Viral Enteritis: A Cause of Disordered Small Intestinal Epithelial Renewal

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Chronic Diarrhea in Children, edited by Emanuel Lebenthal. Nestle, Vevey/Raven Press, New York 1984. Viral Enteritis: A Cause of Disordered Small Intestinal Epithelial Re

1 Chronic Diarrhea in Children, edited by Emanuel Lebenthal. Nestle, Vevey/Raven Press, New York 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 variablefindings that 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: 269

2 270 VIRAL ENTERITIS 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.

3 VIRAL ENTERITIS 271 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 Normal Increased Disaccharidase activities Na + -K + ATPase activity Glucose-stimulated Na + absorption Neutral NaCI absorption Glucose absorption Cyclic AMP, adenylate cyclase activity Thymidine kinase activity

272 VIRAL ENTERITIS In some patients, dietary intake seems closely associated with exacerbations of diarrhea, although in severe cases diarrhea persists on no oral intake.

4 272 VIRAL ENTERITIS 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

5 VIRAL ENTERITIS 273 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

6 274 VIRAL ENTERITIS 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

VIRAL ENTERITIS 275 cases is nutrition; malnutrition states are known to influence intestinal repair, both epithelial migration and maturation.

7 VIRAL ENTERITIS 275 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. REFERENCES 1. Blacklow NR, Cukor G. Viral gastroenteritis. N Engl J Med 1981;304: Snyder JD, Merson MH. The magnitude of the global problem of acute diarrhoeal disease. Bull WHO 1982;60: Keljo D, Perdue M, Butler D, Hamilton R. Impaired Na dependent brush border D-glucose transport in experimental viral diarrhea. Gastroenterology 1981;80:l Kerzner B, Kelly MH, Gall DG, Butler DG, Hamilton JR. Transmissible gastroenteritis: mucosal

8 276 VIRAL ENTERITIS ion transport and the intestinal epithelium during the course of viral enteritis. Gastroenterology 1977;72: Shepherd RW, Gall DG, Butler DG, Hamilton JR. Determinants of diarrhea in viral enteritis. Gastroenterology 1979;76: Davidson GP, Gall DG, Butler DG, Petric M, Hamilton JR. Human rotavirus enteritis induced in conventional piglets. J Clin Invest 1977;60: Larcher VF, Shepherd RW, Frances DEM, Harries JT. Protracted diarrhea: areviewof 82 cases Arch Dis Child 1977;52: Davidson GP, Cutz E, Hamilton JR, Gall DG. Familial enteropathy: a syndrome of protracted diarrhea from birth, failure to thrive and hypoplastic villus atrophy. Gastroenterology 1978;75: Candy DCA, Larcher VF, Cameron DC, Norman AP, Harries JT. Lethal familial diarrhea: 22 cases in 10 families. Arch Dis Child 1981;56: Walker-Smith JA. Cow's milk intolerance as a cause of post enteritis diarrhoea. J Pediatr Gastroenterol Nutr 1982;1: Udall JN, Walker WA. The physiologic and pathologic basis for the transport of macromolecules across the intestinal tract. J Pediatr Gastroenterol Nutr 1982;1: Berant M, Wagner Y, Cohen N. Cholestyramine in the management of infantile diarrhea. J Pediatr 1976;88: Brunser O. Effects of malnutrition on intestinal structure and function in children. Clin Gastroenterol 1977;6: Guiraldes E, Hamilton JR. Effect of chronic malnutrition on intestinal structure, epithelial renewal and enzymes in suckling rats. Pediatr Res 1981;15:930.

Nutritional Therapy of Chronic Diarrhea

Chronic Diarrhea in Children, edited by Emanuel Lebenthal. Nestle, Vevey/Raven Press, New York 1984. Nutritional Therapy of Chronic Diarrhea J. R. Hamilton Department of Pediatrics, University of Toronto,