UW Division of Gastroenterology - Gut Course Syllabus (HuBio 551)

	Updated: 03/13/08 12:05 PM

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Authors: D.R. Saunders, C.E. Rubin, and J.D. Ostrow
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L. Fat Malabsorption

Figure 15

Steatorrhea is a marker of malabsorption

Normally, about 95% of ingested lipid is absorbed. In most diseases associated with impaired absorption, the reduction in the percentage of ingested lipid is not dramatic (10 25% reduction). Nevertheless, these patients often suffer from caloric deficiency and problems associated with malabsorption of protein, carbohydrate, water, electrolytes, divalent cations and fat soluble vitamins.

Again it will prove useful to analyze the various abnormalities of fat absorption anatomically: stomach, duodenojejunum (lumen, absorptive cells, lamina propria, lymphatics) and ileum.

Main function of the stomach is metered delivery of small particles & liquid

Gastric contractions emulsify fats with the aid of food emulsifiers (partially digested proteins, complex carbohydrates, and phospholipids). However, the main contribution of the stomach to fat absorption is to slow the delivery of food to the duodenum and jejunum. Try to deduce what would happen if, instead of eating your dinner tonight, you had it homogenized and instilled all at once via a tube into your duodenum. Solutes in the meal and soluble products from digestion of the meal could yield a hypertonic solution. Shifts of water and electrolytes from plasma to small intestinal lumen could cause fainting. Rapid transit of the meal through the small intestine could cause steatorrhea.

Excess H⁺ denatures enzymes, precipitates bile salts

Let us next consider the situation in a patient with a gastrinoma whose small intestinal luminal pH may be lowered intermittently to 2 instead of its normal 6.0. Gastrinoma (Zollinger-Ellison syndrome) is a tumor which produces excess gastrin and as a result gastric acid secretion is profuse and excessive. In the normal person, how is the intestinal luminal pH of 6.0 maintained despite the acid gastric juice constantly flowing into it? Would pancreatic lipase hydrolyze triglyceride in gastrinoma? Lipase is a delicate enzyme. Would it survive a pH of 2? How would bile salts fare when the pH is 2? A pH of 2 is well below the bile salts' pK (that pH where a substance is half-ionized and half un-ionized; below the pK, it is progressively more unionized and insoluble, and above, more ionized). Even with an intermittently low pH within the jejunal lumen, mixed bile salt micelle formation is impaired.

Bile salts increase absorptive efficiency

Suppose bile salts were completely absent from the intestinal lumen because of an obstructed common bile duct or a biliary fistula which diverts all bile to the exterior via a surgically implanted tube in the common duct. Such patients absorb as much as 75% of ingested dietary triglyceride instead of the normal 95%. Can they form micelles? If not, how do they absorb fat at all? Apparently, their food triglyceride is hydrolyzed by pancreatic lipase and the resultant free fatty acids are dispersed in the luminal water. Without micelles, less fatty acids are available to enter the absorptive cells, but some chylomicrons are formed. Thus fat absorption is less efficient than in normal people and certain nonpolar substances are not absorbed at all. Nevertheless, as much as 75% of ingested fat is absorbed because the ileum and distal jejunum function as backup systems.

Figure 16

Figure 17

Pancreatic insufficiency, gastric lipase becomes crucial

Suppose the exocrine function of the patient's pancreas has been lost because of pancreatectomy or severe chronic pancreatitis. Quantitatively, the steatorrhea is severe (approximately 50% of ingested fat is absorbed). You might reason that, if hydrolysis of triglyceride is totally absent because of lack of pancreatic lipase, no fat at all would be absorbed because intact triglyceride is not absorbed. Actually, some triglyceride is split and some micelles are formed; gastric lipase hydrolyzes some dietary triglyceride.

Stirring of luminal contents is important

Normally there is an unstirred water layer surrounding each villus and it is one of the main barriers which limits the rate of entry of lipid molecules into the absorptive cells. In diseases which impair intestinal motility, intestinal contents may not be stirred. Most of the intestinal lumen may then be regarded as a dead space because absorption can only occur from contents adjacent to absorptive cell surfaces. Passage of molecules by diffusion over distances of more than one micron may take many minutes or even hours and thus a dissolved substance must be stirred if frequent random contact with the plasma membrane of the absorptive cell is to be assured. Inadequate stirring of intestinal contents can lead to overgrowth of bacteria in the lumen and malabsorption.

Mucosal injury in celiac sprue

Absorption is impaired if the absorptive cells of the duodenojejunum are injured and reduced in number. Celiac sprue does this. It is a genetic disease in which the normally tolerated proteins of wheat, barley and rye in food (gluten) have become injurious to the small bowel mucosa. Because of chronic injury by this ingested gluten, villi disappear from the duodenal and proximal jejunal mucosa. The mucosal inflammation is initiated by an HLA-DQ2, or 8 restricted T-cell immune response to gluten peptides after their deamination by tissue transglutaminase which becomes one of the targets of the autoimmune response.

Because ingested gluten is almost completely digested and absorbed in the jejunum, the ileum is little affected. This disease, therefore, usually produces only moderate steatorrhea (% fat absorbed = 80%, normal = 95%). Occasionally, the mucosa of the whole length of the small bowel is injured in this disease; such patients suffer from severe diarrhea and steatorrhea; they are desperately ill.

Figure 18

Steatorrhea can also be caused by inadequate contact between the chyme and the absorptive cells of the small intestine. This occurs after surgical excision or bypass of much of the jejunum and all of the ileum. Such excisions follow massive infarction; surgical bypass of most of the small bowel was used in the recent past as an operation for obesity.

Intestinal ApoB is crucial for chylo-micron formation

Another cause of malabsorption is absorptive cell malfunction. There is one such exceedingly rare familial disease called abetalipoproteinemia. These patients cannot manufacture apoprotein B, the protein essential for VLDL and chylomicron synthesis. In the fasting state, jejunal enterocytes are filled with abnormally large fat particles lying free within the cytosol outside of the SER. No fat particles are seen within the SER or Golgi profiles of the absorptive cells or beyond the cells within intercellular spaces, lamina propria or lacteals. These patients have steatorrhea.

Bacilli in lamina propria impair diffusion and compress lacteals

Whipple's disease is a rare but treatable illness in which the lamina propria is completely stuffed with macrophages containing the indigestible mucopoly-saccharide walls of dead bacilli. The disease is caused by a bacillus which responds dramatically to several broad-spectrum antibiotics. These patients have steatorrhea although their luminal digestion and absorptive cell function are normal. One can observe chylomicrons to be present in the lamina propria during the fasting state when they normally should have long since disappeared into the systemic circulation via the lacteals. Furthermore, many lacteals are dilated and full of chylomicrons when they should be empty in the fasting state.

High-protein lymph may leak from obstructed lymphatics

There is a congenital disease in which lymphatic channels do not make their normal connections during development, and obstruction to lymphatic drainage results in various parts of the body. The small intestinal mucosa frequently contains clusters of dilated lymphatics, some of which can occasionally be seen breaking into the intestinal lumen and spilling their contents. The dilated lymphatics are filled with chylomicrons during the fasting state. In addition to steatorrhea, these patients have low blood protein levels and often have distressing chylous ascites, i.e. their peritoneal cavities are distended by gallons of milky lymph which is filled with chylomicrons.

Ileal resection can cause more problems than jejunal resection

If the proximal small intestine fails to absorb fat because of a luminal or mucosal abnormality, the ileum is always available for back up absorption of some of the fat which the jejunum was unable to assimilate. Ileal absorption is the reason that the coefficient of fat absorption is not lower in a whole variety of proximal abnormalities, i.e., bile fistula, celiac sprue, abetalipoproteinemia, etc. If the ileal function is impaired by Crohn's disease or ablated by resection, then the backup is lost and fatty acids spill into the colon where they impair water and electrolyte absorption and increase the severity of any pre-existing diarrhea. Note that the low concentration of malabsorbed bile salts and fatty acids do not impose a significant osmotic load in the colon; rather they impair absorption of electrolytes and water by colonocytes. Ileal loss produces far worse fat malabsorption than bile fistula.

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