Differential location of growth factors and pancreatic stellate cell activation in chronic pancreatitis.

Pancreatic fibrosis is characterized by the activation of pancreatic stellate cells leading to the expression of smooth muscle actin (α-SMA). Normal pancreatic tissue has predominantly quiescent stellate cells in periductal and perivascular locations, which do not express α-SMA. We aimed at studying the immunohistochemistry (IHC) expression pattern of α-SMA, platelet-derived growth factor (PDGF-BB) and transforming growth factor (TGF-ß) in the resected specimen of chronic pancreatitis. Twenty biopsies from resected specimens of patients with chronic pancreatitis were included. The expression was measured in comparison to positive control biopsies (breast carcinoma for PDGF-BB and TGF-ß and appendicular tissue for α-SMA) and scored based on a semi-quantitative system based on staining intensity. The percentage of positive cells was used for objective scoring, which ranged from 0 to 15. The scoring was done separately for acini, ducts, stroma and islet cell. All patients had undergone surgery for refractory pain and the median duration of symptoms was 48 months. On IHC, α-SMA was not expressed in the acini, ducts or islets, but had high expression in the stromal regions (vs. acini, ducts and islet, p < 0.05), TGF-ß1 was also expressed maximally in islet cells; however, the distribution among all locations was statistically similar. α-SMA expression in the pancreatic stroma is an indicator of the concentration of activated stellate cells in the stroma, a site for genesis of fibrosis under the influence of growth factors in the local milieu.

Falsely elevated anti-tissue transglutaminase antibodies in patients with immunoproliferative small intestinal diseases: A case series.

Immunoproliferative small intestinal disease (IPSID) is an uncommon disease of the small intestine. There is a similarity in the clinical presentations of enteropathic diseases, including celiac disease, tropical sprue, IPSID, and Whipple's disease. A differentiation between them is based on the use of a highly specific serological test for celiac disease and specific histological characteristics. We found that IgA-anti-tissue transglutaminase antibody (IgA-tTG Ab) is falsely elevated in a subset of patients with IPSID. The levels of IgA-tTG Ab fall with the treatment of IPSID. The healthcare professional should be aware of the conditions that lead to a false-positive anti-tTG Ab. Intestinal mucosal biopsies even in the presence of anti-tTG Ab should be done in endemic regions as they provide an opportunity for making a diagnosis of alternative and uncommon diseases before the diagnosis of celiac disease.

Alterations in Autophagy and Mammalian Target of Rapamycin (mTOR) Pathways Mediate Sarcopenia in Patients with Cirrhosis.

Background and aims: The pathophysiology of sarcopenia in cirrhosis is poorly understood. We aimed to evaluate the histological alterations in the muscle tissue of patients with cirrhosis and sarcopenia, and identify the regulators of muscle homeostasis. Methods: Computed tomography images at third lumbar vertebral level were used to assess skeletal muscle index (SMI) in 180 patients. Sarcopenia was diagnosed based on the SMI cut-offs from a population of similar ethnicity. Muscle biopsy was obtained from the vastus lateralis in 10 sarcopenic patients with cirrhosis, and the external oblique in five controls (voluntary kidney donors during nephrectomy). Histological changes were assessed by hematoxylin and eosin staining and immunohistochemistry for phospho-FOXO3, phospho-AKT, phospho-mTOR, and apoptosis markers (annexin V and caspase 3). The messenger ribonucleic acid (mRNA) expressions for MSTN, FoxO3, markers of ubiquitin-proteasome pathway (FBXO32, TRIM63), and markers of autophagy (Beclin-1 and LC3) were also quantified. Results: The prevalence of sarcopenia was 14.4%. Muscle histology in sarcopenics showed atrophic angulated fibers (P = 0.002) compared to controls. Immunohistochemistry showed a significant loss of expression of phospho-mTOR (P = 0.026) and an unaltered phospho-AKT (P = 0.089) in sarcopenic patients. There were no differences in the immunostaining for annexin-V, caspase-3, and phospho-FoxO3 between the two groups. The mRNA expressions of MSTN and Beclin-1 were higher in sarcopenics (P = 0.04 and P = 0.04, respectively). The two groups did not differ in the mRNA levels for TRIM63, FBXO32, and LC3. Conclusions: Significant muscle atrophy, increase in autophagy, MSTN gene expression, and an impaired mTOR signaling were seen in patients with sarcopenia and cirrhosis.

Progressive multifocal leukoencephalopathy in a patient with systemic lupus erythematosus and autoimmune hepatitis.

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating central nervous system illness encountered in the setting of immunosuppressive conditions like human immunodeficiency virus / acquired immunodeficiency syndrome, autoimmune diseases and hematologic malignancies. We had a 54-year-old woman with systemic lupus erythematosus and coexisting autoimmune hepatitis who presented with progressive cognitive decline, right hemiparesis and ataxia who was found to have PML. She had severe CD4 lymphopenia. She was managed with low-dose prednisolone and plasma exchange after which she showed significant clinical improvement. This case highlights the diagnostic and therapeutic challenges encountered in managing a case of PML in the setting of autoimmune conditions with profound lymphopenia.

European Working Group on Sarcopenia in Older People (EWGSOP2) Criteria With Population-Based Skeletal Muscle Index Best Predicts Mortality in Asians With Cirrhosis.

BACKGROUND/AIMS: Multiple definitions of sarcopenia exist and the acceptable criterion that best predicts outcome is lacking. We estimated the prevalence of sarcopenia based on four criteria and assessed their utility in predicting mortality in cirrhotics. METHODS: In a prospective observational study, consecutive Asian patients with cirrhosis underwent testing for handgrip strength (HGS) and estimation of skeletal muscle index (SMI) using computed tomography at the third lumbar vertebra. Sarcopenia was defined based on the Western cut-off (WC; SMI < 50 cm2/m2 for men and <39 cm2/m2 for women), Asian cut-off (AC; SMI < 36.5 cm2/m2 for men and 30.2 cm2/m2 for women), European Working Group on Sarcopenia in Older People-2nd meeting (EWGSOP2) definition incorporating low HGS (<27 kg for men and <16 kg for women) with low SMI (defined by the WC), and EWGSOP2 definition with low HGS and low SMI (defined by AC). Risk factors for mortality were assessed using multivariate Cox-proportional hazards. RESULTS: We included 219 patients with cirrhosis (168 men; mean age 42.6 years) with 50.2% patients having decompensation. Alcohol was the commonest aetiology (33.3%). The prevalence of sarcopenia was highest with the WC (men: 82.1%; women: 62.7%). There was a weak concordance among all criteria (Fleiss' kappa 0.23, 95% confidence interval [CI] 0.10-0.37). Overall, 12-month survival was 86.1% (81.1-91.3%) over a median (interquartile range) follow-up of 12 (6-15) months. Ascites (hazards ratio [HR] 6.27 [95% CI 1.6-24.1]; P < 0.007) and SMI (HR 0.92 [0.85-0.98]; P = 0.021) were independent predictors of mortality. The 12-month mortality rate was higher in patients with sarcopenia, irrespective of criteria (log rank P < 0.05). Low HGS and low SMI (defined by AC) was the best for predicting mortality (HR 3.04 [1.43-6.43]; P = 0.004). CONCLUSION: A weak concordance exists amongst various diagnostic definitions of sarcopenia. Sarcopenia diagnosed by a combination of low HGS and population-specific SMI cut-off (AC) best predicts mortality.

Determinants of Outcomes in Autoimmune Hepatitis Presenting as Acute on Chronic Liver Failure Without Extrahepatic Organ Dysfunction upon Treatment With Steroids.

BACKGROUND AND AIMS: Autoimmune hepatitis presenting as acute on chronic liver failure (AIH-ACLF) is a novel entity with limited data on clinical course and management. We assessed outcomes in patients of AIH-ACLF with no extrahepatic organ dysfunction/failure when administered steroids. METHODS: In this retrospective analysis, clinical data, laboratory parameters, liver biopsy indices and prognostic scores such as model for end-stage liver disease (MELD) and Child-Turcotte-Pugh (CTP) scores at baseline were computed for patients with AIH-ACLF and compared across strata of incident infections and transplant-free survival. The primary outcome was 90-day transplant-free survival. Biochemical remission was assessed, and predictors of end points were identified. RESULTS: Twenty-nine patients of AIH-ACLF were included with a median follow-up of 4 months. The 90- and 180-day transplant-free survival rates of 55.2 [95% confidence interval (CI): 39.7-76.6]% and 30.2(95% CI: 16.7-54.6)%, respectively, were attained on steroids. Three patients (10.3%) underwent liver transplant while 16 (55.2%) deaths occurred. Infections developed in 12 patients (41.3%), leading to worsening prognostic scores, new onset organ dysfunction/failure and 11 deaths. Seven of ten patients (70%) in the transplant-free survivor group attained biochemical remission on follow-up. The MELD score<24 (sensitivity: 68.4%; specificity: 80%) and CTP<11 (sensitivity: 78.9%; specificity: 90%) had best predictive value for survival, in addition to decrease in the MELD score at 2 weeks (sensitivity: 78.9%; specificity: 70%). CONCLUSION: Patients with AIH-ACLF have a morbid disease course despite treatment with steroids. Patients with no extrahepatic organ failure with good baseline prognostic scores may be administered steroids with close monitoring for change in MELD over 2 weeks.

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.

Antitubercular Therapy Given to Differentiate Crohn's Disease From Intestinal Tuberculosis Predisposes to Stricture Formation.

BACKGROUND AND AIM: Treatment trial with antitubercular therapy [ATT] is a common strategy in tuberculosis-endemic countries in case of a diagnostic dilemma between intestinal tuberculosis and Crohn's disease [CD]. Our aim was to determine the long-term clinical course of patients who received ATT before an eventual diagnosis of CD was made. METHODS: We performed retrospective comparison between CD patients who received ≥6 months of ATT vs those who did not receive ATT. Outcomes assessed were change in disease behaviour during follow-up, requirement of surgery and medication use. RESULTS: In all, 760 patients with CD were screened for the study and, after propensity matching for location and behaviour of disease, 79 patients in each group were compared. Progression from inflammatory [B1] to stricturing/fistulising [B2/B3] phenotype was increased among CD patients who received ATT [B1, B2, B3: 73.4%, 26.6%, 0% at baseline vs: 41.8%, 51.9%, 6.3% at follow-up, respectively] as compared with those who did not receive ATT [B1, B2, B3: 73.4%, 26.6%, 0% at baseline vs: 72.2%, 27.8%, 0% at follow-up, respectively] with an odds ratio of 11.05[3.17-38.56]. The usage of 5-aminosalocylates, steroids, immunosuppressants and anti-tumour necrosis factor was similar between both the groups. On survival analysis, CD patients who received ATT had a lower probability of remaining free of surgery [45%] than those who did not [76%] at 14 years of follow-up (hazard ratio [HR] = 3.22, 95% confidence interval [CI], 1.46-7.12, p = 0.004]. CONCLUSIONS: Crohn's disease patients diagnosed after a trial with antitubercular therapy had an unfavourable long-term disease course with higher rate of stricture formation and less chance of remaining free of surgery.

Natural course of chronic pancreatitis and predictors of its progression.

BACKGROUND: The natural course of chronic pancreatitis(CP) and its complications has been inadequately explored. We aimed to describe the natural history and factors affecting the progression of alcoholic(ACP), idiopathic juvenile(IJCP) and idiopathic senile(ISCP) variants of CP. METHODS: This study was a retrospective analysis from a prospectively maintained database of patients with CP following up at a tertiary care centre from 1998 to 2019. Cumulative rates of pain resolution, diabetes, steatorrhea, pseudocysts and pancreatic cancer were computed using Kaplan-Meier analysis, and the factors affecting their incidence were identified on multivariable-adjusted Cox-proportional-hazards model. RESULTS: A total of 1415 patients were included, with 540(38.1%) ACP, 668(47.2%) IJCP and 207(14.6%) ISCP with a median follow-up of 3.5 years(Inter-quartile range: 1.5-7.5 years). Diabetes occurred at 11.5, 28 and 5.8 years(p < 0.001) while steatorrhea occurred at 16, 24 and 18 years(p = 0.004) after onset for ACP, IJCP and ISCP respectively. Local complications including pseudocysts occurred predominantly in ACP(p < 0.001). Ten-year risk of pancreatic cancer was 0.9%, 0.2% and 5.2% in ACP, IJCP and ISCP, respectively(p < 0.001). Pain resolution occurred more frequently in patients with older age of onset[Multivariate Hazard Ratio(HR):1.7(95%CI:1.4-2.0; p < 0.001)], non-smokers[HR:0.51(95%CI:0.34-0.78); p = 0.002] and in non-calcific CP[HR:0.81(0.66-1.0); p = 0.047]. Occurrence of steatorrhea[HR:1.3(1.03-1.7); p = 0.028] and diabetes[HR:2.7(2.2-3.4); p < 0.001] depended primarily on age at onset. Occurrence of pancreatic cancer depended on age at onset[HR:12.1(4.7-31.2); p < 0.001], smoking-history[HR:6.5(2.2-19.0); p < 0.001] and non-alcoholic etiology[HR:0.14(0.05-0.4); p < 0.001]. CONCLUSION: ACP, IJCP and ISCP represent distinct entities with different natural course. Age at onset of CP plays a major prognostic role in all manifestations, with alcohol predominantly causing local inflammatory complications.

Serum creatinine and cystatin C-based index can be a screening biomarker for sarcopenia in older population.

PURPOSE: Considering the clinical impact of sarcopenia, it would be interesting to get a rapid and sensible screening tool. We conducted a cross-sectional study with the motive to use an index based on serum creatinine and cystatin C to screen sarcopenia in older people in outpatient settings. METHODS: 100 participants above the age of 65 years were recruited from the outpatient department of Geriatric medicine of a tertiary care hospital in India. Muscle mass, muscle strength and physical performance were measured by DXA scan, hand-held dynamometer and 4 m gait speed, respectively. Sarcopenia was identified using Asian working group of sarcopenia (AWGS) criteria. Serum creatinine and cystatin C were measured for all participants. Serum creatinine/cystatin C ratio and biochemical total body muscle mass index (TBMM) were calculated and its association was checked with sarcopenia. RESULTS: The prevalence of sarcopenia was 53%. Mean serum creatinine/cystatin C ratio was 74.79 ± 24.91. It was not significantly associated with sarcopenia. Mean biochemical TBMM index of participants was 36.40 ± 7.88 (males-38.77 ± 7.72, females-31.22 ± 5.13). The lower value of biochemical TBMM index was significantly associated with an increased risk of sarcopenia (p < 0.01). Cut-off value of 40.9 in males (sensitivity-79.41%; specificity-61.76%) and 32.2 in females (sensitivity-78.95%; specificity-66.67%) was proposed for identification of sarcopenia. CONCLUSION: Out of the two indices, only low biochemical total body muscle mass index is significantly associated with sarcopenia and a value of less than 40.9 in males and 32.2 in females can be used to screen sarcopenia in older people.