Wednesday, April 28, 2021

Acute Liver Failure Case File

Posted By: Medical Group - 4/28/2021 Post Author : Medical Group Post Date : Wednesday, April 28, 2021 Post Time : 4/28/2021
Acute Liver Failure Case File
Eugene C. Toy, MD, Manuel Suarez, MD, FACCP, Terrence H. Liu, MD, MPH

Case 22
A 26-year-old woman was  brought to the emergency center after being found to  be lethargic and vomiting at home by her roommate. The  roommate, who had been on a business trip, had not seen the patient for 1½ days. On examination, the patient appears lethargic and mildly jaundiced. Her CBC is within normal limits. The serum liver transaminases are (ALT): 2500 IU/L and AST: 3100 IU/L. Serum glucose is 50 mg/dL, and total bilirubin is 2.8 mg/dL. Her prothrombin time is 45 seconds (INR 4}, creatinine level is 2.6 mg/dL, and her arterial pH is 7.35. The serum acetaminophen concentration is 120 mcg/mL (normal <50 mcg/mL). The patient had an NG tube placed in the ED followed by gastric lavage and evacuation of gastric contents. In addition, she had activated charcoal treatment in the ED. She was  later transferred to the ICU.

 What is the next step in treatment? 
 What are the complications associated with this process? 
 What are  other treatment options in addition to medications and supportive measures? 


Acute Liver Failure

Summary: A 26-year-old woman is brought to the hospital with vomiting and lethargy. Her laboratory studies demonstrate marked elevation of the serum transaminases, elevation in her serum bilirubin, and creatinine. Her blood glucose and artery pH are low. Her serum acetaminophen level is elevated. Initial treatment with gastric lavage and activated charcoal has already been given prior to her arrival to the ICU. This is consistent with acute acetaminophen toxicity.
  • Next step: Administer N-acetylcysteine (NAC) therapy by mouth. This can be mixed with a carbonated beverage to improve tolerance. The initial loading dose is 140 mg/kg followed by 70 mg/kg every 4 hours for 17 doses or until the INR decreases to <1.5. If the patient is unable to tolerate oral intake, then intravenous N-acetylcysteine can be administered.
  • Complications: Complications that may occur as the result of acute liver failure include cerebral edema, infections (including bacterial and fungal infections), acute kidney injury, high-output hyperdynamic process, and coagulopathy and bleeding complications.
  • Treatments other than medications and supportive measures: Patients with severe acute liver failures may need liver transplantation. Alternatively, some limited experiences have shown that acellular liver support devices or bioartificial liver support devices may be temporarily implemented to provide support while liver recovery occurs. Alternatively, bioartificial liver devices can also be used as a bridge for the support of patients with fulminant hepatic failure prior to liver transplantation.


  1. To learn the initial evaluation and diagnosis of acute hepatic failure.
  2. To learn the causes of acute hepatic failure.
  3. To learn the management of acute hepatic failure.
  4. To learn to identify patients with acute hepatic failure who may need referral for liver transplantation.

This patient's presentation is highly suspicious for acute liver failure due to acetaminophen overdose. However, because the circumstances of this overdose are uncertain, the initial evaluation must also include a toxicology screen for other possible medications and illicit drug-related causes, and a hepatitis screen for viral hepatitis. In addition, appropriate imaging and blood cultures to rule out sepsis as the potential cause of this multiple organ dysfunction are required. Because there were no witnesses to the ingestion, it is difficult to determine the timing of the overingestion of acetaminophen; therefore, gastric lavage and activated charcoal therapy provided in the emergency department were appropriate early measures. NAC administration is vital to minimize the liver toxicity in this patient, and this should be initiated as early as possible in the emergency department and continued in the ICU. ICU admission for observation is very appropriate for this patient, given her altered mental status, acute kidney injury, and metabolic acidosis that suggest serious toxicity from ingestion. A detailed neurological examination needs to be completed in addition to a CT scan of the brain, given the patient's initial presentation of lethargy. Her neurological presentation suggests possible grade 2 encephalopathy; in which case, the patient would be considered a potential candidate for referral to a liver transplant center. Even though acetaminophen-induced acute hepatic failure is the most common cause of acute liver failure in the United States, the survival is reported to be reasonably good at 78% to 80%, and >80% when NAC can be administered within 12 hours of ingestion.

Approach To:
The Patient with Acute Hepatic Failure


ACUTE HEPATIC FAILURE: Defined as the development of impaired liver synthetic
function, coagulopathy, and hepatic encephalopathy in less than a 2- to 3 -month period in a patient without underlying liver disease.

GRADING OF HEPATIC ENCEPHALOPATHY: The West Haven grading system is based on level of impaired autonomy, level of consciousness, intellectual function, and behavior.

GRADE 1: Trivial lack of awareness, shortened attention span, euphoria or anxiety, impaired performance of simple addition or subtraction, minimal change in level of consciousness.

GRADE 2: Lethargy or apathy, disorientation for place or time, subtle personality change, inappropriate behavior, asterixis.

GRADE 3: Somnolence or semi-stupor but with response to verbal stimuli; marked confusion and disorientation.

GRADE 4: Comatose and unresponsive to verbal or noxious stimuli; decorticate or decerebrate posturing.

N-ACETYLCYSTEINE (NAC): NAC helps detoxify the acetaminophen toxic metabolite (NAPQI). Ideally, NAC is given within 8 to 10 hours after ingestion, and protects against NAPGI-induced liver and renal injuries. NAC administration has been demonstrated to reduce the liver injury associated with acetaminophen overdose even when given within 1 6 hours after ingestion. The recommended dose is 140 mg/kg diluted in oral solution as a loading dose, followed by 70 mg/kg oral doses every 4 hours for 17 doses. Patients who are unable to tolerate oral intake can be given intravenous NAC with an initial loading dose of 150 mg/kg in D5W over 15 minutes, followed by a maintenance infusion dose of 50 mg/kg over 4 hours, and then 100 mg/kg infusion over the next 16 hours.

LIVER SUPPORT SYSTEMS: Liver support devices are categorized as acellular systems that utilize albumin dialysis or bioartificial liver (BAL) support systems. The most common acellular system is the molecular reabsorbent and recirculating system (MARS). MARS has been shown to improve hemodynamic status, decrease encephalopathy, decrease intracranial pressure, and decrease serum bilirubin and creatinine. The bioartificial liver support systems are extracorporeal circulatory systems that utilize a veno-venal dialysis concept, where the patient's blood is circulated through a cell-based bioreactor. The bioreactors are loaded with either transformed human hepatocytes or porcine hepatocytes. Application of the BAL essentially provides patients with temporary liver-filtering and biosynthetic functions. Clinical applications of BAL have been shown to improve the 30-day survival of patients with acute liver failure.

KING'S COLLEGE HOSPITAL (KCH) CRITERIA: This is the most widely applied criteria for the selection of patients with acute liver failure for liver transplantation.

The KCH criteria for acetaminophen-induced failure are:
  1. pH <7.30 after resuscitation, irrespective of encephalopathy grade
  2. Prothrombin time >100 seconds and creatinine >300 μmol/L in patients with grade III or grade IV encephalopathy
Modification to include lactate of >3.5 mmol/L after fluid resuscitation has been proposed by some. Patients with acetaminophen toxicity who meet the KCH criteria have a >90% mortality without liver transplantation. A recent meta-analysis showed that the KCH criteria are associated with sensitivity of 69% and specificity of 92% in predicting death without transplantation.

The KCH criteria are different for patients with acute liver failure not induced by acetaminophen, and these include: prothrombin time >100 seconds or 3 or more of the following criteria:
  1. Age less <10 or >40 years
  2. Acute liver failure caused by non-A, non-B, non-C hepatitis, halothane hepatitis, or idiosyncratic drug reaction
  3. Jaundice present for > 1 week prior to onset of encephalopathy
  4. Prothrombin time >50 seconds
  5. Serum bilirubin >17.5 mg/dL
Acute liver failure can be produced by a variety of causes including toxins, viral infections, metabolic causes, vascular causes, and autoimmune causes. Acute liver injuries from these mechanisms can cause damages leading to hepatocyte apoptosis and/or necrosis. Injuries associated with mitochondrial permeability changes typically lead to apoptosis if the cells' ATP stores are preserved; examples include
acute Wilson disease and Reye syndrome. When injuries producing mitochondrial permeability changes occur in the face of cellular ATP depletion, cell necrosis occur. The site of injury within the liver architecture is important in determining the potential for cellular regeneration and recovery prognosis. Stem cells are located in the portal tract region, and preservation of these cells is important for regeneration; therefore, injury to the portal zone is associated with lower potential for regeneration and worse prognosis.


Toxin-Induced Injuries Liver damage caused by  acetaminophen is  the  most  common type of toxin-induced injury, and can occur with ingestions of 4 g/d, but  more often injuries are caused by the consumption of >10 g/d. Acetaminophen is  metabolized in the  hepatocytes by cytochrome enzymes to the toxic metabolite  N­-acetyl p-benzoquinone imine (NAP-QI), which is normally detoxified by conjugation  with glutathione. Depletion of glutathione can increase the susceptibility of the  individual to acetaminophen-induced liver injury. Acetaminophen-induced injuries  are typically concentrated in the central zones, where the portal tracts are spared.  Based on the architectural site of the   injury, the potential for recovery is generally  very good.

Amanita (mushroom) poisoning is more commonly encountered in Western
Europe than the United States. In the United States, Amanita species are most
frequently encountered in coastal Pacific Northwest, and to lesser extents in the
Blue Ridge Mountains, Pennsylvania, New Jersey, and Ohio. Most Amanitas are
encountered during late summer to early winter. There are over 5000 species of
mushrooms; however, only 50 are poisonous to humans. Three of the Amanita
species are responsible for >90% of all mushroom-related fatalities. Patients with
mushroom poisoning typically present with vomiting, crampy abdominal pain,
and diarrhea within 10 to 12 hours of ingestion. Clinical and laboratory findings associated
with acute liver injury are often not manifested until 2 days after ingestion.
Treatment measures include evacuation of duodenal contents by suction to interrupt
the enterohepatic circulation of amatoxins. Sodium bicarbonate administration
within 2 hours of ingestion may be helpful in elimination of urinary a-amanitin.
Hemodialysis or hemoperfusion utilizing a charcoal filter may also be effective in
removing amatoxins from the circulation. The overall prognosis of patients with
Amanita poisoning is not good, because some patients who recover from the acute
insult will go on to chronic hepatitis and late liver failure.

Viral Hepatitis-Induced Acute Liver Failure Viral hepatitis caused by hepatitis A, B, and E viruses can produce acute liver injuries, which generally result in spontaneous resolution; however, a small percentage of these patients may go on to develop acute hepatic failure. Antiviral treatments have not been demonstrated to reduce the occurrence of viral hepatitis-associated acute liver failure. The acute hepatitis associated with hepatitis B has been shown to be associated with a worse prognosis when coinfection with hepatitis D is present. Antiviral therapy may be indicated for patients with hepatitis B-induced acute liver failure, when the patient is anticipated to require liver transplantation; the use of antiviral therapy in this setting reduces the risk of hepatitis B recurrences in the transplanted liver.

Metabolic Causes of Acute Liver Failure Metabolic causes of acute liver failure include acute fatty liver of pregnancy. This is an unusual metabolic process in which the metabolic abnormality in the fetus causes maternal liver injuries that typically occur during the third trimester of pregnancy, with some patients developing rapid progression of jaundice and liver failure. In approximately 50% of the cases, this process occurs with preeclampsia. Delivery of the fetus is the treatment of choice for most patients. There have been limited reports suggesting that the plasma exchange therapy may also be of benefit in these patients.

Patients with Wilson disease may present with acute liver failure caused by copper toxicosis. Frequently, these patients have underlying chronic liver injuries prior to the onset of the acute injuries. The application of MARS has been shown to reverse some of the acute injuries associated with this process.

Vascular Causes of Acute Liver Failure Acute obstruction of the hepatic veins (Budd-Chiari syndrome) may occur as a result of hypercoagulable states. Once identified, patients may benefit from portal venous decompression procedures such as transhepatic intrahepatic protosystemic shunt (TIPS) or operative portocaval shunts to reduce further liver parenchymal injuries. Ischemia is a common cause of acute liver injury, and this is typically described as "shock liver." This type of injury is typically associated with a severe and/or prolonged hypotensive episode, which causes injuries mostly in the central zone. Treatment is to address the underlying condition causing the global hemodynamic compromise.

Evaluation of Patients with Acute Hepatic Failure
Early recognition of the condition is important in improving prognosis, since early recognition permits for the identification of the inciting events, initiation of cause-specific therapies, and early referral to specialty units for specialized support or transplantation. The history is useful to identify and determine possible substance ingestion and timing of ingestion. In addition, history of preexisting liver diseases or risk factors will help determine the chronicity of the liver injury. During the physical examination, the focus is on assessing the liver and spleen sizes, and the presence or absence of stigmatas of chronic liver disease. The neurological evaluation should be thorough noting the papillary sizes and reactivity, deep tendon responses, mental status, and cognitive functions. The West Haven Criteria and the GCS are both helpful for quantification of neurological functions. It is important to keep in mind that the neurological status may change as the patient's condition changes; therefore, neurological assessments should be repeated frequently to determine progress. Laboratory evaluations should be performed to determine possible causes of injury, metabolic panels, coagulation panels, complete blood count, and blood and tissue typing if liver transplantation is anticipated. Imaging studies should be performed to assess liver characteristic and size, spleen size, and patency of hepatic vasculature. Management of acute liver failure patients is often optimized when a multidisciplinary team including intensivists, transplant surgeons, transplant hepatologists, and nephrologists are involved in the care of patients with the most severe injuries.

Complications Associated with Acute Hepatic Failure
Cerebral edema leading to intracranial hypertension is one of the most lethal complications associated with acute liver failure. Risk factors associated with this complication include grade 3 or 4 encephalopathy, serum ammonia >150 to 200 μM, rapid progression of encephalopathy, superinfection, requirement for vasopressor support, and requirement for renal replacement therapy. Intracranial hypertension can be identified by CT imaging or intracranial pressure monitoring. Intracranial pressure monitoring is the most reliable way of identifying this complication; however, placement of monitors in these patients can be associated with 10% to 20% risk of bleeding complication. Moderate hypothermia (32°C-33°C) has been shown to be an effective treatment for patients with intracranial hypertension.

Hemodynamic failure is commonly seen in patients with acute liver failure. Typically, it is associated with high cardiac output and low systemic vascular resistance. Because this picture closely resembles the septic response, it is important that all infectious causes are ruled out. Support of the blood pressure is important in these patients to maintain cerebral prefusion and vasopressors are often needed.

Hematologic failure with coagulopathy occurs commonly in patients with acute liver failure. Empiric administration of 10 mg of vitamin K intravenously is recommended because subclinical vitamin K deficiency can contribute to coagulopathy. Prophylactic transfusion of blood products to correct coagulopathy has not been shown to improve outcome; however, for bleeding patients or prior to invasive procedures, transfusion to correct the INR to 1.5 and increase the platelet count to >50,000/mm3 is recommended. Cryoprecipitate is recommended for bleeding patients with fibrinogen <100 mg/dL. Recombinant factor 7a is sometime helpful when bleeding patients do not respond to FFP transfusions.

Acute kidney injury may accompany acute liver failure. Urinary sodium levels are low in patients who are volume depleted and in patients with hepatorenal syndrome. Volume assessment is important in these patients with either intravascular monitoring devices or echocardiography. Renal replacement therapy is often needed as the acute kidney injury progresses. For patients requiring renal replacement therapy, continuous venovenal hemofiltration with dialysis is often better tolerated than intermittent dialysis.

Infections occur commonly in the acute liver failure patients, and it is the most common cause of death in this patient population. It is believed that these patients have impaired Kuppfer cell function and abnormal clearance of gut bacteria and bacterial product, which render the patients susceptible to bacterial and fungal infections. Although some groups believe that broad-spectrum prophylactic antibiotics should be administered in patients with acute liver failure, survival has not been shown to improve with prophylaxis. Clinicians should maintain high vigilance for possible infections in these patients who have low threshold for treatment.

Catabolism and nutritional failure occurs commonly i n this patient population. Oral feeding is advisable until patients develop grade 2 to 3 encephalopathies. Caloric targets for patients should be 25 to 30 kcal/kg. Enteral or parenteral nutrition should be initiated when oral intake is not feasible. Protein intake should be limited to 1 g/kg/d to minimize excess ammonia production. Supplemental glutamine should be avoided as it appears to contribute to excess ammonia production and worsening of cerebral edema.

Patients with acute liver failure who do not recover despite appropriate medical care and supportive care should be referred as early as possible for consideration for liver transplantation. The King's College Hospital Criteria are the most commonly used criteria for the selection of patients for transplantation referral. The long-term outcome for patients undergoing transplantation for acute hepatic failure is generally not as good as outcome following liver transplantation for chronic liver diseases. The 1-, 3-, and 5 -year graft survival reported are 63 %, 58%, and 56%, respectively.

  • See also Case 3 ( Scoring System and Prognosis), Case 30 (Altered Mental Status), Case 33 (Multiorgan Dysfunction), and Case 41 (Hemorrhage and Coagulopathy).


22.1 Which of the following statements regarding acetaminophen-induced acute liver failure is most accurate?
A. The recovery/survival is <30%.
B. Hepatocytes in the portal zone are most affected.
C. It is the second most common cause of acute liver failure in the United States behind Amanita ingestion.
D. NAC therapy does not provide any benefits when delayed by more than 4 hours after ingestion.
E. Individuals with glutathione depletion have greater susceptibility to toxicity.

22.2  A 3 2-year-old woman presents with Amanita- induced acute liver failure, whose encephalopathy progresses from grade 1 to grade 3 over the course of 6 hours in the !CU. She is intubated in the ICU for airway protection. Which of the following is the most appropriate next step ?
A. Initiate hemodialysis to eliminate amatoxins
B. Perform CT of the brain
C. Transfer to a liver transplantation center
D. Initiate broad-spectrum antibiotics
E. Put the patient on vasopressors to increase cerebral perfusion pressure

22.3  A 28-year-old man develops acute fulminant hepatic failure following inadvertent ingestion of poisoned Amanita. He is currently undergoing treatment for coagulopathy and respiratory failure that is requiring mechanical ventilation. On day 2 in the ICU, you are notified by his nurse regarding a slight change in his motor response on the left and decreased pupillary responses to light in the right eyes. Which of the following is the most appropriate management at this time ?
A. Change the ventilatory settings to keep PACO2 at 35 mm Hg.
B. Placement of ventriculostomy drain.
C. CT scan of the brain.
D. Referral for liver transplantation.
E. Referral for bioartificial liver support.


22.1  E. Glutathione depletion can increase the susceptibility of individuals to acetaminophen toxicity, and this can be seen in fasting patients and patients with chronic alcohol use. Acetaminophen causes predominant injury to hepatocytes in the central zone, while sparing cells in the periportal zones. Based on this distribution, injuries to the stem cells occur less frequently resulting in good potential for recovery. Survival >80% is expected with acetaminophen induced liver injury. NAC administration has been shown to provide improved liver recovery when given as late as 16 hours after acetaminophen ingestion.

22.2  B. For this patient with rapid progression of encephalopathy, intracranial hypertension from increasing cerebral edema is a major concern. A CT of the brain should be obtained immediately to assess the brain. Alternatively, an intracranial pressure monitor can be placed, but this approach carries a bleeding risk of 10% to 20%. This patient ultimately may need to be referred for liver transplantation consideration, but an acute ICP increase need to be addressed first.

22.3  C. This patient with acute fulminant hepatic failure i s showing signs o f right cerebral hemispheric mass effects. The mass effects are likely produced by intracerebral hemorrhage due to coagulopathy related to hepatic failure. Cerebral edema causing intracranial hypertension can also be a cause of these neurological changes; however, cerebral edema-induced changes are unlikely to be limited to the right hemisphere. Ventriculostomy drain could be helpful to directly measure ICP but could also cause bleeding complications and should not be done until a mass lesion is ruled out with CT. The patient's overall poor liver status could make liver transplantation or bioartificial liver support necessary; however, these options should not be entertained until the question regarding his new neurological findings are addressed.

 Chronic alcohol ingestion  stimulates cytochrome CYP-2E1 activity, inhibits the rate of  glutathione synthesis, and can increase toxicity to acetaminophen. 
 The 1-,  3-, and 5-year survival  following liver transplantation for acute liver failure is 10% to 20% lower than liver transplantation performed for chronic liver diseases. 
 The MARS  and  bioartificial liver (BAL) are useful for the  support  of patients while liver recovery is occurring, and these devices can  be used as bridge to liver transplantation. 
 In  acetaminophen toxicity, NAC helps to detoxify the acetaminophen toxic metabolite (NAPQI). Ideally, when NAC is given within 8 to 10 hours after ingestion it protects against NAPGI-induced liver and renal injuries.


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Stravits RT. Critical management decisions i n patients with acute liver failure. Chest. 2008; 134: 1092- 1 1 02. 

Trotter JF. Practical management of acute liver failure in the intensive care unit. Curr Opin Crit Care . 2009; 1 5 : 1 63 - 1 67 .


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