Gallbladder Disease

• Definition: "Gallbladder disease" spans a continuum driven by one lesion — the gallstone. Cholelithiasis is stones within the gallbladder; biliary colic is transient cystic duct obstruction; acute cholecystitis is sustained obstruction with inflammation; choledocholithiasis is stone migration into the common bile duct, which in turn causes gallstone pancreatitis and ascending cholangitis.
• Why it matters: Biliary disease is among the most common reasons for emergency abdominal surgery in the United States, and laparoscopic cholecystectomy is one of the most frequently performed general surgical operations. The clinical task on exams is almost always to place the patient on this continuum, because each step has a different next test and a different intervention.

Epidemiology worth recalling

• Prevalence: Gallstones are present in roughly 10-15% of US adults, consistent with the article's Quick Facts; the great majority remain silent for life, which is why asymptomatic stones are observed rather than removed.
• Sex and age: Female predominance is roughly 2:1 in reproductive years and narrows after menopause, reflecting estrogen-driven biliary cholesterol secretion and progesterone-driven gallbladder hypomotility. Prevalence rises steadily with age.
• Ancestry: Highest rates in Native American populations (Pima and other Southwestern tribes) and Mexican Americans; intermediate in non-Hispanic Whites; lowest in individuals of African and East Asian descent. A stem naming Native American ancestry is pointing at cholesterol stones.
• Stone type: Cholesterol and mixed stones account for the large majority in Western populations; pigment stones dominate where chronic hemolysis or biliary parasitism is endemic.
• Natural history: Once biliary colic occurs, recurrence is the rule and the risk of progressing to cholecystitis or a ductal complication rises — the rationale for elective cholecystectomy after a first symptomatic attack.
• Malignancy: Gallbladder adenocarcinoma is uncommon but highly lethal, and nearly always arises in a stone-bearing, chronically inflamed gallbladder.

Cholesterol stones (majority in the US) — mechanism is supersaturation, nucleation, and stasis

• Biliary cholesterol supersaturation: Cholesterol is insoluble and held in micelles/vesicles by bile salts and phospholipids. Excess cholesterol secretion or a deficient bile salt pool tips the ratio (Admirand's triangle) and crystals precipitate.
• Bile salt pool depletion: Terminal ileal disease or resection (Crohn disease), and cystic fibrosis, interrupt enterohepatic circulation of bile salts. This is the classic stem: a Crohn patient with cholesterol stones and oxalate kidney stones.
• Gallbladder hypomotility: Pregnancy, prolonged TPN/NPO status, rapid weight loss after bariatric surgery, spinal cord injury, and somatostatin analogs (octreotide) all promote stasis, sludge, and nucleation.

Pigment stones

• Black stones: Chronic hemolysis (sickle cell disease, hereditary spherocytosis, thalassemia, mechanical valve hemolysis) and cirrhosis increase unconjugated bilirubin load → calcium bilirubinate precipitation.
• Brown stones: Biliary infection or stasis; bacterial β-glucuronidase deconjugates bilirubin. Associated with liver flukes (Clonorchis sinensis, Opisthorchis) and Ascaris, and with biliary strictures.

Non-modifiable risk factors

• Female sex, age over 40, family history, Native American or Hispanic ancestry, and hemolytic or ileal disease.

Modifiable risk factors

• Obesity and metabolic syndrome/insulin resistance: increase hepatic cholesterol secretion.
• Rapid weight loss or very-low-calorie diets: mobilize cholesterol and impair emptying — the reason ursodeoxycholic acid is sometimes used prophylactically after bariatric surgery.
• Estrogen exposure: oral contraceptives, hormone therapy, pregnancy.
• Drugs: fibrates (increase biliary cholesterol), ceftriaxone (biliary *pseudolithiasis*/sludge, reversible), octreotide.
• Total parenteral nutrition and prolonged fasting.

• Stone formation: Three conditions must coexist — cholesterol supersaturation, crystal nucleation (accelerated by mucin glycoproteins and calcium, retarded by apolipoproteins), and gallbladder hypomotility that allows crystals time to aggregate. Sludge is the intermediate step between supersaturated bile and a macroscopic stone.
• Biliary colic: A fatty meal releases cholecystokinin from duodenal I cells → gallbladder contraction against a stone lodged in the neck or cystic duct. Intraluminal pressure rises, stretching visceral afferents that travel with sympathetic fibers to T5-T9. Because the signal is visceral and bilateral, pain is poorly localized, epigastric or RUQ, and referred to the right scapula or shoulder. When the stone falls back, pressure normalizes and pain resolves in under several hours — this is why colic is self-limited and there is no fever or leukocytosis.
• Acute cholecystitis: If the stone stays impacted, the sequence is obstruction → continued mucosal secretion → distension → venous and lymphatic congestion → mucosal ischemia. Trapped bile salts and lysolecithin are directly cytotoxic, generating a chemical inflammation; bacterial superinfection (E. coli, Klebsiella, Enterococcus, anaerobes) follows secondarily rather than initiating the process. Once the inflamed serosa contacts the parietal peritoneum, pain becomes somatic — sharply localized to the RUQ, worsened by movement, and reproducibly halting inspiration when the descending gallbladder strikes the examiner's hand (Murphy's sign).
• Systemic response: Cytokine release explains fever, leukocytosis, and elevated CRP; these are the "systemic" limb of the Tokyo Guidelines 2018 diagnostic criteria.
• Ductal complications: A stone passing the cystic duct may impact anywhere along the common bile duct. A stone impacting at the ampulla — at or below the confluence of the pancreatic and bile ducts — obstructs pancreatic outflow and causes gallstone pancreatitis, whereas impaction in the CBD above that confluence produces obstructive jaundice or cholangitis alone. Ductal obstruction raises biliary pressure above the secretory pressure of bile, forcing bacteria into hepatic sinusoids — cholangiovenous reflux, the mechanism of the bacteremia and shock of ascending cholangitis. Cholestasis produces conjugated hyperbilirubinemia with an alkaline phosphatase- and GGT-predominant pattern.

Biliary colic (uncomplicated cholelithiasis)

• Episodic RUQ/epigastric pain: Steady and crescendo-decrescendo rather than true "colic," beginning 30-60 minutes after a fatty meal or at night, plateauing, then resolving within hours as the stone disimpacts. Nausea and vomiting are common.
• Referred right subscapular or shoulder pain: from T5-T9 visceral afferents and phrenic irritation.
• Normal vital signs, normal WBC and liver chemistries, no peritoneal signs — the discriminating feature from cholecystitis.

Acute cholecystitis

• Persistent RUQ pain lasting beyond several hours with anorexia, nausea, and low-grade fever. The stem typically names an obese woman in her forties, or a patient with recent rapid weight loss.
• Murphy's sign: inspiratory arrest on RUQ palpation — reasonably specific but only moderately sensitive; a negative Murphy's sign does not exclude cholecystitis. The sonographic Murphy's sign combined with stones on ultrasound carries the higher predictive value. Reliability falls further in the elderly, in whom presentation may be only anorexia and confusion.
• Boas sign: hyperesthesia below the right scapula.
• Guarding and localized rebound: parietal peritoneal involvement; a palpable tender mass suggests phlegmon or empyema.
• Mild jaundice: unusual; if bilirubin is markedly elevated, think choledocholithiasis or Mirizzi syndrome rather than simple cholecystitis.

Acalculous cholecystitis

• Unexplained fever, leukocytosis, or sepsis in an ICU patient on TPN or vasopressors, often unable to report pain. Suspicion must be volunteered by the clinician.

Ascending cholangitis

• Charcot triad (RUQ pain, fever, jaundice) and, with sepsis, Reynolds pentad (adding hypotension and altered mental status) — typically an older patient, frequently after prior biliary instrumentation.

Chronic cholecystitis / biliary dyskinesia

• Recurrent postprandial pain with fatty food intolerance and bloating, sometimes with a normal-appearing gallbladder on ultrasound.

Initial evaluation

• Laboratory studies: CBC (leukocytosis with left shift), CRP, comprehensive metabolic panel, and lipase. In uncomplicated cholecystitis, liver chemistries are normal or only mildly abnormal; a cholestatic pattern (alkaline phosphatase and conjugated bilirubin elevation) or an elevated lipase redirects you to the bile duct or pancreas.
• Right upper quadrant ultrasound — first-line, per ACR Appropriateness Criteria. Look for: echogenic stones with posterior acoustic shadowing that move with position; gallbladder wall thickening greater than 3 mm; pericholecystic fluid; gallbladder distension; and a sonographic Murphy's sign. A common bile duct diameter above roughly 6 mm in a patient with a gallbladder suggests ductal obstruction (normal caliber increases with age and after cholecystectomy).

Confirmatory testing

• Cholescintigraphy (HIDA): reserved for equivocal ultrasound. Nonvisualization of the gallbladder at 60 minutes indicates cystic duct obstruction and is the most accurate test for acute cholecystitis; false positives occur with prolonged fasting or TPN. Cholecystokinin-stimulated ejection fraction below 35-40% supports biliary dyskinesia.
• CT: not the test of choice for stones (many are radiolucent) but detects perforation, emphysematous change, and alternative diagnoses.
• MRCP or endoscopic ultrasound: for suspected choledocholithiasis without an indication for immediate ERCP.

Named criteria

• Tokyo Guidelines 2018 (TG18) for acute cholecystitis: local inflammatory signs (Murphy's sign, RUQ mass/pain/tenderness) + systemic signs (fever, elevated CRP, elevated WBC) + characteristic imaging = definite diagnosis. Severity is graded I (mild), II (moderate), and III (severe — organ dysfunction). Grade II anchors: WBC greater than 18,000/mm³, a palpable tender RUQ mass, symptom duration beyond 72 hours, or marked local inflammation such as gangrenous or emphysematous cholecystitis, pericholecystic or hepatic abscess, or biliary peritonitis.
• TG18 for acute cholangitis: systemic inflammation + cholestasis + imaging evidence of biliary dilation or etiology.
• ASGE risk stratification for choledocholithiasis: high-risk features (CBD stone visualized on imaging, clinical cholangitis, or a substantially elevated bilirubin with a dilated duct) proceed directly to ERCP; intermediate risk goes to EUS, MRCP, or intraoperative cholangiography first.

Immediate measures for acute cholecystitis

• NPO, isotonic IV fluids, correction of electrolytes, and analgesia. NSAIDs (ketorolac) are effective for biliary pain and may reduce progression; opioids are acceptable — the notion that morphine is forbidden because of sphincter of Oddi spasm is a distractor without clinical outcome data.
• Antibiotics: empiric coverage of enteric gram-negatives and anaerobes, per Tokyo Guidelines 2018 and the Surgical Infection Society/IDSA intra-abdominal infection guidance. Community-acquired mild-to-moderate disease: a third-generation cephalosporin such as ceftriaxone plus metronidazole. Severe, healthcare-associated, or grade III disease: piperacillin-tazobactam or a carbapenem. After uncomplicated cholecystectomy with adequate source control, antibiotics are stopped within about 24 hours.

Definitive management

• Early laparoscopic cholecystectomy is the standard of care for grade I and appropriately selected grade II cholecystitis (TG18, SAGES), performed during the index admission and preferably early in the course rather than after a delayed interval.
• Critical view of safety dissection is the SAGES-endorsed technique to prevent bile duct injury; conversion to open or subtotal cholecystectomy is a sound bailout, not a failure.
• Percutaneous cholecystostomy for grade III disease or prohibitive operative risk, with interval cholecystectomy once stabilized.

Ductal disease

• Choledocholithiasis: ERCP with sphincterotomy and stone extraction, or laparoscopic common bile duct exploration, followed by cholecystectomy.
• Ascending cholangitis: resuscitation and antibiotics, then urgent biliary decompression by ERCP, expedited within about 24 hours and sooner in septic shock (TG18, ASGE).
• Gallstone pancreatitis: per the American College of Gastroenterology, cholecystectomy during the same admission for mild disease; ERCP only if there is concurrent cholangitis or persistent obstruction.

Non-operative and special populations

• Ursodeoxycholic acid dissolves only small, radiolucent cholesterol stones in a functioning gallbladder and relapse is common — not a substitute for surgery.
• Do not perform elective cholecystectomy for asymptomatic stones outside the exceptions already listed.
• Pregnancy: ultrasound is first-line and MRCP is preferred over CT to avoid ionizing radiation; laparoscopic cholecystectomy is safe in any trimester when indicated (historically favored in the second) and is supported by ACOG and SAGES; ERCP with abdominal shielding and minimized fluoroscopy time is acceptable for choledocholithiasis or cholangitis.

Complications of the disease

• Gangrenous cholecystitis — emergency. Progressive ischemia of the distended wall; suspect with high fever, marked leukocytosis, and a paradoxically less tender abdomen as necrosis denervates the wall. Most common in diabetics and older men.
• Perforation — emergency. Free perforation causes bilious peritonitis and shock; contained perforation yields a pericholecystic abscess.
• Emphysematous cholecystitis — emergency. Gas-forming organisms, classically Clostridium perfringens, in diabetic patients; gas within the gallbladder wall on CT or plain film.
• Empyema/hydrops: pus or sterile mucin in an obstructed gallbladder; palpable tender mass.
• Choledocholithiasis and ascending cholangitis: cholangiovenous reflux → bacteremia and septic shock (Reynolds pentad).
• Gallstone pancreatitis: ampullary obstruction; epigastric pain radiating to the back with elevated lipase.
• Cholecystoenteric fistula and gallstone ileus: chronic pressure necrosis erodes into duodenum; Rigler triad of pneumobilia, small bowel obstruction, and an ectopic gallstone. Impaction in the duodenum is Bouveret syndrome.
• Porcelain gallbladder and gallbladder carcinoma: chronic inflammation → dysplasia; painless jaundice with a palpable gallbladder (Courvoisier) suggests malignant obstruction.
• **Chronic cholecystitis with a *Rokitansky-Aschoff sinus*-containing, fibrotic gallbladder**: the histologic endpoint of repeated attacks.

Complications of treatment

• Bile duct injury: the feared laparoscopic complication, usually from misidentifying the CBD as the cystic duct; presents with postoperative pain, jaundice, or biliary ascites — prevented by the critical view of safety (SAGES).
• Cystic duct stump leak: RUQ pain, fever, and a fluid collection days after surgery; diagnosed by HIDA and treated with ERCP stenting.
• Retained CBD stone and post-cholecystectomy syndrome: persistent pain with cholestatic labs.
• Post-ERCP pancreatitis: the most common ERCP complication; ASGE supports periprocedural rectal NSAID (indomethacin) prophylaxis. Bleeding after sphincterotomy, perforation, and cholangitis also occur.
• Cholecystostomy tube dislodgement or bile leak.

• Duration of pain sorts the diagnosis: postprandial RUQ pain resolving within hours, with normal labs, is biliary colic → elective laparoscopic cholecystectomy. Pain persisting beyond several hours with fever and leukocytosis is acute cholecystitis → admit, antibiotics, early cholecystectomy.
• Single best next step for RUQ pain is always ultrasound, per ACR Appropriateness Criteria — not CT, not HIDA. HIDA is the tiebreaker only when the ultrasound is equivocal; nonvisualization of the gallbladder confirms cystic duct obstruction.
• Marked hyperbilirubinemia does not belong to simple cholecystitis. If bilirubin and alkaline phosphatase are clearly elevated, the stone is in the common duct (or compressing it — Mirizzi syndrome), and the pathway shifts to ASGE risk stratification and ERCP.
• Cholangitis is decompression, not just antibiotics. Fluids and antibiotics first, then urgent ERCP with sphincterotomy; delay increases mortality. Reynolds pentad means septic shock.
• The association examiners love: ileal resection or Crohn disease → bile salt malabsorption → cholesterol gallstones plus calcium oxalate kidney stones. Chronic hemolysis (sickle cell, spherocytosis) → black pigment stones.
• Air where it should not be: gas in the gallbladder wall = emphysematous cholecystitis (Clostridium perfringens, diabetic patient, surgical emergency); pneumobilia with small bowel obstruction and an ectopic stone = Rigler triad of gallstone ileus.
• Gallstone pancreatitis: the ACG recommends cholecystectomy during the same hospitalization for mild disease — discharging the patient for "interval" surgery is the wrong answer.
• Common distractors to avoid: morphine is not contraindicated in biliary pain; asymptomatic gallstones do not warrant prophylactic cholecystectomy except for the specific indications already listed; and ursodeoxycholic acid is not a substitute for surgery in a symptomatic patient.

• Cholelithiasis (gallstones) present in 10-15% of population; only 1-3% develop symptoms annually
• Cholecystitis is inflammation (90% from cystic duct obstruction by stone; 10% acalculous)
• Cholangitis = infected bile ducts; medical emergency with Charcot's triad (fever, jaundice, RUQ pain)
• Risk factors: 4 F's = Fat, Female, Forty, Fertile (also: rapid weight loss, cirrhosis, TPN)
• Ultrasound is first-line imaging for suspected gallbladder disease

• Murphy's sign = inspiratory arrest on RUQ palpation during deep breath (specific for acute cholecystitis)
• Courvoisier's sign = palpable gallbladder + painless jaundice (suggests malignancy, not stone)
• Pneumobilia = suggests gallstone ileus (stone erodes through GB→bowel, rare complication)
• Mirizzi syndrome = stone compresses common hepatic duct → jaundice without CBD stones
• HIDA scan = gold standard for cystic duct patency; absent filling = acute cholecystitis
• Transcystic vs. transductal: transcystic ERCP preferred if stones in CBD and patent cystic duct

• Acalculous cholecystitis misses: 30-50% mortality because symptoms atypical and imaging lacks stones—must maintain high suspicion in ICU patients, post-op sepsis, or prolonged NPO; diagnosed by HIDA scan (no stone but no cystic duct filling) or ultrasound with gallbladder wall thickening >3mm
• Cholangitis = medical emergency requiring antibiotics + drainage (not just supportive care); delayed ERCP increases mortality; don't wait for imaging
• Pregnancy caveat: Cholecystectomy safest in 2nd trimester if urgent; acute cholecystitis in pregnancy = high fetal loss if untreated but surgery still indicated for severe cases

• Acute cholecystitis (calculous): NPO, IV fluids, antibiotics (ceftriaxone/fluoroquinolone), laparoscopic cholecystectomy within 72 hours (gold standard); percutaneous cholecystostomy if high operative risk
• Acalculous cholecystitis: Supportive care + address underlying cause (sepsis, restore perfusion); cholecystectomy if no improvement in 48-72 hours or perforation
• Cholangitis: Urgent ERCP + sphincterotomy ± biliary stent after antibiotics; repeat labs, blood cultures; manage sepsis aggressively
• Asymptomatic cholelithiasis: Observation (prophylactic cholecystectomy only for cirrhosis, hemolytic anemia, porcelain GB, or gallbladder cancer risk)