Fat Malabsorption-
J. W. RILEY, M.B., B.S. ROBERT M. GLICKMAN,
M.D.
New York, New York
From the Division of Gastroenterology. College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, New York. Requests for reprints should be addressed to Dr. Robert M. Glickman, Division of Gastroenterology, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032. Manuscript accepted July 26. 1979.
980
December
1979
Advances in Our Understanding
The intestinal absorption of triglyceride constitutes a multistep process with active involvement of the pancreatobiliary system, the intestine and lymphatics. It is only through the integrated function of these organs that dietary triglyceride can be efficiently absorbed and delivered to the peripheral blood for subsequent metabolism. In this review we discuss each aspect of triglyceride absorption and chylomicron formation and illustrate how various diseases may interfere with the process resulting in fat malabsorption. In addition, the role of the intestine as a majbr synthetic source of lipoprotein constituents for circulating lipoproteins is discussed. The average western diet contains approximately 40 per cent of total calories as dietary fat or approximately 100 g of fat. The efficiency of the entire process of fat absorption can be judged by the fact that under normal conditions less than 5 per cent of ingested fat is recovered in the stool. In the past several years, new concepts have greatly added to our understanding of the process by which dietary fat is digested, absorbed and processed in the intestinal epithelial cell for delivery to the body via intestinal lymph and the portal venous system. These newer concepts include an understanding of the physical chemistry of lipids, the physiology of bile salts, and the formation and metabolism of lipoproteins, all directly influencing the process of fat absorption. Fat absorption is a multistep process involving the coordinated participation of several organs (Figure 1). Since fat absorption can become deranged at any step in the process, an understanding of factors important in the process will permit a more complete understanding of conditions of clinical fat malabsorption. As shown in Figure 1 the over-all process of fat absorption can be conveniently considered as being composed of (1) luminal, (2) mucosal and (3) secretory (lymphatic or portal venous transport] phases. In the present discussion the major principles of fat absorption will be stressed and correlated with appropriate examples of how this process may become disordered resulting in steatorrhea. Intraluminal Digestion. Most dietary fat is ingested in the form of triglycerides containing three long chain fatty acids on a glycerol backbone. Triglyceride undergoes little or no hydrolysis in the stomach, although gastric lipase has been described in man [2]. This enzyme activity is present in gastric mucosal homogenates, is induced by fat feeding and acts on medium chain triglycerides. Although it appears to be important and active in suckling rats in releasing medium chain fatty acids from milk fat, its importance in man is not known [3-s].
The American Journal of Medicine
Volume 87
PANCREAS ‘I
I) 1 1poly51,
LIVER \/
JEJUNAL
(2) Mlcellar ’ solubiliratiun with bile acid 0
’ (3) Absorption
MUCOSA
LYMPHATICS \/
(4) Dellverv
>
I
Figure 1. mucosal
Schematic of intestinal fat absorption showing the participation of pancreas, liver and intestina in fat absorption. From Wilson and Dietschy [ 11.
cell
Rather, most triglyceride lipolysis occurs in the duodenum secondary to the action of pancreatic lipases. In the duodenum, the water-insoluble triglyceride is further emulsified by mechanical factors and mixed with pancreatic secretions, particularly bicarbonate and water, which increase duodenal pH to 6 or 6.5. Pancreatic lipase reversibly hydrolyzes triglyceride at the 1.3 positions, leaving p monoglyceride, diglycerides and free fatty acid as the products of lipolysis. Recent evidence has shown that for pancreatic lipase to be active in triglyceride hydrolysis an additional pancreatic factor is required. This is a small molecular weight protein (-10.000) secreted by the pancreas called colipase [6]. It facilitates lipase action by binding to bile salt-lipid surfaces and facilitates the interaction of lipase with triglyceride, permitting efficient hydrolysis. Other requirements for effective hydrolysis are pH greater than 4, as already mentioned, and bile salts which are necessary for optimum lipase activity [7]. The process of intraluminal triglyceride emulsification and hydrolysis requires coordination of pancreatic secretion with the presence of lipid in the upper portion of the small intestine. This is accomplished by release of cholecystokinin-pancreozymin (CCK-PZ] from duodenal epithelial cells in response to the presence of lipid and protein in the lumen [8]. This hormone causes not only pancreatic exocrine secretion but also gallbladder contraction and simultaneous relaxation of the sphincter of Oddi [9,10] to enable bile salt secretion to be synchronous with the presence of fat in the upper part of the intestine. In addition, secretin is released from duodenal mucosa by gastric acid, and this hormone stimulates pancreatic fluid and bicarbonate secretion, an important factor in raising duodenal pH to permit effective lipolysis [ll]. Impaired lipolysis due to clinical disorders can now be classified with respect to the aforementioned considerations’ [Table I).
Bile Salts-Their Role in Intraluminal Fat Absorption. Bile salts are either trihydroxy or dihydroxy bile acids that are conjugated with either taurine or glycine. Eighty per cent of the bile salts released into the bile are primary bile salts, cholic acid and chenodeoxycholic acid, which are synthesized in the liver. The secondary bile salts, which contribute 20 per cent of the pool, are metabolic products of intestinal bacterial action. Deoxycholic acid is derived from cholic acid and lithocholic acid from chenodeoxycholic acid. Approximately 600 to 800 mg of bile salts are synthesized each day by the liver, an amount equal to that lost in the stool. Although the total bile salt pool is only 2 to 4 g, the amount of bile salts actually passing through the intestine each day is 20 to 30 g. This phenomenon is due to an enterohepatic circulation whereby bile salts are actively absorbed in the terminal ileum and returned to the liver by the portal
TABLE I
Conditions Associated with Impaired Lipolysis
Postgastrectomy Rapid transit (“dumping”) Improper emulsification of triglyceride, bicarbonate and lipase, e.g., Billroth II anastomosis Altered duodenal pH Acid hypersecretion-Zollinger-Ellison syndrome Decreased CCK-PZ release Severe intestinal mucosal destruction, e.g., sprue, regional enteritis Pancreatic insufficiency Loss of lipase and bicarbonate secretion Chronic pancreatitis Pancreatic duct obstruction Decreased luminal bile salts See Table II
December 1979
The American Journal of Medicine
Volume 67
981
FAT MALABSORPTION-RILEY,
GLICKMAN
ACID
STEROLS
*.a q-J Liver Figure 2.
Schematic representation of the enterohepatic circulation of bile
salts. enable this molecule to interact with lipids in an aqueous environment and solubilize these moieties. In the presence of the products of lipolysis, multimolecular aggregates of bile salts, monoglyceride, fatty acids and cholesterol form: these are called “micelles.” The lowest concentration of bile salts at which such aggregates are present in solution is termed the “critical micellar concentration.” In a recent report [l3] it is suggested that the traditional concept of micellarization and absorption may be subdivided into several coexisting phases. Using an in vitro technique and directly observing lipolysis by light microscopy, these workers have described an initial crystalline phase of digestion in which calcium and fatty acids are formed, and this is followed by the production of a viscous isotropic phase composed predominantly of monoglycerides and pronated fatty acids. Thus, other
venous system (Figure 2). In order to accommodate the needs of lipid absorption, the bile acid pool may be recycled several times during the course of a single meal
[121. The emulsified products of triglyceride lipolysismonoglyceride, free fatty acids and glycerol-although more water-soluble than the parent triglyceride, still have only limited solubility in the aqueous environment of the intestinal lumen. This is also true for other lipids such as cholesterol and the fat-soluble vitamins. Efficient absorption depends on micellar formation in which these lipid moieties interact with bile salts in mixed aggregates or micelles. A schematic representation of a bile salt micelle containing fatty acids and monoglyceride is shown in Figure 3. It is the particular structural characteristics of the bile salt molecule, consisting of hydrophobic and hydrophilic portions, which Bile salt anions
fatty
acid and monoglycerlde
Bile salt anions
‘Fatty actd and monoglycerlde molecules
molecules
Figure 3. Schematic of fatty acid, monoglyceride bile salt micelle. In both representations the bile salts surround the less polar lipid moieties.
982
December
1979
The American Journal of Medicine
Volume 67
TABLE II
phases may coexist with the micellar phase during fat absorption. However, the exact sequence of events and the quantitative importance of these events require further elucidation. Any condition which results in a reduced concentration of hilt salts within the intestinal lumen (below the critical micellar concentration) will result in impaired micellar solubilization of lipids (Table II]. A particularly graphic example of impaired micelle formation leading to steatorrhea is that associated with ilcal resection [14,15]. As shown in Figure 4, with modest degrees of ileal resection [less than 100 cm), increased hcpatic synthesis of bile salts can compensate for increased fecal loss maintaining the micellar concentration nf bile salts in the jejunum within normal limits. Hence, there is no steatorrhea. With larger degrees of ilcal resection [greater than 100 cm), hepatic synthesis is maximally increased but cannot compensate for these large fecal losses, with the resultant reduction in jejunal bile acid concentration and steatorrhea. In this situation, lipolysis and mucosal epithelial function are normal, and the malabsorption is a “pure” example of bile salt deficiency. This example also illustrates the obligatory requirement of active ileal bile salt absorption, a function which cannot be assumed by the more proximal small bowel. Successful micelMucosal Phase of Fat Absorption. larization of lipids within the intestinal lumen permits these lipid products to diffuse to the surface of the intostinal epithelium and to make intimate contact with tho microvillus membrane. This is particularly important since it has been shown experimentally that covcring the surface of the intestine is an unstirred water layer [IK 17) which functionally may pose a significant
Conditions Associated with impaired Micelle Formation
Decreased hepatic synthesis of bile salts Severe parenchymal liver disease Decreased delivery of bile salts to the intestinal lumen Biliary obstruction (stone, tumor, primary biliary cirrhosis) Cholestatic liver disease Decreased effective concentration of conjugated bile acids Increased acidity (Zollinger-Ellison)-decreased ionization of bile salts with increased proximal absorption Drugs affecting micelle formation-neomycin, cholestyramine Stasis syndromes with secondary bacterial overgrowth and bile salt deconjugation Increased intestinal loss of bile salts lleal disease or resection
barrier to the diffusion of hydrophobic molecules such as lipids. This relatively immobile aqueous layer is more easily penetrated by the micellar complex thus increasing the efficiency of lipid uptake into the intestinal mucosal cell. .The uptake of lipids, such as fatty acids and monoglycerides, across the microvillus membrane is a passive process and results from the solubility of the lipid moieties within the lipid-rich surface membrane of the cpithelial cell. Recently, a low molecular weight cytosolic protein, fatty acid binding protein has been isolated from the intestine [18]. This protein avidly binds fatty acids and appears to function as an intracellular transport protein for long chain fatty acids. Under experimental conditions in which fatty acid binding to this protein is inhibited, less fatty acid is available for triglyceride resynthesis. Thus, it appears that fatty acid
70 60
-
50 -
O
o~--------i--_-l-----. 100
Length
of lIeal
150
resection,cm
Figure 4. Relation between length of ileal resection From Hofmann and Poley [ 151.
December 1979
200
and degree of steatorrhea.
The American Journal of Medicine
Volume 67
983
FAT MALABSORPTION-RILEY,
jF-E$TINAL
GLICKMAN
LIPID ABl3PTlON A ElkSalt 4 Fatty Aad -4
P Monaglycendes
fatlyAcidand Monoplyceride Uptake
ApoE,AI.AlT,AlY
plasmic reticulum [lQ] (Figure 6). As shown in this figure, shortly after lipid absorption the entire apical portion of the intestinal cell is filled with triglyceride droplets Morphologically, with time one can follow the movement of these triglyceride droplets through the profiles of the endoplasmic reticulum to the Golgi apparatus in the supranuclear portion of the cell. Here, clusters of chylomicrons can be seen within the saccules of the Golgi apparatus. Although few details are known concerning the actual mechanisms of lipoprotein egress from the cell, morphologic studies show a migration of Golgi vesicles towards the laterobasal membrane where they appear to fuse with the membrane and discharge their contents into the intercellular space by reverse pinocytosis. Experimental evidence suggests that this directed intracellular movement may, in part, depend on intact microtubular function [20]. Characteristics of Intestinal Lipoproteins. Although the morphologic events of triglyceride transport have been well defined, less is known concerning the biochemical events of chylomicron formation. A great deal can be learned by analyzing the composition of chylomicrons obtained from mesenteric lymph of laboratory animals [21]. Table III shows the chemical composition of rat mesenteric lymph chylomicrons and chylomicrons obtained from the urine of two patients studied in our laboratory with chyluria due to longstanding filarial disease, and documented communications between mesenteric and renal lymphatic systems [22]. It can be
lgure 3. Ycnematrc representation of intestinal epithek cell during fat absorption.
binding protein may serve a transport function within the intestinal epithelium and may direct intracellular fatty acids to the smooth endoplasmic reticulum, the site of triglyceride resynthesis. A schematic representation of events within the cell is shown in Figure 5. Triglyceride resynthesis reduces the effective concentration of free fatty acids within the cell and maintains an effective concentration gradient for the continued passive uptake to continue. In addition, the storage of fatty acids as the more inert triglycerides while awaiting transport from the intestine may spare the cell the potential injurious effects of high intracellular free fatty acid concentration. The enzymes for triglyceride resynthesis have been localized biochemically in the smooth endoplasmic reticulum in the apical portion of the intestinal epithelial cell beneath the microvillus membrane. This is corroborated morphologically in that the earliest time triglyceride can be visualized within the intestinal epithelial ceI1 is within the profiles of the smooth endo-
984
December 1979
The American Journal of Medicine
Figure 6. Electron micrograph of intestinal fat absorption. Droplets of triglyceride are first visible within the profiles of the smooth endoplasmic reticulum beneath the microvillus membrane. The entire apical portion of the cell contains lipid droplets and chylomicrons are abundant in the lateral intercellular spaces.
Volume 67
I::\‘I’ hl~Il,Af3SOKPTlON
TABLE ill -___-_
Characteristics of Rat and Human Lymph Chylomicrons
Chemical Composition Triglyceride Phospholipid Cholesterol Protein Density (g/ml) St value Electrophoresis
PercentageCompositionby Weight Rat [21] Human[22] 84 13 2 1 400 Origin
91 7.5 1.6 1.3 400 Origin
seen that tri$lyceride comprises the major portion of chylomicron lipid which reflects the major physiologic role of this particle in fat absorption. Phospholipid, although a smaller component, is important structurally. Together with free cholesterol and chylomicron protein, it is arranged on the surface of this particle. Although the intestine can synthesize phospholipid de novo for the chylomicron surface, it appears that a variable proportion of chylomicron phospholipid may be derived from luminal sources (i.e., biliary lecithin) after reacylation of absorbed lysolecithin. The protein content of the chylomicrons has been the subject of considerable interest. Although quantitatively small (I per cent of chylomicron mass), it is now apparent that chylomicron apoprotcins contain a charactcristic complement of specific proteins [23,24]. Figure 7 shows the apoprotein composition of rat and human lymph chylomicrons after delipidation and electrophoresis on sodium dodecyl sulphate polyacrylamide gels. There is a remarkable similarity in the protein patterns from these two species. Of particular importance to intestinal lipid transport is apoB. In addition, apoA-I, the major apoprotein of circulating high density lipoprotein in most species is also an important chylomicron component and comprises 20 per cent of chylomicron protein in man [22] and 40 per cent in the rat [25]. This apoprotein is also an activator of lecithin: cholesterol acyltransferase (LCAT] a plasma enzyme responsible for cholesterol esterification. ApoA-IV is a newly described chylomicron apoprotein in man [26,27] and is analogous to a similar apoprotein in the rat [28]. Its metabolic importance remains to be determined. In addition, a group of small molecular weight apoproteins, the C apoproteins, are also found on lymph chylomicrons [23]. One of this group, apoC-II, is an activator of lipoprotein lipase and, hence, is of extreme importance in the catabolism of chylomicrons after secretion [29,30]. In a recent report [31] a man was described with severe hypertriglyceridemia and a complete deficiency of this lipoprotein lipase activator, a~)oC-II, resulting in a marked impairment of chylomicron lipolysis. After partial replacement of apoC-II by transfusion of plasma from a normal subject, the pa-
KIl.E1’. (:I.I(:l
J. W. RILEY, M.B., B.S. ROBERT M. GLICKMAN,
M.D.
New York, New York
From the Division of Gastroenterology. College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, New York. Requests for reprints should be addressed to Dr. Robert M. Glickman, Division of Gastroenterology, College of Physicians & Surgeons, Columbia University, 630 West 168th Street, New York, New York 10032. Manuscript accepted July 26. 1979.
980
December
1979
Advances in Our Understanding
The intestinal absorption of triglyceride constitutes a multistep process with active involvement of the pancreatobiliary system, the intestine and lymphatics. It is only through the integrated function of these organs that dietary triglyceride can be efficiently absorbed and delivered to the peripheral blood for subsequent metabolism. In this review we discuss each aspect of triglyceride absorption and chylomicron formation and illustrate how various diseases may interfere with the process resulting in fat malabsorption. In addition, the role of the intestine as a majbr synthetic source of lipoprotein constituents for circulating lipoproteins is discussed. The average western diet contains approximately 40 per cent of total calories as dietary fat or approximately 100 g of fat. The efficiency of the entire process of fat absorption can be judged by the fact that under normal conditions less than 5 per cent of ingested fat is recovered in the stool. In the past several years, new concepts have greatly added to our understanding of the process by which dietary fat is digested, absorbed and processed in the intestinal epithelial cell for delivery to the body via intestinal lymph and the portal venous system. These newer concepts include an understanding of the physical chemistry of lipids, the physiology of bile salts, and the formation and metabolism of lipoproteins, all directly influencing the process of fat absorption. Fat absorption is a multistep process involving the coordinated participation of several organs (Figure 1). Since fat absorption can become deranged at any step in the process, an understanding of factors important in the process will permit a more complete understanding of conditions of clinical fat malabsorption. As shown in Figure 1 the over-all process of fat absorption can be conveniently considered as being composed of (1) luminal, (2) mucosal and (3) secretory (lymphatic or portal venous transport] phases. In the present discussion the major principles of fat absorption will be stressed and correlated with appropriate examples of how this process may become disordered resulting in steatorrhea. Intraluminal Digestion. Most dietary fat is ingested in the form of triglycerides containing three long chain fatty acids on a glycerol backbone. Triglyceride undergoes little or no hydrolysis in the stomach, although gastric lipase has been described in man [2]. This enzyme activity is present in gastric mucosal homogenates, is induced by fat feeding and acts on medium chain triglycerides. Although it appears to be important and active in suckling rats in releasing medium chain fatty acids from milk fat, its importance in man is not known [3-s].
The American Journal of Medicine
Volume 87
PANCREAS ‘I
I) 1 1poly51,
LIVER \/
JEJUNAL
(2) Mlcellar ’ solubiliratiun with bile acid 0
’ (3) Absorption
MUCOSA
LYMPHATICS \/
(4) Dellverv
>
I
Figure 1. mucosal
Schematic of intestinal fat absorption showing the participation of pancreas, liver and intestina in fat absorption. From Wilson and Dietschy [ 11.
cell
Rather, most triglyceride lipolysis occurs in the duodenum secondary to the action of pancreatic lipases. In the duodenum, the water-insoluble triglyceride is further emulsified by mechanical factors and mixed with pancreatic secretions, particularly bicarbonate and water, which increase duodenal pH to 6 or 6.5. Pancreatic lipase reversibly hydrolyzes triglyceride at the 1.3 positions, leaving p monoglyceride, diglycerides and free fatty acid as the products of lipolysis. Recent evidence has shown that for pancreatic lipase to be active in triglyceride hydrolysis an additional pancreatic factor is required. This is a small molecular weight protein (-10.000) secreted by the pancreas called colipase [6]. It facilitates lipase action by binding to bile salt-lipid surfaces and facilitates the interaction of lipase with triglyceride, permitting efficient hydrolysis. Other requirements for effective hydrolysis are pH greater than 4, as already mentioned, and bile salts which are necessary for optimum lipase activity [7]. The process of intraluminal triglyceride emulsification and hydrolysis requires coordination of pancreatic secretion with the presence of lipid in the upper portion of the small intestine. This is accomplished by release of cholecystokinin-pancreozymin (CCK-PZ] from duodenal epithelial cells in response to the presence of lipid and protein in the lumen [8]. This hormone causes not only pancreatic exocrine secretion but also gallbladder contraction and simultaneous relaxation of the sphincter of Oddi [9,10] to enable bile salt secretion to be synchronous with the presence of fat in the upper part of the intestine. In addition, secretin is released from duodenal mucosa by gastric acid, and this hormone stimulates pancreatic fluid and bicarbonate secretion, an important factor in raising duodenal pH to permit effective lipolysis [ll]. Impaired lipolysis due to clinical disorders can now be classified with respect to the aforementioned considerations’ [Table I).
Bile Salts-Their Role in Intraluminal Fat Absorption. Bile salts are either trihydroxy or dihydroxy bile acids that are conjugated with either taurine or glycine. Eighty per cent of the bile salts released into the bile are primary bile salts, cholic acid and chenodeoxycholic acid, which are synthesized in the liver. The secondary bile salts, which contribute 20 per cent of the pool, are metabolic products of intestinal bacterial action. Deoxycholic acid is derived from cholic acid and lithocholic acid from chenodeoxycholic acid. Approximately 600 to 800 mg of bile salts are synthesized each day by the liver, an amount equal to that lost in the stool. Although the total bile salt pool is only 2 to 4 g, the amount of bile salts actually passing through the intestine each day is 20 to 30 g. This phenomenon is due to an enterohepatic circulation whereby bile salts are actively absorbed in the terminal ileum and returned to the liver by the portal
TABLE I
Conditions Associated with Impaired Lipolysis
Postgastrectomy Rapid transit (“dumping”) Improper emulsification of triglyceride, bicarbonate and lipase, e.g., Billroth II anastomosis Altered duodenal pH Acid hypersecretion-Zollinger-Ellison syndrome Decreased CCK-PZ release Severe intestinal mucosal destruction, e.g., sprue, regional enteritis Pancreatic insufficiency Loss of lipase and bicarbonate secretion Chronic pancreatitis Pancreatic duct obstruction Decreased luminal bile salts See Table II
December 1979
The American Journal of Medicine
Volume 67
981
FAT MALABSORPTION-RILEY,
GLICKMAN
ACID
STEROLS
*.a q-J Liver Figure 2.
Schematic representation of the enterohepatic circulation of bile
salts. enable this molecule to interact with lipids in an aqueous environment and solubilize these moieties. In the presence of the products of lipolysis, multimolecular aggregates of bile salts, monoglyceride, fatty acids and cholesterol form: these are called “micelles.” The lowest concentration of bile salts at which such aggregates are present in solution is termed the “critical micellar concentration.” In a recent report [l3] it is suggested that the traditional concept of micellarization and absorption may be subdivided into several coexisting phases. Using an in vitro technique and directly observing lipolysis by light microscopy, these workers have described an initial crystalline phase of digestion in which calcium and fatty acids are formed, and this is followed by the production of a viscous isotropic phase composed predominantly of monoglycerides and pronated fatty acids. Thus, other
venous system (Figure 2). In order to accommodate the needs of lipid absorption, the bile acid pool may be recycled several times during the course of a single meal
[121. The emulsified products of triglyceride lipolysismonoglyceride, free fatty acids and glycerol-although more water-soluble than the parent triglyceride, still have only limited solubility in the aqueous environment of the intestinal lumen. This is also true for other lipids such as cholesterol and the fat-soluble vitamins. Efficient absorption depends on micellar formation in which these lipid moieties interact with bile salts in mixed aggregates or micelles. A schematic representation of a bile salt micelle containing fatty acids and monoglyceride is shown in Figure 3. It is the particular structural characteristics of the bile salt molecule, consisting of hydrophobic and hydrophilic portions, which Bile salt anions
fatty
acid and monoglycerlde
Bile salt anions
‘Fatty actd and monoglycerlde molecules
molecules
Figure 3. Schematic of fatty acid, monoglyceride bile salt micelle. In both representations the bile salts surround the less polar lipid moieties.
982
December
1979
The American Journal of Medicine
Volume 67
TABLE II
phases may coexist with the micellar phase during fat absorption. However, the exact sequence of events and the quantitative importance of these events require further elucidation. Any condition which results in a reduced concentration of hilt salts within the intestinal lumen (below the critical micellar concentration) will result in impaired micellar solubilization of lipids (Table II]. A particularly graphic example of impaired micelle formation leading to steatorrhea is that associated with ilcal resection [14,15]. As shown in Figure 4, with modest degrees of ileal resection [less than 100 cm), increased hcpatic synthesis of bile salts can compensate for increased fecal loss maintaining the micellar concentration nf bile salts in the jejunum within normal limits. Hence, there is no steatorrhea. With larger degrees of ilcal resection [greater than 100 cm), hepatic synthesis is maximally increased but cannot compensate for these large fecal losses, with the resultant reduction in jejunal bile acid concentration and steatorrhea. In this situation, lipolysis and mucosal epithelial function are normal, and the malabsorption is a “pure” example of bile salt deficiency. This example also illustrates the obligatory requirement of active ileal bile salt absorption, a function which cannot be assumed by the more proximal small bowel. Successful micelMucosal Phase of Fat Absorption. larization of lipids within the intestinal lumen permits these lipid products to diffuse to the surface of the intostinal epithelium and to make intimate contact with tho microvillus membrane. This is particularly important since it has been shown experimentally that covcring the surface of the intestine is an unstirred water layer [IK 17) which functionally may pose a significant
Conditions Associated with impaired Micelle Formation
Decreased hepatic synthesis of bile salts Severe parenchymal liver disease Decreased delivery of bile salts to the intestinal lumen Biliary obstruction (stone, tumor, primary biliary cirrhosis) Cholestatic liver disease Decreased effective concentration of conjugated bile acids Increased acidity (Zollinger-Ellison)-decreased ionization of bile salts with increased proximal absorption Drugs affecting micelle formation-neomycin, cholestyramine Stasis syndromes with secondary bacterial overgrowth and bile salt deconjugation Increased intestinal loss of bile salts lleal disease or resection
barrier to the diffusion of hydrophobic molecules such as lipids. This relatively immobile aqueous layer is more easily penetrated by the micellar complex thus increasing the efficiency of lipid uptake into the intestinal mucosal cell. .The uptake of lipids, such as fatty acids and monoglycerides, across the microvillus membrane is a passive process and results from the solubility of the lipid moieties within the lipid-rich surface membrane of the cpithelial cell. Recently, a low molecular weight cytosolic protein, fatty acid binding protein has been isolated from the intestine [18]. This protein avidly binds fatty acids and appears to function as an intracellular transport protein for long chain fatty acids. Under experimental conditions in which fatty acid binding to this protein is inhibited, less fatty acid is available for triglyceride resynthesis. Thus, it appears that fatty acid
70 60
-
50 -
O
o~--------i--_-l-----. 100
Length
of lIeal
150
resection,cm
Figure 4. Relation between length of ileal resection From Hofmann and Poley [ 151.
December 1979
200
and degree of steatorrhea.
The American Journal of Medicine
Volume 67
983
FAT MALABSORPTION-RILEY,
jF-E$TINAL
GLICKMAN
LIPID ABl3PTlON A ElkSalt 4 Fatty Aad -4
P Monaglycendes
fatlyAcidand Monoplyceride Uptake
ApoE,AI.AlT,AlY
plasmic reticulum [lQ] (Figure 6). As shown in this figure, shortly after lipid absorption the entire apical portion of the intestinal cell is filled with triglyceride droplets Morphologically, with time one can follow the movement of these triglyceride droplets through the profiles of the endoplasmic reticulum to the Golgi apparatus in the supranuclear portion of the cell. Here, clusters of chylomicrons can be seen within the saccules of the Golgi apparatus. Although few details are known concerning the actual mechanisms of lipoprotein egress from the cell, morphologic studies show a migration of Golgi vesicles towards the laterobasal membrane where they appear to fuse with the membrane and discharge their contents into the intercellular space by reverse pinocytosis. Experimental evidence suggests that this directed intracellular movement may, in part, depend on intact microtubular function [20]. Characteristics of Intestinal Lipoproteins. Although the morphologic events of triglyceride transport have been well defined, less is known concerning the biochemical events of chylomicron formation. A great deal can be learned by analyzing the composition of chylomicrons obtained from mesenteric lymph of laboratory animals [21]. Table III shows the chemical composition of rat mesenteric lymph chylomicrons and chylomicrons obtained from the urine of two patients studied in our laboratory with chyluria due to longstanding filarial disease, and documented communications between mesenteric and renal lymphatic systems [22]. It can be
lgure 3. Ycnematrc representation of intestinal epithek cell during fat absorption.
binding protein may serve a transport function within the intestinal epithelium and may direct intracellular fatty acids to the smooth endoplasmic reticulum, the site of triglyceride resynthesis. A schematic representation of events within the cell is shown in Figure 5. Triglyceride resynthesis reduces the effective concentration of free fatty acids within the cell and maintains an effective concentration gradient for the continued passive uptake to continue. In addition, the storage of fatty acids as the more inert triglycerides while awaiting transport from the intestine may spare the cell the potential injurious effects of high intracellular free fatty acid concentration. The enzymes for triglyceride resynthesis have been localized biochemically in the smooth endoplasmic reticulum in the apical portion of the intestinal epithelial cell beneath the microvillus membrane. This is corroborated morphologically in that the earliest time triglyceride can be visualized within the intestinal epithelial ceI1 is within the profiles of the smooth endo-
984
December 1979
The American Journal of Medicine
Figure 6. Electron micrograph of intestinal fat absorption. Droplets of triglyceride are first visible within the profiles of the smooth endoplasmic reticulum beneath the microvillus membrane. The entire apical portion of the cell contains lipid droplets and chylomicrons are abundant in the lateral intercellular spaces.
Volume 67
I::\‘I’ hl~Il,Af3SOKPTlON
TABLE ill -___-_
Characteristics of Rat and Human Lymph Chylomicrons
Chemical Composition Triglyceride Phospholipid Cholesterol Protein Density (g/ml) St value Electrophoresis
PercentageCompositionby Weight Rat [21] Human[22] 84 13 2 1 400 Origin
91 7.5 1.6 1.3 400 Origin
seen that tri$lyceride comprises the major portion of chylomicron lipid which reflects the major physiologic role of this particle in fat absorption. Phospholipid, although a smaller component, is important structurally. Together with free cholesterol and chylomicron protein, it is arranged on the surface of this particle. Although the intestine can synthesize phospholipid de novo for the chylomicron surface, it appears that a variable proportion of chylomicron phospholipid may be derived from luminal sources (i.e., biliary lecithin) after reacylation of absorbed lysolecithin. The protein content of the chylomicrons has been the subject of considerable interest. Although quantitatively small (I per cent of chylomicron mass), it is now apparent that chylomicron apoprotcins contain a charactcristic complement of specific proteins [23,24]. Figure 7 shows the apoprotein composition of rat and human lymph chylomicrons after delipidation and electrophoresis on sodium dodecyl sulphate polyacrylamide gels. There is a remarkable similarity in the protein patterns from these two species. Of particular importance to intestinal lipid transport is apoB. In addition, apoA-I, the major apoprotein of circulating high density lipoprotein in most species is also an important chylomicron component and comprises 20 per cent of chylomicron protein in man [22] and 40 per cent in the rat [25]. This apoprotein is also an activator of lecithin: cholesterol acyltransferase (LCAT] a plasma enzyme responsible for cholesterol esterification. ApoA-IV is a newly described chylomicron apoprotein in man [26,27] and is analogous to a similar apoprotein in the rat [28]. Its metabolic importance remains to be determined. In addition, a group of small molecular weight apoproteins, the C apoproteins, are also found on lymph chylomicrons [23]. One of this group, apoC-II, is an activator of lipoprotein lipase and, hence, is of extreme importance in the catabolism of chylomicrons after secretion [29,30]. In a recent report [31] a man was described with severe hypertriglyceridemia and a complete deficiency of this lipoprotein lipase activator, a~)oC-II, resulting in a marked impairment of chylomicron lipolysis. After partial replacement of apoC-II by transfusion of plasma from a normal subject, the pa-
KIl.E1’. (:I.I(:l
