Oren K. Fix

D-MELD, a Simple Predictor of Post Liver Transplant Mortality for Optimization of Donor/Recipient Matching

Numerous donor and recipient risk factors interact to influence the probability of survival after liver transplantation. We developed a statistic, D‐MELD, the product of donor age and preoperative MELD, calculated from laboratory values. Using the UNOS STAR national transplant data base, we analyzed survival for first liver transplant recipients with chronic liver failure from deceased after brain death donors. Preoperative D‐MELD score effectively stratified posttransplant survival. Using a cutoff D‐MELD score of 1600, we defined a subgroup of donor–recipient matches with significantly poorer short‐ and long‐term outcomes as measured by survival and length of stay (LOS). Avoidance of D‐MELD scores above 1600 improved results for subgroups of high‐risk patients with donor age ≥60 and those with preoperative MELD ≥30. D‐MELD ≥1600 accurately predicted worse outcome in recipients with and without hepatitis C. There is significant regional variation in average D‐MELD scores at transplant, however, regions with larger numbers of high D‐MELD matches do not have higher survival rates. D‐MELD is a simple, highly predictive tool for estimating outcomes after liver transplantation. This statistic could assist surgeons and their patients in making organ acceptance decisions. Applying D‐MELD to liver allocation could eliminate many donor/recipient matches likely to have inferior outcome.

Cardiovascular Risk Assessment of the Liver Transplant Candidate

Liver transplantation (LT) candidates today are increasingly older, have greater medical acuity, and have more cardiovascular comorbidities than ever before. Steadily rising model for end-stage liver disease (MELD) scores at the time of transplant, resulting from high organ demand, reflect the escalating risk profiles of LT candidates. In addition to advanced age and the presence of comorbidities, there are specific cardiovascular responses in cirrhosis that can be detrimental to the LT candidate. Patients with cirrhosis requiring LT usually demonstrate increased cardiac output and a compromised ventricular response to stress, a condition termed cirrhotic cardiomyopathy. These cardiac disturbances are likely mediated by decreased beta-agonist transduction, increased circulating inflammatory mediators with cardiodepressant properties, and repolarization changes. Low systemic vascular resistance and bradycardia are also commonly seen in cirrhosis and can be aggravated by beta-blocker use. These physiologic changes all contribute to the potential for cardiovascular complications, particularly with the altered hemodynamic stresses that LT patients face in the immediate post-operative period. Post-transplant reperfusion may result in cardiac death due to a multitude of causes, including arrhythmia, acute heart failure, and myocardial infarction. Recognizing the hemodynamic challenges encountered by LT patients in the perioperative period and how these responses can be exacerbated by underlying cardiac pathology is critical in developing recommendations for the pre-operative risk assessment and management of these patients. The following provides a review of the cardiovascular challenges in LT candidates, as well as evidence-based recommendations for their evaluation and management.

Long‐term follow‐up of portopulmonary hypertension: Effect of treatment with epoprostenol

Moderate to severe portopulmonary hypertension (PPHTN) increases the risks of orthotopic liver transplantation (OLT). Epoprostenol is an effective treatment of PPHTN, but long‐term effects on pulmonary hemodynamics or liver function in PPHTN are poorly defined. We sought to describe the long‐term effects of treatment with or without epoprostenol on pulmonary hemodynamics, liver biochemistries, and survival in patients with moderate to severe PPHTN at a single center. A large retrospective cohort was identified with moderate to severe PPHTN diagnosed before OLT. Baseline and follow‐up pulmonary hemodynamics and liver biochemistries were compared and outcomes assessed. Nineteen patients were treated with epoprostenol and 17 were not treated with epoprostenol. There were significant improvements in mean pulmonary artery pressure (MPAP, 48.4‐36.1 mm Hg; P < 0.0001), pulmonary vascular resistance (PVR, 632‐282 dynes · s · cm−5; P < 0.0001), and cardiac output (5.7 to 7.7 L/min; P = 0.0009) with epoprostenol after a median of 15.4 months. Liver biochemistries did not change significantly, and survival did not seem to differ between the 2 groups (hazard ratio, 0.85; P = 0.77). In the epoprostenol group, patients who survived had greater absolute changes in MPAP, transpulmonary gradient, and PVR than those who died. Two patients in the epoprostenol group successfully underwent OLT. Long‐term epoprostenol therapy greatly improves pulmonary hemodynamics in patients with PPHTN. Liver biochemistries are not greatly changed. Survival seemed not to differ between treatment groups. A minority of patients treated with epoprostenol will improve sufficiently to undergo OLT. Liver Transpl 13:875–885, 2007.

Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumors within Milan criteria.

We report on the long‐term intention‐to‐treat (ITT) outcome of 118 patients with hepatocellular carcinoma (HCC) undergoing downstaging to within Milan/United Network for Organ Sharing T2 criteria before liver transplantation (LT) since 2002 and compare the results with 488 patients listed for LT with HCC meeting T2 criteria at listing in the same period. The downstaging subgroups include 1 lesion >5 and ≤8 cm (n = 43), 2 or 3 lesions at least one >3 and ≤5 cm with total tumor diameter ≤8 cm (n = 61), or 4‐5 lesions each ≤3 cm with total tumor diameter ≤8 cm (n = 14). In the downstaging group, 64 patients (54.2%) had received LT and 5 (7.5%) developed HCC recurrence. Two of the five patients with HCC recurrence had 4‐5 tumors at presentation. The 1‐ and 2‐year cumulative probabilities for dropout (competing risk) were 24.1% and 34.2% in the downstaging group versus 20.3% and 25.6% in the T2 group (P = 0.04). Kaplan‐Meiers 5‐year post‐transplant survival and recurrence‐free probabilities were 77.8% and 90.8%, respectively, in the downstaging group versus 81% and 88%, respectively, in the T2 group (P = 0.69 and P = 0.66, respectively). The 5‐year ITT survival was 56.1% in the downstaging group versus 63.3% in the T2 group (P = 0.29). Factors predicting dropout in the downstaging group included pretreatment alpha‐fetoprotein ≥1,000 ng/mL (multivariate hazard ratio [HR]: 2.42; P = 0.02) and Childs B versus Childs A cirrhosis (multivariate HR: 2.19; P = 0.04). Conclusion: Successful downstaging of HCC to within T2 criteria was associated with a low rate of HCC recurrence and excellent post‐transplant survival, comparable to those meeting T2 criteria without downstaging. Owing to the small number of patients with 4‐5 tumors, further investigations are needed to confirm the efficacy of downstaging in this subgroup. (Hepatology 2015;61:1968–1977)

Detection of anti‐isoniazid and anti–cytochrome P450 antibodies in patients with isoniazid‐induced liver failure

Isoniazid (INH)‐induced hepatotoxicity remains one of the most common causes of drug‐induced idiosyncratic liver injury and liver failure. This form of liver injury is not believed to be immune‐mediated because it is not usually associated with fever or rash, does not recur more rapidly on rechallenge, and previous studies have failed to identify anti‐INH antibodies (Abs). In this study, we found Abs present in sera of 15 of 19 cases of INH‐induced liver failure. Anti‐INH Abs were present in 8 sera; 11 had anti–cytochrome P450 (CYP)2E1 Abs, 14 had Abs against CYP2E1 modified by INH, 14 had anti‐CYP3A4 antibodies, and 10 had anti‐CYP2C9 Abs. INH was found to form covalent adducts with CYP2E1, CYP3A4, and CYP2C9. None of these Abs were detected in sera from INH‐treated controls without significant liver injury. The presence of a range of antidrug and autoAbs has been observed in other drug‐induced liver injury that is presumed to be immune mediated. Conclusion: These data provide strong evidence that INH induces an immune response that causes INH‐induced liver injury. (Hepatology 2014;59:1084–1093)

Outcomes and complications of intracranial pressure monitoring in acute liver failure: a retrospective cohort study.

Objective:To determine if intracranial pressure monitor placement in patients with acute liver failure is associated with significant clinical outcomes. Design:Retrospective multicenter cohort study. Setting:Academic liver transplant centers comprising the U.S. Acute Liver Failure Study Group. Patients:Adult critically ill patients with acute liver failure presenting with grade III/IV hepatic encephalopathy (n = 629) prospectively enrolled between March 2004 and August 2011. Intervention:Intracranial pressure monitored (n = 140) versus nonmonitored controls (n = 489). Measurements and Main Results:Intracranial pressure monitored patients were younger than controls (35 vs 43 yr, p < 0.001) and more likely to be on renal replacement therapy (52% vs 38%, p = 0.003). Of 87 intracranial pressure monitored patients with detailed information, 44 (51%) had evidence of intracranial hypertension (intracranial pressure > 25 mm Hg) and overall 21-day mortality was higher in patients with intracranial hypertension (43% vs 23%, p = 0.05). During the first 7 days, intracranial pressure monitored patients received more intracranial hypertension–directed therapies (mannitol, 56% vs 21%; hypertonic saline, 14% vs 7%; hypothermia, 24% vs 10%; p < 0.03 for each). Forty-one percent of intracranial pressure monitored patients received liver transplant (vs 18% controls; p < 0.001). Overall 21-day mortality was similar (intracranial pressure monitored 33% vs controls 38%, p = 0.24). Where data were available, hemorrhagic complications were rare in intracranial pressure monitored patients (4 of 56 [7%]; three died). When stratifying by acetaminophen status and adjusting for confounders, intracranial pressure monitor placement did not impact 21-day mortality in acetaminophen patients (p = 0.89). However, intracranial pressure monitor was associated with increased 21-day mortality in nonacetaminophen patients (odds ratio, ~ 3.04; p = 0.014). Conclusions:In intracranial pressure monitored patients with acute liver failure, intracranial hypertension is commonly observed. The use of intracranial pressure monitor in acetaminophen acute liver failure did not confer a significant 21-day mortality benefit, whereas in nonacetaminophen acute liver failure, it may be associated with worse outcomes. Hemorrhagic complications from intracranial pressure monitor placement were uncommon and cannot account for mortality trends. Although our results cannot conclusively confirm or refute the utility of intracranial pressure monitoring in patients with acute liver failure, patient selection and ancillary assessments of cerebral blood flow likely have a significant role. Prospective studies would be required to conclusively account for confounding by illness severity and transplant.

Outcomes in Adults With Acute Liver Failure Between 1998 and 2013: An Observational Cohort Study.

Context Whether changes have occurred in the causes of acute liver failure (ALF), its management, or the survival of patients with the condition (with or without liver transplantation) is not known. Contribution This large cohort study found that despite similar causes and severity of ALF among patients referred to specialty centers from 1998 to 2013, the proportion of patients listed for liver transplantation decreased and survival improved among those who did not receive a transplant as well as those who did. Implication More study is warranted to better understand the specific changes in care that may have led to improved survival of patients with ALF. Acute liver failure (ALF) is defined as severe liver injury with rapid onset that results in hepatic encephalopathy (HE) and coagulopathy in persons without preexisting liver disease. The principal causes of ALF include acetaminophen (N-acetyl-p-aminophenol [APAP]) overdose, ischemic and pregnancy-associated liver injury, acute infection with hepatitis A or B virus, drug-induced liver injury, autoimmune hepatitis, BuddChiari syndrome, and Wilson disease (1, 2). For some causes, such as APAP toxicity, outcomes are favorable and transplant-free survival (TFS) approaches 70%, whereas other causes have unfavorable outcomes, including a much lower likelihood (<30%) of recovery without liver transplantation (2). One-year survival after emergency liver transplantation in patients with ALF in the United States and Europe is reportedly good but is lower than among patients with cirrhosis who receive a transplant (3). Patients with ALF often deteriorate rapidly and therefore receive the most urgent ranking (status 1) in the United Network for Organ Sharing transplantation system. Treatment of ALF in the intensive care unit is largely supportive and includes ventilator and vasopressor support for respiratory and/or circulatory failure, renal replacement therapy, plasma and blood transfusions, antibiotics, and measures to decrease intracranial pressure (46). N-acetylcysteine is used to treat APAP overdose and has shown efficacy in patients with ALF not due to APAP toxicity, particularly those referred early and having only mild HE (7). However, few disease-specific or general treatments are available that yield improved outcomes. In this study, our aim was to update the U.S. experience with ALF at specialized liver disease and transplant centers since the last published overview by the Acute Liver Failure Study Group (ALFSG) in 2002 (2). This group initiated its registry in January 1998 to better characterize the causes, clinical features, and outcomes of this super-orphan condition and aimed to enroll cases prospectively from participating liver transplant centers across North America. Accordingly, we analyzed data on all patients with ALF enrolled between 1998 and 2013, focusing on whether clinical features or outcomes of the ALF syndrome have changed over time. In addition, we sought to determine the relationship between ALF causes and rates of TFS and whether utilization of liver transplantation changed in the 16-year observation period. Methods Study Population From 1 January 1998 through 31 December 2013, adult patients were consecutively enrolled in the ALFSG registry (2) from 31 U.S. academic liver centers (of which only 5 legacy sites participated continuously throughout the 16-year period). All enrolled patients had both coagulopathy (international normalized ratio [INR] 1.5) and any grade of HE (as clinically defined by the classic West Haven criteria [8]) within 26 weeks of the first symptoms and had no evidence of significant chronic liver disease, especially cirrhosis. Patients for whom prior liver transplantation failed (due to primary graft nonfunction or other causes) were excluded. During the 16-year period, the number of sites participating, their geographic locations, and the number of cases contributed per site varied depending on each sites ability to continually identify and enroll patients over time (Appendix Figure 1). Appendix Figure 1. Site enrollment over time. Patients were usually admitted to intensive care units; 82.4% were hospitalized before transfer to the referral tertiary care study site, and the remainder were admitted directly to the study site. All were screened for inclusion according to the ALF criteria defined earlier. Written informed consent was obtained from the legal next of kin. A log of screen failures and consent refusal was maintained. All centers complied with local institutional review board requirements. Data Management and Integrity At enrollment into the study, we prospectively collected patient demographic characteristics (age, sex, race, and ethnicity); a complete medical history, including the timing of the first symptom of ill health, onset of jaundice and HE, and the number of days between the first symptom, hospital admission, transfer to the study site (where relevant), and enrollment in the study; and clinical features, including blood pressure and need for vasopressor support, mechanical ventilation, and renal replacement therapy, which allowed calculation of the systemic inflammatory response syndrome (SIRS) score (9). We also collected standard liver and metabolic test results and clinical data daily for up to 7 days, as well as serologic and other tests to determine the cause. All data were managed and housed on a central server at the Medical University of South Carolina. A data query system and periodic monitoring are in place to manage data integrity. In addition, ALFSG leadership conducted annual visits to clinical sites to verify data and ensure compliance with study procedures. Statistical Analysis Statistical analyses were performed using SAS, version 9.4 (SAS Institute). Missing values were not replaced or estimated. Patients with missing data were excluded from the respective analyses for those variables, and patients who were lost to follow-up before 21 days were excluded from the study. Descriptive statistics were used to characterize the demographic and other clinical variables. Categorical variables were compared using the chi-square test or the Fisher exact test (the latter when expected cell counts were <5). Medians were reported with interquartile ranges (IQRs) and were compared with the Wilcoxon rank-sum test. Survival and transplant outcomes at 21 days after study enrollment were classified as TFS (survival without liver transplantation), liver transplantation, or death (2). Outcomes were also determined at 1 and 2 years after study enrollment, but these data were less complete than the 21-day outcome data. Survival rates over time were assessed descriptively at the individual-site level to verify that changes in TFS were not affected by varying accrual of patients from different sites. Treatment utilization and survival and transplant outcomes were analyzed over time annually for trends and were also stratified into two 8-year periods: early (1998 to 2005) and later (2006 to 2013). Trends over time were analyzed using the CochranArmitage test. A significance level of less than 0.05 was used for all comparisons. Role of the Funding Source This study was funded by the National Institutes of Health. The funding source had no direct role in the design, conduct, or reporting of the study. Results Demographic Characteristics and Comorbidities During the 16-year study, 2070 patients (median age, 39.0 years [IQR, 29.0 to 52.0 years]) were enrolled in the ALFSG registry. Over the same interval, there were 660 confirmed ALF screen failures (286 due to failure to meet inclusion criteria, 212 for whom consent could not be obtained, and 162 for other reasons). Among enrolled patients, 69.3% were women and 76.4% were white (Table 1). Patients did not differ in sex, race, or ethnicity between the two 8-year periods but were significantly older and heavier in the later period. Prevalence of hypertension, heart disease, diabetes, psychiatric illness, and substance dependency all increased significantly between the early and later periods, whereas prevalence of renal disease did not. Table 1. Demographic Characteristics, Comorbidities, Clinical Severity, and Causes at Admission Causes and Clinical Severity of ALF The percentage of enrollment as a reflection of the most common causes of ALF did not change during the two 8-year periods. Hepatotoxicity due to APAP accounted for almost half the cases of ALF for the entire 16-year period (Table 1), with the highest annual prevalence (53.0%) occurring in 2013. Unintentional APAP overdoses (those in which patients took excessive medication over several days for such ailments as pain, malaise, or fever [10, 11]) were more common than intentional (suicidal) overdoses. Hepatitis A virus infection was significantly less evident during the later period (9 cases [0.8%]) than the early period (28 cases [2.8%]) (P< 0.001). Hepatic ischemia and autoimmune hepatitis increased modestly, whereas hepatitis B virus infection, drug-induced liver injury, Wilson disease, and BuddChiari syndrome were less frequently noted. Patients entered either the primary or the referral (study) site more rapidly after initial symptom onset in the later period (2.0 days [IQR, 0.0 to 8.0 days]) than the early period (3.0 days [IQR, 1.0 to 14.0 days]) (P< 0.001) (Table 1). However, the corresponding interval between symptom onset and HE onset was 4.0 days in both the early (IQR, 1.0 to 15.0 days) and later (IQR, 1.0 to 12.0 days) periods, and time from onset of jaundice to enrollment also was unchanged (3.0 days in each period [IQRs, 1.0 to 12.0 and 1.0 to 10.0 days, respectively]). Most patients with ALF were severely ill at study enrollment, with nearly 50% having grade 3 or 4 (that is, deep) HE throughout. Biochemical liver test results varied widely but indicated severe illness in most patients (Appendix Table 1). Appendix Table 1. Laboratory Values at Study Enrollment Laboratory Tests fo

Identifying risk for recurrent hepatocellular carcinoma after liver transplantation: Implications for surveillance studies and new adjuvant therapies

The recurrence of hepatocellular carcinoma (HCC) is a major cause of mortality for patients transplanted with HCC. There currently exists no standard method for identifying those patients with a high risk for recurrence. Identification of factors leading to recurrence is necessary to develop an efficient surveillance protocol and address new potential adjuvant therapies. We conducted a retrospective review of 834 consecutive liver transplants from 1/1/1996 to 12/31/2005 (mean follow‐up 1303 ± 1069 days) at one institution and 352 consecutive transplants from 1/2/2002 to 12/31/2005 (mean follow‐up 836 ± 402 days) at a second institution. The test cohort comprised patients identified with HCC in their explanted livers from 1/1/2001 to 12/31/2005 at the first institution. Explant pathology and donor and recipient characteristics were reviewed to determine factors associated with HCC recurrence. These predictors were validated in the remaining liver transplant recipients. The test cohort had 116 patients with findings of HCC in their explanted livers. Twelve patients developed recurrent HCC. Stepwise logistic regression identified 4 independent significant explant factors predictive of recurrence. Size of one tumor (>4.5 cm), macroinvasion, and bilobar tumor were positive predictors of recurrence, whereas the presence of only well‐differentiated HCC was a negative predictor. Designating each significant factor with points in relation to its odds ratio, a Predicting Cancer Recurrence Score (PCRS) with results ranging from −3 to 6 was developed that accurately determined risk of recurrence. These findings were then applied to the two validation cohorts, which confirmed the high predictive value of this model. In conclusion, patients transplanted for HCC with a PCRS of ≤0 have a low risk of recurrence. Patients with a PCRS of 1 or 2 have a moderate risk of recurrence, and those with a PCRS of ≥3 have a high risk for recurrence. Liver Transpl 14:956–965, 2008.

Critical care of the end‐stage liver disease patient awaiting liver transplantation

Patients with end‐stage liver disease awaiting liver transplantation frequently require intensive care admission and management due to either complications of liver failure or to intercurrent illness, particularly infection. Mortality in such patients is high and the development of an illness necessitating intensive care unit management can influence transplant candidacy. Specialized support frequently requires hemodynamic support, mechanical ventilation, and renal support. In this review, areas of management of particular importance to patients with end‐stage liver disease in the intensive care unit are discussed. These areas are hepatic encephalopathy, infectious diseases, cardiovascular support, mechanical ventilation, renal support and combined transplantation, and decisions regarding delisting. Current knowledge specific to these patients, when available, is discussed, current practice is described, and areas of uncertainty in the evidence are discussed. Liver Transpl 17:496–510, 2011.

Two‐year outcomes in initial survivors with acute liver failure: results from a prospective, multicentre study

The long‐term clinical outcomes in initial survivors with acute liver failure (ALF) are not well known. The aim of this study was to provide an overview of the 2‐year clinical outcomes among initial survivors and liver transplant (LT) recipients that were alive 3 weeks after enrolment in the Acute Liver Failure Study Group (ALFSG).