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Editor's note: Non-hepatotropic viruses are also important pathogens that cause viral hepatitis, and with the advancement of detection methods, the number of cases of hepatitis caused by non-hepatotropic virus infection is gradually increasing. These viral infections can manifest as hepatitis alone or in combination with lesions in other organs. Although most infections cause only mild liver damage, some viruses, such as HHV-6, coxsackievirus, and adenovirus, are predisposed to cause acute liver failure in immunocompromised patients and require a high index of suspicion. At the 1st Jinling Liver Disease Conference in 2024 held recently, Professor Xu Jinghang from Peking University First Hospital gave a keynote report on "Fever Combined with Liver Damage", systematically introduced non-hepatotropic viral hepatitis from the aspects of etiological characteristics, clinical manifestations and diagnosis, and shared relevant clinical cases.
Etiological features
The distribution of the etiology of acute liver failure varies among children of different ages [1]. In North America, the largest number of 531 cases of acute liver failure in children aged 4-17 years were unexplained at 218, accounting for 41%. Drug-induced liver injury, especially acetaminophen (APAP) overdose, was 110 cases, accounting for 21%. Autoimmune liver disease is also a non-negligible cause of acute liver failure in children, accounting for 9% of 48 cases. In addition, hereditary diseases such as Wilson's disease also account for a certain proportion of 7%, involving 36 cases. In addition to APAP, liver injury caused by other drugs accounted for 5%, with a total of 27 cases. Although the proportion of viral hepatitis is relatively low, there are 27 cases, including hepatitis A, hepatitis B, hepatitis C, hepatitis E and other types, as well as hepatitis caused by Epstein-Barr virus and adenovirus. Shock and ischemic injury accounted for 3% of cases, with a total of 17 cases. Other less common causes include HLH, Budd-Chiari syndrome, mushroom poisoning, leukemia, etc.
Non-hepatotropic causes of acute liver failure in adults are diverse, including Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV), human herpesvirus type 6 (HHV-6), adenovirus (HAdV), coxsackievirus, echovirus, rotavirus, measles virus, rubella virus, mumps virus, parainfluenza virus, respiratory syncytial virus, and parvovirus B19 [2].
Clinical presentation
Influenza-related liver damage
Severe cases of influenza can lead to a variety of complications, including viral pneumonia, secondary bacterial pneumonia, acute respiratory distress syndrome, shock, disseminated intravascular coagulation, and extrapulmonary manifestations such as cardiovascular and neurologic manifestations [3]. Although liver failure due to influenza is rare, less than 3 percent of patients are affected by severe influenza A H1N1 infection, which occurs in immunocompromised patients such as children, the elderly, pregnant women, and people with underlying medical conditions [4-5].
Liver injury associated with EBV infection
EBV is associated with a variety of diseases, including neoplastic diseases such as nasopharyngeal carcinoma, lymphoma, Burkitt lymphoma, and non-neoplastic diseases such as infectious mononucleosis, hemophagocytic syndrome, and chronic active EBV infection.
Epstein-Barr virus hepatitis is uncommon [6]. EBV infection is closely related to liver injury and manifests itself in many forms. Among them, acute self-limited hepatitis is the most common manifestation, and its occurrence is related to age, EBV DNA load, and clinical type. In addition, EBV infection may also lead to cholestatic hepatitis and liver failure, and may be associated with chronic hepatitis, cirrhosis, and autoimmune liver disease.
In EBV-IM (infectious mononucleosis)-associated acute self-limited hepatitis, liver injury is common, but most are mild and have a good prognosis. However, aminotransferases may be mildly to moderately elevated, and some patients may also have elevated bile duct enzymes. This liver damage usually appears in the 2-3 weeks of the course of the disease and lasts no more than 3 months. Despite this, a small percentage of patients die or require liver transplantation due to liver failure, especially in older patients, who may have more severe liver damage.
In middle-aged and older people, the liver injury caused by EBV infection may be more severe, but the incidence of lymphadenopathy and the typical triad of IM (fever, angina, and lymphadenopathy) is relatively low [6-9], making early diagnosis difficult. It is important to note that although the proportion of liver damage in middle-aged and elderly IM patients is not high [6,10-11], the liver damage in this population cannot be ignored in the context of population aging.
In the past, EBV hepatitis was often considered a complication of IM, but now studies have shown that in middle-aged and elderly people, many patients may have EBV hepatitis as the main manifestation without typical IM symptoms. This suggests that the IM triad or EBV hepatitis may be a different clinical manifestation in different populations after primary EBV infection.
In terms of acute liver failure due to EBV, data from 1998 to 2012 in the United States showed that only 4 of 1887 adults (0.21 percent) of acute liver failure were caused by EBV [12]. Most of these patients are immunocompromised but also immunocompetent [13-14]. The majority of patients are adolescents, and the case fatality rate of the disease was high in the past, at 87% (14/16), but some patients survived with liver transplantation.
Professor Xu Jinghang et al. wrote an article in the Chinese Journal of Hepatology entitled "Clinical Features of Liver Injury Associated with Epstein-Barr Virus Infection in Adolescents and Adults" [15], which systematically introduced the relevant contents.
Liver injury associated with CMV infection
A retrospective study conducted by Professor Yu Yanyan's team [16] found that in immunocompetent individuals, CMV infection often presents with symptoms similar to IM, but compared with EBV infection, angina is milder and cervical lymphadenopathy is less common. In addition, CMV infection often leads to abnormalities in liver function biochemistry. In immunocompromised patients, CMV infection is more likely to cause multi-organ involvement, including the eyes, gastrointestinal tract, brain, spinal cord and other organs, and the condition is often more complex and severe.
HSV-associated liver injury
Both HSV-1 and HSV-2 can cause hepatitis, which is rare in immunocompetent people and usually occurs at the time of initial HSV infection. However, the risk of HSV hepatitis is significantly increased in immunocompromised populations, such as neonates, patients taking glucocorticoids for a long time, patients with HIV infection, cancer patients, patients with hematologic disorders, and pregnant women [2]. Approximately 30% of patients with HSV hepatitis will have typical oral and/or genital lesions, but the clinical presentation is often non-specific, making early diagnosis difficult. Notably, HSV hepatitis is one of the important causes of early mortality after liver transplantation and is often associated with pulmonary and gastrointestinal involvement, which further complicates and exacerbates the condition [2].
Liver injury associated with VZV infection
People who are immunocompromised are more likely to develop shingles and severe VZV-related complications. These complications may manifest as cutaneous dissemination, which is the presence of widespread multiple vesicular lesions away from the dermatome affected by herpes zoster, as well as visceral involvement such as pneumonia, hepatitis, and encephalitis [17].
It is important to note that some patients who have undergone hematopoietic cell transplantation (HCT) or organ transplantation may experience visceral VZV reactivation. This reactivation may not be preceding the rash and may present directly in the form of hepatitis or pneumonia. In some cases, patients may begin with acute severe abdominal pain, which can be followed by up to 10 to 14 days before the typical skin lesions of herpes zoster develop [17].
HAdV肝炎
Hepatitis associated with HAdV infection occurs mainly in immunocompromised people, such as children after organ transplantation or hematopoietic stem cell transplantation, and the clinical symptoms are nonspecific, with fever being the most common symptom, and other manifestations include fatigue, fever, abdominal pain, diarrhea, and jaundice. The clinical manifestations of infection in different populations and subtypes are summarized below [18] (table 1).
Table 1. Clinical manifestations of HAdV disease
Clinical diagnosis
Clinical presentation is important in diagnosing non-hepatotropic virus infections, and patients may present with systemic inflammatory reactions such as fever and lymphadenopathy, marked with hepatic damage, and may also be accompanied by other site injuries such as rash, ocular symptoms, respiratory and gastrointestinal complaints, and neurologic abnormalities.
In terms of laboratory tests, serum IgM antibodies, virus-specific antigens, PCR amplification of viral nucleic acids, intranuclear inclusion bodies in tissue biopsy, and immunocytochemical staining are all helpful in confirming the diagnosis.
brief summary
Liver injury due to nonhepatotropic viruses is mostly acute and self-limited, but liver failure may also occur, especially in immunocompromised patients. Therefore, such patients should be paid close attention to timely diagnosis and treatment. In some cases, antiviral therapy may be an effective treatment.
References: (Swipe up and down to see more)
1. UpToDate Clinical Consultant: Etiology and Evaluation of Acute Liver Failure in Children
2. UpToDate Clinical Consultant: Etiology, clinical manifestations and diagnosis of acute liver failure in adults
3. Technical Guidelines for Influenza Vaccination in China (2021-2022)
4. Ann Hepatol. 2010; 9(1):107–111.
5. Jpn J Infect Dis. 2019 Sep 19; 72(5):347-349.
6. Food Pharmacol Ther, 2012, 36(1): 16-21.
7. Am J Med, 1976, 61 (3): 333-339.
8. Am J Med Sci, 1988, 295 (2): 122-124. .
9. Rev Infect Dis, 1989, 11 (1): 64-73.
10. GP, 1969, 40 (5) 127-134.
11. Lancet, 1984, 1 (8373): 396-397.
12. Dig Dis Sci, 2014, 59 (7): 1630-1637.
13. Liver Transpl Surg. 1998; 4(6):469-476.
14. Gastroenterology Res. 2016; 9(4-5):74-78.
15. Chinese Journal of Hepatology, Vol. 29, No. 10, Oct. 2021
16. Chinese Journal of Clinical Infectious Diseases,2016,9(5):453-455.
17. UpToDate Clinical Consultant: Epidemiology, Clinical Manifestations, and Diagnosis of Herpes Zoster
18. UpToDate Clinical Consultant: Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection
Source: Editorial Board of International Liver Disease