Hepatic Lobule Zonation Simulator

Sinusoidal Perfusion

Sinusoidal blood flow 1.0×

Wnt/β-catenin signalling strength 1.0×

Hepatotoxin Challenge

Toxin dose (CYP450-activated, e.g. APAP) 0

Hepatic glutathione (GSH) reserve 100

Lobule Readouts

O2 — zone 1 (periportal)

65 mmHg

O2 — zone 3 (pericentral)

6 mmHg

Necrotic hepatocytes

Zone 1Zone 2Zone 3

How it works

Blood enters each hepatic lobule at the portal triad (portal vein + hepatic artery + bile duct) and flows through a sinusoid to the central vein. Hepatocytes consume oxygen as it passes, so O₂ tension falls along the sinusoid — an approximately exponential decay set by flow rate and metabolic demand:

O2(s) = O2_portal · exp(-(k / flow) · s),  s ∈ [0,1] (portal → central)

Independently, the central-vein endothelium secretes Wnt2/Wnt9b and RSPO3, forming a diffusion gradient that rises toward the central vein and switches on the β-catenin target genes of "zone 3" identity (CYP450s, glutamine synthetase, lipogenic enzymes):

Wnt(s) = Wnt_max · exp(-(λ/W) · (1 − s))
Zonation index Z(s) = 0.5·(1 − O2(s)/O2_portal) + 0.5·(Wnt(s)/Wnt_max)

Low Z (zone 1, periportal) hepatocytes run gluconeogenesis, β-oxidation and the urea cycle; high Z (zone 3, pericentral) hepatocytes run glycolysis, lipogenesis and CYP450 drug metabolism — the colour of every hepatocyte in the scene is this same Z value, amber → violet.

Because CYP450 activity tracks Z, a CYP-activated hepatotoxin (the acetaminophen/APAP overdose model) does the most damage in zone 3, where NAPQI production is highest and glutathione (GSH) — the antioxidant that neutralises it — is normally scarcest:

toxic load(s) = (dose/100) · CYP(s),  CYP(s) = Z(s)^1.3
net injury(s) = clamp(toxic load(s) − 0.55·GSH/100, 0, 1)

A hepatocyte with net injury above threshold undergoes necrosis — reproducing the classic centrilobular (zone-3) necrosis pattern seen on liver biopsy after acetaminophen overdose, and explaining why N-acetylcysteine (which replenishes GSH) is the antidote.

Zone 1 — periportal Zone 3 — pericentral Necrotic hepatocyte Portal triad Central vein

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