Lack Of Bile Research Articles

Biliary drainage transiently relieves intractable pruritus in primary biliary cirrhosis

To the Editor: We read with interest the report by Stapelbroek et al. on nasobiliary drainage inducing long-lasting relief of pruritus in benign recurrent intrahepatic cholestasis (BRIC).1 Pruritus may be a severely disabling symptom also for patients with primary biliary cirrhosis (PBC) who do not respond to standard antipruritic treatment with ursodeoxycholic acid, anion exchangers, enzyme inducers, or opiate antagonists.2 In contrast to PBC, severe intractable pruritus is rarely observed in primary sclerosing cholangitis (PSC) when adequate dilatation/short-term stenting of major bile duct strictures of the biliary tree is performed. We applied nasobiliary drainage in patients with PBC to relieve otherwise intractable severe pruritus3-5 and to exclude a component of mechanical biliary obstruction as a contributing factor. Within a period of 3 years (February 2001- February 2004), 107 patients with PBC and 82 patients with PSC were seen on a regular basis in our outpatient clinic in Munich. All patients were treated with ursodeoxycholic acid. Patients with PBC underwent endoscopic retrograde cholangiography (ERC) when severe intractable pruritus as defined by severity of pruritus ≥7 on a scale between 0 and 10 on at least 4 of 7 days despite treatment with colestyramine (≥8 g/day), rifampicin (300-600 mg/day), and naltrexone (50 mg/day), each for ≥4 weeks, was diagnosed. Endoscopic papillotomy (EPT) and nasobiliary drainage for 4 days were scheduled after written informed consent when two of three criteria for defective papillary function were observed (bile duct dilatation, lack of bile in duodenum, delayed release of contrast medium). Serum and biliary bile acid analysis was performed by gas chromatography. Three of 107 patients with PBC (stage II, serum bilirubin <2 mg/dL), but none of 82 patients with PSC regularly seen suffered from severe intractable pruritus during the observation period. All three PBC patients with severe intractable pruritus fulfilled 3 (patient A) or 2 (patients B, C) indirect criteria for papillary dysfunction. ERC, EPT, and nasobiliary drainage for (A) 7, (B) 4, and (C) 1.3 days were performed without complications. Within 24 hours, 2 of 3 patients (A,B) were completely free of pruritus and remained free for 2 weeks and 1 week, respectively, while the third (C) reported major improvement (2/10), but tolerated the nasobiliary tube only one night. Pruritus returned to pretreatment levels after 5 months (A), and 2 weeks (B, C). After a transient decrease, serum bile acids showed no association with intensity of pruritus after nasobiliary drainage, and bile acid pattern was not markedly changed (Table 1). We confirm that severe intractable pruritus is transiently relieved by biliary drainage also in PBC and that mechanical bile duct obstruction might be considered a minor contributing factor not only in PSC, but also in single cases of PBC. A direct role of bile acids in the induction of intractable pruritus in PBC may be questioned in view of a lack of association of bile acid levels and intensity of pruritus after nasobiliary drainage. The data rather favour an indirect effect of bile acids (if any) like transcriptional modulation of expression of an unidentified pruritogen in susceptible individuals. Ulrich Beuers*, Guido Gerken , Thomas Pusl*, * Department of Medicine II, Klinikum Grosshadern, University of Munich, Munich, Germany, Department of Gastroenterology, Klinikum of the University of Essen, Essen, Germany.

Effects of Intraluminal Trypsin and Bile on the Exocrine and Endocrine Pancreas After Pancreaticobiliary Diversion and Biliodigestive Shunt

Pancreaticobiliary diversion (PBD) and biliodigestive shunt (BDS) cause long-standing hypercholecystokininemia followed by pancreatic hyperplasia. These changes have been suggested to be due to the lack of intraluminal trypsin and bile, respectively, in the upper small intestine. The aim of these experiments was to study the effect of restoration of intraluminal trypsin and bile on plasma levels of cholecystokinin (CCK) and the changes found in exocrine and endocrine pancreas after PBD and BDS. Male Sprague-Dawley rats were used. PBD was done in 16 rats, eight of which had trypsin dissolved in 50 mM sodium bicarbonate (SB), and eight had SB only by gastric intubation twice daily. BDS was done in another 16 rats, eight of which had bile dissolved in SB, and eight had SB in a similar manner. Sham-operated rats had SB and served as controls. After 4 weeks, the rats were killed, and the concentrations of circulating CCK, gastrin, glucose, glucagon, and insulin were determined. The pancreas was removed, weighed, and analyzed for contents of water, protein, and DNA. In another study, PBD-operated rats got trypsin in varying dosages or trypsin and taurocholate in combination for 2 weeks before death. The concentrations of plasma CCK and glucagon were elevated after both PBD and BDS. PBD decreased the concentration of gastrin in plasma. PBD caused an increase of pancreatic weight and the contents of protein and DNA. Trypsin substitution to PBD-operated rats did not affect plasma CCK or glucagon levels, but the PBD-induced increases in weight and DNA content were counteracted by trypsin. Higher dosages of trypsin did not further influence the effects seen after PBD. Pancreatic weight and DNA content were increased after BDS. Bile administration completely abolished the increase in plasma CCK and glucagon, as well as the gain in pancreatic weight, and reduced the increase in pancreatic DNA. Substitution with bile to BDS-operated rats abolished the increase in the plasma levels of CCK and glucagon, as well as the trophic effects on the pancreas. Trypsin substitution to PBD-operated rats partly reversed the trophic effects on the pancreas but not the hormonal changes in plasma. Thus the trophic effects on the pancreas exerted by BDS seem to be dependent on the lack of bile in the upper small intestine, whereas the effects of PBD only partly are a consequence of the absence of intraluminal trypsin.

Improvement of bioavailability of menaquinone-4 by dimethyl-beta-cyclodextrin complexation following oral administration

Aqueous solubility of menaquinone-4 (MK-4), a potent antihemorrhagic vitamin K2, largely increased with heptakis(2, 6-di-O-methyl)-β-cyclodextrin (DM-β-CyD), forming the higher-order complexes. By the analysis of phase solubility diagram, the stoichiometric ratio of the main complex was estimated to be 1 : 3 (MK-4/DM-β-CyD) with the stability constant of 46400M-1. Then, the 1 : 3 solid complex was prepared by the kneading method, and its dissolution, absorption, and pharmacological characteristics were compared with those of MK-4. The plasma levels of MK-4 after the oral administration to dogs and rats in the form of complex were significantly higher than the MK-4 alone, particularly in the cases of the fasted state and the lack of bile. When the complex was administered orally to rats under bile duct cannulation, MK-4 was absorbed through both portal and lymphatic routes. The oral administration of DM-β-CyD complex also attained the shortening of the blood-clotting time of MK-4 for warfarin-induced hypoprothrombinemic dogs. The enhanced bioavailability seemed to be mainly ascribable to the increase in dissolution of MK-4 by DM-β-CyD complexation.

Fat digestion and exocrine pancreatic function in primary biliary cirrhosis

Intestinal bile salt deficiency marginally impairs fat absorption in cholestatic patients. The finding of massive steatorrhea in some patients with primary biliary cirrhosis led us to systematically study and compare fat digestion in control subjects (n = 4) and patients with biliary cirrhosis with (n = 11) and without (n = 3) steatorrhea. The jejunum was anatomically and functionally intact in all subjects, as demonstrated by normal gastrointestinal radiology and xylose absorption, respectively. The intestinal contents were recovered during digestion of a fat meal. Lipolysis, pH, and trypsin activity were measured in whole intestinal contents, whereas bile salts, total lipid, and fatty acid were determined in both total and aqueous phases. The results obtained in controls and patients without steatorrhea were similar. Percentage of lipolysis and intraluminal pH were normal in controls and in both patient groups. The intestinal contents of the patients with steatorrhea had a significantly lesser capacity to solubilize both total lipid and fatty acid in relation to abnormally low aqueous bile salt concentrations. No bile salt deconjugation and only minimal bile salt precipitation were found, thus low aqueous bile salts were strictly related to bile secretory failure. Steatorrhea was always present when aqueous bile salt levels were below 3.0 mM. Intestinal trypsin activity was subnormal in patients with steatorrhea; decreased trypsin activity was related (r = 0.82, p < 0.001) to reduced intestinal bile salt levels. One patient was found to have severe exocrine pancreatic failure. Administration of medium chain triglycerides was uniformly effective in improving nutrition in patients with steatorrhea, but the course of the disease was unaffected. These results indicate that overt pancreatic failure is uncommon in primary biliary cirrhosis, and that fat maldigestion and steatorrhea, regardless of what degree, are due mainly to low intestinal bile salt levels secondary to bile secretory failure. Finally, subnormal pancreatic function in this disease appears to be related to the bile secretory failure, suggesting either that the lack of bile or bile salts in the intestine depresses pancreatic exocrine function or that both biliary and pancreatic secretions decrease in parallel as part of a widespread secretory failure syndrome.

Effects of Starvation and Lack of Bile upon Growth, Egg Production and Egg Viability in Established Rat Tapeworms, Hymenolepis diminuta

Lack of bile exerts profound effects upon establishment and persistence of the rat tapeworm, Hymenolepis diminuta, from ingested cysticercoids or after surgical transfaunation of adult worms (Goodchild, 1958). The nature of this influence is as yet unknown, but the effects are so striking and reproducible that further study of the phenomenon in rats seemed to be desirable. Accordingly, in the following study, gross effects on tapeworms, egg production, and egg viability were investigated using single-worm infections in normal Wistar rats, in rats with biliary by-pass to the caecum, and in rats during starvation.

THE EFFECT OF ORAL AND INTRAVENOUS ADMINISTRATION OF VITAMINS K ON THE PROTHROMBIN AND PROCONVERTIN LEVELS OF CHOLECYSTNEPHROSTOMIZED DOGS

Six dogs were prepared with permanent biliary fistulae by cholecystnephrostomy. Chronic bile lack in these animals led to the development of a bleeding tendency and to a significant drop in the levels of proconvertin and prothrombin. A comparison was made of the relative effectiveness of the K-vitamins administered orally and intravenously in restoring the plasma levels of prothrombin and proconvertin. Vitamin K3 (2-methyl-1,4-naphthoquinone, menadione) and Synkavite (2-methyl-1,4-naphthohydroquinone diphosphoric ester tetrasodium salt) were found to be more effective and rapid in returning prothrombin and proconvertin values to normal than vitamin K1 (2-methyl-3-phytyl-1,4-napthoquinone) when given orally on an equimolar basis. Intravenously vitamins K1, K2 (2-methyl-3-difarnesyl-1,4-naphthoquinone), K3, and Synkavite had approximately the same molar biological activity in the immediate correction of prothrombin and proconvertin levels but the effect was less prolonged in the case of vitamin K3, and was only transient with Synkavite. Observations were made of pathological changes in the livers of these animals.

Further observations on the clinical use of vitamin K

1. Several factors of interest to gastro-enterologists are important in the development of hypoprothrombinemia. These include inadequate intake of food that contains Vitamin K, impairment of absorption owing to lack of bile in the intestine and owing to a deficient intestinal absorptive surface, and hepatic injury. Starvation, impaired appetite, vomiting (functional or organic in origin), diarrhea, discharge from intestinal fistulas, continued aspiration of gastric or intestinal content, diseases of the intestinal mucosa, short-circuiting of the intestine, biliary obstruction, external biliary fistula, disease of the liver and operative procedures and complications are factors that may influence the concentration of prothrombin in the plasma. 2. The isolation of Vitamin K, demonstration of its quinoid nature and recognition of the antihemorrhagic properties of a number of naphthoquinones have given us a number of synthetic compounds for clinical trial. We have used four such compounds intravenously with excellent results. The intravenous administration possible with these compounds permits precise dosage, circumvents the variable factor of absorption and assures instant availability of potent antihemorrhagic substances. No local or systemic reactions have occurred and there has been no evidence of toxicity. 3. Evidence is presented to show that the rate of action of these compounds is very rapid. This rapidity of action is suggestive of possible enzymatic activity. 4. Failures with all these compounds were confined to cases of advanced disease of the liver, chiefly cirr-hosis. Failures encountered in the earlier use of Vitamin K have been largely eliminated by prescribing adequate dosage in prophylactic and curative treatment, constant care in suspecting the possibility of hypoprothrombinemia and the use of intravenous preparations.