Sandbox: HS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Differential diagnosis

Abbreviations: COPD= Chronic obstructive pulmonary disease,

Causes of cyanosis Disease Cyanosis Clinical manifestations/association Diagnosis Additional findings Symptoms Signs Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Respiratory Airway disorder Croup ✔ + + Epiglottitis ✔ + − − − − Foreign body aspiration + + − − − Airway trauma + + ± − − Disease Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Additional findings Parenchymal disorder Pulmonary embolism − − − − ABGs D-dimer CXR V/Q scan Spiral CT pulmonary angiogram Dyspnea Tachycardia Pleuretic chest pain Pneumonia − − − − − ABGs Leukocytosis Pancytopenia CXR CT chest Bronchoscopy Shortness of breath Cough Asthma (Late) + − − − − Cystic fibrosis ± ± − − − COPD (Emphysema) ± + Empyema ± + − − − Thoracentesis Chest X-ray Pleural opacity Localization of effusion Physical examination Crackles Egophony Increased tactile fremitus Disease Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Additional findings Chest wall disorders Flail chest − ± − − − Pneumothorax − ± − − − Hemothorax − + ± − − Cardiovascular Congenital heart diseases Disease Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Additional findings Atrioventricular canal defect ✔ + + Ebstein anomaly ✔ Hypoplastic left heart syndrome ✔ Pulmonary atresia ✔ Tetralogy of Fallot ✔ Pulmonic stenosis ✔ Total anomalous pulmonary venous drainage ✔ Transposition of the great vessels ✔ Truncus arteriosus ✔ Disease Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Additional findings Heart failure + − + ± + Valvular heart disease + − − − − Myocardial infarction − − − − − Hematologic Methemoglobinemia ✔ Polycythemia ✔ Central Nervous system Peripheral Central Dyspnea Fever Chest pain Clubbing Peripheral edema Auscultation Lab Findings Imaging Gold standard Additional findings Coma ✔ Seizures ✔ Head trauma ✔ Breath holding spells ✔ Miscellaneous Shock ✔ Smoke inhalation + + + Toxic gases + + + + ± Cold exposure ✔ − − − − − − Fingerstick glucose (Hyperglycemia) Electrocardiogram (ECG) may show J wave, sinus bradycardia and prolongation of all ECG intervals. Serum electrolytes (including potassium and calcium) BUN and creatinine Serum hemoglobin, white blood cell, and platelet counts ( Raised HCT due to volume contraction) Coagulation profile (clotting factors impairment) Serum lactate ( lactic acidosis) Creatine kinase (Rhabdomylosis) Arterial blood gas CXR Drugs† − − − − −

Sinusoidal changes induced by pyrrolizidine alkaloids and myeloablative agents are likely the results of a combination of: i) a direct, dose-related toxicity to sinusoidal and central venous endothelial cell, and ii) the effect of chemotherapy on bone marrow progenitors of endothelial cells that are mobilized for the repair of sinusoidal lesions. It is difficult to ascertain whether the associated liver cell damage is a pure result of sinusoidal injury, or a result of combined sinusoidal injury and direct toxicity on liver cells. There is evidence for a generalized alteration of endothelia in animal models of pyrrolizidine alkaloid toxicity but also in recipients of HSCT, when they develop SOS/VOD [54]. These changes include features of endothelial activation and apoptosis [54]. Sinusoidal changes found in patients receiving chemotherapy for hepatic metastasis of colorectal adenocarcinoma may result from similar mechanisms despite a much less severe clinical and histological expression, or may stem from different pathways implicating proinflammatory mediators. Decreasing the intensity of chemotherapeutic regimen is currently the only proven means to prevent or decrease the severity of sinusoidal changes and their clinical expression. Long-term effect of low intensity regimens will have to be assessed. Indeed, portal hypertension due to nodular regenerative hyperplasia may represent a more common sequela of infraclinical sinusoidal damage than currently recognized [55]. Elucidation of the mechanisms underlying the recently reported SP110 mutations associated familial SOS/VOD occurring in the absence of exposure to chemotherapy or related agents [52] will shed light on the mechanisms involved when such agents. Obliterative endophlebitis in the terminal hepatic veins of the human liver lobule was first reported by a pathologist from Prague in 1905, with the only etiologic suggestion being syphilis.1 In 1954, terminal vein lesions were described in Jamaican drinkers of bush tea, characterized by obliteration of hepatic vein radicals by varying amounts of subendothelial swelling and fine reticulated tissue.2 At later stages, a fibrous pericentral scar developed. In the early 1960's, studies of the effects of ionizing radiation on mammalian tissues documented that the hepatic vasculature could be damaged by this mechanism,3 in the absence of antecedent vascular thrombosis.4,5 The most striking example of an obliterative venous lesion induced by irradiation was documented in humans with lung tumors receiving radiation treatment; both the lung vasculature and that of the dome of the liver that was included in the radiation field developed vascular obliteration, but not the remainder of the unexposed liver.6 Shortly thereafter, induction of obliterative venopathy following heavy irradiation directly of the human liver for metastatic disease was reported in 12 patients receiving upper abdominal irradiation by the Stanford Linear Accelerator.7 Thus, by the mid-1960s, the concept of hepatic veno-occlusive disease was well-established, induced by either chemical or radiation toxicity, and as a lesion separate from Budd-Chiari syndrome and Banti syndrome.8,9

In the late 1970's, similar histologic lesions were reported from outbreaks in India and Israel, attributed to contamination of wheat and traditional herbal remedies with plant toxins.10,11 The histological lesions resembled previously described hepatic veno-occlusive lesions described in rats poisoned with Senecio plant extracts12 or Crotolaria.13 This form of liver toxicity was ultimately attributed to hepatic exposure to plant pyrrolizidine alkaloids,14 establishing these plant toxins as the cause of veno-occlusive disease in users of herbal teas.

Bone marrow transplantation for humans with leukemias became a therapeutic option during the 1960s. Initial challenges to this new therapy were preservation of harvested marrow, and achieving successful marrow engraftment.15 Reports of hepatic veno-occlusive disease in patients undergoing bone marrow transplantation emerged in the 1970's,16 followed by numerous reports which established the following apparent risk factors: bone marrow transplantation for malignancy, involving intense chemotherapeutic and radiation conditioning regimens; patient age over 15 years; and in particular, abnormal pretransplant serum levels of liver enzymes.17–19 The presence of metastatic liver disease in patients undergoing bone marrow transplantation for solid tumors and lymphomas also predisposed to veno-occlusive disease.20,21 In these initial years after recognition of veno-occlusive disease as a complication of induction regimes prior to bone marrow transplantation, the incidence of veno-occlusive disease varied from 21% to 25% in allogeneic graft recipients,19,21,22 to 5% in recipients of autologous marrow.20,23,24 In the four decades since routine use of bone marrow transplantation for solid malignancies, lymphomas and leukemias, induction regimes and therapies have helped improve, but not eliminate, the incidence of this condition in the transplant population. Its incidence now is primarily in the setting of hematopoietic stem cell transplantation, but SOS may occur in other settings as well

A central pathogenic event is toxic destruction of hepatic sinusoidal endothelial cells (SEC), with sloughing and downstream occlusion of terminal hepatic venules.

Sinusoidal obstruction syndrome (SOS) occurs due to obstruction of the hepatic venules and sinusoids rather than hepatic vein or inferior vena cava as seen in Budd Chiari syndrome. Hepatic sinusoidal obstruction syndrome (SOS) is mainly seen in hematopoietic cell transplantation. The development of sinusoidal obstruction syndrome (SOS) begins with the injury to the hepatic venous endothelium. It is thought that preexisting liver disease increases the risk of developing sinusoidal obstruction syndrome (SOS) due to impairment of drug metabolism which predisposes to the endothelial injury. The endothelial cells in patients with hepatitis may have abnormal expression of adhesion molecules and procoagulant factors. The deposition of fibrinogen and factor VIII within the sinusoids leads to their dilation and congestion by erythrocytes. The progressive occlusion of venules leads to widespread zonal liver disruption and centrilobular hemorrhagic necrosis. The later changes in sinusoids include deposition of collagen, sclerosis of venular walls, fibrosis of the lumens and ultimately occlusion of hepatic venules. The severity of symptoms depends on the number of sinusoids involve and severity of the histologic changes.

❑ In the absence of ICP monitors

❑ Hourly neurological evaluation

❑ Monitoring of serum ammonia levels

❑ Transcranial ultrasonography

b) Prophylactic hypertonic saline: (I):❑ Hypertonic saline i.v bolus (20 ml of 30% sodium chloride or 200 ml of 3% sodium chloride) for prophylactic induction of hypernatremia in patients with

❑ Serum ammonia >150 μM

❑ Grade III/IV hepatic encephalopathy

❑ Acute renal failure

❑ Vasopressors requirement to maintain MAP

❑ Maintain serum sodium level of 145-155 mEq/L

c) Intracranial hypertension treatment:

❑ I line therapy: (II-2)

❑ Mannitol i.v bolus (0.5-1.0 gm/kg of body weight or 2 ml of 20% solution/kg of body weight)

❑ Administered as needed as long as serum osmolality <320 mOsm/L

❑ II line therapy: (if refractory to mannitol) (II-3)

❑ Short-acting barbiturates

❑ Hypothermia induction to a core body temperature of 34°-35°C

❑ Indomethacin i.v bolus (0.5 mg/kg) may be used when cerebral hyperemia is also present

❑ Goals of intracranial hypertension treatment

ICP <20 mmHg

CPP >60 mmHg

❑ Hyperventilate to PaCO2 of 25-30 mmHg (in case of impending herniation)

|- | Grade I/II encephalopathy|| ❑ Frequent neurological assessment with avoidance of stimulation and sedation
❑ Small doses of short-acting benzodiazepines in case of unmanageable agitation
❑ Stat brain CT to rule out other causes of altered mental status
❑ Consideration for transfer to a liver transplant facility and listing for transplantation at the earliest
❑ Lactulose (possibly helpful and may interfere with surgical field by increasing bowel distention during liver transplantation) (III)
❑ Infection surveillance
❑ Antibiotic prophylaxis against infections (possibly helpful)
❑ Infection treatment as required |- | Grade III/IV encephalopathy||Besides managing the patient similar to grade I/II encephalopathy

❑ Intubate trachea (might require sedation) (III)

❑ Muscle relaxants for intubation

During intubation: Depolarizing neuro-muscular blocking agents

After intubation: Propofol

❑ Elevate head of bed to 30°

❑ Lidocaine administration during endotracheal suctioning

❑ Immediate treatment of seizures with phenytoin and benzodiazepines with short half-lives (III)

❑ ICP monitoring with devices

❑ Mannitol administration following severe elevation of ICP or first clinical sign of herniation

❑ Hypertonic saline administration to raise serum sodium to 145-155 mmol/L

❑ Hyperventilate patient in case of impending herniation

❑ Monitor and manage hemodynamic and renal parameters as well as glucose, electrolytes and acid/base status

|- | Cardiovascular System|| Hemodynamic abnormalities|| ❑ Fluid resuscitation and maintenance of adequate intravascular volume (initiate hypotension treatment with intravenous normal saline) (III)
❑ Systemic vasopressor support (dopamine, epinephrine, norepinephrine) as needed (II-1)
❑ Vasopressinorterlipressin added to norepinephrine in norepinephrine-refractory cases (used cautiously in severely encephalopathic patients with intracranial hypertension) (II-1)
❑ Ensure appropriate volume status with a volume challenge (pulmonary artery catheterization is rarely necessary since it is associated with significant morbidity) (III)
❑ Echocardiography for low cardiac output and right ventricular failure
❑ Goals of circulatory support: (II)

MAP ≥75 mmHg

CPP 60-80 mmHg

|- |Respiratory System|| Aspiration pneumonitis|| ❑ Neurologic observation to monitor level of consciousness
❑ Early endotracheal intubation for depressed level of consciousness |- |Hepatic System||Hepatic dysfunction|| ❑ NAC administration (acetaminophen as well as non-acetaminophen ALF) |- | Metabolic and Renal System|| Metabolic abnormalities and renal failure|| ❑ Frequent monitoring and correction of derangements in glucose, potassium, magnesium and phosphate (III)
❑ Continuous modes of hemodialysis (if needed) (I) |- | Hematologic System|| Coagulopathy|| ❑ Replacement therapy for thrombocytopenia and/or prolonged prothrombin time with platelet and FFP transfusion respectively in the setting of active bleeding or before invasive procedure (III)
❑ Vitamin K (5-10 mg subcutaneously) (at least one dose)
❑ Plasmapheresis or recombinant activated factor VII (rFVIIa) in case of inadequate correction of severely elevated INR and risks of volume overload
❑ Maintenance of adequate platelet count

In the absence of bleeding: >10,000/mm³

For performing invasive procedures: 50-70,000/ mm³

❑ Prophylaxis for stress ulceration: (I)

❑ I line: H2 blocker or PPI

❑ II line: Sucralfate

|- | Immunologic System|| Infection|| ❑ Periodic surveillance for prompt initiation of antimicrobial treatment of infections at the earliest sign of active infection or deterioration (progression to high grade hepatic encephalopathy or elements of the SIRS) (III)
❑ Antibiotic prophylaxis (possibly helpful in patients with coagulopathy, organ failure, encephalopathy and in whom illness progression is considered likely - not proven) (III) |}

Etiology	Diagnostic Indicators	Management Recommendations
Acetaminophen toxicity	❑ H/o of acetaminophen intake (toxic dose >10 gm/day or >150 mg/kg) ❑ Acetaminophen in blood and/or urine ❑ Aminotransferase levels >3500 IU/L with low bilirubin levels, in the absence of apparent hypotension or cardiovascular collapse (suspected acetaminophen toxicity in the absence of a positive history because acetaminophen is the leading cause of ALF at least in the United States and Europe)	❑Activated charcoal: 1g/kg PO within 1 hour after drug ingestion (may be beneficial even when administered within 3-4 hours after ingestion) and prior to starting NAC (I) ❑ Nomogram (helps determining the likelihood of serious liver damage but does not exclude possible toxicity) ❑ NAC: 140 mg/kg PO or through NGT (diluted to 5% solution), then 70 mg/kg PO q4h x 17 doses or IV loading dose of 150 mg/kg in 5% dextrose over 15 minutes, then maintenance dose of 50 mg/kg IV over the next 4 hours and then 100 mg/kg IV over the following 16 hours *Promptly begin NAC (beneficial even when administered <48 hours after drug ingestion) in all patients with impending or evolving liver injury due to acetaminophen (II-1) *NAC may be used in cases of ALF due to suspected acetaminophen poisoning (III) *NAC is recommended even in case of non-acetaminophen ALF
Acute fatty liver of pregnancy/HELLP	❑ Jaundice and hypertension ❑ Coagulopathy ❑ Thrombocytopenia ❑ Proteinuria ❑ Hypoglycemia ❑ Steatosis in liver imaging or biopsy	❑ Early diagnosis and prompt delivery (III) ❑ Adequate supportive care ❑ Consider transplantation for postpartum deterioration (III)
Acute ischemic injury	❑ H/o cardiac arrest ❑ Any period of significant hypovolemia/hypotension, or severe CHF (hypotension is not documented always) ❑ Any associated renal dysfunction & muscle necrosis ❑ Elevated aminotransferase levels responding to fluid resuscitation	❑ Adequate cardiovascular support (III)
Autoimmune	❑ Positive serum autoantibodies (may be absent) ❑ Positive liver biopsy (confirms diagnosis when autoimmune hepatitis is suspected and autoantibodies are negative) (III)	❑ Prednisolone (start with 40-60 mg/day, especially in the presence of coagulopathy and mild hepatic encephalopathy) (III) ❑ Consider transplantation and do not delay while awaiting response to steroid treatment (III)
Budd-Chiari	❑ Abdominal pain ❑ Ascites ❑ Hepatomegaly ❑ Blood tests positive for hypercoagulability ❑ Positive findings during liver imaging (CT, doppler USG, venography or magnetic resonance venography) (confirms diagnosis)	❑ Liver transplantation (provided underlying malignancy is excluded) (II-3)
Drug induced	❑ H/o hepatotoxic drug intake (usually idiosyncratic hepatotoxic drug intake within first 6 months after drug initiation; continuous usage of potentially hepatotoxic drug for more than 1 to 2 years is unlikely to cause de novo liver damage) ❑ H/o inclusive of details (including onset of ingestion, amount and timing of last dose) concerning all prescription and non-prescription drugs, herbs and dietary supplements taken over the past year (III) ❑ Determine ingredients of non-prescription medications whenever possible (III)	❑ Discontinue all but essential medications in the setting of possible drug hepatotoxicity (III) ❑ NAC (may be beneficial for ALF induced by drugs) (I)
Malignant infiltration	❑ Massive hepatomegaly ❑ Malignant infiltration in liver imaging or liver biopsy (confirms or excludes diagnosis) (III)	❑ Appropriate management of underlying malignancy ❑ Supportive care
Mushroom poisoning	❑ H/o recent mushroom intake ❑ Severe GI symptoms like nausea, vomiting and diarrhea within hours or a day of ingestion (suspected mushroom poisoning in the absence of a positive history)	❑ Early gastric lavage and activated charcoal administration ❑ Penicillin G 300,000-1 million units/kg/day or Silibinin 30-40 mg/kg/day IV or PO, 3-4 days (silymarin in Europe and south America; milk thistle in north America) ❑ NAC (III) ❑ Liver transplantation (the only lifesaving option) (III) ❑ Fluid resuscitation (as needed)
Viral	❑ Toxically appearing patients with skin lesions (HSV) ❑ Positive hepatitis virus serology ❑ HSV positive liver biopsy	❑ Supportive treatment (no virus specific treatment proven to be effective) (III) ❑ Nucleoside and nucleotide analogues (for HBV associated ALF) (III) ❑ Acyclovir (5-10 mg/kg every 8 hours for at least 7 days for HSV or VZV) (III)
Wilson's disease	❑ KF ring ❑ Serum bilirubin >20 mg/dL, ❑ Bilirubin:alkaline phosphatase >2.0 ❑ Low serum ceruloplasmin ❑ Elevated serum & urine copper ❑ High copper levels in liver biopsy (III)	❑ Liver transplantation (III) ❑ Dialysis or hemofiltration or plasmapheresis or plasma exchange
Intermediate etiology	❑ Etiology undetermined after all evaluation	❑ Review drug and toxin intake H/o ❑ Transjugular biopsy (for further evaluation of possible mailgnancy, Wilson disease, autoimmune hepatitis and viral hepatitis) (III)

Liver Biopsy

A liver biopsy done via the transjugular route because of coagulopathy is not usually necessary other than in occasional malignancies.

As the evaluation continues, several important decisions have to be made such as whether to admit the patient to an ICU, or whether to transfer the patient to a transplant facility. Consultation with the transplant centre as early as possible is critical due to possibility of rapid progression of ALF.

2011 AASLD Recommendations for Acute Liver Failure (DO NOT EDIT)

General Measures (DO NOT EDIT)

Class III

1. "Liver biopsy is recommended when autoimmune hepatitis is suspected as the cause of acute liver failure, and autoantibodies are negative."

2. "In patients with acute liver failure who have a previous cancer history or massive hepatomegaly, consider underlying malignancy and obtain imaging and liver biopsy to confirm or exclude the diagnosis."

3. "If the etiological diagnosis remains elusive after extensive initial evaluation, liver biopsy may be appropriate to attempt to identify a specific etiology that might influence treatment strategy."

Acute liver failure is a serious condition which can rapidly progress to death if left untreated. Complications of the illness include cerebral edema, brain herniation, multi-organ failure, systemic inflammatory response syndrome, metabolic derangements, coagulopathy, hemodynamic instability, coma, and death.Several prognostic scoring systems have been devised to predict mortality and to identify who will require early liver transplant. Mortality due to acute liver failure used to be as high as 80%, however this statistic has decreased with the advent of liver transplantation, and better intensive care. There are several prognostic indicator scores used for the prediction of mortality, and to assess the suitability of the patient for transplantation. These include kings college hospital criteria, MELD score, APACHE II and Clichy criteria.

Complications

Complications that can develop as a result of acute liver failure are:

Cerebral Edema and Encephalopathy

• Complications of acute liver failure can include cerebral edema and hepatic encephalopathy.
• The detection of encephalopathy is central to the diagnosis of acute liver failure. It may vary from subtle deficits in higher brain function (e.g. mood, concentration in grade I) to deep coma (grade IV).
• The patients presenting as acute and hyperacute liver failure are at greater risk of developing cerebral edema and grade IV encephalopathy.
• Cerebral edema in acute liver failure can be due to vasogenic and cytotoxic effects. The increased ammonia concentration in liver failure in combination with the glutamine produced by the astrocytes causes excess levels of glutamine with the help of enzyme glutamine synthetase. The excess glutamine is cytotoxic and can disturb the osmotic gradient which can result in brain swelling. In acute liver failure, the increased levels of nitric oxide in the circulation can also disrupt the cerebral autoregulation.. The aim is to maintain intracranial pressures below 25 mmHg, cerebral perfusion pressures above 50 mm Hg.

Coagulopathy

• Coagulopathy is also seen in acute liver failure. The liver has a central role in the synthesis of coagulation factors and some inhibitors of coagulation and fibrinolysis.
• The hepatocyte necrosis leads to impaired synthesis of coagulation factors and their inhibitors. The former produces a prolongation in Prothrombin time which is widely used to monitor the severity of hepatic injury.

Renal Failure

Renal failure is common, present in more than 50% of acute liver failure patients, either due to original insult such as paracetamol resulting in acute tubular necrosis or from hyperdynamic circulation leading to hepatorenal syndrome or functional renal failure.

• Once the renal failure develops, it is progressive and poor prognosis without liver transplantation.

Inflammation and Infection

• About 60% of all acute liver failure patients fulfil the criteria for systemic inflammatory syndrome irrespective of presence or absence of infection.. This often contributes towards multi organ failure.
• The impaired host defence mechanisms due to impaired opsonisation, chemotaxis and intracellular killing substantially increases the risk of sepsis. The sepsis is mostly due gram positive (80%)and fungal (30%) sepsis..

Metabolic Derangements

• The metabolic derrangements seen with acute liver failure include hyponatremia which is due to water retention and shift in intracellular sodium transport from inhibition of Na/K ATPase.
• Hypoglycaemia due to depleted hepatic glycogen stores.
• Hypokalaemia, hypophosphataemia and metabolic alkalosis are often present independent of renal function.
• Lactic acidosis is seen predominantly in paracetamol overdose.

Hemodynamic and Cardio-respiratory Compromise

• Hyperdynamic circulation with peripheral vasodilatation from low systemic vascular resistance leads to hypotension. There is a compensatory increase in cardiac output.
• Adrenal insufficiency has been documented in 60% of acute liver failure and is likely to contribute in haemodynamic compromise. There is also abnormal oxygen transport and utilization. Although delivery of oxygen to the tissues is adequate, there is a decrease in tissue oxygen uptake, resulting in tissue hypoxia and lactic acidosis.
• Pulmonary complication is also seen in acute liver failure.. Severe lung injury and hypoxemia result in high mortality. Most cases of severe lung injury is due to ARDS with or withoutsepsis. Pulmonary haemorrhage, pleural effusions, atelectasis, and intrapulmonary shunts also contribute to respiratory difficulty.

Acute liver failure is a sudden and severe loss of liver function with evidence of encephalopathy and coagulopathy with elevated prothrombin time (PT) and (INR) in a person without preexisting liver disease. The commonly used time duration for an acute liver disease is < 26 weeks.

• Acute liver failure can be hyperacute, acute or subacute depending upon how long the patient has signs and symptoms of liver failure.
• The natural history of acute liver failure depends on the etiology but generally, cerebral edema mainly presents in hyperacute or acute liver failure, whereas renal shutdown and portal hypertension are the main concerns in the subacute liver failure.
• If left untreated, patients with acute liver failure may initially have nonspecific symptoms such as anorexia, fatigue, nausea or vomiting, diffuse or right upper quadrant abdominal pain or jaundice and can eventually progress to develop confusion and the comatose state and death.

• The timely recognition and treatment of some of the causes of acute liver failure can reverse the condition and may improve the patient's prognosis. The timely evaluation can also help in identifying patients who may require liver transplantation.
• In acetaminophen toxicity patients, the time duration between acetaminophen ingestion and treatment with acetylcysteine greatly influence the outcome.

The evaluation of a patient diagnosed with acute liver failure should begin immediately to identify the cause of the acute liver failure. This is crucial because in some cases, early diagnosis and treatment may improve the patient's prognosis. In addition, timely evaluation is required to identify patients who may require urgent liver transplantation Many of the initial symptoms in patients with acute liver failure are nonspecific [14]. They include:

●Fatigue/malaise ●Lethargy ●Anorexia ●Nausea and/or vomiting ●Right upper quadrant pain ●Pruritus ●Jaundice ●Abdominal distension from ascites As the liver failure progresses, patients who were initially anicteric may develop jaundice, and those with subtle mental status changes (eg, lethargy, difficulty sleeping) may become confused or eventually comatose.

Acute liver failure refers to the development of severe acute liver injury with encephalopathy and impaired synthetic function (INR of ≥1.5) in a patient without cirrhosis or preexisting liver disease [2,3]. While the time course that differentiates acute liver failure from chronic liver failure varies between reports, a commonly used cutoff is an illness duration of <26 weeks.

Acute liver failure may also be diagnosed in patients with previously undiagnosed Wilson disease, vertically acquired hepatitis B virus, or autoimmune hepatitis, in whom underlying cirrhosis may be present, provided the disease has been recognized for <26 weeks. On the other hand, patients with acute severe alcoholic hepatitis, even if recognized for <26 weeks, are considered to have acute-on-chronic liver failure since most have a long history of heavy drinking. The approach to such patients is discussed elsewhere. (See "Clinical manifestations and diagnosis of alcoholic fatty liver disease and alcoholic cirrhosis" and "Prognosis and management of alcoholic fatty liver disease and alcoholic cirrhosis".)

Acute liver failure can be subcategorized based upon how long the patient has been ill and various cutoffs have been used. We classify acute liver failure as hyperacute (<7 days), acute (7 to 21 days), or subacute (>21 days and <26 weeks). In patients with hyperacute or acute liver failure, cerebral edema is common, whereas it is rare in subacute liver failure [4]. On the other hand, renal failure and portal hypertension are more frequently observed in patients with subacute liver failure. These subcategories have been associated with prognosis, but the associations reflect the underlying causes, which are the true determinants of prognosis. As an example, patients with hyperacute liver failure tend to have a better prognosis than those with subacute liver failure. The better prognosis is related to the fact that these patients often have acetaminophen toxicity or ischemic hepatopathy, diagnoses associated with a better prognosis than many of the disorders that may result in subacute liver failure, such as Wilson disease [2].

By definition, patients with acute liver failure have severe acute liver injury (demonstrated by liver test abnormalities) with signs of hepatic encephalopathy and a prolonged prothrombin time (INR ≥1.5). Other clinical manifestations may include jaundice, hepatomegaly, and right upper quadrant tenderness.

Symptoms — Many of the initial symptoms in patients with acute liver failure are nonspecific [14]. They include:

●Fatigue/malaise ●Lethargy ●Anorexia ●Nausea and/or vomiting ●Right upper quadrant pain ●Pruritus ●Jaundice ●Abdominal distension from ascites As the liver failure progresses, patients who were initially anicteric may develop jaundice, and those with subtle mental status changes (eg, lethargy, difficulty sleeping) may become confused or eventually comatose.

Acute liver failure results from the loss of normal function of hepatic tissue occurring over a short period of time. It results from the loss of the metabolic, secretory, and regulatory effects of the liver cells. This leads to the rapid accumulation of toxic substances, which then manifests in the patient as an altered sensorium, cerebral edema, hemodynamic abnormalities, and even multiorgan failure. Cytotoxic and vasogenic cerebral edema have been implicated in acute liver failure (ALF) with a preponderance of experimental data favouring cytotoxic mechanisms. Astrocyte swelling is a consistent neuropathological finding in human ALF and ammonia plays a definitive role. The mechanism(s) by which ammonia induces astrocyte swelling remains unclear but glutamine plays a central role inducing oxidative stress, energy failure and ultimately astrocyte swelling. Although complete breakdown of the blood-brain barrier is not evident in human ALF, increased permeation to water and ammonia has been demonstrated.

Cerebral edema in acute liver failure can be vasogenic as well as cytotoxic. The increased ammonia concentration in liver failure in combination with the glutamine produced by the astrocytes causes excess levels of glutamine synthesis with the help of glutamine synthetase. The excess glutamine is cytotoxic and can disturb the osmotic gradient and cause brain swelling. In acute liver failure, the increasesd levels of nitric oxide in the circulation can also disrupt the cerebral autoregulation.

Cerebral edema occurs due to damage to the blood brain barrier and can cause altered sensorium and increased intracranial pressure. Acute liver failure causes increased ammonia concentrations due to the failure of the detoxification system that occurs through the liver. The increased levels of ammonia in combination with the glutamate produced by the astrocytes of brain, cause excess levels of glutamine produced through the enzyme glutamine synthetase. The accumulation of glutamine in high concentrations in the brain is what causes cerebral edema. In acute liver failure, there are also increased levels of nitric oxide in the circulation. Nitric oxide is a potent vasodilator and causes a disruption of the cerebral blood flow. This in turn disrupts cerebral auto-regulation. Multiorgan failure occurs due to severe hypotension which is caused by the decreased systemic vascular resistance.

Classification

Acute liver failure may be classified on the basis of the duration of the symptoms between the onset of jaundice to the onset of encephalopathy. The different classification systems based on the number of weeks from the appearance of jaundice to the encephalopathy are:

Classification system	Duration
O’Grady System	Hyperacute (0 - 1 week) Acute ( From 2nd week - 4 weeks) Subacute ( From 4th week - 12 weeks)
Bernuau System	Fulminant ( 0 - 2 weeks) Subfulminant ( 2 weeks - 12 weeks)
Japanese System	Fulminant (0 - 8 weeks) Acute ( 0 - 1.5 weeks) Subacute ( 1.5 weeks - 8 weeks) Late-Onset ( 8 weeks - 12 weeks)

The 1993 classification defines three subcategories based on the severity and duration of the acute liver failure. The importance of this method of classification is that the pace of the disease evolution strongly influences prognosis. The underlying etiology causing the development of acute liver failure is the other significant determinant in regards to prognosis. This classification system is based upon the duration between onset of jaundice to onset of encephalopathy.

Classification	Time
Hyperacute	1 week
Acute	1 week - 1 month
Subacute	1 week - 3 months

Acute liver failure can also be classified into fulminant or subfulminant. Both of these forms have a poor prognosis. It is based upon the duration between onset of hepatic illness, to the development of encephalopathy.

Classification	Time
Fulminant	within 2 months
Subfulminant	within 2 months to 6 months

O’Grady System

The classification of encephalopathy according to the O’Grady system is as follows.

Hyperacute

Hyperacute encephalopathy is an encephalopathy that occurs within 7 days of onset of jaundice.

Acute

Acute encephalopathy is an encephalopathy that occurs within an interval of 8 to 28 days from onset of jaundice.

Subacute

Subacute encephalopathy is an encephalopathy that occurs within 5 to 12 weeks of onset of jaundice.

Bernuau System

The classification of encephalopathy according to the Bernuau system is as follows.

Fulminant

Fulminant encephalopathy is an encephalopathy that occurs within 2 weeks of onset of jaundice.

Subfulminant

Subfulminant encephalopathy is an encephalopathy that occurs within an interval of 2 to 12 weeks from onset of jaundice.

Japanese System

The classification of encephalopathy according to the Bernuau system is as follows.

Fulminant

Fulminant encephalopathy is an encephalopathy that occurs within 8 weeks of onset of jaundice.

Late-Onset

Late onset encephalopathy is an encephalopathy that occurs within an interval of 8 to 24 weeks from onset of jaundice.

Acute

Acute encephalopathy is an encephalopathy that occurs within 10 days of onset of jaundice

Subacute

Subacute encephalopathy is an encephalopathy that occurs within an interval of 11 to 56 days from onset of jaundice