Development and First Clinical Use of an Extracorporeal Artificial Multiorgan System in Acute-on-Chronic Liver Failure Patients.

Multiple organ failure (MOF) is a common and deadly condition. Patients with liver cirrhosis with acute-on-chronic liver failure (AOCLF) are particularly susceptible. Excess fluid accumulation in tissues makes routine hemodialysis generally ineffective because of cardiovascular instability. Patients with three or more organ failures face a mortality rate of more than 90%. Many cannot survive liver transplantation. Extracorporeal support systems like MARS (Baxter, Deerfield, IL) and Prometheus (Bad Homburg, Germany) have shown promise but fall short in bridging patients to transplantation. A novel Artificial Multi-organ Replacement System (AMOR) was developed at the University of Washington Medical Center. AMOR removes protein-bound toxins through a combination of albumin dialysis, a charcoal sorbent column, and a novel rinsing method to prevent sorbent column saturation. It removes excess fluid through hemodialysis. Ten AOCLF patients with over three organ failures were treated by the AMOR system. All patients showed significant clinical improvement. Fifty percent of the cohort received liver transplants or recovered liver function. AMOR was successful in removing large amounts of excess body fluid, which regular hemodialysis could not. AMOR is cost-effective and user-friendly. It removes excess fluid, supporting the other vital organs such as liver, kidneys, lungs, and heart. This pilot study's results encourage further exploration of AMOR for treating MOF patients.

LIVER TRANSPLANTATION: WILL XENOTRANSPLANTATION BE THE ANSWER TO THE DONOR ORGAN SHORTAGE?

Since the first report of a successful liver transplant in 1968, access to this operation has dramatically improved. In 2018, 8,250 patients underwent liver transplantation in the United States. Despite this remarkable advance, a persistent shortage of donor organs remains the primary obstacle to optimal utilization of this life-saving operation. Over the past two decades, transplant professionals have pursued two broad strategies to overcome this roadblock: increasing the number of donor organs and decreasing the number of patients requiring transplantation through advances in medical interventions. Despite these efforts, more than 13,500 patients remained on liver transplant waiting lists at the end of 2018. Almost 1,200 died while waiting, and 1,350 were removed from wait lists because they had become too sick to survive the operation. Clearly, a dramatic new approach to the donor organ shortage is needed. One effort, first attempted by surgeons in the 1960s, was to utilize donor organs from other species (xenotransplantation). The major obstacle to xenotransplantation acceptance has been the fear of transmitting new infectious diseases from animals to humans. As the twentieth century came to a close, national moratoria on xenotransplantation ended both research and clinical activities in this field. The recent discoveries that modern gene-editing techniques can be used to eliminate the retrovirus that is ubiquitous in pigs and that retrovirus-free pigs can be cloned has reopened the possibility that xenotransplantation may be a potentially game-changing approach to eliminating the donor shortage for liver and other solid organ transplant recipients. In response to these advances, the FDA has released comprehensive industry guidelines regarding all aspects of xenotransplantation. This release has resulted in numerous preclinical studies in which organs from genetically modified pigs are transplanted into various nonhuman primates (NHPs). Use of a variety of gene-editing and immunosuppressive techniques has greatly increased the survival of recipient animals in the past few years. Survival of NHP renal transplant recipients has been extended to 435 days, functional cardiac transplant recipients to 195 days, and liver transplant recipients to 29 days. Current research studies using various gene modification strategies combined with newer immunosuppressive protocols are attempting to further extend the survival of these experimental animals. These encouraging results have raised the possibility that clinical xenotransplantation in humans is just beyond the horizon. The most likely candidates for initial clinical studies probably will be kidney transplant recipients who are difficult to crossmatch for human organs, neonates with severe congenital heart disease, and liver transplant candidates with acute liver failure.

Corticosteroids Reduce Risk of Death Within 28 Days for Patients With Severe Alcoholic Hepatitis, Compared With Pentoxifylline or Placebo-a Meta-analysis of Individual Data From Controlled Trials.

BACKGROUND & AIMS: We performed a meta-analysis of individual patient data from 11 randomized controlled trials comparing corticosteroids, pentoxifylline, or their combination in patients with severe alcoholic hepatitis. We compared the effects of the treatments on survival for 28 days or 6 months, and response to treatment based on the Lille model. METHODS: We searched PubMed for randomized controlled trials of pharmacologic therapy for severe alcoholic hepatitis. Our final analysis comprised 11 studies, of 2111 patients. We performed 4 meta-analyses of the effects of corticosteroids vs placebo or control, corticosteroids vs pentoxifylline, corticosteroids and pentoxifylline vs corticosteroids and placebo or control, and pentoxifylline vs placebo. In each meta-analysis, the effect of treatment on the primary outcome (overall survival at 28 days, defined as the period from the first day of assigned treatment to 28 days) was estimated using a Cox proportional hazards regression model, including trials as random effect. RESULTS: Corticosteroid treatment significantly decreased risk of death within 28 days compared with controls (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.48-0.86) or to pentoxifylline (HR 0.64; 95% CI 0.43-0.95). In multiple-imputation and complete case analyses, the effect of corticosteroids compared with controls remained significant. When we compared corticosteroids vs pentoxifylline, the corticosteroid effect remained significant in the complete case analysis (HR 0.66; P = .04) but not in multiple-imputation analysis (HR 0.71; P = .08). There was no difference in 28-day mortality when patients were given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or between patients given pentoxifylline vs control. In our analysis of secondary outcomes, we found no significant differences in 6-month mortality when any treatments or controls were compared. Corticosteroids were significantly associated with increased response to therapy compared with controls (relative risk 1.24; 95% CI 1.10-1.41) or pentoxifylline (relative risk 1.43; 95% CI 1.20-1.68). We found no difference in response to therapy between patients given a combination of corticosteroids and pentoxifylline vs corticosteroids alone or pentoxifylline vs controls. CONCLUSIONS: In a meta-analysis of 4 controlled trials, we found corticosteroid use to reduce risk of death within 28 days of treatment, but not in the following 6 months. This loss of efficacy over time indicates a need for new therapeutic strategies to improve medium-term outcomes.

Recent trends in liver transplantation for alcoholic liver disease in the United States.

AIM: To examine temporal changes in the indications for liver transplantation (LT) and characteristics of patients transplanted for alcoholic liver disease (ALD). METHODS: We performed a retrospective cohort analysis of trends in the indication for LT using the United Network for Organ Sharing (UNOS) database between 2002 and 2015. Patients were grouped by etiology of the liver disease and characteristics were compared using χ2 and t-tests. Time series analysis was used identifying any year with a significant change in the number of transplants per year for ALD, and before and after eras were modeled using a general linear model. Subgroup analysis of recipients with ALD was performed by age group, gender, UNOS region and etiology (alcoholic cirrhosis, alcoholic hepatitis and hepatitis C - alcoholic cirrhosis dual listing). RESULTS: Of 74216 liver transplant recipients, ALD (n = 9400, 12.7%) was the third leading indication for transplant after hepatitis C and hepatocellular carcinoma. Transplants for ALD, increased from 12.8% (553) in 2002 to 16.5% (1020) in 2015. Time series analysis indicated a significant increase in the number of transplants per year for ALD in 2013 (P = 0.03). There were a stable number of transplants per year between 2002 and 2012 (linear coefficient 3, 95%CI: -4.6, 11.2) an increase of 177 per year between 2013 and 2015 (95%CI: 119, 234). This increase was significant for all age groups except those 71-83 years old, was observed for both genders, and was incompletely explained by a decrease in transplants for hepatitis C and ALD dual listing. All UNOS regions except region 9 saw an increase in the mean number of transplants per year when comparing eras, and this increase was significant in regions 2, 3, 4, 5, 6, 8, 10 and 11. CONCLUSION: There has been a dramatic increase in the number of transplants for ALD starting in 2013.

Hepatitis B Virus--Specific and Global T-Cell Dysfunction in Chronic Hepatitis B.

BACKGROUND & AIMS: T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB). METHODS: We enrolled 200 adults with CHB who participated in the National Institutes of Health-supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion. RESULTS: Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3(+)CD127(-) regulatory T cells and CD4(+) T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg)(+) than HBeAg(-) patients (percent responders: 3% vs 23%; P = .00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg(+) than HBeAg(-) patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls. CONCLUSIONS: HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell-based immune signatures for clinical phenotypes. These findings suggest additional T-cell-independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.

D-MELD risk capping improves post-transplant and overall mortality under markov microsimulation.

AIM: To hypothesize that the product of calculated Model for End-Stage Liver Disease score excluding exception points and donor age (D-MELD) risk capping ± Rule 14 could improve post liver transplant and overall survival after listing. METHODS: Probabilities derived from the United Network for Organ Sharing database between 2002 and 2004 were used to simulate potential outcomes for all patients listed for transplantation. The Markov simulation was then modified by screening matches using a 1200 or 1600 D-MELD risk cap ± allowing transplants for Model for End-Stage Liver Disease (MELD) ≤ 14 (Rule 14). The differential impact of the rule changes was assessed. RESULTS: The Markov simulation accurately reproduced overall and post transplant survival. A 1200 D-MELD risk cap improved post-transplant survival. Both the 1200 and 1600 risk caps improved overall survival for waitlisted patients. The addition of Rule 14 further improved post transplant and overall survival by redistribution of donor livers to recipients in higher MELD subgroups. The mechanism for improved overall and post-transplant survival after listing was due to shifting a larger percentage of transplants to the moderate MELD score subgroup (MELD 15-29) while also ensuring that high MELD recipients have livers of high quality to achieve excellent post transplant survival. CONCLUSION: A 1200 D-MELD risk cap + Rule 14 provided the greatest overall benefit primarily by focusing liver transplantation towards the moderate MELD recipient.

Congestive hepatic fibrosis score: a novel histologic assessment of clinical severity.

Chronic right heart failure predisposes to hepatic passive congestion and centrizonal necrosis that may lead to hepatic fibrosis (cardiac sclerosis). Although there have been several studies on the histologic features of congestive hepatopathy, there is no available grading system. In this study we developed a novel grading system for congestive hepatic fibrosis. Liver biopsies were examined in patients with chronic heart failure of various etiologies including congenital heart disease, idiopathic cardiomyopathy, ischemic heart disease, and valvular heart disease. The cases with available echocardiography and/or right heart catheterization were included. Cases with other types of underlying chronic liver diseases, alcoholic liver disease, significant steatosis (>20%), malignant neoplasm, and acute heart failure or shock were excluded. After exclusion, 42 cases were included in the study. We herein proposed a novel congestive hepatic fibrosis score and correlated it with the right heart structure and function obtained by echocardiography and/or right heart catheterization. Our results showed that congestive hepatic fibrosis score is well correlated with the right atrial pressure (P for trend <0.001). The presence of portal fibrosis (congestive hepatic fibrosis scores 2 and 3) is associated with significantly higher right atrial pressure than those with no fibrosis (P<0.001) or with centrizonal fibrosis only (P=0.02). Congestive hepatic fibrosis score is also significantly associated with increasing severity of right atrial dilatation (P=0.03) and right ventricular dilatation (P=0.02), indicators for chronic volume and/or pressure overload. Other histopathologic features include sinusoidal dilatation and centrizonal hepatocyte atrophy. In summary, although sinusoidal dilatation and centrizonal fibrosis are the hallmarks of hepatic passive congestion, the presence of portal fibrosis is suggestive of more advanced disease, as it correlates with more severe impairment of right heart function, regardless of the etiologies of right heart failure. Congestive hepatic fibrosis score is a useful indicator of clinical severity.

Advancing the high throughput identification of liver fibrosis protein signatures using multiplexed ion mobility spectrometry.

Rapid diagnosis of disease states using less invasive, safer, and more clinically acceptable approaches than presently employed is a crucial direction for the field of medicine. While MS-based proteomics approaches have attempted to meet these objectives, challenges such as the enormous dynamic range of protein concentrations in clinically relevant biofluid samples coupled with the need to address human biodiversity have slowed their employment. Herein, we report on the use of a new instrumental platform that addresses these challenges by coupling technical advances in rapid gas phase multiplexed ion mobility spectrometry separations with liquid chromatography and MS to dramatically increase measurement sensitivity and throughput, further enabling future high throughput MS-based clinical applications. An initial application of the liquid chromatography--ion mobility spectrometry-MS platform analyzing blood serum samples from 60 postliver transplant patients with recurrent fibrosis progression and 60 nontransplant patients illustrates its potential utility for disease characterization.

The HALOS-ND model: a step in the journey of predicting hospital length of stay after liver transplantation.

Hospital length of stay (LOS) after liver transplantation has been determined to correlate with liver disease severity, post-transplant survival rates, and transplant-associated costs. A patient's model for end-stage liver disease (MELD) score and an organ's Donor risk index (DRI) have both been found to be significant predictors of LOS, but these two factors alone are insufficient to form an accurate prediction. Previous studies have identified other factors predictive of LOS, which can be incorporated with MELD and DRI to create more specific results. The objective of this study was to create an algorithm, or models, based on the most significant LOS predictors as identified from national data at different stages of the transplant process. Four models were developed predicting LOS using recipient factors, payment factors, donor factors, and postoperative factors. A medical care team member can enter a patient's data into the model and receive a reasonably accurate prediction of LOS for each phase of the liver transplant process, specifying the impact of each factor. These predictions would help predict the factors most likely to prolong LOS, inform resource allocation, and provide patients with more specific predictions of their LOS following transplantation.

Proteome and computational analyses reveal new insights into the mechanisms of hepatitis C virus-mediated liver disease posttransplantation.

UNLABELLED: Liver transplant tissues offer the unique opportunity to model the longitudinal protein abundance changes occurring during hepatitis C virus (HCV)-associated liver disease progression in vivo. In this study, our goal was to identify molecular signatures, and potential key regulatory proteins, representative of the processes influencing early progression to fibrosis. We performed global protein profiling analyses on 24 liver biopsy specimens obtained from 15 HCV(+) liver transplant recipients at 6 and/or 12 months posttransplantation. Differentially regulated proteins associated with early progression to fibrosis were identified by analysis of the area under the receiver operating characteristic curve. Analysis of serum metabolites was performed on samples obtained from an independent cohort of 60 HCV(+) liver transplant patients. Computational modeling approaches were applied to identify potential key regulatory proteins of liver fibrogenesis. Among 4,324 proteins identified, 250 exhibited significant differential regulation in patients with rapidly progressive fibrosis. Patients with rapid fibrosis progression exhibited enrichment in differentially regulated proteins associated with various immune, hepatoprotective, and fibrogenic processes. The observed increase in proinflammatory activity and impairment in antioxidant defenses suggests that patients who develop significant liver injury experience elevated oxidative stresses. This was supported by an independent study demonstrating the altered abundance of oxidative stress-associated serum metabolites in patients who develop severe liver injury. Computational modeling approaches further highlight a potentially important link between HCV-associated oxidative stress and epigenetic regulatory mechanisms impacting on liver fibrogenesis. CONCLUSION: Our proteome and metabolome analyses provide new insights into the role for increased oxidative stress in the rapid fibrosis progression observed in HCV(+) liver transplant recipients. These findings may prove useful in prognostic applications for predicting early progression to fibrosis.

Early transcriptional programming links progression to hepatitis C virus-induced severe liver disease in transplant patients.

UNLABELLED: Liver failure resulting from chronic hepatitis C virus (HCV) infection is a major cause for liver transplantation worldwide. Recurrent infection of the graft is universal in HCV patients after transplant and results in a rapid progression to severe fibrosis and end-stage liver disease in one third of all patients. No single clinical variable, or combination thereof, has, so far, proven accurate in identifying patients at risk of hepatic decompensation in the transplant setting. A combination of longitudinal, dimensionality reduction and categorical analysis of the transcriptome from 111 liver biopsy specimens taken from 57 HCV-infected patients over time identified a molecular signature of gene expression of patients at risk of developing severe fibrosis. Significantly, alterations in gene expression occur before histologic evidence of liver disease progression, suggesting that events that occur during the acute phase of infection influence patient outcome. Additionally, a common precursor state for different severe clinical outcomes was identified. CONCLUSION: Based on this patient cohort, incidence of severe liver disease is a process initiated early during HCV infection of the donor organ. The probable cellular network at the basis of the initial transition to severe liver disease was identified and characterized.

Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data.

INTRODUCTION: A meta-analysis was performed using individual patient data from the five most recent randomised controlled trials (RCTs) which evaluated corticosteroids in severe alcoholic hepatitis (Maddrey discriminant function (DF) ≥ 32 or encephalopathy). This approach overcomes limitations associated with the use of literature data and improves the relevance of the study and estimates of effect size. AIMS: To compare 28-day survival between corticosteroid- and non-corticosteroid-treated patients and to analyse the response to treatment using the Lille model. METHODS: Individual patient data were obtained from five RCTs comparing corticosteroid treatment with placebo (n=3), enteral nutrition (n=1) or an antioxidant cocktail (n=1). RESULTS: 221 patients allocated to corticosteroid treatment and 197 allocated to non-corticosteroid treatment were analysed. The two groups were similar at baseline. 28-day survival was higher in corticosteroid-treated patients than in non-corticosteroid-treated patients (79.97±2.8% vs 65.7±3.4%, p=0.0005). In multivariate analysis, corticosteroids (p=0.005), DF (p=0.006), leucocytes (p=0.004), Lille score (p<0.00001) and encephalopathy (p=0.003) were independently predictive of 28-day survival. A subgroup analysis was performed according to the percentile distribution of the Lille score. Patients were classified as complete responders (Lille score ≤ 0.16; ≤ 35th percentile), partial responders (Lille score 0.16-0.56; 35th-70th percentile) and null responders (Lille ≥ 0.56; ≥ 70th percentile). 28-day survival was strongly associated with these groupings (91.1±2.7% vs 79.4±3.8% vs 53.3±5.1%, p<0.0001). Corticosteroids had a significant effect on 28-day survival in complete responders (HR 0.18, p=0.006) and in partial responders (HR 0.38, p=0.04) but not in null responders. CONCLUSION: Analysis of individual data from five RCTs showed that corticosteroids significantly improve 28-day survival in patients with severe alcoholic hepatitis. The survival benefit is mainly observed in patients classified as responders by the Lille model.

Use of an automated clinical management system improves outpatient immunosuppressive care following liver transplantation.

OBJECTIVE: Immunosuppressive therapy following transplantation, if not managed well, can lead to increased drug toxicity or rejection episodes. We investigated whether use of an automated clinical management system in our liver transplant program would improve clinical outcomes in managing transplant recipients' immunosuppressive medications. DESIGN: We performed a retrospective cohort study of two patient groups receiving liver transplants at our institution. One group of 301 patients transplanted from January 1, 2004 to November 30, 2006 received outpatient immunosuppressive management using a paper charting system. After instituting an automated clinical management system, the following group of 127 patients transplanted from December 12, 2006 to April 1, 2008 received their outpatient immunosuppressive management with that system. Only patients who received tacrolimus therapy, with or without mycophenolate mofetil or prednisone, were studied. MEASUREMENTS: Our endpoints included percentage of patients having rejection and/or tacrolimus toxicity episodes. Various recipient, intraoperative, donor, and postoperative variables, including managing the immunosuppressive therapy with a paper charting system or an automated management system, were studied to determine which factors were associated with our endpoints. RESULTS: Multivariable logistic regression analysis showed the automated system was significantly associated with fewer rejection episodes and fewer tacrolimus toxicity events. Formal cost-effectiveness analysis of the nurses' salaries for 1 year showed the automated system cost US$197 per patient and the paper system cost US$1703 per patient. The automated system improved quality of life years. CONCLUSION: Use of an automated clinical management system for outpatient immunosuppressive management for liver transplant patients has resulted in a decrease in both tacrolimus toxicity and rejection episodes and is cost-effective.

Genetic diversity of hepatitis C virus predicts recurrent disease after liver transplantation.

Approximately 20% of patients receiving liver transplants for end-stage hepatitis C rapidly develop severe allograph fibrosis within the first 24 months after transplant. Hepatitis C virus (HCV) variants were studied in 56 genotype-1-infected subjects with end-stage hepatitis C disease at the time before and 12 months after liver transplant, and post-transplant outcome was followed with serial liver biopsies. In 15 cases, pre-transplant HCV genetic diversity was studied in detail in liver (n=15), serum (n=15), peripheral blood mononuclear cells (n=13), and perihepatic lymph nodes (n=10). Our results revealed that pre-transplant HCV genetic diversity predicted the histological outcome of recurrent hepatitis C disease after transplant. Mild disease recurrence after transplant was significantly associated with higher genetic diversity and greater diversity changes between the pre- and post-transplant time points (p=0.004). Meanwhile, pre-transplant genetic differences between serum and liver were related to a higher likelihood of development of mild recurrent disease after transplant (p=0.039).

Hepatitis C virus induces oxidative stress, DNA damage and modulates the DNA repair enzyme NEIL1.

BACKGROUND AND AIMS: Hepatitis C virus (HCV)-induced chronic inflammation may induce oxidative stress which could compromise the repair of damaged DNA, rendering cells more susceptible to spontaneous or mutagen-induced alterations, the underlying cause of liver cirrhosis and hepatocellular carcinoma. In the current study we examined the induction of reactive oxygen species (ROS) resulting from HCV infection and evaluated its effect on the host DNA damage and repair machinery. METHODS: HCV infected human hepatoma cells were analyzed to determine (i) ROS, (ii) 8-oxoG and (iii) DNA glycosylases NEIL1, NEIL2, OGG1. Liver biopsies were analyzed for NEIL1. RESULTS: Human hepatoma cells infected with HCV JFH-1 showed 30-60-fold increases in ROS levels compared to uninfected cells. Levels of the oxidatively modified guanosine base 8-oxoguanine (8-oxoG) were significantly increased sixfold in the HCV-infected cells. Because DNA glycosylases are the enzymes that remove oxidized nucleotides, their expression in HCV-infected cells was analyzed. NEIL1 but not OGG1 or NEIL2 gene expression was impaired in HCV-infected cells. In accordance, we found reduced glycosylase (NEIL1-specific) activity in HCV-infected cells. The antioxidant N-acetyl cystein (NAC) efficiently reversed the NEIL1 repression by inhibiting ROS induction by HCV. NEIL1 expression was also partly restored when virus-infected cells were treated with interferon (IFN). HCV core and to a lesser extent NS3-4a and NS5A induced ROS, and downregulated NEIL1 expression. Liver biopsy specimens showed significant impairment of NEIL1 levels in HCV-infected patients with advanced liver disease compared to patients with no disease. CONCLUSION: Collectively, the data indicate that HCV induction of ROS and perturbation of NEIL1 expression may be mechanistically involved in progression of liver disease and suggest that antioxidant and antiviral therapies can reverse these deleterious effects of HCV in part by restoring function of the DNA repair enzyme/s.

Liver transplantation at the extremes of the body mass index.

Controversies exist regarding the morbidity and mortality of patients undergoing liver transplantation at the extremes of the body mass index (BMI). A review of the United Network for Organ Sharing database from 1987 through 2007 revealed 73,538 adult liver transplants. Patients were stratified into 6 BMI categories established by the World Health Organization: underweight, <18.5 kg/m(2); normal weight, 18.5 to <25 kg/m(2); overweight, 25 to <30 kg/m(2); obese, 30 to <35 kg/m(2); severely obese, 35 to <40 kg/m(2); and very severely obese, > or =40 kg/m(2). Survival rates were compared among these 6 categories via Kaplan-Meier survival curves with the log-rank test. The underweight and very severely obese groups had significantly lower survival. There were 1827 patients in the underweight group, 1447 patients in the very severely obese group, and 68,172 patients in the other groups, which became the control. Groups with extreme BMI (<18.5 and > or =40) were compared to the control to assess significant differences. Underweight patients were more likely to die from hemorrhagic complications (P < 0.002) and cerebrovascular accidents (P < 0.04). When compared with the control, the very severely obese patients had a higher number of infectious complications and cancer events (P = 0.02) leading to death. In 3 different eras of liver transplantation, multivariable analysis showed that underweight and very severe obesity were significant predictors of death. In conclusion, liver transplantation holds increased risk for patients at the extremes of BMI. Identifying these patients and instituting aggressive new policies may improve outcomes. Liver Transpl 15:968-977, 2009. (c) 2009 AASLD.

Should liver transplantation in patients with model for end-stage liver disease scores

Studies have shown that liver transplantation offers no survival benefits to patients with Model for End-Stage Liver Disease (MELD) scores or=18 years) listed for or undergoing primary liver transplantation in the United States for chronic liver disease from 1/1/2003 through 12/31/2007 with follow-up until 2/1/2008. The "Rule 14" policy gave a 3% improvement in overall patient survival over the present system at 1, 2, 3, and 4 years and predicted a 13% decrease in overall waitlist time for patients with MELD scores of 15 to 40. Patients with the greatest benefit from a "Rule 14" policy were those with MELD scores of 6 to 10, for whom a 17% survival advantage was predicted from waiting on the list versus undergoing transplantation. Our analysis supports changing the national liver allocation policy to not allow liver transplantation for patients with MELD

Investigation of putative multisubtype hepatitis C virus infections in vivo by heteroduplex mobility analysis of core/envelope subgenomes.

The frequency that multiple different subtypes of hepatitis C virus (HCV) simultaneously infect a given individual is controversial. To address this question, heteroduplex mobility analysis (HMA) of portions of the HCV core and envelope 1 region was optimized for sensitive and specific detection of mixtures of HCV genomes of different genotype or subtype. Using the standard HCV genotyping approach of 5'-untranslated region (UTR) analysis, 28 of 374 (7.5%) chronic hepatitis C research subjects were classified as having either multiple-subtype HCV infections (n = 21) or switching HCV subtypes over time (n = 7), the latter pattern implying viral superinfection. Upon retesting of specimens by HMA, 25 of 28 multiple-subtype results could not be reproduced. All three patients with positive results were injection drug users with potential multiple HCV exposures. To address the hypothesis of tissue sequestration of multiple-subtype HCV infections, liver (n = 22), peripheral blood mononuclear cell (n = 13), perihepatic lymph node (n = 16), and serum (n = 19) specimens from 23 subjects with end-stage hepatitis C were collected and analyzed by the HMA technique. Whereas 5'-UTR results implicated mixed-subtype HCV infections in 2 subjects, HMA testing revealed no evidence of a second HCV subtype in any tissue compartment (0 of 70 compartments [0%]) or within any given subject (0 of 23 subjects [0%]). In summary, a large proportion of mixed-genotype and switching-genotype patterns generated by 5'-UTR analysis were not reproducible using the HMA approach, emphasizing the need for additional study.