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Liver failure

Liver failure is a life-threatening condition in which the liver loses its ability to perform essential functions, such as detoxifying harmful substances, producing proteins and clotting factors, and aiding in digestion, often resulting in the accumulation of toxins, coagulopathy, and multi-organ failure.^[1] It encompasses both acute and chronic forms, where acute liver failure involves rapid deterioration of liver function within days to weeks in individuals without preexisting liver disease, while chronic liver failure develops gradually as the end stage of ongoing liver injury leading to cirrhosis and decompensation.^[2]^[3] Acute liver failure (ALF) is relatively rare, with an estimated 2,000–3,000 cases annually in the United States, corresponding to an incidence of approximately 6–9 cases per million people, and is defined by the onset of severe liver dysfunction, typically evidenced by encephalopathy and coagulopathy (international normalized ratio >1.5) within 26 weeks without prior chronic liver issues.^[1]^[4] Common causes include acetaminophen overdose (accounting for nearly 50% of cases in the United States), viral infections such as hepatitis A or B, drug-induced liver injury, and exposure to toxins like certain mushrooms or industrial chemicals.^[1] In contrast, chronic liver failure arises from prolonged damage due to factors like chronic viral hepatitis (B or C), excessive alcohol consumption, nonalcoholic steatohepatitis (NASH), autoimmune diseases, or metabolic disorders, culminating in extensive scarring (cirrhosis) that impairs liver architecture and function.^[5] Acute-on-chronic liver failure (ACLF) represents a distinct syndrome where an acute insult precipitates rapid decompensation in patients with underlying chronic liver disease, often involving extrahepatic organ failures and carrying a high short-term mortality rate of 20-50%.^[6] Symptoms of liver failure vary by type but commonly include jaundice (yellowing of the skin and eyes due to bilirubin buildup), fatigue, abdominal pain and swelling (ascites), easy bruising or bleeding from impaired clotting, confusion or hepatic encephalopathy from toxin accumulation in the brain, and in advanced stages, kidney failure, infections, or gastrointestinal bleeding.^[2]^[3] Early detection is challenging as initial signs may be nonspecific, but progression can lead to coma or death without intervention.^[1] Management of liver failure focuses on supportive care, addressing the underlying cause, and preventing complications; for acute cases, this may involve N-acetylcysteine for acetaminophen toxicity, antiviral therapies, or urgent liver transplantation, which offers the best survival chance with success rates exceeding 80% in selected patients.^[7] In chronic scenarios, treatments target disease modification (e.g., abstinence from alcohol, antivirals for hepatitis), while end-stage disease often requires transplantation, however, due to limited organ availability, many patients die while awaiting transplantation.^[5]^[8] Prognosis depends on etiology and timeliness of care, with acute liver failure mortality ranging from 20-50% even with treatment, underscoring the need for specialized intensive care.^[1]

Overview and Classification

Definition

Liver failure is a severe clinical syndrome characterized by the liver's inability to perform its essential physiological functions, including detoxification of harmful substances, synthesis of critical proteins, and production of bile, resulting in the accumulation of toxins and widespread metabolic disturbances. This condition arises when hepatocyte damage impairs the organ's capacity to maintain homeostasis, distinguishing it from milder liver dysfunction where some functions remain intact. Unlike simple insufficiency, liver failure leads to systemic complications due to the liver's central role in metabolism, immunity, and nutrient processing.^[9]^[10]^[11] Among the key synthetic functions compromised in liver failure is the production of albumin, a major plasma protein essential for maintaining oncotic pressure and transporting substances, leading to hypoalbuminemia and edema. Similarly, the liver synthesizes most clotting factors, such as II, V, VII, IX, and X, and their deficiency results in coagulopathy, often quantified by an international normalized ratio (INR) greater than 1.5 in acute cases, alongside hepatic encephalopathy as a diagnostic threshold. Bile production failure disrupts fat digestion and excretion of waste products like bilirubin, exacerbating jaundice and nutritional deficits.^[12]00317-0/fulltext)^[1] Detoxification processes are profoundly affected, particularly the conversion of ammonia—a byproduct of protein metabolism—into urea for safe excretion; in liver failure, ammonia accumulates in the blood, crossing the blood-brain barrier and precipitating hepatic encephalopathy, a spectrum of neuropsychiatric abnormalities ranging from confusion to coma. This neurotoxicity underscores the liver's role as a gatekeeper against endogenous toxins.^[13]^[14] The terminology evolved historically, with "fulminant hepatic failure" coined in the 1970s by Trey and Davidson to denote rapid-onset severe acute liver injury with encephalopathy within eight weeks of jaundice onset in previously healthy individuals; today, it is largely synonymous with acute liver failure, while chronic forms represent end-stage progression. Liver failure encompasses acute, chronic, and acute-on-chronic variants, each reflecting different timelines of hepatic decompensation.^[15]^[16]

Types

Liver failure is broadly classified into three main types based on the tempo of onset, underlying liver condition, and clinical progression: acute liver failure (ALF), chronic liver failure, and acute-on-chronic liver failure (ACLF).^[1]00244-1/fulltext) This classification helps guide prognosis and management, with ALF representing a rapid insult to a previously healthy liver, chronic liver failure arising from long-term damage, and ACLF involving sudden decompensation atop existing chronic disease.^[6] Acute liver failure (ALF) is defined as the rapid development of severe acute liver injury with coagulopathy (international normalized ratio >1.5) and hepatic encephalopathy in a patient without preexisting liver disease, occurring within 26 weeks of the initial symptom onset.^[1] It often manifests with encephalopathy within 8 weeks of jaundice, distinguishing it from milder acute liver injury.^[17] ALF is further subdivided based on the interval from the onset of jaundice to the development of encephalopathy: hyperacute (less than 7 days), acute (7 to 28 days), and subacute (4 to 26 weeks).^[18]^[19] The hyperacute form is typically associated with rapid progression and higher risk of cerebral edema, while subacute cases may involve more insidious hepatocyte loss.^[18] Chronic liver failure develops gradually over years as a consequence of progressive chronic liver disease (CLD), most commonly cirrhosis, leading to end-stage liver dysfunction with portal hypertension and synthetic failure.^[1] Unlike ALF, it features a history of underlying conditions such as chronic viral hepatitis or alcohol-related damage, with decompensation marked by ascites, variceal bleeding, or encephalopathy over an extended timeframe.^[20] Acute-on-chronic liver failure (ACLF) describes an acute deterioration in patients with preexisting CLD or cirrhosis, often triggered by a precipitant like infection or bleeding, resulting in multi-organ failure and high short-term mortality (up to 30% at 28 days).00244-1/fulltext)^[21] It is characterized by systemic inflammation and extrahepatic organ dysfunction, setting it apart from simple decompensation of cirrhosis.^[6] There can be overlaps and transitions between these types; for instance, survivors of untreated ALF may develop chronic liver disease if significant fibrosis ensues, while some ACLF cases can evolve from subacute ALF in patients with unrecognized mild CLD.^[1]^[22]

Pathophysiology

General Mechanisms

Liver failure fundamentally involves injury to hepatocytes, the primary functional cells of the liver, which can proceed through necrosis or apoptosis, thereby compromising the organ's regenerative capacity and leading to progressive dysfunction. Necrosis represents an uncontrolled form of cell death triggered by severe insults, resulting in membrane rupture, release of intracellular contents, and subsequent inflammation, while apoptosis is a regulated process involving caspase activation that minimizes inflammatory responses but still reduces viable hepatocyte mass. This dual pathway of cell death disrupts normal liver architecture and impairs the proliferation of remaining hepatocytes, which is essential for tissue repair.^[23]^[24]^[25] The initial hepatocyte damage initiates an inflammatory cascade, marked by the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) from injured cells, Kupffer cells, and infiltrating immune cells. These cytokines promote further hepatocyte apoptosis, recruit additional inflammatory cells, and induce systemic inflammation, creating a vicious cycle that exacerbates liver injury. TNF-α, in particular, activates death receptors on hepatocytes, while IL-6 drives acute-phase responses that can contribute to multi-organ involvement.^[26]^[27]^[28] Portal hypertension emerges as a key hemodynamic consequence, stemming from increased resistance within the hepatic sinusoids due to endothelial cell swelling, extracellular matrix deposition from fibrosis, or regenerative nodules that distort vascular architecture. This elevated resistance impedes portal venous inflow, leading to splanchnic vasodilation and systemic circulatory changes. Sinusoidal endothelial dysfunction, often involving reduced nitric oxide bioavailability, further amplifies this intrahepatic resistance.^[29]^[30]^[31] Coagulopathy in liver failure arises from the liver's impaired synthesis of both pro-coagulant factors (such as II, V, VII, IX, and X) and anti-coagulant proteins (including protein C, protein S, and antithrombin), resulting in a rebalanced but precarious hemostatic state prone to bleeding or thrombosis. Dysfibrinogenemia and thrombocytopenia due to splenic sequestration compound this imbalance, shifting the equilibrium toward hemorrhage without a simple global deficiency.^[32]^[33]^[34] Metabolic disruptions are central to the progression of liver failure, with hypoglycemia developing from exhausted hepatic glycogen stores and defective gluconeogenesis, as the liver fails to maintain glucose homeostasis during fasting or stress. Concurrently, lactic acidosis occurs due to impaired hepatic clearance of lactate, mitochondrial dysfunction, and shunting of blood away from hepatocytes, leading to anaerobic metabolism and acid-base imbalance. These alterations underscore the liver's critical role in intermediary metabolism.^[5]^[1]^[35] The gut-liver axis contributes significantly to the pathogenesis, where portal hypertension and inflammation compromise the intestinal barrier, facilitating bacterial translocation from the gut lumen into the portal circulation and causing endotoxemia. Lipopolysaccharides (LPS) from translocated bacteria activate hepatic Kupffer cells via Toll-like receptor 4, amplifying cytokine production and systemic inflammatory responses that worsen hepatocyte injury. This interplay highlights how gut-derived factors perpetuate liver decompensation.^[36]^[37]^[38]

Mechanisms in Acute Liver Failure

Acute liver failure (ALF) involves rapid and extensive hepatocyte death, typically involving massive parenchymal loss, which surpasses the organ's regenerative capacity and precipitates a profound metabolic crisis. This massive necrosis disrupts critical liver functions, including detoxification, protein synthesis, and glucose homeostasis, leading to coagulopathy, hypoglycemia, and hyperammonemia within days to weeks in patients without prior liver disease. The necrotic process is often triggered by direct hepatotoxins or immune-mediated injury, resulting in zones of centrilobular or panlobular cell death that impair bile flow and vascular integrity.^[1]^[39] Hyperammonemia in ALF contributes to cerebral edema through uptake of ammonia by astrocytes, where it combines with glutamate to form glutamine via glutamine synthetase, causing osmotic swelling and increased intracranial pressure. This astrocyte hypertrophy is compounded by oxidative/nitrosative stress and mitochondrial dysfunction in brain cells, which exacerbate energy failure and blood-brain barrier permeability, potentially leading to herniation and coma. Ammonia levels above 150-200 μmol/L are particularly associated with severe encephalopathy and edema in ALF.^[40]^[41] Extrahepatic complications in ALF include acute kidney injury, frequently presenting as hepatorenal syndrome type 1, defined by a rapid doubling of serum creatinine to >2.5 mg/dL or a 50% reduction in creatinine clearance within two weeks. This arises from splanchnic vasodilation due to portal hypertension and endotoxin release, which lowers effective arterial volume and activates compensatory renal vasoconstriction via the renin-angiotensin-aldosterone system and sympathetic nervous system, reducing glomerular filtration without structural kidney damage.^[42]^[43] ALF elicits a systemic inflammatory response syndrome (SIRS) resembling sepsis, driven by massive release of pro-inflammatory cytokines such as TNF-α and IL-6 from necrotic hepatocytes and Kupffer cells, promoting vasodilation, hypotension, and multi-organ dysfunction. This inflammatory cascade contributes to cardiovascular collapse through myocardial depression and distributive shock, with SIRS present in up to 60-70% of cases and independently predicting high mortality rates exceeding 50% without transplantation.^[44]^[45] In cases of sudden toxin overload, such as acetaminophen overdose, oxidative stress and mitochondrial dysfunction accelerate hepatocyte necrosis by generating reactive oxygen species (ROS) that deplete glutathione and trigger the mitochondrial permeability transition pore. This leads to ATP depletion, calcium dysregulation, and release of damage-associated molecular patterns, amplifying the inflammatory response and preventing recovery. Mitochondrial impairment is a hallmark in toxin-induced ALF, distinguishing it from slower chronic insults.^[46]^[47]

Mechanisms in Chronic Liver Failure

Chronic liver failure develops gradually through repeated insults to the liver, leading to progressive fibrosis and eventual cirrhosis. In this process, hepatic stellate cells (HSCs), normally quiescent and involved in vitamin A storage, become activated in response to chronic injury signals such as transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF). Activated HSCs transdifferentiate into myofibroblast-like cells, proliferating and secreting excessive extracellular matrix (ECM) components, including collagen types I and III, fibronectin, and proteoglycans. This ECM deposition disrupts normal liver architecture, replacing functional hepatocytes with scar tissue and impairing regenerative capacity, ultimately culminating in cirrhosis characterized by nodular regeneration and vascular distortion.^[48]^[49] As fibrosis advances to cirrhosis, the liver enters a compensated phase where synthetic and metabolic functions are maintained despite scarring, but decompensation occurs when these adaptations fail, often triggered by portal hypertension and synthetic dysfunction. Portal hypertension arises from increased intrahepatic resistance due to fibrotic bands and sinusoidal distortion, elevating pressure in the portal vein and leading to complications such as variceal bleeding from esophageal or gastric varices formed by portosystemic collaterals. Concurrently, hypoalbuminemia from impaired hepatic protein synthesis reduces oncotic pressure, while renal sodium retention mediated by the renin-angiotensin-aldosterone system promotes ascites accumulation in the peritoneal cavity. These events mark decompensation, increasing mortality risk through recurrent bleeding, infection, or renal impairment.^[50]^[51] Portosystemic shunting, a hallmark of advanced cirrhosis, further exacerbates hepatic dysfunction by diverting nutrient-rich portal blood away from hepatocytes, bypassing detoxification processes. This shunting allows ammonia and other toxins to enter systemic circulation directly, as the liver's urea cycle—responsible for converting ammonia to urea in periportal hepatocytes—is evaded due to reduced functional mass and altered blood flow. The resulting hyperammonemia contributes to chronic hepatic encephalopathy, manifesting as cognitive impairment, asterixis, and altered consciousness through mechanisms including astrocyte swelling and neurotransmitter imbalances in the brain.^[13]^[52] The chronic inflammatory and regenerative environment in cirrhotic livers significantly increases the risk of hepatocellular carcinoma (HCC), with up to a 100-fold higher incidence compared to the general population in cases such as chronic hepatitis B infection.^[53]^[54]^[55] These nodules arise from attempts at hepatocyte proliferation amid ongoing injury, but accumulated genetic instability—driven by oxidative stress, telomere shortening, and mutations in oncogenes like TP53 or CTNNB1—promotes dysplasia and neoplastic progression. Cirrhosis underscores the need for surveillance in affected patients. Malnutrition and sarcopenia are prevalent in chronic liver failure, stemming from a hypermetabolic state induced by systemic inflammation and inefficient nutrient processing. The liver's diminished capacity to metabolize carbohydrates, proteins, and fats leads to inadequate energy production and muscle protein synthesis, compounded by increased resting energy expenditure (up to 20-30% above normal) due to tumor necrosis factor-alpha and other cytokines. This results in progressive skeletal muscle wasting, reduced strength, and frailty, further worsening prognosis by impairing recovery from decompensation events.^[56]^[57]

Causes

Infectious and Inflammatory Causes

Infectious causes of liver failure primarily involve viral pathogens that directly target hepatocytes, leading to acute or fulminant hepatic injury. Hepatitis A virus (HAV) and hepatitis E virus (HEV) typically cause self-limited acute infections but can precipitate acute liver failure (ALF) in severe cases, with HAV-associated ALF occurring in less than 1% of infections, often requiring liver transplantation in up to 31% of affected patients.^[58] Hepatitis B virus (HBV) and hepatitis C virus (HCV) more commonly drive chronic liver disease progressing to failure, though HBV can induce ALF through acute infection or reactivation in chronic carriers, particularly in immunocompromised individuals, with transplant-free survival rates ranging from 26% to 53%.^[59] HEV stands out as a leading cause of acute viral hepatitis in endemic regions, disproportionately affecting pregnant individuals and those with underlying liver conditions, where it mimics other enteric viruses but escalates to ALF via robust immune-mediated hepatocyte damage.^[60] Bacterial infections contribute to liver failure indirectly by exacerbating decompensation in patients with cirrhosis or through systemic inflammation. Sepsis, often from gram-negative enteric bacteria, can trigger ALF in cirrhotics by inducing multiorgan dysfunction and hepatic ischemia, with bacterial infections accounting for up to 25-31% of infectious complications in this population.^[61] Spontaneous bacterial peritonitis (SBP), a ascitic fluid infection without intra-abdominal source, represents the most common bacterial complication in advanced cirrhosis, occurring in 7-30% of hospitalized patients and significantly increasing mortality risk through cytokine storms and renal impairment.^[62] These infections highlight the gut-liver axis vulnerability in chronic liver disease, where bacterial translocation from the intestine overwhelms impaired hepatic clearance.^[63] Inflammatory etiologies encompass autoimmune and genetic disorders with immune-driven hepatic destruction. Autoimmune hepatitis (AIH) is characterized by T-cell mediated attack on hepatocytes, classified into type 1 (associated with anti-nuclear antibodies, ANA) affecting adults and adolescents, and type 2 (linked to anti-liver kidney microsomal type 1 antibodies, anti-LKM1), more common in children, both progressing to chronic failure and cirrhosis if untreated, with up to 10-20% presenting as ALF requiring urgent immunosuppression or transplantation.^[64] Type 1 AIH predominates globally and responds well to corticosteroids, while type 2 carries a higher risk of early relapse but similar long-term liver outcomes to type 1.^[65] Other autoimmune liver diseases include primary biliary cholangitis (PBC), a chronic cholestatic disease primarily affecting women, characterized by destruction of small intrahepatic bile ducts due to antimitochondrial antibodies, leading to progressive fibrosis, cirrhosis, and end-stage liver failure in 20-50% of untreated cases, with a prevalence of approximately 20-40 per 100,000 in Europe and North America.^[66] Primary sclerosing cholangitis (PSC) involves inflammation and fibrosis of intra- and extrahepatic bile ducts, often associated with inflammatory bowel disease, progressing to biliary cirrhosis and liver failure over 10-20 years in most patients, with an incidence of 0.4-1.3 per 100,000 and higher risk of cholangiocarcinoma.^[67] Wilson's disease, an inherited disorder of copper metabolism, can manifest acutely as ALF in undiagnosed chronic carriers due to massive copper release triggering hemolytic anemia and coagulopathy, mimicking infectious hepatitis and necessitating rapid chelation therapy or liver transplantation for survival.^[68] Diagnostic hallmarks include low serum ceruloplasmin (<20 mg/dL) and Kayser-Fleischer rings, with acute presentations often fulfilling criteria for fulminant failure.^[69] As of 2025, emerging evidence links post-COVID-19 inflammatory syndromes to worsened liver outcomes in chronic patients, where persistent systemic inflammation and cytokine dysregulation exacerbate fibrosis and precipitate decompensation or ALF in those with preexisting cirrhosis.^[70] Long COVID-associated multiorgan involvement, including hepatic enzyme elevations and steatosis progression, heightens risks in vulnerable populations, with liver function abnormalities on admission predicting prolonged inflammatory sequelae.^[71] These syndromes underscore the interplay of viral aftermath and immune dysregulation in amplifying inflammatory liver injury.^[72]

Toxic and Metabolic Causes

Toxic and metabolic causes of liver failure encompass a range of exogenous insults and inherent metabolic disruptions that impair hepatic function, often through dose-dependent toxicity or genetic predispositions. These etiologies contribute significantly to both acute and chronic forms of liver failure, with mechanisms involving direct hepatocyte damage, oxidative stress, and progressive fibrosis. Among them, acetaminophen overdose stands out as a leading cause of acute liver failure in Western countries, accounting for approximately 46% of cases in the United States. This toxicity arises from the metabolism of acetaminophen to N-acetyl-p-benzoquinone imine (NAPQI), a reactive intermediate that depletes hepatic glutathione stores, leading to mitochondrial dysfunction and centrilobular necrosis when glutathione is insufficient for detoxification.^[73]^[74] Alcoholic liver disease represents a spectrum of alcohol-induced hepatic injury, progressing from reversible steatosis to steatohepatitis, fibrosis, and ultimately cirrhosis, with continued heavy consumption accelerating this trajectory. In susceptible individuals, acute alcoholic hepatitis can precipitate acute-on-chronic liver failure, characterized by rapid decompensation in those with underlying cirrhosis, often triggered by binge drinking or superimposed infections. The dose-dependent nature of this condition is evident, as daily intake exceeding 30-40 grams of alcohol in women or 40-60 grams in men over years substantially elevates risk, with oxidative stress from ethanol metabolism playing a central role, though detailed cellular mechanisms are addressed elsewhere.^[75]^[76] Non-alcoholic fatty liver disease (NAFLD), recently reclassified as metabolic dysfunction-associated steatotic liver disease (MASLD), links closely to metabolic syndrome components such as obesity, insulin resistance, and dyslipidemia, driving chronic liver failure through progressive steatosis, inflammation (steatohepatitis), and fibrosis culminating in cirrhosis. This condition affects up to 25-30% of the global population and is projected to become the primary indication for liver transplantation in coming decades due to its association with type 2 diabetes and cardiovascular disease. Genetic factors, including variants in PNPLA3 and TM6SF2 genes, modulate susceptibility, but the core pathophysiology stems from ectopic fat accumulation in hepatocytes, promoting lipotoxicity and fibrogenesis.^[77]^[78] Drug-induced liver injury (DILI) constitutes another major toxic cause, often manifesting as idiosyncratic reactions unpredictable by dose, affecting 1 in 10,000 to 100,000 exposed individuals and ranking as the second most common cause of acute liver failure in the United States after acetaminophen. Antibiotics like amoxicillin-clavulanate and nitrofurantoin, nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, and herbal supplements including green tea extract and kava are frequent culprits, with patterns ranging from hepatocellular necrosis to cholestasis. These reactions involve immune-mediated hypersensitivity or direct toxicity, with genetic polymorphisms in drug-metabolizing enzymes like CYP2E1 influencing severity.^[79]^[80] Hereditary hemochromatosis, an autosomal recessive disorder due to mutations in the HFE gene (most commonly C282Y homozygosity), leads to excessive intestinal iron absorption and deposition in hepatocytes, causing oxidative damage, fibrosis, and cirrhosis in 20-30% of untreated cases, particularly in men, with a prevalence of about 1 in 200-300 individuals of Northern European descent; it accounts for up to 5-10% of cirrhosis in these populations and increases risk of hepatocellular carcinoma.^[81] Inborn errors of metabolism, such as alpha-1 antitrypsin deficiency (A1ATD), exemplify genetic causes of chronic liver failure, where the PI*Z allele leads to misfolded protein accumulation in hepatocytes, triggering endoplasmic reticulum stress, inflammation, and progressive cirrhosis in 10-15% of affected adults. This autosomal codominant disorder affects approximately 1 in 2,500-5,000 individuals of European descent and can present with neonatal cholestasis or later-onset portal hypertension and liver failure, independent of lung involvement. Liver transplantation remains the definitive treatment, as augmentation therapy with alpha-1 antitrypsin does not address the hepatic pathology.^[82]^[83]

Vascular and Other Causes

Vascular causes of liver failure primarily involve obstructions or reductions in hepatic blood flow, leading to congestion, ischemia, or infarction that can manifest as acute liver failure or acute-on-chronic liver failure in susceptible individuals. These disruptions often stem from thrombotic events or hemodynamic instability, exacerbating underlying liver disease by impairing sinusoidal perfusion and promoting hepatocyte necrosis. In chronic settings, such vascular issues may contribute to portal hypertension, a condition characterized by increased pressure in the portal venous system due to resistance to flow within the liver.^[84]^[85]^[86] Budd-Chiari syndrome represents a prototypical vascular cause, defined as hepatic venous outflow obstruction at any level from the small hepatic veins to the inferior vena cava, excluding cardiac or pericardial origins, most commonly due to thrombosis of the hepatic veins or inferior vena cava. This obstruction causes post-sinusoidal portal hypertension, leading to hepatic congestion, centrilobular sinusoidal dilation, and rapid hepatocyte injury, which can progress to acute liver failure with features such as ascites, hepatomegaly, and coagulopathy. The condition is rare, with an incidence of approximately 1-2 per million annually, and hypercoagulable states like myeloproliferative disorders or oral contraceptive use underlie up to 80% of cases, precipitating outflow blockage that compromises liver viability within days to weeks.^[84]^[87]^[84] Portal vein thrombosis (PVT) disrupts inflow to the liver, with chronic forms commonly complicating cirrhosis by promoting cavernous transformation and extrahepatic portal hypertension, which fosters esophageal varices and recurrent gastrointestinal bleeding. In acute presentations, PVT reduces hepatic blood flow by 50-70%, inducing ischemic cholangiopathy or parenchymal infarction, thereby precipitating acute-on-chronic liver failure (ACLF) in up to 10-15% of cirrhotic patients with this event. The prevalence of PVT in cirrhosis ranges from 1-25%, often linked to local factors like sluggish flow or endothelial damage, and acute thrombosis can rapidly worsen decompensation by limiting nutrient delivery to hepatocytes.^[86]^[86]^[88] Ischemic hepatitis, also termed shock liver or hypoxic hepatitis, arises from acute hypoperfusion of the liver due to systemic hypotension or low cardiac output, most frequently in the context of severe heart failure or septic shock. This leads to diffuse hepatocellular necrosis, particularly in zone 3 of the acinus, with marked elevations in aminotransferases (often >1000 IU/L) reflecting the severity of oxygen deprivation, and it accounts for 1-2% of acute liver injury cases but carries a high mortality of 25-50% tied to the underlying hemodynamic insult. In heart failure, passive congestion compounds the ischemia, while sepsis induces microvascular dysfunction, both culminating in transient but profound liver dysfunction that can evolve into failure if perfusion is not restored promptly.^[85]^[85]^[85] Neoplastic causes, particularly hepatocellular carcinoma (HCC), contribute to liver failure through tumor burden overwhelming the cirrhotic liver's reserve, occurring in 85% of HCC cases where underlying cirrhosis amplifies decompensation. Tumor invasion disrupts vascular architecture, induces microvascular thrombosis, and increases intrahepatic resistance, leading to rapid progression of jaundice, encephalopathy, and ascites as functional hepatocyte mass declines below critical thresholds. In cirrhotics, HCC-related decompensation manifests in 20-30% of advanced cases, often via portal vein tumor thrombosis that further impairs inflow and precipitates ACLF.^[89]^[89]^[90] Among other causes, acute fatty liver of pregnancy (AFLP) is a rare but life-threatening disorder linked to fetal long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, affecting 1 in 5,000-20,000 deliveries and causing microvesicular steatosis in maternal hepatocytes. The deficiency impairs beta-oxidation of fatty acids, leading to triglyceride accumulation, mitochondrial dysfunction, and acute liver injury that progresses to failure with hypoglycemia, coagulopathy, and encephalopathy in the third trimester. Maternal mortality has dropped to under 10% with prompt delivery, but 20% of AFLP cases involve heterozygous LCHAD mutations in the mother carrying an affected fetus, highlighting the genetic predisposition to this fulminant hepatic crisis.^[91]^[91]^[92]

Signs and Symptoms

Early Manifestations

Liver failure often presents with nonspecific early symptoms that can be subtle and easily overlooked, particularly in chronic cases, but more abrupt in acute forms. Fatigue and weakness are among the most common initial manifestations, arising from metabolic disturbances due to impaired hepatic glycogen storage and protein synthesis.^[5] These symptoms reflect the liver's reduced capacity to maintain energy homeostasis and can significantly impair daily functioning even before overt liver dysfunction is evident.^[93] Jaundice, characterized by yellowing of the skin and sclerae, emerges from the accumulation of unconjugated and conjugated bilirubin secondary to hepatocyte damage and impaired biliary excretion.^[94] Accompanying pruritus, or intense itching, results from bile salt deposition in the skin, which is more prominent in cholestatic presentations of liver failure.^[95] In acute liver failure (ALF), jaundice typically develops rapidly within days to weeks following the onset of illness, often preceded by dark urine.^[2] Conversely, in chronic liver failure, such as cirrhosis, jaundice progresses insidiously over months, sometimes without initial notice.^[96] Gastrointestinal symptoms including nausea, vomiting, and anorexia frequently appear early, attributed to the buildup of hepatotoxic metabolites and cytokines that affect the central nervous system and gut motility.^[93] These may be more acute and severe in ALF, mimicking viral gastroenteritis, while in chronic cases, they contribute to progressive weight loss.^[97] Signs of early coagulopathy, such as easy bruising and prolonged bleeding from minor trauma, stem from decreased synthesis of clotting factors like prothrombin by the failing liver.^[5] This is particularly evident in chronic liver failure, where thrombocytopenia from splenic sequestration exacerbates the bleeding tendency.^[98]

Advanced Complications

As liver failure progresses, advanced complications arise that affect multiple organ systems, often requiring immediate intervention to prevent mortality. These sequelae, including neurological, abdominal, gastrointestinal, renal, and pulmonary disturbances, underscore the critical nature of end-stage disease, where portal hypertension and impaired detoxification exacerbate systemic dysfunction.^[13] Hepatic encephalopathy represents a spectrum of neuropsychiatric abnormalities due to liver dysfunction and portosystemic shunting, with elevated ammonia playing a key role in its pathogenesis. It is classified into four stages using the West Haven criteria: stage I involves mild confusion, euphoria, or sleep disturbances; stage II features lethargy, disorientation, and asterixis; stage III includes somnolence, marked confusion, and gross disorientation; and stage IV manifests as coma with no response to stimuli. Progression from confusion to coma can occur rapidly, impairing consciousness and increasing infection risk. Management typically involves lactulose to reduce ammonia absorption by acidifying the colon and promoting its excretion.^[13]^[99]^[100] Ascites, the accumulation of fluid in the peritoneal cavity due to portal hypertension and hypoalbuminemia, frequently complicates advanced liver failure and predisposes patients to spontaneous bacterial peritonitis (SBP), an infection of ascitic fluid without an intra-abdominal source. SBP occurs in up to 30% of hospitalized patients with cirrhosis and ascites, leading to fever, abdominal pain, and worsening renal function if untreated. Diagnosis relies on ascitic fluid analysis, where a polymorphonuclear leukocyte count exceeding 250 cells/mm³ confirms infection, often with positive bacterial cultures such as Escherichia coli. Fluid analysis also assesses the serum-ascites albumin gradient to differentiate portal hypertension-related ascites from other causes.^[101]^[102]^[103] Variceal hemorrhage results from the rupture of esophageal varices, dilated submucosal veins formed by portal hypertension, and constitutes a life-threatening emergency with mortality rates up to 20% per episode. These varices develop in approximately 50% of patients with cirrhosis, with bleeding triggered by increased pressure or vessel wall thinning. Initial stabilization includes vasoactive drugs and antibiotics, followed by endoscopic interventions; endoscopic variceal band ligation, which mechanically occludes the varix using elastic bands, achieves hemostasis in over 80% of cases and is preferred over sclerotherapy due to lower rebleeding rates.^[104]^[105]^[106] Hepatorenal syndrome (HRS) is a form of functional renal failure in patients with advanced liver disease, characterized by rapid deterioration of kidney function without identifiable structural damage to the kidneys, such as tubular necrosis. It arises from splanchnic vasodilation leading to renal vasoconstriction and reduced glomerular filtration, affecting up to 40% of patients with cirrhosis awaiting transplantation. HRS is diagnosed after excluding prerenal azotemia, acute tubular necrosis, and other causes, with criteria including serum creatinine >1.5 mg/dL, no improvement after volume expansion, and absence of proteinuria or hematuria. Type 1 HRS progresses rapidly, while type 2 is more insidious, often linked to refractory ascites.^[42]^[107]^[108] Hepatopulmonary syndrome (HPS) involves intrapulmonary vascular dilations in the setting of portal hypertension, causing right-to-left shunting and arterial hypoxemia that worsens with upright posture (platypnea) and breathing (orthodeoxia). It affects 10-30% of patients with cirrhosis, with severity correlating to the extent of shunting, leading to dyspnea and cyanosis. Diagnosis requires liver disease, arterial oxygen tension <80 mmHg, and evidence of intrapulmonary shunting via contrast echocardiography or lung perfusion scanning. HPS significantly impairs quality of life and is a major indication for liver transplantation, as it often resolves post-transplant.^[109]^[110]^[111]

Diagnosis

Clinical Assessment

Clinical assessment of liver failure begins with a thorough history-taking to identify potential risk factors and etiologies. Clinicians inquire about alcohol consumption history, as excessive intake is a leading cause of both acute and chronic liver failure. Travel to endemic areas for viral hepatitis, such as regions with high prevalence of hepatitis A or E, is also explored, along with exposure to infectious agents through contaminated food or water. A detailed medication review is essential, focusing on hepatotoxic drugs like acetaminophen, antibiotics, or herbal supplements, as polypharmacy increases the risk of drug-induced liver injury. Family history of liver disease and recent illnesses are similarly assessed to guide suspicion toward genetic or infectious causes.^[1]^[112]^[113] The physical examination aims to detect signs suggestive of liver dysfunction, distinguishing between acute and chronic presentations. In acute liver failure, findings may include jaundice, altered mental status indicating early encephalopathy, and tender hepatomegaly. For chronic liver failure, characteristic signs emerge such as spider angiomata—small, dilated blood vessels on the skin—and palmar erythema, a reddish discoloration of the palms due to hyperestrogenism from impaired liver metabolism. Asterixis, or flapping tremor, is a key neurological sign elicited by extending the arms and wrists, reflecting hepatic encephalopathy and often more prominent in advanced disease. Ascites, evident as abdominal distension with shifting dullness, and lower extremity edema further indicate portal hypertension in chronic cases. These bedside findings help stratify urgency before confirmatory tests.^[114]^[1]^[115] Severity grading systems integrate clinical and laboratory features to assess chronic liver failure prognosis and guide management. The Child-Pugh score evaluates chronic liver disease severity using five parameters: total bilirubin level, serum albumin, international normalized ratio (INR), presence and severity of ascites, and degree of hepatic encephalopathy. Scores range from 5 to 15, classifying patients into Child-Pugh class A (5-6 points, well-compensated), class B (7-9 points, moderate dysfunction), or class C (10-15 points, severe decompensation), with higher classes indicating worse outcomes. The Model for End-Stage Liver Disease (MELD) score, used for prioritizing liver transplantation, incorporates serum creatinine, total bilirubin, and INR to estimate short-term mortality risk in patients with advanced liver disease. As of 2025, AI-assisted tools are increasingly integrated into history-taking to flag polypharmacy risks, such as potential hepatotoxic interactions in elderly patients, enhancing early detection of medication-related liver injury.^[116]^[117]^[118]^[119]^[120]^[121]

Laboratory and Imaging Tests

Laboratory and imaging tests play a crucial role in confirming the diagnosis of liver failure, assessing its severity, and identifying underlying etiologies. These tests evaluate liver synthetic function, hepatocellular injury, cholestasis, and structural abnormalities, helping to differentiate acute from chronic forms. Etiology-specific laboratory tests are essential to identify the cause of liver failure and guide treatment. These include serologies for viral hepatitis such as IgM antibody to hepatitis A virus, hepatitis B surface antigen, and antibodies to hepatitis C virus; plasma acetaminophen concentration for suspected overdose; autoimmune markers like antinuclear antibody and anti-smooth muscle antibody for autoimmune hepatitis; serum ceruloplasmin for Wilson's disease; and iron studies for hemochromatosis, selected based on clinical suspicion.^[1]^[122] Liver function tests are fundamental in evaluating liver failure. In acute liver failure, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are markedly elevated, often exceeding 10 times the upper limit of normal, reflecting hepatocellular necrosis.^[12] In chronic liver failure, such as cirrhosis, albumin levels are typically low due to impaired hepatic synthesis, while total bilirubin is elevated, with conjugated and unconjugated fractions providing insights into cholestasis or hemolysis.^[123] Alkaline phosphatase and gamma-glutamyl transferase may also rise in cases involving biliary obstruction.^[124] Coagulation studies reveal the liver's role in hemostasis. Prothrombin time (PT) is prolonged and international normalized ratio (INR) elevated in both acute and chronic liver failure due to reduced synthesis of clotting factors II, V, VII, IX, and X.^[7] Fibrinogen levels are often decreased in advanced disease, contributing to bleeding risk, though thrombocytopenia from portal hypertension may compound this.^[33] Additional biomarkers support specific assessments. Serum ammonia levels may be measured in suspected hepatic encephalopathy, though they do not reliably correlate with its presence or severity and are not recommended for routine diagnosis or grading.^[125]^[126] Alpha-fetoprotein (AFP) levels are monitored in chronic liver failure for hepatocellular carcinoma (HCC) screening, with values exceeding 200 ng/mL prompting further evaluation.^[127] Imaging modalities provide structural and vascular insights without invasive procedures. Abdominal ultrasound is the initial test of choice, detecting cirrhosis through nodular contours and ascites, or fatty liver via increased echogenicity; Doppler ultrasound assesses portal vein flow for thrombosis.^[128] Computed tomography (CT) or magnetic resonance imaging (MRI) is used for detailed evaluation of masses, vascular patency, or parenchymal changes in complex cases.^[7] Liver biopsy offers definitive histopathological diagnosis when non-invasive tests are inconclusive. It is indicated to confirm etiologies like autoimmune hepatitis or to stage fibrosis in chronic failure, typically performed percutaneously under imaging guidance.^[129] Risks include pain at the site (up to 80% of cases), bleeding (0.3-0.6% major hemorrhage), and rare complications like bile peritonitis or infection, particularly in coagulopathic patients.^[130]

Treatment

Supportive Management

Supportive management in liver failure focuses on stabilizing the patient, preventing complications, and supporting organ function while awaiting recovery or definitive therapy. This approach is essential for both acute liver failure (ALF) and acute-on-chronic liver failure (ACLF), emphasizing intensive care unit (ICU) admission for close monitoring of vital signs, hemodynamic status, and potential decompensation. Patients require multidisciplinary care involving hepatologists, intensivists, and transplant teams to address multiorgan involvement early.^[1] Fluid and electrolyte balance is a cornerstone of supportive care to maintain hemodynamic stability without exacerbating complications like ascites or cerebral edema. Intravenous crystalloid fluids, such as normal saline or lactated Ringer's, are administered to achieve euvolemia, guided by central venous pressure (CVP) targets of 5-8 mmHg or invasive monitoring in unstable patients. Overhydration must be avoided, as it can worsen portal hypertension and lead to ascites formation or increased intracranial pressure in those with encephalopathy; diuretics like furosemide may be used cautiously if volume overload occurs, with concurrent electrolyte replacement for hyponatremia or hypokalemia, which are common due to renal impairment.^[131]^[1] Nutritional support is critical to counteract catabolism and hepatic encephalopathy, with early enteral feeding preferred over parenteral to preserve gut integrity and reduce infection risk. High-calorie regimens of 35-40 kcal/kg/day and 1.2-1.5 g/kg/day protein are recommended, incorporating branched-chain amino acids (BCAAs) such as leucine, isoleucine, and valine to improve nitrogen balance and ameliorate encephalopathy symptoms without precipitating hepatic coma. In patients unable to tolerate oral or enteral intake, total parenteral nutrition may be initiated temporarily, but with monitoring for hyperglycemia and line-related infections.^[131]^[1] Infection prophylaxis is vital given the high susceptibility to bacterial infections, particularly spontaneous bacterial peritonitis (SBP) in cirrhotic patients with ascites. Prophylactic antibiotics, such as norfloxacin or ceftriaxone, are administered to those with ascites and low ascitic fluid protein (<1.5 g/dL) or prior SBP episodes, reducing infection incidence by up to 50%. Vaccinations against hepatitis A virus (HAV) and hepatitis B virus (HBV) are recommended for non-immune patients to prevent superimposed acute insults. All patients should undergo routine surveillance cultures and receive broad-spectrum antibiotics at the first sign of infection.^[131]^[1] In the ICU, continuous monitoring is imperative, especially for cerebral edema in ALF patients with advanced encephalopathy (grades III-IV). Intracranial pressure (ICP) monitors, such as epidural or intraventricular devices, are placed in select high-risk cases to maintain ICP below 20-25 mmHg, using mannitol or hypertonic saline for elevation control. Multimodal monitoring includes continuous EEG for subclinical seizures and invasive hemodynamics to detect early shock or renal failure.^[1] Recent advances as of 2025 include the expanded use of extracorporeal albumin dialysis, such as the Molecular Adsorbent Recirculating System (MARS), as a bridge therapy in ALF and ACLF to remove protein-bound toxins like bilirubin and ammonia. MARS improves biochemical parameters and short-term survival in randomized trials, allowing time for native liver regeneration or transplant evaluation, though it does not replace transplantation and requires specialized centers. Ongoing studies confirm its role in stabilizing patients with grades III-IV encephalopathy, with sessions typically lasting 6-8 hours daily for several days.^[132]^[133]

Etiology-Specific Therapies

Etiology-specific therapies for liver failure focus on addressing the underlying cause to halt progression and promote recovery, contrasting with general supportive measures. These treatments are tailored to the inciting etiology, such as viral infections, toxic exposures, autoimmune processes, genetic disorders, or alcohol-related damage, and are most effective when initiated early. Selection depends on confirmed diagnosis, disease severity, and patient factors like comorbidities.^[68] For hepatitis B virus (HBV)-induced liver failure, antiviral therapy with tenofovir disoproxil fumarate or tenofovir alafenamide suppresses viral replication and improves liver function. Tenofovir achieves high rates of viral suppression, with over 90% of patients reaching undetectable HBV DNA levels after one year, reducing the risk of decompensation in chronic HBV cases. It is well-tolerated with low resistance rates (<1% after four years) and has shown benefits in acute-on-chronic liver failure by lowering mortality through improved Child-Turcotte-Pugh and Model for End-Stage Liver Disease scores.^[134]^[135] In hepatitis C virus (HCV)-related liver failure, direct-acting antivirals (DAAs) like sofosbuvir-ledipasvir or glecaprevir-pibrentasvir cure infection in over 95% of cases, even in decompensated cirrhosis, leading to fibrosis regression and reduced complications. These oral regimens, typically 8-12 weeks, target viral proteins to inhibit replication and are safe in advanced liver disease, with sustained virologic response rates exceeding 90% in cirrhotic patients. DAAs have transformed outcomes by preventing further hepatocyte damage and improving survival post-cure.^[136]^[137] Acetaminophen overdose, a common toxic cause of acute liver failure, is treated with N-acetylcysteine (NAC), which replenishes glutathione to detoxify the metabolite NAPQI. The standard intravenous protocol involves a loading dose of 150 mg/kg over one hour, followed by 50 mg/kg over four hours, and then 100 mg/kg over 16 hours, achieving near 100% efficacy if started within eight hours of ingestion. Even in established liver failure, NAC reduces mortality by mitigating oxidative stress, with benefits persisting up to 24 hours post-overdose.^[138]^[139] Autoimmune hepatitis leading to liver failure responds to immunosuppressive therapy with prednisone and azathioprine, inducing remission in 80-90% of cases. Initial prednisone dosing starts at 30-60 mg/day, tapered once response occurs, combined with azathioprine at 1-2 mg/kg/day to maintain low-dose steroids and prevent relapse. This regimen controls inflammation, normalizes liver enzymes, and preserves liver function long-term, though monitoring for side effects like osteoporosis is essential.^[140]^[141] Wilson's disease, a genetic copper accumulation disorder causing liver failure, requires chelation therapy with D-penicillamine or trientine to promote urinary copper excretion. Penicillamine, dosed at 750-1500 mg/day, is first-line but can cause hypersensitivity; trientine (750-2000 mg/day) serves as an alternative with fewer side effects and is preferred in decompensated cases. Both agents normalize copper levels within months, stabilizing or reversing hepatic injury when started promptly.^[142]^[143] Alcoholic liver disease progresses to failure with continued drinking, so etiology-specific management emphasizes abstinence through counseling and pharmacotherapy like acamprosate. Behavioral interventions, including cognitive-behavioral therapy and support groups, combined with acamprosate (666 mg three times daily), maintain abstinence in 20-30% more patients than placebo by modulating glutamate to reduce cravings. This approach halts disease progression and allows liver regeneration in early stages.^[144]^[145] Nonalcoholic steatohepatitis (NASH, also termed metabolic dysfunction-associated steatohepatitis or MASH), a leading cause of chronic liver failure, is managed through interventions to reduce hepatic fat accumulation, inflammation, and fibrosis to prevent decompensation. Lifestyle modifications, including sustained weight loss of at least 7-10% through calorie-restricted diet and exercise, are foundational and can lead to NASH resolution in up to 90% of cases with >10% loss. Pharmacotherapies target metabolic pathways; glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide (Wegovy, approved by the FDA in August 2025 for MASH with moderate-to-advanced fibrosis) promote weight loss and improve liver histology, while thyroid hormone receptor-β agonists like resmetirom (approved 2024) reduce steatosis and fibrosis. These agents, used in compensated stages, slow progression to cirrhosis and failure when combined with supportive care.^[146]^[147]

Liver Transplantation

Liver transplantation serves as the definitive curative treatment for end-stage liver failure, replacing the diseased liver with a healthy donor organ to restore normal hepatic function and improve survival in patients with irreversible damage.^[148] This procedure is particularly vital for those with acute liver failure (ALF), chronic decompensated cirrhosis, or acute-on-chronic liver failure (ACLF) who have exhausted medical options.^[149] Successful transplantation can achieve five-year survival rates exceeding 70% in appropriately selected candidates, though outcomes vary based on pre-transplant condition and etiology.^[150] Indications for liver transplantation include ALF complicated by grade III or IV hepatic encephalopathy, where rapid deterioration necessitates urgent intervention to prevent multi-organ failure.^[151] In chronic liver disease, transplantation is recommended for patients with a Model for End-Stage Liver Disease (MELD) score greater than 15, indicating high short-term mortality risk.^[151] For ACLF, particularly cases involving multi-organ failure such as renal or respiratory compromise, transplantation offers the primary means to reverse systemic decompensation and achieve recovery.^[152] Donor livers can be sourced from deceased or living individuals, with deceased donor transplantation being the most common approach, utilizing organs from brain-dead donors matched via allocation systems prioritizing urgency.^[153] Living donor liver transplantation involves surgically removing a portion of the donor's liver, typically the left lateral segment for pediatric recipients or right lobe for adults, allowing regeneration in both donor and recipient within weeks.^[154] To expand the deceased donor pool, split-liver techniques divide a single organ into two grafts—often a smaller left lobe for a child and larger right lobe for an adult—thereby enabling two transplants from one donor while maintaining comparable outcomes to whole-organ procedures.^[155] Post-transplant management relies on immunosuppression to prevent rejection, with tacrolimus-based regimens forming the standard cornerstone due to their efficacy in reducing acute rejection episodes and improving graft survival compared to alternatives like cyclosporine.^[150] Initial therapy typically combines tacrolimus with corticosteroids and mycophenolate mofetil, transitioning to tacrolimus monotherapy after three to six months in stable patients to minimize long-term toxicities such as nephrotoxicity and neurotoxicity.^[156] Absolute contraindications to liver transplantation encompass active sepsis, which poses an unacceptably high risk of post-operative infection and graft loss, and extrahepatic malignancy not meeting criteria for cure, as these conditions compromise overall survival post-transplant.^[157] Other exclusions include uncontrolled substance abuse or severe extrahepatic organ dysfunction that would preclude surgical tolerance.^[158] As of 2025, advances in bridging therapies to transplantation include bioartificial liver devices, such as spheroid reservoir systems using human-induced hepatocytes, which have demonstrated preclinical efficacy in reducing inflammation and supporting regeneration in ALF models, with ongoing clinical trials evaluating their role in stabilizing patients awaiting donors.^[159] Stem cell therapies, particularly hepatocyte-like cells derived from induced pluripotent stem cells, are in phase I/II trials for liver failure, showing promise in restoring hepatic function and serving as a bridge or alternative to transplantation in select cases.^[160]

Prognosis and Complications

Prognostic Indicators

Prognostic indicators in liver failure encompass scoring systems and clinical factors that estimate survival probability, stratify risk, and inform transplant candidacy, particularly distinguishing acute liver failure (ALF) from acute-on-chronic liver failure (ACLF). These tools integrate laboratory parameters, organ function assessments, and disease etiology to guide therapeutic decisions, with static scores providing baseline risk and dynamic evaluations capturing treatment response. Widely adopted criteria emphasize multi-organ involvement and coagulopathy as key predictors of poor outcomes. The King's College Criteria (KCC), established in 1989, remain a cornerstone for prognostication in ALF by identifying patients unlikely to recover spontaneously and thus requiring urgent liver transplantation. These etiology-specific thresholds were derived from retrospective analysis of over 500 cases at King's College Hospital, demonstrating high specificity (up to 95%) for non-survival without intervention. For acetaminophen-induced ALF, indicators of poor prognosis include arterial pH below 7.3 after adequate fluid resuscitation or an international normalized ratio (INR) greater than 6.5, reflecting severe acidosis and coagulopathy. In non-acetaminophen ALF, criteria are tailored to etiology and patient age, such as prothrombin time exceeding 100 seconds (or factor V less than 20% in patients under 40 years) for non-A, non-B hepatitis, underscoring the need for individualized assessment. The Model for End-Stage Liver Disease (MELD) score and its pediatric counterpart, the Pediatric End-Stage Liver Disease (PELD) score, quantify disease severity primarily in decompensated cirrhosis but also apply to ALF for transplant prioritization. Developed from Cox proportional hazards models analyzing survival post-transjugular intrahepatic portosystemic shunt placement, MELD allocates deceased donor livers via the United Network for Organ Sharing by assigning higher scores to sicker patients, with scores ranging from 6 (least urgent) to 40 (most urgent). The formula is:

\text{MELD} = 3.78 \times \ln[\text{serum bilirubin (mg/dL)}] + 11.2 \times \ln[\text{INR}] + 9.57 \times \ln[\text{serum creatinine (mg/dL)}] + 6.43

PELD adapts this for children under 12 years, incorporating growth failure and age adjustments for similar waitlist equity. Scores above 30 correlate with 3-month mortality exceeding 70%, aiding equitable organ distribution. In ACLF, the CLIF-C ACLF score, validated in the CANONIC study across 32 centers, outperforms traditional models by integrating six organ failure domains alongside baseline variables to predict 28- and 90-day mortality. Derived from logistic regression on 1,341 patients with acute decompensation of cirrhosis, it assigns points for hepatic (bilirubin ≥12 mg/dL), renal (creatinine ≥2.0 mg/dL or dialysis), cerebral (West Haven grade III/IV encephalopathy), coagulation (INR ≥2.5), circulatory (hypotension requiring vasopressors), and respiratory (PaO2/FiO2 ≤200 or SpO2/FiO2 ≤214) failures, combined with age, white blood cell count, albumin, and electrolytes. Scores of 64-70 indicate grade 3 ACLF with 80-90% short-term mortality risk, facilitating intensive care triage. Etiology profoundly modulates prognosis, with drug-induced causes like acetaminophen offering better spontaneous resolution than genetic or metabolic disorders. In a U.S. multicenter study of 295 ALF patients, acetaminophen toxicity yielded a 57% spontaneous survival rate, driven by responsiveness to N-acetylcysteine, whereas Wilson's disease showed 0% spontaneous survival and a 94% transplantation rate due to rapid multi-organ failure. This disparity highlights etiology's role in tailoring prognostic expectations, with viral and autoimmune etiologies falling intermediately. Dynamic factors, particularly response to supportive therapy within the first 72 hours, refine static predictions by assessing disease trajectory in ALF. The Acute Liver Failure Early Dynamic (ALFED) model, incorporating serial changes in INR, bilirubin, and encephalopathy over three days, improves accuracy over baseline scores alone, with non-improvement signaling persistent high mortality (up to 80%). Early lactate clearance below 1.5 mmol/L or hemodynamic stabilization post-resuscitation similarly predicts better outcomes, emphasizing serial monitoring for transplant timing.

Long-Term Outcomes

Long-term outcomes in liver failure vary significantly depending on whether the condition is acute (ALF), chronic, or acute-on-chronic (ACLF), as well as the timeliness of interventions like transplantation or etiology-specific treatments. In ALF, spontaneous recovery occurs in approximately 20-30% of cases, particularly for etiologies like acetaminophen toxicity, while overall transplant-free survival hovers around 50% with modern supportive care. Liver transplantation dramatically improves prognosis, achieving 1-year survival rates exceeding 85-90% in adults. However, survivors of ALF often experience persistent impairments in quality of life, including neurocognitive deficits and fatigue, with studies indicating that up to two-thirds report suboptimal health-related quality of life compared to the general population. For chronic liver failure, typically manifesting as decompensated cirrhosis, 5-year survival without transplantation is generally less than 50%, with median survival around 2 years due to recurrent decompensation and complications like variceal bleeding or ascites. Etiology plays a key role; in hepatitis C virus (HCV)-related chronic liver disease, achieving sustained virological response through direct-acting antivirals (DAAs) markedly enhances outcomes, boosting 3-year survival from 65% in the pre-DAA era to 77% and reducing the need for transplantation. Recurrence risks remain elevated post-episode, with up to 40% of survivors experiencing further decompensation within a year, driven by ongoing fibrosis or comorbidities. In ACLF, short-term prognosis is poor, with 3-month mortality ranging from 30-50% without transplantation, escalating to over 70% in cases involving three or more organ failures. Quality of life for ACLF survivors is often compromised by residual multiorgan dysfunction, though early recovery can occur with aggressive management. Post-liver transplantation, 1-year patient survival exceeds 85%, with long-term rates reaching 70-80% at 5 years, though risks of acute rejection (10-20% in the first year) and infections persist, necessitating lifelong immunosuppression. By 2025, widespread early DAA use in HCV patients has reduced hepatocellular carcinoma (HCC) incidence by approximately 70% following viral cure, further improving overall survival and quality of life by mitigating cancer-related recurrence.

Epidemiology and Prevention

Global Burden and Risk Factors

Liver failure encompasses both acute liver failure (ALF), a rare but severe condition, and chronic liver failure, primarily resulting from cirrhosis, which imposes a substantial global health burden. The incidence of ALF is estimated at 1-2 cases per million population annually in most developed regions, though rates can vary up to 63 per million in areas with higher infectious disease prevalence.^[161] Chronic liver failure, driven by cirrhosis, affects approximately 1-2% of the global population, with an estimated 112 million cases of compensated cirrhosis and 10.6 million cases of decompensated cirrhosis reported in 2017.^[162] These figures underscore the condition's rarity in acute forms contrasted with the widespread impact of chronic progression, contributing to over 1.3 million deaths annually from cirrhosis and related complications.^[163] Regional variations in the epidemiology of liver failure reflect differences in predominant etiologies. In Asia and Africa, viral hepatitis, particularly hepatitis B and E, accounts for a significant proportion of ALF cases, exacerbated by higher endemicity and limited access to vaccination or treatment.^[164]^[165] In contrast, Western countries experience higher rates of ALF and chronic failure linked to alcohol consumption and non-alcoholic fatty liver disease (NAFLD), influenced by lifestyle factors and aging populations.^[164] These disparities highlight the role of socioeconomic and environmental determinants in shaping disease patterns. Key risk factors for liver failure include modifiable behaviors and underlying conditions that accelerate hepatic damage. Obesity substantially elevates the risk of NAFLD progression to cirrhosis.^[166] Chronic alcohol intake exceeding 30 grams per day markedly increases the risk of alcoholic liver disease and cirrhosis, with this threshold identified as a critical point for population-level harm.^[167] Viral factors, such as chronic hepatitis B virus (HBV) carriage, affect around 254 million people globally, serving as a major precursor to both acute and chronic failure.^[168] Demographically, liver failure disproportionately impacts males, who bear a higher overall burden of cirrhosis compared to females, potentially due to differences in exposure to risk factors like alcohol and occupational hazards.^[169] For chronic forms, incidence peaks in ages 40-60, aligning with cumulative exposure to etiologies such as metabolic syndrome and viral infections. In pediatric populations, ALF often stems from metabolic disorders, accounting for up to 28% of cases in young children, including conditions like galactosemia and mitochondrial respiratory chain defects.^[170] As of 2025, epidemiological trends indicate a rising burden of NAFLD-related liver failure, driven by the global diabetes epidemic, with projections showing continued increases in prevalence linked to obesity and type 2 diabetes rates.^[171] Conversely, alcoholic liver disease appears to be declining in some high-income regions, attributable to heightened public awareness, reduced per capita alcohol consumption, and policy interventions.^[172] These shifts emphasize the evolving landscape of liver failure amid changing lifestyle and health priorities.

Preventive Strategies

Preventive strategies for liver failure encompass primary, secondary, and tertiary approaches aimed at reducing the incidence, progression, and complications of chronic liver diseases. Primary prevention focuses on avoiding the onset of liver-damaging conditions through vaccination, lifestyle modifications, and public health measures. A cornerstone of primary prevention is the universal vaccination against hepatitis B virus (HBV), which prevents mother-to-child and horizontal transmission, thereby reducing the risk of chronic infection leading to cirrhosis and liver failure.^[173] The recombinant HBV vaccine is approximately 95% effective in preventing chronic infection in healthy individuals when administered as a series of doses. Limiting alcohol consumption is another critical measure; guidelines recommend no more than 14 units per week for both men and women to minimize the risk of alcohol-related liver disease. For obesity, which contributes to non-alcoholic fatty liver disease (NAFLD), management through sustained weight loss via diet and exercise can prevent progression to steatohepatitis and fibrosis.^[174] Secondary prevention targets early detection and intervention in at-risk populations to halt progression to liver failure. In patients with cirrhosis, surveillance for hepatocellular carcinoma (HCC) using abdominal ultrasound every 6 months is recommended by major liver societies to enable early diagnosis and treatment.^[175] Antiviral therapies for chronic HBV and hepatitis C virus (HCV) infections are highly effective in achieving viral suppression or cure, significantly lowering the risk of cirrhosis and subsequent liver failure.^[176] Tertiary prevention addresses complications in advanced liver disease to prevent decompensation and further deterioration. Non-selective beta-blockers, such as propranolol, are used to reduce portal pressure and prevent variceal bleeding in patients with decompensated cirrhosis.^[177] For NAFLD, lifestyle interventions including caloric restriction and physical activity can promote histological reversal of steatosis and fibrosis, improving outcomes post-decompensation. Public health initiatives play a vital role in broader prevention efforts. Harm reduction programs for intravenous drug use, including needle syringe exchange and opioid substitution therapy, effectively curb HBV and HCV transmission among people who inject drugs.^[178] To prevent hepatitis A virus (HAV) infection, which can precipitate acute liver failure in those with underlying liver disease, food safety measures such as proper sanitation, safe drinking water, and hygienic food handling are essential. As of 2025, emerging innovations offer promising avenues for prevention. Gene therapy trials targeting ATP7B gene mutations in Wilson's disease, a genetic cause of liver failure, are underway, with phase I/II studies evaluating adeno-associated virus vectors for sustained copper metabolism correction.^[179] Additionally, AI-powered mobile applications for real-time alcohol consumption tracking and personalized feedback are being integrated into public health campaigns to enhance adherence to safe drinking limits and prevent alcohol-induced liver injury.^[180]

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Liver disease is associated with qualitative and quantitative changes in the intestinal microbiota. In cirrhotic patients the alteration in gut microbiota ...
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Owing to loss of hepatic function, ALF results in hepatic encephalopathy, coagulopathy, and multiorgan failure within a short period of time. Fig. 25.1. Fig.
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Acute liver failure produces cerebral dysfunction and edema, mediated in part by elevated ammonia concentrations, often leading to coma and death.
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