Assessment of Malabsorption1
John K. Dibaise
1Abbreviations: 7αHCO, 7α-hydroxy-4-cholesten-3-one; A1AT, α1-antitrypsin; CT, computed tomography; ePFT, endoscopic pancreatic function test; ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging; PABA, para-aminobenzoic acid; PLE, protein-losing enteropathy; 75SehCAT, selenium-75-homocholic acid taurine; SIBO, small intestinal bacterial overgrowth.
Disorders of malabsorption represent important clinical challenges to clinicians, both in terms of diagnosis and treatment. Malabsorptive conditions remain challenging diagnoses in part because although their clinical features may be identical, their underlying pathophysiologies and therefore treatments may be different. The normal processes of digestion and absorption involve numerous active components, including mechanical mixing and intestinal motility, digestive enzyme and bile acid production, mucosal function, blood supply, and the presence of the commensal gut microbiota. These components work together to allow the normal processing of nutrients that can be summarized into three major steps, which include (a) luminal and brush border digestion primarily by pancreatic and biliary secretions (digestion phase), (b) absorption into the intestinal mucosa to be processed and packaged (mucosal phase), and (c) transport into the vascular or lymphatic circulation (postabsorptive or distributive phase). (The details on the physiology of intestinal food and nutrient digestion and absorption are covered elsewhere in this textbook.) Importantly, malabsorption can result from defects in one or more of the three phases described. Although maldigestion and malabsorption are different pathogenetically, because the digestion and absorption of nutrients are tightly interconnected processes, a consideration of maldigestive and malabsorptive pathologies separately may be overly simplistic. As a consequence, the term “malabsorption” often is used clinically to denote derangements in both processes and is used in this manner throughout this chapter unless otherwise stated. The optimal approach to the diagnosis of malabsorption continues to evolve as new tests are developed. In the sections that follow, specific diagnostic tests are discussed and practical suggestions for the assessment of malabsorption are presented.
WHEN TO SUSPECT MALABSORPTION
The clinical presentation of malabsorption may vary tremendously from severe steatorrhea (bulky, foulsmelling, greasy stools) and weight loss, to gas-bloat and chronic diarrhea, to signs of micronutrient deficiencies, to an incidental asymptomatic abnormality on laboratory testing (Table 75.1). This wide spectrum exists because the clinical features of malabsorption depend on the underlying cause and severity of the malabsorptive process. It is important to recognize that the classical presentation of steatorrhea and weight loss despite an adequate dietary intake is uncommon generally, at least in industrialized countries. In contrast, most patients with malabsorption present with mild, nonspecific symptoms.
Gastrointestinal symptoms are the most common indicators seen in malabsorptive conditions; however, occasionally they may be absent or minimal. Although chronic diarrhea is the most common symptom prompting an evaluation of malabsorption, in the vast majority of cases it is not the result of malabsorption. In contrast, steatorrhea is a hallmark of malabsorption. Steatorrhea results from fat malabsorption, whereas watery diarrhea that occurs as a consequence of malabsorption may result
from the osmotic effects of malabsorbed carbohydrates or the secretory effects of malabsorbed bile acids. Increased gaseousness with excessive belching or flatulence and abdominal bloating and/or distention occurs commonly and typically results from the fermentation of malabsorbed carbohydrates by colonic microbiota. Although weight loss is prevalent in individuals with severe forms of malabsorption, those with less severe forms may not present with weight loss. The pattern of weight loss also may vary, with some individuals losing weight early on in the process with subsequent stabilization, and others with progressive weight loss. Abdominal pain, aside from cramping associated with defecation, is not a common complaint among those with malabsorption. Major exceptions include individuals with chronic pancreatitis or Crohn disease who have undergone multiple bowel resections. Nausea, emesis, borborygmi, and anorexia (or hyperphagia) also may be seen occasionally. In addition to the classic symptoms of steatorrhea noted, other characteristics of stool output should be noted, including typical volumes, number of stools per day, characteristics (e.g., watery, semiformed), presence of visible food, incontinence, and temporal characteristics (e.g., stool outputs in relation to meals).
from the osmotic effects of malabsorbed carbohydrates or the secretory effects of malabsorbed bile acids. Increased gaseousness with excessive belching or flatulence and abdominal bloating and/or distention occurs commonly and typically results from the fermentation of malabsorbed carbohydrates by colonic microbiota. Although weight loss is prevalent in individuals with severe forms of malabsorption, those with less severe forms may not present with weight loss. The pattern of weight loss also may vary, with some individuals losing weight early on in the process with subsequent stabilization, and others with progressive weight loss. Abdominal pain, aside from cramping associated with defecation, is not a common complaint among those with malabsorption. Major exceptions include individuals with chronic pancreatitis or Crohn disease who have undergone multiple bowel resections. Nausea, emesis, borborygmi, and anorexia (or hyperphagia) also may be seen occasionally. In addition to the classic symptoms of steatorrhea noted, other characteristics of stool output should be noted, including typical volumes, number of stools per day, characteristics (e.g., watery, semiformed), presence of visible food, incontinence, and temporal characteristics (e.g., stool outputs in relation to meals).
TABLE 75.1 SYMPTOMS AND LABORATORY EVALUATION OF SPECIFIC NUTRIENT MALABSORPTION | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Other nonspecific signs and symptoms that should prompt a consideration of the presence of a malabsorptive condition include easy bruising or bleeding, edema, hyporeflexia or hyperreflexia, bone pain, unexpected fractures, poor wound healing, paresthesias, tetany, and dysgeusia.
CLASSIFICATION AND DIAGNOSTIC APPROACH TO MALABSORPTION
Malabsorptive disorders may be classified on the basis of the deranged step in the digestive and/or absorptive process (i.e., luminal, mucosal, or postabsorptive), the macronutrient (i.e., carbohydrate, fat, or protein) or micronutrient (i.e., vitamin or trace element) affected, whether multiple nutrients or isolated nutrients are malabsorbed (i.e., global, partial, or selective), or on the basis of clinical manifestations (i.e., overt, subclinical, or asymptomatic). Although an intimate understanding of the normal digestive and absorptive processes is not absolutely necessary to allow a clinician to diagnose a malabsorptive syndrome, this knowledge allows a clinician to achieve a broader differential diagnosis and investigate suspected malabsorption in a more expeditious and, presumably, cost-effective manner (Table 75.2).
The diagnostic approach to malabsorption is twofold: (a) to confirm that malabsorption is present and (b) to determine its cause. Because sometimes the presence of malabsorption is readily apparent, the determination of its cause is the major issue. Frequently, the etiology of malabsorption may be determined from a detailed history and physical examination. Importantly, the history should
include information regarding timing of symptom onset; bowel habits and stool characteristics; presence of growth failure, delayed sexual maturation, and weight loss or gain; associated gastrointestinal and other systemic symptoms; presence of concomitant chronic systemic, gastrointestinal, pancreaticobiliary, or liver disorders; prior surgery to the gastrointestinal tract; history of radiation exposure to the gut; travel history; diet; prescription, alcohol, and illicit drug use; high-risk sexual behavior; and family history. Pertinent aspects on examination to identify include muscle wasting, skin rash/lesions, oral lesions, edema, abdominal distention, tenderness, and organomegaly and other potential signs of micronutrient deficiencies. Together with the history and examination, initial “routine” blood tests such as a complete blood count, chemistry panel, prothrombin time, magnesium, ferritin, folate, and vitamin B12 may provide evidence in support of the presence of malabsorption and further focus the investigative testing required to identify the specific malabsorptive process involved. Celiac serology also should be considered as a first-line diagnostic test in patients suspected of having malabsorption (see the chapter on celiac disease). Stool testing for occult blood and chronic infectious etiologies also should be considered at this stage.
include information regarding timing of symptom onset; bowel habits and stool characteristics; presence of growth failure, delayed sexual maturation, and weight loss or gain; associated gastrointestinal and other systemic symptoms; presence of concomitant chronic systemic, gastrointestinal, pancreaticobiliary, or liver disorders; prior surgery to the gastrointestinal tract; history of radiation exposure to the gut; travel history; diet; prescription, alcohol, and illicit drug use; high-risk sexual behavior; and family history. Pertinent aspects on examination to identify include muscle wasting, skin rash/lesions, oral lesions, edema, abdominal distention, tenderness, and organomegaly and other potential signs of micronutrient deficiencies. Together with the history and examination, initial “routine” blood tests such as a complete blood count, chemistry panel, prothrombin time, magnesium, ferritin, folate, and vitamin B12 may provide evidence in support of the presence of malabsorption and further focus the investigative testing required to identify the specific malabsorptive process involved. Celiac serology also should be considered as a first-line diagnostic test in patients suspected of having malabsorption (see the chapter on celiac disease). Stool testing for occult blood and chronic infectious etiologies also should be considered at this stage.
TABLE 75.2 CAUSES OF MALABSORPTION | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Various tests, both invasive and noninvasive, are available to determine the specific cause of malabsorption. When the history is suggestive of a particular cause, testing can be used to confirm the diagnosis; however, further testing may not be necessary when the presence of malabsorption and its cause are obvious. Clearly, both the sequence of testing and the specific test chosen should be based on both the circumstances and test availability.
FUNCTIONAL TESTS OF MALABSORPTION
Fat Malabsorption Studies
Fat malabsorption is most commonly determined by demonstrating fat in the stool; however, a serum test also is available to screen for fat malabsorption. Diminished serum levels of carotene suggest deficiency in the absorption of fat-soluble vitamins, but also could be related to dietary deficiency. Serum carotene levels have not been studied extensively in patients with malabsorptive conditions but levels typically are low in patients with steatorrhea (1). The sensitivity and specificity of this test compared with the gold standard fecal fat collection (see the following) remains to be determined.
The determination of fecal fat can be made both qualitatively and quantitatively. The advantages of qualitative approaches that make them more acceptable in clinical practice include their simplicity, lower cost, and less cumbersome collection methods. The main disadvantages include their lower sensitivity, reproducibility, and reliability, particularly for mild-to-moderate steatorrhea, making them useful only when positive (2). The most commonly used qualitative approach involves the application of a fat-soluble stain such as Sudan III to a microscope slide smeared with stool mixed with glacial acetic acid, which is then examined under a microscope for stained fat globules. It has been suggested that this technique can provide a semiquantitative assessment of fat excretion by determining both the number and size of the fat globules. Other qualitative techniques described include the acid steatocrit (3), an inexpensive, semiquantitative, gravimetric assay that uses an aliquot of centrifuged, homogenized stool to determine the percentage of fat; near-infrared reflectance analysis, which allows determination not only of fat excretion but also nitrogen and carbohydrate in a single sample (4); and the 14C- (or 13C)-triolein breath
test (5), which involves the measurement of breath CO2 following the ingestion of radiolabeled triolein, a triglyceride. Despite their simplicity and reportedly good test characteristics, none of these tests appears to be widely used in the United States.
test (5), which involves the measurement of breath CO2 following the ingestion of radiolabeled triolein, a triglyceride. Despite their simplicity and reportedly good test characteristics, none of these tests appears to be widely used in the United States.
In contrast, the quantitative approach is more reliable and remains the gold standard but is more complicated and expensive to perform and therefore often is reserved for use in situations in which other tests have provided conflicting results. A 72-hour stool collection period is recommended to reduce variability and allow a better estimation of daily stool weight. A shorter period may be reasonable when moderate-to-severe diarrhea is present. Ingestion of a diet with a known daily fat content (100 g/day often is used for convenience) is necessary for accurate stool fat determination. This requires patient instruction on the proper diet or a recording of all dietary intake during the stool collection from which the daily fat intake can be estimated. Furthermore, because often the ability to process and analyze (e.g., nuclear magnetic resonance spectroscopy, titrimetric, radioisotopic, spectrophotometric) the specimen is not available locally, these samples typically need to be sent to an outside reference laboratory. A normal fat excretion on a 100 g/day of dietary fat is less than 7 g/day; however, because fat excretion increases as stool weight increases, values of up to 14 g/day may result solely from large stool weight. Unfortunately, because of considerable overlap in values, quantitative fecal fat measurement generally is unable to discriminate among causes of steatorrhea. The quantitative fecal fat test often is not needed, because other methods are available to diagnose most relevant diseases of the pancreas, liver, and small bowel.
Carbohydrate Malabsorption Studies
Carbohydrate malabsorption generally occurs either as a part of a global malabsorptive process or as a selective defect usually localized to the epithelium. As mentioned, near-infrared reflectance analysis of the stool has been shown to be a reliable test of carbohydrate malabsorption (6). However, because the direct measurement of carbohydrate excretion in the stool is not considered to accurately measure small intestinal carbohydrate malabsorption, indirect tests generally are used. Indirect tests take advantage of the ability of colonic bacteria to metabolize malabsorbed carbohydrate, which can result in a decrease in stool pH, an increase in stool osmolality, and/or an increase in breath hydrogen or CO2 excretion following a carbohydrate load. A stool pH less than 5.5 and a stool osmolar gap [stool (sodium + potassium) × 2 − 280 mOsm/L] greater than 50 are characteristic of carbohydrate malabsorption, but although suggestive, are insufficiently sensitive or specific to confirm its presence.
Because carbohydrate malabsorption in the presence of a more global malabsorptive process is of lesser importance diagnostically, testing for carbohydrate malabsorption generally focuses on the detection of specific disaccharidase deficiencies. This can be accomplished by breath testing and oral tolerance testing. Although gene testing for lactase persistence has been described in both family and case-control studies, until its clinical role and cost effectiveness become more clear, its use is currently limited to research purposes in the United States (7).
Breath testing involves the oral ingestion of a specific carbohydrate solution (e.g., lactose, fructose, sucrose) followed by the serial collection and measurement of hydrogen in expired breath samples over a period of time. These substrates also may be labeled using radioactive (14C) or stable (13C) isotopes with subsequent measurement of breath CO2. Malabsorbed carbohydrate results in a rise in hydrogen levels of more than 10 to 20 ppm. Breath hydrogen testing may be affected by the presence of hydrogenscavenging methanogenic microorganisms resulting in a false-negative study. The concomitant assessment of breath methane may improve the accuracy of this test (8). Because these indirect tests rely on bacterial fermentation of malabsorbed carbohydrate, the concurrent use of antibiotics may affect the results. The impact of potent antisecretory agents (e.g., proton pump inhibitors) and probiotics remains less certain (9). Oral tolerance tests largely have been replaced by breath testing. In this procedure, the test sugar (most commonly lactose) is ingested and blood glucose concentrations are measured over time. An increase in glucose less than 20 mg/dL plus the development of symptoms is considered to be positive for malabsorption.
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