Helmut V. Ammon

Prednisone for chronic active liver disease: dose titration, standard dose, and combination with azathioprine compared.

Among 120 consecutive patients with chronic active liver disease (CALD) randomized to different treatments, those receiving maintenance doses of prednisone 20 mg daily (Pred), prednisone in doses given on alternate days and titrated to secure resolution of clinical and biochemical abnormalities (Pred-Titrad), or a combination of prednisone 10 mg and azathioprine 50 mg daily (Comb) survived and underwent resolution of clinical and biochemical features of disease more often than a control group receiving placebo or azathioprine 100 mg daily. Histological remission occurred significantly more often with Pred and Comb than with other regimens. Major side-effects of therapy were commoner with Pred than with Comb or Pred-Titrad, which did not differ. We conclude that Comb is the initial treatment of choice for CALD, since clinical, biochemical, and histological resolution of disease activity occurs as often as with Pred, whereas early side-effects are significantly less frequent.

Effects of oleic and ricinoleic acids on net jejunal water and electrolyte movement. Perfusion studies in man.

To examine the effects of oleic acid and ricinoleic acid on jejunal absorption, steady-state jejunal perfusions were performed in healthy volunteers. Taurocholate, used to solubilize the fatty acids, did not influence absorption. Both fatty acids (concentration, 10 mM) reversed electrolyte and water net movement; that is, they induced fluid secretion; this effect was rapidly reversible. Ricinoleic acid (the active principle of castor oil) was the more potent, producing fluid secretion when perfused at concentrations at which oleic acid was without effect. However, ricinoleic acid was absorbed more slowly than was oleic acid, and hence was associated with higher intraluminal concentrations. Addition of lecithin and monoolein did not diminish the secretory effect of ricinoleic acid; addition of a secretory bile acid (taurodeoxycholate) did not enhance the effect. The response of the jejunal mucosa to a known cathartic provides observations pertinent to the pathophysiology of steatorrheal diseases in man. Dietary fatty acid also has secretory properties with respect to the human intestine; bacterial hydration, to hydroxy fatty acids, is not required to induce fluid secretion.

Inhibition of Ileal Water Absorption by Intraluminal Fatty Acids INFLUENCE OF CHAIN LENGTH, HYDROXYLATION, AND CONJUGATION OF FATTY ACIDS

The influence of fatty acids on ileal absorption of water, electrolytes, glucose, and taurocholate was examined in Thirty-Vella fistulas in five mongrel dogs. Fatty acid absorption also was measured. Segments of terminal ileum were perfused at steady state with isotonic electrolyte solutions containing 11.2 mM glucose, 4.5 mM taurocholate, and 0.1-5.0 mM fatty acid. Three C(18) fatty acids, oleic acid, 10(9)-hydroxystearic acid, and ricinoleic acid, completely inhibited water absorption at 5 mM. Sodium, chloride, and potassium absorptions were inhibited in parallel with absorption of water. Differences between the potencies of C(18) fatty acids were apparent when lesser concentrations were perfused. Dodecanoic and decanoic acids were as effective as C(18) fatty acids at 5 mM but octanoic and hexanoic acids were ineffective. The polar group of C(18) fatty acids was modified by conjugating oleic and ricinoleic acids with taurine. When these compounds and a substituted C(18) fatty acid, p-n-decylbenzenesulfonate, were perfused, water absorption was also inhibited. Short-chain fatty acids (C(3) and C(4)) and their hydroxylated derivatives were ineffective at 5 mM. When water absorption was inhibited, absorption of glucose and taurocholate was decreased. We speculate that the phenomenon of inhibition of water and electrolyte absorption by fatty acids may be relevant to steatorrhea and diarrhea in man.

Cl- secretion induced by bile salts. A study of the mechanism of action based on a cultured colonic epithelial cell line.

When applied to the basolateral (serosal) side of the T84 colonic epithelial monolayer, taurodeoxycholate caused net Cl- secretion in a dose-dependent manner with a threshold effect observed at 0.2 mM. In contrast, when applied to the apical (luminal) surface, concentrations of taurodeoxycholate below 1 mM had little or no effect. Only when the concentration of taurodeoxycholate present on the apical side was greater than or equal to 1 mM did apical addition results in an electrolyte transport effect. This apical effect on electrolyte transport was associated with an abrupt increase in the permeability of the monolayer. Cyclic AMP and cyclic GMP in the T84 monolayers were not increased by the bile salt, but in the presence of extracellular Ca2+, free cytosolic Ca2+ increased with a graded dose effect and time course that corresponded approximately to the changes in short circuit current (Isc). The results suggest that luminal bile salts at a relatively high concentration (greater than or equal to 1 mM) increase tight junction permeability. Once tight junction permeability increases, luminal bile salts could reach the basolateral membrane of the epithelial cells where they act to increase free cytosolic Ca2+ from extracellular sources. The resulting increases in free cytosolic Ca2+, rather than in cyclic nucleotides, appear to be involved in transcellular Cl- secretion.

Quantification of carcinoembryonic antigen-like activities in normal, human gastrointestinal secretions.

The secretion of carcinoembryonic antigen‐like (CEA‐like) material into the gastrointestinal tract of 28 fasting normal men was quantified by using intestinal perfusion techniques. CEA‐like material was recovered from all levels of the gastrointestinal tract. The highest secretory rate was in the colon (mean ± SE, 2.41 ± 2.0 μg/minute per colon), followed by pancreatobiliary secretion and pancreatic secretion. The secretory rate from the stomach, duodenum, jejunum, and ileum was less than 20 ng/minute. After perchloric acid extraction, the CEA‐like material from the colon had the same chromatographic and radioimmunologic properties as [125I] CEA. These data suggest that the CEA‐like material is normally secreted into the gastrointestinal tract and particularly into the colon.

Effects of dihydroxy bile acids and hydroxy fatty acids on the absorption of oleic acid in the human jejunum.

Perfusion studies of the normal human jejunum were performed to test whether dihydroxy bile acids and hydroxy fatty acids inhibit the absorption of oleic acid, since previous reports documented their inhibitory effects on the absorption of several other organic solutes. 3 mM deoxycholate and 7 mM glycodeoxycholate inhibited the absorption of 3 mM oleic acid in isotonic micellar solutions while inducing net fluid secretion. Similarly, fractional absorption of oleic acid decreased in the presence of hydroxy fatty acids. However, only the changes induced by 2 mM ricinoleic acid could be distinguished from changes induced by an increase in total fatty acid concentration. Under all experimental conditions, close linear relationships existed between net water movement and fractional absorption of glucose, xylose, and fatty acids, as well as between the absorption rates of these solutes. In contrast, net fluid secretion induced by hypertonic D-mannitol (450 mosmol/liter) had no effect on solute absorption. Our data and observations in the literature do not allow formulation of a hypothesis which would adequately define all effects of dihydroxy bile acids and fatty acids on intestinal transport processes. The observations help explain the malabsorption of fat and other nutrients in patients with the blind loop syndrome.

Comparison of cholesterol and beta-sitosterol: effects on jejunal fluid secretion induced by oleate, and absorption from mixed micellar solutions.

Jejunal fluid secretion induced by perfusion with oleic acid can be reduced by the addition of cholesterol. The present study was performed to test the specificity of this effect by comparing the effects of cholesterol with that of a plant sterol, beta-sitosterol during perfusion of the jejunum in healthy volunteers. In addition, we compared the solubilities of cholesterol and beta-sitosterol in micellar solutions and their jejunal absorption rates. One millimolar beta-sitosterol was as effective as 1 mM cholesterol in reducing jejunal fluid secretion induced by 6 mM oleate (n = 7). In mixed micellar solutions consisting of 10 mM taurocholate and 6 mM oleate, solubility of beta-sitosterol is about one third of cholesterol solubility. When cholesterol was gradually replaced by beta-sitosterol in the incubation mixture, beta-sitosterol reduced cholesterol solubility to a greater extent than would be expected from an equimolar replacement of cholesterol by beta-sitosterol. Absorption of beta-sitosterol was limited by its solubility in mixed micellar solutions and both sterols were absorbed at equal rates as long as their solubility limits were not exceeded (n = 5).

Effect of Taurine Conjugated Bile Salts With and Without Lecithin on Water and Electrolyte Transport in the Canine Gallbladder In Vivo

Because dihydroxy bile salts alter water and electrolyte transport in the intestine, we tested the effects of taurine conjugated bile salts on water and electrolyte transport in the canine gallbladder in vivo. 16.7 mM taurodeoxycholate or taurochenodeoxycholate completely abolished net absorption of water (P less than 0.01). 40 mM taurocholate significantly reduced net water absorption (P less than 0.05), whereas 16.7 mM taurocholate had no significant effect. Net movement of electrolytes was closely related to net water movement. Water and electrolyte absorption continued undisturbed when the gallbladders were exposed to 16.7 mM taurodeoxycholate together with 5.6 mM lecithin. Biliary lecithin, therefore, is important for the protection of the mucosa of the gallbladder from the potentially damaging effects of bile salts.

Effects of oral laxatives on colonic motor complexes in dogs.

The effect of oral laxatives on the organisation of colonic motor complexes was investigated in four conscious dogs. Six strain gauge transducers were implanted on the colon of each dog. After a control period of two to three hours, dogs were orally dosed with 1, 2, or 4 ml/kg of castor oil, or 0.5 g/kg magnesium citrate. Oral olive oil, 4 ml/kg, was used as control. The recording was continued for another 10 hours or until defecation occurred. Each dog showed spontaneous cyclic bursts of contractions (contractile states) at all recording sites during the control period. Contractile states migrating orad or caudad over at least half the length of the colon were called colonic migrating motor complexes (CMMC). Castor oil and magnesium citrate significantly increased the period of colonic motor complexes, but olive oil had no significant effect. None of the above substances changed the percentage of orad migrating motor complexes, as compared with the control values. Periods in which colonic motor activity was completely absent for at least 60 min over at least three consecutive recording sites occurred more frequently after all of the substances. The occurrence of these periods of inhibition, however, was not a consistent feature and there seemed to be no relationship between the occurrence of inhibitory periods and defecation during the recording period. The dogs defecated within 10 hours after administration of magnesium citrate, 1, 2, and 4 ml/kg of castor oil in 12.5, 25, 37.5, and 88.8% of experiments respectively, but never with olive oil. Defecation was generally accompanied by giant migrating contractions in the colon. We conclude that oral laxatives, magnesium citrate and castor oil have a profound effect on colonic motor complexes and colonic motor activity. The period of CMMC is significantly prolonged after their oral administration because of an increased number of non-migrating motor complexes or periods of inhibition of motor activity.

Effect of lecithin on jejunal absorption of micellar lipids in man and on their monomer activity in vitro

The effect of lecithin on jejunal absorption of fatty acids and octadecenoylglycerol was studied in healthy volunteers with a jejunal perfusion system which excluded pancreatic and biliary secretions from the test segment. Lecithin significantly reduced the absorption of oleic acid (P<0.05) and octadecenoylglycerol (P<0.01), while it had no effect on the absorption of ricinoleic acid. In vitro, lecithin reduced monomer activities of all three lipids; the changes were greater for oleic acid and octadecenoylglycerol than for ricinoleic acid (P<0.02). From these data it is concluded that lecithin reduces monomer activity of fatty acids in mixed micellar solutions and that it can thereby reduce the absorption rates of micellar lipids. Intact lecithin is not absorbed under these conditions. Maldigestion of lecithin in pancreatic insufficiency may, therefore, aggravate the steatorrhea observed in this condition.