Acute Liver Failure Differential Diagnosis: A Comprehensive Guide

Introduction

Acute liver failure (ALF) represents a critical clinical syndrome characterized by rapid deterioration of liver function in individuals without pre-existing chronic liver disease. This condition, developing over a period of weeks to less than 26 weeks, is marked by hepatic encephalopathy and impaired hepatic synthetic function, typically indicated by an international normalized ratio (INR) of 1.5 or greater. While ALF is relatively rare, it carries significant morbidity and mortality, necessitating prompt recognition, comprehensive evaluation, and intensive management. The advancements in intensive care and liver transplantation have significantly improved survival rates in recent years, underscoring the importance of early referral to specialized liver centers.

Effective management of ALF hinges on a high degree of clinical suspicion, timely referral to a liver transplant center, and robust supportive care. Continued research into the underlying mechanisms of liver injury and the management of multi-organ failure holds promise for further enhancing patient outcomes. A crucial aspect of managing ALF is establishing an accurate diagnosis, which begins with a thorough consideration of the differential diagnoses.

Etiology of Acute Liver Failure

Identifying the underlying cause of ALF is paramount as it directs specific therapies and influences prognosis. A broad range of factors can precipitate ALF, with viral hepatitis and drug-induced liver injury being the most prevalent globally. Other notable etiologies include ischemic hepatopathy, acute Budd-Chiari syndrome, veno-occlusive disease, Wilson’s disease, amanita mushroom poisoning, sepsis, autoimmune hepatitis, acute fatty liver of pregnancy (AFLP), HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), heatstroke, and liver infiltration by malignancies (such as metastases from breast cancer, small cell lung cancer, and lymphoma).

Drug-induced liver injury (DILI) is a leading cause of ALF in developed nations, with acetaminophen (paracetamol) overdose being the most frequent culprit. Acetaminophen toxicity is typically dose-dependent, although idiosyncratic reactions can occur, albeit less commonly. Unintentional acetaminophen overdose leading to ALF is more often observed in individuals with chronic alcohol use and malnutrition.

Viral hepatitis remains a significant cause of ALF worldwide, particularly in developing countries. Hepatitis A and E viruses are frequently implicated. Hepatitis B can trigger ALF through acute infection or reactivation, especially in immunosuppressed individuals. While hepatitis C alone rarely causes ALF, co-infection with hepatitis B and C can increase the risk. Other viruses associated with ALF include herpes simplex virus (HSV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), parvoviruses, adenovirus, and varicella-zoster virus (VZV).

Epidemiology of Acute Liver Failure

The distribution of ALF etiologies varies considerably between developed and developing countries. In developing nations, viral hepatitis, particularly hepatitis A, B, and E, predominates as the primary cause. Conversely, drug-induced liver injury, especially acetaminophen toxicity, is more commonly observed in developed countries. Epidemiological trends over the past half-century indicate a decline in ALF cases due to hepatitis A and B, while acetaminophen-related ALF has risen, particularly in the United States and Western Europe. This shift underscores the changing landscape of ALF etiologies and highlights the ongoing importance of public health measures to address both viral hepatitis and medication safety.

Pathophysiology of Acute Liver Failure

The pathophysiological mechanisms in ALF are diverse and depend on the underlying cause. However, the majority of ALF cases, excluding conditions like acute fatty liver of pregnancy and Reye’s syndrome, are characterized by massive hepatocyte necrosis and/or apoptosis, culminating in liver failure. Hepatocyte necrosis is often triggered by ATP depletion, leading to cellular swelling and disruption of cell membranes.

Hepatic encephalopathy and cerebral edema, severe complications of ALF, arise from complex, multifactorial processes. These include alterations in the blood-brain barrier (BBB) due to inflammatory mediators, which activate microglia. Ammonia crossing the BBB leads to glutamine accumulation and subsequent oxidative stress, depleting ATP and GTP. This cascade of events ultimately results in astrocyte swelling and cerebral edema. Understanding these intricate pathways is crucial for developing targeted therapeutic strategies to mitigate the neurological consequences of ALF.

Histopathology in Diagnosing Acute Liver Failure

Histopathological examination via liver biopsy is typically reserved for cases where the etiology of ALF remains unclear after thorough clinical assessment, laboratory investigations, and imaging studies. Transjugular liver biopsy may be performed in such situations to ascertain the specific cause of ALF.

In viral hepatitis-induced ALF, histological findings often include inflammatory cell infiltration (neutrophils and lymphocytes) and hepatic necrosis, particularly prominent in herpes simplex hepatitis. Histology is especially valuable in diagnosing infiltrative conditions like malignancies and lymphomas. Special stains for hepatitis B, CMV, EBV, adenovirus, and herpes simplex, along with immunohistochemical stains, can further aid in etiological diagnosis.

History and Physical Examination for Acute Liver Failure

A detailed patient history is indispensable for identifying potential causes of ALF. Pertinent information to gather from the patient, family members, or medical records includes:

• Prior liver disease: History of any pre-existing liver conditions or decompensation.
• Comorbidities: Presence of other relevant chronic health issues.
• Symptom timeline: Detailed chronology of presenting symptoms, especially crucial in acetaminophen toxicity.
• Risk factors: Toxic habits or high-risk behaviors.
• Medication and toxin exposure: Recent medications, including herbal products, or exposure to hepatotoxins.
• Family history: Inquiry about Wilson’s disease and thrombotic disorders.
• Recent surgeries: Consideration of anesthetic agents as potential etiologies.

Physical examination may reveal hypotension, altered mental status, fever (suggesting infectious etiology), right upper quadrant pain or discomfort, tenderness, nausea, jaundice, and signs of fluid overload. These findings, while non-specific, contribute to the overall clinical picture and guide further diagnostic and therapeutic steps.

Evaluation of Acute Liver Failure

Laboratory evaluation in ALF typically reveals a prolonged INR (≥ 1.5), elevated bilirubin and aminotransferases, thrombocytopenia, anemia, hypoglycemia, elevated ammonia levels, and signs of acute kidney injury (elevated serum creatinine) and electrolyte imbalances (hypokalemia, hypophosphatemia).

Imaging studies of the abdomen, pelvis, brain, and chest are often necessary. Abdominal imaging is essential to exclude pre-existing cirrhosis, portal hypertension, hepatocellular carcinoma, vascular thrombosis, lymphadenopathy, and splenomegaly. Doppler ultrasound of the abdomen can be useful in patients with renal injury and suspected vascular thrombosis. Brain imaging (CT or MRI) helps to rule out structural causes of altered mental status, while chest imaging can detect pulmonary edema or pneumonia.

Treatment and Management Strategies for Acute Liver Failure

The management of ALF is multifaceted, encompassing supportive care, prevention and management of complications, etiology-specific treatment, and assessment of prognosis and need for liver support, potentially including liver transplantation. Ideally, patients should be managed in a hospital with liver transplant facilities and expertise.

Supportive and Preventive Care:

1. Hemodynamic stabilization: Assess and manage hemodynamic instability with intravenous fluids, correction of acid-base imbalances, and electrolyte abnormalities. Vasopressors may be needed to maintain a mean arterial pressure ≥ 75 mm Hg to ensure adequate renal and cerebral perfusion.
2. Bleeding risk management: Monitor hematocrit for bleeding, given coagulopathy and impaired platelet function. Blood product transfusions (platelets, fresh frozen plasma) are indicated for active bleeding or before invasive procedures. Proton pump inhibitors are typically administered for gastrointestinal bleed prophylaxis.
3. Infection control: Investigate fever with blood and urine cultures and initiate empirical antibiotics as needed.
4. Hepatic encephalopathy management: Closely monitor for hepatic encephalopathy and protect the airway (aspiration risk), potentially requiring intubation in worsening encephalopathy. Implement protocols to prevent cerebral edema.
5. Nutritional support: Provide adequate nutrition with 1.0 to 1.5 g protein/kg/day.
6. Glucose control: Monitor for hypoglycemia and maintain blood glucose between 160-200 mg/dL.
7. Medication review: Discontinue non-essential home medications.

Etiology-Specific Treatment:

• Acetaminophen toxicity: Activated charcoal (if within 4 hours of ingestion) and prompt N-acetylcysteine (NAC) administration are indicated. NAC is also beneficial in ALF from other causes, especially with early encephalopathy.
• Hepatitis A and E: Supportive care as no specific antiviral therapies are effective.
• Hepatitis B: Nucleos(t)ide analogs for acute or reactivation of hepatitis B.
• Autoimmune hepatitis: Intravenous methylprednisolone (e.g., 60 mg/day) may be beneficial.
• Amanita phalloides poisoning: Gastric lavage, activated charcoal, and intravenous penicillin G (1 g/kg/day) may be used.
• Herpes simplex and varicella-zoster virus hepatitis: Acyclovir (5-10 mg/kg IV q8h).
• Cytomegalovirus hepatitis: Intravenous ganciclovir (5 mg/kg IV q12h).
• Acute fatty liver of pregnancy/HELLP: Prompt delivery of the fetus is recommended, with consideration for liver transplantation if ALF persists.
• Wilson’s disease/Hepatic vein thrombosis: Liver transplantation should be considered. Budd-Chiari syndrome may warrant TIPS placement and anticoagulation.

Management of Complications:

• Renal failure: Manage with vasopressors (norepinephrine or dopamine) for hypotension. Renal replacement therapy (continuous renal replacement therapy preferred in critically ill patients) may be a bridge to liver transplant.
• Sepsis: Broad-spectrum antibiotics for suspected sepsis, including aspiration pneumonia. Surveillance cultures are essential.
• Metabolic disorders: Manage hypoglycemia with glucose infusions, hypophosphatemia with phosphate repletion. Address alkalosis and acidosis. Hypoxemia may require intervention. Seizures can be treated with phenytoin or benzodiazepines.
• Cerebral edema: Implement measures to reduce intracranial pressure (ICP) and maintain cerebral perfusion pressure (CPP), including head elevation, sedation, hyperventilation, mannitol, and potentially ICP monitoring.
• Encephalopathy: Head CT to rule out intracranial bleeding/edema in grade 3 or higher encephalopathy.
• Coagulopathy: Routine correction is not recommended unless active bleeding or before procedures. Transfusions may be needed. Vitamin K may be considered in suspected nutritional deficiency or cholestasis.

Liver Support and Transplantation:

Liver transplantation is a critical option for selected ALF patients. While extracorporeal liver-assist devices have been explored, they have not demonstrated survival benefit in clinical trials. Liver transplantation criteria exist to guide patient selection, though no single criterion is universally accepted. Patients with ALF, particularly those with fulminant Wilson’s disease, may receive high priority for liver transplantation. Contraindications include multiorgan failure, severe cardiopulmonary disease, septic shock, extrahepatic malignancy, irreversible brain injury, severe thrombotic disorder, active substance abuse, multiple suicide attempts, and lack of social support.

Differential Diagnosis of Acute Liver Failure

Establishing a differential diagnosis for acute liver failure is crucial for prompt and accurate management. Many conditions can mimic or contribute to the clinical presentation of ALF, necessitating careful consideration to ensure appropriate diagnostic and therapeutic strategies are implemented. The differential diagnosis for ALF includes:

• Acute Fatty Liver of Pregnancy (AFLP): A condition specific to pregnancy, typically presenting in the third trimester, characterized by microvesicular steatosis and liver dysfunction. It often overlaps with HELLP syndrome but can occur independently. Clinical features include nausea, vomiting, abdominal pain, jaundice, and encephalopathy. Prompt delivery is critical.

• Amanita phalloides Mushroom Poisoning: Ingestion of these toxic mushrooms leads to severe hepatotoxicity due to amatoxins and phallotoxins. Symptoms typically develop 6-24 hours post-ingestion and include gastrointestinal distress followed by liver failure. Early recognition and treatment with activated charcoal, silibinin, and potentially liver transplantation are crucial.

• Bacillus cereus Toxin-Induced Liver Failure: While primarily known for causing food poisoning with diarrheal or emetic syndromes, certain toxins produced by Bacillus cereus can rarely induce severe liver injury and even acute liver failure, particularly in the emetic form linked to cereulide toxin.

• Hereditary Fructose Intolerance: This metabolic disorder, caused by a deficiency in fructose-1-phosphate aldolase, can lead to liver failure in infants and children upon fructose ingestion. Symptoms include vomiting, jaundice, hepatomegaly, and hypoglycemia. Dietary fructose restriction is the mainstay of treatment.

• Galactosemia: Another inherited metabolic disorder, galactosemia, resulting from defects in galactose metabolism, can cause liver failure in neonates. Symptoms include jaundice, hepatomegaly, feeding difficulties, and developmental delay. Diagnosis and galactose-free diet initiation are critical.

• HELLP Syndrome (Hemolysis, Elevated Liver Enzymes, Low Platelets) of Pregnancy: A severe complication of pregnancy, usually associated with pre-eclampsia, HELLP syndrome involves hemolysis, elevated liver enzymes, and thrombocytopenia. Liver involvement can range from mild to severe, rarely progressing to ALF. Delivery is the definitive treatment.

• Hemorrhagic Viral Fevers (Ebola, Lassa, Marburg Viruses): These viral infections can cause severe systemic illness with multi-organ involvement, including liver failure. They are characterized by fever, bleeding, and high mortality rates. Diagnosis is based on travel history, clinical presentation, and specific virological tests.

• Idiopathic Drug-Induced Liver Injury (Idiosyncratic DILI): A subset of DILI where the mechanism is not dose-dependent and is thought to involve individual susceptibility factors. Many drugs have been implicated. Diagnosis is often by exclusion after ruling out other causes.

• Neonatal Hemochromatosis (Neonatal Iron Storage Disease): A rare but severe condition of iron overload in newborns leading to rapid liver failure. The etiology is complex and may involve gestational alloimmune liver disease. Exchange transfusion and antioxidant therapy may be used, and liver transplantation can be life-saving.

• Tyrosinemia Type 1: An inherited metabolic disorder caused by fumarylacetoacetate hydrolase (FAH) deficiency, leading to tyrosine accumulation and liver damage, potentially progressing to ALF in infancy. Diagnosis and treatment with nitisinone and dietary management are crucial. Liver transplantation may be necessary.

Distinguishing ALF from acute-on-chronic liver failure (ACLF) is also important. ACLF occurs in patients with pre-existing chronic liver disease who experience a sudden decompensation. While the clinical presentations may overlap, the underlying liver status and prognosis differ significantly.

Prognosis of Acute Liver Failure

The prognosis of ALF has significantly improved over the past 50 years. Current 1-year survival rates, including patients undergoing liver transplantation, exceed 65%. Registry data from the US and Europe indicate survival rates as high as 79% at 1 year and 72% at 5 years post-transplant.

Prognostic criteria, such as the King’s College Criteria for acetaminophen-induced and non-acetaminophen ALF, and the Clichy criteria (hepatic encephalopathy, factor V level <20-30%, MELD score >30, APACHE II score >15), help assess disease severity and predict outcomes. These criteria aid in identifying patients who may benefit from liver transplantation.

Pearls and Other Issues in Acute Liver Failure

Patients with fulminant Wilson’s disease and ALF are prioritized for liver transplantation in the United States, receiving Status 1A designation due to their high mortality risk without transplantation. Contraindications to liver transplantation in ALF include advanced multiorgan failure, severe cardiopulmonary disease, uncontrolled sepsis, extrahepatic malignancy, irreversible brain injury, severe thrombotic disorders, active substance abuse, recurrent suicide attempts, and inadequate social support.

Enhancing Healthcare Team Outcomes in Acute Liver Failure Management

Given the complexity of ALF and its diverse etiologies, optimal management necessitates a collaborative, interprofessional team. This team ideally includes dietitians, hematologists, liver specialists (hepatologists), gastroenterologists, surgeons, radiologists, pathologists, and intensivists.

Effective management involves supportive care, complication prevention, etiology-specific treatment, and timely consideration of liver transplantation. Pharmacists play a crucial role in medication management, ensuring avoidance of hepatotoxic drugs and monitoring for drug interactions. Prompt consultation with relevant specialists is essential to address the wide range of complications that can arise. Liver transplantation or extracorporeal liver support may be beneficial in selected patients.

The prognosis in ALF is influenced by the underlying cause, the extent of liver damage, comorbidities, treatment response, patient age, and the degree of multi-organ involvement. A coordinated, multidisciplinary approach is critical to optimize outcomes in this challenging condition.

Review Questions

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References

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1.Ramachandran A, Jaeschke H. Acetaminophen Hepatotoxicity. Semin Liver Dis. 2019 May;39(2):221-234. [PMC free article: PMC6800176] [PubMed: 30849782]

2.Lima LCD, Miranda AS, Ferreira RN, Rachid MA, Simões E Silva AC. Hepatic encephalopathy: Lessons from preclinical studies. World J Hepatol. 2019 Feb 27;11(2):173-185. [PMC free article: PMC6393717] [PubMed: 30820267]

3.Chauhan A, Webb G, Ferguson J. Clinical presentations of Hepatitis E: A clinical review with representative case histories. Clin Res Hepatol Gastroenterol. 2019 Nov;43(6):649-657. [PMC free article: PMC6864596] [PubMed: 30808575]

4.Mattos ÂZ, Mattos AA. Letter to the Editor: Acute-on-Chronic Liver Failure: Conceptual Divergences. Hepatology. 2019 Sep;70(3):1076. [PubMed: 30864173]

5.Sundaram V, Jalan R, Wu T, Volk ML, Asrani SK, Klein AS, Wong RJ. Factors Associated with Survival of Patients With Severe Acute-On-Chronic Liver Failure Before and After Liver Transplantation. Gastroenterology. 2019 Apr;156(5):1381-1391.e3. [PubMed: 30576643]

6.Ambrocio GPL, Aguado S, Carrillo J, Laporta R, Lazaro-Carrasco M, Avellon A, Aran-Toha G, Ussetti M, Aguilar M. Hepatitis E Virus Infection in Lung Transplant Recipients: A Case Series. Transplant Proc. 2019 Mar;51(2):376-379. [PubMed: 30879545]

7.Axley P, Ahmed Z, Arora S, Haas A, Kuo YF, Kamath PS, Singal AK. NASH Is the Most Rapidly Growing Etiology for Acute-on-Chronic Liver Failure-Related Hospitalization and Disease Burden in the United States: A Population-Based Study. Liver Transpl. 2019 May;25(5):695-705. [PubMed: 30861321]

8.Colaci CS, Mendizabal M, Bessone F. Idiosyncratic Drug-Induced Acute Liver Failure: A Challenging and Distressing Scenario. Curr Drug Saf. 2019;14(2):94-101. [PubMed: 30767751]

9.Hirode G, Vittinghoff E, Wong RJ. Increasing Burden of Hepatic Encephalopathy Among Hospitalized Adults: An Analysis of the 2010-2014 National Inpatient Sample. Dig Dis Sci. 2019 Jun;64(6):1448-1457. [PubMed: 30863953]

10.Plauth M, Bernal W, Dasarathy S, Merli M, Plank LD, Schütz T, Bischoff SC. ESPEN guideline on clinical nutrition in liver disease. Clin Nutr. 2019 Apr;38(2):485-521. [PMC free article: PMC6686849] [PubMed: 30712783]

11.Artzner T, Michard B, Besch C, Levesque E, Faitot F. Liver transplantation for critically ill cirrhotic patients: Overview and pragmatic proposals. World J Gastroenterol. 2018 Dec 14;24(46):5203-5214. [PMC free article: PMC6295835] [PubMed: 30581269]

12.Kandiah PA, Subramanian RM. Extracorporeal Devices. Crit Care Clin. 2019 Jan;35(1):135-150. [PubMed: 30447776]

13.Cao D, Li DJ, Wang Y, Zhang YH, Chen LY, Wang LC. [Clinical significance of CTP combined with ABIC score in predicting the short-term prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure]. Zhonghua Gan Zang Bing Za Zhi. 2019 Feb 20;27(2):118-122. [PubMed: 30818916]

14.Ferreira Cardoso M, Alexandrino G, Carvalho E Branco J, Anapaz V, Carvalho R, Horta D, Martins A. The impact and evolution of acute-on-chronic liver failure in decompensated cirrhosis: A Portuguese single-center study. Gastroenterol Hepatol. 2019 May;42(5):296-303. [PubMed: 30772084]

15.Sakpal SV, Agarwal SK, Saucedo-Crespo H, Auvenshine C, Santella RN, Donahue S, Steers J. Transplant Critical Care: Is there a Need for Sub-specialized Units? – A Perspective. J Crit Care Med (Targu Mures). 2018 Jul;4(3):83-89. [PMC free article: PMC6294987] [PubMed: 30582000]

16.Sarin SK, Choudhury A. Management of acute-on-chronic liver failure: an algorithmic approach. Hepatol Int. 2018 Sep;12(5):402-416. [PubMed: 30116993]

Disclosure: Niraj Shah declares no relevant financial relationships with ineligible companies.

Disclosure: Amor Royer declares no relevant financial relationships with ineligible companies.

Disclosure: Savio John declares no relevant financial relationships with ineligible companies.