Transcript Factors involved in Normal Digestion and Absorption of Food

‫‪MALABSORPTION‬‬
‫פרופ' יוסף צימרמן‬
‫גסטרואנטרולוגיה‬
‫המרכז הרפואי של הדסה והאוניברסיטה‬
‫העברית‪ ,‬עין כרם‪ ,‬ירושלים‬
MALABSORPTION
• GENERALIZED: Non specific impairment in the
absorption of multiple nutrients;
 Pancreatic insufficiency
 Short Bowel Syndrome
• SPECIFIC: Impairment of digestion or
absorption of a single nutrient;
 Lactase deficiency
When Should We Suspect
Malabsorption?
• Nutritional deficiencies (anemia,
osteoporosis), mainly if dietary intake
appears appropriate;
• Weight loss;
• diarrhea;
Malabsorption: Physical Signs
• Non specific: wasting, bloated abdomen,
edema and signs of specific nutrient
deficiency (glossitis, angular cheilosis,
petechiae, etc.)
• May suggest a diagnosis (clubbing in small
bowel disease etc.)
Pathophysiology
• LUMINAL FACTORS (MALDIGESTION)
• MUCOSAL FACTORS
 Impaired hydrolysis (dissacharidases, peptidases)
 impaired transport;
• POST MUCOSAL FACTORS
 Vascular
 Lymphatic
Dietary Fat is Mostly Triglyceride (TG)
TG DIGESTION:
GASTRIC PHASE
• Initial hydrolysis by the lingual and gastric
lipases.
• These lipases, unlike the pancreatic lipase, are
active at an acid pH (4.5-5.4) and hydrolyze TG
to diglyceride and free fatty acid (FFA).
• While their contribution to overall fat
digestion in the normal adult is small, they are
important in neonates and in patients with
cystic fibrosis.
LIPID EMULSIFICATION IN THE
STOMACH
• Dietary fat, which is partly hydrolyzed by
gastric and lingual lipases, is dispersed in the
gastric contents in small droplets, creating a
lipid emulsion. The motor activity of the
antrum is essential in this process.
• The emulsion is stabilized by FFA’s released
from dietary TG through the action of the
lingual and gastric lipases in the stomach .
GASTRIC EMPYING
• Delivery of chyme from the stomach is
delicately adjusted so it enters the duodenum
at a controlled rate, allowing mixing with
pancreatic secretions and bile.
• Control of gastric emptying is thus critical to
ensure optimal digestion.
Stages of Fat Digestion and Absorption:
Intestinal Phase
• Hydrolysis (pancreatic lipase);
• Solubilization in bile salt micelles;
• Transport across the luminal membrane of the
enterocyte;
• Resynthesis of TG in the enterocyte;
• Incorporation of TG into chylomicrons;
• Elimination of the chylomicrons by the
lymphatic system
Triglyceride Hydrolysis by Pancreatic
Lipase
+
2 FFA
Properties of the Pancreatic Lipase
•
•
•
•
•
•
Secreted in active form (not proenzyme);
Interfacial enzyme, positional specificity;
Secreted in great excess;
Optimum activity at pH ~6;
Destroyed by acid (pH<3);
Requires co-lipase;
Bile Salt Micelle formation
• In order to solubilize fat, bile salts must form
micelles;
• The formation of micelles depends on the
concentration of bile salts, and occurs when
their concentration is > 1.5 mmol/L (CMC).
• Normally, the bile salt concentration in the
duodenum during meal is 5-10 mmol/L.
FUNCTIONS OF INTRALUMINAL BILE SALTS
• Micellar solubilization of fat-soluble vitamins
(A,D,E,K)-essential for their absorption;
• Micellar solubilization of fatty acids and
monoglycerides;
• Protection of pancreatic lipase against tryptic
digestion.
CHYLOMICRON CLEARANCE FROM THE INTESTINE
• Normally, fat absorption is completed in the upper
2/3 of the jejunum.
• Fat malabsorption may result from the following:
 Defective mixing;
 Reduced solubilization;
 Decreased lipolysis;
 Decreased mucosal absorption and chylomicron
formation;
 Defective lymphatic transport of chylomicrons;
CONSEQUENCES OF FAT MALABSORPTION
•
•
•
•
Steatorrhea;
Weight loss;
Diarrhea;
Deficiency in fat-soluble vitamins;
STEATORRHEA
Sudan Stain Test :
A Qualitative Fecal Test for Steatorrhea
FAT BALANCE:
THE TEST FOR STEATORRHEA
 Chemical determination of fecal fat excretion on a
defined fat intake (70-100g/day).
 Requires a complete collection of stools during the
study period (24-72 hours).
 Normally, 95% of dietary fat is absorbed and fecal
fat excretion is≤ 5 grams/day on a 100 gram-daily
fat intake.
 The test is not specific as to etiology.
Disturbances in the Enterohepatic
Circulation of Bile Salts
• Liver Disease;
• Bile ducts;
• Small bowel:
 Malabsorption
 Deconjugation
 Binding or precipitation
BILE SALT MALABSORPTION:
CAUSES
• Ileitis (Crohn’s disease);
• Surgical resection of ileum;
• Idiopathic
BILE SALT MALABSORPTION:
CLINICAL FEATURES
• Diarrhea;
 Bile salts;
 Hydroxy Fatty acids
• Steatorrhea;
• Cholesterol gallstones;
• Enteric hyperoxaluria
Oxalate nephrolithiasis
Bile-Salt-Induced Diarrhea
• Malabsorption of bile acids results in an
increased concentration of bile salts in the
colon.
• At concentrations >1.5 mmol/L, DIHYDROXY
bile salts inhibit electrolyte absorption and
stimulate secretion by the colonic mucosa.
FATTY ACID-INDUCED DIARRHEA
IN BILE ACID MALABSORPTION
In the absence of micelles,
unabsorbed free fatty acids reach the
colon.
FORMATION OF HYDROXY FATTY ACIDS FROM
UNSATURATED FATTY ACIDS
+ H 2O
HYDROXY STEARIC ACID
OLEIC ACID
Ricinoleic acid
Ricinoleic Acid,
a laxative acting by increasing intestinal
Secretion of water
Treatment of Diarrhea Caused by Bile
Acid Malabsorption
• Bile salt binding agents- cholestyramine.
Cholesterol Gallstone Formation in Bile Salt Malabsorption
• Cholesterol solubility in bile (aqueous solution) depends
on the concentration of bile salts.
• Bile salt depletion reduces the solubility of cholesterol in
bile, which precipitates out and forms gallstones in the
gallbladder.
Bile Salt Malabsorption and
Nephrolithiasis
Oxalate
Mechanism of urinary oxalate stones
formation in bile acid deficiency
• Oxalate in food is usually precipitated out as Calcium
oxalate in the lumen and is lost in the stool.
• When lipolysis is normal and bile salts concentration
is <critical micellar concentration, unabsorbed longchain fatty acid compete with oxalate for calcium;
• Consequently, a large amount of oxalate is lost to the
colon, where it is passively absorbed and ultimately
excreted in the kidneys.
Oxalate Crystals in the Urine
Disturbances in the Enterohepatic
Circulation of Bile Salts
• Liver Disease;
• Bile ducts;
• Small bowel:
 Malabsorption
 Deconjugation
 Binding or precipitation
Bile Salt Deconjugation
• Bile salts are secreted from the liver as
conjugates with either glycine or taurine.
• The conjugation increases the acidity of the
bile salt and makes it more hydrophilic1.
• The conjugation decreases passive diffusion of
the bile salts in the jejunum and maintains a
high intraluminal concentration.
1. pKa of unconjugated bile acid≈5; of glycine conjugates ≈ 3.9; of taurine
conjugates ≈2.0.
• Deconjugation of bile salts may occur when
bacteria colonize the proximal small bowel.
• Normally, such colonization is prevented by 2
factors:
 GASTRIC ACID;
 MOTILITY OF THE SMALL BOWEL;
Bacterial counts and Luminal pH in
the Human Alimentary Tract
•Duodenum :
•Jejunum:
•Ileum:
•Cecum
Count
102-1003/ml
102-1003/ml
108/ml
1010-1011/ml
pH
5.5-6.0
6.0-6.5
6.5-7.0
Small Bowel Bacterial Overgrowth
(SIBO)
• Achlorhydria or hypochlorhydria: (PPI
treatment; atrophic gastritis; postoperative
stomach).
• STASIS:
 Motility disorder: diabetic autonomic neuropathy,
scleroderma, chronic intestinal pseudoobstruction).
 Anatomical changes: Strictures, small bowel
diverticula, fistula, blind loop.
CROHN’S DISEASE: ILEAL DISEASE AND FISTULAE
Clinical Features of SIBO
• Underlying disease;
• Deconjugation of Bile salts:
 Steatorrhea (15-30 gram/day).
 Deficiency of fat-soluble vitamins;
• Anemia, usually macrocytic
 Deficiency of vitamin B12;
 Normal or elevated serum folic acid levels;
 Occasional iron deficiency;
• Hypoalbuminemia;
SIBO-DIAGNOSIS
• “Gold Standard”: Aspiration of duodenojejunal fluid with culture and bacterial counts.
• Presence of >105 CFU/mL is diagnostic for
SIBO.
• This test is not routine performed because it is
invasive and complicated.
SIBO-DIAGNOSIS:
Breath Tests
• Principle: bacteria are able to produce H2 after
metabolizing a sugar.
• Bacterially-produced H2 is eliminated via the lungs
and can be detected in the expiratory air.
• An increase of 20 ppm over baseline after ingestion
of glucose is considered diagnostic of SIBO.
• The glucose breath test has a sensitivity of 62% and a
specificity of 83% for SIBO.
SIBO-TREATMENT
• Antibiotics-broad spectrum; In blind loopmetronidazole;
• Rifaximin- a non absorbable antibiotic is
effective at a dose of 400 mgx3/daily for 14
days;
• Recurrences are common and repeated
courses of treatment may be necessary.