A new composite model including metabolic syndrome, alanine aminotransferase and cytokeratin-18 for the diagnosis of non-alcoholic steatohepatitis in morbidly obese patients.

BACKGROUND: Non-invasive approaches are useful to differentiate simple steatosis from non-alcoholic steatohepatitis (NASH) in obese and morbidly obese patients. AIM: To develop a new scoring system to diagnose definitive NASH. METHODS: Preoperative clinical and biological data including serum caspase 3-generated cytokeratin-18 fragments (CK18) and surgical liver biopsies were obtained from 464 morbidly obese patients who had undergone bariatric surgery. The cohort was divided into two groups: training group (n = 310) and validation group (n = 154). Definitive NASH was defined according to Kleiner's classification with a Non-alcoholic fatty liver disease Activity Score (NAS) ≥5. RESULTS: Alanine aminotransferase (ALT), CK18 fragments and the presence of metabolic syndrome were independent predictors for discriminating patients with NAS ≥5 in the training group. These three parameters were used to carry out a scoring system for the prediction of NAS ≥5. Whereas serum CK18 fragment alone had an area under the receiver operating characteristic (AUROC) curve = 0.74, AUROC curves of the scoring system were 0.88 and 0.83 in the training group and the validation group, respectively. CONCLUSION: A simple and non-invasive composite model (the Nice Model) including metabolic syndrome, ALT and CK18 fragments is able to predict accurately a non-alcoholic fatty liver disease activity score ≥5 in morbidly obese subjects.

Predictive factors of bleeding related to post-banding ulcer following endoscopic variceal ligation in cirrhotic patients: a case-control study.

BACKGROUND: Life-threatening bleeding caused by early spontaneous slippage of rubber bands has been described after variceal ligation in cirrhotic patients. AIM: To determine the predictive factors of this complication in cirrhotic patients. METHODS: Among 605 patients, 21 patients (mean age 56.6 +/- 13.5 years) developed 23 spontaneous band slippages with bleeding on post banding ulcer, as confirmed by endoscopy. Cirrhosis was alcoholic in 13 patients (62%), post viral hepatitis in three (14%) and from other causes in five (24%). A case-control study was performed comparing 17 from these patients who presented the complication after a first ligation with 84 of the 584 controls who underwent first endoscopic variceal ligation without bleeding complication. RESULTS: Bleeding occurred 13.5 days +/- 7.3 (2-29) following ligation. Eleven patients died following the bleeding complication (52%). Using a multivariate analysis, previous upper variceal digestive bleeding [OR 12.07, 95%CI (2.3-63.43)], peptic oesophagitis [OR 8.9, 95%CI (1.65-47.8)], high platelet ratio index (APRI) score [OR 1.54, 95%CI (1.11-2.16)] and low prothrombin index [OR 0.54, 95% CI (0.31-0.94)] were independent predictive factors of bleeding. CONCLUSIONS: Bleeding related to post-banding ulcer is a rare, but severe complication. The proposed predictive factors should be looked for and minimized before variceal ligation.

Effect of ondansetron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomised, double blind, placebo controlled study.

BACKGROUND AND AIMS: There are no available effective therapies for fatigue associated with chronic hepatitis C (CHC). The serotonin antagonist ondansetron has been shown to be effective in the chronic fatigue syndrome. In this randomised, placebo controlled, double blind trial, we investigated the effect of orally administered ondansetron on fatigue in CHC. METHODS: Thirty six patients with CHC were included if fatigue was their predominant symptom and they scored more than 4 on a visual analogue scale (0-10). During the study, fatigue and depression were measured on days 0, 15, 30, and 60 using a validated self report questionnaire (fatigue impact scale and Beck depression inventory). Patients were randomised to receive ondansetron tablets 4 mg twice daily or placebo for one month followed by an additional four weeks of observation. RESULTS: Fatigue score was 85.4 (28.2) and 98.2 (26.9) in the ondansetron and placebo groups, respectively (NS). Ondansetron significantly reduced the fatigue score with more than 30% improvement on day 15 (57.1 (38.9); p<0.01), day 30 (54.5 (37.6); p<0.01), and day 60 (60.8 (37.3); p<0.01) whereas placebo did not. Overall, the reduction in fatigue was significantly higher with ondansetron compared with placebo (ANOVA for repeated measurements) for the whole follow up period (p = 0.03) or for the treatment period only (p = 0.04). Ondansetron also significantly reduced depression scores. CONCLUSIONS: The 5-hydroxytryptamine receptor type 3 antagonist ondansetron had a significant positive effect on fatigue in CHC. These observations support the concept that fatigue involves serotoninergic pathways and may encourage further evaluations of the efficacy of ondansetron on fatigue in chronic liver diseases.

Endoscopic argon plasma trimming of biliary and gastrointestinal metallic stents.

BACKGROUND AND STUDY AIMS: The aim of this study was to assess the feasibility and efficiency of plasma argon trimming of gastrointestinal and biliary metallic stents. PATIENTS AND METHODS: A total of 31 patients underwent plasma argon trimming of their metallic stents (14 women, 17 men; mean +/- SD age 73 +/- 12.2 years, range 46 - 96 years). Of these 31 patients, 24 had had covered or noncovered Unistep Wallstents placed in the biliary tract (13 patients with pancreatic neoplasms, five patients with Vater ampulloma, five patients with biliary tract carcinoma and one patient with chronic calcifiying pancreatitis); three patients had noncovered Enteral Unistep Wallstents (pyloroduodenal); two patients with obstructive colorectal carcinoma had a noncovered Bard Memotherm stent inserted; and two patients had noncovered Ultraflex stents placed for esophageal carcinoma. Endoscopic trimming of the stents was performed under propofol-induced general anesthesia, with the power set at 70 - 80 watts and an argon flow of 0.8 liters/minute. RESULTS: Complete and satisfactory trimming of the stents was possible, without complications (mean follow-up 15.8 months), in all patients except one, a patient with a covered biliary Wallstent. In 13 patients with biliary or Enteral Wallstents the trimming procedure was preventive. In eight patients with ulceration and/or hemorrhage (duodenal or rectal), healing was achieved after stent trimming and epinephrine (adrenaline) injection followed by electrocoagulation. Stent trimming restored patency of the duodenal lumen in six patients and of the esophageal lumen in two patients, and was done to allow insertion of a biliary stent in one patient whose duodenal stent was covering the papilla. In one patient with rectal tenesmus, stent shortening resulted in complete resolution of symptoms. CONCLUSIONS: Endsocopic plasma argon trimming of metallic stents is an efficient procedure which allows easy, reproducible and well-tolerated correction of complications that arise due to these prostheses.

Impact of fatigue on the quality of life of patients with primary biliary cirrhosis.

OBJECTIVE: Fatigue is a frustrating symptom frequently reported by patients with primary biliary cirrhosis (PBC), but it is still poorly understood and not well evaluated. Our aim was to determine its importance and its impact on the quality of life and mental health status of patients with PBC. METHODS: Patients with PBC (103 women and 13 men with a mean age of 52.6 yr) completed self-report questionnaires to evaluate the impact of fatigue on their quality of life (Fatigue Impact Scale, FIS), the perception of their own mental health (Symptom Check list-90-R, SCL), and depression (Beck Depression Inventory, BDI). A cohort of age-matched healthy blood donors served as controls. RESULTS: Fatigue was present in 99 patients (85.3%) and was the worst or one of the worst symptoms in about half of them. In PBC patients, the mean FIS and SCL indexes were significantly increased, compared to healthy controls (1.49 +/- 1.11 vs 0.6 +/- 0.6 and 0.72 +/- 0.55 vs 0.36 +/- 0.35, respectively). Unexpectedly, 52 patients (44.8%) could be classified as having depression (BDI score > 10). Significant correlations were found between the FIS and SCL indexes, between the FIS index and the BDI score, as well as between the BDI score and the SCL index. Finally, fatigue was not related to the disease severity parameters, that is, clinical, biochemical, metabolic, and pathological. CONCLUSIONS: Fatigue is a frequent and disabling complaint that impairs the quality of life of PBC patients and their perception of their own mental health, which may be associated with an unexpected depressive condition. In addition, the FIS questionnaire can be considered as a useful tool to assess fatigue in PBC patients and may be used in the evaluation of specific treatments aimed at reducing this complaint in such patients.

Role of Kupffer cells in the survival after rat liver transplantation with long portal vein clamping times.

Applying the orthotopic rat liver transplantation (ORLT) model, postoperative survival has been shown to be mainly dependent on the portal vein clamping time (PVCT). It was hypothesized that prolonged intestinal congestion was responsible for the activation of Kupffer cells (KC) with overproduction of TNF, secondary to splanchnic endotoxin accumulation and release on reperfusion. The role of KCs was directly investigated in the context of long PVCTs by eliminating them (using liposome-encapsulated dichloromethylene diphosphonate), by preventing their activation (using a calcium channel blocker, nisoldipine) and by inhibiting TNF production (using thalidomide). Livers from different groups of rats were transplanted following 24-h cold preservation in the UW solution with long PVCTs (from 18-21 min). KCs depletion, preservation with nisoldipine and pretreatment with thalidomide significantly improved survival in conditions using long PVCTs. KC depletion and nisoldipine preservation had no effect on liver enzymes or pathological findings while lung injury was significantly improved. The present data confirm that, in the context of ORLT with long PVCTs, KCs are directly responsible for the systemic endotoxin-like shock syndrome and their effect is mediated through overproduction of TNF.

Hepatic artery buffer response following left portal vein ligation: its role in liver tissue homeostasis.

Occlusion of a lobar portal vein is known to induce atrophy of downstream liver lobes and hypertrophy of contralateral lobes. Changes in portal flow are known to be compensated by changes in hepatic arterial flow, thus defining the hepatic artery buffer response (HABR). To understand the role of liver flow in liver atrophy, we measured portal flow and hepatic artery flow after different degrees of left portal vein stenosis (LPVS). Surgery was performed to obtain 0, 43, 48, 59, 68, 72, 78, and 100% LPVS. Systemic and splanchnic blood flows were measured at 4 h or 7 days after surgery using radiolabeled microspheres. At 4 h, LPVS produced no changes in systemic hemodynamics. Increasing degrees of LPVS produced a significant decrease in left portal flow (P < 0.0001) and a fully compensatory increase in right portal flow (P < 0.0001) without significantly affecting total portal flow. Left hepatic artery flow increased by 210% (P = 0.002), and right hepatic artery flow decreased by 67% (P = 0.05) after full LPVS. There was a significant inverse correlation between portal and arterial flow changes induced by different degrees of LPVS in the left (r(2) = 0. 61) and right (r(2) = 0.41) lobes. Despite this HABR, we observed a reduction in left liver flow (-45%; P = 0.01) and an increase in right liver flow (+230%; P = 0.01) with 100% LPVS. At 7 days, a significant decrease in the weight of left liver lobes (-75%; P < 0. 0001) and a compensatory increase in the weight of the right lobes (+210%; P < 0.0001) were observed with 100% LPVS. Left and right liver flows were similar to results measured at 4 h, and HABR was still present. However, when expressed per gram of liver, liver flows were identical to results obtained with sham animals. Reduction in lobar portal flow is accompanied by an increase in ipsilateral hepatic artery flow and a compensatory increase in portal flow to the rest of the liver. In a given lobe, when compensatory HABR is overcome, liver weight changes occur so that at the end total liver flow per gram of liver tissue is restored. This suggests that in normal conditions liver flow is a major regulator of liver volume.

Changes in intracellular calcium induced by acute hypothermia in parenchymal, endothelial, and Kupffer cells of the rat liver.

Disturbances in intracellular calcium have been implicated in liver graft damage after cold preservation and warm reperfusion. Despite improvements noted with the use of calcium channel blockers, such as nisoldipine, the exact nature and cellular basis of the presumed changes in intracellular calcium as well as the actual target of these blockers remain unclear. Isolated rat parenchymal, endothelial, and Kupffer cells were cultured and changes in intracellular calcium measured in vitro after acute hypothermia (5-8 degrees C) by fluorescence imaging using FURA-2. Between 50 and 80% of parenchymal, endothelial, and Kupffer cells exhibited significant increases in baseline calcium that were gradual and sustained for the duration of acute hypothermia. Removal of extracellular calcium completely abolished the positive response of hepatocytes and diminished the proportion of responding endothelial and Kupffer cells. The calcium channel blocker nisoldipine (1 microM) slightly diminished the proportion of positive responders in parenchymal but not in endothelial or Kupffer cells. However, nisoldipine did not modify the amplitude of the calcium rise in responding cells of all types. Acute hypothermia causes calcium influx into a majority of parenchymal, endothelial, and Kupffer cells. Nisoldipine does not effectively prevent these changes in intracellular calcium. Pathways of calcium entry resistant to the drug or other than voltage-dependent calcium channels may thus be involved.

Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction.

BACKGROUND & AIMS: Manganese (Mn) deposition could be responsible for the T(1)-weighted magnetic resonance signal hyperintensities observed in cirrhotic patients. These experiments were designed to assess the regional specificity of the Mn increases as well as their relationship to portal-systemic shunting or hepatobiliary dysfunction. METHODS: Mn concentrations were measured in (1) brain samples from basal ganglia structures (pallidum, putamen, caudate nucleus) and cerebral cortical structures (frontal, occipital cortex) obtained at autopsy from 12 cirrhotic patients who died in hepatic coma and from 12 matched controls; and from (2) brain samples (caudate/putamen, globus pallidus, frontal cortex) from groups (n = 8) of rats either with end-to-side portacaval anastomosis, with biliary cirrhosis, or with fulminant hepatic failure as well as from sham-operated and normal rats. RESULTS: Mn content was significantly increased in frontal cortex (by 38%), occipital cortex (by 55%), pallidum (by 186%), putamen (by 66%), and caudate (by 54%) of cirrhotic patients compared with controls. Brain Mn content did not correlate with patient age, etiology of cirrhosis, or history of chronic hepatic encephalopathy. In cirrhotic and portacaval-shunted rats, Mn content was increased in pallidum (by 27% and 57%, respectively) and in caudate/putamen (by 57% and 67%, respectively) compared with control groups. Mn concentration in pallidum was significantly higher in portacaval-shunted rats than in cirrhotic rats. No significant changes in brain Mn concentrations were observed in rats with acute liver failure. CONCLUSIONS: These findings suggest that brain Mn deposition results both from portal-systemic shunting and from liver dysfunction.

Studies on smaller (approximately 315 microM) microcapsules: IV. Feasibility and safety of intrahepatic implantations of small alginate poly-L-lysine microcapsules.

UNLABELLED: The most successful transplantation site of nonencapsulated islets of Langerhans is the liver. Because usual alginate poly-L-lysine microcapsules were too large (700-1200 microm diameter) for intravascular implantations and were almost exclusively implanted intraperitoneally, the question of the preferred implantation site of microencapsulated islets has received little attention. The feasibility of implanting smaller (approximately 315 microm) alginate poly-L-lysine microcapsules into the liver and the effect of such implantations on portal pressure and liver histology was evaluated in Wistar rats. A bolus of 10,000 microcapsules of 315 microm diameter was injected intraportally (group 1; n = 22). The portal pressure increased from 6.4 +/- 1.8 mmHg to a maximum of 19 mmHg, returned to basal levels within 2 h, and remained normal after 2 months. In group 2 (n = 3), following the injection of 10,000 larger microcapsules (420 microm), the portal pressure increased to > 60 mmHg and two out of the three rats died within 3 h. When 5,000 microcapsules of 420-microm diameter were injected (group 3; n = 5), the portal pressure peaked to 30 +/- 8 mmHg and remained elevated after 4 h (12 +/- 3 mmHg), but returned to normal (8 +/- 1 mmHg) after 2 weeks. Histological studies showed normal hepatic architecture without collagen deposition into portal tracts occupied by microcapsules. CONCLUSION: intrahepatic implantations of approximately 315-microm alginate poly-L-lysine microcapsules are feasible and safe. These results justify further investigation of this potential implantation site for microencapsulated islets.

Effects of acute physical exercise on hepatocyte volume and function in rat.

The goal of the present experiment was to measure the volume of the different compartments in liver of exercised rats and to get some insights into the appropriate working of the hepatic function following exercise. Hence, livers from male rats were isolated and perfused after treadmill exercise or rest. This procedure was performed on rats that were overnight semifasted (50% food restriction) or well fed. To evaluate the hepatocyte cell volume, the multiple-indicator dilution curve technique was used after 40 min of perfusion. Radioactive tracers for red blood cells, sucrose, and water were used to measure liver vascular space, liver interstitial space, and water cellular space, respectively. The hepatocyte function was assessed by taurocholate and propanolol clearance. Oxygen consumption, intrahepatic resistance, bile secretion, and lactate dehydrogenase release estimated liver viability. Liver viability and hepatocyte function were not changed following exercise either in the fed or in the semifasted animals. As expected, liver glycogen levels were significantly (P < 0.01) reduced in the food-restricted rats. Consequently, liver glycogen levels following exercise were decreased significantly (P < 0.01) only in the fed rats. Despite this, exercise decreased the hepatocyte water space in both food-restricted and fed groups ( approximately 15%; P < 0.01) without altering the sinusoidal and interstitial space. The present data show that acute exercise decreased the hepatocyte volume and that this volume change is not entirely linked to a decrease in hepatic glycogen level.

Differential effects of jaundice and cirrhosis on beta-adrenoceptor signaling in three rat models of cirrhotic cardiomyopathy.

BACKGROUND/AIMS: Attenuated cardiac function has been reported in cirrhosis as well as in jaundice, but the mechanisms remain unclear. This study aimed to explore the differential effects of jaundice and cirrhosis on the heart. METHODS: Three rat models of cirrhosis were studied: chronic bile duct ligation, bile duct ligation followed by choledochojejunostomy to relieve jaundice, and a less jaundiced model induced by thioacetamide administration. Controls underwent a sham operation. Cardiac function was assessed by measuring isolated ventricular papillary muscle contractility. Cardiac beta-adrenergic receptor signaling was studied by measuring cAMP production stimulated at the receptor, G-protein, and adenylyl cyclase levels in the signaling pathway, using isoproterenol, aluminum fluoride and forskolin, respectively. RESULTS: Serum bilirubin and bile salt levels were markedly elevated in the bile duct-ligated group, moderately increased in the thioacetamide rats, and normal in the choledochojejunostomy and sham-operated controls. Papillary muscle contractile force after maximal beta-adrenergic receptor stimulation was decreased to a similar extent in all three cirrhotic models. In the bile duct-ligated and thioacetamide-induced cirrhotic rats, production of cAMP by all three drugs was significantly attenuated. However, the cAMP production in the choledochojejunostomy group was blunted only with isoproterenol and fluoride, and remained intact with forskolin stimulation. CONCLUSIONS: These results demonstrate that cirrhosis per se impairs cardiac function by attenuating the portion of the beta-adrenergic receptor signaling pathway upstream of adenylyl cyclase. Furthermore, significant jaundice and/or cholemia can inhibit adenylyl cyclase, which may contribute to blunted cardiac contractility in jaundiced patients.

Effects of portal vein clamping time on rat liver microcirculation following extended cold preservation and transplantation.

Orthotopic rat liver transplantation (ORLT) following extended cold preservation in University of Wisconsin (UW) solution has been shown to induce alterations of the hepatic microcirculation, mainly characterized by areas of no-reflow. The present study was performed to determine whether these alterations were related to the portal vein clamping time (PVCT), shown to be the main determinant of survival after ORLT. The hepatic microcirculation was evaluated using the multiple-indicator dilution curve (MIDC) technique after ORLT following 24-hour cold ischemia in UW solution. Two groups of rats were studied: one with PVCTs of less than 14 min (survival conditions) and one with PVCTs of more than 18 min (nonsurvival conditions). Four hours after ORLT, only long PVCTs were associated with small, but significant, nonperfused areas, about 10% of the liver not being perfused by water; however, in both survival and nonsurvival conditions, the sinusoidal sieving function was well-maintained in perfused areas. In addition, liver viability parameters and hepatocyte function were similarly and minimally altered. The hepatic microcirculation is minimally altered 4 h after ORLT following extended cold preservation in UW solution, whatever the survival condition. Although only found after long PVCTs, the low magnitude of areas of no-reflow should not be associated with lethal injury of the transplanted liver, a finding further supporting the concept that survival after ORLT following 24-hour cold preservation in UW solution is mainly influenced by extrahepatic factors.

Decreased survival in rat liver transplantation with extended cold preservation: role of portal vein clamping time.

Primary liver graft dysfunction is currently related to cold ischemia-reperfusion injury, although a wide survival range has been reported using 24-hour preservation in cold University of Wisconsin (UW) solution. We hypothesized that the portal vein clamping time (PVCT) played a more important role than cold preservation injury in the postoperative outcome. Rat liver transplantation was performed using different clamping times after 24-hour cold ischemia in the UW solution. Survival rates, plasma tumor necrosis factor (TNF), and nitrate/nitrite levels were examined. Subsequently, the effect of clamping time was evaluated on hepatocyte and sinusoidal endothelial cell (SEC) function using isolated perfused livers. Survival rate was directly related to clamping time length. Marked increases in TNF and nitrate/nitrite levels were found after surgery, particularly after long clamping times. In perfusion studies, the SEC function was already markedly altered after preservation alone and was not further modified by transplantation. By contrast, the hepatocyte function was moderately altered after transplantation, irrespective of clamping times, even when rats operated with long clamping times were in terminal conditions. In rats, 24-hour preservation in cold UW solution is not a severely compromising condition leading to primary liver nonfunction. Long PVCTs are associated with an endotoxemia-like syndrome more related to a warm intestinal ischemia than to cold ischemia injury of the liver.

Long-term consequence of rat orthotopic liver transplantation with and without hepatic arterial reconstruction: a clinical, pathological, and hemodynamic study.

Our aim was to investigate the time-related changes in various parameters following orthotopic rat liver transplantation with (AOLT) and without (NOLT) arterial reconstruction in male Lewis rats. Body weight and biochemical parameters were measured weekly, and a liver biopsy was obtained at 4, 8, and 12 weeks. Hemodynamics were evaluated at 12 weeks using the microsphere technique and compared with matched controls. Following AOLT, rats gained weight normally without any noticeable complication. In NOLT, two subgroups (NOLT-1 and NOLT-2) could clearly be identified retrospectively. In the NOLT-1 group, the body weight increased normally, although animals presented transient cholestasis. In these rats, the ductular proliferation found at 4 weeks had regressed by the 12th week with near-normal biopsies. By contrast, in the NOLT-2 group, rats did not gain body weight and had persistent cholestasis. Marked ductular proliferation with increasing fibrosis was observed, resulting in a secondary biliary cirrhosis by the 12th week. Surprisingly, rearterialization of the grafted liver occurred in both NOLT-1 and NOLT-2 irrespective of their clinical course. All transplanted rats showed portal hypertension with marked portosystemic shunts, probably caused by the portal cuff. However, a hyperdynamic circulatory state was only observed in the NOLT-2 group with cirrhotic changes. These findings further show the combined role of an intact hepatic innervation and of hepatocellular insufficiency in the genesis of the hyperdynamic circulatory state associated with portal hypertension.

Effect of calcium antagonists on rat liver during extended cold preservation-reperfusion.

BACKGROUND: Nisoldipine, a calcium antagonist, has been reported to improve the quality of grafted rat livers. We thus assessed the protective effect of two calcium antagonists, nisoldipine and nickel, during extended cold ischemia-reperfusion. METHODS: Rat livers were isolated and perfused before or after 24 hr of cold ischemia in University of Wisconsin solution (4 degrees C) with or without nisoldipine or nickel. Sinusoidal endothelial cell and hepatocyte functions were measured by hyaluronic acid and taurocholate elimination, respectively. RESULTS: Similar alterations in hepatocyte and sinusoidal cell functions were found in all groups after cold ischemia with or without calcium antagonists. In a second set of experiments, liver transplantation was performed in two groups of rats with livers stored under identical conditions with or without nisoldipine. Seven of 12 animals (62.5%) in both groups survived for over 10 days after 24-hr preservation in University of Wisconsin solution. Survival rates were similar in both groups. CONCLUSIONS: Calcium antagonists do not appear to have a direct protective effect on sinusoidal endothelial cell and hepatocyte functions, nor on the overall liver preservation after extended cold preservation-reperfusion.

Effects of extended cold preservation and transplantation on the rat liver microcirculation.

Liver sinusoidal endothelial cell impairment and/or microcirculatory disturbances are thought to induce storage-related graft failure; however, the respective roles of changes induced by extended cold preservation and transplantation, as well as their interactions, are still unknown. To this end, the alterations of the liver microcirculation and of hepatocyte and sinusoidal endothelial cell functions induced by extended cold preservation and/or transplantation were assessed using an isolated perfused rat liver model combined to an orthotopic rat liver transplantation model. Liver microcirculation remained minimally altered following extended cold ischemia alone, despite a marked deterioration of sinusoidal endothelial cell function, while liver microcirculation alterations were mainly characterized by areas of no-reflow following transplantation alone. It was only when both procedures were associated that hepatocyte function became markedly compromised, without further deterioration in liver microcirculation. It is concluded that extended cold preservation and transplantation as such are not associated with lethal liver injury. However, the sinusoidal cell impairment and the liver microcirculatory disturbances, induced by both conditions combined, are important factors leading to secondary hepatic nonfunction, which might be triggered by extrahepatic events.

Clearance by the liver in cirrhosis. III. Propranolol uptake by the isolated perfused human liver.

In cirrhosis, intrahepatic shunts and capillarization of sinusoids can result in impaired extraction of substrates by the liver irrespective of the metabolic capacity of the liver (intact hepatocyte theory). To evaluate the role of anomalies of uptake in impaired drug disposition, we studied the steady-state hepatic clearance and single-pass hepatic uptake of propranolol in isolated perfused livers obtained from patients with cirrhosis at the time of transplantation and from organ donors with normal liver architecture. The kinetics of propranolol transport in the liver were characterized by means of the multiple-indicator dilution technique, and the outflow pattern of propranolol in the hepatic veins was resolved into throughput material, which had swept past the hepatocytes along with albumin, and returning material, which had entered the cells but returned in the outflow after escaping cellular sequestration and metabolism. The steady-state clearance of propranolol was decreased in cirrhotics compared with organ donors, and the outflow profile differed between the two groups. In cirrhotic livers, half of the propranolol in the outflow consisted of throughput material and the other half of returning material; in organ donors, all of the propranolol in the outflow was returning material. In the presence of albumin and alpha 1-acid glycoprotein in the perfusate, about 80-85% of propranolol was protein bound; removal of albumin and alpha 1-acid glycoprotein from the perfusate it cirrhotic livers resulted in an increase in the free fraction of propranolol, an increase in steady-state extraction, and a decrease in the throughput component of propranolol in the outflow. We conclude that impaired uptake of protein-bound propranolol, as a result of capillarization and intrahepatic shunts, contributes to its impaired elimination in cirrhosis.

A randomized trial comparing colchicine and ursodeoxycholic acid combination to ursodeoxycholic acid in primary biliary cirrhosis. UDCA-PBC Study Group.

The efficacy of colchicine combined with ursodeoxycholic acid (UDCA) and UDCA alone in the treatment of patients with nonadvanced primary biliary cirrhosis (PBC) was evaluated in a 2-year controlled study. Seventy-four patients with PBC who had been treated previously with UDCA (at least 8 months) but still had abnormal liver test results, especially elevated alkaline phosphatase activity, were randomized to be administered colchicine (1 mg/d, 5 days per week) (n = 37) or a placebo (n = 37). In addition, the patients were treated with UDCA (13-15 mg x kg(-1) x day(-1)). The patients underwent clinical examination and liver tests every 6 months and upper endoscopy and liver biopsy at entry and at 2 years. Procollagen type III aminoterminal peptide (PIIINP), hyaluronic acid, and sulfobromophthalein (BSP) elimination kinetics were determined at entry and after 2 years. After 2 years of treatment, relative to UDCA, colchicine combined with UDCA did not significantly improve symptoms, laboratory findings (serum bilirubin level, alkaline phosphatase and alanine transaminase [ALT] activities, immunoglobulin [Ig] M level), serum markers of fibrosis, or histological features, except lobular inflammation. Colchicine did tend to slightly reduce the progression of esophageal varices; however, the difference was not significant. BSP elimination kinetics (45-minute retention percentage) was significantly improved when treated with colchicine. During the 2-year study, the only clinical complications were variceal bleeding in one patient administered colchicine and two administered the placebo. Two patients died from nonliver causes. One severe adverse effect (peripheral neuromyopathy) was observed in a colchicine-treated patient. In conclusion, this study suggests that colchicine appears to provide a slight advantage relative to UDCA alone in patients with nonadvanced PBC.