- Email: [email protected]
Hepatic energy reserve and nicotinamide methylation
April 1995
AASLD
HEPATIC ENERGY RESERVE AND NICOTINAMIDE METHYLATION. R.Pumpo, R.Cuomo, G.Samelli, P.Cipolletti, GBudillon. Cattedra di Gastroenterologia 2, Universit~t di Napoli " Federico II", Naples, Italy. The decrease of hepatic energy reserve in liver diseases may affect many metabolic pathways that require adenosine triphosphate (ATP), e.g., the synthesis of pyridine nucleotides from nicotinamide (NAM). When exogenous NAM is poorly utilized in this synthesis, it follows a dissipative metabolic pathway and is excreted in urine as Nmethylnicotinamide (NMN). Recently we reported a significant increase of NMN production and excretion in cirrhotic patients both in basal condition and aRer NAM oral load. The aim of this study was to verify NMN production in relation to hepatic content of ATP and NAD+NADH during m vitro perfusion of rat liver, in normal conditions and aRer metabolic stress (obtained by 15-rain saline perfusion before per'fusion with nutritive medium). At 90 rain of rat liver perfusion, the output levels of NMN were 31.50 + 4.72 nmol/g (mean _+ SEM) and 66.40_+13.17 for normal and stressed liver, respectively (p<0.001). At the end ofperfusion, the liver content of ATP and total nicotinamide adenine dinucleotide (NAD+NADH) was significantly decreased in the "stress" experiments (ATP decrease: 47% for normal and 65% for stressed liver; total NAD decrease: 27% for normal and 43% for stressed liver). Liver ATP was inversely related to NMN pr~uction (r=0.93; p<0.0l). These data suggest that NAM methylatio~ is increased in liver damage induced by hypoxia and metabolic stress. The study of NMN production (before and after NAM load) could be a reliable means with which to explore the energy failure of diseased liver in man.
Al151
• TRANSJUGULAR INTRAHEPATIC ?ORTOSYSTEMIC SHUb T (TtPSS) IMPROVES THE PLATELE7 COUNT IN PATIENTS ~ ITH PORTAL HYPERTENSION. K.G. Pursnani; U.M. Patel; L.F. Siliin; D.S. Kaplan; P.S Chopra; R.P. (Dates; Departments of Surgery, Medicine, Radiology, Preventive Medicine and TIPSS Workinf Committee; SUNY Health Science Center at Syracuse, NY 1321 , USA. Patients with portal hypertension(PH) frequently have throrr rocytopenia (TCP) from secondary hypersplenism. TIPSS is a mil~imally invasive procedure designed to reduce PH. Surgical shunts all.
<. . . . . . . . . . (0-7 days) (n=45) 100.8+5 l*
-Post TIPSS ................ > (8-30 c,eys) (n=28" 111.4:H1.9"
Blood transfusion immediately after TIPSS (3.6i0.7 units) in 27 9f 45 patients may have contributed to th ~ initial rise in platelet count. However, the rise in platelet count 8 ~,0 days after TIPSS appeal -. to be due to the procedure. Conclusion: ",'iLesedata indicate that TIi-'3S improves the TCP, at least in the s h . , t term, in patients with secondary hypersplenism due to PH.
• DOES SUBCLINICAL HEPATIC ENCEPHALOPATHY AFFECT QUALITY OF LIFE? J.C. Ouero, I. de Bruijn, I.J.C. Hartmann, S.W. Schalm. Dept of Internal Medicine II (Hepatology section), University Hospital Dijkzigt, Rotterdam, The Netherlands. Subclinical hepatic encephalopathy (SHE) is assumed to have a negative effect on patients' daily functioning, but no quality of life studies have been performed to document this. In order to measure the impact of SHE on the quality of life, 83 consecutive patients (32 female, mean age 50.0 years, SD 13.6, range 15-74) with livercirrhosis and no clinical signs of encephalopathy were screened for SHE using psychometric tests (NCT-A, NCT-B, SDT) with normal values corrected for age and spectraI-EEG. SHE was defined as >. 1 abnormal psychometric test and/or abnormal spectraI-EEG. In addition, quality of life was measured by administering the 'Sickness Impact Profile' (SIP) questionnaire to the patients. According to our definition 26 patients (31%) had SHE. Patients with SHE were significantly older (56.2 yrs, SD 10) compared to those without SHE ( n = 5 7 , 47.3 yrs, SD 14.2). In addition, patients with SHE differed significantly from those without SHE in the total SIP score, based on differences in the physical and independent categories of the SIP. Patients with SHE reported significantly more disturbances of sleep and rest. % dysfunction in Total different categories SIP
no SHE SHE
6.7 11.0
Physical Psychosocial Independent Sleep/rest category category category 2.3 6.7
9.1 11.0
9.0 15.9
11.3 19.2
Conclusions: These results suggest that patients with SHE have a decreased quality of life. However, the clinical association of these findings should be evaluated by measuring quality of life before and after specific therapy for SHE.
EFFECTIVE REDUCTION OF PORTAL HYPERTENSION BY TRANSJUGULAR INTK4HEPATIC PORTOSYSTEMIC SHUNT (TIPS) PROCEDURE HAS NO SHORT TERM EFFECT ON PANCYTOPENIA DUE TO "HYPERSPLENISM". ~ E. Lipinstd, J. Zaeberl, J. Kettenbach, R. Wfldling, A. Gangl, J. Pidiich. Dept. of Gas~oenterology, Surgery, and Interventional Radiology, University of Vienna, Austria Paucytopenia is a common finding among patients with advanced stages of cirrhosis of the liver. This finding, commonly referred to as "hypersplenism", is thought to be due to the portal hypertension and the concomitant accelerated degradation of blood cells in the mostly enlarged spleen. Nevertheless, although effective reduction of portal hypertension has been achieved in the past by a variety, of interventions, the only consismnt improvement of pancytopenia, especially thrombocytopenia, can be seen after liver transplantanon. In our study, 15 patients with advanced stages of cirrhosis of the liver (Child stage B and C) underwent a TIPS-procedure for relief of portal hypertension to alleviate intractable ascitos. The procedure was successful in all 15 patients, effective reduction of portal hypertension and shunt pa~ncy was documented during the study period, and a statistically significant reduction in bodyweight due to increased urinary fluid excretion was observed during short term follow-up. On the contrary, we did not observe a smtastically significant increase in thrombocym- or leukocyte count one or two weeks post TIPS-procedure when compared to pro-TIPS values. After an initial drop right ai~r TIPS-implantation, the thrombocyte count gradually improved over the study period and almost reached pro-TIPS values after 14 days, where it levelled off. This observation, which cerrelazed with a loss of liver function as evidenced by an increase in plasma bilirubin levels, nevertheless did not reach statistical significance. We conclude that the TIPS-procedure, just as other mcthoda of reducing portal hypertension, is not an effective means for short term improvement of paneytopenia, especially thrombopenia, as would be desireablc for surgical interventions in patients with advanced cirrhosis of the liver. The observation e r a drop in thrombocyte count with deteriorating liver-function as well as the fact that liver-transplam remains the only effective way of revering "hypersplenism" suggests a lack of liver-derived growth factors as the main pathogenetic principle for pancytopenia in advanced cirrhosis of the liver.
AASLD
HEPATIC ENERGY RESERVE AND NICOTINAMIDE METHYLATION. R.Pumpo, R.Cuomo, G.Samelli, P.Cipolletti, GBudillon. Cattedra di Gastroenterologia 2, Universit~t di Napoli " Federico II", Naples, Italy. The decrease of hepatic energy reserve in liver diseases may affect many metabolic pathways that require adenosine triphosphate (ATP), e.g., the synthesis of pyridine nucleotides from nicotinamide (NAM). When exogenous NAM is poorly utilized in this synthesis, it follows a dissipative metabolic pathway and is excreted in urine as Nmethylnicotinamide (NMN). Recently we reported a significant increase of NMN production and excretion in cirrhotic patients both in basal condition and aRer NAM oral load. The aim of this study was to verify NMN production in relation to hepatic content of ATP and NAD+NADH during m vitro perfusion of rat liver, in normal conditions and aRer metabolic stress (obtained by 15-rain saline perfusion before per'fusion with nutritive medium). At 90 rain of rat liver perfusion, the output levels of NMN were 31.50 + 4.72 nmol/g (mean _+ SEM) and 66.40_+13.17 for normal and stressed liver, respectively (p<0.001). At the end ofperfusion, the liver content of ATP and total nicotinamide adenine dinucleotide (NAD+NADH) was significantly decreased in the "stress" experiments (ATP decrease: 47% for normal and 65% for stressed liver; total NAD decrease: 27% for normal and 43% for stressed liver). Liver ATP was inversely related to NMN pr~uction (r=0.93; p<0.0l). These data suggest that NAM methylatio~ is increased in liver damage induced by hypoxia and metabolic stress. The study of NMN production (before and after NAM load) could be a reliable means with which to explore the energy failure of diseased liver in man.
Al151
• TRANSJUGULAR INTRAHEPATIC ?ORTOSYSTEMIC SHUb T (TtPSS) IMPROVES THE PLATELE7 COUNT IN PATIENTS ~ ITH PORTAL HYPERTENSION. K.G. Pursnani; U.M. Patel; L.F. Siliin; D.S. Kaplan; P.S Chopra; R.P. (Dates; Departments of Surgery, Medicine, Radiology, Preventive Medicine and TIPSS Workinf Committee; SUNY Health Science Center at Syracuse, NY 1321 , USA. Patients with portal hypertension(PH) frequently have throrr rocytopenia (TCP) from secondary hypersplenism. TIPSS is a mil~imally invasive procedure designed to reduce PH. Surgical shunts all.
<. . . . . . . . . . (0-7 days) (n=45) 100.8+5 l*
-Post TIPSS ................ > (8-30 c,eys) (n=28" 111.4:H1.9"
Blood transfusion immediately after TIPSS (3.6i0.7 units) in 27 9f 45 patients may have contributed to th ~ initial rise in platelet count. However, the rise in platelet count 8 ~,0 days after TIPSS appeal -. to be due to the procedure. Conclusion: ",'iLesedata indicate that TIi-'3S improves the TCP, at least in the s h . , t term, in patients with secondary hypersplenism due to PH.
• DOES SUBCLINICAL HEPATIC ENCEPHALOPATHY AFFECT QUALITY OF LIFE? J.C. Ouero, I. de Bruijn, I.J.C. Hartmann, S.W. Schalm. Dept of Internal Medicine II (Hepatology section), University Hospital Dijkzigt, Rotterdam, The Netherlands. Subclinical hepatic encephalopathy (SHE) is assumed to have a negative effect on patients' daily functioning, but no quality of life studies have been performed to document this. In order to measure the impact of SHE on the quality of life, 83 consecutive patients (32 female, mean age 50.0 years, SD 13.6, range 15-74) with livercirrhosis and no clinical signs of encephalopathy were screened for SHE using psychometric tests (NCT-A, NCT-B, SDT) with normal values corrected for age and spectraI-EEG. SHE was defined as >. 1 abnormal psychometric test and/or abnormal spectraI-EEG. In addition, quality of life was measured by administering the 'Sickness Impact Profile' (SIP) questionnaire to the patients. According to our definition 26 patients (31%) had SHE. Patients with SHE were significantly older (56.2 yrs, SD 10) compared to those without SHE ( n = 5 7 , 47.3 yrs, SD 14.2). In addition, patients with SHE differed significantly from those without SHE in the total SIP score, based on differences in the physical and independent categories of the SIP. Patients with SHE reported significantly more disturbances of sleep and rest. % dysfunction in Total different categories SIP
no SHE SHE
6.7 11.0
Physical Psychosocial Independent Sleep/rest category category category 2.3 6.7
9.1 11.0
9.0 15.9
11.3 19.2
Conclusions: These results suggest that patients with SHE have a decreased quality of life. However, the clinical association of these findings should be evaluated by measuring quality of life before and after specific therapy for SHE.
EFFECTIVE REDUCTION OF PORTAL HYPERTENSION BY TRANSJUGULAR INTK4HEPATIC PORTOSYSTEMIC SHUNT (TIPS) PROCEDURE HAS NO SHORT TERM EFFECT ON PANCYTOPENIA DUE TO "HYPERSPLENISM". ~ E. Lipinstd, J. Zaeberl, J. Kettenbach, R. Wfldling, A. Gangl, J. Pidiich. Dept. of Gas~oenterology, Surgery, and Interventional Radiology, University of Vienna, Austria Paucytopenia is a common finding among patients with advanced stages of cirrhosis of the liver. This finding, commonly referred to as "hypersplenism", is thought to be due to the portal hypertension and the concomitant accelerated degradation of blood cells in the mostly enlarged spleen. Nevertheless, although effective reduction of portal hypertension has been achieved in the past by a variety, of interventions, the only consismnt improvement of pancytopenia, especially thrombocytopenia, can be seen after liver transplantanon. In our study, 15 patients with advanced stages of cirrhosis of the liver (Child stage B and C) underwent a TIPS-procedure for relief of portal hypertension to alleviate intractable ascitos. The procedure was successful in all 15 patients, effective reduction of portal hypertension and shunt pa~ncy was documented during the study period, and a statistically significant reduction in bodyweight due to increased urinary fluid excretion was observed during short term follow-up. On the contrary, we did not observe a smtastically significant increase in thrombocym- or leukocyte count one or two weeks post TIPS-procedure when compared to pro-TIPS values. After an initial drop right ai~r TIPS-implantation, the thrombocyte count gradually improved over the study period and almost reached pro-TIPS values after 14 days, where it levelled off. This observation, which cerrelazed with a loss of liver function as evidenced by an increase in plasma bilirubin levels, nevertheless did not reach statistical significance. We conclude that the TIPS-procedure, just as other mcthoda of reducing portal hypertension, is not an effective means for short term improvement of paneytopenia, especially thrombopenia, as would be desireablc for surgical interventions in patients with advanced cirrhosis of the liver. The observation e r a drop in thrombocyte count with deteriorating liver-function as well as the fact that liver-transplam remains the only effective way of revering "hypersplenism" suggests a lack of liver-derived growth factors as the main pathogenetic principle for pancytopenia in advanced cirrhosis of the liver.