Emricasan (IDN-6556) Lowers Portal Pressure in Patients With Compensated Cirrhosis and Severe Portal Hypertension.

Caspases play a central role in apoptosis, inflammation, and fibrosis. They produce hemodynamically active, proinflammatory microparticles that cause intrahepatic inflammation, vasoconstriction, and extrahepatic splanchnic vasodilation. Emricasan is a pan-caspase inhibitor that lowers portal hypertension (PH) and improves survival in murine models of cirrhosis. This exploratory study assessed whether emricasan lowers PH in patients with compensated cirrhosis. This multicenter, open-label study enrolled 23 subjects with compensated cirrhosis and PH (hepatic vein pressure gradient [HVPG] >5 mm Hg). Emricasan 25 mg twice daily was given for 28 days. HVPG measurements were standardized and performed before and after emricasan. A single expert read all HVPG tracings. Median age was 59 (range 49-80); 70% were male. Cirrhosis etiologies were nonalcoholic steatohepatitis and hepatitis C virus. Subjects were Child class A (87%) with a median Model for End-Stage Liver Disease score of 8 (range 6-15). Twelve had severe PH (HVPG ≥12 mm Hg). Overall, there was no significant change in HVPG after emricasan (mean [standard deviation, SD] -1.1 [4.57] mm Hg). HVPG decreased significantly (mean [SD] -3.7[4.05] mm Hg; P = 0.003) in those with severe PH: 4/12 had a ≥20% decrease, 8/12 had a ≥10% decrease, and 2/12 HVPG decreased below 12 mm Hg. There were no significant changes in blood pressure or heart rate. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) decreased significantly in the entire group and in those with severe PH. Serum cleaved cytokeratin 18 and caspase-3/7 decreased significantly. Emricasan was well tolerated. One subject discontinued for nonserious adverse events. Conclusion: Emricasan administered for 28 days decreased HVPG in patients with compensated cirrhosis and severe PH; an effect upon portal venous inflow is likely, and concomitant decreases in AST/ALT suggest an intrahepatic anti-inflammatory effect.

Preoperative elective transjugular intrahepatic portosystemic shunt for cirrhotic patients undergoing abdominal surgery.

Despite improvements in the surgical techniques, anesthesia and intensive care, abdominal surgery in patients with cirrhosis remains a challenge. Transjugular intrahepatic portosystemic shunt (TIPS) has been used to manage complications of portal hypertension. Preoperative TIPS (prophylactic) can theoretically improve outcomes in this population. Seven original studies were identified with 24 patients who underwent prophylactic TIPS before abdominal surgery. No perioperative mortality or major abdominal bleeding attributable to portal hypertension was reported for this cohort. One patient had poor wound healing post surgery (4.2%), one had right heart failure (4.2%), and five developed hepatic encephalopathy (20.8%) post surgery. More evidence is needed to optimize the timing of surgery post TIPS and the selection of an appropriate stent size to further decrease the associated morbidity. Overall, the decision for prophylactic TIPS placement for cirrhotic patients undergoing abdominal surgery needs individualization to allow its safe use with concomitant improvement in perioperative morbidity.

Gallstone Pancreatitis: A Common but Often Overlooked Cause of Abdominal Pain in Post-Liver-Transplant Patients.

INTRODUCTION: In general population, gallstone pancreatitis is the most common cause of pancreatitis. However, there are very few literatures that address this topic in post-liver-transplant patients. CLINICAL CASE: A 69-year-old female who had a liver transplant in 2015 due to hepatocellular carcinoma and nonalcoholic steatohepatitis (NASH) cirrhosis. She had a recent episode of acute cellular rejection that was treated with high dose methylprednisolone 1 week prior to admission. She presented with severe epigastric abdominal pain associated with nausea and vomiting. Her laboratory studies showed significantly elevated serum lipase, AST, and ALT from her baseline. She underwent urgent Endoscopic Ultrasound (EUS) with Endoscopic Retrograde Cholangiopancreatography (ERCP) that showed common bile duct stone that was extracted. DISCUSSION: Biliary sludge and stones accounted for 22% of late onset acute pancreatitis after liver transplant. Corticosteroids have been identified as one of the potential causes of drug-induced pancreatitis. However, she is more likely to have gall stone pancreatitis since she also had dilated common bile duct and intrahepatic duct. In addition, there was CBD stone noted on ERCP. CONCLUSION: Acute gallstone associated pancreatitis after liver transplant is not uncommon. Patients generally have good outcomes. Further prospective studies are warranted.

Utility of Dobutamine Stress Echocardiography in Cardiac Risk Stratification of Patients Undergoing Orthotopic Liver Transplantation.

Cardiovascular diseases are a major cause of morbidity and mortality in patients after orthotopic liver transplantation (OLT). This review includes major original articles published in the English-language literature of patients who underwent dobutamine stress echocardiography (DSE) before OLT for cardiac risk stratification. Of a total of 10 original articles (total 1699 patients undergoing DSE), 6 studies used DSE to predict major adverse cardiac events (MACE) in patients undergoing OLT and 4 reported the role of DSE in coronary artery disease (CAD) prediction in patients with end-stage liver disease. The composite incidence of MACE was 11.4%. In predicting postoperative MACE, DSE had a composite sensitivity of 0.12 (95% CI, 0.07-0.19), a specificity of 0.96 (95% CI, 0.94-0.97), a positive predictive value (PPV) of 0.26 (95% CI, 0.16-0.38), and a negative predictive value (NPV) of 0.89 (95% CI, 0.88-0.91). The presence of known CAD in a patient was shown to increase the risk of cardiac events after OLT significantly in three of six studies. The average prevalence of CAD was 14.4%. In predicting CAD, DSE had a composite sensitivity of 0.47 (95% CI, 0.32-0.62), specificity of 0.74 (95% CI, 0.68- 0.79), PPV of 0.23 (95% CI, 0.15-0.33), and NPV of 0.89 (95% CI, 0.84-0.93). This review emphasizes the need for standardizing cardiac risk stratification protocol to screen and prevent cardiac morbidity after OLT, standardizing MACE definition to allow more uniform reporting, and the need for safer and efficacious alternatives to DSE in the evaluation of OLT candidates.

Severe Thrombotic Complication of Eltrombopag in a Cirrhotic Patient.

We present a patient with hepatitis C virus (HCV) and cirrhosis who was treated with eltrombopag for idiopathic thrombocytopenic purpura and was incidentally found to have a right atrial thrombus with extension into the left internal jugular vein. Eltrombopag was discontinued and the patient was treated with thrombectomy and anticoagulation. Given the proposed use of eltrombopag in HCV-associated thrombocytopenia, we advise caution when treating cirrhotics who are at higher intrinsic risk of thrombosis.

All Those Liver Masses are not Necessarily from the Liver: A Case of a Giant Adrenal Pseudocyst Mimicking a Hepatic Cyst.

BACKGROUND: Most abdominal cysts, including adrenal pseudocysts, are benign and asymptomatic. Rapid enlargement, hemorrhage, infection, rupture with leakage of cyst contents, or pressure on adjacent organs can cause symptoms. Although usually diagnosed incidentally on imaging, determining the origin of a cyst can sometimes be challenging. In these situations, surgical excision and pathological analysis is crucial to diagnosis and management. We report here a case of a giant symptomatic adrenal pseudocyst that closely mimicked a hepatic cyst at presentation. CASE REPORT: A 50-year-old man, with a history of an incidentally detected hepatic cyst, presented with severe abdominal pain, fevers, leukocytosis, and mildly abnormal liver function tests. CT scan revealed a large well defined cystic space-occupying lesion within the liver, with findings suggesting cyst rupture and possible infection. Early laparotomy was performed, and the origin was determined intraoperatively to be right adrenal, which was later confirmed by pathology. CONCLUSIONS: Contrast-enhanced CT scan is the criterion standard for evaluation for abdominal cystic masses. Precise diagnosis of a giant abdominal cyst can be challenging. Surgery is both diagnostic and curative in such situations. We also discuss the specific situations in which surgery should be considered in cases of adrenal cystic masses.

Evaluating safety and efficacy of rabbit antithymocyte globulin induction in elderly kidney transplant recipients.

OBJECTIVES: The optimal immunosuppression regimen for elderly kidney transplant recipients is poorly defined. We sought to evaluate the short-term efficacy and safety of thymoglobulin in geriatric recipients of deceased-donor kidneys. MATERIALS AND METHODS: A single-center, retrospective analysis was undertaken between elderly (≥ 65 years) (n=137) and nonelderly (n=276) kidney transplant recipients who received rabbit antithymocyte globulin induction and calcineurin inhibitor, mycophenolic acid, and prednisone maintenance. RESULTS: The mean age was 70 versus 52 years. Fewer elderly patients had an earlier transplant or panel reactive antibodies > 20%, but had more machine perfused, older, and extended criteria donor kidneys. Elderly patients received lower rabbit antithymocyte globulin (5.4 vs 5.6 mg/kg; P = .04) and initial mycophenolic acid doses (1620 vs 1774 mg; P = .002), and experienced less delayed graft function (31.1% vs 50.0%; P < .001). Death-censored graft survival and graft function at 3 years and biopsy-proven acute rejection at 1 year were comparable; however, there was lower 3-year patient survival in elderly patients. Donor age was the only factor associated with reduced patient survival. Rates of malignancy, infection, or thrombocytopenia were similar; however, leukopenia occurred less frequently in elderly patients (11.7% vs 19.9%; P = .038). CONCLUSIONS: Elderly kidney transplant recipients receiving rabbit antithymocyte globulin did not experience different short-term graft survival, graft function or rates of infection, malignancy or hematologic adverse reactions than did nonelderly patients; they experienced fewer episodes of delayed graft function, but had lower 3-year patient survival.

Early allograft biopsies performed during delayed graft function may not be necessary under thymoglobulin induction.

OBJECTIVES: Delayed graft function affects up to 50% of kidney transplant recipients. Some guidelines recommend surveillance biopsies beginning 7 days after engraftment. This may be unnecessary with anti-thymocyte globulin induction. MATERIALS AND METHODS: We conducted a retrospective study of deceased-donor renal transplant recipients with delayed graft function. RESULTS: One hundred eleven patients met the inclusion criteria. The incidence of rejections during delayed graft function was 2.7%. They were diagnosed between 9 and 11 days after transplant. The subsequent incidence of rejection at 12-month follow-up was 13.5% (n=15). The median time to rejection after transplant was 10 weeks. Fourteen of 15 patients had subtherapeutic immunosuppression. The only risk factor associated with later rejection after delayed graft function was use of donors after cardiac death. CONCLUSIONS: Early rejection during delayed graft function with anti-thymocyte globulin induction and maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and steroids is rare. When later rejection occurs, it is at a median of 10 weeks after a transplant. Two of the 3 early rejections were antibody mediated. Later rejections were associated with subtherapeutic immunosuppression and donors after cardiac death. Biopsies need not be performed during the early postoperative period when anti-thymocyte globulin is used with tacrolimus, mycophenolate mofetil, and steroids.

Operative start times and complications after kidney transplantation.

The worldwide focus on work hour regulations and patient safety has led to the re-examination of the merits of night-time surgery, including kidney transplantation. The risks of operating during nontraditional work hours with potentially fatigued surgeons and staff must be weighed against the negative effects of prolonged cold ischemic time with resultant graft compromise. The aim of this study was to evaluate the impact of performing renal transplantation procedures during evening versus day time hours. The main outcome measures assessed between the day and night cohorts included comparisons of the postoperative complication rates and survival outcomes for both the renal allograft and the patient. A retrospective review of 633 deceased donor renal transplants performed at a single institution was analyzed. Three statistically significant results were noted, namely, a decrease in vascular complications in the nighttime cohort, an increase in urologic complications on subgroup analysis in the 3 AM to 6 AM cohort, and the 12 AM to 3 AM subgroup had the greatest odds of any complication. There was no statistical difference in either patient or graft survival over a twelve month period following transplantation. We conclude that although the complication rate varied among cohorts this was clinically insignificant and there was no overall clinically relevant impact on patient or graft survival.

Tc-99m-BrIDA hepatobiliary (HIDA) scan has a low sensitivity for detecting biliary complications after orthotopic liver transplantation in patients with hyperbilirubinemia.

BACKGROUND: Tc-99m-BrIDA hepatobiliary scans are noninvasive tests for detecting biliary leaks and obstructions. However, there is low sensitivity and specificity in patients with hyperbilirubinemia. Biliary complications (BC) are the Achilles heel of orthotopic liver transplantation (OLT). We questioned whether hyperbilirubinemia in liver transplant recipients rendered HIDA scanning less dependable. METHODS: HIDA findings were compared to endoscopic retrograde cholangiopancreatography, laparotomy, and clinical course. Results were categorized as follows: true positive (TP), true negative (TN), false positive (FP), false negative (FN), or nondiagnostic/inconclusive. We searched for variables associated with erroneous or nondiagnostic tests which we defined as all examinations determined to be FP, FN and/or nondiagnostic/inconclusive. RESULTS: Thirty-four patients underwent a HIDA scan. The sensitivity and specificity were 70 and 100%. The sensitivity of HIDA improved to 100% in patients with a total bilirubin (TB) <5 mg/dl. Inconclusive and FN patients had a total bilirubin >5 mg/dl. One FN had a TB <5 mg/dl, but was determined inconclusive due to the roux-en-Y. CONCLUSION: HIDA scans performed when the total bilirubin was <5 mg/dl had a high sensitivity and specificity for detecting biliary complications after OLT. However, when the total bilirubin exceeded 5 mg/dl, the specificity was still 100% but the numbers of nondiagnostic/inconclusive and FN exams were increased.

An extended treatment protocol with pegylated interferon and ribavirin for hepatitis C recurrence after liver transplantation.

AIM: To evaluate the efficacy and tolerability of an extended treatment protocol and to determine the predictors of sustained virological response (SVR) after liver transplantation (LT). METHODS: Between August 2005 and November 2008, patients with recurrent hepatitis C virus (HCV) after LT were selected for treatment if liver biopsy showed at least grade 2 inflammation and/or stage 2 fibrosis. All patients were to receive pegylated interferon (PEG)/regimens combining ribavirin (RBV) for an additional 48 wk after HCV undetectability. RESULTS: Extended protocol treatment was initiated in thirty patients. Overall, 73% had end of treatment response and 60% had SVR. Nineteen patients completed treatment per protocol, of them, sixteen (84%) had end of treatment response, and fourteen (74%) achieved SVR. Both early virological response and 24-week virological response were individually associated with SVR but this association was not significant on multivariate analysis. Eleven patients (37%) discontinued therapy due to adverse effects. Cytopenias were the most common and most severe adverse effect, and required frquent growth factor use, dose adjustments and treatment cessations. The risk of rejection was not increased. CONCLUSION: Recurrent HCV after LT can be safely treated with extended virological response-guided therpy using PEG/RBV, but requires close monitoring for treatment-related adverse effects, particularly cytopenias.

Severe hepatitis C virus recurrence is nearly universal after donation after cardiac death liver transplant.

OBJECTIVES: The rate of hepatitis C virus recurrence after donation after cardiac death liver transplant is not clearly defined. MATERIALS AND METHODS: This is a retrospective review of 39 donations after cardiac death-liver transplant recipients. Biopsies were performed at 6, 12, 24, and 36 months for all hepatitis C virus positive donation after cardiac death recipients. RESULTS: The 6-, 12-, 24-, and 36-month severe hepatitis C virus recurrence rates were 60%, 73%, 87%, and 94%. A histologic comparison group of 26 long-surviving hepatitis C virus positive donation after neurologic death recipients had severe hepatitis C virus recurrence 27%, 31%, 42%, and 52% of the time. Six of the 19 hepatitis C virus donation after cardiac death patients developed cirrhosis at a median of 56 months (range, 14-119 months). There was no significant 3-year allograft and patient survival difference between hepatitis C virus and nonhepatitis C virus donation after cardiac death recipients. The factors most associated with decreased survival in the entire cohort included biliary and vascular complications. Organs procured by our institution's attending surgeons were associated with a better 3-year allograft survival. CONCLUSIONS: Severe hepatitis C virus recurrence was nearly universal but did not lead to increased graft loss when compared with nonhepatitis C virus donation after cardiac death at 3 years. These data may justify early interferon treatment in these at-risk patients.

MELD score less than 15 predicts prolonged survival after transjugular intrahepatic portosystemic shunt for refractory ascites after liver transplantation.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is used in the management of refractory ascites (RA) and variceal bleeds. Little data exist on TIPS safety, efficacy, and survival after liver transplantation (LT). METHODS: We conducted a retrospective analysis of patients who underwent TIPS placement after LT for RA. Clinical success was defined as a reduction of portosystemic gradient (PSG) and resolution of RA. RESULTS: Twenty-six patients underwent TIPS. The most common indication for LT was hepatitis C virus (88%). Median time from LT to TIPS was 17 months (1-89 months). Median pre-TIPS model for end-stage liver disease (MELD) score was 15 (7-33). The median pre-TIPS PSG was 18 mm Hg (7-38 mm Hg). Median change in the PSG after TIPS was 11 mm Hg (1-27 mm Hg). Fifty-eight percent (15/26) of TIPS were considered clinically successful. Median post-TIPS patient survival was 15 months (1-109 months). Cumulative 1-year post-TIPS patient survival was 50%. On multivariate analysis, pre-TIPS MELD was a significant and independent predictor of patient survival (P<0.01). The 3- and 6-month patient mortality and graft loss for patients with a pre-TIPS MELD of more than or equal to 15 were significantly higher than those with a pre-TIPS MELD score of less than 15 (P<0.01). The overall median survival for patients with a pre-TIPS MELD score of more than or equal to 15 was 3 months (1-59 months) compared with 45 months (2-109 months) for patients with pre-TIPS MELD score of less than 15. CONCLUSIONS: TIPS after LT can be clinically effective in patients with RA with a MELD score less than 15. This suggests that TIPS could be used as a means to extend posttransplant survival but should be carefully individualized in patients with a MELD score more than or equal to 15.

Guillain-Barre syndrome associated with peginterferon alfa-2a for chronic hepatitis C: A case report.

The recommended therapy for chronic hepatitis C (CHC) infection is the combination of a Pegylated interferon and Ribavirin. Almost all such patients on combination therapy experience one or more adverse events during the course of treatment. Significant neurological side effects are rare. A few cases of Bell's Palsy, chronic inflammatory demyelinating polyneuropathy and even one case of acute demyelinating polyneuropathy with atypical features for Guillain-Barre syndrome (GBS) associated with Interferon therapy have been reported but no report of GBS with typical features has been published. We present a case report of typical GBS associated with Peginterferon alfa-2a and Ribavirin used for treatment of CHC infection.

Racial/ethnic disparity in kidney transplantation outcomes: influence of donor and recipient characteristics.

OBJECTIVE: The purpose of this study was to evaluate the basis for the racial/ethnic disparity in kidney allograft survival. METHODS: We conducted a retrospective study of 2130 patients who underwent kidney transplantation between January 1995 and December 2003. Patient and graft survivals were compared using Kaplan-Meier analysis. RESULTS: Black recipients were more likely than white recipients to have hepatitis C infection (24.6% vs 7.1%), current tobacco use (21.2% vs 13.1%), previous alcohol use (22.6% vs 9.7%), and past illicit drug use (13.6% vs 3.9%). Current employment was less common among blacks. Additionally, black recipients were more likely to have a prior kidney transplant (16.7% vs 11.0%) and to have a cadaver kidney donor (74% vs 56.5%). The 5-year allograft survival rate was 72% for whites and 59% for blacks (p < .01). Previous kidney transplantation, cadaveric donor, donor age, recipient employment status, and recipient tobacco use were associated with allograft survival in a Cox proportional hazard model. CONCLUSIONS: Graft survival rate in black kidney transplant recipients is significantly lower than whites, and this disparity can be partially explained by the low rate of live donors and a higher previous transplantation rate in blacks.