Liver Detoxification and Alcohol

What is the liver’s role in nitrogen metabolism?

It converts toxic nitrogen from amino-acid breakdown, mainly ammonia, into urea for excretion by the kidneys.

Why are alanine and glutamine important in nitrogen metabolism?

They transport nitrogen from peripheral tissues, especially muscle, to the liver

Why is ammonia dangerous, and how is it made safer?

Ammonia is toxic, particularly to the brain. The liver converts it into non-toxic urea through the urea cycle.

Where does the urea cycle occur?

Only Liver

What is the rate-limiting step of the urea cycle?

Formation of carbamoyl phosphate.

How does arginine regulate the urea cycle?

Arginine increases N-acetylglutamate (NAG), which activates the urea cycle by feed-forward regulation.

What is hyperammonaemia?

Dangerous accumulation of ammonia in blood due to failed nitrogen disposal, such as a urea-cycle defect.

What is the purpose of Phase I and Phase II detoxification?

Phase I commonly modifies chemicals by oxidation; Phase II conjugates them to increase solubility and support elimination.

What do cytochrome P450 enzymes do?

They oxidise drugs and xenobiotics; their activity varies between individuals and can be affected by alcohol and smoking.

How are detoxified substances excreted?

Water-soluble products are usually excreted by the kidney in urine; large hydrophobic compounds leave through bile and faeces.

Why are glucose, NADPH, and glutathione linked in detoxification?

Glucose supports NADPH production via the pentose phosphate pathway; NADPH regenerates glutathione, which detoxifies reactive oxygen species and xenobiotics.

State the core alcohol-metabolism pathway.

Ethanol -> acetaldehyde -> acetate. Alcohol dehydrogenase produces acetaldehyde and NADH; aldehyde dehydrogenase produces acetate.

Why does ALDH2 deficiency cause alcohol intolerance?

Acetaldehyde cannot be cleared efficiently, so it accumulates and causes unpleasant toxic effects

What is the key metabolic effect of heavy alcohol intake?

It raises the NADH/NAD+ ratio, disrupting normal liver metabolism.

How does excess NADH cause fatty liver?

It inhibits the TCA cycle and shifts metabolism toward fatty-acid/triglyceride synthesis; acetaldehyde also reduces VLDL-mediated lipid export.

Why can alcohol cause lactic acidosis?

Excess NADH shifts metabolism toward lactate production, causing lactate accumulation.

Why can drinking while fasting cause hypoglycaemia and ketoacidosis?

High NADH inhibits gluconeogenesis; during fasting, low glucose production plus ketone and lactate accumulation can cause hypoglycaemia and acidosis.

What is the progression of alcohol-related liver disease?

Steatosis (fatty liver) -> hepatitis -> fibrosis -> cirrhosis. Early stages can improve with abstinence; cirrhosis is irreversible

What happens to CYP2E1 in chronic alcohol use, and why is this harmful?

CYP2E1 is induced, increasing alcohol metabolism but also reactive oxygen species, acetaldehyde formation, and toxic drug metabolism.

Why does chronic alcohol use increase the danger of paracetamol?

CYP2E1 converts paracetamol to toxic NAPQI; increased NAPQI formation can cause liver necrosis if detoxification is insufficient.

Why can liver failure cause bleeding?

The liver makes many coagulation factors. Reduced production, including impaired vitamin K-dependent factor function, increases bleeding risk.