Hepatocellular carcinoma after direct-acting antivirals for hepatitis C is associated with KIR-HLA types predicting weak NK cell-mediated immunity.

BACKGROUND AND AIMS: Second-generation direct-acting antivirals (2G DAA) to cure HCV have led to dramatic clinical improvements. HCV-associated hepatocellular carcinoma (HCC), however, remains common. Impaired immune tumor surveillance may play a role in HCC development. Our cohort evaluated the effects of innate immune types and clinical variables on outcomes including HCC. METHODS: Participants underwent full HLA class I/KIR typing and long-term HCV follow-up. RESULTS: A total of 353 HCV+ participants were followed for a mean of 7 years. Cirrhosis: 25% at baseline, developed in 12% during follow-up. 158 participants received 2G DAA therapy. HCC developed without HCV therapy in 20 subjects, 24 HCC after HCV therapy, and 10 of these after 2G DAA. Two predictors of HCC among 2G DAA-treated patients: cirrhosis (OR, 10.0, p = 0.002) and HLA/KIR profiles predicting weak natural killer (NK) cell-mediated immunity (NK cell complementation groups 6, 9, 11, 12, OR of 5.1, p = 0.02). Without 2G DAA therapy: cirrhosis was the main clinical predictor of HCC (OR, 30.8, p < 0.0001), and weak NK-cell-mediated immunity did not predict HCC. CONCLUSION: Cirrhosis is the main risk state predisposing to HCC, but weak NK-cell-mediated immunity may predispose to post-2G DAA HCC more than intermediate or strong NK-cell-mediated immunity.

A chair-stand time of greater than 15 seconds is associated with an increased risk of death and hospitalization in cirrhosis.

Background: Frailty is a clinical state of increased vulnerability and is common in patients with cirrhosis. The liver frailty index (LFI) is a validated tool to evaluate frailty in cirrhosis, comprising of grip strength, chair stands, and balance tests. The chair-stand test is an easy to conduct frailty subcomponent that does not require specialized equipment and may be valuable to predict adverse clinical outcomes in cirrhosis. The objective of this study was to determine if the chair-stand test is an independent predictor of mortality and hospitalization in cirrhosis. Methods: A retrospective review of 787 patients with cirrhosis was conducted. Chair-stand times were collected at baseline in person and divided into three groups: <10 seconds (n = 276), 10-15 seconds (n = 290), and >15 seconds (n = 221). Fine-Gray proportional hazards regression models were used to evaluate the association between chair-stand times and the outcomes of mortality and non-elective hospitalization. Results: The hazard of mortality (HR 3.21, 95% CI 2.16%-4.78%, p <0.001) and non-elective hospitalization (HR 2.24, 95% CI 1.73%-2.91%, p <0.001) was increased in group 3 in comparison to group 1. A chair-stand test time >15 seconds had increased all-cause mortality (HR 2.78, 95% CI 2.01%-3.83%, p <0.001) and non-elective hospitalizations (HR 1.84, 95% CI 1.48%-2.29%, p <0.001) compared to <15 seconds. Conclusions: A chair-stand test time of >15 seconds is independently associated with mortality and non-elective hospitalizations. This test holds promise as a rapid prognostication tool in cirrhosis. Future work will include external validation and virtual assessment in this population.

Patient survey augments detection of harmful alcohol relapse after liver transplant for alcohol-associated cirrhosis.

BACKGROUND: Predicting the risk of alcohol relapse after a liver transplant for alcohol-associated liver disease is critical to guide candidate selection and optimize alcohol use disorder management. We aimed to use patient survey to augment the detection of alcohol relapse and its risk factors and to understand patient perceptions of the importance of alcohol abstinence. METHODS: In this retrospective cohort study, we used a telephone survey and chart review to assess the incidence of post-transplant harmful alcohol relapse, risk factors, and long-term outcomes for patients transplanted for alcohol-associated cirrhosis at our center from 2002 to 2016. RESULTS: Over the median follow-up of 5.9 years, 20.4% relapsed, with 9.3% harmful relapse after median of 4.0 years. The survey response rate was 44.0% (n=110). Of survey responders, 44.3% did not recall discussing alcohol in post-transplant clinics, and 17.6% of relapses were identified by the survey alone. In univariate analysis, shorter pretransplant sobriety (OR: 0.96 per month, p=0.02) and history of pretransplant relapse (OR: 2.99, p=0.02) were associated with post-transplant harmful relapse. After adjusting for these factors, High-risk Alcoholism Relapse score ≥4 predicted harmful relapse (OR: 3.43, p=0.049). A total of 27.3% of patients with both pretransplant relapse and High-risk Alcoholism Relapse score ≥4 relapsed to harmful use compared with 5.2% of those with 1 or neither risk factor (p < 0.001). Harmful relapse was associated with increased graft loss (30.4% vs. 17.4%) and inferior 10-year post-liver transplant survival (61.5% vs. 80.7%). CONCLUSIONS: Incorporating patient survey data allowed the detection of relapses otherwise unreported to clinicians, highlighting the need for novel strategies to detect relapse. Utilizing this augmented data, we identified pretransplant sobriety length, pretransplant relapse, and High-risk Alcoholism Relapse score ≥4 as risk factors that should be evaluated pretransplant to guide candidate selection and peritransplant alcohol use disorder management.

Influence of progestin-only hormonal use on hepatocellular adenomas: A retrospective cohort study.

OBJECTIVES: Exogenous estrogen is associated with growth of hepatocellular adenomas (HCAs), although the influence of progestin-only agents is unknown. We therefore evaluated the association of progestin-only agents on HCA progression compared to no hormone exposure and compared to estrogen exposure in female patients. STUDY DESIGN: In this single-center, retrospective cohort study of reproductive-aged female patients (ages 16-45) with diagnosed HCAs between 2003 and 2021, we evaluated radiographic HCA growth during discrete periods of well-defined exogenous hormone exposures. RESULTS: A total of 34 patients were included. Nineteen (55.9%) had follow-up scans during periods without hormone exposure, 7 (20.6%) during estrogen exposure, and 8 (23.5%) during progestin-only exposure. Over a median follow-up of 11 months, percent change in sum of adenoma diameters from baseline to last available scan was -15.0% with progestin-only agents versus 29.4% with estrogen exposure (p = 0.04), and -7.4% with no hormonal exposure (p = 0.52 compared to progestin-only). Greater than 10% growth was observed in two individuals (25.0%) with progestin-only agent use (one patient on high-dose progestin for menorrhagia) versus five individuals (71.4%) with estrogen use (p = 0.13), and 7 (36.8%) with no exogenous hormone use (p = 0.68 vs progestin-only). CONCLUSIONS: During discrete periods of progestin-only use, HCA growth overall declined, similar to declining growth during periods without exogenous hormonal exposure. This differed from discrete periods of exogenous estrogen exposure, during which time HCAs demonstrated overall increased growth. Though larger studies are needed, these findings support recent guidance supporting progestin-only agents for female patients with HCAs seeking non-estrogen alternatives for contraception. IMPLICATIONS: In this small retrospective study, we observed overall decrease in HCA size during discrete periods of progestin-only contraception use, similar to that observed during periods without exogenous hormone exposure, supporting their use as a safe alternative to estrogen-containing contraceptives in this patient population.

Hepatic and renal function impact concentrations of plasma biomarkers of neuropathology.

Introduction: The impact of hepatorenal function on plasma biomarkers of neuropathology is unknown. Herein, we measured several plasma biomarkers in patients with cirrhosis. Methods: Plasma phosphorylated tau (p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (t-tau), and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) were measured in 135 adults with cirrhosis and 22 healthy controls using Simoa. Within cirrhosis, associations between biomarkers and hepatorenal function were explored using linear regression. Results: p-tau181, NfL, t-tau, and UCHL1 were increased 2- to 4-fold in cirrhosis, whereas GFAP was not increased. Within cirrhosis, creatinine moderately correlated with p-tau181 (ß = 0.75, P < .01), NfL (ß = 0.32, P < .01), and t-tau (ß = 0.31, P < .01), but not GFAP (ß = -0.01, P = .88) or UCHL1 (ß = -0.05, P = .60), whereas albumin showed weak, inverse correlations: p-tau181 (ß = -0.18, P < .01), NfL (ß = -0.22, P < .01), GFAP (ß = -0.17, P < .05), t-tau (ß = -0.20, P = .02), and UCHL1 (ß = -0.15, P = .09). Conclusions: Elevated p-tau181, NfL, and t-tau in cirrhosis were associated with renal impairment and hypoalbuminemia, suggesting that hepatorenal function may be important when interpreting plasma biomarkers of neuropathology.

Polycystic ovary syndrome is associated with nonalcoholic steatohepatitis in women of reproductive age.

Polycystic ovary syndrome (PCOS) occurs in approximately 10% of all reproductive-age women, with over 50% of these patients having imaging-confirmed nonalcoholic fatty liver disease (NAFLD). Whether PCOS increases the risk for more clinically relevant disease, such as nonalcoholic steatohepatitis (NASH), is unclear. Such findings are relevant to prognosticating risk of progressive liver disease in the growing population of young adults with NAFLD. Using weighted discharge data from the United States National Inpatient Sample from 2016 to 2018, we evaluated the association of PCOS with the presence of NASH among reproductive-age women with NAFLD. The association of PCOS with NASH was assessed by logistic regression, adjusting for demographic and comprehensive metabolic comorbidities. Other causes of hepatic steatosis and chronic liver diseases were excluded. Our analysis included 189,440 reproductive-age women with NAFLD, 9415 of whom had PCOS. Of those with PCOS, 1390 (15%) had a distinct code for NASH. Women with PCOS were younger (median age, 33 vs. 40 years; p < 0.001) and more likely to have diabetes (37.0% vs. 34.0%), obesity (83.0% vs. 58.0%), dyslipidemia (26.0% vs. 21.0%), and hypertension (38.0% vs. 35.0%) (all p ≤ 0.01). On adjusted analysis accounting for these metabolic comorbidities, PCOS remained independently associated with an increased prevalence of NASH (adjusted odds ratio, 1.22; 95% confidence interval, 1.05-1.42; p = 0.008). Conclusions: Among reproductive-age women with NAFLD, metabolic risk factors were more common in those with PCOS. Despite adjustment for these metabolic comorbidities, PCOS remained associated with a 22% higher odds of having NASH. These findings support efforts to increase NAFLD screening in young women with PCOS and highlight the potential "head start" in progressive liver disease among young women with PCOS.

National experience with living donor liver transplantation for hepatocellular carcinoma.

Living donor liver transplantation (LDLT) is an attractive option to decrease waitlist dropout, particularly for patients with hepatocellular carcinoma (HCC) who face lengthening waiting times. Using the United Network for Organ Sharing (UNOS) national database, trends in LDLT utilization for patients with HCC were evaluated, and post-LT outcomes for LDLT versus deceased donor liver transplantation (DDLT) were compared. From 1998 to 2018, LT was performed in 20,161 patients with HCC including 726 (3.6%) who received LDLT. The highest LDLT utilization was prior to the 2002 HCC Model for End-Stage Liver Disease (MELD) exception policy (17.5%) and dropped thereafter (3.1%) with a slight increase following the 6-month wait policy in 2015 (3.8%). LDLT was more common in patients from long-wait UNOS regions with blood type O, in those with larger total tumor diameter (2.3 vs. 2.1 cm, p = 0.02), and higher alpha-fetoprotein at LT (11.5 vs. 9.0 ng/ml, p = 0.04). The 5-year post-LT survival (LDLT 77% vs. DDLT 75%), graft survival (72% vs. 72%), and HCC recurrence (11% vs. 13%) were similar between groups (all p > 0.20). In conclusion, LDLT utilization for HCC has remained low since 2002 with only a slight increase after the 6-month wait policy introduction in 2015. Given the excellent post-LT survival, LDLT appears to be an underutilized but valuable option for patients with HCC, especially those at high risk for waitlist dropout.

Cognitive Impairment and Physical Frailty in Patients With Cirrhosis.

Physical frailty and impaired cognition are common in patients with cirrhosis. Physical frailty can be assessed using performance-based tests, but the extent to which impaired cognition may impact performance is not well characterized. We assessed the relationship between impaired cognition and physical frailty in patients with cirrhosis. We enrolled 1,623 ambulatory adult patients with cirrhosis waiting for liver transplantation at 10 sites. Frailty was assessed with the liver frailty index (LFI; "frail," LFI ≥ 4.4). Cognition was assessed at the same visit with the number connection test (NCT); continuous "impaired cognition" was examined in primary analysis, with longer NCT (more seconds) indicating worse impaired cognition. For descriptive statistics, "impaired cognition" was NCT ≥ 45 seconds. Linear regression associated frailty and impaired cognition; competing risk regression estimated subhazard ratios (sHRs) of wait-list mortality (i.e., death/delisting for sickness). Median NCT was 41 seconds, and 42% had impaired cognition. Median LFI (4.2 vs. 3.8) and rates of frailty (38% vs. 20%) differed between those with and without impaired cognition. In adjusted analysis, every 10-second NCT increase associated with a 0.08-LFI increase (95% confidence interval [CI], 0.07-0.10). In univariable analysis, both frailty (sHR, 1.63; 95% CI, 1.43-1.87) and impaired cognition (sHR, 1.07; 95% CI, 1.04-1.10) associated with wait-list mortality. After adjustment, frailty but not impaired cognition remained significantly associated with wait-list mortality (sHR, 1.55; 95% CI, 1.33-1.79). Impaired cognition mediated 7.4% (95% CI, 2.0%-16.4%) of the total effect of frailty on 1-year wait-list mortality. Conclusion: Patients with cirrhosis with higher impaired cognition displayed higher rates of physical frailty, yet frailty independently associated with wait-list mortality while impaired cognition did not. Our data provide evidence for using the LFI to understand mortality risk in patients with cirrhosis, even when concurrent impaired cognition varies.

Outcomes of pregnancy in autoimmune hepatitis: A population-based study.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) disproportionately affects young women, which may have implications in pregnancy. However, data on pregnancy outcomes in women with AIH are limited. APPROACH AND RESULTS: Using weighted discharge data from the United States National Inpatient Sample from 2012 to 2016, we evaluated pregnancies after 20 weeks gestation and compared outcomes in AIH to other chronic liver diseases (CLD) or no CLD in pregnancy. The association of AIH with maternal and perinatal outcomes was assessed by logistic regression. Among 18,595,345 pregnancies, 935 (<0.001%) had AIH (60 with cirrhosis) and 120,100 (0.006%) had other CLD (845 with cirrhosis). Temporal trends in pregnancies with AIH remained stable from 2008 to 2016 with 1.4-6.8/100,000 pregnancies per year (p = 0.25). On adjusted analysis, the odds of gestational diabetes (GDM) and hypertensive complications (pre-eclampsia, eclampsia, or hemolysis, elevated liver enzymes, low platelets) were significantly higher in AIH compared to other CLD (GDM: OR 2.2, 95% CI: 1.5-3.9, p < 0.001; hypertensive complications: OR: 1.8, 95% CI: 1.0-3.2, p = 0.05) and also compared to no CLD in pregnancy (GDM: OR: 2.4, 95% CI: 1.6-3.6, p < 0.001; hypertensive complications: OR: 2.4, 95% CI: 1.3-4.1, p = 0.003). AIH was also associated with preterm births when compared with women without CLD (OR: 2.0, 95% CI: 1.2-3.5, p = 0.01). AIH was not associated with postpartum hemorrhage, maternal, or perinatal death. CONCLUSIONS: Rates of pregnancy in women with AIH have remained stable in recent years, although AIH is associated with notable maternal and perinatal risks, such as GDM, hypertensive complications, and preterm birth. Whether these risks are influenced by steroid use and/or AIH disease activity warrants evaluation. These data support a low risk of postpartum hemorrhage and favorable survival of mothers and infants.

Pregnancies With Cirrhosis Are Rising and Associated With Adverse Maternal and Perinatal Outcomes.

INTRODUCTION: Cirrhosis incidence in pregnancies from outside the United States (US) is rising, although contemporary data including maternal and perinatal outcomes within the United States are lacking. METHODS: Using discharge data from the racially diverse US National Inpatient Sample, temporal trends of cirrhosis in pregnancies were compared with noncirrhotic chronic liver disease (CLD) or no CLD. Outcomes included preterm birth, postpartum hemorrhage, hypertensive complications (preeclampsia, eclampsia, and/or hemolysis, elevated liver enzymes, and low platelets syndrome), and maternal or fetal death. Logistic regression was adjusted for age, race, multiple gestation, insurance status, and prepregnancy metabolic comorbidities. RESULTS: Among 18,573,000 deliveries from 2012 to 2016, 895 had cirrhosis, 119,875 had noncirrhotic CLD, and 18,452,230 had no CLD. Pregnancies with cirrhosis increased from 2.5/100,000 in 2007 to 6.5/100,000 in 2016 (P = 0.01). On adjusted analysis, cirrhosis was associated with hypertensive complications (vs no CLD, OR 4.9, 95% confidence intervals [CI] 3.3-7.4; vs noncirrhotic CLD, OR 4.4, 95% CI 3.0-6.7), postpartum hemorrhage (vs no CLD, OR 2.8, 95% CI 1.6-4.8; vs noncirrhotic CLD, OR 2.0, 95% CI 1.2-3.5), and preterm birth (vs no CLD, OR 3.1, 95% CI 1.9-4.9; vs noncirrhotic CLD, OR 2.0, 95% CI 1.3-3.3, P ≤ 0.01). Cirrhosis was statistically associated with maternal mortality, although rarely occurred (≤ 1%). DISCUSSION: In this racially diverse, US population-based study, pregnancies with cirrhosis more than doubled over the past decade. Cirrhosis conferred an increased risk of several adverse events, although maternal and perinatal mortality was uncommon. These data underscore the need for reproductive counseling and multidisciplinary pregnancy management in young women with cirrhosis.

The relationship between frailty and cirrhosis etiology: From the Functional Assessment in Liver Transplantation (FrAILT) Study.

BACKGROUND & AIMS: Cirrhosis leads to malnutrition and muscle wasting that manifests as frailty, which may be influenced by cirrhosis aetiology. We aimed to characterize the relationship between frailty and cirrhosis aetiology. METHODS: Included were adults with cirrhosis listed for liver transplantation (LT) at 10 US centrer who underwent ambulatory testing with the Liver Frailty Index (LFI; 'frail' = LFI ≥ 4.4). We used logistic regression to associate aetiologies and frailty, and competing risk regression (LT as the competing risk) to determine associations with waitlist mortality (death/delisting for sickness). RESULTS: Of 1,623 patients, rates of frailty differed by aetiology: 22% in chronic hepatitis C, 31% in alcohol-associated liver disease (ALD), 32% in non-alcoholic fatty liver disease (NAFLD), 21% in autoimmune/cholestatic and 31% in 'other' (P < .001). In univariable logistic regression, ALD (OR 1.53, 95% CI 1.12-2.09), NAFLD (OR 1.64, 95% CI 1.18-2.29) and 'other' (OR 1.58, 95% CI 1.06-2.36) were associated with frailty. In multivariable logistic regression, only ALD (OR 1.40; 95% 1.01-1.94) and 'other' (OR 1.59; 95% 1.05-2.40) remained associated with frailty. A total of 281 (17%) patients died/were delisted for sickness. In multivariable competing risk regression, LFI was associated with waitlist mortality (sHR 1.05, 95% CI 1.03-1.06), but aetiology was not (P > .05 for each). No interaction between frailty and aetiology on the association with waitlist mortality was found (P > .05 for each interaction term). CONCLUSIONS: Frailty is more common in patients with ALD, NAFLD and 'other' aetiologies. However, frailty was associated with waitlist mortality independent of cirrhosis aetiology, supporting the applicability of frailty across all cirrhosis aetiologies.

Live Donor Liver Transplantation in the United States: Impact of Share 35 on Live Donor Utilization.

BACKGROUND: Share 35 was a policy implemented in 2013 to increase regional sharing of deceased donor livers to patients with model for end-stage liver disease ≥ 35 to decrease waitlist mortality for the sickest patients awaiting liver transplantation (LT). The purpose of this study was to determine whether live donor liver transplantation (LDLT) volume was impacted by the shift in allocation of deceased donor livers to patients with higher model for end-stage liver disease scores. METHODS: Using Network for Organ Sharing/Organ Procurement and Transplantation Network Standard Transplant Analysis and Research files, we identified all adults who received a primary LT between October 1, 2008, and March 31, 2018. LT from October 1, 2008, through June 30, 2013, was designated as the pre-Share 35 era and July 1, 2013, through March 31, 2018, as the post-Share 35 era. Primary outcomes included transplant volumes, graft survival, and patient survival in both eras. RESULTS: In total, 48 779 primary adult single-organ LT occurred during the study period (22 255 pre-Share 35, 26 524 post). LDLT increased significantly (6.8% post versus 5.7% pre, P < 0.001). LDLT volume varied significantly by region (P < 0.001) with regions 2, 4, 5, and 8 demonstrating significant increases in LDLT volume post-Share 35. The number of centers performing LDLT increased only in regions 4, 6, and 11. Throughout the 2 eras, there was no difference in graft or patient survival for LDLT recipients. CONCLUSIONS: Overall, LDLT volume increased following the implementation of Share 35, which was largely due to increased LDLT volume at centers with experience in LDLT, and corresponded to significant geographic variation in LDLT utilization.

Retransplantation After Living Donor Liver Transplantation: Data from the Adult to Adult Living Donor Liver Transplantation Study.

BACKGROUND: The use of living donor liver transplantation (LDLT) for primary liver transplantation (LT) may quell concerns about allocating deceased donor organs if the need for retransplantation (re-LT) arises because the primary LT did not draw from the limited organ pool. However, outcomes of re-LT after LDLT are poorly studied. The purpose of this study was to analyze the Adult to Adult Living Donor Liver Transplantation Study (A2ALL) data to report outcomes of re-LT after LDLT, with a focus on long-term survival after re-LT. METHODS: A retrospective review of A2ALL data collected between 1998 and 2014 was performed. Patients were excluded if they received a deceased donor LT. Demographic data, postoperative outcomes and complications, graft and patient survival, and predictors of re-LT and patient survival were assessed. RESULTS: Of the 1065 patients who underwent LDLT during the study time period, 110 recipients (10.3%) required re-LT. In multivariable analyses, hepatitis C virus, longer length of stay at LDLT, hepatic artery thrombosis, biliary stricture, infection, and disease recurrence were associated with an increased risk of re-LT. Patient survival among re-LT patients was significantly inferior to those who underwent primary transplant only at 1 (86% versus 92%), 5 (64% versus 82%), and 10 years (44% versus 68%). CONCLUSIONS: Approximately 10% of A2ALL patients who underwent primary LDLT required re-LT. Compared with patients who underwent primary LT, survival among re-LT recipients was worse at 1, 5, and 10 years after LT, and re-LT was associated with a significantly increased risk of death in multivariable modeling (hazard ratios, 2.29; P < 0.001).

Retrospective-prospective study of safety and efficacy of sofosbuvir-based direct-acting antivirals in HIV/HCV-coinfected participants with decompensated liver disease pre- or post-liver transplant.

Direct-acting antiviral (DAA) therapy has transformed the management of human immunodeficiency virus (HIV) and hepatitis C (HCV) coinfected patients with advanced liver disease. STOP-Coinfection was a multicenter prospective and retrospective, open-label study using sofosbuvir-based DAA therapy to treat HIV/HCV-coinfected participants pre- or post-liver transplant (LT). Sixty-eight participants with end-stage liver disease (Child-Turcotte-Pugh score ≥7 and Model for End-Stage Liver Disease score 6-29) were enrolled, 26 had hepatocellular carcinoma. Forty-two participants were treated pre-LT and 26 post-LT. All participants completed therapy without need for dose reduction or transfusion; eight required two or more courses of therapy. Ninety-three percent achieved a sustained virologic response and DAA therapy was well tolerated. Despite HCV cure, 12 end-stage liver disease participants required subsequent LT, 7 for decompensated liver disease. Thirteen participants died, 10 with decompensated liver disease pre-LT and three post-LT. Overall, transplant free survival was 42.8% at 4 years and post-LT survival was 87.9% at 5 years. We conclude that sofosbuvir-based DAA therapy is safe and highly effective in HCV-HIV patients with decompensated liver disease and post-LT, with post-LT survival rates comparable to other indications. This removes one of the last barriers to liver transplantation in this challenging cohort of recipients.

Donation After Circulatory Death Is Associated With Similar Posttransplant Survival in All but the Highest-Risk Hepatocellular Carcinoma Patients.

Liver transplantation (LT) recipients with hepatocellular carcinoma (HCC) receive a higher proportion of livers from donation after circulatory death (DCD) donors compared with non-HCC etiologies. Nevertheless, data on outcomes in patients with HCC receiving DCD grafts are limited. We evaluated the influence of DCD livers on post-LT outcome among HCC patients. We identified 7563 patients in the United Network for Organ Sharing (UNOS) database who underwent LT with Model for End-Stage Liver Disease score exceptions from 2012 to 2016, including 567 (7.5%) who received a DCD donor organ and 6996 (92.5%) who received a donation after brain death (DBD) donor organ. Kaplan-Meier probabilities of post-LT HCC recurrence at 3 years were 7.6% for DCD and 6.4% for DBD recipients (P = 0.67) and post-LT survival at 3 years was 81.1% versus 85.5%, respectively (P = 0.008). On multivariate analysis, DCD donor (hazard ratio, 1.38; P = 0.005) was an independent predictor of post-LT mortality. However, a survival difference after LT was only observed in subgroups at higher risk for HCC recurrence including Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score ≥4 (DCD 57.0% versus DBD 72.6%; P = 0.02), alpha-fetoprotein (AFP) ≥100 (60.1% versus 76.9%; P = 0.049), and multiple viable tumors on last imaging before LT (69.9% versus 83.1%; P = 0.002). In this analysis of HCC patients receiving DCD versus DBD livers in the UNOS database, we found that patients with a low-to-moderate risk of HCC recurrence (80%-90% of the DCD cohort) had equivalent survival regardless of donor type. It appears that DCD donation can best be used to increase the donor pool for HCC patients with decompensated cirrhosis or partial response/stable disease after locoregional therapy with AFP at LT <100 ng/mL.

Non-alcoholic fatty liver disease in pregnancy is associated with adverse maternal and perinatal outcomes.

BACKGROUND & AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) is rising in young adults, with potential implications for reproductive-aged women. Whether NAFLD during pregnancy confers more serious risks for maternal or perinatal health is unclear. METHODS: Using weighted discharge data from the US national inpatient sample, we evaluated temporal trends of NAFLD in pregnancies after 20 weeks gestation, and compared outcomes to pregnancies with other chronic liver diseases (CLDs) or no CLD. Study outcomes included preterm birth, postpartum hemorrhage, hypertensive complications (pre-eclampsia, eclampsia, and/or hemolysis, elevated liver enzymes, and low platelets syndrome), and maternal or fetal death. NAFLD prevalence was estimated by calendar year and temporal trends tested by linear regression. Outcomes were analyzed by logistic regression adjusted for age, race, multiple gestation, and pre-pregnancy diabetes, obesity, dyslipidemia and hypertension. RESULTS: Among 18,574,225 pregnancies, 5,640 had NAFLD and 115,210 had other, non-NAFLD CLD. Pregnancies with NAFLD nearly tripled from 10.5/100,000 pregnancies in 2007 to 28.9/100,000 in 2015 (p <0.001). Compared to the other groups, patients with NAFLD during pregnancy more frequently experienced gestational diabetes (7-8% vs. 23%), hypertensive complications (4% vs. 16%), postpartum hemorrhage (3-5% vs. 6%), and preterm birth (5-7% vs. 9%), all p values ≤0.01. On adjusted analysis, compared to no CLD, NAFLD was associated with hypertensive complications, preterm birth, postpartum hemorrhage and possibly maternal (but not fetal) death. CONCLUSION: The prevalence of NAFLD in pregnancy has nearly tripled in the last decade and is independently associated with hypertensive complications, postpartum hemorrhage and preterm birth. NAFLD should be considered a high-risk obstetric condition, with clinical implications for pre-conception counseling and pregnancy care. LAY SUMMARY: The prevalence of non-alcoholic fatty liver disease (NAFLD) in pregnancy has almost tripled over the past 10 years. Having NAFLD during pregnancy increases risks for both the mother and the baby, including hypertensive complications of pregnancy, bleeding after delivery, and preterm birth. Thus, pre-conception counseling is warranted with consideration of high-risk obstetric management among women with NAFLD in pregnancy.

Mortality in adults with chronic hepatitis B infection in the United States: a population-based study.

BACKGROUND: Chronic hepatitis B infection is an important contributor to mortality in the United States, yet impact of available and effective oral antivirals on mortality among infected individuals is unknown. AIMS: To compare risks and predictors of mortality in a recent time period between those with chronic, prior and no hepatitis B infection. METHODS: This is a population-based cohort study of National Health and Nutrition Examination Surveys participants between 1999 and 2014 linked to National Death Index data. Adults aged 20 years or older with hepatitis B serologic testing were included. Outcomes of all-cause and liver-related mortality were evaluated using Cox regression. RESULTS: Of 39 206 participants, 192 (0.5%) had chronic and 2694 (6.9%) had prior hepatitis B infection. The all-cause age/sex-standardised mortality rates for chronic, prior and uninfected were 21.4, 15.1 and 11.8 per 1000 person-years respectively. Liver-related mortality occurred at respective rates of 4.1, 0.3 and 0.1 per 1000 person-years. In multivariable analyses, those with chronic infection had 1.9-fold (95% CI 1.1-3.3) increased hazard of all-cause mortality and 13.3-fold (95% CI 3.9-45.5) increased hazard of liver-related mortality compared to uninfected. Predictors of all-cause mortality among chronic infection included heavy alcohol use (HR 18.3, 95% CI 3.3-100.6) and higher alanine aminotransferase (HR 1.02, 95% CI 1.00-1.03). CONCLUSIONS: Mortality among adults living with chronic hepatitis B infection still exceeds that of uninfected despite availability of improved therapeutics. Identification of chronic infection, initiation of treatment among eligible and modulation of co-factors for disease progression are needed to improve survival.

Living Donor Liver Transplant for Alcoholic Liver Disease: Data from the Adult-to-adult Living Donor Liver Transplantation Study.

BACKGROUND: Alcoholic liver disease (ALD) accounts for 15%-30% of transplants performed in the United States and Europe; however, the data on living donor liver transplantation (LDLT) for ALD remain sparse. The purpose of this study was to examine the outcomes following LDLT for ALD using data from the adult-to-adult living donor liver transplantation (A2ALL) study, which represents the largest Western experience with adult-to-adult LDLT. METHODS: A retrospective review of A2ALL data collected between 1998 and 2014 was performed. Patients were excluded if they received a deceased donor liver transplant. Demographic data, postoperative outcomes and complications, graft and patient survival, and predictors of graft and patient survival were assessed. RESULTS: Of the 1065 patients who underwent LDLT during the study time period, 168 (15.8%) were transplanted for a diagnosis of ALD. Comparing patients who underwent transplant for ALD with those who were transplanted for other etiologies of liver disease, there was no significant difference in graft survival at 1 (88% versus 84%), 5 (76% versus 74%), or 10 years following transplant (55% versus 61%, P = 0.29). Similarly, there was no difference in patient survival at 1 (94% versus 91%), 5 (83% versus 79%), or 10 years following transplant (61% versus 66%, P = 0.32). CONCLUSIONS: LDLT for ALD results in excellent 1-, 5-, and 10-year graft and patient survival. Patients with ALD and impaired renal function have a higher risk of graft loss and death. These findings support the notion that early LDLT for patients with ALD may help optimize outcomes.

National Experience on Down-Staging of Hepatocellular Carcinoma Before Liver Transplant: Influence of Tumor Burden, Alpha-Fetoprotein, and Wait Time.

BACKGROUND AND AIMS: United Network for Organ Sharing (UNOS) recently implemented a national policy granting priority listing for liver transplantation (LT) in patients who achieved down-staging of hepatocellular carcinoma (HCC) to Milan criteria. We aimed to evaluate the national experience on down-staging by comparing two down-staging groups with (1) tumor burden meeting UNOS down-staging (UNOS-DS) inclusion criteria and (2) "all-comers" (AC-DS) with initial tumor burden beyond UNOS-DS criteria versus patients always within Milan. APPROACH AND RESULTS: This is a retrospective analysis of the UNOS database of 3,819 patients who underwent LT from 2012 to 2015, classified as always within Milan (n = 3,276), UNOS-DS (n = 422), and AC-DS (n = 121). Median time to LT was 12.8 months in long wait regions, 6.5 months in mid wait regions (MWR), and 2.6 months in short wait regions (SWR). On explant, vascular invasion was found in 23.7% of AC-DS versus 16.9% of UNOS-DS and 14.4% of Milan (P = 0.002). Kaplan-Meier 3-year post-LT survival was 83.2% for Milan, 79.1% for UNOS-DS (P = 0.17 vs. Milan), and 71.4% for AC-DS (P = 0.04 vs. Milan). Within down-staging groups, risk of post-LT death in multivariable analysis was increased in SWR or MWR (hazard ratio [HR], 3.1; P = 0.005) and with alpha-fetoprotein (AFP) ≥ 100 ng/mL at LT (HR, 2.4; P = 0.009). The 3-year HCC recurrence probability was 6.9% for Milan, 12.8% for UNOS-DS, and 16.7% for AC-DS (P < 0.001). In down-staging groups, AFP ≥ 100 (HR, 2.6; P = 0.02) was the only independent predictor of HCC recurrence. CONCLUSIONS: Our results validated UNOS-DS criteria based on comparable 3-year survival between UNOS-DS and Milan groups. Additional refinements based on AFP and wait time may further improve post-LT outcomes in down-staging groups, especially given that reported 3-year recurrence was higher than in those always within Milan criteria.