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blood > erythropoiesis, heme, hemoglobin, iron > Flashcards

erythropoiesis, heme, hemoglobin, iron Flashcards

1
Q

what is the process of erythropoiesis? (5)

A

MSC→ proerythroblast→ erythroblast→ reticulocytes→ erythrocytes

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2
Q

what are the compounds needed for erythropoiesis + functions? (4)

A
  1. Folate
  2. Vit b12
    for DNA synthesis (proerythroblast→ erythroblast)
  3. Fe
    for synthesis of Hb (erythroblast→ reticulocytes)
  4. erythropoietin (hormone)
    - growth factor for MSC proliferation & differentiation
    - prevents apoptosis
    - increase proerythroblast
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3
Q

how is erythropoiesis regulated?

A

fall in PO2→ HIF1a synthesized & released into system→ increase erythropoietin (EPO) production→ increase erythropoiesis→ increase mature RBCs & O2 carrying capacity

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4
Q

too many RBCs (production>destruction)

A

polycythaemia

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5
Q

too few RBCs (production<destruction)

A

anemia

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6
Q

low & high WBC count:

A

low: leukopenia
high: leokocytosis

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7
Q

terms for low & high platelet count:

A

low: thrombocytopenia
high: thrombocytosis

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8
Q

what does MCV measure?

A

size of RBCs (vol/RBC)

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9
Q

what does MCH measure?

A

absolute amount of Hb per RBC (Hb/RBC)

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10
Q

what does MCHC measure?

A

concentration of hemoglobin (Hb/Vol)

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11
Q

MCV indices

A

microcytic (RBC too small)
normocytic (normal RBC size)
macrocytic (RBC too big)

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12
Q

MCHC indices

A

hypochromic (too little Hb)
normochromic (normal Hb levels)
hyperchromic (too much Hb)

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13
Q

what is anemia?

A

number of RBCs (fall in RBCs) or their oxygen carrying capacity (fall in Hb production) is insufficient to meet physiologic needs

clinical: Hb level below normal reference range

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14
Q

explain how normocytic RBCs can still result in anemia

A

normal size→ problem is with the NUMBER of RBCs
- increase RBC loss
- fall in RBC production

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15
Q

explain causes of microcytic RBCs (leading to anemia)

A
  • insufficient/abnormal Hb synthesis→ small RBC size
  • e.g. Fe deficiencies, hemoglobinopathies
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16
Q

explain causes of macrocytic RBCs and how it can lead to anemia

A
  • impaired DNA synthesis & cellular division (cells grow in size but don’t divide)
  • may not be able to pass through tiny pores in capillaries→ burst (hemolysis)
  • e.g. Vit B12 or folate deficiencies
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17
Q

explain how normochromic RBCs can still lead to anemia

A
  • less likely Hb production issues
  • likely due to increased RBCs lost or decreased RBC production
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18
Q

explain causes of hypochromic RBCs (leads to anemia)

A
  • insufficient/abnormal Hb synthesis
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19
Q

explain causes of hyperchromic RBCs and how it can lead to anemia

A
  • faulty Hb production (overproduced)

ROUND shape/spherocytes (vs biconcave)
- not as elastic→ can’t squeeze through pores→ hemolysis
- fall in SA:vol ratio→ compromised O2 delivery

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20
Q

what does Haematocrit measure?

A

percentage of RBCs in the blood (RBC volume/total blood volume)

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21
Q

what is reticulocyte count for?

A

indication of the rate of erythropoiesis (normal count: 0.5-1.5%)

high reticulocyte count→ high erythropoiesis rate (due to blood loss or hypoxia)

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22
Q

what does peripheral blood film (PBF) show? (4)

A
  1. size (macrocytosis, microcytosis, anisocytosis)
  2. appearances (hypochromic, inclusion bodies, target cells)
  3. shapes (spherocytes, cell fragments due to RBC lysis, poikilocytosis)
  4. maturity (reticulocyte %, erythroblast, megalobalast)
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23
Q

what is heme?

A

prosthetic group of Fe2+ (centre) and porphyrin molecule (ring)

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24
Q

what are the functions of heme in proteins (3)?

A
  1. hemoglobin (O2 binding in RBCs)
  2. myoglobin (O2 binding in muscles)
  3. cytochrome (electron transfer)
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25
Q

where does heme synthesis occur? (which cells and which component)

A

CELL: occurs in all cells but mainly in erythroid cells in marrow (hemoglobin to form RBCs), and the liver (cytochromes for detoxification)

COMPONENTS: mitochondria & cytosol

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26
Q

what is the process of heme synthesis?

A

succinyl CoA + glycine + ALA synthase→ ALA→ PBG→ uroporphyrinogen III→ coproporphyrinogen III→ protoporphyrin IX→ heme!!!

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27
Q

what are the 2 ALA synthase isoforms + what stimulates them + their effect

A

essentially UPregulation of heme synthesis

ALAS1 (liver)
- stimulated by drugs/toxins
- increases heme for cytochromes used for detoxification

ALAS2 (marrow)
- stimulated by hypoxia & EPO
- increases heme for hemoglobin (RBC)

both inhibited by heme/iron (negative feedback)

28
Q

what enzymes in heme synthesis are inhibited by heavy metal ions? (2)

A
  1. ALA dehydratase (ALA → PBG)
  2. ferro-chelatase (protoporphyrin IX → heme)
29
Q

what are the clinical presentations of heavy metal poisoning? (e.g. paint, ceramics) (4)

A
  • abdominal pain
  • pallor (anemia)
  • neuropathy
  • bluish coloration at gum line (Burton’s line)
30
Q

when/how is heme synthesis downregulated? (negative feedback)

A

high levels of heme or iron (prevent overproduction of heme)

31
Q

what can go wrong with heme synthesis (genetic)? + 2 impt examples

A

porphyrias
(deficiencies in heme synthesis pathway)
- acute intermittent porphyria
- porphyria cutanea tarda

32
Q

clinical presentation of acute intermittent porphyria (4)

A
  • inhibits PBG→ uroporphyrinogen
  • increase in/accumulation of 1PBG
  • abdominal pain
  • neuropsychiatric symptoms
  • URINE DARKENS on exposure
33
Q

clinical presentation of porphyria cutanea tarda (2)

A
  • inhibits uroporphyrinogen→ coproporphyrinogen (accumulate uroporphyrinogen)
  • AFTER ring formation
  • PHOTOSENSITIVITY w skin lesions
  • reddish urine
34
Q

what organs/organelles are involved in heme breakdown? (4)

A
  • most of heme (~85%) to be degraded comes from senescent RBCs (~120days)
    1. reticuloendothelial macrophages (tissue/liver/spleen)
    2. liver
    3. gut
    4. kidney
35
Q

what is the process of heme breakdown?

A

macrophages: heme→ biliverdin→ bilirubin
blood: bilirubin + albumin→ bilirubin-albumin
liver: bilirubin-albumin→ bilirubin-diglucuronide (conjugated bilirubin)
bile: bilirubin-diglucuronide→ urobilinogen
gut: urobilinogen→ stercobilin (brown stools)
blood: reabsorption of urobilinogen to liver
kidney: urobilinogen→ urobilin (yellow pee)

36
Q

what enzyme conjugates bilirubin with glucuronic acid?

A

UDP-glucuronyl transferase (in bile)

bilirubin-albumin→ bilirubin diglucuronide

37
Q

why do some newborns have jaundice?

A

UDP-glucuronyl transferase is synthesized slowly after birth→ decreased ability to conjugate & hence excrete bilirubin→ accumulation of UNconjugated bilirubin→ hyperbilirubinemia→ jaundice

38
Q

what colours are biliverdin and bilirubin?

A

biliverdin: green
bilirubin: yellow

39
Q

what is hyperbilirubinemia + presentation?

A

HIGH total bilirubin (unconjugated & conjugated)

hyperbilirubin: >1.2mg/dL)
detectable (jaundice): >2.5-3mg/dL)

presentation: JAUNDICE (yellowing of skin, sclera, mucous membrane)

40
Q

types of jaundice (5)

A
  1. prehepatic
  2. hepatic: conjugation defect
  3. hepatic: excretion defect
  4. hepatic: mixed defect
  5. obstructive
41
Q

parameters of prehepatic jaundice (4)

A

increased hemolysis→ increased unconjugated bilirubin→ exceeds liver’s conjugation capacity→ increased urobilinogen

  • INCREASED unconjugated bilirubin
  • increased urobilinogen
  • coffee-ground dark urine colour if severe (increased free Hb→ hemoglobinuria)
  • decreased haptoglobin (excess free hemoglobin→ binds to haptoglobin)
42
Q

parameters of conjugation defect (hepatic jaundice)

A
  • INCREASED unconjugated bilirubin
  • decreased conjugated bilirubin
  • decreased urine urobilinogen
  • stool colour: pale (if severe)
43
Q

parameters of excretion defect (hepatic jaundice)

A

defects in transporters excreting conjugated bilirubin
- increased unconjugated bilirubin
- INCREASED conjugated bilirubin (can’t get excreted, accumulates)
- urobilin/stercobilin unaffected (defect is insufficient)

44
Q

parameters of early mixed defect (hepatic jaundice)

A
  • increased conjugated bilirubin
  • increased urine urobilinogen
45
Q

parameters of late mixed defect (hepatic jaundice)

A
  • increased unconjugated bilirubin
  • INCREASED conjugated bilirubin
  • decreased urine urobilinogen
  • tea-coloured urine (conjugated bilirubin)
  • pale stool if severe
46
Q

parameters of obstructive jaundice (6)

A

obstruction of bile duct
- increased unconjugated bilirubin (severe obstruction→ backpressure in liver→ decreased conjugation ability)
- INCREASED conjugated bilirubin
- DECREASED urine urobilinogen
- tea-coloured urine (conjugated bilirubin filtered through kidneys)
- pale stools
- increased ALP, GGT (release of enzymes from damaged biliary tract)

47
Q

other parameters of hepatic jaundice

A
  • increased AST & ALT (liver damage→ release liver enzymes)
  • decreased albumin, increased PT/PTT (liver dysfunction→ fall in factors produced by liver)
48
Q

what is the problem with high levels of unconjugated bilirubin?

A

unconjugated bilirubin can cross the BBB causing brain damage (commonly seen in infants with immature BBB→ kernicterus)

49
Q

describe hemoglobin’s (HbA) structure

A
  • tetrameric protein made from 2alpha & 2beta subunits
  • each subunits carries a HEME group containing IRON that binds to and transports O2
50
Q

genes on chromosome 16 (2)

A
  1. ζ
  2. 2x alpha
51
Q

genes on chromosome 11 (4)

A
  1. ε
  2. delta
  3. gamma
  4. beta
52
Q

what are the genes making up the different haemoglobins (4)

A

HbF: alpha, gamma
HbA: alpha, beta
HbA2: alpha, delta
HbGower: ζ, ε

53
Q

what is the order in which Hb is produced? (4)

A
  1. Hb Gower (maj form of Hb produced during devt of embryo)
  2. HbF
  3. HbA2
  4. HbA (maj form of Hb produced in adult)
54
Q

what genetic disease affects hemoglobin synthesis?

A

thalassemia (defect in synthesis of a or B globin proteins (autosomal recessive))

55
Q

what are the clinical consequences of thalassemia? (6)

A
  1. anemia (abnormal Hb→ hemolysis)
  2. jaundice (hemolysis releases heme)
  3. organ damage (hemolysis releases iron)
  4. splenomegaly (breakdown of Hb in spleen)
  5. hepatomegaly (liver compensates for anemia by undergoing hematopoeisis)
  6. bone marrow hematopoeisis (compensate for anemia)
56
Q

what are the functions of iron (2)

A
  • electron carrier by converting from ferrous (Fe2+) → ferric (Fe3+) forms
  • carrier of molecular oxygen (as part of heme)
57
Q

how is iron absorbed?

A
  • Fe2+/heme: absorbed by small intestine

small intestine
- Fe3+→ Fe2+ by Ferric reductase to be absorbed
- Fe2+ enters small intestinal cell by Divalent Metal Transporter 1 (DMT-1)

basal membrane:
- Fe2+ is transported across basement membrane via ferroportin
- Fe2+→ Fe3+ by hephaestin→ attached to transferrin (transported into bloodstream)

58
Q

how is iron transported into cytoplasm?

A
  • Fe3+-transferrin complex is taken up by cells via transferrin receptor (endocytosis)
  • acidification in endosomes release iron into cytoplasm
  • receptor & transferrin are recycled
59
Q

how is (excess) iron stored?

A

excess iron is stored as ferritin (readily mobilizable, detected in plasma) & hemosiderin (excess ferritin, less accessible) in cells

plasma ferritin reflects the body’s iron stores (but may be elevated in chronic inflammation, false positive of high iron stores)

60
Q

how is iron metabolism regulated?

A
  • excess iron cant be actively eliminated from the body
  • can only regulate uptake!!
    small intestine: dietary iron uptake
    liver: iron-transferrin complex uptake
61
Q

what is the regulation of iron in low iron state?

A

small intestine:
- increase DMT-1
- increase ferroportin
increase uptake of dietary iron

liver:
- increase transferrin receptor (increase uptake of iron/transferrin)

62
Q

what is the regulation of iron in high iron state?

A

small intestine:
- decrease DMT-1
- decrease ferroportin by hepcidin
decrease uptake of dietary iron

liver:
- decrease transferrin receptor
- synthesize hepcidin to decrease uptake of iron/transferrin in small intestine
- increase ferritin (increase iron storage)

63
Q

what are the consequences of iron deficiency?

A

decreased intake/increased needs/increased loss→ low iron→ deplete iron stores→ anemia

  • fall in plasma iron
  • fall in transferrin saturation (no Fe to transport)
  • fall in ferritin (iron stores depleted)

deplete iron stores→ fall in heme & Hb production→ anemia

64
Q

what are the consequences of iron excess?

A

increased heme breakdown/increased uptake→ iron overload in tissues→ damage to organs e.g. liver/pancreas/heart (free iron is toxic, produces reactive oxidative species)

  • rise in plasma iron
  • rise in transferrin saturation
  • rise in ferritin
65
Q

what are the symptoms of iron excess?

A

LOCAL:
- nausea/vomiting
- diarrhoea
- GI bleeding

SYSTEMIC:
- oxidative damage
- heart failure

66
Q

how to treat iron overload

A

chelators that bind to iron and excrete them in the urine w reddish appearance (vin de rose)

blood (2 decks)

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