Etiology of Acute Liver Failure Can Yield Surprising Findings

liver affected by cirrhosis and hepatitis
liver affected by cirrhosis and hepatitis
Before the advent of potent antiviral agents, liver transplantation was the only treatment option for patients with hepatitis and a poor prognosis; antiretrovirals can now provide a potentially curative approach.

Acute liver failure (ALF) has a wildly variable course of sequelae. The American Association for the Study of Liver Disease (AASLD) defines it as loss of liver function with evidence of encephalopathy and coagulopathy (international normalized ratio [INR] ≥1.5) with no preexisting cirrhosis or chronic symptoms for >26 weeks.1,2

Much of ALF etiology depends on geography. In the United States, the United Kingdom, Australia, and Northern Europe, drug-induced liver injury (DILI) accounts for >50% of all ALF cases, with nearly half due to acetaminophen intake. 2 Other causes of ALF are attributed to indeterminate sources, hepatitis B, autoimmune hepatitis, and pregnancy-related liver failure. 2 In developing countries, viral hepatitis is responsible for many cases of ALF, with hepatitis A and E frequently implicated.2

Knowing the etiology of ALF is critical for effective treatment and improved prognosis. With hepatitis B virus (HBV) infection, which is now increasingly reactivated after a course of chemotherapy, patients can receive antiretroviral agents to combat the HBV. Before the advent of potent antivirals, liver transplantation was the only treatment option for those with poor prognoses. 2 In some instances, the liver can completely heal itself, but it is difficult to predict which patients will survive ALF. 2

Surprising Viral Sources of ALF

Hepatitis A Virus (HAV). While HAV is not responsible for chronic liver disease, it can cause a mild to severe liver injury. Owing to widespread vaccination in developed countries, HAV is more common in areas with contaminated water.2 In the United States, <1% of ALF cases are linked to HAV.2 Though HAV-caused ALF has a spontaneous recovery rate of 69%, those with severe cases either need urgent liver transplantation or die.2   

Hepatitis B Virus (HBV). HBV causes both acute and chronic liver disease. Adults with chronic disease are usually asymptomatic.2 In many parts of the world, including Asia, perinatal transmission is common.2 Rates of reactivation of HBV are increasing in patients who have undergone chemotherapy or received other immunosuppressant therapies. The AASLD recommends prophylactic nucleoside analog therapy for such patients to prevent reactivation, especially if they test positive for the hepatitis B surface antigen.2 Transplant-free survival rates for HBV-related ALF ranges from 26% to 53%.2  

Hepatitis C Virus (HCV). HCV by itself does not cause ALF, but the chronic condition does raise transaminase levels significantly and can result in hepatic damage.

Hepatitis D Virus (HDV). The rare occurrence of HDV depends on coinfection with HBV because it has just a single protein, the circular RNA strand.1,2 When HBV-HDV coinfection occurs, ALF rates can be as high as 20%. No HDV-specific therapy exists, but it does help to know if there is a coinfection because patients can deteriorate even after an initial recovery.2

Hepatitis E Virus (HEV). The prevalence of HEV is increasing in industrialized countries. What was once considered a rare cause of ALF is being recognized as an overlooked contributor. Researchers estimate the seroprevalence of HEV between 16% and 20% in developed countries.2 In tropical regions, poor hygiene and contaminated water contribute to HEV, while in industrialized countries, zoonotic transmission, especially via consumption of pork products, is a common route.3 There is no commercially available diagnostic test for HEV in the United States; therefore, clinicians must rely on specialty laboratories to ascertain the disease.

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In a 68-study meta-analysis (N=84,257 patients), Horvatits and colleagues were surprised to find that the prevalence of HEV was higher in the United States than in South America and the Caribbean (odds ratio [OR], 1.82; 95% CI, 1.06-3.08; P=.03; OR, 0.67; 95% CI, 0.45-0.98; P=.04; OR, 8.33; 95% CI, 1.15-81.61; P=.04, respectively).3  The meta-analysis of the Americas found that HIV, occupational exposure to pigs and wild animals, and chronic illness were likely contributors to HEV.3  

“The anti-HEV seroprevalence seems to be higher than previously expected, as shown in our study,” said lead author Thomas Horvatits, MD, from the University Medical Center Hamburg-Eppendorf in Hamburg, Germany, in an interview with Infectious Disease Advisor. “At present in the US there is no commercial easy-to-use (and FDA-approved) anti-HEV assay available. Therefore, screening and diagnosis of HEV is mainly performed in specialized laboratories. All patients with clinical signs and laboratory patterns of acute hepatitis, but also cases of unclear acute or chronic liver failure, should be tested for HEV. A combination of serology (IgG and IgM) as well as nucleic acid amplification testing is recommended.”

Other ALF Etiologies

A small subset of ALF in developed countries is caused by autoimmune hepatitis (AIH), amounting to approximately 5% of the ALF population.4 In a retrospective study of 52 patients (mean age, 43.6 years; female, 84.6%), Buechter and colleagues found that the primary characteristics of this enigmatic disease include female sex and presence of the human leukocyte antigen HLA-DR and auto-antibodies. Of the triggering factors implicated in AIH, nonsteroidal anti-inflammatory drugs  and antibiotics dominated, followed by previous surgery and nonhepatitis viral infections, such as Epstein-Barr virus and cytomegalovirus.4   

While some of the patients spontaneously recovered, 17.3% died or needed a liver transplant within 28 days of presentation.4 Risk factors for a poor prognosis included older age, higher MELD score, and higher creatinine levels.4  

“Clinicians should monitor patients with autoimmune hepatitis by treating the patients with steroids and azathioprine, checking liver enzymes, determine IgG level, and performing ultrasound of the liver once a year,” advised co-author Alisan Kahraman, MD, associate professor of medicine and head of the gastroenterological polyclinic at University Hospital Essen in Germany, in an interview with Infectious Disease Advisor.

Summary and Clinical Applicability

Viral hepatitis contributes to a substantial proportion of ALF cases worldwide. The key to treatment is determining the cause of the viral infection as viruses such as HBV can be managed with nucleotide or nucleoside analog therapy. Before the advent of potent antivirals, liver transplantation was the only treatment option.


  1. Sedhom D, D’Souza M, John E, Rustgi V. Viral hepatitis and acute liver failure: still a problem. Clin Liver Dis. 2018;22(2):289-300.
  2. Manka P, Verheyen J, Gerken G, Canbay A. Liver failure due to acute viral hepatitis (A-E).Visc Med. 2016;32(2):80-85.
  3. Horvatits T, Ozga A-K, Westhölter D, et al. Hepatitis E seroprevalence in the Americas: a systematic review and meta-analysis [published online April 16, 2018]. Liver Int. doi: 10.1111/liv.13859
  4. Buechter M, Manka P, Heinemann FM. Potential triggering factors of acute liver failure as a first manifestation of autoimmune hepatitis-a single center experience of 52 adult patients. World J Gastroenterol. 2018;24(13):1410-1418.