Version May 2024
INTRODUCTION — The liver's complex vascular supply and high metabolic activity make it particularly vulnerable to circulatory disturbances. The severity and characteristics of hepatic injury depend upon the blood vessels that are involved and the degree to which injury is related to passive congestion or diminished perfusion [1-4].
There are several well-recognized forms of vascular injury to the liver including Budd-Chiari syndrome, sinusoidal obstruction syndrome (hepatic veno-occlusive disease), passive congestion due to heart failure, hepatic infarction, and ischemic hepatitis. This topic review will focus on the pathogenesis of passive congestion and ischemic hepatitis. Discussions on Budd-Chiari syndrome and sinusoidal obstruction syndrome are presented separately. (See "Budd-Chiari syndrome: Epidemiology, clinical manifestations, and diagnosis" and "Hepatic sinusoidal obstruction syndrome (veno-occlusive disease) in adults".)
HEPATIC BLOOD FLOW — The liver receives approximately 25 percent of cardiac output even though it makes up only approximately 2 to 3 percent of total body weight [5,6]. The portal vein provides approximately two-thirds of the blood supply, while the hepatic artery provides the rest. Blood flowing through the liver is drained via the right, left, and middle hepatic veins into the inferior vena cava and then into the right side of the heart.
The composition of the portal venous and hepatic arterial blood supply differ. While portal venous blood is rich in basic nutrients (such as glucose, amino acids, and triglycerides), it is relatively deficient in oxygen. In contrast, the hepatic artery supplies oxygen-rich blood (accounting for more than 50 percent of the oxygen delivered to the liver and 100 percent to the major bile ducts) but contains fewer basic nutrients.
Despite its importance in providing oxygenated blood, ligation or occlusion of the hepatic artery in humans can be tolerated without adverse consequences. In most patients, collateral arterial flow combined with portal blood flow can provide adequate circulation [7]. In rare patients, disruption of the hepatic arterial flow can cause focal hepatic infarction.
Segmental anatomy — The liver can be divided into the right and left hemi-livers, each of which has its own blood supply. The right hemiliver comprises 50 to 70 percent of the liver mass. The liver can be further subdivided into eight segments based upon the vascular or bile duct distribution.
Microcirculation — Several conceptual models have been proposed relating to the architecture of the hepatic parenchyma. Terminal portal veins and hepatic venules interdigitate between sinusoids. The "lobule" model considers the terminal hepatic venules to be the center of the hepatic microcirculation, while the "acinar" model (also known as the Rappaport classification) considers it to represent the periphery (figure 1).
An appealing feature of the acinar model is that the blood supply to an area of hepatic parenchyma and the bile duct draining it are all located in one "portal triad." The acinus consists of a cluster of hepatocytes (approximately 2 mm in diameter) that are grouped around terminal branches of an hepatic arteriole and portal venule (figure 1). Blood from a branch of the portal vein and hepatic artery enter the acinus in the portal and periportal regions, flow through the hepatic sinusoids, and drain into a terminal hepatic venule.
The acinar model also defines areas or "zones" representing gradients where the nutrient and oxygen content of the hepatic microcirculation differ. The center of the acinus (periportal) is known as zone 1, the periphery (perivenular) as zone 3, and the region in between as zone 2 [8]. Zone 1 receives blood with the highest levels of oxygen and nutrients, compared with zone 3. Thus, zone 3 is particularly vulnerable to a circulatory insult.
Hepatocytes within these zones are adapted to their microlocation ("metabolic zonation"). Zone 1 hepatocytes have high oxidative activities and contain many large mitochondria. Their dominant processes include gluconeogenesis, beta oxidation of fatty acids, amino acid catabolism, ureagenesis, cholesterol synthesis, and bile acid secretion. By contrast, zone 3 hepatocytes are more involved with glycolysis and lipogenesis. Metabolic zonation is maintained by the Wnt/beta-catenin pathway; activation of beta-catenin signaling induces expression of genes associated with centrilobular hepatocytes and repression of genes associated with periportal hepatocytes [9].
PATHOGENESIS — Hepatic ischemia develops when there is an imbalance between hepatic oxygen supply and demand [10]. Multiple underlying factors are responsible in the majority of patients [11].
Regulation of blood flow — Hepatic oxygen delivery is related to the oxygen content of blood perfusing the liver and total hepatic blood flow. Once oxygen delivery is decreased, compensatory mechanisms allow for increased oxygen extraction by hepatocytes, thereby helping to maintain adequate oxygenation. The exact mechanisms by which this occurs are incompletely understood, although autoregulation of blood flow appears to play an important role. Blood flow through the hepatic microvasculature is regulated primarily by the activity of smooth muscle cells that surround hepatic arterioles. Hepatic arterial flow is regulated closely to maintain relatively constant total hepatic blood flow. By contrast, portal venous flow lacks autoregulatory control.
When portal flow declines, smooth muscle cells around hepatic arterioles relax, resulting in increased arteriolar flow, a process mediated by changes in the concentration of adenosine within connective tissue that surrounds hepatic arterioles [12]. The concentration of adenosine is in part determined by the degree to which it is "washed out" by sinusoidal blood flow [5]. Zone 3 of the hepatic acinus is particularly vulnerable to a circulatory insult because it is furthest from the oxygen-rich blood supply, while increased oxygen extraction in zones 1 and 2 further depletes the local oxygen tension.
Blood flow under systemic stress — Under situations of systemic stress (such as sepsis), cardiac output may not increase sufficiently to supply demands of critical organs such as the brain. As a result, there is a compensatory decrease in peripheral and splanchnic blood flow [13]. The resulting decrease in hepatic blood flow may exceed the capacity of the liver to increase oxygen extraction, thereby leading to hepatocellular hypoxia, especially in zone 3 [14].
Reperfusion and other mechanisms of injury — Reperfusion injury contributes further to hepatic injury and appears to account for most of the histologically apparent damage. It is mediated by generation of reactive oxygen species once ischemic hepatocytes are reexposed to oxygen, leading to cell injury via lipid peroxidation [15]. In addition, Kupffer cells react to ischemia by producing cytokines, including tumor necrosis factor alpha, which triggers the recruitment and activation of polymorphonuclear leukocytes.
Ischemia also promotes the conversion of cytosolic xanthine dehydrogenase to xanthine oxidase, leading to the production of superoxide and hydrogen peroxide from accumulated xanthine [16]. Ischemia and reperfusion induce transcription of multiple genes in the hepatocyte via the transcription factors heat-shock factor and nuclear factor kappa B [17]. Sinusoidal endothelial cells are exquisitely sensitive to reperfusion injury, while hepatocytes become vulnerable following a significant ischemic insult [15].
In vitro and animal models suggest that, because of their high metabolic rate, hepatocytes are more vulnerable to hypoxia at physiologic temperatures than other liver cell types such as sinusoidal endothelial cells, Kupffer cells, and biliary epithelial cells [15]. Nutritional status may also have an important influence on hepatocellular sensitivity to hypoxia. Fasted rats are less prone to hepatic ischemia than fed rats, possibly because their diminished glycogen stores provide less substrate for anaerobic glycolysis, thereby decreasing intracellular lactic acid production [18]. The cellular mechanisms of ischemic injury appear to be related to disruption of mitochondrial respiration, with depletion of adenosine triphosphate, a rise in cytosolic calcium levels, and activation of cellular proteases [19,20]. Other effects of heart failure on hepatic metabolism (the "heart-liver metabolic axis") have been described [4,21].
Clinical settings that increase the risk of ischemic injury — There are two relatively common clinical settings that increase the risk of hepatic ischemia.
●Patients who have preexisting liver disease and portal hypertension are particularly susceptible since total hepatic blood flow may already be reduced. Splanchnic blood that normally enters the liver may be shunted through collateral circulation, thereby bypassing the liver (and potentially resulting in varices). Furthermore, decreased functional hepatic mass in patients with chronic liver disease makes them vulnerable to decompensation when there is added injury from an ischemic insult.
●Patients who have preexisting passive congestion of the liver are also at increased risk for ischemic injury. Elevated central venous pressure (as occurs with congestive heart failure) is transmitted to the hepatic veins and small hepatic venules that drain the hepatic acini. Such increased pressure is associated with atrophy of hepatocytes in zone 3 of the hepatic acinus. The mechanism leading to atrophy is in part related to the exudation of protein-rich fluid into the space of Disse due to the sinusoidal congestion [5,22]. The resulting perisinusoidal edema impairs the diffusion of oxygen and flow of nutrients to hepatocytes [22].
In addition to atrophy of hepatocytes, chronic hepatic congestion may lead to the development of fibrosis, most prominently in zone 3 and the space of Disse. The fibrosis further impairs diffusion of nutrients to hepatocytes. The degree of fibrosis varies from one region of the liver to another possibly because of the fibrogenic effects of focal thrombi within the sinusoids, hepatic venules, and portal veins due to chronic vascular stasis [23,24]. Ultimately, bridging fibrosis between central veins produces "reverse lobulation," or "cardiac cirrhosis," which is associated with an increased risk of hepatocellular carcinoma [25]. (See "Pathogenesis of hepatic fibrosis".)
With severe congestion, the excess fluid in the space of Disse overwhelms the drainage capacity of hepatic lymphatics. As a result, high-protein fluid exudes from the surface of the liver into the peritoneal space, leading to high-protein fluid that is characteristic of ascites caused by congestive heart failure [14].
Passive congestion by itself does not appear to be sufficient to cause significant hepatic necrosis without a concomitant decrease in hepatic blood flow. Furthermore, there is no clear correlation between the degree of congestion (as assessed by right atrial pressure) and zone 3 necrosis in patients with congestive heart failure [26]. Significant zone 3 necrosis caused by acute left-sided heart failure has been demonstrated in the absence of right heart failure, suggesting that cardiac output rather than congestion alone is the critical factor leading to hepatic necrosis [27].
Nevertheless, passive congestion coexists in most patients with clinically apparent hepatic ischemia. This observation was supported by a study that focused on 31 patients who were considered to have ischemic hepatitis and were compared with 31 previously healthy patients who sustained major non-hepatic trauma [28]. Both groups had documented systolic blood pressure of <75 mmHg for at least 15 minutes. No patient in the control group developed ischemic hepatitis despite the low blood pressure. All 31 patients with ischemic hepatitis had evidence for underlying heart disease, including 29 (94 percent) who had right-sided heart failure. This finding suggests that passive congestion of the liver predisposes patients to ischemic hepatitis induced by a hypotensive event. (See "Congestive hepatopathy".)
Similar conclusions were reached in another study of patients with ischemic hepatitis in the setting of chronic respiratory disease [29]. All patients who developed ischemic hepatitis had a central venous pressure greater than 10 cm H2O [29].
Other studies of patients with ischemic hepatitis have suggested that the underlying cause of ischemic injury varies according to the clinical setting [30-32]. In a study of 142 patients with ischemic hepatitis, liver hypoxia was thought to result mostly from profound systemic hypoxemia in those with chronic respiratory failure, while in those with toxic/septic shock, oxygen delivered to the liver was not decreased but hepatic oxygen demands were increased [30]. A "shock state" was observed in only 50 percent of cases, leading the authors to suggest abandonment of the terms "shock liver" or "ischemic hepatitis" in favor of "hypoxic hepatitis." By contrast, in other reports, significant hepatic injury has been unusual with systemic hypoxemia alone, although it has been described in some patients with obstructive sleep apnea and in some with exacerbations of acute respiratory failure, particularly in those who also have right-sided heart failure [29,33-35]. Nevertheless, the term "hypoxic liver injury" has been proposed by the European Association for the Study of the Liver [36,37]. (See "Ischemic hepatitis, hepatic infarction, and ischemic cholangiopathy".)
SUMMARY
●Background – Hepatic ischemia develops when there is an imbalance between hepatic oxygen supply and demand. (See 'Pathogenesis' above.)
A shock state is observed in only 50 percent of patients with ischemic hepatic injury. (See 'Clinical settings that increase the risk of ischemic injury' above.)
The risk of ischemic injury is increased in patients with preexisting portal hypertension or passive hepatic congestion, as occurs with right-sided heart failure.
●Hepatic blood flow – Zone 3 of the hepatic acinus is particularly vulnerable to a circulatory insult because it is furthest from the oxygen-rich blood supply and increased oxygen extraction in zones 1 and 2 further depletes the local oxygen tension. (See 'Microcirculation' above.)
●Reperfusion injury – Reperfusion injury contributes further to hepatic injury. (See 'Reperfusion and other mechanisms of injury' above.)
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