William M Lee

University of Texas at Dallas, Richardson, Texas, United States

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Publications (256)2270.67 Total impact

  • Gastroenterology 04/2015; 148(4):S-1098. DOI:10.1016/S0016-5085(15)33745-8 · 13.93 Impact Factor
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    ABSTRACT: Over the last three decades acute liver failure (ALF) has been transformed from a rare and poorly understood condition with a near universally fatal outcome, to one with a well characterized phenotype and disease course. Complex critical care protocols are now applied and emergency liver transplantation (ELT) is an established treatment option. These improvements in care are such that the majority of patients may now be expected to survive (Fig. 1). Key features of the condition have changed dramatically over time, with a remarkable fall in the incidence of cerebral edema and intracranial hypertension, a much feared complication. In this review, we summarize the current understanding of key aspects of the classification, pathophysiology and management of ALF, and discuss the foreseeable challenges that will need to be addressed for further improvements to be achieved. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
    Journal of Hepatology 04/2015; 62(1S):S112-S120. DOI:10.1016/j.jhep.2014.12.016 · 10.40 Impact Factor
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    ABSTRACT: Osteopontin (OPN) is a novel phosphoglycoprotein expressed in Kupffer cells that plays a pivotal role in activating natural killer cells, neutrophils and macrophages. Measuring plasma OPN levels in patients with acute liver failure (ALF) might provide insights into OPN function in the setting of massive hepatocyte injury. OPN levels were measured using a Quantikine® ELISA assay on plasma from 105 consecutive ALF patients enrolled by the US Acute Liver Failure Study Group, as well as controls including 40 with rheumatoid arthritis (RA) and 35 healthy subjects both before, and 1 and 3days after undergoing spine fusion (SF) surgery as a model for acute inflammation. Median plasma OPN levels across all etiologies of ALF patients were elevated 10- to 30-fold: overall median 1055ng/mL; range: 33-19,127), when compared to healthy controls (median in pre-SF patients: 41ng/mL; range 2.6-86.4). RA and SF post op patients had elevated OPN levels (37ng/mL and 198ng/mL respectively), well below those of the ALF patients. Median OPN levels were highest in acetaminophen (3603ng/mL) and ischemia-related ALF (4102ng/mL) as opposed to viral hepatitis (706ng/mL), drug-induced liver injury (353ng/mL) or autoimmune hepatitis (436ng/mL), correlating with the degree of hepatocellular damage, as reflected by aminotransferase values (R value: 0.47 for AST, p<0.001). OPN levels appeared to correlate with degree of liver necrosis in ALF. Very high levels were associated with hyperacute injury and good outcomes. Whether OPN exerts a protective effect in limiting disease progression in this setting remains uncertain. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Cytokine 03/2015; 73(2):270-276. DOI:10.1016/j.cyto.2015.02.021 · 2.87 Impact Factor
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    ABSTRACT: Animal studies suggest that receptor for advanced glycation end-product (RAGE)-dependent mechanisms contribute to acetaminophen-induced liver damage. We examined whether circulating levels of soluble RAGE (sRAGE) or RAGE ligands including extracellular newly identified RAGE binding protein (EN-RAGE), High-Mobility Group Box 1 (HMGB1) and Nε-(Carboxymethyl) lysine-adducts (CML), could aid prognostication following acetaminophen overdose. Sixty well-characterized acetaminophen-related acute liver failure (ALF) patients (30 spontaneous survivors and 30 transplanted and/or died) enrolled in the NIH-sponsored Acute Liver Failure Study Group, matched for age and meeting standard criteria of encephalopathy and INR > 1.5, were retrospectively studied. HMGB1, EN-RAGE, CML and sRAGE were detected by ELISA methods in sera from ALF patients as well as in 30 healthy controls. Levels of sRAGE, EN-RAGE and HMGB1, but not CML, were significantly greater (p < 0.0001) in ALF patients than normal controls. The levels of sRAGE, HMGB1 and EN-RAGE were significantly higher (p = 0.029, p = 0.083, p = 0.033) in patients with systemic inflammatory response syndrome score (SIRS) > 2 than in patients with SIRS ≤ 2. Nevertheless, only sRAGE levels were significantly higher in patients who were transplanted and/or died than in spontaneous survivors (p = 0.0005) and were positively associated with conventional markers of liver disease severity. Multivariate logistic regression identified the encephalopathy grade > 2 as independent predictors of adverse outcome on admission (odds ratio = 13, 95% CI 2.3-73, p = 0.00038). The RAGE-ligand axis may interfere with liver regeneration and should be a promising objective for further research. This article is protected by copyright. All rights reserved. © 2015 American Association for the Study of Liver Diseases.
    Liver Transplantation 03/2015; DOI:10.1002/lt.24129 · 3.79 Impact Factor
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    ABSTRACT: Isoniazid is a leading cause of liver injury but it is not clear how many cases are reported or how many clinicians adhere to American Thoracic Society (ATS) guidelines. We collected data on cases of isoniazid hepatotoxicity and assessed adherence to ATS guidelines and reports to the Center for Disease Control's (CDC) isoniazid severe adverse events program. We analyzed Drug Induced Liver Injury Network (DILIN) cases considered definite, highly likely, or probable for isoniazid injury from 2004 through 2013. We assessed the delays in isoniazid discontinuance according to ATS criteria and hepatotoxicity severity by Severity Index Score. We checked reporting to the CDC by matching cases based on age, latency, indication, reporting period, and comorbidities. Isoniazid was the second most commonly reported agent in the DILIN, with 69 cases; 60 met inclusion criteria. The median age of cases was 49 y (range 4-68 y), 70% were female, 97% had latent tuberculosis, and 62% were hospitalized. Patients took a median of 9 days to stop taking isoniazid (range 0-99 days). Thirty-three of cases (55%) continued taking isoniazid for more than 7 days after the ATS stopping criteria were met. Twenty-four cases (40%) continued isoniazid for more than 14 days after meeting stopping criteria. A delay in stopping was associated with more severe injury (P<.05). Of 13 patients who died or underwent liver transplantation, 9 (70%) continued taking isoniazid for >7 days after meeting stopping criteria. Only 1/25 cases of isoniazid hepatotoxicity eligible for reporting to the CDC were reported. Poor adherence to ATS guidelines is common in cases of hepatotoxicity and is associated with more severe outcomes including hospitalization, death, and liver transplantation. Isoniazid continues to be a leading cause of DILI in the US, and its hepatotoxicity is significantly under-reported. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
    Clinical Gastroenterology and Hepatology 02/2015; DOI:10.1016/j.cgh.2015.02.024 · 6.53 Impact Factor
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    ABSTRACT: Hepatitis B virus (HBV) testing and vaccination rates remain low among Asian-American/Pacific Islanders (APIs) despite high rates of HBV infection. The aim of our study was to assess the effectiveness of an outreach campaign to increase HBV knowledge, testing, and vaccination among a cohort of APIs. Vietnamese Americans were invited to participate in a free HBV screening and vaccination outreach program though pubic service announcements. Attendees completed a survey to assess barriers to vaccination and HBV-related knowledge before and after a 30-min education session by a bilingual board-certified gastroenterologist. Among 98 participants, 100 % (22/22) of HBV naïve patients were provided a HBV vaccination series at no cost and over 75 % (14/18) of HBV-infected patients were connected to further medical care. Notable reported barriers to prior testing and/or vaccination were cost of the vaccine, concern about missing work for evaluation, and lack of provider recommendation. Knowledge levels about HBV risk factors, potential consequences, and treatment options were poor at baseline but significantly increased after the education session (49 vs. 64 %, p < 0.001). Outreach campaigns linked with education can successfully address several barriers to HBV testing and offer an approach to improve HBV awareness and prevention among difficult-to-reach populations.
    Journal of Community Health 12/2014; DOI:10.1007/s10900-014-9975-y · 1.28 Impact Factor
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    ABSTRACT: Background & Aims We investigated whether antimicrobial prophylaxis alters the incidence of bloodstream infection in patients with acute liver failure (ALF), and whether bloodstream infections affect overall mortality within 21 days after development of ALF. Methods We performed a retrospective cohort analysis of 1551 patients with ALF enrolled by the US Acute Liver Failure Study Group from January 1998 through November 2009. We analyzed data on infections in the first 7 days after admission and the effects of prophylaxis with antimicrobial drugs on development of bloodstream infections and 21-day mortality. Results In our study population, 600 patients (39%) received antimicrobial prophylaxis and 226 (14.6%) developed at least 1 bloodstream infection. Exposure to antimicrobial drugs did not affect the proportion of patients who developed bloodstream infections (12.8% in patients with prophylaxis vs 15.7% non-prophylaxed; P=.12) but a greater percentage who received prophylaxis received liver transplants (28% vs 22%; P=.01). After adjusting for confounding factors, overall mortality within 21 days was independently associated with age (odds ratio [OR]=1.014), model for end-stage liver disease score at admission (OR=1.078), and vasopressor administration at admission (OR=2.499). Low grade of coma (OR=0.47) and liver transplantation (OR=0.101) reduced mortality. Although bloodstream infection was significantly associated with 21-day mortality (P=.004), an interaction between bloodstream infection and etiology was detected: blood stream infection affected mortality to a greater extent in non-acetaminophen ALF patients (OR=2.03) than in acetaminophen ALF patients (OR=1.14). Conclusions Based on a large, observational study, antimicrobial prophylaxis does not reduce incidence of bloodstream infection or mortality within 21 days of ALF. However, bloodstream infections were associated with increased 21-day mortality in patients with ALF—to a greater extent in patients without than with acetaminophen-associated ALF. Our findings do not support routine use of antimicrobial prophylaxis in patients with ALF.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 11/2014; DOI:10.1016/j.cgh.2014.03.011 · 6.53 Impact Factor
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    ABSTRACT: Classification of objects into pre-defined groups based on known information is a fundamental problem in the field of statistics. Although approaches for solving this problem exist, finding an accurate classification method can be challenging in an orphan disease setting, where data are minimal and often not normally distributed. The purpose of this paper is to illustrate the application of the random forest (RF) classification procedure in a real clinical setting and discuss typical questions that arise in the general classification framework as well as offer interpretations of RF results. This paper includes methods for assessing predictive performance, importance of predictor variables, and observation-specific information. Copyright © 2014 John Wiley & Sons, Ltd.
    Statistics in Medicine 11/2014; 34(5). DOI:10.1002/sim.6351 · 2.04 Impact Factor
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    ABSTRACT: IntroductionDrug-induced liver injury [DILI] is often caused by innate and adaptive host immune responses. Characterization of inflammatory infiltrates in the liver may improve understanding of the underlying pathogenesis of DILI.AimsTo characterize leukocytes infiltrating liver tissue from subjects with acute DILI [n = 32] vs. non-DILI causes of acute liver injury [n = 25].Methods Immunostains for CD11b/CD4 (Kupffer and T helper cells), CD3/CD20 (T and B cells), and CD8/CD56 (T cytotoxic and NK cells) were evaluated in biopsies from subjects with acute DILI, either immuno-allergic [IAD] or auto-immune [AID] and idiopathic autoimmune (AIH) and viral hepatitis (VH) and correlated with clinical and pathologic features.ResultsAll biopsies showed numerous CD8+ T cells and macrophages. DILI cases had significantly fewer B-lymphocytes than AIH and VH and significantly fewer NK cells than VH. Prominent plasma cells were unusual in IAD (3/10 cases), but were strongly associated with AIH (8/9) and also observed in most with AID (6/9). They were also found in 5/10 cases with VH.Conclusions Liver biopsies from subjects with DILI were characterized by low counts of mature B cells and NK cells in portal triads in contrast to VH. NK cells were only found in cases of VH, whereas AIH and VH both showed higher counts of B cells than DILI. Plasma cells were most strongly associated with AIH and less so with AID, but were uncommon in IAD.
    Clinical & Experimental Immunology 11/2014; 180(1). DOI:10.1111/cei.12558 · 3.28 Impact Factor
  • Digestive Diseases and Sciences 10/2014; 60(1). DOI:10.1007/s10620-014-3374-1 · 2.55 Impact Factor
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    ABSTRACT: Acetaminophen (APAP) overdose is a major cause of acute liver failure (ALF). Numerous studies have shown that APAP hepatotoxicity in mice involves mitochondrial dysfunction, and recent data suggest this is also the case in humans. We have previously shown that glutamate dehydrogenase (GDH), mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) fragments can be measured in circulation of overdose patients as mechanistic biomarkers of mitochondrial damage and damage-associated molecular patterns. In the present study, our goal was to determine if these biomarkers are higher in serum from non-survivors of APAP-induced ALF (AALF) compared with survivors. GDH, mtDNA and nDNA fragments were measured in serum from AALF patients who did (n = 34) or did not (n = 35) recover. Importantly, all three were significantly increased in patients who died compared with those who survived (GDH: 450±73 vs. 930±145 U/L; mtDNA: 21±6 vs. 48±13 and 33±10 vs. 43±7 ng/mL for two different genes; nDNA fragments: 148±13 vs. 210±13 % of control). Receiver operating characteristic (ROC) curve analyses revealed that nDNA fragments, GDH and mtDNA were predictive of outcome (AUC, study admission: 0.73, 0.70 and 0.71 or 0.76, respectively, p < 0.05; AUC, time of peak ALT: 0.78, 0.71 and 0.71 or 0.76, respectively, p < 0.05) and the results were similar to those from the model for end-stage liver disease (MELD) (AUC, peak MELD: 0.77, p < 0.05). Conclusions: Our data suggest that patients with more mitochondrial damage are less likely to survive, demonstrating that mitochondria are central in the mechanisms of APAP hepatotoxicity in humans. Clinically, serum nDNA fragments, GDH and mtDNA could be useful as part of a panel of biomarkers to predict patient outcome. (Hepatology 2014;).
    Hepatology 10/2014; 60(4). DOI:10.1002/hep.27265 · 11.19 Impact Factor
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    ABSTRACT: There have been few reports of acute liver failure (ALF, with encephalopathy and coagulopathy) due to infiltration of the liver by malignant cells. We describe a case series of 27 patients with ALF caused by malignancy. We examined a large, multi-center ALF registry (1910 patients; mean age, 47.1±13.9 years) and found only 27 cases (1.4%) of ALF attributed to malignancy. Twenty cases (74%) presented with abdominal pain and 11 with ascites. The malignancies included lymphoma or leukemia (33%), breast cancer, (30%), and colon cancer (7%); 90% of the patients with lymphoma or leukemia had no history of cancer, compared to 25% of patients with breast cancer. Overall, 44% of the patients had evidence of liver masses by imaging. Diagnosis was confirmed by biopsy in 15 (55%) and autopsy for 6 cases. Twenty-four patients (89%) died within 3 weeks of ALF.
    Clinical Gastroenterology and Hepatology 09/2014; 13(5). DOI:10.1016/j.cgh.2014.09.040 · 6.53 Impact Factor
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    ABSTRACT: Acetaminophen (APAP) - induced acute liver failure (ALF) remains a major clinical problem. While a majority of patients recovers after severe liver injury, a subpopulation of patients proceeds to acute liver failure. Bile acids are generated in the liver and accumulate in blood during liver injury, and as such, have been proposed as biomarkers for liver injury and dysfunction. The goal of this study was to determine if individual bile acid levels could determine outcome in patients with APAP-induced ALF (AALF). Serum bile acid levels were measured in AALF patients using mass spectrometry. Bile acid levels were elevated 5-80 fold above control values in injured patients on day 1 after the overdose and decreased over the course of hospital stay. Interestingly, glycodeoxycholic acid (GDCA) was significantly increased in non-surviving AALF patients compared to survivors. GDCA values obtained at Peak ALT and from Day 1 of admission indicated GDCA could predict survival in these patients by receiver-operating characteristic analysis (AUC=0.70 for Day 1, AUC=0.68 for peak ALT). Of note, AALF patients also had significantly higher levels of serum bile acids than patients with active cholestatic liver injury. These data suggest measurements of GDCA in this patient cohort modestly predicted outcome and may serve as a prognostic biomarker. Furthermore, accumulation of bile acids in serum or plasma may be a result of liver cell dysfunction and not cholestasis, suggesting elevation of circulating bile acid levels may be a consequence and not a cause of liver injury.
    Toxicological Sciences 09/2014; 142(2). DOI:10.1093/toxsci/kfu195 · 4.48 Impact Factor
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    ABSTRACT: MicroRNA-122 (miR-122) is the foremost liver-related micro-RNA, but its role in the hepatocyte is not fully understood. To evaluate whether circulating levels of miR-122 are elevated in chronic-HCV for a reason other than hepatic injury, we compared serum level in patients with chronic hepatitis C to other forms of liver injury including patients with acute liver failure and healthy controls. MiR-122 was quantitated using sera from 35 acute liver failure patients (20 acetaminophen-induced, 15 other etiologies), 39 chronic-HCV patients and 12 controls. In parallel, human genomic DNA (hgDNA) levels were measured to reflect quantitatively the extent of hepatic necrosis. Additionally, six HIV–HCV co-infected patients, who achieved viral clearance after undergoing therapy with interferon and ribavirin, had serial sera miR-122 and hgDNA levels measured before and throughout treatment. Serum miR-122 levels were elevated approximately 100-fold in both acute liver failure and chronic-HCV sera as compared to controls (P < 0.001), whereas hgDNA levels were only elevated in acute liver failure patients as compared to both chronic-HCV and controls (P < 0.001). Subgroup analysis showed that chronic-HCV sera with normal aminotransferase levels showed elevated miR-122 despite low levels of hepatocyte necrosis. All successfully treated HCV patients showed a significant Log10 decrease in miR-122 levels ranging from 0.16 to 1.46, after sustained viral response. Chronic-HCV patients have very elevated serum miR-122 levels in the range of most patients with severe hepatic injury leading to acute liver failure. Eradication of HCV was associated with decreased miR-122 but not hgDNA. An additional mechanism besides hepatic injury may be active in chronic-HCV to explain the exaggerated circulating levels of miR-122 observed. J. Med. Virol. © 2014 Wiley Periodicals, Inc.
    Journal of Medical Virology 09/2014; 86(9). DOI:10.1002/jmv.23987 · 2.22 Impact Factor
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    ABSTRACT: Background The complement system is activated in liver diseases including acute liver failure (ALF); however, the role of the lectin pathway of complement has scarcely been investigated in ALF. The pathway is initiated by soluble pattern recognition molecules: mannan-binding lectin (MBL), M-, L- and H-ficolin and collectin-liver-1 (CL-L1), which are predominantly synthesised in the liver.AimWe aimed to study lectin levels in ALF patients and associations with clinical outcome.Methods: Serum samples from 75 patients enrolled by the U.S. ALF Study Group were collected on days 1 and 3. We included 75 healthy blood donors and 20 cirrhosis patients as controls. Analyses were performed using sandwich-type immunoassays (ELISA, TRIFMA).ResultsAt day 1, the MBL level in ALF patients was 40% lower compared with healthy controls ((median(interquartile range) 0.72 μg/ml(0.91) vs. 1.15(1.92)(p=0.02)), and increased significantly by day 3 (0.83 μg/ml(0.94)(p=0.01)). The M-ficolin level was 60% lower (0.54 μg/ml(0.50) vs. 1.48(1.01)(p<0.0001)). The CL-L1 level at day 1 was slightly higher compared with healthy controls (3.20 μg/ml(2.37) vs. 2.64(0.72)(p=0.11)); this was significant at day 3 (3.35(1.84)(p=0.006)). H- and L-ficolin levels were similar to healthy controls. Spontaneous ALF survivors had higher levels of MBL at day 1 (0.96 μg/ml(1.15) vs. 0.60(0.60)(p=0.02)) and lower levels of L-ficolin by day 3 compared with patients who died or were transplanted (1.61 μg/ml(1.19) vs. 2.17(2.19)(p=0.02)).Conclusion We observed significant dynamics in lectin levels in ALF patients, which may suggest they play a role in ALF pathogenesis. High MBL and low L-ficolin levels are associated with survival.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 09/2014; 35(3). DOI:10.1111/liv.12682 · 4.41 Impact Factor
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    ABSTRACT: Background The long-term clinical outcomes in initial survivors with acute liver failure (ALF) are not well known.AimsThe aim of the current study is to provide an overview of the 2 year clinical outcomes amongst initial survivors and liver transplant (LT) recipients that were alive 3 weeks after enrollment in the Acute Liver Failure Study Group (ALFSG).Methods Outcomes in adult ALFSG patients that were enrolled between 1998 and 2010 were reviewed.Results2-year patient survival was significantly higher in the 262 LT recipients (92.4%) compared to the 306 acetaminophen (APAP) spontaneous survivors (SS) (89.5%) and 200 non-APAP SS (75.5%) (p < 0.0001). The causes of death were similar in the 3 groups but the time to death was significantly longer in the LT recipients (p< 0.0001). Independent predictors of 2-year mortality in the APAP group were a high serum phosphate level and patient age (c-statistic = 0.65 (0.54, 0.76)), patient age and days from jaundice to ALF onset in the non-APAP group (c-statistic =0.69 (0.60, 0.78)), and patient age, days from jaundice, and higher coma grade in the LT recipients (c-statistic=0.74 (0.61, 0.87)). The LT recipients were significantly more likely to be employed and have a higher educational level (p < 0.05).Conclusions Two-year outcomes in initial survivors of ALF are generally good but non-APAP patients have a significantly lower survival which may relate to pre-existing medical co-morbidities. Spontaneous survivors with APAP overdose experience substantial morbidity during follow-up from ongoing psychiatric and substance abuse issues.This article is protected by copyright. All rights reserved.
    Liver international: official journal of the International Association for the Study of the Liver 07/2014; 35(2). DOI:10.1111/liv.12632 · 4.41 Impact Factor
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    ABSTRACT: Background & Aims Patients with acute liver failure (ALF) frequently develop renal dysfunction, yet its overall incidence and outcomes have not been fully assessed. We investigated the incidence of acute kidney injury (AKI) among patients with ALF, using defined criteria to identify risk factors and to evaluate its effect on overall outcomes. Methods We performed a retrospective review of data from 1604 patients enrolled in the Acute Liver Failure Study Group, from 1998 through 2010. Patients were classified by the Acute Kidney Injury Network criteria, as well as for etiology of liver failure (acetaminophen-based, ischemic, and all others). Results Seventy percent of patients with ALF developed AKI, and 30% received renal replacement therapy (RRT). Patients with severe AKI had higher international normalized ratio values than those without renal dysfunction (P<.001), and a higher proportion had advanced-grade coma (coma grade 3 or 4, P<.001) or presented with hypotension requiring vasopressor therapy (P<.001). A greater proportion of patients with acetaminophen-induced ALF had severe kidney injury than of patients with other etiologies of ALF; 34% required RRT, compared to 25% of patients with ALF not associated with acetaminophen or ischemia (P<.002). Of the patients with ALF who were alive at 3 weeks after study entry, significantly fewer with AKI survived for 1 year. Although AKI reduced overall survival time, more than 50% of patients with acetaminophen-associated or ischemic ALF survived without liver transplantation (even with RRT), compared to 19% of patients ALF due to other causes (P<.001). Only 4% of patients requiring RRT became dependent on dialysis. Conclusions Based on a retrospective analysis of data from more than 1600 patients, AKI is common in patients with ALF and affects short- and long-term outcomes, but rarely results in chronic kidney disease. Acetaminophen-induced kidney injury is frequent but patients have better outcomes than those with other forms of ALF.
    Clinical Gastroenterology and Hepatology 07/2014; 13(2). DOI:10.1016/j.cgh.2014.07.011 · 6.53 Impact Factor
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    ABSTRACT: Idiosyncratic drug-induced liver injury (DILI) is a rare adverse drug reaction and it can lead to jaundice, liver failure, or even death. Antimicrobials and herbal and dietary supplements are among the most common therapeutic classes to cause DILI in the Western world. DILI is a diagnosis of exclusion and thus careful history taking and thorough work-up for competing etiologies are essential for its timely diagnosis. In this ACG Clinical Guideline, the authors present an evidence-based approach to diagnosis and management of DILI with special emphasis on DILI due to herbal and dietary supplements and DILI occurring in individuals with underlying liver disease.Am J Gastroenterol advance online publication, 17 June 2014; doi:10.1038/ajg.2014.131.
    The American Journal of Gastroenterology 06/2014; 109(7). DOI:10.1038/ajg.2014.131 · 9.21 Impact Factor
  • Gastroenterology 05/2014; 146(5):S-974. DOI:10.1016/S0016-5085(14)63540-X · 13.93 Impact Factor
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    Imir G Metushi, William M Lee, Jack Uetrecht
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    ABSTRACT: Isoniazid (INH) therapy is associated with a significant incidence of idiosyncratic liver failure. We recently reported eight cases of INH-induced liver failure in which patients had anti-drug and anti-cytochrome P450 antibodies. However, it was unclear what role these antibodies play in the mechanism of INH-induced liver injury. Here, we report that the dominant isotype of anti-INH antibodies was IgG, with IgG3 being the dominant subtype. IgG3 antibodies are associated with a Th1-type immune response and fix complement. IgG3 antibodies have been associated with other forms of liver injury and may play a pathogenic role in INH-induced liver injury.
    Chemical Research in Toxicology 04/2014; 27(5). DOI:10.1021/tx500108u · 4.19 Impact Factor

Publication Stats

16k Citations
2,270.67 Total Impact Points


  • 1995–2015
    • University of Texas at Dallas
      Richardson, Texas, United States
  • 1992–2015
    • University of Texas Southwestern Medical Center
      • • Division of Digestive and Liver Diseases
      • • Department of Internal Medicine
      Dallas, Texas, United States
  • 2013
    • Washington State University
      • College of Veterinary Medicine
      پولمن، واشینگتن, Washington, United States
  • 2012–2013
    • Parkland Memorial Hospital
      Dallas, Texas, United States
  • 2011
    • University of California, Los Angeles
      Los Ángeles, California, United States
  • 2010
    • North Carolina Clinical Research
      Raleigh, North Carolina, United States
  • 2009
    • Arkansas Children's Hospital
      Little Rock, Arkansas, United States
  • 2007
    • Duke University
      Durham, North Carolina, United States
    • University of California, San Diego
      San Diego, California, United States
  • 2005
    • University of Washington Seattle
      • Division of Gastroenterology
      Seattle, WA, United States
  • 2003
    • Northwestern University
      Evanston, Illinois, United States
    • Gold Coast University Hospital
      Southport, Queensland, Australia
  • 2000
    • University of California, San Francisco
      • Division of Hospital Medicine
      San Francisco, California, United States
  • 1983–1990
    • Medical University of South Carolina
      • • Department of Medicine
      • • Division of Gastroenterology and Hepatology
      • • Division of Oral Pathology
      Charleston, SC, United States