chronic diarrhea nejm 95

7/28/2019 Chronic Diarrhea NEJM 95

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Vol. 332 No. 11 CURRENT CONCEPTS 725

REVIEW ARTICLE

CURRENT CONCEPTS

EVALUATION OF PATIENTS WITH CHRONIC

DIARRHEA

MARK DONOWITZ, M.D., FREDDY T. KOKKE, M.D.,AND

R

OXAN

S

AIDI

, M.D.

From the Departments of Medicine and Physiology, Gastroenterology Divi-

sion, the Johns Hopkins University School of Medicine, Baltimore. Address re-print requests to Dr. Donowitz at 918 Ross Research Bldg., Gastroenterology Di-

vision, Department of Medicine, the Johns Hopkins University School ofMedicine, 720 Rutland Ave., Baltimore, MD 212052195.

P

ATIENTS who report having diarrhea for morethan four weeks should be evaluated for chronic

diarrheal diseases, since most infectious enteritidesand other causes of acute diarrhea generally resolve

spontaneously within this period.

1-3

We suggest a two-stage outpatient evaluation, which relies initially onthe history and physical examination to direct studiesand then on a systematic outpatient evaluation, fol-lowed, if necessary, by a third-stage inpatient eval-uation. This approach should lead to a diagnosis inapproximately 90 percent of patients. Patients with di-arrhea experience a change in the consistency or fre-quency of their bowel movements. Diarrheal diseasesare almost always associated with an increase in stool

water. The daily loss of stool water on an American orBritish diet averages 130 ml per 24 hours, and stool isnormally 65 to 85 percent water. Thus, diarrheal dis-

eases can be objectively defined by daily stool weightsof more than 200 g.Before the evaluation, the patient should follow a lac-

tose-free diet for several days, since diarrhea that con-tinues after an acute episode is often due to secondarylactase deficiency. Chronic diarrhea often causes dehy-dration, which should be corrected with oral rehydrationsolutions

4

(premade electrolyte mixtures diluted accord-ing to World Health Organization recommendations oravailable commercially) while further evaluation contin-ues. Popular remedies such as Gatorade, chicken broth,and soft drinks have concentrations of electrolytes toolow to be used in severe forms of diarrhea.

Are there any clues from the initial evaluation thatpredict the presence of an organic as opposed to a func-tional cause of diarrhea? Certain criteria suggest an or-ganic disorder: a shorter duration of diarrhea (usuallyless than three months), predominantly nocturnal diar-rhea, continual rather than intermittent diarrhea, a sud-den onset, weight loss of more than 5 kg, a high eryth-rocyte sedimentation rate, a low hemoglobin level, a lowalbumin level, and an average daily fecal weight ofmore than 400 g.

5-8Although the sensitivity of at least

three of these criteria is poor, the specificity for organicdisorders is 90 percent or higher. No single screeningtest has enough sensitivity to determine an organic basis

for chronic diarrhea. In the absence of the above crite-ria suggesting an organic disorder, a diagnosis of func-tional diarrhea is sometimes made. However, so manyorganic disorders would be missed by this approachthat patients in this category should also be evaluatedthoroughly.

O

UTPATIENT

E

VALUATION

OF

S

PECIFIC

D

ISEASES

The initial examination and a limited laboratoryevaluation often point to the causes of the diarrhea,

which are listed in Table 1 in order of frequency. Ifthe cause of chronic diarrhea is not obvious after theevaluation and laboratory studies, one strategy is to

proceed with an immediate, extensive, and exhaustiveworkup. However, we propose instead a stepwise ap-proach, beginning with the tests outlined in Table 2(stage 1). If the patient is referred after an initial eval-uation, the quality of the studies and not just the resultsmust be reviewed. If the cause is still unclear, a secondseries of more costly and more invasive tests, listed inTable 2 (stage 2), is performed.

Some chronic diarrheal diseases have specific char-acteristics. In giardiasis, the diarrhea is often associat-ed with upper abdominal cramps and frothy stool.Giardia organisms are found predominantly in the duo-denum and proximal jejunum. The examination of up

to three fixed, concentrated stool specimens for ova andparasites has a sensitivity of 60 to 85 percent. An en-zyme-linked immunosorbent assay for giardia antigenin stool (sensitivity, 92 percent; specificity, 98 percent)has largely supplanted intestinal biopsies, wet prepara-tions, and the duodenal string test, particularly sincethe assay becomes negative after therapy.

16,17

Only afterthese studies do we consider an empirical trial ofmetronidazole or quinacrine hydrochloride (Atabrine).

Amebic diarrhea can be either watery or bloody andcan last many years, with a variable presence of fecalleukocytes. Although examination of three fixed speci-mens of stools is the best initial screening test for ame-

biasis (sensitivity, 60 to 90 percent), two factors shouldbe kept in mind concerning the collection of stool. Stoolmust be collected directly into fixative or into a dry con-tainer (urine and water destroy the parasite), and bar-ium in the gastrointestinal tract hampers the detectionof amebae for some time. Chronic diarrhea in hostspositive for the human immunodeficiency virus (HIV),

with or without the acquired immunodeficiency syn-drome, is due to an identifiable infectious agent in 75to 85 percent of cases and has been reviewed else-

where.

9,10

Early in its course, Crohns disease of the small bow-el is often difficult to diagnose radiologically, and a nor-

mal small-bowel series does not eliminate it as a possi-bility. If Crohns is suspected clinically, enteroclysis

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726 THE NEW ENGLAND JOURNAL OF MEDICINE March 16, 1995

should be performed to show more mucosal detail.

18

This procedure involves nasoduodenal intubation andthe administration of barium, cellulose, and air underfluoroscopy to cause optimal distention, and of aircon-trast medium to outline small-bowel mucosa. Collage-nous colitis and microscopic (also called lymphocytic)

colitis often appear normal on colonoscopy, and a diag-nosis is only made by means of colonic biopsies.

Half of patients with steatorrhea have watery diar-rhea, because secretion of colonic water and electro-lytes can be induced by fatty acids and the hydroxy-fatty acids. A history of floating stools indicates notsteatorrhea, but rather gas production by bacteria.

19

More suggestive of steatorrhea is a history of weightloss, greasy or bulky stools that are difficult to flush, abad odor, and oil in the toilet bowl that requires abrush to remove. The presence of steatorrhea is deter-mined by a 72-hour collection of stool fat. There is alinear relation between the amount of long-chain fatty

acids consumed and the amount excreted in the stool.The absorption coefficient for fat is approximately 0.95,and at zero uptake approximately 2 g of fat is excretedin the stool. Thus, the amount of fecal fat associated

with a normal American diet of 75 to 100 g of fat perday is

7 g per 24 hours (100

[100

0.95]

2). How-ever, patients with steatorrhea may consume much lessfat to reduce their diarrhea, and despite instructionsto the contrary, may not increase the amount of fat theyconsume for the test, leading to a falsely low loss of fat

in the stool collection. In addition, diarrhea itself can

cause reduced fat absorption. Experimentally inducedwatery diarrhea produces up to 13 g of fat per 24hours.

20

Therefore, if the patient produces

14 g of fatper 24 hours, he or she has significant steatorrhea. Ifthe daily amount of stool fat is between 7 and 13 g, thesteatorrhea may be secondary to other causes of diar-rhea. A qualitative assay for stool fat with Sudan stainhas a sensitivity of 90 percent when fecal fat measuresmore than 10 g per 24 hours.

The diarrhea of carbohydrate malabsorption can beintermittent and is usually accompanied by symptomsof bloating, flatus, and cramping, since less carbohy-drate is needed to produce excessive gas than to cause

diarrhea. This type of diarrhea can be primary or sec-ondary to viral enteritis, which damages the small in-testinal mucosa, or to antibiotic therapy, which alterscolonic bacteria. Since approximately 30 g of ingestedcarbohydrate enters the colon daily, and is normallyconverted by bacteria into short-chain fatty acids thatare efficiently absorbed,

21

the antibiotic-induced changein bacteria can lead to a colonic osmotic diarrhea. Astool pH of less than 5.3 is diagnostic of carbohydrateintolerance.

22

As many as 4 percent of cases of chronicdiarrhea are due to medications and food additives, in-cluding alcohol and caffeine. Sorbitol (used as a non-absorbable sweetener in diet foods) and fructose in

corn syrup are osmotically active and can cause diar-rhea. In a study of volunteers, 48 percent had diarrhea,

*Causes are listed in order of frequency. The table does not include causes of chronic diar-

rhea in HIV-positive patients, for which the differential diagnosis is reviewed elsewhere.

9,10

Often missed on evaluation.

Table 1. Causes of Chronic Diarrhea.

*

Common causes

Chronic or relapsing gastrointestinal infection: amebiasis, giardiasis, Clostridi-

um difficile

Inflammatory bowel diseases: ulcerative colitis, Crohns disease, collagenouscolitis, microscopic (lymphocytic) colitis

Steatorrhea

Carbohydrate malabsorption: disaccharidase deficiency (lactose, sucrose), poorly

absorbed substances (wheat starch, fiber, lactulose, sorbitol, fructose)

Medications and food additives: commonly antibiotics, antihypertensive drugs,

antiarrhythmic agents, antineoplastic agents, antacids (magnesium-containing),sweeteners (sorbitol, fructose), ethanol, caffeine

Previous surgery: gastrectomy, vagotomy, cholecystectomy, intestinal resection

Endocrine causes: adrenal insufficiency, hyper- or hypothyroidism, diabetes

11

Laxative abuse

Ischemic bowel disease

Radiation enteritis or colitis

12

Paradoxical diarrhea: colon cancer

Idiopathic (functional) diarrhea

Less frequent causes

Hormone-producing tumors: gastrinoma, VIPoma, villous adenoma, medullary

thyroid carcinoma, ganglioneuroma, pheochromocytoma, carcinoid tumor,

mastocytosis

13

Infiltrative disorders: scleroderma, amyloidosis, diffuse gut lymphoma

Epidemic chronic diarrhea (perhaps infectious agent in raw milk, untreated water)

Chronic idiopathic diarrhea, self-limited

Fecal incontinence

14

Food allergy

15

Table 2. Outpatient Evaluation of Chronic Diarrhea.

Stage 1

Stool studiesTests for fecal leukocytes, ova, and parasites three times (before barium studies)

and C. difficiletoxin; measurement of pH, weight in grams per 24 hr (mustbe requested specifically), fat in 72-hr sample while patient consuming 75

100 g of fat per 24 hr

Blood studiesComplete blood count and differential count, measurement of erythrocyte sed-

imentation rate, electrolytes, blood urea nitrogen, creatinine, thyroid-stimu-

lating hormone, thyroxine, gastrin; if diarrhea

1 liter per day and especiallyif there is hypokalemia, measurement of vasoactive intestinal polypeptide,

substance P, calcitonin, histamine (usually available only through a commer-

cial laboratory)Radiologic studies

Plain abdominal radiography (for pancreatic calcification); high-quality bariumstudies of the upper gastrointestinal tract, small bowel, and colon

Endoscopic studies

Sigmoidoscopy and biopsy (before a barium study and without hyperosmoticpreparation)

Other

Nutritionist-supervised trial of lactose-free diet; if there is skin flushing, urine5-hydroxyindoleacetic acid assay

Stage 2 (if stage 1 unrevealing)

Stool studiesEnzyme-linked immunosorbent assay for giardia antigen; alkalinization assay

(for phenolphthalein); measurement of fecal sodium, potassium, sulfate,

phosphate, osmolality (see Table 3)Urine studies

Thin-layer chromatography for bisacodyl, phenolphthalein, anthraquinonesRadiologic studies

Enteroclysis, abdominal computed tomography

Endoscopic studiesColonoscopy and ileoscopy with biopsy (for right-sided colitis, amebiasis,

Crohns disease, and microscopic and collagenous colitis), upper endoscopy

including small-bowel biopsyOther

Test of bile acid or other breath test for bacterial overgrowth



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abdominal pain, and bloating with ingestion of 10 g ofsorbitol (equivalent to the ingestion of four to five sug-ar-free mints).

23

Long resections of the ileum and rightcolon can cause diarrhea due to a lack of absorptivesurface,

24

decreased transit time, malabsorption of bileacids, and a smaller bile acid pool (leading to steator-

rhea that is unresponsive to cholestyramine). Shorterintestinal resections (

100 cm) can lead to bile aciddiarrhea, called cholerheic enteropathy, since malab-sorbed bile acids cause colonic secretion of water andelectrolytes. This diarrhea occurs after meals; usuallyinvolves about 300 g of stool per 24 hours, less than 15to 20 g of stool fat per 24 hours, and a stool pH of morethan 6.8; and responds to fasting and cholestyramine.

25

Most of the specific diarrheal diseases mentionedabove can be diagnosed with the studies listed in Table2, stage 1. If these are normal, inflammatory or primar-ily malabsorptive diarrhea is unlikely, and other causesof watery diarrhea must be sought by more invasive

and costly measures (Table 2, stage 2). Laxative abusewith resulting factitious diarrhea is found in approxi-mately 4 percent of new patients visiting gastroenterol-ogy clinics for evaluation of chronic diarrhea and in asmany as 15 to 20 percent of those evaluated by tertiaryreferral centers.

26

That is also the most common causeof diarrhea of undetermined origin (see below). Thereare five categories of patients with laxative-related fac-titious diarrhea

1

: patients with eating disorders includ-ing anorexia nervosa and bulimia; hysterical patients;patients driven by emotional problems; patients withMunchausens syndrome; and children who are abusedby being given laxatives (the so-called Polle syndrome).

Patients nearly always deny laxative ingestion, and nosingle clinical feature can provide a clue, except thepresence of psychiatric disease and macroscopic mel-anosis coli on sigmoidoscopy. These patients often havemajor metabolic derangements and clinical manifesta-tions that can be confused with those of other chronicdiarrheal diseases. These include hypokalemia (with or

without nephropathy), clubbing, hyperpigmentation ofthe skin, steatorrhea, colonic inflammation, uric acidkidney stones, osteomalacia, and protein-losing enter-opathy. Screening tests for laxatives in urine or stool

water are summarized in Table 3. Several studies doc-ument the frequent failure of physicians to screen for

laxative abuse.

29,30

Laxatives can be used intermittently,although continued use, even by inpatients, occurs sur-prisingly often. Thus, urine should be screened for lax-atives several times by alkalinization and thin-layerchromatography.

Hormone-producing tumors such as those of pancre-atic cholera produce a dramatic diarrhea almost fromthe outset and are often rapidly diagnosed. All the pa-tients studied have had over 0.7 liter of stool per 24hours, 70 percent have over 3 liters per 24 hours, and

volumes of 10 to 21 liters per 24 hours have been re-ported. Hypokalemia is also a sensitive but nonspecificindication of the presence of pancreatic cholera, since

100 percent of patients have low potassium levels and93 percent have levels below 2.5 mmol per liter.

31

Vil-

lous adenomas can present with diarrhea and electro-lyte losses caused by as-yet-unidentified secretagoguesor by prostaglandin E

2

production.

32

These tumors areusually over 3 to 4 cm in diameter and are located inthe distal colon or rectum. Water can be seen pouringfrom the surface, although secretion of water and elec-trolytes in other parts of the gut can occur as well.

Several epidemics of chronic diarrhea (e.g., theBrainerd and Henderson County epidemics) have beenassociated with the ingestion of raw milk

33

or untreatedwater.

34,35

No organism was identified in those epidem-ics, and there was no response to antibiotics; however,the episodes were self-limited. In addition, 11 percent

of patients evaluated for chronic diarrhea in a tertiaryreferral center had negative evaluations, with no clearcause or associated systemic illness ever found. In mostof these patients the onset was sudden. The diarrheapersisted during fasting, was associated with weightloss, and began one to four weeks after travel in theUnited States. The diarrhea did not improve with anti-biotics but eventually resolved over a mean period of 15months (range, 7 to 31 months).

36

There is a large group of patients with chronic wa-tery diarrhea in whom an organic abnormality is notuncovered by the outpatient evaluation described inTable 2 and for whom the course is protracted. If ab-

dominal pain is also present, their condition is diag-nosed as a form of irritable bowel syndrome.

37,38

Some-times this group is described as having functionalillness, but we classify it as idiopathic to avoid a pe-

jorative term and to acknowledge our lack of under-standing of the pathobiology. In three series with ex-haustive evaluations of patients with chronic diarrhea,30 to 60 percent of patients were in this category.

5-7

D

IARRHEA

OF

U

NDETERMINED

O

RIGIN

If no cause of patients chronic diarrhea is foundafter the initial evaluation (not including patients

with irritable bowel who have associated abdominal

pain

38,39

), we consider the patients to have diarrhea ofundetermined origin. They are asked whether they

*These tests are usually done in a commercial or referral laboratory. The stool specimen

should be liquid and frozen. A laxative survey request will usually result in chromatographic,

spectrophotometric, and other methods of detecting anthraquinones, bisacodyl, phenolphthal-

ein, castor oil, mineral oil, magnesium, and phosphate. Docusate sodium, the active ingredient

in Colace, can be detected by thin-layer chromatography but is not measured in the currently

available laxative screens.

Table 3. Laboratory Evaluation for Laxative Abuse.

Barium enema to test for cathartic colon (ahaustral right colon)Sigmoidoscopy for gross presence of melanosis coli (microscopic form is often a

normal variant)

Alkalinization assay of stool: phenolphthalein, some anthraquinones, and rhubarbturn red; bisacodyl turns purple-blue

Spectrophotometry* or thin-layer chromatography*

27

of urine or stool water:

detects anthraquinones, bisacodyl, phenolphthalein; can detect anthraquinones

32 hr after one dose

28

Measurement of stool osmolality: only useful if

250 mOsm per kilogram

(implying dilution of stool with water or urine)Measurement of stool sodium and potassium; calculation of fecal osmotic gap:

290

2

(stool sodium concentration

stool potassium concentration)

Stool osmotic gap: if

50 mOsm per kilogram, measure stool magnesium(normally

45 mmol per liter or

30 meq per day)

Measurement of stool sulfate and phosphate



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728 THE NEW ENGLAND JOURNAL OF MEDICINE March 16, 1995

want further evaluation, especially if hydration is diffi-cult to maintain. Most patients want a definitive causeof the diarrhea to be found. Our experience in the eval-uation of diarrhea of undetermined origin almost en-tirely mimics that of Read et al.

5

They found that of 27patients referred after extensive evaluation for chronic

severe diarrhea, 9 (33 percent) were taking laxatives ordiuretics surreptitiously, 6 (22 percent) had inflamma-tory bowel diseases (2 had ulcerative colitis, and 4 hadmicroscopic colitis), 6 had irritable bowel syndrome,2 (7 percent) had anal-sphincter dysfunction, 2 hadother organic disorders (bacterial overgrowth, beef al-lergy), and only 2 remained undiagnosed. The mostcommon causes found at this stage are laxative abuse,inflammatory bowel diseases (including microscopic[lymphocytic] and collagenous colitis), fecal inconti-nence, and other causes listed in Table 1 that weremissed on the initial evaluation.

I

NPATIENT

E

VALUATION

Inpatient evaluation (Table 4) is necessary becausemany cases of diarrhea elude diagnosis as a result ofpoor tests or inadequate stool collections in the outpa-tient setting. After reviewing these and, if necessary, re-peating them, the next goal is to determine whether thepatient has true diarrhea and whether it responds tofasting. On admission, patients are placed on their usu-al at-home diet, and a 24-hour stool weight is deter-mined. If the stool output is more than 0.5 kg per 24hours, irritable bowel disease is unlikely. If the stooloutput is less than 0.2 kg per 24 hours, the patient doesnot have diarrhea. Rather, the patient is disabled by in-

continence, has irritable bowel syndrome, or has rectaldisease. Incontinence accompanies chronic diarrhea inas many as 50 percent of cases. Patients with incon-tinence who do not have a diarrheal illness oftenprogress to this stage of evaluation for diarrhea of un-determined origin before volunteering incontinence astheir chief symptom.

14

A 72-hour fast with intravenous hydration is the nextpart of the diagnostic evaluation. Recording stool

weights daily, especially during the second and third

day of fasting, allows clinical differentiation of osmoticfrom secretory diarrheas. As Fordtran

40

and Binder

41

have discussed, diarrhea that stops on fasting indicatesthat dietary substances are causing the diarrhea, di-rectly or indirectly. These cases are usually due to ei-ther laxative abuse or unabsorbed carbohydrates, bileacids, or fatty acids (Table 5). There is often a fecalosmotic gap of more than 50 mOsm per kilogram of

water (see Table 3 for the formula for calculating theosmotic gap).

Secretory diarrheal diseases are those in which diar-rhea persists or stops only partially after 48 hours offasting. In these diarrheas, stool electrolytes account

for most of the stool osmolality, and the fecal osmoticgap is less than 50 mOsm per kilogram of water.

22,42

The diseases associated with this type of unresponsivediarrhea are listed in Table 5. Most would have beendiagnosed during the initial outpatient evaluation.

No detailed study has measured the success of theinitial outpatient evaluation of chronic diarrhea, butperhaps one third of cases can be diagnosed on the ba-sis of clues from the history, physical examination, andinitial studies, and half of the remainder can be diag-nosed on the basis of the systematic outpatient evalua-tion we have described. Inpatient evaluation leads to adefinite diagnosis in at least two thirds of patients ad-

mitted for diarrhea of undetermined origin. After com-prehensive outpatient and subsequent inpatient evalua-

Table 4. Stepwise Evaluation of Hospitalized Pa-tients with Diarrhea of Undetermined Origin.

Day 1

Confirmation and review of results of outpatient evaluation

Measurement of stool weight or volume on normal dietUrine laxative screening by thin-layer chromatography

Stool alkalinization assayMeasurement of stool sodium, potassium, sulfate, phos-

phate, stool osmolality; calculation of stool osmotic gap

Days 24

Imposition of 72-hr fast with intravenous hydration (If diar-

rhea stops completely in 24 hr, there is no need to con-

tinue fast. Secretory diarrhea often decreases greatlywith fasting, but continues with

200 g of stool per

24 hr.)

Monitoring of daily stool weights

Days 58

Imposition of diet containing 75100 g of fat per 24 hrMonitoring of 24-hr mean stool weight and fat content on

days 6, 7, and 8

Table 5. Functional Classification of Types of Chron-ic Diarrhea on the Basis of Responsiveness

to Fasting.

Types (or causes) responsive to fasting

Incontinence

Bile acid diarrhea

After cholecystectomyAfter ileal resection

SteatorrheaOsmotic diarrhea

Carbohydrate malabsorption

Excessive carbohydrate ingestionLaxatives (containing poorly absorbable anions: sodium

sulfate, sodium phosphate, or sodium citrate), mag-

nesiumFood allergy

Types (or causes) not responsive or only partly respon-

sive to fasting

Laxative or diuretic abuse

Inflammatory bowel diseasesCeliac sprue

Intestinal lymphoma

Neuroendocrine tumorsZollingerEllison syndrome

Pancreatic choleraCarcinoid tumorMedullary carcinoma of the thyroid

Systemic mastocytosis

Villous adenoma of the rectosigmoidChronic infection (e.g.,Mycobacterium tuberculosis

, giar-

dia, amebae)

HyperthyroidismCongenital diarrhea

Chloridebicarbonate exchange deficiencySodiumhydrogen exchange deficiency

Microvillus inclusion disease

Bacterial overgrowth



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tions, a diagnosis can thus be made in about 90 percentof patients: about a third will have an organic disorder,about 20 percent will be found to be taking laxatives ordiuretics surreptitiously, and the rest will be given a di-agnosis of functional or idiopathic diarrhea. In thelatter group are many with watery diarrhea of recent

acute onset that is self-limited.

5,8

As our understandingof and ability to detect intestinal pathophysiologicconditions improve, more patients with undiagnosedchronic diarrhea will be found to have an organic rath-er than a functional disorder.

R

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