Πέψη, διάρροια, δυσαπορρόφηση. Γεράσιμος Μπαλταγιάννης Ιατρική Σχολή Πανεπιστήμιο Ιωαννίνων

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1 Πέψη, διάρροια, δυσαπορρόφηση Γεράσιμος Μπαλταγιάννης Ιατρική Σχολή Πανεπιστήμιο Ιωαννίνων

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5 Chief of Pepsi-Cola Mnemonics Chief cells of stomach produce Pepsin Parietal cells Produce Acid & Release Intrinsic factor

6 1). Goblet cells Mucus 2). Gastric glands gastric pits gastric juice a). Mucous Neck Cells b). Parietal cells or Oxyntic cells Intrinsic Factor Hydrochloric Acid (HCl) mucosal barrier

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11 Σάκχαρα (υδατάνθρακες) και αμινοξέα Nutrient-coupled absorption of sodium. Sugars and amino acids harness the favorable electrochemical gradient for sodium entry across the apical membrane of enterocytes to drive nutrient absorption. A specific carrier (SGLT-1) with binding sites for both sodium and glucose transports both solutes into the enterocytes. Sodium is extruded across the basolateral membrane by the sodium pump (Na-K ATPase), thereby maintaining the driving force for sodium entry across the apical membrane. Glucose accumulates within the enterocyte and exits through a sodium-independent transporter (GLUT-2) that facilitates diffusion across the basolateral membrane. Similar systems for amino acid absorption are operative in the small intestine. This mechanism is present throughout the small intestine

12 Λήψη λιπών με την τροφή Αποθήκη των χολικών αλάτων Χοληδόχος κύστη Λιπαρά οξέα & χοληστερόλη Λιποκύτταρα ή μυϊκά κύτταρα 1. Τα χολικά άλατα σχηματίζουν μικκύλια με τα λίπη της τροφής 2.Η εντερική λιπάση διασπά τα τριγλυκερίδια 3. Στον εντερικό βλεννογόνο τα λιπαρά οξέα επαναδομούνται σε τριγλυκερίδια Λεπτό έντερο Αγγειακό τριχοειδές Εντερικός βλεννογόνος Λιποπρωτεϊνική λιπάση 5.Η Λιποπρωτεϊνική λιπάση, που ενεργοποιείται από την apoc-ii στα τριχοειδή απελευθερώνει λιπαρά οξέα και γλυκερόλη Χυλομικρά 4. Τα τριγλυκερίδια μετασχηματίζονται σε χυλομικρά με την βοήθεια της χοληστερόλης και των απολιποπρωτεϊνών

13 monosaccharides Process: Salivary amylase in mouth Other pancreatic enzymes & Brush border enzymes on the microvilli break peptides into single amino acids. Pancreatic amylase Brush border enzymes Proteins Pepsin in the stomach trypsin & chymotrypsin in pancreatic juice

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15 Bile salts from liver emulsify the fats In a larger fat globule only the surface lipids are exposed to the enzymes. Lipase from the pancreatic juice cleave off fatty acids

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25 H H H Λιπίδια του πλάσματος H-C-C-C-COO - Λιπαρό οξύ Λιπαρό οξύ Λιπαρό οξύ Τριγλυκερίδιο Λιπαρό οξύ Λιπαρό οξύ P N Φωσφολιπίδιο H H H Λιπαρό οξύ ΗΟ Χοληστερόλη Λιπαρό οξύ Εστέρας Χοληστερόλης

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27 Ira J.Goldberg. Gastroenterology 2006;130: L-FABP=Liver fatty acid binding protein FATP5=Fatty acid transporting protein MTP= microsomal triglyceride transfer protein

28 Αντίσταση στην ινσουλίνη TG FFA Λιπόλυση Εστεροποίηση FFA FFA FFA Λιπώδης ιστός

29 PPARγ=Peroxisome proliferator activated receptor gamma SREBP-1c=sterol regulatory element binding protein MTP=Microsomal triglyceride transfer protein

30 Ορισμός διάρροιας Τουλάχιστον 3 κινήσεις του εντέρου /ημέρα και βάρος κοπράνων >200g/ημέρα.( περιεκτικότητα νερού>75-85%) Οξεία διάρροια :< 4 εβδομάδες Χρόνια διάρροια :>4 εβδομάδες Ψευδο-διάρροια : αύξηση συχνότητας κενώσεων με φυσιολογικό βάρος κοπράνων(σεε, πρωκτίτιδα) Νοσοκομειακή διάρροια: διάρροια μετά από >72 ώρες από την εισαγωγή Παράδοξη διάρροια: εναλλαγή διάρροιας δυσκοιλιότητας (καρκίνωμα σιγμοειδούς ορθού)

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40 Common causes of acute diarrhea Drugs Laxatives Antacids Antibiotics Cholinergic drugs Lactose Guanethidine Quinidine Digitalis Colchicine Potassium supplements Lactulose Bacteria (toxin-mediated, cytotonic) Enterotoxigenic Escherichia coli (both heat-labile and heat-stable toxins) Vibrio cholerae Vibrio parahaemolyticus Clostridium perfringens Bacillus cereus Bacteria (toxin-mediated, cytotoxic) Clostridium difficile Staphylococcus aureus Shigella dysenteriae Campylobacter jejuni Yersinia enterocolitica Bacteria (invasive) Salmonella Enteroinvasive Escherichia coli Bacteria (unknown mechanism) Enteropathogenic Escherichia coli Enteroadherent Escherichia coli Viruses Parvovirus (Norwalk agent) Reovirus (rotavirus) Protozoa Cryptosporidia Giardia lamblia Entamoeba histolytica Parasites Strongyloides Trichuris

41 Gastric Excessive use of antacids* Hypergastrinemia/Zollinger-Ellison syndrome Postoperative unmasked celiac disease, lactase deficiency or pancreatic insufficiency Postoperative dumping syndrome* Small intestine Crohn's disease* Celiac disease* Lymphoma Whipple's disease Bacterial, viral or parasitic infection* Abnormal intestinal integrity: scleroderma, amyloidosis, diabetes Large bowel Colon neoplasia* Irritable bowel syndrome* Inflammatory bowel disease: ulcerative colitis, Crohn's disease* Drugs Antacids* Antibiotics* Alcohol* Antimetabolites Laxatives Digitalis Colchicine Metabolic Hyperthyroidism Hypoparathyroidism Addison's disease Diabetes* Carcinoid syndrome VIPoma syndrome

42 Major disturbance Probable mechanisms Examples/Associated conditions Osmotic Ingestion Antacids, laxatives Maldigestion Pancreatic insufficiency, disaccharidase deficiency Malabsorption Carbohydrate malabsorption, congenital chloridorrhea Disorders of intestinal transit Slow transit ("blind loop syndrome") - excessive contact time Fistulas, strictures (such as in the patient with Crohn's disease), diabetic neuropathy Rapid transit - insufficient contact time Intestinal resection, hyperthyroidism, irritable bowel Secretory Bacterial enterotoxins Vibrio cholerae, enterotoxigenic E. coli Secretagogues Bile acids, fatty acids, ethanol, prostaglandins, phenolphthalein, dioctyl sodium sulfosuccinate, VIP, gastrin, calcitonin Exudative Increased passage of body fluids into lumen Ulcerative colitis, Crohn's disease

43 Διαγνωστική προσέγγιση στη χρόνια διάρροια Fine, KD, Schiller, LR, AGA technical review on the evaluation and management of chronic diarrhea, Gastroenterology 1999; 116:1464.

44 Τα μυστικά της διάρροιας Οσμωτική διάρροια Εκκριτική διάρροια Η διάρροια ελαττώνεται μετά από νηστεία, συμπαγή κόπρανα, απώλεια βάρους, οσμωτικό χάσμα στο νερό των κοπράνων Υδαρής διάρροια, δεν ελαττώνεται μετά διακοπή τροφής, δεν υπάρχει οσμωτικό χάσμα Δυσαπορρόφηση υδατανθράκων, ανεπάρκεια λακτάσης(20%), θεραπεία με λακτουλόζη, μη ανοχή σορβιτόληςφρουκτόζης, κοιλιοκάκη, παγκρεατική ανεπάρκεια εξωκρινούς μοίρας Vibrio cholerae, E.coli, καθαρτικά, μικροσκοπική κολίτιδα, δυσαπορρόφηση χολικών οξέων, καρκινοειδές, γαστρίνωμα, VIPoma, μυελοειδές καρκίνωμα θυρεοειδούς

45 Τα μυστικά της διάρροιας Ερώτηση Μικρή ποσότητα κοπράνων, συχνή κένωση μικρής ποσότητας κοπράνων, κόπρανα καλυμμένα με αίμα ή βλέννα; Μεγάλη ποσότητα κοπράνων; Υδαρή κόπρανα χωρίς ορατό αίμα, μερικές φορές με παρουσία άπεπτων τροφών; Ογκώδη, ιδιαίτερα δύσοσμα κόπρανα επικαλυμμένα με λίπος; Διάρροια μετά από λήψη γάλακτος ή προϊόντων αυτού; Διάρροια που επιμένει την νύχτα ή ανεξάρτητα από τη λήψη τροφής; Φάρμακα; Μετά χειρουργική επέμβαση ή ακτινοβολία; Υποψία για νόσημα του εγκαρσίου-σιγμοειδούς και ορθού. νόσημα του λεπτού εντέρου νόσημα του λεπτού εντέρου παγκρεατική ανεπάρκεια εξωκρινούς μοίρας ή κοιλιοκάκη ανεπάρκεια λακτάσης εκκριτική ή εξιδρωματική διάρροια φαρμακευτική διάρροια μετά Billroth II εκτομή, μετακτινική κολίτιδα

46 Δυσαπορρόφηση Με τον όρο αυτό περιγράφονται διάφορες κλινικές εκδηλώσεις και εργαστηριακά ευρήματα,που οφείλονται στην κακή απορρόφηση από τον πεπτικό σωλήνα των διαφόρων τροφών, βιταμινών και ιχνοστοιχείων

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54 Στην καθημερινή πράξη, η παρουσία συνδρόμου δυσαπορρόφησης πρέπει να συζητείται όταν η κλινική συμπτωματολογία του αρρώστου περιλαμβάνει στεατόρροια, χρόνια διάρροια, εκσεσημασμένη αποβολή αερίων, απώλεια βάρους, αναιμία και ενδείξεις αβιταμινώσεως, κυρίως των λιποδιαλυτών βιταμινών (ΑDEK).

55 Symptoms and Signs Symptoms of malabsorption are caused by the effects of osmotically active substances in the GI tract or by nutritional deficiencies that develop. Some causes of malabsorption have distinct clinical presentations. Dermatitis herpetiformis is often associated with a mild degree of celiac-like enteropathy; biliary cirrhosis and pancreatic cancer cause jaundice; mesenteric ischemia causes abdominal angina; chronic pancreatitis causes boring central abdominal pain; and Zollinger-Ellison syndrome causes severe, persistent ulcerative dyspepsia. Malabsorption causes weight loss, glossitis, carpopedal spasms, absent tendon reflexes, cutaneous bruising, flatulence, and abdominal distention, bloating, or discomfort resulting from increased intestinal bulk and gas production. Symptoms of lactase deficiency include explosive diarrhea with abdominal bloating and gas after milk ingestion. Pancreatic lipase deficiency manifests as greasy stools with undigested dietary fat (triglycerides). Steatorrhea may occur--pale, soft, bulky, malodorous stools that stick to the side of the toilet bowl or float and are difficult to flush away. Steatorrhea is most likely to occur in celiac disease or tropical sprue. Steatorrhea can be present with even relatively normal appearing stools.

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57 Διαγνωστική προσπέλαση 1. Ανεύρεση λίπους στα κόπρανα και τη μέτρησή του (gold standard). To τελευταίο δεν είναι πάντοτε εφικτό και έχει αντικατασταθεί από άλλες δοκιμασίες, που όμως δεν έτυχαν ανάλογης αναγνώρισης(λχ 14 C-triolein breath test). 2.Δοκιμασία απορρόφησης της D-ξυλόζης. 3.Στην χαρακτηριστική ακτινολογική εικόνα όταν υπάρχει.(αποτιτανώσεις παγκρέατος σε περιπτώσεις χρόνιας παγκρεατίτιδας). 4.Βιοψία του λεπτού εντέρου. 5.Σε διάφορες αναπνευστικές δοκιμασίες. 6.Ειδικότερες δοκιμασίες, όπως το schilling test για τη διαπίστωση δυσαπορρόφησης της B12.( Tα αποθέματα της Β12 επαρκούν για 2-3 χρόνια).

58 Diagnosis Direct measurement of fecal fat is the most reliable test for establishing malabsorption. Steatorrhea is absolute evidence of malabsorption but is not always present. For an adult eating a usual Western diet with a daily fat intake of 50 to 150 g, fecal fat > 6 g/day is abnormal. Accuracy of stool collections is important. It is feasible and advantageous to measure fecal fat in ambulatory outpatients; a 3- or 4-day collection is usually adequate. Stool inspection and microscopic examination are valuable. The typical stool appearances described above are unmistakable. The presence of undigested food fragments suggests either extreme hypermotility or intestinal short circuits (eg, gastrocolic fistula). Greasy stools from a jaundiced patient point to biliary cirrhosis or pancreatic cancer. Microscopic examination showing fat globules and undigested meat fiber suggests pancreatic insufficiency. Microscopy permits identification of ova or parasites. Sudan III staining of a stool smear is a relatively simple and direct, but nonquantitative, screening test for fecal fat.

59 Absorption tests help define the lesion. A D-xylose absorption test is an indirect but relatively specific measure of proximal small-bowel absorption. Abnormal findings are usual in primary jejunal disease but rare in other causes. D-Xylose 5 g po is given to the fasting patient, and urine is collected for the next 5 h. This dose is slightly less sensitive than a larger (25-g) dose but does not cause nausea or diarrhea. Provided that urine output is adequate and the GFR is normal, < 1.2 g of D- xylose in the 5-h collection is considered abnormal, and 1.2 to 1.4 g is considered borderline. Although this test is popular in pediatric practice, complete urine collection in young children is difficult, and some investigators prefer measuring blood levels. However, measuring blood levels is less reliable because normal and abnormal levels overlap considerably unless the D-xylose dose was 0.5 g/kg. Iron malabsorption can usually be inferred in a patient whose diet is adequate and who has no chronic blood loss or thalassemia but has an iron-deficiency state, indicated by low serum ferritin or iron levels. Diminished iron storage can be seen on bone marrow evaluation. Folic acid absorption is abnormal if a low serum or RBC folate level is found in a patient eating an adequate diet but not consuming excessive alcohol.

60 Vitamin B12 absorption is abnormal if serum B12 is low. Because stores are extensive, a low level indicates a chronic condition. The Schilling test helps determine the cause of malabsorption. Reduced urinary excretion (< 5%) of radiolabeled B12 indicates malabsorption. If excretion corrects to normal (> 9%) when intrinsic factor-bound radiolabeled B12 is given, the malabsorption is caused by deficient gastric intrinsic factor activity (often, true pernicious anemia). When intrinsic factorbound B12 does not correct excretion, chronic pancreatitis, drugs (eg, aminosalicylic acid), or small-bowel disease (eg, blind loops, jejunal diverticula, ileal disease) must be suspected. Deconjugation of bile salts by intestinal bacteria, which occurs in small-bowel disorders that cause stasis and bacterial overgrowth (eg, blind loops, diverticula, scleroderma), can be tested with carbon 14- labeled glycocholic acid breath test. The test is usually unnecessary and expensive and is often unavailable. X-rays may be nonspecific or diagnostic. An upper GI series with small-bowel follow-through may show dilated bowel loops with thinned mucosal folds (suggesting celiac disease), thickened mucosal folds (suggesting Whipple's disease), and coarse fragmentation of the barium column, but these findings only suggest malabsorption. Diagnostic findings are fistulas, blind loops, or various inter-enteric anastomoses; jejunal diverticulosis; and mucosal patterns suggestive of intestinal lymphoma, scleroderma, or Crohn's disease. A flat plate x- ray may show pancreatic calcification--a sign of chronic pancreatitis. ERCP may also help identify chronic pancreatic insufficiency, but pancreatic calcification is usually sufficient.

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62 Vitamin B12 absorption (Schilling test) in various diseases Test Gastrectomy, pernicious anemia Celiac disease* Bacterial overgrowth Ileal resection or disease Vitamin B12 Low Low Low Low/normal Low Vitamin B12 + intrinsic factor Normal Low Low Low/normal Low Pancreatic insufficiency Vitamin B12 + antibiotics Vitamin B12 + gluten-free diet Vitamin B12 + pancreatic enzymes n/a Low Normal Low/normal Low n/a Normal n/a Low/normal Low n/a n/a n/a n/a Normal

63 Small-bowel biopsy of the jejunum is a routine procedure that simultaneously allows samples of jejunal juice to be taken for microbiologic testing of the intestinal flora. Endoscopic biopsies are also suitable but should be taken beyond the second part of the duodenum. The mucosal sample can be examined grossly by hand lens or dissecting microscope and by light or electron microscopy, and tissue homogenates can be assayed for enzyme activity. Specific diagnoses include Whipple's disease, lymphosarcoma, intestinal lymphangiectasia, and giardiasis (in which the trophozoite may be seen in close association with the villous surface). Jejunal histology (villous atrophy) is also abnormal in celiac disease, tropical sprue, and dermatitis herpetiformis. Two pancreatic function tests are used; both require duodenal intubation: Pancreatic secretion is indirectly stimulated by an oral formula diet, and the Lundh test measures lipase levels in the duodenal aspirate. Pancreatic secretion is directly stimulated by secretin IV. The bentiromide test for pancreatic function has been introduced, but its accuracy and usefulness must be evaluated. The test is based on cleavage of the synthetic peptide bentiromide by the pancreatic enzyme chymotrypsin. The para-aminobenzoic acid moiety is absorbed and excreted in the urine. Accuracy depends on normal gastric emptying, normal absorption, and normal renal function; certain drugs (eg, sulfonamides, acetaminophen) can give false results.

64 Special tests may help diagnose less common causes of malabsorption, such as serum gastrin levels and gastric acid secretion in Zollinger-Ellison syndrome, sweat Cl in cystic fibrosis, lipoprotein electrophoresis in abetalipoproteinemia, and plasma cortisol in Addison's disease.

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66 Malabsorption: mechanisms by which impairments in the luminal, mucosal and processing phases occur Phase and nature of malabsorptive defect Example Luminal phase A. Substrate hydrolysis 1. Digestive enzyme deficiency Chronic pancreatitis 2. Digestive enzyme inactivation Zollinger-Ellison syndrome 3. Dyssynchrony of enzyme release, inadequate mixing Post Billroth II procedure B. Fat solubilization 1. Diminished bile salt synthesis Cirrhosis 2. Impaired bile secretion Chronic cholestasis 3. Bile salt de-conjugation Bacterial overgrowth 4. Increased bile salt loss Ileal disease or resection C. Luminal availability of specific nutrients 1. Diminished gastric acid Atrophic gastritis - vitamin B12 2. Diminished intrinsic factor Pernicious anemia - vitamin B12 3. Bacterial consumption of nutrients Bacterial overgrowth - vitamin B12 Mucosal phase A. Brush border hydrolysis 1. Congenital disaccharidase defect Sucrase-isomaltase deficiency 2. Acquired disaccharidase defect Lactase deficiency B. Epithelial transport 1. Nutrient-specific defects in transport Hartnup's disease 2. Global defects in transport Celiac sprue Postabsorptive, processing phase A. Enterocyte processing Abetalipoproteinemia B. Lymphatic Intestinal lymphangiectasia

67 Signs and symptoms of malabsorption Malabsorption of Clinical features Laboratory findings Calories Fat Weight loss with normal appetite Pale and voluminous stool, diarrhea without flatulence steatorrhea Stool fat > 6 g/day Protein Edema, muscle atrophy, amenorrhea Hypoalbuminemia, hypoproteinemia Carbohydrates Watery diarrhea, flatulence, acidic stool ph, milk intolerance, stool osmotic gap Increased breath hydrogen Vitamin B12 Anemia, subacute combined degeneration of the spinal cord (early symptoms are paresthesias and ataxia associated with loss of vibration and position sense) Macrocytic anemia, vitamin B12 decreased, abnormal Schilling test, serum methylmalonic acid and homocysteine increased Folic acid Vitamin B, general Anemia Cheilosis, painless glossitis, acrodermatitis, angular stomatitis Macrocytic anemia, serum and RBC folate decreased, serum homocysteine increased Iron Microcytic anemia, glossitis, pagophagia Serum iron and ferritin decreased, TIBC increased Calcium and vitamin D Paresthesia, tetany, pathologic fractures due to osteomalacia, positive Chvostek and Trusseau signs Hypocalcemia, serum alkaline phosphatase increased, abnormal bone densitometry Vitamin A Follicular hyperkeratosis, night blindness Serum carotene decreased Vitamin K Hematoma, bleeding disorders Prolonged prothrombin time, vitamin K-dependent coagulation factors decreased

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77 Actions of cholecystokinin Contracts the gallbladder Stimulates pancreatic enzyme secretion Delays gastric emptying Induces satiety Potentiates insulin secretion Regulates intestinal motility Neurotransmitter