Randomized Controlled Trial of Intravenous Ferric Carboxymaltose vs Oral Iron to Treat Iron Deficiency Anemia After Variceal Bleed in Patients With Cirrhosis.

INTRODUCTION: Limited evidence exists on the optimal strategy to correct iron deficiency anemia after variceal bleeding (VB) in cirrhosis. This trial compared the efficacy and safety of intravenous ferric carboxymaltose (IV-FCM) with those of oral iron therapy in this cohort. METHODS: In this open-label, single-center, randomized controlled trial, eligible patients with hemoglobin <10 g/dL and iron deficiency (ferritin <100 ng/mL) after VB received either IV-FCM (1,500-2,000 mg) divided into 2 doses (n = 48) or oral carbonyl iron (100 mg elemental iron/day) (n = 44) for 3 months. The primary outcome was change in hemoglobin at 3 months. Secondary outcomes included improvement in anemia (last hemoglobin >12 g/dL), normalization of iron stores (ferritin >100 ng/mL), liver-related adverse events, adverse drug reactions, and changes in quality of life (CLDQOL questionnaire). RESULTS: Baseline characteristics, including median Child-Turcotte-Pugh score 7 (interquartile range [IQR] 6-9), Model for End-Stage Liver Disease score 12 (IQR 10-17), blood hemoglobin (8.25 ± 1.06 g/dL), and ferritin (30.00 ng/mL [15.00-66.50]), were comparable in both arms. The median increase in hemoglobin at 3 months in the IV and oral arms was 3.65 g/dL (IQR 2.55-5.25) and 1.10 g/dL (IQR 0.05-2.90 g/dL) ( P < 0.001), respectively. Iron stores normalized in 84.6% and 21% of the IV and oral arms, respectively ( P < 0.001). Anemia improved in 50% and 21.9% in the IV and oral arms, respectively ( P < 0.009). Patients in the IV arm showed a significant improvement in all domains of CLDQOL. Liver-related adverse events were comparable in both arms. Transient mild/moderate hypophosphatemia developed in 43% of patients receiving IV-FCM. DISCUSSION: Intravenous iron replacement is efficacious and safe to treat iron deficiency anemia after VB in patients with cirrhosis.

Impact of Diabetes, Drug-Induced Liver Injury, and Sepsis on Outcomes in MAFLD-Related Acute-on-Chronic Liver Failure.

BACKGROUND: The prevalence of Metabolic dysfunction associated fatty liver disease (MAFLD) and its complication, MAFLD-related acute on chronic liver failure (MAFLD-ACLF), is rising. Yet, factors determining patient outcomes in MAFLD-ACLF remain understudied. METHODS: Patients with MAFLD-ACLF were recruited from the AARC registry. The diagnosis of MAFLD-ACLF was made when the treating unit had identified the etiology of chronic liver disease (CLD) as MAFLD (or previous nomenclature such as NAFLD, NASH, or NASH-cirrhosis). Patients with coexisting other etiologies of CLD (such as alcohol, HBV, HCV, etc.) were excluded. Data was randomly split into derivation (n=258) and validation (n=111) cohorts at a 70:30 ratio. The primary outcome was 90-day mortality. Only the baseline clinical, laboratory features and severity scores were considered. RESULTS: The derivation group had 258 patients; 60% were male, with a mean age of 53. Diabetes was noted in 27%, and hypertension in 29%. The dominant precipitants included viral hepatitis (HAV and HEV, 32%), drug-induced injury (DILI, 29%) and sepsis (23%). MELD-Na and AARC scores upon admission averaged 32±6 and 10.4±1.9. At 90 days, 51% survived. Non-viral precipitant, diabetes, bilirubin, INR, and encephalopathy were independent factors influencing mortality. Adding diabetes and precipitant to MELD-Na and AARC scores, the novel MAFLD-MELD-Na score (+12 for diabetes, +12 for non-viral precipitant) and MAFLD-AARC score (+5 for each) were formed. These outperformed the standard scores in both cohorts. CONCLUSION: Almost half of MAFLD-ACLF patients die within 90 days. Diabetes and non-viral precipitants such as DILI and sepsis lead to adverse outcomes. The new MAFLD-MELD-Na and MAFLD-AARC scores provide reliable 90-day mortality predictions for MAFLD-ACLF patients.

Opportunistic screening for osteopathy with routine abdominal computed tomography scan in chronic pancreatitis.

BACKGROUND AND AIMS: Lumbar vertebral bone attenuation, measured in Hounsfield units (HU) can indirectly indicate the bone mineral density (BMD). The aim of this study is to determine the optimal HU threshold on abdominal computed tomography (CT) scans to detect osteopathy in patients with chronic pancreatitis (CP). METHODS: This cross-sectional study included patients with CP who underwent CT scans to measure HU at L1 to L4 vertebrae. The mean lumbar vertebral attenuation of female renal transplant donors, aged 20-30 years was utilized to calculate the T-scoreHU of all patients at each vertebral level. Receiver operator characteristic analysis was used to determine the HU and T-scoreHU for diagnosis of osteopathy in patients with CP. Dual-energy X-ray absorptiometry value was used to categorize osteopenia and osteoporosis. RESULTS: A total of 175 patients (mean age, 34.5 ± 10.9 years; 72 % males) and 33 female renal transplant donors (mean age, 28 ± 2.4 years) were included. A threshold HU value 212 or T scoreHU of -1.80 at L1 vertebra was found to have a 78 % sensitivity and 70 % specificity for differentiating between osteoporosis and non-osteoporosis (osteopenia and normal BMD). Similarly, a threshold HU value of 254 or a T-scoreHU of -0.46 at L1 vertebra had 78 % sensitivity and 71 % specificity for distinguishing between normal and low BMD (osteoporosis and osteopenia). CONCLUSION: Abdominal CT images, which are routinely performed in chronic pancreatitis, can be used for opportunistic screening of osteoporosis and osteopenia without additional cost or radiation exposure.

Increased circulating Th17 cell populations in patients with pancreatic ductal adenocarcinoma.

T-helper 17 (Th17) cells are a subset of CD4+ helper T cells that produce interleukin 17 (IL-17) and play a crucial role in the pathogenesis of inflammatory and autoimmune diseases. Few studies have been conducted to determine the role of Th17 cells in the tumorigenesis and development of pancreatic ductal adenocarcinoma (PDAC); however, its role is still unclear. In this study, the percentage of circulating Th17 cells and serum levels of IL-17A and IL-23 were analyzed using flow cytometry and ELISA, respectively, in 40 PDAC patients, 30 chronic pancreatitis (CP) patients and 30 healthy controls (HC). In addition, the mRNA expression levels of IL-17A, STAT3 and RORγt in tissue samples were quantified by qRT-PCR. The results showed that the percentage of circulating Th17 cells and the concentrations of serum IL-17A and IL-23 were significantly increased in PDAC patients as compared to CP and HC (P < 0.001). In addition, the higher level of IL-17A was significantly correlated with the poor overall survival of the PDAC patients. Furthermore, the frequencies of Th17 cells and IL-17A were significantly higher in stage III+IV PDAC patients versus stage I+II. A significant increase in IL-17A, STAT3 and RORγT mRNA was observed in patients with PDAC. Taken together, these findings suggest that the increased circulating Th17 cells and serum IL-17A may be involved in the development and metastasis of PDAC, and thus represent potential targets for the treatment of PDAC.

Assessing the Risk of Further Decompensation and Survival in Patients With Cirrhosis With Variceal Bleeding as Their First Decompensation Event.

INTRODUCTION: Limited data exist on long-term outcomes of patients with compensated cirrhosis presenting with acute variceal bleeding (AVB) as an index and lone decompensating event. This study aimed to evaluate the incidence of further decompensation, survival, and risk factors of mortality in these patients. METHODS: Patients with otherwise compensated cirrhosis presenting with AVB as their index decompensating event (n = 463) were analyzed in this single-center retrospective study. The incidence of individual decompensation events and survival was estimated using competing risk analysis. Risk factors for poor outcomes were identified. RESULTS: The mean age was 47.4 (13.2) years, with most patients (86.5%) being males. Alcohol-related liver disease (42.3%) and viral cirrhosis (22.4%) were the main etiologies with a median Model for End-Stage Liver Disease score of 14 (11-15) at baseline. Over a median follow-up of 42 (24-62) months, 292 patients experienced further decompensations: ascites (n = 283; 96.9%), rebleeding (n = 157; 53.8%), and hepatic encephalopathy (n = 71; 24.3%). Most events occurred with similar frequency across different etiologies, except acute-on-chronic liver failure, which was more common in nonviral cirrhosis (Gray test, P = 0.042). Patients with viral and nonviral cirrhosis had similar survival (5-year survival: 91% and 80.1%, respectively; P = 0.062). Patients with early further decompensations (onset <6 weeks of index AVB event) (n = 40) had a higher mortality (52.5% vs 20.2% for late decompensations; P < 0.001). Active alcohol consumption (hazard ratio [HR]: 9 [5.31-15.3], P < 0.001), high white blood cell count at presentation (HR: 2.5 [1.4-4.4], P = 0.001), and early decompensation (HR: 6.2 [3.6-10.6], P < 0.001) predicted poor survival. DISCUSSION: Despite a high incidence of further decompensation, 5-year survival of patients at this stage of cirrhosis is more than 80% across all etiologies in the absence of early further decompensation and active alcohol consumption.

Utility of Fecal Elastase-1 to diagnose severe exocrine insufficiency in chronic pancreatitis: Real world experience.

INTRODUCTION: Quantitative fecal fat estimation is the gold standard test to diagnose steatorrhea (fecal fat >7 g/day) in chronic pancreatitis (CP), but cumbersome and inconvenient. So, fecal elastase-1 (FE) is proposed as a good alternative but the data on the diagnostic utility of FE to diagnose steatorrhea is variable. METHODS: This retrospective study included adult CP patients evaluated with both 24-h fecal-fat and FE tests within a 3-month period. The objective was to evaluate the diagnostic performance of FE to diagnose steatorrhea and to evaluate the FE progression over 9-month period. RESULTS: Among the 147 included patients, the frequency of steatorrhea (fecal fat >7 g/day) was 34%. The sensitivity, specificity, and negative likelihood ratio (LR) of FE was 90%, 28.9% and 0.35 at cut-off of <100 µg/g stool to diagnose steatorrhea; and 96%, 11.3% and 0.35 at cut-off of <200 µg/g stool, respectively. The optimal cut-off of FE was <20 on receiver operating characteristic curve (sensitivity 66%; specificity 69%; positive LR 2.14). There was no statistically significant variation in FE levels over 9 months interval among a hundred patients. CONCLUSION: Compared to FE ≥ 200 µg/g stool, FE ≥ 100 can used to exclude steatorrhea (better specificity and negative LR). FE < 20 alone cannot replace fecal fat estimation to confirm steatorrhea but to be interpreted with clinical features. Repeat FE testing for exocrine insufficiency progression can be done at least a year later.

Acute pancreatitis is characterized by generalized intestinal barrier dysfunction in early stage.

BACKGROUND AND AIMS: The role of intestinal-barrier in acute pancreatitis(AP) is poorly understood. We aimed to assess structural and functional changes in the intestinal-barrier in patients with early AP (time from onset<2 weeks) and the effect of enteral nutrition on them. METHODS: In this prospective observational study, patients with early AP not on enteral nutrition were compared with controls for baseline intestinal-permeability(lactulose: mannitol ratio(L:M)), endotoxinemia(serum IgM/IgG anti-endotoxin antibodies), bacterial-translocation(serum bacterial 16S rRNA) and duodenal epithelial tight-junction structure by immunohistochemistry(IHC) for tight-junction proteins(claudin-2,-3,-4, zonula occludens-1(ZO1), junctional adhesion molecule(JAM) and occludin) and electron microscopy. These parameters were reassessed after 2 weeks enteral feeding in a AP patients subset. RESULTS: 96 patients with AP(age: 38.0 ± 14.5 years; etiology: biliary[46.8%]/alcohol[39.6%]; severe:53.2%, mortality:11.4%) and 40 matched controls were recruited. Patients with AP had higher baseline intestinal permeability(median L:M 0.176(IQR 0.073-0.376) vs 0.049(0.024-0.075) in controls; p < 0.001) and more frequent bacteraemia(positive bacterial 16S rRNA in 24/48 AP vs 0/21 controls; p < 0.001) with trend towards higher serum endotoxinemia(median IgG anti-endotoxin 78(51.2-171.6) GMU/ml vs 51.2(26.16-79.2) in controls; p = 0.061). Claudin-2, claudin-3, ZO1 were downregulated in both duodenal crypts and villi while claudin-4 and JAM were downregulated in duodenal villi and crypts respectively. 22 AP patients reassessed after initiation of enteral nutrition showed trend towards improving intestinal permeability, serum endotoxinemia and bacteraemia, with significant improvement in claudin-2,-3 in duodenal villi. CONCLUSION: Patients with AP have significant disturbances in intestinal barrier structure and function in first 2 weeks from onset that persist despite institution of enteral nutrition.

Hyperactive behaviour of growth differentiation factor- 15 (GDF-15) in conjunction with iron trafficking transporters and suppression of Nrf-2 gene in diabetes and metabolic syndrome.

Multiple parallel factors are frequently interrogated with various toxic radicals which are abundantly generated in the liver, heart, and pancreas in stress conditions. They are actively involved in the development of diabetes and metabolic aberrations. However, whether over-activation of GDF-15mRNA and influxes of iron-by-iron trafficking genes are directly suppressing the Nrf-2 gene in patients with diabetes and metabolic aberrations in context with undiagnosed individuals with diabetes and metabolic aberrations? Therefore, we have investigated inter and intra- related Zip8/14 mRNA, GDF-15mRNA, and Nrf-2 mRNA expressions in diabetes and metabolic syndrome as it is expected to be up to 134 million by 2045 in India. We recruited 120 subjects from the Department of Medicine, Endocrinology and Metabolic Clinic, All India Institute of Medical Sciences, New Delhi, India. Various investigations related to anthropometry, nutritional, hematological, biochemical, cytokine, and oxidative stress were measured in diabetes, metabolic syndrome, diabetes with metabolic aberration, and healthy controls. Relative expression of GDF-15, ZIP8, ZIP14, Nrf-2, and housekeeping genes was done in all subjects. Stress-responsive cytokines are highly expressed in patients with metabolic aberration with respect to body weight, IR, waist circumference, and fat mass. IL-1ß, TNF-α, and IL-6 levels were significantly higher in metabolic syndrome, whereas Adiponectin levels were profoundly lower side. MDA levels were significantly raised in diabetes with metabolic syndrome while SOD activities were lowered (p = 0.001). GDF-15 mRNA expression was 1.79-fold upregulated in group III as compared with Group I while 2-threefold down-regulation of Nrf-2 expression was observed in diabetes with metabolic aberration groups. Zip 8 mRNA expressions were downregulated (p = 0.014), and Zip 14 mRNA expressions were upregulated (p = 0.06) in diabetes and metabolic aberrations. The association of GDF-15 and Nrf-2 mRNA expression was found contradictory and highly interlinked with ROS. Zip 8/14mRNA expressions were also dysregulated in diabetes and metabolic-associated complications.

Chronic Pancreatitis in Females is Not Associated With Adverse Pregnancy Outcomes: A Retrospective Analysis.

BACKGROUND: The effects of chronic pancreatitis (CP) on pregnancy and vice versa have not been studied well. We aimed to study the impact of CP on pregnancy-related outcomes and the effect of pregnancy on clinical profile of CP. STUDY AND GOALS: We did a retrospective analysis of all female patients of CP of child-bearing age (above 18 y). The pregnancy-related outcomes of patients with CP were compared with the age-matched 115 controls from the low-risk pregnancy group identified using a simplified antepartum high-risk pregnancy scoring form. The clinical course of CP during pregnancy was compared with the pre-pregnancy course. RESULTS: Among the 338 eligible patients, 46 patients were included after exclusions. All these 46 patients had at least 1 conception and 41 had at least 1 completed pregnancy with a total of 117 conceptions and 96 completed pregnancies. The pregnancy-related outcomes in patients with CP like abortions (21.7% vs. 11.3%; P =0.087), preterm deliveries (14.6% vs. 10.4%; P =0.47), antepartum course (82.7% vs. 82.6%; P =0.58), stillbirths (4.9% vs. 4.3%; P =0.88), cesarean section (36.6% vs. 34%; P =0.849) were comparable with controls. There was overall improvement in the severity and frequency of pain during pregnancy as compared with the pre-pregnancy symptoms ( P =0.001). CONCLUSION: CP is not associated with adverse pregnancy outcomes. Also, there is trend toward improvement in the clinical symptoms because of CP during the pregnancy.

Clinical significance of Notch pathway-associated microRNA-107 in pancreatic ductal adenocarcinoma.

Background & aim: MicroRNAs associated with the Notch pathway play a critical role in the progression of pancreatic carcinoma. Our aim was to study the clinical significance of miR-107 and NOTCH2 in pancreatic ductal adenocarcinoma (PDAC). Methods: The circulating miR-107 levels in PDAC and controls were determined by qPCR. NOTCH2 protein (target) expression in tissue of PDAC, periampullary carcinoma, chronic pancreatitis and normal pancreatic tissue was assessed by immunohistochemistry. Results: The circulating miR-107 levels were found to be significantly reduced in PDAC as compared with controls. Additionally, NOTCH2 protein expression was higher in PDAC tissue as compared with controls and was clinically associated with metastasis. Conclusion: Our findings demonstrate the utility of circulating miR-107 as a potential differentiating marker in PDAC.

Assessment of the Performance of Non-invasive Criteria for the Evaluation of Clinically Significant Portal Hypertension in Patients with Compensated Advanced Chronic Liver Disease.

BACKGROUND AND AIMS: Assessment of clinically significant portal hypertension (CSPH) non-invasively using a combination of liver stiffness measurement (LSM) and platelet counts is proposed as an alternative to hepatic venous pressure gradient (HVPG) estimation. Utility of these criteria in compensated advanced chronic liver disease (cACLD) patients of different etiologies including nonalcoholic steatohepatitis (NASH) with BMI  >  30 kg/m2 was studied in a large cohort. METHODS: Consecutive patients of cACLD with available anthropometric and laboratory details, LSM, and HVPG were included in a retrospective analysis. A LSM of ≥ 25 kPa alone and LSM ≤ 15 kPa plus platelets ≥ 150 × 109/L were evaluated as non-invasive rule-in and rule-out criteria for CSPH, respectively. The NASH-ANTICPATE model (composite of BMI, platelets, and LSM) was evaluated in patients with obese NASH. RESULTS: Patients with cACLD (n = 626) (mean age: 50.8 ± 12.4 years, 74.2% males) with alcohol (ALD, 30.3%), NASH (26.4%), hepatitis C (HCV, 16.6%), hepatitis B (HBV,10.2%) etiology were included. The prevalence of CSPH was  >  80% across all etiologies except in HBV (62.5%) and in obese non-NASH (71-72%). The rule-in criteria had a PPV  >  90% for all etiologies except in HBV (80.8%). The rule-out criteria had a negative predictive value (NPV) of 65%, 53%, and 40% in ALD, HCV, and NASH, respectively. The NASH-ANTCIPATE model had specificity of 100% and NPV of 33% to detect CSPH in obese NASH (n = 62). CONCLUSIONS: LSM ≥ 25 kPa predicted CSPH in most etiologies except HBV. A significant proportion of patients have CSPH despite satisfying the rule-out criteria. The NASH-ANTICIPATE model is specific but fails to exclude CSPH in nearly two-third patients with obesity and NASH. There is a need for precise disease-specific non-invasive models for detecting CSPH.

Vitamin D status & bone health in patients with liver cirrhosis.

Background & objectives: Vitamin D plays an important role in bone metabolism, and liver is the intermediary site of vitamin D metabolism. The purpose of this study was to study the prevalence of vitamin D deficiency and bone health in patients with cirrhosis. Methods: Prospectively, serum 25-hydroxy vitamin D [25(OH)D] level were assessed in cirrhotics by chemiluminescence method. Endocrine Society Clinical practice guideline was used to define deficiency and insufficiency of vitamin D. Bone mineral density (BMD) was assessed using dual-energy X-ray absorptiometry and the World Health Organization criteria was used to define osteoporosis and osteopenia. The lowest T score at the left hip neck or lumbar spine was taken as osteoporosis or osteopenia. The Child-Turcotte-Pugh score was used to assess the severity of cirrhosis. Results: Cirrhotics (n=350, male: 278, compensated: 210) were included. Mean serum 25(OH)D level was 8.75 ng/ml. The prevalence of vitamin D deficiency (VDD) and low-BMD (osteopenia and osteoporosis) was 89.4 and 86 per cent, respectively. VDD, insufficiency and osteoporosis was found in 86.7, 11.9 and 33.8 per cent, respectively, in patients with compensated cirrhosis; and 93.6, 3.6 and 40 per cent, respectively, in patients with decompensated cirrhosis. Body mass index of >25 kg/m2 was protective for bone health. Interpretation & conclusions: VDD and low-BMD is prevalent in Indian patients with cirrhosis and should be looked for in patients with cirrhosis for its prevention.

Malnutrition by GLIM criteria in chronic pancreatitis: Prevalence, predictors, and its impact on quality of life.

INTRODUCTION: Malnutrition in chronic pancreatitis (CP) has prognostic value and there is limited data on the prevalence, predictors of malnutrition in CP and its effect on Quality of life (QoL). METHODS: A retrospective study was conducted in patients with CP to assess the prevalence of malnutrition as per the Global Leadership Initiative on Malnutrition (GLIM) criteria. Multivariable-adjusted regression was used to identify independent predictors of both malnutrition and global QoL. RESULTS: A total of 297 patients were included and the most common etiology of CP was idiopathic (75%) and alcohol (25%). The prevalence of malnutrition was 46.4% as per GLIM criteria. On univariate analysis, the risk of malnutrition was significantly higher in alcoholic etiology (p = 0.001), current alcohol consumption (p = 0.001), smokers (p < 0.001), those having higher cumulative days of pain in last 6 months (p < 0.001) and lower daily calorie intake (p = 0.019). On multivariate analysis, malnutrition was independently associated with current alcohol consumption (Odds ratio: 3.22, p = 0.017), current smokers (OR: 2.23, p = 0.042) and those having higher cumulative days of abdominal pain (OR: 1.01, p < 0.001), while higher daily calorie intake (per 100 kcal) (OR:0.94, p = 0.023) has reduced risk of malnutrition. Malnutrition (p = 0.015) and higher cumulative days of abdominal pain (p < 0.001) were independently associated with lower global QoL in patients with CP. CONCLUSION: Malnutrition is frequent in patients with CP; and current alcohol consumption, smoking and higher cumulative days of abdominal pain independently predicts risk of developing malnutrition. Patients with malnutrition and higher cumulative days of pain has poorer quality of life.

Tumour suppressor role of microRNA-335-5p in esophageal squamous cell carcinoma by targeting TTK (Mps1).

BACKGROUND: Esophageal cancer is an aggressive malignancy. miR-335-5p is reported to possess both tumour suppressor and tumour promoter activities in different cancers. OBJECTIVES: We investigated the role of miR-335-5p in esophageal cancer by expression and functional studies. MATERIALS AND METHODS: The role of miR-335-5p in ESCC was evaluated using MTT assay, cell cycle analysis, colony formation assay, scratch assay, matrigel invasion, and migration assay. RESULTS: Our expression studies showed a significantly decreased expression of tissue and circulating miR-335-5p in esophageal cancer. Our results herein report a key tumour suppressive role of miR-335-5p in esophageal carcinogenesis by inhibiting proliferation, migration, and invasion in ESCC cells. Using RNA-seq and Insilico analysis we found TTK to be a newly identified direct target and confirmed it by using luciferase assay. CONCLUSION: Overall, our expression and functional analysis results demonstrated herein point towards the potential role of miR-335-5p in esophageal tumorigenesis. Moreover, this is the first report showing TTK as a downstream target of miR-335-5p.

Association of inflammatory markers with the disease & mutation status in pancreatic cancer.

Background & objectives: Inflammation has been studied to be an important contributory factor to carcinogenesis through pro-inflammatory markers such as interleukin (IL)-6 and C-reactive protein (CRP). Furthermore, K-ras mutation is an important genetic alteration in the pathogenesis of pancreatic cancer. This study aimed to compare these inflammatory markers in pancreatic ductal adenocarcinoma (PDAC) with the diseased and healthy controls (HCs) and to check for any association between IL-6 and CRP serum levels with the disease status, survival and K-ras mutation status of PDAC patients. Methods: The study included 135 PDAC, 25 chronic pancreatitis (CP) patients and 25 HCs. The serum levels of IL-6 and CRP were detected by enzyme-linked immunosorbent assay and K-ras mutations were detected by polymerase chain reaction-restriction fragment length polymorphism technique. Results: The serum levels of both these markers were elevated in PDAC cases than that in HCs. High IL-6 levels and higher CRP levels were found to be associated with locally advanced disease, lymphatic invasion, metastasis and advanced stage of the PDAC. In patients with unresectable PDAC, higher IL-6 levels were found to be associated with the presence of K-ras mutations. Interpretation & conclusions: Higher IL-6 and CRP levels in patients with advanced PDAC suggest an important role of these inflammatory markers in tumour progression. Furthermore, the association of mutations in the K-ras gene with serum IL-6 indicates cross-talks that may contribute to the progression of the PDAC.

Effect of Vitamin D Supplementation on Vitamin D Level and Bone Mineral Density in Patients With Cirrhosis: A Randomized Clinical Trial.

INTRODUCTION: In patients with cirrhosis, highly prevalent vitamin D deficiency and low bone mineral density (BMD) increase the burden of disease, and role of vitamin D supplementation is not clear. So, our aim was to determine the effect of vitamin D supplementation on vitamin D level and BMD in patients with cirrhosis. METHODS: Patients with cirrhosis (18-60 years) of any etiology were enrolled. We measured serum 25(OH)D, parathyroid hormone, thyroid-stimulating hormone, free T4, bone-specific alkaline phosphatase, insulin-like growth factor (IGF)-1, and health-related quality of life at entry and at 1 year; however, serum calcium was measured at 3-month interval. BMD was measured by dual-energy x-ray absorptiometry at lumbar spine and left hip neck at entry and after 1 year. Statistical analysis was performed according to intention-to-treat analysis. RESULTS: Of 390 screened patients with cirrhosis, 164 participants (82 in each group) were randomized. There was significant increase in 25(OH)D levels in intervention group after 1 year (33.7 [24.3-45.7] ng/mL vs 23.1 [17-28.2] ng/mL; P < 0.001) when compared with placebo. The mean difference in BMD at lumbar spine and left hip neck was not significantly changed after 1 year of intervention with vitamin D between both groups. There was no significant change in both the groups in levels of calcium, thyroid-stimulating hormone, parathyroid hormone, free T4, IGF-1, and bone-specific alkaline phosphatase and quality of life. DISCUSSION: Supplementation with vitamin D for 1 year improves vitamin D levels but did not result in improvement in BMD at lumbar spine and left hip neck in patients with cirrhosis.

Long-Term Outcomes of Endovascular Interventions in More than 500 patients with Budd-Chiari Syndrome.

PURPOSE: To assess and compare the long-term outcomes of various endovascular interventions in patients with Budd-Chiari syndrome (BCS). MATERIALS AND METHODS: In this single-center retrospective study, 510 consecutive patients with BCS who had undergone a total of 618 endovascular procedures from January 2001 to December 2019 were included. Details of the type of endovascular intervention, technical success, clinical success, patency rate, complications, and survival outcomes were analyzed. RESULTS: The overall technical success rate was 96% (593 of 618 procedures; 500 in treatment-naïve patients and 93 repeat interventions for recurrent disease). Endovascular procedures included recanalization procedures (angioplasty and stent placement) in 355 patients (71%) and transjugular intrahepatic portosystemic shunt (TIPS) creation in 145 (29%). Major postprocedure complications occurred in 14 patients (2.8%). Vascular/stent restenosis occurred in 95 patients (19%), and successful repeat intervention was performed in 82 of those 95 (86.3%). An additional 11 of these 82 (13.4%) underwent a third intervention for restenosis. In the recanalization and TIPS groups, the 1- and 5-y cumulative patency rates were 87% and 74% and 95% and 68%, respectively. The 1- and 5-y survival rates were 96% and 89% and 90% and 76%, respectively. CONCLUSIONS: Endovascular interventions for BCS are feasible and safe in the majority of patients, with excellent short- and long-term patency and survival rates.

Development of a machine learning model to predict bleed in esophageal varices in compensated advanced chronic liver disease: A proof of concept.

BACKGROUND AND AIM: Risk stratification beyond the endoscopic classification of esophageal varices (EVs) to predict first episode of variceal bleeding (VB) is currently limited in patients with compensated advanced chronic liver disease (cACLD). We aimed to assess if machine learning (ML) could be used for predicting future VB more accurately. METHODS: In this retrospective analysis, data from patients of cACLD with EVs, laboratory parameters and liver stiffness measurement (LSM) were used to generate an extreme-gradient boosting (XGBoost) algorithm to predict the risk of VB. The performance characteristics of ML and endoscopic classification were compared in internal and external validation cohorts. Bleeding rates were estimated in subgroups identified upon risk stratification with combination of model and endoscopic classification. RESULTS: Eight hundred twenty-eight patients of cACLD with EVs, predominantly related to non-alcoholic fatty liver disease (28.6%), alcohol (23.7%) and hepatitis B (23.1%) were included, with 455 (55%) having the high-risk varices. Over a median follow-up of 24 (12-43) months, 163 patients developed VB. The accuracy of machine learning (ML) based model to predict future VB was 98.7 (97.4-99.5)%, 93.7 (88.8-97.2)%, and 85.7 (82.1-90.5)% in derivation (n = 497), internal validation (n = 149), and external validation (n = 182) cohorts, respectively, which was better than endoscopic classification [58.9 (55.5-62.3)%] alone. Patients stratified high risk on both endoscopy and model had 1-year and 3-year bleeding rates of 31-43% and 64-85%, respectively, whereas those stratified as low risk on both had 1-year and 3-year bleeding rates of 0-1.6% and 0-3.4%, respectively. Endoscopic classification and LSM were the major determinants of model's performance. CONCLUSION: Application of ML model improved the performance of endoscopic stratification to predict VB in patients with cACLD with EVs.

Deciding Among Noninvasive Tools for Predicting Varices Needing Treatment in Chronic Liver Disease: An Analysis of Asian Cohort.

INTRODUCTION: Both transient elastography (TE)-based and non-TE-based criteria exist for detection of varices needing treatment (VNT) in patients with asymptomatic advanced chronic liver disease (CLD). However, their performance in clinical settings at different risk thresholds of detection of VNT and in regions where elastography is not widely available is unknown. We aimed to validate existing noninvasive criteria in our patients with CLD and identify best TE- and non-TE-based criteria for VNT screening at usual risk thresholds. METHODS: Patients with compensated advanced CLD (cACLD) who underwent esophagogastroduodenoscopy and TE within 3 months were included. Diagnostic performance of Baveno VI, expanded Baveno VI, platelet-model for end-stage liver disease, and platelet-albumin (Rete Sicilia Selezione Terapia-hepatitis C virus) criteria were estimated. Decision curve analysis was conducted for different predictors across range of threshold probabilities. A repeat analysis including all patients with compensated CLD (cACLD and non-cACLD) was performed to simulate absence of TE. RESULTS: A total of 1,657 patients (cACLD, 895; non-cACLD, 762) related to hepatitis B virus (38.2%), hepatitis C virus (33.4%), nonalcoholic steatohepatitis (14.7%), and alcohol (11.8%) were included. Baveno VI identified maximum VNT (97.3%) and had best negative predictive value (96.9%), followed by platelet-albumin criteria. Expanded Baveno VI and platelet-model for end-stage liver disease had intermediate performance. At threshold probability of 5%, Baveno VI criteria showed maximum net benefit, and platelet-albumin criteria was next best, with need for 95 additional elastographies to detect 1 additional VNT. Similar results were obtained on including all patients with compensated CLD irrespective of TE. DISCUSSION: Baveno VI criteria maximizes VNT yield at 5% threshold probability. An acceptable alternative is the platelet-albumin criteria in resource-limited settings.

Vascular complications of chronic pancreatitis: A tertiary center experience.

INTRODUCTION: Vascular complications such as venous thrombosis (VT) and pseudoaneurysm are not uncommon in patients with chronic pancreatitis (CP). The aim of this study to was to evaluate the prevalence and risk factors for vascular complications in patients with CP. METHODS: A retrospective analysis of a prospectively maintained database of patients with CP presenting from January 2002 to August 2019 was performed. Venous thrombosis and pseudoaneurysm were identified using radiological imaging, and their risk factors were identified using multivariate Cox-proportional hazards. RESULTS: Of 1363 patients with CP, 166 (12.2%) had vascular complications. Isolated VT was present in 132, pseudoaneurysm in 17, and both in 17 patients. They were more commonly seen in males and alcoholic CP (ACP), and less commonly in patients with pancreatic atrophy and calcification. It involved the vessels in the closest proximity to the pancreas, VT most commonly involving the splenic vein whereas pseudoaneurysm most commonly involved the splenic artery. Alcoholic CP [odds ratio (OR) 2.1, p = 0.002], pseudocyst (OR 4.6, p < 0.001) and inflammatory head mass (OR 3.1, p = 0.006) were independent risk factors for VT, whereas ACP (OR 3.49, p = 0.006) and pseudocyst (OR 3.2, p = 0.002) were independent risk factors for pseudoaneurysm. Gastrointestinal bleed occurred in 3.5% patients, and more commonly in patients with pseudoaneurysm than VT (64.7% vs 15.9%), and in patients with ACP in comparison to other etiologies (p < 0.001). CONCLUSION: Vascular complications are a common complication of CP, VT being more frequent than pseudoaneurysm. Pseudocyst and ACP are independent risk factors for the development of vascular complications.