Lecture 6: Sickle Cell Disease and HH

Question 1

Sickle Cell Anemia (3)

Answer 1

1. most frequent hemoglobinopathy
2. mutation in Hb gene
3. single amino acid change and hb polymerizes in low oxygen, deforms cells, stick in capillaries, are destroyed

Question 2

Hemoglobinopathy

Answer 2

1. Kind of genetic* defect that results in abnormal structure of one of the globin* chains of hb* molecule

Question 3

Genetics of Sickle Cell Disease

Answer 3

1. inherited in autosomal recessive pattern *
2. when offspring inherit both defective genes (homozygous recessive) the result is sickle cell disease
3. when offspring inherit one recessive allele and one normal (heterozygous) they are unaffected but are carrier
   - sickle cell trait

Question 4

Sickle Cell Trait

Answer 4

When a person carries the recessive gene for sickle cell anemia

• heterozygous expression
• *recessive trait (sickle cell) covered up by dominant (normal)

Question 5

Hemoglobin (3)

Answer 5

1. tetramer
2. each of the four globin chains binds a single heme molecule
   - 2 alpha (one from mom, one from dad)
   - 2 beta (one from mom, one from dad)
3. four binging sites for O2
4. function in O2 and CO2 transport

Question 6

Sickle Cell Hb mutation (HbS) (2)

Answer 6

1. point mutation resulting in glutamate to valine substitution at residue 6 or beta-globin chains
2. missense mutaiton

Question 7

HbS

Pathopysiology (4)

Answer 7

1. presence of valine at position 6
   - promotes aggregation of HbS into larger polymers
2. DeoxyHbS is more prone to aggregation than oxyHbS
   - low pH favors aggregation
3. Aggregation of HbS into large polymers alters the shape of RBCs
   - sickled appearance
4. Disease significantly changes the protein Hb A to HbS
   - DOES NOT ALTER HOW PROTEIN TRANSPORTS O2 IN BLOOD

Question 8

Ethnic Variation of Allelic Frequency

Answer 8

1. HbS is more common among persons whose ancestry is geographically connected to
   - sub-Saharan Africa
   - Cuba
   - South America
   - Central America
   - Saudi Arabia
   - India
   - Mediterranean Regions

Question 9

Heterozygote Advantage (3)

Answer 9

1. when a person inherits only one allele for HbS
   - they do not express the disease
2. Heterozygous expression HbS is correcte with lower rates of mortality among carriers* who are of Afrian and Mediterranean descent
   - HbS allele decreased the risk of infection by malarial parasites endemic in those areas
3. Theory: clearance of sickled cells by the spleen may explain the protection against P. falciparum.
   - parasites lower the pH which promotes sickling
   - clearance of infected cells disrupt the parasite’s life cycle

Question 10

Phenotypic Features of Sickle cell disease (9)

Answer 10

1. failure to thrive
2. anemia
3. multiple chronic infection
4. jaundice
5. steeling extremities
6. painful joints
7. priapism
8. loss vision
9. vas occlusive infarction to major organs

Question 11

Clinical Diagnosis and Testing (6)

Answer 11

1. family hx sickle cell disease of parents or proband to be known carriers
2. newborn screening in all 50 states
3. CBC
   - normocytic anemia with target cells
4. hypoxia=sickle cells reported
5. Hb solubility test
6. Hb electrophoresis

Question 12

Thalassemia

4 types

Answer 12

1. collection of inherited blood d/o characterized by low Hb production

a. alpha thalassemia
b. beta thalassemia
c. beta-zero
d. beta-plus

Question 13

Alpha-Thalassemia

Answer 13

one or more of the 4 genes for alpha-Hb are missing

Question 14

Beta-thalassemia

Answer 14

one or two genes genes for beta-Hb are missing

*more severe than alpha

Question 15

Beta-zero thalassemia

Answer 15

no beta chain is produced in Hb

Question 16

Beta-plus

Answer 16

Less beta chain produced

Question 17

Other sickle cell d/o

3 types

Answer 17

1. non-sickling beta Hb d/o such as thalassemia can interact with a sickle cell disease mutation to cause clinically significant disease
   - carrier for sickle cell procreates with thalassemia carrier?

a. sickle beta zero thalassemia
- present as sickle cell disease

b. sickle beta plus thalassemia
- sickle cell disease

c. sickle alpha thalassemia
- sickle cell trait

Question 18

Sickle beta zero thalassemia

Answer 18

clinically present as sickle cell disease

-more severe than sickle beta plus

Question 19

Sickle beta plus

Answer 19

clinically presents as sickle cell disease

Question 20

sickle alpha thalassemia

Answer 20

clinically present as sickle cell trait (NOT DISEASE)

Question 21

Hereditary Hemochromatosis (5)

Answer 21

1. Common d/o iron metabolism
2. too much Iron absorbed
   - toxic accumulation in parenychmal cells- particularly liver, heart, pancreas
3. 20-40 g iron may accumulate
4. excess iron in HH is only whithin body storage compartments
5. Autosomal recessive inheritance*

Question 22

Clinical Hallmark advanced HH (4)

Answer 22

1. cirrhosis
2. diabetes
3. skin pigmentation
4. cardiac failure

Question 23

Phenotypic Features of HH (7)

Answer 23

1. typically presents 40+ years old
2. affected tissues
   - livers
   - pancreas
   - skin
   - heart
   - other organs
3. hyper pigmented skin: bronzed diabetes
4. fatigue
5. joint aches
6. male sexual dysfunction
7. 10x more common in males than females

Question 24

Genetics HH (5)

Answer 24

1. single mutation in HFE gene C282Y
2. HFE protein involved in regulating the amount of dietary iron absorbed
3. mutation causes increased amount iron absorption in intestines
   - increased iron storage in body tissues
4. inherited autosomal recessive pattern
5. mutations exhibit penetrance, variable expressivity, sex-influenced phenotype

Question 25

Diagnosis HH (2)

Answer 25

1. clinical suspicion is based on - family hx - patient presentation at early or later stages of disease 2. elevated transferrin saturation, serum ferritin concentrations and serum liver enzymes

Question 26

Early signs/symptoms HH (3)

Answer 26

1. RUQ pain 2. fatigue 3. arthralgias

Question 27

Later signs/symptoms HH (8)

Answer 27

1. hepatomegaly 2. hepatic cirrhosis 3. hepatocellular carcinoma 4. diabetes mellitus 5. cardiomyopathy 6. hypogonadism 7. arthritis 8. hyper pigmented skin

Question 28

Transferrin

Answer 28

binds and transports iron in blood serum, and functions to deliver iron from absorption centers into the intestines to all tissues

Question 29

Ferritin

Answer 29

protein that stores iron inside cells

Question 30

Genetic Testing/counseling HH (3)

Answer 30

1. routine labs - serum iron levels - serum ferritin levels - total iron binding capacity (TIBC) - transferrin saturation levels 2. liver bx with hepatic iron index > 2 3. PCR for HFE gene