The function of the gastrointestinal (GI) tract is to perform certain mechanical and enzymatic procedures on food to prepare food for absorption, to absorb necessary dietary constituents into the bloodstream, and to excrete whatever is not absorbed. When the usual dietary constituents are not absorbed normally, symptoms may develop that form part of the syndrome known as malabsorption. There are three basic types of malabsorption. The first type involves the interruption of one of the stages in fat absorption; this concerns primarily fat absorption and also those substances dependent on the presence of lipid. The second type is related to intrinsic defect of the small bowel mucosa (category IV, A–D). In this kind of malabsorption there is interference not only with fat and fat-soluble substances but also with absorption of carbohydrates and many other materials. The third type of malabsorption is associated with altered bacterial flora (category IV, E) and also with the deficiency disease called “pernicious anemia.” In malabsorption of this kind, lack of a single specific substance normally produced by the GI tract leads to malabsorption of other substances dependent on that substance for absorption. Some of these conditions and their laboratory diagnosis are discussed in detail elsewhere.

Clinical findings. Steatorrhea, or the appearance of excess quantities of fat in the stool, is a frequent manifestation of most malabsorption syndromes. Many patients with steatorrhea also have diarrhea, but the two are not synonymous; a patient can have steatorrhea without diarrhea. On the other hand, some reports indicate that moderate or severe diarrhea can induce some degree of steatorrhea in about 20%-50% of patients. In children, the principal diseases associated with steatorrhea and malabsorption are celiac disease and cystic fibrosis of the pancreas. In adults, the most common causes are tropical sprue, nontropical sprue (the adult form of celiac disease), and pancreatic insufficiency. The clinical picture of all these diseases is roughly similar but varies according to etiology, severity, and duration. The most common chief complaints in severe malabsorption are diarrhea and weakness, weight loss, and mild functional GI complaints (anorexia, nausea, mild abdominal pain). Physical findings and laboratory test results tend to differ with the various etiologies. In severe cases of sprue, tetany, bone pain, tongue surface atrophy, and even bleeding may be found. Physical examination may show abdominal distention and also peripheral edema in nearly half the patients. In pancreatic insufficiency, physical examination may be normal or show malnutrition. Neurologic symptoms are found with moderate frequency in pernicious anemia but may be present in malabsorption of other causes as well.

Laboratory findings. Laboratory test findings vary according to severity and etiology of the malabsorption, but in sprue they most often include one or more of the following: anemia, steatorrhea, hypoproteinemia, hypocalcemia, and hypoprothrombinemia. In pancreatic insufficiency, the main laboratory test abnormalities are steatorrhea and decreased carbohydrate tolerance (sometimes overt diabetes). In pernicious anemia the patient has only anemia without diarrhea, steatorrhea, or the other test abnormalities previously listed. Most stomach operations do not cause diarrhea or abnormalities of fat absorption.

Steatorrhea is caused by excess excretion of fat in the stools due to inability to absorb lipids. Anemia associated with steatorrhea is most often macrocytic but sometimes is caused by iron deficiency or is a mixed type due to various degrees of deficiency of folic acid, vitamin B12, and iron. Calcium may be decreased both from GI loss due to diarrhea and from artifact due to hypoalbuminemia. Prothrombin formation by the liver is often impaired to some degree because of lack of vitamin K. Vitamin K is a fat-soluble vitamin that is obtained from food and also is produced by bacteria in the small bowel. Long-term oral antibiotic use may reduce the bacterial flora by killing these bacteria and thus may interfere with vitamin K formation. Inability to absorb fat secondarily prevents vitamin K and vitamin A, which are dependent on fat solubility for intestinal absorption, from entering the bloodstream. Malnutrition resulting from lack of fat and carbohydrate absorption leads to hypoalbuminemia because of decreased production of albumin by the liver. This also contributes to the peripheral edema that many patients develop.

Classification of Malabsorptive Disorders (With Comments on Occurrence and Associated Abnormalities)

I. Inadequate mixing of food with bile salts and lipase. Mild chemical steatorrhea common, but clinical steatorrhea uncommon. Actual diarrhea uncommon. Anemia in approximately 15%-35%; most often iron deficiency, rarely megaloblastic.
A. Pyloroplasty
B. Subtotal and total gastrectomy (occasional megaloblastic anemias reported)
C. Gastrojejunostomy
II. Inadequate lipolysis — lack of lipase or normal stimulation of pancreatic secretion. Steatorrhea only in far-advanced pancreatic destruction, and diarrhea even less often.
A. Cystic fibrosis of the pancreas
B. Chronic pancreatitis
C. Cancer of the pancreas or ampulla of Vater
D. Pancreatic fistula
E. Severe protein deficiency
F. Vagus nerve section
III. Inadequate emulsification of fat — lack of bile salts. Clinical steatorrhea uncommon, sometimes occurs in very severe cases. Usually no diarrhea.
A. Obstructive jaundice
B. Severe liver disease
IV. Primary absorptive defect—small bowel.
A. Inadequate length of normal absorptive surface; unusual complication of surgery
1. Surgical resection
2. Internal fistula
3. Gastroileostomy
B. Obstruction of mesenteric lymphatics (rare)
1. Lymphoma
2. Hodgkin’s disease
3. Carcinoma
4. Whipple’s disease
5. Intestinal tuberculosis
C. Inadequate absorptive surface due to extensive mucosal disease; except for Giardia infection and regional enteritis, most of these diseases are uncommon; steatorrhea only if there is extensive bowel involvement
1. Inflammatory
a. Tuberculosis
b. Regional enteritis or enterocolitis (diarrhea very common)
c. Giardia lamblia infection (diarrhea common; malabsorption rare)
2. Neoplastic
3. Amyloid disease
4. Scleroderma
5. Pseudomembranous enterocolitis (diarrhea frequent)
6. Radiation injury
7. Pneumatosis cystoides intestinalis.
D. Biochemical dysfunction of mucosal cells
1. “Gluten-induced” (steatorrhea and diarrhea very common)
a. Celiac disease (childhood)
b. Nontropical sprue (adult)
2. Enzymatic defect
a. Disaccharide malabsorption (diarrhea frequent symptom)
b. Pernicious anemia (deficiency of gastric “intrinsic factor”)
3. Cause unknown; uncommon except for tropical sprue (which is common only in the tropics)
a. Tropical sprue (diarrhea and steatorrhea common)
b. Severe starvation
c. Diabetic visceral neuropathy
d. Endocrine and metabolic disorder (e.g., hypothyroidism)
e. Zollinger-Ellison syndrome (diarrhea common; steatorrhea may be present)
f. Miscellaneous
V. Malabsorption associated with altered bacterial flora (diarrhea fairly common)
1. Small intestinal blind loops, diverticula, anastomoses (rare)
2. Drug (oral antibiotic) administration (infrequent but not rare)

The majority of patients with malabsorption usually present in one of two ways. In the first group the major finding on admission is anemia, and once malabsorption is suspected, either by the finding of megaloblastic bone marrow changes or by other symptoms or signs suggestive of malabsorption, the problem becomes one of differentiating pernicious anemia from other types of malabsorption. In the second group, the patients present with one or more clinical symptoms of malabsorption, either mild or marked in severity. The diagnosis must be firmly established and the etiology investigated. There are several basic tests for malabsorption which, if used appropriately, usually can lead to the diagnosis and in some cases reveal the cause.

Useful individual laboratory tests

Qualitative fecal fat. Fat in the feces can be stained with Sudan III dye. Neutral fat can be seen as bright orange droplets, but the fatty acids normally do not stain. Both these fatty acids and the original neutral fat can be converted to stainable fatty acids by heat and acid hydrolysis. The preparation is then stained and examined a second time to determine if the number of droplets has increased from the first examination. The reliability of this procedure is debated in the literature, but it is reported to be reasonably accurate if the technician is experienced. However, it is sometimes difficult to be certain whether Sudan-positive droplets are fat or some other substance. Naturally, there will be difficulty in distinguishing normal results from low-grade steatorrhea. It is possible to get some idea of etiology by estimating the amount of neutral fat versus fatty acid: lack of fatty acid suggests pancreatic disease.

Quantitative fecal fat. The basic diagnostic test for steatorrhea is quantitative fecal fat. Stool collections are taken over a minimum of 3 full days. The patient should be on a diet containing approximately 50-150 gm/day of fat (average 100 gm/day) beginning 2 days before the test collection. It is necessary to make sure that the patient is actually eating enough of this diet to take in at least 50 gm of fat/day; it is also obviously important to make sure that all the stools are collected and the patient is not incontinent of feces. Patient noncompliance with complete stool collection is probably the most common cause of false negative results. If the patient is constipated (and some are), it may be necessary to use a bedtime laxative. Normal diet results in an average excretion of less than 7 gm of fat/24 hours. Excretion of 5-7 gm/24 hours is equivocal, since many patients with minimal steatorrhea and a small but significant percentage of normal persons have excretion in this range. There are some reports that 24-hour fecal fat excretion less than 9.5 gm/100 gm of stool favors nontropical sprue and celiac disease, whereas excretion greater than 9.5 gm/100 gm of stool favors pancreatic insufficiency, bacterial overgrowth, or biliary tract disease. Finally, some patients with partial or complete malabsorption syndromes may have normal fecal fat excretion. This is most common in tropical sprue.

Plasma carotene. Carotene is the fat-soluble precursor of vitamin A and is adequately present in most normal diets that contain green or yellow vegetables. Normal values are considered 70-300 µg/100 ml (1.3-5.6 µmol/L). Values of 30-70 µg/100 ml are usually considered moderately decreased, and levels less than 30 µg/100 ml (0.56 µmol/L) indicate severe depletion. Other causes of low plasma carotene, besides malabsorption, are poor diet, severe liver disease, and high fever. There is considerable overlap between the carotene values of malabsorption and the carotene values in normal control patients, but such overlap usually is over the 30-µg level. However, this test is valuable mostly as a screening procedure. The patient must be eating a sufficient quantity of carotene-rich food to draw valid conclusions from a low test result.

X-ray examination. A small bowel series is done by letting barium pass into the small intestine. There are several changes in the normal radiologic appearance of the small bowel that are suggestive of malabsorption. These changes appear in 70%-90% of patients, depending on the etiology and severity of the disease and the interpretative skill of the investigator. The radiologic literature agrees that many chronic diseases, especially when associated with fever and cachexia, may interfere with digestion so severely as to produce a pattern that may be confused with sprue. Secondary malabsorption cannot be distinguished from primary malabsorption except in certain rare cases such as tumor. The so-called diagnostic patterns of sprue are thus characteristic of, but not specific for, primary small intestine absorption and are not present in about 20% of patients.

Schilling test. This is the classic test for vitamin B12 malabsorption, since it can differentiate pernicious anemia from other malabsorption etiologies affecting the terminal ileum where B12 is absorbed. This is discussed in Chapter 3.

D-xylose test. Besides quantitative (fecal) fat studies, the most important test for malabsorption is the D-xylose test. Rather than a screening test for malabsorption per se, it is a test that identifies the sprue-type diseases and differentiates them from other malabsorption etiologies. Originally, an oral glucose tolerance test (OGTT) was used in malabsorption, since it was found that most patients with sprue showed a flat curve. A “flat” OGTT is usually defined as an OGTT peak with a value no greater than 25 mg/100 ml (1.4 mmol/L) above the baseline fasting level, although there is some disagreement about this criterion. However, some patients with obvious malabsorption have a normal curve, and it was also found in several large series that up to 20% of apparently normal persons had a flat curve, so this test was abandoned.

Test protocol. D-xylose is a pentose isomer that is absorbed in much the same manner as glucose from the jejunum. The standard test dose is 25 gm of D-xylose in 250 ml of water, followed by another 250 ml of water. The patient is fasted overnight, since xylose absorption is delayed by other food. After the test dose, the patient is kept in bed for 5 hours without food. The normal person’s peak D-xylose blood levels are reached in approximately 2 hours and fall to fasting levels in approximately 5 hours. D-xylose is excreted mostly in the urine with approximately 80%-95% of the excretion in the first 5 hours and the remainder in 24 hours. Side effects of oral D -xylose administration are mild diarrhea and abdominal discomfort in a small number of patients.

Interpretation. Normal values for (2-hour) blood D-xylose levels are more than 25 mg/100 ml (1.66 mmol/L); values of 20-25 mg/100 ml are equivocal, and values less than 20 mg/100 ml (1.33 mmol/L) are strongly suggestive of malabsorption. The 5-hour urinary D-xylose normal values are more than 5 gm/5 hours. It is obviously very important to make sure that urine collection is complete and that there is no fecal contamination of the urine. A catheter may have to be used if the patient is incontinent of urine or if there is a question of fecal contamination, but catheterization should be avoided if at all possible. Two main physiologic circumstances may affect the 5-hour urinary excretion: renal insufficiency and advanced age. There may be abnormally low 5-hour urinary excretion of D-xylose in persons over age 65. However, one study claims that the 24-hour urine collection is normal (also >5 gm) unless actual malabsorption is present. If the serum creatinine level is borderline or elevated, the 5-hour urinary D -xylose excretion is also likely to be abnormally low, and again the 24-hour excretion may be useful. In these cases, however, the 2-hour blood levels may help, because they should be normal and are not affected by age or renal insufficiency. Otherwise, the 5-hour urinary excretion is more reliable than the blood levels, which tend to fluctuate.

Clinical correlation. The D-xylose test may be helpful in determining if the patient has malabsorption and also provides some clues as to etiology. Most patients with cystic fibrosis and pancreatic insufficiency are said to have normal urinary D-xylose values. This is also true of most patients with liver disease. Patients with classic pernicious anemia have normal D-xylose test results, although it must be remembered that many of these patients are aged and for that reason may have low 5-hour urine results. Some patients with megaloblastic anemia of pregnancy have abnormal D-xylose test results, although probably the majority have normal values. A small percentage of patients with partial gastrectomy reportedly have abnormal urine values. Patients with functional diarrhea and duodenal ulcer have normal results.

In malabsorption diseases, there is excellent correlation of D-xylose excretion with proved sprue and celiac disease. The urine results are more often clear-cut than the blood levels. There is no correlation with the degree of steatorrhea. Patients with regional enteritis involving extensive areas of the jejunum may have abnormal results, whereas normal results are associated with this disease when it is localized to the ileum. Patients with Whipple’s disease, “blind loop” syndrome (isolated small intestine area of bacterial overgrowth), postgastrectomy, small intestine lymphoma, multiple jejunal diverticula, and some infants with cow’s milk allergy may also have abnormal results. Certain patients with diseases other than classic malabsorption may have an abnormal D-xylose test result. These diseases include myxedema, diabetic neuropathic diarrhea, rheumatoid arthritis, acute or chronic alcoholism, and occasionally severe congestive heart failure. Ascites is reported to produce abnormal urine excretion with normal plasma levels. Although D-xylose excretion is frequently depressed in myxedema, abnormal test results occur in only a small number of patients with the other conditions listed. Some of these conditions can produce decreased absorption of substances other than D-xylose, although such problems are usually mild or moderate in degree and may be due to multiple factors.

D-xylose tests thus may be abnormal in diseases other than sprue. In nontropical sprue, about 10% of untreated patients have normal D-xylose 5-hour urine test results (literature range, 0%-40%). There is also sufficient overlap in the urine excretion range of 4-5 gm/5 hours from persons without primary small intestine malabsorption to warrant routine collection of a 19-hour urine specimen immediately following the 5-hour specimen (to have a total of 24 hours, if necessary). Several studies found better results in children less than 12 years old using a 5-g oral dose of D-xylose and obtaining a serum specimen (no urine specimen) 1 hour after D-xylose administration. The lower limit of serum reference range was 20 mg/100 ml.

Hydrogen breath test. An oral test dose of a specific carbohydrate is administered. If the carbohydrate is not absorbed normally in the small intestine, it reaches the colon, where bacteria metabolize the carbohydrate and release various metabolic products, among which is hydrogen gas. About 15%-20% of the hydrogen is absorbed and then released from the lungs in expired air. Expired air is collected in a single-breath collection bag or other apparatus and analyzed for hydrogen content by some variant of gas chromatography. This technique has been used to test for various types of malabsorption. It has proved most useful in diagnosis of deficiency involving the enzyme lactase, small intestine “blind loop” syndrome, and some cases of rapid intestine transit (“intestinal hurry syndrome”). In the case of the blind loop syndrome or rapid transit, the test dose consists of a carbohydrate that normally is not absorbed. The hydrogen breath test has not proved reliable in diagnosis of sprue or glutin-associated malabsorption.

There are various conditions that interfere with the test. Recent use of antibiotics can affect the bacterial flora, sometimes when discontinued as long as 2 weeks before the test. Use of colon enemas can partially wash out some of the flora. Delayed or unusually swift gastric emptying can change the quantity of the carbohydrate or the time that it reaches the colon. Breath collected during sleep contains 2-3 times the amount of hydrogen obtained when the patient is awake. Cigarette smoking produces large amounts of hydrogen. Finally, the collection apparatus and the analysis equipment are relatively expensive, and the test is usually available only in larger institutions or medical centers.

Small intestine biopsy. In classic sprue, both tropical and nontropical, the mucosa of the small intestine shows characteristic histologic abnormalities. Instead of the normal monotonous fingerlike villous pattern, the villi are thickened and blunted, with flattening of the cuboidal epithelium, and the villi may eventually fuse or disappear altogether. Depending on the degree of change in the villi, biopsy results may show moderate or severe changes. These same changes may be found to a much lesser degree in many of the other conditions causing malabsorption, including even subtotal gastrectomy. However, these usually are not of the severity seen in sprue and generally can be differentiated by the clinical history or other findings. Other causes of malabsorption, such as the rare Whipple’s disease (which characteristically shows many periodic acid-Schiff-positive macrophages in the mucosa) may be detected on biopsy. In infants less than 1 year of age, transient small intestinal mucosal abnormalities similar to those of sprue have been reported in some patients with acute gastroenteritis and in some with cow’s milk allergy. Eosinophilic gastroenteritis is another cause in older children.