Bilal Hameed

Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial

BACKGROUND The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis. METHODS We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase -24%, 95% CI -45 to -3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0·0024) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498. FINDINGS Between March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group (relative risk 1·9, 95% CI 1·3 to 2·8; p=0·0002). 33 (23%) of 141 patients in the obeticholic acid developed pruritus compared with nine (6%) of 142 in the placebo group. INTERPRETATION Obeticholic acid improved the histological features of non-alcoholic steatohepatitis, but its long-term benefits and safety need further clarification. FUNDING National Institute of Diabetes and Digestive and Kidney Diseases, Intercept Pharmaceuticals.

Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumors within Milan criteria.

We report on the long‐term intention‐to‐treat (ITT) outcome of 118 patients with hepatocellular carcinoma (HCC) undergoing downstaging to within Milan/United Network for Organ Sharing T2 criteria before liver transplantation (LT) since 2002 and compare the results with 488 patients listed for LT with HCC meeting T2 criteria at listing in the same period. The downstaging subgroups include 1 lesion >5 and ≤8 cm (n = 43), 2 or 3 lesions at least one >3 and ≤5 cm with total tumor diameter ≤8 cm (n = 61), or 4‐5 lesions each ≤3 cm with total tumor diameter ≤8 cm (n = 14). In the downstaging group, 64 patients (54.2%) had received LT and 5 (7.5%) developed HCC recurrence. Two of the five patients with HCC recurrence had 4‐5 tumors at presentation. The 1‐ and 2‐year cumulative probabilities for dropout (competing risk) were 24.1% and 34.2% in the downstaging group versus 20.3% and 25.6% in the T2 group (P = 0.04). Kaplan‐Meiers 5‐year post‐transplant survival and recurrence‐free probabilities were 77.8% and 90.8%, respectively, in the downstaging group versus 81% and 88%, respectively, in the T2 group (P = 0.69 and P = 0.66, respectively). The 5‐year ITT survival was 56.1% in the downstaging group versus 63.3% in the T2 group (P = 0.29). Factors predicting dropout in the downstaging group included pretreatment alpha‐fetoprotein ≥1,000 ng/mL (multivariate hazard ratio [HR]: 2.42; P = 0.02) and Childs B versus Childs A cirrhosis (multivariate HR: 2.19; P = 0.04). Conclusion: Successful downstaging of HCC to within T2 criteria was associated with a low rate of HCC recurrence and excellent post‐transplant survival, comparable to those meeting T2 criteria without downstaging. Owing to the small number of patients with 4‐5 tumors, further investigations are needed to confirm the efficacy of downstaging in this subgroup. (Hepatology 2015;61:1968–1977)

Alpha-fetoprotein level > 1000 ng/mL as an exclusion criterion for liver transplantation in patients with hepatocellular carcinoma meeting the Milan criteria.

Serum alpha‐fetoprotein (AFP) has been increasingly recognized as a marker for a poor prognosis after liver transplantation (LT) for hepatocellular carcinoma (HCC). Many published reports, however, have included a large proportion of patients with HCC beyond the Milan criteria, and the effects of incorporating AFP as an exclusion criterion for LT remain unclear. We studied 211 consecutive patients undergoing LT for HCC within the Milan criteria according to imaging under the Model for End‐Stage Liver Disease organ allocation system between June 2002 and January 2009. The majority (93.4%) had locoregional therapy before LT. The median follow‐up was 4.5 years (minimum = 2 years). The Kaplan‐Meier 1‐ and 5‐year patient survival rates were 94.3% and 83.4%, respectively. In a univariate analysis, significant predictors of HCC recurrence included vascular invasion [hazard ratio (HR) = 10, 95% confidence interval (CI) = 3.9‐26, P < 0.001], a pathological tumor stage beyond the University of California San Francisco criteria (HR = 4.1, 95% CI = 1.36‐12.6, P = 0.01), an AFP level > 1000 ng/mL (HR = 4.5, 95% CI = 1.3‐15.3, P = 0.02), and an AFP level > 500 ng/mL (HR = 3.1, 95% CI = 1.04‐9.4, P = 0.04). In a multivariate analysis, vascular invasion was the only significant predictor of tumor recurrence (HR = 5.6, 95% CI = 1.9‐19, P = 0.02). An AFP level > 1000 ng/mL was the strongest pretransplant variable predicting vascular invasion (odds ratio = 6.8, 95% CI = 1.6‐19.1, P = 0.006). The 1‐ and 5‐year rates of survival without recurrence were 90% and 52.7%, respectively, for patients with an AFP level > 1000 ng/mL and 95% and 80.3%, respectively, for patients with an AFP level ≤ 1000 ng/mL (P = 0.026). Applying an AFP level > 1000 ng/mL as a cutoff would have resulted in the exclusion of 4.7% of the patients from LT and a 20% reduction in HCC recurrence. In conclusion, an AFP level > 1000 ng/mL may be a surrogate for vascular invasion and may be used to predict posttransplant HCC recurrence. Incorporating an AFP level > 1000 ng/mL as an exclusion criterion for LT within the Milan criteria may further improve posttransplant outcomes. Liver Transpl 20:945‐951, 2014.

Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients

The characteristics of nonalcoholic fatty liver disease (NAFLD) in elderly patients are unknown. Therefore, we aimed to examine the differences between elderly and nonelderly patients with NAFLD and to identify determinants of nonalcoholic steatohepatitis (NASH) and advanced fibrosis (bridging fibrosis or cirrhosis) in elderly patients. This is a cross‐sectional analysis of adult participants who were prospectively enrolled in the NASH Clinical Research Network studies. Participants were included based on availability of the centrally reviewed liver histology data within 1 year of enrollment, resulting in 61 elderly (age ≥65 years) and 735 nonelderly (18‐64 years) participants. The main outcomes were the presence of NASH and advanced fibrosis. Compared to nonelderly patients with NAFLD, elderly patients had a higher prevalence of NASH (56% versus 72%, P = 0.02), and advanced fibrosis (25% versus 44%, P = 0.002). Compared to nonelderly patients with NASH, elderly patients with NASH had higher rates of advanced fibrosis (35% versus 52%, P = 0.03), as well as other features of severe liver disease including the presence of ballooning degeneration, acidophil bodies, megamitochondria, and Mallory‐Denk bodies (P ≤ 0.05 for each). In multiple logistic regression analyses, independent determinants of NASH in elderly patients included higher aspartate aminotransferase (AST) (odds ratio [OR] = 1.12, P = 0.007) and lower platelets (OR = 0.98, P = 0.02); and independent determinants of advanced fibrosis included higher AST (OR = 1.08, P = 0.007), lower alanine aminotransferase value (OR = 0.91, P = 0.002), and an increased odds of having low high‐density lipoprotein (OR = 8.35, P = 0.02). Conclusion: Elderly patients are more likely to have NASH and advanced fibrosis than nonelderly patients with NAFLD. Liver biopsy may be considered in elderly patients and treatment should be initiated in those with NASH and advanced fibrosis. (HEPATOLOGY 2013;58:1644–1654)

Outcomes in Adults With Acute Liver Failure Between 1998 and 2013: An Observational Cohort Study.

Context Whether changes have occurred in the causes of acute liver failure (ALF), its management, or the survival of patients with the condition (with or without liver transplantation) is not known. Contribution This large cohort study found that despite similar causes and severity of ALF among patients referred to specialty centers from 1998 to 2013, the proportion of patients listed for liver transplantation decreased and survival improved among those who did not receive a transplant as well as those who did. Implication More study is warranted to better understand the specific changes in care that may have led to improved survival of patients with ALF. Acute liver failure (ALF) is defined as severe liver injury with rapid onset that results in hepatic encephalopathy (HE) and coagulopathy in persons without preexisting liver disease. The principal causes of ALF include acetaminophen (N-acetyl-p-aminophenol [APAP]) overdose, ischemic and pregnancy-associated liver injury, acute infection with hepatitis A or B virus, drug-induced liver injury, autoimmune hepatitis, BuddChiari syndrome, and Wilson disease (1, 2). For some causes, such as APAP toxicity, outcomes are favorable and transplant-free survival (TFS) approaches 70%, whereas other causes have unfavorable outcomes, including a much lower likelihood (<30%) of recovery without liver transplantation (2). One-year survival after emergency liver transplantation in patients with ALF in the United States and Europe is reportedly good but is lower than among patients with cirrhosis who receive a transplant (3). Patients with ALF often deteriorate rapidly and therefore receive the most urgent ranking (status 1) in the United Network for Organ Sharing transplantation system. Treatment of ALF in the intensive care unit is largely supportive and includes ventilator and vasopressor support for respiratory and/or circulatory failure, renal replacement therapy, plasma and blood transfusions, antibiotics, and measures to decrease intracranial pressure (46). N-acetylcysteine is used to treat APAP overdose and has shown efficacy in patients with ALF not due to APAP toxicity, particularly those referred early and having only mild HE (7). However, few disease-specific or general treatments are available that yield improved outcomes. In this study, our aim was to update the U.S. experience with ALF at specialized liver disease and transplant centers since the last published overview by the Acute Liver Failure Study Group (ALFSG) in 2002 (2). This group initiated its registry in January 1998 to better characterize the causes, clinical features, and outcomes of this super-orphan condition and aimed to enroll cases prospectively from participating liver transplant centers across North America. Accordingly, we analyzed data on all patients with ALF enrolled between 1998 and 2013, focusing on whether clinical features or outcomes of the ALF syndrome have changed over time. In addition, we sought to determine the relationship between ALF causes and rates of TFS and whether utilization of liver transplantation changed in the 16-year observation period. Methods Study Population From 1 January 1998 through 31 December 2013, adult patients were consecutively enrolled in the ALFSG registry (2) from 31 U.S. academic liver centers (of which only 5 legacy sites participated continuously throughout the 16-year period). All enrolled patients had both coagulopathy (international normalized ratio [INR] 1.5) and any grade of HE (as clinically defined by the classic West Haven criteria [8]) within 26 weeks of the first symptoms and had no evidence of significant chronic liver disease, especially cirrhosis. Patients for whom prior liver transplantation failed (due to primary graft nonfunction or other causes) were excluded. During the 16-year period, the number of sites participating, their geographic locations, and the number of cases contributed per site varied depending on each sites ability to continually identify and enroll patients over time (Appendix Figure 1). Appendix Figure 1. Site enrollment over time. Patients were usually admitted to intensive care units; 82.4% were hospitalized before transfer to the referral tertiary care study site, and the remainder were admitted directly to the study site. All were screened for inclusion according to the ALF criteria defined earlier. Written informed consent was obtained from the legal next of kin. A log of screen failures and consent refusal was maintained. All centers complied with local institutional review board requirements. Data Management and Integrity At enrollment into the study, we prospectively collected patient demographic characteristics (age, sex, race, and ethnicity); a complete medical history, including the timing of the first symptom of ill health, onset of jaundice and HE, and the number of days between the first symptom, hospital admission, transfer to the study site (where relevant), and enrollment in the study; and clinical features, including blood pressure and need for vasopressor support, mechanical ventilation, and renal replacement therapy, which allowed calculation of the systemic inflammatory response syndrome (SIRS) score (9). We also collected standard liver and metabolic test results and clinical data daily for up to 7 days, as well as serologic and other tests to determine the cause. All data were managed and housed on a central server at the Medical University of South Carolina. A data query system and periodic monitoring are in place to manage data integrity. In addition, ALFSG leadership conducted annual visits to clinical sites to verify data and ensure compliance with study procedures. Statistical Analysis Statistical analyses were performed using SAS, version 9.4 (SAS Institute). Missing values were not replaced or estimated. Patients with missing data were excluded from the respective analyses for those variables, and patients who were lost to follow-up before 21 days were excluded from the study. Descriptive statistics were used to characterize the demographic and other clinical variables. Categorical variables were compared using the chi-square test or the Fisher exact test (the latter when expected cell counts were <5). Medians were reported with interquartile ranges (IQRs) and were compared with the Wilcoxon rank-sum test. Survival and transplant outcomes at 21 days after study enrollment were classified as TFS (survival without liver transplantation), liver transplantation, or death (2). Outcomes were also determined at 1 and 2 years after study enrollment, but these data were less complete than the 21-day outcome data. Survival rates over time were assessed descriptively at the individual-site level to verify that changes in TFS were not affected by varying accrual of patients from different sites. Treatment utilization and survival and transplant outcomes were analyzed over time annually for trends and were also stratified into two 8-year periods: early (1998 to 2005) and later (2006 to 2013). Trends over time were analyzed using the CochranArmitage test. A significance level of less than 0.05 was used for all comparisons. Role of the Funding Source This study was funded by the National Institutes of Health. The funding source had no direct role in the design, conduct, or reporting of the study. Results Demographic Characteristics and Comorbidities During the 16-year study, 2070 patients (median age, 39.0 years [IQR, 29.0 to 52.0 years]) were enrolled in the ALFSG registry. Over the same interval, there were 660 confirmed ALF screen failures (286 due to failure to meet inclusion criteria, 212 for whom consent could not be obtained, and 162 for other reasons). Among enrolled patients, 69.3% were women and 76.4% were white (Table 1). Patients did not differ in sex, race, or ethnicity between the two 8-year periods but were significantly older and heavier in the later period. Prevalence of hypertension, heart disease, diabetes, psychiatric illness, and substance dependency all increased significantly between the early and later periods, whereas prevalence of renal disease did not. Table 1. Demographic Characteristics, Comorbidities, Clinical Severity, and Causes at Admission Causes and Clinical Severity of ALF The percentage of enrollment as a reflection of the most common causes of ALF did not change during the two 8-year periods. Hepatotoxicity due to APAP accounted for almost half the cases of ALF for the entire 16-year period (Table 1), with the highest annual prevalence (53.0%) occurring in 2013. Unintentional APAP overdoses (those in which patients took excessive medication over several days for such ailments as pain, malaise, or fever [10, 11]) were more common than intentional (suicidal) overdoses. Hepatitis A virus infection was significantly less evident during the later period (9 cases [0.8%]) than the early period (28 cases [2.8%]) (P< 0.001). Hepatic ischemia and autoimmune hepatitis increased modestly, whereas hepatitis B virus infection, drug-induced liver injury, Wilson disease, and BuddChiari syndrome were less frequently noted. Patients entered either the primary or the referral (study) site more rapidly after initial symptom onset in the later period (2.0 days [IQR, 0.0 to 8.0 days]) than the early period (3.0 days [IQR, 1.0 to 14.0 days]) (P< 0.001) (Table 1). However, the corresponding interval between symptom onset and HE onset was 4.0 days in both the early (IQR, 1.0 to 15.0 days) and later (IQR, 1.0 to 12.0 days) periods, and time from onset of jaundice to enrollment also was unchanged (3.0 days in each period [IQRs, 1.0 to 12.0 and 1.0 to 10.0 days, respectively]). Most patients with ALF were severely ill at study enrollment, with nearly 50% having grade 3 or 4 (that is, deep) HE throughout. Biochemical liver test results varied widely but indicated severe illness in most patients (Appendix Table 1). Appendix Table 1. Laboratory Values at Study Enrollment Laboratory Tests fo

Acute Perfusion and Diffusion Abnormalities Predict Early New MRI Lesions 1 Week After Minor Stroke and Transient Ischemic Attack

Background and Purpose— Transient ischemic attack and minor stroke are associated with high ischemic recurrence in the first week. We prospectively studied the correlation between baseline diffusion/perfusion deficits and development of new ischemic lesions. Methods— Patients with transient ischemic attack and those with minor stroke (n=50) underwent MRI at admission. Acute perfusion-weighted imaging deficit (Tmax+2-second delay) and diffusion-weighted imaging (DWI) lesion volumes were measured planimetrically. Follow-up scans were examined for new DWI/fluid-attenuated inversion recovery lesions at Days 7 and 30. Results— Twenty-eight patients (56%) had acute DWI lesions. New DWI lesions developed in 9 of 50 patients (18%) at 1 week and 11 of 50 (cumulative 22%) at 4 weeks. Patients with new infarcts were more likely to have baseline DWI lesions (&khgr;2=8.264, P=0.003). Baseline DWI lesion volume was significantly larger in those who developed new lesions at Day 7 (median, 13.2 mL; interquartile range, 12 versus median 0.1 mL; interquartile range, 2 mL; P<0.001) and Day 30 (11.1 mL; interquartile range, 13 mL versus 0.1 mL; interquartile range, 13 mL; P<0.001). Thirty-eight patients had baseline perfusion-weighted imaging. Patients with recurrent lesions were more likely to have baseline perfusion deficits (&khgr;2=19.5, P<0.0001). All new lesions developed within the baseline hypoperfused regions. Baseline DWI lesion volume predicted new lesion development at day 7 (OR, 1.17 per mL; CI, 1.05 to 1.30; P=0.005) and Day 30 (OR, 1.39 per mL; CI, 1.03 to 1.26; P=0.009) by regression analysis. Conclusions— Early recurrence of stroke is much more likely in patients with larger baseline DWI and perfusion-weighted imaging lesions. MRI lesion “recurrence” appears to be related to completion of the natural history of the original cerebrovascular syndrome rather than de novo events in most patients.

Oxfordshire Community Stroke Project Classification Poorly Differentiates Small Cortical and Subcortical Infarcts

Background and Purpose— The Oxfordshire Community Stroke Project (OCSP) is a common clinical stroke classification tool. We evaluated the accuracy of OCSP classification with a prospective magnetic resonance imaging (MRI) study. Methods— Stroke/transient ischemic attack patients presenting within 48 hours of onset were included in the study (n=130). Following computed tomography scan, OCSP classification, total anterior circulation infarcts (TACI), partial anterior circulation infarcts (PACI), lacunar circulation infarcts (LACI), and posterior circulation infarcts (POCI) were performed by 3 independent examiners. All patients underwent diffusion-weighted MRI with planimetric volume measurement and classification into OCSP categories, organized by lesion location. Results— Patients were clinically classified as TACI (12 patients), PACI (62 patients), LACI (38 patients), and POCI (18 patients). In 101 patients with diffusion-weighted MRI lesions, correct classification rates were: TACI (83.3%), PACI (83%), LACI (39%), and POCI (86%). OCSP had the following sensitivity (SE), specificity (SP), and positive predictive value (PPV): TACI (SE, 100%; SP, 98%; PPV, 83%), PACI (SE, 73%; SP, 78%; PPV, 83%), LACI (SE, 47%; SP, 83%; PPV, 39%), and POCI (SE, 92%; SP, 98%; PPV, 86%). Sixty-one percent of patients in the LACI group had radiographic appearances consistent with PACI, and 15% of those classified as PACI had lacunar infarcts. No differences in stroke severity existed between patients classified correctly (median National Institutes of Health Stroke Scale [NIHSS]=4; interquartile range [IQR]=7) or incorrectly (median NIHSS=3; IQR=3). Patients classified correctly had larger infarct volume (median=6.75 mL; IQR=33.2) than did those who were incorrectly classified (1.86 mL; IQR=5; P=0.008). Conclusions— OCSP classification does not permit accurate discrimination between lacunar and small-volume cortical infarcts. Differential patterns of investigation for stroke etiology should not be based solely on clinical criteria.

Emergent Orthotopic Liver Transplantation for Hemorrhage from a Giant Cavernous Hepatic Hemangioma: Case Report and Review

IntroductionCavernous hemangiomas represent the most common benign primary hepatic neoplasm, often being incidentally detected. Although the majority of hepatic hemangiomas remain asymptomatic, symptomatic hepatic hemangiomas can present with abdominal pain, hemorrhage, biliary compression, or a consumptive coagulopathy. The optimal surgical management of symptomatic hepatic hemangiomas remains controversial, with resection, enucleation, and both deceased donor and living donor liver transplantation having been reported.Case ReportWe report the case of a patient found to have a unique syndrome of multiorgan cavernous hemangiomatosis involving the liver, lung, omentum, and spleen without cutaneous involvement. Sixteen years following her initial diagnosis, the patient suffered from intra-abdominal hemorrhage due to her giant cavernous hepatic hemangioma. Evidence of continued bleeding, in the setting of Kasabach-Merritt Syndrome and worsening abdominal compartment syndrome, prompted MELD exemption listing. The patient subsequently underwent emergent liver transplantation without complication.ConclusionAlthough cavernous hemangiomas represent the most common benign primary hepatic neoplasm, hepatic hemangioma rupture remains a rare presentation in these patients. Management at a center with expertise in liver transplantation is warranted for those patients presenting with worsening DIC or hemorrhage, given the potential for rapid clinical decompensation.

Combined effects of recipient age and model for end-stage liver disease score on liver transplantation outcomes.

Background The proportion of older patients awaiting liver transplantation (LT) is rising. Although increased age and LT-MELD are known to increase the risk of graft loss, no studies have explored whether there is a synergistic effect between LT-age and LT-MELD. Methods All US adult, non-Status 1 recipients of primary deceased donor LT from 2/05 to 1/10 without MELD exceptions were included (n=15,677). Recipients were categorized by LT-age [18–59 yr (n=11,966), 60–64 yr (n=2181), 65–69 yr (n=1177), and ≥70 yr (n=343)] and LT-MELD [low (<20, n=5290), mid (20–27, n=5112), and high (≥28, n=5265)]. Adjusted Cox models evaluated the independent and combined effects of LT-age and LT-MELD on graft loss (death or re-LT). Results LT-age ≥70 yr (HR=1.65, 95% CI 1.08–1.82) and LT-MELD ≥28 (HR=1.46, 95% CI 1.02–1.47) were independently associated with increased risk of graft loss (P<0.001). In a model allowing for the interaction between LT-age and LT-MELD, the risk of graft loss for recipients ≥70 years with MELD ≥28 was higher than predicted by the additive model (HR=2.38, 95% CI 1.73–3.27, P<0.001) resulting in 1-year graft survival of 56%. However, the increased risk of graft loss in recipients ≥70 years was attenuated at lower LT-MELD <28. Furthermore, the interaction term was not significant for any other LT-age and LT-MELD combination. Conclusion Our analyses suggest that recipients should not be excluded solely based on age; however, LT for recipients ≥70 years at high LT-MELD scores should be undertaken cautiously.

Pretransplant severe hepatic encephalopathy, peritransplant sodium and post‐liver transplantation morbidity and mortality

Hepatic encephalopathy (HE) does not enhance the prediction of model of end‐stage liver disease (MELD) wait‐list mortality, but its influence on post‐liver transplantation (LT) morbidity and mortality is largely unknown.