Differential Diagnosis

1. •

   Severe acute hepatitis, also known as acute liver injury (including alcoholic hepatitis): jaundice and coagulopathy without encephalopathy

2. •

   Acute on chronic liver failure (in patients with liver disease duration >26 weeks)

3. •

   Cirrhosis (includes decompensated cirrhosis)

4. •

   Hepatocellular carcinoma

Workup (Box 3)

1. •

   Fig. 1 describes an algorithm for evaluation of acute liver failure.

   BOX 3Investigations in Fulminant Hepatic Failure

   Baseline essential investigations

   Biochemistry

   1. ○

      Bilirubin, transaminases

   2. ○

      Alkaline phosphatase

   3. ○

      Albumin

   4. ○

      Urea and electrolytes

   5. ○

      Creatinine

   6. ○

      Calcium, phosphate

   7. ○

      Ammonia

   8. ○

      Acid-base, lactate

   9. ○

      Glucose

   Hematology

   1. ○

      Full blood count, platelets

   2. ○

      PT, PTT

   3. ○

      Factors V or VII

   4. ○

      Blood group cross-match

   Septic screen

   Omitting lumbar puncture

   1. ○

      Radiology

   2. ○

      Chest radiograph

   3. ○

      Abdominal ultrasound

   4. ○

      Head CT scan or MRI

   Neurophysiology

   1. ○

      Electroencephalogram

   Diagnostic investigations

   Serum

   1. ○

      Acetaminophen levels

   2. ○

      Cu, ceruloplasmin (>3 yr)

   3. ○

      Autoantibodies

   4. ○

      Immunoglobulins

   5. ○

      Amino acids

   6. ○

      Lactate

   7. ○

      Pyruvate

   8. ○

      Hepatitis A, B, C, E

   9. ○

      EBV, CMV, HSV viral loads

   10. ○

       Other viruses

   Urine

   1. ○

      Toxic metabolites

   2. ○

      Amino acids, succinylacetone

   3. ○

      Organic acids

   4. ○

      Reducing sugars

   CMV, Cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; PT, prothrombin time; PTT, partial thromboplastin time.

   From Fuhrman BP, Zimmerman JJ: Fuhrman and Zimmerman’s pediatric critical care, ed 4, Philadelphia, 2011, Mosby.

   

2. •

   Clinical history is critical and should include medication use (6 month history of prescriptions, over-the-counter medications, herbal supplements), alcohol use, recreational drug use, prior symptoms of jaundice, onset of symptoms, history of suicide attempts, recent travel to endemic areas of viral hepatitis, and family history of liver failure/disease.

3. •

   Grading of hepatic encephalopathy should be performed (Table 1). Perform an asterixis maneuver, consider psychometric tests (i.e., number connection test) to detect subtle degree of encephalopathy.

   TABLE1 Grades of Encephalopathy

   Grade	Description
   I	Changes in behavior with minimal change in level of consciousness (mild confusion, slurred speech, sleep difficulties)
   II	Gross disorientation, drowsiness, possibly asterixis, inappropriate behavior
   III	Marked confusion, incoherent speech, sleeping most of the time but arousable to vocal stimuli
   IV	Comatose, unresponsiveness to pain, decorticate or decerebrate posturing

4. •

   Laboratory evaluation: complete blood count, liver function tests (LFTs) including prothrombin time and INR, chemistry panel (sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, magnesium, phosphate, calcium), arterial blood gas, arterial lactate, blood type and screen, acetaminophen level, ethanol level, toxicology screen, viral hepatitis serologies (hepatitis A IgM, hepatitis B surface antigen, anti–hepatitis B core IgM, anti–hepatitis C antibody [gM and IgG]), hepatitis C viral load (HCV RNA), anti–hepatitis E IgM and IgG, HSV-1 IgM and HSV PCR, EBV DNA PCR, CMV DNA PCR, anti-hepatitis D IgM and IgG, hepatitis D viral load (HDV RNA), ceruloplasmin level (as well as serum copper and 24-hour urine copper if high suspicion), pregnancy test, arterial ammonia level, autoimmune markers (ANA, ASMA, total IgG levels), HIV-1, HIV-2, amylase, lipase.

5. •

   Imaging: abdominal ultrasound with Doppler (hard to diagnose cirrhosis because liver may appear nodular in ALF due to massive necrosis), consider cross-sectional imaging of the liver (triphasic CT, MRCP, or MR with gadolinium), CT/MRI of the head.

6. •

   Prompt liver biopsy (via transjugular approach to decrease risk of bleeding) should be performed in cases in which:

   1. 1.

      The etiology is unknown after the initial workup; or

   2. 2.

      Etiology is thought to be secondary to autoimmune hepatitis, malignancy, or HSV

Laboratory Tests

1. •

   Patients with ALF typically have a prolonged prothrombin time (INR >1.5), elevated transaminases, elevated bilirubin, and may have a low platelet count (<150,000).

2. •

   Other possible lab findings can include an elevated BUN/creatinine (studies show 30% to 50% also have acute kidney injury), hypoglycemia (impairment of gluconeogenesis), hypophosphatemia, hypomagnesemia, hypokalemia, metabolic acidosis or respiratory alkalosis, elevated LDH, and elevated ammonia.

Imaging Studies

1. •

   Abdominal ultrasound with Doppler should be ordered to evaluate for Budd-Chiari syndrome, portal hypertension, hepatic congestion, and hepatic steatosis.

2. •

   CT or MRI scan of the head should be considered to ensure no other causes for altered mental status.

Complications

Complications or progression of liver failure may result in cerebral edema due to increased intracranial pressure (in up to 40% of patients), high-output cardiac failure, hypoglycemia, lactic acidosis, acute respiratory distress syndrome, upper gastrointestinal hemorrhage (in 1.5% of patients), infectious disease from impaired leukocyte function (in nearly 80% patients), acute kidney injury, and pancreatitis (particularly in acetaminophen-induced ALF). Hypotension can occur due to decreased oral intake as well as extravasation of fluid into extravascular space.

Nonpharmacologic Therapy

1. •

   Initial treatment should focus on the patient’s mental status.

   1. ○

      Grade I/II encephalopathy may be managed on a medical ward (neuro vital signs q4h).

   2. ○

      Grade III and IV encephalopathy should be managed in ICU (elevate head of the bed to 30 degrees).

   3. ○

      Decrease stimulation (quiet room, no audible monitor alarms).

   4. ○

      Avoid sedatives and opioids.

   BOX 4Management of Fulminant Hepatic Failure

   No sedation except for procedures

   Minimal handling

   Enteric precautions until infection ruled out

   Monitor:

   1. ○

      Heart and respiratory rate

   2. ○

      Arterial BP, CVP

   3. ○

      Core/toe temperature

   4. ○

      Neurologic observations

   5. ○

      Gastric pH (>5.0)

   6. ○

      Blood glucose (>4 mmol/L)

   7. ○

      Acid-base

   8. ○

      Electrolytes

   9. ○

      PT, PTT

   Fluid balance

   1. ○

      75% maintenance

   2. ○

      Dextrose 10%-50% (provide 6-10 mg/kg/min)

   3. ○

      Sodium (0.5-1 mmol/L)

   4. ○

      Potassium (2-4 mmol/L)

   Maintain circulating volume with colloid/FFP

   Coagulation support only if required

   Drugs

   1. ○

      Vitamin K

   2. ○

      H₂ antagonist

   3. ○

      Antacids

   4. ○

      Lactulose

   5. ○

      N-acetylcysteine for acetaminophen toxicity

   6. ○

      Broad-spectrum antibiotics

   7. ○

      Antifungals

   Nutrition

   1. ○

      Enteral feeding (1-2 g protein/kg/day)

   2. ○

      PN if ventilated

   BP, Blood pressure; CVP, central venous pressure; FFP, fresh frozen plasma; PN, parenteral nutrition; PT, prothrombin time; PTT, partial thromboplastin time.

   From Fuhrman BP, Zimmerman JJ: Fuhrman and Zimmerman’s pediatric critical care, ed 4, Philadelphia, 2011, Mosby.

   BOX 5Hepatic Replacement Therapeutic Options Available to Patients with Fulminant Hepatic Failure

   Liver Transplantation

   1. •

      Cadaveric transplantation

   2. •

      Whole liver

   3. •

      Reduced-size liver

   4. •

      Split liver

   5. •

      Auxiliary partial liver

   6. •

      Orthotopic position

   7. •

      Heterotopic position

   8. •

      Auxiliary whole liver

   9. •

      Living-related transplantation

   10. •

       Left lateral segment

   11. •

       Left lobe

   12. •

       Extended left lobe

   13. •

       Right lobe

   Artificial Liver Assist Devices

   1. •

      Non–cell-based systems

   2. •

      Charcoal hemoperfusion

   3. •

      High-volume plasmapheresis

   4. •

      Continuous high-frequency hemodiafiltration

   5. •

      Molecular adsorbent recirculating system (MARS)

   6. •

      Cell-based systems (bioartificial liver assist devices)

   7. •

      Primary porcine hepatocytes

   8. •

      Human hepatoblastoma cells

   9. •

      Extracorporeal liver assist device (ELAD)

   Hepatocyte Transplantation

   From Vincent JL, Abraham E, Moore FA, et al: Textbook of critical care, ed 6, Philadelphia, 2011, Saunders.

2. •

   A liver specialist should be notified urgently, and arrangements should be made for imminent transfer to a transplant center.

3. •

   Nutritional support should be initiated early. A daily intake goal of 60 g of protein is recommended to prevent catabolism of protein stores.

4. •

   Fluid support should be initiated if patient is not tolerating oral intake, or signs of hypoperfusion are present. Crystalloid solutions (normal saline in hypotensive patients, ½ normal saline + 75 mEq/L NaCO₃ in acidotic patients, normal saline + dextrose in hypoglycemic patients) can be used.

Monitoring

1. •

   Neuro exam q4h

2. •

   Patients with suspected acetaminophen toxicity should have LFTs monitored every 12 hr. Otherwise, LFTs can be monitored daily.

3. •

   Chemistry panels and PT/INR should be monitored every 8-12 hr. Correction of coagulopathy should be avoided because it can interfere with assessment of liver function. In the setting of life-threatening bleeding, fresh frozen plasma (FFP) and recombinant factor VIIa can be considered.

4. •

   Glucose finger sticks should be checked every 4 hr initially to evaluate for hypoglycemia. If hypoglycemia is detected, dextrose should be added to crystalloid solution.

5. •

   Because of the increased risk of infection, daily urine, sputum, and blood cultures should be checked in the absence of signs or symptoms of infection.

Pharmacologic Treatment

1. •

   If acetaminophen is the known or suspected cause, an IV acetylcysteine protocol must be initiated. N-acetylcysteine is not harmful and dramatically alters the course in acetaminophen toxicity, so there should be a low threshold to start, particularly in young patients or those with no known cause of ALF.

   1. ○

      The 20-hr protocol is:

      1. 1.

         Initial loading dose of 150 mg/kg IV given over 60 min followed by

      2. 2.

         12.5 mg/kg IV/hr over 4 hr followed by

      3. 3.

         6.25 mg/kg IV/hr for 16 hr

2. •

   A repeat acetaminophen level and ALT should be checked at hour 18 of NAC treatment. If either the acetaminophen level or the ALT is elevated, the 16-hour portion of treatment (6.25 mg/kg) should be extended and another ALT, INR, or acetaminophen level should be checked every 12 hr. The acetylcysteine can be stopped once the acetaminophen level is undetectable, INR <2, or ALT is shown to be either normal or decreasing. Additional information on acetaminophen overdose is available in the topic “Acetaminophen Poisoning.”

3. •

   N-acetylcysteine therapy outside of acetaminophen poisoning has been investigated and may be beneficial; however, its routine use is not currently recommended by practice guidelines but is center specific.

4. •

   Patients should be placed on stress ulcer prophylaxis given the risk of gastrointestinal bleeding.

5. •

   Antibiotics should be started immediately if infection is suspected. Sources usually include respiratory, urinary, and blood; there is no evidence for empiric antibiotic treatment. Antifungals should be initiated if no initial improvement with antibiotics occurs.

6. •

   Norepinephrine is the initial vasopressor of choice; vasopressin can be added as a second pressor. Persistent hypotension despite fluid resuscitation and pressor support should prompt concern for adrenal insufficiency.

7. •

   Lactulose is not routinely recommended for encephalopathy treatment; neomycin should be avoided due to concerns of nephrotoxicity.

Prognosis

1. •

   Overall mortality from ALF is 30% to 40% and improved significantly over the last 20 years.

2. •

   Transplant-free survival in ALF in the setting of acetaminophen, hepatitis A, shock liver, and pregnancy-related disease is >50%; for all other causes of ALF, transplant-free survival is <25%.

3. •

   Multiple models have been developed to predict spontaneous recovery in ALF patients (King’s College criteria, Clichy criteria, MELD score, APACHE II score).

4. •

   The King’s College criteria form the basis of the model most commonly used for prognostication (Table 2).

   TABLE2 King’s College Hospital Criteria for Liver Transplantation in Acute Liver Failure

   Acetaminophen-Induced Acute Liver Failure	Non–Acetaminophen-Induced Acute Liver Failure
   Arterial pH <7.3 (irrespective of grade of encephalopathy) OR Grade III or IV encephalopathy and Prothrombin time >100 sec and Serum creatinine >3.4 mg/dL	Prothrombin time >100 seconds (irrespective of grade of encephalopathy OR Any of three of the following variables (irrespective of grade of encephalopathy): 1. Age <10 yr or >40 yr 2. Etiology: non–A hepatitis, non–B hepatitis, halothane hepatitis, idiosyncratic drug reactions 3. Duration of jaundice before onset of encephalopathy >7 days 4. Prothrombin time >50 sec 5. Serum bilirubin >18 mg/dL

5. •

   Transplantation.

   1. ○

      Contraindications to listing include: medical history of psychiatric illness severe enough to affect patients’ survival or likelihood of compliance with medications, active sepsis, severe medical comorbidities, increasing dependence on ventilator/inotropic support, acute substance abuse, previous episodes of self-harm (>5 episodes), refractory mental illness.

   2. ○

      Mortality on waiting list is 25%; 1-year and 5-year survival is 66% and 70%, respectively.

   3. ○

      Various prognostic criteria used for liver transplantation in patients with fulminant hepatic failure are summarized in Box 6.

      BOX 6Various Prognostic Criteria Used for Liver Transplantation in Patients with Fulminant Hepatic Failure

      King’s College Criteria

      ACETAMINOPHEN OVERDOSE

      1. •

         Arterial pH < 7.3 (irrespective of grade of encephalopathy)

      2. or

      3. •

         PT > 100 s (INR > 6.5) and

      4. •

         Serum creatinine > 3.4 mg/dL (>300 μmol/L) and

      5. •

         Patients with grade III and IV hepatic encephalopathy

      NON–ACETAMINOPHEN-INDUCED LIVER INJURY

      Acute form (delayed jaundice-encephalopathy <7 days):

      1. •

         PT > 100 s (INR > 6.5) (irrespective of grade of encephalopathy) or any three of the following variables:

      2. •

         Aged <10 or >40 years

      3. •

         Non-A, non-B hepatitis, halothane hepatitis, idiosyncratic drug reactions

      4. •

         Subacute form: delayed encephalopathy >7 days

      5. •

         Serum bilirubin 17.4 mg/dL (300 μmol/L)

      6. •

         PT > 50 s

      Clichy Criteria

      1. •

         Grade III or IV encephalopathy

      2. and

      3. •

         Factor V < 20% in patients <30 years

      4. or

      5. •

         Factor V < 30% in patients >30 years

      Serum Gc Globulin Levels

      Decreasing Gc levels due to dying hepatocytes

      Serum α-Fetoprotein Levels

      Serial increase from day 1 to day 3 has been correlated with survival

      Liver Biopsy

      70% necrosis is discriminant of 90% mortality

      Gc, Plasma group-specific component protein; INR, international normalized ratio; PT, prothrombin time.

      From Vincent JL, Abraham E, Moore FA, et al.: Textbook of Critical Care, ed 7, Philadelphia, 2017, Elsevier.

1. •

   ALF is severe hepatic injury (as evidenced by elevated liver enzymes) with INR >1.5 and hepatic encephalopathy from a disease process that started <26 wk before presentation in a patient with no prior history of liver disease.

2. •

   Close to half of ALF is caused by drug ingestion, usually acetaminophen.

3. •

   Given the potential rapidity of deterioration, referral must be made as soon as possible to a liver transplant center.

4. •

   There should be a low threshold to start N-acetylcysteine.

5. •

   Do not correct coagulopathy unless life-threatening bleeding occurs or it is recommended by the liver transplant hepatologist.

• American Association for the Study of Liver Diseases: Practice Guidelines for Acute Liver Failure. Available at http://www.aasld.org/practiceguidelines/Documents/AcuteLiverFailureUpdate2011.pdf.

• W. Bernal, J. Wendon: Acute liver failure. N Engl J Med. 369 (26):2525–2534 2013 24369077

• J. Hu, Q. Zhang, X. Ren, et al.: Efficacy and safety of acetylcysteine in “non-acetaminophen” acute liver failure: a meta-analysis of prospective clinical trials. Clin Res Hepatol Gastroenterol. 39 (5):594–599 2015 25732608

• W.M. Lee, R.T. Stravitz, A.M. Larson: Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure 2011. Hepatology. 55 (3):965–967 2012 22213561

• A. Reuben: Outcomes in adults with acute liver failure between 1998 and 2013, an observational cohort study. Ann Intern Med. 164:724–732 2016 27043883

• T. Singh, N. Gupta, N. Alkhouri, et al.: A guide to managing acute liver failure. Cleve Clin J Med. 83 (6):453–462 2016 27281258

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1. Acetaminophen Poisoning (Related Key Topic)

2. Ascites (Related Key Topic)

3. Encephalopathy (Related Key Topic)

4. Hepatopulmonary Syndrome (Related Key Topic)

5. Hepatorenal Syndrome (Related Key Topic)