https://www.naspghan.org/files/documents/pdfs/training/curriculum-resources/biliary-disease/aasld-guidelines/EASL_Cholestatic_Dz.pdf

EASL Clinical Practice Guidelines: management of cholestatic liver diseases

Emerging evidence points to a strong association between the gut microbiota and the risk, development and progression of gastrointestinal cancers such as colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Bile acids, produced in the liver, are metabolized by enzymes derived from intestinal bacteria and are critically important for maintaining a healthy gut microbiota, balanced lipid and carbohydrate metabolism, insulin sensitivity and innate immunity. Given the complexity of bile acid signalling and the direct biochemical interactions between the gut microbiota and the host, a systems biology perspective is required to understand the liver-bile acid-microbiota axis and its role in gastrointestinal carcinogenesis to reverse the microbiota-mediated alterations in bile acid metabolism that occur in disease states. An examination of recent research progress in this area is urgently needed. In this Review, we discuss the mechanistic links between bile acids and gastrointestinal carcinogenesis in CRC and HCC, which involve two major bile acid-sensing receptors, farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5). We also highlight the strategies and cutting-edge technologies to target gut-microbiota-dependent alterations in bile acid metabolism in the context of cancer therapy.

/pdf/bile-acid-microbiota-crosstalk-in-gastrointestinal-57g75bmlel.pdf

Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis.

Caloric excess and sedentary lifestyle have led to a global epidemic of obesity and metabolic syndrome. The hepatic consequence of metabolic syndrome and obesity, nonalcoholic fatty liver disease (NAFLD), is estimated to affect up to one-third of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Owing to the high prevalence of NAFLD, especially in industrialized countries but also worldwide, and the consequent burden of progressive liver disease, there is mounting epidemiological evidence that NAFLD has rapidly become a leading aetiology underlying many cases of hepatocellular carcinoma (HCC). In this Review, we discuss NAFLD-associated HCC, including its epidemiology, the key features of the hepatic NAFLD microenvironment (for instance, adaptive and innate immune responses) that promote hepatocarcinogenesis and the management of HCC in patients with obesity and associated metabolic comorbidities. The challenges and future directions of research will also be discussed, including clinically relevant biomarkers for early detection, treatment stratification and monitoring as well as approaches to therapies for both prevention and treatment in those at risk or presenting with NAFLD-associated HCC.

From NASH to HCC: current concepts and future challenges.

Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting β polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) α and β] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

Bile acid transporters

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.21287

Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency.

Objective To determine whether a solution of bupivacaine Marcain [Astra]), adrenaline and cocaine (MAC) is as safe and effective as tetracaine, adrenaline and cocaine (TAC) as topical anaesthesia for wound suturing. Design Double-blind, randomised, prospective trial. Setting Emergency departments of two tertiary referral hospitals (one specialising in paediatric care) in Adelaide, South Australia, between February 1992 and April 1994. Participants 181 patients, aged six or older, with simple dermal lacerations less than 5mm deep, not involving mucous membranes or areas with end-arterial blood supply. Interventions Patients received a weight-adjusted dose of either MAC or TAC. Outcome measures Needle-prick testing of wound for pain before suturing, pain ratings by patients and physicians during suturing, signs and symptoms of cocaine toxicity, wound complications and patient preference for topical anaesthesia. Results Topical anaesthesia was adequate for suturing in 73% of patients (83% or those with head wounds and 56% of those with extremity wounds). MAC and TAC did not differ significantly in efficacy overall or by wound location. Pain ratings from patients treated with MAC and TAC were comparable, as was patients acceptance of topical anesthesia (77%, MAC; 81%, TAC) and the incidence of adverse effects (4% infection rate overall). Conclusions Topical anesthesia is a safe and effective means of anaesthetising selected lacerations for suturing. As we found no significant differences in either the efficacy or safety of the two solutions, we believe that MAC can be substituted for the less readily available TAC whenever expedient.

Topical anaesthesia for minor lacerations: MAC versus TAC.

Aims
This article reports on the quantitative findings from a large mixed method study that determined the extent to which the provision of alternatives to an Emergency Department and Index of Relative Social Disadvantage score influenced non-urgent paediatric Emergency Department use.

Background
In Australia, there is an increasing use of Emergency Departments for the provision of non-urgent care that may be better serviced in the community. Further, despite the plethora of literature describing the characteristics of non-urgent users of Emergency Departments the link to social and community characteristics remains under explored.

Design
This 2010 retrospective analysis of the Hospital Admission Status data from the paediatric Emergency Department provided the information on attendance types and numbers along with postcode details. The postcodes in conjunction with Australia Bureau of Statistics data provided the levels of deprivation from the Index of Relative Social Deprivation scores.

Method
A logistic regression analysis determined the levels of influence of deprivation and General Practitioner or Nurse Practitioner provision on the use of Emergency Departments for non-urgent care.

Findings
Rates of use for non-urgent care is higher for populations who come from areas of deprivation and have limited primary care services, such as low levels of General Practitioners. Children from areas of high deprivation and limited access to primary care were up to six times more likely to use Emergency Department for non-urgent care.

Conclusions
Deprivation impacts on the use of paediatric Emergency Departments for non-urgent care even in countries like Australia where there is government subsidized health care.

Deprivation and its impact on non-urgent Paediatric Emergency Department use: are Nurse Practitioners the answer?

Objective: To determine the number of children with minimal and mild traumatic brain injury (TBI) and their demographic factors, causes, associated signs/symptoms and management.Methods: A cross-sectional analysis of consecutive presentations to a tertiary paediatric centre.Results: There were 2043 presentations of minimal and mild TBI over 3 years (minimal TBI = 79.7% [n = 1628]; mild TBI = 20.3% [n = 415]). Mean age was 5.12 years (SD = 5.14) with children ≤3 years comprising 53.2% (n = 1086). There was a bimodal distribution in mild TBI with peaks at 0–2 and 13–15 years. The male-to-female ratio was 1.6:1. Only 34.6% of GCS scores were documented. Falls caused most injury. Overall, 6.3% (n = 129) required hospital admission and 29.1% (n = 594) were reviewed clinically.Conclusion: Minimal and mild TBI is common, representing a significant burden on individuals, families and healthcare providers. High rates of follow-up impact on the healthcare system and warrant further investigation.

Jeremy Raftos

Papers

Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency.

Topical anaesthesia for minor lacerations: MAC versus TAC.

Deprivation and its impact on non-urgent Paediatric Emergency Department use: are Nurse Practitioners the answer?

Minimal and mild paediatric brain injury: A 3-year cohort of consecutive presentations

Hepatocellular malignancy in ABCB11/BSEP disease (progressive familial intrahepatic cholestasis, type 2): Four patients.