Physiology, Bile Secretion

Cellular Level

The main steps in the formation of bile are the uptake of bile acids and ions from plasma across the basolateral (sinusoidal) membrane, transport through the hepatocyte, and excretion via the canalicular membrane.

Basolateral Membrane

The sodium-potassium ATPase on the basolateral membrane of the hepatocyte maintains sodium and potassium gradients. Because 3 sodium ions are expelled from the cell in return for receiving 2 potassium ions, an electrochemical gradient is formed.[1] The relative negative charge inside the hepatocyte favors the uptake of positively charged ions, while the sodium gradient fuels the sodium-dependent taurocholate cotransporter protein. This transporter allows for the uptake of conjugated bile acids. In contrast, the organic anion transporter protein does not require sodium to import organic anions. There are several other transporters found on the basolateral surface of the hepatocyte, including the sodium-taurocholate co-transporting protein, ion exchangers that regulate pH, such as the sodium-hydrogen exchanger and the sodium-bicarbonate cotransporter, organic anion and cation transporter, and non-esterified fatty acid transporters.

Canalicular Membrane

The transporter proteins found in the canalicular membrane are primarily members of the ATP-binding cassette protein family.[9] These proteins use active transport to secrete molecules and enzymes into the bile. These transporter proteins include the bile salt export pump (BSEP), the multispecific organic anion transporter (MRP2), the multiple drug resistance 1 and 3 (MDR1 and MDR3), ATP dependent phospholipid transporter (flippase), ATP-dependent transporter of organic cations, and the canalicular bicarbonate transporter.[9] The canalicular membrane transporters help secrete molecules into bile against concentration gradients and enzymes such as alkaline phosphatase. Contractile microfilaments facilitate the secretion of bile through the canaliculi. The canalicular membrane accounts for only 1% of the surface area of the hepatocyte.

Development

In normal development, the synthesis of bile acids first occurs during weeks 5 to 9 of gestation, with bile secretion occurring at 12 weeks of gestation and surging after 17 weeks of gestation.[10][11][10] . After birth, the composition of bile acids further changes; in the neonatal period, the ratio of cholic to chenodeoxycholic acid is approximately 2.5, whereas this changes to approximately 1.6 in the adult.[11]

Abnormal development of the biliary tree can cause congenital liver disease. These primary cholangiopathies include ductopenic syndromes, ductal plate malformation syndromes, polycystic liver diseases, and fibro-polycystic liver diseases.[11]

Organ Systems Involved

Hematologic

Bilirubin, the major pigment of bile, is an end product of heme catabolism that travels to the liver bound to albumin. Once inside the liver, the enzyme uridine diphosphate glucuronyltransferase (UDPGT) conjugates bilirubin to form bilirubin glucuronide. The water-soluble conjugated bilirubin is then secreted into bile, providing its characteristic yellow color.[1]

Gastrointestinal/Hepatobiliary

• Liver: Site of bile formation, reuptake of bile acids, and reuptake of urobilinogen
• Bile ducts: Modify and transport bile, secrete ions and water into bile
• Gallbladder: Stores and concentrates bile
• Small intestine:
  • Bacteria form secondary bile acids via dehydroxylation of primary bile acids
  • Bilirubin glucuronide is converted back to bilirubin
  • Bacteria convert bilirubin to urobilinogen
• Duodenum: Site of lipid digestion and absorption facilitated by bile
• Ileum: Site of reabsorption of bile salts
• Portal circulation: Transports reabsorbed bile salts back to the liver
• Rectum: Urobilin and stercobilin (compounds oxidized from urobilinogen) are responsible for dark fecal pigment.

Genitourinary

Some urobilinogen is excreted in the urine.[1]

Function

The main functions of bile are 2-fold:

1. To facilitate lipid absorption and digestion
2. To eliminate waste products from the body 

Lipid Absorption and Digestion

Through emulsification, bile acids break down large lipid droplets into smaller ones, increasing the surface area for digestive enzymes. Emulsification is possible due to the amphipathic properties of bile salts.[1] The hydrophilic portion of the bile salts surrounds the lipid, forcing the lipid to disperse as the negative charges repel each other. Bile salts also allow the products of lipid digestion to be transported as micelles. The core of the micelle contains monoglycerides, lysolecithin, fatty acids, and the hydrophobic portion of the bile salt. The hydrophilic portion of the bile salt surrounds the lipid core, increasing solubility. Without bile salts, the fat-soluble vitamins (A, D, E, K) cannot be absorbed.

Elimination of Waste Products

Cholesterol is eliminated through its conversion into bile acids, allowing the body to maintain cholesterol homeostasis. Bile acid sequestrants are medications intended to lower cholesterol, function by binding bile acids in the small intestine, and increase their excretion in the stool. Bilirubin is also eliminated through its secretion into bile, where it eventually forms the dark pigment of feces.[12]

Pathophysiology

The decrease or cessation of bile formation or flow is known as cholestasis. Cholestasis can result from the impaired canalicular secretion of bile, ductular disease, or obstruction of bile flow through the biliary tree. Causes of decreased canalicular secretion include drugs, sex hormones, and inherited defects. Ductal diseases include primary biliary cirrhosis and primary sclerosing cholangitis. Bile duct obstruction is most commonly due to gallstones but is also seen with cancers of the bile duct or pancreas.[12]

Clinical Significance

Clinically, symptoms of cholestasis include pruritus, dark urine, pale stools, and steatorrhea. Like bilirubin, other substances normally excreted in bile, such as gamma-glutamyl transferase, alkaline phosphatase, and cholesterol, accumulate in the blood. Fat malabsorption may lead to deficiencies of vitamins A, D, E, and K. On examination, non-tender hepatomegaly and scratch marks on the skin due to pruritus may be present. A careful history and exam with appropriate diagnostic testing are necessary to narrow the differential diagnosis of cholestasis and create the proper treatment plan.[13][14][15] 

The principal therapeutic options for symptomatic management of cholestasis are with ursodeoxycholic acid, a hydrophilic bile acid, and cholestyramine, a bile acid sequestrant.[12][11] However, new and emerging therapies, such as gene therapies, hepatocyte transplants, and stem cell infusions, are being developed to improve the treatment of congenital cholestatic disorders with poor morbidity and mortality rates.[11]