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Cholelithiasis Biliary Supersaturation Module

Module cholelithiasis_biliary_supersaturation 0 disorders Pathograph 5
A conserved module representing the final common pathway of cholesterol gallstone formation, the dominant form of cholelithiasis. Hepatic hypersecretion of cholesterol relative to bile salts and phospholipids produces gallbladder bile that is supersaturated with cholesterol. Within this metastable bile, pronucleating mucin and gallbladder factors accelerate the precipitation of solid cholesterol monohydrate crystals, while gallbladder hypomotility and bile stasis provide the residence time needed for crystals to be retained, aggregate, and grow into macroscopic gallstones. The resulting stones cause biliary colic, cystic-duct or biliary obstruction, and cholecystitis. Diverse predisposing factors (ABCG5/G8 and ABCB4 lithogenic variants, obesity, insulin resistance, female sex, rapid weight loss) converge on this supersaturation-nucleation-stasis triad. Conforming disorder entries substitute disorder-specific lithogenic drivers while preserving the conserved causal chain.
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Pathophysiology Nodes

5
5 shared nodes are defined in this module.
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Cell Types

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hepatocyte CL:0000182 gallbladder smooth muscle cell CL:0000192
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Biological Processes

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cholesterol homeostasis GO:0042632 DYSREGULATED bile acid metabolic process GO:0008206 DYSREGULATED smooth muscle contraction GO:0006939 DECREASED cholesterol transport GO:0030301 DYSREGULATED
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Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "cholelithiasis_biliary_supersaturation#Gallbladder Hypomotility and Bile Stasis"). The module defines the conserved cholesterol-gallstone pathway; conforming nodes should include the corresponding cell types, biological processes, and causal edges. Disorder-specific substitutions: monogenic defects substitute the affected hepatic transporter (ABCG5/G8 cholesterol hypersecretion, ABCB4 phospholipid deficiency) at the supersaturation node; metabolic disorders (obesity, type 2 diabetes, hypertriglyceridemia) emphasize insulin-resistance-driven hypersecretion and CCK-1R-related gallbladder hypomotility.
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Used By Disorder Entries

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No disorder entries currently reference this module via conforms_to.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence-backed metadata.
Pathograph: causal mechanism network for Cholelithiasis Biliary Supersaturation Module Interactive directed graph showing how this shared module's pathophysiology nodes connect.
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Pathophysiology

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Biliary Cholesterol Supersaturation
trigger
Hepatic hypersecretion of cholesterol, in excess of the bile salts and phospholipids needed to keep it solubilized in mixed micelles and vesicles, yields gallbladder bile that is supersaturated with cholesterol. This metastable, cholesterol-rich physical-chemical state of bile is the initiating lesion of cholesterol gallstone disease and is driven by lithogenic transporter variants (ABCG5/G8, ABCB4) and metabolic factors such as insulin resistance.
hepatocyte CL:0000182
cholesterol homeostasis GO:0042632 DYSREGULATED bile acid metabolic process GO:0008206 DYSREGULATED
Downstream
  • Pronucleating Cholesterol Crystal Nucleation
Pronucleating Cholesterol Crystal Nucleation
amplifier
Within supersaturated bile, accelerated nucleation drives the phase transition from soluble cholesterol in vesicles and micelles to solid cholesterol monohydrate crystals. Pronucleating factors secreted into the gallbladder lumen, chiefly gallbladder mucin glycoprotein, bind biliary lipids and shorten the cholesterol crystal appearance time, tipping the metastable bile toward crystal precipitation.
Downstream
  • Gallbladder Hypomotility and Bile Stasis
Gallbladder Hypomotility and Bile Stasis
central effector
Impaired gallbladder smooth muscle contraction with incomplete postprandial emptying and enlarged residual volumes produces bile stasis. The prolonged gallbladder residence time allows cholesterol crystals to be retained, aggregate, and grow rather than being expelled. Gallbladder hypomotility frequently antedates stone formation and is linked to cholesterol-laden smooth muscle, lipotoxicity, and impaired CCK-1 receptor signaling.
gallbladder smooth muscle cell CL:0000192
smooth muscle contraction GO:0006939 DECREASED
Downstream
  • Gallstone Aggregation and Growth
Gallstone Aggregation and Growth
effector
Retained cholesterol monohydrate crystals aggregate and, embedded in a mucin gel matrix in the stagnant gallbladder, grow and coalesce into macroscopic cholesterol gallstones. Continued supersaturation and stasis sustain crystal growth, converting microscopic crystals into clinically relevant calculi.
cholesterol transport GO:0030301 DYSREGULATED
Downstream
  • Cholelithiasis
Cholelithiasis
consequence
Macroscopic gallstones in the gallbladder constitute cholelithiasis. When stones become impacted in the gallbladder neck or cystic duct they cause biliary colic and mechanical obstruction, which raises intraluminal pressure and precipitates acute cholecystitis; migration into the biliary tree can cause obstructive complications. This is the clinical phenotype that the conserved supersaturation-nucleation-stasis pathway produces.