Characterisation of an outbreak of acute liver injury after ingestion of plant-based food supplement.

BACKGROUND: In April 2022, French Lentil and Leek Crumble (FLLC), a new frozen food preparation manufactured by Daily Harvest™ (containing Tara flour) was offered as a natural high-protein meal product. Soon thereafter, widespread anecdotal reports of acute gastrointestinal symptoms with liver injury were reported, leading to its voluntary withdrawal in June 2022, after shipment of 28,000 preparations. AIMS: To summarise the clinical and laboratory features of 17 patients with FLLC associated liver injury from the Drug Induced Liver Injury Network (DILIN). METHODS: Patients with FLLC-associated liver injury were enrolled into a prospective protocol and followed for 6 months. Cases were adjudicated by expert opinion causality assessment with summary statistics for data analysis. RESULTS: Enrolled subjects had a mean age of 41 years, 82% were female with mean BMI of 24 kg/m2. All were Caucasian without underlying liver disease. In most cases, abdominal pain and nausea arose within hours of FLLC ingestion. Mean days from ingestion to identification of liver injury was 3.1 days (±2.8). On enrolment, 53% had jaundice, 47% nausea, 24% fever, 59% abdominal pain, 41% itching and 12% rash. The mean initial serum ALT was 475 U/L (±302), AST 315 U/L (±315), alkaline phosphatase 190 U/L (±76), with a total bilirubin of 2.6 mg/dL (±2). In this study, 63% presented with a hepatocellular pattern of liver injury, 6% cholestatic and 31% mixed as determined by the R value. In addition, 24% of patients were hospitalised, and there were no fatalities or liver transplants. Liver biopsy in one subject revealed acute hepatitis with mild ductular reaction, mild lymphocytic and eosinophilic portal inflammation, mild lobular inflammation, preserved bile ducts and absence of interface hepatitis, steatosis, granulomatous reaction or cholestasis. Phylogenetic analysis confirmed the presence of Tara spinosa, the source of Tara flour. CONCLUSIONS: Natural food products are increasingly ubiquitous and may unexpectedly cause significant illness. All clinicians should inquire whether patients are consuming natural food products or herbal supplements and consider them as a potential cause of liver injury.

Social Impact of Hepatic Encephalopathy.

Hepatic encephalopathy is a medical condition that stems from liver dysfunction, leading to the accumulation of toxins in the bloodstream. This can result in cognitive impairments, mood changes, and motor dysfunction. Its social impact includes challenges in employment, relationships, and daily functioning for affected individuals. Stigma and misunderstanding around the condition can further exacerbate the difficulties faced by both patients and their caregivers. Efforts to raise awareness, improve medical management, and provide support systems can help mitigate the social impact of hepatic encephalopathy.

The Evolution of Redo Liver Transplantation Over 35 Years: Analysis of 654 Consecutive Adult Liver Retransplants at a Single Center.

OBJECTIVE: To examine liver retransplantation (ReLT) over 35 years at a single center. BACKGROUND: Despite the durability of liver transplantation (LT), graft failure affects up to 40% of LT recipients. METHODS: All adult ReLTs from 1984 to 2021 were analyzed. Comparisons were made between ReLTs in the pre versus post-model for end-stage liver disease (MELD) eras and between ReLTs and primary-LTs in the modern era. Multivariate analysis was used for prognostic modeling. RESULTS: Six hundred fifty-four ReLTs were performed in 590 recipients. There were 372 pre-MELD ReLTs and 282 post-MELD ReLTs. Of the ReLT recipients, 89% had one previous LT, whereas 11% had ≥2. Primary nonfunction was the most common indication in the pre-MELD era (33%) versus recurrent disease (24%) in the post-MELD era. Post-MELD ReLT recipients were older (53 vs 48, P = 0.001), had higher MELD scores (35 vs 31, P = 0.01), and had more comorbidities. However, post-MELD ReLT patients had superior 1, 5, and 10-year survival compared with pre-MELD ReLT (75%, 60%, and 43% vs 53%, 43%, and 35%, respectively, P < 0.001) and lower in-hospital mortality and rejection rates. Notably, in the post-MELD era, the MELD score did not affect survival. We identified the following risk factors for early mortality (≤12 months after ReLT): coronary artery disease, obesity, ventilatory support, older recipient age, and longer pre-ReLT hospital stay. CONCLUSIONS: This represents the largest single-center ReLT report to date. Despite the increased acuity and complexity of ReLT patients, post-MELD era outcomes have improved. With careful patient selection, these results support the efficacy and survival benefit of ReLT in an acuity-based allocation environment.

Preparation of matrix-matched standards for the analysis of teeth via laser ablation-inductively coupled plasma-mass spectrometry.

Mineralised tissue such as teeth can serve as a retrospective, chronological bioindicator of past exposure to toxic metals. Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) can be used to determine the presence and spatial distribution of toxic metals in teeth, giving a record of when an exposure occurred. Concentrations of these metals are often determined by a one-point calibration against NIST glass using an equation that requires an internal standard factor that accounts for differences in ablation behaviour between the glass and the tooth. However, an ideal external calibration would contain multiple matrix-matched standards to obtain a calibration curve. Here, we investigated optimal procedures for preparing synthetic hydroxyapatite (HA) doped with elements of interest as a calibration material. The materials were examined for homogeneity of metal incorporation, matrix-matched ablation characteristics, linearity, and limits of detection. A homogenised and pelleted HA was the most suitable material, providing improved ablation characteristics over previous HA materials and NIST glass for the analysis of teeth. An ablation yield of 1.1 showed its suitability to analyse teeth, the metals were homogeneously incorporated, and it produced excellent linearity with limits of detection ranging from 0.1-2 µg kg-1 for magnesium, aluminium, nickel, copper, zinc, cadmium, barium and lead. A juvenile incisor from a remote indigenous community in Australia and an adult molar from Sri Lanka were assessed for toxic metal exposure. The molar showed evidence of exposure to cadmium and lead. The synthetic HA material was straightforward to prepare, and will improve confidence in the analysis of teeth and other biomineralised material when assessing toxic metal exposure.

Cost-effective methylome sequencing of cell-free DNA for accurately detecting and locating cancer.

Early cancer detection by cell-free DNA faces multiple challenges: low fraction of tumor cell-free DNA, molecular heterogeneity of cancer, and sample sizes that are not sufficient to reflect diverse patient populations. Here, we develop a cancer detection approach to address these challenges. It consists of an assay, cfMethyl-Seq, for cost-effective sequencing of the cell-free DNA methylome (with > 12-fold enrichment over whole genome bisulfite sequencing in CpG islands), and a computational method to extract methylation information and diagnose patients. Applying our approach to 408 colon, liver, lung, and stomach cancer patients and controls, at 97.9% specificity we achieve 80.7% and 74.5% sensitivity in detecting all-stage and early-stage cancer, and 89.1% and 85.0% accuracy for locating tissue-of-origin of all-stage and early-stage cancer, respectively. Our approach cost-effectively retains methylome profiles of cancer abnormalities, allowing us to learn new features and expand to other cancer types as training cohorts grow.

Barriers for Liver Transplant in Patients with Alcohol-Related Hepatitis.

BACKGROUND: Liver transplantation (LT) for alcohol-related liver disease has historically been reserved for patients who have been six months abstinent. Given the increasing incidence of alcohol-related hepatitis (AH) and dismal survival in patients who fail medical therapy, transplant centers are extending their acceptance criteria for patients with less than 6 months of sobriety. We sought to determine the barriers for listing. METHODS: We conducted a retrospective chart review of all inpatient LT referrals for a diagnosis of AH between September 2019 and December 2020. LT evaluations were performed by a multidisciplinary team. Descriptive statistics were reported using mean and standard deviation (SD) or percentage where appropriate. RESULTS: During our study period, 82 patients were evaluated for LT. Of these 82 patients, 62 were declined for liver transplantation. The mean (SD) age of the 62-patient cohort was 44 years (10.7), and most patients were men. The mean (SD) number of reasons for denial was 2 (0.97). Four patients had medical contraindications for transplant. Twenty-seven (44%) and 35 (56%) patients lacked insight and were at risk of alcohol relapse, respectively. Forty-three (69%) and fourteen (22.5%) patients had insufficient social support and an inability to maintain a therapeutic relationship with the transplant team, respectively. CONCLUSION: Patients are more likely denied for psychosocial factors than medical comorbidities. The majority were due to lack of insight, insufficient social support, and inability to maintain a therapeutic relationship with the transplant team. Resources should be allocated to address these issues.

AL Lambda Amyloidosis Activates Acute Liver Failure in the Absence of Plasma Cell Dyscrasia.

A patient with systemic amyloidosis developed portal hypertension, acute liver failure and multiorgan dysfunction. Extensive testing was unrevealing for paraproteinemia, plasma cell dyscrasia, infectious, or inflammatory conditions. He was transferred to our institution for orthotopic liver transplant evaluation but was ultimately declined given clinical instability and dysautonomia. Post-mortem evaluation revealed extensive amyloid deposition in multiple organs determined to be AL-lambda amyloidosis.

Duodenal Microbiome and Serum Metabolites Predict Hepatocellular Carcinoma in a Multicenter Cohort of Patients with Cirrhosis.

BACKGROUND: Hepatocellular carcinoma (HCC) is rapidly increasing in the U.S. and is a leading cause of mortality for patients with cirrhosis. Discovering novel biomarkers for risk stratification of HCC is paramount. We examined biomarkers of the gut-liver axis in a prospective multicenter cohort. METHODS: Patients with cirrhosis without a history of HCC were recruited between May 2015 and March 2020 and prospectively followed at 3 tertiary care hospitals in Los Angeles. Microbiome analysis was performed on duodenal biopsies and metabolomic analysis was performed on serum samples, collected at the time of enrollment. Optimal microbiome-based survival analysis and Cox proportional hazards regression analysis were used to determine microbiota and metabolite associations with HCC development, respectively. RESULTS: A total of 227 participants with liver cirrhosis contributed a total of 459.58 person-years of follow-up, with 14 incident HCC diagnoses. Male sex (HR = 7.06, 95% CI = 1.02-54.86) and baseline hepatic encephalopathy (HE, HR = 4.65, 95% CI = 1.60-13.52) were associated with developing HCC over follow-up. Adjusting for age, sex, baseline HE, and alkaline phosphatase, an increased risk of HCC were observed for participants with the highest versus lowest three quartiles for duodenal Alloprevotella (HR = 3.22, 95% CI = 1.06-9.73) and serum taurocholic acid (HR = 6.87, 95% CI = 2.32-20.27), methionine (HR = 9.97, 95% CI = 3.02-32.94), and methioninesulfoxide (HR = 5.60, 95% CI = 1.84-17.10). Being in the highest quartile for Alloprevotella or methionine had a sensitivity and specificity for developing HCC of 85.71% and 60.56%, respectively, with an odds ratio of 10.92 (95% CI = 2.23-53.48). CONCLUSION: Alloprevotella and methionine, methioninesulfoxide, and taurocholic acid predicted future HCC development in a high-risk population of participants with liver cirrhosis.

Casting a Wider NET: An Unusual Cause of Acute Liver Failure in a Pregnant Patient.

We present a case patient in her second trimester of pregnancy who developed acute liver failure from metastatic neuroendocrine tumor (NET). Although she underwent prompt induction of a non-viable fetus due to initial concerns of hemolysis, elevated liver enzymes, and low platelet count syndrome, her liver function continued to deteriorate postpartum. She was subsequently transferred to our institution in order to undergo further evaluation that included a transjugular liver biopsy and subsequent diagnosis of high-grade NET. She was given salvage carboplatin-based chemotherapy, as she was not a liver transplant candidate. Unfortunately, the patient expired from cardiovascular collapse as a component of multiorgan failure.

Dietary Protein, Fiber and Coffee Are Associated with Small Intestine Microbiome Composition and Diversity in Patients with Liver Cirrhosis.

: The gut microbiome is a key factor in chronic liver disease progression. In prior research, we found that the duodenal microbiome was associated with sex, ethnicity, and cirrhosis complications. Here, we examined the association between diet and the duodenal microbiome in patients with liver cirrhosis. This study included 51 participants who completed a detailed food frequency questionnaire and donated duodenal biopsies for microbiome characterization by 16S ribosomal RNA gene sequencing. Data were analyzed for alpha diversity, beta diversity, and association of taxa abundance with diet quality and components using QIIME 2 pipelines. Diet quality was assessed through calculation of the Healthy Eating Index 2010. Participants with higher adherence to protein recommendations exhibited increased microbial richness and evenness (p = 0.03) and a different microbial profile compared to those with lower adherence (p = 0.03). Prevotella-9 and Agathobacter were increased in association with increased protein adherence. Fiber consumption was also associated with the duodenal microbial profile (p = 0.01), with several taxa exhibiting significantly decreased or increased abundance in association with fiber intake. Coffee drinking was associated with microbial richness and evenness (p = 0.001), and there was a dose-response association between coffee drinking and relative abundance of Veillonella (p = 0.01). We conclude that protein, fiber, and coffee are associated with diversity and composition of the duodenal microbiome in liver cirrhosis.

Long-term outcomes with oral therapy in liver transplant recipients with hepatitis B.

BACKGROUND: The long-term impact of oral hepatitis B antiviral therapy in liver transplant (LT) recipients is currently underexplored. The objective of this study was to evaluate how oral antiviral agents impact long-term renal function in this population. METHODS: We studied 79 patients who received a LT for hepatitis B and were placed on all-oral antiviral therapy after withdrawing from hepatitis B immune globulin therapy at the University of California, Los Angeles. Laboratory data were obtained through a retrospective chart review. Univariate analysis and two-sided t tests were performed. RESULTS: The mean (±SD [standard deviation]) age at the time of LT was 65.4 (± 8.2) years. The overall mean (±SD) follow-up from LT was 6.5 (±3.3) years. 22.8% (18/79) of recipients on all-oral therapy had worsening of their chronic kidney disease stage, and 17.7% (14/79) had an increase in creatinine of at least 0.3 mg/dL. There were no significant changes in creatinine and GFR in patients while on tenofovir alafenamide. Patient survival was decreased for recipients who developed detectable HBsAg. CONCLUSION: Tenofovir alafenamide appears to have less of an impact on renal function in LT recipients than other antiviral agents. HBV recurrence after transplant is associated with decreased patient survival and remains an important issue to address for LT recipients on oral antiviral therapy.

Hepatitis C Screening: Barriers to Linkage to Care.

Background and Aims: Hepatitis C (HCV) is a medical and public health concern. Once infected individuals are identified, management includes not only education but also the use of antiviral therapy. Although screening for HCV is readily available, barriers exist which prevent assessment and treatment in individuals potentially infected with HCV. Methods: This is a retrospective study of patients screened for HCV within the University of California, Los Angeles Health Care System between February 22 and July 9, 2018. We defined linkage to care as: 1) confirmatory HCV RNA test after screening HCV antibody test found a positive result; and 2) follow-up appointment for treatment was established with a specialist. Demographic and baseline laboratory values were collected. Factors potentially associated with prohibiting linkage of care were evaluated. Results: During the study period, 17,512 individuals were screened for HCV. A total of 238 (1.35%) were found to have detectable HCV antibodies. Of the individuals with detectable HCV antibodies, 48 (20%) did not undergo confirmatory testing with viral levels. Of the 190 individuals who underwent further testing, 70 patients were noted to be viremic. Among them, 17 of the 70 (24%) were not linked to a specialist for further care. Younger patients (p = 0.02) and people who inject drugs (p = 0.02) were less likely to be referred for specialty care. Conclusions: The results of our study highlight that younger patients and people who inject drugs are less likely to be referred to specialty care for HCV treatment. Efforts are needed to engage these populations.

Hyperlipidemia and Nonalcoholic Steatohepatitis Predispose to Hepatocellular Carcinoma Development Without Cirrhosis.

BACKGROUND: Hepatocellular carcinoma (HCC) accounts for 90% of primary hepatic malignancies. With the exception of chronic hepatitis B (CHB), other etiologies of chronic liver disease require progression to cirrhosis before HCC development. Case reports have described HCC in noncirrhotic patients with hepatitis C (HCV) and nonalcoholic fatty liver disease. GOAL: The aim of this study was to determine the prevalence of patients without cirrhosis and CHB who developed HCC among a large cohort of HCC patients and to identify independent variables that are associated with no cirrhosis among patients with HCC. STUDY: From 2005 to 2015, hepatobiliary cancer patients seen in our liver cancer and liver transplant clinics were evaluated. Patients were included if above18 years old and had histologically confirmed HCC from liver biopsy, resection specimen, or explanted livers. Patients with CHB, non-HCC tumors, or missing paired tumor and nontumor liver histology were excluded. Demographic information, pertinent laboratory values, and comorbid conditions were recorded. Potential predictors were evaluated using both backward stepwise logistic regression model and classification tree model. RESULTS: Of the 1927 patients screened, 545 HCC patients (411 transplanted, 43 resected, 74 transarterial chemoembolization/radiofrequency ablation, 17 untreated) included, 29 (5.3%) patients had no cirrhosis histologically. Eleven patients had HCV, 3 had alcoholic liver disease, 3 had nonalcoholic fatty liver, and 12 had cryptogenic liver disease. Logistic regression models show that patients with hyperlipidemia and elevated serum alanine aminotransferase are more likely to develop HCC without cirrhosis (odds ratio, 1.73 and 0.40; P<0.05). CONCLUSIONS: This large cohort, histology-confirmed case-controlled study shows that patients with nonalcoholic fatty liver disease and hyperlipidemia with elevated serum alanine aminotransferase (most likely nonalcoholic steatohepatitis) are significantly associated with the development of HCC in the absence of cirrhosis.

Presumed Consent: A Potential Tool for Countries Experiencing an Organ Donation Crisis.

BACKGROUND: There is currently an inadequate supply of allografts to meet the number of transplant candidates worldwide. A number of controversial policies, including implementation of a presumed consent organ donation system, have been considered to rectify the organ donation crisis. AIMS: A secondary retrospective data analysis aimed to assess the impact of switching to a presumed consent organ donation model on organ donation rates. METHODS: Deceased organ donation rates were compared before and after countries adopted presumed consent. RESULTS: Six countries met entry criteria. All six countries had an increase in liver donation rates, while 4 out of the six countries had an increase in kidney donation rates. The overall mean (± SD) liver donation rate was 3.23 (± 0.97) per million population (pmp) before the transition and 6.46 (± 1.81) pmp after the transition (p < 0.0001). The overall mean (± SD) kidney donation rate was 17.94 (± 3.34) pmp before the transition and 26.58 (± 4.23) pmp after the transition (p < 0.0001). The percentage increase in liver and kidney donation rates varied among countries, ranging from 28 to 1186%. CONCLUSION: The transition from explicit to presumed consent was associated with a significant increase in liver donation rates in all countries that met our criteria, while the effect on kidney donation rates was partially realized. Although presumed consent alone is unlikely to explain the increase in donation rates, the adoption of such a policy may prove to be a worthwhile risk for countries experiencing consistently low organ donation rates.

Elimination of Hepatitis C in Liver Transplant Recipients.

Background and Aims: Recurrent hepatitis C (HCV) disease in liver transplant (LT) recipients is associated with significant morbidity and mortality. With the availability of noninterferon-based therapy, eliminating HCV may be achievable in LT recipients. Methods: We studied all consecutive recipients who underwent LT at the University of California Los Angeles between January 2005 and June 2017. We collected data on date of transplant and last follow-up, as well as laboratory values. We also recorded type and timing of antiviral therapy relative to LT. Analyses were performed to assess the proportion of LT recipients who are viremic after transplant. Results: Six hundred thirty-four patients underwent LT with a diagnosis of HCV. There was a statistically significant trend for patients to be cured before (p < 0.001) and after liver transplantation (p < 0.001) for the study period of 2014 to 2016 relative to 2005 and 2013, respectively. Of the 634 recipients eligible for therapy, 8% and 74% were treated within 12 months of transplant for the study periods 2005 to 2013 and 2014 to 2016, respectively. There was a significant decrease between the two study periods in the proportion of patients undergoing re-LT 1 year after the original LT: 5.5% (n = 28/510) and 1.5% (n = 2/124) respectively for study periods 2005 to 2013 and 2014 to 2016 respectively (p = 0.011). Conclusions: The proportion of LT recipients who are viremic has decreased over time. Eliminating HCV in LT recipients is feasible after the introduction of direct-acting agents. Curing HCV should translate to improved clinical outcomes in LT recipients who were transplanted for HCV infection with longer follow-up. Preliminary results suggest the decreased need for transplant in the direct-acting agents era.