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Imperial > 56. Metabolism, Growth & Appetite > Flashcards

56. Metabolism, Growth & Appetite Flashcards

1
Q
A
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2
Q

Which key area of the hypothalamus is involved in the regulation of food intake?

A

Arcuate nucleus

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3
Q

What feature of this area allows it to integrate central and peripheral inputs?

A

It is a circumventricular organ meaning that it has an incomplete blood-brain barrier This means that the arcuate nucleus is exposed to peripheral hormones

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4
Q

What are the two neuronal populations in the arcuate nucleus?

A

Agrp/NPY = stimulatory (increases food intake) POMC = inhibitory (prevents food intake)

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5
Q

Describe how the melanocortin system works.

A

Under normal conditions, POMC is broken down to alpha-MSH, which stimulates the MC4R receptor and prevents food intake When you need to eat, there will be an increase in Agrp activity Agrp will block the MC4R receptor and stimulate an increase in food intake

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6
Q

State some CNS mutations that affect this system and can causeobesity.

A

POMC deficiency – associated with obesity, red hair and pale skin MC4R mutation – associated with obesity There are NO known Agrp or NPY mutations

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7
Q

What are the features of the leptin deficiency ob/ob mouse?

A

Obesity Diabetes Decreased energy expenditure Decreased body temperature Infertility Stunted linear growth Decreased immune function

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8
Q

What is leptin?

A

It is a 167 amino acid hormone It is produced by adipocytes and signals to the brain, telling it how much fat there is in storage

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9
Q

What effect does centrally administered leptin have on leptin deficient individuals?

A

Decreases food intake Increases thermogenesis

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10
Q

What effect does leptin have on the melanocortin system?

A

Inhibits Agrp/NPY neurones Stimulates POMC Result = decrease in energy expenditure

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11
Q

What issue do obese people without leptin deficiency have, whichmeans that leptin treatment is not effective as an anti-obesity drug?

A

Circulating leptin is usually proportional to body fat mass So a lot of obese people are leptin resistant

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12
Q

Why won’t people with leptin deficiency go through puberty?

A

Leptin has a permissive effect on GnRH release Without GnRH release, you will not get sufficient LH and FSH release to cause puberty This is also the reason why people who are severely underweight get secondary amenorrhoea

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13
Q

Describe the central effects of insulin.

A

Insulin has a similar effect to leptin as it reduces food intake Chronically – reduced body fat Acutely – if you have a big glucose load, you suppress the intake of more sugar

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14
Q

What is ghrelin and how is it activated?

A

It is a hunger hormone released by the stomach (28 amino acids long) It is activated by Ghrelin-O-acyltransferase (GOAT), which adds a fatty acid to the 3rd amino acid in the chain

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15
Q

What effect does ghrelin have on the melanocortin system?

A

Stimulates Agrp/NPY neurones Inhibits POMC neurones Result = increase in food intake

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16
Q

Which cells of the GI tract release PYY and GLP-1?

A

L-cells

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17
Q

What are the effects of PYY and when is it released?

A

PYY stimulates POMC neurones and inhibits NPY neurones It is released post-prandially

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18
Q

What is GLP-1 and what gene encodes it?

A

Glucagon-Like Peptide 1 Encoded by pre-proglucagon gene

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19
Q

What are the effects of GLP-1?

A

Important role in the incretin effect Decreases food intake

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20
Q

Describe the degradation of GLP-1.

A

It is rapidly broken down by dipeptidyl peptidase-4 (DP-IV) It has a half-life of around 1 minute

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21
Q

State a long-acting GLP-1 receptor agonist that is used for diabetes and obesity.

A

Saxenda

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22
Q

What is the problem with PYY 3-36 as a drug target?

A

High levels of PYY can cause nausea There is only a relatively small sweetspot, in terms of concentration, that will have beneficial effects

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23
Q

State some comorbidities associated with obesity.

A

Stroke, MI, cancer, diabetes, hypertension, osteoarthritis etc.

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24
Q

What is the thrifty gene hypothesis?

A

It was evolutionarily sensible to put on extra weight because it meant that we could survive the times when food was scarce (thinner people would die in these times)

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25
Q

What is the adaptive drift hypothesis?

A

There use to be a normal distribution in terms of body weight Predators would kill the fat people But then we got better at evading predators so increased body weight because a neutral change

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26
Q

Name a form of type I diabetes that presents late.

A

Latent Autoimmune Diabetes in Adults (LADA)

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27
Q

State two monogenic causes of diabetes.

A

Mitochondrial Diabetes Maturity Onset Diabetes of the Young

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28
Q

Name a form of type I diabetes that presents late.

A

Latent Autoimmune Diabetes in Adults (LADA)

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29
Q

State two monogenic causes of diabetes.

A

Mitochondrial Diabetes Maturity Onset Diabetes of the Young

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30
Q

Diabetes can also present with endocrine diseases. Name three endocrine diseases that are associated with diabetes.

A

Phaeochromocytoma Cushing’s Syndrome Acromegaly

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31
Q

What conditions and triggers are required for the onset of type 1 diabetes mellitus?

A

Environmental trigger in the presence of a genetic predisposition –> autoimmune attack of islet cells

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32
Q

Which type of diabetes has a bigger genetic component?

A

Type 2 Diabetes Mellitus

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33
Q

What can be measured in the blood to give an indication of insulin function?

A

C-peptide

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34
Q

Describe the pathogenesis of T1DM.

A

You get gradual autoimmune destruction of beta cells resulting in gradually reducing levels of insulin (and C-peptide) One of the first signs will be the loss of first phase insulin There will be eventual destruction of all beta cells

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35
Q

Why is T1DM described as a ‘relapsing-remitting’ disease?

A

Over time the beta cell mass appears to reduce, then stabilise, then reduce again There is a theory that this is due to the imbalance in effector T-cells and regulatory T-cells

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36
Q

What is the importance of the autoimmune basis of T1DM?

A

Increased prevalence of other autoimmune diseases (e.g. rheumatoid arthritis, thyroid disease)

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37
Q

What are the histological features of T1DM?

A

Lymphocyte infiltration of beta cells (which destroys the beta cells)

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38
Q

On which chromosome is the HLA found?

A

Chromosome 6

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39
Q

Which alleles convey a risk of diabetes? Which of these alleles is associated with the most significant risk?

A

DR alleles DR3 and DR4 = significant risk

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40
Q

What are the two most significant markers of diabetes?

A

Islet Cell Antibodies (ICA) Glutamic Acid Decarboxylase Antibodies (GADA)

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41
Q

State two other antibody markers of diabetes that are not used in clinical practice?

A

Insulin Autoantibodies (IAA) Insulinoma-associated-2 autoantibodies (IA-2A)- receptor like family

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42
Q

State some symptoms of T1DM.

A

Polyuria Nocturia Polydipsia Blurring of vision Thrush (due to increased risk of infection) Weight loss Fatigue

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43
Q

What are the signs of T1DM?

A

Dehydration Cachexia Hyperventilation (kussmaul breathing) Smell of ketones Glycosuria Ketonuria

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44
Q

What are the triglycerides in adipocytes broken down to?

A

Glycerol Fatty Acids

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45
Q

What does insulin have a negative effect on?

A

Hepatic glucose output (HGO) Protein breakdown in muscle Ketone body generation by the liver Glycerol release from the fat cells

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46
Q

What does insulin have a positive effect on?

A

Glucose uptake by tissues

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47
Q

State 4 other hormones that increase hepatic glucose output.

A

Catecholamines Cortisol Growth Hormone Glucagon

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48
Q

Describe how insulin deficiency leads to diabetic ketoacidosis (DKA).

A

Insulin has a suppressive effect on hepatic ketone body generation. In insulin deficiency, fatty acids from the breakdown of triglycerides, travel to the liver where they are used to produce ketone bodies.

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49
Q

What is a defining feature of insulin deficiency?

A

Ketone Bodies NOTE: some cases of T2DM can also get DKA but this is mainly a complication of T1DM

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50
Q

State some long-term complications of T1DM.

A

Neuropathy Nephropathy Retinopathy Vascular Disease

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51
Q

What is the main treatment for T1DM?

A

Exogenous insulin

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52
Q

Describe the dietary changes that are recommended in T1DM.

A

Decreased fat Decreased refined carbohydrates Increased complex carbohydrates Increased soluble fibre

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53
Q

Describe the features of the insulin that is given with meals.

A

Short-acting Human Insulin Insulin analogues are genetically engineered to mimic normal physiology

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54
Q

State three forms of insulin that are given with meals.

A

Lipsro Aspart Glulisine

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55
Q

Describe the features of background insulin.

A

Long-acting Non-C bound to zinc or protamine

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56
Q

State three forms of insulin that is given as background insulin.

A

Glargine Detemir Degludec

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57
Q

What do insulin pumps do?

A

Continuous insulin delivery There are pre-programmed basal rates and boluses for meals But these DO NOT measure blood glucose so the feedback loop isn’t complete

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58
Q

Describe the use of islet cell transplants.

A

Islet cells can be harvested from donors and injected into the liver of a patient with diabetes They must be on immunosuppressants for life

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59
Q

How is capillary monitoring done and what does it give a measure of?

A

Prick the finger and test the blood drawn It is a measure of venous blood glucose NOTE: you can also get continuous monitors, which aren’t as accurate (need to be calibrated with capillary glucose)

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60
Q

What is HbA1c level used to gage?

A

Glycaemic control over the past 3 months (red cell life span = 120 days)

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61
Q

What HbA1c level are T1DM patients aiming for?

A

< 7%

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62
Q

When might the HbA1c level not be accurate?

A

In any case of increased haemoglobin turnover e.g. haemolytic anaemia and haemoglobinopathies

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63
Q

What are the main acute complications of T1DM?

A

Hypoglycaemia Metabolic acidosis

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64
Q

What are the two main ketones that circulate in metabolic acidosiscaused by T1DM?

A

Acetoacetone Hydroxybutyrate

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65
Q

DKA tends to be in patients with T1DM, however, some subsets of T2DM also get ketoacidosis. What are these subsets?

A

Black and Asian patients with T2DM May be due to pancreatic insufficiency at a time of stress

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66
Q

Define hypoglycaemia.

A

Blood glucose < 3.6 mmol/L

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67
Q

Define severe hypoglycaemia.

A

Any level of hypoglycaemia that requires another person to treat it

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68
Q

What can recurrent hypos result in?

A

Loss of warning (hypoglycaemia unawareness) This can lead to poor glycaemic control

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69
Q

At what times during the day do hypos tend to happen?

A

Pre-lunch Nocturna

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70
Q

What can trigger a hypo?

A

Unaccustomed exercise Missed meals Inadequate snacks Alcohol (may make you unaware of hypo symptoms) Inappropriate insulin regime

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71
Q

State some signs and symptoms of hypoglycaemia.

A

Signs and symptoms are due to increased sympathetic activity and due to impaired CNS function Palpitations Tremor Sweating Pallor/cold extremities Anxiety Drowsiness Confusion Altered behaviour Focal neurology Coma

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72
Q

How is hypoglycaemia treated?

A

Oral glucose Complex carbohydrate (to maintain blood glucose after initial treatment) Parenteral – if consciousness impaired  IV dextrose (e.g. 10% glucose infusion)  1 mg glucagon IM

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73
Q

Diabetes can also present with endocrine diseases. Name three endocrine diseases that are associated with diabetes.

A

Phaeochromocytoma Cushing’s Syndrome Acromegaly

How well did you know this?
1
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2
3
4
5
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74
Q

What conditions and triggers are required for the onset of type 1 diabetes mellitus?

A

Environmental trigger in the presence of a genetic predisposition –> autoimmune attack of islet cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
75
Q

How is hypoglycaemia treated?

A

Oral glucose Complex carbohydrate (to maintain blood glucose after initial treatment) Parenteral – if consciousness impaired  IV dextrose (e.g. 10% glucose infusion)  1 mg glucagon IM

How well did you know this?
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76
Q

State some signs and symptoms of hypoglycaemia.

A

Signs and symptoms are due to increased sympathetic activity and due to impaired CNS function Palpitations Tremor Sweating Pallor/cold extremities Anxiety Drowsiness Confusion Altered behaviour Focal neurology Coma

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1
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2
3
4
5
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77
Q

What can trigger a hypo?

A

Unaccustomed exercise Missed meals Inadequate snacks Alcohol (may make you unaware of hypo symptoms) Inappropriate insulin regime

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
78
Q

At what times during the day do hypos tend to happen?

A

Pre-lunch Nocturna

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
79
Q

What can recurrent hypos result in?

A

Loss of warning (hypoglycaemia unawareness) This can lead to poor glycaemic control

80
Q

Define severe hypoglycaemia.

A

Any level of hypoglycaemia that requires another person to treat it

81
Q

Define hypoglycaemia.

A

Blood glucose < 3.6 mmol/L

82
Q

DKA tends to be in patients with T1DM, however, some subsets of T2DM also get ketoacidosis. What are these subsets?

A

Black and Asian patients with T2DM May be due to pancreatic insufficiency at a time of stress

83
Q

What are the two main ketones that circulate in metabolic acidosiscaused by T1DM?

A

Acetoacetone Hydroxybutyrate

84
Q

What are the main acute complications of T1DM?

A

Hypoglycaemia Metabolic acidosis

85
Q

When might the HbA1c level not be accurate?

A

In any case of increased haemoglobin turnover e.g. haemolytic anaemia and haemoglobinopathies

86
Q

What HbA1c level are T1DM patients aiming for?

A

< 7%

87
Q

What is HbA1c level used to gage?

A

Glycaemic control over the past 3 months (red cell life span = 120 days)

88
Q

How is capillary monitoring done and what does it give a measure of?

A

Prick the finger and test the blood drawn It is a measure of venous blood glucose NOTE: you can also get continuous monitors, which aren’t as accurate (need to be calibrated with capillary glucose)

89
Q

Describe the use of islet cell transplants.

A

Islet cells can be harvested from donors and injected into the liver of a patient with diabetes They must be on immunosuppressants for life

90
Q

What do insulin pumps do?

A

Continuous insulin delivery There are pre-programmed basal rates and boluses for meals But these DO NOT measure blood glucose so the feedback loop isn’t complete

91
Q

State three forms of insulin that is given as background insulin.

A

Glargine Detemir Degludec

92
Q

Describe the features of background insulin.

A

Long-acting Non-C bound to zinc or protamine

93
Q

State three forms of insulin that are given with meals.

A

Lipsro Aspart Glulisine

94
Q

Describe the features of the insulin that is given with meals.

A

Short-acting Human Insulin Insulin analogues are genetically engineered to mimic normal physiology

95
Q

Describe the dietary changes that are recommended in T1DM.

A

Decreased fat Decreased refined carbohydrates Increased complex carbohydrates Increased soluble fibre

96
Q

What is the main treatment for T1DM?

A

Exogenous insulin

97
Q

State some long-term complications of T1DM.

A

Neuropathy Nephropathy Retinopathy Vascular Disease

98
Q

What is a defining feature of insulin deficiency?

A

Ketone Bodies NOTE: some cases of T2DM can also get DKA but this is mainly a complication of T1DM

99
Q

Describe how insulin deficiency leads to diabetic ketoacidosis (DKA).

A

Insulin has a suppressive effect on hepatic ketone body generation. In insulin deficiency, fatty acids from the breakdown of triglycerides, travel to the liver where they are used to produce ketone bodies.

100
Q

State 4 other hormones that increase hepatic glucose output.

A

Catecholamines Cortisol Growth Hormone Glucagon

101
Q

What does insulin have a positive effect on?

A

Glucose uptake by tissues

102
Q

What does insulin have a negative effect on?

A

Hepatic glucose output (HGO) Protein breakdown in muscle Ketone body generation by the liver Glycerol release from the fat cells

103
Q

What are the triglycerides in adipocytes broken down to?

A

Glycerol Fatty Acids

104
Q

What are the signs of T1DM?

A

Dehydration Cachexia Hyperventilation (kussmaul breathing) Smell of ketones Glycosuria Ketonuria

105
Q

State some symptoms of T1DM.

A

Polyuria Nocturia Polydipsia Blurring of vision Thrush (due to increased risk of infection) Weight loss Fatigue

106
Q

State two other antibody markers of diabetes that are not used in clinical practice?

A

Insulin Autoantibodies (IAA) Insulinoma-associated-2 autoantibodies (IA-2A)- receptor like family

107
Q

What are the two most significant markers of diabetes?

A

Islet Cell Antibodies (ICA) Glutamic Acid Decarboxylase Antibodies (GADA)

108
Q

Which alleles convey a risk of diabetes? Which of these alleles is associated with the most significant risk?

A

DR alleles DR3 and DR4 = significant risk

109
Q

On which chromosome is the HLA found?

A

Chromosome 6

110
Q

What are the histological features of T1DM?

A

Lymphocyte infiltration of beta cells (which destroys the beta cells)

111
Q

What is the importance of the autoimmune basis of T1DM?

A

Increased prevalence of other autoimmune diseases (e.g. rheumatoid arthritis, thyroid disease)

112
Q

Why is T1DM described as a ‘relapsing-remitting’ disease?

A

Over time the beta cell mass appears to reduce, then stabilise, then reduce again There is a theory that this is due to the imbalance in effector T-cells and regulatory T-cells

113
Q

Describe the pathogenesis of T1DM.

A

You get gradual autoimmune destruction of beta cells resulting in gradually reducing levels of insulin (and C-peptide) One of the first signs will be the loss of first phase insulin There will be eventual destruction of all beta cells

114
Q

What can be measured in the blood to give an indication of insulin function?

A

C-peptide

115
Q

Which type of diabetes has a bigger genetic component?

A

Type 2 Diabetes Mellitus

116
Q

What tests are performed to diagnose diabetes and what are the defining values?

A

Fasting Blood Glucose:  Normal < 6  Impaired Fasting Glucose = 6-7  Diabetes > 7 Glucose Tolerance Test (2 hr measurement)  Normal < 7.8  Impaired Glucose Tolerance = 7.8-11.1  Diabetes > 11.1

117
Q

State three factors that influence the pathophysiology of T2DM.

A

Genetics Intrauterine environment Adult environment

118
Q

How is the intrauterine environment important in the pathogenesis of T2DM?

A

There will be epigenetic changes that take place in utero, which affect blood glucose control in the future

119
Q

What is MODY?

A

Mature onset diabetes of the young (8 types) It is autosomal dominant Ineffective pancreatic beta cell insulin production Caused by mutations of transcription factor genes (glucokinase gene) Positive family history with NO obesity

120
Q

What can modulate insulin resistance through adult life beforesomeone develops diabetes?

A

Adipocytokines

121
Q

What type of babies are more likely to develop T2DM in later life?

A

Small babies (low birth weight) This is due to intrauterine growth restriction

122
Q

How does insulin resistance lead to hypertension?

A

Insulin resistance leads to a compensatory hyperinsulinaemia Though the insulin doesn’t affect the glycaemic control pathway, it stimulates the mitogenic pathway causing smooth muscle hypertrophy –> high blood pressure

123
Q

What eventually happens to the beta cells in T2DM?

A

Insulin resistance damages the beta cells and eventually results in beta cell failure

124
Q

Describe how beta cell reserve and insulin resistance change with age.

A

Beta cell reserve decreases with age and insulin resistance increases

125
Q

Describe the presentation of a typical patient with T2DM.

A

Obese (80%) Insulin resistance and insulin secretion deficit Hyperglycaemia and dyslipidaemia Acute and chronic complications

126
Q

What dietary changes can someone with T2DM make to reduce the effect of the missing first phase insulin release?

A

Complex carbohydrates – release glucose more slowly

127
Q

Describe glucose clearance and hepatic glucose output in T2DM.

A

Glucose clearance is decreased Hepatic glucose output is increased

128
Q

What normally happens to insulin secretion as insulin resistance increases?

A

Insulin secretion increases to compensate for the increased insulin resistance

129
Q

Which adipocytes are particularly marked for breakdown of triglycerides?

A

Omental adipocytes (this is why omental fat correlates with risk of heart disease)

130
Q

What happens to fatty acids when they go into the liver?

A

They cannot be used to make glucose so they are converted to very low-density lipoproteins (VLDLs), which are highly atherogenic

131
Q

Describe how gut microbiota is implicated in T2DM.

A

They may be important in host signalling – they ferment various lipopolysaccharides to produce short chain fatty acids, which enter the circulation and modulate bile acids (so they can also affect host metabolism) They are also important in inflammation and adipocytokine pathways

132
Q

What is a very common side effect of diabetes treatment?

A

Weight gain

133
Q

Which diabetes treatment does not cause this problem?

A

Metformin

134
Q

What are the potential complications of T2DM?

A

Stroke Myocardial Infarction Neuropathy Retinopathy Nephropathy Hypoglycaemia

135
Q

What dietary measures are recommended for someone with T2DM?

A

Decreased fat (particularly saturated fats) Decreased refined carbohydrates Increased complex carbohydrates Increased soluble fibre Control total calories/increase exercise

136
Q

What is orlistat and why is it sometimes used in T2DM?

A

Pancreatic Lipase Inhibitor It reduces the break down of fats in the intestines thus reducing the absorption of fats

137
Q

State 5 classes of drugs that are used to treat T2DM and state how they work.

A

Metformin – insulin sensitiser (biguanides) Sulphonylureas – makes the existing pancreas produce more insulin Alpha-glucosidase inhibitors – prolongs the absorption of glucose from the intestine Thiazolidinediones – addresses peripheral insulin resistance (muscle and fat) GLP-1 agonists and DPIV inhibitors – increase insulin secretion

138
Q

When should you NOT use metformin?

A

Severe liver failure Severe cardiac failure Mild renal failure

139
Q

Name one sulphonylurea.

A

Glibenclamide Given to lean patients with T2DM

140
Q

Explain how sulphonylureas work.

A

They bind to receptors and block the ATP-sensitive K+ channel This leads to Ca2+ influx, which causes insulin release

141
Q

Name one alpha-glucosidase inhibitor. Explain how it works and state some side effects.

A

Acarbose It prolongs the absorption of oligosaccharides and allows the body to cope with the loss of first phase insulin Side effect: it means that some sugars get to the colon and are fermented –> flatus

142
Q

Name on thiazolidinedione. What are its effects?

A

Pioglitazone These are peroxisome proliferator-activated receptor (PPAR-) agonists These are insulin sensitises mainly in peripheral tissues (leads to peripheral weight gain)

143
Q

What does GLP-1 do?

A

Responsible for the incretin effect Stimulates insulin and suppresses glucagon

144
Q

What breaks down GLP-1?

A

Dipeptidyl peptidase-4 (DP-IV)

145
Q

What class of drugs prolong the duration of GLP-1?

A

Gliptins They inhibit DP-IV

146
Q

What effect do long-acting GLP-1 agonists and gliptins have on weight gain?

A

GLP-1 agonists = weight loss Gliptins = neutral

147
Q

What other pharmaceutical interventions must be considered with T2DM patients?

A

Many T2DM patients also have dyslipidaemia and hypertension, which need to be dealt with as well

148
Q

What can occur during pregnancy to identify women who are at high risk of getting diabetes in the future?

A

Gestational diabetes

149
Q

What is vitamin B12 and what types of food is it commonly found in?

A

Cobalamin (vitamin B12) is a bacterial product that is ingested and stored by animals. It is found in meat, cheese, salmon, cod, milk, eggs

150
Q

How much B12 is needed every day and how much is found in hepatic stores?

A

1.5-3 mcg/day required Store: 2-5 mg (will last several years)

151
Q

What is Vitamin B12 needed for?

A

DNA synthesis Integrity of the nervous system (involved in myelination)

152
Q

Broadly speaking, what can cause Vitamin B12 deficiency?

A

Dietary deficiency (vegans) Decreased absorption

153
Q

What types of food have lots of folic acid?

A

Leafy green vegetables

154
Q

Broadly speaking, what can cause folic acid deficiency?

A

Dietary deficiency Increased demand for folate Impaired absorption

155
Q

What is the dietary requirement of folic acid?

A

400-600 mcg You run out of folate much quicker than B12

156
Q

What is folic acid required for?

A

DNA synthesis Homocysteine metabolism

157
Q

Describe the passage of vitamin B12 from entry into the GI tract tothe hepatic portal circulation.

A

It enters the stomach and binds to transcobalamin 1 (R protein –produced by the salivary glands) The gastric parietal cells (at the bottom of the stomach) produce intrinsic factor The B12 moves into the duodenum, bound to transcobalamin 1, and then pancreatic enzymes displace B12 from transcobalamin 1 The free B12 then binds to intrinsic factor The B12-intrinsic factor complex continues all the way to the terminal ileum where it binds to specific receptors and is absorbed The B12 then goes into the portal circulation and binds to transcobalamin 2 making active B12

158
Q

Describe the absorption of folic acid.

A

Folic acid enters the GI tract as polyglutamates The acidic pH of the stomach hydrolyses the polyglutamates to monoglutamates The folic acid is absorbed as pteroglutamates It is then methylated in the luminal cells to form methyl tetrahydroflorate

159
Q

Deoxythymidine (dTMP) is a major building block of DNA synthesis. How is it produced?

A

It is produced by the methylation of deoxyuridine (dUMP) For the methylation to take place, you need the release of methyl groups from methyl-tetrahydrofolate by the action of B12 as a cofactor accompanied by the conversion of homocysteine to methionine.

160
Q

In what reaction is B12 a co-factor?

A

The conversion of homocysteine to methionine Enzyme = methionine synthetase

161
Q

State some clinical features of B12 and folate deficiency.

A

Anaemia (macrocytic and megaloblastic) Jaundice (due to ineffective erythropoiesis) Angular Cheilosis Glossitis Sterility Weight loss and change of bowel habit

162
Q

State some causes of macrocytic anaemia.

A

Vitamin B12/Folate deficiency Liver disease and alcoholism Hypothyroidism Haematological disorders:  Myelodysplasia (production of one or all types of blood cells by the bone marrow is disrupted)  Aplastic anaemia (failure of blood cell production resulting in pancytopenia)  Reticulocytosis (in response to haemolytic anaemia or bleeding) Drugs that interfere with DNA synthesis Prolonged nitrous oxide anaesthesia

163
Q

How can you differentiate between the blood film of someone with B12/Folate deficiency and someone with liver disease or alcoholism causing macrocytosis?

A

B12/Folate deficiency = OVAL macrocytes Liver disease and alcoholism = ROUND macrocytes

164
Q

What is a reticulocyte?

A

A young red blood cell with no nucleus

165
Q

Describe how the appearances of cells of the red cell lineage change as they mature.

A

They become smaller and their cytoplasm becomes pinker Their nucleus starts off being quite diffuse (open chromatin) and it becomes more and more compact until it is spit out by the red cell

166
Q

Given your previous answer, what two things do you look at when determining the maturity of a red blood cell?

A

Chromatin – how open is it? Colour of the cytoplasm – how blue is it?

167
Q

What is meant by ‘megaloblastic changes’?

A

These are changes seen in the red blood cell precursors in the bone marrow. Megaloblastic change is when there is asynchronous maturation of the nucleus and cytoplasm. You get an immature, open nucleus with mature cytoplasm.

168
Q

Broadly speaking, what are megaloblastic changes the result of?

A

Defective DNA synthesis

169
Q

Which of the causes of macrocytic anaemia also show megaloblastic changes in the bone marrow?

A

B12/Folate deficiency Myelodysplasia Drugs that interfere with DNA synthesis Prolonged nitrous oxide anaesthesia

170
Q

In megaloblastic anaemia, you see changes in the red blood cellsand the white blood cells. Describe these changes.

A

Red blood cells  Asynchrony between maturation of nucleus and cytoplasm (immature nucleus and mature cytoplasm)  Increase in size of red cell precursors at all stages of maturation  Increase in bone marrow activity because haemopoiesis is ineffective (dysplastic)  Phagocytosis of dysplastic red blood cells White blood cells  Giant metamyelocytes (due to asynchronous maturation)  Hypersegmented neutrophils

171
Q

Which groups are at particular risk of dietary folate deficiency?

A

Elderly, sick, eating disorders, alcoholics

172
Q

What are the consequences of folate deficiency for DNA synthesis?

A

Folate deficiency means that you can’t methylate dUMP to dTMP, which affects DNA synthesis. It also leads to the accumulation of homocysteine (it can’t be converted to methionine without folate)

173
Q

State some physiological and pathological causes of increased folate demand.

A

Physiological (increased growth)  Pregnancy  Adolescence  Premature babies Pathological (rapid cell turnover)  Malignancy  Erythroderma (whole body rash)  Haemolytic anaemia

174
Q

State some causes of malabsorption of folate.

A

Coeliac Disease Surgery or inflammatory bowel disease (e.g. Crohn’s disease) Drugs (e.g. colestyramine, sulfasalazine and methotrexate)

175
Q

What is coeliac disease caused by?

A

Sensitivity to gliadin (group of proteins found in wheat) leads to subtotal villous atrophy with crypt hyperplasia in the duodenum.

176
Q

How can coeliac disease be diagnosed?

A

Anti-gliadin (transglutaminase) antibodies Duodenal biopsy

177
Q

State some tests to identify folate deficiency.

A

Full blood count Blood film Serum folate – useful as a screening test  Shows diurnal variation  Affected by recent changes in diet Red cell folate – useful as confirmatory test

178
Q

What would you expect the serum folate and red cell folate of a patient with B12 deficiency to be and why?

A

Serum folate = high Red cell folate = LOW This is because B12 is required for the folate to enter the red blood cells

179
Q

What are the three main consequences of folate deficiency?

A

Megaloblastic anaemia Neural tube defects Increased risk of venous thromboembolism

180
Q

What are the two types of neural tube defects?

A

Spinal cord = spina bifida Brain = anencephaly

181
Q

What are the NICE guidelines for women of standard and high risk of neural tube defects?

A

Standard Risk – 400 mcg folic acid preconception to 12 weeks gestation High Risk – 5 mg folic acid preconception to 12 weeks gestation Haemolytic anaemia – 5-10 mg before, during and after pregnancy

182
Q

Homocysteine accumulates in folate deficiency. What are the consequences of this?

A

Very high homocysteine levels are associated independently with:  Atherosclerosis  Premature vascular disease Mildly elevated homocysteine is associated with cardiovascular disease and probably with arterial and venous thrombosis.

183
Q

How did the FDA in the USA attempt to reduce the incidence of NTDs due to folate deficiency?

A

Fortify grain with folate

184
Q

Which groups of people are at particular risk of vitamin B12 deficiency due to decreased intake?

A

Vegans

185
Q

State some factors that can affect the absorption of B12.

A

Autoimmune – pernicious anaemia (lack of intrinsic factor) Surgery – resection of parts of the GI tract Inflammatory bowel conditions – Crohn’s, chronic pancreatitis, bacterial overgrowth, parasitic infection

186
Q

What are the two main consequences of B12 deficiency?

A

Macrocytic and megaloblastic anaemia Neurological problems due to demyelination  Subacute combined degeneration of the spinal cord  Neuropathy of central and peripheral nerves  Cognitive impairment due to loss of white matter in the CNS  Optic atrophy

187
Q

What is the relationship between Hb level and neurological symptoms in B12 deficiency?

A

Inverse relationship between Hb level and neurological symptoms

188
Q

What is subacute combined degeneration of the spinal cord and what are the symptoms?

A

Caused by demyelination of the posterior (dorsal) and lateral (pyramidal) tracts of the cervical and thoracic spinal cord Results in loss of joint position sense and vibration sense. Patient may have a wide-based gait and sometimes experience pain.

189
Q

State some symptoms and signs of B12 deficiency.

A

Weak, tired, lethargic Symmetrical parasthesia/numbness Muscle weakness Difficulty walking and loss of balance Anaemia and jaundice giving ‘yellow tinge’ Neurology  Loss of vibration and joint position sense but also cutaneous sensation loss  Absent responses and up-going plantar responses in legs Visual impairment Memory impairment Psychiatric disturbance

190
Q

What is the test for B12 deficiency?

A

Serum cobalamin (B12) level PROBLEM: it measures total cobalamin levels (bound to transobalamin 1, 2 and 3) so you see a lot of healthy patients with low transcobalamin This means that the clinical circumstances must be taken into account when interpreting the results.

191
Q

What is the role of B12 in DNA synthesis?

A

Both B12 and folate are needed for the production of dTMP (deoxythymidine), which is a crucial building block in DNA synthesis

192
Q

State some new tests used to diagnose B12 deficiency.

A

Plasma homocysteine (high in B12 and folate deficiency) Serum methyl malonic acid levels Holotranscobalamin levels (transcobalamin II)

193
Q

What is the Schilling test for B12 absorption?

A

Give two capsules of B12 with different radioisotopes. 1 capsule will be B12 alone 1 capsule will be B12 + intrinsic factor Collect urine for 24 hours after administration and measure the presence and relative proportion of each isotope.

194
Q

What is pernicious anaemia and what does it result in?

A

A form of anaemia resulting from the deficiency of B12 It can be caused by autoimmune atrophic gastritic with the loss of intrinsic factor This results in macrocytic/megaloblastic anaemia with or without neurological damage

195
Q

Which antibodies are found in pernicious anaemia?

A

Anti-intrinsic factor antibodies (in 40-60% of adults with PA) Anti-gastric parietal cell antibodies (in 80-90% of adults with PA)

196
Q

How are folate and B12 deficiency treated?

A

Oral folate or oral cyanobalamin for dietary deficiency or increased demand Parenteral (IM/SC) hydroxycobalamin for malabsorption due to pernicious anaemia or bowel disease

Imperial (23 decks)

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