Question

    Acute Liver Failure

    Marburg virus liver injury[1]

    Acute liver disease is an uncommon disorder characterized by a rapid decline in liver function. Its multiorgan and multisystem involvement results in encephalopathy, altered mental status, and other complications as well.

    Presentation

    Acute liver failure comprises of two types: fulminant liver failure and subfulminant liver failure. The former is defined as the occurrence of encephalopathy within 8 weeks of onset of symptoms (in patients without pre-existing liver disease). Subfulminant liver failure is characterized by a longer duration between symptoms and encephalopathy.

    The clinical picture features a deterioration in mental status, bleeding, purpura, jaundice, and ascites. Nonspecific symptoms include anorexia, malaise, and motor abnormalities. Additionally, fulminant hepatic failure can feature hematemesis or melena due to GI bleeding. A common condition known as fetor hepaticus, which is sweet breath odor, is also a common sign.

    Sequelae of acute liver failure include cerebral edema, seizures, metabolic dysfunction, infection, kidney failure, and hemorrhage. Also, in cases with rapid onset of ascites and abdominal pain, this may indicate hepatic vein thrombosis or Budd-Chiari syndrome.

    Physical exam

    Findings may include right upper quadrant tenderness, smaller liver span, and jaundice. Stigmata associated with chronic liver disease are also common.

    Vital signs may show tachycardia, hypotension, and tachypnea whether in the setting of sepsis or not. Also, patients with cerebral edema exhibit papilledema, bradycardia, and hypertension secondary to elevated intracranial pressure (ICP). These individuals may progress to states such as obtundation or coma.

    Patients with infection may present symptoms related to that such as fever or cough.

    Liver, Gall & Pancreas
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  • neurologic
    Confusion
    • Kidneys lose function Immune system loses function Metabolic dysfunction causes low blood sugar and proteins Symptoms include: Jaundice Ascites Altered mental status such as confusion and drowsiness Malaise Weakness Nausea Anorexia Low blood pressure[symptoma.com]
    • […] days, "acute" as onset between 7 and 28 days, and "subacute" as onset between 28 days and 24 weeks.page 1557 The main features of acute liver failure are rapid-onset jaundice, weakness, and eventually, changes in mental status that can begin as mild confusion[en.wikipedia.org]
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  • Workup

    Individuals with jaundice, bleeding, or alteration in mental status should be suspected of having liver failure. When evaluating a patient for acute liver failure, it is crucial to determine the etiology as the therapy and management depend on the underlying cause. The clinician should ascertain all medications ingested by the patient including prescription and over-the-counter drugs and supplements. The workup further consists of a physical exam and laboratory tests.

    Laboratory tests

    Since acute liver failure may result in multisystem dysfunction, the following studies should be obtained: a complete blood count (CBC), complete metabolic panel (CMP), renal and liver function tests, PT and international normalized ratio (INR), and urinalysis. Upon confirmation of the diagnosis, crucial tests include an arterial blood gas (ABG), amylase, lipase, blood type and screening. Moreover, if an infection in suspected, blood, urine, and ascitic fluid cultures are indicated.

    The findings of the above studies will determine the severity of acute liver disease and the overall clinical picture. Moreover, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are profoundly increased indicating hepatocellular necrosis. Additionally, PT is prolonged and INR is greater than 1.5.

    Also, plasma bilirubin levels are elevated and continue to increase as the disease progresses. In fact, a level above 4 mg/dL is associated with a poor prognosis in acetaminophen toxicity.

    An ABG will reveal any acid-base disturbance. Another serious finding, severe hypoglycemia, may develop secondary to impairment in gluconeogenesis and glycogen production.

    Imaging

    In patients with both altered mental status and coagulopathy, a head CT scan is performed to identify any intracranial bleeding.

    Pathology

    Biopsy
    Liver Biopsy
    • A liver biopsy done via the transjugular route because of coagulopathy is not usually necessary, other than in occasional malignancies.[en.wikipedia.org]
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  • Other Pathologies
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  • Laboratory

    Serum
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  • Treatment

    Due to the life-threatening nature of the disease, intensive care is paramount [9] [10] [11] [12]. When encephalopathy progresses, securing the airway is the top priority. Additionally, the medical team should remain vigilant about the hemodynamics, metabolic function, and nutritional status. Furthermore, early recognition of complications such as GI bleeding and cerebral edema is very important.

    Airway protection

    Intubation may be necessary for encephalopathic patients. Close monitoring is critical especially in those with worsening mental status. The medical team should be cautious when choosing drugs for intubation and agitation since many cause sedation and make it challenging to monitor the patient's mental status.

    Hemodynamic and metabolic management

    The therapeutic approach targets hemodynamic and metabolic stability as it is for all critically ill patients. Of importance, fluid replacement for hypotension should be given carefully since these patients are at risk for cerebral swelling. In refractory cases, 20 mL/kg of crystalloid is used. In extreme conditions, vasopressors may be necessary.

    Special care should be geared towards preventing hypoglycemia, which occurs frequently in liver failure. This can be done through with intravenous infusion of glucose.

    Acute liver disease is associated with protein breakdown, and therefore, protein should be replaced carefully. Less protein is administered in patients with hyperammonemia or intracranial hypertension.

    CBC, CMP, and coagulation panel should be obtained frequently while LFTs and serum bilirubin are performed daily.

    Infection

    Empiric antibiotics are initiated when the patient demonstrates signs of infection including fever and worsening of hemodynamics, renal function, or mental status. When the cultures' results are obtained, the medications can be altered. If an infection is ruled out, then the antibiotics are discontinued.

    Coagulopathy

    In cases with bleeding or severe coagulopathy, fresh frozen plasma (FFP) is important. However, this product can cause volume overload and accentuate cerebral edema. Moreover, use of FFP prohibits the monitoring of PT, which is a value predictive of poor prognosis.

    Acetaminophen overdose

    Acetaminophen poisoning can be challenging to diagnose but should be suspected in cases with not clear etiology. It is treated with N-acetylcysteine.

    Transplantation

    The ultimate treatment of liver failure is liver transplantation. It is correlated with 1-year survival rate of almost 80%. Hence, it is reserved for those with a prognosis that is worse without a liver transplant.

    Other

    Lactulose can be beneficial in patients with encephalopathy. As for seizures, phenytoin is a good choice.

    Prognosis

    There are factors that can provide predictive insight regarding the prognosis. For example, worse prognosis is associated with: 1) Severe encephalopathy such as with stage 3 or 4, 2) Patient age younger than 10 years, or greater than 40 years old, 3) Prolonged prothrombin time (PT), and 4) etiology such as idiosyncratic drug reactions or Wilson disease.

    The outcome is better if acute liver failure is secondary to acetaminophen toxicity or infection with hepatitis A or B.

    Death rates increase with sequelae such as cerebral edema, adult respiratory distress syndrome (ARDS), coagulopathy, renal failure, and infection.

    The mortality rate of fulminant hepatic failure was higher than 80%, but orthotopic liver transplantation (OLT) has improved survival.

    Complications

    Acute Tubular Necrosis
    • Kidney failure is common, present in more than 50% of ALF patients, either due to original insult such as paracetamol resulting in acute tubular necrosis or from hyperdynamic circulation leading to hepatorenal syndrome or functional kidney failure.[en.wikipedia.org]
    Cerebral Edema
    • Cerebral edema Brain involvement includes cerebral edema, which is the predominant cause of morbidity and fatality in acute liver failure.[symptoma.com]
    • However, positive end-expiratory pressure can worsen cerebral edema.[en.wikipedia.org]
    Coma
    • In ALF, hepatic encephalopathy leads to cerebral edema, coma, brain herniation, and eventually death.[en.wikipedia.org]
    • These individuals may progress to states such as obtundation or coma.[symptoma.com]
    Gastrointestinal Hemorrhage
    • The use of gastrointestinal hemorrhage prophylaxis with a histamine-2 (H2) blocker, proton pump inhibitor, or sucralfate is recommended.[en.wikipedia.org]
    Hyperammonemia
    • Less protein is administered in patients with hyperammonemia or intracranial hypertension.[symptoma.com]
    Hypoglycemia
    • Hypoglycemia develops as a result of impaired glycogen production and gluconeogenesis.[symptoma.com]
    • Hypoglycemia occurs in many patients with ALF and is often due to depletion of hepatic glycogen stores and impaired gluconeogenesis.[en.wikipedia.org]
    Hypokalemia
    • Correction of hypokalemia is essential as hypokalemia increases the kidneys' ammonia production, potentially exacerbating encephalopathy.[en.wikipedia.org]
    Hypotension
    • Vital signs may show tachycardia, hypotension, and tachypnea whether in the setting of sepsis or not.[symptoma.com]
    • Hyperdynamic circulation, with peripheral vasodilatation from low systemic vascular resistance, leads to hypotension.[en.wikipedia.org]
    Hypoxia
    • Although delivery of oxygen to the tissues is adequate, there is a decrease in tissue oxygen uptake, resulting in tissue hypoxia and lactic acidosis.[en.wikipedia.org]
    Infection
    • If an infection is ruled out, then the antibiotics are discontinued.[symptoma.com]
    • Bacterial and fungal infections are common in ALF, with one study demonstrating culture-proven infection in 80% of ALF patients.[en.wikipedia.org]
    Lactic Acidosis
    • Lactic acidosis occurs predominantly in paracetomol (also known as acetaminophen) overdose.[en.wikipedia.org]
    Liver Failure
    • Acute liver failure comprises of two types: fulminant liver failure and subfulminant liver failure.[symptoma.com]
    • Wilson's disease (hereditary copper accumulation) may infrequently present with acute liver failure.[en.wikipedia.org]
    Wilson Disease
    • Wilson's disease (hereditary copper accumulation) may infrequently present with acute liver failure.[en.wikipedia.org]
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  • Etiology

    Acute liver failure is more prevalent in developing countries, since hepatitis A, B, and E are leading causes of the condition and they are not particularly prevalent in the industrialized world. However, drug-induced liver damage due to acetaminophen and idiosyncratic drug reactions is the predominant cause of acute liver failure in the United States and Western Europe. In these latter countries, vaccinations and good sanitation practice have resulted in the decline of viral hepatitis infections.

    Other causes

    Primary cardiac or respiratory failure in ill patients can cause ischemic hepatocellular injury, a potential consequence of severe sepsis. This is accompanied by increased serum aminotransferase concentrations [4] [5].

    Epidemiology

    In the United States, the incidence of fulminant liver failure is approximately 2000 cases per year. In acute liver failure, drug-induced hepatotoxicity is responsible for more than half of all cases. Specifically, acetaminophen accounts for 42% of these cases while idiosyncratic drug reactions comprise 12%.

    The occurrence of liver failure is observed in all races. Furthermore, a research study in the United States demonstrated that a large percentage was composed of Caucasian people (74%).

    Autoimmune liver disease shows a gender preference towards women.

    As for age, individuals above 40 years old are associated with a worse prognosis.

    Sex distribution
    Age distribution

    Pathophysiology

    The clinical picture of fulminant hepatic failure resembles that of sepsis, which is a state of reduced systemic vascular resistance. The resultant low blood supply to the organs causes further complications. Hence, acute liver failure affects numerous organs and systems.

    Cerebral edema

    Brain involvement includes cerebral edema, which is the predominant cause of morbidity and fatality in acute liver failure [6] [7] [8]. Cerebral edema is probably a consequence of cytotoxic and vasogenic effects. Additionally, increased cerebral perfusion occurs secondarily to cerebral dysregulation, which is a consequence of elevated levels of the vasodilator, nitric oxide.

    Coagulopathy

    Coagulopathy commonly occurs secondarily to the decreased synthesis of the coagulation factors in the liver.

    Acetaminophen toxicity

    Hepatic metabolism of acetaminophen produces a metabolite more toxic than the drug itself.

    Other

    Some of the main features of acute liver failure include hyperbilirubinemia, which usually manifests at initial presentation.

    Hypoglycemia develops as a result of impaired glycogen production and gluconeogenesis.

    Prevention

    Acute liver failure is associated with numerous etiologies. One of the causes, acetaminophen overdose, can be prevented if the dosage guidelines are followed correctly. The same applies to all medications and supplements as well. Additionally, depending on the type of viral hepatitis, an infection can be prevented through vaccinations, implementation of good hygiene, and practicing a safe and healthy lifestyle.

    Summary

    Acute liver disease is the severe deterioration of hepatic function secondary to liver conditions such as hepatitis, cirrhosis, or overdose of acetaminophen and other drugs. In the United States, the predominant cause is drug toxicity, while viral hepatitis is the main etiology in developing regions. It occurs in less than 10 cases per million annually in developed countries. Also, most cases occur in adults in their 30s without previous liver disorders.

    The potentially fatal condition is classified as fulminant or subfulminant in accordance to the interval between the onset of symptoms and development of encephalopathy [1]. Furthermore, acute liver failure results in coagulopathy, altered mental status, and dysfunction of multiple organs and systems [2] [3].

    The diagnosis is determined through a history, physical, exam, and extensive laboratory testing. Since there are dangerous manifestations, it is important to assess the full clinical picture during the workup.

    The initial goal of therapy involves the identification and treatment of the underlying cause. Since acute liver failure is associated with a high mortality rate, these critically ill patients warrant close monitoring. Specifically, there are crucial aspects to consider such as airway protection, maintenance of the hemodynamic and metabolic status, and prompt recognition of complications such as infection, cerebral edema, and gastrointestinal (GI) bleeding.

    Patient Information

    Acute liver failure is a disease in which there is a rapid decline in the perfomance of the liver. It can be caused by liver disease, viral hepatitis, especially hepatitis B, cirrhosis, or poisoning due to alcohol or medications. In fact, acetaminohen overdose is the most common cause of acute liver failure in the United States, whereas viral hepaitis is the most common cause in the developing world.

    When the liver becomes largely damaged, failure occurs. It can occur over days, weeks, months or years.

    The liver is responsible for many functions. So when it becomes damaged, there are many detrimental consequences such as:

    • A substance in the body called bilirubin builds up and therefore, the patient becomes jaundiced
    • The liver cannot synthesize proteins that clot blood. Therefore, the patient can bleed and bruise easily
    • Fluid builds up in the abdomen. This is known as ascites
    • The toxins that build up affects the brain. This results in encephalopathy
    • New blood vessels form in the esophagus and stomach to bypass the liver. These new vessels are fragile, vulnerable and tend to bleed easily.
    • Kidneys lose function
    • Immune system loses function
    • Metabolic dysfunction causes low blood sugar and proteins

    Symptoms include:

    Acute liver disease is diagnosed through the history, physical exam, and important blood tests that check for liver function, electrolytes, liver proteins, and others.

    As soon as it is diagnosed, liver failure is treated promptly to prevent further complications. These patients are admitted to the intensive care unit (ICU).

    Treatment consists of the following:

    • Low blood pressure is treated with intravenous fluids and possibly drugs
    • Encephalopathy is managed with lactulose
    • Bacterial infection is managed with antibiotics
    • Low blood sugar is treated with intravenous sugar

    Self-assessment

    References

    1. Wlodzimirow KA, Eslami S, Abu-Hanna A,Nieuwoudt M, Chamuleau RA. Systematic review: acute liver failure -- one disease, more than 40 definitions. Alimentary Pharmacology and Therapeutics. 2012; 35(11):1245-1256.
    2. Escorsell A, Mas A, de la Mata M. Acute liver failure in Spain: analysis of 267 cases. Liver Transplantation. 2007; 13(10):1389-1395.
    3. Kumar R, Shalimar, Bhatia V, et al. Antituberculosis therapy-induced acute liver failure: magnitude, profile, prognosis, and predictors of outcome. Hepatology. 2010; 51(5):1665-1674.
    4. Lescot T, Karvellas C, Beaussier M, Magder S. Acquired liver injury in the intensive care unit. Anesthesiology.2012; 117(4):898-904.
    5. Henrion J. Hypoxic hepatitis. Liver International. 2012;32(7):1039-1052.
    6. Jalan R, Olde Damink SW, Deutz NE, Hayes PC, Lee A. Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension. Gastroenterology. 2004; 127(5):1338-46.
    7. Lidofsky SD, Bass NM, Prager MC, et al. Intracranial pressure monitoring and liver transplantation for fulminant hepatic failure. Hepatology. 1992; 16(1):1-7.
    8. Detry O, Arkadopoulos N, Ting P, et al. Intracranial pressure during liver transplantation for fulminant hepatic failure. Transplantation. 1999; 67(5):767-70.
    9. Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology. 2005; 41(5):1179-97.
    10. Stravitz RT, Kramer AH, Davern T, et al. Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group. Critical Care Medicine. 2007; 35(11):2498-508.
    11. Bernal W. Intensive care support therapy. Liver Transpl. 2003; 9(9):15-7.
    12. Jalan R. Acute liver failure: current management and future prospects. Journal of Hepatology. 2005; 42(1):115-23.

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    Media References

    1. Marburg virus liver injury, Public Domain

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