Hepatitis E virus (HEV) is a major contributor to acute hepatitis worldwide. It is estimated to cause at least 20 million infections annually, leading to 3.4 million symptomatic cases and 70,000 deaths. This places a significant burden on health systems around the world [1-3]. While most acute hepatitis E cases are asymptomatic in healthy individuals, the infection can take a severe course in certain populations. Outbreaks of acute hepatitis E in low-income countries have been associated with cases of acute liver failure, with high morbidity and mortality rates, particularly among pregnant women [2-4]. In immunocompromised individuals, such as solid organ transplant recipients, acute HEV infection can progress to chronic infection with rapid development of cirrhosis [2,3]. Additionally, in chronic liver disease patients, HEV infection can lead to acute-on-chronic liver failure (ACLF).

In this review we aimed to focus on several aspects of acute HEV infection as a trigger for ACLF in patients with chronic liver disease, including its prevalence, mortality, diagnosis, pathogenesis, therapy, and prevention.

HEV belongs to the Hepeviridae family, a diverse group of viruses that infect mammals, birds, and fish. While HEV mainly targets the liver, it has also been found to infect other tissues, such as neuronal, kidney and placental tissue, which helps explain some of its extrahepatic manifestations.

HEV is a single positive-stranded RNA virus, 7.2 kb in size. The viral particles have a diameter of 27 to 34 nm. The virions are non-enveloped in faeces and bile, while in blood they circulate in a membrane-associated, quasi-enveloped configuration. The genome consists of three open reading frames (ORFs) encased by noncoding regions, a 5’ cap, and a poly-A tail. ORF1 encodes a non-structural polyprotein essential for viral replication, ORF2 encodes the viral capsid protein, and ORF3 is involved in the release of infectious virions from host cells [3]. HEV is divided into at least 8 different genotypes. HEV 1 to 4 mainly affect humans, HEV 5 and 6 are limited to wild boars, and HEV-7 and 8 infect dromedary and Bactrian camels. In rare cases, humans can be infected by HEV-7. Routes of transmission of the different HEV genotypes are summarized in Figure 1.

HEV genotypes show considerable variation in geographical distribution, modes of transmission, and disease progression. HEV-1 and HEV-2 are mainly spread through faecal-contaminated water, often due to incidents with water supply or natural disasters. These genotypes cause human disease in regions with inadequate sanitary infrastructure, such as parts of Asia (HEV-1), Africa (HEV-1 and HEV-2), and Mexico (HEV-2). In these areas, HEV is known to cause large outbreaks involving thousands or even tens of thousands of individuals, although sporadic cases also occur. Notably, no cases of chronic infection have been reported in relation to HEV-1 or HEV-2 (Fig. 1).

HEV-3 and HEV-4 infect mammalian species, particularly pigs and wild boars. Humans are mainly infected through foodborne zoonotic transmission after consuming undercooked or raw pork, game meat, or shellfish. HEV-3 is found worldwide, whereas HEV-4 is mainly limited to Southeast Asia, although it has also been detected in European pigs. In humans, HEV-3 and HEV-4 cause sporadic cases of acute viral hepatitis in high- and middle-income countries, with fewer cases occurring in low-income countries [5]. Most sporadic acute hepatitis E cases have been reported in Europe, particularly in Southwest France and England [3]. Acute HEV infections related to HEV-3 and HEV-4 can progress to chronic hepatitis and liver cirrhosis, especially in organ transplant recipients and immunocompromised individuals. In addition, HEV-3 has been associated with a risk of inducing extrahepatic manifestations, particularly neurological symptoms [6]. In patients with chronic liver disease, HEV superinfection can progress to ACLF [3].

The first cases of HEV superinfection in patients with chronic liver disease (CLD) were reported by Hamid et al. [7] in Pakistan in 2002. These authors documented 4 cases of HEV superinfection in patients with compensated cirrhosis who developed severe liver decompensation, one of whom died. The diagnosis was based on the presence of IgG anti-HEV, but HEV RNA and genotype were not determined. Overall, 41 of 233 (17.5%) CLD patients tested positive for HEV antibodies. This study was the first to show that HEV superinfection in patients with underlying CLD can cause severe hepatic decompensation, leading to increased morbidity and mortality.

Subsequently, several studies from HEV-endemic regions in Asia and Africa reported HEV infection as a major cause of ACLF in patients with compensated cirrhosis [8-24]. The largest study, from China, included 188 patients with chronic hepatitis B infection. Among the total, 136 had HEV superinfection and 52 had hepatitis A virus (HAV) superinfection [12]. The HEV group experienced a larger percentage of complications (94.9% vs. 61.5%, P<0.001), and liver failure (39.7% vs. 11.5%, P=0.002) compared to the HAV group. Furthermore, mortality was significantly higher in the HEV group (33.8% vs. 1.9%, P<0.001), indicating that chronic hepatitis B patients with HEV superinfection face more severe liver disease and a poorer prognosis than those with HAV superinfection.

Another large Asian study, performed in India [22], analysed 121 cases of ACLF. The precipitating cause of the condition was found to be HEV in 80 (61%) patients, HAV in 33 (27%), and a combination of both in 8 (6%). The underlying liver cirrhosis in these patients had several aetiologies, such as hepatitis B infection, alcohol consumption, Wilson’s disease, hepatitis C infection, autoimmune disorders, Budd-Chiari syndrome, hemochromatosis, and cryptogenic origins. The 3-month mortality rate for the cohort was 45%. On multivariate analysis, grades 3 and 4 hepatic encephalopathy (odds ratio [OR] 32.1), hyponatremia (OR 9.2), and renal failure (OR 16.8) were significant predictors of 3-month mortality.

Neither of these studies conducted in Asia reported data on HEV genotype. However, the epidemiology of HEV is changing in certain countries like China, where the previously dominant HEV genotype 1 has become less common, while zoonotic genotypes 3 and 4 are now the most prevalent [23]. A recent retrospective study from Taiwan by Tseng et al. [20] in patients with chronic hepatitis B infection found a similar percentage of HEV superinfection regardless of liver damage: 10 (2.4%) of 414 patients with cirrhosis and 46 (2.1%) of 2,123 without cirrhosis. However, the 1-year mortality rate after HEV superinfection was higher in patients who developed cirrhosis during follow-up compared to those who did not (50% vs. 2.4%, P=0.001) [20]. This is one of the few Asian studies reporting HEV genotype results. All patients were infected with HEV-4, in contrast to the presumed HEV-1 in previous Asian studies, which may have contributed to the lower ACLF rate.

In Europe, hepatitis E is primarily a zoonotic infection associated with swine and caused mainly by the HEV-3 strain. A prospective study at three United Kingdom centres and one in Toulouse (France) found that hepatitis E was present in a small percentage of patients with decompensated CLD. Among 343 such patients, 11 (3.2%) had acute HEV infection, with five patients infected by HEV-3 [18]. Over a six-month follow-up, three of these patients died. The incidence of hepatitis E was higher in Toulouse than in the UK (7.9% vs 1.2%, P=0.003). Patients with CLD and acute hepatitis E were older (>50 years), predominantly male, and had elevated alanine aminotransferase levels. The main cause of liver disease was alcohol abuse. Mortality rates did not significantly differ between patients with and without hepatitis E infection, although the number of hepatitis E cases was relatively low.

In a retrospective study including 511 cases of acute hepatitis E in Scotland, 58 patients (11%) had pre-existing cirrhosis, and there were 17 (3.3%) HEV-related deaths [24]. The two most important factors predicting mortality were haematological malignancy (OR 51.56; 95% CI 3.40–782.83; P=0.005) and cirrhosis (OR 41.85; 95% CI 2.85–594.16; P=0.006). The findings indicate that HEV causes a significant burden of inpatient admissions and deaths.

In the PREDICT study, a multicentre European study involving 1273 hospitalized patients with acute liver decompensation (no ACLF, n=1,071; ACLF, n=202), the primary precipitating factors were bacterial infection, severe alcoholic hepatitis, gastrointestinal bleeding, and toxic encephalopathy [25]. Only 16 cases of viral hepatitis or other viral infections (etiologic agent not shown) were reported as precipitating factors. The study found no significant difference in acute viral hepatitis rates between patients with ACLF (1.4%) and those without (1.2%), suggesting that viral hepatitis is a rare cause of ACLF in Europe.

Previous studies conducted in Asia found a 12-month mortality rate approaching 70% in HEV-infected patients with underlying CLD [9]. In this line, two small European studies reported that patients with locally acquired HEV infection and pre-existing CLD or alcohol abuse (3 patients in the UK and 7 in France) had an approximate mortality rate of 70% [26,27]. However, recent data from 11 patients with decompensated CLD in UK/France showed that only 3 (27%) died within 180 days of presentation [18]. The discrepancy in mortality could be attributed to differences in the definition of ACLF across studies, which vary in international guidelines due to differences in the precipitating events and underlying aetiology. According to the European Association for the Study of the Liver Chronic Liver Failure (EASL-CLIF) Consortium, ACLF is established based on failure of one of the six major organ systems: liver, kidney, brain, coagulation, circulation, and respiration [28]. In contrast, the Asian Pacific Association for the Study of the Liver (APASL) defines ACLF in patients with CLD as an acute hepatic insult manifesting as jaundice (serum bilirubin≥5 mg/dL) and coagulation dysfunction (international normalized ratio≥1.5), complicated within 4 weeks by overt ascites and/or hepatic encephalopathy [29]. Table 1 shows a selection of studies on the rate and mortality related to hepatitis E virus infection as a trigger of acute-on-chronic liver failure, according to the geographical distribution.

A study by Choi et al. [21] illustrates how the ACLF definition can affect mortality rates. The study, involving 74 Korean patients with acute HEV infection, reported an overall 180- day mortality rate of 9.5%: 3.8% in patients without cirrhosis compared to 22.7% with cirrhosis (P=0.013), an approximately eightfold higher mortality risk in cirrhosis patients [21]. In a further analysis, the authors applied the EASL and APASL ACLF criteria to their results and compared the findings. The 180-day mortality rate was 57.1% following the EASL criteria and 28.6%, according to the APASL criteria. These values were higher than those observed in patients without ACLF or underlying liver disease, suggesting that deterioration of pre-existing liver status and the development of organ failure are both crucial factors influencing the prognosis of patients with acute HEV infection [21].

The EASL guidelines recommend HEV testing for all patients with unexplained flares of chronic liver disease, those with ACLF, and immunosuppressed patients with unexplained abnormal liver function analyses. Recommended tests include anti-HEV IgM, anti-HEV IgG, and HEV RNA for patients with elevated liver enzymes, and HEV RNA for immunocompromised patients [3]. HEV testing rates are generally low, leading to frequent underdiagnoses of this infection [30]. In a recent study, a common finding was significantly higher aspartate aminotransferase (AST) levels in patients with HEV-related ACLF (median AST 2,818 U/L; range 1,176–8,611) compared to matched patients with severe alcoholic hepatitis. However, the number of cases included was very low [29].

Histological damage is not a characteristic feature of ACLF. In a Swiss study of 5 patients who died in the context of HEV-related ACLF, histological analyses showed steatohepatitis on a background of cirrhosis, suggesting an alcoholic or non-alcoholic origin, with no specific signs of HEV infection. Two of these patients had been treated with corticosteroids due to an initial suspicion of alcoholic hepatitis based on the histopathological findings, showing that histopathology can be misleading [31].

Previous research has shown that the host immune response, rather than the virus itself, is the primary driver of HEV-associated liver failure and ACLF [32]. When these conditions occur, a series of changes takes place in both the intrahepatic environment and extrahepatic microenvironment. The immune imbalance is attributed to alterations in the type and distribution of immune cells, particularly infiltrating macrophages and lymphocytes, within liver tissue. Immune cell counts are significantly higher in ACLF patients than in healthy individuals [32]. Although the pathogenesis of ACLF has not been fully elucidated, the differences in lymphocyte counts suggest that cellular immunity is involved in progression of the disease.

Cytotoxic T cells and elevated levels of proinflammatory cytokines and chemokines, such as interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-10 and IL-18, have been linked to adverse outcomes in HEV patients [33]. The gene expression profile in liver tissue of HEV-infected individuals with liver failure shows considerable changes, with many upregulated and downregulated genes associated with immune function compared to healthy liver tissue. In patients with HEV-related ACLF, hepatic levels of proinflammatory cytokines (IFN-γ and TNF-α) are significantly higher than those in healthy individuals, while the expression of anti-inflammatory cytokines (IL-10) remain unchanged. This suggests that an imbalance between proinflammatory and anti-inflammatory cytokine expression may be a crucial factor in the immune response contributing to the pathogenesis of HEV-related ACLF.

Recent studies have identified inborn errors in type I interferon immunity among patients with symptomatic acute hepatitis E. This group showed significant enrichment in type I interferon response pathways, with 10 of 24 patients carrying a damaging variant in one of nine genes involved in this immune response. These genes encode intracellular viral sensors (IFIH1, DDX58, TLR3, POLR3B, POLR3C) or other molecules involved in the type I interferon response [34]. In contrast, no such enrichment was observed in patients with HEV-associated neurological manifestations or in healthy controls, highlighting the essential role of type I interferon in preventing symptomatic acute hepatitis E.

The clinical management of ACLF is generally similar regardless of the etiological agent. It includes hospital admission, supportive care in the intensive care unit (ICU) to address hepatic and extrahepatic complications, support for failing organs, and measures to halt disease progression [28,29]. Early transplantation and priority on the transplant waiting list is often necessary to improve survival due to the high short-term mortality rate associated with ACLF.

Currently, there is no recommended treatment for acute hepatitis E in the EASL clinical practice guidelines, as most HEV infections clear spontaneously [3]. However, certain patients may progress to liver failure. Ribavirin has been suggested for patients with chronic hepatitis E, with therapy leading to rapid normalization of liver enzymes and undetectable HEV RNA within a few days [3,35]. Although very few case reports are available on ribavirin treatment for severe acute HEV infection or ACLF [18,31], the rationale behind its use is that early therapy may shorten the disease course and reduce morbidity, as has been shown in the treatment of acute hepatitis caused by hepatitis B or C. However, due to the high short-term mortality of ACLF, the effectiveness of ribavirin in this situation is difficult to assess. In these cases, ribavirin is administered at a dose of 400 to 600 mg daily, with no new side effects reported [3]. Table 2 shows the cases reported treated with ribavirin [6,24,31,35,36,37].

Corticosteroids have been used in individual cases of ACLF that were later retrospectively identified as being caused by HEV, as well as in some cases of acute liver failure where misinterpretation in the diagnosis occurred [3,31]. Steroid therapy has been associated with improved liver function in acute liver failure, but there is insufficient data on its effectiveness in ACLF. The current evidence does not suffice to support corticosteroid treatment in patients with acute liver failure due to HEV infection.

Individuals at risk of severe acute or chronic HEV infection should avoid consuming foods that may harbour the virus such as undercooked meat from pigs, wild boar, deer, and shellfish. In several case-control studies, previous consumption of certain food products has been conclusively identified as a risk factor for HEV infection [3].

In 2011, a vaccine against HEV was licensed in China. The vaccine is based on a protein containing 239 amino acids from the HEV ORF2 protein (aa 368–606) derived from HEV-1. It demonstrated a 97% efficacy for preventing symptomatic acute hepatitis E infection, with long-term protection confirmed during a 10-year follow-up. Vaccine-induced antibodies against HEV persisted for at least 8.5 years [38,39]. Although the vaccine was tested in China, where HEV genotype 4 is predominant, suggesting cross genotype efficacy, it does not provide sterilizing immunity, which means subclinical infections can still occur. The HEV-239 vaccine has not yet been prequalified by the World Health Organization, a necessary step for its introduction in low- and middle-income countries where the disease burden is highest.

Recently, in response to a hepatitis E outbreak in South Sudan, a vaccination campaign was launched to provide protection for women and girls of reproductive age, who are at the highest risk of death from the disease in case of acute liver failure development [40]. Since October 2022, 299 participants, including pregnant women, have been vaccinated, and the preliminary data suggest strong short-term coverage. Furthermore, the vaccine seems to be safe for use during pregnancy [41].

However, the effectiveness and tolerability of the HEV vaccine has yet to be assessed in other populations at risk of severe infection, such as patients with chronic liver disease and immunosuppressed individuals, particularly those with solid organ transplants who are susceptible to chronic hepatitis and rapid progression to cirrhosis [42]. These populations appear to be ideal candidates, although the effectiveness of the vaccine may be lower in these cases, as was seen with other vaccines. There is an urgent need to test the hepatitis E vaccine in these groups to determine whether it can prevent or mitigate ACLF.

In summary, acute hepatitis E infection is a well-stablished cause of ACLF in patients with CLD, especially in areas where this infection is endemic. In case of ACLF development, supportive care in the ICU is crucial for supporting the failing organs and halting the disease progression. Besides, the majority of these patients may need early transplantation and priority on the transplant waiting list to improve their survival. Ribavirin treatment may be considered in cases of severe acute hepatitis or acute-on-chronic liver failure, though its efficacy and safety require further research.