Non hepatotropic virus induced hepatitis - rising importance in a changing world

Abstract

A knowledge of the epidemiology and clinical aspects of non-hepatotropic viruses is becoming increasingly important in lieu of the rising incidence of acute liver injury caused by them in various circumstances. Broadly, they include the Herpesviridae group, the hemorrhagic fever viruses and certain respiratory viruses that infect the liver. They can affect both the immunocompetent and the immunocompromised individual, more commonly the latter as part of disseminated systemic infection with symptoms ranging from self-limited transaminitis to acute liver failure Various reasons for their rising importance are increased exposure to these viruses by way of: (1) Overcrowding, climatic and environmental changes, increasing tourism and settlement in hitherto unexplored areas where they are endemic and spread either by direct contact or through local fauna which serve as their reservoir host; and (2) Tampering with the normal protective human immunity by using immunomodulator drugs in scenarios of organ transplants, immune and non-immune related inflammatory disorders and various cancers, all of which are rising in incidence due to the aging world population living longer with many comorbidities. As such infections are relatively rare with non-specific presentation, and self-limited clinical course, they are seldom thought of or investigated for in the early disease stages which lead to the development of complications. This review of the most common non-hepatotropic viruses focusses on their epidemiology, etiopathogenesis, clinical manifestations, and management. They should be listed in the differential diagnosis of acute liver injury in appropriate clinical setting like recent travel to endemic areas, immunocompromised state, or exposure to these viruses.

Key Words: Viral hepatitis; Non-hepatotropic virus; Acute liver injury; Acute liver failure; Hemorrhagic fever virus

Core Tip: Liver infection by non-hepatotropic viruses is increasingly being encountered in the setting of emerging and re-emerging viral diseases the world over and the increasing use of immune altering medications in situations like organ transplant, immune mediated diseases and cancers, especially in the aging world population living with many comorbidities. Symptomatology can range from self-limited transaminitis in the immunocompetent to disseminated disease with acute liver failure in the immunocompromised. They are seldom detected as most infections have non-specific presentation and are self-limited. Early diagnosis can prevent complications. This review summarizes their epidemiology, clinical manifestations and management.

INTRODUCTION

Acute liver injury [ALI, including acute hepatitis and acute liver failure (ALF)] can be caused by multiple factors, hepatotropic viral infections (A-E) and drug/toxin being the two commonest. Other etiologies include autoimmune, biliary, metabolic, vascular (acute Budd-Chiari syndrome, veno-occlusive disease), other infectious causes, pregnancy [acute fatty liver of pregnancy and the hemolysis, elevated liver enzyme, low platelet (HELLP) syndrome], heatstroke, liver hypoxia-ischemia and malignant infiltration. However, in spite of detailed investigations, the etiology remains unidentified in significant number of cases. The incidence of ALI due to unknown cause vary considerably in different geographical regions mostly determined by local prevalence of viral etiology, drug/toxin exposure, environmental conditions and extent of investigations done. In older series it varied from 17%-44% in different parts of the world[1]. In more recent series from the western world (which include extensively investigated cases), it still varies from 5.5%-20% in adults[2-4], and 30%-50% in children[5]. The latest Asia Pacific Association for the study of Liver data projects the incidence of ALI and acute-on-chronic liver failure (an important way of initial presentation of ALI in the Asia Pacific) of unknown etiology as 5%-15% in the Asia Pacific[6]. In one Indian study it was found to be 10.1% [caused by cytomegalovirus (CMV) and Epstein Barr virus (EBV)] in adult patients, being much more common in ALI (9.9%) than in acute-on-chronic liver failure (0.01%) group[7]. Among cases of ALI needing liver transplant, the etiology is indeterminate in 4.5% in the European region[1]. Though the etiology in some is likely to be the uncommon ones mentioned above, a significant number may be caused by non-hepatotropic viruses which remain under-studied and under-reported due to their non-specific presentation, relative rarity, and self-limited clinical course and hence remain uninvestigated for. A list of the most common non hepatotropic viruses causing ALI is shown in Table 1.

Table 1 Non hepatotropic viruses causing acute liver injury.

Characteristics	Description
Herpes virus group
Type 1, 2	Herpes simplex virus
Type 3	Varicella zoster virus
Type 4	Epstein Barr virus
Type 5	Cytomegalovirus
Type 6	Human herpes virus
Emerging and re-emerging viruses
Hemorrhagic fever viruses
Flavivirus	Dengue virus subtypes 1-4, Yellow fever virus
Buniyaviridae	Crimean Congo haemorrhagic fever virus, Rift Valley fever virus, Lassa fever virus, Hantavirus
Filovirus	Ebola virus
Coronavirus	SARS-COV-2, SARS-COV-1, MERS COV
Orthomyxovirus	Influenza virus type A and B
Viruses predominantly affecting pediatric population but also immunocompromised adult host	Adenovirus type 41, Adeno-associated virus type 2, Parvovirus B19, Paramyxovirus (measles), Togavirus (rubella), Enterovirus (Coxsackie type A4, A9, B5 and echovirus), Norovirus

SARS-COV: Severe acute respiratory syndrome coronavirus, MERS COV: Middle East respiratory syndrome coronavirus.

IMPORTANCE OF THE EPIDEMIOLOGICAL KNOWHOW OF THESE VIRUSES

Many of the above mentioned viruses (e.g. exotic ones causing hemorrhagic fevers) are emerging or re-emerging in different parts of the world at different times causing high mortality. Possible reasons are: (1) Climatic changes like global warming; (2) Overpopulation, crowding and poor vector control; (3) Rising global tourism especially involving long-distance travel to hitherto unexplored, inaccessible areas with exposure to virgin indigenous flora and fauna helping the spread of local pathogens and vectors to other regions, as also the colonisation of endemic areas by unvaccinated migrants; (4) Increasing contact with wild animals resulting from deforestation, keeping exotic pets, consumption of exotic meat, spreading zoonosis; and (5) Increasing global trade in animal food products. In addition, there is the risk of these agents being used for bioterrorism in the modern times.

Recent outbreaks and potential threats[8]

In the last two decades, a number of major viral epidemics or pandemics have affected human populations, caused by viruses which have the potential to cause hepatitis like the filovirus, coronavirus, flavivirus, alphavirus, norovirus and myxovirus family. In addition, sporadic outbreaks have been caused by zoonotic RNA viruses like bunyaviruses and arenaviruses. In parallel, zoonotic viruses frequently spill into livestock and other animals, which can serve as reservoir hosts for further spillover into humans. Mosquito-borne flaviviruses (that cause dengue, West Nile fever, yellow fever and Rift Valley fever) are novel or re-emerging pathogens defined as category A/B pathogens by the National Institutes of Health. For the dengue virus (DENV), novel strains have caused major epidemics every few years since the early 2000 (2002, 2010, 2014, and 2020). In 2016, the yellow fever virus re-emerged in some west African countries, spreading to China through travel, before being controlled by mass vaccination. Influenza viruses continue to re-emerge after the 1918 H1N1 flu pandemic which killed nearly 50 million people globally e.g. 1957 (H2N2 Asian flu), 1968 (H3N2 Hong Kong flu), 2009 (H1N1 swine flu pandemic) which caused about 250000 deaths globally. In addition, there had been repeated sporadic outbreaks of avian H5N1, H7N9 and other influenza strains, with high mortality rates in humans. Two epidemics of the Ebola virus (defined as category A pathogen by the National Institute of Health) in Africa from 2013-2016 and from 2018-2020 had mortality rates of 40% and 65% respectively. The order Bunyavirales contains multiple viruses (causing hemorrhagic fever) that have caused outbreaks or have outbreak potential, and are listed as category A pathogens by the National Institute of Health owing to their high mortality rates (10%-40%). Among the coronaviruses, severe acute respiratory syndrome coronavirus (SARS-CoV) 1 had fatality rate of about 10%, the Middle East respiratory syndrome coronavirus (MERS-CoV) had fatality rates of 35% (in spite of fewer total cases) and finally, SARS-CoV-2 caused the current coronavirus disease 2019 (COVID-19) pandemic. All of these coronaviruses were traced back to bat origin, some using intermediate hosts such as camels and civet cats. Noro virus is the leading cause of gastrointestinal (GI) infections, triggering multiple epidemics in the last two decades leading to severe disease in children, the elderly and immunocompromised individuals and a projected 70000-200000 deaths per year globally.

With the increasing rate of liver transplantation globally, especially for the indication of acute hepatitis, it has become even more relevant to identify non hepatotropic viral infection as the primary hepatic insult. In general the increasing prevalence of chronic diseases worldwide (due to the rising geriatric population) that drive the need for organ transplants along with the technological advancements that enable transplants lead to their increasing demand. The immunosuppression needed post-transplant is an established cause of reactivation of as well as new infection by a number of viruses that could then indirectly cause hepatic injury (e.g. herpesviruses and others affecting the immunocompromised infants and adults)[9]. In addition, many of these viruses can be transmitted through transplanted organs. The anticipated magnitude of such problem can be gauged from the following. The latest 2022 data from the Global Observatory on Donation and Transplantation indicate that more than 150000 solid organ transplants (≤ 10% of global needs) and about 84000 hematopoietic stem cell transplants are performed annually[10,11]. The global organ transplant immunosuppressant drugs market size valued at 5.51 billion dollars in 2024 is projected to grow at a compound annual growth rate (CAGR) of 4.7% from 2025 to 2030[12]. In addition, the rising incidence of autoimmune disorders, non-autoimmune inflammatory diseases and different cancers furthers the use of immunomodulatory therapies (corticosteroids, monoclonal antibodies, biologics, immunosuppressives, small molecules, co stimulation blockers, etc.) and this drug market is projected to grow globally from 25.94 billion dollars in 2024 to 48.88 billion dollars in 2029 at a CAGR of 13.2%[13]. IARC’s report which shows 20 million new cancer cases in 2022 is projected to rise to 35 million annually by 2050 (77% increase)[14]. The two leading global therapy areas - oncology and immunology - are forecast to grow at 14%-17% and 2%-5% CAGR, respectively, through to 2028[15].

REVIEW OF THE VIRUSES

Non hepatotropic viral hepatitis can occur as an isolated illness but more commonly occurs as part of a systemic illness and its clinical manifestations may range from fever, chills, upper respiratory symptoms, abdominal pain, diarrhoea, myalgia, mild jaundice and transaminitis which are self-limiting. Uncommonly a disseminated disease can lead to ALF. Co-infection with some hepatotropic viruses may further complicate or delay diagnosis[16].

General mechanisms of liver injury in non-hepatotropic virus infections are: (1) Direct hepatocellular damage: Some non-hepatotropic viruses, such as CMV and herpes simplex virus (HSV), can infect hepatocytes directly, replicating within it or inducing a cytolysis. This can cause liver inflammation, necrosis, and even ALF in extreme cases; (2) Immune-mediated liver injury: Many non-hepatotropic viruses trigger immune responses that either damage liver tissue (e.g., an exaggerated T-cell response during EBV infection) or cause systemic inflammation (as in CMV or HSV infection) which adds to the liver dysfunction; (3) Cytokine storm: Viral infections can trigger the sudden release of large number of pro-inflammatory cytokines leading to systemic inflammation, including hepatic injury e.g. the influenza and COVID 19 virus; and (4) Co-infections and secondary effects: Co-infections with hepatotropic and non-hepatotropic viruses (e.g., EBV and hepatitis B) or viral reactivation in immunocompromised individuals (e.g., CMV) may potentiate liver damage.

HERPESVIRUSES[17,18]

CMV

CMV spreads mainly through body fluids (saliva, urine, blood, sexual fluids) and organ transplants. It can establish latency in tissues like epithelium, smooth muscle, and fibroblasts, with reactivation occurring in immunocompromised state. The infection is usually asymptomatic in immunocompetent individuals but may be severe in immunocompromised state with severe cholestatic hepatitis, granulomatous hepatitis, and acute fulminant hepatic failure[19]. In primary infection, the virus spreads to the liver sinusoids hematogenously, then disseminating to the hepatocytes and biliary duct cells causing direct as also cytokine mediated injury[20]. Solid organ transplantation, especially liver transplant, is another independent risk factor where it can mimic acute cellular rejection[9]. It commonly occurs in the first three months post transplantation with an incidence of 2.1%-29%, the risk being highest when the donor is CMV positive and the recipient is negative[21]. It is also observed in patients following COVID-19 infection and the DRESS syndrome[22,23]. It may present as a viral infection (fever, cytopenias) or as tissue invasive disease. The elevation of transaminase level differs among immunocompetent and immunosuppressed hosts. It is up to 10-fold in immunocompetent individuals due to the robust immune response with modest rise in bilirubin (up to 5-9 mg/dL), whereas it is up to two fold in the immunosuppressed but with high rise of alkaline phosphatase (1-10 fold) and gamma-glutamyl transferase (2-30 fold)[21,24].

Diagnosis is done based on a combination of serologic, molecular, culture-based methods, and histology tailored to the clinical context and patient population. CMV specific IgM is elevated within 3-4 weeks of infection and can last for six weeks or longer, hence it can be positive both in new infection or reactivation[16]. The differentiation (important for treatment and risk of complications) is done by the IgG avidity test where low IgG avidity indicates a recent primary infection (needing more aggressive therapy and closer monitoring), while high avidity suggested a past infection or reactivation[25]. Quantitative assay of CMV DNA by polymerase chain reaction (PCR) from the whole blood is more sensitive and predicts the risk and severity of infection but it may be absent in tissue invasive disease. The affected cells show typical nuclear and cytoplasmic inclusions (owl’s eye) in the absence of which immunohistochemical staining (for pp65 antigen) can be used. Mild cases are self-limiting, and needs only supportive treatment. Tissue invasive severe cases need intravenous ganciclovir 5 mg/kg twice a day or oral valganciclovir 900 mg twice a day for three weeks. Since the drug acts on DNA, myelosuppression, hepatotoxicity, and teratogenesis can occur so its use should initially be for 2-3 weeks. Treatment response should be monitored by measuring CMV DNA PCR weekly and discontinued when the virus is shown to be eradicated by repeat testing on one or two occasions[26]. Foscarnet and leflunomide may be considered in case of drug resistance (failure to lower CMV level even after 6 weeks)[27].

EBV

EBV infects the B lymphocytes (and is implicated in their immortalization and hyper-replication as in Burkitt’s lymphoma, MALToma of stomach, etc.). It spreads through saliva, genital secretions, organ transplants, and blood transfusions[28,29]. It infects over 90% of the world’s population, especially children and adolescents, presenting as infectious mononucleosis with fever, sweats, myalgias, with or without lymphadenopathy and organomegaly. Hepatic involvement occurs in 90%, majority being self-limited or subclinical. The transaminase elevation is 2-3 folds in majority but jaundice is seen in < 5% cases[30], with a cholestatic biochemical picture in about 65%[31] particularly in individuals > 40 years old[32]. Rarely liver involvement can manifest as isolated chronic hepatitis (mimicking autoimmune hepatitis, granulomatous hepatitis or vanishing bile duct syndrome). In the rare patients who progress to ALF, high transaminases > 1000 IU/L have been reported and in the United States its incidence was 0.21% in liver transplantation recipients with a high mortality[33]. Due to the B cell proliferation, it causes 60%-85% of post-transplant lymphoproliferative disorders with some involving the liver allograft[34]. In severe cases, it involves lymph nodes, GI tract, central nervous system, liver, lung, tonsils, and salivary gland needing multimodality treatment with surgery, chemotherapy and radiotherapy, whereas milder variety may improve with reduction of immunosuppressive drug dosage. It should be investigated for in cases of unexplained hepatitis in immunosuppressed individuals[35].

Liver injury is mostly immune mediated and diagnosed by serology and confirmatory PCR testing. The primary serological markers used are viral capsid antigen (VCA) IgM and IgG, Epstein-Barr Nuclear Antigen IgG, and heterophile antibodies. VCA IgM antibodies typically indicates an acute or recent primary infection, but it lacks specificity due to cross reactivity with other viruses and non-related antigens. VCA and Epstein-Barr Nuclear Antigen IgG antibodies indicate past infection[36]. Heterophile antibodies (detected by the monospot test) usually become detectable between 6-10 days following symptom onset and can persist for up to a year but false positives and negatives can occur[37,38]. Infection is suspected when transaminitis is coupled with lymphocytosis or splenomegaly. Histopathology is characterized by non-specific dense lymphocytic infiltrates in the portal tracts with a beaded appearance in a single file pattern (“string of beads”)[39], interface hepatitis, and mild fibrosis. Most recover within 4-6 weeks with supportive therapy. Acyclovir, a nucleoside analogue, and valacyclovir is approved for decreasing the transmission of EBV but also improve the hepatitis. Other drugs approved are ganciclovir, omacyclovir, maribavir, cidofovir[40].

HSV

Both HSV-1 and HSV-2 can cause florid hepatitis in all age groups, but more than 60% of the cases have been attributed to HSV-2. It is a rare and aggressive form of acute hepatitis that can rapidly progress to ALF without significant grade of encephalopathy. It accounts for about 0.7% and 1.4% of all ALF cases and 8.7% and 4.7% of the viral causes of ALF in the American and French series, respectively[18,41,42]. HSV hepatitis may occur as a primary infection or secondary to reactivation brought on by “stressors” such as immunocompromised state, malignancy, pregnancy, or inhalation anesthetic agents[43]. A review of 137 cases revealed it in 24% immune competent, 23% pregnancy, 30% transplant immunosuppressed individuals, and 23% non-transplant immunosuppressed persons. Concomitant herpetic rash was present in 44% cases. Only 42.4% of cases were diagnosed antemortem and 22.9% by clinical suspicion[42]. In pregnancy, it is often confused with acute fatty liver of pregnancy or the HELLP syndrome. In addition to fever, coagulopathy and encephalopathy, there is marked transaminitis [aspartate transaminase (AST) > alanine transaminase (ALT)] without significant jaundice and lymphopenia. Early identification is crucial for preventing mortality. IgM anti HSV serology has low specificity, the serum HSV DNA PCR test, although highly sensitive, is not easily available and liver biopsy, the preferred diagnostic procedure, may be contraindicated[44,45]. Gross liver morphology shows tan colored lesions and histopathology shows scattered acidophilic bodies, confluent areas of hemorrhagic necrosis, inflammation, intranuclear inclusions, and HSV + immunostaining. Mortality rates are high and early empirical acyclovir therapy on clinical suspicion (administered intravenously at 10 mg/kg every eight hours for up to 21 days or more depending on clinical status) without waiting for confirmatory test reports may improve outcome. In a review of published cases, the mortality was 51% with acyclovir treatment compared to 88% without treatment, indicating the importance of timely initiation of this treatment. Indicators of poor outcome were age over 40 years, male sex, ALT over 5000 IU/L, immunocompromised state, coagulopathy, encephalopathy, thrombocytopenia and absence of antiviral therapy[42]. HSV resistance to acyclovir has been observed in 3%-10% of the cases, and vidarabine, cidofovir or foscarnet can be used as alternatives[46].

Varicella Zoster virus

Primary Varicella Zoster virus (VZV) infection typically causes vesicular rash (chickenpox) mostly in children while reactivation (from the dormant state in the dorsal root ganglia) causes zoster (shingles) in adults, especially when immune compromised. Liver involvement ranges from mild hepatitis to ALF (rarely), especially in immunocompromised state [with or without additional involvement of lungs (interstitial pneumonitis), heart (myocarditis), pancreas (pancreatitis), and brain (meningoencephalitis)]. Elevation in liver enzymes is reported in up to 3.4% of the children with chickenpox and but in adult transplant recipients VZV infection can occur without cutaneous lesions. A modest 2-5 folds increase in transaminase is usual but in fulminant hepatic failure, the enzymes may be > 10 folds above normal[47-49].

Diagnosis is confirmed through histological examination (inclusion bodies), immunohistochemistry, and molecular techniques such as VZV PCR which is very sensitive for establishing the diagnosis from skin lesions. IgM tests have poor specificity (as specific IgM antibodies are transiently produced) and cannot discriminate between a primary infection and reinfection or reactivation. Prompt treatment with intravenous acyclovir is recommended for immunocompromised patients as also varicella zoster immunoglobulin[50,51]. For immunocompetent patients oral valacyclovir 1000 mg three times a day for seven days or acyclovir 800 mg five times a day for 7-10 days is recommended[48,52]. Varicella zoster immunoglobulin prophylaxis is recommended for susceptible seronegative patients following virus exposure. An inactivated vaccine (Shingrix) is administered especially in pre-liver transplant setting with questionable efficacy in such setting.

Human herpes virus-6 (human B cell-lymphotropic virus) variant B is mostly responsible for symptomatic infections and most primary infection occurs within the first 3 years of life (rubeola). It may get reactivated in post transplant setting due to immunosuppression causing fever, rash, cytopenia, interstitial pneumonitis, and hepatitis. PCR is the best diagnostic method. Antiviral agents include those active against CMV, including ganciclovir, foscarnet, and cidofovir[53].

EMERGING AND RE-EMERGING VIRUSES[54]

Hemorrhagic fever viruses

Majority of infections caused by these viruses are either subclinical or produce mild flu like symptoms (fever, malaise, body aches, nausea and bowel disturbance) which are self-limiting. Liver is affected as part of disseminated systemic disease with multiorgan involvement (kidney, brain, lungs) in a minority of patients. Transaminases are elevated 5-10 folds (or even more in dengue), which correlates with severity, but with relatively less elevation of bilirubin (except yellow fever). Platelet counts are low and the prothrombin time is deranged with/without disseminated intravascular coagulation. There is direct cytopathic effect of the virus and also the effect of the inflammatory cytokines produced by the infection on hepatocyte and vascular endothelial cells which result in liver failure and hemorrhage. Hepatic involvement is most extensive in yellow fever, dengue hemorrhagic fever, Crimean Congo hemorrhagic fever and Rift Valley fever. The epidemiological features of these viruses are summarized in Table 2 and other clinical features of the most widely prevalent of these i.e. the DENV are discussed below.

Table 2 Epidemiologic features of viruses causing hemorrhagic fever.

Virus name	Geographic areas, incubation period	Vector, host and transmission	Diagnosis, treatment, case fatality rate (in severe cases)	Prevention
Crimean Congo hemorrhagic fever	Africa, Asia and southern Europe (Balkan region)	Ixodid tick of Hyalomma spp	RT-PCR	Avoid tick bite; no vaccine available
		Cattle and other mammals	Ribavirin, methyl prednisolone
	1-5 days following a tick bite or 5-7 days following contact with infected blood	Humans acquire disease as accidental host by direct tick bite or contact with infected blood	5%-40%
Ebola fever	Mostly central and West Africa	Fruit bats reservoir	RT-PCR or ELISA for Ab	2 vaccines: (1) Ervebo (rVSV-ZEBOVGP), a live-attenuated vaccine, has very high efficacy after a single shot (up to 97.5%); and (2) One shot of Zabdeno (Ad26. ZEBOV-GP) followed by a shot of Mvabea (MVA-BN-Filo) 8 weeks later requires more time to induce protection (so not suitable for immediate effect in an outbreak) but protects over a longer period
	2-21 (6-10) days	Transmitted by direct contact or via bodily fluids of vector host (primates including humans)	Inmazeb (REGN-EB3), a mixture of 3 monoclonal Ab (atoltivimab/ maftivimab/odesivimab) given: 50 mg/kg in a single IV infusion, and Ebanga (Ansuvimab-zykl), a human monoclonal Ab 50 mg/kg administered within 1 hour
			50% (30% with treatment)
Lassa fever	West Africa	Rodents (multimammate rat of Mastomys spp)	RT-PCR. ELISA for IgM and IgG Ab	Avoid exposure to rhodents
	1-3 weeks	Inhalation of virus containing aerosolised rat excreta (urine, feces) or consuming contaminated foods or by direct contact with abraded skin. Human-to-human transmission may occur through direct contact with blood or bodily secretions from infected persons	Supportive and start ribavirin as early as possible: 15 mg/kg/day × 10 days	No vaccine available
			15%-20% (among 20% severe cases)
Hanta fever	Liver involvement only in HFRS (caused by Seoul type virus) found in Europe and Asia	Rodents	ELISA for Ab or immunofluorescence assay	Avoid contact with rhodents
	2-4 weeks	Virus containing aerosols in rodent excreta	Early ribavirin	No vaccine available
Rift Valley fever	Africa and the Arabian Peninsula	Arthropod borne, predominantly mosquitoes (Aedes and Culex species) from natural host i.e. livestock	RT-PCR, ELISA	Vaccinating livestock. Early detection in them and avoid contact
	2-6 days	Human transmission is by contact with animals	Ribavirin, favipiravir show in vitro effect only	No human vaccine available
			50% (among 5% severe cases)
Dengue fever	(Sub) tropical areas of America, Africa, Middle East, Asia and Pacific islands	Aedes aegypti, Aedes albopictus mosquitoes	RT-PCR, ELISA for IgM and IgG Ab, NS1 antigen	Mosquito repellent. Two WHO approved vaccines: (1) Dengvaxia (3 doses six months apart) for people aged 6-60 years but to be given only in laboratory-confirmed previous dengue virus infection; and (2) Qdenga (2 doses three months apart) in children aged 6-16 (upto 60 years for those with comorbidities) in high dengue transmission settings
	4-7 days	Mammals (mostly humans)	Supportive
			5% severe, acute liver failure in 0.5%
Yellow fever	(Sub) tropical Africa and South America	Sylvatic (forest) cycle: Africa (Aedes africanus), South America (Haemagogus and Sabethes species and urban cycle: Aedes aegypti (both Africa and South America). Primates	IgM Ab by ELISA	Mosquito repellent
	3-6 days		Supportive, ribavirin, sofosbuvir has been tried	Live attenuated vaccine given to 9 months or older individuals
			20%-60% (among 15% severe cases)	Other live vaccines are in phase III-IV trial

RT-PCR: Reverse transcriptase polymerase chain reaction; ELISA: Enzyme linked immunosorbent assay; HFRS: Hemorrhagic fever with renal syndrome; Ab: Antibodies.

DENV hepatitis[18]

50% of the world population is at risk of DENV infection and each year 100-400 million cases occur of which about 70% is in Asia[55,56]. All 4 serotypes are associated with hepatitis and ALF. The symptom range varies from asymptomatic infection to mild fever with body ache (80%) to life-threatening dengue hemorrhagic fever and dengue shock syndrome (5%). Severe infections are associated with secondary infections by heterologous serotypes. Reinfections are possible as there is no cross immunity.

The liver is commonly involved in DENV infection and manifest with no or minimal elevation of transaminases to moderate elevation > 10 folds (4-15% cases)[57]. Severe injury caused massive rise in transaminases > 1000 (rarely > 20000) IU/L and rarely progress to ALF with relatively mild hyperbilirubinemia (0.3%-0.7% cases)[58,59]. Such level of transaminase elevation along with hepatomegaly and ascites are listed as warning signs of severe dengue infection by the World Health Organization (WHO)[60]. Usually, AST is more than ALT levels.

ALF presents with catastrophic suddenness in the afebrile or defervescence (recovery) phase of the disease. In a large Indian series spanning from 2014 to 2017, 36 of 10108 patients with DENV infection (0.35%) exhibited features of ALF (72% having features of hyperacute liver failure)[57]. Another study from Thailand reported 6/1926 (0.3%) ALF among dengue cases[61].

However, the degree of transaminase elevation, though correlates with disease severity, does not distinguish between survivors and non survivors[58], and so also the degree of bilirubinemia and the presence of coagulopathy despite their levels being higher in non-survivors. The predictors of mortality were other features of systemic involvement like admission acidemia, serum lactate, and hemoglobin[62]. Other chronic liver conditions, such as preexisting cirrhosis, or overweight/obese patients who have co-existing steatotic liver disease have higher mortality[63,64].

Pathogenesis of liver injury involves various combinations of direct cytopathic effects, host immune response affecting the hepatocytes, apoptosis, micro vesicular or macrovesicular steatosis (via disruption of mitochondrial machinery), circulatory compromise (causing hypoxic or ischemic hepatitis), intrahepatic sinusoidal microcirculatory dysfunction, localized vascular leakage and rhabdomyolysis (causing more AST elevation). A second bout of infection which elicit a specific range of antibody may cause severe illness and liver injury by a mechanism known as antibody-dependent enhancement of disease[65].

DENV infection in children appears to cause more severe disease than adults resulting from hemophagocytic lymphohistiocytosis which presents with prolonged fever, worsening cytopenia, hepatosplenomegaly and confirmed by a bone marrow aspiration/biopsy.

The diagnosis is established by the NS1 antigen test and detection of IgM antibody against DENV. Treatment is largely supportive. Patients with severe disease need treatment in advanced facilities through maintaining hydration, blood pressure, and supporting organ failure when it happens which is the key to reducing morbidity and mortality. Although used, the role of N-acetyl cysteine in patients with ALF is controversial and not evidence based.

Coronavirus

Liver involvement in SARS-CoV-1 infection was 60%, MERS CoV was 60%, and SARS-CoV-2 infection (which caused COVID-19) is 14.8%-53%, more in severe disease and in those with digestive symptoms, as diagnosed based on liver enzyme elevation and decrease in albumin level[66,67]. In COVID-19, hepatic injury is defined by elevation in ALT or AST > 3 folds, alkaline phosphatase or gamma-glutamyl transferase > 2 folds, or total bilirubin[66,68]. The incidence of liver injury in severe COVID-19 patients (74.4%) was higher than in mild disease (43%) and that in COVID-19-associated deaths was 58%. Pathological findings were non-specific including steatosis, prominent mitosis, acidophilic bodies, and mild to moderate portal tract and lobular lymphocytic inflammation. COVID-19-associated liver symptoms are generally mild and self-limiting and treatment is supportive. Factors involved in hepatic injury include direct viral cytopathic effects, exaggerated immune responses/systemic inflammatory response syndrome, hypoxia-induced changes, vascular changes and endothelitis due to coagulopathy and microcirculatory dysfunction, hepatic congestion from right heart failure, gut dysbiosis with disruption of gut–mucosal barrier and drug-induced liver injury[67,69]. Other contributory factors are shown in Figure 1. The management is mostly supportive in majority of patients without pre-existing liver disease (with possible avoidance or use of hepatotoxic drugs in lower dose). However, special emphasis is needed in patients with steatotic liver disease, alcohol related liver disease, hepatitis B and C infections, cirrhosis, hepatocellular carcinoma, and in liver transplant recipients. Treatment is continued for hepatitis B and C, autoimmune hepatitis, post liver transplant, and hepatocellular carcinoma. Steatotic liver disease (with associated obesity, diabetes mellitus, alcohol use) have higher risk of severe COVID-19 and higher liver involvement. Cirrhosis patients have higher mortality than non cirrhotics, and so also those with higher Child-Turcotte-Pugh grade[66].

Figure 1 Factors affecting severity of liver injury in coronavirus disease 2019 infection. SLD: Steatotic liver disease; ARLD: Alcohol related liver disease; HCC: Hepatocellular cancer; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ALP: Alkaline phosphatase; GGT: Gamma glutamyl transferase; SARS-CoV: Severe acute respiratory syndrome coronavirus.

Degree of liver dysfunction (higher ALT/AST and lower albumin) are directly related to severity and mortality in patients with COVID-19. Those with severe liver injury (ALT > 5 folds elevated) had more severe clinical outcomes, including higher intensive care unit (ICU) admission rates (69% vs 42% vs 16%), intubation (65% vs 38% vs 13%), renal replacement therapy (33% vs 15% vs 7.5%), and in hospital mortality (42% vs 23% vs 21%) as compared to those with lesser degree or no elevation of transaminases respectively. Among patients with severe liver injury, 70% required vasopressors, 39% were paralyzed, 12% received inotropes, 10% needed proning, and 2.8% required extracorporeal membrane oxygenation[70].

An international registry found higher mortality in cirrhotic patients (32%) compared to non cirrhotics (8%) with a strong correlation between the stage of liver disease and the rate of ICU admissions, renal replacement therapy and death, though respiratory symptoms were similar among the groups at admission. Majority (71%) of deaths were respiratory cause related but 19% had liver related cause. GI side effects were comparatively higher in cirrhotics. Furthermore, baseline liver disease stage and alcohol-related liver disease were risk factors for death[71].

Influenza virus

While influenza primarily affects the respiratory system, it has been linked to liver dysfunction and hepatitis in some instances, especially during severe infection or in immunocompromised individuals. In the 2004 H5N1 influenza (bird flu) outbreak, about 60% of patients with pneumonia had deranged liver function tests with GI symptoms such as vomiting, abdominal pain and diarrhoea on initial presentation[72]. A global pooled analysis showed higher odds of hospitalisation, ICU admission and mortality in influenza affected chronic liver disease patients in the 2009 HINI pandemic[73]. Similarly a multicenter study from 2013 to 2014 reported a two-fold increased risk of hospitalization, specifically due to influenza virus infection in liver disease patients[74]. Influenza causes hepatic decompensation and high mortality in cirrhosis patients[75-77].

Adenovirus

In the waning period of the COVID-19 pandemic in 2022, a sudden surge of acute hepatitis of unknown etiology in children surfaced in the United Kingdom[78] following which the WHO issued the Multicountry Disease Outbreak News on Acute hepatitis of unknown aetiology on 23 April 2022. Since then, such affliction among young children have been reported from all over the world. As of 22 June 2022, 920 probable cases fitting the WHO case definition [any child up to 16 years of age presenting with non A-E hepatitis with serum transaminases > 500 IU/L (AST or ALT)] have been reported from 33 countries in five WHO Regions. The majority (n = 460; 50%) are from the WHO European Region (22 countries), among whom the majority (70%) are from the Great Britain and Northern Ireland alone. Others are from the Region of the Americas (n = 383, 39.1%, 50% from United States), Western Pacific Region (n = 61), the South-East Asia Region (n = 14) and Eastern Mediterranean Region (n = 2). Of the etiologies identified, 327 (35.5%) were caused by adenovirus, 44 (4.8%) by adenovirus type 41 and 64 (7%) by SARS-COV-2 + adenovirus[79]. Some had co-infections with CMV, EBV and enterovirus also[80]. While most patients recovered uneventfully with conservative management, 45 children required liver transplantation[81], but case reports of using corticosteroids and intravenous cidofovir as treatment are also available[82].

In a Romanian study of adenoviruses in children mostly from the prepandemic period, overall viral co-infection was present in 22.9% (mostly rotavirus and norovirus but also EBV, CMV, SARS-COV-2, enterovirus, influenza, measles and respiratory syncytial virus). 21.5% had altered liver function test of which 75% had increased AST only (6 had > 500 IU/L, all with 3 coinfecting viruses). Coinfection rate was similar among those with (34.1%) and without (30.8%) transaminitis. This not only shows that adenovirus itself can cause hepatitis but coinfection with other non-hepatotropic viruses can often occur in such patients[83].

It is postulated that adenovirus acts as a trigger in presence of a cofactor like adeno associated virus (AAV) type 2 (AAV2, which needs the adenovirus to complete its lytic replication cycle) or human herpesvirus type 6[17,84] leading to liver injury by immunological mechanisms, This is supported by the presence of higher concentrations of AAV2 in liver and body fluids of patients than in controls, the absence of adenovirus in explant livers and increased incidence of AAV2 in patients post COVID-19[85,86]. In a recent report from Egypt, adenovirus etiology has also been identified in adults with acute hepatitis due to unknown cause, some with coinfection with hepatotropic viruses[87]. In addition to severe hepatitis, adenoviruses can cause a variety of other clinical syndromes especially in immunocompromised individuals, as it can establish latency in human tissue over prolonged periods. Its transmission with the donated organ is a risk factor for hepatitis in pediatric liver transplantation[88].

OTHER VIRUSES

The following viruses predominantly affects children, most being mildly symptomatic and self contained. Rarely they can lead to hepatitis and ALF in the setting of multisystem involvement[89]. They can potentially affect adults also, especially if immunocompromised.

Enteroviruses

Coxsackievirus A (type 4, 9) and B (type 5) and echovirus can cause viral hepatitis in severe cases, often seen in children and is a relevant cause of ALF in neonates as part of multisystem involvement. Patients generally have a good prognosis with mild symptoms with rare instances of severe jaundice or elevated ALT, AST level[90].

Parvovirus B19

Hepatitis typically occurs with systemic infection in pediatric patients. Histologic findings include extensive hepatocyte necrosis, marked extramedullary hematopoiesis and characteristic “ground-glass” intranuclear inclusions within the hematopoietic cells[91]. It is also believed to cause chronic hepatitis, though evidence remains limited.

Paramyxoviruses

Measles can lead to a variety of systemic complications, including hepatitis in some cases. Out of a total of 80 adult patients with measles, liver enzymes were elevated in 65 (81%) upon admission, over 5 folds in 18 (22.5%) and over 10 folds in 5 (6.25%) patients[92]. Rubella Virus can sometimes cause hepatitis as part of the infection process[93,94].

Norovirus

In a detailed literature search from 1967 to 2019, only 17 adult cases were identified[95].

CONCLUSION

NHV are an emerging cause of acute hepatitis in both healthy and immunocompromised individuals. These viruses include the Herpesviridae group, hemorrhagic fever viruses and some respiratory ones that can infect the liver (adenovirus, coronavirus, influenza virus). Most infections are self-limiting, presenting with non-specific signs and symptoms with or without mild transaminitis and jaundice. Liver involvement can be prominent in HSV, VZV, adenovirus, yellow fever, dengue hemorrhagic fever, Crimean Congo hemorrhagic fever and Rift Valley fever infections. Knowledge of the epidemiology and clinical manifestations of these viruses can help clinicians, in both endemic and nonendemic areas, to suspect them early and to apply adequate diagnostic methods in appropriate clinical setting like recent travel, exposure to vectors and viruses, and immunosuppressed state. Elevation of transaminase can be of varying levels but correlates with disease severity and often with AST > ALT. Viral detection by serum PCR is the best method for diagnosis but IgM antibodies can also help in some cases. Some of the herpesviruses responds well to acyclovir, ganciclovir and their prodrugs if initiated early. Other drugs such as vidarabine, cidofovir, foscarnet, omacyclovir, maribavir, leflunomide have limited efficacy and are under trial. For other viruses, the treatment is virtually always supportive and, except for yellow fever, vaccines are still under development. Therefore, it is best to initiate necessary control measures in case of outbreaks, as also to detect these viruses timely to prevent morbidity and mortality.