Timothy R Morgan

VA Long Beach Healthcare System, Long Beach, California, United States

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Publications (143)1304.38 Total impact

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    ABSTRACT: Background The risk of alcohol-related liver cirrhosis increases with increasing alcohol consumption, but many people with very high intake escape from liver disease. We postulate that susceptibility to alcoholic cirrhosis has a complex genetic component and propose that this can be dissected through a large and sufficiently powered genomewide association study (GWAS).Methods The GenomALC Consortium comprises researchers from Australia, France, Germany, Switzerland, United Kingdom, and United States, with a joint aim of exploring the genetic and genomic basis of alcoholic cirrhosis. For this National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism funded study, we are recruiting high-risk drinkers who are either cases (with alcoholic cirrhosis) or controls (drinking comparable amounts over similar time, but free of significant liver disease). Extensive phenotypic data are obtained using semistructured interviews and patient records, and blood samples are collected.ResultsWe have successfully recruited 859 participants including 538 matched case–control samples as of September 2014, using study-specific inclusion–exclusion criteria and data collection protocols. Of these, 580 are cases (442 men and 138 women) and 279 are controls (205 men and 74 women). Duration of excessive drinking was slightly greater in cases than controls and was significantly less in women than men. Cases had significantly lower lifetime alcohol intake than controls. Both cases and controls had a high prevalence of reported parental alcohol problems, but cases were significantly more likely to report that a father with alcohol problems had died from liver disease (odds ratio 2.53, 95% confidence interval 1.31 to 4.87, p = 0.0055).Conclusions Recruitment of participants for a GWAS of alcoholic cirrhosis has proved feasible across countries with multiple sites. Affected patients often consume less alcohol than unaffected ones, emphasizing the existence of individual vulnerability factors. Cases are more likely to report liver disease in a father with alcohol problems than controls, consistent with a potential genetic component to the risk of alcoholic cirrhosis.
    Alcoholism Clinical and Experimental Research 05/2015; 39(5). DOI:10.1111/acer.12693 · 3.31 Impact Factor
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    ABSTRACT: & Aims: Several models have been used to determine prognoses of patients with alcoholic hepatitis. These include static systems (the Maddrey discriminant function; the age, bilirubin, international normalized ratio, creatinine [ABIC] score; and model for end-stage liver disease [MELD] score) and dynamic models (the Lille model). We aimed to combine features of all these models to develop a better method to predict outcomes of patients with alcoholic hepatitis. We collected data from several databases of patients with severe alcoholic hepatitis treated with corticosteroids in France and the UK to create a model to predict patient survival (derivation cohort, n=538 patients). We compared the performances of 3 joint-effect models (Maddrey+Lille, MELD+Lille, ABIC+Lille) to determine which combination had the best prognostic value, based on known patient outcomes. The model was validated using data from trials of the effects of corticosteroids in patients in the US, France, Korea, and Belgium (n=604 patients). We created a joint-effect model to predict patient survival after 2 and 6 months; in the derivation and validation cohorts, it predicted outcome significantly better than either static or dynamic models alone (P<.01 for all comparisons). The joint model accurately predicted patient survival regardless of patient risk level. The MELD+Lille combination was better than the Maddrey+Lille or ABIC+Lille in predicting patient survival, with Akaike information criterion values of 1305, 1313, and 1312 respectively. For example, based on the MELD+Lille combination model, predicted 6-month mortality of complete responders with MELD scores of 15-45 (Lille score 0.16) was 8.5% to 49.7%, compared with 16.4%-75.2% for non-responders (Lille score 0.45). According to the joint-effect model, for 2 patients with the same baseline MELD score of 21, the patient with a Lille score of 0.45 had a 1.9-fold higher risk of death than the patient with a Lille score of 0.16 (23.7% vs 12.5%). By combining results from static and dynamic scoring systems for liver disease, we can better predict outcomes of patients with alcoholic hepatitis, compared with either model alone. This may help patient management and design of clinical trials. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
    Gastroenterology 04/2015; DOI:10.1053/j.gastro.2015.04.044 · 13.93 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-1002. DOI:10.1016/S0016-5085(15)33420-X · 13.93 Impact Factor
  • Journal of Hepatology 04/2015; 62:S757-S758. DOI:10.1016/S0168-8278(15)31285-X · 10.40 Impact Factor
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    ABSTRACT: Colorectal cancer (CRC) progresses through multiple distinct stages that are potentially amenable to chemopreventative intervention. Epidermal Growth Factor Receptor (EGFR) inhibitors are efficacious in advanced tumors including CRC. There is significant evidence that EGFR also plays important roles in CRC initiation, and that EGFR inhibitors block tumorigenesis. We performed a double-blind randomized clinical trial to test whether the EGFR inhibitor erlotinib given for up to 30 days had an acceptable safety and efficacy profile to reduce EGFR signaling biomarkers in colorectal aberrant crypt foci (ACF), a subset of which progress to CRC, and normal rectal tissue. A total of N=45 patients were randomized to one of three erlotinib doses (25 mg, 50 mg, 100 mg) with randomization stratified by non-steroidal anti-inflammatory drug (NSAID) use. There were no unanticipated adverse events with Erlotinib therapy. Erlotinib was detected in both normal rectal mucosa and ACFs. Colorectal ACF phosphoERK, phosphoEGFR and total EGFR signaling changes from baseline were modest and there was no dose response. Overall, this trial did not meet is primary efficacy endpoint. Colorectal EGFR signaling inhibition by erlotinib is therefore likely insufficient to merit further studies without additional pre-screening stratification or potentially longer duration of use.
    Cancer Prevention Research 01/2015; 8(3). DOI:10.1158/1940-6207.CAPR-14-0148 · 5.27 Impact Factor
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    ABSTRACT: Chronic liver disease increases the socioeconomic and emotional burden on the patient's caregiver. This is important because a patient's adherence to therapy and transplant eligibility is dependent on the caregiver's ability to handle these challenges. This was a prospective, cross-sectional study of 50 primary caregivers of patients with advanced liver disease. Caregivers completed the RAND 36-item (Short Form [SF-36]) Health Survey and the Zarit Burden Scale survey. Caregiver quality of life, based on the SF-36, was compared using t-tests with the scores of the National reference population as controls. In our cohort, the mean age of caregivers was 56.9±11.4 years, 40 (83.3%) were female, and 34 (70.8%) were spouses/significant others of the patient. Compared with the adjusted National norm data, caregivers scored substantially lower in categories of role limitations due to emotional problems (P<0.001), vitality (P=0.025), mental health (P=0.005), and social functioning (P=0.002). While the adjusted physical component score of the caregivers was comparable to the National mean, the mental component score (MCS) was lower than the National average (42.4±13.3 vs. 50.0±10, P<0.001). Though only 8 of 50 (16.0%) subjects reported a formal diagnosis of depression or anxiety, 23 (46.0%) had MCS <42, a strong predictor of clinical depression, based on previous studies. Primary caregivers of patients with advanced liver disease have significantly lower SF-36 mental health scores compared with the general population. Comparison of SF-36 scores to caregiver history suggests under recognition of mental health problems in this population.
    Annals of Gastroenterology 01/2015; 28(1):124-129.
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    Timothy R. Morgan
    Journal of Hepatology 12/2014; DOI:10.1016/j.jhep.2014.12.021 · 10.40 Impact Factor
  • Cancer Research 10/2014; 74(19 Supplement):3247-3247. DOI:10.1158/1538-7445.AM2014-3247 · 9.28 Impact Factor
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    ABSTRACT: Binge drinking, a common pattern of alcohol ingestion, is known to potentiate liver injury caused by chronic alcohol abuse. This study was aimed to investigate the effects of acute binge alcohol on hypoxia-inducible factor-1α (HIF-1α)-mediated liver injury and roles of alcohol metabolizing enzymes in alcohol-induced hypoxia and hepatotoxicity. Mice and human specimens assigned as binge or non-binge group were analyzed for blood alcohol concentration (BAC), alcohol metabolizing enzymes, HIF-1α-related protein nitration and apoptosis. Binge alcohol promoted acute liver injury in mice with elevated levels of ethanol-inducible cytochrome P450-2E1 (CYP2E1) and hypoxia, both of which were co-localized in centrilobular areas. We observed positive correlations among elevated BAC, CYP2E1, and HIF-1α in mice and humans exposed to binge alcohol. The CYP2E1 protein levels (r=0.629, p=0.001) and activities (r=0.641, p=0.001) showed significantly positive correlation with BACs in human livers. HIF-1α levels were also positively correlated with BACs (r=0.745, p<0.001) or CYP2E1 activities (r=0.792, p<0.001) in humans. Binge alcohol promoted protein nitration and apoptosis with significant correlations observed between inducible nitric oxide synthase and BACs, CYP2E1, or HIF-1α in human specimens. Binge alcohol-induced HIF-1α activation and subsequent protein nitration or apoptosis seen in wild-type were significantly alleviated in the corresponding Cyp2e1-null mice while pretreatment with an HIF-1α inhibitor PX-478 prevented HIF-1α elevation with a trend of decreased levels of 3-nitrotyrosine and apoptosis, supporting the roles of CYP2E1and HIF-1α in binge alcohol-mediated protein nitration and hepatotoxicity. Thus binge alcohol promotes acute liver injury in mice and humans at least partly through a CYP2E1-HIF-1α-dependent apoptosis pathway.
    Free Radical Biology and Medicine 09/2014; 77. DOI:10.1016/j.freeradbiomed.2014.08.030 · 5.71 Impact Factor
  • Gregory J. Botwin, Timothy R. Morgan
    Hepatology International 09/2014; 8(S2):467-474. DOI:10.1007/s12072-014-9522-z · 2.47 Impact Factor
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    ABSTRACT: Recent studies indicate that the inflammasome activation plays important roles in the pathogenesis of alcoholic hepatitis (AH). Nod-like receptor protein 3 (NLRP3) is a key component of the macromolecular complex that is so called the inflammasome that triggers caspase 1-dependent maturation of the precursors of IL-1β and IL-18 cytokines. It is also known that the adaptor proteins including apoptosis-associated speck-like protein containing CARD (ASC) and the mitochondrial antiviral signaling protein (MAVS) are necessary for NLRP3-dependent inflammasome function. Steatohepatitis frequently includes Mallory-Denk body (MDB) formation. In the case of alcoholic steatohepatitis, MDB formation occurs in 80% of biopsies (French 1981; French 1981). While previous studies have focused on in vitro cell lines and mouse models, we are the first group to investigate inflammasome activation in AH liver biopsy specimen and correlate it with MDB formation. Expression of NOD1, NLRP3, ASC, NAIP, MAVS, caspase 1, IL-1β, IL-18, and other inflammatory components including IL-6, IL-10, TNF-α, IFN-γ, STAT3, and p65 was measured in three to eight formalin-fixed paraffin-embedded AH specimens and control normal liver specimens by immunofluorescence staining and quantified by immunofluorescence intensity. The specimens were double stained with ubiquitin to demonstrate the relationship between inflammasome activation and MDB formation. MAVS, caspase1, IL-18, and TNF-α showed increases in expression in AH compared to the controls (p<0.05), and NAIP expression markedly increased in AH compared to the controls (p<0.01). There was a trend that levels of NLRP3, ASC, caspase1, IL-18, IL-10, and p65 expression correlated with the number of MDBs found in the same field of measurement (correlation coefficients were between 0.62 and 0.93, p<0.05). Our results demonstrate the activation of the inflammasome in AH and suggest that MDB could be an indicator of the extent of inflammasome activation.
    Experimental and Molecular Pathology 08/2014; DOI:10.1016/j.yexmp.2014.08.006 · 2.88 Impact Factor
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    ABSTRACT: Activation of Toll-like receptor (TLR) signaling which stimulates inflammatory and proliferative pathways is the key element in the pathogenesis of Mallory-Denk bodies (MDBs) in mice fed DDC. However, little is known as to how TLR signaling is regulated in MDB formation during chronic liver disease development. The first systematic study of TLR signaling pathway transcript regulation in human archived formalin-fixed, paraffin-embedded (FFPE) liver biopsies with MDB formation is presented here. When compared to the activation of Toll-like signaling in alcoholic hepatitis (AH) and Non alcoholic steatohepatitis (NASH) patients, striking similarities and obvious differences were observed. Similar TLRs (TLR3 and TLR4, etc.), TLR downstream adaptors (MyD88 and TRIF, etc.) and transcript factors (NFκB and IRF7, etc.) were all up regulated in the patients' livers. MyD88, TLR3 and TLR4 were significantly induced in the livers of AH and NASH compared to normal subjects, while TRIF and IRF7 mRNA were only slightly up regulated in AH patients. This is a different pathway from the induction of the TLR4-MyD88-independent pathway in the AH and NASH patients with MDBs present. Importantly, chemokine receptor 4 and 7 (CXCR4/7) mRNAs were found to be induced in the patients livers in FAT10 positive hepatocytes. The CXCR7 pathway was significantly up regulated in patients with AH and the CXCR4 was markedly up regulated in patients with NASH, indicating that CXCR4/7 is crucial in liver MDB formation. This data constitutes the first demonstration of the up regulation of the MyD88-dependent TLR4/ NFκB pathway in AH and NASH where MDBs formed, via the NFκB-CXCR4/7 pathway, and provides further insight into the mechanism of MDB formation in human liver diseases.
    Experimental and Molecular Pathology 07/2014; DOI:10.1016/j.yexmp.2014.07.001 · 2.88 Impact Factor
  • Hepatology 06/2014; 59(6). DOI:10.1002/hep.26771 · 11.19 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-950. DOI:10.1016/S0016-5085(14)63453-3 · 13.93 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-1004-S-1005. DOI:10.1016/S0016-5085(14)63654-4 · 13.93 Impact Factor
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    ABSTRACT: Patients with chronic hepatitis C (HCV) frequently discontinued dual therapy with pegylated interferon alfa (Peg-IFN) plus ribavirin (RBV) before reaching the recommended duration of 48 or 24 weeks for genotypes (G) 1/4 or 2/3, respectively. We quantified rates of discontinuation despite efficacy (non-LOE) versus lack of efficacy (LOE) versus discontinuation for unknown reasons in a national database of United States veterans. We identified a population-based cohort of U.S. veterans with encounters from 2004 through 2009 who had lab-confirmed HCV infection and initiated therapy with Peg-IFN plus RBV in Veterans Health Administration medical centers. Pharmacy data were used to determine therapy duration, defined as the sum of Peg-IFN days supplied. Patients "discontinued" if they failed to receive at least 44 (G1/4) or 20 weeks (G2/3) of therapy. We classified discontinuations as due to non-LOE, LOE, or unknown reasons using a classification rule based on treatment duration and laboratory confirmed response. Of 321,238 diagnosed HCV patients during the evaluation period, 9.7% initiated therapy and 6.4% met all other inclusion criteria. 54.9% of patients discontinued early; of these, 41.2% discontinued due to non-LOE reasons, 12.5% discontinued for LOE reasons, and 46.3% discontinued for unknown reasons. Among non-LOE discontinuers, most (60.1%) discontinued in the first 4 weeks of therapy, which constitutes 13.6% of all treated patients. We observed a high proportion of early discontinuations with dual-therapy regimens in a national cohort of HCV-infected veterans. If this trend persists in the triple-therapy era, then efforts must be undertaken to improve adherence.
    BMC Research Notes 04/2014; 7(1):266. DOI:10.1186/1756-0500-7-266
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    ABSTRACT: Many patients with chronic hepatitis C virus (HCV) being treated with pegylated interferon (peg-IFN) plus ribavirin (RBV) do not respond to therapy and do not clear the virus. Standard of care during the era of dual therapy was to discontinue the patient's therapy based on insufficient decreases in viral load after 12 and/or 24 weeks on therapy. We identified patient characteristics that were significant predictors of discontinuation as a result of lack of efficacy (LOE) in a national database of US veterans with genotypes 1 and 4. We identified US veterans who received care at Veterans Affairs medical centers in 2004-2009 and who had lab-confirmed HCV diagnoses and initiated therapy with peg-IFN plus RBV. Patients who discontinued therapy early were classified as either LOE or non-LOE discontinuers based on pharmacy refill patterns and laboratory response data. Predictors of LOE discontinuation were identified using univariate and multivariable Cox proportional hazards modeling. Of 321 238 HCV patients with an ICD-9 diagnosis code, 31 215 (9.7%) initiated dual therapy with peg-IFN plus RBV, and 10 333 (3.2%) met all inclusion criteria and were included in the analysis. Overall, 13.6% of the cohort was classified as LOE. Significant predictors of LOE discontinuation included treatment for drug abuse (hazard ratio [HR] = 2.18), age >65 years (HR = 1.75), antiretroviral therapy for HIV (HR = 1.48), black race (HR = 1.47), platelet count >100/mm(3) (HR = 1.46), and drug therapy for insomnia (HR = 1.40). We identified risk factors for discontinuation caused by LOE. Future work should focus on determining whether these characteristics are also predictive of triple-therapy LOE discontinuations.
    Annals of Pharmacotherapy 04/2014; 48(7). DOI:10.1177/1060028014531724 · 2.92 Impact Factor
  • Daniel Chao, Gregory J Botwin, Timothy R Morgan
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    ABSTRACT: Chronic hepatitis C virus (HCV) infection affects millions of individuals and is a significant cause of chronic liver disease and cirrhosis. Early treatment regimens relied on an immune-mediated response caused by interferon and only recently have medications acting directly on viral structures been discovered. In December 2013, two new medications, sofosbuvir and simeprevir, were approved by the US Food and Drug Administration (FDA) for treatment of chronic hepatitis C. This article reviews the approved treatment protocols for these two new medications and the clinical trials that fueled their development.
    Current Treatment Options in Gastroenterology 03/2014; 12(2). DOI:10.1007/s11938-014-0013-z
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    ABSTRACT: Mitochondrial abnormalities are suggested to be associated with the development of nonalcoholic fatty liver. Liver mitochondrial content and function have been shown to improve in oral feeding of acetyl-l-carnitine (ALC) to rodents. Carnitine is involved in the transport of acyl-coenzyme A across the mitochondrial membrane to be used in mitochondrial β-oxidation. We hypothesized that oral administration ALC with the antioxidant lipoic acid (ALC + LA) would benefit nonalcoholic fatty liver. To test our hypothesis, we fed Balb/C mice a standard diet (SF) or SF with ALC + LA or high-fat diet (HF) or HF with ALC + LA for 6 months. Acetyl-l-carnitine and LA were dissolved at 0.2:0.1% (wt/vol) in drinking water, and mice were allowed free access to food and water. Along with physical parameters, insulin resistance (blood glucose, insulin, glucose tolerance), liver function (alanine transaminase [ALT], aspartate transaminase [AST]), liver histology (hematoxylin and eosin), oxidative stress (malondialdehyde), and mitochondrial abnormalities (carbamoyl phosphate synthase 1 and electron microscopy) were done. Compared with SF, HF had higher body, liver, liver-to-body weight ratio, white adipose tissue, ALT, AST, liver fat, oxidative stress, and insulin resistance. Coadministration of ALC + LA to HF animals significantly improved the mitochondrial marker carbamoyl phosphate synthase 1 and the size of the mitochondria in liver. Alanine transaminase and AST levels were decreased. In a nonalcoholic fatty liver mice model, ALC + LA combination improved liver mitochondrial content, size, serum ALT, and AST without significant changes in oxidative stress, insulin resistance, and liver fat accumulation.
    Nutrition research 11/2013; 33(11):932-41. DOI:10.1016/j.nutres.2013.08.001 · 2.59 Impact Factor

Publication Stats

7k Citations
1,304.38 Total Impact Points

Institutions

  • 2005–2015
    • VA Long Beach Healthcare System
      Long Beach, California, United States
  • 2003–2015
    • University of California, Irvine
      • Division of Gastroenterology
      Irvine, California, United States
  • 1992–2014
    • Long Beach Memorial Medical Center
      Long Beach, California, United States
  • 2010
    • Massachusetts General Hospital
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2001–2010
    • California State University, Long Beach
      Long Beach, California, United States
  • 2009
    • University of Wisconsin, Madison
      • Department of Medicine
      Madison, MS, United States
    • National Institutes of Health
      • Branch of Liver Diseases Branch (LDB)
      Bethesda, MD, United States
  • 2008
    • VA Palo Alto Health Care System
      Palo Alto, California, United States
  • 2006
    • Long Beach City College
      Long Beach, California, United States
  • 2001–2005
    • Harbor-UCLA Medical Center
      • Department of Pediatrics
      Torrance, California, United States
  • 2004
    • University of Texas Southwestern Medical Center
      • Division of Digestive and Liver Diseases
      Dallas, Texas, United States