Acute liver failure comprises of two types: fulminant liver failure and subfulminant liver failure. The former is defined as the occurrence of encephalopathy within 8 weeks of onset of symptoms (in patients without pre-existing liver disease). Subfulminant liver failure is characterized by a longer duration between symptoms and encephalopathy.

The clinical picture features a deterioration in mental status, bleeding, purpura, jaundice, and ascites. Nonspecific symptoms include anorexia, malaise, and motor abnormalities. Additionally, fulminant hepatic failure can feature hematemesis or melena due to GI bleeding. A common condition known as fetor hepaticus, which is sweet breath odor, is also a common sign.

Sequelae of acute liver failure include cerebral edema, seizures, metabolic dysfunction, infection, kidney failure, and hemorrhage. Also, in cases with rapid onset of ascites and abdominal pain, this may indicate hepatic vein thrombosis or Budd-Chiari syndrome.

Physical exam

Findings may include right upper quadrant tenderness, smaller liver span, and jaundice. Stigmata associated with chronic liver disease are also common.

Vital signs may show tachycardia, hypotension, and tachypnea whether in the setting of sepsis or not. Also, patients with cerebral edema exhibit papilledema, bradycardia, and hypertension secondary to elevated intracranial pressure (ICP). These individuals may progress to states such as obtundation or coma.

Patients with infection may present symptoms related to that such as fever or cough.

• Gastric Lavage

  Although she was treated with gastric lavage, oral activated charcoal, and intravenous hydration with sodium bicarbonate, her hepatic and renal function gradually deteriorated and serum amylase levels increased. [ncbi.nlm.nih.gov]

  If early enough, gastric lavage and activated charcoal administration should be performed in cases of suspected mushroom poisoning. Penicillin G and silibinin (silymarin) are the accepted antidotes. [em-consulte.com]

  Activated charcoal and gastric lavage via nasogastric tube may be useful during initial hours after ingestion of mushroom. [clevelandclinicmeded.com]

• Aspiration

  For encephalopathy, the head of the bed is elevated 30° to reduce risk of aspiration; intubation should be considered early. [merckmanuals.com]

  Erythromycin or metoclopramide are used as pro-kinetic agents in patients with large gastric aspirates. Patients with ALF have both peripheral and hepatological insulin resistance. [doi.org]

  At the time of onset, serum enzymes are usually markedly elevated with serum alanine and aspirate aminotransferase levels 10 to 100 times the upper limit of the normal range, accompanied by mild or at most moderate elevations in alkaline phosphatase levels [livertox.nih.gov]

• Right Upper Quadrant Tenderness

  Physical exam Findings may include right upper quadrant tenderness, smaller liver span, and jaundice. Stigmata associated with chronic liver disease are also common. [symptoma.com]

  upper quadrant tenderness: Variably present Change in liver span: May be small due to hepatic necrosis or may be enlarged due to heart failure, viral hepatitis, or Budd-Chiari syndrome Hematemesis or melena: Due to upper gastrointestinal (GI) bleeding [emedicine.com]

• Hypotension

  Drugs that could worsen manifestations of acute liver failure (eg, hypotension, sedation) should be avoided or used in the lowest possible doses. For hypotension and acute kidney injury, the goal of treatment is maximizing tissue perfusion. [merckmanuals.com]

  Clinical examination showed an extensive coagulation disorder, diffuse hematomas, hypotension and tachypnea. [ncbi.nlm.nih.gov]

  Vascular: "Shock liver" from extreme hypotension, Budd-Chiari, Veno-occlusive disease 4. [errolozdalga.com]

• Thrombosis

  The postoperative course was complicated by deep vein thrombosis and impending hepatic artery thrombosis treated with unfractionated heparin, aspirin, and intravenous prostacyclin. The patient survived and made a full neurological recovery. [ncbi.nlm.nih.gov]

  Porte, Pathogenesis, prevention, and management of bleeding and thrombosis in patients with liver diseases, Research and Practice in Thrombosis and Haemostasis, 1, 2, (150-161), (2017). Prem A. [doi.org]

  […] acute failure may include the following: Encephalopathy Cerebral edema: May lead to signs of increased intracranial pressure (ICP) (eg, papilledema, hypertension, bradycardia) Jaundice: Often present but not always Ascites: Potential for hepatic vein thrombosis [emedicine.com]

• Asterixis

  The diagnosis of acute liver failure is actually based upon the appearance of clinical symptoms of hepatic encephalopathy, such as mental clouding, confusion, asterixis, somnolence, stupor and coma. [livertox.nih.gov]

  Liver palms are red and an hepatic flap, also called asterixis, may be present: Hyperextend the fingers and wrist, gently pushing back and a slow clonic movement is the liver flap. [patient.info]

  In older children, signs and symptoms are identical to those in adults but the classical symptoms of asterixis, tremors, and fetor hepaticus are often absent. Hepatic encephalopathy has been classified into four grades [ 3 ]. [em-consulte.com]

  Grade 1 is defined as altered behavior with euphoria, anxiety, and decreased attention span; grade 2 is marked by disorientation, lethargy or asterixis; grade 3 is associated with marked disorientation, incoherent speech, and somnolence; and grade 4 being [clevelandclinicmeded.com]

• Scleral Icterus

  Jaundice (yellowing of the skin) and scleral icterus (yellowing of the eyes) are often present, but may not be initially noted by patients or their families until relatively late in the course of the illness. [surgery.ucsf.edu]

• Muscle Cramp

  Upon arrival she was moribund with coma, diffuse bleeding, and severe muscle cramps. She died within 20 min, at 13 h after the meal. [doi.org]

• Flushing

  In anticipation of the longer lung preservation time, cold flushed lungs were preserved on a portable lung perfusion device for ex vivo normothermic perfusion for 11 h 15 min, transplanted sequentially off-pump, and reperfused after a total ex vivo time [ncbi.nlm.nih.gov]

• Confusion

  A 64 year-old Caucasian female presented with confusion and generalized tonic-clonic seizures, 5 days after initiation of regorafenib for advanced rectal cancer. [ncbi.nlm.nih.gov]

  Older children may seem angry, have a hard time falling asleep, forget things, be confused, or feel drowsy. Lab studies and a physical exam can tell if there are signs of a liver problem. [cincinnatichildrens.org]

  Confusion, abdominal swelling, and abnormal bleeding are also common. Can acute liver failure be prevented? You can prevent some of the underlying causes of acute liver failure. [hopkinsmedicine.org]

  They may include: Jaundice (yellow skin and eyes) Abdominal pain Nausea Vomiting General malaise Disorientation, confusion, inability to concentrate Sleepiness Acute liver failure may be diagnosed with blood tests, imaging with ultrasound, and biopsy [columbiasurgery.org]

  Liver encephalopathy is marked by confusion, disorientation, irritability, sluggishness, drowsiness, insomnia and/or coma. [lahey.org]

• Altered Mental Status

  Individuals with jaundice, bleeding, or alteration in mental status should be suspected of having liver failure. [symptoma.com]

  A 79-year-old woman admitted with atrial flutter was being treated with intravenous (IV) amiodarone when she abruptly developed coagulopathy, altered mental status and liver enzyme derangement. [ncbi.nlm.nih.gov]

  Symptoms and Signs Characteristic manifestations are altered mental status (usually part of portosystemic encephalopathy), bleeding, purpura, jaundice, and ascites. [merckmanuals.com]

  It contributes to altered mental status, and thus the true extent of hepatic encephalopathy may be unclear in the presence of hypoglycemia. [clevelandclinicmeded.com]

• Somnolence

  The diagnosis of acute liver failure is actually based upon the appearance of clinical symptoms of hepatic encephalopathy, such as mental clouding, confusion, asterixis, somnolence, stupor and coma. [livertox.nih.gov]

  When he became somnolent, he was admitted to a district hospital, where he was found to be icteric and afebrile, with tachycardia but otherwise normal cardiac function, a blood pressure of 115/70 mm Hg, and pain in the upper right quadrant of the abdomen [doi.org]

  Grade 1 is defined as altered behavior with euphoria, anxiety, and decreased attention span; grade 2 is marked by disorientation, lethargy or asterixis; grade 3 is associated with marked disorientation, incoherent speech, and somnolence; and grade 4 being [clevelandclinicmeded.com]

Individuals with jaundice, bleeding, or alteration in mental status should be suspected of having liver failure. When evaluating a patient for acute liver failure, it is crucial to determine the etiology as the therapy and management depend on the underlying cause. The clinician should ascertain all medications ingested by the patient including prescription and over-the-counter drugs and supplements. The workup further consists of a physical exam and laboratory tests.

Laboratory tests

Since acute liver failure may result in multisystem dysfunction, the following studies should be obtained: a complete blood count (CBC), complete metabolic panel (CMP), renal and liver function tests, PT and international normalized ratio (INR), and urinalysis. Upon confirmation of the diagnosis, crucial tests include an arterial blood gas (ABG), amylase, lipase, blood type and screening. Moreover, if an infection in suspected, blood, urine, and ascitic fluid cultures are indicated.

The findings of the above studies will determine the severity of acute liver disease and the overall clinical picture. Moreover, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are profoundly increased indicating hepatocellular necrosis. Additionally, PT is prolonged and INR is greater than 1.5.

Also, plasma bilirubin levels are elevated and continue to increase as the disease progresses. In fact, a level above 4 mg/dL is associated with a poor prognosis in acetaminophen toxicity.

An ABG will reveal any acid-base disturbance. Another serious finding, severe hypoglycemia, may develop secondary to impairment in gluconeogenesis and glycogen production.

Imaging

In patients with both altered mental status and coagulopathy, a head CT scan is performed to identify any intracranial bleeding.

• Bilirubin Increased

  Bilirubin increases to more than 171 mmol/L, prothrombin time (PT) decreases to less than 40%, progressive shrinkage of liver, significant deterioration of liver function, deviation of enzyme and bilirubin, and inversion of albumin/globulin ratio. [doi.org]

• Hyponatremia

  Paolo Angeli, Florence Wong, Hugh Watson and Pere Ginès, Hyponatremia in cirrhosis: Results of a patient population survey, Hepatology, 44, 6, (1535-1542), (2006). Julia A. [doi.org]

  Also, severe electrolye abnormalities (hyponatremia, hypophosphatemia, hypokalemia, hypomagnesemia, also metabolic acidosis). Patients often need CVVH. 5. [errolozdalga.com]

  Hypoglycemia, hyponatremia, and metabolic disturbances from renal failure may also require continual attention. Whenever possible, transfer to a liver transplant center should be considered for any patient with severe acute liver failure. [pulmccm.org]

  Electrolyte abnormalities such as hyponatremia, hypokalemia, hypophosphatemia, and acid-base imbalances such as respiratory acidosis are commonly seen in ALF. Hyponatremia, when present, is usually due to hypervolemia. [clevelandclinicmeded.com]

• Prothrombin Time Prolonged

  C Payen, A Dachraoui, C Pulce and J Descotes, Prothrombin time prolongation in paracetamol poisoning: a relevant marker of hepatic failure?, Human & Experimental Toxicology, 22, 11, (617), (2003). Javier Vaquero and Andres T. [doi.org]

• Hepatic Necrosis

  Abstract Of 170 patients with biopsy-documented acute viral hepatitis, 52 exhibited zones of hepatic necrosis and collapse that bridged adjacent portal triads or central veins (or both), a lesion classified as subacute hepatic necrosis (SHN). [doi.org]

  Acute hepatic necrosis Acute liver failure Acute necrosis of liver Hepatic necrosis, subacute Subacute hepatic necrosis Subacute liver failure ICD-10-CM K72.00 is grouped within Diagnostic Related Group(s) (MS-DRG v 36.0): 441 Disorders of liver except [icd10data.com]

  The condition is also referred to as a fulminant hepatic failure, acute hepatic necrosis, fulminant hepatic necrosis, and fulminant hepatitis. It occurs when cells of the liver are injured so quickly that the organ cannot repair itself fast enough. [verywell.com]

  The onset was "hyperacute" and typical of acute hepatic necrosis, with immediate appearance of hepatic failure and liver injury arising within days of starting the high doses of the medication. [livertox.nih.gov]

  Elevated serum concentrations of bacterial endotoxins, tumor necrosis factor–alpha (TNF-α), interleukin (IL)–1, and IL-6 have been found in fulminant hepatic failure. [emedicine.com]

• Liver Biopsy

  The authors considered liver transplantation, but the patient's liver function spontaneously recovered. Liver biopsy revealed massive infiltration of neutrophils, but the cause of the acute hepatitis was not identified. [ncbi.nlm.nih.gov]

  Liver biopsy is a procedure that has an uncertain role in ALF. Liver biopsy could add diagnostic information that is helpful and could provide prognostic information that helps with the decision to proceed with liver transplantation. [gastro.org]

Due to the life-threatening nature of the disease, intensive care is paramount [9] [10] [11] [12]. When encephalopathy progresses, securing the airway is the top priority. Additionally, the medical team should remain vigilant about the hemodynamics, metabolic function, and nutritional status. Furthermore, early recognition of complications such as GI bleeding and cerebral edema is very important.

Airway protection

Intubation may be necessary for encephalopathic patients. Close monitoring is critical especially in those with worsening mental status. The medical team should be cautious when choosing drugs for intubation and agitation since many cause sedation and make it challenging to monitor the patient's mental status.

Hemodynamic and metabolic management

The therapeutic approach targets hemodynamic and metabolic stability as it is for all critically ill patients. Of importance, fluid replacement for hypotension should be given carefully since these patients are at risk for cerebral swelling. In refractory cases, 20 mL/kg of crystalloid is used. In extreme conditions, vasopressors may be necessary.

Special care should be geared towards preventing hypoglycemia, which occurs frequently in liver failure. This can be done through with intravenous infusion of glucose.

Acute liver disease is associated with protein breakdown, and therefore, protein should be replaced carefully. Less protein is administered in patients with hyperammonemia or intracranial hypertension.

CBC, CMP, and coagulation panel should be obtained frequently while LFTs and serum bilirubin are performed daily.

Infection

Empiric antibiotics are initiated when the patient demonstrates signs of infection including fever and worsening of hemodynamics, renal function, or mental status. When the cultures' results are obtained, the medications can be altered. If an infection is ruled out, then the antibiotics are discontinued.

Coagulopathy

In cases with bleeding or severe coagulopathy, fresh frozen plasma (FFP) is important. However, this product can cause volume overload and accentuate cerebral edema. Moreover, use of FFP prohibits the monitoring of PT, which is a value predictive of poor prognosis.

Acetaminophen overdose

Acetaminophen poisoning can be challenging to diagnose but should be suspected in cases with not clear etiology. It is treated with N-acetylcysteine.

Transplantation

The ultimate treatment of liver failure is liver transplantation. It is correlated with 1-year survival rate of almost 80%. Hence, it is reserved for those with a prognosis that is worse without a liver transplant.

Other

Lactulose can be beneficial in patients with encephalopathy. As for seizures, phenytoin is a good choice.

There are factors that can provide predictive insight regarding the prognosis. For example, worse prognosis is associated with: 1) Severe encephalopathy such as with stage 3 or 4, 2) Patient age younger than 10 years, or greater than 40 years old, 3) Prolonged prothrombin time (PT), and 4) etiology such as idiosyncratic drug reactions or Wilson disease.

The outcome is better if acute liver failure is secondary to acetaminophen toxicity or infection with hepatitis A or B.

Death rates increase with sequelae such as cerebral edema, adult respiratory distress syndrome (ARDS), coagulopathy, renal failure, and infection.

The mortality rate of fulminant hepatic failure was higher than 80%, but orthotopic liver transplantation (OLT) has improved survival.

Acute liver failure is more prevalent in developing countries, since hepatitis A, B, and E are leading causes of the condition and they are not particularly prevalent in the industrialized world. However, drug-induced liver damage due to acetaminophen and idiosyncratic drug reactions is the predominant cause of acute liver failure in the United States and Western Europe. In these latter countries, vaccinations and good sanitation practice have resulted in the decline of viral hepatitis infections.

Other causes

Primary cardiac or respiratory failure in ill patients can cause ischemic hepatocellular injury, a potential consequence of severe sepsis. This is accompanied by increased serum aminotransferase concentrations [4] [5].

In the United States, the incidence of fulminant liver failure is approximately 2000 cases per year. In acute liver failure, drug-induced hepatotoxicity is responsible for more than half of all cases. Specifically, acetaminophen accounts for 42% of these cases while idiosyncratic drug reactions comprise 12%.

The occurrence of liver failure is observed in all races. Furthermore, a research study in the United States demonstrated that a large percentage was composed of Caucasian people (74%).

Autoimmune liver disease shows a gender preference towards women.

As for age, individuals above 40 years old are associated with a worse prognosis.

The clinical picture of fulminant hepatic failure resembles that of sepsis, which is a state of reduced systemic vascular resistance. The resultant low blood supply to the organs causes further complications. Hence, acute liver failure affects numerous organs and systems.

Cerebral edema

Brain involvement includes cerebral edema, which is the predominant cause of morbidity and fatality in acute liver failure [6] [7] [8]. Cerebral edema is probably a consequence of cytotoxic and vasogenic effects. Additionally, increased cerebral perfusion occurs secondarily to cerebral dysregulation, which is a consequence of elevated levels of the vasodilator, nitric oxide.

Coagulopathy

Coagulopathy commonly occurs secondarily to the decreased synthesis of the coagulation factors in the liver.

Acetaminophen toxicity

Hepatic metabolism of acetaminophen produces a metabolite more toxic than the drug itself.

Other

Some of the main features of acute liver failure include hyperbilirubinemia, which usually manifests at initial presentation.

Hypoglycemia develops as a result of impaired glycogen production and gluconeogenesis.

Acute liver failure is associated with numerous etiologies. One of the causes, acetaminophen overdose, can be prevented if the dosage guidelines are followed correctly. The same applies to all medications and supplements as well. Additionally, depending on the type of viral hepatitis, an infection can be prevented through vaccinations, implementation of good hygiene, and practicing a safe and healthy lifestyle.

Acute liver disease is the severe deterioration of hepatic function secondary to liver conditions such as hepatitis, cirrhosis, or overdose of acetaminophen and other drugs. In the United States, the predominant cause is drug toxicity, while viral hepatitis is the main etiology in developing regions. It occurs in less than 10 cases per million annually in developed countries. Also, most cases occur in adults in their 30s without previous liver disorders.

The potentially fatal condition is classified as fulminant or subfulminant in accordance to the interval between the onset of symptoms and development of encephalopathy [1]. Furthermore, acute liver failure results in coagulopathy, altered mental status, and dysfunction of multiple organs and systems [2] [3].

The diagnosis is determined through a history, physical, exam, and extensive laboratory testing. Since there are dangerous manifestations, it is important to assess the full clinical picture during the workup.

The initial goal of therapy involves the identification and treatment of the underlying cause. Since acute liver failure is associated with a high mortality rate, these critically ill patients warrant close monitoring. Specifically, there are crucial aspects to consider such as airway protection, maintenance of the hemodynamic and metabolic status, and prompt recognition of complications such as infection, cerebral edema, and gastrointestinal (GI) bleeding.

Acute liver failure is a disease in which there is a rapid decline in the perfomance of the liver. It can be caused by liver disease, viral hepatitis, especially hepatitis B, cirrhosis, or poisoning due to alcohol or medications. In fact, acetaminohen overdose is the most common cause of acute liver failure in the United States, whereas viral hepaitis is the most common cause in the developing world.

When the liver becomes largely damaged, failure occurs. It can occur over days, weeks, months or years.

The liver is responsible for many functions. So when it becomes damaged, there are many detrimental consequences such as:

• A substance in the body called bilirubin builds up and therefore, the patient becomes jaundiced
• The liver cannot synthesize proteins that clot blood. Therefore, the patient can bleed and bruise easily
• Fluid builds up in the abdomen. This is known as ascites
• The toxins that build up affects the brain. This results in encephalopathy
• New blood vessels form in the esophagus and stomach to bypass the liver. These new vessels are fragile, vulnerable and tend to bleed easily.
• Kidneys lose function
• Immune system loses function
• Metabolic dysfunction causes low blood sugar and proteins

Symptoms include:

• Jaundice
• Ascites
• Altered mental status such as confusion and drowsiness
• Malaise
• Weakness
• Nausea
• Anorexia
• Low blood pressure

Acute liver disease is diagnosed through the history, physical exam, and important blood tests that check for liver function, electrolytes, liver proteins, and others.

As soon as it is diagnosed, liver failure is treated promptly to prevent further complications. These patients are admitted to the intensive care unit (ICU).

Treatment consists of the following:

• Low blood pressure is treated with intravenous fluids and possibly drugs
• Encephalopathy is managed with lactulose
• Bacterial infection is managed with antibiotics
• Low blood sugar is treated with intravenous sugar

1. Wlodzimirow KA, Eslami S, Abu-Hanna A,Nieuwoudt M, Chamuleau RA. Systematic review: acute liver failure -- one disease, more than 40 definitions. Alimentary Pharmacology and Therapeutics. 2012; 35(11):1245-1256.
2. Escorsell A, Mas A, de la Mata M. Acute liver failure in Spain: analysis of 267 cases. Liver Transplantation. 2007; 13(10):1389-1395.
3. Kumar R, Shalimar, Bhatia V, et al. Antituberculosis therapy-induced acute liver failure: magnitude, profile, prognosis, and predictors of outcome. Hepatology. 2010; 51(5):1665-1674.
4. Lescot T, Karvellas C, Beaussier M, Magder S. Acquired liver injury in the intensive care unit. Anesthesiology.2012; 117(4):898-904.
5. Henrion J. Hypoxic hepatitis. Liver International. 2012;32(7):1039-1052.
6. Jalan R, Olde Damink SW, Deutz NE, Hayes PC, Lee A. Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension. Gastroenterology. 2004; 127(5):1338-46.
7. Lidofsky SD, Bass NM, Prager MC, et al. Intracranial pressure monitoring and liver transplantation for fulminant hepatic failure. Hepatology. 1992; 16(1):1-7.
8. Detry O, Arkadopoulos N, Ting P, et al. Intracranial pressure during liver transplantation for fulminant hepatic failure. Transplantation. 1999; 67(5):767-70.
9. Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology. 2005; 41(5):1179-97.
10. Stravitz RT, Kramer AH, Davern T, et al. Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group. Critical Care Medicine. 2007; 35(11):2498-508.
11. Bernal W. Intensive care support therapy. Liver Transpl. 2003; 9(9):15-7.
12. Jalan R. Acute liver failure: current management and future prospects. Journal of Hepatology. 2005; 42(1):115-23.