Potential utility of a multi-component coagulation factor panel to calculate MELD scores and assess the risk of portal vein thrombosis in chronic liver disease.

BACKGROUND: Current quantitative approaches to assess chronic liver disease (CLD) severity have limitations. Further, portal vein thrombosis (PVT) pre-liver transplant (LT) is a major contributor to morbidity in CLD; the means of detecting and/or predicting PVT are limited. We sought to explore whether plasma coagulation factor activity levels can serve as a substitute for prothrombin time/international normalized ratio (PT/INR) in the Model for End-stage Liver Disease (MELD), and/or help assess the risk of PVT. METHODS: Plasma activity levels of Factor V (FV), Factor VIII (FVIII), Protein C (PC), and Protein S (PS) and the concentrations of D-dimer, sP-selectin, and asTF were assessed in two cohorts of CLD patients (ambulatory, n = 42; LT, n = 43). RESULTS: FV and PC activity levels strongly correlated with MELD scores, which enabled the development of a novel scoring system based on multiple linear regressions of the correlations of FV and PC activity with MELD-Na that substitutes PT/INR. Six-month and 1-year follow-up revealed that our novel approach was non-inferior to MELD-Na at predicting mortality. A significant inverse correlation between FVIII activity levels and PVT was found in the LT cohort (p = 0.010); FV and PS activity levels were in-trend (p = 0.069, p = 0.064). We developed a logistic regression-based compensation score to identify patients at risk of PVT. CONCLUSIONS: We demonstrate that FV and PC activity levels may be used to replace PT/INR in MELD scoring. We also show the potential of using the combination of FV, FVIII, and PS activity levels to assess the risk of PVT in CLD.

Expanding the Donor Pool: First Use of Hepatitis B Virus Nat Positive Solid Organ Allografts Into Seronegative Recipients.

OBJECTIVES: The aim of this study was to assess the 1-year safety and effectiveness of HBV Nucleic Acid Test positive (HBV NAT+) allografts in seronegative kidney transplant (KT) and liver transplant (LT) recipients. SUMMARY BACKGROUND DATA: Despite an ongoing organ shortage, the utilization of HBV NAT+ allografts into seronegative recipients has not been investigated. METHODS: From January 2017 to October 2020, a prospective cohort study was conducted among consecutive KT and LT recipients at a single institution. Primary endpoints were post-transplant HBV viremia, graft and patient survival. RESULTS: With median follow-up of 1-year, there were no HBV-related complications in the 89 HBV NAT+ recipients. Only 9 of 56 KTs (16.1%) and 9 of 33 LTs (27.3%) experienced post-transplant HBV viremia at a median of 185 (KT) and 269 (LT) days postoperatively. Overall, viremic episodes resolved to undetected HBV DNA after a median of 80 days of entecavir therapy in 16 of 18 recipients. Presently, 100% of KT recipients and 93.9% of LT recipients are HBV NAT- with median follow-up of 13 months, whereas 0 KT and 8 LT (24.2%) recipients are HBV surface antigen positive indicating chronic infection. KT and LT patient and allograft survival were not different between HBV NAT+ and HBV NAT- recipients (P > 0.05), whereas HBV NAT+ KT recipients had decreased waitlist time and pretransplant duration on dialysis (P < 0.01). CONCLUSIONS: This is the largest series describing the transplantation of HBV NAT+ kidney and liver allografts into HBV seronegative recipients without chronic HBV viremia or decreased 1-year patient and graft survival. Increasing the utilization of HBV NAT+ organs in nonviremic recipients can play a role in decreasing the national organ shortage.

Safety and Efficacy of Budesonide for Liver Transplant Immune Suppression: Results of a Pilot Phase 2a Trial.

Despite adverse effects like hyperglycemia, new-onset diabetes after transplant (NODAT), and infectious complications, corticosteroid use remains an important part of liver transplantation (LT) immune suppression. Budesonide, a synthetic corticosteroid, undergoes extensive first-pass hepatic metabolism with only 10% systemic bioavailability, providing an opportunity for an improved toxicity-therapeutic ratio. Although effective in the treatment of autoimmune hepatitis, the effects of budesonide for LT immune suppression are unknown. We conducted a single-center phase 2a trial to study the safety and efficacy of budesonide immunosuppressive therapy. From July 2017 to November 2018, 20 patients undergoing a first LT received budesonide tapering doses (from 9 to 3 mg) for 12 weeks. Patients were compared with matched control patients who received prednisone from the same time period. Additionally, both groups received calcineurin inhibitors and mycophenolate mofetil. Outcome measures at week 24 included rates of biopsy-proven acute cellular rejection (ACR), NODAT (hemoglobin A1c >6.4%), and infectious complications. In the budesonide arm, 1 patient developed ACR at week 5 and was removed from the study. Another patient stopped the study drug at week 8 due to persistent nausea. Rates of ACR were similar between the budesonide and control groups (5% versus 5%, P = 1.00). Three patients in the control group developed NODAT versus none in the budesonide group (15% versus 0%; P = 0.23). There were 6 infections in the control group compared with none in the budesonide group (30% versus 0; P = 0.02). These pilot data suggest that budesonide has the potential to be a safe and effective alternative to prednisone for LT immune suppression while reducing steroid-induced infections and NODAT. Randomized controlled trials are required to validate these findings.

Use of Hepatitis C Nucleic Acid Test-Positive Liver Allografts in Hepatitis C Virus Seronegative Recipients.

Because of underutilization of liver allografts, our center previously showed that hepatitis C virus (HCV) antibody-positive/nucleic acid test (NAT)-negative livers when transplanted into HCV nonviremic recipients were safe with a 10% risk of HCV transmission. Herein, we present our single-center prospective experience of using HCV NAT+ liver allografts transplanted into HCV NAT- recipients. An institutional review board-approved matched cohort study was conducted examining post- liver transplantation (LT) outcomes of HCV- patients who received HCV NAT+ organs (treatment group) compared with matched recipients with HCV NAT- organs (matched comparator group) between June 2018 to October 2019. The primary endpoint was success of HCV treatment and elimination of HCV infection. The secondary outcomes included the 30-day and 1-year graft and patient survival as well as perioperative complications. There were 32 recipients enrolled into each group. Because of 1 death in the index admission, 30/31 patients (97%) were given HCV treatment at a median starting time of 47 days (18-140 days) after LT. A total of 19 (63%) patients achieved sustained virological response at week 12 (SVR12). Another 6 patients achieved end-of-treatment response, while 5 remained on therapy and 1 is yet to start treatment. No HCV treatment failure has been noted. There were no differences in 30-day and 1-year graft and patient survival, length of hospital stay, biliary or vascular complications, or cytomegalovirus viremia between the 2 groups. In this interim analysis of a matched cohort study, which is the first and largest study to date, the patients who received the HCV NAT+ organs had similar outcomes regarding graft function, patient survival, and post-LT complications.

Sarcoidosis Involving the Gastrointestinal Tract: Diagnostic and Therapeutic Management.

Involvement of the gastrointestinal (GI) tract is an infrequent extrathoracic presentation of sarcoidosis. We reviewed 305 cases of GI involvement reported in 238 patients, in whom GI sarcoidosis was the first sign of the disease in half the cases. The disease does not affect the GI tract uniformly, with a clear oral-anal gradient (80% of reported cases involved the esophagus, stomach, and duodenum). Clinicopathological mechanisms of damage may include diffuse mucosal infiltration, endoluminal exophytic lesions, involvement of the myenteric plexus, and extrinsic compressions. Ten percent of patients presented with asymptomatic or subclinical disease found on endoscopy. The diagnosis is relevant clinically because 22% of cases reviewed presented as life threatening. In addition, initial clinical/endoscopic findings may be highly suggestive of GI cancer. The therapeutic approach is heterogeneous and included wait-and-see or symptomatic approaches, glucocorticoid/immunosuppressive therapy, and surgery. Sarcoidosis of the gut is a heterogeneous, potentially life-threatening condition that requires a multidisciplinary approach and early clinical suspicion to institute personalized therapeutic management and follow-up.

Delayed Sleeve Gastrectomy Following Liver Transplantation: A 5-Year Experience.

Obesity has become an epidemic in the United States over the past decade, and recent studies have shown this trend in the liver transplantation (LT) population. These patients may be candidates for laparoscopic sleeve gastrectomy (LSG) to promote significant and sustained weight loss to prevent recurrence of nonalcoholic steatohepatitis. However, safety remains a concern, and efficacy in this setting is uncertain. A single-institution database from 2014 to 2018 was queried for patients undergoing LSG following LT. The selection criteria for surgery were consistent with National Institutes of Health guidelines, and patients were at least 6 months after LT. A total of 15 patients (median age, 59.0 years; Caucasian, 86.7%; and female, 60%) underwent LSG following LT. Median time from LT to LSG was 2.2 years with a median follow-up period of 2.6 years. The median hospital length of stay (LOS) was 2 days after LSG. Mortality and rate of liver allograft rejection was 0, and there was 1 postoperative complication (a surgical site infection). Following LSG, body mass index (BMI) decreased from 42.7 to 35.9 kg/m2 (P < 0.01), and in 12 patients with at least 1 year of follow-up, the total body weight loss was 20.6%. Following LSG in patients with diabetes, the median daily insulin requirements decreased from 98 (49-118) to 0 (0-29) units/day (P = 0.02), and 60% discontinued insulin. Post-LT patients had a similar decrease in BMI and reduction in comorbidities at 1 year compared with a matched non-LT patient cohort. In the largest patient series to date, we show that LSG following LT is safe, effective, and does not increase the incidence of liver allograft rejection. Larger longer-term studies are needed to confirm underlying metabolic changes following LSG.

Hepatitis C transmission from seropositive, nonviremic donors to non-hepatitis C liver transplant recipients.

Breakthroughs in hepatitis C virus (HCV) treatment and rising rates of intravenous drug use have led to an increase in the number of organ donors who are HCV antibody-positive but serum nucleic acid test (NAT)-negative. The risk of HCV transmission from the liver grafts of these donors to recipients is unknown. To estimate the incidence of HCV transmission, we prospectively followed 26 consecutive HCV antibody-negative (n = 25) or NAT-negative (n = 1) transplant recipients who received a liver graft from donors who were HCV antibody-positive but serum NAT-negative between March 2016 and March 2017. HCV transmission was considered to have occurred if recipients exhibited a positive HCV PCR test by 3 months following transplantation. Drug overdose was listed as the cause of death in 15 (60%) of the donors. One recipient died 18 days after transplantation from primary graft nonfunction and was excluded. Of the remaining 25 recipients, HCV transmission occurred in 4 (16%), at a median follow-up of 11 months, all from donors who died of drug overdose. Three of these patients were treated with direct-acting antiviral therapy, with two achieving a sustained virologic response and one an end-of-treatment response. One patient with HCV transmission died after a complicated postoperative course and did not receive antiviral therapy. CONCLUSION: In this prospective cohort of non-HCV liver recipients receiving grafts from HCV antibody-positive/NAT-negative donors, the incidence of HCV transmission was 16%, with the highest risk conferred by donors who died of drug overdose; given the availability of safe and highly effective antiviral therapies, use of such organs could be considered to expand the donor pool. (Hepatology 2018;67:1673-1682).

Serum Albumin Can Identify Patients With Compensated Cirrhosis With a Good Prognosis.

BACKGROUND: Many prognostic studies in cirrhosis were performed without distinguishing between compensated and decompensated patients and/or have evaluated the prognostic role of variables that are not routinely used. The aim was to evaluate predictors of survival in compensated and decompensated cirrhosis separately but in a concurrent cohort and focused on routine clinical variables. METHODS: Secondary analysis of a prospective cohort with cirrhosis collected in a tertiary center between August 2000 and May 2002 and followed until death or April 2006. Univariate, stratified univariate analysis, and multivariate Cox regression analysis were performed. Receiving operating characteristics curves were used to identify the best cutoff of variables predictive of death. RESULTS: A total of 242 patients were included (122 compensated, 120 decompensated). In a median follow-up of 30 months (range, 6 to 50 mo), 62 (26%) deaths occurred, 24 (20%) in the compensated and 38 (32%) in the decompensated group. In the whole cohort, decompensation was the strongest predictor of death. In the compensated group, age, albumin, and platelets and in the decompensated group model for end-stage liver disease, platelets, and albumin were identified as independent predictors of death. A serum albumin of 4 g/dL was the best cutoff to identify patients at risk for death in the compensated group with a hazard ratio of 13.3 [95% confidence interval, 1.8-98.8] in those with an albumin of <4.0 g/dL. CONCLUSIONS: Albumin is a predictor of death in compensated and decompensated cirrhosis. In compensated cirrhosis a subset patients with particularly good prognosis can be identified. Different predictors were observed in both stages, confirming that compensated and decompensated cirrhosis are 2 separate disease stages.

The combination of octreotide and midodrine is not superior to albumin in preventing recurrence of ascites after large-volume paracentesis.

BACKGROUND & AIMS: Large-volume paracentesis (LVP) is the treatment of choice for patients with cirrhosis and refractory ascites. However, LVP can lead to postparacentesis circulatory dysfunction (PCD), which is associated with faster ascites recurrence and renal failure. PCD results from vasodilatation, which reduces effective blood volume, and is prevented by intravenous administration of albumin. Vasoconstrictors could be used instead of albumin and, with longer use, prevent PCD and delay ascites recurrence. METHODS: We performed a multicenter, randomized, double-blind, placebo-controlled trial to compare albumin with the vasoconstrictor combination of octreotide and midodrine in patients with refractory ascites who underwent LVP. Patients in the albumin group received a single intravenous dose of albumin at the time of LVP plus placebos for midodrine and octreotide (n = 13). Patients in the vasoconstrictor group received saline solution (as a placebo for albumin), 10 mg of oral midodrine (3 times/day), and a monthly 20-mg intramuscular injection of long-acting octreotide (n = 12). Patients were followed up until recurrence of ascites. RESULTS: The median times to recurrence of ascites were 10 days in the albumin group and 8 days in the vasoconstrictor group (P = .318). There were no significant differences in PCD between the albumin group (18%) and the vasoconstrictor group (25%, P = .574). When ascites recurred, serum levels of creatinine were higher in the vasoconstrictor group (1.2 vs 0.9 mg/dL in the albumin group; P = .051). CONCLUSIONS: The combination of midodrine and octreotide after LVP is not superior to albumin in delaying recurrence of ascites or preventing PCD in patients with cirrhosis. Outcomes appear to be worse in patients given octreotide and midodrine. ClinicalTrials.gov number, NCT00108355.

Optimizing the Selection of Patients for Simultaneous Liver-Kidney Transplant.

Simultaneous liver-kidney transplantation has increased significantly in the Model for End Stage Liver Disease era. The transplantation policy has evolved significantly since the implementation of allocation based on the Model for End Stage Liver Disease. Current policy takes into account the medical eligibility criteria for simultaneous liver-kidney transplantation listing. It also provides a safety net option and prioritizes kidney transplant after liver transplant recipients who are unlikely to recover their renal function within 60 to 365 days after liver transplant alone. This review seeks to understand the underlying challenges in carefully selecting the candidates while optimizing the patient selection.

"Ohio River valley fever" presenting as isolated granulomatous hepatitis: a case report.

Histoplasmosis is endemic to the midwestern and east central states in the United States near the Mississippi and the Ohio River valleys. Ninety-nine percent of patients exposed to histoplasmosis develop only subclinical infection. Liver involvement as a part of disseminated histoplasmosis is well known; however, isolated hepatic histoplasmosis without any other stigmata of dissemination is extremely rare and the literature is limited to only two case reports. We present a rare case of isolated granulomatous hepatitis due to histoplasmosis in a 35-year-old female with dermatomyositis receiving low-dose prednisone and methotrexate. There was no evidence of fungal dissemination elsewhere. High clinical suspicion is critical for early diagnosis and treatment.

Use of Hepatitis C Virus Antibody-Positive Donor Livers in Hepatitis C Nonviremic Liver Transplant Recipients.

BACKGROUND: Given the shortage of available liver grafts, transplantation (LTx) of hepatitis C virus antibody-positive, nucleic acid test-negative (HCV Ab+/NAT-) livers into nonviremic HCV recipients can expand the donor pool. Having previously described the sentinel experience of HCV Ab+/NAT- allografts in nonviremic recipients, we report the growth and extended follow-up of this program for 55 patients compared with recipients of Public Health Services (PHS) increased-risk donor HCV Ab-/NAT- allografts. STUDY DESIGN: A prospective review of all HCV nonviremic LTx patients receiving HCV Ab+/NAT- organs between March 2016 and August 2018 was performed. All HCV Ab+/NAT- organ recipients underwent HCV testing at 3 months and 1-year post-LTx to determine HCV transmission. RESULTS: Fifty-five HCV nonviremic candidates received HCV Ab+/NAT- organs; 64% male, median age 59 years (range 36 to 69 years) and median Model for End-Stage Liver Disease score of 22.5. Two recipients were excluded due to death before HCV testing. The HCV disease transmission occurred in 5 recipients (9%). Of these, 4 (80%) underwent anti-HCV treatment with eradication of virus. No patient found to be negative at 3 months seroconverted at 1-year follow-up. No patients who received PHS increased-risk donor HCV Ab-/NAT- organs had viremia develop (0 of 57) and there was no difference in graft and renal function, complications, or survival between HCV Ab+/NAT- recipients and PHS increased-risk donor HCV Ab-/NAT- recipients. CONCLUSIONS: We report the largest experience with LTx from HCV Ab+/NAT- donors into 55 seronegative recipients with a HCV transmission rate of 9% with no late conversions at 1 year and no difference in function or graft loss compared with PHS increased-risk donor HCV Ab-/NAT- recipients. Due to availability of safe and effective HCV therapies, the use of such organs should be strongly considered to increase the donor organ pool.

Downstaging therapy followed by liver transplantation for hepatocellular carcinoma beyond Milan criteria.

BACKGROUND: Orthotopic liver transplantation is a curative treatment for hepatocellular carcinoma within Milan criteria, but these criteria preclude many patients from transplant candidacy. Recent studies have demonstrated that downstaging therapy can reduce tumor burden to meet conventional criteria. The present study reports a single-center experience with tumor downstaging and its effects on post-orthotopic liver transplantation outcomes. METHODS: All patients with hepatocellular carcinoma who were evaluated by our multidisciplinary liver services team from 2012 to 2016 were identified (N = 214). Orthotopic liver transplantation candidates presenting outside of Milan criteria at initial radiographic diagnosis and/or an initial alpha-fetoprotein >400 ng/mL were categorized as at high risk for tumor recurrence and post-transplant mortality. RESULTS: Of the 214 patients newly diagnosed with hepatocellular carcinoma, 73 (34.1%) eventually underwent orthotopic liver transplantation. The majority of patients who did not undergo orthotopic liver transplantation were deceased or lost to follow-up (47.5%), with 14 of 141 (9.9%) currently listed for transplantation. Among transplanted patients, 21 of 73 (28.8%) were considered high-risk candidates. All 21 patients were downstaged to within Milan criteria with an alpha-fetoprotein <400 ng/mL before orthotopic liver transplantation, through locoregional therapies. Recurrence of hepatocellular carcinoma was higher but acceptable between downstaged high-risk and traditional candidates (9.5% vs 1.9%; P > .05) at a median follow-up period of 17 months. Downstaged high-risk candidates had a similar overall survival compared with those transplanted within Milan criteria (log-rank P > .05). CONCLUSIONS: In highly selected cases, patients with hepatocellular carcinoma outside of traditional criteria for orthotopic liver transplantation may undergo downstaging therapy in a multidisciplinary fashion with excellent post-transplant outcomes. These data support an aggressive downstaging approach for selected patients who would otherwise be deemed ineligible for transplantation.

Chronic Kidney Disease and Related Long-Term Complications After Liver Transplantation.

Liver transplantation is the standard of care for patients with decompensated cirrhosis. Liver transplantation recipients have excellent short-term and long-term outcomes including patient and graft survival. Since the adoption of model for end-stage liver disease (MELD)-based allocation policy, the incidence of post-transplant end stage renal disease has risen significantly. Occurrence of Stage 4 chronic kidney disease and end stage renal disease substantially increases the risk of post-transplant deaths. Because majority of late post-transplant mortality is due to nonhepatic post-transplant comorbidities, personalized care directed toward risk factor modification may further improve post-transplant survival.

Emphysematous Cholecystitis Resulting in Secondary Biliary Cirrhosis: A Rare Complication of Endoscopic Retrograde Cholangiopancreatography.

A 48-year-old female developed acute emphysematous cholecystitis after an endoscopic retrograde cholangiopancreatography (ERCP) for evaluation of sphincter of Oddi dysfunction. Cholecystectomy was performed 2 days later. Cultures grew Clostridium perfringens. The patient received broad-spectrum antibiotics but developed recurrent cholangitic abscesses and intra- and extra-hepatic biliary necrosis. She was managed by percutaneous transhepatic biliary drains. For next 3 years, patient had recurrent episodes of biliary obstruction, cholangitis, and sepsis, resulting in secondary biliary cirrhosis requiring a liver transplantation. Emphysematous cholecystitis is a rare complication of ERCP. Prompt diagnosis and surgical management can prevent further spread of infection to biliary tree.