Liver health and the interplay between obesity, alcohol and bariatric surgery.

The prevalence of obesity and metabolic consequences, including non-alcoholic fatty liver disease (NAFLD) has become a global health problem. Obesity has an important impact on chronic liver disease even beyond NAFLD, as it accelerates the progression of alcohol liver disease. Conversely, even moderate alcohol use can affect NAFLD disease severity. Weight loss is the gold standard treatment but adherence to lifestyle changes is very low in the clinical setting. Bariatric surgery can improve metabolic components and cause long-term weight loss. Therefore, bariatric surgery could serve as an attractive treatment option for NAFLD patients. A pitfall is the use of alcohol after bariatric surgery. This short review integrates data about the influence of obesity and alcohol on liver function and the role of bariatric surgery.

Diagnostic and prognostic scoring systems for autoimmune hepatitis: a review.

INTRODUCTION: Auto-immune hepatitis (AIH) is a rare condition which primarily affects young women. Several diagnostic scoring systems exist based on clinical, biochemical, immunologic and histologic characteristics of AIH. Additionally, prognostic parameters can be identified. The purpose of this literature review is to compare the clinical value, strengths and limitations of these diagnostic and prognostic scoring systems. METHODS: A literature search was performed in two databases and selected based on diagnostic and prognostic criteria. Only studies concerning AIH in adults were included. RESULTS: The backbone of scoring systems remains the revised AIH criteria published in 1999 and the simplified from 2008. The revised system shows a higher sensitivity, lower specificity and lower diagnostic accuracy compared to the simplified. Limitations to these scoring systems include limited diagnostic accuracy in acute or fulminant liver failure, insufficient inclusion of atypical auto-antibodies and lacking diagnostic power in presence of overlap syndromes. Concerning these overlap syndromes, the Paris criteria show a higher diagnostic accuracy compared to the scoring systems for AIH. Presently, no clinical prognostic scoring systems are available. However, a first system based on response to treatment accurately predicts long-term survival in AIH. CONCLUSION: Diagnostic scoring systems are useful in diagnosing AIH and have complementary value. However, they are no substitute for the gold standard of appropriate clinical assessment and are mostly useful in defining cohorts for research purposes. An evolution towards a more dynamic scoring system, using prognostic parameters and the progression of typical features, seems more valuable than the current diagnostic systems.

Recent advances in the approach to hepatopulmonary syndrome and portopulmonary hypertension.

Liver disease, cirrhosis and portal hypertension can be complicated by pulmonary vascular disease, which may affect prognosis and influence liver transplantation (LT) candidacy. Pulmonary vascular complications comprise hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH). Although these two conditions develop on a same background and share a common trigger, pulmonary responses are distinct and occur at different anatomical sites of the pulmonary circulation. HPS affects 10-30% of patients referred for LT, and is characterized by gas exchange abnormalities due to pulmonary vasodilation and right-to-left shunting. POPH occurs in 5%, and is defined by pulmonary arterial hypertension due to increased pulmonary vascular resistance, which leads to hemodynamic failure. Even though HPS and POPH may have a substantial negative impact on survival, both entities are clinically underrecognized and frequently misdiagnosed. Without intervention, the 5-year survival rate is 23% in HPS and 14% in POPH. Their presence should be actively sought by organized screening in patients presenting with dyspnea and in all patients on the waitlist for LT, also because clinical symptoms are commonly non-specific or even absent. LT may lead to resolution, however, advanced stages of either HPS or POPH may jeopardize safe and successful LT. This implicates the need of proper identification of HPS and POPH cases, as well as the need to be able to successfully 'bridge' patients to LT by medical intervention. A review article on this topic has been published in this journal in 2007 (1). This updated review focuses on recent advances in the diagnosis and management of these 2 liver-induced pulmonary vascular disorders and incorporates results from our recent work.

Angiogenesis in the progression of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and an increasing cause of liver cirrhosis and hepatocellular carcinoma. Angiogenesis, the formation of new blood vessels from pre-existing ones, is a key pathophysiological mechanism contributing to NAFLD progression. Major triggers for angiogenesis in NAFLD include tissue hypoxia, structural and dynamic endothelial cell dysfunction, stellate cell activation and macrophage-mediated inflammation. In turn, angiogenesis drives inflammation and is closely linked to the progression of liver fibrosis and the development of liver cancer. In particular, the molecular crosstalk between pro-angiogenic endothelial cells and activated stellate cells can result in a positive feedback loop in which angiogenesis and fibrosis develop in parallel. In this review, we highlight the molecular mechanisms, drivers and consequences of angiogenesis in the progression of NAFLD to NASH, fibrosis and hepatocellular carcinoma. Evidence from animal and clinical studies suggests that mediators of angiogenesis and endothelial dysfunction are promising disease biomarkers, and that inhibiting angiogenesis may improve the course of NAFLD.

Update on liver transplantation for cholangiocarcinoma : a review of the recent literature.

Cholangiocarcinoma (CC) represent 3% of all gastrointestinal tumours and can be classified anatomically in 3 types: intrahepatic (ICC), perihilar (PCC) and distal (DCC) cholangiocarcinomas. Resection is the treatment of choice but is only achieved in a few cases (<20%) because of invasion of the biliary tract and/or vascular structures. The outcome of advanced CC is poor with an overall survival (OS) of maximum 15 months with chemotherapy. In the 1990s, CC was regarded as a contraindication for liver transplantation (LT). LT has recently been proposed as potentially curative option for ICC and PCC. Careful patient selection has changed OS. This article provides an update on current status of LT for patients with unresectable CC.

The potential of glycomics as prognostic biomarkers in liver disease and liver transplantation.

The study of glycomics is a novel and fascinating approach for the development of biomarkers. It has become clear that in the field of liver disease specific glycomic patters are present in specific disease states, which has led to the development of diagnostic biomarkers. In this manuscript, we will describe two new applications of this technology for the development of prognostic biomarkers. The first biomarker is associated with the risk of hepatocellular carcinoma development in patients with compensated cirrhosis. The second biomarker is present in perfusate and is related to the risk of primary non function occurrence after liver transplantation. The technology used for these biomarkers could easily be implemented on routine capillary electrophoresis equipment.

Preclinical and Clinical Therapeutic Strategies Affecting Tumor-Associated Macrophages in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) most often develops in patients with underlying liver disease characterized by chronic nonresolving inflammation. Tumor-associated macrophages (TAMs) are one of the most abundant immune cell populations within the tumoral microenvironment. As key actors of cancer-related inflammation, they promote tumor growth by suppression of effective anticancer immunity, stimulation of angiogenesis, and tissue remodeling. Therefore, they have become an attractive and promising target for immunotherapy. The heterogeneity of TAM subtypes and their origin and dynamic phenotype during the initiation and progression of HCC has been partially unraveled and forms the base for the development of therapeutic agents. Current approaches are aimed at decreasing the population of TAMs by depleting macrophages present in the tumor, blocking the recruitment of bone marrow-derived monocytes, and/or functionally reprogramming TAMs to antitumoral behavior. In this review, the preclinical evolution and hitherto clinical trials for TAM-targeted therapy in HCC will be highlighted.

Hepatic Changes in the Fontan Circulation: Identification of Liver Dysfunction and an Attempt to Streamline Follow-up Screening.

We tried to identify structural and functional liver aberrances in a palliated Fontan population and sought to determine useful screening modalities, in order to propose a screening protocol to detect patients at risk. Twenty nine patients, median age 23.7 years (interquartile range (IQR) 20.5-27.2) and median Fontan interval 19.7 years (IQR 4.5-21.4), were prospectively studied with echocardiography, blood analysis (including serum fibrosis scores Forns, APRI and FIB4), liver imaging (ultrasound (US), Doppler), and shear wave elastography to determine liver stiffness (LS). Laboratory tests predominantly showed abnormal values for gamma-glutamyltransferase. Forns index indicated moderate fibrosis in 29% of patients and correlated with Fontan interval (p = 0.034). US liver morphology was deviant in 46% of patients, with surface nodularity in 21% and nodular hyperplasia in 29%. Doppler assessment of flow velocities was within normal ranges for most patients. LS (mean 10.4 ± 3.7 kPa) was elevated in 96% of our population and higher LS values were significantly related to longer Fontan interval (p = 0.018). Adolescent and adult Fontan patients show moderate signs of liver dysfunction. Usefulness of serum parameters and fibrosis scores in post-Fontan screening remains ambiguous. The high percentage of morphologic liver changes in palliated patients supports the use of US in periodic follow-up. LS likely overestimates fibrosis due to liver congestion, arguing for the need of validation through sequential measurements. Screening should minimally encompass US assessment in combination with selective liver fibrosis scores. The role of LS measurement in Fontan follow-up and liver screening needs to be further elucidated.

The Belgian Association for Study of the Liver Guidance Document on the Management of Adult and Paediatric Non-Alcoholic Fatty Liver Disease.

Non-Alcoholic Fatty Liver Disease (NAFLD) is highly prevalent and associated with considerable liver-related and non-liverrelated morbidity and mortality. There is, however, a lot of uncertainty on how to handle NAFLD in clinical practice. The current guidance document, compiled under the aegis of the Belgian Association for the Study of the Liver by a panel of experts in NAFLD, from a broad range of different specialties, covers many questions encountered in daily clinical practice regarding diagnosis, screening, therapy and follow-up in adult and paediatric patients. Guidance statements in this document are based on the available evidence whenever possible. In case of absence of evidence or inconsistency of the data, guidance statements were formulated based on consensus of the expert panel. This guidance document is intended as a help for clinicians (general practitioners and all involved specialties) to implement the most recent evidence and insights in the field of NAFLD within a Belgian perspective.

Serum vascular cell adhesion molecule-1 predicts significant liver fibrosis in non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and is strongly associated with obesity, dyslipidemia and insulin resistance. NAFLD often presents as simple steatosis (NAFL) but can progress to non-alcoholic steatohepatitis (NASH) and fibrosis. Current non-invasive biomarkers are not tailored to identify significant (⩾F2) fibrosis, although recent guidelines recommend a stringent follow-up of this patient population. We and others have reported on the role of pathological angiogenesis in the pathogenesis of NAFLD, highlighting pro-angiogenic factors as potential diagnostic markers. OBJECTIVE: To investigate the applicability of angiogenic and endothelial dysfunction markers as non-invasive diagnostic tools for NASH or NASH-associated fibrosis in obese patients. METHODS: In a prospective cross-sectional study, male patients undergoing bariatric surgery (n=61) and control patients (n=35) were recruited. Serum protein levels and visceral adipose tissue gene expression of endothelial dysfunction and angiogenic markers were analyzed by multiplex bead-based assay and quantitative RT-PCR, respectively. For validation, we recruited a second cohort of patients undergoing bariatric surgery (n=40) and a cohort of NAFLD patients from our outpatient clinic (n=30). RESULTS: We identified serum vascular cell adhesion molecule-1 (VCAM-1) as an independent predictor for ⩾F2 fibrosis (median 14.0 vs 8.7 ng ml-1 in patients with and without significant fibrosis; P<0.0001) with an area under the receiver-operating characteristics (AUROC) curve of 0.80. The cutoff point of 13.2 ng ml-1 showed a sensitivity of 80% and specificity of 83%. In line with these results, VCAM-1 visceral adipose tissue gene expression was also elevated in patients with fibrosis (P=0.030). In the bariatric surgery and clinical validation cohorts, VCAM-1 displayed similar AUROCs of 0.89 and 0.85, respectively. CONCLUSIONS: VCAM-1 levels are able to accurately predict significant (⩾F2) fibrosis in NAFLD patients.

Thermal tolerance in the keystone species Daphnia magna-a candidate gene and an outlier analysis approach.

Changes in temperature have occurred throughout Earth's history. However, current warming trends exacerbated by human activities impose severe and rapid loss of biodiversity. Although understanding the mechanisms orchestrating organismal response to climate change is important, remarkably few studies document their role in nature. This is because only few systems enable the combined analysis of genetic and plastic responses to environmental change over long time spans. Here, we characterize genetic and plastic responses to temperature increase in the aquatic keystone grazer Daphnia magna combining a candidate gene and an outlier analysis approach. We capitalize on the short generation time of our species, facilitating experimental evolution, and the production of dormant eggs enabling the analysis of long-term response to environmental change through a resurrection ecology approach. We quantify plasticity in the expression of 35 candidate genes in D. magna populations resurrected from a lake that experienced changes in average temperature over the past century and from experimental populations differing in thermal tolerance isolated from a selection experiment. By measuring expression in multiple genotypes from each of these populations in control and heat treatments, we assess plastic responses to extreme temperature events. By measuring evolutionary changes in gene expression between warm- and cold-adapted populations, we assess evolutionary response to temperature changes. Evolutionary response to temperature increase is also assessed via an outlier analysis using EST-linked microsatellite loci. This study provides the first insights into the role of plasticity and genetic adaptation in orchestrating adaptive responses to environmental change in D. magna.

The development of locomotor kinetics in the foal and the effect of osteochondrosis.

REASON FOR PERFORMING STUDY: Foals stand and walk immediately after birth, but insight into the subsequent longitudinal development of their gait kinetics in the early juvenile phase and the possible influence of osteochondrosis thereon is lacking. OBJECTIVES: To quantify gait kinetics in foals during the first half year of life, taking into account their osteochondrosis status. STUDY DESIGN: Prospective, cohort study performed at a single stud farm. METHODS: Pressure plate measurements at walk and trot from 11 Dutch Warmblood foals during the first 24 weeks of life were used to determine body mass normalised peak vertical force, normalised vertical impulse and stance duration. Coefficients of variation of peak vertical force and stance duration were used as measures for gait maturity. Radiographs of tarsocrural and femoropatellar joints were taken at age 4-6 weeks and after 6 months to check for osteochondrosis. A linear mixed model was used to determine the effects of age, limb, presence of osteochondrosis and speed on gait parameters. RESULTS: Mean walking and trotting velocity increased over time as did stance duration and normalised vertical impulse, normalised peak vertical force values however remained relatively constant. During the first weeks of their life only the coefficient of variation of stance duration decreased significantly, while the coefficient of variation of peak vertical force did not. None of the foals was visibly lame, but the presence of osteochondrosis resulted in a temporarily but significantly reduced normalised peak vertical force. MAIN LIMITATIONS: This study is a relatively small sample size of one breed from a single stud farm. A stand-alone pressure plate was used and body mass was estimated rather than measured. CONCLUSIONS: Despite being precocious, foals need time to mature their gait. During growth, velocity at walk and trot increases, but normalised peak vertical force remains relatively constant. Although not visibly lame, a temporary reduction in normalised peak vertical force was detected in osteochondrosis positive foals using a pressure plate.

Game Maturity Model for Health Care.

This article introduces the Game Maturity Model for the healthcare industry as an extension to the general Game Maturity Model and describes the usage by two case studies of applied health games. The Game Maturity Model for healthcare provides a practical and value-adding method to assess existing games and to determine strategic considerations for application of applied health games. Our forecast is that within 5 years the use and development of applied games will have a role in our daily lives and the way we organize health care that will be similar to the role social media has today.

Association of recently described adipokines with liver histology in biopsy-proven non-alcoholic fatty liver disease: a systematic review.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising, as is the prevalence of obesity and type 2 diabetes. It is increasingly recognized that an impaired pattern in adipokine secretion could play a pivotal role in the development of NAFLD. We performed a systematic review to evaluate the potential link between newly described adipokines and liver histology in biopsy-proven NAFLD patients. A computerized literature search was performed in PubMed, EMBASE and Web of Science electronic databases. Thirty-one cross-sectional studies were included, resulting in a total of seven different investigated adipokines. Studies included in this review mainly had a good methodological quality. Most adipokines were suggested to be involved in the inflammatory response that develops within the context of NAFLD, either at hepatic or systemic level, and/or hepatic insulin resistance. Based on literature, clinical studies suggest that chemerin, resistin and adipocyte-fatty-acid-binding protein potentially are involved in NAFLD pathogenesis and/or progression. However, major inconsistency still exists, and there is a high need for larger studies, together with the need of standardized assays to determine adipokine levels.

IgG4-related cholangitis: Case report and literature review.

CASE PRESENTATION: We describe a case of a patient who presents with jaundice, elevated cholestatic liver enzymes, an extreme weight loss and a midcholedochal stricture very suspect for a cholangiocarcinoma. In the conviction of malignancy, although the absence of anatomopathological prove, the patient underwent a choledochal resection. The anatomopathological specimen revealed no malignancy. In the year following resection, the patient keeps presenting with bile duct strictures and further weight loss. Ultimately the diagnosis of Ig G4-related cholangitis is withheld. Therapy with corticosteroids is initiated with a spectacular clinical, biochemical and radiographical result. DISCUSSION: IgG4-related cholangitis is the biliary presentation of IgG4-related disease, a recently discovered entity of fibroinflammatory masses which can affect virtually every organ in the body. It is characterized by a dense lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis and a presence of > 30 IgG4-positive plasma cells per high power field. Main differential diagnosis contains cholangiocarcinoma and primary sclerosing cholangitis. Corticoids are cornerstone of therapy, with azathioprine frequently used as a maintenance in case of relapse. CONCLUSIONS: With this case we want to draw the attention to a rather uncommon cause of biliary obstruction, easily mistaken for a cholangiocarcinoma.