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Hypogammaglobulinemia as a novel marker for favorable prognosis in patients with chronic hepatitis C virus infection
with ConA(20mg/kg). Serum and liver tissues were collectedat 0, 8, 20 and 30hrs after ConA injection. We measuredthe levels of tumor necrosis factor (TNF)-oL,cyclooxygenase(COX)2, inducible nitric oxide synthase (iNOS), and macrophagemigration inhibitory factor (MIF) mRNAs in the liver using relative quantitative RT-PCR.Apoptosis was detected in the liver by the TUNEL method and by using the anti-M30 antibody which recognizesthe early stage of apoptosis. Hep-G2 cells were treated with DHEA(10/~M); apoptosis, induced with TNFotand actinomycinD (ActD), was detected by PI/Hoechst33342 staining. RESULTS: In the DHEA-treated mice, the serum level of ALT was significantly decreasedand expression of cytokines, including TNF-a, iNOS was also dramatically decreased.The number of apoptotic cells was much lower than in control mouse liver. Furthermore, histochemistry showed that the inflammatory infiltration of cells in the liver was markedly decreasedin the DHEA-treated mice. In Hep-G2 cells, fewer apoptotic cells were seen in the DHEA-treatedcells than in the controls. CONCLUSION:The present results suggest that DHEAcan reduce inflammation in the liver via inhibition of expression of several inflammatory cytokines and via inhibition of apuptosis. Thus, DHEA may be a candidatefor a novel therapy for liver injury. 1875 Comparison of Hepatocellular Necrosis and Apoptosis AHer Hypothermic Preservation in UW, HTK and Celsior in the Isolated Perfused Liver Model. Irene H. Straatsburg, Salomon L. Abrahamse,Acad Medical Ctr, Amsterdam Netherlands; Shag W. Song, Dept Organ Transplantation, China Medical Univ, Shen Yang People'SRep Of China; Thomas M. Van Gulik, Acad Medical Ctr, Amsterdam Netherlands
UW and HTK solutions have been successfully used in hypothermic preservation of liver grafts. In Celsior, a potentially superior multi-organ solution, key components of UW and HTK are combined. We compared UW, HTK and Celsior using an isolated pertused rat liver model. Livers of male Wistar rats (n=69) were flushed in situ through the portal vein with cold UW, HTK or Celsior (50 ml, 4°C). Excised livers were stored on ice for O, 8, 16 and 24 h, transferred to a cabinet and perfused with a recirculating, carbogen-saturated,KrebsHenseleit solution at 37°C for 90 min. Samples were collected at O, 15, 30, 60 and 90 min of perfusion. Organ damage was assessed by measuring perfusate flow rate at a constant pressure of 20 cm H20, bile production, and SGOT,SGPTand LDH levels in the perfusate.For quantification of apoptosis, levels of low molecular weight histon-associatedDNA-fragmeots (histon-DNA) were measured in perfusate. Membrane-hound 5'-Nucleotidase (5'-NT) and cytoplasmic LDH activity were analysed in frozen liver sections by enzyme histochemistry. At 30 min pertusion, a constant flow rate of 27 _ 1 ml/min (mean - sem, n=69) was obtained for all livers, irrespective of preservation solution and time. Bile production was significantly higher in UW livers than in HTK livers and intermediate in Celsior livers when stored up to 24 h (415 _+ 27 vs. 243 _+ 19 and 295 _+ 52 p.I/90 rain, resp., n=5-6). SCOT leakage of UW livers stored for 8, 16 and 24 h was significantly lower than SGOTleakageof HTK livers, and intermediatefor Celsior livers (21 _+ 4 vs. 107 _+ 17 and 81 +_ 15 IU/I for 24 h storage and 90 rain reperfusion, n = 5-6; p
Background: The prevalenceof hepatitis C(HCV) in renal failure patients can range from 1040%. Many of these patients are awaiting cadavedcor living donor transplantation.Aim: This study was done to determine if there was a graft or patient survival disadvantagein renal failure patients with HCV undergoing kidney transplantation (KT). Methods: Data fron~ 207 patients undergoing both cadavedc(105)and living donor renal transplantation in the 1990s were evaluated retrospectively. Patients were on a combination of prednisone and either cyclosporine or tacrolimus post KT. 77 patients were HCV Ab+ and RNA positive, and compared to 130 controls matchedfor age, gender, and race. The averageage of the HCV+ group was 44 (vs. 47) and the risk for acquisition of HCV was 5-20 years prior to transplant. 70% of the HCV+ group were male vs 61% in the control group. The pre- to post-transplant AST and ALl values were determined as a marker of liver inflammation. Viral loads were not availablepost transplant on most patients. Length of stay post transplant was also determined in both groups, as was graft and patient survival. Pearson chi square test was used to determine statistical differences between outcomes. Results: The averagelength of stay post transplant in the HCV+ and control patients was 7.2 vs 10 days(NS).The meanAST increase after KT in the HCV+ group was 30.4 versus 12.5 in the controls (p=0.18). Mean ALT increase was 25.5 vs. 11, respectively (p=0.16). While there was clearly an increase in transaminases in the HCV+ group, this was not found to be significant. The three year survival data for grafts and patients is shown in the table. Conclusions: While patients with HCV and renal failure undergoing KT do well in the immediate post operative period, there is a trend toward higher graft loss and patient death. Further studies need to define if the group at highest risk are those with advancedfibrosis, or if there are other characteristics that will predict outcome.
A-365
Patient and Graft Survival Patient
Graft Survival
Patient Survival
HCV Pos HCV Neg p value
75% 85% 0.071
82% 90% 0.091
1877 Biochemical, Histological and Clinical Comparisons Between African-American and Caucasian Patients with Chronic Hepatitis C in an Urban Clinic Population Firdous Siddiqui, Paul H. Naylor, Murray N. Ehdnpreis, Ravi Dher, Jerrold R. Turner, Ravi Murthy, Prasad Kulkarni, Julie Boag, Milton G. Mutchnick, Wayne State Univ Sch of Medicine, Detroit, Mt
Background: Chronic hepatitis C (CHC), a leading cause of chronic liver disease and liver transplantation, has emergedas a major health care issue. Aim: To comparethe biochemical, histological and clinical differences between African-American (AA) and Caucasian patients with CHC in the city of Detroit. Methods: Retrospective analysis of a database containing information on patients with CHC seen at a university medical center between January 1995 to August 2000. Results: Fifteen hundred and forty-seven (1547) patients presenting with a positive hepatitis C antibody were evaluated.The presence of HCV RNA was confirmed by PCR in 93% of patients while 7% had a negative PCR, suggestive of spontaneousclearance. The majority of patients with CHC were AA (70%), followed by Caucasians (24%), with the remaining 6% either Asians or Hispanics. Males were predominant at 57%. As noted in previous studies, the majority of these patients (53%) were in the 41-50 yr age group, those in their sixth and fourth decadesconstituted 21% and 20% respectively.Risk factor analysis revealed injection drug use alone was prevalent in 40%, blood transfusion alone in 17%, more than one risk factor in 17%, no risk factor in 17% and in the remaining 9%, dialysis, multiple sexual partners, intranasal cocaine and needle stick injuries were noted. AA were more likely than Caucasiansto have IDU as a risk factor, 54% vs. 46% (p= <0.01). Two thirds of patients had greater than 2 million viral copies/ml, and there was no statistically significant difference in viral load between AA and Caucasians.Genotype 1 was seen in 85% of the patients and was significantly higher in AA compared to Caucasians, 91% vs. 75% respectively (p=
BACKGROUND/OBJECTIVE:Hypergammaglobulinemia occurs commonly in patients with chronic viral hepatitis and cirrhosis. It was noted anecdotallythat hypogammaglobulinemia (HG) was present in some patients with hepatitis C virus infection. We sought to determine the frequency of HCV patients with HG and to characterizepatients from a clinical standpoint with HG. METHODS:108 consecutive patients (60 men, 48 women) evaluatedbetweenApril 1999 and July 2000 with chronic HCV infection (positive HCV RNA) were studied. Serum protein electmphoresis (SPEP) was obtained at initial evaluation. Patients were divided into subgroups (normal gammaglobulinemia, hypergammaglobulinemia, hypogammaglobulinemia). Demographic,biochemical,virological, and histological assessmentswere performed and comparisonswere made betweenthe subgroups. RESULTS:10/108 (9.3%) patientswere found to have hypogammaglobulinemia.In comparison, 63/108 (68.3%) patients had normal gammaglobulinlevels,and 35/108 (32.4%) had hypergammaglobulinemia.8/10 (80%) patients with HGwere men. 100% were genotype1, and all had high viral loads (>2 million copies/ml). Biochemical parameters (albumin, INR, AST/ALT ratio, platelet count, alkaline phosphetase, bilirubin, and alpha-fetopmtein) were abnormal in a greater percentage of patients with elevated gammaglobulins than in patients with decreasedgammaglobulins. All HG patients who underwent liver biopsy had minimal inflammation and no fibrosis, in marked contrast to the histologicalfindings in the normal (14.3% moderate/severeinflammationand 40.5% with extensive fibrosis/cirrhosis) and hypergammaglobulin subgroups (31.2% moderate/severe inflammation and 43.7% with extensivefibrosis/cirrhosis}. CONCLUSIONS:Hypogammaglobulinemia is seen in 9.3% of patients with chronic HCV infection. Hypogammaglobulinemic patients were more likely to be men. All patients with hypogammaglobulinemiahad genotype 1 and high viral loads. Patients with hypogammaglobulinemiahad less inflammation and no fibrosis on liver biopsy in comparison to patientswith normal and increasedgammaglobulins. Hypogammaglobulinemia may represent an immunological advantage which predisposes patients with chronic HCV infection to a more favorable outcome.
UW and HTK solutions have been successfully used in hypothermic preservation of liver grafts. In Celsior, a potentially superior multi-organ solution, key components of UW and HTK are combined. We compared UW, HTK and Celsior using an isolated pertused rat liver model. Livers of male Wistar rats (n=69) were flushed in situ through the portal vein with cold UW, HTK or Celsior (50 ml, 4°C). Excised livers were stored on ice for O, 8, 16 and 24 h, transferred to a cabinet and perfused with a recirculating, carbogen-saturated,KrebsHenseleit solution at 37°C for 90 min. Samples were collected at O, 15, 30, 60 and 90 min of perfusion. Organ damage was assessed by measuring perfusate flow rate at a constant pressure of 20 cm H20, bile production, and SGOT,SGPTand LDH levels in the perfusate.For quantification of apoptosis, levels of low molecular weight histon-associatedDNA-fragmeots (histon-DNA) were measured in perfusate. Membrane-hound 5'-Nucleotidase (5'-NT) and cytoplasmic LDH activity were analysed in frozen liver sections by enzyme histochemistry. At 30 min pertusion, a constant flow rate of 27 _ 1 ml/min (mean - sem, n=69) was obtained for all livers, irrespective of preservation solution and time. Bile production was significantly higher in UW livers than in HTK livers and intermediate in Celsior livers when stored up to 24 h (415 _+ 27 vs. 243 _+ 19 and 295 _+ 52 p.I/90 rain, resp., n=5-6). SCOT leakage of UW livers stored for 8, 16 and 24 h was significantly lower than SGOTleakageof HTK livers, and intermediatefor Celsior livers (21 _+ 4 vs. 107 _+ 17 and 81 +_ 15 IU/I for 24 h storage and 90 rain reperfusion, n = 5-6; p
Background: The prevalenceof hepatitis C(HCV) in renal failure patients can range from 1040%. Many of these patients are awaiting cadavedcor living donor transplantation.Aim: This study was done to determine if there was a graft or patient survival disadvantagein renal failure patients with HCV undergoing kidney transplantation (KT). Methods: Data fron~ 207 patients undergoing both cadavedc(105)and living donor renal transplantation in the 1990s were evaluated retrospectively. Patients were on a combination of prednisone and either cyclosporine or tacrolimus post KT. 77 patients were HCV Ab+ and RNA positive, and compared to 130 controls matchedfor age, gender, and race. The averageage of the HCV+ group was 44 (vs. 47) and the risk for acquisition of HCV was 5-20 years prior to transplant. 70% of the HCV+ group were male vs 61% in the control group. The pre- to post-transplant AST and ALl values were determined as a marker of liver inflammation. Viral loads were not availablepost transplant on most patients. Length of stay post transplant was also determined in both groups, as was graft and patient survival. Pearson chi square test was used to determine statistical differences between outcomes. Results: The averagelength of stay post transplant in the HCV+ and control patients was 7.2 vs 10 days(NS).The meanAST increase after KT in the HCV+ group was 30.4 versus 12.5 in the controls (p=0.18). Mean ALT increase was 25.5 vs. 11, respectively (p=0.16). While there was clearly an increase in transaminases in the HCV+ group, this was not found to be significant. The three year survival data for grafts and patients is shown in the table. Conclusions: While patients with HCV and renal failure undergoing KT do well in the immediate post operative period, there is a trend toward higher graft loss and patient death. Further studies need to define if the group at highest risk are those with advancedfibrosis, or if there are other characteristics that will predict outcome.
A-365
Patient and Graft Survival Patient
Graft Survival
Patient Survival
HCV Pos HCV Neg p value
75% 85% 0.071
82% 90% 0.091
1877 Biochemical, Histological and Clinical Comparisons Between African-American and Caucasian Patients with Chronic Hepatitis C in an Urban Clinic Population Firdous Siddiqui, Paul H. Naylor, Murray N. Ehdnpreis, Ravi Dher, Jerrold R. Turner, Ravi Murthy, Prasad Kulkarni, Julie Boag, Milton G. Mutchnick, Wayne State Univ Sch of Medicine, Detroit, Mt
Background: Chronic hepatitis C (CHC), a leading cause of chronic liver disease and liver transplantation, has emergedas a major health care issue. Aim: To comparethe biochemical, histological and clinical differences between African-American (AA) and Caucasian patients with CHC in the city of Detroit. Methods: Retrospective analysis of a database containing information on patients with CHC seen at a university medical center between January 1995 to August 2000. Results: Fifteen hundred and forty-seven (1547) patients presenting with a positive hepatitis C antibody were evaluated.The presence of HCV RNA was confirmed by PCR in 93% of patients while 7% had a negative PCR, suggestive of spontaneousclearance. The majority of patients with CHC were AA (70%), followed by Caucasians (24%), with the remaining 6% either Asians or Hispanics. Males were predominant at 57%. As noted in previous studies, the majority of these patients (53%) were in the 41-50 yr age group, those in their sixth and fourth decadesconstituted 21% and 20% respectively.Risk factor analysis revealed injection drug use alone was prevalent in 40%, blood transfusion alone in 17%, more than one risk factor in 17%, no risk factor in 17% and in the remaining 9%, dialysis, multiple sexual partners, intranasal cocaine and needle stick injuries were noted. AA were more likely than Caucasiansto have IDU as a risk factor, 54% vs. 46% (p= <0.01). Two thirds of patients had greater than 2 million viral copies/ml, and there was no statistically significant difference in viral load between AA and Caucasians.Genotype 1 was seen in 85% of the patients and was significantly higher in AA compared to Caucasians, 91% vs. 75% respectively (p=
BACKGROUND/OBJECTIVE:Hypergammaglobulinemia occurs commonly in patients with chronic viral hepatitis and cirrhosis. It was noted anecdotallythat hypogammaglobulinemia (HG) was present in some patients with hepatitis C virus infection. We sought to determine the frequency of HCV patients with HG and to characterizepatients from a clinical standpoint with HG. METHODS:108 consecutive patients (60 men, 48 women) evaluatedbetweenApril 1999 and July 2000 with chronic HCV infection (positive HCV RNA) were studied. Serum protein electmphoresis (SPEP) was obtained at initial evaluation. Patients were divided into subgroups (normal gammaglobulinemia, hypergammaglobulinemia, hypogammaglobulinemia). Demographic,biochemical,virological, and histological assessmentswere performed and comparisonswere made betweenthe subgroups. RESULTS:10/108 (9.3%) patientswere found to have hypogammaglobulinemia.In comparison, 63/108 (68.3%) patients had normal gammaglobulinlevels,and 35/108 (32.4%) had hypergammaglobulinemia.8/10 (80%) patients with HGwere men. 100% were genotype1, and all had high viral loads (>2 million copies/ml). Biochemical parameters (albumin, INR, AST/ALT ratio, platelet count, alkaline phosphetase, bilirubin, and alpha-fetopmtein) were abnormal in a greater percentage of patients with elevated gammaglobulins than in patients with decreasedgammaglobulins. All HG patients who underwent liver biopsy had minimal inflammation and no fibrosis, in marked contrast to the histologicalfindings in the normal (14.3% moderate/severeinflammationand 40.5% with extensive fibrosis/cirrhosis) and hypergammaglobulin subgroups (31.2% moderate/severe inflammation and 43.7% with extensivefibrosis/cirrhosis}. CONCLUSIONS:Hypogammaglobulinemia is seen in 9.3% of patients with chronic HCV infection. Hypogammaglobulinemic patients were more likely to be men. All patients with hypogammaglobulinemiahad genotype 1 and high viral loads. Patients with hypogammaglobulinemiahad less inflammation and no fibrosis on liver biopsy in comparison to patientswith normal and increasedgammaglobulins. Hypogammaglobulinemia may represent an immunological advantage which predisposes patients with chronic HCV infection to a more favorable outcome.