A double-blind randomized placebo-controlled trial of albumin in outpatients with hepatic encephalopathy: HEAL study.

BACKGROUND & AIMS: Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life (QoL), can persist. A double-blind, placebo-controlled randomized clinical trial was performed to determine the impact of albumin vs. saline on MHE and QoL in individuals with prior HE already on standard of care. METHODS: Outpatients with cirrhosis and prior HE, MHE and hypoalbuminemia already on treatment for HE were included. Patients on regular IV albumin infusions were excluded. Participants were randomized 1:1 to receive either weekly infusions of 25% IV albumin 1.5 g/kg or saline over 5 weeks. MHE was defined using either psychometric hepatic encephalopathy score (PHES), Stroop or critical clicker frequency. MHE, QoL (based on sickness impact profile [SIP] total, physical, psychosocial domain) and serum markers (inflammation, endothelial dysfunction, and ischemia-modified albumin) were compared between baseline, the final infusion visit (end-of-drug [EOD]) and 1-week post final infusion (end-of-study [EOS]). RESULTS: Forty-eight (24/group) participants were randomized and balanced (including by HE medication use) at baseline. Adverse events were similar, with MELD and ammonia remaining stable between/within groups. Albumin levels increased and ischemia-modified albumin decreased only in the albumin group at EOD and EOS vs. baseline. PHES and Stroop MHE reversal and improvement were greater in the albumin group at EOD and persisted at EOS. SIP total and psychosocial, but not physical, domain improved only in the albumin group at EOD and EOS vs. baseline. A significant reduction in IL-1ß and endothelial dysfunction markers was also observed in the albumin group. CONCLUSION: In a double-blind, placebo-controlled trial of outpatients with cirrhosis, prior HE and current MHE, albumin infusions were associated with improved cognitive function and psychosocial QoL, likely due to amelioration of endothelial dysfunction. CLINICAL TRIALS REGISTRATION: www. CLINICALTRIALS: gov NCT03585257. IMPACT AND IMPLICATIONS: Even after recovery from overt hepatic encephalopathy (HE), minimal HE (MHE), which impairs quality of life, can persist. We found that intravenous albumin infusions were associated with improved cognitive function and psychosocial quality of life, likely owing to amelioration of endothelial dysfunction, compared to placebo in outpatients with prior HE and current MHE. In patients who continue to demonstrate cognitive dysfunction and impaired quality of life despite standard of care therapy for HE, albumin infusions could be considered if these results are validated.

Metabolic reprogramming of the intestinal microbiome with functional bile acid changes underlie the development of NAFLD.

BACKGROUND AND AIMS: Bile acids are hepatic metabolites and have many properties considered to be relevant to the pathophysiology of NAFLD. Circulating levels of the intestinal microbiome-modified bile acid deoxycholate are increased in cirrhosis. APPROACH AND RESULTS: To further elucidate the role of bile acids and intestinal microbiota linked to bile acids in progressively severe NAFLD, a multiomic study of feces including 16S rRNA sequencing, microbial transcriptomics and metabolomics was performed in a cohort with varying phenotypes of NAFLD. Several bile acids of microbial origin derived from deoxycholic acid (DCA) (glycodeoxycholate, 7-ketodeoxycholic acid, dehydrocholic acid) increased with disease activity and fibrosis stage. These were linked to increased expression of microbial bile salt hydrolase, bile acid operon (BaiCD) and hydroxysteroid dehydrogenases (hdhA) required for DCA and downstream metabolite synthesis providing a mechanistic basis for altered bile acid profiles with disease progression. Bacteroidetes and several genera of Lachnospiraceae family containing DCA generating genes increased with increasing disease severity, whereas several potentially beneficial microbes sensitive to antibacterial effects of DCA e.g., Ruminococcaceae were decreased. The clinical relevance of these data was confirmed in an independent cohort enrolled in a clinical trial for NASH where at entry DCA and its conjugates were associated with advanced fibrosis. In patients treated with placebo, DCA declined in those with fibrosis regression and increased in those with fibrosis progression. DCA rose further in those with compensated cirrhosis when they experienced decompensation. CONCLUSIONS: These findings demonstrate a role for bile acids and the bile acid dependent microbiome in the development and progression of NAFLD and set the stage to leverage these findings for NASH biomarker development and for therapeutics.

Association Between Lipoprotein Particles and Atherosclerotic Events in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease,1 is independently associated with increased risk of cardiovascular disease (CVD), which is the leading cause of mortality in patients with NAFLD.2 This is likely caused by the centrality of the liver in lipid homeostasis. Prior cross-sectional studies have shown that NAFLD is associated with perturbations in lipid profile and atherogenic lipoprotein subparticles.3 Although statins improve lipid profile and CVD-associated mortality, residual CVD risk has been demonstrated in major statin trials.4,5 A key contributor to this residual risk is the limited ability of the standard lipid profile to precisely quantify atherogenic lipoprotein subparticles, such as small dense low-density lipoprotein (sdLDL), which might confer higher atherogenic risk. There are currently no studies evaluating the longitudinal impact of sdLDL on atherosclerotic events in NAFLD. Thus, we conducted a prospective study in patients with histologically confirmed NAFLD to better define the relationship among NAFLD, residual CVD risk, and sdLDL.

Prevalence and Severity of Nonalcoholic Fatty Liver Disease Among Caregivers of Patients With Nonalcoholic Fatty Liver Disease Cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, affecting nearly 1 in 3 Americans.1 Nonalcoholic steatohepatitis (NASH), the clinically aggressive variant of NAFLD, has a propensity of fibrosis progression and increased risk of cirrhosis and hepatocellular carcinoma. NASH-related cirrhosis is now the most rapidly growing indication for liver transplantation (LT).2 Disease recurrence and progression to advanced fibrosis after LT are high3; however, the key contributors of these are unknown. We hypothesized that patients with NASH cirrhosis reside in a microenvironment conducive to not only development of NASH but also fibrosis progression, which likely persist after LT and contribute to disease recurrence. The hypothesis was tested by performing vibration-controlled transient elastography (VCTE) in primary caregivers and cohabitants of patients with decompensated cirrhosis awaiting LT.

The presence and severity of nonalcoholic steatohepatitis is associated with specific changes in circulating bile acids.

The histologic spectrum of nonalcoholic fatty liver disease (NAFLD) includes fatty liver (NAFL) and steatohepatitis (NASH), which can progress to cirrhosis in up to 20% of NASH patients. Bile acids (BA) are linked to the pathogenesis and therapy of NASH. We (1) characterized the plasma BA profile in biopsy-proven NAFL and NASH and compared to controls and (2) related the plasma BA profile to liver histologic features, disease activity, and fibrosis. Liquid chromatography/mass spectrometry quantified BAs. Descriptive statistics, paired and multiple group comparisons, and regression analyses were performed. Of 86 patients (24 controls, 25 NAFL, and 37 NASH; mean age 51.8 years and body mass index 31.9 kg/m2 ), 66% were women. Increased total primary BAs and decreased secondary BAs (both P < 0.05) characterized NASH. Total conjugated primary BAs were significantly higher in NASH versus NAFL (P = 0.047) and versus controls (P < 0.0001). NASH had higher conjugated to unconjugated chenodeoxycholate (P = 0.04), cholate (P = 0.0004), and total primary BAs (P < 0.0001). The total cholate to chenodeoxycholate ratio was significantly higher in NAFLD without (P = 0.005) and with (P = 0.02) diabetes. Increased key BAs were associated with higher grades of steatosis (taurocholate), lobular (glycocholate) and portal inflammation (taurolithocholate), and hepatocyte ballooning (taurocholate). Conjugated cholate and taurocholate directly and secondary to primary BA ratio inversely correlated to NAFLD activity score. A higher ratio of total secondary to primary BA decreased (odds ratio, 0.57; P = 0.004) and higher conjugated cholate increased the likelihood of significant fibrosis (F≥2) (P = 0.007). Conclusion: NAFLD is associated with significantly altered circulating BA composition, likely unaffected by type 2 diabetes, and correlated with histological features of NASH; these observations provide the foundation for future hypothesis-driven studies of specific effects of BAs on specific aspects of NASH. (Hepatology 2018;67:534-548).

Coronary artery disease in decompensated patients undergoing liver transplantation evaluation.

Coronary artery disease (CAD) is an important contributor to morbidity and mortality in patients undergoing liver transplantation (LT). However, the current literature is limited by sampling bias and nondefinitive assessment of CAD. The current study examines the prevalence of CAD via per protocol coronary angiography and its relationship to etiology of liver disease in patients undergoing liver transplantation evaluation (LTE). Data on 228 patients were prospectively collected who had coronary angiography as part of LTE between 2011 and 2014. Coronary angiography was done in all patients age ≥50 years or with CAD risk factors. CAD was defined as any coronary artery stenosis, whereas stenosis ≥ 70% in distribution of 1 or 3 major coronary arteries was considered as single- or triple-vessel disease. CAD was detected in 36.8% of patients, with the highest prevalence among nonalcoholic steatohepatitis (NASH) patients with cirrhosis (52.8%). Prevalence of single-vessel disease was higher among patients with NASH compared with hepatitis C virus (HCV) and alcoholic cirrhosis (15.1% versus 4.6% versus 6.6%; P = 0.02). Similarly, patients with NASH were more likely to have triple-vessel disease when compared with HCV and alcoholic cirrhosis (9.4% versus 0.9% versus 0%; P = 0.001). While adjusting for traditional risk factors for CAD, only NASH as etiology of liver disease remained significantly associated with CAD. Complications from diagnostic coronary angiography or percutaneous coronary intervention were low (2.6%). In conclusion, patients undergoing LTE have a high prevalence of CAD, which varies widely depending on etiology of liver cirrhosis. The procedural complications from coronary angiography are low. Liver Transplantation 24 333-342 2018 AASLD.

Symptom Domain Groups of the Patient-Reported Outcomes Measurement Information System Tools Independently Predict Hospitalizations and Re-hospitalizations in Cirrhosis.

BACKGROUND: Patient-Reported Outcomes Measurement Information System (PROMIS) tools can identify health-related quality of life (HRQOL) domains that could differentially affect disease progression. Cirrhotics are highly prone to hospitalizations and re-hospitalizations, but the current clinical prognostic models may be insufficient, and thus studying the contribution of individual HRQOL domains could improve prognostication. AIM: Analyze the impact of individual HRQOL PROMIS domains in predicting time to all non-elective hospitalizations and re-hospitalizations in cirrhosis. METHODS: Outpatient cirrhotics were administered PROMIS computerized tools. The first non-elective hospitalization and subsequent re-hospitalizations after enrollment were recorded. Individual PROMIS domains significantly contributing toward these outcomes were generated using principal component analysis. Factor analysis revealed three major PROMIS domain groups: daily function (fatigue, physical function, social roles/activities and sleep issues), mood (anxiety, anger, and depression), and pain (pain behavior/impact) accounted for 77% of the variability. Cox proportional hazards regression modeling was used for these groups to evaluate time to first hospitalization and re-hospitalization. RESULTS: A total of 286 patients [57 years, MELD 13, 67% men, 40% hepatic encephalopathy (HE)] were enrolled. Patients were followed at 6-month (mth) intervals for a median of 38 mths (IQR 22-47), during which 31% were hospitalized [median IQR mths 12.5 (3-27)] and 12% were re-hospitalized [10.5 mths (3-28)]. Time to first hospitalization was predicted by HE, HR 1.5 (CI 1.01-2.5, p = 0.04) and daily function PROMIS group HR 1.4 (CI 1.1-1.8, p = 0.01), independently. In contrast, the pain PROMIS group were predictive of the time to re-hospitalization HR 1.6 (CI 1.1-2.3, p = 0.03) as was HE, HR 2.1 (CI 1.1-4.3, p = 0.03). CONCLUSIONS: Daily function and pain HRQOL domain groups using PROMIS tools independently predict hospitalizations and re-hospitalizations in cirrhotic patients.

Performance of non-invasive models of fibrosis in predicting mild to moderate fibrosis in patients with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: In non-alcoholic fatty liver disease, presence of fibrosis is predictive of long-term liver-related complications. Currently, there are no reliable and non-invasive means of quantifying fibrosis in those with non-alcoholic fatty liver disease. Therefore, we aimed to evaluate the performance of a panel of non-invasive models in predicting fibrosis in non-alcoholic fatty liver disease. METHODS: The accuracy of FibroMeter non-alcoholic fatty liver disease, fibrosis 4 and four other non-invasive models in predicting fibrosis in those with biopsy proven non-alcoholic fatty liver disease was compared. These models were constructed post hoc in patients who had necessary clinical information collected within 2 months of a liver biopsy. The areas under receiver operating characteristics curves were compared for each model using Delong analysis. Optimum cut-off for each model and fibrosis stage were calculated using the Youden index. RESULTS: The area under receiver operating characteristics curves for F ≥ 1 fibrosis for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease was 0.821 and 0.801 respectively. For F ≥ 3, the area under receiver operating characteristics curves was 0.866 for fibrosis 4 and 0.862 for FibroMeter non-alcoholic fatty liver disease. Delong analysis showed the area under receiver operating characteristics curves was statistically different for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease compared with BARD, BAAT and aspartate aminotransferase:alanine aminotransferase ratio for F ≥ 1 and F ≥ 3. Area under receiver operating characteristics curves were significantly different for fibrosis 4 and FibroMeter non-alcoholic fatty liver disease for F ≥ 3 compared with non-alcoholic fatty liver disease fibrosis score. At a fixed sensitivity of 90%, FibroMeter non-alcoholic fatty liver disease had the highest specificity for F ≥ 1 (52.4%) and F ≥ 3 (63.8%). In contrast, at a fixed specificity of 90%, fibrosis 4 outperformed other models with a sensitivity of 60.2% for F ≥ 1 and 70.6% for F ≥ 3 fibrosis. CONCLUSION: These non-invasive models of fibrosis can predict varying degrees of fibrosis from routinely collected clinical information in non-alcoholic fatty liver disease.

Severity of nonalcoholic fatty liver disease and progression to cirrhosis are associated with atherogenic lipoprotein profile.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is associated independently with increased cardiovascular mortality. Although NAFLD is associated with dyslipidemia, it is not clear whether recently identified markers of cardiovascular risk indicate liver disease progression in patients with histologically confirmed NAFLD. We evaluated an extensive panel of serum markers of cardiovascular risk in nondiabetic patients with histologically proven NAFLD. METHODS: We performed a case-control study in which we compared serum levels of laboratory markers of cardiovascular risk among 81 nondiabetic subjects with histologically confirmed NAFLD vs lean (N = 81) and obese (N = 81) individuals without NAFLD (based on liver fat score, controls). For ex vivo studies, liver tissues were obtained from subjects undergoing elective cholecystectomy or from a tissue repository. RESULTS: Subjects with NAFLD had increased serum levels of insulin, triglycerides, and apolipoprotein B; increased size and concentration of very large density lipoprotein particles; increased concentrations of low-density lipoprotein (LDL) particles and small dense LDL (sdLDL) cholesterol, and an increased percentage of sdLDL, compared with controls. Although nonalcoholic steatohepatitis was associated with a worse profile of serum atherogenic markers than NAFLD, these differences did not reach statistical significance. Despite hyperinsulinemia, triglyceride and apolipoprotein B levels, concentrations of LDL particles and LDL cholesterol, and sdLDL-related parameters decreased significantly in patients with cirrhosis. Ex vivo studies showed that patients with NAFLD had increased sensitivity of hepatic triglyceride levels and cholesterol synthesis to insulin, and that sensitivity increased the development of cirrhosis. CONCLUSIONS: Atherogenic dyslipidemia is related to increased insulin-induced hepatic lipid synthesis in patients with NAFLD. Reduced dyslipidemia in patients with cirrhosis is associated with increased insulin resistance and possibly failed lipid synthesis.

De novo hepatic steatosis drives atherogenic risk in liver transplantation recipients.

Nonalcoholic fatty liver disease is associated with cardiovascular disease (CVD) in the general population. Despite a high prevalence of de novo hepatic steatosis after liver transplantation (LT), there are no data exploring the association between hepatic steatosis after LT and atherogenic risk. The aim of the study was to explore the impact of hepatic steatosis on serum atherogenic markers in liver transplantation recipients (LTRs). Biomarkers of CVD risk were compared in 89 LTRs with no known history of dyslipidemia, ischemic heart disease, or graft cirrhosis. To avoid potential confounders, LTRs on oral hypoglycemic agents, exogenous insulin, corticosteroids, or lipid-lowering therapy were excluded. Only patients for whom histological assessment was available after LT were included in the study. Thirty-five LTRs had de novo hepatic steatosis after LT, whereas 54 did not. Both cohorts were similar with regards to age, sex, ethnicity, and follow-up from LT. Additionally, the traditional lipid profile was similar between the 2 cohorts. LTRs with hepatic steatosis had higher serum concentrations of small-dense low-density lipoprotein cholesterol (sdLDL-C; 34.8 ± 16.9 versus 22.7 ± 11.2 mg/dL; P < 0.001), sdLDL-C to low-density lipoprotein cholesterol ratio (32.6 ± 11.6 versus 24.6 ± 10.2; P < 0.01), small-dense low-density lipoprotein particle concentration (sdLDL-P; 770 ± 440 versus 486 ± 402 nmol/L; P < 0.01), very low density lipoprotein particle concentration (VLDL-P; 7.90 ± 7.91 versus 3.86 ± 3.18 nmol/L; P < 0.01), and very low density lipoprotein size (VLDL-size; 51.9 ± 6.4 versus 48.7 ± 6.3 nm; P = 0.06). LTRs with hepatic steatosis had higher serum insulin concentrations (27.8 ± 41.8 versus 11.7 ± 7.8 uU/mL; P < 0.01) but similar fasting glucose and hemoglobin A1c. Steatosis grade was directly related to sdLDL-C, sdLDL-P, insulin, VLDL-P, and VLDL-size. In multivariate analysis, the association between steatosis grade and sdLDL-C (ß = 0.03; P = 0.029), VLDL-size (ß = 0.316; P = 0.04), and low-density lipoprotein particle size (ß = -0.27; P = 0.05) was independent of sex, body mass index, age, diabetes mellitus, time from transplant, and indication for LT. In conclusion, de novo hepatic steatosis after LT is associated with atherogenic lipoproteins and independent of traditional CVD risk factors.

Nonalcoholic Steatohepatitis (NASH) Is Associated with a Decline in Pancreatic Beta Cell (ß-Cell) Function.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) represents a histological spectrum ranging from benign hepatic steatosis (NAFL) to nonalcoholic steatohepatitis (NASH). NAFLD is closely associated with insulin resistance (IR), and although the role of IR in NAFLD has been an area of intense investigation, there are limited data on pancreatic ß-cell function. AIM: To evaluate the pancreatic ß-cell function in NAFLD using the homeostatic model assessment-ß (HOMA-ß) and ß-cell index (BI). METHODS: HOMA-ß was measured in ninety-nine non-diabetic subjects with histologically confirmed NAFLD and compared to lean (age- and gender-matched) and obese (age-, gender-, and BMI-matched) controls. Using the values from an oral glucose tolerance test, BI was compared in 31 non-diabetic, non-cirrhotic subjects with NASH and gender- and BMI-matched controls. RESULTS: The subjects with NAFLD had higher HOMA-ß compared to both lean and obese controls (43.1 vs. 9 vs. 22.1 %, respectively, P < 0.05). HOMA-ß was directly related to serum alkaline phosphate, total bilirubin, and weight and inversely related to age. There was no difference in HOMA-ß between subjects with NAFL and NASH. Subjects with NASH had lower ß-cell function as measured by a lower BI (2.09 ± 1.64 vs. 7.74 ± 25.12; P = 0.04). In patients with NASH, BI was inversely associated with fibrosis independent of age, BMI, and serum ALT levels. In contrast, HOMA-ß was directly associated with fibrosis stage. CONCLUSION: NASH is associated with strained pancreatic ß-cell function in non-diabetic subjects. Future studies are necessary to evaluate the temporal relationship between ß-cell function and hepatic histology.

Immunochip analyses identify a novel risk locus for primary biliary cirrhosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants.

To further characterize the genetic basis of primary biliary cirrhosis (PBC), we genotyped 2426 PBC patients and 5731 unaffected controls from three independent cohorts using a single nucleotide polymorphism (SNP) array (Immunochip) enriched for autoimmune disease risk loci. Meta-analysis of the genotype data sets identified a novel disease-associated locus near the TNFSF11 gene at 13q14, provided evidence for association at six additional immune-related loci not previously implicated in PBC and confirmed associations at 19 of 22 established risk loci. Results of conditional analyses also provided evidence for multiple independent association signals at four risk loci, with haplotype analyses suggesting independent SNP effects at the 2q32 and 16p13 loci, but complex haplotype driven effects at the 3q25 and 6p21 loci. By imputing classical HLA alleles from this data set, four class II alleles independently contributing to the association signal from this region were identified. Imputation of genotypes at the non-HLA loci also provided additional associations, but none with stronger effects than the genotyped variants. An epistatic interaction between the IL12RB2 risk locus at 1p31and the IRF5 risk locus at 7q32 was also identified and suggests a complementary effect of these loci in predisposing to disease. These data expand the repertoire of genes with potential roles in PBC pathogenesis that need to be explored by follow-up biological studies.

Association between high-normal levels of alanine aminotransferase and risk factors for atherogenesis.

BACKGROUND & AIMS: Liver disease has been associated with cardiovascular disorders, but little is known about the relationship between serum levels of alanine aminotransferase (ALT) and markers of atherogenesis. We investigated the relationship between low-normal and high-normal levels of ALT and an extended panel of cardiovascular risk factors among individuals with no known diseases in a primary care setting. METHODS: We performed a retrospective analysis of data collected from 6442 asymptomatic patients at wellness visits to a primary care setting in central Virginia from 2010 through 2011. Serum levels of ALT were compared with levels of lipids and lipoproteins, as well as metabolic, inflammatory, and coagulation-related factors associated with risk for cardiovascular disease. RESULTS: Serum levels of ALT were higher than 40 IU/L in 12% of subjects, and in the high-normal range (19-40 IU/L in women and 31-40 IU/L in men) in 25% of subjects. ALT level was associated with the apolipoprotein B level, concentration and particle size of very-low-density lipoproteins, concentration of low-density lipoprotein (LDL) particles (LDL-P), and percentages of small dense LDL (sdLDL) and sdLDL-cholesterol (sdLDL-C) (P < .0001 for all). A high-normal level of ALT was associated with higher levels of LDL-C, LDL-P, sdLDL-C, and sdLDL particles (P < .001 for all). These effects were independent of age, body mass index, and hyperinsulinemia. Increasing levels of ALT and fasting hyperinsulinemia (>12 µU/mL) synergized with increasing levels of triglycerides, very-low-density lipoprotein particles, LDL-P, sdLDL-C, and percentage of sdLDL-C. Levels of APOA1, high-density lipoprotein-cholesterol, and high-density lipoprotein-class 2 were associated inversely with serum level of ALT (P < .0001 for all). CONCLUSIONS: In an analysis of asymptomatic individuals, increased serum levels of ALT (even high-normal levels) are associated with markers of cardiovascular disease.

Covert hepatic encephalopathy is independently associated with poor survival and increased risk of hospitalization.

OBJECTIVES: Despite the high prevalence of covert hepatic encephalopathy (CHE) in cirrhotics without previous overt HE (OHE), its independent impact on predicting clinically relevant outcomes is unclear. The aim of this study was to define the impact of CHE on time to OHE, hospitalization, and death/transplant in prospectively followed up patients without previous OHE. METHODS: Outpatient cirrhotics without OHE were enrolled and were administered a standard paper-pencil cognitive battery for CHE diagnosis. They were systematically followed up and time to first OHE development, hospitalization (liver-related/unrelated), and transplant/death were compared between CHE and no-CHE patients at baseline using Cox regression. RESULTS: A total of 170 cirrhotic patients (55 years, 58% men, 14 years of education, Model for End-Stage Liver Disease (MELD 9), 53% hepatitis C virus (HCV), 20% nonalcoholic etiology) were included, of whom 56% had CHE. The entire population was followed up for 13.0 ± 14.6 months, during which time 30% developed their first OHE episode, 42% were hospitalized, and 19% had a composite death/transplant outcome. Age, gender, etiology, the MELD score, and CHE status were included in Cox regression models for time to first OHE episode, hospitalization, death, and composite death/transplant outcomes. On Cox regression, despite controlling for MELD, those with CHE had a higher risk of developing OHE (hazard ratio: 2.1, 95% confidence interval 1.01-4.5), hospitalization (hazard ratio: 2.5, 95% confidence interval 1.4-4.5), and death/transplant (hazard ratio: 3.4, 95% confidence interval 1.2-9.7) in the follow-up period. CONCLUSIONS: Covert HE is associated with worsened survival and increased risk of hospitalization and OHE development, despite controlling for the MELD score. Strategies to detect and treat CHE may improve these risks.

Long term changes in liver histology following treatment of chronic hepatitis C virus.

BACKGROUND AND AIMS: The histologic hallmarks of chronic HCV include inflammation and fibrosis. The impact of interferon therapy on liver histology was evaluated. MATERIAL AND METHODS: The study population consisted of 348 patients with chronic HCV who underwent a baseline liver biopsy, received either no treatment or a single course of interferon based therapy, were followed for 5 years without any treatment or additional treatment and then underwent a repeat liver biopsy. The patients were divided into 3 groups; deferred treatment (NoTx = 47), received interferon based therapy but failed to achieve SVR (NoSVR = 189) and achieved SVR (SVR = 112). RESULTS: Patients with NoTx and NoSVR had significant increases in mean inflammation scores (from 4.3 to 6.3 and 5.4 to 6.7 respectively; p < 0.001 for both) and fibrosis scores (from 0.9 to 1.8 and 1.9 to 2.5; p < 0.001 for both). The amounts by which inflammation, fibrosis and rate of fibrosis progression increased were not significantly different between the two groups. Increases in total inflammation and the piecemeal necrosis sub-score over time were strongly associated with fibrosis progression. Patients with SVR had a significant decline in mean inflammation and fibrosis scores (from 6.7 to 2.2 and 3.3 to 1.8; p < 0.001 for both); 40% of patients resolved all fibrosis and 50% of patients resolved cirrhosis. CONCLUSION: Increases in inflammation are associated with fibrosis progression and in the absence of SVR interferon treatment does not appear to affect the long term natural history of this process. Patients with SVR have resolution of inflammation and fibrosis and many resolve cirrhosis.

Minimal effects of acute liver injury/acute liver failure on hemostasis as assessed by thromboelastography.

BACKGROUND & AIMS: Patients with acute liver injury/failure (ALI/ALF) are assumed to have a bleeding diathesis on the basis of elevated INR; however, clinically significant bleeding is rare. We hypothesized that patients with ALI/ALF have normal hemostasis despite elevated INR. METHODS: Fifty-one patients with ALI/ALF were studied prospectively using thromboelastography (TEG), which measures the dynamics and physical properties of clot formation in whole blood. ALI was defined as an INR ≥1.5 in a patient with no previous liver disease, and ALF as ALI with hepatic encephalopathy. RESULTS: Thirty-seven of 51 patients (73%) had ALF and 22 patients (43%) underwent liver transplantation or died. Despite a mean INR of 3.4±1.7 (range 1.5-9.6), mean TEG parameters were normal, and 5 individual TEG parameters were normal in 32 (63%). Low maximum amplitude, the measure of ultimate clot strength, was confined to patients with platelet counts <126×10(9)/L. Maximum amplitude was higher in patients with ALF than ALI and correlated directly with venous ammonia concentrations and with increasing severity of liver injury assessed by elements of the systemic inflammatory response syndrome. All patients had markedly decreased procoagulant factor V and VII levels, which were proportional to decreases in anticoagulant proteins and inversely proportional to elevated factor VIII levels. CONCLUSIONS: Despite elevated INR, most patients with ALI/ALF maintain normal hemostasis by TEG, the mechanisms of which include an increase in clot strength with increasing severity of liver injury, increased factor VIII levels, and a commensurate decline in pro- and anticoagulant proteins.

Substitution of tenofovir/emtricitabine for Hepatitis B immune globulin prevents recurrence of Hepatitis B after liver transplantation.

BACKGROUND: Hepatitis B immune globulin (HBIg) with or without nucleos(t)ide analogue (NA) inhibitors has been shown to prevent recurrence of hepatitis B virus (HBV) following orthotopic liver transplantation (OLT). However, the use of HBIg has many disadvantages. AIMS: The present study was performed to determine if converting patients from HBIg ± NA to combination NA therapy could prevent recurrence of HBV. METHODS: Twenty-one recipients without evidence of HBV recurrence on HBIg ± NA for ≥ 6 months were enrolled. Patients received their last injection of HBIg at the time they initiated tenofovir disoproxil fumarate/emtricitabine (TDF/FTC; Truvada(®) ) and were followed up for 31.1 ± 9.0 [range 15-47] months. RESULTS: After 1 year, 3 patients (14%) had detectable HBsAg, one of whom was non-compliant. Two of 3 with recurrence cleared HBsAg by last follow-up on TDF/FTC; the non-compliant patient became HBV DNA-undetectable with re-institution of TDF/FTC. TDF/FTC saved $12,469/year over our standard-of-care, monthly intramuscular HBIg/lamivudine. There was no evidence of a general adverse effect of TDF/FTC on renal function. However, 3 patients developed reversible acute renal failure; on renal biopsy, 1 had possible TDF/FTC-induced acute tubular necrosis. CONCLUSIONS: Substitution of TDF/FTC for HBIg prevented recurrence of HBV DNA in 100% (20/20) of patients who were compliant with the medication and led to substantial cost savings over HBIg-containing regimens.

High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis.

OBJECTIVES: Some studies have suggested that ursodeoxycholic acid (UDCA) may have a chemopreventive effect on the development of colorectal neoplasia in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We examined the effects of high-dose (28-30 mg/kg/day) UDCA on the development of colorectal neoplasia in patients with UC and PSC. METHODS: Patients with UC and PSC enrolled in a prior, multicenter randomized placebo-controlled trial of high-dose UDCA were evaluated for the development of colorectal neoplasia. Patients with UC and PSC who received UDCA were compared with those who received placebo. We reviewed the pathology and colonoscopy reports for the development of low-grade or high-grade dysplasia or colorectal cancer. RESULTS: Fifty-six subjects were followed for a total of 235 patient years. Baseline characteristics (including duration of PSC and UC, medications, patient age, family history of colorectal cancer, and smoking status) were similar for both the groups. Patients who received high-dose UDCA had a significantly higher risk of developing colorectal neoplasia (dysplasia and cancer) during the study compared with those who received placebo (hazard ratio: 4.44, 95% confidence interval: 1.30-20.10, P=0.02). CONCLUSIONS: Long-term use of high-dose UDCA is associated with an increased risk of colorectal neoplasia in patients with UC and PSC.

The predictors of the presence of varices in patients with primary sclerosing cholangitis.

UNLABELLED: The predictors for developing varices in patients with primary sclerosing cholangitis (PSC) have not been well studied prospectively. We sought to define the predictors for the presence of varices at baseline and for newly developing varices in patients with PSC. We used prospectively collected data from a multicenter randomized trial of high dose ursodeoxycholic acid for PSC. All 150 patients enrolled were reviewed for predictors of varices and we excluded 26 patients who had esophageal varices at baseline so that predictors of newly developing varices could be determined. Clinical examination, blood tests, and upper endoscopy were done before randomization, at 2 years and after 5 years. Liver biopsy was performed at entry and at 5 years. The median age (interquartile range) of patients was 45.9 years (35.8, 54.9). In a multivariable logistic regression, a higher Mayo risk score (> or =0.87) or a higher aspartate/alanine aminotransferase (AST/ALT) ratio (> or =1.12) were significantly associated with the presence of varices at initial endoscopy (odds ratio = 1.9 and 3.9). By the end of the study, 25 patients had new varices (20.2%). In a Cox model, after adjustment for baseline variables lower platelet count and higher total bilirubin at 2 years were significantly associated with the presence of new varices. The platelet count of 205 (x 10(9)/L) and the total bilirubin level of 1.7 mg/dL were the best cutoff values for the detection of new varices. CONCLUSION: A higher Mayo risk score and higher AST/ALT ratio were significantly associated with the presence of varices at initial endoscopy. Lower platelet count and higher total bilirubin at 2 years were significantly associated with an increased risk of developing new varices in patients with PSC.