Flashcards in 8. Heme Catabolism and Bile Salts Deck (63):
___ g hemoglobin synthesized to replace heme from normal turnover
__% of total iron present as heme in RBCs
What step of heme catabolism happens in macrophages of the reticuloendothelial system?
Heme ring opens -> biliverbin -> bilirubin
How are heme byproducts transported to the liver?
Albumin transports bilirubin through the blood to the liver
What step of heme catabolism occurs in the liver?
Bilirubin is conjugated with glucuronic acid and excreted
What step of heme catabolism occurs in the GI tract?
Conjugated bilirubin is deconjugated by bacteria to urobiliogen
What step of heme catabolism occurs in the kidney?
Urobilinogen is converted to urobilin and excreted in the urine
What form of bilirubin is excreted in the feces? Urine?
Jaundice or icterus results from:
Accumulation of elevated bilirubin in the skin or sclera
Inherited disorders of bilirubin metabolism lead to:
80% of heme catabolism occurs from
Immature RBCs and cytochromes in nonerythroid tissues
What is the first stem of heme catabolism catalyzed by? What is required?
Heme oxygenase (HO-1): cleaves the ferroprotoporphyrin ring
**requires electrons from NADPH cytochrome P450 oxidoreductase
What is released from the rxn catalyzed by HO-1?
CO--bound by hb
FE-- bound by ferritin
What enzyme uses NADPH or NADH to convert biliverdin to bilirubin?
Bilirubin dissociated from albumin before entering the hepatocyte, and how is it kept in solution once inside?
Interactions with cytosolic proteins called LIGANDINS
**temporary storage within hepatocyte
What does efficient excretion of bilirubin across the bile canaliculus require?
Conversion to polar conjugates by esterification or propionic acid carboxyl groups
What is the conjugation rxn of bilirubin catalyzed by?
Uridine diphosphate glucuronocyltransferase (UGT1A1)
UGT1A1 is specific for bilirubin and is primarily located:
In the ER of the hepatocyte
What are the products of the rxn catalyzed by UGT1A1?
** one or two glucounronic acid moieties or UDP-glucuronic acid are transferred
What is responsible for bilirubin excretion upon conjugation?
ATP dependent multiorganic anion transporter (MOAT) in canalicular membranes
What happens to conjugated bilirubin upon entry into the GI tract?
Degraded by intestinal bacteria into urobilinogen products (present in deconjugated state, but unclear if deconjugation occurs before or after degradation of dilibrubin to urobilinogen)
What color change occurs when bilirubin is converted to urobilinogen?
Yellow-orange to colorless
What is the major pigment of feces?
What are the four distinct stages of the hepatic processing of bilirubin?
1. Uptake from the circulation
2. Intracellular binding
4. Biliary excretion
How can disorders of hyperbilirubinemia be divided?
What is the clinical lab test for serum bilirubin?
Van den Bergh assay: in water, measures conjugated/direct bilirubin. in methanol, measures total bilirubin (allows calculation of unconjugated/indirect)
What is the basis for neonatal janudice?
Delayed maturation of the liver leads to low activity of UGT1A1 at birth
What are the three factors that lead to jaundice at 5 days of life with neonatal jaundice?
1. Low activity of UGT1A1
2. Decreased excretory capacity of the hepatocytes
3. Increased bilirubin production secondary to accelerated destruction of fetal erythrocytes
In neonatal jaundice, serum bilirubin is mostly _____
What can happen in neonatal jaundice is untreated?
Damage to regions of the brain (basal ganglia) from unconjugated bilirubin accumulation
Kernicterus: bilirubin encephalopathy causing athetoid (writhing) cerebral palsy and hearing loss
Majority of neonatal jaundice is inocuous, and why may it be beneficial?
Important antioxidant defense--bilirubin can inhibit lipid peroxidation based on ability to donate hydrogen ions
Why is unconjugated bilirubin toxic while conjugated is not?
Conjugated is soluble, while unconjugated can be deposited in tissues
What is the most common tx for neonatal jaundice?
Phototherapy with light from the blue-green spectrum (430-490 nm, NOT UV)
Changes the configuration of unconjugated bilirubin to an isomer that can be excreted without conjugation
The three inherited unconjugated hyperbilirubinemia syndromes discussed are related to:
Disorders in UGT1A1 expression, resulting in lowered hepatic conjugation of bilirubin
What are the three disorder of UGT1A1 in order of increasing severity? (with UGT level)
Gilbert syndrome: reduced to 30%
Crigler-Najjar syndrome Type II: reduced to under 20%
Crigler-Najjar syndrome Type I: absent
What are the two inhertied syndromes that lead to high levels of conjugated bilirubin? Defect?
Dubin-Johnson: defect in organic ion transporter MOAT
Rotor syndrome: not characterized
What is the appearance of the liver in Dubin Johnson syndrome?
Grossly black (normal appearing in Rotor syndrome)
What happens in jaundice caused by hemolysis?
RBC destruction leads to high levels of indirect bilirubin, overwhelming the ocnjugation mechanism
What happens in obstruction causing jaundice?
Blocking of the bile ducts leads to conjugated bilirubin backing up, appearing in the plasma rather than the intestine
Dubin-Johnson and Rotor syndrome are characterized by inability
to secrete conjugated bile into the bile canaliculi, leading to conjugated bile returning to the blood
What happens with hepatocellular defects causing jaundice?
Damage to the liver by toxins, poisons, cardiac failure, acute/chronic disease impairing the liver's conjugation ability and increasing the levels of unconjugated bilirubin in the plasma
Bile acids are synthesized form ____ in the liver
Bile acids are secreted from the hepatocytes into:
Bile canaliculi--specialized channels formed by adjacent hepatocytes
What is the role of bile acids
Emulsifying agents that prepare dietary triglycerides for hydrolysis by pancreatic lipase
Facilitate the absorption of fat-soluble vitamins, like vitamin D, from the intestine
The most abundant bile acids are derivatives of:
Cholic acid (primary bile acid that has extra OH groups, more water soluble than cholesterol)
How are primary bile acids converted to secondary bile acids?
Bacteria in the gut via dehydroxylation reactions
What are two key primary bile acids? Secondary?
Cholic acid and chenodeoxylcholic acid
Doxycholic acid and lithocholic acid
Where are primary and secondary bile acids reabsorbed? What happens to them next?
Lower ileum into portal blood
Taken up by hepatocytes and conjugated to glycine or taurine to form bile salts
What is the conjugation of bile acids in the liver after absorption from the gut important?
Converts the bile acids into molecules with a lower pKa, rendering them soluble in the small intestine
What does gut bacteria convert cholic acid to? Chenodeoxycholic acid? What are the secondary bile salts conjugated with?
Deoxycholic acid --> glycine
Lithocholic acid --> taurine
Bile acids emulsify fats to prepare dietary TGs for hydrolysis by
And facilitating the absorption of
Fat soluble vitamins
The capacity of the liver to product bile acids in insufficient to meet physiologic demands so the body relies on efficient
Enterohepatic circulation--carries bile acids from the intestine back to the liver
What is the major mechanism by which cholesterol is excreted?
What is elevated in the blood in Familial Hypercholesterolemia ?
Elevated concentration of LDL in the plasma
What are two physical findings with Familial Hypercholesterolemia?
Deposition of LDL-derived cholesterol in the tendons and skin (xanthomas) and arteries (atheromas)
What is the inheritance pattern of Familial Hypercholesterolemia?
Inheritance as an autosomal dominant trait with a gene dosage effect (homozygotes more affected than heterozygotes
What is the defect in Familial Hypercholesterolemia?
Mutation in the gene encoding the LDL receptor
FH heterozygotes are 1 in ___
What is the dual role of the LDL receptor?
Limits LDL production by enhanging the removal of the precursor, IDLfrom circulation
2. Enhances LDL degradation by mediating cellular uptake of LDL (apo B-100)
What are three methods to treat FH heterozygotes?
1. Bile acid binding resins (cholestyramine and colestipol)
2. HMG-CoA reductase inhibitors (statins)
3. Diet low in cholesterol and fats
How do bile acid binding resins like cholestyramine and colestipol work?
Bind bile acids in the intestinal lumen, preventing their absorption from the lumen
Increased fecal excretion of bile acids leads to conversion of chol to bile acids in the liver
Resulting cholesterol deficiency stimulates an increase in production of LDL receptors
Combined with bile acid resins, statins can decrease LDL cholesterol by __%`
Alone, a diet low in cholesterol and fats and decrease in LDL chol by __%