11/22/2009

Outline of talk Bile Acids: Pathophysiology and Application

Core Curriculum Lecture October 27, 2009 Fred Park Attending: Alan F. Hofmann, M.D.

What are bile acids? The enterohepatic circulation of bile acids The role of bile acids in disease and therapy

Outline of talk
What are bile acids? The enterohepatic circulation of bile acids The role of bile acids in disease and therapy

Bile acids are the end products of cholesterol metabolism

Cholesterol 3-sulfate: an insoluble (skin) lipid

Flat non-polar molecule; membrane lipid

3OSO OS

is converted into conjugated bile acids highly water-soluble, amphipathic, membranolytic molecules

Kinked, hydrophilic anion; membrane disruptor

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Five main bile acids in man

Chenodeoxycholic acid (3OH,7OH) Lithocholic acid (3OH) Ursodeoxycholic acid (3OH,7OH)

BILE ACIDS ARE PLANAR AMPHIPATHS

Cholic acid (3OH,7OH,12OH) Deoxycholic 3OH,12OH)

Negative charge

Bile acid anions convert bilayers to mixed micelles

(1975)

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The Enterohepatic Circulation

Outline of talk
What are bile acids? The enterohepatic circulation of bile acids The role of bile acids in disease and therapy

of Bile Acids (simplified)

Synthesis (input of primary BA) Secretion

Intestinal conservation Fecal excretion

The Terminal Ileum actively Transports Conjugated Bile Acids

(Lack and Weiner, 1960)

Bile acid transport by the liver

Most bile acids are transported by the periportal cells.. These are old bile acids returning from the intestine Bile acid biosynthesis occurs in the pericentral cells and is less than 5% of the bile acids transported by the liver

Everted intestinal loops from guinea pig Equal concentrations on both sides Read out: serosal/mucosal ratio

Serosal/ mucosal ratio Jejunum Ileum

Unconjugated dihydroxy bile acids are membrane permeable

C5 side chain (isopentanoic acid; a weak acid

COOH

Plasma bile acids increase postprandially because of increased absorption into portal venous plasma and constant first pass hepatic extraction (bile acid structure dependent- 50-90%)

HO

OH

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CONJUGATED BILE ACID STRUCTURE (strong acids, ionized at physiological pH)*

EFFECTS OF BILE SALT CONJUGATION WITH GLYCINE OR TAURINE

Conversion of a weak acid to a strong acid
Complete ionization at physiological pH Increased solubility at acidic pH of small intestine Impermeability to cell membranes Resistance to Ca2+ precipitation

C-NCH2CH2SO3O HO OH
Strong acidic group; always ionized

Result is minimal absorption, thereby promoting high intraluminal concentration

State of conjugation of bile acids in the EHC

Bile -- > 98% conjugated Feces -- > 98% unconjugated

The EHC of bile acids has two inputs primary BA from de novo synthesis and secondary BA from bacterial modification of primary bile acids

Synthesis (input of primary BA)

Input of secondary BAs from colon

ILLUSTRATING THE EHC OF BA

Secondary bile acid formation by bacteria reversal of steps in biosynthesis; result: decreased aqueous solubility Deconjugation Dehydroxylation (only at C-7) Epimerization at C-3
Synthesis
Hepatic repairor detoxification

Secretion

Bacterial damage

Conservation Fecal excretion

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The Enterohepatic Circulation of Bile Acids

Outline of talk
What are bile acids? The enterohepatic circulation of bile acids The role of bile acids in disease and therapy

Bile acid replacement in bile acid deficiency states

Inborn errors of bile acid biosynthesis
Presents as intrahepatic cholestasis Extremely rare Natural unconjugated bile acids (cholic, CDCA) are lifesaving

Bile acid replacement in bile acid deficiency states

Short bowel syndrome, ileal resection
Decompensated EHC, lack of BA conservation Watery diarrhea results from both loss of ileal surface and increased colonic secretion due to fatty acid malabsorption. May restore micelles by feeding conjugated BA (cholylsarcosine), improving lipid absorption and weight gain. But may not be better than giving medium chain triglycerides whose fatty acids (C8 - C12) do not require bile acids for efficient absorption

Bile acid replacement in bile acid deficiency states

Cirrhosis:
Deficiency of bile acids due to decreased bile acid synthesis and secretion. As bile acids have antimicrobial effects, deficiency leads to bacterial overgrowth and increased deconjugation, leading to less ileal resorption. In animals, conjugated bile acid feeding abolishes bacterial overgrowth, decreases bacterial translocation to lymph nodes and endotoxemia. Human studies not yet performed.

Bile acid displacement: change the composition or circulating bile acids

Decrease cholesterol saturation of bile
CDCA and/or UDCA (Ursodiol) for cholesterol gallstone dissolution (mostly replaced by lap cholecystectomy)

Decrease cytotoxicity of circulating bile acids

UDCA for PBC, PSC, cholestasis of pregnancy(improves fetal outcomes)

Increase bile flow by choleretic effects

UDCA (and ? norUDCA) for cystic fibrosis, PSC

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Primary Biliary Cirrhosis

Autoimmune destruction of cholangiocytes causing obstruction at ductular level. Bile acid retention causes increased synthesis of alkaline phosphatase. Bile acids are cytotoxic molecules whose retention in liver causes cirrhosis and elevation in plasma causes pruritus. Ursodiol (UDCA) improves liver tests, decreases pruritus, and increases transplant-free survival.

Chemical structure of norUDCA (4 carbons in side chain) and UDCA (5 carbons in side chain)

Nor-UDCA

UDCA

Unique properties of norUDCA

Not conjugated with glycine/taurine; hepatocyte handles norUDCA like a drug Excreted unchanged into bile Absorbed in biliary ductules, returns to the liver, and is resecreted; does this multiple times (called cholehepatic shunting) Each cycle generates more bile flow Potent therapeutic properties in an animal model of ductular disease (mdr2 knockout) Currently in preclinical trials

Cholehepatic shunting of norUDCA

Bile acid sequestration

Cationic polymers that bind bile acids
Cholestyramine, Colestipol plastic resin Colesevelam hydrogel, more efficient

Summary
Bile acids are planar amphipathic molecules that facilitate fat absorption by dispersion of the products of fat hydrolysis into micelles. The enterohepatic circulation involves interesting mechanisms to maintain a constant pool of bile acids. The replacement, displacement, and sequestration of bile acids are important in the therapy of human diseases.

Indications:
Pruritus due to elevated serum bile acids Hypercholesterolemia: adjunct to statins, increase cholesterol synthesis and upregulate LDL receptors DM type 2: mild insulin sensitizing effect Diarrhea due to bile acid malabsorption