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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
Bilirubin diglucuronide in bile is broken down via ___________ into ________ in the _____.
Bacterial action Urobilinogen Gut
26
What are the ways Urobilinogen can be excreted?
1) Oxidised in GIT → Stercobilin → brown stools 2) Re-enter circulation → Kidneys → Urobilin → yellow urine
27
What are the 3 broad classification of jaundice?
1) Prehepatic 2) Hepatic 3) Obstructive
28
When does prehepatic jaundice occur?
Excessive RBC breakdown (> Liver processing capacity ~3g/day)
29
What are some examples of conditions that can lead to prehepatic jaundice?
1) G6PD deficiency 2) Pyruvate kinase (PK) deficiency 3) Malaria
30
What are the biochemical parameters that indicate prehepatic jaundice?
1) ↑↑ unconjugated bilirubin 2) ↑ Urine urobilinogen 3) ↓ Haptoglobin (excess Hb binds to haptoglobin) ## Footnote ** normal conjugated bilirubin conc.**
31
What does Coffee-ground coloured urine indicate?
Severe prehepatic jaundice
32
When does hepatic jaundice occur?
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
33
What are 2 examples of genetic bilirubin excretion/transport defects?
1) Dubin-Johnson syndrome - MRP2 transporter mutation (for conjugated) - black liver 2) Rotor syndrome - SLCO1B1/B3 transporter mutation
34
What are the biochemical parameters that indicate bilirubin excretion/transport defects (hepatic jaundice)?
1) ↑ unconjugated bilirubin 2) ↑↑ conjugated bilirubin (less excreted, more stuck)
35
What are at least 3 examples of bilirubin conjugation defects?
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
36
What are the biochemical parameters that indicate bilirubin conjugation defects (hepatic jaundice)?
1) ↑↑ unconjugated bilirubin 2) ↓ conjugated bilirubin 3) ↓ urine urobilinogen + Pale stools (if severe)
37
What are some causes of mixed defects in hepatic jaundice?
1) Infection 2) Toxicity 3) Autoimmunity
38
What are the 2 stages of mixed defect-caused hepatic jaundice?
Early and progressive
39
In mixed-defect hepatic jaundice, there are defects in ___________ and ___________, leading to an initial __________________, followed by ___________ as it progresses and the defect in ___________ predominates.
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
What are some biochemical parameters that indicate hepatic jaundice? (other than bilirubin, urine or or stool analyses)
If liver dmg: ↑ release of liver enzymes → ↑ AST/ALT If liver is functioning: ↓ factor prod. → ↑PT/PTT + ↓ albumin
41
What are some causes of obstructive jaundice?
Anything that obstructs bile duct 1) Congenital (eg. cysts, atresia) 2) Acquired (eg. bile duct stones, carcinoma, infection)
42
What are the biochemical parameters that indicate obstructive jaundice?
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
Why does urine colour turn dark in prehepatic jaundice?
Excessive breakdown of Hb → excreted in urine → dark red/brown coffee colour
44
Why does urine colour turn tea coloured in: (i) late-stage mixed-defect hepatic jaundice (ii) obstructive jaundice?
severe defect in excretion → accumulation of conjugated bilirubin → excreted in urine → dark tea colour
45
Why does stool colour turn pale in: (i) conjugation-defect hepatic jaundice (ii) late-phase mixed-defect hepatic jaundice (iii) Obstructive jaundice
defect in excretion → ↓ urobilinogen in gut → ↓ oxidised to stercobilin (brown/dark) → light coloured stools
46
Why is neonatal jaundice common?
1) ↑RBC no./lysis 2) ↓ bilirubin conjugation (liver f(x))
47
When can neonatal jaundice be pathological?
Overaccumulation of unconjugated bilirubin → cross immature BBB → kernicterus (neurological degeneration)
48
What are some risk factors that predispose neonates to jaundice?
*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
What are 2 possible treatments for neonatal jaundice?
1) Blue light photo therapy - insoluble Z,Z-bilirubin → soluble E,E-isomer → excrete in urine 2) Exchange transfusion - rapidly ↓bilirubin
50
Hemoglobin consists of 1 ____ group and ____ ______ subunits.
1 heme group 4 globin subunits
51
What is the major form of hemoglobin in adults?
HbA: alpha2beta2
52
What is the main form of hemoglobin in fetuses?
HbF: alpha2gamma2
53
Hemoglobin is a _____ protein.
Tetrameric
54
The conversion of hemoglobin to deoxyhemoglobin is ________ regulated.
Allosterically regulated
55
Deoxyhemoglobin contains ________, which _______ its O2 binding affinity.
2,3-BPG, which decreases O2 binding capacity
56
What are the 2 forms of alpha type globins?
Zeta and alpha
57
What are the 4 forms of beta globlin?
1) Epsilon 2) Delta 3) Gamma 4) Beta
58
There are ____ copies of alpha globin and _____copies of the beta globin gene.
2 alpha 1 beta
59
What is the order of hemoglobin forms during development?
1) Hb Gower (low in embryo and fetal) 2) HbF (fetal) 3) HbA/A2 (adult)
60
Thalassemia is a genetic disorder what follows______ inheritance pattern.
AR
61
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
Abnormal hemoglobin which leads to precipitation and hemolysis 1) increased heme: Jaundice 2) increased iron: organ damage 3) hepatosplenomegaly
62
What genotype results in HbH disease?
only 1/4 normal copies of the alpha globin gene (form of alpha thalassemia)
63
What is the pathogenesis of alpha-thalassemia?
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
What are the different possible genotype/phenotypic presentations for alpha-thalassemia?
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
What is the pathogenesis of Beta-thalassemia?
>/= 1 defective gene *defective beta globin synthesis*: - decreased HbA (alpha2beta2) - increased alpha2delta2/HbF (alpha2gamma2) (stlll stable and usable) - *alpha4 (unstable) > precipitate > hemolysis
66
What are the different possible genotype/phenotypic presentations for beta-thalassemia?
1) Normal 2) Mild (1 defective allele) 3) Severe (2 defective alleles)
67
What are the similarities and differences between alpha and beta-thalassemia?
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
Why is Iron toxic?
It produces ROS (requires glutathione to breakdown)
69
What are the two forms iron exist in in the body and their respective charges?
1) Ferrous (2+) 2) Ferric (3+) (thRICe = ferRIC)
70
What are the 2 main functions of iron in the body?
1) molecular oxygen carrier (heme) 2) e- carrier (ferrous oxidised to release-)
71
Where is most iron stored in the body?
Liver
72
How does the absorption of iron differ between heme and non-heme sources?
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
Can ferric ions by absorbed by the small intestine by DMT-1?
No
74
How does iron enter circulation after absorption by the small intestine?
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
How is ferric iron in circulation stored in cells?
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
What are the 2 forms of stored iron in cells?
Ferritin: readily mobilisable Hemosiderin: less accessible, usually in macrophages
77
What is the biochemical parameter used to assess the body´s iron stores?
Plasma ferritin levels
78
Is elevated plasma ferritin levels indicative of excess iron stores?
Not necessarily, it can also be elevated in chronic inflammation
79
How is excess iron actively eliminated from the body?
It cant
80
How is iron homeostasis controlled?
1) Uptake of dietary Fe by small intestine 2) Uptake of plasma Fe by Liver
81
How does the body respond to low Fe levels?
Transporters increase: 1) DMT-1 on brush border 2) Ferroportin on luminal surface 3) Transferrin receptors at target sites
82
How does the body respond to high Fe levels?
Transporters decrease 1) DMT-1 at brush border 2) Ferroportin at luminal surface by increased Hepcidin 3) Transferrin receptors at target sites
83
What kind of anemia is caused by iron deficiency?
Hypochromic microcytic anemia
84
What can be used px with high iron levels?
Chelators (excreted in urine: vin de rose)
85
What biochemical parameter is correlated with total transferrin?
Total Iron Binding Capacity (TIBC)
86
How is transferrin saturation calculated?
Plasma iron (bound to transferrin)/TIBC
87
What are the biochemical parameters associated with Fe deficiency?
1) Decreased Plasma iron 2) Decreased Transferrin saturation 3) Decreased Ferritin (can still increase with chronic inflammation)
88
What are some causes of Fe deficiency?
1) Diet 2) Increased Dd (eg.pregnancy) 3) Increased loss (eg. excessive bleeding)
89
What are the biochemical parameters associated with Fe excess/overdose?
1) Increased plasma iron 2) Increased transferrin saturation 3) Increased ferritin
90
What are some possible causes of Fe overdose/excess?
1) Increased breakdown (eg.toxins, transfursion rxn, thalassemia) 2) Increased uptake (eg. supplements, hemochromatosis)
91
What are some presentations in px with acute Fe overdose?
1) Local (GIT) - Nausea/vomiting - Diarrhoea - GI bleeding 2) Systemic - Oxidative damage - Heart failure

Haematology (9 decks)

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