Biliary Secretion: Liver and Gallbladder Function Lecture (TEST 2)

Question 1

Liver Physiology and its Role in GI Function

Answer 1

• The Liver receives Portal Blood from the Stomach, Small Intestine, Large Intestine, Pancreas, and Spleen
• The Liver is ideally located to receive ABSORBED NUTRIENTS and to DETOXIFY Drugs and Toxins

Functions of the Liver:

1) Bile Production and Secretion
2) Metabolism of Carbs, Proteins, and Lipids
3) Bilirubin production and Excretion
4) Detoxification of Substances

Question 2

Bile aids in the Digestion and Absorption of Lipids in the Small Intestine

Answer 2

• Bile is a MIXTURE of Salts, Pigments, and Cholesterol that solves the insolubility problem of Lipids
  1) Bile Salts (50%)
  2) Bile Pigments, ex Bilirubin (2%)
  3) Cholesterol (4%)
  4) Phospholipids, ex Lecithin (40%)
  5) Ions
  6) H2O
• Bile is produces and Secreted by the Liver
• Bile also serves as a Vehicle for the elimination of a variety of Substances from the Body

Question 3

Cirrhosis

Answer 3

• Chorines Liver disease in which normal liver cells are damaged and replaced by Scar Tissue
• Excessive Alcohol intake e is MOST COMMON CAUSE of Cirrhosis
• Alcohol abuse leads to accumulation of Fat within Hepatocytes
• Fatty Liver leads to STEATOHEPATITIS
• STEATOHEPATITIS is FATTY LIVER Accompanied by INFLAMMATION, which leads to scarring of Liver and Cirrhosis

Question 4

Formation of Bile Acids

Answer 4

Relative amount of the Four Bile Acids:
CHOLIC Acid > CHENODEOXYCHOLIC Acid > DEOXYCHOLIC Acid > LITHOCHOLIC Acid

Primary Bile Acids:
- Synthesis in Hepatocytes (Liver)

Secondary Bile Acids:
- Synthesis in Lumen of Small Intestine

Bile Salts:
- Conjugated in the Liver

Question 5

Properties and Function of Bile Components

Answer 5

BILE SALTS:

• AMPHIPATHIC Molecules
• Role: Emulsify Lipids and Form MICELLES
• Primary Bile Salts are more EFFECTIVE at Solubilizing Lipids than Secondary Bile Salts

PHOSPHOLIPIDS:

• AMPHIPATHIC Molecules, but are NOT SOLUBLE in H2O
• Bile Salts solubilize Phospholipids forming Micelles

CHOLESTEROL:

• It is solubilized as part of Micelle
• Weakly POLAR Molecule, it is in the Interior of Micelle

BILE PIGMENTS:

• Bilirubin is the Most Important
• Do NOT take par in Micellar formation

IONS and H2O:

• Predominant CATION is Na+, predominant ANIONS are Cl- and HCO3-
• The Secretion of Bile Acids carries H2O and Ions into the Bile by OSMOTIC FILTRATION
• Additional Ions and H2O are supplied by the Cells lining the Ducts (this secretion is stimulated by SECRETIN)

Question 6

Bile Salts form Micelles with the products of Lipid Digestion

Answer 6

• The behavior of Bile Acids depends on THIER CONCENTRATION
• At LOW Concentrations, NO AGGREGATION among Bile Acid Molecules, whereas at HIGH Concentration Micelle formation TAKES PLACE
• The point of Micelle formation is called the CRITICAL MICELLAR CONCENTRATION
• The HYDROPHOBIC portions of the Bile Salts, Phospholipids, Monoglycerides, and Fatty Acids interact in the Interior of the Micelle
• Within the Liver, Ducts, and Gallbladder, Bile is NORMALLY present as a MICELLAR SOLUTION

Question 7

Biel Secretion results from the Concerted actions of Biliary System’s Organs

Answer 7

Components of the Biliary System:

• Liver
• Gallbladder and Bile Duct
• Duodenum
• Ileum
• Portal Circulation

Question 8

Mechanism of Bile Secretion and Absorption of Bile Salts

Answer 8

1) Synthesis and Secretion of Bile Salts
2) Bile Salts are STORED and CONCENTRATED in the Gallbladder (Absorption of Ions and H2O)
3) CCK Induced Gallbladder Contraction and Sphincter of Oddi Relaxation
4) Absorption of Bile Salts into the Portal Circulation
5) Delivery of Bile Salts to the Liver

Question 9

Bile Salts are Secreted ACTIVELY across the Canalicular Membrane

Answer 9

• Together with NEWLY SYNTHESIZED Bile Acids, the returning Bile Acids are Secreted into the bile Canaliculi
• Canalicular Bile is secreted by DUCTULE CELLS in response to the Osmotic Effects of Anion Transport

Question 10

Biel Salts are Recirculated to the Liver via the ENTEROHEPATIC CIRCULATION

Answer 10

1) Bile Salts are transported form the ILEUM to the PORTAL BLOOD
2) Bile Salts go BACK TO the Liver
3) Synthesis of Bile Salts to replace the amount that was lost (Small)

Uptake across the Apical membrane of the Enterocytes is mediated by TWO Types of Systems:
1) Na+ DEPENDENT Transport protein, Sodium Taurocholate Cotransporting Polypeptide (NTCP)

2) Na+ INDEPENDENT Transport Protein, Organic Anion Transport Proteins (OATPs)

Question 11

Enterohepatic Circulation of Bile Acids is carried out by BOTH Active and Passive Transport Processes

Answer 11

• The ILEAL Transport process is HIGHLY Efficient, delivering more than 90% of the Bile Acids to the Portal Blood
• Only a Small portion of Bile Acids (3 to 5%) are Excreted into the Feces

Question 12

Relationships between rates of Bile Acid Synthesis and Secretion

Answer 12

• INCREASE Bile Secretion normally INCREASES the Rate of return of Bile Acids to the Liver via PORTAL BLOOD, which exerts a NEGATIVE FEEDBACK on Synthesis
• Cholesterol 7 Alpha-Hydroxylate is INHIBITED BY BILE SALTS
• Interruption of the Enterohepatic Circulation (Ex Ileal Resection) can INCREASE SYNTHESIS to values more than 10-fold Higher than Normal

Question 13

Bile Secretion occurs via Two mechanisms

Answer 13

1) Almost all Bile Formation is driven by Bile Acids (Bile-Acid Dependent)
2) A small portion of Bile is stimulated by Secretin and is secreted from the Ducts (Bile Acid- Independent or Ductular Secretion)
- Secretion of Bile Acids is accompanied by the PASSIVE movement of Cations into the Canaliculus
- Canalicular Bile is PRIMARILY an Ultrafiltrate of Plasma
- Secretin stimulates the Secretion of HCO3- and H2O from the Ductile Cells, resulting in a significant INCREASE in Bile Volume, HCO3- Concentration and pH, and a DECREASE in the Concentration of Bile Salts

Question 14

Bile Flow between Periods of Digestion

Answer 14

INTERDIGESTIVE PERIOD:

1) Gallbladder fills with Bile:
- Gallbladder is Relaxed
- Sphincter of Oddi is CLOSED

ON EATING:

1) CCK Mediated:
- Contraction of the Gallbladder
- Relaxation of the Sphincter of Oddi

Question 15

Overview of Bilirubin Production and Excretion

Answer 15

• UDP GLUCURONYL TRANSFERASE is SYNTHESIZED slowly after Birth. Some Newborns DEVLOP JAUNDICE!
• ***CONJUGATED BILIRUBIN:
• Bilirubin Glucuronide
• Account for Bile’s Yellow Color

** URIBILIN and STERCOBILIN give Stool its Dark Color

Question 16

Physiological Neonatal jaundice

Answer 16

• Infant has INCREASED Levels of UNCONJUGATED BILIRUBIN in the Blood during the first week of life
• Bilirubin levels usually Decline to about 34 micro mol/L (2mg/dL) for two weeks, eventually mimicking Adult Values

Two Main Causes:

1) Bilirubin production is ELEVATED because of INCREASED Breakdown of Fetal Erythrocytes
- Shortened lifespan of Fetal Erythrocytes

2) Low Activity of UDP GLUCURONYL TRANSFERASE, the Enzyme responsible for Binding Bilirubin to Glucuronic Acid, thus making Bilirubin Water Soluble (CONJUGATION)

JAUNDICE:

• Yellow Color of the skin begins on the Face and then moves down to the Chest, Belly area, Legs, and Soles of the Feet
• Sometimes, infants with a lot of Jaundice may be very tired and feed porrly

Question 17

Jaundice

Answer 17

• Crigler- Najjar Syndromes (Type 1 and 2), Gilbert’s Syndrome, Dubin-Johnson Syndrome and Rotor Syndrome, make up five known Hereditary defects in Bilirubin metabolism

Question 18

Hemolytic Anemia

Answer 18

• Form of Anemia due to Hemolysis
• The Breakdown of Red Blood Cells leads to JAUNDICE
• Any cause of Hemolytic Anemia would lead to INCREASED Production of Bilirubin
• Increased bilirubin level overwhelmed Liver’s Capacity to produce CONJUGATED Bilirubin, resulting in INCREASED UNCONJUGATED BILIRUBIN

Question 19

Gilbert’s Syndrome

Answer 19

• Also known as CONSTITUTIONAL HEPATIC DYSFUNCTION and FAMILIAL NONHEMOLYTIC JAUNDICE
• INCREASED Levels of UNCONJUGATED BILIRUBIN in the Blood (Unconjugated Hyperbilirubinemia)
  a) Relatively Mild
  b) Is usually recognized during Adolescence
  c) If people with this condition have Episodes of Hyperbilirubinemia, these episodes are generally mild and typically occur when the body is under Physiological stress
• Due to Mutation in Gene that codes the URIDINE DIPHOSPHATE GLUCURONOSYLTRANSFERASE (UDP Glucuronyltransferase) Enzyme (Found in Liver Cells)

a) Additional Factors that interferes with the Glucuronidation process may be necessary for Development of the Condition
* ***Ex: Movement of Bilirubin into the Liver, where it would be Glucuronidated, may be Impaired

• ~30% of people with Gilbert Syndrome have no Signs or Symptoms of the Condition

Question 20

Crigler-Najjar Syndrome

Answer 20

• INCREASED Levels of Uncojugated Bilirubin in the Blood (Unconjugated Hyperbilirubinemia)
• NONHEMOLYTIC Jaundice
• Mutations in the Gene that code for UDP GLUCURONYLTRANSFERASE are related to this Syndrome

Divided into two types

Question 21

Crigler-Najjar Syndrome Type I

Answer 21

VERY SEVERE*

• Starts Early in life
• Jaundice is apparent at Birth or in Infancy
• No Function of UDP GLucuronyltransferase
• KERNICTERUS: form of Brain Damage caused by the Accumulation of UNCONJUGATED BILIRUBIN in the Brain and Nerve Tissues
• Babbies are often Lethargic and Exhibit Weak Muscle Tone (HYPOTONIA)
• Can lead to other Neurological Problems (Ex Involuntary Writhing movements of the Body, Hearing Problems, or Intellectual Disability)
• Before the availability of PHOTOTHERAPY, patients died of KERNICTERUS or Survived until Early Adulthood with Clear Neurological Impairment

Question 22

Crigler-Najjar Syndrome Type II

Answer 22

** LESS SEVERE*

• Starts LATER in Life
• Less than 20% Function of UDP GLUCURONYLTRANSFERASE
• LESS LIKELY TO DEVELOP KERNICTERUS
• Most affected Individuals survive into Adulthood

Treatment:

• LIGHT Treatment (Phototherapy) is needed throughout a Person’s life
  a) In infants, this is done using Bilirubin Light (Blue Lights)
• **Phototherapy does not work as well after age 4, because thickened skin blocks the light
• Blood Transfusion may help control the amount of Bilirubin in Blood
• ORAL CALCIUM PHOSPHATE and CARBONATE to form complexes with Bilirubin int he Gut
• A Liver Transplant can be done in some people with Type I
• The Drug PHENOBARBITAL is sometimes used to treat Type II to aid in the Conjugation of Bilirubin
• ** No response to treatment with Phenobarbital for patients with Type I**

Question 23

Dubin- Johnson

Answer 23

• INCREASED Conjugated Bilirubin in the Serum without Elevation of Liver Enzymes
  a) DEFECT IN THE ABILITY OF HEPATOCYTES TO SECRETE CONJUGATED BILIRUBIN INTO THE BILE
• **Mutations in Multidrug Resistance Protein 2 (MDRP 2) which usually transports Bilirubin OUT of Liver Cells and Into Bile
• Mild Jaundice throughout life
  a) May not appear until Puberty or Adulthood
  b) Usually the Only Symptom
  c) May be made worse by: Alcohol, Birth Control Pills, Infection, Pregnancy
• LIVER HAS BLACK PIGMENTATION
  a) Result of an Intracellular Melanin-like Substance but is otherwise Histologically Normal
• Although it occurs in people of all Ethnic Backgrounds, it is more COMMON among IRANIAN and MOROCCAN JEWS living in Israel!!!!

Question 24

Rotor Syndrome

Answer 24

• Buildup of BOTH Conjugated and Unconjugated Bilirubin in the blood, but eh Majority is CONJUGATED
• Similar to Dubin-Johnson
• Gene Mutations that lead to ABNORMALLY SHORT, NONFUNCTIONAL OATP1B1 and OATP1B3 proteins or an Absence of these proteins
  a) These proteins NORMALLY Transport Bilirubin and other compounds from the Blood into the Liver so that they can be cleared from the Body
• Liver cells ARE NOT PIGMENTED!!!!

Question 25

Phototherapy is the Primary Treatment in Neonates with Unconjugated Hyperbilirubinemia

Answer 25

• Any newborn with a total Serum Bilirubin greater than 21 mg/dL should receive PHOTOTHERAPY
• Phototherapy works through a process of Isomerization that changes Trans-Bilirubin into the Water-Soluble CIS-BILIRUBIN ISOMER!!!!!!
• Transformation Trans-Bilirubin into Cis-Bilirubin allows the newborn to Excrete Bilirubin via Urine and Stools

Question 26

Introduction to Gallstones (Cholelithiasis)

Answer 26

• Gallstones are Concretions that form in the Biliary System

- Gallstones occur when there is Excess in either: Pigment of Bilirubin breakdown or Cholesterol

Question 27

Gallstones (Cholelithiasis)

Answer 27

• Large Gallstones that stay in the Gallbladder are usually Asymptomatic
• Small stones, if small enough, can pass to the Biliary Duct getting stuck there (CHOLEDOCHOLIATHIASIS)
  a) Can lead to Inflammation of the Gallbladder (CHOLECYSTITIS)
  b) Causes intermittent Crampy Pain, classically in the RIGHT UPPER QUADRANT
• If the Stone passes all the way to the Entrance of the Duct to the Duodenum and Obstruct the PANCREATIC Duct, PANCREATITIS might develop
• GALLSTONE ILEUS occurs when the Stone passes into the Duodenum and Obstructs it!!!!!
• Gallstones predispose to the Development of Cancer

Question 28

Detoxification of Substances

Answer 28

• The Liver modifies Drugs or Toxic Substances through the “First Pass Metabolism”

Question 29

Metabolic Functions of the Liver

Answer 29

1) CARBOHYDRATE METABOLISM:
- Gluconeogenesis

• Storage of Glucose as GLYCOGEN
• Release of Glucose

2) PROTEIN METABOLISM
- Synthesis of NONESSENTIAL AMINO ACIDS

• Modification of Amino Acids for use in BIOSYNTHETIC PATHWAYS for Carbohydrate
• Synthesis of ALMOST ALL PLASMA PROTEIN (Ex: Albumin and Clotting Factors)
• LIVER FAILURE can result in HYPOALBUMINEMIA, which may lead to EDEMA!!!!!!!!!!!!!
• Conversion of AMMONIA (Byproduct of Protein Catabolism) to UREA

3) LIPID METABOLISM
- Fatty Acid Oxidation

• Synthesis of Lipoproteins, Cholesterol, and Phospholipids

Question 30

Bile Salts are RECIRCULATED to the Liver via the ENTEROHEPATIC CIRCULATION

Answer 30

• Sodium (Na+) TAUROCHOLATE Cotransporting Polypeptide (NTCP)
• Into Hepatocyte**
• Organic Solute Transporter Alpha-Beta (OST Alpha- OST Beta)
• Out of Enterocyte
• Bile Salt Excretory Pump (BSEP)
• Hepatocyte into BILE CANALICULUS*
• Miltidrug Resistance Protein 2 (MRP2)
• Hepatocyte into BILE CANALICULUS*
• Apical Sodium Dependent Bile Acid Transporter (ASBT)
• Biliary Excretion into ENTEROCYTE*

Question 31

Overview of Drug Metabolism

Answer 31

• Liver Enzymes can Modify both DRUGS, Endogenous and Exogenous Toxins to render them Water-Soluble, which allows the Excretion of these Substances through BILE or URINE
  1) PHASE I: Drugs are PROCESSED via CYTOCHROME P450 Enzymes

2) PHASE II: Conjugation step follows, for further DETOXIFICATION of the Drug
- CONJUGATION with Glucoronide, Sulfate, Amino Acids, or Glutathione