This article has an accompanying continuing medical education activity, also eligible for MOC credit, on page e19. Learning Objective: Upon completion of this CME activity, successful learners will be able to (1) explain the risk factors for and outcomes of acute-on-chronic liver failure (ACLF), (2) determine when supportive care for these patients may be futile, and (3) recognize factors associated with reduced patient survival after liver transplantation.

NASH is currently the second leading cause for LT waitlist registration/liver transplantation overall, and in females, the leading cause. Given the rate of increase, NASH will likely rise to become the leading indication for LT in males as well.

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Hereditary hemochromatosis (HH) is one of the most common genetic disorders among persons of northern European descent. There have been recent advances in the diagnosis, management, and treatment of HH. The availability of molecular diagnostic testing for HH has made possible confirmation of the diagnosis for most patients. Several genotype-phenotype correlation studies have clarified the differences in clinical features between patients with the C282Y homozygous genotypes and other HFE mutation patterns. The increasing use of noninvasive tests such as MRI T2* has made quantification of hepatic iron deposition easier and eliminated the need for liver biopsy in most patients. Serum ferritin of <1,000 ng/mL at diagnosis remains an important diagnostic test to identify patients with a low risk of advanced hepatic fibrosis and should be used routinely as part of the initial diagnostic evaluation. Genetic testing for other types of HH is available but is expensive and generally not useful in most clinical settings. Serum ferritin may be elevated among patients with nonalcoholic fatty liver disease and in those with alcoholic liver disease. These diagnoses are more common than HH among patients with elevated serum ferritin who are not C282Y homozygotes or C282Y/H63D compound heterozygotes. A secondary cause for liver disease should be excluded among patients with suspected iron overload who are not C282Y homozygotes. Phlebotomy remains the mainstay of therapy, but emerging novel therapies such as new chelating agents may have a role for selected patients.

A complex balance exists between endogenous procoagulants and the anticoagulant system in liver disease patients. Hypercoagulable events occur in cirrhosis patients despite the well-known bleeding diathesis of liver disease. These events may be clinically evident, such as in portal vein thrombosis or pulmonary embolism, but these conditions may also be a silent contributor to certain disease states, such as portopulmonary hypertension or parenchymal extinction with liver atrophy as well as thrombosis of extracorporeal circuits in dialysis or liver assist devices. Moreover, liver disease-related hypercoagulability may contribute to vascular disease in the increasingly common condition of non-alcoholic fatty liver disease. Despite the incidence of these problems, there are few widely accessible and practical laboratory tests to evaluate the risk of a hypercoagulable event in cirrhosis patients. Furthermore, there is little research on the use of commonly accepted anticoagulants in patients with liver disease. This article is a result of an international symposium on coagulation disorders in liver disease and addresses several areas of specific interest in hypercoagulation in liver disease. Critical areas lacking clinical information are highlighted and future areas of research interest are defined with an aim to foster clinical research in this field.

Direct‐acting antiviral (DAA) therapy has altered the frequency and outcome of liver transplantation (LT) for hepatitis C virus (HCV). The high efficacy and tolerability of DAA therapy has also created a rationale for utilizing HCV‐viremic (HCV‐RNA–positive) donors, including into HCV‐negative recipients. We examined trends in frequency of organ utilization and graft survival in recipients of HCV‐viremic donors (HCV‐RNA positive as measured by nucleic acid testing [NAT]). Data were collected from the Scientific Registry of Transplant Recipients (SRTR) on adult patients who underwent a primary, single‐organ, deceased donor LT from January 1, 2008 to January 31, 2018. Outcomes of HCV‐negative transplant recipients (R–) who received an allograft from donors who were HCV‐RNA positive (DNAT+) were compared to outcomes for R– patients who received organs from donors who were HCV‐RNA negative (DNAT–). There were 11,270 DNAT–/R–; 4,748 DNAT–/R+; 87 DNAT+/R–; and 753 DNAT+/R+ patients, with 2‐year graft survival similar across all groups: DNAT–/R– 88%; DNAT–/R+ 88%; DNAT+/R– 86%; and DNAT+/R+ 90%. Additionally, there were 2,635 LTs using HCV antibody‐positive donors (DAb+): 2,378 DAb+/R+ and 257 DAb+/R–. The annual number of DAb+/R– transplants increased from seven in 2008 to 107 in 2017. In the post‐DAA era, graft survival improved for all recipients, with 3‐year survival of DAb+/R– patients and DAb+/R+ patients increasing to 88% from 79% and to 85% from 78%, respectively. Conclusion: The post‐DAA era has seen increased utilization of HCV‐viremic donor livers, including HCV‐viremic livers into HCV‐negative recipients. Early graft outcomes are similar to those of HCV‐negative recipients. These results support utilization of HCV‐viremic organs in selected recipients both with and without HCV infection.

Background and aims: Acute on chronic liver failure (ACLF) yields the highest risk of short-term mortality, along the spectrum of cirrhosis. We evaluated whether the rising prevalence of nonalcoholic steatohepatitis (NASH) in the United States is reflected among waitlist registrants with ACLF. Methods: We analyzed the United Network for Organ Sharing (UNOS) registry, years 2005-2017. Patients with ACLF were identified using the EASL-CLIF criteria and categorized into those with NASH, alcoholic liver disease (ALD), and hepatitis C virus (HCV) infection. Statistical analysis included linear regression and Chow's test to determine significance and divergence in trends, and Fine and Grey's competing risks and Cox proportional hazards regression to assess waitlist outcomes. Results: Between 2005 and 2017, waitlist registrants for NASH-ACLF rose 331.6% (p<0.001). ALD-ACLF increased 206.3% (p<0.001), while HCV-ACLF declined 45.2% (p=0.018). This increase in NASH-ACLF occurred across all UNOS regions, rising by 666.7% in region 11. The NASH-ACLF population is aging, and currently 31.5% of the group is age 65 or older. Although NASH-ACLF candidates did not have greater 90-day waitlist mortality (SHR=0.84, 95% CI 0.77-0.92) relative to other etiologies, since 2014, 90-day waitlist mortality has improved for ALD-ACLF (HR=0.78, 95% CI 0.70-0.88) and HCV-ACLF (HR=0.76, 95% CI 0.67-0.85) but not for NASH (HR=0.93, 95% CI 0.81-1.08). Conclusions: NASH is the fastest rising etiology of cirrhosis among transplant registrants with ACLF in the United States. Since 2014, waitlist outcomes have 4 improved for ALD-ACLF and HCV-ACLF, but not for NASH-ACLF. With the aging NASH population, patients with NASH-ACLF may eventually have the highest risk of death on the waiting list.

Medical‐refractory severe alcoholic hepatitis (AH) has a high mortality. The national frequency, longer term outcomes and regional practices of AH liver transplantation (LT) in the United States are not well described, despite the increasing mortality from alcohol‐associated liver disease. We analyzed the trends in frequency and outcomes of UNOS data on 39 455 adult patients who underwent LT from 2014 to 2019, including AH LT recipients. LTs for AH increased 5‐fold, from 28 in 2014 to 138 in 2019, varying 8‐fold between UNOS regions. Three transplant centers accounted for 50%‐90% of AH LTs within each region. The number of transplant centers performing AH LTs increased from 14 in 2014 to 47 in 2019. AH patients were younger (mean = 39.4 years), had higher MELD scores (mean = 36.8), and were more often on dialysis (46.0%) and in ICU (38.4%), compared to other indications (all P < .05). One‐ and 5‐year graft survivals for AH LT recipients were 91.7% and 81.9%, respectively. The frequency of AH LT is increasing rapidly, with excellent medium‐term outcomes. An impact of AH recurrence on patient or graft survival is not apparent in this national analysis. There are marked geographic variations in practices, highlighting the lack of selection criteria standardization.