The future of liver transplantation in the United States: Ongoing optimism and concerns with a prescription for change.

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Epidemiology and Management of Infections in Liver Transplant Recipients.

Background: Improvements in liver transplant (LT) outcomes are attributed to advances in surgical techniques, use of potent immunosuppressants, and rigorous pre-LT testing. Despite these improvements, post-LT infections remain the most common complication in this population. Bacteria constitute the most common infectious agents, while fungal and viral infections are also frequently encountered. Multi-drug-resistant bacterial infections develop because of polymicrobial overuse and prolonged hospital stays. Immediate post-LT infections are commonly caused by viruses. Conclusions: Appropriate vaccination, screening of both donor and recipients before LT and antiviral prophylaxis in high-risk individuals are recommended. Antimicrobial drug resistance is common in high-risk LT and associated with poor outcomes; epidemiology and management of these cases is discussed. Additionally, we also discuss the effect of coronavirus disease 2019 (COVID-19) infection and monkeypox in the LT population.

Improved outcomes of liver resection for hepatitis C-related hepatocellular carcinoma after the introduction of direct-acting antiviral therapy.

BACKGROUND: Assess impact of direct-acting antivirals introduction on outcomes after liver resection for hepatocellular carcinoma. METHODS: 391 patients (1991-2021) treated with resection for hepatocellular carcinoma on Hepatitis C background were divided according to receiving Hepatitis C treatment, treatment type, achievement of sustained virological response (SVR), time of resection pre- (Era 1, 1991-2011) and post-direct acting antivirals introduction (Era 2, 2012-2021). Survival was estimated with Kaplan-Meier curves, Cox regression analysis performed to identify survival predictors. RESULTS: Majority of patients had single lesion (67.8%), diameter >2 cm in 60.6%, no evidence of macroscopic vascular invasion on imaging. Pathology showed vascular invasion in 69.6% of patients, 76.5% microvascular. Recurrence developed in 247 patients (63.2%). 194 patients (49.6%) achieved SVR. Overall survival at 1-, 3-, 5-years was 94.6%, 85.7%, 78.8% for patients who achieved SVR, 80.1%, 48.1%, 29.9% in those who did not (p < 0.001). 220 patients (56.3%) were in Era 1, 171 (43.7%) in Era 2. Survival at 1-, 3-, 5-years was 76.1%, 49%, 36% in Era 1, 94.5%, 82.5%, 70.3% in Era 2 (p < 0.001). SVR was an independent predictor of survival on multiple Cox Regression analysis. CONCLUSION: While many aspects of HCC management have evolved, SVR following direct-acting antivirals independently improves HCC resection outcomes.

Sepsis during short bowel syndrome hospitalizations: Identifying trends, disparities, and clinical outcomes in the United States.

BACKGROUND: Short bowel syndrome (SBS) hospitalizations are often complicated with sepsis. There is a significant paucity of data on adult SBS hospitalizations in the United States and across the globe. AIM: To assess trends and outcomes of SBS hospitalizations complicated by sepsis in the United States. METHODS: The National Inpatient Sample was utilized to identify all adult SBS hospitalizations between 2005-2014. The study cohort was further divided based on the presence or absence of sepsis. Trends were identified, and hospitalization characteristics and clinical outcomes were compared. Predictors of mortality for SBS hospitalizations complicated with sepsis were assessed. RESULTS: Of 247097 SBS hospitalizations, 21.7% were complicated by sepsis. Septic SBS hospitalizations had a rising trend of hospitalizations from 20.8% in 2005 to 23.5% in 2014 (P trend < 0.0001). Compared to non-septic SBS hospitalizations, septic SBS hospitalizations had a higher proportion of males (32.8% vs 29.3%, P < 0.0001), patients in the 35-49 (45.9% vs 42.5%, P < 0.0001) and 50-64 (32.1% vs 31.1%, P < 0.0001) age groups, and ethnic minorities, i.e., Blacks (12.4% vs 11.3%, P < 0.0001) and Hispanics (6.7% vs 5.5%, P < 0.0001). Furthermore, septic SBS hospitalizations had a higher proportion of patients with intestinal transplantation (0.33% vs 0.22%, P < 0.0001), inpatient mortality (8.5% vs 1.4%, P < 0.0001), and mean length of stay (16.1 d vs 7.7 d, P < 0.0001) compared to the non-sepsis cohort. A younger age, female gender, White race, and presence of comorbidities such as anemia and depression were identified to be independent predictors of inpatient mortality for septic SBS hospitalizations. CONCLUSION: Septic SBS hospitalizations had a rising trend between 2005-2014 and were associated with higher inpatient mortality compared to non-septic SBS hospitalizations.

Outcomes after kidney transplant alone in patients with cirrhosis-A case-control study.

BACKGROUND: Guidelines recommend kidney transplant alone (KTA) in compensated cirrhosis based on a few small studies, but this is not widely performed despite its potential benefit to patients and the organ supply. Our aim was to determine the outcomes of KTA in patients with compensated cirrhosis. STUDY DESIGN: From 1/2012 to 12/2021, outcomes in KTA recipients with compensated cirrhosis were retrospectively compared to patients with chronic liver disease (CLD) but no cirrhosis. Patients with compensated cirrhosis were also compared to a matched cohort (based on age, time on hemodialysis, sex, and ethnicity) of KTA recipients without CLD. The outcomes included patient survival, allograft failure, allograft rejection, serious infection, liver decompensation, and length of stay (LOS). RESULTS: Over 9 years, 1562 KTAs were performed, with 150 (9.6%) patients having CLD mostly due to chronic hepatitis C, and a median follow-up of 3.5 years. 32/150 (21%) had compensated cirrhosis at the time of KTA with a mean MELD-Na of 22 (1.5). Matched controls (n = 189) were identified. We found no differences in patient survival (p = .07), allograft failure (p = .6), allograft rejection (p = .43), rates of serious infection (p = .31), as well as LOS (p = .61) among patients with compensated cirrhosis compared to patients with CLD but no cirrhosis, but with higher rates of liver decompensation (p = .004). Similarly, compared to patients without CLD, patients with cirrhosis had similar rates of patient survival (p = .20), allograft failure (p = .27), allograft rejection (p = .62) and LOS (p = .19) but with higher rates of serious infections (p = .001). CONCLUSIONS: Our study supports the safety and efficacy of KTA in patients with compensated cirrhosis.

Summary of a consensus conference on heart-liver transplantation.

Patients with severe heart disease may have coexisting 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 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 multiorgan transplantation were also debated. The findings and consensus statements are presented.

Utilization of aquapheresis among hospitalized patients with end-stage liver disease: A case series and literature review.

Third-spacing of fluid is a common complication in hospitalized patients with decompensated cirrhosis. In addition to ascites, patients with advanced cirrhosis may develop significant peripheral edema, which may limit mobility and exacerbate debility and muscle wasting. Concomitant kidney failure and cardiac dysfunction may lead to worsening hypervolemia, which may ultimately result in pulmonary edema and respiratory compromise. Diuretic use in such patients may be limited by kidney dysfunction and electrolyte abnormalities, including hyponatremia and hypokalemia. A slow, continuous form of ultrafiltration known as aquapheresis is a method of extracorporeal fluid removal whereby a pump generates a transmembrane pressure that forces an isotonic ultrafiltrate across a semipermeable membrane. This leads to removal of an ultrafiltrate that is isotonic to blood without the need for dialysate or replacement fluid as is necessary in other forms of continuous kidney replacement therapy. This technique has been utilized in other conditions including acute decompensated heart failure, with trials showing mixed, but generally favorable results. Herein, we present a series of our own experience using aquapheresis among patients with cirrhosis, review the literature regarding its use in other hypervolemic states, and discuss how we may apply lessons learned from use of aquapheresis in heart failure to patients with end-stage liver disease.

Systemic Disease and the Liver-Part 1: Systemic Lupus Erythematosus, Celiac Disease, Rheumatoid Arthritis, and COVID-19.

The development of liver dysfunction in patients having various systemic diseases is common and has a broad differential diagnosis, at times being the initial manifestation of the disorder. Liver injury associated with systemic lupus erythematosus is heterogeneous and may present with nonspecific histology. Differentiating autoimmune hepatitis from lupus hepatitis is challenging on histologic grounds alone. Other systemic diseases that may present mostly with nonspecific findings are rheumatoid arthritis and celiac disease. More recently COVID-19 cholangiopathy and secondary sclerosing cholangitis have become increasingly recognized as distinct liver conditions. Many patients may also have intrinsic liver disease or may develop drug-induced liver injury from the treatment of the systemic disease. Timely identification of the cause of the liver dysfunction is essential and liver biopsy may help the clinician in diagnosis and management.

Systemic Disease and the Liver Part 2: Pregnancy-Related Liver Injury, Sepsis/Critical Illness, Hypoxia, Psoriasis, Scleroderma/Sjogren's Syndrome, Sarcoidosis, Common Variable Immune Deficiency, Cystic Fibrosis, Inflammatory Bowel Disease, and Hematologic Disorders.

The liver is involved in many multisystem diseases and commonly may manifest with abnormal liver chemistry tests. The liver test perturbations may be multifactorial in nature, however, as patients are receiving many different medications and can also have intrinsic liver disease that may be exacerbated by the systemic disorder. Some disorders have typical histologic findings that can be diagnosed on liver biopsy, whereas others will show a more nonspecific histology. Clinicians should be aware of these conditions so as to consider the performance of a liver biopsy at the most opportune time and setting to help establish the diagnosis of acute or chronic liver disease.

Clinician Perspectives on Palliative Care for People with Hepatocellular Carcinoma: Facilitators of and Barriers to Referral.

(1) Background: Little is known about facilitators of and barriers to palliative care referral for people with hepatocellular carcinoma (HCC). The objective of this study is to identify facilitators and barriers of palliative care referral described by HCC-treating clinicians. (2) Methods: Semi-structured interviews (n = 16) were conducted with HCC-treating clinicians at two centers, focusing on referral patterns, palliative care needs, and disease course. A code book was created, axial coding was used to code all interviews, and selective coding was used to identify facilitators and barriers of palliative care referral. (3) Results: Facilitators included helpfulness at times of transition; help with management of certain symptoms; provision of psychosocial support; and positive experiences with referral. Barriers included feasibility concerns; lack of information about palliative care and who is appropriate; lack of symptoms requiring outside referral; and concerns that palliative care conveys loss of hope. (4) Conclusions: Participants noted the helpfulness of palliative care at specific points in the disease trajectory and cited barriers related to feasibility, lack of need, lack of awareness, and loss of hope. The results show actionable issues that can be addressed in future research to leverage the benefits of and overcome the barriers to palliative care for people with HCC.

Early neurologic complications after liver transplant are associated with reduced long-term survival and increased rates of rejection.

Neurologic complications (NCs) are common following liver transplantation (LT) and have been associated with impaired short-term survival. The impact of NC on long-term survival is less defined. We aimed to characterize these outcomes and assess for risk factors for post-LT NC. We performed a single-center, retrospective review of 521 patients with LT from 2016 to 2020. Baseline clinical and laboratory factors, intraoperative events, and outcomes were compared between patients with and without NC. The 5-year overall and rejection-free survival was estimated using the Kaplan-Meier analysis. Multivariable logistic regression assessed for an independent relationship between risk factors and the development of NC. Among 521 LT recipients, 24% experienced post-LT NC. Overall and rejection-free survival at 5 years was, respectively, 69% and 75% among those with NC versus 87% and 88% among those without NC (log-rank < 0.001). Among those who survived the first 3 months after LT, overall survival but not rejection-free survival was reduced among patients with NC. Risk factors for developing NC included peri-LT serum sodium (ΔSNa) ≥ 6 (29.4% vs. 20.5%, p = 0.04), grade 3 or 4 HE pre-LT, SNa < 125 pre-LT, and more intraoperative transfusions. In a multivariable logistic regression model controlling for described variables, SNa < 125 (or 0.21, 95% CI, 0.06-0.74) at LT and pre-LT HE grade 3 or 4 (or 0.45, 95% CI, 0.26-0.76) was independently associated with NC. Long-term survival was reduced among patients who developed NC in the immediate post-transplant period, even when censoring those who died in the first 3 months. Post-LT NC was associated with perioperative ΔSNa ≥ 6. Optimization of SNa pre-LT > 125 and limiting perioperative ΔSNa <6 mEq/L might have a beneficial impact in decreasing NC post-LT, which may improve long-term post-LT survival.

Hepatocellular carcinoma in patients cured of chronic hepatitis C: Minimal steatosis.

BACKGROUND: Successful treatment of hepatitis C reduces liver inflammation and fibrosis; however, patients remain at risk of developing hepatocellular carcinoma (HCC). AIMS: To identify risk factors for new-onset HCC in patients cured of hepatitis C. METHODS: Imaging, histological, and clinical data on patients whose first HCC was diagnosed >12 months of post-SVR were analyzed. Histology of 20 nontumor tissues was analyzed in a blinded manner using the Knodel/Ishak/HAI system for necroinflammation and fibrosis/cirrhosis stage and the Brunt system for steatosis/steatohepatitis. Factors associated with post-SVR HCC were identified by comparison with HALT-C participants who did not develop post-SVR HCC. RESULTS: Hepatocellular carcinoma was diagnosed in 54 patients (45 M/9F), a median of 6 years of post-SVR [interquartile range (IQR) =1.4-10y] at a median age of 61 years (IQR, 59-67). Approximately one-third lacked cirrhosis, and only 11% had steatosis on imaging. The majority (60%) had no steatosis/steatohepatitis in histopathology. The median HAI score was 3 (1.25-4), indicating mild necroinflammation. In a multivariable logistic regression model, post-SVR HCC was positively associated with non-Caucasian race (p = 0.03), smoking (p = 0.03), age > 60 years at HCC diagnosis (p = 0.03), albumin<3.5 g/dL (p = 0.02), AST/ALT>1 (p = 0.05), and platelets <100 × 103 cells/µL (p < 0.001). Alpha fetoprotein ≥4.75 ng/mL had 90% specificity and 71% sensitivity for HCC occurrence. Noncirrhotic patients had larger tumors (p = 0.002) and a higher prevalence of vascular invasion (p = 0.016) than cirrhotic patients. CONCLUSIONS: One-third of patients with post-SVR HCC did not have liver cirrhosis; most had no steatosis/steatohepatitis. Hepatocellular carcinomas were more advanced in noncirrhotic patients. Results support AFP as a promising marker of post-SVR HCC risk.

Histologic and Clinical Outcomes of Patients Developing Post-Liver Transplant Plasma Cell-Rich Rejection.

OBJECTIVES: Plasma cell-rich rejection (PCCR), also known as "plasma cell hepatitis" or "de novo autoimmune hepatitis," is a cause of allograft dysfunction occurring post-liver transplantation (LT). Patients often develop allograft failure and may require repeat LT. PCRR may fall within the spectrum of different histologies associated with antibody-mediated rejection (AMR), which is associated with donor-specific antibodies (DSAs) and positive complement component C4 (C4d) immunostaining. We sought to analyze the histologic and clinical outcomes of patients having biopsy-proven PCRR as well as to examine its C4d staining and DSA profiles. METHODS: We identified patients having PCRR between 2000 and 2020 using the electronic pathology database at our institution. We included patients who underwent at least one follow-up liver biopsy after establishing the PCRR diagnosis to assess future histologic progression and outcomes. Mean fluorescence intensity for at least one single DSA of 2,000 or higher was considered positive. Histologic diagnosis of PCRR was independently made by an experienced liver pathologist. RESULTS: A total of 35 patients were included in the study. Hepatitis C virus was the most common etiology for LT (59.5%). Mean ± SD age at LT was 49.0 ± 12.7 years. Forty percent of patients developed PCRR within 2 years of LT. Most patients (68.5%) had negative outcomes, with progression from PCRR to cirrhosis or chronic ductopenic rejection (CDR). Patients who had hepatitis C virus were more likely to develop cirrhosis rather than CDR following the PCRR diagnosis (P = .01). Twenty-three (65.7%) patients had at least one prior episode of T-cell-mediated rejection before being diagnosed with PCRR. DSAs were positive in 16 of 19 patients assessed, and C4d immunostaining was positive in 9 of 10 patients. CONCLUSIONS: Development of PCRR negatively affects liver allograft outcomes and patient survival after LT. The presence of DSA and C4d in PCRR patients supports it to be within the histologic spectrum of AMR.

The Importance of Segment 4 Anatomy on Outcomes Following Living Donor Left Lateral Segmentectomy.

BACKGROUND: During left lateral section (LLS) resection for live liver donation, the vascular inflow and the bile drainage of segment 4 (S4) are compromised. We investigated the long-term changes of S4 after donation and their potential prognostic impact on living liver donors. MATERIALS AND METHODS: This was a retrospective analysis of 42 consecutive left lateral (LLS, S2/3) liver resections for living donation. RESULTS: There were 25 female and 17 male donors. Median age was 33 y and median body mass index was 26. Median LLS, S2/3, volume was 262 cc, and median sS4 volume was 160 cc. Complications were encountered in three donors (7%). An independent extrahepatic S4 artery (S4A) (with a proximal left heptic artery or a right hepatic artery origin) was identified in 41% of the donors. Ligation of the independent S4A was not associated with the rate of post resection liver dysfunction, complications, or the degree of S4 atrophy. Having a dominant S4 portal triad pedicle feeding the right anterior sectors, segment 5/8, of the liver was associated with increased parenchymal damage as evidenced by a higher peak of alanine aminotransferase but was not associated with postoperative complications. The median degree of atrophy of S4 at 1 y post donation as noted on imaging was 66%. The presence of a dominant S4 portal triad pedicle and the peak alanine aminotransferase early postoperatively were both predictors of the degree of S4 atrophy post donation. CONCLUSIONS: The presence of an independent S4A or dominant S4 portal triad pedicle feeding the liver right anterior sectors, segment 5/8, should not be a contraindication for left lateral segment living donation.

DCD Hepatitis C Virus-positive Donor Livers Can Achieve Favorable Outcomes With Liver Transplantation and Are Underutilized.

BACKGROUND: Hepatitis C virus (HCV)-positive donors (antibody-positive [Ab + ] or nucleic acid test positive [NAT + ] donors) have been underutilized. The aim of this study was to evaluate the utilization of livers from HCV-positive with donation after circulatory death (DCD) and to assess outcomes in recipients of these grafts. METHODS: Data between 2015 and 2019 were obtained from the United Network for Organ Sharing database. The utilization rates and graft survival among 8455 DCD liver and nonliver donors and 2278 adult DCD liver transplantation (LT) recipients were reviewed on the basis of donor HCV Ab/NAT status. RESULTS: The utilization of Ab + /NAT - donors <40 y and Ab + /NAT + donors ≥40 y was low than utilization of HCV-negative donors ( P < 0.001). Multivariate analysis identified HCV status (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.06-2.48 in Ab + /NAT - , and OR, 1.49; 95% CI, 1.09-2.05 in Ab + /NAT + ) as an independent predictor of nonutilization of liver grafts. The rate of significant liver fibrosis was comparable in Ab + /NAT - (3.5%; P = 0.84) but was higher in Ab + /NAT + (8.7%; P = 0.03) than that in Ab - /NAT - donors. Kaplan-Meier survival curves demonstrated comparable 3-y patient survival in recipients of HCV-positive grafts compared with recipients of HCV-negative grafts ( P = 0.63; 85.6% in Ab - /NAT - , 80.4% in Ab + /NAT - , and 88.7% in Ab + /NAT + ). CONCLUSIONS: Patient and graft survival rates are similar between HCV-positive and HCV-negative DCD LT. However, HCV-positive donors are particularly underutilized for DCD LT.

Outcomes after Liver Transplantation with Steatotic Grafts: Redefining Acceptable Cutoffs for Steatotic Grafts.

Background: Graft macrosteatosis can predispose to a higher risk of graft loss so we sought to redefine acceptable cutoffs for graft steatosis. Methods: Data of 26,103 donors who underwent liver transplantation (LT) between January 2004 and December 2018 from the UNOS-STAR database were utilized. A high-risk steatotic (HRS) graft and a low-risk steatotic (LRS) graft were defined as ≥20% and <20% macrosteatosis, respectively. High-risk steatotic grafts were further classified as grafts with 20-29% (G1S grafts), 30-39% (G2S grafts), and ≥40% steatosis (G3S grafts). Outcomes between groups were compared. Results: LRS grafts had excellent graft (93.3 and 87.7%) and overall survival (95.4 and 90.5%) at 90 days and 1 year. Compared to LRS grafts, G1S, G2S, and G3S grafts had worse graft and overall survival at 90 days and 1-year (p <0.001). There was no difference in graft or overall survival of G1S or G3S grafts compared to G2S grafts until after adjustment in which G3S grafts were found to be associated with an increased risk of graft loss-aHR 1.27 (1.03-1.57), p = 0.02. Discussion: Liver grafts can be categorized into three categories: (1) <20% or "very low risk", (2) 20-39% or "low-to-moderate risk", and usually acceptable, and (3) ≥40% steatosis or "moderate-to-high risk". How to cite this article: Da BL, Satiya J, Heda RP, et al. Outcomes after Liver Transplantation with Steatotic Grafts: Redefining Acceptable Cutoffs for Steatotic Grafts. Euroasian J Hepato-Gastroenterol 2022;12(Suppl 1):S5-S14.