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Y1 TP2 Metabolism, Endocrinolo, Haemotology > 4. Glycogen Storage And Hypoglycaemia > Flashcards

4. Glycogen Storage And Hypoglycaemia Flashcards

1
Q

What is anaemia?

A

—> haemoglobin (Hb) concentration lower than the normal (age, sex and ethnicity vary normal range)
Anaemia is a manifestation of an underlyinng disease – find cause and mechanisms of anemia

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2
Q

anaemia symptoms

A
  • Yellowing of eyes – jaundic effect
    • Paleness
    • Coldness
    • Yellow skin tinge
    • Shortness of breath
    • Muscular weakness
    • Changed stool colour
    • Fatigue
    • Dizziness
    • Fainting
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3
Q

Anaemia effects on body

A
  • Palpitations
    • Low bp
    • Rapid heart rate
    • Spleen enalrgement
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4
Q

3 Body mechanisms to compensate for anaemia

A

Body tries to adjust to lower haemoglobin

* Increase Concentration of 2,3 Biophosphoglycerate in erythrocytes (red blood cells) to promote oxygen dissociation 
* Increase Cardiac stroke volume and tachycardia
* Increase  Blood volume to tissues
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5
Q

Development of anaemia

A
  • Anaemia develops slowly, body tries to adapt

* As haemoglobin concentration decreases (Hb) = chronic- mild symptoms

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6
Q

3 causes of anaemia

A

Bone marrow
Peripheral RBC
Removal

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7
Q

2 ways bone marrow can cause anaemia

A
  • Abnormal Erythropoiesis - rbc formation

* Abnormal haemoglobin synthesis

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8
Q

3 ways peripheral rbc can cause anaemia

A
  • Abnormal function (due to high 2,3 BPG)
    • Abnormal structure (damage in bloodstream)
    • Abnormal metabolism (not broken down properly)
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9
Q

2 ways removal of rbc can cause anaemia

A
  • Excessive blood loss

* Abnormal function of reticuloendothelial system – increase rbc removal

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10
Q

Causes Abnormal erytthropoiessis

A

• Exposure of the bone marrow to: Benzene, ionising radiation Infection with parvovirus Autoimmunity

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11
Q

Pancytopenia

A

•reduced red, white blood cells and platelets (anaemia, leucopoenia and thrombocytopenia). Occurs when there is a problem with blood-forming stem cells in bone marrow

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12
Q

Aplastic anaemia

A

inability of haematopoietic stem cells to generate mature blood cells

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13
Q

2 examples of abnormal erythropoiesis

A

Pancytopenia

Aplastic anaemia

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14
Q

Causes of abnormal haemoglobin synthesis

A
  • Iron deficiency anaemia: iron supply is inadequate for Hb production
  • Anaemia of chronic disease: results in a functional loss of iron limiting haemoglobin synthesis
  • Globin gene mutation:
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15
Q

2 gene globin mutations

A

– Sickle cell disease (alter function of haemoglobin molecule)
– Thalassaemia (alter the amount of haemoglobin produced)

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16
Q

Rbc life cycle stages

A
  1. RBC goes to spleen
    1. Macrophages in spleen – engulf rbc (old and damaged)
    2. Rbc broken into components to be excreted or reused
      • Globin = broken to amino aicds and reused
      • Haem – biliverdin –> bilirubin
      • Iron – 3+ iron from haem is bound to transferrin to be carried to liver
    3. Liver
      • Bilirubin can be reused or excreted (via kidney or small intestine)
      • Iron can either be stored in ferritin or hemosiderin (iron stores)
    4. Iron can be transported by transferrin back to bone – where rbc are made
      • Iron 3+, globin, vitamin b12 and erythropoietin can be used to make rbc in bone marrow
    5. RBC released back into circulation for at least 120 days
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17
Q

How long do rbc exist in circulation

A

Approx. 120 days

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18
Q

Breakdown products of rbc

A
  • Globin = broken to amino aicds
    • Haem – biliverdin –> bilirubin
    • Iron – 3+ iron from haem is bound to transferrin to be carried to liver
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19
Q

How is anaemia classified

A

—-> commonly classified according to the effect the underlying condition has on the average size of red blood cells

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20
Q

3 classifications of andiemicandemia

A
  • Macrocytic – causes large rbc
    • Microcytic – casues small rbc
    • Normocytic – average rbc size, but mutations may cuase reduction of haemoglobin
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21
Q

Macrocytic anaemia

A
  • B12 or folate deficiency
  • chronic liver disease
  • Alcohol
  • haemolytic anaemias

Form large cells

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22
Q

Microcytic ancremia anaemia

A
  • Iron deficiency
  • anemia of chronic diseases
  • thalassemias

From small rbc

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23
Q

Normocytic anaemia

A

Form avergae rbc size, but mutations may cuase reduction of haemoglobin

  • sickle cell disease
  • early iron deficiency
  • blood loss
  • anaemia of chronic diseases
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24
Q

2 molecules required for dna synthesis

A

• Vitamin B12 (Cobalmin) and folate (vitamin B9) are required for DNA synthesis.

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25
Q

Megaloblastic anaemia definition.

A

Bone marrow produces unusually large, structurally abnormal immature rbc (retinaculocytes)

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26
Q

Megaloblastic anaemia cause

A

• Vitamin B12 (Cobalmin) and folate (vitamin B9) Deficiency leads to megaloblastic anaemia due to an inability of red cells precursor cells to synthesise DNA and therefore to divide

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27
Q

Cells produced in Megaloblastic anaemia

A

– large (‘mega’) red cell precursors are released into bloodstream with large nuclei and open chromatin – macrocytic erythrocyte – big blood cell
– ovalocytes – oval rbc
○ Have less rbcs as you don’t have enough things to produce them – but in response to this bone marrow pushes out rbc earlier than they should be (with large nuclei and chromatin) - not matured

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28
Q

Symptoms of megaloblastic anaemia

A
  • “Lemon yellow” skin and angular glossitus

* ‘‘Beefy” red tongue – not enough things required for cell turnover

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29
Q

Macrocytosis definition

A

—> It is an increase in the mean red cell volume to above the normal range (greater than 100 femto litres)

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30
Q

Causes of macrocytic anciemia

A
  • Megaloblastic anaemia
  • Drugs (antimetabolites, such as hydroxycarbamide, methotrexate, and azathioprim)
    • Don’t give folic acid with methotrexate as it can block folic acid action
  • Pregnancy and the neonatal period
  • Severe thyroid deficiency (hypothyroidism)
  • Smoking
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31
Q

b12 deficiency symptoms

A
  • can be physical or mental
    • Weak muscles, numb/tingling feeling in hands and feet, nausea, decreased appetite, weight loss, irritability, fatigue, diarrhoea, smooth and tender tongue, fast heart rate
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32
Q

Sources of b12

A

B12 - is only found in aminal products

• Some foods are fortified with vit B- possible to take supplements

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33
Q

Absorption of B12

A
  1. Either ingested as free B12 or as a complex
    1. B12 released from proteins by proteases first form a complex with proteins called haptocorrins (R-binder)
      • B12 is very sensitive to hydrochloric acid in stomach so it binds to haptocorrins – to help it pass through stomach
    2. B12 haptocorrin complex passes through stomach is digested by pancreatic proteases in the small intestine releasing the B12
    3. B12 is sensitive so it binds to a glycoprotein called intrinsic factor produced by cells
      • A deficiency in intrinsic factor results in pernicious anaemia- a lack of vit B12 absorption
      ○ If cells aren’t producing intrinsic factor
      ○ Or part of the gut producing intrinsic factor has been removed
    4. Once internalised B12 forms a complex with transcobalmin and is released in blood for various tissues
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34
Q

Vitamin B12 deficiency more often results in:

A

– a reversible peripheral neuropathy
– subacute combined degeneration of the cord (degeneration of the posterior and lateral columns of the spinal cord), weakness numbness and tingling in legs, arms and trunk, change in mental status and irreversible nervous system damage if you don’t treat in time

35
Q

Functions of B12

A
    1. The brain and central nervous system as it helps with the formation of myelin.
      * To create DNA
    • Needed for healthy red blood cell formation
    • Vitamin B12 also helps with digestion
    • Heart health; a vitamin B12 deficiency can lead to an increased risk for heart disease.
    • Liver takes up about half of the dietary B12 and acts as a store of this vitamin. Liver can supply B12 requirements of the body for 3-6 years
36
Q

Folate – B9

Sources

A

• Synthesised in bacteria and plants

– Consumed from leafy vegetables/grain fortification

37
Q

Folate – B9 deficiency symptoms

A

• Extreme tiredness, fatigue, pins and needles (paraesthesia), mouth ulcers, muscle weakness, disturbed vision, psychological problems, which may include depression and confusion.

38
Q

Folate – B9 uses

A

• Required for DNA methylation during development
Used in
– DNA Creation,
– red blood cell formation

39
Q

Folate and pregnancy

A
  • Foetal growth and development are characterized by widespread cell division.
    • That’s why women who want to get prgantn or are pregnant are asked to increase their follic acid intake
40
Q

• Neural tube defects (NTDs):

A

– Arise from failure of embryonic neural tube closure between the 21st and 27th days after conception
– Inadequate concentrations of folate in a pregnant woman

41
Q

Vitamin B12 is required for two metabolic reactions in the body:

A
  1. It transfers a methyl group from L–methyl malonyl - CoA to form Succinyl CoA
  2. It is also required for the transfer of a methyl group from tetrahydrofolate (FH4) to homocysteine to form methionine without which can affect folate metabolism (‘trap’ folate):
42
Q

3 effects of vitamin b12

A
    1. Elevated levels of methylmalonyl coenzyme A (CoA)
    1. Homocysteine (amino acid) levels rise:
    1. Folate trap
43
Q

How do. Homocysteine (amino acid) levels rise:

A

– DNA and Red Blood Cell production may slow
– Methyl folate trap > Associated with inflammation
○ b12 needed to transfer homocysteine to methionine and folate also effects this conversion, if there is not enough B12 to do this conversion , 5 methyl TH4 folate isn’t being converted to TH4- folate so there is a build up
– Tend to be higher in people with vitamin B12 deficiency

44
Q

Folate trap

A

B12 required for transfer of a methyl group from tetrahydrofolate (FH4) to homocysteine to form methionine
• Deficiency prevents its use in other reactions (as it is trapped in FH4 stable form) such as nucleotide synthesis required for DNA synthesis
• This leads to a ‘functional folate deficiency’ despite good diet of folate

45
Q

How do Folate deficiency/ B12deficiney

Impact blood

A
  • Low haematocrit
    • High mean cell volume (bigger cells)
    • Increase homocysteine amino acid
46
Q

Features of megaloblastic anaemia

A
  • Fewer RBC and so lower haematocrit
    • Larger cells – increased mean cell volume
    • Hypersegmented neutrophils – more lobes
    • Increased levels of homocysteine
47
Q

Treatment of megaloblastic anaemia

A

—> • Folic acid administration alone reverses the hematologic abnormality

BUT
• masks the B12 deficiency that can then proceed to severe neurologic dysfunction and pathology
• Therefore, megaloblastic anaemia should not be treated with folic acid alone

• SO treat with Combination of folate and vitamin B12

48
Q

Vitamin B12 replacement therapy (hydroxocobalmin)

A

– For people with no neurological involvement Initially administer hydroxocobalamin 1 mg intramuscularly three times a week for 2 weeks. (patients tend to be complient due to positive effects of injection)

The maintenance oral dose depends on whether deficiency is diet related or not.
– dietary advice

49
Q

Thalassaemias

A

Thalassaemia –> due to reduced globin chain synthesis
• Alpha thalassemia – absence of alpha globin
• Beta thalassemia –absence of beta globin

50
Q

Causes of microcytic anaemias

A

Thalassaemia –> due to reduced globin chain synthesis
• Alpha thalassemia – absence of alpha globin
• Beta thalassemia –absence of beta globin

Anaemia of chronic disease
• Hepcidin results in functional iron ddeficiency

Iron deficiency
• Lack of iron to synthesise heam

Lead poisioning
• Acquired defect, inhibitis enzymes involved in hame synthesis

Sideroblastic anaemia
• Inherited defect in haem synthesis ringed sideroblasts

51
Q

Iron

A

—-> free iron is very toxic to cells – can change from Fe2+ to Fe3+ causing oxidative stresss
• Can be used by macrophages to destroy bacteria

52
Q

Uses of iron

A 
• Oxygen carriers (myoglobin, haemoglobin)
	• Co factor in many enzymes 
		○ Cytochrome P450
		○ Krebs cycle
		○ Cytochromes
		○ Catalase
53
Q

Excretion of iron

A

Body can’t excrete iron.

- it is constantly recycled and maintained through dietary uptake

54
Q

Two oxidation states of iron

A

Feerous iron – Fe2+
• Reduced form

Ferric iron – Fe3+
• Oxidised form

Iron musts be reduced to ferrous iron before it can be absorbed from the diet. Can’t absorb ferric ion

55
Q

Absorption of iron

A

Iron musts be reduced to ferrous iron before it can be absorbed from the diet. Can’t absorb ferric ion

• Need 10-15 mg/day dietary iron (higher for menstruating women) (U.K. Dietary Reference Values 8.7mg per day for men and 14.8mg for women)

  • Greater for women of child bearing age
  • Absorption occurs in duodenum and upper jejunum (early in small intestine)
  • Haem iron best source (most readily absorbed)
56
Q

Iron in infection

A
  • Pathogens require iron

* Can be exploited by macrophages and inflammatory mechanisms

57
Q

Dietary iron

A
  • Mix of haem iron (2+) and non haem iron which is a mixture of 2+ and 3+ form
    • Ferric iron 3+ must be reduced to ferrous iron 2+ before it can be absorbed from diet
    • Animal sources of iron
    • Vegetable sources of iron – need something with it like vitamin C to reduce the iron and help absroption
58
Q

Dietary iron absorption

A
  1. Duodenal crypt cells sense iron status through transferrin and gene complex
    1. In the apix – ferric iron must be converted to ferrrous iron for absorption
    2. Apical Cell is where iron is reduced by reductase
      • Dietary iron is reduced on brush border
      • Absorption facilitated by divalent metal transport (DMT1)
      • Transfer iron via ferritin to ferroportin (dependent on hepcidin)
      • Hephaestin oxidises iron from ferrous to ferric (fe2+ in the cell and then when transported by transferrin it is fe3+)
      • Transported as transferrin
    3. Hepcidin – can inhibit this, downregulate export of iron through cells, decrease export of iron
59
Q

3 regulators of iron absorption

A
  • Amount available to absorb – diet
    • Stores
    • Bone marrow - erythropoiesis
60
Q

Vitamin C

A

• Increase vitamin c intake with iron increase iron absorption
○ Vit c helps reduced ferric to ferrous iron

61
Q

Negative influence (bad sources of iron)

A

Can bind non-haem iron in the intestine.
Reduces absorption

Dictary antioxidants
• Tannins in tea
• Phytates – chapatis and pulses
• Fibre

• Antacids - Gaviscon creduce iron uptake)
62
Q

Postive influence

A

Increase iron absorption

Vitamin C and citrate

  • prevent formation of insoluble iron compounds
  • help reduce ferric iron- ferrous
63
Q

Functional iron sources

A
  • Haemoglobin
    • myoglobin
    • Enzymes – cytochromes
    • Transported iron – transferrin
64
Q

Stored iron

A

• Ferritin – soluble

Haemosiderin – insoluble,less available - granuoles found in macrophages

65
Q

Cellular iron uptake

A

DMT-1 – dimetaltransporter 1
• Takes non bound iron into cells

1. 3+  bound transferrin bind to receptor and enters cytosol with receptor mediated endocytosis
2. 3+ with endosome released by acidic microenvironemnt and reduced to 2+
3. 2+ transported hy DMT-1
4. In cytosol 2+ stored in ferritin, exported by ferroprolein or taken up by mitochondria to use in cytochrome enzymes
66
Q

DMT-1

A

DMT-1 – dimetaltransporter 1

• Takes non bound iron into cells

67
Q

Iron recycling

A

• Only gain a very small amount of iron from diet, most are recycled

* Old RBC engulfed by macrophages – phagocytosis 
* Mainly by splenic macrophages and kupffer cells of liver
* Macrophages catabolism haem release from bc
* Amino acids reused or deaminated by amino acid metabolism
* Iron exported to blood by transferrin or returned to storage as ferritin
68
Q

What does Regulation of iron absorption

Depend on?

A

• Depends on diet, bone marrow, stores

Dietary iron levels sensed by enterocytes

69
Q

Control mechanisms of regulation of iron tra absorption

A

• Regulate transporters - less transports. Less Iron
• Regulate receptors
• Hepcidin (block export of iron from enterocytes at time of infection - as iron can help bacteria) and cytokines
• Crosstalk between epithelail cell and other cells like macrophages
=

70
Q

hepicidin

A

Increse – in times of iron overload
Decrease – when lots of rbc are produced – high erythropoietic activity

→ Hepcidin induces internalisation and degradation of ferroportin

71
Q

Pathology of anaemia

A

Causes release of cytokines

Causing Increased hepicidin levels – in response to cytokines produced in inflamamtory response
• Inhibits ferroportin
• Decrease iron release from rectoendothelial system
• Decrease iron absorption from gut

Cytokines also inhibit erythropoietin production in kidney, decrease erythropoeisis in bone marrow,

72
Q

Iron homeostasis

A 
• Bone marrow --> make new RBC 
	• Macrophages destroy erythrocytes 
Plasma iron pool – iron 3+ boudn to transferrin 
Loss of iron 
Dietary iron absorption 
Iron stores – lvier
73
Q

Iron deficiency causes

A
  • Insufficient iron in diet – vegan and veggie
    • Malabsorption of iron – vegan and veggie
    • Bleeding - menustration
    • Increase requirement – pregnancy, rapid growth
    • Anaemia of chronic disease - IBD
74
Q

Iron deficiency

A

Is a sign not a diagnosis

	○ Need to understand why the patient has low iron 
	○ Due to maybe diet or pregnancy etc. - what is the reason for iron deficiency
75
Q

Iron deficiency - at risk groups

A

– Infants
– Children
– Women of child bearing age
– Older adults

76
Q

Iron deficiency - symptoms and signs

A
  • Tiredness
    • Pallor
    • Reduced exercise tolerance
    • Caridac – angina, plapitations
    • Increased respiratory rate
    • Heafache, dizzyness
    • Pica = cravings for weird things – dirt, ices
    • Cold hands and read

Epithelail changes
• Glossy tongue
• Spoon nails

77
Q

Blood counts showing!

A
78
Q

Excess iron

A

—> can’t be excreted

Fenton reaction with iron free radicals 
	• Hydroxyl and hydroperoxyl radical can cause damge to cells (oxidative stress)
		○ Lipid peroxidarion 
		○ Damage to proteins 
		○ Damage to DNA
79
Q

Iron deficiency - treatment

A
  • Dietary advice
    • Supplements
    • Iv iron
    • Intramuscular iron injections
    • Blood transfusion
80
Q

Iron deficiency - iron amounts

A
  • Low iron
    • Low transferrin
    • High iron binding capacity
81
Q

Transfusion associated hoemosiderosis

A

—> accumualtion of iron after regular transfusions

Manage with chelating agents to delay effects

Problems accumulation of iron can cause:
	• Liver cirrohsis 
	• Diabetes 
	• Cariomyopathy 
	• Increased skin pigmentation
82
Q

Hereditary haemochromatosis

A

Mutation in HFE - can’t bind to transferrin so the negative influence on iron uptake is lost

• More iron in cell 
• More accumulates in end organs  Treat with venesection
83
Q

Treatment Hereditary haemochromatosis

A

Why is there only one way to manage Hereditary Haemochromatosis?
• No way of excreting iron
• Can only lose iron through bleeding as it accumulates

Why might venesection need to be repeated?

Why might some drugs e.g. proton pump inhibitors reduce the need for venesection?
• Ppi raises stomach ph, so more iron remains in ferric form
• Lower acid levels, less iron gets broken away from foods.

Y1 TP2 Metabolism, Endocrinolo, Haemotology (5 decks)

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