Hepatobiliary Function (Physiology) Flashcards
What are the physiological roles of the Liver?
- the liver functions to absorb nutrients & to detoxify drugs/toxins
- main functions:
- bile production and secretion; metabolism of carbs,
proteins, & lipids once absorbed from a macromolecular
state; bilirubin production & excretion; detoxification of
substances
The Hepatic Portal System connects 2 beds
One from the abdominal & pelvic parts of the gut (derived from the abdominal aorta) to the portal vein on the opposite side of the system
What are the metabolic functions of the liver?
Carbohydrate metabolism- gluconeogenesis, storage of glucose in the form of glycogen, release of glucose from glycogenolysis
Protein metabolism- synthesis of nonessential AAs, modification of the a.a.’s to be used for biosynthetic pathways for carbohydrate metabolism, synthesis of almost all plasma proteins
* When protein metabolism goes wrong–>
hypoalbuminemia–> edema that gets caught in the
interstitual fluid
Lipid metabolism- Fatty Acid Beta Oxidation; synthesis of lipoproteins, cholesterol, phospholipids
What is Cirrhosis?
Chronic liver disease; leads to the destruction of hepatocytes that causes the accumulation of scar tissue
*Alcohol abuse can lead to steatoheaptitis–> “Fatty Liver”
- fatty liver accompanied by inflammation causes
scarring of liver and cirrhosis
**Technically, you have the fatty liver before you have full-blown scarring of the liver via Cirrhosis.
What is portal hypertension?
Portal hypertension is the resistance to flow of blood into the liver from the hepatic vein which caused the blood to pool backwards which caused the development of varicocele like structures in the abdominal area.
What are the esophageal varices?
The esophageal varices are swollen connections between systemic and portal systems at the inferior end of the esophagus
What are the caput medusae?
The swollen connections between systemic & portal systems around the umbilicus
Liver Dysfunction and Hepatic Encephalopathy
Urea Cycle is inhibited due to Liver dysfunction; this leads to the back up of the Urea Cycle and this leads to the accumulation of NH3.
***NH3 accumulation causes the backup of the NH3 into
the systemic circulation where it leads to the Blood-
Brain Barrier
+ (NH3 markedly enters the Brain Afterwards!!!!!!)
What is the importance of the Biliary Secretion
Biliary Secretion: produced by the liver + secreted by the liver
What is the composition of the Bile?
Bile Salts (50%)**** Phospholipids (40%)*** Cholesterol (4%) Bile Pigments (2%) ------------------------------------ Ions & H20 (4%)
How does Bile Function?
Bile Functions to:
1.) Increase the vehicle of elimination of substances from the body
2.) Solves the insolubility problem of fats with the Bile
What are the relative amounts of the 4 Bile Acids?
- ) Cholic Acid (synthesized in the Liver)
- ) Chenodeoxycholic Acid (synthesized in the Liver)
- ———————————————————————————– - ) Deoxycholic Acid (Lumen of the small intestine)
- ) Lithocholic Acid (lumen of the small intestine)
What is the general pathway for Bile secretion & the processes occurring in the small intestine?
Liver- Acinar Cells: produce bile acids
Ductal Cells: secretion of HC03- & Electrolytes
Gall Bladder- Storage and concentration of bile between
meals (charges up before the next meal)
————————————————————————————
*Duodenum- functions to emulsify and digest the fats
*Jejunum- micelle formation & fat absorption
*Ileum- active absorption of the Bile acids & Intrinsic
Factor Absorption
Portal Circulation- absorption of all the nutrients from the small intestine into the hepatic portal vein
How does Bile get secreted into the duodenum?
Bile is secreted via CCK activation -> The Sphincter of Oddi Relaxes & Gallbladder contraction occurs
What is the function of the canalicular membrane?
Bile salts are produced in the Hepatocytes and then secreted across the cannalicular membrane.
***Here the bile salts will enter and be secreted through the ductule cells.
What happens to Bile salts?
***Bile salts are absorbed through the Jejuno-ileum and
ileum where the bile salts are absorbed through the
hepatic portal vein BACK INTO THE LIVER.
How are Bile Salts absorbed back into the hepatocytes?
1.) Bile salts are absorbed by the ileum. By the ASBT
Channels (apical) + released via (OSTa-OSTb
Channels) into the hepatic portal vein.
2.) The Bile salts will run through the hepatic portal vein.
3.) The Bile salts will be absorbed from Basolateral Side:
A.)Na+-dependent transport proteins (NTCP Channels)
B.) Na+-independent transport, organic anion
transport proteins (OATP Channels)
4.) Bile Salts will be secreted on the apical side of the hepatocyte via BSEP channels (Biliary Salt Excretory Pumps)
What is the relationship of bile secretion and bile absorption with the enzyme cholesterol-7-alpha-hydroxylase?
The relationship is that the more the bile salts are secreted into the duodenum, the more that is absorbed (90%) through the ileum.
*** As more is secreted, more is absorbed. As this
occurs, cholesterol-7 alpha hydroxylase becomes
more and more inhibited leading to the inhibition
of the production of bile salts.
Bile flow between periods of digestion
Interdigestive periods: Bile is secreted and stored in the gall bladder: gallbladder is relaxed & the Sphincter of Oddi is CLOSED
Upon EATING Period: CCK-Mediated contraction of the gall-bladder with relaxation of the Sphincter of Oddi
+ into the duodenum
Overview of Bilirubin Production & Excretion
Reticuloendothelial System is the system within Macrophages:
- used to phagocytose RBCs via macrophages
A.) Hepatic Portal Vein and Macrophages
- ) RBCs swallow the Phagocytes leading to conversion of the Hemoglobin Protein Units from Hemoglobin-> Biliverdin-> Bilirubin within the phagocytes
- ) Bilirubin is linked with albumin creating “Bilirubin-Albumin Complex”
B.) Liver Conversion of the Bilirubin-Albumin Complex
1.) Bilirubin deposited and UDP glucuronyl transferase
creates CONJUGATED BILIRUBIN
2 Paths for the Conjugated Bilirubin:
A.) Excretion into the urine
B.) Excretion into the Duodenum
2.) Then the conversion of Conjugated Bilirubin-> Urobilinogen (which goes through the enterohepatic circulation) OR-> Urobilin -> Stercobilin -> Excreted into Feces
RESULTS:
UROBILIN & STERCOBILIN GIVE STOOL ITS DARK COLOR
What are the signs of Jaundice (Icterus)?
- Hyperbilirubinemia in the blood
- Yellow discoloration of the sclera, skin, & mucous
membranes
*Bilirubin Tests (Conjugated/Direct), Indirect (Unconjugated), or Total Bilirubin Tests
What is Hemolytic Anemia?
+ Hemolytic Anemia is undue copious amounts of
hemolysis
+ any cause of hemolytic anemia could lead to increased
production of bilirubin
Results: Increased Bilirubin Level overwhelmed
liver’s capacity to produce conjugated
bilirubin, resulting in INCREASED
UNCONJUGATED BILIRUBIN
What is physiological neonatal jaundice?
+ Increased unconjugated bilirubin in blood DURING 1ST
WEEK OF BIRTH (Post Natal Age):
2 main causes for physiological neonatal jaundice:
a.)*Bilirubin production is elevated because of
increased breakdown of fetal erythrocytes
+shortened lifespan of the RBC in the blood
b.) Low activity of the UDP- Glucoronyl Transferase
Enzyme (immature enzyme that lacks conjugation)
SX: 1 week old or less feels very tired and doesn’t feed
well
What is Gilbert’s Syndrome?
- Increased Levels of Unconjugated Bilirubin in the blood
*Due to mutation in the gene that codes for Uridine Diphosphate Glucoronosyltransferase (UGT1A1 Activity Level of ~ 30% of normal)
Characteristics: usually discovered in Adolescence; episodes of hyperbilirubinemia are mild & typically occur when the body is UNDER PHYSIOLOGICAL STRESS
What is Crigler-Najjar Syndrome?
- Increased Levels of Unconjugated Bilirubin in the Blood
- Mutations in the gene that codes for UDP glucoronyltransferase (UGT1A1 Activity)
*Divided into 2 types:
+ Type 1 (Crigler-Najjar Syndrome)- VERY SEVERE
+ Type 2 (Crigler-Najjar Syndrome)- less severe
Criggler Najar Syndrome Type 1
- starts earlier in life
- Jaundice is apparent at birth or in infancy
- NO FUNCTIONALITY TO THE UDP GLUCORONYLTRANSFERASE ENZYME
Why is Criggler Najar Syndrome Type 1 so severe?
The syndrome causes dysfunctional and useless UDP-Glucoronyltransferase enzyme:
***THIS LEADS TO KERNICTERUS–> form of brain damage caused by the accumulation of unconjugated bilirubin in the brain & nerve tissues
Tx: Phototherapy
***used until early adulthood which then turned into neurological impairment and death in early adulthood
The complications CNS Type 1 and Kernicterus
Kernicterus causes permanent neurological sequelae of bilirubin-induced neurologic dysfunction:
+ known to show signs during 1st year of postnatal birth
+ neurological features: cerebral palsy, sensory-neural
hearing loss, & gaze abnormalities
Crigler-Najjar Syndrome Type 2 Syndrome
+ Starts later in life
+ x<20% functional UDP Glucuronyltransferase
+Less-likely to develop kernicterus
(why? because you still have x<20% functional UDP
glucoronyltransferase)
Different Treatments for Crigler-Najjar Syndrome
CN Syndrome Type 1: Liver Transplant NEEDED
CN Syndrome Type 2: Phenobarbitol (aids in conjugation)
Dubin-Johnson Syndrome
Increased Conjugated Bilirubin; DJ Syndrome is a result of the inability to secrete conjugated bilirubin
* MUTATIONS in multidrug resistance protein 2
(MRP2)
+ Causes a problem with the release of
bilirubin out of the liver cells & into the bile
Sx: Liver has BLACK PIGMENTATION
SEVERITY: Mild jaundice throughout life (that’s the only symptom that you will experience; no other sx will be there!)
Rotor Syndrome
- Gene mutations that lead to abnormally short, nonfunctional OATP1B1 and OATP1B3 proteins or an absence of these proteins which leads to problems with absorption of the unconjugated bilirubin into the liver.
- Conjugated Bilirubin also gets accumulated into the Blood
Criteria for giving phototherapy
- Any newborn with greater than x>21 mg/dl should
receive phototherapy
What is the cause of Gallstones/ Cholelithiasis?
- ) Too much water absorption from bile
- ) Too much absorption of bile acids from bile
- ) Too much cholesterol in bile
- ) Inflammation of epithelium lining the gallbladder
What are liver function tests and how can bilirubin used to measure the performance of the liver?
Bilirubin is used to test the liver’s ability to detoxify metabolites & transport organic anions into the bile
**Makes sense because Bilirubin production,
conjugation, and secretion go through the liver
Hypoalbunemia causes 2 things, what are they?
Two Diseases: Liver Disease, Kidney Glomerular Disease
PT Time Measures what?
PT time measures the degree of hepatic synthetic dysfunction
Drug Metabolism in the Liver in 2 Phases
Phase I: Drugs are processed via cytochrome p450 enzyme
Phase II: Conjugation of the drug follows by glucoronide, sulfate, amino acids, glutathione
