Case Launch (M1 4/12)

Question 1

There’s no LO’s

Answer 1

.

Question 2

1. What percentage of the worlds population above 18 has diabetes?
2. What percentage of UK diabetics have type 1 diabetes?
3. How much glucose does a brain consume daily?

Answer 2

1. 9%
2. 90%
3. 130g

Question 3

How does the body get energy in the fed state?

Answer 3

1. In fed state blood glucose levels are high
2. This causes an increase in insulin and decrease in glucagon enzyme.
3. Glucose goes to the liver and is converted into glucose 6 phosphate:
   
   • Some will be converted into glycogen to be used later.
   • Some will go through glycolysis to become pyruvate. Then it will fo through oxidative carboxylation/ link cycle to get acetyl coA. Excess acetyl coA is a building block of fatty acids. The fatty acids are packaged as triacidglycerides (TAGs) and then as very low density lipoproteins (VLDL) which then go to the fat cells/ adipocytes.
4. Glucose also goes to skeletal muscle (all muscle apart from smooth muscle in hallow organs and cardiac) and used for energy, but some is stored as glycogen.
5. Brain uses glucose for energy
6. Some glucose is converted into fatty acids and stored as TAGs in adipocytes
7. Fats/ chlomicrons are processed by the liver into TAGs and then VLDL and then to the fat cells for storage.

Question 4

How does the body get energy in the fasting state?

Answer 4

1. Insulin release inhibited, glucagon enzyme release increased in pancreas
2. The liver releases glucose into the bloodstream. This is what maintains blood glucose in the original period of the fast.
   
   • It can do this by converting glycogen and pyruvate into glucose 6 phosphate and then glucose
   • The liver gets pyruvate from the breakdown of TAG in the adipocytes to become glycerorol and fatty acids. Glycerol is a gluconeogenic precursor and so are amino acids from skeletal muscle which become pyruvate in the liver.
3. The liver can also make ketone bodies. Fatty acids from the breakdown of TAGs in the adipocytes, become acetyl coA in the liver and then form ketone bodies which all tissues, and the brain can use for energy.
4. Fatty acids from the breakdown of TAGs in the adipocytes can also be used in the mitochondria of tissues to generate acetyl coA and then be used for energy. Only the brain can’t do this.

Question 5

What happens to proteins in the fed state?

Answer 5

1. Amino acids are used by skeletal muscle to make proteins.
2. Amino acids are absorbed by all tissues and incorporated into nitrogen containing compounds like DNA.
3. In the liver amino acids can be used to:
   
   • to form proteins
   • If there is an excess of amino acids, the liver turns amino acids into pyruvate, then glucose, then glycogen.
   • It can turn ketogenic amino acids into acetyl coA, then FA, then TAGs, lastly VLDL.

Question 6

What happens to proteins in the fasting state?

Answer 6

Proteins are broken down into amino acids and released into blood. Gluconeogenic amino acids are then used to maked gluconeogenic precursors to make glucose. The ketogenic amino acids are converted into acetyl coA, and then ketone bodies.

Question 7

How is metabolism disrupted in diabetes?

Answer 7

• In T2D, obesity/overweight causes insulin resistance. This makes the liver over produce insulin, hyper-insulinemia. Eventually the liver will stop producing insulin because it is not having an effect, there will be a decline of beta-cell function.
• In T1D, the beta cells are destroyed, due to some enviromental/immune trigger. This means no insulin is produced.
• Both types result in disrupted metabolism.
  
  1. There is increasd protein breakdown in skeletal muscle. It causes gluconeogenic precursors (gluconeogenic amino acids to be made).
  2. There will be increased glycogenolysis, so more glucose released.
  3. There will be decreased cellular glucose uptake.
• These all cause more glucose to be made and hyperglycemia.
• TAG breakdown happens in adipocytes, causing increased FA in the blood. This explains increased cardiovascular risk in diabetics.
• FA are converted into acetyl coA in liver, and then into ketone bodies. This can cause ketoacidosis. This is rare in T2D, as there is still a tiny amount of insulin preventing the breakdown of TAGs.

Question 8

In an EU country (not the UK) a 8 week old baby who was previously healthy contracted an Upper respiratory tract infection. Up to this point the baby was being fed approximately every 2-3 hours. After not feeding for 6 hours the parents were concerned that the baby was drowsy and unresponsive. They immediately went to A and E. Tests were carried out and they showed that the baby had: severe hypoglycemia and hypoketonuria.

A follow up test on the same sample showed the following: Elevated levels of C8 acylcarnitine, with lesser elevation of C6 and C10 acylcarnitines.

What is the most likely diagnosis?

Answer 8

Elevation of C8, and lesser elevation of C6 and C10 acylcarnitines (metabolites from fatty acid metabolism) is absolutaly diagnostic of MCADD (medium chain acyl-coA dehydrogenase deficiency). Need to do mass spec to check for this.

You get elevation of these acylcarnitines, because:

• An individual with MCAD can’t process medium chain fatty acids, so they have a build up of them
• The body recognises this and tries to do something elese with the- omega oxidation. This is not very efficient.
• These acylcarnitines are metabolites of omega oxidation. They are actually toxic, and inhibit gluconeogenesis enzymes.

Question 9

In an EU country (not the UK) a 8 week old baby who was previously healthy contracted an Upper respiratory tract infection. Up to this point the baby was being fed approximately every 2-3 hours. After not feeding for 6 hours the parents were concerned that the baby was drowsy and unresponsive. They immediately went to A and E. Tests were carried out and they showed that the baby had: severe hypoglycemia and hypoketonuria.

A follow up test on the same sample showed the following: Elevated levels of C8 acylcarnitine, with lesser elevation of C6 and C10 acylcarnitines.

Using your understanding of metabolic pathways describe why this child was hypoglycaemic and hypoketotic?

Answer 9

• Fatty acid beta-oxidation provides energy after the body has used up its stores of glucose and glycogen.
• In beta oxidation fatty acids are broken down into acetyl coA which then enters the Kreb’s cycle and is used for energy.
• Everytime we take two carbons off our fatty acid, there are four reactions powered by four different enzymes.
• Acyl-coA dehydrogenase enzymes are length specific. So if you are missing medium chain acyl-coA dehydrogenase, you can not beta oxidise fatty acids coA that are 12 carbon long. This means very little ATP is produced, little acetyl coA is produced so less ketone bodies produced, and dn’t have energy for anabolic proccesses like gluconeogenesis to happen.
• This means you can’t use your fat stores properly, to make ketones. This makes the child hypoketotic.
• Infection, not feeding = hypoglycaemic

Question 10

In an EU country (not the UK) a 8 week old baby who was previously healthy contracted an Upper respiratory tract infection. Up to this point the baby was being fed approximately every 2-3 hours. After not feeding for 6 hours the parents were concerned that the baby was drowsy and unresponsive. They immediately went to A and E. Tests were carried out and they showed that the baby had: severe hypoglycemia and hypoketonuria.

A follow up test on the same sample showed the following: Elevated levels of C8 acylcarnitine, with lesser elevation of C6 and C10 acylcarnitines.

What is the treatment for those diagnosed with this condition?

Answer 10

Treatment involves avoiding fasting, and regular meals, so never have to use fat stores.

Question 11

In an EU country (not the UK) a 8 week old baby who was previously healthy contracted an Upper respiratory tract infection. Up to this point the baby was being fed approximately every 2-3 hours. After not feeding for 6 hours the parents were concerned that the baby was drowsy and unresponsive. They immediately went to A and E. Tests were carried out and they showed that the baby had: severe hypoglycemia and hypoketonuria.

A follow up test on the same sample showed the following: Elevated levels of C8 acylcarnitine, with lesser elevation of C6 and C10 acylcarnitines.

Why is such a diagnosis rare in the UK?

Answer 11

Screening at 5 days.

Question 12

Sum up the problem of MCADD

Answer 12

• People with MCAD deficiency lack Medium Chain Acyl-coA Dehydrogenase.
• Normally, when you have eaten you use up your glucose from the meal, then your glycogen stores. Then normally gluconeogenesis happens.
• People with MCAD can’t do gluconeogenesis because this is an anabolic process and requires energy, and they produce less ATP from beta oxidation as can’t use medium chain FA, and also because gluconeogenic enzymes are inhibited by C8, C6, C10 acylcarnitines made in omega oxidation.
• Then ketone bodies normally step in to take the pressure off glucose. But in MCAD defiency, you can’t use your fatty acid stores to make ketone bodies.
• Double whammy: lost glucose/ ability to make it, and no ability to make ketone bodies.

Question 13

Don’t need to know the pathways for this one

It is 2013 in England a 2 day year old child was not feeding well and vomiting. A decreased level of consciousness was observed along with seizures and hypothermia. There was a noticeable sweaty smell from the child.

Blood analysis revealed:

• Acidosis
• Hyperammonemia,
• Hypoglycemia
• Urine analysis revealed
• Ketonuria

Further urine analysis revealed

• Isovalerylglycine

1. What is the most likely diagnosis?
2. Describe the metabolic pathway disrupted by this likely diagnosis?
3. What is the treatment for those diagnosed with this condition?
4. Why is such a diagnosis now rare in the UK?

Answer 13

Don’t need to know the pathways for this one

1. Symptoms diagnostic of isovaleric acidaemia: sweaty smell and isovalerylglycine in urine.
2. Catabolism/ breaking down of leucine disrupted.
3. Treatment: low protein diet, and avoiding catabolic states, like fasting.
4. Rare: tested at 5 days after 2013.

Question 14

Phenylketonuria

Answer 14

• Caused by defiency in phenylalanine hydroxylase enzyme that converts phenylalanine into tyrosine.
• So get accumulation of phenylalanine and lack of tyrosine.
• Causes hypopigmentation, musty smell and mental retardation.

Question 15

Which 6 metabolic diseases are tested for in newborn blood spot testing?

Answer 15

1. phenylketonuria (PKU): KNOW A BIT
2. medium-chain acyl-CoA dehydrogenase deficiency (MCADD): LEARN
3. maple syrup urine disease (MSUD): JUST NAME
4. isovaleric acidaemia (IVA) : JUST NAME
5. glutaric aciduria type 1 (GA1) : JUST NAME
6. homocystinuria (pyridoxine unresponsive) (HCU) : JUST NAME

So basically, MCADD, isovaleric acidemia and phenylketonuria. And the homo-cyst-in-uria made a maple syrup urine disease sandwich with glutaric acid T1.