There are many pathogens that cause liver infections, and common pathogens include various pathogenic microorganisms, such as viruses, bacteria, fungi, spirochetes and parasites, which can cause a variety of infectious liver diseases and different clinical manifestations. The most common pathogens are viruses, including hepatitis virus (HAV~HEV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), coxackie virus (Coxackie virus), herpes simplex virus type 1/2 (HSV-1/2), human herpesvirus type 6 (HHV-6), and microvirus B19 (PHV B19). Infectious toxic liver disease can also be caused by systemic viral infections, such as hemorrhagic fever virus, measles virus, rubella virus, etc.
Viral hepatitis caused by hepatitis viruses is the most common infectious liver disease. In addition to this, relatively common are CMV hepatitis, EBV hepatitis, and coxsackievirus hepatitis. They usually present as acute hepatitis, and a few cases of acute liver failure have been reported. The diagnosis and differential diagnosis can be established by detection of serum-specific IgM antibodies or (and) detection of viral nucleic acids in plasma or blood mononuclear cells by PCR. The disease is mostly self-limiting. Some of the lesions and manifestations of the primary infection are common, but they may also present as chronic active lesions or persistent states. There is no specific treatment, but antiviral drugs are available. The prognosis is good and the disease is mostly self-limiting.
CMV hepatitis
Cytomegalovirus hepatitis is a liver disease caused by human cytomegalovirus (HCMV) with jaundice, liver enlargement and liver function impairment as the main clinical manifestations.
CMV is one of the eight human herpes viruses, which can infect both humans and animals, and there are several genera, but each has its own species specificity. CMV infects humans in two ways: (1) active infection; and (2) latent infection, and has a wide range of cellular susceptibility to epithelial cells, endothelial cells, and leukocytes, as well as to specific parenchymal cells such as brain and retinal nerve cells, gastrointestinal cells, and hepatocytes. The prevalence of CMV infection varies widely around the world. In developed countries such as the United Kingdom and the United States, the rate of CMV antibody positivity is 50% to 80% among people of moderate to high socioeconomic standards, and nearly 20% of children under 15 years of age and 50% to 60% of people under 25 to 30 years of age are infected with CMV; while in developing countries, 80% of children are infected before the age of 3 years, and the incidence of congenital CMV infection is about 0.3% to 2.4%, and in adulthood, the infection rate can even The incidence of congenital CMV infection is about 0.3-2.4%, and in adulthood, the infection rate may even reach 100%.
CMV can infect a variety of cells in the liver, including hepatocytes, bile duct epithelial cells, and vascular endothelial cells. CMV infection of hepatocytes produces typical intracellular Cowdry type A inclusion bodies and enlarges the infected cells. It may be accompanied by basophilic, granular inclusions in the cytoplasm. These large intranuclear and cytoplasmic inclusions contain the viral capsid and specific antigens. Typical intracellular inclusions are diagnostic. Liver biopsy reveals multiple focal hepatic necrosis, hepatocyte steatosis or macrocytosis, scattered infiltration of single nucleated cells in the confluent and central venous areas, extramedullary hematopoiesis and cholestasis. The extent and degree of hepatocyte involvement determines the clinical presentation.
HCMV causes acute and chronic hepatitis in the general population and can even cause acute liver failure and cirrhosis. there is no gender or seasonal variation in CMV hepatitis. the clinical presentation of acute CMV hepatitis can be characterized by varying degrees of fever, and most patients have varying degrees of jaundice and generally sludge bile.
The clinical diagnosis of cytomegalic hepatitis must exclude hepatitis A to E virus infection and other liver damage-causing pathogens (e.g., EBV), metabolic liver disease, drug and toxic hepatitis, and positive serum CMV-IgM, positive PCR test or isolation of CMV.
Positive anti-CMV IgG indicates CMV infection. A switch from negative to positive anti-CMV IgG indicated primary infection. A 4-fold or greater increase or decrease in the level of specific I gG antibodies in the two previous sera may also indicate the development of a virulent infection in vivo. Because of the interference of rheumatoid factor and I gG competing antigens, the specimen should be pre-treated to remove them to avoid false positives. Repeated lysis of serum should be avoided to ensure good reproducibility and specificity of the test. Immunohistochemistry is used to detect CMV antigens such as pp 65 in the peripheral blood leukocytes of patients, which can be used not only as a basis for antigenemia, but also to quantify the degree of CMV infection and to follow up the changes of disease and treatment effect. In situ PCR can be used to detect DNA in tissue cells. In addition, if the specific CMV mRNA is detected, a positive result can indicate an active infection.
Antiviral therapy: Ganciclovir, as a broad-spectrum anti-DNA virus drug, has a significant anti-CMV effect. However, it only works in virus-infected cells. However, ganciclovir is only a viral inhibitor that can only suppress virulent infections and terminate further virus damage to the liver, but cannot completely destroy the virus; viral mutations (mainly in the UL 97 phosphotransferase and UL 54 DNA polymutase genes of CMV, resulting in drug resistance) have been found in adult patients. Valganciclovir (an ester of ganciclovir and valine) is available for oral use in adult patients. However, the safety and efficacy of valganciclovir have been reported to be no better than those of acyclovir and ganciclovir. Ganciclovir combined with gammaglobulin and methylprednisolone is effective in the treatment of cholestasis. Phosphonoformic acid is an antiviral complex of trisodium phosphonoformate, which can inhibit the DNA polymerase of human herpesvirus, and therefore can be used against CMV. The drug is excreted in urine, and up to 30% of each dose is deposited in bone. The dosage for adults is 60 mg/kg every 8 hours for 14-21 days, and then 90-120 mg/kg once daily for maintenance. The drug is rarely used in pediatric patients because of its nephrotoxicity and skeletal deposition.
EBV infection causes liver damage
EBV infection has a 90% prevalence in the population and is associated with many human diseases, including infectious mononucleosis, EBV-associated lymphoproliferative phagocytic syndrome, chronic active EBV infection, EBV-associated immunodeficiency disease, and EBV infection-associated tumors (e.g., nasopharyngeal carcinoma, gastric cancer, Burkitt’s lymphoma, Hodgkin’s disease, T/N K-cell lymphoma, etc.).
EBV is a B lymphocyte-loving human herpesvirus that primarily invades B lymphocytes and has an affinity for human B lymphocytes, pharynx and glandular cells. EBV receptors are also found in the parotid ducts, pharynx, and some epithelial cells outside the cervix.
In a study of chronic active EBV infection, a Japanese clinical study of 82 patients aged 5 months to 53 years showed that 79.3% of patients had hepatomegaly and 67.1% had abnormal liver function. In a study of acute infectious mononucleosis, the results of a study of acute infectious mononucleosis in adults in China showed that 81-91.3% of patients had lesions involving the liver with clinical manifestations of abnormal liver function. The mechanism of EBV damage to hepatocytes has been reported to be through the hyper-radicalization of lipid peroxidation in EBV-infected cells, which has a toxic effect on hepatocytes, while EBV itself does not have a direct cytocidal effect on hepatocytes.
Currently, the most accurate, convenient and rapid method of detecting EBV in clinical practice is the serological antibody test. A significant increase in IgM antibody titer in the early stages of EBV infection indicates the presence of primary EBV infection, and a positive IgM antibody indicates acute infection.
The traditional laboratory diagnosis of EBV infection is based on an antibody test that detects a positive VCA-IgM and a negative EBNA-IgG to confirm the infection, but the VCA-IgM is short-lived and therefore not sensitive enough. Nowadays, serum EBV load is measured to confirm EBV infection. It has also been suggested that testing EBV DNA in pharyngeal swabs is more sensitive than testing EBV DNA in serum. For chronic EBV infection, a positive tissue biopsy for EBV DNA has diagnostic significance.
There is a lack of uniform and effective treatment protocols. The use of antiviral drugs such as acyclovir and ganciclovir can temporarily reduce viral load, which is restored after discontinuation of the drugs. There are individual reports of effective treatment with interferon and IL-2. Immunochemotherapy with hormones, etoposide, cyclosporine, etc. can be applied in severe cases. Transfusion of autologous or donor EBV-specific T cells or hematopoietic stem cell transplantation can re-establish effective immunity in the body, but there is a higher risk of complications.
Liver injury due to coxsackievirus infection
Coxsackievirus is an enterovirus, a small RNA virus. It is named after the Coxsackie virus that was isolated in 1948 in the Coxsackie area of New York State, USA. Coxsackievirus infection is a common clinical disease, and in the past, the understanding of the disease was limited because serum immunological testing was not commonly performed. In recent years, the availability of serum coxsackievirus antigen (CBV-A g) and antibody (CBV-IgM) tests has improved the diagnosis of coxsackievirus infection.
Coxsackievirus infects humans through fecal-oral, respiratory, and insect-borne transmission, and further forms viremia, with the main target organs being the meninges, heart, skin, and muscles, but any organ in the body can be affected, and the clinical manifestations are complex and varied. The pathogenesis of the disease is not only related to virus replication and damage to target cells, but also to the host’s immune response to the virus. Clinically, some patients present with infectious mononucleosis-like disease, with liver enlargement in about 31.6% of patients and abnormal liver function in 16.3% of patients.
Familial clusters have been reported, and pregnant women and newborns are critically ill with high fever, liver failure and coagulation disorders, with a poor prognosis.
There are data from pediatric populations showing that interferon shortens the course of the disease. It has also been shown that in the absence of selenium and vitamin E, coxsackieviruses are susceptible to point mutations that cause phenotypic changes and increase pathogenicity. There is evidence that micronutrients including copper, iron, and selenium are directly involved in the replication of coxsackievirus. Therefore, attention to vitamin and trace element supplementation to regulate the body’s immune function is beneficial in the prevention and treatment of coxsackievirus infection.
Liver injury caused by human herpesvirus 6
Human herpesvirus type 6 is a new type of herpesvirus discovered in 1986. It was named after the first isolation from peripheral blood mononuclear cells of six patients with AIDS and lymphoproliferative disorders. Its morphological structure is similar to that of other members of the herpesvirus family, but its immunology and molecular virology are different from those of known herpesviruses such as HSV, VZV, CMV and EBV. HHV-6 infection has been found to be very common in healthy populations and has been associated with many clinical conditions such as: early childhood rash, chronic fatigue syndrome, organ transplant recipients, AIDS, infectious mononucleosis, multiple sclerosis, aseptic meningitis and encephalitis.
Primary infection with HHV-6 usually occurs in infancy and childhood, and then remains latent in the host for a long time without causing clinical symptoms. Primary infections rarely occur in adults. When the body’s resistance is weakened and immune function is low, the latent HHV-6 infection in the body can be activated and develop into a persistent infection.
Re-emergence of HHV-6 is very common after liver transplantation. Most patients are asymptomatic and only test positive; only a small percentage of patients develop fever, rash, myelosuppression, hepatitis, pneumonia, or even encephalitis. Previously, in immunocompetent adults, herpesvirus infections including HSV, HZV, HHV-6, EBV, and CMV mostly presented as mild, self-limiting acute hepatitis. However, more and more recent reports have confirmed that all these herpes viruses can cause acute liver failure in immunocompetent adults. HHV-6 has also been reported to cause fatal fulminant myocarditis combined with fulminant hepatitis. In addition, HHV-6 can increase rejection and aggravate liver lesions in concert with CMV and HCV.
The diagnosis of HHV-6 infection is based on virological, serological and molecular biological tests. In the acute phase, the virus can be isolated from saliva, peripheral blood lymphocytes, and tracheal secretions of the sick child. Rapid diagnosis can be made by indirect immunofluorescence tests. Viral DNA can also be detected by in situ hybridization, PCR techniques, immunoblotting, etc.
Ganciclovir and valganciclovir have been reported to prevent HHV-6 infection after liver transplantation. Treatment with ganciclovir, cidofovir, and phosphonate has been shown to be effective in suppressing HHV-6 replication in patients with confirmed HHV-6 infection. However, they are mostly in vitro tests and cannot make accurate predictions of in vivo drug susceptibility, so they are rarely used clinically.
Liver injury due to human microvirus B19
HPV B19 infection is a common infectious disease in humans. HPV B19 infection is widespread in the healthy population, with a population prevalence of more than 60%. Human microvirus B19 is the only virus in the genus Microvirus that is known to be closely associated with human diseases, including fulminant hepatitis, erythrodermatitis, remittent crisis, chronic anemia, and arthritis.
Human microvirus B19 can cause acute liver failure in patients in an immunosuppressed state and in some immunocompetent infected patients. In a Japanese study, 35.7% of 47 patients with fulminant hepatitis after liver transplantation were identified as having HPV B19, and there have been several reports this year of acute liver failure and eventual liver transplantation in immunocompetent adults infected with this virus. It has also been shown that the non-structural protein NS1 of HPV B19 induces hepatocyte regulation in the pathogenesis of acute liver failure, and the possible mechanism is the inhibition of sodium-hydrogen ion exchange activity by HPV B19 NS1, which induces apoptosis by altering intracellular pH.
The EL ISA method is commonly used to detect HPV B19 antibody IgG and IgM. Positive HPV B19 IgM indicates recent and acute infection and is suitable for the early diagnosis of HPV B19. Fluorescent quantitative PCR is simple, rapid, specific, sensitive, reliable, stable and quantitative, and can be used for blood screening in patients with acute and chronic stages of HPV B19 virus infection and in the blood donor population. Some studies have confirmed the persistent HPV B19 infection status by detecting HPV DNA in patients’ serum and the CD4+ T cell-specific viral protein VP1.
There are no uniformly effective treatment regimens. Vaccine studies are still in the early stages of in vitro research.