Chronic Protracted Diarrhea of Infancy: A Nutritional Disease

Chronic

Protracted

Diarrhea

of Infancy:

A Nutritional

Disease

Clifford

W. Lo, MD, MPH,

and W. Allan

Walker,

MD

From the Pediatric Gastrointestinal and Nutrition Unit, Massachusetts General Hospital, Harvard Medical School, Boston; and Department of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge

ABSTRACT.

morbidity in infancy. Occasionally, it becomes protracted, leading to a vicious cycle of malabsorption, malnutrition,

and failure to thrive. A number of causes of chronic

diarrhea in infancy are discussed, including

postinfec-tious enteritis, celiac sprue, cow’s milk allergy, and

par-asitic infection. Although many mechanisms may

con-tribute to diarrhea, a similar pathophysiologic syndrome

of mucosal atrophy, inflammation, and malabsorption

results. Attention should be paid to recognition of

mal-nutrition as well as etiologic diagnosis. Therapeutic

ef-forts should concentrate on nutritional rehabilitation,

through appropriate oral elemental formulas or total

parenteral nutrition. However, encouragement of

breast-feeding is probably a more effective way of preventing

this difficult problem. Pediatrics 1983;72:786-800;

chronic diarrhea, malabsorption, malnutrition, failure to

thrive.

“Like the diet prescribed by doctors which neither

re-stores the strength of the patient nor allows him to suc-cumb. “-Demosthenes (385-322 Bc)

Diarrhea! diseases continue to be the leading

cause of morbidity and mortality in the world today,

with estimates of 3 to 5 billion cases per year (an

average of roughly one per person per year).’ The

burden is especially severe on children less than the

age of 5 in Asia, Africa, and Latin America, with

approximately 500 million episodes of diarrhea

leading to 5 to 18 million deaths per year.2 Even in

industrialized countries, mortality of infants

hos-pitalized for diarrhea still exceeds 1 % , half of these

from complications of prolonged chronic

diar-Received for publication March 15, 1982; accepted March 23

1983.

Reprint requests to (W.A.W.) Pediatric Gastrointestinal and Nutrition Unit, Massachusetts General Hospital, Boston, MA

02114.

PEDIATRICS (ISSN 0031 4005). Copyright © 1983 by the American Academy of Pediatrics.

rhea”4 In the United States, diarrhea! diseases were

the leading cause of infant mortality until 50 years

ago,5 especially the dread summer “cholera

infan-tum” which appeared about the middle of the 18th

century6 and reached its peak at the end of the 19th

century. This occurred almost exclusively among

artificially fed babies, contributing to an overall

mortality of 80% to 90% in this group.5’3”

In 1968, Avery et a!7 defined intractable diarrhea

of infancy by the following criteria: (1) lasting more

than 2 weeks, (2) onset in infants less than 3

months of age, and (3) with three or more negative

cultures for Shigella, Salmonella, Escherichia coli,

and ova and parasites. Larcher et a!8 reported 82

cases of protracted diarrhea of four or more loose

stools per day for longer than 2 weeks with infants

suffering failure to thrive. Of these, 33% had celiac

disease, 12% had secondary disaccharidase

defi-ciency (possibly postinfectious), and 11% had cow’s

milk protein intolerance; in 28%, however, no

di-agnosis could be established. Overall mortality was

5%, much improved over the earlier experience of

Avery et al of 45% mortality, and this improvement

was attributed to the use of an elemental

chicken-based formula. Sunshine et al9 reviewed the subject

and cited 42 additional cases, in which the largest

category (48% ) consisted of a nonspecific

entero-colitis secondary to an infectious gastroenteritis or

cow’s milk protein intolerance, with a mortality of

28%. Other reports of persistent diarrhea in

infants’#{176}’ claim much reduced morbidity and

mor-tality with improved methods for delivery of oral or

intravenous alimentation.

Other reviews of chronic diarrhea in children’4’6 stress the wide range of etiologic and

pathophysio-logic mechanisms that may be involved in this

problematic syndrome. Much of the problem lies

with the lack of a common definition of diarrhea.

said 2,000 years ago to be “the discharge of

undi-gested food in a fluid state,” but more quantitative

definitions are elusive. In addition to the two liters

of fluid ingested daily by the average adult human,

seven additional liters of salivary, gastric, biliary,

pancreatic, and intestinal fluid are also secreted

into the intestine.’7 With a high degree of efficiency,

95% to 98% of the water, fat, carbohydrate, and

protein ingested or secreted into the intestinal

lu-men is normally reabsorbed. The consistency of

stools is not solely determined by the water content,

and the average stool weighing 100 to 200 g in

adults contains 60% to 85% water, whereas

diar-rheal stools may also contain 60% to 95% water.’8

Stool frequency in adults usually ranges from twice

weekly to twice daily and from one to four times

daily in children.’9 However, it is not uncommon to

see a healthy breast-fed infant pass six to eight or

more seedy, yellow stools per day. Likewise, the

usual stool weight of less than 10 g/kg of body

weight per day (up to 200 g maximum) is often

exceeded on a high-fiber diet, as observed in Africa.

Thus, neither stool frequency, stool weight, or stool

consistency is always reliable in determining

patho-logic diarrhea. Any attempt to assess the severity

of diarrhea in children, whether by mothers’ reports

or weighing of stools, should also include attention

to its acute or long-term effects such as

dehydra-tion, malabsorption, malnutrition, and failure to

thrive.

The syndrome of chronic nonspecific diarrhea is

distinguished from intractable diarrhea by lack of

any evidence of malabsorption, growth retardation,

or dehydration.20’2’ Occurring classically between 6

and 30 months of age, this syndrome is thought to

be the childhood counterpart of the all-too-common

irritable bowel syndrome22 and has a strong

psycho-logical component.23 It may be associated with

ele-vated levels of plasma prostaglandin24 possibly due

to decreased gut transit time and disordered gut

motility.25 After noticing a correlation with dietary fat restriction designed to prevent atherosclerosis,26

Cohen et a! recently advocated empiric treatment

by increasing dietary fat intake.27

Intractable diarrhea, on the other hand, is much

more serious because malabsorption of essential

nutrients leads to malnutrition and failure to thrive.

Indeed, intractable diarrhea may be seen as the

end-stage of chronic malabsorption, which may be

life-threatening if effective intervention is not

,available. Originally described by Aretaeus the

Cap-padocian in the first century AD, the “coeliac

dia-thesis” was associated with general emaciation, and

was noted by Samuel Gee (1839_1911)28 to be

“es-pecially apt to affect children between one and five

years old.” The malabsorption syndrome now

in-cludes a long list of specific diseases, some

exceed-ingly rare2933 (see Table 1). A comprehensive

dis-cussion of such causes is beyond the scope of this

review, and only the most common underlying

causes of intractable diarrhea, (1) celiac sprue, (2)

cow’s milk allergy, (3) giardiasis, and (4)

postin-fectious diarrhea, will be discussed here. Most of

the other causes will not be seen commonly,

al-though two autosomally recessive inherited

disor-ders, cystic fibrosis and congenital

sucrase-isomal-tase deficiency,33 should not be forgotten.

ETIOLOGY

Celiac

Sprue

Celiac sprue was observed to be related to wheat

in the diet, after certain Dutch children’s health

improved when bread was temporarily unavailable

during World War II. Thought to be autosomal

dominant with incomplete penetrance,34 celiac

sprue has a strong association with

histocompati-bility type HLA-B8. The prevalence of celiac

dis-ease is reported to be as high as 1/300 in Ireland,

but much lower in other parts of Europe and the

United States.35 “Gluten-sensitive enteropathy”

has been proposed as an alternative term,36

inas-much as challenges with the gluten protein produce

TABLE 1. Causes of Protracted Diarrhea

Postinfectious diarrhea

Shigella, Salmonella, Escherichia coli, Yersinia,

Cam-pylobacter

Rotavirus, Norwalk agent, adenovirus, calcivirus,

co-ronavirus, astrovirus, other enteroviruses Celiac sprue

Allergic gastroenteropathy

Cow’s milk allergy

Soy protein intolerance Pancreatic insufficiency

Cystic fibrosis

Shwachman-Diamond syndrome

Congenital enzyme deficiencies

Sucrose-isomaltase deficiency, enterokinase

defi-ciency, glucose-galactose malabsorption, lactase

de-ficiency, congenital chloridorrhea Parasitic infection

Giardiasis, strongyloidiasis, amebiasis, capillariasis, coccidiosis

Bacterial overgrowth, stasis syndromes

Clostridium difficile

Short-bowel syndromes

Drugs

Laxatives, phenolphthlalein, antibiotics, antacids,

sorbitol Miscellaneous

Intestinal lymphangiectasia, abetalipoproteinemia,

Wolman’s syndrome, Hirschsprung’s disease,

a characteristic (but nonspecific) intestinal villous

atrophy.37 Nevertheless, the basic pathogenesis of

the toxic reaction to the alcohol-soluble gliadin

fraction of gluten is still not completely clear.38

Celiac disease may represent a primary or

second-ary immune response to gluten. To support this

hypothesis, a wide range of immunologic

disturb-ances have been described, including

immunoglob-ulin deficiencies,39 a transfer factor defect,4#{176} the

presence of antireticulin antibodies,4’ food

anti-bodies and immune complexes,42’43 altered

cell-me-diated immunity,44 and leukocyte migration

inhi-bition factors,45 as well as associations with

der-matitis herpetiformis and other immunologic

dis-eases.46

The characteristic flat intestinal lesion of villous

atrophy, crypt hyperplasia, and cellular

inflamma-tory response after challenge and rechallenge with

gluten, is no longer thought to be specific;47 it occurs

also in cow’s milk intolerance,48’49 soy protein

in-tolerance,5#{176} eosinophilic gastroenteropathy,5’

im-munodeficiency,52 tropical sprue,53’54 bacterial

over-growth, giardiasis, acute gastroenteritis, and other

chronic diarrhea! dieases.55 Steatorrhea is

accom-panied by secondary disaccharidase deficiency,37’5#{176}

disturbed bile and pancreatic secretion, and

secre-tory imbalance.38 Although some patients may

re-main asymptomatic or have only transient gluten

intolerance, long-term dietary avoidance of gluten

(wheat, rye, barley, and oats) remains essential57’58

to prevent relapses of intractable diarrhea and

growth failure.

Cow’s Milk Allergy

Although recognized since the time of

Hippo-crates, cow’s milk intolerance has been a topic of

increasing interest as the effects of widespread use

of cow’s milk-based formulas in infant nutrition

have become apparent. The manifestations of cow’s

milk allergy are protean; in addition to diarrhea

and a variety of other gastrointestinal (GI)

symp-toms, they may include respiratory, dermatologic,

hematologic, neurologic, and cardiovascular signs

and symptoms. From a series of children with cow’s

milk allergy,59 Lebenthal60 lists presenting

symp-toms as diarrhea, 88%; vomiting, 44%; abdominal

pain or colic, 39%; atopic dermatitis, 33%; rhinitis,

31%; asthma, 31%; urticaria, 13%; and anaphylaxis,

12%. Cow’s milk allergy usually occurs before the

age of 6 months, but diagnosis is not always clearly

documented, leading to reports of incidence ranging

from 0.3% to 75%6162 This is partly due to the

difficulty of fulfilling the strict criteria of Goldman

et al:63 (1) symptoms subsiding after milk

elimina-tion; (2) symptoms occurring within 48 hours

fol-lowing a trial feeding of milk; (3) three such positive

challenges similar in onset, duration, and clinical

features; and (4) symptoms subsiding following

each challenge reaction. Inasmuch as many

work-ers64’65 feel that three challenges are impractical, an

alternative approach to diagnosis is serial intestinal

biopsies after a single challenge, yielding a mucosal

villous atrophy of varying severity which resolves

on a milk-free diet.48’66’67 However, in view of the

diverse pathogenesis and manifestations of the

dis-ease, abnormal morphologic findings during small

bowel biopsy are neither specific nor consistently

detectable.’69

A large number of immunologic tests have been

reported to be variably abnormal in cow’s milk

intolerance, including skin tests,7#{176} hemagglutinin

and milk precipitin antibodies,7’ secretory

coproan-tibodies, eosinophilia, elevated serum

immunoglob-ulin E (IgE) levels, and positive radioallergosorbent

test (RAST),72 immune complexes, leukocyte

his-tamine release, lymphoblast transformation, and

lymphokine production.73 However, most of these

tests have poor sensitivity and specificity, and no

single simple test that can easily be performed has

gained wide acceptance.

Indeed, a number of immunologic mechanisms

may be involved in the variety of clinical

manifes-tations. The local small intestinal response may be

mediated by antibodies of the secretory IgA class

and possibly IgG and 1gM.74 Colitis, occurring

dis-tally,75 may involve a systemic type II Arthus

re-sponse mediated by IgG and complement.76 Of

course, the term cow’s milk allergy suggests an

immediate IgE type I hypersensitivity.77 Delayed

hypersensitivity mediated by T lymphocytes might

explain late reactions, lymphokine release,

lympho-blast transformation, and eosinophilia.78

Cow’s milk allergy may be due to early exposure

to cow’s milk protein at a time when there is

excessive intestinal antigenic uptake of

macro-molecules;79’60 thus it may be prevented by

breast-feeding through the first months of life. Increased

macromolecular transport may also occur after an

episode of infectious diarrhea,82 producing a

sec-ondary cow’s milk intolerance.60M This may

pro-long the duration of mucosal damage during

refeed-ing, leading to secondary lactase deficiency, lactose

malabsorption, malnutrition, and failure to

thrive.m The main fractions of proteins in cow’s

milk, (-lactoglobulin, a-lactalbumin, albumin,

ca-sein, and rny-globulin, are all demonstrably antigenic,

and may be processed by partial digestion into as

many as 100 or more additional different antigenic

protein fragments.74

The reports of similar or concomitant reactions

to soy protein5”87’ suggest a relationship to a larger

category of GI food allergy89 that may even include

syn-drome usually disappears spontaneously by age 2

years,83 but affected children may suffer from other

allergic complaints. There is evidence that

diso-dium cromoglycate may be effective in

prophy-laxis,#{176}but the best prevention is avoidance of cow’s

milk, preferably by institution of breast-feeding.9’

Giardia and Other Parasites

Giardiasis is another condition that is becoming

more frequently recognized as a cause of chronic

diarrhea. Although more common in countries with

contaminated water sources, infection with Giardia

lamblia also occurs frequently in some parts of the

United States (such as along the Colorado River),

and worldwide reports of prevalence range from 1%

to as high as 3#{216}%#{149}9293However, most infections are

asymptomatic, and the clinical syndrome of

ma!-absorption, steatorrhea, and severe acute or chronic

diarrhea is not directly related to the number of

parasites or the severity of the mucosal injury.94’95

Thus, Giardia cysts might not be found in stools of

some symptomatic patients, and a small-bowel

bi-opsy, duodenal aspirate or entero-string test may

be necessary for positive diagnosisY

The pathogenesis of disease in giardiasis is still

unclear, and theories of mucosal invasion,

compe-tition for nutrients, toxin production, or a

para-sitic mechanical barrier to absorption have been

proposed.97’98 Mucosal damage with reduction of

brush border sucrase and lactase activity has been

shown.99 Patients with a variety of B-cell

immu-nodeficiencies, including nodular lymphoid

hyper-plasia and “hypogammaglobulinemic sprue,” have

a predilection for Giardia infections accompanied

by villous flattening and malabsorption,’#{176}#{176}”#{176}’again

illustrating an interaction between immunity,

in-fection, diarrhea, and malnutrition. Infection is

usually cured by quinacrine or metronidazole for

ten days, but relapses or treatment failures

occa-sionally OCCUr’#{176}2

Entamoeba histolytica is the other common

par-asite that can cause a chronic dysentary or diarrhea;

the case fatality rate may be as high as 27%.b03

Invasive amebiasis results from a variable virulence

affected by bacterial flora and diet of the host.’#{176}4

Trophozoites attach to the colonic mucosa and

release cytotoxic factors and cytoplasmic enzymes

to create characteristic flask-shaped ulcers. The

range of the disease is variable, from asymptomatic

to ulcerative postdysenteric colitis, peritonitis,

strictures, ameboma, cutaneous infections, and

liver abscess’05 Treatment of amebiasis depends on

the form of the disease, but metronidazole (750 mg

three times daily for five to ten days) is suggested

for dysentery as well as extraintestinal amebiasis.’#{176}

Other parasites that may occasionally produce

chronic diarrhea and malabsorption include

Stron-gyloides stercoralis, Isopora belli, Capillaria

philip-pinensis, and hookworm,29 and even the ubiquitous Ascaris lumbricoides’#{176}7; all cause some degree of

mucosal damage.

Postinfectious Diarrhea

Postinfectious diarrhea is probably the most

common cause of intractable diarrhea, especially in

developing countries, but much remains to be

un-derstood about the progression of disease and

pro-longation of diarrhea. It is now clear that the

uni-tarian idea of infectious diarrhea as a bacillary

dysentery caused by Shigella, Salmonella, or E Coli

is far from the entire truth.’#{176} Only between 4%

and 33% of diarrhea! stools yield these specific

bacterial pathogens.’#{176} The virulence of these

bac-teria has been classically attributed to mucosal

adherence and proliferation and invasion of the

mucosal cell, which produce an inflammatory

ileo-colitis with loss of water, blood, and mucus from

the damaged mucosa.”#{176}”2 However, at least in

some E coli and Shigella infections, there is also production of enterotoxin, which initiates secretory

diarrhea in the proximal small intestine, such as in

cholera.”3”6 Indeed, it may be more relevant to

look for enterotoxigenic E coli strains than the

probably outdated list of enteropathogenic E coli

‘7

Recently, other bacterial and viral pathogens

have been receiving increased attention as causes

of infectious diarrheas in children.”’2#{176} Yersinia

enterocolitica produces a bloody diarrhea when it

invades the intestinal mucosa, but it may also

pro-duce an enterotoxin.’2’’24 Occasionally, it can cause

a chronic inflammation of the bowel, appendicitis,

or a chronic diarrhea lasting for months.’25

Cam-pylobacter fetus likewise produces a febrile illness

with bloody diarrhea’26”27 may mimic ulcerative

colitis,’28 and has been associated with consumption

of unpasteurized milk.’29

However, the real advance in the diagnosis of infectious diarrhea has come in the identification

of viral agents, especially rotavirus.’30’33 Although

many viruses, including adeno-, corona-, echo-, and

myxoviruses had been isolated from patients with

diarrhea,’34 it was not until a 27-nm particle in

diarrheal stool filtrate from an epidemic in

Nor-walk, OH was used to infect volunteers that a viral

etiology for diarrhea was confirmed.’35 In addition

to the Norwalk agent, a 70-nm rotavirus has been

identified as one of the most common causes of

diarrhea in children less than 3 years of age.’35

Originally detected by immune electron

micro-scopy’37”38 because of difficulty in cell culture

counterimmunoelectrophoresis,’41”42 and especially

ELISA (enzyme-linked immunosorbent

as-say),’43”44 have disclosed a surprisingly high

fre-quency. Rotavirus has been detected in stools of up

to 40% to 70% of infants with gastroenteritis in

both developing countries and in the United

States.’45 Indeed, one study showed that 64% of

children had evidence of exposure by age 3 years

and 85% by age 5 years.’46 Rotavirus, although

mainly affecting children less than 3 years of age,

has also been found in epidemics among

school-children’47 and adults.’48

PATHOGENESIS

Viral gastroenteritis causes structural

abnormal-ities similar to those found with celiac disease, with

villous atrophy, crypt hypertrophy, and

inflamma-tory infiltrate.’49’52 Animal studies show viral

in-vasion of the intestinal epithelium, with replication

and shedding of the villous enterocytes. These are

replaced by premature migration of

less-differen-tiated crypt cells, which causes an altered mucosal

surface and derangement of sodium-glucose

trans-port.’53 A severe decrease in effective absorptive

area after viral gastroenteritis has been

demon-strated by careful examination of small-bowel

biop-sies.’54 Disaccharidase activity, particularly

lac-tase,’55”56 located on the microvillous brush border,

is consequently impaired, and secondary

ma!-absorption of lactose may persist for some

time.’57”” Undigested carbohydrates cause large

volumes of water to enter the lumen of the bowel

in an osmotic diarrhea.’59 The presence of

unab-sorbed sugars in the lumen also encourages a

pro-liferation of enteric microflora in the small

intes-tine,’60”6’ which causes further malabsorption and

diarrhea.’62 In the colon, bacterial fermentation of

undigested sugars produces lactic acid, releases

hy-drogen, and lowers the pH of the stool.’63

In diarrhea caused by enterotoxigenic E coli

or cholera, active secretion of large quantities

of sodium chloride and water is stimulated by

cAMP.’’67 Other causes of secretory diarrhea in

children include congenital chloridorrhea,1

non-beta islet cell hyperplasia producing vasoactive

in-testinal peptide’69 and hormone-producing

tu-mors.’7#{176} Although cAMP may not be involved in

rotavirus gastroenteritis or celiac sprue, secretory

diarrhea also occurs, perhaps because of the

prolif-eration of “leaky” immature crypt cells.’7”72

Malabsorption of fat in protracted diarrhea

usu-ally produces obvious steatorrhea, but may also

occur without clinical evidence.’73 In some cases,

this may be due to bile salt malabsorption in the

enterohepatic circulation’74’76 or their

deconjuga-tion by bacteria;’77 bile salt depletion leads to

in-adequate micellar formation.

Protein malabsorption is another major factor’78

and may be due to reduced enterokinase and trypsin

activity’79 or protein-losing enteropathy’tm with loss

of plasma proteins’8’ as well as sloughing of

intes-tinal mucosa.’82 If negative nitrogen balance

per-sists because of prolonged reliance on protein-free

oral or intravenous glucose-electrolyte solutions,

weight loss, malnutrition, and failure to thrive will

eventually ensue. Protein-calorie malnutrition, in

turn, further prolongs diarrhea, disaccharide

into!-erance,’83 and ma!absorption of fats, protein,

car-bohydrate, and vitaminsMm (see Table 2). Indeed,

the small intestinal mucosa in malnutrition

typi-cally ranges from nonspecific shortening of villi in

marasmus to a sprue-like flat intestinal lesion in

kwashiorkor (Fig Thus, malnutrition not

only contributes to delayed recovery from

intrac-table diarrhea but is the major consequence of it.

Secondary malnutrition, with respect to protein or

other specific nutrients, leads to impaired host

de-fenses, particularly in decreased cell-mediated

im-munity, secretory antibodies, phagocyte function,

and complement levels’89’94 and thus increases

sus-ceptibility to further infection.19520’ This vicious

cycle of diarrhea, malabsorption, malnutrition,

im-paired immunity, and infection202’203 has serious

effects not only on immediate morbidity but also

on long-term behavioral and intellectual

devel-opment204208 (see Fig 2).

DIAGNOSIS

The great majority of acute infectious diarrheas

resolve after a few days of treatment with

glucose-electrolyte solutions. Occasionally, however, the

diarrhea fails to resolve despite many changes of

formula. In this case, the value of a detailed dietary

history is apparent. Not infrequently, a mother who

is breast-feeding is counseled to change to an

arti-ficial formula, and things can go from bad to worse.

Diarrhea can occur when an infant is receiving

breast milk, but most studies document a strikingly

lower incidence in breast-fed babies.2#{176}2’5 Sorting

TABLE 2. Gastrointestinal Changes in Malnutrition*

Subtotal villous atrophy

Decreased functional surface area

Disrupted mucosal barrier Enzymes

Antibodies

I

Decreased crypt cell turnover

Migration of cells

Altered intestinal flora

Relative pancreatic insufficiency

* From Walker WA: Cellular and immune changes in the

gastrointestinal tract, in Winick M (ed): Nutrition and

Fig 1. Flattened mucosa similar to that produced by

celiac disease in kwashiorkor. Top, Low-power view

shows absence of villi and flat surface. There is moderate

infiltration of lamina propria with lymphocytes and

plasma cells (periodic acid-Schiff). Bottom, High-power

view shows low surface epithelium with irregularly

dis-tributed nuclei. Brush border is irregular and sparse

(hematoxylin and eosin). Reproduced with permission

from 0. Brunser, A. Reid, F. Monckeberg, et a!: Jejunal

biopsies in infant malnutrition: With special reference to mitotic index. Pediatrics 1966;38:608.

out the various formula changes and their effects

on stool frequency can take some time and requires

some familiarity with the composition of infant

formulas.

A careful history of travel, illnesses, medications,

development, family history, and especially social

situation can sometimes provide the only clue to

the origin of the diarrhea. Giardiasis or amebiasis

can be contracted during travel through an endemic

area, such as on a camping trip in the Rocky

Moun-tains. Cystic fibrosis or congenital carbohydrate

intolerance216 may be suggested by a positive family

history. Ampicillin and most other antibiotics have

been implicated in diarrhea and colitis, now known

to be due to an overgrowth of Clostridium

diffi-cile.21722#{176}Not infrequently, a disturbed social

situ-ation may be the clue to diarrhea induced by the

mother or a relative surreptitiously administering

a laxative to the infant.

Much important information is gained by

plot-ting the infant’s growth curve with serial

measure-ments of weight, height, and weight for height. The

widely used Gomez classification22’ defines mild

(grade I) malnutrition as between 75% and 90% of

standard weight for age; moderate (grade II) as

between 60% and 75%; and severe (grade III) as

less than 60% weight for age. Values less than 80%

of standard weight for height, or values below the

fifth percentile of the new National Center for

Health Statistics (NCHS) standards have been

widely used as the criteria for chronic malnutrition.

Other anthropometric measurements in common

use include the mid-arm circumference (for muscle

mass) and the triceps fatfold (for subcutaneous fat),

but unless these measurements are performed with

standardized equipment and careful technique, they

are subject to wide intraobserver variation

espe-cially in infants less than 1 year of age.222

On physical examination, the general appearance

of a child with chronic diarrhea can often separate

those with benign nonspecific loose stools and those

with chronic malabsorption and malnutrition. The

clinical picture of severe marasmus includes

leth-argy, emaciation, muscle wasting, hypotonia, and

sunken cheeks,223 but these signs may be more

subtle in mild or moderate malnutrition.

Occasion-ally, edema, a distended abdomen, and “flaky paint”

dermatitis are seen, classic signs of kwashiorkor.224

Pallor may reflect an anemia, most likely iron

de-ficiency, but could also be due to a deficiency of

vitamin C, B6, B,2, folate, or vitamin E. Clinical

signs of specific nutrient deficiencies are not

com-mon in the United States, but include areas of rapid

cell turnover, such as the skin, hair, mucous

mem-branes, bones, as well as the intestinal mucosa. A

dermatitis might indicate a deficiency of riboflavin,

niacin, protein, zinc, or essential fatty acids.

Pete-chiae or purpura may be manifestations of vitamin

A or C deficiency. Glossitis, cheilosis, and angular

stomatitis are nonspecific signs that may

accom-pany lack of niacin or riboflavin. Bone deformities

such as costochondral beading (“rachitic rosary”),

craniotabes, or epiphyseal swelling may be signs of

rickets (vitamin D deficiency) or scurvy (lack of

vitamin C).

Pale, thin, brittle hair may result from protein or

essential fatty acid deficiency. Eye findings include

Bitot’s spots, xerophthalmia, and keratomalacia

(vitamin A deficiency) and cornea! vascu!arization

(ariboflavinosis). Neurologic signs may be found in

deficiencies of folate, vitamin B,2, thiamin, pyridox-me, or niacin.

Occasionally, physical signs may suggest the

cause of the diarrhea. Nasal polyps or rectal

pro-lapse are characteristic features of cystic fibrosis.

Fig 2. Hypothetical pathogenesis for nutritional cause of intractable diarrhea of infancy.

protean manifestations of neurob!astoma. Eczema

is associated with cow’s milk allergy and ce!iac

disease. Infants with acute dehydration from

gas-troenteritis, superimposed on their chronic

malnu-trition, will show loss of skin turgor with “tenting”

of the skin, sunken eyes, dry lips, and concentrated

urine. Such a state requires prompt attention to

fluid needs.

Laboratory Findings

Laboratory examination of the stool is often

overlooked, but usually provides far more

informa-tion than most biochemical serum tests in the

di-agnosis of chronic diarrhea. With no equipment

other than a microscope, the liquid portion of the

stool sample can easily and quickly be tested for

weight, acidity, sugars (reducing substances), occult

blood, fat globules, leukocytes, ova, and parasites.

A stool pH less than 6.0 suggests bacterial action

on malabsorbed carbohydrates; however, this may

be a normal finding in breast-fed infants.

Malab-sorption of reducing sugars (glucose, lactose, but

not sucrose) can be detected by greater than 0.5%

reading by a Clinitest tablet dropped into equal

portions of liquid stool and water. If the infant is

receiving a sucrose formula (as is the case with soy

formula), the mixture must be heated with 0.1 N

hydrochloric acid for a few minutes to hydrolyze

the sugar. A positive stool guaiac test suggests some

source of GI bleeding, but can also be positive if the

diet contains meat. Excessive fat globules can be

seen easily under low-power microscope, but this

may be normal in young infants whose coefficient

of absorption on a fecal fat collection may be as

low as 85% instead of the 95% expected in adults.

Fecal leukocytes, seen with a methylene blue stain,

usually indicate bacillary dysentery caused by E

coli, Salmonella, Yersinia, or especially Shigella.225

The same methylene blue stain may reveal

char-acteristic Giardia trophozoites, amebic cysts, or

he!-minth ova.

Biochemical tests of nutritional status tend to be

too expensive and limited for most situations, but

a good initial screen might include a complete blood

count (CBC) with differential and red cell

mor-phology, serum electrolytes, total protein, and

a!-bumin. In a hospital setting, serum carotene,

cal-cium, phosphorus, iron, transferrin, zinc, copper,

thyroxine, cholesterol, triglycerides, or liver

func-tion tests (SGPT, SGOT, bilirubin, alkaline

phos-phatase, 5‘-nucleotidase, -y-glutamyl

transpepti-dase, and prothrombin time) might be among those

considered for further investigation. A sweat

chlo-ride test should be performed at a reliable center as

this test, when done properly, is a sensitive and

specific test for cystic fibrosis. Stool cultures,

mu!-tiple samples for ova and parasites, and a 72-hour

collection for fecal fat can be done on an inpatient

or outpatient basis, although this may be difficult

in infants.

To assess carbohydrate absorption, oral

carbo-hydrate tolerance tests may be given with 2 g of

lactose, sucrose, or glucose per kilogram of body

weight, up to 50 g in children or 100 g in adults, or

5 to 25 g of xylose.226 Traditionally, increased stool

output with presence of sugar, symptoms of

CHRONIC DIARRHEA

MANAGEMENT

L

No

dehydration

Total parenteral

nutrition

mulas should be selected according to persistence or

resolution of carbohydrate malabsorption, progressing

along a graded sequence from intravenous to elemental

to lactose-free to regular diets as malabsorption resolves,

or vice versa if it persists. Abbreviations used are: BE,

barium enema; UGI, upper gastrointestinal.

glucose concentration at 30, 60, or 90 minutes have

been used as bases for a positive test. Breath

hy-drogen analysis allows a quantitative, noninvasive

method of detecting carbohydrate

malabsorp-tion.227229 Lactose or sucrose that is ingested but

malabsorbed in the small intestine progresses to

the colon where it is metabolized by bacteria,

re-leasing excess quantities of hydrogen gas, which

can be detected in the breath. However, various

factors such as stool flora and pH changes can affect

breath hydrogen, making its diagnostic use in acute

diarrhea unreliable. Fat malabsorption can also be

measured using radioactive ‘4C23#{176}or stable

‘3C-labeled substrates. Unfortunately, this latter

tech-nique requires a mass spectrometer for breath

anal-ysis and is only available presently at a few research

centers.

One of the most important tools for investigation

of chronic diarrhea and failure to thrive is

hospi-ta!ization for observation of stool pattern and

weight gain. It is best to leave the infant on the diet

currently producing the diarrhea. Daily weights,

careful input and output records, and serial

mea-surements of stool weight, pH, and reducing

sub-stances, will quantitatively document the severity

of the diarrhea and ma!absorption. Occasionally,

an upper GI contrast series with small bowel

follow-through, a barium enema, ultrasound studies, a

small bowel biopsy and duodenal aspirate,

sigmoid-oscopy, or colonoscopy may be necessary to reveal

the underlying cause (Fig 3).

Management

The basic principles of the treatment of diarrhea

are nutritional, replenishing not only sodium,

po-tassium, and water losses, but also, protein, calorie,

and other nutrient stores. Although fluid

rehydra-tion was known as a treatment for cholera as early

as 150 years ago, high mortality continued until the

use of intravenous sodium and potassium salt

so-lutions gained widespread acceptance 100 years

later.23’234 Although complex calculations of

so-dium and potassium maintenance and deficit

re-quirements were 3236 less attention was paid

to protein and calorie needs, and infants were

sub-jected to a prolonged fast for “bowel rest.” This

concept has been 32 and recent

evi-dence suggests that both gut villous morphology

and disaccharidase activity improved faster when

DIAGNOSIS

History & physical Serial weights

Stool exam, pH, guaiac, reducing sugars Urinalysis

CBC & diff, ESR Serum electrolytes Total protein, albumin Stool cultures

Serial stool exams

D-xylose test

Lactose tolerance test or breath H2 test

72 h stool fat

Sweat chloride

Liver function tests

Iminunoglobulins

X-rays (BE, UGI) Sigmoidoscopy

Small bowel biopsy Nutritional monitoring:

Ca, Mg, P, electrolytes, Zn, Cu, etc.

Fig 3. Diagnostic tests and treatment alternatives in

management of chronic diarrhea. Diagnostic tests are listed by groups in suggested order ranging from initial outpatient screening tests to more involved inpatient

procedures. Not all tests need be or should be performed unless specifically indicated. Therapeutic changes of

for-Dehydration or

vomiting

Ir Hospitalization,

Oral or intravenous

glucose-electrolyte

solution

t

1otio1

YS/

Elemental formula

actose-free formula

Outpatient,

Oral

glucose-electrolyte solution

Regular

Dextrose

Carbohydrate Fat Protein kcal/mL mosm/L

* Abbreviation used is: MCT, medium-chain triglyceride.

Nonfat cow’s milk 0.67 260

stimulated by early enteral feedings than with

pro-longed “bowel rest” and intravenous

alimenta-tion.239242

Oral glucose-electrolyte solutions have been used

increasingly as initial therapy in diarrhea and

de-hydration due to a wide variety of infectious

agents.243246 They contain simple monosaccharides

and minerals which are usually absorbed by active

transport across partly damaged gut mucosal

sur-faces without normal villi.247249 However, the

ca-loric value of clear liquids is low, and they contain

no protein source that can be used to heal damaged

gut epithelium.25#{176} Therefore, clear liquids alone

should not be used for more than a few days without

the provision of additional calorie or nitrogen

sources.

Oral elemental diets containing simply

monosac-charides, amino acids, and safflower oil (eg,

Preges-timi!) are essentially completely predigested and

are usually well tolerated by infants no matter how

badly the gut is 2252 However, as their

high osmolarity may provoke an osmotic diarrhea,

elemental diets must usually be diluted for use in

infants. Other elemental formulas containing

ca-sein hydrolysates (short-chain polypeptides),

me-dium-chain triglycerides (eight- to ten-carbon

syn-thetic fatty acids which can be absorbed without

bile acids or micelles), and sucrose or glucose

pol-ymers instead of lactose, can be tailored to the

individual patient’s absorptive capacities as tested

by tolerance or breath tests253255 (Table 3). These

elemental formulas, claimed to be hypoallergenic,

are also useful if the problem involves milk or soy

protein allergy. If bo!us feedings cannot be

toler-ated, a slow continuous drip through a nasogastric

tube may be tried.

TABLE 3. Formula Composition*

Although oral elemental formulas will be

suffi-cient in most cases, occasionally total parenteral

nutrition may be necessary if diarrhea and

malab-sorption 2256 Peripheral administration

of protein dextrose solutions with fat emulsions

have been used to provide maintenance calories.’3

However, this does not allow the large amount of

extra calories to be administered, up to 200 kcal/

kg/d or more, which an extremely malnourished

infant or child might require for growth. Therefore,

placement of a central venous catheter for infusion

of hypertonic solutions becomes necessary for

treat-ment of prolonged diarrhea or severe malabsorption

problems.257259 The presence of an indwelling

cath-eter for prolonged periods has raised appropriate

concern over the high rates of infection observed in

early 2626k but the use of Silastic

cathe-262263 strict aseptic technique, and increased

experience has lowered complications to acceptable

levels.

Drug treatment of chronic diarrhea in children is

usually not warranted. No advantage has been

found in giving antibiotics in diarrhea due to E coli,

Salmonella, or nonspecific infections22; Shigelkz

is the specific exception. Intestinal paralytic agents,

such as diphenoxylate-atropine (Lomotil), may

re-lieve symptoms by decreasing fluid transit through

the gut, but without reducing secretion. The excess

water will instead tend to pool in distended loops

of bowel, masking dehydration and delaying the

usual excretion of infectious organisms.267

Adsorb-ents such as kaolin-pectin suspension (Kaopectate)

may actually cause increased sodium and potassium

losses.2 Bismuth subsalicylate (Pepto-Bismol) has

recently been shown to be of use in traveler’s

diar-rhea, possibly by enhancing the mucosal barrier or

Glucose-electrolyte

so-lutions

Pedialyte Lytren

Elemental formulas

Vivonex Pregestimil

Nutramigen Portagen

Lactose-free formulas

Isomil ProSobee Nursoy

Regular infant formulas

Similac Enfami! SMA

Glucose

Glucose polymers

Sucrose Sucrose

Glucose polymers

Lactose

Safflower oil

60% Corn oil, 40% MCT

Corn oil

90% MCT

Soy oil

80% Soy oil, 20%

coconut oil

Amino acids Casein hydrolysate

Casein hydro!ysate

Casein hydrolysate

Soy protein

0.20 400

1.00 550

0.67 300

0.67 400

0.67 200

by affecting prostag!andins,26927#{176} but the large

quantities necessary may put young infants at risk

for toxic salicylism. Other common antidiarrheal

agents are probably useless and may actually

pro-long diarrhea and be hazardous in young

chil-dren.27’

Prevention

Rehabilitation from severe intractable diarrhea

with protein-calorie malnutrition requires a long,

expensive hospitalization, with not inconsiderable

morbidity and mortality.272274 If diarrhea does

de-velop, proper attention to the infant’s nutritional

needs by the mother and the physician and

avoid-ance of prolonged iatrogenic starvation on clear

liquids or diluted formulas will prevent further

de-terioration into the vicious cycle of malnutrition,

infection, and malabsorption (Fig 1).

Increasing evidence is being accumulated on the

anti-infective properties of breast milk,275277 and

specific protection against Salmonella,278

rotavi-rus,279 and E coli’#{176}has been demonstrated. Even in

the United States, fewer hospitalizations and

infec-tious illnesses were found in infants breast-fed for

prolonged periods.2”215 Obviously, cow’s milk

in-tolerance will not be a problem in exclusively

breast-fed infants, but there is some evidence that

other allergic illness is also prevented.208

SUMMARY

Diarrhea! diseases are a major health problem in

the world today. Even in Western countries, such

morbidity and mortality result from complications

of prolonged intractable diarrhea. Although

diar-rhea is difficult to define quantitatively, intractable

diarrhea is distinguished from the chronic

nonspe-cific diarrhea syndrome by malabsorption,

malnu-trition, and failure to thrive. Most commonly

caused by allergic (celiac sprue, cow’s milk allergy)

or infectious (postinfectious enterocolitis,

giardi-asis) disease, a similar pathophysiologic syndrome

often develops. Mucosal villous atrophy, crypt

pro-liferation, and inflammation lead to carbohydrate,

fat, and protein malabsorption. The resulting

diar-rhea may involve several mechanisms including

osmotic and secretory diarrhea, bacterial

over-growth, and disordered motility. Eventually,

ma!-nutrition and failure to thrive may develop into a

vicious cycle with failure to heal mucosal damage

and further debilitation. Diagnosis of chronic

diar-rheal disease should include a careful dietary

his-tory and attention to signs of malnutrition and

tests of specific malabsorption. Management is

chiefly directed at providing adequate nutrition

through oral elemental diets or total parenteral

nutrition. However, long rehabilitation may be

nec-essary if early intervention is not instituted.

Pre-vention of the original causes can be most

effec-tively implemented by encouraging breast-feeding.

ACKNOWLEDGMENTS

This work was supported in part by National Institutes

of Health Grants AM16269, GM 21700, and HD 12437.

Dr Lo is supported by Public Health Service Training

Grant T32AM07070-07.

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