Non-immunological biomarkers for assessment of villous abnormalities in patients with celiac disease.

BACKGROUND AND AIM: Demonstration of villous abnormalities is an essential component of diagnosis of celiac disease (CeD) that requires duodenal biopsies. There is a need for non-invasive biomarker(s) that can predict the presence of villous abnormalities. METHODS: Levels of plasma citrulline, plasma intestinal fatty acid binding protein (I-FABP), and serum regenerating gene 1α (Reg1α) were estimated in treatment naïve patients with CeD and controls. The levels of these biomarkers and their cyclical pattern were validated in a predicted model of enteropathy. Optimum diagnostic cut-off values were derived, and the results were further validated in a prospective validation cohort. RESULTS: While level of plasma citrulline was significantly lower, the levels of plasma I-FABP and serum Reg1α were significantly higher in patients with CeD (n = 131) in comparison with healthy (n = 216) and disease controls (n = 133), and their levels reversed after a gluten-free diet (GFD). In the model of predicted enteropathy (n = 70), a sequential decrease and then increase in the level of plasma citrulline was observed; such a sequential change was not observed with I-FABP and Reg1α. The diagnostic accuracy for prediction of presence of villous abnormality was 89% and 78% if citrulline level was  ≤ 30 µM/L and I-FABP levels were ≥ 1100 pg/mL, respectively. The results were validated in a prospective validation cohort (n = 104) with a sensitivity and specificity of 79.5% and 83.1%, respectively, for predicting villous abnormalities of modified Marsh grade > 2 at calculated cut-off values of citrulline and I-FABP. CONCLUSIONS: Plasma citrulline  ≤ 30 µM/L is the most consistent, highly reproducible non-invasive biomarker that can predict the presence of villous abnormality and has the potential for avoiding duodenal biopsies in 78% patients suspected to have CeD.

Prevalence of coeliac disease in idiopathic hypoparathyroidism and effect of gluten-free diet on calcaemic control.

BACKGROUND: Patients with idiopathic hypoparathyroidism (IH) require variable doses of calcium and 1-α-(OH)D. The reasons for such variability are not clear. As autoimmune mechanisms may play a role in IH, there is a possibility of coexistent coeliac disease with calcium/vitamin D malabsorption. OBJECTIVE: We assessed the prevalence of coeliac disease and antitissue transglutaminase autoantibodies (anti-tTGAbs) in IH and analysed the effect of a gluten-free diet on calcaemic control. METHOD: A total of 171 patients with IH and 126 healthy controls were screened for anti-tTGAb. IH patients with anti-tTGAb >20 RU/ml underwent duodenoscopy and intestinal biopsy; those with biopsy-proven coeliac disease were followed up on a gluten-free diet. RESULTS: Eleven of 171 (6·4%) patients with IH and seven of 126 (5·6%) controls had anti-tTGAb (P = 0·81). There was no difference in the clinical and biochemical parameters at diagnosis and during long-term follow-up of 7·2 ± 4·8 year (mean serum total calcium = 1·88 ± 0·16 vs 1·82 ± 0·36 mmol/l, P = 0·52; phosphorus = 1·81 ± 0·17 vs 1·87 ± 0·36 mmol/l, P = 0·53) in IH patients with and without anti-tTGAb. Although CaSRAb positivity was comparable in the two groups, IH patients with anti-tTGAb had higher TPOAb positivity (45·5% vs 12·8%, P = 0·02). Coeliac disease was diagnosed in only 2/9 patients with IH on biopsy, both of whom showed improved calcaemic control with a gluten-free diet. CONCLUSION: The prevalence of coeliac autoimmunity (6·4%) and coeliac disease (1·2%) in patients with IH seems to be similar to that in the general population. Notwithstanding this modest prevalence, it is important to be aware of the potential occurrence of coeliac disease with IH and the beneficial effect of a gluten-free diet on calcium control.

Acute on chronic liver failure because of acute hepatic insults: Etiologies, course, extrahepatic organ failure and predictors of mortality.

BACKGROUND AND AIM: Acute on chronic liver failure (ACLF) because of precipitating factors (variceal bleed/infections) identifies cirrhotics at risk for high short-term mortality. Information on ACLF because of acute hepatic insults is lacking. The aim of the study was to evaluate acute hepatic insults in ACLF and their effect on the course and outcome. METHODS: In a prospective study, 213 consecutive patients of ACLF because of acute hepatic insults were included. Etiology of acute hepatic insult, frequency of silent, and overt chronic liver disease (CLD), organ failure (OF), and outcomes were assessed. Prognostic models such as model for endstage liver disease (MELD), acute physiology and chronic health evaluation (APACHE II), and chronic liver failure-sequential organ failure (CLIF-SOFA) were evaluated. RESULTS: Etiologies of acute hepatic insult were hepatitis virus(es)- 81 (38%; HBV-42, HEV-39), continuous alcohol consumption-77 (33.3%), antituberculosis drugs-11 (5.2%), autoimmune hepatitis flare-5(2.3%), cryptogenic-44 (20.7%). The common causes of CLD were alcohol (n = 85/40%), HBV(n = 52/24%), and cryptogenic(n = 50/20%). The MELD, APACHE II, and CLIF-SOFA scores were similar among silent and overt CLD and did not influence outcome. Predominant etiologies of ACLF were hepatitis virus(es) reactivation or superinfection in silent CLD(52/112, 46.4%) and alcohol among overt CLD(43/101, 43%). Independent predictors of mortality included hepatic-encephalopathy (early, HR: 4.01; advanced, HR: 6.10), serum creatinine ≥1.5 mg/dl (HR: 4.53), CLIF-SOFA ≥8(HR: 1.69), and etiology of acute hepatic insult (alcohol, HR: 4.08; cryptogenic, HR: 3.18). HEV-ACLF had lower mortality (12.8% vs. 33-54% in other etiologies;P < 0.001). OF was major determinant of mortality. With increasing number of OF, mortality increased linearly(P = 0.001). CONCLUSIONS: Hepatitis virus(es) and continuous alcohol consumption are important causes of ACLF caused by acute hepatic insults. HEV-ACLF has lower mortality. OF is an important prognostic predictor.

Prognostic significance of extracellular matrix degrading enzymes-cathepsin L and matrix metalloproteases-2 [MMP-2] in human pancreatic cancer.

In the present study, we assessed the expression of extracellular matrix (ECM) degrading proteases-cathepsin L and matrix metalloprotease-2 (MMP-2) in pancreatic cancer tissue and correlated their levels with clinicopathological parameters and survival. Both the proteases were expressed in the majority of the tumor tissues examined. Staining intensity of cathepsin L was significantly higher in the tumor stroma compared to tumor epithelium while MMP-2 staining showed no such difference. Both proteases showed correlation with some of the clinicopathological parameters but only cathepsin L expression in tumor epithelium predicted a poor prognosis for the disease.

Fibroscan can avoid liver biopsy in Indian patients with chronic hepatitis B.

BACKGROUND AND AIM: Liver fibrosis is an established determinant of prognosis and therapy in chronic hepatitis B (CHB). The role of fibroscan in assessing fibrosis in CHB remains unclear. Present study was designed to correlate fibroscan with liver biopsy and determine whether fibroscan can avoid liver biopsy in patients with CHB. METHODS: Fibroscan and liver biopsy were performed in 382 consecutive patients with CHB. Biopsies were reviewed by pathologist blinded to the fibroscan value. Discriminant values of liver stiffness measurement (LSM) to reasonably exclude and predict significant fibrosis were calculated from receiver operating characteristic (ROC) curves. The factors affecting LSM independent of fibrosis were assessed. RESULTS: Three hundred fifty-seven patients were included (mean age 30.1 ± 9.7 years, male : female 17 : 3). There was significant correlation between LSM and histological fibrosis (r = 0.58, P < 0.001). The area under ROC curve of LSM for significant fibrosis (F0-1 vs. F2-4), bridging fibrosis (F0-2 vs. F3-4), and cirrhosis (F0-3 vs. F4) was 0.84 (95% CI: 0.78-0.89), 0.94 (95% CI: 0.89-0.99), and 0.93 (95% CI: 0.85-1.00), respectively. LSM < 6.0 KPa could exclude significant (F ≥ 2) and bridging fibrosis (F ≥ 3) with a negative predictive value (NPV) of 92.4% and 99.5%, respectively. Cut-off of 9 KPa could detect significant (F ≥ 2) and bridging fibrosis (F ≥ 3) with specificity of 95% and 97%, respectively, and had a positive predictive value (PPV) of 84.3% in predicting significant fibrosis. LSM < 6 KPa and > 9 KPa matched with histological fibrosis in 227/250 (91%) patients. Therefore, fibroscan could avoid liver biopsy in 70% (250/357) patients with an accuracy > 90%. Histological fibrosis, ALT > 5 times, and age > 40 years were independent determinants of increased liver stiffness. CONCLUSIONS: Fibroscan accurately assessed fibrosis and could avoid liver biopsy in more than two-thirds of patients with CHB.

Effect of addition of short course of prednisolone to gluten-free diet on mucosal epithelial cell regeneration and apoptosis in celiac disease: a pilot randomized controlled trial.

BACKGROUND: Identification of adjuvant treatment is necessary for rapid and effective treatment in patients with celiac disease. In a pilot randomized controlled trial, the effect of prednisolone on enterocyte apoptosis and regeneration in celiac disease was investigated. PATIENTS AND METHODS: Thirty-three treatment-naïve patients with celiac disease were randomized to either gluten-free diet (GFD, n = 17) or GFD + prednisolone (1 mg/kg for 4 weeks, n = 16). Duodenal biopsies were taken at baseline and at 4 and 8 weeks posttreatment. Six patients with functional dyspepsia were recruited as controls. All these biopsies were stained for markers of intrinsic apoptotic pathway (AIF, H2AX, p53), common apoptotic pathway (CC3, M30), apoptotic inhibitors (XIAP, Bcl2), and epithelial proliferation (Ki-67). Apoptotic (AI) and proliferation indices (PI) were compared. RESULTS: At baseline duodenal biopsies, the end apoptotic products H2AX and M30 were significantly increased. In comparison with those treated with GFD alone, after 4 weeks of GFD + prednisolone treatment, some markers of both intrinsic and common apoptotic pathways showed rapid decline. After prednisolone withdrawal, there was overexpression of H2AX, CC3, and p53 in the latter group. In comparison with those treated with only GFD, patients treated with prednisolone showed suppression of mucosal PI, which started rising again after withdrawal of prednisolone. CONCLUSIONS: Apoptosis takes place in mucosal epithelium in celiac disease. Addition of short course of prednisolone suppresses apoptosis rapidly. However, it also suppresses epithelial regeneration; hence, if used, it should be withdrawn after an initial short course.

Histologic Changes in Core-Needle Liver Biopsies From Patients With Acute-on-Chronic Liver Failure and Independent Histologic Predictors of 28-Day Mortality.

CONTEXT.­: The histologic features in patients with acute-on-chronic liver failure (ACLF) are evolving, and histologic indicators of patients' poor prognosis are not yet fully established. OBJECTIVE.­: To evaluate the independent histologic predictors of 28-day mortality in ACLF patients on core-needle liver biopsies. DESIGN.­: Core-needle biopsies from patients with a diagnosis of ACLF (n = 152) as per the European Association for the Study of the Liver criteria were included during 8 years. Liver biopsies from 98 patients with compensated chronic liver disease were included as disease controls for histologic comparison. Features of ongoing changes, such as hepatic necrosis, hepatic apoptosis, cholestasis, hepatocyte degeneration, bile ductular proliferation, Mallory-Denk bodies, steatosis, and extent of liver fibrosis, were analyzed for predicting short-term mortality (28 days). A P value of <.05 was considered significant. RESULTS.­: In our cohort of ACLF patients, the following etiologies for acute decompensation were identified: alcohol, 47 of 152 (30.9%); sepsis, 24 of 152 (15.7%); hepatotropic viruses, 20 of 152 (13.1%); drug-induced liver injury, 11 of 152 (7.2%); autoimmune flare, 9 of 152 (5.9%); mixed etiologies, 5 of 152 (3.2%); and cryptogenic, 36 of 152 (23.6%). On histologic examination, hepatic necrosis (P < .001), dense lobular inflammation (P = .03), cholestasis (P < .001), ductular reaction (P = .001), hepatocyte degeneration (P < .001), and absence of advanced fibrosis stages (P < .001) were identified significantly more othen in ACLF patients than in disease controls on univariate analysis. On multivariate Cox regression analysis, the absence of advanced Ishak histologic activity index fibrosis stages (P = .02) and the presence of dense lobular inflammation (P = .04) were associated with increased 28-day mortality in ACLF patients. After adjusting the clinical causes of acute decompensation, only dense lobular inflammation was found as an independent predictor of short-term mortality (P = .04) in ACLF patients. CONCLUSIONS.­: Dense lobular necroinflammatory activity is a clinically independent histologic predictor of 28-day short-term mortality in patients with ACLF.

Erratum to 'Indian National Association for the Study of Liver Consensus Statement on Acute Liver Failure (Part-2): Management of Acute Liver Failure' [J Clin Exp Hepatol 10 (2020) 477-517].

[This corrects the article DOI: 10.1016/j.jceh.2020.04.011.].

Prevalence of celiac disease in the northern part of India: a community based study.

BACKGROUND AND AIM: While celiac disease is estimated to affect about 1% of the world's population, it is thought to be uncommon not only in India but in Asia also. There is a lack of studies on the prevalence of celiac disease from Asian nations. The aim of the present study was to estimate the prevalence of celiac disease in the community. METHODS: In a cross sectional study, we estimated the prevalence of celiac disease in urban and rural populations in the National Capital Region, Delhi, India. A structured questionnaire was administered, by door-to-door visits, to all participants to collect socio-demographic data and to screen for features of celiac disease, namely chronic or recurrent diarrhea and, anemia. In children, additional features, namely short stature (linear height below 5th percentile for age) and failure to thrive/gain weight were also used. All respondents who were screen positive (any one of above) and 10% of screen negative individuals were called for serological testing, which is anti-tissue transglutaminase antibody. All serologically positive respondents were invited to undergo further evaluation including endoscopic biopsy. Celiac disease was diagnosed on the basis of a positive serology, the presence of villous atrophy and/or response to gluten free diet. RESULT: Among 12,573 contacted, 10,488 (83.4%) (50.6% male) agreed to participate. Based on screening, 5622 (53.6%) participants were screen positive. Of all those screen positive, 2167 (38.5%) agreed for serological testing; additionally 712 (14%) negatives were also tested. The overall sero-prevalence of celiac disease was 1.44% (95% confidence interval [CI] 1.22 1.69) and the overall prevalence of celiac disease was 1.04% (95% CI 0.85 1.25). CONCLUSION: The prevalence of celiac disease in this north Indian community is 1 in 96. Celiac disease is more common than is recognized in India.

Liver involvement in patients with coeliac disease: proof of causality using IgA/anti-TG2 colocalisation techniques.

AIMS: Despite clinical evidence of liver involvement in patients with coeliac disease (CeD), there is a lack of a method to prove this association. METHODS: Of 146 treatment-naive patients with CeD, 26 had liver dysfunction. Liver biopsies and corresponding small intestinal biopsies were obtained from these 26 patients. Multicolour immunohistochemical and immunofluorescence confocal microscopic studies were performed on paraffin-embedded tissue to detect the IgA/anti-TG2 deposits. Follow-up liver biopsies were taken after a gluten-free diet. RESULTS: Twenty-six out of the 146 patients (17.8%) with suspected coeliac-associated liver disease on histological examination revealed irregular sinusoidal dilatation in 15 (57.6%), steatohepatitis in 4 (15.3%), non-specific chronic hepatitis in 3 (11.5%), autoimmune hepatitis in 2 (7.6%) biopsies, including cirrhosis in one of them, irregular perisinusoidal fibrosis and changes of non-cirrhotic portal fibrosis in one biopsy each (3.8%). IgA/anti-tTG deposits were observed in 22 (84.6%) liver biopsies by dual immunohistochemistry technique, and in 24 (92.3%) by confocal immunofluorescence technique and in all corresponding duodenal biopsies (100%). Overall, IgA/anti-tTG deposits showed 100% sensitivity, 77% specificity and 85% positive predictive value for establishing an association of extraintestinal pathology and CeD using archived tissues. Follow-up liver biopsies could be obtained in five patients; four of them showed not only resolution of the histological lesions but disappearance of IgA/anti-tTG co-localisation. CONCLUSIONS: Data of the present study adds to the body of evidence that liver lesions in patients with CeD are disease related and may have been caused by a similar pathogenic mechanism that causes intestinal changes.

Clinical significance of TC21 overexpression in oral cancer.

BACKGROUND: In search of novel molecular markers for oral cancer, we reported increased levels of TC21/R-Ras2 transcripts in oral squamous cell carcinoma by differential display. The aim of this study was to determine the clinical significance of TC21 in oral cancer. METHODS: Immunohistochemical analysis of TC21 protein expression was carried out in 120 leukoplakias, 83 OSCCs and 30 non-malignant tissues, confirmed by immunoblotting, and correlated with clinicopathological parameters as well as disease prognosis. Co-immunoprecipitation assays were carried out to identify the interaction partners of TC21 protein in oral cancer cells and tissues. RESULTS: TC21 nuclear expression increased from normal oral tissues to leukoplakia and frank malignancy (P < 0.001). TC21 overexpression was observed in 74.2% leukoplakia with no dysplasia, 75.9% dysplasias and 79.5% OSCCs in comparison with normal oral tissues. Receiver operating characteristic analysis showed that the area-under-the curve values were 0.895, 0.885, and 0.919, while the positive predictive values were 95.8%, 95.6%, and 97.1%, for nuclear immunostaining for normal versus leukoplakia with no dysplasia, leukoplakic lesions with dysplasia, and OSCCs, respectively. Immunoblotting confirmed overexpression of TC21 in oral lesions. Using co-immunoprecipitation assays, we showed interactions of TC21 with Erk2, PI3-K, 14-3-3zeta and 14-3-3sigma proteins in oral cancer cells. CONCLUSION: Our findings suggested that alteration in TC21 expression is an early event in oral cancer and correlates with poor prognosis of OSCCs. TC21 interactions with Erk2, PI3-K, 14-3-3zeta and 14-3-3sigma proteins in oral cancer cells and tissues suggests the involvement of TC21 in signaling pathways in oral cancer.

Surgical and Neurological Outcome of Minimally Invasive Thymectomy in Patients With Myasthenia Gravis: An Experience of 100 Cases Over 6 Years at a Tertiary Care Center in North India.

BACKGROUND: Minimally invasive thymectomy (MIT) is emerging as an effective alternative to open thymectomy in the management of patients with myasthenia gravis (MG). The primary objective of our study is to assess the surgical and neurological outcome of MIT in patients with MG. MATERIALS AND METHODS: It is a retrospective evaluation of prospectively collected data of 100 patients with MG, who underwent MIT from April 2012 to January 2018 at a tertiary care center in India. Surgical outcome was assessed for success of minimal invasive approach, conversion, perioperative morbidity, and postoperative hospital course. Neurological outcome was assessed, after at least 1 year of follow-up, according to Myasthenia Gravis Foundation of America postintervention status. Factors predicting complete stable remission (CSR) were evaluated. RESULTS: MIT was successfully performed in 98% patients with 2% conversion. There was no mortality. Overall, 10% of patients had perioperative morbidity with 5% having exacerbation of neurological symptoms. Two of these needed postoperative ventilation, whereas 3 recovered on conservative treatment. Median operative time and hospital stay were 140 minutes and 3 days, respectively. At a median follow-up of 47 months, CSR was seen in 20% with improvement in 73.3%. Overall, 63% patients were taken off steroids and patients requiring 3 drugs decreased by 70.7%. There was significant reduction in the dosage of pyridostigmine (P<0.001), prednisolone (P<0.001), and azathioprine (P=0.002) after thymectomy. Milder disease (Myasthenia Gravis Foundation of America class 1 and 2) predicted CSR on multivariate analysis. CONCLUSIONS: MIT is a safe and effective procedure that leads to improvement in neurological status with significant reduction in number and dosage of medications after thymectomy. Mild disease predicts CSR.

2019 Update of Indian National Association for Study of the Liver Consensus on Prevention, Diagnosis, and Management of Hepatocellular Carcinoma in India: The Puri II Recommendations.

Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality, and healthcare expenditure in patients with chronic liver disease in India. The Indian National Association for Study of the Liver (INASL) had published its first guidelines on diagnosis and management of HCC (The Puri Recommendations) in 2014, and these guidelines were very well received by the healthcare community involved in diagnosis and management of HCC in India and neighboring countries. However, since 2014, many new developments have taken place in the field of HCC diagnosis and management, hence INASL endeavored to update its 2014 consensus guidelines. A new Task Force on HCC was constituted that reviewed the previous guidelines as well as the recent developments in various aspects of HCC that needed to be incorporated in the new guidelines. A 2-day round table discussion was held on 5th and 6th May 2018 at Puri, Odisha, to discuss, debate, and finalize the revised consensus statements. Each statement of the guideline was graded according to the Grading of Recommendations Assessment Development and Evaluation system with minor modifications. We present here the 2019 Update of INASL Consensus on Prevention, Diagnosis, and Management of Hepatocellular Carcinoma in India: The Puri-2 Recommendations.

Indian National Association for the Study of the Liver Consensus Statement on Acute Liver Failure (Part 1): Epidemiology, Pathogenesis, Presentation and Prognosis.

Acute liver failure (ALF) is an infrequent, unpredictable, potentially fatal complication of acute liver injury (ALI) consequent to varied etiologies. Etiologies of ALF as reported in the literature have regional differences, which affects the clinical presentation and natural course. In this part of the consensus article designed to reflect the clinical practices in India, disease burden, epidemiology, clinical presentation, monitoring, and prognostication have been discussed. In India, viral hepatitis is the most frequent cause of ALF, with drug-induced hepatitis due to antituberculosis drugs being the second most frequent cause. The clinical presentation of ALF is characterized by jaundice, coagulopathy, and encephalopathy. It is important to differentiate ALF from other causes of liver failure, including acute on chronic liver failure, subacute liver failure, as well as certain tropical infections which can mimic this presentation. The disease often has a fulminant clinical course with high short-term mortality. Death is usually attributable to cerebral complications, infections, and resultant multiorgan failure. Timely liver transplantation (LT) can change the outcome, and hence, it is vital to provide intensive care to patients until LT can be arranged. It is equally important to assess prognosis to select patients who are suitable for LT. Several prognostic scores have been proposed, and their comparisons show that indigenously developed dynamic scores have an edge over scores described from the Western world. Management of ALF will be described in part 2 of this document.

Indian National Association for the Study of Liver Consensus Statement on Acute Liver Failure (Part-2): Management of Acute Liver Failure.

Acute liver failure (ALF) is not an uncommon complication of a common disease such as acute hepatitis. Viral hepatitis followed by antituberculosis drug-induced hepatotoxicity are the commonest causes of ALF in India. Clinically, such patients present with appearance of jaundice, encephalopathy, and coagulopathy. Hepatic encephalopathy (HE) and cerebral edema are central and most important clinical event in the course of ALF, followed by superadded infections, and determine the outcome in these patients. The pathogenesis of encephalopathy and cerebral edema in ALF is unique and multifactorial. Ammonia plays a crucial role in the pathogenesis, and several therapies aim to correct this abnormality. The role of newer ammonia-lowering agents is still evolving. These patients are best managed at a tertiary care hospital with facility for liver transplantation (LT). Aggressive intensive medical management has been documented to salvage a substantial proportion of patients. In those with poor prognostic factors, LT is the only effective therapy that has been shown to improve survival. However, recognizing suitable patients with poor prognosis has remained a challenge. Close monitoring, early identification and treatment of complications, and couseling for transplant form the first-line approach to manage such patients. Recent research shows that use of dynamic prognostic models is better for selecting patients undergoing liver transplantation and timely transplant can save life of patients with ALF with poor prognostic factors.

Utility of transient elastography (fibroscan) and impact of bariatric surgery on nonalcoholic fatty liver disease (NAFLD) in morbidly obese patients.

BACKGROUND: Controlled attenuation parameter (CAP) is a novel, noninvasive technique for assessing hepatic steatosis. However, its role in morbidly obese individuals is unclear. The effect of bariatric surgery on inflammation and fibrosis needs to be explored. OBJECTIVES: To assess the utility of CAP for assessment of hepatic steatosis in morbidly obese individuals and evaluate the effect of bariatric surgery on hepatic steatosis and fibrosis. SETTING: A tertiary care academic hospital. METHODS: Baseline details of anthropometric data, laboratory parameters, FibroScan (XL probe), and liver biopsy were collected. Follow-up liver biopsy was done at 1 year. RESULTS: Of the 124 patients screened, 76 patients were included; mean body mass index was 45.2 ± 7.1 kg/m2. FibroScan success rate was 87.9%. The median liver stiffness measurement (LSM) and CAP were 7.0 (5.0-9.5) kPa and 326.5 (301-360.5) dB/m, respectively. On liver histopathology, severe steatosis and nonalcoholic steatohepatitis were present in 5.3% and 15.8%; significant fibrosis (≥stage 2) and cirrhosis in 39.5% and 2.6%, respectively. Area under receiver operator characteristic curve of LSM for prediction of significant fibrosis (F2-4 versus F0-1) and advanced fibrosis (F3-4 versus F0-2) was .65 (95% confidence interval [CI]: .52-.77) and .83 (95% CI: .72-.94), respectively. The area under receiver operator characteristic curve of CAP for differentiating moderate hepatic steatosis (S2-3 versus S0-1) and severe hepatic steatosis (S3 versus S0-2) was .74 (95% CI: .62-.86) and .82 (95% CI: .73-.91), respectively. At 1-year follow-up, 32 patients underwent liver biopsy. In these patients, there was significant improvement in hepatic steatosis (P = .001), lobular inflammation (P = .033), ballooning (P<.001), and fibrosis (P = .003). Nonalcoholic steatohepatitis was resolved in 3 of 4 (75%) patients. LSM and CAP significantly declined. CONCLUSIONS: LSM and CAP are feasible and accurate at diagnosing advanced fibrosis and severe hepatic steatosis in morbidly obese individuals. Bariatric surgery is associated with significant improvement in LSM, CAP, steatohepatitis, and fibrosis.

Progression of Chronic Pancreatitis to Pancreatic Cancer: Is There a Role of Gene Mutations as a Screening Tool?

OBJECTIVES: Early detection of pancreatic ductal adenocarcinoma still remains a challenge. Patients with chronic pancreatitis (CP) have a markedly increased risk of pancreatic cancer. Mutations in oncogenes and/or tumor suppressor genes play a role in development of pancreatic ductal adenocarcinoma. This study assessed mutations in KRAS and p53 gene in blood as a screening tool for malignant transformation in CP patients. METHODS: This was a cohort, single-center study including 294 CP patients. DNA was isolated from plasma of CP patients, and KRAS mutations were identified using polymerase chain reaction-restriction fragment length polymorphism. Patients with positive KRAS mutation were screened for malignancy using positron emission tomography or endoscopic ultrasound. Mutations in p53 gene were analyzed by sequencing. Tissue samples from CP and pancreatic cancer patients were also tested for mutations in KRAS and p53 genes. RESULTS: The plasma samples of 64 CP patients were positive for KRAS mutation, and 4 had mutation in p53 gene also. No patient positive for KRAS mutation and/or p53 mutation was found to have malignant transformation. CONCLUSION: Detection of KRAS or p53 mutation in plasma is not an effective screening tool for pancreatic cancer because accumulation of multiple mutations is required for malignant transformation in the pancreas.

Immunohistochemical Expression of Antitissue Transglutaminase 2 in Tissue Injuries: An Interpretation Beyond Celiac Disease.

Tissue transglutaminase 2 enzyme plays a diverse role in intracellular and extracellular functioning. Aberrant expression of anti-TG2 antibody has recently been proposed for extraintestinal identification of celiac disease (CeD), but its utility is questionable. To examine whether anti-TG2 immunohistochemical (IHC) staining can be of diagnostic value in identifying extraintestinal involvement in CeD, tissue blocks of patients with IgA nephropathies (IgAN), minimal change disease, membranous glomerulonephritis, membrano-proliferative glomerulonephritis, normal kidney, intestinal biopsies from CeD, tropical sprue, nonspecific duodenitis, and inflammatory bowel disease; liver biopsies from patients with chronic hepatitis B and C, acute liver failure (ALF), and CeD-associated liver diseases were retrieved and subjected to IHC staining for anti-tissue transglutaminase 2 enzyme. H-score was calculated by multiplying the area of positivity and stain intensity. Anti-TG2 stain H-scores were almost similar in IgAN and non-IgANs (H-score 6.31±3 vs. 7.03±2.7); however, H-scores in both of these groups were significantly higher than in normal renal parenchyma (1.6±1.5). Only 6.2% patients with IgAN with anti-TG2 immunostain positivity showed a positive anti-tTG antibody serology and villous abnormalities, suggestive of CeD. Intestinal biopsies from patients with CeD, tropical sprue, nonspecific duodenitis, and inflammatory bowel disease also showed high anti-TG2 H-scores, with no statistically significant differences. Liver biopsies from patients with both ALF, as well as chronic liver diseases showed high anti-TG2 H-scores; with highest stain expression in ALF. In conclusion, IHC expression of anti-TG2 stain correlates with both acute and chronic tissue injuries, irrespective of etiology and organ involvement. It is not a reliable marker for diagnosis of CeD.

Cathepsin L and B as Potential Markers for Liver Fibrosis: Insights From Patients and Experimental Models.

OBJECTIVES: Cathepsin L (CTSL) and B (CTSB) have a crucial role in extracellular matrix (ECM) degradation and tissue remodeling, which is a prominent feature of fibrogenesis. The aim of this study was to determine the role and clinical significance of these cathepsins in liver fibrosis. METHODS: Hepatic histological CTSL and CTSB expression were assessed in experimental models of liver fibrosis, patients with liver cirrhosis, chronic viral hepatitis, and controls by real-time PCR and immunohistochemistry. Plasma levels of CTSL and CTSB were analyzed in 51 liver cirrhosis patients (Child-Pugh stages A, B and C) and 15 controls. RESULTS: Significantly enhanced CTSL mRNA (P=0.02) and protein (P=0.01) levels were observed in the liver of carbon tetrachloride-treated mice compared with controls. Similarly, hepatic CTSL and CTSB mRNA levels (P=0.02) were markedly increased in Abcb4-/- (ATP-binding cassette transporter knockout) mice compared with wild-type littermates. Elevated levels of CTSL and CTSB were also found in the liver (P=0.001) and plasma (P<0.0001) of patients with hepatic cirrhosis compared with healthy controls. Furthermore, CTSL and CTSB levels correlated well with the hepatic collagen (r=0.5, P=0.007; r=0.64, P=0.0001). CTSL and CTSB levels increased with the Child-Pugh stage of liver cirrhosis and correlated with total bilirubin content (r=0.4/0.2; P≤0.05). CTSL, CTSB, and their combination had a high diagnostic accuracy (area under the curve: 0.91, 0.89 and 0.96, respectively) for distinguishing patients from controls. CONCLUSIONS: Our data demonstrate the overexpression of CTSL and CTSB in patients and experimental mouse models, suggesting their potential as diagnostic biomarkers for chronic liver diseases.

Pancreatic heterotropia in wall of extra-hepatic choledochal cysts: A retrospective analysis of thirteen of such cases from north India.

INTRODUCTION: Heterotopic pancreas (HP) has rarely been identified in the wall of choledochal cyst (CC). METHODS: Retrospectively we screened 200 excised specimens of CC received at our Institute over a period of last eight years and looked for presence of HP rests in them. All the specimens were processed in their entirety. RESULT: HP was identified in the wall of 13 (6.5%) CCs, out of which 11 were Heinrich Type 2, and two were Heinrich Type 1. In half of the cases peribiliary mucous glands were observed intermingled with the HP rests. Features of chronic fibrosing pancreatitis were identified in these rests, with ulceration of overlying cyst lining. CONCLUSIONS: HP rests in the wall of CC though rare; their coexistence with peribiliary glands may possibly indicate their common embryonic origin. As a common site of inflammation, HP rest may be one of the common causes of CC.