Trajectory of Serum Bilirubin Predicts Spontaneous Recovery in a Real-World Cohort of Patients With Alcoholic Hepatitis.

BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is a severe condition with poor short-term prognosis. Specific treatment with corticosteroids slightly improves short-term survival but is associated with infection and is not used in many centers. A reliable method to identify patients who will recover spontaneously will minimise the numbers of patients who experience side effects of available treatments. METHODS: We analysed the trajectory of serum bilirubin concentration over the course of hospital admissions in patients with AH to predict spontaneous survival and the need for treatment. RESULTS: data from 426 patients were analysed. Based on bilirubin trajectory, patients were categorized into three groups: 'fast fallers' (bilirubin <0.8 x admission value at day 7), 'static' (bilirubin of >0.9 - <1.2 x admission value) and 'rapid risers' (bilirubin of ≥1.2 x admission bilirubin). Fast fallers had significantly better 90-day survival compared to other groups (log rank p < .001), and showed no benefit of corticosteroid therapy (OR for survival at 28 days of treatment, 0.94, 95% CI 0.06 - 8.41). These findings remained even amongst patients with severe disease based on initial DF, GAHS or MELD scores. CONCLUSIONS: We present an intuitive method of classifying patients with AH based on the trajectory of bilirubin over the first week of admission. It is complimentary to existing scores that identify candidates for corticosteroid treatment or assess response to treatment. This method identifies a group of patients with AH who recover spontaneously and can avoid corticosteroid therapy.

An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium.

The exit of antigen-presenting cells and lymphocytes from inflamed skin to afferent lymph is vital for the initiation and maintenance of dermal immune responses. How such an exit is achieved and how cells transmigrate the distinct endothelium of lymphatic vessels are unknown. We show that inflammatory cytokines trigger activation of dermal lymphatic endothelial cells (LECs), leading to expression of the key leukocyte adhesion receptors intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin, as well as a discrete panel of chemokines and other potential regulators of leukocyte transmigration. Furthermore, we show that both ICAM-1 and VCAM-1 are induced in the dermal lymphatic vessels of mice exposed to skin contact hypersensitivity where they mediate lymph node trafficking of dendritic cells (DCs) via afferent lymphatics. Lastly, we show that tumor necrosis factor alpha stimulates both DC adhesion and transmigration of dermal LEC monolayers in vitro and that the process is efficiently inhibited by ICAM-1 and VCAM-1 adhesion-blocking monoclonal antibodies. These results reveal a CAM-mediated mechanism for recruiting leukocytes to the lymph nodes in inflammation and highlight the process of lymphatic transmigration as a potential new target for antiinflammatory therapy.

CX(3)CR1 and vascular adhesion protein-1-dependent recruitment of CD16(+) monocytes across human liver sinusoidal endothelium.

UNLABELLED: The liver contains macrophages and myeloid dendritic cells (mDCs) that are critical for the regulation of hepatic inflammation. Most hepatic macrophages and mDCs are derived from monocytes recruited from the blood through poorly understood interactions with hepatic sinusoidal endothelial cells (HSECs). Human CD16(+) monocytes are thought to contain the precursor populations for tissue macrophages and mDCs. We report that CD16(+) cells localize to areas of active inflammation and fibrosis in chronic inflammatory liver disease and that a unique combination of cell surface receptors promotes the transendothelial migration of CD16(+) monocytes through human HSECs under physiological flow. CX(3)CR1 activation was the dominant pertussis-sensitive mechanism controlling transendothelial migration under flow, and expression of the CX(3)CR1 ligand CX(3)CL1 is increased on hepatic sinusoids in chronic inflammatory liver disease. Exposure of CD16(+) monocytes to immobilized purified CX(3)CL1 triggered beta1-integrin-mediated adhesion to vascular cell adhesion molecule-1 and induced the development of a migratory phenotype. Following transmigration or exposure to soluble CX(3)CL1, CD16(+) monocytes rapidly but transiently lost expression of CX(3)CR1. Adhesion and transmigration across HSECs under flow was also dependent on vascular adhesion protein-1 (VAP-1) on the HSECs. CONCLUSION: Our data suggest that CD16(+) monocytes are recruited by a combination of adhesive signals involving VAP-1 and CX(3)CR1 mediated integrin-activation. Thus a novel combination of surface molecules, including VAP-1 and CX(3)CL1 promotes the recruitment of CD16(+) monocytes to the liver, allowing them to localize at sites of chronic inflammation and fibrosis.

Liver myofibroblasts regulate infiltration and positioning of lymphocytes in human liver.

BACKGROUND & AIMS: The recruitment of lymphocytes to tissues via endothelium has been studied extensively but less is known about the signals that direct migration and positioning within tissues. Liver myofibroblasts associate with lymphocytes in hepatitis and are positioned below the sinusoidal endothelium, through which lymphocytes are recruited to the liver. We investigated whether activated human liver myofibroblasts (aLMF) affect the migration and accumulation of lymphocytes within the inflamed liver. METHODS: The ability of human aLMF and hepatic stellate cells to promote lymphocyte chemotaxis, adhesion, and migration was studied in vitro. RESULTS: When cultured in vitro, aLMF from diseased human liver and hepatic stellate cells from noninflamed liver secrete a distinct profile of cytokines comprising interleukin (IL)-6, IL-12, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and the chemokines CCL2, CCL3, CCL5, CXCL8, CXCL9, and CXCL10. aLMF-conditioned media had chemotactic activity for lymphocytes, which partially was inhibited by pertussis toxin. IL-6, HGF, and VEGF all contributed to G-protein-coupled receptor-independent chemotaxis of lymphocytes. Lymphocytes adhered to aLMF via intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 and a proportion of adherent cells migrated through the fibroblast monolayer, mediated by IL-6, HGF, and VEGF. CONCLUSIONS: Human aLMF support G-protein coupled receptor-dependent and -independent lymphocyte adhesion and migration and thereby regulate the recruitment and positioning of lymphocytes in chronic hepatitis.

Emerging drugs for complications of end-stage liver disease.

BACKGROUND: The prevalence of end-stage liver disease is rising rapidly and constitutes a major healthcare burden currently. Many cases are diagnosed at a later stage when liver transplantation is the only effective treatment option. There is thus an urgent need for novel treatments to reverse the earlier stages of cirrhosis as well as to treat the many associated life-threatening complications. OBJECTIVES: To review the current drugs available for treating the complications of advanced liver disease. To address novel treatment strategies that are in development, with particular reference to the rapidly developing area of antifibrotic therapy. To assess how the obstacles that have so far impeded the development of effective new drugs for end-stage liver disease may be overcome in the future. METHODS: The literature was reviewed to define current therapies and therapies in clinical trials. We used the current models of the molecular basis of liver fibrogenesis to determine potential new therapeutic targets for antifibrotic therapy. CONCLUSIONS: Insights into the pathogenesis of liver injury and fibrosis have opened up new avenues for therapy and there are now candidates and targets with real potential for the development of a new generation of antifibrotic therapies.

A prospective study of standardized nonsurgical therapy in the management of biliary anastomotic strictures complicating liver transplantation.

BACKGROUND: Biliary anastomotic strictures are a common complication of liver transplantation, occurring in up to 7% of patients at our center. Endoscopic therapy has started to replace surgical biliary reconstruction as the favored means of managing these patients in some centers, although the utility of this approach has never been tested in the setting of a standardized prospective study. METHODS: This was a standardized, prospective observational study in the liver transplantation unit, Queen Elizabeth Hospital, Birmingham, United Kingdom. Between June 2000 and August 2006, a total of 791 adults underwent liver transplantation at the Birmingham liver unit and 53 patients were diagnosed with biliary anastomotic strictures. All 53 patients chose to undergo endoscopic therapy and were managed according to the unit's standardized treatment protocol. Data and information from the patient records was collated prospectively, stored in a specific database, and analyzed by intention-to-treat. RESULTS: Endoscopic therapy was successful in 69% of patients referred with anastomotic strictures with a median stent free follow up of 18 months. Most patients required a median of 3 endoscopic procedures and two 24F balloon dilatations to adequately treat the stricture. The median continuous indwelling stent period was 11 months. Two patients were re-stented because of jaundice although only one patient had recurrence of the anastomotic stricture (3%). CONCLUSIONS: Endoscopic balloon dilatation and stenting is a safe and effective means of treating biliary anastomotic strictures complicating liver transplantation.

Effect of the cortex on ultrasonic backscatter measurements of cancellous bone.

Ultrasonic backscatter techniques offer a promising new approach for detecting changes in bone caused by osteoporosis. However, several challenges impede clinical implementation of backscatter techniques. This study examines how the dense outer surface of bone (the cortex) affects backscatter measurements of interior regions of porous (cancellous) bone tissue. Fifty-two specimens of bone were prepared from 13 human femoral heads so that the same region of cancellous bone could be ultrasonically interrogated through the cortex or along directions that avoided the cortex. Backscatter signals were analyzed over a frequency range of 0.8-3.0 MHz to determine two ultrasonic parameters: apparent integrated backscatter (AIB) and frequency slope of apparent backscatter (FSAB). The term 'apparent' means that the parameters are sensitive to the frequency-dependent effects of diffraction and attenuation. Significant (p < 0.001) changes in AIB and FSAB indicated that measurements through the cortex decreased the apparent backscattered power and increased the frequency dependence of the power. However, the cortex did not affect the correlation of AIB and FSAB with the x-ray bone mineral density of the specimens. This suggests that results from many previous in vitro backscatter studies of specimens of purely cancellous bone may be extrapolated with greater confidence to in vivo conditions.

Immune interactions in hepatic fibrosis.

Liver cirrhosis is caused by iterative cycles of tissue injury, inflammation, and repair. Although most causes of acute hepatitis resolve without scarring, chronic hepatitis is associated with persistent inflammation and matrix remodeling, which leads to fibrosis and, eventually, cirrhosis. The mechanisms that govern wound healing involve interactions between the innate and adaptive immune systems and stromal cells within a microenvironment composed of cytokines, growth factors, and modified matricellular proteins. The immune system plays a central role in the regulation of fibrosis, tissue repair, and recovery that is vital for the maintenance of tissue homeostasis. Chronic inflammation and fibrosis are inextricably linked and the cellular interactions between immune effector cells, local fibroblasts, and tissue macrophages at sites of scar formation determine the outcome of liver injury and the development of scarring.

Immune-mediated liver injury.

Diseases with different pathogeneses share common pathways of immune-mediated injury. Autoreactive T cells destroy hepatocytes or cholangiocytes in autoimmune disease and virus-specific T cells destroy infected hepatocytes in viral hepatitis. In these conditions, antigen-specific mechanisms can be implicated but immune-mediated injury is central to diseases where there is a less-defined role for specific antigens. In all these diseases, "bystander cells" activated by the local microenvironment rather than a specific antigen are major players and amplify effector responses by recruiting natural killer and natural killer T cells, macrophages, neutrophils, eosinophils, and even platelets. Immune-mediated liver injury is driven by repeated cycles of inflammation and damage sustained by continuing recruitment, retention, and survival of effector leukocytes within the inflamed liver. These processes depend on complex interactions involving epithelial cells, stromal cells, and leukocytes shaped by the local cytokine microenvironment. Understanding these interactions will elucidate the pathogenesis of liver disease and suggest new therapies.

Palliation of patients with malignant gastroduodenal obstruction with self-expanding metallic stents: the treatment of choice?

BACKGROUND: Gastroduodenal obstruction is a common preterminal event for patients with gastric and pancreatic cancer who often undergo palliative surgical bypass. Endoscopic palliation with self-expanding metallic stents has emerged as a safe and an effective alternative to surgery, but experience with the technique remains limited. METHODS: Twenty-eight patients hospitalized with GI obstruction because of incurable gastric or pancreatic cancer were recruited for a prospective study of palliation with self-expanding metallic stents. Complications and clinical outcomes were assessed. OBSERVATIONS: Stent insertion was technically successful in 26 patients. Thereafter, 24 patients resumed an adequate liquid or semisolid diet. Stent insertion facilitated hospital discharge for 20 patients. Occlusion of the stent because of tumor ingrowth occurred in 3 patients, but there was no complication related to stent insertion or the stent itself. CONCLUSIONS: Endoscopic placement of a self-expanding metallic stent is a simple, effective means of palliation for patients with malignant gastroduodenal obstruction.