Investigational farnesoid X receptor agonists for the treatment of primary biliary cholangitis.

INTRODUCTION: Up to 40% of Primary biliary cholangitis (PBC) patients have a suboptimal response to Ursodeoxycholic acid (UDCA). Close to half of such patients show a remarkable improvement when additionally treated with Obeticholic acid (OCA) but have a dose-dependent increase of pruritus. This relative success of OCA, a first-in-class Farnesoid receptor (FXR) agonist, has positioned FXR as an attractive target for drug development. Novel candidates have since emerged, providing hope for this subgroup of patients who lack effective and safe treatments. AREAS COVERED: We discussed the role of bile acids in PBC pathogenesis and how the FXR agonists provide therapeutic value by affecting bile acid synthesis and transport. Novel FXR agonists undergoing pre-clinical and clinical trials for PBC were enlisted via literature search by including the terms 'FXR agonists,' 'FXR PBC,' 'PBC clinical trials' on PubMed, MEDLINE via Ovid, and Clinicaltrials.gov. EXPERT OPINION: Novel FXR agonists currently under investigation for PBC improve the disease surrogate markers in early trials. However, as with OCA, pruritus remains a concern with the newer drugs despite targeted chemical modifications to increase FXR specificity. Directing future resources toward studying the molecular mechanisms behind pruritus may lead to better drug design and efficacious yet safer drugs.

Serum miRNA profiles are altered in patients with primary sclerosing cholangitis receiving high-dose ursodeoxycholic acid.

Background & Aims: Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease that can lead to end-stage liver disease and cholangiocarcinoma. High-dose ursodeoxycholic acid (hd-UDCA, 28-30 mg/kg/day) was evaluated in a previous multicentre, randomised placebo-controlled trial; however, the study was discontinued early because of increased liver-related serious adverse events (SAEs), despite improvement in serum liver biochemical tests. We investigated longitudinal changes in serum miRNA and cytokine profiles over time among patients treated with either hd-UDCA or placebo in this trial as potential biomarkers for PSC and response to hd-UDCA, as well as to understand the toxicity associated with hd-UDCA treatment. Methods: Thirty-eight patients with PSC were enrolled in a multicentred, randomised, double-blinded trial of hd-UDCA vs. placebo. Results: Significant alterations in serum miRNA profiles were found over time in both patients treated with hd-UDCA or placebo. Additionally, there were striking differences between miRNA profiles in patients treated with hd-UDCA compared with placebo. In patients treated with placebo, the changes in concentration of serum miRNAs miR-26a, miR-199b-5p, miR-373, and miR-663 suggest alterations of inflammatory and cell proliferative processes consistent with disease progression. However, patients treated with hd-UDCA exhibited a more pronounced differential expression of serum miRNAs, suggesting that hd-UDCA induces significant cellular miRNA changes and tissue injury. Pathway enrichment analysis for UDCA-associated miRNAs suggested unique dysregulation of cell cycle and inflammatory response pathways. Conclusions: Patients with PSC have distinct miRNAs in the serum and bile, although the implications of these unique patterns have not been studied longitudinally or in relation to adverse events related to hd-UDCA. Our study demonstrates marked changes in miRNA serum profiles with hd-UDCA treatment and suggests mechanisms for the increased liver toxicity with therapy. Impact and implications: Using serum samples from patients with PSC enrolled in a clinical trial comparing hd-UDCA with placebo, our study found distinct miRNA changes in patients with PSC who are treated with hd-UDCA over a period of time. Our study also noted distinct miRNA patterns in patients who developed SAEs during the study period.

Hepcidin Signaling in Health and Disease: Ironing Out the Details.

Hepcidin, a peptide hormone produced by hepatocytes, is the central regulator of systemic iron homeostasis through its interaction with ferroportin, the major cellular iron export protein. Hepcidin binding to ferroportin results in reduced iron export from macrophages and intestinal absorptive cells, leading to decreased serum iron levels. Hepcidin expression is influenced by several factors that include serum and liver iron stores, erythropoiesis, hypoxia, inflammation, and infection. Erythropoietic drive and hypoxia suppress hepcidin expression and promote red cell production. In contrast, inflammation and infection are associated with increased hepcidin production to sequester iron intracellularly as a means of depriving microorganisms of iron. Chronic inflammation may up-regulate hepcidin expression through the interleukin-6 (IL-6)-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway. The bone morphogenetic protein (BMP)-mothers against decapentaplegic homolog (SMAD) pathway is a major positive driver of hepcidin expression in response to either increased circulating iron in the form of transferrin or iron loading in organs. Hereditary hemochromatosis (HH) consists of several inherited disorders that cause inappropriately reduced hepcidin expression in response to body iron stores, leading to increased iron absorption from a normal diet. The most common form of HH is due to a mutation in the HFE gene, which causes a failure in the hepatocyte iron-sensing mechanism, leading to reduced hepcidin expression; the clinical manifestations of HFE-HH include increased serum transferrin-iron saturation and progressive iron loading in the liver and other tissues over time among patients who express the disease phenotype. In this article, we review the physiologic mechanisms and cellular pathways by which hepcidin expression is regulated, and the different forms of HH resulting from various mutations that cause hepcidin deficiency. We also review other drivers of hepcidin expression and the associated pathophysiologic consequences.

Investigational drugs in early phase development for primary biliary cholangitis.

Introduction: With a large percentage of patients having an incomplete response or intolerance to current FDA approved medications, new therapies for the treatment of primary biliary cholangitis are in great demand. Areas covered: In this review, we assess currently available drugs as well as promising new therapies for the treatment of primary biliary cholangitis. A literature search was performed with the following search terms: 'PBC treatment,' 'PBC therapeutics,' 'PBC clinical trials,' and included original articles, meta-analyses, and systematic reviews from 1 January 1981, to 1 January 2020. ClinicalTrials.gov was accessed for data from ongoing trials. Expert opinion: Targeted drug therapies offer an alternative for patients who are unable to meet their therapeutic goals with either of the two currently approved treatment options. Specifically, new drugs targeting bile-acid regulation, immune-modulation, and fibrogenic pathways are currently in development with multiple agents showing encouraging early results with the ultimate goal of developing therapies that will achieve high rates of biochemical remission, will be well tolerated, and improve symptoms and quality of life in patients with primary biliary cholangitis. Based on a review of the current literature, PPAR agonists appear to be promising agents, along with FGF19 analogs and FXR agonists.

Rectal indomethacin reduces the risk of post-endoscopic retrograde cholangiopancreatography pancreatitis in low-risk patients.

BACKGROUND: Evidence shows that rectal indomethacin (RI) reduces the risk of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in high-risk patients. The prophylactic role of RI in low-risk patients has not yet been identified. The objective of our study was to evaluate the impact of RI in preventing PEP in low-risk patients. METHODS: A retrospective cohort study was conducted to evaluate the impact of RI in preventing PEP. RI was available starting November 2012. Patient characteristics and procedure details were collected. RESULTS: The study population included 2238 patients who underwent ERCP (1055 in the RI group and 1183 in the control group). PEP was diagnosed in 107 patients (4.8%). In a multivariate model of consecutive patients, RI reduced the incidence of PEP by 55% (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.36-0.94; P=0.03). In a multivariate model that included 1874 (84%) low-risk patients, RI reduced the incidence of PEP by 62% (OR 0.38, 95%CI 0.19-0.74; P=0.004). Propensity-matched group analysis was performed for low-risk native papilla patients. RI reduced the incidence of PEP by 61% (OR 0.39, 95%CI 0.18-0.8; P=0.009). CONCLUSION: RI reduced PEP in consecutive as well as low-risk patients. RI should be administrated in consecutive patients unless contraindicated. Larger prospective studies are needed to confirm our results.

Primary Sclerosing Cholangitis: Epidemiology, Genetics, Diagnosis, and Current Management.

http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-reading-gochanour a video presentation of this article http://aasldpubs.onlinelibrary.wiley.com/hub/journal/10.1002/(ISSN)2046-2484/video/15-3-interview-kowdley an interview with the author.

Current perspectives into the evaluation and management of hepatitis B: a review.

Hepatitis B is a widespread disease which affects millions of people worldwide. Chronic hepatitis B (CHB) can lead to significant morbidity and mortality due to complications such as cirrhosis and hepatocellular carcinoma. The pathophysiology of hepatitis is critical to diagnosing CHB. Deciding which patients with CHB should be treated is an important decision as treatment can often lead to better outcomes in the appropriate patient population. The nucleos(t)ide analog inhibitors entecavir and tenofovir are currently the mainstay of treatment as they are able to successfully suppress the virus and lead to fewer complications. Novel therapies are currently being developed which may offer a potential cure for this disease in the future.

Impact of body mass index on the incidence and severity of post-endoscopic retrograde cholangiopancreatography pancreatitis.

BACKGROUND: Pancreatitis is a potential major complication after endoscopic retrograde cholangiopancreatography (post-ERCP pancreatitis; PEP). Obesity has been associated with increased severity of acute pancreatitis. However, the correlation between obesity and PEP is controversial. Therefore, our study aimed to clarify the relationship between body mass index (BMI) and the incidence and severity of PEP. METHODS: A retrospective cohort study was conducted to elucidate the relationship between BMI and PEP in all patients who underwent ERCP in a tertiary referral center between January 2009 and October 2016. Patient characteristics and procedure details were collected. PEP was defined by consensus criteria. Multivariate logistic regression was used to determine the association between BMI and PEP. RESULTS: The analysis included 2236 patients whose BMI was recorded and had adequate follow up (921 with BMI≥30 kg/m2, 1315 with BMI<30 kg/m2). PEP was diagnosed in 107 (4.8%) patients. PEP was seen in 49 obese patients (5.3%) and 58 non-obese patients (4.4%). In the univariate and multivariate analysis BMI≥30 kg/m2 was not associated with PEP (odds ratio 1.2, 95%CI 0.8-1.8; P=0.32). A subgroup analysis of different BMI subcategories found that BMI was not associated with the incidence or severity of PEP. CONCLUSION: In the largest study to date, neither obesity nor low body weight increased the incidence or severity of PEP.

Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis.

We have previously demonstrated that iron overload in hepatic reticuloendothelial system cells (RES) is associated with severe nonalcoholic steatohepatitis (NASH) and advanced fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). Recruited myeloid-derived macrophages have gained a pivotal position as drivers of NASH progression and fibrosis. In this study, we used bone marrow-derived macrophages (BMDM) from C57Bl6 mice as surrogates for recruited macrophages and examined the effect of iron on macrophage polarization. Treatment with iron (ferric ammonium citrate, FAC) led to increased expression levels of M1 markers: CCL2, CD14, iNOS, IL-1ß, IL-6, and TNF-α; it also increased protein levels of CD68, TNF-α, IL-1ß, and IL-6 by flow cytometry. This effect could be reversed by desferrioxamine, an iron chelator. Furthermore, iron loading of macrophages in the presence of IL-4 led to the down-regulation of M2 markers: arginase-1, Mgl-1, and M2-specific transcriptional regulator, KLF4. Iron loading of macrophages with IL-4 also resulted in reduced phosphorylation of STAT6, another transcriptional regulator of M2 activation. Dietary iron overload of C57Bl6 mice led to hepatic macrophage M1 activation. Iron overload also stimulated hepatic fibrogenesis. Histologic analysis revealed that iron overload resulted in steatohepatitis. Furthermore, NAFLD patients with hepatic RES iron deposition had increased hepatic gene expression levels of M1 markers, IL-6, IL-1ß, and CD40 and reduced gene expression of an M2 marker, TGM2, relative to patients with hepatocellular iron deposition pattern. We conclude that iron disrupts the balance between M1/M2 macrophage polarization and leads to macrophage-driven inflammation and fibrogenesis in NAFLD.

Fiducial placement for recurrent gastric cancer.

A 53-year-old male was diagnosed with invasive adenocarcinoma of the pre-pyloric region. Imaging studies ruled out metastatic disease. The patient underwent neo-adjuvant chemotherapy followed by a partial gastrectomy. CT scan at 18 months' post-resection demonstrated right upper quadrant lesions suspicious for metastatic disease. EUS exam shows two round hypoechoic lesions. Fine needle aspiration with suction was performed with on-site cytology confirming malignant cells in the masses. Five gold fiducial markers were placed. Final pathology confirmed adenocarcinoma. The patient was subsequently started on stereotactic body radiation therapy (SBRT) with good results. This is the first case report EUS-guided fiducial markers for recurrent gastric cancer post-gastrectomy.

Clinical outcomes of hemiarthroplasty and biological resurfacing in patients aged younger than 50 years.

BACKGROUND: Total shoulder arthroplasty as a treatment for glenohumeral degenerative joint disease is well accepted but has been less predictable with regard to outcomes and durability in a younger aged population, typically aged younger than 50 years. This younger population has a greater potential for glenoid component loosening. This has led surgeons to perform hemiarthroplasty or hemiarthroplasty with biological resurfacing of the glenoid in an effort to avoid the potential problems with a polyethylene glenoid and obtain durable and acceptable results for these patients. METHODS: The study included 44 patients, with 23 undergoing hemiarthroplasty alone and 21 undergoing hemiarthroplasty with biological resurfacing of the glenoid. All patients were aged younger than 50 years. Preoperative diagnoses, comorbidities, demographics, and range of motion were collected. Preoperative and postoperative radiographs were obtained. Preoperative and postoperative objective scoring measures (Single Assessment Numeric Evaluation, American Shoulder and Elbow Surgeons score, visual analog scale, Simple Shoulder Test, Constant-Murley) were used. RESULTS: Mean follow-up was 3.8 years for the hemiarthroplasty group and 3.6 years for the biological resurfacing group. Six patients in the hemiarthroplasty and 12 patients in the biological resurfacing group were considered failures due to revision surgery or an American Shoulder and Elbow Surgeons score <50. The hemiarthroplasty group had significantly better visual analog scale and Single Assessment Numeric Evaluation scores. CONCLUSIONS: There was a significant failure rate in the hemiarthroplasty and the biologic resurfacing groups compared with results in the literature. Improved outcomes and lower failure rates were observed in the hemiarthroplasty group compared with the biological resurfacing group in this study.

Glenohumeral joint injections: a review.

CONTEXT: Intra-articular injections into the glenohumeral joint are commonly performed by musculoskeletal providers, including orthopaedic surgeons, family medicine physicians, rheumatologists, and physician assistants. Despite their frequent use, there is little guidance for injectable treatments to the glenohumeral joint for conditions such as osteoarthritis, adhesive capsulitis, and rheumatoid arthritis. EVIDENCE ACQUISITION: We performed a comprehensive review of the available literature on glenohumeral injections to help clarify the current evidence-based practice and identify deficits in our understanding. We searched MEDLINE (1948 to December 2011 [week 1]) and EMBASE (1980 to 2011 [week 49]) using various permutations of intra-articular injections AND (corticosteroid OR hyaluronic acid) and (adhesive capsulitis OR arthritis). RESULTS: We identified 1 and 7 studies that investigated intra-articular corticosteroid injections for the treatment of osteoarthritis and adhesive capsulitis, respectively. Two and 3 studies investigated the use of hyaluronic acid in osteoarthritis and adhesive capsulitis, respectively. One study compared corticosteroids and hyaluronic acid injections in the treatment of osteoarthritis, and another discussed adhesive capsulitis. CONCLUSION: Based on existing studies and their level of evidence, there is only expert opinion to guide corticosteroid injection for osteoarthritis as well as hyaluronic acid injection for osteoarthritis and adhesive capsulitis.

Arthroscopic repair for posterior shoulder instability.

PURPOSE: The purpose of this study was to evaluate outcomes of a consistent arthroscopic stabilization technique for recurrent posterior instability. METHODS: Thirty-four consecutive shoulders with symptomatic recurrent posterior instability were treated with arthroscopic repair and evaluated at a mean follow-up of 36 months (range, 12 to 67 months). Two patients were excluded because of prior surgery, leaving 32 for further analysis. The mean age was 21.4 years (range, 15 to 33 years). There were 26 male and 6 female patients, and in 59% the dominant shoulder was affected. A known traumatic injury had occurred in 25 (78%), but only 2 (6%) had a documented dislocation. Arthroscopic repair was performed with the patient in the lateral decubitus position through an anterosuperior 12-o'clock viewing portal. Suture anchor repairs were performed in 30 cases and plication to the intact labrum in 4. A sling and derotation wedge were used for 4 weeks, followed by progressive active range of motion, with weight lifting at 3 months and return to contact sports at 6 months. Of the 34 cases, 22 met the inclusion and exclusion criteria and had complete preoperative and postoperative shoulder outcome scores. RESULTS: Significant improvement (P = .001) from preoperatively to final follow-up was seen for American Shoulder and Elbow Surgeons scores, from 68 to 93; Simple Shoulder Test scores, from 9.3 to 11.6; and visual analog scale scores, from 3.5 to 0.8. All patients returned to their previous level of athletic activity. Two patients reported postoperative instability; none required reoperation. There were no other postoperative complications. CONCLUSIONS: This study represents a consecutive series of patients with recurrent posterior instability who underwent arthroscopic posterior stabilization. In this population arthroscopic posterior labral repair and capsular plication provided significant clinical improvement and low rates of recurrent instability and revision surgery. LEVEL OF EVIDENCE: Level IV, therapeutic case series.