Transcription
The liver is one of the most important and complex organs in the human body, possessing a remarkable capacity of regeneration. In this part of the lecture, however, we will focus primarily on the liver as a regulatory organ, particularly in regulation to the circulatory system and its blood supply. The liver performs a vast number of functions, and discussing all of them would easily require several lectures. For now, we will concentrate on those functions most relevant to circulation.
One of the most important is, of course, glucose metabolism, which we have already touched upon. Let me highlight several specific liver functions related to glucose that we did not fully cover when discussing diabetes. First, there is glycogenesis. This is the process of converting glucose into glycogen for storage, and it occurs in the presence of insulin. The opposite process is glycogenolysis, which is the breakdown of glycogen back into glucose. This process occurs under the influence of glucagon. And there is also another glucose-related function that we have not yet discussed: gluconeogenesis. The prefix "neo" indicates that something is being created anew. In other words, gluconeogenesis is the production of new glucose from non-carbohydrate sources. Glucose can be synthesized from amino acids, glycerol, and lactate. This process becomes particularly important during fasting when carbohydrates are not being consumed.
That is why I have specifically highlighted lactate metabolism here. The liver is able to remove lactate from the bloodstream. Lactate is produced by skeletal muscles during anaerobic metabolism. As a reminder, when skeletal muscle generates ATP without sufficient oxygen, one of the end products is lactic acid or lactate. Lactate enters the bloodstream and is transported to the liver. The liver then converts lactate back into glucose through the process of gluconeogenesis. The newly formed glucose can then be released back to the skeletal muscle, where it can again serve as a source of energy. This cycle serves two important purposes. Firstly, it prevents excessive accumulation of lactate, and secondly, it helps maintain energy supply to the muscle. If lactate were allowed to accumulate, its acidic nature could contribute to metabolic acidosis. Thus, the liver plays a key role in preventing this.
In the setting of cardiopulmonary bypass and perfusion monitoring, lactate is one of the most important markers reflecting tissue perfusion, oxygen delivery, and metabolic stress. Therefore, this liver function is particularly important to remember. An important point is that lactate is not merely a marker of tissue perfusion; it is also a marker of liver function. As a perfusionist, whenever you observe a rising lactate level, you should ask, "Is lactate increasing because of inadequate tissue perfusion, or because the liver is no longer able to clear it effectively?"
Then, another important function is the removal of cytokines from the blood. As you already know, cytokines are signaling molecules involved in inflammation. During severe inflammatory states, they can accumulate excessively and contribute to a cytokine storm. The liver helps regulate cytokine levels through several mechanisms. One of the most important ones is phagocytosis performed by liver macrophages. You may remember that macrophages in different organs often have specific names. For example, in the lungs, we discussed specialized macrophages known as dust cells. In the liver, these resident macrophages are called Kupffer cells. Conceptually, however, they are still macrophages, and it is perfectly acceptable to refer to them as such. Kupffer cells help remove cytokines through phagocytosis and thereby reduce the likelihood of uncontrolled inflammatory responses, such as a cytokine storm.
We also know that the liver is responsible for much of the metabolism and breakdown of medications and anesthetic agents. Taken together, these and many other liver functions mean that when liver function deteriorates, numerous physiological systems begin to lose their normal regulation. With that in mind, let us now turn to the circulation of the liver and its blood supply.
As a brief reminder, let's review normal liver perfusion. This image shows the inferior surface of the liver. The lower surface of the liver is relatively flat and faces the abdominal organs. On this surface, there are two longitudinal grooves and one transverse groove, which divide the liver into several lobes. The transverse groove contains the porta hepatis, or liver hilum, through which important structures enter and leave the liver. These are the vessels we will focus on entering the liver. Here are the hepatic artery and the hepatic portal vein, also called just the portal vein. Nerves also pass through the porta hepatis, and by the way, the Latin term porta hepatis literally means "gate of the liver." The liver hilum also contains the common hepatic bile duct. Liver cells continuously produce bile, which first enters tiny bile canaliculi and then progressively larger bile ducts, and bile eventually leaves the liver through the right and left hepatic ducts, which merge into a common duct. This then joins the duct from the gallbladder, if there is one, forming the common bile duct, which ultimately empties into the duodenum, where bile is released when food enters the small intestine. But bile is not our main concern right now. We are primarily interested in the blood supply.
The hepatic artery supplies the liver with oxygen-rich arterial blood originating from the heart. The portal vein, on the other hand, delivers venous blood rich in absorbed nutrients. The blood comes from the gastrointestinal tract. In fact, almost the entire digestive tract, apart from a few regions at the very beginning and the very end, is connected to the portal venous system. As a result, most substances absorbed from the gastrointestinal tract pass through the liver before entering the systemic circulation. In this way, the liver acts as a major metabolic and filtering organ. The portal vein also receives blood from the spleen and the pancreas. Therefore, blood carrying nutrients, metabolites, hormones, and other substances from these organs also reaches the liver through the portal circulation before being distributed elsewhere in the body.
So, the key takeaway points here are: hepatic artery supplies oxygenated arterial blood; portal vein supplies nutrient-rich venous blood from the GI tract; both enter the liver through the liver hilum; and the liver hilum also contains nerves, hepatic ducts, bile ducts, and most absorbed substances from the digestive tract pass through the portal circulation and are processed by the liver before reaching the rest of the body.
So, what are the unique features of the liver's blood supply, except the ones discussed already? The liver receives a remarkably large proportion of the cardiac output. In fact, about 1.5 L of blood per minute, or approximately 30% of the cardiac output, passes through the liver at rest. What makes the liver unique from a circulatory standpoint is this dual blood supply. What we discussed: approximately 70% to 75% of hepatic blood flow comes from the portal vein, while only 25% to 30% comes from the hepatic artery.
So, now, what happens during cardiopulmonary bypass? During bypass, portal perfusion virtually disappears. This is because the gastrointestinal tract is no longer perfused in the normal physiological manner. So, venous return from the intestines decreases dramatically, and portal venous flow is greatly reduced. However, hepatic arterial flow remains present. This means that liver perfusion becomes almost entirely dependent on the hepatic artery. The cardiopulmonary bypass circuit maintains arterial pressure and provides arterial blood flow to organs connected to the systemic circulation. Nevertheless, the liver becomes much more dependent on arterial perfusion and therefore on an adequate mean arterial pressure. A relatively low mean arterial pressure may be tolerated by some organs, but for the liver, it can result in clinically significant hypoperfusion. So, the liver does not tolerate prolonged periods of low perfusion pressure particularly well.
Another important aspect occurs during reperfusion. At that moment, the liver once again receives full hepatic arterial flow and restored portal venous flow, and the large influx of metabolites arriving from the gastrointestinal tract. As a consequence, there may be an increase in lactate levels and cytokine concentrations. The cytokines, in particular, activate the liver's resident macrophages, the Kupffer cells. These cells then participate in the hepatic inflammatory and immune response that accompanies reperfusion. Now, reperfusion also amplifies the systemic inflammatory response.
Now, if a patient develops liver dysfunction, in other words, if the liver is no longer functioning properly, then naturally, a number of problems arise. Let me emphasize the point about lactate once again. When the liver is dysfunctional, lactate levels will, of course, become elevated. Therefore, if persistently high lactate levels are observed after cardiopulmonary bypass, it does not necessarily mean that tissue perfusion was inadequate. It may also indicate that the liver is unable to restore normal metabolic function and clear lactate effectively. This is an important point of interpretation for perfusionists. In other words, elevated lactate does not always mean poor perfusion. The problem may instead lie in the liver.
Liver dysfunction can also lead to unstable blood glucose levels. As you have already seen, the liver plays a major role in glucose metabolism alongside the pancreas. In addition, impaired liver function means reduced cytokine clearance. This increases the risk of developing systemic inflammatory response syndrome, or SIRS, after cardiopulmonary bypass. We discussed this previously in hematology. Once this occurs, the patient enters a higher risk category with an increased likelihood of developing multiple organ dysfunction.
And finally, there is a very practical consequence of liver dysfunction. If the liver is less capable of performing its normal functions, then drug metabolism is impaired, and if the liver is not functioning properly, anesthetic agents remain active for a longer period of time. And with that, we conclude our discussion of these remarkable liver functions.