Cholelithiasis (นิ่วน้ำดี นิ่วถุงน้ำดี นิ่วท่อน้ำดี)

• ICD10:
  • K80.0 – Calculus of gallbladder with acute cholecystitis
  • K80.2 – Calculus of gallbladder without cholecystitis
  • K80.3 – Calculus of bile duct with cholangitis
  • K80.5 – Calculus of bile duct without cholangitis or cholecystitis
  • K80.8 – Other cholelithiasis
• ICD11:
  • DB51.0 – Calculus of gallbladder with cholecystitis
  • DB51.1 – Calculus of gallbladder without cholecystitis
  • DB51.2 – Calculus of bile duct with cholangitis
  • DB51.3 – Calculus of bile duct without cholangitis or cholecystitis
  • DB51.Z – Other specified or unspecified cholelithiasis

Overview

Cholelithiasis refers to the formation or presence of gallstones within the biliary tract, encompassing stones in the gallbladder (cholecystolithiasis), common bile duct (choledocholithiasis), or intrahepatic bile ducts (hepatolithiasis). Gallstones are crystalline concretions that develop from components of bile — primarily cholesterol, bilirubin, and calcium salts. The pathogenesis involves an imbalance between bile components, biliary stasis, and mucosal factors promoting nucleation.

Clinically, gallstones may remain asymptomatic or present with biliary colic, jaundice, or complications such as acute cholecystitis, cholangitis, and pancreatitis. While up to 70–80% of patients with gallstones remain asymptomatic, complications can be life-threatening when stones migrate or obstruct bile flow.

Diagnosis primarily relies on abdominal ultrasonography, which provides high sensitivity for gallbladder stones. For common bile duct stones, magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) is used. Management ranges from conservative observation in asymptomatic patients to laparoscopic cholecystectomy or endoscopic stone extraction in symptomatic or complicated cases.

Epidemiology

Gallstone disease is one of the most prevalent gastrointestinal disorders worldwide, affecting approximately 10–20% of the adult population. The incidence increases with age, and women are more commonly affected than men due to hormonal influences from oestrogen, which increases biliary cholesterol saturation.

Risk factors for cholelithiasis are classically summarised as the “four F’s”: female, fat, fertile, and forty. Additional risk factors include obesity, rapid weight loss, diabetes mellitus, dyslipidaemia, pregnancy, and certain medications (e.g., oestrogen therapy, fibrates). Pigment stones are associated with chronic haemolytic states (e.g., thalassemia, sickle cell disease), biliary infections, or cirrhosis.

Epidemiological distribution varies geographically. Cholesterol stones predominate in Western populations, while pigment stones are more prevalent in Asia due to higher rates of biliary infections and parasitic infestations. In Thailand and other Southeast Asian countries, hepatolithiasis (intrahepatic duct stones) remains relatively common. With modern imaging and minimally invasive techniques, early detection and treatment have significantly reduced morbidity and mortality from gallstone-related complications.

Biliary Anatomy

The biliary system consists of the intrahepatic and extrahepatic ducts responsible for transporting bile from the liver to the duodenum. Intrahepatic bile ducts begin with canaliculi formed between hepatocytes, merging into segmental ducts and larger hepatic ducts. The right and left hepatic ducts join to form the common hepatic duct (CHD). From the gallbladder, bile drains via the cystic duct, which meets the CHD to form the common bile duct (CBD). The CBD travels posterior to the pancreas and enters the second portion of the duodenum through the ampulla of Vater, regulated by the sphincter of Oddi. The gallbladder functions as a reservoir, concentrating bile during fasting and contracting in response to cholecystokinin (CCK) after meals. This anatomical arrangement influences where gallstones can lodge, determining clinical presentation — gallbladder stones cause biliary colic, CBD stones lead to obstructive jaundice or cholangitis, and intrahepatic stones trigger recurrent cholangitis.

Classification of Gallstones

Gallstones are broadly categorised into three main types: cholesterol stones, pigment stones, and mixed stones. Each type forms through distinct biochemical mechanisms and is associated with different risk factors and clinical patterns.

1. Cholesterol stones Cholesterol stones account for approximately 70–80% of gallstones in Western populations. They develop when bile becomes supersaturated with cholesterol, leading to crystallisation and stone formation. Factors contributing include obesity, metabolic syndrome, diabetes, oestrogen therapy, pregnancy, and rapid weight loss. Reduced gallbladder motility (hypomotility) also promotes stasis, allowing crystals to aggregate. These stones are typically yellow-to-green and radiolucent on plain radiography. Cholesterol stones most commonly form in the gallbladder but may migrate to the common bile duct.

2. Pigment stones Pigment stones are subdivided into black and brown stones. Black pigment stones form primarily in sterile environments such as the gallbladder and are associated with chronic haemolytic disorders (e.g., thalassemia, sickle cell disease), cirrhosis, and increased bilirubin load. They consist primarily of calcium bilirubinate and are often radiopaque on imaging. Brown pigment stones, on the other hand, form in infected bile ducts and are linked to biliary stasis, parasitic infections, and bacterial β-glucuronidase activity. They are softer, brown in colour, and more common in East and Southeast Asia, especially in intrahepatic ducts.

3. Mixed stones Mixed stones contain varying proportions of cholesterol, calcium salts, and bilirubin. They arise due to a combination of metabolic and infectious mechanisms. These stones often originate as cholesterol stones but become impregnated with calcium salts as inflammation progresses. Mixed stones are common in patients who have chronic gallbladder inflammation or intermittent biliary obstruction.

Overall, understanding gallstone classification assists clinicians in predicting clinical complications, choosing imaging modalities, and selecting appropriate interventions such as ERCP for ductal stones or laparoscopic cholecystectomy for gallbladder stones.

Pathophysiology

Gallstone formation is a complex, multi-step process arising from biochemical imbalances within bile, gallbladder dysmotility, and intraductal environmental changes. Although gallstones vary in composition (cholesterol, black pigment, brown pigment, or mixed), the underlying mechanisms share common principles involving supersaturation, nucleation, crystal growth, aggregation, and impaired bile flow. The pathophysiology differs slightly between gallbladder stones, common bile duct (CBD) stones, and intrahepatic duct stones; however, they share overlapping mechanisms driven by changes in bile chemistry, inflammation, and microbial activity.

1. Cholesterol Supersaturation: The Initiating Step

Cholesterol stones—the most prevalent type—develop when bile becomes supersaturated with cholesterol relative to bile salts and phospholipids. Normally, cholesterol is solubilised in mixed micelles composed of bile salts and lecithin. When cholesterol exceeds the solubilising capacity of micelles, the excess precipitates as cholesterol monohydrate crystals. This supersaturation results from:

• Increased hepatic cholesterol secretion: Often due to obesity, insulin resistance, oestrogen exposure, pregnancy, and high-calorie diets.
• Decreased bile salt synthesis: Seen in Crohn’s disease, ileal resection, cirrhosis, and malabsorption.
• Increased lecithin excretion imbalance: Alters micelle composition, promoting phase separation.

The “lithogenic bile” environment primes the biliary tract for stone formation.

2. Nucleation and Crystal Formation

Once cholesterol becomes supersaturated, crystallisation begins. Nucleation is accelerated when there is inflammation of the gallbladder mucosa, which releases mucin glycoproteins. Mucin acts as a scaffold that traps cholesterol monohydrate crystals and allows them to grow. Pro-nucleating factors include:

• Mucin hypersecretion from chronic cholecystitis
• Bacterial β-glucuronidase activity (particularly in brown pigment stones)
• Calcium salts, which promote crystal aggregation
• Reduced concentrations of anti-nucleating proteins such as apolipoproteins AI and AII

In the gallbladder, inflamed epithelium contributes directly to mucus hypersecretion, increasing viscosity and promoting the entrapment of crystals.

3. Gallbladder Hypomotility and Biliary Stasis

Stasis is a key event in cholesterol stone formation because stagnant bile provides time for crystals to aggregate into macroscopic stones. Gallbladder hypomotility occurs due to:

• Pregnancy (progesterone-induced muscle relaxation)
• Prolonged fasting or total parenteral nutrition
• Spinal cord injury
• Diabetes-related autonomic neuropathy
• Gallbladder inflammation (decreased contractile response to CCK)

A poorly emptying gallbladder allows cholesterol crystals to accumulate layer by layer, developing into cholesterol stones ranging from small grains (“sludge”) to large solitary stones.

4. Pathophysiology of Pigment Stones

4.1 Black Pigment Stones

Black pigment stones form primarily in the gallbladder under sterile conditions. They consist of polymerised calcium bilirubinate mixed with inorganic salts. They arise due to increased unconjugated bilirubin load, most commonly from:

• Chronic haemolysis (thalassemia, sickle cell disease, hereditary spherocytosis)
• Cirrhosis and impaired bilirubin conjugation
• Ineffective erythropoiesis

Unconjugated bilirubin binds to calcium to form insoluble complexes that precipitate and crystallise. Chronic gallbladder stasis and mucosal injury accelerate precipitation and stone growth.

4.2 Brown Pigment Stones

Brown pigment stones form within infected bile ducts (CBD or intrahepatic ducts) and are strongly associated with bacterial infection or parasitic infestation. Common pathogens include E. coli, Klebsiella, Enterococcus, and Clonorchis/Opisthorchis species. Bacterial β-glucuronidase, phospholipase, and hydrolase enzymes deconjugate bilirubin and hydrolyse phospholipids, producing calcium bilirubinate and free fatty acids, which aggregate to form soft, friable brown stones.

These stones are common in Southeast Asia and often recur due to underlying biliary strictures, postoperative anatomy, or parasitic disease. They tend to form within narrowed ducts where bile flow is sluggish.

5. Intrahepatic Duct Stones (Hepatolithiasis)

Intrahepatic duct stones form due to a combination of stasis, recurrent infection, and strictures within segmental bile ducts. These stones are usually brown pigment stones and highly associated with chronic hepatobiliary infections, particularly in East and Southeast Asia. Mechanisms include:

• Intrahepatic duct strictures → impaired bile drainage
• Chronic bacterial colonisation → enzymatic alteration of bile
• Mucin secretion from inflamed ducts → nucleation matrix
• Cholestasis and impaired bile acid secretion

Hepatolithiasis predisposes to recurrent cholangitis, biliary cirrhosis, portal hypertension, and cholangiocarcinoma. Its pathophysiology is distinctively driven by infection–stasis cycles rather than metabolic factors.

6. Role of Inflammation and Gallbladder Wall Changes

Inflammation contributes significantly to stone pathogenesis by altering the gallbladder microenvironment. Chronic cholecystitis leads to:

• Mucin hypersecretion → traps crystals
• Increased prostaglandin synthesis → enhances mucus production
• Epithelium damage → exposes surface for crystal attachment
• Reduced contractility → worsens bile stasis

These changes accelerate both nucleation and stone growth.

7. Crystal Aggregation and Stone Maturation

After initial nucleation, crystals undergo aggregation and fusion. Calcium plays a crucial role by binding to cholesterol crystals and bilirubinate, creating a solid matrix. Over time, stones enlarge through repetitive cycles of:

• Cholesterol crystal deposition
• Mucin trapping
• Layer-by-layer mineralisation
• Biliary stasis

Mixed stones form when cholesterol stones become coated with calcium bilirubinate or when infection superimposes on pre-existing cholesterol stones.

8. Migration and Ductal Stone Pathophysiology

Gallbladder stones may migrate into the common bile duct, becoming secondary CBD stones. In contrast, primary ductal stones form within the duct itself, typically due to stasis, strictures, or infection.

CBD stones obstruct bile flow, leading to:

• Obstructive jaundice from elevated conjugated bilirubin
• Cholangitis from bacterial ascent and biliary stasis (Charcot’s triad: fever, jaundice, RUQ pain)
• Biliary pancreatitis due to obstruction of the pancreatic duct

The physiologic consequences depend heavily on obstruction severity and infection status.

9. Summary

Gallstone formation is a multifactorial process driven by biochemical imbalance, biliary stasis, infection, and inflammation. Cholesterol stones arise primarily from metabolic alterations and gallbladder hypomotility, whereas pigment stones are usually related to haemolysis or infection. Intrahepatic stones reflect chronic infectious–obstructive processes. Understanding these mechanisms is essential for diagnosing complications, guiding treatment—such as ERCP or cholecystectomy—and predicting recurrence, particularly in patients with anatomical or infectious risk factors.

Risk Factors of Stone Formation

Gallstone formation results from a combination of metabolic, genetic, infectious, and environmental factors that alter bile composition, impair gallbladder motility, or promote biliary stasis. These risk factors differ slightly between cholesterol stones, pigment stones, and intrahepatic duct stones, but many mechanisms overlap. Understanding these risks is essential for identifying high-risk populations and guiding preventive strategies.

1. Metabolic and Lifestyle Factors Cholesterol gallstones are strongly associated with metabolic syndrome, obesity, insulin resistance, dyslipidaemia, and rapid weight loss. High body mass increases hepatic cholesterol synthesis and biliary excretion, promoting supersaturated bile. Diets high in calories, refined carbohydrates, and saturated fats further increase lithogenic risk. Prolonged fasting or very-low-calorie diets also precipitate stone formation due to gallbladder hypomotility.

2. Hormonal and Gender-Related Factors Women have a significantly higher incidence of gallstones due to the effects of oestrogen, which increases hepatic cholesterol secretion, and progesterone, which reduces gallbladder motility. Therefore, pregnancy, oral contraceptive use, and hormone replacement therapy are established risk factors. The classic “Four F’s”—female, fat, fertile, forty—summarise this hormonal influence.

3. Haemolytic and Hepatic Disorders Conditions associated with chronic haemolysis, such as thalassemia, sickle cell disease, hereditary spherocytosis, and mechanical heart valves, increase bilirubin turnover and predispose to black pigment stones. Cirrhosis also elevates unconjugated bilirubin levels and alters bile acid composition, contributing to stone formation.

4. Biliary Infection and Parasitic Exposure Brown pigment stones commonly arise in the setting of biliary infection. Bacteria such as E. coli, Klebsiella, and Enterococcus produce β-glucuronidase, which deconjugates bilirubin and promotes calcium bilirubinate precipitation. Parasitic infections (Clonorchis sinensis, Opisthorchis viverrini) and biliary strictures are major contributors to intrahepatic stones, especially in Southeast Asia.

5. Gallbladder Motility Disorders Chronic gallbladder stasis is a major risk factor for cholesterol stone formation. Hypomotility occurs in pregnancy, diabetes (autonomic neuropathy), spinal injury, and prolonged fasting. Inflammation from chronic cholecystitis also reduces contractile responsiveness, promoting sludge and stone formation.

6. Genetic and Familial Predisposition Variants in genes related to cholesterol transport (ABCG5/ABCG8) increase biliary cholesterol secretion, significantly elevating gallstone risk. Family history is a well-recognised predisposing factor.

In summary, gallstone formation is multifactorial, driven by metabolic imbalance, hormonal effects, biliary infection, stasis, and genetic susceptibility. Identifying these risks allows clinicians to anticipate complications and counsel patients appropriately.

Complication

Complications of cholelithiasis arise when gallstones obstruct the biliary tract, leading to inflammation, infection, or pancreatic involvement. While many gallstones remain asymptomatic, obstruction at various anatomical sites produces distinct clinical syndromes with characteristic signs and symptoms. Complications include acute cholecystitis (cystic duct obstruction), choledocholithiasis (common bile duct obstruction), acute cholangitis (infected biliary obstruction), gallstone pancreatitis (ampullary obstruction), Mirizzi syndrome (external compression of the common hepatic duct), and gallbladder empyema or perforation. Because symptoms may resemble other abdominal or hepatobiliary diseases, these complications often require careful differential diagnosis and timely imaging. Each condition may also link to broader topics in hepatobiliary pathology, such as obstructive jaundice, ascending cholangitis, and acute pancreatitis, which should be consulted for deeper understanding.

Complication	Pathogenesis	Frequency	Key Clinical Features / DDx Consideration
Acute Cholecystitis	Obstruction of the cystic duct → bile stasis → inflammation of the gallbladder wall → secondary bacterial infection may occur.	Common (10–20% of symptomatic gallstones)	RUQ pain, fever, Murphy’s sign positive. DDx: peptic ulcer disease, hepatitis, pancreatitis. Link: “Acute Cholecystitis Article”.
Choledocholithiasis	Stone obstructs the common bile duct → impaired bile drainage → rise in bilirubin and alkaline phosphatase.	~10–15% of patients with gallstones	Jaundice, dark urine, pale stool, RUQ discomfort. DDx: obstructive jaundice from tumour (e.g., pancreatic cancer, cholangiocarcinoma). Link: “Obstructive Jaundice Overview”.
Acute Cholangitis	Infected biliary obstruction → bacterial ascent from duodenum → systemic inflammatory response.	Potentially life-threatening but less common	Charcot’s triad: fever, jaundice, RUQ pain. Reynolds’ pentad with hypotension & confusion indicates severe sepsis. DDx: sepsis from other intra-abdominal infections. Link: “Cholangitis Management Guideline”.
Gallstone Pancreatitis	Stone lodges at the ampulla of Vater → obstructs pancreatic outflow → premature enzyme activation → pancreatic inflammation.	5–10% of gallstone patients	Severe epigastric pain radiating to back, elevated lipase/amylase. DDx: alcoholic pancreatitis, perforated ulcer. Link: “Acute Pancreatitis Article”.
Mirizzi Syndrome	Impacted stone in gallbladder neck or cystic duct compresses the common hepatic duct externally → obstructive jaundice.	Rare (<1%)	Jaundice plus cholecystitis-like pain; may mimic cholangiocarcinoma. DDx: biliary stricture, bile duct tumour. Link: “Biliary Stricture Evaluation”.
Gallbladder Empyema	Progression of acute cholecystitis → pus accumulation in gallbladder → high risk of sepsis.	Uncommon but serious	High fever, leukocytosis, toxic appearance. DDx: liver abscess, severe cholangitis. Link: “Gallbladder Infection Complications”.
Gallbladder Perforation	Untreated cholecystitis → ischemia → necrosis → perforation → bile leakage → peritonitis.	Rare (<1–2%)	Sudden worsening abdominal pain, guarding, signs of peritonitis. DDx: perforated peptic ulcer, ruptured appendix. Link: “Acute Abdomen (Peritonitis)”.
Biliary Enteric Fistula / Gallstone Ileus	Large gallstone erodes into bowel → obstruction at ileocecal valve.	Very rare	Small bowel obstruction symptoms: vomiting, distension. DDx: adhesions, hernia. Link: “Small Bowel Obstruction Article”.

Investigation

Evaluation of cholelithiasis and its complications focuses on detecting gallstones, identifying the site of obstruction, and assessing for infection or organ dysfunction. Ultrasound is the first-line modality because it is highly sensitive for gallbladder stones and can detect signs of inflammation such as gallbladder wall thickening or pericholecystic fluid. Common bile duct stones require more advanced imaging such as MRCP or EUS, while ERCP is reserved for therapeutic intervention. Laboratory tests help differentiate uncomplicated gallstones from cholangitis, pancreatitis, and other hepatobiliary diseases.

Prevention

Prevention of gallstone formation focuses on modifying metabolic, dietary, and lifestyle factors that contribute to cholesterol supersaturation and biliary stasis. Achieving and maintaining a healthy weight is one of the most important strategies, as obesity and rapid weight loss both increase the risk of cholesterol stone formation. Patients should avoid extreme diets, prolonged fasting, and very-low-calorie regimens that impair gallbladder emptying.

Dietary modifications include increasing fiber intake, consuming healthy fats (e.g., fish oils, olive oil), and reducing refined carbohydrates and trans fats. Regular physical activity enhances insulin sensitivity and reduces hepatic cholesterol secretion. For at-risk patients such as those undergoing bariatric surgery, prophylactic ursodeoxycholic acid can reduce stone formation by stabilising bile composition.

Prevention of pigment stones involves reducing infection-related risks. In endemic regions, prevention of liver fluke infections through proper food hygiene and parasite control programs is essential. Treating chronic haemolytic disorders and maintaining adequate hydration further reduce risk. Overall, prevention relies on addressing metabolic, infectious, and structural contributors to lithogenesis.

Quiz (USMLE OSCE)

Frequently Asked Questions (FAQ)

What symptoms suggest that gallstones have caused a complication?

Complicated cholelithiasis typically presents with more severe symptoms than simple biliary colic. Warning signs include persistent right upper quadrant pain lasting >6 hours, fever, jaundice, vomiting, dark urine, pale stools, or signs of sepsis. These may indicate acute cholecystitis, cholangitis, or gallstone pancreatitis. Patients with these symptoms should seek urgent medical evaluation.

Can gallstones occur without symptoms?

Yes. Up to 70–80% of gallstones are asymptomatic and discovered incidentally on imaging. Asymptomatic stones often require no treatment; however, certain high-risk groups—such as patients with large stones (>3 cm), gallbladder polyps, porcelain gallbladder, or hemolytic disease—may benefit from preventive cholecystectomy due to increased risk of complications.

How can I differentiate gallstone pain from acid reflux or gastritis?

Gallstone pain (biliary colic) typically occurs in the right upper quadrant or epigastrium, starts suddenly, peaks within minutes, and lasts 30 minutes to several hours. Acid reflux or gastritis usually presents with burning epigastric discomfort, often associated with meals and improving with antacids. Gallstone pain does not usually respond to antacids and may radiate to the scapula or back.

Are common bile duct stones always painful?

No. Choledocholithiasis can be silent, especially if obstruction is partial. However, complete obstruction leads to jaundice, cholangitis, or pancreatitis. Laboratory abnormalities such as elevated ALP or bilirubin may be the first clue. MRCP or EUS helps identify silent ductal stones.

Can gallstones come back after surgery?

After cholecystectomy, recurrent stones may still form in the bile ducts, especially in patients with persistent infection, biliary strictures, or liver fluke exposure. These are called primary ductal stones and differ from stones that originally migrated from the gallbladder. Maintaining good liver health and treating underlying risk factors reduces recurrence.