Viral etiologies of acute liver failure

Abstract

Acute liver failure (ALF) is a rare cause of liver-related mortality worldwide, with an estimated annual global incidence of more than one million cases. While drug-induced liver injury, including acetaminophen toxicity, is the leading cause of ALF in the Western world, viral infections remain a significant cause of ALF and the most common cause in many developing nations. Given the high mortality rates associated with ALF, healthcare providers should be aware of the broad range of viral infections that have been implicated to enable early diagnosis, rapid treatment initiation when possible, and optimal management, which may include liver transplantation. This review aims to provide a summary of viral causes of ALF, diagnostic approaches, treatment options, and expected outcomes.

Key Words: Acute liver failure; Viral hepatitis; Hepatitis B; Hepatitis C; Hepatitis A; Liver disease; Hepatology

Core Tip: Acute liver failure (ALF) is a rare cause of liver-related mortality worldwide, with viral infections remaining a leading global cause. Healthcare providers should be aware of the broad range of viral etiologies that have been implicated to cause ALF given its heterogeneous presentations and high mortality rate. This review aims to provide a summary of known viral etiologies for ALF so that early diagnosis, rapid treatment initiation when possible, and optimal management including liver transplantation can be pursued. Further, this review intends to underscore the importance of further study and characterization of ALF to improve our care and understanding of this condition.

INTRODUCTION

Acute liver failure (ALF) is a rare condition which presents heterogeneously. ALF is clinically characterized by severe acute liver injury (ALI) for less than 26 weeks in duration, impaired hepatic synthetic function as indicated by an elevated international normalized ratio of greater than 1.5, and encephalopathy in a patient without cirrhosis or other pre-existing liver disease[1]. The development of ALF is associated with high morbidity and mortality and is an indication for emergency liver transplant (LT) evaluation. The global incidence of ALF is estimated to be more one million cases annually[2]. Mortality rates are drastically higher in low and middle-income countries compared to upper-middle and high-income countries[3]. Etiologies of ALF vary considerably between geographic regions. While acetaminophen and other drug-induced liver injury comprise most ALF cases in countries such as the United States and the United Kingdom, acute viral hepatitis remains the most common cause of ALF in many other parts of the world[4]. The precise global burden of viral-induced ALF has historically been difficult to determine given challenges employing diagnostic criteria, accurate diagnosis of viral-infections, and the relative rarity of ALF[3]. Numerous viral pathogens have been implicated in ALF, including hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), hepatitis E virus (HEV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), parvovirus B19, herpes simplex virus (HSV), yellow fever (YF), dengue virus (DENV), and human adenovirus (HAdV). Table 1 summarizes high-yield points from this review.

Table 1 Known viral etiologies of acute liver failure with associated viral genetic material, common symptoms, diagnostic approach, possible treatment options, indication for liver transplant and whether a vaccine is available.

Virus	Virus genetic material	Symptoms	Diagnosis	Possible treatment options	Indication for LT evaluation in ALF?	Dedicated vaccine available?
HAV	RNA	Diarrhea, fever, malaise, anorexia, nausea, vomiting, abdominal pain, headache	Serologic	Supportive	Yes	Yes
HBV	DNA	Anorexia, jaundice, abdominal pain, constitutional symptoms	Serologic + viral DNA	Entecavir, tenofovir	Yes	Yes
HCV	RNA	Fatigue, myalgia, low-grade fever, nausea, vomiting, jaundice	Serologic + viral RNA	DAA requires further study in ALF	Yes	No
HDV	RNA	Fatigue, anorexia, lethargy, nausea	Serologic + viral RNA	Requires further study in ALF, demonstrated effectiveness of bulevirtide + peginterferon alfa-2α in chronic HDV	Yes	No
HEV	RNA	Fatigue, anorexia, lethargy, nausea	Viral RNA	Ribavrin, glycyrrhizin	Yes	Yes2
CMV	DNA	Pharyngitis, lymphadenopathy, arthralgia, lymphocytosis, splenomegaly, hepatitis	Serologic + viral DNA	Transplantation in ALF; ganciclovir, valganciclovir, foscarnet and cidofovir in ALI	Yes	No
EBV	DNA	Fever, sore throat, lymphadenopathy, mononucleosis syndrome	Viral DNA	Acyclovir, ganciclovir, famcilovir, valganciclovir +/- corticosteroids	Yes	No
VZV	DNA	Blistering, erythematous rash, “shingles”	Viral DNA	Acyclovir, IVIG1	Yes	Yes
Parvovirus B19	DNA	Erythema infectiosum: Fever, rash, arthralgias	Serologic	IVIG, hydroxyurea, cidofovir/brincidofovir, coumarin	Yes	No
HSV	DNA	Painful oral or genital sore; non-specific systemic symptoms	Serologic + viral DNA	Acyclovir	Yes	No
YF	RNA	Fever, headache, myalgias, nausea	Serologic + viral RNA	Sofosbuvir1	Yes	Yes
SARS-CoV-2	RNA	Upper and/or lower respiratory tract infection, cough, fever, anorexia	Serologic or viral RNA	Supportive	Yes	Yes
DENV	RNA	Fever, headache, body pains, chills, sore throat, rash	Serologic or viral RNA	NAC1	Yes	Yes
HAdV	DNA	Localized upper or lower respiratory tract infection, gastroenteritis	Histologic4	Cidofovir	Yes	Yes3

¹Requires further study.

²Only available in China.

³Only routinely available for military recruits.

⁴May require further testing for human adenovirus speciation.

ALT: Acute liver failure; LT: Liver transplant; HAV: Hepatitis A virus; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HDV: Hepatitis D virus; HEV: Hepatitis E virus; CMV: Cytomegalovirus; EBV: Epstein-Barr virus; VZV: Varicella zoster virus; HSV: Herpes simplex virus; YF: Yellow fever; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; DENV: Dengue virus; HAdV: Human adenovirus; ALI: Acute liver injury; DAA: Direct-acting antivirals; IVIG: Intravenous immune globulin; NAC: N-acetylcysteine; ALF: Acute liver failure.

HAV

HAV is a nonenveloped RNA virus transmitted by fecal-oral contamination that is endemic in all parts of the world[5]. HAV has an incubation period of about 28 days and typically causes a self-limited diarrheal illness. The acute HAV clinical course consists of a pre-icteric phase of about one week of fever, malaise, anorexia, nausea, vomiting, abdominal pain, and headache followed by an icteric phase which can persist for a month or more[6]. Symptomatic disease seems to be age-related; around 70% of infected adults develop jaundice, compared to 30% of infected children[6]. An estimated 0.1%-0.5% of acute HAV infections progress to ALF[7]. HAV replicates in hepatocytes and the gastrointestinal epithelium. Hepatocellular injury in HAV is attributed to a cytotoxic response to virus-infected cells[8]. Cytotoxic damage from natural killer (NK), NK T-cells, non-HAV specific CD8+ T-cells, and virus-specific cytotoxic T-cells have been shown to contribute to hepatocyte injury and death. There is also emerging evidence that HAV can induce intrinsic apoptosis of hepatocytes in animal models. Virus-specific cytotoxic T-lymphocytes can cause direct hepatocellular injury via cell lysis[9]. Non-virus specific lymphocytes are also thought to contribute to hepatocellular injury; this has been demonstrated in a study from Kim et al[10] where high levels of interleukin (IL)-15 and upregulation of NKG2D ligands were observed in HAV-infected and uninfected hepatocytes, with severity of liver injury correlating with the activation of non-virus specific CD8+ T cells. Further, studies in mice models have suggested that type I interferon (IFN) receptor-mediated signaling may be involved in intrinsic apoptosis of HAV-infected hepatocytes[9]. HAV-induced ALF can cause the histologic features of massive hepatocyte necrosis, inflammatory cellular infiltrate, and bile ductular proliferation[11]. The precise mechanism underlying progression of severe HAV infection to ALF requires further study.

Diagnosis of acute HAV is made via detection of anti-HAV immunoglobulin M (IgM) via blood testing in the appropriate clinical context. Anti-HAV IgM can typically be detected 5-10 days before symptom onset. Treatment of severe HAV is supportive, and LT evaluation is indicated for those who progress to ALF[12]. While LT for HAV is extremely rare, reported 5-year post-LT survival in this population is reported to be 69%[4].

Vaccination against HAV has considerably decreased the prevalence of acute infection. The World Health Organization (WHO) recommends universal childhood HAV vaccination in endemic countries and targeted vaccination efforts for high-risk grounds in areas of low endemicity[13]. The combined point-prevalence of HAV-induced ALF in countries with routine HAV vaccination is around 2% (95% confidence interval: 1-3), compared to roughly 27% (95% confidence interval: 13-43) in countries without routine immunization[3]. One study in Argentina showed that the incidence of HAV-induced ALF in children decreased from 54.6% (March 1993 to July 2005) to 27.7% after the implementation of routine single-dose HAV vaccine in 2005 (August 2005 to December 2008). The same study reported zero cases of HAV-induced ALF beyond November 2006[14].

HBV

HBV is a partially double-stranded circular DNA virus and one of the leading causes of chronic hepatitis, cirrhosis, and hepatocellular carcinoma worldwide. It is estimated that < 0.5% to 1% of persons who experience acute or reactivation of HBV will progress to HBV-induced ALF[15,16]. Acute HBV has an incubation period of 1-4 months. Initial illness symptoms can include a serum sickness-like illness followed by anorexia, jaundice, abdominal pain, and constitutional symptoms[16]. Mortality resulting from HBV-induced ALF is high, with LT-free survival of about 25%[4]. While the pathophysiology of hepatic necrosis is not fully understood, HBV core promoter mutations encourage enhanced viral replication, strong humoral immunity response (evidenced by massive accumulation of IgG and IgM secreting plasma cells in necrotic hepatic tissues of patients with HBV-induced ALF), and intrinsic viral induction of apoptosis may contribute to the development of ALF[12]. Mice models have shown that hepatocellular damage is also mediated by cytokines including tumor necrosis factor (TNF)-α and IFN-γ, sensitizing hepatocytes to immune-mediated damage and exacerbating liver injury[17]. HBV can also have direct cytopathic effects, which has been demonstrated in hepatoma models expressing HBV large-surface proteins causing vacuole formation and apoptosis and in mice models where HBV core protein has been shown to interfere with hepatocyte mitochondrial recycling, increasing apoptotic hepatocyte death[18,19]. Histologically, HBV-induced ALF is characterized by high production of IgG and IgM secondary to an overwhelming B-cell response with complement deposition leading to massive or sub-massive hepatocyte necrosis[20]. HBV is estimated to cause up to 18% of ALF cases in Europe, 15% in Bangladesh and India, 22% in Sudan, and 7% in the United States[21]. Of note, HBV can cause ALF during an acute infection as well as an acute-on-chronic flare of disease[22].

Increasing use of immunomodulating and immunosuppressive therapies in autoimmune diseases and malignancies have caused significantly more episodes of HBV reactivation, which can occur indirectly through down-regulation of cytotoxic T-cells or B-cell inhibition. Glucocorticoids and anti-TNF therapies are also capable of directly stimulating upregulation of HBV expression[23]. The Association for the Study of Liver Diseases defines HBV reactivation in people receiving cytotoxic or immunosuppressive therapy as ≥ 2 Log increase compared to baseline HBV DNA levels, ≥ 3 Log increase in a patient with previously undetectable HBV DNA levels, new appearance of HBV DNA levels in patients who are HBV surface antigen (HBsAg)-positive and anti-HBV core antigen (anti-HBc) positive, or newly detectable HBV DNA or reappearance of HBsAg in patients who are HBsAg-negative and anti-HBc-positive[24]. Patients who are HBsAg-positive are at higher risk for HBV reactivation than HBsAg-negative and anti-HBc-positive patients. HBsAg-positive patients receiving immunosuppressive/cytotoxic therapy or HBsAg-negative/anti-HBc-positive patients undergoing high-risk therapy (anti-CD20 therapy, stem cell transplantation) are recommended to receive HBV-directed antiviral prophylaxis given the high risk of viral reactivation[24]. In immunocompetent patients with HBV, interruption of HBV-directed antiviral therapy has been associated with a statistically significant risk of HBV-reactivation leading to hepatic failure and increased 28- and 90-day mortality[25].

Diagnosis of HBV as a cause of ALF is largely serologic based on the detection of anti-HBc IgM and HBsAg. HBV DNA polymerase chain reaction (PCR) testing may not result quickly enough to be of clinical utility. The hallmark of diagnosing acute HBV is the detection of anti-HBc IgM; anti-HBc IgM can become detectable 1-2 weeks after the appearance of HBsAg[26]. However, it is important to note that anti-HBc IgM can also reappear during severe reactivation flares of chronic HBV in patients receiving chemotherapeutic or immunosuppressive medications[27]. HBV DNA will be detectable in HBV-induced ALF. Previous studies have found that viral loads are lower at initial presentation for patients who progressed to ALF, perhaps reflecting a more robust immune response predisposing patients to increased hepatocyte damage. A superinfection or coinfection of another hepatitis virus, such as HDV, should also be tested for in those with suspected HBV reactivations[21]. In HBV-induced ALF, antiviral treatment is recommended with entecavir, tenofovir disoproxil fumarate or tenofovir alafenamide[24]. Recent data suggest that early treatment may improve LT-free survival in HBV-induced ALF[28]. HBV-directed antiviral treatment should be continued indefinitely in those who undergo LT or until HBsAg clearance is confirmed[22].

The HBV vaccine is effective in preventing HBV infection and is therefore recommended by the WHO to be included in all national immunization programs[29]. HBV immunization significantly reduces the risk of complications related to HBV, including chronic liver disease, hepatocellular carcinoma, and ALF[30]. In those chronically infected with HBV, achieving functional cure (sustained loss of HBsAg and undetectable HBV DNA after a finite treatment course) has the potential to decrease HBV transmission and thereby the risk of HBV-induced ALF. A primary challenge to HBV functional cure remains the virus’ long half-life and covalently closed circular DNA, persistent production of HBsAg from integrated HBV DNA, and host immune exhaustion. The latest approaches to HBV functional cure involve combination therapy aimed to suppress HBV DNA replication and HBsAg production with subsequent stimulation of the HBV-specific immune response. Therapeutic approaches to functional HBV cure currently in testing involve viral suppression with nucleotide or nucleoside therapy in combination with pegylated IFN or immunomodulators[31].

HCV

HCV is a single-stranded RNA virus with seven identified genotypes and 67 subtypes[32]. Acute HCV leads to chronic infection in 70%-80% of cases, placing affected patients at risk of developing cirrhosis and/or hepatocellular carcinoma[33]. Acute infection with HCV is most often asymptomatic but can also present with fatigue, myalgia, low-grade fever, nausea, vomiting and jaundice[34]. HCV is thought to damage hepatocytes through several mechanisms including direct viral injury, secondary oxidative damage and host immune response. HCV can cause direct stress within the endoplasmic reticulum of hepatocytes, with HCV-encoded proteins activating pro-inflammatory molecules such as transcription factor nuclear factor-κB. HCV-infected hepatocytes increase the production of pro-fibrotic signals such as transforming growth factor-. HCV core and NS3 proteins are also thought to promote inflammation by stimulating IL-1 receptor-associated kinase activity, increasing p38 phosphorylation and activating extracellular regulated kinase and c-Jun N-terminal kinase[35]. Further, HCV infection has been shown to induce oxidative stress and cellular damage via multiple mechanisms, including of increased production of reactive oxygen species and decreased glutathione stores[36]. HCV also causes hepatocellular injury via host immune response, with cytotoxic lymphocytes destroying HCV-infected cells with the release of Fas-ligand and inflammatory cytokines, including IFN-γ and TNF, causing injury to uninfected cells[37].

HCV as an isolated cause of ALF is controversial but has been reported, and acute HCV infection is known to be capable of causing severe ALI, particularly in immunosuppressed patients[12,38]. Severely immunocompromised individuals, such as kidney or LT recipients, are also predisposed to direct HCV-induced viral injury via fibrosing cholestatic hepatitis (FCH) which is a rare, rapidly progressive form of cholestatic liver injury with marked jaundice and high HCV viral load[39]. FCH manifests histologically with hepatocyte swelling, cholestasis, periportal peritrabecular fibrosis, and mild inflammation and can progress to ALF[40]. There has also been documentation of HCV-induced ALF in patients with concurrent chronic HBV infection[41].

The gold standard for diagnosis of HCV infection is detection of HCV RNA by PCR, and routine screening for HCV infection can be performed via detection of anti-HCV antibodies. While curative HCV therapy is now widely available, the development of an HCV-vaccine is an active area of research with several neutralizing antibody candidates identified and several vaccine studies ongoing[42]. More research is required to clarify the role of direct-acting antivirals (DAA) in HCV-induced ALF. DAA treatment has shown clinical benefit and sustained virologic response in severe HCV infection including FCH[43].

HDV

HDV is a satellite RNA virus which relies on HBV for viral replication as it utilizes the HBsAg viral envelope for hepatocyte receptor viral entry. A recent systematic review estimated that the global anti-HDV prevalence to be 4.5% in those known to be hepatitis B surface-antigen positive[44]. This translates to a worldwide prevalence of HDV/HBV coinfection of 20-40 million people, although some estimates are as high as 72 millions[45]. Because HDV requires HBV to propagate, infections occur simultaneously as a coinfection or sequentially as a superinfection in patients with a preexisting HBV-infection[44]. Acute HDV infection presents non-specifically following a 3-7 week incubation period with fatigue, anorexia, lethargy and nausea followed by an icteric phase with the appearance of frank jaundice, dark urine and light-colored stools[46]. Mouse models have demonstrated that cytokine inflammation from TNF-α mediates hepatocellular injury in HDV infection[47]. In human cell models, it has also been shown that small HDV antigen may be capable of direct cellular toxicity by binding to mRNA downregulating protective proteins such as glutathione S-transferase P1[48]. Histologically, HDV-induced liver injury is similar to other viral hepatitis infections with hepatocyte necrosis, inflammatory infiltrates with lymphocytes and macrophages, and cytoplasmic eosinophilia[49]. An HDV superinfection in an HBV-infected individual tends to be more severe with a higher chance of progressing to ALF than HBV mono-infection or HBV/HDV coinfection[46].

Diagnosis of HDV is by detection of HBsAg and anti-HDV antibodies. Acute HDV infection is confirmed by the presence of HDV Ag and anti-HDV IgM[26]. However, HDV Ag is not always detectable and cannot necessarily help distinguish between resolved, chronic or acute infections, and thus HDV RNA detection via PCR is the gold standard for HDV diagnosis when available[50]. Anti-HBV core IgM is only present in HDV/HBV coinfection and not acute HDV superinfection, providing an ability to distinguish between these two clinical scenarios[45].

As HDV requires HBV to replicate, vaccinations programs for HBV are the most effective measure to prevent HDV infection. There is no HDV-specific vaccine available. In the United States, there are no specific antiviral treatments approved for acute HDV[51]. Until the approval of bulevirtide in Europe in 2020, pegylated IFN-α was the primary drug of choice for HDV infection[45]. Bulevirtide acts by blocking the entry receptor for HBV/HDV on hepatocytes, sodium taurocholate co-transporting polypeptide[52]. A recently published study from Asselah et al[53] in patients chronically infected with HDV showed that combination bulevirtide plus peginterferon alfa-2a was superior to bulevirtide alone in achieving undetectable serum HDV RNA. Treatment of HDV should also focus on treatment of concurrent HBV infection[54]. For HDV-induced ALF, data are lacking regarding treatments including bulevirtide, and the definitive therapy is LT[45].

HEV

HEV is a nonenveloped single-stranded RNA virus with eight genotypes that is most often transmitted via the fecal-oral route involving contaminated water[55]. HEV is the most common cause of acute viral hepatitis worldwide, with HEV1 and HEV2 (likely human reservoir) usually leading to self-limiting acute viral hepatitis while and HEV3 and HEV4 (thought to be zoonotic viruses with the primary animal host being pigs) have been found to cause chronic hepatitis in immunocompromised patients[55,56]. The estimated incidence of HEV is observed to vary by region, with an estimated 2 million cases annually in Europe and 3.4 million symptomatic cases annually in Asia[56,57]. Hepatitis E outbreaks are usually related to contaminated drinking water reservoirs. Pregnant women are most likely to be affected during outbreaks. Further, acute HEV has been found to progress to ALF more often in pregnant women (22%) compared to non-pregnant women (0%) and men (2%)[58]. Liver injury in HEV-induced ALF is thought to primarily be driven by immune response to HEV infection[59]. HEV is thought to cause hepatocyte damage via host immune response in the presence of pro-inflammatory cytokines TNF-α and IFN-γ; direct HEV cytotoxic effects are an active area of inquiry[58]. HEV-induced ALF has been noted to be histologically heterogenous, attributed to the diversity of prevalent genotypes. However, a study of 11 biopsies from HEV-induced ALF showed varying degrees of necrosis, ballooning hepatocyte degeneration (70%), councilman bodies (90%), pseudo-rosettes (70%), Kupffer cell prominence (100%), intracytoplasmic (80%) and canicular (90%) cholestasis, biliary ductular proliferation (90%) and less plasma cell portal inflammation (20%)[60]. While HEV-related mortality is typically comparable to that seen with other acute viral hepatitis infections (0.2%-1%), the mortality rate among pregnant women is estimated to be as high as 20%. The hypothesized mechanism for the increased risk of ALF in pregnancy is related to immunologic changes discouraging antigenic sensitization to the fetus, causing decreases in cellular immunity which predispose to more severe HEV disease[61].

The rapid diagnosis of HEV with indirect immunoglobulin assays is complicated by virologic heterogeneity and lack of understanding of how different HEV genotypes influence the production of diagnostic antigens, making these results difficult to interpret in acute disease[62]. In a recent case series of ALF in the United States attributed to drug-induced liver injury, 9 of 318 cases reviewed had serologic evidence of ongoing acute HEV infection with positive anti-HEV IgM, while 4 of the cases had detectable HEV3 RNA in the serum. Therefore, acute HEV may comprise a small but significant percent of ALF cases of indeterminate cause[63]. Direct testing by HEV PCR, if available, may provide the highly sensitive and specific diagnostic screening test that is required in severe, acute HEV infection[62].

A vaccine against HEV, HEV 239, has been available in China since 2012, but is not presently available in other countries. A phase 3 double-blind placebo-controlled study of this vaccine demonstrated a 10-year efficacy of 83.1% in intention-to-treat analysis and 86.6% in the per protocol analysis and was shown to induce durable anti-HEV antibodies for at least 8.5 years[64]. Despite promising data for HEV 239 in China, the WHO’s current position is that available data are insufficient for children under 16 years old as well as cross-protection against HEV genotypes 1, 2 and 3. The WHO does not currently recommend that HEV 239 be incorporated into routine vaccination programs[65]. While there is no established treatment for HEV-induced ALF, ribavirin monotherapy has been shown to encourage viral clearance in immunocompetent and immunosuppressed patients experiencing severe, acute HEV infection. While ribavirin is otherwise contraindicated during pregnancy due to teratogenic effects, case studies have reported normal pregnancy outcomes after fetal ribavirin exposure, suggesting that treatment with ribavirin may outweigh the risk of untreated HEV in pregnancy[66]. There is also low-quality evidence in acute moderate to severe HEV that glycyrrhizin, an extracted component of licorice root, can lead to clinical improvement and normalization of ALT and AST within 30 days of commencing therapy[67]. In chronically infected immunosuppressed solid-organ patients, ribavirin improves viral clearance and sustained virologic response[68]. Unfortunately, a safe ribavirin doses has not been established for HEV-related ALF. Further research should focus on whether the availability of the HEV 239 reduces the incidence of HEV-induced ALF and other associated complications.

CMV

CMV is a double-stranded DNA herpesvirus with a worldwide seroprevalence of 60%-100%. While CMV can cause clinically significant disease with high morbidity and mortality in immunocompromised populations, only 10% of immunocompetent individuals present with symptomatic infection. Reported symptoms are often mild and self-limited, including pharyngitis, lymphadenopathy, arthralgia, lymphocytosis, splenomegaly, and hepatitis[69]. CMV hepatitis causes non-specific symptoms, and cases of ALF attributed to CMV are exceedingly rare[70,71]. While CMV can cause direct cytopathic damage to hepatocytes and cholangiocytes, immune-mediated CD8+ T-cell response and cytokines IFN-γ and TNF has been shown in mouse models to be important to the progression of CMV hepatitis in severe cases[72]. While no diagnostic criteria exist for CMV-induced ALF, an active CMV infection is diagnosed by a detectable CMV DNA PCR test in combination with a positive CMV IgM or an increase in CMV IgG greater than 4-fold the upper limit of normal[69]. Liver biopsy can assist in cases of diagnostic uncertainty. Histologic features of CMV hepatitis include the presence of cytoplasmic and intranuclear inclusion bodies, lobular hepatitis, hepatocellular necrosis, portal mononuclear infiltrates and micro-abscesses[73].

Immunosuppressed individuals, especially solid-organ transplant recipients, are at highest risk of CMV-related complications. There is no CMV vaccine available, and prevention in immunosuppressed individuals is primarily achieved with prophylactic antiviral medications. Valganciclovir and ganciclovir are common choices for CMV viral prophylaxis in LT, and immunosuppressed, patients[74]. While letermovir has been shown to be effective in hematopoietic stem cell transplants, a recently published case series suggests that letermovir may be effective for secondary CMV-prophylaxis in solid organ transplant patients, including LT patients[75]. For CMV-related hepatitis, treatment targets the CMV DNA polymerase and ganciclovir, valganciclovir, foscarnet and cidofovir have been used[73]. However, once CMV-induced hepatic injury has advanced to ALF, it is thought to be unresponsive to antivirals and is therefore an indication for emergent LT evaluation. Suppressive antiviral therapy is essential in patients who undergo LT, as CMV-induced ALF is an identified risk factor for clinically significant CMV disease following LT[69,76]. Further study of comparative effectiveness of treatments for acute CMV-induced hepatitis and whether there are differences in progression to ALF are needed.

EBV

EBV is a double-stranded DNA herpesvirus with a seroprevalence of over 90% worldwide. Infection most commonly causes mild, self-limited fever, sore throat, lymphadenopathy, and mononucleosis syndrome[77]. EBV preferentially infects B lymphocytes by binding the gp350 glycoprotein on CD21. Although EBV can cause a mild subclinical and self-limiting hepatitis as a part of the mononucleosis syndrome, it can also cause ALF. Patients at risk present with a triad of atypical lymphocytosis, splenomegaly, and jaundice. Interestingly, EBV-induced ALI tends to predominantly present in a cholestatic pattern of injury[78]. EBV is nonhepatotropic, and instead is understood to cause hepatic damage via EBV-infected lymphocytes with subsequent predominant CD8+ T-cell immune response causing inflammation and hepatocellular damage[79]. Histopathology typically shows diffuse lymphocytic sinusoidal infiltrates in a string of beads pattern, a lymphocytic infiltrate causing expansion of portal tracts, and, in severe cases, massive hepatic necrosis[73]. Immunosuppression is thought to be a risk-factor for severe disease related to viral reactivation in EBV-exposed individuals[80]. A study from the United States Acute Liver Failure Study Group found that only 4 patients in their database of 1887 patients had ALF attributed to EBV. Of these 4, all were young, immunocompetent adults (< 30 years old) who had been experiencing symptoms for 2-3 weeks prior to presentation[81].

Diagnosis can be challenging given nonspecific pathologic biopsy findings and difficult-to-interpret EBV serum tests (including serum viral load levels)[81]. In terms of diagnostic testing, EBV DNA PCR is more reliable than EBV serologies given the high degree of cross-reactivity to other herpesviruses (e.g., CMV and HEV). EBV IgG, IgM, and heterophile antibody testing can be utilized for initial screening[73]. Ancillary studies such as EBV-encoded RNA histopathologic testing can be used as an additional diagnostic study when available but does not exclude EBV-hepatitis as a diagnosis[82]. Definitive diagnosis of EBV-associated ALF is made by DNA detection by PCR in the appropriate clinical context.

There is currently no EBV vaccine available. Research for an EBV-vaccine is of interest given the virus’ implication in multiple malignancies and auto-immune conditions; however, vaccine development is complicated by the virus’ complex life cycle, lack of robust animal models, and uncertainty around optimal antigen target and delivery methods[83]. Some of the latest EBV vaccine candidates utilize poxvirus and adenovirus vectors or peptide vaccines[84]. In terms of treatment, the antiviral agents acyclovir, ganciclovir, famcilovir, and valganciclovir, sometimes in combination with corticosteroids, are utilized for EBV-associated hepatitis and severe EBV-disease[69,81]. The relative efficacy of respective antiviral regimens in EBV-induced ALF has yet to be established. However, the United States Acute Liver Failure Study Group recommends initiation of antiviral treatment in severe EBV hepatitis based on available reports. Ultimately, EBV-induced ALF is an indication for LT evaluation[81].

VZV

VZV, or human herpesvirus 3, is double-stranded DNA virus that typically causes the mild disease known as chickenpox. This virus then becomes quiescent in ganglionic neurons and can reemerge as herpes zoster, or shingles, which classically causes a blistering, erythematous, and painful rash in a dermatomal distribution[85]. Disseminated VZV infection is rare and typically only arises in immunocompromised individuals such as those taking immunosuppressive therapies[86]. ALF in disseminated VZV is extremely rare. A literature review from Fang et al[86] found 18 case reports, 12 of which occurred in immunocompromised patients. Of the remaining 6 patients, 3 had recently started oral steroid therapy. This study reported a case fatality rate of 77.8%. Documented initial presentations can be nonspecific, including fever, abdominal pain, nausea, vomiting and rash, or isolated chest pain[86]. VZV has been shown to have direct hepatocellular toxicity with intracellular replication with further liver injury thought to be caused by immune-mediate responses to infection[87]. Histologically, necrosis, micro-abscesses, infiltration of inflammatory cells and eosinophilic nuclear bodies have been described[88]. Diagnosis of disseminated Varicella is made by DNA PCR detection of VZV[89].

There are no guidelines for treatment of VZV-induced ALF. Acyclovir is typically administered when VZV-induced ALF is considered, and delays in its initiation should be avoided. Fang et al[86] found that of 3 patients with ALF who received intravenous immune globulin, 2 survived, suggesting a possible benefit. Given the rarity of VZV-induced ALF in immunocompetent patients, the American Gastroenterological Association conditionally recommends against routine VZV screening in immunocompetent patients presenting with ALF[90]. VZV-induced ALF is an indication for LT evaluation, and outcomes have been reported to be favorable[91].

The VZV vaccine is a live-attenuated vaccine which is recommended for all healthy patients. The WHO recommends including the VZV vaccine in all universal routine vaccination schedules[92]. The VZV vaccine is not recommended for highly immunocompromised patients including primary immunodeficiency, solid organ transplant recipients, patients receiving active chemotherapy, human immunodeficiency virus infection with CD4 cell count < 200 × 10⁹/L, high dose corticosteroid therapy ≥ 20 mg prednisone for at least 14 days, and some stem cell transplant patients owing to concerns regarding low likelihood of response[93]. While widespread VZV vaccination remains a WHO public health goal, trends in epidemiology and cost-effectiveness of the vaccination have led to slow adoption of universal VZV vaccination[94].

PARVOVIRUS B19

Parvovirus B19 is a single-stranded DNA virus and part of the Parvoviridae family that infects and replicates in erythroid precursor cells. It is commonly known to cause erythema infectiosum or “fifth disease”, characterized by fever and rash in children as well as rash with clinically significant arthralgias in adults[95]. Parvovirus B19 can also infect hepatocytes and other cells that possess globosides and glycospingolipids in their cell membrane and induce apoptosis[96]. Parvovirus B19 is thought to cause hepatocyte damage primarily through direct cytopathology of the NS1 protein which is capable of binding and cleaving both host and viral and host DNA, resulting in damage that ultimately leads to hepatocyte apoptosis via the caspase pathway[97]. Histologically, these mechanisms are reflected in parvovirus B19-induced ALF biopsy specimens which demonstrate confluent necrosis with evidence of widespread hepatocyte apoptosis referred to as hepatocellular dropout[98].

While hepatitis related to parvovirus B19 infection is estimated to occur in 4.1% of patients infected, parvovirus B19-induced ALF remains an extremely rare clinical entity[96]. Diagnosis of acute parvovirus B19 disease relies on detection of anti-parvovirus B19 IgM, which may not become detectable until 10-14 days post-infection. Direct testing for parvovirus B19 DNA may be the preferred method in immunocompromised individuals or those with suspected severe acute infection[26]. Most of the literature relating to ALF in acute parvovirus B19 infection involves children. Case reports in adults have described an acute hepatitis with spontaneous remission, indicating that parvovirus B19 disease is generally less severe in this population. Treatment of severe parvovirus B19 is typically symptom-directed (e.g., transfusions to treat anemia, non-steroidal anti-inflammatory drugs for arthralgia, etc). Studies regarding management of parvovirus B19-related ALF are lacking, although administration of large-doses of human intravenous immune globulin are thought to contain high levels of anti-parvovirus B19 antibodies capable of reducing viral load[99]. Novel therapies actively being studied for parvovirus B19 include hydroxyurea given its antiproliferative effect on erythrocytes, cidofovir and brincidofovir given their broad activity against DNA viruses, and newer coumarin derivatives and flavonoid molecules. However, these candidates are not being studied specifically in parvovirus B19-associated hepatitis or ALF[99]. Future study of these treatments may inform whether they also reduce the incidence or severity of liver injury in parvovirus B19 infection. LT evaluation and transplantation has been reported for parvovirus B19-induced hepatitis progressing to ALF[100,101]. There are no currently available vaccines against parvovirus B19, although development of a vaccine is an area of active inquiry[102].

HSV

HSV types 1 and 2 are double-stranded DNA viruses. Infections with HSV are common, with estimates in 2016 of 491 million people living with HSV type 2 (genital) infection and 3583.5 million living with HSV type 1 (oral) in people younger than 50 years old[103]. HSV-induced hepatitis is a rare complication which commonly leads to ALF in 74% of cases. It is associated with a mortality rate of 90% due to delayed diagnosis and treatment. Diagnosis of HSV hepatitis can be complicated by non-specific presenting symptoms. For example, more than half of patients with HSV-associated hepatitis present without mucocutaneous lesions. Anicteric hepatitis with low or normal bilirubin levels but profound transaminase elevations is common in HSV-induced hepatitis and ALF[104]. HSV has direct cytopathic effects, with mouse models showing that infection results in DNA-fragmentation and activation of caspase-3 enzyme and Fas-ligand, facilitating rapid hepatocyte apoptosis[105]. Histologically, HSV-induced ALF is characterized by coagulative necrosis, Cowdry’s type A intranuclear inclusion bodies, evidence of hepatocyte apoptosis and inflammatory cell infiltrates (notably lymphocytes and plasma cells)[106].

Diagnosis of HSV-induced ALF can be challenging. In a small study of patients with ALF (n = 63), 6 of the patients with an indeterminate cause of ALF and 1 of the patients with pregnancy-related ALF were found to have positive HSV IgM antibodies but a negative HSV-PCR, while all 4 of the patients with confirmed HSV-induced ALF had high viral load by HSV PCR (only 2 of which had a positive HSV IgM)[107]. This indicates that when HSV-associated ALF is suspected or the diagnosis is unclear, detection of HSV DNA in the blood by PCR should be pursued early. While no specific guidelines exist for treatment of HSV-induced ALF, acyclovir treatment has been associated with reduced mortality and a decreased need for LT[69]. Further, pregnant patients and neonates are at higher risk for developing disseminated HSV, with mortality rates in pregnant patients approaching 40% in HSV-induced hepatitis. Acyclovir has been shown to have favorable survival outcomes in HSV-induced hepatitis in pregnancy and be of no additional risk to the fetus, justifying early empiric administration in pregnant women when HSV-induced hepatitis is suspected[108]. LT evaluation is indicated for HSV-associated ALF, and lifelong suppressive antiviral therapy is recommended following transplant given the risk of recurrence of disseminated HSV[69].

There is no vaccine available for HSV type 1 or 2. Vaccine development to date has been hampered by viral latency and HSV’s ability to evade the innate and adaptive immune system. While a preventative vaccine against HSV is the ultimate goal, there is also active research into therapeutic vaccines that may discourage reactivation of latent infection. There are presently multiple vaccine candidates against HSV in various stages of development[109].

YF VIRUS

VF virus is a mosquito-borne positive-single-stranded RNA flavivirus. YF is endemic to areas of Africa and Central/South America. It is transmitted by the Aedes mosquito in Africa and the Haemagogus or Sabethes species in South America. YF virus presents primarily with mild and self-limited disease characterized by fever, myalgias, headache, and nausea following an incubation period of 3-6 or up to 15 days[110]. YF can directly infect hepatocytes, with a study from da Costa Lopes et al[111] demonstrating that hepatocyte injury in VF infection may be associated with increased apoptosis, as evidenced by the presence of associated markers, caspase 3, caspase 8, BAX, Fas, Fasl, granzyme B and survivin. Histologically, YF-induced liver injury shows lytic midzonal hepatocyte necrosis, hepatocyte apoptosis, and portal and acinar inflammatory infiltrate disproportionate to the extent of hepatic injury observed[112].

Diagnosis of YF is typically based on clinical suspicion and requires serologic confirmation via detection of VF IgM or YF RNA PCR[113]. Around 12% of patients develop severe YF with involvement of various organ systems, including ALF[110]. Once severe YF develops, the treatment is supportive. IFN-α and high-dose ribavirin have not proven to be effective[114]. There is emerging evidence that the anti-HCV antiviral, sofosbuvir, may have therapeutic benefit in severe YF-related disease. This remains an area of study in Brazil given the ongoing YF outbreak in the country[115,116]. LT for YF-induced ALF has been reported in small studies. One such study of 7 LT patients with YF-induced ALF showed that 3 survived, while the 4 who died had histologic evidence of graft-infection with YF[117]. Further study of patients who undergo LT for YF-induced ALF is needed.

A live virus vaccine is available against YF. The YF vaccine is recommended for those aged ≥ 9 months who are traveling to or living in endemic areas; the vaccine is contraindicated in people with a history of thymoma/thymus dysfunction, acquired immunodeficiency syndrome, or those receiving immunosuppressive drugs or chemotherapies[118,119]. The WHO recommends routine YF vaccine to all infants ≥ 9 months, at the same time as the measles vaccine in areas with reported YF cases, and for YF surveillance so that reactive mass-vaccination programs can be launched in response to outbreaks[120]. The YF vaccine is intended to reduce the risk of people developing severe YF-disease[119]. Further study to understand whether vaccination reduces the incidence of YF-induced ALF is needed, although the low number of annual events poses a barrier to the timeliness of reaching this conclusion.

SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS 2

The novel strain of coronavirus, an RNA virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). While ALF has been observed in patients with COVID-19 disease, treatment with hepatotoxic medications including remdesivir and acetaminophen as well as hypoxic liver injury secondary to pulmonary disease and micro-thrombosis may be responsible for these cases as opposed to a direct hepatotoxicity of SARS-CoV-2 virus[121,122]. A potential mechanism for direct viral injury to hepatocytes involves binding to the angiotensin-converting enzyme 2 receptor on cell surfaces following by S-protein activation by transmembrane protease serine 2, both of which are present on liver parenchymal cells and cholangiocytes. While COVID-19-related hepatitis and cholangiopathy are well documented, case reports of ALF without respiratory disease are very rare. Furthermore, pathologic analyses of related liver specimens have demonstrated confounded by features of hypoxia or ischemia; studies to date imply that direct viral infection of the liver is uncommon in COVID-19[123]. The pathogenicity of SARS-CoV-2 as a potential cause of ALF requires further study.

COVID-19-induced ALF has sparing case reports, with the two identified for this review documenting resolution of ALF without requiring LT[124,125]. However, there are documented cases of COVID-19-associated cholangiopathy and sclerosing cholangitis requiring LT evaluation and ultimate organ transplantation[126,127]. Further study of SARS-CoV-2 is needed to clarify risks and natural course of hepatobiliary manifestations of COVID-19.

Vaccines against SARS-CoV-2 remain widely available in the United States. On 5 May 2023, COVID-19 was no longer considered a public health emergency by the WHO; given high rates of population immunity the organization only recommends routine revaccination in special populations including pregnant people, older adults, those who are immunocompromised, and healthcare workers[128]. Vaccination has been shown to reduce the severity of COVID-19 infection and reduce the risk of liver function abnormalities in patients with metabolic-dysfunction associated steatotic liver disease[129]. Available research does not address whether SARS-CoV-2 vaccination modifies individual risk for developing ALF in COVID-19 disease but may be an area of future inquiry.

DENV

DENV is an RNA virus carried principally by the Aedes mosquito vector in tropical and subtropical regions of the world. It is caused by a flavivirus with four distinct subtypes (DENV-1, DENV-2, DENV-3, and DENV-4) defined by different antigens. DENV is estimated to have an incidence of around 400 million cases and causes 22000 deaths worldwide per annum[130]. DENV classically presents in the febrile phase as an acute illness with headache, body pains, chills, sore throat, rash (petechiae or ecchymosis) and laboratory evidence of thrombocytopenia and leukopenia. DENV can defervesce and resolve or enter the critical phase of illness with severe capillary leakage, shock and organ damage[131]. The reported incidence of DENV-induced ALF in adults ranges from 0.31%-0.71%, with younger adults being at higher risk[132]. The pathophysiology of ALF in DENV fever is hypothesized to occur via direct cytopathic effects of the virus infecting endothelial cells, Kupffer cells and hepatocytes causing cell damage and apoptosis and indirectly via host immune response to infection, microvascular leakage and shock[133].

Diagnosis of dengue is most commonly made by detection of dengue RNA or NS1 antigen during the first 7 days of illness or via DENV IgM after day 4[130]. While treatment of DENV is typically supportive, small studies in DENV-induced ALF suggest that N-acetylcysteine (NAC) may be beneficial in this population. Giri et al’s scoping review found a retrospective cohort study of 33 pediatric patients with DENV-associated ALF in Thailand that demonstrated a recovery rate of 75% for those treated with NAC versus 53% in those who received standard medical treatment, although the results were not statistically significant[132]. Another case series found a potential benefit of NAC in reducing the severity of ALF in DENV infection but no survival benefit[132]. LT for DENV-induced ALF is not common but has been reported. A recently published case series from Rajakumar et al[134] reported four cases of DENV-induced ALF, two of which recovered spontaneously and two required LT with one dying immediately post-transplant. Clinicians evaluating a patient for ALF should consider DENV as a cause if a patient has recently traveled to an endemic area.

There is a DENV vaccine available, CYD-tetravalent DENV vaccine, which has been shown to reduce the risk of severe DENV disease in secondary or subsequent infection where the risk for severe disease is higher[135]. The WHO recommends the use of CYD-tetravalent DENV vaccine in individuals ≥ 9 years old with serologic evidence of a previous DENV infection. In May of 2024 with the advent of data from the TAK-003 DENV vaccine, the WHO updated their recommendation encouraging countries to consider the introduction of TAK-003 into routine immunization programs, targeting children aged 6-16 years, in areas of high DENV transmission[136]. Further study is needed to understand if countries adopt TAK-003 in line with the WHO’s recommendation, and whether routine administration of vaccines confer protection against DENV-induced ALF.

HADV

HAdV is a non-enveloped double-stranded DNA virus which can cause mild, localized upper or lower respiratory tract infections, keratoconjunctivitis, and gastroenteritis in immunocompetent hosts[137]. HAdV has more than 100 genotypes and 52 serotypes identified to date. HAdV has been further classified into seven species, HAdV-A through -G, with different species demonstrating different affinities for various tissues of the body[138]. HAdV species A, F and G target the gastrointestinal tract and are known to cause gastroenteritis and diarrhea. In 2022, there was a documented outbreak of severe hepatitis in otherwise healthy young children in countries around the world, with more than 1000 children requiring hospitalization. In the United States, the CDC reported 6% of children in this cohort ultimately required LT, and 4% died. 299 of these patients were tested for HAdV, with 45% testing positive. HAdV-F41 was the most common HAdV species identified[139].

HAdV as a cause for severe ALI or ALF is extremely rare, predominantly occurring in immunocompromised hosts such as solid organ transplant recipients, bone marrow transplant recipients, or patients receiving active chemotherapy[140]. HAdV-induced ALF has a high mortality rate, estimated around 60%[137]. While not entirely understood, HAdV causes liver injury via direct cellular cytotoxicity and apoptosis, with viral uptake in hepatocytes and Kupffer cells having been demonstrated to be facilitated at least in part by viral binding to coagulation factor IX and complement component C4[141]. Further, HAdV is known to cause liver toxicity via immune-mediated mechanisms in response to IFN-γ and C-X-C motif ligand 9 production and signaling[142]. Diagnosis of HAdV-induced ALF can be established via liver biopsy, with possible histopathologic findings showing nonzonal coagulative hepatic necrosis, hepatocyte and intranuclear viral inclusions, and possible lack of inflammation[143]. When available, serum HAdV viral load may help support the diagnosis of HAdV-induced ALF in the appropriate clinical context[137].

Routine HAdV vaccination is only recommended for military recruits in the United States, who obtain a live oral vaccination for HAdV type 4 and type 7 to prevent febrile acute respiratory disease[144]. The WHO does not have specific HAdV vaccination recommendations. For treatment of HAdV-induced ALF, there is some indication, primarily in pediatric patients with ALI/ALF, that early administration of cidofovir may be an effective therapy[145,146]. In severe disease that has progressed to ALF, LT evaluation is warranted, and good graft function and post-transplant survival has been reported[147]. HAdV should be included as part of an initial broad diagnostic evaluation in a patient with a clinical and laboratory picture concerning for ALF, particularly in the setting of a viral-like illness. Further research of HAdV, and especially research into species and subspecies known to have gastrointestinal and hepatic tropism, is needed to understand whether HAdV is an underrecognized cause for ALI and ALF.

CONCLUSION

ALF is a rare, highly morbid, and fatal condition. A variety of acute viral infections are capable of causing massive hepatic necrosis which can lead to ALF. When ALF is suspected, a broad diagnostic workup including viral and non-viral causes is necessary for rapid diagnosis, appropriate treatment, and possible referral for LT evaluation. Further research involving novel diagnostic approaches, treatment efficacy, and patient outcomes in ALF will be critical to advancing our understanding of this heterogenous condition.