Showing papers by "Robert J. Fontana published in 2012"

Effectiveness of hepatocellular carcinoma surveillance in patients with cirrhosis.

Abstract: Background: Surveillance for hepatocellular carcinoma (HCC) is recommended in patients with cirrhosis, but the effectiveness of a surveillance program in clinical practice has yet to be established. Aims: To evaluate the effectiveness of a surveillance program with ultrasound and alpha-fetoprotein (AFP) to detect early HCCs. Methods: Four hundred and forty-six patients with Child A/B cirrhosis were prospectively enrolled between January 2004 and September 2006 and followed until July 2010. HCC surveillance using ultrasound and AFP was conducted per the treating hepatologist, although the standard was every 6 to 12 months. HCC was diagnosed using American Association for the Study of Liver Disease (AASLD) guidelines and early HCC defined by Barcelona Clinic Liver Cancer (BCLC) staging. Performance characteristics were determined for surveillance using AFP, ultrasound, or the combination. Results: After a median follow-up of 3.5 years, 41 patients developed HCCs, of whom 30 (73.2%) had early HCCs. The annual incidence of HCC was 2.8%, with cumulative 3- and 5-year incidence rates of 5.7% and 9.1%, respectively. Surveillance ultrasound and AFP had sensitivities of 44% and 66% and specificities of 92% and 91%, respectively, for the detection of HCCs. Sensitivity significantly improved to 90%, with minimal loss in specificity (83%) when these tests were used in combination. Conclusions: When used as a surveillance program in a real-world clinical setting, combination of ultrasound and AFP is the most effective strategy to detect HCC at an early stage. Impact: Our results differ from the guidelines of the AASLD. Cancer Epidemiol Biomarkers Prev; 1–7. ©2012 AACR .

Limited contribution of common genetic variants to risk for liver injury due to a variety of drugs

Abstract: Background and aims Drug-induced liver injury (DILI) is a serious adverse drug event that is suspected to have a heritable component. We carried out a genome-wide association study of 783 individuals of European ancestry who experienced DILI due to more than 200 implicated drugs.

Meta-analysis: oral anti-viral agents in adults with decompensated hepatitis B virus cirrhosis.

Abstract: Summary Background The optimal oral anti-viral agent to use in patients with decompensated HBV cirrhosis remains unclear. Aim We performed a meta-analysis of the oral nucleos(t)ide analogues in patients with decompensated HBV cirrhosis. Methods One year efficacy and safety outcomes in 22 studies published in English between95 and 2010 were analysed. Results Substantial heterogeneity was noted in the inclusion/exclusion criteria, controls, and sensitivity of the HBV DNA assay used. Pooled 1-year data showed benefit favouring lamivudine (LAM) vs. untreated controls for Child-Turcotte-Pugh (CTP) score improvement by ≥2 (OR: 117 (15 921), P ≤ 0.0001) and transplant-free survival (OR: 3.2 (1.2, 9), P = 0.022). Adefovir (ADV) led to undetectable HBV DNA at 1-year in 41% compared to 83% with LAM and 80% with entecavir (ETV). Overall, 1-year transplant-free survival rates varied from 78% with LAM to 95% and 94% with Tenofovir (TDF) and Telbivudine (TBV), respectively. The 1-year incidence of drug resistant HBV was 0% with ADV, ETV and TDF and 11% with LAM although TBV was associated with a 29% incidence at 2 years. Drug-related adverse events were infrequently reported. Conclusions All the oral anti-viral agents were associated with improved virological, biochemical and clinical parameters at 1-year. However, the efficacy of lamivudine and telbivudine is limited by drug resistance, and adefovir is limited by its potency and slower onset of action. Additional studies of tenofovir and entecavir are needed to determine the optimal agent(s) for treatment naive patients and in those with drug-resistant decompensated HBV cirrhosis.

Serum proteomic profiling in patients with drug-induced liver injury

Abstract: Background Idiosyncratic drug-induced liver injury (DILI) is a complex disorder that is difficult to predict, diagnose and treat.

Incidence and risk factors of hepatocellular carcinoma recurrence after liver transplantation in the MELD era.

Abstract: Background and Aims Deceased donor liver transplantation (DDLT) rates for candidates with hepatocellular carcinoma (HCC) have significantly increased in the MELD era because of the extra priority given to these candidates. We examined the incidence and pre-DDLT radiological and donor factors associated with post-DDLT HCC recurrence in the MELD era.

Adherence to nucleos(t)ide analogues for chronic hepatitis B in clinical practice and correlation with virological breakthroughs.

Abstract: SUMMARY. Medication adherence is important for the success of nucleos(t)ide analogue (NUC) treatment for chronic hepatitis B. The aims of this study were to determine adherence to NUCs and factors associated with NUC adherence and to correlate NUC adherence with the occurrence of virological breakthroughs in patients with chronic hepatitis B. Consecutive patients with chronic hepatitis B receiving NUC were asked to complete a survey every 3 months. Adherence was also assessed by healthcare providers in the clinic. Adherence rate was defined as the per cent of days the patients took their hepatitis B virus medications during the last 30 days. A total of 111 patients were studied. The mean age was 47.7 years, 73.9% were men, 57.7% were Asian, 42.3% had postgraduate education and 80% had private insurance. Sixtynine (74.1%) patients reported 100% adherence in the survey, while 78 (83.9%) reported 100% adherence to their healthcare providers. Patients with 100% adherence based on the survey were older (P = 0.02), more likely to be men (P = 0.006), and had higher annual household income (P = 0.04) than those with <100% adherence. In the 80 patients who completed three surveys, viral breakthrough was observed in 1/46 (2.2%) with 100% adherence on all three surveys, 1/18 (5.6%) with <100% adherence on one survey and 3/16 (18.8%) with <100% adherence on ‡2 surveys, (P = 0.06). In conclusion, adherence to NUC therapy in our patients with chronic hepatitis B was high but self-reporting of adherence to healthcare providers may be inflated. Patients with chronic hepatitis B with better adherence to NUC therapy had a trend towards a lower rate of viral breakthroughs.

Acute Liver Injury due to Flavocoxid (Limbrel), a Medical Food for Osteoarthritis: A Case Series

Abstract: Background Flavocoxid is a prescription medical food that is used to treat osteoarthritis. It is a proprietary blend of 2 flavonoids, baicalin and catechins, which are derived from the botanicals Scutellaria baicalensis and Acacia catechu, respectively. Objective To describe characteristics of patients with acute liver injury suspected of being caused by flavocoxid. Design Case series. Setting Drug-Induced Liver Injury Network Prospective Study ongoing at multiple academic medical centers since 2004. Patients Four adults with liver injury. Measurements Clinical characteristics, liver biochemistry values, and outcomes. Results Among 877 patients enrolled in the prospective study, 4 had liver injury suspected to have been caused by flavocoxid. All were women; ages ranged from 57 to 68 years. All developed symptoms and signs of liver injury within 1 to 3 months after initiating flavocoxid. Liver injury was characterized by marked elevations in levels of alanine aminotransferase (mean peak, 1268 U/L; range, 741 to 1540 U/L), alkaline phosphatase (mean peak, 510 U/L; range, 286 to 770 U/L), and serum bilirubin (mean peak, 160.7 µmol/L [9.4 mg/dL]; range, 34.2 to 356 µmol/L [2.0 to 20.8 mg/dL]). Liver biochemistry values decreased to the normal range within 3 to 12 weeks after flavocoxid was stopped, and all patients recovered without experiencing acute liver failure or chronic liver injury. Causality was adjudicated as highly likely in 3 patients and as possible in 1 patient. Limitation The frequency and mechanism of liver injury could not be assessed. Conclusion Flavocoxid can cause clinically significant liver injury, which seems to resolve within weeks after cessation.

Short and Long-Term Outcomes in Patients with Acute Liver Failure Due to Ischemic Hepatitis

Abstract: Aims The purpose of this study is to describe the incidence and presenting features of patients with acute liver failure (ALF) due to ischemic hepatitis and the prognostic factors associated with short (three-week) and long-term outcomes.

Meta‐analysis: IL‐28B genotype and sustained viral clearance in HCV genotype 1 patients

Abstract: Summary Background Polymorphisms in the IL-28B region are a strong predictor of sustained virologic response (SVR) in individual studies of HCV genotype 1 patients receiving peginterferon (pegIFN) and ribavirin. Aim To obtain a pooled odds ratio (OR) of SVR in patients of varying race with the favourable IL-28B genotype compared to those with the unfavourable genotype. Methods A literature search was conducted using online databases and a review of conference abstracts. A random effects meta-analysis was performed and study heterogeneity and publication bias were assessed. Results There were 21 individual studies of HCV genotype 1 patients of varying ethnicity treated with pegIFN and ribavirin. The pooled prevalence of the favourable IL-28B genotype varied by race (73% vs. 41% vs. 13% in 2612 Asians, 3110 Caucasians and 452 African-Americans, respectively, P < 0.001). However, the strength of association of the IL-28B genotype with SVR was similar in all three racial groups (Caucasians: odds ratio (OR) 3.88, 2.75–5.49, African-Americans: OR 4.63, 2.52–8.50 and Asians OR 5.66, 3.99–8.02, all P < 0.001). The IL-28B genotype was also associated with SVR in 263 HIV/HCV co-infected Caucasians (OR 5.49, 3.02–9.96, P < 0.001). Study quality score and anti-viral treatment regimen did not impact the strength of the association in patient subgroups nor in the pooled population. Conclusions IL-28B genotype is significantly associated with SVR in HCV genotype 1 patients of varying race, as well as in HIV co-infected patients, receiving pegIFN and ribavirin. IL-28B testing in conjunction with other pre-treatment parameters may prove useful in counselling HCV patients.

YKL-40 genetic polymorphisms and the risk of liver disease progression in patients with advanced fibrosis due to chronic hepatitis C.

Abstract: Background/Aims The aim of this study was to explore the association of a functional YKL-40 promoter polymorphism (rs4950928) with baseline disease stage, response to antiviral therapy and risk of liver disease progression in a group of patients with chronic hepatitis C (CHC). Methods YKL-40 promoter polymorphisms were determined in 456 Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial patients with bridging fibrosis or cirrhosis entering a prerandomization lead-in peginterferon/ribavirin 24-week treatment phase and in 462 patients followed for a mean of 3.8 years after randomization to maintenance peginterferon or observation. Results Mean patient age was 49.5 years, 70.4% were men and 71.2% were Caucasian. The 17% frequency of the YKL-40 minor allele (T) was similar to that reported in the general population. YKL-40 genotype was associated significantly with baseline serum YKL-40 levels but was not associated with the likelihood of a virological response following 24–48 weeks of peginterferon/ribavirin therapy. Serum YKL-40 levels remained significantly lower during follow-up in the randomized TT homozygotes compared with CT heterozygotes and CC homozygotes (P < 0.001). Despite this association, YKL-40 genotype was not associated with the risk of clinical or histological liver disease progression. Conclusions A reduced frequency of the protective YKL-40 promoter polymorphism was not observed in the HALT-C Trial patient population. The absence of an association between YKL-40 promoter polymorphisms and baseline liver disease severity as well as with the risk of liver disease progression over time suggests that this polymorphism is not associated with disease progression in CHC patients with established fibrosis.

Lenalidomide-associated hepatotoxicity--a case report and literature review.

Abstract: Background: Lenalidomide is an immunomodulatory drug frequently used for treatment of patients with multiple myeloma and myelodysplastic syndromes. This report presents a rare case of lenalidomide-associated hepatotoxicity and reviews the available literature. Case Report: A 67-year-old male with multiple myeloma was hospitalized with nausea, vomiting and jaundice, while treated with a second three-week course of lenalidomide. The patient was found to have acutely elevated bilirubin, alkaline phosphatase, AST and ALT. He also had acute on chronic renal function impairment. Serology for viral hepatitis, abdominal ultrasound, magnetic resonance cholangiopancreatography and hepatobiliary scan revealed no abnormalities. Lenalidomide was stopped, resulting in subsequent (8 days) clinical improvement and normalization of the liver abnormalities. The RUCAM causality assessment score was 8, consistent with probable lenalidomide-associated hepatotoxicity. Literature review revealed four other published cases of lenalidomide-associated hepatotoxicity with clinical presentation varying between cholestatic-, hepatocellular- or mixed-pattern of liver injury. All patients had clinical and laboratory improvement soon after lenalidomide discontinuation. Renal function impairment was present in 3 of the 5 reported cases. The exact mechanism of lenalidomide- associated liver injury remains unclear as only 2 patients had liver biopsies without specific findings. Conclusion: Physicians should be aware of the potential for lenalidomide-associated hepatotoxicity, particularly in patients with underlying renal insufficiency. Background

Antigen-specific t lymphocyte proliferation decreases over time in advanced chronic hepatitis c

Abstract: SUMMARY. To evaluate T cell immunity in advanced liver disease, antigen-specific lymphoproliferative (LP) responses were prospectively studied in the context of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis trial. Peripheral blood responses to hepatitis C virus (HCV), tetanus and Candida protein antigens were measured at baseline, month 12 (M12), M24, M36 and M48 in 186 patients randomized to either low-dose peginterferon-alfa-2a (PEG-IFN) onlyorobservation.Liverhistologywasevaluatedatbaseline, M24 and M48. Patients with cirrhosis (Ishak 5‐6) were less likely to have positive LP responses to HCV at baseline than patients with fibrosis (15% vs 29%, P = 0.03) and had lower levels of HCV c100 responses at baseline, M24 and M48 (P = 0.11, P = 0.05, P = 0.02, respectively). For 97 patients with complete longitudinal data, the frequency of positive LP responses to HCV, tetanus and Candida antigens declined over time (P < 0.003), and the slope of this decline was greater in the PEG-IFN treatment group than the observation group (P < 0.02). Lower levels of tetanus LP responses were associatedwithfibrosisprogressionandclinicaloutcomes(P= 0.009). Poorer CD4+ T cell proliferative function was associated with more advanced liver disease in chronic hepatitis C and may be further affected by long-term PEG-IFN treatment.

Acute Liver Injury due to Flavocoxid (Limbrel), a Medical Food for Osteoarthritis

Abstract: This case series describes 4 adults who developed symptoms and signs of liver injury within 3 months after initiating flavocoxid—a proprietary prescription medical food used to treat osteoarthritis...

Lipopolysaccharide binding protein is down-regulated during acute liver failure.

Abstract: Background and Aims Lipopolysaccharide binding protein (LBP) is involved in the modulation of acute liver injury and failure caused by acetaminophen (APAP) Although the biological activity of LBP is concentration dependent, little is known about its levels in acute liver failure