preterm delivery, and increased postprandial total SBA levels are predictive for low APGAR in ICP patients.

Features of systemic lupus erythematosus in patients with autoimmune hepatitis.

Although systemic lupus erythematosus (SLE) and autoimmune hepatitis (AIH) are distinct diseases, in clinical practice differentiation of one from other may be difficult. The aim of this study was to asses features of SLE in patients with diagnosis of AIH.Thirty patients [mean age: 52.4 ± 11.8 years; 23 (76.7 %) female] were included in the study. Seven (23.3 %) of the patients full filled 4 or more criteria for classification of SLE. None of the patients had muco-cutaneous lesions characteristic to SLE. Three patients had rheumatoid factor negative arthritis, and 2 patients had pericardial effusion. Four patients had significant thrombocytopenia (<100 × 10(3)/µL), and one of these patients had pancytopenia. None of the patients had hematuria, but 3 patients had proteinuria which did not affect renal function during the study period. One patient died due to pancytopenia-associated pulmonary infection. Among the treated patients with SLE features, 2/5 (40 %) achieved ALT normalization and 9/12 (75 %) of the remaining patients achieved ALT normalization (Fisher's exact test; p = 0.28) during the study period. Although the difference is non-significant, treatment response of AIH patients with SLE features seemed to be delayed and incomplete compared to other patients, but with the limited number of patients it is inconvenient to reach a definitive conclusion. Further studies are needed to identify role of features of SLE on treatment response in patients with AIH.

Safety of endoscopic ultrasonography in elderly patients: a single center prospective trial.

BACKGROUND AND AIMS: The aim of this prospective study is to evaluate the safety of both diagnostic and therapeutic endosonography (EUS) in geriatric population. METHODS: The study population, consisting of 222 patients who underwent endosonographic evaluation for different indications, was divided into two groups. Group I consisted of 165 patients, ≥ 65 years old; Group II consisted of 57 controls, <65 years old. The demographic information with clinical parameters, procedure medication used and complications was noted. RESULTS: The median age of Group I was 72 years (range 65-93 years) vs. 46 years (range 26-64 years) for Group II. Female-to-male ratio was 82/83 in Group I, while 32/25 in Group II. Pulse rate (84 vs. 89 beats/min, p = 0.024) and basal oxygen saturation (94 vs. 97 %, p < 0.001) levels were lower in Group I when compared with the control group, while systolic blood pressure measurements (150 vs. 130 mmHg, p < 0.001) were significantly higher in Group I. No cases of procedure-related bleeding, perforation and mortality were observed in both groups. CONCLUSION: Despite the well-known relative increased procedural risks, advanced age is not a contraindication for advanced endoscopic interventions. EUS can be regarded as a safe and effective procedure in ≥ 65 years old population.

Genetic Investigations in Turkish Idiopathic Pancreatitis Patients Show Unique Characteristics.

BACKGROUND/AIMS: Pancreatitis is one of the leading causes of digestive system-related hospital admissions, and it has a genetic background in a considerable portion of the patients. In this study, we aimed to investigate the genetic risk factors of idiopathic pancreatitis in Turkish patients and the contribution of copy number variations to the pathogenesis. MATERIALS AND METHODS: Idiopathic pancreatitis is defined as failure to detect risk factors despite comprehensive clinical assessments. Next-generation sequencing and multiple ligand-dependent probe amplification of PRSS1, SPINK1, CTRC, and CFTR were performed. For further genotype-phenotype correlations, patients were also questioned for the age of onset, family history, and pancreatic divisum. RESULTS: A total of 68 idiopathic pancreatitis cases were enrolled. Variants with potential clinical significance of PRSS1 were identified in 13.4%, SPINK1 in 6.3%, CTRC in 4.7%, and CFTR in 26.5% of the patients. No copy number variants were seen in any of these genes. At least 7.4% of the participants had complex genetic etiology involving 2 genes. CONCLUSIONS: At least 42.6% of the participants had a potential genetic risk factor. Five novel genetic variants were identified, and distinctive genetic risk factors of Turkish population were shown. The results showed that genetic etiology was frequent in pancreatitis and it was even more prominent in patients with early-onset disease. Considering that genetic risk factors may be informative for decisionmaking in the treatment options in addition to providing extensive prognostic value and familial genetic consultation; clinicians need to be more eager to offer genetic tests to pancreatitis patients.

The impact of endoscopic retrograde cholangiopancreatography education on radiation exposure to experienced endoscopist: 'trainee effect'.

BACKGROUND: Endoscopic retrograde cholangiopancreatography(ERCP), as with other fluoroscopic procedures, carries the risk of exposure of staff to radiation. However, over the last two decades, only a few studies have investigated this risk. OBJECTIVE: The aim of this work was to evaluate the dose of radiation exposure to staff participating in ERCP procedures in a busy teaching hospital that performs more than 1,850 procedures annually. METHODS: The entire ERCP staff consisted of the experienced endoscopist, the assistant, and two nurses who were responsible for monitoring patients as well as keeping their heads in position during the procedure. RAD DOSE NEB.226 dosimeters, which were provided by the Turkish Atomic Energy Authority, were used for this study. RESULTS: Data on 110 consecutive therapeutic ERCP procedures was recorded. The mean fluoroscopy time was 5.65 ± 4.71 min. The mean fluoroscopy time of the 61 procedures performed by an experienced endoscopist alone was 5.41 ± 4.65 min, whereas the mean fluoroscopy time for the 49 procedures during which an assistant was involved was 5.94 ± 4.81 min (p = 0.56). In terms of median dose of ionizing radiation exposure to the eyes, the dose measurement per procedure in which the primary endoscopist participated alone was 72 microsievert (µSv), compared to 92 µSv when an assistant took part in theproceedings. Considering that the recommended annual equivalent dose limit to the lens of the eye is 150 mSv, by performing 1,850 procedures annually, the primary endoscopist exceeds this limit. CONCLUSIONS: Based on our results, taking into consideration the heavy workload in our hospital, it would seem that more experienced endoscopists are required to help provide training in ERCP, and that the use of lead acrylic goggles is required to decrease radiation exposure to the eyes.

Can red cell distribution width help to discriminate benign from malignant biliary obstruction? A retrospective single center analysis.

BACKGROUND/AIMS: Differentiation of benign obstructive jaundice from malignant obstructive jaundice still remains difficult, despite improvements in diagnostic modalities. The aim of this study is to evaluate the usefulness of red cell distribution width (RDW) in differentiating benign and malignant causes of obstructive jaundice. METHODOLOGY: One hundred and ninety four consecutive patients (101 malignant, 93 benign) with a history of obstructive jaundice were reviewed in the period between January 2008 and August 2009. Definition of biliary strictures was suggested by cholangiographic features and supported by brush cytology, fine needle aspiration (FNA) and the presence of mass or metastases by imaging and/or clinical followup. Patients were divided into two groups, benign and malignant, based on the discharge diagnosis. RESULTS: The receiver operating characteristic analysis showed that a RDW of 14.8% was the best cut-off value for predicting a malignant biliary stricture with a sensitivity of 72% and a specificity of 69% (AUC=0.755, 95% CI=0.649-0.810). RDW was increased (>14.8%) in 31.6% of benign cases and 68.4% of malignancies. Depressed RDW levels (<14.8%) were found in 72.9% of benign cases and 27.1% of malignancies, which was statistically significant (p<0.001). CONCLUSIONS: Our results show that RDW is useful in the differentiation of benign from malignant causes of biliary obstruction when using an optimized cut-off value. In patients in whom biliary obstruction is suspected, an elevated RDW value may be a reliable additional predictor for differentiating the underlying etiology of biliary obstruction.

The role of mean platelet volume in the diagnosis of hepatocellular carcinoma in patients with chronic liver disease.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) has poor long-term prognosis so we need new diagnostic techniques and markers to detect HCC in the early phases. The aim of this study was to analyze the levels of serum mean platelet volume in HCC. METHODOLOGY: The clinical data of 230 subjects with normal, chronic hepatitis, cirrhosis and HCC were retrospectively analyzed at our hospital between January 2009 and December 2009. The levels of MPV were determined in patients with liver disease and compared between patient groups and with healthy persons. RESULTS: Serum MPV levels were significantly increased compared to the patients with chronic hepatitis, cirrhosis, and the control group (p<0.01). The cut-off value for MPV for the detection of HCC in cirrhotic patients was calculated as ≥9.2fl using ROC analysis [Sensitivity: 68.3%, specificity: 62.1%, AUC: 0.676 (0.580-0.773), p<0.001]. Additionally, serum MPV levels show higher sensitivity for diagnosis of HCC than AFP. An AFP of more than 7.4IU/mL and an MPV of ≥9.2fl, both put together, had a specificity of 95.2%, while when used separately, they have a sensitivity of 87.5%. CONCLUSIONS: MPV may be a potential or adjunctive marker of HCC in patients with chronic liver disease.

Does interleukin-18 play a role in the pathogenesis of hepatic encephalopathy?

BACKGROUND/AIMS: It has been suggested that the presence of inflammation may accentuate the neuropsychologic alterations in hepatic encephalopathy (HE). The aim of the study was to investigate any association between alterations in plasma levels of the pro-inflammatory cytokine IL-18 and HE. METHODOLOGY: The study population included 63 patients with cirrhosis and 20 healthy controls. Laboratory data included international normalized ratio, plasma albumin, bilirubin, urea, creatinine, hsCRP and IL-18 (pg/mL). HE was assessed using West Haven criteria and critical flicker frequency (CFF) measurement. RESULTS: Forty-two of the 63 cirrhotic patients had HE (4, 16, 21 and 1 patients in grade 0, 1, 2, 3, respectively). hsCRP and IL-18 were significantly increased in patients with HE compared with the control group (1.6 +/- 4.8 vs 0.5 +/- 0.8, p<0.001 and 121.4 (13.6-2043.6) vs 56.3 (13.0-174.0), p=0.006, respectively). The levels of hsCRP and IL-18 were significantly higher in the all cirrhotic patients than in the control subjects (p=0.002 and p=0.008 respectively). hsCRP was significantly higher in patients with HE (2.2 +/- 6) than in patients without HE (0.7 +/- 1.2) (p=0.013). The levels of IL-18 were found higher in patients with HE than in patients without HE [121.4 (13.6-2043.6) vs 103.8 (13.0-828.0)] but the difference was not significant (p=0.215). IL-18 was higher in patients with elevated hsCRP [124.6 (13.6-2043.6)] compared with those who had normal hsCRP [75.6 (13.0-753.2)] (p=0.029). CONCLUSION: There is an inflammatory response in the presence of cirrhosis and HE; and IL-18 may play a role in the perpetuation of chronic inflammation.

Incidence, Risk Factors, and Treatment of Proximally Migrated Pancreatic Stents.

AIM: The aim of this study was to investigate the incidence, risk factors, and treatment strategies of proximally migrated pancreatic stents. MATERIALS AND METHODS: The data of 626 sessions of 421 patients with pancreatic duct stenting were retrospectively analyzed between 2010 and 2018, and patients with proximally migrated stents were included in the study. RESULTS: Of 626 stents examined, 77 migrated proximally (12%). The migration rate (MR) was 16%, 2%, and 7%, respectively, in patients treated with chronic pancreatitis, malignancy, and pancreatic leakage indication. The MR was 14% in procedures with pancreatic duct stenosis, 21% in procedures with pancreatic sphincterotomy, and 27% in procedures performed from minor papillae. The MR of the 5, 7, and 10 Fr stents was 4%, 17%, and 10%, respectively. Of the 77 migrated stents, 64 were successfully removed (83%). This success rate (SR) was 84% in procedures with chronic pancreatitis indication, 83% in procedures with pancreatic duct stenosis, 79% in procedures with sphincterotomy, and 75% in procedures performed from minor papillae. The SR of the 5, 7, and 10 Fr stents was 100%, 79%, and 92%, respectively. It was also determined that 33 stents were fractured and migrated (43%). The SR of the fractured stents was 76%. Moreover, of the stents that were successfully removed, 35 were removed with forceps (55%) and 15 (23%) were removed with a balloon. Furthermore, in 47 cases, the stent was removed in the first session (73%). Acute pancreatitis occurred in 5 patients (8%) and perforation occurred in 1 patient (2%). CONCLUSION: In this study, it was shown that proximal migration of pancreatic stents is frequent and most of these stents can be removed successfully.