Regional variations in the concentrations of ketone bodies in cirrhosis and hepatic encephalopathy: a study in patients with TIPSS.

BACKGROUND: Little is known about the metabolism of acetoacetate and ß-hydroxybutyrate in patients with cirrhosis and encephalopathy. AIMS: We investigated the fate of ketone bodies in these conditions. MATERIALS AND METHODS: We studied 18 cirrhotic patients with encephalopathy and 17 cirrhotics without. At the time of insertion of a transjugular intrahepatic portosystemic stent shunt (TIPSS) or at the time of portographical assessment of the shunt's patency, we collected blood from the internal jugular, the right atrium, the inferior vena cava, the hepatic, the portal, the splenic veins and the radial artery. We used nuclear magnetic resonance spectroscopy to measure the concentrations of acetoacetate and ß-hydroxybutyrate. RESULTS: There was no difference in the total ketone body concentrations between the two groups. The mitochondrial redox potential was significantly higher in the encephalopathics (142/54=2.63 vs 52/83=0.62) (P<0.01). ß-hydroxybutyrate was significantly lower in the portal vein of encephalopathics (52 ± 4 vs 28 ± 3) (P<0.02) and in the splenic vein (48 ± 6 vs 32 ± 5) (P<0.04). Acetoacetate was significantly higher in encephalopathics in the internal jugular vein (134 ± 12 vs 92 ± 16) (P<0.03), the right atrium (112 ± 18 vs 68 ± 11) (P<0.03), the hepatic vein (162 ± 25 vs 115 ± 19) (P<0.05), the portal vein (133 ± 20 vs 81 ± 14) (P<0.02) and the splenic vein (167 ± 24 vs 122 ± 21) (P<0.04). All measurements are expressed in µmols/L. CONCLUSIONS: There are significant variations in the regional concentrations of the ketone bodies in encephalopathy.

Improved clinical outcome with transjugular intrahepatic portosystemic stent-shunt utilizing polytetrafluoroethylene-covered stents.

BACKGROUND AND AIMS: Transjugular intrahepatic portosystemic stent-shunt (TIPSS) with standard uncovered stents has a 50% one-year primary patency rate, and is complicated by hepatic encephalopathy in 35% of patients. Newer covered stents appear to have improved patency. This large study aimed to assess the shunt function and clinical efficacy of polytetrafluoroethylene-covered stents in a single centre. METHODS: A total of 316 patients with uncovered stents before the introduction of covered stents (group 1) and 157 patients with the Viatorr Gore polytetrafluoroethylene-covered stents at the time of TIPSS creation (group 2) were studied. RESULTS: The mean follow-up was 22.8+/-25.4 and 13.1+/-12.5 months, respectively (P<0.01). Shunt insufficiency was greater in group 1 [54 versus 8% at 12 months; relative hazard (RH) 8.6; 95% confidence interval (CI) 4.8-15.5; P<0.001]. The incidence of variceal rebleeding was greater in group 1 (11 versus 6% at 12 months; RH 2.4; 95% CI 1.1-5.1; P<0.05). The incidence of hepatic encephalopathy was greater in group 1 (32 versus 22% at 12 months; RH 1.5; 95% CI 1.1-2.3; P<0.05). Mortality was similar in the two groups. CONCLUSION: The Viatorr type of polytetrafluoroethylene-covered stent results in vastly improved patency compared with uncovered stents, with reduced rates of variceal rebleeding and hepatic encephalopathy. This type of covered stent has the potential for superior clinical efficacy compared with uncovered stents.

Transjugular intrahepatic portosystemic stent-shunt and its effects on orthotopic liver transplantation.

BACKGROUND: It has been reported that preoperative transjugular intrahepatic portosystemic stent-shunt (TIPSS) reduces peri-operative transfusion requirements during orthotopic liver transplant, and may result in fewer episodes of poor, early graft function by reducing portosystemic shunting, thus improving portal blood supply to the graft. OBJECTIVE: To test the hypotheses that TIPSS improves early graft function and reduces transfusion requirements. METHODS: A retrospective review of 82 liver transplant recipients between 1993 and 1999 was performed. The subgroups comprised 29 patients who had TIPSS prior to first orthotopic liver transplant and 53 matched controls without TIPSS. RESULTS: There was no significant difference in the early graft function in the two groups. The prothrombin time before an orthotopic liver transplant was independently predictive of initial poor function. Transfusion requirements and total operating times were similar for both groups, although transfusion requirements were greater in those patients where TIPSS led to technical difficulties during the operation (n = 6). The TIPSS patients required a longer hospital stay than the non-TIPSS patients (41 +/- 8 vs 26 +/- 4 days, P < 0.05). There were significantly more patients needing dialysis in the TIPSS group (41.3% vs 9.4%, P < 0.001). Pulmonary infection was less common in the TIPSS group (P < 0.05), with a trend to reduced wound infections. The 12 month patient and graft survival were similar in both groups. Serum albumin levels assessed before orthotopic liver transplant independently predicted 12 month graft survival. CONCLUSIONS: TIPSS does not improve early graft function, nor reduce blood transfusion requirements perioperatively. The longer post-operative hospital stay in the TIPSS group is worthy of further study. TIPSS prior to transplantation, despite having the potential for technical operative complications, has no detrimental effects on patient and graft survival, and if required should be undertaken.

Impact of transjugular intrahepatic portosystemic stent-shunt for secondary prophylaxis of oesophageal variceal haemorrhage: a single-centre study over an 11-year period.

AIMS: The role of various treatments for variceal haemorrhage is currently being evaluated. The purpose of this study was to analyse the impact of the use of endoscopic variceal sclerotherapy (EVS), variceal band ligation (VBL) and transjugular intrahepatic portosystemic stent-shunt (TIPSS) for secondary prophylaxis on the outcome of cirrhotic patients with the first episode of variceal haemorrhage presenting to a single centre. METHODS: Between 1986 and 1996, data from 225 consecutive patients with the first episode of variceal haemorrhage were analysed. The modality of treatment for secondary prophylaxis between 1986 and 1991 was EVS (group I: n = 83; Child class C, 29%; mean follow-up 36 +/- 3 months), between 1991 and 1993 VBL (group II: n = 56; Child class C, 38%; mean follow-up 24 +/- 3 months), and between 1995 and 1996 TIPSS (group III: n = 86; Child class C, 60%; mean follow-up 17 +/- 1 months). Half of the patients between 1993 and 1995 underwent VBL and the other half had TIPSS. Data regarding rebleeding, mortality and encephalopathy were analysed using the Kaplan-Meier method. Cox's proportional hazard regression was used to test the significance of prognostic factors. RESULTS: Seventy-five per cent of patients re-bled in group I, 40% in group II, and 16% in group III (P < 0.0001). Mortality was significantly lower in the patients with Child class C disease in group III patients compared with those in groups I and II (P < 0.02). TIPSS was associated independently with reduced early mortality and re-bleeding. CONCLUSION: The results of this study suggest that TIPSS improves survival in patients with advanced liver disease and variceal haemorrhage, and should be considered for secondary prophylaxis in high-risk patients.

Ten years' follow-up of 472 patients following transjugular intrahepatic portosystemic stent-shunt insertion at a single centre.

BACKGROUND: Transjugular intrahepatic portosystemic stent-shunt (TIPSS) is increasingly used for the management of portal hypertension. We report on 10 years' experience at a single centre. METHODS: Data held in a dedicated database was retrieved on 497 patients referred for TIPSS. The efficacy of TIPSS and its complications were assessed. RESULTS: Most patients were male (59.4%) with alcoholic liver disease (63.6%), and bleeding varices (86.8%). Technical success was achieved in 474 (95.4%) patients. A total of 13.4% of patients bled at portal pressure gradients < or = 12 mmHg, principally from gastric and ectopic varices. Procedure-related mortality was 1.2%. The mean follow-up period of surviving patients was 33.3 +/- 1.9 months. Primary shunt patency rates were 45.4% and 26.0% at 1 and 2 years, respectively, while the overall secondary assisted patency rate was 72.2%. Variceal rebleeding rate was 13.7%, with all episodes occurring within 2 years of TIPSS insertion, and almost all due to shunt dysfunction. The overall mortality rate was 60.4%, mainly resulting from end-stage liver failure (42.5%). Patients who bled from gastric varices had lower mortality than those from oesophageal varices (53.9% versus 61.5%, P < 0.01). The overall rate of hepatic encephalopathy was 29.9% (de novo encephalopathy was 11.5%), with pre-TIPSS encephalopathy being an independent predicting variable. Refractory ascites responded to TIPSS in 72% of cases, although the incidence of encephalopathy was high in this group (36.0%). CONCLUSIONS: TIPSS is effective in the management of variceal bleeding, and has a low complication rate. With surveillance, good patency can be achieved. Careful selection of patients is needed to reduce the encephalopathy rate.

Tipsitis: incidence and outcome-a single centre experience.

INTRODUCTION: Infection of transjugular intrahepatic portosystemic stent shunt (TIPSS) called 'Tipsitis' has been reported but appears unusual. We report here our experience of patients who were diagnosed to have Tipsitis at our centre. METHODS: Retrospective single centre study. Patients identified from a dedicated data base. Patients with TIPSS with otherwise unexplained sustained bacteraemia were included. RESULTS: Over 14 years of age, of 785 patients with TIPSS, eight (1%) had Tipsitis. Indication for TIPSS: variceal bleed, seven; refractory ascites, one. Child-Pugh score: 8.3 (1.4). Seven patients had overlapping stents in situ. Duration to Tipsitis: 21.6 (7.1) months. At diagnosis, TIPSS was occluded in four and patent in three. Tipsitis developed within 2 weeks of shunt interventions in two patients and was owing to development of bilio-venous fistula in one. The organisms identified were: Lactobacillus rhamnosus, Escherichia coli, Enterobacter cloacae, Enterococcusfaecium and Staphylococcus aureus. Median duration of antibiotic therapy: 3 (0.3-3) months. Symptoms initially resolved in all but one. Symptoms recurred in three and this was related to premature cessation of antibiotics in two. Five patients died at a median 1.3 (0.3 to 33) months after Tipsitis with Tipsitis contributing to death in three. CONCLUSION: Tipsitis is a rare but serious problem. It should be suspected in patients with TIPSS and unexplained sustained bacteraemia. Shunt interventions, where TIPSS is inserted for variceal bleed, and use of overlapping shunts at TIPSS insertion may be risk factors for its development. Prolonged antibiotics are usually required but Tipsitis may recur despite apparently successful treatment.

Cortisol release from adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 in humans.

OBJECTIVE: 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates cortisol from cortisone. 11beta-HSD1 mRNA and activity are increased in vitro in subcutaneous adipose tissue from obese patients. Inhibition of 11beta-HSD1 is a promising therapeutic approach in type 2 diabetes. However, release of cortisol by 11beta-HSD1 from adipose tissue and its effect on portal vein cortisol concentrations have not been quantified in vivo. RESEARCH DESIGN AND METHODS: Six healthy men underwent 9,11,12,12-[(2)H](4)-cortisol infusions with simultaneous sampling of arterialized and superficial epigastric vein blood sampling. Four men with stable chronic liver disease and a transjugular intrahepatic porto-systemic shunt in situ underwent tracer infusion with simultaneous sampling from the portal vein, hepatic vein, and an arterialized peripheral vein. RESULTS: Significant cortisol and 9,12,12-[(2)H](3)-cortisol release were observed from subcutaneous adipose tissue (15.0 [95% CI 0.4-29.5] and 8.7 [0.2-17.2] pmol . min(-1) . 100 g(-1) adipose tissue, respectively). Splanchnic release of cortisol and 9,12,12-[(2)H](3)-cortisol (13.5 [3.6-23.5] and 8.0 [2.6-13.5] nmol/min, respectively) was accounted for entirely by the liver; release of cortisol from visceral tissues into portal vein was not detected. CONCLUSIONS: Cortisol is released from subcutaneous adipose tissue by 11beta-HSD1 in humans, and increased enzyme expression in obesity is likely to increase local glucocorticoid signaling and contribute to whole-body cortisol regeneration. However, visceral adipose 11beta-HSD1 activity is insufficient to increase portal vein cortisol concentrations and hence to influence intrahepatic glucocorticoid signaling.

Isoleucine infusion during "simulated" upper gastrointestinal bleeding improves liver and muscle protein synthesis in cirrhotic patients.

UNLABELLED: Upper gastrointestinal (GI) bleeding in cirrhotic patients has a high incidence of mortality and morbidity. Postbleeding catabolism has been hypothesized to be partly due to the low biological value of hemoglobin, which lacks the essential amino acid isoleucine. The aims were to study the metabolic consequences of a "simulated" upper GI bleed in patients with cirrhosis of the liver and the effects of intravenous infusion of isoleucine. Portal drained viscera, liver, muscle, and kidney protein kinetics were quantified using a multicatheterization technique during routine portography. Sixteen overnight-fasted, metabolically stable patients who received an intragastric infusion of an amino acid solution mimicking hemoglobin every 4 hours were randomized to saline or isoleucine infusion and received a mixture of stable isotopes (L-[ring-2H5]phenylalanine, L-[ring-2H4]tyrosine, and L-[ring-2H2]tyrosine) to determine organ protein kinetics. This simulated bleed resulted in hypoisoleucinemia that was attenuated by isoleucine infusion. Isoleucine infusion during the bleed resulted in a positive net balance of phenylalanine across liver and muscle, whereas renal and portal drained viscera protein kinetics were unaffected. In the control group, no significant effect was shown. CONCLUSION: The present study investigated hepatic and portal drained viscera protein metabolism selectively in humans. The data show that hepatic and muscle protein synthesis is stimulated by improving the amino acid composition of the upper GI bleed by simultaneous intravenous isoleucine administration.

Effect of major liver resection on hepatic ureagenesis in humans.

Changes in hepatic ureagenesis following major hepatectomy are not well characterized. We studied the relation between urea synthesis and liver mass before and after major hepatectomy in humans. Fifteen patients scheduled for resection of malignancies in otherwise healthy livers were studied. Pre- and postoperative liver volume was assessed by computerized tomography-volumetry. During surgery, a primed, continuous infusion of [(13)C]urea was administered intravenously, and arterial blood samples were obtained hourly. Indocyanine green clearance was determined before and after resection. Seven patients underwent major hepatectomy, and eight patients underwent minor [<5% functional liver volume (total volume -- tumor volume)] or no resection, serving as controls. Resected functional liver volume in the major hepatectomy group averaged 60%. Urea synthesis per gram of functional liver tissue increased 2.6-fold following major hepatectomy, maintaining whole body urea synthesis. Arterial ammonia remained unchanged throughout the study, whereas following hepatectomy a hyperaminoacidemia occurred. In conclusion, immediately following major hepatectomy, urea synthesis per gram of functional liver tissue increases rapidly and proportionately to the amount of liver tissue resected, maintaining whole body urea synthesis at preoperative levels. This rapid and complete adaptation suggests that the capacity of urea synthesis is not limiting the maximum resectable volume in otherwise healthy livers.

The natural history of parallel transjugular intrahepatic portosystemic stent shunts using uncovered stent: the role of host-related factors.

OBJECTIVES: Parallel shunts (PS) are used in the management of transjugular intrahepatic portosystemic stent-shunt (TIPS) insufficiency, a major limitation of the technique. This study describes the natural history of PS, and uses them as a model to assess the role of host factors in the development of primary shunt insufficiency. METHODS: Out of 338 patients with TIPS, 40 (11.8%) patients required insertion of a PS. Baseline and follow-up data of these patients were collected. Regular shunt surveillance involved biannual clinic visits and transjugular portography. RESULTS: The non-PS group (group 1; n = 298) and the PS group (group 2; n = 40) had similar baseline demographic and disease characteristics. Index shunts of both groups and the PS produced a significant portal pressure gradient drop (P < 0.001), which was less in the index shunts of Group 2 (P < 0.02 for both). PS had similar cumulative shunt patency rates to those of the index shunts of Group 1, and both were greater than those of index shunts in Group 2 (P < 0.001 for both). The intervention rate (number of interventions/number of check portograms x 100) was similar for PS and the index shunts of Group 1 (38.7% and 43% respectively), but was significantly higher in the index shunts of Group 2 (85.6%; P < 0.01 for both). In Group 1 and Group 2, 144 patients (48.3%) and 21 patients (52.5%) died during follow-up after a median period of 23.4 and 8.9 months respectively. CONCLUSIONS: These findings do not support the hypothesis that shunt insufficiency is related to host factors.

Kidney plays a major role in ammonia homeostasis after portasystemic shunting in patients with cirrhosis.

The kidney plays an important role in ammonia metabolism. In this study the hypothesis was tested that the kidney can acutely diminish ammonia release after portacaval shunting. Thirteen patients with cirrhosis (6 female/7 male, age 54.4 +/- 3.3 yr) were studied. Blood was sampled prior to and 1 h after transjugular intrahepatic stent-shunt (TIPSS) insertion from the portal vein, a hepatic vein, the right renal vein, and the femoral vein, and renal and liver plasma flow were measured. Prior to TIPSS, renal ammonia release was significantly higher than ammonia release from the splanchnic region, which was not significantly different from zero. TIPSS insertion did not change arterial ammonia concentration or ammonia release from the splanchnic region but reduced renal ammonia release into the circulation (P < 0.05) to values that were not different from zero. TIPSS resulted in a tendency toward increased venous-arterial ammonia concentration differences across leg muscle. Post-TIPSS ammonia efflux via portasystemic shunts was estimated to be seven times higher than renal efflux. Kidneys have the ability to acutely diminish systemic ammonia release after portacaval shunting. Diminished renal ammonia release and enhanced muscle ammonia uptake are important mechanisms by which the cirrhotic patient maintains ammonia homeostasis after portasystemic shunting.

The adaptive response of the reticuloendothelial system to major liver resection in humans.

OBJECTIVE: To evaluate the contribution of the liver to total circulatory reticuloendothelial system (RES) phagocytosis capacity in patients undergoing liver resection and to compare it with values in end-stage chronic liver disease. SUMMARY BACKGROUND DATA: The mechanism whereby major liver resection is associated with a high incidence of infection is unknown. Significant impairment of RES phagocytosis has been described in liver failure, rendering such patients susceptible to infection; and we hypothesized that similar impairment might occur following major liver resection. METHODS: A prospective study was conducted in which Tc-albumin microspheres blood clearance served as a parameter for RES phagocytosis and was studied together with indocyanine green blood clearance, actual liver volume measured by three-dimensional image analysis, and a clinical score of hepatic dysfunction in 17 patients undergoing liver resection and in 8 patients with end-stage chronic liver disease assessed for liver transplantation. RESULTS: When expressed relative to volume unit of residual liver, microspheres clearance increased significantly in the immediate postoperative period (day 1) following major (0.009% versus 0.022% min(-1) mL(-1), P < 0.001), but not minor liver resection. In contrast, the absolute rate of microsphere clearance decreased following major resection (15% min(-1) versus 10% min(-1), P < 0.001) and was comparable with the rate observed in end-stage chronic liver disease (9% min(-1)). This decrease in circulatory microspheres clearance after resection paralleled a decrease in indocyanine green clearance (R2 = 0.511, P = 0.006), and there was a trend for those with moderate liver dysfunction to have lower microspheres clearance rates (P = 0.068). CONCLUSION: Preservation of a minimum volume of functioning liver is a prerequisite for adequate RES phagocytosis capacity, and failure of this system may predispose patients undergoing major liver resection to infection as observed in clinical studies.

Systemic and regional changes in plasma endothelin following transient increase in portal pressure.

An acute increase in portal pressure or reduction in portal inflow has been shown to decrease renal plasma flow (RPF). The aim of the study was to evaluate regional and systemic hemodynamics after acute occlusion of a transjugular intrahepatic portosystemic stent-shunt (TIPSS) and study the effect of the same on plasma endothelin (ET-1) levels in the systemic circulation, renal vein, and hepatic vein. Sixteen patients attending for portography after previous TIPSS placement were studied. The shunt was acutely occluded with an angioplasty balloon for 12 minutes. Changes in portal pressure gradient (PPG), hepatic plasma flow (HPF), RPF, cardiac output (CO), and systemic vascular resistance (SVR) were measured before and after shunt occlusion. Blood was collected from the femoral artery and hepatic and renal veins for ET-1 measurement. At T = 0, SVR correlated with circulating arterial ET-1 level (r = 0.74; P <.05). After shunt occlusion (T = 12 minutes), heart rate, CO, and mean arterial pressure decreased (P <.05), whereas PPG increased (P <.05). RPF decreased from 485 +/- 55 to 282 +/- 47 mL/min (P <.01), whereas HPF increased from 700 +/- 39 to 779 +/- 33 mL/min (P <.001). There was a significant increase in arterial concentration and renal production, and decrease in hepatic production of ET-1. Veno-arterial (V-A) concentration difference in ET-1 level in the renal vein, as well as renal flux of ET-1, increased significantly, whereas hepatic vein V-A concentration difference and hepatic flux of ET-1 decreased significantly. At T = 12 minutes, ET-1 renal output correlated negatively with RPF (r = 0.72; P <.05). Results of this study show that an acute increase in portal pressure and reduction in portal inflow brought about by occlusion of a TIPSS shunt decreases RPF and increases HPF. These hemodynamic changes are accompanied by increases in arterial, renal vein, and hepatic vein ET-1 concentrations, which may possibly mediate the observed findings.

Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS.

Ammonia is central to the pathogenesis of hepatic encephalopathy. This study was designed to determine the quantitative dynamics of ammonia metabolism in patients with cirrhosis and previous treatment with a transjugular intrahepatic portosystemic stent shunt (TIPSS). We studied 24 patients with cirrhosis who underwent TIPSS portography. Blood was sampled and blood flows were measured across portal drained viscera, leg, kidney, and liver, and arteriovenous differences across the spleen and the inferior and superior mesenteric veins. The highest amount of ammonia was produced by the portal drained viscera. The kidneys also produced ammonia in amounts that equaled total hepatosplanchnic area production. Skeletal muscle removed more ammonia than the cirrhotic liver. The amount of nitrogen that was taken up by muscle in the form of ammonia was less than the glutamine that was released. The portal drained viscera consumed glutamine and produced ammonia, alanine, and citrulline. Urea was released in the splenic and superior mesenteric vein, contributing to whole-body ureagenesis in these cirrhotic patients. In conclusion, hyperammonemia in metabolically stable, overnight-fasted patients with cirrhosis of the liver and a TIPSS results from portosystemic shunting and renal ammonia production. Skeletal muscle removes more ammonia from the circulation than the cirrhotic liver. Muscle releases excessive amounts of the nontoxic nitrogen carrier glutamine, which can lead to ammonia production in the portal drained viscera (PDV) and kidneys. Urinary ammonia excretion and urea synthesis appear to be the only way to remove ammonia from the body.

The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis.

Upper gastrointestinal (UGI) bleeding in cirrhosis is associated with enhanced ammoniagenesis, the site of which is thought to be the colon. The aims of this study were to evaluate interorgan metabolism of ammonia following an UGI bleed in patients with cirrhosis. Study 1: UGI bleed was simulated in 8 patients with cirrhosis and a transjugular intrahepatic portasystemic stent-shunt (TIPSS) by intragastric infusion of an amino acid solution that mimics the hemoglobin molecule. We sampled blood from the femoral artery and a femoral, renal, portal, and hepatic vein for 4 hours during the simulated bleed and measured plasma flows across these organs. Study 2: In 9 cirrhotic patients with an acute UGI bleed that underwent TIPSS insertion, blood was sampled from an artery and a hepatic, renal, and portal vein, and plasma flows were measured. Study 1: During the simulated bleed, arterial concentrations of ammonia increased significantly (P =.002). There was no change in ammonia production from the portal drained viscera, but renal ammonia production increased 6-fold (P =.008). In contrast to an unchanged ammonia removal by the liver, a significant increase in muscle ammonia removal was observed. Study 2: In patients with an acute UGI bleed, ammonia was only produced by the kidneys (572 [184] nmol/kg bw/min) and not by the splanchnic area (-121 [87] nmol/kg bw/min). In conclusion, enhanced renal ammonia release has an important role in the hyperammonemia that follows an UGI bleed in patients with cirrhosis. During this hyperammonemic state, muscle is the major site of ammonia removal.