William M Lee

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

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Publications (267)2530.06 Total impact

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    ABSTRACT: Background/aim: Acetaminophen (APAP) hepatotoxicity is related to the formation of N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified through conjugation with reduced glutathione (GSH). Ophthalmic acid (OA) is an analogue of GSH in which cysteine is replaced with 2-aminobutyrate. Metabolomics studies of mice with APAP-induced acute liver failure (APAP-ALF) identified OA as a marker of oxidative stress and hepatic GSH consumption. The aim of the current study was to determine whether OA is detectable in APAP-ALF human patients either early (day 2) or late (day 4) and whether OA levels were associated with in-hospital survival in the absence of liver transplant. Methods: Serum samples from 130 APAP-ALF patients (82 survivors, 48 non-survivors) were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and correlated with clinical data from the United States Acute Liver Failure Study Group (US ALFSG) Registry (2004-2011). Results: Survivors had significantly lower admission bilirubin (4.2 vs. 5.7 mg/dl) and lactate levels (3.3 vs. 6.5 μmol/l, p<0.05 for all). During the first 7 days of the study, survivors were less likely to require mechanical ventilation (55% vs. 88%), vasopressor support (9.8% vs. 67%) or renal replacement therapy (26% vs. 63%, p< 0.001 for all). Non-survivors were more likely to have detectable OA levels early (31% vs. 15%, p = 0.034) and late (27% vs. 11%, p = 0.02). However there were no significant differences in mean OA levels between non-survivors and survivors (early 0.48 vs. 0.36, late 0.43 vs. 0.37, P > 0.5 for all). Conclusion: OA was detectable more frequently in APAP-ALF non-survivors but mean OA levels were not associated with survival. The routine clinical administration of N-acetyl cysteine could replenish GSH levels and prevent OA production.
    PLoS ONE 09/2015; 10(9):e0139299. DOI:10.1371/journal.pone.0139299 · 3.23 Impact Factor
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    ABSTRACT: Background: Because acute liver failure (ALF) patients share many clinical features with severe sepsis and septic shock, identifying bacterial infection clinically in ALF patients is challenging. Procalcitonin (PCT) has proven to be a useful marker in detecting bacterial infection. We sought to determine whether PCT discriminated between presence and absence of infection in patients with ALF. Method: Retrospective analysis of data and samples of 115 ALF patients from the United States Acute Liver Failure Study Group randomly selected from 1863 patients were classified for disease severity and ALF etiology. Twenty uninfected chronic liver disease (CLD) subjects served as controls. Results: Procalcitonin concentrations in most samples were elevated, with median values for all ALF groups near or above a 2.0 ng/mL cut-off that generally indicates severe sepsis. While PCT concentrations increased somewhat with apparent liver injury severity, there were no differences in PCT levels between the pre-defined severity groups-non-SIRS and SIRS groups with no documented infections and Severe Sepsis and Septic Shock groups with documented infections, (p = 0.169). PCT values from CLD patients differed from all ALF groups (median CLD PCT value 0.104 ng/mL, (p ≤0.001)). Subjects with acetaminophen (APAP) toxicity, many without evidence of infection, demonstrated median PCT >2.0 ng/mL, regardless of SIRS features, while some culture positive subjects had PCT values <2.0 ng/mL. Summary/conclusions: While PCT appears to be a robust assay for detecting bacterial infection in the general population, there was poor discrimination between ALF patients with or without bacterial infection presumably because of the massive inflammation observed. Severe hepatocyte necrosis with inflammation results in elevated PCT levels, rendering this biomarker unreliable in the ALF setting.
    PLoS ONE 09/2015; 10(9):e0138566. DOI:10.1371/journal.pone.0138566 · 3.23 Impact Factor
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    ABSTRACT: Objectives: The long-term outcomes of patients with drug induced liver injury (DILI) are not well described. The aim of this study was to determine the frequency and severity of persistent liver biochemistry abnormalities in DILI patients followed over 2 years. Methods: Subjects with evidence of liver injury at 6 months after DILI onset were offered a month 12 and 24 study visit. Results: Amongst the 99 patients with definite, probable, or very likely DILI and available laboratory data at 12 months after DILI onset, 74 (75%) had persistent liver injury (persisters) defined as a serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 × upper limit of normal (ULN) or an alkaline phosphatase >ULN, while 25 (25%) had resolved liver injury (resolvers). On multivariate analysis, month 12 persisters were significantly older (52.6 vs. 43.7 years, P=0.01) and more likely to have a cholestatic lab profile at DILI onset (54 vs. 20%, P<0.01) than resolvers. The month 12 persisters also had significantly poorer SF-36 physical summary scores at DILI onset and throughout follow-up compared with the resolvers (P<0.01). Amongst the 17 subjects with a liver biopsy obtained at a median of 387 days after DILI onset, 9 had chronic cholestasis, 3 had steatohepatitis, and 3 had chronic hepatitis. Conclusions: In all, 75% of subjects with liver injury at 6 months after DILI onset have laboratory evidence of persistent liver injury during prolonged follow-up. Higher serum alkaline phosphatase levels at presentation and older patient age were independent predictors of persistent liver injury. Subjects with persistent liver injury at 12 months after DILI onset should be carefully monitored and assessed for liver disease progression.Am J Gastroenterol advance online publication, 8 September 2015; doi:10.1038/ajg.2015.283.
    The American Journal of Gastroenterology 09/2015; DOI:10.1038/ajg.2015.283 · 10.76 Impact Factor
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    ABSTRACT: Occult hepatitis B infection (OBI), the presence of low hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels in patients without detectable hepatitis B surface antigen (HBsAg), has significant implications for understanding the natural history of hepatitis B infection. We determined the prevalence of OBI in African patients using a sensitive polymerase chain reaction (PCR) assay and describe here the characteristics of OBI in an urban African hospital population. Routine serological testing as well as molecular studies were performed on sera from 314 patients who were part of a previous study from an urban hospital emergency room in Kampala, Uganda, detecting HBV DNA using a nested PCR with amplification of two regions of the HBV genome. HBV viral loads (VL) were determined by real-time PCR (rtPCR) and sequencing performed to determine HBV genotype and S gene mutations. Among 314 subjects tested, 50 (16%) had chronic HBV infection, 94 (30%) had detectable HBV DNA despite testing HBsAg negative (OBI), and 170 (54%) were not infected. VLs of OBI subjects were relatively low although 19 (20%) had VL exceeding 10(4) IU mL(-) . Subjects with chronic HBV infection had a higher median VL compared to OBI patients (P < 0 · 001). All chronic HBV sequenced (10) and 83/89 OBI sequences were genotype A, the remaining six being genotype D. S-gene mutations were present in some but not all OBI patients (48%). OBI is more prevalent among African patients than previously thought. This may have implications for clinical management and transfusion-related HBV transmission. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Medical Virology 09/2015; DOI:10.1002/jmv.24372 · 2.35 Impact Factor
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    ABSTRACT: Acetaminophen (APAP) is the most common cause of acute liver failure (ALF) in the west. It is unknown if APAP overdose in combination with diphenhydramine or opioids confers a different clinical presentation or prognosis. Study objectives were to compare (1) baseline patient characteristics; (2) initial clinical presentation; and (3) clinical outcomes among patients with ALF due to APAP alone or in combination with diphenhydramine or opioids. We analyzed 666 cases of APAP-related liver failure using the Acute Liver Failure Study Group database from 1998 to 2012. The database contains detailed demographic, laboratory, and clinical outcome data, including hemodialysis, transplantation, and death and in-hospital complications such as arrhythmia and infection. The final sample included 666 patients with APAP liver injury. A total 30.3% of patients were overdosed with APAP alone, 14.1% with APAP/diphenhydramine, and 56.6% with APAP/opioids. Patients taking APAP with opioids were older, had more comorbidities, and were more likely to have unintentional overdose (all P<0.0001). On presentation, 58% in the APAP/opioid group had advanced encephalopathy as compared with 43% with APAP alone (P=0.001) The APAP/diphenhydramine group presented with the highest serum aminotransferase levels, no differences in laboratory values were noted at 3 days postenrollment. No significant differences were observed in clinical outcomes among the groups. Most patients with APAP-induced ALF were taking APAP combination products. There were significant differences in patient characteristics and clinical presentation based on the type of product ingested, however, there were no differences noted in delayed hepatotoxicity or clinical outcomes.
    Journal of clinical gastroenterology 07/2015; DOI:10.1097/MCG.0000000000000378 · 3.50 Impact Factor
  • Gastroenterology 04/2015; 148(4):S-1098. DOI:10.1016/S0016-5085(15)33745-8 · 16.72 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 · 11.34 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 · 2.66 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; 21(6). DOI:10.1002/lt.24129 · 4.24 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 · 7.90 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; 40(4). 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; 12(11). DOI:10.1016/j.cgh.2014.03.011 · 7.90 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 · 1.83 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 · 3.04 Impact Factor
  • Digestive Diseases and Sciences 10/2014; 60(1). DOI:10.1007/s10620-014-3374-1 · 2.61 Impact Factor
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    ABSTRACT: Unlabelled: 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 that 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 aim was to determine whether these biomarkers are higher in serum from nonsurvivors of APAP-induced ALF (AALF), compared to 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 to 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 (area under the curve [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;60:1336-1345).
    Hepatology 10/2014; 60(4). DOI:10.1002/hep.27265 · 11.06 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 · 7.90 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 · 3.85 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 · 2.35 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 · 4.85 Impact Factor

Publication Stats

18k Citations
2,530.06 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
  • 2012–2013
    • Parkland Memorial Hospital
      Dallas, Texas, United States
  • 2011
    • University of California, Los Angeles
      Los Ángeles, California, United States
  • 2009
    • Arkansas Children's Hospital
      Little Rock, Arkansas, United States
  • 2007
    • University of California, San Diego
      San Diego, California, United States
    • Duke University
      Durham, North Carolina, 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
  • 1983–1987
    • Medical University of South Carolina
      • • Division of Gastroenterology and Hepatology
      • • Department of Medicine
      • • Division of Oral Pathology
      Charleston, SC, United States