QUESTIONS, ANSWERS, CRITIQUES, & SPECIFIC REFERENCES.

1. A 67-year-old woman presented because of a three-year history of watery

bowel movements. She had been in good health except for arthritis treated with

ibuprofen and heartburn treated with omeprazole. The onset of diarrhea had

been insidious. There was no accompanying weight loss and no blood in her

stools. She always had unformed bowel movements, ranging in consistency

from pure water to milkshake-like. She typically had a few bowel movements

after breakfast and lunch; symptoms would then settle down for the day. She

had no bowel movements at night. Defecation typically was urgent and she had

several episodes of fecal incontinence. There had been little improvement with

over-the-counter loperamide.

She had recently been widowed after her husband had succumbed to a

long illness. She has been reclusive and is unwilling to leave the house because

of fear of having to move her bowels. She was brought in by her daughter who

was quite concerned about her mothers health. She had no previous evaluation.

Physical examination shows a well-nourished older woman in no distress.

T98, P 86 regular, R 16, BP 150/85. Height: 65 inches, weight: 160 pounds.

There were no skin lesions. She had no jaundice. Mucous membranes were

well-hydrated. Her chest was clear and cardiac examination was normal.

Abdomen was soft; there was no organomegaly or mass. Digital rectal

examination revealed reduced anal sphincter tone, adequate squeeze pressure,

and no stool in the rectal vault.

Initial laboratory testing included a normal complete blood count. Serum

chemistries showed: BUN 25 mg/dL, creatinine 1.1 mg/dL, K+ 3.2 mmol/L, Na+

134 mmol/L, and albumin 3.5 g/dL. Liver tests were normal. TSH and T4 were

normal.

Urinalysis revealed a specific gravity of 1.020 and pH of 5.5; dipstick was

negative.

Stool culture yielded normal flora; stool examination for ova and parasites was

negative; stool Clostridium difficile toxin was negative.

The test most likely to give a definitive diagnosis in this patient is:

A. Stool for giardia antigen

B. 48-hour quantitative stool collection for electrolytes and fat

C. Biopsy of colonic mucosa

D. Biopsy of small bowel mucosa

E. Fat pad biopsy

The recommended response is C.

Selection of a definitive test depends on the utility of the test in making a

particular diagnosis and the pre-test probability of that diagnosis. This

relationship is formalized as Bayes theorem and is usedconsciously or notby

physicians as they evaluate patients with specific problems. Utility is assessed

by sensitivity (the likelihood that a patient with the problem will be detected, i.e.,

true positive) and specificity (the likelihood that a patient without the problem will
not have a positive test, i.e., true negative). These are characteristics of the test

and are not affected by the frequency of the problem in the population. The

higher the sensitivity and specificity are, the more definitive the test is. Even a

definitive test will yield false positives on occasion, however. This is most likely

to occur when the prevalence of a condition is low and many more people

without the condition will be tested in the hope of identifying those that do have

the condition. In those situations preliminary testing to enrich the population to

be tested with affected individuals makes sense. On the other hand, if a

diagnosis is very likely based on presentation and initial testing, use of a

definitive test can confirm the diagnosis with a high degree of certainty.

In the case presented an older woman has developed watery diarrhea

without evidence for malabsorption. The onset was not precipitous; she had no

bleeding, had been in good health except for arthritis and heartburn, and had

been ill for a long time. These features make a diagnosis of microscopic colitis

(lymphocytic colitis or collagenous colitis) more likely than any other competing

diagnosis. It is therefore quite reasonable to proceed with a definitive test (e.g.,

colonoscopy) that is likely to confirm the diagnosis, rather than proceeding with a

screening test (e.g., stool analysis) to narrow down the differential diagnosis by

identifying the type of diarrhea (i.e., secretory vs. inflammatory vs. fatty), as in

Answer B. Answers A, D and E are all definitive tests for less likely diagnoses,

such as giardiasis (course too long), celiac disease (unlikely to present at this

age), and amyloidosis (a rare disease).

References:

Schiller LR. Chronic diarrhea. Gastroenterology 2004;127:287-93.

Chande N, Driman DK, Reynolds RP. Collagenous colitis and lymphocytic

colitis: patient characteristics and clinical presentation. Scand J

Gastroenterol 2005; 40:343-7.

Stroehlein JR. Microscopic colitis. Curr Opin Gastroenterol 2004;20:27-

31.

2. A 20-year-old man presented to the Emergency Room with severe weakness.

He gave a history of loose stools since childhood. Admission laboratory data

included: serum sodium 134 mmol/L, serum potassium 2.1 mmol/L, serum

chloride 85 mmol/L, serum bicarbonate 45 mmol/L and creatinine 3.5 mg/dL. He

received 6 liters of normal saline with potassium intravenously over the first 24

hours in the hospital and serum electrolyte concentrations normalized. Spot

stool sample revealed [Na+] of 80 mmol/L. [K+] of 50 mmol/L, and [Cl-] of 95

mmol/L.

His condition is most likely due to a mutation of what gene?

A. APC (adenomatous polyposis coli)

B. DRA (down-regulated in adenoma)

C. CFTR (cystic fibrosis transmembrane regulator)

D. MEN-1 (multiple endocrine neoplasia-type 1)

 E. NBC1 (Na+-bicarbonate cotransporter-1)

The recommended response is B.

This patient with congenital diarrhea with alkalosis suffers from chloridorrhea,

also known as congential chloride diarrhea. The condition is characterized by

watery diarrhea present from birth, elevated serum bicarbonate concentration,

and very high stool chloride concentration (>90 mmol/L). It is due to a mutation

in the DRA (down-regulated in adenoma) gene, also known as SLC26A3

(Answer B). This gene is one member of a family of solute-linked carrier (SLC)

molecules that are involved with the transport of chloride, bicarbonate, sulfate,

iodide, oxalate, formate, hydroxyl and fructose across plasma membranes.

SLC26A3 is an electroneutral chloridebicarbonate exchanger that is present in

the ileum and colon. Mutations in this gene make chloride poorly absorbable in

the distal intestine and result in retention of fluid within the lumen in proportion to

the unabsorbed ions. Diarrhea can be reduced by reducing the number of

chloride ions in the lumen by inhibiting gastric HCl secretion with a proton-pump

inhibitor or by stimulating an alternative pathway for chloride absorption by

administering butyrate.

The APC gene (Answer A) is mutated in patients with familial polyposis

syndrome and has nothing to do with chloride transport. CFTR (Answer C) is a

chloride channel in the mucosa that is active in mucosal chloride secretion;

mutations in its gene are responsible for cystic fibrosis. MEN-1 (Answer D) is the
gene that is mutated in multiple endocrine neoplasia, type 1. NBC1 (Answer E)

is a sodiumbicarbonate cotransporter in the proximal tubule; mutations of its

gene are associated with renal tubular acidosis with ocular abnormalities.

References:

Dawson PA, Markovich D. Pathogenetics of the human SLC26

transporters. Curr Med Chem 2005;12:385-96.

Canani RB, Terrin G, Cirillo P, Castaldo G, Salvatore F, Cardillo G,

Coruzzo A, Troncone R. Butyrate as an effective treatment of congenital chloride

diarrhea. Gastroenterology 2004;127:630-4.

3. A 75-year-old woman presents for evaluation of chronic diarrhea and weight

loss. She has had loose stools and excessive flatus for six months. During that

time her weight has decreased from 110 pounds to 90 pounds (height 67 inches).

Diarrhea mainly occurs after meals, but sometimes wakes her from sleep. Stools

are especially malodorous and are of varying consistency, but rarely formed.

She occasionally notes oil on the surface of the water in the commode. There is

no blood in the stool.

Twenty years ago she had an antrectomy and vagotomy for a bleeding

prepyloric ulcer. She had intermittent heartburn and was taking omeprazole for

suspected reflux disease. She did not have diabetes, heart, or liver disease.

Physical examination showed a thin elderly woman in no distress.

Abdomen was slightly distended and the percussion note was tympanitic. Bowel
sounds were active. Anal sphincter tone was reduced and squeeze was weak.

Stool was brown and fecal occult blood test was negative.

Laboratory tests revealed: hemoglobin 11.5 g/dL, MCV 105 fL, total

protein 5.0 g/dL, albumin 2.9 g/dL, serum vitamin B12 level 100 pmol/L, and

serum folate 18 ng/mL.

Her diarrhea is most likely due to:

A. Vitamin B12 deficiency

B. Post-vagotomy dumping syndrome

C. Superior mesenteric artery syndrome

D. Small bowel bacterial overgrowth

E. Chronic pancreatitis

The recommended response is D.

Diarrhea in the elderly can have many causes. Since so many patients are on

multiple medications, drug-induced diarrhea must be considered. She has been

taking omeprazole, and diarrhea is a common side-effect of all proton-pump

inhibitors. She has had previous gastric surgery which is also a risk factor for

diarrhea. Post-gastrectomy diarrhea can be due to anatomical changes

produced by the surgery or to complications of the surgery. Anatomical changes

can produce dumping syndrome due to unregulated gastric emptying (Answer B),

but symptoms typically begin soon after surgery and not years later. B12
deficiency (Answer A) takes some time to develop after surgery due to relatively

large body stores and the time it takes to develop atrophic gastritis post-

operatively. Although this patient has documented B12 deficiency, by itself B12

deficiency is an unlikely cause for chronic diarrhea. Other problems that can

develop over time include gastrocolic fistula and small bowel bacterial

overgrowth.

Small bowel bacterial overgrowth (Answer D) is a relatively common

cause for diarrhea and weight loss in the elderly. Factors associated with an

increased likelihood of a positive glucose breath hydrogen test include increasing

age, low serum vitamin B12 level, low serum albumin concentration, previous

partial gastrectomy, previous right hemicolectomy, the presence of small bowel

diverticula, and use of a proton pump inhibitor. Elderly patients with chronic

diarrhea and any of these risk factors should be considered to have small bowel

bacterial overgrowth until proven otherwise. Small bowel bacterial overgrowth

may occur without any of these factors and may be due to motility disorders in

the small bowel.

Superior mesenteric artery syndrome (Answer C) occurs when weight loss

leads to reduction of the mesenteric fat pad and obstruction of the duodenum by

the superior mesenteric artery. This produces vomiting and abdominal pain, but

is not a cause of chronic diarrhea. Chronic pancreatitis (Answer E) can cause

steatorrhea and weight loss, but she had no particular predisposing factors for

this condition.
References:

Elphick DA, Chew TS, Higham SE, Bird N, Ahmad A, Sanders DS. Small

bowel bacterial overgrowth in symptomatic older people: can it be diagnosed

earlier? Gerontology 2005;51:396-401.

Teo M, Chung L, Tran C, Kritas S, Butler R, Cummins A. Small bowel

bacterial overgrowth is a common cause of chronic diarrhea. J Gastroenterol

Hepatol 2004;19:904-9.

Singh VV, Toskes PP. Small bowel bacterial overgrowth: presentation,

diagnosis, and treatment. Curr Treat Options Gastroenterol 2004;7:19-28.

4. Probiotics have been suggested to be helpful in all of the following clinical

situations EXCEPT:

A. Irritable bowel syndrome

B. Inflammatory bowel disease

C. Small bowel bacterial overgrowth

D. Recurrent Clostridium difficile colitis

E. Bile reflux gastritis

The recommended response is E.

Probiotics have received a great deal of attention in the last few years as

attention has focused on the interaction of the normal gut flora with the

gastrointestinal tract. The gastrointestinal immune system seems to cultivate the

growth of some species and suppress the growth of pathogenic species.

Conversely, probiotic bacteria and yeast seem to influence the function of the

gastrointestinal immune system, moderating excessive activation and promoting

more normal barrier function by effects mediated by cytokines.

These multiple effects and observations from clinical studies suggest that

some probiotic bacteria may be effective in the management of a number of

gastrointestinal disorders, although proof of effect is lacking for most of these

conditions. There are probably important differences in effectiveness between

different strains or combinations of strains in various conditions, but these

differences have not been well investigated yet. In most cases data are

preliminary or limited with varying results, but the overall impression is that there

may be a therapeutic effect in several conditions.

The rationale for treating irritable bowel syndrome (Answer A) with

probiotics is that IBS may be associated with low-level inflammatory changes that

may be modified by probiotics. The study by OMahoney et al cited below

showed benefit of bifidobacterium, but not lactobacillus and correlated the

improvement with normalization in cytokine profiles. Variable effects have been

noted with other preparations, but study design has not always been optimal.

Inflammatory bowel disease (Answer B) also has been treated with

probiotics with some evidence of efficacy. Ulcerative colitis and pouchitis appear

to be most successfully managed by probiotics, and immune responses may be

modified in patients with Crohns disease with these bacteria. The role of

probiotic treatment in these conditions remains to be determined.

 Although somewhat counterintuitive, small bowel bacterial overgrowth

(Answer C) also may be positively affected by probiotic therapy. Limited studies

in patients with short bowel syndrome suggest some benefit with some strains.

Additional studies are needed in other clinical settings.

Recurrence of Clostridium difficile colitis (Answer D) is a major problem.

Use of Saccharomyces boulardii or Lactobacillus spp. seems to reduce the risk

of recurrence.

Although probiotics have been suggested as being of potential help in

treatment of Helicobacter pylori gastritis, there have been no studies of patients

with bile reflux gastritis (Answer E).

References:

Sartor RB. Probiotic therapy of intestinal inflammation and infections. Curr

Opin Gastroenterol 2005;21:44-50.

OMahoney L, McCarthy J, Kelly P, Hurley G, Luo F, Chen K, OSullivan

GC,Kiely B, Collins JK, Shanahan F, Quigley EM. Lactobacillus and

bifidobacterium in irritable bowel syndrome: symptom responses and relationship

to cytokine profiles. Gastroenterology 2005;128:541-51.

Bibiloni R, Fedorak RN, Tannock GW, Madsen KL, Gionchetti P, Campieri

M, DeSimone C, Sartor RB. VSL#3 probiotic-mixture induces remission in

patients with active ulcerative colitis. Am J Gastroenterol 2005;100:1539-46.

Matarese LE, Seidner DL, Steiger E. The role of probiotics in

gastrointestinal disease. Nutr Clin Pract 2003;18:507-16.

Surawicz CM. Treatment of recurrent Clostridium difficile-associated

disease. Nat Clin Pract Gastroenterol Hepatol 2004;1:32-8.

5. A 30-year-old man presents with intermittent nausea, vomiting, diarrhea, and

flushing for two years. He has a history of allergies and intermittent hives.

Diarrhea is predominantly postprandial and is watery. The flushing is

erythematous and mainly on the head and neck. His weight has dropped from

150 to 130 pounds (height 67 inches). He has had no fevers or chills.

Physical examination showed a thin man in no acute distress. Vital signs

were normal. Skin showed small pigmented urticaria scattered over the trunk.

Dermatographism was present. Lymph nodes were palpable in the neck and

groin. The spleen was enlarged; there was no hepatomegaly. A trace of

peripheral edema was noted at the ankles.

Laboratory testing showed a hemoglobin of 10 g/dL, WBC of 12,000/mm3

with 12% eosinophils. Total protein was 6 g/dL with a serum albumin of 3.2 g/dL.

CT scan of the abdomen and pelvis showed splenomegaly and mesenteric

adenopathy; no masses in the liver. Small bowel biopsy was interpreted as

showing nonspecific inflammation.

The most likely diagnosis is:

A. Systemic mastocytosis

B. Gastric carcinoid tumor

C. Ileal carcinoid tumor

D. Non-Hodgkins lymphoma
 E. Mycobacterium avium intracellulare complex

The recommended response is A.

Systemic mastocytosis (Answer A) is defined as an accumulation of mast cells in

one or more organs that results in symptoms due to production of mast cell

mediators or to infiltration of tissues. Mast cells are normal constituents of the

innate immune system derived from bone marrow precursors and distributed in

tissues throughout the body. They respond to a number of stimuli with

production of a number of mediators including histamine, leukotrienes,

prostanoids, proteases, cytokines and chemokines. Mastocytosis can be limited

to the skin (cutaneous mastocytosis) which is a benign condition that may

regress spontaneously. Systemic mastocytosis can be indolent, aggressive,

associated with clonal non-mast cell proliferation, or part of mast cell leukemia.

Indolent and aggressive systemic mastocytosis is associated with a somatic c-kit

mutation at codon 816 (usually D816V). The more neoplastic forms of the

disease have additional mutations. Although the c-kit mutation might be

expected to provide a target for tyrosine kinase inhibitors, systemic mastocytosis

is relatively resistant to imatinib (Gleevac)). Symptoms in indolent and early

aggressive systemic mastocytosis are largely driven by mediator release and

treatment is targeted at preventing mediator release with oral cromolyn sodium

and blocking mediator effects with antihistamines, H2-receptor antagonists, and

NSAIDs. Cytoreductive therapy is reserved for patients in whom infiltration with

mast cells is producing organ dysfunction.

 Clinical features that suggest mastocytosis include the presence of

dermatographism and urticaria pigmentosa, The flush is a typical histamine flush

which is erythematous rather than violaceous. Elevation of blood histamine level

has been suggested as a diagnostic test for this condition, but formal analysis of

the utility of this test is not available. Mast cells do not stain well with

hematoxylin and eosin and so they can be overlooked in routine biopsy

specimens; toluidine blue or immunological staining must be used for

identification. None of the alternative diagnoses (Answers B, C, D, or E) match

the clinical scenario as well as systemic mastocytosis.

References:

Krishnaswamy G, Ajitawi O, Chi DS. The human mast cell: an overview.

Methods Mol Biol 2006;315:13-34.

Valent P, Akin C, Sperr WR, Mayerhofer M, Fodinger M, Fritsche-Polanz

R, Sotlar K, Escribano L, Arock M, Horny HP, Metcalfe DD. Mastocytosis:

pathology, genetics, and current options for therapy. Leuk Lymphoma

2005;46:35-48.

6. A 50-year-old woman presented with chronic diarrhea for 2 years. Diarrhea

woke her from sleep at 5 AM and she typically had 4 watery stools each morning.

Symptoms settled down after lunch. She had no pain and no fecal incontinence.

The diarrhea began soon after she had a cholecystectomy for symptomatic

cholelithiasis. Histologic findings were consistent with chronic cholecystitis.

Colonoscopy done six months ago was normal and colon biopsies were normal.

She had tried loperamide 4 mg QID, diphenoxylate with atropine 2 tablets QID,

hyoscyamine 0.125 mg QID, and cholestyramine 4 g each morning without

benefit.

The next step in management should be:

A. 48-h stool collection for electrolytes and fat output

B. CT scan of the abdomen and pelvis

C. Alosetron 1 mg BID

D. Metamucil 4 g hs

E. Colestipol 4 g hs

The recommended response is E.

Alteration of stool consistency is a frequent consequence of cholecystectomy.

Relatively few patients present for evaluation of diarrhea after cholecystectomy,

however, and so many have only modest problems that they learn to live with.

The mechanism of diarrhea after cholecystectomy is not entirely understood, but

probably involves bile acid malabsorption. Some have said that diarrhea after

cholecystectomy only occurs in patients with irritable bowel syndrome, but since

there is no test for IBS, this is just conjecture. One scheme for diarrhea is based

on the fact that while fasting overnight bile acid which is normally stored in the

gall bladder is present in the lumen of the small intestine where it is subject to the
migrating motor complex and can be swept into the colon. Since relatively little

fluid is swept into the colon along with the bile acid, the concentration of bile acid

in the colon may exceed the cathartic threshold and produce a laxative effect.

This accounts for the prominence of morning diarrhea in this population and the

need to give a bedtime dose of bile acid-binding resin so that the bile acid

concentration in the cecum can be reduced below the cathartic threshold.

Studies of patients with diarrhea and idiopathic bile acid malabsorption suggest

that these patients have more rapid transit through the small bowel and colon

than healthy subjects.

The patient presented had the onset of diarrhea soon after

cholecystectomy; this is not always the case, since alterations in bowel motility

occurring later in time may upset the status quo. The morning diarrhea and

failure to respond to drugs given during the day are typical.

Management options include further evaluation or empiric trials of other

drug regimens. Further evaluation makes sense if the history of cholecystectomy

was not available or was overlooked. Measurement of electrolyte concentrations

and fat output can be used to categorize the type of diarrhea and reduce the

differential diagnosis to a more manageable length. CT scanning can be used to

identify tumors and is increasingly valuable as a means of looking at the

intestinal wall for diffuse inflammation or obstruction. The diagnostic test that

might be of most value is some measurement of bile acid malabsorption. In

Europe the Se-HCAT test can be used to measure bile acid retention after a

dose of radiolabeled bile acid is administered. This test has not been approved
in the United States where only research laboratories make any effort to measure

bile acid excretion. The utility of such a test is uncertain since many patients with

chronic diarrhea will have bile acid malabsorption and this is not always

predictive of the effect of bile acid binders.

Probably the best test for the significance of bile acid malabsorption as a

cause for diarrhea is an empiric trial of a bile acid-binding resin given at an

appropriate time (bedtime). Thus answer E is the correct response. Further

diagnostic tests (Answers A and B) are looking for diagnoses that have a lower

pre-test probability than bile acid malabsorption. Therapy with alosetron (Answer

C) is limited to women with irritable bowel syndrome characterized by diarrhea;

this patient had no pain and thus did not have IBS. Metamucil (Answer D) might

improve stool consistency, but is unlikely to treat the diarrhea as effectively as

other options.

References:

Sadik R, Abrahamsson H, Ung KA, Stotzer PO. Accelerated regional

bowel transit and overweight shown in idiopathic bile acid malabsorption. Am J

Gastroenterol 2004;99:711-8.

Robb BW, Matthews JB. Bile salt diarrhea. Curr Gastroenterol Rep

2005;7:379-83.

7. A 57-year-old man presents for evaluation of long-standing diabetes. He has

had insulin-dependent diabetes mellitus for 25 years. He has developed severe

peripheral neuropathy and has a difficult time keeping his blood sugar below 200

mg%. Over the last 5 years he has had continuous diarrhea and has lost 50

pounds (210 pounds to 160 pounds, height 66 inches). He has frequent bouts of

fecal incontinence. 48-hour stool collection yielded a fecal fat output of 24 g/24h.

Likely causes for this picture include all of the following EXCEPT:

A. Diabetic neuropathy

B. Excessive sorbitol ingestion

C. Small bowel bacterial overgrowth

D. Celiac disease

E. Pancreatic exocrine insufficiency

The recommended response is B.

Long-standing insulin-dependent diabetics frequently develop diabetic

neuropathy which can affect both peripheral and autonomic nerves. Diarrhea is

a frequent complication occurring in upwards of 20% of these patients.

The key distinction to make in assessing such patients is to distinguish

patients with steatorrhea from those without it. Small bowel bacterial overgrowth,

celiac disease and pancreatic exocrine insufficiency occur with greater frequency

in diabetics than in the general population and should be sought with appropriate

tests in diabetics with steatorrhea. Diabetics without steatorrhea may have a

secretory diarrhea that seems to be due to reduction in adrenergic input to the

enterocytes, probably due to diabetic autonomic neuropathy. Other problems

such as ingestion of excess sorbitol, a sweetener used in many dietetic products,

produce an osmotic diarrhea without steatorrhea.

In this patient steatorrhea is present, making Answers C, D, and E likely

and answer B unlikely. Answer A, diabetic autonomic neuropathy, is probably

the explanation for his fecal incontinence. Incontinence is not just a

manifestation of severe diarrhea, but instead usually represents a problem with

the neuromuscular apparatus preserving continence. Defects in diabetics with

fecal incontinence include impaired sensation and decreased anal sphincter

strength, both probably due to neuropathy.

References:

Folwaczny C, Riepl R, Tschop M, Landgraf R. Gastrointestinal

involvement in patients with diabetes mellitus: Part I (first of two parts).

Epidemiology, pathophysiology, clinical findings. Z Gastroenterol 1999;37:803-

15.

Ziegler D. Diagnosis and treatment of diabetic autonomic neuropathy.

Curr Diab Rep 2001;1:216-27.

8. A 22-year-old woman presents with a seven-year history of abdominal pain

and diarrhea. The pain is crampy and is located in the left lower quadrant. It is

accentuated before bowel movements and goes away after evacuation. Stools
are loose and free of blood. She has weeks of symptoms followed by a few

weeks with formed stools and without problems. Stress seems to magnify her

symptoms. She does not awake at night with diarrhea, has urgency but not

incontinence. The problems first began after a trip to Mexico that was

complicated by travelers diarrhea.

Her family physician ordered a complete blood count, comprehensive

metabolic profile, thyroid-stimulating hormone level, stool culture, stool ova and

parasite examination, and stool Clostridium difficile toxin test. All tests were

negative or normal. Physical examination was normal.

She tried fiber supplements, loperamide, hyoscyamine, dicyclomine,

clidinium with chlordiazepoxide, and methylscopolamine without benefit. Her

symptoms were affecting her ability to work and to enjoy an active social life.

The therapy shown by controlled trials to be most likely to result in improvement

in this setting is:

A. Diphenoxylate with atropine

B. Amitriptyline

C. Alosetron

D. Tegaserod

E. Paroxetine

The recommended response is C.

This patient has classical irritable bowel syndrome with diarrhea. Although

almost everyone with chronic diarrhea is diagnosed at least initially with irritable

bowel syndrome, the diagnosis should be restricted to individuals like this patient

who have abdominal pain that is closely linked to abnormal stool frequency or

consistency. When individuals meet this criterion, it is very likely that they have

IBS and not some other diagnosis and further work-up can be avoided unless

alarm symptoms are present, such as blood in the stool or weight loss.

Recent attention has focused on post-infectious IBS as a potential clue to

the etiology of IBS. Many patientslike this oneseem to first develop IBS

symptoms in the wake of an infectious enteritis. The concept is that infection

leads to sensitization of the enteric nervous system to normal stimuli perhaps

due to persisting low grade inflammation. Whether this mechanism is accurate

or not, it seems as though at least 3% of individuals experiencing bacterial

enteritis end up with chronic symptoms.

Treatment of IBS with diarrhea has improved as more drugs are

developed and tested using modern experimental designs. Symptomatic therapy

with antispasmodics, such as anticholinergic drugs, and antidiarrheals, such as

diphenoxylate with atropine (Answer A) is time-honored, but has been poorly

studied in the IBS population. The effectiveness of symptomatic therapy has not

been assessed with modern methods and it seems likely that several agents may

be needed to deal with all of the symptoms of IBS. Controlling diarrhea does not

necessarily impact symptoms such as bloating or pain. Tricyclic antidepressant

drugs (Answer B) and more modern antidepressants (Answer E) have been

suggested as pain-modifying drugs that may be useful in treating IBS. Again,

clinical studies have been limited in the IBS population. One recent study

(Drossman et al. 2003) suggests that desipramine can be helpful in patients with

functional bowel problems. The few published studies with selective serotonin

reuptake inhibitors (SSRIs) have not been convincing as yet.

Alosetron (Answer C) and tegaserod (Answer D) represent two drugs that

are similar in that they work at serotonin receptors in the enteric nervous system,

but which are two very different drugs in their actions. Alosetron is a selective 5-

HT3-receptor antagonist that blocks the effect of serotonin on nerve endings that

are thought to convey sensation to higher centers and help to stimulate

peristalsis. Administration of this drug reduces sensations from the gut and

peristalsis. Tegaserod is a 5-HT4-receptor agonist that stimulates 5-HT4

receptors (largely located presynaptically in the enteric nervous system) to

accentuate the release of neurotransmitters in the peristaltic reflex and speed

aboral transit. Sensation is reduced by tegaserod by an unknown mechanism.

Alosetron is used in IBS with diarrhea and reduces pain and tends to normalize

bowel habits. Tegaserod is used in IBS with constipation to reduce discomfort

and bloating and to increase the frequency of bowel movements; diarrhea is its

main side-effect. Since this patient has IBS with diarrhea, alosetron is the drug

of choice in this situation (Answer C).

Alosetron has been associated with an increased incidence of ischemic

colitis in patients with IBS, whosomewhat surprisinglyare at increased risk of

colon ischemia in the first place. This caused the drug to be withdrawn and then
reintroduced with controls on its use. It should only be given to patients with

refractory IBS with diarrhea. The presence of constipation is a contraindication

to its use. Patients should be given low doses to start (0.5 mg once or twice a

day) and then be monitored closely for constipation or new abdominal pain as the

dose is increased. The vast majority of patients given alosetron do not have

serious side-effects and many do quite well with it.

References:

Tillisch K, Chang L. Diagnosis and treatment of irritable bowel syndrome:

state of the art. Curr Gastroenterol Rep 2005;7:249-56.

Schoenfeld P. Efficacy of current drug therapies in irritable bowel

syndrome: what works and does not work. Gastroenterol Clin North Am

2005;34:319-35.

Drossman DA, Toner BB, Whitehead WE, Diamant NE, Dalton CB,

Duncan S, Emmott S, Proffitt V, Akman D, Frusciante K, Le T, Meyer K,

Bradshaw B, Mikula K, Morris CB, Blackman CJ, Hu Y, Jia H, Li JZ, Kock GG,

Bangdiwala SI. Cognitive-behavioral therapy versus education and desipramine

versus placebo for moderate to severe functional bowel disorders.

Gastroenterology 2003;125:19-31.

Connor BA. Sequelae of travelers diarrhea: focus on postinfectious

irritable bowel syndrome. Clin Infect Dis 2005;41(Suppl 8):S577-86.

Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical

review on irritable bowel syndrome. Gastroenterology 2002;123:2108-31.

9. The prevalence of celiac disease varies in different populations. Which

column represents the best current estimate of the prevalence of celiac disease

in average-risk and at-risk Western European populations in North America and

Europe?

Population A B C D E

General population ~0.01% ~0.01% ~0.1% ~1% ~5%

First-degree relatives ~1% ~5% ~10% ~20% ~50%

Symptomatic iron deficiency ~0.1 13% 57% 10-15% 20-25%

Diabetics ~0.1% ~0.5% 12% 36% 10-15%

Osteoporosis ~0.01% ~0.01% ~0.5% 13% 5-7%

The recommended response is D.

Celiac disease is more common than previously thought, particularly in special

populations. The best estimates from a systemic review published in 2005 are

shown in Column D. The prevalence in a gastroenterology clinic depends on the

mix of patients seen and the reasons for suspecting celiac disease. The

relatively high pretest probabilities of celiac disease and the precision of

screening tests for celiac disease (particularly antiendomysial and anti-tissue

transglutaminase IgA antibodies) makes screening worthwhile in patients

presenting with a variety of gastrointestinal complaints, especiallybut not limited

tochronic diarrhea.

Although much has been learned about the molecular pathogenesis of

celiac disease, the factors that determine whether symptoms develop, when

symptoms develop, and which symptoms develop are largely unknown. It is

clear that an interplay of genetic and environmental factors is required.

References:

Dube C, Rostom A, Sy R, Cranney A, Saloojee N, Garritty C, Sampson M,

Zhang L, Yazdi F, Mamaladze V, Pan I, Macneil J, Mack D, Patel D, Moher D.

The prevalence of celiac disease in average-risk and at-risk Western European

populations: a systematic review. Gastroenterology 2005;128(4 Suppl 1):S57-

67.

Duggan JM. Coeliac disease: the great imitator. Med J Aust

2004;180:524-6.

10. The most commonly recognized bacterial cause of diarrhea in patients with

HIV infection is:

A. Clostridium difficile

B. Shigella flexneri

C. Yersinia enterocolitica

D. Escherichia coli

E. Mycobacterium avium intracellulare

The recommended response is A.

HIV disease has changed with time as more patients receive highly effective

antiretroviral therapy and maintain immune competence for longer periods of

time. An epidemiological survey of HIV-infected persons receiving medical care

in the United States showed that the annual incidence of bacterial diarrhea was

7.2 cases per 1000 person-years in the entire cohort. Although opportunistic

infections typically are considered in patients with HIV infection, Clostridium

difficile was the most commonly recognized bacterial cause of diarrhea with an

incidence of 4.1 cases per 1000 person-years. Patients with a diagnosis of AIDS

were more than twice as likely to have bacterial diarrhea than those without

AIDS, with more severe cases having a higher attack rate. The overall incidence

of bacterial diarrhea in patients with AIDS fell by 60% from 1992 to 2002, but the

attack rate in the cohort of HIV-infected patients without AIDS was unchanged.

Bacterial diarrhea remains an important issue in HIV-infected patients.

References:

Sanchez TH, Brooks JT, Sullivan PS, Juhasz M, Mintz E, Dworkin MS,

Jones JL. Bacterial diarrhea in persons with HIV infection, United States, 1992

2002. Clin Infect Dis 2005;41:1621-7.

Thom K, Forrest G. Gastrointestinal infections in immunocompromised

hosts. Curr Opin Gastroenterol 2006;22:18-23.

11. An 18-year-old previously healthy man presents with diarrhea following a trip

to Mexico at Spring break.

The second most likely cause of diarrhea (after enterotoxigenic E. coli) is:

A. Enteroinvasive E. coli

B. Shigella flexneri

C. Norovirus

D. Giardia

E. Entameba histolytica

The recommended response is C.

Travelers diarrhea remains an important problem. It is clear that the spectrum of

organisms likely to cause travelers diarrhea depends on where one travels.

Likewise efforts to prevent acute diarrhea during travel must be tailored to the

area in which travel takes place. For example, while a poorly absorbable

antibiotic would work well in travelers diarrhea acquired in Mexico (mainly due to

E. coli), it might be less successful in Southeast Asia where ciprofloxacin-

resistant, invasive Campylobacter is a problem.

Non-invasive entertoxigenic E. coli is still the most likely cause of diarrhea

in travelers to Mexico (approximately 47% of isolates), but other infectious agents

are also identifiable. The second most common isolate in a recent study by
DuPont was norovirus (previously known as Norwalk agent). This is a frequent

cause of common-source outbreaks of diarrhea in other settings, such as

evacuees from Hurricane Katrina being housed in temporary facilities. The

organism is quite easy to acquire and produces the clinical spectrum of acute

gastroenteritis, including significant nausea and vomiting. Attack rates are ~80%

even though about 50% of adults have evidence of previous exposure, probably

because of the large number of strains. In students from the US traveling to

Mexico 17% of episodes of travelers diarrhea were due to noroviruses.

Preventative treatment of travelers diarrhea with antibiotics, particularly

the poorly absorbed antibiotic, rifaximin, has been proposed for travelers with

special needs to avoid diarrhea (e.g., people on a tight schedule who can not

afford any time for illness). Antibiotics will not prevent travelers diarrhea due to

this virus, however.

Reference:

Ko G, Garcia C, Jiang ZD, Okhuysen PC, Belkind-Gerson J, Glass RI,

DuPont HL. Noroviruses as a cause of travelers diarrhea among students from

the United States visiting Mexico. J Clin Microbiol 2005;43:6126-9.

DuPont HL. Travelers diarrhea: antimicrobial therapy and

chemoprevention. Nat Clin Pract Gastroenterol Hepatol 2005;2:191-8.

Thielman NM, Guerrant RL. Clinical practice. Acute infectious diarrhea. N

Engl J Med 2004;350:38-47.

12. A 30-year-old woman developed diarrhea three weeks prior to her office

visit. She had been camping out in the mountains with her family immediately

prior to the onset of diarrhea. No other family members had become ill. She had

no fever, chills, rectal bleeding or vomiting, but did have some epigastric distress

after meals and increased flatus. She had lost 10 pounds during the illness. The

diarrhea had shown no tendency to improve over the three weeks. Physical

examination was unremarkable.

The most likely cause for this scenario is:

A. Enterotoxigenic E. coli

B. Shigella flexneri

C. Norovirus

D. Amebiasis

E. Giardiasis

The recommended response is E.

Diarrhea lasting more than a week but less than a month has been characterized

as persistent diarrhea to distinguish it from more acute diarrheas that typically

run their courses within one week and are due to predominantly self-limited

infections and also from chronic diarrheas that last longer and are unlikely to

have an infectious etiology. Whereas the typical bacterial or viral diarrheas

(Answers A, B and C) last less than a week, persistent diarrhea include bacterial
infections that have a longer time course (e.g., Clostridium difficile, Pleisiomonas

spp., and Aeromonas spp.) and protozoal diarrheas (e.g., giardiasis,

cryptosporidiosis, microsporidiosis).

The clinical scenario may give some additional clues to diagnosis. The

fact that this developed during a camping trip suggests that it may be protozoal

diarrhea due to giardiasis (Answer E) or cryptosporidiosis. Amebiasis is less

likely because it is due to an invasive organism that may produce rectal bleeding

or fever as part of a dysentery syndrome.

Diagnosis of protozoal diarrheas may be difficult and expensive. Ova and

parasite examination is operator-dependent and has limited sensitivity. Enzyme-

linked immunoassays and other advanced techniques to detect giardia and

cryptosporidium antigens have been reported to have sensitivities well over 90%.

This means that fewer repeat specimens would be required to rule out protozoal

diarrhea. Any of these tests may cost well over $100 per specimen.

Treatment of protozoal diarrheas has become somewhat simpler with the

development of new agents. Giardiasis can be cured in 80100% of patients

with a single 2 g dose of tinidazole or with 500 mg of nitazoxanide twice a day for

three days.

Cryptosporidiosis responds to the same dose of nitazoxanide. Amebiasis can be

treated with tinidazole 2 g daily for three days. Metronidazole can be used to

treat giardiasis and amebiasis, but the duration of therapy is longer than with

either of the new agents.

References:

Caccio SM, Thompson RC, McLauchlin J, Smith HV. Unravelling

cryptosporidium and giardia epidemiology. Trends Parasitol 2005;21:430-7.

Petri WA. Treatment of giardiasis. Curr Treat Options Gastroenterol

2005;8:13-17.

Smith HV, Corcoran GD. New drugs and treatment for cryptosporidiosis.

Curr Opin Infect Dis 2004;17:557-64.

13. A 48-year-old woman presented to the hospital with severe abdominal pain

and anorexia. The pain had started suddenly earlier that day. Initially it was

located in the periumbilical region, but it then localized to the right lower

quadrant. CT scan in the Emergency Room showed acute appendicitis and she

was taken to the operating room for an appendectomy. During the surgery the

appendix ruptured and drains were placed.

Two weeks later she developed a small bowel obstruction. After

conservative therapy with nasogastric suction failed, she underwent exploratory

laparotomy. Extensive adhesions were found and a right hemicolectomy and

extensive ileectomy were done. An ileo-transverse colostomy was created.

She recovered from surgery, but had voluminous diarrhea. Treatment

with loperamide and then diphenoxylate with atropine failed to control the

diarrhea. She was given cholestyramine 4 g QID without improvement. She

required total parenteral nutrition to maintain her weight and serum albumin.

Six months later she was no better and further evaluation commenced.
Stool collection on a diet that included 100 g fat/day yielded 2100 g of stool

containing 40 g of fat. Stool [Na+] was 80 mmol/L and stool [K+] was 40 mmol/L.

Small bowel follow-through x-ray showed no evidence of bowel obstruction.

Approximately 7 feet of small bowel was present. Colonoscopy showed her

anastomosis to be patent; colon mucosal biopsies were normal histologically.

Upper gastrointestinal endoscopy was normal as were small bowel biopsies.

Reasonable management options include administration of all of the following

EXCEPT:

A. Deodorized tincture of opium

B. Belladonna

C. Cyanocobalamin

D. Conjugated bile acid

E. Bile acid binding resin

The recommended response is E.

Post-resection diarrhea is a common side-effect of extensive intestinal resection

that has impacts on nutrition, fluid and electrolyte balance, and quality of life.

Patients quickly learn that eating increases diarrhea and that fasting can reduce

diarrhea. Food intake suffers and leads to weight loss and malnutrition.

Malabsorption also limits nutrition, but sufficient protein and calories can be

absorbed from a few feet of small bowel to maintain body weight in most
individuals. Thus the goal is to utilize the remaining bowel as efficiently as

possible.

Keeping nutrients available to the absorbing surface can be done by small

frequent feedings, slowing intestinal motility with potent opiates (typically opium

or morphine) and anticholinergics, such as belladonna (Answers A and B). Fat

absorption is a particular problem. Patients with extensive ileal resections cannot

reabsorb enough bile acid and the liver can not synthesize enough new bile acid

to maintain the bile acid pool sufficiently to solubilize dietary fat. Exogenous

conjugated bile acid (available as a dietary supplement from health food stores or

internet sources) can be given with each meal to replace the missing

endogenous bile acid (Answer D). The risk of this is that exogenous bile acid can

work as a laxative in the colon. It can only do so if the luminal concentration is

sufficiently high, though, and this does not generally happen because so much

small bowel is missing that unabsorbed fluid from the small bowel dilutes bile

acid in the colon. Most post-resection patients can tolerate 1 g of conjugated bile

acid with each meal without increasing stool output dramatically. The nutritional

benefit is enormous and can allow a closer return to a normal body weight.

Bile acid binders, such as cholestyramine, are of no use in this situation

(resection of >100 cm of ileum) because bile acid concentrations in the colon are

not high enough to cause diarrhea and so lowering them has little or no effect

(Answer E).

Replacement of specific nutrients that can no longer be absorbed, such as

vitamin B12, is also important (Answer C). Another intervention that may be of
benefit is administration of recombinant human growth hormone. A controlled

showed that four weeks of treatment in association with glutamine and a modified

diet reducedbut did not necessarily eliminaterequirements for parenteral fluid

and nutrition for at least two months following discontinuation of growth hormone

treatment. The use of growth hormone remains controversial, but has been

approved by the Food and Drug Administration. Initial studies with a glucagon-

like peptide 2 analogue, teduglutide, have been promising, but some have

concerns about the potential of growth factors to stimulate neoplastic polyps in

the colon.

References:

Matarese LE, Seidner DL, Steiger E, Fazio V. Practical guide to intestinal

rehabilitation for postresection intestinal failure: a case study. Nutr Clin Pract

2005;20:551-8.

Byrne TA, Wilmore DW, Iyer K, Dibaise J, Clancy K, Robinson MK, Chang

P, Gertner JM, Lautz D. Growth hormone, glutamine, and an optimal diet reduces

parenteral nutrition in patients with short bowel syndrome: a prospective,

randomized, placebo-controlled, double-blind clinical trial. Ann Surg

2005;242:655-61.

Jeppesen PB, Sanguinetti EL, Buchman A, Howard L, Scolapio JS,

Ziegler TR, Gregory J, Tappenden KA, Holst J, Mortensen PB. Teduglutide

(ALX-0600), a dipeptidyl peptidase IV resistant glucagon-like peptide 2 analogue,

improves intestinal function in short bowel syndrome patients. Gut

2005;54:1224-31.

Scolapio JS. Current update of short-bowel syndrome. Curr Opin

Gastroenterol 2004;20:143-5.

14. A 27-year-old woman presents to her family practitioners office for

evaluation of abdominal pain and constipation. She had normal bowel habits

until high school. At that time she developed recurrent episodes of abdominal

pain that would become increasingly severe over 45 days. During that time

she had no bowel movements and felt more and more bloated. She would then

take bisacodyl to induce a bowel movement. This would cause some cramping

that would be relieved by moving her bowels. After the passage of stool

symptoms would remit for a couple of weeks and then the cycle would start

again. She had no blood in her stools and had not lost any weight. She tried to

consume a diet high in fiber; estimated fiber intake was 20 g/day. She came in at

this time because she was requiring more bisacodyl tablets to induce a bowel

movement.

Physical examination was unremarkable. Her abdomen was soft and not

distended although she claimed to have 7/10 bloating at the time. Rectal

examination was normal; no stool was present in the rectal vault and pelvic floor

muscles seemed to behave normally when defecation was simulated during the

digital examination.

Which one of the following statements is true based on published evidence?

 A. Colonoscopy is indicated to exclude an obstructing lesion

B. Barium enema is indicated to exclude an obstructing lesion

C. Serum thyroid stimulating hormone level should be drawn to

exclude hypothyroidism

D. Defecography should be done to exclude outlet obstruction

E. No additional evaluation is needed at this time

The recommended response is E.

The diagnosis of irritable bowel syndrome with constipation is symptom-

based; there is currently no diagnostic test that will establish this diagnosis.

Patients who meet the symptomatic criteria can be said to have that diagnosis

without additional tests as long as there are no alarm criteria (Answer E). In this

case the patient meets the Rome criteria for IBS with constipation: 12 or more

weeks in the last 52 with abdominal pain that is associated with altered stool

consistency or frequency. No alarm criteria, such as weight loss or rectal

bleeding, are present to warrant further investigation. A diagnosis of IBS made

this way is unlikely to be changed, even over years of observation.

Many gastroenterologists feel obligated to exclude structural lesions, such

as tumors or strictures, in patients with constipation with colonoscopy (Answer A)

or barium enema (Answer B). In truth these studies rarely are positive for

clinically significant lesions in the setting of a young person with longstanding

constipation. Older patients (>50 years old) should be considered for screening
colonoscopy for cancer prevention (if not done previously), but not only for the

purpose of finding a cause for constipation.

Likewise, although constipation can be a symptom of hypothyroidism, it is

rarely the only manifestation of that condition. In the absence of other clinical

evidence of hypothyroidism, the prevalence of hypothyroidism is similar in people

with constipation and the general population. Measurement of TSH (Answer C)

is not necessary in this case.

Finally, although physiological testing, such as anorectal manometry,

defecography (Answer D), and colon marker transit studies, may be of use in the

evaluation of patients with chronic constipation, there is no evidence that it is

helpful in patients who have IBS with constipation. Even in patients with chronic

constipation, these tests do not add much to the initial evaluation of the patient

and should be reserved for patients who prove to be refractory to simple

measures.

References:

Cash BD, Chey WD. Irritable bowel syndrome - an evidence-based

approach todiagnosis. Aliment Pharmacol Ther 2004;19:1235-45.

Cash BD, Chey WD. Diagnosis of irritable bowel syndrome.

Gastroenterol Clin North Am 2005;34:205-20.

Rao SS, Ozturk R, Laine L. Clinical utility of diagnostic tests for

constipation in adults: a systematic review. Am J Gastroenterol 2005;100:1605-1

15. A 46-year-old woman presents to your office because of refractory

constipation present since childhood. She has marked infrequency of defecation

when not using laxatives or enemas, but has no problem expelling stool that is in

the rectum. She has tried various laxatives (milk of magnesia, polyethylene

glycol, lactulose, bisacodyl, senna) which have proven ineffective, even when

given in very large doses. In addition, she has taken cisapride, tegaserod,

misoprostol, colchicine, and bethanechol with some transient success, but

ultimate failure. She was currently keeping her bowels open with large volume

tap water enemas twice a week. She had no abdominal pain of note and was not

depressed.

Physical examination showed no evidence of systemic illness. Her

abdomen was soft and not distended. Bowel sounds were active. No fecal

masses were palpable. Rectal examination showed normal anal sphincter tone.

No stool was present in the rectum. The rectal outlet opened appropriately when

simulating defecation during digital examination.

Since medications had not worked, she is interested in surgery for her

problem.

The procedure of choice for her problem would be:

A. Subtotal colectomy with ileorectal anastomosis

B. Subtotal colectomy with ileoanal anastomosis

C. Segmental resection of the rectosigmoid colon

 D. Pelvic floor reconstruction

E. Anal sphincterotomy

The recommended response is A.

Patients with refractory constipation sometimes are referred for consideration of

surgical approaches to their problem. Surgery can improve a desperate

situation, but patient selection is the key to success. Patients who have pain as

a major complaint, who have depression, or who have unrealistic expectations

about the outcome of surgery are poor prospects. Surgery can improve bowel

frequency and reduce the time and bother required to keep ones bowels open,

but it does not necessarily reduce pain, ease depression or improve

interpersonal relationships. Patients who have significant depression or pain

often have more problemsparticularly bowel obstructionpost- operatively than

those who dont have these comorbidities.

The procedure of choice for severe slow transit constipation is subtotal

colectomy with ileorectal anastomosis (Answer A). Ileostomy is an alternative,

but generally less satisfactory option. Subtotal colectomy with ileoanal

anastomosis (Answer B) is a technically more challenging procedure that is

usually not needed for this indication; technical failure requiring resection of the

ileal pouch results in mandatory creation of an end-ileostomy. Lesser resections,

such as segmental resection of the sigmoid colon, almost never are successful

regardless of how redundant the sigmoid colon appears to be; the problem with
severe slow transit constipation seems to be a pancolonic process. Her history is

not consistent with functional outlet obstruction or dyssynergia and operations on

her pelvic floor (Answer D) or anal sphincter (Answer E) are not going to be

helpful.

References:

Pampati V, Fogel R. Treatment options for primary constipation. Curr

Treat Options Gastroenterol 2004;7:225-233.

FitzHarris GP, Garcia-Aguilar J, Parker SC, Bullard KM, Madoff RD,

Goldberg SM, Lowry A. Quality of life after subtotal colectomy for slow-transit

constipation: both quality and quantity count. Dis Colon Rectum 2003;46:433-40.

Bharucha AE, Philips SF. Slow-transit constipation. Curr Treat Options

Gastroenterol 2001;4:309-315.

16. All of the following tests are reasonable parts of the preoperative evaluation

for the patient discussed in Question 15 EXCEPT:

A. Anorectal manometry

B. Balloon expulsion test

C. Defecography

D. Radiopaque colon-marker transit study

E. Colon biopsies

The recommended response is E.

Before considering any surgical intervention for refractory slow-transit

constipation two points must be established: 1) that slow-transit constipation is in

fact present, and 2) that functional outlet obstruction or dyssynergia is not

present. A small number of patients with refractory symptoms will have normal

transit constipation or IBS with constipation and should not have surgical

management. A somewhat larger number will have functional outlet obstruction

or dyssynergia; these patients should not be considered for subtotal colectomy

with ileorectal anastomosis until the outlet problem is corrected because they will

fail to improve postoperatively.

A variety of tests can be considered for these purposes. To ensure that

slow-transit is present, a radiopaque colon-marker transit study (Answer D)

should be done. In this study the progress of radiopaque markers is followed

radiographically as they pass through the colon. Several different protocols have

been proposed; each has its pluses and minuses. The easiest of these is to give

one capsule containing 24 markers and then make an ordinary radiogram of the

abdomen 5 days later. Retention of any markers at that point in time is abnormal

and indicates slow transit.

To exclude outlet problems several tests are used, including anorectal

manometry (Answer A), balloon expulsion study (Answer B), and defecography

(Answer C). Expertise in these studies varies from institution to institution and to

some extent they can be used interchangeably. Anorectal manometry is the gold

standard for dyssynergic defecation and balloon expulsion can be used as a

simpler screening test for this problem. Defecography is highly operator- and

protocol-dependent. In its original version, thickened barium with a stool-like

consistency was introduced into the rectum and the ability to evacuate this bolus

was assessed fluoroscopically. Use of a few ounces of more liquid barium may

be more useful clinically since it allows better assessment of mucosal prolapse

and the presence of a rectocele than the stool-like surrogate contrast. No single

one of these tests picks up all patients with outlet dysfunction.

Colon biopsies (Answer E) have little role to play in the assessment of

patients with constipation at the present time. Melanosis coli can be

demonstrated, if present, but has no significance other than confirming chronic

anthraquinone laxative use. At some future time biochemical or genetic analysis

of mucosal biopsy specimens may be used to identify subtypes of functional

bowel disease.

References:

Rao SS, Ozturk R, Laine L. Clinical utility of diagnostic tests for

constipation in adults: a systematic review. Am J Gastroenterol 2005;100:1605-

15.

Kaidar-Person O, Rosen SA, Wexner SD. Pelvic outlet obstruction. Curr

Treat Options Gastroenterol 2005;8:337-45.

17. A 28-year-old woman presents for evaluation of chronic constipation. She

has had problems for a few years and has tried laxatives and enemas without
much luck. She feels as though she always is full and needs to have a bowel

movement, even immediately after producing a stool. Her stools are small and

hard and she has to strain in order to evacuate. Lately she has found that

splinting her perineum with her hand or pushing the posterior wall of the vagina

backwards with a finger can facilitate evacuation.

Positive findings are limited to the rectal examination. Sphincter tone is

high; insertion of the examining finger is painful. The puborectalis muscle is

bulky and contracts when she simulates defecation during the digital

examination. No fissure or hemorrhoids are visualized.

Anorectal manometry shows a pattern of dyssynergic defecation: anal

sphincter pressure increases during attempted defecation. Defecography

confirms incomplete puborectalis muscle relaxation with defecation and inability

to open the rectoanal angle.

The treatment most likely to improve her defecation pattern is:

A. Tap water enemas

B. Polyethylene glycol laxative

C. Tegaserod

D. Biofeedback training

E. Lateral internal sphincterotomy

The recommended response is D.

This patient has a classical history, physical examination and diagnostic tests for

functional outlet obstruction or dyssynergic defecation. The etiology of this

condition is unknown, but theories include miseducation during toilet training in

childhood, psychodynamic factors at puberty, and learned misbehaviors in

adulthood. The exact frequency of outlet dysfunction in the population of patients

with constipation is unknown; estimates vary widely, but probably about 2040%

of constipated patients have outlet dysfunction as a sole or as a concomitant

mechanism of constipation. In addition to dyssynergia, outlet dysfunction

includes intrarectal mucosal intussusception or anterior rectal wall prolapse into

the anal canal, either of which can produce transient blockage of the anal canal.

Some patients with severe perineal descent also may be unable to open the

rectoanal angle because of descent of the rectoanal junction when straining,

even though they do not actively contract the puborectalis muscle and therefore

technically do not have dyssynergia.

Clinical clues to the presence of an outlet problem include lack of

response to laxatives unless stools are liquified, the sensation of incomplete

evacuation (often due to mucosal prolapse into the anal canal), and use of

fingers to assist defecation by pressing up on the perineum or backwards on the

posterior vaginal wall. The presence of a rectocele (in the absence of prior birth

trauma) also suggests puborectalis muscle dysfunction and misdirected forces

during attempted defecation. The diagnosis can be confirmed with anorectal

manometry and/or defecography.

Management of outlet dysfunction has been poorly studied until recently

due to confusion about diagnosis and the tendency of investigators to lump all

outlet problems together. Dyssynergia is best managed with biofeedback

training (Answer D) if an experienced therapist is available. Biofeedback for

dyssynergia is very different than biofeedback training for fecal incontinence. For

incontinent patients the goal is to learn to contract the external anal sphincter and

puborectalis muscle in response to rectal distention. This can usually be

accomplished in a single session lasting 4560 minutes. Biofeedback training for

dyssynergia involves daily sessions for several weeks during which the abnormal

contraction in response to attempted defecation is extinguished and proper

defecation habits are taught. The success rate is about 70% in patients who

actually have dyssynergia and are considered to be adequate candidates for

training (i.e., able to follow instructions and cooperate with the exercises).

Patients with isolated slow transit constipation do not benefit from biofeedback

training.

The alternative answers are each less successful than biofeedback.

When biofeedback training is not available, regular evacuation with the help of

voluminous doses of osmotic laxatives or enemas (Answers A and B) and

education about proper defecation techniques (and perhaps skeletal muscle

relaxants) may be helpful, but the efficacy of this approach has not been studied

scientifically. Tegaserod (Answer C) has not been studied in a group of patients

with outlet problems, but perhaps would not be very successful since the outlet

must open for evacuation to occur. Surgery on the sphincter (Answer E) should

be avoided except in patients with anal fissure where it may be of some value.
References:

Chiarioni G, Salandini L, Whitehead WE. Biofeedback benefits only

patients with outlet dysfunction, not patients with isolated slow transit

constipation. Gastroenterology 2005;129:86-97.

Kaidar-Person O, Rosen SA, Wexner SD. Pelvic outlet obstruction. Curr

Treat Options Gastroenterol 2005;8:337-45.

18. True statements about osmotic laxatives include all of the following

EXCEPT:

A. Osmotic laxatives work by retaining additional water intraluminally.

B. The osmotic activity of a lactulose solution can be approximated by

dividing its concentration (g/L) by the gram-molecular weight of lactulose

(342.3).

C. The osmotic activity of a polyethylene glycol (PEG) solution can be

approximated by dividing its concentration (g/L) by the gram-molecular

weight of PEG (3350).

D. The laxative effectiveness of magnesium hydroxide is reduced by

intestinal absorption of magnesium (approximately 7%)

E. The laxative effectiveness of sodium phosphate is reduced by intestinal

absorption of phosphate (approximately 30%)

The recommended response is C.

Most regions of the gastrointestinal tract (except for the stomach) are highly

permeable to water and so osmotic gradients are rapidly dissipated by movement

of water across the mucosa. Functionally this means that intestinal contents are

in equilibrium with plasma osmolality from the jejunum to the rectum. If additional

osmoles are present intraluminally, water will enter the intestine to dilute those

osmoles to plasma osmolality. Thus osmotic laxatives retain water intraluminally

(Answer A). For most nonionized molecules osmolality can be calculated by

dividing the concentration of a substance by its molecular weight. This is true for

lactulose (Answer B), which is a typical small, unionized molecule. This is not

true for polyethylene glycol (Answer C) a large molecule which is a polymer that

exerts an anomalous osmotic activity proportional to the number of monomers in

the polymer and not its molecular weight. (If PEG behaved normally like

lactulose, the dose to exert a similar osmotic effect would be roughly 10 times

higher, about 200 g instead of 17 g per dose.) This peculiarity is shared with

many other polymers that can interact with water molecules and effectively

remove some water molecules from the solution, raising the physicochemical

activity of other solutes in the remaining solution. For magnesium hydroxide

(Answer D) and sodium phosphate (Answer E), some of the osmoles are

removed from the lumen by mucosal absorption and so less remain intraluminally

to retain water and have an osmotic effect.

References:
 Schiller LR. Review article: the therapy of constipation. Aliment

Pharmacol Ther 2001;15:749-63.

Schiller LR, Emmett M, Santa Ana CA, Fordtran JS. Osmotic effects of

polyethylene glycol. Gastroenterology 1988;94:933-41.

19. All of the following drugs frequently are associated with the development of

constipation EXCEPT:

A. Amitriptyline

B. Amlodipine

C. Amoxicillin

D. Aluminum hydroxide

E. Antihistamines

The recommended response is C.

Drugs are a common cause of constipation and it is essential to go over a

complete list of all prescription, over-the-counter, and herbal preparations that a

patient is taking. Anticholinergic drugs and drugs with anticholinergic side-effects

like the tricyclic antidepressants frequently produce constipation (Answer A).

Calcium channel blockers are another category of drugs that may cause

constipation (Answer B). Aluminum and calcium salts also tend to be

constipating (Answer D). Antihistamines (both sedating and non-sedating) may

cause constipation (Answer E). Not listed but probably the most problematic are

narcotics. These agents routinely cause constipation at doses used to produce

analgesia. Stimulant laxatives such as senna may be needed to maintain regular

bowel movements.

Reference:

Thorpe DM. Management of opioid-induced constipation. Curr Pain

Headache Rep 2001;5:237-40.

20. An 18-year-old man presented for evaluation of constipation. His mother

told him that he had problems with stooling from the second half of his first year

of life and he required enemas on a regular basis. Toilet training was relatively

easy; he never soiled himself. During childhood he had clogged the commode

regularly when defecating. During high school his use of enemas declined.

Spontaneous bowel movements now occurred only every two weeks.

Physical examination revealed a large fecal mass filling the sigmoid colon

and extending up to the umbilicus. Rectal examination showed a large soft fecal

impaction in the rectum. Anal sphincter resting tone was normal. Sphincter

squeeze was normal.

Following disimpaction with the use of a colon lavage solution, his colon

was kept empty for one month by ingestion of one glassful of lavage solution

nightly. He then presented for anorectal manometry. This showed an elevated

distention threshold for rectal sensation (60 mL) and absence of the rectoanal

inhibitory reflex. Barium contrast study showed megarectum and enlargement

and lengthening of the sigmoid colon.

The most likely diagnosis in this case is:

A. Hirschsprungs disease

B. Ultrashort segment Hirschsprungs disease

C. Idiopathic megarectum

D. Encopresis

E. Pelvic floor dyssynergia.

The recommended response is B.

Young adults who present with constipation dating back to infancy need to be

evaluated for a congenital problem such as Hirschsprungs disease (Answer A).

Classical Hirschsprungs disease starts during the first weeks of life and is

associated with failure of formation of the more distal ganglia in the enteric

nervous system. The aganglionic segment is contracted and the colon proximal

to the aganglionic segment (which is innervated normally) is dilated. In addition

to the lack of enteric ganglia in the most distal parts of the colon, nerve trunks

with increased acetylcholinesterase activity are noted in the lamina propria. Most

cases are associated with a variety of mutations of the RET receptor tyrosine

kinase gene, the same gene associated with multiple endocrine neoplasia, type

2.

A variant of Hirschsprungs disease is ultrashort-segment Hirschsprungs

disease (Answer B) in which only the internal anal sphincter and a short cuff of
distal rectum lack appropriate innervation. This condition starts clinically slightly

later (second half of the first year), may be less severe than classical

Hirschsprungs disease, and often is not discovered until young adulthood. It can

be confused with other causes of megarectum and must be distinguished from

those by the absence of the rectoanal inhibitory reflex (RAIR) which is mediated

by the intrinsic nerves of the myenteric plexus or by careful histologic evaluation

of a full-thickness biopsy. In cases of ultrashort-segment Hirschsprungs disease

a posterior anorectal myectomy can be used for both diagnostic and therapeutic

purposes. In that surgery a 1-cm-wide strip of muscularis is removed from the

internal anal sphincter extending up to the rectum. Ganglia normally are not

present within 2 cm of the internal anal sphincter and so the myectomy needs to

be extended proximally at least that far.

Idiopathic megarectum (Answer C) appears to be an acquired problem,

probably related to chronic distention of the rectum by stool-holding. The

rectoanal inhibitory reflex is present in these individuals, but the threshold

distending volume may be greater than usual so that the distending balloon can

stretch the dilated rectal wall.

Encopresis (Answer D) is equivalent to overflow incontinence in children.

Fecal impaction produces chronic rectal distention and reflex relaxation of the

internal anal sphincter, allowing liquid stool to escape around the impacted stool.

Complete removal of impacted stool and a regular laxative program to prevent

stool from reaccumulating in the rectum are essential for management of

encopresis. Biofeedback training as used for fecal incontinence can be used in

older children and adolescents with this problem to resolve incontinence.

Pelvic floor dyssynergia (Answer E) is an unlikely cause of this problem.

Anorectal manometry could be used to distinguish dyssynergia from ultrashort-

segment Hirschsprungs disease.

Of all the possibilities ultrashort-segment Hirschsprungs disease is the

most consistent with the history and laboratory findings.

References:

Kashuk CS, Stone EA, Grice EA, Portnoy ME, Green ED, Sidow A,

Chakravarti A, McCallion AS. Phenotype-genotype correlation in Hirschsprung

disease is illuminated by comparative analysis of the RET protein sequence.

Proc Natl Acad Sci USA 2005;102:8949-54.

Angerpointner TA. Diagnosis and therapy of ultrashort Hirschsprungs

disease. J Pediatr Surg 2005;40:1217.

21. Systematic reviews conclude that there is moderate to good evidence

(Grade A and Grade B) of efficacy in the treatment of chronic constipation for all

of the following medications EXCEPT:

A. Tegaserod

B. Polyethylene glycol

C. Lactulose

D. Milk of magnesia

E. Psyllium
The recommended response is D.

As therapies for chronic constipation evolve, it is good to revisit the evidence

base for existing treatment options. Systematic reviews conducted using the

tenets of evidence-based medicine offer the best opportunity for a bias-free

assessment of treatments. Such reviews use grading systems to evaluate the

level of evidence and the strength of recommendations based on that evidence.

For example, one system assigns a grade of A to recommendations based on

two or more well-designed randomized, controlled trials that provide good

evidence of efficacy, a grade of B to recommendations based on less well-

designed comparative studies that provide moderate evidence of efficacy, and a

grade of C to recommendations based on poorly-designed studies or expert

opinions alone that provide little support for efficacy.

Recently introduced medications have had to conduct rigorously designed

controlled trials in order to gain approval from the Food and Drug Administration.

These studies meet most of the criteria for excellent study design and have

produced Grade A recommendations for the use of tegaserod, polyethylene

glycol, and lactulose for chronic constipation. Medications that were studied 15

20 years ago used somewhat less vigorous study designs than more recent

studies, largely because criteria for quality investigations are a new development.

These older studies provide Grade B recommendations for the use of psyllium in

constipation. Drugs inherited from antiquity or those that were developed more
than 20 years ago lack quality data regarding their efficacy. These include

agents such as milk of magnesia (Answer D), senna, bisacodyl, and stool

softeners. That is not to say that these drugs do not work or are unsafe, only that

they have not been subjected to vigorous study by high quality clinical trials.

References:

Ramkumar D, Rao SS. Efficacy and safety of traditional medical therapies

for chronic constipation: systematic review. Am J Gastroenterol 2005;100:936-

71.

Brandt LJ, Prather CM, Quigley EM, Schiller LR, Schoenfeld P, Talley NJ.

Systematic review on the management of chronic constipation in North America.

Am J Gastroenterol 2005;100(Suppl 1):S1-S21.

22. A 36-year-old woman undergoes EGD for diarrhea, weight loss, and

abdominal bloating. The endoscopic view of the descending duodenum is shown

in Figure 8. Which of the following test results is most likely to be abnormal?

A. Eosinophil count

B. Serum ferritin

C. Stool test for ova and parasite

D. Gastric emptying nuclear scan

E. Amylase and lipase

The recommended response is B.

The endoscopic view shows mucosal pallor and scalloping of the small intestinal

mucosa in the second portion of the duodenum, highly suggestive of celiac

disease. These changes have been shown to correlate with degree of villous

atrophy. However, the endoscopic appearance of normal duodenal mucosa

cannot be used to rule out celiac disease. The use of magnifying endoscopes

can enhance the ability to identify villous atrophy, but offer no advantage

compared to the gold standard of mucosal biopsy.

Iron deficiency anemia is one of the most common clinical manifestations of

celiac disease because iron is absorbed in the proximal duodenum. Thus, an

abnormally low serum ferritin level is a common laboratory finding in celiac

disease. Eosinophilia is not associated with celiac disease, but is associated with

eosinophilic gastroenteritis, crohns disease, and parasitic infestations. Stool

examination for ova and parasite is useful when the infestation is suspected.

However, the endoscopic view in the case is not suggestive of any infection.

Gastric emptying nuclear scan and pancreatic enzymes are normal in patients

with celiac disease.

Dewar DH, Ciclitira PJ. Clinical features and diagnosis of celiac disease.

Gastroenterology 2005;128(4 Suppl 1);S19-S24.

Bardella MT, Minoli G, Radaelli F, et al. Reevaluation of duodenal endoscopic

markers in the diagnosis of celiac disease. Gastrointest Endosc 2000;51(6):714-

716.

23. A 50-year-old woman presents with a two-year history of occasional episodes

of diarrhea. The endoscopic view of rectum and sigmoid colon is shown in Figure

9? Which of the following is the most likely cause of diarrhea?

A. Chronic ingestion of charcoal tablets

B. Chronic ingestion of iron supplements

C. Chronic ingestion of anthraquinone laxatives

D. Chronic ingestion of osmotic laxatives

E. Chronic ingestion of diphenolic laxatives

The recommended response is C.

The endoscopic figure shows brown or black pigmentation of colonic mucosa,

consistent with melanosis coli. The most likely cause of diarrhea in this patient is

chronic ingestion of anthraquinone laxatives. Melanosis coli is a benign condition

characterized by the typical endoscopic finding of dark brown discoloration of the

colonic mucosa caused by the accumulation of pigment in macrophages of the

lamina propria. The findings are usually evident in the rectum and sigmoid colon,

although the entire colon may be involved. The association between melanosis
coli and chronic use of anthraquinone laxatives is firmly established and

supported by the development of characteristic pigmentation in laboratory

animals after administration of anthraquinones. More than 70% of persons who

use anthraquinone laxatives (cascara sagrada, senna. aloe, Dantron, rhubarb,

and frangula) develop melanosis coli within 4-12 months of continuous use, with

an average of 9 months. This condition is reversible. The disappearance of the

pigment generally occurs within 1 year after discontinuation of laxatives.

Histology of mucosal biopsy shows pigment-laden macrophages in the lamina

propria and muscularis propria. No treatment is needed.

Charcoal tablets and iron supplements may turn the color of stool black, but will

not result in mucosal discoloration. Melanosis coli is not seen with osmotic or

diphenolic laxatives.

Ghadially FN, Walley VM. Melanoses of the gastrointestinal tract. Histopathology

1994;25(3):197-207.

Nusko G, Schneider B, Schneider I, et al. Anthranoid laxative use is not a risk

factor for colorectal neoplasia: results of a prospective case control study. Gut

2000;46(5):651-655.

24. A 35-year-old woman complains of intermittent episodes of hematochezia

with bowel movements. She also notes tenesmus, mild rectal pain, and the need
to strain during bowel movement. She occasionally needs to manually assist her

defecation. Colonoscopy is performed and the endoscopic view of rectum is

shown in Figure 10. Which of the following is not the pathology finding of this

condition?

A. Obliteration of the lamina propria by fibromuscular proliferation

B. Cryptitis and crypt abscess

C. Thickened muscularis mucosae

D. Branched and distorted crypts

E. Collagen infiltration of the lamina propria

The recommended response is B.

The endoscopic figure shows a solitary rectal ulcer. Solitary rectal ulcer

syndrome is a spectrum of clinicopathological abnormalities which can affect

both adults and children. The pathogenesis remains obscure, but seems to

involve abnormal contraction of the pelvic floor and rectal prolapse, resulting in

rectal mucosal ischemia. The clinical characteristics of this syndrome include

rectal bleeding, mucus in the stool, tenesmus, and straining to defecate. Patients

often instrument their own rectum because of a sensation of incomplete

evacuation. Endoscopic appearance varies from erythema (18%) to ulceration

(57%) or polypoid lesions (28%). These lesions are usually found on the anterior

rectal wall and could be single or multiple, measuring between 0.5 and 5.0 cm in

diameter. This condition is rare and may be misdiagnosed as inflammatory bowel

disease or cancer. Defecography or proctography may be useful to evaluate

pelvic floor dysfunction. Evidence of rectal prolapse, either external or internal,

with or without abnormal perineal descent on evacuation may be detected.

Biopsy specimens show obliteration of the lamina propria by fibromuscular

proliferation, thickended muscularis mucosae, branched and distorted crypts, and

collagen infiltration of the lamina propria. Treatment should be aimed at restoring

a normal pattern of defecation pattern. The patient should be instructed to avoid

excessive straining and to regulate defecation habits by biofeedback behavioral

retraining and fiber supplements. Modest osmotic laxatives can be considered.

Topical steroids and 5-ASA enemas are not effective. Sucralfate enemas and

local applications of human fibrin sealant have provided some improvement in

small case series. If these local measures do not resolve the problem, surgical

treatment may be considered.

Vaizey CJ, van den Bogaerde JB, Emmanuel AV, et al. Solitary rectal ulcer

syndrome. Br J Surg 1998;85(12):1617-1623.

Felt-Bersma RJ, Cuesta MA. Rectal prolapse, rectal intussusception, rectocele,

and solitary rectal ulcer syndrome. Gastroenterol Clin North Am 2001;30(1):199-

222.
Jarrett ME, Emmanuel AV, Vaizey CJ, et al. Behavioral therapy (biofeedback) for

solitary rectal ulcer syndrome improves symptoms and mucosal blood flow. Gut

2004;53(3):386-370.
Figures

Figure 8
Figure 9
Figure 10