#Hepatic circulation

#Outline the anatomy and physiology of liver blood flow

#Normal values

Total hepatic blood flow:

• ~ 1500 mL/min
• ~ 100 mL/100 g/min (liver mass ~ 1500 g)

Accounts for ~ 25% of cardiac output.

#Anatomy

Hepatic artery (arterial supply)

• Coeliac trunk → common hepatic artery → hepatic artery proper → sinusoids
• Contributes:
  • ~30% of total hepatic blood flow
  • ~50% of hepatic oxygen delivery (DO₂)

Portal vein (venous inflow)

• Mesenteric veins → portal vein → sinusoids
• Contributes:
  • ~70% of hepatic blood flow
  • ~50% of hepatic oxygen delivery
• Portal venous oxygen saturation:
  • ~85% in the fasted state
  • ~70% in the fed state (due to consumption of O₂ by GI tract)

Hepatic vein (venous outflow)

• Sinusoids → central (lobular) veins → hepatic veins → inferior vena cava

Sinusoids

• specialised, highly fenestrated capillaries unique to the liver
• allow exchange of oxygen and nutrients from the hepatic artery and portal vein with hepatocytes
• waste products are carried to the venous system
• descibed in more detail here

#Physiology

The determinants of blood flow in a regional circulation (like the liver) are best described when considering the following concepts:

• Autoregulation
  • the intrinsic ability of a regional circulation to maintain relatively constant blood flow across a range of perfusion pressures or other conditions
• Ohm's law
  • Describes the relationship between driving pressure, flow and resistance
  • $\Delta \text{Pressure} = \text{Flow} \times \text{Resistance}$
  • Rearranged, we get: $\text{Flow} = {\Delta \text{Pressure} \over \text{Resistance}}$
  • Simplified to: $\text{Q} = {\Delta \text{P} \over \text{R}}$
• Hagen-Poiseuille equation
  • Describes the resistance to flow in a cylindrical tube (like a blood vessel!)
  • $\text{Resistance} = {{8 \times \text{viscosity} \times \text{length}} \over \pi \times \text{radius}^4}$
  • Simplified to: $R = {8ηL \over πr^4}$
  • Requires assumptions:
    • that blood flow is laminar (mostly true).
    • that blood is a Newtonian fluid, meaning it has constant viscosity (not true).
    • even though blood does not satisfy our assumptions, this equation still gives us a framework for describing resistance.
• These equations can be combined to a single 'comprehensive' equation that describes the determinants of blood flow:
  • $R = {\Delta \text{P} πr^4 \over 8ηL }$
• Putting this together, we find that:
  • Increased pressure difference across the liver increases blood flow.
    • This could be due to a higher hepatic artery or portal vein pressure,
    • or a lower hepatic vein pressure.
  • Increased blood viscosity or blood vessel length increases resistance, which decreases blood flow.
  • Increased blood vessel radius decreases resistance, which increases blood flow.
    • Radius is the biggest determinant of resistance because it is raised to the 4th power in the Hagen-Poiseuille equation.
    • It is also more easily altered (by vasodilation or constriction) than other factors.

#Autoregulation

Myogenic (pressure-dependent)

• Hepatic arterioles dilate in response to reduced perfusion pressure.
• Fails when SBP < ~80 mmHg.
• Below this threshold, hepatic blood flow (HBF) becomes pressure dependent.

Hepatic arterial buffer response (interdependence)

• Portal vein flow is not autoregulated and varies with portal pressure
• A fall in portal venous flow triggers adenosine-mediated dilation of the hepatic artery
  • Adenosine activates A2 receptors on the arterial endothelium.
  • A2 receptors are Gs-coupled receptors.
  • Activation leads to ↑cAMP → calcium ion influx → vasodilation
  • Exact mechanism of adenosine release remains incompletely understood
• Helps stabilise total hepatic blood flow and oxygen delivery
• This mechanism only works in one direction. If hepatic arterial flow decreases, the portal vein does not dilate to compensate.

Metabolic autoregulation

• Increased oxygen demand is usually met by increased oxygen extraction, rather than increased blood flow (due to high baseline flow)
• Increased metabolic activity produces local metabolites (CO₂, H+, K+, adenosine) which promote vasodilation → ↑HBF.

#Other determinants

Flow/shear-stress

• Increased flow or shear stress stimulates endothelial nitric oxide (NO) release → vasodilation → ↑HBF.

Adrenergic / sympathetic activity

• Hepatic artery
  • Initial α-mediated vasoconstriction
  • Followed by β-mediated vasodilation
• Portal vein
  • α-mediated vasoconstriction only (due to few β-receptors)

Extrinsic factors

• ↓ hepatic artery flow → ↓HBF
  • e.g. due to ↓ cardiac output
  • e.g. due to PEEP
• ↓ portal vein flow → ↓HBF
  • e.g. due to fasting
• ↑ blood viscosity → ↓HBF
  • due to ↑ resistance
  • e.g. due to high haematocrit, hyperlipidaemia, hyperproteinaemia
• ↑ blood vessel length → ↓HBF
  • due to ↑ resistance
  • effectively fixed and cannot be modified
  • varies with body size

#Explain the changes to drug metabolism when liver blood flow decreases

Hepatic clearance ($Cl_H$) is the volume of drug cleared by the liver per unit of time.

Hepatic extraction ratio ($E_H$) is the fraction of drug presented to the liver that is cleared in a single pass. It depends on:

• Unbound fraction of drug ($f_u$)
• Intrinsic clearance ($Cl_{int}$), reflecting hepatic enzyme activity
• Hepatic blood flow
• Mathematically, $E_H = (f_u × Cl_\text{{int}}) / (\text{HBF} + f_u × Cl_\text{{int}})$

The relationship between hepatic clearance, extraction and hepatic blood flow (HBF) can be expressed as:

$$Cl_H = \text{HBF} × E_H$$

A reduction in hepatic blood flow therefore leads to reduced hepatic drug clearance. This effect is most pronounced for drugs with a high extraction ratio (e.g. propofol). For these drugs, extraction is already efficient so blood flow becomes the limiting factor for drug clearance.

Reduced hepatic blood flow also increases the hepatic extraction ratio. This can be thought of as the concentration of hepatic enzyme activity on a smaller volume of blood, leading to greater proportion of the drug being cleared. This effect will not overcome the overall decrease in hepatic clearance described above.