Association of Body Surface Area With Access to Deceased Donor Liver Transplant and Novel Allocation Policies.

Importance: Small waitlist candidates are significantly less likely than larger candidates to receive a liver transplant. Objective: To investigate the magnitude of the size disparity and test potential policy solutions. Design, Setting, and Participants: A decision analytical model was generated to match liver transplant donors to waitlist candidates based on predefined body surface area (BSA) ratio limits (donor BSA divided by recipient BSA). Participants included adult deceased liver transplant donors and waitlist candidates in the Organ Procurement and Transplantation Network database from June 18, 2013, to March 20, 2020. Data were analyzed from January 2021 to September 2021. Exposures: Candidates were categorized into 6 groups according to BSA from smallest (group 1) to largest (group 6). Waitlist outcomes were examined. A match run was created for each donor under the current acuity circle liver allocation policy, and the proportion of candidates eligible for a liver based on BSA ratio was calculated. Novel allocation models were then tested. Main Outcomes and Measures: Time on the waitlist, assigned Model for End-Stage Liver Disease (MELD) score, and proportion of patients undergoing a transplant were compared by BSA group. Modeling under the current allocation policies was used to determine baseline access to transplant by group. Simulation of novel allocation policies was performed to examine change in access. Results: There were 41 341 donors (24 842 [60.1%] male and 16 499 [39.9%] female) and 84 201 waitlist candidates (53 724 [63.8%] male and 30 477 [36.2%] female) in the study. The median age of the donors was 42 years (IQR, 28-55) and waitlist candidates, 57 years (IQR, 50-63). Females were overrepresented in the 2 smallest BSA groups (7100 [84.0%] and 7922 [61.1%] in groups 1 and 2, respectively). For each increase in group number, waitlist time decreased (234 days [IQR, 48-700] for group 1 vs 179 days [IQR, 26-503] for group 6; P < .001) and the proportion of the group undergoing transplant likewise improved (3890 [46%] in group 1 vs 4932 [57%] in group 6; P < .001). The smallest 2 groups of candidates were disadvantaged under the current acuity circle allocation model, with 37% and 7.4% fewer livers allocated relative to their proportional representation on the waitlist. Allocation of the smallest 10% of donors (by BSA) to the smallest 15% of candidates overcame this disparity, as did performing split liver transplants. Conclusions and Relevance: In this study, liver waitlist candidates with the smallest BSAs had a disadvantage due to size. Prioritizing allocation of smaller liver donors to smaller candidates may help overcome this disparity.

A Simple Measure of Hepatocellular Carcinoma Burden Predicts Tumor Recurrence After Liver Transplantation: The Recurrent Hepatocellular Carcinoma-Initial, Maximum, Last Classification.

Risk of recurrent hepatocellular carcinoma (rHCC) after liver transplantation (LT) depends on the pre-LT HCC burden, tumor behavior, and response to locoregional therapy (LRT). In December 2017, LT priority for HCC was expanded to select patients outside the Milan criteria who respond to LRT. Our aims were to develop a novel objective measure of pre-LT HCC burden (model of recurrent hepatocellular carcinoma-initial, maximum, last [RH-IML]), incorporating tumor behavior over time, and to apply RH-IML to model post-LT rHCC. Using United Network for Organ Sharing data from between 2002-2014 (development) and 2015-2017 (validation), we identified adult LT recipients with HCC and assessed pre-LT HCC tumor behavior and post-LT rHCC. For each patient, HCC burden was measured at 3 points on the waiting list: initial (I), maximum (M) total tumor diameter, and last (L) exception petition. HCC burden at these 3 points were classified as (A) Milan to University of California, San Francisco (UCSF), and (D) >UCSF, resulting in each patient having a 3-letter RH-IML designation. Of 16,558 recipients with HCC, 1233 (7%) had any post-LT rHCC. rHCC rates were highest in RH-IML group CCC (15%) and DDD (18%). When M and L tumor burdens did not exceed Milan (class B or A), rHCC was low (≤10%) as in AAA, ABA, ABB, BBA, BBB; rHCC was also low (≤10%) with successful downstaging when L was A (

Neutrophil-to-Lymphocyte Ratio Associates Independently With Mortality in Hospitalized Patients With Cirrhosis.

BACKGROUND & AIMS: The neutrophil to lymphocyte ratio (NLR) is a biomarker of immune dysregulation in patients with cirrhosis and is inexpensive to measure. We investigated the association between NLR and mortality in hospitalized patients with cirrhosis at 4 liver transplant centers, controlling for severity of acute-on-chronic liver failure (ACLF). METHODS: We performed a retrospective study using data from the North American Consortium for the Study of End-stage Liver Disease on patients with index hospitalizations for cirrhosis from December 2011 through December 2016. We collected data on patient demographics, NLR, model for end-stage liver disease (MELD) scores, serum levels of Na, cirrhosis stages, infections, hepatocellular carcinomas, and ACLF severity (based on number of organ failures). Competing risk regression analysis evaluated mortality within 1 year after hospital discharge, accounting for competing events (liver transplant). RESULTS: At admission, the patients' mean age was 57 years, mean MELD score was 21, and mean serum level of Na was 134 mmol/L. Sixty-eight patients had no organ failure, 21 patients had 1 organ failures, 7 patients had 2 organ failures, 4 patients had 3 organ failures, and 1 patient had 4 organ failures; 36% of the patients had confirmed or suspected infections. In univariate models, risk of death associated with increasing NLR, up to a value of 8 (hazard ratio [HR]= 1.14; 95% CI, 1.07-1.20; P < .001), and NLR quartile (for NLR range of 3-5, HR = 2.17; for NLR range of >5-9, HR=2.46; for NLR quartile >9, HR=2.84 vs the lowest quartile [NLR<3]) (P ≤ .001). The NLR remained statistically significant in multivariable models, adjusting for age, MELD score, hepatocellular carcinoma, and ACLF severity. Additionally, NLR was a statistically significant independent predictor of length of index hospital stay and mortality within 90 days after discharge. CONCLUSION: In a retrospective analysis of patients with cirrhosis, we found NLR to associate with death within 1 year after non-elective hospitalization. In these patients, the risk of death associated with acute immune dysregulation persists long after their initial hospitalization.

Neutrophil-to-lymphocyte ratio correlates with proinflammatory neutrophils and predicts death in low model for end-stage liver disease patients with cirrhosis.

The Model for End-Stage Liver Disease (MELD) score has reduced accuracy for liver transplantation (LT) wait-list mortality when MELD ≤ 20. Neutrophil-to-lymphocyte ratio (NLR) is a biomarker associated with systemic inflammation and may predict cirrhotic decompensation and death. We aimed to evaluate the prognostic utility of high NLR (≥4) for liver-related death among low MELD patients listed for LT, controlling for stage of cirrhosis. In a nested case-control study of cirrhotic adults awaiting LT (February 2002 to May 2011), cases were LT candidates with a liver-related death and MELD ≤ 20 within 90 days of death. Controls were similar LT candidates who were alive for ≥90 days after LT listing. NLR and other covariates were assessed at the date of lowest MELD, within 90 days of death for cases and within 90 days after listing for controls. There were 41 cases and 66 controls; MELD scores were similar. NLR 25th, 50th, 75th percentile cutoffs were 1.9, 3.1, and 6.8. NLR was ≥ 4 in 25/41 (61%) cases and in 17/66 (26%) controls. In univariate analysis, NLR (continuous ≥ 1.9, ≥ 4, ≥ 6.8), increasing cirrhosis stage, jaundice, encephalopathy, serum sodium, and albumin and nonselective beta-blocker use were significantly (P < 0.01) associated with liver-related death. In multivariate analysis, NLR of ≥1.9, ≥ 4, ≥ 6.8 were each associated with liver-related death. Furthermore, we found that NLR correlated with the frequency of circulating low-density granulocytes, previously identified as displaying proinflammatory properties, as well as monocytes. In conclusion, elevated NLR is associated with liver-related death, independent of MELD and cirrhosis stage. High NLR may aid in determining risk for cirrhotic decompensation, need for increased monitoring, and urgency for expedited LT in candidates with low MELD. Liver Transplantation 23 155-165 2017 AASLD.

The corrected donor age for hepatitis C virus-infected liver transplant recipients.

Donor age has become the dominant donor factor used to predict graft failure (GF) after liver transplantation (LT) in hepatitis C virus (HCV) recipients. The purpose of this study was to develop and validate a model of corrected donor age (CDA) for HCV LT recipients that transforms the risk of other donor factors into the scale of donor age. We analyzed all first LT recipients with HCV in the United Network for Organ Sharing (UNOS) registry from January 1998 to December 2007 (development cohort, n = 14,538) and January 2008 to December 2011 (validation cohort, n = 7502) using Cox regression, excluding early GF (<90 days from LT). Accuracy in predicting 1 year GF (death or repeat LT) was assessed with the net reclassification index (NRI). In the development cohort, after controlling for pre-LT recipient factors and geotemporal trends (UNOS region, LT year), the following donor factors were independent predictors of GF, all P < 0.05: donor age (hazard ratio [HR], 1.02/year), donation after cardiac death (DCD; HR, 1.31), diabetes (HR, 1.23), height < 160 cm (HR, 1.13), aspartate aminotransferase (AST) ≥ 120 U/L (HR, 1.10), female (HR, 0.94), cold ischemia time (CIT; HR, 1.02/hour), and non-African American (non-AA) donor-African American (AA) recipient (HR, 1.65). Transforming these risk factors into the donor age scale yielded the following: DCD = +16 years; diabetes = +12 years; height < 160 cm = +7 years; AST ≥ 120 U/L = +5 years; female = -4 years; and CIT = +1 year/hour > 8 hours and -1 year/hour < 8 hours. There was a large effect of donor-recipient race combinations: +29 years for non-AA donor and an AA recipient but only +5 years for an AA donor and an AA recipient, and -2 years for an AA donor and a non-AA recipient. In a validation cohort, CDA better classified risk of 1-year GF versus actual age (NRI, 4.9%; P = 0.009) and versus the donor risk index (9.0%, P < 0.001). The CDA, compared to actual donor age, provides an intuitive and superior estimation of graft quality for HCV-positive LT recipients because it incorporates additional factors that impact LT GF rates.

Low, rather than high, body mass index confers increased risk for post-liver transplant death and graft loss: Risk modulated by model for end-stage liver disease.

With increasing attention being paid to optimizing patient outcomes, it has been proposed that liver transplantation (LT) for individuals with elevated body mass index (BMI) values and high Model for End-Stage Liver Disease (MELD) scores may adversely affect post-LT outcomes. We investigated the impact of BMI on post-LT outcomes in the context of MELD at LT. Using United Network for Organ Sharing data, we identified all adult (≥ 18 years) primary LT recipients from March 1, 2002 to September 30, 2011. BMI categories included the following: underweight, normal, overweight, class I obese, class II obese, and class III obese (<18.5; 18.5-24.9; 25-29.9; 30-34.9; 35-39.9; ≥ 40 kg/m(2), respectively). One-year post-LT death and graft loss were modeled using Cox regression, including interactions between BMI and MELD. A total of 45,551 adult recipients were identified: 68% male; median (interquartile range [IQR]) age 55 years (IQR, 49-60 years); MELD, 19 (IQR, 13-26); and donor risk index, 1.39 (IQR, 1.12-1.69). Representations in the BMI categories were underweight (n = 863, 2%), normal (n = 13,262, 29%), overweight (n = 16,329, 36%), class I obese (n = 9639, 21%), class II obese (n = 4062, 9%), and class III obese (n = 1396, 3%). In adjusted analyses, elevated BMI was not associated with increased risk for death or graft loss. Among the underweight, there were significant interactions between BMI and MELD with respect to death (P = 0.02) and graft loss (P = 0.01), with significantly increased risks for death (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.38-2.09; P = 0.006) and graft loss (HR, 1.45; 95% CI, 1.21-1.74; P = 0.02) among those with low MELD (≤ 26), compared to normal BMI recipients with low MELD. In conclusion, overweight and obese LT recipients do not have increased risk of death or graft loss regardless of MELD. Underweight patients are at increased risk for poor outcomes post-LT, specifically underweight recipients with low MELD have increased risk for death and graft loss. Mechanisms underlying this phenomenon warrant further investigation.

Optimizing repeat liver transplant graft utility through strategic matching of donor and recipient characteristics.

Repeat liver transplantation (LT) is controversial because of inferior outcomes versus primary LT. A minimum 1-year expected post-re-LT survival of 50% has been proposed. We aimed to identify combinations of Model for End-Stage Liver Disease (MELD), donor risk index (DRI), and recipient characteristics achieving this graft survival threshold. We identified re-LT recipients listed in the United States from March 2002 to January 2010 with > 90 days between primary LT and listing for re-LT. Using Cox regression, we estimated the expected probability of 1-year graft survival and identified combinations of MELD, DRI, and recipient characteristics attaining >50% expected 1-year graft survival. Re-LT recipients (n = 1418) had a median MELD of 26 and median age of 52 years. Expected 1-year graft survival exceeded 50% regardless of MELD or DRI in Caucasian recipients who were not infected with hepatitis C virus (HCV) of all ages and Caucasian HCV-infected recipients <50 years old. As age increased in HCV-infected Caucasian and non-HCV-infected African American recipients, lower MELD scores or lower DRI grafts were needed to attain the graft survival threshold. As MELD scores increased in HCV-infected African American recipients, lower-DRI livers were required to achieve the graft survival threshold. Use of high-DRI livers (>1.44) in HCV-infected recipients with a MELD score > 26 at re-LT failed to achieve the graft survival threshold with recipient age ≥ 60 years (any race), as well as at age ≥ 50 years for Caucasians and at age < 50 years for African Americans. Strategic donor selection can achieve >50% expected 1-year graft survival even in high-risk re-LT recipients (HCV infected, older age, African American race, high MELD scores). Low-risk transplant recipients (age < 50 years, non-HCV-infected) can achieve the survival threshold with varying DRI and MELD scores.

Risk factors associated with acute heart failure during liver transplant surgery: a case control study.

BACKGROUND: Acute intraoperative heart failure (HF) is a rare but often fatal complication of liver transplant surgery. Little is known about the clinical course or predictive variables. Our aims were to provide a detailed clinical description and conduct a systematic search for characteristics associated with intraoperative HF. METHODS: A matched case-control study of adults undergoing primary liver transplant from 2009 to 2011 was conducted. Cases showed new onset HF with an ejection fraction less than 50% during liver transplant surgery. Controls were recipients without signs or symptoms of HF. Matching was based on: age, sex, model for end-stage liver disease at the time of transplant, type 2 diabetes, and ß-blocker use. Conditional logistic regression analyses were conducted. RESULTS: From 2009 to 2011, seven (3%) of 256 recipients developed intraoperative HF with one resulting death. All survivors regained normal systolic function within 6 months of surgery. Decreasing preoperative serum sodium (odds ratio, 1.41; 95% confidence interval, 1.02-1.94; P = 0.039) and increasing number of units of packed red blood cells transfused intraoperatively (odds ratio=1.2, 95% confidence interval, 1.001-1.467, P = 0.048) were associated with HF. CONCLUSION: No preoperative echocardiographic parameter predicted HF in affected patients. Two possible explanations are: our patients suffered from stress cardiomyopathy and therefore had no evidence of impaired contraction before the event or echocardiographic predictors of HF were masked by circulatory changes in patients with cirrhosis. Lower serum sodium and more red blood cell transfusions were associated with intraoperative HF. Lower mortality of our intraoperative cases compared to others may be influenced by earlier diagnosis and intervention.

Low awareness of nonalcoholic fatty liver disease among patients at high metabolic risk.

GOALS: To assess awareness of nonalcoholic fatty liver disease (NAFLD) as a disease entity among individuals with and without metabolic risk factors in an outpatient clinical setting, and to evaluate interest in patient-centered education on NAFLD. BACKGROUND: NAFLD is the most common chronic liver disease in the United States with up to 30% of the adult population affected. Individuals with metabolic risk factors, particularly, insulin resistance, diabetes, and overweight/obesity, have a high prevalence of NAFLD estimated up to 70%, yet little is known about the understanding and perceptions of NAFLD in these high-risk patients. STUDY: A self-administered paper questionnaire was given to 368 adult patients presenting to an outpatient endocrinology clinic from February 2012 to October 2012. RESULTS: A total of 302 surveys were completed for a response rate of 82%. Overall, 18% of all respondents reported awareness of NAFLD. Even among patients with self-reported major risk factors for NAFLD (overweight/obese, insulin resistant, or both overweight/obese and insulin resistant), the rates of awareness of NAFLD were low (19%, 23%, and 24%, respectively). A majority of survey respondents expressed interest in receiving patient-centered education on NAFLD (73%). CONCLUSIONS: Among high metabolic risk individuals there is low awareness of NAFLD. The majority of those surveyed expressed interest in learning about NAFLD. These findings suggest opportunities to raise public awareness of NAFLD, particularly among patients at high metabolic risk, and to provide education to high-risk individuals with the goal of implementing early prevention strategies and optimizing care.

Stage of cirrhosis predicts the risk of liver-related death in patients with low Model for End-Stage Liver Disease scores and cirrhosis awaiting liver transplantation.

The Model for End-Stage Liver Disease (MELD) score has reduced predictive ability in patients with cirrhosis and MELD scores ≤ 20. We aimed to assess whether a 5-stage clinical model could identify liver transplantation (LT) candidates with low MELD scores who are at increased risk for death. We conducted a case-control study of subjects with cirrhosis and MELD scores ≤ 20 who were awaiting LT at a single academic medical center between February 2002 and May 2011. Conditional logistic regression was used to evaluate the risk of liver-related death according to the cirrhosis stage. We identified 41 case subjects who died from liver-related causes with MELD scores ≤ 20 within 90 days of death while they were waiting for LT. The cases were matched with up to 3 controls (66 controls in all) on the basis of the listing year, age, sex, liver disease etiology, presence of hepatocellular carcinoma, and MELD score. The cirrhosis stage was assessed for all subjects: (1) no varices or ascites, (2) varices, (3) variceal bleeding, (4) ascites, and (5) ascites and variceal bleeding. The MELD scores were similar for cases and controls. Clinical states contributing to death in cases were: sepsis 49%, spontaneous bacterial peritonitis 15%, variceal bleeding 24%, and hepatorenal syndrome 22%. In a univariate analysis, variceal bleeding [odds ratio (OR) = 5.6, P = 0.003], albumin (OR = 0.5, P = 0.041), an increasing cirrhosis stage (P = 0.003), reaching cirrhosis stage 2, 3, or 4 versus lower stages (OR = 3.6, P = 0.048; OR = 7.4, P < 0.001; and OR = 4.1, P = 0.008), a sodium level < 135 mmol/L (OR = 3.4, P = 0.006), and hepatic encephalopathy (OR = 2.3, P = 0.082) were associated with liver-related death. In a multivariate model including the cirrhosis stage, albumin, sodium, and hepatic encephalopathy, an increasing cirrhosis stage (P = 0.010) was independently associated with liver-related death. In conclusion, assessing the cirrhosis stage in patients with low MELD scores awaiting LT may help to select candidates for more aggressive monitoring or for living or extended criteria donation.

Identifying practice gaps to optimize medical care for patients with nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease. Primary care providers (PCPs), in contrast to gastroenterology/hepatology (GI/Hep) providers, are the first medical contact for the majority of patients with, or at risk for, NAFLD. PCP awareness of and facility with NAFLD is critical for management of these patients. AIM: The purpose of this study was to assess understanding and practice patterns of PCPs and non-GI/Hep subspecialty providers with respect to the diagnosis and management of NAFLD. METHODS: We administered an online, 61-question survey to 479 providers in internal medicine, family medicine, endocrinology, cardiology, and obstetrics and gynecology (ObGyn) across three health systems: academic medical center, safety-net health system and managed care health system. RESULTS: There were 246 respondents (51 %), with the majority (87 %) being PCPs (internal medicine, family medicine, ObGyn). Only 31 % of providers identified NAFLD as a clinically important diagnosis in their practice. Although 65 % of providers reported some degree of facility in diagnosing NAFLD, less than half (47 %) were comfortable managing NAFLD. Only 33 % refer patients with suspected NAFLD to GI/Hep. Subspecialists in endocrinology and cardiology reported greater clinical concern over NAFLD and were more likely (67 %) to refer patients with suspected NAFLD to GI/Hep. CONCLUSIONS: The majority of providers do not identify NAFLD as a clinically important diagnosis and do not refer to GI/Hep. However, 83 % expressed a need for education on NAFLD. Our data reveal practice gaps within NAFLD care and identify opportunities for targeted education to guide PCPs in the evaluation and management of NAFLD.

Differential effects of donor and recipient IL28B and DDX58 SNPs on severity of HCV after liver transplantation.

BACKGROUND & AIMS: IL28B single nucleotide polymorphisms are strongly associated with spontaneous HCV clearance and treatment response in non-transplant populations. A DDX58 single nucleotide polymorphism is associated with the antiviral response of innate lymphocytes. We aimed at evaluating the associations of donor and recipient IL28B (rs12979860 and rs8099917) and DDX58 (rs10813831) genotypes with severity of HCV recurrence after liver transplantation. METHODS: In a case-control study of 523 liver transplantation recipients with HCV, we matched severe with mild recurrent HCV based on 2-year clinical and histologic follow-up. A total of 440 liver transplantation recipients (severe, n=235; mild, n=205) with recipient DNA and 225 (severe, n=123; mild, n=102) with both recipient and donor DNA were analyzed. RESULTS: IL28B [rs12979860, non-CC (vs. CC) and rs8099917, non-TT (vs. TT)] in the recipient-only analysis had higher risk of severe recurrent HCV [OR 1.57 and 1.58, p<0.05]. However, for the 225 with donor and recipient DNA, IL28B rs12979860 CC (vs. non-CC) and rs8099917 TT (vs. non-TT) and DDX58 rs10813831 non-GG (vs. GG) were associated with more (not less) severe recurrent HCV. The greatest risk of severe recurrent HCV was for rs12979860 CC donors in non-CC recipients (OR 7.02, p <0.001, vs. non-CC donor/recipient) and for rs8099917 TT donors in non-TT recipients (OR 5.78, p=0.001, vs. non-TT donor/recipient). These associations persisted after controlling for donor age, donor race, and donor risk index. CONCLUSIONS: IL28B and DDX58 single nucleotide polymorphisms that are favorable when present in the non-transplant setting or in the recipient are unfavorable when present in a donor liver graft.

Projected future increase in aging hepatitis C virus-infected liver transplant candidates: a potential effect of hepatocellular carcinoma.

In the United States, the peak hepatitis C virus (HCV) antibody prevalence of 4% occurred in persons born in the calendar years 1940-1965. The goal of this study was to examine observed and projected age-specific trends in the demand for liver transplantation (LT) among patients with HCV-associated liver disease stratified by concurrent hepatocellular carcinoma (HCC). All new adult LT candidates registered with the Organ Procurement and Transplantation Network for LT between 1995 and 2010 were identified. Patients who had primary, secondary, or text field diagnoses of HCV with or without HCC were identified. There were 126,862 new primary registrants for LT, and 52,540 (41%) had HCV. The number of new registrants with HCV dramatically differed by the age at calendar year, and this suggested a birth cohort effect. When the candidates were stratified by birth year in 5-year intervals, the birth cohorts with the highest frequency of HCV were as follows (in decreasing order): 1951-1955, 1956-1960, 1946-1950, and 1941-1945. These 4 birth cohorts, spanning from 1941 to 1960, accounted for 81% of all new registrants with HCV. A 4-fold increase in new registrants with HCV and HCC occurred between the calendar years 2000 and 2010 in the 1941-1960 birth cohorts. By 2015, we anticipate that an increasing proportion of new registrants with HCV will have HCC and be ≥60 years old (born in or before 1955). In conclusion, the greatest demand for LT due to HCV-associated liver disease is occurring among individuals born between 1941 and 1960. This demand appears to be driven by the development of HCC in patients with HCV. During the coming decade, the projected increase in the demand for LT from an aging HCV-infected population will challenge the transplant community to reconsider current treatment paradigms.

Race- and gender-related variation in natural killer p46 expression associated with differential anti-hepatitis C virus immunity.

UNLABELLED: Major racial and gender differences have been documented in the natural history and treatment responses of chronic hepatitis C virus (HCV) infection; however, distinct mechanisms have remained enigmatic. We hypothesized that racial- and gender-related differences in natural killer (NK) cell populations may explain altered natural history and treatment responses. Our study cohort consisted of 29 African-American (AA; 55% male) and 29 Caucasian-American (CA; 48% male) healthy uninfected control subjects. Multiparameter flow cytometric analysis was used to characterize levels, phenotype with respect to 14 NK receptors, and lymphokine-activated killing (LAK) function. Gene expression was assessed by real-time reverse-transcriptase polymerase chain reaction after 6-hour in vitro stimulation with Toll-like receptor (TLR) ligands. The ability to control HCV infection was assessed in the Huh-7.5/JFH-1 coculture system. NK expression of natural cytotoxicity receptor NKp46 was strongly associated with CA race and female gender and correlated positively with LAK activity (P = 0.0054). NKp46(high) NKs were more efficient at controlling HCV than their NKp46(low) counterparts (P < 0.001). Similarly, ligation of NKp46 on isolated NK cells resulted in a significant reduction in the HCV copy number detected in Huh-7.5/JFH-1 coculture (multiplicity of infection: 0.01) at an effector:target ratio of 5:1 (P < 0.005). After TLR stimulation, genes involved in cytotoxicity, but not cytokine genes, were significantly up-regulated in NKp46(high) NKs. Cytokine stimulation (interleukin [IL]-12 and IL-15) demonstrated that NKp46(high) NK cells have significantly higher interferon-gamma production than NKp46(low) cells. TLR stimulation significantly induced degranulation as well as tumor necrosis factor alpha (TNF-α)-related apoptosis-inducing ligand, Fas, and TNF-α protein expression in NKp46(high) NKs. NKp46 ligand was induced on HCV-infected hepatocytes. CONCLUSIONS: NKp46 expression may contribute to differential HCV responses. NKp46 expression correlates with anti-HCV activity in vitro and thus may prove to be a useful therapeutic target.

Natural killer inhibitory receptor expression associated with treatment failure and interleukin-28B genotype in patients with chronic hepatitis C.

UNLABELLED: Natural killer (NK) cells constitute a first line of defense against viral infections; their function is governed by the integration of signals from multiple activating and inhibitory surface receptors. We hypothesized that because NKs become rapidly activated by cytokines, response to anti-hepatitis C virus (HCV) therapy would be predicted by the phenotype and function of NKs. We used a cohort of 101 patients (55 African, 46 Caucasian-American) who received pegylated-interferon (IFN) and ribavirin for 48 weeks. Multiparameter FACS analysis was used to examine relative expression of 14 different inhibitory/activating receptors. Interleukin (IL)-28B genotyping (rs12979860) was also performed. Pretreatment levels of inhibitory receptors CD158a, CD158b, and CD158e were higher in patients who demonstrated poor viral decline within the first 28 days of therapy. Higher expression levels of inhibitory receptors NKG2A, CD158b, and CD158e were demonstrable in patients who failed to achieve sustained virologic response (SVR). Patients carrying the IL-28B T allele had higher NKG2A expression on effector NKs. We created a mathematical regression model incorporating race, viral level, and two inhibitory receptors. The area-under-the curve was 0.88, which is highly predictive of SVR. Moreover, the model performed complementarily with IL-28B across the CC, CT, and TT genotypes. Purified NKG2A(neg) NKs treated with pegylated-IFN-α for 4 hours demonstrated higher levels of IFN-γ-inducible protein-10 (IP-10) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) compared with their NKG2A(pos) counterparts. CONCLUSIONS: These results provide novel insights into the associations of NK phenotype with IL-28B genotype and gene expression patterns, as well as the role of NKs in mediating IFN-induced viral clearance of chronic HCV infection.

Inequities of the Model for End-Stage Liver Disease: an examination of current components and future additions.

PURPOSE OF REVIEW: The aim of this article is to examine the limitations of the Model for End-Stage Liver Disease (MELD) components and summarize data on promising new predictor variables. RECENT FINDINGS: Promising modifications to MELD have been aimed at identifying more accurate measurements of the current MELD components and at improving survival prediction in earlier stages of cirrhosis. Incorporation of new measurements of cholestasis, coagulopathy and renal dysfunction should improve accuracy and reliability of MELD in predicting mortality in end stage liver disease. Direct bilirubin may be a more specific surrogate marker of liver disease than total bilirubin and further investigation of its use in liver mortality risk models in warranted. The recently developed liver-specific international normalized ratio may mitigate thromboplastin-related variation in international normalized ratio measurements. The incorporation of more accurate assessments of renal function into MELD should improve prognostic accuracy and would avert systematic biases associated with serum creatinine. Hepatic venous pressure gradient and serum sodium are promising predictors of liver-related mortality that may warrant further consideration. SUMMARY: Modification to MELD, particularly if intended for use in liver transplant allocation, should be based upon objective, reliable, reproducible and readily available predictors; and be able to withstand rigorous model development and validation.