Anemias Caused by Defects of DNA Metabolism Flashcards
= causes systemic effects by impairing production of all rapidly dividing cells of the body
Impaired DNA
rapidly dividing cells of the body
• Cells of skin
• Epithelium of Gl tract
• Hematopoietic tissue
• Impaired DNA
• Hematologic effect =________
• Hallmark of the disease affecting DNA metabolism
MEGALOBLASTIC ANEMIA
Megaloblastic anemia
ROOT CAUSE:
impaired DNA synthesis
Effects of megaloblastic anemia
in bone marrow and cell division
• Very large cells of the bone marrow
• Reduction in the number of cell divisions
MA
T or F
One example of macrocytic anemia
True
VITAMIN B12 (aka)
COBALAMIN
VITAMIN B12 (COBALAMIN)
• Essential nutrient consisting of a_____
• Containing cobalt that is attached to___
tetrapyrrole (corrin) ring
5,6-dimethylbenzimidazolyl ribonucleotide
Vit B12 (Cobalamin)
• VARIOUS ANALOGS: 5
Hydroxycobalamin
Cyanocobalamin
coenzyme form
methylcobalamin
5’-deoxyadenosylcobalamin
Physiologic Roles of Vitamin B12
2 biochemical reaction:
- Isomerization of methylmalonyl coenzyme A (CoA) to succinyl CoA
- Transfer of a methyl group from 5-methyltetrahydrofolate (5-methyl THF) to Homocysteine = generates methionine
absense of Vitamim B12= impaired activity of methylmalonyl CoA mutase leads to a high level of serum_____
methylmalonic acid (MMA).
• General term used for any form of the vitamin folic acid.
FOLATE
• General term used for any form of the vitamin folic acid.
FOLATE
FOLATE
• Consist of a_____ ring attached to ________ with one or more glutamate residues.
pteridine ring
para-aminobenzoate
- synthetic form of folate in supplements and fortified food
FOLIC ACID
• Folate circulates in the blood is predominantly as ______
5-Methyltetrahydrofolate (5-MTHF)
• 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.
Folate
• Deficiency of vitamin = leads to impaired cell replication and other metabolic alterations
Folate
DEFICIENT VITAMIN B12 & FOLATE =___________ is impaired
THYMIDINE nucleotide production for DNA synthesis is IMPAIRED
Explain what happens when ther eis no thymidine nucleotide production
THYMIDINE(deminished) = URIDINE incorporated to DNA =>
BREAKS TO FRAGMENTATION OF DNA =>
DNA unfunctional =>
DNA replication is INCOMPLETE
=>
CELL DIVISION IS HALTED =>
LYSIS/ APOPTOSIS
T or F
• FOLATE DEFICIENCY- indirect effect
• VITAMIN B12 DEFICIENCY- direct effect
FALSE
• FOLATE DEFICIENCY- direct effect
• VITAMIN B12 DEFICIENCY- indirect effect
FOLATE DEFICIENCY- direct effect
Preventing the methylation of dUMP - deoxyuridine monophosphate (dUMP)
• VITAMIN B12 DEFICIENCY- indirect effect
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.
T or F and WHY?
• RNA - is not affected by vitamin B12 or Folate deficiency
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.
Other causes of Megaloblastosis
- Dysplastic erythroid precursors in myelodyplastic syndrome (MDS)
- Congenital dyserythropoietic anemia (CDA) types I and III
- Acute erythroid leukemia (FAB M6)
- Reverse Transcriptase Inhibitors (treatment for HIV infection)
Systemic Manifestation of Folate and Vitamin B12 deficiency
General Symptoms:
fatigue, weakness, and shortness of breath
Systemic Manifestation of Folate and Vitamin B12 deficiency
Vitamin B12:
• Neurologic symptoms
• Neurophyschiatric symptoms
Systemic Manifestation of Folate and Vitamin B12 deficiency
Folate:
• Cardiovascular Disease
• Can cause neural tube defect (spina bifida)
VITAMIN DEFICIENCIES
FOLATE DEFICIENCY
INADEQUATE INTAKE => DUE TO POOR DIET
• FOLATE:
• Synthesized by microorganisms and higher plants.
• Ubiquitous in foods
• Good source of folate:
• Leafy vegetables
• Dried beans
• Liver
• Beef
• Fortified breakfast cereals
• Oranges
VITAMIN DEFICIENCIES
FOLATE DEFICIENCY
> INCREASE NEED
- DURING PREGNANCY
- LACTATION
VITAMIN DEFICIENCIES
FOLATE DEFICIENCY
> IMPAIRED ABSORPTION:
• Folate must be hydrolyzed in the____ before absorption to_____
___% = available for absorption
gut
small intestine
50%
Rare autosomal recessive deficiency of a folate transporter protein (PCFT)
• Severely decreases intestinal absorption of folate.
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.
Intestinal Disease that causes folate deficiency
SPRUE & CELIAC DISEAE
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.
Tropical Sprue
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.
Celiac Disease (Nontropical Sprue)
VITAMIN DEFICIENCIES
FOLATE DEFICIENCY
> IMPAIRED ABSORPTION:
- Rare autosomal recessive deficiency
- Intestinal Disease (SPRUE & CELIAC DISEAE)
- Surgical resection
- Inflammatory bowel disease
VITAMIN DEFICIENCIES
FOLATE DEFICIENCY
> IMPAIRED USE OF FOLATE:
• Numerous drugs decrease absorption of folic acid or impair folate metabolism
• Antineoplasic, Antibaterial and Antiseizure agents, Anticancer drug
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
kidney
DIALYSATE; folic acid
• Rare
• Possible: Strict Vegetarian (Vegans)
INADEQUATE INTAKE
Strict Vegetarian (Vegans) deficient in
Vit b12
Best Source of b12
Animal product such as liver, dairy products, fish, shellfish and eggs
T or F
• B12 not destroyed by cooking
True
VITAMIN B12 DEFICIENCY
> INCREASE NEED
- DURING PREGNANCY:
- LACTATION
- GROWTH
VITAMIN B12 DEFICIENCY
- IMPAIRED ABSORPTION
• It is released from food proteins primarily in the acid environment of the…
stomach (PEPSIN)
B12
• Bound by a salivary protein,____ (AKA:______)
haptocorrin
R Protein or Transcobalamin I
B12
• PLASMA =___to___ bound to______
70% bound to________
10% to 30%
trasncobalamin
transcobalamin I and Ill (Haptocorrin)
= Holotrasncobalamin (holoTC)
• Vitamib B12 + Transcobalamin complex
• Vitamib B12 + Transcobalamin complex =
Holotrasncobalamin (holoTC)
• 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
Holotrasncobalamin (holoTC)
2 organs??? : Reserved absorbed vitamin B12
- KIDNEY AND HEPATOCYTES
VITAMIN B12 DEFICIENCY
> IMPAIRED ABSORPTION
- Failure to separate vitamin B12 from food protein in the stomach
- Failure to separate vitamin B12 from haptocorrin in the intestine
VITAMIN B12 DEFICIENCY
> IMPAIRED ABSORPTION
- Failure to separate vitamin B12 from food protein in the stomach
- Failure to separate vitamin B12 from haptocorrin in the intestine
- Lack of Intrinsic factor (Pernicious Anemia),
- Malabsorption
- Competition for available vitamin B12
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
hypochlorhydria
Failure to separate vitamin B12 from haptocorrin in the intestine
• Chronic Pancreatic Disease Lack of_____ or _____
gastric acidity or lack or trypsin
IMPAIRED ABSORPTION
- Absorption of Vitamin B12 can be impaired by
- Lack of Intrinsic factor (_____)
Pernicious Anemia
IMPAIRED ABSORPTION
- Absorption of Vitamin B12 can be impaired by
- Malabsorption
• 3.
Celiac disease, tropical sprue and inflammatory bowel disease
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
Diphyllobothrium latum
Blind Loops
SCREENING TEST (3)
• COMPLETE BLOOD COUNT &
RETICULOCYTE COUNT
• WHITE BLOOD CELL MANUAL
DIFFERENTIATION COUNT
• BILIRUBIN AND LACTATE
DEHYDROGENASE LEVELS
• SPECIFIC DIAGNOSTIC TEST
•
Bone marrow examination
