Chemical Pathology

Question 1

Define Diabetes.

Answer 1

Collection of Pathologies
Uncontrolled hyperglycemia due to deficient insulin action.
Diabetes is an inappropriate and exaggerated starvation response due to lack of insulin

Question 2

What are the short-term consequences of complete loss of insulin action?

Answer 2

Blood glucose rises- the renal tubules cannot reabsorb all-osmotic diuresis- polyuria and polydipsia.
The osmolarity of ECF increases- drawing H2O out of cells, eg cerebral dehydration.
Uncontrolled release of FA from adipocytes, conversion to Ketones, keto-acidosis.

Question 3

What is the endogenous marker of insulin?

Answer 3

C-peptide
Half-life 30min-2,5hrs

Question 4

Define Type-1 Diabetes.

Answer 4

B cell destruction usually leads to absolute insulin deficiency.
AI or Genetic
<30
lean
acute onset
symptomatic
Prone to ketoacidosis

Question 5

Describe Type-2 Diabetes.

Answer 5

Insulin resistance

Question 6

Describe Gestational Diabetes

Answer 6

Hormonal Changes during pregnancy:
Cortisol, proges, oest, and Human placental lactogen lead to insulin resistance.

Mom-
This leads to increase glucose levels and this is transported across the placenta.
Baby-
Becomes adapted to the high glucose levels, leading to the baby having an increase in insulin secretion.
Birth-
Baby is macrosomia- larger than usual, with potential birth complications.
Baby has transient hyperinsulinism. The high glucose supply from the mother is removed, however, the insulin levels remain high for some time and this leads to Hypoglycaemia.
Both-
Risk of DIabetes Type 2 increases.

Question 7

Describe other types of diabetes.

Answer 7

Endocrine-
Cushing syndrome
Acromegaly

Drug-induced-
Glucocorticoids

Question 8

Describe an HBA1c test.

Answer 8

A random blood glucose test.
Glucose binds irreversibly to N-terminal valine on the B chain of Hb, dependent on glucose concentration
A good indicator of long-term average blood glucose, 120 days

Question 9

Why is the blood drawn for OGTT kept in a Sodium Floride tube?

Answer 9

Sodium fluoride is an enzyme inhibitor that prevents glucose from being metabolized by the cells. Flouride ions prevent glycolysis by binding magnesium that is required by the glycolytic enzymes.

Question 10

How do patients and clinicians manage diabetes?

Answer 10

Patient
Glucometer- blood glucose
weight,

Clinician
Urine testing- Reflects several hours ago
Dipstix-glucose
Ketones-DKA
HBA1c
Urinary Albumin +eGFR renal impairment KDIGO
Lipid profile and BP

Question 11

What are the clinical signs of DKA?

Answer 11

Polyuria/polydipsia
Urine glucose and +++ketones
Kussmaul breathing Metabolic acidosis
Acetone breath- green apples
ABG=anion gap acidosis increases

Major sequelae of DKA
Severe dehydration due to osmotic diuresis
Intracellular dehydration (cerebral) and dilutional hyponatremia due to the osmotic effect of glucose
Whole body depletion of Potassium, Phosphate, and Magnesium despite normal plasma levels

Question 12

What are the biochemical markers of DKA, and explain their mechanisms?

Answer 12

Hyperglycaemia
Lack of insulin, no GLUT channels,
Gluconeogenesis- leads to higher urea (deamination of Amino acids, NH3) levels, hypoV, and compromises renal failure

Metabolic Acidosis
Ketone bodies are lost in the urine, but H+ is retained, as it circulates it loses a Proton
Bicarb used up, reduced
Replaced by anions, the anion gap increases
acetoacetate spontaneously decarboxylated, acetone.

Lactic Acidosis
poor perfusion to the muscle (low O2)

Sodium Water
Dilutional Sodium- (Hyperglycaemia draws water out of cells, loss through kidneys)

Potassium
Leaves the cell in ketoacidosis.
Accumulating H replaces K, slightly elevated K that is lost by the kidneys, treatment causes the K to move quickly back into the cell–> HypoK

Phosphate
Release from enzymes in Glycolysis, a sudden drop of Ph after insulin, death.

Question 13

How do you treat DKA?

Answer 13

Rehydration,
Insulin administration
Monitor and replace lost intracellular ions
Look for and treat predisposing causes, eg infection

Question 14

Describe Hyperosmotic Non-Ketotic Coma- HONK.

Answer 14

Type 2, poorly controlled
Insulin levels are high enough to prevent the FFA oxidation to Ketones, but cannot control Glucose.
Onset unnoticed, because the patient doesn’t get sick,
Osmotic Diuresis results in progressive dehydration, coma
Complications
severe dehydration
Intracellular dehydration
Increased blood viscosity – thrombosis
Whole body electrolyte losses (same mechanism as in DKA)

Question 15

What is hypoglycaemia?

Answer 15

Reduced glucose in the blood
All causes of hypoglycemia are due to failure or interference in this normal physiological response to hypoglycemia.

Question 16

Which gluconeogenic precursors cannot form with the consumption of ethanol in a hypoglycemic state?

Answer 16

Lactate and cytosolic oxaloacetate

Question 17

Define CoA trapping.

Answer 17

Any intermediate metabolite that accumulates as a CoA ester will result in decreased levels of acetyl-CoA in liver mitochondria.

Require in the first step of gluconeogenesis.

Occurs in metabolic acidaemias.

Question 18

Describe Glutaric aciduria type 1 (GCDH).

Answer 18

These babies are born normally but when they fast for the first time (eg gastroenteritis) the liver cannot produce enough glucose and the brain starts to use lysine/tryptophan for energy.

This results in the accumulation of toxic metabolites that cause permanent brain damage.

Other common acidaemias are, Propionic and methylmalonic

Question 19

How can diabetic treatment lead to Hypoglycaemia and its complication?

Answer 19

Type 1
Injection of insulin
-tightly controlled, eating too little and exercising to much can lead to hypoglycemia, unaware

Type 2-
Sulfonylureas

Other
Alcohol
Beta-blockers can exacerbate, neuroglycaemia- adrenergically