The Metabolic Role of the Microbiome: Implications for NAFLD and the Metabolic Syndrome.

Nonalcoholic fatty liver disease (NAFLD) has rapidly emerged as one of the most prevalent liver diseases worldwide and is set to achieve virtually epidemic proportions if current trends in obesity continue. A considerable volume of data from animal experiments has revealed the magnitude of the metabolic contribution of the gut microbiome and how a disordered microbial population could contribute to the development of obesity and its complications, including NAFLD. Although considerable progress has been made in developing a role for the microbiome in NAFLD and nonalcoholic steatosis (NASH), there are still many issues to be resolved, including the nature and location of the altered microbiome (i.e., small intestine or colon, or both); the specificity of deficits in intestinal integrity to NAFLD/NASH versus liver disease in general; the metabolic pathways, in man, that are key to the influence of the microbiome; and finally, the therapeutic interventions that are likely to be of benefit to our patients.As always, the situation in man is somewhat more complex than in animal models, but the role of the microbiota and of interventions that modulate the microbiome, though not yet ready for clinical practice, continue to be fertile areas for basic and clinical research.

Efficacy and cost-effectiveness of voriconazole prophylaxis for prevention of invasive aspergillosis in high-risk liver transplant recipients.

Aspergillus infection remains a significant and deadly complication after liver transplantation (LT). We sought to determine whether the antifungal prophylactic use of voriconazole reduces the incidence of invasive aspergillosis (IA) in high-risk LT recipients without prohibitively increasing cost. During the study era (April 2008 to April 2014), 339 deceased donor LTs were performed. Of those patients, 174 high-risk recipients were administered antifungal prophylaxis with voriconazole. The median biological Model for End-Stage Liver Disease score at the time of LT was 33 (range, 18-49) with 56% requiring continuous renal replacement therapy and 50% requiring ventilatory support immediately before transplantation. Diagnosis of IA was stratified as proven, probable, or possible according to previously published definitions. No IA was documented in patients receiving voriconazole prophylaxis. At 90 days after LT, the institutional cost of prophylaxis was $5324 or 5.6% of the predicted cost associated with post-LT aspergillosis. There was no documentation of resistant strains isolated from any recipient who received voriconazole. In conclusion, these data suggest that voriconazole prophylaxis is safe, clinically effective, and cost-effective in high-risk LT recipients.

The Gut Microbiota and Nonalcoholic Fatty Liver Disease.

With the recognition of the various metabolic functions of the gut microbiome and of its putative role in obesity, an investigation of the contribution of the bacterial populations of the gastrointestinal tract to the metabolic syndrome and its hepatic manifestation-nonalcoholic liver disease (NAFLD)-became inevitable. Furthermore, the central role of an altered microbiome in the precipitation of infectious and noninfectious complications of liver disease was described decades ago. The contribution of the microbiome to the pathogenesis of NAFLD has been extensively studied in animal models. Convincing evidence for a central role for an altered microbiome (through multiple mechanisms), coupled with such phenomena as impaired gut barrier function and an aberrant host immune response, has been amply demonstrated. The accumulation of a similar level of evidence from human studies has proven more challenging; however, incriminating data accumulate. Although animal studies have demonstrated the benefits of interventions that modulate the microbiome and of probiotics, in particular, in reducing steatosis and preventing progression to steatohepatitis, data in man are scanty and high-quality clinical trials of probiotics and other strategies are needed.

Comparison of anti-Xa and activated partial thromboplastin time monitoring for heparin dosing in patients with cirrhosis.

BACKGROUND: Cirrhosis of the liver results in complex hemostatic changes that place patients at risk for both bleeding and thrombotic events. This study evaluates the adverse effects of anticoagulation with unfractionated heparin among patients with cirrhosis and analyzes the discrepancy between anti-Xa and activated partial thromboplastin time (aPTT) values for heparin monitoring among cirrhotics. METHODS: Patients with cirrhosis receiving unfractionated heparin were matched 2:1 to patients without evidence of cirrhosis anticoagulated with unfractioned heparin. Markers of bleeding events including blood product administration and use of heparin reversal were analyzed between groups. Patients from both groups with aPTT and anti-Xa values obtained at the same time were also analyzed. RESULTS: A higher incidence of blood product administration or use of heparin reversal was observed among patients with cirrhosis [35/105 (33.3%) versus 37/210 (17.6%), P = 0.002]. This finding was consistent among those receiving anticoagulation through an established anti-Xa-based heparin dosing protocol [23/62 (37.1%) versus 25/124 (20.2%), P = 0.013]. A decrease in hemoglobin greater than 2 g/dL or a platelet decrease 50% or greater from baseline was also more frequently identified among cirrhotics when receiving heparin therapy [20/105 (19%) versus 23/210 (11%), P = 0.049 and 21/105 (20%) versus 12/210 (6%), P < 0.001, respectively]. A total of 88 correlated anti-Xa and aPTT values from 35 patients with cirrhosis demonstrated supratherapeutic aPTT values for anti-Xa levels within the therapeutic range (P < 0.001). This discrepancy was not observed among controls. CONCLUSIONS: A greater use of blood products among the cirrhotic population may indicate potential bleeding events on therapy. A discrepancy in correlated anti-Xa and aPTT values among patients with cirrhosis may explain the propensity for adverse effects. Further study is required to identify effective heparin anticoagulation monitoring strategies in liver disease.

Targeting the microbiota in the management of gastrointestinal and liver disease.

Thanks to rapid advances in technology the details of the human microbiome and its functions in health and disease are being progressively revealed. Though many reports have linked various disease states with an altered microbiome and while some associations between the microbiome and disease states are well established, many of these studies are largely descriptive and the changes reported in the microbiome have yet to be shown to be causative. A number of strategies are available to modify the microbiota; some such as the use of antibiotics for specific indications, are well established, others such as the use of probiotics and prebiotics in a variety of disease states are supported by more limited data. Fecal transplantation has emerged as an exciting, albeit rather drastic, intervention for intestinal and, perhaps, other disorders. Other approaches, such as the isolation, purification and formulation of small molecules with specific biological actions, derived from the microbiota look very promising.

Outcomes of Liver Transplantation for Hepatocellular Carcinoma Beyond the University of California San Francisco Criteria: A Single-center Experience.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor. Currently, liver transplantation may be the optimal treatment for HCC in cirrhotic patients. Patient selection is currently based on tumor size. We developed a program to offer liver transplantation to selected patients with HCC outside of traditional criteria. METHODS: Retrospective review for patients transplanted with HCC between April 2008 and June 2017. Patients were grouped by tumor size according to Milan, University of California San Francisco (UCSF), and outside UCSF criteria. Patient demographics, laboratory values, and outcomes were compared. Patients radiographically outside Milan criteria were selected based on tumor control with locoregional therapy (LRT) and 9 months of stability from LRT. α-fetoprotein values were not exclusionary. RESULTS: Two hundred twenty HCC patients were transplanted, 138 inside Milan, 23 inside UCSF, and 59 beyond UCSF criteria. Patient survival was equivalent at 1, 3, or 5 years despite pathologic tumor size. Waiting time to transplantation was not significantly different at an average of 344 days. In patients outside UCSF, tumor recurrence was equivalent to Milan and UCSF criteria recipients who waited >9 months from LRT. Although tumor recurrence was more likely in outside of UCSF patients (3% versus 9% versus 15%; P = 0.02), recurrence-free survival only trended toward significance among the groups (P = 0.053). CONCLUSIONS: Selective patients outside of traditional size criteria can be effectively transplanted with equivalent survival to patients with smaller tumors, even when pathologic tumor burden is considered. Tumor stability over time can be used to help select patients for transplantation.

Liver transplantation for locally advanced intrahepatic cholangiocarcinoma treated with neoadjuvant therapy: a prospective case-series.

BACKGROUND: At present, intrahepatic cholangiocarcinoma is a contraindication for liver transplantation. However, previous studies in this field did not preselect patients on the basis of chemosensitivity or disease trajectory after neoadjuvant therapy. Experience with hilar cholangiocarcinoma has indicated that neoadjuvant therapy followed by liver transplantation in patients without disease progression results in a long-term survival benefit. We aimed to establish the potential efficacy of liver transplantation in patients with biologically responsive intrahepatic cholangiocarcinoma who have had sustained tumour stability or regression with neoadjuvant therapy. METHODS: In this prospective case-series, patients with locally advanced, unresectable intrahepatic cholangiocarcinoma, without extrahepatic disease or vascular involvement, were treated at a single liver transplant centre according to a non-randomised, centre-approved clinical management protocol with neoadjuvant chemotherapy followed by liver transplantation. Neoadjuvant therapy consisted of gemcitabine-based chemotherapy, such as gemcitabine-cisplatin or gemcitabine-capecitabine, with second-line or third-line therapies given per institutional standards. Patients with a minimum of 6 months of radiographic response or stability were listed for liver transplantation. The primary endpoints were overall survival and recurrence-free survival after liver transplantation, assessed with Kaplan-Meier analysis. This report includes interim data from the initial case-series treated under this ongoing clinical management protocol, censored on Dec 1, 2017. FINDINGS: Between Jan 1, 2010, and Dec 1, 2017, 21 patients were referred for evaluation and 12 patients were accepted, of whom six patients have undergone liver transplantation for intrahepatic cholangiocarcinoma. Three patients received livers from extended criteria deceased donors that would otherwise have been discarded, two from domino living donors, and one from a standard criteria liver donor. Median duration from diagnosis to transplantation was 26 months (IQR 17-33) and median follow-up from transplantation was 36 months (29-51). All patients received neoadjuvant chemotherapy while awaiting liver transplantation. Overall survival was 100% (95% CI 100-100) at 1 year, 83·3% (27·3-97·5) at 3 years, and 83·3% (27·3-97·5) at 5 years. Three patients developed recurrent disease at a median of 7·6 months (IQR 5·8-8·6) after transplantation, with 50% (95% CI 11·1-80·4) recurrence-free survival at 1, 3, and 5 years. Adverse events after liver transplantation included one patient with postoperative ileus (grade 3) and one patient with acute kidney injury requiring temporary dialysis (grade 4). INTERPRETATION: Selected patients with locally advanced intrahepatic cholangiocarcinoma who show pre-transplant disease stability on neoadjuvant therapy might benefit from liver transplantation. FUNDING: None.

TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury.

Tissue-resident immune cells play a key role in local and systemic immune responses. The liver, in particular, hosts a large number of invariant natural killer T (iNKT) cells, which are involved in diverse immune responses. However, the mechanisms that regulate survival and homeostasis of liver iNKT cells are poorly defined. Here we have found that liver iNKT cells constitutively express the costimulatory TNF superfamily receptor OX40 and that OX40 stimulation results in massive pyroptotic death of iNKT cells, characterized by the release of potent proinflammatory cytokines that induce liver injury. This OX40/NKT pyroptosis pathway also plays a key role in concanavalin A-induced murine hepatitis. Mechanistically, we demonstrated that liver iNKT cells express high levels of caspase 1 and that OX40 stimulation activates caspase 1 via TNF receptor-associated factor 6-mediated recruitment of the paracaspase MALT1. We also found that activation of caspase 1 in iNKT cells results in processing of pro-IL-1ß to mature IL-1ß as well as cleavage of the pyroptotic protein gasdermin D, which generates a membrane pore-forming fragment to produce pyroptotic cell death. Thus, our study has identified OX40 as a death receptor for iNKT cells and uncovered a molecular mechanism of pyroptotic cell death. These findings may have important clinical implications in the development of OX40-directed therapies.

Hepatocellular carcinoma: a review.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a leading cause of cancer-related death worldwide. In the United States, HCC is the ninth leading cause of cancer deaths. Despite advances in prevention techniques, screening, and new technologies in both diagnosis and treatment, incidence and mortality continue to rise. Cirrhosis remains the most important risk factor for the development of HCC regardless of etiology. Hepatitis B and C are independent risk factors for the development of cirrhosis. Alcohol consumption remains an important additional risk factor in the United States as alcohol abuse is five times higher than hepatitis C. Diagnosis is confirmed without pathologic confirmation. Screening includes both radiologic tests, such as ultrasound, computerized tomography, and magnetic resonance imaging, and serological markers such as α-fetoprotein at 6-month intervals. Multiple treatment modalities exist; however, only orthotopic liver transplantation (OLT) or surgical resection is curative. OLT is available for patients who meet or are downstaged into the Milan or University of San Francisco criteria. Additional treatment modalities include transarterial chemoembolization, radiofrequency ablation, microwave ablation, percutaneous ethanol injection, cryoablation, radiation therapy, systemic chemotherapy, and molecularly targeted therapies. Selection of a treatment modality is based on tumor size, location, extrahepatic spread, and underlying liver function. HCC is an aggressive cancer that occurs in the setting of cirrhosis and commonly presents in advanced stages. HCC can be prevented if there are appropriate measures taken, including hepatitis B virus vaccination, universal screening of blood products, use of safe injection practices, treatment and education of alcoholics and intravenous drug users, and initiation of antiviral therapy. Continued improvement in both surgical and nonsurgical approaches has demonstrated significant benefits in overall survival. While OLT remains the only curative surgical procedure, the shortage of available organs precludes this therapy for many patients with HCC.

Gastrointestinal bleeding after continuous-flow left ventricular device implantation: review of pathophysiology and management.

Gastrointestinal bleeding is one of the most common complications in patients with continuous-flow left ventricular assist devices. Though the exact pathophysiology is still unclear, continuous-flow physiology, acquired Von Willebrand disease, and formation of arteriovenous malformations in the gastrointestinal tract are implicated. An individualized plan of endoscopic therapy and anticoagulation management is required when caring for these patients.

Acute Hepatitis E in the US Today Occurs in Diverse Patient Populations: Case Reports.

Hepatitis E has long been thought of as an infection confined to the developing world. However, there has been an increased incidence of locally acquired cases in developed countries especially in transplant patients. Our first case is a 56-year-old Caucasian female post-heart transplant patient who presented with diarrhea and abdominal pain. She was found to be acutely infected with hepatitis E and progressed to stage 3 liver fibrosis. Our second patient was an otherwise healthy 76-year-old Vietnamese female who presented with abdominal pain, jaundice and fatigue. She was diagnosed with acute hepatitis E complicated by acute renal failure. There have only been a few reported cases of acute hepatitis E complicated by renal failure.

Patients with cirrhosis show a relative increase in thrombin generation that is correlated with lower antithrombin levels.

Predicting the risk of bleeding or thrombosis in cirrhotic patients is difficult due to reduced levels and dysregulation of both procoagulant and anticoagulant factors. We utilized thrombin generation and microvesicle analysis to better understand the regulation of haemostasis in cirrhotic patients. We studied 24 patients with cirrhosis vs. 21 healthy controls. Cirrhotic patients had reduced prothrombin activity (40 ±â€Š9 vs. 112 ±â€Š15), protein C activity (36 ±â€Š10 vs. 114 ±â€Š19) and antithrombin activity (43 ±â€Š14 vs. 109 ±â€Š10). Peak thrombin generation was reduced in cirrhotic patients (165 ±â€Š47 vs. 232 ±â€Š101), but the ratio of peak thrombin generation to prothrombin activity was increased in cirrhotic patients (4.2 ±â€Š1.0 vs. 2.1 ±â€Š0.9) indicating a relative increase in thrombin generation in cirrhosis. The termination time ratio was increased in cirrhotic patients (7.2 ±â€Š1.9 vs. 3.1 ±â€Š0.7) and correlated with reduced antithrombin levels, indicating that cirrhotic patients took longer to stop thrombin generation than controls. Cirrhotic patients showed reduced procoagulant microvesicles from platelets (39 500 ±â€Š24 800 vs. 107 700 ±â€Š74 200) and other cells, but levels overlapped with controls. Cirrhotic patients showed a wide range of procoagulant and anticoagulant levels leading to variability in the regulation of thrombin generation. In conclusion, compared with healthy controls, patients with cirrhosis have lower antithrombin levels that lead to slower downregulation of thrombin generation and more overall thrombin being produced for a given procoagulant level in blood, but also low normal levels of procoagulant microvesicles that would slow initiation of thrombin generation. Whether an individual cirrhosis patient is at a greater risk of bleeding vs. thrombosis may depend on their specific imbalance in procoagulants vs. anticoagulants.

The gut microbiota and the liver: implications for clinical practice.

While a central role for the microbiota in the precipitation of infectious and non-infectious complications of liver disease has been long established, evidence for a more fundamental role in the etiology of several liver diseases continues to accumulate. However, though progress is rapidly occurring in this area, the definitive delineation of the precise relevance of changes in the microbiota to various forms and stages of liver disease is still far from complete. While high quality clinical evidence supports the use of antibiotic therapy, in the management of hepatic encephalopathy, spontaneous bacterial peritonitis and other infectious complications, how these interventions impact on the microbiota and microbiota-host interactions has not been clearly defined. Although probiotics and even, perhaps, fecal transplantation hold promise in the management of liver disease, and the potential impact of probiotics is supported by a considerable amount of laboratory data, high-quality clinical evidence is scanty.

Fatty liver: a link to cardiovascular disease--its natural history, pathogenesis, and treatment.

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease in western society and is increasing in parallel with the worldwide epidemic of obesity. It exists in a simple form, steatosis, or a more complex and more dangerous form, steatohepatitis, and it is often but not always associated with the metabolic syndrome. NAFLD can progress to cirrhosis and hepatocellular carcinoma. It is responsible for the majority of cryptogenic cirrhosis cases. Increasingly, NAFLD and its more sinister form, steatohepatitis, have been linked to the increased incidence of cardiovascular disease (CVD) worldwide, independent of the metabolic syndrome. Death from CVD surpasses death from liver complications, but that is beginning to change as people are living longer with CVD. In this article, we will review nonalcoholic fatty liver disease and its epidemiology, prevalence, pathology, and link to CVD.

Targeting the microbiota in the management of gastrointestinal and liver disease / Apuntando a la microbiota en el manejo de las enfermedades gastrointestinales y hepáticas

Thanks to rapid advances in technology the details of the human microbiome and its functions in health and disease are being progressively revealed. Though many reports have linked various disease states with an altered microbiome and while some associations between the microbiome and disease states are well established, many of these studies are largely descriptive and the changes reported in the microbiome have yet to be shown to be causative. A number of strategies are available to modify the microbiota; some such as the use of antibiotics for specific indications, are well established, others such as the use of probiotics and prebiotics in a variety of disease states are supported by more limited data. Fecal transplantation has emerged as an exciting, albeit rather drastic, intervention for intestinal and, perhaps, other disorders. Other approaches, such as the isolation, purification and formulation of small molecules with specific biological actions, derived from the microbiota look very promising.

Gracias al rápido avance de la tecnología los detalles del microbioma humano y sus funciones en salud y enfermedad están siendo conocidos progresivamente. A pesar que muchos reportes han relacionado varios estados de enfermedad con un microbioma alterado y mientras algunas asociaciones entre el microbioma y estados de enfermedad están bien establecidas, muchos de estos estudios son solo descriptivos y los cambios reportados en el microbioma todavía tienen que demostrarse que son la causa. Existen muchas estrategias para cambiar la microbiota; algunas como el uso de antibióticos para indicaciones específicas, están muy bien determinadas, otras, como el uso de probióticos y prebióticos en una gran variedad de enfermedades, están sustentadas en data más limitada. El trasplante fecal ha surgido como una alternativa muy emocionante, aunque algo drástica, para las enfermedades intestinales y quizás también para otras patologías. Otros abordajes como el aislamiento, purificación y formulación de pequeñas moléculas con acciones biológicas específicas, derivados de la microbiota aparecen como muy prometedoras.