enzyme deficiencies

define anemia, is it a disease?
it is a symptom, not a disease. decrease of hemoglobin conc. below normal levels. (14-18 g/dL men and 12-16 g/dL in women)
define hematocrit
simple/crude test to determine anemia, % vol in blood occupied by cells
what are 2 reasons for decreased production of erythrocytes?
iron defiency and folate or vit B11 deficiency
what does folate or vitamin B12 deficiency do to RBCs?
both are involved in the one carbon metabolism, which is part of nucleotide synthesis -> if not enough nucleotides, the cells can’t divide, and will grow more, causing megaloblastic anemia
what population is vit B12 deficiency common in?
aging populations, either they don’t take enough in or they have a deficiency in the intrinsic factor for B12
what is the most prevalent form of anemia? what are the 2 forms?
iron deficiency. the 2 kinds are: microcytic – b/c RBCs are small and there is not enough iron to build heme moiety. hypochromatic – not enough Hb being produced
what are 2 ways the erythrocytes are lost or destroyed due to enzymatic deficiency? what pathways are they associated with?
pyruvate kinase/hexokinase deficiency,(glycolysis), glucose 6 phosphate dehydrogenase deficiency, (PPP)
what are the 2 ways that RBCs can produce ATPs?
glycolysis -> lactate, or through the PPP
what is the purpose of the glutathione pathway in RBCs?
to create gluathione, which serves to de-toxicfy RBC from hydrogen peroxide, (H2O2)
why does adding glucose to sugar not allow it to keep for any period of time? what can be added to blood to increase it’s shelf-life?
hexokinase is an unstable enzyme, so adding glucose only works for a short amount of time. adding adenosine will allow blood to keep for a length of time, it eventually becomes ribose-5-phosphate
why do pts with anemia show difficulty in exertion, pallor, and jaundice?
difficulty in exertion b/c not enough energy, due to lack of O2 due to lack of RBCs. pallor is due to lack of RBCs in circulation. jaundice is due to bilirubin metabolites from RBC destruction building up in fatty tissues, (conjugated or unconjugated)
what is the cause for dark or red urine?
conjugated bilirubin in the urine, (UNCONJUGATED BILIRUBIN IS NEVER IN URINE), also Hb may color urin red
how do oxidizing agents/H2O2 cause hemolysis?
damage to the RBC membrane
what is metHb?
derivative of Hb with iron oxidized from Fe2+ to Fe3+, (which cannot bind O2)
what molecules can oxidize Hb to metHb? how does this happen?
O2, toxic compounds in food/their metabolic products, and reactive oxygen species. electrons can jump from the oxygen to the iron.
what reactive oxygen species are there, and are some worse than others?
hydroxyl radical, OH – formed from H2O2 oxidizing Hb is the worst. the super oxide anion, (O2/w extra electron), is formed when O2 oxidizes Hb, (will disturb lipids), and finally H2O2
do we normally have metHb in our bodies?
yes ~5%
what will happen if superoxides are not dealt with in the RBC?
hemolysis
how do RBCs convert metHb back to Hb? why is the glycolytic cycle important this?
metHb reductase utilizes cytochrome b5 along with NADH to change Fe3+ back to 2+. the glycolytic cycle is important for this as it provides NADH
what happens with a metHb deficiency?
the metHb will be around 70% and pts will be blue and weak
what is the main producer of superoxides?
the electron transport chain. coenzyme Q carries one electron at a time, which sometimes will jump to O2
how does the body respond to superoxides?
superoxide dismutase converts the superoxide to H2O2, which either catalase or glutathione peroxidase, (using reduced glutathione) converts to water and oxygen
what does hexokinase do and what happens if it is deficient?
it normally allows passage and capture of glucose inside the RBC for both the glycolytic and PPP. if deficient, the pt will have hemolytic anemia
how does a hexokinase deficiency lead to hemolytic anemia?
glucose will be unable to enter the cell, superoxides will not be inactivated properly, and the membranes will burst
are there other symptoms of a hexokinase deficiency other than hemolysis? was is usual tx?
weakness, elevated bilirubin, (due to increased destruction of RBCs). tx consists of preventing the toxic effects of bilirubin
hexokinase deficiency is rare, but what 2 enzyme deficiencies are more common?
glucose 6 phosphate dehydrogenase and pyruvate kinase deficiencies
where is pyruvate kinase located relative to the glycolytic cycle? what does its deficiency cause directly?
pyruvate kinase is found at the end of the glycolytic pathway, and its deficiency will cause an underproduction of ATP
in the case of a pyruvate kinase deficiency, how does the underproduction of ATP affect the cell?
ATP is needed to maintain membrane integrity through Na/K pumps, and its lack will cause hemolysis
what allows pts with pyruvate kinase deficiencies to have periods of time where they can function moderately well?
2,3 bisphosphoglycerate is a glycolytic substrate that produces metabolites able to bind Hb and unload O2, allowing pts to tolerate anemia easier
what are considerations for treating people with pyruvate kinase deficiencies? ways of IDing it?
pts w/pyruvate kinase deficiencies usually have acute symptoms after viral infections, which can lead to hyperbilirubinemia and jaundice. phototherapy is used to treat children, who are particularly susceptible to it’s toxic neurologic effects. phototherapy degrades the bilirubin into smaller water soluble compounds. family hx is the best way of IDing this condition
why is has glucose 6 phosphate dehydrogenase deficiency been associated with fava beans?
fava beans contain 2 chemicals that have an oxidizing effect of the dissociation of metHb with oxygen and studies have shown that people who react to this have a glucose 6 phosphate dehydrogenase deficiency
why is a glucose 6 phosphate dehydrogenase deficiency more serious in RBCs than in other places?
RBCs have much less glucose 6 phosphate dehydrogenase than other cells
what are symptoms of a glucose 6 phosphate dehydrogenase deficiency?
prolonged neonatal jaundice, possibly leading to kernicterus, hemolytic crises in response to illness, (especially infections), certain drugs, diabetic ketoacidosis, fava beans
what is the current theory as to why sickle cell and glucose 6 phosphate dehydrogenase deficiencies affect more in equatorial regions?
these areas correlate with higher levels of malaria, and if RBCs are destroyed quicker, the parasite has less ability to remain
what drug and other types of compounds are found to cause hemolytic events in people with glucose 6 phosphate dehydrogenase deficiencies?
primaquine, other chemicals with nitrogen rings -> dissociates complex of metHb+oxygen and makes superoxide anion/metHb
what is a heinz body?
dark spot on RBC, created by a Hb cluster where free SH groups on globin portion of Hb are oxidized, forming clumps
how do pts with glucose 6 phosphate dehydrogenase deficiencies return to normal Hb levels after hemolytic events?
a signal is sent to erythropoiten in the bone marrow to produce more RBCs, and the maintenance of Hb conc is thus kept by reticulocytes, (young RBCs)

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