ICL 3.1: Disorders of Hemoglobin Flashcards
why do you want iron on the inside the porphyrin ring of heme?
oxygen doesn’t dissolve in water and we are mostly water
so oxygen has to be held to the iron on the inside so it can be carried around the body
how many Hb molecules are there in one RBC?
280 million
in what population is it not okay to have low Fe?
kids
you need the iron for growth
what chromosome are the alpha globin chain genes on?
16
4 alleles, 2 on each chromosome 16
what type of Hb do you have when you’re an embryo vs fetus vs adult
embryo: ζ2ε2
fetus: α2γ2
adult: α2β2
what chromosome are the ζ globin genes on?
chromsome 16
what chromosome are the β globin genes on?
chromsome 11
1 allele each
what chromosome are the γ globin genes on?
chromosome 11
2 alleles each
what chromosome is the ε globin chain on?
chromosome 11
1 allele each
what is the structure of hemoglobin?
4 globin chain
each globin chain holds on to one porphyrin ring and each porphyrin ring holds onto one iron molecule
how many AA make up each α globin chain?
141 AA
how many AA make up each β globin chain?
146 AA
how many total AA does HbA1 have?
574 AA
what holds together the four subunits of hemoglobin?
non-covalent interactions
ex. hydrophobic, ionic and hydrogen bonds
what types of hemoglobin are in an adult?
HbA1 (95%)
HbA2 (<3%)
HbF (1-2%)
how is oxygen released?
CO2 has more affinity to Hb than oxygen
so when oxygen gets to the tissues, CO2 displaces oxygen and it’s released
if you give a patient with a Hb=3.5 a blood transfusion, what will happen?
they will die from circulatory overload
in chronic anemia, their body overtime has adjusted and is used to a Hb this low
what’s a normal WBC count?
4000-10,000 /μL
what’s a normal RBC count?
male: 4.6-6 x 10ˆ6/μL
female: 4.2-5.4x10ˆ6/μL
what’s a normal Hb level?
male: 14-18 g/dL
female: 12-16 g/dL
what’s a normal Hct level?
male: 42-50%
female: 37-47%
what’s a normal MCV?
75-100 fL
what’s a hemoglobinopathy?
genetic defect that results in abnormal structure of one of the globin chains of the Hb molecules
inherited single-gene disorders
what is hereditary persistence of fetal hemoglobin?
HPFH
failure to silence genes
what’s a quantitative defect type of Hb abnormality?
thalassemia
imbalance of chain synthesis
what is a qualitative defect type of Hb abnormality?
sickle cell
additional, substitutions or deletions of AA
what is the HbC mutation?
Glu6Lys point mutation
what is the HbD mutation?
Glu121Gln point mutation
what is the HbE mutation?
Glu26Lys point mutation
what are Howell-Jolly bodies?
denatured DNA
seen in sickle cell disease
this tells you that the person has no spleen! the spleen should be removing anything that is abnormal and Howell-Jolly bodies aren’t normal
what is seen in the blood smear of alpha thalassemia?
Heinz bodies
how do you diagnose an alpha thalassemia silent carrier?
must do genetic testing!
their Hb electrophoresis will look normal
Hb electrophoresis works for everything else
what globin chains get up or down-regulated in alpha thalassemia?
nothing gets down or upregulated
the only other Hb gene on chromosome 16 is ζ but it’s gone so NOTHING gets upregulated in alpha thalassemia
what is seen on x-rays of Hb disorders?
bone marrow expansion leads to hair-on-end X ray
seen in sickle cell and thalassemia and other Hb disorders
you will never see this in iron deficiencies
what is commonly seen on the blood smear of a thalassemia?
target cells
what populations have thalassemia?
african
mediterranean
how are iron levels effected in thalassemia?
they’re either normal or high
chronic hemolysis is happening which leads to iron overload states
what is the sickle cell mutation?
glu6val in the B chain
- to neutral charge
hydrophobic val stick together and sickle
MCV normal
what’s the benefit to having sickle cell trait?
sick cell trail = 1 normal B chain and 1 sickle B chain
protects against malaria
what problems does sickle cell disease cause?
microvascular occlusion
sticky RBCs
decreased NO by free Hb
what is SC disease?
Hemoglobin Sickle cell Disease
one HbS B chain and one HbC b chain
milder disease
MCV normal
what is S-thalassemia?
1 sickle B chain and 1 B chain thalassemia type
mildest disease because increased HbF helps compensate
sickled and target cells
decreased MCV = microcytic
what are the 5 types of sickle cell crisis?
- sequestration crisis
- aplastic crisis*
- hemolytic crisis*
- megaloblastic crisis
- vaso-occlusive crisis*
what is sequestration crisis?
kids only
acute splenomegaly
hypotension
possible death
what do sickle cell patients need a supplement of?
folate
to keep up with RBC production that’s needed due to all the hemolysis
what is dactylitis?
seen in kids only
really puffy red swollen hands
what is acute chest syndrome?
lots of sickling in the lungs
you have to do a transfusion to replace sickled RBCs with normal RBCs
what things have improved sickle cell patient life spans?
- penicillin antibiotics
- transfusions
- hydroxyurea
what is HbC disease?
glu6lys substitution
because + lysin, HbC moves more slowly on electrophoresis compared to HbA and HbS
mild hemolytic anemia
no specific therapy is recommended because it’s usually not that bad!
what is porphyria?
heme synthesis enzyme deficiency
if you’re missing an enzyme in the heme synthesis pathway, it all back-up and the rest of the enzymes build up
you can’t make heme so you need oxygen and you can’t go out into the sun because the porphyrin precursors have a lot of photosensitivity = this is where the myths of vampires comes from!
how is HepC related to porphyria?
HepC can cause porphyria!!
so treat HepC and you can fix the porphyria
what is the classical symptom combination associated with porphyria?
abdominal symptoms
AND
neuropsychiatric symptoms
what symptoms are associated with porphyria?
- abdominal
- neuropsychiatric
- skin rashes
- dark urine when exposed to sunlight
what are the two ways porphyria can be classified?
- symptomatically
- acute
- cutaneous - pathophysiology
- hepatic
- erythropoietic
based on the sites of accumulation of heme precursors, either in the liver or bone marrow and RBC
everything except one porphyria is hepatic
what are the types of acute porphyria?
ALA-D deficiency porphyria
acute intermittent porphyria
variegate porphyria
hereditary coproporphyria
what are the types of non-acute porphyria
porphyria cutanea tarda
erythropoietic prootophorphyria
congenital erythropoietic porphyria
what is acute intermittent porphyria?
type of inherited hepatic porphyria
uroporphyrinogen I synthase deficiency = porphobilinogen deaminase
normally, porphobilinigoen –> hydroxymethylbilane via UPSI but without it, porphobilinogen and ALA build up
increased excretion of porphobilinogen & γ-ALA
urine gets darkened on exposure to air due to conversion of porphobilinogen to porphobilin & porphyrin
what enzyme is effected in acute intermittent porphyria?
uroporphyrinogen I synthase
when is acute intermittent porphyria expressed?
after puberty
what’s the inheritance of acute intermittent porphyria?
autosomal dominant
in what population is acute intermittent porphyria most common?
affects all races and ethnicities
more common in caucasians
occurs predominantly in woman (80%)
what acute porphyria is most common?
acute intermittent porphyria
what are the aggravating factors for acute porphyrias?
- drugs and chemicals (anti-seizure medications)
- luteal phase of menstrual cycle
- pregnancy
- post-partum period
- infection
- stress/exhaustion
- fasting/starvation
- surgery
some of these reasons are why women are the ones effected by acute intermittent porphyria 80%
what are some porphyria treatment options?
liver transplant
stop medications that triggered symptoms
treat infections that may have caused symptoms
IV glucose
IV fluids
hemin injections production of porphyrin
how does IV glucose help treat porphyria?
IV glucose inhibits porphyrin pathway via negative feedback
injections of what helps with porphyria?
hemin injections
a form of heme but help limit the body’s production of porphyrin
what is methemoglobinemia?
increased levels of methemoglobin
methemoglobin is a form of Hb that has ferric Fe+3 which can’t bind oxygen!
normal Hb goes from Fe+2 to Fe+3 when it binds oxygen so methemoglobin is already in Fe+3 state
oxygen binding to methemoglobin increases the affinity for oxygen in the hemes with Fe+2 which decreases the ability of the RBC to release oxygen
can be acquired or born with it
where in the US do you find people born with methemoglobinemia?
appalachian areas because there’s inbreeding
what are the two types of methemoglobinemia?
- inherited
2. acquired (more common; usually from antibiotics)
what are the types of inherited methemoglobinemia?
- cytochrome b5 reductase deficiency
2. hemoglobin M disease
what are the types of cytochrome b5 reductase deficiencies?
type I: limited to RBCs
type II: all cells - most die in infancy
what are some methemoglobin-inducing agents?
lots of common things can cause it!
*naphthalene = moth balls!
nitrofurantoin = common antibiotic for UTI
amyl nitrite
aniline dyes
chlorates
food additives
inks
lidocaine
local anesthetics
nitrates
shoe dye/polish
what are the symptoms of methemoglobinemia?
based on methemoglobin concentration
0-3%: no symptoms
10-20%: mild symptoms, cyanosis, chocolate brown blood from high methemoglobin levels
20-50%: dyspnea, decreased exercise tolerance, fatigue, HA, dizziness, tachycardia
> 50%: CNS hypoxia, seizures, coma, dysrhythmias, ischemia, tachypnea, metabolic acidosis
> 70%: death
what’s a hallmark of methemoglobinemia?
brown blood!!!
it’s from the methemoglobinemia that’s brown in color
how do you treat methemoglobinemia?
methylene blue! it’s an antiseptic dye
methb-reductase turns MetHb (Fe+3) –> Hb (Fe+2)
vitamin C can also reduce Fe+3 to Fe+2
how does CO poisoning happen?
CO binds super tightly to Hb and displaces oxygen from Hb
this only happens when CO concentration gets high
**cherry red skin
what are some sources of CO?
tons of common stuff!
gas or wood-burning fireplace
car left running in garage
portable generators
portable kerosene gas heaters
loose vent pipes
improperly installed kitchen range/vent
what are the symptoms of carbon monoxide poisoning?
depends on the % of CO in blood
<10%: none
20-30%:drowsiness, headache, increased respiratory rate, dizziness, headache, nausea
30-40%: impaired judgement, difficulty breathing, blurry vision, bad headache, more drowsiness, stomach pain
40-50%: confusion, pounding headache, uncontrolled sleep, vertigo, chest pain, memory loss
> 50%: seizure, unconsciousness, heart attack
how do you treat CO poisoning?
hyperbaric oxygen for about 5 hours to displace CO
it can only go out through the lungs! Just have to breath it out
keep giving till confusion stops
what does the oxygen association curve look like for CO poisoning?
oxygen tension vs. HbO2% saturation
shifted to the left
CO is staying attached to Hb
