The following vignette applies to questions 1–6

A 40‐year‐old man presents to the emergency department complaining of severe abdominal pain, nausea, and intractable vomiting for the last 8 hours. The most recent vomitus contained blood and bile‐stained fluid. He is somnolent and markedly jaundiced. His wife says that they recently had a major disagreement and a few hours later she found him writhing in pain on the bathroom floor, with 3 unmarked pill bottles lying empty nearby. After much counseling, the patient finally agrees to have his blood taken for some tests.

Question 1:

1. His LFTs are in the 1000s IU/L and his INR is 3.2. He has no prior history of liver disease. What is the definition of acute liver failure?
   
   
   
   1. Signs of severe liver injury, encephalopathy, and impaired liver synthetic function (INR greater than 1.5), with the onset of range of symptoms occurring in less than 26 weeks, in a patient without pre‐existing liver disease or cirrhosis.
      
   2. Signs of severe liver injury, renal failure, and portal hypertension, with the onset of range of symptoms occurring in less than 12 weeks, in a patient without pre‐existing liver disease or cirrhosis.
      
   3. Mixed hyperbilirubinemia, AST and ALT levels greater than 500 IU/L, and signs of cardiogenic shock, with the onset of range of symptoms occurring in less than 12 weeks, in a patient without pre‐existing liver disease or cirrhosis.
      
   4. The onset of acute encephalopathy in cirrhotic patients with impaired liver function tests, with the onset of worsening symptoms occurring over more than 26 weeks.
      
   5. None of the above.

Question 2:

1. In the developed world, what is the most common cause of drug‐induced acute liver failure?
   
   
   
   1. Antituberculous drugs, such as isoniazid
      
   2. Antiretroviral drugs, such as didanosine
      
   3. Lipid‐lowering medications, such as statins
      
   4. Acetaminophen
      
   5. Antiepileptic drugs, such as valproic acid
   
   

   Acute liver failure (ALF) is a rare but life‐threatening disease. The most widely accepted definition of ALF is signs of acute severe liver injury (such as hyperbilirubinemia, and markedly raised LFTs), an abnormal liver synthetic function (such as an INR ≥ 1.5), and any degree of encephalopathy in a patient without cirrhosis or pre‐existing liver disease. The timeframe for ALF is less than 26 weeks for the development of the full range of symptoms and signs. If it occurs over a longer period, it is characterized as chronic liver failure (CLF). ALF may then be further subdivided into hyperacute (< 7 days), acute (7–21 days), and subacute (> 21 days but < 26 weeks). Although there may additionally be signs and symptoms of renal failure (due to hepatorenal syndrome) or cardiogenic shock (as ALF frequently leads to multi‐organ failure), the presence of encephalopathy is a cornerstone of diagnosis. Cirrhosis, pre‐existing liver disease, and portal hypertension are all inconsistent with a diagnosis of ALF. The exceptions to this strict definition of ALF include patients with Wilson disease, vertically acquired hepatitis B virus, and Budd‐Chiari syndrome where there is underlying cirrhosis or liver disease; illness duration has been less than 26 weeks overall. Hyperbilirubinemia and deranged LFTs are markers of severe liver injury, but are not prerequisites for a diagnosis.

   
   

   This patient has taken a large number of unknown pills; however, in the developed world, the most common cause of drug‐induced, and indeed of all causes of ALF, is acetaminophen toxicity. Although the other options are all possible causes of drug‐induced ALF, they are not as common as acetaminophen. Conversely, in the developing world, virus‐induced ALF has been implicated as the most common cause of ALF, particularly hepatitis B virus (HBV).

   
   

   Q1 Answer: A

   
   

   Q2 Answer: D

   
   

   Bernal W, Auzinger G, Dhawan A, Wendon J . Acute liver failure. The Lancet 2010; 376(9736):190–201.

   
   

   Khan R, and Koppe S . Modern management of acute liver failure. Gastroenterology Clinics 2018; 47(2):313–326.

   
   

   Lee WM, Larson AM, and Stravitz RT . AASLD position paper: the management of acute liver failure: update 2011. Hepatology 2011;55( 55):965–967.

Question 3:

1. Regarding N‐acetylcysteine:
   
   
   
   1. Its use is not recommended for acute liver failure.
      
   2. Its use is only recommended for acetaminophen‐induced liver failure.
      
   3. Its use is especially recommended in acetaminophen‐induced liver failure but also provides a survival benefit in other causes of acute liver failure if administered before the onset of advanced encephalopathy.
      
   4. Its use is recommended for all causes of acute liver failure and should be prescribed for up to 10 days.
      
   5. Its main mechanism of action is to act as a pro‐inflammatory agent that supports the immune system and prevents nosocomial infections in patients with acute liver failure.
   
   

   N‐acetylcysteine acts by replenishing reduced glutathione stores in the liver and has general anti‐inflammatory properties. The replenishment of reduced glutathione in the liver counteracts the depletion caused by toxic metabolites of acetaminophen, and the anti‐inflammatory properties aid in reducing the cytokine surge and inflammation associated with ALF. Although especially beneficial in cases of acetaminophen‐induced ALF, its use is also recommended in all other causes of ALF, as long as advanced (grade III or IV) encephalopathy has not yet developed. It may only be prescribed for up to 5 days, as there is a risk of significant immunosuppression due to its anti‐inflammatory properties.

   
   

   Answer: C

   
   

   Albalawi MA, Albalawi SA, Albalawi THS, Almuhawwis KS, Alswilem AM, Aldakhil F, et al. Evaluation of recent updates regarding acetaminophen‐induced acute liver failure. Archives of Pharmacy Practice 2019; 1:56.

   
   

   Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM, et al. Intravenous N‐acetylcysteine improves transplant‐free survival in early stage non‐acetaminophen acute liver failure. Gastroenterology 2009; 137(3):856–864.e1.

   
   

   Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH . Efficacy of oral N‐acetylcysteine in the treatment of acetaminophen overdose. New England Journal of Medicine 1988; 319(24):1557–1562.

Question 4:

1. The patient is diagnosed with acute liver failure. He becomes unconscious and unresponsive. His blood test reveals very high levels of acetaminophen. He is intubated, mechanically ventilated, and given IV fluids and N‐acetylcysteine. His right pupil is dilated and nonreactive. The attending physician is concerned about raised ICP in this patient. Which of the following indicate a higher risk for intracranial hypertension in a patient with acute liver failure?
   
   
   
   1. Shorter symptom‐to‐encephalopathy interval, and higher grades of encephalopathy
      
   2. Younger age and vasopressors
      
   3. Renal impairment
      
   4. Sustained arterial ammonia of greater than 150–200 μmol/L
      
   5. All of the above

Question 5:

1. Regarding possible intracranial hypertension in this patient:
   
   
   
   1. An ICP monitor should be placed to quantitatively measure the ICP.
      
   2. He should be given barbiturates to induce a coma.
      
   3. He should be given corticosteroids to reduce cerebral vasogenic edema.
      
   4. He should be hyperventilated and given either mannitol or hypertonic saline.
      
   5. All of the above are appropriate.
   
   

   Patients with ALF are at high risk for intracranial hypertension. There is a strong body of evidence that suggests raised ammonia levels in ALF cause encephalopathy, cerebral edema, and subsequent intracranial hypertension. Although invasive intracranial ICP monitoring is often recommended for other patients with raised ICP, it is not usually recommended in patients with ALF due to their poor coagulation status and the risk of an intracranial bleed. In addition, barbiturate coma induction would also be unwise as it would worsen encephalopathy. Although corticosteroids are routinely administered to reduce vasogenic edema in infectious and malignant causes of intracranial hypertension, they are not routinely recommended in ALF because of the immunosuppression associated with their use and a lack of survival benefit. The only exception to the use of corticosteroids to treat intracranial hypertension in ALF is when the cause of ALF is biopsy‐ or biomarker‐proven autoimmune hepatitis. Hypertonic saline and mannitol are optimal for treating intracranial hypertension in ALF, especially hypertonic saline as ALF patients are often hyponatremic. Hyperventilation is a temporizing measure as its effects on ICP do not last longer than 3–6 hours. Therapeutic hypothermia and propofol sedation can also help improve ICP and stabilize the patient for liver transplantation.

   
   

   A 2007 prospective study on 265 ALF patients admitted to a specialized Liver Intensive Therapy Unit (LITU) concluded that shorter symptom‐to‐encephalopathy interval, higher grades of encephalopathy, younger age, a requirement for vasopressors, renal impairment, sustained arterial ammonia greater than 150–200 μmol/L all were independently associated with a higher risk of developing intracranial hypertension in ALF patients.

   
   

   Q4 Answer: E

   
   

   Q5 Answer: D

   
   

   Bernal W, Auzinger G, Dhawan A, Wendon J . Acute liver failure. The Lancet 2010; 376(9736):190–201.

   
   

   Bernal W, Hall C, Karvellas CJ, Auzinger G, Sizer E, Wendon J . Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatology 2007; 46(6):1844–1852.

   
   

   Lee WM, Larson AM, Stravitz RT . AASLD position paper: the management of acute liver failure: update 2011. Hepatology 2011;55( 55):965–967.

   
   

   Maher SZ and Schreibman IR . The clinical spectrum and manifestations of acute liver failure. Clinics in Liver Disease 2018; 22(2):361–374.

   
   

   Mohsenin V . Assessment and management of cerebral edema and intracranial hypertension in acute liver failure. Journal of Critical Care 2013; 28(5):783–791.

Question 6:

1. The patient is no longer having any ongoing bleeding. However, his INR is still 3.2. There are no invasive procedures planned for the patient currently. With regards to his coagulation status, what should the next step in management be?
   
   
   
   1. Subcutaneous vitamin K infusion
      
   2. Fresh frozen plasma transfusion
      
   3. Prothrombin complex concentrate transfusion
      
   4. Recombinant factor VIIa infusion
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