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Structure of the Small Intestine
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The small intestine is several meters long and extends from the pyloric sphincter of the stomach to the junction with the large intestine at the ileocecal sphincter. It has three regions: the short duodenum proximally and the jejunum and the ileum distally. Exocrine secretions from the salivary glands, the stomach, and the pancreas and liver, plus secretions of the small intestine itself, are mixed with food for digestion and absorption. Several anatomic features of the small intestine amplify the surface area for absorption, including transverse folds in the mucosa (plicae circulares), the arrangement of the mucosa into villi, and the presence of microvilli on the enterocytes that line the small intestine (Figure 7-25).
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The villus is the functional unit of the intestine. The villus epithelium consists of enterocytes, mucous-secreting goblet cells, and endocrine cells. Three regions of a villus form a functional continuum: the crypt, the maturation zone, and the villus tip.
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The crypt contains rapidly dividing stem cells that force migration of cells up the side of a villus. The cells initially produced in the intestinal crypts are immature and do not express enzymes or membrane transporters for nutrient absorption. Crypt cells are the source of intestinal fluid secretion.
The maturation zone is an intermediate zone where cells are moving toward the tip of the villus and are beginning to expresses enzymes and absorptive membrane transport proteins.
At the villus tip, enterocytes are fully differentiated and undertake the absorption of nutrients, electrolytes, and fluid. After 3–4 days, the cells are sloughed off the villus tip as a defense mechanism against insults from the luminal contents.
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Celiac sprue is a malabsorption syndrome caused by hypersensitivity to wheat gluten and gliadin, resulting in immune-mediated destruction and denudation of the small intestinal villi. The denuded small intestine results in malabsorption of nutrients, causing diarrhea (excess fecal fluid) and steatorrhea (excess fecal fat), with associated abdominal bloating and flatulence. Removal of gluten from the diet will resolve the condition. However, resolution of the malabsorption will not occur immediately upon dietary change because the crypt cells require a few days to mature and rebuild the absorptive intestinal villi.
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During the fed state, there is a great deal of motor activity in the small intestine. The three functions of small intestinal motility during the fed state are:
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Mixing of foodstuffs with digestive secretions and enzymes.
Distribution of the luminal contents around the mucosa for absorption.
Propulsion of the luminal contents in the aboral direction (away from the mouth).
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When nutrients enter the small intestine, transit is initially fast and chyme is spread along the small bowel; transit then slows to promote absorption. There are two major types of motility that occur in the small intestine during the fed state (Figure 7-26):
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Segmentation contractions produce a string of segments that constantly form and reform. The main function of segmentation contractions is mixing of the luminal contents.
Peristalsis consists of a wave of contractions that moves a bolus aborally. The function of peristalsis is propulsion of luminal material. Peristalsis is a reflex, and the main stimulus is moderate distension of the gut wall. The circular muscle contracts in the upstream contracting segment, forcing the bolus forward; receptive relaxation of the circular muscle in the downstream segment reduces the force needed to move the bolus aborally.
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The numerous contractions of the small intestine in the presence of food appear chaotic, and there is overlap in the function between peristaltic and segmenting contractions. Most peristaltic contractions travel less than 2 cm and thus contribute to mixing. Segmenting patterns are faster in the upper small intestine than in more distal areas; this gradient of segmentation rate creates a pressure gradient that assists aboral propulsion (Figure 7-26). An alternative classification of intestinal movements defines three variations:
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Tonic contraction of sphincters.
Rhythmic phasic contractions (small peristaltic contractions and segmentation).
Giant migrating contractions (powerful peristaltic contractions).
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The intestine receives a large daily fluid load that must be absorbed. A typical daily fluid load to the jejunum is 7–10 L per day, consisting of about 1–2 L each of dietary water, saliva, gastric juice, pancreatic juice, and intestinal secretion, and about 0.5 L of bile. The small intestine reabsorbs about 6–8 L per day of fluid by isosmotic transport, with a maximum possible absorption rate of approximately 12 L per day. The rate of absorption of small intestinal fluid is not subject to significant physiologic regulation by the mechanisms that govern the extracellular fluid volume (e.g., renin-angiotensin-aldosterone system).
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Because of the high epithelial water permeability of the small intestine, there is rapid osmotic equilibration between the duodenal chyme and plasma. If food has a high water content and is hypotonic to plasma, there is rapid water uptake. More frequently, a meal is hypertonic and water initially enters the small intestine from the extracellular fluid by osmosis. Subsequent absorption of fluid depends on the active transport of nutrients and electrolytes (Figure 7-27). Na+ uptake at the luminal membrane is driven by low intracellular Na+ concentration. The driving force for Na+ uptake is maintained by active Na+ extrusion at the basolateral membrane by the Na+/K+-ATPase. Fluid absorption in the upper small intestine is mainly coupled to Na+/nutrient uptake, although Na+/H+ exchange is also present in this area of the gut. By the time the food reaches the ileum, most sugars have been absorbed and fluid absorption is more dependent on NaCl reabsorption.
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Approximately 2 L per day of fluid is delivered to the large intestine, which is roughly the initial dietary fluid load. The colon absorbs approximately 1.9 L, leaving about 0.1 L per day in feces. The maximum reabsorptive capacity of the colon is approximately 5 L per day; diarrhea results if the total fluid delivery to the colon exceeds 5 L per day.
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Both the small intestine and the large intestine secrete fluid from the crypt cells. Secretion is necessary for lubrication, as evidenced by the high incidence of obstruction of the gut when secretion is impaired in diseases such as cystic fibrosis. Fluid secretion also provides a source of Na+ for coupling to nutrient absorption, which is needed when a meal contains insufficient Na+ for sugar and amino acid uptake. Antibodies secreted in the area of the intestinal crypts also require fluid secretions to reach the lumen in the gut.
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The mechanism of intestinal fluid secretion is clinically important because it is activated by a number of bacterial enterotoxins that cause secretory diarrhea. The key step in the mechanism of fluid secretion from the crypt enterocytes is opening of the Cl− channels in the luminal cell membrane (Figure 7-28). There are two types of Cl− channels present:
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cAMP-activated Cl− channels, for which the ENS neurotransmitter VIP is an important secretagogue.
Ca2+-activated Cl− channels, for which acetylcholine from ENS neurons and serotonin from the EC cells are both secretagogues.
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Enterotoxic Escherichia coli (traveler's diarrhea due to E coli) and Vibrio cholera (cholera due to V cholera) both produce enterotoxins that utilize cAMP to induce secretory diarrhea. Cholera, for example, irreversibly activates adenylyl cyclase, causing continuous production of cAMP and a severe Cl−-rich watery diarrhea. There can be a significant fluid loss, and death can occur if there is a delay in rehydration and electrolyte replacement.
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Intestinal Ca2+ Absorption
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Ca2+ is reabsorbed in the duodenum and upper jejunum; about 30–80% of dietary Ca2+ typically is absorbed. About one third of the net Ca2+ uptake occurs passively via the paracellular route across the tight junctions. The remaining fraction occurs actively through regulated Ca2+ transport pathways in the enterocytes (Figure 7-29):
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Ca2+ enters the enterocytes down a steep electrochemical gradient via the Ca2+ channels.
To prevent an increase in intracellular free Ca2+ concentration, Ca2+ binds to the protein calbindin within the cytoplasm.
Extrusion of Ca2+ from the cells occurs by primary active transport (Ca2+-ATPase) and secondary active transport (3Na+/Ca2+ exchange), against a large electrochemical gradient.
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The Ca2+uptake mechanism is stimulated by vitamin D (see Chapter 8).
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Sarcoidosis is a systemic disease of unknown etiology. It produces noncaseating granulomas that secrete a vitamin D-like substance, resulting in increased intestinal Ca2+ absorption and hypercalcemia in some patients.
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The regulation of iron homeostasis is unusual compared to other minerals because it centers on the control of dietary uptake rather than on renal excretion. Tight regulation of iron levels is important because iron is highly reactive due to its redox chemistry and alternates between Fe3 + (ferric, oxidized iron) and Fe2+ (ferrous, reduced iron). About 70% of total body iron is associated with hemoglobin, and an additional 3% is associated with the muscle oxygen-binding protein myoglobin. Most of the remainder of total body iron is in a tissue storage form bound to the protein ferritin.
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Iron is transported in blood plasma using a binding protein called transferrin. The iron bound to transferrin is in equilibrium with the very small amounts of free Fe2+ in the extracellular fluid and with iron that is bound to ferritin in the tissues. The total amount of iron in the body is subject to negative feedback regulation (Figure 7-30A). When the iron ferritin store in the liver is full, the liver releases an iron regulatory factor called hepcidin. Increased hepcidin inhibits Fe2+ uptake by the intestinal enterocytes, preventing iron overload.
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Normal daily losses of iron are small, with only 0.6 mg per day in men and about double this amount in women (due to variable menstrual loss). Iron intake generally exceeds 20 mg per day in the typical Western diet, so only a small fraction of ingested iron needs to be absorbed. However, in the developing world, dietary iron deficiency is the most common cause of anemia. Intestinal iron absorption occurs through several mechanisms (see Figure 7-30B):
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In a typical nonvegetarian diet, most dietary iron arrives associated with heme, which has its own intestinal transport protein; iron is released by the action of heme oxygenase within the enterocyte.
Other sources of dietary iron only become available following exposure to the low pH gastric environment. This accounts for the high incidence of iron deficiency anemia in patients who have had a gastrectomy.
Most free dietary iron is presented in the Fe3+ form and must be converted to Fe2+ prior to uptake via the enzyme Fe3+ reductase in the brush-border membrane.
Most Fe2+ absorption occurs via a divalent cation transporter (DCT1). Uptake of Fe2+ also occurs by endocytosis of transferrin, which is secreted by enterocytes into the intestinal lumen, where it binds free Fe2+.
Once inside the enterocyte, iron can either bind to ferritin or is transported across the basolateral cell membrane via the transport protein ferroportin.
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Hemochromatosis is an autosomal recessive disease caused by mutations in a gene referred to as HFE. The abnormal HFE gene is unable to regulate iron absorption, resulting in toxic iron overload. Although the pathogenesis is not completely understood, the hepcidin system becomes less effective, which results in loss of negative feedback to stop excess iron absorption. The most common tissues (and toxic manifestations) affected by the iron toxicity are the liver (cirrhosis), the skin (bronze discoloration), and the pancreas (diabetes). Changes in the skin and pancreas illustrate why hemochromatosis is said to cause “bronze diabetes.”
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Nutrient Digestion and Absorption
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The major classes of nutrients are carbohydrates, proteins, and fats. Most nutrients are large molecules that must be broken down into smaller molecules that can be absorbed. Digestion is the chemical breakdown of food by enzymes and can occur at three sites (Figure 7-31A):
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Luminal digestion occurs within the lumen of the gastrointestinal tract and is mediated by enzymes from the salivary glands, the stomach, and the pancreas.
Membrane digestion is the action of enzymes fixed to the brush-border membrane of enterocytes. Such enzymes are synthesized by enterocytes and inserted into the membrane.
Intracellular digestion is mediated by cytoplasmic enzymes within enterocytes.
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Nutrient absorption occurs in the small intestine (see Figure 7-31B). The proximal small intestine absorbs almost all of the iron and Ca2+ that is assimilated from food.
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Carbohydrates can be absorbed along all parts of the small intestine, but their absorption is usually completed in the proximal small intestine. Absorption of other nutrients (including protein, fat, salts, and water) is spread more uniformly along the small intestine. Bile acids and vitamin B12 are absorbed specifically in the distal ileum.
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Carbohydrate Digestion
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Carbohydrates are the major source of calories in the Western diet, with about 400 g per day consumed. Approximately 60% is starch, about 30% is sucrose, and about 10% is lactose. Digestion reduces carbohydrates to their component monosaccharides: glucose, galactose, and fructose. Figure 7-32A summarizes the main dietary carbohydrates, the specific enzymes that break down the carbohydrates, and the final products of digestion.
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Starch is a polymer of glucose; its luminal digestion begins with salivary amylase and is completed by pancreatic amylase. Although salivary amylase has a neutral pH optimum, it remains active for a long time in the stomach within a food bolus, where it is buffered from gastric acidity. Amylase breaks the α-1,4 glucose linkages to produce oligosaccharides of various lengths, known as dextrins. Much of the oligosaccharide and disaccharide digestion occurs by membrane digestion. The enzymes glucoamylase and isomaltase break down oligosaccharides; the disaccharides sucrose, lactose, and maltose are broken down by sucrase, lactase, and maltase, respectively.
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Lactase deficiency is common in adults from nonwhite populations and results in milk intolerance, with manifestations of osmotic diarrhea and bloating due to fermentation of lactose in the colon.
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Carbohydrate Absorption
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The small intestine has a very large capacity for absorption of sugars, which are all absorbed as monosaccharides (see Figure 7-32B).
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Glucose and galactose uptake from the gut lumen occur, with equal affinity, by secondary active transport via the Na+-coupled cotransporter SGLT-1. Oral rehydration therapy is effective at restoring body fluid volume because the ingested fluid contains Na+ and glucose, and their uptake drives fluid absorption.
Fructose is taken up by facilitated diffusion across the brush border membrane via GLUT5. Fructose, glucose, and galactose all exit enterocytes via the facilitated diffusion carrier GLUT2 in the basolateral cell membranes. A small number of patients do not express functional SGLT-1 and are unable to reabsorb glucose; these patients can survive with adequate dietary fructose because it can be absorbed via GLUT5 and converted into glucose by the liver.
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Dietary protein is assimilated either as amino acids or small peptides. A combination of luminal digestion, membrane digestion, and intracellular digestion is used to break down proteins. Luminal digestion begins with pepsin in the stomach. The partially digested proteins that enter the small intestine are hydrolyzed by three pancreatic endopeptidases (acting on internal peptide bonds): elastase, chymotrypsin, and trypsin. The oligopeptides produced by endopeptidases are further broken down by ectopeptidases, which act from the carboxy terminus of a peptide to remove one amino acid at a time. Carboxypeptidase A digests the products produced by the actions of chymotrypsin and elastase, and carboxypeptidase B acts on the products of trypsin digestion. The enzyme aminooligopeptidase is anchored to the enterocyte brush-border membrane and acts at the amino terminus of short peptides to release amino acids.
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Amino Acid and Peptide Absorption
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Amino acids are a chemically diverse group of molecules, and several transport systems are needed for their absorption. Most of the systems are cotransporters that couple amino acid entry to that of Na+; others are facilitated diffusion carriers, which are Na+ independent. The normal mixture of amino acids and small peptides produced by enzyme digestion are absorbed faster than the same quantity of only amino acids. This phenomenon is called kinetic advantage and is explained by the mechanism of H+-linked cotransport systems for dipeptides and tripeptides, which operate independent of amino acid carriers (Figure 7-33). Short peptides that are absorbed by enterocytes are quickly broken down inside the cell to amino acids and are transported across the basolateral membrane into the blood. Each transport cycle of a dipeptide or a tripeptide carrier transports the equivalent of two or three amino acids into the enterocyte, accounting for rapid net uptake of protein products from the lumen through this pathway.
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Triglycerides are the most abundant dietary form of lipid. Other lipids include phospholipids, sphingolipids, sterols, and the fat-soluble vitamins A, D, E, and K. Nondietary sources of fats include lecithins and cholesterol from bile, sloughed enterocytes, and microbes. Lipid digestion involves a mechanical phase and a chemical phase.
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The mechanical phase includes chewing and grinding peristalsis in the stomach, which together create an emulsion with large fat droplets being sheared into smaller droplets. When chyme enters the small intestine, bile is added. Bile salts reduce surface tension at the fat droplet and water interface and further aid the formation of a fine emulsion.
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The chemical phase of fat digestion occurs when lipases remove fatty acids from the triglyceride molecules. Lipases are termed as acid or alkaline lipases, based on their pH optimum. Lingual lipase from the salivary glands and gastric lipase from the fundus of the stomach are acid lipases with a pH optimum between 3.5 and 5.5. In adults, acid lipases account for about 20% of total lipolysis, but in neonates this can be over 50% of the total lipolytic activity. Alkaline lipase is secreted by the pancreas and has a pH optimum between 6 and 8. The action of pancreatic lipase on triglycerides produces a monoglyceride and two free fatty acids. Pancreatic lipase requires colipase to effectively hydrolyze fats. Colipase is secreted by the pancreas and acts at the surface of a micelle by displacing a bile salt molecule, thereby providing a binding site for pancreatic lipase. Long-chain fatty acids produced by the action of pancreatic lipase are insoluble in water and must enter the core of a micelle to be dissolved. Other lipases include phospholipase A2 , which degrades lecithins and other phospholipids, and carboxyl ester lipase (nonspecific lipase), which is able to hydrolyze cholesterol esters.
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Because the pancreas normally oversecretes lipase, ingested fats can be hydrolyzed with only 10% of the lipase secreted. A patient with chronic pancreatic insufficiency is likely to have experienced very extensive destruction of the gland by the time the clinical signs of maldigestion become apparent (e.g., steatorrhea, bloating, colonic distension, gas, and nutrient excretion in feces).
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Medium-chain fatty acids are able to freely diffuse from the intestinal lumen into the blood without modification; however, most triglyceride digestion produces long-chain fatty acids. Absorption occurs via the following steps (Figure 7-34):
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Long-chain fatty acids dissolve in micelles, which provide a means for hydrophobic molecules to diffuse through an unstirred fluid layer at the intestinal surface (Figure 7-34A).
The unstirred fluid layer has a lower pH than the neutralized chyme, which destabilizes micelles as they approach surface cells; long-chain fatty acids escape the micelle and enter the enterocyte by diffusion through the plasma membrane.
Enterocytes convert long-chain fatty acids back into triglycerides within the smooth endoplasmic reticulum.
Triglycerides are complexed with apoproteins within the smooth endoplasmic reticulum.
The Golgi apparatus delivers the lipoprotein complexes in large vesicles called chylomicrons, which are transported across the basolateral membrane by exocytosis. Chylomicrons are too large to pass across the capillary endothelia and instead enter the lymphatic vessels.
Chylomicrons enter the systemic blood when lymph drains into the venous system.
The action of the enzyme endothelial lipoprotein lipase liberates fatty acids from chylomicrons, primarily for uptake by adipose tissue and muscle cells; the remnant chylomicrons are processed by the liver.
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Fat malabsorption results in increased levels of fecal fat excretion. Steatorrhea is the presence of more than 7 g per day of fatty acids in the stool. There are many potential causes of fat malabsorption, including:
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Fat emulsification is poor in patients who have had a gastrectomy and who experience rapid dumping of ingested food into the small intestine.
Patients with hypersecretion of gastric acid (e.g., Zollinger-Ellison syndrome) may have an acidic duodenal environment that inhibits pancreatic lipase.
Biliary obstruction or cholecystectomy (removal of the gallbladder) reduces the availability of bile.
Patients with pancreatic insufficiency (e.g., cystic fibrosis) have inadequate pancreatic lipase secretion.
Abetalipoproteinemia is a rare condition in which the assembly of triglyceride and apoproteins is defective.
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Vitamins are organic molecules that are required for metabolism but cannot be synthesized in the body; therefore vitamins must be present in the diet. Table 7-2 lists recognized vitamins, summarizes their major functions, and describes the main features of vitamin deficiencies. Vitamins A, D, E, and K are fat-soluble; a meal must contain fat if these vitamins are to be assimilated from food. Fat-soluble vitamins enter micelles and are absorbed into enterocytes by simple diffusion; they appear in chylomicrons unaltered by metabolic processes in the enterocyte. Fat malabsorption is associated with a deficiency of fat-soluble vitamins because the vitamins are excreted along with excess fecal fat.
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The water-soluble group of vitamins includes the B vitamins, vitamin C, folate, biotin, and pantothenic acid. Intestinal absorption of these water-soluble molecules by simple diffusion is slow. Although not yet fully understood, separate carrier-mediated transport mechanisms have recently been identified for each of the water-soluble vitamins.
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Vitamin B12 deficiency may take months to manifest clinically because the liver stores a significant amount of the vitamin. Untreated vitamin B12 deficiency results in anemia.
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The following steps are involved in vitamin B12 uptake (Figure 7-35):
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When vitamin B12 is ingested, it is bound to the proteins in food and must be released in the stomach by the action of pepsin.
Vitamin B12 forms a complex with a glycoprotein called haptocorrin, which is secreted into the saliva and gastric juice.
Pancreatic proteases hydrolyze haptocorrin to liberate vitamin B12, which is then available to bind to intrinsic factor within the small intestine.
The vitamin B12-intrinsic factor complex is required for vitamin B12 absorption via a specific receptor-mediated mechanism in the distal ileum.
Vitamin B12 encounters the binding protein transcobalamin in blood, which carries it to the liver for storage.
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The mechanism for assimilation of vitamin B12 requires normal function in several gastrointestinal organs. As a result, there are multiple etiologies that lead to vitamin B12 deficiency, including:
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Dietary deficiency.
Lack of intrinsic factor (known as pernicious anemia), which may be caused, for example, by autoimmune destruction of the parietal cells or by gastric atrophy.
Pancreatic insufficiency (e.g., cystic fibrosis).
Surgical resection of the ileum.
Terminal ileum disease (e.g., Crohn's ileitis); the ileum is the most common location of Crohn's disease.
Intestinal organisms (e.g., Diphyllobothrium latum, a fish tapeworm).
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Regardless of its cause, vitamin B12 deficiency manifests as megaloblastic anemia and neurologic degeneration caused by demyelination of the peripheral nerves, the spinal cord, and the cerebrum. Treatment of vitamin B12 deficiency with only supplemental folic acid should never be attempted; the folic acid will resolve the anemia but without vitamin B12 replacement, the patient will have irreversible neurologic dysfunction.