Cholelithiasis and Cholecystitis

• Bile Supersaturation and Crystallization: The hepatocyte synthesizes bile containing cholesterol, phospholipids (primarily lecithin), and bile acids in a micellar solution. When hepatic cholesterol secretion increases (from increased dietary cholesterol, obesity, rapid weight loss, or genetic factors) or bile acid synthesis decreases (ileal disease, medications), the cholesterol-to-phospholipid-bile acid ratio exceeds the solubilizing capacity of mixed micelles. Excess cholesterol precipitates as monohydrate crystals, which aggregate into macroscopic stones. This process typically occurs in the gallbladder fundus where bile is concentrated; cholesterol accounts for 80-90% of stones in developed countries (cholesterol gallstones), while pigment stones (bilirubin-based) predominate in hemolytic disease and cirrhosis.

• Gallbladder Dysfunction and Stasis: Reduced gallbladder contractility (from prolonged fasting, total parenteral nutrition, diabetes, pregnancy, or medications) impairs bile turnover and promotes crystal nucleation and stone growth. Mucin hypersecretion by gallbladder epithelial cells, driven by altered eicosanoid metabolism and cytokine release, creates a gel-like matrix that traps cholesterol crystals and bile pigments. Bacterial overgrowth within stagnant bile may further promote pigment stone formation and inflammation.

• Cystic Duct Obstruction and Acute Inflammation: When a stone impacts the cystic duct, bile becomes sequestered, creating increased intraluminal pressure (up to 20 mmHg, normally <5 mmHg), which initiates a cascade of inflammatory responses. Ischemia from sustained pressure impairs mucosal barrier integrity, allowing transepithelial migration of bacteria and bacterial lipopolysaccharide (LPS) into the gallbladder wall. Resident macrophages and infiltrating neutrophils release tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8, amplifying mural inflammation and edema. Phospholipase A₂ released from damaged epithelium generates arachidonic acid metabolites (prostaglandins, leukotrienes) that further perpetuate inflammation. In uncomplicated acute cholecystitis, the inflammation remains contained to the gallbladder wall; however, if ischemia progresses to transmural necrosis, perforation may occur within 48-72 hours, leading to localized abscess formation or generalized bile peritonitis.

• Secondary Bacterial Infection: Initially, acute cholecystitis is sterile (chemical inflammation), but secondary bacterial infection occurs in 50-80% of cases by 24-48 hours. Common organisms include Escherichia coli, Klebsiella pneumoniae, Enterococcus faecalis, and anaerobes (Bacteroides fragilis, Clostridium species), typically reflecting normal biliary flora ascending from the duodenum. Acalculous cholecystitis (5-10% of cases), occurring without gallstones in critically ill patients, involves direct bacterial invasion or ischemia and carries higher morbidity and mortality.

• Chronic Cholecystitis: Repeated episodes of acute or subclinical inflammation lead to chronic changes: fibrosis and thickening of the gallbladder wall, epithelial ulceration, and eventually chronic cholecystitis characterized by mononuclear infiltration, fibrosis, and loss of normal contractility. Chronic inflammation may also predispose to gallbladder cancer, particularly when associated with porcelain gallbladder (calcified wall).

• Cholesterol Gallstones (80-90% of stones): Result from supersaturation of bile with cholesterol. Risk factors include obesity (BMI >30 kg/m²; relative risk 2-4), rapid weight loss (>1.5 kg/week activates lipolysis and increases hepatic cholesterol secretion), female sex (estrogen increases cholesterol secretion and reduces bile acid synthesis), age >40 years (reduced bile acid pool size), pregnancy and postpartum period (progesterone impairs contractility), family history (genetic predisposition to altered lipid metabolism), dyslipidemia, diabetes mellitus (associated with bile stasis and altered composition), and certain medications (estrogens, fibrates, octreotide). Dietary factors include high saturated fat intake and low fiber intake.

• Pigment Gallstones (10-20% of stones): Subdivided into black pigment stones and brown pigment stones. Black pigment stones (unconjugated bilirubin) predominate in hemolytic anemias (hereditary spherocytosis, sickle cell disease, thalassemia), cirrhosis, and chronic hemolysis; they are radiopaque in 10-15% of cases. Brown pigment stones (calcium bilirubinate, fatty acids) are associated with biliary stasis, ascending cholangitis, and parasitic infections (Clonorchis sinensis, Ascaris lumbricoides); they are more common in East Asian populations.

• Acalculous Cholecystitis: Accounts for 5-10% of acute cholecystitis cases. Risk factors include critical illness (sepsis, trauma, major surgery, prolonged mechanical ventilation), prolonged fasting or TPN, ischemia (atherosclerotic vascular disease, hypotension, vasculitis), infectious agents (cytomegalovirus in immunocompromised hosts, Salmonella, Leptospira), and biliary dyskinesia (reduced gallbladder ejection fraction <35% on hepatobiliary scintigraphy).

• Other Predisposing Conditions: Primary sclerosing cholangitis (increased risk of gallstones and cholangiocarcinoma), inflammatory bowel disease (terminal ileum disease reduces bile acid reabsorption), cystic fibrosis (inspissated bile and duct obstruction), and hemolytic transfusion reactions.

• Biliary Colic (Uncomplicated Symptomatic Cholelithiasis): Sudden onset of severe, steady right upper quadrant (RUQ) or epigastric pain, typically beginning 30 minutes to 2 hours after fatty meal ingestion (fat stimulates cholecystokinin secretion and gallbladder contraction, propelling stones against the cystic duct). Pain peaks within 15-30 minutes and usually resolves within 30 minutes to several hours. Patients often describe deep, aching discomfort rather than sharp pain. Associated symptoms include nausea and vomiting (from visceral afferent stimulation). Pain may radiate to the interscapular region, right shoulder, or epigastrium. Importantly, pain that persists >6 hours suggests acute cholecystitis rather than simple biliary colic.

• Acute Cholecystitis: Presents with constant RUQ pain (not colicky), typically lasting >6 hours, often accompanied by fever, nausea, and vomiting. Inflammatory mediators (TNF-α, IL-1β) and bacterial endotoxins trigger the systemic inflammatory response. Fever (>38°C) and systemic toxicity suggest bacterial invasion or perforation. Patients may report antecedent episodes of biliary colic.

• Right Upper Quadrant Tenderness: Physical examination reveals RUQ guarding and rebound tenderness reflecting peritoneal inflammation. Murphy's sign (inspiratory arrest during deep palpation of the RUQ as the descending diaphragm pushes the inflamed gallbladder fundus against the examiner's hand) is highly specific (95%) but only moderately sensitive (60-80%) for acute cholecystitis. A positive Murphy's sign requires hepatic tenderness during inspiration without preceding tenderness, as false positives occur with pleurisy or right lower lobe pneumonia. Courvoisier's sign (painless palpable gallbladder in a jaundiced patient) suggests malignant obstruction of the common bile duct rather than cholelithiasis.

• Jaundice and Cholangitis Features: Present if choledocholithiasis (stones in the common bile duct) occurs, causing biliary obstruction and ascending infection. Charcot's triad (fever, jaundice, RUQ pain) or Reynolds' pentad (Charcot's triad plus altered mental status and hypotension) indicates acute bacterial cholangitis, a medical emergency requiring urgent decompression.

• Chronic Cholecystitis: May present with dyspepsia, postprandial bloating, and chronic RUQ pain without acute exacerbations; symptoms often prove refractory to cholecystectomy, highlighting the overlap with functional dyspepsia.

• Atypical Presentations: Elderly patients and diabetics may present with subtle or atypical symptoms (absence of fever despite significant infection), delayed presentations, and higher rates of complications (emphysematous cholecystitis, perforation). Pregnant patients may present with more severe pain due to altered gallbladder physiology.

• Clinical History and Examination: Establish timing, character, location, and triggers of pain. Assess for biliary colic (postprandial, colicky) versus acute cholecystitis (constant, prolonged). Elicit risk factors (female, forty, fat, family history). Perform thorough RUQ examination, assess for Murphy's sign, and evaluate for signs of systemic infection (fever, tachycardia, tachypnea). Assess for jaundice (suggesting choledocholithiasis) and inspect skin/sclera.

• Laboratory Tests:
• Complete Blood Count (CBC): White blood cell (WBC) count >11,000/µL supports acute inflammation; markedly elevated counts (>15,000/µL) or left shift suggest complicated disease or perforation.
• Liver Function Tests (LFTs): Typically normal in uncomplicated cholelithiasis and biliary colic. In acute cholecystitis, mild elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) may occur (usually <4× upper limit of normal). Elevated alkaline phosphatase and hyperbilirubinemia (>3 mg/dL, conjugated >50%) suggest choledocholithiasis or common bile duct obstruction; amylase elevation raises concern for acute pancreatitis triggered by gallstone passage through the ampulla.
• Prothrombin Time (PT)/International Normalized Ratio (INR): Prolongation in cholestasis (impaired vitamin K absorption) or hepatic synthetic dysfunction.

• Hepatobiliary Ultrasound (Gold Standard for Cholelithiasis):
• Diagnostic Criteria for Gallstones: Echogenic intraluminal objects with acoustic shadowing, >2 mm in diameter, mobile within the gallbladder lumen. Sensitivity and specificity both exceed 95% for stones >2 mm.
• Murphy's Sign on Ultrasound: Localized tenderness directly over the gallbladder fossa during scanning (patient inspiration arrests when inflamed gallbladder fundus contacts the probe) increases specificity for acute cholecystitis.
• Acute Cholecystitis Findings: Gallbladder wall thickening (>3-4 mm; normal <3 mm), pericholecystic fluid (edema/peritonitis), increased echogenicity of the bile (sludge or infected bile), and absence of normal gallbladder distension. Sonographic Murphy's sign (focal tenderness) is present.
• Sensitivity: 95-98% for gallstones; 80-90% for acute cholecystitis (lower if acalculous).

• Hepatobiliary Scintigraphy (HIDA Scan): Uses technetium-99m iminodiacetic acid derivatives taken up by hepatocytes and excreted into bile.
• Normal: Hepatic uptake (5 minutes), biliary excretion into ducts and gallbladder (20 minutes), and duodenal activity (30-60 minutes).
• Acute Cholecystitis: Non-filling of the gallbladder after 4 hours despite duodenal activity (cystic duct obstruction); sensitivity 90-95%, specificity 85-95%.
• Utility: Reserved for equivocal ultrasounds or suspected acalculous cholecystitis (where ultrasound sensitivity is lower, 50-60%).

• CT Imaging: Not first-line but useful for assessing complications (perforation, abscess, emphysematous cholecystitis). CT shows gallstones, wall thickening, and free fluid. Multidetector CT can identify choledocholithiasis (ductal dilation, stone visualization), biliary pancreatitis, and alternative diagnoses.

• Diagnostic Criteria for Acute Cholecystitis (Tokyo Guidelines, revised 2018; used worldwide):
• Definite acute cholecystitis: Characteristic symptoms (RUQ/epigastric pain >6 hours) + imaging findings of gallstones/cystic duct obstruction + imaging signs of acute inflammation (gallbladder wall thickening, pericholecystic fluid, sonographic/ultrasound Murphy's sign).
• Grade I (mild): Local inflammation without organ dysfunction.
• Grade II (moderate): Local complications (abscess, fistula) or systemic inflammation (WBC >11,000, fever >38°C, palpable mass, pain >72 hours).
• Grade III (severe): Organ dysfunction (sepsis, acute renal failure, acute respiratory distress syndrome).

• Differential Diagnosis: Acute myocardial infarction (right ventricular infarction), pulmonary embolism, pneumonia, pleurisy, perforated peptic ulcer, acute appendicitis, acute pancreatitis (elevated amylase), renal colic (flank pain, hematuria, CT imaging), and hepatitis (diffuse LFT elevation, viral serology).

First-Line Treatment for Acute Cholecystitis

• Cholecystectomy (Definitive Treatment): Early laparoscopic cholecystectomy (within 72 hours of symptom onset) is the gold standard for uncomplicated acute cholecystitis in all patient populations. Advantages include lower morbidity, shorter hospitalization, faster recovery, and reduced risk of recurrent biliary events compared to delayed surgery. Conversion to open cholecystectomy occurs in 5-10% of cases, particularly in complicated disease, cirrhosis, or obesity. Laparoscopic approach has 90-95% success rate with complication rates <1% for bile duct injury (most feared complication; incidence 0.3-0.5%). In high-risk surgical candidates or during pandemics when surgery is delayed, percutaneous cholecystostomy (percutaneous drainage catheter placed under imaging guidance) serves as a temporizing measure.

• Supportive Care and Antibiotics:
• Fluid and Electrolyte Resuscitation: Aggressive IV hydration (normal saline bolus 500-1000 mL followed by maintenance fluids) corrects dehydration from vomiting and third-spacing.
• Nil Per Os (NPO): Bowel rest reduces gallbladder stimulation.
• Antiemetics: Ondansetron 4-8 mg IV every 8 hours for nausea/vomiting.
• Antimicrobial Therapy: Empiric broad-spectrum antibiotics covering gram-negative aerobic bacteria (E. coli, Klebsiella) and anaerobes are given if fever, leukocyt

Complications of the disease

• Gangrenous cholecystitis (surgical emergency): sustained intraluminal pressure compresses mural vessels, producing transmural necrosis. Suspect with high fever, marked leukocytosis, pain out of proportion, or a non-tender gallbladder after prior tenderness (denervated necrotic wall); imaging shows irregular/striated wall, intraluminal membranes, and absent wall enhancement on CT. Most common in elderly diabetic men and the usual precursor to perforation.
• Perforation with bile peritonitis or pericholecystic abscess (emergency): necrosis breaches the fundus (poorest blood supply). Localized perforation walls off as an abscess; free perforation causes diffuse peritonitis and septic shock.
• Emphysematous cholecystitis (emergency): ischemia plus gas-forming organisms (Clostridium perfringens, E. coli); classic in diabetics. Air in the gallbladder wall or lumen on plain film/CT is the signature finding; requires urgent source control.
• Empyema/hydrops: suppurative bile behind an obstructed cystic duct (empyema) versus sterile mucus accumulation with a chronically obstructed duct (hydrops/mucocele, palpable non-tender RUQ mass).
• Mirizzi syndrome: a stone impacted in the cystic duct or Hartmann pouch extrinsically compresses the common hepatic duct — obstructive jaundice with a normal-caliber distal duct; raises operative bile duct injury risk.
• Cholecystoenteric fistula and gallstone ileus: chronic pressure necrosis erodes into the duodenum; a large stone lodges at the ileocecal valve. Rigler triad: pneumobilia, small bowel obstruction, ectopic radiopaque stone. Stone impacted in the duodenum causing gastric outlet obstruction is Bouveret syndrome.
• Choledocholithiasis, gallstone pancreatitis, and ascending cholangitis (cholangitis is an emergency): per Tokyo Guidelines 2018 and ASGE, cholangitis requires antibiotics plus urgent biliary decompression (ERCP), not antibiotics alone.
• Porcelain gallbladder and gallbladder carcinoma: chronic inflammation with mural calcification; cholecystectomy is advised because of the associated malignancy risk.

Complications of treatment

• Bile duct injury: the most feared operative complication; SAGES emphasizes the critical view of safety for prevention. Presents postoperatively with pain, jaundice, or bilious drain output.
• Cystic duct stump leak/biloma: fever, ileus, ascites; diagnosed by HIDA or CT and managed with ERCP stenting plus drainage.
• Retained CBD stone and post-cholecystectomy syndrome: persistent pain, cholestatic labs, or bile-acid diarrhea; MRCP/ERCP clarifies.
• Percutaneous cholecystostomy: bleeding, tube dislodgement, bile leak; a bridge, not definitive therapy.

• Duration is the discriminator: biliary colic resolves in hours with normal labs; pain persisting >6 hours with fever and leukocytosis is acute cholecystitis. The single best next step in either case is right upper quadrant ultrasound, not CT — CT is for suspected complications.
• HIDA is the tiebreaker: if ultrasound is equivocal (or acalculous disease is suspected in an ICU patient on TPN), non-visualization of the gallbladder with duodenal filling confirms cystic duct obstruction. This is the classic "ultrasound negative but story positive" stem.
• Bilirubin should be near-normal in simple cholecystitis: significant hyperbilirubinemia or a dilated common bile duct means choledocholithiasis, cholangitis, or Mirizzi syndrome — the stem is steering you toward ERCP/MRCP, not straight to the operating room.
• Charcot triad / Reynolds pentad = cholangitis: per Tokyo Guidelines 2018, antibiotics alone are insufficient; urgent biliary decompression (ERCP) is the answer. Failing to decompress is the most commonly tested management error.
• Air in the gallbladder wall in a diabetic = emphysematous cholecystitis; Rigler triad (pneumobilia, small bowel obstruction, ectopic stone) = gallstone ileus — remove the obstructing stone first, address the fistula later.
• Asymptomatic gallstones are not an indication for surgery — the classic distractor. Prophylactic cholecystectomy is reserved for porcelain gallbladder, gallbladder polyps at size threshold, and selected patients with hemolytic anemia undergoing splenectomy.
• Gallstone pancreatitis: the ACG recommends cholecystectomy during the same admission for mild disease; discharging with plans for interval surgery is the wrong answer.
• Association examiners love: pigment stones with chronic hemolysis (sickle cell, hereditary spherocytosis), *ceftriaxone*-induced biliary pseudolithiasis/sludge, and rapid weight loss after bariatric surgery.
• Murphy sign is specific, not sensitive — a negative sign in an elderly or diabetic patient does not exclude cholecystitis, and these patients present late with gangrene.