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ABSTRACT: BACKGROUND & AIMS: Despite advances in critical care medicine, mortality is high among critically ill patients with cirrhosis. We aimed to identify factors that predict early (7 day) mortality among patients with cirrhosis admitted to the intensive care unit (ICU) and to develop a risk stratification model. METHODS: We collected data from patients with cirrhosis admitted to the ICU at Indiana University (IU-ICU) from December 1 2006 through December 31 2009 (n=185) or at the University of Pennsylvania (Penn-ICU) from May 1 2005 through December 31 2010 (n=206). Factors associated with mortality within 7 days of admission (7-day mortality) were determined by logistic regression analyses. A model was constructed based on the predictive parameters available on the first day of ICU admission in the IU-ICU cohort and then validated in the Penn-ICU cohort. RESULTS: Median model for end-stage liver disease (MELD) scores upon ICU admission were 25 in the IU-ICU cohort (inter-quartile range [IQR], 23-34) and 32 in the Penn-ICU cohort (IQR, 26-41); corresponding 7-day mortalities were 28.3% and 53.6%. MELD score (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.07-1.2) and mechanical ventilation (OR, 5.7; 95% CI 2.3-14.1) were independently associated with 7-day mortality in the IU-ICU. A model based on these 2 variables separated IU-ICU patients into low-, medium-, and high-risk groups; these groups had 7-day mortalities of 9%, 27%, and 74%, respectively, (c-index 0.80, 95% CI, 0.72-0.87;P <10-(8)). The model was applied to the Penn-ICU cohort; the low-, medium-, and high-risk groups had 7-day mortalities of 33%, 56%, and 71%, respectively (c-index 0.67; 95% CI, 0.59-0.74;P <10-(4)). CONCLUSIONS: A model based on MELD score and mechanical ventilation on day 1 can stratify risk of early mortality in patients with cirrhosis admitted to the ICU. More studies are needed to validate this model and to enhance its clinical utility.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 04/2013; · 5.64 Impact Factor
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ABSTRACT: OBJECTIVE: Hepcidin is regulated by anemia and inflammation. It is primarily expressed in the liver but studies have reported its expression in adipose tissue. We investigated the relationship between BMI and serum hepcidin and also examined the relationship between liver histology and serum hepcidin in the morbidly obese. DESIGN AND METHODS: Serum and liver tissue from patients undergoing bariatric surgery (bariatric cohort, n=105) and serum from healthy blood donors(n=60) were used to conduct this study. Serum hepcidin was measured using sandwich ELISA, highly specific for hepcidin-25.Serum ferritin, IL-6, IL-1βand liverfunction biochemistries were also measured. RESULTS: After controlling for covariates, BMI ≥ 35 kg/m2 was significantly associated with higher serum hepcidin level compared to individuals with lower BMI groups (17.7± 11.5 vs. 3.3± 4.7 ng/ml, P=0.002). Presence of NAFLD was not associated with higher serum levels of hepcidin (multivariate P=0.37) There was no association between serum hepcidin levels and liver histology (presence of steatohepatitis, advanced fibrosis, or NAFLD activity score) in the bariatric cohort. CONCLUSIONS: Obesity, but not the presence of NAFLD was associated with serum hepcidin levels. There was no association between serum hepcidin and liver histology in the morbidly obese undergoing bariatric surgery.
Obesity 03/2013; · 4.28 Impact Factor
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ABSTRACT: BACKGROUND AND AIMS:: Idiosyncratic drug-induced liver injury (DILI) can be caused by intravenous (IV) medications, but the characteristics of DILI caused by these agents are not known. The aim of this study is to characterize the clinical features of subjects with suspected DILI associated with IV agents enrolled into the Drug Induced Liver Injury Network Prospective Study. METHODS:: Subjects with suspected DILI due to IV medications with probable, highly likely, or definite casuality scores were eligible. RESULTS:: Between 2004 and October 2010, 542 cases of DILI were adjudicated for causality, of which 32 were eligible for inclusion in this study. DILI was ascribed to a single IV agent in 27 subjects, and to multiple IV agents in 5 subjects. Antimicrobial agents (62%), antineoplastic agents (16%), and phenytoin (9%) were most commonly implicated. The pattern of liver injury was hepatocellular in 30%, mixed in 33%, and cholestatic in 37%. The peak alanine aminotransferase (ALT), alkaline phosphatase (AlkP), and total bilirubin were 686±915 U/L, 623±563 U/L, and 8.7±10.3 mg/dL, respectively. The duration for ≥50% improvement from peak ALT, AlkP, and total bilirubin were 25±37, 59±69, and 20±28 days, respectively. DILI severity was mild in 37%, moderate in 47%, severe in 13%, and fatal in 3%, with no liver transplantation. Their causality was adjudicated as definite in 5, very likely in 17, and probable in 10 subjects. The frequency of chronic DILI was 13%. CONCLUSIONS:: Antimicrobial and antineoplastic agents are the most common IV agents to cause DILI. DILI ascribed to IV agents is relatively infrequent, but its outcomes are similar to those of the overall Drug Induced Liver Injury Network cohort.
Journal of clinical gastroenterology 02/2013; · 2.21 Impact Factor
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ABSTRACT: OBJECTIVE:: We conducted a pharmacokinetic (PK) study and a pharmacodynamic (PD) study to assess whether Roux-en-Y gastric bypass (RYGB) surgery is associated with significant changes to PK and PD of oral medications. BACKGROUND:: The effect of RYGB on oral drug disposition is not well understood. METHODS:: An oral cocktail of probe drugs for major drug-metabolizing enzymes (caffeine, tolbutamide, omeprazole, dextromethorphan, and oral and intravenous midazolam) was administered to 18 RYGB recipients and 18 controls. Timed blood and urine samples were obtained for PK analyses. Forty mg of oral furosemide was administered to 13 RYGB recipients and 14 controls, and urine and blood samples were collected for assessing furosemidePK, and urine volume and urine sodium excretion for PD analyses. RESULTS:: Compared with controls, the RYGB group had significantly lower time to maximum plasma concentration (tmax) for caffeine (0.58 ± 0.5 vs 2.1 ± 2.2 hours, P < 0.0001), tolbutamide (1.4 ± 1.8 vs 2.1 ± 2.2 hours, P = 0.0001), omeprazole (1.1 ± 1.1 vs 4.4 ± 1.3 hours, P < 0.0001), and oral midazolam (0.5 ± 0.2 vs 0.7 ± 0.4 hours, P < 0.01). However, maximum plasma concentration, half-life, area under the curve, and oral bioavailability were not different. Compared with controls, the RYGB group had brisk natriuresis, with significantly lower tmax for urine sodium (1.3 ± 0.5 vs 3.1 ± 2.3 hours, P < 0.02) and correspondingly lower tmax for furosemide (1.8 ± 0.3 vs 4.2 ± 1.2 hours, P = 0.006). However, 6-hour urine sodium and 6-hour urine volume were not different between the two groups. CONCLUSIONS:: RYGB recipients have significantly shorter tmax for the studied orally administered medications, but otherwise no other significant changes in PK were reported.
Annals of surgery 12/2012; · 7.90 Impact Factor
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Thomas J Urban,
Yufeng Shen,
Andrew Stolz, Naga Chalasani,
Robert J Fontana,
James Rochon,
Dongliang Ge,
Kevin V Shianna,
Ann K Daly,
M Isabel Lucena, [......],
Aris Floratos,
Itsik Pe'er,
Jose Serrano,
Herbert Bonkovsky,
Timothy J Davern,
William M Lee,
Victor J Navarro,
Jayant A Talwalkar,
David B Goldstein,
Paul B Watkins
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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. METHODS: DILI patients from the US-based Drug-Induced Liver Injury Network (n=401) and three international registries (n=382) were genotyped with the Illumina 1Mduo BeadChip and compared with population controls (n=3001). Potential associations were tested in 307 independent Drug-Induced Liver Injury Network cases. RESULTS: After accounting for known major histocompatibility complex risk alleles for flucloxacillin-DILI and amoxicillin/clavulanate-DILI, there were no genome-wide significant associations, including in the major histocompatibility complex region. Stratification of DILI cases according to clinical phenotypes (injury type, latency, age of onset) also did not show significant associations. An analysis of hepatocellular DILI (n=285) restricted to 193 single-nucleotide polymorphisms previously associated with autoimmune disease showed a trend association for rs7574865, in the vicinity of signal transducer and activator of transcription 4 (STAT4) (P=4.5×10). This association was replicated in an independent cohort of 168 hepatocellular DILI cases (P=0.011 and 1.5×10 for combined cohorts). No significant associations were found with stratification by other clinical or demographic variables. CONCLUSION: Although not significant at the genome-wide level, the association between hepatocellular DILI and STAT4 is consistent with the emerging role of the immune system in DILI. However, the lack of genome-wide association study findings supports the idea that strong genetic determinants of DILI may be largely drug-specific or may reflect rare genetic variations, which were not assessed in our study.
Pharmacogenetics and Genomics 09/2012; 22(11):784-795. · 3.48 Impact Factor
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ABSTRACT: Patients with cirrhosis often experience muscle cramps with varying severity. We investigated the factors associated with the prevalence and morbidity associated with muscle cramps.
A total of 150 adult patients with cirrhosis were enrolled consecutively. Cramp questionnaire with visual analogue scale for pain, Chronic Liver Disease Questionnaire (CLDQ), and blood for measurement of 25-(OH) vitamin D levels were obtained after informed consent.
A total of 101 patients (67%) reported muscle cramps in the preceding 3 months. Patients with cramps had significantly lower serum albumin (3.1±0.6 g/dL vs 3.3±0.7 g/dL, P=.04) and CLDQ scores (107±37 vs 137±34, P<.0001) compared with those without cramps. The median composite symptom score, defined as product of frequency and severity of cramps, in the study cohort was 12 with a range of 0.3 to 200. There were no clinical or biochemical predictors for occurrence of any cramps or severe cramps (composite symptom score>12). Muscle cramps (P<.001) and hepatic encephalopathy (P=.009) were associated independently with decreased CLDQ scores. Vitamin D deficiency was seen in 66% of the study cohort, but the serum 25-(OH) vitamin D levels were not significantly different between patients with and without cramps (18.0±8.9 ng/mL vs 19.6±9.5 ng/mL, P=.49).
Muscle cramps are associated with significantly diminished quality of life in patients with cirrhosis. More research is needed to better understand their mechanism to develop effective treatment.
The American journal of medicine 07/2012; 125(10):1019-25. · 4.47 Impact Factor
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ABSTRACT: AIMS: To determine the extent and time-course of hepatic and intestinal cytochrome P450 3A (CYP3A) inactivation due to the mechanism-based inhibitor clarithromycin. METHODS: Intestinal and hepatic CYP3A inhibition was examined in 12 healthy volunteers following the administration of single and multiple doses of oral clarithromycin (500 mg). Intestinal biopsies were obtained under intravenous midazolam sedation at baseline and after the first dose, on days 2-4, and on days 6-8 of the clarithromycin treatment. The formation of 1'-hydroxymidazolam in biopsy tissue and the serum 1'-hydroxymidazolam:midazolam ratio were indicators of intestinal and hepatic CYP3A activity, respectively. RESULTS: Intestinal CYP3A activity decreased by 64 % (p = 0.0029) following the first dose of clarithromycin, but hepatic CYP3A activity did not significantly decrease. Repeated dosing of clarithromycin caused a significant decrease in hepatic CYP3A activity (p = 0.005), while intestinal activity showed little further decline. The CYP3A5 or CYP3A4*1B genotype were unable to account for inter-individual variability in CYP3A activity. CONCLUSIONS: Following the administration of clarithromycin, the onset of hepatic CYP3A inactivation is delayed compared to that of intestinal CYP3A. The time-course of drug-drug interactions due to clarithromycin will vary with the relative contribution of intestinal and hepatic CYP3A to the clearance and bioavailability of a victim substrate.
European Journal of Clinical Pharmacology 07/2012; · 2.85 Impact Factor
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ABSTRACT: It is generally recommended that patients with nonalcoholic fatty liver disease (NAFLD) not consume alcohol. However, because these patients are at increased cardiovascular risk, and light to moderate alcohol consumption may have hepatic benefits in people with or at risk for NAFLD, this recommendation may be ill-advised. We reviewed the literature on alcohol consumption and NAFLD and conclude that (i) heavy consumption has many harmful effects, including those on the liver, and should be discouraged whether a person has NAFLD or not; (ii) it is unknown whether cardiovascular and metabolic benefits of light to moderate consumption observed in the general population extend to those with NAFLD; (iii) epidemiological and cohort studies suggesting that light to moderate drinking may have hepatic benefits are largely cross-sectional and used surrogate end points; and (iv) until further data from rigorous prospective studies become available, people with NAFLD should avoid alcohol of any type or amount.
The American Journal of Gastroenterology 07/2012; 107(7):976-8. · 7.28 Impact Factor
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ABSTRACT: 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.
To describe characteristics of patients with acute liver injury suspected of being caused by flavocoxid.
Case series.
Drug-Induced Liver Injury Network Prospective Study ongoing at multiple academic medical centers since 2004.
Four adults with liver injury.
Clinical characteristics, liver biochemistry values, and outcomes.
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.
The frequency and mechanism of liver injury could not be assessed.
Flavocoxid can cause clinically significant liver injury, which seems to resolve within weeks after cessation.
Annals of internal medicine 06/2012; 156(12):857-60, W297-300. · 16.73 Impact Factor
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The American Journal of Gastroenterology 06/2012; 107(6):811-26. · 7.28 Impact Factor
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Gastroenterology 06/2012; 142(7):1592-609. · 11.68 Impact Factor
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Lauren N Bell,
Jiangxia Wang,
Sriya Muralidharan,
Sadhana Chalasani,
Allison M Fullenkamp,
Laura A Wilson,
Arun J Sanyal,
Kris V Kowdley,
Brent A Neuschwander-Tetri,
Elizabeth M Brunt,
Arthur J McCullough,
Nathan M Bass,
Anna Mae Diehl,
Aynur Unalp-Arida, Naga Chalasani
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ABSTRACT: The PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis [NASH]) trial demonstrated that pioglitazone and vitamin E improved liver histology to varying degrees, but the mechanisms are unknown. We conducted a study to examine the changes in adipose tissue insulin resistance (Adipo-IR) during the PIVENS trial and its relationship to histological endpoints. Adipo-IR (fasting nonesterified fatty acids [NEFAs] × fasting insulin) was calculated at baseline and after 16 and 96 weeks of therapy. Compared to placebo, the baseline Adipo-IR was not different in either the vitamin E group (P = 0.34) or the pioglitazone group (P = 0.29). Baseline Adipo-IR was significantly associated with fibrosis score (P = 0.02), but not with other histological features or nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 16 weeks, compared to placebo, the pioglitazone group had a significant reduction in Adipo-IR (-15.7 versus -1.91; P = 0.02), but this effect did not persist at 96 weeks (-3.25 versus -4.28; P = 0.31). Compared to placebo, Adipo-IR in the vitamin E group did not change significantly either after 16 weeks (P = 0.70) or after 96 weeks (P = 0.85). Change in Adipo-IR at week 16 was not associated with changes in any histological parameters at week 96, but improvement in Adipo-IR at week 96 was significantly associated with improvement in ballooning (P = 0.03), fibrosis (P = 0.004), and NAS (P = 0.01). Conclusion: Vitamin E improved liver histology independent of changes in Adipo-IR, and pioglitazone treatment acutely improved Adipo-IR, but this was not sustained. Changes in Adipo-IR were associated with changes in liver histology, including fibrosis. (HEPATOLOGY 2012).
Hepatology 04/2012; 56(4):1311-1318. · 11.66 Impact Factor
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Vlad Ratziu,
Muhammad Y Sheikh,
Arun J Sanyal,
Joseph K Lim,
Hari Conjeevaram, Naga Chalasani,
Manal Abdelmalek,
Anezi Bakken,
Christophe Renou,
Melissa Palmer,
Robert A Levine,
B Raj Bhandari,
Melanie Cornpropst,
Wei Liang,
Benjamin King,
Elsa Mondou,
Franck S Rousseau,
John McHutchison,
Mario Chojkier
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ABSTRACT: In nonalcoholic steatohepatitis (NASH), the extent of hepatocyte apoptosis correlates with disease severity. Reducing hepatocyte apoptosis with the selective caspase inhibitor GS-9450 has a potential for altering the course of the liver disease. In this phase 2, double-blind study, 124 subjects with biopsy-proven NASH were randomized to once-daily placebo or 1, 5, 10, or 40 mg GS-9450 for 4 weeks. Absolute and percent changes from baseline in ALT levels, AST levels, and caspase-3-cleaved cytokeratin (CK)-18 fragments at week 4 were assessed by an analysis of covariance model with adjustment for baseline values. In the 40-mg group, mean (SD) ALT decreased by 47 (43) U/L from baseline to week 4 (P < 0.0001 versus placebo), and the proportion of subjects with normal ALT increased from 0% to 35% at week 4. In the 40-mg group, mean AST decreased by 13 U/L from baseline (not significant), and the proportion with normal AST increased from 20% at baseline to 48% at week 4. By week 4, mean CK-18 fragment levels had decreased to 393 (723) U/L in the GS-9450 10-mg group and 125 (212) U/L in the 40-mg group, but these reductions were not statistically significant. No serious adverse events were reported during treatment, and the percentage of subjects with at least one treatment-emergent grade 3 or 4 laboratory abnormality ranged from 11.5% to 17% across the GS-9450 treatment groups versus 35% in the placebo group. CONCLUSION: GS-9450 treatment induced significant reductions in ALT levels in NASH patients. Reductions in CK-18 fragment levels also occurred, although they were not statistically significant. At appropriate therapeutic indices, selective caspase inhibitors may be a promising treatment option in patients with NASH.
Hepatology 02/2012; 55(2):419-28. · 11.66 Impact Factor
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ABSTRACT: Patients with nonalcoholic fatty liver disease (NAFLD) often have dyslipidemia along with other features of metabolic syndrome such as obesity, diabetes mellitus, and hypertension. The dyslipidemia in NAFLD is characterized by increased serum triglycerides, increased small, dense low-density lipoprotein (LDL nontype A) particles, and low high-density lipoprotein (HDL) cholesterol. The pathogenesis of dyslipidemia in NAFLD is not well understood, but it is likely related to hepatic overproduction of the very low-density lipoprotein particles and dysregulated clearance of lipoproteins from the circulation. There is unequivocal evidence that cardiovascular disease is the most common cause of mortality in patients with NAFLD. Aggressive treatment of dyslipidemia plays a critical role in the overall management of patients with NAFLD. Statins are the first-line agents to treat high cholesterol and their dosage should be adjusted based on achieving therapeutic targets and tolerability. Although all statins appear to be effective in improving cholesterol levels in patients with NAFLD, there is more experience with atorvastatin in patients with NAFLD; furthermore, it is the only statin to date to show a reduced cardiovascular morbidity in patients with NAFLD. The risk for serious liver injury from statins is quite rare and patients with NAFLD are not at increased risk for statin hepatotoxicity. Omega-3 fatty acids are perhaps the first choice to treat hypertriglyceridemia because of their safety, tolerability, and efficacy in improving serum triglycerides, as well as their potential to improve liver disease.
Seminars in Liver Disease 02/2012; 32(1):22-9. · 7.05 Impact Factor
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ABSTRACT: Genetic variation in the expression of human xenobiotic metabolism enzymes and transporters (XMETs) leads to inter-individual variability in metabolism of therapeutic agents as well as differed susceptibility to various diseases. Recent expression quantitative traits loci (eQTL) mapping in a few human cells/tissues have identified a number of single nucleotide polymorphisms (SNPs) significantly associated with mRNA expression of many XMET genes. These eQTLs are therefore important candidate markers for pharmacogenetic studies. However, questions remain about whether these SNPs are causative and in what mechanism these SNPs may function. Given the important role of microRNAs (miRs) in gene transcription regulation, we hypothesize that those eQTLs or their proxies in strong linkage disequilibrium (LD) altering miR targeting are likely causative SNPs affecting gene expression. The aim of this study is to identify eQTLs potentially regulating major XMETs via interference with miR targeting. To this end, we performed a genome-wide screening for eQTLs for 409 genes encoding major drug metabolism enzymes, transporters and transcription factors, in publically available eQTL datasets generated from the HapMap lymphoblastoid cell lines and human liver and brain tissue. As a result, 308 eQTLs significantly (p < 10(-5)) associated with mRNA expression of 101 genes were identified. We further identified 7,869 SNPs in strong LD (r(2) ≥ 0.8) with these eQTLs using the 1,000 Genome SNP data. Among these 8,177 SNPs, 27 are located in the 3'-UTR of 14 genes. Using two algorithms predicting miR-SNP interaction, we found that almost all these SNPs (26 out of 27) were predicted to create, abolish, or change the target site for miRs in both algorithms. Many of these miRs were also expressed in the same tissue that the eQTL were identified. Our study provides a strong rationale for continued investigation for the functions of these eQTLs in pharmacogenetic settings.
Frontiers in genetics. 01/2012; 3:248.
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ABSTRACT: Vitamin D is now widely recognized to have multiple extraskeletal health functions. The liver is one of the major organs involved in its metabolism. Recent studies have demonstrated a very high prevalence of vitamin D deficiency and insufficiency in patients with chronic liver disease and cirrhosis. There is an emerging interest to explore the relationship between vitamin D deficiency and prevalence and severity of non-alcoholic liver disease and response to antiviral therapy in hepatitis C. In this review, we discuss the current status of our understanding of vitamin D metabolism and vitamin D deficiency in patients with chronic liver disease and cirrhosis.
Current Gastroenterology Reports 11/2011; 14(1):67-73.
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ABSTRACT: Serum ferritin (SF) levels are commonly elevated in patients with nonalcoholic fatty liver disease (NAFLD) because of systemic inflammation, increased iron stores, or both. The aim of this study was to examine the relationship between elevated SF and NAFLD severity. Demographic, clinical, histologic, laboratory, and anthropometric data were analyzed in 628 adult patients with NAFLD (age, ≥ 18 years) with biopsy-proven NAFLD and an SF measurement within 6 months of their liver biopsy. A threshold SF >1.5 × upper limit of normal (ULN) (i.e., >300 ng/mL in women and >450 ng/mL in men) was significantly associated with male sex, elevated serum alanine aminotransferase, aspartate aminotransferase, iron, transferrin-iron saturation, iron stain grade, and decreased platelets (P < 0.01). Histologic features of NAFLD were more severe among patients with SF >1.5 × ULN, including steatosis, fibrosis, hepatocellular ballooning, and diagnosis of NASH (P < 0.026). On multiple regression analysis, SF >1.5 × ULN was independently associated with advanced hepatic fibrosis (odds ratio [OR], 1.66; 95% confidence interval [CI], 1.05-2.62; P = 0.028) and increased NAFLD Activity Score (NAS) (OR, 1.99; 95% CI, 1.06-3.75; P = 0.033). CONCLUSIONS: A SF >1.5 × ULN is associated with hepatic iron deposition, a diagnosis of NASH, and worsened histologic activity and is an independent predictor of advanced hepatic fibrosis among patients with NAFLD. Furthermore, elevated SF is independently associated with higher NAS, even among patients without hepatic iron deposition. We conclude that SF is useful to identify NAFLD patients at risk for NASH and advanced fibrosis.
Hepatology 09/2011; 55(1):77-85. · 11.66 Impact Factor
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ABSTRACT: Several enveloped viruses including human immunodeficiency virus type 1 (HIV-1), cytomegalovirus (CMV), herpes simplex virus 1 (HSV-1), Ebola virus, vaccinia virus, and influenza virus have been found to incorporate host regulators of complement activation (RCA) into their viral envelopes and, as a result, escape antibody-dependent complement-mediated lysis (ADCML). Hepatitis C virus (HCV) is an enveloped virus of the family Flaviviridae and incorporates more than 10 host lipoproteins. Patients chronically infected with HCV develop high-titer and crossreactive neutralizing antibodies (nAbs), yet fail to clear the virus, raising the possibility that HCV may also use the similar strategy of RCA incorporation to escape ADCML. The current study was therefore undertaken to determine whether HCV virions incorporate biologically functional CD59, a key member of RCA. Our experiments provided several lines of evidence demonstrating that CD59 was associated with the external membrane of HCV particles derived from either Huh7.5.1 cells or plasma samples from HCV-infected patients. First, HCV particles were captured by CD59-specific Abs. Second, CD59 was detected in purified HCV particles by immunoblot analysis and in the cell-free supernatant from HCV-infected Huh7.5.1 cells, but not from uninfected or adenovirus serotype 5 (Ad5) (a nonenveloped cytolytic virus)-infected Huh7.5.1 cells by enzyme-linked immunosorbent assay. Last, abrogation of CD59 function with its blockers increased the sensitivity of HCV virions to ADCML, resulting in a significant reduction of HCV infectivity. Additionally, direct addition of CD59 blockers into plasma samples from HCV-infected patients increased autologous virolysis. CONCLUSION: Our study, for the first time, demonstrates that CD59 is incorporated into both cell line-derived and plasma primary HCV virions at levels that protect against ADCML. This is also the first report to show that direct addition of RCA blockers into plasma from HCV-infected patients renders endogenous plasma virions sensitive to ADCML.
Hepatology 09/2011; 55(2):354-63. · 11.66 Impact Factor
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ABSTRACT: Liver biopsies from patients with nonalcoholic fatty liver disease (NAFLD) sometimes exhibit non-zonal aggregates of hepatocytes with microvesicular steatosis, but its prevalence and significance are unclear. In this study, we have evaluated the frequency of microvesicular steatosis and assessed its association with histological markers of disease severity in a large sample of NAFLD liver biopsies.
Liver biopsies from a large cohort of adults who participated in two studies conducted by the NASH Clinical Research Network (NASH CRN) were included in this cross-sectional study. Liver histology was assessed centrally and various histological features scored in a systematic fashion. The relationship between microvesicular steatosis and various histological features that characterize NAFLD was tested by multiple logistic regression, after controlling for age, gender, race, body mass index, and diabetes.
Among 1022 liver biopsies included, 102 (10%) had microvesicular steatosis. No demographic differences were noted between patients with or without microvesicular steatosis. The presence of microvesicular steatosis was associated with higher grades of steatosis (p<0.001), ballooning cell injury (p<0.001), presence of Mallory-Denk bodies (p<0.007), presence of megamitochondria (p<0.0001), higher NAS scores (p<0.0001), more advanced fibrosis (p<0.0001), and diagnosis of borderline or definite NASH (p<0.0001).
Microvesicular steatosis correlates with more advanced histology of NAFLD. Longitudinal studies are needed to address the role of microvesicular steatosis in mediating cellular injury and disease progression in NAFLD.
Journal of Hepatology 09/2011; 55(3):654-9. · 9.26 Impact Factor
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Timothy J Davern, Naga Chalasani,
Robert J Fontana,
Paul H Hayashi,
Petr Protiva,
David E Kleiner,
Ronald E Engle,
Hanh Nguyen,
Suzanne U Emerson,
Robert H Purcell,
Hans L Tillmann,
Jiezhun Gu,
Jose Serrano,
Jay H Hoofnagle
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ABSTRACT: The diagnosis of drug-induced liver injury relies on exclusion of other causes, including viral hepatitis A, B, and C. Hepatitis E virus (HEV) infection has been proposed as another cause of suspected drug-induced liver disease. We assessed the frequency of HEV infection among patients with drug-induced liver injury in the United States.
The Drug-Induced Liver Injury Network (DILIN) is a prospective study of patients with suspected drug-induced liver injury; clinical information and biological samples are collected to investigate pathogenesis and disease progression. We analyzed serum samples, collected from patients enrolled in DILIN, for immunoglobulin (Ig) G and IgM against HEV; selected samples were tested for HEV RNA.
Among 318 patients with suspected drug-induced liver injury, 50 (16%) tested positive for anti-HEV IgG and 9 (3%) for anti-HEV IgM. The samples that contained anti-HEV IgM (collected 2 to 24 weeks after onset of symptoms) included 4 that tested positive for HEV RNA genotype 3. Samples from the 6-month follow-up visit were available from 4 patients; they were negative for anti-HEV IgM, but levels of anti-HEV IgG increased with time. Patients who had anti-HEV IgM were mostly older men (89%; mean age, 67 years), and 2 were human immunodeficiency virus positive. Clinical reassessment of the 9 patients with anti-HEV IgM indicated that acute hepatitis E was the most likely diagnosis for 7 and might be the primary diagnosis for 2.
HEV infection contributes to a small but important proportion of cases of acute liver injury that are suspected to be drug induced. Serologic testing for HEV infection should be performed, particularly if clinical features are compatible with acute viral hepatitis.
Gastroenterology 08/2011; 141(5):1665-72.e1-9. · 11.68 Impact Factor
