Allison Kwong

All Publications

• Impact of donor characteristics on hepatocellular carcinoma recurrence after liver transplantation. The British journal of surgery Akabane, M., Bekki, Y., Imaoka, Y., Inaba, Y., Esquivel, C. O., Melcher, M. L., Kwong, A., Sasaki, K. 2024; 111 (4)

  View details for DOI 10.1093/bjs/znae080

  View details for PubMedID 38630794

• Excess waitlist mortality among candidates for multivisceral liver-intestine transplant in acuity circle allocation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Kwong, A. J., Schnellinger, E., Foutz, J., Cafarella, M., Nagai, S., Biggins, S. W., Pomposelli, J., Trotter, J. 2024

  Abstract

  Candidates for multivisceral transplant (MVT) have experienced decreased access to transplant in recent years. Using OPTN data, transplant and waiting list outcomes for MVT (i.e., liver-intestine, liver-intestine-pancreas, and liver-intestine-kidney-pancreas) candidates listed 2/4/2018-2/3/2022 were analyzed, including MELD/PELD and exception scores by era (before and after acuity circle [AC] implementation 2/4/2020) and age group (pediatric and adult). Of 284 MVT waitlist registrations (45.6% pediatric), fewer had exception points at listing post-AC compared to pre-AC (10.0% vs. 19.1%), and they were less likely to receive transplant (19.1% vs. 35.9% at 90 days; 35.7% vs. 57.2% at 1 year). Of 177 MVT recipients, exception points at transplant were more common post-AC compared to pre-AC (30.8% vs. 20.2%). Post-policy, adult MVT candidates were more likely to be removed due to death/too sick compared to liver-alone candidates (13.5% v. 5.6% at 90 days; 24.2% v. 9.8% at 1 year), whereas no excess waitlist mortality was observed among pediatric MVT candidates. Under current allocation policy, multivisceral candidates experience inferior waitlist outcomes compared to liver-alone candidates. Clarification of guidance around submission and approval of multivisceral exception requests may help improve their access to transplantation and achieve equity between multivisceral and liver-alone candidates on the liver transplant waiting list.

  View details for DOI 10.1016/j.ajt.2024.02.021

  View details for PubMedID 38408641

• Management of ascites and volume overload in patients with cirrhosis. Clinical liver disease Kwong, A. J., Norman, J., Biggins, S. W. 2024; 23 (1): e0115

  View details for DOI 10.1097/CLD.0000000000000115

  View details for PubMedID 38343635

  View details for PubMedCentralID PMC10857675

• OPTN/SRTR 2022 Annual Data Report: Liver. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Kwong, A. J., Kim, W. R., Lake, J. R., Schladt, D. P., Schnellinger, E. M., Gauntt, K., McDermott, M., Weiss, S., Handarova, D. K., Snyder, J. J., Israni, A. K. 2024; 24 (2S1): S176-S265

  Abstract

  In 2022, liver transplant activity continued to increase in the United States, with an all-time high of 9,527 transplants performed, representing a 52% increase over the past decade (2012-2022). Of these transplants, 8,924 (93.7%) were from deceased donors and 603 (6.3%) were from living donors. Liver transplant recipients were 94.5% adult and 5.5% pediatric. The overall size of the liver transplant waiting list contracted, with more patients being removed than added, although 10,548 adult patients still remained on the waiting list at the end of 2022. Alcohol-associated liver disease continued to be the leading diagnosis among both candidates and recipients, followed by metabolic dysfunction-associated steatohepatitis. Simultaneous liver-kidney transplant was the most common multiorgan combination, with 800 liver-kidney transplants performed in 2022; in addition, there were 303 new listings for kidney transplant via the safety net mechanism. Among adults added to the liver waiting list in 2021, 39.9% received a deceased donor liver transplant within 3 months; 45.7%, within 6 months; and 54.5%, within 1 year. Pretransplant mortality decreased to 12.3 deaths per 100 patient-years in 2022, although still 15.6% of removals from the waiting list were for death or being too sick for transplant. Graft and patient survival outcomes after deceased donor liver transplant improved, approximating pre-COVID-19 pandemic levels, with 5.1% mortality observed at 6 months; 6.8%, at 1 year; 12.7%, at 3 years; 19.8%, at 5 years; and 35.7%, at 10 years. Five-year graft and patient survival rates after living donor liver transplant exceeded those of deceased donor liver transplant. Candidates receiving model for end-stage liver disease exception points for hepatocellular carcinoma constituted 15.5% of transplants performed in 2022, with similar transplant rates and posttransplant outcomes compared to cases without hepatocellular carcinoma exception. In 2022, more pediatric liver transplant candidates were added to the waiting list and underwent transplant compared with either of the preceding 2 years, with an uptick in living donor liver transplant volume. Although pretransplant mortality has improved after the recent policy change prioritizing pediatric donors for pediatric recipients, still, in 2022, 50 children died or were removed from the waiting list for being too sick to undergo transplant. Posttransplant mortality among pediatric liver transplant recipients remained notable, with death occurring in 4.0% at 6 months, 6.0% at 1 year, 8.2% at 3 years, 9.8% at 5 years, and 13.9% at 10 years. Similar to adult living donor recipients, pediatric living donor recipients had better 5-year patient survival compared with deceased donor recipients.

  View details for DOI 10.1016/j.ajt.2024.01.014

  View details for PubMedID 38431359

• Liver transplant activity for alcohol associated hepatitis after OPTN diagnosis updates. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Folta, K., Chung, N., Biggins, S. W., Kwong, A. J. 2024

  View details for DOI 10.1097/LVT.0000000000000332

  View details for PubMedID 38270587

• Introducing W. Ray Kim, MD, our 2024 AASLD president. Hepatology (Baltimore, Md.) Lim, Y. S., Kwong, A. J., Allen, A. M. 2024; 79 (1): 21-24

  View details for DOI 10.1097/HEP.0000000000000650

  View details for PubMedID 38099648

• Summary of a Consensus Conference on Heart-Liver Transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Kobashigawa, J., VanWagner, L. B., Hall, S., Emamaullee, J., Entwistle, J. W., Ganger, D., Gebel, H., Jeevanandam, V., Kaldas, F., Kilic, A., Kittleson, M., Kushwaha, S., Kwong, A., Lui, G. K., Motayagheni, N., Patel, J., Patel, N., Pereira, N., Potter, L., Sani, M., Schiano, T. D., Shingina, A. 2023

  Abstract

  Patients with severe heart disease may have co-existing liver disease from various causes. The incidence of combined heart-liver transplant (CHLT) is increasing as more patients with congenital heart disease survive to adulthood and develop advanced heart failure with associated liver disease from chronic right-sided heart or Fontan failure. However, the criteria for CHLT have not been established. To address this unmet need, a virtual consensus conference was organized on June 10, 2022, endorsed by the American Society of Transplantation. The conference represented a collaborative effort by experts in cardiothoracic and liver transplantation from across the United States to assess interdisciplinary criteria for liver transplantation in the CHLT candidate, surgical considerations of CHLT, current allocation system that generally results in the liver following the heart for CHLT, and the optimal post-CHLT management. The conference served as a forum to unify criteria between the different specialties and to forge a pathway for patients who may need dual organ transplantation. Due to the continuing shortage of available donor organs, ethical issues related to multi-organ transplantation were also debated. The findings and consensus statements are presented.

  View details for DOI 10.1016/j.ajt.2023.12.002

  View details for PubMedID 38072122

• Breaking distance barriers in liver transplantation: Risk factors and outcomes of long-distance liver grafts. Surgery Imaoka, Y., Bozhilov, K. K., Bekki, Y., Akabane, M., Kwong, A. J., Ohira, M., Ohdan, H., Esquivel, C. O., Melcher, M. L., Sasaki, K. 2023

  Abstract

  Long-distance-traveling liver grafts in liver transplantation present challenges due to prolonged cold ischemic time and increased risk of ischemia-reperfusion injury. We identified long-distance-traveling liver graft donor and recipient characteristics and risk factors associated with long-distance-traveling liver graft use.We conducted a retrospective analysis of data from donor liver transplantation patients registered from 2014 to 2020 in the United Network for Organ Sharing registry database. Donor, recipient, and transplant factors of graft survival were compared between short-travel grafts and long-distance-traveling liver grafts (traveled >500 miles).During the study period, 28,265 patients received a donation after brainstem death liver transplantation and 3,250 a donation after circulatory death liver transplantation. The long-distance-traveling liver graft rate was 6.2% in donation after brainstem death liver transplantation and 7.1% in donation after circulatory death liver transplantation. The 90-day graft survival rates were significantly worse for long-distance-traveling liver grafts (donation after brainstem death: 95.7% vs 94.5%, donation after circulatory death: 94.5% vs 93.9%). The 3-year graft survival rates were similar for long-distance-traveling liver grafts (donation after brainstem death: 85.5% vs 85.1%, donation after circulatory death: 81.0% vs 80.4%). Cubic spline regression analyses revealed that travel distance did not linearly worsen the prognosis of 3-year graft survival. On the other hand, younger donor age, lower donor body mass index, and shorter cold ischemic time mitigated the negative impact of 90-day graft survival in long-distance-traveling liver grafts.The use of long-distance-traveling liver grafts negatively impacts 90-day graft survival but not 3-year graft survival. Moreover, long-distance-traveling liver grafts are more feasible with appropriate donor and recipient factors offsetting the extended cold ischemic time. Mechanical perfusion can improve long-distance-traveling liver graft use. Enhanced collaboration between organ procurement organizations and transplant centers and optimized transportation systems are essential for increasing long-distance-traveling liver graft use, ultimately expanding the donor pool.

  View details for DOI 10.1016/j.surg.2023.09.052

  View details for PubMedID 37980203

• Alcohol Use in Liver Transplant Recipients With Alcohol-related Liver Disease: A Comparative Assessment of Relapse Prediction Models. Transplantation Sedki, M., Kwong, A., Bhargava, M., Ahmed, A., Daugherty, T., Kwo, P., Dronamraju, D., Kumari, R., Kim, W. R., Esquivel, C., Melcher, M., Bonham, C. A., Gallo, A., Nelson, A., Norwood, A., Hussain, F., Goel, A. 2023

  Abstract

  The selection of liver transplant (LT) candidates with alcohol-related liver disease (ALD) is influenced by the risk of alcohol relapse (AR), yet the ability to predict AR is limited. We evaluate psychosocial factors associated with post-LT AR and compare the performance of high-risk alcoholism risk (HRAR), sustained alcohol use post-LT (SALT), and the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) scores in predicting relapse.A retrospective analysis of ALD patients undergoing LT from 2015 to 2021 at a single US transplant center was performed. Risk factors associated with post-LT AR were evaluated and test characteristics of 3 prediction models were compared.Of 219 ALD LT recipients, 23 (11%) had AR during a median study follow-up of 37.5 mo. On multivariate analysis, comorbid psychiatric illness (odds ratio 5.22) and continued alcohol use after advice from a health care provider (odds ratio 3.8) were found to be significantly associated with post-LT AR. On sensitivity analysis, SIPAT of 30 was optimal on discriminating between ALD LT recipients with and without post-LT AR. SIPAT outperformed both the HRAR and SALT scores (c-statistic 0.67 versus 0.59 and 0.62, respectively) in identifying post-LT AR. However, all scores had poor positive predictive value (<25%).AR after LT is associated with comorbid psychiatric illness and lack of heeding health care provider advice to abstain from alcohol. Although SIPAT outperformed the HRAR and SALT scores in predicting AR, all are poor predictors. The current tools to predict post-LT AR should not be used to exclude LT candidacy.

  View details for DOI 10.1097/TP.0000000000004800

  View details for PubMedID 37899485

• Introducing W. Ray Kim, MD, Our 2024 AASLD president HEPATOLOGY Lim, Y., Kwong, A., Allen, A. M. 2023

  View details for DOI 10.1097/HEP.0000000000000650

  View details for Web of Science ID 001110232200001

• The short and long-term prognostic influences of liver grafts with high bilirubin levels at the time of organ recovery. Clinical transplantation Akabane, M., Bekki, Y., Imaoka, Y., Inaba, Y., Kwong, A. J., Esquivel, C. O., Melcher, M. L., Sasaki, K. 2023: e15155

  Abstract

  Donors with hyperbilirubinemia are often not utilized for liver transplantation (LT) due to concerns about potential liver dysfunction and graft survival. The potential to mitigate organ shortages using such donors remains unclear.This study analyzed adult deceased donor data from the United Network for Organ Sharing database (2002-2022). Hyperbilirubinemia was categorized as high total bilirubin (3.0-5.0 mg/dL) and very high bilirubin (≥5.0 mg/dL) in brain-dead donors. We assessed the impact of donor hyperbilirubinemia on 3-month and 3-year graft survival, comparing these outcomes to donors after circulatory death (DCD).Of 138 622 donors, 3452 (2.5%) had high bilirubin and 1999 (1.4%) had very high bilirubin levels. Utilization rates for normal, high, and very high bilirubin groups were 73.5%, 56.4%, and 29.2%, respectively. No significant differences were found in 3-month and 3-year graft survival between groups. Donors with high bilirubin had superior 3-year graft survival compared to DCD (hazard ratio .83, p = .02). Factors associated with inferior short-term graft survival included recipient medical condition in intensive care unit (ICU) and longer cold ischemic time; factors associated with inferior long-term graft survival included older donor age, recipient medical condition in ICU, older recipient age, and longer cold ischemic time. Donors with ≥10% macrosteatosis in the very high bilirubin group were also associated with worse 3-year graft survival (p = .04).The study suggests that despite many grafts with hyperbilirubinemia being non-utilized, acceptable post-LT outcomes can be achieved using donors with hyperbilirubinemia. Careful selection may increase utilization and expand the donor pool without negatively affecting graft outcome.

  View details for DOI 10.1111/ctr.15155

  View details for PubMedID 37812571

• LIVER VOLUME PREDICTS MORTALITY IN ALCOHOL ASSOCIATED LIVER DISEASE Manikat, R., Wu, W., Kwo, P., Kothary, N., Chaudhari, A., Kwong, A. J. LIPPINCOTT WILLIAMS & WILKINS. 2023: S1622-S1623

  View details for Web of Science ID 001094865404050

• Has the risk of liver re-transplantation improved over the two decades? Clinical transplantation Akabane, M., Bekki, Y., Imaoka, Y., Inaba, Y., Esquivel, C. O., Kwong, A., Melcher, M. L., Sasaki, K. 2023: e15127

  Abstract

  Despite advancements in liver transplantation (LT) over the past two decades, liver re-transplantation (re-LT) presents challenges. This study aimed to assess improvements in re-LT outcomes and contributing factors.Data from the United Network for Organ Sharing database (2002-2021) were analyzed, with recipients categorized into four-year intervals. Trends in re-LT characteristics and postoperative outcomes were evaluated.Of 128,462 LT patients, 7254 received re-LT. Graft survival (GS) for re-LT improved (91.3%, 82.1%, and 70.8% at 30 days, 1 year, and 3 years post-LT from 2018 to 2021). However, hazard ratios (HRs) for GS remained elevated compared to marginal donors including donors after circulatory death (DCD), although the difference in HRs decreased in long-term GS. Changes in re-LT causes included a reduction in hepatitis C recurrence and an increase in graft failure post-primary LT involving DCD. Trends identified included recent decreased cold ischemic time (CIT) and increased distance from donor hospital in re-LT group. Meanwhile, DCD cohort exhibited less significant increase in distance and more marked decrease in CIT. The shortest CIT was recorded in urgent re-LT group. The highest Model for End-Stage Liver Disease score was observed in urgent re-LT group, while the lowest was recorded in DCD group. Analysis revealed shorter time interval between previous LT and re-listing, leading to worse outcomes, and varying primary graft failure causes influencing overall survival post-re-LT.While short-term re-LT outcomes improved, challenges persist compared to DCD. Further enhancements are required, with ongoing research focusing on optimizing risk stratification models and allocation systems for better LT outcomes.

  View details for DOI 10.1111/ctr.15127

  View details for PubMedID 37772621

• Hepatitis C Screening in Post-Baby Boomer Generation Americans: One Size Does Not Fit All. Mayo Clinic proceedings Sripongpun, P., Udompap, P., Mannalithara, A., Downing, N. L., Vidovszky, A. A., Kwong, A. J., Goel, A., Kwo, P. Y., Kim, W. R. 2023; 98 (9): 1335-1344

  Abstract

  To analyze the impact of access to routine health care, as estimated by health insurance coverage, on hepatitis C virus (HCV) infection prevalence in US adults born after 1965 (post-baby boomer birth cohort [post-BBBC]) and to use the data to formulate strategies to optimize population screening for HCV.Adult examinees in the National Health and Nutrition Examination Survey with available anti-HCV data were divided into era 1 (1999-2008) and era 2 (2009-2016). The prevalence of HCV infection, as defined by detectable serum HCV RNA, was determined in post-BBBC adults. In low prevalence groups, prescreening modalities were considered to increase the pretest probability.Of 16,966 eligible post-BBBC examinees, 0.5% had HCV infection. In both eras, more than 50% had no insurance. In era 2, HCV prevalence was 0.26% and 0.83% in those with and without insurance, respectively (P<.01). As a prescreening test, low alanine aminotransferase level (<23 U/L in women and 32 U/L in men) would identify 54% of post-BBBC adults with an extremely low (0.02%) HCV prevalence. Based on these data, a tiered approach that tests all uninsured directly for HCV and prescreens the insured with alanine aminotransferase would reduce the number to test by 56.5 million while missing less than 1% infections.For HCV elimination, passive "universal" screening in routine health care settings is insufficient, although the efficiency of screening may be improved with alanine aminotransferase prescreening. Importantly, for individuals with limited access to health care, proactive outreach programs for HCV screening are still needed.

  View details for DOI 10.1016/j.mayocp.2023.02.009

  View details for PubMedID 37661141

• Implementation of a national liver review board for exception requests in the united states: A two-year monitoring report. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Kwong, A. J., Foutz, J., Cafarella, M., Biggins, S. W., Shah, N. D., Eason, J., Perito, E. R., Pomposelli, J., Trotter, J. 2023

  Abstract

  The exception point system for liver allocation in the United States allows for additional waitlist priority for candidates where the Model for End-Stage Liver Disease or Pediatric End-Stage Liver Disease does not effectively represent their urgency or need for transplant. In May 2019, the review process for liver exception cases transitioned from 11 Regional Review Boards (RRBs) to one National Liver Review Board (NLRB), intended to increase consistency nationwide, improve efficiency, and balance transplant access for candidates with and without exception scores. This report provides a review of liver exception request and review practices, waitlist outcomes, and transplant activity in the first two years after implementation of the NLRB and Acuity Circle-based distribution in the United States.We compared initial and extension exception request forms submitted from 05/13/2017 to 05/13/2019 (pre-policy or RRB era), to the period from 02/04/2020 to 02/03/2022 (post-policy or NLRB era). During this time, the NLRB reviewed 10,083 initial exception requests and 12,686 extension requests. Notable post-policy highlights include: (1) increase in the proportion of initial and extension requests that were automatically approved instead of manually reviewed; (2) decrease in the overall approval rates of initial exception requests (87.8% for adult HCC, 64.3% for adult other diagnoses, and 71.5% for pediatric); and (3) reduction in the time from exception request submission to adjudication, to a median of 3.73 days. The proportions of waitlist registration and deceased donor liver transplants for patients with exception scores decreased, and waitlist outcomes between patients with and without exception scores are now comparable.Implementation of the NLRB improved efficiency, reduced case workloads, and standardized criteria for exception cases, with similar waitlist outcomes between patients with and without exception scores and improved equity in terms of access to liver transplant.

  View details for DOI 10.1097/LVT.0000000000000248

  View details for PubMedID 37639285

• Cost-effectiveness analysis of interventional liver-directed therapies for downstaging of hepatocellular carcinoma before liver transplant. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Wu, X., Kwong, A., Heller, M., Lokken, R. P., Fidelman, N., Mehta, N. 2023

  Abstract

  Transarterial chemoembolization (TACE) and radioembolization (TARE) are two most used modalities for patients with hepatocellular carcinoma (HCC) while awaiting liver transplant (LT). The purpose of this study is to perform a cost-effectiveness analysis comparing TACE and TARE for downstaging patients with HCC.A cost-effectiveness analysis was performed comparing TACE and TARE in downstaging HCC over a 5-year time horizon from a payer's perspective. The clinical course, including those who achieved successful downstaging leading to LT and those that failed downstaging with possible disease progression, were obtained from the United Network for Organ Sharing. Costs and effectiveness were measured in US dollars and quality-adjusted life years (QALYs). Probabilistic and deterministic sensitivity analyses were performed.TARE achieved a higher effectiveness 2.51 QALY (TACE: 2.29 QALY) at a higher cost $172,162 (TACE: $159,706), with the incremental cost-effectiveness ratio of $55,964 /QALY, making TARE the more cost-effective strategy. The difference in outcome was equivalent to 104 days (nearly 3.5 months) in compensated cirrhosis state. Probabilistic sensitivity analyses showed TARE was more cost-effective in 91.69% of 10,000 Monte Carlo simulations. TARE was more effective if greater than 48.2% of patients who received TACE or TARE were successfully downstaged (base case: 74.6% from pooled analysis of multiple published cohorts). TARE became more cost-effective when the cost of TACE exceeded $4,831 (base case: $12,722) or when the cost of TARE was lower than $43,542 (base case: $30,609). Subgroup analyses identified TARE to be the more cost-effective strategy if the TARE cohort required one fewer LRT than the TACE cohort.TARE is the more cost-effective downstaging strategy for patients with HCC exceeding Milan criteria when compared to TACE.

  View details for DOI 10.1097/LVT.0000000000000249

  View details for PubMedID 37639286

• Overcoming the hurdles of steatotic grafts in liver transplantation: insights into survival and prognostic factors. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Akabane, M., Imaoka, Y., Esquivel, C. O., Melcher, M. L., Kwong, A., Sasaki, K. 2023

  Abstract

  With increasing metabolic dysfunction associated steatotic liver disease (MASLD), the use of steatotic grafts in liver transplantation (LT) and their impact on postoperative graft survival (GS) needs further exploration.Analyzing adult LT recipient data (2002-2022) from the United Network for Organ Sharing database, outcomes of LT using steatotic (≥30% macrosteatosis) and non-steatotic donor livers, donors after circulatory death (DCD), and standard-risk older donors (age 45-50) were compared. GS predictors were evaluated using Kaplan-Meier and Cox regression analyses.Of the 35,345 LT donors, 8.9% (3,155) were fatty livers. Initial 30-day postoperative period revealed significant challenges with fatty livers, demonstrating inferior GS. However, the GS discrepancy between fatty and non-fatty livers subsided over time (p=0.10 at 5 y). Long-term GS outcomes showed comparable or even superior results in fatty livers relative to non-steatotic livers, conditional on surviving the initial 90 postoperative days (p=0.90 at 1 y) or 1 year (p=0.03 at 5 y). In the multivariable Cox regression analysis, high body surface area (BSA) ratio (≥1.1) (hazard ratio [HR] 1.42, p=0.02), calculated as donor BSA divided by recipient BSA, long cold ischemic time (≥6.5 hours) (HR 1.72, p<0.01), and recipient medical condition (ICU hospitalization) (HR 2.53, p<0.01) emerged as significant adverse prognostic factors. Young (<40 y) fatty donors showed a high BSA ratio, diabetes, and ICU hospitalization as significant indicators of worse prognosis (p<0.01).Our study emphasizes the initial postoperative 30-day survival challenge in LT using fatty livers. However, with careful donor-recipient matching, e.g. avoiding use of steatotic donors with long cold ischemic time and high BSA ratios for recipients in the ICU, it is possible to enhance immediate GS, and in a longer time, outcomes comparable to those using non-fatty livers, DCD livers, or standard-risk older donors, can be anticipated. These novel insights into decision-making criteria for steatotic liver use provide invaluable guidance for clinicians.

  View details for DOI 10.1097/LVT.0000000000000245

  View details for PubMedID 37616509

• Decreased Utilization Rate of Grafts for Liver Transplantation After Implementation of Acuity Circle-based Allocation. Transplantation Bekki, Y., Myers, B., Tomiyama, K., Imaoka, Y., Akabane, M., Kwong, A. J., Melcher, M. L., Sasaki, K. 2023

  Abstract

  The allocation system for livers began using acuity circles (AC) in 2020. In this study, we sought to evaluate the impact of AC policy on the utilization rate for liver transplantation (LT).Using the US national registry data between 2018 and 2022, LTs were equally divided into 2 eras: pre-AC (before February 4, 2020) and post-AC (February 4, 2020, and after). Deceased potential liver donors were defined as deceased donors from whom at least 1 organ was procured.The annual number of deceased potential liver donors increased post-AC (from 10 423 to 12 259), approaching equal to that of new waitlist registrations for LT (n = 12 801). Although the discard risk index of liver grafts was comparable between the pre- and post-AC eras, liver utilization rates in donation after brain death (DBD) and donation after circulatory death (DCD) donors were lower post-AC (P < 0.01; 79.8% versus 83.4% and 23.7% versus 26.0%, respectively). Recipient factors, ie, no recipient located, recipient determined unsuitable, or time constraints, were more likely to be reasons for nonutilization after implementation of the AC allocation system compared to the pre-AC era (20.0% versus 12.3% for DBD donors and 50.1% versus 40.8% for DCD donors). Among non-high-volume centers, centers with lower utilization of marginal DBD donors or DCD donors were more likely to decrease LT volume post-AC.Although the number of deceased potential liver donors has increased, overall liver utilization among deceased donors has decreased in the post-AC era. To maximize the donor pool for LT, future efforts should target specific reasons for liver nonutilization.

  View details for DOI 10.1097/TP.0000000000004751

  View details for PubMedID 37585345

• Optimizing liver transplant prioritization for hepatocellular carcinoma through risk stratification. Current opinion in organ transplantation Norman, J., Mehta, N., Kwong, A. 2023

  Abstract

  In the United States, candidates with hepatocellular carcinoma (HCC) meeting standardized qualifying criteria receive similar priority on the liver transplant waiting list through Model for End-Stage Liver Disease exception points, without consideration of the dropout risk or relative expected benefit from liver transplantation. A more nuanced allocation scheme for HCC is needed to better represent the individual urgency for liver transplant and optimize organ utility. In this review, we discuss the development of HCC risk prediction models for practical use in liver allocation.HCC is a heterogenous disease that requires improved risk stratification for patients who fall within current transplant eligibility criteria. Several models have been proposed, though none have been adopted in clinical practice or liver allocation to date, due to various limitations.Improved HCC risk stratification for liver transplant candidates is needed to more accurately represent their urgency for transplant, with continued attention to the potential impact on post-liver transplant outcomes. Plans to implement a continuous distribution model for liver allocation in the United States may provide an opportunity to re-consider a more equitable allocation scheme for patients with HCC.

  View details for DOI 10.1097/MOT.0000000000001080

  View details for PubMedID 37339511

• One size does not fit all: Differential benefits of simultaneous liver-kidney transplantation by eligibility criteria. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Cheng, X. S., McElroy, L. M., Sanoff, S. L., Kwong, A. J. 2023

  Abstract

  Standard eligibility criteria for simultaneous liver-kidney transplantation (SLK) are in place in the United States (US). We hypothesize that the benefit associated with SLK over liver transplant alone differs by patient, depending on the specific SLK criteria met. We analyzed a retrospective US cohort of 5,446 adult liver transplant or SLK recipients between January 1, 2015 and December 31, 2018 who potentially qualified for SLK. Exposure was receipt of SLK. We tested effect modification by the specific SLK eligibility criteria met (endstage kidney disease [ESKD], acute kidney injury [AKI], chronic kidney disease [CKD], or unknown). Primary outcome was death within 1 year of liver transplant. We used a modified Cox regression analysis containing an interaction term of SLK  time from transplant. 210 (9%) SLK recipients and 351 (11%) liver-alone recipients died in 1 year. In the overall population, SLK was associated with a mortality benefit over liver transplant on the day of transplant, without adjustment (hazard ratio [HR] 0.59 [95% confidence interval [CI] 0.46-0.76]) and with adjustment (aHR 0.50 [95% CI 0.35-0.71]). However, when SLK eligibility criteria was included, only in patients with ESKD was SLK associated with a sustained survival benefit at day 0 (HR 0.17 [0.08-0.35]) up to 288 (95% CI 120-649) days posttransplant. Benefit within the first year posttransplant associated with SLK over liver-alone transplantation was only pronounced in patients with ESKD, but not present in patients meeting other criteria for SLK. A "strict SLK liberal Safety Net" strategy may warrant consideration at the national policy level.

  View details for DOI 10.1097/LVT.0000000000000191

  View details for PubMedID 37329171

• MELD 3.0 for adolescent liver transplant candidates. Hepatology (Baltimore, Md.) Kwong, A. J., Zhang, K. Y., Ebel, N., Mannalithara, A., Kim, W. R. 2023

  Abstract

  Adolescents constitute a unique waitlist cohort that is distinct from younger children. MELD 3.0, which was developed in an adult population of liver transplant candidates, is planned to replace MELD-Na in the current liver allocation system for both adult and adolescents aged 12-17. We evaluated the predictive performance of MELD-Na, MELD 3.0, and PELD, for 90-day waitlist mortality risk among adolescent liver transplant registrants.New waitlist registrations for primary liver transplant among individuals aged 12-17 and aged 18-25 for comparison were identified using OPTN data from Nov 17 2004 to Dec 31 2021. The predictive performance of the current and proposed MELD and PELD scores was assessed using the Harrell's concordance (c) statistic.There were 1,238 eligible listings for adolescents aged 12-17, and 1,740 young adults aged 18-25. In the adolescent group, 90-day survival was 97.8%, compared to 95.9% in those aged 18-25 (log-rank p = 0.005), with no significant differences when stratified by sex or indication. Among adolescents, increasing MELD 3.0 was associated with an increased hazard of mortality (HR 1.27, 95% CI 1.18-1.37), and the c-statistic for 90-day waitlist survival using MELD 3.0 was 0.893, compared with 0.871 using MELD-Na, and 0.852 using PELD.The discriminative ability of MELD 3.0 to rank adolescents according to the risk of death within 90 days was robust. Although MELD 3.0 was initially developed and validated in adults, MELD 3.0 may also improve the prediction of waitlist mortality in adolescents and better represent their urgency for liver transplant.

  View details for DOI 10.1097/HEP.0000000000000352

  View details for PubMedID 36943091

• Evaluating the outcomes of donor-recipient age differences in young adults undergoing liver transplantation. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Snyder, A., Kojima, L., Imaoka, Y., Akabane, M., Kwong, A., Melcher, M. L., Sasaki, K. 2023

  Abstract

  BACKGROUND: The current liver allocation system may be disadvantaging younger adult recipients as it does not incorporate the donor-recipient age difference. Given the longer life expectancy of younger recipients, the influences of older donor grafts on their long-term prognosis should be elucidated. This study sought to reveal the long-term prognostic influence of the donor-recipient age difference in young adult recipients.METHODS: Adult patients who received initial liver transplants from deceased donors between 2002-2021 were identified from the UNOS database. Young recipients (patients ≤45 y.o) were categorized into 4 groups: donor age younger than the recipient, 0-9 years older, 10-19 years older, or ≥20 years older. Older recipients were defined as patients ≥65 y.o. To examine the influence of the age difference in long-term survivors, conditional graft survival (CGS) analysis was conducted on both younger and older recipients.RESULTS: Among 91,952 transplant recipients, 15,170 patients were ≤45 years old (16.5%); these were categorized into 6,114 (40.3%), 3,315 (21.9%), 2,970 (19.6%), and 2,771 (18.3%) for groups 1-4, respectively. Group 1 demonstrated the highest probability of survival followed by groups 2, 3, and 4 for the actual graft survival and CGS analyses. In younger recipients who survived at least 5 years post-transplant, inferior long-term survival was observed when there was an age difference of ≥10 years (86.9% vs. 80.6%, log-rank P<0.01) while there was no difference in older recipients (72.6% vs. 74.2%, log-rank P=0.89).CONCLUSION: In younger patients who are not in emergent need of a transplant, preferential allocation of younger aged donor offers would optimize organ utility by increasing postoperative graft survival time.

  View details for DOI 10.1097/LVT.0000000000000109

  View details for PubMedID 36847140

• Cost-Effectiveness Analysis of Interventional Liver-Directed Therapies for a Single, Small Hepatocellular Carcinoma in Liver Transplant Candidates. Journal of vascular and interventional radiology : JVIR Wu, X., Heller, M., Kwong, A., Fidelman, N., Mehta, N. 2023

  Abstract

  PURPOSE: To assess the cost-effectiveness of the three main LRTs (transarterial chemoembolization (TACE), radioembolization (TARE), and percutaneous ablation) as bridging therapy.METHODS: A cost-effectiveness analysis was performed comparing three LRTs for patients with single ≤ 3 cm HCC over a 5-year time horizon from a payer's perspective. The clinical course, including the transplantation, decompensation resulting in delisting, and need for a second LRT, were based on data from the United Network for Organ Sharing (2016-2019). Costs and effectiveness were measured in US dollars and quality-adjusted life years (QALYs). Probabilistic and deterministic sensitivity analyses were performed.RESULTS: In patients with a single, small (≤ 3 cm) HCC, a total of 2,594, 1,576, and 903 patients, underwent TACE, ablation, and TARE. Ablation was the dominant strategy with the lowest expected cost and highest effectiveness. Probabilistic sensitivity analysis demonstrated that ablation was the most cost-effective strategy in 93.89% of the simulations. Subgroup analysis was performed for different wait times with ablation remaining the most cost-effective strategy. Sensitivity analysis showed ablation was most effective if the risk of waitlist dropout was <2.00% and the rate of transplantation >15.1% quarterly. TARE was most effective if the dropout risk was <1.19% and the rate of transplantation was >24.0%. TACE was most effective if the dropout risk was <1.01% and rate of transplantation >45.7%. Ablation remained the most cost-effective modality until its procedural cost was >$34,843.CONCLUSION: Ablation is the most cost-effective bridging strategy for patients with single, small (≤ 3 cm) HCC prior to liver transplant. The conclusion remained robust in multiple sensitivity analyses.

  View details for DOI 10.1016/j.jvir.2023.02.016

  View details for PubMedID 36804296

• OPTN/SRTR 2021 Annual Data Report: Liver. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Kwong, A. J., Ebel, N. H., Kim, W. R., Lake, J. R., Smith, J. M., Schladt, D. P., Schnellinger, E. M., Handarova, D., Weiss, S., Cafarella, M., Snyder, J. J., Israni, A. K., Kasiske, B. L. 2023; 23 (2S1): S178-S263

  Abstract

  In 2021, liver transplant volume continued to grow, with a record 9,234 transplants performed in the United States, 8,665 (93.8%) from deceased donors and 569 (6.2%) from living donors. There were 8,733 (94.6%) adult and 501 (5.4%) pediatric liver transplant recipients. An increase in the number of deceased donor livers corresponded to an increase in the overall transplant rate and shorter waiting times, although still 10.0% of livers that were recovered were not transplanted. Alcohol-associated liver disease was the leading indication for both waitlist registration and liver transplant in adults, outpacing nonalcoholic steatohepatitis, while biliary atresia remained the leading indication for children. Related to allocation policy changes implemented in 2019, the proportion of liver transplants performed for hepatocellular carcinoma has decreased. Among adult candidates listed for liver transplant in 2020, 37.7% received a deceased donor liver transplant within 3 months, 43.8% within 6 months, and 53.3% within 1 year. Pretransplant mortality improved for children following implementation of acuity circle-based distribution. Short-term graft and patient survival outcomes up to 1 year worsened for adult deceased and living donor liver transplant recipients, which is a reversal of previous trends and coincided with the onset of the COVID-19 pandemic in early 2020. Longer-term outcomes among adult deceased donor liver transplant recipients were unaffected, with overall posttransplant mortality rates of 13.3% at 3 years, 18.6% at 5 years, and 35.9% at 10 years. Pretransplant mortality improved for children following implementation of acuity circle-based distribution and prioritization of pediatric donors to pediatric recipients in 2020. Pediatric living donor recipients had superior graft and patient survival outcomes compared with deceased donor recipients at all time points.

  View details for DOI 10.1016/j.ajt.2023.02.006

  View details for PubMedID 37132348

• Serum biomarkers of liver fibrosis identify globus pallidus vulnerability. NeuroImage. Clinical Kwong, A. J., Zahr, N. M. 2023; 37: 103333

  Abstract

  The CNS manifestation of chronic liver disease can include magnetic resonance (MR) signal hyperintensities in basal ganglia structures. Here, relations between liver (serum-derived fibrosis scores) and brain (regional T1-weighted signal intensities and volumes) integrity were evaluated in a sample of 457 individuals including those with alcohol use disorders (AUD), people living with human immunodeficiency virus (HIV), those comorbid for AUD and HIV, and healthy controls. Liver fibrosis was identified from cutoff scores as follows: aspartate aminotransferase to platelet ratio index (APRI) > 0.7 in 9.4% (n = 43) of the cohort; fibrosis score (FIB4) > 1.5 in 28.0% (n = 128) of the cohort; and non-alcoholic fatty liver disease fibrosis score (NFS) > -1.4 in 30.2% (n = 138) of the cohort. Presence of serum-derived liver fibrosis was associated with high signal intensities selective to basal ganglia (i.e., caudate, putamen, and pallidum) structures. High signal intensities in the pallidum, however, explained a significant portion of the variance in APRI (25.0%) and FIB4 (23.6%) cutoff scores. Further, among the regions evaluated, only the globus pallidus showed a correlation between greater signal intensity and smaller volume (r = -0.44, p <.0001). Finally, higher pallidal signal intensity correlated worse ataxia (eyes open ρ = -0.23, p =.0002; eyes closed ρ = -0.21, p =.0005). This study suggests that clinically relevant serum biomarkers of liver fibrosis such as the APRI may identify individuals vulnerable to globus pallidus pathology and contribute to problems with postural balance.

  View details for DOI 10.1016/j.nicl.2023.103333

  View details for PubMedID 36868044

• Title: On Building a Better Mousetrap Response to: "Towards Optimally Replacing the Current Version of MELD". Journal of hepatology Ge, J., Kim, W. R., Lai, J. C., Kwong, A. J. 2022

  View details for DOI 10.1016/j.jhep.2022.11.008

  View details for PubMedID 36402449

• Reevaluating Liver Donor Risk in the Era of Improved Hepatitis C Virus Treatment. JAMA surgery Handley, T. J., Arnow, K., Sasaki, K., Kwong, A., Melcher, M. L. 2022

  Abstract

  This cohort study examines the risk of graft failure associated with donors with hepatitis C virus (HCV) infection before and after the introduction of direct-acting antiviral medications.

  View details for DOI 10.1001/jamasurg.2022.3922

  View details for PubMedID 36197654

• Clinical characteristics and outcomes in those with primary extrahepatic malignancy and malignant ascites. BMC gastroenterology Alshuwaykh, O., Cheung, A., Goel, A., Kwong, A., Dhanasekaran, R., Ghaziani, T. T., Ahmed, A., Daugherty, T., Dronamraju, D., Kumari, R., Nguyen, M., Kim, W. R., Kwo, P. Y. 2022; 22 (1): 410

  Abstract

  BACKGROUND: Malignancy-related ascites accounts for approximately 10% of causes of ascites. Our AIM was to characterize the ascites fluid and correlate clinical outcomes in those with extrahepatic malignancy and ascites.METHODS: 241 subjects with extrahepatic solid tumors and ascites were reviewed from 1/1/2000 to 12/31/2019, 119 without liver metastasis and 122 with liver metastasis.RESULTS: Ascites fluid consistent with peritoneal carcinomatosis (PC) was most common, 150/241 (62%), followed by fluid reflecting the presence of portal hypertension (PH), 69/241 (29%). 22/241 (9%) had low SAAG and low ascites fluid total protein, with evidence of PC on cytology and or imaging in 20/22. Lung cancer was the most common malignancy in subjects with ascites due to PC at 36/150 (24%), pancreatic cancer was the most common in subjects with ascites with features of PH at 16/69 (23%). Chemotherapy or immunotherapy alone was the most common management approach. Significantly higher 5-year, 3-year and 1-year mortality rate were noted in subjects with evidence of PC on cytology/imaging versus subjects with no evidence of PC, and in subjects with liver metastasis compared to subjects without liver metastasis. Subjects with pancreatic cancer and evidence of PC on cytology/imaging had higher 1 and 5-year mortality rates compared to subjects without PC.CONCLUSIONS: Ascites in solid tumor malignancy is most commonly due to PC. We also observed ascites fluid with characteristics of PH in 29% of subjects. Higher mortality rates in subjects with peritoneal carcinomatosis and liver metastasis were noted. These findings may help inform prognosis and treatment strategies.

  View details for DOI 10.1186/s12876-022-02487-4

  View details for PubMedID 36064324

• Mortality in End Stage Liver Patients Above MELD 3.0 of 40. Hepatology (Baltimore, Md.) Tarlow, B. D., Kim, W. R., Mannalithara, A., Kwo, P. Y., Bonham, C. A., Kwong, A. 2022

  Abstract

  Since implementation of the MELD score to determine waitlist priority in liver transplant (LT) in 2002, the score has been capped at 40. Recently, the MELD 3.0 score was proposed to improve upon MELD-Na. Here, we examine waitlist mortality and LT outcomes in patients with MELD 3.0 ≥40 to assess the potential impact of uncapping the score.Adult waitlist registrations for LT from January, 2016 to December, 2021 were identified in the registry data from the Organ Procurement and Transplant Network. All MELD 3.0 scores were calculated at registration and thereafter. Waitlist mortality for up to 30 days was calculated as well as post-LT survival. There were 54,060 new waitlist registrations during the study period, of whom 2,820 (5.2%) had MELD 3.0 ≥40 at listing. The 30-day waitlist mortality was high in these patients; yet it increased further in proportion with MELD 3.0 up to a score of 55 with 30-day mortality of 58.3% for MELD 3.0 40-44 and 82.4% for ≥50. The multivariable hazard ratio was 1.13 for each point of MELD 3.0, adjusting for several variables including acute-on-chronic liver failure. The number of LT recipients with MELD 40 at transplant increased from 155 in 2002 to 752 in 2021. Post-transplant survival were comparable across MELD strata including MELD 35-39.MELD 3.0 scores beyond 40 are associated with increasing waitlist mortality without adversely affecting post-transplant outcome. Uncapping the MELD score in waitlist candidates may lead to greater survival benefit from LT.

  View details for DOI 10.1002/hep.32770

  View details for PubMedID 36052665

• Assessment of Donor quality and risk of graft failure after liver transplantation: The ID2 EAL score. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Asrani, S. K., Saracino, G., Wall, A., Trotter, J. F., Testa, G., Hernaez, R., Sharma, P., Kwong, A., Banerjee, S., McKenna, G. 2022

  Abstract

  Accurate assessment of donor quality at the time of organ offer for liver transplantation candidates may be inadequately captured by the donor risk index (DRI). We sought to develop and validate a novel objective and simple model to assess donor risk using donor level variables available at the time of organ offer. We utilized national data from candidates undergoing primary LT (2013-2019) and assessed prediction of graft failure 1 year after LT. ID2 EAL score: The final components were donor Insulin dependent diabetes mellitus, Donor type (DCD or DBD), cause of Death=CVA, serum creatinine, Age, height and weight (length). The ID2 EAL score had better discrimination than DRI using bootstrap corrected concordant index over time, especially in the current era. We explored donor-recipient matching. Relative risk of graft failure ranged from 1.15-3.5 based on relevant donor-recipient matching by the ID2 EAL score. As an example, for certain recipients, a young DCD donor offer was preferable to an older DBD with relevant comorbidities. The ID2 EAL score may serve as an important tool for patient discussion about donor risk and decisions regarding offer acceptance. In addition, the score may be preferable to succinctly capture donor risk in future organ allocation that considers continuous distribution.

  View details for DOI 10.1111/ajt.17191

  View details for PubMedID 36053559

• Impact of Donor Liver Macrovesicular Steatosis on Deceased Donor Yield and Posttransplant Outcome. Transplantation Kwong, A. J., Kim, W. R., Lake, J., Stock, P. G., Wang, C. J., Wetmore, J. B., Melcher, M. L., Wey, A., Salkowski, N., Snyder, J. J., Israni, A. K. 2022

  Abstract

  The Scientific Registry of Transplant Recipients (SRTR) had not traditionally considered biopsy results in risk-adjustment models, yet biopsy results may influence outcomes and thus decisions regarding organ acceptance.Using SRTR data, which includes data on all donors, waitlisted candidates, and transplant recipients in the United States, we assessed (1) the impact of macrovesicular steatosis on deceased donor yield (defined as number of livers transplanted per donor) and 1-y posttransplant graft failure and (2) the effect of incorporating this variable into existing SRTR risk-adjustment models.There were 21 559 donors with any recovered organ and 17 801 liver transplant recipients included for analysis. Increasing levels of macrovesicular steatosis on donor liver biopsy predicted lower organ yield: ≥31% macrovesicular steatosis on liver biopsy was associated with 87% to 95% lower odds of utilization, with 55% of these livers being discarded. The hazard ratio for graft failure with these livers was 1.53, compared with those with no pretransplant liver biopsy and 0% to 10% steatosis. There was minimal change on organ procurement organization-specific deceased donor yield or program-specific posttransplant outcome assessments when macrovesicular steatosis was added to the risk-adjustment models.Donor livers with macrovesicular steatosis are disproportionately not transplanted relative to their risk for graft failure. To avoid undue risk aversion, SRTR now accounts for macrovesicular steatosis in the SRTR risk-adjustment models to help facilitate use of these higher-risk organs. Increased recognition of this variable may also encourage further efforts to standardize the reporting of liver biopsy results.

  View details for DOI 10.1097/TP.0000000000004291

  View details for PubMedID 36042548

• Incidence of hepatocellular carcinoma in chronic hepatitis B virus infection in those not meeting criteria for antiviral therapy. Hepatology communications Alshuwaykh, O., Daugherty, T., Cheung, A., Goel, A., Dhanasekaran, R., Ghaziani, T. T., Ahmed, A., Dronamraju, D., Kumari, R., Kwong, A., Nguyen, M., Kim, W. R., Kwo, P. Y. 2022

  Abstract

  Chronic hepatitis B virus (HBV) infection is the leading risk factor for hepatocellular carcinoma (HCC). The aim of this study was to explore the incidence of HCC in a cohort of subjects with HBV and correlate with HBV treatment current guidance. We identified 2846 subjects with HBV over the study period. HCC was diagnosed in 386 of 2846 (14%) subjects; 209 of 386 (54%) were on nucleos(t)ide analogue (NA) therapy at time of HCC diagnosis, and 177 of 386 (46%) were not on NA therapy. Of the 177 subjects not on NAs who developed HCC during follow-up, 153 of 177 (86%) had cirrhosis. Within the 177 subjects not on NAs, 158 of 177 (89%) had undetectable HBV DNA, 10 of 177 (6%) had detectable HBV DNA < 2000 IU/L, and 9 of 177 (5%) had HBV DNA > 2000 IU/L. Of those with cirrhosis and undetectable HBV DNA, 115 of 141 had compensated cirrhosis, and 26 of 141 had decompensated cirrhosis. Significant predictors of HCC on time to event analysis included cirrhosis (hazard ratio [HR] 10, 95% confidence interval [CI] 5.8-17.5; p < 0.001), alanine aminotransferase level (HR 1.004, 95% CI 1.002-1.006; p < 0.001), age (HR 1.04, 95% CI 1.03-1.06; p < 0.001), (HR 1.9, 95% CI 1.2-3.1; p 0.007), and nonalcoholic fatty liver disease (HR 1.7, 95% CI 1.1-2.8; p 0.02). Kaplan-Meier analysis demonstrated the cumulative incidence of HCC in subjects with compensated cirrhosis receiving NA therapy was significantly lower compared to subjects with compensated cirrhosis outside current HBV treatment practice guidance (undetectable HBV DNA) (32% vs. 51%; p < 0.001). Conclusion: Those with untreated compensated cirrhosis with undetectable HBV DNA who do not meet current guidance for treatment had higher rates of HCC than those with compensated cirrhosis and suppressed HBV DNA by NA therapy. This study highlights the need for earlier diagnosis and treatment of HBV.

  View details for DOI 10.1002/hep4.2064

  View details for PubMedID 36004713

• Liver allocation policies for hepatocellular carcinoma have leveled the playing field - but who should be playing? Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Kwong, A. J., Mehta, N. 2022

  View details for DOI 10.1002/lt.26555

  View details for PubMedID 35959967

• Heterogeneity in Center Practices in Liver Transplantation for Alcohol-associated Liver Disease in the United States. The American journal of gastroenterology Lim, N., Kwong, A. J., Jafri, S., Jesse, M. T., Kriss, M., Nair, K., Pillai, A., Shingina, A., Tang, Q., Desai, A. P. 2022

  Abstract

  INTRODUCTION: Alcohol-related liver disease (ALD) is now the leading indication for liver transplantation (LT) in the United States (US). It remains unclear how centers are managing the medical and psychosocial issues associated with these patients.METHODS: We conducted a web-based survey of LT centers in the US to identify center-level details on peri-LT management of ALD and related issues.RESULTS: Of the 117 adult LT centers, 100 (85.5%) responses were collected, representing all OPTN regions. For alcohol-associated cirrhosis (AAC), 70.0% of centers reported no minimum sobriety requirement, while 21.0% required 6 months sobriety. LT for severe alcohol-associated hepatitis (AAH) was performed at 85.0% centers. Monitoring protocols for pre- and post-LT alcohol use varied among centers.CONCLUSIONS: Our findings highlight a change in center attitudes towards LT for ALD, particularly for severe AAH.

  View details for DOI 10.14309/ajg.0000000000001863

  View details for PubMedID 35916539

• "Beyond MELD" - Emerging strategies and technologies for improving mortality prediction, organ allocation and outcomes in liver transplantation. Journal of hepatology Ge, J., Kim, W. R., Lai, J. C., Kwong, A. J. 2022; 76 (6): 1318-1329

  Abstract

  In this review article, we discuss the model for end-stage liver disease (MELD) score and its dual purpose in general and transplant hepatology. As the landscape of liver disease and transplantation has evolved considerably since the advent of the MELD score, we summarise emerging concepts, methodologies, and technologies that may improve mortality prognostication in the future. Finally, we explore how these novel concepts and technologies may be incorporated into clinical practice.

  View details for DOI 10.1016/j.jhep.2022.03.003

  View details for PubMedID 35589253

• The steatosis-associated fibrosis estimator (SAFE) score: A tool to detect low-risk non-alcoholic fatty liver disease in primary care. Hepatology (Baltimore, Md.) Sripongpun, P., Kim, W. R., Mannalithara, A., Charu, V., Vidovszky, A., Asch, S., Desai, M., Kim, S. H., Kwong, A. J. 2022

  Abstract

  Non-alcoholic fatty liver disease (NAFLD) is common in primary care. Liver fibrosis stage 2 or higher (≥F2) increases future risk of morbidity and mortality. We developed and validated a score to aid in the initial assessment of liver fibrosis for NAFLD in primary care.Biopsy-proven NAFLD patients' data were extracted from the 'NASH CRN' observational study (n = 676). Using logistic regression and machine-learning methods, we constructed prediction models to distinguish ≥F2 from F0/1. The models were tested in participants in a trial ('FLINT', n = 280) and local NAFLD patients with magnetic resonance elastography data (n = 130). The final model was applied to examinees in the National Health and Nutrition Examination Survey III (NHANES, n = 11,953) to correlate with longterm mortality.A multivariable logistic regression model was selected as the Steatosis-Associated Fibrosis Estimator (SAFE) score, which consists of age, body mass index, diabetes, platelets, aspartate and alanine aminotransferases and globulins (total serum protein minus albumin). The model yielded areas under receiver operating characteristic curves ≥0.80 in distinguishing F0/1 from ≥F2 in testing datasets, consistently higher than those of FIB-4 and NAFLD Fibrosis Scores. The negative predictive values in ruling out ≥F2 at SAFE of 0 were 88% and 92% in the two testing sets. In the NHANES III set, survival up to 25 years of subjects with SAFE <0 was comparable to that of those without steatosis (p = 0.34), while increasing SAFE scores correlated with shorter survival with an adjusted hazard ratio of 1.54 (p < 0.01) for subjects with SAFE>100.The SAFE score, which uses widely available variables to estimate liver fibrosis in patients diagnosed with NAFLD, may be used in primary care to recognize low-risk NAFLD.

  View details for DOI 10.1002/hep.32545

  View details for PubMedID 35477908

• CAQ Corner: Disease Recurrence After Liver Transplantation. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Goel, A., Kwong, A. 2022

  View details for DOI 10.1002/lt.26492

  View details for PubMedID 35466545

• Author response to "MELD 3.0: The Model for End-stage Liver Disease Updated for the Modern Era". Gastroenterology Kwong, A., Kim, W. R. 1800

  View details for DOI 10.1053/j.gastro.2022.01.017

  View details for PubMedID 35063443

• Machine learning to predict waitlist dropout among liver transplant candidates with hepatocellular carcinoma. Cancer medicine Kwong, A., Hameed, B., Syed, S., Ho, R., Mard, H., Arshad, S., Ho, I., Suleman, T., Yao, F., Mehta, N. 1800

  Abstract

  BACKGROUND: Accurate prediction of outcome among liver transplant candidates with hepatocellular carcinoma (HCC) remains challenging. We developed a prediction model for waitlist dropout among liver transplant candidates with HCC.METHODS: The study included 18,920 adult liver transplant candidates in the United States listed with a diagnosis of HCC, with data provided by the Organ Procurement and Transplantation Network. The primary outcomes were 3-, 6-, and 12-month waitlist dropout, defined as removal from the liver transplant waitlist due to death or clinical deterioration.RESULTS: Using 1,181 unique variables, the random forest model and Spearman's correlation analyses converged on 12 predictive features involving 5 variables, including AFP (maximum and average), largest tumor size (minimum, average, and most recent), bilirubin (minimum and average), INR (minimum and average), and ascites (maximum, average, and most recent). The final Cox proportional hazards model had a concordance statistic of 0.74 in the validation set. An online calculator was created for clinical use and can be found at: http://hcclivercalc.cloudmedxhealth.com/.CONCLUSION: In summary, a simple, interpretable 5-variable model predicted 3-, 6-, and 12-month waitlist dropout among patients with HCC. This prediction can be used to appropriately prioritize patients with HCC and their imminent need for transplant.

  View details for DOI 10.1002/cam4.4538

  View details for PubMedID 35029055

• Decreased urgency among liver transplant candidates with hepatocellular carcinoma in the United States. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Kwong, A. J., Ghaziani, T. T., Mehta, N. 2021

  Abstract

  Early-stage hepatocellular carcinoma (HCC) has been an accepted indication for liver transplantation now for over 20 years. Allocation policy in the United States (US) has been continually refined to maintain equity and optimize the utility of transplant for HCC, yet all patients qualifying for HCC exception still receive the same number of points. This group is quite heterogeneous, with varying risk of waitlist dropout dependent on tumor characteristics including number and size of lesions and alpha-fetoprotein (AFP) level, as well as baseline liver function. In addition, changing demographics of liver disease, including the rising incidence of NASH, effective antiviral therapy for hepatitis C virus, and earlier detection of HCC due to improved screening programs and awareness, may influence the overall survival benefit to liver transplantation.

  View details for DOI 10.1002/lt.26373

  View details for PubMedID 34806834

• Correcting the sex disparity in access to liver transplantation - Lest perfect be the enemy of better. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Kwong, A. J., Lai, J. C., Kim, W. R. 2021

  Abstract

  The implementation of the Model for End-Stage Liver Disease (MELD) as the backbone of liver allocation policy in the United States in 2002 has overall improved waitlist outcomes and standardized access to liver transplantation for patients with end-stage liver disease. However, women experience higher waitlist mortality and lower transplant rates compared to men, attributed in part to underestimation of renal dysfunction by the use of serum creatinine in MELD and MELD-Na.1-3 Alternative models have been proposed to reduce this gap, including replacement of serum creatinine with estimated glomerular filtration rate or granting additional MELD points to women, but what has been lacking in the literature has been quantification and comparison of the potential impact of these models on the sex disparity itself.

  View details for DOI 10.1111/ajt.16805

  View details for PubMedID 34403193

• National Trends and Waitlist Outcomes of Locoregional Therapy among Liver Transplant Candidates with Hepatocellular Carcinoma in the United States. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association Kwong, A. J., Ghaziani, T. T., Yao, F., Sze, D., Mannalithara, A., Mehta, N. 2021

  Abstract

  BACKGROUND & AIMS: Policy changes in the United States (US) have overall lengthened waiting times for patients with hepatocellular carcinoma (HCC). We investigate temporal trends in utilization of locoregional therapy (LRT) and associated waitlist outcomes among liver transplant (LT) candidates in the US.METHODS: Data for primary adult LT candidates listed from 2003-2018 who received HCC exception were extracted from the OPTN database. Explant histology was examined, and multivariable competing risk analysis was used to evaluate the association between LRT type and waitlist dropout.RESULTS: There were 31,609 eligible patients with at least one approved HCC exception, and 34,610 treatments among 24,145 LT candidates. The proportion with at least one LRT recorded increased from 42.3% in 2003 to 92.4% in 2018. Chemoembolization remains the most frequent type, followed by thermal ablation, with a notable increase in radioembolization from 3% in 2013 to 19% in 2018. Increased incidence of LRT was observed among patients with tumor burden beyond Milan, higher AFP, and more compensated liver disease. Receipt of any type of LRT was associated with a lower risk of waitlist dropout; there were no significant differences by number of LRT. In IPTW-adjusted analysis, radioembolization or ablation as the first LRT was associated with reduced risk of waitlist dropout compared to chemoembolization.CONCLUSIONS: In a large nationwide cohort of LT candidates with HCC, LRT and in particular radioembolization was increasingly used to bridge to LT. Patients with greater tumor burden and those with more compensated liver disease received more treatments while awaiting LT. Bridging LRT was associated with a lower risk of waitlist dropout.

  View details for DOI 10.1016/j.cgh.2021.07.048

  View details for PubMedID 34358718

• Preliminary Evidence for a Relationship between Elevated Plasma TNF alpha and Smaller Subcortical White Matter Volume in HCV Infection Irrespective of HIV or AUD Comorbidity INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Zahr, N. M., Pohl, K. M., Kwong, A. J., Sullivan, E. V., Pfefferbaum, A. 2021; 22 (9)

  View details for DOI 10.3390/ijms22094953

  View details for Web of Science ID 000650336900001

• Feasibility and Effectiveness of Norepinephrine Outside the Intensive Care Setting for Treatment of Hepatorenal Syndrome. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Kwong, A., Kim, W. R., Kwo, P. Y., Wang, U., Cheng, X. 2021

  Abstract

  BACKGROUND & AIMS: Vasoconstrictors are the treatment of choice for hepatorenal syndrome (HRS), a potentially lethal complication of end-stage liver disease. We evaluate the real-life effectiveness of a sequential vasoconstrictor regimen of midodrine-octreotide followed by norepinephrine in a non-ICU setting in the United States, where terlipressin is not available.APPROACH & RESULTS: Adult patients diagnosed with HRS were treated with oral midodrine and subcutaneous octreotide in conjunction with albumin. The diagnosis of HRS and definitions of acute kidney injury were based on 2015 guidelines from the International Club of Ascites. A partial response was defined as regression of acute kidney injury (AKI) stage with reduction in serum creatinine to ≥0.3 mg/dL above baseline, whereas a full response was regression of AKI stage with return to a value within 0.3 mg/dL of baseline. In patients without partial or full response, norepinephrine was administered at a starting dose of 5 mcg/min, with a goal to achieve a mean arterial pressure (MAP) of 10 mmHg above baseline. We assessed predictors of response and treatment outcomes. 61 patients received midodrine and octreotide for the treatment of HRS, with a 28% response rate. The median MELD-Na was 30 (IQR 24-35), with median MAP of 73 mmHg (IQR 67-79) at the start of treatment. Responders were more likely to have alcohol-related liver disease and lower ACLF grade. Of the non-responders, 20 then received norepinephrine, of whom 45% achieved full or partial response. Achieving MAP increase of ≥10 mmHg was associated with a greater probability of response. Patients who responded to norepinephrine experienced improved transplant-free survival at 90 days (88% v. 27%, p=0.02). Five of 20 patients experienced norepinephrine treatment-related adverse events, namely arrhythmias.CONCLUSION: Norepinephrine can be effectively used in a non-ICU setting as rescue therapy in patients who have not responded to midodrine and octreotide. Based on these data, we propose a practical stepwise algorithm for vasoconstrictor therapy to manage HRS in situations where terlipressin is not an option.

  View details for DOI 10.1002/lt.26065

  View details for PubMedID 33837624

• Expanding the Limits of Liver Transplantation for Hepatocellular Carcinoma Is There a Limit? CLINICS IN LIVER DISEASE Kwong, A., Mehta, N. 2021; 25 (1): 19–33

  View details for DOI 10.1016/j.cld.2020.08.002

  View details for Web of Science ID 000593716300003

• OPTN/SRTR 2019 Annual Data Report: Liver. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Kwong, A. J., Kim, W. R., Lake, J. R., Smith, J. M., Schladt, D. P., Skeans, M. A., Noreen, S. M., Foutz, J., Booker, S. E., Cafarella, M., Snyder, J. J., Israni, A. K., Kasiske, B. L. 2021; 21 Suppl 2: 208–315

  Abstract

  This year was notable for changes to exception points determined by the geographic median allocation Model for End-Stage Liver Disease (MELD) and implementation of the National Liver Review Board, which took place on May 14, 2019. The national acuity circle liver distribution policy was also implemented but reverted to donor service area- and region-based boundaries after 1 week. In 2019, growth continued in the number of new waiting list registrations (12,767) and transplants performed (8,896), including living-donor transplants (524). Compared with 2018, living-donor liver transplants increased 31%. Women continued to have a lower deceased-donor transplant rate and a higher pretransplant mortality rate than men. The median waiting time for candidates with a MELD of 15-34 decreased, while the number of transplants performed for patients with exception points decreased. These changes may have been related to the policy changes that took effect in May 2019, which increased waiting list priority for candidates without exception status. Hepatitis C continued to decline as an indication for liver transplant, as the proportion of liver transplant recipients with alcohol-related liver disease and clinical profiles consistent with non-alcoholic steatohepatitis increased. Graft and patient survival have improved despite changing recipient demographics including older age, higher MELD, and higher prevalence of obesity and diabetes.

  View details for DOI 10.1111/ajt.16494

  View details for PubMedID 33595192

• MELD 3.0: The Model for End-stage Liver Disease Updated for the Modern Era. Gastroenterology Kim, W. R., Mannalithara, A., Heimbach, J. K., Kamath, P. S., Asrani, S. K., Biggins, S. W., Wood, N. L., Gentry, S. E., Kwong, A. J. 2021

  Abstract

  The model for end-stage liver disease (MELD) has been established as a reliable indicator of short-term survival in patients with end-stage liver disease. The current version (MELDNa), consisting of INR and serum bilirubin, creatinine, and sodium, has been used to determine organ allocation priorities for liver transplantation in the United States (US). The objective was to optimize MELD further by taking into account additional variables and updating coefficients with contemporary data.All candidates registered on the liver transplant waitlist in the US national registry from Jan 2016 - Dec 2018 were included. Uni- and multivariable Cox models were developed to predict survival up to 90 days after waitlist registration. Model fit was tested using the concordance statistic and reclassification, and the liver simulated allocation model (LSAM) was used to estimate the impact of replacing MELDNa with the new model.The final multivariable model was characterized by (1) additional variables of female sex and serum albumin, (2) interactions between bilirubin and sodium and between albumin and creatinine, and (3) an upper bound for creatinine at 3.0mg/dL. The final model (MELD 3.0, henceforth), had better discrimination than MELDNa (concordance statistic 0.869 versus 0.862, p<0.01). Importantly, MELD 3.0 correctly reclassified a net of 8.8% of decedents to a higher MELD tier, affording them a meaningfully higher chance of transplant, particularly in women. In the LSAM analysis, MELD 3.0 resulted in fewer waitlist deaths compared to MELDNa (7,788 versus 7,850, p=0.02).MELD 3.0 affords more accurate mortality prediction in general than MELDNa and addresses determinants of waitlist outcomes including the sex disparity.

  View details for DOI 10.1053/j.gastro.2021.08.050

  View details for PubMedID 34481845

• Research methodologies to address clinical unmet needs and challenges in alcohol-associated liver disease. Hepatology (Baltimore, Md.) Singal, A. K., Kwo, P., Kwong, A., Liangpunsakul, S., Louvet, A., Mandrekar, P., McClain, C., Mellinger, J., Szabo, G., Terrault, N., Thursz, M., Winder, G. S., Kim, W. R., Shah, V. H. 2021

  Abstract

  Alcohol-associated liver disease (ALD) is emerging worldwide as the leading cause of liver-related morbidity, mortality, and indication for liver transplantation. The ALD Special Interest Group and the Clinical Research Committee at the digital AASLD meeting in November 2020 held the scientific sessions to identify clinical unmet needs in ALD, and addressing these needs using clinical research methodologies. Of several research methodologies, the sessions were focused to a) study disease burden of ALD using large administrative databases, b) develop biomarkers for non-invasive diagnosis of alcoholic hepatitis (AH) and estimation of disease prognosis, c) identify novel therapeutic targets for ALD and AH, d) derive accurate models to predict prognosis or post-transplant alcohol relapse as a basis for developing treatment algorithm and a uniform protocol on patient selection criteria for liver transplantation, and e) examine qualitative research methodologies in studying the barriers to implementation of multidisciplinary integrated care model by hepatology and addiction teams for the management of dual pathology of liver disease and of alcohol use disorder. Prospective multicenter studies are required to address many of these clinical unmet needs. Further, multidisciplinary care models are needed to improve long-term outcomes in patients with ALD.

  View details for DOI 10.1002/hep.32143

  View details for PubMedID 34496071

• Predicting survival after liver transplant: A noble pursuit or a fool's errand? Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Kwong, A. J., Kim, W. R. 2021

  Abstract

  Organ shortage continues to limit our ability to provide transplant to all in need of liver transplantation. The current urgency-based system is based on the laboratory MELD-Na score, which efficiently and effectively rank orders patients by their estimated risk for 90-day waitlist mortality, with a c-statistic of 0.88.1 MELD-Na is agnostic to factors such as age, etiology of liver disease, and co-morbidity, as well as one's expected post-transplant survival. Transplant centers are entrusted, according to the Final Rule, to ensure that candidates meet a minimal threshold of utility where liver transplant would benefit the patient.

  View details for DOI 10.1002/lt.26057

  View details for PubMedID 33773023

• Predictors of Outcomes of Patients Referred to a Transplant Center for Urgent Liver Transplantation Evaluation HEPATOLOGY COMMUNICATIONS Alshuwaykh, O., Kwong, A., Goel, A., Cheung, A., Dhanasekaran, R., Ahmed, A., Daugherty, T., Dronamraju, D., Kumari, R., Kim, W., Esquivel, C. O., Concepcion, W., Melcher, M., Bonham, A., Pham, T., Gallo, A., Kwo, P. 2020

  View details for DOI 10.1002/hep4.1644

  View details for Web of Science ID 000602465100001

• Outcomes of Liver Transplantation Among Older Recipients With Nonalcoholic Steatohepatitis in a Large Multicenter US Cohort: the Re-Evaluating Age Limits in Transplantation Consortium. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Kwong, A. J., Devuni, D., Wang, C., Boike, J., Jo, J., VanWagner, L., Serper, M., Jones, L., Sharma, R., Verna, E. C., Shor, J., German, M. N., Hristov, A., Lee, A., Spengler, E., Koteish, A. A., Sehmbey, G., Seetharam, A., John, N., Patel, Y., Kappus, M. R., Couri, T., Paul, S., Salgia, R. J., Nhu, Q., Frenette, C. T., Lai, J. C., Goel, A., Re-Evaluating Age Limits in Transplantation (REALT) Consortium 2020

  Abstract

  The liver transplantation (LT) population is aging, with the need for transplant being driven by the growing prevalence of nonalcoholic steatohepatitis (NASH). Older LT recipients with NASH may be at an increased risk for adverse outcomes after LT. Our objective is to characterize outcomes in these recipients in a large multicenter cohort. All primary LT recipients ≥65years from 2010 to 2016 at 13 centers in the Re-Evaluating Age Limits in Transplantation (REALT) consortium were included. Of 1023 LT recipients, 226 (22.1%) were over 70 years old, and 207 (20.2%) had NASH. Compared with other LT recipients, NASH recipients were older (68.0 versus 67.3years), more likely to be female (47.3% versus 32.8%), White (78.3% versus 68.0%), Hispanic (12.1% versus 9.2%), and had higher Model for End-Stage Liver Disease-sodium (21 versus 18) at LT (P<0.05 for all). Specific cardiac risk factors including diabetes with or without chronic complications (69.6%), hypertension (66.3%), hyperlipidemia (46.3%), coronary artery disease (36.7%), and moderate-to-severe renal disease (44.4%) were highly prevalent among NASH LT recipients. Graft survival among NASH patients was 90.3% at 1year and 82.4% at 3years compared with 88.9% at 1year and 80.4% at 3years for non-NASH patients (log-rank P=0.58 and P=0.59, respectively). Within 1 year after LT, the incidence of graft rejection (17.4%), biliary strictures (20.9%), and solid organ cancers (4.9%) were comparable. Rates of cardiovascular (CV) complications, renal failure, and infection were also similar in both groups. We observed similar posttransplant morbidity and mortality outcomes for NASH and non-NASH LT recipients. Certain CV risk factors were more prevalent in this population, although posttransplant outcomes within 1 year including CV events and renal failure were similar to non-NASH LT recipients.

  View details for DOI 10.1002/lt.25863

  View details for PubMedID 33047893

• Center variation in intention to treat survival among patients listed for liver transplant. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Kwong, A. J., Flores, A., Saracino, G., Boutte, J., McKenna, G., Giuliano, T., Bahirwani, R., Wall, A., Kim, W. R., Klintmalm, G., Trotter, J. F., Asrani, S. K. 2020

  Abstract

  BACKGROUND & AIMS: Currently liver transplant (LT) centers are evaluated by patient survival within 1 year after LT, but tight clustering of outcomes allow only a narrow window for evaluation of center variation for quality improvement. Alternate measures more relevant to patients and the transplant community are needed.APPROACH & RESULTS: We examined adults listed for LT in the United States, using data submitted to Scientific Registry of Transplant Recipients. Intention to treat (ITT) survival was defined as survival within 1 year from listing, regardless of transplant. Mixed effects/frailty models were used to assess center variation in ITT survival. Between 1/2010 and 12/2016, there were 66,428 new listings at 113 centers. Overall, median 1-year ITT survival was 79.8% (IQR 76.1-83.4), while 1-year WL survival was 75.8% (IQR 71.2-79.4), and 1-year post-LT survival was 90.0% (IQR 87.9-91.8). Higher rates of ITT mortality were correlated with increased WL mortality (correlation, r=0.76), increased post-LT mortality (r=0.31), lower volume centers (r=-0.34), and lower transplant rate ratio (r=-0.25). Similar patterns were observed in the subgroup of WL candidates listed with MELD ≥25: median 1-year ITT survival was 65.2% (IQR 60.2-72.6), while 1-year post-LT survival was 87.5% (IQR 84.0-90.9), and 1-year WL survival was 36.6% (IQR 27.9-47.0). In mixed effects modeling, center was an independent predictor of ITT survival even after adjustment for age, sex, MELD, and sociodemographic variables. Center variation for ITT survival was larger compared to post-LT survival.CONCLUSIONS: Measurement of ITT outcome offers a complementary method to assess center performance. This is a first step toward understanding differences in program quality beyond patient and graft survival after LT.

  View details for DOI 10.1002/lt.25852

  View details for PubMedID 32725923

• Tenofovir Alafenamide Attenuates Effects of Diabetes and Body Mass on Serum Alanine Aminotransferase Activities in Patients with Chronic Hepatitis B. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association Sripongpun, P. n., Kim, W. R., Mannalithara, A. n., Kwong, A. n., Daugherty, T. n., Goel, A. n., Kwo, P. Y. 2020

  View details for DOI 10.1016/j.cgh.2020.11.047

  View details for PubMedID 33285291

• Editorial: glecaprevir/pibrentasvir for the treatment of hepatitis C virus-do baseline resistance-associated substitutions matter? Alimentary pharmacology & therapeutics Kwong, A. J., Kwo, P. Y. 2020; 51 (7): 739–40

  View details for DOI 10.1111/apt.15656

  View details for PubMedID 32162374

• OPTN/SRTR 2018 Annual Data Report: Liver. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Kwong, A., Kim, W. R., Lake, J. R., Smith, J. M., Schladt, D. P., Skeans, M. A., Noreen, S. M., Foutz, J., Miller, E., Snyder, J. J., Israni, A. K., Kasiske, B. L. 2020; 20 Suppl s1: 193–299

  Abstract

  Data on adult liver transplants performed in the US in 2018 are notable for (1) continued growth in numbers of new waitlist registrants (11,844) and transplants performed (8250); (2) continued increase in the transplant rate (54.5 per 100 waitlist-years); (3) a precipitous decline in waitlist registrations and transplants for hepatitis-C-related indications; (4) increases in waitlist registrants and recipients with alcoholic liver disease and with clinical profiles consistent with non-alcoholic fatty liver disease; (5) increased use of hepatitis C virus antibody-positive donor livers; and (6) continued improvement in graft survival despite changing recipient characteristics such as older age and higher rates of obesity and diabetes. Variability in transplant rates remained by candidate race, hepatocellular carcinoma status, urgency status, and geography. The volume of pediatric liver transplants was relatively unchanged. The highest rate of pre-transplant mortality persisted for children aged younger than 1 year. Children underwent transplant at higher acuity than in the past, as evidenced by higher model for end-stage liver disease/pediatric end-stage liver disease scores and listings at status 1A and 1B at transplant. Despite higher illness severity scores at transplant, pediatric graft and patient survival posttransplant have improved over time.

  View details for DOI 10.1111/ajt.15674

  View details for PubMedID 31898413

• Reply to: "The decreasing predictive power of MELD in an era of changing etiology of liver disease". American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Kwong, A., Mannalithara, A., Kim, W. R. 2019

  Abstract

  We read with interest the recent article by Godfrey et al.(1) regarding the predictive power of the Model for End-Stage Liver Disease (MELD), the score used for allocation of donor livers, over time. The authors report that the discriminative ability of MELD for the prediction of 90-day waitlist mortality, as measured by the concordance statistic (c-statistic), had declined from 0.80 in 2002 to 0.70in 2015 among new waitlist registrants. These values are inconsistent with previously published estimates.

  View details for DOI 10.1111/ajt.15733

  View details for PubMedID 31814299

• Migration of Patients for Liver Transplantation and Waitlist Outcomes. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association Kwong, A. J., Mannalithara, A. n., Heimbach, J. n., Prentice, M. A., Kim, W. R. 2019

  Abstract

  Patients in need of liver transplantation may travel to improve their chance of receiving an organ. We evaluated factors to determine which transplant candidates travel to other regions to increase their chances of receiving a liver and effects of travel on waitlist outcomes.We performed a retrospective cohort study of all adult patients registered for primary deceased donor liver transplantation in the United States from January 2004 to December 2016. Zip code data were used to calculate the distance of travel from a patient's residence to centers at which they were on the waitlist or received a liver transplant. Distant listing and migration were defined as placement on a waitlist and receipt of liver transplantation, respectively, outside the home transplantation region and greater than 500 miles from the home zip code. We assessed the effect of distant listing on outcomes (death and liver transplantation) and predictors of distant listing or migration using multivariable analyses.There were 104,914 waitlist registrations during the study period; 2930 (2.8%) pursued listing at a distant center. Of waitlist registrants, 60,985 received liver transplants, of whom 1985 (3.3%) had migrated. In a multivariable competing risk analysis in which liver transplantation considered as a competing event, distant listing was associated with an 22% reduction in the risk of death within 1 year (subhazard ratio, 0.78; 95% CI, 0.70-0.88). Distant listing and migration were associated with non-black race, non-Medicaid payer, residence in a higher income area, and education beyond high school.Placement on a liver transplant waitlist outside the home transplantation region is associated with reduced waitlist mortality and an increased probability of receiving a liver transplant. Geographic disparities in access to liver transplantation have disproportionate effects on patients who are minorities, have lower levels of education, or have public insurance.

  View details for PubMedID 31077826

• Trends in Endoscopic Mucosal Resection for Nonmalignant Colorectal Polyps in the United States. Gastrointestinal endoscopy Yu, J. X., Lin, J. L., Oliver, M. n., Soetikno, R. n., Chang, M. S., Kwong, A. J., Limketkai, B. N., Bhattacharya, J. n., Kaltenbach, T. n. 2019

  Abstract

  Although most large nonpedunculated colorectal lesions can be safely and efficaciously removed using endoscopic mucosal resection (EMR), the use of colectomy for benign colorectal lesions appears to be increasing. The reason(s) is unclear. We aimed to determine the utilization and the adverse events of EMR in the United States.We used Optum's de-identified Clinformatics Data Mart Database (2003-2016), a database from a large national insurance provider, to identify all colonoscopies performed with either EMR or simple polypectomy on adult patients from January 1, 2011, through December 31, 2015. We measured time trends, regional variation, and adverse event rates. We assessed risk factors for adverse events using multivariate logistic regression.EMR is increasingly used in the United States, from 1.62% of all colonoscopies in 2011 to 2.48% of colonoscopies in 2015 (p<0.001). There were, however, significant regional differences in the utilization of EMRs, from 2.4% of colonoscopies in the western United States to 2.0% of colonoscopies in the southern United States. From 2011 to 2015, we found stable rates of perforation, gastrointestinal bleeding (GIB), infections, and cardiac adverse events, and decreasing rates of admissions after EMR. In our multivariate model, EMR was an independent risk factor for adverse events, albeit the rates of adverse events were low (1.35% GIB, 0.22% perforation).EMR is increasingly used in the United States, although there is significant regional variation. The rates of adverse events after EMR and polypectomies were low and stable, confirming the continuing safety of EMR procedures. A better understanding of the regional barriers and facilitators may improve the use of EMR as the standard management for benign colorectal lesions throughout the United States.

  View details for DOI 10.1016/j.gie.2019.08.004

  View details for PubMedID 31437455

• Liver Transplantation for HCV Non-Viremic Recipients with HCV Viremic Donors. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Kwong, A. J., Wall, A., Melcher, M., Wang, U., Ahmed, A., Subramanian, A., Kwo, P. Y. 2018

  Abstract

  In the context of organ shortage, the opioid epidemic, and effective direct-acting antiviral (DAA) therapy for hepatitis C (HCV), more HCV-infected donor organs may be used for liver transplantation. Current data regarding outcomes after donor-derived HCV in previously non-viremic liver transplant recipients are limited. Clinical data for adult liver transplant recipients with donor-derived HCV infection from March 2017 to January 2018 at our institution were extracted from the medical record. Ten patients received livers from donors known to be infected with HCV based on positive nucleic acid testing (NAT). Seven had a prior diagnosis of HCV and were treated before liver transplantation. All recipients were non-viremic at the time of transplantation. All 10 recipients derived hepatitis C infection from their donor and achieved sustained virologic response at 12 weeks post-treatment (SVR-12) with DAA-based regimens, with a median time from transplant to treatment initiation of 43 days (IQR 20-59). There have been no instances of graft loss or death, with median follow-up of 380 days (IQR 263-434) post-transplant. Transplantation of HCV-viremic livers into non-viremic recipients results in acceptable short-term outcomes. Such strategies may be used to expand the donor pool and increase access to liver transplantation. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30378723

• Risk Prediction Models for Graft Failure after Liver Transplantation: A Machine-Learning Approach Kwong, A. J., O'Connell, C., Kanzawa, M., Hufker, K., Lindsay, N., Kim, W. WILEY. 2018: 668A–669A

  View details for Web of Science ID 000446020501379

• Prediction of Mortality Risk in Decompensated Cirrhosis Due to Primary Biliary Cholangitis Kwong, A. J., Goel, A., Mannalithara, A., Iloeje, U., Feng, C., Kim, W. WILEY. 2018: 1098A–1099A

  View details for Web of Science ID 000446020503155

• Hospital Cirrhosis Volume and Readmission in Patients with Cirrhosis in California. Digestive diseases and sciences Wei, M. n., Ford, J. n., Li, Q. n., Jeong, D. n., Kwong, A. J., Nguyen, M. H., Chang, M. S. 2018

  Abstract

  Patients with cirrhosis are at high readmission risk. Using a large statewide database, we evaluated the effect of hospital cirrhosis-related patient volume on 30-day readmissions in patients with cirrhosis.We conducted a retrospective study of the Healthcare Cost and Utilization Project State Inpatient Database for adult patients with cirrhosis, as defined by International Classification of Diseases, Ninth Revision (ICD-9) codes, hospitalized in California between 2009 and 2011. Multivariable logistic regression analysis was performed to evaluate the effect of hospital volume on 30-day readmissions.A total of 69,612 patients with cirrhosis were identified in 405 hospitals; 24,062 patients were discharged from the top 10% of hospitals (N = 41) by cirrhosis volume, and 45,550 patients in the bottom 90% (N = 364). Compared with higher-volume centers, lower-volume hospitals cared for patients with similar average Quan-Charlson-Deyo (QCD) comorbidity scores (6.54 vs. 6.68), similar proportion of hepatitis B and fatty liver disease, lower proportion of hepatitis C (34.8 vs. 41.5%) but greater proportion of alcoholic liver disease (53.1 vs. 47.4%). Multivariable logistic regression analysis demonstrated admission to a lower-volume hospital did not predict 30-day readmission (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.92-1.01) after adjusting for sociodemographics, QCD score, cirrhosis severity, and hospital characteristics. Instead, liver transplant center status significantly decreased the risk of readmission (OR 0.87, 95% CI 0.80-0.94). Ascites, hepatic encephalopathy, hepatocellular carcinoma, higher QCD, and presence of alcoholic liver disease and hepatitis C were also independent predictors.Readmissions within 30 days were common among patients with cirrhosis hospitalized in California. While hospital cirrhosis volume did not predict 30-day readmissions, liver transplant center status was protective of readmissions. Medically complicated patients with cirrhosis at hospitals without liver transplant centers may benefit from additional support to prevent readmission.

  View details for PubMedID 29457210

• The effects of a transjugular intrahepatic portosystemic shunt on the diagnosis of hepatocellular cancer. PloS one Wong, K., Ozeki, K., Kwong, A., Patel, B. N., Kwo, P. 2018; 13 (12): e0208233

  Abstract

  BACKGROUND AND AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) may be placed to treat complications of portal hypertension by creating a conduit between the hepatic and portal vein. The diagnosis of hepatocellular carcinoma (HCC) is typically made by multiphasic imaging studies demonstrating arterial enhancement with washout on arterial, portal venous, and delayed phase imaging. The aim of our study was to determine how the presence of TIPS would affect the imaging diagnosis of HCC.METHODS: This was a single-center electronic database review of all patients who underwent multiphasic imaging with MRI or CT scan for HCC screening between January 2000 and July 2017 and who were subsequently diagnosed with HCC. Data collected included patient demographics, liver disease characteristics including CPT score, MELD-Na, AFP, type of imaging, tumor stage, and lab values at the time of HCC diagnosis. The diagnosis of HCC was made using LI-RADS criteria on contrast-enhanced CT or MR imaging and confirmed by chart abstraction as documented by the treating clinician. Demographic and imaging characteristics for HCC patients with and without TIPS were compared.RESULTS: A total of 279 patients met eligibility criteria for the study, 37 (13.2%) of whom had TIPS placed prior to diagnosis of HCC. There was no significant difference in demographics or liver disease characteristics between patients with and without TIPS. Compared to cirrhotic patients with no TIPS prior to HCC diagnosis, patients with TIPS had significantly more scans with a longer duration of surveillance until HCC diagnosis. However, LI-RADS criteria and stage of HCC at diagnosis were not significantly different between both groups. There were no differences in outcomes including liver transplant and survival.CONCLUSION: The presence of TIPS does not lead to a delayed diagnosis of HCC. It is associated, however, with greater duration of time from first scan to diagnosis of HCC.

  View details for PubMedID 30592722

• De Novo Hepatocellular Carcinoma Among Liver Transplant Registrants in the Direct Acting Antiviral Era. Hepatology (Baltimore, Md.) Kwong, A. J., Kim, W. R., Flemming, J. A. 2018

  Abstract

  The risk of hepatocellular carcinoma (HCC) in patients with hepatitis C (HCV) receiving direct acting antivirals (DAA) has been debated. This study aims to describe the incidence of HCC among patients listed for liver transplantation (LT) in the DAA era.Individuals with cirrhosis listed for LT from January 2003 to December 2015 were identified using the Scientific Registry for Transplant Recipients database. Patients with HCC at listing or HCC exception within 180 days were excluded. Patients were divided into 3 eras based on listing date: Eras 1 (2003-2010), 2 (2011-2013), and 3 (2014-2015). Incidence rates of HCC were calculated by era and compared using incident rate ratios (IRR). The association between HCC and listing era was evaluated using Cox regression and competing risk analyses, the latter considering death and LT as competing events.Of 48,158 eligible waitlist registrants, 3,112 (6.5%) received HCC exceptions after a median of 493 days. In 20,039 individuals with HCV, the incidence of HCC was 49% higher in Era 3 vs. 1 (IRR 1.49, 95% CI 1.24-1.79). In multivariate analysis, those in Era 3 had a higher hazard of HCC compared to Era 1 (HR 1.22, 95% CI 1.01-1.48). However, in multivariable competing risks analysis with death and LT considered as competing events for de novo HCC, era was no longer associated with HCC (sHR 0.83, 95% CI 0.69-1.00).In this large population-based cohort of LT registrants, the incidence of HCC among HCV patients has increased in the DAA era. Competing risks analysis suggests that this may be explained by changes in rates of LT and waitlist mortality in the HCV population during this time. This article is protected by copyright. All rights reserved.

  View details for PubMedID 29672886

• Peripartum Care for Mothers Diagnosed with Hepatitis B During Pregnancy: A Survey of Provider Practices. Maternal and child health journal Kwong, A. J., Chang, M. S., Tuomala, R. E., Riley, L. E., Robinson, J. N., Mutinga, M. L., Andersson, K. L., Brown, R. S., Oken, E. n., Ukomadu, C. n., Rutherford, A. E. 2018

  Abstract

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

  View details for PubMedID 29512054

• Decreasing Mortality and Disease Severity in Hepatitis C Patients Awaiting Liver Transplantation in the United States. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Kwong, A., Kim, W. R., Mannalithara, A., Heo, N. Y., Udompap, P., Kim, D. 2017

  Abstract

  Hepatitis C virus (HCV) infection has been the leading indication for liver transplantation (LT) in the United States. Since 2013, interferon-free antiviral therapy has led to sustained virologic response in many LT candidates. We compared the waitlist mortality of HCV patients with that of patients with other chronic liver diseases.Data for primary LT candidates were obtained from the Organ Procurement and Transplantation Network database. Adult waitlist registrants were divided into three cohorts: Cohort 1 included patients on the waitlist as of January 1, 2004; Cohort 2 as of January 1, 2009; and Cohort 3 as of January 1, 2014. The primary outcome was waitlist mortality, and the secondary outcome was the rate of change in Model for End-stage Liver Disease (MELD). Multivariable Cox proportional hazards analysis was performed to evaluate 12-month waitlist mortality.The cohorts included 7,627 LT candidates with HCV and 13,748 patients without HCV. Compared with Cohort 2, HCV patients in Cohort 3 had a 21% lower risk of death (hazard ratio [HR] 0.79, 95% CI 0.67-0.93). Among patients with non-HCV liver disease, no difference in mortality was seen between Cohorts 2 and 3 (HR 0.97, 95% CI 0.86-1.09). Among HCV patients, the mean rate of change in MELD decreased from 2.35 per year for Cohort 2 to 1.90 per year for Cohort 3, compared to 1.90 and 1.66 in Cohorts 2 and 3, respectively, among non-HCV patients.In this population-based study, waitlist mortality and progression of disease severity decreased in recent HCV patients for whom direct-acting antiviral agents were available. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/lt.24973

  View details for PubMedID 29125676

• Improved Post-Transplant Mortality After Share 35 for Liver Transplantation. Hepatology (Baltimore, Md.) Kwong, A. J., Goel, A., Mannalithara, A., Kim, W. R. 2017

  Abstract

  The Share 35 policy was implemented in June 2013 to improve equity in access to liver transplantation (LT) between patients with fulminant liver failure and those with cirrhosis and severe hepatic decompensation. The aim of this study was to assess post-LT outcomes after Share 35.Relevant donor, procurement, and recipient data were extracted from the OPTN/UNOS database. All adult deceased donor LT from January 1, 2010 to March 31, 2016 were included in the analysis. One-year patient survival before and after Share 35 was assessed by multivariable Cox proportional hazards analysis, with adjustment for variables known to affect graft survival.Of 34,975 adult LT recipients, 16,472 (47.1%) were transplanted after the implementation of Share 35, of whom 4,599 (27.9%) had a Model for End-Stage Liver Disease (MELD) ≥35. One-year patient survival improved from 83.9% to 88.4% after Share 35 (p<0.01) for patients with MELD ≥35. There was no significant impact on survival of patients with MELD <35 (p=0.69). Quality of donor organs, as measured by Donor Risk Index without the regional share component, improved for patients with MELD ≥35 (p<0.01) and worsened for patients with lower MELD (p<0.01). In multivariable Cox regression analysis, Share 35 was associated with improved one-year patient survival (hazard ratio 0.69, 95% confidence interval 0.60-0.80) in recipients with MELD ≥35.Share 35 has had a positive impact on survival after transplantation in patients with MELD ≥35, without a reciprocal detriment in patients with lower acuity. This was in part a result of a more favorable donor-recipient matching. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/hep.29301

  View details for PubMedID 28586179

• Artificial Neural Networks and liver transplantation: Are we ready for self-driving cars? Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society Kwong, A. J., Asrani, S. K. 2017

  View details for PubMedID 29211925

• Evaluation of a Resident-Led Project to Decrease Phlebotomy Rates in the Hospital: Think Twice, Stick Once JAMA INTERNAL MEDICINE Wheeler, D., Marcus, P., Nguyen, J., Kwong, A., Khaki, A. R., Valencia, V., Moriates, C. 2016; 176 (5): 708-710

  View details for DOI 10.1001/jamainternmed.2016.0549

  View details for Web of Science ID 000375292500037

  View details for PubMedID 27043912

• Outcomes for liver transplant candidates listed with low model for end-stage liver disease score LIVER TRANSPLANTATION Kwong, A. J., Lai, J. C., Dodge, J. L., Roberts, J. P. 2015; 21 (11): 1403-1409

  Abstract

  The Model for End-Stage Liver Disease (MELD) score, which estimates mortality within 90 days, determines priority for liver transplantation (LT). However, longer-term outcomes on the wait list for patients who are initially listed with low MELD scores are not well characterized. All adults listed for primary LT at a single, high-volume center from 2005 to 2012 with an initial laboratory MELD score of 22 or lower were evaluated. Excluded were those patients listed with MELD exception points who underwent living donor liver transplantation (LDLT) or transplantation at another center, or who were removed from the wait list for nonmedical reasons. Outcomes and causes of death were identified by United Network for Organ Sharing, the National Death Index, and an electronic medical record review. Multivariate competing risk analysis evaluated predictors of death compared to deceased donor liver transplantation (DDLT); 893 patients were listed from 2005 to 2012. By the end of follow-up, 27% had undergone DDLT, and 31% were removed from the wait list for death or clinical deterioration. In a competing risks assessment, only MELD score of 6-9, older age, lower serum albumin, lower body mass index, and diabetes conferred an increased risk of wait-list dropout compared to DDLT. Listing for simultaneous liver-kidney transplantation was protective against wait-list dropout. Of the patients included, 275 patients died or were delisted for being too sick; 87% of the identifiable causes of death were directly related to end-stage liver disease or hepatocellular carcinoma. In conclusion, patients with low listing MELD scores remain at a significant risk for death due to liver-related causes and may benefit from early access to transplantation, such as LDLT or acceptance of high-risk donor livers. Predictors of death compared to transplantation may allow for early identification of patients who are at risk for wait-list mortality.

  View details for DOI 10.1002/lt.24307

  View details for Web of Science ID 000363693800010

  View details for PubMedID 26289624

  View details for PubMedCentralID PMC4838198

• Update on the management of the liver transplant patient CURRENT OPINION IN GASTROENTEROLOGY Kwong, A. J., Fix, O. K. 2015; 31 (3): 224-232

  Abstract

  To review and highlight recent literature regarding the medical management of adult patients undergoing liver transplantation.The addition of serum sodium concentration to the model for end-stage liver disease (MELD) score more accurately predicts 90-day waitlist mortality. Predictors of waitlist mortality and posttransplant survival include lower albumin and the presence of ascites, varices, and encephalopathy, as well as more nontraditional predictors such as older age, obesity, frailty, and sarcopenia. Indications for liver transplantation are evolving with the advent of effective therapy for hepatitis C and the increased prevalence of nonalcoholic steatohepatitis. Disparities persist in the current allocation system, including geographic variation and MELD inflation for hepatocellular carcinoma. Share 35 allows for broader regional sharing of organs for patients with the highest need, without detrimental effects on waitlist mortality or survival. Everolimus is a recently approved option for posttransplant immunosuppression that spares renal function.The MELD score has enabled the liver transplant community to equitably allocate organs. Recent literature has focused on the limitations of the MELD score and the disparities inherent in the current system. The next steps for liver transplantation will be to develop strategies to further optimize waitlist prioritization and organ allocation.

  View details for DOI 10.1097/MOG.0000000000000173

  View details for Web of Science ID 000353312700008

  View details for PubMedID 25774445

• Reduced Hepatic Stellate Cell Expression of Kruppel-Like Factor 6 Tumor Suppressor Isoforms Amplifies Fibrosis During Acute and Chronic Rodent Liver Injury HEPATOLOGY Ghiassi-nejad, Z., Hernandez-Gea, V., Woodrell, C., Lang, U. E., Dumic, K., Kwong, A., Friedman, S. L. 2013; 57 (2): 786-796

  Abstract

  Kruppel-like factor 6 (KLF6), a zinc finger transcription factor and tumor suppressor, is induced as an immediate-early gene during hepatic stellate cell (HSC) activation. The paradoxical induction of a tumor suppressor in HSCs during proliferation led us to explore the biology of wildtype KLF6 (KLF6(WT) ) and its antagonistic, alternatively spliced isoform KLF6(SV1) in cultured HSCs and animal models. The animal models generated include a global heterozygous KLF6 mouse (Klf6+/-), and transgenic mice expressing either hKLF6(WT) or hKLF6(SV1) under the control of the Collagen α2 (I) promoter to drive HSC-specific gene expression following injury. The rat Klf6 transcript has multiple splice forms that are homologous to those of the human KLF6 gene. Following a transient increase, all rat Klf6 isoforms decreased in response to acute carbon tetrachloride (CCl(4)) liver injury and culture-induced activation. After acute CCl(4), Klf6+/- mice developed significantly increased fibrosis and enhanced fibrogenic messenger RNA (mRNA) and protein expression. In contrast, HSC-specific transgenic mice overexpressing KLF6(WT) or KLF6(SV1) developed significantly diminished fibrosis with reduced expression of fibrogenic genes. Chromatin IP and quantitative reverse-transcription polymerase chain reaction in mouse HSCs overexpressing KLF6(WT) demonstrated KLF6(WT) binding to GC boxes in promoters of Colα1 (I), Colα2 (I), and beta-platelet-derived growth factor receptor (β-Pdgfr) with reduced gene expression, consistent with transcriptional repression by KLF6. Stellate cells overexpressing either KLF6(WT) or KLF6(SV1) were more susceptible to apoptotic stress based on poly (ADP-ribose) polymerase (PARP) cleavage.KLF6 reduces fibrogenic activity of HSCs by way of two distinct mechanisms, direct transcriptional repression of target fibrogenic genes and increased apoptosis of activated HSCs. These results suggest that following its initial induction, sustained down-regulation of KLF6 in liver injury may allow de-repression of fibrogenic genes and decreased stellate cell clearance by inhibiting apoptosis.

  View details for DOI 10.1002/hep.26056

  View details for Web of Science ID 000315643400037

  View details for PubMedID 22961688

• Does it matter what day of the week you have your colonoscopy? Gastrointestinal endoscopy Kwong, A. J., Eaton, E. E., Cohen, L. B., Miller, K. M., Aisenberg, J. A. 2012; 76 (3): 700-702

  View details for DOI 10.1016/j.gie.2012.04.002

  View details for PubMedID 22898429

• Liver Fibrosis in Elderly Cadavers: Localization of Collagen Types I, III, and IV, alpha-Smooth Muscle Actin, and Elastic Fibers ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY Mak, K. M., Chu, E., Lau, K. H., Kwong, A. J. 2012; 295 (7): 1159-1167

  Abstract

  We have shown a high prevalence of liver fibrosis in elderly cadavers with diverse causes of death by Sirius red stain; however, the various collagen types in these samples have yet to be evaluated. To further characterize the histopathology of the fibrotic lesions in the livers of these elderly cadavers, this study used immunohistochemistry and histochemistry to identify the principal collagens produced in liver fibrosis, fibrogenic cells and elastic fibers. Collagen I and III immunoreactions were found to colocalize in collagen fibers of fibrotic central veins, perisinusoidal fibrotic foci, portal tract stroma, and fibrous septa. α-Smooth muscle actin-expressing perisinusoidal hepatic stellate cells (HSCs), as well as perivenular, portal, and septal myofibroblasts, were closely associated with collagen fibers, reflecting their fibrogenic functions. HSCs and myofibroblasts were also noted to express collagen IV, which may contribute to production of basal lamina-like structures. In fibrotic livers, the sinusoidal lining showed variable immunostaining for collagen IV. Collagen IV immunostaining revealed vascular proliferation and atypical ductular reaction at the portal-septal parenchymal borders, as well as capillary-like vessels in the lobular parenchyma. While elastic fibers were absent in the space of Disse, they were found to codistribute with collagens in portal tracts, fibrous septa and central veins. Our combined assessment of collagen types, HSCs, myofibroblasts, and elastic fibers is significant in understanding the histopathology of fibrosis in the aging liver.

  View details for DOI 10.1002/ar.22504

  View details for Web of Science ID 000305238200010

  View details for PubMedID 22644959

• Hepatic Steatosis, Fibrosis, and Cancer in Elderly Cadavers ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY Mak, K. M., Kwong, A. J., Chu, E., Hoo, N. M. 2012; 295 (1): 40-50

  Abstract

  The incidence of hepatic steatosis, fibrosis, and cancer in the elderly population remains unknown. Human cadavers used in anatomy teaching, which come largely from older adults, may provide liver tissue for examining their pathologies. Livers were obtained from 68 cadavers (mean age 82.1 ± 10.4 years) with diverse causes of death in the Anatomy course at Mount Sinai School of Medicine. Paraffin sections were stained with hematoxylin and eosin and Sirius red and evaluated for steatosis, fibrosis, cancer, and lipofuscin. Tissue preservation was graded as good in 38.2% of the embalmed livers, fair in 36.7%, and poor in 25.0%. Steatosis was observed in 35.3% of the livers, central vein fibrosis in 49.2%, perisinusoidal fibrosis in 63.2%, portal tract (PT) fibrosis in 47.0%, septa formation in 44.1%, bridging fibrosis in 30.8%, and cirrhosis in 4.4%. One hepatocellular carcinoma (HCC) and six metastatic tumors were detected. Lobular inflammation occurred in 20.8% of the livers and PT inflammation in 38.8%. Nine livers showed minimal change. Lipofuscin was detected in 60.2% of the livers. Steatosis, fibrosis, and cancer are highly prevalent in elderly cadavers with diverse causes of death. The prevalence of steatosis and fibrosis is consistent with the data in patients with specific liver diseases. Steatosis alongside fibrosis can accelerate the progression of fibrosis to cirrhosis and ultimately HCC. Though not indicated as the primary cause of death, the liver injury may have compromised hepatic functions and enhanced disease susceptibility, thereby exacerbating the health conditions in this elderly population.

  View details for DOI 10.1002/ar.21525

  View details for Web of Science ID 000298090200006

  View details for PubMedID 22139908

• Downregulation of Hepatic Stellate Cell Activation by Retinol and Palmitate Mediated by Adipose Differentiation-Related Protein (ADRP) JOURNAL OF CELLULAR PHYSIOLOGY Lee, T. F., Mak, K. M., Rackovsky, O., Lin, Y., Kwong, A. J., Loke, J. C., Friedman, S. L. 2010; 223 (3): 648-657

  Abstract

  Hepatic stellate cells (HSCs) store retinoids and triacylglycerols in cytoplasmic lipid droplets. Two prominent features of HSC activation in liver fibrosis are loss of lipid droplets along with increase of alpha-smooth muscle actin (alpha-SMA), but the link between these responses and HSC activation remains elusive. In non-adipose cells, adipose differentiation-related protein (ADRP) coats lipid droplets and regulates their formation and lipolysis; however its function in HSCs is unknown. Here, we observed, in human liver sections or primary HSC culture, ADRP localization to lipid droplets of HSCs, and reduced staining coincident with loss of lipid droplets in liver fibrosis and in culture-activated HSCs, consistent with HSC activation. In the LX-2 human immortalized HSCs, with scant lipid droplets and features of activated HSCs, we found that the upregulation of ADRP mRNA by palmitate is potentiated by retinol, accompanied by increased ADRP protein, generation of retinyl palmitate, and lipid droplet formation. ADRP induction also led to decreased expression of alpha-SMA mRNA and its protein, while ADRP knockdown with small interfering RNA (siRNA) normalized alpha-SMA expression. Furthermore, ADRP induction by retinol and palmitate resulted in decreased expression of collagen I and matrix metalloproteinase-2 mRNA, fibrogenic genes associated with activated HSCs, while increasing matrix metalloproteinase-1 mRNA; ADRP knockdown with siRNA reversed these changes. Tissue inhibitor of metalloproteinase-1 was not affected. Thus, ADRP upregulation mediated by retinol and palmitate promotes downregulation of HSC activation and is functionally linked to the expression of fibrogenic genes.

  View details for DOI 10.1002/jcp.22063

  View details for Web of Science ID 000277482900013

  View details for PubMedID 20143336