Search

Liver fibrosis is associated with poor patient-reported outcomes (PROs), but the impact of steatosis is unknown. We aimed to evaluate the impact of steatosis on PROs independent of liver fibrosis. We evaluated the impact of steatosis, measured by Controlled-Attenuation Parameter (CAP) on transient elastography, and PROs using the 2017–2018 National Health and Nutrition Examination Survey (NHANES) database. We used univariate and multivariate logistic and ordinal regression to evaluate categorical CAP score with PROs measuring physical disability, general health and depression. Of 4,509 participants included, 38% had severe steatosis (> 280 dB/m). Those with severe steatosis were older and more likely to be male (56% vs. 43% and 51%). On univariate analysis, severe steatosis was associated with more difficulty walking (P = 0.01), dressing (P = 0.005), lifting objects (P = 0.02), bending (P

Background. Liver transplantation is indicated in end-stage liver disease due to autoimmune diseases. The liver allocation system can be affected by disparities such as decreased liver transplant referrals for racial minorities, especially African Americans that negatively impact the pre- and posttransplant outcomes. Aim. To determine differences in waitlist survival and posttransplant graft survival rates between African American and Caucasian patients with autoimmune liver diseases. Study. The United Network for Organ Sharing database was used to identify all patients with autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis who underwent liver transplant from 1988 to 2019. We compared waitlist survival and posttransplant graft survival between Caucasians and African Americans using Kaplan–Meier curves and Cox regression models. We also evaluated the cumulative incidence of death or delisting for deterioration and posttransplant incidence of death and retransplantation using competing risk analysis. Results. African Americans were more likely to be removed from the waitlist for death or clinical deterioration (subdistribution hazard ratio (SHR) 1.26, 95% CI 1–1.58, P = 0.046 ) using competing risk analysis. On multivariate Cox regression analysis, there was no difference in posttransplant graft survival among the two groups (hazard ratio (HR) 1.10, 95% CI 0.98–1.23, P = 0.081 ). Conclusions. Despite the current efforts to reduce racial disparities, we found that African Americans are more likely to die on the waitlist for liver transplant and are less likely to be transplanted, with no differences in graft survival rates. The persistence of healthcare disparities continues to negatively impact African Americans.

OBJECTIVES Model for End-Stage Liver Disease (MELD) alone and with sodium (MELD-Na) have decreasing predictive capacity as trends in liver disease evolve. We sought to combine transient elastography (TE) with MELD-Na to improve its predictive ability. METHODS This is a retrospective cohort study comparing the use of TE, MELD-Na, and composite MELD-Na-TE to predict liver transplantation and all-cause mortality, with hepatic decompensation as a secondary outcome. Cox proportional hazards regression was used to measure predictive ability and control for confounders. RESULTS Of the 214 patients, the mean age was 53 years with 35% being female and 76% being Caucasian. Hepatitis C (59%) and nonalcoholic fatty liver disease (22%) were the most frequent liver disease etiologies. On univariable analysis, MELD-Na [hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.06-1.2, P < 0.001], TE (HR 1.04, 95% CI 1.03-1.06, P < 0.001) and composite MELD-Na-TE (HR 1.13, 95% CI 1.08-1.19, P < 0.001) were associated with death or transplant. On multivariable analysis, MELD-Na was no longer significant (HR 1.08, 95% CI 0.95-1.22, P = 0.27) after adjusting for TE (HR 1.05, 95% CI 1.03-1.07, P < 0.001) while composite MELD-Na-TE remained significant (HR 1.16, 95% CI 1.09-1.24, P < 0.001). Composite MELD-Na-TE predicts mortality or liver transplant with the highest C-statistic of 0.81. Age (HR 1.05, 95% CI 1-1.09, P = 0.04), TE (HR 1.04, 95% CI 1.03-1.06, P < 0.001) and composite MELD-Na-TE (HR 1.11, 95% CI 1.06-1.15, P < 0.001) were significantly associated with hepatic decompensation. CONCLUSION Composite MELD-Na-TE better predicts liver transplantation, death, and hepatic decompensation compared to MELD/MELD-Na or TE alone.

Background: Metabolic syndrome increases adverse outcomes in coronavirus disease 2019 (COVID-19) infection. Hepatic steatosis may increase risk of COVID-19 severity. Current studies evaluating steatosis lack reliable definitions. We aimed to evaluate the association of radiographic hepatic steatosis and clinical outcomes of COVID-19 severity in a diverse cohort.Methods: We retrospectively identified patients with COVID-19 infection admitted to two US academic hospitals. Outcomes were length of stay, intensive care unit use, mechanical ventilation, and in-hospital mortality. We used Mann-Whitney U-test for continuous measures and Chi-square or Fisher’s exact test for categorical measures. Multivariable linear and logistic regression analyses were used to adjust for confounders.Results: Of the 319 patients, 14% had hepatic steatosis. There were no differences in length of stay (6 (4 - 16) vs. 9 (4 - 18) days, P = 0.6), intensive care unit (24% vs. 32%, P = 0.3), mechanical ventilation (28% vs. 38%, P = 0.32), or in-hospital mortality (7% vs. 17%, P = 0.12). After adjustment, there was no difference in length of stay (β: -14.37, 95% confidence interval (CI): -30.5 - 1.77, P = 0.08), intensive care unit (odds ratio (OR): 0.31, 95% CI: 0.03 - 1.09, P = 0.06), mechanical ventilation (OR: 0.13, 95% CI: 0.02 - 1.09, P = 0.06), or in-hospital mortality (OR: 0.27, 95% CI: 0.06 - 1.16, P = 0.08) among patients with hepatic steatosis.Conclusion: Radiographic hepatic steatosis was not associated with worse outcomes among patients hospitalized with COVID-19.Gastroenterol Res. 2021;14(3):179-183doi: https://doi.org/10.14740/gr1389

Introduction and Objectives: Noninvasive liver assessment in type 2 diabetes (T2DM) in a primary care population identifies higher risk non-alcoholic fatty liver disease (NAFLD). We aimed to evaluate the association of T2DM with liver fibrosis and steatosis by transient elastography (TE). Materials and Methods: This is a retrospective study of a TE referral program where primary care physicians were able to order TE. Patients with alcohol abuse were excluded. TE and Controlled Attenuation Parameter (CAP) scores were obtained. Multivariable linear and logistic regression models were used to adjust for confounders. Results: 28% had T2DM. The mean TE score in T2DM patients was 8.3 (±6) kilopascal (kPa) and 6.4 (±3.7) kPa in those without T2DM (p = 0.0001). Those with T2DM had a higher CAP (322 ± 51 dB/m vs. 296 ± 57 dB/m, p

Background and study aims The COVID-19 pandemic has had a profound impact on gastroenterology training programs. We aimed to objectively evaluate procedural training volume and impact of COVID-19 on gastroenterology fellowship programs in the United States. Methods This was a retrospective, multicenter study. Procedure volume data on upper and lower endoscopies performed by gastroenterology fellows was abstracted directly from the electronic medical record. The study period was stratified into 2 time periods: Study Period 1, SP1 (03/15/2020 to 06/30/2020) and Study Period 2, SP2 (07/01/2020 to 12/15/2020). Procedure volumes during SP1 and SP2 were compared to Historic Period 1 (HP1) (03/15/2019 to 06/30/2019) and Historic Period 2 (HP2) (07/01/2019 to 12/15/2019) as historical reference. Results Data from 23 gastroenterology fellowship programs (total procedures = 127,958) with a median of 284 fellows (range 273–289; representing 17.8 % of all trainees in the United States) were collected. Compared to HP1, fellows performed 53.6 % less procedures in SP1 (total volume: 28,808 vs 13,378; mean 105.52 ± 71.94 vs 47.61 ± 41.43 per fellow; P Conclusions Although there was a significant reduction in fellows’ endoscopy volume in the initial stages of the pandemic, adaptive mechanisms have resulted in a return of procedure volume to near baseline without ongoing impact on endoscopy training.

Primary biliary cholangitis (PBC) is a chronic, cholestatic condition associated with symptoms that directly impact the quality of life in those afflicted with the disease. In addition to pruritus and fatigue, patients with PBC may develop metabolic bone disease from reduced bone density, such as osteopenia and osteoporosis. Osteoporosis increases the risk of fractures, as well as morbidity and mortality. The prevalence of osteoporosis in PBC is expected to increase in conjunction with the rising prevalence of PBC as a whole. Timely diagnosis, prevention and management of osteoporosis are crucial in order to optimize the quality of life. There is a paucity of data evaluating the management of osteoporosis in PBC. The optimal timing for diagnosis and monitoring is not yet established and is guided by expert opinion. National guidelines recommend screening for osteoporosis at the time of diagnosis of PBC. Monitoring strategies are based on results of initial screening and individual risk factors for bone disease. Identifying reduced bone density is imperative to institute timely preventive and treatment strategies. However, treatment remains challenging as efficacious therapies are currently lacking. The data on treatment of osteoporosis in PBC are mostly extrapolated from postmenopausal osteoporosis literature. However, this data has not directly translated to useful treatment strategies for PBC-related osteoporosis, partly because of the different pathophysiological mechanisms of the two diseases. The lack of useful preventive measures and efficacious treatment strategies remains the largest pitfall that challenges the management of patients with PBC. In this review, we comprehensively outline the epidemiology, clinical implications and challenges, as well as management strategies of PBC-related osteoporosis.

BACKGROUND & AIMS Racial/ethnic disparities in liver transplantation (LT) are well-recognized. Although Hispanics represent the largest and youngest minority group in the United States, limited data exist on long-term outcomes. We aimed to investigate long-term post-liver transplant outcomes in Hispanic patients and identify potential disparities compared to a baseline demographic of non-Hispanic white patients. METHODS We performed a retrospective cohort study of first-time liver transplant recipients using the United Network for Organ Sharing database from 2002 to 2013, with follow-up through 2018. The primary outcomes of interest were overall patient and graft survival after LT. RESULTS 45 767 patients underwent LT (85.0% non-Hispanic white, 15.0% Hispanic). Hispanics had lower socioeconomic status, higher prevalence of pretransplant comorbidities and more severe liver disease compared to non-Hispanic whites. Hispanics had similar patient (76.6% vs 75.6%; P = .12) and graft (71.7% vs 70.8%; P = .28) survival at 5 years and significantly better patient (62.9% vs 59.7%; P

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the Western world. It is more prevalent in male gender, and with increasing age, obesity, and insulin resistance. Besides weight loss, there are limited treatment options. The use of anti-diabetic medications has been studied with mixed results. In this review, we discuss the use of anti-diabetic medications in the management of NAFLD with a specific focus on sodium-glucose cotransporter 2 inhibitors. We shed light on the evidence supporting their use in detail and discuss limitations and future directions.

Cirrhosis, a rising cause of death in the United States, has an extended preclinical phase characterized by progressive liver fibrosis. Despite the developments in noninvasive fibrosis measurement, there is no recommended screening, in part due to an incomplete understanding of the disease epidemiology on a national scale. Herein, we aim to define the prevalence of liver fibrosis and compare strategies to identify the at-risk population. We analyzed 4,510 US adults with complete liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) in the 2017-2018 National Health and Nutrition Examination Survey to estimate the disease burden of increased liver stiffness. An estimated 11.6 million (95% confidence interval [C.I.], 8.1-15.0 million) US adults had LSM ≥9.5 kPa, indicating advanced fibrosis and representing 1 in every 18 adults. Among them, 7.1 million (95% CI, 5.0-9.1 million) had LSM ≥12.5 kPa, which is concerning for cirrhosis. LSM ≥9.5 kPa is associated with male sex (S), history of other liver diseases (O), diabetes (D), advanced age (A), and an elevated BMI (B). A simple SODA-2B score had a sensitivity of 96.4% in identifying individuals at risk for advanced cirrhosis (LSM ≥9.5 kPa) and a negative predictive value of 99.3% in stratifying more than half of the adult population. When the liver function test (LFT) is available, the inclusion of abnormal LFT and elevated fibrosis-4 index can further increase screening efficiency. Conclusion: Elevated liver stiffness is prevalent among US adults. A SODA-2B score can risk stratify adults for VCTE-based fibrosis screening.

Bouveret's syndrome is a rare complication of cholelithiasis. It is characterized by a gallstone entering the intestine through a cholecystoenteric fistula, impacting the duodenum and causing gastric outlet obstruction. Rarely, it presents with hematemesis and melena. The diagnosis involves computed tomography (CT) and the treatment depends on the patient's stability, the location of the obstruction, stone size, and the fistula. Endoscopy or minimally invasive lithotripsy can be considered initially. If this fails, surgical intervention is recommended. We present a case of upper gastrointestinal bleeding (UGIB) preceding the development of Bouveret's syndrome.

Background Systemic mastocytosis (SM), a clonal expansion of mast cells affecting multiple organs including the skeletal system, puts patients at risk for osteoporosis and fractures. Various aspects of skeletal disease in SM have been reported among European cohorts. Objective To determine fracture prevalence and risk predictors in SM in a North American (NA) cohort and compare findings with studies of other populations. Methods Fifty patients, aged 25-74 years, were grouped based on fracture type and history. Data collected included laboratory findings and radiographic markers such as serum tryptase, bone turnover markers, dual-energy x-ray absorptiometry images, and trabecular bone scores. We performed univariate and multivariate analyses of these findings. Results Fracture history was found in 74% of patients. Significantly different median age, body mass index, dual-energy x-ray absorptiometry scores, and alkaline phosphatase levels were observed between fracture groups, consistent with French and Dutch studies. Significant findings included the difference in trabecular bone scores among fracture groups, the association between alkaline phosphatase and fracture type and occurrence, and the model for predicting fracture risk based on DXA spine T-scores, alkaline phosphatase, and age (81.3% accuracy and 77.1% sensitivity). Conclusions Our findings in an NA cohort are in overall agreement with those reported in European studies of skeletal disease and fracture risk for individuals with SM. We include an interactive calculator designed from a predictive model based on the NA cohort, which may be used for improved screening for fracture risk.

Background and Aim: The prevalence and clinical significance of extrahepatic autoimmune diseases (EHAIDs) have not been evaluated in a large cohort of primary biliary cholangitis (PBC). Methods: The medical records of 1554 patients with PBC from 20 international centers were retrospectively reviewed. Development of decompensated cirrhosis (ascites, variceal bleeding, and/or hepatic encephalopathy) and hepatocellular carcinoma were considered clinical endpoints. Results: A total of 35 different EHAIDs were diagnosed in 440 (28.3%) patients with PBC. Patients with EHAIDs were more often female (92.5% vs 86.1%, P&nbsp

Cirrhosis contributes significantly to morbidity and mortality worldwide. Infections in patients with cirrhosis are common and significantly impact health-related quality of life. As our understanding of immune dysfunction associated with cirrhosis grows and as rates of drug-resistant organisms increase, the management of infections in cirrhosis has become increasingly nuanced. In this review, we discuss the current understanding of cirrhosis-associated immune deficiency, review the most common infections in patients with cirrhosis, and highlight techniques for the general clinician in the prevention and treatment of infections in this high-risk population.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide, with rising rates in parallel to those of obesity, type 2 diabetes, and metabolic syndrome. NAFLD encompasses a wide spectrum of pathology from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis, which are linked to poor outcomes. Studies confirm a significant amount of undiagnosed NAFLD and related fibrosis within the community, increasing the overall burden of the disease. NAFLD appears to be more prevalent in certain populations, such as those with type 2 diabetes and metabolic syndrome. Early detection and lifestyle modifications, including weight loss and regular exercise, have been shown to improve outcomes. Adverse cardiovascular events are a key contributor to NAFLD-associated morbidity and mortality, and efforts to minimize their occurrence are essential. A targeted and algorithmic approach using noninvasive diagnostic techniques is promptly required to identify and risk-stratify patients with NAFLD. Patients at low risk of progression to NASH and advanced fibrosis can be managed in the primary care setting, while those at high risk of disease progression should be referred to hepatology specialists for surveillance and treatment. This review summarizes the key data of NAFLD's impact within primary care populations and proposes a potential algorithmic approach to identifying and managing such patients.

Fatigue is the most common complication of primary biliary cholangitis (PBC) and can be debilitating. Numerous interventions have been trialed targeting several proposed mechanisms of PBC-associated fatigue. We sought to summarize and perform a meta-analysis to determine the efficacy of these interventions. A comprehensive database search was conducted from inception through March 27, 2018. The primary outcome was proportion of fatigued patients or reduction in degree of fatigue. Adverse events were a secondary outcome. We assessed studies for risk of bias, graded quality of evidence, and used meta-analysis to obtain overall effect by pooling studies of the same class. We identified 16 studies evaluating ursodeoxycholic acid (UDCA) (7), liver transplantation (2), serotonin reuptake inhibitors (2), colchicine (1), methotrexate (1), cyclosporine (1), modafinil (1), and obeticholic acid (1). On meta-analysis, UDCA was not associated with a reduction in risk of fatigue (RR = 0.86, 95% CI 0.69–1.08, p = 0.19, I2 = 56.2%). While liver transplantation did reduce degree of fatigue (SMD − 0.57, 95% CI − 0.89 to − 0.24, p = 0.001, I2 = 67.3%), fatigue did not return to baseline indicating the underlying cause may not be addressed. While there is some improvement in fatigue with liver transplantation, there is a lack of high-quality evidence supporting the efficacy of any other intervention in the treatment of PBC-related fatigue. Further research into the underlying pathophysiology may help guide future trials.

Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease with multiple debilitating complications. Osteoporosis is a common complication of PBC resulting in frequent fractures and leading to significant morbidity in this population, yet evidence for effective therapy is lacking. We sought to summarize our current understanding of the pathophysiology of osteoporosis in PBC, as well as current and emerging therapies in order to guide future research directions. A complete search with a comprehensive literature review was performed with studies from PubMed, EMBASE, Web of Science, Cochrane database, and the Countway Library. Osteoporosis in PBC is driven primarily by decreased bone formation, which differs from the increased bone resorption seen in postmenopausal osteoporosis. Despite this fundamental difference, current treatment recommendations are based primarily on experience with postmenopausal osteoporosis. Trials specific to PBC-related osteoporosis are small and have not consistently demonstrated a benefit in this population. As it stands, prevention of osteoporosis in PBC relies on the mitigation of risk factors such as smoking and alcohol use, as well as encouraging a healthy diet and weight-bearing exercise. The primary medical intervention for the treatment of osteoporosis in PBC remains bisphosphonates though a benefit in terms of fracture reduction has never been shown. This review outlines what is known regarding the pathogenesis of bone disease in PBC and summarizes current and emerging therapies.

Hepatitis C infection in patients with chronic kidney disease or kidney transplant carries higher morbidity and mortality compared to noninfected patients. Historically, patients with advanced kidney disease and kidney transplant recipients were undertreated given the multiple adverse effects and limited efficacy of interferon-based therapies for chronic hepatitis C. The development of direct-acting antivirals in the past few years has opened an unprecedented opportunity for treating these populations. However, the impaired renal clearance of some of these medications in patients with kidney disease, and the potential interactions of antiviral therapies with immunosuppressants after kidney transplantation, present some challenges in choosing the proper regimen. This review provides an overview of the essential pharmacokinetics and drug interactions of relevant antiviral therapies in the treatment of chronic hepatitis C in patients with advanced kidney disease and after kidney transplantation.

Chronic liver disease poses various challenges for women of reproductive age. Cirrhosis, particularly if decompensated, and liver transplantation may impact gestation and perinatal outcomes. Tailored management of underlying liver disease is critical to optimize maternal and fetal wellbeing. Early education, timely intervention, close monitoring, and a multidisciplinary approach are key elements required to minimize complications and increase chances of a safe and successful pregnancy. In this review, we focus on the pregnancy-related implications of chronic liver disease and liver transplantation on women of reproductive age and highlight disease-specific management considerations.

Cirrhosis is associated with debilitating complications that significantly impact on a patient’s physical function and reduce quality of life. Owing to highly prevalent sarcopenia, malnutrition and hepatic encephalopathy, functional impairment or frailty is a common complication of cirrhosis. Frailty in turn increases the patient’s risk of hospitalization, accidental falls and fractures, and death. The management of frailty and its associated adverse effects is imperative in improving the overall prognosis of patients with advanced liver disease. The cornerstone of therapy revolves around optimizing physical function with appropriate nutrition and exercise. Nutritional therapy with protein supplementation has shown significant benefit, while studies on exercise have been controversial. However, newly emerging studies trend towards a beneficial effect of physical exercise with improvement in quality of life. The implementation of technology in liver disease management shows future promise. Fitbits and other wearable devices can be used to help monitor a patient’s personal progress in physical exercise and nutritional optimization. Additionally, the progressive development of new smartphone applications to help aid in the diagnosis and monitoring of complications of cirrhosis provides a sophisticated avenue for improving care of patients with cirrhosis.

SummaryBackground Chylous ascites is rare, accounting for less than 1% of cases. An appropriate and stepwise approach to its diagnosis and management is of key importance. Aim To review the current diagnostic approach and management of chylous ascites. Methods A literature search was conducted using PubMed using the key words ‘chylous’, ‘ascites’, ‘cirrhosis’, ‘pathophysiology’, ‘nutritional therapy’, ‘paracentesis”, “transjugular intrahepatic portosystemic shunt” and “TIPSS’. Only articles in English were included. Results Chylous ascites is caused by the traumatic or obstructive disruption of the lymphatic system that leads to extravasation of thoracic or intestinal lymph into the abdominal space and the accumulation of a milky fluid rich in triglycerides. The most common causes are malignancy, cirrhosis and trauma after abdominal surgery. This condition can lead to chyle depletion, which results in nutritional, immunologic and metabolic deficiencies. An ascitic triglyceride concentration above 200 mg/dL is consistent with chylous ascites. Treatment is based on management of the underlying cause and nutritional support. Conclusions Chylous ascites is mostly due to malignancy and cirrhosis in adults, and congenital lymphatic disorders in children. Treatment with nutritional optimization and management of the underlying etiology are the cornerstones of therapy. When conservative measures fail, other interventions such as octreotide/somatostatin analogues, surgical ligation, embolization and transjugular intrahepatic portosystemic shunt in patients with cirrhosis can be considered.

Autoimmune enteropathy is a rare condition seen in adults with limited therapeutic options available. It manifests with profuse diarrhea and malnourishment. The diagnosis is made through a combination of clinical, serologic, and histologic parameters. The cornerstone of therapy revolves around nutritional optimization and immunosuppression, most commonly in the form of corticosteroids. Alternate therapies, such as antitumor necrosis factor agents, can be considered if there is an inadequate response to steroids. We report a case of autoimmune enteropathy that was successfully treated with adalimumab, a rare treatment for an infrequent disease.

EgeUn###, INTRODUCTION: Risk stratification based on biochemical variables is a useful tool for monitoring ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC). Several UDCA response criteria and scoring systems have been proposed for risk prediction in PBC, but these have not been validated in large external cohorts. METHODS: We performed a study on data of 1746 UDCA-treated patients with PBC from 25 centers in Europe, United States, and Canada. The prognostic performance of the risk scoring systems (GLOBE and UK-PBC) and the UDCA response criteria (Barcelona, Paris I, Paris II, Rotterdam, and Toronto) were evaluated. We regarded cirrhosis-related complications (ascites, variceal bleeding, and/or hepatic encephalopathy) as clinical end points. RESULTS: A total of 171 patients reached a clinical end point during a median 7 years (range 1-16 years) of follow-up. The 5-, 10- and 15-year adverse outcome-free survivals were 95%, 85%, and 77%. The GLOBE and UK-PBC scores predicted cirrhosis-related complications better than the UDCA response criteria. The hazard ratio (HR) for a 1 standard deviation increase was HR 5.05 (95% confidence interval (CI): 4.43-5.74, P < 0.001) for the GLOBE score and HR 3.39 (95% CI: 3.10-3.72, P < 0.001) for the UK-PBC score. Overall, the GLOBE and UK-PBC risk scores showed similar and excellent prognostic performance (C-statistic, 0.93; 95% CI: 0.91%-95% vs 0.94; 95% CI: 0.91%-0.96%). DISCUSSION: In our international, multicenter PBC cohort, the GLOBE and UK-PBC risk scoring systems were good predictors of future cirrhosis-related complications.

Eosinophilic leukocytes develop in the bone marrow and migrate from peripheral blood to tissues, where they maintain homeostasis and promote dysfunction via release of preformed immunomodulatory mediators. In this study, we explore human eosinophil heterogeneity with a specific focus on naturally occurring variations in cytokine content. We found that human eosinophil-associated cytokines varied on a continuum from minimally (coefficient of variation [CV] ≤ 50%) to moderately variable (50% < CV ≤ 90%). Within the moderately variable group, we detected immunoreactive IL-27 (953 ± 504 pg/mg lysate), a mediator not previously associated with human eosinophils. However, our major finding was the distinct and profound variability of eosinophil-associated IL-16 (CV = 103%). Interestingly, eosinophil IL-16 content correlated directly with body mass index (R2 = 0.60, ***p < 0.0001) in one donor subset. We found no direct correlation between eosinophil IL-16 content and donor age, sex, total leukocytes, lymphocytes, or eosinophils (cells per microliter), nor was there any relationship between IL-16 content and the characterized −295T/C IL-16 promoter polymorphism. Likewise, although eosinophil IL-1β, IL-1α, and IL-6 levels correlated with one another, there was no direct association between any of these cytokines and eosinophil IL-16 content. Finally, a moderate increase in total dietary fat resulted in a 2.7-fold reduction in eosinophil IL-16 content among C57BL/6-IL5tg mice. Overall, these results suggest that relationships between energy metabolism, eosinophils, and IL-16 content are not direct or straightforward. Nonetheless, given our current understanding of the connections between asthma and obesity, these findings suggest important eosinophil-focused directions for further exploration.

Introduction: Osteoporosis is a common complication of primary biliary cholangitis (PBC) yet evidence for effective therapy is lacking. We sought to review all randomized controlled trials evaluating pharmacotherapy against placebo or no intervention for treatment of osteoporosis in PBC. Methodology: A comprehensive database search was conducted from inception through 29 March 2017. The primary outcome was incidence of fractures; secondary outcomes were change in bone mineral density (BMD) and adverse events. We assessed studies for risk of bias, graded quality of evidence, and used meta-analysis to obtain overall effect by pooling studies of the same drug class. Results: We identified 11 randomized controlled trials evaluating bisphosphonates (3), hormone replacement therapy (2), ursodeoxycholic acid (1), obeticholic acid (1), cyclosporin A (1), vitamin K (1), calcitriol (1), and sodium fluoride (1). No intervention significantly reduced fractures compared to control. Although significant improvement in BMD was seen in one study with alendronate, a third-generation bisphosphonate, no significant improvement was seen on pooled analysis of all bisphosphonates including first-generation bisphosphonates (standard mean difference 0.41, p = 0.68). On pooled analysis, hormone replacement therapy modestly improved lumbar BMD (standard mean difference 0.69, p = 0.02), but with significantly increased adverse events (odds ratio 8.82, p = 0.01). Conclusions: There is a lack of high-quality evidence supporting the efficacy of any treatment of osteoporosis in PBC. This may be explained by lack of power in the included studies. However, our current understanding of PBC-related osteoporosis indicates that it results from decreased bone formation, which may explain the attenuated effect of traditional antiresorptive agents. Future studies should investigate newer anabolic bone agents.

Primary biliary cholangitis (PBC) is an immunological condition that causes a significant health disturbance and dramatically reduces the quality of life for those affected with the disease. It is a potentially fatal disease that can lead to multiple hepatic and extrahepatic complications. Having adequate therapeutic interventions that can improve the course of the disease is imperative in reducing the associated morbidity and mortality. Ursodeoxycholic acid (UDCA) is the gold standard therapy. However, it has been associated with suboptimal response rates in a significant proportion of patients. Despite UDCA, approximately 35%-40% of individuals with PBC still experience a progression of the disease, leading to liver failure and requiring liver transplantation. Recent studies of new pharmacological approaches have shown beneficial outcomes. Some of these agents can now be applied to a clinical scenario. In this review article, we will outline the new and emerging treatments for PBC.

Osteoporosis is the most common bone disease in chronic liver disease (CLD) resulting in frequent fractures and leading to significant morbidity in this population. In addition to patients with cirrhosis and chronic cholestasis, patients with CLD from other etiologies may be affected in the absence of cirrhosis. The mechanism of osteoporosis in CLD varies according to etiology, but in cirrhosis and cholestatic liver disease it is driven primarily by decreased bone formation, which differs from the increased bone resorption seen in postmenopausal osteoporosis. Direct toxic effects from iron and alcohol play a role in hemochromatosis and alcoholic liver disease, respectively. Chronic inflammation also has been proposed to mediate bone disease in viral hepatitis and nonalcoholic fatty liver disease. Treatment trials specific to osteoporosis in CLD are small, confined to primary biliary cholangitis and post-transplant patients, and have not consistently demonstrated a benefit in this population. As it stands, prevention of osteoporosis in CLD relies on the mitigation of risk factors such as smoking and alcohol use, treatment of underlying hypogonadism, and encouraging a healthy diet and weight-bearing exercise. The primary medical intervention for the treatment of osteoporosis in CLD remains bisphosphonates though a benefit in terms of fracture reduction has never been shown. This review outlines what is known regarding the pathogenesis of bone disease in CLD and summarizes current and emerging therapies.

Significant advancements in the diagnosis and treatment of chronic hepatitis C infection and its associated fibrosis have revolutionized treatment of these patients over the last several years. Liver biopsy, the gold standard diagnostic method for evaluating liver fibrosis level, was routinely used prior to initiation of hepatitis C therapy, placing patients at an inherent risk of adverse events. The recent advent of noninvasive serologic and nonserologic measures of hepatic fibrosis level has reduced the need for liver biopsy significantly, thereby minimizing its associated risks. These noninvasive methods have been extensively studied in the era of interferon therapies and are increasingly recognized in the realm of direct acting antiviral agents as well. Their validation of use after having achieved a sustained virologic response is yet to occur, but the future remains promising. This review focuses on the various non-invasive diagnostic modalities of liver fibrosis and discusses how they can be applied to the care of patients undergoing direct acting antiviral therapy for hepatitis C. In the constantly evolving landscape of hepatitis C therapy, the review underscores the important prognostic value of fibrosis staging prior to HCV treatment and suggests potential uses for non-invasive fibrosis assessment following successful HCV eradication.

Patients with autosomal dominant vibratory urticaria have localized hives and systemic manifestations in response to dermal vibration, with coincident degranulation of mast cells and increased histamine levels in serum. We identified a previously unknown missense substitution in ADGRE2 (also known as EMR2), which was predicted to result in the replacement of cysteine with tyrosine at amino acid position 492 (p.C492Y), as the only nonsynonymous variant cosegregating with vibratory urticaria in two large kindreds. The ADGRE2 receptor undergoes autocatalytic cleavage, producing an extracellular subunit that noncovalently binds a transmembrane subunit. We showed that the variant probably destabilizes an autoinhibitory subunit interaction, sensitizing mast cells to IgE-independent vibration-induced degranulation. (Funded by the National Institutes of Health.)

The presence of cirrhosis poses an increased risk of both thrombosis and bleeding in individuals with chronic liver disease. This duality is a result of a dynamic disequilibrium between procoagulant and anticoagulant states in individuals with cirrhosis. The mechanism of this imbalance in cirrhosis remains unclear. It is known that the progression of cirrhosis leads to decreased synthetic function and a concurrent lack of natural anticoagulants. Other proposed mechanisms contributing to this hemostatic imbalance include decreased platelet production, increased platelet destruction from hypersplenism, decreased synthesis of Vitamin K-dependent and independent clotting factors and anticoagulant factors, and alterations in purinergic signaling pathways. Given the current state of flux in our understanding of bleeding and thrombophilia in cirrhosis, the recommendations for treatment of these conditions are still evolving. We provide a current update on the proposed pathophysiology of altered hemostasis and thrombophilia in cirrhosis. We discuss recent studies in portal vein thrombosis (PVT) and venous thromboembolism (VTE), which are the common thrombotic consequences of cirrhosis, resulting in substantive morbidity and mortality. To address these, we discuss new prophylactic interventions and current treatment options to manage the heightened risk of thrombosis in cirrhosis, while limiting hemorrhagic complications.

Objective To provide a clinical rationale for including impulse oscillometry (IOS) as a part of standard office-based asthma assessment. Data Sources PubMed and Google search, limited to English language and human disease, with the keywords IOS and asthma . Study Selections Articles included in this review were based on the expert opinion and previous publications by the authors. Results In children, IOS was more useful than spirometry in identifying asthma and uncontrolled asthma and predicting loss of control and exacerbations. IOS predicts young children at risk for loss of lung function with age and the potential for early intervention to prevent further sequelae. In adults, peripheral airway impairment detected by IOS or spirometry (ie, forced expiratory flow between 25% and 75%) commonly occurs across severity, and each measure may be complementary in predicting loss of control even with normal forced expiratory volume in 1 second. Extrafine inhaled corticosteroids with or without long-acting β-agonists proved superior to standard particle aerosols in improving IOS-detected peripheral airway obstruction. Our data also suggest that currently available commercial reference values for lung resistance at 5 Hz and lung reactance at 5 Hz are applicable across diverse populations, but further studies are needed. Conclusion The findings of this review suggest that IOS can add value to traditional clinical and spirometric assessment and thus improve management of asthma in children and adults, as well as have the potential to detect early dysfunction of the peripheral airways, which may result in better outcomes.

Primary biliary cholangitis is an autoimmune condition characterized by destruction of intrahepatic bile ducts. It causes debilitating symptoms that dramatically affect the patient's quality of life. Pruritus affects 60% to 70% of individuals with primary biliary cholangitis and leads to sleep disturbances, fatigue, depression, and suicidal ideation. A complete search was performed with studies from PubMed, EMBASE, Web of Science, Cochrane database, Countway Library, and CINAHL with specific search terms. This narrative review was prepared after a comprehensive literature review. Treating patients with cholestatic pruritus is challenging and may have a profound impact on quality of life. The standard of therapy for primary biliary cholangitis, ursodeoxycholic acid, does not have a beneficial effect in cholestatic pruritus. Patients often do not respond to conventional therapies such as cholestyramine, rifampicin, opioid antagonists, and sertraline. These therapies lack long-term efficacy and have side effects. Patients who have not responded to these initial treatments can be considered for experimental therapies or clinical trials. This review outlines the current and emerging treatment modalities for patients with primary biliary cholangitis who have pruritus.

OBJECTIVE: To estimate the relationship between antiallergy drug prescription rates and suicide across the United States and over time. The relationship between allergy, allergens, and suicidal behavior and suggestions of a possible immune mediation led us to hypothesize that intranasal corticosteroids, known to reduce local airway production of T-helper cell type 2 cytokines, may be associated with reduced risk of suicide relative to antihistamines, which only secondarily affect cytokine production. METHOD: The authors evaluated the relationship of suicide rates at the county level in the United States (N = 120,076 suicides) with prescriptions for intranasal corticosteroids and nonsedating antihistamines, in interaction with antidepressant prescriptions and other socioeconomic variables, for the period from 1999 to 2002. Suicide rate data were derived from state vital record systems based on local death certificate registries, and county-level allergy and antidepressant prescription data were obtained from IMS Health Incorporated (Plymouth Meeting, Pennsylvania). RESULTS: The prescription volume of intranasal corticosteroids was associated with a lower suicide risk (P = .0004), while that of antihistamines was associated with a modestly greater suicide risk (P = .0001). Adjustment for antidepressant prescriptions did not affect these relationships. CONCLUSIONS: This is the first study, to our knowledge, to find a possible association between completed suicide and medications for allergic rhinitis and also the first report of an association of intranasal corticosteroid use with a lower suicide rate. This association should be considered preliminary and deserving of further investigation. Language: en

Background The ability to objectively measure lung function in children is critical in the assessment and treatment of asthma in this age group. We thus determined the effectiveness of impulse oscillometry (IOS) as a non-invasive technique to assess lung function in children and in comparison to spirometry for sensitivity and specificity, testing variability, and the order effect of sequential testing of IOS and spirometry.

Objective To provide an overview of impulse oscillometry and its application to the evaluation of children with diseases of the airways. Data Sources Medline and PubMed search, limited to English language and human disease, with keywords forced oscillation, impulse oscillometry , and asthma . Study Selections The opinions of the authors were used to select studies for inclusion in this review. Results Impulse oscillometry is a noninvasive and rapid technique requiring only passive cooperation by the patient. Pressure oscillations are applied at the mouth to measure pulmonary resistance and reactance. It is employed by health care professionals to help diagnose pediatric pulmonary diseases such asthma and cystic fibrosis; assess therapeutic responses; and measure airway resistance during provocation testing. Conclusions Impulse oscillometry provides a rapid, noninvasive measure of airway impedance. It may be easily employed in the diagnosis and management of diseases of the airways in children.

Urticaria is a common pruritic skin disorder that is often seen in the office and varies in severity and chronicity. The etiologic cause is frequently not identifiable. Urticaria may be associated with physical factors and triggers, including foods or medications. A significant percentage of patients with chronic urticaria have circulating autoantibodies directed toward immunoglobulin-E or the high-affinity receptor for immunoglobulin-E (FcepsilonRI), or have antithyroid antibodies that might play a role in the activation of the final common pathway in urticaria: mast cell activation and degranulation. Management begins with a careful investigation and elimination of eliciting factors when identified, followed by treatment of underlying disease. Antihistamines are the current mainstay of pharmacotherapy for urticaria, which provide symptomatic relief in most cases. In severe cases, corticosteroids, hydroxychloroquine sulfate (Plaquenil; Sanofi-Synthelabo, New York, NY), and immunosuppressive agents, including cyclosporin, are sometimes used by specialists.

Adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) is characterized by impaired T-, B- and NK-cell function. Affected children, in addition to early onset of infections, manifest non-immunologic symptoms including pulmonary dysfunction likely attributable to elevated systemic adenosine levels. Lung disease assessment has primarily employed repetitive radiography and effort-dependent functional studies. Through impulse oscillometry (IOS), which is effort-independent, we prospectively obtained objective measures of lung dysfunction in 10 children with ADA-SCID. These results support the use of IOS in the identification and monitoring of lung function abnormalities in children with primary immunodeficiencies. Electronic supplementary material The online version of this article (doi:10.1186/s13023-015-0365-z) contains supplementary material, which is available to authorized users.

Tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS) is an autosomal dominant systemic autoinflammatory disease associated with heterozygous mutations in TNF receptor 1 (TNFR1). Here we examined the structural and functional alterations caused by 9 distinct TRAPS-associated TNFR1 mutations in transfected cells and a mouse “knock-in” model of TRAPS. We found that these TNFR1 mutants did not generate soluble versions of the receptor, either through membrane cleavage or in exosomes. Mutant receptors did not bind TNF and failed to function as dominant-negative inhibitors of TNFR1-induced apoptosis. Instead, TRAPS mutant TNFR1 formed abnormal disulfide-linked oligomers that failed to interact with wild-type TNFR1 molecules through the preligand assembly domain (PLAD) that normally governs receptor self-association. TRAPS mutant TNFR1 molecules were retained intracellularly and colocalized with endoplasmic reticulum (ER) markers. The capacity of mutant receptors to spontaneously induce both apoptosis and nuclear factor κB (NF-κB) activity was reduced. In contrast, the R92Q variant of TNFR1 behaved like the wild-type receptor in all of these assays. The inflammatory phenotype of TRAPS may be due to consequences of mutant TNFR1 protein misfolding and ER retention.

Allergic diseases are common in all age groups and locations around the world. In the United States, allergic diseases affect 20 to 40 million people annually, including 10% to 30% of adults and close to 40% of children. An estimated 15 million people in the United States have been diagnosed as having asthma, with this number on the rise. Concomitant asthma affects 67% of patients who have allergic rhinitis. As a result of the increase in ventilation during exercise, athletes in particular experience significant symptoms of allergy triggered by exposure to aeroallergens. The allergic response causes nasal and conjunctival congestion, tearing, breathing difficulties, pruritus, fatigue, and mood changes, which affect athletic performance. Systemic symptoms of anaphylaxis from allergy, although rare, can be life threatening. Several decades ago it was inconceivable that an athlete who had asthma could perform competitively, let alone win Olympic gold medals. Today, with proper diagnosis, education, and optimal therapeutic management, the allergic athlete can achieve great strides in all sports endeavors. To avoid seasonal allergic flares and maximize performance, the physician providing care for an athlete who has seasonal allergies must be aware of the climatic patterns of aeroallergen expression, and adjust exercise and pharmacologic regimens accordingly. This article summarizes the effects of allergic disease on exercise and highlights the challenges that seasonal allergy place on athletic performance. Doping considerations grant additional complexity to this issue and underscore the need for a competent, skillful, informed, and ethical approach to treating seasonal allergy in the competitive athlete.

Background & Aims Inflammatory bowel diseases (IBDs) (Crohn's disease [CD], ulcerative colitis) are global diseases. Similarities and differences in disease presentation and outcomes across different geographic regions and ethnic groups have not been compared previously. Methods We performed a systematic review and meta-analysis of population-based cohort studies examining the phenotype and outcome of IBD across ethnic groups categorized as Whites, Blacks, Hispanics, and Asians. Further stratification was performed by migration status (native or immigrant). Pooled proportions of disease location, behavior, medication, and surgery use were calculated by using a random-effects model and compared statistically. Results Our final analysis included 198 unique studies reporting outcomes on 525,425 IBD patients (Caucasian, 65%; Asian, 30%; Hispanic, 2%; and Black, 1%). CD in Asians but not other ethnicities demonstrated a strong male predominance. Family history of IBD was infrequent in Asian patients. Both Black and Asian CD patients demonstrated perianal involvement more frequently. Surgery for both CD and UC was less common in Asians than Caucasians. Compared with native residents, a family history of IBD was reported more often among immigrant IBD patients, but no significant differences were noted in phenotype. Conclusions We demonstrate significant variation in the demographic distribution, familial predisposition, phenotype, and outcomes of IBD between Caucasians, Blacks, Hispanics, and Asians. There is need for further study to understand the biology behind this variation.