Protocolized screening and detection of occult alcohol use before and after liver transplant: Lessons learned from a quality improvement initiative.

INTRODUCTION: Detection of alcohol (ETOH) use with biomarkers provides an opportunity to intervene and treat patients with alcohol use disorder before and after liver transplant (LT). We describe our center's experience using urine ethyl glucuronide (EtG) and serum phosphatidylethanol (PEth) in alcohol screening protocols. METHODS: Single-center, retrospective review of patients presenting for LT evaluation, patients waitlisted for LT for alcohol-associated liver disease (ALD), and patients who received a LT for ALD over a 12-month period, from October 1, 2019 through September 30, 2020. Patients were followed from waitlisting to LT, or for up to 12 months post-LT. We monitored protocol adherence to screening for ETOH use- defined as completion of all possible tests over the follow-up period- at the initial LT visit, while on the LT waitlist and after LT. RESULTS: During the study period, 227 patients were evaluated for LT (median age 57 years, 58% male, 78% white, 54.2% ALD). Thirty-one patients with ALD were placed on the waitlist, and 38 patients underwent LT for ALD during this time period. Protocolized adherence to screening for alcohol use was higher for PEth for all LT evaluation patients (191 [84.1%] vs. 146 [67%] eligible patients, p < .001), in patients with ALD waitlisted for LT (22 [71%] vs. 14 (48%] eligible patients, p = .04) and after LT for ALD, 20 (33 [86.8%] vs. 20 [52.6%] eligible patients, p < .01). Few patients with a positive test in any group completed chemical dependency treatment. CONCLUSIONS: When screening for ETOH use in pre- and post-LT patients, protocol adherence is higher using PEth compared to EtG. While protocolized biomarker screening can detect recurrent ETOH use in this population, engagement of patients into chemical dependency treatment remains challenging.

The evolving microenvironment of the human hepatocyte: Healthy vs. cirrhotic liver vs. isolated cells.

The study of the liver microenvironment and hepatocyte's response to this environment in the setting of healthy liver, cirrhotic liver or cultured primary human hepatocytes (PHHs) addresses key questions for the development of novel liver therapies and predicts relevance of ex vivo PHHs models in liver biology. This study compared quantitative gene and protein expression of the inflammatory profile, oxidative stress response, angiogenesis and homing mechanisms in the biopsies of healthy and cirrhotic human livers and isolated PHHs. These profiles were correlated with the metabolic health of liver and PHHs defined by albumin production. The analysis demonstrated that cirrhotic liver and PHHs exhibited a distinct upregulation of the pro-inflammatory, oxidative stress and homing mechanism markers when compared to normal liver. The upregulation of the oxidative stress markers in PHHs inversely correlated with the albumin production. PHHs had diverse secretion of matrix metalloproteinases and their inhibitors, reflective of the cellular response to non-physiological culture conditions. The current study suggests that ex vivo PHHs manifest adaptive behavior by upregulating stress mechanisms (similar to the cirrhotic liver), downregulating normal metabolic function and upregulating matrix turnover. The ex vivo profile of PHHs may limit their therapeutic functionality and metabolic capacity to serve as in vitro metabolism and toxicology models.

The prognostic significance of glutamic acid decarboxylase antibodies in patients with chronic pancreatitis undergoing total pancreatectomy with islet autotransplantation.

AIM: Islet autotransplantation (IAT) is considered a 'non-immune' model of islet transplant, with no risk for autoimmune-mediated beta cell loss, but we have previously observed de novo type 1 diabetes in one total pancreatectomy with islet autotransplantation (TPIAT) recipient. We aimed to investigate the clinical significance of glutamic acid decarboxylase antibodies (GADA), as a sensitive marker for autoimmune diabetes mellitus (DM), in patients with chronic pancreatitis undergoing TPIAT. METHODS: We identified 9 patients undergoing TPIAT with elevated GADA pre-TPIAT (8 non-diabetic and 1 with C-peptide positive DM), otherwise demographically similar to GADA negative TPIAT recipients (n=341). Metabolic and clinical measures related to islet cell function were recorded both before and after TPIAT. RESULTS: None of the 9 TPIAT patients achieved insulin independence after surgery, vs. 33% of GADA negative patients (n=318 with 1-yr follow-up). The two patients with the highest titters of GADA (>250 IU/mL) both experienced islet graft failure, despite normoglycaemia pre-TPIAT and high islet mass transplanted (5276 and 9378 IEQ per kg), with elevated HbA1c levels post-TPIAT (8.3%, 9.6%). The remaining 7 seven were insulin dependent with partial graft function and HbA1c levels <7%. CONCLUSION: Insulin dependence was more frequent in 9 patients with elevated GADA prior to TPIAT than in GADA negative TPIAT recipients, with graft failure in 2 cases. We speculate that beta-cell autoimmunity may occur in a small subset of TPIAT recipients and that beta cell antibody testing prior to TPIAT may be warranted to identify individuals at higher risk for insulin dependence.

PROviding Better ACcess To ORgans: A comprehensive overview of organ-access initiatives from the ASTS PROACTOR Task Force.

The American Society of Transplant Surgeons (ASTS) PROviding better Access To Organs (PROACTOR) Task Force was created to inform ongoing ASTS organ access efforts. Task force members were charged with comprehensively cataloguing current organ access activities and organizing them according to stakeholder type. This white paper summarizes the task force findings and makes recommendations for future ASTS organ access initiatives.

Continuous Paravertebral Infusions as an Effective Adjunct for Postoperative Pain Management in Living Liver Donors: A Retrospective Observational Study.

We analyzed the effectiveness of paravertebral-block for immediate postoperative pain control in living liver donors. Specifically, we sought to determine whether or not the addition of paravertebral catheters with continuous ropivacaine infusion would decrease postoperative opioid use and reduce the incidence of adverse effects and complications. We reviewed the records of 26 patients who underwent right-lobe living donor hepatectomy (RLDH): 16 with and 10 without such catheters. The primary outcome was opioid use on postoperative day (POD) 1 through 3. For each of those 3 days, we calculated each patient's opioid use in morphine equivalents (mg). We also noted pain scores, adverse effects, and complications. The rate of decrease in morphine equivalents was higher in the catheter group (rate of change = -22.72; P = .038) for POD 1 (0-24 hours) and POD 2 (25-48 hours) than in the noncatheter group. For POD 2 alone, the catheter group used, on average, 20.98 mg fewer morphine equivalents than the noncatheter group (P = .023). The catheter group had a markedly reduced pain trajectory postoperatively (P = .014) than the noncatheter group. The catheter placement procedure itself was safe.

Unmethylated Insulin DNA Is Elevated After Total Pancreatectomy With Islet Autotransplantation: Assessment of a Novel Beta Cell Marker.

Beta cell death may occur both after islet isolation and during infusion back into recipients undergoing total pancreatectomy with islet autotransplantation (TPIAT) for chronic pancreatitis. We measured the novel beta cell death marker unmethylated insulin (INS) DNA in TPIAT recipients before and immediately after islet infusion (n = 21) and again 90 days after TPIAT, concurrent with metabolic functional assessments (n = 25). As expected, INS DNA decreased after pancreatectomy (p = 0.0002). All TPIAT recipients had an elevated unmethylated INS DNA ratio in the first hours following islet infusion. In four samples (three patients), INS DNA was also assessed immediately after islet isolation and again before islet infusion to assess the impact of the isolation process: Unmethylated and methylated INS DNA fractions both increased over this interval, suggesting death of beta cells and exocrine tissue before islet infusion. Higher glucose excursion with mixed-meal tolerance testing was associated with persistently elevated INS DNA at day 90. In conclusion, we observed universal early elevations in the beta cell death marker INS DNA after TPIAT, with pronounced elevations in the islet supernatant before infusion, likely reflecting beta cell death induced by islet isolation. Persistent posttransplant elevation of INS DNA predicted greater hyperglycemia at 90 days.

Sitagliptin Treatment After Total Pancreatectomy With Islet Autotransplantation: A Randomized, Placebo-Controlled Study.

Insulin independence after total pancreatectomy and islet autotransplant (TPIAT) for chronic pancreatitis is limited by a high rate of postprocedure beta cell apoptosis. Endogenous glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are increased by dipeptidyl peptidase 4 inhibitor therapy (sitagliptin) may protect against beta cell apoptosis. To determine the effect of sitagliptin after TPIAT, 83 adult TPIAT recipients were randomized to receive sitagliptin (n = 54) or placebo (n = 29) for 12 months after TPIAT. At 12 and 18 months after TPIAT, participants were assessed for insulin independence; metabolic testing was performed with mixed meal tolerance testing and frequent sample intravenous glucose tolerance testing. Insulin independence did not differ between the sitagliptin and placebo groups at 12 months (42% vs. 45%, p = 0.82) or 18 months (36% vs. 44%, p = 0.48). At 12 months, insulin dose was 9.0 (standard error 1.7) units/day and 7.9 (2.2) units/day in the sitagliptin and placebo groups, respectively (p = 0.67) and at 18 months 10.3 (1.9) and 7.1 (2.6) units/day, respectively (p = 0.32). Hemoglobin A1c levels and insulin secretory measures were similar in the two groups, as were adverse events. In conclusion, sitagliptin could be safely administered but did not improve metabolic outcomes after TPIAT.

Defining the Tipping Point in Surgical Performance for Laparoscopic Donor Nephrectomy Among Transplant Surgery Fellows: A Risk-Adjusted Cumulative Summation Learning Curve Analysis.

The United Network for Organ Sharing recommends that fellowship-trained surgeons participate in 15 laparoscopic donor nephrectomy (LDN) procedures to be considered proficient. The American Society of Transplant Surgeons (ASTS) mandates 12 LDNs during an abdominal transplant surgery fellowship. We performed a retrospective intraoperative case analysis to create a risk-adjusted cumulative summation (RACUSUM) model to assess the learning curve of novice transplant surgery fellows (TSFs). Between January 2000 and December 2014, 30 novice TSFs participated in the organ procurement rotation of our ASTS-approved abdominal transplant surgery fellowship. Measures of surgical performance included intraoperative time, estimated blood loss, and incidence of intraoperative complications. The performance of senior TSFs was used to benchmark novice TSF performance. Scores were tabulated in a learning curve model, adjusting for case complexity and prior TSF case volume. Rates of adverse surgical events were significantly higher for novice TSFs than for senior TSFs. In univariable analysis, multiple renal arteries, high BMI, prior abdominal surgery, male donor, and nephrolithiasis were correlated with higher incidence of adverse surgical events. Based on the RACUSUM model, high intraoperative time is mitigated after 28 procedures, incidence of intraoperative complications tends to diminish after 24 procedures, and improvement in estimated blood loss did not remain consistent. TSFs exhibit a tipping point in LDN performance by 24-28 cases and proficiency by 35-38 cases.