wk 11, lec 3 Flashcards
1
Q
what is the different between iron deficiency anemia and anemias of inflamamtion
A
o Similar CBC
o Different iron handling
2
Q
causes of anemias of inflammation
A
infection (TB, HIV), autoimmune (RA, lupus), IBD, malignancies
3
Q
what suppress erythropoeisi in anemias of inflammation
A
- Cytokines suppress erythropoiesis
o Decrease erythropoeitein production
o Iron sequestration
o Effect early myeloid progenitors
4
Q
rheumatoid arthritis and neoplasm and bacterial infection do what cytokines in anemias of inflmmation
A
- RA: IL-1 and IFN-y
- Neoplasm and infection: TNF and IFN-B
5
Q
what is suppressed in anemias of inflammation
A
- Suppress EPO release: IL-1 and TNF-alpha
- Suppress RBC precursors; IFNs
o IFN release is also stimulated by TNFa and IL-1
6
Q
how do anemias of inflammation sequester iron away from bone marroe
A
Il-1 and TNFa stimulate IL-6 increase hepcidin production decrease iron availability for hematopoiesis
7
Q
what is the function of hepcidin
A
- Decrease absorption in intestines
- Decrease transfer of iron from transferrin to hepatocytes
- Decrease liberation of iron from reticuloendothelial system (i.e. iron that’s rescued from degraded RBCs in the spleen)
8
Q
symptoms of anemia’s of inflammation
A
- Symptoms of underlying dieases i.e. fatigue
9
Q
labs of anemia’s of inflammation
A
- Labs vary depending on causes
o Increased iron sequestration smaller RBCs
o Decreased marrow production but close to normal iron availability- RBCs normocytic or mildly microcytic
10
Q
anemia of chronic kidney disease is what type of anemai
A
- Hypoproliferative anemia (inadequate production of RBCs)
11
Q
Anemia of chronic kidney disease (CKD) does what to EPO and RBCs? what do the RBCs look like?
A
- Decreased EPO and reduced RBC survival
- RBCs are normocytic and normochromic
o Decreased reticulocyte counts
12
Q
how to treat Anemia of chronic kidney disease (CKD)
A
EPO (bc its decreased)
13
Q
symptoms of Anemia of chronic kidney disease (CKD)
A
- Symptoms: fatigue, exercise intolerance
14
Q
which markers are lower in early iron store depletion
A
marrow iron stores, serum ferritin, TIBC
15
Q
iron deficient erythropoises has what abnormal
A
abnormal serum iron (SI) and % transferrin saturation
16
Q
what are some types of anemias of abnormal RBC (Hb) synthesis
A
- Sickle cell anemia
- Thalassemia (alpha and beta)
- Genetic metabolic or cytoskeletal disorders
o G-6-PD deficiency
o Hereditary spherocytosis
17
Q
what is the most common anemia from cytoskeletal elements defects
A
Hereditary spherocytosis
18
Q
who is Hereditary spherocytosis most common in
A
europeans
19
Q
type of mutation in Hereditary spherocytosis
A
nnkyrin + anion exchanger 1 (AE1) (band 3)
20
Q
mutation in Hereditary spherocytosis
A
o Autosomal dominant mutation in ankyrin (anchors spectrin and actin to cell membrane), anion exchanger 1 (AE1) (band 3) (fluid exchange across RBC and anchors cytoskeleton)
21
Q
mild vs severe hereditary spherocytosis
A
- Severe: early in life, transfusions for anemia; splenomegaly, jaundice, enlarged spleen
- Mild: later in life; gallstones, splenomegaly, jaundice
22
Q
RBC size, effect on RDW and MCHC in hereditary spherocytosis
A
- Normocytic anemia with increased RDW and MCHC
o Spherocytes cant deform therefore die early
23
Q
Hereditary Spherocytosis (HS)
A
is an inherited disorder of the red blood cells (RBCs) that leads to the production of abnormally shaped RBCs, known as spherocytes. These spherical RBCs are more prone to hemolysis (destruction) and are less flexible than normal, biconcave-shaped RBCs.
24
Q
what is G-6-PD a source of
A
- Source of NADPH and to reduce glutathione
(pentose phosphate pathway; protect RBC from oxidative stress)
25
what does G-6-PD deficiency protect against?
malaria
26
when do you get symptoms in G-6-PD deficiency
- Symptoms when RBCs get oxidative stress – i.e. medications, intravascular inflammation, fava beans
27
what happened in G-6-PD deficiency
- Reduced enzyme activity, reduced NADPH production, no glutathione for ROS
28
who does G-6-PD deficiency effect more
men because x linked
29
clinical features of G-6-PD deficiency attacks
- Attacks:
o Malaise, weak, ab/back pain, jaundice, hyperbilirubinuria
o Anemia: reduced Hb, anisocytosis, spherocytes, bite cells
o Elevate lactate dehydrogenase and reduce haptoglobin (iron scavenger to sequester free Hb)
30
G-6-PD deficiency is what type of anemia
- Hemolytic anemia precipitated by oxidative insults to RBCs
(premature destruction of RBCs)
31
what does the Embden-meyerhof pathway (glycolysis) generate for RBCs?
ATP and NADH
- Embden-meyerhof pathway (glycolysis) generates ATP
- Generate NADH for hemoglobin to stay in reduced state
32
what does the Hexose monophosphate shunt make for RBC metabolism
NADPH
- Hexose monophosphate shunt makes NADPH to reduce glutathoione (protect against oxidant stress)
33
what enzyme effects oxygens affinity for hemoglobin
- 2, 3 bisphosphoglycerate levels for oxygen affinity of hemoglobin
34
what is the most deficient enzyme in - Embden-meyerhof pathway (glycolysis)
: glucose 6 phosphate dehydrogenase (G6PD)
35
what are thalamssemias
- Mutation that reduce synthesis of adult hemoglobin – HbA
36
which hemoglobin chain is typically impacted in thalassemias
o Absent or reduced beta-globin chains (chromosome 11)
Non sense mutations or effect splicing
o Less commonly absent alpha-globin (chromosome 16)
37
who do thalassemias impact the most
o Mediterranean, middle east, Africa, India
38
what is beta thalassemia
- RBCs with reduced hemoglobin, deficient beta chain
39
how does beta thalassemias effect erythrocytes and RBC production
- Abnormal erythrocyte shape (get phagocytosed)
o Poor RBC production (ineffective erythropoiesis) and increased RBC destruction (hemolysis)
40
what other systems are effected by beta thalassemia
liver, spleen, heart, bony marrow
- Bony abnormalities to keep up with RBC production
- extramedullary hematopoiesis in spleen and liver (enlarged)
- blood transfusion and increased iron absorption cause iron overload (damage heart and liver)
41
how can you get secondary hemochromatosis in beta thalasemia
transfusion and increased iron absorption cause iron overload (damage heart and liver)
42
clinic features in beta thalassemias major vs minor
- Clinical features of beta thalassemia major
o Present when adult hemoglobin should replace fetal hemoglobin
o Anemia, bony deformities, hepatosplenomegaly, jaundice, stunted growth
o Iron overload in heart and liver
o Without transfusion- poor survival rate
- Clinical features of beta thalamssemia minor
o Minor anemia, asymptomatic, good prognosis
43
minor vs intermedia vs major beta thalassemias
minor: microcytic anemia, low MCV
intermedia: occasional transfusions
major: splenomegaly, anemia, bone deformities, need blood transfusions, splenectomy
44
alpha thalasemia is
- Reduced or absent alpha chains (4 in normal)
45
alpha thalamssemia is similar to beta...
- Identical clinical picture to beta-thalassemia minor if 2 alpha chains missing
46
HbH (hemoglobin h) disease of alpha thalassemias
3 alpha chains missing; resembles beta-thalassemia intermedia
47
hydrops fetalis of alpha thalassemias
4 missing alpha chains
o Hb are beta chain tetramers, poor oxygen, anemia, need transfusions, fatal
48
types of alpha thalassemias
can have 1-4 alleles affected
49
what is sickle cell disease a type of
- Hemoglobinopathy
50
who does sickle cell disease effect the most
-10% heterozygous in Africans
51
what is the change in the beta chain in hemoglobin in sickle cell disease ?
- Replaced glutamate with valine at codon 6 in beta-globin gene
52
why are sickle cells shaped differetnly
- Replaced glutamate with valine at codon 6 in beta-globin gene
o Sickle shape from polymerization and crystal formation during deoxygenation
53
heterozygous for sickle cell disease benefits
resistant to malaria
54
what does sickle cell anemia protect against
o Malarial parasites decrease O2 in RBCs sickling remove cell and parasite in spleen
o Reduced PfEMP-1 that increases sticking and infarct
55
what does sickling cause
- Sickling causes micro-infarcts
o In hypoxia, inflammation and low pH
Prolonged transit time occlusion in blood vessel
56
type of anemia in sickle cell disease
hemolytic anemia
57
clinical features in sickle cell disease
o Hemolytic anemia
o Worse in crises: hypoxia (in bones, lungs, spleen, brain, liver, penis), hypovolemia and shock
o Hypoxia impairs growth and kidney failure
o Micro-infarcts impair cognition, heart failure, spleen
58
what makes sickle cell worse
hypoxia
59
prognosis of sickle cell anemia
o 90% survive beyond age 20, 50% beyond age 50
o Hydroxyurea increases fetal hemoglobin and reduces sickling
60
type of malaria that most common and causes most death
- P. falciparum most common and causes most deaths
o Invades rapidly, not dormant, no relapses
61
how do you get malaria
- Female anopheles mosquitoes
- P. falciparum
62
life cycle in malaria
1. Mosquito blood meal; inject human with plasmodial sporozoites via its saliva glands
2. The parasite is carries to the liver and invades hepatic parenchymal cells and then reproduces asexually
a. P. vivax and p. ovale can be dormant “hypnozoites” for a while
3. Infected liver cells burst and discharge motile merozoites into blood stream
4. Merozoites invade RBCs and become trophozoites
a. Consumes RBC hemoglobin and occupies most of cell
b. When RBC ruptures can infect new RBCs
5. When become dense in blood = symptoms
- Can transmit to another person when become sexual gametocytes and reproduce during another blood meal
- Infection of human host is asexual though
63
what does the malaria do to RBCs
costume RBC hemoglobin and occupy cell space
64
what does malaria induce the expression of in RBCs? how does this effect blood flow?
- Induce RBCs to express parasitic protein PfEMP1
o Attaches RBCs to receptor of capillaries and veins blocks them and interferes with blood flow (esp in brain)
65
mild vs severe malaria
- Mild: fever, headache, ab pain, muscle aches
- Severe: >2% erythrocyte infestation anemia, convulsion, hypoglycemia, jaundice, renal failure, pulmonary edema
o Cerebral malaria: coma, obtundation, delirium
o Retinal hemorrhages, papilledema, neck stiffness, death
o Acidosis
66
types of neoplasms of blood cells
- Lymphoid neoplasms
o Hodgkins’s lymphoma
o Non-Hodgkin’s lymphoma (NHL)
o Lymphocytic leukemia
- Myeloid neoplasms
o Acute myelogenous leukemias
o Chronic myeloproliferative disorders
67
what is leukemia
- Tumors in bone marrow bone marrow suppression, immature cells in peripheral blood smear
68
what is lymphoma
- In lymphatic tissue (sometimes solid organs)
- Can invade bone marrow
can overlap in clinical presentation with leukemia ; type of cell in tumour important, not location
69
what is important differentiation between leukemia and lymphoma
type of cell in tumour important, not location
* Lymphoma: Involves lymphocytes (a type of white blood cell).
* Leukemia: Involves abnormal white blood cells (can be myeloid or lymphoid).
70
what is the locations of leukemia and lymphoma
leukemia in bone marrow
lymphoma in lymph then can go to bone marrow or solid organs
* Lymphoma: Starts in the lymphatic system and forms solid tumors in lymph nodes or organs.
* Leukemia: Starts in the bone marrow and primarily affects circulating blood cells, causing abnormal white blood cell proliferation.
71
acute lymphoblastic leukemia/lymphoma
- Lymphoblasts with condensed nuclear chromatin, small nucleoili, scant agranula cytoplasm
72
acute myeloid leukemia without maturation
- Myeloblasts have delicate nuclear chromatin, prominent nucleoili and fine axurophilic granules in cytoplasm
73
Acute lymphoblastic leukemia/lymphoma vs Acute myeloid leukemia without maturation
ALL is a leukemia/lymphoma of lymphoid cells (B or T cells), while AML-WM is a leukemia of myeloid cells that is characterized by a lack of maturation.
74
what type of cells do lymphoid neoplasms happen in?
- B cell precursors
o Malignancy via antibody class switching or recombination events to increase antibody affinity
75
location in body of Hodgkin vs non Hodgkin lymphoma
- Non-hodgkin lymphoma more widespread
- Hodkin lymphoma more localized along lymph nodes
76
lymphs in lymphomas
100% hodgkins and 2/3 NHL have enlarged lymphs (other 1/3 NHL is solid organ)
o Later can involve bone marrow and cause pancytopenia
77
findings on blood smear in leukemia and where they can invade
pancytopenia (decrease blood cell size) and malignant cell in peripheral blood smear
o Can later invade lymph (enlarge), skin, CNS
78
what are the main white cell malignancies
B cell neoplasms bc of antibody rearrangement
79
causes of white cell malignancies
- Chronic inflammation (lymphocytic mitosis and lymphoma)
o Celiac, chronic gastritis
- Viral infection
o i.e. EBV associated with Hodgkin and NHL
o i.e. HIV – NHL
80
B cell neoplasms
which 2 enzymes
o enzymes (AID = activation-induced cytosine deaminase and recombinases/RAGs) create breaks in antibody genes for:
Class switching (mostly AID)
Hypermutation to aid antibody affinity (mostly recombinases but also AID)
81
chromosomal translocation in B cell neoplasms
o Chromosomal translocations decrease apoptosis, increase growth
82
white cell malignancies - how is cell division increased?
- Increase cell division (MYC, RTK, Ras, MAPK, PI-3K)
- Disrupt apoptotic pathways
- Halt normal differentiation
83
acute lymphoblastic leukemia (ALL) is from what type of cells
- From precursor B and T cells (85% B cell)
84
acute lymphoblastic leukemia (ALL) is similar to
- Similar presentation to acute myelogenous leukemia but different response to treatment
85
acute lymphoblastic leukemia (ALL) involves
solid organs
86
what is the most common childhood cancer
acute lymphoblastic leukemia (ALL)
87
acute lymphoblastic leukemia (ALL) pathophysiology
- Immature leukemic blast cells are blocked in differentiation
o <10 mutations
o Accumulate immature non functional blast cells:
Crowd out normal cells and bone marrow fails
Encourage self renewal in bone marrow
88
symptoms and sings in acute lymphoblastic leukemia (ALL)
o Fatigue, infection (neutropenia), bleeding, bone pain, solid organs metastases (spleen, liver, testes, lymph, meninges)
o Lymphadenopathy, splenomegaly, hepatomegaly,
o CNS: cranial nerve palsy, headache, vomit
89
diagnosis of Acute lymphoblastic leukemia (ALL)? what is the WBC?
o Blast cells in bone marrow and peripheral blood smears
o WBC count elevated or depressed
o Chromosomal abnormalities or overexpression of enzymes (hyperdiploidy)
90
prognosis of Acute lymphoblastic leukemia (ALL)
o Kids 2-10 yrs do good with treatment bc usually B cell (older kids are bad bc T cell)
91
chronić lymphocytic leukemia (CLL) is the most common leukemia in
adults of western world
92
what cells are effected in Chronic lymphocytic leukemia (CLL)
- Tumor in mature B cells, expressing CD 19, CD 20, CD 23
o Mutation in memory cells
o Depress B cell function, induce autoantibodies
Hypogammaglobulinemia
Deficient T-cell response
93
symptoms of Chronic lymphocytic leukemia (CLL)
o Asymptomatic
o Usually based on elevated lymphocyte count
o Weight loss, fatigue, anorexia
o Lymphadenopathy or splenomegaly
o Susceptible to bacterial infection die
o Hemolytic anemia and thrombocytopenia from autoantibodies
94
prognosis of Chronic lymphocytic leukemia (CLL)
o Slow growing tumor usually
95
non-hodgkins lymphoma is a cancer of what type of cells
- Cancer of mature B, T, and NK cells
o 90% are B cell origin MYC and BCL6 and BCL2
96
b cell genes effected in non-hodgkins lymphoma
MYC and BCL6 and BCL2
97
what's more common; Hodgkin or non-hodgkin
non hodgkin
hodgkin is - 10% of lymphoma cases
98
risks for Non- Hodgkin’s lymphoma
- Risks: agriculture chemicals, EBV, HIV, immunosuppression, autoimmune, Hodgkin’s treatment, relatives with NHL
99
2 subtypes of Non-Hodgkin’s lymphoma-
Non-Hodgkin’s lymphoma- diffuse large b-cell lymphoma
Non-Hodgkin’s lymphoma- follicular lymphoma
100
most common subtype of Non-Hodgkin’s lymphoma-
- Most common NHL subtype (1/3)
101
age and progression in Non-Hodgkin’s lymphoma- diffuse large b-cell lymphoma
- Age 64 ; rapid aggressive growth
102
risks of Non-Hodgkin’s lymphoma- diffuse large b-cell lymphoma
family, immunodeficneiy, autoimmune (EBV), immunosuppression
103
symptoms Non-Hodgkin’s lymphoma- diffuse large b-cell lymphoma
B symptoms (fever, night sweats, weight loss), elevated LDH
104
area affected in Non-Hodgkin’s lymphoma- diffuse large b-cell lymphoma
- Extranodal: Bone marrow involvement and CNS dissemination
o Also GI, thyroid, liver, skin
105
genes in Non-Hodgkin’s lymphoma- diffuse large b-cell lymphoma
- Genes: BCL2, BCL6, MYC, double hit (2 of these)
106
Non-Hodgkin’s lymphoma- follicular lymphoma symptoms
- Painless lymphadenopathy; epitrochlear nodes and extranodal
107
Non-Hodgkin’s lymphoma- follicular lymphoma imaging
- Imaging: CT, PET
o Best is follicular lymphoma international prognostic index (FLIPI)
108
Hodgkins lymphoma effects
mature b cells
109
what is effected in hodking vs non-hodgkins
hodgkin= mature b cells
non= B, T, or NK cells , but usually B cells
110
2 types of Hodgkin’s lymphoma
- 2 types: classical Hodgkin's lymphoma (cHL) and nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL).
o NLPHL resembles cHL a bit but more so NHL
111
virus in hodgkin lymphoma
EBV and HIV
112
what are Reed-sternberg (HRS) cells
- Reed-sternberg (HRS) cells: large cells with abundant cytoplasm and multiple nuclei
o Diagnostic of cHL
o Express EBV protein LMP-1
o Express PD-1
113
what lymphoma is Reed-sternberg (HRS) cells diagnostic over
classical Hodgkin's lymphoma (cHL
114
features of Hodgkin lymphoma
o Palpable, nontender lymphadenopathy (early: cervical, supraclavicular, axillary)
o B symptoms: fever, weight loss, night sweats
115
labs in hodgkin lymphoma
o CBC with diff, ESR, hepatic and renal labs, HIV and hepatitis testing
o Imaging: PET and CT
