An overview of pathophysiologic mechanisms of maldigestion and malabsorption is provided in Table 101-2. This table also shows the ingested substrates primarily affected by the individual pathophysiologic mechanisms and lists examples of etiologic disorders for these mechanisms.

Table 101-2 Mechanisms of Malabsorption, Malabsorbed Substrates, and Representative Causes

MECHANISM	MALABSORBED SUBSTRATE(S)	REPRESENTATIVE CAUSES
Maldigestion
Conjugated bile acid deficiency	Fat Fat-soluble vitamins Calcium Magnesium

Hepatic parenchymal disease

Biliary obstruction

Bacterial overgrowth with bile acid deconjugation

Ileal bile acid malabsorption

CCK deficiency

Pancreatic insufficiency

Vitamin B₁₂ (cobalamin)

Congenital defects

Chronic pancreatitis

Pancreatic tumors

Inactivation of pancreatic enzymes (e.g., Zollinger-Ellison syndrome)

Reduced mucosal digestion

Carbohydrate

Protein

Congenital defects (see Table 101-14)

Acquired lactase deficiency

Generalized mucosal disease (e.g., celiac disease, Crohn’s disease)

Intraluminal consumption of nutrients Vitamin B₁₂ (cobalamin)

Small intestinal bacterial overgrowth

Helminthic infections (e.g., Diphyllobothrium latum infection)

Malabsorption Reduced mucosal absorption

Congenital transport defects (see Table 101-14)

Generalized mucosal diseases (e.g., celiac disease, Crohn’s disease)

Previous intestinal resection or bypass

Infections

Intestinal lymphoma

Decreased transport from the intestine

Fat

Protein

Intestinal lymphangiectasia

Primary

Secondary (e.g., solid tumors, Whipple’s disease, lymphomas)

Venous stasis (e.g., from congestive heart failure)

Other Mechanisms Decreased gastric acid and/or intrinsic factor secretion Vitamin B₁₂

Pernicious anemia

Atrophic gastritis

Previous gastric resection

Decreased gastric mixing and/or rapid gastric emptying

Fat

Calcium

Protein

Previous gastric resection

Autonomic neuropathy

Rapid intestinal transit Fat

Autonomic neuropathy

Hyperthyroidism

CCK, cholecystokinin.

FATS

DEFECTIVE MIXING

For sufficient digestion and absorption of lipids, dietary fat must adequately mix with digestive secretions. Gastric resections or gastrointestinal motility disorders that result in rapid gastric emptying or rapid intestinal transit, such as autonomic neuropathy resulting from diabetes mellitus or amyloidosis, can cause fat malabsorption consequent to impaired gastrointestinal mixing of dietary fat.¹

REDUCED SOLUBILIZATION OF FAT

Fat malabsorption due to decreased formation of micelles occurs if the luminal concentrations of conjugated bile acids are lower than the critical concentration required for forming micelles.^2,³ Table 101-3 ^1,⁴ details the pathophysiologic mechanisms and representative diseases that cause luminal bile acid deficiency.

Table 101-3 Pathophysiologic Mechanisms That Result in Deficiency of Luminal Conjugated Bile Acids

PATHOPHYSIOLOGIC MECHANISM	CAUSES
Decreased synthesis and/or secretion of conjugated bile acids	Parenchymal liver diseases (e.g., cirrhosis, primary biliary cirrhosis) Biliary obstruction (e.g., tumors) Biliary fistulas Inborn errors of bile acid synthesis CCK deficiency

Intestinal loss of conjugated bile acids

Ileal resection

Severe ileal mucosal disease

Congenital defects of the ileal sodium–bile acid cotransporter

Luminal deconjugation of bile acids Small intestinal bacterial overgrowth Binding of bile salts or insolubilization of bile salts due to low luminal pH

Cholestyramine (binding)

Zollinger-Ellison syndrome (low pH)

Exocrine pancreatic insufficiency (low pH)

CCK, cholecystokinin.

If exocrine pancreatic function is severely reduced, impairment of pancreatic lipase and colipase secretion results in decreased luminal hydrolysis of dietary fat.⁵ Chronic pancreatitis, cystic fibrosis, pancreatic duct obstruction by pancreatic and ampullary tumors, and pancreatic resection are the most common causes of pancreatic insufficiency.¹ Even when pancreatic enzyme concentrations are normal, reduced pancreatic lipase activity due to a low luminal pH,⁶ excessive calcium ingestion,⁷ or ingestion of the specific lipase inhibitor orlistat⁸ can cause pancreatic steatorrhea. Selective congenital lipase or colipase deficiency is a rare cause of pancreatic fat malabsorption.⁹

DECREASED MUCOSAL ABSORPTION AND CHYLOMICRON FORMATION

Generalized mucosal diseases, such as celiac disease or tropical sprue, often are associated with fat malabsorption. Defective uptake of free fatty acids and monoglycerides results from reduced mucosal surface area because of villus shortening, reduced enterocyte function, and mucosal inflammation.¹ Intestinal fat absorption also is 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.¹⁰

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 due to metastatic solid tumors, lymphoma, Whipple’s disease, retroperitoneal fibrosis, or trauma ⁶ (see Chapter 28). Usually, lymphatic vessels in the mucosa become dilated (lymphangiectasia), and chylomicrons are lost into the intestinal lumen postprandially and also in the fasting state¹¹; steatorrhea in these situations usually is only mild to moderate.¹⁰

PROTEINS AND AMINO ACIDS

Defective digestion or absorption of dietary proteins has to be differentiated from excessive loss of serum proteins into the gastrointestinal tract, which is termed protein-losing enteropathy (see Chapter 28).

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. Defective proteolysis also occurs with exocrine pancreatic insufficiency.^1,^12,¹³ In congenital diseases, pancreatic proteolysis can be impaired by inborn errors in the synthesis of proteolytic enzymes (trypsinogen deficiency)¹³ or by defective activation of pancreatic proenzymes resulting from congenital deficiency of intestinal enterokinase (see later).¹⁴

DEFECTIVE MUCOSAL HYDROLYSIS OF PEPTIDES AND DECREASED ABSORPTION OF OLIGOPEPTIDES AND AMINO ACIDS

Generalized mucosal diseases, such as celiac disease and tropical sprue, result in global malabsorption, which includes malabsorption of oligopeptides and amino acids due to lack of mucosal hydrolysis of oligopeptides and defective mucosal absorption.¹³ Reduction of intestinal absorptive surface, as in short bowel syndrome or jejunoileal bypass, also results in protein and amino acid malabsorption.^13,¹⁵ Congenital defects of amino acid transporters on the enterocytes, such as Hartnup’s disease and lysinuric protein intolerance, can lead to selective malabsorption of a subgroup of amino acids (see later on).

CARBOHYDRATES

DEFECTIVE INTRALUMINAL HYDROLYSIS OF CARBOHYDRATES

Pancreatic α-amylase normally is secreted in excess into the intestinal lumen. In mild forms of pancreatic insufficiency, carbohydrate digestion usually is at least partially preserved,¹⁶ but severe pancreatic insufficiency results in clinically apparent carbohydrate malabsorption and diarrhea due to decreased luminal hydrolysis of ingested starch.¹⁷

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 more 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 disease or Crohn’s disease, or temporarily after self-limited gastrointestinal infections (postinfection carbohydrate malabsorption).^16,¹⁷ The pathophysiologic mechanisms of carbohydrate malabsorption are reduction of the intestinal mucosal surface area and a reduced activity or expression of intestinal oligo- and disaccharidases or transport proteins for monosaccharides.¹⁶ Congenital disaccharidase deficiencies (lactase, sucrase-isomaltase, and trehalase)¹⁸ and congenital deficiency or malfunction of transport molecules as in congenital glucose-galactose malabsorption¹⁹ can cause early onset of malabsorption of mono- or disaccharides (see later on). Intolerance of fructose is discussed in a subsequent section.

VITAMINS

FAT-SOLUBLE VITAMINS

Diseases causing malabsorption of dietary fat commonly cause malabsorption of fat-soluble vitamins, because they require similar absorptive mechanisms. This is especially important in diseases that result in impaired micelle formation from bile salt deficiency.²⁰ Fat-soluble vitamins also are malabsorbed in diffuse diseases of the mucosal surface area, in diseases affecting chylomicron formation and transport,²¹ and in exocrine pancreatic insufficiency.²² Some authors have suggested that absorption of fat-soluble vitamins is less affected by exocrine pancreatic insufficiency than by small intestinal diseases resulting in steatorrhea.²³

WATER-SOLUBLE VITAMINS

Vitamin B₁₂ (Cobalamin)

Decreased release of dietary vitamin B₁₂ from food sources because of impaired pepsin and acid secretion, as in atrophic gastritis ²⁴ or use of acid inhibitory drugs such as proton pump inhibitors,²⁵ usually results in only mild cobalamin malabsorption without clinical consequences. By contrast, deficiency of gastric intrinsic factor secretion, as occurs in pernicious anemia or after gastric resections, or secretion of an abnormal intrinsic factor, as in some congenital diseases, results in severe vitamin B₁₂ malabsorption with clinical consequences.²⁴

Autoimmune gastritis of pernicious anemia is the most common cause of vitamin B₁₂ malabsorption.²⁶ Cobalamin malabsorption in pernicious anemia is caused by decreased intrinsic factor secretion resulting from parietal cell destruction and by blocking autoantibodies that inhibit intrinsic factor binding to vitamin B₁₂.²⁶ Mild cobalamin malabsorption may be found in patients with pancreatic insufficiency and in patients with Zollinger-Ellison syndrome, owing to decreased proteolytic release of vitamin B₁₂ from its complex with R-binding protein^24,²⁷ (see Chapters 32, 59 and 100).

In bacterial overgrowth syndrome (see Chapter 102) or helminthic infection with Diphyllobothrium latum (see Chapter 110), dietary cobalamin is made unavailable to the host or is consumed by the microorganisms or parasites in the intestinal lumen and, therefore, is not available for intestinal absorption.²⁶

Diseases and conditions affecting the ileal mucosa, such as Crohn’s disease or ileal resection, lead to a reduction of specific absorptive sites for the intrinsic factor-vitamin B₁₂ complex.²⁴ Ileal resections of more than 60 cm usually result in clinically significant vitamin B₁₂ malabsorption.²⁸ Imerslund-Gräsbeck syndrome, a disease of autosomal recessive inheritance due to malfunction of the cubilin-amnionless (AMN) complex, is characterized by selective ileal malabsorption of the intrinsic factor–vitamin B₁₂ complex despite normal ileal morphology.^24,²⁹ Congenital diseases affecting transcobalamin II also result in malabsorption of cobalamin.^24,³⁰

In previously healthy persons it usually takes several years of vitamin B₁₂ malabsorption before cobalamin deficiency develops, because the body stores contain large amounts of cobalamin and the daily requirement is relatively small.

Folate

Folate malabsorption occurs with mucosal diseases affecting the proximal small intestine, such as celiac disease, Whipple’s disease, and tropical sprue.³¹ Folate deficiency is common in chronic alcoholism, in which it is postulated to be caused by decreased dietary intake as well as decreased intestinal absorption of folate.³² As discussed later, several drugs result in impaired intestinal uptake of folate, and an inherited form of selective folate malabsorption has been described. In contrast with cobalamin, body stores of folate are small relative to the daily requirements; therefore, folate deficiency develops faster than cobalamin deficiency in the setting of malabsorption. Increased serum folate levels resulting from bacterial formation of tetrahydrofolate have been reported in small intestinal bacterial overgrowth states.³³

Other Water-Soluble Vitamins

Other water-soluble vitamins, such as ascorbic acid and the B-complex vitamins, are absorbed in the small intestine either by carrier-mediated transport or by passive diffusion. Generalized malabsorption syndromes from intestinal causes impair the absorption of these vitamins, thereby leading to deficiency states.^34,³⁵ Deficiency of these water-soluble vitamins also occurs in chronic alcoholism, probably owing to decreased oral intake and reduced intestinal absorption.³²

MINERALS

CALCIUM

Severe calcium malabsorption can occur in diseases that affect the small intestinal mucosa, such as celiac disease. In these disease states, calcium absorption is impaired directly because of the reduction of the intestinal surface area and indirectly because of formation of insoluble calcium soaps with malabsorbed long-chain fatty acids. Therefore, diseases causing malabsorption of long-chain fatty acids by other mechanisms, such as bile acid deficiency, also can result in calcium malabsorption.²¹ In many of these diseases, malabsorption and deficiency of vitamin D further contribute to intestinal calcium malabsorption.²¹ Selective intestinal malabsorption of calcium—that is, 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.²¹ Calcium malabsorption also occurs commonly after gastric resection (see subsequent section, “Malabsorption after Gastric Resection”).

MAGNESIUM

In many generalized malabsorptive disorders, magnesium malabsorption can result in magnesium deficiency.³⁶ Malabsorption is due to the reduction in mucosal absorptive surface area and to luminal binding of magnesium by malabsorbed fatty acids; a congenital form of selective intestinal magnesium malabsorption also has been reported.³⁷

IRON

Iron deficiency is common in patients with gastric resection or with celiac disease. Reduction in the mucosal surface area of the small intestine as a result of diffuse mucosal disease, intestinal resection, or intestinal bypass also can result in impaired iron absorption, potentially leading to iron deficiency ³⁸; a congenital form of iron malabsorption also has been described (see Table 101-14).³⁹ Intestinal loss of iron from chronic gastrointestinal bleeding is, however, the most common gastrointestinal cause of iron deficiency.⁴⁰ Worldwide, hookworm infection is a common cause of iron deficiency.

ZINC

Zinc, like other minerals, is malabsorbed in generalized mucosal diseases of the small intestine.⁴¹ A congenital selective defect of zinc absorption, acrodermatitis enteropathica, is caused by a defect in the zinc transport protein hZIP4.⁴²

OTHERS

Generalized malabsorption can cause deficiency of copper and selenium.^43,⁴⁴ In Menkes disease (kinky hair disease), an inherited disorder of cellular copper transport, selective intestinal copper malabsorption results (see later on). It is uncertain whether malabsorptive diseases result in deficiencies of chromium and manganese.⁴¹

MECHANISMS THAT COMPENSATE FOR MALABSORPTION

ROLE OF THE COLON

The colon has the capacity to absorb a limited number but a wide variety of substances and nutrients including sodium, chloride, water, oxalate, short chain fatty acids, calcium, and vitamin K. Although colonic nutrient absorption does not play a major role in health, the nutritive role of the colon in patients with severe malabsorption is clinically relevant.⁴⁵ Colonic preservation of malabsorbed nutrients also can result in symptoms and complications of malabsorption,⁴⁶ such as colonic hyperabsorption of oxalate, which contributes to formation of renal stones (see later on).

Colonic Salvage of Incompletely Absorbed Carbohydrates

In healthy people, between 2% and 20% of ingested starch escapes absorption in the small intestine ⁴⁷; pancreatic insufficiency or severe intestinal disorders further increase this amount.¹⁷ Carbohydrates that reach the colon cannot be absorbed by the colonic mucosa, but they can be metabolized by the colonic bacterial flora. Metabolism by anaerobic bacteria results in the breakdown of oligosaccharides and polysaccharides to mono- and disaccharides, which are metabolized further to lactic acid; short-chain (C2 to C4) fatty acids (SCFAs) such as acetate, propionate, and butyrate; and to odorless gases, including hydrogen, methane, and carbon dioxide.⁴⁸

Studies in normal subjects have suggested that the 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.¹⁷ Colonic absorption of SCFAs results in a reduction of the osmotic load and, as a result, in mitigation of osmotic diarrhea.⁴⁹ 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 mucosa⁵⁰ (Fig. 101-1). Chronic carbohydrate malabsorption causes adaptive changes in bacterial metabolic activity that result in an even higher efficiency of the bacterial flora to digest carbohydrates,⁵¹ although at the expense of increased flatus production (see later).

Figure 101-1. Carbohydrate metabolism and absorption of metabolic products in the colon. Up to 80 g of carbohydrate that reaches the colon can be metabolized by colonic bacteria to organic acids—lactic acid and the short-chain fatty acids acetate, proprionate, and butyrate—and to hydrogen, carbon dioxide, and methane. Approximately 90% of the organic acid produced is absorbed by colonic mucosa, which permits salvage of calories. Osmotic diarrhea results when organic acids that escape absorption and carbohydrate that escapes bacterial metabolism accumulate in the colon. Between 20% and 90% of gases produced in the colon is absorbed by the colonic mucosa; the remainder is excreted as flatus. CHO, carbohydrate; OA, organic acid.

Because SCFAs have caloric values between 3.4 and 5.95 kcal/g,⁵² 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 that a substantial part of the colon remains in continuity with the small intestine.⁵³ Not all SCFAs are absorbed by the colon, and those that are not absorbed contribute to osmotic diarrhea.

The beneficial effects of colonic bacterial carbohydrate metabolism may be accompanied by side effects due to gas production (see Chapter 16). Up to 10-fold differences in the volume of gas produced in the colon have been observed in normal persons.⁵⁴ The colon also can absorb gas. 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%⁵⁴ (Fig. 101-2). 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.⁵⁵

Figure 101-2. Relationship between flatus volume and colonic hydrogen absorption during fasting (open circles) and after ingestion of 12.5 grams of lactose (closed circles). At high flatus volumes, the fraction of hydrogen that is excreted in breath decreases to approximately 20% of total hydrogen excretion. The remaining 80% is excreted in flatus.

(From Hammer HF. Colonic hydrogen absorption: Quantification of its effect on hydrogen accumulation caused by bacterial fermentation of carbohydrates. Gut 1993;34:818.)

Impaired colonic salvage of carbohydrates has been suggested to contribute to the diarrhea in Crohn’s disease ⁵⁶ and ulcerative colitis.⁵⁷ Bacterial carbohydrate metabolism may be lessened by antibiotic treatment.⁵⁸ In some patients, antibiotic-associated diarrhea may be the result of impaired colonic salvage of carbohydrates that normally are not absorbed or the result of dietary fiber that can accumulate in stool because of decreased bacterial fermentation.⁵⁹

Role of the Colon in Fat Malabsorption

Long-chain triglycerides or fatty acids, which constitute most dietary fat, cannot be absorbed by the human colon. Long-chain fatty acids bind calcium in the colon, thereby increasing the amount of sodium oxalate that is absorbed.⁶⁰ Fatty acids with chain lengths longer than 12 carbons can cause diarrhea, because they increase mucosal permeability and inhibit colonic absorption of fluid and electrolytes.⁶¹ An increase in colonic permeability due to long-chain fatty acids also may be a contributing factor for the increased colonic oxalate absorption seen in patients with steatorrhea and hyperoxaluria.⁶²

Patients with short bowel syndrome can gain caloric energy from colonic absorption of medium-chain fatty acids, coming from medium-chain triglyceride supplementation, if they have at least part of the colon in continuity with the remaining small intestine.⁶³ In the rat colon, absorption of octanoate is not affected by the simultaneous presence of other luminal substrates.⁶⁴

Colonic Salvage of Calcium

Although most unabsorbed calcium is insoluble when it reaches the terminal ileum,⁶⁵ preservation of at least half of the colon in patients with extensive small bowel resection improves calcium absorption by about 40%, compared with calcium absorption in patients who have an ileostomy.⁶⁶ Absorption of calcium requires solubilization of calcium salts. Bacterial metabolism of dietary fiber or incompletely absorbed carbohydrates can help solubilize calcium by causing a decrease in the pH of luminal contents in the colon. Once calcium is solubilized, it can contact the cecal mucosa, which in the rat has been demonstrated to be the site with the highest calcium absorption rate per surface area in the entire intestine.⁶⁵ Calcium solubilization in the colon from bacterial fermentation of malabsorbed lactose also can occur in patients with lactose malabsorption, because in this condition, the bioavailability of calcium from milk is greater than that from mineral water.⁶⁷ In addition to their effect on luminal pH, the SCFAs acetate and propionate, which are products of bacterial metabolism of lactose, have been shown to enhance calcium absorption directly in the human colon.⁶⁸

ROLE OF INTESTINAL TRANSIT IN THE SALVAGE OF MALABSORBED NUTRIENTS

The lower parts of the gastrointestinal tract do not normally contact nutrients, and when they do, intestinal transit time is prolonged.^69,⁷⁰ This delay in transit could contribute to the compensation mechanisms in malabsorptive diseases; however, nutritional salvage by this mechanism has not been quantitated.

CLINICAL FEATURES AND EVALUATION

Diagnosis of malabsorption requires suspecting its presence, confirming its existence, and demonstrating its cause. Malabsorption usually is suspected on the basis of the patient’s history, signs and symptoms, or findings on routine laboratory evaluations. Malabsorption of an ingested nutrient or substrate can be confirmed by measuring its increased stool concentration or its decreased serum concentration or urinary excretion. Finding the cause of malabsorption often requires tests such as endoscopy with small intestinal biopsy; under certain clinical circumstances, noninvasive tests or radiologic imaging are helpful in providing a specific diagnosis.

SUSPECTING AND CONFIRMING THE PRESENCE OF MALABSORPTION

History and Physical Examination

Table 101-4 lists symptoms and signs suggestive of malabsorption, although virtually all can have causes other than malabsorption. For example, greasy stools might indicate malabsorption, but a greasy appearance also can be due to mucus in stool. Floating of stool in the toilet water can be due to a high stool fat content, but it also can be caused by high gas content. Nevertheless, such symptoms and signs are helpful in raising the clinician’s index of suspicion and in guiding the physician as to which specific laboratory tests, structural evaluations, or function tests should be ordered.

Table 101-4 Symptoms and Signs of Malabsorption and Relevant Pathophysiology

SYMPTOM OR SIGN	PATHOPHYSIOLOGIC EXPLANATION
Gastrointestinal
Diarrhea	Osmotic activity of carbohydrates or short-chain fatty acids Secretory effect of bile acids and fatty acids Decreased absorptive surface Intestinal loss of conjugated bile acids Ileal resection Severe ileal mucosal disease Congenital defects of the ileal sodium–bile acid cotransporter

Abdominal distention, flatulence Bacterial gas production from carbohydrates in colon, small intestinal bacterial overgrowth Foul-smelling flatulence or stool Malabsorption of proteins or intestinal protein loss Pain Gaseous distention of intestine Ascites Protein loss or malabsorption Musculoskeletal Tetany, muscle weakness, paresthesias Malabsorption of vitamin D, calcium, magnesium, and phosphate Bone pain, osteomalacia, fractures Protein, calcium, or vitamin D deficiency; secondary hyperparathyroidism Cutoneous and Mucosal Easy bruisability, ecchymoses, petechiae Vitamin K deficiency and vitamin C deficiency (scurvy) Glossitis, cheilosis, stomatitis Vitamin B complex, vitamin B₁₂, folate, or iron deficiency Edema Protein loss or malabsorption Acrodermatitis, scaly dermatitis Zinc and essential fatty acid deficiency Follicular hyperkeratosis Vitamin A deficiency Hyperpigmented dermatitis Niacin deficiency (pellagra) Thin nails with spoon-shaped deformity Iron deficiency Perifollicular hemorrhage Malabsorption of vitamin C Spiral or curly hair Malabsorption of vitamin C Other Weight loss, hyperphagia Nutrient malabsorption Growth and weight retardation, infantilism Nutrient malabsorption in childhood and adolescence Anemia Iron, folate, or vitamin B₁₂ deficiency Kidney stones Increased colonic oxalate absorption Amenorrhea, impotence, infertility Multifactorial (including protein malabsorption, secondary hypopituitarism, anemia) Night blindness, xerophthalmia Vitamin A deficiency Peripheral neuropathy Vitamin B₁₂ or thiamine deficiency Fatigue, weakness Calorie depletion, iron and folate deficiency, anemia Neurologic symptoms, ataxia Vitamin B₁₂, vitamin E, or folate deficiency

The current obesity epidemic has led to a changing picture of malabsorption; for example, few patients today with celiac disease are underweight at diagnosis and some are even overweight. These patients have been reported to be less likely to present with classic features, such as diarrhea or anemia. In these patients, a further increase in weight after dietary gluten exclusion may be a cause of morbidity.⁷¹

Laboratory Findings

Certain blood tests might yield abnormal results in malabsorption, but with rare exceptions they are not specific for malabsorptive diseases. Blood tests also can be used as a screening tool to help the physician decide how vigorously to evaluate malabsorption. Table 101-5 lists blood tests in which abnormal results should raise the suspicion of malabsorption and stool tests that should be used to confirm the suspicion of malabsorption.

Table 101-5 Laboratory Tests That Are Useful in Patients with Suspected Malabsorption and for Establishing Possible Nutrient Deficiencies

TEST	COMMENT(S)
Blood Cell Count
Hematocrit, hemoglobin	Decreased in iron, vitamin B₁₂, and folate malabsorption or with blood loss
Mean corpuscular hemoglobin or mean corpuscular volume	Decreased in iron malabsorption; increased in folate and vitamin B₁₂ malabsorption
White blood cells, differential	Decreased in vitamin B₁₂ and folate malabsorption; low lymphocyte count in lymphangiectasia
Biochemical Tests (Serum)
Triglycerides	Decreased in severe fat malabsorption
Cholesterol	Decreased in bile acid malabsorption or severe fat malabsorption
Albumin	Decreased in severe malnutrition, lymphangiectasia, protein-losing enteropathy
Alkaline phosphatase	Increased in calcium and vitamin D malabsorption (severe steatorrhea); decreased in zinc deficiency
Calcium, phosphorus, magnesium	Decreased in extensive small intestinal mucosal disease, after extensive intestinal resection, or in vitamin D deficiency
Zinc	Decreased in extensive small intestinal mucosal disease or intestinal resection
Iron, ferritin	Decreased in celiac disease, in other extensive small intestinal mucosal diseases, and with chronic blood loss
Other Serum Tests
Prothrombin time	Prolonged in vitamin K malabsorption
β-Carotene	Decreased in fat malabsorption from hepatobiliary or intestinal diseases
Immunoglobulins	Decreased in lymphangiectasia, diffuse lymphoma
Folic acid	Decreased in extensive small intestinal mucosal diseases, with anticonvulsant use, in pregnancy; may be increased in small intestinal bacterial overgrowth
Vitamin B₁₂	Decreased after gastrectomy, in pernicious anemia, terminal ileal disease, and small intestinal bacterial overgrowth
Methylmalonic acid	Markedly elevated in vitamin B₁₂ deficiency
Homocysteine	Markedly elevated in vitamin B₁₂ or folate deficiency
Citrulline	May be decreased in destructive small intestinal mucosal disease or intestinal resection
Stool Tests
Fat	Qualitative or quantitative increase in fat malabsorption
Elastase, chymotrypsin	Decreased concentration and output in exocrine pancreatic insufficiency
pH	Less than 5.5 in carbohydrate malabsorption

Quantitative fecal fat measurement followed by measurement of fecal chymotrypsin or elastase concentration may be helpful, both in establishing malabsorption and in differentiating between pancreatic and intestinal causes of malabsorption. Low levels of serum β-carotene, cholesterol, triglycerides, and calcium and a prolonged prothrombin time suggest malabsorption of fat and fat-soluble vitamins. Low levels of vitamin B₁₂, folate, iron, and albumin suggest malabsorption of water-soluble substances and, therefore, indicate intestinal disease rather than pancreatic or biliary disease. Severe deficiency of fat-soluble vitamins might indicate intestinal or biliary disorders. Low levels of plasma citrulline are associated with destructive small intestinal disease, such as celiac disease, or can follow intestinal resection,⁷² although fasting plasma citrulline tests are poor predictors of enterocyte dysfunction in clinical practice; an oral citrulline generation test has been proposed to improve its predictive value.⁷³

DIAGNOSTIC APPROACH

Clinical Clues to the Presence of Specific Diseases

Clinical clues (Table 101-6) or results of laboratory tests (Table 101-7)⁷⁴ can indicate the presence of a specific underlying disease or can help in the differential diagnosis. In addition, the following questions may be helpful and should be asked as part of the history before physical examination:

Has the patient undergone previous surgery, such as gastric or small bowel resection or a gastrointestinal bypass operation?

Is there a family or childhood history of celiac disease?

Is there a history of travel to endemic areas of tropical sprue, giardiasis, or other gastrointestinal infections?

Is there excessive alcohol consumption?

Does the patient have a history of chronic pancreatitis or symptoms suggesting a pancreatic tumor?

Does the patient have clinical features of thyrotoxicosis, Addison’s disease, Whipple’s disease, biliary or liver disease, or diabetic neuropathy?

Does the patient eat a diet high in poorly absorbable carbohydrates (sweeteners such as sorbitol or fructose) or fat substitutes or an unbalanced diet that could result in malnutrition?

Is there a likelihood of human immunodeficiency virus infection?

Is the patient receiving treatment with a drug that can cause malabsorption?

Does the patient have a history of stem cell or organ transplantation or abdominal radiation?

Does the patient have a history of extraintestinal manifestations of inflammatory bowel disease, celiac disease, or Whipple’s disease

Table 101-6 Cardinal Clinical Features of Specific Malabsorptive Disorders

DISORDER	CARDINAL CLINICAL FEATURES
Adrenal insufficiency	Skin darkening, hyponatremia, hyperkalemia
Amyloidosis	Renal disease, nephrotic syndrome, cardiomyopathy, neuropathy, carpal tunnel syndrome, macroglossia, hepatosplenomegaly
Bile acid deficiency	Ileal resection or disease, liver disease
Carcinoid syndrome	Flushing, cardiac murmur
Celiac disease	Variable symptoms: dermatitis herpetiformis, alopecia, aphthous mouth ulcers, arthropathy, neurologic symptoms, and (life-threatening) malnutrition; abnormal liver biochemical test results, mild iron deficiency
Crohn’s disease	Arthritis, aphthous mouth ulcers, episcleritis, uveitis, pyoderma gangrenosum, erythema nodosum, abdominal mass, fistulas, primary sclerosing cholangitis (PSC), laboratory signs of inflammation
Cystic fibrosis	Chronic sinopulmonary disease, meconium ileus, distal intestinal obstruction syndrome (DIOS), elevated sweat chloride
Cystinuria, Hartnup’s disease	Kidney stones, dermatosis
Diabetes mellitus	Long history of diabetes and diabetic complications
Disaccharidase deficiency	Bloating and cramping, intermittent diarrhea
Gastrointestinal fistulas	Previous intestinal surgery or trauma, Crohn’s disease
Glucagonoma	Migratory necrolytic erythema
Hyperthyroidism, hypothyroidism	Symptoms and signs of thyroid disease
Hypogammaglobulinemia	Recurrent infections
Intestinal ischemia	Other ischemic organ manifestations; abdominal pain with eating (chronic mesenteric ischemia)
Lymphoma	Enlarged mesenteric or retroperitoneal lymph nodes, abdominal mass, abdominal pain, fever
Mastocytosis	Urticaria pigmentosum, peptic ulcer
Mycobacterium-avium complex infection	Acquired immunodeficiency syndrome
Pancreatic insufficiency	History of pancreatitis, abdominal pain; or alcoholism; large-volume fatty, oily stools
Parasitic infection	History of travel to endemic areas
Primary biliary cirrhosis	Jaundice, itching
Scleroderma	Dysphagia, Raynaud’s phenomenon, skin tightening
Small intestinal bacterial overgrowth	Previous intestinal surgery, motility disorder (scleroderma, pseudo-obstruction), small intestinal diverticula, strictures
Tropical sprue	History of travel to endemic area
Tuberculosis	Specific history of exposure, living in or travel to endemic area, immunosuppression, abdominal mass or intestinal obstruction, ascites
Whipple’s disease	Lymphadenopathy, fever, arthritis, cerebral symptoms, heart murmur
Zollinger-Ellison syndrome	Peptic ulcers, diarrhea

Table 101-7 Laboratory Tests That Are Useful in the Differential Diagnosis of Malabsorption

TEST	COMMENT
Blood Cell Count
Acanthocytes	Abetalipoproteinemia
Nuclear remnants in erythrocytes (Howell-Jolly bodies)	Splenic atrophy in celiac disease, inflammatory bowel disease, radiation enteritis, amyloidosis
White blood cells, differential	Eosinophilia in eosinophilic gastroenteritis and parasitic disease Low lymphocyte count in lymphangiectasia, tuberculosis, protein-losing enteropathy Low CD4⁺ count in AIDS

Platelets Increased in inflammatory diseases Other Tests ESR, C-reactive protein Increased in Crohn’s disease, Whipple’s disease, lymphoma Ferritin Increased in inflammatory diseases, lymphoma; decreased in iron deficiency Iron Decreased in celiac disease, chronic occult intestinal bleeding, chronic inflammatory diseases Liver biochemical tests Increased in primary biliary cirrhosis and other liver diseases, celiac disease Immunologic Markers Immunoglobulins IgA deficiency, immunodeficiency syndromes Allergen-specific IgE IgE-mediated hypersensitivity Autoantibodies (e.g., ANA) Connective tissue diseases HLA-DQ2 or HLA-DQ8 Celiac disease, refractory sprue Antimitochondrial autoantibodies Primary biliary cirrhosis HIV-ELISA/Western blot AIDS Neuroendocrine Markers ACTH, cortisol Abnormal values in Addison’s disease Chromogranin A Elevated in neuroendocrine tumors 5-Hydroxyindoleacetic acid in urine Elevated in carcinoid syndrome Gastrin* Elevated in Zollinger-Ellison syndrome Glucagon* Elevated in glucagonoma Serum TSH Decreased in hyperthyroidism; increased in hypothyroidism Somatostatin* Elevated in somatostatinoma (normal in duodenal somatostatinoma) Tissue transglutaminase antibodies, EMA Celiac disease Stool Tests Occult blood test Erosive or ulcerative intestinal disease or tumor Ova and parasites Repeated samples may be needed to detect Giardia lamblia Leukocytes Present in some inflammatory diseases of the intestine

ACTH, adrenocorticotropic hormone; AIDS, acquired immunodeficiency syndrome; ANA, antinuclear antibodies; EMA, endomysial antibodies; ESR, erythrocyte sedimentation rate; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; Ig, immunoglobulin; TSH, thyroid-stimulating hormone.

* Perform this test if there is a strong suspicion of an underlying neuroendocrine tumor.⁷⁷

A rational approach to establishing the cause of malabsorption can require several diagnostic steps. Depending on the clinician’s background, the availability of different tests, and the patient’s preferences, different diagnostic approaches may be used. If time constraints are not a consideration, a stepwise approach may be used, starting with noninvasive evaluations that can guide further invasive procedures or even provide a diagnosis. In other instances, the physician may choose a more invasive test in the hope of reaching a diagnosis with the fewest possible tests and in the shortest possible time. Diagnostic approaches differ depending on the epidemiologic or ethnic background of an individual patient. For example, if parasitic infections are a likely possibility, stool examination can provide a rapid diagnosis by noninvasive testing. In populations with a very low prevalence of lactose intolerance, a secondary cause of lactose malabsorption is more likely than it would be in populations with a high prevalence of acquired primary lactase deficiency, and therefore, additional tests are appropriate.

The sequence of tests thus depends on the affected person’s symptoms and history, as well as results of previous testing (Table 101-8). Tests that can detect the most common causes of malabsorption or are noninvasive or inexpensive usually should be performed initially (first-line tests). In some patients, testing for rarer causes of malabsorption and use of more invasive or more expensive tests may be necessary to establish the diagnosis (second-line tests). For unusually difficult cases, additional tests may be required that may be available only in specialized centers (third-line tests).

Table 101-8 Tests to Establish the Cause of Malabsorption Based on Main Symptoms

Weight Loss, Osteomalacia or Osteopenia, Diarrhea, Suspected Steatorrhea, or Deficiency of Fat-Soluble Vitamins

First-line Tests

Abdominal ultrasonography

Chymotrypsin and/or elastase concentration in stool

EGD with small intestinal biopsies

Endomysial and tissue transglutaminase antibodies

Laboratory tests (complete blood cell count, white blood cell differential, cholesterol, triglycerides, electrolytes, calcium, magnesium, serum ALT, AST, AP, bilirubin levels, prothrombin time, serum albumin level, erythrocyte sedimentation rate and C-reactive protein, TSH)

Ova, parasites, and leukocytes in stool

Second-line Tests

Abdominal CT, MRI

Endoscopic examination of the terminal ileum, including ileal biopsies

ERCP/MRCP

More extensive laboratory investigation (immunoglobulins, human immunodeficiency virus ELISA, antinuclear antibodies, ferritin, food allergen–specific IgE, adrenocorticotropic hormone, cortisol, chromogranin A, gastrin, urinary 5-HIAA)

Quantitative fecal fat

Quantitative small intestinal culture or breath tests for bacterial overgrowth

Small bowel series/small bowel MRI

Special staining of small intestinal biopsies (e.g., Congo red for amyloid, PAS for Whipple’s disease)

Therapeutic trial of pancreatic enzymes, antibiotics (tetracycline, metronidazole), or a gluten-free diet

Video capsule endoscopy

Tests in Unusually Difficult Cases (Third-line Tests)

Abdominal angiography

Antienterocyte antibodies

Endoscopic ultrasonography

Enteroscopy, including biopsies

Magnetic resonance angiography

Positron emission tomography

Serum or plasma glucagon, somatostatin

Somatostatin (octreotide) scan

Special tests of intestinal biopsies (e.g., flow cytometry of intraepithelial lymphocytes for lymphoma and refractory celiac disease, PCR for Tropheryma whipplei or other infective organisms, chromogranin A stain for enteroendocrine cells)

Spiral CT of the pancreas

Tests for bile acid malabsorption

Tube test for exocrine pancreatic secretion (secretin, cholecystokinin, or Lundh test)

Bloating, with or without Diarrhea First-line Tests

Fructose H₂ breath test

Lactose H₂ breath test

Lactose tolerance test

Second-line Tests

Chymotrypsin and/or elastase concentration in stool

EGD with duodenal biopsies

Endomysial and tissue transglutaminase antibodies

Genetic testing for hypolactasia

Quantitative small intestinal culture or breath tests for bacterial overgrowth

Stool pH (in patients with diarrhea)

Anemia and Suspected Malabsorption Microcytic or hypochromic anemia (low MCV, MCH)

EGD with duodenal biopsies

Endomysial and tissue transglutaminase antibodies

Iron, ferritin, and transferrin in serum

Ova and parasites in stool

Video capsule endoscopy

Macrocytic anemia (high MCV, MCH) First-line Tests

Folic acid in serum or red blood cells

Vitamin B₁₂ in serum

Second-line Tests in Cases of Vitamin B₁₂ Deficiency

CT, small bowel series, enteroclysis, video capsule endoscopy

EGD with gastric and duodenal biopsies

Endomysial and tissue transglutaminase antibodies

Evaluation of ileum (e.g., double balloon enteroscopy with biopsy, colonoscopy to ileum with biopsy)

Ova and parasites in stool

Quantitative small intestinal culture or breath tests for bacterial overgrowth

Schilling test (with and without intrinsic factor)

Second-line Tests in Cases of Folate Deficiency

EGD with duodenal biopsies

Endomysial and tissue transglutaminase antibodies

ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; CT, computed tomography; EGD, esophagogastroduodenoscopy; ERCP, endoscopic retrograde cholangiopancreatography; 5-HIAA, 5-hydroxyindoleacetic acid; IgE, immunoglobulin E; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume; MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging; PAS, periodic acid–Schiff; PCR, polymerase chain reaction; TSH, thyroid-stimulating hormone.

For some disorders, such as bile acid malabsorption, lactose malabsorption, and bacterial overgrowth, it may be difficult to establish a causal link between symptoms and the malabsorbed substrate. In these conditions, observation of the response to therapy may be critical in proving or disproving a causal relationship.

ANATOMIC INVESTIGATIONS

Endoscopic examination of the stomach, duodenum, or ileum and histologic examination of mucosal biopsy specimens can establish a diagnosis of some conditions causing malabsorption. The role of radiologic imaging examinations is limited mostly to answering questions about abdominal regions not easily accessible to endoscopy, such as parts of the small intestine, parenchymatous organs, the peritoneal cavity, the mesentery, or the retroperitoneum. Capsule endoscopy and magnetic resonance imaging (MRI) are contributing to making these areas more accessible to diagnostic evaluation. Radiologic studies of the small intestine can show evidence of stasis, blind loops, diverticula, fistulas, rapid transit, and other abnormalities that can assist in diagnosis (see later on).

ENDOSCOPY, BIOPSY, AND DUODENAL ASPIRATION

Endoscopy

Endoscopic inspection of the duodenal mucosa can provide clues to some causes of malabsorption. Aphthae suggest Crohn’s disease, and small, diffuse, white, punctate lesions can be seen in primary or secondary lymphangiectasia. Mosaic-like scalloping of duodenal folds (Fig. 101-3) and reduction in the number of duodenal folds are highly suggestive of villus atrophy in celiac disease, although these abnormalities may be seen in other diseases (see Chapter 104).⁷⁵ Villus atrophy may be seen endoscopically using magnification endoscopy⁷⁶ and chromoendoscopy with indigocarmine staining; however, a normal duodenal fold pattern should not deter the endoscopist from taking mucosal biopsy specimens. Endocrine tumors causing malabsorption, such as duodenal gastrinomas or somatostatinomas or ampullary tumors obstructing the pancreatic duct, also can be detected during endoscopy. If ileal disease is the suspected cause of malabsorption, visual examination and biopsy of the ileal mucosa may be required to establish a diagnosis; this can be accomplished by retrograde intubation of the ileum at colonoscopy or by double-balloon endoscopy.

Figure 101-3. Endoscopic image showing scalloping of the duodenal folds in a patient with celiac disease.

Biopsy

Examination of endoscopic biopsy specimens from the duodenum may be diagnostic or highly suggestive of a variety of small bowel disorders resulting in malabsorption (Table 101-9); follow-up small intestinal biopsy can be used to assess treatment effects. Duodenal biopsy specimens should be obtained from patients with atypical or nonspecific gastrointestinal symptoms, including abdominal pain, bloating, and weight loss, and should not be limited only to patients with diarrhea.^77,⁷⁸ Endoscopic biopsy is an adequate substitute for jejunal suction biopsy,⁷⁹ and its advantages over capsule biopsy are that multiple specimens are more easily obtained and focal or patchy lesions can be identified and targeted for sampling.⁸⁰ Compared with duodenal biopsies, endoscopically obtained biopsies from the jejunum to find changes of celiac disease are helpful in only very few patients.⁸¹ The adequacy of mucosal biopsy specimens is a function of their size and the number obtained.⁸² If large specimens can be obtained using jumbo biopsy forceps, they can be oriented on a piece of filter paper before they are put into a fixing solution⁸³; two or three jumbo biopsy specimens usually are sufficient to allow histologic sectioning parallel to the villi and crypts. Specimens also may be obtained with smaller forceps, although the number of specimens obtained must then be increased to four to six. Specimens can be inspected with a low-power dissecting microscope or by magnification endoscopy to obtain an initial impression of the villus architecture and to ensure proper orientation before they are placed in formalin.

Table 101-9 Causes of Malabsorption That Can Be Diagnosed by Small Bowel Biopsy

CAUSE OF MALABSORPTION	MAIN HISTOLOGIC FEATURES
Generalized Histologic Abnormalities
Abetalipoproteinemia, hypobetalipoproteinemia	Lipid accumulation and vacuolization of enterocytes
Collagenous sprue (Chapter 104)	Collagenous band below atrophic epithelium
Mycobacterium-avium complex infection (Chapter 33)	Acid-fast bacilli, foam cells
Whipple’s disease (Chapter 106)	Foamy macrophages with PAS-positive inclusion bodies
Patchy Histologic Abnormalities
Amyloidosis (Chapter 35)	Congo red–stained deposits with apple-green birefringence in polarized light
Crohn’s disease (Chapter 111)	Epithelioid granulomas and characteristic focal inflammation
Eosinophilic gastroenteritis (Chapter 27)	Eosinophilic infiltration
Lymphangiectasia (Chapter 28)	Ectatic lymph vessels
Lymphoma (Chapter 29)	Clonal expansion of lymphocytes
Mastocytosis (Chapter 35)	Diffuse infiltration with mast cells
Parasites (Giardia lamblia, Strongyloides stercoralis, coccidia) (Chapters 109, 110)	Some parasites may be seen on histologic examination

PAS, periodic acid–Schiff.

Modified from Riddell RH. Small intestinal biopsy: Who? how? what are the findings? In Barkin JS, Rogers AI, editors. Difficult Decisions in Digestive Diseases. Chicago: Year Book; 1989. p 326.

The diagnostic yield of biopsy is influenced by the distribution of histologic abnormalities, which in some diseases is diffuse but in other diseases is patchy. Tropical diarrhea malabsorption syndrome (tropical sprue; see Chapter 105), abetalipoproteinemia, and immunodeficiency usually result in a diffuse alteration of small intestinal mucosa. Thus, a completely normal appearance of a duodenal biopsy specimen rules out these disorders. Primary lymphangiectasia has a patchy distribution, so that a single mucosal biopsy might not rule out the disorder (see Chapter 28). Patchy distribution also has been described for the histologic changes in some patients with celiac disease, especially when symptoms are subtle, although this disorder usually affects the small intestine diffusely.⁸⁴ Other possible sources of error and misdiagnosis include poorly oriented specimens and those obtained proximally, where peptic injury can be the cause of mucosal alterations. Additional biopsy specimens from the stomach and duodenal bulb can help the pathologist to establish the extent of peptic injuries in the upper gastrointestinal tract and to interpret inflammatory changes in the duodenum in relation to these lesions. Distortion of villus architecture over Brunner’s glands or lymphoid aggregates, common in the duodenum, should be interpreted with caution.

Specific histologic features may be diagnostic for some rare causes of malabsorption (see Table 101-9)⁸⁵ such as Whipple’s disease (Fig. 101-4), abetalipoproteinemia or hypobetalipoproteinemia, intestinal lymphangiectasia, giardiasis (Fig. 101-5), lymphoma, or collagenous sprue. In most patients with small intestinal disorders, however, histologic examination is not diagnostic⁸⁵ (Table 101-10) and reveals a spectrum of mucosal responses ranging from infiltration by lymphocytic cells to a flat mucosa with villus atrophy and crypt hyperplasia (Fig. 101-6). In many parts of the world, celiac disease is by far the most common cause of this type of histologic alteration, but a definite diagnosis of celiac disease cannot be established by mucosal biopsy alone (see Chapter 104).

Figure 101-4. Duodenal biopsy specimen from a patient with Whipple’s disease. A, Hematoxylin and eosin staining shows villus blunting. The lamina propria is infiltrated with pale-staining foamy macrophages.

(Courtesy of Cord Langner, MD.)

B, High-power view demonstrates purple-red macrophages. (Periodic acid–Schiff stain.)

(Courtesy of Günter J. Krejs, MD, Graz, Austria.)

Figure 101-5. Small bowel biopsy specimen from an immunocompetent patient with giardiasis. A normal-appearing villus and adjacent pear-shaped organisms with red-staining nuclei are evident.

(Courtesy of Cord Langner, MD.)

Table 101-10 Malabsorptive Diseases with Abnormal but Not Diagnostic Small Intestinal Histologic Findings

Increased Lymphocyte Infiltration with or without Crypt Hyperplasia

AIDS enteropathy (Chapter 33)

Celiac disease (Chapter 104)

Infection (due to Giardia lamblia, Cryptosporidium [Chapter 109]; viral enteritis [Chapter 107])

Tropical sprue (Chapter 105)

Flat Lesion with or without Mucosal Inflammation

Celiac disease (Chapter 104)

Drug-induced enteropathy (NSAIDs, colchicine, neomycin)

Food protein hypersensitivity (rye, barley, egg, fish, rice, poultry) (Chapters 9, 27)

Immunodeficiency (hypogammaglobulinemia) (Chapter 2)

Immunoproliferative small intestinal disease (IPSID) (Chapters 29, 104, and 115)

Infection (due to Giardia lamblia, Cryptosporidium) (Chapter 109)

Intestinal transplantation (Chapter 34)

Lymphoma (Chapter 29)

Nongranulomatous chronic idiopathic enterocolitis

Autoimmune enteropathy

Prolonged folate or cobalamin deficiency

Protein-calorie malnutrition

Traumatic injury

Tropical sprue (Chapter 105)

Atrophic Lesion

Chronic radiation damage (Chapter 39)

Cicatrizing Crohn’s disease (Chapter 111)

Diffuse lymphoma (Chapter 29)

Idiopathic diarrhea of infancy (microvillus inclusion disease) (Chapter 96)

Unresponsive gluten sensitivity (lymphoma or ulcerative jejunitis) (Chapter 104)

AIDS, acquired immunodeficiency syndrome; NSAIDs, nonsteroidal anti-inflammatory drugs.

Modified from Riddell RH. Small intestinal biopsy: Who? how? what are the findings? In Barkin JS, Rogers AI, editors. Difficult Decisions in Digestive Diseases. Chicago: Year Book; 1989. p 326.

Figure 101-6. Duodenal biopsy specimen from a patient with untreated celiac disease. A, Subtotal villus atrophy, crypt elongation, and lymphoplasmacytic infiltration of the lamina propria can be seen. B, High-power view demonstrates villus blunting with increased intraepithelial lymphocytes. (Hematoxylin and eosin stain.)

(Courtesy of Cord Langner, MD.)

Some disease states can be identified only with use of special histologic stains, such as Congo red (intestinal amyloidosis), periodic acid–Schiff (PAS) (Whipple’s disease), or immunohistochemical techniques for detecting refractory celiac disease, small intestinal lymphoma, or enteroendocrine insufficiency (see later on). Polymerase chain reaction analysis of intestinal biopsy specimens for Tropheryma whipplei may be helpful in evaluating patients in whom Whipple’s disease is suspected (see Chapter 106).⁸⁶ In cases in which these diseases are a possibility, the clinician has to request these specific tests. Measurement of mucosal enzyme activities in a jejunal biopsy can be used to confirm disaccharidase deficiency, although this is not recommended for routine clinical use.

Aspiration

Fluid aspirated from the descending part of the duodenum may be examined microscopically for Giardia lamblia (see Chapter 109) or cultured to detect bacterial overgrowth in patients with diffuse small intestinal motility disorders (see Chapters 97 and 102).

Video Capsule Endoscopy

Video capsule endoscopy (VCE) is an increasingly popular technique for diagnosing diseases of the small intestine. VCE was initially introduced for evaluating suspected bleeding in the small intestine, but subsequently it has been used to diagnose a wider range of diseases such as Crohn’s disease, celiac disease, and other malabsorptive disorders. In several studies, lesions suggesting Crohn’s disease were detected by VCE when they had been missed by conventional diagnostic procedures.⁸⁷ These reports need to be interpreted carefully, because no biopsy specimens were obtained, and long-term evaluations to confirm the diagnosis are lacking.

VCE appears to be superior to conventional radiologic imaging of the small intestine and to computed tomography (CT) with small bowel enteroclysis to detect subtle mucosal changes, such as aphthous or erosive lesions of the small intestine.⁸⁷ In celiac disease, the detection of villus atrophy by VCE has a good correlation to villus atrophy seen in duodenal biopsy specimens,^88,⁸⁹ but it is questionable if this procedure can detect subtle changes, such as Marsh 1 and 2 lesions. Changes on VCE that suggest villus atrophy are scalloping, mosaic pattern, and fissuring. In a recent study of VCE in patients with celiac sprue, villus atrophy was seen in the duodenum and jejunum in 59% of cases, in the duodenum only in 32%, and in the jejunum only in 3%.⁸⁹

In refractory celiac disease, VCE can detect changes such as ulcerations and strictures that suggest T-cell lymphoma but that are missed by conventional techniques.⁹⁰ This test may be used in patients with established malabsorption in whom no diagnosis has been established despite extensive diagnostic workup.

ABDOMINAL IMAGING

Small Bowel Follow-through and Small Bowel Enteroclysis

The principal role of small bowel radiologic series in evaluating malabsorption is to identify focal or diffuse abnormalities and alterations that predispose to bacterial overgrowth, including diverticula, stagnant loops of intestine, generalized intestinal hypomotility or dilatation, intestinal fistulas, and tumors.⁹¹

Small bowel enteroclysis is preferred to small bowel follow-through examinations, because distention of the lumen results in better demonstration of the small bowel contour.⁹² Double-contrast enteroclysis, in which intubation of the upper jejunum is used to instill contrast material directly into the upper jejunum, has a higher sensitivity than small bowel series for detecting mucosal changes, although it is less acceptable to the patient and can miss focal changes in the duodenum, such as diverticula. Use of an intravenous agent such as glucagon to reduce motility enables overlapping loops of small intestine to be separated and imaged more distinctly.

Alterations associated with diffuse, localized, or distal mucosal changes that might have been missed by proximal mucosal biopsy also may be identified. Normal findings on small bowel series do not rule out intestinal causes of malabsorption and should not dissuade the clinician from performing biopsy of the small intestine.

Ulcerations and strictures may be seen in various malabsorptive disorders, including Crohn’s disease, radiation enteritis, celiac disease, intestinal lymphoma, and tuberculosis. Aphthous ulcers and cobblestoning of the mucosa, either alone or with thickened and distorted folds, are features of Crohn’s disease but also can be present in other conditions. Reduced numbers of jejunal folds and an increased number of and thickening of ileal folds can suggest celiac disease.⁹¹ Mass lesions can be found with intestinal lymphoma or, rarely, with hormone-producing tumors.

The disadvantage of conventional enteroclysis is that direct imaging of the bowel wall and surrounding structures is not possible, and overlapping bowel loops potentially impair complete visualization of the whole small bowel—hence the rationale for combining enteroclysis with CT or MRI scanning.⁹³

Abdominal Computed Tomography

Abdominal CT for small bowel investigation is performed after administration of oral or intravenous contrast agents.⁹⁴ Small intestinal CT scanning is useful to detect focal intestinal lesions, such as thickening of the small bowel wall in Crohn’s disease or small intestinal lymphoma, intestinal fistula, and dilated bowel loops; however, mild mucosal changes such as aphthae in Crohn’s disease or villus atrophy of various causes are missed by this technique. Diffuse thickening of the small bowel may be seen in Whipple’s disease and in graft-versus-host disease.⁹⁴ In some cases of celiac disease, reversal of the jejunoileal fold pattern is observed.⁹⁵ CT is a sensitive test for detecting enlarged abdominal lymph nodes, which can be present in disorders such as Whipple’s disease, small bowel lymphoma, or small intestinal inflammatory diseases such as Crohn’s disease. Evidence for pancreatic disease that may be detected on CT includes calcifications of the pancreas, dilatation of the pancreatic duct, and pancreatic atrophy. Tumors obstructing the pancreatic duct or hormone-secreting neuroendocrine tumors also can be located by CT.

Magnetic Resonance Imaging of the Small Intestine

MRI may be used to image the small intestine either with administration of oral contrast solutions or by enteroclysis. Segmental bowel wall thickening with inflammatory involvement of the mesentery, cobblestoning, and ulcerations may be seen in Crohn’s disease; this method is very sensitive for demonstrating complications of Crohn’s disease, such as intestinal fistula formation. In celiac disease, small bowel MRI with oral contrast can demonstrate small intestinal dilatation, mucosal thickening, and an increased number of folds in the ileum (ileal jejunization) with flattening of the jejunal folds.⁹⁶ Most of these signs also are found in other inflammatory diseases of the intestine, but the fold pattern abnormalities are most specific for celiac disease.⁹⁶ This method also is very useful to detect changes suggesting complications, such as lymphoma or carcinoma. With MRI enteroclysis, subtle mucosal changes might be missed and be more evident on conventional small bowel enteroclysis⁹⁷ or capsule endoscopy.⁸⁷ Because MRI or CT imaging of the small intestine requires no tube placement, these techniques have largely replaced classic small bowel enteroclysis.

Other Radiologic Studies

A plain film of the abdomen may be helpful to detect pancreatic calcifications if exocrine pancreatic insufficiency is suspected. However, morphologic signs of chronic pancreatitis alone do not prove a pancreatic cause of malabsorption, because the function of the exocrine pancreas must be severely impaired before malabsorption becomes evident. A plain film of the abdomen also can document dilated loops of intestine; dilated loops predispose to small bowel bacterial overgrowth or suggest the presence of an obstruction.

Endoscopic retrograde cholangiopancreatography (ERCP) can help establish the cause of pancreatic insufficiency (see Chapter 59). It can help distinguish chronic pancreatitis from pancreatic tumor and can document pancreatic duct stones. ERCP and endoscopic ultrasound (EUS) are the methods of choice for documenting various causes of biliary obstruction. Magnetic resonance pancreatography (MRCP) is increasingly being used to replace diagnostic ERCP. If a neuroendocrine tumor (e.g., gastrinoma, somatostatinoma) is the suspected cause of malabsorption, an indium-111 octreotide scintigraphic scan, positron emission tomography (PET), or an EUS examination of the pancreas may be helpful in establishing the diagnosis or demonstrating the extent of disease (see Chapters 31 and 32).

Transabdominal ultrasound examination has the advantage of no radiation exposure and therefore can be used in pregnant patients. Ultrasonography often is used to investigate the pancreas, although the sensitivity for detecting pancreatic tumors is lower than that of ERCP or CT. Nevertheless, obstruction of the biliary tract, pancreatic calcifications, dilatation of the pancreatic duct, or stones within the pancreatic duct may be demonstrated. Ultrasound examination also may be used to document thickening of the bowel wall, abscesses, and fistula in Crohn’s disease.

NONINVASIVE EVALUATION OF GASTROINTESTINAL DIGESTIVE AND ABSORPTIVE FUNCTION

Some conditions causing malabsorption can be diagnosed with noninvasive tests, although, as pointed out in Table 101-11, diagnostic accuracy may be limited, and further tests may be necessary to identify underlying diseases or to differentiate primary and secondary causes. Apart from providing a diagnosis, tests evaluating gastrointestinal absorptive and digestive function may be helpful in evaluating complex disease presentations. For most or all of the following tests, the potential benefits with regard to the costs of workup or to patient acceptability have not been established. Because test procedures and analytical methods can vary among laboratories,⁹⁸ each laboratory should establish its own reference values for these tests.

Table 101-11 Malabsorptive Diseases or Conditions in Which Noninvasive Tests Can Establish Malabsorption or Provide a Diagnosis

DISEASE OR CONDITION	DIAGNOSTIC TEST(S)*	COMMENT(S)
Lactose malabsorption	Lactose hydrogen breath test Lactose tolerance test

Tests do not differentiate between primary and secondary lactose malabsorption Fructose malabsorption Fructose hydrogen breath test Questionable clinical relevance Small intestinal bacterial overgrowth (see Chapter 102)

¹⁴C-d-xylose breath test

Glucose hydrogen breath test

Schilling test with and without antibiotics

A predisposing factor should be sought if the result of any of the tests is positive Bile acid malabsorption SeHCAT test, ¹⁴C-TCA test Does not differentiate between primary and secondary causes Exocrine pancreatic insufficiency Quantitative fecal fat determination To establish malabsorption in chronic pancreatitis Fecal elastase or chymotrypsin, tubeless tests (see Chapters 56 and 59) Variable sensitivity and specificity, depending on type of test and stage of the disease Vitamin B₁₂ malabsorption Schilling test Test is performed without intrinsic factor and, depending on result with intrinsic factor, with antibiotics or with pancreatic enzymes (see text). Further tests are needed if small intestinal bacterial overgrowth, terminal ileal disease, or pancreatic disease is suspected

SeHCAT, selenium-75-homotaurocholic acid test; TCA, taurocholic acid.

* See text for diagnostic accuracy of the different tests listed.

Fat Malabsorption

Quantitative Fecal Fat Analysis

The van de Kamer method is the quantitative titration of fatty acid equivalents in which the results are expressed as fecal output of fat in grams per 24 hours. This method is considered the gold standard for fecal fat analysis.⁹⁹ Modifications in which the extracted fats are weighed rather than titrated¹⁰⁰ have an excellent correlation with the results of the van de Kamer method. Near-infrared reflectance analysis may be a less-cumbersome method to quantify fecal fat output in stool collections¹⁰¹ because it requires less handling of stool by laboratory personnel, but it still requires a 48- to 72-hour collection to exclude the influence of day-to-day variability; the stool must be mixed before a sample is obtained for analysis.

Fecal fat excretion of less than 7 g per day with a fat intake of 100 g per day usually is considered normal. However, the volume effect of diarrhea by itself increases fecal fat output to levels of up to 14 g per day (secondary fat malabsorption)¹⁰² (Fig 101-7); this latter value could be used as the upper limit of normal in patients with diarrhea. Diet is important in considering causes of steatorrhea; for example, elevated fecal fat values can be observed in patients consuming a diet rich in the fat substitute olestra.¹⁰⁰

Figure 101-7. Graph showing fecal fat output (average of a three-day stool collection) plotted as a function of fecal weight from normal subjects () and from subjects with induced diarrhea (•). The washout effect of diarrhea increases fecal excretion of fat to levels above the upper limit of normal (7 g/day). With significant diarrhea, therefore, a fecal fat excretion of 14 g/day should be used as the upper limit of normal.

(From Fine KD, Fordtran JS. The effect of diarrhea on fecal fat excretion. Gastroenterology 1936;12;102.)

Quantitative fecal fat analysis is available routinely now only in a few centers. Reasons for the limited clinical use of quantitative fecal fat measurements are as follows: (1) If the main symptom of malabsorption is chronic diarrhea, measurement of fecal fat might not influence the subsequent workup, because the diagnostic tests performed to establish the etiology of diarrhea are similar to the tests for the workup of steatorrhea. (2) An elevated fecal fat level usually cannot differentiate among biliary, pancreatic, and enteric causes of malabsorption. (3) In many patients with severe steatorrhea, the stools have the characteristic porridge-like appearance, and quantitative studies are not necessary to establish fat malabsorption. (4) Fat absorption may be normal despite malabsorption of other nutrients, so a normal fat balance does not imply normal absorptive function of the gastrointestinal tract. (5) Finally, accuracy depends on quantitative stool collections for 48 to 72 hours, adherence to a diet comprising 80 to 100 g of fat daily, and a diet diary to determine fat intake. Science aside, quantitative fecal fat analysis has never been popular among patients, physicians, or laboratory personnel performing the test.

Despite the limitations of quantitative fecal fat analysis, it nevertheless is still useful in several clinical circumstances: to establish malabsorption and avoid nutritional deterioration ¹⁰³ when overt features of intestinal or pancreatic disorders are lacking, as in some cases of osteoporosis, osteomalacia, anemia, or weight loss; to monitor treatment in patients with established malabsorptive disorders, such as exocrine pancreatic insufficiency or short bowel syndrome; to estimate fecal calorie loss in patients with severe malabsorption syndromes; and to quantitate fecal fat excretion in patients with diarrhea who have undergone ileal resection, thereby distinguishing steatorrhea due to bile acid deficiency from secretory diarrhea caused by bile acid loss.¹⁰⁴

Semiquantitative Fat Analysis

For the acid steatocrit test,¹⁰⁵ a sample of stool is diluted 1 : 3 with distilled water in a test tube. The diluted stool is homogenized, and a 500-µL aliquot is pipetted into a tube. Then 100 mL of 5M HClO₄ is added to allow better fat extraction and separation of the lipid layer. An aliquot of the diluted stool-HClO₄ mixture is put into a nonheparinized microcapillary tube and sealed on one end. After centrifugation of this aliquot at 13,000 rpm for 15 minutes, the fatty layer (FL) and the solid layer (SL) are measured, and the acid steatocrit (AS) is determined according to the following equation:

An acid steatocrit of less than 31% is normal. In a small study, the acid steatocrit for random spot stool samples had a high sensitivity and specificity for detection of steatorrhea, compared with the van de Kamer method, which is performed on a 72-hour stool collection. A linear correlation also was found between results obtained with the acid steatocrit and those of the van de Kamer method, although results were quite divergent in some patients.¹⁰⁵ Because quantitative fecal fat measurements are based on 48- to 72-hour stool collections (to minimize the effect of day-to-day variability in fecal fat excretion), however, the acid steatocrit cannot be expected to replace quantitative measurement of fat output in borderline cases or in cases in which exact measurement of fecal fat loss is required.

Qualitative Fecal Fat Analysis

Fat analysis by microscopic examination of random stool samples might provide a clue to the presence of steatorrhea, although it cannot be used to exclude steatorrhea; its sole advantage is its ease of performance. A sample of stool is placed on a glass slide to which several drops of glacial acetic acid and Sudan III stain are added. Acidification of stool samples improves fat extraction and separation of the lipid layer.¹⁰⁵ The slide is held over a flame-burner and the acidified mixture is heated to boiling and then examined while still warm for presence of orange fat globules. A count of up to 100 globules with a diameter less than 4 mm per high-power field is normal.⁶

Results of qualitative fat analysis by this method and of quantitative fat analysis do not correlate very well.¹⁰⁶ In a small study, Sudan staining of spot stool samples had a sensitivity of 78% and a specificity of 70% for the detection of steatorrhea.¹⁰⁵ A quantitative microscopic method of counting and measuring fat globules using the Sudan stain has been shown to correlate well with chemically measured fecal fat output.¹⁰⁷

Breath Tests for Fat Malabsorption

The principle of the ¹⁴C-triolein breath test is to measure ¹⁴CO₂ in the breath after ingestion of a triglyceride that has been radiolabeled with ¹⁴C. Fat malabsorption results in decreased pulmonary excretion of ¹⁴CO₂.¹⁰⁸ Because of erroneous results in a variety of metabolic and pulmonary diseases, lack of sensitivity in mild malabsorption, radiation exposure to the patient, cost of the substrate, and the need for expensive equipment, this test has not found widespread acceptance for clinical use; the nonradioactive isotope ¹³C is used to label triglycerides instead (see later on).

Serum Tests for Fat Malabsorption

The photometric measurement of β-carotene at 456 nm ¹⁰⁹ has been suggested as a useful screening test for steatorrhea, although experience with this technique is limited; values less than 100 mg per 100 mL suggest the presence of steatorrhea, and values less than 47 mg per 100 mL strongly indicate steatorrhea. Concentrations in excess of 100 mg per 100 mL do not exclude mild steatorrhea, although they make steatorrhea with fat losses in excess of 16 g per day very unlikely. Normal values also have been established in the pediatric population.¹¹⁰ β-Carotene can be falsely low in patients with liver disease or in alcoholics who consume a diet deficient in β-carotene. Disorders in lipoproteins or intake of carotene-containing food additives also can influence the results.

Carbohydrate Malabsorption

The hydrogen breath test is a noninvasive test that takes advantage of the fact that in most people, bacterial metabolism of carbohydrate results in accumulation of hydrogen, which then is absorbed by the colonic mucosa and excreted in the breath. Using different carbohydrates, such as lactose or fructose, the hydrogen breath test can be used to detect malabsorption of these carbohydrates. Measurement of breath hydrogen excretion after ingestion of lactulose has been used to assess orocecal transit time, and glucose has been used as a substrate to detect small bowel bacterial overgrowth, although sensitivity and specificity are poor.¹¹¹ Unfortunately, up to 18% of people are hydrogen nonexcretors,¹¹² and in these persons, hydrogen breath test results may be falsely negative because hydrogen is metabolized by bacteria to methane. Such limitations and pitfalls of breath hydrogen testing have to be taken into account when test results are interpreted.¹¹³

The diagnosis of lactose malabsorption is established if an increase in breath hydrogen concentration of greater than 20 parts per million over baseline occurs after ingestion of 20 to 50 grams of lactose. An increase within the first 30 minutes after ingestion of lactose has to be disregarded, because it may be due to bacterial degradation of lactose in the oral cavity. Up to four hours may be required for the increase in breath hydrogen concentration to occur. Breath hydrogen measurements obtained before and at 30, 60, 90, 180, and 240 minutes after ingestion of 50 grams of lactose provide the best diagnostic yield with the fewest possible measurements.¹¹²

The lactose hydrogen breath test still is performed by most clinicians for evaluating lactose malabsorption, but this test can miss the disorder in hydrogen nonexcretors. In these patients, a lactose tolerance test—measurement of blood glucose levels before and 30 minutes after ingestion of 50 grams of lactose—can be used. An increase in glucose concentration of less than 20 mg/dL over baseline within 30 minutes of ingestion of 50 grams of lactose indicates lactose malabsorption. The lactose tolerance test has a lower sensitivity than the lactose hydrogen breath test for diagnosing lactose malabsorption.¹¹²

Lactase deficiency in acquired primary lactase deficiency (adult-type hypolactasia) is not caused by mutations in the gene coding for intestinal lactase (LPH gene). It has been shown, however, that a single-nucleotide polymorphism (SNP), either the C or T nucleotide −13910 upstream of the LPH gene, is involved in the regulation of intestinal lactase expression.¹¹⁴ A CC genotype at −13910 C/T is associated with acquired primary lactase deficiency (adult-type hypolactasia), whereas TC and TT genotypes are linked with lactase persistence.^115,¹¹⁶ This polymorphism can be used as a diagnostic test for adult-type hypolactasia.¹¹⁶ This SNP is only associated with adult-type hypolactasia in whites; other SNPs are linked to adult-type hypolactasia or lactase persistence in Africans.¹¹⁷ In patients with diarrhea, a stool test to detect a fecal pH lower than 5.5 can serve as a qualitative indicator of carbohydrate malabsorption.¹¹⁸ In the research setting, fecal carbohydrates can be determined by the anthrone method, which measures carbohydrates on a weight basis.¹¹⁹ By contrast, the reducing sugar method gives results on a molar basis and, therefore, provides information about the osmotic activity of malabsorbed carbohydrates.¹⁷ Total SCFAs and lactic acid, which are the products of bacterial carbohydrate metabolism, can be measured in stool by titration.¹²⁰ Individual SCFAs can be determined by gas chromatography.¹²¹

Protein Malabsorption

The classic test to quantify protein malabsorption, measurement of fecal nitrogen content in a quantitatively collected stool specimen,¹² rarely is used today. For research purposes, a combined ¹⁴C–octanoic acid–¹³C–egg white breath test, accompanied by measurement of the urinary output of phenol and p-cresol, has been used to assess the effect of gastric acid on protein digestion.¹²² In this method, labeling of the ¹³C–egg protein test meal with ¹⁴C–octanoic acid allows the simultaneous measurement of protein assimilation and gastric emptying rate. Phenol and p-cresol are the quantitatively most important phenolic compounds in the feces and urine and are specific metabolites of tyrosine, produced by bacterial fermentation in the colon. They result from protein that has escaped digestion and absorption in the small intestine and are rapidly absorbed in the colon, detoxified, and excreted in urine. Recovery of higher amounts of urinary phenols observed after omeprazole treatment in the study of this test indicated an increased availability of protein in the colon.

Vitamin B₁₂ (Cobalamin) Malabsorption

The Schilling Test

The Schilling test can be used clinically to distinguish between gastric and ileal causes of vitamin B₁₂ deficiency. Because both intrinsic factor and hydrochloric acid are produced by parietal cells in humans, alternative approaches to diagnosing pernicious anemia are to document atrophic gastritis by endoscopy and biopsy, to confirm achlorhydria by acid secretion analysis and increased serum gastrin levels, and to look for antibodies in the serum directed against parietal cells or intrinsic factor.^26,¹²³ Because the intrinsic factor used in the Schilling test is of bovine origin, the test is not commercially available in some countries.

The Schilling test is performed by administering a small oral dose of radiolabeled vitamin B₁₂ and, simultaneously or within one or two hours, a large intramuscular flushing dose of nonradiolabeled vitamin B₁₂. The unlabeled B₁₂ saturates vitamin B₁₂ carriers; thus, any radioactive vitamin B₁₂ absorbed by the intestine is excreted in the urine. If less than 7% to 10% of the administered dose is recovered in urine within 24 hours, vitamin B₁₂ malabsorption is confirmed. To specify the site of vitamin B₁₂ malabsorption, a second phase of the Schilling test is performed subsequently with oral administration of intrinsic factor. In patients with pernicious anemia, the results of the Schilling test normalize after oral administration of intrinsic factor.^24,¹²³

Patients with pancreatic exocrine insufficiency might have an abnormal result on the Schilling test, with or without added intrinsic factor, but results normalize with addition of pancreatic enzymes (Chapter 59). In small bowel bacterial overgrowth the results of the Schilling test can improve after antibiotic therapy (Chapter 102). In ileal disease or following ileal resection, abnormal results of the Schilling test persist despite intrinsic factor. Schilling test results are normal in patients with dietary vitamin B₁₂ deficiency, in protein-bound (food-bound) vitamin B₁₂ malabsorption,²⁴ and sometimes in congenital transcobalamin II deficiency.¹²⁴ False-positive results on the Schilling test can result from renal dysfunction or inadequate urine collection.¹²³ The value of this test is diminished by the need for accurately timed urine collections. Results in the 5% to 10% excretion range often are difficult to interpret. A variation of the standard Schilling test is the dual-isotope or single-stage Schilling test, in which two different cobalamin isotopes are given simultaneously, one of them bound to intrinsic factor. This makes it possible to perform the first two phases of the Schilling test in one day; however, the results of this test are not as accurate as those obtained with the standard protocol.^24,¹²³

Serum Test for Vitamin B₁₂ and Folate Deficiency

Measurements of serum cobalamin and folate concentrations commonly are used to detect deficiency states of these vitamins. The sensitivity and specificity of these tests are unknown because no gold standard test has been established and because serum levels do not always correlate with body stores.^24,¹²⁵ Furthermore, results of vitamin B₁₂ levels vary with different commercial tests.¹²⁶

Several causes of misleading serum cobalamin levels have been established. Serum vitamin B₁₂ levels can be normal despite depleted body stores in small intestinal bacterial overgrowth (as a result of production of inactive cobalamin analogs by the bacteria), liver disease, myeloproliferative disorders, congenital transcobalamin II deficiency, and with high levels of intrinsic factor antibodies. In contrast, oral contraceptives, pregnancy, and folate deficiency can cause low serum cobalamin levels despite normal body stores.¹²³ Therefore, if there is a high suspicion, especially for cobalamin deficiency, parenteral replacement with monitoring of the clinical response is recommended.¹²⁶ Measurement of methylmalonic acid, homocysteine, and holotranscobalamin are of limited clinical use in establishing vitamin B₁₂ deficiency.¹²⁶

Serum folate concentrations decrease within a few days of dietary folate restriction, even if tissue stores are normal. Feeding also influences serum folate levels; therefore, determination of folate in the fasting state is recommended. Measurement of red blood cell folate concentration has been considered a better estimate of folate tissue stores than serum folate levels by some authors.¹²³

Small Intestinal Bacterial Overgrowth

Tests for the diagnosis of bacterial overgrowth are covered in more detail in Chapter 102. Briefly, tests used to diagnose bacterial overgrowth are the quantitative culture of a small intestinal aspirate (which is considered to be the gold standard diagnostic test), measurement of deconjugated bile acids or vitamin B₁₂ analogs in intestinal aspirates, measurement of serum folate, and several breath tests, including the ¹⁴C-glycocholate breath test, the ¹⁴C-d-xylose breath test, the lactulose hydrogen breath test, and the glucose hydrogen breath test. The rationale for the breath tests is the production by intraluminal bacteria of volatile metabolites (i.e., ¹⁴CO₂ or H₂), from the administered substances, which can be measured in the exhaled breath.

Exocrine Pancreatic Insufficiency

Pancreatic function tests are discussed in detail in Chapters 56 and 59. Invasive pancreatic function tests require duodenal intubation and measurement of pancreatic enzyme, volume, and bicarbonate output after pancreatic stimulation by a liquid test meal (the Lundh test) or by injection of cholecystokinin (CCK) or secretin. Noninvasive tests include measurement of fecal chymotrypsin or elastase concentration, the fluorescein dilaurate test, and the N-benzoyl-l-tyrosyl para-aminobenzoic acid (NBT-PABA) test. Elastase has a higher sensitivity for the detection of exocrine pancreatic insufficiency compared with chymotrypsin,¹²⁷ but the specificity of elastase is low.¹²⁸

Measurement of pancreatic enzymes and components of pancreatic fluid in duodenal aspirates obtained during endoscopy and after intravenous stimulation with secretin and CCK can have an excellent correlation with the more classic intubation tests for secretory function.¹²⁹

Bile Salt Malabsorption

In patients with steatorrhea due to ileal disease or resection, bile salt malabsorption usually is present, but measurement of bile acid malabsorption is of limited clinical value. In patients with diarrhea without steatorrhea, bile salt malabsorption may be present in the absence of overt ileal disease, and in such cases, measurement of bile salt absorption is helpful.

Measurement of Fecal Bile Acid Output

Elevated fecal bile acid concentrations or output can indicate intestinal bile acid malabsorption.¹³⁰ Under steady-state conditions, the increased fecal bile acid output reflects increased hepatic synthesis of bile acids.¹³¹ In severe bile acid malabsorption, fecal bile acid output can be reduced if hepatic synthesis of bile acids is impaired. The measurement can be performed by enzymatic methods or by gas chromatography. This test requires a quantitative stool collection, and the analytic techniques are time consuming and require considerable expertise. Enzymatic methods may be unreliable in severe steatorrhea.¹³²

Carbon-14–Taurocholate Bile Acid Absorption Test

The ¹⁴C-taurocholate bile acid absorption test requires a 72-hour stool collection after ingestion of radioactively labeled bile acid. The rate of intestinal bile acid absorption is calculated from the fecal recovery of ¹⁴C-labeled taurocholic acid (¹⁴C-TCA). Normal values for this test have been established in normal persons with laxative-induced diarrhea, because diarrhea by itself can increase fecal losses of bile acids,¹³¹ presumably because of accelerated intestinal transit.¹³³ Clinical limitations of this test are that it requires substantial analytical work, access to a gamma camera, and a time-consuming stool collection.

Therapeutic Trial of Bile Acid–Binding Resins (Cholestyramine)

A therapeutic trial of cholestyramine or other bile acid–binding resins can be used to diagnose bile acid malabsorption as a cause of diarrhea. It is, however, controversial to what extent a clinical response to cholestyramine correlates with the presence of bile acid malabsorption, because cholestyramine may have a nonspecific constipating effect in patients with diarrhea from other causes. Failure of diarrhea to remit within three days of initiation of cholestyramine makes bile acid malabsorption an unlikely cause of diarrhea; however, some patients respond only to large doses of cholestyramine.

In patients with established bile acid malabsorption in whom no improvement is obtained with bile acid–binding resins, it is very unlikely that bile acid malabsorption is the cause of diarrhea. In these patients, bile acid malabsorption is considered a secondary phenomenon due to a washout effect.¹³¹ In patients with severe bile acid malabsorption resulting in steatorrhea, cholestyramine might even aggravate fat malabsorption and diarrhea.³ Therefore, without further testing for bile acid malabsorption, neither a positive nor a negative result of a therapeutic trial of cholestyramine constitutes proof of the presence or absence, respectively, of bile acid malabsorption.

Selenium-75–Labeled Homotaurocholic Acid Test

The radioactive taurocholic acid analog used for this test is resistant to bacterial deconjugation. After it has been administered orally, the patient undergoes serial gamma scintigraphy to measure whole-body bile acid retention or, as suggested by some authors, bile acid retention in the gallbladder.¹³⁴ A limitation of this test is that normal values for bile acid retention, which are used to compare normal and abnormal bile acid absorption, were obtained only in healthy persons without diarrhea.¹³⁵ However, secondary bile acid malabsorption can be induced by diarrhea itself and is proportional to the stool weight, as demonstrated with the ¹⁴C-TCA test.^131,¹³³ For this test to be clinically useful, normal values need to be established for patients with diarrhea. Finally, this test is very time consuming, because bile acid retention needs to be measured either four or seven days (depending on the protocol) after the bile acid administration.

D-Xylose Test

Absorption of the pentose d-xylose is facilitated by passive diffusion. Approximately 50% of the absorbed d-xylose is metabolized, and the remainder is excreted in urine. After an overnight fast, a 25-g dose of d-xylose is swallowed, and the patient is encouraged to drink sufficient volumes of fluid to maintain good urine output. Urine is collected for the next five hours. As an alternative, one hour after ingestion of d-xylose, a venous sample may be obtained.¹³⁶ Less than 4 grams (16% excretion) of d-xylose in the urine collection or a serum xylose concentration below 20 mg/dL indicates abnormal intestinal absorption. The traditional urine test appears to be more reliable than the one-hour blood test.

False-positive results occur if the duration of urine collection is too short or if the patient is dehydrated or has renal dysfunction, significant ascites, delayed gastric emptying, or portal hypertension. d-Xylose absorption may be normal in patients with only mild impairment of mucosal function or with predominantly distal small intestinal disease. Because d-xylose is susceptible to bacterial metabolism, absorption is diminished in patients with bacterial overgrowth, although the test has a poor sensitivity for detecting this.¹³⁷ The test is of limited clinical value today and mostly has been replaced by small intestinal biopsy.

Intestinal Permeability Tests

Intestinal permeability tests mostly are used in studies of the pathophysiology of intestinal disorders; they do not provide a specific diagnosis.¹³⁸

Most current permeability tests are based on the differential absorption of mono- and disaccharides. Damage to the mucosa can result in an increased permeability for disaccharides and oligosaccharides consequent to epithelial injury, and it can result in a decreased permeability of monosaccharides due to reduction of mucosal surface area.¹³⁹ Absorption is measured by urinary excretion. Expression of results as the absorption ratio of the mono- and disaccharide minimizes the influences of gastric emptying, intestinal transit, renal and hepatic function, and variations in time of urine collections.¹⁴⁰

Increased intestinal permeability has been shown to predict the development of Crohn’s disease or relapse in patients with this disease.¹⁴¹ In celiac disease, the finding of considerably increased permeability is a sensitive marker for advanced disease; permeability tests also have been used to judge response to a gluten-free diet¹⁴² or to screen first-degree relatives for celiac disease. Elevated serum aminotransferase levels in patients with celiac disease correlate with increased intestinal permeability.¹⁴³ Disturbances of intestinal permeability have been documented in users of nonsteroidal anti-inflammatory drugs,¹⁴⁴ in inflammatory joint disease,¹⁴⁵ and in diabetic diarrhea.¹⁴⁶

Carbon-13 Breath Tests

The increasing availability of stable isotopes has raised interest in replacing radioactive ¹⁴C with nonradioactive ¹³C for breath tests.^111,¹⁴⁷ In malabsorptive diseases, ¹³C-labeled substrates have been evaluated in the diagnosis of steatorrhea,¹⁴⁸ small bowel bacterial overgrowth, and exocrine pancreatic insufficiency¹⁴⁹ and in the evaluation of the digestibility of egg protein. Because of concerns about diagnostic accuracy, cost, and limited availability, these tests have not gained widespread acceptance.

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