Nutritional Anemia HLS/ Biochemistry · Nutritional Anemia ... H 4 folate is converted to N...

Nutritional Anemia

HLS/ Biochemistry الفريق الطبي األكاديمي

لكــية الطب البرشي

البلقاء التطبيقية / املركز

2016/2022أ حياها و من

Done By: Shady Soghayr & Shatha Khtoum

Nutritional Anemia و من أحياها

2016/2022

Nutritional Megaloblastic Anemias

Today we will talk about macrocytic anemias and the biochemical aspects

about macrocytic anemias.

- in this topic we will talk about the function and biochemical aspects of these

two vitamins; B12 and folic acid and the deficiencies of these two vitamins

cause some types of anemias mainly; macrocytic or megaloblastic anemia.

Definition: Macrocytic Anemia

MCV>100fL mean corpuscular volume is more than 100 fL, the normal

range is 80-90 fL. But if it less than 80 fL it called microcytic anemia. Each

one of them have its indications.

when you do a CBC -complete blood count- you will see the Hb concentration,

hematocrit, WBCs and RBCs.

Impaired DNA formation due to lack of:

B12 or folate in ultimately active form

use of antimetabolite drugs

this type of anemia called macrocytic anemia, when there is a problem in

making the DNA for the red blood cells while its maturating in the bone

marrow. There is a problem in the DNA replication because there is a shortage

of some substrates that are needed for DNA replication, so the maturating of

red blood cells will not be completed and they will escape the bone marrow

immaturely and go to the peripheral blood and they will be nucleated and

unfunctional cells so they cannot carry Hb.

Macrocytosis also caused by

Liver disease with inadequate cholesterol esterification

Alcohol abuse independent of folate (MCV 100-105)

Myelodysplasia

Post-splenectomy


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HIV drugs

Dilantin

Usually the Hb range is 13.5 – 17.5 for men and 12 – 15.5 for women. If it less

than these values, there is a shortage of red cells production and it’s called

anemia.

Vitamin B12: Cobalamin

• Meat and dairy products only

• Minimum daily requirement 6-9 mcg/d

• Total body store 2-5 mg (half in liver) • Helps to synthesize thymine, thus deficiency leads to problems with

DNA replication

Vitamin B12 structure:

You are not supposed to remember the structure** -The structure of B12 is based on a corrin ring, which is similar to the porphyrin ring found in heme, chlorophyll, and cytochrome. The central metal ion is cobalt. You can see these side chains like methyl and some nucleotides.


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-Cobalamin is a general term that is referred to a number of compounds, that have cobalt ion in the middle. -And it could be attached to adenosyl, cyano or methyl group. They will be called then adenosylcobalamin, cyanocobalamin or methylcobalamin. B12: Cobalamin absorption.

• Initially bound to protein in diet, liberated by acid and pepsin, then binds to R factors in saliva and gastric acids

• Freed from R factors by pancreatic proteases then binds to Intrinsic Factor secreted by gastric parietal cells

• Absorbed together (Cbl + IF) in ileum • Released from IF in ileal cell then exocytosed bound to trans-Cbl II • Cbl bound to transcobalamin II binds to cell surface receptors and is

endocytosed In the bone marrow, the transcobalamin will leave the vitamin B12 and then it’s just vitamin B12 in order to start synthesis the blood component. If we have any problem with those proteins or factors (transporting or absorption) that will lead to malabsorption of vitamin B12 and this will cause macrocytic anemia.


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Function of vitamin B12

1) deoxyadenosylcobalamin form is a co-enzyme methylmalonyl CoA

mutase.

You know when fatty acid oxidized they will produce different numbers of

acetyl CoAs; ex: 10 carbon fatty acid chain will produce 5 acetyl CoA.

But if you have an odd number of carbon in fatty acid, ex; 15 carbon fatty acid

when oxidized, will produce 6 CoA and something called propionyl CoA. This

propionyl CoA will be carboxylated to D-Methylmalonyl CoA, and then by

isomerization a L-Methylmalonyl CoA and then by Methylmalonyl CoA mutase

it will produce succinyl CoA, and here; this enzyme needs B12 as a coenzyme.


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If you don’t have enough B12 this process will be stopped and you will have no

succinyl CoA so, less or no heme will be synthesized here and this will affect the

production of red blood cells.

2) Coenzyme in reaction involved in methionine metabolism.

H4folate is converted to N5-methyl-H4folate in a number of different reactions

as it accepts methyl groups. The methyl group can only be removed and the

H4folate regenerated by the above reaction.

(See folic acid)

The homocysteine is used for the synthesis of methionine so the enzyme

methionine synthase requires B12 as a coenzyme. Now this enzyme also

requires N5-methyl-H4folate to provide a methyl group and add it to

homocysteine to give methionine


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After the H4folate doe's it's work (like other enzymes) it must be converted

back to N5-methyl-H4folate

If the Methionine synthase was deficient so no more H4folate will be produced

and all the folate will be at the N5-methyl-H4folate form (in many cases inactive

form)

In order bone marrow to synthesis RBC's it need's H4folate, so if it was deficient

it will cause megaloblastic anemia

If there was a deficiency of methionine synthase or H4folate (because of the

B12 deficiency) there will be disturbances in the synthesis of RBC'S in bone

marrow

******functions of vitamin B12

Methylmalonyl-CoA comes from propionell-CoA


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Methylmalonyl-CoA mutase requires B12 (if deficient no more synthesis of

Succinyl-CoA)

Succinyl-CoA is important in heme synthesis

Homocystine requires B12 and folate to be converted to Methionine by

methionine synthase

• Causes of B12 Deficiency: Autoantibody to Intrinsic Factor .

– 2 types of anti-IF antibody • Blocks attachment of Cbl to IF • Blocks attachment of Cbl-IF complex to ileal

receptors • Chronic atrophic gastritis

– Autoantibody against parietal cells (H-K-ATPase) – Increased risk of gastric cancer (carcinoid and intestinal-

type)

There are studies showing a connection between helicobacter and B12

absorption problems and will lead to macrocytic anemia or pernicious anemia


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Folate

Our body can't synthesis it so we need to get it from the diet

• Animal products (liver), yeast and leafy vegetables

• Normal requirement 400mcg/day

• Pregnancy/Lactation: 500-800mcg/day

• Body stores: 5-10mg

Our cells can't attach para-aminobenzoic acid to pteridine nor glutamic acid to

para-aminobenzoic acid so we need to take it from the diet

Positions 7 and 8 carry hydrogens in dihydrofolate (DHF)

positions 5–8 carry hydrogens in tetrahydrofolate (THF)


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Functions of folate:

• The function of THF derivatives is to carry and transfer various forms of one carbon units during biosynthetic reactions. The one carbon units are either methyl, methylene, methenyl, formyl or formimino groups.

These one carbon transfer reactions are required in the biosynthesis of serine,

methionine, glycine, choline and the purine nucleotides and dTMP


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So if there was a deficiency in purines and pyrimidines (important in DNA

replication) because of folate deficiency it will affect the production of blood or

will cause immature RBC's to be produced (nonfunctional)and they will cause

macrocytic or megalocitic anemia

Folate Metabolism

• folic acid exists in a polyglutamate form. • Intestinal mucosal cells remove some of the glutamate residues

through the action of the lysosomal enzyme, conjugase. • The removal of glutamate residues makes folate less negatively

charged (from the polyglutamic acids) and therefore more capable of passing through the basal lamenal membrane of the epithelial cells of the intestine and into the bloodstream.

• Binds to folate receptor, becomes polyglutamated intracellularly

• Many drugs (trimethoprim, methotrexate, pyrimethamine) inhibit dihydrofolate reductase


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Causes of Folate Deficiency:

• Malnutrition: Destroyed by heat during cooking • Alcoholism (decreased in 2-4 days): impairs enterohepatic cycle and

inhibits absorption • Increased requirement in hemolytic anemia, pregnancy, skin disease • celiac sprue • Drugs

Trimethoprim, Methotrexate, Primethamine (inhib DHFR)

Lab testing for diagnosis

Intrisic factor antibody assay can be falsely positive if pt has recently received a B12 shot with B12 >800, thus important to add-on.

N5

-methyl-tetrahydrofolate in relation to vitamin B12

biochemistry

N5-Methyl-tetrahydrofolate + Homocysteine

↓

Tetrahydrofolate + Methionine


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This is the only reaction regenerating tetrahydrofolate from N5-methyl-tetrahydrofolate. Without it all the tetrahydrofolate will eventually end up trapped as N5-methyl-tetrahydrofolate.

Synthesis of Deoxythymidylate (dTMP),

N5,N10-methylene tetrahydrofolate transfers a methyl group to deoxyuridylate

(dUMP) to form dTMP: Essential for DNA synthesis

• N5,N10-methylene tetrahydrofolate is absolutely essential for

DNA synthesis in cells that are dividing rapidly such as red blood cell

producing bone marrow cells, hair follicles, intestinal mucosa cells and

cancer cells (rapidly dividing cells need to replicate their DNA often).

• Methotrexate (analogue of folic acid) binds to folate reductase 1000

times more tightly than folate.This inhibits the conversion of folate and

dihydrofolate into active tetrahydrofolate

• Methotrexate is used to treat leukemia. It works by inhibiting the

production of tetrahydrofolate which in turn limits the amount of

N5,N10-methylene tetrahydrofolate available for dTMP synthesis


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• Different forms of folate that will provide the 1 carbon for the biochemical

reactions

Folic acid is not the active form of the vitamin. It needs to be reduced to

tetrahydrofolate (H4folate).

Megaloblastic anaemia and folic acid deficiency

Folic acid deficiency reduces the capacity of the body to make

dTMP which affects the rapidly dividing bone marrow cells associated

with red blood cell production.

Pernicious anaemia due to primary deficiency of vitamin B12

giving

secondary deficiency of folic acid because all the folate ends up trapped

as N5

-methyl-tetrahydrofolate


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To diagnose the deficiency of B12 or folic acid you take a blood sample

and ask to lab to determine either the B12 or folic acid ,and there are normal

ranges for each of them and according to it you can treat or manage the

deficiency.

Pain is temporary victory is forever

Aatrox


2016/2022

Nutritional Anemia HLS/ Biochemistry · Nutritional Anemia ... H 4 folate is converted to N...

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