Timothy R Morgan

Publications (61)573.21 Total impact

• Article: Alcoholic liver disease - Hepatocellular carcinoma transformation.

  Samuel W French, James Lee, Jim Zhong, Timothy R Morgan, Virgil Buslon, William Lungo, Barbara A French
  Journal of gastrointestinal oncology 09/2012; 3(3):174-81.
• Article: Reduction in Hepatic Inflammation Is Associated With Less Fibrosis Progression and Fewer Clinical Outcomes in Advanced Hepatitis C.

  Chihiro Morishima, Mitchell L Shiffman, Jules L Dienstag, Karen L Lindsay, Gyongyi Szabo, Gregory T Everson, Anna S Lok, Adrian M Di Bisceglie, Marc G Ghany, Deepa Naishadham, Timothy R Morgan, Elizabeth C Wright
  [show abstract] [hide abstract]
  ABSTRACT: OBJECTIVES:During the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial, 3.5 years of maintenance peginterferon-alfa-2a therapy did not affect liver fibrosis progression or clinical outcomes among 1,050 previous interferon nonresponders with advanced fibrosis or cirrhosis. We investigated whether reduced hepatic inflammation was associated with clinical benefit in 834 patients with a baseline and follow-up biopsy 1.5 years after randomization to peginterferon or observation.METHODS:Relationships between change in hepatic inflammation (Ishak hepatic activity index, (HAI)) and serum alanine aminotransferase level, fibrosis progression and clinical outcomes after randomization, and hepatitis C virus (HCV) RNA decline before and after randomization were evaluated. Histological change was defined as a ≥2-point difference in HAI or Ishak fibrosis score between biopsies.RESULTS:Among 657 patients who received full-dose peginterferon/ribavirin "lead-in" therapy before randomization, year-1.5 HAI improvement was associated with lead-in HCV RNA suppression in both the randomized treated (P<0.0001) and control (P=0.0001) groups, even in the presence of recurrent viremia. This relationship persisted at year 3.5 in both the treated (P=0.001) and control (P=0.01) groups. Among 834 patients followed for a median of 6 years, fewer clinical outcomes occurred in patients with improved HAI at year 1.5 compared with those without such improvement in both the treated (P=0.03) and control (P=0.05) groups. Among patients with Ishak 3-4 fibrosis at baseline, those with improved HAI at year 1.5 had less fibrosis progression at year 1.5 in both the treated (P=0.0003) and control (P=0.02) groups.CONCLUSIONS:Reduced hepatic inflammation (measured 1.5 and 3.5 years after randomization) was associated with profound virological suppression during lead-in treatment with full-dose peginterferon/ribavirin and with decreased fibrosis progression and clinical outcomes, independent of randomized treatment.Am J Gastroenterol advance online publication, 12 June 2012; doi:10.1038/ajg.2012.137.
  The American Journal of Gastroenterology 06/2012; · 7.28 Impact Factor
• Article: Alcohol abuse and chronic hepatitis C

  Tom Nguyen, M. Mazen Jamal, Timothy R. Morgan
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  ABSTRACT: AbstractChronic infection with hepatitis C virus (HCV) and alcohol abuse are two of the most common causes of chronic liver disease in the United States. These two entities often coexist and contribute to accelerated development of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although the effect of one drink per day in the setting of chronic HCV infection is unclear, there is overwhelming evidence for the deleterious effects of heavy alcohol use on HCV liver disease. The mechanisms by which alcohol increases liver injury in hepatitis C are poorly understood. Potential pathways include impaired host immune systems and increased viral replication. Alcohol use may decrease the success of treatment. Physicians should encourage patients with chronic hepatitis C to abstain from regular alcohol use.
  Current Hepatitis Reports 04/2012; 6(3):119-124.
• Article: Quantitative liver function tests improve the prediction of clinical outcomes in chronic hepatitis C: results from the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis Trial.

  Gregory T Everson, Mitchell L Shiffman, John C Hoefs, Timothy R Morgan, Richard K Sterling, David A Wagner, Shannon Lauriski, Teresa M Curto, Anne Stoddard, Elizabeth C Wright
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  ABSTRACT: Risk for future clinical outcomes is proportional to the severity of liver disease in patients with chronic hepatitis C virus (HCV). We measured disease severity by quantitative liver function tests (QLFTs) to determine cutoffs for QLFTs that identified patients who were at low and high risk for a clinical outcome. Two hundred and twenty-seven participants in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) Trial underwent baseline QLFTs and were followed for a median of 5.5 years for clinical outcomes. QLFTs were repeated in 196 patients at month 24 and in 165 patients at month 48. Caffeine elimination rate (k(elim)), antipyrine (AP) clearance (Cl), MEGX concentration, methionine breath test (MBT), galactose elimination capacity (GEC), dual cholate (CA) clearances and shunt, perfused hepatic mass (PHM), and liver and spleen volumes (by single-photon emission computed tomography) were measured. Baseline QLFTs were significantly worse (P = 0.0017 to P < 0.0001) and spleen volumes were larger (P < 0.0001) in the 54 patients who subsequently experienced clinical outcomes. QLFT cutoffs that characterized patients as "low" and "high risk" for clinical outcome yielded hazard ratios ranging from 2.21 (95% confidence interval [CI]: 1.29-3.78) for GEC to 6.52 (95% CI: 3.63-11.71) for CA clearance after oral administration (Cl(oral)). QLFTs independently predicted outcome in models with Ishak fibrosis score, platelet count, and standard laboratory tests. In serial studies, patients with high-risk results for CA Cl(oral) or PHM had a nearly 15-fold increase in risk for clinical outcome. Less than 5% of patients with "low risk" QLFTs experienced a clinical outcome. Conclusion: QLFTs independently predict risk for future clinical outcomes. By improving risk assessment, QLFTs could enhance the noninvasive monitoring, counseling, and management of patients with chronic HCV.
  Hepatology 10/2011; 55(4):1019-29. · 11.66 Impact Factor
• Article: Frequency of elevated hepatocellular carcinoma (HCC) biomarkers in patients with advanced hepatitis C.

  Richard K Sterling, Elizabeth C Wright, Timothy R Morgan, Leonard B Seeff, John C Hoefs, Adrian M Di Bisceglie, Jules L Dienstag, Anna S Lok
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  ABSTRACT: Prospective studies of serum hepatocellular carcinoma (HCC) biomarkers in patients with advanced hepatitis C are lacking. The aim of this study was to determine the frequencies and performance of elevated α-fetoprotein (AFP), AFP-L3, and des-γ-carboxy prothrombin (DCP) levels as HCC biomarkers in advanced hepatitis C. Patients in the HALT-C Trial were tested every 3 months for 42 months. Screening ultrasound was performed every 12 months. Levels of biomarkers were compared in patients in whom HCC did or did not develop. In all, 855 patients were evaluated; HCC developed in 46. Among patients without HCC, 73.2% had AFP consistently <20, 24.5% had at least one AFP between 20 and 199, and 2.3% had at least one AFP value ≥200 ng/ml; 73.7% had DCP consistently <90, 11.6% had at least one DCP between 90 and 149, and 14.7% had at least one DCP value ≥150 mAU/ml. AFP-L3 ≥10% was present at least once in 9.0% and in 17.1% of those with AFP ≥20 ng/ml. Among all patients with elevated biomarkers, a diagnosis of HCC was made in 0-31.6% (depending on the biomarker and cutoff) during the subsequent 24 months. AFP ≥200 ng/ml had the highest specificity (99%), but sensitivity was ≤20%. DCP ≥40 mAU/ml had the highest sensitivity (76%), but specificity was ≤58%. Independent predictors of elevated AFP were gender (female), race (Black), more advanced disease, and HCC. Elevated DCP was associated with more advanced disease and HCC. Mild-moderate elevations in total AFP and DCP but not in AFP-L3 occur frequently in patients with chronic hepatitis C and advanced fibrosis, are related to factors other than HCC, and are poor predictors of HCC.
  The American Journal of Gastroenterology 09/2011; 107(1):64-74. · 7.28 Impact Factor
• Source

  Available from: Gyongyi Szabo

  Article: A prospective study of the rate of progression in compensated, histologically advanced chronic hepatitis C.

  Jules L Dienstag, Marc G Ghany, Timothy R Morgan, Adrian M Di Bisceglie, Herbert L Bonkovsky, Hae-Young Kim, Leonard B Seeff, Gyongyi Szabo, Elizabeth C Wright, Richard K Sterling, Gregory T Everson, Karen L Lindsay, William M Lee, Anna S Lok, Chihiro Morishima, Anne M Stoddard, James E Everhart
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  ABSTRACT: The incidence of liver disease progression among subjects with histologically advanced but compensated chronic hepatitis C is incomplete. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial was a randomized study of 3.5 years of maintenance peginterferon treatment on liver disease progression among patients who had not cleared virus on peginterferon and ribavirin therapy. Patients were followed subsequently off therapy. Because maintenance peginterferon treatment did not alter liver disease progression, we analyzed treated and control patients together. Among 1,050 subjects (60% advanced fibrosis, 40% cirrhosis), we determined the rate of progression to cirrhosis over 4 years and of clinical outcomes over 8 years. Among patients with fibrosis, the incidence of cirrhosis was 9.9% per year. Six hundred seventy-nine clinical outcomes occurred among 329 subjects. Initial clinical outcomes occurred more frequently among subjects with cirrhosis (7.5% per year) than subjects with fibrosis (3.3% per year) (P<0.0001). Child-Turcotte-Pugh (CTP) score≥7 was the most common first outcome, followed by hepatocellular carcinoma. Following occurrence of a CTP score≥7, the rate of subsequent events increased to 12.9% per year, including a death rate of 10% per year. Age and sex did not influence outcome rates. Baseline platelet count was a strong predictor of all clinical outcomes. During the 8 years of follow-up, death or liver transplantation occurred among 12.2% of patients with advanced fibrosis and 31.5% of those with cirrhosis. CONCLUSION: Among patients with advanced hepatitis C who failed peginterferon and ribavirin therapy, the rate of liver-related outcomes, including death and liver transplantation, is high, especially once the CTP score reaches at least 7.
  Hepatology 04/2011; 54(2):396-405. · 11.66 Impact Factor
• Article: Excess mortality in patients with advanced chronic hepatitis C treated with long-term peginterferon.

  Adrian M Di Bisceglie, Anne M Stoddard, Jules L Dienstag, Mitchell L Shiffman, Leonard B Seeff, Herbert L Bonkovsky, Chihiro Morishima, Elizabeth C Wright, Kristin K Snow, William M Lee, Robert J Fontana, Timothy R Morgan, Marc G Ghany
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  ABSTRACT: Chronic hepatitis C virus infection can cause chronic liver disease, cirrhosis and liver cancer. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial was a prospective, randomized controlled study of long-term, low-dose peginterferon therapy in patients with advanced chronic hepatitis C who failed to respond to a previous course of optimal antiviral therapy. The aim of this follow-up analysis is to describe the frequency and causes of death among this cohort of patients. Deaths occurring during and after the HALT-C Trial were reviewed by a committee of investigators to determine the cause of death and to categorize each death as liver- or nonliver-related and as related or not to complications of peginterferon. Rates of liver transplantation were also assessed. Over a median of 5.7 years, 122 deaths occurred among 1,050 randomized patients (12%), of which 76 were considered liver-related (62%) and 46 nonliver-related (38%); 74 patients (7%) underwent liver transplantation. At 7 years the cumulative mortality rate was higher in the treatment compared to the control group (20% versus 15%, P = 0.049); the primary difference in mortality was in patients in the fibrosis compared to the cirrhosis stratum (14% versus 7%, P = 0.01); comparable differences were observed when liver transplantation was included. Excess mortality, emerging after 3 years of treatment, was related largely to nonliver-related death; liver-related mortality was similar in the treatment and control groups. No specific cause of death accounted for the excess mortality and only one death was suspected to be a direct complication of peginterferon. CONCLUSION: Long-term maintenance peginterferon in patients with advanced chronic hepatitis C is associated with an excess overall mortality, which was primarily due to nonliver-related causes among patients with bridging fibrosis.
  Hepatology 04/2011; 53(4):1100-8. · 11.66 Impact Factor
• Source

  Available from: umich.edu

  Article: Reply.

  Leonard B Seeff, Gregory T Everson, Timothy R Morgan, Teresa M Curto, William M Lee, Marc G Ghany, Mitchell L Shiffman, Robert J Fontana, Adrian M Di Bisceglie, Herbert L Bonkovsky, Jules L Dienstag
  Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 03/2011; 9(3):278-9. · 5.64 Impact Factor
• Source

  Available from: udea.edu.co

  Article: Occult and previous hepatitis B virus infection are not associated with hepatocellular carcinoma in United States patients with chronic hepatitis C.

  Anna S Lok, James E Everhart, Adrian M Di Bisceglie, Hae-Young Kim, Munira Hussain, Timothy R Morgan
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  ABSTRACT: Previous studies have suggested that prior exposure to hepatitis B virus (HBV) infection may increase the risk of development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. The aim of this study was to compare the prevalence of previous or occult HBV infection in a cohort of hepatitis B surface antigen-negative patients with histologically advanced chronic hepatitis C in the United States who did or did not develop HCC. Stored sera from 91 patients with HCC and 182 matched controls who participated in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial were tested for hepatitis B core antibody (anti-HBc), hepatitis B surface antibody, and HBV DNA. Frozen liver samples from 28 HCC cases and 55 controls were tested for HBV DNA by way of real-time polymerase chain reaction. Anti-HBc (as a marker of previous HBV infection) was present in the serum of 41.8% HCC cases and 45.6% controls (P=0.54); anti-HBc alone was present in 16.5% of HCC cases and 24.7% of controls. HBV DNA was detected in the serum of only one control subject and no patients with HCC. HBV DNA (as a marker of occult HBV infection) was detected in the livers of 10.7% of HCC cases and 23.6% of controls (P=0.18). CONCLUSION: Although almost half the patients in the HALT-C Trial had serological evidence of previous HBV infection, there was no difference in prevalence of anti-HBc in serum or HBV DNA in liver between patients who did or did not develop HCC. In the United States, neither previous nor occult HBV infection is an important factor in HCC development among patients with advanced chronic hepatitis C.
  Hepatology 03/2011; 54(2):434-42. · 11.66 Impact Factor
• Article: Iron levels in hepatocytes and portal tract cells predict progression and outcomes of patients with advanced chronic hepatitis C.

  Richard W Lambrecht, Richard K Sterling, Deepa Naishadham, Anne M Stoddard, Thomas Rogers, Chihiro Morishima, Timothy R Morgan, Herbert L Bonkovsky
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  ABSTRACT: Iron may influence severity and progression of non-hemochromatotic liver diseases. Our aim was to assess the relationship of iron and HFE genetic variations to progression and outcomes in the HALT-C Trial and whether PegIFN therapy influenced iron variables. Participants were randomized to receive long-term PegIFN [n = 400] or no therapy [n = 413] for 3.5 y, with follow-up for up to 8.7 y [median 6.0 y]. Associations of patient characteristics with iron variables at baseline and over time were carried out using Kaplan-Meier analyses, Cox regression models, and repeated measures analysis of covariance. Participants who developed clinical outcomes [CTP > 7, ascites, encephalopathy, variceal bleeding, SBP, HCC, death] had significantly higher baseline scores for stainable iron in hepatocytes and in portal tract cells than those without. There were significant direct correlations between stainable iron in portal triads and lobular and total Ishak inflammatory and fibrosis scores [P < 0.0001]. Iron in triads at baseline increased risk of outcomes (HR = 1.35, P = 0.02). Stainable iron in hepatocytes decreased, whereas that in portal stromal cells increased significantly [P < 0.0001] over time. Serum iron and TIBC fell significantly over time [P < 0.0001], as did serum ferritin [P = 0.0003]. Chronic PegIFN treatment did not affect stainable iron. HFE genetic variations did not correlate with outcomes, including development of hepatocellular carcinoma. Stainable iron in hepatocytes and portal tract cells is a predictor of progression and clinical and histological outcomes in advanced chronic hepatitis C. Chronic low-dose PegIFN therapy did not improve outcomes, nor iron variables.
  Gastroenterology 02/2011; 140(5):1490-500.e3. · 11.68 Impact Factor
• Article: Chemoprevention of hepatocellular carcinoma in chronic hepatitis C.

  Timothy R Morgan
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  ABSTRACT: Hepatitis C virus (HCV) infection causes chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma (HCC). The incidence of hepatocellular carcinoma in the United States tripled between 1975 and 2005, and is expected to increase further, and to remain elevated for more than 20 years. Curing hepatitis C infection in patients with cirrhosis through treatment with peginterferon and ribavirin reduces the risk of developing hepatocellular carcinoma. Several noncurative treatments also appear to reduce the risk of hepatocellular carcinoma in patients with chronic hepatitis C. Prospective studies report a reduced incidence of hepatocellular carcinoma among patients treated with a mixture of carotenoids with or without myo-inositol, with vitamin K₂, or with polyprenoic acid (an acyclic retinoid). Uncontrolled and/or retrospective studies have reported beneficial effects of treatment with Sho-saiko-to, glycyrrhizin and ursodeoxycholic acid on hepatocellular carcinoma incidence. Meta-analyses of epidemiologic studies show a reduced risk of hepatocellular carcinoma among liver disease patients who drink two or more cups of coffee per day. Numerous agents prevent or reduce hepatocarcinogenesis in animal models. An ongoing Phase II clinical trial is evaluating S-adenosylmethionine (SAMe) as a potential chemopreventive agent in hepatitis C cirrhosis. Overall, these data suggest that chemoprevention of hepatocellular carcinoma in patients with chronic hepatitis C is an achievable objective.
  Recent results in cancer research. Fortschritte der Krebsforschung. Progrès dans les recherches sur le cancer 01/2011; 188:85-99.
• Source

  Available from: PubMed Central

  Article: An IL28B genotype-based clinical prediction model for treatment of chronic hepatitis C.

  Thomas R O'Brien, James E Everhart, Timothy R Morgan, Anna S Lok, Raymond T Chung, Yongwu Shao, Mitchell L Shiffman, Myhanh Dotrang, John J Sninsky, Herbert L Bonkovsky, Ruth M Pfeiffer
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  ABSTRACT: Genetic variation in IL28B and other factors are associated with sustained virological response (SVR) after pegylated-interferon/ribavirin treatment for chronic hepatitis C (CHC). Using data from the HALT-C Trial, we developed a model to predict a patient's probability of SVR based on IL28B genotype and clinical variables. HALT-C enrolled patients with advanced CHC who had failed previous interferon-based treatment. Subjects were re-treated with pegylated-interferon/ribavirin during trial lead-in. We used step-wise logistic regression to calculate adjusted odds ratios (aOR) and create the predictive model. Leave-one-out cross-validation was used to predict a priori probabilities of SVR and determine area under the receiver operator characteristics curve (AUC). Among 646 HCV genotype 1-infected European American patients, 14.2% achieved SVR. IL28B rs12979860-CC genotype was the strongest predictor of SVR (aOR, 7.56; p<.0001); the model also included HCV RNA (log10 IU/ml), AST:ALT ratio, Ishak fibrosis score and prior ribavirin treatment. For this model AUC was 78.5%, compared to 73.0% for a model restricted to the four clinical predictors and 60.0% for a model restricted to IL28B genotype (p<0.001). Subjects with a predicted probability of SVR <10% had an observed SVR rate of 3.8%; subjects with a predicted probability >10% (43.3% of subjects) had an SVR rate of 27.9% and accounted for 84.8% of subjects actually achieving SVR. To verify that consideration of both IL28B genotype and clinical variables is required for treatment decisions, we calculated AUC values from published data for the IDEAL Study. A clinical prediction model based on IL28B genotype and clinical variables can yield useful individualized predictions of the probability of treatment success that could increase SVR rates and decrease the frequency of futile treatment among patients with CHC.
  PLoS ONE 01/2011; 6(7):e20904. · 4.09 Impact Factor
• Article: Development and progression of portal hypertensive gastropathy in patients with chronic hepatitis C.

  Robert J Fontana, Arun J Sanyal, Marc G Ghany, Herbert L Bonkovsky, Timothy R Morgan, Heather J Litman, Andrea E Reid, William M Lee, Deepa Naishadham
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  ABSTRACT: The objective of this study was to determine the incidence and risk factors associated with new-onset and worsening portal hypertensive gastropathy (PHG) in patients with chronic hepatitis C (CHC). A total of 831 CHC patients with bridging fibrosis or cirrhosis at the time of entry were prospectively monitored for clinical and histological liver disease progression while receiving either low-dose peginterferon α2a or no antiviral therapy in the HALT-C (Hepatitis C Antiviral Long-term Treatment against Cirrhosis) trial. Upper endoscopy with grading of PHG was performed at baseline and at year 4 of the study. The presence and severity of PHG were determined using the NIEC (New Italian Endoscopy Conference) criteria, and worsening PHG was defined as a score increase of ≥1 point. During a median follow-up of 3.85 years, 50% of 514 subjects without PHG developed new-onset PHG, whereas 26% of 317 patients with baseline PHG had worsening PHG. Independent predictors of new-onset PHG included higher alkaline phosphatase and being diabetic, whereas predictors of worsening PHG were Caucasian race, lower albumin, as well as higher serum aspartate transaminase/alanine transaminase ratio and homeostatic model assessment levels. New-onset and worsening PHG were significantly associated with clinical and histological progression. They were also associated with new-onset and worsening gastroesophageal varices. New-onset and worsening PHG develop at a rate of 12.9% per year and 6.7% per year, respectively, in non-responder CHC patients with advanced fibrosis. If confirmed in other studies, endoscopic surveillance for PHG may need to be tailored to individual patient risk factors.
  The American Journal of Gastroenterology 12/2010; 106(5):884-93. · 7.28 Impact Factor
• Article: IL28B-genotype testing now and in the era of direct-acting antiviral agents.

  Timothy R Morgan, Thomas R O'Brien
  Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 12/2010; 9(4):293-4. · 5.64 Impact Factor
• Article: Maintenance peginterferon therapy and other factors associated with hepatocellular carcinoma in patients with advanced hepatitis C.

  Anna S Lok, James E Everhart, Elizabeth C Wright, Adrian M Di Bisceglie, Hae-Young Kim, Richard K Sterling, Gregory T Everson, Karen L Lindsay, William M Lee, Herbert L Bonkovsky, Jules L Dienstag, Marc G Ghany, Chihiro Morishima, Timothy R Morgan
  [show abstract] [hide abstract]
  ABSTRACT: Interferon reportedly decreases the incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. The Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial showed that 4 years of maintenance therapy with pegylated interferon (peginterferon) does not reduce liver disease progression. We investigated whether peginterferon decreases the incidence of HCC in the HALT-C cohort over a longer posttreatment follow-up period. The study included 1048 patients with chronic hepatitis C (Ishak fibrosis scores ≥ 3) who did not have a sustained virologic response (SVR) to therapy. They were randomly assigned to groups given a half-dose of peginterferon or no treatment (controls) for 3.5 years and followed up for a median of 6.1 (maximum, 8.7) years. Eighty-eight patients developed HCC (68 definite, 20 presumed): 37 of 515 who were given peginterferon (7.2%) and 51 of 533 controls (9.6%; P = .24). There was a significantly lower incidence of HCC among patients given peginterferon therapy who had cirrhosis, but not fibrosis, based on analysis of baseline biopsy samples. After 7 years, the cumulative incidences of HCC in treated and control patients with cirrhosis were 7.8% and 24.2%, respectively (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.24-0.83); in treated and control patients with fibrosis, incidences were 8.3% and 6.8%, respectively (HR, 1.44; 95% CI, 0.77-2.69). Treated patients with a ≥ 2-point decrease in the histologic activity index, based on a follow-up biopsy, had a lower incidence of HCC than those with unchanged or increased scores (2.9% vs 9.4%; P = .03). Extended analysis of the HALT-C cohort showed that long-term peginterferon therapy does not reduce the incidence of HCC among patients with advanced hepatitis C who did not achieve SVRs. Patients with cirrhosis who received peginterferon treatment had a lower risk of HCC than controls.
  Gastroenterology 12/2010; 140(3):840-9; quiz e12. · 11.68 Impact Factor
• Article: Betaine improves nonalcoholic fatty liver and associated hepatic insulin resistance: a potential mechanism for hepatoprotection by betaine.

  Elango Kathirvel, Kengathevy Morgan, Ganesh Nandgiri, Brian C Sandoval, Marie A Caudill, Teodoro Bottiglieri, Samuel W French, Timothy R Morgan
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  ABSTRACT: Nonalcoholic fatty liver (NAFL) is a common liver disease, associated with insulin resistance. Betaine has been tested as a treatment for NAFL in animal models and in small clinical trials, with mixed results. The present study aims to determine whether betaine treatment would prevent or treat NAFL in mice and to understand how betaine reverses hepatic insulin resistance. Male mice were fed a moderate high-fat diet (mHF) containing 20% of calories from fat for 7 (mHF) or 8 (mHF8) mo without betaine, with betaine (mHFB), or with betaine for the last 6 wk (mHF8B). Control mice were fed standard chow containing 9% of calories from fat for 7 mo (SF) or 8 mo (SF8). HepG2 cells were made insulin resistant and then studied with or without betaine. mHF mice had higher body weight, fasting glucose, insulin, and triglycerides and greater hepatic fat than SF mice. Betaine reduced fasting glucose, insulin, triglycerides, and hepatic fat. In the mHF8B group, betaine treatment significantly improved insulin resistance and hepatic steatosis. Hepatic betaine content significantly decreased in mHF and increased significantly in mHFB. Betaine treatment reversed the inhibition of hepatic insulin signaling in mHF and in insulin-resistant HepG2 cells, including normalization of insulin receptor substrate 1 (IRS1) phosphorylation and of downstream signaling pathways for gluconeogenesis and glycogen synthesis. Betaine treatment prevents and treats fatty liver in a moderate high-dietary-fat model of NAFL in mice. Betaine also reverses hepatic insulin resistance in part by increasing the activation of IRS1, with resultant improvement in downstream signaling pathways.
  AJP Gastrointestinal and Liver Physiology 11/2010; 299(5):G1068-77. · 3.43 Impact Factor
• Article: Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data.

  Philippe Mathurin, John O'Grady, Robert L Carithers, Martin Phillips, Alexandre Louvet, Charles L Mendenhall, Marie-José Ramond, Sylvie Naveau, Willis C Maddrey, Timothy R Morgan
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  ABSTRACT: A meta-analysis was performed using individual patient data from the five most recent randomised controlled trials (RCTs) which evaluated corticosteroids in severe alcoholic hepatitis (Maddrey discriminant function (DF) ≥ 32 or encephalopathy). This approach overcomes limitations associated with the use of literature data and improves the relevance of the study and estimates of effect size. To compare 28-day survival between corticosteroid- and non-corticosteroid-treated patients and to analyse the response to treatment using the Lille model. Individual patient data were obtained from five RCTs comparing corticosteroid treatment with placebo (n=3), enteral nutrition (n=1) or an antioxidant cocktail (n=1). 221 patients allocated to corticosteroid treatment and 197 allocated to non-corticosteroid treatment were analysed. The two groups were similar at baseline. 28-day survival was higher in corticosteroid-treated patients than in non-corticosteroid-treated patients (79.97±2.8% vs 65.7±3.4%, p=0.0005). In multivariate analysis, corticosteroids (p=0.005), DF (p=0.006), leucocytes (p=0.004), Lille score (p<0.00001) and encephalopathy (p=0.003) were independently predictive of 28-day survival. A subgroup analysis was performed according to the percentile distribution of the Lille score. Patients were classified as complete responders (Lille score ≤ 0.16; ≤ 35th percentile), partial responders (Lille score 0.16-0.56; 35th-70th percentile) and null responders (Lille ≥ 0.56; ≥ 70th percentile). 28-day survival was strongly associated with these groupings (91.1±2.7% vs 79.4±3.8% vs 53.3±5.1%, p<0.0001). Corticosteroids had a significant effect on 28-day survival in complete responders (HR 0.18, p=0.006) and in partial responders (HR 0.38, p=0.04) but not in null responders. Analysis of individual data from five RCTs showed that corticosteroids significantly improve 28-day survival in patients with severe alcoholic hepatitis. The survival benefit is mainly observed in patients classified as responders by the Lille model.
  Gut 10/2010; 60(2):255-60. · 10.11 Impact Factor
• Source

  Available from: natap.org

  Article: Outcome of sustained virological responders with histologically advanced chronic hepatitis C.

  Timothy R Morgan, Marc G Ghany, Hae-Young Kim, Kristin K Snow, Mitchell L Shiffman, Jennifer L De Santo, William M Lee, Adrian M Di Bisceglie, Herbert L Bonkovsky, Jules L Dienstag, Chihiro Morishima, Karen L Lindsay, Anna S F Lok
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  ABSTRACT: Retrospective studies suggest that subjects with chronic hepatitis C and advanced fibrosis who achieve a sustained virological response (SVR) have a lower risk of hepatic decompensation and hepatocellular carcinoma (HCC). In this prospective analysis, we compared the rate of death from any cause or liver transplantation, and of liver-related morbidity and mortality, after antiviral therapy among patients who achieved SVR, virologic nonresponders (NR), and those with initial viral clearance but subsequent breakthrough or relapse (BT/R) in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) Trial. Laboratory and/or clinical outcome data were available for 140 of the 180 patients who achieved SVR. Patients with nonresponse (NR; n = 309) or who experienced breakthrough or relapse (BT/R; n = 77) were evaluated every 3 months for 3.5 years and then every 6 months thereafter. Outcomes included death, liver-related death, liver transplantation, decompensated liver disease, and HCC. Median follow-up for the SVR, BT/R, and NR groups of patients was 86, 85, and 79 months, respectively. At 7.5 years, the adjusted cumulative rate of death/liver transplantation and of liver-related morbidity/mortality in the SVR group (2.2% and 2.7%, respectively) was significantly lower than that of the NR group (21.3% and 27.2%, P < 0.001 for both) but not the BT/R group (4.4% and 8.7%). The adjusted hazard ratio (HR) for time to death/liver transplantation (HR = 0.17, 95% confidence interval [CI] = 0.06-0.46) or development of liver-related morbidity/mortality (HR = 0.15, 95% CI = 0.06-0.38) or HCC (HR = 0.19, 95% CI = 0.04-0.80) was significant for SVR compared to NR. Laboratory tests related to liver disease severity improved following SVR. CONCLUSION: Patients with advanced chronic hepatitis C who achieved SVR had a marked reduction in death/liver transplantation, and in liver-related morbidity/mortality, although they remain at risk for HCC.
  Hepatology 09/2010; 52(3):833-44. · 11.66 Impact Factor
• Article: Oxidative stress and regulation of anti-oxidant enzymes in cytochrome P4502E1 transgenic mouse model of non-alcoholic fatty liver.

  Elango Kathirvel, Philip Chen, Kengathevy Morgan, Samuel W French, Timothy R Morgan
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  ABSTRACT: Reactive oxygen species produced by cytochrome P4502E1 (CYP2E1) are believed to play a role in pathophysiology of non-alcoholic fatty liver disease (NAFLD). However, little is known about the expression, protein content and activity of anti-oxidant enzymes and the role of inducible nitric oxide synthase (iNOS), a source of reactive nitrogen species, in NAFLD. In the present study, we evaluate gene expression, protein content and activity of anti-oxidant enzymes, and iNOS, in a CYP2E1 overexpressing model of non-alcoholic fatty liver (NAFL). Non-transgenic (nTg) and CYP2E1 transgenic (Tg) mice were fed rodent chow for 8 months. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver triglycerides, malondialdehyde and protein carbonyls were measured. Gene expression of NF-E2-related factor (Nrf2), superoxide dismutase-1, -2 (SOD-1,2), catalase (CAT), glutathione peroxidase (GPx), heme oxygenase-1 (HO-1) and iNOS were determined. Protein content, activity and nitrosylation of the enzymes were also measured. Tg mice had greater CYP2E1 activity and histological liver injury. MDA and protein carbonyls were increased, indicating insufficient anti-oxidant response. Gene expression of Nrf2, CAT, GPx, HO-1 and iNOS were significantly increased. Protein content and enzyme activities of most anti-oxidant enzymes were not correspondingly increased. iNOS activity and nitrosylation of CAT and SOD was greater in Tg mice liver. Hepatocyte-specific CYP2E1 overexpression results in increased oxidative stress and nitrosative stress. Several anti-oxidant enzymes are upregulated. Failure of corresponding increase in total protein and activity of anti-oxidant enzymes suggests modification/degradation, possibly by nitrosylation, due to increased iNOS activity in a CYP2E1 overexpressing NAFL mouse model.
  Journal of Gastroenterology and Hepatology 06/2010; 25(6):1136-43. · 2.87 Impact Factor
• Article: Factors that determine the development and progression of gastroesophageal varices in patients with chronic hepatitis C.

  Robert J Fontana, Arun J Sanyal, Marc G Ghany, William M Lee, Andrea E Reid, Deepa Naishadham, Gregory T Everson, Jeffrey A Kahn, Adrian M Di Bisceglie, Gyongyi Szabo, Timothy R Morgan, James E Everhart
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  ABSTRACT: We aimed to identify the incidence and predictors of de novo gastroesophageal variceal formation and progression in a large cohort of patients with chronic hepatitis C and advanced fibrosis. All participants in the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial were offered an endoscopy before treatment and again after 4 years. Patients with varices at baseline also had an endoscopy at 2 years. Baseline laboratory and clinical parameters were analyzed as predictors of de novo variceal formation and variceal progression. De novo varices developed in 157 of the 598 (26.2%) patients. Most of the new varices were small (76.4%) and only 1% of patients developed variceal hemorrhage. The likelihood of developing varices was associated with subject race (Hispanic > Caucasian > African American; P = .0005), lower baseline levels of albumin (P = .051), and higher levels of hyaluronic acid (P < .001) with an area under the receiver operating characteristic curve = .70. Among 210 patients with existing gastroesophageal varices, 74 (35.2%) had variceal progression or bleeding during follow-up. Patients with higher baseline ratios of serum aspartate/alanine aminotransferase (P = .028) and lower platelet counts (P = .0002) were at greatest risk of variceal progression (area under the receiver operating characteristic = .72). Prolonged, low-dose peginterferon-alpha2a therapy and beta-blockers did not influence the risk of developing new or enlarging varices. Development of varices in patients with chronic hepatitis C is associated with patient race/ethnicity and laboratory markers of disease severity. Prolonged low-dose peginterferon-alpha2a therapy and beta-blockers do not reduce the risk of variceal development or progression.
  Gastroenterology 03/2010; 138(7):2321-31, 2331.e1-2. · 11.68 Impact Factor