This chapter is relevant to Section G4(ii) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "describe the distribution of blood volume and flow in the various regional circulations ... including autoregulation... These include, but not limited to, the cerebral and spinal cord, hepatic and splanchnic, coronary, renal and utero-placental circulations". The hepatic circulation has come up five times in the past papers (compared to four times for the cerebral circulation, making it 25% more important). Historical SAQs have included:
- 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 (SaO2= 95%; 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 (SvO2=85%; 50-60% of the DO2)
- Total hepatic blood flow: 25% of the total cardiac output, or 1200ml/min.
- This is about 100ml/100g of tissue/minute
- Hepatic oxygen consumption is 6ml/100g/min
- Hepatic venous oxygen saturation is ~ 65% normally
- Hepatic microcirculation:
- Consists of the anastomosis of hepatic arterioles and portal venules
- These vessels join to form hepatic sinusoids
- Sinusoids are highly modified large-caliber capillaries with discontinuous endothelium
- Unique features:
- 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), causing 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, and vice versa.
- 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
Abshagen et al (2015) would make an excellent single reference point to somebody trying to revise this topic, if only it were not paywalled by Springer. For the freegan, Eipel et al (2010) offer essentially the same material, at no cost. And as usual, in a specialised field, there turns up an author who seems to be responsible for the bulk of the literature, who in this case is W. Wayne Lautt from the University of Manitoba; pretty much anything by his team seems to be gold.
The arterial supply of the liver is maintained by the hepatic artery proper, a branch of the common hepatic artery (a short offshoot of the coeliac trunk which also gives rise to the gastroduodenal and right gastric arteries). Omitting the usual complaint about the pointlessness of showing true anatomical relations to the person who will never see them, the author presents this lovely squidlike diagram from Chamberlain (2012):
In textbooks, this artery is said to carry approximately 350ml/min of oxygenated blood to the liver, at a proper arterial pressure with a MAP of around 65-90 mmHg. Thus, with sats of 100% and a standard anaemic ICU-patient-like haemoglobin of 100g/L, the hepatic arterial DO2 ends up being about 48ml/min. However, owing to its ability to self-regulate, the actual flow rate in any given artery is going to be quite different. As an example, here is a table from Tygstrup et al (1962). The authors measured these values directly from cannulated hepatic vessels of human subjects. The average value was around 550ml/min, or 35% of the total hepatic blood supply, but this was within a massive range (from 166ml to over 1L/min):
The portal venous circulation is basically a passively flowing sewer of rather toxic oxygen-depleted blood, which is made up of a system of valveless vessels with little smooth muscle in their walls. The superior mesenteric vein and the splenic vein join behind the body of the pancreas to form the portal vein, which is a short fat vessel with a relatively unexciting wall microstructure. The vandalised anatomical art here is stolen from anatomycorner.com:
As mentioned, this is a system of venous vessels which have no valves. Why, is a question open for debate. Certainly, that's not the sort of thing you could ever expect high-grade clinical trial evidence for, which means all we have is the speculation of experts. Some may point to the need to maintain unimpeded flow with a relatively low pressure gradient; supposedly venous valves would obstruct the lumen and act as resistors, which would be counterproductive. Others suggest that it has no need for valves, as it lives in the low-pressure environment of the abdomen. In the calves, for example, compartment pressure constantly changes, squeezing the veins - if there were no valves, this would produce retrograde flow into the foot, which would be totally counterproductive. In the abdomen the compartment pressure is constant (and normally, low), which means the portal vein can expect a reliable unidirectional flow to be maintained without valves.
Flow through the portal circulation is driven mainly by the transmitted pressure of the blood being pushed up through the splanchnic arterioles. As a result, this flow is nonpulsatile, and under little pressure. Balfour et al (1954) directly measured portal venous pressures of around 8-10 mmHg in healthy(ish) patients. The vascular resistance here produces a pressure drop from 8-10 mmHg in the portal vein, down to 2-4 mHg in the central veins, which Lautt at al (1967) localised to small post-sinusoidal venules (vessels beyond the sinusoidal anastomosis which drain into the hepatic vein and which are about 2mm in diameter).
So, in spite of the low driving pressure, because the vascular resistance is very low this system is capable of conducting vast flows of blood. Most textbooks will quote something between 800 to 1200 ml/min, and obviously this will depend on whose liver you are asking. Brown et al (1989) asked forty-five normal Caucasian livers and arrived at a mean value of 864 ml/min in the supine position, which dropped to 662 ml/min when the subjects were upright.
Oxygen saturation of portal venous blood is only about 85%, which drops even lower after a meal. Hardin et al (1963) directly cannulated the portal veins of anaesthetised dogs and measured a mean value of 81%, though the values ranged as low as 65% in some. Following a meal, this value dropped as low as 69-76%. However, because the blood flow through this system is so large, the total flux of oxygen delivery remains high. Using the conventional equations, one can calculate that a flow of 800ml/min with sats of 80% and a Hb of 100 gives a DO2 of 88ml/min. This is about double of what is provided by the hepatic artery. In other words, the hepatic artery contributes only about 30-40% of the total oxygen supply of the liver, even though many textbooks will report that it is a 50:50 split with the portal vein (eg. Dancygier, 2010). The origin of this 50% value is probably the old article by Tygstrup et al (1962). They reported numerous interesting human measurements (eg. mean pressures in hepatic vessels, their blood flows, their resistance, etc), and this has made their paper an attractive reference for several generations of textbook authors.
From thus weird dual blood supply, the liver receives a massive total blood flow of around 1200-1800 ml/min, which ends up being about 20-25% of the cardiac output. Logically, hepatic venous blood outflow is equal to this inflow, and hepatic veins are suitably large. There are usually three of them (right, middle and left), but there appears to be a substantial variation in their anatomy from person to person, which is a problem for anatomists who have decided to use these veins to define the segments of the liver. Wherever anatomical arrangement is factory-standard, the right hepatic vein is usually dominant, accounting for most of the venous drainage.
The liver extracts about 6ml/100g/min of oxygen from its dual blood supply, which delivers an average of 16ml/100g/min of oxygen (Lutz et al, 1975). This gives an oxygen extraction ratio of around 37%. From this, you would expect a hepatic venous oxygen saturation of something like 60%, which is almost exactly what was measured by Finnnerty et al (2019). Or at least, that's the sort of number you might expect when everything is well. As will be explained below, the oxygen extraction varies considerably, depending on the adequacy of supply and the magnitude of demand.
This deserves a mention here because it is fairly unique from a circulatory perspective. It would be tempting to dive deep into this subject here, but for the time being, the reader will instead be redirected to such excellent free articles as Wake & Kato (2015). In short, portal venules and hepatic arterioles merge anastomotically into hepatic sinusoids, which then drain into post-sinusoidal venules.
The terminal vessels of the portal venous network maintain a low resistance even down to a very narrow calibre, which means that most of the pressure from the portal vein is transmitted directly to the hepatic sinusoids. These sinusoids might be called "capillaries" in any other organ, but they are structurally quite different, being much wider in diameter than a normal capillary, and having a discontinuous epithelium. The pressure gradient across these vessels is relatively low; according to Henriksen & Lassen (1988), it is no more than 3-5mmHg under normal conditions. With such a low driving pressure, the flow here has an unusually low velocity, allowing maximal extraction of oxygen and other molecules. The low pressure also helps to maintain the pressure gradient between the portal circulation and the sinusoids, which protects this valveless system from retrograde flow.
In textbooks, much is made of the storage function of the liver. It is a heavy blood-filled organ, which is about 25% blood by weight (Greenway & Stark, 1971), as can be appreciated from this cast of the portal system (Okudaira, 1991), the black and white original colourised in garish red presumably for some sort of blood-like effect:
If one were designing a circulatory system for such an active and accident-prone organism as man, one might be tempted to make this vast reservoir of blood accessible by the body in times of haemorrhage or exercise. That is in fact what happens in many mammals. For example, in the dog, Guntheroth & Mullins (1963) were able to demonstrate the mobilisation of a stored hepatosplenic volume equivalent to 8% of the total circulation, triggered by catecholamine release. Other animal studies generally produce similar findings, and though there does not appear to be any human data to support this, generally textbooks tend to agree that it probably also happens in humans, and describe the liver as an important storage organ.
From the discussions above, one might fall into the trap of thinking that the portal vein plays little role in managing in its own flow. In that case, it would be of course facetious to title this section "regulation of portal venous blood flow" if it were totally unregulated. The portal vein would therefore be viewed as a stupid organ which acts as a passive conduit for blood, incapable of doing anything more intelligent than forming a clot to block itself. That, of course, is not the case.
It is true that flow in the portal vein is mainly determined by the flow in the splanchnic arteries, which determine the amount of blood delivered to the portal system. From this, it logically follows that portal blood flow should be susceptible to manipulation by altering the vascular resistance of the splanchnic arterial circulation. This indeed appears to be the case, as splanchnic vasoconstrictors (such as terlipressin) decrease portal venous flow. In fact, a 2mg dose of terlipressin decreased portal venous flow by almost 40% in a study by Baik et al (2005), which is the basis of its therapeutic effect in the control of variceal bleeding.
Thus, the portal vein does in fact have smooth muscle, and receptors for all the major vasoactive substances. Richardson & Withrington (1981) list a whole host of vasopressors, and Blei (1989) lists multiple vasodilators, of which the following list is a conservative abridgment:
Thus, the portal venous circulation responds to a variety of stimuli, some of which can double or halve its resistance (which admittedly is not saying much, as it is very low to begin with). The response to endogenous vasopressors is likely related to the liver's apparent role as a blood reservoir, in which case it would make sense to decrease the portal venous volume and "flush" the extra blood into the systemic circulation. The attentive reader will also have identified some splanchnic hormones in the list above, which might suggest some sort of digestion-related regulatory mechanisms. This is in fact true. Dauzat et al (1994) were able to investigate this in healthy volunteers using noninvasive measurement techniques, and found that the portal vein increases in crossectional area by 40% following a "standard meal" (apparently, that's 470ml of Ensure), which was associated with a massive 80% increase in flow.
The hepatic artery, being a muscular member of the systemic circulation, is affected by all sorts of clearly defined regulatory mechanisms. If one had to classify them, they would fall into two messy overlapping categories:
Arterial autoregulatory mechanisms are discussed in greater detail elsewhere, as they are fairly generic and are applicable to all arterial regional circulatory systems. These generic factors can be further classified into local and systemic:
The hepatic arterial buffer response is also known by the mellifluous name, "hepatic arterial-portal venous semi-reciprocal interrelationship". The basic principle can be summarised very simply. When portal venous flow goes down, hepatic arterial flow goes up. In other words, hepatic arterial vascular resistance is proportional to portal venous blood flow. Lautt et al (1990) were able to demonstrate that this relationship is relatively linear, over a normal range of flows:
This relationship operates over a fairly rapid timeframe. When the portal vein is clamped intraoperatively, hepatic arterial flow increases by about 30% almost immediately (Jacab et al, 1995). Though this relationship is often described as "semi-reciprocal", as in most relationships one partner ends up doing all the work; if the hepatic artery is clamped, the portal vein does nothing to increase its flow.
How does this happen? The most plausible explanation is the "adenosine washout hypothesis". This was proposed by Lautt et al (1985), and has persisted in the literature, in spite of having fairly shaky evidence to support it. In summary:
This idea seems to have the sort of longevity which one might expect from a theory which is in fact correct, and the main challengers seem to mainly dispute the nature of the washed-out mediator (i.e. some claim it must be nitric oxide, ATP, carbon monoxide, and so on). For the sake of the reader's sanity, these details will be left to lay on the shore where they were found.
From all of the above discussion, one might correctly conclude that, though the blood supply of the liver is clearly subject to some regulation, it does not seem to be particularly closely tied to its metabolic rate - certainly not to the same extent as the cerebral circulation is tied to cerebral metabolism, for example. This is reasonably correct. The most important regulatory mechanisms, such as the portal post-prandial flow increase or the hepatic arterial buffer response, are really not designed to match supply to demand - they appear to be focused on the management of substrate delivery for the whole organism, rather than the liver itself.
Thus, the liver must adjust to fluctuating oxygen delivery in other ways. Namely, it alters its oxygen extraction ratio. Lutz et al (1975) found that the relationship between oxygen extraction and blood flow was essentially linear, i.e. as oxygen delivery to the liver decreased, it extracted more and more oxygen, until essentially all of it was gone and the hepatic venous blood ran black with anoxia. As one can clearly see from this diagram from the original paper, the extraction ratio trends towards 100%.
The reason this is included here is because in the college comments to Question 13 from the second paper of 2016, the examiners expected a good answer to "revolve around how the liver blood flow is controlled... ...with respect to intrinsic and extrinsic factors". What are these extrinsic factors? Looking at how they are represented elsewhere, one comes to the conclusion that the list must be impossibly broad, and could include factors like "being punched in the liver" and "circulatory death". Rather than describing these as "control mechanisms" or "regulatory factors", it would be more honest to describe them as "external influences which affect hepatic blood flow, often dramatically, in spite of which the liver still somehow functions". To summarise them:
Question 13 from the second paper of 2016 also asked the trainees to "explain the changes to drug metabolism when liver blood flow decreases". This is really a question about hepatic clearance, which is discussed in detail in the pharmacokinetics section. To reduce the number of clicks involved in one's exam revision, the important points are reproduced here in the shortest possible form.
where the hepatic extraction ratio here is represented by everything beyond the "×" symbol.
With decreasing hepatic blood flow, hepatic extraction ratio will increase for all drugs.