Allison Kwong

All Publications

• BEYOND THE BIRTH COHORT: STRATEGIES FOR HEPATITIS C SCREENING FOR AMERICANS BORN AFTER 1965 Sripongpun, P., Udompap, P., Mannalithara, A., Kwong, A. J., Kim, W. WILEY. 2019: 348A–349A

  View details for Web of Science ID 000488653501120

• OUTCOMES OF LIVER TRANSPLANTATION AMONG OLDER RECIPIENTS WITH NASH IN A LARGE MULTICENTER US COHORT (REALT) Kwong, A. J., Devuni, D., Wang, C., Boike, J., Jo, J., VanWagner, L. B., Serper, M., Jones, L., Sharma, R., Verna, E. C., Shor, J., German, M. N., Hristov, A., Lee, A., Spengler, E. K., Koteish, A. A., Sehmbey, G., Seetharam, A. B., John, N., Patel, Y., Kappus, M. R., Couri, T., Paul, S., Salgia, R. J., Nhu, Q., Frenette, C. T., Lai, J., Goel, A., REALT Re-Evaluating Age Limits WILEY. 2019: 684A–685A

  View details for Web of Science ID 000488653502282

• ACCEPTABLE LIVER TRANSPLANTATION OUTCOMES AMONG OLDER RECIPIENTS WITH HCC DESPITE HIGHER-RISK FEATURES ON EXPLANT IN A LARGE MULTICENTER US COHORT (REALT) Kwong, A. J., Devuni, D., Wang, C., Boike, J., Jo, J., VanWagner, L. B., Serper, M., Jones, L., Sharma, R., Verna, E. C., Shor, J., German, M. N., Hristov, A., Lee, A., Spengler, E. K., Koteish, A. A., Sehmbey, G., Seetharam, A. B., John, N., Patel, Y., Kappus, M. R., Couri, T., Paul, S., Salgia, R. J., Nhu, Q., Frenette, C. T., Lai, J., Goel, A., REALT Re-Evaluating Age Limits WILEY. 2019: 147A

  View details for Web of Science ID 000488653500225

• MORTALITY RISK OF PATIENTS WITH HEPATIC DECOMPENSATION FROM PRIMARY BILIARY CHOLANGITIS IN THE OBETICHOLIC ACID ERA Mannalithara, A., Kim, W., Sripongpun, P., Kwong, A. J., Goel, A. WILEY. 2019: 783A

  View details for Web of Science ID 000488653502437

• 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., Heimbach, J., 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., Soetikno, R., Chang, M. S., Kwong, A. J., Limketkai, B. N., Bhattacharya, J., Kaltenbach, T. 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

• DIRECT-ACTING ORAL ANTICOAGULANT (DOAC) USE IS NOT ASSOCIATED WITH INCREASED RISK OF COMPLICATIONS AFTER POLYPECTOMY Yu, J. X., Oliver, M., Lin, J., Chang, M. S., Kwong, A. J., Limketkai, B., Soetikno, R. M., Bhattacharya, J., Kaltenbach, T. R. MOSBY-ELSEVIER. 2018: AB392

  View details for Web of Science ID 000435509900105

• Hospital Cirrhosis Volume and Readmission in Patients with Cirrhosis in California. Digestive diseases and sciences Wei, M., Ford, J., Li, Q., Jeong, D., 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

• 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

• 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

• 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., Ukomadu, C., 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

• Donor Age and Allograft Survival in Recipients with Hepatitis C Virus in the Direct-Acting Antiviral Era Kwong, A. J., Kim, N. G., Stoltz, D., Mannalithara, A., Kim, W. WILEY. 2017: 886A–887A

  View details for Web of Science ID 000412089802019

• Reduced Incidence of Kidney Waitlisting After Liver Transplantation in the Post-Share 35 Era Kwong, A. J., Mannalithara, A., Asrani, S. K., Biggins, S. W., Heimbach, J., Brandman, D., Abt, P. L., Kim, W. WILEY. 2017: 15A

  View details for Web of Science ID 000412089800027

• Trajectory of Serum Creatinine in Liver Transplant Candidates Identifies Patients at High Risk of Mortality Kwong, A. J., Mannalithara, A., Biggins, S. W., Asrani, S. K., Brandman, D., Abt, P. L., Heimbach, J., Kim, W. WILEY. 2017: 947A

  View details for Web of Science ID 000412089802136

• 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

• 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 PubMedID 29125676

• 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