How Do the Gallbladder and Pancreas Go Wrong? — Two Streams Sharing One Outlet, and the Stone That Blocks It

"They Say I Have Stones in My Gallbladder"

A person who gets an abdominal ultrasound during a health checkup hears the words, "A few small stones are visible in the gallbladder." They wonder if they need surgery even though it doesn't hurt, or if it is okay to just leave it alone. There are people around them who live well even after having their gallbladder removed, and news reports say that "pancreatic cancer is discovered late."

Gallbladder is another name for the gall bladder. The gallbladder and the pancreas seem to do different things, but the liquids they release enter the intestine near the same exit. Once you know that exit, stones in the gallbladder, inflammation of the pancreas, and living without a gallbladder connect in a single line.

This article follows that exit to travel the path where the gallbladder and pancreas break down. It covers stones that are common but mostly quiet, inflammation of the pancreas that usually passes lightly but is heavy in some cases, and pancreatic cancer, which is frequently found late.

The Exit Where Two Streams Meet

First, we look right below the stomach, where two streams of liquid flow in.

The duodenum is the first part of the small intestine that follows right after the exit of the stomach. Two streams reach this place.

The first stream starts in the liver. The liver is the largest organ inside the body, located in the upper right side of the belly, and it receives blood coming from the gut first to store, change, and send out nutrients. Bile is a liquid made by the liver and sent out to the gut, and it breaks down fat into tiny bits so that digestive enzymes can reach it.

A digestive enzyme is a protein that chops large molecules in food into small pieces that the body can absorb. The bile duct is the tube through which bile made in the liver flows down to the duodenum.

Bile does not just flow straight down. The gallbladder is a small pouch attached beneath the liver, which gathers bile and squeezes it out when food comes in. The gallbladder hangs at the end of a short tube branching off the bile duct, so bile gathers in the gallbladder, comes back out into the bile duct when squeezed, and reaches the duodenum.

The second stream comes from behind the stomach. The pancreas is an organ lying horizontally behind the stomach, which does two things together: it makes digestive juices and sends them to the gut, and it releases hormones that handle blood sugar into the blood.

Pancreatic juice is the digestive juice made by the pancreas and sent to the gut, and it contains many digestive enzymes. The pancreatic duct is the tube through which pancreatic juice passes inside the pancreas and goes out to the duodenum.

The two tubes usually meet near the exit, and the two streams share that end part. The spot where a gallstone gets stuck is precisely this end part shared by the bile duct and the pancreatic duct (PMID 19322914).

The stream of bile and the stream of pancreatic juice usually meet near the exit opening into the duodenum, and share a single exit.

Stones Formed When Bile Hardens

Gallstones are stones that form inside the gallbladder or bile ducts when substances in bile harden. The biggest reason stones form is an imbalance in the proportions of bile components.

Let us name those components first. Cholesterol is an oil-like ingredient that does not dissolve in water, which animal bodies use to build cell membranes, hormones, and bile. Bile acids are substances that the liver makes by cutting down cholesterol and sending them out to the intestines.

Gallstones mostly form when cholesterol in bile exceeds the amount that can dissolve, bile acids decrease, and bile stays pooled in the gallbladder for a long time (PMID 42203606). Most gallstones are made of cholesterol, followed next by stones made of pigment (PMID 27121416).

Gallstones are common. As many as 20% of adults develop gallstones (PMID 27121416), and in most Western countries, 10% to 20% have gallstones (PMID 17390223). In one population-based study that examined 11,229 people aged 29 to 69 using ultrasound, 7.1% had gallstones (PMID 20492328). How common they are varies quite a bit depending on region and ethnicity (PMID 26771377).

Things that increase the risk of gallstones include age, being female, pregnancy, obesity, weight fluctuating rapidly, and certain medications and diseases (PMID 42203606, PMID 27121416).

Asymptomatic gallstones refer to cases where gallstones are present, but there has never been any pain or other symptoms caused by those stones (PMID 15471318). Nearly two-thirds of people with gallstones fall into this category (PMID 15471318), and looking at the time of diagnosis, 50% to 70% have no symptoms (PMID 17390223). As abdominal ultrasounds are performed more often for other reasons, symptomless gallstones are discovered more and more frequently (PMID 17390223).

Gallstones are stones formed when bile components harden, are common in adults, and are mostly without symptoms when discovered.

Most Pass Quietly

If you follow people with symptomless gallstones over a long period, most of them remain quiet. When followed for 10 years, the cumulative probability of first experiencing abdominal pain from gallstones is 15–25%, and other complications are much rarer (PMID 15471318).

The population study cited above followed people with gallstones for an average of 8.7 years. Among the 580 people who initially had no symptoms, 78.1% remained symptom-free to the end, 10.5% developed mild symptoms, and 11.4% developed severe symptoms. Out of the 189 gallbladder surgeries performed in this study, 41.3% were done on people who had been symptom-free. The researchers concluded that both present and absent gallstone symptoms generally run a mild course, and that for most people, watching and waiting remains a reasonable choice (PMID 20492328). This is the result of a single population-based cohort study.

The time when pain begins is concentrated in the first few years. In a study of 213 people reviewing records from three hospitals and clinics in Malaysia, the rate at which symptomless gallstones began to hurt was highest in the first two years and decreased as the years went on. Women began to hurt much more often than men, with lifetime risks estimated at 6.15% for men and 22.1% for women. The researchers noted that watching and waiting is recommended for men who discover symptomless gallstones, whereas surgery may be better for young women (PMID 26988206). This is a small study from a single country.

Because of this clinical course, symptomless gallstones are usually watched and waited on. One review article notes that most authors agree on managing the vast majority of symptomless people with observation alone, and that removing the gallbladder in all symptomless people is an overly aggressive choice. The same review reports that surgery can be selectively performed in a few high-risk groups, and adds that the options should be discussed thoroughly with the patient so that the patient participates in the decision (PMID 17390223).

Another review also recommends conservative observation when there are no symptoms, but makes exceptions for situations where there is a risk of gallbladder cancer, such as large stones or certain polyps in the gallbladder (PMID 42203606).

Proposals in another direction also exist. A 2025 review moves beyond the two-pronged choice of "surgery versus observation," suggesting instead that people be stratified—preventing unnecessary surgery in low-risk individuals while planning early surgery for some high-risk individuals. At the same time, it recommends presenting surgery as an option to everyone with symptomless gallstones and deciding together (PMID 41357627).

The position of the review articles is that since symptomless gallstones mostly pass quietly, they are usually watched and waited on, but there are exception conditions, and which path to take is decided together with the patient.

When Stones Block the Path

Biliary colic is an abdominal pain attack originating from the gallbladder and bile ducts, usually caused by gallstones. When the gallbladder squeezes out bile and a stone catches in the gallbladder outlet, this pain occurs.

Roughly 20% of people with gallstones develop biliary colic or heavy complications (PMID 42203606). Most complications of gallstones arrive after experiencing biliary colic at least once beforehand (PMID 17390223). Complications vary depending on where the stone gets stuck.

Cholecystitis is inflammation that has formed in the gallbladder. A person with acute cholecystitis hurts in the right upper abdomen, has a fever, and shows increased white blood cells on a blood test (PMID 29132521).

Sometimes a stone escapes the gallbladder and descends into the bile duct (PMID 42203606). A bile duct stone is a gallstone settled inside the bile duct. Noted serious complications of bile duct stones include cholangitis and gallstone pancreatitis (PMID 29132521). Among them, gallstone pancreatitis is a site where the water channel for bile and the water channel for pancreatic juice run into trouble together.

Cholangitis is inflammation and infection that have occurred in the bile duct. Acute cholangitis is a state that can threaten life, and treatment enters fluids, painkillers, and antibiotics, along with pulling bile out of the blocked bile duct to lower pressure (PMID 29132521).

Jaundice is also among the complications of gallstones (PMID 26771377). Bilirubin is a yellow pigment produced when red cells that have finished their lifespan are broken down, and the liver receives it and sends it out into bile. Jaundice is when bilirubin piles up in the blood so that the whites of the eyes and the skin turn yellow. Because bilirubin is loaded onto bile and goes out, if the bile duct is blocked with stones, the bilirubin the liver has processed can pile up in the blood and bring on jaundice (PMID 28145671). The various branches of jaundice can be seen in "What Does the Liver Do, and What Do Liver Tests Measure? — The Factory at the Gate, and the Signal That Leaks Through the Wall".

A cholecystectomy is surgery to take out the gallbladder entirely. For gallstones that have developed symptoms or complications, a laparoscopic cholecystectomy—making small holes in the belly and doing the surgery—is the standard treatment (PMID 42203606). One review records that an early laparoscopic cholecystectomy is best for biliary colic and acute cholecystitis (PMID 22986769).

Even after symptoms occur once, some people do not hurt again. A 1993 review recorded that a person who has experienced biliary colic once has a high likelihood of hurting again, but roughly 30% do not hurt again. The same review, while recommending surgery to most people who have had symptoms, concluded that a person who wants to watch and wait for a while to see if pain returns can do so, and non-surgical treatment may be right for a person with a high surgical risk (PMID 8363172). In an earlier cohort study as well, a little over half of the people who initially had symptoms saw their symptoms disappear during follow-up (PMID 20492328).

Stones in the bile duct are handled differently from stones inside the gallbladder. The European Society of Gastrointestinal Endoscopy (ESGE) guidelines advise that if there are stones in the bile duct, whether symptoms are present or not, one should suggest a procedure to pull out the stones to everyone who can withstand the procedure. The guidelines themselves recorded that this recommendation is a strong recommendation, but the quality of evidence is low (PMID 30943551). Stones in the bile duct are usually pulled out by sending an endoscope put in through the mouth down to the duodenum and passing through the outlet of the bile duct (PMID 26771377).

There are also counterarguments to this recommendation. One review records that in symptom-free bile duct stones, complications of this endoscopic procedure, particularly pancreatitis arising after the procedure, were reported to be more frequent than in symptomatic cases, and random trials comparing whether the procedure is better than leaving it alone do not yet exist. The same review holds that whether routinely pulling out symptom-free bile duct stones is justified needs more research (PMID 34025069).

When gallstones produce symptoms, they often start as biliary colic, and if a stone descends into the bile duct and blocks the outlet, the two water channels of bile and pancreatic juice can run into trouble together.

After Removing the Gallbladder

Digestion continues even after a cholecystectomy. Bile is produced by liver cells and enters the intestine by traveling along increasingly thick ducts, passing through the gallbladder and bile duct (PMID 23897680). Because the gallbladder is a pouch that stores this bile, after it is removed, the bile made by the liver does not collect and instead flows straight through the bile duct into the duodenum.

Following surgery, the proportion of people whose biliary colic disappears is high, ranging from 66 to 100%. Indigestion improves in 41 to 91% of cases but can also newly develop after surgery, and diarrhea newly begins in 14 to 17%. Even in randomized trials that selected only people with biliary colic, 30 to 40% still had pain remaining after surgery. Nonetheless, satisfaction after surgery is high (PMID 36902684).

The same review concludes that methods of selecting people for surgery based on symptoms alone have reached their limits, and that we must find objective indicators to screen out who will have their pain improved by surgery (PMID 36902684).

There are also risks to the surgery itself. The mortality rate for planned cholecystectomies is below 0.5%, but it is higher in people over the age of 60, especially those with complications such as acute cholecystitis (PMID 15471318).

Even when the gallbladder is removed, the liver continues to make and release bile, and most biliary colic disappears after surgery, but even in trials selecting only people with biliary pain, 30 to 40% were left with pain, and some people newly develop diarrhea.

When the Pancreas Melts Itself

Even though the pancreas makes more than twenty proteins essential for digestion, it is equipped with multiple layers of safety mechanisms to prevent itself from being digested by those enzymes (PMID 3890660). As one of these mechanisms, the proteins that cut other proteins are manufactured in a turned-off state and are only turned on after they reach the intestine.

Acute pancreatitis is inflammation that develops suddenly in the pancreas. When the protective mechanisms inside the pancreatic cells that prevent the enzymes from turning on can no longer cope, the enzymes turn on inside the pancreas, digest the pancreas itself, and cause inflammation (PMID 19322914). Exactly how this process happens has been a matter of debate for a long time (PMID 19322914, PMID 3890660), and a recent review summarizes that multiple strands of cellular damage overlap alongside the activation of enzymes (PMID 41530118).

Two main causes account for the majority. German guidelines state that 30 to 50% of acute pancreatitis is due to gallstones, and another 30 to 50% is due to alcohol (PMID 35945698). Very high triglyceride levels in the blood are also listed as a common cause, and the proportion by cause varies across regions (PMID 41530118). In 15 to 25% of cases, the cause cannot be found (PMID 18191686).

The path by which gallstones cause acute pancreatitis connects to the exit we saw earlier. A gallstone getting stuck in the end part shared by the bile duct and the pancreatic duct is the most common cause of acute pancreatitis, and many researchers accept that this blockage and the excessive stimulation of the pancreas raise the pressure inside the pancreatic duct as the main factors in gallstone pancreatitis (PMID 19322914). The idea that a stone blocking the waterway of bile can also block the waterway of pancreatic juice is what many researchers think explains gallstone pancreatitis.

A diagnosis is made when two out of three are met. They are abdominal pain radiating to the back, blood pancreatic enzyme levels rising to more than three times the upper limit of normal, and the appearance of pancreatitis seen on CT or MRI (PMID 39941188).

Most cases pass mildly. A 2008 review that divided cases into two streams—mild and severe—noted that 80% of patients have mild pancreatic damage and recover without complications (PMID 18191686). The 2012 revised classification most widely used today divides severity into three stages (PMID 40401586). Most are mild, and only a portion progress to moderately severe, where local complications of the pancreas develop, or severe, where organ function continues to break down (PMID 30026919). In severe necrotizing patients where pancreatic tissue is dying, the mortality rate reaches as high as 30% (PMID 20937458). There is still no scoring system that accurately screens in advance who will progress to severe disease (PMID 40401586). Although the mortality rate of acute pancreatitis has decreased over the past decades as treatments have improved, the number of people suffering from acute pancreatitis has increased recently (PMID 39941188).

Preventing recurrence also follows the cause. If it is mild acute pancreatitis caused by gallstones, a review recommends performing a gallbladder removal surgery during the same hospital stay, and if it is severe, surgery is delayed, though the exact timing is not yet clear. The same review concludes that treatment varies depending on severity, but gauging that severity is difficult (PMID 38691369). To prevent recurrence, reviews also list quitting alcohol and smoking (PMID 30026919, PMID 39941188).

Acute pancreatitis is inflammation caused by multiple overlapping forms of damage, including enzymes turning on inside the pancreas; its two main causes are gallstones and alcohol; and most cases pass mildly while a portion proceed to a heavy course involving complications.

The Scars Left by Long-Standing Inflammation

The point we saw in "How Do Fatty Liver, Hepatitis and Cirrhosis Connect? — Ground That Hardens as Scars Build Up, and the Stretch Where You Can Still Turn Back", which covers the path of a liver growing stiff, applies to the pancreas as well. Fibrosis is the process in which scar tissue accumulates to repair long-standing damage and inflammation, causing an organ to stiffen.

Chronic pancreatitis is a disease in which inflammation of the pancreas persists for a long time, scar tissue builds up, and the pancreas gradually loses the work it used to do. As inflammation continues, the parts that make digestive juices and the parts that make hormones shrink or get replaced by scar tissue, reducing in size. As a result, recurrent or ongoing belly pain, diabetes, and trouble digesting food properly occur (PMID 28880010). The mechanisms are not yet fully understood (PMID 28880010).

Diabetes is a condition where blood sugar stays higher than the normal range for a long time. What diabetes is and how it develops is covered in "What Is Diabetes? — The Letter That Never Comes, the Letter That Isn't Read".

Chronic pancreatitis affects 42 to 73 out of 100,000 American adults. About 80% visit the hospital for recurrent or long-lasting upper belly pain, and over time, 38 to 40% develop diabetes, while 30 to 48% experience a decline in the digestive function of the pancreas (PMID 31860051). Guidelines from the American College of Gastroenterology (ACG) note that the decline in digestive function and diabetes develop at vastly different speeds from person to person (PMID 32022720).

The most common causes are alcohol, smoking, genetic variants, and recurrent acute pancreatitis, but many people have never had acute pancreatitis (PMID 32022720). Acute pancreatitis can recur or progress to chronic pancreatitis, and once chronic pancreatitis develops, the risk of pancreatic cancer also rises (PMID 36074322).

Exocrine pancreatic insufficiency is a state where the digestive juices released by the pancreas drop below the amount needed to properly digest food. Pancreatic diseases and pancreatic surgery are the main causes, and because nutrients are not properly absorbed, deficiencies occur and quality of life drops (PMID 39639485). Among the things that fall short, the pancreatic enzyme that breaks down fat is a particular problem (PMID 30962702). The foundation of treatment is replacing the lacking pancreatic enzymes with medication and providing dietary counseling and support (PMID 39639485).

One review concludes that chronic pancreatitis commonly leaves behind long-lasting belly pain, and that treatment mainly consists of stopping alcohol and smoking, pain control, replacing lacking digestive function, and for some people, procedures to open blocked pancreatic ducts (PMID 31860051).

Chronic pancreatitis is a disease where long-standing inflammation turns the pancreas into scars, and when digestive juices fall short, exocrine pancreatic insufficiency follows, while when blood sugar hormones fall short, diabetes follows.

A Disease Seen Late from Deep Within

Pancreatic cancer is cancer that begins in the pancreas. It is a relatively rare cancer (PMID 32135127), but in 2022, over 510,000 people worldwide were newly diagnosed and more than 460,000 died from it (PMID 39992560).

Early symptoms of pancreatic cancer are vague and come on gradually, so it is often diagnosed at an advanced stage (PMID 40971231). Only 15 to 20% of people can have the cancer removed by surgery at the time of diagnosis (PMID 40971231).

The 5-year survival rate is the proportion of people diagnosed with a disease who are still alive 5 years later. A 2025 review's global estimate puts the 5-year survival rate for all pancreatic cancer patients at 10%, which is only slightly improved over the past decade. The main reasons cited for low survival are late diagnosis and the lack of effective screening methods (PMID 39992560). Values range widely from 3 to 15% across different reports (PMID 32135127). US data show that 5-year survival for pancreatic cancer improved between 2001 and 2018, but incidence and mortality continued to rise over the same period (PMID 36301149).

Smoking is a known cause of pancreatic cancer (PMID 27956793). Chronic pancreatitis, diabetes, obesity, and family history are also cited as factors related to pancreatic cancer (PMID 40971231).

New-onset diabetes is also receiving attention. New-onset diabetes is increasingly recognized as an early symptom of pancreatic cancer, especially in older people who are losing weight (PMID 37166325). Still, the vast majority of people newly diagnosed with diabetes do not have pancreatic cancer. In an analysis pooling 22 observational studies, 3,560 out of 576,210 people newly diagnosed with diabetes had pancreatic cancer. Among them, factors more strongly associated with pancreatic cancer were older age, family history, a history of gallstones or pancreatitis, weight loss, and rapid increases in blood sugar, and the researchers wrote that these factors could be used to build a model for selecting people to test (PMID 36230607).

Screening is a test aimed at finding people who have a disease in advance among those without symptoms. The American Gastroenterological Association (AGA) recommends against screening for pancreatic cancer in people at average risk (PMID 32416142). One review lists two reasons for this: pancreatic cancer is rare in the general population, so no test predicts results well, and there is no direct evidence that finding it early increases survival (PMID 37166325).

A few individuals at high risk are handled differently. For people who have a close relative with pancreatic cancer and two or more affected family members, or who have genetic conditions or gene mutations that increase pancreatic cancer risk, the AGA states that screening should be considered (PMID 32416142). The International Cancer of the Pancreas Screening (CAPS) consortium recommends such surveillance, but concluded that it should be performed by expert teams in a research setting, and that its benefits, risks, and costs require further evaluation (PMID 31672839).

Methods to find it early are also being studied. Blood-test markers, more sensitive imaging, and methods using electronic health records and artificial intelligence to screen out high-risk people are among them (PMID 32135127, PMID 40722803).

Pancreatic cancer is relatively rare, but because early symptoms are vague it is often discovered late, screening is not recommended by guidelines for people at average risk, and surveillance for a few high-risk individuals along with methods to find it early are being studied.

Following That Night

A middle-aged office worker wakes up a few hours after dinner with pain in the upper right part of the belly. They were told at a health checkup a few years ago that they had a stone in their gallbladder, but nothing had happened since.

The gallbladder is a pouch that squeezes out and sends out the bile it has gathered. Inside that gallbladder, there was a stone that had been quiet for a long time. Even if you follow asymptomatic gallstones for 10 years, most remain quiet, but 15 to 25% start hurting for the first time (PMID 15471318). If this pain is due to a gallstone, its name is biliary colic.

There is a path where the pain subsides and does not return. Many people hurt again, but about 30% do not hurt again (PMID 8363172). If it hurts again, you consider a cholecystectomy. After surgery, biliary colic mostly disappears, but even in trials selecting only people who had biliary colic, 30 to 40% had residual pain (PMID 36902684).

There is also a path where fever comes along. A person with acute cholecystitis has upper right belly pain and fever, and a blood test shows an increased white blood cell count (PMID 29132521). However, this appearance alone does not determine the branch.

If the stone descends into the bile duct, it can lead to cholangitis or acute pancreatitis caused by the blockage of the end part that both water channels share (PMID 29132521, PMID 19322914).

One review classifies acute cholecystitis, acute cholangitis, and gallstone pancreatitis as three complications of gallstones that can threaten life (PMID 27121416), and another review lists jaundice, where the eyes and skin turn yellow, as a complication of gallstones as well (PMID 26771377). Jaundice in adults is treated as something that can be a sign of a serious underlying disease (PMID 28145671).

The diagnosis of gallstones is made by putting symptoms, blood tests, and imaging together, and an abdominal ultrasound is the basic test to find gallstones (PMID 26771377).

Even the pain of the same night branches from biliary colic that subsides on its own to cholecystitis, cholangitis, and acute pancreatitis depending on where the stone is caught, and that branch is sorted out not just by symptoms, but with blood tests and imaging.

Where to Look Next

There are also questions where answers are still divided. The line on who should be recommended surgery for asymptomatic gallstones is still debated today (PMID 41357627), and one review notes that the natural history of asymptomatic gallstones is not well enough known to recommend a definitive treatment strategy (PMID 15471318). Exactly how beneficial pancreatic cancer screening is for high-risk individuals is also not yet clear. The same review notes that evidence is emerging of opportunities to find pre-cancerous lesions and early cancer in such individuals (PMID 28840303).

The big picture of how food is broken down and absorbed in the small intestine, and how bile disperses fat, can be seen in "How Does Digestion Work? — A Tube Through the Body, and a Wall Only Small Pieces Can Cross". The liver that makes bile, jaundice, and the liver tests on your health checkup report are covered by "What Does the Liver Do, and What Do Liver Tests Measure? — The Factory at the Gate, and the Signal That Leaks Through the Wall", while the path by which fibrosis accumulates in the liver is covered by "How Do Fatty Liver, Hepatitis and Cirrhosis Connect? — Ground That Hardens as Scars Build Up, and the Stretch Where You Can Still Turn Back".

The blood sugar hormones that the pancreas sends into the blood are covered in "How Blood Sugar Stays Steady — A Letter to Store, a Letter to Release", and the disease where those hormones are lacking or do not work is continued in "What Is Diabetes? — The Letter That Never Comes, the Letter That Isn't Read". Why tests that look for rare diseases in the general population do not work well is covered by "What a Test Actually Tells You — An Introduction to Sensitivity, Specificity, and Pretest Probability". What happens at the end of the digestive tract, in the wall of the large intestine, is covered in other parts of this series.

Source Papers

• "Acute pancreatitis." (1985) — PMID 3890660 — The exocrine pancreas secretes over 20 digestive proteins into the gut as needed, and self-digestion within the body is prevented by multiple natural safeguards; acute pancreatitis is caused by the inappropriate activation of enzymes inside the pancreas (the exact mechanism of self-digestion remains unclear).
• "Bile formation and secretion." (2013) — PMID 23897680 — Bile is a digestive fluid produced by hepatocytes in the liver, flowing from canaliculi through progressively larger bile ducts into the gallbladder, common bile duct, and intestine.
• "Evaluation of Jaundice in Adults." (2017) — PMID 28145671 — Jaundice in adults can be an indicator of a serious underlying disorder, and conjugated hyperbilirubinemia occurs in cholestatic conditions such as common bile duct stones or neoplastic biliary obstruction.
• "Acute pancreatitis: etiology and common pathogenesis." (2009) — PMID 19322914 — The most common cause is a gallstone lodged in the distal common pancreatobiliary channel; many researchers accept pancreatic hyperstimulation and pancreatobiliary duct obstruction (elevated ductal pressure, reflux of active trypsin) as main drivers of gallstone pancreatitis. When cellular protective mechanisms are overwhelmed, intra-pancreatic enzyme activation leads to self-digestion and local inflammation, though pathogenetic theories remain debated (with a common pathogenesis being the authors' hypothesis).
• "Gallstones: Physiopathology and treatment of cholelithiasis (part 1)." (2026) — PMID 42203606 — Annual clinical manifestation risk is 1–4%; formed by cholesterol supersaturation, reduced bile acids, and gallbladder stasis, with risk factors including age, female sex, rapid weight fluctuation, medications, pregnancy, and medical conditions. About 20% experience biliary colic or complications (acute cholecystitis, stone migration, cholangitis, acute pancreatitis). Symptomatic cases standardly undergo laparoscopic cholecystectomy, whereas conservative management is generally recommended for asymptomatic cases (barring risk of malignant transformation). Acute cholecystitis is treated from early surgery to percutaneous drainage depending on severity.
• "Gallstones." (2016) — PMID 27121416 — Gallstones grow inside the gallbladder and biliary tree, predominantly as cholesterol stones, alongside pigment stones. Up to 20% of adults have gallstones, with over 20% of those developing symptoms or complications. Risk factors include female sex, age, pregnancy, physical inactivity, obesity, and overnutrition. Symptoms frequently precede three potentially life-threatening complications: acute cholecystitis, acute cholangitis, and gallstone pancreatitis.
• "Asymptomatic cholelithiasis: is cholecystectomy really needed? A critical reappraisal 15 years after the introduction of laparoscopic cholecystectomy." (2007) — PMID 17390223 — In most Western countries, 10–20% have gallstones, of which 50–70% are asymptomatic at diagnosis. Progression from asymptomatic to symptomatic occurs in 10–25%. Most patients do not develop complications or even a single episode of biliary colic, and the vast majority are managed with observation alone (largely agreed upon by authors). Defined high-risk subgroups undergo selective surgery, while routine surgery for all asymptomatic cases is overly aggressive, requiring thorough discussion of options with patients for active participation in decisions.
• "Natural history of gallstone disease: Expectant management or active treatment? Results from a population-based cohort study." (2010) — PMID 20492328 — In a population-based ultrasound cohort of 11,229 individuals aged 29–69, the prevalence of gallstones was 7.1%, with 580 participants (73.1%) asymptomatic at enrollment. Over a mean follow-up of 8.7 years, 78.1% of asymptomatic individuals remained asymptomatic, 10.5% developed mild symptoms, and 11.4% developed severe symptoms. Just over half of symptomatic patients experienced resolution of symptoms. Out of 189 cholecystectomies, 41.3% were performed on asymptomatic individuals. Conclusion: Both asymptomatic and symptomatic gallstones generally follow a benign course, with most patients never experiencing further biliary colic. A substantial number of surgeries are performed on asymptomatic individuals, and expectant management remains valid for the majority.
• "Diagnosis and management of bile stone disease and its complications." (2016) — PMID 26771377 — There are large geographical and ethnic differences in prevalence. Gallstones may be asymptomatic or cause biliary colic, acute cholecystitis, jaundice, cholangitis, or acute pancreatitis. Diagnosis relies on a combination of clinical, laboratory, and imaging findings, with transabdominal ultrasound as the standard for gallstone diagnosis. Common bile duct stones are standardly treated with ERCP, sphincterotomy, and stone extraction.
• "Silent gallstones: a therapeutic dilemma." (2004) — PMID 15471318 — Approximately two-thirds of gallstone patients are asymptomatic. The 10-year cumulative probability of biliary colic is 15–25%, while other complications are much less frequent. Elective cholecystectomy carries a surgical mortality rate of less than 0.5%, which increases beyond age 60, especially with comorbidities. Most decision analyses do not support prophylactic surgery.
• "Natural history of asymptomatic gallstones: differential behaviour in male and female subjects." (2015) — PMID 26988206 — In a retrospective cohort of 213 patients at one hospital and two clinics in Malaysia, 10.8% developed pain over a mean of 4.02 years. Conversion rates were highest in the first 2 years and decreased by year 10. The hazard ratio for females was 3.23, with a lifetime conversion risk of 6.15% for men versus 22.1% for women. Conclusion: Conservative treatment is recommended for men, whereas surgery may be preferable for young women.
• "Asymptomatic gallstone disease: Re-evaluating the threshold for surgical options in the era of precision medicine." (2025) — PMID 41357627 — Management of asymptomatic gallstones remains controversial, and overcoming the "surgery versus observation" dichotomy is proposed by offering cholecystectomy as an option to all asymptomatic gallstone patients via shared decision-making.
• "Gallbladder Dysfunction: Cholecystitis, Choledocholithiasis, Cholangitis, and Biliary Dyskinesia." (2017) — PMID 29132521 — Acute cholecystitis presents with right upper quadrant pain, fever, and leukocytosis. Severe complications of common bile duct stones include cholangitis and gallstone pancreatitis, and acute ascending cholangitis is a life-threatening acute inflammation and infection of the common bile duct requiring fluids, analgesics, antibiotics, biliary drainage, and decompression.
• "Evidence-based current surgical practice: calculous gallbladder disease." (2012) — PMID 22986769 — Early laparoscopic cholecystectomy is best for biliary colic and acute cholecystitis, while mild gallstone pancreatitis warrants cholecystectomy during the same hospital admission to prevent recurrence.
• "Treatment of gallstones." (1993) — PMID 8363172 — A review including decision-tree modeling. Asymptomatic gallstones have a benign natural history, so treatment is generally not recommended. Symptomatic gallstones carry a high subsequent pain rate, though about 30% never hurt again. Conclusion: Prophylactic surgery is recommended for most symptomatic gallstones (though patients willing to wait out recurrent pain may opt for observation), non-surgical treatment is indicated for high surgical risk, and observation is best for asymptomatic cases.
• "Endoscopic management of common bile duct stones: European Society of Gastrointestinal Endoscopy (ESGE) guideline." (2019) — PMID 30943551 — Stone extraction is suggested for all patients with common bile duct stones who can tolerate the procedure, regardless of symptoms (strong recommendation, low-quality evidence).
• "Remaining issues of recommended management in current guidelines for asymptomatic common bile duct stones." (2021) — PMID 34025069 — Asymptomatic common bile duct stones are reported to have higher ERCP complication rates (particularly post-procedure pancreatitis) than symptomatic ones. There are no randomized trials comparing ERCP with no treatment, and further studies are needed to justify routine endoscopic therapy.
• "The Symptomatic Outcomes of Cholecystectomy for Gallstones." (2023) — PMID 36902684 — Postoperative resolution of biliary colic ranges from 66% to 100%, and dyspepsia resolution from 41% to 91% (though new-onset dyspepsia can occur post-surgery). Diarrhea newly begins in 14–17%. Even in randomized controlled trials of patients with only biliary colic, pain persists in 30–40%. Satisfaction is high. Conclusion: Strategies selecting patients based on symptoms alone have limitations, and objective determinants of pain relief need to be explored.
• "Acute pancreatitis: mechanisms and therapeutic approaches." (2026) — PMID 41530118 — Common causes (gallstones, hypertriglyceridemia, alcohol) vary by region. Multilayered pathophysiology involves abnormal enzyme activation, calcium overload, autophagy impairment, inflammation, and multiple forms of acinar cell death.
• "Clinical Practice Guideline—Acute and Chronic Pancreatitis." (2022) — PMID 35945698 — German guidelines note that 30–50% of acute pancreatitis is due to gallstones and 30–50% to alcohol abuse, with diagnosis requiring two of three criteria. Conclusion: Long-term management of uncomplicated pancreatitis is the responsibility of primary care physicians and gastroenterologists.
• "Management of Gallstone Pancreatitis: A Review." (2024) — PMID 38691369 — Gallstone pancreatitis accounts for about 50% of acute pancreatitis cases as the leading cause. Mild isolated gallstone pancreatitis warrants cholecystectomy during the same admission (early surgery within 48 hours of admission is supported by multiple randomized controlled trials), whereas severe cases are delayed with an unclear optimal timing.
• "Acute pancreatitis." (2008) — PMID 18191686 — Eighty percent of patients have mild pancreatic injury and recover without complications, while the remainder experience severe local or systemic complications, with 15–25% of unknown etiology.
• "Recent advances in understanding and managing acute pancreatitis." (2018) — PMID 30026919 — Most cases are mild; moderately severe implies local complications, and severe implies persistent organ failure. Abstinence from alcohol and smoking, along with same-admission cholecystectomy for gallstone pancreatitis, prevents readmission and recurrence.
• "Acute pancreatitis with an emphasis on infection." (2010) — PMID 20937458 — Approximately 80% are mild and self-limiting, while severe necrotizing forms carry a mortality rate of up to 30%.
• "Treatment of acute pancreatitis." (2025) — PMID 40401586 — The main causes are gallstone migration and alcohol consumption. Severe cases carry a high risk of mortality, with no definitive prognostic scoring system to accurately predict severity, and initial management for both mild and severe cases is supportive care.
• "Diagnosis and Management of Acute Pancreatitis." (2025) — PMID 39941188 — Diagnosis requires two of three criteria (abdominal pain radiating to the back, lipase or amylase levels at least 3 times the upper limit of normal, and CT or MRI findings). Initial treatment includes oxygen, fluids, analgesics, and nutrition; recurrence is prevented by abstaining from alcohol and smoking, and mortality has decreased over the past decades due to better management.
• "ACG Clinical Guideline: Chronic Pancreatitis." (2020) — PMID 32022720 — Chronic pancreatitis is a pathologic fibro-inflammatory syndrome of the pancreas. The most common symptom is abdominal pain, while exocrine insufficiency and diabetes occur at highly variable frequencies. Major causes include toxins such as alcohol and smoking, genetic polymorphisms, and recurrent acute pancreatitis, though many patients lack a history of acute pancreatitis.
• "Chronic pancreatitis." (2017) — PMID 28880010 — Persistent inflammation leads to progressive loss of endocrine and exocrine components through atrophy and fibrous tissue replacement, resulting in recurrent or persistent abdominal pain, diabetes mellitus, and digestive impairment. The mechanisms are not fully understood.
• "Diagnosis and Management of Chronic Pancreatitis: A Review." (2019) — PMID 31860051 — Affects 42–73 per 100,000 U.S. adults, with about 80% experiencing recurrent or chronic upper abdominal pain, and long-term diabetes occurring in 38–40% and exocrine insufficiency in 30–48%. Conclusion: Frequently causes chronic abdominal pain, with heavy alcohol use, smoking, and genetic mutations as the most common causes. Treatment focuses on alcohol and smoking cessation, pain control, enzyme supplementation, and drainage of obstructed pancreatic ducts in selected cases.
• "Acute Pancreatitis: Diagnosis and Treatment." (2022) — PMID 36074322 — Long-term, aggressive management is needed to reduce recurrences and progression to chronic pancreatitis, which increases the risk of pancreatic cancer.
• "European guidelines for the diagnosis and treatment of pancreatic exocrine insufficiency: UEG, EPC, EDS, ESPEN, ESPGHAN, ESDO, and ESPCG evidence-based recommendations." (2025) — PMID 39639485 — Exocrine pancreatic insufficiency is defined as a reduction in pancreatic exocrine function below the level required for normal digestion of nutrients, primarily caused by pancreatic diseases or surgery, leading to malabsorption, deficiencies, and impaired quality of life. The pillars of treatment are pancreatic enzyme replacement therapy, dietary advice, and support.
• "Exocrine pancreatic insufficiency: prevalence, diagnosis, and management." (2019) — PMID 30962702 — Decreased secretion and activity of pancreatic juice and its enzymes, particularly pancreatic lipase.
• "Early detection of pancreatic cancer." (2020) — PMID 32135127 — Pancreatic ductal adenocarcinoma is usually detected at an advanced stage, with a 5-year survival rate of 3–15%. Because it is relatively rare, screening the asymptomatic adult population is not currently feasible or recommended, though it is advised for high-risk groups. Research focuses on early detection through new-onset diabetes, medical record prediction models, and AI imaging.
• "Trends in the Global Incidence of Pancreatic Cancer and a Brief Review of its Histologic and Molecular Subtypes." (2025) — PMID 39992560 — In 2022, there were 510,922 new global cases and 467,409 deaths, with a worldwide 5-year survival rate of 10% (a slight improvement over the past decade). Low survival is attributed to late diagnosis and the lack of effective screening, and screening the asymptomatic population is not recommended.
• "Advances in pancreatic cancer early diagnosis, prevention, and treatment: The past, the present, and the future." (2026) — PMID 40971231 — Risk factors include chronic pancreatitis, diabetes, smoking, obesity, and familial predisposition. Initial symptoms are vague and insidious, often leading to diagnosis at an advanced stage, with only 15–20% resectable at diagnosis.
• "Annual report to the nation on the status of cancer, part 1: National cancer statistics." (2022) — PMID 36301149 — In the United States from 2001 to 2018, 5-year survival for pancreatic adenocarcinoma and neuroendocrine tumors improved, while incidence (2001–2018) and mortality (2001–2019) continued to increase.
• "Epidemiology of pancreatic cancer." (2016) — PMID 27956793 — Smoking is a known cause of pancreatic cancer, and there are currently no recommendations for pancreatic cancer screening.
• "Early Detection of Pancreatic Cancer." (2023) — PMID 37166325 — Screening the general population is not recommended due to low disease prevalence rendering tests uninformative, and a lack of direct evidence that early diagnosis extends survival. New-onset diabetes is increasingly recognized as an early manifestation, particularly in elderly patients experiencing weight loss.
• "Risk Factors for Pancreatic Cancer in Patients with New-Onset Diabetes: A Systematic Review and Meta-Analysis." (2022) — PMID 36230607 — A meta-analysis of 22 observational studies identified pancreatic ductal adenocarcinoma in 3,560 out of 576,210 patients with new-onset diabetes. Major risk factors are age, family history, and gallstones or pancreatitis, with symptoms including weight loss and rapid blood sugar elevation. Conclusion: Diagnostic models can be developed using these factors for screening.
• "AGA Clinical Practice Update on Pancreas Cancer Screening in High-Risk Individuals: Expert Review." (2020) — PMID 32416142 — Average-risk individuals should not be screened, whereas screening should be considered for first-degree relatives from families with two or more genetically linked patients, as well as carriers of genetic syndromes or mutations.
• "Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium." (2020) — PMID 31672839 — Conclusion: Surveillance is recommended for selected high-risk individuals in a research setting by a specialized multidisciplinary team, while benefits, risks, and costs require further evaluation.
• "Early Detection of Pancreatic Cancer: Current Advances and Future Opportunities." (2025) — PMID 40722803 — High-risk groups comprise those with new-onset diabetes after age 50, chronic pancreatitis, cystic precursor lesions, and genetic syndromes, benefiting from new biomarkers, imaging, and AI risk-prediction tools.
• "Pancreatic cancer screening." (2018) — PMID 28840303 — Conclusion: The precise benefits of pancreatic cancer screening remain unclear, though evidence is emerging that high-risk groups offer a window of opportunity to detect precursor lesions and early cancers.