Lecture 29+30 Flashcards
synthesis of heme is by what AA?
glycine
what is the regulated step of heme synthesis
this step is catalyzed by ALA synthase
takes succinyl CoA and glycine to produce alpha-aminolevulinic acid
PLP or B6 is needed as a co-enzyme
regulation of ALA synthase in the liver and bone marrow?
Liver:
contain the gene ALAS1
inhibited by high heme and glucose
stimulated by low heme
bone marrow:
contain the gene ALAS2
inhibited by low iron
hemoglobin synthesis in bone marrow
erythropoietin is released by the kidney at low oxygen levels in tissues; this leads to RBC and hemoglobin synthesis
iron dependent heme synthesis
ALAS2 is regulated by iron levels and not inhibited by heme
sideroblastic anemia
the gene for ALAS2 is found in on X chromosome
deficiency leads to this X-linked disorder
role of ALA dehydratase
uses two ALA’s to form porphobilinogen
Zinc is needed!!
Role of PBG deaminase
aligns and deaminates 4 porphobilinogens’ to form linear HMB
inhibition of heme synthesis?
deficiency of vitamin B6:
this vitamin is needed for ALA synthase
lead poisoning:
ALA dehydratase and ferrochelatase need zinc as a co-factor
this heavy metal interacts with zinc and thus less heme synthesis
ALA and protoporphyrin IX will accumulate in blood and urine
Isoniazid
used for the treatment of tuberculosis treatment
this drug along with other drugs lead to the depletion of B6
thus B6 supplementation is needed
Porphyria’s
caused by a specific enzyme deficiency
can lead to the accumulation of intermediates of heme synthesis in the blood, tissues, and urine
features: severe abdominal pain neurological dysfunction mental disturbance (you mean psychiatric symptoms?) photosensitivity of the skin
often groups as hepatic or erythropoietic
hepatic porphyria
treatment with IV glucose or hemin and saline
a metabolite of glucose inhibits ALAS1. hypoglycemia usually induces heme synthesis
symptoms worsen by drugs that induce hepatic cytochrome P450
Acute intermittent porphyria (AIP)
how? symptoms? detection
HMB synthase deficiency or PBG deaminase
accumulation of ALA and porphobilinogen as the synthesis of ALAS1 is stimulated by low heme levels
features: severe abdominal pain constipation and abdominal colic weakness of lower extremities arterial hypertension agitated state with mental symptoms tachycardia and breathing issues NOT photosensitive
detect:
urine analysis for ALA and porphobilinogen
urine color change (red,purple,black) after exposed to light/air
AIP onset and treatment?
AIP can be stimulated by drugs that stimulate heme synthesis
infections, alcohol abuse, or estrogen hormone therapy
the severity of actue symptoms can be diminished by saline and IV glucose or hemin
DO NOT prescribe barbiturates to these patients
stimulates P450 synthesis
Congenital Erythropoietic porphyria
defect is only in the bone marrow
deficiency in the erythroid isozyme of uroporphyrinogen III synthase
autosomal recessive
leads to abnormal porphyrins and skin photosensitivity
clinical:
ROS damage leads to poor wound healing, severe blisters, and ulcers
the teeth can be reddish-brown
hypertrichosis (hairy face and arms)
urine is red (uroporphyrin I and coproporphyrin I accumulation)
CEP onset and treatment
onset is childhood or earlier due to hereditary defect
(have severe pain when in contact with UV light)
Hemin IV treatment is not effective as ALAS2 gene expression is not inhibited by heme
bone marrow transplant may help
Porphyria cutanea tarda (PCT)
deficiency in uroporphyrinogen III decarboxylase
uroporphyrinogen…. uroporphrin III accumulates in the liver, skin, and blood
seen to have photosensitivity with cutaneous lesions
the urine is red in natural light or pink under UV light
PCT onset and treatment
occurs between 40-50 years old
type I: acquired due to chronic disease of the liver like hepatitis or ethanol abuse
Type II: familial
clinical expression is influenced by:
hepatic iron overload
exposure to sunlight
alcohol consumption in access
treatment:
avoidance of sunlight and alcohol and reduction in iron intake
Jaundice
clinical sign:
yellow discoloration of the skin, mucus membranes, sclera, and nail beds
binding of bilirubin (bile pigment) to connective tissues
occurs when serum bilirubin levels are greater than 2 mg/dL (hyperbilirubinemia)
stages of heme degradation
- formation of bilirubin from heme in the reticuloendothelial system
- transport of bilirubin in blood from RES to liver
- uptake and conjugation in liver to excretion into bile
- formation of urobilinogen in large intestine
- formation of stercobilin and loss in feces
- absorption of urobilinogen and excretion of urobilinogen in urine
bilirubin formation in the macrophage?
heme is converted to biliverdin by the enzyme heme oxygenase
biliverdin is converted to bilirubin by biliverdin reductase
transport of bilirubin in blood to liver
binds albumin for transport in the blood
albumin prevents its excretion in the urine
drugs can displace bilirubin from albumin (salicylates, sulfonamides)
Kernicterus
administration of drugs displaces bilirubin from albumin and this free form of bilirubin cross the BBB in infants
also could be from hypoalbuminemia and low pH
unconjugated bilirubin crosses the BBB and deposits in the basal ganglia
symptoms: lethargy altered muscle tone high pitched cry intellectual impairment ataxia muscular rigidity
from unconjugated bilirubin to conjugated?
unconjugated bilirubin enters the liver by specific transporters on the hepatocytes
within hepatocyte, unconjugated bilirubin will bind to ligandin
converted to conjugated bilirubin (more water soluble) by adding two glucuronic acids by the enzyme UDP-glucuronyl transferase
can be inducted by phenobarbital
conjugated bilirubin can be moved to the bile canaliculi by ABC transporters (MRP2)
will be released into second part of duodenum by common bile duct
Dubin- Johnson syndrome
defect in MRP2 (a ABC transporter)
seen in young adults and adolescents
elevated conjugated bilirubin
normal AST, ALT, ALP
formation of urobilinogen??
formation of stercobilin?
conjugated bilirubin is acted on by the gut flora
it undergoes deconjugation and converted to urobilinogen
further bacterial action in the LI forms stercobilin which is a brown color
only some urobilinogen is reabsorbed
urobilin??
majority of the urobilinogen that is reabsorbed by the GI goes to the liver
majority of urobilinogen is converted to urobilin and excreted in the urine (yellow color)
different kinds of jaundice??
prehepatic (hemolytic) jaundice: increased breakdown of RBC’s
hepatic jaundice: decreased conjugation capacity of liver and decreased excretion of bilirubin
posthepatic (obstructive / cholestatic): decreased excretion of bilirubin via bile
pre-hepatic jaundice labs
increased total bilirubin serum unconjugated bilirubin is increased urine bilirubin is absent urine urobilinogen is high normal urine color
hepatic jaundice labs
increased total bilirubin
increased serum conjugated bilirubin
increased unconjugated bilirubin
urine bilirubin is present
no or low urine urobilinogen
elevated ALT and AST
urine is odd color
post-hepatic jaundice
serum total bilirubin is high
serum conjugated bilirubin is high
NO unconjugated bilirubin
urine bilirubin is present
urine urobilinogen is low or absent
jaundice in a newborn?
- low hepatic UDP-glucuronyl transferase (mainly seen in premature infants)
- increased RBC production that overloads the liver
- mother detoxifies and excretes bilirubin prior to birth
what bilirubin is increased?
unconjugated bilirubin!!
treatment:
can try photo therapy
Inherited Unconjugated hyperbilirubinemia
varying deficiency of bilirubin UDP-glucuronyl transferase
have there kinds Crigler-Najjar syndrome I + II
gilbert syndrome
crigler-Najjar syndrome I
most severe; very low enzyme activity
jaundice in neonate or infant
serum unconjugated bilirubin are up to 50
Kernicterus and developmental delay
daily photo therapy is recommended
does not respond to phenobarbital
fatal if not treated properly
cringler-Najjar syndrome II (arias syndrome)
lower activity of bilirubin glucuronyl transferase
jaundice.. but less severe 6-22
responds to phenobarbital
photo therapy
Gilbert syndrome
seen in adolescents and young adults
mild jaundice can be seen following illness or stress or starvation
bilirubin glucuronyl transferase activity is 50 percent normal
mild increase in unconjugated bilirubin
normal AST, ALT, and ALP levels
