Thomas D Boyer

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• Boyer, T. D., Sanyal, A. J., Wong, F., Frederick, R. T., Lake, J. R., O'Leary, J. G., Ganger, D., Jamil, K., Pappas, S. C., & , R. S. (2016). Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1. Gastroenterology.
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  Hepatorenal syndrome type 1 (HRS-1) in patients with cirrhosis and ascites is a functional, potentially reversible form of acute kidney injury characterized by rapid (
• Angeli, P., Gines, P., Wong, F., Bernardi, M., Boyer, T. D., Gerbes, A., Moreau, R., Jalan, R., Sarin, S. K., Piano, S., Moore, K., Lee, S. S., Durand, F., Salerno, F., Caraceni, P., Kim, W. R., Arroyo, V., Garcia-Tsao, G., & , I. C. (2015). Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. Gut, 64(4), 531-7.
• Angeli, P., Ginès, P., Wong, F., Bernardi, M., Boyer, T. D., Gerbes, A., Moreau, R., Jalan, R., Sarin, S. K., Piano, S., Moore, K., Lee, S. S., Durand, F., Salerno, F., Caraceni, P., Kim, W. R., Arroyo, V., & Garcia-Tsao, G. (2015). Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. Journal of hepatology, 62(4), 968-74.
• Berzigotti, A., Boyer, T. D., Castéra, L., de Franchis, R., Genescà, J., & Pinzani, M. (2015). Reply to "Points to be considered when using transient elastography for diagnosis of portal hypertension according to the Baveno's VI consensus". Journal of hepatology, 63(4), 1049-50.
• Boyer, T. D., & Habib, S. (2015). Big spleens and hypersplenism: fix it or forget it?. Liver international : official journal of the International Association for the Study of the Liver, 35(5), 1492-8.
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  Hypersplenism is a common manifestation of portal hypertension in the cirrhotic. More than half of cirrhotics will have low platelet counts, but neutropenia is much less common. Despite being common in the cirrhotic population, the presence of hypersplenism is of little clinical consequence. The presence of hypersplenism suggests more advanced liver disease and an increase in risk of complications, but there is no data showing that correcting the hypersplenism improves patient survival. In most series, the most common indications for treating the hypersplenism is to increase platelet and white blood cell counts to allow for use of drugs that suppress the bone marrow such as interferon alpha and chemotherapeutic agents. There are several approaches used to treat hypersplenism. Portosystemic shunts are of questionable benefit. Splenectomy, either open or laparoscopically, is the most effective but is associated with a significant risk of portal vein thrombosis. Partial splenic artery embolization and radiofrequency ablation are effective methods for treating hypersplenism, but counts tend to fall back to baseline long-term. Pharmacological agents are also effective in increasing platelet counts. Development of direct acting antivirals against hepatitis C will eliminate the most common indication for treatment. We lack controlled trials designed to determine if treating the hypersplenism has benefits other than raising the platelet and white blood cell counts. In the absence of such studies, hypersplenism in most patients should be considered a laboratory abnormality and not treated, in other words forget it.
• Boyer, T. D., & Habib, S. (2015). Successful treatment of hepatitis B and C: don't forget the liver!!!. The American journal of medicine, 128(1), 3-4.
• Morgan, T. R., Osann, K., Bottiglieri, T., Pimstone, N., Hoefs, J. C., Hu, K., Hassanein, T., Boyer, T. D., Kong, L., Chen, W., Richmond, E., Gonzalez, R., Rodriguez, L. M., & Meyskens, F. L. (2015). A Phase II Randomized, Controlled Trial of S-Adenosylmethionine in Reducing Serum α-Fetoprotein in Patients with Hepatitis C Cirrhosis and Elevated AFP. Cancer prevention research (Philadelphia, Pa.), 8(9), 864-72.
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  In animal models of hepatocellular carcinoma (HCC), deficiency of S-adenosylmethionine (SAMe) increased the risk of HCC whereas administration of SAMe reduced HCC. The aim of this trial was to determine whether oral SAMe administration to patients with hepatitis C cirrhosis would decrease serum α-fetoprotein (AFP) level, a biomarker of HCC risk in hepatitis C. This was a prospective, randomized, placebo-controlled, double-blind trial of SAMe, up to 2.4 g/d, for 24 weeks as compared with placebo among subjects with hepatitis C cirrhosis and a mildly elevated serum AFP. Primary outcome was change in AFP between baseline and week 24. Secondary outcomes included changes in routine tests of liver function and injury, other biomarkers of HCC risk, SAMe metabolites, markers of oxidative stress, and quality of life. One hundred ten subjects were randomized and 87 (44 SAMe and 43 placebo) completed treatment. There was no difference in the change in AFP during 24 weeks among subjects receiving SAMe as compared with placebo. Changes in markers of liver function, liver injury, and hepatitis C viral level were not significantly different between groups. Similarly, SAMe did not change markers of oxidative stress or serum glutathione level. SAMe blood level increased significantly among subjects receiving SAMe. Changes in quality of life did not differ between groups. Overall, this trial did not find that SAMe treatment improved serum AFP in subjects with advanced hepatitis C cirrhosis and a mildly elevated AFP. SAMe did not improve tests of liver function or injury or markers of oxidative stress or antioxidant potential.
• Berzigotti, A., Bosch, J., & Boyer, T. D. (2014). Use of noninvasive markers of portal hypertension and timing of screening endoscopy for gastroesophageal varices in patients with chronic liver disease. Hepatology (Baltimore, Md.), 59(2), 729-31.
• Chatrath, H., Allen, L., & Boyer, T. D. (2014). Use of sirolimus in the treatment of refractory autoimmune hepatitis. The American journal of medicine, 127(11), 1128-31.
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  Corticosteroids and azathioprine are widely accepted as the initial therapy for autoimmune hepatitis. However, the disease is refractory to steroids in about 10%-20% of patients, for whom currently there is no standardized treatment. Here we describe our experience with sirolimus in treatment of steroid refractory autoimmune hepatitis.
• Singh, B., Biboa, J., Musuku, S., Patel, C., Pugh, J. L., & Boyer, T. D. (2013). Reversal of severe hepatitis with infliximab in adult-onset Still's disease. The American journal of medicine, 126(2), e3-4.
• Rial, N. S., Gilchrist, K. B., Henderson, J. T., Bhattacharyya, A. K., Boyer, T. D., Nadir, A., & Cunningham, J. T. (2011). Endoscopic ultrasound with biopsy of omental mass for cholangiocarcinoma diagnosis in cirrhosis. World journal of gastrointestinal endoscopy, 3(6), 124-8.
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  In this report, a patient had a previous diagnosis of cholangiocarcinoma with an extended cholecystectomy. Three years later, he was evaluated for recurrent ascites. The patient had several large volume paracentesis, without evidence of malignant cells. Subsequently, endoscopic ultrasound (EUS) with fine needle aspiration (FNA) of both lymph and omental nodules was utilized. While the lymph nodes were negative for malignancy, the omental nodule was interrogated with multiple antibodies and was found to be positive for neoplasia. EUS with FNA can safely be used in patients with cirrhosis to spare the patient invasive evaluation such as exploratory laparotomy (ex-lap) for diagnosis and staging of cholangiocarcinoma.
• Lucey, M. R., Connor, J. T., Boyer, T. D., Henderson, J. M., Rikkers, L. F., & , D. S. (2008). Alcohol consumption by cirrhotic subjects: patterns of use and effects on liver function. The American journal of gastroenterology, 103(7), 1698-706.
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  We investigated patterns of use of alcohol and its clinical effects among cirrhotic subjects who participated in a randomized clinical trial comparing the efficacy of transjugular intravenous portosystemic shunt and distal splenorenal shunt.
• Peters, M. G., Di Bisceglie, A. M., Kowdley, K. V., Flye, N. L., Luketic, V. A., Munoz, S. J., Garcia-Tsao, G., Boyer, T. D., Lake, J. R., Bonacini, M., Combes, B., & , P. G. (2007). Differences between Caucasian, African American, and Hispanic patients with primary biliary cirrhosis in the United States. Hepatology (Baltimore, Md.), 46(3), 769-75.
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  Primary biliary cirrhosis (PBC) is an uncommon chronic cholestatic liver disease that primarily afflicts young and middle-aged Caucasian women; there are limited data on the clinical presentation and disease severity among non-Caucasian patients with this disease. The goal of this study was to examine differences in the severity of liver disease between Caucasian and non-Caucasian patients with PBC screened for enrollment in a large national multicenter clinical trial. Demographic features, symptoms, physical findings, and laboratory tests obtained during screening were examined in 535 patients with PBC with respect to ethnicity, gender, and antimitochondrial antibody (AMA) status; 73 of 535 (13.6%) were non-Caucasian (21 were African American, and 42 were Hispanic). Non-Caucasians were more likely than Caucasians to be ineligible for participation in the clinical trial (46.5% versus 25.1%, P = 0.0001), primarily because of greater disease severity. African Americans and Hispanics were also more likely to have a lower activity level, more severe pruritus, and more advanced disease. However, the mean age, male-to-female ratio, and seroprevalence of AMA positivity were similar between the 2 groups.
• Henderson, J. M., Boyer, T. D., Kutner, M. H., Galloway, J. R., Rikkers, L. F., Jeffers, L. J., Abu-Elmagd, K., Connor, J., & , D. S. (2006). Distal splenorenal shunt versus transjugular intrahepatic portal systematic shunt for variceal bleeding: a randomized trial. Gastroenterology, 130(6), 1643-51.
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  Variceal bleeding refractory to medical treatment with beta-blockers and endoscopic therapy can be managed by variceal decompression with either surgical shunts or transjugular intrahepatic portal systemic shunts (TIPS). This prospective randomized trial tested the hypothesis that patients receiving distal splenorenal shunts (DSRS) would have significantly lower rebleeding and encephalopathy rates than TIPS in management of refractory variceal bleeding.
• Chalasani, N., & Boyer, T. D. (2005). Primary prophylaxis against variceal bleeding: beta-blockers, endoscopic ligation, or both?. The American journal of gastroenterology, 100(4), 805-7.
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  Variceal bleeding is one of the complications of cirrhosis that leads to significant morbidity and mortality. It is recommended that all patients with cirrhosis be screened for gastroesophageal varices and those with large varices should be offered primary prophylaxis. Nonselective beta-blockers (nadolol or propranolol) are the treatment of choice for primary prophylaxis but there are a number of limitations to their use. A number of studies have evaluated the efficacy of variceal band ligation (VBL) in providing primary prophylaxis, either in comparison to no treatment or to beta-blockers. VBL is very effective in preventing the initial bleed when compared to no treatment, but it is not superior to beta-blockers. In this issue of the journal the effect of beta-blockers on bleeding in patients undergoing VBL is examined and no benefit compared to VBL alone is shown. Thus, patients with large varices should be treated with beta-blockers and VBL should be offered to those cirrhotics who are unable to take beta-blockers. Further study is required to determine if VBL in combination with beta-blockers is more effective than the beta-blockers alone.
• Combes, B., Emerson, S. S., Flye, N. L., Munoz, S. J., Luketic, V. A., Mayo, M. J., McCashland, T. M., Zetterman, R. K., Peters, M. G., Di Bisceglie, A. M., Benner, K. G., Kowdley, K. V., Carithers, R. L., Rosoff, L., Garcia-Tsao, G., Boyer, J. L., Boyer, T. D., Martinez, E. J., Bass, N. M., , Lake, J. R., et al. (2005). Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology (Baltimore, Md.), 42(5), 1184-93.
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  This placebo-controlled, randomized, multicenter trial compared the effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopathy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwig's histological staging and then randomized to MTX 15 mg/m2 body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6-8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopathy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility. In conclusion, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone.
• Fried, M. W., Duncan, A., Soroka, S., Connaghan, D. G., Farrand, A., Peter, J., Strauss, R. M., Boyer, T. D., & McDonald, G. B. (2001). Serum hyaluronic acid in patients with veno-occlusive disease following bone marrow transplantation. Bone marrow transplantation, 27(6), 635-9.
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  The development of hepatic veno-occlusive disease following bone marrow transplantation is associated with high-dose combination cytoreductive therapy. Experimental models have suggested that drug-induced injury to hepatic sinusoidal endothelial cells is involved in the pathogenesis of this syndrome. Hyaluronic acid is a polysaccharide that is metabolized, almost exclusively, by hepatic sinusoidal endothelial cells. The aim of the present study was to evaluate serum hyaluronic acid as a marker for endothelial cell injury in patients with veno-occlusive disease following bone marrow transplantation. Hyaluronic acid was measured in sera from patients with and without veno-occlusive disease using an enzyme-linked protein binding assay. Mean peak serum hyaluronic acid levels were significantly greater in patients who had a diagnosis of VOD compared to those transplant patients who did not, 1173.4 +/- 982.9 vs 444.9 +/- 735.6 ng/ml (P = 0.01). Serial serum samples obtained from a separate cohort of patients also demonstrated that serum hyaluronic acid levels were higher in patients with moderate or severe veno-occlusive disease compared to those with none or mild disease at days 7, 17 and 25 following transplantation (greatest difference at day 25: 366 +/- 327 vs 126 +/- 151, P = 0.01). Serum hyaluronic acid levels are increased in veno-occlusive disease and increase over time in patients with severe disease. Further studies are required to determine if elevated serum hyaluronic acid levels are due to decreased clearance by injured hepatic sinusoidal endothelial cells or increased production from early hepatic fibrogenesis associated with the acute liver injury.
• Lim, K. N., Casanova, R. L., Boyer, T. D., & Bruno, C. J. (2001). Autoimmune hepatitis in African Americans: presenting features and response to therapy. The American journal of gastroenterology, 96(12), 3390-4.
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  African Americans are at an increased risk for certain diseases and more frequently suffer complications of those diseases relative to their white counterparts. Most studies of autoimmune hepatitis consist of entirely white populations. The Emory University system of hospitals serves a large African American population, including a significant number of African Americans with autoimmune hepatitis. The goal of this study was to determine if the presentation and response to therapy in African Americans is, like other diseases, different than in whites.
• Reddy, K. R., Wright, T. L., Pockros, P. J., Shiffman, M., Everson, G., Reindollar, R., Fried, M. W., Purdum, P. P., Jensen, D., Smith, C., Lee, W. M., Boyer, T. D., Lin, A., Pedder, S., & DePamphilis, J. (2001). Efficacy and safety of pegylated (40-kd) interferon alpha-2a compared with interferon alpha-2a in noncirrhotic patients with chronic hepatitis C. Hepatology (Baltimore, Md.), 33(2), 433-8.
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  Administration of interferon (IFN) 3 times weekly in patients with chronic hepatitis C (CHC) is associated with low sustained responses, which may be, in part, related to this regimen's inability to maintain IFN concentrations sufficient to suppress viral replication. An enhanced IFN molecule produced by the covalent attachment of a branched 40-kd polyethylene glycol moiety to IFN alpha-2a (PEG[40kd] IFN alpha-2a) exhibits sustained absorption, a restricted volume of distribution, and reduced clearance compared with unmodified IFN alpha-2a. One hundred fifty-nine patients with CHC participated in a randomized, ascending-dose (45 or 90, 180, 270 microg) study comparing PEG(40kd) IFN alpha-2a administered once weekly with 3 MIU IFN alpha-2a administered 3 times weekly for 48 weeks to determine the most appropriate PEG(40kd) IFN alpha-2a dose for subsequent clinical trials. Efficacy was assessed by measuring hepatitis C virus (HCV) RNA following a 24-week treatment-free period. Sustained virological responses for PEG(40kd) IFN alpha-2a once weekly were 10% (45 microg; not significant), 30% (90 microg; P = .009), 36% (180 microg; P = .0006), and 29% (270 microg; P = .004), compared with 3% for the 3-times-weekly 3-MIU IFN alpha-2a regimen. The types and frequencies of adverse events and laboratory abnormalities were similar among all groups. In conclusion, once-weekly PEG(40kd) IFN alpha-2a was associated with a higher number of sustained virological responses compared with IFN alpha-2a 3 times weekly in patients with CHC, but had a similar safety profile. The 180-microg PEG(40kd) IFN alpha-2a dose appeared to be the optimal dose based on sustained virological response and its associated side-effect profile.
• Aweeka, F. T., Gottwald, M. D., Gambertoglio, J. G., Wright, T. L., Boyer, T. D., Pollock, A. S., Eldon, M. A., Kugler, A. R., & Alldredge, B. K. (1999). Pharmacokinetics of fosphenytoin in patients with hepatic or renal disease. Epilepsia, 40(6), 777-82.
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  The pharmacokinetic behavior of fosphenytoin (FOS), the water-soluble prodrug of phenytoin (PHT), has been characterized in normal subjects. This is the first study of the effect of hepatic or renal disease on the rate and extent of conversion of FOS to PHT.
• Branum, G. D., Selim, N., Liu, X., Whalen, R., & Boyer, T. D. (1998). Ischaemia and reperfusion injury of rat liver increases expression of glutathione S-transferase A1/A2 in zone 3 of the hepatic lobule. The Biochemical journal, 330 ( Pt 1), 73-9.
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  Effects of ischaemia-reperfusion injury (I/R) of liver on expression of rat glutathione S-transferase (rGST) isoenzymes that metabolize products of oxidative stress were examined. Rats underwent lobar liver ischaemia for 30 min followed by reperfusion. In ischaemic lobes, rGSTA1/A2 transcript levels increased significantly 12 h after I/R (2.94-fold) and protein levels increased significantly at 24 h (1.45-fold); increased transcript levels were also observed in nonischaemic lobes (1.78-fold). Superoxide dismutase prevented I/R and the increases in transcript and protein levels in ischaemic and non-ischaemic lobes. By in-situ hybridization, increases in transcript levels at 6 h were present in zones 2 and 3 of the ischaemic lobes and peaked at 12 h (2.5-fold zone 2, 4.5-fold zone 3). Significant increases in transcript levels also were observed at 24 h in zones 2 (2.0-fold) and 3 (2.9-fold) of non-ischaemic lobes. Nuclear run-off assays showed a 1.8-fold increase in rGSTA1/A2 transcription rates in ischaemic lobes at 3 h. We conclude that I/R causes increased rGSTA1/A2 expression in the zone of the hepatic lobule most susceptible to oxidative injury and that this expression may be an important defence against injury.
• Fried, M. W., Khudyakov, Y. E., Smallwood, G. A., Cong, M., Nichols, B., Diaz, E., Siefert, P., Gutekunst, K., Gordon, R. D., Boyer, T. D., & Fields, H. A. (1997). Hepatitis G virus co-infection in liver transplantation recipients with chronic hepatitis C and nonviral chronic liver disease. Hepatology (Baltimore, Md.), 25(5), 1271-5.
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  Hepatitis G virus (HGV) is a newly described RNA virus that is parenterally transmitted and has been found frequently in patients with chronic hepatitis C infection. To determine the impact of hepatitis G virus co-infection on morbidity and mortality following liver transplantation, we measured HGV RNA by polymerase chain reaction in pre and posttransplantation sera from a cohort of patients transplanted for chronic hepatitis C and a control group of patients transplanted for nonviral causes who were negative for hepatitis C virus (HCV) RNA in serum. The overall prevalence rate of HGV RNA in transplanted patients with chronic hepatitis C was 20.7%. HGV infection was present before transplantation in 13% while it appeared to have been acquired at the time of transplantation in 7.4%. Mean serum alanine aminotransferase activity, hepatic histological activity, and patient and graft survival were similar between HGV-positive and HGV-negative patients. The prevalence rate of HGV RNA in transplanted controls was 64% (P < .01) with a significantly higher rate of acquisition of HGV infection following transplantation (53%, P < .001) when compared with patients with chronic hepatitis C. Mean serum alanine aminotransferase activity was significantly lower in the control patients with HGV infection alone following transplantation than in patients co-infected with hepatitis C (37 +/- 9 vs. 70 +/- 33 U/L, P < .01). Thus, HGV is frequently found in transplantation patients co-infected with hepatitis C although it appears to have minimal clinical impact. In patients transplanted for nonviral causes of end-stage liver disease, a high rate of hepatitis G acquisition at the time of transplantation may occur but does not appear to predispose to chronic hepatitis.
• Fried, M. W., Connaghan, D. G., Sharma, S., Martin, L. G., Devine, S., Holland, K., Zuckerman, A., Kaufman, S., Wingard, J., & Boyer, T. D. (1996). Transjugular intrahepatic portosystemic shunt for the management of severe venoocclusive disease following bone marrow transplantation. Hepatology (Baltimore, Md.), 24(3), 588-91.
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  Hepatic venoocclusive disease (VOD) is a common, life-threatening complication of bone marrow transplantation (BMT). Portal hypertension is usually present and accounts for many of the clinical manifestations of this syndrome. We describe the results of transjugular intrahepatic portosystemic shunt (TIPS) for the management of VOD after BMT TIPS was performed in six patients with histologically confirmed VOD who had progressive jaundice and ascites. Portal hypertension was improved by TIPS in all patients (mean portal pressure gradient before TIPS, 20.2 +/- 4.6 vs. 6.7 +/- 1.9 mm Hg post-TIPS, P < .004). Three patients who underwent TIPS late in the course of VOD did not demonstrate any clinical improvement after TIPS and expired within 2 weeks of the procedure. The remaining three patients had less advanced disease and demonstrated decreases in serum bilirubin, improvement in coagulopathy, and decreased ascites after TIPS. Two patients subsequently expired, one with persistent histological changes of VOD. The lone survivor continues to do well with resolution of ascites, jaundice, and coagulopathy as of her last outpatient visit. TIPS was an effective method for portal decompression in patients with VOD after BMT, and was associated with clinical improvement in some patients. However, these effects may be transient and may not improve overall survival.
• Vessey, D. A., Lee, K. H., & Boyer, T. D. (1995). Differentiation-induced enhancement of the ability of cultured human keratinocytes to suppress oxidative stress. The Journal of investigative dermatology, 104(3), 355-8.
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  Human keratinocytes in culture were harvested at different stages of differentiation. Both the level of antioxidants and the response of cells to oxidative stress were measured as a function of growth and differentiation. As the keratinocyte cultures became confluent and began to differentiate, the cellular levels of glutathione, glutathione peroxidase, glutathione S transferase, and glucose-6-phosphate dehydrogenase increased. This higher level of antioxidants was maintained until the cells began to lose viability. Further, as the keratinocyte cultures began to differentiate, they became more resistant to the toxic effect of cumene hydroperoxide in terms of both of the rate of loss of cell mass and total glutathione and of the rate of decline in the activity of oxidation-sensitive enzymes. To determine how tightly the observed effects are linked to the calcium-dependent aspects of differentiation and to rule out effects related to time in culture, the cells were switched from 1.2 mM Ca++ to 0.03 mM Ca++ to suppress Ca(++)-dependent differentiation. After 4 d, these cells were then treated with 0.5 mM cumene hydroperoxide. The switch to 0.03 mM Ca++ blocked the normal increases in both glutathione peroxidase and glucose-6-phosphate dehydrogenase activities. Further, cells in 0.03 mM Ca++ had reduced resistance to cumene hydroperoxide relative to cells cultured for the same length of time in 1.2 mM Ca++. This indicates that there is a differentiation-associated, Ca(++)-specific increase in both the level of antioxidants and in tolerance to organic hydroperoxides.
• Greenstein, D., Henderson, J. M., & Boyer, T. D. (1994). Liver hemorrhage: recurrent episodes during pregnancy complicated by preeclampsia. Gastroenterology, 106(6), 1668-71.
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  Intrahepatic hemorrhage with rupture is the most serious and potentially life-threatening liver complication of pregnancy. With improved management, more patients are surviving this complication, and therefore, a number of patients are at risk of a recurrence should they again become pregnant. This case describes a patient who suffered two episodes of intrahepatic hemorrhage in two different pregnancies. Each episode was associated with mild preeclampsia. The first hemorrhage was limited by the liver capsule and treated conservatively, whereas with the second hemorrhage, the subcapsular hematoma ruptured, requiring arterial embolization followed by surgery. An arteriogram performed during the second episode of hemorrhage showed numerous pseudoaneurysms in the area of bleeding, suggesting that a vasculopathy plays a primary role in the pathogenesis of the intrahepatic hemorrhage associated with pregnancy. This case shows that intrahepatic hemorrhage may recur with future pregnancies, and individuals who suffer this complication of pregnancy and again become pregnant should be carefully monitored for the development of preeclampsia.
• Kurz, M. A., Boyer, T. D., Whalen, R., Peterson, T. E., & Harrison, D. G. (1993). Nitroglycerin metabolism in vascular tissue: role of glutathione S-transferases and relationship between NO. and NO2- formation. The Biochemical journal, 292 ( Pt 2), 545-50.
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  Nitroglycerin is a commonly employed pharmacological agent which produces vasodilatation by release of nitric oxide (NO.). The mechanism by which nitroglycerin releases NO. remains undefined. Recently, glutathione S-transferases have been implicated as important contributors to this process. They are known to release NO2- from nitroglycerin, but have not been shown to release NO.. The present studies were designed to examine the role of endogenous glutathione S-transferases in this metabolic process. Homogenates of dog carotid artery were incubated anaerobically with nitroglycerin, and NO. and NO2- production was determined by chemiluminescence. The role of glutathione S-transferases was studied by incubating homogenates with nitroglycerin in the presence of 1 mM GSH or 1 mM S-hexyl-glutathione, a potent inhibitor of glutathione S-transferases. Homogenates released 163 pmol of NO./h per mg of protein from nitroglycerin, and 2370 pmol of NO2-/h per mg. Adding GSH decreased NO. production by 82% and increased NO2- production by 98%. S-Hexylglutathione inhibited glutathione S-transferase activity by 96% and decreased NO2- production by 78%, but had no effect on NO. release. A linear relationship between glutathione S-transferase activity and NO2- production was observed, whereas glutathione S-transferase activity and NO. release were unrelated. Western-blot analysis demonstrated that dog carotid vascular smooth muscle contained Pi and Mu forms of glutathione S-transferases, with a predominance of the former. Purified preparations of human Pi and rat Mu isoforms metabolized nitroglycerin only to NO2- and not to NO.. On the basis of these findings, we conclude that (1) glutathione S-transferases do not contribute to the bioconversion of nitroglycerin to NO., but instead act as a degradative pathway for nitroglycerin, and (2) the release of NO. from nitroglycerin is not dependent on the formation of NO2-.
• Henderson, J. M., Gilmore, G. T., Hooks, M. A., Galloway, J. R., Dodson, T. F., Hood, M. M., Kutner, M. H., & Boyer, T. D. (1992). Selective shunt in the management of variceal bleeding in the era of liver transplantation. Annals of surgery, 216(3), 248-54; discussion 254-5.
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  This study reports the Emory experience with 147 distal splenorenal shunts (DSRS) and 110 orthotopic liver transplants (OLT) between January 1987 and December 1991. The purpose was to clarify which patients with variceal bleeding should be treated by DSRS versus OLT. Distal splenorenal shunts were selected for patients with adequate or good liver function. Orthotopic liver transplant was offered to patients with end-stage liver disease who fulfilled other selection criteria. The DSRS group comprised 71 Child's A, 70 Child's B, and 6 Child's C patients. The mean galactose elimination capacity for all DSRS patients was 330 +/- 98 mg/minute, which was significantly (p less than 0.01) above the galactose elimination capacity of 237 +/- 82 mg/minute in the OLT group. Survival analysis for the DSRS group showed 91% 1-year and 77% 3-year survival, which was better than the 74% 1-year and 60% 3-year survivals in the OLT group. Variceal bleeding as a major component of end-stage disease leading to OLT had significantly (p less than 0.05) poorer survival (50%) at 1 year compared with patients without variceal bleeding (80%). Hepatic function was maintained after DSRS, as measured by serum albumin and prothrombin time, but galactose elimination capacity decreased significantly (p less than 0.05) to 298 +/- 97 mg/minute. Quality of life, measured by a self-assessment questionnaire, was not significantly different in the DSRS and OLT groups. Hospital charges were significantly higher for OLT (median, $113,733) compared with DSRS ($32,674). These data support a role for selective shunt in the management of patients with variceal bleeding who require surgery and have good hepatic function. Transplantation should be reserved for patients with end-stage liver disease. A thorough evaluation, including tests of liver function, help in selection of the most appropriate therapeutic approach.
• Blacker, K. L., Olson, E., Vessey, D. A., & Boyer, T. D. (1991). Characterization of glutathione S-transferase in cultured human keratinocytes. The Journal of investigative dermatology, 97(3), 442-6.
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  The glutathione S-transferase activity and isozymic composition of cultured human keratinocytes were characterized. Keratinocytes were grown in culture and harvested at different stages of differentiation. Glutathione S-transferase activity was found in the soluble cell fraction but not in the microsomal cell fraction. The glutathione S-transferase specific activity of the soluble cell fraction was found to increase as the keratinocytes differentiated in culture. All of the enzymatic activity was found to reside with a single isozymic form that was concluded to be the pi form of the enzyme based on substrate specificity, sensitivity to inhibitors, molecular weight, and reactivity towards antibodies raised to alpha, mu, and pi forms of the enzyme. It is concluded that all of the isozymic forms of glutathione S-transferase noted in whole skin, with the exception of pi, are of extra-keratinocyte origin.
• Vessey, D. A., & Boyer, T. D. (1988). Characterization of the activation of rat liver glutathione S-transferases by nonsubstrate ligands. Toxicology and applied pharmacology, 93(2), 275-80.
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  In previous work (D.A. Vessey and T.D. Boyer, 1986, Biochem. Pharmacol., 35, 289-295) the activity of glutathione S-transferase form YcYc from rat liver was found to be stimulated by the herbicide 2,4,5-T. We have extended that work and examined the effect of over 40 structural analogs on the activity of YcYc. Over half of these compounds stimulated by 10 to 232% when added to assays at a concentration of 1 mM. The best activators all contained the "2,4,5-trichlorophenyl-" structure. While 2,4,5-T gave the greatest activation at 1 mM (2.3-fold), 2,4,5-trichlorobenzene sulfonate gave the greatest maximum activation (6.0-fold). Compounds that had no effect on activity did not affect activation by 2,4,5-T suggesting that they have a poor affinity for the enzyme. Two of the analogs tested (chloramine-T and 6-hydroxydopamine) proved to be good inhibitors and ethacrynic acid was an extremely potent inhibitor. Indomethacin activated at low concentrations but inhibited above 2 mM. Activations were greater at low temperature (5 degrees C) and decreased with increasing temperature. The extent of activation was largely unaffected by the concentration of either substrate. Examination of the organic peroxidase activity of the enzyme revealed inhibition by 2,4,5-T and 2,4-D rather than activation.
• Lindwall, G., & Boyer, T. D. (1987). Excretion of glutathione conjugates by primary cultured rat hepatocytes. The Journal of biological chemistry, 262(11), 5151-8.
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  Conjugation of xenobiotics with glutathione occurs commonly within the liver, and these glutathione conjugates are then preferentially excreted into bile. We have characterized this excretory process using primary cultured hepatocytes (24 h). 1-Chloro-2,4-dinitrobenzene rapidly entered the cells and formed a glutathione conjugate, S-(dinitrophenyl)glutathione, irrespective of the temperature of incubation. In contrast, the efflux of the glutathione conjugate was essentially absent in the cold but recovered rapidly upon rewarming of the cells. Therefore, initial rates of efflux of the conjugate at 37 degrees C were measured from cells preloaded biosynthetically at 10 degrees C. Efflux was a saturable process with respect to intracellular S-(dinitrophenyl)glutathione with an apparent Km of 0.58 +/- 0.12 mM and Vmax of 0.15 +/- 0.05 nmol/min/mg of protein. The excretion of S-(dinitrophenyl)glutathione had an energy of activation of 15.3 kcal/mol. The glutathione conjugate of p-nitrobenzylchloride when formed within the hepatocytes acted as a competitive inhibitor of S-(dinitrophenyl)glutathione efflux. Cultured hepatocytes, therefore, appeared to have a specific transport process for the excretion of glutathione conjugates. The addition of S-(dinitrophenyl)glutathione, but not GSH, GSSG, or methionine, to the medium caused a decrease in the rate of efflux of radiolabeled S-(dinitrophenyl)glutathione. The hepatocytes were able, however, to excrete the glutathione conjugate against an excess of extracellular S-(dinitrophenyl)glutathione. This observation suggested that extracellular S-(dinitrophenyl)glutathione, although capable of binding to the carrier, entered the hepatocytes quite slowly relative to rates of efflux. This carrier may function in a manner that would minimize the reuptake by hepatocytes of conjugates that have been excreted into the bile.
• Goldman, I. S., Winkler, M. L., Raper, S. E., Barker, M. E., Keung, E., Goldberg, H. I., & Boyer, T. D. (1985). Increased hepatic density and phospholipidosis due to amiodarone. AJR. American journal of roentgenology, 144(3), 541-6.
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  Amiodarone is an amphiphilic iodinated compound that is used as a treatment for refractory ventricular arrhythmias. During evaluation for possible pulmonary toxicity, a patient receiving amiodarone was noted to have an increase in the density of his liver as seen on computed tomographic (CT) scanning of the abdomen. Six additional patients who were receiving amiodarone were subsequently evaluated to ascertain the frequency of this finding. The CT density of the liver was increased in all patients. Values obtained varied from 95 to 145 H, with a mean of 117 +/- 8.9 (normal, 30-70). The alkaline phosphatase was elevated in four patients, but only one had an elevation of either the alanine or aspartate aminotransferase. Two patients underwent liver biopsies, and both revealed membranous lamellar phospholipid-containing structures within hepatocytes. Animal studies done to recreate these findings revealed that amiodarone accumulated in the liver at concentrations 175-500 times greater than those found in serum. Quantitative measurements of iodine in samples from the same liver showed that the iodine levels were correspondingly elevated. In the treated animals, there was a small but statistically significant increase in the CT density of the liver, whereas the values for untreated animals were unchanged. Treatment with amiodarone leads to an accumulation in the liver of this iodinated compound and hence an increase in the CT density of the liver. This accumulation of the drug in hepatic lysosomes apparently causes a secondary phospholipidosis.
• Vessey, D. A., & Boyer, T. D. (1984). Differential activation and inhibition of different forms of rat liver glutathione S-transferase by the herbicides 2,4-dichlorophenoxyacetate (2,4-D) and 2,4,5-trichlorophenoxyacetate (2,4,5-T). Toxicology and applied pharmacology, 73(3), 492-9.
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  The predominant forms of the dimeric enzyme glutathione S-transferase were purified from rat liver. Forms YbY'b and YbYb (also known as forms C and A, respectively) could be almost completely inhibited by 2,4-dichlorophenoxyacetate (2,4-D). Half-maximal inhibition was obtained at 0.5 mM 2,4-D. Inhibition was seen even at extrapolated infinite concentrations of both substrates for YbYb but not YbY'b. These same forms could also be inhibited 70 to 80% by 2,4,5-trichlorophenoxyacetate (2,4,5-T) with half maximal inhibition occurring at 0.2 mM. Glutathione S-transferase form YaYa was maximally inhibited by 72 and 30%, respectively, by 2,4-D and 2,4,5-T. The 30% inhibition of YaYa caused by 2,4,5-T was shown to reduce the nearly complete inhibition caused by a previously characterized inhibitor, namely bile acids. This suggests competition for a common binding site on the enzyme. In contrast to the above results, it was found that form YcYc (also termed AA) was activated 2.7-fold by 2,4,5-T and 1.4-fold by 2,4-D. This activation could be blocked by chenodeoxycholate which, by itself, did not affect the activity of the enzyme. The effects of 2,4,5-T and 2,4-D on the heterodimer YaYc (also termed form B) were intermediate between their effects on YaYa and YcYc, suggesting that each subunit contributes its unique property to the heterodimer. The microsomal membrane-bound form of glutathione S-transferase was also examined and found to be inhibited by both 2,4-D and 2,4,5-T. However, unlike the inhibitions of soluble forms, 2,4,5-T caused more extensive inhibition than 2,4-D.(ABSTRACT TRUNCATED AT 250 WORDS)