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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: 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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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: 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: 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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ABSTRACT: Oxidative stress plays an important role in the pathogenesis of many liver diseases. Investigators often measure markers of oxidative stress in peripheral veins as a reflection of hepatic oxidative stress as it is not always feasible to measure oxidative stress in liver tissue. However, it is unknown whether markers of oxidative stress measured from peripheral sites accurately reflect hepatic tissue oxidative stress. The aim of this study is to examine the relationship of oxidative stress marker among hepatic tissue, hepatic and peripheral veins and urine.
Malondialdehyde (MDA), a marker of oxidative stress was measured in hepatic vein, peripheral vein and urine samples from 26 consecutive patients undergoing transjugular liver procedures. In 19 patients undergoing liver biopsies, we measured MDA by immunohistochemical staining of paraffin-embedded liver tissue.
Peripheral venous MDA levels showed significant correlation with hepatic venous MDA levels (r = 0.62, P = 0.02), but they did not correlate with hepatic tissue MDA content (r = 0.22, P = 0.4). Hepatic venous MDA levels did not correlate with hepatic tissue MDA content (r = -0.01, P = 0.9). Subgroup analysis of patients without portal hypertension showed a positive correlation between hepatic venous and hepatic tissue MDA levels, but this was not statistically significant (r = 0.45, P = 0.22). Urinary MDA did not correlate with MDA from any other sampling location.
Oxidative stress measured from the peripheral venous samples is poorly reflective of hepatic tissue oxidative stress. Hepatic venous sampling might be suitable for assessing hepatic tissue oxidative stress in patients without portal hypertension, but a larger study is needed to examine this possibility.
The American Journal of the Medical Sciences 06/2011; 342(4):314-7. · 1.39 Impact Factor
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ABSTRACT: To compare hepatic lipid peroxidation and cytochrome P-450 2E1 (CYP2E1) protein content in liver biopsies from children with nonalcoholic fatty liver disease (NAFLD) and 2 control groups.
Elevated hepatic lipid peroxidation resulting from increased hepatic CYP2E1 enzyme activity is involved in the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) in adults, but studies in children are lacking.
Liver biopsies from 59 children with NAFLD (49 with NASH), 10 children with normal liver histology, and 9 children with mild chronic hepatitis C (HCV) infection were examined. Hepatic malondialdehyde (a measure of lipid peroxidation) levels and CYP2E1 protein content were quantitated, as a percentage of the total area, by immunohistochemical staining of liver biopsy material followed by digital image quantitation.
Lipid peroxidation was significantly greater in NAFLD liver biopsies (46.7 ± 20.8%) compared with biopsies from children with normal liver histology (7.6 ± 9.4%; P<0.001) or HCV infection (7.7 ± 7.6%; P<0.001). However, hepatic CYP2E1 expression was not different across the NAFLD, normal liver histology, and HCV groups (60.7 ± 8.7%, 53.5 ± 10.7%, and 60.0 ± 11.9%, respectively; P=0.116). Among children with NAFLD, lipid peroxidation and CYP2E1 protein content did not differ between biopsies with and without NASH. Body mass index was independently associated with hepatic lipid peroxidation levels (r=0.549; P<0.001).
Hepatic lipid peroxidation is increased in children with NAFLD but this is not related to hepatic CYP2E1 expression. No difference in lipid peroxidation in pediatric NAFLD versus NASH argues against a role in disease progression.
Journal of clinical gastroenterology 05/2011; 45(9):800-7. · 2.21 Impact Factor
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ABSTRACT: PURPOSE: Some studies have suggested that autoantibodies might define a subcategory and phenotype of nonalcoholic fatty liver disease (NAFLD) associated with advanced histological features. We evaluated the relationship between the presence of serum autoantibodies and liver histology in a large cohort of well-characterized patients with NAFLD. METHODS: A total of 864 NAFLD patients participating in two prospective multicentre clinical studies underwent testing for serum autoantibodies within 24 months of a liver biopsy. Liver histology was compared between the patients with and without ANA ≥ 1:160 or ASMA ≥ 1:40 or both. RESULTS: Autoantibodies were present in 182 patients (21%). There was no difference in age, gender, race, body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), or history of diabetes between the two groups. Biopsies in subjects with autoantibodies were less likely to have moderate-to-severe steatosis (i.e., >33%) compared to controls (57.1 vs. 43.0%, P value = 0.0006). Lobular inflammation (46.7 vs. 47.5%), ballooning degeneration (38.5 vs. 42.5%), and advanced fibrosis (33.2 vs. 29.3%) were not different between the two groups. Histologic evidence of 'definite' NASH did not differ significantly between the two groups (55.5 vs. 58.9%). After adjusting for age, gender, BMI, race, and diabetes, the presence of autoantibodies was independently associated with lower prevalence of moderate-to-severe steatosis [odds ratio (OR), 0.58; 95% confidence interval (CI), 0.41-0.82; P = 0.01]. CONCLUSION: Autoantibodies are frequently positive in NAFLD in the absence of autoimmune hepatitis and their occurrence is not associated with more advanced histologic features.
Hepatology International 05/2011; · 2.64 Impact Factor
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ABSTRACT: The rate of readmission to the hospital 30 days after discharge (30-day readmission rate) is used as a quality measure for hospitalized patients, but it has not been studied adequately for patients with advanced liver disease. We investigated the incidence and factors that predict this rate and its relationship with mortality at 90 days.
We analyzed data from patients with advanced liver disease who were hospitalized to an inpatient hepatology service at 2 large academic medical centers in 2008. Patients with elective admission and recipients of liver transplants were not included. During the study period, there were 447 patients and a total of 554 eligible admissions. Multivariate analyses were performed to identify variables associated with 30-day readmission and to examine its relationship with mortality at 90 days.
The 30-day readmission rate was 20%. After adjusting for multiple covariates, readmission within 30 days was associated independently with model for end-stage liver disease scores at discharge (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02-1.09; P = .002), the presence of diabetes (OR, 1.78; 95% CI, 1.07-2.95; P = .027), and male sex (OR, 1.73; 95% CI, 1.03-2.89; P = .038). After adjusting for age, sex, and model for end-stage liver disease score at discharge, the 90-day mortality rate was significantly higher among patients who were readmitted to the hospital within 30 days than those who were not (26.8% vs 9.8%; OR, 2.6; 95% CI, 1.36-5.02; P = .004).
Patients with advanced liver disease frequently are readmitted to the hospital within 30 days after discharge; these patients have a higher 90-day mortality rate than those who are not readmitted in 30 days. These data might be used to develop strategies to reduce early readmission of hospitalized patients with cirrhosis.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 03/2011; 9(3):254-9. · 5.64 Impact Factor
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ABSTRACT: The recently developed histologic scoring system for nonalcoholic fatty liver disease (NAFLD) by the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) is becoming increasingly popular. However, its generalizability to a community setting has not been evaluated. We conducted a study to compare a community general pathologist to an expert hepatopathologist in assessing NAFLD using the NASH CRN scoring system.
Forty-eight consecutive patients with suspected NAFLD underwent liver biopsy. Histologic features of interest such as steatosis, lobular inflammation, balloon degeneration, fibrosis, NAFLD Activity Score (NAS), and the presence of NASH were scored in a blinded fashion by the 2 pathologists on 2 separate occasions 3 months apart.
The mean (± SD) length of the liver biopsy samples was 25 ± 5 mm. Interobserver agreement (κ) between 2 pathologists was 0.62 (0.45-0.80) for steatosis, 0.44 (0.23-0.65) for lobular inflammation, 0.25 (0.11-0.38) for ballooning, 0.40 for NAS (0.28-0.52), and 0.35 (0.19-0.52) for fibrosis. The 2 pathologists diagnosed "definite NASH" in a similar proportion of patients (56% vs. 57%), but their interobserver agreement was only 0.46 (0.24-0.67) as they both diagnosed different levels of NASH (borderline vs. definite) in different subjects. Intraobserver agreement was generally comparable for steatosis, lobular inflammation, NAS, and diagnosis of NASH, but not for fibrosis.
Clinically important differences exist between community general pathologist and expert hepatopathologist in assessing NAFLD using the NASH CRN scoring system. More studies are needed to investigate its suitability for community-based clinical practice.
Journal of clinical gastroenterology 01/2011; 45(1):55-8. · 2.21 Impact Factor
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Kenneth Berman,
Sweta Tandra, Raj Vuppalanchi,
Raj Vuppalanch,
Marwan Ghabril,
Kumaresan Sandrasegaran,
James Nguyen,
Helena Caffrey,
Suthat Liangpunsakul,
Lawrence Lumeng,
Paul Kwo,
Naga Chalasani
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ABSTRACT: We conducted a retrospective cohort study in cirrhotic patients to understand (i) the risk of developing hepatocellular carcinoma (HCC) after an initial negative screening computed tomography (CT) scan and its relationship with underlying etiology and (ii) the risk of extrahepatic cancers (EHCs).
Our cohort consisted of 952 cirrhotics who had at least one contrast-enhanced CT scan over a 5-year period from 1997 to 2002. We assessed their risk of HCC and EHC until the study closure (31 December 2007). Using data from the Indiana State Cancer Registry (ISCR), standardized incidence ratios (SIRs) were calculated for HCC and EHC.
The cohort's follow-up was 4.7±3.0 years. The frequency of HCC at baseline and during follow-up was 6.9 and 7.2%, respectively. The 1-, 3-, and 5-year HCC incidence after an initial negative CT scan was 1.2, 4.4, and 7.8%, respectively. The 1-, 3-, and 5-year EHC incidence was 2.2, 4.5, and 6.8%, respectively. The most common EHCs were breast, lung, and lymphoma. Incidence of both HCC (P=0.016) and EHC (P=0.004) varied significantly by the etiology of underlying cirrhosis. The SIRs for HCC and EHC were 186 (95% confidence interval (CI) 140-238) and 1.83 (95% CI 1.36-2.36), respectively. Compared with adjusted ISCR data, cirrhosis due to alcohol (SIR 2.73, 95% CI 1.14-4.33) but not other etiologies had significantly higher incidence of EHC.
This study furthers our understanding of HCC and EHC risk in cirrhosis. If confirmed by other studies, these data will assist in developing optimal strategies for monitoring of cancer in individuals with cirrhosis.
The American Journal of Gastroenterology 12/2010; 106(5):899-906. · 7.28 Impact Factor
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ABSTRACT: Nearly 40% of cytochrome P450 3A (CYP3A) activity is located in the small intestine. An earlier study has shown that cirrhotics with transjugular intrahepatic portosystemic shunts (TIPS) have diminished intestinal CYP3A activity. We hypothesized that oral CYP3A substrates known to prolong QT interval may cause further prolongation of the QT interval in cirrhotic patients with TIPS.
A total of 23 patients (9 healthy controls, 6 cirrhotics without and 8 cirrhotics with TIPS) participated in a study that tested this hypothesis using erythromycin as the probe drug. Participants with cirrhosis with and without TIPS were matched for age, sex, race, BMI and etiology of liver disease. Serial electrocardiograms were obtained at baseline, after single dose of erythromycin 500 milligrams, and after 7 days of erythromycin (500 milligrams orally twice daily). QT intervals were measured in 3 consecutive beats in 3 leads and corrected QT intervals (QTc) were obtained using various correction formulae. The maximal QTc change (ΔQTc Max) after single and multiple dose administration was the primary outcome.
At baseline, the QTc intervals (mean±S.E) in cirrhotics with TIPS (418±6 msec) and cirrhosis (431±6 msec) were significantly higher compared with controls (388±9 msec, P=0.021). After a single dose of erythromycin, there was no significant difference among the 3 groups in ΔQTc Max (P=0.7). However, after a 7 day course, cirrhotics with TIPS developed significantly greater ΔQTc Max (179.5±67.8 msec) compared with cirrhotics (31.2±9.5 msec) and healthy controls (38.3±3.3 msec) (P=0.03).
This study suggests that patients with TIPS are potentially at increased risk for abnormal QT prolongation when exposed to oral CYP 3A substrates with QT prolonging effect.
Journal of clinical gastroenterology 10/2010; 45(7):638-42. · 2.21 Impact Factor
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ABSTRACT: To evaluate the effects of surgical weight loss on hepatic lipid peroxidation levels and cytochrome P-450 protein expression in patients with nonalcoholic fatty liver disease (NAFLD).
NAFLD and nonalcoholic steatohepatitis (NASH) affect hepatic cytochrome P-450 (CYP) protein expression and activity, and CYP2E1 may play a role in the pathogenesis of NAFLD and NASH through induction of oxidative stress and lipid peroxidation. NAFLD and NASH are associated with increased systemic lipid peroxidation levels and elevated hepatic CYP2E1 activity, but hepatic CYP3A4/5 activity is decreased.
Liver biopsies from 20 patients with NAFLD who underwent bariatric surgery were obtained intraoperatively and at 15 +/- 7 months following surgery. Hepatic malondialdehyde (MDA) levels (a marker of lipid peroxidation), CYP2E1 and CYP3A4/5 protein expression, and steatosis, as a percent of total area, were measured by immunohistochemistry followed by digital image quantitation.
Following weight loss, as reflected by reduced BMI (54 +/- 9 vs. 37 +/- 9 kg/m2; P < 0.001), features of the metabolic syndrome, grade and stage of liver disease, and liver histology were all significantly improved (P < 0.01). Hepatic MDA staining (35 +/- 18% vs. 23 +/- 14%; P = 0.02), CYP2E1 protein content (68 +/- 9% vs. 56 +/- 11%; P < 0.001), and steatosis (17 +/- 7% vs. 2 +/- 3%; P < 0.001) were significantly reduced following weight loss. CYP3A4/5 protein content was unchanged (57 +/- 13% vs. 55 +/- 13%; P = 0.433). The reduction in lipid peroxidation was independently associated with changes in CYP2E1 protein expression after bariatric surgery (r = 0.477; P = 0.033).
Elevations in hepatic lipid peroxidation and CYP2E1 expression that are seen in NAFLD improve significantly with weight loss induced by bariatric surgery.
Annals of surgery 06/2010; 251(6):1041-8. · 7.90 Impact Factor
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ABSTRACT: We recently developed a nutritional model of steatohepatitis and metabolic syndrome in Ossabaw pigs. Here we describe changes in the serum proteome of pigs fed standard chow (control group; n = 7), atherogenic diet (n = 5), or modified atherogenic diet (M-ath diet group; n = 6). Pigs fed atherogenic diet developed metabolic syndrome and mildly abnormal liver histology, whereas pigs fed M-ath diet exhibited severe metabolic syndrome and liver injury closely resembling human nonalcoholic steatohepatitis (NASH). Using a label-free mass spectrometry-based proteomics approach, we identified 1,096 serum proteins, 162 of which changed significantly between any two diet groups (false discovery rate <5%). Biological classification of proteins with significant changes revealed functions previously implicated in development of NASH in humans, including immune system regulation and inflammation (orosomucoid 1, serum amyloid P component, paraoxonase 1, protein similar to alpha-2-macroglobulin precursor, beta-2-microglobulin, p101 protein, and complement components 2 and C8G), lipid metabolism (apolipoproteins C-III, E, E precursor, B, and N), structural and extracellular matrix proteins (transthyretin and endopeptidase 24.16 type M2), and coagulation [carboxypeptidase B2 (plasma)]. Several proteins with significant differential expression in pigs were also identified in our recent human proteomics study as changing significantly in serum from patients across the spectrum of nonalcoholic fatty liver disease, including apolipoproteins C-III and B, orosomucoid 1, serum amyloid P component, transthyretin, paraoxonase 1, and a protein similar to alpha-2-macroglobulin precursor. This serum proteomic analysis provides additional information about the pathogenesis of NASH and further characterizes our large animal model of diet-induced steatohepatitis and metabolic syndrome in Ossabaw pigs.
AJP Gastrointestinal and Liver Physiology 02/2010; 298(5):G746-54. · 3.43 Impact Factor
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ABSTRACT: Cardiovascular disease is as common in individuals with chronic liver disease as in the general population. Moreover, recent data suggest that patients with nonalcoholic fatty liver disease (NAFLD) may have a cardiovascular risk greater than that conferred by the conventional risk factors. There is unequivocal evidence that cardiovascular disease is an important cause of morbidity and mortality in this patient population and thus requires consideration of aggressive therapy with lipid-lowering agents such as statins. Because all statins are hepatically cleared and can cause elevations in liver biochemistries, there is a concern that patients with underlying liver disease may be at increased risk for hepatotoxicity. However, recent data, along with an assessment of statin safety by the Liver Expert Panel, suggest that statins are generally well tolerated in patients with chronic liver disease such as NAFLD, primary biliary cirrhosis, and hepatitis C virus. These drugs also appear to be safe in patients with stable/compensated cirrhosis. However, decompensated cirrhosis and acute liver failure should be considered contraindications for lipid-lowering therapy as these patients are unlikely to benefit because of their generally grave prognosis. Although routine hepatic biochemical test monitoring is recommended, the cost-effectiveness of this approach has been questioned. The benefit of statins in patients with underlying liver disease who are otherwise important candidates for statin therapy far outweighs the risk of a very rare event of serious liver injury.
Current Treatment Options in Cardiovascular Medicine 09/2009; 11(4):272-8.
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ABSTRACT: Nonalcoholic fatty liver disease (NAFLD), ranging from relatively benign simple steatosis to progressive nonalcoholic steatohepatitis (NASH) and fibrosis, is an increasingly common chronic liver disease. Liver biopsy is currently the only reliable tool for staging the subtypes of NAFLD; therefore, noninvasive serum biomarkers for evaluation of liver disease and fibrosis are urgently needed. We performed this study to describe changes in the serum proteome and identify biomarker candidates in serum samples from 69 patients with varying stages of NAFLD (simple steatosis, NASH, and NASH with advanced bridging [F3/F4] fibrosis) and 16 obese controls. Using a label-free mass spectrometry-based approach we identified over 1,700 serum proteins with a peptide identification (ID) confidence level of >75%, 605 of which changed significantly between any two patient groups (false discovery rate <5%). Importantly, expression levels of 55 and 15 proteins changed significantly between the simple steatosis and NASH F3/F4 group and the NASH and NASH F3/F4 group, respectively. Classification of proteins with significant changes showed involvement in immune system regulation and inflammation, coagulation, cellular and extracellular matrix structure and function, and roles as carrier proteins in the blood. Further, many of these proteins are synthesized exclusively by the liver and could potentially serve as diagnostic biomarkers for identifying and staging NAFLD. Conclusion: This proteomic analysis reveals important information regarding the pathogenesis/progression of NAFLD and NASH and demonstrates key changes in serum protein expression levels between control subjects and patients with different stages of fatty liver. Future validation of these potential biomarkers is needed such that these proteins may be used in place of liver biopsy to facilitate diagnosis and treatment of patients with NAFLD.
Hepatology 09/2009; 51(1):111-20. · 11.66 Impact Factor
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ABSTRACT: Liver biopsy is required to diagnose nonalcoholic steatohepatitis (NASH) in patients with suspected non-alcoholic fatty liver disease (NAFLD); recent studies suggested significant sampling variability. Using percutaneous liver biopsy samples from patients with suspected NAFLD, we examined the relationship between histological yield and length of biopsies, number of cores and number of independent readings.
Three cores of liver tissue were collected, by percutaneous liver biopsy, from each of 50 patients suspected to have NAFLD. The diagnostic yield (percent with definite NASH) and other histological findings from 2 independent, blinded examinations of 2 cores and from all 3 cores combined were assessed.
Steatosis, lobular inflammation and fibrosis scores were significantly higher when 3 samples were analyzed, compared with 2. However, between groups, there were no significant differences in hepatocyte ballooning, proportion with an NAFLD activity score > or =4 or proportion with definite NASH (57% vs 61%, P = .3). The length of the biopsy sample correlated with percentage of patients found to have definite NASH (29%, 46%, 56%, and 65% in biopsies measuring <10 mm, 10-14 mm, 15-24 mm, and > or =25 mm, respectively; P < .0001). When biopsy specimens were read twice by the same pathologist, the composite of the 2 independent readings yielded a significantly higher yield for several histological features, compared with the first reading.
There is a significant relationship between histological yield and sample length and number of independent readings of liver biopsy samples. More studies are needed to optimize the strategy for liver biopsy, to more effectively assess histology in patients with suspected NAFLD.
Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 12/2008; 7(4):481-6. · 5.64 Impact Factor
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Digestive Diseases and Sciences 10/2008; 54(6):1375-6. · 2.12 Impact Factor
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ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is among the most common causes of chronic liver disease in the western world. It is now recognized that these patients have myriad of important co-morbidities (e.g., diabetes, hypothyroidism and metabolic syndrome). The workup of patients with suspected NAFLD should consist of excluding competing etiologies and systemic evaluation of metabolic comorbidities. NAFLD is histologically categorized into steatosis and steatohepatitis, two states with fairly dichotomous natural history. While significant progress has been made in terms of noninvasively predicting advanced fibrosis, insufficient progress has been made in predicting steatohepatitis. Currently, liver biopsy remains the gold standard for the histological stratification of NAFLD. While sustained weight loss can be effective to treat NASH, it is often difficult to achieve. Foregut bariatric surgery can be quite effective in improving hepatic histology in selected patients without liver failure or significant portal hypertension. Thiazolidinediones have shown promise and the results from the ongoing, large multicenter study should become available soon. Large multicenter studies of CB, receptor anatagonists are also underway but their results will not be available for several years. Several recent studies have highlighted that cardiovascular disease is the single most important cause of morbidity and mortality in this patient population. Conclusion: Health care providers should not only focus on liver disease but also concentrate on aggressively modifying and treating their cardiovascular risk factors.
Hepatology 10/2008; 49(1):306-17. · 11.66 Impact Factor
