A review of the utility of tacrolimus in the management of adults with autoimmune hepatitis.

BACKGROUND: There is paucity of data on alternative drug therapies for patients with autoimmune hepatitis (AIH). Tacrolimus (TAC) is a promising salvage agent. We present a review of TAC therapy in AIH patients. METHODS: A search for studies with keywords 'autoimmune hepatitis' and 'tacrolimus' was performed. Reviews, studies of AIH post-transplant and AIH in children were excluded. Diagnosis of AIH was based on criteria established by the International Autoimmune Hepatitis Group. Complete biochemical response was defined as normalisation of aspartate aminotransferase (AST <45) and alanine aminotransferase (ALT <50). No biochemical response was defined as failure to return to normalisation at the end of follow-up. Demographic information and details of pre- and post-treatment liver biopsy were collected. RESULTS: Seven articles achieved the inclusion criteria and reported data for a total of 162 adult patients. The majority of studies reported average ages approximately 35 years old. Treatment duration ranged from 1 to 136 months. Indications for therapy were mostly AIH refractory to steroid treatment or inability to tolerate standard steroid treatment. Eighty-three patients (51.2%) were reported to have pre-therapy liver biopsy. Of 49 patients for whom stage was reported, 6 patients were stage 1, 16 were stage 2, 14 were stage 3 and 13 were stage 4. Of 40 patients for whom grade was reported, 1 patient was grade 0, 3 were grade 1, 9 were grade 2, 14 were grade 3 and 13 were grade 4. Dosing regimens were between 1 and 8 mg/day. Target trough TAC serum concentrations ranged from 0.5 to 10.7 ng/mL TAC was discontinued in 28 (17.3%) patients for various reasons. Renal function remained stable in most patients. One hundred and twenty-one patients (74.7%) demonstrated complete biochemical response to treatment. Post-therapy liver biopsy was obtained for 30 (18.5%) patients, and 25 (15.4%) of these patients were noted to have histological remission according to the grade of inflammation or stage of fibrosis. CONCLUSION: TAC is relatively effective in the treatment of AIH refractory to traditional therapy. It appears that liver function can be enhanced at a minimal cost to renal function. Key Points There is a cohort of patients with autoimmune hepatitis (AIH) who do not respond to standard therapy. Alternative treatment options for these patients have been explored, but outcomes have not been comprehensively examined. We report the use and efficacy of tacrolimus (TAC) in patients with AIH. We found that TAC can be safely and effectively used in patients with AIH with minimal side effects. TAC can be a potential treatment option for patients with AIH refractory to standard therapy.

Transjugular Intrahepatic Porto-Systemic Shunt in Patients with Liver Cirrhosis and Model for End-Stage Liver Disease ≥15.

BACKGROUND: It is not known whether transjugular intrahepatic porto-systemic shunt (TIPS) is safe in patients with advanced liver cirrhosis. The aim of our study was to evaluate the impact of TIPS on transplant-free survival in patients with liver cirrhosis and MELD score ≥15. METHODS: All adult patients who underwent TIPS at our institution between 2004 and 2011 were identified (N = 470). A total of 144 patients had MELD ≥15 at the time of TIPS. These patients were matched 1:1 to patients with liver cirrhosis who did not undergo TIPS based on age and MELD score using the greedy algorithm. Patients were followed up until time of death or liver transplantation. Kaplan-Meier curves and log-rank tests were used to test for differences in survival outcome between the two groups. RESULTS: A total of 288 patients with liver cirrhosis were included, of whom 144 underwent TIPS and 144 did not. The two groups were matched based on age and MELD score and were comparable with regard to gender and ethnicity. Mean MELD and Child-Pugh scores in the study population were 20.9 ± 6.5 and 10.5 ± 1.8, respectively. The most common indication for TIPS was varices (49 %), followed by refractory ascites (42 %). In the first 2 months post-TIPS, there was increased mortality or liver transplantation in patients who had TIPS compared to those who did not, but this did not reach statistical significance (p = 0.07). However, after 2 months, TIPS is associated with 56 % lower risk of dying or needing liver transplantation (p < 0.01) than cirrhotic patients who did not undergo TIPS. CONCLUSION: In patients with liver cirrhosis and MELD ≥15, TIPS might improve transplant-free survival for patients who live for at least 2 months after the procedure.

Increasing Burden of Chronic Liver Disease Among Adolescents and Young Adults in the USA: A Silent Epidemic.

BACKGROUND AND AIMS: Chronic liver disease (CLD) starts or becomes established in the adolescent and young adult (AYA) age group. This study aimed to estimate trends in CLD prevalence among US AYAs and to assess factors associated with CLD. METHODS: Cross-sectional data from 14,547 AYAs (population-weighted N = 68,274,386) aged 15-39 years enrolled in the National Health and Nutrition Examination Survey from 1988 to 2012 were used. Nonalcoholic fatty liver disease (NAFLD) was defined as elevated alanine aminotransferase (>19 U/L for females and >30 U/L for males) in subjects with BMI ≥ 25 kg/m2; alcoholic liver disease (ALD) as excessive alcohol use (≥3 drinks/day for men and ≥2 drinks/day for women) and elevated aminotransferases after excluding alternative etiologies. Participants were considered hepatitis C virus (HCV) positive if antibody to HCV and HCV-RNA was positive. RESULTS: There was a sharp increase in the prevalence of CLD from 12.9% in 1988-1994 to 28.5% in 1999-2004 that remained stable after that (27.7%). NAFLD was the most common etiology accounting for 22% of all CLD in the later period. The prevalence of ALD has been steadily increasing throughout the years, while HCV has been decreasing. On multivariate analysis, being overweight/obese, Mexican-American ethnicity, later study period, older age, and male gender, were associated with higher odds of having CLD. CONCLUSION: More than one quarter of US AYAs might be affected by CLD. CLD prevalence in this age group has more than doubled over the past three decades mainly due to rise in NAFLD prevalence.

Sofosbuvir and simeprevir without ribavirin effectively treat hepatitis C virus genotype 1 infection after liver transplantation in a two-center experience.

BACKGROUND: The interferon-free antiviral regimen, sofosbuvir (SOF) and simeprevir (SIM) without ribavirin has been reported to achieve high sustained virologic response (SVR) rates with few adverse effects when treating patients with hepatitis C genotype 1 (HCV GT1) infection. However, there is scarcity of safety and efficacy data in this regimen after liver transplantation (LT). AIM AND METHODS: We aim to report the safety, tolerability and efficacy of SOF + SIM to treat LT recipients with recurrent HCV GT1 in a multicenter cohort study. RESULTS: Eighty-one patients with HCV GT1 met criteria to be considered for treatment. Sixty-seven patients received SOF + SIM following LT to date: 69% male, 39% with HCV RNA >6 000 000 IU/mL, 22% advanced hepatic fibrosis (stage 3-4), 6% cholestatic recurrence. Fifty-eight percent previously failed or did not tolerate interferon-based treatments. Mean time from LT to treatment was 6.1 ± 5.2 yr. All patients had estimated GFR >30 mL/min. Tacrolimus was primary immunosuppression in 84% of patients and minimal immunosuppression dose adjustments were required during treatment. In intention-to-treat analysis, 90% achieved end-of-treatment virologic response and 88% achieved SVR. CONCLUSIONS: Sofosbuvir + SIM combination therapy without ribavirin is well tolerated and results in high virologic response rates in recurrent HCV GT1 infection after liver transplantation.

Three-dimensional printing and pediatric liver disease.

PURPOSE OF REVIEW: Enthusiastic physicians and medical researchers are investigating the role of three-dimensional printing in medicine. The purpose of the current review is to provide a concise summary of the role of three-dimensional printing technology as it relates to the field of pediatric hepatology and liver transplantation. RECENT FINDINGS: Our group and others have recently demonstrated the feasibility of printing three-dimensional livers with identical anatomical and geometrical landmarks to the native liver to facilitate presurgical planning of complex liver surgeries. Medical educators are exploring the use of three-dimensional printed organs in anatomy classes and surgical residencies. Moreover, mini-livers are being developed by regenerative medicine scientist as a way to test new drugs and, eventually, whole livers will be grown in the laboratory to replace organs with end-stage disease solving the organ shortage problem. SUMMARY: From presurgical planning to medical education to ultimately the bioprinting of whole organs for transplantation, three-dimensional printing will change medicine as we know in the next few years.

Liver transplantation for nonalcoholic steatohepatitis in young patients.

Nonalcoholic steatohepatitis (NASH) is the hepatic manifestation of obesity and insulin resistance. The aim of this study was to determine the frequency of NASH as an indication for liver transplantation (LT) in children and young adults and to characterize patient and graft survival. The study included all children and young adult patients (up to the age of 40 years) who underwent LT in the United States for NASH cirrhosis from the 1987 to 2012 United Network for Organ Sharing (UNOS) database. Kaplan-Meier analysis was used to assess patient and graft survival. A total of 330 patients were included, 68% were Caucasian, and the mean BMI was 33.6 ± 6.3. Age at time of LT ranged between 4 and 40 years (mean 33.9 ± 6.6 years). Fourteen subjects were <18 years of age at time of LT and 20 were between the ages of 18 and 25 years. Median follow-up after 1st LT was 45.8 months [10.7, 97.3]. During this time, 30% of subjects (n = 100) died and 11.5% (n = 38) were retransplanted including 13 for NASH recurrence. In conclusion, NASH can progress to end-stage liver disease requiring LT in childhood and early adulthood. A significant number of young patients transplanted for NASH cirrhosis required retransplantation.

Portal Hypertension Complications Are Frequently the First Presentation of NAFLD in Patients Undergoing Liver Transplantation Evaluation.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is likely to replace Hepatitis C as the leading cause of cirrhosis resulting in liver transplantation (LT) within a few years. Unfortunately, due to the lack of established guidelines for the screening of NAFLD in high-risk populations, many patients present with portal hypertension complications as their first manifestation of NAFLD require a LT evaluation. We aimed to investigate what proportion of patients who underwent LT for NAFLD-cirrhosis had knowledge of their liver disease prior to presenting with portal hypertension complications and to identify differences in clinical parameters between those with and without knowledge of preexisting NAFLD. METHODS: Consecutive patients who underwent LT for NAFLD-cirrhosis at a tertiary referral center were included in the study. Demographic and clinical data at the time of the first LT evaluation visit were collected, and patient knowledge of previous NAFLD was documented. Ascites, variceal bleeding, hepatic encephalopathy, and thrombocytopenia leading to diagnosis of underlying cirrhosis were considered as the presenting symptoms of portal hypertension. A p < 0.05 was considered statistically significant. RESULTS: A total of 124 subjects who received LT for NAFLD-cirrhosis were included, 58 % (n = 72) were male. At the time of the first LT evaluation visit, 60 % had diabetes, the mean body mass index was 33.2 [28.6, 37.6] kg/m(2), and the mean Model for End-Stage Liver Disease (MELD) score was 14.0 [11.0, 19.0]. More importantly, 85/124 patients (68.5 %) had no knowledge of preexisting NAFLD prior to presentation with symptoms of portal hypertension. The presenting symptoms were new-onset ascites in 61 %, hepatic encephalopathy in 25 %, variceal bleeding in 18 %, thrombocytopenia in 9 %, and other in 9 % (non-exclusive). Patients with no prior knowledge of NAFLD were less likely to have a diagnosis of hypercholesterolemia (30 vs. 50 %, p = 0.035) and had a trend toward having higher MELD scores at the time of the first LT evaluation visit (15 vs. 13.5, p = 0.05) and presenting with encephalopathy (25 vs. 10 %, p = 0.06) compared to those with previous knowledge of NAFLD diagnosis. CONCLUSION: The majority of patients undergoing liver transplant evaluation for NAFLD-cirrhosis are not aware of underlying NAFLD until they present with features of portal hypertension. New guidelines should consider screening for NAFLD in certain high-risk groups as more effective treatments for NAFLD are emerging.

The breathprints in patients with liver disease identify novel breath biomarkers in alcoholic hepatitis.

BACKGROUND & AIMS: Selected-ion flow-tube mass spectrometry can precisely identify trace gases in the human breath, in the parts-per-billion range. We investigated whether concentrations of volatile compounds in breath samples correlate with the diagnosis of alcoholic hepatitis (AH) and the severity of liver disease in patients with AH. METHODS: We recruited patients with liver disease from a single tertiary care center. The study population was divided between those with AH with cirrhosis (n = 40) and those with cirrhosis with acute decompensation from etiologies other than alcohol (n = 40); individuals without liver disease served as control subjects (n = 43). We used selected-ion flow-tube mass spectrometry to identify and measure 14 volatile compounds in breath samples from fasted subjects. We used various statistical analyses to compare clinical characteristics and breath levels of compounds among groups and to test the correlation between levels of compounds and severity of liver disease. Logistic regression analysis was performed to build a predictive model for AH. RESULTS: We identified 6 compounds (2-propanol, acetaldehyde, acetone, ethanol, pentane, and trimethylamine [TMA]) whose levels were increased in patients with liver disease compared with control subjects. Mean concentrations of TMA and pentane (TAP) were particularly high in breath samples from patients with AH, compared with those with acute decompensation or control subjects (for both, P < .001). Using receiver operating characteristic curve analysis, we developed a model for the diagnosis of AH based on breath levels of TAP. TAP scores of 36 or higher identified the patients with AH (area under the receiver operating characteristic curves = 0.92) with 90% sensitivity and 80% specificity. The levels of exhaled TMA had a low level of correlation with the severity of AH based on model for end-stage liver disease score (r = 0.38; 95% confidence interval, 0.07-0.69; P = .018). CONCLUSIONS: Based on levels of volatile compounds in breath samples, we can identify patients with AH vs patients with acute decompensation or individuals without liver disease. Levels of exhaled TMA moderately correlate with the severity of AH. These findings might be used in diagnosis of AH or in determining patient prognosis.

Impact of pretransplant rifaximin therapy on early post-liver transplant infections.

Bacterial and fungal infections are major causes of morbidity and mortality after liver transplantation (LT). The role of intestinal decontamination in the prevention of post-LT infections is controversial. Rifaximin is widely used for the treatment of hepatic encephalopathy. The effect of rifaximin on post-LT infections is unknown. The aim of our study was to determine the effect of rifaximin therapy in the pretransplant period on early bacterial infections (EBIs) and fungal infections within the first 30 days after LT. All adult patients who underwent LT at our institution (January 2009 to July 2011) were included in this retrospective cohort study. Patients receiving antibiotics other than pretransplant protocol antibiotics were excluded. Patients were stratified into 2 groups based on the presence or absence of rifaximin therapy for at least 2 days before LT. Infections were defined by the isolation of any bacterial or fungal organisms within 30 days of LT. Multivariate regression analysis, Student t tests, and Pearson's chi-square tests were used to compare the 2 groups. Two hundred sixty-eight patients were included, and 71 of these patients (26.5%) were on rifaximin at the time of LT. The 2 groups were comparable with respect to age, sex, race, and Model for End-Stage Liver Disease score. There were no significant differences in the rates of EBIs (30% for the non-rifaximin group and 25% for the rifaximin group, P = 0.48) or fungal infections between the 2 groups. There was no increase in antimicrobial resistance among the infecting organisms. There was no difference in survival between the rifaximin and non-rifaximin groups (98% versus 97%, P = 0.36). In conclusion, the use of rifaximin in the pre-LT period was not associated with an increased risk of bacterial or fungal infections in the early post-LT period.

Diagnosis of celiac disease in adults based on serology test results, without small-bowel biopsy.

BACKGROUND & AIMS: Celiac disease is underdiagnosed, with nonspecific symptoms and high morbidity. New diagnostic factors are needed. We aimed to estimate the frequency at which adult patients with positive results from serology tests are referred for small-bowel biopsies and to identify factors that improve the diagnosis of celiac disease. METHODS: We performed a retrospective analysis of data from 2477 subjects who received serology tests for celiac disease between 2005 and 2007. We analyzed results for total levels of IgA, IgA against human tissue transglutaminase (hTTG), IgA and IgG against gliadin, as well as dilution titers of IgA against endomysial antibodies (EMA). Biopsy samples were analyzed by pathologists experienced in detecting mucosal changes associated with celiac disease and graded according to the Marsh system. RESULTS: Of the 2477 patients, 610 (25%) had abnormal results from serology tests, and 39% of these patients (240 of 610) underwent small-bowel biopsy analyses. Of these patients, 50 (21%) had biopsy findings consistent with celiac disease (Marsh 3 lesions) and were placed on gluten-free diets. Titers of IgA hTTG greater than 118 U identified patients with celiac disease with a 2% false-positive rate. Titers of 21 to 118 U, in combination with an EMA dilution titer of 1:160 or greater, had a positive predictive value of 83% for celiac disease. IgA hTTG levels less than 20 U, in combination with an EMA dilution titer less than 1:10, had a negative predictive value of 92% for celiac disease. CONCLUSIONS: Serum levels of IgA hTTG greater than 118 U, or 21 to 118 U in combination with an EMA dilution titer of 1:160 or greater, can be used to identify adult symptomatic patients with celiac disease, in the absence of a small-bowel biopsy.

Three-dimensional print of a liver for preoperative planning in living donor liver transplantation.

The growing demand for liver transplantation and the concomitant scarcity of cadaveric livers have increased the need for living donor liver transplantation (LDLT). Ensuring the safety of donors and recipients is critical. The preoperative identification of the vascular and biliary tract anatomy with 3-dimensional (3D) printing may allow better preoperative surgical planning, avert unnecessary surgery in patients with potentially unsuitable anatomy, and thereby decrease the complications of liver transplant surgery. We developed a protocol and successfully 3D-printed synthetic livers (along with their complex networks of vascular and biliary structures) replicating the native livers of 6 patients: 3 living donors and 3 respective recipients who underwent LDLT. To our knowledge, these are the first complete 3D-printed livers. Using standardized preoperative, intraoperative, and postoperative assessments, we demonstrated identical anatomical and geometrical landmarks in the 3D-printed models and native livers.

CD4+ T-Cell function and the risk for developing spontaneous bacterial peritonitis in patients with cirrhosis.

BACKGROUND/GOALS: Spontaneous bacterial peritonitis (SBP) is common in cirrhotic patients and has high associated mortality. SBP is preventable with antibiotic prophylaxis. The aim of this study was to identify patients at high risk to develop SBP based on their peripheral blood CD4 T-cell function. METHODS: Fifty-seven patients with cirrhosis and ascites were followed for the development of SBP. All patients had CD4 assay performed through phytohemagglutinin stimulation of peripheral blood, which was quantified by measuring adenosine triphosphate (ATP) release by luciferin/luciferase assay. A receiver operating characteristic curve was used to evaluate the CD4 assay as a predictor of SBP. A time to SBP or death analysis was performed and Kaplan-Meier plots were used to assess the association between CD4 ATP concentration and hazard of SBP or mortality. RESULTS: The median follow-up time was 7.3 (4.8, 13) months. Patients who developed a first episode of SBP had a lower median CD4 ATP concentration compared to patients without SBP (120 vs. 239 ng/mL; P<0.001). The best independent predictor of SBP was peripheral CD4 function and an ATP level of ≤201 ng/mL provides 83% sensitivity and 71% specificity for future prediction of SBP. Patients with ATP concentration ≤201 ng/mL had a 4.7 times greater hazard of developing SBP than those with ATP level >201 ng/mL (P<0.001). Patients with SBP had 7.9 times higher hazard of mortality then those without SBP (P=0.008). CONCLUSION: The risk of developing SBP was significantly increased in patients with cirrhosis and ascites who had depressed CD4 T-cell function.

Hepatitis B immunity and response to booster vaccination in children with inflammatory bowel disease treated with infliximab.

OBJECTIVES: Hepatitis B virus (HBV) reactivation has been described in patients treated with infliximab for inflammatory bowel disease (IBD). This has resulted in a "black box" warning. Although universal vaccination against hepatitis B was implemented in the United States in 1991, up to 10% of vaccine recipients fail to respond with adequate anti-hepatitis B surface antibodies (anti-HBs) levels after a primary series of vaccinations. In addition, anti-HBs levels are expected to decline with time. The objectives of this study were to determine HBV immunity in children with IBD on infliximab therapy and to determine response to a booster dose of the HBV vaccine in patients who were found to be non-immune. METHODS: This was a prospective cross-sectional, single-center study that included 100 pediatric IBD patients on infliximab. Serologic specimens were tested for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), and anti-HBs. Patients with an anti-HBs level ≥10 mIU/ml were considered to be immune. One booster dose was given to non-immune patients and a serum sample was collected after 4 weeks to assess the presence of anamnestic response (anti-HBs level ≥10 mIU/ml after booster). RESULTS: The mean age of the patients was 17.9 (±4.0) years. None of the patients were positive for HBsAg or anti-HBc. In all, 87 patients were vaccinated against HBV and 49/87 (56%) had immunity to HBV as defined by anti-HBs level ≥10 mIU/ml. The mean concentration of anti-HBs levels in immune patients was 295.6 (±350.6) mIU/ml. Older age, lower albumin levels, and the presence of pancolitis were associated with the absence of protective antibodies; however, infliximab dose, frequency, duration, and the concurrent use of immunomodulators were not significantly different between immune and non-immune patients. Thirty-four patients received booster immunization and 26/34 (76%) had an anamnestic response. Interestingly, non-responders were given infliximab with higher frequency (every 5.9 ± 1.2 weeks vs. every 7.1 ± 1.8 weeks, P=0.01). Overall, 75/87 (86%) of previously immunized patients were considered immune against HBV infection. CONCLUSIONS: In pediatric IBD patients seen at a large, urban tertiary care facility in the United States, a significant minority (13%) have not been vaccinated against HBV. Nearly one-half of all patients (and 44% of previously vaccinated patients) did not have protective anti-HBs levels. Moreover, of those previously vaccinated, a significant minority (14%) appear at risk for HBV because protective anti-HBs levels were absent and could not be elicited through booster immunization. Given the high risk for severe HBV infection in this group, efforts should be made to screen for HBV immunity at the time of IBD diagnosis. Booster immunization should be considered in patients without protective antibodies.

Cumulative risk of cardiovascular events after orthotopic liver transplantation.

As survival after orthotopic liver transplantation (OLT) improves, cardiovascular (CV) disease has emerged as the leading cause of non-graft-related deaths. The aims of our study were to determine the cumulative risk of CV events after OLT and to analyze predictive risk factors for those experiencing a CV event after OLT. We identified all adult patients who underwent OLT at our institution for end-stage liver disease between October 1996 and July 2008. The cumulative risk of CV events after OLT was analyzed with the Kaplan-Meier method. Multivariate logistic regression analysis was used to identify factors independently associated with CV events after OLT. In all, 775 patients were included in our study cohort (mean age of 53.3 years, female proportion = 44%, Caucasian proportion = 84%, median follow-up = 40 months). The most common indications for OLT were hepatitis C virus (33.2%), alcohol (14.5%), and cryptogenic cirrhosis (12.7%). Eighty-three patients suffered 1 or more CV events after OLT. Posttransplant metabolic syndrome was more prevalent in patients with CV events versus patients with no CV events (61.4% versus 34.1%, P < 0.001). According to a multivariate analysis, independent predictors of CV events were an older age at transplantation [odds ratio (OR) = 1.2, addition of 95% confidence interval (CI) = 1.1-1.3, P = 0.006], male sex (OR = 2.0, 95% CI = 1.2-3.3, P = 0.01), posttransplant diabetes (OR = 2.0, 95% CI = 1.3-3.3, P = 0.003), posttransplant hypertension (OR = 1.8, 95% CI = 1.1-3.0, P = 0.02), and mycophenolate mofetil (OR = 2.0, 95% CI = 1.3-3.2, P = 0.003). Among post-OLT patients, the cumulative risk at 5 years of 13.5%, respectively. In conclusion, cardiac complications after liver transplantation are common (Approximately 10% of patients experience 1 or move cv events). Patients with posttransplant hypertension and diabetes, which are modifiable risk factors, are approximately twice as likely to experience a CV event.

Neutrophil to lymphocyte ratio: a new marker for predicting steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic steatohepatitis (NASH), the most severe form of nonalcoholic fatty liver disease (NAFLD), is associated with inflammation and increased oxidative stress. The neutrophil/lymphocyte ratio (N/L) integrates information on the inflammatory milieu and physiological stress. AIMS: The aim of this study was to determine the utility of N/L ratio to predict the presence of NASH in patients with NAFLD. METHODS: Our cohort consisted of 101 consecutive patients undergoing liver biopsy for clinical suspicion of NAFLD. Patients were divided into two groups: NASH group (n = 50) and not NASH group (n = 51). The stage of fibrosis was measured using a 4-point scale. The total white cell count, neutrophil and lymphocyte counts were recorded, and the N/L ratio was calculated. RESULTS: The mean age was 49.5 (± 10.8) years and the mean BMI was 31.4 (± 4.9) kg/m(2) . Patients with NASH had a higher N/L ratio compared with patients with not NASH [2.5 (1.9-3.3) and 1.6 (1.2-2.0), respectively, P < 0.001]. The N/L ratio correlated with the NAFLD activity score and its individual components (steatosis, inflammation and ballooning P < 0.001). Patients with advanced fibrosis (F3-4) had an elevated N/L ratio [2.9 (2.0-3.9)] compared with patients with fibrosis stage 1-2 [1.8 (1.2-2.2)], P < 0.001. For each one-unit increase in N/L ratio, the likelihood of having NASH increased by 70% and the likelihood of having fibrosis increased by 50%. CONCLUSION: The N/L ratio is higher in patients with NASH and advanced fibrosis. This ratio can be used as a novel noninvasive marker to predict advanced disease.

The role of rifaximin in the primary prophylaxis of spontaneous bacterial peritonitis in patients with liver cirrhosis.

BACKGROUND: Primary prophylaxis of spontaneous bacterial peritonitis (SBP) may provide a survival advantage in cirrhotic patients with ascites and has become an integral part of clinical practice. Rifaximin is a poorly absorbable antibiotic with a broad spectrum of antibacterial action and has low risk of introducing bacterial resistance. AIM: To determine whether rifaximin is associated with decreasing the risk of SBP and improving transplant-free survival in cirrhotic patients with ascites. METHODS: The medical records of all adult patients with liver cirrhosis and large ascites justifying paracentesis evaluated in our clinic (2003 to 2007) were reviewed. Patients were stratified into 2 groups by the use of rifaximin. Patients were excluded if they had received another antibiotic for SBP prophylaxis or had a history of SBP before rifaximin therapy. RESULTS: A total of 404 patients were included, of whom 49 (12%) received rifaximin. The rifaximin and nonrifaximin groups were comparable with regards to age, sex, and race. The median follow-up time was 4.2 [1.0, 17.1] months. During this time period, 89% of patients on rifaximin remained SBP free compared with 68% of those not on rifaximin (P=0.002). After adjusting for Model of End-Stage Liver Disease score, Child-Pugh score, serum sodium, and ascitic fluid total protein, there was a 72% reduction in the rate of SBP in the rifaximin group (hazard ratio=0.28; 95% confidence interval, 0.11-0.71; P=0.007). The group treated with rifaximin also demonstrated a transplant-free survival benefit compared with those not on rifaximin (72% vs. 57%, P=0.045). CONCLUSIONS: Intestinal decontamination with rifaximin may prevent SBP in cirrhotic patients with ascites. Prospective randomized controlled trials are needed to confirm this finding.

Hepatitis C virus-associated primary hepatocellular carcinoma in non-cirrhotic patients.

BACKGROUND: There is limited literature on hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) infection in the absence of cirrhosis. AIMS: To investigate the relationship between HCV and HCC in the absence of cirrhosis and to characterize patients with HCV infection presenting with HCC in the absence of cirrhosis. METHODS: We identified all adult patients with histological confirmation of HCC between 1994 and 2007 (404 patients). A case-control design (four controls for each case with non-cirrhotic HCC) was chosen to compare characteristics and survival of HCV in HCC patients without (cases) and with (controls) cirrhosis. Conditional logistic regression analysis was used to identify factors independently associated with HCV in non-cirrhotic HCC. RESULTS: Eighty-seven patients with non-cirrhotic HCC were identified, six (7 %) had HCV infection in comparison with 107 of 317 (55.7 %) with cirrhotic HCC (P < 0.001). Compared with the HCV-associated HCC cirrhotic group, patients with HCV-associated HCC in the absence of cirrhosis were more likely to present with a single nodule (100 vs. 66.7 %), larger nodule size (>5 cm) (100 vs. 16.7 %), and macrovascular invasion (66.7 vs. 17.4 %) at time of diagnosis. Four of six patients with HCV-associated HCC in the absence of cirrhosis where alive at three years (all had resection), which was better survival than for HCC arising in cirrhotic livers of HCV-infected individuals (66.7 vs. 39.1 %). CONCLUSION: We found that HCV is responsible for a small minority of non-cirrhotic HCC cases representing an uncommon and poorly defined subgroup of HCC.

An apoptosis panel for nonalcoholic steatohepatitis diagnosis.

BACKGROUND & AIMS: The extrinsic death receptor-mediated pathway of apoptosis is involved in nonalcoholic steatohepatitis (NASH) development. Our aims were to create and validate a noninvasive prediction model for NASH diagnosis based on specific circulating markers of apoptosis. METHODS: Our initial cohort consisted of 95 consecutive patients undergoing a liver biopsy for clinically suspected NASH. Blood was obtained from each patient at the time of liver biopsy. Plasma caspase 3 generated cytokeratin-18 fragments (CK-18), soluble Fas (sFas), and soluble Fas ligand (sFasL) were measured. Histology was assessed by an experienced hepatopathologist. The validation cohort consisted of 82 consecutive patients that underwent liver biopsy at the time of bariatric surgery. RESULTS: Patients with NASH had significantly higher levels of CK-18 and sFas than patients in the "not NASH" group [median (25th, 75th percentile): 508 (280, 846) U/L versus 176 (131, 224) U/L (p<0.001), and 11.8 (7.8, 12.5) ng/ml versus 5.9 (4.8, 8.3) ng/ml (p<0.001), respectively]. A significant positive correlation was revealed between the apoptosis markers and liver histopathology independent of other metabolic factors. A prediction model was generated including CK-18 fragments and sFas levels that showed an AUC of 0.93 and 0.79 in the initial and validation cohorts, respectively. A cutoff value using this model predicted NASH with a sensitivity and specificity of 88% and 89%, respectively. CONCLUSIONS: Quantification of circulating levels of two apoptotic markers accurately predicts the presence of NASH, supporting the potential usefulness of these markers in clinical practice for noninvasive diagnosis of NASH.

The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis.

UNLABELLED: Nonalcoholic steatohepatitis (NASH) is a well-recognized cause of cirrhosis and has been increasingly associated with the development of hepatocellular carcinoma (HCC). The aims of this study were to (1) estimate the incidence of HCC in patients with NASH-related cirrhosis, (2) compare incidence in NASH-related cirrhosis with hepatitis C virus (HCV)-related cirrhosis, and (3) identify risk factors of HCC in patients with NASH-related cirrhosis compared with HCV-related cirrhosis. Adult patients with cirrhosis secondary to chronic HCV (n = 315) or NASH (n = 195) were evaluated at our hepatobiliary clinic between 2003 and 2007. To assess for HCC development, all patients were monitored using serial abdominal computed tomography and serum alpha-fetoprotein every 6 months. Kaplan-Meier analysis was performed to estimate the cumulative incidence of HCC. Descriptive statistics were computed for all factors. Univariate and multivariate Cox regression analysis were used to assess associations between HCC and factors of interest. The median follow-up was 3.2 years (25th percentile [P25], 75th percentile [P75]: 1.7, 5.7) during which 25/195 (12.8%) of NASH-cirrhotic and 64/315 (20.3 %) of HCV-cirrhotic patients developed HCC (P = 0.03). Yearly cumulative incidence of HCC was found to be 2.6% in patients with NASH-cirrhosis, compared with 4.0% in patients with HCV cirrhosis (P = 0.09). Multivariate regression analysis revealed that older age (P = 0.006) and alcohol consumption (P = 0.002) were independent variables associated with development of HCC in patients with NASH-cirrhosis. Compared with nondrinkers, patients who reported any regular alcohol consumption were at greater risk for HCC development (hazard ratio: 3.6; P25, P75: 1.5, 8.3). CONCLUSION: Patients with NASH cirrhosis have a greatly increased risk of liver cancer. Alcohol consumption, a modifiable risk factor, appears to be the most significant factor associated with risk of HCC development in our study population.