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Increased insulin resistance in the patients with chronic HCV infection is mediated by elevated serum TNFα
552A
AASLD ABSTRACTS
HEPATOLOGY October 2001
1519
1520
INCREASED INSULIN RESISTANCE IN THE PATIENTS W I T H CHRONIC HCV INFECTION IS MEDIATED BY ELEVATED SERUM TNFa. Tadashi Maeno, Akihiko Okumura, Tetsuya Ishikawa, Kenichi Yamamoto, Naoki Hotta, Kagumi Yoshida, Masamichi Ito, Tsuneaki Tagaya, Yoshitaka Fukuzawa, Shinichi Kakumu, Aichi Medical Univ Sch of Medicine, Aichi-gun, Aichi-ken Japan
TITLE: WATER APPARENT DIFFUSION COEFFICIENT (ADC) IS INCREASED IN THE BRAIN OF CIRRHOTIC PATIENTS. Raffaele Lodi, Andrea Stacciari, Stefano Iotti, Gabriele Donati, Maria Guarino, V Clementi, Luigi Bolondi, Bruno Barbiroli, Univ of Bologna, Bologna Italy
Background and aims: Recently several studies point to a link between HCV infection and the development of diabetes mellitns (DM). Our previous study showed that rate of the patients diagnosed as DM was significantly higher in the patients with chronic HCV infection (20.8%) compared to those with chronic HBV infection (11.8%)(p < 0.02). In the present study, we evaluated insulin resistance by HOMA (Homeostasis Model Assessment), and analyzed the factors responsible for the elevated insulin resistance in the patients with chronic HCV infection. Patients and methods: 43 patients with chronic HCV infection were included. Fasting serum insulin, fasting plasma glucose, H b A l c and serum TNFawere measured simahaneously. The stage of hepatitis was determined based on the histological findings of liver biopsy specimen. The patients to whom liver biopsy was not applicable were classified into 4 groups according to the platelet counts; FI: >15x104/ml, F2: 13x104/ml, 15x104/ml, F3: 10x104/ml, 13x104/ml, F4: <10x104/ml. HOMA ratio (HOMA-R) was calculated according to the following formula; HOMA-R = fasting serum insulin (mU/ml) x fasting plasma glucose (retool/l) +22.5 (Matthews DR, et al. Diabetologia 28: 412-419, 1985) Results: 19 patients were classified to F1 or F2, and 24 patients to F3 or F4. Only 2 patients were diagnosed as DM in F l e F 2 group, whereas 11 patients in F3oF4 group were diagnosed as DM (p<0.05). The patients in F3eF4 group showed significantly higher HOMA-R compared with FIOF2 group (1.71-+1.00 vs. 6.55-+5.66, p = 0.0023). Non-diabetic patients in FIoF2 group also showed slightly elevated HOMA-R. Among these non-diabetic patients with milder fibrotic changes, TNF~(r=0.730, p=0.0008) and AST (r=0.713, p=0.0013) showed strong correlation to HOMA-R, whereas body mass index (BMI) and viral load did not. Although non-diabetic patients in F3oF4 group showed much higher HOMA-R compared to those in F l e F 2 group, there was no single factor that correlated to HOMA-R. Conclusions: Our results indicate that elevated TNFcdevels in the patients with chronic HCV infection might play important roles in the development of insulin resistance. Thus increased insulin resistance may account for a high incidence of DM in the patients with chronic HCV infection.
BACKGROUND: Brain oedema has been recently described in patients with end-stage liver cirrhosis, Glutamine increase and myo-inositol depletion have been implicated in brain cell swelling and aherated cell osmoregulation, respectively. It has been shown that inhibition of glutamine synthesis with methionine-sulfoximine prevents the development of ammonia-induced brain oedema and decreases astrocyte swelling in rats and that myo-inositol contributes to cell volume regulation in cultures of primary astrocytes. From these experimental evidences changes in water ADC are expected to occur in patients with chronic liver disease even in the absence of brain oedema detectable by conventional magnetic resonance imaging (MRI). METHODS: Five patients with viral liver cirrhosis (4 HCV and 1 HBV, 3 males; 56-70 years) and 9 healthy controls were studied in a 1.5 Tesla GE Signa Horizon LX system. Four patients showed no clinical encephalopathy and one grade II encephalopathy. T1 and T2-weighted spin-echo MR images did not show evidence of brain oedema in any of the patients. 20 to 24 axial DW images were obtained (thickness = 5 ram, inter-slice gap = 1 ram) using a single-shot echo-planar imaging sequence (matrix size = 256 x 256 mm). Separate applications of orthogonal x, y, and z diffusion encoding gradient were made and four gradient strengths corresponding to b-values ranging from 0 to 900 s/ram2 were applied to calculate the average diffusivity maps. Regions of interest (ROI) were outlined manually by an observer unaware of the subjects status and mean water ADC constants were calculated on a pixel by pixel basis. ROIs included left and right frontal and parietal white matter areas and left and right lentiform nucleus areas. RESULTS: ADC values in cirrhotic patients were significantly increased in white (0.837x10-3 mm2/s -+ 0.131) and grey matter areas (0.794 -4- 0.052) compared to controls (0.732 - 0.049, p<0.0001; 0.702 - 0.027, p<0.0001, respectively). Among cirrhotics the patient with grade II encephalopathy showed the highest ADC values in both grey and white matter. CONCLUSIONS: Water ADC is increased in the brain of cirrhotic patients in the absence of structural evidence of brain oedema. The highest values found in the patient with the most severe CNS involvement indicates that assessment of water ADC can be useful in monitoring patients with hepatic encephalopathy and preventing brain oedema.
1521
1522
THE EFFECT OF LOW DOSE LOSARTAN, AN ANGIOTENSIN II RECEPTOR ANTAGONIST, ON THE POSTURE RELATED CHANGES IN SYSTEMIC AND RENAL HEMODYNAMICS AND SODIUM HOMEOSTASIS IN PRE-ASCITIC CIRRItOSIS. Florence S Wong, Laurence M Blendis, Toronto Gen Hosp, Toronto, ON Canada
AUTOANTIBODIES TO ASIALOGLYCOPROTEIN RECEPTOR IN CHRONIC HEPATITIS PATIENTS. Petr Hnsa, Pavel Chalupa, Department of Infectious Diseases, Teaching Hospital Brno, Brno Czech Republic; Hana Stroblova, Department of Microbiology, Teaching Hospital Bruo, Brno Czech Republic; Libuse Husova, Medical Gastroenterogical Department, Teaching Hospital Brno, Brno Czech Republic; Jaroslav Zajic, Pavel Slesinger, Department of Infectious Diseases, Teaching Hospital Brno, Brno Czech Republic
Pre-ascitic cirrhotic patients have been shown to have subtle sodium (Na) retention, evident only in the erect posture, due to activation of the renin-angiotensin-aldosterone system (RAAS). Low dose 7.5rag losartan can reverse this Na handling abnormality (Girgrah et al Gut 2000; 46: 114). It is unclear whether this is related to improved renal hemodynamics or a direct tubular effects of Ang 11blockade in the erect(E) posture. Aim: To assess the effects of 7.5rag losartan on the posture induced sodium retention in preascitic cirrhosis. Methods: 10 male well-compensated, pre-ascitic, biopsy proven cirrhotics, mean age 54.9±3.8 years were studied before, and after 1 day and 1 month of 7.5mg losartan daily in both the supine (S) and erect (E) postures while maintained on 200retool Na/day diet. Inulin and para-aminohippurate clearances were used as indices ofglomerular filtration rate and renal plasma flow respectively. Proximal tubular reabsorption of Na (PTRNa) was assessed using lithium clearance. Distal tubular reabsorption of Na (DTRNa), fractional excretion ofNa (FENa) and renal vascular resistance (RVR)were calculated from standard formulae. Systemic hemodynamics was assessed using mean arterial blood pressure and heart rate. Plasma renin activity (PRA), Ang II, aldosterone (Aldo) and plasma norepinephrine (PNE) were assessed in both postures at all time points. Nine age-matched (mean age 53.5 ± 3.0 years) healthy male volunteers served as controls. Results: At baseline, pre-ascit-ic cirrhotics had significant renal sodium retention in the erect posture ( +0.07 ± 0.02/zmol/min) (p<0.05 versus controls), associated with significant increases in both PTRNa (+6.12±0.98%) (p<0.05 versus controls), DTRNa (+8.73+- 1.12%) (p<0.05 versus controls), and KAASactivity (Table), but unchanged systemic and renal hemodynamics. A single dose of 7.Smg losartan did not alter systemic or renal hemodynamics, but prevented the erect posture induced increases in PTRNa (+2.81±0.61%) (p>0.05 versus controls) and DTRNa (+2.13+-0.44%) (p>0.05 versus controls), thereby improving the FENa, despite similar increases in neurohormone levels. 7.5rag of losartan for 1 month normalized renal Na handling, with further reductions in both PTRNa (+ 1.23---0.21%) and DTRNa(+0.98+-0.12%) in the erect posture, despite further increases in RAASactivity. Systemic and renal hemodynamics remained unchanged at 1 month. Conclusions: Pre-ascitic cirrhotic patients retain Na in the erect posture. This is related to activation of the RAASactivity. Low dose 7.5mg losartan acutely improves renal Na handling, by inhibiting the Na retaining effects of Ang II on the renal tubules related to the erect posture. This natriuretic effect of low dose losartan is well maintained with chronic administrationfor 1 month. The effects of low dose Iosartan on R/k/kSactivity ........
An9 U{s)
Ang 11~)
~do {S)
A]do (E)
pnlol/I pmol/I .... pmol/I pmol/I B 3.1±0.5 7.7±3.5" 138~:23 384_+83' Day1 3.8_+1.1 9,1±3.5" 131-+36 309_+52* Month1 5 , ~ 1 : 8 ¶ 17~8_+,§~6~ 134-+19 337±56" B = Baseline, * p < 0,05 versus supine, ¶ p < 0.08 versus baseline.
PRA (S)
PRA (E)
....ag/lls ng/I/s 0.2t+0.03 0.40+_0.11" 0.31_+0,10 0.86_+0,35* 0.24+0,08 0.98-+0.28*
Objective: Determination of the incidence rate of antibodies to asialoglycoprotein receptor anti-ASGPR) in chronic hepatitis C patients. Methods: Serum samples from 79 chronic hepatitis C patients (41 males, 38 females, age range 18 - 72 years, median 41 years, all anti-HCV and HCV-RNA positive) were analyzed for presence of anti-ASGPR using the enzyme immunoassay Medizym anti-ASGPR (Medipan Diagnostica). Results: The ASGPR antibodies were detected in 13,9 % of chronic hepatitis C patients. There were found no significant differences between the anti-ASGPR positive and negative patients in age, ALT activity, histological findings and response to interferon therapy (3 MU recombinant IFN alfa tiw for 48 weeks), Sustained virological response was achieved in 2/10 (20 %) of anti-ASGPR positive and 7/44 (15,9 %) of anti-ASGPR negative patients. Sustained biochemical response was observed in 2/10 (20 %) in positive and 8/44 (18,2 %) in negative groups. Tolerance to therapy was similar in both groups and there were observed no major therapyrelated adverse effects. The male predominance was statistically significant in the anti-ASGPR positive group (p<0.05), the negative group was virtually balanced in sexes. Surprising was the fact that other antibodies (antinuclear antibodies-ANA, smooth muscle antibodies-SMA, type 1 liver-kidney microsomal antibodies-LKM- 1, anti-thyroglobulin and thyroid microsomes antibodies) were detected significantly more frequently in the anti-ASGPR negative group (p<0.01). Analogical situation was observed in increased levels of immunoglobulins in the anti-ASGPR negative group. Conclusions: As other autoantihodies, the ant/bodies to asialoglycoprotein receptor are found in many patients with chronic hepatitis C. If there are no clinical symptoms of autoimmune disease, clinical importance of this finding is probably limited. However, these antibodies are organ-specific and their occurrence brings up the need of more frequent and detailed control examinations during interferon alfa administration.
AASLD ABSTRACTS
HEPATOLOGY October 2001
1519
1520
INCREASED INSULIN RESISTANCE IN THE PATIENTS W I T H CHRONIC HCV INFECTION IS MEDIATED BY ELEVATED SERUM TNFa. Tadashi Maeno, Akihiko Okumura, Tetsuya Ishikawa, Kenichi Yamamoto, Naoki Hotta, Kagumi Yoshida, Masamichi Ito, Tsuneaki Tagaya, Yoshitaka Fukuzawa, Shinichi Kakumu, Aichi Medical Univ Sch of Medicine, Aichi-gun, Aichi-ken Japan
TITLE: WATER APPARENT DIFFUSION COEFFICIENT (ADC) IS INCREASED IN THE BRAIN OF CIRRHOTIC PATIENTS. Raffaele Lodi, Andrea Stacciari, Stefano Iotti, Gabriele Donati, Maria Guarino, V Clementi, Luigi Bolondi, Bruno Barbiroli, Univ of Bologna, Bologna Italy
Background and aims: Recently several studies point to a link between HCV infection and the development of diabetes mellitns (DM). Our previous study showed that rate of the patients diagnosed as DM was significantly higher in the patients with chronic HCV infection (20.8%) compared to those with chronic HBV infection (11.8%)(p < 0.02). In the present study, we evaluated insulin resistance by HOMA (Homeostasis Model Assessment), and analyzed the factors responsible for the elevated insulin resistance in the patients with chronic HCV infection. Patients and methods: 43 patients with chronic HCV infection were included. Fasting serum insulin, fasting plasma glucose, H b A l c and serum TNFawere measured simahaneously. The stage of hepatitis was determined based on the histological findings of liver biopsy specimen. The patients to whom liver biopsy was not applicable were classified into 4 groups according to the platelet counts; FI: >15x104/ml, F2: 13x104/ml, 15x104/ml, F3: 10x104/ml, 13x104/ml, F4: <10x104/ml. HOMA ratio (HOMA-R) was calculated according to the following formula; HOMA-R = fasting serum insulin (mU/ml) x fasting plasma glucose (retool/l) +22.5 (Matthews DR, et al. Diabetologia 28: 412-419, 1985) Results: 19 patients were classified to F1 or F2, and 24 patients to F3 or F4. Only 2 patients were diagnosed as DM in F l e F 2 group, whereas 11 patients in F3oF4 group were diagnosed as DM (p<0.05). The patients in F3eF4 group showed significantly higher HOMA-R compared with FIOF2 group (1.71-+1.00 vs. 6.55-+5.66, p = 0.0023). Non-diabetic patients in FIoF2 group also showed slightly elevated HOMA-R. Among these non-diabetic patients with milder fibrotic changes, TNF~(r=0.730, p=0.0008) and AST (r=0.713, p=0.0013) showed strong correlation to HOMA-R, whereas body mass index (BMI) and viral load did not. Although non-diabetic patients in F3oF4 group showed much higher HOMA-R compared to those in F l e F 2 group, there was no single factor that correlated to HOMA-R. Conclusions: Our results indicate that elevated TNFcdevels in the patients with chronic HCV infection might play important roles in the development of insulin resistance. Thus increased insulin resistance may account for a high incidence of DM in the patients with chronic HCV infection.
BACKGROUND: Brain oedema has been recently described in patients with end-stage liver cirrhosis, Glutamine increase and myo-inositol depletion have been implicated in brain cell swelling and aherated cell osmoregulation, respectively. It has been shown that inhibition of glutamine synthesis with methionine-sulfoximine prevents the development of ammonia-induced brain oedema and decreases astrocyte swelling in rats and that myo-inositol contributes to cell volume regulation in cultures of primary astrocytes. From these experimental evidences changes in water ADC are expected to occur in patients with chronic liver disease even in the absence of brain oedema detectable by conventional magnetic resonance imaging (MRI). METHODS: Five patients with viral liver cirrhosis (4 HCV and 1 HBV, 3 males; 56-70 years) and 9 healthy controls were studied in a 1.5 Tesla GE Signa Horizon LX system. Four patients showed no clinical encephalopathy and one grade II encephalopathy. T1 and T2-weighted spin-echo MR images did not show evidence of brain oedema in any of the patients. 20 to 24 axial DW images were obtained (thickness = 5 ram, inter-slice gap = 1 ram) using a single-shot echo-planar imaging sequence (matrix size = 256 x 256 mm). Separate applications of orthogonal x, y, and z diffusion encoding gradient were made and four gradient strengths corresponding to b-values ranging from 0 to 900 s/ram2 were applied to calculate the average diffusivity maps. Regions of interest (ROI) were outlined manually by an observer unaware of the subjects status and mean water ADC constants were calculated on a pixel by pixel basis. ROIs included left and right frontal and parietal white matter areas and left and right lentiform nucleus areas. RESULTS: ADC values in cirrhotic patients were significantly increased in white (0.837x10-3 mm2/s -+ 0.131) and grey matter areas (0.794 -4- 0.052) compared to controls (0.732 - 0.049, p<0.0001; 0.702 - 0.027, p<0.0001, respectively). Among cirrhotics the patient with grade II encephalopathy showed the highest ADC values in both grey and white matter. CONCLUSIONS: Water ADC is increased in the brain of cirrhotic patients in the absence of structural evidence of brain oedema. The highest values found in the patient with the most severe CNS involvement indicates that assessment of water ADC can be useful in monitoring patients with hepatic encephalopathy and preventing brain oedema.
1521
1522
THE EFFECT OF LOW DOSE LOSARTAN, AN ANGIOTENSIN II RECEPTOR ANTAGONIST, ON THE POSTURE RELATED CHANGES IN SYSTEMIC AND RENAL HEMODYNAMICS AND SODIUM HOMEOSTASIS IN PRE-ASCITIC CIRRItOSIS. Florence S Wong, Laurence M Blendis, Toronto Gen Hosp, Toronto, ON Canada
AUTOANTIBODIES TO ASIALOGLYCOPROTEIN RECEPTOR IN CHRONIC HEPATITIS PATIENTS. Petr Hnsa, Pavel Chalupa, Department of Infectious Diseases, Teaching Hospital Brno, Brno Czech Republic; Hana Stroblova, Department of Microbiology, Teaching Hospital Bruo, Brno Czech Republic; Libuse Husova, Medical Gastroenterogical Department, Teaching Hospital Brno, Brno Czech Republic; Jaroslav Zajic, Pavel Slesinger, Department of Infectious Diseases, Teaching Hospital Brno, Brno Czech Republic
Pre-ascitic cirrhotic patients have been shown to have subtle sodium (Na) retention, evident only in the erect posture, due to activation of the renin-angiotensin-aldosterone system (RAAS). Low dose 7.5rag losartan can reverse this Na handling abnormality (Girgrah et al Gut 2000; 46: 114). It is unclear whether this is related to improved renal hemodynamics or a direct tubular effects of Ang 11blockade in the erect(E) posture. Aim: To assess the effects of 7.5rag losartan on the posture induced sodium retention in preascitic cirrhosis. Methods: 10 male well-compensated, pre-ascitic, biopsy proven cirrhotics, mean age 54.9±3.8 years were studied before, and after 1 day and 1 month of 7.5mg losartan daily in both the supine (S) and erect (E) postures while maintained on 200retool Na/day diet. Inulin and para-aminohippurate clearances were used as indices ofglomerular filtration rate and renal plasma flow respectively. Proximal tubular reabsorption of Na (PTRNa) was assessed using lithium clearance. Distal tubular reabsorption of Na (DTRNa), fractional excretion ofNa (FENa) and renal vascular resistance (RVR)were calculated from standard formulae. Systemic hemodynamics was assessed using mean arterial blood pressure and heart rate. Plasma renin activity (PRA), Ang II, aldosterone (Aldo) and plasma norepinephrine (PNE) were assessed in both postures at all time points. Nine age-matched (mean age 53.5 ± 3.0 years) healthy male volunteers served as controls. Results: At baseline, pre-ascit-ic cirrhotics had significant renal sodium retention in the erect posture ( +0.07 ± 0.02/zmol/min) (p<0.05 versus controls), associated with significant increases in both PTRNa (+6.12±0.98%) (p<0.05 versus controls), DTRNa (+8.73+- 1.12%) (p<0.05 versus controls), and KAASactivity (Table), but unchanged systemic and renal hemodynamics. A single dose of 7.Smg losartan did not alter systemic or renal hemodynamics, but prevented the erect posture induced increases in PTRNa (+2.81±0.61%) (p>0.05 versus controls) and DTRNa (+2.13+-0.44%) (p>0.05 versus controls), thereby improving the FENa, despite similar increases in neurohormone levels. 7.5rag of losartan for 1 month normalized renal Na handling, with further reductions in both PTRNa (+ 1.23---0.21%) and DTRNa(+0.98+-0.12%) in the erect posture, despite further increases in RAASactivity. Systemic and renal hemodynamics remained unchanged at 1 month. Conclusions: Pre-ascitic cirrhotic patients retain Na in the erect posture. This is related to activation of the RAASactivity. Low dose 7.5mg losartan acutely improves renal Na handling, by inhibiting the Na retaining effects of Ang II on the renal tubules related to the erect posture. This natriuretic effect of low dose losartan is well maintained with chronic administrationfor 1 month. The effects of low dose Iosartan on R/k/kSactivity ........
An9 U{s)
Ang 11~)
~do {S)
A]do (E)
pnlol/I pmol/I .... pmol/I pmol/I B 3.1±0.5 7.7±3.5" 138~:23 384_+83' Day1 3.8_+1.1 9,1±3.5" 131-+36 309_+52* Month1 5 , ~ 1 : 8 ¶ 17~8_+,§~6~ 134-+19 337±56" B = Baseline, * p < 0,05 versus supine, ¶ p < 0.08 versus baseline.
PRA (S)
PRA (E)
....ag/lls ng/I/s 0.2t+0.03 0.40+_0.11" 0.31_+0,10 0.86_+0,35* 0.24+0,08 0.98-+0.28*
Objective: Determination of the incidence rate of antibodies to asialoglycoprotein receptor anti-ASGPR) in chronic hepatitis C patients. Methods: Serum samples from 79 chronic hepatitis C patients (41 males, 38 females, age range 18 - 72 years, median 41 years, all anti-HCV and HCV-RNA positive) were analyzed for presence of anti-ASGPR using the enzyme immunoassay Medizym anti-ASGPR (Medipan Diagnostica). Results: The ASGPR antibodies were detected in 13,9 % of chronic hepatitis C patients. There were found no significant differences between the anti-ASGPR positive and negative patients in age, ALT activity, histological findings and response to interferon therapy (3 MU recombinant IFN alfa tiw for 48 weeks), Sustained virological response was achieved in 2/10 (20 %) of anti-ASGPR positive and 7/44 (15,9 %) of anti-ASGPR negative patients. Sustained biochemical response was observed in 2/10 (20 %) in positive and 8/44 (18,2 %) in negative groups. Tolerance to therapy was similar in both groups and there were observed no major therapyrelated adverse effects. The male predominance was statistically significant in the anti-ASGPR positive group (p<0.05), the negative group was virtually balanced in sexes. Surprising was the fact that other antibodies (antinuclear antibodies-ANA, smooth muscle antibodies-SMA, type 1 liver-kidney microsomal antibodies-LKM- 1, anti-thyroglobulin and thyroid microsomes antibodies) were detected significantly more frequently in the anti-ASGPR negative group (p<0.01). Analogical situation was observed in increased levels of immunoglobulins in the anti-ASGPR negative group. Conclusions: As other autoantihodies, the ant/bodies to asialoglycoprotein receptor are found in many patients with chronic hepatitis C. If there are no clinical symptoms of autoimmune disease, clinical importance of this finding is probably limited. However, these antibodies are organ-specific and their occurrence brings up the need of more frequent and detailed control examinations during interferon alfa administration.