Liver failure is caused by a variety of pathological factors caused by large-scale and severe destruction of liver cells, which in turn causes serious liver dysfunction. In the actual diagnosis and treatment process, clinical manifestations such as ascites, jaundice, hepatorenal syndrome, and infection are usually the mainstay, and they are often accompanied by systemic inflammatory response syndrome. Its onset is rapid, the disease progresses rapidly, there are many complications, the condition is very dangerous, and even endangers the patient's life. Acute pancreatitis is an inflammatory reaction caused by various stimuli in the pancreatic acinar, and even an acute abdomen that can lead to organ dysfunction. The incidence of liver failure complicated with acute pancreatitis is about 40%, and acute pancreatitis can further aggravate liver damage, leading to further deterioration of liver function, extremely poor prognosis, and high mortality rate. The clinical symptoms of acute pancreatitis are very similar to those of liver failure, which are easy to be ignored and missed. This article expounds the mechanism and preventive measures of liver failure complicated by acute pancreatitis, so as to provide a certain reference for the prevention and treatment of acute pancreatitis in patients with clinical liver failure.
1. Inflammatory response
During the evolution of liver failure, the inflammatory response triggered by M1 macrophages releases several cytokines, such as IL-1β, IL-6, IL-10, IL-18, IL-33, TNF-α, and macrophage migration inhibitory factor (MIF), resulting in an inflammatory response in the pancreas. Studies related to liver failure have shown that the expression level of B-cell nuclear transcription factor (NF-κB) in the hepatocyte nucleus will be significantly increased during its development. NF-κB activation is an early core event in the inflammatory progression of acute pancreatitis, and the expression levels of multiple cytokines in vivo are significantly increased during liver failure, thereby inducing the progression of acute pancreatitis. The effects of cytokines on the pancreas during liver failure are shown in Table 1.
The numerous cytokines released during the progression of liver failure form the material basis for the initiation of acute pancreatitis. Upon stimulation by cholinergic agonists such as cholecystokininin-8 or carbachocholine, protein kinase C undergoes a process of phosphorylation and activation, which in turn activates the NF-κB pathway and releases inflammatory factors, resulting in an inflammatory response. The pathway for JAK to release inflammatory cytokines is similar. The inflammatory factor TNF-α released during liver failure can activate T lymphocytes, stimulate the activation of NF-κB signaling pathway, and induce systemic progression of inflammatory response. TNF-α can also promote the production of NO, reactive oxygen species and other inflammatory cytokines by increasing the levels of intercellular ICAM and vascular cell adhesion molecules. P21-activated kinase 1 can promote the production of TNF-α, IL-6, and IL-1β inflammatory factors by activating the NF-κB and p38 pathways, and mediate inflammatory responses. Toll-like receptor 4 (TLR4) has the ability to recognize pancreatic enzymes secreted by the pancreas and signal multiple cytokines, further releasing the first signal that triggers the inflammatory response, thereby causing a cascade of inflammation. This process activates and increases the protein level of TNF receptor association factor 6, thereby enhancing downstream signaling and transferring the NF-κB subunit from the cytoplasm to the nucleus. Within the nucleus, NF-κB transcription factors stimulate the expression of inflammatory cytokine genes. In hepatocytes, high mobility group protein 1 (HMGB1) is the last and longest-lasting mediator of late inflammation in systemic inflammation, which can activate MAPK and NF-κB signaling pathways by binding to TLR4, promote the release of inflammatory factor MIF, and further aggravate the inflammatory response. NLRP-3 inflammasome can mediate the activation of inflammatory factors such as IL-1β and IL-18 by caspase-1, aggravate the inflammatory response in the process of acute pancreatitis, and even further induce the aggravation of liver failure (Fig. 1).
Fig.1 Mechanism of inflammation in liver failure complicated by acute pancreatitis
2. Duodenal papilla dysfunction
Duodenal papillary dysfunction includes duodenal sphincter stenosis and motility disorders. Duodenal sphincter stenosis includes partial or total narrowing of the duodenal sphincter due to inflammation or secondary fibrosis. Motility disorders are caused by alterations in normal physiological movements, resulting in the inability of bile or pancreatic juice to drain into the duodenum. Duodenal papilla dysfunction can not only induce inflammation, but also lead to intestinal and biliary dysbiliary flora, and increase the pathogenic flora. During the progression of liver failure, the tissue structure of the liver is destroyed, and bile flows through the common bile duct through the duodenal sphincter into the duodenum, where the duodenal sphincter spasms and bile refluxes into the pancreatic duct. Causing biliary duct obstruction increases pancreatic duct pressure, trypnogen activation, and pancreatic autodigestion, inducing acute pancreatitis. Trypsinogen activation in acinar plays a key role in pancreatitis, and in transgenic mouse models where trypsinogen is specifically activated, trypsin activity increases, resulting in tissue edema, serum amylase, inflammatory cell infiltration, and acinar cell apoptosis inducing acute pancreatitis, while duodenal papilla dysfunction leads to mitochondrial dysfunction in pancreatic duct cells, which in turn leads to premature activation of trypsinogen in the pancreatic duct and triggers acute pancreatitis.
3. Intestinal flora dysbiosis
Intestinal microbiota refers to various microorganisms that inhabit the intestines, including intestinal protection, optimization of metabolism, regulation of the immune system, anti-inflammatory and anti-tumor. In the case of liver failure, the balance of microflora will be disrupted. Moreover, the degree of dysbiosis was directly proportional to the degree of hepatocellular injury. In the process of gradual liver failure, the intestinal microbiota is unbalanced, the microbiota is overproliferated, the microbiota is translocated, and the intestinal mucosal barrier is disordered. These adverse conditions will further accelerate the occurrence and development of pancreatitis. Decreased intestinal lactic acid bacteria and dysfunction of Paneth cells can worsen pancreatic damage. However, the translocation of E. coli in the process of liver failure causes intestinal inflammation, and it is speculated that human NOD-like receptor family protein 3 (NLPR3) may be an important factor in the occurrence of intestinal microbiota-pancreatitis. Butyric acid and its derived salts help protect the host gut from pathogen attack and stop the migration of pathogenic bacteria in the gut. The decline of its beneficial bacteria may lead to increased permeability of the human intestinal mucosa and dysfunction of the intestinal mucosal barrier, allowing pathogenic bacteria to pass through the damaged intestinal mucosa and enter the bloodstream, thereby promoting the development of pancreatitis.
4. Oxidative stress
Cytokines produced during liver failure are the basis of the inflammatory response. The inflammatory response is accompanied by an oxidative imbalance within the cell. Oxidative stress occurs when the balance between free radicals and the antioxidant system is disrupted, which leads to the accumulation of specific scavenging enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GST). In the process of liver failure, the cytokines produced enter the pancreas, which in turn inhibits the activity of certain enzymes such as SOD, CAT, GST, hindering energy metabolism and converting oxygen into oxygen radicals (OFR). However, excessive accumulation of OFR may cause lipid peroxidation, calcium homeostasis disturbances, and DNA damage, which can increase pancreatic cell damage and ultimately lead to pancreatic cell death. Mitochondrial dysfunction leads to pancreatic stress, impaired autophagy, and dysregulation of lipid metabolism; It also leads to the accumulation of ROS in the body, and the accumulated ROS enters the pancreas, which promotes the activation of JNK by apoptosis signal-regulated kinase 1 (ASK1) in a stressful state, and the phosphorylation of JNK and p38MAPK in the pancreas increases, which also induces high expression levels of inflammatory cytokines such as TNF-α and IL-6. Thiodoxin-interacting protein (TXNIP) is an important protein involved in the redox response of inflammatory response, which plays a role in regulating inflammatory response and oxidative stress through ASK1-dependent activation of JNK/p38 pathway. Oxidative stress-inducible heme oxygenase-1 (HO-1) attenuates pancreatic injury in mice by mediating anti-inflammatory and antioxidant activity and inhibition of NF-κB pathway activation. Nuclear factor E2-related factor 2 (Nrf2) is a widely distributed transcription factor that has the ability to regulate the production of antioxidants and toxic molecules in cells, and self-activation of the Nrf2-ARE pathway during oxidative stress can increase the activity of HO-1 and therefore alleviate damage to the pancreas (Figure 2).
Fig.2 Mechanism of oxidative stress in liver failure complicated by acute pancreatitis
5. Microcirculation disorders
The microcirculation of the pancreas is composed of a network of arterioles, venules and capillaries, which is affected by the smooth muscle contraction state of blood vessels, which is regulated by both hormones and nerves. In pathological cases, disturbances in pancreatic circulation usually lead to decreased tissue perfusion and ischemia, which promotes the occurrence of acute pancreatitis. Endothelin-1 (ET-1) is an important factor in the microcirculation disorder of liver failure complicated by acute pancreatitis, and the binding of ET-1 to endothelin-A receptor induces strong contraction and spasm of vascular smooth muscle, resulting in poor capillary perfusion, which can cause local blood stasis and tissue ischemia and hypoxia in the pancreas in the early stage, and continuous microvascular spasm will aggravate pancreatic damage and necrosis. On the other hand, when ET-1 interacts with endothelin-A and activates the cGMP pathway, it leads to an overload of intracellular Ca2+. Due to the excess of calcium ions, the mitochondrial production capacity is insufficient, so that a large amount of zymogen cannot be successfully released and accumulates in the acinar cells, thus promoting the development of acute pancreatitis. ET can also stimulate ROS production, and is involved in the activation of transcription factor NF-κB and the expression of pro-inflammatory cytokines TNF-α, IL-1 and IL-6 under inflammatory stress conditions. At the same time, endothelial cell damage and increased permeability of the pancreatic microcirculation will further lead to ischemia and hypoxia of the pancreatic microvessels, causing inflammatory cascade reaction. The inflammatory response will further aggravate the damage of endothelial cells and the permeability of blood vessels, causing hemoconcentration, forming thrombosis, and affecting the blood perfusion of microcirculation.
6. Prevention
In a number of previous clinical observations, the incidence of acute pancreatitis complicated by liver failure accounted for about 40%, and the clinical symptoms of some patients with acute pancreatitis were relatively insidious and difficult to find. According to the mechanism study of liver failure complicated with acute pancreatitis in the above five aspects, the occurrence of acute pancreatitis complicated by liver failure can be prevented clinically through the following aspects.
6.1 Active treatment of the underlying disease
During the development of liver failure, aggressive treatment of the underlying disease can avoid further deterioration of the disease and control the progression of the disease and the occurrence of complications. Intravenous albumin infusion can restore immune function by modulating systemic oxidative stress and inflammation, and early and adequate human albumin supplementation can reduce the risk of acute pancreatitis and improve prognosis. Artificial liver plasmapheresis can be used to remove endotoxins and inflammatory mediators and to replace albumin to improve survival in patients with liver failure and reduce the risk of acute pancreatitis by inhibiting the progression of the inflammatory response. Mesenchymal stem cells migrate to the liver through circulation and downregulate the pro-inflammatory response, which may inhibit the inflammatory response and reduce oxidative stress by regulating the TLR4/NF-κBp65 pathway, thereby reducing the incidence of acute pancreatitis. Liver transplantation is still the definitive treatment for patients with liver failure, but due to its high cost and lack of liver donors, it is not suitable for all patients, and complications such as acute pancreatitis are prone to occur after liver transplantation. Active treatment of the primary disease can further regulate systemic oxidative stress and inflammatory response, restore the immune barrier, and prevent the occurrence of acute pancreatitis.
6.2 Control inflammation
Cytokines produced during liver failure are the basis for the development of inflammatory responses. Controlling the inflammatory response during liver failure can control the progression of inflammation and avoid the development of acute pancreatitis. Glucocorticoids are commonly used to control the progression of inflammation in patients with liver failure. Glucocorticoids can induce apoptosis of inflammatory cells and inhibit antigen presentation and the production and release of pro-inflammatory cytokines (IL-1, IL-6, TNF-α and IL-17), while glucocorticoids have a significant stabilizing effect on cell membranes, which can prevent hepatocyte disintegration and necrosis, thereby slowing down the process of liver injury. However, when glucocorticoids are used, the risk of secondary infection, spread or even worsening of the primary disease will increase, and even sepsis will occur. At the same time, it can also inhibit gastric mucus secretion, increase gastric acid and pepsin secretion, and increase the possibility of gastrointestinal ulcers, perforation and gastrointestinal bleeding. In addition, due to the pharmacological properties of glucocorticoids, some develop abnormalities in electrolytes, blood glucose, and blood pressure, potentially increasing the risk of hepatic encephalopathy, hepatorenal syndrome, and other consequences of liver failure. Although glucocorticoids increase the risk of infection and upper gastrointestinal bleeding and other complications, their side effects are manageable. Timely use of glucocorticoids in patients with liver failure can significantly improve the survival rate of patients, so timely use of glucocorticoids can not only control the progression of systemic inflammatory response, but also further avoid the occurrence of acute pancreatitis.
6.3 Infection control
Infection is one of the common complications of liver failure, and the secondary infection of patients with liver failure is mainly gram-negative bacteria, and the most common infection sites are the biliary tract, lungs and thoracic cavity, while the probability of complications in patients with liver failure and infection is increased, and the prognosis is significantly worsened. However, the clinical symptoms of patients with liver failure are not typical, and the positive rates of procalcitonin, leukocytes and hypersensitive C-reactive protein in the clinic have high diagnostic value in the case of liver failure and infection. Once signs of infection appear, antibiotic therapy can be empirically chosen, and antibiotics can be adjusted according to susceptibility results after the relevant etiological examination is complete.
6.4 Improve duodenal papilla dysfunction
In view of the pathogenesis of duodenal papillary sphincter dysfunction, it is particularly important for the treatment of acute pancreatitis to relieve biliary obstructive factors, relieve biliary tract pressure, and make bile and pancreatic juice flow smoothly. Endoscopic retrograde cholangiopancreatography is one of the most commonly used surgical methods in clinical practice, which has the advantages of taking into account both examination and treatment and small trauma, which can effectively control bile duct retrograde infection, reduce the inflammatory response of multiple organs in the body, and also reduce the reflux of bile and pancreatic juice into the pancreatic duct, inhibit pancreatic enzyme activation, and effectively control pancreatitis. Octreotide can significantly reduce the basal pressure and contraction amplitude of the duodenal sphincter without affecting the contraction frequency and intraluminal pressure, reduce tryptic activation and pancreatic autodigestion, and avoid the occurrence of acute pancreatitis to a certain extent. Ursodeoxycholic acid can promote the excretion of bile acids through its protective effect on hepatocytes and bile duct epithelial cells, improve the pressure of the duodenal sphincter, avoid acidosis in the pancreatic duct, and reduce the release of inflammatory mediators, thereby avoiding the occurrence of acute pancreatitis.
6.5 Adjust the intestinal flora
In the case of liver failure, the balance of intestinal flora will be disrupted. Moreover, the degree of dysbiosis was directly proportional to the degree of hepatocellular injury. Rifaximin, as a commonly used drug to prevent intestinal infection in patients with liver failure in clinical practice, is a broad-spectrum antibiotic that only acts on the intestine, which can regulate the imbalance of intestinal flora, and the application of rifaximin can reduce pancreatic injury and inflammatory response in mice with acute pancreatitis by regulating the TLR4/NF-κB inflammatory signaling pathway; Although prophylactic rifaximin does not significantly reduce the incidence of complications of acute pancreatitis, it can significantly improve systemic inflammation. Bifidobacterium triple viable capsules combined with enteral nutrition can actively improve the treatment effect of acute pancreatitis. The use of probiotics in animal models of acute pancreatitis reduces the incidence of infectious complications, improves pancreatic histological scores, and reduces mortality in rats, presumably reducing the overgrowth of potentially pathogenic bacteria in the duodenum, thereby reducing the migration of intestinal bacteria outside the intestinal lumen (including the pancreas), thereby reducing infectious complications and mortality from acute pancreatitis. Actively adjusting the intestinal flora can prevent and reduce pancreatic damage and avoid the occurrence of acute pancreatitis.
7 Summary
In clinical practice, the number of patients with liver failure complicated by acute pancreatitis has increased greatly, and the clinical manifestations of acute pancreatitis are similar to the gastrointestinal symptoms of liver failure, which are easy to be ignored, and in the development of acute pancreatitis, if not controlled, hepatocyte damage will occur, and even induce multi-organ failure. Although the specific causes of acute pancreatitis complicated by liver failure are not well understood, this article attempts to analyze this problem from five perspectives, and points out that these factors do not exist independently, but affect each other and promote the development of the disease. The prevention of acute pancreatitis complicated by liver failure is proposed from these five perspectives, but there are few clinical and experimental research data on the prevention of acute pancreatitis complicated by liver failure. According to the current research status, more consideration should be given to the integrity of liver, intestine, pancreas and other tissues in actual clinical work. In the process of liver failure, active treatment of the primary disease, improving the function of duodenal papillary sphincter, adjusting intestinal flora, controlling inflammation and infection, is conducive to avoiding the possibility of liver failure complicated by acute pancreatitis.
全文下载 PDF & HTML
https://www.lcgdbzz.org/cn/article/doi/10.12449/JCH240434
引证本文 Citation
Lu Xingyu, Yang Jing, Li Pan, et al . Mechanism and prevention of liver failure complicated by acute pancreatitis[J]. Journal of Clinical Hepatobiliary Diseases, 2024, 40(4): 850-856
扩展阅读 Read more
Special attention is paid to the mechanism of hepatic mitochondrial dysfunction in the pathogenesis of nonalcoholic fatty liver disease
Of particular interest is the effect of direct-acting antiviral therapy on the prognosis of extrahepatic disease in patients with hepatitis C
Trends and projections of acute hepatitis B disease burden in China
Special attention is paid to the mechanism of liver injury caused by antiviral drugs in novel coronavirus infection
Special attention is paid to the use of Mendelian randomization in liver cancer research
关于本刊 About us
■ The first professional journal of hepatobiliary diseases in mainland China
■ 金色开放获取期刊（Golden OA）
■ International Committee of Medical Journal Editors (ICMJE) canonical journal■ Member journal of the International Society of Management and Technical Editors (ISMTE).
■ Included in 13 important international databases such as Embase and Scopus
■ 100 outstanding academic journals in China
■ China's high-quality scientific and technological journals
■ China's Top 100 University Science and Technology Journals
■ Journals included in the World Impact Index Report of Scientific and Technological Journals
■ Core Chinese journals of Peking University Library
■ Statistical source journal of Chinese scientific and technological papers
■ RCCSE China Core Academic Journal
Official website: lcgdbzz.org
官方微信：lcgdbzz1985
Submission consultation: 0431-88782044
Review consultation: 0431-88783542
Reviewer application portal: Click to view