Gastroenterology
Volume 138, Issue 2 , Pages 429-433, February 2010

The Role of Bile Acids in Gallstone-Induced Pancreatitis

  • Markus M. Lerch

      Affiliations

    • Corresponding Author InformationReprint requests Address requests for reprints to: Markus M. Lerch MD, FRCP, Department of Medicine A, Ernst-Moritz-Arndt-Universität Greifswald, Friedrich-Loeffler-Str. 23A, 17475 Greifswald, Germany
    • ,
  • Ali A. Aghdassi

published online 23 December 2009.

Article Outline

 

See “Biliary acute pancreatitis in mice is mediated by the G-protein–coupled cell surface bile acid receptor Gpbar1,” by Perides G, Laukkarinen JM, Vassileva G, et al, on page 715.

It is well established that, once a gallstone begins to migrate through the biliary tract, it poses a risk for developing pancreatitis.1 The question remains how gallstones cause pancreatitis during their passage towards the duodenum. In 1901, the pathologist Eugene Opie published 2 hypotheses to answer this question.2, 3 Both reports were based on autopsy findings and supported by carefully conducted animal experiments. The first premise suggested that obstruction of the pancreatic duct by the impacted gallstone leads to blocked pancreatic secretion and triggers pancreatitis (Figure 1A). In the context of this first hypothesis it remains immaterial whether or not the bile duct is also occluded. Opie's second hypothesis postulated that an impacted gallstone at the papilla creates a communication behind the stone—the so-called common channel—connecting the common bile duct to the pancreatic duct. Through this common channel bile acids could enter the pancreas (Figure 1B). In the common channel hypothesis, the action of bile on the pancreas represents the triggering event for pancreatitis.

  • View full-size image.
  • Figure 1. 

    Three different mechanisms through which gallstone migration could trigger pancreatitis. (A) The first Opie hypothesis predicts that obstruction of pancreatic outflow by an impacted gallstone represents the trigger for disease onset. It is immaterial whether or not bile flow is also impaired. (B) Opie's common channel hypothesis states that a gallstone impacted at the papilla creates a communication between the pancreatic and bile duct behind it, through which bile could enter the pancreatic duct and potentially reach the acinar cells. (C) In this scenario, the gallstone obstructs both ducts without the potential for bile reflux into the pancreas. Pancreatic outflow obstruction triggers the disease, but an additional bile duct obstruction would act as an aggravating factor by increasing circulating or interstitial bile acid concentrations.

A number of observations, however, suggest that the common channel hypothesis is inaccurate. In humans and most animal species, the secretory pressure in the pancreatic duct is generally much higher than in the bile duct.4, 5, 6 In the event of a common channel formation, pancreatic juice would therefore flow into the biliary tract rather than bile into the pancreas. A second argument against the common channel hypothesis is the shortness of the common section between the pancreatic duct and the bile duct near the papilla. Not only do some patients with pancreatitis have completely separate duodenal orifices for the pancreatic and bile duct,7 but in most patients the communication between both ducts is too short to permit bile to enter the pancreas.8 Instead, an impacted gallstone would cause simultaneous blockage of both ducts (Figure 1C). A third argument is the observation that bile in the pancreatic duct does not cause harm when perfused without the unphysiologic pressure that is required to disrupt ductal integrity.9, 10

The strongest argument against the common channel hypothesis comes from animal studies, specifically those using the American opossum. These studies demonstrated that pancreatic outflow obstruction alone is sufficient to induce necrotizing pancreatitis and that the initial events affect acinar cells.11, 12 Observations in humans have since confirmed that transient obstruction of the pancreatic duct can be a sufficient trigger for acute pancreatitis, including endoscopic retrograde cholangiopancreatography-induced pancreatitis, and that bile reflux into the pancreas is neither required nor likely to occur.13, 14, 15

Subsequent investigations have therefore focused on the mechanisms through which a blockage of pancreatic secretion would trigger acinar cell necrosis. Essential events that were identified are colocalization and transactivation of lysosomal cathepsins with zymogens and a pathologic Ca++-release from intracellular stores. Both processes were found to be of critical importance not only in supramaximal stimulation-induced models of pancreatitis,16, 17 but also in clinically more relevant duct obstruction-induced pancreatitis.18, 19

Two inconsistencies of the duct ligation models of pancreatitis have led to renewed interest in the role of bile in the disease onset. The first was that duct ligation alone, with the notable exception of the opossum, induces mostly mild pancreatitis, rather than fully developed necrosis.19 The second inconsistency was that some studies employing the opossum model, while still refuting the common channel hypothesis, reported that bile duct ligation, when added to pancreatic duct-ligation, increased the severity of the disease.20 This suggests that elevated bile acids in the systemic circulation could aggravate the disease process.

A first confirmation for this assumption came from studies reporting that bile acids have a direct effect on pancreatic acinar cells and elicit an oscillatory release of Ca++ from intracellular stores.21 This bile acid effect on [Ca++]i is either mediated via bile acid inhibition of the sarco/endoplasmic reticulum Ca++-ATPase (SERCA) pump with consecutive depletion of ER Ca++ stores and activation of significant capacitative Ca++ entry into the cytosol22, 23 or, alternatively, by potentiation of Ca++ release from the ER and apical (vesicular) Ca++ stores.21, 24, 25 Most studies agree that monohydroxy bile acids, such as taurolithocholic acid 3 sulfate (TLC-S) have a more potent effect on acinar cells than dihydroxy bile acids (ie, TCDC) or trihydroxy bile acids and can cause damage independently of their properties as detergents or ionophores. Most important, TLC-S can induce pathologic Ca++ signals and lead to trypsinogen activation at concentrations that correspond with those found in the serum of patients with gallstone-induced biliary obstruction.24, 26 The disease-aggravating effect of common bile duct obstruction in pancreatitis (Figure 1C) would therefore not require bile reflux into the pancreatic duct, but could be elicited readily by bile acids in the serum or interstitial space of jaundiced patients.

The question remains as to how bile acids enter the acinar cell and whether this entry occurs from the basolateral or the luminal surface. An elegant study by Kim et al22 identified 2 potential mechanisms (Figure 2). The first involves a Na+-dependent co-transporter (Na+ taurocholate co-transporting polypeptide [NTCP]), which accounts for approximately 25% of the bile acid uptake and is predominantly operative at the luminal membrane. Bile acid uptake via this transporter would thus require bile reflux to reach the pancreatic acinar cell. The other uptake mechanism involves an HCO3–-dependent exchanger (organic anion transporting polypeptide 1), which operates from the basolateral acinar cell surface and could thus be supplied with serum or interstitial bile acids.

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  • Figure 2. 

    Bile acid uptake and targets in pancreatic acinar cells. The scheme depicts the modes of bile acid entry via Na+-dependent co-transporters (NTCP) from the luminal surface or via HCO3–-dependent bile acid exchangers (OATP1) from the basolateral membrane. Perides et al27 report bile acid (TLC-S) stimulation of a G-protein–coupled bile acid receptor 1 (Gpbar1) at the luminal surface. Previously reported inward-directed signals and targets of bile acid action in acinar cells involved: release of Ca++ from intercellular stores (Ca++), inhibition of SERCA-pumps, activation of PI3-kinase, Ryanodin receptors (RyRs) and IP3-receptors (IP3Rs), and Ca++-independent mitochondrial depolarization.

Perides et al27 in the current issue of Gastroenterology have identified an additional and novel mechanism for the effects of bile acid on pancreatic acinar cells, through the following means: (1) it seems to require action only at the luminal cell surface; 2) is independent of bile acid uptake mechanisms into the cell; and 3) involves G-protein-receptor–coupled signaling events elicited by TLC-S, which suggests biliary pancreatitis to be a surface receptor-mediated disease. The authors used a mouse strain deleted for the G-protein–coupled bile acid receptor-1 (Gpbar1).28 Pancreatitis was induced by injecting very small amounts of bile acids (50 μl 3 mmol/L TLC-S or Na+-taurocholate) into the pancreatic duct, which results in mild acute pancreatitis involving only the head of the pancreas and is not burdened with the high mortality of the established Na+-taurocholate–induced models of pancreatitis.29 Interestingly, only TLC-S injection results in pancreatitis in this setting whereas Na+-taurocholate does not. Gpbar1–/– mice were completely protected against TLC-S–induced pancreatitis.

When isolated acini from the knock-out animals were incubated with low 500 μmol/L TLC-S (but not with 200 μmol/l TLC-S or 500 μmol/L taurocholate), they responded with increased rates of pathologic Ca++ signals, intracellular trypsinogen activation, and acinar cell injury (lactate dehydrogenase release), hallmarks of pancreatitis and mostly abolished in acini from Gpbar1–/– mice. Unlike the TLC-S effect on these pathologic events, the amylase secretion from acini that is elicited by TLC-S (500 μmol/L) was independent of the presence or absence of Gpbar1 but depended on [Ca++]i. Doubling the concentration of TLC-S to 1 mmol/L, on the other hand, induced amylase secretion that was neither dependent on Gpbar1 nor inhibited by the Ca++ chelator BAPTA.

This study has several important consequences for our understanding of biliary pancreatitis. The dramatic effect of Gpbar1 deletion on pancreatitis induced by TLC-S injection into the pancreatic duct clearly indicates that an important part of the disease pathology in this model represents a surface receptor–mediated event and is independent of the uptake of bile acids into the acinar cell by co-transporters or exchangers or bile acid effects on intracellular receptor systems such as LXRS or FXR. The fact that acinar cells express Gpbar1 at the luminal surface allows for such a receptor-mediated mechanism to be established in the intraductal TLC-S model of pancreatitis. Whether or not this makes the common channel hypothesis more probable in view of the fact that bile is not likely to ever reach the luminal surface of human acinar cells remains a matter of debate because basolateral mechanisms for bile acid uptake have been established previously and are clearly operative at similar TLC-S concentrations.22 Corresponding G-protein–coupled bile acid receptors are conceivably at the basolateral membrane of acinar cells, although they have so far been identified only in the liver. A second important point is the relationship between secretion and acinar cell injury elicited by TLC-S. In all previous models of pancreatitis, premature protease activation and acinar cell injury were consistently linked to blockage in secretion. This paradigm may now be obsolete because TLC-S, at increasing concentrations, raises the level of injury in parallel with the level of amylase release—without ever causing an apparent blockage of secretion in this study of Perides et al.27

How TLC-S induces these effects remains puzzling. Perides et al27 show that cell damage induced by TLC-S depends on the presence of functional Gpbar1, pathologic Ca++ signals, and undisturbed pH regulation. The TLC-S action on amylase secretion, on the other hand, seems to be independent of Gpbar1 and, at higher concentrations, even independent of [Ca++]i. In previous studies mitochondrial depolarisation by very low concentrations of TLC-S (10–100 μmol/L),24 or acinar cell depolarization,26 or acinar cell injury22 were also shown to be partially independent of Ca++ signalling. These discrepancies suggest that bile acids have a complex mode of action on acinar cells that not only involve surface receptor–linked but also non–receptor-dependent mechanisms at different surfaces and on different organelles. The precise mechanisms remain to be elucidated. The present study by Perides et al27 raises several exciting new aspects, namely that of surface receptors, which are responsive to very low concentrations of bile acids, and challenges the paradigm of a link between pancreatic injury and blocked secretion in pancreatitis.

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Acknowledgments 

We thank J. Mayerle for valuable discussion and suggestions.

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References 

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 Conflicts of interest The authors disclose no conflicts.

 Funding The authors' own work is supported by grants from the Deutsche Forschungsgemeinschaft LE 625/8-1, LE 625/9-1, DFG GRK 840 E3 and E4, Mildred Scheel Stiftung 10-2031-Le I and 10-6977-Re, BMBF-NBL3 01 ZZ 0403, Novartis Foundation, the Gerhard-Domagk-Graduate School of Greifswald University, and Alfried-Krupp Foundation (Graduiertenkolleg Tumorbiologie).

PII: S0016-5085(09)02154-4

doi:10.1053/j.gastro.2009.12.012

Refers to article:

  • Additional Online Content AvailableEditorial Accompanies Article Biliary Acute Pancreatitis in Mice is Mediated by the G-Protein−Coupled Cell Surface Bile Acid Receptor Gpbar1 , 09 November 2009

    George Perides, Johanna M. Laukkarinen, Galya Vassileva, Michael L. Steer
    Gastroenterology February 2010 (Vol. 138, Issue 2, Pages 715-725)

Gastroenterology
Volume 138, Issue 2 , Pages 429-433, February 2010