Mechanisms of the development of the chronic phase of diseases of the small intestine

The results of studying mechanisms underlying chronicity of functional (chronic enteritis ) and severe organic (celiac disease) lesions of the small intestine have been analyzed. Mechanisms causing the diseases take a chronic course appeared very similar. They involve bacterial proliferation in the intestine with consequent impairment of the digestion, absorption and motility resultant in derangement of metabolism. Defects in protein and lipid metabolism proved most essential. Chronic enteritis is associated with a favorable outcome provided there are no grave malabsorption symptoms. Combined treatment as a rule produces good therapeutic response in chronic enteritis and celiac disease. Relevant schemes are presented.     

The role of disorders of secretion of pancreatic enzymes and bile and bacterial contamination of the small intestine in the pathogenesis of diarrhea in patients with celiac disease

The study of 53 patients with celiac disease provided evidence for the impotent role of the inhibited hyposecretion of pancreatic enzymes, atony of the gallbladder responsible for abnormal bile acids introduction into the intestinal lumen in digestion, elevated concentrations of free bile acids at the expense of lowjugated ones in duodenal and jejunal contents as well as bacterial dissemination of the proximal portion of the small intestine in pathogenesis of diarrhea observed in celiac disease. It is concluded that inclusion of continuous courses of enzyme preparations and light cholagogues in the treatment schemes of celiac disease and administration in its exacerbation of adsorbents, astringents, antibacterial preparations should be necessary therapeutic measures.     

Cholagenic diarrhea

AIM: To characterize cholagenic diarrhea as a nosological entity with its specific features of etiology, pathogenesis, clinical picture and treatment. MATERIAL AND METHODS: A total of 167 patients with chronic diarrhea (CD) participated in the trial. Of them, 25 patients have undergone resection of the small intestine, 98--cholecystectomy for cholelithiasis, 44 had concurrent hypokinesia of the gall bladder caused by celiac disease (n = 30) or biliary dyskinesia (n = 14). The examination included estimation of cholic acid in the duodenal content (40% glucose solution or cholecystokinin were used as stimulators); 24-h fecal mass; fecal mass for 24 hours, fat, potassium and sodium content in the feces; electromotor activity (EMA) of the gall bladder, small intestine and colon. RESULTS: Duodenal intubation with 40% glucose in patients with extensive resection of the small intes- tine detected a fall in cholic acid content in vesical bile to 408 +/- 58.39 mg compared to normal (910 +/- 97.29 mg%). In intravenous administration of cholecystokinin cholic acid concentration rose insignificantly (547.0 +/- 94.7 mg%) and was accompanied with bile loss with feces, polyfecalia, steatorrhea and high sodium concentration in feces. In celiac disease patients bile with high cholic acid concentration was secreted only in administration of cholecystokinin (1673 +/- 175.9 mg/%, normal 1701 +/- 140.6 mg/%). In patients after cholecystectomy colon EMA was primarily slow-wave and middle-amplitude, typical for hypermotor dyskinesia. CONCLUSION: CD develops after extensive resection and in inflammatory ileac diseases, suppression of contractile function of the gall bladder and after cholecystectomy. CD after cholecystectomy can be considered as a variant of postcholecystectomy syndrome. The treatment of CD should include drugs binding excessive bile acids in the colon, in hypokinesia of the gall bladder the treatment should include stimulators of its contractile function.     

Morphofunctional alterations of the small intestine in patients with psoriasis and concomitant chronic opisthorchiasis

To characterize the small intestine clinically and functionally in psoriasis combination with chronic opisthorhiasis, 60 patients were examined with this combination, 45 with psoriasis but no helminthosis, 30 patients with chronic opisthorchiasis and 15 healthy subjects. Small intestinal absorption was studied by fat and carbohydrates absorption; bioelectric small intestinal activity--by electroenterography. Absorption in the small intestine of patients with mixed pathology was impaired. Pathogenetic mechanisms of such impairment were the following: low amplitude of bioelectrical activity of the small intestine, subnormal concentration of bile acids in the vesical bile, defects in microbial biocenosis of the intestine, structural disorders of the upper small intestine. Abnormal absorption in the small intestine correlated with psoriasis clinical picture (stages, duration, size of the lesion, disease severity).     

Characterization and effect of phospholipid on bile acid absorption by villi isolated from hamster small intestine

The effects of phospholipid on absorption of bile acids by hamster small intestine were studied to determine if this compound inhibits absorption of bile acids. Absorption of taurocholic and cholic acids was studied using a new in vitro technique that relates uptake rates to the weight of the villi present on the intestinal sample rather than to the weight of the entire segment of intestine used for the study. This procedure removes from consideration various components of the intestinal wall that are not directly involved with the absorptive process. Using radioactive techniques absorption of each type of bile acid was determined over a broad range of concentrations both in the presence and absence of phospholipid in the incubation medium. Absorption of taurocholic acid by villi from jejunum was determined to be a passive process, as previously reported by others. Villi from ileum absorbed both bile acids by an apparent active process when initial concentrations of bile acids were below 2.0 mM. Above this concentration bile acid absorption by the ileum appeared to be mainly passive. Phospholipid was found to inhibit bile acid absorption by ileum when initial bile acid concentrations were moderately high. However, at low substrate concentration, phospholipid has no appreciable effect on bile acid transport.     

Biological and medical aspects of active ileal transport of bile acids

The active transport of conjugated bile acids by the ileum is responsible for the enterohepatic circulation of bile acids, a physiological process that ensures an ample supply to the intestine of these key biological surfactants, irrespective of the rate of their biosynthesis from cholesterol. The ileal bile acid transport system is a high capacity, low affinity secondary active Na+ co-transport system that differs in substrate specificity from that present in the hepatocyte. Ileal transport is homeostatically regulated by feedback inhibition of the bile acids that are transported. The enterohepatic circulation is responsible for the concentration profile present in the intestine--high concentrations in the small intestine and low concentrations in the large intestine. Loss of ileal absorption, when mild, leads to a sequence of events that result in increased concentrations in the large intestine causing diarrhea. Severe bile acid malabsorption causes decreased concentrations in the small intestine which in turn lead to fat maldigestion and fat malabsorption. The increased passage of fatty acids into the colon contributes to diarrhea. Fat maldigestion and malabsorption also causes increased absorption of dietary oxalate from the colon which causes hyperoxaluria and contributes to nephrolithiasis. In cholestatic liver disease, inappropriate upregulation of ileal bile acid transport is likely to cause retention of hepatotoxic endogenous bile acids. In familial hypercholesterolemia, efficient bile acid absorption contributes to downregulation of LDL receptors and the maintenance of elevated plasma cholesterol levels; upregulation of bile acid transport during bile acid sequestrant therapy could diminish its efficacy. Efforts are in progress to develop a suitable bile acid analogue to be administered orally for conditions of bile acid deficiency in the small intestine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pathogenesis of lipid metabolism disorders in patients with chronic enteritis

A total of 156 patients with chronic enteritis have been examined for the bile lipid and bile acid composition, the small and large intestine proximal portions microflora, membranous digestion and absorption of the lipids, blood serum lipid composition; morphometry of the small intestine proximal portion mucosa has been carried out. The findings have been processed in correlation and regression analysis, that has revealed a number of relationships between these parameters. This helped specify some aspects in the pathogenesis of lipid metabolism disorders associated with the small intestine abnormalities and select the tests most valuable for the diagnosis and prognosis of the condition. The authors recommend a wider application of such analysis to clinical studies.     

Disorders of lipid metabolism in patients with chronic diseases of the small intestine

Lipid metabolism was evaluated in patients with chronic enteritis, celiac disease, general variable immunodeficiency (GVI), short-bowel syndrome. In chronic enteritis with malabsorption syndrome degree I and II changes in metabolism were characterized by hyperlipidemia due to high lipid fractions, mainly triglycerides; in malabsorption syndrome degree III (celiac disease, general variable immunodeficiency, short-bowel syndrome) by a drop of serum total lipids, phospholipids, cholesterol, beta-lipoproteins, free fatty acids, elevated concentrations of triglycerides. Changes in fatty acid composition of blood serum in patients with malabsorption syndrome degree III manifested by derangement of polyunsaturated fatty acids ratio. Arachidonic acid concentration was reduced in 100% of cases, linolenic acid in 45%. In all the patients with celiac disease and malabsorption syndrome degree III there was hypoactivity of lipolytic blood enzymes lipase and tributyrinase.     

Comparative characteristics of biliary lipids in celiac disease and chronic enteritis

The lipid components of duodenal contents (DC) and of gallbladder bile (GB), i.e. bile acids, phospholipids, and neutral lipids, as well as the fatty-acid composition of common lipids in celiac disease and chronic enteritis (CEN) were found, in the course of this study, to be specific and to differ between themselves to a great extent. The determination of the ratio of indices for 16:0 and 18:1 fatty acids and level 20:4 of an acid in the composition of common lipids of DC and GB could be used as a criteria in the differential diagnosis of celiac disease and CEN.     

Unconjugated serum bile acids as a marker of small intestinal bacterial overgrowth

Non-invasive methods to detect small intestinal bacterial overgrowth often lack specificity in patients who have undergone an ileal resection or have an accelerated intestinal transit. Since elevated serum unconjugated bile acid levels have been found in patients with clinical signs of bacterial overgrowth, we studied the clinical value of unconjugated serum bile acids as a marker of small intestinal bacterial overgrowth. Patients with culture-proven bacterial overgrowth had significantly elevated fasting unconjugated serum bile acid levels (median and range: 4.5; 1.4-21.5 mumol l-1) as compared to healthy subjects (0.9; 0.3-1.7 mumol l-1, P less than 0.005), to persons with an accelerated intestinal transit (1.0; 0.3-1.9 mumol l-1, P less than 0.005) and to persons who have undergone an ileal resection (2.1; 0.7-3.6 mumol l-1, P less than 0.005). The same was true 30 and 60 min after ingestion of a Lundh meal. Serum unconjugated bile acid levels above 4 mumol l-1 were found in eight of 10 patients with culture-proven small intestinal bacterial overgrowth whereas serum levels above 4 mumol l-1 were found in none of the patients from the three control groups. These results suggest that determination of unconjugated serum bile acids is of clinical value in the evaluation of patients suspected of small intestine bacterial overgrowth.     

In vitro determination of active bile acid absorption in small biopsy specimens obtained endoscopically or surgically from the human intestine

BACKGROUND: In the construction of a Kock reservoir for continent urinary diversion, 70 cm of the distal ileum are used. Impaired absorption of bile acids in these patients might cause diarrhoea. Data on the absorption of bile acids in different parts of the human intestine are limited. METHODS: Biopsies were taken during endoscopy from the duodenum, the terminal ileum or the right colon, and during surgery 10, 50, 100 and 150 cm proximally to the ileo-caecal valve using standard endoscopy biopsy forceps. The biopsy specimens were incubated in vitro with radio-labelled taurocholic acid at 37 degrees C for 22 or 45 min The radioactivity was determined using the liquid scintillation technique. RESULTS: A linear increase in the uptake was observed, with increased concentrations of taurocholic acid between 100 and 500 microm in all specimens tested, that represented passive uptake or unspecific binding. The active uptake could be calculated from the intercept of the line representing passive uptake with the ordinate. The active uptake in the terminal ileum was 3-4 times greater than 100 cm proximal to the valve. CONCLUSIONS: The active absorption of bile acids in humans can be determined in small biopsy specimens taken using standard biopsy forceps during endoscopy or surgery. This method is suitable for clinical studies of bile acid absorption. Active uptake of bile acids not only takes place in the very distal part of the ileum but also to a considerable degree 100 cm proximally to the ileo-colonic valve. This should be taken into account when selecting the ileal segment for continent urinary diversion.     

Effects of controlled interruption of the enterohepatic circulation of bile salts by biliary diversion and by ileal resection on bile salt secretion, synthesis, and pool size in the rhesus monkey

The effects of controlled interruption of the enterohepatic circulation (EHC) of bile salts by biliary diversion on bile volume, bile salt secretion and synthesis rates, bile salt pool size, and the relationship to fecal fat excretion were studied in 16 rhesus monkeys.Bile from a chronic bile fistula was returned to the intestine through an electronic stream-splitter which, by diverting different percentages of bile to a collecting system, provided graded and controlled interruption of the EHC.The increase in hepatic bile salt synthesis in response to interruption of the EHC was limited and reached a maximum rate at 20% interruption of the EHC. Up to this level of biliary diversion, the increased hepatic synthesis compensated for bile salt loss so that bile salt secretion and pool size were maintained at normal levels. With diversion of 33% or more, there was no further increase in hepatic bile salt synthesis to compensate for external loss, and as a result there was diminished bile salt secretion, a reduction in bile salt pool size, and steatorrhea was observed.The effects of interruption of the EHC by the streamsplitter were compared with those produced by resection of the distal one-third or two-thirds of small bowel. While ileal resection appreciably reduced bile salt secretion, the EHC was by no means abolished. Bile salt reabsorption from the residual intestine was greater after one-third than after two-thirds small bowel resection. These observations suggest that jejunal reabsorption of bile salts occurs and may well contribute to the normal EHC.     

Bile salt regulation of fatty acid absorption and esterification in rat everted jejunal sacs in vitro and into thoracic duct lymph in vivo

This study was performed to investigate whether the malabsorption of fat in the blind loop syndrome is due to the presence of free bile acids or to a deficiency of conjugated bile salts produced by bacterial degradation of normal bile salts, as well as to learn something of the mechanisms by which bile salts might regulate fat absorption. In the everted gut sac of the rat in vitro, conjugated bile salts were necessary for maximal rates of fatty acid esterification to triglycerides, whereas free bile acids inhibited this process even in the presence of physiologically normal or higher concentrations of conjugated bile salts. In contrast, in the living animal the addition of similar or higher concentrations of free bile acids to infusions of fatty acids in taurocholate micellar solutions produced no reduction in the amount of fatty acid absorbed into lymph or the amount of fatty acid esterified into lymph triglyceride. Both in vitro and in the living animal, reduction in the conjugated bile salt concentration reduced both the rate of fatty acid uptake by the intestine and the esterification into triglycerides. It is concluded that the steatorrhea of the blind loop syndrome or other conditions in which upper intestinal stasis allows bacterial proliferation is not due to presence of increased gut luminal concentrations of free bile acids, but rather is a consequence of lowered concentrations of conjugated bile salts.     

Jejunal and ileal absorption in patients with chronic renal disease. Effect of 1alpha-hydroxycholecalciferol.

Calcium absorption in 30-cm segments of small intestine was measured by constant perfusion of test solutions containing different concentrations of calcium gluconate. In both the jejunum and ileum, calcium absorption rates increased progressively as luminal calcium concentration was increased stepwise between 1 and 20 mM. Although calcium transport was not saturable within these limits, unidirectional flux ratios of calcium (47Ca) suggest that calcium absorption is active in both the jejunum and ileum. Calcium absorption in patients with chronic renal disease was markedly depressed in both regions of the small intestine. This was due to decreased flux out of the lumen; flux in the reverse direction was normal. Flux ratios in the renal disease patients showed no evidence for active calcium transport. Treatment of these patients for 1 wk within 2 mug/day of 1alpha-hydroxycholecalciferol [1alpha-(OH)-D3] restored net calcium absorption and unidirectional calcium flux out of the lumen to normal values in the jejunum; in the ileum, 1alpha-(OH)-D3 increased calcium absorption 60-83% of normal at the various luminal calcium concentrations. 1alpha(OH)-D3 had no effect on unidirectional calcium flux into the lumen or on xylose and electrolyte absorption in either area of the small intestine.     

Clinical importance of the determination of intestinal dipeptidase and enterokinase activity in patients with chronic enteritis

The activity of enterokinase and some dipeptidases (glycylalanine, glycylleucine, glycylvaline and glycylglycine) was studied in the intestinal mucosa biopsy specimens of 52 patients with chronic enteritis. Hydroxyproline excretion in the urine was defined before and after gelatin tolerance testing which showed a decrease in hydrolysis and protein absorption in the small intestine in chronic enteritis. A decrease in the level of dipeptidases and enterokinase involved in membranous digestion was noted whereas the level of glycylglycine acting intracellularly was practically unchanged. A decrease in the enzymatic activity correlated with a degree of gravity of disease and a degree of change in a morphological picture of the intestinal mucosa.     

Inhibition of active hexose and amino acid transport by conjugated bile salts in rat ileum

Abstract. The effect of conjugated trihydroxy bile salts, tauro- and glycocholate, and of deoxycholate on tissue uptake and mucosal to serosal transfer of actively transported hex-oses and amino acids has been examined in rat small intestine in vitro. Conjugated trihydroxy bile salts and deoxycholate markedly inhibited active transport of hexoses and amino acids in the ileum of rat small intestine, whereas in the jejunum, deoxycholate alone was inhibitory. The inhibitory effect of tauro- and glycocholate increased with incubation time. It persisted after washing of the tissue and reincubation with hexoses in a bile salt free medium, and could be observed with only 2 × 10^-4 M taurocholate. Taurocholate was able to evoke an increase of transmural potential difference (PD) in the ileum, but did not affect PD in the jejunum. Prein cubation of ileal small intestine with taurocholate depressed subsequent glucose-induced PD-increments. In the jejunum, however, taurocholate did not affect PD-increments induced by D-glucose. It is concluded that conjugated trihydroxy bile salts have to enter intestinal mucosal epithelial cells to an appreciable extent in order to affect other active, energy-requiring transport systems in rat small intestine. Previous results showing a failure of conjugated bile salts to inhibit active transport of hexoses and amino acids are explained by the fact that only jejunal transport had been examined.     

Bile salt malabsorption in regional ileitis,ileal resection and mannitol-induced diarrhea

Fecal bile salt excretion was studied in healthy volunteers, patients with regional ileitis, and patients with ileal resection. 10 muc of carboxyl-(14)C-cholic acid was given orally. Stools and urine were collected daily for 5-10 days, the bile salts extracted, and the radioactivity assayed. Urinary excretion was negligible. All patients with ileal resection excreted bile salts in the feces significantly faster than controls, and five of the six excreted 50% of the radioactivity within 24 hr. Their mean intestinal transit time was 5.6 hr compared to 26 hr for the controls. Two of the three patients with regional ileitis excreted bile salts almost as rapidly as patients with ileal resection. Vitamin B(12) absorption was also defective in those patients, but the intestinal transit time was not decreased.To study the effect of rapid intestinal transit on bile salt excretion, four of the control subjects were given orally 1200 ml of 10% mannitol for 7 days, and the labeled cholic acid excretion rate was again studied. The mean intestinal transit time was markedly shortened, mild steatorrhea developed, and the fecal bile salt excretion rate increased slightly.It is concluded that ileal resection and ileal disease are major factors and rapid intestinal transit is a minor factor in causing excessive fecal bile salt loss. The relevance of bile salt wastage to lipid malabsorption is unknown because of insufficient information about compensatory jejunal absorption, maximum rate of hepatic bile salt synthesis, and the minimum necessary intraluminal concentration of conjugated bile salt.     

Algorithm for diagnosis of small intestinal diseases

AIM: To review diagnostic approaches in chronic diseases of the small intestine. MATERIAL AND METHODS: A total of 1096 patients with chronic diseases of the small intestine were admitted to the clinic of the Central Research Institute of Gastroenterological Diseases in 1987-2006. RESULTS: Most of the patients (90.5%) had celiac disease, hypolactasia and other types of disaccharidase deficiency, yersiniosis ileitis, Krohn's disease, postresection syndrome of a short small intestine, mesenterial ischemia and endocrine enteropathy. Rare diseases (general variable hypogammaglobulinemia, lymphoma, Wipple's disease and diverticulosis of the small intestine) were diagnosed in 5.8% cases. Primary amyloidosis of the small intestine, eosinophilic gastroenteritis, arteriomesenterial obstruction, primary intestinal pseudoobstruction, hypogammaglobulinemic spru, primary intestinal lymphangiectasia, tuberculosis, total polyposis, Peutz-Eggers and Cronkhite-Canada syndromes, collagenic sprue, erosive-ulcerative jejunoileitis, adenocarcinoma and heavy alpha-chain disease were detected in 3.7% examinees. These diseases were encountered in one to 5 cases for the latest 20 years. CONCLUSION: Clinical diagnosis of small intestinal diseases is based on the syndromes of chronic diarrhea, defective absorption, enteral protein loss, small intestinal obstruction and intestinal hemorrhage. Differential diagnosis of the nosological entities employs x-ray, endoscopic, histological, immunological and other methods. Most of the small intestinal diseases including rare can be diagnosed in any gastroentorological department.     

Lesions of the digestive organs in Sjogren's disease

The clinicofunctional and morphological status of the stomach, biliferous system, pancreas, large and small intestine was studied in 83 patients with Sjogren's syndrome and disease (SS and SD). Chronic gastritis with secretory insufficiency was shown to develop in SD. Morphological changes of the gastric mucosa were represented by chronic gastritis with glandular involvement and chronic atrophic gastritis of immune genesis. Pathology of the extrahepatic system of bilification was detected in 87% of patients. The most common pathologies diagnosed in these patients were chronic cholecystitis (51%) and biliary dyskinesia (25%). Changes of the chemical composition of the bile (arise of its lythogenic properties) were observed. Various disorders of pancreatic function were detected in 85% of SS and SD patients. X-ray and endoscopic investigations revealed duodenal, intestinal and colon hypokinesia, less frequently signs of enteritis and colitis in one-third of the patients. The irritable colon syndrome was found in 40%. On the whole, involvement of different parts of the intestine was observed in 92%. Morphological changes in the duodenal and sigmoid colon mucosa were typical of chronic diffuse duodenitis and sigmoiditis in a subacute SD course, and chronic atrophic duodenitis and sigmoiditis in a chronic SD and SS course.     

Relationship between Faecal Bile Acids, Absorption of Fat and Vitamin B12, and Serum Lipids in Patients with Ileal Resections

Abstract. Faecal bile salt, neutral steroid and fat excretion, vitamin B₁₂ absorption, and jejunal lipids, bile acids and cholesterol during fat digestion, serum cholesterol and cholesterol synthesis were measured in 3 patients with incomplete (IIR) and 9 patients with complete (CIR) resection of the terminal ileum. These parameters were virtually normal in IIR and in one case with CIR while in other cases they were frequently abnormal, bile salt excretion being increased up to 12-fold. The finding that faecal bile salts correlated positively with faecal fat and cholesterol synthesis, and negatively with jejunal constituents and serum cholesterol, supports the previously unproved concept that augmented elimination of cholesterol into faeces as bile acids proportionately depletes serum cholesterol despite increased cholesterol synthesis, proportionately decreases jejunal bile salts despite markedly augmented bile acid production and proportionately impairs micellar solubilization of lipids during fat absorption, leading to steatorrhoea. Furthermore, faecal bile salts showed a positive correlation with faecal water and a negative one with the Schilling test values. Faecal bile salts are suggested to be a sensitive indicator of ileal dysfunction.