A Meta-Analysis of Cumulative Incidence of Hepatocellular Carcinoma After the Fontan Operation.

BACKGROUND: Hepatic complications are increasingly recognized after the Fontan operation. The development of hepatocellular carcinoma (HCC) is associated with high mortality when diagnosed, but its incidence and risk factors are poorly understood. We conducted a systematic review and meta-analysis of the cumulative incidence of HCC after Fontan and associated risk factors. METHODS: We searched PubMed, CINAHL, and MEDLINE databases for articles reporting the cumulative incidence of HCC after Fontan operation on March 21, 2023. A single-arm random effects meta-analysis was conducted to assess cumulative incidence at 10, 20, and 30 years after Fontan. Meta-analysis of the difference of the medians was used to assess the influence of risk factors on the development of HCC. RESULTS: Four studies including a total of 1320 patients reported cumulative incidence. The cumulative incidence of HCC at 10, 20, and 30 years after Fontan was 0% (95% CI 0.00-0.01), 2% (0.01-0.06), and 7% (0.03-0.17) respectively. Seven studies including 6,250 patients reported overall incidence of HCC and associated risk factors. At a median 18.4 (IQR 11.9-24.9) years of follow-up, incidence of HCC was 2% (0.01-0.04). Only use of anticoagulation was associated with a lower risk of HCC (RR 0.3, 95% CI 0.1-0.88). DISCUSSION: By 30 years after Fontan, cumulative incidence of HCC is high (7%). Risk of HCC development prior to 10 years post-Fontan is low (0%), though the decision to defer HCC surveillance in this period may require future investigation based on larger studies. Screening with ultrasound every 6 months starting 20 years post-Fontan is reasonable, however, further research regarding timing, cost-effectiveness, additional risk factors associated with HCC risk, and different screening modalities is required.

Split liver transplantation is utilized infrequently and concentrated at few transplant centers in the United States.

Split liver transplantation (SLT) is 1 strategy for maximizing the number of deceased donor liver transplants. Recent reports suggest that utilization of SLT in the United States remains low. We examined deceased donor offers that were ultimately split between 2010 and 2014. SLTs were categorized as "primary" and "secondary" transplants. We analyzed allocation patterns and used logistic regression to evaluate factors associated with secondary split discard. Four hundred eighteen livers were split: 54% from adult, 46% from pediatric donors. Of the 227 adult donor livers split, 61% met United Network for Organ Sharing "optimal" split criteria. A total of 770 recipients (418 primary and 352 secondary) were transplanted, indicating 16% discard. Ninety-two percent of the 418 primary recipients were children, and 47% were accepted on the first offer. Eighty-seven percent of the 352 secondary recipients were adults, and 7% were accepted on the first offer. Of the 352 pairs, 99% were transplanted in the same region, 36% at the same center. In logistic regression, shorter donor height was associated with secondary discard (odds ratio 0.97 per cm, 95% CI 0.94-1.00, P = .02). SLT volume by center was not predictive of secondary discard. Current policy proposals that incentivize SLT in the United States could increase the number of transplants to children and adults.

Receipt of a pediatric liver offer as the first offer reduces waitlist mortality for adult women.

In liver transplantation, adults with small stature have a greater susceptibility to waitlist mortality. This may explain the persistent waitlist mortality disparity that exists for women. We hypothesized that women who receive early offers of pediatric donor livers have improved waitlist survival, and that preferentially offering these organs to women mitigates this sex-based disparity. We analyzed donor liver offers from 2010 to 2014. Adult candidates who received a first offer that ranked within the first three match run positions from the donors' perspective were classified based on gender and whether they received a pediatric versus adult offer. We used competing risks regression to associate first offer type and waitlist mortality. A total of 8,101 waitlist candidates received a first offer that was ranked within the first three match run positions: 5.6% (293/5,202) men and 6.2% (179/2,899) women received a pediatric donor liver as their first offer. In multivariable analyses, compared with adult-first men, adult-first women (subhazard ratio [sHR] 1.33, 95% confidence interval 1.17-1.51, P < 0.01) had an increased pretransplant mortality risk while pediatric-first men and pediatric-first women had noninferior risks of morality. Pediatric-to-adult and adult-to-adult recipients had similar risks of graft failure and posttransplant mortality. CONCLUSION: Our study examines allograft selection by donor age, recipient sex, and in effect size as a means to address disparities in waitlist mortality. We found that women who received a pediatric donor liver as the first offer had a lower risk of waitlist mortality compared with those who receive adult offers. Our data provides a simple approach to mitigating the increased waitlist mortality experienced by women by incorporating donor and recipient size as variables into organ allocation. (Hepatology 2018).

Share 35 changes in center-level liver acceptance practices.

Share 35 was implemented to provide improved access to organs for patients with Model for End-Stage Liver Disease (MELD) scores ≥ 35. However, little is known about the impact of Share 35 on organ offer acceptance rates. We evaluated all liver offers to adult patients who were ultimately transplanted between January 1, 2011 and December 31, 2015. The analyses focused on patients ranked in the top 5 positions of a given match run and used multilevel mixed-effects models, clustering on individual wait-list candidate and transplant center. There was a significant interaction between Share 35 era and MELD category (P < 0.001). Comparing offers to MELD score ≥ 35 patients, offers after Share 35 were 36% less likely to be accepted compared with offers to MELD score ≥ 35 patients before Share 35 (adjusted odds ratio, 0.64). There was no clinically meaningful difference in the donor risk index of livers that were declined for patients with an allocation MELD score ≥35 in the pre- versus post-Share 35 era. Organ offer acceptance rates for patients with an allocation MELD ≥ 35 decreased in every region after Share 35; the magnitude of these changes was bigger in regions 2, 3, 4, 5, 6, 7, and 11, compared with regions 8 and 9 that had regional sharing in place before Share 35. There were significant changes in organ offer acceptance rates at the center level before versus after Share 35, and these changes varied across centers (P < 0.001). In conclusion, in liver transplantation candidates achieving a MELD score ≥ 35, liver acceptance of offers declined significantly after implementation of Share 35. The alterations in behavior at the center level suggest that practice patterns changed as a direct result of Share 35. Changes in organ acceptance under even broader organ sharing (redistricting) would likely be even greater, posing major logistical and operational challenges, while potentially increasing discard rates, thus decreasing the total number of transplants nationally. Liver Transplantation 23 604-613 2017 AASLD.

Liver transplant center variability in accepting organ offers and its impact on patient survival.

BACKGROUND & AIMS: Despite an allocation system designed to give deceased-donor livers to the sickest patients, many transplantable livers are declined by U.S. transplant centers. It is unknown whether centers vary in their propensities to decline organs for the highest priority patients, and how these decisions directly impact patient outcomes. METHODS: We analyzed Organ Procurement and Transplantation Network (OPTN) data from 5/1/07-6/17/13, and included all adult liver-alone waitlist candidates offered an organ that was ultimately transplanted. We evaluated acceptance rates of liver offers for the highest ranked patients and their subsequent waitlist mortality. RESULTS: Of the 23,740 unique organ offers, 8882 (37.4%) were accepted for the first-ranked patient. Despite adjusting for organ quality and recipient severity of illness, transplant centers within and across geographic regions varied strikingly (p<0.001) in the percentage of organ offers they accepted for the highest priority patients. Among all patients ranked first on waitlists, the adjusted center-specific organ acceptance rates ranged from 15.7% to 58.1%. In multivariable models, there was a 27% increased odds of waitlist mortality for every 5% absolute decrease in a center's adjusted organ offer acceptance rate (adjusted OR: 1.27, 95% CI: 1.20-1.32). However, the absolute difference in median 5-year adjusted graft survival was 4% between livers accepted for the first-ranked patient, compared to those declined and transplanted at a lower position. CONCLUSION: There is marked variability in center practices regarding accepting livers allocated to the highest priority patients. Center-level decisions to decline organs substantially increased patients' odds of dying on the waitlist without a transplant.

Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection after liver transplantation.

BACKGROUND & AIMS: Interferon alfa-based regimens used to treat recurrent hepatitis C virus (HCV) infection after liver transplantation are poorly tolerated, associated with generally modest efficacy, and can interact with immunosuppressive agents. We evaluated the efficacy and safety of an interferon-free regimen of the nucleotide polymerase inhibitor sofosbuvir combined with ribavirin for 24 weeks in treating post-transplantation HCV infection. METHODS: In a prospective, multicenter, open-label pilot study, we enrolled patients with compensated recurrent HCV infection of any genotype after a primary or secondary liver transplantation. All patients received 24 weeks of sofosbuvir 400 mg daily and ribavirin starting at 400 mg daily, which was adjusted according to creatinine clearance and hemoglobin values. The primary end point was sustained virologic response 12 weeks after treatment. RESULTS: Of the 40 patients enrolled and treated, 78% were male, 85% were white, 83% had HCV genotype 1, 40% had cirrhosis (based on biopsy), and 88% had been previously treated with interferon. Sustained virologic response 12 weeks after treatment was achieved by 28 of 40 patients (70%; 90% confidence interval: 56%-82%). Relapse accounted for all cases of virologic failure. No patients had detectable viral resistance during or after treatment. The most common adverse events were fatigue (30%), diarrhea (28%), and headache (25%). In addition, 20% of the subjects experienced anemia. Two patients discontinued study treatment because of adverse events, which were considered unrelated to study treatment. No deaths, graft losses, or episodes of rejection occurred. No interactions with any concomitant immunosuppressive agents were reported. CONCLUSIONS: Sofosbuvir and ribavirin combination therapy for 24 weeks is an effective and well-tolerated interferon-free treatment for post-transplantation HCV infection. EudraCT, Number: 2012-002417-19; ClinicalTrials.gov, Number: NCT01687270.

Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease.

BACKGROUND & AIMS: There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. METHODS: In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS: We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%-89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%-98% of patients without cirrhosis or with compensated cirrhosis, by 85%-88% of patients with moderate hepatic impairment, by 60%-75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. CONCLUSION: The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.

Donor PNPLA3 rs738409 genotype affects fibrosis progression in liver transplantation for hepatitis C.

UNLABELLED: The rs738409 G>C single nucleotide polymorphism occurring in the patatin-like phospholipase 3 gene has been identified as a novel genetic marker for hepatic steatosis. Recent studies also associated rs738409 with fibrosis in hepatitis C (HCV). Therefore, we sought to determine the impact of donor and recipient rs738409 genotype on the progression of fibrosis after liver transplantation for HCV. This cohort study included 101 patients infected with HCV who underwent liver transplantation between January 2008, and June 2011. Donor and recipient rs738409 genotypes were determined from donor wedge biopsies and recipient explants. The time to Ishak stage 3 fibrosis, or HCV-related mortality/graft loss was analyzed by the Cox model adjusting for HCV-Donor Risk Index, warm ischemic time, pretransplant Model for Endstage Liver Disease (MELD) and viral load. The rs738409 CC variant was present in 56% of donors and 57% of recipients. The median follow-up period was 620 days. A total of 39 patients developed the primary outcome of ≥stage 3 fibrosis or HCV-related mortality/graft loss, the time to which differed by donor (P = 0.019) but not recipient (P = 0.89) genotype. In the multivariate model, donor GC or GG variants had 2.53 times the risk (95% confidence interval [CI] 1.25-5.02, P = 0.008) compared to CC variants. In the alternative endpoint: stage 3 fibrosis or all-cause mortality/graft loss, the effect of donor genotype was attenuated but remained significant at 1.98 (95% CI 1.11-3.53). CONCLUSIONS: The rs738409 genotype is an important predictor of posttransplant outcome in HCV. Liver, and not adipocytes, is the site at which this effect occurs. Our finding may be useful in donor selection for liver transplantation with HCV, and may guide decisions regarding early antiviral treatment.

Emergency Department Visits Related to Inflammatory Bowel Disease: Results From Nationwide Emergency Department Sample.

We analyzed a national US database to study the presentation of children with inflammatory bowel disease (IBD) to the emergency department (ED). Our results indicate that from 2006 to 2010, there was a significant increase in the number of ED visits related to children with IBD accompanied by a contemporaneous decline in the rate of hospitalization that followed these ED visits. Earlier published results have highlighted an increased overall rate of hospitalizations in the United States related to children with IBD. In this context, our results support the evidence for an increased prevalence of pediatric IBD in the United States in recent years.

The utility of lower endoscopic ultrasound-guided fine needle aspiration for the diagnosis of benign and malignant pelvic diseases.

BACKGROUND: The utility of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for the diagnosis of pelvic masses has been suggested but limited data are available in the literature regarding its diagnostic accuracy. GOALS: To report our institutional experience with EUS-FNA for the diagnosis of a variety of pelvic diseases. METHODS: Patients who were referred for the evaluation of pelvic lesions using lower EUS-FNA were included in this retrospective analysis if they had available surgical pathology (obtained after EUS) which was considered the gold standard against which the EUS-FNA findings would have been compared. The diagnostic accuracy of EUS-FNA for pelvic masses was analyzed and any early or late complications after the procedure were reported. A pelvic mass was defined in the study as any mass seen with an imaging modality in the pelvic area including those involving the colonic wall. RESULTS: Twenty patients had EUS-FNA followed by surgery for whom FNA cytology and surgical pathology findings were available. EUS-FNA reached the correct diagnosis in 19 out of 20 patients, whereas for the missing 1 malignant lymph node wherein FNA revealed benign cytology, surgical specimen confirmed metastatic colon cancer. The sensitivity and specificity of EUS-FNA were 90% and 100%, respectively, with positive and negative predictive values of 100% and 90%, respectively. No early or late complications were encountered with this procedure for the sampling of cystic and noncystic masses. CONCLUSIONS: EUS-FNA has excellent diagnostic accuracy for pelvic masses. It represents a safe procedure with excellent yield and thus may be used as a first line modality for the evaluation and diagnosis of pelvic masses within its reach.

Safety and efficacy of teduglutide after 52 weeks of treatment in patients with short bowel intestinal failure.

BACKGROUND & AIMS: Although home parenteral nutrition (PN) can save the lives of patients with massive bowel loss that results in short-bowel syndrome and intestinal failure, quality of life is impaired by PN and its complications. We examined the 12-month tolerability and efficacy of teduglutide to reduce PN dependency. METHODS: Patients who received teduglutide (0.05 or 0.10 mg/kg/d) for 24 weeks in a randomized controlled trial were eligible for a 28-week double-blind extension study; 52 patients were given 52 weeks of the same doses of teduglutide. We investigated the safety, tolerability, and clinical efficacy (defined as a clinically meaningful ≥20% reduction in weekly PN volume from baseline) at week 52. RESULTS: The most common adverse events reported included headache (35%), nausea (31%), and abdominal pain (25%); 7 patients withdrew because of adverse events (gastrointestinal disorders in 4). Both groups had progressive reduction in PN. At week 52, 68% of the 0.05-mg/kg/d and 52% of the 0.10-mg/kg/d dose group had a ≥20% reduction in PN, with a reduction of 1 or more days of PN dependency in 68% and 37%, respectively. Four patients achieved complete independence from PN. CONCLUSIONS: For patients with short-bowel syndrome intestinal failure, the efficacy of teduglutide was maintained over 52 weeks and the safety profile was sufficient for it to be considered for long-term use. Further studies are needed to determine whether these effects will translate into improved quality of life and reduced PN complications. ClinicalTrials.gov number, NCT00172185.

IL28B genotype and the expression of ISGs in normal liver.

BACKGROUND & AIMS: Both polymorphisms in the IL28B gene locus and ISG expression levels are associated with the outcome of hepatitis C virus (HCV) infection. The two are also interrelated, although the mechanism is unknown. Favourable CC genotype at rs12979860 expresses lower baseline ISG levels and responds better to treatment than unfavourable CT and TT genotypes. Little is known about this relationship in normal, uninfected liver. This study sought to explore this relationship. METHODS: Normal human liver specimens (64) and HCV positive human liver specimens (95) were genotyped for IL28B rs12979860 C > T. mRNA levels of ISGs and other relevant genes were studied by qPCR. RESULTS: Most studied ISGs had significantly different expression by IL28B genotype in normal liver. CC genotype expressed the highest levels, CT intermediate and TT the lowest. This is opposite to the pattern seen in HCV patients. Principal component analysis of IL28B genotype and ISG expression further revealed a distinct set of genes correlated with the C allele (ISG15, HTATIP2, LGALS3BP, IRF2 and BCL2) and T allele (IFNα, ß, γ, λ3 and CD80). CONCLUSION: A subset of ISGs was found to be differentially expressed in normal liver by IL28B genotype. This suggests a relationship between IL28B genotype and gene expression before HCV infection.

Implementation of Incidental Liver Lesion Clinically Integrated Workflow Increases Compliance With ACR Follow-Up Guidelines, Closing Care Gaps.

OBJECTIVE: Follow established management guidelines from the ACR and improve adherence to follow-up recommendations for incidental liver lesions (ILLs) for all patients undergoing CT abdomen and pelvis with contrast (CTAPw) examinations, with advocacy from a multidisciplinary care team. METHODS: A mandatory structured radiology reporting module was developed for use in CTAPw reports for ILL recommendations. Data from the electronic medical record describing patients with radiology-reported ILLs and their clinical risk diagnosis categories were tabulated in a queryable electronic database. A nurse co-ordinator initiated workflow to communicate the need for ILL follow-up MRI to ordering physicians and primary care providers. MRIs were ordered by the ILL team. An interactive process was undertaken with continuous review to improve identification of eligible patients and adherence to recommendations. RESULTS: During the initial launch phase from December 2020 to March 2021, 1,577 ILLs were detected on 20,667 CTAPw examinations, and for those with the characterize now recommendation, 36 of 114 (31.6%) received follow-up in 30 days. Between January 2021 and June 2022, 117,520 CTAPws were performed and 4,371 ILLs were detected. Using the ILL workflow, in the MRI now cohort, follow-up occurred within 30 days in 202 of 542 (36.2%) patients, and a total of 368 of 542 (67.9%) patients have completed their follow-up to date. DISCUSSION: Using a focused effort to close a gap in ILL care, adherence to follow-up recommendations improved over the long term, although there remains a gap in adherence to short-term interventions. A multidisciplinary approach, radiology reporting, and software solutions were leveraged to improve a complex process.

Performance of a Prospective Anticoagulation Stratification Algorithm After Liver Transplantation.

Venous thromboembolism (VTE) occurs in 0.4% to 15.5% and bleeding occurs in 20% to 35% of patients after liver transplantation (LT). Balancing the risk of bleeding from therapeutic anticoagulation and risk of thrombosis in the postoperative period is challenging. Little evidence exists regarding the best treatment strategy for these patients. We hypothesized that a subset of LT patients who develop postoperative deep vein thromboses (DVTs) could be managed without therapeutic anticoagulation. We implemented a quality improvement (QI) initiative using a standardized Doppler ultrasound-based VTE risk stratification algorithm to guide parsimonious implementation of therapeutic anticoagulation with heparin drip. Methods: In a prospective management QI initiative for DVT management, we compared 87 LT historical patients (control group; January 2016-December 2017) to 182 LT patients (study group; January 2018-March 2021). We analyzed the rates of immediate therapeutic anticoagulation after DVT diagnosis within 14 d of LT, clinically significant bleeding, return to the operating room, readmission, pulmonary embolism, and death within 30 d of LT before and after the QI initiative. Results: Ten patients (11.5%) in the control group and 23 patients (12.6%; P = 0.9) in the study group developed DVTs after LT. Immediate therapeutic anticoagulation was used in 7 of 10 and 5 of 23 patients in the control and study groups, respectively (P = 0.024). The study group had lower odds of receiving immediate therapeutic anticoagulation after VTE (21.7% versus 70%; odds ratio = 0.12; 95% confidence interval, 0.019-0.587; P = 0.013) and a lower rate of postoperative bleeding (8.7% versus 40%; odds ratio = 0.14, 95% confidence interval, 0.02-0.91; P = 0.048). All other outcomes were similar. Conclusions: Implementing a risk-stratified VTE treatment algorithm for immediate post-LT patients appears to be safe and feasible. We observed a decrease in the use of therapeutic anticoagulation and a lower rate of postoperative bleeding without adverse impacts on early outcomes.

Alteration of hepatic nuclear receptor-mediated signaling pathways in hepatitis C virus patients with and without a history of alcohol drinking.

UNLABELLED: The current study tests a hypothesis that nuclear receptor signaling is altered in chronic hepatitis C patients and that the altered pattern is specific to alcohol drinking history. The expression of a panel of more than 100 genes encoding nuclear receptors, coregulators, and their direct/indirect targets was studied in human livers. Gene expression pattern was compared between 15 normal donor livers and 23 hepatitis C virus (HCV) genotype 1-positive livers from patients without a drinking history (matched for age, sex, and body mass index). HCV infection increased the expression of nuclear receptors small heterodimer partner and constitutive androstane receptor (CAR) as well as genes involved in fatty acid trafficking, bile acid synthesis and uptake, and inflammatory response. However, the expression of retinoid X receptor (RXR) α, peroxisomal proliferator-activated receptor (PPAR) α and ß as well as steroid regulatory element-binding protein (SREBP)-1c was decreased in HCV-infected livers. Gene expression pattern was compared in chronic hepatitis C patients with and without a drinking history. Alcohol drinking increased the expression of genes involved in fatty acid uptake, trafficking, and oxidation, but decreased the expression of genes responsible for gluconeogenesis. These changes were consistent with reduced fasting plasma glucose levels and altered expression of upstream regulators that include RXRα, PPARα, and CAR. The messenger RNA levels of fibroblast growth factor 21, interleukin-10, and fatty acid synthase, which are all regulated by nuclear receptors, showed independent correlation with hepatic HCV RNA levels. CONCLUSION: Our findings suggest that those genes and pathways that showed altered expression could potentially be therapeutic targets for HCV infection and/or alcohol drinking-induced liver injury.