• Shuffle
    Toggle On
    Toggle Off
  • Alphabetize
    Toggle On
    Toggle Off
  • Front First
    Toggle On
    Toggle Off
  • Both Sides
    Toggle On
    Toggle Off
  • Read
    Toggle On
    Toggle Off
Reading...
Front

Card Range To Study

through

image

Play button

image

Play button

image

Progress

1/96

Click to flip

Use LEFT and RIGHT arrow keys to navigate between flashcards;

Use UP and DOWN arrow keys to flip the card;

H to show hint;

A reads text to speech;

96 Cards in this Set

  • Front
  • Back
How much hemoglobin is synthesized per day? Why?
6-7g to replace heme lost through the normal turnover of RBCs
How much of the total iron is present as heme iron in RBCs?
~70%
During heme catabolism, what does the body need to deal with?
- Handling the hydrophobic products of porphyrin ring cleavage
- Retention, safe mobilization, and re-utilization of iron
When a macrophage phagocytoses a RBC, what components is hemoglobin broken down into?
- Globin chains
- Heme (iron and protoporphyrin)
- Leakage of some hemoglobin which binds to haptoglobin
Which protein binds free hemoglobin?
Haptoglobin
What happens to globin chains in a macrophage that has phagocytosed a RBC?
Breaks it down into amino acids in the lysosome
What happens to heme in a macrophage that has phagocytosed a RBC?
Broken down into:
- Iron → stored
- Protoporphyrin → Unconjugated bilirubin → Blood → Liver
How is bilirubin, made in the macrophage, carried in the blood to the liver?
Albumin binds Bilirubin because it is very hydrophobic and can't float freely in the blood
What happens to bilirubin once it gets to the liver from the macrophage?
- Taken up into liver hepatocytes
- Bilirubin is modified and conjugated w/ glucuronic acid (negatively charged carbohydrate) to make it more water soluble and more readily excreted by hepatocytes
What does Bilirubin get conjugated to in the hepatocytes? Why?
- Glucuronic acid (negatively charged carbohydrate)
- Makes Bilirubin more water soluble and more readily excreted by hepatocytes
What happens once Bilirubin is conjugated and excreted from the liver?
- Enters the GI tract
- Conjugated bilirubin is converted by bacteria to remove the glucuronic acid (ie, deconjugated)
- Converted to urobilinogen
- From here it can be reabsorbed into the portal circulation or it can go to kidney
- Enters the GI tract
- Conjugated bilirubin is converted by bacteria to remove the glucuronic acid (ie, deconjugated)
- Converted to urobilinogen
- From here it can be reabsorbed into the portal circulation or it can go to kidney
What happens if urobilinogen that was created in the GI tract is sent to the kidney?
- Urobilinogen is converted to Urobilin
- Urobilin is excreted in the urine
- Urobilinogen is converted to Urobilin
- Urobilin is excreted in the urine
Which form of Bilirubin is excreted in the urine? How does it get to this form?
Urobilin:
- Bilirubin is conjugated in liver and unconjugated in GI by bacteria 
- Converted to make urobilinogen in GI
- Sent to the kidney by the systemic circulation where it is converted to Urobilin
- Excreted in urine
Urobilin:
- Bilirubin is conjugated in liver and unconjugated in GI by bacteria
- Converted to make urobilinogen in GI
- Sent to the kidney by the systemic circulation where it is converted to Urobilin
- Excreted in urine
Where does glucuronidation of bilirubin occur?
Liver hepatocytes
Liver hepatocytes
Where is the glucuronic acid removed (deconjugated) from Bilirubin?
GI Tract by bacteria
GI Tract by bacteria
Which form of Bilirubin is excreted in the feces?
Stercobilin
Stercobilin
What is the result of accumulation of elevated bilirubin in the skin and sclera?
Jaundice or Icterus - imparts a yellow color to the skin and sclera, respectively
What do inherited disorders of bilirubin metabolism lead to?
Hyperbilirubinemia
Heme catabolism comes from what processes?
- 80% from senescent (aged) RBCs
- 20% from turnover of immature RBCs and various cytochromes in non-erythroid tissues
What happens when RBCs become senescent (at about 120 days)?
RBCs are taken up by macrophages of the Reticuloendothelial System of the Liver and Spleen
What color is Bilirubin? What are its characteristics?
- Orange pigment
- Potentially toxic waste product that is generally harmless because of binding to serum albumin
What happens in the first part of the first step in heme catabolism?
Heme ring opening (in the macrophage):
- Heme Oxygenase (HO-1) cleaves Ferroprotoporphyrin IX ring
- Requires e- from NADPH cytochrome P450 oxidoreductase (CYPOR)
Heme ring opening (in the macrophage):
- Heme Oxygenase (HO-1) cleaves Ferroprotoporphyrin IX ring
- Requires e- from NADPH cytochrome P450 oxidoreductase (CYPOR)
What happens in the second part of the first step of heme catabolism, after Heme Oxygenase (HO-1) has cleaved the ferroprotoporphyrin IX ring?
Heme ring opening (in the macrophage):
- Nonenzymatic oxidation by molecular O2 with the elimination of CO
- Releases iron after adding electrons
- Product: Biliverdin (green pigment)
Heme ring opening (in the macrophage):
- Nonenzymatic oxidation by molecular O2 with the elimination of CO
- Releases iron after adding electrons
- Product: Biliverdin (green pigment)
What happens to the products of the first two parts of step 1 of heme catabolism (heme ring opening)?
Endogenous compounds are toxic in free form:
- Fe2+/3+ is bound by Ferritin
- CO is bound by Hemoglobin
Endogenous compounds are toxic in free form:
- Fe2+/3+ is bound by Ferritin
- CO is bound by Hemoglobin
What happens in the second step of heme catabolism, after Fe2+/3+ and CO have been eliminated to form Biliverdin?
Conversion of Biliverdin (green) to Bilirubin (orange) - in macrophage:
- Catalyzed by Biliverdin Reductase (cytosolic enzyme)
- Uses NADH or NADPH
Conversion of Biliverdin (green) to Bilirubin (orange) - in macrophage:
- Catalyzed by Biliverdin Reductase (cytosolic enzyme)
- Uses NADH or NADPH
What are the benefits of converting Biliverdin (green) to Bilirubin (orange) in step 2 of heme catabolism?
- Bilirubin is less polar than Biliverdin
- Bilirubin crosses membranes more readily
- Bilirubin is an Antioxidant and is important during neonatal period when concentrations of other antioxidants are low in body fluids
- Bilirubin is less polar than Biliverdin
- Bilirubin crosses membranes more readily
- Bilirubin is an Antioxidant and is important during neonatal period when concentrations of other antioxidants are low in body fluids
How does the color of a bruise change with time?
Green (biliverdin) --> Orange (bilirubin)
- Manifestation of the intermediates that occur during heme catabolism
Green (biliverdin) --> Orange (bilirubin)
- Manifestation of the intermediates that occur during heme catabolism
What happens in the third step of heme catabolism after the conversion of biliverdin to bilirubin?
Binding of bilirubin to Albumin (occurs in blood)
Binding of bilirubin to Albumin (occurs in blood)
What is the purpose of of Albumin binding to Bilirubin?
What is the purpose of of Albumin binding to Bilirubin?
Critical for the disposition of bilirubin in the body:
- Keeps bilirubin in solution
- Transports it from its primary sites of production (red pulp macrophages of spleen and Kupffer cells of liver) to primary site of excretion (liver)
Critical for the disposition of bilirubin in the body:
- Keeps bilirubin in solution
- Transports it from its primary sites of production (red pulp macrophages of spleen and Kupffer cells of liver) to primary site of excretion (liver)
What is the primary site of production of Bilirubin?
Red pulp macrophages of spleen and Kupffer cells of liver
What happens in the fourth step of heme catabolism after Bilirubin binds to Albumin?
Uptake, storage, conjugation, and excretion of Bilirubin (occurs in liver)
- Bilirubin bound to albumin rapidly dissociates
- Once inside the hepatocyte, bilirubin is kept in solution through interactions with cytosolic proteins, termed Ligandins
Uptake, storage, conjugation, and excretion of Bilirubin (occurs in liver)
- Bilirubin bound to albumin rapidly dissociates
- Once inside the hepatocyte, bilirubin is kept in solution through interactions with cytosolic proteins, termed Ligandins
What does Bilirubin bind to once inside the hepatocyte and after dissociating from Albumin?
Ligandins - this inhibits efflux of Bilirubin back into the circulation and also represents a form of temporary storage within the hepatocyte
Ligandins - this inhibits efflux of Bilirubin back into the circulation and also represents a form of temporary storage within the hepatocyte
Which enzyme conjugates the Bilirubin that is trapped in hepatocytes? Function?
UGT1A1 - adds Glucuronic Acid to Biliburin either once (BMG) or twice (BDG)
UGT1A1 - adds Glucuronic Acid to Biliburin either once (BMG) or twice (BDG)
What is necessary for efficient excretion of bilirubin across the bile canaliculus?
Conversion to polar conjugates by esterification of the propionic acid carboxyl groups
Conversion to polar conjugates by esterification of the propionic acid carboxyl groups
What ist he major conjugating group to bilirubin? What catalyzes this reaction? Where?
- Glucuronic acid
- Glucuronidation is catalyzed by Uridine Diphosphate Glucuronosyltransferase (UGT1A1)
- Located in ER of hepatocyte
- Converts hydrophobic molecule to a more polar, water soluble molecule that is more readily excreted
- Glucuronic acid
- Glucuronidation is catalyzed by Uridine Diphosphate Glucuronosyltransferase (UGT1A1)
- Located in ER of hepatocyte
- Converts hydrophobic molecule to a more polar, water soluble molecule that is more readily excreted
Once bilirubin is conjugated to glucuronic acid as BMG or BDG, how does it get excreted?
ATP-dependent multi-organic anion transporter (MOAT) excretes bilirubin across the Canalicular membrane
What happens to Bilirubin in the GI tract?
- Bilirubin reaches the intestinal tract mainly conjugated and is not substantially reabsorbed
- Bilirubin is degraded by intestinal bacteria into a series of Urobilinogen products
- Urobilinogens are in the deconjugated state (lost glucuronic acid)
What forms of bilirubin can Ligandin bind?
Conjugated or Unconjugated bilirubin
What is the immediate precursor in the synthesis of urobilin? Colors?
Bilirubin (orange) --> Urobilinogen (colorless) --> Urobilin (yellow)
What is the major pigment of feces?
Stercobilin (brown)
The hepatic processing of bilirubin involves what four distinct but interrelated stages?
1) Uptake from circulation
2) Intracellular binding and storage
3) Conjugation
4) Biliary excretion
How can disorders causing hyperbilirubinemia be divided?
- Unconjugated
- Conjugated
How can you indirectly quantify the total bilirubin?
Intensity of yellow discoloration of the skin
How can you directly quantify the total bilirubin?
Van den Bergh assay
What happens in the Van den Bergh assay to quantify the total bilirubin directly?
- Electrophilic attack of a diazonium ion of the reagent on the 9 and 11 positions of bilirubin
- Heme catabolite can be classified into direct and indirect reacting species

- Only the water soluble, conjugated bilirubin reacts rapidly
- Unconjugated bilirubin reacts slowly and is not detected
With the regular van den Bergh assay, which forms of bilirubin react?
- Only the water soluble, conjugated bilirubin reacts rapidly
- Unconjugated bilirubin reacts slowly and is not detected

Gives you a value for DIRECT (conjugated bilirubin)
With the van den Bergh assay conducted in methanol, which forms of bilirubin react?
Both forms of bilirubin are soluble and react rapidly, yielding a value for TOTAL bilirubin
How do you calculate Direct, Indirect, and Total bilirubin?
- Direct: Regular van den Bergh assay detects only the direct bilirubin

- Total: van den Bergh assay in methanol detects both direct and indirect bilirubin

- Indirect: Total - Direct values
By adults standards, what are the levels of bilirubin in a newborn baby? What impact does this have on the baby?
- They have hyperbilirubinemia due to delayed maturation of the liver to dispose of bilirubin
- This is caused by low activity of the bilirubin conjugating enzyme UGT1A1
- About half of newborns become clinically jaundiced during first 5 days of life
Why do half of newborns become clinically jaundiced during the first 5 days of life?
- Low activity of UGT1A1 (carries out conjugation on bilirubin)
- Decreased excretory capacity of hepatocytes
- Increased bilirubin production secondary to accelerated destruction of fetal erythrocytes
What are the detriments to a newborn with neonatal jaundice?
- Serum bilirubin is predominantly unconjugated
- If untreated, high bilirubin levels can damage regions of the brain, such as the basal ganglia, which is responsible for controlling muscle movement
- Kernicterus is a specific form of brain dama...
- Serum bilirubin is predominantly unconjugated
- If untreated, high bilirubin levels can damage regions of the brain, such as the basal ganglia, which is responsible for controlling muscle movement
- Kernicterus is a specific form of brain damage (bilirubin encephalopathy) causing Athetoid (writhing) cerebral palsy and hearing loss

- However, neonatal jaundice is innocuous
What happens in Kernicterus?
A specific form of brain damage (bilirubin encephalopathy) causing Athetoid (writhing) cerebral palsy and hearing loss
A specific form of brain damage (bilirubin encephalopathy) causing Athetoid (writhing) cerebral palsy and hearing loss
What may be the benefit to newborns to have higher bilirubin levels?
Bilirubin may be an important antioxidant defense for the newborn (it can inhibit lipid peroxidation based on its ability to donate hydrogen ions)
What causes the basal ganglia to be yellow?
What causes the basal ganglia to be yellow?
- Accumulation of unconjugated bilirubin (low UGT1A1 activity)
- In contrast, conjugated bilirubin is water-soluble and non-toxic
- Accumulation of unconjugated bilirubin (low UGT1A1 activity)
- In contrast, conjugated bilirubin is water-soluble and non-toxic
How do you treat neonates with jaundice?
Phototherapy
- Exposure of bilirubin to blue-green spectrum (430-490 nm) - not UV light though!
- Changes the configuration to an isomer that can be excreted in bile without conjugation
Phototherapy
- Exposure of bilirubin to blue-green spectrum (430-490 nm) - not UV light though!
- Changes the configuration to an isomer that can be excreted in bile without conjugation
What are the Inherited Unconjugated Hyperbilirubinemia disorders? What causes them?
- Crigler-Najjar Syndrome (Type 1) - absent UGT1A1
- Crigler-Najjar Syndrome (Type 2) - <20% UGT1A1 activity
- Gilbert Syndrome - ~30% UGT1A1 activity
- Crigler-Najjar Syndrome (Type 1) - absent UGT1A1
- Crigler-Najjar Syndrome (Type 2) - <20% UGT1A1 activity
- Gilbert Syndrome - ~30% UGT1A1 activity
What are the Inherited Unconjugated Hyperbilirubinemia disorders? What are the relative serum bilirubin levels?
- Crigler-Najjar Syndrome (Type 1) - highest 
- Crigler-Najjar Syndrome (Type 2) - medium
- Gilbert Syndrome - lowest 

*Decreasing UGT1A1 activity results in increasing unconjugated bilirubin levels*
- Crigler-Najjar Syndrome (Type 1) - highest
- Crigler-Najjar Syndrome (Type 2) - medium
- Gilbert Syndrome - lowest

*Decreasing UGT1A1 activity results in increasing unconjugated bilirubin levels*
What are the implications of a lack of or decreased UGT1A1 activity, caused by autosomal recessive inheritance?
Inherited Unconjugated Hyperbilirubinemia
- Crigler-Najjar Syndrome (Type 1) - absent UGT1A1
- Crigler-Najjar Syndrome (Type 2) - <20% UGT1A1 activity
- Gilbert Syndrome - ~30% UGT1A1 activity
Inherited Unconjugated Hyperbilirubinemia
- Crigler-Najjar Syndrome (Type 1) - absent UGT1A1
- Crigler-Najjar Syndrome (Type 2) - <20% UGT1A1 activity
- Gilbert Syndrome - ~30% UGT1A1 activity
Which of the Inherited Unconjugated Hyperbilirubinemia disorders is the most severe? Least severe?
- Most severe: Crigler-Najjar Syndrome (Type 1)
- Least severe: Gilbert Syndrome
- Most severe: Crigler-Najjar Syndrome (Type 1)
- Least severe: Gilbert Syndrome
What causes Conjugated Hyperbilirubinemia?
- Inherited (autosomal recessive) defects in bilirubin secretion caused by an inability of hepatocytes to secrete conjugated bilirubin
- Relatively mild
- Conjugated bilirubin returns to the blood
- Inherited (autosomal recessive) defects in bilirubin secretion caused by an inability of hepatocytes to secrete conjugated bilirubin
- Relatively mild
- Conjugated bilirubin returns to the blood
What are the types of Conjugated Hyperbilirubinemia disorders? What causes these?
- Dubin-Johnson Syndrome - defect in MOAT (organic ion transport)
- Rotor Syndrome - rare and not characterized at molecular level
- Dubin-Johnson Syndrome - defect in MOAT (organic ion transport)
- Rotor Syndrome - rare and not characterized at molecular level
Besides the Inherited Unconjugated and Conjugated Hyperbilirubinemia, what are some other causes of jaundice?
- Hemolytic (increased indirect / unconjugated)
- Obstructive (increased direct / conjugated)
- Hepatocellular (increased indirect / unconjugated)
What are the results of excessive RBC destruction / hemolysis?
- Formation of bilirubin in amounts exceeding the conjugating ability of the liver
- Unable to excrete the unconjugated bile, which leads to increases in the plasma
* Increased indirect / unconjugated bilirubin --> Jaundice
What are the results of partial or complete blocking / obstruction of the bile ducts?
- Conjugated bilirubin is prevented from being excreted into the intestine
- Consequently it appears in increased amounts in the plasma
* Increased direct / conjugated bilirubin --> Jaundice
What can cause hepatocellular damage? What are the results of this?
- Damage to the liver by toxins, poisons, cardiac failure, or acute or chronic disease
- Impairs the liver's capacity to conjugate circulating bilirubin and hence excrete it
* Increased indirect / unconjugated bilirubin --> Jaundice
How do we get cholesterol?
- Diet
- Synthesized de novo in virtually all cells
What is the precursor to bile acids? Where does synthesis of bile acids occur?
Bile acids are synthesized from cholesterol in the liver
Where are bile acids secreted?
Into bile canaliculi - specialized channels formed by adjacent hepatocytes
Where are bile acids taken after excretion from the liver?
- Gallbladder - storage
- Small intestine - excreted ultimately
What is the function of bile acids?
- Emulsifying agents to prepare dietary TGs for hydrolysis by pancreatic lipase
- Facilitate absorption of fat-soluble vitamins, such as vitamin D, from the intestine
How is cholesterol excreted? What is the most abundant form?
- Primarily as bile acids (cholic acid is the predominant form)
- The carbon skeleton is not degraded but is excreted with a few modifications (oxidized to CO2 and H2O)
- Primarily as bile acids (cholic acid is the predominant form)
- The carbon skeleton is not degraded but is excreted with a few modifications (oxidized to CO2 and H2O)
What are the forms of bile acids?
Primary bile acids synthesized in hepatocytes directly from cholesterol:
- Cholesterol → Cholic Acid and Chenodeoxycholic Acid

Primary bile acids are converted to secondary bile acids by bacteria in the gut via dehydroxylation reactions:
- Deoxycholic acid & Lithocholic Acid
What happens to primary and secondary bile acids after they are secreted?
- Reabsorbed by the intestine (lower ileum) into portal blood
- Taken up by hepatocytes when they are conjugated to glycine or taurine, forming bile salts
What are bile acids conjugated to once reabsorbed? Why?
- Conjugated to glycine or taurine
- Forms bile salts with a lower pK value
- Lower pK value renders them more soluble in the small intestine
- Conjugated to glycine or taurine
- Forms bile salts with a lower pK value
- Lower pK value renders them more soluble in the small intestine
Which bile acid binds to glycine to form a bile salt?
Deoxycholic acid
Deoxycholic acid
Which bile acid binds to taurine to form a bile salt?
Lithocholic acid
Lithocholic acid
How much bile acid is synthesized per day? Where?
0.2 - 0.6 g in the liver - stored int he gallbladder
How much bile acid is stored in the gallbladder?
2-4 g
At what efficiency are bile acids reabsorbed from the intestine?
>95% (12-32 g / day)
How does the capacity of the liver to produce bile acids compare to the needs for digestion? How does the body compensate?
- Liver is insufficient to meet the demands for bile acids
- Body relies on the efficient enterohepatic circulation that carries bile acids from the intestine back to the liver
What are the characteristics of Familial Hypercholesterolemia (FH)?
- Elevated concentration of LDL in plasma
- Deposition of LDL-derived cholesterol in tendons and skin (xanthomas) and in arteries (atheromas)
- Inheritance is autosomal dominant w/ a gene dosage effect (homozygotes more severely affected than he...
- Elevated concentration of LDL in plasma
- Deposition of LDL-derived cholesterol in tendons and skin (xanthomas) and in arteries (atheromas)
- Inheritance is autosomal dominant w/ a gene dosage effect (homozygotes more severely affected than heterozygotes)
What is a xanthoma?
Deposition of LDL-derived cholesterol in tendons and skin
Deposition of LDL-derived cholesterol in tendons and skin
What is an atheroma?
Deposition of LDL-derived cholesterol in arteries
Deposition of LDL-derived cholesterol in arteries
What is the defect in Familial Hypercholesterolemia (FH)?
Mutation in the gene encoding the LDL receptor
How common is heterozygous Familial Hypercholesterolemia (FH)? Characteristics?
- 1 in 500 persons
- Twofold elevations in plasma cholesterol from birth
* Most common inborn error of metabolism
How common is homozygous Familial Hypercholesterolemia (FH)? Characteristics?
- 1 in 1 million persons
- Severe hypercholesterolemia (650 to 1000 mg/dl)
- Coronary heart disease begins in childhood
What is the general treatment goal for Familial Hypercholesterolemia (FH)?
Try to lower the plasma level of LDL
What is the function of the LDL receptor?
1) LDL receptor limits LDL production by enhancing the removal of the precursor IDL from the circulation
2) LDL receptor enhances LDL degradation by mediating cellular uptake of LDL

* LDL receptors are important modulators of plasma LDL levels *
How do you specifically treat heterozygotes with Familial Hypercholesterolemia (FH)?
Treatments act by stimulating the single normal LDL receptor gene:
1) Bile acid binding resins (cholestyramin and colestiopol)
2) HMG-CoA reductase inhibitors (statins)
3) Diet low in cholesterol and fats
How do bile acid binding resins treat heterozygous Familial Hypercholesterolemia (FH)? Which drugs do this? Efficacy?
- Cholestyramine and Colestipol
- Binds bile acids in the intestinal lumen, preventing their absorption from the ileum
- Increased fecal excretion of bile acids elicits an increased conversion of cholesterol to bile acids in the liver
- Liver responds to cholesterol deficiency by increasing production of LDL receptors
* Alone decreases LDL cholesterol by 10-20% *
How do HMG-CoA reductase inhibitors treat heterozygous Familial Hypercholesterolemia (FH)? Which drugs do this? Efficacy?
- Statins
- Inhibits synthesis of cholesterol
* Combined w/ bile acid binding resins, can decrease LDL cholesterol by > 60% *
How effective is a diet low in cholesterol and fats for treating heterozygous Familial Hypercholesterolemia (FH)?
Alone can decrease LDL cholesterol levels by 10-20%
Which is true about bile acid binding resins, cholestyramine and colestiopol:

a) increase LDL cholesterol levels in the circulation by 10-20%
b) decrease fecal excretion of bile acids
c) increase production of LDL receptors in the liver
d) decrease activity of HMG-CoA reductase
e) are used for the effective treatment of patients homozygous for familial hypercholesterolemia
C - increases production of LDL receptors in the liver

(E is wrong because homozygotes don't have an effective receptor so no point in trying to up-regulate the LDL receptor)
T/F: primary, but not secondary, bile acids can be conjugated to glycine or taurine in hepatocytes?
False - both primary and secondary bile acids can be conjugated to glycine or taurine
What charge are bile salts at physiological pH?
Negatively charged
Which of the following statements concerning bile is INCORRECT?
a) Bile acids and bile salts act as emulsifying agents and facilitate the hydrolysis of dietary triacylglycerols by pancreatic lipase.
b) Primary and secondary bile acids are reabsorbed by the intestine, actively transported into the portal blood, and are actively taken up by liver cells.
c) Secondary bile acids are synthesized in the lumen of the gut.
d) Bile salts are synthesized in the liver, secreted into the bile, and are subsequently stored in the gallbladder.
e) During enterohepatic circulation, a major fraction of the total bile acids and bile salts are excreted in the feces
E- During enterohepatic circulation, a major fraction of the total bile acids and bile salts are excreted in the feces (wrong, >95% are recycled)