Exocrine pancreas
A gland that makes enough enzyme to digest a meal, or itself — so almost everything about it is a safety catch, and almost every disease here is a safety catch failing.
What it normally does
Acinar cells build the digestive enzymes and ship the protein-cutters out switched off (as zymogens, chiefly trypsinogen). They sit sealed in granules, are normally activated only in the duodenum by enteropeptidase (enterokinase) on the brush border, and any trypsin that fires early is mopped up by a built-in blocker (SPINK1) and by trypsin's own habit of cutting itself up.
Explains acute pancreatitis: the gland only digests itself when these safety catches are overwhelmed.
Duct cells pour out a watery alkaline juice. CFTR in the apical membrane conducts both chloride and bicarbonate, and the chloride it recycles into the lumen drives SLC26 chloride/bicarbonate exchangers, so bicarbonate ends up in the duct with water dragged osmotically behind it. This neutralises stomach acid and flushes the enzymes downstream before they can settle.
Explains why lipase fails in an acid duodenum, and why cystic fibrosis destroys the pancreas from the ducts inwards.
The duodenum runs the gland by hormone. Acid arriving triggers secretin from S cells, which calls for the bicarbonate juice. Fat and protein arriving trigger cholecystokinin (CCK) from I cells, which calls for the enzyme-rich juice — largely through vagal reflexes — and squeezes the gallbladder.
Explains why eating brings on the pain of chronic pancreatitis, and why a stone stuck at the shared outlet is a catastrophe.
There is enormous spare capacity, and fat is the weak link. Digesting fat depends almost entirely on pancreatic lipase, with only minor gastric lipase to fall back on, yet you must lose around 90% of output before fat appears in the stool (steatorrhoea).
Explains why exocrine insufficiency turns up late and quietly, and why greasy stool, not protein loss, is the first sign.
What goes wrong
- Acute pancreatitis← from “Acinar cells build the digestive enzymes and s…”
A gallstone jams at the ampulla and blocks the outflow, or alcohol makes acinar cells leaky and the duct juice thick and protein-rich. Either way, trypsinogen switches on inside the cell. The built-in inhibitor is swamped, active trypsin then activates every other zymogen, and the gland digests itself and the fat around it. Damaged acinar cells pour out cytokines, capillaries leak, litres of fluid move into the retroperitoneum, and the illness stops being local — that is where the organ failure comes from.
Diagnosis (revised Atlanta) is two of three: typical pain, lipase or amylase over 3x ULN, or characteristic imaging — so with the first two you do not need an early CT. Gallstones then alcohol are the two big causes in Australia, together about 70%. Enzyme height does not grade severity — persistent organ failure does. Ultrasound every case to look for stones, because in gallstone pancreatitis the definitive treatment is cholecystectomy, ideally on the index admission, not a drug.
You would find: Severe constant epigastric pain boring through to the back, better sitting forward, with vomiting. Serum lipase more than three times the upper limit of normal. Calcium may drop, because fat necrosis binds it into soap (saponification).
- Chronic pancreatitis← from “Acinar cells build the digestive enzymes and s…”
Injury that keeps happening — alcohol, smoking, repeated attacks, a genetic hit in the trypsin safety system. Stellate cells respond by laying down scar. The working gland is replaced by fibrosis, ducts stricture, protein plugs calcify inside them, and the nerves running through the scar become sensitised. You lose exocrine tissue and eventually the islets too.
The end state is a triad: pain, steatorrhoea, diabetes. That diabetes (type 3c) is brittle, because the alpha cells making glucagon are lost alongside the beta cells, so counter-regulation is impaired and hypoglycaemia comes easily. Alcohol is the commonest cause in Australia and smoking is an independent driver — stopping smoking is a real intervention. Hospitalisation rates for pancreatitis are several times higher in Aboriginal and Torres Strait Islander communities, sitting on top of higher rates of pancreatic cancer and of harmful alcohol exposure driven by dispossession and disadvantage rather than anything intrinsic.
You would find: Recurring epigastric pain, often worse after eating (food calls for CCK and a gland that cannot answer), weight loss, and calcification visible on CT. Diabetes arrives late.
- Exocrine pancreatic insufficiency← from “There is enormous spare capacity, and fat is t…”
Lipase output falls below roughly a tenth of normal. Triglyceride is largely left unsplit, so it cannot be absorbed. Unabsorbed fat travels to the colon where bacteria convert it to hydroxy fatty acids that draw water in and drive diarrhoea, and the fat-soluble vitamins A, D, E and K ride out with it because they were dissolved in the fat you failed to absorb.
Faecal elastase under 200 micrograms per gram supports it, under 100 makes it likely (a watery sample can give a falsely low result). Causes: chronic pancreatitis, cystic fibrosis, cancer in the pancreatic head, pancreatic resection. Treat with enzyme replacement at every meal plus fat-soluble vitamins — do not put the patient on a low-fat diet, which only worsens the malnutrition you are trying to fix.
You would find: Pale, greasy, foul, hard-to-flush stools and weight loss in someone who is eating. Faecal elastase-1 low. Low vitamin D, easy bruising from low vitamin K, night blindness from low vitamin A in severe or long-standing cases.
- Cystic fibrosis pancreatic destruction← from “Duct cells pour out a watery alkaline juice. C…”
Broken CFTR means duct cells cannot move chloride and bicarbonate into the lumen, so no water follows. The juice is thick, scanty and acidic. Enzymes stall in the ducts instead of being flushed to the duodenum, activate where they sit, and plug and destroy the gland — a process that starts before birth.
Roughly 1 in 2500 to 3000 Australian births; every newborn is screened, with a raised IRT taken on to genetic testing and a sweat test. The IRT screen works precisely because the ducts are obstructed. Genotype predicts phenotype — F508del homozygotes are almost all pancreatic insufficient. Bicarbonate failure matters twice over: no enzymes get out, and any enzyme you swallow as replacement meets an acid duodenum that will not dissolve its coating.
You would find: About 85% of people with CF are pancreatic insufficient, most of them already at diagnosis: greasy stools, failure to thrive despite a good appetite, and in some, meconium ileus at birth. Picked up on newborn screening by a high immunoreactive trypsinogen — the zymogen leaking backwards into the blood from a blocked gland.
What we give, and how it works
Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.
- Binds
- No receptor. The drug is the enzyme, and its substrate is the food: lipase hydrolyses triglyceride, protease cleaves peptide bonds, amylase cleaves starch.
- Which does
- The enteric coating on the granules holds in the stomach and dissolves once duodenal pH climbs above about 5.5. Lipase splits triglyceride into fatty acids and monoglycerides, which bile salts then carry in mixed micelles to the mucosa for absorption.
- So you see
- Stools firm up and lose the grease and the smell. Weight goes on, children grow, and fat-soluble vitamin levels improve.
- And the same mechanism causes
- The dose is counted in lipase units and the action is local, so the harm is local and dose-related: sustained very high daily lipase doses have been associated with scarring and stricture of the right (ascending) colon — fibrosing colonopathy — first described in children with cystic fibrosis, which is why total daily lipase is kept within recommended limits. Protease left sitting on skin digests skin, hence perioral and perianal irritation when granules are held in the mouth or the powder is not swallowed promptly.
- Handling
- Take with food, starting with the first mouthfuls; for a large or slow meal the dose is split across it so enzyme leaves the stomach alongside the food. Capsules may be swallowed whole or opened and the granules sprinkled on a small amount of acidic soft food (for example apple puree) and swallowed straight away — but the granules themselves must never be crushed or chewed, because the coating is the only thing standing between the lipase and gastric acid. It is porcine, which some patients need told.
Catches people out: It replaces digestion and little else. It is not reliable analgesia for the pain of chronic pancreatitis and it does nothing for the diabetes.
- Binds
- The H+/K+ ATPase (proton pump) on the canalicular membrane of the gastric parietal cell.
- Which does
- The drug is a weak base that concentrates in the acid canaliculus, converts there to its active sulfenamide and covalently blocks the pump. The cell has to build new pumps to recover, which is why one dose lasts far longer than the drug stays in blood.
- So you see
- Gastric and then duodenal pH rise. The coated granules open where they should, lipase survives the trip, stool fat falls and the same enzyme dose suddenly works.
- And the same mechanism causes
- What follows directly from removing acid is malabsorption of the nutrients whose uptake depends on it: acid and pepsin free vitamin B12 from food protein, and acid keeps iron in the more absorbable ferrous form and dissolves calcium salts, so long-term use is associated with lower B12 and iron and with a small excess of fracture. Hypomagnesaemia is also well described but does not follow from solubility — it appears to reflect impaired active TRPM6/7-mediated magnesium uptake in the gut, so it is a recognised class effect to remember rather than something you can derive from the acid story.
- Handling
- Take it before the meal; it only blocks pumps that are actively secreting.
Catches people out: Acid is also the barrier that sterilises the upper gut. Losing it raises rates of Clostridioides difficile and campylobacter, and of small intestinal bacterial overgrowth — which causes a diarrhoea easily mistaken for the insufficiency you were treating.
- Binds
- The mu opioid receptor, a Gi-coupled receptor on dorsal horn neurones and in the descending pain-control pathways of the midbrain and brainstem.
- Which does
- Gi coupling drops cAMP, opens potassium channels and closes calcium channels. The neurone hyperpolarises and releases less transmitter, so the pain signal climbing to the brain is turned down.
- So you see
- Pain settles. The patient stops splinting the diaphragm, can take a deep breath, cough and mobilise — which is how you avoid the atelectasis and pneumonia that follow a rigid abdomen.
- And the same mechanism causes
- The identical mu receptor sits on the myenteric plexus in the gut wall and quietens those neurones the same way — motility falls and constipation is near-universal, not an idiosyncrasy. In the brainstem the same receptor blunts the ventilatory response to rising CO2, and that is what kills in overdose.
- Handling
- Expect the constipation and address it from the start rather than waiting for it.
Catches people out: Morphine does raise sphincter of Oddi pressure, but the old teaching that this worsens pancreatitis has never translated into worse clinical outcomes, and trials show no harm from opioids here. Do not withhold analgesia on the strength of it.
- Binds
- The mutant CFTR protein. Correctors (elexacaftor, tezacaftor) bind at distinct sites and act while the protein is still folding in the endoplasmic reticulum; the potentiator (ivacaftor) binds the channel at the membrane.
- Which does
- Correctors help the misfolded F508del protein fold and traffic to the cell surface instead of being degraded. Ivacaftor increases the channel's open probability, so chloride and bicarbonate actually flow out, and water follows them.
- So you see
- Duct secretions thin and turn alkaline again, sweat chloride falls, lung function and weight improve. In infants treated before the gland scars there is emerging evidence that exocrine function can be preserved — faecal elastase may stay normal — but this is prevention, not repair.
- And the same mechanism causes
- Two things to hold apart. Directly mechanistic: CFTR is not a pancreas-only protein — the same channel sits in airway, sweat duct, intestinal and biliary epithelium, so the drug's effects are body-wide, not organ-selective. Not mechanistic: transaminase rise and, rarely, serious drug-induced liver injury is the common practical problem, and cataracts have been reported in children on ivacaftor-containing regimens. Neither is derivable from CFTR biology — they are off-target findings, which is exactly why liver enzymes are monitored on treatment and children have ophthalmological review.
- Handling
- All three components are CYP3A4 substrates, so strong inducers (rifampicin, carbamazepine, St John's wort) and strong inhibitors matter a great deal.
Catches people out: A pancreas already replaced by fibrosis does not come back. Those patients still need enzyme replacement for life.
Order lipase, not amylase: amylase falls back to normal within about three to five days and also rises with a perforated ulcer, a bowel infarct or an inflamed parotid. And faecal elastase stays low even while the patient is taking Creon — the assay uses a monoclonal antibody specific for human elastase-1 and is blind to pig enzyme — so you never stop the capsules to do the test.
Now test whether it stuck
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