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The prognostic value of serum laminin compared with child classification for chronic liver disease
HEPATOLOGY Vol. 22, No. 4, Pt. 2, 1995
AASLD ABSTRACTS
1337 IMPAIRED BARORECEPTOR
SENSITIVITY IN RATS W I T H BILIARY CIRRHOSIS. KI Kroeker and SS Lee. Liver Unit, University of Calgary, Calgary, Canada.
Cirrhosis is associated with cardiovascular abnormalities, including changes in baroreflex sensitivity, although this has not been uniformly demonstrated in all studies. We aimed to clarify the baroreflex function in cirrhotic rats, using the best available quantitative method of baroreflex sensitivity. Bile duct ligation was utilized to induce cirrhosis, which was present 4 weeks post-operative (n=8), while controls underwent sham operation (n=9). Blood pressure and heart rate were monitored via a femoral artery cannula. In pentobarbital anesthetized rats, the beat-to-beat relationship between changes in heart rate and systolic blood pressure following intravenous phenylephrine injection (1.5~Lg) was plotted and the slope determined. This slope has been shown to reliably quantitate baroreflex sensitivity. Further, we calculated the dose of atropine required to completely paralyze the reflex arc by injecting 3 cumulative doses of atropine sulfate (2.0, 4.0, 6.01ttg). The baroreflex slope of the cirrhotic rats was significantly lower than the control (0.116+0.090 vs. 0.257+0.169msec/mmHg, p<0.05). The atropine blocking dose was also lowered in the cirrhotic rats (0.014_+0.007 vs. 0.026_+0.019mg/kg atropine sulfate), although this did not quite reach statistical significance (p=0.07), These results demonstrate that there is a decreased baroreflex sensitivity associated with cirrhosis. Furthermore, the decreased atropine blocking dose, associated with cirrhosis suggests that this impairment in baroreflex function may be secondary to alterations in the afferent arc of the baroreflex due to a decrease in parasympathetic tone.
1339 RESPONSE TO 100% INSPIRED OXYGEN IN PATIENTS WITH HEPATOPULMONARY SYNDROME. MJ Krowka. M Castro. DA Cortese, JR Sulvev. Mayo Clinic Jacksonville, Jacksonville, FL Hepatopulmonarysyndrome (HPS) is a pulmonary vascular complication of liver disease which can result in clinically significant arterial hypoxemiawhile breathing room air (R.A). The degree of hypoxemiabreathing RA may not fullycharacterize the severity of the oxygenationabnormality. We sought to determine the effect of breathing 100% inspired oxygenon PaO2 in this syndrome. Methods: 20 adult patients with well documented HPS due to chronic liver disease were prospectivelystudied. Contrast echocardiography, 99roTe macroaggregated albumin lung scanning or pulmonary angiography was used to establish the diagnosis of HPS. Arterial oxygenation was measured via radial artery catheterization by determining PaO2 in the supine and standing positions while breathing RA and 100% inspired oxygen (via nasal dips and sealed mouth piece). Results: The severity of hypoxemiabreathing RA in the supine position (mean PaO2 56+-7 mmHg; range 44-70) or standing position (mean PaO2 44±6 mmHg; range 36-54) correlated poorly with PaO2 determinations breathing 100% inspired 02 in the supine or standing position, respectively: RA versus 100% inspired 02 Mean Pat:)2 (range) Spearman Rank Correlation Position breathing 100% 02* "r" r2 p-value Supine
409+110 mmHg (184-566)
.44
.19
NS
Standing
276+157 mmHg (84-522)
.24
.06
NS
* supine vs standing significantlydifferent; p < .0001 Response to 100% inspired oxygen in patients with HPS was extremely variable. PaO2 determinations breathing room air had poor predictive value in identifying PaO2 response to 100% 02 and, therefore, potentially underestimated the severityof the oxygenationproblem. This observation may be of prognostic and clinical importance in liver transplant candidates concerning the reversibility and morbidity associated with this syndrome. Conclusion:
441A
1338 THE PROGNOSTIC VALUE OF SERUM LAMININ COMPARED WITH CHILD CLASSIFICATION FOR CHRONIC LIVER DISEASE. J Kronf. TH Ktmer, AM Gressner. Dept. of Clinical Chemistry and Central Laboratory, Philipps University, 35033 Marburg, Baldingerst., Germany The high-molecular weight glyeoprotein laminin, a main extraeellular constituent of basal membranes, is found in increased concentrations in blood of patients with chronic liver disease. In liver cirrhosis a significant correlation between the concentration of serum laminin and portal hypertension has been reported. We here present the results of a prospective study evaluating the diagnostic value of serum laminin in elinieaily severe complications of progressive liver cirrhosis. During a mean follow-up period of 12.5 ± 3.5 months hi 38 patients with liver fibrosis (n = 4) and liver cirrhosis (Child A: n = 17, B: n = 7, C: n = 10) the serum levels of laminin were determined using the RIA kit from Behring-Hoechst (FRG). Portal hypertension was assessed by endoscopic control of the esophageal varioosis and by Doppler sonography of the portal blood flow. While the concentration of laminin was significantly increased (P < 0.01) in higher Child stages, there was no significant correlation between laminin and portal hypertension. There was, however, a highly significant association (P < 0.001) between an increase of serum laminin in the group with complications of liver cirrhosis (3.25 ± 0.2 U/mI) in comparison to patients without complications (2.13 ± 0.26). Using a cut-off value of 2.6 U/ml for lamiain, the sensiti;Aty and specificity for diagnosis of severe complications of liver cirrhosis was 0.71 and 0.86, respectively. The positive predictive value was 0.86. These diagnostic figures were better than those obtained by using the Child classification. This result is especially renmrkable because the diagnostic efficacy of the Child classification is positively biased by including some of the criteria of complications of liver cirrhosis, e.g. aseites.
1340 GLUCAGON SECRETION IN DIABETIC AND NON-DIABETIC CIRRHOTIC PATIENTS Yolanta Kruszynska, Spires Goulas, and Neil McIntvre. Depts. Medicine, University of California, San Diego and Royal Free Hospital, London, UK. Cirrhotic patients are glucose intolerant and many develop diabetes. Hypersecretion of glucagon in cirrhosis is wall-recognised. It is unclear if diabetes further enhances glucagon secretion and whether the regulation of glucagon secretion by glucose is normal in non-diabetic (NDC) and diabetic cirrhotics (DC). We studied 6 controls, 6 NDC and 5 DC (fasting blood glucose, 8.3_+0.4 mmol/t). The ability of hyperglycaemia to suppress plasma glucagon levels was examined by performing short (35 rain) glucose clamps at 12, 19 and 28 mmol/t glucose with a 2h "washout" between clamps to restore normoglycaemia which required infusion of insulin in diabetics. The inhibitory effect of glucose on the acute glucagon (2-5min) response to arginine (5g IV over 1 rain) was studied at basal glucose (5.0 mmol/1) and after 35 rain at 12, 19 and 28 mmol. Fasting ghicagon was higher in NDC (212 + 40 ng/l) than controls (86 + 11, p<0.05) but lower than in DC (389 + 36,p<0.05). Plasma glucagon remained higher in NDC than controls at 12 mmol/l (88 _+ 11 vs 49 + 8 p<0.05) but fell to similar low levels after 35 rain at t9 and 28retool/1 glucose. Suppression of glucagon by hyperglycaemia was impaired in DC: at 28 mmol/l glucose, plasma glucagon was much higher in DC (197 + 53 ng/l) than in controls (23_+4, p<0.01) or NDC (26+5, p<0.01). The incremental glucagon response to arginine at 5.0 mmolfl glucose was greater in NDC (271 + 48 ng/l) than controls (103 + 21, p<0.01) and much greater in DC (963 + 162, p<0.001). The incremental ghicagon response to arginine was much lower at high glucose levels in NDC and controls (at 28 retool/1 glucose: NDC, 155 + 25; controls, 58 + 10 ng/1) but not in DC in whom the very high response to arginine was unaffected (at 28 retool/1 glucose: 951 + 184 ng/1, p<0.001 vs controls). Glucagon secretion in cirrhosis is hypcr-responsive to arginine and this is markedly enhanced by concomitant diabetes. The inhibitory effect of glucose on basal and arginine induced glucagon secretion is impaired in cirrhosis, particularly those with diabetes. Increased glucagon secretion in DC would be expected to affect hepatic glucose handling and contribute to hypcrglycaemia after a proteincontaining mixed meal.
AASLD ABSTRACTS
1337 IMPAIRED BARORECEPTOR
SENSITIVITY IN RATS W I T H BILIARY CIRRHOSIS. KI Kroeker and SS Lee. Liver Unit, University of Calgary, Calgary, Canada.
Cirrhosis is associated with cardiovascular abnormalities, including changes in baroreflex sensitivity, although this has not been uniformly demonstrated in all studies. We aimed to clarify the baroreflex function in cirrhotic rats, using the best available quantitative method of baroreflex sensitivity. Bile duct ligation was utilized to induce cirrhosis, which was present 4 weeks post-operative (n=8), while controls underwent sham operation (n=9). Blood pressure and heart rate were monitored via a femoral artery cannula. In pentobarbital anesthetized rats, the beat-to-beat relationship between changes in heart rate and systolic blood pressure following intravenous phenylephrine injection (1.5~Lg) was plotted and the slope determined. This slope has been shown to reliably quantitate baroreflex sensitivity. Further, we calculated the dose of atropine required to completely paralyze the reflex arc by injecting 3 cumulative doses of atropine sulfate (2.0, 4.0, 6.01ttg). The baroreflex slope of the cirrhotic rats was significantly lower than the control (0.116+0.090 vs. 0.257+0.169msec/mmHg, p<0.05). The atropine blocking dose was also lowered in the cirrhotic rats (0.014_+0.007 vs. 0.026_+0.019mg/kg atropine sulfate), although this did not quite reach statistical significance (p=0.07), These results demonstrate that there is a decreased baroreflex sensitivity associated with cirrhosis. Furthermore, the decreased atropine blocking dose, associated with cirrhosis suggests that this impairment in baroreflex function may be secondary to alterations in the afferent arc of the baroreflex due to a decrease in parasympathetic tone.
1339 RESPONSE TO 100% INSPIRED OXYGEN IN PATIENTS WITH HEPATOPULMONARY SYNDROME. MJ Krowka. M Castro. DA Cortese, JR Sulvev. Mayo Clinic Jacksonville, Jacksonville, FL Hepatopulmonarysyndrome (HPS) is a pulmonary vascular complication of liver disease which can result in clinically significant arterial hypoxemiawhile breathing room air (R.A). The degree of hypoxemiabreathing RA may not fullycharacterize the severity of the oxygenationabnormality. We sought to determine the effect of breathing 100% inspired oxygenon PaO2 in this syndrome. Methods: 20 adult patients with well documented HPS due to chronic liver disease were prospectivelystudied. Contrast echocardiography, 99roTe macroaggregated albumin lung scanning or pulmonary angiography was used to establish the diagnosis of HPS. Arterial oxygenation was measured via radial artery catheterization by determining PaO2 in the supine and standing positions while breathing RA and 100% inspired oxygen (via nasal dips and sealed mouth piece). Results: The severity of hypoxemiabreathing RA in the supine position (mean PaO2 56+-7 mmHg; range 44-70) or standing position (mean PaO2 44±6 mmHg; range 36-54) correlated poorly with PaO2 determinations breathing 100% inspired 02 in the supine or standing position, respectively: RA versus 100% inspired 02 Mean Pat:)2 (range) Spearman Rank Correlation Position breathing 100% 02* "r" r2 p-value Supine
409+110 mmHg (184-566)
.44
.19
NS
Standing
276+157 mmHg (84-522)
.24
.06
NS
* supine vs standing significantlydifferent; p < .0001 Response to 100% inspired oxygen in patients with HPS was extremely variable. PaO2 determinations breathing room air had poor predictive value in identifying PaO2 response to 100% 02 and, therefore, potentially underestimated the severityof the oxygenationproblem. This observation may be of prognostic and clinical importance in liver transplant candidates concerning the reversibility and morbidity associated with this syndrome. Conclusion:
441A
1338 THE PROGNOSTIC VALUE OF SERUM LAMININ COMPARED WITH CHILD CLASSIFICATION FOR CHRONIC LIVER DISEASE. J Kronf. TH Ktmer, AM Gressner. Dept. of Clinical Chemistry and Central Laboratory, Philipps University, 35033 Marburg, Baldingerst., Germany The high-molecular weight glyeoprotein laminin, a main extraeellular constituent of basal membranes, is found in increased concentrations in blood of patients with chronic liver disease. In liver cirrhosis a significant correlation between the concentration of serum laminin and portal hypertension has been reported. We here present the results of a prospective study evaluating the diagnostic value of serum laminin in elinieaily severe complications of progressive liver cirrhosis. During a mean follow-up period of 12.5 ± 3.5 months hi 38 patients with liver fibrosis (n = 4) and liver cirrhosis (Child A: n = 17, B: n = 7, C: n = 10) the serum levels of laminin were determined using the RIA kit from Behring-Hoechst (FRG). Portal hypertension was assessed by endoscopic control of the esophageal varioosis and by Doppler sonography of the portal blood flow. While the concentration of laminin was significantly increased (P < 0.01) in higher Child stages, there was no significant correlation between laminin and portal hypertension. There was, however, a highly significant association (P < 0.001) between an increase of serum laminin in the group with complications of liver cirrhosis (3.25 ± 0.2 U/mI) in comparison to patients without complications (2.13 ± 0.26). Using a cut-off value of 2.6 U/ml for lamiain, the sensiti;Aty and specificity for diagnosis of severe complications of liver cirrhosis was 0.71 and 0.86, respectively. The positive predictive value was 0.86. These diagnostic figures were better than those obtained by using the Child classification. This result is especially renmrkable because the diagnostic efficacy of the Child classification is positively biased by including some of the criteria of complications of liver cirrhosis, e.g. aseites.
1340 GLUCAGON SECRETION IN DIABETIC AND NON-DIABETIC CIRRHOTIC PATIENTS Yolanta Kruszynska, Spires Goulas, and Neil McIntvre. Depts. Medicine, University of California, San Diego and Royal Free Hospital, London, UK. Cirrhotic patients are glucose intolerant and many develop diabetes. Hypersecretion of glucagon in cirrhosis is wall-recognised. It is unclear if diabetes further enhances glucagon secretion and whether the regulation of glucagon secretion by glucose is normal in non-diabetic (NDC) and diabetic cirrhotics (DC). We studied 6 controls, 6 NDC and 5 DC (fasting blood glucose, 8.3_+0.4 mmol/t). The ability of hyperglycaemia to suppress plasma glucagon levels was examined by performing short (35 rain) glucose clamps at 12, 19 and 28 mmol/t glucose with a 2h "washout" between clamps to restore normoglycaemia which required infusion of insulin in diabetics. The inhibitory effect of glucose on the acute glucagon (2-5min) response to arginine (5g IV over 1 rain) was studied at basal glucose (5.0 mmol/1) and after 35 rain at 12, 19 and 28 mmol. Fasting ghicagon was higher in NDC (212 + 40 ng/l) than controls (86 + 11, p<0.05) but lower than in DC (389 + 36,p<0.05). Plasma glucagon remained higher in NDC than controls at 12 mmol/l (88 _+ 11 vs 49 + 8 p<0.05) but fell to similar low levels after 35 rain at t9 and 28retool/1 glucose. Suppression of glucagon by hyperglycaemia was impaired in DC: at 28 mmol/l glucose, plasma glucagon was much higher in DC (197 + 53 ng/l) than in controls (23_+4, p<0.01) or NDC (26+5, p<0.01). The incremental glucagon response to arginine at 5.0 mmolfl glucose was greater in NDC (271 + 48 ng/l) than controls (103 + 21, p<0.01) and much greater in DC (963 + 162, p<0.001). The incremental ghicagon response to arginine was much lower at high glucose levels in NDC and controls (at 28 retool/1 glucose: NDC, 155 + 25; controls, 58 + 10 ng/1) but not in DC in whom the very high response to arginine was unaffected (at 28 retool/1 glucose: 951 + 184 ng/1, p<0.001 vs controls). Glucagon secretion in cirrhosis is hypcr-responsive to arginine and this is markedly enhanced by concomitant diabetes. The inhibitory effect of glucose on basal and arginine induced glucagon secretion is impaired in cirrhosis, particularly those with diabetes. Increased glucagon secretion in DC would be expected to affect hepatic glucose handling and contribute to hypcrglycaemia after a proteincontaining mixed meal.