Gastrointestinal function in obesity: motility, secretion, and absorption following a liquid test meal.

Digestive responses to a 300-mL liquid fat-rich meal (432 kcal) in a group of massively obese patients were compared with those observed in a group of healthy lean subjects of variable body weight. Gastric and intestinal propulsion, digestive secretions, and absorption in the proximal 70 cm of intestine were measured using a multiple-marker dilution method. The average gastric emptying of energy, acid, volumes, and meal marker were similar in the two groups 80 minutes after intake, justifying a comparison of intestinal processing of the meal. Compared with lean subjects, the obese subjects responded with less pancreatic secretion (P less than .05) and gallbladder emptying, but absorbed a larger proportion of the emptied energy in the test segment (P less than .01) during a similar or shorter transit time. In addition, when the entire meals were compared, the obese group generally absorbed the test meal more effectively and rapidly in the upper part of the intestine. As a consequence, the flow volumes at the exit of the test segment were lower (P less than .05), and less of the test meal was propulsed to distal parts of the intestine. In the lean subjects, the body weight or height correlated positively with the gastric emptying rate, peak gastric acid output, and pancreatic responses, and negatively with (P less than .05) the segment transit time. The taller the subject, the greater the proportion of the meal which was rapidly propulsed unabsorbed to lower parts of the intestine, indicating that a large intestinal area was exposed for rapid energy uptake. No such correlations were observed in the obese group.

Impaired pancreatico-biliary response to vagal stimulation and to cholecystokinin in human obesity.

We previously found that massively obese patients respond with less gastric acid secretion in response to vagal stimulation. This is compatible with the described association between experimental obesity and altered vagal function in the rat. To confirm this observation, the pancreatic and biliary responses to vagal stimulation were examined in nine nondiabetic obese patients against a background secretin infusion of 15 CU x h-1, and monitored after a subsequent injection of 75 IDU of cholecystokinin. Two separate marker perfusion systems were used in the stomach and duodenum, respectively, and blood samples were drawn for hormone analyses. In contrast to controls having normal body weight, the obese patients failed to respond with increments of pancreatic enzyme secretion and duodenal bile acids after stimulation with modified sham feeding. Cholecystokinin stimulated the pancreatic secretion of trypsin, amylase, and lipase, the emptying of bile acids, and the release of gastrin, but the patients' responses were only half that of the controls. In the resting state the obese had higher outputs of bile and pancreatic enzymes and higher plasma levels of pancreatic polypeptide compared with controls, but the pancreatic bicarbonate secretion rate was not different. The almost complete suppression of the basal gastric acid secretion by a low dose of intravenous (IV) secretin in controls did not occur in the obese. We conclude that massive obesity is associated with a reduced pancreatic and biliary response to vagal stimulation. Compared with controls, the digestive functions of the obese patients seem to be less sensitive to stimulation by exogenous cholecystokinin.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunoextracted calcitonin in human gastric secretion.

Immunoreactive calcitonin (iCT) has been demonstrated in human gastric juice after immunoextraction with immobilized antibodies and subsequent radioimmunoassay. The basal levels were 4.5 +/- 3.1 (mean +/- SD) pg-Eq/ml gastric juice; range 1.2-9.1 pg-Eq/ml; n = 7, and after stimulatory gastric secretion test with pentagastrin 0.3 +/- 0.2 pg-Eq/ml; range 0.1-0.7 pg-Eq/ml; n = 7 (p less than 0.01). The main fraction of iCT from gastric juice eluted in the same region as synthetic human calcitonin (hCT) on Sephadex G-75 gel chromatography. Reverse phase chromatography in a fast protein liquid chromatography (FPLC) system revealed a slightly less hydrophobic character of the iCT from gastric juice compared to synthetic monomeric hCT. The results were further confirmed by using an additional antiserum. In plasma, the calcitonin (CT) levels were after immunoextraction at the basal state 6.6 +/- 1.7 pg-Eq/ml (mean +/- SD); range 5.1-10.1 pg-Eq/ml; n = 7 and after pentagastrin stimulation 9.4 +/- 5.4 pg-Eq/ml; range 6.3-18.5 pg-Eq/ml; n = 7.

Plasma concentrations of regulatory peptides in obesity following modified sham feeding (MSF) and a liquid test meal.

Plasma concentrations of regulatory peptides were monitored in groups of obese and normal-weight subjects following modified sham feeding and a liquid fatty meal. Following modified sham feeding a significant increase in immunoreactive cholecystokinin (CCK) in plasma was recorded in both groups. In the obese subjects, however, the concentrations following sham feeding were significantly lower than in normal-weight subjects, and the initial part of the response was negative. Basal and modified sham feeding stimulated immunoreactive pancreatic polypeptide (PP) concentrations in plasma did not differ between the groups. After the liquid fatty meal plasma CCK concentrations increased similarly in both groups. In contrast immunoreactive neurotensin and somatostatin concentrations following the meal were lower in the obese group, and a changed concentration-time pattern for somatostatin was observed in the obese group. Postprandial concentrations of PP and immunoreactive gastrin were not different in the groups. The results indicate that the plasma concentration patterns of CCK, somatostatin and NT are disarranged in obesity. The changes may promote rapid propulsion and absorption of ingested food, and facilitate deposition of fat in adipose tissue in obesity and thus may be of pathophysiological importance.

Factors Affecting the Short-Term Prognosis of Alcohol Dependent Patients Undergoing Inpatient Detoxification.

Stable measures of psychological functioning require a considerable period of abstinence. However, the duration of inpatient detoxification programs has decreased dramatically in most health care systems, posing a novel challenge for clinical evaluation of patients. The present study was carried out to examine whether factors predicting short-term prognosis can be identified in alcohol dependent subjects during early stages of inpatient detoxification. Self-reports of mood states were obtained, and executive cognitive functioning was examined. Outcome was studied at 2-3 months. No correlation was found between self-reported symptoms of depression, hopelessness, and anxiety, and percentage of nondrinking days. A significant positive correlation was found between Wisconsin Card Sorting Test (WCST) performance and short-term prognosis measured by this parameter. Thus, in addition to transient withdrawal-related effects, impairments of WCST performance in early stages of alcohol detoxification may reflect more long standing deficits in problem-solving strategies, of possible relevance for matching patients to treatment services.

Hemostasis in Crohn's disease: low factor XIII levels in active disease.

Massive gastrointestinal hemorrhage sometimes occurs in Crohn's disease. To examine the possible role of acquired disorders of hemostasis contributing to such events, several laboratory indicators of hemostasis (APT time, Normotest, platelet count, bleeding time, fibrinogen, factor VIII activity, vWF:Ag, factor X, factor XIII, antithrombin III, fibrinopeptide A, and B beta(15-42] were studied in 10 patients with active Crohn's disease (Crohn's disease activity index (CDAI) greater than 150) and 10 patients with quiescent disease (CDAI less than 150). Marked thrombocytosis was seen in three patients with active disease. Factor VIII activity and fibrinogen levels were significantly elevated in patients with Crohn's disease (p less than 0.001), and the factor VIII activity levels were significantly higher (p less than 0.05) in the patients with active disease than in those with quiescent disease. Factor XIII levels were significantly lower (p less than 0.02) in patients with active disease. Three of the patients with active disease had factor XIII levels below the lower reference limit. The two patients with the lowest levels had hemorrhagic diarrhea and spontaneous bleeding from the rectal mucosa. Fibrinopeptide A and B beta(15-42) levels were significantly elevated in both groups. The other coagulation analyses were essentially normal in both patient groups. The results suggest that factor XIII deficiency acquired through gastrointestinal leakage may contribute to gastrointestinal hemorrhage in some patients with active Crohn's disease.

Caffeine metabolism in patients with chronic liver disease.

An oral load of 200 mg (1030 mumol) caffeine (CA) was given to 13 patients with chronic liver diseases and to 11 healthy controls. The metabolism of CA was determined by following plasma concentrations and urinary excretion of CA and its metabolites. In addition, [2-14C]-caffeine was given orally to six patients to confirm the excretion through the different pathways. CA and its 14 main metabolites were separated and quantified by high performance liquid chromatography and capillary electrophoresis. Median (interquartile range) half-lives of CA were 19 (6.3-32) h in the patients and 3.8 (3.4-4.7) h in the controls. The wide range in the patients indicated varying degrees of liver dysfunction. Only 3 (2-4)% of administered CA was excreted unmetabolized in urine in the controls and the main degradation was through the paraxanthine (PX) pathway 82 (75-83)%. The combined theobromine (TB) and theophylline (TP) pathways (TB + TP) accounted for 15 (13-21)% of CA metabolism. Although the excretion of unmetabolized CA in the patients 6 (3-8)%, was similar to that in the controls, the metabolism through the PX pathway, 62 (44-65)%, decreased (p < 0.01 vs. controls), whereas the metabolism through the TB + TP pathways increased to 33 (30-47)%, p < 0.01. In controls, N3-, N7- and N1-demethylations were observed in 86 (83-89)%, 66 (62-70)% and 13 (9-18)%, respectively, of excreted metabolites. In patients the N3-demethylations, 71 (66-77)%, and N7-demethylations, 54 (48-59)%, decreased (p < 0.01 vs. controls), whereas N1-demethylation increased 30 (21-46)%, p < 0.01. The major C8-oxidation reaction, the oxidation of 1-methylxanthine, increased in patients (p < 0.01). We conclude that the slowed metabolism of CA in chronic liver disease is due to reduced N3- and N7-demethylations affecting biotransformation through the PX pathway.

Gastrointestinal motility in obesity.

Gastrointestinal motility is closely linked to the rate at which nutrients become systemically available. Regulation of gastric emptying represents the most important brake against delivery of nutrients to the intestine in excess of digestive and absorptive capacity. In man, gastric emptying is slowed in proportion to the energy density of the meal, which will level out the rate of energy delivery to the duodenum. Studies suggest a more rapid gastric emptying in obesity, although the opposite has been reported in some experimental settings. Moreover, gastric volume is larger in obese individuals and appropriate satiety signals are not triggered in response to gastric distension. Postprandial intestinal transit time in obesity is similar to that in normal-weight subjects, however, despite this fact, intestinal absorption of nutrients is more efficient in obesity. Several regulatory mechanisms for gastrointestinal motility, such as the autonomous and enteric nervous systems and gastrointestinal regulatory peptides, are also of importance for feeding behaviour and metabolism. Dysfunction of the autonomous nervous system has been observed, the sensitivity to cholecystokinin is decreased in obesity, and plasma concentrations of somatostatin and neurotensin are lower than in normal-weight subjects. These changes in regulatory mechanisms favour rapid gastrointestinal transit of ingested nutrients and promote rapid intestinal absorption in obesity and decreased satiety in response to ingested food. It is presently not known whether the observed changes in gastrointestinal motility in obesity represent a primary feature linked to the pathogenesis of such disease.

Gastric secretion in massive obesity. Evidence for abnormal response to vagal stimulation.

Studies in animals and man suggest involvement of the vagal nerve in the pathophysiology of massive obesity. An abnormal vagal response pattern has been found in the obese rat, but corresponding functional studies in obese man are nonexistent. The gastric acid secretion was therefore examined in 13 nondiabetic grossly obese patients (average body weight 120 kg) and compared to 16 age-matched controls of normal body weight. The gastric acid response to modified sham feeding was significantly (P less than 0.05) reduced in obese patients, being on average 60% of the control output. The obese patients had a higher maximal gastric acid response to graded intravenous pentagastrin, 36.6 +/- 2.9 mmol/hr, compared to 27.1 +/- 2.4 mmol/hr in controls (P less than 0.05). In addition, the patients seemed to need less pentagastrin to reach a secretory plateau. Basal acid secretion rates were similar in obese and control groups. Plasma gastrin and blood glucose were not significantly different in obese patients and controls, but patients had significantly elevated plasma insulin levels. The change of plasma insulin during the sham-feeding procedure correlated with the magnitude of the secretory response in obese and control subjects. The reduced gastric acid response to vagal stimulation in the absence of impaired parietal cell function in obese patients is indicative of an association between massive obesity and altered vagal function in man.

Transport of serum bile acids in patients with liver cirrhosis and hyperbilirubinaemia.

From 12 patients with liver cirrhosis and hyperbilirubinaemia, the different conjugates of bilirubin and bile acids in the serum were separated and determined. The serum of the patients contained varying amounts of unconjugated bilirubin, which was not correlated to total serum bilirubin. No correlation between bilirubin conjugates and different conjugates of bile acids could be found, indicating different elimination processes for these substances. To examine whether a changed plasma transport of bile acids, which may contribute to the different excretion pattern of bilirubin and bile acids, occurs in liver cirrhosis, the bile acids in the different serum lipoprotein fractions were determined in seven of the patients. It was found that 40% of serum bile acids were bound to serum lipoproteins, despite decreased serum lipoprotein levels. The degree of lipoprotein binding of bile acids was not correlated to total serum bile acid concentrations. Cholic acid conjugates were present to a higher extent in the lipoprotein fractions than those of chenodeoxycholic acid or of deoxycholic acid. Determination was made of the distribution of individual conjugates between different lipoproteins and it was found that most of the glycine conjugates were present in high density lipoprotein, whereas the main part of sulphates and taurine conjugates were present in low density lipoprotein. These results indicate that a higher fraction of bile acids in liver cirrhosis is transported by lipoproteins in plasma, which may be of importance for the hepatic elimination of bile acids in cases with this disease.

Excretion of [24-14C] glycochenodeoxycholate-3-sulphate in patients with liver cirrhosis.

[24-14C] glycochenodeoxycholate-3-sulphate (GCDC-3S) was given intravenously to seven patients with liver cirrhosis and the elimination of the isotope from blood and the isotope excretion in urine and faeces followed. The bile acid conjugates in serum and urine were separated by HPLC and the change in specific activity in isolated conjugates determined. [24-14C] GCDC-3S was rapidly eliminated either by urinary excretion or faecal excretion and the half-life of the labelled conjugates varied between 76-198 min. No deamination or desulphation of the isotope occurred prior to urinary excretion. Only small amounts of GCDC-3S excreted in bile were absorbed from the intestine, as no isotope was recovered in other bile acid conjugates in serum.

Enzyme substitution in pancreatic disease: is colipase activity sufficient?

The aim of the present study was to determine colipase activity in various pancreatic enzyme tablets to ascertain whether these contained sufficient amounts of colipase to activate lipase during fat digestion. Colipase activity in all preparations tested exceeded that of lipase activity by a factor of 1.4-1.9 on a molar activity basis. Since optimal activity of lipase is obtained with colipase being present in a colipase to lipase molar activity ratio of 1.0, it is concluded that these preparations contain a sufficient amount of colipase to activate lipase.

Equilibration of labelled and endogenous bile acids in patients with liver cirrhosis after administration of (24-14C)cholic and chenodeoxycholic acids.

On separate occasions (24-14C)cholic acid and (24-14C)chenodeoxycholic acid were administered intravenously to patients with liver cirrhosis and the isotope excretion in urine and faeces monitored. Bile acids in serum, urine and faeces were extracted and separated into unconjugated bile acids, glycine- and taurine conjugates, glucuronides and sulphates. Individual bile acid conjugates were separated by high-performance liquid chromatography (HPLC) and the unconjugated bile acids were separated by gas-liquid chromatography (GLC) and identified by gas chromatography-mass spectrometry (GC-MS). Individual bile acid conjugates were quantified and their isotope contents determined. In serum, isotope contents declined rapidly during the first day, followed by a markedly slow rate of reduction. In accordance with this, the excretion of isotope from the patients was found to be very slow and the routes of bile acid excretion were changed, which resulted in an increased ratio of urine/faeces isotope excretion. Studies of the ratio of labelled to endogenous bile acid conjugates indicated that a continuous transformation of the labelled compounds occurred during the period of study. As judged from serum bile acids, conjugation to glycine- or taurine conjugates was rapid. The specific activities of labelled sulphate esters were consistently lower than for other conjugates during the 300-min observation period. During the first day, the urinary bile acids contained a high proportion of unconjugated labelled bile acids, which gradually disappeared. Labelled primary bile acids were slowly converted into microbial products, mainly 7-alpha dehydroxylated derivatives. The observed slow transformations resulted in a much delayed equilibration of labelled and endogenous bile acid derivatives, which invalidates isotope techniques for calculation of kinetic data of bile acid turnover. However, the observed very slow turnover of labelled bile acids in cirrhosis, owing to the persistent high rate of intestinal absorption and low capacity for urinary excretion, makes it possible for the intestinal flora to markedly change the composition of the bile acids in the pool. Studies of endogenous urinary and faecal bile acid excretion revealed the changed route of bile acid excretion with a high urinary/faeces ratio and the decreased synthesis of bile acids in cirrhosis.

Release of gastrin and somatostatin into the gastric lumen of healthy subjects and patients with duodenal ulcer and achlorhydria.

Gastrin and somatostatin were measured in alkaline gastric instillates in normal subjects, patients with duodenal ulcer disease in quiescent state and in patients with achlorhydria. Both peptides were released into the lumen. The gastrin-somatostatin ratio (G/S) in healthy subjects was approximately three. Duodenal ulcer patients had significantly lower G/S ratio due to lower gastrin and higher somatostatin levels whereas in patients with achlorhydria, the G/S ratio did not differ from normal subjects.

Serum concentrations and excretion of bile acids in cirrhosis.

Bile acid concentrations in serum, and urinary and faecal excretion of bile acids have been studied in ten patients with liver cirrhosis as a consequence of alcohol abuse. Eight of the patients were categorized as Child group A, whereas the remaining two patients comprised Child group C. Individual bile acids were isolated and identified by gas chromatography coupled to mass spectrometry. Total fasting serum bile acid concentrations were elevated in all patients, but not correlated to conventional tests of liver function. Eight of the patients had increased urinary excretion of bile acids. Faecal bile acid-excretion was highly variable between patients, and also between Child's group A and C patients. Total fasting serum bile acid concentrations were not correlated to either urinary, faecal, or total bile acid excretion (= synthesis of bile acids) or to the ratio between urinary and faecal excretion of bile acids. The daily synthesis of bile acids showed a large overlap between Child's group A and C patients. The percentage of chenodeoxycholic acid and its metabolites relative to total daily excretion of bile acids did not correlate, indicating that the synthesis pathways for the primary bile acids does not systematically change in relation to the rate of synthesis. We conclude that even in mild cirrhosis, serum bile acid concentrations are elevated. However, no consistent changes in synthesis of bile acids or synthesis pathways was observed in such patients.

Faecal bile acid excretion during detoxification in patients with alcohol abuse.

BACKGROUND: We wanted to ascertain whether alcohol abuse is associated with a changed faecal bile acid excretion. METHODS: Faecal bile acid excretion was studied in seven chronic alcoholic subjects when admitted to hospital for detoxification. Bile acids in faeces and serum were quantified by gas-liquid chromatography and identified by mass spectrometry. RESULTS: Daily faecal bile acid excretion was on average 948 mumol in the patients at admission, compared with 400 mumol in eight healthy controls (P < 0.01). The daily faecal bile acid excretion decreased slowly during the detoxification period but was still higher in the patients than in controls after 9 days of detoxification (P < 0.05). Faecal bile acid excretion varied greatly between the different patients, with poor correlation to diarrhoea. In one patient the faecal bile acid excretion was remarkably high, amounting to an average of 6800 mumol day-1 during the first 3 days. The percentage metabolites of total faecal bile acids in the patients did not differ significantly from that of controls. The faecal wet weight was higher in the patients than in the controls, although significantly so only after the first 3 days of detoxification. CONCLUSIONS: Faecal bile acid excretion is increased after alcohol abuse. A gradual decrease in faecal bile acid excretion was observed during the 9-day observation period when the subjects abstained from alcohol.

Bile constituents in ascitic fluid.

Bile acids and other bile constituents were determined in serum and ascites from eight patients with liver cirrhosis and in ascites secondary to malignancy in six patients. In cirrhotic ascites, total bile acid levels averaged 53% of the serum levels. A positive correlation was evident between ascites and serum levels for both cholic and chenodeoxycholic acid. For cholic acid, the ascites to serum ratio was higher in all patients compared with the corresponding ratio for chenodeoxycholic acid. The ascites to serum ratios for glycine, taurine and sulphate conjugates were similar, no tendency being shown by any of the conjugates to leak more easily into ascites. The high levels of bile acids in cirrhotic ascites suggests that the abdominal cavity harbours a fraction of the bile acid pool, which should be taken into account when studying bile acid turnover in liver cirrhosis. Bilirubin levels in cirrhotic ascites averaged 24% of the serum values. A positive correlation between ascites and serum levels for unconjugated bilirubin was recorded, whereas the occurrence of bilirubin conjugates in ascites was variable. Albumin levels in cirrhotic ascites were 25% of the serum levels. The ascites to serum ratios for other proteins such as IgG, IgA and IgM and also cholesterol and phospholipids were lower than that for albumin. In malignant ascites, a pattern different from that in liver cirrhosis was seen, low bile acid levels being found. No difference between bilirubin levels was observed, while albumin and cholesterol levels were higher in malignant ascites, with no overlap between the patient groups. These results indicate that the complex mechanisms of ascites formation result in variable levels of bile constituents in ascitic fluid, which are further dependent on the underlying disease.

Serum bilirubin subfractions in patients with alcohol abuse during detoxication.

Sera were obtained from 41 alcohol abusers consecutively admitted for detoxication. Blood samples were withdrawn on the second, fourth and seventh days of abstention. Initial bilirubin values were moderately elevated in 10 patients. Determination of the bilirubin subfractions by high performance liquid chromatography showed elevated values of unconjugated (alpha), monoconjugated (beta), diconjugated (gamma) and albumin-bound (delta) bilirubin, in 8, 15, 4 and 15 patients, respectively. During abstention, the total bilirubin value normalized rapidly, only three patients still had values above the upper reference limit after 7 days. In patients with initially elevated values of bilirubin subfractions, only a few had elevated beta and gamma levels on the seventh day, whereas delta levels decreased at a slower rate and remained virtually unchanged. On admission, 27 patients exhibited elevated levels of serum bile acids; these values decreased during abstention and after 7 days only six patients had slightly elevated values. Only five patients had initially elevated levels of alkaline phosphatase (ALP). These became normalized in all but two patients during abstention. The results suggest that mild cholestasis is common among alcohol-abusers without clinically evident liver disease and that these changes are reversible on abstention.

Meal energy density as a determinant of postprandial gastrointestinal adaptation in man.

The relationships between the meal energy density and postprandial gastric emptying, intestinal propulsion and absorption, and pancreaticobiliary secretions were investigated. Nine different 300-ml liquid test meals with energy densities ranging from 2.5 to 7.2 MJ l-1 were studied by means of a multiple-indicator dilution technique. The higher the energy density of the meal, the slower the gastric emptying of the test meal marker (P < 0.01). Despite slowing of gastric emptying of the meal marker the higher the energy density of the meal, the more energy was emptied to the duodenum during the 1st h after meal intake (P < 0.01). The small-intestinal transit time for the mid-portion of the meal correlated positively with energy density of the test meal (P < 0.05). Despite the prolonged time for transit through the jejunal test segment after meals with high energy density, the fractional absorption of energy varied only 50-70%, with no correlation to the energy density of the meal. As a consequence, more energy passed unabsorbed from the test segment to lower parts of the intestine after meals with high energy density (P < 0.05). We conclude that the energy density of a liquid meal is a strong determinant for the subsequent gastrointestinal adaptation. This relates not only to gastric emptying but also to intestinal transit and absorption of nutrients. The early onset of regulation suggests a role for the gastrointestinal tract in modulating the availability of systemic energy, which might be of importance for short-term regulation of food intake.