Hepatotoxicity from high-dose methotrexate in primary central nervous system lymphoma.

Background: High-dose methotrexate (HDMTX) is a mainstay of primary central nervous system lymphoma (PCNSL) treatment. Transient hepatotoxicity from HDMTX has been characterized in pediatric patients but not in adults. We sought to characterize hepatotoxicity in adult PCNSL patients undergoing HDMTX treatment. Methods: Retrospective study of 65 PCNSL patients treated at the University of Virginia from 02/01/2002 to 04/01/2020 was performed. Hepatotoxicity was defined using National Cancer Institute Common Toxicity Criteria (CTC) for adverse events, fifth version. High-grade hepatotoxicity was defined as a bilirubin or aminotransferase CTC grade of 3 or 4. Relationships between clinical factors and hepatotoxicity were assessed with logistic regression. Results: Most patients (90.8%) had a rise of at least one aminotransferase CTC grade during HDMTX treatment. 46.2% had high-grade hepatotoxicity based on aminotransferase CTC grade. No patients developed high-grade bilirubin CTC grades during chemotherapy. Liver enzyme test values decreased to low CTC grade or normal in 93.8% of patients after the conclusion of HDMTX treatment without treatment regimen changes. Prior ALT elevation (P = .0120) was a statistically significant predictor of high-grade hepatotoxicity during treatment. Prior history of hypertension was associated with increased risk of toxic serum methotrexate levels during any cycle (P = .0036). Conclusions: Hepatotoxicity develops in the majority of HDMTX-treated PCNSL patients. Transaminase values decreased to low or normal CTC grades in almost all patients after treatment, without modification of MTX dosage. Prior ALT elevation may predict patients' increased hepatotoxicity risk, and hypertension history may be a risk factor for delayed MTX excretion.

Concordance of ICD-10 Codes and the Clinical Diagnosis of Alcoholic Hepatitis.

INTRODUCTION: Many studies on alcoholic hepatitis (AH) use the International Classification of Disease (ICD) coding to identify patients. Data regarding the diagnostic accuracy of ICD codes for AH are limited. METHODS: A total of 151 patients with ICD-10 codes for AH were reviewed for the presence or absence of AH using standardized diagnostic criteria. RESULTS: Sixty-eight of the 151 patients met AH criteria, corresponding to a positive predictive value of 45%. Patients with AH experienced higher model for end-stage liver disease and mortality than those who did not ( P < 0.05). DISCUSSION: Our results suggest ICD-10 codes are not reliable for identifying AH. Studies using the ICD codes should be interpreted cautiously.

Split liver transplantation with extended right grafts on adult recipients: A propensity score matching analysis.

INTRODUCTION: Split liver transplantation (SLT) emerged due to its potential to contribute to the organ pool and reduce organ shortage. However, SLT is technically challenging and has been associated with higher rates of postoperative complications leading to concerns about graft and patient survival. Moreover, there are few studies on matched-pair adult recipients of SLT and whole-liver transplant (WLT), with conflicting results. METHODS: This retrospective study analyze outcomes among adults who underwent SLT at our institution from 2010 to 2019. A 1:1 propensity score matching analysis was performed based on important donor and recipient variables. Baseline characteristics and postoperative outcomes were analyzed and compared between groups. Actuarial graft and patient survival were analyzed by KM curves. RESULTS: Out of 592 adults receiving a LT in our institution, 21 SLT adult recipients were identified and matched with 21 adults undergoing WLT. As expected donor age was significantly lower in SLT recipients (16 (15-22) vs. 32 (17-47), P = .012). Additional donor characteristics, including anthropometrics, and ischemic times were similar between groups. Baseline recipient characteristics and postoperative outcomes, including length of stay, vascular complications, biliary complications, and re-transplantation were comparable between SLT and WLT recipients. Graft (95/95/95 vs. 100/94/94, P = .98) and patient (100/100/100 vs. 100/94/94, P = .30) survival at 1-, 3-, 5-years, were similar between the SLT- and WLT group, respectively. CONCLUSION: Split liver transplantation has the potential to increase the availability of organs for adult recipients without compromising individual outcomes.

Outcomes in Adult Liver Transplant Recipients Using Pediatric Deceased Donor Liver Grafts.

Background: The use of pediatric grafts for liver transplantation (LT) into adult recipients is rare, and reported outcomes are conflicting. The aim of this study is to evaluate the outcomes in adult recipients following LT with grafts from deceased pediatric donors. Methods: A retrospective study identifying adult LT between 2010 and 2020 using pediatric deceased donor liver grafts was conducted. Adults undergoing LT with deceased donor pediatric grafts (age ≤ 12) were identified and matched 1:2 with adults receiving adult grafts (age ≥ 18) based on recipient age (±10 y), model for end-stage liver disease (MELD) score at transplant (±5 points) and etiology of liver disease. To assess real liver size differences between the pediatric-donor and adult-donor groups, patients receiving a graft from a donor between 13 and 17 y were excluded from the main analysis and studied independently. Outcomes between the groups were compared. Complication rates were identified and graded using Clavien-Dindo classification. Graft and patient survival were assessed by Kaplan-Meier curves. Results: Twelve adult LT recipients with whole liver grafts from deceased pediatric donors were matched with 24 adult recipients of adult donors. Recipient age and MELD score were similar between groups. Recipients of pediatric grafts were more likely to be female (66.7% versus 16.7%, P = 0.007) and leaner (body mass index = 24.4 versus 29.9, P = 0.013). Alcohol-related cirrhosis was the most prevalent liver disease etiology in both groups (P = 0.96). There was no significant difference in length of stay, readmissions, early complications, or major complications between groups. Vascular and biliary complication rates were similar. Actuarial graft and patient survival at 1, 3, and 5 y were 100/100/100 versus 96/96/96 (P = 0.48). Conclusions: Excellent patient and graft survival is achievable with LT using young pediatric deceased donor grafts in smaller adult recipients. Outcomes are comparable with recipients of age and MELD-matched adult donors. Careful donor MELD-score recipient matching and close monitoring for potential biliary and vascular complications are crucial to achieve acceptable outcomes.

Liver Transplantation With Grafts From Super Obese Donors.

There are limited data on liver transplant (LT) outcomes with grafts from super obese donors. The present study aims to evaluate a unique cohort of recipients following LT using grafts from donors with body mass index (BMI) ≥50. METHODS: Patients receiving grafts from donors with BMI ≥50 and BMI <50 from 2010 to 2019 were identified. A 1:2 case-control match was conducted to compare outcomes between the groups. Survival was analyzed using the Kaplan-Meier curves. RESULTS: Six hundred sixty-five adult LTs were performed in the study period. Eighteen patients receiving a graft from a donor with BMI ≥50 were identified and matched to 36 patients receiving a graft from a donor with BMI <50. Grafts from male donors were significantly lower in the donor BMI ≥50 group when compared with the donor BMI <50 group (16.7% versus 66.7%, P = 0.001). Liver biopsy was performed in 77.8% of grafts in the donor BMI ≥50 group, whereas only in 38.8% of the grafts in the donor BMI <50 group (P = 0.007). Recipients in the donor BMI ≥50 group had a significantly higher diagnosis rate of hepatocellular carcinoma pretransplant versus the donor BMI <50 group (38.9% versus 8.3%, respectively; P = 0.006). Major complications within 30 d did not differ statistically between groups. Biliary complications within the first 30 d were equal among groups (16.7%). Subanalysis comparing the super obese donor group versus the nonobese donor group showed no differences in terms of postoperative complications, readmission rate, graft rejection, or major complications including the need for reoperation, retransplantation, or mortality. Graft and patient survival at 1-, 3-, and 5-y graft were similar between the donor BMI ≥50 group versus donor BMI <50 group (94%/89%/89% versus 88%/88%/88%, P = 0.89, and 94%/94%/94% versus 88%/88%/88%, P = 0.48, respectively). CONCLUSIONS: LT with carefully selected grafts from super obese donors can be safely performed with outcomes comparable with non-super obese donor livers. Therefore, these types of grafts could represent a safe means to expand the donor pool.

Evaluation of Serum-Derived Bovine Immunoglobulin Protein Isolate in Subjects With Decompensated Cirrhosis With Ascites.

Background Bacterial translocation plays a pivotal role in the natural course of cirrhosis and its complications. Serum-derived bovine immunoglobulin (SBI) is an oral medical food that has been shown to both reduce inflammation in the intestines and neutralize bacteria. It represents a unique intervention that has not been studied in this population. Methodology We conducted a prospective open-label trial with an eight-week treatment phase of SBI. Individuals were assessed using lactulose breath testing, serum markers for enterocyte damage and bacterial translocation, and the Chronic Liver Disease Questionnaire (CLDQ) prior to and after completion of the treatment phase. Results We evaluated nine patients with a diagnosis of decompensated cirrhosis with ascites. Subjects had a mean Model for End-Stage Liver Disease (MELD) score of 11.6 ± 3.0 and were not taking lactulose or antibiotics. All subjects tolerated SBI well with no significant adverse events or changes to any of the six domains of the CLDQ. Laboratory tests including liver tests and MELD score remained stable over the course of treatment. There were no significant changes in the rates of small intestinal bacterial overgrowth (55.6% vs 55.6%, p = 1.00) or serum levels of lipopolysaccharide-binding protein, intestinal fatty acid-binding protein, or soluble CD14 (p-values 0.883, 0.765, and 0.748, respectively) when comparing values prior to and immediately after treatment. Conclusions No adverse events or significant changes to the quality of life were detected while on treatment. There were no statistically significant differences in our outcomes when comparing individuals before and after treatment in this small prospective proof-of-concept pilot study. Further prospective randomized studies could be beneficial.

Management of Portal Vein Thrombosis in Cirrhosis.

While portal vein thrombosis (PVT) is a frequently encountered complication in the cirrhosis population, its management can be challenging for even the most experienced clinicians. Multiple factors must be considered with regards to management, including the degree of underlying portal hypertension and liver dysfunction, risks of therapies including anticoagulation and transjugular intrahepatic portosystemic shunt placement, and extent of the thrombosis. Interpreting the available literature to determine the best treatment strategy for any individual patient can be especially challenging given the lack of prospective, randomized controlled trials and the heterogeneity of cohorts studied. This review will provide an overview of PVT in the cirrhosis population, including necessary steps in evaluation and the potential benefits and drawbacks of different treatment approaches.

Transfusion with Cryoprecipitate for Very Low Fibrinogen Levels Does Not Affect Bleeding or Survival in Critically Ill Cirrhosis Patients.

BACKGROUND: Fibrinogen (FIB) levels less than 150 mg/dL have been associated with increased rates of bleeding and lower survival in critically ill cirrhosis patients. OBJECTIVE: We aimed to determine if treatment with cryoprecipitate (CRYO) for low FIB levels is associated with bleeding outcomes or survival. METHODS: A total of 237 cirrhosis patients admitted to an intensive care unit at a tertiary care liver transplant center with initial FIB levels less than 150 mg/dL were retrospectively assessed for CRYO transfusion, bleeding events, and survival outcomes. RESULTS: The mean MELD score was 27.2 (95% confidence interval [CI]: 26.0-28.3) and CLIF-C acute on chronic liver failure score was 53.4 (51.9-54.8). Ninety-nine (41.8%) were admitted for acute bleeding and the remainder were admitted for nonbleeding illnesses. FIB level on admission correlated strongly with disease severity. After adjusting for disease severity, FIB on admission was not an independent predictor of 30-day survival (hazard ratio [HR]: 0.99, 95% CI: 0.99-1.01, p = 0.68). CRYO transfusion increased FIB levels but had no independent effect on mortality or bleeding complications (HR: 1.10, 95% CI: 0.72-1.70, p = 0.65). CONCLUSION: In cirrhosis patients with critical illness, low FIB levels on presentation reflect severity of illness but are not independently associated with 30-day mortality. Treatment of low FIB with CRYO also does not affect survival or bleeding complications, suggesting FIB is an additional marker of severity of illness but is not itself a direct factor in the pathophysiology of bleeding in critically ill cirrhosis patients.

Rates of Bleeding and Discontinuation of Direct Oral Anticoagulants in Patients With Decompensated Cirrhosis.

BACKGROUND & AIMS: Studies of the effects of direct oral anticoagulants (DOACs) in patients with cirrhosis have been limited by their small sample size, inclusion of patients with well-compensated cirrhosis, short follow-up times, inadequate validation of cirrhosis diagnoses, and non-standard definitions of bleeding. We aimed to systematically determine the characteristics, indications, and outcomes of patients with cirrhosis of all severity classes who received DOACs. METHODS: We performed a retrospective study of 138 patients with confirmed cirrhosis (93 with Child-Turcotte-Pugh scores of B or C) at a single center who started DOAC therapy (58,984 person-days; median, 181 days per patient) from September 2011 through April 2019. We collected data on clinical characteristics, indications for DOAC use, and outcomes. Standardized and validated definitions for bleeding complications were used. RESULTS: Twenty-nine patients (21%) stopped therapy due to a diagnosis of or perceived bleeding. The most common bleeding events were non-variceal upper and lower intestinal bleeding. No pretreatment laboratory parameters were associated with bleeding while patients received treatment, including platelet count (P = .50), international normalized ratio (P = .34), creatinine (P = .27), and model for end-stage liver disease score (P = .22). Frequency of bleeding events related to DOAC did not differ significantly among patients of different Child-Turcotte-Pugh classes (P = .81), DOAC indications (P = .60), or DOAC dosages (P = .10). Higher proportions of patients with hepatocellular carcinoma (P = .01) had major bleeding while receiving. CONCLUSIONS: Patients with decompensated cirrhosis have significant bleeding and rates of discontinuation of DOACs when they take them long term. Pretreatment laboratory parameters, DOAC dose, and Child-Turcotte-Pugh class were not associated with bleeding; hepatocellular carcinoma was associated with major bleeding.

The Changing Burden of Alcoholic Hepatitis: Rising Incidence and Associations with Age, Gender, Race, and Geography.

Alcoholic hepatitis is a major cause of morbidity and mortality. However, there are limited population-based data on its incidence, demographics, and temporal trends. We performed a retrospective cohort study using the State Inpatient Databases from Florida, Massachusetts, New York, and Washington from 2010 to 2014. We included patients aged 20-79 years admitted with alcoholic hepatitis and calculated incidence using population denominators obtained from the Centers for Disease Control and Prevention WONDER database. We fit multivariable Poisson regression models to explore interactions between alcoholic hepatitis incidence rates and several predictors including state, calendar year, age, race/ethnicity, and gender. Among 56,973 unique individuals with alcoholic hepatitis, the majority were male (39,702; 69.7%) and white non-Hispanic (40,934; 72.0%). In multivariable Poisson models, there was a significant interaction between calendar year and age group (p < 0.001), with the highest incidence rates in those ages 40-49 and 50-59 across all years. The absolute increase in incidence rate across calendar years was highest in the 20-29 and 30-39 age groups in every state. Female gender was associated with a lower rate (incidence rate ratio (IRR) 0.42, 95% confidence interval (CI) 0.41-0.42, p < 0.001). Compared to white non-Hispanics, black non-Hispanics (IRR 0.79, CI 0.77-0.81, p < 0.001) and Hispanics (0.66, CI 0.65-0.68, p < 0.001) had lower incidence rates. The incidence of alcoholic hepatitis in the USA varies by age, gender, race/ethnicity, and state of residence. The group with the fastest rising incidence is those aged 20-39. More work is needed to evaluate the reasons for the temporal trends for admissions for alcoholic hepatitis.

The Spectrum of Disease Severity in Cirrhosis and Its Implications for Hemostasis.

Bleeding and thrombosis are both common complications that patients with advanced liver disease experience. While hemostatic pathways remain largely intact with cirrhosis, this balance can quickly shift in the direction of bleeding or clotting in an unpredictable manner. A growing body of literature is attempting to shed light on difficult scenarios that clinicians often face, ranging from predicting and mitigating bleeding risk in those who need invasive procedures to determining the best strategies to manage both bleeding and thrombotic complications when they occur. Studies examining hemostasis in those with advanced liver disease, however, often include heterogeneous cohorts with varied methodology. While these studies often select a cohort of all types and degrees of cirrhosis, emerging evidence suggests significant differences in underlying systemic inflammation and hemostatic abnormalities among specific phenotypes of liver disease, ranging from compensated cirrhosis to decompensated cirrhosis and acute-on-chronic liver failure. It is paramount that future studies account for these differing disease severities if we hope to address the many critical knowledge gaps in this field.

Coagulation testing and management in liver disease patients.

PURPOSE OF REVIEW: The present article aims to provide clinicians with an overview of coagulation testing in individuals with liver disease, to discuss available procoagulants and the rationale for their use, and to provide management strategies in a variety of common clinical scenarios. RECENT FINDINGS: Clinicians and researchers are gaining an increased understanding of the shortfalls of assessing bleeding risk using traditional tests of coagulation. The use of global tests of clot formation, including viscoelastic testing and thrombin generation analysis, continues to evolve and guide the management of these patients. SUMMARY: Abnormal coagulation testing in individuals with cirrhosis leads to a variety of difficult clinical scenarios that can be challenging for practitioners. With advanced liver disease, changes in the traditional tests of hemostasis such as the international normalized ratio reflect decreased synthesis of procoagulant factors but do not capture concomitant decreases in anticoagulant factors. In this setting, transfusion thresholds targeting platelet and fibrinogen goals may provide an effective strategy to optimize clot formation. Global tests of clot formation provide practical information to clinicians and can help guide decision making, although optimal target levels have not been validated.

Rate and predictors of successful cardiopulmonary resuscitation in end-stage liver disease.

BACKGROUND: Cardiopulmonary resuscitation (CPR) after cardiac arrest in terminally ill patients is controversial. End-stage liver disease (ESLD) patients are unique from other terminally ill as they are generally younger and may be candidates for curative liver transplantation, but multiple studies have suggested poor outcomes when these patients require CPR. Predictors of success of CPR in ESLD have not been fully investigated, limiting end-of-life discussions. AIM: The aim of this study was to quantify the rate and predictors of successful CPR in ESLD. METHODS: We performed a retrospective chart review of patients with ESLD who received CPR from 2/2002 to 12/2013 at a single institution. Pre-cardiac arrest variables were collected for analysis as predictors of survival. Our primary outcome was survival to hospital discharge. RESULTS: Of the 38 patients who underwent CPR, six survived to hospital discharge. When comparing those who survived to discharge with those who did not, we found no significant difference in age (p = 0.34), gender (p = 0.85), presence of ascites (p = 0.67), location at time of arrest (p = 0.39), concurrent GI bleeding (p = 0.48), and multiple individual lab values. Significant predictors of not surviving to hospital discharge were a model for end-stage liver disease (MELD) ≥ 20 (OR 6.0, p = 0.044) and presentation with a non-shockable rhythm (PEA/asystole) (OR 29, p < 0.001). CONCLUSION: ESLD patients requiring CPR have worse outcomes as their MELD score increases. CPR in ESLD when MELD is <20 or with a shockable rhythm has a greater likelihood of success.