Other Alterations in Granulocytes and Monocytes Flashcards
Genetic mutation where phagocytes are unable to produce superoxide and reactive oxygen series
Chronic Granulomatous Disease (CGD)
Chronic Granulomatous Disease
- 2 most common modes of inheritance
- Sex-linked (X linked recessive; more common in males)
- Autosomal recessive
Chronic Granulomatous Disease
- Prognosis
Death usually around 5-7 years due to bacterial infection
Chronic Granulomatous Disease
- Manifestations
- Defective or absent respiratory burst
- Reduced membrane NADH or NADPH
- Absence of superoxide anion and H2O2
Chronic Granulomatous Disease
- Physical manifestations
- Chronic pyogenic infections of all systems
- Abscess formation
- Lymphadenopathy
- Hepatosplenomegaly
- Anemia of chronic inflammation
Chronic Granulomatous Disease
- PB findings
- Toxic granulation
- Hypogranulation
- Vacuolization
- Doehle bodies
- Immature granulocytes
Chronic Granulomatous Disease
- Testing
- Nitroblue tetrazolium reduction (NBT test)
In a NBT test, normally the dye is reduced by NADPH oxidase to form black formazan deposits. What happens in a cell w/ CGD?
There is no dye reduction in CGD, and no color change because NADPH oxidase is not functional
Results in the inability of neutrophils and monocytes to exit the blood vessel and enter the tissues
Leukocyte Adhesion Deficiency (LAD)
Results in repeated infections despite leukocytosis
Leukocyte adhesion deficiency
Leukocyte adhesion deficiency
- Inheritance mode
Rare autosomal recessive
Mutation resulting in reduced or defective beta2 integrin subunits (CD18) which are found on the leukocytes
Type 1 Leukocyte adhesion deficiency
Mutation resulting in faulty selectins (CD62E) which are found on the endothelial cells
Type 2 Leukocyte adhesion deficiency
Mutation resulting in a faulty binding mechanism between the b2 intern subunits and the selections on the endothelial cells
Type 3 Leukocyte adhesion deficiency
Leukocyte adhesion deficiency
- Hallmark of the disease
- 3 different mutations each resulting in a different defect in the leukocyte adhesion process
- Patient has marked leukocytosis
- Recurrent infections
Leukocyte adhesion deficiency
- “Cure”
BM or stem cell transplantation
Caused by inborn errors of metabolism in which specific enzyme deficiencies allow the accumulation of products of cellular metabolism w/in lysosomes
Lysosomal storage disorders (LSD)
What are the two broad categories of lysosomal storage disorders?
- Mucopolysaccharide storage disorders
- Lipid storage disease
Membrane bound structures present in cytoplasm of most cells. They contain hydrolytic enzymes that usually digest complex macromolecules that are normal products of cell metabolism.
Lysosome
What cells are rich in lysosomes?
Cells of monocyte/macrophage system
Pathogenesis of lysosomal storage disorders
- Enzyme deficiency leads to accumulation of cell metabolism and disrupts normal architecture
- Spleen and liver are often enlarged
- BM may be replace by macrophages
- Pancytopenia
- Vacuolated lymphocytes
- CNS may be involved
Lysosomal storage disorder
- Mode of inheritance
Autosomal recessive
Lysosomal storage disorder
- Broad diagnosis
- Hepatomegaly and/or splenomegaly
- Slow physical and/or mental development
- If CNS involved, seizures or blindness my occur
This may be seen in many of the lysosomal storage disorders, but most characteristic in Tay Sachs
Cherry-red spot on back of the eye
Lysosomal storage disorder
- Treatment
- Enzyme replacement therapy
- BM transplant
What are the 4 lysosomal storage disorders?
- Mucopolysaccharidoses (MPS) (aka Alder-Reilly anomaly)
- Gaucher disease
- Neimann-Pick disease
- Tay-Sachs disease
Deficiency in the beta-glucocerebrosidase leading to an increase in glucocerebroside
Gaucher disease
General pathogenesis of all 3 types of Gaucher disease
- Spleen and liver enlargement
- Anemia
- Thrombocytopenia
- Growth Retardation
- May have effects on skeletal system and nervous system
Most common form of Gaucher disease; reduced levels of glucocerebrosidase; involves liver, spleen, lymph nodes, BM; may have skeletal effects; slight decrease in life expectancy
Type 1 Gaucher disease
Most severe form of Gaucher disease; acute neuronopathic; undetectable levels of glucocerebrosidase; involves ALL tissues, including brain; mortality in early childhood
Type 2 Gaucher disease
Form of Gaucher disease w/ intermediate enzyme levels; subacute neuronopathic; gradual onset; life expentancy 20-40 years
Type 3 Gaucher disease
Large, lipid filled macrophages; oval eccentric nuclei; faint blue cytoplasm; chicken-scratch or crumpled tissue paper appearance
Gaucher cells
Where are Gaucher cells found?
Found in BM, spleen, liver, and LNs
Type 1 Gaucher disease
- Treatment
- Supportive care
- BM transplant
- Enzyme replacement
- Splenectomy
(treatment very successful)
Enzyme replacement in Gaucher Disease are very expensive. What are two of them and what are they made from?
Cerezyme and Vpriv
made from Chinese Hamster ovary cells
Type 2 Gaucher disease
- Treatment
- Failure to thrive
- Hepatomegaly
- Life expectancy: < 2 years
Type 3 Gaucher disease
- Treatment
- Less rapid progressive than type 2
- Life expectancy: 20-40 years
Deficiency of the enzyme sphingomyelinase leading to an incrase in spingomyelin
Type A and B Niemann-Pick disease
Eccentric nucleus w/ foamy cytoplasm, filled w/ droplets of lipids; pale blue and also may contain sea-blue histiocytes
Niemann-Pick cells
The body cannot properly breakdown or transport LDL and it accumulates in which type of Niemann-Pick disease?
Type C Niemann-Pick disease
Type A Niemann-Pick disease
- Amount of sphingomyelinase
< 5% of normal levels (usually undetectable)
Type A Niemann-Pick disease
- Treatment
- No effective treatment
- Death < age 2
Type B Niemann-Pick disease
- Amount of sphingomyelinase
- Survival
- 27x as much sphingomyelinase
- Survival into adulthood
Type C Niemann-Pick disease
- Increase in what?
- Survival
- Increase in LDL
- Survival into 20s and 30s
Niemann-Pick disease
- Treatment
No successful treatment
Deficiency of hexoaminidase A leads to an increase in ganglioside GM2 in neurons
Tay-Sachs disease
About 1 in 20 of these people carry the gene for the infantile and adult forms of Tay-Sachs
Ashkenzai Jews
Three types of Tay-Sachs disease
- Classic infantile
- Juvenile
- Adult
Symptoms develop at 6 months and progressively worsen. Death usually occurs before 4. No cure.
Classic infantile Tay-Sachs disease
Symptoms occur between 2 and 10 years old. Death occurs before the patient is 15
Juvenile Tay-Sachs disease
Symptoms between 30 and 40. Progressive neurological deterioration, survive to ages of 60-70
Adult Tay-Sachs disease
What disease?
- 1 in 280 are carriers in Ashkenazi population
- Deficiencies in both alpha and beta subunits of hexosaminidase
- Presents similarly to classical infantile Tay-Sachs; however, there may be some organomegaly
- No cure
Standoff disease
Tay-Sachs disease
- Treatment
- No cure
- Supportive care
- Little success w/ other modalities due to difficulty in delivering enzyme to nerve tissues
