5PANCREASEXOCRINEFUNCTIONS
Objectives
After studying this chapter you should be able to:
b Describe the macroscopic and microscopic anatomy of the pancreas and relatethese to its function.
c Describe the components of exocrine function of the pancreas and apply thisknowledge in understanding the pathological conditions of acute and chronicpancreatitis and cystic fibrosis.
sphincter muscle relaxes and allows the pancreaticjuice and bile into the small intestine. The control of thesphincter of Oddi is discussed in Chapter 7. Exocrinedysfunction of the pancreas may be due to disorders ofthe pancreas itself, or to blockage of the main ductswhich prevents the exocrine secretions reaching theduodenum. Duct blockage may also result in impairedbile flow from the liver and so cause jaundice.
In the small intestine, pancreatic juice, bile, and thejuices secreted by the walls of the intestines, mix withthe fluid (chyme) arriving from the stomach. Pan-creatic juice provides most of the important digestiveenzymes. In addition, by virtue of its HCO3
- content,it helps to provide the appropriate pH in the intestinallumen for the enzymes to act on their nutrient sub-strates. The functional importance of the pancreas tothe digestive processes can be illustrated by the prob-lems arising in an individual suffering from chronicpancreatitis, a condition in which pancreatic tissue isdestroyed.
Introduction
The pancreas contains exocrine tissue which secretespancreatic juice, a major digestive secretion, andendocrine tissue which secretes the hormones insulinand glucagon. The hormones are important in thecontrol of metabolism and their roles in the absorptiveand postabsorptive metabolic states will be discussedin Chapter 9. This chapter will be mainly concernedwith the exocrine secretions of the pancreas, their func-tions, and the mechanisms whereby the secretoryprocesses are controlled.
Pancreatic juice finds its way into the duodenum viathe pancreatic duct which opens into the duodenum atthe same location as the common bile duct (see Chapter1). Entry of both pancreatic juice and bile into the duo-denum is controlled by the sphincter of Oddi. Thesmooth muscle of the sphincter is contracted betweenmeals so that the junction is sealed. When a meal is being processed in the gastrointestinal tract, the
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Chronic pancreatitis Box 1
Chronic pancreatitis
A forty-year-old man who had been a heavy drinker formany years, went to see his general practitioner. Hehad made two previous visits over the past year due tohis experiencing recurrent episodes of abdominal pain.Although the pain had been intermittent at first, it wasnow continuous. The patient also said that he had losta considerable amount of weight since his last visit.Upon enquiry the pain was described to originate in theepigastrum, and to radiate through to the back. Inappearance the patient was very thin and the doctornoticed that he was mildly jaundiced. The doctorarranged for the patient to be admitted to hospital fora few days for tests so that his condition could be diagnosed. He was submitted to an x-ray examination,and serum and urine analyses were performed. Thepatient’s stools were collected over three days. Thesewere seen to be pale-coloured and bulky, indicating ahigh fat content (steatorrhoea). He was told to abstainfrom food the next morning so that a glucose tolerancetest could be performed. The patient’s response tosecretin was also tested. This involved an injection ofsecretin (1CU/kg body weight) and continuous aspira-tion of the duodenal contents until the water andbicarbonate output had returned to the initial level.
The blood tests showed a reduced serum pancreaticisoamylase, but increased bilirubin and alkaline phos-phatase. The glucose tolerance test showed an abnor-mally high and prolonged rise in serum glucose, and
urine analysis confirmed the presence of glycosuria(glucose in the urine), indicating that the patient wasdiabetic. The secretin test indicated a decreased pan-creatic secretory response as manifest by a low level ofHCO3
- secretion. The presumptive diagnosis was chronicpancreatitis. The patient was prescribed pethidine tocontrol the pain. He was advised to abstain completelyfrom alcohol, and to try to eat regular meals.
Examination of the details of this case gives rise tothe following questions:
b Is the primary defect in chronic pancreatitis known?What might the x-ray have revealed? What could bethe cause of the condition in this patient?
c How are the exocrine and endocrine functions of the pancreas impaired in chronic pancreatitis? How isthis condition diagnosed? What did the high faecal fatcontent indicate? What is the basis of a) the secretintest, b) the glucose tolerance test? Why has diabetesmellitus developed in this patient? Why was the patientjaundiced? Why were the patient’s serum bilirubin andalkaline phosphatase abnormally high?
d What are the main physiological consequences ofthis disease and how can the condition be treated ormanaged?
We shall address these questions in this chapter.
Anatomy
The pancreas is an elongated gland which lies in theabdominal cavity. It can be divided into three regions:the head, the body and the tail (Figs 5.1 and 5.2). Thehead is an expanded portion that lies in the C-shapedregion of the duodenum to which it is intimatelyattached by connective tissue, and which is connectedby a common blood supply. The body and tail extendacross the midline of the body toward the hilum of thespleen. The pancreatic duct (duct of Wirsung) extendsthrough the long axis of the gland to the duodenum.Pancreatic juice empties from this duct into the duo-denum via the ampulla of Vater. In some individualsthere is also an accessory pancreatic duct. Bile in thecommon bile duct from the liver also enters the duo-denum at the ampulla of Vater.
Exocrine tissue
The exocrine units of the pancreas are tubuloacinarglands which are organised like bunches of grapes, ina similar manner to the units in the salivary glands(Fig. 5.3). These exocrine units surround the islets ofLangerhans, the endocrine units of the pancreas. A thinlayer of loose connective tissue surrounds the gland.Septa extend from this layer into the gland, dividing itinto lobules, giving it an irregular surface. Larger areasof connective tissue surround the main ducts and theblood vessels and nerve fibres that penetrate the gland.Small mucous glands situated within the connectivetissue surrounding the pancreatic duct secrete mucusinto the duct.
Endocrine tissue
The endocrine units, or islets of Langerhans, are mostnumerous in the tail region of the pancreas. Theyconsist of clusters of cells which are surrounded by thepancreatic acini (Fig. 5.3). The islets vary considerablyin size. As with all endocrine tissue, the hormones they produce are secreted into the blood. The major
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Cystic duct
Head
Common bile duct
PancreasDuodenum
Sphincterof Oddi
Ductopenings
Duodenum
Accessory pancreatic duct
Body
Tail
Main pancreatic duct
Fig. 5.1The pancreas and its innervation and blood supply.
A
C
D D
B
A
Fig. 5.2Computerised tomography (CT) scan: cross section ofthe abdomen showing a swollen pancreas caused bypancreatitis (A) lying posteriorally on the abdominalwall. The spleen (B), lower border of liver (C) andkidneys (D) are also seen.
lum, the site of production of the digestive enzymes.Small mitochondria are situated throughout the cell.The apical portion of the cell contains the Golgi appa-ratus, and numerous zymogen granules which containthe pancreatic enzymes or enzyme precursors. Theapical region therefore stains with acid dyes such aseosin. Microvilli extend from the apical surface of theacinar cell into the lumen. The apical poles of neigh-bouring cells are joined by tight junctions, known aszonulae adherens. These junctions separate the fluid inthe lumen of the acinus from the fluid in the intercellu-lar spaces that bathes the basolateral surfaces of thecells. The tight junctions are impermeable to macromol-ecules, such as digestive enzymes, in the luminal fluid,but permit the exchange of water and ions between the
endocrine cell types present are a, b, D, and PP cellswhich secrete glucagon, insulin, somatostatin, andpancreatic polypeptide, respectively (for more infor-mation see Chapters 8 and 9). Different types ofendocrine cells can be distinguished under the electronmicroscope by the different appearance of the granuleswithin them. The islet cells have the general featuresof APUD cells (see Chapter 1). In addition there are afew (less than 5%) small ‘clear’ cells with as yet noclearly defined function.
Glucagon and insulin, the hormones produced bythe a and b cells respectively are taken up by the localblood vessels to act systemically. Somatostatin actslocally in a paracrine manner to inhibit the secretion ofthe a and b cells, as well as the exocrine secretions ofthe acinar and duct cells. Pancreatic polypeptide actsin a paracrine manner to inhibit the exocrine secretionsof the pancreas.
Oxygenated blood is supplied to the pancreas bybranches of the coeliac and superior mesenteric arter-ies. The blood drains from the pancreas via the portalvein to the liver. The acini and ducts are surroundedby separate capillary beds. Some of the capillaries thatsupply the islets converge to form efferent arterioleswhich then enter further capillary networks aroundthe acini. This arrangement is important for theparacrine control of pancreatic exocrine secretion.
Cholinergic preganglionic fibres of the vagus nerveenter the pancreas. These synapse with postganglioniccholinergic nerve fibres which lie within the pancreatictissue and innervate both acinar and islet cells. Post-ganglionic sympathetic nerves from the coeliac andsuperior mesenteric plexi innervate the pancreaticblood vessels as well as the acinar and duct cells.
Histology of the exocrine tissue
Figure 5.3 shows the structure of a pancreatic lobule.The exocrine units of the pancreas, or pancreatons, eachconsist of a terminal acinar portion and a duct (Fig. 5.4).The duct that drains the acinus is known as an interca-lated duct. These empty into larger intralobular ducts.The intralobular ducts in each lobule drain into a largerextralobular duct which empties the secretions of thatlobule into still larger ducts, and the latter converge intothe main collecting duct, the pancreatic duct.
The acinus is a rounded structure consisting ofmainly pyramidal epithelial cells (Fig. 5.4). These cellssecrete the digestive enzymes of the pancreatic juice.They display polarised features which are common tosecretory cells (Fig. 5.3). The nucleus of the acinar cellis situated at the base of the cell. The cytoplasm in thebasal region can be stained with haematoxylin or basicdyes due to the presence of rough endoplasmic reticu-
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Zymogen granules
Intercalatedducts
A
B
C
Pancreaticlobule
Interlobularducts
Extralobularduct
Maincollecting
duct
Duct cell
Lumen
Islet ofLangerhans
Acinar cell
Tight junction(zonulae adherens)
Mitochondrion
Roughendoplasmic
reticulum
Microvilli
Golgi apparatus
Nucleus
Fig. 5.3(A) A lobule of the pancreas indicating the duct system,(B) the relationship of an exocrine unit and an islet ofLangerhans, (C) an acinar cell.
Pancreatic juice
Composition of pancreatic juice
The pancreatic juice entering the duodenum is amixture of two types of secretion, an enzyme-richsecretion and an aqueous alkaline secretion. If the ductsare ligated near the acini, which results in acinar cellsdegeneration, the secretion of the alkaline componentof the juice is largely unaltered, but the secretion ofenzymes is markedly reduced. This indicates that theenzymes are secreted by the acinar cells, and the alka-line fluid by the duct cells. The alkaline secretion orig-inates largely from the centroacinar cells and the ductcells of the intralobular and small interlobular ducts.These relationships are illustrated in Figure 5.4.
Alkaline secretion
Composition
The cells of the upper ducts secrete an isotonic juicewhich is rich in bicarbonate but contains only traces ofenzymes. There is a continuous resting secretion of thisjuice, but it can be stimulated up to 14-fold during ameal. It contains Na+, K+, HCO3
-, Mg2+, Ca2+, Cl- andother ions, present in concentrations similar to those ofplasma. It therefore resembles an ultrafiltrate of plasma.It is alkaline by virtue of its high HCO3
- content.
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Enzyme
HCO3-/Cl-
exchangeDuct cell
HCO3-
Centrocinar cell
Acinar cell
Fig. 5.4Secretory unit showing the cellular locations of thedifferent secretions.
A
C
B
Fig. 5.5Plain abdominal X-ray showing calcified stones in thepancreatic duct (A), from a patient with chronicpancreatitis secondary to alcoholism. Gas in the leftcolon (B) and overlying stomach (C) are also seen.
interstitial spaces and the lumen of the acinus. Disrup-tion of these junctions may be an aetiological factor inthe development of chronic pancreatitis (see Casehistory 5, page 80). Gap junctions between neighbour-ing cells allow rapid changes in membrane potential tobe transmitted between the cells. They also permit theexchange of low molecular weight molecules (less than1400kDa mass) between cells.
The intercalated duct begins within the acinus. Thisis a unique feature of secretory glands. The duct cellswithin the acinus are known as centroacinar cells (Fig.5.4). These stain lightly with eosin. They are squamouscells with a centrally placed nucleus. These cells arecontinuous with those of the short intercalated ductthat lies outside the acinus and drains it. The interca-lated ducts are lined by flattened squamous epithelialcells. The neighbouring duct cells are joined by tightjunctions as in the acinus. These separate the ductlumen from the intercellular spaces and function toexclude large molecules from the spaces. They alsohave gap junctions which permit the transmission ofmembrane electrical changes between the cells. Theseducts lead into the intralobular ducts which are linedwith cuboidal or low columnar epithelium. Largerducts contain interlobular connective tissue cells andAPUD cells.
depends on the formation in the intestinal lumen ofmicelles, a process which only takes place at neutral orslightly alkaline pH values, iii) it protects the intestinalmucosa because excess acid in the duodenum candamage the mucosa and lead to the formation of ulcers.
Cellular mechanism of secretion
The mechanisms involved in the production of intra-cellular HCO3
- in the centroacinar and upper duct cells
Functions
The pancreatic juice arriving in the duodenum is mixedwith the chyme by contractions of the smooth muscleof the small intestine. The function of the alkaline pan-creatic secretion, together with the other alkaline secre-tions (bile and intestinal juices) that act in the smallintestine, is to neutralise the acid chyme arriving fromthe stomach. This is important for several reasons: i)the pancreatic enzymes require a neutral or slightlyalkaline pH for their activity, ii) the absorption of fat
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Chronic pancreatitis Box 2
Defect and causes
Now we can ask what the primary defect in chronicpancreatitis might be and how the use of x-rays canreveal it. We can also ask what is the likely cause of thecondition in this patient.
The primary malfunction in chronic pancreatitis isprobably defective ductal secretion of bicarbonate andwater which results in a high protein concentration inthe pancreatic juice in the ducts. This results in the pre-cipitation of protein, and the formation of proteinplugs, and consequently dilatation of the proximalducts. The effect of blockage of the ducts is the gener-ation of a high pressure in the ducts which causes pain.Secondary back pressure may lead to disruption of theintegrity of the ductal epithelium and result in destruc-tion of the pancreatic tissue. This can lead to an inflam-matory and fibrotic process in and around thepancreatic tissue. This in time leads to pancreatic insuf-ficiency. Fibrosis around the autonomic nerves whichsurround the pancreas may result in back pain, whichis a common feature of this condition.
Chronic pancreatitis is characterised by progressivefunctional damage to the pancreas, with or withoutevidence of inflammation. There is permanent destruc-tion of pancreatic tissue, and exocrine and endocrinepancreatic insufficiency usually follows. However,owing to the tremendous reserve of pancreatic tissue,the insufficiency may be subclinical and tests of pan-creatic function may be necessary to reveal it. Thehistopathology indicates irregularly distributed fibrosis,reduced number and size of islets of Langerhans, andvariable obstruction of pancreatic ducts of all sizes.Protein precipitation initially occurs in the lobular andinterlobular ducts, leading to the formation of plugsthat calcify by surface accretion. Concentric lamellarprotein precipitates appear in the major pancreaticducts and these subsequently also calcify to formstones. A specific protein, called stone protein, anormal constituent of pancreatic juice, which has a highaffinity for Ca2+, appears to be the major protein
present in pancreatic stones. The calculi contain calciumbicarbonate or hydroxyapatite (calcium phosphate andcalcium bicarbonate). The stones can be seen in x-radiographs (see Fig. 5.5) Foci of acinar ectasia arepresent, and acinar atrophy, chronic inflammation, and fibrosis, in areas of ductal obstruction. These,together with stricture formation due to periductalfibrosis eventually lead to ductal eclesia. The chronicinflammation may extend to adjacent organs, causingconstriction of the duodenum, stomach antrum,common bile duct, or transverse colon. Central epigas-tric pain is a common feature of chronic pancreatitisand is due to referred pain from the embryologicalforegut. Fibrosis and inflammation around the pan-creas may involve the coeliac plexus of autonomicnerves resulting from the chronic pain that may accom-pany this condition.
In 90 per cent of patients with chronic pancreatitisthere is a history of excessive alcohol intake. Howeverthe incidence of the disease is low, being approximately30 per 100000 in the United Kingdom. Onset is usuallyin middle age. The disease is approximately three timesmore common in males than females. Affected patientsare presumably susceptible to pancreatic damage byalcohol, although the genetic mechanism is poorlyunderstood. Rare autosomal dominant inherited formsof the disease have been described. Most alcoholicpatients already have sustained permanent structuraland functional damage to the pancreas by the time oftheir first attack of abdominal pain. Moreover the mor-phological changes seen in chronic pancreatitis areevident at post mortem examination in many alcoholicswho had no symptoms of pancreatic disease during life.Asymptomatic alcoholics often exhibit abnormalexocrine function when subjected to the secretin test.
It is not precisely known how alcohol causes chronicpancreatitis. It may promote pancreatic duct obstruc-tion through causing precipitation of proteins that aresecreted by the pancreatic tissue.
are illustrated in Figure 5.6. The initial intracellularstep involves the reaction of CO2 and water. SecretedH+ ions react with HCO3
- ions in the blood perfusingthe gland and this generates CO2, some of which dif-fuses into the duct cell. More than 90% of the HCO3
-
in pancreatic juice is derived from blood CO2. In thecell the CO2 combines with intracellular water to gen-erate carbonic acid, in a reaction which is catalysed bycarbonic anhydrase II, an enzyme present in the cen-troacinar and upper duct cells. The carbonic acid dis-sociates to give HCO3
- and H+. Whilst bicarbonate isbeing secreted the partial pressure of CO2 (pCO2) in thecells is lower than in the blood as it is being used upin the production of HCO3
- ions, and the higher therate of secretion the greater the downhill gradient fordiffusion of CO2 into the cell. The HCO3
- ions are
secreted from the luminal membrane by Cl-/ HCO3-
exchange, and the H+ ions are secreted into the blood.Thus for every HCO3
- ion that is secreted into the ductlumen one H+ ion is secreted into the blood. Thereforethe blood flowing through the pancreas becomes tran-siently acid when it is secreting HCO3
-. The H+ ions inthe blood help to neutralise the ‘alkaline tide’ pro-duced during a meal by the secreting stomach (seeChapter 3), by combining with plasma HCO3
- toproduce CO2. In post-surgical conditions where thepatient has been provided with a draining pancreaticfistula, the pancreatic juice drains to the outside andthe patient incurs considerable losses of HCO3
-. A pan-creatic fistula that is in direct communication from themain pancreatic duct to the skin does not contain sig-nificant quantities of activated enzymes. However ifthe fistula communicates from the duodenum to theskin then the digestive enzymes are active and cancause a significant amount of skin excoriation anddamage. This will result in considerable managementproblems until the fistula closes. Loss of HCO3
- resultsin a metabolic acidosis. This is usually compensatedfor by renal and respiratory mechanisms. Fluid andelectrolyte losses, however, can be more difficult tomanage because the patient may have a restricted oral intake. Replacement via intravenous infusion isnecessary.
The exchange mechanism in the centroacinar andupper duct cells, whereby HCO3
- is secreted inexchange for Cl-, obviously depends on the presenceof Cl- in the fluid in the lumen. Cl- ion flux out of the cell into the lumen is via a chloride conductancechannel known as the cystic fibrosis transmembraneconductance regulator (CFTR) which is regulated bycyclic AMP. Immunocytochemical studies using fluo-rescent antibodies against the CFTR have shown thatit is localised to the apical region of centroacinar andintralobular duct cells. The CFTR is coupled to theHCO3
-/Cl- exchanger. Failure of this secretory mecha-nism is seen in cystic fibrosis (see below). It results ina high concentration of protein in the pancreatic ductswhich can block the lumen. This results in secondarypancreatic damage; a process similar to that whichoccurs in chronic pancreatitis.
The Cl- channel is present in clusters in the apicalplasma membranes. When the gland is stimulated (by secretin or by an increase in cAMP), the channelclusters disaggregate (see Fig. 5.6) increasing thenumber of open channels. The channel is regulated intwo ways: i) via phosphorylation and dephospho-rylation by protein kinase A and a phosphatase re-spectively, which serves as a molecular switchinvolved in the gating of the channel, and ii) via acti-vation of the channel by hydrolysis of ATP and othernucleotides.
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Lumen of ductResting duct cell
Aggregates of CFTR(Cl- channels)
Tubulovesicleswith H+ pumps
Stimulation of duct cell(increase in intracellular cAMP)
Disaggregation andactivation of CFTR
Tubulovesicles move tothe basolateral membrane
Secreting duct cell
Secretion of HCO3- in
exchange for Cl- via CFTRsat the luminal membrane,
i.e. HCO3- Cl-
Secretion of H+ via the pumpswhich have fused with the
basolateral membrane
H+ + HCO3-
H+
H+ + HCO3-
CO2 + H2O
c.a.
CO2
HCO3- Cl-
Cl-
Fig. 5.6Cellular mechanisms involved in the production of HCO3
- and H+ in a duct cell. c.a., Carbonic anhydrase.Based on a diagram from ‘Gastroenterology’, Raeder M. G., London: WB Saunders, 1992.
Variation in composition with rate of flow
The bicarbonate concentration in the pancreatic juicethat enters the duodenum ranges from 25 to 150mM.The electrolyte composition of the juice varies with theflow rate. Figure 5.7 shows the changes in concentra-tions of HCO3
- and Cl- ions with increasing rates offlow. There is a reciprocal relationship between theconcentrations of the two ions. The concentration ofHCO3
- increases with increasing flow rate and the con-centration of Cl- decreases. The sum of the concentra-tions of the two ions is kept constant by the action ofthe ion exchange pumps. As the HCO3
- concentrationincreases, the juice becomes more alkaline.
The changes in the ionic composition of the juicewith rate of flow are due to the presence of transportsystems in the membranes of the duct cells. Theprimary alkaline juice secreted at the tops of the ductsis modified as it passes down the ducts by transportsystems in the cells lower down in the extralobularducts, and in the main ducts. At high flow rates thetime the juice spends in contact with the cells is notsufficient for appreciable modification via HCO3
-/Cl-
exchange and other processes to take place. Thereforethe composition of the juice produced at high flowrates resembles that of the primary secretion moreclosely than juice secreted at low flow rates.
The main features of the ion transport relationshipsin the pancreatic duct cell are shown in Figure 5.6. Ithas been observed, using electron microscopy, thatwhen the cell is not being stimulated it contains nu-merous tubulovesicles in its apical cytoplasm. Themembranes of these vesicles contain proton pumpswhich are ATPases. When the cell is stimulated, thetubulovesicles are translocated to the basolateralsurface and their membranes fuse with the basolateralplasma membrane. Thus the proton pumps are incor-porated into the membrane. Then H+ ions are activelypumped out of the cell into the interstitial fluid in thelateral spaces, and from there they diffuse into theplasma. Electron microscope studies have shown thatstimulation of secretion involves a change in the shapeof the cell. This is associated with expansion of thebasolateral plasma membranes as the membrane of thevesicles fuse with it. The fusion of the membranes is anactive process that derives its energy from the break-down of ATP which is catalysed by the ATPase of thepumps.
Cl- ions are secreted by the cells into the lumen viathe CFTR (see above). Na+ and K+ ions reach the pan-creatic juice by the paracellular route (between thecells), travelling down the electrochemical gradient.Water flows down the osmotic gradient (created by theion transport) either transcellularly or paracellularly,from the lateral spaces. A Na+/K+-ATPase pump in thelateral borders of the cell transports Na+ out of the celland this maintains a low intracellular concentrationand high extracellular concentration of Na+ ions. ANa+/H+ exchange mechanism also operates at thebasolateral pole of the cell to keep the intracellular pHstable, but this mechanism is probably not activatedduring secretion.
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160
120
80
40Con
cent
ratio
n (m
mol
/L)
0
Secretion rate (g/10 min)0 0.2 0.4 0.6 0.8 1.0 1.2
Cl-
HCO3-
Fig. 5.7Variation in the composition of pancreatic juice withrespect to Cl- and HCO3
-, with rate of flow.
A
B
Fig. 5.8Plain abdominal X-ray taken from a baby with cysticfibrosis. The meconium stool has obstructed the boweland can be seen in the caecum (A). The proximal smallbowel loops have dilated (B) and are filled with gas.
Cystic fibrosis
In the autosomal recessive inherited disorder known ascystic fibrosis the biochemical lesion is a defect in cyclicAMP-regulated chloride conductance via the CFTR.The defect is manifest in epithelial cells of the wet sur-faces of the gastrointestinal tract, the respiratory tract,the reproductive tract, and the sweat glands. In thepancreas the defect in the CFTR is associated withdefective secretion of bicarbonate and water. This leadsto the formation of inspissated protein plugs whichobstruct the proximal intralobular ducts. Reduced fluidsecretion in the gastrointestinal tract results in mucousplugging of the intestinal lumen, and, in severe neona-tal cases, gastrointestinal obstruction can develop. Thisis known as meconium ileus (Fig. 5.8). The sameprocess of mucous plugging results in blockage of thebronchioles. This leads to recurrent respiratory infec-tion and, later to respiratory failure.
Pancreatic enzymes
The enzymes released from the pancreatic acinar cellscomprise the major enzymes involved in the digestionof foodstuffs. Many of these are secreted as inactiveprecursors. The acinar cells contain zymogen granules,
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which are the locus of storage of enzyme or enzymeprecursor protein. The enzyme precursors producedby the acinar cells include those of the proteolyticenzymes, trypsin, chymotrypsin, carboxypeptidaseand elastase, and that of phospholipase A. Lipase, a-amylase, ribonuclease, and deoxyribonuclease aresecreted as active enzymes. The release of enzymes asinactive precursors ensures that the activated enzymesdo not autodigest the pancreatic tissue.
Secretion of enzymes and precursors: cellular mechanisms
The mechanism of secretion in the acinar cell is illus-trated in Figure 5.9. This scheme was first discoveredby Palade in the 1970s. He was awarded a Nobel prizefor the work. The enzymes or precursors are synthe-sised on the rough endoplasmic reticulum of the cell.The molecules are then released into the cisternae of theendoplasmic reticulum. Buds containing the enzymesor enzyme precursors break off the cisternal mem-branes and the buds coalesce in the region of the Goljicomplex to form ‘condensing vacuoles’. The vacuolesmigrate towards the luminal membrane. If the cells arestained for zymogen the vacuoles can be seen to bemore and more densely stained as they approach the
Zymogen granule
Release of enzymes
Lumenof acinus
Luminalmembrane
Condensing vacuole
Bud coalescingclose to Golgi
complex
Bud containing zymogen
Golgicomplex
Rough endoplasmic reticulum
Bud
Cisternae
Fig. 5.9Mechanism of enzyme secretion in the acinar cell.
surface. At the luminal membrane the membraneswhich surround the ‘zymogen’ granules fuse with thecell membrane and the vesicles break open to releasetheir contents, a process known as exocytosis. The dif-ferent enzymes are packaged together in each zymogengranule and they are probably released together in con-stant proportions. The zymogen granule membrane israpidly recycled from the surface membrane.
It is exocytosis, rather than the synthesis or seques-tration of the enzyme proteins which is under physio-logical control by hormones and neurotransmitters.Exocytosis is triggered by an increase in intracellularCa2+. The rise in intracellular Ca2+ when the cell is stimulated is via influx from the extracellular spaces or release from intracellular stores.
Activation of enzyme precursors
The enzyme precursors secreted by the acinar cells areactivated in the lumen of the duodenum and jejunum.Trypsinogen is converted to trypsin plus a shortpeptide, in a reaction catalysed by enterokinase, anenzyme present in the brush border of the epithelialcells of the small intestine. Once a small amount of acti-vated trypsin has been formed it can catalyse the con-version of more trypsinogen to trypsin. Trypsin is apowerful proteolytic enzyme which can convert chy-motrypsinogen, procarboxypeptidase, proelastase andprophospholipase A to their activated forms. Thusonce a small amount of trypsin is formed a catalyticchain reaction occurs (Table 5.1).
Acute pancreatitis
Acute pancreatitis is a disease in which the pancreatictissue is destroyed by digestive enzymes. The physio-logical mechanisms underlying acute pancreatitis areincompletely understood. They probably involveabnormal release of enzymes (into the ducts) wherethey become activated in some way. The consequenceof this is autodigestion of the pancreatic tissue.
The pancreas normally secretes a polypeptideknown as Kazal inhibitor, that inhibits any smallamounts of activated trypsin which may find its wayinto the ducts, by complexing with it. Another factor,enzyme Y, which is activated by traces of active trypsindegrades zymogen, exhibiting a protective function.The alkaline pH (8.0–9.5) and low Ca2+ concentration inpancreatic secretions promote the degradation ratherthan the activation of trypsinogen. In acute pancreati-tis activated trypsin and other enzymes are present inthe ducts of the pancreas. Trypsin then proteolyticallyactivates more trypsinogen and other proteolyticenzyme precursors (chymotrypsinogen, proelastase,and procarboxypeptidase) and prophospholipase A.
The active enzymes digest the pancreatic tissue.When the walls of the acini on the surface of the pan-creas are digested, the enzymes leak into the abdomi-nal cavity and a generalised peritonitis results. In 5%of cases the condition is extremely serious and theblood vessels are digested by pancreatic elastase withthe formation of a haematoma. This haematoma is alsodigested by the enzymes and ischaemia results. Thecondition is then known as haemorrhagic necrotisingpancreatitis which has an 80% mortality rate.
It is not known how activated digestive enzymesappear in the pancreatic ducts in acute pancreatitis, butit may be due to reflux of intestinal chyme containingactivated enzymes, into the pancreatic duct. The con-dition is often associated with the presence of gall-stones in the bile ducts. Ultrasonography maydemonstrate gallstones or a swollen pancreas (Figs5.10 and 5.11, page 86). It is likely that small gallstoneslodge at the ampulla of Vater and splint the sphincterof Oddi. This process may allow duodenal juice con-taining activated enzymes to reflux into the pancreaticduct.
The diagnosis of acute pancreatitis depends on thepresence of high concentrations of a-amylase in theblood. This occurs because this enzyme, together withothers, leaks from the necrotic tissue into the blood. a-Amylase is also high in the urine because it is not reab-sorbed adequately in the tubules. Hypocalcaemia mayalso be present. This is partly due to loss of albumen,with bound Ca2+, in the protein-rich exudate. This exu-dation also causes a rise in the haematocrit due to lossof plasma.
Control of secretion
The control of the exocrine secretion of the acinar and duct cells of the pancreas is via peptides such asthe hormones secretin and CCK, and somatostatinwhich acts mainly as a paracrine factor, and via neurotransmitters.
Hormonal control
The major hormones involved in stimulating secretionare secretin, which stimulates the secretion of the alka-line aqueous component, and cholecystokinin (CCK)which stimulates the secretion of the enzyme compo-nent. These hormones are produced by the APUD cellsin the duodenal mucosa (see Chapter 1) in response tofood constituents in the duodenal chyme (see below).As secretion of the two components of pancreatic juiceis controlled by separate regulatory mechanisms, thecomposition of the juice entering the duodenum can
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Chronic pancreatitis Box 3
Impairment of functions
Both exocrine and endocrine secretions of the pancreasare impaired in chronic pancreatitis.
The blockage of the secretory ducts and loss of acinartissue leads to a decrease in secretion of both alkalinejuice and enzymes. The low alkaline secretion from thepancreas in chronic pancreatitis leads to i) impairedenzyme activity which results in malabsorption andweight loss, ii) impaired micelle formation which leadsto steatorrhoea (high fat content in the stools), iii) insome cases duodenal ulceration, a consequence of thehigh acidity.
Destruction of islet tissue in chronic pancreatitis canlead to decreased secretion of the hormones insulinand glucagon, both of which are involved in the controlof glucose metabolism. Insulin lowers the blood glucoseby increasing the uptake of glucose into tissues (seeChapter 9), whilst glucagon increases blood glucose bystimulating glucose release from the liver. Thus the twohormones have opposite effects on blood glucose con-centration. Insulin is normally released from the pan-creas in response to an increase in blood glucose duringa meal.
The glucose tolerance test measures the insulinresponse to ingestion of a glucose solution (100gglucose in 100ml of water). It involves measuring theblood glucose levels at intervals after the glucose load.The insulin response is impaired early in chronic pan-creatitis: the time taken for the blood glucose to returnto normal is prolonged due to hormone insufficiencycaused by damage to the islet tissue. Early in the courseof the disease, the rise in plasma glucose may stillappear normal because there is a concomitant impair-
ment of glucagon release from the pancreas. However,overt diabetes eventually develops in many patientswith chronic pancreatitis. Some develop hypoglycaemiaafter their regular insulin injection owing to a combi-nation of glucagon deficiency, their irregular eatinghabits (often due to the continuous pain), and malnu-trition. Brittle diabetes is sometimes seen after totalpancreatectomy and in chronic pancreatitis. This is pre-sumed to be due to the severe impairment of glucosemetabolism resulting from the loss of both insulin andglucagon function.
Epigastric pain that radiates through to the centre ofthe back is a common feature of chronic pancreatitis.It occurs because of damage to the pancreas itself, andinflammation or fibrosis of the surrounding tissue (seeCase history, page 80).
Chronic progressive jaundice may also be seen inchronic pancreatitis. This is due to fibrosis around the lower end of the common bile duct as it passesthrough the head of the pancreas. The fibrosis preventsthe access of bile to the small intestine and results in a raised serum bilirubin because of reflux of bile constituents into the systemic circulation. Raised serum alkaline phosphatase is also seen as this enzymeis released by damaged cells lining the biliary tree. In chronic pancreatitis, however, there may also becoexisting alcoholic liver disease. This makes it dif-ficult to determine whether the jaundice is primar-ily due to disease of the pancreas or to underlying cirrhosis of the liver. A liver biopsy and histologicalassessment of the tissue may be required in this circumstance.
Table 5.1Activation of enzyme precursors in the small intestine
Precursor Active enzyme
enterokinase, trypsinTrypsinogen trypsin + peptide
trypsinChymotrypsinogen chymotrypsin + peptide
trypsinProelastase elastase + peptide
trypsinProcarboxypeptidase carboxypeptidase + peptide
trypsinProphospholipase A phospholipase A + peptide
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Octreotide is an octapeptide which contains thetetrapeptide sequence which is known to be essentialfor somatostatin activity. Somatostatin itself, wheninjected, has a short half life (less than 4 minutes).However, octreotide injected subcutaneously, has ahalf life of approximately 100 minutes and its action istherefore relatively long-lasting. This is important inthe clinical setting as somatostatin is only effective ifgiven as a continuous infusion, whereas analoguessuch as octreotide are effective if given as a bolus twoor three times per day.
Nervous control
The nervous control of pancreatic secretion is via bothparasympathetic and sympathetic nerves. Stimulationof cholinergic fibres in the vagus nerve enhances therate of secretion of both enzyme and alkaline fluid.Stimulation of the sympathetic nerves inhibits secre-tion, mainly by reducing the blood flow to the gland(via vasoconstriction of the arterioles) which decreasesthe volume of juice secreted. However, stimulation ofthe sympathetic nerves to the pancreas depresses theenzyme content of the secretion as well as the volumeof juice secreted.
Control of secretion during a mealThe control of the secretion of pancreatic juice duringa meal depends on the volume and composition of thefood. Ingested material present at different locations
BA
C
D
C
Fig. 5.11CT scan of the same patient as Fig. 5.10, showing thecalcified stone at the lower end of the common bileduct (A) lying within a swollen head of the pancreas(B). The kidneys (C) and spleen (D) are also visible.
vary with respect to its enzyme protein content. It cancontain between 1% and 10% protein.
CCK and gastrin compete for the same receptor onthe acinar cell. CCK, gastrin and acetylcholine allincrease enzyme protein synthesis and secretion via i)increase in phosphatidylinositol turnover and ii)increase in intracellular Ca2+ concentration (Fig. 5.12).Secretin and VIP act on the acinar cell to increase theintracellular levels of cAMP. This increase in cAMP bysecretin and VIP potentiates the effect of CCK, gastrinand acetylcholine. Thus the enzyme secretion isgreater when the two types of secretogogue are actingtogether.
SomatostatinSomatostatin, which is present in D cells in the isletsof Langerhans of the pancreas, is a powerful inhibitorof pancreatic secretion. It acts in a paracrine manner toinhibit the release of the exocrine alkaline and enzymesecretions, as well as the pancreatic hormones insulinand glucagon. In addition it inhibits the release of anumber of gastrointestinal hormones, including CCK,secretin, and gastrin. Circulating somatostatin prob-ably augments the actions of the locally releasedhormone. It originates from a number of sites in thebody, including various locations in the gastrointesti-nal tract. Pancreatic somatostatin is predominantly the teradecapeptide form, S-14. The release of thishormone is stimulated by CCK, gastrin and secretin.
Analogues of somatostatin such as octreotide areused clinically to inhibit pancreatic enzyme secretionin acute pancreatitis, and following pancreatic surgery.
BA
Fig. 5.10Ultrasound scan of the bilary tree, showing a calcifiedstone in the common bile duct (A) which is dilatedaround the stone. The adjacent gallbladder is also seen(B).
within the gastrointestinal tract affects the control ofthe secretions in different ways. The control during ameal can accordingly be divided into three phases (seeChapter 1) according to the location of the food orchyme; i) the cephalic phase, due to the approach of food or the presence of food in the mouth, ii) the gastric phase, when food is in the stomach, and iii)the intestinal phase when food material is in the duodenum.
Cephalic phaseThe sight and smell of food, or other sensory stimuliassociated with the impending arrival of food, elicitincreased pancreatic secretion via a ‘conditioned’reflex. The presence of food in the mouth stimulatessecretion via a ‘non-conditioned’ reflex. The controlduring this phase is therefore nervous. It is mediatedby impulses in cholinergic fibres in the vagus nerve.The juice secreted is mainly the enzyme-rich secretion,containing very little HCO3
-.In response to vagal stimulation, the acinar cells also
secrete kallikreins, which catalyse the production ofbradykinin, a vasodilator. This results in increasedblood flow to the pancreas, and increased volume ofsecretion. The mechanism involved in this effect issimilar to that which occurs in the control of salivarysecretion which is described in Chapter 2.
Gastric phaseThe presence of food in the stomach stimulates thesecretion of pancreatic juice via a hormonal mecha-nism. Activation of chemoreceptors in the walls of thestomach by peptides, and the activation of mechano-receptors, causes the release of the hormone gastrinfrom G cells, into the local circulation. Stimulation ofcholinergic nerves is also involved in this phase ofcontrol. During the gastric phase the secretion of boththe enzyme-rich and the alkaline components of pan-creatic juice is increased.
Intestinal phaseThe intestinal phase of control is probably the mostimportant phase of the response to food. Food mater-ial in the duodenum stimulates both the alkaline andthe enzyme-rich components of pancreatic juice. Thealkaline component of pancreatic juice is secreted inresponse mainly to acid in the duodenal contents. Acidstimulates the release of secretin from APUD cells inthe walls of the intestine and this hormone stimulatesthe duct cells to secrete the alkaline fluid. This is a feed-back control mechanism which helps to control the pHof the duodenal contents.
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Increasedenzymesecretion
Increase inPI turnoverACh
CCKgastrin
SecretinVIP
+
+
M
CCK-A
VIP
Increase inCa2+
Increase incAMP
Fig. 5.12Cellular mechanisms of control in the acinar cell. M,muscarinic receptor; PL, phosphatidylinositol.
Chronic pancreatitis Box 4
Physiological consequences, treatment and management
The main consequences of malabsorption and dia-betes mellitus are malnutrition and weight loss. Lackof alkaline secretion can lead to alkalosis because thealkaline tide in the blood which results from gastricacid secretion (see Chapter 3) is normally partiallyneutralised by an ‘acid’ tide which results from thesecretion of alkaline juice. However, in chronic pan-creatitis, the alkalosis is normally compensated byrespiratory and renal mechanisms.
Complications of chronic pancreatitis include pan-creatic necrosis, haemorrhage, acute pseudocysts,and pancreatic abcesses. Treatment is usually non-surgical in uncomplicated chronic pancreatitis. Theneed for complete abstention from alcohol is empha-sised. Pain relief is initially via aspirin treatment, andthen, if necessary, via opiates. Nutritional support inthe form of simple nutrients (amino acids, glucose,fatty acids) may be advised. Oral pancreatic extractcan be prescribed to replace the pancreatic enzymes.Usually the extract is enriched with lipase as thesecretion of this enzyme tends to decrease morerapidly than that of proteolytic enzymes. The enzymepreparation can be administered together withantacids or the anti-ulcer drug cimetidine to reducethe acid production by the stomach as this inactivatesthe enzymes. Alternatively the pancreatic enzymepreparation can be administered in the form of gran-ules within which the enzymes are enclosed in a pH-dependent polymer. The protective coating dissolvesonly when the pH is more alkaline than 6.0, i.e. notin the stomach but hopefully in the duodenum orupper jejunum.
The metabolic complications of diabetes are dis-cussed in Chapter 9. If diabetes is present it is treatedwith insulin.
Secretin exerts a permissive effect on the secretion ofenzymes; it does not stimulate enzyme secretion on itsown, but it enhances the effect of CCK. Likewise CCKexerts a permissive effect on the secretion of the alka-line fluid by secretin. Stimulation of the vagus nervecauses the release of mainly the enzyme-rich secretion,but if the vagi are sectioned, the alkaline secretionelicited in response to secretin is reduced by 50%,indicting a functional overlap between the effects ofvagal stimulation and secretin. Thus the vagal mecha-nism may enhance the effect of secretin.
The enzyme-rich juice is released during the in-testinal phase in response to fat and peptides in the food. The fats and peptides cause the release of CCK from the walls of the duodenum into the blood. CCK stimulates the acinar cells to secreteenzymes. Trypsin in the duodenum inhibits the release of enzymes via inhibition of CCK release. This is another feedback control mechanism, which limits the quantity of enzymes present in the intestines, and may have some protective function.
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Self-assessment case study: cystic fibrosis
A twelve-year-boy who was suffering from cystic fibrosis wastaken to the outpatient clinic for his regular checkup. Hiscondition had been diagnosed soon after birth and he hadboth pancreatic and respiratory tract involvement. He hadbeen asked to bring a sample of his stool. This was pale-coloured, poorly formed, and oily in appearance. It was sentto the laboratory for analysis to assess his pancreatic function.His exocrine pancreatic insufficiency was being treated with apancreatic enzyme preparation and the anti-ulcer drugcimetidine.
After studying this chapter you should be able to suggestthe answers to the following questions:
b What is the inherited defect in this condition?
c How is the defect manifest in the pancreas? Whatabnormalities of pancreatic function result from thispathology?
d Why is the child being treated with an enzyme preparation?What are the problems with having to give such apreparation by mouth. Why is the boy being treated withcimetidine? Would you expect enteric coated preparations
to be more effective than a powder? Would you expectbicarbonate by mouth to be helpful? Would you expect anyabnormalities in the acid bases status of this patient?
e Why was the boy’s stool pale-coloured? What tests wouldbe performed on the sample?
Self-assessment questions
b What exocrine cell types are present in the pancreas? Whatis the composition of each type of juice secreted?
c Can you describe the cellular mechanisms involved in thesecretion of alkaline pancreatic juice? How is the CFTRinvolved in this process?
d Can you describe the cellular mechanisms of secretion ofpancreatic enzymes? What part of this process is underphysiological regulation by hormones?
e How is the secretion of each component of pancreatic juicecontrolled by food in a) the mouth, b) the stomach, c) theduodenum?
