Acute Pancreatitis: Acute Pancreatitis: From Acinar Cell to Severity

0:00Welcome to Board Pearls. This is episode one of three of the Acute Pancreatitis chapter, in the Pancreatic and Biliary Disease module. This episode takes acute pancreatitis from the acinar cell to the call on severity. A woman with epigastric pain and gallstones shows what goes wrong inside the pancreas, why patients can worsen after admission, how the diagnosis is made without a computed tomography, CT, scan on day one, and why lipase is the better enzyme. A man with milky blood shows how very high triglycerides can hide the diagnosis and how they cause it. A man with a first attack and no obvious cause shows the rest of the workup, from drugs and calcium to the tumor that has to be excluded after forty. And a man whose hematocrit won't fall shows how severity is defined, which scores help and which don't, the bedside markers that matter most in the first day, and when the CT finally earns its place. Two last women show who can be expected to do well.

0:59Here's the first patient. A forty-six-year-old woman has had six hours of steady, severe epigastric pain going through to her back. She's vomited several times, and eating made it worse. Her epigastrium is tender and her bowel sounds are quiet. Her lipase is five times the upper limit of normal, her ultrasound shows gallstones, and her alanine aminotransferase, ALT, is two hundred forty. She drinks a glass of wine on weekends and takes no regular medicines. The emergency physician has ordered a contrast CT to confirm the diagnosis.

1:32Steady epigastric pain through to the back, vomiting, a lipase five times normal, gallstones, and a raised ALT add up to acute gallstone pancreatitis, and the CT won't add anything. Acute pancreatitis is premature activation of trypsinogen to trypsin inside the acinar cell. Trypsin then activates the rest of the digestive enzymes, chymotrypsinogen, proelastase, prophospholipase A2, and procarboxypeptidase, before they ever reach the duodenum, and the gland starts to digest itself.

2:07Her trigger is a stone at the ampulla, which raises ductal pressure and forces bile or pancreatic juice back toward the acinus. Other causes start differently. Alcohol sensitizes the acinar cell and impairs how its enzymes are packaged, high triglycerides deliver free fatty acids that injure the cell membrane and disturb calcium signaling, and hypercalcemia raises calcium inside the cell directly. But the final pathway is shared. A sustained rise in cytosolic calcium brings zymogen granules together with lysosomal enzymes, especially cathepsin B, which activates trypsinogen inside the cell, and the autodigestion spreads to the tissue around the pancreas. SPINK1 and the pancreas's own trypsin inhibitor normally stop this cascade, which is why more than ninety-five percent of heavy drinkers never get pancreatitis.

2:57She may get worse after admission, and the reason is systemic. Escaped trypsin activates nuclear factor kappa B. Dying acinar cells release danger signals that recruit neutrophils and macrophages, and tumor necrosis factor alpha and interleukins one, six, and eight drive a systemic inflammatory response. Capillary leak moves fluid into the retroperitoneum, the gut wall, and the lungs, and circulating volume falls. As the pancreatic microcirculation fails, ischemia and reperfusion injury can turn edematous pancreatitis into necrotizing pancreatitis, and that takes seventy-two to ninety-six hours to show on CT, because the gland has to lose perfusion long enough for the non-enhancement to be visible.

3:42The same cascade explains what's watched at the bedside. It produces hemoconcentration with a rising hematocrit and blood urea nitrogen, BUN, persistent systemic inflammation, acute kidney injury, acute respiratory distress syndrome, hypotension, and hypocalcemia from saponification, as free fatty acids in fat necrosis bind calcium into soaps. Cullen sign, bruising around the umbilicus, and Grey-Turner sign, bruising in the flank, are uncommon. They mean retroperitoneal hemorrhage from vessels eroded by enzymes, with blood tracking along fascial planes, and they imply severe disease with a poor prognosis. The first forty-eight to seventy-two hours are when fluids, the severity assessment, and finding biliary obstruction with cholangitis change outcomes.

4:29Her diagnosis meets the formal criteria. The Revised Atlanta Classification requires two of three. The first is characteristic upper abdominal pain, typically epigastric, often radiating to the back, peaking within minutes to hours, and worse with eating, because food stimulates the pancreas further. The second is a lipase or amylase over three times the upper limit of normal. The third is characteristic findings on CT or magnetic resonance imaging, such as an enlarged gland, stranding around it, or fluid collections. The pain is steady rather than colicky, radiates to the back in about half, and comes with nausea, vomiting, and loss of appetite, with quiet bowel sounds from peritoneal irritation and ileus. Her pain and her lipase make two of three.

5:15So the CT should be cancelled. Imaging is reserved for diagnostic uncertainty, meaning an atypical presentation or enzymes below the threshold, for failure to improve at forty-eight to seventy-two hours, and for suspected complications. A routine CT before seventy-two hours misclassifies severity, because a gland that enhances normally on day one can be completely non-perfused forty-eight hours later. Her ultrasound was the right test.

5:42Her lipase was the right enzyme to measure. Lipase is more specific to the pancreas, rises within four to eight hours of injury, and stays elevated for eight to fourteen days. Amylase falls within three to five days and also rises with parotitis, tubo-ovarian disease, macroamylasemia, and renal failure, so a patient who presents late may have a normal amylase and a raised lipase. How high either enzyme goes reflects how much was released, not the inflammatory cascade that drives organ failure, so it doesn't predict severity. The hematocrit, BUN, blood pressure, oxygenation, creatinine, and calcium are followed instead.

6:20The second patient shows when the enzymes can't be trusted. A thirty-nine-year-old man has severe epigastric pain radiating to his back. His blood is visibly milky, his sodium is reported low, and his lipase and amylase are normal. Severe hypertriglyceridemia interferes with the colorimetric enzyme assays and can produce falsely normal values, and lipemic serum with pseudohyponatremia are the clues. His clinical picture is still diagnostic, but with the enzymes unable to supply the second criterion, imaging earns its place: his CT shows a swollen pancreas with stranding around it, and his triglycerides are two thousand four hundred.

6:59With the diagnosis made, the cause decides what has to happen before discharge, and the search starts with the two common ones. Gallstones cause forty to fifty percent of acute pancreatitis and alcohol twenty-five to thirty-five percent. A right upper quadrant ultrasound is mandatory at presentation in every patient, because gallstones mean cholecystectomy during the same admission, which is covered in episode two. An ALT over one hundred fifty, three times normal, carries a ninety-five percent positive predictive value for gallstone pancreatitis, so with her stones, her ALT of two hundred forty makes the cause clear. Transabdominal ultrasound is poorly sensitive for distal common bile duct stones, so suspected persistent obstruction or cholangitis despite a non-diagnostic ultrasound calls for magnetic resonance cholangiopancreatography, MRCP, or endoscopic ultrasound, EUS. Her normal bilirubin and lack of fever show neither. Chapter twenty-seven covers gallstone disease.

8:02Her weekend wine doesn't explain her attack. Alcohol-induced pancreatitis needs more than five years of moderate to heavy drinking, typically over fifty grams a day, and even then fewer than five percent of heavy drinkers develop it, because alcohol sensitizes the acinar cell to injury rather than causing it alone. Smoking and the CLDN2 gene locus modify the risk. A heavy drinker still gets an ultrasound, and a heavy drinker with gallstones needs both a cholecystectomy and treatment of the drinking.

8:33The man's triglycerides explain his attack. Hypertriglyceridemia is causal above one thousand milligrams per deciliter, with clinically significant risk often quoted at two thousand. Causes include uncontrolled diabetes with severe hyperglycemia, familial chylomicronemia, alcohol, and medicines, namely estrogens, thiazides, and tamoxifen. His glucose is four hundred twenty, and he's never been told he has diabetes. Acute treatment is fasting for at least twenty-four hours plus an insulin drip, because insulin upregulates lipoprotein lipase and speeds the clearance of triglyceride from chylomicrons. His fasting triglycerides are rechecked four to six weeks after the attack, because the pancreatitis itself can raise them transiently. For familial chylomicronemia syndrome, two drugs that silence APOC3 are now approved by the Food and Drug Administration, olezarsen in December twenty twenty-four and plozasiran in November twenty twenty-five. They lower triglycerides sharply and reduced pancreatitis events in their trials.

9:35The third patient has neither common cause, and his workup shows what's left to find. A fifty-two-year-old man has a first attack. He doesn't drink, his ultrasound shows no gallstones, and his triglycerides are normal. His medicine list is the next place to look. The strongest evidence supports didanosine, azathioprine, and six-mercaptopurine. Azathioprine causes an idiosyncratic reaction four to eight weeks after it's started, specific to the drug rather than its class, with rapid recurrence on rechallenge, so it's stopped and not restarted. Valproate and didanosine are thought to act through toxic metabolites, and thiazides and tamoxifen through raised triglycerides.

10:12Other drugs implicated include furosemide, sulfonamides, tetracycline, L-asparaginase, estrogens, pentamidine, sulfasalazine, and mesalamine, and statins are weakly associated. The incretin drugs are mixed. Glucagon-like peptide one receptor agonists show no clear association in pooled data but are usually avoided after an attack, and dipeptidyl peptidase four inhibitors carry a possible increased risk. Immune checkpoint inhibitors cause an asymptomatic rise in lipase in about three percent of patients and clinical pancreatitis in about two percent, and there high-dose steroids may help, because the injury is immune-mediated rather than direct toxicity to the acinar cell. He takes none of these.

10:57His calcium is checked next, because it acts through the same pathway as every other cause. Hypercalcemia from primary hyperparathyroidism, malignancy, sarcoidosis, vitamin D toxicity, or milk-alkali syndrome raises calcium inside the acinar cell, and chronic hypercalcemia can also form calcium phosphate stones in the pancreatic duct that obstruct it. Unexplained pancreatitis gets a serum calcium, an ionized calcium when available, and a parathyroid hormone, PTH, level, because correcting the calcium is the only durable treatment. His calcium is normal.

11:33His age is what decides the next step. Obstruction of the pancreatic duct by an adenocarcinoma, a neuroendocrine tumor, an intraductal papillary mucinous neoplasm, IPMN, plugging the duct with mucin, or an ampullary lesion can present as unexplained pancreatitis, particularly over forty. So once his attack settles, he needs follow-up cross-sectional imaging, because skipping it risks missing a cancer that announced itself through obstruction.

12:00His imaging also looks for the structural causes. Trauma and instrumentation injure the duct directly. A choledochocele, a cyst inside the duodenal wall, can obstruct the pancreatic duct opening intermittently, and an annular pancreas is another congenital cause. Pancreas divisum, in which the dorsal and ventral ducts fail to fuse and most of the gland drains through the minor papilla, is debated as a cause, and it likely contributes only in genetically predisposed patients, because most people with divisum never get pancreatitis.

12:31Autoimmune pancreatitis can present the same way. Type two, idiopathic duct-centric pancreatitis, presents acutely most often in a patient with inflammatory bowel disease. Type one, related to immunoglobulin G4, IgG4, presents with painless obstructive jaundice and a sausage-shaped gland. The difficulty is telling it from adenocarcinoma, so steroids wait until cancer has been excluded. Chapter twenty-six covers both types.

12:58Genetics enters for younger patients rather than for him. Testing for hereditary pancreatitis is warranted under thirty-five with recurrent attacks, especially with a family history. PRSS1, the cationic trypsinogen gene, with the R122H and N29I variants, is autosomal dominant and gain-of-function, with about eighty percent penetrance and a fifty-fold lifetime risk of adenocarcinoma that drives surveillance. SPINK1 is a permissive loss-of-function modifier, and it dominates tropical pancreatitis, where undernutrition is a co-factor. CFTR variants impair ductal bicarbonate secretion and produce a picture that overlaps with mild cystic fibrosis. CTRC variants impair the breakdown of trypsin, and CASR variants disturb calcium inside the acinar cell. Each one means more trypsin, less inhibitor, or more calcium. Recurrent attacks are also the main path to chronic pancreatitis, and episode three follows a young woman with a second attack through this testing.

13:58With the cause found, the question for every patient becomes how sick they'll get, and the fourth patient shows why it can't be answered on day one. A sixty-three-year-old man with a body mass index, BMI, of thirty-three has gallstone pancreatitis. At admission his heart rate is one hundred eight, his respiratory rate twenty-four, his white count fifteen thousand, his hematocrit forty-eight, and his BUN twenty-eight. His chest film shows a small left pleural effusion, and he's alert. Twelve hours later, despite fluids, his hematocrit is still forty-eight and his BUN has risen to thirty-four.

14:36A hematocrit that won't fall and a BUN that rises despite fluids are warning signs, and what they warn of is organ failure, which is what kills patients with pancreatitis. Mortality is under two percent without organ failure, even when necrosis is present, while persistent failure of several organs pushes it toward fifty percent. Necrosis and organ failure don't track each other directly, because many patients with necrosis never develop organ failure, though infected necrosis after seven to fourteen days independently raises mortality.

15:08Organ failure is measured with the modified Marshall score, which covers three systems, and a score of two or more in any one defines failure. For blood pressure, a systolic under ninety that doesn't respond to fluid scores two, and one that does respond scores one. For the lungs, a ratio of arterial oxygen pressure to inspired oxygen fraction, PaO2 to FiO2, under three hundred scores two. For the kidneys, a creatinine of one point nine to three point six milligrams per deciliter scores two, and over three point six scores three.

15:41The Revised Atlanta Classification grades severity from that score. Mild pancreatitis, about seventy-five percent of cases, has no organ failure and no local or systemic complication. Moderately severe pancreatitis has transient organ failure lasting under forty-eight hours, or local or systemic complications without persistent failure. Severe pancreatitis requires organ failure persisting beyond forty-eight hours. Severity declares itself only over forty-eight to seventy-two hours, and most patients who die look mild on day one, so watching closely through the first seventy-two hours is the central discipline.

16:20Early scores try to predict where he's headed. Systemic inflammatory response syndrome, SIRS, is two or more of a temperature under thirty-six or over thirty-eight degrees, a heart rate over ninety, a respiratory rate over twenty or an arterial carbon dioxide pressure under thirty-two, and a white count under four thousand, over twelve thousand, or with more than ten percent bands. He meets three. SIRS persisting beyond forty-eight hours strongly predicts severe disease, because it means the cytokine cascade hasn't been contained. The Bedside Index for Severity in Acute Pancreatitis, BISAP, uses five variables at presentation: a BUN over twenty-five, impaired mental status, SIRS, age over sixty, and a pleural effusion. It has moderate accuracy, and a score of three or more carries an in-hospital mortality of roughly five to twenty percent. He scores four.

17:14The older scores are slower or harder to use. The Ranson criteria use five variables at admission: age over fifty-five, a white count over sixteen thousand, a glucose over two hundred, an aspartate aminotransferase, AST, over two hundred fifty, and a lactate dehydrogenase, LDH, over three hundred fifty. They add six at forty-eight hours: a fall in hematocrit of more than ten percent, a rise in BUN of more than five, a calcium under eight, a PaO2 under sixty, a base deficit over four, and fluid sequestration over six liters. Three or more predicts severe disease, but the full score takes forty-eight hours. The Acute Physiology and Chronic Health Evaluation, APACHE, two is the most validated, but it needs an arterial blood gas and twelve physiologic measurements plus age and chronic health points, so it's rarely used at the bedside.

18:13No score, single test, or image reliably predicts severe disease early, so patient risk factors are combined with them: age over sixty, a BMI over thirty, multiple comorbidities, a pleural effusion or infiltrates on the first chest film, and SIRS beyond forty-eight hours. He has three of these already, and he'll have the fourth if his SIRS persists.

18:34His bedside markers carry the most weight in the first twenty-four hours. Third-spacing leaves the pancreas underperfused, and underperfusion drives necrosis, so hemoconcentration stands in for pancreatic hypoperfusion. A hematocrit over forty-four at admission, a hematocrit that fails to fall over the first twenty-four hours, or a BUN that rises within twenty-four hours is each associated with necrosis and higher mortality. All three are moving the wrong way in him, which warrants escalation and consideration of the intensive care unit, ICU, before overt organ failure appears. Other markers help less early. A C-reactive protein, CRP, over one hundred fifty milligrams per liter at forty-eight hours predicts severe disease but lags too far behind for admission decisions. Procalcitonin refines the risk of infected necrosis after seventy-two hours but isn't sensitive enough for decisions at admission. A corrected calcium below eight reflects fat necrosis and predicts severity.

19:36The CT belongs later, once necrosis can show. The CT severity index combines a Balthazar grade, A through E, based on changes in the gland and fluid around it, with a necrosis score of zero to six based on how much of the gland doesn't enhance, for a total of zero to ten. A score of seven to ten predicts a mortality of about seventeen percent and morbidity of ninety-two percent. On day two his creatinine rises to two point two, a renal Marshall score of two. Despite fluid it's two point four on day three, and his SIRS persists. That's severe acute pancreatitis, and his CT on day four shows thirty percent necrosis. The first woman, by contrast, had a creatinine of two on day two that was back to normal within thirty-six hours. That's transient organ failure, so her pancreatitis was moderately severe.

20:22The last two patients show who can be expected to do well. A thirty-one-year-old woman with mild gallstone pancreatitis has no rebound or guarding and a normal hematocrit and creatinine. The Harmless Acute Pancreatitis Score, HAPS, negative on all three, identifies patients unlikely to develop severe disease and supports earlier cholecystectomy and discharge planning, while the watch continues through seventy-two hours. A fifty-eight-year-old woman has forty percent necrosis on day four but a normal blood pressure, oxygenation, and creatinine throughout, and her mortality is under two percent. Her necrosis matters because it can become infected after seven to fourteen days, but without organ failure it doesn't make her disease severe.

21:05Here are the traps the boards set in these patients. A CT on day one adds nothing when two criteria are already met, and an early CT with normal enhancement doesn't exclude necrosis. Amylase can be normal in a patient who presents late. Normal enzymes in a lipemic sample don't rule out pancreatitis. The height of the lipase says nothing about severity. A patient who looks mild on day one may not stay mild, and transient organ failure isn't the same as persistent failure. Cullen and Grey-Turner signs mean severe disease.

21:38The traps around the cause are just as predictable. A patient who drinks still needs an ultrasound, and gallstone pancreatitis shouldn't be discharged without a plan for cholecystectomy. A normal ultrasound doesn't exclude a distal duct stone. Light drinking doesn't explain an attack. Fasting triglycerides need a recheck at four to six weeks. Azathioprine pancreatitis appears four to eight weeks after starting the drug. Calcium and PTH belong in every unexplained workup. A first unexplained attack after forty needs imaging for a tumor, and a young patient with recurrent attacks should be offered genetic testing.

22:15The severity traps come last. No admission score predicts severity reliably, and waiting forty-eight hours for Ranson delays action. A hematocrit over forty-four that doesn't fall, or a rising BUN, calls for escalation before organ failure appears. The CT severity index belongs after seventy-two hours. And necrosis alone doesn't make pancreatitis severe.

22:40So, start to finish. Acute pancreatitis is premature activation of trypsin inside the acinar cell, driven by sustained calcium whatever the trigger, followed by capillary leak, third-spacing, and necrosis that takes seventy-two to ninety-six hours to show. Diagnose it with two of three: typical pain, a lipase over three times normal, or typical imaging, without a CT on day one. Very high triglycerides can mask the enzymes, and enzyme height doesn't predict severity.

23:08Ultrasound every patient, because gallstones mean cholecystectomy before discharge, and an ALT over one hundred fifty points to a biliary cause. Alcohol needs years of heavy use. Triglycerides over one thousand are causal and get fasting and insulin, with a recheck at four to six weeks. Check calcium and PTH, review the drugs, image a first unexplained attack after forty, and offer genetic testing under thirty-five with recurrent attacks.

23:37Organ failure decides mortality. A Marshall score of two or more in any system is failure, and failure beyond forty-eight hours is severe disease. No score predicts reliably on day one, so follow the hematocrit, BUN, and SIRS, and escalate when they move the wrong way. Get the CT severity index after seventy-two hours, and use a negative HAPS to plan early discharge without ending the watch.

24:01Episode two is the first days of treatment: fluids, feeding, and gallstone pancreatitis, with endoscopic retrograde cholangiopancreatography, ERCP, and cholecystectomy.

24:13For the full chapter, the practice vignettes, and the topic-tagged question bank, head to board pearls dot com. You'll find the rest of the series on Apple Podcasts, Spotify, or wherever you listen to podcasts. That brings us to the end of episode one of three of chapter twenty-five, and I'll see you in the next one.