Anemias Caused by Defects of DNA Metabolism

Question 1

= causes systemic effects by impairing production of all rapidly dividing cells of the body

Answer 1

Impaired DNA

Question 2

rapidly dividing cells of the body

Answer 2

• Cells of skin

• Epithelium of Gl tract

• Hematopoietic tissue

Question 3

• Impaired DNA

• Hematologic effect =________

• Hallmark of the disease affecting DNA metabolism

Answer 3

MEGALOBLASTIC ANEMIA

Question 4

Megaloblastic anemia

ROOT CAUSE:

Answer 4

impaired DNA synthesis

Question 5

Effects of megaloblastic anemia

in bone marrow and cell division

Answer 5

• Very large cells of the bone marrow
• Reduction in the number of cell divisions

Question 6

MA

T or F

One example of macrocytic anemia

Answer 6

True

Question 7

VITAMIN B12 (aka)

Answer 7

COBALAMIN

Question 8

VITAMIN B12 (COBALAMIN)
• Essential nutrient consisting of a_____

• Containing cobalt that is attached to___

Answer 8

tetrapyrrole (corrin) ring

5,6-dimethylbenzimidazolyl ribonucleotide

Question 9

Vit B12 (Cobalamin)

• VARIOUS ANALOGS: 5

Answer 9

Hydroxycobalamin

Cyanocobalamin

coenzyme form

methylcobalamin

5’-deoxyadenosylcobalamin

Question 10

Physiologic Roles of Vitamin B12

2 biochemical reaction:

Answer 10

1. Isomerization of methylmalonyl coenzyme A (CoA) to succinyl CoA
2. Transfer of a methyl group from 5-methyltetrahydrofolate (5-methyl THF) to Homocysteine = generates methionine

Question 11

absense of Vitamim B12= impaired activity of methylmalonyl CoA mutase leads to a high level of serum_____

Answer 11

methylmalonic acid (MMA).

Question 12

• General term used for any form of the vitamin folic acid.

Answer 12

FOLATE

Question 13

• General term used for any form of the vitamin folic acid.

Answer 13

FOLATE

Question 14

FOLATE

• Consist of a_____ ring attached to ________ with one or more glutamate residues.

Answer 14

pteridine ring
para-aminobenzoate

Question 15

• synthetic form of folate in supplements and fortified food

Answer 15

FOLIC ACID

Question 16

• Folate circulates in the blood is predominantly as ______

Answer 16

5-Methyltetrahydrofolate (5-MTHF)

Question 17

• FUNCTION:
1. Transfer carbon units in the form of methyl groups from donors to receptors.
2. Plays an important role in the metabolism of amino acids and nucleotides.

Answer 17

Folate

Question 18

• Deficiency of vitamin = leads to impaired cell replication and other metabolic alterations

Answer 18

Folate

Question 19

DEFICIENT VITAMIN B12 & FOLATE =___________ is impaired

Answer 19

THYMIDINE nucleotide production for DNA synthesis is IMPAIRED

Question 20

Explain what happens when ther eis no thymidine nucleotide production

Answer 20

THYMIDINE(deminished) = URIDINE incorporated to DNA =>

BREAKS TO FRAGMENTATION OF DNA =>

DNA unfunctional =>

DNA replication is INCOMPLETE
=>

CELL DIVISION IS HALTED =>

LYSIS/ APOPTOSIS

Question 21

T or F

• FOLATE DEFICIENCY- indirect effect

• VITAMIN B12 DEFICIENCY- direct effect

Answer 21

FALSE

• FOLATE DEFICIENCY- direct effect
• VITAMIN B12 DEFICIENCY- indirect effect

Question 22

FOLATE DEFICIENCY- direct effect

Answer 22

Preventing the methylation of dUMP - deoxyuridine monophosphate (dUMP)

Question 23

• VITAMIN B12 DEFICIENCY- indirect effect

Answer 23

The conversion of 5-methyl THF to THF is disrupted, causing 5-methyl THF to accumulate.

This accumulation is termed the “folate trap,” as folate is metabolically trapped in its 5-methyl THF form and cannot be converted to other forms of THF needed for DNA synthesis and cell division.

As a result:
Homocysteine levels increase because it cannot be converted to methionine without the involvement of vitamin B12.

Question 24

T or F and WHY?

• RNA - is not affected by vitamin B12 or Folate deficiency

Answer 24

True!

RNA synthesis is not affected by vitamin B12 or folate deficiency because RNA synthesis relies on uridine (U) rather than thymidine (T), which is specific to DNA.

Question 25

Other causes of Megaloblastosis

Answer 25

1. Dysplastic erythroid precursors in myelodyplastic syndrome (MDS) 2. Congenital dyserythropoietic anemia (CDA) types I and III 3. Acute erythroid leukemia (FAB M6) 4. Reverse Transcriptase Inhibitors (treatment for HIV infection)

Question 26

Systemic Manifestation of Folate and Vitamin B12 deficiency General Symptoms:

Answer 26

fatigue, weakness, and shortness of breath

Question 27

Systemic Manifestation of Folate and Vitamin B12 deficiency Vitamin B12:

Answer 27

• Neurologic symptoms • Neurophyschiatric symptoms

Question 28

Systemic Manifestation of Folate and Vitamin B12 deficiency Folate:

Answer 28

• Cardiovascular Disease • Can cause neural tube defect (spina bifida)

Question 29

VITAMIN DEFICIENCIES FOLATE DEFICIENCY

Answer 29

INADEQUATE INTAKE => DUE TO POOR DIET

Question 30

• FOLATE: • Synthesized by microorganisms and higher plants. • Ubiquitous in foods • Good source of folate:

Answer 30

• Leafy vegetables • Dried beans • Liver • Beef • Fortified breakfast cereals • Oranges

Question 31

VITAMIN DEFICIENCIES FOLATE DEFICIENCY > INCREASE NEED

Answer 31

1. DURING PREGNANCY 2. LACTATION

Question 32

VITAMIN DEFICIENCIES FOLATE DEFICIENCY > IMPAIRED ABSORPTION: • Folate must be hydrolyzed in the____ before absorption to_____ ___% = available for absorption

Answer 32

gut small intestine 50%

Question 33

Rare autosomal recessive deficiency of a ***folate transporter protein (PCFT)*** • Severely decreases intestinal absorption of folate.

Answer 33

proton-coupled folate transporter (PCFT) PCFT is crucial for absorbing folate from the intestine into the bloodstream. When this transporter is deficient, the body cannot absorb enough folate, leading to low folate levels even if dietary intake is sufficient.

Question 34

Intestinal Disease that causes folate deficiency

Answer 34

SPRUE & CELIAC DISEAE

Question 35

due to an overgrowth of bacteria or other pathogens in the intestines. These pathogens damage the intestinal lining, reducing the body’s ability to absorb nutrients, including folate and vitamin B12.

Answer 35

Tropical Sprue

Question 36

is an ***autoimmune reaction to gluten*** (a protein found in wheat, barley, and rye). INTOLERANCE TO GLUTEN In people with this disease, consuming gluten triggers an immune response that damages the lining of the small intestine, impairing nutrient absorption. This damage also leads to folate deficiency, as the body cannot absorb folate efficiently.

Answer 36

Celiac Disease (Nontropical Sprue)

Question 37

VITAMIN DEFICIENCIES FOLATE DEFICIENCY > IMPAIRED ABSORPTION:

Answer 37

1. Rare autosomal recessive deficiency 2. Intestinal Disease (SPRUE & CELIAC DISEAE) 3. Surgical resection 4. Inflammatory bowel disease

Question 38

VITAMIN DEFICIENCIES FOLATE DEFICIENCY > IMPAIRED USE OF FOLATE:

Answer 38

• Numerous drugs decrease absorption of folic acid or impair folate metabolism • Antineoplasic, Antibaterial and Antiseizure agents, Anticancer drug

Question 39

VITAMIN DEFICIENCIES FOLATE DEFICIENCY ***EXCESSIVE LOSS OF FOLATE:*** • Physiologic loss of folate occurs through_____ • Small and cannot cause deficiency ***RENAL DIALYSIS*** • LOSE FOLATE IN THE___ • Supplemental_____ is routinely provided

Answer 39

kidney DIALYSATE; folic acid

Question 40

VITAMIN B12 DEFICIENCY - • Rare • Possible: Strict Vegetarian (Vegans)

Answer 40

INADEQUATE INTAKE

Question 41

Strict Vegetarian (Vegans) deficient in

Answer 41

Vit b12

Question 42

Best Source of b12

Answer 42

Animal product such as liver, dairy products, fish, shellfish and eggs

Question 43

T or F • B12 not destroyed by cooking

Answer 43

True

Question 44

VITAMIN B12 DEFICIENCY > INCREASE NEED

Answer 44

1. DURING PREGNANCY: 2. LACTATION 3. GROWTH

Question 45

VITAMIN B12 DEFICIENCY - IMPAIRED ABSORPTION • It is released from food proteins primarily in the acid environment of the…

Answer 45

stomach (PEPSIN)

Question 46

B12 • Bound by a salivary protein,____ (AKA:______)

Answer 46

haptocorrin R Protein or Transcobalamin I

Question 47

B12 • PLASMA =___to___ bound to______ 70% bound to________

Answer 47

10% to 30% trasncobalamin transcobalamin I and Ill (Haptocorrin)

Question 48

= Holotrasncobalamin (holoTC)

Answer 48

• Vitamib B12 + Transcobalamin complex

Question 49

• Vitamib B12 + Transcobalamin complex =

Answer 49

Holotrasncobalamin (holoTC)

Question 50

• Metabolically active form of Vitamin B12 • Binds to specific receptor in the surfaces of many different cells by endocytosis and subsequent release of of Vitamin B12 from the carrier

Answer 50

Holotrasncobalamin (holoTC)

Question 51

2 organs??? : Reserved absorbed vitamin B12

Answer 51

- KIDNEY AND HEPATOCYTES

Question 52

VITAMIN B12 DEFICIENCY > IMPAIRED ABSORPTION

Answer 52

1. Failure to separate vitamin B12 from food protein in the stomach 2. Failure to separate vitamin B12 from haptocorrin in the intestine

Question 53

VITAMIN B12 DEFICIENCY > IMPAIRED ABSORPTION

Answer 53

1. Failure to separate vitamin B12 from food protein in the stomach 2. Failure to separate vitamin B12 from haptocorrin in the intestine 3. Lack of Intrinsic factor (Pernicious Anemia), 4. Malabsorption 5. Competition for available vitamin B12

Question 54

***Failure to separate vitamin B12 from food protein in the stomach*** • Food cobalamin malabsorption =______ • Reduced gastric acidity (increasing age) • Atrophy of stomach lining • Gastric bypass surgery • Long-term use of histamine type 2 receptor blockers • Proton pumps inhibitors

Answer 54

hypochlorhydria

Question 55

***Failure to separate vitamin B12 from haptocorrin in the intestine*** • Chronic Pancreatic Disease Lack of_____ or _____

Answer 55

gastric acidity or lack or trypsin

Question 56

IMPAIRED ABSORPTION - Absorption of Vitamin B12 can be impaired by 3. Lack of Intrinsic factor (_____)

Answer 56

Pernicious Anemia

Question 57

IMPAIRED ABSORPTION - Absorption of Vitamin B12 can be impaired by 4. Malabsorption • 3.

Answer 57

Celiac disease, tropical sprue and inflammatory bowel disease

Question 58

IMPAIRED ABSORPTION - Absorption of Vitamin B12 can be impaired by Competition for available vitamin B12 •_______ • Able to split vitamin B12 from intrinsic factor •______ • Intestines that are stenotic as a result of surgery or inflammation • Over grown bacteria competes with the B12

Answer 58

Diphyllobothrium latum Blind Loops

Question 59

SCREENING TEST (3)

Answer 59

• COMPLETE BLOOD COUNT & RETICULOCYTE COUNT • WHITE BLOOD CELL MANUAL DIFFERENTIATION COUNT • BILIRUBIN AND LACTATE DEHYDROGENASE LEVELS

Question 60

• SPECIFIC DIAGNOSTIC TEST •

Answer 60

Bone marrow examination