A model of ischemic isolated acute liver failure in pigs: standardizing monitoring and treatment.

BACKGROUND: Acute liver failure (ALF) models in pigs have been widely used for evaluating newly developed liver support systems. But hardly any guidelines are available for the surgical methods and the clinical management. METHODS: The study validated several standard operating procedures describing in detail the surgical method and intensive care monitoring and treatment (control of potassium, glucose and bicarbonate levels, cardiovascular and intracranial pressure monitoring, etc.). ALF was induced in animals with a mean of 56 kg. Two surgical methods were compared: ligation of hepatic arteries with either end-to-side portacaval shunt (ESPS) and bile duct ligation or side-to-side portacaval shunt (SSPS) without bile duct ligation. RESULTS: During total portal vein clamping, the animals in the ESPS group developed severe hypotension, splanchnic congestion and metabolic acidosis. One animal died after approximately 1.5 h. This model therefore represents a multiorgan failure model rather than an isolated ALF model. In the SSPS group, none of these side effects were observed, while clinical, laboratory and histopathological signs of ALF were evident. CONCLUSIONS: A reproducible model in pigs representing ALF can be established with the help of the standardized monitoring and treatment procedures presented.

Albumin dialysis: effective removal of copper in a patient with fulminant Wilson disease and successful bridging to liver transplantation: a new possibility for the elimination of protein-bound toxins.

BACKGROUND: Acute liver failure may be the first manifestation of Wilson disease. If copper elimination fails, liver transplantation is the only remaining therapeutic option. Albumin dialysis, a new method for the removal of protein-bound toxins, was performed in a patient with fulminant Wilson disease. METHODS: An 18-year-old man with Wilson disease presented with hyperacute liver failure, hepatic encephalopathy III, oligo-anuric renal failure, haemolytic anaemia, rhabdomyolysis, pancreatitis and thrombocytopenia. He was treated with albumin dialysis using a 44 g/l albumin-containing dialysate and a slow dialysate flow rate (1-2 l/h). The other details of the technique used are similar to routine continuous veno-venous haemodiafiltration. RESULTS: One hundred and five milligrams of copper were removed by albumin dialysis within the first six treatments, resulting in normalisation of blood-copper levels. Successful treatment of the multiorgan failure was achieved. Hepatic encephalopathy improved within 2 days. The patient initially refused liver transplantation. Therefore 35 additional albumin dialysis treatments were performed. Forty-three grams of bilirubin (an indicator of detoxified substances in the liver) and 196 mg of copper were removed. Multiorgan failure, in particular hepatic encephalopathy, did not recur during 59 days of treatment. Eventually, the patient agreed to liver transplantation and that was successful. CONCLUSION: Albumin dialysis is a new method for the effective treatment of fulminant Wilson disease, resulting in the removal of protein-bound toxins copper and bilirubin. It may serve as a new treatment option in hyperacute liver failure of other origin, acting as an extracorporeal detoxifier.

Developmental patterns of glucagon-like peptide-1-(7-36) amide and peptide-YY in rat pancreas and gut.

Glucagon-like peptide-(17-36) amide [GLP-1-(7-36) amide] and peptide tyrosine tyrosine (PYY) are both products of the enteroglucagon cell. To examine the changes occurring during development, we analyzed by RIA the pancreatic concentrations of these two peptides in fetal and neonatal rats. The levels obtained were compared with those of the classical islet hormones, insulin, somatostatin, and glucagon. The total hormone content of the pancreas increased with age for insulin, glucagon, and somatostatin. The amounts of GLP-1-(7-36) amide immunoreactivity (IR) and PYY, however, remained approximately constant in the 3-, 8-, and 30-day-old and adult pancreas. GLP-1-(7-36) amide IR showed only a single peak by gel chromatography, but further analysis by anion exchange chromatography showed that during the fetal period (-18 days) and 3 days postpartum GLP-1-(7-36) amide was the main product, whereas 30 days postpartum and in adult pancreas mainly GLP-1 and an intermediate form were found. Similar analyses of gut extracts revealed that only GLP-1-(7-36) amide is produced during intestinal development. The gut content of GLP-1-(7-36) amide IR and PYY IR increased approximately 100 times between the fetus and the 30-day-old rat. This study reveals a complex and specific regulation of posttranslational processing during maturation for these two peptides.

Glucagon-like peptide-1 (7-36)-NH2: a physiological inhibitor of gastric acid secretion in man.

Glucagon-like peptide (GLP)-1 (7-36)-NH2 is a peptide found in the mucosal endocrine cells of the intestine, and plasma levels of GLP-1 (7-36)-NH2 immunoreactivity show a rise after the ingestion of a fat or mixed-component meal. We investigated the effects of physiological infusion of GLP-1 (7-36)-NH2 on a submaximal gastric acid secretion in healthy volunteers at a rate known to mimic the observed postprandial rise in plasma concentrations. Corrected gastric acid output decreased to less than 50% and volume output to 33% of stimulated values. After the infusion, the secretion of gastric acid recovered immediately to preinhibition values. These results suggest a novel role for GLP-1 (7-36)-NH2 as a physiological inhibitor of gastric acid secretion in man.

Characterization of glucagon-like peptide-1-(7-36)amide in the hypothalamus.

The distribution of glucagon-like peptide-1-(7-36)amide like immunoreactivity (GLP-1-(7-36)NH2 IR) in rat brain was determined. Highest concentrations were found in the hypothalamus. A combination of gel chromatography and anion exchange chromatography showed that the majority of hypothalamic immunoreactivity exactly corresponded in position to synthetic GLP-1-(7-36)NH2. Chromatographic analyses of rat ileum demonstrated a similar pattern, whereas in rat pancreas mainly a large proglucagon fragment and GLP-1 were indicated. Determination of the subcellular distribution by differential centrifugation of hypothalamic tissue revealed that most of the GLP-1-(7-36)NH2 IR was present in the synaptosome fraction. GLP-1-(7-36)NH2 was released from hypothalamic tissue slices in a calcium-dependent fashion by potassium-induced depolarization. Thus GLP-1-(7-36)NH2 appears to fulfil two criteria for a neurotransmitter. No change was found in its hypothalamic content in streptozocin-induced diabetic rats compared to normal controls but a decrease was seen in hyperinsulinemic hyperglycemic KKAy mice compared to KK mice.

Isolation and characterisation of GLP-1 7-36 amide from rat intestine. Elevated levels in diabetic rats.

Glucagon-like peptide-1 (GLP-1) was purified to homogeneity by HPLC and anion-exchange chromatography. A molecular mass of 3297.4 Da was obtained by FAB mass spectrometry which corresponded exactly to GLP-1 7-36 NH2, providing evidence that amidation occurs at an arginine residue during the post-translational processing of GLP-1. The distribution of GLP-1 7-36 NH2-like immunoreactivity (GLP-1 7-36 NH2 IR) was determined in the rat gastrointestinal tract. Highest concentrations were found in terminal ileum and colon. Streptozocin-induced diabetic rats, who showed a significant increase in food intake, had a significant increase of GLP-1 7-36 NH2 IR in the colon.

Identification and characterization of glucagon-like peptide-1 7-36 amide-binding sites in the rat brain and lung.

High-affinity binding sites for glucagon-like peptide-1 7-36 amide (GLP-1 7-36 NH2) were identified in rat brain and lung membranes. Binding of [125I]GLP-1 7-36 NH2 was rapid, reversible, specific, saturable and pH dependent. Specific binding in the central nervous system was particularly high in the hypothalamus and the brain stem. Oxyntomodulin, glucagon-like peptide-1, glucagon-like peptide-2 and glucagon were 100-1000-fold less potent than GLP-1 7-36 NH2 in competition for this binding site.

Glucagon-like peptide-1 7-36: a physiological incretin in man.

The physiological role of glucagon-like peptide-1 7-36 amide (GLP-1 7-36) in man was investigated. GLP-1 7-36-like immunoreactivity was found in the human bowel; its circulating level rose after oral glucose and after a test breakfast. When it was infused into seven volunteers at a rate to mimic its postprandial plasma concentration in the fasting state, plasma insulin levels rose significantly and glucose and glucagon concentrations fell. During an intravenous glucose load, it greatly enhanced insulin release and significantly reduced peak plasma glucose concentrations, compared with a control saline infusion, even inducing postinfusion reactive hypoglycaemia. By comparison, infusion of glucose-dependent insulinotropic peptide (GIP) to physiological levels was less effective in stimulating insulin release. These observations suggest that GLP-1 7-36 is a physiological incretin and that it is more powerful than GIP. The observation of greatly increased postprandial plasma GLP-1 7-36 levels in patients with postgastrectomy dumping syndrome suggests that it may mediate the hyperinsulinaemia and reactive hypoglycaemia of this disorder.