Bilirubin Diseases Flashcards
what is the turnover rate for Hb?
6-7 new Hg/day
what enzymes are involved in detoxification process for Heme?
Cytochrome P450
what specific hepatic enzyme is resonsible for drug metabolism and where does this process take place?
microsomal CYP monooxygenase located in mitochonria of hepatocytes
what are the rate-limiting steps of hemo synthesis?
1, 6, 7, & 8
what TCA intermediates are the starting material for heme biosynthesis
glycine & succinyl CoA
what is the primary enzyme involved in step 1 of heme biosynthesis
ALAS
what happens when heme is in excess?
heme conversion to hemin (Fe3+) which inhibits transcription and importation of ALAS and increases ALAS mRNA degradation
What co-enzyme is required for activation of ALAS1?
Pyridoxal phosphate (PLP); this is the active form of Pyridoxine or Vit. B6
What is the physiological consequence if there is an enzyme or co-enzyme deficiency in the 1st step of heme biosynthesis
SIDEROBLASTIC ANEMIA:
elevated serum levels of Iron
High saturation of TIBC
what is the pathogenesis of X-linked sideroblastic anemia
X-linked recessive disorder resulting in a deficiency of ALAS2
what is the principal enzyme involved in step 2 of heme biosynthesis
ALA dehydratase
What is an essential cofactor for activation of the ALA dehydratase
Zinc (Zn2+)
describe the pathogenesis of lead poisoning for step 2 in heme biosythesis?
lead can replace Zn2+ and inhibit ALA dehydratase resulting in autoxidation of ALA which increases levels of ROS
Exposure to lead for long periods of time leads to the accumulation of ALA in plasma which can induce neurologic side effects:
ALA structure is similar to GABA
what is the principal enzyme of step 8 heme synthesis?
ferrochelatase: catalases rate of introduction of Fe2 into protoporphyrin
What heavy metal inhibits step 8 of heme synthesis?
lead
what is the substrate for step 3 of heme synthesis
porphobilinogen
what is the end product of step 4 in heme synthesis?
uroporphyrinogen
What is the umbrella definition for all porphyrias?
accumulation & increased excretion of porphyrins and/or porphyrin precursors
what common lab findings are found in all types of porphyria?
decreased heme; increased ALAS1
decribe the pathogenesis of Acute Intermittent Porphyria?
defective porphobilinogen deaminase leads to accumulation of upstream intermediates
List the 5 P’s assoc. w/ AIP?
painful abdomen
port wine-colored urine
polyneuropathy
psychological disturbances
precipitated by CYP inducers, alcohol, & progesterone
Describe the pathogenesis of porphyria cutanea Tarda?
defective uroporphyrinogen decarboxylase
list the clinical manifestations of PCT
cutaneous red dots & pale-red colored urine
describe the pathogenesis of erythropoietic protoporphyria.
defective ferrochelatase leading to accumulation of Protoporphyrin IX
what are the clinical manifestations of EPP?
Vampire Disease:
photosensitivity resulting in blistering of skin
Symptoms relieved by exogenous heme enzymes
what cells degrade heme?
macrophages
what is the rate limiting step of heme degradation?
Step 1: lysis of heme rings to generate biliverdin
principle enzyme: heme oxygenase
bilverdin reductase reduces bivlverdin to what?
bilirubin
Compare/Contrast pigmentation of biliverdin & bilirubin?
biliverdin: green pigment
bilirubin: red-orange pigment
unconjugated bilirubin has poor solubiltiy. how is it transpored into the bllod
albumin
where does bilirubin conjugation take place?
in hepatocytes
what hepatic enzyme is the principle of bilirubin conjugation?
bilirubin UDP-glucuronosyltransferase
what amino acids are invovled in bilitrubin conjugation
glucuronic acids
what is the rate limiting step of bilirubin degradation
secretion of conjugated bilirubin into bile
bile carrying conjugated bilirubin is transported into the intestine to be excreted; describe this metabolic process.
bacteria remove glucuronic acid and converts conjugated bilrubin to urobilinogen
what is the ultimate fate of urobilinogen that escapes intestinal excretion that gets reabsorbed into portal circulation
gets converted in the kidney into yellow urobilin which gives urine its distinctive yellow color
before urobilinogen gets excreted fecally, it is further oxidized. describe this metabolic process
urobilinogen is oxidized by intestinal bacteria to brown stercobilin giving feces its distinctive brown color
Porphyria of step 1-3 of the heme pathway leads to what physiologic consequences
accumulation of ALA and porphobilinogen causing neuropsychiatric symptoms
porphyria of steps 4-8 of the heme pathway lead to what physiologic consequences
photosensitivity & accumulation of porphyrinogens in skin
what are mechanisms of hyperbilirubinemia
overporduction of bilirubin; dyserythropoiesis; decreased uptake of bilirubin; defects in hepatic metabolism
what lab findings would you expect for suspected hemolytic jaundice
elevated blood levels of UCB; increased CB in bile; increased urobilinogen in urine
why are sickel cell patients at an increased risk for developing jaundice
extensive hemolysis causes hemolytic jaundice
what lab findings are indicative of hepatocellular jaundice
elevated UCB; reduced production of CB in intestines; increased urobilinogen in urine
what are the 2 most common causes of hepatocellular juandice
cirrhosis & hepatitis
pale, clay colored stool is due to what?
decreased converstion of urobilinogen to sterocoblin
what is the pathogenesis of obstructive jaundice
occlusion of common bile duct leading to increased CB in blood & urine; urobilinogen is absent; reduced levels of intestinal CB
what is the pathogenesis of dubin-Johnson syndrome
mutation of ABCC2 gene: transports bilirubin out of the liver and into bile; however, symptoms are relatively benign
describe the pathogenesis of gilbert syndrome?
decreased activity of conjugating enzyme UGT; relatively harmless w/ mild increase of UCB
This syndrome involves the same enzyme as gilbert syndrome but assoc. w/ a much more severe phenotype b/c UGT is either completly absent or defective
Crigler-Najjar syndrome Type 1
what is the pathogenesis of Rotor syndrome?
deficient uptake of bilirubin into the liver due to mutated hepatic OATs; relatively benign w/ buildup of both UCB & CB
describe the pathogenesis of junadince in neonates
majority of neonates show elevated UBC within first week of life; this is b/c hepatic bilirubin UGT is still low
what complications can arrise from persistently high levels of UCB in the blood stream?
high accumulation of bilirubin in blood promotes diffusion of bilrubin into the basal nucleus causing kernicterus (toxic encephalopathy)
what is used for managment of EPP
exogenous intake of b-carotene
what can be given to treat AIP
hemin & glucose
PCT can be treated w/ what drugs
hydroxychloroquine or chloroquine
what is an important distinction b/t PCT & EPP
PCT: blistering skin
EPP: nonblistering skin
erythropoietic porphyrias occur in which region in the body?
bone marrow
What drugs are CI for pts. w/ AIP?
barbiturates & rifampin
List hepatic type porphyrias
AIP; PCT
what are the physiological consequences of X-linked erythropoietic protoporphyria
acute photosensitivity; sideroblastic anemia
which porphyrias are assoc. w/ acute neurovisceral attacks?
ALAD porphyria & AIP
what porphyrin would you expect to find elevated in the serum of a pt. w/ PCT?
uroporphyrinogen
what porphyrin would you expect to find elevated in the serum of a pt. w/ ALAD porphyria
aminolevulinic acid (ALA)
what porphyrin would you expect to find elevated in the serum of a pt. w/ AIP
porphobilinogen
