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Rabaan, A.A.;  Bakhrebah, M.A.;  Nassar, M.S.;  Natto, Z.S.;  Mutair, A.A.;  Alhumaid, S.;  Aljeldah, M.;  Garout, M.;  Alfouzan, W.A.;  Alshahrani, F.S.; et al. Emerging HEPATITIS Caused by Suspected Adenovirus. Encyclopedia. Available online: https://encyclopedia.pub/entry/24662 (accessed on 22 June 2025).
Rabaan AA,  Bakhrebah MA,  Nassar MS,  Natto ZS,  Mutair AA,  Alhumaid S, et al. Emerging HEPATITIS Caused by Suspected Adenovirus. Encyclopedia. Available at: https://encyclopedia.pub/entry/24662. Accessed June 22, 2025.
Rabaan, Ali A., Muhammed A. Bakhrebah, Majed S. Nassar, Zuhair S. Natto, Abbas Al Mutair, Saad Alhumaid, Mohammed Aljeldah, Mohammed Garout, Wadha A. Alfouzan, Fatimah S. Alshahrani, et al. "Emerging HEPATITIS Caused by Suspected Adenovirus" Encyclopedia, https://encyclopedia.pub/entry/24662 (accessed June 22, 2025).
Rabaan, A.A.,  Bakhrebah, M.A.,  Nassar, M.S.,  Natto, Z.S.,  Mutair, A.A.,  Alhumaid, S.,  Aljeldah, M.,  Garout, M.,  Alfouzan, W.A.,  Alshahrani, F.S.,  Sulaiman, T.,  Alfonaisan, M.K.,  Alfaresi, M.,  Alshamrani, S.A.,  Nainu, F.,  Yong, S.J.,  Choudhary, O.P., & Ahmed, N. (2022, June 30). Emerging HEPATITIS Caused by Suspected Adenovirus. In Encyclopedia. https://encyclopedia.pub/entry/24662
Rabaan, Ali A., et al. "Emerging HEPATITIS Caused by Suspected Adenovirus." Encyclopedia. Web. 30 June, 2022.
Emerging HEPATITIS Caused by Suspected Adenovirus
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This entry is adapted from the peer-reviewed paper 10.3390/pathogens11070712

In October 2021, a case of acute hepatic failure without any known cause was identified in the United States of America. Upon further investigation, other children aged 1–6 years were reported to have the same liver failure, and some of them were positive for adenovirus 41 type F. On 21 April 2022, the Centers for Disease Control and Prevention (CDC) released an alert after 74 cases were identified in United Kingdom (UK) between 5 and 8 April in children below 10 years of age, some of whom were also found to be positive for SARS-CoV-2. All the patients showed symptoms such as vomiting, diarrhea, jaundice, and abdominal pain. The patients’ liver enzymes were remarkably increased. A total of 650 cases had been reported from 33 countries as of 27 May 2022, among which 222 cases were reported in the UK alone. No connection with SARS-CoV-2 or its vaccine has been found so far.

autoimmune hepatitis acute hepatitis molecular mimicry pathology

1. Hepatitis

The inflammation of the liver is referred to as hepatitis. The liver is an important organ that helps the body to digest nutrients, filter blood, and fight various infections [1]. The functions of the liver might be affected when it is inflamed or damaged. Hepatitis can be caused by excessive alcohol consumption, pollutants, certain drugs, and infections, especially those that are due to viruses and certain other medical disorders [2]. Despite having different routes of transmission, viruses can affect the liver initially and are known as viral liver infections. Hepatitis A, B, C, and D are common types of hepatitis. Patients with this kind of infection are also prone to cytomegalovirus (CMV) and EBV [3].

1.1. Pathophysiology of Viral Hepatitis

Viruses enter the blood stream through different transmission routes. When an adenovirus infects a person, it replicates in the epithelial cells of the lungs and other gastrointestinal organs. The virus begins to block host macromolecular synthesis and mRNA transport to the cytoplasm after many replication cycles. These cellular disruptions damage host cells and may produce symptoms of disease in their hosts, such as respiratory stress [4]. Studies have suggested that the penton protein of adenoviruses seems to be virulent, in addition to the symptoms caused by cell lysis and the inhibition of cellular synthesis. In laboratory settings, the penton protein causes cells to separate from monolayers. However, the significance of this discovery has not yet been determined in a clinical environment. Adenoviruses are known for their long latency. The virus may stay latent in the host even after the disease symptoms have faded [5].
The three stages of symptoms are prodromal, icteric, and convalescent. The symptoms differ depending on the clinical/infection phase of the patient [6]. When the virus enters the bloodstream, it starts releasing compounds throughout the prodromal stage. Fever, exhaustion, headache, vomiting, nausea, joint problems, and skin rashes are among the symptoms caused by these substances. Because the bile ducts and hepatocytes are damaged in the icteric stage, conjugated bilirubin and transaminases are released into the blood [7]. The patient appears yellow and produces dark urine because of the conjugated and unconjugated bilirubin. The symptoms start to improve and the patient returns to normal conditions during the recovery stage [8].

1.2. Severe Acute Hepatic Failure

In children, hepatitis is not uncommon, although the severity of previously reported infections is not too severe compared to the recently reported cases [9]. In young children, the known causes of hepatitis are still a potential source of the disease. Early diagnostic evidence raises the suspicion of adenovirus, but further evidence is needed before reaching a reasonable conclusion [10]. Adenoviruses have previously been linked to severe hepatitis in children, but there are other factors and infectious agents that have not yet been investigated [11].

1.3. Laboratory Assessment

At present, there are no specific diagnostic criteria available to diagnose this acute hepatitis of unknown origin. However, serum ALT and AST levels (>500 U/L), with or without elevated bilirubin levels could be evaluated in suspected cases (patients presenting indications of acute hepatitis), as well as initial screening tests for hepatitis A–E virus infections [12]. Elevated ammonia levels and prolonged prothrombin time on testing could also be used to determine the progression of disease. Lipid profiling, kidney function tests, complete stool analysis, routine urine analysis, and complete blood counts could also be very helpful in the diagnosis of severe acute hepatitis. Immunoglobulins, lymphocyte subsets, creatine kinase, cardiac enzymes, C-reactive protein, autoimmune hepatitis antibodies, anti-nuclear antibody, screening pf poisons, and heavy metals may be tested in accordance with the signs and symptoms [13][14].
Apart from these clinical laboratory examinations, the use of abdominal ultrasound could also be beneficial to rule out other diseases. If the radiological examination supports a clear diagnosis of severe acute hepatitis, nasal pharyngeal swabs, whole-blood samples, vomit samples, urine, and stool can be collected immediately for further etiological diagnosis purposes. If possible, a liver biopsy should be collected and submitted to histopathological examination [15][16].

2. Adenovirus

Adenoviruses are non-enveloped, icosahedral viruses of medium size (90–100 nm) that contain double-stranded DNA [11]. Human infections can be caused by more than 50 immunologically different adenovirus types. Common disinfectants are unable to kill adenoviruses, although they can be found on surfaces such as doorknobs, items, and even the water of swimming pools and small lakes. Adenoviruses usually infect the respiratory tract, eyes, urinary tract, intestines, and central nervous system [17]. Fever, sore throats, coughing, pink eye, and diarrhea are all frequent symptoms. Infections affect children more frequently than adults, but adenovirus can affect any age group [3].
These infections normally only cause minor symptoms and clear up on their own after a few days. They are, however, more dangerous in those with weakened immune systems, particularly young children [18]. Individuals with compromised immune systems are especially vulnerable to adenovirus infection, which can cause serious sickness. Some people with adenovirus infections, particularly those with weakened immune systems, can have undiagnosed infections in their tonsils, adenoids, and intestines [16]. They can spread their infection for extended periods of time. Certain individuals can shed the virus for weeks or months without showing any symptoms [18]. The diagnostic methods for adenovirus include antigen detection, polymerase chain reaction (PCR), virus isolation, and serology. Molecular approaches are typically used to identify adenoviruses [18].

2.1. Adenovirus and Hepatitis

Despite the fact that adenoviruses are prevalent diseases that normally result in self-limiting diseases [16]. They can, however, produce severe infections involving many body organs, including the liver, in the immunocompromised host. A review of Stanford University Medical Center’s pathology database from 1995 to 2016 found 12 cases of viral hepatitis, including biopsies and autopsy samples [8]. There were eight pediatric cases, seven of whom underwent orthotropic liver transplants and one of whom underwent lymphoblastic leukemia chemotherapy. There were four adult patients, one of whom underwent chemotherapy for chronic lymphocytic leukemia, while the other two received hematopoietic stem-cell transplants for malignant tumors. One child had lympho-plasmacytic cancer and underwent chemotherapy over one year before contracting adenovirus hepatitis, but he did not receive treatment at the time. Nonzonal coagulative hepatocyte necrosis and distinctive intra-nuclear inclusions were seen in all these cases. The extent of hepatocyte necrosis ranged from minor to severe. There was no concomitant inflammation in the majority of cases (7/12; 58%). If inflammation was detected, it was localized and lympho-histiocytic. The results were localized within the liver in one case, necessitating an image-guided biopsy. Adenovirus was not found in this patient’s non-targeted liver biopsy, which showed no histologic evidence of the virus. In the juvenile sample, 63 percent (5/8) of patients died from organ failure, but the adult population had a 100% (4/4) death rate [19].
In immunocompromised hosts, adenovirus hepatitis is a rapidly progressing and highly deadly infection [20]. Infections were particularly prevalent in patients who had received liver transplantation in the pediatric context. All of the adults, on the other hand, had hematologic malignancies and underwent chemotherapy or hematopoietic stem cell transplantation [21]. Coagulative necrosis and distinctive intra-nuclear inclusions are common histologic findings. Although this virus has been linked to severe hepatitis in immunocompromised individuals, it has not been linked to severe hepatitis in children with healthy immune systems. This is question remains unresolved [5].

2.2. Adenovirus 41 Type F

Type F41 of the adenovirus is a common cause of severe diarrhea and diarrhea-related death in young children across the world. It was first discovered in the stool of a child with gastroenteritis in the Netherlands in 1973 [22]. Type F41 has also been known to cause severe gastroenteritis in children; it is characterized by fever, vomiting, and diarrhea [23]. Adenovirus type F41 gastroenteritis may be life-threatening and is a common reason for hospitalization. The symptoms of acute gastroenteritis caused by adenovirus F41 are similar to those caused by other viruses. This intestinal adenovirus varies from respiratory and ocular adenoviruses in tissue tropism and pathogenicity, but the structural basis for this divergence remains unclear [24].
The findings reveal that adenovirus F41 often follows a varied endemic pattern of illness with rare outbreaks, suggesting that short-term cross-sectional, case-control, or cohort studies may be at danger of misrepresenting local incidence estimates [24]. The recent reported prevalence of adenovirus F41 infections in children with diarrhea was 13% in Guatemala [25], 5.1% in Nigeria [26], 1.5% in Brazil [27], 21.5% in Ethiopia [28], 56.9% in China [29], 28.5% in Thailand [30], and 62.5% in Iran [31]. The epidemiology and burden of adenovirus F41 remain poorly described because of the endemic pattern of the disease, with seasonal changes in incidence, and the requirement of molecular diagnostics to sensitively detect the organism [23].

3. SARS-CoV-2 and Hepatitis

A new clinical syndrome, known as COVID-19-induced hepatitis (CIH) has been discovered in SARS-CoV-2 patients and is defined as a benign new form of transient hepatitis, with characteristics such as gradual onset, elevated levels of AST and ALT, dilated sinusoids with lymphocytic infiltration of the liver parenchyma, non-obstructive jaundice, stable underlying liver disease, and no radiological change [32]. There is no evidence that COVID-19 has been involved in hepatitis infections among children [12]. However, it is not clear whether these two viruses are interacting. The intensity of this outbreak may be due to an enhanced vulnerability among young children that emerged during the COVID-19 pandemic, as a result of reduced adenovirus circulation in the past two years [33].
During the COVID-19 Omicron-variant wave in early 2022, the reported cases of COVID-19 infections in the US among children surged substantially, leading to 1,150,000 reported cases in one week. Nearly 88,000 COVID-19 cases among children were reported in the second week of June 2022 [34]. A recent study from the UK reported that between 28 December 2020 and 8 July 2021, a total of 109,626 UK children aged 5 to 17 years were proxy-reported. Of these children, a total of 60,050 (20,054 younger and 39,996 older) were tested for COVID-19 using PCR tests and 4,078 children were found positive [35]. However, a study from Israel from February 2020 to November 2021 reported that of the total hospitalization cases due to COVID-19 infections, 41% were children (5–11 years) [33].
Several respiratory viruses, including adenoviruses, persisted at lower levels during the COVID-19 pandemic, including adenoviruses in adults and children. A past or concurrent COVID-19 infection might influence the severity of adenovirus infections [13]. According to a study, 20 children (suspected adenovirus infected) have also tested positive for COVID-19 infection [36]. However, according to local officials, not all children were initially tested for COVID-19, and it was also unclear how many children had previously been infected with COVID-19. In fact, children with COVID-19 have been reported to have hepatic involvement. However, this involvement is usually accompanied by mild hepatitis and normal liver function. Rare incidences of severe hepatitis in children have been reported in the literature as part of COVID-19 or multiorgan dysfunction syndrome. The impact of concurrent or coincidental adenovirus/COVID-19 coinfections is still unknown [36].
To determine whether the combined effects of SARS-CoV-2 and adenovirus are more harmful to the liver, further research studies are needed. This may help, although the sensitivity and specificity of GADOUR criteria have not yet been demonstrated. Overly sensitive scoring systems require extensive statistical research before they can be established.

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Subjects: Infectious Diseases
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Ali A. Rabaan
,
Muhammed A. Bakhrebah
,
Majed S. Nassar
,
Zuhair S. Natto
,
Abbas Al Mutair
,
Saad Alhumaid
,
Mohammed Aljeldah
,
Mohammed Garout
,
Wadha A. Alfouzan
,
Fatimah S. Alshahrani
,
Tarek Sulaiman
,
Meshal K. AlFonaisan
,
Mubarak Alfaresi
,
Saleh A. Alshamrani
,
Firzan Nainu
,
Shin Jie Yong
,
Om Prakash Choudhary
,
Naveed Ahmed
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Update Date: 01 Jul 2022
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