Acute Liver Disease and Acute Liver Failure

Acute Liver Disease and Acute Liver Failure (Part 2)

Learning Outcomes

• Describe the causes and clinical features of acute liver failure.

• Describe the differential diagnosis of acute liver failure.

• Understand the primary and secondary causes of acute liver failure and when urgent liver transplantation might be indicated.

Definition and Key Features of Acute Liver Failure (ALF)

• Definition: Rapid deterioration of liver function characterized by coagulopathy and hepatic encephalopathy in an individual with no pre-existing liver disease. It represents a severe acute liver injury.

• Previously Normal Liver: This condition occurs in a person who previously had normal liver function.

• Key Features:

  • Severe Acute Liver Injury: No underlying chronic liver disease.

  • Elevated Transaminases: Indicating significant liver cell damage.

  • Impaired Liver Function: Evidenced by:

    • Coagulopathy: Impaired blood clotting, often reflected by a prolonged International Normalized Ratio (INR).

    • Encephalopathy: Brain dysfunction due to liver failure.

• Forms of ALF:

  • Hyperacute: Encephalopathy develops within $7$ days of the onset of jaundice. This form is typically associated with paracetamol (acetaminophen) overdose.

  • Acute: Encephalopathy develops within $28$ days of jaundice onset.

  • Subacute: Encephalopathy develops within $12$ weeks of jaundice onset. This form is often seen in cases of hepatitis B flares or drug-induced liver injury.

• Medical Emergency: ALF is a serious medical emergency requiring prompt recognition and immediate, effective management in any healthcare or community setting.

Principal Causes of Acute Liver Failure

• Viruses:

  • Most Common: Hepatitis B virus.

  • Significant in Specific Regions: Hepatitis A and Hepatitis E (particularly in parts of the world like India, Bangladesh, and Pakistan, where Hepatitis E is a significant cause, especially in young pregnant women).

  • Rarely a Cause: Hepatitis C virus.

  • Less Frequent: Cytomegalovirus (CMV), Herpes Simplex Virus (HSV), Varicella-Zoster Virus (VZV), or Dengue virus.

• Toxins:

  • Highly Topical: Amanita phalloides (death cap mushroom) poisoning is a well-recognized cause.

• Drugs (Most Common Etiology Overall):

  • Leading Cause (e.g., Australia): Paracetamol (acetaminophen) overdose, accounting for over $50\%$ of cases in Australia. Always suspect paracetamol overdose until another cause is identified.

  • Other Drugs: Anti-tuberculous medications, chemotherapy agents, statins (rarely), nonsteroidal anti-inflammatory drugs (NSAIDs), phenytoin, carbamazepine, ecstasy, flucloxacillin, and increasingly, various herbal, dietary, and weight loss supplements.

• Vascular Disorders:

  • Hypoxic or Ischemic Hepatitis: Liver injury due to reduced oxygen supply.

  • Budd-Chiari Syndrome: Occlusion of the hepatic veins, impairing blood outflow from the liver.

• Pregnancy-Related:

  • Preeclampsia: A hypertensive disorder of pregnancy, sometimes associated with liver rupture.

  • HELLP Syndrome: Hemolysis, elevated liver enzymes, low platelet count.

  • Acute Fatty Liver of Pregnancy (AFLP): A rare but severe complication.

• Other Causes:

  • Wilson's Disease: A genetic disorder of copper metabolism that can present fulminantly.

  • Autoimmune Hepatitis: An immune system attack on liver cells.

  • Infiltrative Diseases: Such as lymphoma or other malignancies infiltrating the liver.

  • Hemophagocytic Lymphohistiocytosis (HLH): A severe systemic inflammatory syndrome.

Global Epidemiology of ALF Causes

• The causes of ALF vary significantly worldwide.

• United Kingdom and Australia: Acetaminophen/paracetamol accounts for over $50\%$ of ALF cases.

• India, Bangladesh, Pakistan: Hepatitis E is responsible for a significant proportion of ALF, especially in young women during pregnancy.

Clinical Features of Acute Liver Failure

ALF affects the entire body due to the liver's central role in metabolism and detoxification.

• Central Nervous System (CNS):

  • Hepatic Encephalopathy (HE): Impaired brain function.

  • Cerebral Edema and Intracranial Hypertension (ICH): Swelling of the brain and increased pressure within the skull. Historically, ICH was the leading cause of death in ALF, but neuroprotective treatments have significantly reduced mortality from this complication, though it still occurs.

• Respiratory System:

  • Acute Lung Injury (ALI) / Acute Respiratory Distress Syndrome (ARDS): Severe lung inflammation.

• Cardiovascular System:

  • High Output State: Patients often have high cardiac output.

  • Myocardial Injury: Rare, but can be problematic in patients with pre-existing heart disease.

• Metabolic Dysfunction (Directly due to Liver Failure):

  • Hypoglycemia: Reduced gluconeogenesis leads to low blood sugar.

  • Lactic Acidosis: Reduced lactate clearance results in accumulation of lactic acid.

  • Hyperammonemia: Reduced ammonia clearance leads to high blood ammonia levels (a key feature often monitored).

  • Impaired Synthetic Capacity: Manifests primarily as coagulopathy with a significantly prolonged INR and individual clotting factors.

• Pancreas:

  • Pancreatitis: Inflammation of the pancreas, which can be challenging to diagnose in the setting of ALF, particularly with paracetamol overdose.

• Adrenal Glands: May be affected.

• Kidneys:

  • Kidney Dysfunction and Failure: Very common.

• Bone Marrow:

  • Bone Marrow Suppression: Can occur.

  • Aplastic Anemia: Especially common in children with ALF, often thought to be related to the viral etiology.

• Portal Hypertension (especially in subacute ALF):

  • Manifestations like ascites (fluid accumulation in the abdomen) and splenomegaly (enlarged spleen) can develop rapidly within months.

• Systemic Inflammatory Response Syndrome (SIRS):

  • Patients often present with signs mimicking sepsis (fever, tachycardia, hypotension), and a high white cell count, even in the absence of documented infection. This 'sepsis-like' presentation requires careful differentiation from true sepsis.

Assessment and Management of Acute Liver Failure

• Determine Etiology: This is paramount as the underlying cause dictates specific treatments, informs prognosis, and guides the decision-making process for liver transplantation.

• Classification of Causes:

  • Primary Causes of ALF: These are conditions where the primary insult is directly to the liver, leading to failure in a previously healthy liver. This category generally includes:

    • Drug-related (e.g., paracetamol overdose).

    • Acute viral hepatitis.

    • Toxin-induced (e.g., mushroom poisoning).

  • Chronic Liver Disease Presenting as Fulminant ALF: In some cases, a patient may have undiagnosed or asymptomatic chronic liver disease that suddenly decompensates in a fulminant manner, clinically resembling ALF. Examples include:

    • Fulminant presentations of Wilson's disease.

    • Autoimmune liver disease.

    • Budd-Chiari syndrome.

    • Reactivation of quiescent chronic Hepatitis B (e.g., triggered by chemotherapy).

  • Extrahepatic or Secondary Liver Causes / Acute on Chronic Liver Failure (ACLF): These involve an acute liver injury occurring in the context of other systemic diseases or pre-existing chronic liver failure, or when the primary insult is not directly to the liver but affects it secondarily. Examples include:

    • Hypoxic or ischemic hepatitis (due to severe systemic hypoperfusion).

    • Underlying systemic diseases (as previously outlined).

    • Liver failure following liver resection for liver cancer, if insufficient remnant liver tissue remains.

    • Alcoholic hepatitis in the setting of long-term alcohol use.

• Consideration for Emergency Liver Transplantation:

  • Indications (often in green on diagrams): Generally considered for primary causes of ALF (drug-related, acute viral hepatitis, toxin-induced). Increasingly, it is also being considered for severe alcoholic hepatitis.

  • Contraindications (often in red on diagrams): For extrahepatic or secondary causes, there is typically no indication for emergency liver transplantation.

  • Exceptional Cases: Liver transplantation may be considered for patients who develop liver failure after liver resection, particularly if the resected tumor was small and potentially curable.

• Differential Diagnosis: The diagnostic process relies heavily on clinical features.

  • Positive Diagnosis Possible For: Paracetamol-related ALF, acute Budd-Chiari, Wilson's disease, mushroom poisoning, and autoimmune hepatitis.

  • Malignant Infiltration: If a patient presents with massive hepatomegaly alongside acute liver failure, malignant infiltration is a significant concern. In such cases, a liver biopsy is invariably performed to establish a diagnosis.

Conclusion

• Etiology is Key: A thorough understanding of the cause of ALF is critical for determining the pathogenesis, predicting the likelihood of recovery, and making appropriate decisions regarding liver transplantation.

• Primary vs. Secondary Causes: Distinguishing between primary and secondary causes is important as some secondary causes may be absolute contraindications to liver transplantation.

• Transplantation Access: While liver transplantation is a life-saving option for indicated ALF patients (e.g., in Australia), it may not be available in many parts of the world. In Australia, most patients with an indication for transplant receive one.