bile salt

SYNTHESIS: Primary bile acids (cholic acid and chenodeoxycholic acid) are made in hepatocytes from cholesterol. Rate-limiting step: cholesterol 7α-hydroxylase (CYP7A1, smooth ER). CYP7A1 is upregulated by cholesterol and downregulated by bile acids (negative feedback via FXR/FGF19). Conjugation with glycine (more common, ~3:1) or taurine yields bile salts, which are more water soluble, have a lower pKa, and remain ionized at intestinal pH, so they are poorly absorbed passively and stay in the lumen.

SECRETION AND FUNCTION: Bile salts are secreted across the canalicular membrane by BSEP (ABCB11), stored and concentrated in the gallbladder, and released in response to CCK (gallbladder contraction and sphincter of Oddi relaxation). They are amphipathic, so they emulsify fats and form mixed micelles. Micelles carry fatty acids, monoglycerides, cholesterol, and fat-soluble vitamins (A, D, E, K) to the brush border. They also help pancreatic lipase act, via colipase.

ENTEROHEPATIC CIRCULATION: About 95% of bile salts are reabsorbed in the terminal ileum by the apical sodium-dependent bile acid transporter (ASBT) and return to the liver via the portal vein. The total pool is about 3 to 4 g and recycles 6 to 10 times per day. About 5% (0.5 g/day) is lost in feces and replaced by new synthesis. In the colon, bacteria deconjugate and dehydroxylate primary bile acids into secondary bile acids (deoxycholic and lithocholic acid).

CLINICAL CORRELATES: - Terminal ileum disease or resection (Crohn disease): bile acid malabsorption leads to steatorrhea, fat-soluble vitamin deficiency, and gallstones (cholesterol stones, because the bile salt pool is depleted). Bile acid diarrhea (choleretic diarrhea) can occur, and it is treated with cholestyramine. - Cholesterol gallstones: they form when bile has too much cholesterol relative to bile salts and phospholipids (lecithin). Risk factors are the "4 Fs" (female, fat, fertile, forty), rapid weight loss, and clofibrate. Ursodeoxycholic acid (ursodiol) can dissolve small stones and treats primary biliary cholangitis. - Bile acid sequestrants (cholestyramine, colestipol, colesevelam): they bind bile acids in the gut, which lowers LDL by increasing hepatic conversion of cholesterol to bile acids. Adverse effects are bloating, constipation, hypertriglyceridemia, and impaired absorption of fat-soluble vitamins and drugs. - Obeticholic acid: an FXR agonist used in PBC. - Cholestasis (biliary obstruction, PBC, PSC): bile salts regurgitate into the blood, causing pruritus, jaundice, pale stools, and dark urine. Bile salts are normally absent from urine (the Hay test historically detected them). - Chenodeoxycholic acid: a drug that dissolves gallstones. It is hepatotoxic and teratogenic. - Dubin-Johnson syndrome and Rotor syndrome: they involve conjugated bilirubin excretion, not bile salt transport. PFIC type 2 is caused by BSEP defects.

HIGH-YIELD TAKEAWAYS: Rate-limiting enzyme = CYP7A1. Cholesterol is the precursor. Bile salts are the major route of cholesterol elimination. Reabsorption happens in the terminal ileum. CCK triggers release. Bile salts are essential for fat digestion and absorption.