Clinical Biochemistry

Biochemistry — Clinical Biochemistry, NMC MBBS licence examination syllabus (Nepal Medical Council).

Clinical Biochemistry: metabolism as an explanation for illness

Diabetic ketoacidosis happens in a patient whose blood is full of glucose. Biochemistry is what explains that contradiction.

Biochemistry learned as pathway diagrams is forgotten within weeks and is not what a licensing examination asks about. Learned as the reason a patient is unwell, it becomes memorable and useful.

This chapter covers the switch that runs metabolism, why the brain is a special case, how inborn errors present, and the vitamin deficiencies with pictures you can recognise at the bedside.

The fed–fasting switch

Almost all of metabolic regulation reduces to one question: is the body storing or releasing? Insulin is the signal that decides.

Fed state, insulin high. Fuel is abundant, so the instruction is to store it: glucose is taken into cells and stored as glycogen, and excess is converted to fat. Breakdown pathways are switched off.

Fasting state, insulin low. Fuel must be released. Glycogen is broken down first, then fat, and eventually the liver manufactures new glucose. Throughout, the priority is keeping the brain supplied.

Now the contradiction resolves. In diabetic ketoacidosis, blood glucose is very high — but without insulin, cells cannot take it up, so the body reads the situation as starvation. It breaks down fat for fuel, ketones accumulate as the by-product, and the blood becomes acidotic. That is why the treatment is insulin rather than simply lowering the glucose: the glucose is a symptom of the signalling failure, not the problem itself.

This single idea explains far more of the diabetic emergencies chapter than any pathway diagram would.

Why the brain is a special case

Most tissues will burn fatty acids happily when glucose is short. The brain cannot — fatty acids do not cross into it in useful quantities — and it stores almost no fuel of its own.

So the brain requires a continuous glucose supply, and much of the fasting response exists to protect it.

In prolonged fasting the brain adapts, partly. It becomes able to use ketones for a large share of its energy, which is genuinely useful: it reduces how much glucose must be manufactured, and therefore how much muscle protein must be broken down to supply the raw material. Starvation would be far more rapidly fatal without this adaptation.

But adaptation takes days. In acute hypoglycaemia there are no ketones available yet and no substitute fuel, which is why hypoglycaemia produces confusion, seizures and death within minutes rather than hours — and why it is treated immediately rather than investigated first.

Inborn errors: one blocked step, three consequences

There are hundreds of inborn errors and no purpose in memorising them. There is one shape that nearly all of them share, and knowing it lets you reason about an unfamiliar one.

An enzyme in a pathway is deficient. Three things follow:

The substrate accumulates behind the block. If that substance is toxic, the accumulation is what harms the patient.
The product is missing beyond the block. Sometimes the deficiency matters more than the accumulation.
Minor alternative pathways open up, producing metabolites that are normally negligible — and those unusual metabolites are often what appears in the urine and gives the diagnosis.

Treatment follows the same three-part logic, which is why it is worth learning the shape rather than the list: restrict what accumulates (dietary restriction), replace what is missing (supply the product), or remove what is toxic. Ask which of the three applies and you have the principle of management even for a condition you have not met.

How an inborn error presents

The classical presentation is a baby who is completely normal at birth and then deteriorates once feeding is established.

Why the delay? Because before birth, the placenta was clearing the accumulating metabolite through the mother's circulation. Delivery removes that, and feeding supplies the substrate — so the metabolite builds up over the first days.

The clinical picture is poor feeding, vomiting, lethargy, seizures — which is indistinguishable from neonatal sepsis, a far commoner condition. So sepsis is treated, correctly, and the metabolic cause is missed.

💡 The practical trigger to remember: consider a metabolic cause when a baby treated for sepsis does not improve as expected. Two further features raise the possibility sharply — consanguinity in the parents, since most of these conditions are recessive, and an unexplained neonatal death in a previous sibling. Asking those two questions costs nothing and occasionally changes everything.

Vitamin deficiencies with recognisable pictures

Several deficiencies produce patterns distinctive enough to be diagnosed clinically, and two of them carry an important management point.

Thiamine (B1). Deficiency causes a characteristic neurological syndrome — confusion, eye movement abnormalities and unsteadiness — and, in a different form, high-output cardiac failure. It is associated with chronic alcohol use and with any state of prolonged poor nutrition.

The safety point that matters at the bedside: giving glucose to a thiamine-deficient patient can precipitate the acute neurological syndrome, because metabolising that glucose consumes the little thiamine remaining. So in a malnourished or alcohol-dependent patient who needs glucose, thiamine is given first or alongside. This is one of the few biochemistry facts that changes what you do in the next five minutes.

B12 and folate both cause a macrocytic anaemia, and the blood film cannot separate them. But only B12 deficiency damages the nervous system — and treating with folate alone can correct the anaemia while the neurological damage continues and becomes irreversible. That is why both are measured before treating a macrocytic anaemia, rather than simply supplementing.

Vitamin D deficiency impairs bone mineralisation, giving rickets in growing children and osteomalacia in adults. Vitamin A deficiency causes night blindness first and can progress to corneal damage and blindness. Vitamin C deficiency impairs collagen formation, so it presents with bleeding gums, poor wound healing and easy bruising.

Two more clinically useful points

Enzymes in blood indicate where damage is, not how severe it is. A raised transaminase means hepatocytes have leaked; a raised amylase means pancreatic acinar cells have. The pattern localises the injury. But the height of the number correlates poorly with severity — a failing liver with few remaining cells may release less enzyme than a mildly injured healthy one. Interpret the pattern, not the magnitude.

Plasma proteins explain oedema in liver disease and in malnutrition. Albumin holds fluid inside vessels by osmotic pressure. When the liver cannot make it, or protein intake is inadequate, that pressure falls and fluid leaks into the tissues — which is why oedema appears in both cirrhosis and severe malnutrition despite entirely different causes.

Putting it together

Insulin is the store-or-release switch — and its absence makes the body behave as if starving, which is what ketoacidosis actually is.
The brain cannot burn fat, adapts to ketones only over days, and therefore has no defence against acute hypoglycaemia.
One blocked step gives three consequences — accumulation, deficiency, alternative pathways — and treatment addresses whichever matters.
A normal newborn who deteriorates after feeds begin may have a metabolic disorder; ask about consanguinity and previous sibling deaths.
Thiamine before glucose in the malnourished patient.
Folate alone can mask B12 deficiency while nerve damage becomes permanent.

No reference ranges, requirement figures or supplement doses appear here: ranges differ between laboratories and requirements between national bodies. Use your laboratory's ranges and your national guideline.

Syllabus points

Insulin as the store-or-release switch
Why ketoacidosis happens in high blood glucose
The brain cannot burn fat; ketone adaptation takes days
One blocked step, three consequences
Inborn errors present after feeding starts
Consanguinity and previous sibling death
Thiamine before glucose
Folate can mask B12 deficiency

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