Post-Transplant Management and Complications of Autoimmune Hepatitis, Primary Biliary Cholangitis, and Primary Sclerosing Cholangitis including Disease Recurrence.

Autoimmune liver diseases have unique post-transplant considerations. These recipients are at increased risk of rejection, and recurrent disease may also develop, which can progress to graft loss and increase mortality. Monitoring for and managing these complications is therefore important, though data on associated risk factors and immunosuppression strategies has in most cases been mixed. There are also other disease-specific complications that require management and may impact these decisions, including inflammatory bowel disease in PSC. Further work to better understand the optimal management strategies for these patients post-transplant is needed.

Health Care Transition for Adolescents and Young Adults With Pediatric-Onset Liver Disease and Transplantation: A Position Paper by the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition.

Advances in medical therapies and liver transplantation have resulted in a greater number of pediatric patients reaching young adulthood. However, there is an increased risk for medical complications and morbidity surrounding transfer from pediatric to adult hepatology and transplant services. Health care transition (HCT) is the process of moving from a child/family-centered model of care to an adult or patient-centered model of health care. Successful HCT requires a partnership between pediatric and adult providers across all disciplines resulting in a transition process that does not end at the time of transfer but continues throughout early adulthood. Joint consensus guidelines in collaboration with the American Society of Transplantation are presented to facilitate the adoption of a structured, multidisciplinary approach to transition planning utilizing The Six Core Elements of Health Care Transition TM for use by both pediatric and adult specialists. This paper provides guidance and seeks support for the implementation of an HCT program which spans across both pediatric and adult hepatology and transplant centers.

Itching to find a diagnosis.

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More Than Meets the Eye?

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Need for Pretransplant Midodrine Does Not Negatively Impact Simultaneous Liver-kidney Transplant Outcomes.

BACKGROUND: Midodrine is often needed pretransplant to improve hemodynamics in simultaneous liver-kidney transplant candidates. Previous research has shown that patients requiring midodrine before kidney transplant alone have increased posttransplant risk for delayed allograft function, graft failure, and death. However, the impact of pretransplant midodrine use on outcomes after simultaneous liver-kidney transplant is unknown. METHODS: We performed a retrospective study of all adult (age ≥18 y) simultaneous liver-kidney transplant recipients from a single academic transplant center from February 1, 2002, to June 30, 2019. RESULTS: Sixty-four simultaneous liver-kidney transplants were performed in our institution during this time period, of which, 43 were not on midodrine before transplant, 17 were on midodrine alone, and 4 were on intravenous (IV) vasopressor therapy. Despite the midodrine group having a higher MELD-Na at listing, higher MELD-Na at transplant, and being older, there were no significant differences in key outcomes including delayed renal allograft function, estimated glomerular filtration rate at transplant discharge, and estimated glomerular filtration rate at 1 y after transplant compared with the nonmidodrine group. There was no significant difference in graft failure or survival at last follow-up. CONCLUSIONS: Our study suggests that need for pretransplant midodrine should not be a barrier to simultaneous liver-kidney transplant.

LI-RADS Treatment Response Algorithm: Performance and Diagnostic Accuracy.

Background In 2017, the Liver Imaging Reporting and Data System (LI-RADS) included an algorithm for the assessment of hepatocellular carcinoma (HCC) treated with local-regional therapy. The aim of the algorithm was to enable standardized evaluation of treatment response to guide subsequent therapy. However, the performance of the algorithm has not yet been validated in the literature. Purpose To evaluate the performance of the LI-RADS 2017 Treatment Response algorithm for assessing the histopathologic viability of HCC treated with bland arterial embolization. Materials and Methods This retrospective study included patients who underwent bland arterial embolization for HCC between 2006 and 2016 and subsequent liver transplantation. Three radiologists independently assessed all treated lesions by using the CT/MRI LI-RADS 2017 Treatment Response algorithm. Radiology and posttransplant histopathology reports were then compared. Lesions were categorized on the basis of explant pathologic findings as either completely (100%) or incompletely (<100%) necrotic, and performance characteristics and predictive values for the LI-RADS Treatment Response (LR-TR) Viable and Nonviable categories were calculated for each reader. Interreader association was calculated by using the Fleiss κ. Results A total of 45 adults (mean age, 57.1 years ± 8.2; 13 women) with 63 total lesions were included. For predicting incomplete histopathologic tumor necrosis, the accuracy of the LR-TR Viable category for the three readers was 60%-65%, and the positive predictive value was 86%-96%. For predicting complete histopathologic tumor necrosis, the accuracy of the LR-TR Nonviable category was 67%-71%, and the negative predictive value was 81%-87%. By consensus, 17 (27%) of 63 lesions were categorized as LR-TR Equivocal, and 12 of these lesions were incompletely necrotic. Interreader association for the LR-TR category was moderate (κ = 0.55; 95% confidence interval: 0.47, 0.67). Conclusion The Liver Imaging Reporting and Data System 2017 Treatment Response algorithm had high predictive value and moderate interreader association for the histopathologic viability of hepatocellular carcinoma treated with bland arterial embolization when lesions were assessed as Viable or Nonviable. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Gervais in this issue.

Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: Results from two prospective cohort studies.

Type 2 diabetes (T2D) is a risk factor for hepatocellular carcinoma (HCC). However, it is unknown whether T2D duration or additional metabolic comorbidities further contribute to HCC risk. From the Nurses' Health Study (NHS), 120,826 women were enrolled in 1980, and from the Health Professionals Follow-up Study (HPFS), 50,284 men were enrolled in 1986 and followed through 2012. Physician-diagnosed T2D was ascertained at baseline and updated biennially. Cox proportional hazards regression models were used to calculate age- and multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident HCC. Over 32 years of follow-up (4,488,410 person-years), we documented 112 cases of HCC (69 women, 43 men). T2D was associated with an increased HCC risk (multivariable HR, 4.59; 95% CI, 2.98-7.07), as was an increasing T2D duration (Ptrend < 0.001). Compared to nondiabetics, the multivariable HRs for HCC were 2.96 (95% CI, 1.57-5.60) for 0-<2 years; 6.08 (95% CI, 2.96-12.50) for 2-<10 years; and 7.52 (95% CI, 3.88-14.58) for ≥10 years. Increasing number of metabolic comorbidities (T2D, obesity, hypertension, and dyslipidemia) was associated with increased HCC risk (Ptrend < 0.001); compared to individuals without metabolic comorbidity, those with four metabolic comorbidities had an 8.1-fold increased HCC risk (95% CI, 2.48-26.7). In T2D, neither insulin use nor oral hypoglycemic use was significantly associated with HCC risk (HR, 2.04 [95% CI, 0.69-6.09] and HR, 1.45 [95% CI, 0.69-3.07], respectively). CONCLUSION: T2D is independently associated with increased risk for HCC in two prospective cohorts of U.S. men and women. This risk is enhanced with prolonged diabetes duration and with comorbid metabolic conditions, suggesting the importance of insulin resistance in the pathogenesis of HCC. (Hepatology 2018;67:1797-1806).

Cost-Effectiveness of Risk Score-Stratified Hepatocellular Carcinoma Screening in Patients with Cirrhosis.

OBJECTIVES: Hepatocellular carcinoma (HCC) surveillance with biannual ultrasound is currently recommended for all patients with cirrhosis. However, clinical implementation of this "one-size-fits-all" approach is challenging as evidenced by its low application rate. We aimed to evaluate the cost-effectiveness of risk-stratified HCC surveillance strategies in patients with cirrhosis. METHODS: A Markov decision-analytic modeling was performed to simulate a cohort of 50-year-old subjects with compensated cirrhosis. Risk-stratified HCC surveillance strategies was implemented, in which patients were stratified into high-, intermediate-, or low-risk groups by HCC risk biomarker-based scores and assigned to surveillance modalities tailored to HCC risk (2 non-risk-stratified and 14 risk-stratified strategies) and compared with non-stratified biannual ultrasound. RESULTS: Quality-adjusted life expectancy gains for biannual ultrasound in all patients and risk-stratified strategies compared with no surveillance were 1.3 and 0.9-2.1 years, respectively. Compared with the current standard of biannual ultrasound in all cirrhosis patients, risk-stratified strategies applying magnetic resonance imaging (MRI) and/or ultrasound only in high- and intermediate-risk patients, without screening in low-risk patients, were cost-effective. Abbreviated MRI (AMRI) for high- and intermediate-risk patients had the lowest incremental cost-effectiveness ratio (ICER) of $2,100 per quality-adjusted life year gained. AMRI in intermediate- and high-risk patients had ICERs <$3,000 across a wide range of HCC incidences. CONCLUSIONS: Risk-stratified HCC surveillance strategies targeting high- and intermediate-risk patients with cirrhosis are cost-effective and outperform the currently recommended non-stratified biannual ultrasound in all patients with cirrhosis.

Differences in Phenotypes and Liver Transplantation Outcomes by Age Group in Patients with Primary Sclerosing Cholangitis.

BACKGROUND: There is increasing evidence for a heterogeneity of phenotypes in primary sclerosing cholangitis (PSC), but differences across the age spectrum in adults with PSC have not been well characterized. AIMS: To characterize phenotypic variations and liver transplantation outcomes by age group in adults with PSC. METHODS: The United Network for Organ Sharing database was used to identify waitlist registrations for primary liver transplantation in adults with PSC. Patients were split into three age groups: 18-39 (young), 40-59 (middle-aged), and ≥60 (older). Their clinical characteristics and outcomes on the waitlist and post-transplant were compared. RESULTS: Overall, 8272 adults with PSC were listed for liver transplantation during the study period, of which 28.9% were young, 52.0% were middle-aged, and 19.1% were older. The young age group had the greatest male predominance (70.0 vs. 66.2 vs. 65.1%, p = 0.001), the highest proportion of black individuals (20.0 vs. 11.0 vs. 5.5%, p < 0.001), and the most patients listed with concomitant autoimmune hepatitis (2.2 vs. 1.0 vs. 0.8%, p < 0.001). Older patients experienced the greatest waitlist and post-transplant mortality. Graft survival was greatest in the middle-aged group. Young patients were most likely to experience acute rejection (31 vs. 22.8 vs. 18.0%, p < 0.001) and have graft failure due to chronic rejection or PSC recurrence (47.8 vs. 42.3 vs. 17.9%, p < 0.001). CONCLUSIONS: Age-related differences exist among adults with PSC and are associated with outcomes pre- and post-transplant. Young patients may have a more robust immune-related phenotype that is associated with poorer graft survival. Future studies are needed to further investigate these findings.

Outcomes of liver retransplantation in patients with primary sclerosing cholangitis.

Liver retransplantation in patients with primary sclerosing cholangitis (PSC) has not been well studied. The aims of this study were to characterize patients with PSC listed for and undergoing retransplantation and to describe the outcomes in these patients. The United Network for Organ Sharing/Organ Procurement and Transplantation Network database was used to identify all primary liver transplantations and subsequent relistings and first retransplantations in adults with PSC between 1987 and 2015. A total of 5080 adults underwent primary transplantation for PSC during this period, and of the 1803 who experienced graft failure (GF), 762 were relisted, and 636 underwent retransplantation. Younger patients and patients with GF due to vascular thrombosis or biliary complications were more likely to be relisted, whereas those with Medicaid insurance or GF due to infection were less likely. Both 5-year graft and patient survival after retransplantation were inferior to primary transplantation (P < 0.001). Five-year survival after retransplantation for disease recurrence (REC), however, was similar to primary transplantation (graft survival, P = 0.45; patient survival, P = 0.09) and superior to other indications for retransplantation (graft and patient survival, P < 0.001). On multivariate analysis, mechanical ventilation, creatinine, bilirubin, albumin, advanced donor age, and a living donor were associated with poorer outcomes after retransplantation. In conclusion, although survival after liver retransplantation in patients with PSC was overall inferior to primary transplantation, outcomes after retransplantation for PSC REC were similar to primary transplantation at 5 years. Retransplantation may therefore represent a treatment option with the potential for excellent outcomes in patients with REC of PSC in the appropriate clinical circumstances. Liver Transplantation 23 769-780 2017 AASLD.

Impact of EGF, IL28B, and PNPLA3 polymorphisms on the outcome of allograft hepatitis C: a multicenter study.

Hepatitis C virus (HCV) infection is accelerated following liver transplantation (LT). Single nucleotide polymorphisms (SNPs) near the epidermal growth factor (EGF) (rs4444903), IL28B (rs12979860), and PNPLA3 (rs738409) loci are associated with treatment response, fibrosis, and hepatocellular carcinoma in non-transplant hepatitis C, but allograft population data are limited. We sought to determine the role of these SNPs in 264 patients with HCV who underwent LT between 1990 and 2008. Genotypes were determined from donor wedge/allograft biopsies and recipient explants. Cox proportional hazards model was used to assess time to cirrhosis, liver-related death, and retransplantation, adjusting for donor age and sustained virological response (SVR). Over a median follow-up of 6.3 yr, a trend toward increased progression to graft cirrhosis was observed among recipients of an EGF non-AA vs. AA donor liver (adjusted HR 2.01; 95% CI 0.93-4.34; p = 0.08). No other genotypes predicted cirrhosis development or graft survival. The CC IL28B variant in both recipients and donors was associated with increased rate of SVR (R-CC/D-CC 8/12[67%], R-non-CC/D-CC or R-CC/D-non-CC 23/52[44%], R-non-CC/D-non-CC 12/45[27%], p linear trend = 0.009). Recipient EGF, IL28B, and PNPLA3, and donor IL28B and PNPLA3 genotypes do not predict adverse outcomes in HCV LT recipients. A potential association exists between donor EGF genotype and cirrhosis.

Diagnostic and Therapeutic Yield of Endoscopy in Patients with Elevated INR and Gastrointestinal Bleeding.

BACKGROUND: Gastrointestinal bleeding is a well-known risk of systemic anticoagulation. However, bleeding in the setting of supratherapeutic anticoagulation may have a milder natural history than unprovoked bleeding. It is a common clinical gestalt that endoscopy is common, but bleeding source identification or intervention is uncommon, yet few data exist to inform this clinical impression. Consequently, we sought to examine our institutional experience with gastrointestinal bleeding in the setting of supratherapeutic international normalized ratio (INR) with the aim of identifying predictors of endoscopically identifiable lesions, interventions, and outcomes. METHODS: A retrospective review was conducted at a tertiary referral academic medical center to identify patients presenting with gastrointestinal bleeding in the setting of warfarin and a supratherapeutic INR (>3.5) who underwent an endoscopic procedure. Relevant clinical covariates, endoscopic findings, need for intervention, and outcomes were collected by review of the medical record. Logistic regression adjusting for potential confounders identified predictors of endoscopically significant lesions as well as intervention and outcomes. RESULTS: A total of 134 patients with INR 3.5 or greater (mean 5.5, range 3.5-17.1) presented with symptoms of gastrointestinal bleeding, most commonly as melena or symptomatic anemia. Antiplatelet agents were used by 54% of patients, and 60% of patients were on concomitant acid suppression on admission. Procedures included esophagogastroduodenoscopy (upper endoscopy; EGD) (n = 128), colonoscopy (n = 73), and video capsule endoscopy (n = 32). Active bleeding at first EGD or colonoscopy was found in only 19 patients (18%), with endoscopic intervention in only 26 patients (25%). At a critical threshold of INR 7.5 at presentation, the likelihood of finding an endoscopically significant lesion fell to <20%. On multivariate logistic regression, concomitant antiplatelet therapy (odds ratio [OR] 2.59; 95% confidence interval [CI], 1.13-5.94), timing of EGD within 12 hours of presentation (OR 3.71; 95% CI, 1.05-13.08), and INR level (OR 0.79; 95% CI, 0.64-0.98) were the only significant independent predictors of identifying a source of bleeding. A risk score incorporating these covariates performed modestly in identifying risk of significant finding on EGD (area under the curve 0.68). We found no association between identification of a significant lesion at EGD and future readmission for gastrointestinal bleeding. CONCLUSION: This study demonstrates that the relationship between INR elevation and identification of a bleeding source or endoscopic intervention at EGD are indeed antiparallel. Concomitant antiplatelet therapy increases the likelihood of bleeding source identification and intervention, as does EGD within 12 hours of presentation. However, regardless of source identification or endoscopic intervention, important clinical outcomes were unchanged, suggesting that decisions about endoscopy should be made on a case-by-case basis, particularly in patients with INR > 7.5. Future prospective studies on appropriate indications and timing of endoscopy in such patients are warranted.

Circulating Soluble CD163 is Associated with Steatohepatitis and Advanced Fibrosis in Nonalcoholic Fatty Liver Disease.

OBJECTIVES: Soluble CD163 (sCD163), a marker of Kupffer cell activation detectable in serum, correlates with inflammation and fibrosis in chronic viral hepatitis, but its role in nonalcoholic fatty liver disease is unknown. We hypothesized that sCD163 would correlate with nonalcoholic fatty liver disease activity and fibrosis. METHODS: Liver biopsies and serum were obtained from 145 obese subjects undergoing gastric bypass surgery. Subjects were divided into four groups based on fibrosis stage and nonalcoholic fatty liver disease activity score (NAS); Group 1: F0, NAS=0; Group 2: F<2, 0

NSAID Use and Risk of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma: The Liver Cancer Pooling Project.

Chronic inflammation plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common types of liver cancer. A number of prior experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen, may potentially protect against liver cancer. However, no observational study has examined the association between aspirin duration and dose or other over-the-counter non-aspirin NSAIDs, such as ibuprofen, and liver cancer incidence. Furthermore, the association between NSAID use and risk of ICC is unclear. As part of the Liver Cancer Pooling Project, we harmonized data on 1,084,133 individuals (HCC = 679, ICC = 225) from 10 U.S.-based prospective cohort studies. Cox proportional hazards regression models were used to evaluate multivariable-adjusted HRs and 95% confidence intervals (CI). Current aspirin use, versus nonuse, was inversely associated with HCC (HR, 0.68; 95% CI, 0.57-0.81), which persisted when restricted to individuals not using non-aspirin NSAIDs and in a 5- and 10-year lag analysis. The association between aspirin use and HCC risk was stronger for users who reported daily use, longer duration use, and lower dosage. Ibuprofen use was not associated with HCC risk. Aspirin use was associated with a reduced ICC risk in men (HR, 0.64; 95% CI, 0.42-0.98) but not women (HR, 1.34; 95% CI, 0.89-2.01; P(interaction) = 0.01). The observed inverse association between aspirin use and liver cancer in our study, together with previous data, suggests the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC.

Coffee Consumption and Risk of Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma by Sex: The Liver Cancer Pooling Project.

BACKGROUND: Coffee consumption has been reported to be inversely associated with hepatocellular carcinoma (HCC), the most common type of liver cancer. Caffeine has chemopreventive properties, but whether caffeine is responsible for the coffee-HCC association is not well studied. In addition, few studies have examined the relationship by sex, and no studies have examined whether there is an association between coffee and intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. METHODS: In the Liver Cancer Pooling Project, a consortium of U.S.-based cohort studies, data from 1,212,893 individuals (HCC, n = 860; ICC, n = 260) in nine cohorts were pooled. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using proportional hazards regression. RESULTS: Higher coffee consumption was associated with lower risk of HCC (HR>3 cups/day vs. non-drinker, 0.73; 95% CI, 0.53-0.99; Ptrend cups/day = <0.0001). More notable reduced risk was seen among women than men (Pinteraction = 0.07). Women who consumed more than three cups of coffee per day were at a 54% lower risk of HCC (HR, 0.46; 95% CI, 0.26-0.81), whereas men had more modest reduced risk of HCC (HR, 0.93; 95% CI, 0.63-1.37). The associations were stronger for caffeinated coffee (HR>3 cups/day vs. non-drinker, 0.71; 95% CI, 0.50-1.01) than decaffeinated coffee (HR, 0.92; 95% CI, 0.55-1.54). There was no association between coffee consumption and ICC. CONCLUSIONS: These findings suggest that, in a U.S. population, coffee consumption is associated with reduced risk of HCC. IMPACT: Further research into specific coffee compounds and mechanisms that may account for these associations is needed.