PHYS - Hepatobiliary Secretion & Function Flashcards by Colin Hemond

What are the main functions of the liver?

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

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How does liver failure lead to edema?

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

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What is cirrhosis?

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

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What is steatohepatitis?

Fatty liver disease.

Can be caused by excessive alcohol consumption

Can lead to cirrhosis

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What is hepatic encephalopathy?

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

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What is ascites?

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)

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What is splenomegaly, and what can cause it?

Splenomegaly is when a patient has abnormally enlarged spleen

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

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

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)

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What is the composition of bile?

Bile salts
Bile pigments (billirubin)
Water
Phospholipids
Cholesterol
Ions

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What is the function of bile?

Assists in lipid digestion

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

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

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What are the steps biliary cycle?

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

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What does CCK do in regards to the biliary system?

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

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

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

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

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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?

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

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

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

BSEP (Bile Salt Excretory Pump)

MRP2 (Multidrug Resistant Protein 2)

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

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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?

Jejunum - Passive transport

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

Colon - Passive transport

What is the role of secretin in the biliary system?

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

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

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

How is bilirubin produced from RBCs?

Hemoglobin –> Biliverdin –> Bilirubin

How is bilirubin transported to the liver?

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

What happens to bilirubin once it reaches the liver?

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

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

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

What test is done for a patient with jaundice?

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

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

Unconjugated jaundice RBCs die in circulation, releasing unconjugated bilirubin contents into blood. Conjugation occurs in the liver

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

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

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

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

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

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

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

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

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

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

What are the two causes of physiologic neonatal jaundice?

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

What is Crigler-Najjar Syndrome Type 1?

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

What is Crigler-Najjar Syndrome Type 2?

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

How is Crigler-Najjar syndrome treated?

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

What are important features of Dubin-Johnson Syndrome?

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

What are important features of Rotor Syndrome?

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)

What does phototherapy do to treat jaundice?

Blue light works by isomerization Changes trans-bilirubin into water soluble cis-bilirubin isomer

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

Elevated serum aminotrasnferase tells you that a hepatocyte injury is present

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

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

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

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

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

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)