2458 PART 10 Disorders of the Gastrointestinal System

Other unusual causes of this form of gastritis include sarcoidosis, idiopathic granulomatous gastritis, and eosinophilic granulomas involving

the stomach. Establishing the specific etiologic agent in this form of

gastritis can be difficult, at times requiring repeat endoscopy with

biopsy and cytology. Occasionally, a surgically obtained full-thickness

biopsy of the stomach may be required to exclude malignancy.

Russell body gastritis (RBG) is a mucosal lesion of unknown etiology that has a pseudotumoral endoscopic appearance. Histologically, it

is defined by the presence of numerous plasma cells containing Russell

bodies (RBs) that express kappa and lambda light chains. Only 10 cases

have been reported, and 7 of these have been associated with H. pylori

infection. The lesion can be confused with a neoplastic process, but it

is benign in nature, and the natural history of the lesion is not known.

There have been cases of resolution of the lesion when H. pylori was

eradicated.

Immune checkpoint inhibitor–induced enterocolitis and gastritis

are recognized sequelae of these oncologic therapies. The gastritis

typically occurs later in the course of therapy. The diagnosis is made

by the histologic findings on gastric mucosal biopsies obtained endoscopically. This is an important diagnosis to make since therapy with

glucocorticoids and potentially IL-6 receptor blockers will be required.

Moreover, this side effect will have an effect on the oncologic therapy

prescribed.

■ MÉNÉTRIER’S DISEASE

Ménétrier’s disease (MD) is a very rare gastropathy characterized by

large, tortuous mucosal folds. MD has an average age of onset of

40–60 years with a male predominance. The differential diagnosis

of large gastric folds includes ZES, malignancy (lymphoma, infiltrating carcinoma), infectious etiologies (CMV, histoplasmosis, syphilis,

tuberculosis), gastritis polyposa profunda, and infiltrative disorders

such as sarcoidosis. MD is most commonly confused with large or

multiple gastric polyps (prolonged PPI use) or familial polyposis syndromes. The mucosal folds in MD are often most prominent in the

body and fundus, sparing the antrum. Histologically, massive foveolar

hyperplasia (hyperplasia of surface and glandular mucous cells) and a

marked reduction in oxyntic glands and parietal cells and chief cells are

noted. This hyperplasia produces the prominent folds observed. The

pits of the gastric glands elongate and may become extremely dilated

and tortuous. Although the lamina propria may contain a mild chronic

inflammatory infiltrate including eosinophils and plasma cells, MD is

not considered a form of gastritis. The etiology of this unusual clinical

picture in children is often CMV, but the etiology in adults is unknown.

Overexpression of the growth factor TGF-α has been demonstrated in

patients with MD. The overexpression of TGF-α in turn results in overstimulation of the epidermal growth factor receptor (EGFR) pathway

and increased proliferation of mucus cells, resulting in the observed

foveolar hyperplasia.

The clinical presentation in adults is usually insidious and progressive. Epigastric pain, nausea, vomiting, anorexia, peripheral edema,

and weight loss are signs and symptoms in patients with MD. Occult GI

bleeding may occur, but overt bleeding is unusual and, when present,

is due to superficial mucosal erosions. In fact, bleeding is more often

seen in one of the common mimics of MD, gastric polyposis. Twenty

to 100% of patients (depending on time of presentation) develop a

protein-losing gastropathy due to hypersecretion of gastric mucus

accompanied by hypoalbuminemia and edema. Gastric acid secretion

is usually reduced or absent because of the decreased parietal cells.

Large gastric folds are readily detectable by either radiographic (barium meal) or endoscopic methods. Endoscopy with deep mucosal

biopsy, preferably full thickness with a snare technique, is required

to establish the diagnosis and exclude other entities that may present

similarly. A nondiagnostic biopsy may lead to a surgically obtained

full-thickness biopsy to exclude malignancy. Although MD is considered premalignant by some, the risk of neoplastic progression is not

defined. Complete blood count, serum gastrin, serum albumin, CMV

and H. pylori serology, and pH testing of gastric aspirate during endoscopy should be included as part of the initial evaluation of patients with

large gastric folds.

TREATMENT

Ménétrier’s Disease

Medical therapy with anticholinergic agents, prostaglandins, PPIs,

prednisone, somatostatin analogues (octreotide), and H2

 receptor

antagonists yields varying results. Ulcers should be treated with

a standard approach. The discovery that MD is associated with

overstimulation of the EGFR pathway has led to the successful

use of the EGF inhibitory antibody, cetuximab, in these patients.

Specifically, four of seven patients who completed a 1-month trial

with this agent demonstrated near complete histologic remission

and improvement in symptoms. Cetuximab is now considered the

first-line treatment for MD, leaving partial or total gastrectomy for

severe disease with persistent and substantial protein loss despite

therapy with this agent.

■ FURTHER READING

Bindu S et al: Non-steroidal anti-inflammatory drugs (NSAIDs)

and organ damage: A current perspective. Biochem Pharmacol

180:114147, 2020.

Bjarnason I et al: Mechanisms of damage to the gastrointestinal

tract from nonsteroidal anti-inflammatory drugs. Gastroenterology

154:500, 2018.

Brandi ML et al: Multiple endocrine neoplasia type 1: Latest insights.

Endocr Rev 42:133, 2021.

Chey WD et al: ACG clinical guideline: Treatment of Helicobacter

pylori infection. Am J Gastroenterol 112:212, 2017.

Engevik AC et al: The physiology of the gastric parietal cell. Physiol

Rev 100:573, 2019.

Jensen RT, Ito T: Gastrinoma; Endotext [internet]. South Dartmouth,

MA, 2020. https://europepmc.org/article/NBK/nbk279075.

Kavitt RT et al: Diagnosis and treatment of peptic ulcer disease. Am

J Med 132:447, 2019.

Pennelli G et al: Gastritis: Update on etiological features and histological practice approach. Pathologica 112:153, 2020.

Savarino V et al: Proton pump inhibitors: Use and misuse in the clinical setting. Expert Rev Clin Pharmacol 11:1123, 2018.

Yao X, Smolka AJ: Gastric parietal cell physiology and Helicobacter

pylori-induced disease. Gastroenterology 156:2158, 2019.

325 Disorders of Absorption

Deborah C. Rubin

A wide range of diseases affect gastrointestinal (GI) absorptive function and may result in malabsorption syndromes. These disorders

affect one or more of the three phases of enteral nutrient processing.

Luminal digestion is initiated by lingual and gastric lipase and gastric pepsin, and continues in the small bowel by the actions of pancreatic enzymes and bile salts. Small intestinal mucosal digestion

and absorption are mediated by enterocyte brush border enzymes

including disaccharidases, enterokinases, and peptidases, which digest

nutrients upon contact, and by mixed micelles containing lipids and

bile salts. Protein and carbohydrate digestive products are transported

into the enterocyte by carriers and transporters, and lipids enter by

diffusion mediated by micelles. Once in the enterocyte, nutrients may

be reprocessed for post mucosal absorption and entry into lymphatics

(long-chain triglycerides as part of chylomicrons) or are transported

into the bloodstream. Malabsorptive diseases or syndromes can be

classified by their effects on one or more of these three phases of

absorption (Table 325-1).

2459 Disorders of Absorption CHAPTER 325

and present with isolated iron deficiency, or may cause diffuse intestinal mucosal disease, affecting the absorption of multiple nutrients and

causing a constellation of symptoms and clinical presentations.

Definition of Diarrhea Diarrhea is the most common symptom

associated with disorders of absorption. For most patients, diarrhea as

a symptom is defined as an increase in stool number or frequency, or a

change in consistency. Because normal bowel patterns may vary from

as many as two to four bowel movements per day to one stool per week,

it is critical to use an objective measure of diarrhea to help direct evaluation. In health, stool volume or weight is <200 mL or <200 g respectively in 24 h. Collection of stool for weight/volume determination is

one of the most useful tools for an evaluation of diarrhea. In particular,

a 72-h collection for weight/volume and fecal fat determination is the

gold standard for documenting the presence of steatorrhea, or fatty

stool. Steatorrhea, defined as increased stool fat excretion to >7% of

dietary fat, is a common manifestation of malabsorption. Steatorrhea

often results in large, bulky, and malodorous stools. Malabsorption

of single nutrients like lactose may result in an osmotic diarrhea, in

which the osmotically active unabsorbed nutrient causes fluid to be

drawn into the GI tract lumen. Malabsorptive diarrhea frequently is

precipitated by eating and resolves or significantly decreases at night,

with fasting, and thus can frequently be distinguished from secretory

diarrheas, for example from infectious causes such as bacterial enterotoxigenic Escherichia coli. In this circumstance, intestinal fluid and

electrolyte secretion is stimulated by enterotoxin and will continue

even during fasting.

OVERVIEW: NUTRIENT DIGESTION

AND ABSORPTION

Luminal digestive processes begin in the mouth and proceed throughout the GI tract, mediated by salivary amylase, lingual and gastric

lipases, gastric acid, pancreatic enzymes, and bile salts. As nutrients are

digested in the lumen of the proximal GI tract, they are further processed by enterocyte brush border enzymes including disaccharidases

such as lactase and sucrase-isomaltase, which produce monosaccharides, and peptidases, which hydrolyze polypeptides into tripeptides

and dipeptides and amino acids. Lipids in mixed micelles are then

absorbed into enterocytes.

The surface area of the small bowel, which is normally 6–12 ft

long, is further enhanced by circular folds, villi, and microvilli. 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. The intestine is also presented

with 7–9 L of fluid daily, a volume comprising dietary fluid intake

(1–2 L/day) and salivary, gastric, pancreatic, biliary, and intestinal

fluid (6–7 L/day). In health, almost all of this fluid is reabsorbed by the

small bowel and colon, resulting in a normal stool volume of <200 mL

or stool weight of <200 g.

■ SPECIFIC NUTRIENTS

Lipids Lipid absorption is a complex process that requires hydrolysis by pancreatic enzymes and bile salts for physiochemical dispersion

of fats, followed by absorption of processed lipid nutrients dispersed

in bile salt–mixed micelles across the intestinal epithelium. Bile acids

are synthesized in the liver, secreted into the intestinal lumen, and

constantly recirculated by absorption in the ileum. The ileum expresses

fibroblast growth factor 19 (FGF19), which is a physiologic bile acid

sensor. FGF19 is secreted from the ileum into the bloodstream in

response to bile acid flux and negatively regulates hepatic bile acid

synthesis by affecting the transcription of hepatic CYP7A1.

Thus assimilation of dietary lipid requires three integrated processes: an intraluminal or digestive phase, a mucosal or absorptive

phase, and a delivery or postabsorptive phase (Table 325-2).

Gastric lipases begin the lipolytic process. Following entry into

the small bowel, long-chain triglycerides, with carbon lengths >12

and that are the major component of dietary lipid, are hydrolyzed by

pancreatic lipases into fatty acids and monoglyceride during a process

TABLE 325-1 Classification of Malabsorption Syndromes

Inadequate digestion

Postgastrectomya

Deficiency or inactivation of pancreatic lipase

 Exocrine pancreatic insufficiency

 Chronic pancreatitis

 Pancreatic carcinoma

 Cystic fibrosis

 Pancreatic insufficiency—congenital or acquired

Gastrinoma—acid inactivation of lipase

Drugs—orlistat

Reduced intraduodenal bile-acid concentration/impaired micelle formation

Liver disease

 Parenchymal liver disease

 Cholestatic liver disease

Bacterial overgrowth in small intestine:

 Anatomic stasis Functional stasis

 Afferent loop Diabetesa

 Stasis/blind Sclerodermaa

 Loop/strictures/fistulae Intestinal pseudo-obstruction

Interrupted enterohepatic circulation of bile salts

 Ileal resection

 Crohn’s disease

Drugs (binding or precipitating bile salts)—neomycin, cholestyramine, calcium

carbonate

Impaired mucosal absorption/mucosal loss or defect

 Intestinal resection or bypassa

 Inflammation, infiltration, or infection:

 Crohn’s diseasea Celiac disease

 Amyloidosis Collagenous sprue

 Sclerodermaa Whipple’s diseasea

 Lymphomaa Radiation enteritisa

 Eosinophilic enteritis Folate and vitamin B12 deficiency

 Mastocytosis Infections—giardiasis

 Tropical sprue Graft vs host disease

Genetic disorders

 Disaccharidase deficiency

 Agammaglobulinemia

 Abetalipoproteinemia

 Hartnup disease

 Cystinuria

Impaired nutrient delivery to and/or from intestine:

Lymphatic obstruction Circulatory disorders

 Lymphomaa Congestive heart failure

 Lymphangiectasia Constrictive pericarditis

Mesenteric artery atherosclerosis

Vasculitis

Endocrine and metabolic disorders

Diabetesa

Hypoparathyroidism

Adrenal insufficiency

Hyperthyroidism

Carcinoid syndrome

a

Malabsorption caused by more than one mechanism.

Disorders of absorption also have diverse clinical presentations. For

example, the deficiency of a single brush border membrane protein

such as lactase causes symptoms of diarrhea by affecting the absorption

of one nutrient, lactose. Celiac sprue may be localized to the duodenum

2460 PART 10 Disorders of the Gastrointestinal System

called lipolysis (Fig. 325-1). Long-chain free fatty acids are dispersed

by bile salts into mixed micelles, which contact the brush border and

permit fatty acid absorption into enterocytes across this specialized

apical membrane. The other two types of fatty acids that compose fats,

medium-chain and short-chain fatty acids, are soluble in the unstirred

water layer. Medium-chain triglycerides with carbon chain lengths of

8–12 are found in coconut oil. Long-chain fatty acids are re-esterified

to triglycerides in enterocytes, packaged into chylomicrons that contain apolipoproteins on the surface, which are subsequently secreted

into the extracellular space, and because of their size, are excluded

from capillaries and enter the lymphatics. Medium-chain triglycerides

do not require micelle formation or pancreatic lipolysis as they are

directly absorbed intact from the small bowel into the bloodstream,

and short-chain fatty acids (carbon length <8) are produced by and

absorbed in the colon.

Carbohydrates Dietary carbohydrate consists of starch, sucrose,

lactose, maltose, and monosaccharides such as glucose and fructose.

Starch is digested by salivary α-amylase in the mouth, followed by

pancreatic amylase. The main products include maltotriose, maltose,

and α-dextrins. These are further digested on the brush border membrane by disaccharidases such as glucoamylase and sucrase-isomaltase.

Dietary lactose is digested by brush border lactase, sucrose by sucrase,

and trehalose by trehalase. The final digested products are glucose,

fructose, and galactose, which are transported into the enterocyte by

transporters such as SLCA5 (formerly SGLT-1), which transports glucose or galactose in a sodium-dependent manner, and GLUT-5, which

transports fructose by facilitated diffusion. Glucose, galactose, and

fructose exit the cell via GLUT-2. Triglycerides

Lipolysis Micellar

Solubilization

with Bile Acid

Absorption

Fatty acids

To tissues

for utilization

of fat Cholesterol

Phospholipid

β–Lipoprotein

Triglycerides

β-Monoglyceride

β-Monoglyceride

Fatty acids

Delivery

Pancreas Liver Jejunal Mucosa

(1) Esterification

Lymphatics

(2) Chylomicron

 formation

FIGURE 325-1 Schematic representation of lipid digestion and absorption. Dietary lipid is in the form of

long-chain triglycerides. The overall process can be divided into (1) a digestive phase that includes both

lipolysis and micelle formation requiring pancreatic lipase and conjugated bile acids, respectively, in the

duodenum; (2) an absorptive phase for mucosal uptake and re-esterification; and (3) a postabsorptive phase

that includes chylomicron formation and exit from the intestinal epithelial cell via lymphatics. (Courtesy of

John M. Dietschy, MD; with permission.)

TABLE 325-2 Defects in Lipid Digestion and Absorption in Steatorrhea

PHASE, PROCESS

PATHOPHYSIOLOGIC

DEFECT DISEASE EXAMPLE

Digestive

Lipolysis formation Decreased lipase

secretion

Chronic pancreatitis

Micelle formation Decreased intraduodenal

bile acids

Absorptive

Mucosal uptake and

re-esterification

Mucosal dysfunction Celiac disease

Postabsorptive

Chylomicron formation Absent β-lipoproteins Abetalipoproteinemia

Delivery from intestine Abnormal lymphatics Intestinal

lymphangiectasia

Proteins Dietary protein digestion begins in the stomach by pepsin.

Pancreatic proteases including endopeptidases, exopeptidases, and

trypsin are activated in the small-bowel lumen. Trypsinogen is activated by brush border enterokinase to generate active trypsin. Trypsin

in turn activates chymotrypsinogen to chymotrypsin, proelastase to

elastase, and procarboxypeptidases to carboxypeptidases A and B.

These enzymes digest protein into di peptides, tripeptides, larger polypeptides, or free amino acids. At the brush border, peptidases digest

larger peptides into dipeptides and tripeptides or free amino acids,

which enter the enterocyte via specialized carriers. Most dipeptides

and tripeptides are further metabolized intracellularly by cytoplasmic

peptidase into amino acids, which directly enter the bloodstream via

carriers in the basolateral membrane. Small amounts of dipeptides and

tripeptides may also enter the bloodstream.

■ LUMINAL PHASE OF DIGESTION

The luminal phase of digestion begins in the mouth, starting with

mastication and lipase secretion by the tongue and salivary glands.

The stomach continues the luminal digestive process, via gastric acid,

gastric lipase, and pepsin secretion as well as mechanical trituration

of contents. In the small-bowel lumen, pancreatic enzymes (amylase,

lipases, carboxypeptidase, trypsin, and other endopeptidases) contribute to carbohydrate, lipid, and protein digestion, respectively. Bile salts

produced by the liver are secreted into the intestinal lumen (and reabsorbed in the ileum via the enterohepatic circulation) and are required

for efficient lipid absorption.

Disorders That Affect the Luminal Phase of Digestion The

luminal phase may be disrupted by disorders of gastric and intestinal

motility including the sequelae of gastric surgery, systemic diseases

such as scleroderma, or endocrine disorders such as diabetes mellitus, pancreatic diseases leading to pancreatic insufficiency with

reduced pancreatic enzyme secretion, or luminal bile salt deficiency

caused by hepatobiliary disease, ileal disease, or small-bowel bacterial

overgrowth.

Gastric Resection Surgical procedures that remove or bypass part

of the stomach and duodenal bulb such as Roux-en-Y gastric bypass for

weight loss, or resection of the gastric antrum and duodenal bulb with

creation of a Billroth II anastomosis for treatment of peptic ulcer disease, result in rapid gastric emptying into the jejunum, which leads to

diarrhea and weight loss due to inadequate mixing of luminal nutrients

with bile and pancreatic secretions.

Disordered Intestinal Motility Hyperthyroidism may cause

diarrhea and malabsorption due to increased intestinal motility with

rapid transit, also resulting in inadequate nutrient mixing with pancreaticobiliary secretions. Long-standing diabetes mellitus may result

in damage to the enteric nervous system resulting

in increased motility and diarrhea, or reduced

motility and constipation. Disorders that affect

the intestinal smooth muscle such as connective

tissue disorders including scleroderma may have

profound effects on GI motility.

Pancreatic Disorders Chronic pancreatitis

(see Chap. 348) may result in a marked reduction in pancreatic enzyme secretion and pancreatic insufficiency, with subsequent fat, protein,

and carbohydrate malabsorption. Patients with

chronic pancreatitis present with steatorrhea, or

fatty stools, which are often voluminous, bulky,

and malodorous. Patients with steatorrhea also

develop deficiency of fat-soluble vitamins including vitamins A, E, and most commonly, vitamins

D and K, which depend on the same lipid absorption mechanisms, and thus are malabsorbed

along with dietary fat. Weight loss is common.

For a discussion of causes of acute and chronic

pancreatitis, please see Chap. 348.

2461 Disorders of Absorption CHAPTER 325

Disorders That Result in Luminal Bile Salt Deficiency Bile

acid synthesis and the enterohepatic circulation (Fig. 325-2): Bile

acids are synthesized from cholesterol in the liver. The two primary

bile acids are cholic acid and chenodeoxycholic acid. These are conjugated in the liver to taurine and glycine and are secreted into bile

ducts, stored in the gallbladder, and then delivered to the intestinal

lumen. Conjugation prevents bile acids from passive diffusion in the

small-bowel lumen, retaining bile acid concentrations required for

lipid absorption. Bile acids emulsify fats and fat-soluble vitamins to

facilitate their absorption. Bile acids are efficiently reabsorbed in the

ileum into the portal circulation and are extracted by the liver in a

process called enterohepatic circulation (Fig. 325-2). Small amounts

are deconjugated in the ileum by bacteria, or pass into the colon and

are deconjugated and metabolized by colonic bacteria to become secondary bile acids. The two major secondary bile acids are lithocholic

acid and deoxycholic acid.

Processes that affect any of the above pathways may result in luminal

bile salt deficiency and malabsorption. Thus, hepatobiliary diseases,

intestinal ileal resection, extensive disease such as Crohn’s disease, and

small-bowel bacterial overgrowth may result in luminal bile salt deficiency and malabsorption (Table 325-3).

Hepatobiliary Disease Hepatic disorders that result in decreased

bile acid synthesis due to hepatocyte dysfunction or reduced secretion

of bile into the gut lumen caused by diseases of the bile ducts such as

primary sclerosing cholangitis or primary biliary cirrhosis may result

in luminal bile salt deficiency and fat malabsorption. These are discussed in Chap. 346.

Ileal Resection or Ileal Disease Diseases that involve the ileal

mucosa or that result in ileal resection may lead to reduced recycling of

bile acids by the enterohepatic circulation and increased entry into and

concentration of bile acids in the colon, which produces a secretory

diarrhea, or malabsorption due to inadequate bile acid concentrations

in the small-bowel lumen. In general, resection or disease involving

<100 cm of ileum results in bile acid spillage into the colon; resections of >100 cm result in loss of bile acids that exceed liver synthetic

capacity, and malabsorption becomes the dominant pathophysiologic

mechanism for diarrhea, due to bile acid deficiency (Table 325-4). The

most common disorder of the GI tract that targets the ileum is Crohn’s

disease (Chap. 326), which is a chronic inflammatory disorder that

may involve the entire GI tract, but most commonly the ileum and

colon. If severe or refractory to treatment, Crohn’s disease may lead to

chronic inflammation, marked epithelial dysfunction, and structuring

and fibrosis, and surgical resection may be required to treat smallbowel obstruction or refractory disease.

Primary Bile Acid Diarrhea A subset of patients with functional

diarrhea or irritable bowel syndrome with diarrhea have been recently

shown to have bile acid malabsorption. Although the mechanisms are

still being elucidated, reduced FGF19 secretion by ileal enterocytes has

been observed. FGF19 regulates serum 7alpha-hydroxy-4-cholesten3-one (C4) levels; reductions in circulating FGF19 lead to increased

hepatic bile acid synthesis via increased C4 expression. Chronic diarrhea results from increased bile acid spillage into the colon, which

induces a secretory diarrhea.

Treatment Bile acid sequestrants are effective in reducing diarrhea

by binding bile acids to prevent spillage into the colon. Hepatic synthesis of bile acids is sufficient to maintain intraluminal concentrations

that are adequate for fat absorption.

Small-Bowel Bacterial Overgrowth The intestine contains a

rich microbiome. Bacterial titers increase along the horizontal axis of

the gut from duodenum to ileum. However, intestinal disorders affecting motility or causing stasis of bowel contents may lead to small-bowel

bacterial overgrowth. These include scleroderma bowel, chronic intestinal pseudo-obstruction, the creation of blind surgical loops such as

Billroth II anastomosis, small-bowel strictures, or fibrosis from inflammatory disorders such as Crohn’s disease, and diffuse diverticulosis

(Fig. 325-3). Surgical resection of the ileocecal valve increases ileal

bacterial counts from the colon. Bacterial overgrowth causes deconjugation of bile acids, which facilitates their absorption in the proximal

bowel and results in luminal bile acid deficiency, which in turn causes

malabsorptive diarrhea with steatorrhea. Bacterial overgrowth may

also damage the brush border and result in carbohydrate maldigestion

and short-chain fatty acid production in the colon, with diarrhea and

gas. These patients are also at risk for B12 deficiency due to bacterial

metabolism of B12 resulting in macrocytic anemia and peripheral neuropathy. In contrast, elevated serum folate levels may also be observed,

derived from bacterial synthesis of folate.

Small-bowel bacterial overgrowth has also been observed in patients

with diarrhea-predominant irritable bowel syndrome. The underlying

Cholesterol

Bile acids

 0.5 g synthesized

 per day

NORMAL

Bile acid

 pool size

 4.0 g

[Bile acids]

 >4 mM

Jejunum

Ileum

Na

0.5 g

Bile acids

 excreted per day

COLON

FIGURE 325-2 Schematic representation of the enterohepatic circulation of bile

acids. Bile-acid synthesis is cholesterol catabolism and occurs in the liver. Bile

acids are secreted in bile and are stored in the gallbladder between meals and

at night. Food in the duodenum induces the release of cholecystokinin, a potent

stimulus for gallbladder contraction resulting in bile-acid entry into the duodenum.

Bile acids are primarily absorbed via an Na-dependent transport process that is

located only in the ileum. A relatively small quantity of bile acids (~500 mg) is not

absorbed in a 24-h period and is lost in stool. Fecal bile-acid losses are matched by

bile-acid synthesis. The bile-acid pool (the total amount of bile acids in the body) is

~4 g and is circulated twice during each meal or six to eight times in a 24-h period.

TABLE 325-3 Defects in Enterohepatic Circulation of Bile Acids

PROCESS

PATHOPHYSIOLOGIC

DEFECT DISEASE EXAMPLE

Synthesis Decreased hepatic

function

Cirrhosis

Biliary secretion Altered canalicular

function

Primary biliary cirrhosis

Maintenance of

conjugated bile acids

Bacterial overgrowth Jejunal diverticulosis

Reabsorption Abnormal ileal function Crohn’s disease

TABLE 325-4 Comparison of Bile Acid and Fatty Acid Diarrhea

BILE ACID DIARRHEA FATTY ACID DIARRHEA

Extent of ileal disease Limited Extensive

Ileal bile-acid absorption Reduced Reduced

Fecal bile-acid excretion Increased Increased

Fecal bile-acid loss

compensated by hepatic

synthesis

Yes No

Bile-acid pool size Normal Reduced

Intraduodenal (bile acid) Normal Reduced

Steatorrhea None or mild >20 g

Response to cholestyramine Yes No

Response to low-fat diet No Yes

2462 PART 10 Disorders of the Gastrointestinal System

mechanisms are unclear, but treatment of bacterial overgrowth leads

to resolution of symptoms in a subset of irritable bowel syndrome

patients.

Diagnosis Duodenal aspirate for bacterial titers is the gold standard

but is not generally available to most practitioners. Breath hydrogen

testing with administration of lactulose, a nondigestible disaccharide, is widely available but must be interpreted carefully to avoid

false-positive results. Many clinicians choose to treat empirically with

antibiotics (see Treatment) and observe for resolution of symptoms.

Treatment When possible, surgical correction of blind loops,

endoscopic or surgical treatment of strictures, and removal of large

diverticula can be pursued for definitive therapy, in addition to treatment of underlying disorders such as Crohn’s disease to avoid recurrent

stricture formation or fibrosis. Other disorders such as scleroderma or

other diffuse motility disorders may not be easily treated. In these circumstances, treatment with the nonabsorbable antibiotic, rifaximin, or

with other antibiotics such as metronidazole, doxycycline, amoxicillinclavulinic acid, or cephalosporins for several weeks is often pursued.

Patients may require retreatment or even chronic therapy with rotating

antibiotics depending on the severity of symptoms.

■ MUCOSAL PHASE OF DIGESTION

AND ABSORPTION

The intestinal epithelium (also known as the mucosa) plays a critical

role in continued digestion of nutrients and absorption from the intestinal lumen into the bloodstream and lymphatics.

The small-bowel epithelial or mucosal digestive and absorptive

phase is mediated by enterocytic brush border enzymes, including

peptidases and hydrolases. Brush border enterokinase is required for

the conversion of pancreatic trypsinogen to trypsin, which further

activates trypsinogen and other pancreatic protease proenzymes. The

brush border membrane of the small-bowel epithelium expresses

a wide variety of disaccharidases, peptidases, and other hydrolases

that continue the digestive process for carbohydrates and proteins,

with enzymatic digestion of disaccharides to monosaccharides and

dipeptidases to amino acids, which are then absorbed by specific

transporters. Long-chain fatty acids are re-esterified to triglycerides in

enterocytes, packaged into chylomicrons with apolipoproteins on the

surface, which are subsequently secreted into the extracellular space,

and because of their size, are excluded from capillaries and enter the

lymphatics.

INTESTINAL MUCOSAL DISORDERS

■ DISORDERS OF ENTEROCYTE CARBOHYDRATE

TRANSPORTERS AND ENZYME DEFICIENCIES

Lactose Intolerance Due to Lactase Deficiency This is the

most common brush border disaccharidase deficiency and is a frequent

cause of diarrhea, abdominal pain, gassiness, and bloating. Lactose is

present in many dairy products but is also a “hidden” component of a

vast number of processed foods.

Lactose malabsorption can result from lactase deficiency, which is

regulated by primary genetic mechanisms (adult-type hypolactasia)

or secondary due to damage to the epithelial (mucosal) lining of the

gut, from infections (viral, bacterial, or parasitic) or from intestinal

mucosal diseases. Congenital lactase deficiency is very rare and is an

autosomal recessive disorder. Hypolactasia in adulthood is very common throughout the world and is considered to be the genetic wildtype; lactase persistence results from a C to T mutation (LACTASE

LCT-13910CT and LCT-13910TT) and adults with hypolactasia have

absence of this “persistence” allele. Lactose is metabolized by lactase

FIGURE 325-3 Barium contrast small-intestinal radiologic examinations. A. Normal individual. B. Celiac disease. C. Jejunal diverticulosis. D. Crohn’s disease. (Courtesy of

Morton Burrell, MD, Yale University; with permission.)

2463 Disorders of Absorption CHAPTER 325

into glucose and galactose, which are both absorbed by transporters at

the enterocyte surface. Patients who are lactase deficient have elevated

luminal lactose levels upon ingestion of lactose. The mechanism for

diarrhea in lactase deficiency is complex. Undigested lactose acts as an

osmotic substance to draw fluid into the small-bowel lumen. In addition, when unabsorbed lactose enters the colon, luminal bacteria ferment lactose producing intestinal gas (hydrogen, carbon dioxide, and

methane), bloating, and abdominal pain. Luminal lactose is metabolized by bacteria into short-chain fatty acids that can be absorbed by

the colon, but watery diarrhea may occur when a large lactose load

exceeds the colon’s absorptive capacity.

Diagnosis When lactose intolerance is suspected, a common initial

approach is to institute a lactose-exclusion diet and assess for resolution

of symptoms. This is a rapid and generally effective diagnostic and therapeutic method. Patients are provided with a list of lactose-containing

foods and lactose-free alternatives. Patients are also counseled on

alternative calcium sources, because dairy-containing foods are a

major source of dietary calcium, which is important for osteoporosis

prevention.

Should the results of dietary exclusion be ambiguous, a lactosetolerance test or breath hydrogen test may prove useful. For the lactose-tolerance test, patients ingest a standardized liquid lactose solution (usually 50 g of lactose) followed by timed measurements of serum

glucose for 90 min. If lactose digestion is normal, glucose levels should

rise by >20 mg/L. Serum glucose rise <20 mg/L plus the presence of

symptoms of lactose intolerance (abdominal discomfort, gassiness,

and diarrhea) is considered a positive test. A breath hydrogen test is

performed by measuring breath hydrogen levels following ingestion of

a standardized lactose load. Breath hydrogen levels should not exceed

>20 ppm above the fasting baseline. Generally the peak occurs between

2–4 h. Both methods may be inaccurate if the patient has abnormal

gastric emptying or abnormal intestinal transit. Breath hydrogen measurements may be abnormal in the setting of bacterial overgrowth,

which may cause very similar symptoms.

Treatment Patients may elect to completely eliminate lactose from

their diets. It is very important to consider calcium and vitamin D

supplementation because elimination of milk and soft cheeses removes

important dietary sources. They also may need to consult a dietitian

for guidance about hidden lactose in prepared or other foods. An alternative is to consider using lactase supplementation, which is available

over the counter, but which may need to be titrated to avoid symptoms.

Glucose Galactose Malabsorption This rare congenital disorder is an autosomal recessive disease in which mutations occur in

the SLC5A1 gene (also known as SGLT1). SLC5A1 is a brush border

protein and member of the sodium-dependent glucose transporter

family; mutations in this gene result in malabsorption of glucose and

galactose. Gene sequencing has shown that most patients have loss

of function single-nucleotide variations. SLC5A1 actively transports

glucose or galactose coupled to sodium cotransport; patients who are

homozygous for these loss-of-function variants have severe congenital

diarrhea and death if unrecognized. Treatment focuses on eliminating

glucose- and galactose-containing foods and substituting fructosecontaining foods. Fructose is absorbed by the brush border transporter

GLUT5 by facilitated diffusion and is not dependent on SLC5A1.

Abetalipoproteinemia Abetalipoproteinemia is a rare disorder of

lipid metabolism associated with abnormal erythrocytes (acanthocytes),

neurologic symptoms, and steatorrhea (see Chap. 407). Lipolysis,

micelle formation, and lipid uptake are all normal in patients with

abetalipoproteinemia, but the re-esterified triglyceride cannot exit the

epithelial cell because of the failure to produce chylomicrons. This

disorder results from mutation of microsomal triglyceride transfer

protein, which catalyzes the transfer of triglyceride onto nascent apolipoprotein B containing particles. Mutations in MTP decrease this

transfer and decrease formation of chylomicrons. Small-intestinal

biopsy samples obtained from these rare patients in the postprandial

state reveal lipid-laden small-intestinal epithelial cells that become

normal in appearance after a 72- to 96-h fast.

■ INTESTINAL MUCOSAL DISORDERS THAT RESULT

IN MALABSORPTION OF MULTIPLE NUTRIENTS

Celiac Disease Celiac disease, also known as celiac sprue or

gluten-sensitive enteropathy, is a small intestinal enteropathy that

results from an immune response to gluten ingestion and is characterized by autoantibodies to tissue transglutaminase. Gluten is found in

foods produced from wheat, rye, barley, and some varieties of oats, and

it is a common additive to prepared foods and pharmaceuticals. Tissue

transglutaminase is involved in the pathogenesis of this disorder, as it

deamidates glutamine residues of gluten-derived peptides, facilitating

their presentation by antigen-presenting cells.

Epidemiology and Genetics The incidence and prevalence of

celiac disease have been increasing worldwide. Increased awareness

among clinicians and patients has led to increases in detection, but

there is evidence that the true incidence appears to be increasing as

well. Global prevalence has been measured at 1.4%. In the United

States, data from the National Health and Nutrition Examination survey showed seroprevalence of 0.2% in non-Hispanic black populations,

0.3% in Hispanic individuals, and 1.0% in white populations.

The prevalence of celiac disease is 10–15% in first-degree relatives.

Host genetic factors include histocompatibility locus antigens HLADQ2

and DQ8; the presence of one of the two haplotypes is necessary but

not sufficient for developing celiac disease. HLADQ2 and DQ8 are

found in 25–35% of the general population; because most carriers

never develop celiac disease, detection of these alleles is not useful for

diagnosis. However, a negative test is very useful for ruling out celiac

disease, with a negative predictive value of >99%. This is particularly

helpful in patients who self-discontinued gluten ingestion prior to

serologic or endoscopic testing.

Presentation Patients with celiac disease have a wide variety of

disease manifestations, ranging from being asymptomatic, to having

isolated iron-deficiency anemia due to duodenal disease, to severe

diarrhea, weight loss, and malabsorption of multiple nutrients with

more diffuse disease. Celiac disease primarily affects the proximal

small intestine; it may involve the duodenum only or may cause widespread jejunal disease resulting in severe symptoms.

Diarrhea, weight loss, and growth failure in children are common

presenting complaints, but additional signs and symptoms have become

increasingly recognized to be associated with celiac disease, including

bloating and irregular bowel habits, migraine headaches, and ataxia. In

addition, patients may be identified after presenting with osteoporosis,

iron-deficiency anemia, or detection of abnormal liver enzymes.

Mechanism of Diarrhea Patients with celiac disease have villus

atrophy in the proximal small intestine and thus develop steatorrhea

from mucosal malabsorption and may have lactase deficiency. However,

they also develop a secretory component due to crypt hyperplasia and

fluid hypersecretion from the crypt epithelium.

Associated Diseases Patients with celiac disease have a higher

incidence of other autoimmune disorders such as type 1 diabetes

mellitus and autoimmune thyroid disease. Dermatitis herpetiformis is

a skin disorder that is highly associated with celiac disease, characterized by a vesicular rash mediated by IgA deposits in the skin. Down

syndrome and Turner syndrome patients also have an increased risk

of celiac disease.

Diagnosis Patients are screened for celiac disease first by testing

for serum antibodies, including tissue transglutaminase IgA, antiendomysial, and deamidated anti-gliadin antibodies. Serum IgA levels are measured to detect false-negative results from IgA deficiency.

Deamidated anti-gliadin IgG antibodies or tissue transglutaminase

IgG antibodies are detectable and diagnostic in IgA-deficient patients.

The diagnosis in adults with positive antibody levels is confirmed by

endoscopy with small-intestinal biopsy. Biopsies typically show characteristic villus blunting, crypt hyperplasia, and inflammation, including

increased intraepithelial lymphocytes. The Marsh classification categorizes different types of celiac disease–related lesions and is currently

used to quantify severity of disease involvement.

2464 PART 10 Disorders of the Gastrointestinal System

Family members of patients with celiac disease are screened if symptomatic; recommendations regarding screening asymptomatic family

members are still controversial.

Complications Complications of celiac disease include refractory

celiac disease, enteropathy-associated T-cell lymphoma, hyposplenism,

and small-bowel adenocarcinoma.

Refractory Celiac Disease This complication is most common

in patients with ongoing active celiac disease, found in about 10% of

patients with persistent active disease. Patients have ongoing diarrhea

and weight loss with persistent villus atrophy on biopsy after 1 year of

following a strict gluten-free diet. These patients also have negative

celiac serology, confirming their adherence to the gluten-free diet.

Type 1 refractory celiac disease has a normal intraepithelial lymphocyte population whereas type 2 disease has clonal expansion of CD3+

intraepithelial lymphocytes that also contain a monoclonal rearrangement of the gamma chain of the T-cell receptor. Type 2 refractory

celiac disease has a worse prognosis due to its association with T-cell

lymphoma, which occurs in 33–50% of cases after 5 years. The therapy

for celiac disease–related lymphoma is intense and includes high-dose

chemotherapy and sometimes stem cell transplantation.

Small-bowel adenocarcinoma is a very rare cancer in the general

population but is increased in celiac disease patients.

Therapy and Follow-up The mainstay of celiac disease treatment

is institution of a strict gluten-free diet. This is challenging for patients

because of the widespread presence of gluten in both raw and prepared

foods, inaccurate food labeling, and cross-contamination during food

preparation. Patients must receive rigorous dietary instruction from a

dietitian and adhere lifelong to a gluten-free diet.

For those patients whose symptoms resolve, serologic follow-up

is generally recommended to confirm compliance with a gluten-free

diet. A follow-up biopsy to document complete healing of villus atrophy is also generally recommended. However, subsequent biopsies

are not recommended unless symptoms recur. For patients without

symptom resolution, a biopsy is required to determine the degree of

disease activity and to rule out other causes of persistent diarrhea and

complications such as refractory celiac disease or T-cell lymphoma.

The most common cause of residual disease activity is dietary nonadherence or inadvertent gluten exposure. These patients pursue repeat

consultation with a dietitian and efforts to reduce restaurant or other

out-of-the-home exposure or cross-contamination at home. If biopsies

are negative but symptoms persist, other causes of abdominal pain

and diarrhea that are associated with celiac disease are considered,

including irritable bowel syndrome, microscopic colitis, small-bowel

bacterial overgrowth, and lactose or fructose intolerance.

Nonceliac Gluten Sensitivity Recently a subset of patients has

been described with symptoms consistent with celiac disease but with

negative serology and negative biopsies. Upon discontinuation of gluten, they have relief of abdominal pain, diarrhea, headaches/migraines,

and other celiac disease–type symptoms. The etiology of this disorder

is unknown.

■ WHIPPLE’S DISEASE

Whipple’s disease is a chronic, multiorgan disease caused by Tropheryma whipplei, a gram-positive non-acid-fast, periodic acid–Schiff

(PAS) positive rod, which is ubiquitous in the environment. Whipple’s

disease most commonly occurs in middle-aged men. Classic Whipple’s

disease is defined by the presence of arthralgias, weight loss, diarrhea,

and abdominal pain. Other manifestations including central nervous

system (CNS) and cardiac involvement are common and occur later in

the disease. T. whipplei can be detected by polymerase chain reaction

on involved tissue and is difficult to detect in the bloodstream. The

intestinal lesion is also characterized by PAS-positive macrophages.

Clinical Presentation Arthralgias and arthritis are present for an

average of 6 years before the GI symptoms begin, consistent with a persistent and substantial lag in diagnosis, which is still a problem today.

Joint disease is present in >80% of patients. GI manifestations include

diarrhea, abdominal pain, and weight loss from malabsorption. CNS

involvement is common and may include symptoms such as psychiatric manifestations or memory problems. Dementia and encephalitis

may occur in later stages. Cardiac involvement may include endocarditis, pericarditis, and myocarditis.

Diagnosis For patients with GI manifestations, endoscopy with

biopsies is performed and tissue is tested for T. whipplei by polymerase

chain reaction. Tissue is also stained for PAS-positive macrophages and

immunohistochemistry may also be performed to detect T. whipplei.

Treatment Prolonged antibiotics are recommended although the

optimal regimen is still uncertain. Relapses are common, and often

associated with the first manifestations of CNS involvement.

■ TROPICAL SPRUE

Tropical sprue is a poorly understood syndrome that is manifested by

chronic diarrhea, steatorrhea, weight loss, and nutritional deficiencies,

including both folate and vitamin B12. Malabsorption of two unrelated

substances is required for diagnosis. This disease occurs in 8–20% of

people who have had an attack of infectious gastroenteritis in India,

and is considered by some to be a postinfectious complication. It is

prevalent in some but not all tropical areas, including southern India,

Pakistan, the Philippines, Puerto Rico, Haiti, and Cuba. It occurs in

residents of as well as visitors to these areas.

Chronic diarrhea in a tropical environment is most often caused

by infectious agents, including Giardia lamblia, Yersinia enterocolitica,

Entamoeba histolytica, C. difficile, Cryptosporidium parvum, Isospora

belli, Strongyloides stercoralis, and Cyclospora cayetanensis. Tropical

sprue should not be entertained as a possible diagnosis until the presence of cysts and trophozoites has been excluded in three stool samples. Chronic infections of the GI tract and diarrhea are discussed in

Chaps. 46, 133, 134, 163–168, and 223.

In the past few years, the term environmental enteropathy has been

introduced as the diagnosis of many patients (especially infants and

children) who had previously been diagnosed as tropical sprue. However, exact delineation of this newly designated entity is lacking.

Etiology Because tropical sprue responds to antibiotics, the consensus is that it may be caused by one or more infectious agents. Nonetheless, the etiology and pathogenesis of tropical sprue are uncertain.

First, its occurrence is not evenly distributed in all tropical areas; it is

rarely observed in Africa, Jamaica, or Southeast Asia. Second, an occasional individual does not develop symptoms of tropical sprue until

long after having left an endemic area. For this reason, celiac disease

(often referred to as celiac sprue) was originally called nontropical sprue

to distinguish it from tropical sprue. Third, multiple microorganisms

have been identified in jejunal aspirates, with relatively little consistency among studies. Klebsiella pneumoniae, Enterobacter cloacae, and

E. coli have been implicated in some studies of tropical sprue, while

other studies have favored a role for a toxin produced by one or more

of these bacteria. Fourth, the incidence of tropical sprue appears to

have decreased substantially during the past two or three decades,

perhaps in relation to improved sanitation in many tropical countries

during this time. Some have speculated that the reduced occurrence is

attributable to the wider use of antibiotics in acute diarrhea, especially

in travelers to tropical areas from temperate countries. Fifth, the role

of folic acid deficiency in the pathogenesis of tropical sprue requires

clarification. Folic acid is absorbed exclusively in the duodenum and

proximal jejunum, and most patients with tropical sprue have evidence

of folate malabsorption and depletion. Although folate deficiency can

cause changes in small-intestinal mucosa that are corrected by folate

replacement, several earlier studies reporting that tropical sprue could

be cured by folic acid did not provide an explanation for the “insult”

that was initially responsible for folate malabsorption.

The clinical pattern of tropical sprue varies in different areas of

the world (e.g., India vs Puerto Rico). Not infrequently, individuals in

southern India initially report the occurrence of acute enteritis before

the development of steatorrhea and malabsorption. In contrast, in

Puerto Rico, a more insidious onset of symptoms and a more dramatic