Motoji Kitagawa

Nationwide epidemiological survey of chronic pancreatitis in Japan.

Abstract: The aim of this study was to estimate the number of patients treated for chronic pancreatitis in 1994 in Japan and to explore the clinico-epidemiological features of chronic pancreatitis. Two surveys were conducted. Stratified random sampling was used to select departments in which patients with chronic pancreatitis were treated, and two different questionnaires were administered to obtain relevant information. From the first survey, the total number of patients treated for chronic pancreatitis in Japan in the year 1994 was estimated as 32 000 (95% confidence interval, 25 000–39 000). Clinico-epidemiological features, based on the 2523 patients reported from the second survey, were subsequently clarified. The sex ratio (male/female) of the patients was 3.5. Alcoholic pancreatitis was the most common type in males (68.5%), and idiopathic pancreatitis in females (69.6%). Compared with the findings in the last survey in 1985, the proportion of patients with alcoholic pancreatitis has decreased slightly, from 58.7% to 55.5%, while that of idiopathic chronic pancreatitis has increased in both males and females. Patients diagnosed by advanced techniques such as computed tomography (CT) and endoscopic retrograde cholangiopancreatography (ERCP) accounted for 68.1% of the total. The number of patients with chronic pancreatitis treated in 1994 in Japan, was estimated as 32 000, with an overall prevalence rate of 45.4 per 100 000 population in males and 12.4 per 100 000 population in females.

Fluid secretion in interlobular ducts isolated from guinea‐pig pancreas

1 Pancreatic HCO3− and fluid secretion were studied by monitoring luminal pH (pHL) and luminal volume simultaneously in interlobular duct segments isolated from guinea‐pig pancreas. The secretory rate and HCO3− flux were estimated from fluorescence images obtained following microinjection of BCECF‐dextran (70 kDa, 20 μM) into the duct lumen. 2 Ducts filled initially with a Cl−‐rich solution swelled steadily (2.0 nl min−1 mm−2) when HCO3−/CO2 was introduced, and the luminal pH increased to 8.08. When Cl− was replaced by glucuronate, spontaneous fluid secretion was reduced by 75 %, and pHL did not rise above 7.3. 3 Cl−‐dependent spontaneous secretion was largely blocked by luminal H2DIDS (500 μM). We conclude that, in unstimulated ducts, HCO3− transport across the luminal membrane is probably mediated by Cl−‐HCO3− exchange. 4 Secretin (10 nM) and forskolin (1 μM) both stimulated HCO3− and fluid secretion. The final value of pHL (8.4) and the increase in secretory rate (1.5 nl min−1 mm−2) after secretin stimulation were unaffected by substitution of Cl−. 5 The Cl−‐independent component of secretin‐evoked secretion was not affected by luminal H2DIDS. This suggests that a Cl−‐independent mechanism provides the main pathway for luminal HCO3− transport in secretin‐stimulated ducts. 6 Ducts filled initially with a HCO3−‐rich fluid (125 mM HCO3−, 23 mM Cl−) secreted a Cl−‐rich fluid while unstimulated. This became HCO3−‐rich when secretin was applied. 7 Addition of H2DIDS and MIA (10 μM) to the bath reduced the secretory rate by 56 and 18 %, respectively. Applied together they completely blocked fluid secretion. We conclude that basolateral HCO3− transport is mediated mainly by Na+‐HCO3− cotransport rather than by Na+‐H+ exchange.

Luminal ATP stimulates fluid and HCO3− secretion in guinea‐pig pancreatic duct

1 The location of purinoceptors in the pancreatic duct and their role in regulating ductal secretion have been investigated by applying ATP and UTP to basolateral and luminal surfaces of pancreatic ducts isolated from the guinea‐pig pancreas. 2 Changes in intracellular Ca2+ concentration were measured by microfluorometry in microperfused interlobular duct segments. Fluid and HCO3− secretion were estimated by monitoring luminal pH and luminal volume in sealed duct segments microinjected with BCECF‐dextran. 3 Both ATP and UTP (1 μm) caused biphasic increases in intracellular Ca2+ concentration in pancreatic duct cells when applied to either the basolateral or luminal membrane. 4 Luminal application of both ATP and UTP evoked fluid and HCO3− secretion. The maximum response to 1 μm ATP or UTP was about 75 % of that evoked by secretin. By contrast, basolateral application of ATP or UTP inhibited spontaneous secretion by 52 % and 73 %, respectively, and secretin‐evoked secretion by 41 % and 38 %, respectively. 5 The data suggest that luminal nucleotides may act in an autocrine or paracrine fashion to enhance ductal secretion while basolateral nucleotides, perhaps released from nerve terminals, may have an inhibitory effect. The fact that both apical and basolateral purinoceptors elevate intracellular Ca2+, but that they have opposite effects on secretion, suggests that additional signalling pathways are involved.

Membrane potential and bicarbonate secretion in isolated interlobular ducts from guinea-pig pancreas

The interlobular duct cells of the guinea-pig pancreas secrete HCO3 − across their luminal membrane into a HCO3 −-rich (125 mM) luminal fluid against a sixfold concentration gradient. Since HCO3 − transport cannot be achieved by luminal Cl−/HCO3 − exchange under these conditions, we have investigated the possibility that it is mediated by an anion conductance. To determine whether the electrochemical potential gradient across the luminal membrane would favor HCO3 − efflux, we have measured the intracellular potential (Vm) in microperfused, interlobular duct segments under various physiological conditions. When the lumen was perfused with a 124 mM Cl−-25 mM HCO3 − solution, a condition similar to the basal state, the resting potential was approximately −60 mV. Stimulation with dbcAMP or secretin caused a transient hyperpolarization (∼5 mV) due to activation of electrogenic Na+-HCO3 − cotransport at the basolateral membrane. This was followed by depolarization to a steady-state value of approximately −50 mV as a result of anion efflux across the luminal membrane. Raising the luminal HCO3 − concentration to 125 mM caused a hyperpolarization (∼10 mV) in both stimulated and unstimulated ducts. These results can be explained by a model in which the depolarizing effect of Cl− efflux across the luminal membrane is minimized by the depletion of intracellular Cl− and offset by the hyperpolarizing effects of Na+-HCO3 − cotransport at the basolateral membrane. The net effect is a luminally directed electrochemical potential gradient for HCO3 − that is sustained during maximal stimulation. Our calculations indicate that the electrodiffusive efflux of HCO3 − to the lumen via CFTR, driven by this gradient, would be sufficient to fully account for the observed secretory flux of HCO3 −.

CO2 permeability and bicarbonate transport in microperfused interlobular ducts isolated from guinea‐pig pancreas

1 Permeabilities of the luminal and basolateral membranes of pancreatic duct cells to CO2 and HCO3− were examined in interlobular duct segments isolated from guinea‐pig pancreas. Intracellular pH (pHi) was measured by microfluorometry in unstimulated, microperfused ducts loaded with the pH‐sensitive fluoroprobe 2′7′‐bis(2‐carboxyethyl)‐5(6)‐carboxyfluorescein (BCECF). 2 When HCO3−/CO2 was admitted to the bath, pHi decreased transiently as a result of CO2 diffusion and then increased to a higher value as a result of HCO3− uptake across the basolateral membrane by Na+‐HCO3− cotransport. 3 When HCO3−/CO2 was admitted to the lumen, pHi again decreased but no subsequent increase was observed, indicating that the luminal membrane was permeable to CO2 but did not allow HCO3− entry to the cells from the lumen. Only when the luminal HCO3− concentration was raised above 125 mm was HCO3− entry detected. The same was true of duct cells stimulated with forskolin. 4 Recovery of pHi from an acid load, induced by exposure to an NH4+ pulse, was dependent on basolateral but not luminal Na+ and could be blocked by basolateral application of methylisobutylamiloride and H2DIDS. This indicates that the Na+‐H+ exchangers and Na+‐HCO3− cotransporters are located exclusively at the basolateral membrane. 5 In the presence of HCO3−/CO2, substitution of basolateral Cl− with glucuronate caused larger increases in pHi than substitution of luminal Cl−. This suggests that the anion exchanger activity in the basolateral membrane is greater than that in the luminal membrane. 6 We conclude that the luminal and basolateral membranes are both freely permeable to CO2, but while the basolateral membrane has both uptake and efflux pathways for HCO3−, the luminal membrane presents a significant barrier to the re‐entry of secreted HCO3−, largely through the inhibition of the luminal anion exchanger by high luminal HCO3− concentrations.

Chronic alcoholism and evolution of pain and prognosis in chronic pancreatitis.

To evaluate the influence of chronic alcoholism on clinical features of chronic pancreatitis in Japan, pain evolution, pancreatic insufficiency, and long-term prognosis were studied by comparing chronic alcoholic pancreatitis (N=88)with idiopathic pancreatitis (N=67).The 155 patients with known course of the disease over three years were followed-up further for five more years, and pain evolution was evaluated once at the start and once at the end of the follow-up period. At the time of diagnosis, severe pain (59 vs 33%, P < 0.001), pancreatic calcification (63 vs 31%, P<0.001), advanced exocrine pancreatic insufficiency (72 vs 60%, NS),and overt diabetes (48 vs 17%, P<0.007)were more common in alcoholic than in idiopathic pancreatitis, respectively. Pain evolution was similar in both pancreatitis, and the pain decreased with time. The rate of abstinence was higher in groups with pain relief than without in alcoholic pancreatitis. Cumulative mortality rate during the five years was higher in alcoholic than idiopathic pancreatitis (26 vs 10%, P<0.01).These results suggest more favorable evolution of the disease can be expected by abstinence from alcohol.

5-hydroxytryptamine strongly inhibits fluid secretion in guinea pig pancreatic duct cells

We studied the distribution of 5-hydroxytryptamine- (5-HT-) containing cells in the guinea pig pancreas and examined the effects of 5-HT on fluid secretion by interlobular pancreatic ducts. The 5-HT-immunoreactive cells with morphological characteristics of enterochromaffin (EC) cells were scattered throughout the duct system and were enriched in islets of Langerhans. The fluid secretory rate in the isolated interlobular ducts was measured by videomicroscopy. Basolateral applications of 5-HT strongly but reversibly reduced HCO(3)-dependent, as well as secretin- and acetylcholine- (ACh-) stimulated, fluid secretion, whereas 5-HT applied into the lumen had no such effects. Secretin-stimulated fluid secretion could be inhibited by a 5-HT(3) receptor agonist, but not by agonists of the 5-HT(1), 5-HT(2), or 5-HT(4) receptors. Under the stimulation with secretin, 5-HT decreased the intracellular pH (pH(i)) and reduced the rate of pH(i) recovery after acid loading with NH(4)(+), suggesting that 5-HT inhibits the intracellular accumulation of HCO3(-). The elevation of intraductal pressure in vivo reduced secretin-stimulated fluid secretion, an effect that could be attenuated by a 5-HT(3) receptor antagonist. Thus, 5-HT, acting through basolateral 5-HT(3) receptors, strongly inhibits spontaneous, secretin-, and ACh-stimulated fluid secretion by guinea pig pancreatic ducts. 5-HT released from pancreatic ductal EC cells on elevation of the intraductal pressure may regulate fluid secretion of neighboring duct cells in a paracrine fashion.

Nutritional factors and risk of pancreatic cancer: a population-based case-control study based on direct interview in Japan

BackgroundFew epidemiologic studies have examined the role of nutrient intake in the development of pancreatic cancer in Japan. We addressed this association in a population-based case-control study.MethodsThe cases were 109 patients who were newly diagnosed with pancreatic cancer between January 2000 and March 2002, and controls were selected by a random procedure from the general population. Data on dietary intake were collected by in-person interview, with the use of a food-frequency questionnaire. The risk of pancreatic cancer associated with nutrient intake was estimated by using the odds ratios (ORs) and 95% confidence intervals (CIs) derived from a conditional logistic model.ResultsA statistically positive trend in risk was observed with increasing cholesterol intake, with subjects in the highest tertile experiencing a two fold increased risk (OR, 2.06; 95% CI, 1.11–3.85; Ptrend = 0.02). Vitamin C intake was negatively associated with risk of pancreatic cancer. The OR was 0.45 (95% CI, 0.22–0.94) for subjects in the highest tertile compared to the lowest tertile (Ptrend = 0.04).ConclusionsOur study indicates that high cholesterol intake is significantly associated with an increased risk of pancreatic cancer and that high vitamin C intake decreases the risk of pancreatic cancer.

Chloride transport in microperfused interlobular ducts isolated from guinea‐pig pancreas

Isolated interlobular ducts from the guinea‐pig pancreas secrete a HCO3−‐rich fluid in response to secretin. To determine the role of Cl− transporters in this process, intracellular Cl− concentration ([Cl−]i) was measured in ducts loaded with the Cl−‐sensitive fluoroprobe, 6‐methoxy‐N‐ethylquinolinium chloride (MEQ). [Cl−]i decreased when the luminal Cl− concentration was reduced. This effect was stimulated by forskolin, was not dependent on HCO3− and was not inhibited by application of the anion channel/transporter inhibitor H2DIDS to the luminal membrane. It is therefore attributed to a cAMP‐stimulated Cl− conductance, probably the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel. [Cl−]i also decreased when the basolateral Cl− concentration was reduced. This effect was not stimulated by forskolin, was largely dependent on HCO3− and was inhibited by basolateral H2DIDS. It is therefore mediated mainly by Cl−/HCO3− exchange. With high Cl− and low HCO3− concentrations in the lumen, steady‐state [Cl−]i was 25‐35 mm in unstimulated cells. Stimulation with forskolin caused [Cl−]i to increase by approximately 4 mm due to activation of the luminal anion exchanger. With low Cl− and high HCO3− concentrations in the lumen to simulate physiological conditions, steady‐state [Cl−]i was 10–15 mm in unstimulated cells. Upon stimulation with forskolin, [Cl−]i fell to approximately 7 mm due to increased Cl− efflux via the luminal conductance. We conclude that, during stimulation under physiological conditions, [Cl−]i decreases to very low levels in guinea‐pig pancreatic duct cells, largely as a result of the limited capacity of the basolateral transporters for Cl− uptake. The resulting lack of competition from intracellular Cl− may therefore favour HCO3− secretion via anion conductances in the luminal membrane, possibly CFTR.

Genetic evidence for CFTR dysfunction in Japanese: background for chronic pancreatitis

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP regulated Cl− channel that is expressed in many epithelial tissues.1 In the pancreas CFTR plays a key role in the apical HCO3– transport in duct cells.2–5 Loss of its function due to mutations in the CFTR gene causes cystic fibrosis (CF) of the pancreas with exocrine insufficiency, chronic airway disease, and abnormally elevated sweat chloride concentration. Over 1000 mutations and 200 polymorphic loci in CFTR have now been identified.6 These mutations and polymorphisms confer quite variable phenotypes from classic CF to atypical CF with less severe pulmonary lesions, pancreatic sufficiency, and normal or borderline sweat chloride concentration.7,8 It is now well recognised that the spectrum of CFTR related disease is much broader than previously thought.9 Some individuals may exhibit an apparently single clinical feature or a monosymptomatic disease, such as chronic sinusitis, congenital bilateral absence of the vas deferens (CBAVD), and sweat chloride abnormalities. Recent evidence10–12 suggests that chronic pancreatitis, in at least a subset of the patients, belongs to this group of disease.13 Chronic pancreatitis is a progressive inflammatory disease of the pancreas that causes the loss of pancreatic acinar cells, ductal abnormalities often with intraductal stones, and irregular fibrosis. Alcohol is the most common cause of chronic pancreatitis in men but idiopathic pancreatitis is more common in women. The incidence of chronic pancreatitis in Western countries (about 4 per 100 000 population) is similar to that (5.4−5.9 per 100 000) in Japan.14 However, the incidence of CF in Japanese is very low (1 per 350 000) compared with whites (1 per 2500 live births).7,15 The apparent large difference of the incidence of CF and chronic pancreatitis may not support the presence of …