Background & Aims: Glucagon-like peptide 2 (GLP-2) is intestinotrophic, antisecretory, and transit-modulating in rodents, and it is mainly secreted from the intestinal mucosa of the terminal ileum and colon after food ingestion. We assessed the effect of GLP-2 on the gastrointestinal function in patients without a terminal ileum and colon who have functional short-bowel syndrome with severe malabsorption of wet weight (>1.5 kg/day) and energy (>2.3 MJ/day) and no postprandial secretion of GLP-2. Methods: Balance studies were performed before and after treatment with GLP-2, 400 g subcutaneously twice a day for 35 days, in 8 patients (4 -17 years from last bowel resection; 6 with Crohn's disease). Four patients received home parenteral nutrition (mean residual jejunum, 83 cm), and 4 did not (mean ileum resection, 106 cm). Biopsy specimens were taken from jejunal/ileal stomas, transit was measured by scintigraphy, and body composition was measured by dual-energy x-ray absorptiometry. Results: Treatment with GLP-2 improved the intestinal absorption of energy 3.5% ؎ 4.0% (mean ؎ SD) from 49.9% to 53.4% (P ‫؍‬ 0.04), wet weight 11% ؎ 12% from 25% to 36% (P ‫؍‬ 0.04), and nitrogen 4.7% ؎ 5.4% from 47.4% to 52.1% (P ‫؍‬ 0.04). Body weight increased 1.2 ؎ 1.0 kg (P ‫؍‬ 0.01), lean body mass increased 2.9 ؎ 1.9 kg (P ‫؍‬ 0.004), fat mass decreased 1.8 ؎ 1.3 kg (P ‫؍‬ 0.007), and 24-hour urine creatinine excretion increased (P ‫؍‬ 0.02). The time to 50% gastric emptying of solids increased 30 ؎ 16 minutes from 89 to 119 minutes (P < 0.05). Small bowel transit time was not changed. Crypt depth and villus height were increased in 5 and 6 patients, respectively. Conclusions: Treatment with GLP-2 improves intestinal absorption and nutritional status in short-bowel patients with impaired postprandial GLP-2 secretion in whom the terminal ileum and the colon have been resected.

Extracorporeal albumin dialysis (ECAD) may improve severe hepatic encephalopathy (HE) in patients with advanced cirrhosis via the removal of protein or non-protein-bound toxins. A prospective, randomized, controlled, multicenter trial of the efficacy, safety, and tolerability of ECAD using molecular adsorbent recirculating system (MARS) was conducted in such patients. Patients were randomized to ECAD and standard medical therapy (SMT) or SMT alone. ECAD was provided daily for 6 hours for 5 days or until the patient had a 2-grade improvement in HE. HE grades (West Haven criteria) were evaluated every 12 hours using a scoring algorithm. The primary endpoint was the difference in improvement proportion of HE between the 2 groups. A total of 70 subjects [median age, 53; 56% male; 56% HE grade 3; 44% HE grade 4; median model for end-stage liver disease (MELD) 32 (11-50) and CPT 13 (10-15)] were enrolled in 8 tertiary centers. Patients were randomized to ECAD ؉ SMT (n ‫؍‬ 39) or SMT alone (n ‫؍‬ 31). Groups were matched in demographics and clinical variables. The improvement proportion of HE was higher in ECAD (mean, 34%; median, 30%) versus the SMT group (mean, 18.9%; median, 0%) (P ‫؍‬ 0.044) and was reached faster and more frequently than in the SMT group (P ‫؍‬ 0.045). H epatic encephalopathy (HE) is a complex neuropsychiatric syndrome commonly seen in patients with advanced liver disease. HE arises from the effects of circulating toxins on cerebral functions. Putative toxic molecules accumulate in patients with liver decompensation because of increased production, portal-systemic shunting, or lack of hepatic detoxification. 1 Patients with advanced cirrhosis and a superimposed acute liver injury often decompensate and present with manifestations of hepatic failure, including worsening HE and coma. 2 .Current therapy for HE includes the use of nonabsorbable disaccharides or poorly absorbable antibiotics, as proposed more than 3 decades ago. 3 However, standard therapy is less effective in patients with severe degrees of liver failure. 4,5 Under these circumstances, the concept of supporting the failing liver for a time while correcting the precipitating event might help patients recover from HE or be stabilized until they receive a liver transplant. 6 Extracorporeal albumin dialysis (ECAD) using the molecular adsorbent recirculating system (MARS) is a new method of hemodiafiltration whereby blood is dialyzed against an albumin-containing solution across a high-flux membrane. 7 The technique allows combined removal of albumin-bound and water-soluble toxins. [8][9][10][11][12] In uncontrolled trials of ECAD using the MARS device, patients had a reduction in ammonia levels, clear-

In this prospective study of patients with fulminant hepatic failure (FHF), we tested the hypothesis that arterial hyperammonemia results in cerebral accumulation of the osmotic active amino acids glutamine and alanine, processes that were expected to correlate with intracranial pressure (ICP). By using in vivo brain microdialysis technique together with ICP monitoring in 17 FHF patients (10 females/7 males; median age 49 (range 18 to 66) years), we found that arterial ammonia concentration correlated to brain content of glutamine (r=0.47; P<0.05) but not to alanine. A persisting high arterial ammonia concentration (above 200 micromol/L) characterized patients who developed high ICP (n=8) while patients who did not experience surges of increased ICP (n=9) had a decline in the ammonia level (P<0.05). Moreover, brain glutamine and alanine concentrations were higher at baseline and increased further in patients who developed intracranial hypertension compared with patients who experienced no surges of high ICP. Brain glutamine concentration increased 32% from baseline to 6536 (697 to 9712) micromol/L (P<0.05), and alanine 44% from baseline to 104 (81 to 381) micromol/L (P<0.05). Brain concentration of glutamine (r=0.59, P<0.05), but not alanine, correlated to ICP. Also arterial ammonia concentration correlated to ICP (r=0.73, P<0.01). To conclude, this study shows that persistence of arterial hyperammonemia is associated with profound changes in the cerebral concentration of glutamine and alanine. The elevation of brain glutamine concentration correlated to ICP in patients with FHF.

A 5-week GLP-2 administration significantly increased spinal BMD in short-bowel patients with no colon. The mechanism by which GLP-2 affects bone metabolism remains unclear, but may be related to an increased mineralization of bone resulting from an improved intestinal calcium absorption.

Summary: Uncontrolled increase in intracranial pressure (ICP) continues to be one of the most significant causes of early death in patients with acute liver failure (ALF). In this study, we aimed to determine the effects of indomethacin on ICP and cerebral perfusion pressure in twelve patients with ALF and brain edema (9 females/3 males, median age 49,5 (range 21 to 64) yrs.). Also changes in cerebral perfusion determined by transcranial Doppler technique (Vmean) and jugular bulb oxygen saturation (SvjO2) were measured, as well as brain content of lactate and glutamate by microdialysis technique. Finally, we determined the cerebral blood flow autoregulation before and after indomethacin injection. We found that indomethacin reduced ICP from 30 (7 to 53) to 12 (4 to 33) mmHg (P < 0.05). The cerebral perfusion pressure increased from 48 (0 to 119) to 65 (42 to 129) mmHg (P < 0.05), while Vmean and SvjO2 on average remained unchanged at 68 (34 to 126) cm/s and 67 (28 to 82) %, respectively. The lactate and glutamate in the brain tissue were not altered (2.1 (1.8 to 7.8) mmol/l and 34 (2 to 268) mol/l, respectively) after injection of indomethacin. Cerebral blood flow autoregulation was impaired in all patients before injection of indomethacin, but was not restored after administration of indomethacin. We conclude that a bolus injection of indomethacin reduces ICP and increases cerebral perfusion pressure without compromising cerebral perfusion or oxidative metabolism in patients with ALF. This finding indicates that indomethacin may be valuable as rescue treatment of uncontrolled intracranial hypertension in fulminant hepatic failure.

Fulminant hepatic failure (FHF) is often complicated by high intracranial pressure (ICP) and fatal brain damage. In this study, we determined if a rise in [glutamate]ec and [lactate]ec preceded surges of high ICP in patients with FHF (median age, 42; range, 20-55 years; 7 women; 3 men) by inserting a microdialysis catheter into the brain-cortex together with an ICP catheter. The microdialysis catheter was perfused with artificial cerebrospinal-fluid at a rate of 0.3 microL/min. Dialysate was collected approximately every 30 minutes or when ICP increased. A total of 352 microdialysis samples were collected during a median of 3 days and allowed for approximately 1,760 bedside analyses of the collected dialysate. In 5 patients that later developed surges of high ICP, the initial values of [glutamate]ec and [lactate]ec were 2 to 5 times higher compared with patients with normal ICP. [Glutamate]ec then tended to vanish with time in both groups of patients. An increase in [glutamate]ec did not precede high ICP in any of the cases. In contrast, [lactate]ec was high throughout the study in the high ICP group and increased further before surges of high ICP. We conclude that in patients with FHF, cerebral [glutamate]ec and [lactate]ec are elevated. However, the elevated [glutamate]ec is not correlated to high ICP. In contrast, elevations in [lactate]ec preceded surges of high ICP. In conclusion, accelerated glycolysis with lactate accumulation is implicated in vasodilatation and high ICP in patients with FHF. The data suggest that bedside cerebral microdialysis is a valuable tool in monitoring patients with FHF and severe hyperammonemia.

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MARS treatment tends to normalize the arterial amino acid concentrations in patients with hepatic encephalopathy. Even though the overall reduction in plasma amino acids and improvement in amino acid dysbalance may well be beneficial, it was not accompanied by any immediate improvement in cerebral amino acid metabolism in patients with FHF or AoCLF.