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2.2 Haematology > Red Cell Metabolism and Enzyme Deficiencies > Flashcards

Red Cell Metabolism and Enzyme Deficiencies Flashcards

1
Q

Write about red cell metabolism

A

RBCs contain no mitochondria so they cannot carry out respiration, no citric acid cycle, no oxidation of fatty acids or ketone bodies

Energy in the form of ATP is obtained only from the glycolytic breakdown of glucose with the production of lactate (anaerobic glycolysis)

ATP produced is being used for keeping the biconcave shape of RBCs and in the regulation of transport of ions and water in and out of the red blood cells

Three areas of RBC metabolism are crucial for RBC survival and function:
- RBC membrane
- Haemoglobin structure and function
- RBC metabolic pathways = cellular energy

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2
Q

How does the RBC obtain ATP

A

Energy in the form of ATP is obtained only from the glycolytic breakdown of glucose with the production of lactate (anaerobic glycolysis)

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3
Q

What does the RBC do with the ATP produced

A

ATP produced is being used for keeping the biconcave shape of RBCs and in the regulation of transport of ions and water in and out of the red blood cells

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4
Q

What three areas of RBC metabolism are crucial for RBC survival

A
  • RBC membrane
  • Haemoglobin structure and function
  • RBC metabolic pathways = cellular energy
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5
Q

What are the functions of ATP in RBCs

A

Protection against oxidative stress

Initiation of glycolysis

Glutathione synthesis

Reduction of haem iron to ferrous form

Na/K exchanger

Red Cell Biconcave shape

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6
Q

What are some requirements of the red cell

A

Must be able to pass repeatedly through the microcirculation in order to carry Hb into close contact with tissues and for successful gaseous exchange

The RBCs total journey throughout its 120 day lifespan has been estimated to be 480km

Hb must be maintained in a reduced (ferrous) state

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7
Q

Write about the biconcave feature of red blood cells
(3)

A

Flexible

With an ability to generate energy as ATP by an anaerobic glycolytic pathways (anaerobic glycolysis) and to generate reducing power as NADH by this pathway

Generates energy as reduced NADH by the Pentose Phosphate pathway

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8
Q

What are the two main metabolic pathways in the mature RBC

A
  1. Anaerobic glycolysis (90%)
  2. Pentose Phosphate Pathway (10%)
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9
Q

What are the main metabolic intermediates of anaerobic glycolysis

A

ATP: the main energy compound of the RBC

NADH: an essential reducing agent cofactor

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10
Q

What are the main metabolic intermediate of the pentose phosphate pathway

A

Reduced NADPH

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11
Q

Write about anaerobic glycolysis

A

The pathway consists of a highly complex series of metabolic reactions whereby energy (in the form of ATP, NADH and NADPH) is generated from glucose

An early step in this pathway is the generation of glucose-6-phosphate

Most of the glucose-6-phosphate proceeds along the glycolytic pathway to form two molecules of glyceraldehyde-3-phosphate

For each molecule of glucose used, two molecules of ATP and thus two high-energy phosphate bonds are generated

10% of the G6P is diverted to a sub-pathway, the pentose phosphate pathway, where an atom of hydrogen is transferred to NADP, to generate the hydrogen carrier NADPH

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12
Q

What happens to 90% of the G6P in anaerobic glycolysis?

A

It proceeds along the glycolytic pathway to form two molecules of glyceraldehyde-3-phosphate

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13
Q

What does the RBC do with the ATP produced in anaerobic glycolysis

A

ATP provides energy for RC volume, shape and flexibility

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14
Q

What happens to 10% of the G6P in anaerobic glycolysis

A

10% is diverted to the pentose-phosphate pathway

Here an atom of hydrogen is transferred to NADP to generate the hydrogen carrier NADPH

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15
Q

What three energy molecules are produced by anaerobic glycolysis

A

ATP
NADH
NADPH

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16
Q

What is the methemoglobin reductase pathway
(3)

A

Anaerobic glycolysis produces NADH which is used in the methemoglobin reductase pathway

NADH is used to reduce functionally dead methaemoglobin (oxidised Hb) containing ferric iron to functionally active, reduced Hb

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17
Q

What is methaemoglobin

A

Oxidised Hb

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18
Q

How is ferric iron produced

A

Produced by oxidation of approximately 3% of Hb each day

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19
Q

What is the function of the methemoglobin reductase pathway?

A

Maintains iron in the ferrous state (Fe+++)

In the absence of the enzyme (methemoglobin reductase), methemoglobin accumulates and it cannot carry oxygen

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20
Q

What is 2,3-DPG

A

2, 3-diphosphoglycerate

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21
Q

What does 2,3-DPG do

A

Competes for oxygen for binding to Hb, in lung and tissue

It decreases affinity of Hb for oxygen so it helps oxyhaemoglobin to unload oxygen

Storing blood results in a decrease of 2,3-DPG leading to high oxygen affinity Hb. This leads to oxygen trap

6-24 hours are needed to restore the depleted 2,3 DPG

Maximum storage time for RBC’s is 21-42 days

In people with high-altitude adaptation or smokers the concentration of 2,3-DPG in the blood is increased (low oxygen supply)

Foetal Hb has a low DPG affinity: the higher the O2 affinity facilitates the transfer of O2 to the foetus via the placenta

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22
Q

When is increased DPG concentration seen

A

High-altitude adaptation

smokers

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23
Q

What form of Hb has a low affinity for DPG and why

A

Foetal Hb

The higher O2 affinity facilitates the transfer of O2 to the foetus via the placenta

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24
Q

Write about the Pentose Phosphate Pathway
(7)

A

Approximately 10% of glucose metabolism occurs by this oxidative pathway in which G6P is converted to ribulose-5-phosphatase

NADPH is the main intermediate of the pathway and is required for the reduction of glutathione

Reduced glutathione is essential for the protection of Hb and for the reduction of cellular intermediates that can cause cellular damage

This pathway protects the RBC from oxidative injury

This pathway can be increased up to 30% in times of oxidant stress

Oxidant stress can arise due to natural metabolism or can be drug induced. It can cause damage to Hb, membrane proteins and intracellular enzymes

If the pathway is deficient, intracellular oxidants can’t be neutralised and globin denatures and then precipitates. The precipitates are referred to as Heinz bodies

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25
Q

What happens to G6P in the pentose phosphate pathway

A

Approximately 10% of glucose metabolism occurs by this oxidative pathway in which G6P is converted to ribulose-5-phosphatase

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26
Q

What is the main intermediate in the pentose phosphate pathway?

A

NADPH is the main intermediate of the pathway and is required for the reduction of glutathione

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27
Q

What is reduced glutathione essential for
(2)

A

The protection of Hb and for the reduction of cellular intermediates that can cause cellular damage

This pathway protects the RBC from oxidative injury

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28
Q

What happens to the pentose phosphate pathway in times of oxidant stress

A

This pathway can be increased up to 30% in times of oxidant stress

29
Q

What might cause oxidative stress

A

Oxidant stress can arise due to natural metabolism or can be drug induced. It can cause damage to Hb, membrane proteins and intracellular enzymes

30
Q

What happens if the pentose phosphate pathway is deficient

A

If the pathway is deficient, intracellular oxidants can’t be neutralised and globin denatures and then precipitates.

The precipitates are referred to as Heinz bodies

31
Q

What can cause oxidant stress

A

Favism - fava beans
Drugs
Infection

32
Q

What does oxidative stress do
(4)

A

Damages cell components e.g. haemoglobin and lipids

Heinz bodies start to precipitate

Permeability of RC membrane and deformability reduced

Damaged RC removed by extravascular haemolysis

33
Q

Write about the history of enzyme deficiencies
(4)

A

Haemolysis first noted in plantation workers who received anti-malarial drugs (quinine)

Anaemias were originally called hereditary non-spherocytic haemolytic anaemia

The patients were seen not to contain abnormal haemoglobin, the antiglobulin test was negative and the osmotic fragility test was normal

They were later identified to have arisen due to enzyme deficiencies in the RBC

34
Q

What are the two main enzyme defects

A

PK deficiency
G6PD deficiency

35
Q

What is PK deficiency

A

Deficiencies in glycolytic pathway which results in shortened red cell survival and chronic haemolytic anaemia

36
Q

What is G6PD deficiency

A

Defects in PPP are associated with periodic acute haemolytic episodes due to oxidant stress (drugs, chemicals or infections)

37
Q

Define G6PD

A

A genetic disorder that affects red blood cells and may contribute to anaemia

The sever form is called favism which causes more symptoms and poses more risks than other types of G6P deficiency

38
Q

What are the signs and symptoms of G6PD

A

Yellow of the eyes
Confusion and difficulty concentrating
Higher risk for enlarged spleen
Sudden rise in blood temperature
Rapid heart rate
Darker urine colour
Fatigue and weakness

39
Q

Write about G6PD Deficiency (PPP)

A

Most common enzyme defect

Found worldwide but high prevalence in central Africa, southern Europe, Indian subcontinent the Middle East and SE Asia

X linked -> more prevalent in males

Confers a relative resistance against plasmodium falciparum

400 variants

Majority of variants function normally and are differentiated by the electrophoretic mobility

40
Q

Write about the pathology associated with G6PD Deficiency

A

GP6D deficiency renders the RC susceptible to oxidant stress

Over 50 mutations identified - nearly all point mutations

Deficiency account for over 90% of haemolytic anaemia due to enzyme deficiency

G6PD is a rate limiting step in the PPP

G6PD is responsible for removing the hydrogen from its substrate G6P and the eventual production of the crucial antioxidant glutathione (GSH)

41
Q

What are the functions of G6PD

A

G6PD is a rate limiting step in the PPP

G6PD is responsible for removing the hydrogen from its substrate G6P and the eventual production of the crucial antioxidant glutathione (GSH)

42
Q

How is G6PD deficiency classified

A

I
II
III
IV
V

43
Q

Write about class I G6PD deficiency

A

Most severe
Less than 1% enzyme activity
Cant deal with any oxidative stress
Chronic haemolytic anaemia

44
Q

Write about class II G6PD

A

Less than 10% activity
Acute haemolytic anaemia (fava bean and drug-dependent)

45
Q

Write about class III G6PD deficiency

A

Between 10 and 60% activity
Occasional acute haemolytic anaemia
Very frequent in malaria areas -> coverage from malaria with minimal symptoms

46
Q

Write about class IV G6PD deficiency

A

Between 60 and 90% activity
Asymptomatic

47
Q

Write about class V deficiency

A

> 110% increased activity
Asymptomatic

48
Q

What are the clinical presentations of G6PD
(3)

A

Acute haemolytic anaemia -> majority are asymptomatic but will develop acute haemolytic anaemia if exposed to oxidative stress

Neonatal jaundice -> higher risk in G6PD patients than in normal newborns due to reduced liver activity

Chronic non spherocytic haemolytic anaemia -> can be seen in G6PD patients when stimulated by factors that cause acute haemolytic anaemia

49
Q

What is the laboratory diagnosis for G6PD deficiency

A

Hb low
MCV normal, MCH normal
Bite cells (very characteristic of G6PDD)
Hemighosts
Polychromasia
NRBC
Reticulocytes high
Heinz bodies
Haemoglobinuria
Haptoglobin low
LDH and bilirubin high

50
Q

What test do we carry out to investigate G6PDD

A

Heinz body stains - precipitates of oxidatively denatured Hb stained by crystal violet or methylene blue

MetHb reduction test

A fluorescent spot screening test
G6PD enzyme assay

DNA analysis

51
Q

What is the MetHb reduction test

A

Where G6PD erythrocytes fail to reduce metHb in the presence of methylene blue

52
Q

What is the fluorescent spot screening test

A

G6P, NADP are mixed with the patients blood and spotted onto filter paper

G6PD should reduce the NADP to NADPH and fluorescence will occur on the conversion of NADP to NADPH

53
Q

Write about controls and EQA for G6PD

A

2 samples received bi-monthly from UK NEQAs

G6PD control normal, control deficient and control intermediate

Controls ran alongside each test (2 tests)

54
Q

What morphology is associated with G6PD deficiency

A

Blood film with bite cells
Heinz bodies
Hemighosts or bull’s eye cells

55
Q

How is G6PD treated

A

Offending drug is stopped

Any underlying infection is treated

A high urine output is maintained

Blood transfusion is undertaken where necessary for sever anaemia

G6PD-deficient babies are prone to neonatal jaundice and in severe cases phototherapy and exchange transfusion may be needed

The jaundice is usually not caused by excess haemolysis but by deficiency of G6PD affecting neonatal liver function

Splenectomy if severe

56
Q

Write about G6PD and plasmodium vivax

A

Treatment of plasmodium vivax with primaquine poses a potential risk of mild to severe acute haemolytic anaemia in G6PD deficient people

There remains a lack of consensus on the requirement for G6PD deficiency testing before prescribing primaquine radical cure regimens

57
Q

Write about anaerobic glycolysis deficiencies

A

Deficiency of any of the enzymes involved results in haemolysis due to:
- reduced levels of ATP and NADH
- accumulation of intermediate substrates including 2,3-DPG and MetHb

58
Q

What are the 7 main enzymes that cause anaerobic glycolysis deficiency

A

Pyruvate kinase (most common)
G6P isomerase (next most common)
Glyceraldehyde-3-phosphate-dehydrogenase
Phosphofructokinase
Triose phosphate isomerase
Hexokinase deficiency (very rare)
Methaemoglobin reductase

59
Q

Write about pyruvate kinase deficiency

A

Most significant defect of anaerobic glycolysis

About 20 different mutations causing haemolytic anaemia

Inherited as an autosomal recessive condition

Worldwide in distribution

Severity of the haemolytic episodes varies from mild to severe depending on the properties of the mutant enzymes

60
Q

What are some features of pyruvate kinase deficiency?
(4)

A

Severe neonatal jaundice and anaemia

Severe CNSHA requiring repeated transfusions

Moderate haemolysis with exacerbation during infection or pregnancy

Symptomless compensated haemolysis with only a minor apparent anaemia

61
Q

Write about the pathogenesis of PK deficiency

A

A reduction of ATP and decrease in NADH

Extravascular haemolysis occurs mostly but intravascular haemolysis may occur under oxidative stress

PK deficiency causes an increase in 2, 3 DPG, this causes a decrease in oxygen affinity, due to a shift in the oxygen association curve to the right, and results in increased oxygen delivery to the tissues

This results in more efficient use of oxygen at a lower haemoglobin level

The reticulocyte count may be moderately raised

62
Q

Write about the epidemiology of pyruvate kinase deficiency
(3)

A

Occurs worldwide but most cases have been reported in northern Europe, Japan and the USA. Many cases are found in the Amish population of Pennsylvania

The prevalence is estimated at 51 cases per million by gene frequency studies but the observed prevalence in one northern england region was found to be 3.3 cases per million

Family history consistent with autosomal recessive inheritance. More than 150 different causative mutations have been identified

63
Q

How is PK Deficiency Treated

A

Treatment is supportive in mild-to-moderate cases, some transfusion-dependent patients have benefited from splenectomy but haemolysis still occurs.
BMT has been successful

64
Q

What are the laboratory findings for PK deficiency

A

Hb low

MCV normal and MCH normal

Echinocytes

Polychromasia

NRBCs

Reticulocytes

LDH and bilirubin up

Haptoglobin down

65
Q

How do we test for Pyruvate kinase deficiency?

A

Fluorescence screening test

PK enzyme assay

DNA analysis

66
Q

What is the fluorescence screening test

A

In PK deficiency the fluorescence will persist beyond 30 minutes

67
Q

How is PK deficiency treated?
(6)

A

Blood tranfusion

Folic acid supplements

Phototherapy and or change transfusion

Chelation therapy

Splenectomy

Partial splenectomy

68
Q

Why is splenectomy rarely done for PK deficiency

A

Risk of thromboembolic disease post splenectomy

Some patients developed splenic and portal vein thrombosis

69
Q

How long did it take a BM transplant patient to be cured of PKD

A

Took 3 year for PK levels to return to normal

2.2 Haematology (38 decks)

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