Vanishing Bile Duct Syndrome Associated With Estrogen.

Vanishing bile duct syndrome (VBDS) refers to a form of cholestatic liver disease with many etiologies. Vanishing bile duct syndrome is characterized by biliary ductopenia and chronic cholestasis. This is a challenging condition for clinicians because of its rarity and unclear pathophysiology. Presented is an 18-year-old woman who developed cholestatic liver injury and intrahepatic biliary ductopenia after a course of oral contraceptives and intravenous estrogen for uterine bleeding. A year later, this patient did not have significant improvement in liver biomarkers and was referred for transplantation.

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.

Emerging drugs for the treatment of non-alcoholic steatohepatitis: a focused review of farnesoid X receptor agonists.

INTRODUCTION: The discovery of the farnesoid X receptor and its role in bile and lipid homeostasis has led to the investigation of FXR agonists as a therapy in cholestatic disorders and in NAFLD. With increasing prevalence of obesity and metabolic syndrome, NAFLD has grown to become the most prevalent chronic liver disease, present in a quarter of the worldwide population. FXR agonists represent a promising avenue for this burgeoning disease with few options for pharmacologic therapy. AREAS COVERED: A brief overview of the epidemiology of NAFLD/NASH and a review of current evidence on available treatments is provided. For FXR agonists, a review is performed of mechanisms of action, efficacy, and adverse effects. Finally, hurdles to widespread adoption of this drug class in treatment of NASH are described. Prospective clinical trials were reviewed on the US National Library of Medicine database at clinicaltrials.gov, along with a literature search of meta-analyses, reviews, and original research. EXPERT OPINION: FXR agonists show promise for treating NASH with positive effects on several surrogate markers of disease including liver fibrosis on biopsy, fat reduction on MRI, and decrease in liver enzymes. However, their long-term tolerability, safety, and efficacy on liver-related outcomes need to be established.

Obeticholic acid for the treatment of nonalcoholic steatohepatitis.

INTRODUCTION: NAFLD has grown to become the most prevalent liver disease in the world, with a quarter of the general population estimated to have the disease. NASH, characterized as NAFLD with inflammation, is associated with worsening fibrosis along with increased incidence of HCC. Despite high prevalence of this disease, no pharmacologic treatments approved by regulatory agencies are available. AREAS COVERED: This review briefly discusses present understanding of NASH pathology and currently available treatments. We also discuss data on the role of OCA as an FXR agonist in modulating disease in NASH. A comprehensive literature search of review articles, original research articles, and prospective clinical trials from 1998 to the present was performed. EXPERT OPINION: Based on 18-month interim findings of the REGENERATE trial, OCA likely improves fibrosis in NASH and therefore may have a beneficial effect in delaying or even preventing cirrhosis. The side effect of an atherogenic lipoprotein profile may adversely affect long-term outcomes, though studies have shown that co-administration of statins is able to mitigate this effect. OCA is likely to become an option for treatment, but the specific context within which it may be prescribed still needs to be clarified.

Current and potential treatments for primary biliary cholangitis.

Up to 40% of patients with primary biliary cholangitis have an incomplete response to first-line treatment with ursodeoxycholic acid. Obeticholic acid was approved by the US Food and Drug Administration in 2016 as a second-line treatment for patients with primary biliary cholangitis who are unresponsive to ursodeoxycholic acid; however, approximately 50% of patients might need additional treatments to reach therapeutic goals. A considerable need exists for effective treatment options to prevent progression to liver transplantation or death in these patients. Drugs that might modulate immunological abnormalities in primary biliary cholangitis have been studied but their effectiveness varies. Budesonide, ciclosporin, and rituximab have shown potential in modifying the disease process. Bezafibrate, a pan-peroxisome proliferator-activated receptor agonist, has been shown to ameliorate deranged bile acid homoeostasis and attenuate raised concentrations of liver enzymes associated with primary biliary cholangitis. As the mechanisms underlying the pathogenesis and progression of primary biliary cholangitis are further clarified, specific targeted therapies are under development with promising early results. Various therapeutic target bile acid homeostasis, immune dysfunction, and fibrogenetic pathways are being studied. A better understanding of the biochemical and clinical effects of the therapies in development bear discussion, both to guide the discovery of new therapies and to inform clinicians so that rational treatment regimens can be tailored to patients once they become available.

Mechanisms and Treatments of Pruritus in Primary Biliary Cholangitis.

Pruritus is a frustrating and sometimes debilitating symptom that commonly accompanies primary biliary cholangitis (PBC). The mechanism by which this symptom manifests remains elusive but extensive research has now shown that the itch is not just "weak pain" as had been the commonly held belief for decades. As this research now shines a light on the many diverse paths by which pruritus might be experienced, the necessity for a comprehensive approach to the symptom becomes clear. Understanding the interplay between the pathophysiology of PBC and delicately balanced neural circuitry is paramount to guiding the search for definitive treatment. Most relevant to providers today is the efficacy of currently available treatments and the side effects that may accompany them. Anion exchange resins, while remaining an important element in therapy, are no longer the only available medication to arrest pruritus. Rifampin, opioid antagonists, and other adjunctive therapies have quickly become a mainstay. Newer therapies such as the molecular adsorbent recycling system now also have a role in treatment. Increased recognition of these modalities may serve to alleviate the often debilitating pruritus experienced by patient suffering from PBC and might ultimately allow them to live more meaningful lives.

Transesophageal approach to lung, adrenal biopsy and fiducial placement using endoscopic ultrasonography (EUS): An interventional pulmonology experience. Initial experience of the UCSF-FRETOC (fresno tracheobronchial & oesophageal center) study group.

BACKGROUND: Routine lung cancer surveillance has resulted in early detection of pulmonary nodules and masses. Combined endobronchial ultrasound (EBUS) and trans-esophageal endoscopic ultrasound (EUS) are approved methods for sampling lymph nodes or masses. Furthermore, EUS allows for adrenal sampling as part of staging, and can assist with fiducial placement for stereotactic body radiation therapy (SBRT). OBJECTIVES: Promote use of EUS by interventional pulmonologists in the United States when diagnosing and staging lung cancer or when placing fiducials. METHODS: All patients undergoing EUS and/or EBUS were serially entered into a prospectively maintained database. Only patients undergoing EUS guided lung and/or adrenal biopsy and/or fiducial placement were selected for analysis. All patients underwent a post-procedure chest radiograph and were followed outpatient. RESULTS: 20 of 39 patients underwent sampling of a suspicious lung mass. An adequate sample was obtained in 19 of 20 patients. In all 19 patients a definitive diagnosis was achieved (95%). In all 13 patients who underwent adrenal sampling, presence or absence of metastasis was conclusively established. 6 patients successfully underwent fiducial placement. In all 39 patients, no major procedure related complications were noted for a period of 30 days. One patient had a small pneumothorax that resolved spontaneously. CONCLUSIONS: EUS can be safely performed by a trained interventional pulmonologist for the diagnosis of lung, adrenal masses and placement of fiducials. We think that interventional pulmonologists in the United States involved in lung cancer staging should receive training in EUS techniques.

Combined Endosonography Reduces Time to Diagnose Pulmonary Coccidioidomycosis.

Coccidioidomycosis causes significant morbidity in endemic areas. In the absence of sensitive diagnostic serologic testing, clinicians have increasingly relied on lung and lymph node biopsies for diagnosis. Recently, endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) has been shown to be an excellent sampling method for the diagnosis and staging of lung cancers, especially when combined with endoscopic ultrasound guided fine needle aspiration (EUS-FNA). We present 13 consecutive cases where EBUS-TBNA and/or EUS-FNA of pulmonary lymph nodes were performed as part of the workup for pulmonary coccidioidomycosis. EBUS-TBNA+EUS-FNA led to diagnosis in all nine cases in which they were performed concurrently, and in the remaining 4 in which either was performed individually. BAL was performed in all cases with positive results in 5 (38%). The mean time to diagnose by EBUS/EUS (1.6 d) was significantly shorter than by bronchoalveolar lavage (6.3 d) (P=0.003). The findings indicate that combined EBUS-TBNA+EUS-FNA for lymph node biopsy facilitates early and accurate diagnosis of pulmonary coccidioidomycosis.

Calcium influx through L-type CaV1.2 Ca2+ channels regulates mandibular development.

The identification of a gain-of-function mutation in CACNA1C as the cause of Timothy Syndrome (TS), a rare disorder characterized by cardiac arrhythmias and syndactyly, highlighted unexpected roles for the L-type voltage-gated Ca2+ channel CaV1.2 in nonexcitable cells. How abnormal Ca2+ influx through CaV1.2 underlies phenotypes such as the accompanying syndactyly or craniofacial abnormalities in the majority of affected individuals is not readily explained by established CaV1.2 roles. Here, we show that CaV1.2 is expressed in the first and second pharyngeal arches within the subset of cells that give rise to jaw primordia. Gain-of-function and loss-of-function studies in mouse, in concert with knockdown/rescue and pharmacological approaches in zebrafish, demonstrated that Ca2+ influx through CaV1.2 regulates jaw development. Cranial neural crest migration was unaffected by CaV1.2 knockdown, suggesting a role for CaV1.2 later in development. Focusing on the mandible, we observed that cellular hypertrophy and hyperplasia depended upon Ca2+ signals through CaV1.2, including those that activated the calcineurin signaling pathway. Together, these results provide new insights into the role of voltage-gated Ca2+ channels in nonexcitable cells during development.