D ISORDERS OF A BSORPTION

Disorders of absorption constitute a broad spectrum of conditions with multiple etiologies and varied clinical manifestations. Almost all of these clinical problems are associated with diminished intestinal absorption of one or more dietary nutrients and are often referred to as the malabsorption syndrome.

D IARRHEA Diarrhea as a symptom (i.e., when used by patients to describe their bowel movement pattern) may be a decrease in stool consistency, an increase in stool volume, an increase in number of bowel movements, or any combination of these three changes. In contrast, diarrhea as a sign is a quantitative increase in stool water or weight of> mL or gram per 24 h, when a Western-type diet is consumed. Individuals consuming a diet with higher fiber content may normally have a stool weight of up to 400 g/24 h.

It is also critical: to establish whether a patient's diarrhea is secondary to diminished absorption of one or more dietary nutrients, in contrast to diarrhea that is due to small- and/or large-intestinal fluid and electrolyte secretion. The former has often been termed osmotic diarrhea, while the latter has been referred to as secretory diarrhea.

malabsorption of a dietary nutrient. a substantial decrease in stool output while fasting during a quantitative stool collection of at least 24 h is presumptive evidence that the diarrhea is related to malabsorption of a dietary nutrient. secretorythat the cause of diarrhea is not a dietary nutrient. The persistence of stool output while fasting indicates that the diarrhea is likely secretory and that the cause of diarrhea is not a dietary nutrient.

NUTRIENT DIGESTION AND ABSORPTION

300 cm and 80 cm The lengths of the small intestine and colon are 300 cm and 80 cm, However, the effective functional surface area is approximately 600- fold greater than that of a hollow tube as a result of the presence of folds, villi (in the smaIl intestine), and microvilli.

In addition to nutrient digestion and absorption, the intestinal epithelia have several other functions: 1. Barrier and immune defense. 2. Fluid and electrolyte absorption and secretion. 3.Synthesis and secretion of several proteins. 4. Production of several bioactive amines and peptides.

48-72 h Intestinal epithelial cells are continuously renewed, with new proliferating epithelial cells at the base of the crypt migrating over h to the tip of the villus (or surface of the colon), where they are well-developed epithelial cells with digestive and absorptive function. This high rate of cell turnover explains the relatively rapid resolution of diarrhea

Nutrients, minerals, and vitamins Nutrients, minerals, and vitamins are absorbed by one or more active transport mechanisms. Active transport mechanisms are energy-dependent and mediated by membrane transport proteins.

The movement of these actively transported nutrients against a concentration gradient is Na" -dependent and is due to a Na" gradient across the apical membrane. The Na" gradient is maintained by Na", Kt-adenosine triphosphatase (A‘T'Pase) active glucose absorption and glucose-stimulated Na" absorption require both the apical membrane transport protein, SGLTl, and the basolateral Na", K+- ATPase. In addition to glucose absorption being Na"- dependent, glucose also stimulates Na" and fluid absorption, which is the physiologic basis of oral rehydration therapy for the treatment of diarrhea

ENTEROHEPATIC CIRCULATION OF BILE ACIDS

The primary functions of bile acids are: (1) to promote bile flow, (2) to solubilize cholesterol and phospholipid in the gallbladder by mixed micelle formation, (3) to enhance dietary lipid digestion and absorption by forming mixed micelles in the proximal small intestine.

Bile acids are primarily absorbed by an active, Na" –dependent process that is located exclusively in the ileum, though bile acids can also be absorbed to a lesser extent by non-carrier-mediated transport processes in the jejunum, ileum, and colon. Conjugated bile acids that enter the colon are deconjugated by colonic bacterial enzymes to unconjugated bile acids and are rapidly absorbed by nonionic diffusion.

Patients with limited ileal disease or resection will often have diarrhea but not steatorrhea. The diarrhea, a result of bile acids in the colon stimulating active Cl secretion, has been called bile acid diarrhea, or choleretic enteropathy, and responds promptly to cholestyramine, an anion-binding resin.

diarrhea and steatorrhea In contrast, patients with greater degrees of ileal disease and/or resection will often have diarrhea and steatorrhea that do not respond to cholestyrarnine. fatty acid diarrhea. hepatic synthesis can no longer increase sufficiently to maintain the bile acid pool size. This second situation is often called fatty acid diarrhea. Cholestyramine may not be effective (and may even increase the diarrhea by further depleting the intraduodenal bile acid concentration); however, a low-fat diet to reduce fatty acids entering the colon can be effective.

LIPIDS

Three types of fatty acids compose fats: long-chain fatty acids (LCFAs), medium-chain fatty acids (MCFAs), short-chain fatty acids (SCFAs) Dietary fat is exclusively composed of long-chain triglycerides (LCTs), While the majority of dietary LCFAs have carbon chain lengths of 16 or 18, fatty acids of carbon chain length >12 are metabolized in the same manner; saturated and unsaturated fatty acids are handled identically.

Assimilation of dietary lipid requires three integrated processes: (I) an intraluminal, or digestive, phase; (2) a mucosal, or absorptive, phase; (3) a delivery, or postabsorptive, phase. An abnormality at any site of this process can cause steatorrhea

The SCFAs present in stool are primarily: acetate, propionate, butyrate, Butyrate is the primary nutrient for colonic epithelial cells SCFAs conserve calories and carbohydrate, because carbohydrates not completely absorbed in the small intestine will not be absorbed in the large intestine due to the absence of both disaccharidases and SGLT1 In contrast, SCFAs are rapidly absorbed and stimulate colonic Na-Cl and fluid absorption

Steatorrhea can be responsible for diarrhea; if the primary cause of the steatorrhea has not been identified, a low-fat diet can often ameliorate the diarrhea by decreasing fecal fat excretion. Steatorrhea is often associated with fat- soluble vitamin deficiency, which will require replacement with water-soluble preparations of these vitamins.

CARBOHYDRATES

Carbohydrates in the diet are present in the form of starch, disaccharides (sucrose and lactose), and glucose. Carbohydrates are absorbed only in the small intestine and only in the form of monosaccharides. Therefore, before their absorption, starch and disaccharides must first be digested by pancreatic amylase and intestinal brush border Monosaccharide absorption occurs by a Na- dependent process mediated by the brush border transport protein SGLT1.

Lactose malabsorption is the only clinically important disorder of carbohydrate absorption. Lactose, the disaccharide present in milk, requires digestion by brush border lactase to its two constituent monosaccharides, glucose and galactose.

Development of symptoms of lactose intolerance is related to several factors: 1. Amount of lactose in the diet. 2. Rate of gastric emptying. 3. Small-intestinal transit time. 4. Colonic compensation by production of SCFAs from nonabsorbed lactose.

PROTEINS

Protein is present in food almost exclusively as polypeptides and requires extensive hydrolysis to di- and tripeptides and amino acids before absorption. Proteolysis occurs in both the stomach and small intestine; it is mediated by pepsin secreted as pepsinogen by gastric chief cells and trypsinogen and other peptidases from pancreatic acinar cells. These proenzymes, pepsinogen and trypsinogen, must be activated to pepsin (by pepsin in the presence of a pH <5) and to trypsin (by the intestinal brush border enzyme enterokinase and subsequently by trypsin), respectively.

Proteins are absorbed by separate transport systems for di- and tripeptides and for different types of amino acids, e.g., neutral and dibasic. Alterations in either protein or amino acid digestion and absorption are rarely observed clinically, even in the presence of extensive small-intestinal mucosal inflammation.

A PPROACH TO THE PATIENT WITH MALABSORPTION

The clues provided by: the history, symptoms, initial preliminary observations will serve to limit extensive, ill- focused, and expensive laboratory and imaging studies.

For example, a clinician evaluating a patient with symptoms suggestive of malabsorption, who recently had extensive small-intestinal resection for mesenteric ischemia, should direct the initial assessment almost exclusively to define whether a short bowel syndrome might explain the entire clinical picture. Similarly, the development of a pattern of bowel movements suggestive of steatorrhea in a patient with long-standing alcohol abuse and chronic pancreatitis should lead toward assessing pancreatic exocrine function.

Although diarrhea can be caused by changes in fluid and electrolyte movement in either the small or the large intestine, dietary nutrients are absorbed almost exclusively in the small intestine. Therefore, the demonstration of diminished absorption of a dietary nutrient provides unequivocal evidence of small-intestinal disease,

calcium, iron, and folic acid are exclusively absorbed by active transport processes in the proximal small intestine, especially the duodenum; in contrast, the active transport mechanisms for both cobalamin and bile acids are present only in the ileum.

Some nutrients, e.g., glucose, amino acids, and lipids, are absorbed throughout the small intestine, though their rate of absorption is greater in the proximal than in the distal segments. However, following segmental resection of the small intestine, the remaining segments undergo both morphologic and functional " adaptation" to enhance absorption..

Establishing the presence of steatorrhea and identifying its specific cause are often quite difficult. The " gold standard " still remains a timed, quantitative stool fat determination. A qualitative test-Sudan III stain -has long been available to establish the presence of an increase in stool fat. This test is rapid and inexpensive but, as a qualitative test, does not establish the degree of fat malabsorption and is best used as a preliminary screening study.

Despite this situation, the use of routine laboratory studies: (i.e., complete blood count, prothrombin time, serum protein determination, alkaline phosphatase ) may suggest the presence of dietary nutrient depletion, especially iron, folate, cobalamin, and vitamins D and K. Additional studies include measurement of serum carotene, cholesterol, albumin, iron, folate, and cobalamin levels. The serum carotene level can also be reduced if the patient has poor dietary intake of leafy vegetables.

If steatorrhea and/or altered absorption of other nutrients are suspected: the history, clinical observations, laboratory testing can help detect deficiency of a nutrient, especially: the fat-soluble vitamins A, D, E, or K.

Thus, evidence of metabolic bone disease with : elevated alkaline phosphatase and/or reduced serum calcium levels would suggest vitamin D malabsorption.

A deficiency of vitamin K would be suggested by : an elevated prothrombin time in an individual without liver disease who was not taking anticoagulants

The presence of iron-deficiency anemia in the absence of occult bleeding from the gastrointestinal tract in either a male or a nonmenstruating female would require : evaluation of iron malabsorption and the exclusion of celiac disease, as iron is absorbed exclusively in the proximal small intestine

Macrocytic anemia would lead to evaluation of whether cobalamin or folic acid malabsorption was present..

a timed (72 h) quantitative stool collection, preferably on a defined diet, must be obtained to determine stool fat content and establish the presence of steatorrhea. The presence of steatorrhea then requires further assessment to establish the pathophysiologic process(es) responsible for the defect in dietary lipid digestion-absorption

other studies include : the Schilling test, D-xylose test, duodenal mucosal biopsy, small-intestinal radiologic examination, tests of pancreatic exocrine function.

URINARY D-XYLOSE TEST The urinary D-xylose test for carbohydrate absorption provides an assessment of proximal small intestinal mucosal function.

D-Xylose, a pentose, is absorbed almost exclusively in the proximal small intestine. The D-xylose test is usually performed by giving 25 g D-xylose and collecting urine for 5 h. An abnormal test (<4.5 g excretion) primarily reflects the presence of duodenal/jejunal mucosal disease.

RADIOLOGIC EXAMINATION Radiologic examination of the small intestine using barium contrast (small- bowel series or study) can provide important information in the evaluation of the patient with presumed or suspected malabsorption.

Other imaging studies to assess the integrity of small intestinal morphology are : CT enteroclysis magnetic resonance (MR) enteroclysis capsule endoscopy double-barrel enteroscopy

BIOPSY OF SMALL-INTESTINAL MUCOSA is essential in the evaluation of a patient with documented steatorrhea or chronic diarrhea (lasting >3 weeks) histologic material of proximal small-intestinal mucosa The ready availability of endoscopic equipment to examine the stomach and duodenum has led to its almost uniform use as the preferred method to obtain histologic material of proximal small-intestinal mucosa..

The primary indications for a small-intestinal biopsy are : (1) evaluation of a patient either with documented or suspected steatorrhea or with chronic diarrhea (2) diffuse or focal abnormalities of the small intestine defined on a small- intestinal series