Lec 11 heme synthesis Flashcards
structure of Hemeoglobin
Porphyrin ring with iron present at the center (ferrous)
4 5 membered rings (pyrrole)
Phase 1 of heme synthesis
Phase II of heme synthesis
Phase III of heme synthesis
Lead poisoning and heme production
Lead inactivates ALA dehydratase and ferrochelatase
ALA and protoporphyrin ix accumulate
ALA is neurotoxic
causes anemia
impact energy production no cytochromes synthesized
What is Porphyrias
example of porphyrias that affect the erythropoietic
Congenital erythropoietic porphyria
defect in uroporphyrinogen III synthase (erythrocytes)
Photo sensitivity red urine
Auto recessive
buld up uroporphyrinogen I oxidise to uroporphrin I
Porphyrias that affect hepatic
Acute intermittent porphyria
defect in PBG deaminase (in liver)
too much ALA and PBG
Auto dom
ab pain and neuro dysfunction
Variegate porphyria (famous people had it)
defect protoporphyrinogen ix oxidase
Auto dom
photosens.
porphyria that affect hepatoerythropoietic
Porphyria cutanea tarda (PCT)
most common in us
defect uroporphyrinogen decarboxylase
auto dom
Heme degradation is under what system?
Reticulo-endothelial system
Globin broken down into what?
what happens to heme?
Globin broken down into aa
heme removed for degradation
Difference between heme and bilirubin?
What does heme oxygenase require?
what does it release?
oxygen
releases Carbon monoxide
What happens to the Fe2+ in heme once broken open?
changes into ferric iron Fe3+
Pathway from heme into billirubin
What happens once we have bilirubin?
- Released to bloodstream.
- Free/unconjugated/indirect BR insoluble
- so bound to albumin
- BR/albumin transport to liver
what assists uptake of BR in hepatic tissue?
protein carrier
what happens to Bilirubin in the liver?
UDP- glucuronate and bilirubin ix go to
bilirubin-monoglucuronide (direct)
via UDP-glucuronyltransferase
another UDP-glucuronate is added to this with same enzyme making
bilirubin-diglucuronide (direct)
are bilirubin mono and di- glucuonide indirect?
no they are direct or conjugated and are now soluble
(conjugated with glucuronic acid)
UDP-glucuronate formation
UDP-glucose converted UDP-glucuronic acid
via UDP glucuse dehydrogensase
Bilirubin-diglucuronide in liver then does what?
moves to the gallbladder (part of bile)
From gallbladder what happens (Path 1)
bilirubin-diglucuronide goes to bilirubin
bilirubin goes to urobilinogen
via microbial reduction
Urobilinogen gets reabsorb to kidneys
goes to urobilin (yellow color of urine)
From gallbladder what happens (path two)
bilirubin-diglucuronide goes to bilirubin
bilirubin goes to urobilinogen
via microbial reduction
urobilinogen goes under further microbial reduction to red-brown stercobilin (feces color)
Jaundice
hyperbilirubinemia
elevated levels of BR in blood stream
unconjugated/indirect (.2-.9)
conjugated/direct (.1-.3)
imbalance between production and exrecretion
types of jaundice
pre-hepatic
intra-hepatic
post-hepatic
Pre-hepatic jaundice (causes)
increased production of unconjugated BR
- excess hemolysis (hemolytic anemias)
- internal hemorrhage
- liver capacity (uptake, conjugate, excrete)
- glucose 6 PO4 dehydrog defic
- incompatibility of maternal-fetal blood groups
pre-hepatic findings
elevated blood levels unconj or indirect BR
normal conjugated BR
normal alanine aminotransferase (ALT) and aspartate aminotransferase AST
urobilinogen in urine (conjugate not impaired)
direct BR absent in urine
Intra-hepatic causes
impaired hepatic uptake, conjugation, or secreition of conjugated BR
- Hepatic dysfunction
- liver cirrhosis
- viral hepatitis
- criggler-najjar syndrome
- Gilbert syndrome
Intra-hepatic findings
- variable increases in unconjugated and conjugated BR depending on the cause (pre post conjugation)
- increse in ALT AST in serum (hepatic dysfun)
- urobilinogen levels normal
- conjugated BR detected in urine
Post-hepatic causes
problems with BR excretion
AKA cholestatic jaundice (decrease bile flow)
obstruct liver of bile duct
gall stone
carcinoma
liver disease
lesions
drugs
Post-hepatic findings
elevated blood levels of conjugated BR
small increase in unconjugated form
Normal AST ALT
elevated ALP
conjugated BR in urine (dark)
no urobilinogen in urine
no stercobilin in feces (pale stool)
Neonatal jaundice
Phototherapy and neonatal jaundice
crigler-Najjar syndrome
(type 1) deficiency of UDP-GT
complete absence of gene
BR accumulate in brain of babies (serious)
- blood transfustions
- phototherapy
- heme oxygenase inhibitors
- calcuim phosphate and carbonate (complex in gut
- liver transplant
criggler-Najjar syndrome type II
benign form
mutation in UDP-GT gene
10% activity
(not as severe)
Gilbert syndrome
relatively common
reduced activity UDP-GT (25%)
BR <6mg/dL may icrease with fasting, stress
or alcohol consumption
Hepatitis
inflammation of liver (liver dysfunction)
viral infec, alcohol cirrhosis, liver cancer
- increased levels of unconj and conj BR
- BR accum in skin and sclera yellow discolor
- tea colored urine
Bruises and their colors
breakdown of hemoglobin diff colors
- Hemoglobin
- heme-red
- biliverdin-green
- bilirubin-orange
- iron-reddish brown (hemosiderin)
