PHYS - Hepatobiliary Secretion & Function

Question 1

What are the main functions of the liver?

Answer 1

Production and secretion of bile
Metabolism of Carbs, Proteins, Lipids
Production and excretion of billirubin
Detoxification of substances

Question 2

How does liver failure lead to edema?

Answer 2

The liver is primarily responsible for synthesizing all plasma proteins (like albumin)

Liver failure can lead to hypoalbunemia, which leads to decreased oncotic pressure in the vessel.

This change in fluid pressure dynamics causes greater movement of fluids out of the blood vessels and into interstitial space, causing edema

Question 3

What is cirrhosis?

Answer 3

Chronic liver disease, essentially fibrosis of the liver.

Scar tissue builds up in liver, increasing resistance to blood flow

Caused by alcohol consumption

Excessive alcohol consumption leads to Steatohepatitis (fatty liver disease)

Steatohepatitis leads to scarring liver and cirrhosis

Question 4

What is steatohepatitis?

Answer 4

Fatty liver disease.

Can be caused by excessive alcohol consumption

Can lead to cirrhosis

Question 5

What is hepatic encephalopathy?

Answer 5

Condition that causes loss of brain function due to an increase in toxins in blood, specifically ammonia.

Normal, healthy liver carries out the urea cycle, which converts ammonia to urea, which can be safely excreted in urine.

A cirrhotic liver will not effectively conduct the urea cycle, leaving ammonia to circulate the blood stream and freely cross the Blood-Brain Barrier

Question 6

What is ascites?

Answer 6

Build up of fluid in the abdominal cavity

Caused by liver cirrhosis, which leads to portal hypertension as well as hypoalbunemia (decreased plasma albumin due to decreased liver function)

Question 7

What is splenomegaly, and what can cause it?

Answer 7

Splenomegaly is when a patient has abnormally enlarged spleen

Can be caused by portal hypertension, which can be caused by cirrhosis

Question 8

What clinical manifestations occur as a result of Portal Hypertension and how do they occur?

Answer 8

Esophageal Varicies: Anastemosis formed from Left Gastric Vein (from hepatic portal vein) and Esophageal Vein (from Azygous Vein)

Caput Medusae: Anastemosis formed from Paraumbilical veins (from hepatic portal vein) and Epigastric Veins

Hemroids: Anastemosis formed from Superior Rectal Vein (from inferior mesenteric vein, which is from hepatic portal vein) and from Middle and Inferior Rectal Veins (from internal iliac veins)

Question 9

What is the composition of bile?

Answer 9

Bile salts
Bile pigments (billirubin)
Water
Phospholipids
Cholesterol
Ions

Question 10

What is the function of bile?

Answer 10

Assists in lipid digestion

Question 11

Describe the evolution of cholesterol into bile salts and list where each step takes place

Answer 11

Cholesterol is converted into Primary Bile Acid via 7alpha-hydroxylase in the Liver

Primary Bile acid is ionized to form Secondary Bile Acid in the lumen of the small intestine

Secondary bile acid is conjugated into a Bile salt in the liver

Question 12

What are the steps biliary cycle?

Answer 12

Bile is stored in gallbladder between meals

Bile is excreted into the duodenum during a meal

Bile helps emulsify and digest fats in the duodenum, forms micelles and aids in lipid absorption in the jejunum, then bile acids are actively reabsorbed in the ileum.

Portal circulation returns bile acids to liver where they are secreted back into the biliary system

Question 13

What does CCK do in regards to the biliary system?

Answer 13

CCK stimulates the contraction of the gallbladder and the relaxation of the sphincter of Oddi

Question 14

What transporters are responsible for moving bile salts from the portal circulation into the hepatocytes?

Answer 14

Na+-dependent transport protein: NTCP (NA+ taurocholate cotransporting Polypeptide)

Na+-independent transport protein: OATP (organic anion transport proteins)

Question 15

What transporters are found in the enterocyte that are responsible for removing bile salts from the intestinal lumen and putting them in the portal circulation?

Answer 15

ASBT (Apical Sodium-Dependent Bile Acid Transporter); found on the apical membrane

OSTalpha-OSTbeta (Organic solute transporter alpha-beta); found on the basolateral membrane

Question 16

What transporter is responsible for the removing bile from hepatocytes and putting them into the bile canaliculi?

Answer 16

BSEP (Bile Salt Excretory Pump)

MRP2 (Multidrug Resistant Protein 2)

Both on the basolateral membrane (facing bile canaliculi; not sinusoids)

Question 17

Which forms of transport are utilized at each segment of the bowel (not duodenum) to remove bile acids and put them in the portal circulation?

Answer 17

Jejunum - Passive transport

Ileum - Active and Passive transport (90% of bile acids)

Colon - Passive transport

Question 18

What is the role of secretin in the biliary system?

Answer 18

Secretin promotes the movement of HCO3-, Na+, and H2O into the canaliculi

It has a small role in stimulating bile acid secretion

Causes a significant increase in bile volume and pH, as well as an increase in bile salt concentration

Question 19

What are the two mechanisms of bile secretion into the canaliculi?

Answer 19

1) Bile Acid dependent secretion
- Almost all bile acid formation is driven by bile acids

2) Bile Acid Independent secretion - secretin stimulates secretion of a small portion of bile

Question 20

How is bilirubin produced from RBCs?

Answer 20

Hemoglobin –> Biliverdin –> Bilirubin

Question 21

How is bilirubin transported to the liver?

Answer 21

It cannot circulate in the blood stream on its own, it is bound to albumin (Bilirubin-albumin complex)

Question 22

What happens to bilirubin once it reaches the liver?

Answer 22

Bilirubin is conjugated by the enzyme UDP glucuronyl Transferase.

Conjugated bilirubin can then be excreted in urine or into bile and then into the small intestine

Question 23

What happens to bilirubin once it is in the small intestine?

Answer 23

Conjugated bilirubin is carried through the small intestine where it is eventually converted into Urobilinogen in the distal ileum.

Urobilinogen can be absorbed in the distal ileum where it will be returned to the liver. OR Urobilinogen continues into the colon where it is converted into Urobilin and Stercobilin (both of which are responsible for giving stools their dark brown color

Question 24

What test is done for a patient with jaundice?

Answer 24

Bilirubin test

Determines total bilirubin present as well as whether it is conjugated or unconjugated, which gives an idea as to which stage of RBC hemoglobin recycling is defective

Question 25

What form of jaundice results from hemolytic anemia, and why?

Answer 25

Unconjugated jaundice

RBCs die in circulation, releasing unconjugated bilirubin contents into blood.

Conjugation occurs in the liver

Question 26

What form of jaundice results from Gilbert’s syndrome, and why?

Answer 26

Unconjugated jaundice

Gilbert’s syndrome is a genetic disorder that disrupts the livers ability to uptake circulating bilirubin.

Gilbert’s syndrome primarily affects the gene responsible for UDP Glucuronyl Transferase, which normally conjugates bilirubin

Conjugation of bilirubin occurs in the liver

Question 27

What form of jaundice results from biliary tree obstruction, and why?

Answer 27

Conjugated jaundice.

Bilirubin is conjugated in the liver and then secreted into the bile.

Thus if the biliary tree is blocked, you have a collection of conjugated bilirubin

Question 28

What form of jaundice results from Rotor syndrome, and why?

Answer 28

Conjugated jaundice

Rotor syndrome is a genetic disorder that disrupts excretion of conjugated bilirubin into the canaliculi

Question 29

What form of jaundice results from Crigler-Najjar syndrome, and why?

Answer 29

Unconjugated jaundice

Crigler-Najjar syndrome is a genetic disorder that disrupts the liver’s ability to conjugate absorbed bilirubin.

Question 30

What form of jaundice results from Dubin-Johnson Syndrome, and why?

Answer 30

Conjugated jaundice

Dubin Johnson syndrome is a genetic disorder that disrupts the liver’s ability to secrete conjugated bilirubin into bile.

Question 31

What are the two causes of physiologic neonatal jaundice?

Answer 31

1) Large number of degenerating fetal erythrocytes, increases amount of bilirubin generated
2) UDP Glucuronyl transferase levels are low, as baby doesnt start generating these enzymes until after birth

Question 32

What is Crigler-Najjar Syndrome Type 1?

Answer 32

Very Severe

Starts early in life

UDP glucuronyl transferase does not function causing accumulation of unconjugated bilirubin

Causes Kernicterus, which is brain damage as a result of unconjugated bilirubin in the brain and nerves

Treated with phototherapy early in life

Question 33

What is Crigler-Najjar Syndrome Type 2?

Answer 33

Less Severe

Starts later in life

Less than 20% function of UDP glucuronyl transferase

Less likely to develop Kernicterus (unconjugated bilirubin toxicity in the brain)

Most individuals survive into adulthood

Treated with phototherapy early in life

Question 34

How is Crigler-Najjar syndrome treated?

Answer 34

Phototerapy unti the age of 4 (skin too thick)

Blood transfusions

Oral calcium phosphate and calcium carbonate - to form complexes with unconjugated bilirubin in blood

Liver transplant (for type 1)

Phenobarbitol - helps with conjugation of bilirubin, only for type 2

Question 35

What are important features of Dubin-Johnson Syndrome?

Answer 35

Genetic disorder that disrupts the secretion of conjugated bilirubin into the bile

Specifically a mutation of the MRP2 (multidrug resistant protein 2) channel

Liver is black

Question 36

What are important features of Rotor Syndrome?

Answer 36

Genetic disorder that results in the buildup of both conjugated and unconjugated bilirubin, BUT MOSTLY CONJUGATED

Specifically a mutation of the OATP1B1 and OATP1B3 proteins. These proteins allow bilirubin to be taken from the blood into the liver.

Similar to Dubin Johnson, but liver is not black (no pigmentation)

Question 37

What does phototherapy do to treat jaundice?

Answer 37

Blue light works by isomerization

Changes trans-bilirubin into water soluble cis-bilirubin isomer

Question 38

What does elevated serum aminotransferase levels tell you in a Liver Function Test?

Answer 38

Elevated serum aminotrasnferase tells you that a hepatocyte injury is present

Question 39

What does elevated serum alkaline phosphatase levels tell you in a Liver Function Test?

Answer 39

Elevated serum alkalin phosphatase tells you that there is a bile duct injury

Question 40

What does a hyperbilirubinemia tell you in a liver function test?

Answer 40

Depends on whether the bilrubin is conjugated or unconjugated.

Generally speaking however, elevated bilirubin tells you there is an impairment in the liver’s ability to detoxify metabolites and transport organic molecules into bile

Question 41

What does hypoalbuminemia tell you in a liver function test, and what is a caveat to consider with this result?

Answer 41

Albumin is exclusively synthesized in the liver.

Low serum albumin can tell you that there is sever damage to hepatocytes, usually indicative of cirrhosis

HOWEVER, low serum albumin can also be caused by kidney glomerular disease (increased excretion of albumin in urine rather than decrease in synthesis of albumin)