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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
  • Dyspnea
  • Tachycardia
  • Pleuretic chest pain
Pneumonia
  • ABGs
  • Leukocytosis
  • Pancytopenia
  • CXR
  • CT chest
  • Bronchoscopy
  • Shortness of breath
  • Cough
Asthma

(Late)

+
Cystic fibrosis ± ±
COPD

(Emphysema)

± +
Empyema ± + Chest X-ray
  • Pleural opacity
  • Localization of effusion
Physical examination
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
* Mild hypothermia: core temperature 32 to 35°C ; patient presents with confusion, tachycardia, and increased shivering.
  • Moderate hypothermia: 28 to 32°C patient presents with lethargy, bradycardia and arrhythmia and decreased shivering.
  • Severe hypothermia: below 28°C patient presents with coma, hypotension, arrhythmia, pulmonary edema, and rigidity.
Drugs†

2011 AASLD Recommendations for Acute Liver Failure (DO NOT EDIT) [1]

General Measures (DO NOT EDIT)[1]

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.[2][3].[4] The aim is to maintain intracranial pressures below 25 mmHg, cerebral perfusion pressures above 50 mm Hg.

Coagulopathy

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

Metabolic Derangements

Hemodynamic and Cardio-respiratory Compromise




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. [10] 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.[11] 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.[12]

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.[13]

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.[14]

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.[15]

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

  1. 1.0 1.1 "www.aasld.org" (PDF). Retrieved 2012-10-26.
  2. Hazell AS, Butterworth RF (1999). "Hepatic encephalopathy: An update of pathophysiologic mechanisms". Proc. Soc. Exp. Biol. Med. 222 (2): 99–112. PMID 10564534.
  3. Larsen FS, Wendon J (2002). "Brain edema in liver failure: basic physiologic principles and management". Liver Transpl. 8 (11): 983–9. doi:10.1053/jlts.2002.35779. PMID 12424710.
  4. Armstrong IR, Pollok A, Lee A (1993). "Complications of intracranial pressure monitoring in fulminant hepatic failure". Lancet. 341 (8846): 690–1. PMID 8095592.
  5. Schmidt LE, Larsen FS (2006). "hyperlactatemia". Crit. Care Med. 34 (2): 337–43. PMID 16424712.
  6. Gimson AE (1996). "Fulminant and late onset hepatic failure". British journal of anaesthesia. 77 (1): 90–8. PMID 8703634.
  7. Harry R, Auzinger G, Wendon J (2002). "The clinical importance of adrenal insufficiency in acute hepatic dysfunction". Hepatology. 36 (2): 395–402. doi:10.1053/jhep.2002.34514. PMID 12143048.
  8. Bihari D, Gimson AE, Waterson M, Williams R (1985). "Tissue hypoxia during fulminant hepatic failure". Crit. Care Med. 13 (12): 1034–9. PMID 3933911.
  9. Trewby PN, Warren R, Contini S; et al. (1978). "Incidence and pathophysiology of pulmonary edema in fulminant hepatic failure". Gastroenterology. 74 (5 Pt 1): 859–65. PMID 346431.
  10. O'Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet 1993;342:273-5. PMID 8101303.
  11. O'Grady JG (2005). "Acute liver failure". Postgraduate medical journal. 81 (953): 148–54. doi:10.1136/pgmj.2004.026005. PMID 15749789.
  12. Williams R (1996). "Classification, etiology, and considerations of outcome in acute liver failure". Seminars in Liver Disease. 16 (4): 343–8. doi:10.1055/s-2007-1007247. PMID 9027947. Retrieved 2012-10-26. Unknown parameter |month= ignored (help)
  13. O'Grady, JG.; Schalm, SW.; Williams, R. (1993). "Acute liver failure: redefining the syndromes". Lancet. 342 (8866): 273–5. PMID 8101303. Unknown parameter |month= ignored (help)
  14. Bernuau, J.; Rueff, B.; Benhamou, JP. (1986). "Fulminant and subfulminant liver failure: definitions and causes". Semin Liver Dis. 6 (2): 97–106. doi:10.1055/s-2008-1040593. PMID 3529410. Unknown parameter |month= ignored (help)
  15. Mochida, S.; Nakayama, N.; Matsui, A.; Nagoshi, S.; Fujiwara, K. (2008). "Re-evaluation of the Guideline published by the Acute Liver Failure Study Group of Japan in 1996 to determine the indications of liver transplantation in patients with fulminant hepatitis". Hepatol Res. 38 (10): 970–9. doi:10.1111/j.1872-034X.2008.00368.x. PMID 18462374. Unknown parameter |month= ignored (help)