Aynur Unalp
Johns Hopkins University
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Featured researches published by Aynur Unalp.
The New England Journal of Medicine | 2010
Arun J. Sanyal; Naga Chalasani; Kris V. Kowdley; Arthur J. McCullough; Anna Mae Diehl; Nathan M. Bass; Brent A. Neuschwander-Tetri; Joel E. Lavine; James Tonascia; Aynur Unalp; Mark L. Van Natta; Jeanne M. Clark; Elizabeth M. Brunt; David E. Kleiner; Jay H. Hoofnagle; Patricia R. Robuck
BACKGROUND Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrhosis. Currently, there is no established treatment for this disease. METHODS We randomly assigned 247 adults with nonalcoholic steatohepatitis and without diabetes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The primary outcome was an improvement in histologic features of nonalcoholic steatohepatitis, as assessed with the use of a composite of standardized scores for steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indicate statistical significance. RESULTS Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P=0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P=0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P=0.005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P=0.02 for vitamin E and P=0.004 for pioglitazone) but not with improvement in fibrosis scores (P=0.24 for vitamin E and P=0.12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. CONCLUSIONS Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT00063622.)
JAMA | 2011
Joel E. Lavine; Jeffrey B. Schwimmer; Mark L. Van Natta; Jean P. Molleston; Karen F. Murray; Philip J. Rosenthal; Stephanie H. Abrams; Ann O. Scheimann; Arun J. Sanyal; Naga Chalasani; James Tonascia; Aynur Unalp; Jeanne M. Clark; Elizabeth M. Brunt; David E. Kleiner; Jay H. Hoofnagle; Patricia R. Robuck
CONTEXT Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in US children and adolescents and can present with advanced fibrosis or nonalcoholic steatohepatitis (NASH). No treatment has been established. OBJECTIVE To determine whether children with NAFLD would improve from therapeutic intervention with vitamin E or metformin. DESIGN, SETTING, AND PATIENTS Randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted at 10 university clinical research centers in 173 patients (aged 8-17 years) with biopsy-confirmed NAFLD conducted between September 2005 and March 2010. Interventions Daily dosing of 800 IU of vitamin E (58 patients), 1000 mg of metformin (57 patients), or placebo (58 patients) for 96 weeks. MAIN OUTCOME MEASURES The primary outcome was sustained reduction in alanine aminotransferase (ALT) defined as 50% or less of the baseline level or 40 U/L or less at visits every 12 weeks from 48 to 96 weeks of treatment. Improvements in histological features of NAFLD and resolution of NASH were secondary outcome measures. RESULTS Sustained reduction in ALT level was similar to placebo (10/58; 17%; 95% CI, 9% to 29%) in both the vitamin E (15/58; 26%; 95% CI, 15% to 39%; P = .26) and metformin treatment groups (9/57; 16%; 95% CI, 7% to 28%; P = .83). The mean change in ALT level from baseline to 96 weeks was -35.2 U/L (95% CI, -56.9 to -13.5) with placebo vs -48.3 U/L (95% CI, -66.8 to -29.8) with vitamin E (P = .07) and -41.7 U/L (95% CI, -62.9 to -20.5) with metformin (P = .40). The mean change at 96 weeks in hepatocellular ballooning scores was 0.1 with placebo (95% CI, -0.2 to 0.3) vs -0.5 with vitamin E (95% CI, -0.8 to -0.3; P = .006) and -0.3 with metformin (95% CI, -0.6 to -0.0; P = .04); and in NAFLD activity score, -0.7 with placebo (95% CI, -1.3 to -0.2) vs -1.8 with vitamin E (95% CI, -2.4 to -1.2; P = .02) and -1.1 with metformin (95% CI, -1.7 to -0.5; P = .25). Among children with NASH, the proportion who resolved at 96 weeks was 28% with placebo (95% CI, 15% to 45%; 11/39) vs 58% with vitamin E (95% CI, 42% to 73%; 25/43; P = .006) and 41% with metformin (95% CI, 26% to 58%; 16/39; P = .23). Compared with placebo, neither therapy demonstrated significant improvements in other histological features. CONCLUSION Neither vitamin E nor metformin was superior to placebo in attaining the primary outcome of sustained reduction in ALT level in patients with pediatric NAFLD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00063635.
Hepatology | 2009
Elizabeth M. Brunt; David E. Kleiner; Laura Wilson; Aynur Unalp; Cynthia E. Behling; Joel E. Lavine; Brent A. Neuschwander-Tetri
Adult nonalcoholic fatty liver disease (NAFLD) is characterized by absent or mild portal chronic inflammation (CI); in children, portal CI may be predominant. This study correlated clinical features with portal CI. Centrally‐graded biopsies and temporally‐related clinical parameters from 728 adults and 205 children. From the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) were evaluated. Mild, more than mild and no portal CI were found in 60%, 23% and 16% of adult biopsies and 76%, 14% and 10% of pediatric biopsies. Autoantibodies, and elevated alanine aminotransferase were not associated with portal CI. Clinical features associated with “more than mild” in adults were older age (P < 0.0001), female gender (P = 0.001), higher body mass index (P < 0.0001), elevated insulin levels (P = 0.001), higher homeostasis model assessment of insulin resistance score (HOMA‐IR) (P < 0.0001), and medications used for NAFLD (P = 0.0004), diabetes (P < 0.0001), and hypertension (P < 0.0001). “More than mild” in the pediatric biopsies correlated with younger age (P = 0.01), but not with body mass index, insulin or HOMA‐IR. In both groups, lobular and portal inflammation scores had no association, but there was an association with definite steatohepatitis (P < 0.0001). Features associated in the adult biopsies with “more than mild” were steatosis amount (P = 0.01) and location (P < 0.0001), ballooning (P < 0.0001), and advanced fibrosis (P < 0.0001). In the pediatric biopsies, “more than mild” was associated with steatosis location (P = 0.0008) and fibrosis score (P < 0.0001), specifically, the portal/periportal fibrosis or greater fibrosis) (P < 0.01). Conclusion: Increased portal CI is associated with many clinical and pathologic features of progressive NAFLD in both adults and children, but not with ALT, autoantibodies, or lobular inflammation. More than mild portal CI in liver biopsies of untreated NAFLD may be considered a marker of advanced disease. (HEPATOLOGY 2009.)
Hepatology | 2012
Rohit Loomba; Maria Roselle Abraham; Aynur Unalp; Laura Wilson; Joel E. Lavine; Ed Doo; Nathan M. Bass
Previous studies have shown familial aggregation of insulin resistance and nonalcoholic fatty liver disease (NAFLD). Therefore, we aimed to examine whether family history of diabetes mellitus (DM) is associated with nonalcoholic steatohepatitis (NASH) and fibrosis in patients with NAFLD. This was a cross‐sectional analysis in participants of the NAFLD Database study and PIVENS trial who had available data on family history of DM. One thousand and sixty‐nine patients (63% women), with mean age of 49.6 (± 11.8) years and body mass index (BMI) of 34.2 (± 6.4) kg/m2, were included. Thirty percent had DM, and 56% had a family history of DM. Both personal history of DM and family history of DM were significantly associated with NASH, with an odds ratio (OR) of 1.93 (95% confidence interval [CI]: 1.37‐2.73; P <0.001) and 1.48 (95% CI: 1.11‐1.97; P = 0.01) and any fibrosis with an OR of 3.31 (95% CI: 2.26‐4.85; P < 0.001) and 1.66 (95% CI: 1.25‐2.20; P < 0.001), respectively. When the models were adjusted for age, sex, BMI, ethnicity, and metabolic traits, the association between diabetes and family history of DM with NASH showed an increased adjusted OR of 1.76 (95% CI: 1.13‐2.72; P < 0.001) and 1.34 (95% CI: 0.99‐1.81; P = 0.06), respectively, and with any fibrosis with a significant adjusted OR of 2.57 (95% CI: 1.61‐4.11; P < 0.0001) and 1.38 (95% CI: 1.02‐1.87; P = 0.04), respectively. After excluding patients with personal history of diabetes, family history of DM was significantly associated with the presence of NASH and any fibrosis with an adjusted OR of 1.51 (95% CI: 1.01‐2.25; P = 0.04) and 1.49 (95% CI: 1.01‐2.20; P = 0.04), respectively. Conclusions: Diabetes is strongly associated with risk of NASH, fibrosis, and advanced fibrosis. Family history of diabetes, especially among nondiabetics, is associated with NASH and fibrosis in NAFLD. (HEPATOLOGY 2012;56:943–951)
Journal of Hepatology | 2008
Naga Chalasani; Laura Wilson; David E. Kleiner; Oscar W. Cummings; Elizabeth M. Brunt; Aynur Unalp
BACKGROUND/AIMS The relationship between severity and zonal location of steatosis and the presence of steatohepatitis and various histological features that define NASH has not been formally studied. METHODS We conducted a study to examine the relationship of severity and zonal location of steatosis to the presence of NASH and to other histological features that define NASH in adult patients with NAFLD. Steatosis was graded as mild, moderate or severe. We examined the relationship between severity and zonal location of steatosis and the following: lobular inflammation, presence of ballooning, Mallory bodies, fibrosis score, and definite steatohepatitis. RESULTS Mild, moderate and severe steatosis was present in 44%, 31% and 25% of biopsies, respectively. Definite steatohepatitis was present in 59% and advanced fibrosis in 29% of liver biopsies. Increasing levels of steatosis severity were positively associated with lobular inflammation (p<0.0001), zone 3 fibrosis (p<0.001), and definite steatohepatitis (p=0.02), but were unrelated to ballooning, Mallory bodies, or advanced fibrosis. As compared to zone 3 steatosis, pan-acinar steatosis was more often associated with ballooning, Mallory bodies, and advanced fibrosis. CONCLUSIONS Patients with severe steatosis are more likely to have steatohepatitis. More studies are needed to confirm this observation and to explore its significance.
Hepatology | 2012
Cynthia D. Guy; Ayako Suzuki; Marzena Zdanowicz; Manal F. Abdelmalek; James L. Burchette; Aynur Unalp; Anna Mae Diehl
The Hedgehog (HH)‐signaling pathway mediates several processes that are deregulated in patients with metabolic syndrome (e.g., fat mass regulation, vascular/endothelial remodeling, liver injury and repair, and carcinogenesis). The severity of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome generally correlate. Therefore, we hypothesized that the level of HH‐pathway activation would increase in parallel with the severity of liver damage in NAFLD. To assess potential correlations between known histologic and clinical predictors of advanced liver disease and HH‐pathway activation, immunohistochemistry was performed on liver biopsies from a large, well‐characterized cohort of NAFLD patients (n = 90) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Database 1 study. Increased HH activity (evidenced by accumulation of HH‐ligand–producing cells and HH‐responsive target cells) strongly correlated with portal inflammation, ballooning, and fibrosis stage (each P < 0.0001), supporting a relationship between HH‐pathway activation and liver damage. Pathway activity also correlated significantly with markers of liver repair, including numbers of hepatic progenitors and myofibroblastic cells (both P < 0.03). In addition, various clinical parameters that have been linked to histologically advanced NAFLD, including increased patient age (P < 0.005), body mass index (P < 0.002), waist circumference (P < 0.0007), homeostatic model assessment of insulin resistance (P < 0.0001), and hypertension (P < 0.02), correlated with hepatic HH activity. Conclusion: In NAFLD patients, the level of hepatic HH‐pathway activity is highly correlated with the severity of liver damage and with metabolic syndrome parameters that are known to be predictive of advanced liver disease. Hence, deregulation of the HH‐signaling network may contribute to the pathogenesis and sequelae of liver damage that develops with metabolic syndrome. (HEPATOLOGY 2012;55:1711–1721)
Clinical Gastroenterology and Hepatology | 2009
Raj Vuppalanchi; Aynur Unalp; Mark L. Van Natta; Oscar W. Cummings; Kumar Sandrasegaran; Tariq A. Hameed; James Tonascia; Naga Chalasani
BACKGROUND & AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.
Contemporary Clinical Trials | 2009
Naga Chalasani; Arun J. Sanyal; Kris V. Kowdley; Patricia R. Robuck; Jay H. Hoofnagle; David E. Kleiner; Aynur Unalp; James Tonascia
BACKGROUND Non-alcoholic steatohepatitis (NASH) is a common liver disease associated with obesity and diabetes. NASH is a progressive disorder that can lead to cirrhosis and liver failure. Insulin resistance and oxidative stress are thought to play important roles in its pathogenesis. There is no definitive treatment for NASH. OBJECTIVES PIVENS is conducted to test the hypotheses that treatment with pioglitazone, a thiazolidinedione insulin sensitizer, or vitamin E, a naturally available antioxidant, will lead to improvement in hepatic histology in non-diabetic adults with biopsy proven NASH. DESIGN PIVENS is a randomized, multicenter, double-masked, placebo-controlled trial to evaluate whether 96 weeks of treatment with pioglitazone or vitamin E improves hepatic histology in non-diabetic adults with NASH compared to treatment with placebo. Before and post-treatment liver biopsies are read centrally in a masked fashion for an assessment of steatohepatitis and a NAFLD Activity Score (NAS) consisting of steatosis, lobular inflammation, and hepatocyte ballooning. The primary outcome measure is defined as either an improvement in NAS by 2 or more in at least two NAS features, or a post-treatment NAS of 3 or less, and improvement in hepatocyte ballooning by 1 or more, and no worsening of fibrosis. METHODS PIVENS enrollment started in January 2005 and ended in January 2007 with 247 patients randomized to receive either pioglitazone (30 mg q.d.), vitamin E (800 IU q.d.), or placebo for 96 weeks. Participants will be followed for an additional 24 weeks after stopping the treatment. The study protocol incorporates the use of several validated questionnaires and specimen banking. This protocol was approved by all participating center Institutional Review Boards (IRBs) and an independent Data and Safety Monitoring Board (DSMB) which was established for monitoring the accumulated interim data as the trial progresses to ensure patient safety and to review efficacy as well as the quality of data collection and overall study management. (ClinicalTrials.gov number, NCT00063622).
Journal of Hepatology | 2011
Claudia O. Zein; Aynur Unalp; Ryan Colvin; Yao Chang Liu; Arthur J. McCullough
BACKGROUND & AIMS Although many predictors of disease severity of nonalcoholic fatty liver disease (NAFLD) have been proposed, studies of the potential effects of specific environmental exposures on human NAFLD are lacking. Smoking increases insulin resistance. Given the pathophysiological role of insulin resistance in NAFLD, characterization of the influence of smoking in NAFLD is warranted. The aim of this paper was to study the potential association between cigarette smoking and advanced fibrosis in NAFLD. METHODS All adults enrolled in the NASH CRN studies, between October 2004 and February 2008, who had liver biopsies, were included (n=1091). Advanced fibrosis was defined as stages 3-4. Analyses were performed. RESULTS Significant bivariate associations were demonstrated between advanced fibrosis and age, gender, ethnicity, diabetes, and smoking history. History of smoking ≥ 10 pack-years was more common (p <0.0001) among patients with advanced fibrosis. Multivariate analysis demonstrated an association between smoking history of ≥ 10 pack-years and advanced fibrosis (OR=1.63). Among non-diabetics, history of ≥ 10 pack-years was associated with an OR of 2.48 for advanced fibrosis. High frequencies of advanced fibrosis were observed among diabetics (with or without ≥ 10 pack-years history) and non-diabetics with ≥ 10 pack-years history as compared to non-diabetics without significant smoking history. CONCLUSIONS Smoking history was associated with advanced liver fibrosis in this large multicenter cohort of NAFLD patients. The results indicate that smoking may enhance the progression of NAFLD partly through its effect on insulin resistance. Our results are consistent with recent animal studies suggesting that cigarette smoke may aggravate fatty liver. To our knowledge, this is the first study to show that cigarette smoking is associated with increased fibrosis severity in human NALFD, suggesting it may accelerate disease progression. These results may support a formal recommendation of smoking cessation in patients with NAFLD.
Journal of Pediatric Gastroenterology and Nutrition | 2012
Miriam B. Vos; Ryan Colvin; Patricia Belt; Jean P. Molleston; Karen F. Murray; Philip J. Rosenthal; Jeffrey B. Schwimmer; James Tonascia; Aynur Unalp; Joel E. Lavine
Objectives: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children in the United States. Although changes in diet are often recommended to improve NAFLD, little is known regarding the influence of diet on histologic features of the disease. Subjects and Methods: This was a prospective, cross-sectional registry-based study. Children (n = 149) enrolled in the multicenter nonalcoholic steatohepatitis (NASH) Clinical Research Network had demographic, anthropometric, clinical, laboratory, and histology data obtained, including the Block Brief Food Questionnaire. Subjects were grouped by presence or absence of steatohepatitis and grades of histologic features according to NASH Clinical Research Network criteria. Results: No significant differences were found between children with steatosis compared with steatohepatitis for fraction of energy from fat, carbohydrates, and protein. Sugar-sweetened beverage consumption was low and did not correlate with histologic features, although uric acid, a surrogate marker for fructose intake, was significantly increased in those with definite NASH (P = 0.008). For all groups, vitamin E consumption was insufficient compared with the recommended daily allowance. Median consumption of vitamin E was lower in children with higher grade of steatosis (8.4 vs 6.1 vs 6.9 for grades I, II, and III, respectively, P = 0.05). Those consuming less vitamin C had increased ballooning degeneration (P = 0.05). Conclusions: Children with NAFLD have a diet that is insufficient in vitamin E and this may contribute to the pathophysiology of NAFLD. In children with NAFLD, reported sugar-sweetened beverage consumption is low; however, uric acid, which may reflect total fructose consumption, was significantly associated with NASH and should be further evaluated.