Editor’s Note: Non-hepatotropic viruses are significant pathogens in viral hepatitis. With advancements in diagnostic techniques, cases of hepatitis caused by non-hepatotropic viral infections are increasingly recognized in clinical settings. These viruses can manifest solely as hepatitis or in conjunction with other organ disorders. While most infections cause only mild liver damage, viruses such as HHV-6, Coxsackievirus, and adenovirus can lead to acute liver failure in immunocompromised patients, necessitating vigilant monitoring. At the recent 2024 First Jinling Hepatology Conference, Professor Jinghang Xu from Peking University First Hospital delivered a keynote lecture on “Fever with Hepatic Damage,” systematically introducing the etiological characteristics, clinical manifestations, and diagnosis of non-hepatotropic viral hepatitis, and shared relevant clinical cases.
The causes of acute liver failure in children vary by age group. In North America, an analysis of 531 cases of acute liver failure among children aged 4-17 years showed that the most common cause was indeterminate, accounting for 218 cases or 41%. Drug-induced liver injury, particularly from acetaminophen (APAP) overdose, accounted for 110 cases or 21%. Autoimmune liver disease was also a significant cause, accounting for 9%, with 48 cases. Genetic diseases such as Wilson’s disease were present in 7%, involving 36 cases. Apart from APAP, other drugs caused liver damage in 5%, with 27 cases. Although viral hepatitis was less common, it still accounted for 27 cases, including various types such as hepatitis A, B, C, and E, as well as those caused by EB virus, adenovirus, and others. Shock and ischemic injuries accounted for 3%, with 17 cases. Other less common causes included HLH, Budd-Chiari syndrome, mushroom poisoning, and leukemia.
The causes of acute liver failure in adults from non-hepatotropic viruses are diverse, including EB virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), varicella-zoster virus (VZV), human herpesvirus 6 (HHV-6), adenovirus (HAdV), Coxsackievirus, echovirus, rotavirus, measles virus, rubella virus, mumps virus, parainfluenza virus, respiratory syncytial virus, and parvovirus B19.
Clinical Manifestations
Influenza-Associated Liver Damage
Severe cases of influenza can lead to multiple complications, including viral pneumonia, secondary bacterial pneumonia, acute respiratory distress syndrome, shock, disseminated intravascular coagulation, and extrapulmonary manifestations in cardiovascular and neurological systems. Although liver failure due to influenza is rare, in severe cases of influenza A H1N1 infection, liver involvement occurs in less than 3% of cases, predominantly among patients with compromised immune systems, such as children, the elderly, pregnant women, and those with underlying health conditions.
EBV-Associated Liver Damage
EBV is associated with various diseases, including oncogenic conditions like nasopharyngeal carcinoma, lymphomas, and Burkitt lymphoma, as well as non-oncogenic diseases such as infectious mononucleosis, hemophagocytic syndrome, and chronic active EBV infection.
EBV hepatitis is uncommon. There is a close relationship between EBV infection and liver damage, which can manifest in several forms. Acute self-limiting hepatitis is the most common, with occurrence linked to age, EBV DNA load, and clinical type. Additionally, EBV infection can cause cholestatic hepatitis and liver failure, and may also be associated with chronic hepatitis, cirrhosis, and autoimmune liver disease.
In EBV-associated infectious mononucleosis (EBV-IM) related acute self-limiting hepatitis, liver damage is common but usually mild, with a good prognosis. However, transaminase levels can be mildly to moderately elevated, and some patients may also show increased cholangiocyte enzymes. This liver damage typically appears in the second to third week of illness and lasts no longer than three months. Despite this, a small number of patients may die from liver failure or require liver transplantation, particularly older patients, whose liver damage may be more severe.
For the middle-aged and elderly population, EBV infection leading to infectious mononucleosis (IM) may cause more severe liver damage. However, the incidence of enlarged lymph nodes and the classic triad of IM symptoms (fever, pharyngitis, and lymphadenopathy) is relatively lower, making early diagnosis challenging. It is important to note that while the proportion of liver damage among middle-aged and elderly IM patients is not high, given the aging population, this group’s liver damage should not be overlooked.
Previously, EBV hepatitis was often considered a complication of IM, but recent studies indicate that many middle-aged and elderly individuals may present with EBV hepatitis as the primary manifestation without typical IM symptoms. This suggests that the IM triad or EBV hepatitis may represent different clinical presentations of primary EBV infection across different populations.
Regarding EBV-induced acute liver failure, data from the United States from 1998 to 2012 show that out of 1,887 cases of adult acute liver failure, only 4 cases (0.21%) were caused by EBV. These patients often had compromised immune function, but there were also cases with normal immune function. The patients were predominantly adolescents, and historically, the mortality rate for this condition was high, reaching 87% (14/16), but some survived through liver transplantation.
Professor Jinghang Xu and colleagues have systematically introduced the clinical features of adolescent and adult EBV infection-related liver damage in the Chinese Journal of Hepatology.
CMV-Associated Liver Damage
Professor Yu Yanyan’s team conducted a retrospective study that found that in immunocompetent individuals, CMV infection often presents with symptoms similar to IM. However, compared to EBV infection, pharyngitis is milder, and cervical lymphadenopathy is less common. Additionally, CMV infection often leads to abnormalities in liver biochemical markers. In immunocompromised patients, CMV infection is more likely to affect multiple organs, including the eyes, gastrointestinal system, brain, and spinal cord, often resulting in more complex and severe conditions.
HSV-Related Liver Damage
Both HSV-1 and HSV-2 can cause hepatitis, which is rare in the immunocompetent population and typically occurs during the primary HSV infection. However, for immunocompromised individuals, such as newborns, long-term users of corticosteroids, HIV patients, cancer patients, hematological patients, and pregnant women, the risk of HSV hepatitis significantly increases. About 30% of HSV hepatitis patients have typical oral and/or genital lesions, but the clinical manifestations often lack specificity, making early diagnosis difficult. Notably, HSV hepatitis is one of the significant causes of early death after liver transplantation and often involves complications in the lungs and gastrointestinal tract, adding complexity and severity to the condition.
VZV-Related Liver Damage
Immunocompromised individuals are more susceptible to shingles and severe VZV-related complications. These complications may manifest as skin dissemination, i.e., extensive vesicular lesions far from the affected dermatomal area, as well as involvement of internal organs such as pneumonia, hepatitis, and encephalitis.
It’s important to note that some patients undergoing hematopoietic stem cell transplantation (HCT) or organ transplantation may experience visceral VZV reactivation. This reactivation might occur without preceding rash, presenting directly as hepatitis or pneumonia. In some cases, patients may initially experience acute severe abdominal pain, with the typical dermatomal rash appearing only 10-14 days later.
HAdV Hepatitis
HAdV-related hepatitis primarily occurs in immunocompromised populations, such as children who have undergone organ or hematopoietic stem cell transplantation. The clinical symptoms are nonspecific, with fever being the most common symptom. Other manifestations include fatigue, fever, abdominal pain, diarrhea, and jaundice.
Clinical Diagnosis
When diagnosing non-hepatotropic viral infections, clinical manifestations are an important reference. Patients may exhibit systemic inflammatory responses such as fever and lymphadenopathy, prominent liver damage symptoms, and may also have injuries in other areas, such as rashes, eye symptoms, respiratory and gastrointestinal discomfort, and neurological abnormalities.
In terms of laboratory examinations, methods such as non-hepatotropic virus-specific IgM antibodies, viral-specific antigens, PCR amplification of viral nucleic acids, and immunohistochemical staining in tissue biopsies help confirm the diagnosis. Although virus isolation is the gold standard, it is less commonly used in clinical practice due to its complexity.
In most cases, liver damage caused by non-hepatotropic viruses presents as acute and self-limiting, but it may also progress to liver failure, particularly in immunocompromised patients. Therefore, these patients should be given special attention for timely diagnosis and treatment. In some cases, antiviral therapy may be an effective treatment option.
