Maldigestion and Malabsorption

Defective Mixing

For sufficient digestion and absorption of lipids, dietary fat must adequately mix with digestive secretions. Gastric resections or GI motility disorders that result in rapid gastric emptying or rapid intestinal transit, such as autonomic neuropathy due to diabetes mellitus or amyloidosis, can cause fat malabsorption consequent to impaired GI mixing of dietary fat.

Reduced Solubilization of Fat

Fat malabsorption resulting from decreased formation of micelles occurs if the luminal concentrations of conjugated bile acids (BAs) are lower than the critical concentration required for forming micelles. Table 104.2 details the pathophysiologic mechanisms and representative diseases that cause luminal BA deficiency.

Decreased Lipolysis

If exocrine pancreatic function is severely reduced, impairment of pancreatic lipase and co-lipase secretion results in decreased luminal hydrolysis of dietary fat. Chronic pancreatitis, cystic fibrosis, pancreatic duct obstruction by pancreatic and ampullary tumors, and pancreatic resection are the most common causes of pancreatic insufficiency. Even when pancreatic enzyme concentrations are normal, reduced pancreatic lipase activity resulting from low luminal pH, excessive calcium ingestion, or ingestion of the specific lipase inhibitor orlistat can cause pancreatic steatorrhea. Selective congenital lipase or co-lipase deficiency is a rare cause of pancreatic fat malabsorption.

Decreased Mucosal Absorption and Chylomicron Formation

Generalized mucosal diseases such as celiac disease are often associated with fat malabsorption. Defective uptake of free fatty acids and monoglycerides results from reduced mucosal surface area secondary to villus shortening, reduced enterocyte function, and mucosal inflammation. Intestinal fat absorption is also impaired in diseases that result in disturbance of intracellular formation of chylomicrons and accumulation of lipids within the enterocytes, including abetalipoproteinemia, hypobetalipoproteinemia, and chylomicron retention disease.

Defective Lymphatic Transport of Chylomicrons

Impairment of lymphatic transport of chylomicrons is a cause for postmucosal malabsorption of dietary fat. Decreased lymphatic transport can result from congenital diseases such as primary intestinal lymphangiectasia or from obstruction of lymphatic vessels as a result of metastatic solid tumors, lymphoma, Whipple disease, retroperitoneal fibrosis, or trauma (see Chapter 31 ). Usually, lymphatic vessels in the mucosa become dilated (lymphangiectasia), and chylomicrons are lost post-prandially into the intestinal lumen and also in the fasting state ; steatorrhea in these situations usually is only mild to moderate.

Defective Intraluminal Proteolysis

Protein digestion may be impaired in patients who have undergone partial or total gastric resection, presumably as a result of poor mixing with digestive secretions, although gastric pepsin deficiency could be contributory. Impaired activation of pepsin due to acid inhibition by PPIs can result in an increased risk of food allergy with manifestations such as childhood asthma, owing to decreased gastric digestion of proteins (see Chapter 10 ). Defective proteolysis also occurs with exocrine pancreatic insufficiency. In congenital diseases, pancreatic proteolysis can be impaired by inborn errors in the synthesis of proteolytic enzymes (trypsinogen deficiency) or by defective activation of pancreatic proenzymes resulting from congenital deficiency of intestinal enterokinase (see Congenital Defects).

Defective Mucosal Hydrolysis of Peptides and Decreased Absorption of Oligopeptides and Amino Acids

Generalized mucosal diseases, such as celiac disease, result in global malabsorption, which includes malabsorption of oligopeptides and AAs secondary to lack of mucosal hydrolysis of oligopeptides and defective mucosal absorption. Reduction of intestinal absorptive surface, as in short bowel syndrome (see Chapter 106 ) or jejunoileal bypass, also results in protein and AA malabsorption. Congenital defects of AA transporters on the enterocytes (e.g., Hartnup disease, lysinuric protein intolerance) can lead to selective malabsorption of a subgroup of AAs (see Chapter 102 and see Congenital Defects).

Defective Intraluminal Hydrolysis of Carbohydrates

Pancreatic α-amylase is normally secreted in excess into the intestinal lumen. In mild forms of pancreatic insufficiency, carbohydrate digestion usually is at least partially preserved, but severe pancreatic insufficiency results in clinically apparent carbohydrate malabsorption and diarrhea due to decreased luminal hydrolysis of ingested starch.

Mucosal Defects of Carbohydrate Digestion and Absorption

The most common cause of carbohydrate malabsorption is late-onset lactose malabsorption due to decreased levels of the intestinal brush border enzyme lactase (adult-type hypolactasia, acquired primary lactase deficiency). Depending on ethnic background, lactase is present in less than 5% to greater than 90% of the adult population; its deficiency results in a selective malabsorption of lactose. Acquired malabsorption of carbohydrates occurs commonly after extensive intestinal resections, in diffuse mucosal diseases such as celiac or Crohn disease, or temporarily after self-limited GI infections (postinfection carbohydrate malabsorption). The pathophysiologic mechanisms of carbohydrate malabsorption are reduction of the intestinal mucosal surface area and reduced activity or expression of intestinal oligo- and disaccharidases or transport proteins for monosaccharides. Congenital disaccharidase deficiencies (lactase, sucrase-isomaltase, trehalase) and congenital deficiency or malfunction of transport molecules, as in congenital glucose-galactose malabsorption, can cause early onset of malabsorption of mono- or disaccharides (see Congential Defects). Intolerance of fructose is discussed in a subsequent section.

Fat-Soluble Vitamins

Diseases that cause malabsorption of dietary fat commonly cause malabsorption of fat-soluble vitamins because they require similar absorptive mechanisms. This is especially relevant in diseases that result in impaired micelle formation because of bile salt deficiency. Fat-soluble vitamins also are malabsorbed in diffuse diseases of the mucosal surface area, in diseases affecting chylomicron formation and transport, and in exocrine pancreatic insufficiency. Some authors have suggested that absorption of fat-soluble vitamins is less affected by exocrine pancreatic insufficiency than by small intestinal diseases with resultant steatorrhea. Genetic defects of BA conjugation may also result in malabsorption of fat-soluble vitamins.

Water-Soluble Vitamins

Calcium

Severe calcium malabsorption can occur in diseases that affect the small intestinal mucosa (e.g., celiac disease) and luminal malabsorption (e.g., exocrine pancreatic insufficiency), and has been shown to result in low-trauma fractures. In these disease states, calcium absorption is impaired directly because of the reduction of the intestinal surface area (celiac disease) and indirectly because of formation of insoluble calcium soaps with malabsorbed long-chain fatty acids (pancreatic insufficiency). Diseases that cause malabsorption of long-chain fatty acids by other mechanisms, such as bile acid deficiency, can also result in calcium malabsorption. In many of these diseases, malabsorption and deficiency of vitamin D further contribute to intestinal calcium malabsorption. Selective intestinal malabsorption of calcium (i.e., without fat malabsorption) can occur in renal disease, hypoparathyroidism, and inborn defects in formation of 1α,25-dihydroxyvitamin D or in the intestinal vitamin D receptor. Calcium malabsorption also commonly occurs after gastric resection (see “Malabsorption after Gastric Resection” [later]). Dosage of PPIs and duration of gastric acid suppression are associated with increased risk of hip fractures, presumably due in part to decreased or impaired absorption of dietary calcium, although both the magnitude and exact explanation of risk are controversial.

Magnesium

In many generalized malabsorptive disorders, magnesium deficiency due to magnesium malabsorption results from a reduction in mucosal absorptive surface area and luminal binding of magnesium by malabsorbed fatty acids. A congenital form of selective intestinal magnesium malabsorption has also been reported.

Iron

Iron deficiency is common in patients with gastric resection or celiac disease. Also, achlorhydria may result in iron deficiency because the absorption of iron in these patients is less than the physiologic iron losses, a phenomenon which is not overcome by the adaptive increase in duodenal iron absorption that occurs in response to iron deficiency. Reduction in the mucosal surface area of the small intestine as a result of diffuse mucosal disease, intestinal resection, or intestinal bypass can result in impaired iron absorption, potentially leading to iron deficiency. A congenital form of iron malabsorption has also been described (see Table 104.10 ). Intestinal loss of iron from chronic GI bleeding is, however, the most common GI cause of iron deficiency. Hookworm infection is the most common cause of iron deficiency worldwide (see Chapter 114 ).

Zinc

Zinc, like other minerals, is malabsorbed in generalized mucosal diseases of the small intestine. A congenital selective defect of zinc absorption, acrodermatitis enteropathica, is caused by a defect in the zinc transport protein hZIP4 (see Table 104.10 ).

Others

Generalized malabsorption can cause deficiency of copper and selenium. In Menkes disease (kinky hair disease), an inherited disorder of cellular copper transport, selective intestinal copper malabsorption results (see later). It is uncertain whether malabsorptive diseases result in deficiencies of chromium and manganese.

Role of the Colon

The colon has the capacity to absorb a limited number but wide variety of substances and nutrients, including sodium, chloride, water, oxalate, short-chain fatty acids, calcium, water-soluble vitamins (biotin, folate, pantothenic acid [B ₅ ], pyridoxine [B ₆ ], riboflavin [B ₂ ], thiamine [B ₁ ]), and vitamin K (see Chapter 103 ). Although colonic nutrient absorption plays a lesser role in health, the nutritive role of the colon in patients with severe malabsorption is clinically relevant. Colonic salvage of malabsorbed nutrients can also result in symptoms and complications such as colonic hyperabsorption of oxalate, which contributes to the formation of renal stones (see later).

The role of the colon in the pathogenesis of symptoms related to lactose malabsorption and incomplete fructose absorption (fructose malabsorption), such as bloating, abdominal cramps, and diarrhea, is unclear. A discrepancy between malabsorption, as demonstrated by hydrogen breath testing (HBT), and these intolerance symptoms have been demonstrated in adults and children.

Colonic Salvage of Incompletely Absorbed Carbohydrates

In healthy people, between 2% and 20% of ingested starch escapes absorption in the small intestine; pancreatic insufficiency or severe intestinal disorders further increase this amount. Carbohydrates that reach the colon cannot be absorbed by the colonic mucosa but can be metabolized by colonic bacteria. Metabolism by anaerobic bacteria results in breakdown of oligosaccharides and polysaccharides to mono- and disaccharides, which are further metabolized to lactic acid, short-chain (C2 to C4) fatty acids (SCFAs; e.g., acetate, propionate, butyrate), and odorless gases (e.g., hydrogen, methane, carbon dioxide).

Studies in normal subjects have suggested that bacterial metabolism of starch to small carbohydrate moieties is a rapid process in the normal colon. The rate-limiting step in the overall conversion of polysaccharides to SCFAs appears to be the conversion of monosaccharides to SCFAs. Colonic absorption of SCFAs results in the reduction of the osmotic load and, as a result, mitigation of osmotic diarrhea. In normal subjects, more than 45 g of carbohydrates must reach the colon to cause diarrhea, and up to 80 g of carbohydrates per day can be metabolized by bacteria to SCFAs; approximately 90% of these SCFAs are absorbed by colonic mucosa ( Fig. 104.1 ). Chronic carbohydrate malabsorption causes adaptive changes in bacterial metabolic activity that result in even higher efficiency of the bacterial microbiota to digest carbohydrates, but at the expense of increased flatus production.

Because SCFAs have caloric values between 3.4 and 5.95 kcal/g, their colonic absorption can contribute positively to overall calorie balance. In patients with short bowel syndrome, colonic salvage of malabsorbed carbohydrates can save up to 700 to 950 kcal/day, provided a substantial part of the colon remains in continuity with the small intestine (see Chapter 106 ). Not all SCFAs are absorbed by the colon, and those not absorbed contribute to osmotic diarrhea.

The benefits of colonic bacterial carbohydrate metabolism may be offset by side effects due to gas production (see Chapter 17 ). Up to 10-fold differences in the volume of gas produced in the colon have been observed in normal persons. The colon also can absorb gas, and if intracolonic gas volumes are low, up to 90% of the volume of intracolonic gas can be absorbed; if gas volumes are high, however, this proportion can decrease to 20% ( Fig. 104.2 ). Therefore persons who have the disadvantage of producing more gas in their colons have an additional disadvantage of absorbing a smaller fraction of the gas. Gas produced from bacterial carbohydrate metabolism is odorless. The odor of flatus is due to volatile sulfur-containing substrates that result from bacterial metabolism of protein.

Impaired colonic salvage of carbohydrates has been suggested to contribute to the diarrhea in Crohn disease and UC. Bacterial carbohydrate metabolism may be lessened by antibiotic treatment. In some patients, antibiotic-associated diarrhea may be the result of impaired colonic salvage of carbohydrates or the result of dietary fiber that can accumulate in stool because of decreased bacterial fermentation.

Role of Intestinal Transit in the Salvage of Malabsorbed Nutrients

The lower parts of the GI tract do not normally contact nutrients, but upon doing so, intestinal transit time becomes prolonged. This delay in transit could contribute to compensatory mechanisms in malabsorptive diseases, although nutritional salvage by this mechanism has not been quantitated. SCFAs prolong colonic transit time and, hence, increase the contact time of liminal contents with the colonic mucosa.

Suspecting and Confirming the Presence of Malabsorption