Hypoglycaemia

Question 1

What is hypoglycaemia?

Answer 1

Defined as a blood glucose level of below 4 mM (72 mg/dL)

Symptoms may develop at higher levels if there is rapid fall of previously elevated levels, although some individuals may show no effects even below 4 mM

Question 2

Give the symptoms of hypoglycaemia

Answer 2

A rapid fall in blood glucose may produce a phase of sweating, tachycardia and agitation due to release of adrenalin
Symptoms: equivalent to cerebral anoxia and may include moodiness, faintness, numbness in arms and hands, blurred vision, dizziness or lethargy that may progress to coma which if untreated results in death or permanent cerebral damage

Question 3

What are some serious consequences of hypoglycaemia?

Answer 3

Serious consequences of hypoglycaemia relate to effects on the brain – loss of cognitive function, seizures and coma

Question 4

When does loss of consciousness occur?

Answer 4

Loss of consciousness occurs at blood glucose levels of 2.5 mmol/L (45 mg/dL)

Question 5

List some causes of hypoglycaemia

Answer 5

Hypoglycemia in healthy individuals is normally mild and may be due to fasting or exercise.
Other causes of hypoglycaemia include:
- Hypernatraemia (e.g. diabetes insipidus)
- Hypovolaemia from vomiting, dehydration, etc.
- Ingestion of alcohols
- Pathologies such as adrenal insufficiency

Question 6

What is alcohol induced hypoglycaemia?

Answer 6

Develops several hours after alcohol ingestion

Occurs on depletion of glycogen stores when blood glucose is reliant on hepatic gluconeogenesis

Consumption of alcohol places additional stresses on gluconeogenesis, as alcohol is metabolised primarily in the liver by an unregulated process

Gluconeogenesis may also be decreased by liver damage and reduced muscle mass (longer term)

Question 7

How does alcohol induce hypoglycaemia?

Answer 7

Ethanol is rapidly metabolised by the enzyme alcohol dehydrogenase in the liver
This reaction requires NAD+ as co-enzyme
Results in high NADH:NAD+ ratio in cytosol
Acetaldehyde produced is transported into the mitochondria where it is oxidised to acetate by acetaldehyde dehydrogenase
Results in high NADH:NAD+ ratio in the mitochondria
Ethanol metabolism in the liver increases NADH + H+ and shifts the equilibrium
Reduces the availability of substrates for entry into gluconeogenesis to maintain plasma glucose levels i.e. pyruvate and oxaloacetate

Question 8

What are some physiological responses to alcohol induced hypoglycaemia?

Answer 8

Fall in blood glucose leads to a stress response (rapid heart beat, clammy skin), in an effort to enhance the stimulation of gluconeogenesis by combined action of glucagon and adrenalin

Rapid breathing is a physiologic response to metabolic acidosis, resulting from excess of lactic acid

Question 9

How does alcohol consumption affect fatty acids?

Answer 9

High levels of NADH inhibit fatty acid oxidation; instead the excess NADH signals that conditions are right for fatty acid synthesis

TGs accumulate in the liver causing a condition known as ‘fatty liver’. Also exported as VLDL.

Question 10

What can happen to acetate after long term alcohol consumption?

Answer 10

Acetate produced from EtOH can be converted into acetyl-CoA
BUT further processing of acetyl-CoA in TCA cycle prevented because high levels of NADH inhibits both isocitrate dehydrogenase and α-ketoglutarate dehydrogenase

Question 11

What are the 2 consequences of acetyl CoA accumulation?

Answer 11

• Production of ketone bodies which are released into the blood. Exacerbates the already acidic conditions resulting from high lactate levels
• Processing of acetate in the liver becomes inefficient, leading to build-up of acetaldehyde
  Acetaldehyde, the immediate end-product of alcohol metabolism, is highly toxic

Question 12

What is hepatomegaly and how is it caused?

Answer 12

Alcohol consumption decreases the activity of the proteosome

Leads to accumulation of protein, which causes enlargement of the liver

Decreased proteosome activity also increases oxidative stress

Question 13

What are the consequences of alcohol metabolism?

Answer 13

Ethanol enters the hepatocytes from the portal circulation and is converted to acetaldehyde by ADH (and MEOS)
Acetaldehyde enters the mitochondria where it is converted to acetate by ALDH. Both of these processes reduce NAD+ to NADH and generate oxidative stress by increasing ROS (reactive oxygen species).
The large amounts of NADH formed stimulates synthesis of fatty acids and triacylglycerols and prevents oxidation of lactate to pyruvate inhibiting gluconeogenesis and generating lactic acidosis.
The large amounts of acetate formed are converted to acetyl-CoA or are exported from the liver
Large amounts of acetyl-CoA results in production of ketone bodies and supports TG synthesis by conversion to fatty acyl CoAs

Question 14

What is thiamine deficiency?

Answer 14

Chronic alcoholics frequently have deficient intakes of micronutrients (e.g. vitamins B1, A, C, E and folate) and minerals (e.g. zinc and selenium).
50% of alcoholics with liver disease will have thiamine deficiency (B1)

Question 15

How is thiamine deficiency caused?

Answer 15

Malnourishment

Ethanol interferes with GI absorption

Hepatic dysfunction, which hinders storage and activation to thiamine pyrophosphate

Question 16

Why is thiamine important?

Answer 16

Cofactor for many enzymes

Question 17

Why can thiamine deficiency occur quickly?

Answer 17

Half life of 10-20 days, therefore deficiency can occur rapidly during depletion

Question 18

What are glycogen storage diseases?

Answer 18

Inherited diseases in which the stores of glycogen are affected by defects in either the enzymes of synthesis or degradation of glycogen.

10 different types depending on which enzyme is affected

They are all autosomal recessive except for type IX which is sex-linked

All result in the production of an abnormal amount or abnormal type of glycogen

May affect any of the
enzymes involved in glycogen synthesis and
breakdown

Question 19

What is type 1 von Gierke’s disease?

Answer 19

Affects mainly the liver and kidneys caused by a deficiency in glucose 6-phosphatase (hydrolysis of G-6-P liberates glucose into the blood)
Excess glucose 6-phosphate and consequent storage of excess glycogen and liver enlargement; and inability to release glucose during fasting leads to hypoglycaemia

Deficiency of glucose-6-phosphatase in liver, kidneys and intestines

G-6-P ———> GLUCOSE + Pi

Most common GSD – 25% OF GSDs
Catalyzes the terminal reaction of glycogenolysis and gluconeogenesis.
Results in impaired production of glucose from these two pathways between meals with hypoglycaemia that does not respond to glucagon.

Lack of glucose-6-phosphatase means that glucose cannot be exported from the liver.

High levels of G-6-P results in:
Abnormal levels of glycogen accumulation in the liver and kidney
Increased glycolysis leading to lactic acidosis
Increased fatty acid, TAG and VLDL synthesis and excretion.

Question 20

What is Type II. Pompe’s disease?

Answer 20

A deficiency of alpha-1,4 glucosidase activity in the lysosomes. Can be one of the most devastating of the glycogen storage diseases. Causes death by cardiorespiratory failure

Question 21

What is Type III Cori’s disease?

Answer 21

The amylo 1,6 glucosidase (de-branching enzyme) is deficient. Unable to break down glycogen, resulting in hypoglycaemia. Strangely, symptoms often disappear at puberty.

Question 22

What is Type IV Andersen’s disease?

Answer 22

One of the most severe of these diseases. Liver glycogen in normal amounts but comprises long unbranched chains that have low solubility. Sufferers seldom live beyond four years.

Question 23

What is Type V. McArdle’s syndrome?

Answer 23

Affects muscle glycogen phosphorylase (liver enzyme is normal). Muscle cannot break down glycogen (which accumulates)

Sufferers have a low tolerance to exercise and fatigue easily, with painful muscle cramps after exercise. Otherwise they have a normal life-span

Question 24

What are the symptoms of type 1 Von Gierke’s disease?

Answer 24

Patients suffer with enlarged livers and/or kidneys, stunted growth, severe tendencies to hypoglycaemia (convulsions), hyperlactemia and hyperlipidemia.

May also show hyperuricaemia and neutropenia the latter being associated with recurrent bacterial infections.

Symptoms appear when intervals between feeds increases and the infant sleeps through the night, or when an illness prevents normal feeding routine.

Question 25

How does the body respond to type 1 Von Gierke’s disease?

Answer 25

Body attempts to compensate for hypoglycaemia by:
releasing glucagon (hyperglucagonaemia) and adrenalin resulting in mobilisation of fat stores and release of fatty acids.
Conversion of fatty acids to TAGs and VLDL in the liver resulting in accumulation of fat in liver and hyperlipidaemia. May lead to hepatomas. Accumulation of fat in cheeks and buttocks.
Young infants are fed glucose through nasogastric tubes while older children are fed glucose drinks at 2-3 hour intervals night and day to prevent fall in blood glucose and cerebral damage.
Uncooked cornstarch may be used to prolong period between feeds.