Outline the anatomy and physiology of liver blood flow (60% of marks).

Explain the changes to drug metabolism when liver blood flow decreases (40% of marks).

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College Answer

A statement regarding the quantum of hepatic blood flow with recognition of the contributions 
made by the Hepatic Artery and Portal Vein, drainage into the sinusoids before entering the 
hepatic vein which drains into the IVC would have been a good start. Discussion was then 
expected to revolve around how the liver blood flow is controlled. Answering this with respect 
to intrinsic and extrinsic factors along with an understanding of the semi-reciprocal relationship 

between hepatic arterial and portal venous blood flow would have rounded out a good answer 
to the first part of the question.
The second part of the question required recognition that hepatic clearance is the product of 
hepatic blood flow and the hepatic extraction ratio and considering the impact on drugs with a 
high or a low extraction ratio.
Many answers failed to adequately mention how hepatic blood flow was controlled/regulated 
thus limiting the marks available. Similarly, in the second part of the question, many candidates 
spent considerable time mentioning the principals of drug metabolism rather than focusing on 
the question asked. 
The concept of hepatic drug clearance as the product of blood flow and its extraction ratio was 
poorly appreciated.

Discussion

The anatomy and physiology of hepatic blood flow is a difficult topic to write a short coherent answer for. What follows is a summary of a summary, made as short as possible without losing what the author considers to be key elements. Even with this level of distillation, it ended up being humongous and unwieldy, such that no normal person could ever reproduce it in ten minutes, even if it were memorised and regurgitated verbatim. It is therefore remarkable that 55% of candidates passed this SAQ, and it would be very interesting to see what they wrote and which corners they cut.

Anyway:

  • Hepatic blood supply:
    • From the hepatic artery (a branch of the coeliac trunk)
      • Under aortic pressure (MAP ~65-90 mmHg)
      • 30-40% of the blood flow (SvO2= 85%; 40-50% of the DO2)
    • From the portal vein (confluence of mesenteric and splenic veins)
      • Valveless, low pressure venous system (8-10 mmHg)
      • 70% of the total blood flow (SaO2=95%;  50-60% of the DO2)
    • Total hepatic blood flow: 1200-1500ml/min, or 100ml/100g/minute 
  • Hepatic microcirculation:
    • Hepatic arterioles and portal venules join to form hepatic sinusoids
      • Low pressure, to prevent retrograde flow in the valveless portal system
      • Low flow velocity, to enhance extraction of oxygen and other molecules of interest
  • Hepatic blood flow regulation
    • Portal venous flow regulation:
      • Flow rate is mainly determined by splanchnic arterial flow rate
      • Resistance changes in response to:
        • Humoural signals (eg. catecholamines), in shock
        • Local endocrine signals (eg. VIP and secretin), causing portal vasodilation following a meal
    • Hepatic arterial flow regulation:
      • Standard arterial regulatory mechanisms: myogenic, flow(shear)-mediated, conducted vasomotor responses, immunologically mediated by inflammatory molecules.
      • Hepatic arterial buffer response: hepatic arterial flow increases if portal venous flow decreases; mediated by adenosine
  • External factors which influence hepatic blood flow:
    • Venous return: affects hepatic venous drainage (eg. during positive pressure ventilation or heart failure)
    • Cardiac output: influences hepatic arterial flow directly, and portal flow indirectly (eg. in heart failue)
    • Shock states and exercise: decrease splanchnic blood flow, both portal and hepatic

As for the changes to drug metabolism when liver blood flow decreases:

  • Rate of drug metabolism will decrease for most drugs when hepatic blood flow decreases, because hepatic blood flow is an important determinant of hepatic clearance:
    • Hepatic clearance is the product of hepatic blood flow and the hepatic extraction ratio:

      hepatic clearance equation

      where everything beyond the "×" symbol represents the hepatic extraction ratio 

  • What happens to drug metabolism with decreasing liver blood flow depends on the intrinsic hepatic clearance of that drug.
    • The higher the intrinsic clearance, the more blood-flow-dependent the clearance of that drug.
    • Thus, for drugs with low intrinsic clearance, hepatic clearance will not decrease significantly with increasing blood flow.
    • For drugs with high intrinsic clearance, hepatic clearance will decrease in proportion to decreasing hepatic blood flow.

References

Eipel, Christian, Kerstin Abshagen, and Brigitte Vollmar. "Regulation of hepatic blood flow: the hepatic arterial buffer response revisited." World journal of gastroenterology: WJG 16.48 (2010): 6046.

Abshagen, K., et al. "Anatomy and physiology of the hepatic circulation." PanVascular Medicine (2015): 3607-3629.

Greenway, C. V., and R. D. Stark. "Hepatic vascular bed." Physiological reviews 51.1 (1971): 23-65.

Dancygier, Henryk. "Hepatic Circulation." Clinical Hepatology. Springer, Berlin, Heidelberg, 2010. 55-

Wilkinson, Grant R., and David G. Shand. "A physiological approach to hepatic drug clearance." Clinical Pharmacology & Therapeutics 18.4 (1975): 377-390.