Physiology, Bile


Article Author:
Ali Almajid


Article Editor:
Kavin Sugumar


Editors In Chief:
Chaddie Doerr


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
6/4/2019 10:42:50 AM

Introduction

Bile is a fundamental and unique secretion of the liver. It is a yellow-greenish fluid that is secreted from the hepatocytes and altered as it passes through the biliary tree by the epithelial cells lining the bile-duct (cholangiocytes). After its secretion, bile is stored and concentrated in the gallbladder. The presence of lipids in the duodenum stimulates the release of cholecystokinin which in turn stimulates gallbladder wall contraction, resulting in the release of the bile into the cystic duct and common bile duct.[1] The bile is composed mainly of water and electrolytes and other substances which include bile salts, cholesterol, bilirubin, lecithin, amino acids, drugs, toxins, heavy metals, and vitamins.[1] It is also possible to find some hormones, proteins, and peptides in the bile secretions.[2]

Cellular

In the hepatocytes, the Golgi apparatus, microtubules, and microfilaments participate in bile formation. The Golgi complex provides the vesicles for the substances that will get secreted into the bile. The ATP-binding-cassette (ABC) that are newly synthesized will be transferred from the Golgi complex to the canalicular membrane to function as a transporter. This process needs intact microtubules and microfilaments.[2]

Functionally the liver might be divided into three zones. Zone 3 is the zone that is around the central vein while zone 1 is the zone that is most distal from the central vein and surrounds the portal triad (portal vein, hepatic artery, and bile duct) and hence it is also called the periportal zone. Zone 2 lies between zone 3 and zone 1.[2]

Estimates are that the bile flow in humans averages 620 mL/day. The flow of bile is either dependent or independent on the osmotic force of bile acids. When the bile flow is dependent on the osmotic force of bile acids, it is the bile-acid dependent fraction of bile (BADF) while if the flow is not dependent on the osmotic force of bile acids, it is bile acid-independent fraction of bile (BAIF). Moreover, there is a linear realtionship between the amount of water that follows bile acids osmotically and the bile acids in the bile. Certain bile acids retain the capacity to induce a higher volume of bile (hypercholeresis). One classic example is ursodeoxycholic acid. There is a proposal that the hyperocholeresis might be due to the reabsorption of ursodeoxycholic acids from the epithelial cells that line the bile ducts into the bloodstream and then into the hepatic sinusoids. From the hepatic sinusoids, these hypercholeretic bile acids will be taken by the hepatocytes. In the hepatocytes, the hypercholeretic bile acids will be re-secreted into the bile canaliculi thereby increasing the bile-acid dependent fraction of bile flow and resulting in the so-called hypercholeresis. This pathway is called the cholehepatic shunt pathway. The bile acids in the BADF are either newly synthesized in the liver or else they come from the enterohepatic circulation of bile acid.[2] Of note, ursodeoxycholic acid (hypercholeretic bile acid) is used in primary biliary cholangitis (formerly, cirrhosis) a condition in which there is cholestasis and decreased bile secretion.

The mediation of uptake of bile acids from the sinusoids is via Na-dependent bile acid transporter and Na-independent bile acid transporters. The Na-dependent bile acid transporter is called sodium taurocholate-cotransporting polypeptide (NTCP). NCTP does not express at the canalicular membrane; it only expresses at the basolateral membrane. The Na-independent mechanism involves organic anion transporting polypeptides (OATPs) transporter. OATP transporter transports bile acids into the hepatocytes in exchange for bicarbonate or glutathione. Certain Na-independent bile acid transporters (OST/alpha and OST/beta) are present at the basal membrane of cholangiocytes and hepatocytes. In the cholangiocytes, these transporters may participate in the cholehepatic shunt pathway (explained above) while in the hepatocytes these transporters may participate in bile acid efflux into the bloodstream in cases of bile accumulation in the hepatocytes (cholestasis). After the uptake of bile acids from the sinusoids or after they are synthesized endogenously from cholesterol, the unconjugated and conjugated bile acids will get secreted into the canaliculi through a special energy-dependent transporter called bile salt export pump (BSEP). BSEP not only transports bile acids into the canaliculi, but they also aid in the excretion of certain drugs as well. The BAIF of bile flow is mainly determined by the ATP-dependent transport of glutathione through the multidrug resistance-associated protein 2 (MRP2). Cholesterol and sterols are secreted by ABCG5/G8 protein while phospholipids and lipophilic cationic drugs are secreted by multidrug resistance-P glycoprotein 3 (MDR-3) and MDR1, respectively.[2]

Hormonal and neural mechanisms regulate the secretion of bile. The hormonal mechanism involves secretin, somatostatin, dopamine, and gastrin while the neuronal mechanism involves acetylcholine through the vagus nerve. Vasoactive intestinal polypeptide(VIP), in part, also increases secretin-mediated bile flow. Secretin increases the secretion of sodium bicarbonate-rich fluid by binding to its receptors at the basolateral side cholangiocytes. Dopamine, gastrin, and somatostatin inhibit the secretion of secretin-mediated sodium bicarbonate-rich fluid secretion.[2] The secretion of an alkaline fluid is the function of the cholangiocytes.   

Development

The liver tissue develops as a diverticulum from the ventral foregut endoderm. The ventral foregut endoderm has two portions, the cranial and caudal portions. The intrahepatic duct develops from the cranial portion while the extrahepatic bile ducts develop from the caudal portion of the ventral foregut endoderm.[3][4][5]

Around the eighth week of gestation, the epithelium of the intrahepatic duct begins to develop and centrifugally it proceeds from the hilum to the periphery of the liver. The intrahepatic biliary epithelium becomes completely mature only during the first year of life.[6][7][8]

The extrahepatic biliary epithelium develops before the intrahepatic duct. Both of the ducts will combine at the level of the hepatic hilum.[9]

Organ Systems Involved

The organ systems involved are the hematologic system, gastrointestinal (GI) system, and hepatobiliary system. The hematologic system contributes through the formation of bilirubin from biliverdin. Biliverdin forms from the oxidation of heme in old RBCs in the reticuloendothelial system. The GI system is responsible for regulating the alkaline secretions of bile, secreting CCK which causes contraction of the gallbladder, active absorption of bile salts in the terminal ileum, excretion of cholesterol, and excretion of bilirubin in the form of stercobilin. Stercobilin forms by the action of the colonic bacterial flora which converts urobilinogen into stercobilin.  The hepatobiliary system is responsible for the formation, secretion, and storage of bile.

Function

The bile has five main functions:

  1. Aids in the digestion of fat via fat emulsification
  2. Absorption of fat and fat-soluble vitamins
  3. Excretion of bilirubin and excess cholesterol
  4. Provides an alkaline fluid in the duodenum to neutralize the acidic pH of the chyme that comes from the stomach
  5. It provides bactericidal activity against microorganisms present in the ingested food

Mechanism

Bile is synthesized in the hepatocytes and secreted into the bile canaliculi until it reaches the sphincter of Oddi. If the sphincter closes, the bile is refluxed back up into the gallbladder to be stored and concentrated there. Bile becomes concentrated by the reabsorption of water and electrolytes and to some extent by the reabsorption of bile salts. Once the food is present in the duodenum (especially fatty food), the I cells are stimulated to secrete CCK which in turn causes gallbladder wall contraction as well as relaxation of the sphincter of Oddi. The bile then flows into the second part of the duodenum and causes emulsification of large fat droplets into small ones. The formation of micelles aid in the absorption of fat and fat-soluble particles.; this is because the micelle has a central hydrophobic core and peripheral hydrophilic form. The fat and fat-soluble vitamins will become incorporated into the central hydrophobic part of micelle for reabsorption. 

Related Testing

Testing for bile pathology includes imaging and blood tests. Imaging tests include ultrasonography for gallbladder pathology (e.g., cholecystitis and gallstones), Magnetic resonance cholangiopancreatography (MRCP) for visualization of the biliary tree (e.g., primary sclerosing cholangitis), abdominal computed tomography (CT), abdominal magnetic resonance imaging (MRI), and hepatobiliary iminodiacetic acid (HIDA) scan. HIDA scan is particularly useful in confirming acute cholecystitis when ultrasonography is not conclusive. Absence visualization of the gallbladder on HIDA scan suggests acute cholecystitis. Blood test includes CBC and liver function tests (LFT).

CBC may show leukocytosis which accompanies many hepatobiliary pathologies (e.g., cholecystitis and ascending cholangitis). LFT includes alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), prothrombin time (INR), indirect (unconjugated bilirubin), direct (conjugated) bilirubin, total bilirubin, and serum albumin.

 Marked elevation in GGT and ALP with direct hyperbilirubinemia with or without a minimal elevation in AST and ALT indicates a cholestatic pathology. Normal LFT except for high ALP would point to a bone pathology rather than a hepatobiliary pathology. Markedly elevated GGT with slightly abnormal LFT would point to an infiltrative liver pathology (e.g., metastasis).

Pathophysiology

The biliary system pathology includes autoimmune diseases, obstructive cholestasis, non-obstructive cholestasis, infections, and malignancy. The autoimmune diseases are primary biliary cholangitis (PBC) and primary sclerosing cholangitis. In primary biliary cholangitis, there is autoimmune-mediated progressive destruction of intrahepatic small-medium sized bile ducts which results in impaired bile secretion and intrahepatic cholestasis [10]. In primary sclerosing cholangitis, there is intrahepatic and extrahepatic destruction of bile ducts. PSC is strongly associated with ulcerative colitis. The autoimmune basis for both conditions (PBC and PSC) presents in the histologic findings as well as the presence of specific antibodies in patients with these two conditions. Moreover, both conditions are often associated with other autoimmune diseases which further supports the autoimmune basis.  

Cholestasis occurs whenever there is impaired bile secretion from the hepatocytes or obstruction to the bile flow. The obstruction might be due to gallstones (most common) or any other cause such as external compression of the biliary tree or narrowing of the biliary tree as seen in PSC. Adenocarcinoma of the head of the pancreas is an important cause of painless jaundice secondary to obstruction of the bile duct by the enlarging head of the pancreas. Once cholestasis occurs, bilirubin starts accumulating in the body resulting in yellowish discoloration of the sclera and skin. Moreover, the accumulation of bile acids secondary to cholestasis might be responsible for the pruritus seen in these patients.

Infections of the bile ducts are not uncommon, and it might present as fever, right upper quadrant pain, and jaundice. Inflammation of the gallbladder (cholecystitis) is also common, and it is usually associated with gallstones (i.e., acute calculous cholecystitis).

Clinical Significance

Understanding the pathophysiology of jaundice and how bile is synthesized and secreted is essential to make a proper diagnosis and hence provide the proper treatment. Signs and Symptoms of biliary tract pathology include jaundice, pruritus, fever, xanthomas, steatorrhea (due to fat malabsorption), right upper quadrant pain (RUQ), and fatty dyspepsia (a feature of bile obstruction) (10). Biliary tract pathology may result in a decrease in the absorption of fat and fat-soluble vitamins (A, D, E, and K). Deficiency in vitamin K would cause bleeding while a deficiency in vitamin D may cause rickets in children and osteomalacia in adults due to decreased calcium absorption from the gut. Deficiency in vitamin A may lead to night blindness.         


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Physiology, Bile - Questions

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A 40-year-old male patient with Crohn disease presents complaining of diarrhea for a one-week duration and a foul-smelling pale stool. The past surgical history is significant for ileal resection secondary to severe ileal inflammation. What is the main defect that caused the steatorrhea and diarrhea in this patient?



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A 30-year-old obese woman presents to the hospital complaining of right upper quadrant pain that increases with ingestion of fatty meals. She states that her urine has become darker than normal and her stool is pale and has a foul-smelling odor. The clinical examination is unremarkable except for yellowish discoloration of the sclera. Deficiency in which of the following substances caused the foul-smelling stool?



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A 50-year-old gentleman presents to the hospital complaining of epigastric pain for three weeks duration and diarrhea that persists even with fasting. The pain increases with food intake and is not relieved by antacids. The diarrhea is watery in consistency. Endoscopy revealed multiple ulcerations in the stomach and duodenum. Fasting serum gastrin level was found to be high. What is the hormone that has receptors on cholangiocytes and can be used in the diagnosis of this condition?



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An 8-year-old boy is brought to the hospital by his parents because the child's skin and eye have become yellow in the last week. The history and physical examination are unremarkable except for hepatomegaly. Laboratory findings reveal high direct bilirubin, normal complete blood count, and normal liver enzymes. If the liver on gross examination is enlarged and black, which of the following is the most likely underlying cause of this condition?



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A 40-year-old obese woman with sickle cell disease presents to the emergency department complaining of right upper quadrant pain that has started two days prior to the presentation. The pain does not radiate to the back and is not relieved by leaning forward. The pain is colicky in nature and associated with nausea and vomiting. She also noticed that her urine has become darker in the last two days. Clinical examination is remarkable for yellowish discoloration of the sclera. Her vitals are stable and a diagnosis of gallstones was made by ultrasonography. If a pale stool is found in this case, what would be the cause?



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A 40-year-old white woman presents to the hospital complaining of progressive itching and yellowish discoloration of the eyes. Upon history taking, she also has dryness of the mouth. Physical examination is unremarkable except for scleral jaundice. Laboratory workup reveals circulating antimitochondrial antibodies (AMA). What substance is expected to accumulate in the liver of this patient?



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A 5-year-old boy is brought to the clinic by his parents because he looks yellow. Physical examination reveals yellowish discoloration of the sclera, yellow skin, and weakness. Investigations reveal high total bilirubin, undetectable direct bilirubin, AST of 9 U/L, ALT of 12 U/L, normal albumin, negative Coombs test, and normal complete blood count. Mutation in which of the following enzyme/protein is expected to be seen in this case?



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A 55-year-old male patient presented with upper abdominal pain that has started one week ago. The pain does not radiate and is not referred to the back and not relieved by antacids. Upon history taking, the patient admits using antacids for previous similar attacks in the past. Upper endoscopy was done and showed multiple ulcerations in the stomach and duodenum. A secretin stimulation test was performed, and it was positive. Where are the secretin receptors found?



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A 30-year-old obese woman presents to the emergency department with right upper quadrant pain that is increased with the ingestion of a fatty meal. Upon presentation, the pain is constant and severe. The pain does not radiate to the shoulder and Murphy sign is negative. Gallbladder ultrasonography reveals gallstones in the gallbladder neck. Which of the following best explains why the pain increases after ingestion of a fatty meal?



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A 45-year-old male patient known to have Crohn disease and sickle cell disease presents to the hospital with right upper quadrant pain that increases with the ingestion of a fatty meal. Past surgical history is significant for ileal resection due to stricture formation and ileal inflammation. Ultrasonography was performed and showed gallstones in the gallbladder. If the gallstones in the gallbladder are mainly composed of cholesterol, what would be the most likely predisposing factor?



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An 18-year-old lady is brought to the emergency department by her parents because she ingested 28 tablets of an unknown medication 9 hours before presentation. The lady has nausea, vomiting, right upper quadrant tenderness, and scleral icterus. Her vitals are normal except for tachycardia. The lady has a very low mood and odd affect. After initial investigations, she was managed with intravenous N-acetylcysteine and intravenous fluids. Histologically, which of the following is the first zone to be damaged in this case?



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Physiology, Bile - References

References

Boyer JL, Bile formation and secretion. Comprehensive Physiology. 2013 Jul;     [PubMed]
Esteller A, Physiology of bile secretion. World journal of gastroenterology. 2008 Oct 7;     [PubMed]
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Roskams T,Desmet V, Embryology of extra- and intrahepatic bile ducts, the ductal plate. Anatomical record (Hoboken, N.J. : 2007). 2008 Jun;     [PubMed]
Tan J,Hytiroglou P,Wieczorek R,Park YN,Thung SN,Arias B,Theise ND, Immunohistochemical evidence for hepatic progenitor cells in liver diseases. Liver. 2002 Oct;     [PubMed]
Van Eyken P,Sciot R,Callea F,Van der Steen K,Moerman P,Desmet VJ, The development of the intrahepatic bile ducts in man: a keratin-immunohistochemical study. Hepatology (Baltimore, Md.). 1988 Nov-Dec;     [PubMed]
Desmet VJ, Congenital diseases of intrahepatic bile ducts: variations on the theme     [PubMed]
Desmet VJ, Ludwig symposium on biliary disorders--part I. Pathogenesis of ductal plate abnormalities. Mayo Clinic proceedings. 1998 Jan;     [PubMed]
Strazzabosco M,Fabris L, Development of the bile ducts: essentials for the clinical hepatologist. Journal of hepatology. 2012 May;     [PubMed]
Bowlus CL,Gershwin ME, The diagnosis of primary biliary cirrhosis. Autoimmunity reviews. 2014 Apr-May;     [PubMed]

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