Download Viral Enteritis: A Cause of Disordered Small Intestinal Epithelial

Chronic Diarrhea in Children,
edited by Emanuel Lebenthal. Nestle,
Vevey/Raven Press, New York © 1984.
Viral Enteritis: A Cause of Disordered Small
Intestinal Epithelial Renewal
J. R. Hamilton
Department of Pediatrics, University of Toronto and the Hospital for Sick Children,
Toronto, Ontario MSG 1X8, Canada
In the past decade, human rotavirus (HRV) enteritis has been identified as
the most common cause of significant acute diarrheal illness among infants and
young children (1,2). However, a cause is rarely found for the enormous number
of infants throughout the world who suffer from chronic diarrheal symptoms.
As interactions between invasive enteric viruses and the small intestinal mucosa
have been elucidated, it has become tempting to speculate that viral damage
might initiate not only acute diarrhea but, in some cases, chronic intestinal
dysfunction.
Severe chronic diarrhea is a particular problem of infants and young children.
This age prevalence, as yet unexplained, might reflect the particular vulnerability
of the young intestine and its developing and immature transport, immunological,
and epithelial renewal capacity. Also, the increased susceptibility to malnutrition
and to enteric infection of the young host is a possible factor in the apparent
age distribution of the problem.
This chapter describes the pattern of small intestinal epithelial damage after
acute viral infection and the less well described and more variablefindingsthat
characterize children with severe chronic diarrhea. Then, it speculates on how
the former acute stage might evolve into a chronic one.
ACUTE VIRAL DIARRHEA
Our understanding of the lesion of acute viral enteritis rests on a limited
number of clinical studies and extensive animal experimentation, much of which
has utilized a specific piglet enteric pathogen, transmissible gastroenteritis (TGE)
(3-5). This agent, a coronavirus, obviously differs from human rotavirus, but
studies indicate that the responses of the small intestinal mucosa to these two
agents are identical (6). Not only is the human disease identical to the piglet
disease, but when the piglet is infected with HRV, the resultant disease and
intestinal transport abnormalities are the same as those observed in TGE. The
main features of the interaction between these enteric viral pathogens and the
small intestinal mucosa causing acute diarrhea can be summarized as follows:
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1. Virus invades the small intestinal enterocytes, primarily those on villi
rather than those on crypts. The proximal jejunum is involved, but the infection
may extend for a variable distance to include the entire small bowel. Neither
HRV nor TGE seems to involve the colon to a significant degree.
2. The small intestinal mucosa responds with accelerated proliferation of
cells in the crypts and cells along the villi. There may be a microscopic lesion
characterized by villi and deepened crypts (Fig. la). More crucial to the function
of the bowel than the mere loss of surface area appears to be the qualitative
changes in transport function that develop at the same time. These functional
abnormalities result from impaired differentiation of cells after they divide in
FIG. 1. Low-power photomicrographs of distal duodenal mucosa samples obtained from two
sick infants with diarrhea. H&E stain, a: Acute rotavirus enteritis. The villus structure is flattened,
and the crypts are elongated, b: Idiopathic chronic diarrhea. Villi are flattened, and the crypts
are normal.
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the crypts and migrate up onto villi, so that the entire epithelium becomes
composed of crypt-type cells.
3. The functional abnormalities that characterize acute viral enteritis are, in
general, similar to those considered normal features of crypt cells. They are
listed in Table 1. Each contributes to defective solute assimilation and excessive
retention of water, electrolytes, and nonelectrolyte solute in the lumen of the
small intestine. If the lesion extends over a large portion of the upper intestine,
the distal regions may not be able to adequately compensate for this defect,
leading to excessive volumes entering the colonic lumen. Although the colon
is not usually diseased, its compensatory capacity is limited and easily overwhelmed, so that diarrhea develops.
* IDIOPATHIC CHRONIC DIARRHEA
Clinical data are few and difficult to obtain because most young children
a with chronic diarrhea are very fragile. Furthermore, as their illness drags on,
the secondary impact of malnutrition, notably, exocrine pancreatic insufficiency,
A is encountered. From the literature, from other chapters in this volume, and
t from personal experience, there does seem to be a consensus on the features of
I this disorder, which, in the future, may become regarded as several diseases (7).
First and foremost, it is an intestinal lesion, not a primary pancreatic problem,
that characterizes this chronic diarrheal disorder. Often, a structural lesion with
shortened villi is seen (Fig. lb). The enterocytes are not grossly deranged; the
crypts may look proliferative and deepened with many mitotic figures, or they
may appear almost hypoplastic (8). In fact, a microscopic lesion may not be
seen (9).
However, small intestinal dysfunction is very apparent. The defect is global
but dominated by problems with glucose and ion transport and reduced disaccharidase activities. Although these findings are reminiscent of the acute viral
lesion described above, neither virus nor any other known pathogen is seen in
stools or tissue. Studies of some patients have shown a predominately secretory
activity in the small intestine in the absence of a structural lesion. Many of the
findingsfitwith the concept of a mucosal epithelium dominated by crypt cells,
which are considered secretory rather than absorptive villus cells.
TABLE 1. Enterocyte function in acute viral enteritis
Decreased
Disaccharidase activities
Na + -K + ATPase activity
Glucose-stimulated Na+ absorption
Neutral NaCI absorption
Glucose absorption
Normal
Cyclic AMP, adenylate cyclase activity
Increased
Thymidine kinase activity
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In some patients, dietary intake seems closely associated with exacerbations
of diarrhea, although in severe cases diarrhea persists on no oral intake. Often,
the relationship between diet and diarrhea is based on the increased solute or
disaccharide load on the limited ion-transporting or disaccharidase capacities
of the infant's small intestine. In other cases specific dietary proteins, notably
cow's milk, appear capable of inducing microscopic abnormalities and intestinal
dysfunction directly.
PROLONGED DIARRHEA AFTER ACUTE VIRAL ENTERITIS
Prolonged, even intractable, diarrhea may begin during infancy in babies who
previously have been well. Given the global prevalence of rotavirus enteritis
and its capacity to damage the small intestinal mucosa, it is tempting to speculate
that this invasive virus, which normally causes self-limited disease, could initiate
events that might evolve into a state of chronic life-threatening dysfunction.
Not only is this speculation unproven, but the mechanisms for any ongoing
bowel dysfunction after acute damage are not known. Nevertheless, recent developments in our understanding of the function and dynamics of the small
bowel allow one to develop some rational concepts for discussion and evaluation.
From currently available data on both the acute and chronic diarrheal states,
it seems appropriate to focus on the intestinal epithelium as having a major
role in the pathogenesis of prolonged diarrhea. In doing so, the potential role
of vascular, lymphatic, hormonal, or motility-mediated phenomena should not
be forgotten. Systematic studies have not yet been undertaken, but a major
primary role for disordered vascular, lymphatic, hormonal, or smooth muscle
function has not been demonstrated in these chronically ill babies. This chapter
discusses potential epithelial phenomena, summarized in Table 2, that might
play a role in perpetuating intestinal function after acute damage. In theory,
mucosal damage, either microscopic or functional, might continue because of
persisting injury to the mucosa or because of a breakdown in the normal processes
of repair after acute viral damage. It will be difficult to prove which, if any, of
these factors is truly significant.
Persisting Injury
Several possible mechanisms exist for ongoing damage to the small intestinal
mucosa; more is known about some of these than about others. In evaluating
afflicted patients, the first step often is to consider the known specific chronic
diseases that can cause chronic diarrhea. These range from specific inherited
transport defects (e.g., glucose-galactose malabsorption, chloride-losing diarrhea)
to inherited enzyme deficiencies (e.g., sucrase-isomaltase deficiency) to anatomical anomalies and less well understood but well-characterized diseases such
as celiac disease or cystic fibrosis. Diagnostic procedures, including clinical
evaluation, X-rays, and mucosal biopsies, are available to identify these rather
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TABLE 2. Theoretical epithelial mechanisms for diarrhea persisting after acute enteric
infection
Persisting mucosal injury
Underlying mucosal disease
Celiac disease
Others
Persisting infection, infestation
Normal mucosal barrier
Abnormal mucosal barrier
congenital immune deficiency
acquired immune deficiency
malnutrition
drugs
others
"Allergic" reactions
Dietary antigens
Microbial antigens
Intraluminal factors
Disaccharides, organic acids
Bile salts
Delayed repair
Underlying defect
Malnutrition
Protein-calorie depletion
Micronutrient deficiency
Drugs (e.g., antimetabolites)
rare and well-defined conditions. However, in by far the majority of cases, these
diagnoses are excluded, yet the child's diarrhea marches on.
One potential cause for persisting injury to the mucosal epithelium is persisting
or recurring infection. Normally, the rotavirus is quickly shed, within a few
days of symptoms beginning. Some bacteria (Salmonella, Campylobacter, Yersinia and Giardia lamblia) may persist for long periods and cause diarrhea, but
these organisms are rarely found after rotavirus enteritis ceases. The answer
therefore seems unlikely to lie in persisting or secondary infection with known
pathogens. In fact, the acute diarrheal state, if anything, should protect against
further infection. However, children with certain types of immune deficiency
are known to harbor enteric pathogens for prolonged periods—human rotavirus
in the case of combined immune deficiency, Giardia lamblia in the case of IgA
deficiency. In other cases, one suspects that organisms not usually considered
pathogenic may turn on a vulnerable mucosa. The possibility remains that some
children with defective resistance affecting their mucosal barrier seem capable
of harboring enteric organisms. One could speculate therefore that it is such
patients with congenital or acquired mucosal barrier problems that go on to
chronic diarrhea after acute intestinal injury.
Another potential instigator of chronic mucosal injury is food, more specifically, dietary antigens (10). On this particular subject passions are intense but
data are few. Unquestionably, some children exhibit an intestinal reaction to
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certain dietary components, particularly cow's milk protein. These children
often exhibit manifestations of atopic disease and a clear-cutrelationshipbetween
milk ingestion and symptoms. When it was found that antigenically significant
quantities of protein could be absorbed intact in man, it was speculated that
mucosal injury and the attendant crypt-like epithelium of acute viral enteritis
might be more permeable to dietary antigen (11). Allan Walker's studies and
preliminary data by David Keljo in our laboratory indicate that this may be
the case in piglets with experimental acute viral (TGE) enteritis. However, even
if these hypotheses are eventually proven, mechanisms remain to be determined
to account for ongoing mucosal damage in response to an absorbed potential
antigen. The observed small intestinal mucosal damage related to milk ingestion
in some children and apparent intolerance to milk after proven acute enteritis
not mediated by lactose support the view that dietary antigens could play a role
in the pathogenesis of some cases of persisting diarrhea.
Clearly, the secondary effects of acute viral damage do not normally have
the potential to perpetuate the lesion and the diarrhea in most cases, since most
cases are very brief. However, unabsorbed sugars are broken down in the distal
regions to acids—lactic acid, for example, that under experimental conditions
can damage the mucosa. If the distal intestine is diseased, bile acid reabsorption
might result and, in theory, colonic secretion might develop. Our own unpublished efforts to pursue this latter hypothesis included examination of an agent
that binds intraluminal bile salts, cholestyramine, given to infants with persisting
diarrhea. We failed to demonstrate improved fluid balance in patients with
persisting diarrhea, though another study has suggested a favorable clinical
response (12).
Defective Repair
Theoretically, diarrhea could persist after acute viral damage in the absence
of ongoing injury if the epithelial repair process were compromised. This hypothetical repair defect would presumably interfere in some way with intestinal
maturation. A few infants have been described with what appears to be an
inborn defect in epithelial turnover and profoundly inadequate absorptive function. These rare cases demonstrate the profound impact of an apparent congenital
epithelial repair defect on gut function (8). As described above, the typical
response to acute viral invasion is a rapid acceleration of the migration of
enterocytes up from the crypts to repopulate the villi. More important to function,
however, are the maturational changes that occur in these cells as they migrate.
Although it can be stated that a defect in this maturational process might be
expected to cause chronic dysfunction and diarrhea, few data are available on
the critical determinants of that maturational process. Clearly, antimetabolic
drugs have an impact on the rapidly dividing intestinal epithelium and they
may influence cell differentiation. One factor of potential relevance to most
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cases is nutrition; malnutrition states are known to influence intestinal repair,
both epithelial migration and maturation.
In many respects, the small intestine could be considered relatively untouched
by chronic undernutrition, either protein-calorie or micronutrient malnutrition
(13). Under conditions of severe chronic experimental undernutrition, though
it may demonstrate microscopic abnormalities, the small bowel functions relatively well. However, in most such studies, epithelial repair is delayed, as
manifested by reduced rates of cell turnover (14). These phenomena have not
been examined in a variety of micronutrient deficiencies, zinc or folic acid
deficiency, for example, but one suspects that similar delay might be seen. With
Decker Butzner, in our laboratory, preliminary studies in TGE-infected gnotobiotic pigs support the clinical observations of prolonged symptoms in the
malnourished host. However, again, more extensive data on this point are needed
before this important issue is resolved.
A second aspect of the impact of malnutrition on the host pertains to immune
function. A range of significant immunological defects has been attributed to
protein-calorie malnutrition and to zinc deficiency. The relevance of these
findings to the mucosal barrier remains to be seen, but in theory, the malnourished
host may be more susceptible to infection, less capable of clearing organisms
from the gut, and less able to repair after acute viral damage. Clinical studies
of malnourished children have certainly demonstrated a wealth of abnormal
bacterial flora in their upper intestines. It is not yet clear whether these findings
are a consequence of the malnourished state or of the dreadful hygenic conditions
that seem to go hand in hand with malnutrition.
SUMMARY
Although certain specific disease states are known to cause severe prolonged
diarrhea in young children, neither the cause nor the mechanisms for diarrhea
are known in the majority of cases. Recent developments in our understanding
of the pathogenesis of acute viral enteritis are compatible with the hypothesis
that a proportion of these chronic cases begin as an attack of acute viral enteritis.
Possible mechanisms for the prolongation of diarrhea after what is normally a
transient disease include persisting infection, food-induced mucosal injury, and
delayed epithelial repair resulting from malnutrition.
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