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Haematology > Heme and Haemoglobin > Flashcards

Heme and Haemoglobin Flashcards

1
Q

Name 3 examples of heme in proteins used in the body.

A

1) Haemoglobin in RBC (O2 binding)
2) Myoglobin in muscle (O2 binding)
3) Cytochrome (e- transfer)

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2
Q

In which cells do heme synthesis occur?

A

All nucleated cell but primarily in (i) bone marrow (Hb synthesis) and (ii) liver (cytochromes for detoxification)

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3
Q

Where in cells does heme synthesis occur?

A

In the cytosol (Step 2-4) and mitochondria (Step 1,5,6)

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4
Q

What are the different isoforms of ALA synthase?

A

ALAS1 (non-erythroid): cytochrome
ALAS2 (erythroid): RBC

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5
Q

Where does the first step of heme synthesis occur?

A

In the mitochondria

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6
Q

How is the first step of heme synthesis regulated?

A

ALAS1 stimulated by Drugs and toxins
ALAS2 stimulated by Hypoxia/EPO
Both inhibited by Heme & Fe (-ve feedback)

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7
Q

What inhibits PBG synthesis?

A

Heavy metals (eg. Pb)

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8
Q

What is the name of the condition and 3 symptoms/signs of porphobilinogen deaminase deficiency?

A

Acute Porphyria
1) Non-specific abdominal pain
2) Neuropsychiatric symptoms
3) Darkening of urine upon light exposure

Only happens if defects are before hydroxymethylbilane synthesis (eg. prophobilinogen deaminase defiency)

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9
Q

What is the name of the condition and 2 symptoms/signs of uroporphyrinogen decarboxylase deficiency?

A

Porphyria Cutanea Tarda (most common)
1) Photosensitivity with skin lesions
2) Red urine

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10
Q

Where do steps 2-4 of heme synthesis occur?

A

In the cytosol

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11
Q

What inhibits the last step of heme synthesis?

A

Heavy metals

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12
Q

Where do steps 5-6 of heme synthesis occur?

A

In the mitochondria

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13
Q

What are 2 examples of genetic heme synthesis disorders?

A

Porphyria:
1) Acute intermittent porphyria (porphobilinogen deaminase in step 3)

2) Porphyria cutanea tarda
(Uroporphyrinogen decarboxylase in step 5)

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14
Q

Give an example of an acquired heme synthesis disorder.

A

Heavy metal poisoning
- Pb in paint/ceramics → deposition
→ inhibit ALA dehydratase and Ferrochelatase
→ Burton’s line (blue coloration at gum line, Pallor, Abdominal pain, Neuropathy

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15
Q

Describe the path of haemoglobin in senescent RBCs due for destruction.

A

1) Reticuloendothelial macrophages
- Heme → Biliverdin → Bilirubin

2) Blood circulation
- binding to albumin

3) Liver
- Conjugation

4) Gut (as bile)
- Bacterial digestion

5) Excretion
a) Back to Liver (via hepatic portal)
b) Back to blood and kidney (in urine)
c) Into colon (oxidised and in stool)

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16
Q

Describe the breakdown of heme in reticuloendothelial macrophages

A

1) Heme to Biliverdin (breakdown of ring + oxidation of Fe)
- via Heme oxygenase

2) Biliverdin to Bilirubin (reduction)
- Biliverdin reductase

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17
Q

What is the key reducing agent used in the breakdown of heme to bilirubin?

A

NADPH

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18
Q

Explain why bruises are deep purplish red, green, and yellow.

A

The breakdown of heme (deep red) into biliverdin (green) and bilirubin (yellow) by reticuloendothelial macrophages

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19
Q

What protein binds to bilirubin while in circulation?

A

Albumin

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20
Q

What can happen when bilirubin levels increase?

A

If bilirubin conc. exceed albumin binding, unbound bilirubin can cross the BBB → neurotoxicity

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21
Q

What happens to albumin-bound bilirubin in the liver?

A

1) Conjugated to glucuronic acid (by UGT) to from Bilirubin diglucuronide (BDG) to ↑ solubility
2) Active transport into bile canuli (as bile)

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22
Q

The flow of bile is _____ that of blood in the Liver?

A

opposite

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23
Q

What are the bilirubin/bilirubin diglucuronide-associated vessels in the Liver?

A

Afferent blood vessels:
- Hepatic artery (from heart)
- Hepatic portal vein (from GIT)

Efferent blood vessel
- Central vein (to heart)

Bile duct (to GIT)

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24
Q

________ bilirubin in _______ is transport to the GIT via _________.

A

Conjugated
Bile
Bile Duct

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25
Q

Bilirubin diglucuronide in bile is broken down via ___________ into ________ in the _____.

A

Bacterial action
Urobilinogen
Gut

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26
Q

What are the ways Urobilinogen can be excreted?

A

1) Oxidised in GIT → Stercobilin → brown stools
2) Re-enter circulation → Kidneys → Urobilin → yellow urine

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27
Q

What are the 3 broad classification of jaundice?

A

1) Prehepatic
2) Hepatic
3) Obstructive

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28
Q

When does prehepatic jaundice occur?

A

Excessive RBC breakdown (> Liver processing capacity ~3g/day)

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29
Q

What are some examples of conditions that can lead to prehepatic jaundice?

A

1) G6PD deficiency
2) Pyruvate kinase (PK) deficiency
3) Malaria

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30
Q

What are the biochemical parameters that indicate prehepatic jaundice?

A

1) ↑↑ unconjugated bilirubin
2) ↑ Urine urobilinogen
3) ↓ Haptoglobin (excess Hb binds to haptoglobin)

** normal conjugated bilirubin conc.**

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31
Q

What does Coffee-ground coloured urine indicate?

A

Severe prehepatic jaundice

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32
Q

When does hepatic jaundice occur?

A

Dysfunction in liver cells → defective metabolism/excretion
1) Reabsorption of urobilinogen → ↑urine urobilinogen

2) Transport conjugated bilirubin → ↓urine urobilinogen ↑conjugated bilirubin

3) Bilirubin conjugation → ↑unconjugated bilirubin

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33
Q

What are 2 examples of genetic bilirubin excretion/transport defects?

A

1) Dubin-Johnson syndrome
- MRP2 transporter mutation (for conjugated)
- black liver

2) Rotor syndrome
- SLCO1B1/B3 transporter mutation

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34
Q

What are the biochemical parameters that indicate bilirubin excretion/transport defects (hepatic jaundice)?

A

1) ↑ unconjugated bilirubin
2) ↑↑ conjugated bilirubin

(less excreted, more stuck)

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35
Q

What are at least 3 examples of bilirubin conjugation defects?

A

Genetic (UDP glucuronosyltransferase mutation):
1) Gilbert’s syndrome (AR, benign, 30% UGT activity)
2) Crigler-Najjar syndrome

Hormones/Drugs
1) Thyroxin
2) Estradiol/estrogen contraceptive

Physiological
1) Neonatal immaturity

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36
Q

What are the biochemical parameters that indicate bilirubin conjugation defects (hepatic jaundice)?

A

1) ↑↑ unconjugated bilirubin
2) ↓ conjugated bilirubin
3) ↓ urine urobilinogen
+ Pale stools (if severe)

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37
Q

What are some causes of mixed defects in hepatic jaundice?

A

1) Infection
2) Toxicity
3) Autoimmunity

38
Q

What are the 2 stages of mixed defect-caused hepatic jaundice?

A

Early and progressive

39
Q

In mixed-defect hepatic jaundice, there are defects in ___________ and ___________, leading to an initial __________________, followed by ___________ as it progresses and the defect in ___________ predominates.

A

Defects in reabsorption and transport

leading to an initial ↑conjugated bilirubin and ↑ urinary urobilinogen

followed by ↑unconjugated, ↑↑conjugated bilirubin, ↓urine urobilinogen, tea-coloured urine and pale stools as it progressed

defect in transport predominates

40
Q

What are some biochemical parameters that indicate hepatic jaundice? (other than bilirubin, urine or or stool analyses)

A

If liver dmg:
↑ release of liver enzymes
→ ↑ AST/ALT

If liver is functioning:
↓ factor prod. → ↑PT/PTT + ↓ albumin

41
Q

What are some causes of obstructive jaundice?

A

Anything that obstructs bile duct
1) Congenital (eg. cysts, atresia)
2) Acquired (eg. bile duct stones, carcinoma, infection)

42
Q

What are the biochemical parameters that indicate obstructive jaundice?

A

1) ↑unconjugated bilirubin (only later)
2) ↑↑ conjugated bilirubin
3) ↓↓ urine urobilinogen
4) ↑GGT/ALP (from release of biliary enzymes)
+ Tea coloured urine
+ pale stools

43
Q

Why does urine colour turn dark in prehepatic jaundice?

A

Excessive breakdown of Hb → excreted in urine → dark red/brown coffee colour

44
Q

Why does urine colour turn tea coloured in:
(i) late-stage mixed-defect hepatic jaundice
(ii) obstructive jaundice?

A

severe defect in excretion
→ accumulation of conjugated bilirubin
→ excreted in urine
→ dark tea colour

45
Q

Why does stool colour turn pale in:
(i) conjugation-defect hepatic jaundice
(ii) late-phase mixed-defect hepatic jaundice
(iii) Obstructive jaundice

A

defect in excretion
→ ↓ urobilinogen in gut
→ ↓ oxidised to stercobilin (brown/dark)
→ light coloured stools

46
Q

Why is neonatal jaundice common?

A

1) ↑RBC no./lysis
2) ↓ bilirubin conjugation (liver f(x))

47
Q

When can neonatal jaundice be pathological?

A

Overaccumulation of unconjugated bilirubin
→ cross immature BBB
→ kernicterus (neurological degeneration)

48
Q

What are some risk factors that predispose neonates to jaundice?

A

think anything that ↑RBC lysis or ↓conjugation/excretion
1) Blood grp incompatibility
2) G6PD deficiency
3) Prematurity
4) Low albumin
5) Race (chinese ↑risk due to UGT mutation: Gilbert’s syndrome ~40% in SG)

49
Q

What are 2 possible treatments for neonatal jaundice?

A

1) Blue light photo therapy
- insoluble Z,Z-bilirubin → soluble E,E-isomer → excrete in urine

2) Exchange transfusion
- rapidly ↓bilirubin

50
Q

Hemoglobin consists of 1 ____ group and ____ ______ subunits.

A

1 heme group
4 globin subunits

51
Q

What is the major form of hemoglobin in adults?

A

HbA: alpha2beta2

52
Q

What is the main form of hemoglobin in fetuses?

A

HbF: alpha2gamma2

53
Q

Hemoglobin is a _____ protein.

A

Tetrameric

54
Q

The conversion of hemoglobin to deoxyhemoglobin is ________ regulated.

A

Allosterically regulated

55
Q

Deoxyhemoglobin contains ________, which _______ its O2 binding affinity.

A

2,3-BPG, which decreases O2 binding capacity

56
Q

What are the 2 forms of alpha type globins?

A

Zeta and alpha

57
Q

What are the 4 forms of beta globlin?

A

1) Epsilon
2) Delta
3) Gamma
4) Beta

58
Q

There are ____ copies of alpha globin and _____copies of the beta globin gene.

A

2 alpha
1 beta

59
Q

What is the order of hemoglobin forms during development?

A

1) Hb Gower (low in embryo and fetal)
2) HbF (fetal)
3) HbA/A2 (adult)

60
Q

Thalassemia is a genetic disorder what follows______ inheritance pattern.

A

AR

61
Q

In Thalassemia, px have defects in globin synthesis resulting in _______ which leads to _____.This can cause:
1) _____ which leads to jaundice
2) ______ which leads to organ damage
3) ________ as a result of increased destruction and extramedullary hematopoiesis

A

Abnormal hemoglobin which leads to precipitation and hemolysis

1) increased heme: Jaundice
2) increased iron: organ damage
3) hepatosplenomegaly

62
Q

What genotype results in HbH disease?

A

only 1/4 normal copies of the alpha globin gene
(form of alpha thalassemia)

63
Q

What is the pathogenesis of alpha-thalassemia?

A

Since it is AR and alpha globin has 2 gene copies in the genome, px must have >2 defective alleles

defective alpha globin synthesis:
- decreased HbA (alpha2beta2)
- increased gamma4/beta4 (unstable) > precipitate > hemolysis

64
Q

What are the different possible genotype/phenotypic presentations for alpha-thalassemia?

A

1) Normal (all 4 alleles normal)
2) Carrier (1 allele affected)
3) Mild symptoms (2 alleles affected)
4) Severe (>2 alleles affected)

(alpha globin has 2 copies of genes)

65
Q

What is the pathogenesis of Beta-thalassemia?

A

> /= 1 defective gene
defective beta globin synthesis:
- decreased HbA (alpha2beta2)
- increased alpha2delta2/HbF (alpha2gamma2) (stlll stable and usable)
- *alpha4 (unstable) > precipitate > hemolysis

66
Q

What are the different possible genotype/phenotypic presentations for beta-thalassemia?

A

1) Normal
2) Mild (1 defective allele)
3) Severe (2 defective alleles)

67
Q

What are the similarities and differences between alpha and beta-thalassemia?

A

Similarities:
1) both result in hemolysis, jaundice, organ damage, hepatosplenomegaly
2) both have AR inheritance pattern

Differences:
1) alpha > fatal if all defective
2) carrier in alpha can be asymptomatic
3) unstable chain (alpha: beta4, gamma4; beta: alpha4)
4) HbH disease only for alpha

68
Q

Why is Iron toxic?

A

It produces ROS (requires glutathione to breakdown)

69
Q

What are the two forms iron exist in in the body and their respective charges?

A

1) Ferrous (2+)
2) Ferric (3+)
(thRICe = ferRIC)

70
Q

What are the 2 main functions of iron in the body?

A

1) molecular oxygen carrier (heme)
2) e- carrier (ferrous oxidised to release-)

71
Q

Where is most iron stored in the body?

A

Liver

72
Q

How does the absorption of iron differ between heme and non-heme sources?

A

Heme: directly absorbed by small intestine then broken down to ferrous form

Non-heme:
1) ligand removed in stomach by low pH
2) converted to ferrous form by ferric reductase
3) transported into small intestine by DMT-1 on brush border

73
Q

Can ferric ions by absorbed by the small intestine by DMT-1?

A

No

74
Q

How does iron enter circulation after absorption by the small intestine?

A

1) Hephaestin oxidises ferrous into ferric for transport into bloodstream by Ferroportin on Basal membrane
2) Ferric ion forms complex with transferrin and circulates in bloodstream

75
Q

How is ferric iron in circulation stored in cells?

A

1) Fe3+-transferrin complex taken up by cells via transferrin receptor
2) Acidification in endosomes release Ferric ions into cytosol
3) Transferrin receptor recycled
4) Fe stored as Ferritin (mobilisable) or Hemosiderin (excess, normally in macrophages)

76
Q

What are the 2 forms of stored iron in cells?

A

Ferritin: readily mobilisable
Hemosiderin: less accessible, usually in macrophages

77
Q

What is the biochemical parameter used to assess the body´s iron stores?

A

Plasma ferritin levels

78
Q

Is elevated plasma ferritin levels indicative of excess iron stores?

A

Not necessarily, it can also be elevated in chronic inflammation

79
Q

How is excess iron actively eliminated from the body?

A

It cant

80
Q

How is iron homeostasis controlled?

A

1) Uptake of dietary Fe by small intestine
2) Uptake of plasma Fe by Liver

81
Q

How does the body respond to low Fe levels?

A

Transporters increase:
1) DMT-1 on brush border
2) Ferroportin on luminal surface
3) Transferrin receptors at target sites

82
Q

How does the body respond to high Fe levels?

A

Transporters decrease
1) DMT-1 at brush border
2) Ferroportin at luminal surface by increased Hepcidin
3) Transferrin receptors at target sites

83
Q

What kind of anemia is caused by iron deficiency?

A

Hypochromic microcytic anemia

84
Q

What can be used px with high iron levels?

A

Chelators

(excreted in urine: vin de rose)

85
Q

What biochemical parameter is correlated with total transferrin?

A

Total Iron Binding Capacity (TIBC)

86
Q

How is transferrin saturation calculated?

A

Plasma iron (bound to transferrin)/TIBC

87
Q

What are the biochemical parameters associated with Fe deficiency?

A

1) Decreased Plasma iron
2) Decreased Transferrin saturation
3) Decreased Ferritin (can still increase with chronic inflammation)

88
Q

What are some causes of Fe deficiency?

A

1) Diet
2) Increased Dd (eg.pregnancy)
3) Increased loss (eg. excessive bleeding)

89
Q

What are the biochemical parameters associated with Fe excess/overdose?

A

1) Increased plasma iron
2) Increased transferrin saturation
3) Increased ferritin

90
Q

What are some possible causes of Fe overdose/excess?

A

1) Increased breakdown (eg.toxins, transfursion rxn, thalassemia)
2) Increased uptake (eg. supplements, hemochromatosis)

91
Q

What are some presentations in px with acute Fe overdose?

A

1) Local (GIT)
- Nausea/vomiting
- Diarrhoea
- GI bleeding

2) Systemic
- Oxidative damage
- Heart failure

Haematology (9 decks)

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