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Primary Malformations 25

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Annular pancreas is frequently associated with other anomalies such as duodenal stenosis or atresia (40%), tracheoesophageal fistula (9%), congenital heart defects (7%), intestinal malrotation, and anal atresia [17]. A considerable number of affected individuals have chromosomal disorders, particularly Down syndrome (11–16%)[18]. This suggests that annular pancreas represents an early embryologic malformation. Agenesis of the dorsal pancreas may also be associated with annular pancreas[17].

Although most cases of annular pancreas are sporadic, there have been some cases of familial recurrence with different patterns of transmission. Annular pancreas can be found in Mitchell–Riley syndrome, in Martinez–Frias syndrome, and in congenital alveolar capillary dysplasia with misalignment of pulmonary veins[19].

Annular pancreas may manifest at any age or remain asymptomatic. The majority of symptomatic cases present in the first week of life as duodenal compression with bilious vomiting and feeding intolerance[18]. The diagnosis is suggested in >50% of cases during prenatal ultrasonography. A plain abdominal radiograph may demonstrate two large air filled spaces, the so-

called “double- bubble” sign, if the obstruction is complete: Due to post- duodenal obstruction not only the stomach but also the upper duodenum is filled with gas.

Patients in whom annular pancreas becomes symptomatic later in life may suffer from recurrent vomiting, chronic gastric distension, pain resulting from pancreatitis, or peptic ulcers[20]. Upper gastrointestinal studies or a contrast- enhanced CT or MRI, which allow direct visualization of the ring, can aid the diagnosis.

Surgical therapy with duodenal bypass either in the form of a duodeno- duodenostomy or a duodenojejunostomy eliminates the obstruction with an excellent long- term prognosis[18]. Resection of the ring is not recommended because of the risk of pancreatic peritonitis, postoperative pancreatitis, fistulae, and late fibrosis. The prognosis depends on the age of onset and shows the highest mortality in the newborn period due to thehigh proportion of other coexisting organ malformations.

The estimated incidence varies from about 4–14% in autopsy series. Diagnosis relies on MRCP, especially secretin-

enhanced MRCP. Endoscopic ultrasound and

ERCP are invasive second- line investigations (Fig.3.2).

The clinical significance of the pancreas divisum is disputed: while some consider it an insignificant normal variant, others postulate that the narrow opening of the minor papilla leads to a relative, functional stenosis and thus predisposes to obstructive pancreatitis. Since the prevalence in patients with chronic pancreatitis is similar to the frequency in the population, it is unlikely to cause pancreatitis alone[21]. Thus, other exogenous or genetic factors probably must be present. Interestingly, PRSS1, SPINK1, and CFTR mutations are more common in patients with chronic pancreatitis and pancreas divisum than in patients without this anomaly [22]. In chronic pancreatitis, the question arises whether endoscopic sphincterotomy and stent insertion at the minor papilla is beneficial and influences the natural course[23].

Anomalies ofthe Pancreaticobiliary Junction

The junction of the main duct of the pancreas with the bile duct is also very variable and most abnormalities are harmless variations in the norm and are incidental

Pancreas Divisum

The fusion of the ventral and dorsal pancreas also merges the ducts of both parts of the gland. As a result, various anatomical variants of the pancreatic duct system can occur. In pancreas divisum, the most common anatomic variant, there is a separate outflow of the ventral part into the major papilla and the dorsal part via the Santorini duct into the minor papilla, which drains about 80% of the pancreatic juice[12]. Sometimes a small side branch connects both duct systems (incomplete pancreas divisum).

Figure3.2 Pancreas divisum on ERCP. Whereas the intra- and

extrahepatic bile ducts are of regular size and proportions, the pancreatic duct is short and tender (already overfilled with contrast medium) and supplies only the head of the pancreas.

Congenital andInherited Anomalies ofthe Pancreas

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findings on endoscopy, ERCP, or MRI/MRCP [24]. Pancreaticobiliary maljunctions, in which the common bile duct and the ventral pancreatic duct unite outside the duodenal wall, result in a long common segment (long common channel) found in 1.5–3% of individuals [25]. This promotes the reflux of pancreatic secretions into the bile duct, as shown by dynamic MRCP after secretin stimulation. Reflux can lead to biliary duct inflammation and dilatation with choledochal cyst formation, pancreatitis, and, in the long term, malignant transformation resulting in biliary carcinoma. The incidence of pancreatitis is 3–31% in patients with pancreaticobiliary abnormalities[26]. The reflux of bile into the pancreatic duct system, conversely, is controversially discussed as a cause of pancreatitis and is less likely since pancreatic secretion pressure constantly exceeds the bile duct secretion pressure. Inherited choledochal cysts, which are often associated with pancreaticobiliary maljunctions, may manifest as acute or recurrent pancreatitis.

Congenital Cysts

Most pancreatic cysts are acquired pseudocysts of inflammatory origin and are found in the context of pancreatitis or cystic fibrosis (Fig.3.3). In contrast, congenital pancreatic cysts are epithelial-

lined and are rare, accounting for less than 1% of pancreatic cysts diagnosed in children. However, with improved radiological imaging, the diagnosis of incidental cystic lesions is on the rise. In a population- based MRCP study, small cysts (<1 cm) of unknown etiology were found in about a quarter of healthy volunteers (mean age 51.9 ± 13.4 years)[24]. In children, congenital cysts have a female predominance

and may present as an asymptomatic palpable mass or with epigastric pain, jaundice, and vomiting by the compression of adjacent intestinal or biliary structures[27]. Symptoms often appear in the first two years of life. The cysts are more frequently located in the pancreatic tail or body than in the head, are more often unilocular than multilocular, and more often single than multiple [28]. Ductal communication is rare and, if present, suggests a pancreatitis-

associated pseudocyst. The cysts are usually anechoic on ultrasound and are low attenuating structures without wall enhancement in CT or MRI studies. Associated anomalies may include renal tubular ectasia, polydactyly, anorectal malformations, polycystic kidneys, and asphyxiating thoracic dystrophy[28]. Multiple pancreatic cysts occur in about 10% of patients with polycystic kidney disease and in 30–70% of patients with von Hippel- Lindau disease (see below), but the cysts are rarely congenital in either disease.

Congenital Exocrine Insufficiency

Congenital exocrine pancreatic insufficiency is rare. Cystic fibrosis, which leads to progressive destruction of the pancreas and may result in clinical symptoms of secretory insufficiency from birth, account for the majority of cases with congenital exocrine pancreatic insufficiency. Cystic fibrosis and hereditary pancreatitis are discussed in dedicated chapters of this book.

Congenital exocrine pancreatic insufficiency, if complete, manifests from birth with loose and bulky stools, steatorrhea, failure to thrive, and hypoproteinemia leading to edema. Due to the large reserve capacity of the exocrine pancreas, clinical symptoms only appear when more than 90% of the exocrine cells are destroyed [29]. Pancreatic secretory insufficiency reflects either an isolated enzyme deficiency or early- onset degeneration of acinar cells resulting in fibrosis or lipomatosis of the gland.

Figure3.3 Large cysts in the pancreatic head and tail in a patient

with chronic pancreatitis.

Isolated Enzyme Deficiencies

Isolated inherited deficiencies of pancreatic digestive enzymes or duodenal enteropeptidase (enterokinase) are extremely rare. So far, isolated deficiencies of lipase, colipase, amylase, trypsin, and enteropeptidase as well as combined deficiencies of lipase and colipase have been reported[30]. Of clinical relevance are mainly deficiencies of trypsin and enteropeptidase, which manifest with failure to thrive, diarrhea, hypoproteinemia, and edema. In all deficiencies, enzyme replacement therapy is very effective.

When fat- digesting enzymes are affected, chronic diarrhea and steatorrhea are the leading symptoms, but failure to thrive is absent. Congenital deficiency of pancreatic lipase (PNLIP) is inherited in an autosomal recessive

Congenital Exocrine Insufficiency 27

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manner and is caused by loss- of- function mutations in PNLIP [31]. Interestingly, PNLIP variants that lead to increased proteolytic degradation by trypsin are associated with early- onset chronic pancreatitis [32]. Colipase deficiency has been reported in two brothers and the combined deficiency of lipase and colipase in another family and in a single case. Pancreatic amylase deficiency may lead to diarrhea induced by a high- starch diet, but the functional capacity of the carbohydrate- digesting enzymes is quite high, and so the deficiency ismostly compensated. To date, two children withtrypsinogen and about a dozen patients with enteropeptidase deficiency have been described [33]. Enteropeptidase (TMPRSS15) is a transmembrane serine protease that localized to the brush border of the intestinal mucosa. Although enteropeptidase is not a pancreatic enzyme, its deficiency manifests clinically as a trypsin defect, since it activates trypsinogen.

Shwachman–Bodian–Diamond Syndrome

After cystic fibrosis, Shwachman–Bodian–Diamond syndrome (SBDS) is the second most common inherited cause of exocrine pancreatic insufficiency with an estimated incidence of 1 : 50,000. SBDS is inherited in an autosomal recessive manner and is characterized by the triad exocrine pancreatic insufficiency, bone marrow dysfunction, and skeletal abnormalities. Histologically, there is hypoplasia of the acinar cells with replacement by adipose tissue (lipomatosis) (Fig. 3.4) [34]. The islet cells and the ductal architecture are preserved. In contrast to cystic fibrosis, water and bicarbonate secretion are not restricted. Exocrine insufficiency improves with age: while 90% of infants suffer from steatorrhea,

around half of patients in the second decade of life are pancreatic sufficient. Neither diabetes nor pancreatitis are consistent features of SBDS.

The main hematological change is intermittent or permanent neutropenia, sometimes accompanied by anemia, thrombocytopenia, or pancytopenia. Infants in particular are at risk from serious bacterial infections. About 10–30% of patients develop myelodysplastic syndrome or acute leukemia[35].

Other manifestations include short stature, skeletal abnormalities (metaphyseal chondrodysplasia, shortened ribs), enamel defects with increased tooth decay,liver involvement with hepatomegaly and elevated transaminase levels, and often mild mental retardation[35].

In 90%, the syndrome is caused by gene conversion mutations in the SBDS gene[36]. Recently, the elongation factor-

like 1 (EFL1) has been identified as second disease- causing gene [37]. Moreover, mutations in the genes encoding the DnaJ heat shock protein family (Hsp40) member C21 (DNAJC21) and the signal recognition particle 54 (SRP54) have also been associated with a SBDS- like phenotype[37].

Interestingly, all four genes are involved in ribosome biogenesis, reinforcing the postulate that the syndrome is a ribosomopathy. SBDS promotes by direct interaction with EFL1 the removal of the eukaryotic initiation factor 6 (eIF6) 60S subunit of the ribosome. This allows the 60S subunit to bind to the 40S subunit to generate a functional 80S ribosome. DNAJC21 is involved in the release of maturation factors from the pre- 60S subunit. SRP54 recognizes the signal peptide of secretory proteins and mediates the targeting of the ribosome and the associated nascent polypeptide chain to the endoplasmic reticulum[37].

The diagnosis of SBDS is based on the clinical symptoms, imaging methods (skeletal X- ray, diffuse fatty degeneration of the pancreas in the MRI) and the corresponding laboratory parameters and should be confirmed by a mutation analysis. Because cytopenia can be cyclic, blood cell status should be measured repeatedly. Differential diagnoses include cystic fibrosis and other causes of neutropenia such as Diamond- Blackfan or Fanconi anemia, and congenital dyskeratosis.

Treatment is symptomatic. Because exocrine dysfunction improves with age, approximately 50% of patients in their second decade of life no longer require enzyme replacement therapy.

Figure3.4 Fatty replacement of the entire pancreas (black central

structure on the abdominal CT) in Shwachman–Bodian–Diamond syndrome. Source: Wilschanski M etal. (1994). Reproduced with permission of Wolters Kluwer Health.

Pearson Marrow Pancreas Syndrome

Pearson syndrome is a rare multisystem mitochondrial disorder caused by deletions of mitochondrial DNA (mtDNA) [38]. Clinical characteristics are refractory

Congenital andInherited Anomalies ofthe Pancreas

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sideroblastic anemia with vacuolization of marrow precursors and variable exocrine pancreatic insufficiency [39]. Severe, transfusion- dependent, macrocytic anemia usually starts in infancy and may be accompanied by thrombocytopenia and neutropenia. Other features include lactate acidosis, renal tubulopathy, liver cholestasis and/or fibrosis, adrenal insufficiency, diabetes mellitus, cardiomegaly, and cardiac conduction defects [39]. Some patients have recurrent episodes of acute pancreatitis [39]. In contrast to the Shwachman syndrome, the pancreas in Pearson syndrome shows fibrosis instead of lipomatosis. The disorders also differ in bone marrow morphology. A phenotypic shift from a predominantly hematopoietic disorder (Pearson syndrome) to a disease with overt muscle dysfunction (mitochondrial myopathy) was repeatedly observed, up to a fully developed Kearns–Sayre syndrome[39].

In laboratory tests, a subset of patients show complex organic aciduria with 3- methylglutaconic aciduria. Therapy is symptomatic and in selected cases bone marrow transplantation can be considered. The prognosis is poor and patients usually die in early childhood from intractable metabolic acidosis, sepsis, or liver failure[39].

Figure3.5 Aplasia of the nasal wings as a characteristic feature or

Johanson–Blizzard syndrome.

Johanson–Blizzard Syndrome

Johanson–Blizzard syndrome (JBS) is characterized by congenital exocrine pancreatic insufficiency, a peculiar nasal malformation with hypo- or aplasia of the nasal wings (Fig. 3.5), and oligodontia of permanent teeth [40]. These three characteristics are present in virtually all patients[41]. The majority of patients also present with hearing impairment, scalp defects, varying degrees of cognitive impairment, and short stature. Hypothyroidism, microcephaly, intrauterine growth retardation, congenital heart defects, urogenital and anorectal malformations, renal anomalies, and diabetes with onset during adolescence are additional features of the syndrome[41].

The condition is inherited as an autosomal recessive trait and has an estimated incidence of 1

: 250,000 [42]. JBS is caused by UBR1 mutations that lead to severe deficiency of the homonymous ubiquitin ligase of the N- end rule pathway[42]. As this pathway is responsible for degradation of intracellular proteins, it is likely that the excess or increased half- life of hitherto unknown proteins are involved in the pathogenesis of the pancreatic and other defects. While >95% of patients with a clinical diagnosis have UBR1 defects, CAPN15 mutations may cause a phenotype overlapping with JBS.

Histologically, there is an almost complete absence of acinar cells, which are replaced by fat and connective tissue, whereas ductal architecture and islets are less

affected. Thus, the ductular output of fluid and electrolytes is preserved, while the secretion of zymogens is decreased. The acinar cell loss is likely caused by intrauterine destruction, resembling pancreatitis of prenatal onset [43]. However, UBR1 variants are not associated with chronic pancreatitis. Ubr1 deficient mice have milder pancreatic dysfunction such as decreased zymogen secretion and increased susceptibility to experimental pancreatitis[42].

Diagnosis of JBS is based on the characteristic clinical picture and can be confirmed by UBR1 sequencing. Therapy is symptomatic and consists of the substitution of pancreatic enzymes and, if necessary, of thyroid hormones as well as the provision of hearing aids and surgical correction of the malformations. The prognosis depends on the associated malformations. Lethal malformations such as bilateral renal dysplasia are rare. Mental retardation is variable, but about a third of those affected show normal intelligence.

Other Hereditary Disorders Affecting thePancreas

Pancreatic abnormalities have been described in a number of congenital or inherited multisystem disorders, in which they are rarely a cardinal symptom or may even remain clinically inapparent.

References 29

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Polycystic Kidney Disease

Multiple cysts of the pancreas can be present in autosomal recessive (ARPKD) and autosomal dominant polycystic (ADPKD) disease. Both diseases are genetically heterogeneous[44]. The estimated incidence of ARPKD is about 1 to 20,000 and of ADPKD about 1 to 400– 1,000[44]. The clinical presentation of ARPKD is highly variable. Newborns have markedly enlarged polycystic kidneys that can be associated with pulmonary hypoplasia. Liver involvement is evident in about half of infants and comprises cysts and periportal fibrosis. Pancreatic cysts and pancreatic fibrosis have been repeatedly reported on imaging or autopsy in children with ARPKD, but clinical significant pancreatic disease is exceptional. The same applies to ADPKD, in which sonographically detectable pancreatic cysts are much more frequent and are present in about 10% of adult patients but are rare in infancy. Occasionally, the cysts may lead to pancreatitis. Pancreatic involvement is typically less severe than renal and hepatic affection.

Von Hippel–Lindau Syndrome

Von Hippel–Lindau syndrome (VHL) is an autosomal dominant familial cancer syndrome with an estimated incidence of 1 : 36,000. It is caused by mutations in the VHL tumor suppressor gene[45], but genetic changes in cyclin D1 (CCND1) may further modify the phenotype. About 80% of cases are familial. Affected subjects are at risk of developing cerebellar, spinal, and retinal hemangioblastomas, renal cell carcinoma, pheochromocytoma, pancreatic neuroendocrine tumors, pancreatic and renal cysts, and epididymal cystadenoma[46].

About 35–70% of patients with VHL present with pancreatic findings. Pancreatic cysts are reported in up to 30% of patients on imaging studies but can be found in up to 72% of patients at autopsy; however, they are typically not congenital[27]. Involvement ranges from a single cyst to multiple cysts virtually replacing the pancreas. Usually the cysts are multiple but asymptomatic. These cysts may precede any other manifestation by several years. In about 12% of patients, pancreatic cysts are the only sign of the disease.

Serous cystadenomas and neuroendocrine tumors are other pancreatic manifestations. By replacing the pancreatic parenchyma, cysts and cystadenomas can compress adjacent structures and may cause exocrine or

endocrine deficiency. Neuroendocrine tumors become malignant and metastatic in 8% of patients [46]. Pancreatic carcinoma and adenocarcinoma of the ampulla of Vater have also been reported.

Beckwith–Wiedemann Syndrome

The cardinal features of Beckwith–Wiedemann syndrome (BWS) are (asymmetric) macrosomia, macroglossia, and exomphalos in the neonate. Pancreatic hypertrophy is an imaging feature, and severe hypoglycemia due to transient hyperinsulinism occurs in 30–50% of neonates with BWS. Histology of resected pancreatic tissue shows an increase in the volume of endocrine relative to acinar tissue with expanded islets and preservation of lobular architecture [47]. Other clinical features include abdominal wall defects, ear anomalies, naevus flammeus, organomegaly, and nephroureteral malformations [48]. About 10% of patients develop embryonic tumors such as nephroblastoma, hepatoblastoma, and neuroblastoma during infanc y[48]. Pancreatoblastomas have been described in a few cases and usually present in infants aged 3 months and younger. BWS is genetically heterogeneous. Loss or gain of methylation, paternal uniparental disomy, and CDKN1C loss- of- function mutations result in epigenetic or genetic defects on chromosome 11p15.5 with disrupted expression of imprinted genes [48]. About 85% of cases are sporadic.

Jeune Syndrome andOther Ciliopathies

Ciliopathies constitute a large group of multisystem disorders with considerable clinical and genetic heterogeneity, and pancreatic involvement is part of the phenotypic spectrum. Jeune syndrome (asphyxiating thoracic dystrophy) belongs to the skeletal ciliopathies and is a rare autosomal recessive osteochondrodysplasia with characteristic skeletal abnormalities, nephronophthisis, retinal abnormalities, pulmonary insufficiency, and hepatic fibrosis. It may be associated with pancreatic cysts and pancreatic fibrosis, leading to exocrine insufficiency[49].

Fibrotic and cystic changes of the pancreas may also be

found in renal-

hepatic- pancreatic dysplasia and in other

ciliopathies[50].

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Section 2

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Physiology andPathophysiology ofPancreatic Functions

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Physiology ofAcinar Cell Secretion

Ole H. Petersen

Cardiff School of Biosciences, Cardiff University, Cardiff, UK

Introduction

The acinar cell is the dominant cell type in the pancreas. In terms of percentage volume, the pancreas consists of 82% acinar cells, 4% duct cells, 4% blood vessels, 2% endocrine cells, and 8% extracellular matrix [1]. However, the acinar cell itself is not the functional unit in the exocrine pancreatic tissue because acinar cells are organized into acini consisting of up to several hundred acinar cells linked by numerous gap- junctional channels that allow both direct chemical and electrical intercellular communication [2,3]. There is an additional cell type that has not previously featured much in descriptions of acinar cell function, namely the pancreatic stellate cells (PSC). These very thin periacinar cells come very close to the acinar cells, but are nevertheless functionally isolated from the acinar cells[4–6]. The PSC play an important role under pathophysiologic conditions where they exert effects on the acinar cells [4–7], but it is unknown whether they have any physiologic role in the control of acinar cell secretion.

The principal function of the acinar cells is to secrete a potent mixture of digestive enzymes in response to food intake. This secretory response is mediated by vagal nerve stimulation, releasing acetylcholine (ACh) from nerve endings close to the acinar cells, and the circulating hormone cholecystokinin (CCK). The digestive (pro) enzymes are packaged into secretory vesicles called zymogen granules (ZG) and the secretion process itself occurs by exocytosis, that is, fusion of the granule membrane with the apical (luminal) cell membrane and subsequent opening of a pathway (pore) allowing direct movement of the zymogens from the granule interior to the acinar lumen[7]. In order to move the zymogens into the duct system and thereafter into the gut, there is also

a need for fluid secretion. The acinar cells secrete a neu-

−

tral Cl with ACh and CCK [7,8]. Additionally, the small ducts secrete a HCO

- rich fluid, produced in response to stimulation

−

- rich fluid when stimulated by the hor-

mone secretin[7]. The aim of this chapter is to explain the cellular mechanisms underlying the very acute and finely controlled normal physiologic regulation of acinar fluid and enzyme secretion.

Composition ofPancreatic Acinar Juice

ACh or CCK activates acinar cells to secrete an isotonic NaCl- rich fluid (Fig. 4.1a) containing a multitude of enzymes and precursor enzymes. The protease precursors are trypsinogen, chymotrypsinogen, and procarboxypeptidases. These precursors are activated in the small intestine, initiated by conversion of trypsinogen to trypsin by the intestinal enzyme enteropeptidase. Trypsin then activates trypsinogen autocatalytically and also activates the other precursors. The acinar fluid also contains active

amylase, lipases, and colipase as well as various other

αenzymes (e.g., collagenase, elastase, phospholipase A, and ribonuclease)[11]. The neutral NaCl- rich fluid containing these enzymes and enzyme precursors is delivered to the small ducts, where it is mixed with the HCO

−

- rich fluid

produced by the duct cells in response to stimulation with secretin (Fig.4.1b, c).

Acinar Fluid andEnzyme Secretion

There is separate control of acinar and duct secretion, as shown in experiments on the isolated perfused pancreas

The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler, RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/beger/thepancreas4e

Physiology ofAcinar Cell Secretion

(a)

Time (h)

(c)

Secretin

(b)

https://t.me/medicina_free

6 Na

1.98

1.32

0.66

Pancreatic juice ( µ L /min)

ACh

CCK

5K 3K 6Cl

3Na 3Na

Caerulein

(CCK)

Fluid

Amylase

[Ca2]

TJs

Secretin

2 _

free EGTA 0.1 mM

100

Lumen

6 Na 6 Cl

Acinar cell

Amylase output (U/min)

Fluid Enzymes

Duct cell

ACh

CCK

Pancreatic acinar unit

Figure4.1 Fluid and enzyme secretion from acinar cells. (a) Acinar transport model illustrating the individual ion transport events that

work together to produce an isotonic NaCl- rich fluid. For graphical convenience, different aspects of the processes are shown in separate cells. In the top cell it is shown that ACh or CCK binding to their respective specific receptors on the basolateral membrane elicits a rise in the cytosolic Ca basolateral membrane (for graphical convenience all events in the basolateral membrane are shown only in the basal membrane). The middle cell illustrates transcellular Cl basal membrane and it is indicated that the net transport event is uptake of Cl simply occurs through a Cl potential difference. The Na the transport of cations (K

concentration ([Ca2+]i), which in turn activates Cl+ channels in the apical (luminal) membrane and K+ channels in the

−

transport. The Na+/K+/2Cl− cotransporter, the K+ channel, and the Na+/K+ pump are shown in the

−

channel. The lower cell illustrates the overall electrical circuit and explains the transepithelial electrical

+/K+

/2Cl− cotransporter is electrically neutral, so the only electrogenic event at the basolateral membrane is

and Na+) through the K+ channel and Na+/K+ pump (3Na+ pumped out for 2K+ taken in). This net outward

−

, whereas at the apical membrane Cl− exit into the lumen

(cation exit) current has to be matched by an inward (anion exit) current across the apical membrane and the completion of the circuit depends on the high conductance of the so- called tight junctions (TJs). Source: Adapted from[8] / With permission of American Physiological Society. (b) Model drawing of acinar unit with small duct segment attached. The polarity of acinar cells is shown with the nucleus (N) surrounded by endoplasmic reticulum (ER) in the basal part and zymogen granules (ZG) in the apical part. Source: Adapted from[9] / With permission of Springer Nature. (c) Fluid and amylase secretion from isolated perfused rat pancreas stimulated by the frog skin peptide cerulein (analog of CCK) and secretin. Source:Adapted from[10] / With permission of The Royal Society.

(Fig.4.1c). Sustained fluid and enzyme secretion, due to stimulation with either ACh or CCK, is acutely dependent on the presence of Ca whereas the HCO

in the extracellular solution,

−

- rich fluid secretion evoked by secre-

tin in the ducts occurs normally in the complete absence of external Ca2+ (Fig.4.1c).

It is well established that exocytosis in general is

activated by a rise in cytosolic Ca2+ concentration

([Ca2+]i)[7,11]. In nerve and endocrine cells, exocytosis is normally activated by Ca2+ entering the cell interior via special voltage- activated Ca

channels in the plasma membrane, which open on membrane depolarization caused by action potentials [11]. However, the pancreatic acinar cell is electrically nonexcitable and cannot fire action potentials [12]. Ca

needed for

stimulus–secretion coupling is therefore delivered to

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