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L-l-13C phenylalanine breath test reflects phenylalanine hydroxylase activity of the whole liver
clinical profile may affect the cause of death in HCC patients according to the difference of HBV or HCV refection, (Method) We analyzed 1768 consecutively-enrolled HCC patients between 1997 and 2002, 749 patients died during the period. Of these patients, 105 patients were excluded fi'om the analysis because the causes of death were gastrointestinal hemorrhage and other causes of death (infection, cerebral hemorrhage, etc). 644 patients comprised of 123 patients with HBV-related HCC and 521 patients with HCW~related HCC. Death of cancer is defined as follows: tntal tumor volume is more than 50% of liver volume or macroscopic portal vein invasion or intraperitoneal rupture of tumor. Of the 644 patients, 522 patients (70%) died of cancer, 122 patients (16%) died of hepatic failure. We analyzed base-fine variables of patients affecting the cause of death. (Result) Clinical profile of HBVrelated HCC showed that the size of tumor was large (mean=61mm) and the portal vein invasion (PVI) was frequent (51%) in contrast to HCV-related HCC. (mean size=42mm, P~/1=24%, each P<0.001) Univariate analysis indicated that the factors contributing to HBV-related patient deaths were tumor size, portal vein invasion and platelet count (each P<0.01). The factors contributing to HCV-related patient deaths were tumor size, serum albumin, total bflirubin, platelet count, age of the patients and portal vein invasion (P<0.01) by univariate analysis. Multivariate logistic regression analysis revealed that tumor size (P<0.01), baseline total bflirubin (P=0.03) and albumiu level (P=0.04) were found to contribute to HCV-related patient deaths. (Conchision) In patients with HCV-related HCC, tumor size and the condition of underlying liver disease (bilirubin, albumin) at the detection of HCC were the major factors contributing to the cause of death. On the other band, advanced tumor stage, such as portal vein invasmn, contributed to the cause of death in patients with HBV-refated HCC These data may reflect the diflerence of base-line tumor features between HCV-rdated FICC and HBu HCC.
M1416
Impact of Diabetes on Chronic Hepatitis C Furqaan Ahmed, P W. Canchis, Andrew H Talal, Lydia M. Petrovic, Ira M. Jacohson Background: Data from the NtL4NES IIl trial has suggested that type 2 diabetes (DM) is more prevalent in patients with chronic hepatitis C (Ann Imem Med. 2000;133:592-9). We sought to describe clinical features of patients with chronic hepatitis C (CHC) and DM and to determine the impact of DM on the natural history of CHC and its tream:tent. Methods: We performed a retrospective case control study of 60 patients with CHC and DM and 60 controls with HCV alone who were matched for age, gender, race, genotype, and treatment status. Comparisons were made of BM1, liver histology', ffl~rosis progression rates, and response to antiwral therapy. We also assessed the effect of antiviral therapy on DM managemerit. Resuhs: Mtbough there were more overweight patients (BM1 -> 25) in the CHC and DM group (83% vs 53%, p=0.02), the average BMI was smiilar in the 2 groups (28.3 vs. 26k, p = 0.09) Forlymine of Ihe diabetics and 53 controls l~ad liver biopsy. Patients with CHC and DM were more fikely to have advanced fibrosis on liver biopsy (Metavir stage 3&4) fhan controls (61% vs. 28%, p = 0.04). Steatosis was also more common in the CHC and DM group when compared wifi~ controls (65% vs. 40%, p = 0.8) although this difference was riot statistically significant The severity ot steatosis was similar in both groups. Of the 79 patients with a knmvn estimated duration of intectiou, CHC and DM patients had significantly" higher overall fibrosis progression rates than controls (0.142 fu/}r • vs. 0.078 tgeyr • 0047, p = 00001). Even in the absence of steatnsis, patients with CHC and DM had higher fibrosis progression rates than patients without DM (0126• vs. 0.067 • 0035, p = 001 ). CHC and DM patients bad lower overall SVR rates to CHC treatment than controls (14% vs 32%, p = 049) although this difference disappeared when response rates to PEGIFN/RBV were looked at alone (33% vs 31%). While on CHC treatment, 37% (13/35) of CHC and DM patients required changes in their DM management. These changes included new diagnosis of DM (n = 3), the addition of a new m'al hypoglycemic agent (OHA; n = 3 ) , an increase in OHA or insulin dose (n= 5), and change from OHA to insulin while on therapy (n=2). Conclusions: (1) Patients with CHC and DM are heavier than those without DM. (2) Patients with DM have more steatosis and significantly more fibrosis on liver biopsy when compared with controls. (3) Patients with DM have significantly higher fibrosis progression rates even in the absence of steatosis (4) Changes in DM management whde on CHC treatment are common (5) Further studies on this population are warranted.
M1419 L - l q 3 C phenylalanine breath test reflects phenylalanine hydroxylase activity of the whole liver Yukimoto lshii, Shigeru Suzuki, Tomohisa Kohno, Masaru Aoki, Tadatoshi Takayama, Satoshi Asai Object: The purpose of this study was to perform L-I-13C phenyfalainne breath test (PBT), measure phenylalanine hydroxylase (PAH) activity in liver tissue biopsies from patients, analyze the relationship between PBT results and PAH activity, and determine the timepoint at which measurements best reflect PAH activity in liver tissue. Methods: PBT was performed in 25 patients ( 10 with a normal liver and 15 with liver cirrhosis), Atter administering 10 mg/kg DI-13C phenylalamne, 300 ml expired air was collected over 90 minutes at 15-minute intervals. The rate of hepatic phenylafanine oxidation (%13C dose/h) at each time point was calculated fiom the amount of 13CO2 in the breath, assuming a CO2 production rate of 300 mmol m d body surface area per hour. Subsequently, we examined the relationship between the results of PBT and PAH activity, Results: PAH activity of the whole liver was significantly decreased in hepatic cirrhosis patients (P<0.05). The results of PBT % 13C dose/h correlated with the PAH activity/hver, with correlation coefficients at 30, 45 and 60 minutes of morn than 0,7, and the maximum correlation was at 30 minutes (r=0.82I, P<0.O001). %13C cumulative excretion correlated with the PAH activityAiver with correlation coefficients of more than 0.7, after 45 minutes, The maximum correlation was at 90 minutes (r=0.770, P=0.001). Conclusion: PBT values reflect PAH activity in the whole fiver and, in particular, the %13C dose/tl at 30 rain after oral administration highly correlates with PAH activity, provnling an important indicator lbr monitoring changes in whole live PAH acti~ity.
M1417
En~hropoietic Response to Anemia is Decreased in Patients Infected With Hepatitis C Virus (HCV) Receiving Combination Ribavirin and Pegylated Interferon (RBV~EG-IFN) Therapy Vilayan Bafan, George Y Wu, Andrew J Muir, Emmet B. Keeffe, Peter J. Bowers background: Studies in anemic patients (pts) with cancer and HIV infection show that the inverse relationship between serum erytbmpoietin (sEPO) and hemoglobin (Hb) seen in control pts wifh iron deficiency anemia (IDA) is decreased, suggesting that these pts have a blunted erythropoietie response (Spivak et al, JAMA 1989; Miller et al, NEjM 1990). The present study was conducted to describe the patterns of change in Hb, sEPO, and reticulocytes (reties) to evaluate if HCV-int~'cted pts treated with RBV~EGdFN therapy (tx) also show a diminished eryfnropoietie response to anemia. Historic control pts with IDA were used as a comparator. Methods: A muhicenter, observational, &week (wk) study is being conducted in 100 HCVqntected pts scheduled to receive their initial course of RBV/PEG-1FN ix. Laboratory" parameters are"measured weekly tot 8 wks or until earl}, withdrawal (endpoint). Primary variables include changes in Fib, sEPO, and retics. Interim results are presented. Results: The interim analysis included 65 pts (mean age, 46.9 yrs; 373% men). Mean Hb decreased by" 2.7 • 1.4 g/dL from Day 1 (D1) to endpoint. Mean sEPO and retics increased from D1 to endpoint; however, regression amllysis showed that the estimated erythmpoietie response (defined as the slope of the relation between sEPO and Hb) was lower (sEPO = I 8 3 Hb + 264 [r = -0.51/) than in historic control pts with IDA (sEPO = -25.8 Hb + 316 [r = -0.90], sEPO = -45.0 Hb + 518 {r = -0.71D. The mean initial dose of RBV was 982 rag/day versus 906 rag/day at endpoint. A total of 9.2%, 92% and 1.5% of pts find 200, 4 0 0 and 600 mg/&~y RBV dose reductinns, respectively, from D1 and at Wk 8. There was no change in mean PEG-IFN doses from D1 (1.54 mcg/kg) to Wk 8 (1.49 mcg/ kg). There were 7 pt withdrawals due to side effects of HCA: ix. Conclusion: Simifar to other pt groups, HCV-infected pts treated with RBV/PEGdFN showed diminished production of endogenous sEPO fur their degree of anemia when compared with historic control pts with IDA. These data point to a muhifactorial etiology" fbr the anemia seen with combination HCV ix, which, as shown hi preliminary studies (Dieterich et al, AASLD 2002; Sulkowski et aI, &r 2001), could be responsive to treatment with recombinant human erythropoietin (rHuEPO),
m lib (g/dL) 14.5 1.4 sEPO (mlU/mL) 10,7 5,0 Me.reties(%) 1,3 0,9 * Data on pts who completed 8 wks,
v~8 118 13 46=6 45.0 Z4 1A
c~p
M1420 Splenic Size Correlates with Degree of Liver Fibrosis in HCV Infected Patients Edward j. Barharito, lnthu Surendran, Joan Skumiek, Jerome Levine, George Nikias OBJECTDT: Liver biopsy remains the gold standard for the assessment of disease severity in patients with chronic H O / infection, but is associated with sampling error, risk of complications and patient discomfort. Noninvasive serologic markers of liver fibrosis are under investigation, but no single test has been proven sufficiently accurate for routine clinical use. The aim of this study was to determine whether splenic enlargement is associated with fibrosis progression in patients with chronic HCV infection. METHODS: We retmspectB,'ely studied patients with chronic HCV infection evaluated at our facility from 1999 to 2002. Ultrasonographicafly determined maximal cranio
fromt~ tolt~,8 -2,7 1.4 37,0 '- 44.4 1,1 1A
M1418 The Causes of Mortality in Patients with Hepatocellular Carcinoma Are Different Between Hepatitis B Virus*Related and Hepatitis C Virus-Related Hcc Yoshiyuki gobayashi Nnbupaki Toshikuin, Shiniehiro Nakamura, Eiji Matsumoto, Hironori Tanaka Kazuhiro Nouso, Kohsaku Sakaguchi, Yasushi Shiratori, Yasuyuki Ar'aki, Hiroshi Ikeda, Mitsuhiko Kawaguchi, Haruhiko Kobashi (Background) Hepatocdlular carcinoma (HCC) occurs in patients with chronic liver diseases of HBV and HCV infecnon There are two mafor causes of death in patients with HCC: tumor expansion and liver failure. The aim of this study is to evaluate whether base-line
A-751
AASLD Abstracts
M1416
Impact of Diabetes on Chronic Hepatitis C Furqaan Ahmed, P W. Canchis, Andrew H Talal, Lydia M. Petrovic, Ira M. Jacohson Background: Data from the NtL4NES IIl trial has suggested that type 2 diabetes (DM) is more prevalent in patients with chronic hepatitis C (Ann Imem Med. 2000;133:592-9). We sought to describe clinical features of patients with chronic hepatitis C (CHC) and DM and to determine the impact of DM on the natural history of CHC and its tream:tent. Methods: We performed a retrospective case control study of 60 patients with CHC and DM and 60 controls with HCV alone who were matched for age, gender, race, genotype, and treatment status. Comparisons were made of BM1, liver histology', ffl~rosis progression rates, and response to antiwral therapy. We also assessed the effect of antiviral therapy on DM managemerit. Resuhs: Mtbough there were more overweight patients (BM1 -> 25) in the CHC and DM group (83% vs 53%, p=0.02), the average BMI was smiilar in the 2 groups (28.3 vs. 26k, p = 0.09) Forlymine of Ihe diabetics and 53 controls l~ad liver biopsy. Patients with CHC and DM were more fikely to have advanced fibrosis on liver biopsy (Metavir stage 3&4) fhan controls (61% vs. 28%, p = 0.04). Steatosis was also more common in the CHC and DM group when compared wifi~ controls (65% vs. 40%, p = 0.8) although this difference was riot statistically significant The severity ot steatosis was similar in both groups. Of the 79 patients with a knmvn estimated duration of intectiou, CHC and DM patients had significantly" higher overall fibrosis progression rates than controls (0.142 fu/}r • vs. 0.078 tgeyr • 0047, p = 00001). Even in the absence of steatnsis, patients with CHC and DM had higher fibrosis progression rates than patients without DM (0126• vs. 0.067 • 0035, p = 001 ). CHC and DM patients bad lower overall SVR rates to CHC treatment than controls (14% vs 32%, p = 049) although this difference disappeared when response rates to PEGIFN/RBV were looked at alone (33% vs 31%). While on CHC treatment, 37% (13/35) of CHC and DM patients required changes in their DM management. These changes included new diagnosis of DM (n = 3), the addition of a new m'al hypoglycemic agent (OHA; n = 3 ) , an increase in OHA or insulin dose (n= 5), and change from OHA to insulin while on therapy (n=2). Conclusions: (1) Patients with CHC and DM are heavier than those without DM. (2) Patients with DM have more steatosis and significantly more fibrosis on liver biopsy when compared with controls. (3) Patients with DM have significantly higher fibrosis progression rates even in the absence of steatosis (4) Changes in DM management whde on CHC treatment are common (5) Further studies on this population are warranted.
M1419 L - l q 3 C phenylalanine breath test reflects phenylalanine hydroxylase activity of the whole liver Yukimoto lshii, Shigeru Suzuki, Tomohisa Kohno, Masaru Aoki, Tadatoshi Takayama, Satoshi Asai Object: The purpose of this study was to perform L-I-13C phenyfalainne breath test (PBT), measure phenylalanine hydroxylase (PAH) activity in liver tissue biopsies from patients, analyze the relationship between PBT results and PAH activity, and determine the timepoint at which measurements best reflect PAH activity in liver tissue. Methods: PBT was performed in 25 patients ( 10 with a normal liver and 15 with liver cirrhosis), Atter administering 10 mg/kg DI-13C phenylalamne, 300 ml expired air was collected over 90 minutes at 15-minute intervals. The rate of hepatic phenylafanine oxidation (%13C dose/h) at each time point was calculated fiom the amount of 13CO2 in the breath, assuming a CO2 production rate of 300 mmol m d body surface area per hour. Subsequently, we examined the relationship between the results of PBT and PAH activity, Results: PAH activity of the whole liver was significantly decreased in hepatic cirrhosis patients (P<0.05). The results of PBT % 13C dose/h correlated with the PAH activity/hver, with correlation coefficients at 30, 45 and 60 minutes of morn than 0,7, and the maximum correlation was at 30 minutes (r=0.82I, P<0.O001). %13C cumulative excretion correlated with the PAH activityAiver with correlation coefficients of more than 0.7, after 45 minutes, The maximum correlation was at 90 minutes (r=0.770, P=0.001). Conclusion: PBT values reflect PAH activity in the whole fiver and, in particular, the %13C dose/tl at 30 rain after oral administration highly correlates with PAH activity, provnling an important indicator lbr monitoring changes in whole live PAH acti~ity.
M1417
En~hropoietic Response to Anemia is Decreased in Patients Infected With Hepatitis C Virus (HCV) Receiving Combination Ribavirin and Pegylated Interferon (RBV~EG-IFN) Therapy Vilayan Bafan, George Y Wu, Andrew J Muir, Emmet B. Keeffe, Peter J. Bowers background: Studies in anemic patients (pts) with cancer and HIV infection show that the inverse relationship between serum erytbmpoietin (sEPO) and hemoglobin (Hb) seen in control pts wifh iron deficiency anemia (IDA) is decreased, suggesting that these pts have a blunted erythropoietie response (Spivak et al, JAMA 1989; Miller et al, NEjM 1990). The present study was conducted to describe the patterns of change in Hb, sEPO, and reticulocytes (reties) to evaluate if HCV-int~'cted pts treated with RBV~EGdFN therapy (tx) also show a diminished eryfnropoietie response to anemia. Historic control pts with IDA were used as a comparator. Methods: A muhicenter, observational, &week (wk) study is being conducted in 100 HCVqntected pts scheduled to receive their initial course of RBV/PEG-1FN ix. Laboratory" parameters are"measured weekly tot 8 wks or until earl}, withdrawal (endpoint). Primary variables include changes in Fib, sEPO, and retics. Interim results are presented. Results: The interim analysis included 65 pts (mean age, 46.9 yrs; 373% men). Mean Hb decreased by" 2.7 • 1.4 g/dL from Day 1 (D1) to endpoint. Mean sEPO and retics increased from D1 to endpoint; however, regression amllysis showed that the estimated erythmpoietie response (defined as the slope of the relation between sEPO and Hb) was lower (sEPO = I 8 3 Hb + 264 [r = -0.51/) than in historic control pts with IDA (sEPO = -25.8 Hb + 316 [r = -0.90], sEPO = -45.0 Hb + 518 {r = -0.71D. The mean initial dose of RBV was 982 rag/day versus 906 rag/day at endpoint. A total of 9.2%, 92% and 1.5% of pts find 200, 4 0 0 and 600 mg/&~y RBV dose reductinns, respectively, from D1 and at Wk 8. There was no change in mean PEG-IFN doses from D1 (1.54 mcg/kg) to Wk 8 (1.49 mcg/ kg). There were 7 pt withdrawals due to side effects of HCA: ix. Conclusion: Simifar to other pt groups, HCV-infected pts treated with RBV/PEGdFN showed diminished production of endogenous sEPO fur their degree of anemia when compared with historic control pts with IDA. These data point to a muhifactorial etiology" fbr the anemia seen with combination HCV ix, which, as shown hi preliminary studies (Dieterich et al, AASLD 2002; Sulkowski et aI, &r 2001), could be responsive to treatment with recombinant human erythropoietin (rHuEPO),
m lib (g/dL) 14.5 1.4 sEPO (mlU/mL) 10,7 5,0 Me.reties(%) 1,3 0,9 * Data on pts who completed 8 wks,
v~8 118 13 46=6 45.0 Z4 1A
c~p
M1420 Splenic Size Correlates with Degree of Liver Fibrosis in HCV Infected Patients Edward j. Barharito, lnthu Surendran, Joan Skumiek, Jerome Levine, George Nikias OBJECTDT: Liver biopsy remains the gold standard for the assessment of disease severity in patients with chronic H O / infection, but is associated with sampling error, risk of complications and patient discomfort. Noninvasive serologic markers of liver fibrosis are under investigation, but no single test has been proven sufficiently accurate for routine clinical use. The aim of this study was to determine whether splenic enlargement is associated with fibrosis progression in patients with chronic HCV infection. METHODS: We retmspectB,'ely studied patients with chronic HCV infection evaluated at our facility from 1999 to 2002. Ultrasonographicafly determined maximal cranio
fromt~ tolt~,8 -2,7 1.4 37,0 '- 44.4 1,1 1A
M1418 The Causes of Mortality in Patients with Hepatocellular Carcinoma Are Different Between Hepatitis B Virus*Related and Hepatitis C Virus-Related Hcc Yoshiyuki gobayashi Nnbupaki Toshikuin, Shiniehiro Nakamura, Eiji Matsumoto, Hironori Tanaka Kazuhiro Nouso, Kohsaku Sakaguchi, Yasushi Shiratori, Yasuyuki Ar'aki, Hiroshi Ikeda, Mitsuhiko Kawaguchi, Haruhiko Kobashi (Background) Hepatocdlular carcinoma (HCC) occurs in patients with chronic liver diseases of HBV and HCV infecnon There are two mafor causes of death in patients with HCC: tumor expansion and liver failure. The aim of this study is to evaluate whether base-line
A-751
AASLD Abstracts