Although great advances have recently been made in understanding the genetic defects in cystic fibrosis (1,2) and how the defects cause the previously observed malfunction of epithelial chloride transport (3-6), many aspects of gastrointestinal (GI) function in cystic fibrosis (CF) are still poorly understood.
Intestinal obstruction, whether as meconium ileus in newborns or as distal ileal obstruction syndrome (DIOS) in older patients, remains a major complication in CF. Constipation is also a widespread problem, especially in the adult CF population. Furthermore, although the maldigestion and malnutrition resulting from pancreatic insufficiency are greatly improved by pancreatic enzyme supplementation, normalizing dietary fat digestion/obsorption has not always been possible, despite administration of high doses of enteric-coated enzyme supplements (7-9) even with addition of gastric acid inhibitors such as cimetidine or omeprazole (10). Last, a new GI problem has recently emerged: Fibrosing colonopathy (11-14), colonic obstruction due to submucosal fibrosis mainly in the ascending colon, has been reported in a few young CF patients. This new pathology has been suggested to be linked to the recent use of high-strength enzyme supplements, with fibrosis resulting from inappropriate high enzyme delivery to or release in the colon.
In the present study, using the data banks from Medline, Embase, Biosis, and SciSearch (1966-1994), I reviewed GI pH, motility/transit, and permeability in CF. These parameters, widely reported to be disturbed in CF, are important in determining the efficacy of enteric-coated enzyme supplements and/or could play a role in the pathogenesis of fibrosing colonopathy. I conducted the review in an attempt to clarify present knowledge and to highlight the controversies that still exist.
GENERAL COMMENTS ON ENTERIC-COATED PANCREATIC ENZYME SUPPLEMENTS
Because pancreatic lipase is rapidly denatured at pH <4.0 (15,16), most pancreatic enzyme supplements are enteric-coated (acid resistant) minitablet or microsphere preparations (ECMP). Optimal efficacy of these preparations in correcting maldigestion requires that they mix well with the food in the stomach, empty from the stomach together with the food, and release enzymes in the proximal small intestine.
The size and density of the minitablets/microspheres are important for good mixing with the food and the required pattern of gastric emptying (17). Because different fractions of a meal or different types of a meal may empty at different rates (18,19), the optimum microsphere/minitablet size, presently believed to be 1.4 mm, still must be confirmed by use of a range of diets.
Different acid-resistant coatings are used to protect the enzymes and, depending on which coating is used, the enzymes are released (at differing rates) only as the pH increases to 5 and 6 or greater (16,20). Therefore, to understand the site of enzyme release in the intestine, we must accurately define the pH along the GI tract.
Data from mostly small comparative studies (21-24) indicate that basal and stimulated gastric acid secretion are greater than normal in CF. However, this matter is controversial. Other groups of investigators have noted no differences in basal or stimulated acid secretion between CF and healthy age-matched controls (25,26) or only isolated cases in which acid secretion was enhanced (27). One confusing factor may be that CF patients are mostly underweight, and acid secretion is generally expressed relative to body weight. Therefore, whether gastric hypersecretion occurs in most or in only a subset of CF patients has not yet been clearly established.
No evidence of hypergastrinemia has been observed, but some researchers suggest that some other gastric acid secretagogue may be present in CF plasma (22), although no such substance has yet been identified. The increased levels of peptide YY (PYY), neurotensin, and enteroglucagon in CF (28-30) would be likely to reduce rather than increase gastric acid secretion (31). However, chronic obstructive pulmonary disease, which is common in CF, could be a factor contributing to gastric hypersecretion, since gastric acid secretion is stimulated by hypercapnia and hypoxia (32).
Whether or not CF patients have gastric hypersecretion, no marked difference is evident in pre- or postprandial gastric pH between CF patients and healthy subjects. In both CF patients and healthy subjects, the fasting values (25,27,33-37) vary between pH 0.5 and 5, generally between pH 1 and 3. When a meal is ingested, gastric pH increases (37) according to the buffering capacity of the meal (generally to ≈ pH 5), then gradually decreases to <3 after 1 h and to 2 by 2 h in both CF patients (21,27,34,38) and normal subjects (35,37,39).
If gastric pH increases to >5, some of the pancreatic enzymes administered probably are released in the stomach (16,20), with the amount released depending on the pH reached and the amount of time pH remains >5. The released amylase and lipase especially, which are not rapidly emptied from the stomach, are liable to denaturation by proteases and decreasing pH (16), which will decrease the therapeutic efficacy of the administered enzymes.
There is a steep pH gradient between the pylorus and midduodenum in normal subjects, but a much smaller gradient between midduodenum and proximal jejunum (36). I therefore confined the comparison to the mid- to distal-duodenal pH values in CF patients and controls. The comparison showed that both fasting and postprandial duodenal pH are considerably lower in CF patients than in healthy controls (Table 1). Fasting duodenal pH values of 5-7, with a mean value generally of ≈6 in controls (33,35,40-43) and of ≈5 in CF patients (33,34,42), have been reported. An even greater difference between CF patients and healthy subjects lies in the postprandial pH, (33,34,44,45); indeed, CF patients with severe steatorrhea may have a more acid pH than CF patients with moderate steatorrhea (44). In general, during a 4-h postprandial period, controls have a pH in the range of 5-7 (33,35,36,39,43-45); there is a transient increase upon ingestion of a meal, followed by a gradual decrease, reaching pH ≈5 in midduodenum after 2-4 h, after which the pH returns toward baseline values (36,39,44,45). Comparison of patients in all CF studies with the controls I reviewed showed postprandial duodenal pH to be a mean of 1.4 U lower in CF patients (Table 1), generally in the range of 3-6 in a 4-h postprandial period (31,33,34,44), presumably as a result of reduced pancreatic bicarbonate secretion, since similar findings have also been reported in chronic pancreatitis patients with pancreatic insufficiency (39,43).
Whether duodenal bicarbonate secretion is also reduced in CF remains to be determined, but cystic fibrosis transmembrane regulator (CFTR) was recently reported to be present in mammalian duodenum (46). If CFTR is involved in duodenal bicarbonate secretion, this would probably be low in CF.
Jejunal pH has seldom been measured in CF. One study showed that in a 3-h postprandial period ≈38% of CF jejunal contents were pH <5 and only 41% were >6 (47), in comparison to those of controls in whom only 18% of contents were pH <5 and 56% were pH >6 (48). Another study (49) showed that CF jejunal pH 5.75-6.75 (mean 6.2) was significantly, although only marginally, lower than that of controls (6.5-6.75, mean 6.6). In contrast, other researchers have reported similar jejunal pH values (5.5-6.5) in controls (36,50) and CF patients (21,51). These discrepancies remain to be clarified.
Still less information exists regarding ileal pH in CF patients, especially in the postprandial state, but it appears to be generally similar to that of healthy controls. Fasting ileal pH values of 6.0 were reported in 10 CF patients as compared to pH 6.5 in 10 controls (33), whereas values of pH >6 were noted throughout the ileum in both CF patients and controls in another study (51); at the terminal ileum, pH was 7.2 in 6 CF patients as compared to pH 7.5 in controls (52). Indeed, ileal pH was <6.0 for <1% of the time in both CF patients and controls, and a mean time of 4.5 h was spent at pH >6.0 during passage through the entire small intestine in this small group of CF patients (52).
In control subjects, the pH in the mid-small intestine was the same as that in the distal small intestine (50); such information is lacking in CF patients. Further, preferably larger, studies in the postprandial state are still needed to clarify ileal and jejunal pH values in CF patients to establish the pH gradient in such patients and to determine from that gradient the pH characteristics required of an enteric-coated preparation for optimum enzyme release.
The absolute pH values recorded in the large intestine depend largely on the amount of fermentable fiber or carbohydrate delivered, but also on the rate at which the digesta passes through; stool pH values of 5.8-7.9 have been recorded in healthy subjects (53,54). Stool pH tends to increase during constipation; conversely, ingestion of cathartics tends to decrease stool pH (55). At least with lactulose (56), the major effect occurs in the right colon, in which pH decreases markedly, from 5.5-7.5 (median 6.0) to 3.5-6.1 (median 4.85).
The cecal pH of 6.4 (50,52) represents a sharp decrease as compared with that in the terminal ileum (7.5). A large study of healthy volunteers (50), showed a gradual, progressive increase in pH in aboral passage through the colon, reaching a final value of 7.0 in the left colon.
Cecal or colonic pH values in CF have not been reported, but one small study (51) showed surprisingly similar stool pH values in controls (6.6), CF patients with severe steatorrhea (6.4), and CF patients with mild steatorrhea (6.5). At present, we can only speculate whether ECMP release enzymes after reaching the colon intact. In principle, colonic release of enzymes is possible, since colonic pH generally is >5 (unless lactulose is given) and colonic transit time is much greater than small intestinal transit time (Table 2). However, if ECMP reach the colon intact, small intestinal pH in these patients may be lower than in patients in the studies reviewed. Because colonic pH is lower than small intestinal pH, especially if much undigested (fermentable) food is present, colonic release of enzymes in these patients is unlikely and may explain how intact ECMP can appear in the stools (12).
Although GI motility is widely believed to be disturbed in CF, direct measurement of motility itself in CF has very rarely been performed; most studies have instead assessed transit.
CF patients have a high incidence of (primary) gastroesophageal reflux (of acid) (58,59), especially young CF patients (60,61). Resting LESP appears to be normal (58,59), but incidence of inappropriate LES relaxations is increased (62). A reduced amplitude of esophageal contractions and occurrence of uncoordinated esophageal contractions may also be important (62), but these conditions have not been observed by all researchers (59).
Because CF patients with GERD have significantly reduced lung function as compared with those without GERD, pulmonary disease, cough, increased thoracoabdominal pressure gradient, and especially the drugs used to achieve bronchodilatation have been suggested to contribute to the high level of GERD (52). However, other workers failed to detect a significant relation between symptoms of GERD and bronchodilator therapy (59). Furthermore, prokinetic therapy of reflux dramatically improves many of the respiratory symptoms as well as symptoms of GERD (60,61), suggesting that GERD is not a consequence of respiratory symptoms but may instead contribute to them.
Gastric emptying (GE) of liquid meals is reported to be normal (21,63-65) or accelerated in at least some CF patients (63). GE of nonhomogenized fat in a liquid meal is accelerated when enzyme supplements are withheld (66), similar to the rapid GE of liquid fatty meals (67) and of lipids in solid-liquid meals (68) in (non-CF) pancreatic insufficiency. No studies have yet been published of GE of solid meals in CF!
One CF patient with severely delayed GE of a mixed liquid meal, absence of a fed motility pattern, and GERD has been described (69). Whether this is only an isolated abnormality is not clear, but the therapeutic efficacy of prokinetic agents to treat GERD suggests that GE could be generally delayed in such patients.
Other than in the case just described (69), no direct measurements of small intestinal motility or transit have been reported, but several studies of oro-cecal transit time, using the lactulose/hydrogen breath test, have been made. The test is useful and noninvasive, but care must be taken in comparing different studies since the transit time can vary markedly according to the amount and concentration of lactulose given and whether it is given with or without a meal (70,71). However, the transit time apparently does not vary much with age or length of the intestine; therefore, similar transit times were reported in children aged 5-17 years even though intestinal length may double in this age span (70).
Although one study (49) showed that oro-cecal transit was only slowed in CF with DIOS, all other studies (72-74)(Table 2) reported prolonged transit in fasted CF patients (range 50-390 min, mean 136 min) as compared with healthy subjects (range 30-150 min, mean in reviewed studies 88 min). If GE is not delayed (still to be established; discussed herein) the slowing can be attributed to a decrease in the rate of small intestinal transit. Since the slowing is seen in persons in the fasted state a primary disturbance of transit may be involved. Other evidence that regulation of GI motility is disturbed in CF is that plasma levels of the gut hormones motilin, enteroglucagon, neurotensin, and peptide YY are all significantly increased (28-30). Nevertheless, it is rather surprising that pancreatic enzyme supplementation had no influence on the transit time of lactulose/nutrient meal in such patients (28,75). Maldigested or malabsorbed nutrients in the ileum (ileal brake), as a result of pancreatic insufficiency, would have been expected to have had an added inhibitory effect on oro-cecal transit (76).
Despite these apparently clear-cut findings, caution must nevertheless be exercised so long as delayed oro-cecal transit time in CF is based only on measurement by the hydrogen breath test. This test relies on fermentation of lactulose by (colonic) bacteria and subsequent release of hydrogen, which is measured in the exhaled breath. False transit times could be assigned if the bacterial population were disturbed in some way. In CF patients, the chronic use of antibiotics to combat respiratory infections must also seriously alter the intestinal flora and the measurement of transit times by this method could be influenced. Measurement by some other method is therefore recommended to confirm that transit is delayed in CF.
By far the longest GI residence time is that in the colon. Measurement of colonic transit time in healthy individuals has shown that there is considerable variability in “normal” values between persons as well as in day-to-day values in individual persons (77), which emphasizes the importance of averaging the measurement of transit time over several days. Even then, depending on the marker used, control mouth-anus transit times vary between 25 and 55 h (78,79)(Table 2), with women having longer transit times than men (77,80); however, there appears to be no difference in colonic transit between children (81) and adults (80) when the transit times are measured with the same marker. Most studies showed equal residence time of markers in the right, left, and rectosigmoid colon, although Proano et al. proposed that transit is actually slowest in the cecum, ascending, and transverse colon (82).
Whether CF patients have primary abnormalities of colonic motility and transit is not clear because of the lack of studies, especially in patients with adequate pancreatic enzyme supplementation. Colonic transit rate is strongly influenced by the nature (especially the level of bile salts and fats) of the luminal contents (78). Maldigestion/malabsorption of fats and excess loss of bile salts are common problems in CF and a rapid rate of colonic transit was noted in CF patients with steatorrhea; i.e., a mouth-anus transit time of 13 h as compared to a control transit time of 25 h (79), but this time was not different from the 14 h in non-CF patients with diarrhea (79). Conversely, constipation (slowed colonic transit) is also a common complication in CF, with a prevalence of 32% (83). The incidence of constipation increases with age, to >70% in patients aged >30 years (83); this is especially important because patients who do not respond to therapy are in danger of developing DIOS.
DIOS is characterized by isolated or, more often, repeated attacks of complete or partial obstruction of the ileocecal region. Its prevalence, like that of constipation, has been reported to increase with increasing age of CF patients; overall, it occurs in ≈2-47% of CF (mainly male) patients (83-85).
Intestinal obstruction occurs through deposition of a highly viscous mixture of undigested food or fecal material and excessive amounts of sticky mucus secretions which are resistant to tryptic digestion (86,87). The etiology is still uncertain, but CF patients with poorly controlled steatorrhea or constipation (83) appear to have the highest risk; inadequate fluid intake, dietary indiscretions, omission of enzyme supplementation, and use of medications that slow GI transit have also been associated with DIOS onset. Therefore, pancreatic insufficiency, abnormal mucus, slowed GI transit, and reduced pancreatic and intestinal secretions may all be important pathogenetic factors (85,87-89).
In healthy subjects, the intestinal mucosa represents a defensive barrier preventing entry of toxic substances from the intestinal lumen. This barrier is selective, however, not absolute. Permeability depends on the lipid solubility or affinity for active/facilitated uptake mechanisms of the substance on the one hand and on its molecular size on the other.
In general, intestinal permeability refers to uptake by purely passive diffusion of a water-soluble substance across the mucosal membrane. The exact route of passage of the various solutes remains controversial and may be transcellular or paracellular (90,91). Low molecular weight, passively absorbed solutes (such as mannitol or rhamnose or other monosaccharides) appear to diffuse through the mucosa (transcellular route) through aqueous pores; these water channels are believed to have an effective radius of ≈0.78 nm in human jejunum, ≈0.34 nm in ileum (92), and <0.23 nm in the colon (93). Larger molecules (such as lactulose, cellobiose, raffinose, dextran, CrEDTA) permeate much more slowly, probably through the intercellular “tight junctions,” i.e., the paracellular route (90,91). Intestinal permeation by polyethylene glycol (PEG) polymers appears to follow some as yet undefined but separate pathway (90,91).
Intestinal permeability to “inert markers,” such as those just described, gives an indication of the state of the intestine since permeability to specific markers increases in different ways in some disease states, e.g., CF, celiac disease, gastroenteritis, Crohn's disease, or food allergy, or after administration of nonsteroidal antiinflammatory drugs (NSAIDs) (90,94).
Small intestinal permeability is best measured as a combination of the absolute percent urinary excretion and the urinary excretion ratio, over a time span of a few hours, of two such inert markers of trans- and paracellular transport (most commonly lactulose and mannitol) ingested simultaneously (90,95). Such measurement avoids possible complications from other factors such as rate of GE, intestinal transit rate, dilution by intestinal secretion, or the extent of renal clearance that could cause spurious results.
The results from several such tests indicate a 4- to 10-fold increase in small intestinal paracellular but no change in transcellular permeability in CF (73,96,97); i.e., the paracellular pathway leaks large, water-soluble molecules more freely in CF, whereas the passive transcellular uptake of small or lipid-soluble molecules is essentially normal. These suggestions are supported by the histological findings of normal brush border morphology (98) but of abnormalities of intestinal epithelial cell tight junctions (99) in CF. The tight junctions are responsible for the paracellular resistance.
The extent to which these permeability changes are due to CF itself is not clear, since pancreatic insufficiency (in non-CF patients) also increases intestinal permeability to lactulose (100). However, because almost all CF patients were receiving pancreatic enzyme supplementation when shown to have increased intestinal permeability (73,74,96,97,100-102), CF itself probably increases intestinal permeability to a greater degree than do any effects of pancreatic insufficiency.
Whether colonic permeability is also increased in CF is still undetermined. The large increase in fecal bile acids in CF and whether or not they are bound to the solid phase of the stool (57) could be relevant to this question. Relatively low concentrations of bile acids can increase colonic permeability by damaging the integrity of tight junctional complexes (103). Because fecal bile acid loss in CF patients decreases progressively with increase in age (104), bile acids could have a role in the onset of fibrosing colonopathy, which occurs only in young CF patients.
Last, intestinal permeability may also be affected, in both directions, by changes in the protective layer of mucus. This mucus layer is abnormal in CF (87) and often blocks the intestinal crypts (98), which in itself could lead to a reduction in the unstirred water layer and thus to increased permeability. On the other hand, in CF, the mucus is very viscous, possibly owing to the lack of Cl- secretion (105). As a result, a thicker than normal layer of mucus often adheres tightly to the villous cells (87,98) and this might be expected to cause a reduction in permeability.
Almost all the studies we reviewed were performed with very small numbers of patients, probably for ethical reasons since historically at least most patients were children. However, as a result, few findings are free from controversy and, because of the increasing life expectancy of CF patients, it may be important to investigate some of these parameters in adults as well. Indeed, GI function in CF patients, as demonstrated by GERD (61), constipation (83), DIOS (83), and loss of bile salts (104) may change with the age of the patients.
This review confirms that disturbances of GI motility/transit, pH, and permeability have been reported (from 1966 to 1994) in CF patients, but to a lesser degree and with more controversial findings than is generally believed. The only definite abnormalities demonstrated are: considerably more acid pre- and postprandial duodenal contents in CF, a high incidence of GERD, and increased small intestinal permeability; little else is certain.
Disturbances in GI motility itself in CF patients, excluding the LES and esophagus, have been reported in only one patient. Delayed orocecal transit time, determined by the hydrogen breath test, is common in CF patients. However, as already discussed, this finding must be viewed with some caution until it is confirmed by another method, particularly in light of the recent finding that lactulose itself alters GE and small intestinal transit in healthy subjects (106). However, if small intestinal-transit time is abnormally long in CF patients, no evidence indicates what causes the abnormality; e.g., is it just a mechanical effect of the more viscous luminal contents, is it secondary to constipation, or does an actual motility abnormality exist? Moreover, whether a general GE abnormality exists in CF is unclear, especially of a normal solid/liquid meal. If such an abnormality exists, does it disappear when adequate enzyme supplementation is administered? What is the colonic transit rate during adequate enzyme supplementation? Clarifying these points, and others described herein, is of importance in achieving better understanding and ultimately better treatment of GI symptoms in CF patients.
With regard to GI pH, it is still unclear whether most or only a subgroup of CF patients have gastric hypersecretion. Furthermore, the pH profile through the length of the small intestine must be clarified, especially in the fed state, and especially that of CF patients whose fat digestion does not normalize with enzyme supplementation. Accurate knowledge of these factors is of great importance in determining the intestinal site or sites at which the enzymes are released (from enteric-coated microspheres or minitablets) and could lead to reconsideration of the optimal pH characteristics of the enteric coating. At present, we do not know how much enzyme activity (activity of released enzymes is also highly pH dependent; e.g., trypsin has only 40% of its maximum activity at pH 5) or enzyme release occurs in the colon or, alternatively, how much of the enzyme activity will be bound by undigested food or fiber present (107). Nonetheless, knowledge of these factors may be of importance with regard to the etiology of fibrosing colonopathy.
Establishing whether or not large as well as small intestinal permeability is increased in CF patients may be of importance in relation to colonic exposure to bacteria and their toxins. It may also be relevant to the pathogenesis of fibrosing colonopathy, in which dramatic submucosal fibrosis occurs, but generally with little mucosal damage or inflammation; i.e., could it follow submucosal exposure (due to increased permeability) to some as yet unidentified substance rather than occur as repair to enzyme damage? Indeed, after the finding of fibrosing colonopathy in children receiving standard-strengh enzymes (108), it was suggested that the enteric coating material, not the enzymes, may be the causative factor (109). This suggestion warrants further consideration, since enzyme-induced pathology might have been expected to include ulceration and inflammation (110), such as was recently reported in another CF patient (111). Furthermore, the U.K. epidemiology study showed that only enzyme products given as minitablets, but not microspheres, are associated with this pathology (112). Finally, it may be significant that intestinal transit times do not vary much with age despite large changes in intestinal length; moreover, colonic surface area relative to body weight is much smaller in young children than in adults (van Velzen, personal communication). Therefore, any poorly absorbed, orally administered therapeutic or excipient agent will have relatively much greater colonic exposure in small children than in adults when administered in dosage per kilogram of body weight, which may explain, in part, why fibrosing colonopathy has been observed only in young children.
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Keywords:© Lippincott-Raven Publishers
Cystic fibrosis; Gastrointestinal pH; Gastrointestinal motility; Intestinal transit; Intestinal permeability