Development and First Clinical Use of an Extracorporeal Artificial Multiorgan System in Acute-on-Chronic Liver Failure Patients.

Multiple organ failure (MOF) is a common and deadly condition. Patients with liver cirrhosis with acute-on-chronic liver failure (AOCLF) are particularly susceptible. Excess fluid accumulation in tissues makes routine hemodialysis generally ineffective because of cardiovascular instability. Patients with three or more organ failures face a mortality rate of more than 90%. Many cannot survive liver transplantation. Extracorporeal support systems like MARS (Baxter, Deerfield, IL) and Prometheus (Bad Homburg, Germany) have shown promise but fall short in bridging patients to transplantation. A novel Artificial Multi-organ Replacement System (AMOR) was developed at the University of Washington Medical Center. AMOR removes protein-bound toxins through a combination of albumin dialysis, a charcoal sorbent column, and a novel rinsing method to prevent sorbent column saturation. It removes excess fluid through hemodialysis. Ten AOCLF patients with over three organ failures were treated by the AMOR system. All patients showed significant clinical improvement. Fifty percent of the cohort received liver transplants or recovered liver function. AMOR was successful in removing large amounts of excess body fluid, which regular hemodialysis could not. AMOR is cost-effective and user-friendly. It removes excess fluid, supporting the other vital organs such as liver, kidneys, lungs, and heart. This pilot study's results encourage further exploration of AMOR for treating MOF patients.

Role of Underlying Liver Pathology in the Development of Immune-Related Hepatitis: A Case-Control Study.

BACKGROUND: Immune-related hepatitis (irH) is a serious immune-related adverse event (IRAE) that may result in morbidity, immune checkpoint inhibitor (ICI) therapy interruption and, rarely, mortality. The impact of underlying liver pathology, including liver metastasis, on the incidence of irH remains poorly understood. OBJECTIVES: We hypothesized that the presence of underlying liver pathology increased the risk of irH in patients with cancer treated with ICI. PATIENTS AND METHODS: We conducted a retrospective case-control study of irH in patients with cancer receiving first ICI treatment from 2016-2020. Provider documented cases of ≥ grade 2 irH were identified and control matched in a 2:1 ratio based on age, sex, time of ICI initiation, and follow-up time. Conditional logistic regression was used to estimate the relationship between irH and liver metastasis at ICI initiation. RESULTS: Ninety-seven cases of irH were identified, 29% of which had liver metastases at time of ICI initiation. Thirty-eight percent of patients developed grade 2, 47% grade 3, and 14% grade 4 irH. When adjusted for covariates/confounders, the presence of liver metastasis was associated with increased odds of irH (aOR 2.79 95% CI 1.37-5.66, p = 0.005). The presence of liver metastases did not correlate with irH grade or rate of irH recurrence after ICI rechallenge. CONCLUSIONS: Presence of liver metastases increased the odds of irH in patients with first-time ICI therapy. Limitations include the retrospective nature, moderate sample size, possible selection bias and confounding. Our findings are hypothesis-generating and warrant external validation as well as tissue and circulating biomarker exploration.

Copper Deficiency in Liver Diseases: A Case Series and Pathophysiological Considerations.

Copper is an indispensable trace element. It serves as a cofactor for enzymes involved in cellular energy metabolism, antioxidant defense, iron transport, and fibrogenesis. Although these processes are central in the pathogenesis of liver disorders, few studies have attributed them to copper deficiency. We herein describe in detail a case series of liver disease patients (n = 12) who presented with signs of copper deficiency based on serum and liver copper measurements. Median age of the group at the time of presentation was 39 (range 18-64 years). Six patients were female. The median serum copper was 46 µg/dL (normal range: 80-155 µg/dL for women and 70-140 µg/dL for men). Seven of the 12 patients had hepatic copper concentration less than 10 µg/g dry weight (normal range: 10-35 µg/g). Most cases presented with acute-on-chronic liver failure (n = 4) and decompensated cirrhosis (n = 5). Only 3 patients had a condition known to be associated with copper deficiency (ileocolonic Crohn's disease following resection n = 1, Roux-en-Y gastric bypass n = 2) before presenting with hepatic dysfunction. Notable clinical features included steatohepatitis, iron overload, malnutrition, and recurrent infections. In 2 of the 3 patients who received copper supplementation, there was an improvement in serum copper, ceruloplasmin, and liver function parameters. Conclusion: Copper deficiency in the serum or liver occurs in a wide range of liver diseases. Given the biological essentiality of copper, the mechanism and clinical significance of this association require systematic study.

Toward consensus reporting of radiation-induced liver toxicity in the treatment of primary liver malignancies: Defining clinically relevant endpoints.

BACKGROUND: Our purpose was to define the most clinically relevant "nonclassic" radiation-induced liver disease (RILD) endpoints in cirrhotic patients receiving stereotactic body radiation therapy or proton beam therapy for primary liver cancer. METHODS AND MATERIALS: We retrospectively collected pretreatment, detailed toxicity (≤6 months posttreatment), and outcomes data from 48 patients. Deaths were examined for association with RILD. Univariate and multivariate Cox models defined significant predictors of overall survival (OS)/RILD-specific survival (RILD-SS). RESULTS: With median follow-up of 13 months, 23 patients (48%) had an increase in Child-Pugh (CP) score (≥2, 25%) and 3 (6%) had ≥G3 transaminase elevation. Of 18 deaths, 6 were potentially ascribed to RILD. Univariate analysis showed that CP score increases of ≥1 and ≥2 and CP class change predicted OS, as did ≥G3 aspartate transaminase (AST) elevation and ≥1 Common Terminology Criteria for Adverse Events (CTCAE) AST toxicity grade change. On multivariate analysis, CP score increase of ≥2 and ≥1 CTCAE AST toxicity grade change were the strongest independent nonclassic RILD predictors of OS. For RILD-SS, CP score increases of ≥2, ≥grade 3 CTCAE alanine transaminase, and ≥grade 2 bilirubin elevations were predictive. CONCLUSIONS: Increased CP score ≥2 strongly predicts for both OS and RILD-SS and should be reported in future studies along with transaminase elevations, which are also predictive of outcomes.

Acute Liver Failure Due to Echovirus 9 Associated With Persistent B-Cell Depletion From Rituximab.

We describe a case of fatal acute liver failure due to echovirus 9 in the setting of persistent B-cell depletion and hypogammaglobulinemia 3 years after rituximab therapy. Metagenomic next-generation sequencing further specified the etiologic agent. Early recognition may provide an opportunity for interventions including intravenous immunoglobulin and liver transplantation.

Measuring total liver function on sulfur colloid SPECT/CT for improved risk stratification and outcome prediction of hepatocellular carcinoma patients.

BACKGROUND: Assessment of liver function is critical in hepatocellular carcinoma (HCC) patient management. We evaluated parameters of [(99m)Tc] sulfur colloid (SC) SPECT/CT liver uptake for association with clinical measures of liver function and outcome in HCC patients. METHODS: Thirty patients with HCC and variable Child-Turcotte-Pugh scores (CTP A5-C10) underwent [(99m)Tc]SC SPECT/CT scans for radiotherapy planning. Gross tumor volume (GTV), anatomic liver volume (ALV), and spleen were contoured on CT. SC SPECT image parameters include threshold-based functional liver volumes (FLV) relative to ALV, mean liver-to-spleen uptake ratio (L/Smean), and total liver function (TLF) ratio derived from the product of FLV and L/Smean. Optimal SC uptake thresholds were determined by ROC analysis for maximizing CTP classification accuracy. Image metrics were tested for rank correlation to composite scores and clinical liver function parameters. Image parameters of liver function were tested for association to overall survival with Cox proportional hazard regression. RESULTS: Optimized thresholds on SC SPECT were 58 % of maximum uptake for FLV, 38 % for L/Smean, and 58 % for TLF. TLF produced the highest CTP classification accuracy (AUC = 0.93) at threshold of 0.35 (sensitivity = 0.88, specificity = 0.86). Higher TLF was associated with lower CTP score: TLFA = 0.6 (0.4-0.8) versus TLFB = 0.2 (0.1-0.3), p < 10(-4). TLF was rank correlated to albumin and bilirubin (|R| > 0.63). Only TLF >0.30 was independently associated with overall survival when adjusting for CTP class (HR = 0.12, 95 % CI = 0.02-0.58, p = 0.008). CONCLUSIONS: SC SPECT/CT liver uptake correlated with differential liver function. TLF was associated with improved overall survival and may aid in personalized oncologic management of HCC patients.

Association Between Transjugular Intrahepatic Portosystemic Shunt and Survival in Patients With Cirrhosis.

BACKGROUND & AIMS: A transjugular intrahepatic portosystemic shunt (TIPS) is an effective treatment of refractory ascites and variceal bleeding. However, it is unclear whether a TIPS affects long-term survival. We investigated whether a TIPS is associated with survival in patients with cirrhosis awaiting liver transplantation. METHODS: By using the United Network for Organ Sharing registries from 2002 to 2013, we followed up a cohort of transplant-naive adults with cirrhosis (N = 97,063) from the time of transplant listing until the time of death or transplantation. We used Cox proportional hazards and competing-risks analyses to compare these primary outcomes between patients with a TIPS (n = 7475; 7.7%) and without a TIPS (n = 89,588; 92.3%) at the time of listing, adjusting for baseline characteristics. RESULTS: During an average follow-up period of 1.61 years, 23,305 (24%) patients died before undergoing transplantation, 47,563 (49%) underwent transplantation, and the remaining 26,195 (27%) still were alive without having received a liver transplant. Compared with patients without a TIPS, patients with a TIPS had a lower risk of death (adjusted subhazard ratio, 0.95; 95% confidence interval, 0.9-0.99), transplantation (adjusted subhazard ratio, 0.92, 95% confidence interval, 0.88-0.95), or the combined outcome of death or transplantation (adjusted hazard ratio, 0.85; 95% confidence interval, 0.83-0.88). CONCLUSIONS: Among patients with cirrhosis awaiting liver transplantation, patients with a TIPS had a lower mortality rate than patients without a TIPS.

Aging of Liver Transplant Registrants and Recipients: Trends and Impact on Waitlist Outcomes, Post-Transplantation Outcomes, and Transplant-Related Survival Benefit.

BACKGROUND & AIMS: Epidemiologic factors have generated increased demand for liver transplantation among older patients. We aimed to describe trends in age among liver transplant registrants and recipients and the effect of age on waitlist and post-transplantation outcomes and on transplant-related survival benefit. METHODS: We obtained data from the United Network for Organ Sharing on adults who were listed for liver transplantation (N = 122,606) or underwent liver transplantation (N = 60,820) from 2002 to 2014 in the United States. Competing risks analysis was used to model waitlist outcomes and Cox proportional hazards analysis to model post-transplantation survival. These models were also used to estimate 5-year transplant-related survival benefit for different age groups, calculated as the difference between waitlist and post-transplantation life expectancy. RESULTS: Between 2002 and 2014, the mean age of liver transplant registrants increased from 51.2 to 55.7 years, with a more prominent increase in hepatitis C virus-positive (50.9-57.9 years) than hepatitis C virus-negative (51.3-54.3 years) registrants. The proportion of registrants aged ≥60 years increased from 19% to 41%. In hepatitis C virus-negative patients, aging trends were driven by increasing proportions of patients with hepatocellular carcinoma or nonalcoholic steatohepatitis. Among transplant registrants, increasing age was associated with increasing mortality before transplantation and decreasing likelihood of transplantation. Among transplant recipients, increasing age was associated with increasing post-transplantation mortality. There was little difference in 5-year transplant-related survival benefit between different age groups who had the same Model for End-Stage Liver Disease score. CONCLUSIONS: Dramatic aging of liver transplant registrants and recipients occurred from 2002 to 2014, driven by aging of the hepatitis C virus-positive cohort and increased prevalence of nonalcoholic steatohepatitis and hepatocellular carcinoma. Increasing age does not affect transplant-related survival benefit substantially because age diminishes both post-transplantation survival and waitlist survival approximately equally.

Comprehensive Care of Patients with Chronic Liver Disease.

Chronic liver disease results from a wide range of conditions, for which individual management is beyond the scope of this article. General education, counseling, and harm reduction practices are important to the primary care of these patients, as are monitoring for cirrhosis and management of its complications. For patients with advanced liver disease, comprehensive care includes considering referral for liver transplantation, educating and empowering patients to prioritize goals of care, and optimizing symptom relief.

Transjugular Intrahepatic Portosystemic Shunt Placement During Pregnancy: A Case Series of Five Patients.

BACKGROUND AND AIMS: Complications of portal hypertension, such as variceal hemorrhage and ascites, are associated with significant increases in both mortality and complications during pregnancy. Transjugular intrahepatic portosystemic shunt (TIPS) is a well-established procedure for treating portal hypertension, but the safety of TIPS during pregnancy is largely unknown. In this series, we review five patients who underwent TIPS placement while pregnant and describe their clinical outcomes. METHODS: Five pregnant patients with cirrhosis and portal hypertension underwent elective TIPS for complications of portal hypertension (four for secondary prevention of variceal bleeding and one for refractory ascites). Outcomes measured were recurrent bleeding episodes or need for further paracenteses during pregnancy, estimated radiation dose to the fetus and gestational age at delivery. All patients were followed after delivery to evaluate technical and clinical success of the procedure. RESULTS: All five patients survived pregnancy and went on to deliver successfully. When TIPS was performed for secondary prevention of variceal bleeding (n = 4), no patients demonstrated variceal bleeding after TIPS placement. When TIPS was performed for refractory ascites (n = 1), no further paracenteses were required. All patients delivered successfully, albeit prematurely. Average radiation dose estimated to the fetus was 16.3 mGy. CONCLUSIONS: This series suggests that TIPS can be performed in selective pregnant patients with portal hypertension, with little added risk to the mother or fetus.

Portal vein thrombosis is not associated with increased mortality among patients with cirrhosis.

BACKGROUND & AIMS: Portal vein thrombosis (PVT) is common in patients with cirrhosis and may have adverse clinical consequences. We investigated whether PVT is associated with survival in patients with cirrhosis. METHODS: Using the United Network for Organ Sharing registries from 2002 through 2013, we followed a cohort of transplant-naive adults with cirrhosis without hepatocellular carcinoma (N = 66,506) from the time of transplant listing until the time of liver transplantation or death before transplantation. We used Cox proportional hazards analysis and competing risks analysis to compare patients who had PVT at the time of listing (n = 2207) with those who did not (n = 64,299) with regard to the risk of transplantation or death before transplantation, after adjusting for important baseline characteristics. RESULTS: During a mean follow-up period of 1.78 years, 17,757 (27%) patients died before liver transplantation, 29,179 (44%) patients underwent transplantation, and 19,570 (29%) patients were still alive without having undergone transplantation. Compared with patients who did not have PVT, patients with PVT had lower mortality (adjusted hazard ratio [AHR], 0.88; 95% confidence interval [CI], 0.81-0.96), a similar risk of transplantation (AHR, 0.95; 95% CI, 0.89-1.02), and a lower risk of the combined outcome of death or transplantation (AHR, 0.92; 95% CI, 0.88-0.97). Similar results were found by competing risks analyses. Independent predictors of mortality included age, model for end-stage liver disease score, serum albumin level, ascites, encephalopathy, diabetes, hepatitis C virus infection, and low body mass index (<24.4 kg/m(2)). CONCLUSIONS: Among patients with cirrhosis on liver transplant waiting lists, patients with PVT have lower mortality than patients without PVT.

D-MELD risk capping improves post-transplant and overall mortality under markov microsimulation.

AIM: To hypothesize that the product of calculated Model for End-Stage Liver Disease score excluding exception points and donor age (D-MELD) risk capping ± Rule 14 could improve post liver transplant and overall survival after listing. METHODS: Probabilities derived from the United Network for Organ Sharing database between 2002 and 2004 were used to simulate potential outcomes for all patients listed for transplantation. The Markov simulation was then modified by screening matches using a 1200 or 1600 D-MELD risk cap ± allowing transplants for Model for End-Stage Liver Disease (MELD) ≤ 14 (Rule 14). The differential impact of the rule changes was assessed. RESULTS: The Markov simulation accurately reproduced overall and post transplant survival. A 1200 D-MELD risk cap improved post-transplant survival. Both the 1200 and 1600 risk caps improved overall survival for waitlisted patients. The addition of Rule 14 further improved post transplant and overall survival by redistribution of donor livers to recipients in higher MELD subgroups. The mechanism for improved overall and post-transplant survival after listing was due to shifting a larger percentage of transplants to the moderate MELD score subgroup (MELD 15-29) while also ensuring that high MELD recipients have livers of high quality to achieve excellent post transplant survival. CONCLUSION: A 1200 D-MELD risk cap + Rule 14 provided the greatest overall benefit primarily by focusing liver transplantation towards the moderate MELD recipient.

Congestive hepatic fibrosis score: a novel histologic assessment of clinical severity.

Chronic right heart failure predisposes to hepatic passive congestion and centrizonal necrosis that may lead to hepatic fibrosis (cardiac sclerosis). Although there have been several studies on the histologic features of congestive hepatopathy, there is no available grading system. In this study we developed a novel grading system for congestive hepatic fibrosis. Liver biopsies were examined in patients with chronic heart failure of various etiologies including congenital heart disease, idiopathic cardiomyopathy, ischemic heart disease, and valvular heart disease. The cases with available echocardiography and/or right heart catheterization were included. Cases with other types of underlying chronic liver diseases, alcoholic liver disease, significant steatosis (>20%), malignant neoplasm, and acute heart failure or shock were excluded. After exclusion, 42 cases were included in the study. We herein proposed a novel congestive hepatic fibrosis score and correlated it with the right heart structure and function obtained by echocardiography and/or right heart catheterization. Our results showed that congestive hepatic fibrosis score is well correlated with the right atrial pressure (P for trend <0.001). The presence of portal fibrosis (congestive hepatic fibrosis scores 2 and 3) is associated with significantly higher right atrial pressure than those with no fibrosis (P<0.001) or with centrizonal fibrosis only (P=0.02). Congestive hepatic fibrosis score is also significantly associated with increasing severity of right atrial dilatation (P=0.03) and right ventricular dilatation (P=0.02), indicators for chronic volume and/or pressure overload. Other histopathologic features include sinusoidal dilatation and centrizonal hepatocyte atrophy. In summary, although sinusoidal dilatation and centrizonal fibrosis are the hallmarks of hepatic passive congestion, the presence of portal fibrosis is suggestive of more advanced disease, as it correlates with more severe impairment of right heart function, regardless of the etiologies of right heart failure. Congestive hepatic fibrosis score is a useful indicator of clinical severity.

Management of end-stage liver disease.

Patients with cirrhosis who experience hepatic decompensation, such as the development of ascites, SBP, variceal hemorrhage, or hepatic encephalopathy, or who develop HCC, are at a higher risk of mortality. Management should be focused on the prevention of recurrence of complications, and these patients should be referred for consideration of liver transplantation.

Proteome and computational analyses reveal new insights into the mechanisms of hepatitis C virus-mediated liver disease posttransplantation.

UNLABELLED: Liver transplant tissues offer the unique opportunity to model the longitudinal protein abundance changes occurring during hepatitis C virus (HCV)-associated liver disease progression in vivo. In this study, our goal was to identify molecular signatures, and potential key regulatory proteins, representative of the processes influencing early progression to fibrosis. We performed global protein profiling analyses on 24 liver biopsy specimens obtained from 15 HCV(+) liver transplant recipients at 6 and/or 12 months posttransplantation. Differentially regulated proteins associated with early progression to fibrosis were identified by analysis of the area under the receiver operating characteristic curve. Analysis of serum metabolites was performed on samples obtained from an independent cohort of 60 HCV(+) liver transplant patients. Computational modeling approaches were applied to identify potential key regulatory proteins of liver fibrogenesis. Among 4,324 proteins identified, 250 exhibited significant differential regulation in patients with rapidly progressive fibrosis. Patients with rapid fibrosis progression exhibited enrichment in differentially regulated proteins associated with various immune, hepatoprotective, and fibrogenic processes. The observed increase in proinflammatory activity and impairment in antioxidant defenses suggests that patients who develop significant liver injury experience elevated oxidative stresses. This was supported by an independent study demonstrating the altered abundance of oxidative stress-associated serum metabolites in patients who develop severe liver injury. Computational modeling approaches further highlight a potentially important link between HCV-associated oxidative stress and epigenetic regulatory mechanisms impacting on liver fibrogenesis. CONCLUSION: Our proteome and metabolome analyses provide new insights into the role for increased oxidative stress in the rapid fibrosis progression observed in HCV(+) liver transplant recipients. These findings may prove useful in prognostic applications for predicting early progression to fibrosis.

Role of liver transplantation in acute liver failure.

Orthotopic liver transplantation is employed as salvage therapy for individuals who are unable to recover from acute liver failure. Prognostic models are helpful but not entirely accurate in predicting those who will eventually require liver transplantation. There are specific criteria for United Network for Organ Sharing category 1a (urgent) listing of these patients. Unfortunately, clinical deterioration develops rapidly and many require removal from the waiting list prior to transplantation. With advances in critical care management and surgical technique, 1-year post-transplant survival rates have improved to 60 to 80%. Alternatives to conventional orthotopic liver transplantation include living donor liver transplantation, ABO-incompatible grafts, and auxiliary liver transplantation. There are many ethical and psychosocial issues inherent to transplanting these sick patients due to the urgent nature of acute liver failure. Fortunately, the long-term survival and quality of life in these transplant recipients is good.