2465 Disorders of Absorption CHAPTER 325

response to antibiotics are seen compared with some other locations.

Tropical sprue in different areas of the world may not be the same disease, and similar clinical entities may have different etiologies.

Diagnosis The diagnosis of tropical sprue is based on an abnormal

small-intestinal mucosal biopsy in an individual with chronic diarrhea

and evidence of malabsorption who is either residing or has recently

lived in a tropical country. The small-intestinal biopsy in tropical sprue

does not reveal pathognomonic features but resembles, and can often

be indistinguishable from, that seen in celiac disease (Fig. 325-4). The

biopsy sample in tropical sprue has less villous architectural alteration

and more mononuclear cell infiltrate in the lamina propria. In contrast

to those of celiac disease, the histologic features of tropical sprue manifest with a similar degree of severity throughout the small intestine,

and a gluten-free diet does not result in either clinical or histologic

improvement in tropical sprue.

TREATMENT

Tropical Sprue

Broad-spectrum antibiotics and folic acid are most often curative,

especially if the patient leaves the tropical area and does not return.

Tetracycline should be used for up to 6 months and may be associated with improvement within 1–2 weeks. Folic acid alone induces

hematologic remission as well as improvement in appetite, weight

gain, and some morphologic changes in small-intestinal biopsy.

Because of marked folate deficiency, folic acid is most often given

together with antibiotics.

SHORT-BOWEL SYNDROME

■ OVERVIEW

Short-bowel syndrome results from intestinal resection to treat a multitude of disorders including Crohn’s disease, vascular diseases such

as mesenteric arterial or venous thrombosis resulting in intestinal

ischemia, volvulus, trauma, internal herniation, radiation enteritis,

and diffuse carcinoma, among others. In children, the most common

causes of short-bowel syndrome are necrotizing enterocolitis, intestinal

atresias, volvulus, and malrotation. Short-bowel syndrome is defined

as extensive removal of small intestine resulting in <200 cm remaining small bowel. Intestinal failure is functionally defined as persistent

parenteral nutrition dependence, generally found in patients who have

<100 cm of remaining small bowel and no residual colon in continuity.

Clinical Features Loss of small-bowel surface area in short-bowel

syndrome results in severe diarrhea, weight loss, and malabsorption

of multiple nutrients, including fat, protein, and carbohydrate. The

severity of symptoms and ultimate dependence on parenteral nutrition

are generally related to the extent of resection, presence or absence

of residual colon in continuity, retention of the ileocecal valve, and

FIGURE 325-4 Small-intestinal mucosal biopsies. A. Normal individual. B. Untreated celiac disease. C. Treated celiac disease. D. Intestinal lymphangiectasia. E. Whipple’s

disease. F. Lymphoma. G. Giardiasis. (Courtesy of Marie Robert, MD, Yale University; with permission.)

2466 PART 10 Disorders of the Gastrointestinal System

severity of the underlying disease. The intestine has a remarkable

capacity to adapt to loss of small-bowel surface area, but this adaptive

process is variable from patient to patient. Following resection, the

adapting residual intestine exhibits an increase in crypt cell proliferation resulting in epithelial hyperplasia. The adaptive process generally

continues for up to 2 years post resection, but improvements in nutrient, fluid, and electrolyte absorptive capacity have been reported even

as late as 3–5 years after surgery. Massive diarrhea generally occurs in

the first three postoperative months, associated with increased gastric

acid secretion and malabsorption. Gradually, patients show enhanced

functional capacity and reduced diarrhea. Specific nutrient deficiencies are dependent upon which segment of gut has been removed. For

example, resection of the ileum results in loss of B12 absorptive and bile

salt reabsorptive capacity. Malabsorbed bile salts reach the colon and

cause a secretory diarrhea. In addition, resection of >100 cm of ileum

results in such severe bile salt malabsorption that the liver cannot

compensate by increased synthesis, thus precipitating fat malabsorption due to bile salt insufficiency/deficiency. Substantial resection of

the colon also results in fluid and electrolyte loss and imbalance. The

colon also plays a role in nutrient absorption because it metabolizes

malabsorbed carbohydrate into short-chain fatty acids that can be

absorbed by the colon and can contribute several hundred additional

calories per day.

Long-Term Complications Because massive resection often leads

to severe fat malabsorption, fat-soluble vitamin deficiency is common,

and vitamin D deficiency can be very difficult to treat even with highdose oral vitamin D supplementation, resulting in an increased risk of

osteoporosis. Patients with a history of multiple surgeries often have

extensive adhesive disease, and the residual intestine may have markedly abnormal motility or areas of structuring and narrowing, resulting

in recurrent bacterial overgrowth. The frequency of renal calcium

oxalate stones increases in patients with a shortened small bowel with

an intact colon in continuity; calcium is saponified in the intestinal

luminal contents that contain fatty acids, freeing oxalate to be absorbed

in the colon resulting in hyperoxaluria.

Treatment The major focus of treatment for short-bowel syndrome

is to control diarrhea and normalize nutrient, fluid, and electrolyte

absorption so that patients can maintain their weight and have a

healthy nutritional status without the support of parenteral nutrition.

Medications include opiates and derivatives including loperamide

and diphenoxylate-atropine, which slow intestinal motility to allow

for more contact time between luminal nutrients and the small-bowel

mucosal surface. In the first year following resection, acid-blocking

medications are used to treat gastric hypersecretion, including proton

pump inhibitors or histamine 2 antagonists. Small-bowel bacterial

overgrowth is common and is treated with antibiotics if suspected. The

only medication that is specific for short-bowel syndrome but limited

for use in parenteral nutrition or intravenous fluid–dependent patients

is teduglutide, a glucagon-like 2 peptide analog that enhances crypt cell

proliferation and villus hyperplasia, and increases nutrient and fluid

and electrolyte absorption. Patients treated with teduglutide have an

average reduction of 20% of their parenteral nutrition requirements.

Greater efficacy has been noted for patients without a residual colon,

likely due to lower circulating endogenous GLP-2 levels compared to

those with a colon in continuity.

Dietary Therapy Patients with short-bowel syndrome must consume three to four times their normal caloric intake to maintain their

weight. The presence of luminal nutrients is required for the adaptive

process to occur, so early feeding is recommended, even if parenteral

nutrition is also required. These effects are most likely mediated by

direct contact with the mucosa as well as stimulation of secretion of gut

hormones such as glucagon-like 2.

If the patient has all or part of their colon remaining in continuity,

a low-fat diet is instituted to reduce the concentration of malabsorbed

fatty acids that induce a secretory diarrhea. High complex carbohydrates are encouraged because when malabsorbed and present in the

colon, they are converted to short-chain fatty acids and are absorbed,

contributing several hundred additional kilocalories per day. All

patients are asked to take a high-potency multivitamin on a daily basis.

Patients in whom oral nutrition fails are fed with parenteral nutrition.

Monitoring SBS patients are at high risk for osteoporosis due to

dietary calcium and vitamin D malabsorption, so they are periodically

monitored for vitamin D deficiency and calcium levels and with DEXA

studies to assess bone density. Malabsorption of vitamins and minerals is common; therefore, fat-soluble vitamins, vitamin B12, folic acid,

iron, magnesium, and zinc are monitored periodically. More unusual

deficiencies include copper, selenium and chromium, but these are

usually in PN-dependent patients and can be corrected by adjusting

daily intravenous dosages. Signs and symptoms of vitamin and mineral

deficiency are also carefully monitored (hair loss, skin and nail changes,

neurologic symptoms such as peripheral neuropathy, etc.).

■ DISORDERS OF POST-MUCOSAL ABSORPTION

Following uptake into enterocytes, nutrients are further processed and

transported into the lymphatics or into the portal circulation for use

by other cells throughout the body. Primary or secondary disorders

of the lymphatics may result in significant diarrhea and malabsorption. Primary disorders of the intestinal lymphatics include intestinal

lymphangiectasia, which may be congenital or acquired. Secondary

causes of intestinal lymphatic damage or blockage include retroperitoneal fibrosis, fibrosing mesenteritis, and lymphoma. Circulatory causes

of impaired delivery of nutrients from the intestine include Fontan

physiology, congestive heart failure, and constrictive pericarditis. The

end result of damage to lymphatic channels is malabsorption and diarrhea with concomitant protein-losing enteropathy.

PROTEIN-LOSING ENTEROPATHY

Protein-losing enteropathy refers to a large group of GI and non-GI

disorders characterized by hypoproteinemia and edema in the absence

of liver disease with reduced protein synthesis, or kidney disease with

proteinuria. These diseases are characterized by excess protein loss in

the GI tract. Diseases that may result in increased protein loss into the

GI tract can be classified into three groups: (1) mucosal ulceration,

such that the protein loss primarily represents exudation across damaged mucosa (e.g., ulcerative colitis, GI carcinomas); (2) nonulcerated

mucosa, but with evidence of mucosal damage so that the protein

loss represents loss across epithelia with altered permeability (e.g.,

celiac disease and Ménétrier’s disease [hypertrophic gastropathy] in

the small intestine and stomach, respectively); and (3) lymphatic dysfunction, representing either primary lymphatic disease or lymphatic

disease secondary to partial lymphatic obstruction that may occur

as a result of enlarged lymph nodes or cardiac disease. These result in

increased lymphatic pressure causing exudation of protein into the GI

tract lumen.

Diagnosis The diagnosis of protein-losing enteropathy is suggested

by diarrhea, peripheral edema, and low serum albumin and globulin

levels in the absence of renal and hepatic disease. An individual with

protein-losing enteropathy rarely has selective loss of only albumin or

only globulins. Therefore, marked reduction of serum albumin with

normal serum globulins should suggest renal and/or hepatic disease.

Likewise, reduced serum globulins with normal serum albumin levels are more likely a result of reduced globulin synthesis rather than

enhanced globulin loss into the intestine. Alpha-1 antitrypsin, a protein that accounts for ~4% of total serum proteins and is resistant to

proteolysis, can be used to detect enhanced rates of serum protein loss

into the intestinal tract but cannot be used to assess gastric protein loss

because of its degradation in an acid milieu. Alpha-1 antitrypsin can

be measured in a spot or 24-h stool collection and if elevated, is diagnostic. A more accurate determination is alpha-1 antitrypsin clearance,

measured by determining stool volume as well as both stool and plasma

alpha-1 antitrypsin concentrations. In addition to the loss of protein

via abnormal and distended lymphatics, peripheral lymphocytes may

be lost via lymphatics, with consequent relative lymphopenia and

specifically loss of CD3+ T cells. Thus, lymphopenia in a patient with

hypoproteinemia indicates increased loss of protein into the GI tract.

2467 Disorders of Absorption CHAPTER 325

Patients with increased protein loss into the GI tract from lymphatic

obstruction often have steatorrhea and diarrhea. The steatorrhea is a

result of altered lymphatic flow as lipid-containing chylomicrons exit

from intestinal epithelial cells via intestinal lymphatics (Table 325-2;

Fig. 325-4). In the absence of mechanical or anatomic lymphatic

obstruction, intrinsic intestinal lymphatic dysfunction—with or without lymphatic dysfunction in the peripheral extremities—has been designated intestinal lymphangiectasia. Similarly, ~50% of individuals with

intrinsic peripheral lymphatic disease (Milroy’s disease) also have intestinal lymphangiectasia and hypoproteinemia. Other than steatorrhea

and enhanced protein loss into the GI tract, all other aspects of intestinal absorptive function are normal in intestinal lymphangiectasia.

Endoscopy and Imaging Endoscopy with biopsy and video

capsule endoscopy may be performed to rule out mucosal disease.

Magnetic resonance enterography may be helpful in children with

lymphangiectasia.

Other Causes Patients who have idiopathic protein-losing enteropathy without evidence of GI disease should be examined for cardiac disease. As more patients with congenital heart disease reach

adulthood, Fontan physiology has become a more common cause of

protein-losing enteropathy. Other cardiac causes include right-sided

valvular disease and chronic pericarditis (Chaps. 268 and 270).

Ménétrier’s disease (also called hypertrophic gastropathy) is an uncommon entity that involves the body and fundus of the stomach and is

characterized by large gastric folds, reduced gastric acid secretion, and,

at times, enhanced protein loss into the stomach.

TREATMENT

Protein-Losing Enteropathy

As excess protein loss into the GI tract is most often secondary to

a specific disease, treatment should be directed primarily to the

underlying disease process and not to the hypoproteinemia. When

enhanced protein loss is secondary to lymphatic obstruction, it is

critical to establish the nature of this obstruction. Identification of

mesenteric nodes or lymphoma may be possible by imaging studies.

Similarly, it is important to exclude cardiac disease as a cause of

protein-losing enteropathy. Patients with congenital heart disease

may be examined by intranodal lymphangiography or noncontrast

magnetic resonance lymphangiography, and may undergo surgical

lymphatic interventions to decompress the lymphatic system or to

target exclusion of abnormal lymphatic channels.

The increased protein loss that occurs in intestinal lymphangiectasia is a result of distended lymphatics associated with lipid

malabsorption. The hypoproteinemia is treated with a low-fat,

high-protein diet and the administration of medium-chain triglycerides, which do not exit from the intestinal epithelial cells via

lymphatics but are delivered to the body via the portal vein. Other

medical therapies including octreotide, a somatostatin analog,

intravenous heparin, and budesonide have been studied but have

generally been ineffective.

APPROACH TO THE PATIENT

Evaluation of the Patient with Suspected

Malabsorption

The evaluation of patients with malabsorption is often challenging

due to the large number of underlying disorders and the wide array

of available tests. Thus an extensive history and careful physical

examination are essential to develop a more limited differential

diagnosis, and thereby avoid extensive and unnecessary testing.

HISTORY

A careful history should include questions about symptoms

including abdominal pain, diarrhea, weight loss, bloating,

symptoms or signs of selective nutrient deficiency including

iron deficiency anemia, bone fracture, or osteoporosis suggesting vitamin D and/or calcium deficiency, peripheral neuropathy

resulting from vitamin B12 deficiency, hair loss that may result

from generalized protein deficiency, predisposing disorders such

as chronic pancreatitis or liver disease particularly involving the

bile ducts such as primary biliary cholangitis or primary sclerosing cholangitis, history of small-bowel resection (due to Crohn’s

disease, trauma, ischemic bowel disease, etc.), and travel history. A

multitude of nonspecific symptoms such as fatigue and weakness

may also be reported. The protean manifestations of malabsorption

and the underlying pathophysiology of clinical manifestations are

summarized in Table 325-5.

PHYSICAL EXAMINATION

A careful physical examination may provide clues to underlying

nutrient deficiencies and help assess severity of the malabsorptive

process. For example, evidence of significant weight loss may be

detected by bitemporal wasting and reduced arm circumference,

iron deficiency may cause nail spooning, and vitamin B12 deficiency

may result in significant peripheral neuropathy resulting in sensory

reduction with tingling or numbness.

LABORATORY EXAMINATION (TABLE 325-6)

Diseases that exclusively affect the proximal small intestine

(e.g., celiac disease limited to the duodenum) may result in

iron-deficiency anemia. Resection or disease of the terminal ileum

frequently results in B12 deficiency since B12 absorption occurs

exclusively in the ileum, causing a macrocytic anemia. Disorders

that cause steatorrhea are almost invariably associated with fatsoluble vitamin deficiency, specifically vitamin D (very common),

vitamin E, vitamin A, and vitamin K. The functional result of

vitamin K deficiency is an elevated prothrombin time/international

normalized ratio (INR) so this blood test is frequently measured

instead of vitamin K levels. Serum carotene levels can suggest fat

malabsorption but may decrease simply due to poor dietary consumption of leafy vegetables.

To diagnose steatorrhea, a spot stool can be submitted for Sudan

III staining, which is specific for fecal fat. This is a useful qualitative

but not quantitative test. Stool for elastase is helpful for diagnosing

pancreatic insufficiency. A 24-h assessment of stool volume/weight

may useful to establish the presence of clinically significant absorptive or secretory diarrhea vs diarrhea from other causes such as

proctitis, which causes frequent, small, low-volume stools. The gold

standard for documenting steatorrhea is the 72-h fecal fat collection, which is performed in concert with the patient’s consumption

of a 100-g fat diet. This test is highly accurate but difficult to obtain

due to patient reluctance to collect stool. Also patients with fat malabsorption may poorly tolerate a 100-g fat diet. A diet with strictly

quantified albeit reduced fat calories may be substituted. Finally,

the calculation of the stool osmotic gap is a very useful and easy

way to diagnose an osmotic diarrhea. A spot stool sample is sent

to the lab for quantitation of fecal sodium and potassium concentration. Although stool osmolality can also be measured in the lab,

measurements are often inaccurate due to bacterial degradation of

nonabsorbed carbohydrate as the stool sits prior to examination.

Because normal stool osmolality reflects serum osmolality at 290

mOsm/kg H2O, the osmotic gap may be calculated as follows:

290 – 2 (stool [Na+] + stool [K+]).

If >50–100, a stool osmotic gap is present indicating the presence of unmeasured osmoles (e.g., malabsorbed lactose), and

osmotic diarrhea can be diagnosed. If <50, one can presume a

secretory component. Of note, malabsorbed fatty acids may also

cause a secretory diarrhea by inducing secretion in the colon, so

a malabsorptive diarrhea may have both an osmotic and secretory

component. Extensive celiac disease may cause both osmotic diarrhea due to malabsorbed carbohydrate and also secretory diarrhea

due to crypt hyperplasia.

2468 PART 10 Disorders of the Gastrointestinal System

TABLE 325-5 Pathophysiology of Clinical Manifestations of

Malabsorption Disorders

SYMPTOM OR SIGN MECHANISM

Weight loss/malnutrition Anorexia, malabsorption of nutrients

Diarrhea Impaired absorption or secretion of water and

electrolytes; colonic fluid secretion secondary

to unabsorbed dihydroxy bile acids and fatty

acids

Flatus Bacterial fermentation of unabsorbed

carbohydrate

Glossitis, cheilosis, stomatitis Deficiency of iron, vitamin B12, folate, and

vitamin A

Abdominal pain Bowel distention or inflammation, pancreatitis

Bone pain Calcium, vitamin D malabsorption, protein

deficiency, osteoporosis

Tetany, paresthesia Calcium and magnesium malabsorption

Weakness Anemia, electrolyte depletion (particularly K+

)

Azotemia, hypotension Fluid and electrolyte depletion

Amenorrhea, decreased libido Protein depletion, decreased calories,

secondary hypopituitarism

Anemia Impaired absorption of iron, folate, vitamin B12

Bleeding Vitamin K malabsorption, hypoprothrombinemia

Night blindness/xerophthalmia Vitamin A malabsorption

Peripheral neuropathy Vitamin B12 and thiamine deficiency

Dermatitis Deficiency of vitamin A, zinc, and essential

fatty acid

with documented steatorrhea or chronic diarrhea, as well as to

evaluate abnormalities detected by radiologic imaging or by capsule endoscopy. In patients with documented steatorrhea and no

evidence of pancreatic or hepatobiliary disease, an upper endoscopy

and possible small-bowel enteroscopy are required to examine the

small-bowel mucosa and to take biopsies for analysis. An upper

endoscopy will visualize the stomach and duodenum; the maximum reach of the typical upper endoscopy scope is the ligament

of Treitz. Small-bowel enteroscopy using a longer scope such as a

pediatric colonoscope can be used to visualize the jejunum. Singleand double-balloon enteroscopy provide a means for examining

much more of the jejunum and, if successful, will reach the ileum.

Capsule endoscopy provides another means for visualizing the

entire small bowel. Colonoscopy can be used for a retrograde view

and biopsy of the terminal ileum.

Biopsy Analysis Small-bowel pathology may be divided into the

three groups (Table 325-7) described below.

1. Diffuse histopathologic findings involving the entire or majority of the mucosa which are specific for a particular disease

entity; these include Whipple’s disease, agammaglobulinemia

(for example, combined variable immunodeficiency), and abetalipoproteinemia. Whipple’s disease exhibits PAS-positive macrophages and immunohistochemical analysis can detect the

pathogenic organism. Immune globulin deficiency is associated

with a variety of histopathologic findings on small-intestinal

mucosal biopsy. The characteristic feature is the absence of or

substantial reduction in the number of plasma cells in the lamina

propria; the mucosal architecture may be either perfectly normal

or flat (i.e., villous atrophy). Abetalipoproteinemia is characterized by a normal mucosal appearance except for the presence of

mucosal absorptive cells that contain lipid postprandially and

disappear after a prolonged period of either fat-free intake or

fasting.

2. Patchy lesions that are specific for a disease entity include, for

example, intestinal lymphoma or intestinal lymphangiectasia.

Several diseases feature an abnormal small-intestinal mucosa

with a patchy distribution. As a result, biopsy samples obtained

randomly or in the absence of endoscopically visualized abnormalities may not reveal diagnostic features. Intestinal lymphoma

can at times be diagnosed on mucosal biopsy by the identification of malignant lymphoma cells in the lamina propria and

submucosa (Chap. 108). Dilated lymphatics in the submucosa

and sometimes in the lamina propria indicate lymphangiectasia

associated with hypoproteinemia secondary to protein loss into

the intestine. Eosinophilic gastroenteritis comprises a heterogeneous group of disorders with a spectrum of presentations and

symptoms, with an eosinophilic infiltrate of the lamina propria,

and with or without peripheral eosinophilia. The patchy nature

of the infiltrate and its presence in the submucosa often lead to

an absence of histopathologic findings on mucosal biopsy. As the

involvement of the duodenum in Crohn’s disease is also submucosal and not necessarily continuous, mucosal biopsies are not

the most direct approach to the diagnosis of duodenal Crohn’s

disease (Chap. 326). Amyloid deposition can be identified by

TABLE 325-6 Comparison of Different Types of Fatty Acids

LONG-CHAIN MEDIUM-CHAIN SHORT-CHAIN

Carbon chain length >12 8–12 <8

Present in diet In large amounts In small amounts No

Origin In diet as triglycerides Only in small amounts in diet as

triglycerides

Bacterial degradation in colon of

nonabsorbed carbohydrate to fatty acids

Primary site of absorption Small intestine Small intestine Colon

Requires pancreatic lipolysis Yes No No

Requires micelle formation Yes No No

Present in stool Minimal No Substantial

Urinary D-xylose Test The urinary D-xylose test for carbohydrate

absorption provides a measure of proximal small-bowel absorptive

function. d-Xylose, a pentose, is absorbed almost exclusively in the

proximal small intestine and is excreted in the urine. The d-xylose

test is usually performed by administering 25 g of d-xylose and

collecting urine for 5 h. An abnormal test (excretion of <4.5 g)

primarily reflects duodenal/jejunal mucosal disease. The d-xylose

test can also be abnormal in patients with delayed gastric emptying, impaired renal function, and sequestration in patients with

large collections of fluid in a third space (i.e., ascites, pleural fluid).

The ease of obtaining a mucosal biopsy of the small intestine by

endoscopy and the false-negative rate of the d-xylose test have led

to its diminished use. When small-intestinal mucosal disease is

suspected, a small-intestinal mucosal biopsy should be performed.

Radiologic Examination A small-bowel follow-through barium

examination may be very useful for detecting evidence of smallbowel diseases such as celiac disease, jejunal diverticulosis that

predisposes to small-bowel bacterial overgrowth, or Crohn’s disease

(Fig. 325-3). Magnetic resonance enterography and CT enterography are commonly used for diagnosis and management of inflammatory, stricturing disorders such as Crohn’s disease and as an initial

assessment of malabsorption, providing a means to visualize the

entire luminal GI tract as well as the hepatobiliary tree and pancreas.

Endoscopic Evaluation and Small-Bowel Biopsies Endoscopy

with small-bowel biopsy is essential in the evaluation of patients

2469 Inflammatory Bowel Disease CHAPTER 326

Congo Red staining in some patients with amyloidosis involving

the duodenum (Chap. 112).

3. Diffuse nonspecific lesions may be found in more than one

disorder. For example, villus atrophy/absence may be found in

celiac disease, tropical sprue, or bacterial overgrowth, among

other disorders. Several microorganisms can be identified in

small-intestinal biopsy samples, establishing a correct diagnosis. At times, the biopsy is performed specifically to diagnose

infection (e.g., Whipple’s disease or giardiasis). In most other

instances, the infection is detected incidentally during the

workup for diarrhea or other abdominal symptoms. Many of

these infections occur in immunocompromised patients with

diarrhea; the etiologic agents include Cryptosporidium, Isospora

belli, microsporidia, Cyclospora, Toxoplasma, cytomegalovirus,

adenovirus, Mycobacterium avium-intracellulare, and G. lamblia.

In immunocompromised patients, when Candida, Aspergillus,

Cryptococcus, or Histoplasma organisms are seen on duodenal

biopsy, their presence generally reflects systemic infection. Apart

from Whipple’s disease and infections in the immunocompromised host, small-bowel biopsy is seldom used as the primary

mode of diagnosis of infection. Even giardiasis is more easily

diagnosed by stool antigen studies and/or duodenal aspiration

than by duodenal biopsy.

SUMMARY

The evaluation and management of patients with disorders of absorption is challenging due to the complexity of the underlying pathophysiology and the large number of associated diseases. A diagnostic

approach based on the information summarized in Tables 325-1 and

325-5 should prove useful for guiding the care of these challenging

patients.

Acknowledgments

Henry Binder wrote this chapter in prior editions and some material from

his chapter has been retained.

■ FURTHER READING

Boutte HJ, Rubin DC: Short bowel syndrome, in Gastrointestinal

Motility Disorders: A Point-of-Care Clinical Guide. E Bardan, R Shaker

(eds). Cham, Switzerland, Springer International Publishing, 2017.

Bushyhead D, Quigley EM: Small intestinal bacterial overgrowth.

Gastroenterol Clin North Am 50:463, 2021.

Caio G et al: Celiac disease: A comprehensive current review. BMC

Med 17:142, 2019.

Camilleri M, Vijayvargiya P: The role of bile acids in chronic diarrhea. Am J Gastroenterol 115:1596, 2020.

Elli L et al: Protein-losing enteropathy. Curr Opin Gastroenterol

36:238, 2020.

Johnson LR: Digestion and absorption of nutrients, in Gastrointestinal Physiology, 9th ed. LR Johnson. Philadelphia, Elsevier, 2019, pp

102-120.

Lagier JC, Raoult D: Whipple’s disease and Tropheryma whipplei

infections: When to suspect them and how to diagnose and treat

them. Curr Opin Infect Dis 31:463, 2018.

Lebwohl B, Rubio-Tapa A: Epidemiology, presentation and diagnosis

of celiac disease. Gastroenterology 160:63, 2021.

Levitt DG, Levitt MD: Protein losing enteropathy: comprehensive

review of the mechanistic association with clinical and subclinical

disease states. Clin Exper Gastro 10:247, 2017.

Misselwitz B et al: Update on lactose malabsorption and intolerance:

pathogenesis, diagnosis and clinical management. Gut 68: 2080, 2019.

TABLE 325-7 Diseases That Can Be Diagnosed by Small-Intestinal

Mucosal Biopsies

LESIONS PATHOLOGIC FINDINGS

Diffuse, Specific

Whipple’s disease Lamina propria includes macrophages

containing material positive on periodic

acid–Schiff staining

Agammaglobulinemia No plasma cells; either normal or absent villi

(“flat mucosa”)

Abetalipoproteinemia Normal villi; epithelial cells vacuolated with fat

postprandially

Patchy, Specific

Intestinal lymphoma Malignant cells in lamina propria and

submucosa

Intestinal lymphangiectasia Dilated lymphatics; clubbed villi

Eosinophilic gastroenteritis Eosinophil infiltration of lamina propria and

mucosa

Amyloidosis Amyloid deposits

Crohn’s disease Noncaseating granulomas

Infection by one or more

microorganisms (see text)

Specific organisms

Mastocytosis Mast cell infiltration of lamina propria

Diffuse, Nonspecific

Celiac disease Short or absent villi; mononuclear infiltrate;

epithelial cell damage; hypertrophy of crypts

Tropical sprue Similar to celiac disease

Bacterial overgrowth Patchy damage to villi; lymphocyte infiltration

Folate deficiency Short villi; decreased mitosis in crypts;

megalocytosis

Vitamin B12 deficiency Similar to folate deficiency

Radiation enteritis Similar to folate deficiency

Zollinger-Ellison syndrome Mucosal ulceration and erosion from acid

Protein-calorie malnutrition Villous atrophy; secondary bacterial overgrowth

Drug-induced enteritis Variable histology

326 Inflammatory Bowel

Disease

Sonia Friedman, Richard S. Blumberg

Inflammatory bowel disease (IBD) is a chronic idiopathic inflammatory disease of the gastrointestinal tract. Ulcerative colitis (UC) and

Crohn’s disease (CD) are the two major types of IBD.

■ GLOBAL CONSIDERATIONS: EPIDEMIOLOGY

UC and CD have emerged as global diseases in the twenty-first century. They affect >2 million individuals in North America, 3.2 million

in Europe, and millions more worldwide. Since the late 1990s, the

majority of studies on CD and UC show stable or falling incidence in

the Western world. The disease burden remains high, with a prevalence

of >0.3% in North America, Oceania, and most countries in Europe.

In newly industrialized countries in Africa, Asia, and South America

where there is increased urbanization and Westernization, the incidence of IBD has been rising and mirrors the prior increase of IBD in

the Western world in the twentieth century. For example, in Brazil, the

annual percent change is +11.1% (95% confidence interval [CI], 4.8–

17.8%) for CD and +14.9% (95% CI, 10.4–19.6%) for UC, whereas in

Taiwan, the annual percent change is +4.0% (95% CI, 1.0–7.1%) for CD

and +4.8% (95% CI, 1.8–8.0%) for UC. In a study of newly diagnosed

IBD cases between 2011 and 2013 from 13 countries or regions in the

Asia Pacific, the mean annual IBD incidence per 100,000 was 1.50 (95%

CI, 1.43–1.57). India (9.31; 95% CI, 8.38–10.31) and China (3.64; 95%

CI, 2.97–4.42) had the highest IBD incidences in Asia. The highest

reported prevalence values were in Europe (UC, 505 per 100,000 in

2470 PART 10 Disorders of the Gastrointestinal System

TABLE 326-1 Epidemiology of IBD

ULCERATIVE COLITIS CROHN’S DISEASE

Age of onset Second to fourth

decades and seventh to

ninth decades

Second to fourth

decades and seventh to

ninth decades

Ethnicity Jewish > non-Jewish white > black > Latinx > Asian

Female-to-male ratio 0.51–1.58 0.34–1.65

Smoking May prevent disease

(odds ratio 0.58)

May cause disease (odds

ratio 1.76)

Oral contraceptives No increased risk Hazard ratio 2.82

Appendectomy Protective (risk reduction

13–26%)

Not protective

Monozygotic twins 6–18% concordance 38–58% concordance

Dizygotic twins 0–2% concordance 4% concordance

Infections in the first year

of life

1.6 and 3 times the risk of developing IBD by age 10

and 20 years

Abbreviation: IBD, inflammatory bowel disease.

Norway; CD, 322 per 100,000 in Germany) and North America (UC,

286 per 100,000 in the United States; CD, 319 per 100,000 in Canada).

The most likely factors that explain the geographic variability of IBD

rates, especially the rising incidence in developing countries and urban

areas, are environmental variables including changes in diet (with

downstream effects on the intestinal microbiota), exposure to sunlight

or temperature differences, and socioeconomic status and hygiene

(Table 326-1).

Increasing immigration to Western societies also has an impact on

the incidence and prevalence of IBD. The prevalence of UC among

southern Asians who immigrated to the United Kingdom (UK) was

higher in comparison to the European UK population (17 cases per

100,000 persons vs 7 per 100,000). Spanish patients who emigrated

within Europe, but not those who immigrated to Latin America, developed IBD more frequently than controls. Individuals who have immigrated to Westernized countries and then returned to their country of

birth also continue to demonstrate an increased risk of developing IBD.

Peak incidence of UC and CD is in the second to fourth decades,

with 78% of CD studies and 51% of UC studies reporting the highest

incidence among those aged 20–29 years old. A second modest rise

in incidence occurs between the seventh and ninth decades of life.

The female-to-male ratio ranges from 0.51 to 1.58 for UC studies and

0.34 to 1.65 for CD studies, suggesting that the diagnosis of IBD is not

gender-specific. Pediatric IBD (patients <17 years old) composes

~20–25% of all IBD patients, and ~5% of all IBD patients are <10 years

old. Children with IBD are also grouped as those with early-onset (EO)

IBD (patients <10 years old), very-early-onset (VEO) IBD (patients

<6 years old), and infantile IBD (patients <2 years old). VEOIBD and

infantile IBD mainly affect the colon and are resistant to standard medications, and patients often have a strong family history of IBD, with

at least one first-degree relative affected. In infantile IBD or VEOIBD,

a number of rare, single genetic mutations have been identified as the

basis for this susceptibility in up to 10% of patients, suggesting a simple

Mendelian origin of the disease in these cases.

The greatest incidence of IBD is among white and Jewish people, but

the incidence of IBD in Latinx and Asian people is increasing, as noted

above. Urban areas have a higher prevalence of IBD than rural areas,

and high socioeconomic classes have a higher prevalence than lower

socioeconomic classes.

Epidemiologic studies have identified a number of potential environmental factors that are associated with disease risk (Fig. 326-1).

In Caucasian populations, smoking is an important risk factor in IBD

with opposite effects on UC (odds ratio [OR] 0.58) and CD (OR 1.76),

whereas in other ethnic groups with different genetic susceptibility,

smoking may play a lesser role. Previous appendectomy with confirmed appendicitis (risk reduction of 13–26%), particularly at a young

age, has a protective effect on the development of UC across different

geographical regions and populations. Appendectomy is modestly

associated with the development of CD, but this may be due to

diagnostic bias. Oral contraceptive use is associated with an increased

risk of CD, with a reported hazard ratio as high as 2.82 among current

users and 1.39 among past users. The association between oral contraceptive use and UC is limited to women with a history of smoking.

Infections in the first year of life are associated with development of

IBD, especially before the ages of 10 and 20 years. Breast-feeding may

also protect against the development of IBD. Infectious gastroenteritis

with pathogens (e.g., Salmonella, Shigella, Campylobacter spp., Clostridium difficile) increases IBD risk by two- to threefold. Diets high in

animal protein, sugars, sweets, oils, fish and shellfish, and dietary fat,

especially ω-6 fatty acids, and low in ω-3 fatty acids have been implicated in increasing the risk of IBD. A protective effect of vitamin D on

the risk of CD has been reported.

IBD is a familial disease in 5–10% of patients (Fig. 326-2), and the

strongest risk factor for the development of IBD is a first-degree relative with the disease. The children of mothers and fathers with UC have

an approximately fourfold increased risk of UC, and the children of

mothers and fathers with CD have an almost eightfold increased risk of

CD. Some of these patients may exhibit early-onset disease during the

first decade of life and, in CD, a concordance of anatomic site and clinical type within families. In twin studies, 38–58% of monozygotic twins

are concordant for CD, and 6–18% are concordant for UC, whereas 4%

of dizygotic twins are concordant for CD, and 0–2% are concordant for

UC in Swedish and Danish cohorts. In the remainder of patients, IBD

is observed in the absence of a family history (i.e., sporadic disease).

GLOBAL CONSIDERATIONS: IBD

PHENOTYPES

IBD location and behavior show racial differences that may reflect

underlying genetic variations and have important implications for

diagnosis and management of disease. Blacks and Latinxs tend to

have an ileocolonic CD distribution. Data from East Asia show that

ileocolonic CD is the most common CD phenotype (50.5–71%) and

perianal disease is more common in East Asian patients (30.3–58.8%)

than whites (25.1–29.6%). Pancolonic disease is more common than

left-sided colitis or proctitis among black, Latinx, and Asian patients

with UC. Older Asian patients with UC (age >60) tend to have a more

aggressive disease course. Among blacks, joint involvement is the

predominant extraintestinal manifestation (EIM) reported and ranges

from 15.7 to 29.6%. Ocular involvement is also common in African

Americans and ranges from 7.1 to 13%. Dermatologic manifestations

are the most common EIMs reported in Latinxs (10–13%). Few data

shed light on all aspects of disease in Hispanics, on the incidence and

prevalence of IBD in blacks, and in Asians with IBD outside of Asia.

These ethnic variations indicate the importance of different genetic

and/or environmental factors in the pathogenesis of this disorder.

ETIOLOGY AND PATHOGENESIS

Under physiologic conditions, homeostasis normally exists between

the commensal microbiota, epithelial cells that line the interior of the

intestines (intestinal epithelial cells [IECs]), and immune cells within

the tissues (Fig. 326-1). A consensus hypothesis is that each of these

three major host compartments that function together as an integrated

“supraorganism” (microbiota, IECs, and immune cells) are affected by

specific environmental (e.g., smoking, antibiotics, enteropathogens)

and genetic factors that, in a susceptible host, cumulatively and interactively disrupt homeostasis during the course of one’s life and, in so

doing, culminate in a chronic state of dysregulated inflammation; i.e.,

IBD. Although chronic activation of the mucosal immune system may

represent an appropriate response to an infectious agent, a search for

such an agent has thus far been unrewarding in IBD. As such, IBD is

currently considered an inappropriate immune response to the endogenous (autochthonous) commensal microbiota within the intestines,

with or without some component of autoimmunity. Importantly, the

normal, uninflamed intestines contain a large number of immune cells

that are in a unique state of activation, in which the gut is restrained

from full immunologic responses to the commensal microbiota and

dietary antigens by very powerful regulatory pathways that function

within the immune system (e.g., T regulatory cells that express the