Download Anemia of Chronic Disease

‫‪Diseases of blood cells‬‬
‫‪Pharmacology Students‬‬
‫د‪ .‬طارق العديلي‬
‫الساعات المكتبية‪ :‬األحد ‪1-12‬‬
‫عنوان المكتب‪ :‬مستشفى الجامعة األردنية‬
‫مبنى العيادات‪ ،‬الطابق الثالث‪ ،‬مختبر أمراض الدم‬
‫‪Email: [email protected]‬‬
‫تلفون ‪ 06/5353666‬فرعي ‪2645‬‬
RBC DISORDERS
Anemia
• Reduction of total RBC MASS below average
levels
• Reduction of oxygen carrying capacity of the
blood, leads to tissue hypoxia
• Practically, measured by Hemoglobin
concentration, and Hematocrit (ratio of
packed RBCs to total blood volume)
Classification of anemia
according to cause
• Blood loss: acute, chronic
• Diminished RBC production
• Increased destruction “hemolytic anemia”
Clinical features of anemia
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Dizziness
Fatigue
Pallor
Hypotension
Tachycardia
Tachypnia
Anemia of acute blood loss
• Symptoms are related to decreased intravascular
volume, might cause cardiovascular shock and death
• Body responds by shifting fluid from interstitial to
intravascular space, causing dilutional anemia and
hypoxia
• Erythropoietin secretion is stimulated, activating BM
erythropoiesis
• Mature RBCs as well as Reticulocytes appear in blood
after 5 days
• The anemia is normochromic normocytic, with
reticulocytosis
Anemia of chronic blood loss
• Occurs when the rate of RBC loss exceeds
regeneration
• Usually occurs in GI and gynecologic diseases
• Body loses iron in lost RBCs, resulting in iron
deficiency anemia lately
• Anemia begins normochromic normocytic,
then hypochromic microcytic
Hemolytic Anemia
• Normally, RBCs age is around 120 days, aged RBCs
are engulfed by phagocytic cells in spleen
• In Hemolytic anemia; premature destruction of RBCs
• Accumulation of Hg degradation products (bilirubin),
causing jaudince
Glucose-6-Phosphate Dehydrogenase
Deficiency
• G6PD reduces nicotinamide adenine
dinucleotide phosphate (NADP) to NADPH
while oxidizing glucose-6-phosphate
• NADPH neutralizes H2O2
• G6PD deficiency is a recessive X-linked trait,
placing males at higher risk for symptomatic
disease. The enzyme is deficient (African type)
or non-functioning (Mediterranean)
Pathogenesis
• High levels of oxidants causes the cross-linking of
globin chains, which become denatured and form
membrane-bound precipitates known as Heinz
bodies, stained with crystal violet stain, which tear
membrane and causes hemolysis
• Splenic macrophages identify Heinz bodies and pluck
them out resulting in indentation. The remaining RBC
is known as “bite cells”
Causes of hemolytic crisis
• Hemolysis happens upon exposure to oxidant
stress
• The most common triggers are:
• (1) infections, in which oxygen-derived free
radicals are produced by activated leukocytes
• (2) Drugs (anti malaria, sulfonamides)
• (3) Fava beans (favism)
• Hemolysis occurs 2-3 days post exposure,
appears as sudden drop in Hg level with pain
Thalassemia
• The thalassemia syndromes are a
heterogeneous group of disorders caused by
inherited mutations that decrease the
synthesis of adult hemoglobin, HgA (α2β2)
• Endemic in Middle East, tropical Africa, India,
Asia
• β-Thalassemia is caused by deficient synthesis
of β chains, whereas α-thalassemia is caused
by deficient synthesis of α chains
Pathogenesis
• RBCs have low content of Hg (hypochromic
micocytic)
• Persistent tissue hypoxia
• Persistent high erythropoietin, (high RBC
count, extramedullay erythropoiesis,
hepatosplenomegaly)
• Unpaired excess chains are insoluble, causing
hemolysis
• Excessive erythroid precursors in bone
marrow, steals oxygen from bone cells,
causing bone growth abnormality
Morphology of thalassemia
• Blood film: hypochromic microcytic anemia,
target cells
Sickle Cell Anemia
• Common in Africa and middle east
• AR inheritance
• Sickle cell disease is caused by a point
mutation in the sixth codon of β-globin that
leads to the replacement of a glutamate
residue with a valine residue
• The abnormal physiochemical properties of
the resulting sickle hemoglobin (HbS) are
responsible for the disease
• Sickle Cell Trait: heterozygosity of HgS,
carriers are largely asymptomatic, HgS ≈ 40%
• Sickle Cell Disease: homozygosity of HbS,
symptomatic, HgS ≈ 80%
• Both types of Hg are protective against
Malaria falciparum infection
Pathogenesis
• HbS molecules undergo polymerization when
deoxygenated
• HbS molecules assemble into long needle-like
fibers within red cells, producing a distorted
sickle shape, then damages cell membrane
and cause intravascular hemolysis
• Sickle cells are removed by macrophages,
leading to extravascular hemolysis too
Pathogenesis
• Acidosis, dehydration, hypoxia and infections
aggravate cell sickling causing crises
• Sickled RBCs can aggregate and occlude
capillaries
• Occluded vessels results in ischemia and tissue
necrosis (vaso-occlusive crisis):
• Heart: myocardial infarction
• Bone: necrosis, severe pain, aplastic anemia
• Lung: acute chest syndrome
• Skin: ulcers
Diagnosis
• Blood film: (sickle cells)
ANEMIAS OF DIMINISHED
ERYTHROPOIESIS
Anemias secondary to inadequate RBC
production
• Nutritional
• Renal failure
• Chronic inflammation
• Bone marrow failure
Iron deficiency anemia
• The most common anemia worldwide
• Nutritional or blood loss
• People at increased risk of anemia are: infants,
elderly, teenagers, low socioeconomic class
• Iron is stored as ferritin in the bone marrow
• IDA develops insidiously, begins with
decreased stored ferritin, and lastly the serum
iron is decreased
• RBCs appear as microcytic and hypochromic,
Target cells
• Response to iron therapy
Megaloblastic anemia
• Anemia associated with impairment in DNA
synthesis in hematopoietic cells special
morphologic features (large immature erythroid
precursors)
• Two types: Vitamin B12 and folate deficiency
• Vitamin B12 and folate are coenzymes required
for synthesis of thymidine
• Vitamin B12 is essential for myelin synthesis,
deficiency causes anemia and neurologic disease
Causes of Vit B12 deficiency
• Low intake (vegans)
• Impaired GI absorption (pernicous anemia,
malabsorption disease, gastrectomy)
• Pernicious anemia: autoimmune disease,
destruction to parietal cells, impaired
absorption
Causes of folate deficiency
• Low intake (inadequate diet, infancy)
• Impaired absorption (malabsorption, chronic
alcoholism, anti-convulsants, oral
contraceptives)
• Impaired utilization (methotrexate, Vit B12
deficiency)
• Increased demand: pregnancy
Morphology
• PB: RBCs are large and oval and no central
pallor
• Reticulocytes are low
• Neutrophils are large and have
hypersegmented nuclear lobes (5 or more)
• BM: Megaloblastic changes in erythroid
precursors (large size and immature nucleus
despite cytoplasmic maturation)
Anemia of Chronic Disease
• Most common anemia in hospitalized people
• Occurs in chronic inflammatory diseases
(infection, autoimmune, cancer)
• IL-6 activates the synthesis of Hepcidin in the
liver, which suppresses erythropoietin and
prevents the transfer of iron to erythroid cells
• Anemia is normochromic normocytic, or
hypochromic microcytic
Aplastic Anemia
• Bone marrow fail to produce the 3 cell lines
• 60% of cases are idiopathic. The rest are
secondary to drugs (chloramphenicol),
chemicals (benzene), or autoimmune process
POLYCYTHEMIA
• increase in hemoglobin concentration and
hematochrit
• Primary polycythemia (polycythemia vera) is a
clonal, neoplastic myeloproliferative disorder
• Secondary polycythemia occurs as an Adaptive
process (lung disease, high-altitude living,
cyanotic heart disease),
Paraneoplastic: erythropoietin-secreting tumors
(e.g., renal cell carcinoma), or
Surreptitious: endurance athletes
White blood cell disorders
Leukopenia
• Neutropenia: occurs as part of aplastic
anemia, drug reaction (anti-epileptic, antithyroid, chemotherapy), congenital. Patients
develop severe bacterial infections
• Lymphopenia is much less common; it is
associated with congenital immunodeficiency
diseases, advanced human immunodeficiency
virus (HIV) infection, and treatment with high
doses of corticosteroids
Reactive Leukocytosis
• An increase in the number of white cells in the
blood is common in a variety of inflammatory
states caused by microbial and nonmicrobial
stimuli
Neutrophilia
• Infection (bacterial)
• Burn
• Tissue necrosis (myocardial infarction)
Eosinophilia
• Allergic reactions
• Parasitic infections
• Drug reactions
Lymphocytosis
• Viral infections
• Tuberculosis
Reactive Lymphadenitis
• Any immune response against foreign antigens can
lead to lymph node enlargement (lymphadenopathy)
Acute lymphadenitis: neutrophilic infiltration (bacterial),
painful
Chronic lymphadenitis (painless):
• HIV
• rheumatologic diseases
• drug reaction
• post vaccination
Mimic lymphoma
Lymphoma
• Malignant tumor of lymphocyte
• Most commonly arise from lymph nodes
• 1/3 arise in extranodal sites, GI and mediastinum are the most
common sites
• Malignant lymphocytes may circulate the blood and reach the bone
marrow, called lymphoid leukemia
• Generally classified as Hodgkin and non-Hodgkin lymphomas
• Non-Hodgkin lymphoma is classified as B or T-cell lymphoma, which
both are further classified as low or high grade
• B-cell lymphomas express CD20 (rituximab)
• T-cell lymphomas express CD3
• Hodgkin lymphomas express CD30 (brentuximab)
• Patients with lymphoma have disturbed immune system
Chronic Lymphocytic Leukemia
• Low grade B-cell lymphoma
• Cells are small, round, mature looking similar
to normal lymphocytes, but very high in
number
• The most common leukemia in elderly
Hodgkin Lymphoma
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Neoplasm of B-cell origin
Malignant cells are called Reed-Sternberg cells
Giant size, two nuclei
Do not express CD20, instead, CD30
common in children and young adults
Affects only lymph nodes and mediastinum
Acute Leukemia
• An aggressive, high-grade neoplasm
• Arises from immature cells of the bone marrow, called
blast
• Acute myeloid leukemia: arises from myeloblasts, that
differentiates into WBC, affects all ages
• Acute lymphoblastic leukemia: arises from
lymphoblasts which differentiate into B or Tlymphocytes, common in children
• Patients have high number of WBC in blood and bone
marrow, destroying normal cells
• Patients present with sudden fever (infection), bleeding
and anemia
Chronic Myelogenous Leukemia
• Low grade leukemia, high number of neutrophils
(not blasts)
• translocation between chromosomes 9 (ABL
gene) and 22 (BCR)
• The new chromosome is known as Philadelphia
chromosome
• The new fusion gene (BCR-ABL) gain a new
“Tyrosine-Kinase” function, which activates cell
proliferation and prolonged its survival
• Imatinib blocks BCR-ABL gene