Takatsugu Yamamoto

Effects of Proton Pump Inhibitors on Gastric Emptying: A Systematic Review

The proton pump inhibitor (PPI) is widely used for the treatment of gastroesophageal reflux disease, peptic ulcer diseases, and functional dyspepsia. The pathogenesis of these acid-related and/or functional upper gastrointestinal disorders is potentially associated with abnormal gastric emptying. To date, variable effects of PPIs on gastric emptying have been reported. Therefore, it is relevant to gather and analyze published information on this topic. A systematic literature search has been performed, showing that the delaying effect of PPIs on gastric emptying of solid meals is consistent, whereas the effect of PPIs on the emptying of liquids is inconsistent. The underlying mechanisms whereby PPIs may affect gastric emptying have been discussed, most of which still remain hypothetic. Gastric emptying of solids involves a process of peptic hydrolysis. PPIs impair the hydrolytic digestion by inhibiting acid-dependent peptic activity, thereby delaying the solid emptying. Gastric emptying of liquids largely depends on volume and energy density of intragastric contents. PPIs variably modify the volume and the energy density by reducing gastric fluid secretion, thereby modifying the liquid emptying in an unpredictable manner. Hypergastrinemia has been considered to delay gastric emptying, but it seems of minor importance in the regulation of gastric emptying during PPI use. The delayed emptying of solids due to PPI therapy may have clinical implications in the management of gastroesophageal reflux disease, functional dyspepsia, as well as diabetes.

EFFECTS OF AGAR AND PECTIN ON GASTRIC EMPTYING AND POST‐PRANDIAL GLYCAEMIC PROFILES IN HEALTHY HUMAN VOLUNTEERS

1 Dietary fibre, such as pectin, delays gastric emptying and may enhance post‐prandial glucose tolerance. Agar, which is high in fibre content, is widely used in the traditional Japanese diet. Although long‐term diet therapy with agar decreases fasting plasma glucose levels in diabetes, knowledge is lacking about the acute effects of agar on gastric emptying and the post‐prandial glycaemic profiles. The present study was designed to investigate the acute effects of agar. 2 Ten healthy male volunteers were studied on three occasions with three different test meals (450 kcal/500 mL): (i) a fibre‐free meal; (ii) a meal with 2.0 g agar; or (iii) a meal with 5.2 g pectin. On each occasion, participants underwent a [13C]‐acetate breath test along with serial blood sampling. To quantify gastric emptying, the half [13CO2] excretion time () and the time for maximal [13CO2] excretion rate (tlag) were determined. The post‐prandial glycaemic response was expressed as an incremental change from the fasting value at each sampling time. Data were analysed using repeated‐measures analysis of variance (anova), followed by a post hoc paired Students t‐test with Bonferroni adjustment. 3 The time‐course for respiratory [13CO2] excretion differed significantly among the three test meals (P = 0.0004, anova). Compared with the control meal, [13CO2] excretion was significantly lower following consumption of the agar meal (between 40 and 105 min post‐prandially; P < 0.025, Students t‐test) and the pectin meal (between 40 and 180 min post‐prandially; P < 0.025, Students t‐test). Among the three meals, significant differences were found in (P = 0.002, anova) and tlag (P = 0.011, anova). Compared with the control meal, the agar and pectin meals exhibited a significantly prolonged (P = 0.007 and P < 0.0001, respectively, Students t‐test) and tlag (P = 0.006 and P = 0.002, respectively, Students t‐test). Neither the agar nor pectin meal affected the post‐prandial glucose profile. 4 In healthy adults, agar and pectin delay gastric emptying but have no impact on the post‐prandial glucose response.

Comparison between gastric scintigraphy and the [13C]-acetate breath test with Wagner-Nelson analysis in humans.

1 The [13C]‐acetate breath test (ABT) quantifies gastric emptying as the half [13CO2]‐excretion time (T1/2b), but T1/2b differs from the scintigraphic half‐emptying time (T1/2s). The aims of the present study were to accurately determine the half‐emptying time by ABT with Wagner–Nelson analysis (T1/2WN), to compare T1/2WN with T1/2s and to validate the Wagner–Nelson strategy in ABT. 2 For a comparative study, eight volunteers simultaneously underwent ABT and scintigraphy. Anterior images were acquired and breath samples were collected every 15 min for 4.0 h after ingestion of a 200 kcal liquid meal labelled with 37 MBq [99mTc]‐colloidal sulphur and 100 mg [13C]‐acetate. For the validation experiment, another six volunteers underwent ABT, on two randomized occasions, using the 200 kcal liquid meal with 100 mg [13C]‐acetate. On either of the two occasions, a gel‐forming agent was stirred into the meal to intentionally delay gastric emptying by increasing meal viscosity. Breath samples were collected at regular 15 min intervals for 4 h post ingestion. 3 The Wagner–Nelson equation for ABT is F(t) = (Abreath(t) + C(t)/0.65)/Abreath(∞), where F(t) is a fractional dose of the [13C] label emptied, C(t) is the [13CO2] excretion (% dose/h), Abreath(t) is the area under the C(t) curve (% dose) and Abreath(∞) is the ultimate [13CO2] recovery in breath (% dose). The percentage gastric retention was estimated as 100 × (1 − F(t)). The time plots of scintigraphic activity and 100 × (1 − F(t)) were fitted to y(t) = 100 × e−K×t, K values were estimated mathematically for each plot by regression analysis and T1/2s and T1/2WN were calculated as (ln2)/K. The time versus pulmonary [13CO2] excretion plots were fitted to z(t) = m × k × β × e−kt(1 − e−k×t)β−1, where m, k and β are constants; T1/2b was calculated as –(ln(1 − 2−1/β)]/k. 4 Values of T1/2WN were closer to T1/2s than T1/2b, although T1/2WN and T1/2b yielded significant under‐ and overestimation of T1/2s, respectively. The high viscosity meal significantly prolonged T1/2WN and T1/2b; T1/2WN could detect the delayed transit of the viscous meal more sensitively than T1/2b. 5 The Wagner–Nelson method improves the accuracy of the ABT.

The Wagner-Nelson Method Can Generate an Accurate Gastric Emptying Flow Curve from 13CO2 Data Obtained by a 13C-Labeled Substrate Breath Test

Background: In pharmacokinetics, the Wagner-Nelson (W-N) method can accurately estimate the rate of drug absorption from its urinary elimination rate. A stable isotope (¹³C) breath test attempts to estimate the rate of absorption of ¹³C, as an index of gastric emptying rate, from the rate of pulmonary elimination of ¹³CO₂. The time-gastric emptying curve determined by the breath test is quite different from that determined by scintigraphy or ultrasonography. In this report, we have shown that the W-N method can adjust the difference. Methods: The W-N equation to estimate gastric emptying from breath data is as follows: the fractional cumulative amount of gastric contents emptied by time t = A_breath(t)/A_breath(∞) + (1/0.65)·d[A_breath(t)/A_breath(∞)]/dt, where A_breath(t) = the cumulative recovery of ¹³CO₂ in breath by time t and A_breath(∞) = the ultimate cumulative ¹³CO₂ recovery. The emptying flow curve generated by ultrasonography was compared with that generated by the W-N method-adjusted breath test in 6 volunteers. Results: The emptying curves by the W-N method were almost identical to those by ultrasound. Conclusions: The W-N method can generate an accurate emptying flow curve from ¹³CO₂ data, and it can adjust the difference between ultrasonography and the breath test.

Retention, fixation, and loss of the [13C] label: a review for the understanding of gastric emptying breath tests.

A [13C]-breath test is a promising method for measuring gastric emptying. The methodological relevance is based on a close correspondence between gastric emptying of [13C]-acetate/octanoate (input) and pulmonary excretion of [13CO2] (output). Despite the close input-output correspondence, the pulmonary output is quite remote from the gastric input: the pulmonary output is delayed compared to the gastric input, and the total recovery of [13CO2] in the breath is incomplete. This review focuses on the kinetics of [13C]-acetate/octanoate in the body and suggests that (1) the delayed pulmonary output results from temporal retention of [13CO2] in the well-perfused tissues (heart, brain, etc.), (2) the incomplete recovery results from incorporation of the label into metabolic products (ketone bodies, amino acids, etc.) or from fixation of [13CO2] in the low-perfused tissues (bone, skeletal muscle, etc.), and (3) knowledge on the retention is the key to appropriate interpretations of breath test results. Recognition of these kinetic aspects is essential for appropriate interpretations of these breath test results.

Effect of cigarette smoking on gastric emptying of solids in Japanese smokers: a crossover study using the 13C-octanoic acid breath test

BackgroundCigarette smoking is associated with an increased risk of peptic ulcer and gastroesophageal reflux disease. Gastric emptying disorders may play a role in the development of these upper gastrointestinal diseases. Thus, studies examining a link between smoking and gastric emptying disorders have clinical relevance. This study was conducted to investigate the effect of smoking on gastric emptying of solids in Japanese smokers.MethodsThe 13C-octanoic acid breath test was performed in eight male habitual smokers on two randomized occasions (either sham smoking or actively smoking). The time vs 13CO2 excretion rate curve was mathematically fitted to a conventional formula of y (t) = m*k*β*e−k*t*(1 − e−k*t)β−1, and the parameters of k and β were determined: under the crossover protocol, a larger (smaller) β indicates slower (faster) emptying in the early phase, and a larger (smaller) k indicates faster (slower) emptying in the later phase. The half 13CO2 excretion time (t1/2b = −[ln(1 − 2−1/β)]/k) and the time of maximal 13CO2 excretion rate (tmax = [lnβ]/k) were also calculated. Between the two occasions, k, β, t1/2b, and tmax were compared by the Wilcoxon signed-rank test.ResultsAfter smoking, k was significantly increased. No significant differences were found in β, t1/2, and tmax between the two occasions.ConclusionsThe increase in k suggests the acceleration of gastric emptying in the later phase. For the first time, this study has revealed that acute smoking speeds the gastric emptying of solids in Japanese habitual smokers.

Theoretical flaws in the gastric emptying breath test: why is it dubious?

To logically reply to these questions, precise kinetics of 13C in the human body should be recalled (Figure 1) (5). 13C-Octanoate is rapidly absorbed once it is emptied from the stomach. Then 13C-octanoate reaches the liver, where it undergoes preferential oxidation to CO2. Subsequently, CO2 appears in the systemic circulation, enters the pulmonary artery, and is exhaled quickly by the lung. As the rate of CO2 exhalation is regulated according to first-order kinetics (6), a certain portion of the CO2 survives the pulmonary elimination, and the survivor circulates throughout the body. Circulating CO2 distributes into the fast and slowly exchanging CO2 pools and is eliminated via the respiratory and nonrespiratory routes. The distribution and the elimination occur simultaneously. Note that the rate at which CO2 appears in the systemic circulation is the surrogate measure of gastric emptying rate in OBT (Figure 1). 1. It has long been believed that the relevance of OBT is based on the assumption that GE is the rate-limiting step for CO2 exhalation (1). However, we think this is incorrect. For the assumption to be correct, the postgastric processes should be much more rapid than GE; in other words, there should be no barriers to the intestinal absorption, the hepatic oxidation, and the pulmonary elimination (7). Previous works elucidated that 13C is transferred from the small gut to the systemic circulation so quickly that the barriers to the absorption and oxidation could effectively be overlooked (1, 8). On the other hand, no studies on OBT have clearly stated whether or not the barrier to elimination exists. Physiologic experiments showed that, both after intraduodenal administration of 13C-octanoate and after an intravenous bolus injection of 13C-sodium bicarbonate, the time-vs.-pulmonary CO2 excretion rate curve exhibits an exponentially decreasing elimination phase, characterized by a half-life of about 60 min (7, 9). Because the route of 13C administration little modifies the CO2 elimination kinetics (10), it is reasonable to consider that it takes 60 min for CO2 to be eliminated by half. The half-elimination time of 60 min is substantially long, indicating the presence of the barrier to the elimination. If GE is more rapid than the elimination (the half-GE time is shorter than 60 min), the elimination step limits the pulmonary CO2 excretion. Supposing the situation is converse, GE is, in turn, the rate-limiting step for CO2 excretion. This phenomenon is a common sense in pharmacokinetics (11). The postgastric processing is more uniform than GE within and between individuals (1, 8, 12). This just warrants an interpretation that the variation in CO2 excretion pattern mainly originates from the variation in GE rather than the postgastric events. On this basis, the relevance of OBT is ensured. 2. Conventionally, it has been explained that the time required for the absorption and oxidation processes is responsible for the apparent discrepancy between the CO2 recovery curve and the scintigraphic GE curve (1). However, this explanation contradicts the fact that the two processes are so rapid as to be bypassed effectively (1, 8). On the other hand, the distribution of CO2 operates much more slowly than the absorption and oxidation (Figure 1). It takes several hours to reach equilibrium between the blood and the slowly exchanging CO2 pool, and CO2 returns to the blood stream much later (7). This slow distribution prolongs the residence time of CO2 in the body, resulting in delayed exhalation of CO2. In addition, the barrier to elimination also delays CO2 exhalation. These are the more likely reasons for the discrepancy between OBT and scintigraphy. Accordingly, the half-emptying time, determined from the CO2 recovery profile, inherently involves the time for not only GE but also the distribution and elimination (3). Thus, the reliability of the halfemptying time is limited, despite its widespread use. For a more realistic estimation of GE, it is necessary to offset the additional time due to distribution and elimination. For this purpose, the deconvolution technique (8) and the Wagner– Nelson method (5) may be available. The deconvolution describes mathematical separation of a GE flow curve from a global CO2 excretion curve, and the separated GE profile yields an accurate half-emptying time comparable with a scintigraphic half-time. The Wagner–Nelson analysis allows estimation of the rate at which CO2 appears

Early gallbladder carcinoma associated with primary sclerosing cholangitis and ulcerative colitis.

Patients troubled with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) are at high risk for cholangiocarcinoma, whereas cancer of the gallbladder (GBC) is rarely reported to develop in that population. A Japanese man aged 62 years with a 14-year history of PSC and UC had been found to have a protruding lesion of the gallbladder by screening sonography. The preoperative examination suggested the lesion to be GBC at an early stage. Pathology examination after cholecystectomy proved that the lesion was papillary adenocarcinoma localized in the mucosal layer. Although the prognosis of GBC is poor, the outcome of cholecystectomy against early GBC is relatively good. Early detection of the tumor is required for a better prognosis of patients with GBC. According to the review of the literature, PSC and UC patients are regarded as a high-risk group not only for cholangiocarcinoma but also GBC. It is advocated that clinicians perform repeated radiographic examinations including sonography for patients with PSC and UC even if the diseases are being controlled.

Arousals in obstructive sleep apnea patients with laryngopharyngeal and gastroesophageal reflux

OBJECTIVE We hypothesized that differences exist in the effect of apnea severity and those of laryngopharyngeal reflex (LPR) versus gastroesophageal reflex (GER) on arousals during sleep in patients with obstructive sleep apnea syndrome (OSAS). METHODS Japanese patients having witnessed snoring or excessive daytime sleepiness with a frequency scale for symptoms of GER of 10 or more or with visualization of inflammatory changes on pharyngolaryngeal endoscopy underwent polysomnography with pH monitoring using double pH catheter in a sleep laboratory. RESULTS Most reflux events in patients with severe OSAS with LPR (n=16) and GER (n=21) were accompanied with respiratory arousals. On the other hand, among patients with mild-to-moderate OSAS, 64.0% and 24.8% of reflux events were accompanied with spontaneous arousals in those with LPR (n=12) and GER (n=12), respectively, and 9.4% and 8.3% of reflux events were not accompanied by arousals. There were no significant differences in other sleep parameters between mild-to-moderate OSAS patients with LPR versus GER and between severe OSAS patients with LPR versus GER. CONCLUSIONS Among patients with reflux, the types of arousal differed significantly between those with mild-to-moderate versus severe OSAS. In patients with mild-to-moderate OSAS, LPR induces more spontaneous arousals than does GER.

Gastroduodenal Mucosal Injury in Patients Taking Low-Dose Aspirin and the Role of Gastric Mucoprotective Drugs: Possible Effect of Rebamipide

The present study was conducted to investigate the prevalence of mucosal injury in patients taking low-dose aspirin in Japan and examine the effect of gastric mucoprotective drugs on aspirin-related gastroduodenal toxicity. We selected 530 patients who had taken low-dose aspirin for 1 month or more after undergoing esophagogastroduodenoscopy from 2005 through 2006 at Teikyo University Hospital, Tokyo, Japan. Endoscopic records were retrospectively reviewed to determine the presence of massive bleeding and mucosal injury (ulcer or erosion). The influence of clinical factors, including co-administration of gastroprotective drugs, was also examined. Hemorrhage was observed in 25 patients (3.7%) and mucosal injury (36.2%) in 192 patients. The presence of Helicobacter pylori antibody was a significant risk factor associated with mucosal injury. Patients taking any gastroprotective drug showed a significantly lower rate of mucosal injury than those not taking these drugs. Patients taking rebamipide concomitantly with proton pump inhibitors or histamine 2 receptor antagonists had mucosal injury less frequently than those taking acid suppressants plus other mucoprotective drugs. In conclusion, these results show the possible gastroprotective effects of rebamipide, suggesting that it may be a good choice in aspirin users with gastroduodenal toxicity that is not suppressed by acid suppressants alone.