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DM > Lecture 29+30 > Flashcards

Lecture 29+30 Flashcards

1
Q

synthesis of heme is by what AA?

A

glycine

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2
Q

what is the regulated step of heme synthesis

A

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

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3
Q

regulation of ALA synthase in the liver and bone marrow?

A

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

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4
Q

hemoglobin synthesis in bone marrow

A

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

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5
Q

sideroblastic anemia

A

the gene for ALAS2 is found in on X chromosome

deficiency leads to this X-linked disorder

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6
Q

role of ALA dehydratase

A

uses two ALA’s to form porphobilinogen

Zinc is needed!!

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7
Q

Role of PBG deaminase

A

aligns and deaminates 4 porphobilinogens’ to form linear HMB

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8
Q

inhibition of heme synthesis?

A

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

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9
Q

Isoniazid

A

used for the treatment of tuberculosis treatment

this drug along with other drugs lead to the depletion of B6

thus B6 supplementation is needed

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10
Q

Porphyria’s

A

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

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11
Q

hepatic porphyria

A

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

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12
Q

Acute intermittent porphyria (AIP)

how? symptoms? detection

A

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

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13
Q

AIP onset and treatment?

A

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

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14
Q

Congenital Erythropoietic porphyria

A

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)

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15
Q

CEP onset and treatment

A

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

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16
Q

Porphyria cutanea tarda (PCT)

A

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

17
Q

PCT onset and treatment

A

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

18
Q

Jaundice

A

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)

19
Q

stages of heme degradation

A
  1. formation of bilirubin from heme in the reticuloendothelial system
  2. transport of bilirubin in blood from RES to liver
  3. uptake and conjugation in liver to excretion into bile
  4. formation of urobilinogen in large intestine
  5. formation of stercobilin and loss in feces
  6. absorption of urobilinogen and excretion of urobilinogen in urine
20
Q

bilirubin formation in the macrophage?

A

heme is converted to biliverdin by the enzyme heme oxygenase

biliverdin is converted to bilirubin by biliverdin reductase

21
Q

transport of bilirubin in blood to liver

A

binds albumin for transport in the blood
albumin prevents its excretion in the urine

drugs can displace bilirubin from albumin (salicylates, sulfonamides)

22
Q

Kernicterus

A

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
23
Q

from unconjugated bilirubin to conjugated?

A

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

24
Q

Dubin- Johnson syndrome

A

defect in MRP2 (a ABC transporter)

seen in young adults and adolescents

elevated conjugated bilirubin

normal AST, ALT, ALP

25
Q

formation of urobilinogen??

formation of stercobilin?

A

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

26
Q

urobilin??

A

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)

27
Q

different kinds of jaundice??

A

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

28
Q

pre-hepatic jaundice labs

A 
increased total bilirubin 
serum unconjugated bilirubin is increased
urine bilirubin is absent 
urine urobilinogen is high 
normal urine color
29
Q

hepatic jaundice labs

A

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

30
Q

post-hepatic jaundice

A

serum total bilirubin is high
serum conjugated bilirubin is high

NO unconjugated bilirubin
urine bilirubin is present
urine urobilinogen is low or absent

31
Q

jaundice in a newborn?

A
  1. low hepatic UDP-glucuronyl transferase (mainly seen in premature infants)
  2. increased RBC production that overloads the liver
  3. mother detoxifies and excretes bilirubin prior to birth

what bilirubin is increased?
unconjugated bilirubin!!

treatment:
can try photo therapy

32
Q

Inherited Unconjugated hyperbilirubinemia

A

varying deficiency of bilirubin UDP-glucuronyl transferase

have there kinds Crigler-Najjar syndrome I + II
gilbert syndrome

33
Q

crigler-Najjar syndrome I

A

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

34
Q

cringler-Najjar syndrome II (arias syndrome)

A

lower activity of bilirubin glucuronyl transferase

jaundice.. but less severe 6-22

responds to phenobarbital
photo therapy

35
Q

Gilbert syndrome

A

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

DM (21 decks)

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