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Review / Wrong Answers > DIT review - Heme 2 > Flashcards

DIT review - Heme 2 Flashcards

1
Q

Where does erythropoeisis occur in early life and later life

A
  • Fetal development - liver
  • After 28 weeks - bone marrow
    • Infancy and childhood:
      • Flat bones
      • Sternum, pelvis, ribs, cranial bones, vertebrae, long bones of leg
    • Later adolescence and adulthood
      • Axial skeleton
      • Vertebrae, sternum, ribs, and pelvis
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2
Q

What is the rate limiting enzyme of heme synthesis

A

ALA synthase:

Succinyl CoA + Glycine –> ALA

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3
Q

What is the cofactor required for ALA synthase

A

B6

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4
Q

What are causes of polycythemia (increased RBC)

A
  • Polycythemia vera – monoclonal proliferation of red cells
  • Chronic hypoxia – need to increase O2 carrying capacity so kidney produces more erythropoietin to make more RBCs
    • Pulmonary disease
    • Cyanotic heart disease
    • High altitudes
  • Inappropriate elevation of EPO – e.g. EPO-producing tumor
  • Trisomy 21
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5
Q

What are the EPO-producing tumors?

A

THINK: Potentially Really High Hematocrit

  • Pheochromocytoma
  • Renal cell carcinoma
  • Hepatocellular carcinoma
  • Hemangioblastoma
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6
Q

What is the enzyme deficiency in Acute intermittent porphyria

A

Porphobilinogen (PBG) deaminase

THINK:

o Acute intermittent = guys hollering “damn” (deam-inase) intermittently at A CUTE pretty big girl (PBG)

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7
Q

Presentation of acute intermittent porphyria

A

§ Symptoms – 5 P’s

· Painful abdomen

· Port wine colored urine (due to increase PGB)

· Polyneuropathy

· Psychological disturbances

· Precipitated by drugs (CYP450 inducers – e.g. Rifampin), alcohol, and starvation

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8
Q

Treatment of acute intermittent porphyria

A

· Glucose + heme = inhibition of ALA synthase

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9
Q

What is the deficienct enzyme in porphyria cutanea tarda?

A

Uroporphyrinogen carboxylase

THINK of a homeless man living in a cardboard box (carbox)

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10
Q

Presentatin of porphyria cutanea tarda

A

§ Symptoms

· Blistering cutaneous photosensitivity

· Hyperpigmentation

· Hyerptrichosis (extra hair)

· Tea colored urine

· Exacerbated with alcohol consumption

· Associated with Hepatitis C

§ (THINK of a stereotypical homeless man)

· Alcoholic, face blistered and dark from sun, facial hair, liver disease

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11
Q

Enzyme defiecient in lead poisoning

A

ALA dehydratase and Ferrochelatase

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12
Q

Presentation of lead poisoning

A
  • GI (abd pain, constipation, anorexia)
  • Neuro (cognitive defects, peripheral neuropathy, encephalopathy, memory loss, delirium)
  • Hematologic (microcytic anemia with basophilic stippling, ringed sideroblasts in marrow)
  • Burton lines – lead lines in gingiva and gums
  • Hyper dense lines on metaphysis of long bones
  • Renal failure
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13
Q

What are the different causes of microcytic anemia

A

Iron deficiency

Anemia of chronic disease (late)

Thalassemia

Lead poisoning

Sideroblastic anemia

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14
Q

What is the basic principle behing microcytic anemia

A
  • MCV < 80
  • Due to decreased production of hemoglobin = extra division to maintain Hb concentration
    • Hemoglobin = heme + globin
      • Heme = iron + protoporphyrin
  • Cells are small and hypochromic (pale)
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15
Q

What are lab values of iron deficiency anemia (ferritin, serum iron, TIBC, % saturation)

A
  • Low ferritin (low iron stores)
  • Low serum iron
  • Low % saturation (of transferrin – iron transporter)
  • High TIBC (Total iron-binding capacity = # of transferrin molecules in the blood – will be elevated because the liver is pumping out more in a state of low iron in order to replenish iron
    • Ferritin and TIBC are always opposite
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16
Q

What is the molecule responsible for anemia of chronic disease

A

Hepcidin sequesters iron into storage sites

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17
Q

What are lab values of anemia of chronic disease(ferritin, serum iron, TIBC, % saturation)

A
  • Labs:
    • High ferritin
    • Low TIBC
    • Low serum iron
    • Low % saturation
  • Early disease presents as nonhemolytic, normocytic anemia
  • Late disease presents as microcytic anemia
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18
Q

Describe the defect in alpha thalassemia

A
  • Defect in a-globin synthesis
  • Alpha Thalassemia
    • Due to alpha-globin gene deletion = decreased alpha-globin synthesis
    • There are 4 alpha genes on chromosome 16
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19
Q

Describe the different types of alpha-thalassemia

A
  • 1 gene deleted = asymptomatic
  • 2 genes deleted = mild anemia
    • Cis = increased risk in offspring – Asians
    • Trans = Africans
  • 3 genes deleted
    • Beta chains form tetramers – B4 = Hemoglobin H (HbH)
  • 4 genes deleted
    • No a-globin at all
    • Gamma (y) chains form tetramer – y4 = Hemoglobin Barts (Hb Barts)
    • Incompatible with life – hydrops fetalis
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20
Q

Describe the defect in beta thalassemia

A
  • Due to beta globin gene mutation
  • There are 2 beta genes on chromosome 11
    • Mutations can result in absent (B0) or diminished (B+) production of b-globin
  • Seen in Mediterranean populations
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21
Q

Describe beta-thalassemia minor (genes, presentation, types of Hb, histology)

A
  • B-thalassemia minor (B/B+)
    • Decreased amount of B-globin
    • Minimal anemia
    • Increased HbA2 (a2d2) and HbF (a2y2)
    • Will see target cells
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22
Q

Describe beta thalassemia major (genes, presentation, histology)

A
  • B-thalassemia major (B0/B0)
    • No B-globin at all
    • Severe anemia requiring blood transfusions
      • Risk of hemochromatosis
    • High HbF at birth is temporarily protective
    • Will see target cells
    • Erythroid hyperplasia – hematopoiesis occurring in unusual places, such as face, skull, liver, spleen
      • “Crewcut” appearance on X-ray (“hair-on-end”)
      • “Chipmunk” facies
      • Hepatosplenomegaly
    • Risk of aplastic crisis with Parvovirus B19 infection of erythroid precursors
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23
Q

Describe the defect and causes of sideroblastic anemia

A
  • Defect in heme synthesis
    • Defect in protoporphyrin synthesis leads to iron buildup in the mitochondria = iron-laden mitochondria form a ring around nucleus of erythroid precursors
  • Causes:
    • Congenital:
      • ALA synthetase deficiency
    • Acquired:
      • Lead poisoning
      • Vitamin B6 deficiency (cofactor for ALA synthetase)
      • Alcohol
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24
Q

What are the lab values of sideroblastic anemia (ferritin, TIBC, serum iron, % saturation)

A
  • High ferritin
  • Low TIBC
  • High serum iron
  • High % saturation
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25
Describe the defect and presentation of lead poisoning
* Lead poisoning inhibits ferrochelatase and ALA dehydratase, thus inhibiting heme synthesis and increasing protoporphyrin * Presentation: * Lead lines on gingivae (Burton lines) and on metaphyses of long bones * Encephalopathy * RBC basophilic stippling * Abdominal colic * Sideroblastic anemia * Wrist and foot drop
26
What are the causes of macrocytic anemia
* Megaloblastic anemia * Folate deficiency * B12 deficiency * Orotic aciduria * Alcoholism * Liver disease * Drugs
27
Describe how folate and B12 are involved in the synthesis of DNA precursors
* Folate circulates as methyl THF * Methyl is transferred from THF to B12 so that THF can participate in DNA synthesis * Methyl is transferred from B12 to homocysteine, creating methionine
28
How can you differentiate folate and B12 deficiency
Both will have megaloblastic anemia with hypersegmented neutrophils * Folate deficiency: * Elevated serum homocysteine * Normal methylmalonic acid * No neuro symptoms * B12 deficiency: * Elevated serum homocysteine * Elevated methylmalonic acid * Neuro symptoms
29
Describe the absorption of B12
* Dietary B12 bound to meat * Salivary enzymes free B12 from meat, and bind it to R-binder to carry through the stomach * Pancreatic proteases detach B12 from R-binder * B12 binds to intrinsic factor (IF), created by gastric parietal cells * IF-B12 absorbed in the ileum
30
Causes of B12 deficiency
* Malnutrition * Pernicious anemia = B12 deficiency due to autoimmune destruction of gastric mucosa (parietal cells in the stomach), which leads to IF deficiency * Pancreatic insufficiency = no enzyme to cleave B12 from R-binder * Damage to terminal ileum (e.g. Crohn’s) à site of absorption * Diphyllobothrium latum (tapeworm)
31
What cause neuro defects in B12 deficiency
* B12 needed to convert methylmalonic acid to Succinyl CoA * Decreased B12 = increased MMA = MMA builds up in myelin of spinal cord leading to degeneration
32
Describe defect in orotic aciduria
* Inability to convert orotic acid to UMP (de novo pyrimidine synthesis pathway)
33
What are the main 3 causes of normocytic anemia
* (I) Underproduction (nonhemolytic) * (II) Extravascular hemolysis * (III) Intravascular hemolysis
34
Causes of nonhemolytic normocytic anemia
* Anemia of chronic disease (early) * Iron deficiency anemia (early) * Aplastic anemia * Chronic kindey disease
35
Describe the presentation and histology of aplastic anemia
* Bone marrow stops making cells – pancytopenia * Anemia * Fatigue, malaise, pallor * Leukopenia * Infection * Thrombocytopenia * Purpura, petechiae, bleeding * Histology will show hypocellular bone marrow with fatty infiltration (“cobweb”)
36
Causes of aplastic anemia
* Radiation * Drugs * Viral infections: Parvovirus B19, EBV, HIV * Fanconi anemia (DNA repair defect causing bone marrow failure) * Idiopathic
37
Differentiate extra- vs. intravascular hemolysi
* Extravascular hemolysis: * RBC destruction by reticuloendothelial system (macrophages of spleen, liver, and lymph nodes) * Intravascular hemolysis: * Destruction of RBCs within vessels
38
What is the defect in hereditary spherocytosis and is it extravascular or intravascular hemolysis
Extravascular * Defect of RBC cytoskeleton proteins * Ankyrin, spectrin, band 3 * Membranes are formed and lost over time * Loss of membrane = spherocytes * Spherocytes cannot maneuver through splenic sinusoids so are consumed by macrophages
39
What findings will you see in hereditary spherocytosis
* Spherocytes with loss of central pallor * Increased RDW – cells of all different sizes * Increased MCHC (mean corpuscular hemoglobin concentration) – cell shrinks but Hb remains the same * Splenomegaly and jaundice * Aplastic crisis
40
Diagnostic test of hereditary spherocytosis
* Osmotic fragility test – High percentage of lysis of RBCs in hypotonic solution
41
Treatment of hereditary spherocytosis
Splenomegaly
42
Describe how G6PD deficiency causes anemia
* Glutathione neutralizes H2O2 but becomes oxidized in the process * NADPH needed to reduce glutathione * In G6PD deficiency, NADPH is not produced
43
Histology of G6PD deficiency
* Heinz bodies – precipitation of Hb within RBC due to oxidative stress * Bit cells – spleen removing Heinz bodies
44
What are oxidant stresses that causes hemolytic anemia is G6PD
* Sulfa drugs, antimalarials, infection, fava beans
45
Describe how pyruvate kinase deficiency causes anemia
* Glycolytic enzyme deficiency = inability to generate ATP * Cannot maintain Na+/K+ ATPase = RBC swelling and lysis
46
What is the mutation in sickle cell disease
* HbS due to mutation of b-hemoglobin * Single amino acid replacement: glutamic acid to valine
47
What are triggers of RBC sickling
* Hypoxemia * Dehydration * Acidosis
48
Describe findings of sickle cell disease
* Causes both extra- and intravascular hemolysis * Autosplenectomy * Increased infection by encapsulated organisms * Howell-Jolly bodies * Increased risk of salmonella osteomyelitis * Aplastic crisis due to parvo B19 * Pain crises due to malocclusion * Dactylitis * Acute chest syndrome * Renal papillary necrosis * Erythroid hyperplasia: * “Crewcut”/”Hair-on-end” X-ray * Chipmunk facies
49
What will you see on histology of sickle cell disease
* Sickle cells and target cells
50
Treatment of sickle cell disease
* Hydroxyurea – increases production of HbF * Bone marrow transplant
51
Describe mutation in Hemoglobin C disease
* HbC due to mutation of b-globin * Single amino acid replacement: glutamic acid à lysine * HbC forms hexagonal crystals in the cells * Milder than sickle cell disease
52
53
What is the protein that carries Hb to spleen in intravascular hemolysis
Haptoglobin
54
Describe general clinical findings of intravascular hemolysis
* Hemoglobinemia, hemoglobinuria, hemosiderinuria (due to iron taken up by renal tubular cells, which later shed), _decreased serum haptoglobin_, corrected reticulocyte count \> 3%
55
Differentiate the 2 types of autoimmune hemolytic anemia
* (a) Autoimmune hemolytic anemia * Antibody-mediated destruction of RBCs * Subtypes: * Warm agglutinins * IgG antibodies attach to RBCs and cause them to agglutinate * Involves extravascular hemolysis * Occurs in central body * Associated with lupus, CLL, and different drugs * Cold agglutinins * IgM antibodies bind RBCs and activate complement * Occurs in periphery * Associated with EBV and mycoplasma pneumonia
56
How do you diagnose autoimmune hemolytic anemia
* Direct Coombs * Detects antibody-coated RBCs * Prepared antibodies added to patient’s RBC to see if they bind to existing antibodies on the RBC * Adding an antibody that binds to antibody * Indirect Coombs * Detects free antibodies in serum * Patient’s serum incubated with normal RBC
57
Describe the defect in Paroxysmal nocturnal hemoglobinuria
* Deficiency of GPI, which usually anchors DAF (CD55) to RBC membrane to protect from complement destruction * Complement is activated in acidic situations * Lysis occurs at night due mild respiratory acidosis
58
Diagnosis of paroxysmal nocturnal hemoglobinuria
* Ham’s test – add acid to lower the pH and check for RBC lysis
59
Describe the problem and causes of microangiopathic anemia
* RBCS are mechanically damaged as they pass through the lumen of an obstructed or narrowed vessel * Schistocytes * Causes of microthrombi: * TTP = platelet thrombi due to lack of ADAMS13 * HUS = platelet thrombi due to toxin from E. Coli * DIC = platelet and fibrin thrombi * HELLP = in pregnant women
60
Causes of macroangiopathic anemia
* RBCs are mechanically damaged by forces in larger vessels * Causes: * Prosthetic heart valves * Aortic stenosis

Review / Wrong Answers (140 decks)

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