Materiały źródłowe

• #1 Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis – UpToDate

  https://www.uptodate.com/contents/acute-liver-failure-in-adults-etiology-clinical-manifestations-and-diagnosis

  Acute liver failure is characterized by acute liver injury, hepatic encephalopathy (altered mental status), and an elevated prothrombin time/international normalized ratio (INR). […] Acute liver failure refers to the development of severe acute liver injury with impaired synthetic function (INR of ≥1.5) and altered mental status in a patient without cirrhosis or preexisting liver disease. […] A commonly used cutoff to define acute liver failure is an illness duration of <26 weeks. [...] Acute liver failure may also be diagnosed in patients with previously undiagnosed Wilson disease, vertically acquired or reactivation of hepatitis B virus, or autoimmune hepatitis, in whom underlying cirrhosis may be present, provided the disease has been recognized for <26 weeks.

• #2 Liver failure – Wikipedia

  https://en.wikipedia.org/wiki/Liver_failure

  Acute liver failure is defined as „the rapid development of hepatocellular dysfunction, specifically coagulopathy and mental status changes (encephalopathy) in a patient without known prior liver disease”. […] The disease process is associated with the development of a coagulopathy of liver aetiology, and clinically apparent altered level of consciousness due to hepatic encephalopathy. […] The diagnosis of acute liver failure is based on a physical exam, laboratory findings, patient history, and past medical history to establish mental status changes, coagulopathy, rapidity of onset, and absence of known prior liver disease respectively. […] The exact definition of „rapid” is somewhat debatable, and different sub-divisions exist, which are based on the time from onset of first hepatic symptoms to onset of encephalopathy. […] „Acute on chronic liver failure (ACLF)” is said to exist when someone with chronic liver disease develops features of liver failure.

• #3 Acute Liver Failure Basic Pathophysiology and Management | PPT

  https://www.slideshare.net/slideshow/acute-liver-failure-basic-pathophysiology-and-management/266493343

  Acute liver failure is defined by encephalopathy, coagulopathy, and jaundice in a patient without pre-existing liver disease. […] The most common causes are viral hepatitis, drug overdose, and indeterminate causes. […] Fulminant Hepatic Failure is a potentially reversible condition and a consequence of severe liver injury. […] Hepatic encephalopathy is an alteration in mental status and cognitive function occurring in the presence of liver failure. […] Liver failure leads to portal hypertension, splanchnic vasodilation, hypoalbuminemia, and reduced plasma oncotic pressure, which leads to ascites and organ edema. […] Hepatic encephalopathy and hyperammonaemia are significant complications of acute liver failure. […] Acute liver failure is a catabolic state characterized by negative nitrogen balance and immunodeficiency. […] Orthotopic liver transplant is the definitive treatment for patients who meet the criteria. […] The pathophysiology involves massive hepatocyte destruction and impaired regeneration. […] The prognosis depends on the cause and stage of encephalopathy.

• #4 Acute Liver Failure – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK482374/

  Acute liver failure (ALF) is a rare and often heterogeneous presentation of severe liver dysfunction in a patient with otherwise no pre-existing liver disease. Though it has high morbidity and mortality, its overall survival has improved through intensive care management and emergency liver transplantation advancements. A high index of suspicion, early referral to a specialist liver transplantation center, and adequate supportive management remain the cornerstone for the management of ALF. Future better understanding and knowledge of the pathophysiology of liver injury and management of multi-organ failure will help improve outcomes. […] The pathophysiology depends on the etiology of the ALF. Most cases of ALF (except acute fatty liver of pregnancy and Reye syndrome) will have massive hepatocyte necrosis and/or apoptosis leading to liver failure. Hepatocyte necrosis occurs due to ATP depletion causing cellular swelling and cell membrane disruption. The pathophysiology of cerebral edema and hepatic encephalopathy is seen in ALF is multi-factorial and includes altered blood-brain barrier (BBB) secondary to inflammatory mediators leading to microglial activation, accumulation of glutamine secondary to ammonia crossing the BBB and subsequent oxidative stress leading to depletion of adenosine triphosphate (ATP) and guanosine triphosphate (GTP). This ultimately leads to astrocyte swelling and cerebral edema.

• #5

  https://discovery.ucl.ac.uk/id/eprint/10115342/

  Acute liver failure is a life-threatening illness precipitated by an acute liver injury in patients with no pre-existing liver disease. Acute viral hepatitis and drug-induced liver injury account for most cases, the clinical course characterized by the development of coagulopathy and hepatic encephalopathy, often progressing to multi-organ disease, which is associated with high fatality rates. […] The outcomes have improved significantly over time with improving standards of organ system support and access to liver transplantation for very sick individuals. […] The King’s College criteria are the most commonly used tool for determination of prognosis and consideration for transplantation. […] Prompt diagnosis, immediate initiation of supportive care and aetiology-specific treatment, where applicable, as well as early discussions and transfer to a transplant centre, are the keys to successful outcome.

• #6 Acute Liver Failure | Cleveland Clinic

  https://my.clevelandclinic.org/departments/digestive/medical-professionals/hepatology/acute-liver-failure

  Acute liver failure (ALF) is a rare but a life-threatening condition. ALF causes severe injury and massive necrosis of hepatocytes resulting in severe liver dysfunction that can lead to multi-organ failure and death. […] The pathophysiology includes loss of hepatocyte function and the release of toxins and cytokines due to liver necrosis causing severe systemic inflammation and secondary bacterial infections from decreased immunity in ALF. […] The pathogenesis of hepatic encephalopathy is not fully understood. It has been linked to the presence of inflammatory mediators and circulatory neurotoxins such as ammonia. Acute liver failure leads to both systemic inflammation and local inflammation in the brain, resulting in the release of cytokines and neurotoxins. These products alter the cerebral blood flow and the blood-brain permeability barrier causing astrocyte swelling, cerebral edema, and encephalopathy.

• #7 Acute liver failure – Wikipedia

  https://en.wikipedia.org/wiki/Acute_liver_failure

  Acute liver failure is the appearance of severe complications rapidly after the first signs (such as jaundice) of liver disease, and indicates that the liver has sustained severe damage (loss of function of 80-90% of liver cells). The pathogenesis remains unclear, but is likely to be a consequence of several phenomena. There is a buildup of toxic substances like ammonia, mercaptan, serotonin and tryptophan in the brain. This affects neurotransmitter level and neuroreceptor activation. Autoregulation of cerebral blood flow is impaired, and is associated with anaerobic glycolysis and oxidative stress. Neuronal cell astrocytes are susceptible to these changes, and they swell up, resulting in increased intracranial pressure. Inflammatory mediators also play important role. […] In the majority of acute liver failure (ALF) there is widespread hepatocellular necrosis beginning in the centrizonal distribution and progressing towards portal tracts. The degree of parenchymal inflammation is variable and is proportional to duration of disease. Zone 1 (periportal) occurs in phosphorus poisoning or eclampsia. Zone 2 (mid-zonal), although rare, is seen in yellow fever. Zone 3 (centrilobular) occurs with ischemic injury, toxic effects, carbon tetrachloride exposure, or chloroform ingestion. In acute acetaminophen overdose, toxification occurs, mostly in Zone III which has the highest level of P450 micro-enzymes. That fact along with Zone III’s decreased oxygen level helps to explain why it is preferentially one of the initial sites of damage.

• #8 A guide to managing acute liver failure | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/83/6/453

  Nearly 2,000 cases of acute liver failure occur each year in the United States. This disease carries a high mortality rate, and early recognition and transfer to a tertiary medical care center with transplant facilities is critical. This article reviews the definition, epidemiology, etiology, and management of acute liver failure. […] In the United States, the most common cause of acute liver failure is acetaminophen toxicity, followed by viral hepatitis. […] The most common cause of acute liver failure in the United States and other Western countries is acetaminophen toxicity, followed by viral hepatitis. In contrast, viral hepatitis is the most common cause in developing countries. […] After ingestion, 52% to 57% of acetaminophen is converted to glucuronide conjugates, and 30% to 44% is converted to sulfate conjugates. These compounds are nontoxic, water-soluble, and rapidly excreted in the urine.

• #9 A guide to managing acute liver failure | Cleveland Clinic Journal of Medicine

  https://www.ccjm.org/content/83/6/453

  However, about 5% to 10% of ingested acetaminophen is shunted to the cytochrome P450 system. P450 2E1 is the main isoenzyme involved in acetaminophen metabolism, but 1A2, 3A4, and 2A6 also contribute. […] Metabolism of acetaminophen through the cytochrome P450 pathway results in production of N-acetyl-p-benzoquinone imine (NAPQI), the compound that damages the liver. NAPQI is rendered nontoxic by binding to glutathione, forming NAPQI-glutathione adducts. […] With too much acetaminophen, glutathione becomes depleted and NAPQI accumulates, binds with proteins to form adducts, and leads to necrosis of hepatocytes. […] Acetylcysteine, used in treating acetaminophen toxicity, is a substrate for glutathione synthesis and ultimately increases the amount of glutathione available to bind NAPQI and prevent damage to hepatocytes.

• #10 Acute Liver Failure: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/177354-overview

  An increase in intracranial blood volume and cerebral blood flow is a factor in acute liver failure. The increased cerebral blood flow results because of the disruption of cerebral autoregulation. The disruption of cerebral autoregulation is thought to be mediated by elevated systemic concentrations of nitric oxide, which acts as a potent vasodilator. […] Another consequence of fulminant hepatic failure is multisystem organ failure, which is often observed in the context of a hyperdynamic circulatory state that mimics sepsis (low systemic vascular resistance); therefore, circulatory insufficiency and poor organ perfusion possibly either initiate or promote complications of fulminant hepatic failure. […] The development of liver failure represents the final common outcome of a wide variety of potential causes, as the broad differential diagnosis suggests. As with many drugs that undergo hepatic metabolism (in this case, by cytochrome P-450), the oxidative metabolite of acetaminophen is more toxic than the drug. The highly reactive active metabolite N-acetyl-p-benzoquinone-imine (NAPQI) appears to mediate much of the acetaminophen-related damage to liver tissue by forming covalent bonds with cellular proteins.

• #10 Acute Liver Failure: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/177354-overview

  The development of cerebral edema is the major cause of morbidity and mortality in patients with acute liver failure. The etiology of this intracranial hypertension (ICH) is not fully understood, but it is considered to be multifactorial. […] Briefly, hyperammonemia may be involved in the development of cerebral edema. Brain edema is thought to be both cytotoxic and vasogenic in origin. […] Cytotoxic edema is the consequence of impaired cellular osmoregulation in the brain, resulting in astrocyte edema. Cortical astrocyte swelling is the most common observation in neuropathologic studies of brain edema in acute liver failure. […] In the brain, ammonia is detoxified to glutamine via amidation of glutamate by glutamine synthetase. The accumulation of glutamine in astrocytes results in astrocyte swelling and brain edema. There is clear evidence of increased brain concentration of glutamine in animal models of acute liver failure. The relationship between high ammonia and glutamine levels and raised ICH has been reported in humans.

• #11 Acute Liver Failure: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/177354-overview

  Ordinarily, NAPQI is metabolized in the presence of glutathione to N-acetyl-p-aminophenol-mercaptopurine. Glutathione quenches this reactive metabolite and acts to prevent nonspecific oxidation of cellular structures, which might result in severe hepatocellular dysfunction. […] This mechanism fails in two different yet equally important settings. The first is an overdose (accidental or intentional) of acetaminophen. Acetaminophen ingestion of more than 10 g simply overwhelms the normal hepatic stores of glutathione, allowing reactive metabolites to escape. […] The second and less obvious scenario occurs in a patient who consumes alcohol regularly. This does not necessarily require a history of alcohol abuse or alcoholism. Even a moderate or social drinker who consistently consumes one to two drinks daily may sufficiently deplete intrahepatic glutathione reserves. This results in potentially lethal hepatotoxicity from what is otherwise a safe dose of acetaminophen in an unsuspecting individual.

• #12 Pathophysiology of Acute Liver Failure – PubMed

  https://pubmed.ncbi.nlm.nih.gov/31840297/

  Acute liver failure (ALF) is a rare syndrome resulting from an acute insult to the liver in patients without known underlying chronic liver disease. It is characterized by loss of synthetic function in the form of jaundice and coagulopathy and development of hepatic encephalopathy. Multiorgan failure (MOF) eventually develops, leading to death. Many different etiologies have been identified, with acetaminophen (APAP) overdose and viral hepatitis being the most common causes worldwide. The pathophysiology of ALF can be divided into cause-specific liver injury pathophysiologies and pathophysiology related to occurrence of secondary MOF. […] In terms of liver injury pathophysiology, APAP toxicity is the most well known. Secondary MOF is often a result of the initial massive proinflammatory response generating a systemic inflammatory response syndrome followed by a compensatory anti-inflammatory response leading to immune cell dysfunction and sepsis. As the liver is a tremendously important metabolic organ involved in energy metabolism, protein synthesis, fat metabolism, and glycemic control, multiple aspects of nutrition also need to be considered as part of the overall pathophysiology of ALF.

• #13 Role of cytokines and immune mechanisms in acute liver failure (Chapter 7) – Acute Liver Failure

  https://www.cambridge.org/core/books/acute-liver-failure/role-of-cytokines-and-immune-mechanisms-in-acute-liver-failure/788F79B367A8516A487BD29454AF2E3A

  Acute liver failure (ALF) is a syndrome which results from a large number of inciting agents including viruses and toxins, whose common endpoint is massive hepatic necrosis. […] Although the inciting agent may directly damage hepatocytes, recent evidence has suggested that inflammatory cells and their products contribute to the hepatic necrosis. […] Furthermore, in patients with liver failure, endotoxemia occurs which contributes to the pathogenesis of this disorder. […] A number of studies have implicated the resident cell population of the liver, especially Kupffer and endothelial cells, in combination with elements of the immune system as key participants in the destructive process which ultimately leads to liver failure. […] Of particular interest is the rapidly increasing body of evidence identifying biological modifiers such as cytokines which are thought to play a major role in the pathogenesis of liver injury. […] Cytokines have numerous effects including increasing the expression of adhesion molecules, production of nitric oxide and activation of the immune coagulation system all of which have been implicated in the pathogenesis of liver injury.

• #14

  https://journals.lww.com/cld/fulltext/2019/09000/pathogenesis_of_acute_on_chronic_liver_failure_in.4.aspx

  Acuteonchronic liver failure (ACLF) can develop in patients with cirrhosis both at the compensated and decompensated stages of liver disease. The clinical symptoms of ACLF include acute liver decompensation, organ failure (or multiorgan failure), and increased shortterm mortality. The triggers for ACLF could be different events including infections, gastrointestinal bleeding, alcohol binge, largevolume paracentesis, transjugular intrahepatic portosystemic shunt, and surgery, although the precipitating factor cannot be identified in some cases of ACLF. Most studies found infection as the most frequent cause of ACLF. Infection and ACLS is a dangerous combination for clinical outcomes for several reasons. In patients with ACLS caused by different etiologies, the presence of bacterial infection was associated with significantly lower 90day survival compared with ACLF with no infection. Furthermore, the probability of acquiring infections in ACLS is increased in the presence of cirrhosis. Key elements of immune responses are impaired in patients with cirrhosis, including antigen presentation capacity of monocytes and decreased phagocytic function of macrophages that is pivotal for antibacterial immune defense. The combination of these impaired immune cell functions results in dysfunctional immune response to infections and pathogens. Pathogens that trigger ACLF can include bacterial, fungal, and viral pathogens that are mostly exogenous but can also be host derived from gut microbial translocation, the oral cavity, or skin sources. Infections, inflammation, and immune responses play an integral role in ACLF. Immune and molecular recognition of infection is triggered by pathogenderived signals, also referred to as pathogenassociated molecular patterns (PAMPs), through recognition by pattern recognition receptors such as Tolllike receptors (TLRs), intracellular helicase receptors, and nucleotide oligomerization domainlike receptors (NLRs). Activation of these receptors triggers innate immune responses in forms of proinflammatory cytokines and type I interferons. In the setting of cirrhosisrelated immune dysfunction, the host response to PAMPs is not always effective, resulting in systemic and/or prolonged infections. Infection and related sepsis are the most common causes of ACLF. Furthermore, increased levels of proinflammatory cytokines and chemokines contribute to organ dysfunction and multiorgan failure syndrome that dramatically increase mortality in ACLF. In ACLF, organ failure and mortality have a direct relationship. Plasma inflammatory cytokine levels, including tumor necrosis factor (TNF), interleukin (IL)6, IL8, monocyte chemoattractant protein 1, IL10, and IL1ra, are all significantly increased in ACLF compared with normal controls or patients with cirrhosis with no ACLF. Recent studies suggest that neutrophil leukocytes may play an important role not only in infection but also in ACLF. In persistent inflammatory states combined with sepsis, such as ACLF, the immune system is often debilitated by impaired and delayed adaptive immune responses in combination with persistent inflammation and immunosuppression. In summary, infections trigger inflammation and ACLF via TLR and NLR sensor/receptors. ACLF is associated with intense systemic inflammation indicated by increased circulating cytokine levels. Inflammatory cytokines mediate many of the clinical symptoms of ACLF and contribute to SIRS and multiorgan dysfunction syndrome (MODS). Preexisting immune dysfunction associated with cirrhosis compromises resolution of infections and complicates the clinical picture of ACLF.

• #15 Physiological consequences of acute liver failure | Deranged Physiology

  https://derangedphysiology.com/main/required-reading/gastrointestinal-intensive-care/Chapter-112/physiological-consequences-acute-liver-failure

  The following immunological problems have been identified in acute liver failure patients: Complement deficiency due to impaired synthesis, defective opsonisation as the consequence of decreased complement, impaired phagocytosis of encapsulated organisms due to defective opsonisation, impaired chemotaxis, impaired neutrophil function.

• #15 Physiological consequences of acute liver failure | Deranged Physiology

  https://derangedphysiology.com/main/required-reading/gastrointestinal-intensive-care/Chapter-112/physiological-consequences-acute-liver-failure

  Acute liver failure is a major inconvenience, adversely affecting all the organ systems. Among the possible complications, one might expect ARDS, circulatory collapse from SIRS, encephalopathy and raised ICP, a metabolic acidosis, renal failure due to hepatorenal syndrome, bone marrow failure, coagulopathy and immune suppression. […] Acute liver failure patients frequently develop a severe vasoplegia. Characteristically, this gives rise to a hyperdynamic circulation. This is well studied in patients who undergo liver transplantation, which is a pretty good model of acute liver failure. […] This vasoplegia is thought to be due to the activation of induceable nitric oxide synthase by exposure to bacterial endotoxin of enteric origin. […] In acute liver failure, the process is analogous. The swollen necrotic liver obstructs portal venous flow, and shunts open. Even if there is little shunting, one must consider that the acutely failing liver is unlikely to perform the usual tasks of clearing endotoxin from portal blood, and it ends up in the systemic circulation.

• #15 Physiological consequences of acute liver failure | Deranged Physiology

  https://derangedphysiology.com/main/required-reading/gastrointestinal-intensive-care/Chapter-112/physiological-consequences-acute-liver-failure

  The major difference in the setting of liver failure is the poor tolerance for high CO2, as the patients will have ammonia-induced increased ICP. […] The shocked patient with acute hepatic failure may be hypotensive because of their impaired response to ACTH. […] This is discussed in great detail in the chapter on hepatorenal syndrome. Suffice to say, it is a diagnosis of exclusion, and there are several diagnostic criteria to remember. […] When one uses the term „coagulopathy”, one typically refers to a tendency of increased bleeding. In acute liver failure there may also be a prothrombotic tendency because of the failure of Protein C and Protein S synthesis. […] Ranging from mildly depressed function to complete failure with aplastic anaemia, bone marrow dysfunction is a known association of acute liver disease.

• #16 Acute Liver Failure | Cleveland Clinic

  https://my.clevelandclinic.org/departments/digestive/medical-professionals/hepatology/acute-liver-failure

  Ammonia is a byproduct of the catabolism of nitrogen compounds and is toxic at high concentrations. The human body excretes ammonia through the urea cycle, which takes place mainly in the liver. […] In ALF, increased levels of ammonia and other nitrogenous wastes in the circulating blood result increased exposure to ammonia by the brain. This leads to increased production of glutamine in the astrocytes and because glutamine is an osmolyte, water moves into the astrocytes causing them to swell. This results in cerebral edema and encephalopathy. […] Any condition that results in acute ischemic injury to the liver can lead to ALF. Budd Chiari syndrome, prolonged systemic hypotension and sepsis are some of the clinical conditions that can cause hepatic ischemia, hepatocyte injury and necrosis, and subsequent ALF.

• #17 Mechanism of glycyrrhizin on ferroptosis during acute liver failure by inhibiting oxidative stress

  https://www.spandidos-publications.com/10.3892/mmr.2019.10660

  The present study aimed to investigate the antiferroptosis effects of the HMGB1 inhibitor glycyrrhizin (GLY). […] Acute liver failure (ALF) is a serious disorder or decompensation caused by various factors, including liver synthesis, detoxification, excretion and biotransformation, and the mortality rate of ALF caused by hepatitis B virus (HBV) is more than 50% in China. […] Oxidative stress is the key pathogenic link with ALF and could promote ALF. […] Ferroptosis is also characterized by the accumulation of reactive oxygen species (ROS) under high oxidative stress. […] The results of the present study indicated that HMGB1 is involved in the process of ferroptosis. The HMGB1 inhibitor GLY significantly reduced the degree of ferroptosis during ALF by inhibiting oxidative stress. […] The key process of ferroptosis is the Fenton reaction, in which Fe2+ converts lipid peroxide into ROS.

• #18 Mechanism of glycyrrhizin on ferroptosis during acute liver failure by inhibiting oxidative stress

  https://www.spandidos-publications.com/10.3892/mmr.2019.10660

  The excessive production of ROS is important to induce ferroptosis. […] Therefore, if oxidative stress can be prevented through the Nrf2/HO-1/HMGB1 pathway to inhibit ferroptosis, ALF can be alleviated. […] The present study indicated that GLY could increase anti-oxidative capacity, GSH and GPX4 levels, and active the Nrf2/HO-1/HMGB1 pathway, inhibiting ferroptosis in an LPS/D-GalN-induced ALF model.

• #19 Why would we consider plasma exchange in Acute Liver Failure and Acute-on-Chronic Liver Failure? | AASLD

  https://www.aasld.org/liver-fellow-network/core-series/why-series/why-would-we-consider-plasma-exchange-acute-liver

  Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are associated with high mortality unless treated appropriately. Therapeutic plasma exchange (TPE) may be used in ALF and ACLF either as a bridge to liver transplantation (LT) or as a part of medical management in patients who are unfit for LT. TPE is a process by which the plasma of an individual is filtered through an extracorporeal circuit which helps remove endotoxins, cytokines, and damage-associated molecular patterns (DAMPS), which are then replaced by fresh frozen plasma (FFP) alone or in combination with plasma expanders. By removing these cytokines, toxins, and autoantibodies, TPE provides the native liver a chance to rest and recover. […] Majority of ALF are precipitated by viral agents, drugs or toxins. Pathogen associated molecular patterns (PAMPs) and DAMPs produced due to hepatic injury stimulates the immune system to produces pro-inflammatory cytokines, tumor necrosis factor (TNF)-, interleukins (IL-6, IL-10, IL-1) and reactive oxygen species (ROS). These cytokines may lead to an uncontrolled immune response resulting in secondary organ injury, endothelial dysfunction, cerebral edema, microvascular injury and monocyte dysfunction. In such a clinical setting, TPE removes the offending cytokines and DAMPs from the plasma which restores vascular tone, prevents endothelial dysfunction, maintains adequate organ perfusion and helps ameliorate the immune response.

• #20 The role of infection and inflammation in the pathogenesis of hepatic encephalopathy and cerebral edema in acute liver failure | Nature Reviews Gastroenterology & Hepatology

  https://www.nature.com/articles/ncpgasthep0417

  Hepatic encephalopathy produces a wide spectrum of manifestations in patients with liver disease, ranging from mild neuropsychiatric alterations in patients with cirrhosis, to rapidly progressive coma, cerebral edema and death in patients with acute liver failure (ALF). […] Recent studies have suggested a role for infection and inflammation in the pathogenesis of hepatic encephalopathy, with evidence that the molecular mediators of infection and inflammation might act synergistically with ammonia to exacerbate the condition. […] Infection is a common precipitant of hepatic encephalopathy in patients with chronic liver disease and ALF. In ALF patients, two large studies have demonstrated the role of the SYSTEMIC INFLAMMATORY RESPONSE SYNDROME (SIRS) and infection in the progression and severity of hepatic encephalopathy. The presence of two or more SIRS criteria or the development of overt infection was associated with progression of encephalopathy, higher intracranial pressures and increased mortality.

• #21 Acute Liver Failure – Hepatic and Biliary Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/hepatic-and-biliary-disorders/approach-to-the-patient-with-liver-disease/acute-liver-failure

  In acute liver failure, multiple organ systems malfunction, often for unknown reasons and by unknown mechanisms. Affected systems include […] Hyperbilirubinemia is almost always present at presentation. The degree of hyperbilirubinemia is one indicator of the severity of liver failure. Coagulopathy due to impaired hepatic synthesis of coagulation factors is common. Hepatocellular necrosis, indicated by increased aminotransferase levels, is present. […] Portosystemic encephalopathy occurs, possibly secondary to increased ammonia production by nitrogenous substances in the gut. Cerebral edema is common among patients with severe encephalopathy secondary to acute liver failure; uncal herniation is possible and usually fatal. […] For unknown reasons, acute kidney injury occurs in up to 50% of patients.

• #22 Acute Liver Failure – Hepatic and Biliary Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/hepatic-and-biliary-disorders/approach-to-the-patient-with-liver-disease/acute-liver-failure

  Immune system defects develop; they include defective opsonization, deficient complement, and dysfunctional white blood cells and killer cells. […] Both metabolic and respiratory alkalosis may occur early. If shock develops, metabolic acidosis can supervene. […] Noncardiogenic pulmonary edema may develop.

• #23 The liver in sepsis: molecular mechanism of liver failure and their potential for clinical translation | Molecular Medicine | Full Text

  https://molmed.biomedcentral.com/articles/10.1186/s10020-022-00510-8

  The importance of hepatocytes as a non-specialized immune cell with no phagocytic activity for immune control is astonishing. […] Cell death mechanisms in hepatocytes are multifactorial events resulting from intracellular alterations of the micro-milieu. […] In sepsis, the metabolism of hepatocytes is modified toward the inflammatory response and cell death. […] The type of cell death execution, in particular necrosis or apoptosis, is a continuing debate. […] In septic liver injury, pyroptosis in hepatocytes is considered a defense mechanism against intracellular bacterial infections that PAMPs and DAMPs recognize. […] In contrast, excessive pyroptosis conduces to the development of liver diseases. […] This shows that NETs possess antimicrobial activities to capture virulence factors and damage extracellular microbes.

• #24

  https://www.xiahepublishing.com/2310-8819/JCTH-2023-00557

  Acute liver failure (ALF) is a life-threatening clinical problem with limited treatment options. Administration of human umbilical cord mesenchymal stem cells (hUC-MSCs) may be a promising approach for ALF. This study aimed to explore the role of hUC-MSCs in the treatment of ALF and the underlying mechanisms. […] ALF occurs when the rate and extent of hepatocyte death exceed the capacity of liver to repair. The massive death of hepatocytes during ALF progression results in the activation of innate immune cells, leading to the massive production of cytokines and chemokines. […] Apoptosis is a model of cell death that finally leads to ALF. […] Strategies approaching macrophage polarization as the therapeutic target may have the potential to alleviate ALF. […] hUC-MSCs could alleviate ALF by regulating hepatocyte apoptosis and macrophage polarization, thus hUC-MSC-based cell therapy may be an alternative option for patients with ALF.

• #25 The liver in sepsis: molecular mechanism of liver failure and their potential for clinical translation | Molecular Medicine | Full Text

  https://molmed.biomedcentral.com/articles/10.1186/s10020-022-00510-8

  Ferroptosis represents a new entity, inducing cell death by increased non-transferrin-bound or catalytic iron, catalyzing ROS synthesis, leading to lipid peroxidation and cell damage. […] The liver has a tremendous tolerogenic capacity maintained through a complex intercellular network of immune and parenchymal cells that provide sufficient anti-inflammatory signals to inflammatory signals constantly flooding in from the gut. […] Disturbance of this balance results in a fragile state where pro-inflammatory signals can result in decompensation and life-threatening acute phase and liver dysfunction associated with poor prognosis.

• #26 Current concepts in acute liver failure | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-current-concepts-in-acute-liver-S1665268119300638

  Acute liver failure (ALF) is a severe condition secondary to a myriad of causes associated with poor outcomes. The prompt diagnosis and identification of the aetiology allow the administration of specific treatments plus supportive strategies and to define the overall prognosis, the probability of developing complications and the need for liver transplantation. Pivotal issues are adequate monitoring and the institution of prophylactic strategies to reduce the risk of complications, such as progressive liver failure, cerebral oedema, renal failure, coagulopathies or infections. […] ALF is defined as the acute development of jaundice, synthetic failure and hepatic encephalopathy in patients without a previous history of liver disease. It is a severe and complex condition that results from acute and massive hepatocellular destruction. Thus, ALF has a very poor prognosis, with an approximately 80% mortality rate in historical series. A better understanding of the causes of ALF, specific treatments, improvements in intensive care management and the availability of liver transplantation (LT) have dramatically enhanced the prognosis for patients with ALF.

• #27 Current concepts in acute liver failure | Annals of Hepatology

  https://www.elsevier.es/en-revista-annals-hepatology-16-articulo-current-concepts-in-acute-liver-S1665268119300638

  The aetiology of ALF differs significantly worldwide, and it is a very important aspect define treatment and prognosis. Notably, indeterminate aetiology accounts for 20-45% of all ALF cases. […] Thus, early identification of ALF, the administration of general and specific supportive treatments and the availability of LT are pivotal factors that can improve the outcomes for these patients.

• #28 Why would we consider plasma exchange in Acute Liver Failure and Acute-on-Chronic Liver Failure? | AASLD

  https://www.aasld.org/liver-fellow-network/core-series/why-series/why-would-we-consider-plasma-exchange-acute-liver

  TPE dampens systemic inflammation and improve hepatocyte regeneration by removing DAMPs, cytokines, bile acids and endotoxins. Studies from China and India have demonstrated a reduction in serum concentrations of IFN-, interleukins and TNF- among patients of ACLF undergoing TPE as compared to SMT. The reduction in pro-inflammatory cytokines helps control the systemic inflammation which is the primary driver of outcomes in ACLF. It prevents the development of further organ failures and immune fatigue. […] TPE reduces the inflammatory burden in patients with ALF and ACLF and may prevent MOF when initiated early in the disease course. Majority of studies support the role of TPE in improving survival among patients with ALF. There is paucity of granular data on effects of TPE on outcomes of ACLF. Combination of TPE with DPMAS or other filtration techniques may improve its efficacy while reducing its adverse effects.

• #29

  https://www.xiahepublishing.com/2310-8819/JCTH-2023-00557

  hUC-MSCs treatment decreased the levels of serum alanine aminotransferase and aspartate aminotransferase, reduced pathological damage, alleviated hepatocyte apoptosis, and reduced mortality in vivo. […] The hUC-MSCs treatment inhibited the activation of phosphorylated (p)-C-Jun N-terminal kinase and p-nuclear factor-kappa B not only in liver tissues but also in AML12 and RAW264.7 cells co-cultured with hUC-MSCs. […] hUC-MSCs may suppress hepatocyte apoptosis in LPS/D-GalN-induced ALF by inhibiting JNK/NF-B activation. […] The hUC-MSCs treatment significantly decreased the levels of TNF-, IL-6, and IL-1, which is consistent with previous findings that substantiate the anti-inflammatory effects of stem cells. […] The aforementioned results suggest that hUC-MSCs can protect against LPS/D-GalN-induced ALF through their immunomodulatory properties, as indicated by the regulation of macrophage polarization and the decreased level of circulating inflammatory cytokines.

• #30 Assessing Liver Function in Rat Models of Acute Liver Failure Using Single-Photon Emission Computed Tomography and Cytokine Levels | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0323531

  Dynamic hepatobiliary SPECT imaging is a valuable imaging tool for diagnosis and assessing the severity of different types of liver failure. It offers noninvasive and direct monitoring of liver function. SPECT imaging, combined with the calculated indexes and the evaluation of cytokine levels, can become an effective method for assessing liver function of patients with acute liver failure.

• #31 Viral etiologies of acute liver failure

  https://www.wjgnet.com/2220-3249/full/v13/i3/97973.htm

  Acute liver failure (ALF) is a rare cause of liver-related mortality worldwide, with an estimated annual global incidence of more than one million cases. […] While drug-induced liver injury, including acetaminophen toxicity, is the leading cause of ALF in the Western world, viral infections remain a significant cause of ALF and the most common cause in many developing nations. […] Given the high mortality rates associated with ALF, healthcare providers should be aware of the broad range of viral infections that have been implicated to enable early diagnosis, rapid treatment initiation when possible, and optimal management, which may include liver transplantation. […] This review aims to provide a summary of viral causes of ALF, diagnostic approaches, treatment options, and expected outcomes.

• #32 Acute Liver Failure: Pathogenesis and clinical findings | Calgary Guide

  https://calgaryguide.ucalgary.ca/acute-liver-failure-pathogenesis-and-clinical-findings/acute-liver-failure/

  Acute Liver Failure: Pathogenesis and clinical findings […] Accumulation of toxic NAPQI (a metabolite of acetaminophen) NAPQI binds hepatocellular proteins […] Metabolism of drugs by the liver can produce reactive drug metabolites Intracellular stress, mitochondrial injury, or immune response […] Acute infection or infection flare provokes an immune response against infected hepatocytes […] Autoimmune antibodies attack hepatocytes […] O2 delivery to the liver Hepatocellular hypoxia […] Heritable mutation in the ATP7B gene Biliary excretion of copper Hepatic copper accumulation injures hepatocytes […] Accelerated rate of hepatocellular necrosis or apoptosis Hepatocyte death exceeds regeneration such that liver function is compromised within a short amount of time.

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