Normally the human gastrointestinal tract digests and absorbs dietary nutrients with remarkable efficiency. A typical Western diet ingested by an adult includes approximately 100 g of fat, 400 g of carbohydrate, 100 g of protein, 2 L of fluid, and the required sodium, potassium, chloride, calcium, vitamins, and other elements. Salivary, gastric, intestinal, hepatic, and pancreatic secretions add an additional 7–8 L of protein-, lipid-, and electrolyte-containing fluid to intestinal contents. This massive load is reduced by the small and large intestines to less than 200 g of stool that contains less than 8 g of fat, 1–2 g of nitrogen, and less than 20 mM each of Na⁺, K⁺, Cl^–, HCO₃^–, Ca²⁺, or Mg²⁺.

If there is impairment of any of the many steps involved in the complex process of nutrient digestion and absorption, intestinal malabsorption may ensue. If the abnormality involves a single step in the absorptive process, as in primary lactase deficiency, or if the disease process is limited to the very proximal small intestine, selective malabsorption of only a single nutrient (iron or folate) may occur. However, generalized malabsorption of multiple dietary nutrients develops when the disease process is extensive, thus disturbing several digestive and absorptive processes, as occurs in celiac disease with extensive involvement of the small intestine.

Many authors classify diseases associated with malabsorption into three major categories: (1) those associated with impaired intraluminal digestion; (2) those associated with impaired mucosal digestion and absorption; and (3) those associated with impaired postmucosal nutrient transport (Table 20–1). Indeed, these are the major mechanisms of intestinal absorption and some disease entities fit neatly into these specific categories. For example, impaired delivery of pancreatic lipase, proteases, and bicarbonate in pancreatic insufficiency and impaired delivery of hepatobiliary secretions, notably bile salts in biliary obstruction, into the intestinal lumen may result in profound intraluminal maldigestion and may induce malabsorption, especially steatorrhea. In diseases such as abetalipoproteinemia or lactase deficiency, in which the evident pathology is confined to the intestinal mucosa, deficient mucosal digestion or absorption, or both, produce nutrient malabsorption. Impaired intestinal lymphatic drainage, whether due to primary or secondary postmucosal obstruction of intestinal lymphatics, results in impaired fat absorption and fecal protein loss.

However, such a classification of malabsorption diseases has its limitations; although one mechanism may dominate in any given disease, in many instances, others contribute. For example, in short bowel syndrome, the marked reduction in mucosal surface and brush border hydrolases result in impaired mucosal absorption and digestion, but if the ileum is absent, bile salt deficiency results in impaired intraluminal digestion; in small intestinal bacterial overgrowth, bacteria impair intraluminal lipid digestion but also damage brush border hydrolases and may induce significant mucosal inflammation impairing mucosal digestion and absorption as well; in Whipple disease, the mucosal infiltration by macrophages and T whipplei impair mucosal absorption, but mesenteric and retroperitoneal lymph node involvement may produce lymphatic obstruction, impairing postmucosal delivery and systemic distribution of absorbed dietary lipids.

See Table 20–2.

A. Signs and Symptoms

1. Gastrointestinal manifestations

Depending on the nature of the disease process causing malabsorption and its extent, gastrointestinal symptoms may range from severe to subtle or may even be totally absent. Diarrhea, weight loss, flatulence, abdominal bloating, abdominal cramps, and pain may be present. Although diarrhea is a common complaint, the character and frequency of stools may vary considerably, ranging from over 10 watery stools per day to less than one voluminous putty-like stool, the latter causing some patients to complain of constipation. On the other hand, stool mass is invariably increased above the normal of 150–200 g/day in patients with generalized malabsorption and significant steatorrhea. Not only do unabsorbed nutrients contribute to stool mass, but secretion of mucosal fluid and electrolyte is also increased in diseases associated with mucosal inflammation such as celiac disease. In addition, unabsorbed fatty acids, converted to hydroxy-fatty acids by colonic flora, as well as unabsorbed bile acids impair absorption and induce secretion of water and electrolytes by the colon adding to stool mass.

Weight loss is common among patients with significant intestinal malabsorption but must be evaluated in the context of caloric intake. Some patients compensate for fecal wastage of unabsorbed nutrients by significantly increasing their oral intake. Eliciting a careful dietary history from patients with suspected malabsorption is therefore crucial.

Excessive flatus and abdominal bloating may reflect excessive gas production due to fermentation of unabsorbed carbohydrate, especially among patients with primary or secondary disaccharidase deficiency. Malabsorption of dietary nutrients and excessive fluid secretion by inflamed small intestine also contribute to abdominal distention and bloating.

Prevalence, severity, and character of abdominal pain vary considerably among the various disease processes associated with intestinal malabsorption. For example, pain is common in patients with chronic pancreatitis or pancreatic cancer and Crohn disease, but it is absent in many patients with celiac disease or postgastrectomy malabsorption.

2. Extraintestinal manifestations

A substantial number of patients with intestinal malabsorption present initially with symptoms or laboratory abnormalities that point to other organ systems in the absence of or overshadowing symptoms referable to the gastrointestinal tract (see Table 20–2). For example, there is increasing epidemiologic evidence that more patients with celiac disease present with anemia and osteopenic bone disease in the absence of significant gastrointestinal symptoms than present with classic gastrointestinal symptomatology. Microcytic, macrocytic, or dimorphic anemia may reflect impaired iron, folate, or vitamin B₁₂ malabsorption. Purpura, subconjunctival hemorrhage, or even frank bleeding may reflect hypoprothrombinemia secondary to vitamin K malabsorption. Osteopenic bone disease is common, especially in the presence of steatorrhea. Impaired calcium and vitamin D absorption and chelation of calcium by unabsorbed fatty acids resulting in fecal loss of calcium may all contribute. If calcium deficiency is prolonged, secondary hyperparathyroidism may develop. Prolonged malnutrition may induce amenorrhea, infertility, and impotence. Edema and even ascites may reflect hypoproteinemia associated with protein-losing enteropathy caused by lymphatic obstruction or extensive mucosal inflammation. Dermatitis and peripheral neuropathy may be caused by malabsorption of specific vitamins or micronutrients and essential fatty acids.

B. Laboratory and Imaging Studies

1. Stool studies

Descriptions of bowel movements by patients are subjective and often inaccurate. Therefore, careful inspection of the stool by the physician is an important component of the malabsorption evaluation. Steatorrheic stool may be loose or formed but is usually pale, greasy, often bulky, and has a characteristic rancid odor. Sudan stain of a spot stool sample for fat is a simple and useful screening test for steatorrhea. Although some fat is present in normal stool, the number and size of fat droplets are markedly increased if there is substantial steatorrhea. Quantitative determination of fat in a pooled 48- or 72-hour stool collection, although cumbersome, remains the definitive test for steatorrhea. Ideally the patient should be placed on an 80–100-g fat diet for a day or two before the stool collection is begun and maintain that intake throughout the collection period. Unabsorbable fat, such as mineral oil, Olestra, and fat-based suppositories, must be avoided. The collection should be refrigerated until assay to minimize bacterial metabolism of long-chain fatty acids. Excretion of more than 7–8% of fat intake connotes steatorrhea. The collection should be weighed so that stool fat concentration can be calculated; a stool fat concentration over 9.5% suggests intraluminal maldigestion, whereas a stool fat concentration less than 9.5% suggests mucosal disease as intestinal fluid secretion and malabsorption of other nutrients dilute stool fat in the latter situation (Table 20–3).

Measurements of the pancreatic enzyme, elastase, in the stool assayed using a monoclonal or polyclonal enzyme-linked immunosorbent assay (ELISA) is useful for detecting severe pancreatic exocrine deficiency, but its role in detecting milder disease is limited due to its lack of sensitivity. The secretin/cholecystokinin stimulation test, although cumbersome and rarely done nowadays, remains the gold standard for detecting pancreatic insufficiency (see Chapter 27).

Stool samples should be evaluated for ova and parasites and for specific parasitic antigens in patients with suspected malabsorption, especially if diarrhea is present. Several protozoal diseases, including giardiasis, cryptosporidiosis, microsporidiosis, and Cystoisospora belli infection, can produce significant malabsorption.

2. Blood studies

Abnormalities in the formed elements of the peripheral blood are quite common in patients with diseases that produce malabsorption. Anemia is common. Diffuse lesions of the proximal intestine as occur in celiac disease or Whipple disease interfere with iron absorption and folate absorption resulting in microcytic (iron deficiency or blood loss), macrocytic (folate or B₁₂ deficiency), or dimorphic anemia (combined iron and folate or B₁₂ deficiency). Ileal resection or severe ileal disease as well as intraluminal bacterial overgrowth and, rarely, severe pancreatic exocrine insufficiency interfere with vitamin B₁₂ absorption and may produce macrocytic anemia. Concomitantly, serum iron saturation, serum ferritin, iron, folate, and B₁₂ levels are decreased. Normocytic anemia may reflect acute or subacute blood loss as may occur in Crohn disease, intestinal lymphoma, or Whipple disease. Peripheral leukocytosis is unusual, but the differential count may reveal eosinophilia in eosinophilic enteritis or some parasitic diseases or profound lymphopenia in patients with intestinal lymphangiectasia. Thrombocytosis, if present, may reflect hyposplenism, which occurs in some adults with celiac disease.

A number of other blood chemistries and serologies may be abnormal and may provide clues that malabsorption is present and, in some instances, help define a specific diagnosis. Low serum carotene and cholesterol are nonspecific indicators of fat malabsorption, but the serum carotene also largely reflects recent dietary carotene intake. Low serum calcium in patients with malabsorption may reflect poor absorption in mucosal disease, intraluminal formation of insoluble calcium soaps by interaction with unabsorbed fatty acids, as well as coexistent vitamin D deficiency, all resulting in fecal wastage of calcium. Low serum calcium may also accompany hypoalbuminemia, especially in patients with mucosal disease or lymphangiectasia, causing exudative enteric protein loss. The prothrombin time may be prolonged as vitamin K is fat soluble, but in the absence of liver disease, the international normalized ratio (INR) should normalize following intravenous vitamin K replacement. Levels of immunoglobulin A (IgA) anti–tissue trans-glutaminase or IgA antiendomysial antibody, or both, should be obtained if celiac disease is suspected.

3. Specific oral absorption tests and breath tests

Where available, the D-xylose absorption test may help to differentiate malabsorption caused by small intestinal mucosal disease from malabsorption due to impaired intraluminal digestion or lymphatic obstruction. This pentose sugar requires no intraluminal processing and is absorbed by facilitated diffusion. After administration of a 25-g dose orally to a well-hydrated patient, 5 g or more are normally excreted in the urine over 5 hours, and blood levels should reach 25 mg/dL 2 hours after the test dose. Low urine excretion and blood levels suggest disease of the mucosa of the proximal small intestine such as celiac disease. However, the test has significant limitations. It is dependent on normal gastric emptying and normal renal function; delayed gastric emptying will lower both urine xylose excretion and blood xylose levels giving a potentially false-positive result; impaired renal function will reduce urine xylose excretion but not blood xylose levels in the face of normal gastric emptying. Ascites and edema may result in sequestration of absorbed xylose and produce a false-positive test result. Additionally, in patients with bacterial overgrowth in the proximal small intestine, the xylose absorption test may be positive as some bacterial species metabolize xylose, reducing its availability for absorption.

To screen for intestinal lactase or, less commonly, sucrase deficiency, either breath hydrogen excretion or blood glucose can be measured following an orally administered test dose of lactose or sucrose. Determination of breath hydrogen excretion has virtually supplanted measurement of blood glucose when testing for lactase deficiency because of its simplicity and because no venipuncture is needed. If lactose is malabsorbed, it travels to the distal small intestine where the bacterial flora metabolize the sugar releasing hydrogen, which is excreted by the lungs and can be readily measured in the breath. After a test dose of 2 g/kg (25 g maximum), a rise of less than 10 parts per million (ppm) is normal, whereas a rise to 20 ppm suggests lactase deficiency. Limitations include impaired gastric emptying, chronic pulmonary disease, recent antibiotic usage, or absence of hydrogen-producing bacteria, all of which reduce breath hydrogen excretion, potentially giving rise to falsely negative results. On the other hand, proximal small bacterial overgrowth may result in a false-positive result, causing hydrogen release before the sugar can be normally absorbed. Disaccharidase enzyme levels can also be directly measured biochemically if fresh mucosal biopsy tissue is available for this purpose; however, this is rarely done in the clinical setting today. It is important to emphasize that neither oral absorption tests nor hydrogen breath tests, nor direct measurements of disaccharidase enzymes in mucosal tissues, distinguish primary enzyme deficiency from secondary enzyme deficiency caused by other disease processes that damage the epithelium mucosa of the small intestine.

Several substrates have been used in breath tests to screen for small intestinal intraluminal bacterial overgrowth. These include ¹⁴C-xylose, glucose, and lactulose. In all instances, the presence of bacteria in the proximal small intestine should result in rapid bacterial metabolism of the sugars and hence appearance in the breath of ¹⁴CO₂ after ¹⁴C-xylose and of hydrogen after glucose as well as early peak breath hydrogen levels after lactulose administration. Under normal circumstances, lactulose is not metabolized until it reaches the distal ileal and colonic flora, resulting in later peak hydrogen levels, whereas glucose and xylose are fully absorbed in the proximal intestine before there is opportunity for bacterial metabolism. All three tests have significant limitations. Delayed gastric emptying, rapid small intestinal transit, absence of hydrogen-producing colonic flora in those whose microbiota instead produce methane, and significant pulmonary disease all reduce sensitivity or specificity when compared with the gold standard for diagnosing intraluminal bacterial overgrowth, namely, quantitative culture of an aspirate of proximal jejunal intraluminal contents.

4. Imaging studies

Various imaging studies are available to help clarify the nature of pancreatic and hepatobiliary disease that may cause or contribute to intestinal malabsorption. These include endoscopic retrograde cholangiopancreatography (ERCP), magnetic resonance cholangiopancreatography (MRCP), abdominal computed tomography (CT), abdominal magnetic resonance imaging (MRI), and abdominal and endoscopic ultrasonography. They are discussed in some detail in Chapter 9 of this text.

For many years, conventional barium contrast studies of the small intestine were the standard for evaluating the gross structure of the small intestine in suspected or proven malabsorption. However, both sensitivity and specificity of the conventional small intestinal contrast series are low. Sensitivity, especially for detection of focal lesions, can be improved by utilizing double-contrast enteroclysis performed by instilling both barium and carboxymethyl cellulose into the duodenal lumen and fluoroscopically following the contrast material as it transits the small intestine. However, enteroclysis is labor intensive and results in substantial exposure of the patient to radiation. More recently, computed tomographic enterography (CTE), has become widely used for detecting small intestinal abnormalities. CTE is performed with administration of oral and intravenous contrast material. Both sagittal and cross-sectional images are obtained. MRI enterography provides similar information as CTE. Both techniques are useful, for example, in the detection of diffuse mucosal disease as well as focal abnormalities such as strictures and neoplasms, evaluation of bowel wall thickness, evaluation of visceral as well as mucosal blood flow, and assessing the length of remaining small intestine after major intestinal resections. MRI enterography has the distinct benefit of avoiding exposure to ionizing radiation, especially important in the evaluation of pregnant patients, pediatric patients and patients such as those with Crohn disease likely to require multiple studies over time,

5. Endoscopic and biopsy studies

Visualization of the mucosal surface of the small intestine within the reach of the endoscope allows the detection of abnormal gross mucosal surface features. These include the diminution and scalloping of mucosal folds, absence or apparent blunting of villi (common in celiac disease), and whitish-appearing dilated lymphatic lacteals within villi commonly found in Whipple disease and intestinal lymphangiectasia. However, both the sensitivity and specificity of such endoscopic findings are low. Rather, the greatest contribution of direct endoscopy to the evaluation of patients with malabsorption is its facilitation of mucosal biopsy under direct vision. As indicated in Table 20–4, some diseases, such as Whipple disease, amyloidosis, and giardiasis, are associated with a specific lesion, and biopsy is often diagnostic. Other diseases are characterized by histologic features that, although abnormal, lack specificity and require additional clinical information for a definitive diagnosis. However, even when the biopsy specimen is not in and of itself diagnostic, it is often of great value as it establishes unequivocally the presence of mucosal disease. The definitive diagnosis is then established by additional diagnostic studies or by a response to specific therapy.

Because intestinal malabsorption may occur in a number of diseases in which mucosal involvement may be patchy (see Table 20–4), multiple biopsy specimens (at least four, preferably six to eight) should be obtained from several sites in the duodenum or proximal jejunum. A biopsy or two should be obtained from the duodenal bulb as lesions consistent with celiac disease were observed only in the bulb in about 10% of celiacs in several recent studies. Samples of luminal fluid can also be obtained at the time of endoscopy, facilitating the diagnosis of parasitic infestation such as giardiasis and coccidioses and, if sophisticated culture facilities are available, intestinal intraluminal bacterial overgrowth.

Wireless capsule endoscopy using a swallowed camera that transmits color images of high quality of the mucosal surface as it tumbles through the gastrointestinal tract is a relatively new modality for imaging of the intestinal mucosa, including that of the mid and distal small intestine (see Chapter 34). It has been particularly useful in detecting focal lesions beyond the reach of the endoscope, especially among patients with gastrointestinal bleeding of previously unknown cause. Like direct endoscopy, it also provides useful views of the gross structure of the mucosa and detects the fold scalloping, flat mucosa, and distended lymphatic lacteals when these lesions are well developed. A limitation of capsule endoscopy is that it provides no tissue for pathologic evaluation. Hence, its role in the diagnosis of intestinal malabsorption is complementary to endoscopy and biopsy. The capsule camera may cause intestinal obstruction if tight strictures are present; hence, it must be used with caution in patients with suspected malignancy or suspected stricturing Crohn disease.

1. Pancreatic & Hepatobiliary Diseases

Delivery of adequate amounts of pancreatic lipase, colipase, proteases, and amylases as well as bicarbonate into the proximal intestine is essential for normal intraluminal digestion of dietary lipids, proteins, and complex carbohydrates. Pancreatic reserve is substantial, and significant malabsorption generally does not occur unless there is 85–90% reduction in pancreatic enzyme secretion. The diagnostic and clinical ramifications of chronic pancreatic insufficiency are discussed in detail in the chapters that deal with pancreatitis (see Chapter 26) and pancreatic neoplasms (see Chapter 29). As described earlier, determination of stool fat concentration (see Table 20–3

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