Anna E. Rutherford

Acute liver failure: mechanisms of hepatocyte injury and regeneration.

Acute liver failure (ALF) occurs when the extent of hepatocyte death exceeds the livers regenerative capacity. Despite vast differences in causes, the mode of cell death typically follows one of two patterns: necrosis or apoptosis. Necrosis and apoptosis have traditionally been considered separate entities within various etiologies of ALF; however, there is increasing evidence that they are alternative outcomes of the same initiating factors and signaling pathways, a process known as necroapoptosis. Here we review mechanisms of liver cell injury in ALF, including evolving knowledge of pathways leading to apoptosis, necrosis, and necroapoptosis, as well as how these pathways are potential therapeutic targets in ALF. We also discuss hepatic regeneration and the cytokines and growth factors involved in both the replication of differentiated hepatocytes as well as activation of intrahepatic progenitor cells, two pathways of hepatocyte regeneration that are dependent on the type and extent of hepatic insult in ALF.

Development of an Accurate Index for Predicting Outcomes of Patients With Acute Liver Failure

BACKGROUND & AIMS Patients with acute liver failure (ALF) have high mortality and frequently require liver transplantation (LT); few reliable prognostic markers are available. Levels of M30, a cleavage product of cytokeratin-18 caspase, are significantly increased in serum samples from patients with ALF who die or undergo LT. We developed a prognostic index for ALF based on level of M30 and commonly measured clinical variables (called the Acute Liver Failure Study Group [ALFSG] index) and compared its accuracy with that of the Kings College criteria (KCC) and Model for End Stage Liver Disease (MELD). We also validated our model in an independent group of patients with ALF. METHODS Serum levels of M30 and M65 antigen (the total cytokeratin-18 fragment, a marker of apoptosis and necrosis) were measured on 3 of the first 4 days following admission of 250 patients with ALF. Logistic regression was used to determine whether the following factors, measured on day 1, were associated with LT or death: age, etiology; coma grade; international normalized ratio (INR); serum pH; body mass index; levels of creatinine, bilirubin, phosphorus, arterial ammonia, and lactate; and log(10) M30 and log(10) M65. The area under the receiver operating characteristic (AUROC) was calculated for the ALFSG and other indices. RESULTS Coma grade, INR, levels of bilirubin and phosphorus, and log(10) M30 value at study entry most accurately identified patients who would require LT or die. The ALFSG index identified these patients with 85.6% sensitivity and 64.7% specificity. Based on comparison of AUROC values, the ALFSG Index (AUROC, 0.822) better identified patients most likely to require LT or die than the KCC (AUROC, 0.654) or MELD (AUROC, 0.704) (P = .0002 and P = .0010, respectively). We validated these findings in a separate group of 250 patients with ALF. CONCLUSIONS The ALFSG index, a combination of clinical markers and measurements of the apoptosis biomarker M30, better predicts outcomes of patients with ALF than the KCC or MELD.

Pretransplant depression, antidepressant use, and outcomes of orthotopic liver transplantation.

Depression is a common problem among patients awaiting organ transplantation, but little is known about the impact of depression and its treatment on the outcomes of liver transplantation. In this retrospective cohort analysis, we studied all patients over 18 years of age who underwent liver transplantation during a 5‐year period (2004‐2008) at a single center. Among 179 recipients, 65 patients had depression, as defined by a health care provider assessment, before transplantation. Depression was defined as past or active depression or an adjustment disorder. The associations between pretransplant depression and various outcomes (time to death, graft failure, first acute cellular rejection episode, first infection, and first rehospitalization) were assessed. In the entire sample, more patients with depression required posttransplant psychiatric care (37% versus 18%); the adjusted hazard ratio was 2.28 (1.27‐4.11). The rates of other outcomes, including hospital readmission, acute cellular rejection, graft failure, mortality, and infection, were similar for patients with depression and patients without depression. Among those with depression, patients on antidepressants at the time of transplantation had acute cellular rejection less frequently than those not taking antidepressants (13% versus 40%); the adjusted hazard ratio was 0.14 (0.03‐0.62). The rates of other outcomes were similar between these 2 groups. These data indicate that depression affects posttransplant psychiatric morbidity but not other medical outcomes of liver transplantation. Pharmacological treatment of depression may significantly reduce the incidence of acute cellular rejection in patients undergoing liver transplantation. However, future prospective studies of mental health and liver transplantation are required to definitively assess the effects of antidepressant medications on medical outcomes. Liver Transpl, 2011.

Cholestasis and cholestatic syndromes

Purpose of review This review focuses on the recent advances in cholestatic liver diseases. While there is an emphasis placed on translational and treatment-focused studies, basic science studies with the greatest impact on the field are also covered. Recent findings Highlights include new discoveries for the role of the farsenoid X receptor and sodium-dependent taurocholate cotransporting polypeptide; new insights into the pathogenesis of progressive familial intrahepatic cholestasis type 1, biliary atresia, intrahepatic cholestasis of pregnancy, and primary biliary cirrhosis; new information for assessing prognosis in biliary atresia and primary biliary cirrhosis; and important clinical trials in intrahepatic cholestasis of pregnancy, primary biliary cirrhosis and primary sclerosing cholangitis. Summary The studies of 2006 have furthered our understanding of cholestasis and cholestatic syndromes. While we continue to add to our knowledge of pathogenesis and treatment for many of these diseases, much work remains.

Efficacy and Safety of Direct Acting Antivirals in Kidney Transplant Recipients with Chronic Hepatitis C Virus Infection

The prevalence of Hepatitis C Virus (HCV) infection is significantly higher in patients with end-stage renal disease compared to the general population and poses important clinical challenges in patients who undergo kidney transplantation. Historically, interferon-based treatment options have been limited by low rates of efficacy and significant side effects, including risk of precipitating rejection. Limited data exist on the use of all-oral, interferon-free direct-acting antiviral (DAA) therapies in kidney transplant recipients. In this study, we performed a retrospective chart review with prospective clinical follow-up of post-kidney transplant patients treated with DAA therapies at three major hospitals in Boston, MA. A total of 24 kidney recipients with HCV infection received all-oral DAA therapy post-transplant. Patients were predominantly male (79%) with a median age of 60 years (range 34–70 years), median creatinine of 1.2 mg/dL (0.66–1.76), and 42% had advanced fibrosis or cirrhosis. The majority had HCV genotype 1a infection (58%). All patients received full-dose sofosbuvir; it was paired with simeprevir (9 patients without and 3 patients with ribavirin), ledipasvir (7 patients without and 1 patient with ribavirin) or ribavirin alone (4 patients). The overall sustained virologic response (SVR12) was 91% (21 out of 23 patients). One patient achieved SVR4 but demised prior to SVR12 check point due to treatment unrelated cause. Two treatment failures were successfully retreated with alternative DAA regimens and achieved SVR. Both initials failures occurred in patients with advanced fibrosis or cirrhosis, with genotype 1a infection, and prior HCV treatment failure. Adverse events were reported in 11 patients (46%) and were managed clinically without discontinuation of therapy. Calcineurin inhibitor trough levels did not significantly change during therapy. In this multi-center series of patients, all-oral DAA therapy appears to be safe and effective in post-kidney transplant patients with chronic HCV infection.

Implementing clinical pathways for patients admitted to a medical service: lessons learned.

In an attempt to improve quality of care for patients admitted to our medical service we have implemented the use of pathways. These are printed standards of care and a mechanism for daily multidisciplinary documentation. The goals of our pathways are to: improve quality using printed standards of care; improve documentation of the care delivered; improve communication about daily goals between all team members, patients and families; standardize our in-patient chart format throughout the hospital; and increase efficiency of care. Pathways were designed to provide physicians and nurses with the standards for care and provide a mechanism for multidisciplinary documentation on our in-patient charts. We now have 2 pathways in use on our medical service. One is a clinical care plan (CCP) and the other is a Pancreatitis Pathway (PP) for patients admitted with acute pancreatitis and the other a guideline for care for all patients. The pathways were developed by teams including attending physicians (General Internists and Gastroenterologists), medicine house officers, nurses, and care coordinators. The pathways are used for all patients admitted to our medical service if they are admitted to one of 2 floors. This paper includes a comparison of outcomes for our first 9 patients who were managed using the pancreatitis pathway versus 7 patients cared for without the pathway. Significant differences in the pancreatitis pathway treated patients included: 1) less intense pain on day 2, (P = 0.04); 2) less pain on day of refeeding (P = 0.004); and 3) less IV fluids administered (P = 0.05). We also describe several lessons we have learned about using pathways for in-patients on a medical service in an academic medical center. We have learned the following lessons. Nursing documentation is improved. Physicians need ongoing encouragement and education about the value of pathways. There is considerable work involved for unit coordinators, care coordinators, and nursing in using pathways on a medical-surgical floor. There must be physician and nurse champions. There must be ongoing feedback to users. There must be input from users and edits. We believe the use of pathways as a process to remind clinicians of quality standards will improve the care of our patients by decreasing variation, improving team communication, and enhancing patient and family education.

Postpartum Laboratory Follow-up in Women With Hepatitis B in Massachusetts From 2007 to 2012.

Goals: To determine postpartum hepatitis B virus (HBV) laboratory testing rates and identify factors associated with a lack of follow-up testing in Massachusetts. Background: Screening for HBV infection in pregnant women is standard of care. Guidelines recommend that patients with chronic HBV have ongoing care and laboratory testing, but little is known about postpartum maternal HBV care outcomes. Study: We conducted a retrospective cohort study using Massachusetts Virtual Epidemiologic Network, an electronic public health surveillance system maintained by the Massachusetts Department of Public Health. We identified women who tested hepatitis B surface antigen positive during their first reported (index) pregnancy in Massachusetts from 2007 to 2012 and measured HBV-related laboratory tests reported to Massachusetts Department of Public Health during and after pregnancy. Results: We identified 983 hepatitis B surface antigen positive pregnant women. Half (492/983) did not have evidence of additional postpartum HBV laboratory testing following their index pregnancy. Women who had postpartum laboratory tests reported were younger [mean age (SD): 29 (5.3) vs. 31 (5.5) y, P=0.0001] and more likely to have >1 pregnancy during the study period (41% vs. 1%, P<0.0001). There were no differences in race, ethnicity, and US born status. On multivariable logistic regression, older age predicted a lower likelihood of having postpartum laboratory testing (odds ratio, 0.77; 95% confidence interval, 0.70-0.90). Conclusions: Postpartum maternal HBV follow-up laboratory testing occurred in only half of Massachusetts women and did not vary by race, ethnicity, or US born status. Our results were limited to a single state surveillance database, which likely underestimates the number of tests ordered.

Spontaneous bacterial peritonitis is a risk factor for renal failure requiring dialysis in waitlisted liver transplant candidates.

To examine the relationship between and impact of spontaneous bacteria peritonitis (SBP) and renal failure requiring dialysis in waitlisted liver transplant (LT) candidates.

Hemodynamic Effects of Paracentesis in a Patient With a Fontan Circulation

Recurrent ascites is a common manifestation of failing Fontan circulation. We present the hemodynamic response to large-volume paracentesis in a patient with Fontan circulation and Fontan-associated liver disease, documenting an immediate and substantial decline in systemic venous pressure and increase in cardiac output. These preliminary observations may have implications for the management of ascites in adults with Fontan circulation.

Peripartum Care for Mothers Diagnosed with Hepatitis B During Pregnancy: A Survey of Provider Practices

Objectives Hepatitis B (HBV) remains a significant public health burden, despite effective therapy. Routine HBV screening is recommended during pregnancy to reduce the risk of vertical transmission, but the rates of follow-up care peri-partum are low. The aim of this study was to evaluate physician practices and knowledge regarding HBV in women diagnosed perinatally. Methods A survey was distributed to obstetricians and midwives within the Partners HealthCare system at Brigham and Women’s Hospital and Massachusetts General Hospital. Results Of 118 survey respondents (response rate 56%), 97% reported that they always tested for hepatitis B, and 77% referred new diagnoses of HBV during pregnancy to a HBV specialist for further care. Only 10% of respondents reported that there was formal referral mechanism in place to facilitate follow-up care for mothers diagnosed with hepatitis B infection. 91% of survey respondents selected hepatitis B surface antigen as the correct screening test, and 76% selected hepatitis B immune globulin with vaccination for the newborn as the correct prophylaxis regimen. Only 40 and 51% of respondents accurately identified serologies that were consistent with acute and chronic infection, respectively. Conclusions for Practice Routine screening for HBV in this population presents an important opportunity to identify cases and to reduce the public health burden of this disease. Providers were somewhat knowledgeable about HBV, but the lack of formal referral mechanism may explain why HBV follow-up is suboptimal in this healthcare system. Supplemental provider education and formal linkage to care programs may increase rates of follow-up HBV care.