Physiology, Biliary


Article Author:
Heeransh Dave


Article Editor:
Nader Al Obaidi


Editors In Chief:
Jonathan dela Cruz
Therese Mead


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Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
1/4/2019 2:45:09 PM

Introduction

Bile is a unique alkaline secretion of the body. It is secreted from the hepatocytes and is further altered and refined by the epithelial cells lining the biliary tract. The gallbladder stores this fluid, where it gets concentrated and subsequently released into the digestive tract via the common bile duct.  On receiving stimulation via the hormone cholecystokinin from the intestinal tract due to the presence of food in the intestinal lumen, the gallbladder contracts and secretes the bile into the duodenum.[1]  The composition of bile is predominantly water with multiple dissolved substances which include cholesterol, amino acids, enzymes, vitamins, heavy metals, bile salts, bilirubin, phospholipids and other constituents such as drugs and toxins.[1] The cells lining the intrahepatic and extrahepatic biliary ducts are collectively referred to as cholangiocytes. Their primary role is to alter and refine the contents of the hepatically synthesized bile via a complex mechanism controlled by a multitude of molecules, hormones as well as neurotransmitters.[2]

Cellular

Hepatocytes have specific transporters on their apical as well as basolateral membranes that play a central role in the synthesis of canalicular bile. There are two components of the canalicular bile: Bile acids dependent canalicular fraction and bile acids independent canalicular fraction. There is a direct correlation of the amount of individual bile acids secreted into bile and the amount of water osmotically driven into the bile. Due to the enterohepatic circulation and re-secretion of specific bile acids such as ursodeoxycholic acid, these bile acids have higher choleretic activity and contributes to generating a larger volume of bile.[3]

There are three main transporters present on the basolateral membrane of the hepatocytes that helps in facilitating sinusoidal uptake of the bile acids. The most important Na+ dependent transporter is the sodium taurocholate co-transporting polypeptide (NTCP). The Na+ independent transporter is the organic anion- transporting polypeptides OATP that brings in the bile acids in exchange for molecules like HCO3-, glutathione, etc. Another sodium-independent bile acid transporter is the OST alpha/ OST beta transporter. This protein helps in bile acid removal from the hepatocytes in case of an excess of bile acids accumulation.[3]

For the secretion of the bile acids, there are specific transporters on the canalicular membrane of the hepatocytes. The ATP dependent bile acid efflux gets carried by BSEP (Bile Salt Export Pump). There are other apical ATP binding cassette (ABC) transporters - multidrug resistance-P glycoprotein 3 (MDR3) for phospholipids, MDR1 for lipophilic cationic drugs, multidrug resistance-associated protein 2 (MRP2) for non-bile acid organic anions and the protein ABCG5/G8 for the secretion of cholesterol and other sterols.[3]

Various regulatory hormones and substances tightly control the formation and secretion of the bile. There are secretin receptors on the cholangiocytes. These receptors, when stimulated, increase the HCO3 - secretion in the bile. Other hormones such as acetylcholine and VIP increase the biliary HCO3 - secretion whereas the hormones such as dopamine, somatostatin, and gastrin inhibit the secretin-stimulated efflux of bicarbonate in the bile.[3]

Development

The hepatic tissue begins to evolve as a diverticulum from the ventral foregut endoderm that extends into the septum transversum. There are two parts of the ventral foregut endoderm. The cranial part gives rise to the intrahepatic bile ducts whereas the caudal portion leads to the development of the extrahepatic biliary tree.[4][5][6] Around the 8th week of gestation, the intrahepatic bile ducts begin to develop. The development commences at the hilum and extends to the periphery along the portal venous system.[7][8][9] Formation of ductal plate occurs when the periportal hepatoblasts, close to the portal mesenchyme near the portal vein tributary, start to get arranged in a uni-layered pattern of small flat epithelial cells. Soon, there occurs regeneration and multiplication of cells in specific portions of the ductal plate forming the bilayered ductal plate — these plates than enlarge and organize into a tubular shape. These tubules undergo further differentiation and maturation to become individualized intrahepatic bile ducts.[10] The development of the extrahepatic bile ducts occurs earlier than that of the intrahepatic biliary ducts. These two ductal systems connect later at the level of hepatic hilum.[10]

Organ Systems Involved

The various organ systems involved in the biliary physiology are the hepatobiliary system, the gastrointestinal system, and the hematologic system. The breakdown of the hemoglobin stored in the red blood cells occurs in the reticuloendothelial system to form the unconjugated bilirubin. The blood transports unconjugated attached to albumin. Once it enters hepatocytes, it gets conjugated by the enzyme UDP glucuronyl transferase and gets secreted in the bile. The bile passes through the intrahepatic and extrahepatic bile ducts to the gallbladder for storage. The bile secretes into the duodenum regulated by various hormones. In the intestines, the conjugated bilirubin converts into urobilinogen, urobilin and -stercobilin. With the enterohepatic recirculation, the majority of the bile salts get reabsorbed back to the liver. 

Function

Bile is a yellowish, green colored fluid whose primary function is in the emulsification of lipids and to assist in the absorption and digestion of dietary fats by solubilizing them using bile acids. Since the primary function of the bile is the facilitation of fat absorption, it plays a key role in the absorption of fat-soluble vitamins like Vitamin A, D, E, and K. The bile salts present in the bile are bactericidal thereby destroying most of the pathogenic microorganisms present in the ingested food. Since the pH of the bile is alkaline, bile plays a vital role in neutralizing excess stomach acid emptied into the duodenum. The excess cholesterol from the body is also converted to bile acids and is eliminated through bile, thereby maintaining cholesterol hemostasis.

Related Testing

Blood tests, including a comprehensive basic metabolic panel (BMP) and complete blood count (CBC), provide information regarding leucocytosis that might be present due to an infection (related to the biliary system as well). AST, ALT, alkaline phosphatase, total bilirubin, direct bilirubin, INR, total protein, albumin - these tests help to determine liver function as well as determine if the injury is hepatocellular versus cholestatic. Fractionalization of alkaline phosphatase enzyme as well as testing for the enzyme gamma-glutamyl transferase helps to determine the site of origin of the enzyme such as liver versus bone. In terms of imaging, a right upper quadrant abdominal ultrasound can help determine the presence or absence of gallstones, thickening of the gallbladder wall, pericholecystic fluid as well as the sonographic Murphy sign.  (Where the sonographer pushes directly on the gallbladder and elicits pain greater than pushing on other areas.) Abdominal CT scan/MRI can further provide additional details of the abdominal organs. A HIDA scan (hepatobiliary iminodiacetic acid scan) also known as cholescintigraphy can help determine the site of obstruction to bile flow as well as other hepatobiliary pathologies. 

Pathophysiology

Anything that decreases the bile secretion or hinders the bile flow causes pathology. Cholestasis can be due to impaired secretion of bile from the hepatocytes (potentially due to some drugs or hormonal imbalance) or any obstruction of the biliary outflow either due to the intrinsic pathology of the biliary tract or external compression of the biliary tract by possibly a mass/tumor of the bile duct and/or pancreas. The cause of biliary tract pathology may be diseases such as primary sclerosing cholangitis, primary biliary cirrhosis, biliary atresia, etc. The most common reason for bile duct obstruction is due to gallstones which eventually cause inflammation of the gall-bladder (acute or chronic cholecystitis).

Clinical Significance

Obstruction or dysfunction of the biliary pathway can lead to many pathologies. The symptoms of cholestasis include pruritus, dark urine, pale stools, and steatorrhea. As a result of biliary obstruction, the substances normally excreted in the bile increases in the blood which includes cholesterol, conjugated bilirubin, alkaline phosphatase and GGT (gamma-glutamyl transferase). Fat malabsorption causes a deficiency of fat-soluble vitamins like A, D, E, and K and symptoms including osteomalacia, muscle weakness, easy bruising, petechial rash, etc. may manifest. Scratch marks may be present on the skin on careful examination due to intense itching. Some of the pathologies of the biliary tract include gallstones, biliary malignancy, common bile duct obstruction, strictures, primary biliary cirrhosis, primary sclerosing cholangitis, cholecystitis, cholangitis, etc.


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Physiology, Biliary - Questions

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A 40-year-old female presents with jaundice, severe right upper quadrant, and epigastric abdominal pain, fever, and chills. She also reported that her urine turned very dark and that she has been noticing pale stools for the past one week as well. On an abdominal ultrasound, she was found to have gallstones. Magnetic resonance cholangiopancreatography was ordered which revealed a stone obstructing the common bile duct. The patient underwent emergent endoscopic retrograde cholangiopancreatography and stone removal. The bile must pass through which structure along its pathway from the hepatocyte to the duodenum?



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Which hormone stimulates contraction of the gallbladder?



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A 25-year-old male presents with yellow discoloration of the skin and pruritus for the past week. He reports having high-stress levels recently due to work-related deadlines. He also reports having symptoms of weakness and abdominal pain. He admits to having this constellation of symptoms in the past in association with stress. The deficiency of which of the following enzymes is responsible for his condition?



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Which transporter is present on the basolateral membrane of hepatocytes?



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A 42-year-old female with severe, refractory Crohn disease undergoes resection of the ileum and ascending colon to treat her disease. About 3 weeks later, she presents with diarrhea and fecal incontinence. Which part of the gastrointestinal tract is responsible for the reabsorption of bile salts?



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Physiology, Biliary - References

References

Boyer JL, Bile formation and secretion. Comprehensive Physiology. 2013 Jul     [PubMed]
Tabibian JH,Masyuk AI,Masyuk TV,O'Hara SP,LaRusso NF, Physiology of cholangiocytes. Comprehensive Physiology. 2013 Jan     [PubMed]
Esteller A, Physiology of bile secretion. World journal of gastroenterology. 2008 Oct 7     [PubMed]
Lemaigre FP, Mechanisms of liver development: concepts for understanding liver disorders and design of novel therapies. Gastroenterology. 2009 Jul     [PubMed]
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]
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]
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]
Strazzabosco M,Fabris L, Development of the bile ducts: essentials for the clinical hepatologist. Journal of hepatology. 2012 May     [PubMed]

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